MKSAP 15: Medical Knowledge Self-Assessment Program (Companion Book)

MKSAP 15 Medical knowledge self-Assessment program Cardiovascular Medicine Contributors Please note that a "1" followi...

Author: ACP (American College of Physicians)

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MKSAP 15 Medical knowledge self-Assessment program

Cardiovascular Medicine Contributors Please note that a "1" following a contributor's name indicates that he or she has no relationships to disclose. A "2" indicates that the contributor has disclosed relationships. Please scroll down to view all disclosures. •

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Catherine M. Otto, MD, FACP, Book Editor1 J. Ward Kennedy-Hamilton Endowed Professor of Cardiology Professor of Medicine Director, Cardiology Fellowship Programs University of Washington School of Medicine Seattle, Washington Howard H. Weitz, MD, FACP, Associate Editor2 Professor of Medicine Director, Division of Cardiology Vice-Chairman, Department of Medicine Jefferson Medical College, Thomas Jefferson University Philadelphia, Pennsylvania R. Michael Benitez, MD1 Associate Professor of Medicine Fellowship Program Director Division of Cardiology University of Maryland School of Medicine Baltimore, Maryland Heidi M. Connolly, MD1 Professor of Medicine Mayo Clinic College of Medicine Rochester, Minnesota Rosario V. Freeman, MD, MS2 Associate Professor Division of Cardiology University of Washington Seattle, Washington Kristen K. Patton, MD2 Assistant Professor Division of Cardiology University of Washington Seattle, Washington David M. Shavelle, MD2 Associate Clinical Professor David Geffen School of Medicine at UCLA Division of Cardiology Director, Interventional Cardiology Director, Interventional Cardiology Fellowship

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Los Angeles County/Harbor-UCLA Medical Center Torrance, California Marcus F. Stoddard, MD1 Professor of Medicine Clinical Chief Division of Cardiovascular Medicine Department of Medicine The University of Louisville Louisville, Kentucky Andrew Wang, MD2 Associate Professor of Medicine Director, Fellowship Training Program Division of Cardiovascular Medicine Duke University Medical Center Durham, North Carolina Audrey H. Wu, MD, MPH1 Clinical Assistant Professor Division of Cardiovascular Medicine University of Michigan Health System Ann Arbor, Michigan

Editor-in-Chief Patrick C. Alguire, MD, FACP1 Director, Education and Career Development American College of Physicians Philadelphia, Pennsylvania

Cardiovascular Medicine Reviewers • • • • • • • •

Philip Altus, MD, MACP2 Gloria Fioravanti, DO, FACP1 John D. Goldman, MD, FACP2 Jose A. Joglar, MD1 Warren J. Manning, MD, FACP1 Michael W. Peterson, MD, FACP1 Ileana L. Piña, MD2 Mark D. Siegel, MD1

Cardiovascular Medicine ACP Editorial Staff • • • • •

Becky Krumm, Senior Staff Editor Sean McKinney, Director, Self-Assessment Programs Margaret Wells, Managing Editor Charles Rossi, Senior Associate of Clinical Content Development John Murray, Editorial Coordinator

ACP Principal Staff Steven E. Weinberger, MD, FACP2 Deputy Executive Vice President Senior Vice President, Medical Education and Publishing D. Theresa Kanya, MBA1 Vice President, Medical Education and Publishing Sean McKinney1 Director, Self-Assessment Programs Margaret Wells1 Managing Editor Charles Rossi1 Senior Associate of Clinical Content Development Becky Krumm1 Senior Staff Editor Ellen McDonald, PhD1 Senior Staff Editor Amanda Neiley1 Staff Editor Katie Idell1 Production Administrator/Editor Valerie Dangovetsky1 Program Administrator John Murray1 Editorial Coordinator Shannon O'Sullivan1 Editorial Coordinator Developed by the American College of Physicians 1. Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. See below.

Conflicts of Interest The following contributors and ACP staff members have disclosed relationships with commercial companies: Philip Altus, MD, MACP Consultantship: King Pharmaceuticals, Sanofi-Aventis Speakers Bureau: Bristol-Myers Squibb, King Pharmaceuticals, Sanofi-Aventis Rosario V. Freeman, MD, MS Employment (Spouse): Philips Medical Systems John D. Goldman, MD, FACP Employment: Pinnacle Health Kristen K. Patton, MD Research Grants/Contracts: Boston Scientific (includes Guidant products), Medtronic, Inc. Ileana L. Piña, MD Speakers Bureau: AstraZeneca, GlaxoSmithKline, Novartis, Sanofi-Aventis David M. Shavelle, MD Research Grants/Contracts: Takeda, GlaxoSmithKline, eV3, Inc., Boston Scientific, Abbott Vascular, Atritech, Inc., St. Jude, Inc., Possis, Inc., Cordis, Inc., Boehringer Ingelheim, AstraZeneca, Cardiomems Andrew Wang, MD Research Grants/Contracts: Evalve, Inc., Radiant Medical, Medtronic, Inc. Steven E. Weinberger, MD, FACP Stock Options/Holdings: Abbott, GlaxoSmithKline Howard H. Weitz, MD, FACP Other: GlaxoSmithKline (member of adverse events review committee of a clinical research trial)

Dermatology Contributors Please note that a "1" following a contributor's name indicates that he or she has no relationships to disclose. A "2" indicates that the contributor has disclosed relationships. Please scroll down to view all disclosures.

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Kathryn Schwarzenberger, MD, Book Editor2 Associate Professor of Medicine (Dermatology) Associate Chief and Residency Program Director Division of Dermatology University of Vermont College of Medicine Burlington, Vermont Jack Ende, MD, MACP, Associate Editor1 Professor of Medicine University of Pennsylvania Chief, Department of Medicine Penn Presbyterian Medical Center Philadelphia, Pennsylvania Jeffrey P. Callen, MD, FACP2 Professor of Medicine (Dermatology) Chief, Division of Dermatology University of Louisville School of Medicine Louisville, Kentucky Dirk Elston, MD2 Director, Department of Dermatology Geisinger Medical Center Danville, Pennsylvania Lindy P. Fox, MD2 Assistant Professor of Clinical Dermatology Director, Hospital Consultation Service Department of Dermatology University of California, San Francisco San Francisco, California William D. James, MD1 Paul R. Gross Professor and Vice Chair Department of Dermatology University of Pennsylvania Philadelphia, Pennsylvania


Dermatology Reviewers • • • •

Richard Fatica, MD1 Lisa Inouye, MD, MPH, FACP1 Khalid J. Qazi, MD, MACP1 Steven F. Reichert, MD, FACP1

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Leonard H. Sigal, MD, FACP2 Laura J. Zakowski, MD1

Dermatology ACP Editorial Staff • • • • •

Katie Idell, Production Administrator/Editor Sean McKinney, Director, Self-Assessment Programs Margaret Wells, Managing Editor Charles Rossi, Senior Associate of Clinical Content Development Shannon O'Sullivan, Editorial Coordinator

ACP Principal Staff Steven E. Weinberger, MD, FACP2 Deputy Executive Vice President Senior Vice President, Medical Education and Publishing D. Theresa Kanya, MBA1 Vice President, Medical Education and Publishing Sean McKinney1 Director, Self-Assessment Programs Margaret Wells1 Managing Editor Charles Rossi1 Senior Associate of Clinical Content Development Becky Krumm1 Senior Staff Editor Ellen McDonald, PhD1 Senior Staff Editor Amanda Neiley1 Staff Editor Katie Idell1 Production Administrator/Editor Valerie Dangovetsky1 Program Administrator John Murray1 Editorial Coordinator

Shannon O'Sullivan1 Editorial Coordinator Developed by the American College of Physicians 1. Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. See below.

Conflicts of Interest The following contributors and ACP staff members have disclosed relationships with commercial companies: Jeffrey P. Callen, MD, FACP Honoraria: Stiefel Laboratories Consultantship: Amgen, Centocor, Abbott, EOS, Genentech, Medicis, VSLT Royalties: Elsevier Speakers Bureau: Amgen Other: Genmab (Safety Monitoring Committee) Dirk Elston, MD Consultantship: Abbott, Medicis Lindy P. Fox, MD Honoraria: Bristol-Myers Squibb, Galderma, Elsevier Kathryn Schwarzenberger, MD Research Grants/Contracts: Galderma, Genentech, Amgen Honoraria: Abbott Leonard H. Sigal, MD, FACP Employment: Bristol-Myers Squibb Steven E. Weinberger, MD, FACP Stock Options/Holdings: Abbott, GlaxoSmithKline

Endocrinology and Metabolism Contributors

Please note that a "1" following a contributor's name indicates that he or she has no relationships to disclose. A "2" indicates that the contributor has disclosed relationships. Please scroll down to view all disclosures. •

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Henry B. Burch, MD, Book Editor1 Chief, Endocrinology Walter Reed Army Medical Center Professor of Medicine and Chair, Endocrinology Division Uniformed Services University of the Health Sciences Bethesda, Maryland Howard H. Weitz, MD, FACP, Associate Editor2 Professor of Medicine Director, Division of Cardiology Vice-Chairman, Department of Medicine Jefferson Medical College, Thomas Jefferson University Philadelphia, Pennsylvania Baha M. Arafah, MD2 Professor of Medicine Director, Clinical Program & Fellowship Training Program Division of Endocrinology Case Western Reserve University and University Hospitals Case Medical Center Cleveland, Ohio Richard J. Auchus, MD, PhD2 The Charles A. and Elizabeth Ann Sanders Chair in Translational Research Professor of Internal Medicine Division of Endocrinology and Metabolism University of Texas Southwestern Medical Center at Dallas Dallas, Texas Victor J. Bernet, MD, FACP1 Director, National Capital Consortium Endocrinology Fellowship Program Walter Reed Army Medical Center-Bethesda Naval Medical Center Associate Professor Uniformed Services University of the Health Sciences Bethesda, Maryland Silvio E. Inzucchi, MD2 Professor of Medicine Clinical Director, Section of Endocrinology Director, Yale Diabetes Center Yale University School of Medicine New Haven, Connecticut Mark E. Molitch, MD, FACP2 Professor of Medicine Division of Endocrinology, Metabolism and Molecular Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois

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Meeta Sharma, MD2 Assistant Chief Division of Endocrinology Director, Diabetes Team Washington Hospital Center Washington, DC


Endocrinology and Metabolism Reviewers • • • • • • • • •

Amindra S. Arora, MD1 Arnold A. Asp, MD, FACP1 Dawn E. DeWitt, MD, MSc, FACP2 Cheryl A. Fassler, MD, FACP2 Jason L. Gaglia, MD1 William James Howard, MD, MACP2 Steven Ricanati, MD1 Ingram Roberts, MD, FACP2 Cynthia M. Tracy, MD2

Endocrinology and Metabolism ACP Editorial Staff • • • • •

Ellen McDonald, PhD, Senior Staff Editor Sean McKinney, Director, Self-Assessment Programs Margaret Wells, Managing Editor Charles Rossi, Senior Associate of Clinical Content Development Shannon O'Sullivan, Editorial Coordinator

ACP Principal Staff Steven E. Weinberger, MD, FACP2 Deputy Executive Vice President Senior Vice President, Medical Education and Publishing D. Theresa Kanya, MBA1 Vice President, Medical Education and Publishing Sean McKinney1 Director, Self-Assessment Programs

Margaret Wells1 Managing Editor Charles Rossi1 Senior Associate of Clinical Content Development Becky Krumm1 Senior Staff Editor Ellen McDonald, PhD1 Senior Staff Editor Amanda Neiley1 Staff Editor Katie Idell1 Production Administrator/Editor Valerie Dangovetsky1 Program Administrator John Murray1 Editorial Coordinator Shannon O'Sullivan1 Editorial Coordinator Developed by the American College of Physicians 1. Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. See below.

Conflicts of Interest The following contributors and ACP staff members have disclosed relationships with commercial companies: Baha M. Arafah, MD Consultantship: Novartis Richard J. Auchus, MD, PhD Consultantship: Cougar Biotechnology, Takeda Stock Options/Holdings: Merck, Bristol-Myers Squibb Research Grants/Contracts: Novartis

Dawn E. DeWitt, MD, MSc, FACP Honoraria: Sanofi-Aventis Consultantship: Sanofi-Aventis Other: Sanofi-Aventis Cheryl A. Fassler, MD, FACP Stock Options/Holdings: Amgen Research Grants/Contracts: Eli Lilly Speakers Bureau: Tercica, Sanofi-Aventis William James Howard, MD, MACP Research Grants/Contracts: Pfizer, AstraZeneca Honoraria: Pfizer, AstraZeneca, Merck, Schering-Plough, Abbott, Sankyo Consultantship: Merck, Schering-Plough Speakers Bureau: Pfizer, AstraZeneca, Merck, Schering-Plough, Abbott, Sankyo Silvio E. Inzucchi, MD Research Grants/Contracts: Eli Lilly Honoraria: Pfizer, Takeda, Novartis, Merck, NovoNordisk Consultantship: Takeda, Novartis, Merck, Daiichi-Sankyo, Amylin Speakers Bureau: Takeda, Merck Mark E. Molitch, MD, FACP Research Grants/Contracts: Amgen, Tercica, Ardana, Lilly Consultantship: Sanofi-Aventis, Abbott, Tercica, Novartis Speakers Bureau: Sanofi-Aventis, Abbott, Merck Stock Options/Holdings: Amgen, Abbott, Pfizer Ingram Roberts, MD, FACP Royalties: UpToDate Meeta Sharma, MD Honoraria: Procter & Gamble, Takeda, Merck, Sanofi-Aventis Speakers Bureau: Procter & Gamble, Takeda, Merck, Sanofi-Aventis Cynthia M. Tracy, MD Honoraria: Medtronic Steven E. Weinberger, MD, FACP Stock Options/Holdings: Abbott, GlaxoSmithKline Howard H. Weitz, MD, FACP Other: GlaxoSmithKline (member of adverse events review committee of a clinical research trial)

Gastroenterology and Hepatology Contributors Please note that a "1" following a contributor's name indicates that he or she has no relationships to disclose. A "2" indicates that the contributor has disclosed relationships. Please scroll down to view all disclosures. •

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Steven K. Herrine, MD, FACP, Book Editor2 Professor of Medicine Division of Gastroenterology and Hepatology Thomas Jefferson University Philadelphia, Pennsylvania Thomas Fekete, MD, FACP, Associate Editor1 Professor of Medicine Associate Professor of Microbiology Temple University Medical School Philadelphia, Pennsylvania Brian P. Bosworth, MD2 Assistant Professor of Medicine Weill Medical College of Cornell University New York, New York Patricia Kozuch, MD2 Assistant Professor of Medicine Division of Gastroenterology and Hepatology Thomas Jefferson University Philadelphia, Pennsylvania David E. Loren, MD2 Assistant Professor of Medicine Division of Gastroenterology and Hepatology Thomas Jefferson University Philadelphia, Pennsylvania Victor J. Navarro, MD2 Professor of Medicine, Pharmacology and Experimental Therapeutics Hepatology and Liver Transplantation Thomas Jefferson University Philadelphia, Pennsylvania Amy S. Oxentenko, MD, FACP2 Assistant Professor of Medicine College of Medicine, Mayo Clinic Rochester, Minnesota Patrick R. Pfau, MD1 Associate Professor of Medicine University of Wisconsin Madison, Wisconsin

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Simona Rossi, MD2 Assistant Professor of Medicine Division of Gastroenterology and Hepatology Thomas Jefferson University Philadelphia, Pennsylvania


Gastroenterology and Hepatology Reviewers • • • • • • • • • •

Amindra S. Arora, MD1 Raymond F. Bianchi, MD, FACP1 Douglas Einstadter, MD, MPH, FACP2 Asad Khan Mohmand, MD1 Darrell S. Pardi, MD2 Amir Qaseem, MD, PhD, MHA, FACP 2 Darius A. Rastegar, MD, FACP1 Joel E. Richter, MD, FACP2 Ingram M. Roberts, MD, FACP1 Suzanne Rose, MD, MSEd, FACP2

Gastroenterology and Hepatology ACP Editorial Staff • • • •

Charles Rossi, Senior Associate of Clinical Content Development Sean McKinney, Director, Self-Assessment Programs Margaret Wells, Managing Editor Katie Idell, Production Administrator/Editor

ACP Principal Staff Steven E. Weinberger, MD, FACP2 Deputy Executive Vice President Senior Vice President, Medical Education and Publishing D. Theresa Kanya, MBA1 Vice President, Medical Education and Publishing Sean McKinney1 Director, Self-Assessment Programs

Margaret Wells1 Managing Editor Charles Rossi1 Senior Associate of Clinical Content Development Becky Krumm1 Senior Staff Editor Ellen McDonald, PhD1 Senior Staff Editor Amanda Neiley1 Staff Editor Katie Idell1 Production Administrator/Editor Valerie Dangovetsky1 Program Administrator John Murray1 Editorial Coordinator Shannon O'Sullivan1 Editorial Coordinator Developed by the American College of Physicians 1. Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. See below.

Conflicts of Interest The following contributors and ACP staff members have disclosed relationships with commercial companies: Brian P. Bosworth, MD Stock Options/Holdings: Schering-Plough Research Grants/Contracts: Abbott, Centocor, Cerimon, PDL Biopharma, Salix, UCB, Procter & Gamble Douglas Einstadter, MD, MPH, FACP Consultantship: Medical Mutual of Ohio

Steven K. Herrine, MD, FACP Research Grants/Contracts: Human Genome Sciences, Roche, Schering-Plough, Bristol-Myers Squibb, McNeil Consumer Products, Sanofi-Aventis Speakers Bureau: Roche, Schering-Plough Patricia Kozuch, MD Consultantship: UCB, Abbott Speakers Bureau: Scientific American Frontiers Research Grants/Contracts: Sub investigator for Abbott, Ocera, Celltech, Berlex, Otsuka, Prometheus, Given Imaging, Alba Therapeutics, AstraZeneca, Salix, PDL Biopharma; Primary investigator for Abbott, Centocor Other (Educational Speaking, Ad Board): UCB, Centocor, Abbott, Elan David E. Loren, MD Speakers Bureau: Olympus America, Boston Scientific Research Grants/Contracts: Boston Scientific, Protherics Victor J. Navarro, MD Consultantship: Merck, Alza, Amgen, Bristol-Myers Squibb, Theravance, Metabasis, Janssen, Viropharma, Johnson & Johnson Research Grants/Contracts: Alza, Biotrin, Bristol-Myers Squibb, Janssen, McNeil Consumer Products, Madaus Pharma, Merck, Metabasis, Roche, Sanofi-Aventis, Theravance Amy S. Oxentenko, MD, FACP Research Grants/Contracts: PDL Biopharma Darrell S. Pardi, MD Research Grants/Contracts: Salix, AstraZeneca, Procter & Gamble Consultantship: Biobalance Corporation, Lonza, Salix, Elan Amir Qaseem, MD, PhD, MHA, FACP Employment: American College of Physicians Honoraria: NovoNordisk Joel E. Richter, MD, FACP Honoraria: AstraZeneca, TAP Speakers Bureau: AstraZeneca, TAP Suzanne Rose, MD, MSEd, FACP Royalties: Hayes-Barton Press Consultantship: Takeda, Novartis Speakers Bureau: Takeda, TAP Simona Rossi, MD Research Grants/Contracts: Bristol-Myers Squibb, Human Genome Sciences, McNeil Consumer Products, Novartis Pharmaceuticals, Roche, Sanofi-Aventis, Schering-Plough, Gilead Sciences,

Inc. Honoraria: Gilead Steven E. Weinberger, MD, FACP Stock Options/Holdings: Abbott, GlaxoSmithKline

General Internal Medicine •

ed directly to the syllabus content by clicking on the tabs.

Contributors Please note that a "1" following a contributor's name indicates that he or she has no relationships to disclose. A "2" indicates that the contributor has disclosed relationships. Please scroll down to view all disclosures. •

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Kurt Kroenke, MD, MACP, Book Editor2 Professor of Medicine Indiana University School of Medicine Research Scientist, Regenstrief Institute Indianapolis, Indiana Jack Ende, MD, MACP, Associate Editor1 Professor of Medicine University of Pennsylvania Chief, Department of Medicine Penn Presbyterian Medical Center Philadelphia, Pennsylvania Brent W. Beasley, MD, FACP1 Associate Professor of Medicine University of Missouri-Kansas City Program Director, Internal Medicine Residency Kansas City, Missouri Steven L. Cohn, MD, FACP2 Director, Medical Consultation Service Kings County Hospital Center Clinical Professor of Medicine SUNY Downstate Brooklyn, New York Paul A. Hemmer, MD, MPH, FACP1* Bethesda, Maryland John T. Philbrick, MD, FACP1 Professor of Medicine Division of General Medicine, Geriatrics, and Palliative Medicine

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University of Virginia School of Medicine Charlottesville, Virginia Michael J. Roy, MD, MPH, FACP1* Colonel, Medical Corps, US Army Professor of Medicine Uniformed Services University of the Health Sciences Bethesda, Maryland Stephen M. Salerno, MD, MPH, FACP1* Associate Professor of Medicine, USUHS Director of Medical Education Madigan Army Medical Center Tacoma, Washington Gary H. Tabas, MD, FACP1 Professor of Medicine Division of General Internal Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania


General Internal Medicine Reviewers • • • • • • • •

Raymond F. Bianchi, MD, FACP1 John K. Chamberlain, MD, MACP1 John H. Holbrook, MD, FACP1 Robert T. Means, Jr., MD, FACP2 Patrick G. O'Malley, MD, MPH, FACP1 Amir Qaseem, MD, PhD, MHA, FACP1 Darius A. Rastegar, MD, FACP1 Robert E. Wright, MD, FACP1

General Internal Medicine ACP Editorial Staff • • • • •

Becky Krumm, Senior Staff Editor Sean McKinney, Director, Self-Assessment Programs Margaret Wells, Managing Editor Charles Rossi, Senior Associate of Clinical Content Development Shannon O'Sullivan, Editorial Coordinator

ACP Principal Staff

Steven E. Weinberger, MD, FACP2 Deputy Executive Vice President Senior Vice President, Medical Education and Publishing D. Theresa Kanya, MBA1 Vice President, Medical Education and Publishing Sean McKinney1 Director, Self-Assessment Programs Margaret Wells1 Managing Editor Charles Rossi1 Senior Associate of Clinical Content Development Becky Krumm1 Senior Staff Editor Ellen McDonald, PhD1 Senior Staff Editor Amanda Neiley1 Staff Editor Katie Idell1 Production Administrator/Editor Valerie Dangovetsky1 Program Administrator John Murray1 Editorial Coordinator Shannon O'Sullivan1 Editorial Coordinator Developed by the American College of Physicians 1. Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. See below. *

The views expressed here are those of the authors only and are not to be construed as those of the Department of Army, Department of Air Force, or Department of Defense.

Conflicts of Interest The following contributors and ACP staff members have disclosed relationships with commercial companies: Steven L. Cohn, MD, FACP Stock Options/Holdings: Pfizer, GlaxoSmithKline, Merck, AstraZeneca Speakers Bureau: Sanofi-Aventis, Pfizer Kurt Kroenke, MD, MACP Research Grants/Contracts: Eli Lilly Consultantship: Eli Lilly, Pfizer, Forest Robert T. Means, Jr., MD, FACP Honoraria: Beckman Coulter Steven E. Weinberger, MD, FACP Stock Options/Holdings: Abbott, GlaxoSmithKline

Hematology and Oncology Contributors Please note that a "1" following a contributor's name indicates that he or she has no relationships to disclose. A "2" indicates that the contributor has disclosed relationships. Please scroll down to view all disclosures.

Hematology •

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Jack E. Ansell, MD, FACP, Book Editor2 Chairman, Department of Medicine Lenox Hill Hospital New York, New York Marc J. Kahn, MD, FACP1 Professor of Medicine Hematology/Medical Oncology Senior Associate Dean for Admissions and Student Affairs Tulane University School of Medicine New Orleans, Louisiana Randy L. Levine, MD, FACP1 Director of Research for Hematology and Oncology Fellowship Director of Blood Bank and Transfusion Services

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Lenox Hill Hospital New York, New York Karen Quillen, MD2 Associate Professor of Medicine Director, Blood Bank Boston University School of Medicine Boston, Massachusetts Vaishali Sanchorawala, MD2 Associate Professor of Medicine Boston University School of Medicine Director, Stem Cell Transplant Program Boston Medical Center Boston, Massachusetts

Oncology •

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Bernard A. Mason, MD, FACP, Book Editor1 University of Pennsylvania School of Medicine Clinical Professor of Medicine Pennsylvania Hospital Philadelphia, Pennsylvania Mary E. Cianfrocca, DO2 Assistant Professor Division of Hematology/Oncology Feinberg School of Medicine Northwestern University Chicago, Illinois Nancy L. Lewis, MD2 Director, Phase I Clinical Trial Program Cooper Cancer Institute Voorhees, New Jersey Jyoti D. Patel, MD2 Assistant Professor Division of Hematology/Oncology Feinberg School of Medicine Northwestern University Chicago, Illinois Russell J. Schilder, MD2 Senior Member Director, Graduate Medical Education Fox Chase Cancer Center Philadelphia, Pennsylvania

Associate Editor

Richard S. Eisenstaedt, MD, FACP2 Clinical Professor of Medicine Temple University School of Medicine Chair, Department of Medicine Abington Memorial Hospital Abington, Pennsylvania


Hematology and Oncology Reviewers • • • • • • • •

John E. Bennett, MD, MACP1 Lee Berkowitz, MD, FACP1 Duane R. Hospenthal, MD, PhD, COL, MC, FACP2 Dan L. Longo, MD, FACP1 Robert T. Means, Jr., MD, FACP2 Richard H. Moseley, MD, FACP1 Steven Ricanati, MD1 Barbara L. Schuster, MD, MACP2

Hematology and Oncology Editorial Staff • • • •

Margaret Wells, Managing Editor Sean McKinney, Director, Self-Assessment Programs Charles Rossi, Senior Associate of Clinical Content Development John Murray, Editorial Coordinator

ACP Principal Staff Steven E. Weinberger, MD, FACP2 Deputy Executive Vice President Senior Vice President, Medical Education and Publishing D. Theresa Kanya, MBA1 Vice President, Medical Education and Publishing Sean McKinney1 Director, Self-Assessment Programs Margaret Wells1 Managing Editor

Charles Rossi1 Senior Associate of Clinical Content Development Becky Krumm1 Senior Staff Editor Ellen McDonald, PhD1 Senior Staff Editor Amanda Neiley1 Staff Editor Katie Idell1 Production Administrator/Editor Valerie Dangovetsky1 Program Administrator John Murray1 Editorial Coordinator Shannon O'Sullivan1 Editorial Coordinator Developed by the American College of Physicians 1. Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. See below.

Conflicts of Interest The following contributors and ACP staff members have disclosed relationships with commercial companies: Jack E. Ansell, MD, FACP Consultantship: Bristol-Myers Squibb, Bayer/Scios, Sanofi-Aventis, St. Jude Medical, Roche Diagnostics, HemoSense, Aryx Pharma, Aton Pharma, Instrumentation Labs, Regado Biosciences, ITC, Inc. Mary E. Cianfrocca, DO Research Grants/Contracts: GlaxoSmithKline Speakers Bureau: GlaxoSmithKline, Genentech, Genomic Health

Richard S. Eisenstaedt, MD, FACP Speakers Bureau: Ortho Biotech Duane R. Hospenthal, MD, PhD, COL, MC, FACP Research Grants/Contracts: Schering-Plough, Merck Speakers Bureau: Merck, Pfizer Nancy L. Lewis, MD Research Grants/Contracts: Pfizer, Raven, Boehringer-Ingelheim, Wyeth, Incyte, PharmaMar USA Inc., Merck, Novartis, Sonus, EMD Pharmaceuticals, AstraZeneca, PharmaMar, Amgen, Lilly, BiPar Sciences, Bristol-Myers Squibb Robert T. Means, Jr., MD, FACP Honoraria: Beckman Coulter Jyoti D. Patel, MD Speakers Bureau: Genentech Research Grants/Contracts: Lilly Pharmaceuticals, Genentech Karen Quillen, MD Research Grants/Contracts: Novo Nordisk Vaishali Sanchorawala, MD Research Grants/Contracts: Celgene, Millenium Pharmaceuticals Speakers Bureau: Ortho Biotech, LLP Russell J. Schilder, MD Research Grants/Contracts: Bristol-Myers Squibb Consultantship: Biogen Idec Speakers Bureau: Biogen Idec, Ortho Biotech, Lilly Barbara L. Schuster, MD, MACP Honoraria: American Journal of Medicine (Editorial Board) Steven E. Weinberger, MD, FACP Stock Options/Holdings: Abbott, GlaxoSmithKline

Infectious Disease Contributors Please note that a "1" following a contributor's name indicates that he or she has no relationships to disclose. A "2" indicates that the contributor has disclosed relationships. Please scroll down to view all disclosures.

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John N. Goldman, MD, Book Editor1 Professor Emeritus Pennsylvania State University College of Medicine Hershey, Pennsylvania Thomas Fekete, MD, FACP, Associate Editor1 Professor of Medicine Associate Professor of Microbiology Temple University Medical School Philadelphia, Pennsylvania Emily J. Erbelding, MD, MPH2 Associate Professor of Medicine Division of Infectious Diseases Johns Hopkins Bayview Medical Center Baltimore, Maryland Stephen Gluckman, MD, FACP1 Professor of Medicine University of Pennsylvania School of Medicine Chief Infectious Disease Clinical Services Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Visiting Professor of Infectious Diseases University of Botswana Joseph A. Hassey, MD1 Clinical Assistant Professor of Medicine Drexel University College of Medicine Department of Medicine Division of Infectious Diseases Abington Memorial Hospital Abington, Pennsylvania Fred A. Lopez, MD, FACP2 Richard Vial Professor of Medicine Professor and Vice Chair Louisiana State University Department of Medicine Assistant Dean Louisiana State University School of Medicine New Orleans, Louisiana Carlene A. Muto, MD, MS1 Medical Director of Infection Control and Hospital Epidemiology University of Pittsburgh Medical Center (UPMC) Presbyterian Center for Quality Improvement and Innovation, UPMC Health System Associate Professor of Medicine and Epidemiology Division of Infectious Diseases University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Judith A. O'Donnell, MD2 Associate Professor of Clinical Medicine

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Division of Infectious Diseases University of Pennsylvania School of Medicine Hospital Epidemiologist and Director Department of Infection Prevention and Control Penn Presbyterian Medical Center Philadelphia, Pennsylvania William R. Short, MD, MPH2 Assistant Professor of Medicine Division of Infectious Diseases Jefferson Medical College of Thomas Jefferson University Philadelphia, Pennsylvania Allan R. Tunkel, MD, PhD, MACP1 Professor of Medicine Drexel University College of Medicine Chair, Department of Medicine Monmouth Medical Center Long Branch, New Jersey


Infectious Disease Reviewers • • • • • • • • • • •

Robert D. Arbeit, MD, FACP2 Rabeh Elzuway, MD1 Thomas E. Finucane, MD, FACP1 John D. Goldman, MD, FACP1 Duane R. Hospenthal, MD, PhD, FACP2 Leigh K. Hunter, MD, FACP2 Jeffrey L. Jackson, MD, FACP1 Richard H. Moseley, MD, FACP1 Michael W. Peterson, MD, FACP1 Peter H. Wiernik, MD, FACP2 John Zurlo, MD2

Infectious Disease ACP Editorial Staff • • • •

Margaret Wells, Managing Editor Sean McKinney, Director, Self-Assessment Programs Charles Rossi, Senior Associate of Clinical Content Development John Murray, Editorial Coordinator

ACP Principal Staff Steven E. Weinberger, MD, FACP2 Deputy Executive Vice President Senior Vice President, Medical Education and Publishing D. Theresa Kanya, MBA1 Vice President, Medical Education and Publishing Sean McKinney1 Director, Self-Assessment Programs Margaret Wells1 Managing Editor Charles Rossi1 Senior Associate of Clinical Content Development Becky Krumm1 Senior Staff Editor Ellen McDonald, PhD1 Senior Staff Editor Amanda Neiley1 Staff Editor Katie Idell1 Production Administrator/Editor Valerie Dangovetsky1 Program Administrator John Murray1 Editorial Coordinator Shannon O'Sullivan1 Editorial Coordinator Developed by the American College of Physicians 1. Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. See below.

Conflicts of Interest The following contributors and ACP staff members have disclosed relationships with commercial companies: Robert D. Arbeit, MD, FACP Employment: Paratek Pharmaceuticals Stock Options/Holdings: Paratek Pharmaceuticals Emily J. Erbelding, MD, MPH Employment: Johns Hopkins University Research Grants/Contracts: Health Services Resource Administration, King Pharmaceuticals Consultantship: Accordia Global Health Foundation (formerly known as the Academic Alliance for Care and Prevention of AIDS in Africa) Duane R. Hospenthal, MD, PhD, FACP Speakers Bureau: Merck, Pfizer Leigh K. Hunter, MD, FACP Employment: Methodist Health Systems Speakers Bureau: Cubist Fred A. Lopez, MD, FACP Royalties: UpToDate Judith A. O'Donnell, MD Employment: Spouse works for Viropharma William R. Short, MD, MPH Consultantship: Abbott, Tibotec, Gilead Speakers Bureau: Tibotec, Gilead, Merck Steven E. Weinberger, MD, FACP Stock Options/Holdings: Abbott, GlaxoSmithKline Peter H. Wiernik, MD, FACP Research Grants/Contracts: Favrille, Celgene Honoraria: Celgene John Zurlo, MD Research Grants/Contracts: Tibotec, Gilead

Nephrology


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Phyllis August, MD, MPH, Book Editor2 Ralph A. Baer Professor of Medical Research Professor of Medicine and Public Health Professor of Medicine in Obstetrics and Gynecology Division of Nephrology and Hypertension Weill Medical College of Cornell University New York, New York Virginia U. Collier, MD, FACP, Associate Editor2 Hugh R. Sharp, Jr. Chair of Medicine Christiana Care Health System Newark, Delaware Professor of Medicine Jefferson Medical College of Thomas Jefferson University Philadelphia, Pennsylvania Arlene Chapman, MD2 Professor of Medicine Department of Medicine, Renal Division Emory University School of Medicine Atlanta, Georgia Gerald A. Hladik, MD1 Associate Professor of Medicine Division of Nephrology and Hypertension University of North Carolina Kidney Center The University of North Carolina at Chapel Hill Chapel Hill, North Carolina Michelle A. Josephson, MD, FACP2 Professor of Medicine Section of Nephrology University of Chicago Hospitals Chicago, Illinois Michelle Whittier Krause, MD, MPH1 Associate Professor of Medicine Division of Nephrology University of Arkansas for Medical Sciences Little Rock, Arkansas Biff F. Palmer, MD, FACP, FASN2 Professor of Internal Medicine Department of Internal Medicine Nephrology Fellowship Program Director Division of Nephrology

University of Texas Southwestern Medical Center Dallas, Texas


Nephrology Reviewers • • • • • • • • • •

Sharon Adler, MD, FACP2 Robert J. Anderson, MD, MACP1 Lee Berkowitz, MD, FACP1 Frantz Duffoo, MD, FACP1 Kent A. Kirchner, MD, FACP1 Richard I. Kopelman, MD, FACP1 Dan L. Longo, MD, FACP1 Mark E. Pasanen, MD, FACP1 Barbara L. Schuster, MD, MACP1 Jerry L. Spivak, MD, FACP2

Nephrology ACP Editorial Staff • • • • •

Amanda Neiley, Staff Editor Sean McKinney, Director, Self-Assessment Programs Margaret Wells, Managing Editor Charles Rossi, Senior Associate of Clinical Content Development John Murray, Editorial Coordinator

ACP Principal Staff Steven E. Weinberger, MD, FACP2 Deputy Executive Vice President Senior Vice President, Medical Education and Publishing D. Theresa Kanya, MBA1 Vice President, Medical Education and Publishing Sean McKinney1 Director, Self-Assessment Programs Margaret Wells1 Managing Editor

Charles Rossi1 Senior Associate of Clinical Content Development Becky Krumm1 Senior Staff Editor Ellen McDonald, PhD1 Senior Staff Editor Amanda Neiley1 Staff Editor Katie Idell1 Production Administrator/Editor Valerie Dangovetsky1 Program Administrator John Murray1 Editorial Coordinator Shannon O'Sullivan1 Editorial Coordinator Developed by the American College of Physicians 1. Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. See below.

Conflicts of Interest The following contributors and ACP staff members have disclosed relationships with commercial companies: Sharon Adler, MD, FACP Research Grants/Contracts: Asprevia, Genzyme, Genentech, Novartis Consultantship: Genentech Phyllis August, MD, MPH Stock Options/Holdings: Pfizer, Merck Arlene Chapman, MD Research Grants/Contracts: HALT Trial/NIH, Otsuka America Pharmaceuticals

Virginia U. Collier, MD, FACP Stock Options/Holdings: Celgene, Pfizer, Merck, Schering-Plough, Abbott, Johnson & Johnson, Medtronic, McKesson, Amgen Michelle A. Josephson, MD, FACP Speakers Bureau: Roche Pharmaceuticals Research Grants/Contracts: Astellas, Wyeth, Roche Pharmaceuticals Biff F. Palmer, MD, FACP, FASN Speakers Bureau: Novartis Jerry L. Spivak, MD, FACP Consultantship: Ortho, Roche, Novartis, Pfizer Steven E. Weinberger, MD, FACP Stock Options/Holdings: Abbott, GlaxoSmithKline

Neurology Contributors Please note that a "1" following a contributor's name indicates that he or she has no relationships to disclose. A "2" indicates that the contributor has disclosed relationships. Please scroll down to view all disclosures. •

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David W. Dodick, MD, Book Editor2 Professor of Neurology Neurology Residency Program Director Mayo Clinic Arizona Phoenix, Arizona Jack Ende, MD, MACP, Associate Editor1 Professor of Medicine University of Pennsylvania Chief, Department of Medicine Penn Presbyterian Medical Center Philadelphia, Pennsylvania Patrick C. Alguire, MD, FACP, Editor-in-Chief1 Director, Education and Career Development American College of Physicians Philadelphia, Pennsylvania Richard J. Caselli, MD1 Professor and Chair Department of Neurology

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Mayo Clinic Arizona Scottsdale, Arizona Bart M. Demaerschalk, MD, MSc, FRCP(C) 2 Director, Cerebrovascular Diseases Center Associate Professor of Neurology Division of Cerebrovascular Diseases Division of Critical Care Neurology Department of Neurology Mayo Clinic Arizona Phoenix, Arizona Brent P. Goodman, MD1 Assistant Professor of Neurology Department of Neurology Mayo Clinic Arizona Scottsdale, Arizona Katherine H. Noe, MD, PhD1 Assistant Professor of Neurology Department of Neurology Mayo Clinic Arizona Phoenix, Arizona Dean M. Wingerchuk, MD, MSc, FRCP(C) 2 Professor of Neurology Multiple Sclerosis Clinic Division of Demyelinating Diseases Mayo Clinic Arizona Scottsdale, Arizona


Neurology Reviewers • • • • • • • • • •

Dawn E. DeWitt, MD, MSc, FACP, FRACP2 Richard A. Fatica, MD1 Thomas E. Finucane, MD, FACP1 Faith T. Fitzgerald, MD, MACP1 Jeffrey L. Jackson, MD, MPH, FACP1 Kevin A. Kahn, MD2 Bashar Katirji, MD, FACP1 Steven L. Lewis, MD1 Mark E. Pasanen, MD, FACP1 Steven F. Reichert, MD, FACP1

Neurology ACP Editorial Staff • • • • •

Ellen McDonald, PhD, Senior Staff Editor Sean McKinney, Director, Self-Assessment Programs Margaret Wells, Managing Editor Charles Rossi, Senior Associate of Clinical Content Development Shannon O'Sullivan, Editorial Coordinator

ACP Principal Staff Steven E. Weinberger, MD, FACP2 Deputy Executive Vice President Senior Vice President, Medical Education and Publishing D. Theresa Kanya, MBA1 Vice President, Medical Education and Publishing Sean McKinney1 Director, Self-Assessment Programs Margaret Wells1 Managing Editor Charles Rossi1 Senior Associate of Clinical Content Development Becky Krumm1 Senior Staff Editor Ellen McDonald, PhD1 Senior Staff Editor Amanda Neiley1 Staff Editor Katie Idell1 Production Administrator/Editor Valerie Dangovetsky1 Program Administrator John Murray1 Editorial Coordinator Shannon O'Sullivan1 Editorial Coordinator

Developed by the American College of Physicians 1. Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. See below.

Conflicts of Interest The following contributors and ACP staff members have disclosed relationships with commercial companies: Bart M. Demaerschalk, MD, MSc, FRCP(C) Research Grants/Contracts: Abbott (CHOICE, ACT I), Vernalis UK, Neurobiological Technologies, AGA, St. Jude Medical Honoraria: Genentech, Hoffman Roche Consultantship: Genentech Other: Neurobiological Technologies, Neuralieve Dawn DeWitt, MD, MSc, FACP, FRACP Consultantship: Sanofi-Aventis David W. Dodick, MD Research Grants/Contracts: Abbott (CHOICE, ACT I), Allergan, AstraZeneca, Advanced Bionics, Advanced Neurostimulation Systems, Medtronic, Alexza Honoraria: Merck, GlaxoSmithKline, Neuralieve, Solvay, Ortho-McNeil, Coherex, MAP, Eli Lilly, Endo, Minster Consultantship: Merck, GlaxoSmithKline, Neuralieve, Eli Lilly, St. Jude Medical, OrthoMcNeil, Solvay, Coherex, MAP, Endo, Minster Kevin A. Kahn, MD Employment: UNC Hospitals, Dept. of Neurology Research Grants/Contracts: UCB Pharmaceuticals Honoraria: Pfizer, Ortho-McNeil Speakers Bureau: Pfizer, Ortho-McNeil Steven E. Weinberger, MD, FACP Stock Options/Holdings: Abbott, GlaxoSmithKline Dean M. Wingerchuk, MD, MSc, FRCP(C) Research Grants/Contracts: Genentech, Genzyme Consultantship: Genentech

Pulmonary and Critical Care Medicine


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Scott F. Davies, MD, FACP, Book Editor1 Professor of Medicine University of Minnesota Chief of Medicine Hennepin County Medical Center Minneapolis, Minnesota Richard S. Eisenstaedt, MD, FACP, Associate Editor2 Clinical Professor of Medicine Temple University School of Medicine Chair, Department of Medicine Abington Memorial Hospital Abington, Pennsylvania Marie R. Baldisseri, MD, FCCM2 Associate Professor of Critical Care Medicine Department of Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Craig E. Daniels, MD2 Assistant Professor of Medicine Section Head, Critical Care Medicine Division of Pulmonary & Critical Care Medicine Mayo Clinic Rochester, Minnesota E. Wesley Ely, MD, MPH, FACP2 Professor of Medicine Allergy, Pulmonary and Critical Care Health Services Research Center Associate Director of Aging Research, VA GRECC Vanderbilt University School of Medicine Health Services Research Center Nashville, Tennessee Stanley B. Fiel, MD, FACP, FCCP2 Professor of Medicine Mt. Sinai School of Medicine Regional Chairman, Department of Medicine/Atlantic Health The deNeufville Professor and Chairman Department of Medicine Morristown Memorial Hospital Morristown, New Jersey

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Nizar N. Jarjour, MD, FACP, FCCP2 Professor and Head Section of Allergy, Pulmonary and Critical Care Department of Medicine University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Robert Kempainen, MD2 Associate Professor of Medicine University of Minnesota Hennepin County Medical Center Minneapolis, Minnesota David E. Midthun, MD, FACP2 Professor of Medicine Consultant, Division of Pulmonary and Critical Care Medicine Mayo Clinic Rochester, Minnesota Timothy Morris, MD2 Professor of Medicine Clinical Service Chief Division of Pulmonary and Critical Care Medicine University of California, San Diego San Diego, California

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E. Brigitte Gottschall, MD, MSPH1 Assistant Professor Division of Environmental and Occupational Health Sciences National Jewish Health University of Colorado Denver School of Medicine Denver, Colorado Teofilo Lee-Chiong, MD2 Head, Division of Sleep Medicine Department of Medicine Associate Professor of Medicine National Jewish Health University of Colorado Denver School of Medicine Denver, Colorado Steven A. Sahn, MD, FACP2 Professor of Medicine and Director Division of Pulmonary, Critical Care, Allergy and Sleep Medicine Medical University of South Carolina Charleston, South Carolina

Editor-in-Chief

Patrick C. Alguire, MD, FACP1 Director, Education and Career Development American College of Physicians Philadelphia, Pennsylvania

Pulmonary and Critical Care Medicine Reviewers • • • • • • • • • •

Donna D. Carstens, MD2 John R. Cohn, MD2 Lois J. Geist, MD, FACP1 Nora Goldschlager, MD, MACP2 Joseph John Padinjarayveetil, MD1 Trish M. Perl, MD2 Ileana L. Piña, MD2 Mark D. Siegel, MD1 Jean-Louis Vincent, MD2 Steven E. Weinberger, MD, FACP2

Pulmonary and Critical Care Medicine ACP Editorial Staff • • • • •

Charles Rossi, Senior Associate of Clinical Content Development Sean McKinney, Director, Self-Assessment Programs Margaret Wells, Managing Editor Katie Idell, Production Administrator/Editor John Murray, Editorial Coordinator

ACP Principal Staff Steven E. Weinberger, MD, FACP2 Deputy Executive Vice President Senior Vice President, Medical Education and Publishing D. Theresa Kanya, MBA1 Vice President, Medical Education and Publishing Sean McKinney1 Director, Self-Assessment Programs Margaret Wells1 Managing Editor Charles Rossi1 Senior Associate of Clinical Content Development Becky Krumm1 Senior Staff Editor

Ellen McDonald, PhD1 Senior Staff Editor Amanda Neiley1 Staff Editor Katie Idell1 Production Administrator/Editor Valerie Dangovetsky1 Program Administrator John Murray1 Editorial Coordinator Shannon O'Sullivan1 Editorial Coordinator Developed by the American College of Physicians 1. Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. See below.

Conflicts of Interest The following contributors and ACP staff members have disclosed relationships with commercial companies: Marie R. Baldisseri, MD, FCCM Royalties: UpToDate Donna D. Carstens, MD Speakers Bureau: GlaxoSmithKline John R. Cohn, MD Employment: Asthma, Allergy & Pulmonary Associates Research Grants/Contracts: GlaxoSmithKline, Dyax, Novartis, Genentech, Allergan, ScheringPlough Speakers Bureau: Schering-Plough, Novartis, GlaxoSmithKline, AstraZeneca Craig E. Daniels, MD Research Grants/Contracts: Novartis, Genzyme, Cambridge Antibody Technology

Richard S. Eisenstaedt, MD, FACP Speakers Bureau: Ortho Biotech E. Wesley Ely, MD, MPH, FACP Research Grants/Contracts: Pfizer, Lilly, Hospira, Aspect Honoraria: Lilly, Hospira, Pfizer Speakers Bureau: Lilly, Hospira, Pfizer Stanley B. Fiel, MD, FACP, FCCP Research Grants/Contracts: Novartis, Genetech, Gilead, Transave, Cystic Fibrosis Foundation Speakers Bureau: GlaxoSmithKline, Boehringer Ingelheim, Novartis, Pfizer Consultantship: Novartis, GlaxoSmithKline Nora Goldschlager, MD, MACP Honoraria: St. Jude Medical Nizar N. Jarjour, MD, FACP, FCCP Research Grants/Contracts: GlaxoSmithKline, Dey, Genentech, Merck Consultantship: Genentech, GlaxoSmithKline, Asthmatx Honoraria: Merck, Novartis Robert Kempainen, MD Research Grants/Contracts: Hill-Rom, Inc. Teofilo Lee-Chiong, MD Research Grants/Contracts: Respironics, Restore, Cephalon, Takeda, Saunders, Wiley, Elsevier, Oxford University Press, Lippincott Williams and Wilkins Consultantship: Saunders, Elsevier, Covidien Speakers Bureau: GlaxoSmithKline David E. Midthun, MD, FACP Royalties: UpToDate Honoraria: ACP (PIER) Timothy Morris, MD Research Grants/Contracts: Agen Biomedical, Ltd. Trish M. Perl, MD Research Grants/Contracts: 3M, Sage, Astellas Honoraria: Merck, GlaxoSmithKline, 3M, Baxter Consultantship: IHI Ileana L. Piña, MD Speakers Bureau: AstraZeneca, Sanofi-Aventis, Innovia, Merck, Solvay, Novartis

Steven A. Sahn, MD, FACP Research Grants/Contracts: Novartis, AstraZeneca, Intermune, Boehringer Ingelheim, Actelion, Gilead, Centocor, NIH IPFnet Royalties: UpToDate Honoraria: ACCP (PCCU) Consultantship: Intermune, Pilot, LAM Foundation Speakers Bureau: Intermune, Boehringer Ingelheim, Pilot Jean-Louis Vincent, MD Research Grants/Contracts: Abbott, AM Pharma, Apex, Artisan-Asahi, AstraZeneca, Biosite, Biotest, BioMerieux, Brahms, Covidien, DaiichiSanyo, Discovery, Drager, Edwards Lifesciences, Eli Lilly, Esai, Ferring, GlasxoSmithKline, Hutchinson, Intercell, Merck, Novartis, NovaLung, Novo Nordisk, Organon, Pfizer, Philips, PICIS, Roche Diagnostics, Spectral, Takeda, Teva, Tyco, Vasamed, Wyeth Lederle, Zeneus Honoraria: Eli Lilly, Edwards Lifesciences, Esai, GlaxoSmithKline, Novartis, Novo Nordisk, Pfizer Consultantship: AM Pharma, Apex, Artisan-Asahi, AstraZeneca, Biosite, BioMerieux, Covidien, Edwards Lifesciences, Eli Lilly, Esai, Ferring, GlaxoSmithKline, Instrumentation Labs, Intercell, Merck, Novartis, Novo Nordisk, Organon, Pfizer, Philips, Roche Diagnostics, Spacelabs, Spectral, Takeda, Wyeth Lederle Speakers Bureau: Eli Lilly, Edwards Lifesciences, Esai, GlaxoSmithKline, Novartis, Novo Nordisk, Pfizer Steven E. Weinberger, MD, FACP Stock Options/Holdings: Abbott, GlaxoSmithKline

Rheumatology Contributors Please note that a "1" following a contributor's name indicates that he or she has no relationships to disclose. A "2" indicates that the contributor has disclosed relationships. Please scroll down to view all disclosures. •

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Marcy B. Bolster, MD, FACP, Book Editor2 Professor of Medicine Director, Rheumatology Training Program Medical University of South Carolina Charleston, South Carolina Virginia U. Collier, MD, FACP, Associate Editor2 Hugh R. Sharp, Jr. Chair of Medicine Christiana Care Health System Newark, Delaware Professor of Medicine Jefferson Medical College of Thomas Jefferson University Philadelphia, Pennsylvania

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Anne R. Bass, MD, FACP2 Associate Professor of Clinical Medicine Weill Cornell Medical College Rheumatology Fellowship Program Director Hospital for Special Surgery New York, New York Richard D. Brasington, Jr., MD, FACP2 Professor of Medicine Director, Rheumatology Training Program Division of Rheumatology Washington University School of Medicine St. Louis, Missouri Alan N. Brown, MD, FACP2 Associate Professor of Medicine Medical University of South Carolina Charleston, South Carolina Beth Jonas, MD2 Director, Rheumatology Training Program Assistant Professor of Medicine Division of Rheumatology University of North Carolina School of Medicine Chapel Hill, North Carolina Leslie S. Staudt, MD1 Assistant Professor of Medicine Director, Rheumatology Training Program University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma


Rheumatology Reviewers • • • • • • • • •

Robert D. Arbeit, MD, FACP2 Stewart Babbott, MD, FACP1 Frantz Duffoo, MD, FACP1 Barri J. Fessler, MD, FACP2 Lois J. Geist, MD, FACP1 Kent A. Kirchner, MD, FACP1 Carlos J. Lozada, MD, FACP2 Joseph J. Padinjarayveetil, MD1 Trish M. Perl, MD, MSc2

Rheumatology ACP Editorial Staff • • • • •

Amanda Neiley, Staff Editor Sean McKinney, Director, Self-Assessment Programs Margaret Wells, Managing Editor Charles Rossi, Senior Associate of Clinical Content Development Shannon O'Sullivan, Editorial Coordinator

ACP Principal Staff Steven E. Weinberger, MD, FACP2 Deputy Executive Vice President Senior Vice President, Medical Education and Publishing D. Theresa Kanya, MBA1 Vice President, Medical Education and Publishing Sean McKinney1 Director, Self-Assessment Programs Margaret Wells1 Managing Editor Charles Rossi1 Senior Associate of Clinical Content Development Becky Krumm1 Senior Staff Editor Ellen McDonald, PhD1 Senior Staff Editor Amanda Neiley1 Staff Editor Katie Idell1 Production Administrator/Editor Valerie Dangovetsky1 Program Administrator John Murray1 Editorial Coordinator Shannon O'Sullivan1 Editorial Coordinator

Developed by the American College of Physicians 1. Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2. Has disclosed relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. See below.

Conflicts of Interest The following contributors and ACP staff members have disclosed relationships with commercial companies: Robert D. Arbeit, MD, FACP Employment: Paratek Pharmaceuticals Anne R. Bass, MD, FACP Research Grants/Contracts: Centocor Marcy B. Bolster, MD, FACP Research Grants/Contracts: Procter & Gamble Speakers Bureau: Genentech, Merck, Novartis Other: Abbott, UCB Richard D. Brasington, Jr., MD, FACP Speakers Bureau: Centocor, Genentech, Bristol-Myers Squibb, Biogen Idec, Abbott Alan N. Brown, MD, FACP Speakers Bureau: Abbott Other: UCB, Genentech Virginia U. Collier, MD, FACP Stock Options/Holdings: Celgene, Pfizer, Merck, Schering-Plough, Abbott, Johnson & Johnson, Medtronic, McKesson, Amgen Barri J. Fessler, MD, FACP Research Grants/Contracts: Actelion Consultantship: Gilead, Abbott Immunology Speakers Bureau: Actelion, Gilead, Encysive Pharmaceuticals Beth Jonas, MD Research Grants/Contracts: Stryker Biotech, Roche, Pfizer Other: Abbott Carlos J. Lozada, MD, FACP Honoraria: Wyeth, Amgen, Abbott, Bristol-Myers Squibb Speakers Bureau: Wyeth, Amgen, Abbott, Bristol-Myers Squibb

Trish M. Perl, MD, MSc Stock Options/Holdings: Visicu Research Grants/Contracts: 3M, Sage Honoraria: Pfizer, Ortho-McNeil Consultantship: VHA, IHI, Theradoc Steven E. Weinberger, MD, FACP Stock Options/Holdings: Abbott, GlaxoSmithKline

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Overview Women and Cardiovascular Disease Ethnicity and Cardiovascular Disease Diabetes Mellitus and Cardiovascular Disease Metabolic Syndrome and Cardiovascular Disease Cancer and Cardiovascular Disease Systemic Inflammatory Conditions and Cardiovascular Disease Lifestyle Factors and Cardiovascular Disease

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Cardiovascular disease is the leading cause of death in the United States, and among persons 75 years and older, more than twice as many die from cardiovascular disease than from cancer-related causes. More women than men die of cardiovascular disease each year, and the number of women dying of cardiovascular disease has not decreased over time. The prevalence of cardiovascular disease and the death rate due to cardiovascular disease are 2 to 4 times higher among persons with diabetes than those without diabetes. Microalbuminuria in persons with diabetes is strongly associated with cardiovascular disease and poorer cardiovascular disease outcomes. Patients treated with radiation therapy have higher than expected rates of valvular and coronary artery disease. Cardiomyopathy occurs in approximately 2% of patients treated with anthracyclines; it is directly related to the cumulative dose and is associated with a mortality rate of nearly 50%. Trastuzumab is associated with a high risk of cardiotoxicity, and cardiac function should be closely monitored during and after treatment.

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Overview More than 80 million adult Americans (1 in 3) have cardiovascular disease, with approximately 47% of these persons older than 60 years. If high blood pressure is excluded, approximately 10% of the adult U.S. population has cardiovascular disease (coronary artery disease, heart failure, stroke). The incidence of a first cardiovascular event increases directly with age, occurring in 10 per 1000 men between ages 45 and 54 years and increasing to 59 per 1000 men for ages 75 to 84

years (Figure 1). The incidence of a first cardiovascular event for women also increases substantially with age, with a delay of approximately one decade in rates compared with men. Cardiovascular disease is the most common cause of death in the United States; although cancerrelated deaths slightly exceed deaths related to cardiovascular disease for persons ages 45 to 74 years, deaths due to cardiovascular disease are more than twice as frequent as cancer-related deaths for persons older than 74 years.

Figure 1. Incidence of Cardiovascular Disease by Age and Sex. Cardiovascular disease consists of coronary artery disease, heart failure, cerebrovascular accident, or intermittent claudication. Framingham Heart Study 1980-2003. Data from National Heart, Lung, and Blood Institute. Incidence and Prevalence: 2006 Chartbook on Cardiovascular and Lung Diseases. www.nhlbi.nih.gov/resources/docs/cht-book_ip.htm. Published May, 2006. Accessed February 2, 2009. Chart 2-1.

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Women and Cardiovascular Disease

Women develop cardiovascular disease at later ages than men, but the prevalence of cardiovascular disease is similar for both sexes. The average lifetime risk for a woman to develop cardiovascular disease is approximately 1 in 2. Cardiovascular disease is the leading cause of death among women; 1 of 3 women die of cardiovascular disease, compared with 1 of 5 women dying from cancer-related causes. More women than men in the United States die of cardiovascular disease each year. Over the past 25 years, the number of cardiovascular deaths among men has declined significantly, but the number among women has remained essentially unchanged.

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Ethnicity and Cardiovascular Disease In 2005 in the United States, the prevalence of myocardial infarction or coronary heart disease/angina was approximately 5% for Asians, 6% for whites and blacks, 7% for Hispanics, and 11% for American Indian/Alaskan natives. This variable prevalence is largely attributable to the presence of risk factors in these ethnic groups: two or more risk factors for heart disease and stroke are found in nearly 50% of blacks and American Indian/Alaskan natives but in 25% of Asian adults. The prevalence of hypertension and stroke also has significant ethnic variability. Approximately 30% of the adult American population have high blood pressure: 16% of Asians, 19% of Hispanics or Latinos, 32% of whites, and 41% of blacks. The prevalence in American blacks is among the highest in the world. Compared with whites, blacks develop high blood pressure at a younger age, have higher average blood pressure measurements, and carry a much greater risk of end-organ complications such as stroke and end-stage kidney disease.

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Diabetes Mellitus and Cardiovascular Disease Approximately 10% of the U.S. adult population has diabetes mellitus, 95% of whom have type 2 diabetes. Since 1990, the prevalence of diabetes has increased 61%. The prevalence is approximately 1.5- to 2-fold higher in blacks, Hispanic Americans, and American Indian/native Alaskan adults than in whites. Diabetes is a risk factor for coronary artery disease, heart failure, and stroke, and adults with diabetes are 2 to 4 times more likely to have heart disease or experience a stroke than persons without diabetes. In 2000, the prevalence of any self-reported cardiovascular condition among persons with diabetes older than 35 years was greater than 30%. At least 65% of people with diabetes eventually die of cardiovascular disease, which is the leading cause of premature death among patients with diabetes. Although the cardiovascular disease mortality rate has declined in the United States, the relative reduction in mortality is much lower in persons with diabetes than in those without. Among persons with diabetes, the presence of microalbuminuria is strongly associated with coronary artery disease, left ventricular hypertrophy, and peripheral vascular disease.

Microalbuminuria is an adverse prognostic indicator for cardiovascular disease outcomes and allcause mortality in persons with diabetes.

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Metabolic Syndrome and Cardiovascular Disease The term metabolic syndrome refers to the clustering of risk factors for cardiovascular disease and type 2 diabetes. The most commonly utilized definition in the United States is the presence of at least three of the following five risk factors: 1. Fasting plasma glucose level ≥110 mg/dL (6.11 mmol/L) 2. HDL cholesterol level 40 years 2. Presence of malignancy 3. Blood urea nitrogen >27 mg/dL (9.64 mmol/L)

4. Plasma glucose >252 mg/dL (13.99 mmol/L) 5. Pulse rate >120/min 6. Serum bicarbonate 10% body surface area Points Mortality Rate 0-1 3.2% 2 12.1% 3 35.3% 4 58.3% ≥5 90.0% *One point is assigned for each criterion. Data from Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;115(2):149-153. [PMID: 10951229]

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Diagnosis and Management The evaluation of patients with suspected SJS or TEN begins with a thorough history, which includes medications (including over-the-counter NSAIDs), allergies, and family history of adverse cutaneous drug eruptions. A complete examination of the skin and mucous membranes should be performed. Abnormal laboratory findings may include an elevated erythrocyte sedimentation rate, electrolyte abnormalities, elevated serum aminotransferase levels, leukocytosis, eosinophilia, anemia, proteinuria, and microscopic hematuria. The diagnosis of SJS or TEN is usually made clinically, but a skin biopsy, possibly with frozen sections, can confirm the diagnosis. The prognosis of patients with SJS or TEN improves with early diagnosis and removal of the offending agent. The appropriate management for SJS/TEN consists of prompt discontinuation of suspected causative medications and supportive care. Many patients with SJS and all patients with TEN should be managed in a hospital setting, ideally an intensive care burn unit. Patients should receive meticulous wound care, management of fluids and electrolytes, nutritional support, and monitoring and treatment of superinfections. Because the epidermal barrier is severely compromised, death in patients with SJS or TEN usually is caused by infection. Appropriate antibiotics should be administered when infection is suspected; however, there is no role for prophylactic antibiotics in SJS or TEN because the goal is to minimize medication exposures. Because ocular involvement can be a source of major morbidity, patients with SJS and TEN should be monitored by an ophthalmologist. Gynecologic evaluation is also appropriate for

women, who may experience sloughing of the vulvar and vaginal mucosa. No controlled randomized clinical trials have identified an ideal therapy for SJS or TEN. The use of corticosteroids in SJS/TEN is controversial, as their use may be associated with an increased risk of infection; however, many practicing dermatologists use corticosteroids as part of the management of SJS or TEN. Accumulating data suggest that intravenous immune globulin may halt epidermal necrosis and decrease overall mortality, especially in the setting of TEN, when administered early in the course of the disease and in adequate doses (greater than 2 g/kg total dose).

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Erythroderma Erythroderma is defined as redness and scaling of more than 90% of the body surface area. It primarily affects middle-aged men. In at least 50% of affected patients, erythroderma is the result of slow (months to years) evolution, often of a known cutaneous disease such as atopic dermatitis, psoriasis, or cutaneous T-cell lymphoma. Evolution over a shorter (days- to weekslong) period may occur as a result of drug eruptions, pityriasis rubra pilaris, pemphigus foliaceus, and pustular psoriasis.

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Causes The most common causes of erythroderma are drug eruptions, psoriasis, atopic dermatitis, and cutaneous T-cell lymphoma; up to 47% of cases are idiopathic (Figure 119). The diagnosis of idiopathic erythroderma is one of exclusion. Adult onset of atopic dermatitis in a person without a personal or family history of atopy is rare; caution should be used when making this diagnosis because cutaneous T-cell lymphoma can also present with a similar widespread dermatitis or erythroderma. Patients with a history of psoriasis who are treated with systemic corticosteroids, often for another condition, may develop a widespread erythrodermic or pustular flare when the corticosteroids are discontinued. This is considered a medical emergency. Included in the differential diagnosis of erythroderma are conditions that cause widespread erythema without diffuse scaling, such as staphylococcal scalded skin syndrome, staphylococcal toxic shock syndrome, streptococcal toxic shock syndrome, Kawasaki disease, and early toxic epidermal necrolysis.

Figure 119. Erythroderma due to drug hypersensitivity.

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Diagnosis and Management Most patients with erythroderma experience severe pruritus, and approximately 50% of patients will have lymphadenopathy. All patients with erythroderma have the potential for systemic complications including hypo- or hyperthermia, edema, intravascular fluid loss, tachycardia, high-output heart failure, and bacterial superinfection, primarily with Staphylococcus aureus (Figure 120). It is often difficult to determine the underlying cause of erythroderma during the acute phase. Clinical clues to the diagnosis of the most common causes of erythroderma appear in Table 30. Alopecia, nail dystrophy, ectropion, and thickening of the palms and soles suggest that the erythroderma is long-standing. The presence of lymphadenopathy should prompt an excisional lymph node biopsy if lymphoma is suspected. Laboratory findings are nonspecific but may demonstrate leukocytosis, anemia, eosinophilia, lymphocytosis, an increased erythrocyte sedimentation rate, an elevated serum creatinine level, and a low serum protein level. Imaging of the chest, abdomen, and pelvis is often performed when the underlying cause of erythroderma is not obvious and lymphoma is suspected. Skin biopsy with routine hematoxylin and eosin staining should be performed in every patient with erythroderma; however, histopathologic findings diagnostic of the underlying cause are present in only 50% of patients. If the initial biopsy is negative, repeated biopsies may be useful and are recommended.

All patients with erythroderma should receive supportive hospital care, which includes close monitoring of fluids and electrolytes, nutrition, hypothermia, and bacterial superinfection. Intensive topical care with emollients, topical corticosteroids, and oral antihistamines is often used to control pruritus. Systemic corticosteroids or other immunosuppressants may be required, but these should be used with caution under the supervision of a dermatologist. Treatment should be aimed at the underlying disease, once identified.

Figure 120. Typical erythema and scale with overlying honey-crusting in a patient with erythroderma and Staphylococcus aureus secondary infection.

Table 30. Clinical Clues to the Diagnosis of Selected Causes of Erythroderma Cause

History

Atopic dermatitis

Physical Examination Laboratory Findings Findings Lichenification Eosinophilia; elevated serum IgE level

Personal or family history of atopic dermatitis, allergic rhinitis, or asthma; preexisting skin lesions; severe pruritus Nail pitting, oil droplet Psoriasis Personal or family sign, onycholysis; history of psoriasis; preexisting psoriatic skin psoriatic arthritis lesions; history of corticosteroid withdrawal Cutaneous T-cell Slowly progressive; Lymphadenopathy; lymphoma/Sézary extreme, intractable painful, fissured syndrome pruritus keratoderma; alopecia; leonine facies Hypersensitivity drug eruption

Onset 3-6 weeks after start of a new medication; most common causative medications are allopurinol, aromatic anticonvulsants, dapsone, NSAIDs, sulfonamides, lamotrigine

Skin biopsy may be diagnostic

Peripheral blood smear with >20% Sézary cells; clonal T-cell population in skin, blood, and/or lymph node Facial edema; cervical Leukocytosis with lymphadenopathy; fine eosinophilia or atypical scale around nose; lymphocytosis; elevated hepatosplenomegaly serum aminotransferases; elevated blood urea nitrogen or serum creatinine levels

Bibliography • • •

Akhyani M, Ghodsi ZS, Toosi S, Dabbaghian H. Erythroderma: a clinical study of 97 cases. BMC Dermatol. 2005;5:5. [PMID:15882451]. See PubMed French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding. Allergol Int. 2006;55(1):9-16. [PMID:17075281]. See PubMed Mockenhaupt M, Viboud C, Dunant A, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed

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drugs. The EuroSCAR study. J Invest Dermatol. 2008;128(1):35-44. [PMID:17805350]. See PubMed Rothe MJ, Bernstein ML, Grant-Kels JM. Life-threatening erythroderma: diagnosing and treating the “red man.” Clin Dermatol. 2005;23(2):206-217. [PMID:15802214]. See PubMed

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Alopecia • • •

Overview Nonscarring Alopecia Scarring Alopecia

Key Points • • •

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Alopecia areata typically presents with round patches of smooth alopecia without scarring, with exclamation-point hairs and tapered fractures. Trichorrhexis nodosa is characterized by hairs with broomlike, pigmented ends and patches of dense, short hairs with normal follicular density. Pattern alopecia in men presents with hair thinning on the crown or recession in the area of the temples; women with pattern alopecia present with hair thinning of the crown, a frontal hairline that is preserved, and a part that is distinctly wider anteriorly. Scarring alopecia is characterized by patches of hair loss with no visible follicular openings.

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Overview Alopecia consists of generalized or patchy hair loss, usually from the scalp, but it occurs at other sites as well. The initial step in the evaluation is to determine if hair loss is scarring or nonscarring. In nonscarring alopecia, the follicular openings are preserved, whereas they are lost in scarring alopecia.

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Nonscarring Alopecia Patient history and physical examination are sufficient to establish the cause of most cases of nonscarring alopecia. A few inexpensive laboratory tests, such as thyroid-stimulating hormone measurement and iron studies, may be necessary, but extensive panels of endocrine studies are

seldom of any clinical value. The most common causes of nonscarring alopecia are alopecia areata, trichorrhexis nodosa, pattern alopecia, telogen effluvium, and tinea capitis (see Common Skin and Nail Infections).

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Alopecia Areata Patients with alopecia areata have well-defined, round, smooth areas of hair loss (Figure 121). Short, fractured, exclamation-point hairs may be visible at the periphery. Easily extracted hairs at the periphery demonstrate a tapered “pencil-point” fracture. Nail pitting is often present. Alopecia areata is an autoimmune disorder, but screening for other autoimmune disorders is only necessary in the presence of suggestive signs or symptoms. The major differential diagnosis is syphilis, which commonly presents with patchy, “moth-eaten” alopecia and a generalized papulosquamous rash that also involves the palms and soles. Local patches of alopecia areata respond to intralesional injections of triamcinolone. An occasional patient will respond to potent topical corticosteroids, but scalp atrophy and depigmentation may result. Further information is available from the National Alopecia Areata Foundation (www.naaf.org).

Figure 121. A well-defined, round, smooth area of hair loss with preserved follicular openings in a patient with alopecia areata.

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Trichorrhexis Nodosa Trichorrhexis nodosa (fracture of the hair shaft) is common in black patients who straighten their hair. A hair with a broomlike, pigmented end is diagnostic of trichorrhexis nodosa. Patches of dense, short hairs with normal follicular density are typical of trichorrhexis nodosa. Patients with trichorrhexis nodosa will regrow healthy hair if gentle hair-care practices are adopted.

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Pattern Alopecia Pattern alopecia presents with hair thinning on the crown or recession in the area of the temples. In men, pattern alopecia may be treated with 2% to 5% topical minoxidil or oral finasteride. Women with pattern alopecia present with hair thinning of the crown, a frontal hairline that is preserved, and a part that is distinctly wider anteriorly (Figure 122). They respond best to topical minoxidil. Finasteride is of no benefit to the majority of women with pattern alopecia and is a pregnancy risk category X drug. Oral antiandrogens such as spironolactone may be effective. Women with temporal recession or frank virilization require an endocrine evaluation for polycystic ovary syndrome.

Figure 122. Pattern alopecia in a female patient, characterized by a frontal hairline that is preserved and a part that is distinctly wider anteriorly.

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Telogen Effluvium Telogen effluvium presents as a sudden increase in shedding of hairs with white bulbs, usually 3 to 5 months after a period of stress, such as a crash diet, serious illness, surgery, or childbirth. Seborrheic dermatitis, psoriasis, iron deficiency, and thyroid disease may also cause telogen effluvium.

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Scarring Alopecia Scarring alopecia is characterized by patches of hair loss with no visible follicular openings (Figure 123). Scarring alopecia begins with erythema at the base of the hairs and evolves to clusters of hairs (“doll's hair”) emerging from an inflammatory base. It results in permanent hair loss. Progression is often slow but without appropriate treatment will result in permanent scarring. A scalp biopsy is generally required to establish the diagnosis. Patients with scarring alopecia should be referred to a dermatologist.

Figure 123. Scarring alopecia with no visible follicular openings.


Dinh QQ, Sinclair R. Female pattern hair loss: current treatment concepts. Clin Interv Aging. 2007;2(2):189-199. [PMID: 18044135]. See PubMed Otberg N, Wu WY, McElwee KJ, Shapiro J. Diagnosis and management of primary cicatricial alopecia: part I. Skinmed. 2008;7(1):19-26. [PMID:18174797]. See PubMed Sperling LC. Hair and systemic disease. Dermatol Clin. 2001;19(4):711-726. [PMID:11705356]. See PubMed

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Leg Ulcers • • • • •

Overview Venous Stasis Ulcers Neuropathic Ulcers Arterial Ulcers Nonhealing Ulcers

Key Points • • • • • • • • •

Venous stasis ulcers are associated with chronic venous insufficiency and typically occur on the medial aspect of the lower leg, especially over the medial malleolus. Venous stasis ulcers should be treated with compression. Neuropathic ulcers occur primarily over the plantar aspects of the foot and are common in patients with diabetes mellitus and severe peripheral neuropathy. Management of neuropathic ulcers requires debridement of necrotic tissue followed by offloading of pressure. Arterial ulcers are the result of severe peripheral vascular disease and are typically located on the most distal portions of the extremities and over pressure points. Patients with arterial ulcers should be referred to a vascular surgeon for evaluation of their potential for revascularization. Nonhealing ulcers or those with an atypical appearance should be biopsied. Systemic antibiotics should be reserved for clinically infected ulcers. Pentoxifylline, when combined with compression, may aid in the resolution of venous ulcers.

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Overview Leg ulcers are common in patients with diabetes mellitus, peripheral artery disease, lymphedema, and venous stasis. Some leg ulcers have mixed causes, but the vast majority can be classified as venous (stasis), neuropathic, or arterial (ischemic).

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Venous Stasis Ulcers Venous stasis ulcers are associated with chronic venous insufficiency and typically occur on the medial aspect of the lower leg, especially near the medial malleolus overlying a perforating vein (Figure 124). These ulcers are irregularly shaped, tender, and shallow with a red base that may occasionally be purulent. Ulcers may be single or multiple, but they do not occur on the foot or above the knee. Accompanying signs of venous insufficiency include edema and hemosiderin

staining, which results in a copper to brown coloration of the skin. Skin affected by chronic stasis dermatitis may be thickened and sclerotic, a condition known as lipodermatosclerosis. Patients with severe pain usually also suffer from segmental hyalinizing vasculopathy and demonstrate reticulated areas of white scarring (atrophie blanche). Venous stasis ulcers respond to compression, and compression may be the essential element in healing. There are no randomized controlled trials of compression therapy, but cohort studies suggest that healing is more likely to occur and at a greater rate among patients compliant with compression therapy. Two types of compression devices are available, elastic (stockings) and inelastic. The zinc-oxide–impregnated paste bandage (Unna boot) is an example of an inelastic compression system. High compression is more effective than low compression, but arterial disease should be excluded prior to initiating compression therapy. Dressings are important to protect the wound and provide a moist environment for wound healing. A systematic review of multiple dressing types found no difference in healing rates among the various dressings used. Hydrocolloid or foam dressings are most often used to cover the ulcer and can be applied beneath elastic dressings and under an Unna boot, and a mid- to high-potency corticosteroid ointment can be applied to surrounding skin if there is associated stasis dermatitis. Oral, rather than topical, antibiotics should be used if there is any suggestion of infection, as there is a significant risk of developing allergic contact dermatitis to topical antibiotics used in this setting. The boot is typically changed weekly. Healing occurs over a course of weeks to months. Mechanical compression pumps can be helpful if severe edema is present. Refractory ulcers may benefit from pentoxifylline. Some patients benefit from surgical treatment of incompetent vessels, although this is not needed in the majority of patients; evaluation by a vascular surgeon is appropriate, particularly if there appears to be involvement of the deep venous system. All patients should wear elastic compression hose following healing of the ulcer. Two pairs of kneehigh stockings providing at least 20 mm Hg of pressure should be supplied and should be replaced every 3 to 6 months.

Figure 124. Venous stasis ulcers are typically minimally symptomatic and occur on the medial side of the lower leg in areas of hyperpigmentation.

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Neuropathic Ulcers Neuropathic ulcers occur in insensate limbs. The usual patient with a neuropathic ulcer has diabetes mellitus and severe peripheral neuropathy (see MKSAP 15 Endocrinology and Metabolism). As a result, the ulcers are usually asymptomatic except for associated diabetic paresthesia. Neuropathic ulcers occur primarily over the plantar aspects of the foot, especially in the region of the metatarsal heads (Figure 125). Thick surrounding hyperkeratosis is typically present. The ulcers are usually much deeper and wider than their surface appearance suggests. If not recognized promptly and managed properly, associated osteomyelitis can lead to amputation (see MKSAP 15 Infectious Disease).

Management usually requires assessment of infection, including the possibility of osteomyelitis, assessment of vascular supply, and debridement of necrotic tissue followed by offloading of pressure, usually by means of total-contact casting.

Figure 125. Neuropathic ulcers have a hyperkeratotic rim and occur over pressure points such as the metatarsal heads.

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Arterial Ulcers Arterial ulcers (also called ischemic ulcers) are the result of severe peripheral vascular disease and are typically located on the most distal portions of the extremities (Figure 126). They commonly overlie bony prominences that are subject to trauma or pressure. The surrounding skin is typically red, taut, and atrophic. Skin markings and hair are absent, pulses are difficult to palpate, and capillary refill is poor. The ulcer may appear punched-out or stellate, and a black or yellow eschar may be present. Pain is typically severe and worsens when the leg is elevated.

An ankle-brachial index below 0.6 suggests arterial compromise. Infarction of the toes and livedo reticularis suggest the possibility of cholesterol embolization (Figure 127). Renal function should be assessed in a patient with these findings, as emboli commonly involve the kidneys. Patients with ischemic ulcers should be evaluated by a vascular surgeon. For those who are not candidates for revascularization, slow healing may be possible with gentle debridement and moist wound care. Infection should be treated if present.

Figure 126. Arterial ulcers are intensely painful and occur on the distal portions of the extremities.

Figure 127. Cholesterol embolization typically presents with distal infarctive lesions. The limb typically demonstrates livedo reticularis.

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Nonhealing Ulcers

Nonhealing ulcers suggest the possibility of invasive infection, leukocytoclastic vasculitis, or squamous cell carcinoma. Other reasons for nonhealing may be related to an incomplete treatment plan (inadequate pressure, elevation, dressings) or patient noncompliance. Refractory ulcers or those with an atypical appearance should be biopsied. Diseases as diverse as squamous cell carcinoma, pyoderma gangrenosum, rheumatoid vasculitis, thrombotic disorders, and prolidase deficiency may present with nonhealing leg ulcers. Nutritional deficiency may compromise wound healing. Systemic antibiotics are indicated only if the ulcer is clinically infected. Signs and symptoms of infection include pain or increasing tenderness, a foul smell, purulent drainage, necrosis, spreading redness, warmth, and induration. Refractory ulcers may benefit from pentoxifylline. A systematic review of 11 trials concluded that pentoxifylline was more effective for complete or partial venous ulcer healing than placebo or no treatment and was most effective when used in conjunction with compression. Several growth factors, including platelet-derived growth factor, epidermal growth factor, fibroblast growth factors, transforming growth factors, and insulin-like growth factors, have been used to treat refractory ulcers. The few randomized clinical trials that have assessed their efficacy have generally found conflicting results. The use of growth factors is expensive and not without risk. Postmarketing studies have recently identified an increased risk of cancer mortality in patients who have used three or more tubes of becaplermin gel, and caution is advised in using it in patients with known malignancy. Based on uncontrolled trials and expert opinion, skin grafting and skin substitutes can be of benefit in refractory ulcers.

Bibliography •

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Fonder MA, Lazarus GS, Cowan DA, Aronson-Cook B, Kohli AR, Mamelak AJ. Treating the chronic wound: a practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol. 2008;58(2):185-206. [PMID:18222318]. See PubMed Jones JE, Nelson EA. Skin grafting for venous leg ulcers. Cochrane Database Syst Rev. 2007;(2):CD001737. [PMID:17443510]. See PubMed Khan MN, Davies CG. Advances in the management of leg ulcers—the potential role of growth factors. Int Wound J. 2006;3(2):113-120. [PMID:17007341]. See PubMed Marston W. Evaluation and treatment of leg ulcers associated with chronic venous insufficiency. Clin Plast Surg. 2007;34(4):717-730. [PMID:17967625]. See PubMed

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Special Populations • • • •

Skin in Elderly Patients Dermatologic Diseases of Immunosuppressed Patients Dermatologic Diseases in Skin of Color Dermatologic Diseases in Obesity

Key Points

• • • •

• • • • • • • • • • •

As skin ages, it thins, loses moisture and elasticity, and declines in physical and immune function. Pruritus due to dry skin is one of the most common skin problems in the elderly. Gentle skin care with regular use of emollients should be recommended to all older persons to help maintain skin hydration and barrier integrity. In patients with HIV infection, initiation of antiretroviral therapy can lead to dramatic improvement in psoriasis, photodermatitis, prurigo nodularis, molluscum contagiosum, and drug reactions. Eczema, xerosis, warts, and Kaposi sarcoma that are associated with HIV infection do not improve with antiretroviral therapy. The most common skin diseases in the transplant population are infections or malignancy. Skin cancers in organ-transplant patients are common, behave aggressively, and have a significantly increased risk of metastasis and death. Vitiligo is characterized by depigmentation that is usually found on the face, genitals, and dorsal hands, usually in a bilaterally symmetric distribution. Vitiligo may precede the appearance of Hashimoto thyroiditis, Graves disease, diabetes mellitus, alopecia areata, pernicious anemia, and rheumatoid arthritis. Squamous cell carcinomas in black patients occur most frequently on the legs and in non–sun-exposed areas. Melanomas in persons of color occur frequently in non–sun-exposed areas such as the palms, soles, and mucous membranes. Advanced lymphedema is characterized by nonpitting “peau d'orange” edema and by hyperkeratosis and papillomatosis. Lipodermatosclerosis, stasis dermatitis, and leg ulcers are common complications of chronic venous insufficiency. Intertrigo is caused by increased moisture and friction and may become colonized or overtly infected by Candida or Staphylococcus. In patients with intertrigo, the presence of satellite pustules at the periphery suggests candidiasis.

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Skin in Elderly Patients As the skin ages, it thins and loses moisture and elasticity. Elderly patients tend to have dry and flaky skin, particularly on the lower extremities. Loss of elasticity coupled with a loss of subcutaneous tissues leads to sagging skin. Much of what is considered “aging” in the skin, however, is actually the result of chronic sun damage, or photoaging (Figure 128). Common features of aged and sun-damaged skin are listed in Table 31. Aged skin is less able to regulate temperature, maintain hydration, and repair damage. Sebum and sweat production decrease. Immune responsiveness declines, as does vitamin D production.

Figure 128. Photoaged skin with accentuated wrinkles, telangiectasia, and yellowish discoloration from degeneration of elastin in the skin.

Table 31. Common Skin Findings of Aged Versus Photoaged Skin Intrinsic Aging Thinning of skin Thinned epidermis Loss of subcutaneous fat Fine wrinkles Dry, flaky skin Loss of elasticity Skin pallor Decreased skin temperature

Photoaging Accentuated wrinkling Coarse furrows Fine wrinkles Irregular pigmentation Diffuse pigmentation; “bronzing” Lentigenes Pebbly texture of skin (elastosis) Solar purpura

Loss of hair Telangiectasia Graying of hair Venous lakes Development of seborrheic keratoses, cherry angiomas Comedones Actinic keratoses, skin cancers

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Common Clinical Problems of Aging Skin Xerosis (dry skin) is one of the most common causes of pruritus in older persons. Because the skin is fragile, lacerations occur easily, and wound healing may be prolonged or complicated by the development of ulcers. Certain cutaneous infections occur with increased frequency in the elderly, notably varicella zoster, and many older persons have chronic onychomycosis and tinea pedis. A variety of benign and malignant tumors appear as patients age. Nevi involute and may disappear completely by the sixth or seventh decade of life. Seborrheic keratoses, cherry angiomas, and lentigenes begin to develop in middle age and increase over time (Figure 129). Solar or actinic purpura occurs frequently in individuals who have extensive photodamage of the skin. Minimal trauma, which may or may not have been recognized, causes large, asymptomatic ecchymoses. Drug reactions are more common in elderly persons, likely because of increased exposure. This may also be due to decreased drug clearance or altered metabolism.

Figure 129. Seborrheic keratoses (waxy tan to brown, “stuck-on”–appearing papules) and cherry angiomas (nonblanchable, pink to red, small papules) are frequently seen together on the chest and back of older patients.

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Management of Aging Skin Gentle skin care with regular use of emollients should be recommended to all older persons to help maintain skin hydration and barrier integrity. Sun protection is important even in older adults, because cumulative sun damage continues to accrue. Many cosmeceutical products are available to treat photodamaged skin, and their beneficial effects (and prices) vary widely. Generally, products that contain retinol or α-hydroxy or β-hydroxy acids may have some beneficial effects. Topical tretinoin reduces fine wrinkles and

other evidence of sun damage and is U.S. Food and Drug Administration–approved for the treatment of wrinkling; however, insurance companies and Medicare rarely cover its use for what is considered cosmetic purposes. Decreased estrogen levels after menopause are thought to contribute to many age-related skin changes in women. Use of hormone therapy and selective estrogen receptor modulators may improve skin elasticity and decrease wrinkling. However, the U.S. Preventive Services Task Force recommends against the use of estrogen or estrogen plus progestin for the prevention of chronic diseases after menopause because of the increase in cardiovascular disease and cancer risk. Cigarette smoking exacerbates wrinkling, particularly in women.

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Dermatologic Diseases of Immunosuppressed Patients • •

Skin Diseases in HIV Skin Diseases in Hematopoietic Stem Cell Transplant and Organ Transplant Recipients

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Skin Diseases in HIV Since the advent of antiretroviral therapy, the incidence of many skin diseases that were once common in HIV-positive patients (such as seborrheic dermatitis, fungal infections, psoriasis, and cutaneous manifestations of opportunistic infections) has decreased. However, patients with a CD4 cell count less than 200/µL who are not on antiretroviral therapy commonly have psoriasis, photodermatitis, prurigo nodularis, molluscum contagiosum, and drug reactions. In all of these conditions, initiation of antiretroviral therapy can lead to dramatic improvement. Psoriasis in patients with a low CD4 cell count can be severe, affect more than 50% of the body surface area, and present in an atypical fashion (more severe, explosive onset) (Figure 130). Treatment includes antiretroviral therapy, topical corticosteroids, and acitretin. Photodermatitis in patients with HIV infection may be caused by the virus itself and concomitant administration of photosensitizing medications. Treatment consists of sunscreen, high-potency topical corticosteroids, emollients, and antihistamines. Pruritus in HIV infection may be the result of skin disorders common in HIV (xerosis, scabies, psoriasis), secondary to internal disease (lymphoma), or a manifestation of early infection. Eosinophilic folliculitis is also found in advanced HIV disease and is characterized by recurrent, pruritic crops of 3- to 5-mm red papules centered around hair follicles found primarily on the scalp, face, neck, and upper chest. Treatment includes high-potency topical corticosteroids and sometimes thalidomide.

Molluscum contagiosum (see Common Skin and Nail Infections) can be very severe in patients with low CD4 cell counts. First-line treatment is antiretroviral therapy. Imiquimod and cidofovir have been used off-label to treat widespread or recalcitrant disease. Drug reactions are very common in patients with CD4 cell counts less than 50/µL. A subset of HIV-associated skin diseases does not improve with antiretroviral therapy. These include eczema, xerosis, warts, and Kaposi sarcoma. With the use of antiretroviral therapy, the presentation of Kaposi sarcoma has changed from large violaceous or plum-colored plaques to more subtle purple patches (Figure 131). Despite favorable CD4 cell counts (>300/µL) and low viral loads, Kaposi sarcoma persists in the HIV-positive patient population.

Figure 130. Widespread, coalescing, erythematous plaques with overlying adherent scale of psoriasis in a patient with HIV infection.

Figure 131. Kaposi sarcoma, presenting as firm purple nodules in a patient with HIV infection (left). Purple palatal nodules of Kaposi sarcoma in a patient with HIV infection (right).

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Skin Diseases in Hematopoietic Stem Cell Transplant and Organ Transplant Recipients The most common skin diseases in the transplant population are infections or malignancy. Infections that are increased in patients who have undergone transplantation include herpes simplex, warts, herpes zoster, and superficial fungal infections with Candida, Malassezia, and dermatophytes (Trichophyton species). Also important to recognize are disseminated fungal infections with organisms such as Candida, Aspergillus, Fusarium, and fungi of the Zygomycetes class. When these infections disseminate to the skin, they most commonly present as purpuric papules and/or nodules (Figure 132). Disseminated fungal infection should be suspected in any febrile, neutropenic patient with purpuric skin lesions who fails to respond to broad-spectrum antibiotics and antiviral agents. A skin biopsy for routine histology, special stains for fungal organisms, and culture will aid in the diagnosis.

The incidence of cutaneous malignancies is increasing dramatically as patients survive longer after solid-organ transplantation. The incidence of squamous cell carcinoma, basal cell carcinoma, melanoma, and Kaposi sarcoma has increased significantly in this patient population (see MKSAP 15 Hematology and Oncology). The risk of developing skin cancers increases with time from transplantation. These skin cancers are more likely to be multiple, occur at a younger age, and behave more aggressively with a significantly increased risk of metastasis and death. Treatment for individual lesions is surgical excision. Overall risk reduction can be achieved through reduction of immunosuppression and use of oral retinoids (off label).

Figure 132. Purpuric nodule as the presenting sign of disseminated candidiasis in a patient with acute lymphoblastic leukemia.

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Dermatologic Diseases in Skin of Color

Patients with darker skin color are predisposed to develop a number of diseases at a higher frequency or with greater severity and impact on quality of life than those with lighter pigmentation. Abnormalities of pigmentation are common problems.

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Postinflammatory Hyper- and Hypopigmentation As the skin in patients with darker skin color recovers from an acute inflammatory disease such as an acne lesion, it may become hyperpigmented (known as postinflammatory hyperpigmentation) (Figure 133). The time required for the area of postinflammatory hyperpigmentation to fade to normal skin color is highly variable and relates to the patient's normal skin tone and the intensity and type of inflammation. Postinflammatory hyperpigmentation may take months or sometimes years to recover and can be psychologically distressing. Treatment with peeling agents such as glycolic or salicylic acid or with bleaching agents such as hydroquinone may help; however, they do not always result in the desired improvement. Certain conditions may lighten the skin as they resolve. Discoid lupus erythematosus frequently causes scarring and hypopigmentation, as can seborrheic dermatitis, tinea versicolor, atopic dermatitis, and sarcoidosis. In scarred areas, the pigment alteration may be permanent; however, postinflammatory hypopigmentation generally recovers more quickly without treatment than does postinflammatory hyperpigmentation.

Figure 133. Postinflammatory hyperpigmentation may occur in patients with darker skin color as skin recovers from an acute inflammatory disease, such as an acne lesion.

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Vitiligo

Vitiligo is characterized by depigmentation, which is a complete absence of color (Figure 134). White macules are most frequently found on the face, genitals, and dorsal hands and are often bilaterally symmetric in distribution. Vitiligo affects between 0.1% and 2% of the population and is most common in children or young adults. It has no racial or ethnic predisposition; however, the social and psychological impact is most devastating in patients of color. Loss of pigment results from death of melanocytes in the affected skin. It is likely due to a cellular autoimmune response, and associations with other autoimmune diseases (particularly those of the thyroid) are common. Hashimoto thyroiditis, Graves disease, diabetes mellitus, alopecia areata, pernicious anemia, and rheumatoid arthritis are seen with increased frequency in patients with vitiligo. The skin disease often occurs before the associated endocrinopathy. Vitiligo is most commonly treated with topical corticosteroids, topical immunomodulators, or phototherapy.

Figure 134. Vitiligo in a black patient, characterized by absence of color.

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Disorders of Skin Appendages

Because black patients' hair may be tightly coiled, shaving may result in ingrown hairs; these can lead to inflammatory papules and pustules that may cause keloids. Abnormalities of hair, such as pseudofolliculitis barbae, acne keloidalis nuchae, and central centrifugal scarring alopecia, are particularly prevalent and distressing. Pseudofolliculitis barbae (shaving bumps) affects up to 80% of black men and is characterized by the formation of firm, skin-colored, erythematous or hyperpigmented papules. Acne keloidalis nuchae is an inflammatory folliculitis that is manifested by papules, pustules, and keloid formation at the nape of the neck (Figure 135). Black women have a higher prevalence of acne keloidalis nuchae in the vertex areas of the scalp. Central centrifugal scarring alopecia is a slowly progressive, permanent hair loss that begins on the crown and advances to the surrounding area. All three diseases can be treated with topical (and sometimes intralesional) corticosteroids and oral antibiotics. Response to treatment is variable. For patients with pseudofolliculitis barbae, no shaving or shaving in the direction of hair growth (rather than “against the grain”) may be recommended. For central centrifugal scarring alopecia, patients should be told to avoid tight braiding of hair and the use of hot oils for styling and straightening.

Figure 135.

Acne keloidalis nuchae is an inflammatory folliculitis that is manifested by keloid formation at the nape of the neck.

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Keloids Keloids are more common and reach a larger size in black patients than in patients of other races. Treatment with intralesional corticosteroids may decrease their size and symptoms; however, the skin rarely completely recovers (see Common Neoplasms).

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Dermatosis Papulosa Nigra Dermatosis papulosa nigra is characterized by small, hyperpigmented papules that first occur in the periorbital region and slowly increase in number on the face over time (Figure 136). These occur in about 35% of black patients and also are seen frequently in Asian patients. They are benign and asymptomatic and are likely related to seborrheic keratoses. They can be removed for cosmetic reasons, but they do not require treatment.

Figure 136. Dermatosis papulosa nigra, characterized by small, hyperpigmented papules that first occur in the periorbital region and slowly increase in number on the face over time.

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Skin Cancers Skin cancers are relatively uncommon in darker-skinned individuals. Basal cell carcinomas occur infrequently in persons of color; patients with lighter skin tone and those exposed to high levels of ultraviolet light are at highest risk. When basal cell carcinoma does occur in darker-skinned individuals, it is almost always of the pigmented subtype. Squamous cell carcinomas are the most common skin cancer in black patients, in whom they occur most frequently on the legs and in non–sun-exposed areas. This is in contrast to squamous cell carcinomas in light-skinned persons, which usually occur on sun-damaged skin. Melanomas in persons of color also frequently occur in non–sun-exposed areas, such as the palms, soles, and mucous membranes. Because there is, in general, a low index of suspicion for skin cancer in persons of color, the diagnosis may be delayed, leading to a worse outcome. Suspicious lesions in an individual of any skin color should be promptly and appropriately evaluated.

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Dermatologic Diseases in Obesity • • • • •

Acanthosis Nigricans Lymphedema and Chronic Venous Insufficiency Skin Infections and Intertrigo Striae Distensae Cellulite

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Acanthosis Nigricans Acanthosis nigricans is a velvety, dark thickening of the skin that involves primarily the flexural sites of the neck, axillae, and groin (Figure 137). The dorsal hands and elbows may also be affected. Nearly 75% of obese patients develop acanthosis nigricans. Acrochordons (skin tags) develop in similar areas and may accompany acanthosis nigricans. All non–malignancyassociated cases of acanthosis nigricans are associated with insulin resistance. Acanthosis nigricans and insulin resistance are also associated with hyperandrogenism and such androgendependent conditions as acne, hidradenitis suppurativa, and androgenic alopecia. Weight loss and improved control of hyperinsulinemia are the primary interventions required.

Figure 137. Acanthosis nigricans, characterized by a velvety brown plaque with skin tags, in the axilla of an obese patient.

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Lymphedema and Chronic Venous Insufficiency

Lymphedema and chronic venous insufficiency are common in obese individuals. Chronic venous insufficiency results from persistent venous hypertension caused by venous incompetence or occlusion. Manifestations of chronic venous insufficiency include edema, skin hyperpigmentation, stasis dermatitis, varicose veins, lipodermatosclerosis, cellulitis, and ulceration. Lower-extremity lymphedema is initially characterized by unilateral or bilateral aching leg pain, heaviness, and pitting edema. Early in its course, lymphedema may be confused with chronic venous insufficiency. Advanced lymphedema is recognized by the characteristic nonpitting “peau d'orange” edema resulting from progressive fibrosis of cutaneous and subcutaneous tissue and by hyperkeratosis and papillomatosis. Massive localized lymphedema presenting as masses (pseudosarcoma) affecting the pendulous abdomen, upper arms, and thighs has recently been described. Massive localized lymphedema usually occurs in patients weighing over 181.4 kg (400 lb.). As with lower-extremity lymphedema, the affected area becomes firm and fibrotic over time and with increasing severity. Vesicles, bullae, and oozing of lymphatic fluid may also be seen. Surgical excision of the localized mass of lymphedema is the only reported successful therapy.

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Skin Infections and Intertrigo The incidence of skin infections is increased in obese patients because the moist, warm, protected environment in skin folds is conducive to the growth of both bacteria and fungi. Intertrigo is caused by increased moisture and friction and is not itself an infectious condition. It does, however, frequently become colonized and, at times, infected by Candida or, less commonly, Staphylococcus. The presence of satellite pustules at the periphery suggests candidiasis. Uncomplicated intertrigo responds to low-potency hydrocortisone or tacrolimus ointment, but topical antifungal medications are often required as well because of concomitant fungal infection. Combination corticosteroid-antifungal preparations should be avoided in these areas, as the corticosteroid is excessively strong and may cause striae. Dermatophyte infection of the interdigital spaces of the feet and the toenails occurs with increased frequency in obese patients. These require topical antifungal agents, or, in patients with onychomycosis, oral antifungal agents.

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Striae Distensae Striae distensae are linear atrophic marks found most commonly on the abdomen, breasts, buttocks, and thighs in obese individuals. Their orientation is perpendicular to the greatest force of tension. Early lesions may be raised and pink, but over time they become white and atrophic.

Similar stretch marks occur in Cushing syndrome but are wider, more atrophic, and more likely to be purple than those seen in simple obesity (Figure 138).

Figure 138. Wide purple striae along the lateral abdomen in a patient with Cushing syndrome.

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Cellulite Gynoid lipodystrophy, or cellulite, is a dimpled, irregular contour of the skin of the thighs, buttocks, and abdomen. This is present to some degree in most postadolescent women but is more pronounced in those with increased subcutaneous fat. Weight loss has a variable effect on this appearance, and current therapies are also not reliably effective in improving the appearance. Body contouring with liposuction is the most commonly performed cosmetic surgical procedure in the United States. Obese patients may seek this procedure, but the large volumes of

subcutaneous fat that must be removed significantly increase the complication rate and may be associated with an increased proportion of visceral adipose tissue. This latter effect may increase the metabolic effects of obesity.

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Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002;47(1):1-17. [PMID:12077575]. See PubMed Grimes PE. New insights and new therapies in vitiligo. JAMA. 2005;293(6):730-735. [PMID:15701915]. See PubMed Maurer T, Ponte M, Leslie K. HIV-associated Kaposi's sarcoma with a high CD4 count and a low viral load. N Engl J Med. 2007;357(13):1352-1353. [PMID:17898112]. See PubMed Raju S, Neglén P. Chronic venous insufficiency and varicose veins. N Engl J Med. 2009;360(22):2319-2327. [PMID:19474429]. See PubMed Stevenson S, Thornton J. Effect of estrogens on skin aging and the potential role of SERMs. Clin Interv Aging. 2007;2(3):283-297. [PMID:18044179]. See PubMed Venkatesan P, Perfect JR, Myers SA. Evaluation and management of fungal infections in immunocompromised patients. Dermatol Ther. 2005;18(1):44-57. [PMID:15842612]. See PubMed Yaar M, Gilchrest BA. Skin aging: postulated mechanisms and consequent changes in structure and function. Clin Geriatr Med. 2001;17(4):617-630. [PMID:11535419]. See PubMed Yosipovitch G, DeVore A, Dawn A. Obesity and the skin: skin physiology and skin manifestations of obesity. J Am Acad Dermatol. 2007;56(6):901-916. [PMID:17504714]. See PubMed

Diabetes Mellitus • • • •

Diagnosis and Classification of Diabetes Mellitus Treatment of Diabetes Mellitus Complications of Diabetes Mellitus Hypoglycemia in Patients Without Diabetes Mellitus


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Patients with impaired fasting glucose levels and impaired glucose tolerance are at increased risk for developing type 2 diabetes mellitus. Women with a history of gestational diabetes mellitus are at very high risk (~50%) of developing type 2 diabetes within a decade. Metformin is widely considered the best first-line antihyperglycemic agent for type 2 diabetes mellitus and may help prevent progression from prediabetes to diabetes; sulfonylureas are typically used as second-line therapy. In type 1 diabetes mellitus, an intensive insulin regimen involving at least three to four daily insulin injections or a continuous subcutaneous insulin infusion with a programmable insulin pump is preferable. Glycemic control needs to be maintained compulsively throughout gestation, with current glucose targets of 60 to 90 mg/dL (3.3 to 5.0 mmol/L) premeal and less than 120 mg/dL (6.7 mmol/L) 1 hour postmeal. The mainstays of therapy for diabetic ketoacidosis are intravenous insulin and intravenous fluids. Microvascular complications in diabetes mellitus involve the kidneys (diabetic nephropathy), retinae (diabetic retinopathy), and peripheral nerves (diabetic neuropathy); macrovascular complications involve the coronary, carotid, and cerebral arteries (myocardial infarction); the aorta (stroke); and the arterial supply to the lower extremities (gangrene). Aggressive blood pressure control, particularly with angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers, slows the progression of diabetic nephropathy. Clinical evaluation of the diabetic foot includes assessment of the vascular status of the leg and an evaluation of foot sensation with a standard 10-g monofilament. Barring contraindications, all adult patients with diabetes mellitus who are older than 40 years are now advised to take daily aspirin.

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Diagnosis and Classification of Diabetes Mellitus Diabetes mellitus, a chronic metabolic disease characterized by increased circulating blood glucose levels, results from the inadequate supply or action of insulin. Insulin is the main hormonal regulator of intermediary metabolism. Its most prominent effects are the stimulation of

glucose uptake by peripheral tissues (mainly skeletal muscle) and the suppression of endogenous glucose production (mostly by the liver). This anabolic hormone also suppresses lipolysis in adipocytes and proteolysis in muscle. Patients with diabetes mellitus exhibit variable degrees of hyperglycemia in both fasting and postprandial states that is related to specific defects in insulin secretion, the response to insulin, or both. Hyperglycemia is associated with an increased risk of chronic micro- and macrovascular complications. The two major forms of diabetes are type 1 and type 2 (Table 1). Type 1 diabetes is usually diagnosed early in life and results from autoimmune destruction of insulin-producing pancreatic beta cells. The more common type 2 diabetes typically results from both insulin resistance and relative insulin deficiency. The prediabetic states of impaired fasting glucose and impaired glucose tolerance are transitional phases; patients with these conditions are at increased risk for type 2 diabetes. The diagnostic criteria for diabetes and prediabetes are shown in Table 2. Diabetes mellitus is diagnosed in most patients on the basis of their fasting plasma glucose level. The more sensitive oral glucose tolerance test is less frequently performed, although it remains a standard way to diagnose diabetes during gestation. A diagnosis of diabetes also can be made if a random plasma glucose level equals or exceeds 200 mg/dL (11.1 mmol/L) in the setting of symptomatic hyperglycemia, such as polyuria, polydipsia, or blurred vision. The hemoglobin A1c value is a long-term (2-3 month) marker of glycemic control. A recent expert committee statement recommended that the hemoglobin A1c test be used to diagnose diabetes, but major professional organizations have not yet endorsed this recommendation. Although a recent literature review for the U.S. Preventive Services Task Force (USPSTF) found no direct evidence of health benefits with mass screening for diabetes, the USPSTF does recommend screening for type 2 diabetes in asymptomatic adults with a sustained blood pressure greater than 135/80 mm Hg (either treated or untreated). The more comprehensive American Diabetes Association (ADA) guidelines for diabetes screening are listed in Table 3.

Table 1. Classification of Diabetes Mellitus Type 1 Diabetes Mellitus Beta cell destruction, usually leading to absolute insulin deficiency Autoimmune Idiopathic (“seronegative”) Type 2 Diabetes Mellitus Ranging from predominant insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistance Gestational Diabetes Mellitus Similar pathogenesis to that of type 2 diabetes Other Specific Types Genetic defects in beta cell function (including MODY syndromes)

Genetic defects in insulin action Diseases of the exocrine pancreas (pancreatitis, pancreatic cancer, cystic fibrosis, hemochromatosis) Endocrinopathies (Cushing syndrome, acromegaly, glucagonoma, pheochromocytoma) Drug- or chemically induced (corticosteroids, niacin, diazoxide) Infections (CMV, congenital rubella) Rare forms of immune-mediated diabetes Other genetic syndromes associated with diabetes (Down, Turner, Klinefelter, Prader-Willi, Laurence-Moon-Biedl syndromes; myotonic dystrophy; Huntington chorea) CMV = cytomegalovirus; MODY = maturity-onset diabetes of the young. Adapted with permission from American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2008;31 Suppl 1:S58. [PMID:18165338]

Table 2. Diagnostic Criteria for Diabetes Mellitus and Prediabetic States Diagnosis Normal glucose homeostasis Impaired glucose metabolism (“prediabetes”) Diabetes

a

Fasting Plasma Glucose 102 cm (>40 in) Women >88 cm (>35 in) Triglycerides ≥150 mg/dL (1.70 mmol/L) HDL-cholesterol Men 1 cm is 6% to

11%. Nevertheless, colonoscopy is the preferred screening modality by most U.S. physicians and medical societies.

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Double-Contrast Barium Enema The most recent recommendations from the U.S. Multi-Society Task Force and the National Comprehensive Cancer Network include double-contrast barium enema among the options for colorectal cancer screening. However, the U.S. Preventive Services Task Force no longer lists barium enema amongst the screening options. Double-contrast barium enema has not been shown to reduce the incidence of colorectal cancer or cancer-related mortality. The rate of detection of both small and large polyps is half that of colonoscopy, and the cancer detection rate is 83% compared with 95% for colonoscopy. The current role of double-contrast barium enema is limited to the patient in whom a complete examination of the colon is desired but cannot be performed by other methods.

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CT Colonography CT colonography (virtual colonoscopy) is an emerging modality for colorectal cancer screening and has been endorsed by the U.S. Multi-Society Task Force as an acceptable mode of screening. The optimal procedure requires a bowel preparation similar to that for colonoscopy, insertion of a rectal tube and insufflation to establish pneumocolon. Scanning is then performed supine, and the procedure repeated in the prone position. Sensitivity for polyp detection by CT colonography is extremely variable. The sensitivity of CT colonography for polyps 55%), presence of HFE gene mutations Young, movement disorders, Hemolysis, low alkaline psychiatric disease, Kayserphosphatase, low Fleischer rings ceruloplasmin Lung disease Low serum A1AT, liver

deficiency

biopsy

ALT = alanine aminotransferase; AST = aspartate aminotransferase; HBsAg = hepatitis B surface antigen; Anti-HCV = antibody to hepatitis C virus; A1AT = α1-antitrypsin.

Table 41. Characteristics of Cholestatic Liver Diseases Liver Biochemistry Pattern Disease AP TBili Historical Features Diagnostic Evaluation ↑ More common in women, fatigue, Antimitochondrial Primary biliary ↑↑ cirrhosis pruritus antibodies present in 95%, liver biopsy Primary ↑↑ ↑ More common in men, history of Cholangiography sclerosing inflammatory bowel disease cholangitis ↑ Pain and fever Cholangiography Large bile duct ↑↑ obstruction Drug-induced ↑↑ ↑ History of drug/medication use Improvement with cholestasis within 3 months, often of a drug cessation previously associated with liver injury Infiltrative ↑↑ CT, MRI, liver biopsy liver disease AP = alkaline phosphatase; TBili = total bilirubin.

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Viral Hepatitis • • • • •

Hepatitis A Virus Hepatitis B Virus Hepatitis C Hepatitis D Hepatitis E

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Hepatitis A Virus Hepatitis A virus (HAV) causes approximately half of the cases of acute hepatitis in the United States. Most patients who contract hepatitis A develop a clinical syndrome consisting of malaise, jaundice, and such nonspecific gastrointestinal symptoms as nausea and poor appetite. The typical incubation period is 2 to 3 weeks. The major routes of infection include ingestion of contaminated food or water and close contact with an infected person. Persons at high risk for acquisition of hepatitis A include men who have sex with men and those who travel to areas of the world where hepatitis A infection is endemic. The diagnosis of acute hepatitis A depends on detecting an IgM antibody to hepatitis A virus (IgM anti-HAV), which is the earliest marker of infection, arising at the onset of symptomatic illness and becoming undetectable by 6 months; thereafter, IgG anti-HAV becomes detectable. The IgG antibody indicates prior infection and immunity; there is no chronic state of hepatitis A infection. Prevention of hepatitis A infection consists of judicious use of hepatitis A immune globulin and the hepatitis A vaccine. Immune globulin and the vaccine should be given to all nonimmune contacts within 2 weeks of exposure to an infected person. In addition, persons at high risk and those with chronic liver disease should be vaccinated. The vaccine schedule is two doses separated by 6 to 12 months. There is also a combined hepatitis A/hepatitis B vaccine available.

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Hepatitis B Virus An estimated 350 million persons worldwide are infected with hepatitis B virus (HBV); approximately 1.25 million persons in the United States are chronically infected. Hepatitis B virus causes approximately one third of cases of acute viral hepatitis in the United States and approximately 15% of cases of chronic viral hepatitis. Hepatitis B is transmitted parenterally by percutaneous exposure, for example, by sharing needles or syringes in injection drug use and intimate person-to-person contact with an infected person, including sexual contact (especially in men who have sex with men). In addition, perinatal acquisition can occur and is most common in newly developing countries and Eastern Europe and Russia.

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Diagnosis The diagnosis of hepatitis B depends on accurately interpreting serologic tests (Table 42). The HBV DNA assays are commonly used. Most assays are based on polymerase chain reaction

technology with lower limits of detection of 50 to 200 IU/mL (corresponding to 25 to 1000 copies/mL). Newer assays have increased sensitivity, with a lower limit of detection of 5 to 10 IU/mL. High levels of HBV DNA are associated with more severe disease, and treatment is monitored for effectiveness by dropping HBV DNA levels. Various subgroups of infected patients reflect the natural history of infection: these subgroups include the immune-tolerant patient, the patient in a phase of immune clearance, and the inactive carrier. The immune-tolerant patient acquired HBV perinatally, is HBeAg positive, and has high levels of HBV DNA. As such patients age, the risk for active hepatitis increases. The patient with detectable HBeAg, high HBV DNA, elevated serum ALT levels, and inflammation on liver biopsy is in a phase of immune clearance (that is, the phase when the immune system is attempting to eliminate the virus). In this phase, elevations in liver enzymes may indicate the onset of HBeAg seroconversion. The inactive carrier is a patient in whom spontaneous seroconversion to HBeAg negativity occurs. In these patients, there is low or undetectable HBV DNA with little or no inflammation on liver biopsy. In this group, periodic reversions back to HBeAg positivity may occur and be associated with elevation of liver tests and an increase in HBV DNA levels. Patients with serologic findings characterized by the presence of HBsAg but absence of HBeAg may harbor HBV variants in the precore or promoter regions. Such patients tend to be older and have lower HBV DNA levels and more advanced disease. Most adults who acquire hepatitis B develop symptoms during an incubation period of between 1 and 4 months after exposure. These symptoms are similar to those of hepatitis A and may include jaundice as well as other nonspecific constitutional complaints. In most patients the acute infection resolves within 6 months, that is, they become HBsAg-negative and develop antiHBsAb. Patients with persistent HBsAg positivity beyond 6 months have chronic infection. Even in patients with chronic infection, HBsAg clears at a rate of approximately 0.5% per year. Various risk factors have been associated with the development of HBV-associated liver disease in patients with chronic infection (Table 43).

Table 42. Interpretation of Hepatitis B Diagnostic Serologies Interpretation

HBsAg

Anti- IgM anti- IgG anti- HBeAg AntiHBV HBs HBc HBc HBe DNA Positive Negative Positive Negative Positive Negative Positive Positive Negative Negative Positive Negative Positive Negative

Acute infection Chronic infection, nonreplicative Chronic infection, Positive Negative Negative replicative Chronic infection, Positive Negative Negative replicative, eAg negative Immune, prior infection Negative Positive Negative

Positive

Positive Negative Positive

Positive

Negative Positive Positive

Positive

Negative Negative Negative

HBsAg = hepatitis B surface antigen; Anti-HBs = antibody to hepatitis B surface antigen; IgM anti-HBc = IgG antibody to hepatitis B core antigen; IgG anti-HBc = IgG antibody to hepatitis B core antigen; HBeAg = hepatitis B e antigen; anti-HBe = antibody to hepatitis B e antigen; HBV DNA = hepatitis B virus DNA.

Table 43. Factors Associated with Progression of HBVAssociated Liver Disease HBV-Associated Liver Disease Cirrhosis Hepatocellular Carcinoma Older age Older age Longer duration of infection Male sex High HBV DNA High HBV DNA Long-term alcohol use Family history of hepatocellular carcinoma HIV or HCV coinfection Presence of cirrhosis Smoking History of reversion to HBeAg positivity from negative HBV genotype C Core promoter mutation HCV coinfection HBV = hepatitis B virus; HBV DNA = hepatitis B virus DNA; HCV = hepatitis C virus; HBeAg = hepatitis B e antigen.

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Management Management of acute hepatitis B consists of history and physical examination and laboratory tests, including hepatitis B serologic tests and measurement of liver enzymes and prothrombin time. The clinical examination should be alert to the development of asterixis or any subtle neurologic changes, such as somnolence, or changes in mental status. Such clinical findings signal the onset of encephalopathy, which defines the patient as having fulminant hepatic failure. A patient suspected of being at high risk for development of fulminant hepatic failure should be transferred to a liver transplantation center for an expedited liver transplant evaluation. Transfer to a transplantation facility should ideally be arranged when a patient shows signs of worsening liver function marked by a rising prothrombin time and worsening liver function tests but before the development of mental status changes. After mental status changes develop, the patient needs to be closely monitored for the development of cerebral edema, which in extreme cases can lead to cerebral herniation and death before liver transplantation can be performed. The physical examination should involve a thorough and frequent neurologic and ophthalmologic examination

ensuring that the pupils remain equal and reactive to light. Dilation or fixation of the pupils is often a sign of worsening cerebral edema and may signify cerebral herniation. If there are no clinical or laboratory findings consistent with liver failure, management consists of observation and follow-up testing. It is prudent to reassess the hepatitis B serologic profile every 1 to 3 months until the acute infection resolves (signified by loss of HBsAg and appearance of anti-HBsAb). Acute hepatitis B may rarely cause severe illness with impaired liver function. In such cases, antiviral therapy (usually consisting of lamivudine or entecavir in combination with adefovir) is indicated. This therapy offers the immediate potency of lamivudine/entecavir, with the reduced risk of resistance resulting from the combination with adefovir. Management of patients with chronic hepatitis B virus infection with active viral replication and some degree of liver disease includes hepatitis B serologies to include an HBeAg and, if positive, HBV DNA. Figure 28 shows a suggested management approach guided by the results of these tests. The goals of therapy in chronic hepatitis B are suppression of viral replication, conversion of a positive HBeAg to negative, and mitigation of hepatic inflammation as evidenced by a reduction in the serum concentration of liver enzymes. An additional goal of therapy is sustained suppression of viral replication, indicated by lack of recurrent HBV DNA after antiviral therapy is discontinued. There are six approved therapies for chronic, replicative hepatitis B: interferon (standard and pegylated), lamivudine, adefovir, entecavir, and telbivudine (Table 44). The advantages of interferon are its limited duration of therapy, the lack of resistance, and the high response rate. However, patients with advanced liver disease or decompensated cirrhosis should not be given interferon therapy because they may be at risk for decompensation of liver disease and infection. In such patients, the oral agents are used; however, these agents are limited in their ability to achieve a sustained suppression of viral replication, cost, and propensity for drug resistance.

Figure 28. Management of chronic hepatitis B virus infection.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; HBeAg = hepatitis B e antigen; HBV = hepatitis B virus.

Table 44. Therapies for Chronic Hepatitis B Duration of Therapy Therapy HBeAg+ HBeAg− Potency HBeAg + HBsAg + Resistance Cost/Year to − to − conversion conversion 1 year 27% 5-10% None $$$$ Subcutaneous 1 year Pegylated Interferon Lamivudine Until 6 months Until ++ 20% Rare Very high $ after loss of seroconversion HBsAg to HBeAg– Adefovir Until 6 months Until + 15% Rare Moderate $$ loss of after seroconversion HBsAg to HBeAg– +++ 21% Rare Low $$$ Entecavir Until 6 months Until loss of after seroconversion HBsAg to HBeAg– Telbivudine Until 6 months Until ++ 22% Rare Low $$ after loss of seroconversion HBsAg to HBeAg–

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Screening and Prevention Prevention of hepatitis B is predicated on providing prophylaxis and immunization to patients recently exposed or at risk for exposure. It is now universal practice to provide the hepatitis B vaccine to all newborns. However, those persons who were born before the onset of universal vaccination should be offered vaccination especially if they are at risk of being exposed. Such persons include all children and adolescents who did not get the vaccine when they were younger. Other people who should be vaccinated include sex partners of people infected with HBV, men who have sex with men, people who inject street drugs, people with more than one

sex partner, people with chronic liver or kidney disease, people with jobs that expose them to human blood, household contacts of people infected with HBV, residents and staff in institutions for the developmentally disabled, kidney dialysis patients, people who travel to countries where HBV is common, and people with HIV infection. If someone is suspected of having been exposed to HBV and has not been previously vaccinated, that patient should receive passive immunization with hepatitis B immune globulin followed by the vaccination series as soon as possible. Patients with established chronic infection must be monitored for the development of cirrhosis and hepatocellular carcinoma. Hepatic ultrasonography and measurement of serum α-fetoprotein every 6 to 12 months are adequate to screen for hepatocellular carcinoma. In general, patients with chronic infection should be counseled to avoid alcohol and be immunized against hepatitis A; close contacts should also be immunized. Infected pregnant women should be given hepatitis B immune globulin immediately after delivery, and the infant should be vaccinated, which can result in a 95% reduction in prenatal transmission.

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Hepatitis C Hepatitis C virus (HCV) infection is the most prevalent bloodborne infection in the United States, affecting an estimated 4 million persons. Most patients acutely infected with HCV are asymptomatic and do not clear the infection spontaneously; approximately 85% develop chronic infection. Of patients with chronic infection, 20% to 25% develop cirrhosis over 20 years. Of patients who develop cirrhosis, the risk for hepatocellular carcinoma is approximately 5% per year. The incidence of acute infections has been declining owing to better hygiene practices among injection drug users. Patients at risk for hepatitis C include persons who have ever injected illegal drugs, have received hemodialysis, or were born to an infected mother and health care workers who have sustained needlestick accidents. The anti-HCV antibody test is the screening test for at-risk persons; a positive test in a person with one of the risk factors confirms exposure to the virus. The HCV RNA test is required to determine active infection rather than just exposure to the virus. In patients with none of the risk factors who have a positive anti-HCV antibody test and a negative HCV RNA test, the recombinant immunoblot assay (RIBA), which detects antibodies to any of several viral antigens, should be done. A positive RIBA, in the absence of detectable HCV RNA confirms that the patient has been infected with hepatitis C but has spontaneously cleared the infection. Liver biopsy is not required for the diagnosis of hepatitis C infection; however, biopsy is useful in some patients to determine the extent of fibrosis and degree of inflammation. In infected patients with persistently normal liver tests, biopsy may also identify those who have minimal inflammation and the absence of fibrosis and may, therefore, forgo therapy and opt for observation. Enzyme levels might be normal in the presence of significant fibrosis rather than inflammation; patients with normal enzymes who undergo liver biopsy, therefore, may at that

point opt for treatment based on advanced histology rather than false reassurance of normal aminotransferases. Therapy for hepatitis C infection consists of the combination of pegylated interferon and ribavirin. The ideal candidate for therapy is the patient with detectable virus, some indication of hepatic inflammation (elevated liver tests or inflammation on the biopsy), and no contraindication to therapy. The goal of therapy is to achieve a sustained virologic response, which is defined as undetectable HCV beyond 6 months after the end of treatment. Eleven distinct genotypes of the virus have been identified; the genotypes differ in their pathogenicity and in their response to therapy. The most important variable affecting the response rate is the genotype of the virus. Patients infected with genotype 1 have an approximately 45% sustained response rate if treated for 48 weeks. Patients who achieve at least a two-log reduction in the HCV RNA by the twelfth week have a higher likelihood (approximately 66%) of achieving a sustained response. Failure to achieve this degree of viral suppression by the twelfth week of therapy is associated with a sustained response of approximately 1%, and treatment can be stopped at that time. Patients with genotypes 2 and 3 have a sustained virologic response rate in excess of 80% and require only 24 weeks of therapy; the dosage of ribavirin can also be reduced in these patients. Most patients treated with pegylated interferon and ribavirin experience side effects, which include a flulike illness, bone marrow suppression, depression, and thyroid inflammation. Contraindications to therapy include severe preexisting bone marrow suppression, severe depression, and advanced liver disease.

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Hepatitis D Hepatitis D virus (HDV or delta agent) depends upon the presence of HBsAg for its replication and, therefore, cannot survive on its own. In an HBV-infected patient, HDV infection may present as an acute hepatitis (in which case it is a coinfection) or an exacerbation of preexisting chronic hepatitis (in which case it is a superinfection). Patients with a history of injection drug use are at greatest risk for acquiring HDV infection.

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Hepatitis E Hepatitis E virus (HEV) can produce an acute hepatitis and is most likely to occur in residents of or recent travelers to underdeveloped nations. It results from fecal-oral transmission. Pregnant woman with acute HEV infection are at greatest risk for developing severe hepatitis or liver failure.

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Alcohol- and Drug-Induced Liver Disease • •

Alcohol-Induced Liver Disease Drug- and Toxin-Induced Liver Injury

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Alcohol-Induced Liver Disease Alcohol-induced liver injury begins with fatty infiltration and then progresses to inflammation, fibrosis, and cirrhosis. Men who consume more than 60 grams of ethanol a day (six or more alcoholic drinks) and women who consume more than 30 grams a day (approximately three alcoholic drinks) for more than 10 years are at risk for alcohol-related cirrhosis. Other factors, including genetic predisposition and underlying liver disease, may influence alcohol“s effects on the liver. Acute alcoholic hepatitis is diagnosed by finding hepatic inflammation in a patient with recent alcohol consumption. Inflammation is indicated by modest elevation of liver tests, with the serum AST concentration usually being less than 400 U/L and approximately twice the concentration of the serum ALT. Affected patients may present with leukocytosis, jaundice, hepatomegaly, and right upper quadrant pain, findings that may suggest infection. Liver biopsy specimen shows fat with acute inflammation and sinusoidal fibrosis. However, biopsy is not required in these patients, and the risk is often greater than the benefit. Assessment of the severity of acute alcoholic hepatitis is important because, in addition to abstinence from alcohol and nutritional therapy, pharmacologic therapy may be beneficial. The discriminant function (DF) calculation, which helps to identify patients whose short-term survival is improved by corticosteroid therapy, is calculated as follows:

Patients with a DF greater than 32 have a more than 50% short-term (30-day) mortality risk. Such patients are candidates for therapy with prednisone, 40 mg/d, for 30 days. Corticosteroid therapy is also beneficial in patients with acute alcoholic hepatitis and encephalopathy. Patients with renal failure were excluded from the initial corticosteroid trials, and some patients with infection may not be candidates for this therapy. An alternative therapy shown to have benefit on renal function and survival is pentoxifylline.

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Drug- and Toxin-Induced Liver Injury Any drug, including complementary and alternative medications, can cause liver injury through such mechanisms as the formation of protein adducts that disrupt cell membranes, an immunologic response, and the generation of injurious free radicals. Drug-induced liver injury may be either dose-dependent and predictable or idiosyncratic. The classic example of a dosedependent hepatotoxin is acetaminophen; a massive single ingestion of more than 12 grams can lead to fatal hepatic necrosis. Acetaminophen toxicity is the most common cause of acute liver failure in the United States. Patients who consume alcohol or who are malnourished may experience acetaminophen injury, even in the absence of massive ingestion. There are many idiosyncratic hepatotoxins, but a few have become known for their patterns of injury, sometimes termed “signature hepatotoxicity” (Table 45). However, other causes of liver injury must be excluded before a diagnosis of drug-induced hepatotoxicity is made, and it must be established that the patient took the drug before the onset of injury. Figure 29 shows a differential diagnostic approach to a suspected case of drug-associated liver injury. Treatment of drug-induced liver injury is primarily supportive and involves withdrawal of the suspected offending agent. However, there are a few specific antidotes, including Nacetylcysteine for acetaminophen intoxication and silymarin or penicillin for Amanita phalloides (mushroom) poisoning. If a drug is implicated as a cause of idiosyncratic liver injury, therapy with the agent must not be restarted because the hepatic response may be more vigorous and injurious than the initial event.

Figure 29. Diagnosing drug-related hepatotoxicity. A1AT = α1-antitrypsin; ALT = alanine aminotransferase; AST = aspartate aminotransferase; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging; TIBC = total iron binding capacity.

Table 45. Signature Pattern of Drug-induced Hepatotoxicity Signature Pattern

Specific Agents

Acute liver injury Acetaminophen, isoniazid Chronic liver injury Nitrofurantoin, minocycline, methyldopa Fibrosis and Cirrhosis Methotrexate, vitamin A Jaundice Erythromycin, amoxicillin/clavulanic acid, chlorpromazine, estrogens Hypersensitivity Phenytoin Fatty liver Amiodarone, tamoxifen, valproic acid, didanosine

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Autoimmune Hepatitis Autoimmune hepatitis is a chronic condition characterized by fluctuating degrees of clinical, biochemical, and histologic manifestations. The diagnosis of autoimmune hepatitis depends on the presence of certain serologic and histologic findings and the exclusion of other causes of liver disease (Table 46). Autoimmune hepatitis is more common in women and usually presents in adulthood. Approximately 50% of patients are asymptomatic and are diagnosed as a result of screening tests; some patients have nonspecific symptoms such as malaise, rash, and arthralgias. Findings on physical examination are also nonspecific. Some patients have only hepatomegaly, whereas others have jaundice or signs of hepatic decompensation, such as ascites or encephalopathy. The presence of other autoimmune disorders may also be a clue to the diagnosis. Patients who present with a very severe form of autoimmune hepatitis, either with or without cirrhosis, are at risk for hepatic necrosis and fulminant hepatic failure. No single biochemical test can confirm or exclude the diagnosis. In most cases, serum aminotransferases are elevated, ranging from mild increases in serum concentrations to values greater than 1000 U/L. Hyperbilirubinemia may occur with a normal or near-normal serum alkaline phosphatase level. Certain autoantibodies may be elevated, including anti-smoothmuscle antibody, antinuclear antibody, and rarely anti-liver-kidney-microsomal antibody type 1 (anti-LKM1). In addition, serum IgG and IgM are also elevated. In some patients, the diagnosis has to be confirmed by histologic evaluation, which typically reveals a predominant lymphocytic and plasmacytic periportal infiltrate. However, in severe cases, the lobule can also be involved and hepatocyte necrosis occurs, with or without cirrhosis. Early recognition of autoimmune hepatitis, especially in patients who present with a subfulminant course, can favorably affect the outcome. Prednisone is the first-line treatment of active disease and may induce remission. Generally, patients who present with greater than a fivefold increase in serum aminotransferase concentrations and who have active inflammation on liver biopsy specimen should be considered for treatment. Patients who present with very high aminotransferase levels can have up to a 40% 6-month mortality rate, and patients with hepatic necrosis on biopsy even without cirrhosis have a 45% 5-year mortality rate. The decision to initiate treatment is unambiguous in these patients. However, the decision to treat is less clear in patients with milder biochemical and/or histologic findings. Progression to cirrhosis is much less

likely in these patients. The decision to start treatment in these patients with medications that have significant side effects must be individualized. Treatment is generally not recommended for patients with inactive cirrhosis, that is, advanced fibrosis in the absence of significant hepatitis. Treatment for autoimmune hepatitis consists of prednisone alone or more commonly in combination with azathioprine, with the goal of reducing the dosage of prednisone to the lowest level possible and continuing azathioprine. Treatment can be discontinued once remission is achieved; however, histologic remission often lags behind biochemical remission by at least 6 months. Relapse occurs in 20% to 100% of cases; however, reinitiation of treatment usually induces remission in patients who relapse. Indefinite low-dose treatment should be considered after relapse.

Table 46. Features Supporting or Militating Against a Diagnosis of Autoimmune Hepatitis Positive Features Female sex Elevates serum aminotransferases Low serum alkaline phosphatase Hypergammaglobulinemia with elevated serum IgG ANA, SMA, anti-LKM1, pANNA, or antiSLA/LP positive AMA seronegative Negative drug and alcohol history Interface hepatitis on liver biopsy Concurrent immunologic disorders in patient or family Compatible HLA markers Response to corticosteroid therapy

Negative Features High serum alkaline phosphatase AMA seropositive Positive hepatotropic virus serology Positive drug/alcohol history Morphologic changes in liver biopsy specimen suggestive of other cause

AMA = antimitochondrial antibodies; ANA = antinuclear antibodies; SMA = anti–smooth muscle antibodies; anti-LKM1 = type 1 liver–kidney microsomal antibodies; pANNA = peripheral anti-neutrophil nuclear antibodies; anti-SLA/LP = anti-soluble liver antigen/liverpancreas antigen antibodies; HLA = human leukocyte antigen. Reproduced from McFarlane IG. Definition and classification of autoimmune hepatitis. Seminars in Liver Disease. 2002;22(4):317-24. [PMID: 12447704]. Copyright 2002, reprinted with permission from Thieme.

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Metabolic Liver Disease • • • •

Nonalcoholic Fatty Liver Disease Wilson Disease Hereditary Hemochromatosis α1-Antitrypsin Deficiency

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Nonalcoholic Fatty Liver Disease Nonalcoholic fatty liver disease consists of variable degrees of fat accumulation, inflammation, and fibrosis in the absence of significant alcohol intake. It is increasingly recognized as possibly the most common form of liver disease in the United States and accounts for a large portion of previously termed cryptogenic liver disease. Fatty liver disease in the absence of inflammation is more common in women than in men and occurs in 60% of obese patients. Steatohepatitis, the presence of inflammation in patients with fatty liver disease, occurs in about 20% of obese patients, and 2% to 3% have cirrhosis. This spectrum of fatty liver disease is most commonly seen in patients with underlying consequences of obesity, including insulin resistance, hypertension, and/or hyperlipidemia, the classic metabolic syndrome. It is estimated that up to 75% of patients with insulin resistance have some degree of fatty liver disease. The pathophysiology of fatty liver disease is generally believed to be the result of a “two-hit” phenomenon, involving first the abnormal accumulation of fat in the liver from underlying risk factors. The second “hit” involves beta oxidation as well as lipid peroxidation of fatty acids, leading to the accumulation of reactive oxidative species and to mitochondrial and cell injury, which can progress to cirrhosis. The diagnosis is usually made when patients with characteristic clinical risk factors are found to have mildly to moderately elevated serum aminotransferase concentrations. Imaging with ultrasonography, CT, or MRI can confirm the presence of steatosis, although all these imaging modalities are considered insensitive for mild degrees of steatosis. There is no definitive treatment for nonalcoholic fatty liver disease. The reduction of underlying risk factors is essential. Weight loss, exercise, and aggressive control of plasma glucose, lipids, and blood pressure are the mainstay of treatment. Antioxidant drugs, including S-adenosyl-Lmethionine (SAMe) and betaine are ineffective. Silymarin is under study as a potential agent. Numerous studies have evaluated oral hypoglycemic drugs in this disorder. The thiazolidinediones have shown promising results, as have previous studies with metformin. Patients with fatty liver disease are not necessarily at increased risk from statin therapy than nonaffected patients, and statins are treatment options in these patients.

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Wilson Disease Wilson disease is a rare autosomal recessive disorder that affects 1 in 30,000 to 1 in 100,000 people. It is characterized by the reduced excretion of copper into the bile secondary to a transport abnormality, leading to the pathologic accumulation of copper in the liver and other tissues, particularly the brain. The gene responsible for Wilson disease is ATP7B located on chromosome 13. Affected patients can present with neurologic, psychiatric, ophthalmologic (Figure 30), hematologic, or hepatologic abnormalities. Patients may present with fulminant disease, although underlying liver injury may already be established even in patients who present in this manner from previously undiagnosed and therefore untreated disease. Patients with fulminant hepatic failure from Wilson disease have elevated serum aminotransferase concentrations in the setting of hemolytic anemia. Such patients also usually have normal or even reduced serum alkaline phosphatase levels. These patients are at risk of progressive hepatic necrosis and may require urgent evaluation for liver transplantation. Less fulminant presentations can be difficult to diagnose, and Wilson disease should be suspected in a young patient with liver disease and associated neuropsychiatric symptoms. The diagnosis of Wilson disease can be confirmed by liver biopsy; nonspecific early histologic changes include the presence of steatosis or steatohepatitis. An elevated hepatic copper content in the absence of long-standing cholestasis, which can also elevate the intrahepatic copper content, is often diagnostic of the disease. Other helpful biochemical findings include a low serum ceruloplasmin and an increased serum copper concentration and urinary copper excretion. Treatment of Wilson disease is directed at reducing the copper overload with the use of various copper chelators, such as penicillamine and trientine, or the use of agents that reduce copper absorption, such as zinc. Ammonium tetrathiomolybdate, which both chelates copper and reduces its absorption, is also effective, although it is not available in the United States. Use of penicillamine can be associated with hypersensitivity reactions, neurologic deterioration, and proteinuria, as well as blood dyscrasias. Therefore, trientine may be a better first-line agent. First-degree relatives of patients with Wilson disease should be screened for the disorder by measurement of serum copper and ceruloplasmin and urinary copper excretion, along with liver tests.

Figure 30. Kayser-Fleischer ring characteristic of Wilson disease. Note the circumferential discoloration that occurs at the sclera-iris border due to copper deposition in Descemet membrane.

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Hereditary Hemochromatosis

Hereditary hemochromatosis is a common genetic disorder in white persons, characterized by excessive iron deposition in tissues, especially the liver, heart, pancreas, and pituitary gland. The iron overload in these tissues can lead to cirrhosis, heart disease, and diabetes mellitus. The gene mutations leading to phenotypic hereditary hemochromatosis are the C282Y mutation and H63D mutation of the HFE gene. Patients with abnormal liver studies should be screened for hemochromatosis. Patients who are suspected of having iron overload or patients older than 20 years who have a first-degree relative with hereditary hemochromatosis should also be screened (Figure 31). Initial evaluation involves measuring the transferrin saturation and the serum ferritin. If the fasting transferrin saturation is greater than 50% in women and greater than 60% in men, the diagnosis should be strongly suspected. Other disease states that elevate the iron saturation include alcohol use, hepatitis C virus infection, fatty liver disease, and neoplasms. Patients with none of these other causes of elevated iron saturation should undergo genetic screening. Liver biopsy is indicated to determine the degree of fibrosis and in cases where the diagnosis remains uncertain. Iron will stain blue with Prussian blue stain. The hepatic iron index, which consists of the hepatic iron concentration in micromoles per gram divided by the patient“s age in years, is used to evaluate for the degree of iron overload. A hepatic iron index greater than 1.9 µmoL/g/y is diagnostic. Treatment of hereditary hemochromatosis involves therapeutic phlebotomy to extract excess iron or to prevent accumulation of iron before symptomatic overload occurs (Table 47).

Figure 31. Screening for hereditary hemochromatosis. ALT = alanine aminotransferase; AST = aspartate aminotransferase; HH = hereditary hemochromatosis; HIC = hepatic iron concentration; TS = transferrin saturation. Reproduced with permission from Tavill AS; American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association. Diagnosis and management of hemochromatosis. Hepatology. 2001 May;33(5):1321-1328. [PMID: 11343262] Copyright 2001, John Wiley & Sons.

Table 47. Treatment of Iron Overload Hereditary Hemochromatosis One phlebotomy (removal of 500 mL of blood) weekly or biweekly Check hematocrit before each phlebotomy; allow hematocrit to fall by no more than 20% of previous level Check serum ferritin level every 10 to 12 phlebotomies Stop frequent phlebotomy when serum ferritin level falls below 50 ng/mL (50 mg/L) Continue phlebotomy at intervals to keep serum ferritin level between 25 and 50 ng/mL (25-50 mg/L) Avoid vitamin C supplements Secondary Iron Overload Due to Dyserythropoiesis Deferoxamine, 20 to 40 mg/kg body weight per day Consider follow-up liver biopsy to ascertain adequacy of iron removal Avoid vitamin C supplements Reproduced with permission from Tavill AS; American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association. Diagnosis and management of hemochromatosis. Hepatology. 2001;33:1321-8. [PMID:11343262]. Copyright 2001, John Wiley & Sons Inc.

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α1-Antitrypsin Deficiency α1-Antitrypsin deficiency affects the liver, lungs, and skin. Disease in the liver is the result of the abnormal accumulation of the variant protein, which accumulates in hepatocytes and can be identified as inclusions that stain with the PAS stain. Intrahepatic disease occurs only in patients with either the homozygous ZZ alleles or the heterozygous MZ alleles. The disease can manifest in early childhood or in adulthood and is associated with an increased risk of cirrhosis and hepatocellular carcinoma, which can occur even in the absence of cirrhosis. Although there is no treatment for hepatic disease, liver transplantation is an option for patients who develop hepatic decompensation. First-degree relatives of affected patients should be screened.

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Cholestatic Liver Disease •

Primary Biliary Cirrhosis

•

Primary Sclerosing Cholangitis

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Primary Biliary Cirrhosis Primary biliary cirrhosis is a slowly progressive autoimmune disease that mainly affects women older than 25 years. In the United States, the reported prevalence is between 160 and 402 per million. There is a familial predisposition to the disorder, and female first-degree relatives of affected patients are at increased risk. Other risk factors include the presence of other autoimmune disorders, a history of tobacco smoking, a history of urinary tract infection, and possibly exposure to environmental causes, such as bacteria, viruses, and toxins. Because of an increased awareness of the disease, more patients are being diagnosed while asymptomatic. In symptomatic patients, fatigue and pruritus are the most common presenting symptoms. Pruritus usually predates the development of jaundice, which can occur months to years thereafter. Other clinical findings largely depend on the stage of the disease. However, immune disorders such as hypothyroidism, Sjögren disease, sicca syndrome, and systemic sclerosis (scleroderma) may coexist with primary biliary cirrhosis. As the disease progresses, patients may manifest the effects of chronic malabsorption of the fat-soluble vitamins A, D, E, and K. They are thus likely to have hyperlipidemia and osteoporosis. Other than excoriations from pruritus or xanthelasmas from hyperlipidemia, most patients do not have any characteristic findings until advanced liver disease develops. Serologic and biochemical findings are useful in making the diagnosis of primary biliary cirrhosis. Most patients have antimitochondrial antibodies and elevated serum IgM and alkaline phosphatase levels, sometimes with elevations in aminotransferase levels. The serum bilirubin level is usually increased in progressive disease. Liver biopsy is not necessary to make the diagnosis of primary biliary cirrhosis, but it can help determine the stage of disease. The progression of primary biliary cirrhosis is affected by when the diagnosis is made and ursodeoxycholic acid therapy is initiated. A recent study found that initiation of treatment in patients diagnosed with stage I or II disease resulted in a long-term survival similar to that of healthy matched controls. However, in patients diagnosed with later stages, the disease is progressive, and despite treatment many of these patients die of the disease or require liver transplantation. More recently, a systematic review and meta-analysis of randomized controlled trials of treatment with ursodeoxycholic acid in patients with primary biliary cirrhosis calls into question the impact of this agent on the mortality and morbidity outcomes of these patients despite the stage of disease. Ursodeoxycholic acid acts as a choleretic agent, which if used early in the disease can delay progression. A large part of the treatment of advanced primary biliary cirrhosis involves symptom management. Pruritus that does not respond to topical lotions can be managed with bile acid resins such as cholestyramine. For refractory pruritus, hydroxyzine, rifampin, and opioid antagonists can be considered. Ursodeoxycholic acid also may have antipruritic effects. Patients should be screened for deficiencies of vitamins A, D, E, and K, and appropriate supplementation should be instituted. Although patients with primary biliary

cirrhosis often have hypercholesterolemia, they have not been shown to have increased cardiovascular risk as a result of the hypercholesterolemia.

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Primary Sclerosing Cholangitis Primary sclerosing cholangitis is a chronic condition that usually presents in the fourth or fifth decade of life; it is more common in men than in women and is characterized by progressive bile duct inflammation and destruction and ultimately fibrosis of both the intrahepatic and extrahepatic bile ducts, leading to cirrhosis. The cause of the disorder is unknown, but there is a strong association with ulcerative colitis, which is present in 80% of patients with primary sclerosing cholangitis. However, the severity of ulcerative colitis does not correlate with the severity of primary sclerosing cholangitis, and treatment of ulcerative colitis does not significantly affect the prognosis of cholangitis. The most common symptoms of primary sclerosing cholangitis are pruritus and fatigue; as the disease progresses, most patients develop jaundice. Cholangiocarcinoma occurs in approximately 10% of affected patients, is not always related to severity of disease, and is associated with a poor prognosis. Primary sclerosing cholangitis is also commonly complicated by cholangitis and is frequently a consequence of endoscopic intervention. The disorder variably affects the bile ducts: 75% of patients have involvement of both large and small ducts; 15% have involvement of the small ducts only; and 10% have involvement of the large duct only. The diagnosis of primary sclerosing cholangitis depends on detecting multifocal strictures with beading of the bile ducts on cholangiographic imaging usually with ERCP (Figure 32). This classic finding often occurs in association with cholestatic biochemical abnormalities, including elevated alkaline phosphatase with mild elevations of aminotransferase levels. Liver biopsy is not required to make the diagnosis, and in patients with small duct involvement, the liver biopsy specimen may appear normal. In disease affecting larger ducts, biopsy specimen shows the classic “onion-skin” lesion, which is caused by concentric fibrosis of the bile ducts. As the disease progresses, the smaller involved ducts become obliterated, and the portal tracts become infiltrated with inflammatory cells, which leads to periportal fibrosis, bridging fibrosis, and ultimately cirrhosis. No medical therapy affects the natural history of primary sclerosing cholangitis or the prognosis of affected patients. Ursodeoxycholic acid therapy may alleviate the biochemical abnormalities associated with the disease, but it does not affect the clinical or histologic course. Patients with primary sclerosing cholangitis, like those with advanced primary biliary cirrhosis, develop steatorrhea with complications from deficiencies of fat-soluble vitamins. Complications related to progressive duct destruction include recurrent cholangitis, bile duct stones, large strictures, and cholangiocarcinoma. Dominant strictures can sometimes be managed by placement of endoscopic stents across the stricture. However, liver transplantation is the only

treatment that reverses the complications of end-stage liver disease in primary sclerosing cholangitis, and patients who undergo transplantation have a favorable survival outcome.

Figure 32. Endoscopic retrograde cholangiopancreatography showing primary sclerosing cholangitis. Note the beading of the bile ducts.

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Complications of Liver Disease

• • • • • • •

Portal Hypertension and Gastroesophageal Varices Ascites Spontaneous Bacterial Peritonitis Hepatorenal Syndrome Hepatopulmonary Syndrome Hepatic Encephalopathy Hepatocellular Carcinoma

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Portal Hypertension and Gastroesophageal Varices Cirrhosis is the predominant cause of portal hypertension, which results from a combination of increased splanchnic blood flow secondary to splanchnic vasodilation and increased resistance to blood flow secondary to intrahepatic fibrosis and endothelial dysfunction. Portal hypertension is calculated by measuring the pressure gradient in the liver, that is, the difference in pressure between the portal vein and the hepatic veins. A gradient greater than 6 mm Hg defines portal hypertension. Thrombocytopenia in the setting of cirrhosis should raise suspicion for the presence of portal hypertension and congestive splenomegaly. One of the most significant complications of portal hypertension is gastroesophageal variceal bleeding. Although varices can occur anywhere along the gastrointestinal tract, including the small intestine and the rectum, the most dangerous site relative to bleeding is the area nearest the gastroesophageal junction. The risk for variceal bleeding is increased when the pressure gradient exceeds 12 mm Hg. The lifetime risk for a first-time variceal bleed in the setting of cirrhosis is 30% and carries a mortality risk of 30% to 50%. Therefore, primary prophylaxis is crucial. All patients with a diagnosis of cirrhosis should undergo endoscopic screening for varices. Primary prophylaxis with a nonselective β-blocker, such as nadolol or propranolol, should be initiated if large varices are detected, especially if they have stigmata of bleeding such as red wale signs (longitudinal red streaks on the variceal surface). Primary prophylaxis decreases the risk of a first variceal bleed by 30% to 40%. An acute variceal bleed should be treated in the intensive care unit. Appropriate resuscitation should be performed with correction of hypovolemia and coagulopathy. Medical treatment includes initiation of prophylactic antibiotics because these patients are at increased risk of bacterial infection. Splanchnic vasoconstrictors such as octreotide should also be used to reduce portal blood flow. However, the mainstay of treatment of an acute variceal bleed is endoscopic band ligation and/or endoscopic sclerotherapy. Esophageal band ligation is the first line of endoscopic therapy because of the complications associated with sclerotherapy. If band ligation does not control primary bleeding, or if bleeding recurs or is due to gastric varices, balloon tamponade followed by portal decompression by placement of a transjugular intrahepatic portosystemic shunt (TIPS) can be performed. The incidence of rebleeding is reported to be as high as 70%, and the use of nonselective β-blockers to prevent rebleeding is recommended; the goal of this therapy is a reduction in the heart rate of 25% or attaining a systolic blood pressure of 90 mm Hg or less.

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Ascites Ascites is the most common complication of portal hypertension secondary to cirrhosis. Any patient who develops new-onset ascites should undergo diagnostic paracentesis. Coagulopathy in the absence of disseminated intravascular coagulation is not a contraindication to paracentesis. Initial evaluation of ascitic fluid should include measurement of albumin along with cell count with differential, Gram stain, and culture (Table 48). The serum-to-ascites albumin gradient is calculated by subtracting the ascitic fluid albumin level from the serum albumin level. A gradient >1.1 indicates that the patient has portal hypertension (Table 49). Management of ascites secondary to portal hypertension involves dietary restriction of sodium to less than 2 g/d and implementation of diuretics. A combination of spironolactone and furosemide as a one-time morning dose is the initial therapy. The dose-limiting factor of diuretic therapy is the development of significant hyponatremia and/or renal insufficiency or failure to achieve a response at very high doses. The occurrence of such complications defines diuretic-resistant ascites or refractory ascites. In this setting large volume paracentesis can be performed with the use of albumin supplementation when greater than 5 liters of fluid are removed at one time to prevent hemodynamic instability. A TIPS can also be placed; however, this can result in worsening synthetic function and difficult-to-manage encephalopathy and therefore should be considered with caution in advanced cirrhosis.

Table 48. Test Used in Evaluation of Ascites Initial Evaluation Protein Albumin Cytology Cell count with differential Gram stain Blood culture Special Tests Tuberculosis culture Repeat cytology Bilirubin Amylase Triglycerides

Table 49. Disease Associations with Serum to Ascites Albumin Gradient (SAAG) SAAG >1.1

SAAG 250/µL or a positive ascitic fluid culture. Treatment consists of a third-generation cephalosporin for at least 5 days. Diagnostic paracentesis should be repeated to document successful therapy if the patient does not show clinical improvement. Any patient who has had spontaneous bacterial peritonitis should receive antibiotic prophylaxis indefinitely. Any patient who is hospitalized and has a total ascitic fluid protein concentration 3 drinks per occasion At risk for adverse consequences from alcohol Alcohol is causing physical or psychological harm One or more of the following events in a 12-month period: • Recurrent use resulting in failure to fulfill major role obligations • Recurrent use in hazardous situations • Recurrent alcohol-related legal problems • Continued use despite social or interpersonal problems caused or exacerbated by alcohol use Three or more of the following events in a 12-month period: • Tolerance (increased amounts to achieve effect or diminished effect from same amount) • Withdrawal • Great deal of time spent obtaining alcohol, using it, or recovering from its effects • Important activities given up or reduced because of alcohol • Drinking more or longer than intended • Persistent desire or unsuccessful efforts to cut down or control alcohol use • Use continued despite knowledge of having a psychological problem caused or exacerbated by alcohol

APA = American Psychiatric Association; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders IV; NIAAA = National Institute on Alcohol Abuse and Alcoholism; WHO = World Health Organization.

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Drugs The USPSTF does not recommend for or against screening for substance abuse in the general population. However, if the internist wishes to inquire about substance abuse, it is often best to start with socially accepted substances such as nicotine and caffeine, move on to alcohol, and finally ask about illicit drugs. The CAGE-AID questionnaire—the CAGE instrument with the phrase “or drug use” added to each item—has been found to be useful in settings of high likelihood of alcohol or drug abuse, such as emergency departments or sexually transmitted disease clinics. Family members, friends, and other contacts may provide useful information. Clues for chemical dependency include unexpected behavioral changes, acute intoxication, frequent job changes, unexplained financial problems, family history of substance abuse, frequent problems with law enforcement agencies, having a partner with substance abuse, and medical sequelae of drug abuse (for example, endocarditis, nasal perforation, hepatitis, needle tracks). Patients addicted to prescription drugs may request increased doses and refills more often than anticipated, repeatedly “lose” prescriptions, and get prescriptions from multiple physicians (often revealed by calls to or from pharmacies). Urine testing is widely used to confirm recent drug use. Drug abusers often deny their addiction and express ambivalence about discontinuing their drug use. In the office, the internist may use brief counseling techniques similar to those used for smoking and alcohol abuse to motivate patients to take action to change their behavior. Often this means the patient following through with a referral to a substance abuse treatment program.

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Sexual Behavior A sexual history should be obtained with respect and a nonjudgmental attitude. Because rates of many sexually transmitted diseases (STDs) are highest among adolescents and men who have sex with men, a sexual history is particularly important for those groups. Table 7 provides one recommended approach to obtaining a sexual history. Risk factors for acquiring an STD include history of an STD, multiple sex partners, contact with sex workers, new sex partner, meeting partners on the Internet, illegal drug use, imprisonment or admission to a juvenile detention center, younger age, unmarried status, and living in an urban area. Table 8 outlines CDC recommendations for STD screening and prevention.

Table 7. “Five P’s” of a Sexual History 1. Partners

“Do you have sex with men, women, or both?” “In the past 2 months, how many partners have you had sex with?” “In the past 12 months, how many partners have you had sex with?” 2. Prevention of Pregnancy “Are you or your partner trying to get pregnant?” If no, “What are you doing to prevent pregnancy?” 3. Protection from STDs “What do you do to protect yourself from STDs and HIV?” 4. Practices “To understand your risks for STDs, I need to understand the kind of sex you have had recently.” “Have you had vaginal sex, meaning ‘penis in vagina sex’”? If yes, “Do you use condoms: never, sometimes, or always?” “Have you had anal sex, meaning ‘penis in rectum/anus sex’”? If yes, “Do you use condoms: never, sometimes, or always?” “Have you had oral sex, meaning ‘mouth on penis/vagina’”? For condom answers: If “never”: “Why don’t you use condoms?” If “sometimes”: “In what situations, or with whom, do you not use condoms?” 5. Past History of STDs “Have you ever had an STD?” “Have any of your partners had an STD?” Additional Questions to Identify HIV and Hepatitis Risk: “Have you or any of your partners ever injected drugs?” “Have any of your partners exchanged money or drugs for sex?” “Is there anything else about your sexual practices that I need to know about?” STD = sexually transmitted disease. Information from Centers for Disease Control and Prevention, Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006;55(RR11):1-94. [PMID: 16888612]

Table 8. Recommendations for Screening and Prevention of Sexually Transmitted Diseases Effective prevention strategies include reducing the number of sex partners, being in a mutually monogamous relationship with a person free of sexually transmitted diseases (STDs), screening for STDs before initiating sexual contact with a new partner, and abstinence. Condom use by men reduces transmission of HIV, Chlamydia, gonorrhea, Trichomonas, herpes virus, and human papillomavirus. The female condom, if used correctly, may provide similar

benefits. HIV testing and prevention counseling should be offered when evaluating for STDs. Asymptomatic women with risk factors for STDs should be screened for gonorrhea and chlamydial infection during their annual pelvic examinations. Immunization for hepatitis A and B viruses and human papillomavirus should be offered as appropriate. Herpes simplex virus-2 sexual transmission can be reduced by the use of suppressive antiviral agents by the infected person, by using condoms, or by both. Partners of infected persons should be advised that sexual transmission can occur during asymptomatic periods. Men who have sex with men should have annual testing for HIV infections, gonorrhea, chlamydial infection, and syphilis. Pregnant women should be screened for syphilis, chlamydial infection, HIV infection, and hepatitis B.

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Domestic Violence Domestic violence is defined as intentional controlling or violent behavior by a person who is or was in an intimate relationship with the victim. The behavior may take the form of physical abuse, sexual assault, emotional abuse, economic control, or social isolation of the victim. Domestic violence frequently remains undiagnosed because patients conceal that they are in abusive relationships, and the signs and symptoms of abuse may be subtle or absent. As many as 31% of women report abuse at some time in their lifetime. Elder abuse occurs in 4% to 6% of the elderly and can result in loss of independence, home, life savings, health, and dignity. There is controversy regarding routine screening for domestic violence. While such screening is acceptable to patients and increases the identification of domestic violence, the USPSTF has concluded that there is insufficient evidence that the subsequent interventions lead to improved outcomes. Other groups, however, advocate routine screening, particularly at initial visits. When screening for domestic violence, it is important to provide a safe environment, including assurances regarding confidentiality, a private examination room, and availability of posters, pamphlets, and referral cards. Screening questions should be integrated into history taking. Consider introducing the subject in a general way; for example: “Because violence is so common in many people’s lives, I’ve started to ask about it routinely.” Finally, the choice of screening question or questions used is important. A screen consisting of the following single question has been shown to increase detection: “At any time, has a partner (or family member or caretaker) hit, kicked, or otherwise hurt or threatened you?” However, the single question “Do you feel safe at home?” has been found to be insensitive for detection of domestic violence and should not be used alone. The four-item SAFE screening questionnaire also can be used:

• • • •

S Stress/safety: “Do you feel safe in your relationship?” A Afraid/abused: “Have you ever been in a relationship where you were threatened, hurt, or afraid?” F Friends/family: “Are your friends or family aware that you have been hurt? Could you tell them and would they be able to give you support?” E Emergency plan: “Do you have a safe place to go and the resources you need in an emergency?”

Clues to an abusive relationship that could trigger an inquiry are shown in Table 9. When an abusive situation is identified, a patient may not be ready to leave his or her abuser because of fear of retaliation, financial dependence on the abuser, having no place to go, a belief that the abuse will stop, or a belief that the abuse is the patient’s fault. Important interventions for patients who are in abusive situations include: • •

• •

• • •

•

Validate the patient’s perceptions that he or she is being abused, confirm the patient’s worth, and assure the patient that you will support him or her. Assess for safety: Inquire about escalating verbal or physical abuse and recent weapons purchases. Discuss safety planning in detail, including whether the patient wants to leave home, return home, or have the abuser removed from the household. Ask if the patient wants to file a police report or obtain a restraining order. Provide information about community resources, including local domestic violence hot lines, the National Domestic Violence Hotline (800-799-SAFE begin_of_the_skype_highlighting 800-799SAFE end_of_the_skype_highlighting; www.ndvh.org), shelters, legal advocacy groups, and social services. In some instances, calling from the office and going directly to a shelter may be appropriate. Refer to mental health services if appropriate. Carefully document the encounter in case the patient decides to seek legal redress. Documentation may include photographs or detailed sketches of injuries. For domestic violence involving a child or an incompetent adult, reporting to the local department of social services is mandatory. A minority of states require reporting injuries from domestic violence against competent adults.

Table 9. Potential Clues to an Abusive Relationship

Inconsistent explanation of injuries or a delay in seeking treatment Somatic complaints (abdominal and pelvic pain, headaches, fatigue) Depression, anxiety, or sleep disturbances Exacerbations or poor control of chronic medical conditions Sexually transmitted diseases and unplanned pregnancies Frequent, unexplained appointment changes Overly solicitous partner or one who refuses to leave the examination room Suicide attempts Substance abuse

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Armstrong K, Moye E, Williams S, Berlin JA, Reynolds EE. Screening mammography in women 40 to 49 years of age: a systematic review for the American College of Physicians. Ann Intern Med. 2007;146(7):516-526. [PMID:17404354]. See PubMed Barry MJ. Screening for Prostate Cancer–The controversy that refuses to die. N Engl J Med. 2009;360(13):1351-1354. [PMID:19297564]. See PubMed Boulware LE, Marinopoulos S, Phillips KA, et al. Systematic review: the value of the periodic health evaluation. Ann Intern Med. 2007;146(4):289-300. [PMID:17310053]. See PubMed Burke W, Psaty BM. Personalized medicine in the era of genomics. JAMA. 2007;298(14):1682-1684. [PMID:17925520]. See PubMed Centers for Disease Control and Prevention, Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006;55(RR11):1-94. [PMID:16888612]. See PubMed Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service. May 2008. Fraser CG, Matthew CM, Mowat NA, Wilson JA, Carey FA, Steele RJ. Immunochemical testing of individuals positive for guaiac faecal occult blood test in a screening programme for colorectal cancer: an observational study. Lancet Oncol. 2006;7(2):127131. [PMID:16455476]. See PubMed Garland SM, Hernandez-Avila M, Wheeler CM, et al; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent Vaccine against Human Papillomavirus to Prevent Anogenital Diseases. N Engl J Med. 2007;356(19):1928-1943. [PMID:17494926]. See PubMed Goldstein MG, Whitlock EP, DePue J; Planning Committee of the Addressing Multiple Behavioral Risk Factors in Primary Care Project. Multiple behavioral risk factor interventions in primary care: summary of research evidence. Am J Prev Med. 2004;27(2 Suppl):61-79. [PMID:15275675]. See PubMed Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendations for adults from the American College of Sports Medicine and the American Heart Association. Circulation. 2007;116(9):1081-1093. [PMID:17671237]. See PubMed Levin B, Lieberman DA, McFarland B, et al; Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008;58(3):130-160. [PMID:18322143]. See PubMed Murff HJ, Spigel DR, Syngal S. Does this patient have a family history of cancer? An evidence-based analysis of the accuracy of family cancer history. JAMA. 2004;292(12):1480-1489. [PMID:15383520]. See PubMed

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Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352(22):2271-2284. [PMID:15930418]. See PubMed Qaseem A, Snow V, Shekelle P, Hopkins R Jr., Owens DK; Clinical Efficacy Assessment Subcommittee, American College of Physicians. Screening for HIV in health care settings: a guidance statement from the American College of Physicians and HIV Medicine Association. Ann Intern Med. 2009;150(2):125-31. [PMID:19047022]. See PubMed Rich EC, Burke W, Heaton CJ, et al. Reconsidering the family history in primary care. J Gen Intern Med. 2004;19(3):273-280. [PMID:15009784]. See PubMed U.S. Preventive Services Task Force. Screening and behavioral counseling interventions in primary care to reduce alcohol misuse: recommendation statement. Ann Intern Med. 2004;140(7):554-556. [PMID:15068984]. See PubMed U.S. Preventive Services Task Force. Screening for family and intimate partner violence: recommendation statement. Ann Intern Med. 2004;140(5):382-386. [PMID:14996680]. See PubMed

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Patient Safety • • • • •

Data on Adverse Events Principles of Patient Safety Quality Improvement Models Diagnostic Errors National Patient Safety Goals

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Diagnostic error is typically multifactorial, with an average of 5.9 system-related or cognitive factors contributing to a single diagnostic error. Strategies for building redundancy into a health care system’s safety processes include checklist systems, time-out policies, and force functions, such as automatic checks and reminders. The Plan-Do-Study-Act (PDSA) cycle is an effective means for performance improvement teams to implement changes to address specific patient safety problems. A key strategy for reducing diagnostic error is to compile a complete differential diagnosis to avoid “premature closure.” The best practice for patient hand-off includes person-to-person communication and information that is accurate and concise.

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Data on Adverse Events The Institute of Medicine (IOM) reported in 2000 that nearly 100,000 patients die as a result of medical errors each year. A Brigham and Women’s Hospital self-audit from 2005 found 233 serious errors and 54 preventable adverse events during 1490 patient-days. The most common serious errors were medication-related (61%); 53% of performance-level failures were slips and lapses (rather than rule-based or knowledge-based errors). Two-thirds of adverse events do not cause direct harm to the patient, and many are “near-misses.” The IOM estimates that preventable errors cost approximately $20 billion in hospitals alone.

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Principles of Patient Safety A root-cause analysis is a group exercise used to determine the contributors to an adverse event. Often, a fishbone pattern is used to illustrate causation, beginning with a problem or error at the fish’s head. Working back down the spine, the team is asked repetitively, “And what contributed to this?” This continues until an investigatory team has reached as many prime factors as possible. Factors that should be addressed in such a root-cause analysis are outlined in Table 10. Graber and colleagues studied factors that contributed to diagnostic error in 100 cases and found an average of 5.9 system-related or cognitive factors contributing to the diagnostic error in each case. This finding confirms the “Swiss cheese” model of error in a medical environment—that there must be a breakdown of several layers in a system to actually cause an injury (Figure 1). Therefore, a health system must build redundancy into its safety processes with the factors listed in Table 10 addressed in order to build in multiple layers of protection between a patient and any potential harm. For example, an airline pilots’ checklist model has been used in intensive care units to ensure that important initiatives, such as sedation holidays, ventilator weaning, and infection prophylaxis, are addressed daily on morning rounds. Likewise, a “time-out” policy to ensure proper matching of patient with procedure has quickly become a national norm. As an example, a surgical nurse may be the point person empowered to call “time out” before an operation commences. Then, the patient and the team, including the anesthesiologist, the surgeons, and any technicians, confirm the correct patient name, the kind of planned surgery, and the correct surgical site. Technology initiatives, such as electronic medical record (EMR) systems, can be used to design “force functions” to decrease human error. For example, an EMR’s physician order entry screen can ensure medication safety with automatic checks and offer reminders for important quality indicators (“Please consider an ACE inhibitor in this patient with heart failure”). Safe health care systems set up a culture of safety, in which the health care team openly discusses errors, teams are encouraged to analyze problems, and collaboration occurs across disciplines to find solutions in a systems-based approach.

Figure 1. “Swiss Cheese” model of error. Adapted with permission from Reason J. Human error: models and management. BMJ. 2000;320(7237):768-770. [PMID: 10720363] Copyright 2000, BMJ Publishing Group Ltd.

Table 10. Questions to Consider in a Root-Cause Analysis of an Adverse Event Were issues related to patient assessment a factor in this situation? Were issues related to staff training or staff competency a factor in this event? Was equipment involved in this event in any way? Was the work environment a factor in this event? Was the lack of information (or misinterpretation of information) a factor in this event? Was communication a factor in this event? Were appropriate rules/policies/procedures—or the lack thereof—a factor in this event? Was the failure of a barrier—designed to protect the patient, staff, equipment, or environment—a factor in this event? Were personnel or personal issues a factor in this event?

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Quality Improvement Models Most major health care organizations now have quality departments that are being converted from reporting groups (for reporting quality data measures) into proactive departments that facilitate performance improvement (PI) teams that are chartered to address particular problems. Rather than labeling people in the health care team as the source of errors, these teams focus on the processes involved in care delivery. A common methodology used by such teams is the PDSA, or Plan-Do-Study-Act, cycle (Figure 2). For example, to improve the timing of administering antibiotics to patients with pneumonia, a PI team might plan a test of a simplified system (consisting of fewer steps) for giving antibiotics after an order is given, do the test by trying the new protocol on a limited number of patients, study the results and summarize what was learned, and act by refining the protocol based on what was learned and planning the next test. Another quality management model used in health care is total quality management (TQM), typified by the Baldrige National Quality Program, which publishes evidence-based criteria by which an organization can judge its management (www.quality.nist.gov). The goal of TQM is to build quality processes into every level of the health care organization.

Figure 2. Plan-Do-Study-Act (PDSA) cycle. The Plan-Do-Study-Act cycle is a widely used method for rapidly testing a change.

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Diagnostic Errors

A burgeoning science has evolved to teach physicians how to avoid errors in diagnosis. Analyses of clinicians’ heuristics seek to understand common shortcuts in reasoning and how these shortcuts can lead to diagnostic errors. Availability heuristic errors arise when a clinician has encountered a similar presentation and jumps to the conclusion that the current diagnosis must be the same as in the previous case. Anchoring heuristic errors occur when a clinician holds to an initial impression, such as might occur when a referring physician has provided a diagnosis that is then accepted at face value. Blind obedience to an authority (such as of a resident to an attending physician) as well as premature closure of the thought process can prevent the important expansion of a differential diagnosis. Strategies to reduce diagnostic errors include: (1) orienting physicians to common diagnostic pitfalls using simulations; (2) compiling a complete differential diagnosis to avoid premature closure (the most common cognitive factor leading to error); and (3) using “prospective hindsight” by assuming that a working diagnosis is incorrect and asking, “What alternatives should be considered?”

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National Patient Safety Goals Beyond individual organizations and clinicians, external organizations have required major quality initiatives for accreditation, payment, insurance contracts, and national recognition. The Joint Commission’s 2009 National Patient Safety Goals (Table 11) encourage wholesale organizational commitment to standards to improve health care safety on a national level (www.jointcommission.org/PatientSafety/NationalPatientSafetyGoals). Organizations without safety initiatives in these areas may be judged to be out of compliance and receive sanctions. A survey of the goals reveals a focus on making safe the day-to-day activities of the hospital environment, including communication, medication administration, and risk reduction (infection, surgery, falls). The Joint Commission’s goal to implement a standardized approach to hand-off communications is particularly crucial for physicians. With the advent of resident work-hour restrictions and the increased use of hospitalist teams, there has been a corresponding increase in the number of patient hand-offs between physicians. This increases the potential for error, given the likely omission of important information (such as allergies, important past history, pending tests). The best practice for hand-off includes person-to-person communication, providing an opportunity to ask and respond to questions, and providing information that is accurate and concise (including name, location, history, diagnoses, medication and problem lists, status, recent procedures, a “to do” list that has “if/then” statements, severity of illness, and contingency plans).

Table 11. The Joint Commission’s 2009 National Patient Safety Goals for Hospitals Improve the accuracy of patient identification

Improve the effectiveness of communication among caregivers Improve the safety of using medications Reduce the risk of health care–associated infections Accurately and completely reconcile medications across the continuum of care Reduce the risk of patient harm resulting from falls Encourage patients’ active involvement in their own care as a patient safety strategy Identify safety risks inherent in the organization’s patient population Improve recognition and response to changes in a patient’s condition Universal Protocol: Conducting a pre-procedure verification process, marking the procedure site, performing a time-out Adapted from The Joint Commission. 2009 National Patient Safety Goals. www.jointcommission.org/PatientSafety/NationalPatientSafetyGoals. Accessed July 13, 2009.


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Graber ML, Franklin N, Gordon R. Diagnostic Error in Internal Medicine. Arch Intern Med. 2005;165(13):1493-1499. [PMID:16009864]. See PubMed Redelmeier DA. Improving patient care. The cognitive psychology of missed diagnoses. Ann Intern Med. 2005;142(2):115-120. [PMID:15657159]. See PubMed Rothschild JM, Landrigan CP, Cronin JW, et al. The Critical Care Safety Study: The incidence and nature of adverse events and serious medical errors in intensive care. Crit Care Med. 2005;33(8):1694-1700. [PMID:16096443]. See PubMed Vidyarthi A, Arora V, Schnipper J, Wall S, Wachter R. Managing discontinuity in academic medical centers: strategies for a safe and effective resident sign-out. J Hosp Med. 2006;1(4):257-266. [PMID:17219508]. See PubMed

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Professionalism and Ethics • • • • • • • • •

Professionalism Decision-Making and Informed Consent Withholding or Withdrawing Treatment Physician-Assisted Suicide and Euthanasia Confidentiality Conflicts of Interest Medical Error Reporting Sexual Contact between Physician and Patient The Impaired Physician and Colleague Responsibility

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The three fundamental principles of medical professionalism are the primacy of patient welfare, patient autonomy, and social justice. Advance directives include instructions about what kind of care should be provided (living wills) and who should make the decisions if the patient cannot do so (proxy designations). The three elements required for informed consent include disclosure of relevant information, comprehension by the patient, and lack of coercion. Decision-making competency assessment can range from less to more stringent, depending on the consequences of the decision, and may include the patient’s ability to express a choice, general decision-making capacity, comprehension of specific information, rational reasons, and reasonable outcomes. Life support measures need not be started or continued if they are thought to be medically futile; however, legal opinion may vary and if doubt exists, the wishes of the patient or surrogate are usually favored. A request for physician-assisted suicide is often a signal that a patient has unmet needs, including fear, hopelessness, difficult social circumstances, and severe pain and suffering. Despite mixed public opinion, physician-assisted suicide is illegal in most of the United States, and active euthanasia is illegal in all states. Discussions of patient information should not take place in public places. The physician should not release any private, identifiable patient information without the patient’s consent. Conflicts of interest include potential for overuse in a fee-for-service setting, for underuse in a managed care setting, acceptance of gifts from pharmaceutical companies or medical device manufacturers, and certain business arrangements regarding referrals. Conflicts of interest should be avoided, if possible; if avoidance is not possible, they should be disclosed. Sexual relationships between a physician and a patient are considered unethical because of the inequality of power, potentially placing the patient in a vulnerable and dependent role. Signs of impairment in a physician colleague may include frequent absences from work, missed appointments, secretive or inappropriate behavior, mood swings, conflict with colleagues, and poor personal hygiene. Every physician is responsible for protecting patients from an impaired physician and should report any concerns to the hospital impaired physician program or other appropriate authority.

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Professionalism The Charter on Medical Professionalism was a product of several years of collaborative work by leading organizations of internal medicine. The charter contains three fundamental principles and ten professional commitments (Table 12). The first principle, that of the primacy of patient

welfare, dates from ancient times. There is concern, however, that in today’s health care environment, the physician’s commitment to the patient is being challenged by the conditions of medical practice and external forces. The second principle, that of patient autonomy, has a more recent history. Only in the latter part of the twentieth century did the public begin to view the physician as an advisor, often one of many, to an autonomous patient. Finally, the principle of social justice calls upon the profession to promote a fair distribution of health care resources. The American College of Physicians (ACP) has highlighted four areas for professional commitment on the part of physicians and their professional organizations as part of an initiative to revitalize internal medicine: (1) advocacy for patients and for the patient-physician relationship; (2) enhanced communications with patients and colleagues in order to foster health care partnerships and improve coordination of the health care team; (3) a renewed commitment to “mastery,” both in expanding and applying the internal medicine knowledge base and in developing and implementing improvements in the processes and coordination of care; and (4) development and implementation of performance measures linked to quality improvement and accountability in a manner that respects the patient-physician relationship. To achieve these goals, it was acknowledged that society—comprising health plans, purchasers, government, clinicians, and patients—must promote the appropriate context for health care delivery by providing consistent support for sustained patient-physician relationships within which physicians can fulfill their ethical obligations to patients. Finally, the ACP affirms that all parties to health care delivery should foster an ethical health care environment, including universal access and a reimbursement mechanism that encourages physicians to take the time required to provide and coordinate appropriate care for adult patients throughout the aging process.

Table 12. Principles and Commitments of Professionalism Principle or Comment Commitment Fundamental Principle Primacy of Altruism is a central trust factor in the physician-patient relationship. Market patient welfare forces, societal pressures, and administrative exigencies must not compromise this principle. Patient autonomy Patients’ decisions about their care must be paramount, as long as those decisions are in keeping with ethical practice and do not lead to demands for inappropriate care. Social justice Physicians should work actively to eliminate discrimination in health care, whether based on race, gender, socioeconomic status, ethnicity, religion, or any other social category. Professional Commitment Competence Physicians must be committed to lifelong learning and to maintaining the medical knowledge and clinical and team skills necessary for the provision of quality care.

Honesty with patients

Obtain informed consent for treatment or research. Report and analyze medical errors in order to maintain trust, improve care, and provide appropriate compensation to injured parties. Patient Privacy of information is essential to patient trust and even more pressing with confidentiality electronic medical records. Appropriate Given the inherent vulnerability and dependency of patients, physicians patient relations should never exploit patients for any sexual advantage, personal financial gain, or other private purpose. Improve quality Work collaboratively with other professionals to reduce medical errors, of care increase patient safety, minimize overuse of health care resources, and optimize the outcomes of care. Improve access Work to eliminate barriers to access based on education, laws, finances, to care geography, and social discrimination. Equity requires the promotion of public health and preventive medicine, as well as public advocacy, without concern for the self-interest of the physician or the profession. Just distribution Work with other physicians, hospitals, and payers to develop guidelines for of resources cost-effective care. Providing unnecessary services not only exposes one’s patients to avoidable harm and expense but also diminishes the resources available for others. Scientific Uphold scientific standards, promote research, create new knowledge, and knowledge ensure its appropriate use. Manage conflicts Medical professionals and their organizations have many opportunities to of interest compromise their professional responsibilities by pursuing private gain or personal advantage. Such compromises are especially threatening with forprofit industries, including medical equipment manufacturers, insurance companies, and pharmaceutical firms. Physicians have an obligation to recognize, disclose to the general public, and deal with conflicts of interest that arise. Professional Undergo self-assessment and external scrutiny of all aspects of one’s responsibilities performance. Participate in the processes of self-regulation, including remediation and discipline of members who have failed to meet professional standards. Adapted with permission from ABIM Foundation. American Board of Internal Medicine; ACPASIM Foundation. American College of Physicians-American Society of Internal Medicine; European Federation of Internal Medicine. Medical professionalism in the new millennium: a physician charter. Ann Intern Med. 2002;136(3):243-246. [PMID: 11827500] Copyright 2002, American College of Physicians.

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Decision-Making and Informed Consent • • •

Assessing Decision-Making Capacity Advance Directives and Surrogate Decision-Making Informed Consent

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Assessing Decision-Making Capacity The legal concept of competency covers a wide range of decision-making abilities, including both medical (competency to make treatment decisions, competency to consent to research) as well as nonmedical (competency to manage one’s financial affairs, competency to stand trial). Whereas competency is a legal concept, its application in a clinical setting requires the assessment of a patient’s ability to exercise his or her autonomy. To avoid confusion, many clinicians and researchers use competency as the legal ability and capacity as the medical or psychological ability to make certain decisions. There is no single or absolute standard for determining a patient’s medical decision-making capacity. Instead, there are various criteria levels ranging from low to high stringency (Table 13). More stringent criteria typically come into play as the consequences of what the clinician deems an uninformed or incompetent decision become more serious, especially in terms of riskbenefit ratio. For example, one might demand more stringent evidence of decision-making capacity in a young person who is septic and confused who refuses antibiotic therapy compared with an elderly person with advanced dementia and metastatic cancer with a gram-negative bacteremia who refuses treatment.

Table 13. Criteria Clinicians May Consider in Assessing Medical Decision-Making Capacity Criterion

Stringency

Evidencing a choice Low Capacity: Ability to understand in general Medium sense Comprehension: Actual understanding of Medium specific information provided

Test Answer yes or no Mental status testing Can you repeat what I have just told you?

Who Might Fail? Comatose Dementia (advanced) Anxiety Low education Language barriers

Rational reasons for choice

High

Reasonable outcome expected

High

Cultural barriers Why are you choosing Psychosis; this? delirium Does the decision make Depression sense in terms of: • Disease prognosis • Patient's values

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Advance Directives and Surrogate Decision-Making Advance directives include instructions about what kind of care should be provided (living wills) and who should make the decisions if the patient cannot do so (proxy designations). Though helpful as a means of expressing general views regarding end-of-life care, living wills often use vague terms such as “heroic measures,” “terminally ill,” or “facing imminent death.” Some living wills provide concrete instructions for care in a variety of clinical situations, such as the use of feeding tubes or ventilators in the event of permanent unconsciousness. Even detailed directives, however, cannot describe all of the situations and special circumstances in which patients may find themselves. Thus, it is also desirable, either instead of or in addition to a living will, to specify a surrogate decision-maker rather than focusing solely on all of the possible decisions that may be necessary. Naming a family member or friend to serve as a health care proxy through a durable power of attorney for health care identifies someone physicians can talk to if and when clinical circumstances occur wherein the patient is not able to speak for him- or herself. A surrogate decision-maker should be that person most familiar with the patient’s previous beliefs and aims, and having no conflicts of interest. Sometimes, but not always, a surrogate decision-maker is formally identified by means of a durable power of attorney. If the patient’s preference has not been designated in advance, the surrogate is typically a family member; for adults, this may be the spouse, an adult child, parents, and siblings, in order of priority. However, other factors may determine who is the surrogate in the absence of the patient’s expressed preferences, including the presence of a domestic partner, estrangement of a spouse or other family members, disagreement among family members, and differences among state laws.

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Informed Consent Three elements of informed consent are required when discussing a medical treatment or course of action: (1) disclosure of all relevant information, including the benefits, risks, and alternatives

with respect to the treatment or research study; (2) adequate understanding of the information by the patient or subject; and (3) voluntary decision-making by the patient or subject. These can be thought of as the “three C’s” of informed consent—communication, comprehension, and no coercion. What information should be disclosed? At the beginning of the twentieth century, disclosure was guided by the professional practice standard (whatever the physician felt should be disclosed). Case law and contemporary bioethics have gradually transitioned informed consent to the prudent person standard, whereby the physician must disclose what a reasonable person would want to know before making a decision, particularly potential risks. A reasonable guideline is to describe the complications or side effects that either have a high likelihood of occurring even if they are minor (nausea or transient fever) or have a low likelihood of occurring but are so serious that a prudent person would want to know when making decisions (for example, 5% chance of dying). After disclosing what a reasonable person would want to know, it is important to ask the patient or subject whether he or she needs any other information to make a decision. This allows the person to ask questions that may be unique to their own values and concerns and thus sets an even higher standard, a subjective or individual patient standard.

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Withholding or Withdrawing Treatment Withholding or withdrawing therapy that is deemed futile or according to patient preference is justifiable from both an ethical and a legal perspective. The best strategy to avoid subjecting a patient to a life support measure that was unwanted is to discuss end-of-life care with the patient as early as possible. Patient preferences for do-not-resuscitate orders as well as issues of artificial feeding, hydration, and other life prolonging measures, should be clearly documented in the medical record. While patients have a right to refuse unwanted life-sustaining treatments, it is less clear whether these treatments must be provided (if requested by a patient or family member) once it is clear the prognosis is dismal. Qualitative futility means that the treatment will not improve the patient’s already poor quality of life. Quantitative futility uses a numeric probability to decide when treatment should not be offered, as the patient is unlikely to survive even with the intervention. Physiologic futility means that it is impossible for the intervention to significantly improve the patient’s condition. In discussing decisions to withhold or withdraw treatments, the physician should carefully address any family concerns regarding the decision, such as the belief that discontinuing a feeding tube will result in the patient suffering from hunger or thirst, despite evidence to the contrary. Cardiopulmonary resuscitation is not appropriate for patients with terminal, irreversible disease or imminent death. However, do-not-resuscitate orders do not preclude provision of other lifeprolonging measures or palliative care. Occasionally, treatments are withheld based on the fear that once started, they cannot be withdrawn. A limited trial of a therapy can be used to assess a patient’s response, after which the treatment plan can be reviewed and revised. The decision to institute or withdraw life-prolonging measures needs to be discussed with the patient (if competent) and family. If the patient is unable to make these decisions, an advance directive

allows health care providers to follow the patient’s wishes or have a surrogate make decisions. When there is no advance directive, the physicians and surrogate should make decisions based on substituted judgment—what do they think the patient would have wanted—or, if this is not possible, based on what they believe is in the patient’s best interests. Laws and processes for these decisions vary from state to state. In making quality-of-life determinations, priority tends to be given to patient or surrogate assessment of whether the treatment is worthwhile; however, when there is a significant conflict, the physician should not be forced to administer a treatment that violates his or her values or is medically futile. In these instances, a discussion with the family and an ethics committee is warranted, and if no consensus can be reached, consideration should be given to transferring the patient to another physician or health care facility. Rarely, a legal decision may be necessary.

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Physician-Assisted Suicide and Euthanasia Physician-assisted suicide involves knowingly prescribing a potentially lethal amount of medication to a patient for self-administration. Whether or not it is ever ethical for a physician to do this has been debated for years. The Hippocratic Oath does not support physician-assisted suicide, and both the ACP and American Medical Association have issued statements opposing the practice. However, some physicians feel that it is not immoral to honor patient autonomy and assist in the rational suicide of a terminally ill patient. In the United States, physician-assisted suicide is currently illegal in all states except Oregon and Washington, where legal safeguards have been established to protect the autonomy of the patient. Active euthanasia, whereby a physician, with the patient’s consent, directly and intentionally administers a substance to cause death, is illegal in all states. A request for physician-assisted suicide should be construed as a signal that the patient has unmet needs and should trigger further assessment to determine the fears, social circumstances, and level of pain and suffering that may have brought about this decision. The physician’s obligations are to provide appropriate palliative care, including relief of pain; control of symptoms related to the illness; evaluation and treatment of depression; and counseling and support. Inadequate pain management remains a problem, often owing to physician inexperience or fear of prescribing high-dose narcotics.

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Confidentiality Confidentiality is fundamental to medical care, and the physician should respect patient privacy and encourage candid discussion of any problems the patient may have. The physician should not release any private, identifiable patient information (“privileged communication”) without

the patient’s consent. If a patient is incapacitated, the physician can disclose protected health information to a caregiver (for example, a spouse or relative) if, in the physician’s professional judgment, the disclosure is in the best interests of the patient. Discussions about patients in a public place (office waiting room, hospital elevator, hallway, cafeteria) violate confidentiality and must be avoided. The Health Insurance Portability and Accountability Act (HIPAA) established federal standards for privacy protection of medical records, and physicians, clinical practices, and institutions must have policies and procedures related to disclosure of medical information to ensure confidentiality of these records. However, the advent of electronic medical records, prescriptions, and computerized databases has raised concerns regarding the security of confidential information. This information should still be protected under the physician-patient relationship, and legislation provides guidelines and penalties with respect to standards for handling and disclosure of patient information contained in these electronic media. Strategies to maintain protection of electronic medical records include not sharing passwords or allowing unauthorized persons access to the system and logging off before leaving a computer station. A delicate situation may arise when a patient requests that certain information not be recorded in the medical record (substance abuse, sexual preference, test results). Although the physician has an ethical obligation to maintain a complete and accurate record, release of this sensitive information may be detrimental to the patient, and the physician cannot guarantee confidentiality. Confidentiality, however, is not absolute and may need to be overridden in certain cases. Some of these possible exceptions to confidentiality include exceptions to protect the patient (for example, disclosure of domestic violence) and exceptions to protect third parties (reporting infectious diseases or impaired drivers to public health officials, partner notification by public health officials, injuries caused by weapons or crimes, warnings by physicians to persons at risk, and violence by psychiatric patients). In such cases, the physician should attempt to discuss these issues with the patient whenever possible prior to breaching confidentiality, and the disclosure should be done in a manner to minimize harm to the patient and to comply with the law. A physician may receive information from sources other than the patient and be asked to withhold that information or its source from the patient. Although the physician is not legally obligated to keep such information from the patient, he or she should first encourage discussion between the informant and the patient and then decide, based on the best interests of the patient, whether or not to reveal the information.

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Conflicts of Interest A conflict of interest exists when a physician’s professional duty to the patient conflicts (or gives the appearance that it conflicts) with another interest, such as personal financial gain, insurance or contractual obligation, or other arrangements or commitments. The physician’s main responsibility is to the patient—to make recommendations based on medical merit and to practice effective and efficient health care using available resources wisely.

Financial conflicts of interest arise when physician reimbursement potentially drives decision making and actions that are not necessarily in the patient’s best interest. Examples include financial incentives for overuse in a fee-for-service setting or underuse in a managed care setting. Physicians must be cognizant of the system conditions under which they practice and should always act to benefit the patient. Participating in certain business arrangements involving referrals within a group or to an outside group or facility in which the physician or a family member has a financial interest is potentially illegal under the so-called Stark laws, which govern physician self-referral. Gifts, trips, and subsidies offered by pharmaceutical and medical device industries may create conflicts of interest wherein the physician’s interest coincides more with the business than with the patient. These influences may subtly change the physician’s attitude and behavior in a manner favoring the company involved, resulting in higher medical costs to the patient. Even more subtle may be the influence of industry on continuing medical education (CME) and clinical practice guidelines. As a result, new policies and standards have been developed that demand explicit disclosure of financial conflicts of interest by guideline committee members and CME providers. The two primary methods for dealing with conflicts of interest are disclosure and avoidance. Disclosure alone does little to protect patients, however, and avoidance is preferable. Physicians should try to avoid all significant conflicts of interest; if a potential conflict is unavoidable or less serious, it should be acknowledged and disclosed to the patient.

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Medical Error Reporting The Institute of Medicine defines a medical error as the failure of a planned action to be completed as intended (error of execution) or the use of a wrong plan to achieve an aim (error of planning). Knowledge of previous medical errors is important to efforts to reduce the incidence of future errors; however, the frequent failure to report medical errors hampers these efforts. Although failure to report a medical error is considered unethical, fear of damage to reputation and potential legal ramifications often hinder physicians and hospitals from disclosing these errors. The Patient Safety and Quality Improvement Act established a federal system for voluntary reporting of medical errors (www.pso.ahrq.gov/index.html) and provides protection for health care providers who submit information intended to improve patient safety. (See Patient Safety section for strategies to reduce medical errors.)

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Sexual Contact between Physician and Patient

The American Medical Association and the ACP both state that it is unethical for a physician to become sexually involved with a current patient even if the patient initiates or consents to the relationship. The rationale for these recommendations is that there is inequality between the parties (one-way intimacy with the patient in a vulnerable and dependent position), and the physician may betray the patient’s trust (using confidential information) or not act in the patient’s best interest. There are legal and regulatory sanctions against these relationships, ranging from criminal charges to sanctions by state licensing boards. Sexual contact or a romantic relationship between a physician and a former patient may also be unethical irrespective of the length of time elapsed since ending the professional relationship. It has also been suggested that physicians refrain from such relationships with a family member or surrogate of a patient if there may be an appearance that the professional relationship has been exploited. Increased patient autonomy has attenuated the imbalance of power, however, theoretically reducing patient vulnerability. In any case, a physician should consult with a colleague or other professional prior to becoming sexually involved with a former patient. Despite these prohibitions, it has been reported that 5% to 10% of psychiatrists have had sexual contact with a patient; it is unknown what percentage of practitioners in other specialties have had similar relationships. Physicians aware of instances of sexual misconduct have an obligation to report them. A request by a patient or physician for a chaperone to be present during the physical examination should be accommodated, but the physician should respect the patient’s right to confidentiality and not discuss patient issues while the chaperone is in the room.

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The Impaired Physician and Colleague Responsibility The impaired physician is one who is no longer able to safely carry out his or her professional duties because of physical, psychological, or substance abuse problems. Approximately 15% of physicians will be impaired at some point in their career. Risks for abuse include male sex and underlying mood or personality disorders. The highest rates of substance abuse are among emergency department physicians (most commonly using marijuana and cocaine), psychiatrists (most commonly using benzodiazepines), and solo practitioners. An increasing number of impaired physicians are older physicians, impaired by age-related conditions, who delay retirement. The first signs of impairment may occur at home and include marital strife. Signs at work may include frequent absences, missed appointments, secretive or inappropriate behavior, mood swings, conflict with colleagues, and heavy drinking at hospital functions. Impaired physicians may exhibit poor personal hygiene, bloodshot eyes, stumbling, or changes in speech patterns. Substance abuse should be considered in residents who experience academic or interpersonal difficulties. Changes in professional performance indicate advanced impairment.

Many physicians are reluctant to report suspected physician impairment because of the desire to protect colleagues, fear of mislabeling them as impaired, and fear of reprisals. The American Medical Association states that physicians have an ethical obligation to report impaired colleagues, but only 20% of states in the United States require the reporting of suspected substance abuse. Physicians should report concerns about colleagues to the hospital impaired physician program or other appropriate authority. Treatment for substance abuse is more effective among physicians than in the general population. Approximately 75% to 85% of physicians return to work after treatment. Treatment should always be confidential and may include referral to an employee assistance program or an addiction specialist. All states now have treatment programs sponsored by state medical societies, and these programs are independent of state licensing boards. The best success is seen in treatment programs that include 2 to 4 weeks of intensive inpatient treatment.

Bibliography •

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American College of Physicians. Medical Professionalism in the Changing Health Care Environment: Revitalizing Internal Medicine by Focusing on the Patient–Physician Relationship. Philadelphia: American College of Physicians;2005: Position Paper. Baldisseri MR. Impaired healthcare professional. Crit Care Med. 2007;35(2 Suppl):S106S116. [PMID:17242598]. See PubMed Gillick MR. Advance care planning. N Engl J Med. 2004;350(1):7-8. [PMID:14702421]. See PubMed Jones JW, McCullough LB, Richman BW. Ethical nuances of combining romance with medical practice. J Vasc Surg. 2005;41(1):174-175. [PMID:15696065]. See PubMed Murphy JG, Stee L, McEvoy MT, Oshiro J. Journal reporting of medical errors: the wisdom of Solomon, the bravery of Achilles, and the foolishness of Pan. Chest. 2007;131(3):890-896. [PMID:17356109]. See PubMed Snyder L, Leffler C; Ethics and Human Rights Committee; American College of Physicians. Ethics Manual: fifth edition. Ann Intern Med. 2005;142(7):560-582. [PMID:15809467]. See PubMed Terry PB. Informed consent in clinical medicine. Chest. 2007;131(2): 563-568. [PMID:17296662]. See PubMed Tonelli MR. Conflict of interest in clinical practice. Chest. 2007; 132(2):664-670. [PMID:17699138]. See PubMed

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Palliative Care • • •

Palliative Care Assessment and Communication Symptom Management Caregiver Stressors and Bereavement

Key Points

• • • • • • • • •

Mild pain can usually be adequately treated with aspirin, acetaminophen, and NSAIDs. In the treatment of moderate pain, low-dose opioid drugs are added to aspirin, acetaminophen, or NSAIDS. A strategy incorporating long-acting narcotics with a plan for breakthrough pain control should be started in patients requiring multiple doses of daily narcotics. Patients requiring daily narcotics should receive scheduled doses of a stool softener and laxative to prevent narcotic-related constipation. Tricyclic antidepressants, venlafaxine, duloxetine, gabapentin, and pregabalin may be useful as adjunct therapy for neuropathic pain. Oxygen is not helpful in treating cancer-related dyspnea in the absence of hypoxemia. Morphine is effective in treating cancer-related dyspnea as well as dyspnea related to end-stage cardiopulmonary disorders. Depression is common in terminally ill patients, and physicians should have a low threshold for initiating therapy. Delirium is common in terminally ill patients and can be treated with small doses of haloperidol while reversible causes are investigated.

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Palliative Care Assessment and Communication Many terminally ill patients are reluctant to initiate end-of-life discussions with their families, and the physician can play an important role as facilitator. The dialogue may be emotionally charged, and a series of visits may be needed to cover all appropriate areas. It is important to stress to patients that a discussion of end-of-life care is not a discussion of withdrawal of treatment or patient abandonment. A comprehensive palliative care discussion should include information about the diagnosis causing the terminal condition, with expected clinical symptoms and strategies to relieve them. Patients should be asked what symptoms they fear most, and they should be presented with a plan for symptom assessment and treatment titration. The discussion should also include patient preferences for surrogate decision making, an assessment of the patient’s emotional and spiritual health, and an understanding of family support systems and community resources that are available. The patient should be asked to give his or her opinion on advance directives for cardiopulmonary resuscitation, other invasive procedures, and artificial nutrition and hydration. Patients with medical hardware such as pacemakers and intracardiac defibrillators or who undergo chronic life-sustaining treatments such as dialysis require special consideration, as such technologies may unduly prolong life unless decisions are made regarding explicitly discontinuing them. Patients may also wish to discontinue other treatment not directly related to their comfort, especially medications when swallowing becomes difficult. Physicians must be clear about the possible consequences of treatment withdrawal with patients and their surrogate decision makers and not infer consent to discontinue these treatments under the broader context of an advance directive. Discussions on withdrawal of active treatments should take place when patients’ functional status and quality of life start to decline but before they lose their ability to vocalize their preferences. Some physicians may feel uncomfortable honoring a patient’s request

to discontinue treatment for a disorder not related to the underlying cause of death. The input of a clinical ethics committee may be helpful in such situations. Determining prognosis in terminally ill patients, especially those with nonmalignant disorders, can be challenging for physicians and frustrating for patients. The Palliative Performance Scale is a useful validated tool to provide general estimates of prognosis (Table 14).

Table 14. Palliative Performance Scale Scorea,b Ambulation Activity Level/Evidence of Disease 100 Full Normal activity and work (no evidence of disease) 90 Full Normal activity and work (some evidence of disease) 80 Full Normal activity and work with effort (some disease) 70 Reduced Unable to do normal job or work (significant disease) 60 Reduced Unable to do hobbies or housework (significant disease) 50 Reduced Unable to do any work (extensive disease) 40 Mainly sit or Unable to do most lie activities (extensive disease) 30 Bed-bound Unable to do any activity (extensive disease) 20 Bed-bound Unable to do any activity (extensive disease) 10 Bed-bound Unable to do any activity (extensive disease) 0 Death —

Self-Care Full

Normal

Level of Consciousness Full

Full

Normal

Full

Full

Normal or Full reduced Normal or Full reduced

Full

Intake

Occasional assistance

Normal or Full or confusion reduced

Considerable assistance Mainly assistance

Normal or Full or confusion reduced Normal or Full or drowsy +/reduced confusion

Total care

Normal or Full or drowsy +/reduced confusion Minimal to Full or drowsy +/sips confusion Mouth Drowsy or coma care only +/-confusion — —

Total care Total care —

a

In a mixed cohort of cancer and noncancer patients, 100% of patients with a score of ≤60 died within 1 year, more than 96% of patients with a score of ≤30 died within 2 months, and more than 95% of those with a score of ≤20 died within 2 weeks. b

Begin at the left column and read downwards until the appropriate ambulation level is reached, then read across to the next column and downwards again until the activity/evidence of disease is

located. These steps are repeated until all five columns are covered before assigning the actual palliative performance scale score for that patient. Adapted with permission from Lau F, Downing GM, Lesperance M, Shaw J, Kuziemsky C. Use of Palliative Performance Scale in End-of-Life Prognostication. J Palliat Med. 2006;9(5):10661075. [PMID: 17040144] Copyright 2006, Mary Ann Leibert, Inc. publishers.

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Symptom Management In palliative care, physicians focus on short-term outcomes designed to improve patient comfort and quality of life. The most common patient symptoms encountered are pain, dyspnea, anorexia and weight loss, depression, and delirium.

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Pain The World Health Organization pain relief ladder represents a useful framework for pharmacologic treatment of pain (Figure 3). Non-narcotic treatments, such as aspirin, acetaminophen, or NSAIDs, are used for mild pain (a score of 1-3 on the 0-10 pain intensity scale). Moderate pain (pain score of 4-6) is treated with a combination of opioids and nonnarcotic pain relievers. If these agents are combined in a single pill (such as oxycodone and acetaminophen) to reduce polypharmacy, care must be taken to avoid inadvertent overdosing of the non-narcotic component when need for the opioid ingredient increases. The daily cumulative acetaminophen dose (30 mL/d) sputum production with purulent exacerbations. Chest radiograph and high-resolution CT may be diagnostic, showing thickened bronchial walls in a “tram-line” pattern. Bronchiectasis should be treated with antibiotics selected on the basis of sputum cultures and with chest physiotherapy. Although most smokers have a chronic cough, they are not the group of patients who commonly seek medical attention for cough. After smoking cessation, cough has been shown to resolve or markedly decrease in 94% to 100% of patients. In 54% of these patients, cough resolution occurred within 4 weeks. Cough due to ACE inhibitors is a class effect, not dose related, and may occur a few hours to weeks or months after a patient takes the first dose of an ACE inhibitor. The diagnosis of ACE inhibitor–induced cough can only be established when cough disappears with elimination of the drug. The median time to resolution is 26 days. Substituting an angiotensin-receptor blocker for the ACE inhibitor can also eliminate an ACE inhibitor–induced cough. Other drugs may induce cough as well (Table 16). Clinical evaluation of chronic cough includes a careful history and physical examination focusing on the common causes of chronic cough (Figure 4). All patients should undergo chest radiography. Smoking cessation and discontinuation of ACE inhibitors should be recommended for 4 weeks before additional workup. Causes of cough may be determined by observing which therapy eliminates the symptoms associated with cough. Because cough may be caused by more than one condition, a second or third intervention should be added in the event of partial initial response. If chronic cough does not abate with empiric therapeutic trials, objective assessment should be undertaken and can include spirometry, methacholine challenge testing (if spirometry is normal), 24-hour esophageal pH monitoring, and chest CT.

Figure 4. Evaluation of chronic cough. ACEI = angiotensin-converting enzyme inhibitor; LTRA = leukotriene receptor antagonist. Reproduced with permission from: Irwin RS, Baumann MH, Bolser DC, et al; American College of Chest Physicians (ACCP). Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 Suppl):4S. [PMID: 16428686] Copyright 2006 American College of Chest Physicians.

Table 16. Potential Causes of Drug-Induced Cough Angiotensin-converting enzyme inhibitors Inhaled medications Mycophenolate mofetil Nitrofurantoin Propofol Aspirin NSAIDs β-Blockers Antibiotics (amphotericin B, erythromycin, sulfonamides, aminoglycosides) Chemotherapeutic agents Information from Prakash UB. Uncommon causes of cough: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 Suppl):206S-219S. [PMID: 16428713]

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Cough in the Immunocompromised Patient Management of acute, subacute, and chronic cough in immunocompromised patients should be similar to management in the general population, but with the patient’s specific immune deficiency and geographic location addressed as important factors in the history. Immunocompromised patients are more susceptible to a wide variety of pathogens that may be specific to where they live or have traveled. HIV-positive patients with cough and a CD4 cell count below 200/µL (or above 200/µL and with warning signs such as fever, weight loss, night sweats, or thrush) should be evaluated for opportunistic infections, tuberculosis, and pneumocystis pneumonia.

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Hemoptysis

Hemoptysis is defined as coughing up blood from the lower respiratory tract. It can sometimes be difficult to differentiate from hematemesis (vomiting blood) or pseudohemoptysis (spitting of blood from sources other than the lungs or bronchial system). The sputum from hemoptysis is often frothy, bright red or pink, liquid, or clotted. Treatment of hemoptysis is directed at the underlying cause. The most commonly encountered causes of hemoptysis in ambulatory patients are infection (bronchitis or pneumonia) and malignancy. Elevated pulmonary pressure from left-sided heart failure or pulmonary embolism may cause hemoptysis, although hemoptysis alone is not sufficiently sensitive or specific to diagnose pulmonary embolism. In up to 30% of patients, the cause is not identified (cryptogenic hemoptysis). A diagnosis of cryptogenic hemoptysis should not be made until the patient has undergone thorough evaluation. All patients with hemoptysis should have a chest radiograph. Risk factors that increase the risk of malignancy include male sex, age older than 40 years, a smoking history of more than 40 packyears, and symptoms lasting for more than 1 week. These patients should be referred for chest CT and fiberoptic bronchoscopy even if the chest radiograph is normal. Massive hemoptysis (>200 mL/d of blood) represents a medical emergency. Such high rates of bleeding may indicate bleeding from the bronchial arterial system rather than the pulmonary venous system. These patients should be managed in an intensive care unit with hemodynamic and airway stabilization and prompt consultation with a pulmonologist and cardiothoracic surgeon for diagnostic and therapeutic intervention.

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Chronic Fatigue and Chronic Fatigue Syndrome Chronic fatigue is fatigue that has been present for at least 6 months and is associated with functional impairment. Chronic fatigue is common, identified in nearly 20% of respondents to a large community survey. For approximately two thirds of these cases, however, the fatigue was attributable to a known medical or psychiatric condition, leaving about 6% to 7% of respondents with idiopathic chronic fatigue. The chronic fatigue syndrome was defined for research purposes by the U.S. Centers for Disease Control and Prevention, but the definition does have some prognostic utility, as those who meet full criteria have worse outcomes than those who do not. Chronic fatigue syndrome is defined by 6 months or more of medically unexplained, debilitating fatigue, with four or more of the following features: subjective memory impairment, sore throat, tender lymph nodes, muscle pain, joint pain, headache, unrefreshing sleep, and postexertional malaise that lasts at least 24 hours. Chronic fatigue syndrome has a highly variable prevalence in community surveys, from 0.2% to 2.6%.

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Evaluation of Chronic Fatigue There is no test that is diagnostic for chronic fatigue syndrome. An appropriate medical history and physical examination in a patient presenting with chronic fatigue should include an assessment for common causes of fatigue. This should include a sleep history, and those with a history of loud snoring, apneic spells, or frequent limb movements during sleep should be considered for a sleep study to evaluate for sleep apnea or restless legs syndrome. All patients with fatigue should be assessed for depression and anxiety disorders. Because patients with hypothyroidism may present with fatigue in the absence of other clear findings, it is reasonable to order a thyroid-stimulating hormone level. If significant weight loss, lymphadenopathy, or fever is detected on physical examination, assessment for malignancy and chronic infections such as tuberculosis should ensue. A complete blood count should be obtained to rule out anemia as well as to look for evidence of lymphoma or leukemia. A metabolic profile is reasonable to rule out diabetes mellitus, kidney disease, and liver disease. An erythrocyte sedimentation rate can help assess for polymyalgia rheumatica or an active inflammatory process in older patients. No additional studies are routinely indicated, but such studies may be warranted in selected patients based on the history and physical examination findings. Although Epstein-Barr virus and a host of other infectious agents have been considered in the pathogenesis of chronic fatigue syndrome, none have been borne out by careful study, and testing for such agents is not routinely indicated.

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Treatment of Chronic Fatigue There is no evidence that management of chronic fatigue syndrome should differ from that for chronic fatigue that does not meet full criteria for the syndrome. Treatment of chronic fatigue syndrome has proved difficult, but a few interventions have shown some benefit, although study results have been mixed. A graded exercise program can help reduce fatigue and improve functional status. It is important to start slowly and very gradually increase the duration and intensity of the exercise regimen. Physicians or ancillary staff may need to be quite specific in their instructions and follow up closely to ensure that patients avoid progressing too quickly, resulting in relapse. One sensible approach favors exercise in the form of walking, jogging, biking, or swimming at a comfortable intensity level every other day, with an initial duration of 10 minutes or less for the first 2 weeks. Patients record their rating of perceived exertion with each session (for example, using the Borg Rating of Perceived Exertion Scale, which runs from “very, very light” at 6-7 points, to “very, very hard” at 19-20 points). This should be followed by a medical appointment to review the 2-week experience and to establish a plan for the ensuing 2 weeks, with an increase in duration of 2 to 5 minutes if the exertion ratings were at an acceptable level (for example, “somewhat hard,” or 14 or lower, on the Borg scale), while holding the intensity level constant. Ensuing 2-week cycles should be maintained until the duration of exercise reaches 30 minutes, with progression in the intensity of the exercise to be initiated only at that point (for example, by increasing to a “hard” exertion level for the first 1-2 minutes of the exercise session).

There is also evidence to support the use of cognitive-behavioral therapy for chronic fatigue syndrome. Cognitive-behavioral therapy in this setting is targeted in part at breaking the cycle of effort avoidance, decline in physical conditioning, and increase in fatigue, and can work well in combination with graduated exercise in this regard. Cognitive-behavioral therapy reduces fatigue and improves functional status. Interestingly, one study found that cognitive-behavioral therapy reduced self-reported cognitive impairment despite failure to improve neuropsychological test performance. This suggests that the patient’s perception of impairment may be more significant than the actual level of function. Finally, for the large percentage of patients with chronic fatigue syndrome with significant symptoms of depression, there is some evidence that treatment with an antidepressant such as the selective serotonin reuptake inhibitor fluoxetine may improve the depressive symptoms, although not necessarily the nondepressive symptoms. Pharmacotherapy should not, therefore, be initiated as the sole intervention. A variety of other medications have been tried, including corticosteroids, mineralocorticoids, growth hormone, melatonin, and acyclovir, but with no clear evidence of benefit.

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Dizziness The clinical syndrome of dizziness may be divided into vertigo, presyncope, disequilibrium, and nonspecific dizziness. Vertigo is the illusion of motion, often spinning, and is commonly associated with vestibular and central nervous system causes. Presyncope is the sensation of nearly losing consciousness. Disequilibrium is a general feeling of being unsteady when moving. Nonspecific dizziness is dizziness that does not fit neatly into the other categories.

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Evaluation of Dizziness Patients with dizziness often have difficulty precisely articulating the quality of their symptoms. One study showed that patients had poor internal validity when asked to classify their symptoms as light-headedness, vertigo, or unsteadiness and were asked the same questions 6 minutes later. In contrast, patients were able to consistently identify the length and periodicity, as well as the triggers, for their dizzy spells. These features may be just as useful in the differential diagnosis and more reliable than the quality of the dizziness. New medications are a common cause of dizziness, and a complete medication history is especially important. As the history is often nonspecific, a thorough physical examination and selected testing are important to help make a diagnosis (Table 17). Orthostatic vital signs and a complete cardiac examination are important in patients with a history of presyncope or an unclear history. An electrocardiogram has a low yield in the evaluation of dizziness but may be indicated in the

elderly, patients with cardiovascular disease, or patients with syncope. A neurologic and otologic examination is useful for detecting vestibular and central nervous system causes of dizziness. Nystagmus elicited by a Dix-Hallpike maneuver may be helpful in differentiating peripheral vestibular from central nervous system causes of vertigo. While seated on the examination table, the patient is asked to lie down quickly, first with one ear turned toward the table, and then with the other ear turned toward the table. The finding of 10 to 20 seconds of nystagmus (and possibly vertigo) is abnormal. With peripheral causes of vertigo, the nystagmus is horizontal or rotatory, lasts seconds in duration, may be delayed in onset, and fatigues with repetition. Symptoms of vertigo are typically more pronounced with peripheral causes. Central causes of vertigo typically elicit nystagmus that is vertical or changes direction with different head positions, is longer in duration, has no latent period, and is nonfatiguing. Although head-hanging maneuvers may be suggestive of a diagnosis, they can be difficult to perform and have insufficient sensitivity and specificity to conclusively pinpoint the source of vertigo.

Table 17. Differential Diagnosis of Dizziness Syndromes Type of Dizziness Suggestive History and Examination Features Benign paroxysmal positional vertigo

Vestibular neuritis

Migraine headache Meniere disease

Disequilibrium

Stroke or transient ischemic attack

Acoustic neuroma

Diagnostic Testing Results Recurrent, brief episodes of vertigo precipitated Peripheral nystagmus and by head motion with otherwise normal neurologic reproduction of examination symptoms on DixHallpike maneuver Peripheral nystagmus on Sudden onset of severe and persistent vertigo with nausea and vomiting but no other neurologic examination symptoms. Antecedent infection may be present. Lasts days to weeks. Headache, duration of vertigo minutes to hours, Central or peripheral may have associated triggers nystagmus Vertigo, tinnitus, fullness in ear, and hearing loss. Peripheral nystagmus, Recurrent episodes lasting hours. unilateral low-frequency hearing loss on audiometry Nonspecific sense of unsteadiness, typically Risk factors revealed by while moving. Typically a geriatric patient with history and physical multifactorial causes, such as impaired eyesight, examination peripheral neuropathy, deconditioning, and polypharmacy. Older patient with cardiovascular risk factors. Central nystagmus, Typically single episode (stroke) or one or more abnormal neurologic transient episodes lasting at least minutes. examination, abnormal Associated neurologic symptoms, such as motor MRI or angiography paresis, dysarthria, and other cranial nerve abnormalities, are common. Mild to moderate unsteadiness when walking; Central nystagmus,

Hyperventilation

Psychiatric

Presyncope

unilateral tinnitus; hearing loss abnormal MRI Triggered by stressful situations; builds up slowly Reproduction of and persists for 20 minutes or longer symptoms during 2minute hyperventilation test History of psychiatric illness, especially anxiety Diagnosis of exclusion disorders after other causes ruled out Sensation of almost passing out Depends on cause

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Vestibular and Peripheral Nerve Causes of Dizziness Vestibular causes of dizziness are often—but not always—associated with vertigo. Vestibular dizziness is typically of short duration and is recurrent or episodic. Unlike orthostatic hypotension, vestibular dizziness may occur in the supine position. It is most commonly exacerbated by head movement. A recent upper respiratory tract infection, hearing loss, tinnitus, or head trauma may suggest vestibular causes of dizziness. Benign paroxysmal positional vertigo (BPPV) is the most common cause of vestibular dizziness. BPPV is thought to be caused by otolith debris within the semicircular canal. Patients typically describe vertigo lasting minutes in duration, with multiple episodes occurring over weeks to months. Tinnitus, ear pain, and hearing loss are absent, and nausea that is sufficiently severe or prolonged to cause vomiting is rare. Further diagnostic testing of BPPV is not needed in the absence of other central nervous system symptoms. The natural history of BPPV is to spontaneously remit over a period of several weeks. Recurrences are common, with up to a 30% relapse rate over 3 years. Otolith repositioning, commonly known as the Epley maneuver, has been shown helpful in resolving symptoms of BPPV (Figure 5). In this maneuver, the head is sequentially moved in four different positions after waiting for 30 seconds on each turn. The maneuver has no significant adverse effects, and variants of the maneuver can be taught to patients if the symptoms of BPPV return. If these maneuvers fail, medications may be considered in patients with frequently recurring episodes. Anticholinergic medications (scopolamine), antihistamines (meclizine or diphenhydramine), benzodiazepines, or phenothiazine may be useful until symptoms subside. Vestibular neuronitis is another common cause of peripheral vertigo and dizziness. The suspected cause is postviral inflammation of the vestibular portion of the eighth cranial nerve, but a history of antecedent infection is found in fewer than 50% of patients. Symptoms of vertigo, nausea, vomiting, and gait instability are often disabling. Patients do not usually have other neurologic findings, and hearing is usually preserved. When hearing is impaired, the disorder is termed acute viral labyrinthitis.

Vestibular neuronitis differs from BPPV in that the symptoms are usually persistent and tend to be more severe. Patients with vestibular neuronitis do not have recurrent bouts of disease and over several days have a progressive return of equilibrium and cessation of vertigo. A 21-day taper of methylprednisolone may result in faster symptom resolution. Herpes zoster oticus (Ramsay Hunt syndrome) is a specific type of vestibular neuronitis associated with vertigo, hearing loss, ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle (see Ear, Nose, Mouth, and Throat Disorders). It is treated with standard therapy for herpes zoster (corticosteroids, appropriate antiviral agents). Meniere disease is a cause of episodic vertigo accompanied by sensorineural hearing loss, fullness, and tinnitus in the affected ear. The vertigo tends to last from 20 minutes up to several hours at a time, in contrast to shorter episodes with BPPV. Fixed hearing loss involving tones of all pitches develops over time. Autoimmune vasculitis, trauma, aminoglycoside toxicity, and acoustic neuroma are less common causes of vertigo. Audiometry may be useful in determining the etiology of dizziness symptoms associated with cochlear symptoms.

Figure 5. Epley maneuver for relieving benign paroxysmal positional vertigo. The patient sits on the examination table, with eyes open and head turned 45 degrees to the right (A). The physician supports the patient’s head as the patient lies back quickly from a sitting to supine position, ending with the head hanging 20 degrees off the end of the examination table (B). The physician turns the patient’s head 90 degrees to the left side. The patient remains in this position for 30 seconds (C). The physician turns the patient’s head an additional 90 degrees to the left while the patient rotates his or her body 90 degrees in the same direction. The patient remains in this position for 30 seconds (D). The patient sits up on the left side of the examination table (E). The procedure may be repeated on either side until the patient experiences relief of symptoms.

© Maria Hartsock, CMI. Reprinted from Swartz R, Longwell P. Treatment of Vertigo. Am Fam Physician. 2005; 71(6):1115-1122, 1129-1130. [PMID: 15791890]

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Central Nervous System Causes of Dizziness Tumors are found in fewer than 1% of dizzy patients. The most common tumor associated with dizziness is acoustic neuroma, for which cochlear symptoms (tinnitus and hearing loss) often predominate. Unilateral cochlear symptoms raise the suspicion of acoustic neuroma, whereas bilateral symptoms more likely represent presbycusis rather than a tumor. Posterior circulation cerebrovascular disease can also cause vertigo but is usually associated with other neurologic symptoms and findings, such as ipsilateral limb ataxia, temperature and pain sensation loss on the contralateral body and ipsilateral face, ipsilateral Horner syndrome, dysarthria, and dysphagia. A high index of suspicion should be observed in older patients with vascular risk factors, such as smoking, hypertension, diabetes, and hyperlipidemia. Duration of symptoms for longer than a few seconds is useful in differentiating either a vertebrobasilar transient ischemic attack or stroke from BPPV. Unlike Meniere disease, simultaneous vestibular and cochlear symptoms are uncommon in patients with cerebrovascular disease. However, it can be difficult to differentiate posterior cerebrovascular ischemic syndromes from vestibular neuronitis. Migraine headaches may be associated with dizziness described as vertigo. Clues may include antecedent aura and a recurrent nature of symptoms that last from minutes to hours. As headaches and vertigo may occur with more serious disorders such as cerebellar hemorrhage, the initial diagnosis of migrainous vertigo is one of exclusion. MRI is indicated when clinical symptoms, audiometric testing, and the neurologic examination suggest an infarct, a tumor, or a demyelinating disorder such as multiple sclerosis. The addition of MRI angiography may be useful in ruling out posterior circulation vascular disease in a patient with intermittent neurologic symptoms.

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Disequilibrium Disequilibrium is a sensation of unsteadiness while walking. It often has multiple causes, with deconditioning, peripheral neuropathy, poor hearing, poor eyesight, and polypharmacy the most common contributing factors. Medications that contribute to disequilibrium include anticholinergic agents, narcotics, benzodiazepines, and antihypertensive agents. In a study of

1087 community-living persons older than 72 years, 24% had dizziness. More than half of those with dizziness had multiple symptom descriptions, and nearly 75% of those with dizziness reported more than one triggering activity. Risk factors for dizziness were impaired hearing, anxiety, depressive symptoms, polypharmacy, postural hypotension, prior myocardial infarction, and impaired balance. Treatment of disequilibrium involves reducing polypharmacy, installing safety features in patient’s homes, providing assistive devices such as walkers and canes, correcting eyesight and hearing if possible, and instituting physical therapy to improve muscle strength.

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Nonspecific Dizziness Often, after an exhaustive evaluation, no specific neurologic or cardiovascular cause of dizziness is revealed. Other systemic problems that may cause a feeling of dizziness include hypoglycemia, medications, thyroid disease, and anemia. Dizziness associated with hyperventilation is typically triggered by stressful situations. Reproduction of the dizziness in an office setting is useful but does not rule out other underlying causes, and hyperventilation is a common secondary component of multifactorial dizziness. Diagnosis of psychiatric illness may be related to nonspecific dizziness. In a study of 345 patients with dizziness present most days for more than 3 months, 60% met criteria for diagnosis of an anxiety disorder; in 30% of these patients with anxiety, no other potential causes of dizziness were found. Other common causes of chronic dizziness in the study included traumatic brain injury and migraine headache.

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Insomnia Insomnia is difficulty falling asleep or maintaining sleep, waking up too early, or sleep that is chronically nonrestorative despite the opportunity and circumstances for sleep; and is associated with daytime impairment or distress. Acute insomnia lasts less than 1 week, short-term insomnia lasts 1 to 3 weeks, and chronic insomnia occurs at least three times weekly for more than 1 month. One in three Americans have insomnia at some point in their lives, and one in ten have chronic insomnia. Insomnia can occur at any age but is more common as people age, with prevalence rates of 12% to 30% in patients older than 65 years. Older adults take longer to initiate sleep, the amount of time in lighter levels of sleep increases, overall sleep time decreases, and the amount of rapid eye movement (REM) sleep also decreases. Regardless of age, adults need approximately 7 to 8 hours of sleep nightly. Insomnia has significant personal and societal costs. Insomnia can lead to daytime somnolence, irritability, increased health care utilization, decreased quality of life, higher accident rates (2.5-

4.5 times more likely than controls), and impaired job performance (including higher rates of absenteeism). Insomnia may be a harbinger to or a consequence of depression, anxiety, and mood disorders. Insomnia may lead to substance abuse such as alcohol and other medications (prescription and nonprescription). The total direct costs related to insomnia in the United States in 1995 were $13.9 billion. At least 80% of insomnia cases are secondary to an underlying condition such as pain, mental health disorders, dementia, cardiopulmonary disease, situational worry, a primary sleep disorder, or medications (Table 18). Primary insomnia is that which is not due to an underlying condition and lasts for a period of more than 1 month. It can be triggered by long-lasting emotional distress, travel (jet lag), or work-related changes (shift work). Some of the habits that develop to deal with the insomnia, such as napping, going to bed early, or worrying about sleep, can perpetuate the problem. The medical history should focus on underlying medical conditions (heart failure, chronic obstructive pulmonary disease), psychiatric conditions (depression, anxiety, posttraumatic stress disorder), and environmental conditions (light, circadian rhythm disturbances, noise, sleep partner problems) that may cause or contribute to the insomnia. A sleep history is essential for characterizing the patient’s concerns and identifying any possible underlying sleep disorder (Table 19). Self-administered questionnaires such as the Pittsburgh Sleep Quality Index may be helpful to establish the cause of insomnia and to plan effective treatment. A patient-recorded sleep diary for 1 to 2 weeks documenting bedtime, wake time, hours of sleep, and number of awakenings may help obtain a more accurate record of sleep habits than general questioning. The physical examination should be tailored to confirming problems identified in the history. Any diagnostic testing should be guided by judgment about associated medical conditions (for example, iron deficiency and renal disease with restless legs syndrome). Referral for polysomnography is indicated when a primary sleep disorder is suspected (obstructive sleep apnea, restless legs syndrome, periodic limb movement disorder). A sleep study may also include multiple sleep latency testing, in which a patient takes four or five 20-minute naps, and sleep latency (the time from deciding to sleep to actually falling asleep) is measured. Sleep latency of less than 8 minutes is associated with hypersomnia, which occurs with sleep disorders such as narcolepsy, insufficient sleep syndrome, medication adverse effects, sleep apnea syndromes, and periodic limb movements in sleep. Treatment of insomnia involves addressing and correcting precipitating factors. Any intervention—pharmacologic or nonpharmacologic—begins by focusing on ensuring adequate sleep hygiene, as poor sleep hygiene can contribute to sleep fragmentation, circadian rhythm disturbance, discomfort, and overstimulation. Sleep hygiene should be tailored to an individual patient’s needs (Table 20). The technique of sleep restriction should be considered in patients with insomnia with no underlying medical or psychological disorder in whom sleep hygiene measures have been unsuccessful. Sleep restriction involves limiting the time spent in bed and gradually moving bedtime later in an effort to consolidate sleep. A patient undergoing sleep restriction should maintain a sleep log for 1 to 2 weeks documenting bedtime, sleep time, nocturnal waking, and rising time. The patient should then limit the time spent in bed to the average time reported sleeping in the sleep log, but no less than 5 hours. A strict rising time each day should be

maintained. If sleep efficiency (total time asleep/total time in bed) is greater than 90%, bedtime can be moved earlier in 15-minute increments, being careful to maintain 90% sleep efficiency. Successful sleep restriction technique results in improved total sleep time. Patients should be warned that sleep restriction has the potential to significantly increase daytime sleepiness and to be cautious driving or engaging in other daytime activities that require attention. In cognitive-behavioral therapy for insomnia, patients are provided with correct information about sleep (such as the need for 7-8 hours/night and normal changes in sleep associated with aging), and negative concerns and beliefs that have arisen about sleep are addressed. In certain populations, behavioral techniques such as cognitive-behavioral therapy have been shown to decrease awake time more effectively than drugs in randomized trials. Biofeedback and progressive muscle relaxation techniques may also be helpful. Pharmacologic therapy for insomnia involves both nonprescription and prescription medications. Nonprescription antihistamines (diphenhydramine or doxylamine) are widely available, but evidence of their efficacy is limited and they are associated with significant adverse effects (daytime somnolence, impairment of complex tasks such as driving, anticholinergic side effects). Melatonin may be effective for circadian rhythm disturbances (for example, jet lag) but its role, as well as that of alternative therapies such as St. John’s wort, valerian, and kava, is unproven, and these agents are generally discouraged for chronic insomnia. Prescription medications are commonly used for treating insomnia but caution must be exercised. Consensus opinion and the FDA recommend limiting the use of sedative hypnotics to 1 month. The FDA has issued warnings regarding severe allergic reactions and anaphylaxis as well as complex sleep-related behaviors (such as sleep-driving or sleep-eating; often associated with amnesia of the events) for many commonly used agents. It is important to avoid hypnotics in patients with underlying disorders in which their use can be counterproductive. For example, a patient with obstructive sleep apnea syndrome would not be aided and would potentially be harmed by sleeping pills. In addition, patients should be cautioned to avoid using alcohol while taking any sedative-hypnotic sleep medication. Finally, several studies suggest that nondrug therapies may be more effective if not used in conjunction with drugs. In general, nonbenzodiazepine hypnotics, such as zolpidem, zaleplon, and eszopiclone, have more favorable effects on sleep and fewer side effects than benzodiazepines. Benzodiazepines have the potential for dependency and may lose effectiveness after 30 days; tapering the dose at discontinuation may mitigate withdrawal or rebound insomnia. The minimally effective dose for the shortest duration should be used. Antidepressants should be used to treat underlying depression and should not be used solely to treat insomnia. Dopaminergic agents can be helpful in treating symptoms of restless legs syndrome (when other reversible causes such as iron deficiency, thyroid disease, and caffeine use have been eliminated); if these agents are unhelpful or contraindicated, clonazepam or gabapentin may help restless legs syndrome.

Table 18. Common Causes of Insomnia Cause Psychophysiologic

Characteristics Disturbed sleep resulting from conditioned arousal usually to the

insomnia

bedroom. Look for a history of sleep improvement when away from the bedroom. Patients may have an inordinate concern over sleep. Restless legs syndrome An uncomfortable or restless feeling in legs most prominent at night and at rest associated with an urge to move and alleviated by movement. Approximately 80% of patients with RLS have PLMD on polysomnography. Periodic limb Repetitive stereotypic leg movement during sleep. Polysomnography is movement disorder necessary for diagnosis. Sleep state Objectively normal sleep in the face of the patient’s report of misperception insufficient sleep. Central sleep apnea Repetitive pauses in breathing during sleep without upper airway syndrome occlusion. Look for associated history of CHF or CNS disease. Polysomnography is necessary for diagnosis. Obstructive sleep Upper airway obstruction during inspiration in sleep. Look for a history apnea syndrome of snoring, witnessed pauses in respiration, and daytime sleepiness. Polysomnography is necessary for diagnosis. Inadequate sleep Disturbed sleep associated with caffeine, tobacco, alcohol use, or hygiene irregular sleep habits (e.g., college students). Comprehensive sleep history will facilitate the diagnosis. Environmental sleep Disturbed sleep associated with environmental elements. disorder Comprehensive sleep history will facilitate the diagnosis. Hypnotic-dependent Disturbed sleep associated with tolerance to or withdrawal from sleep disorder hypnotic drugs. Positive history of sustained hypnotic drug use with development of tolerance leading to increased dose. Alcohol-dependent Alcohol used to initiate sleep; sleep that follows is fragmented. Ask for sleep disorder patient’s history of alcohol use to facilitate sleep for at least the last 30 days. Shift-work sleep Symptoms of insomnia as a consequence of shift-work. Shift work disorder includes those patients working a permanent night shift. Time zone change Time zone changes secondary to travel, leading to poor sleep, daytime syndrome (jet lag) sleepiness, or both. Anxiety and depressive May trigger sleep initiation or sleep maintenance problem. Most patients disorders with anxiety and insomnia will present with anxiety first or concomitant with insomnia. In contrast, depression tends to follow insomnia. Dementia Insomnia associated with dementia and manifested by wandering, aggressive behavior, verbalization, and delirium in the early evening hours. CHF = congestive heart failure; CNS = central nervous system; PLMD = periodic limb movement disorder; RLS = restless legs syndrome.

Table 19. Elements of a Comprehensive Sleep History

Problems of sleep initiation, sleep maintenance, early morning waking, or nonrestorative sleep Duration of symptoms Stability or progression of symptoms (stable, worsening, or improving) Precipitating causes of insomnia Bedtime, waking time, length of sleep time Bedtime routine, including activities 1-2 hours before sleep and activities while in bed (such as watching television) that may delay sleep Caffeine use (within 8 hours of bedtime) Alcohol use (in general or as sleep aid) Any current or previous behavioral therapies used to treat insomnia Previous over-the-counter or prescription sleep remedies Shift work or irregular sleep schedule Potential acute stressors, such as: Medical or psychiatric illness Medication use, both prescribed and illicit Acute stress at home or work Circadian rhythm stressors (jet lag)

Table 20. Sleep Hygiene and Stimulus Control Behaviors Maintain stable bedtimes and rising times, even if there is trouble initiating or maintaining sleep on a given night Spend no more than 8 hours in bed Experience regular daytime light exposure Maintain a quiet, dark bedroom Associate the bedroom with rest and sleep: avoid activities such as watching television or reading in bed Maintain adequate nutrition Avoid sleep-fragmenting substances, such as caffeine, nicotine, and alcohol Caffeine within 8 hours of bedtime can fragment sleep Avoid using alcohol to initiate sleep Alcohol may promote drowsiness but impairs deeper levels of sleep Avoid clock-watching If unable to initiate sleep within 20 minutes of attempting sleep, advise patients to leave the bedroom, undertake nonstimulating activities (such as reading) elsewhere, and return to bed when sleepy Maintain regular exercise Avoid heavy exercise within 2 hours of bedtime Avoid bright light before bedtime

Maintain a 30-minute relaxation period before bedtime

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Syncope Syncope is a sudden and transient loss of consciousness and posture, typically caused by a lack of blood flow to the brain. Presyncope is a sensation of nearly losing consciousness and has the same general causes as syncope. Common findings on the history and physical examination associated with various types of syncope are described in Table 21.

Table 21. Differential Diagnosis of Syncope Possible Diagnosis Seizures Vasovagal syncope Carotid sinus syncope Orthostatic hypotension

Associated Findings Tongue biting, incontinence, preceding emotional stress, loss of memory or confusion after the event, a prodrome of déjà vu or jamais vu Prodrome of nausea, diaphoresis, and pallor before syncope. Triggers such as fear, pain, prolonged standing, phlebotomy, coughing, urinating, defecating, and drinking cold liquids. Head turning or other pressure on carotid sinus

Syncope on standing from sitting or supine position, history of drugs associated with orthostatic hypotension, diseases associated with autonomic failure (such as Parkinson disease) Stroke Associated focal neurologic symptoms, headache Structural heart Abnormal murmur on cardiac examination, exertional syncope, abnormal ECG, disease history of heart disease Arrhythmia History of coronary artery disease or heart failure, exertional syncope, palpitations, absence of a prodrome, family history of sudden death, drugs prolonging QT interval, abnormal baseline ECG Systemic causes History of labile diabetes, anemia, volume depletion, adrenal insufficiency Psychiatric Frequent episodes, odd associated symptoms, no heart disease syncope ECG = electrocardiogram.

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Neurologic Causes of Syncope Seizures are a common cause of loss of consciousness and should be considered when there are no witnesses to the event or a suggestive history is elicited. There are several clues on history that may help differentiate syncope from seizures. Loss of consciousness associated with tongue biting, incontinence, preceding emotional stress, loss of memory or confusion after the event, head turning during the event, and a prodrome of déjà vu or jamais vu (a false sensation of unfamiliarity with a situation) are all suggestive of seizure. A history of prior lightheaded spells, diaphoresis preceding spells, and spells after prolonged sitting or standing are more suggestive of causes of syncope that are not seizure related. Cerebrovascular disease is an uncommon cause of syncope. Syncope can be associated with stroke, subarachnoid hemorrhage, vertebrobasilar insufficiency, and subclavian steal syndrome but rarely occurs without other findings on neurologic examination. In some disorders, such as large subdural hematomas, it is difficult to determine whether the finding is a result of a fall caused by syncope or a contributing factor to the syncope itself.

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Neurocardiogenic Syncope Neurocardiogenic or vasovagal syncope is one of the most common causes of syncope. In neurocardiogenic syncope, triggers lead to increased parasympathetic tone, causing a drop in heart rate and blood pressure (cardioinhibitory response); decreased sympathetic tone, causing vasodilation and hypotension (vasodepressor response); or a combination of the two. The increased vagal tone seen in neurocardiogenic syncope typically causes a prodrome of nausea, diaphoresis, and pallor. Common triggers include fear, pain, prolonged standing, phlebotomy, coughing, urinating, defecating, and drinking cold liquids. Neurocardiogenic syncope is frequently diagnosed when other causes of syncope are excluded or with a suggestive history in a low-risk patient. It may also be diagnosed by characteristic bradycardia and hypotension during an upright tilt-table test. Carotid sinus hypersensitivity causes neurocardiogenic syncope when mechanical pressure on the carotid sinus stimulates the glossopharyngeal nerve, altering sympathetic and parasympathetic tone. Recent studies suggest that carotid sinus hypersensitivity is common in the elderly, occurring in up to 35% of asymptomatic patients. It is a diagnosis of exclusion when other causes of syncope have been eliminated. Treatment of neurocardiogenic syncope is based on trigger avoidance and assumption of a supine position with legs elevated when symptoms arise. Other nonpharmacologic treatments include compression stockings, tilt training, and volume expansion. In patients with frequent episodes, pharmacologic therapy with β-blockers may be considered. A dual-chamber pacemaker can be

considered in selected patients with inappropriate bradycardia when medical therapy is ineffective, episodes are particularly severe and frequent, and a predominant cardioinhibitory response is found on tilt-table testing.

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Orthostatic Hypotension Orthostatic hypotension is a frequent cause of syncope and presyncope. It is defined as a systolic blood pressure decrease of at least 20 mm Hg or a diastolic blood pressure decrease of at least 10 mm Hg within 3 minutes of standing. Orthostatic hypotension may be classified into medicationinduced, neurogenic, and nonneurogenic categories. Common medications associated with orthostatic hypotension include α-adrenergic blockers, nitrates, diuretics and other antihypertensive agents, phosphodiesterase inhibitors, and antidepressants. Initiation of a new medicine is often temporally related to symptoms. Examples of diseases causing neurogenic orthostatic hypotension are diabetic or alcoholic polyneuropathy, multiple sclerosis, and multiple systems atrophy. Nonneurogenic orthostatic hypotension may be caused by disorders such as adrenal insufficiency, venous pooling, or volume depletion from an acute medical illness. Patients with orthostatic hypotension should be educated to avoid rising to standing positions quickly, to wear elastic support hose, and to avoid volume depletion and large meals. In patients in whom these measures fail and no offending medications are being given, a trial of fludrocortisone or a sympathomimetic agent may be useful.

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Cardiac Disease Three major groups of disorders cause syncope of cardiac origin. These disorders are cardiac outflow obstruction, arrhythmias, and cardiac ischemia. Causes of obstructed cardiac output leading to syncope include severe aortic stenosis, hypertrophic obstructive cardiomyopathy, and pulmonary embolism. Coronary artery disease is an uncommon cause of syncope and typically occurs with symptoms of cardiac ischemia, abnormal cardiac enzyme levels, or an abnormal electrocardiogram. Ventricular tachycardia, atrial arrhythmias, and bradyarrhythmias can cause syncope. Atrial tachyarrhythmias are more likely to cause palpitations and lightheadedness than syncope. Ventricular tachycardia (VT) is perhaps the most feared cause of syncope because of its tendency to recur and cause sudden cardiac death. VT is most commonly seen in patients with advanced systolic heart failure and underlying ischemic heart disease (see MKSAP 15 Cardiovascular Medicine). Less common causes include long QT syndrome, catecholaminergic polymorphic

VT, and Brugada syndrome. Patients at risk for recurrent VT should receive electrophysiologic testing and consideration of an implantable cardioverter-defibrillator. Syncope may also be associated with long (>3 seconds) sinus pauses and advanced heart block. These conditions are readily treated by pacemaker insertion.

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Risk Stratification and Hospitalization The decision to hospitalize a patient with syncope should be based on concern for a short-term risk for arrhythmia or sudden death that will be detected during the observation period. Several recent studies have tried and failed to define prediction rules with sufficient sensitivity to detect life-threatening causes. While no rule has been validated for widespread use, the literature has identified several factors associated with a significantly increased risk of adverse events (Table 22). Patients with these characteristics should be considered for admission or observation. Age and other comorbidities are also important factors in deciding whether to admit a patient. The American College of Emergency Physicians considers age a risk factor for adverse longer-term outcomes in patients with syncope but felt there were insufficient data to recommend a specific age cutoff for which they would recommend admission.

Table 22. Risk Factors for Short-Term Adverse Outcomes from Syncope (American College of Emergency Physicians) Abnormal ECG Acute ischemia New changes on ECG Any rhythm other than sinus Significant conduction abnormalities Hematocrit 50 y Multiple risk factors present

Fever; injection drug use; recent infection Cauda equina Urinary retention; motor deficits at syndrome multiple levels; fecal incontinence; saddle anesthesia Vertebral History of osteoporosis; use of compression fracture corticosteroids; older age Ankylosing Morning stiffness; improvement with spondylitis exercise; alternating buttock pain; awakening due to back pain during the second part of the night; younger age Severe/progressive Progressive motor weakness neurologic deficits Herniated disk Back pain with leg pain in an L4, L5, or S1 nerve root distribution; positive straight-leg-raise test or crossed straightleg-raise test Symptoms present >1 month

Imaginga MRI

Additional Studiesa ESR

Lumbosacral ESR plain radiography Plain radiography ESR or MRI MRI ESR and/or CRP Emergent MRI None

Lumbosacral plain radiography Anteriorposterior pelvis plain radiography

None

MRI

Consider EMG/NCV None

None

MRI

ESR and/or CRP, HLAB27

Consider EMG/NCV

Spinal stenosis

Radiating leg pain; older age (pseudoclaudication a weak predictor) Symptoms present >1 month

None

None

MRI

Consider EMG/NCV

CRP = C-reactive protein; EMG = electromyography; ESR = erythrocyte sedimentation rate; NCV = nerve conduction velocity. a

Level of evidence for diagnostic evaluation is variable.

Adapted with permission from Chou R, Qaseem A, Snow V, et al; Clinical Efficacy Assessment Subcommittee of the American College of Physicians; American College of Physicians; American Pain Society Low Back Pain Guidelines Panel. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society [erratum in Ann Intern Med. 2008;148(3):247-248]. Ann Intern Med. 2007;147(7):481. [PMID: 17909209] Copyright 2007, American College of Physicians.

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Treatment A patient-centered approach is important in the management of acute episodes of low back pain. Patients should be provided with evidence-based information regarding their expected course as well as effective self-care options. Patients should be advised to stay active and continue normal activities if possible; bed rest is not an effective treatment plan and may actually lengthen disability. First-line medications for low back pain are acetaminophen and NSAIDs. Opiates increase the risk of side effects (odds ratio = 2.5) compared with acetaminophen alone, and muscle relaxants have twice the number of central nervous system side effects. In addition, muscle relaxants have a risk of dependency after just 1 week of treatment. Most patients with a herniated disk without major neurologic concern experience resolution of their pain spontaneously over the course of a few weeks. For those who do not, diskectomy or epidural corticosteroid injections may be an option. Exercise during the acute phase has the potential to increase the time to recovery; however, exercise, spinal manipulation, and yoga have some evidence of efficacy in the management of subacute or chronic low back pain in selected patients. Spinal manipulation may be helpful in some patients with acute low back pain. Patients are most likely to benefit from spinal manipulation if they meet four of the following five criteria: symptom duration less than 16 days, no symptoms distal to knee, a score of less than 19 on the Fear-Avoidance Beliefs Questionnaire

(FABQ), at least one hypomobile lumbar segment (as compared with the mobility in the segment above and below), and at least one hip with more than 35 degrees of internal rotation. For chronic back pain, tricyclic antidepressants are an option and may be of added benefit in treating depressive syndromes that often accompany chronic pain. Patients with psychosocial factors that place them at greater risk for chronic pain and disability may respond better to a multidisciplinary approach to rehabilitation.

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Neck Pain • •

Diagnosis and Evaluation Treatment

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Diagnosis and Evaluation Population studies have shown a lifetime prevalence of neck pain of 66%. The evidence is less robust for the optimal workup and treatment of neck pain than for back pain but centers on similar diagnostic triage, dividing neck pain into three categories: soft tissue strain, neurologic pain, and systemic disease. Important elements in the history of a patient with neck pain include trauma, gradual versus sudden onset, radiation into the arms or frank muscle weakness (associated with disk herniation), fever and weight loss, and characteristics of the pain. There is evidence that neck pain is associated with work-related risk factors: neck flexion, arm force, arm posture, duration of sitting, twisting or bending of the trunk, hand-arm vibration, and workplace design. Gradual onset of pain is associated with repetitive motion. The physical examination should focus on palpation to elicit tender points (facets, disk spaces, musculature), evaluation of strength and reflexes in the upper extremities, lower extremity strength and gait, and a search for upper motor neuron signs (Table 25). Laboratory data (including complete blood count, erythrocyte sedimentation rate, alkaline phosphatase level) are mainly important when considering systemic disease. Radiography is necessary to rule out fracture if there is a history of trauma; it is not helpful in evaluating acute nontraumatic injury. Three-view plain radiography may be useful if pain has not resolved after 4 to 8 weeks. In patients with distal neurologic changes, cervical MRI or CT myelography should be obtained. Diseases involving the deeper neck structures (carotid arteritis, carotid artery dissection, thyroiditis, lymphadenitis) at times can cause neck pain and must be considered when no musculoskeletal cause can be found.

Table 25. Evaluation of Neck Pain Category History Mechanical neck pain Pain (usually episodic, deep, dull, (muscle, ligament, and aching) and stiffness facet, intervertebral disk) Symptom may be precipitated or aggravated by excessive or unaccustomed activity or sustaining an awkward posture without a specific injury Ligament, muscle, and facet pain are localized and asymmetric

Physical Examination Decrease in active and passive range of motion Superficial tenderness indicates soft tissue pain; deep tenderness indicates muscle or bone pain Pain on extension or ipsilateral lateral flexion usually indicates facet pain; pain on flexion or contralateral lateral flexion usually indicates soft tissue pain

Pain from upper cervical segments is referred toward the head; pain from lower segments is referred to the upper limb girdle Neurologic neck pain Significant root pain; sharp, intense, Neurologic examination may show motor weakness, usually involving (cervical nerve root often described as a burning sensation; may radiate to the several cervical levels and often and/or spinal cord) trapezial and periscapular regions or asymmetric, affecting one or both down the arm arms Look for plantar extensor response, Numbness in a dermatomal distribution and motor weakness in gait disorder, and spasticity in a myotomal distribution patients with spinal cord involvement Symptoms often more severe with certain movement Bilateral or multilevel involvement indicates more severe pathology Neck pain associated Fever, malaise, or pain in areas in Complete physical examination may show underlying systemic disease, with systemic disease addition to the neck such as inflammatory joint disease, Pain is usually severe, relentless, organ infection, or neoplastic and progressive process Symptoms or signs may be progressive despite treatment Adapted with permission from Huang S, Tsang IK. Neck Pain. http://pier.acponline.org/physicians/diseases/d103/tables/d103-tables.html (login required). In PIER (online database). Philadelphia: American College of Physicians, 2009. Accessed July 7, 2009.

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Treatment For patients with neck pain caused by musculoskeletal strain, the mainstays of therapy are NSAIDs and physical therapy. The rationale for physical therapy is the belief that exercise helps to maintain posture and strengthen the neck muscles, thereby decreasing pain and preventing progression of symptoms. Although clinical studies may show some degree of effectiveness of various nondrug therapies for neck pain, the effectiveness of these therapies is dependent entirely on the skill of the therapist. Most industries have workplace analysis to reduce the risk of repetitive motion injuries to the neck. Mobilization, manipulation, and exercise may play a role in recovery. There is little evidence that transcutaneous electrical nerve stimulation (TENS) units or massage is helpful. Isometric resistance exercises of the neck and shoulder musculature for chronic or frequent neck disorders appear to be somewhat helpful in preventing recurrence of pain. In patients with radicular symptoms, epidural corticosteroid injections have improved patient recovery at 2 weeks and may be worth trying before consulting a surgeon. Surgery is not indicated in patients without neurologic symptoms and signs.

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Shoulder Pain • • • • •

Diagnosis and Evaluation Rotator Cuff Tendinitis Impingement Syndrome Adhesive Capsulitis Acromioclavicular Ligament Injuries

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Diagnosis and Evaluation Causes of shoulder pain and associated findings on history and physical examination are listed in Table 26. Pain in the shoulder after a traumatic injury or fall may be caused by a partial or full rupture of a rotator cuff tendon. Pain that has gradually developed and is associated with repetitive motion may be more indicative of tendinitis. Bursa pain is often described as a burning sensation. Poorly localized pain may be referred pain caused by disease in other structures, such

as cervical radiculopathy, cardiac ischemia, diaphragmatic irritation, or pulmonary diseases. These external causes of shoulder pain are not related to shoulder movement and do not impair range of motion. On inspection of the shoulder, asymmetry indicates a possible dislocation. The major anatomic landmarks should be palpated, including the subacromial space below the tip of the acromion process, the acromioclavicular joint, the biceps tendon groove, the cervical spine, and the scapula. Range of motion testing should be performed in several directions. The patient should be asked to fully extend the arms above the head; if the patient is unable to do so, the examiner should attempt with gentle pressure to assist (passive range of motion). The Apley scratch tests consist of several maneuvers to assess range of motion (Figure 7). Checking passive range of motion if the patient is unable to achieve the expected range helps define areas of pain or weakness. Particular tests of the rotator cuff tendons may be performed by standing across from the patient and assuming a posture of “shaking hands” with the patient and holding the patient’s elbow with the other hand (Figure 8). From this position, the examiner can direct the patient to apply pressure in various directions to check the strength and competence of the rotator cuff tendons. Frank weakness, sometimes without pain, occurs if there is a complete tear of the tendon. To test for impingement, the Hawkins test (Figure 9) is 92% sensitive. In order to determine the stability of a shoulder, the apprehension test is performed (Figure 10). If the patient has pain or apprehension of possible dislocation of the shoulder, the test is positive and indicative of a loose shoulder, as seen in weak musculature or in rotator cuff tears.

Figure 7. Apley scratch test. This test assesses range of motion of the rotator cuff. The patient attempts to reach across the chest with the ipsilateral hand to scratch the contralateral shoulder (left), reach over the ipsilateral trapezius muscle to scratch the spinous processes of the thoracic spine (center), and reach behind the back by internal rotation of the shoulder to scratch the contralateral scapula (right).

Figure 8. Rotator cuff tendon assessment maneuvers. To assess rotator cuff function, the examiner stands across from the patient and assumes a posture of shaking hands with the patient, holding the patient’s elbow with the other hand. Pain with resistance in these directions may indicate tendinitis: (1) resisted internal rotation (subscapularis); (2) resisted external rotation (infraspinatus); (3) resisted abduction (supraspinatus).

Figure 9. Hawkins test for shoulder impingement. The patient holds the arm extended anteriorly at 90 degrees with the forearm bent to 90 degrees (at 12 o’clock), as if holding a shield. The scapula should be stabilized by the examiner. The arm is then internally rotated to cross in front of the body. A positive test elicits pain in the shoulder.

Figure 10. Apprehension test. The patient is placed supine on a table. With the arm abducted at 90 degrees and the forearm flexed, the examiner stands at the bedside facing the patient and places one hand under the affected shoulder. With the other hand, gentle pressure is placed on the forearm. Pain or apprehension constitutes a positive test.

Table 26. Common Causes of Shoulder Pain Condition Characteristics Rotator cuff tendinitis Lateral shoulder pain aggravated by reaching, raising arm overhead, lying on side. Subacromial pain on palpation and with passive/resisted abduction. Rotator cuff tear Shoulder weakness, loss of function, tendinitis symptoms, nocturnal pain.

Bicipital tendinitis/rupture Adhesive capsulitis

Acromioclavicular syndromes Glenohumeral arthritis

Similar to tendinitis examination plus weakness with abduction and external rotation, positive drop-arm test. Anterior shoulder pain with lifting, overhead reaching, flexion; reduced pain after rupture. Bicipital groove tenderness, pain with resisted elbow flexion, “Popeye” lump in antecubital fossa following rupture. Progressive decrease in range of motion, more from stiffness than pain. Loss of external rotation, abduction: unable to scratch lower back or fully lift arm straight overhead. Anterior shoulder pain/deformity, usually from trauma or overuse. Localized joint tenderness and deformity (osteophytes, separation), pain with adduction. An uncommon cause of shoulder pain. Gradual onset of anterior pain, stiffness. Anterior joint-line tenderness, decreased range of motion, crepitation.

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Rotator Cuff Tendinitis The most common cause of shoulder pain in primary care practices is rotator cuff tendinitis (29%). When the history and physical examination are consistent with rotator cuff tendinitis and there is no history of trauma, radiography will not likely add to the management. If the pain is relieved by a subacromial lidocaine injection in the affected shoulder and the strength is normal, the diagnosis is nearly confirmed. During the acute phase (2 weeks), patients may be treated with corticosteroid injection, NSAIDs, and rest; physical therapy can be added in the subacute phase. Subacromial corticosteroid injections are effective for rotator cuff tendinitis for up to 9 months. These injections have been found more effective in higher doses and are probably more effective than NSAIDs. Physical therapy alone, however, is insufficient. Patients should be instructed that during the resting (acute) phase, range of motion exercises must be done daily to help prevent adhesive capsulitis, or frozen shoulder.

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Impingement Syndrome Impingement syndrome is a special category of supraspinatus tendinitis caused by irritation of the subacromial bursa or rotator cuff tendon from mechanical impingement between the humeral head and the coracoacromial arch, which includes the acromion, coracoacromial ligament, and the coracoid process (Figure 11). Chronic overhead activity may contribute to narrowing of this space, which can lead to recurrent microtrauma and chronic local inflammation of rotator cuff tendons. Pain on the Hawkins test that resolves with injection of lidocaine into the subacromial space helps establish the diagnosis. Initial treatment is similar to rotator cuff tendinitis; however,

persistence of symptoms after 3 months, which occurs in 10% to 25% of patients, may warrant an orthopedic referral.

Figure 11. Shoulder impingement syndrome. Reproduced with permission from Rencic J. Approach to knee and shoulder pain. In: Internal Medicine Essentials for Clerkship Students 2. Philadelphia, PA: American College of Physicians; 2009:310. Copyright 2009, American College of Physicians.

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Adhesive Capsulitis

Range that is limited on both active and passive motion may be a sign of adhesive capsulitis. Chronic adhesive capsulitis may be painless. Adhesive capsulitis typically occurs in patients with long-standing shoulder problems; occasionally, however, the patient does not recall an initial insult. Adhesive capsulitis usually occurs in middle or older age. When NSAIDs, joint corticosteroid injection, and physical therapy are ineffective after 3 months, a patient’s shoulder may need to be manipulated under general anesthesia, or alternatively undergo arthroscopy, to break the adhesions.

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Acromioclavicular Ligament Injuries A fall onto the superior portion of the shoulder or onto an outstretched hand (FOOSH injury) is a common cause of acromioclavicular ligament strain or tear. These injuries are graded into six categories based on the severity of involvement of both the acromioclavicular (A-C) ligament and the coracoclavicular (C-C) ligament. Grade I is a partial tear of the A-C ligament, and is recognized by the physical examination maneuver of bringing the outstretched arm across the chest, which elicits sharp pain in the A-C joint. Grade II is a full tear of the A-C ligament and a partial tear of the C-C ligament, possibly accompanied by A-C joint widening (normal is 55y • Tenderness at the head of the fibula or isolated to the patella • Inability to bear weight for at least four steps of walking • Inability to flex knee to at least 90 degrees Is there an effusion? Arthrocentesis (especially to rule out infectious or crystalline arthritis) Does the physical examination suggest meniscal or Orthopedic referral (for examination and ligamentous injury or history of locking or give-way decision on need for MRI or arthroscopy) sensation? Adapted with permission from Jackson JL, O’Malley PG, Kroenke K. Evaluation of acute knee pain in primary care. Ann Intern Med. 2003;139(7):575-88. [PMID: 14530229] Copyright 2003, American College of Physicians.

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Trauma Trauma may result in a fracture or ligament tear, which produces a noticeable “popping” sensation in 50% of patients. Typically, a large effusion collects rapidly. Anterior cruciate ligament tears occur with sudden twisting and hyperextension injuries, collateral ligament tears occur with medial or lateral force without twisting, and posterior cruciate ligament tears occur with trauma to a flexed knee. Only 10% of knee radiographs ordered for acute knee pain demonstrate a fracture; therefore, candidates for knee radiography must be carefully selected. The Ottawa Decision Rules are nearly 100% sensitive for fracture following a fall, and radiography should not be ordered unless these criteria are met. When the history suggests meniscal or ligamentous injury (the knee locking or giving way), several physical examination maneuvers have a high degree of specificity for identifying these injuries (Figure 13). An audible or palpable snap on the McMurray test has a 97% specificity for meniscal damage. The Lachman test is 87% sensitive and 93% specific for anterior cruciate ligamentous injury. If a meniscal or ligamentous injury is suspected based on the physical examination, the patient should be referred to an orthopedic surgeon. The decision to order an MRI should generally be made by a specialist, rather than by the internist prior to referral.

Figure 13. Common knee maneuvers for assessing possible ligamentous and meniscal damage. (Top left) Anterior drawer test (anterior cruciate ligament): Place patient supine, flex the hip to 45 degrees and the knee to 90 degrees. Sit on the dorsum of the foot, wrap your hands around the hamstrings (ensuring that these muscles are relaxed), then pull and push the proximal part of the leg, testing the movement of the tibia on the femur. Do these maneuvers in three positions of tibial rotation: neutral, 30 degrees externally, and 30 degrees internally rotated. A normal test result is no more than 6 to 8 mm of laxity. (Top right) Lachman test (anterior cruciate ligament): Place patient supine on examining table, leg at the examiner’s side, slightly externally rotated and flexed (20-30 degrees). Stabilize the femur with one hand and apply pressure to the back of the knee with the other hand with the thumb of the hand exerting pressure placed on the joint line. A positive test result is movement of the knee with a soft or mushy end point. (Bottom left) Pivot test (anterior cruciate ligament): Fully extend the knee, rotate the foot internally. Apply a valgus stress while progressively flexing the knee, watching and feeling for translation of the tibia on the femur. (Bottom right) McMurray test (meniscus): Flex the hip and knee maximally. Apply a valgus (abduction) force to the knee while externally rotating the foot and passively extending the knee. An audible or palpable snap during extension suggests a tear of the medial

meniscus. For the lateral meniscus, apply a varus (adduction) stress during internal rotation of the foot and passive extension of the knee. Reproduced with permission from Jackson JL, O’Malley PG, Kroenke K. Evaluation of acute knee pain in primary care. Ann Intern Med. 2003;139(7):580. [PMID: 14530229] Copyright 2009, American College of Physicians.

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Patellofemoral Syndrome The most common cause of knee pain in patients younger than 45 years, especially in women, is the patellofemoral syndrome. The pain is peripatellar and exacerbated by overuse (such as running), descending stairs, or prolonged sitting. Diagnosis is confirmed by firmly compressing the patella against the femur and moving it up and down along the groove of the femur, reproducing pain or crepitation. The condition is self-limited; NSAIDs and minimizing highimpact activity improve symptoms.

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Bursitis Bursitis, which may result from either trauma or overuse, is characterized by local tenderness and burning pain. The pes anserine bursa is palpated on the medial side of the knee, approximately 6 cm below the joint line and at about the same level as the tibial tuberosity. Pes anserine bursitis cause medial pain that worsens with activity and at night. The prepatellar bursa sits directly over the patella; prepatellar bursitis is associated with anterior knee pain and swelling anterior to the patella and is often caused by trauma or repetitive kneeling. The suprapatellar bursa sits directly under the distal portion of the gastrocnemius muscle; suprapatellar bursitis can be confused with the pain associated with chondromalacia of the patella, given that the location of the pain is in the same general area. However, suprapatellar bursitis is very tender when the examiner presses above the patella on a passively extended leg. Treatment of knee bursitis may include rest, ice, NSAIDs, and corticosteroid injections.

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Iliotibial Band Syndrome Iliotibial band syndrome is a common cause of knife-like lateral knee pain that occurs with vigorous flexion-extension activities of the knee, such as running. It is treated conservatively with rest and stretching exercises.

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Baker Cyst In the popliteal fossa, Baker cysts can form from synovia because of arthritis or torn cartilage. A Baker cyst can be painful if it ruptures. Ultrasonography is useful for diagnosing a ruptured Baker cyst, as it may be confused with a deep venous thrombosis.

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Ankle and Foot Pain • • • •

Ankle Sprain Hind Foot Pain Midfoot Pain Forefoot Pain

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Ankle Sprain Eighty-five percent of ankle injuries are from inversion sprains. Grade I sprains have no evidence of ligamentous tear and carry an excellent prognosis. Grade II sprains involve partial tears and are accompanied by moderate pain and disability and some difficulty bearing weight. Grade III sprains involve complete rupture of ligaments with an inability to bear weight. Although the inability to bear weight is common with severe sprains, it also raises the suspicion of a fracture. Pain in other locations along with the ankle also raises the possibility of fracture. The age of the patient is important in assessment of ankle injuries because an epiphyseal injury may occur in younger bones. Examination of an injured ankle begins with noting any petechiae or ecchymoses around the joint (suggesting bleeding in the region of a torn ligament) and any swelling or obvious deformity. Pain elicited by the “squeeze test” (squeezing the tibia and fibula together at the distal calf) indicates rupture of the syndesmotic ligaments joining the two bones at their distal ends. A normal gait rules out fracture or severe sprain. The Ottawa ankle and foot rules (Figure 14) are a highly sensitive means of selecting appropriate patients for radiography. If a patient has none of the indications for radiography, the negative likelihood ratio of fracture is 0.08. Conservative treatment is recommended for ankle sprains. The Institute for Clinical Systems Improvement has developed an evidence-based guideline using the acronym PRICE: Protect against further injury with support; Rest and avoid activities that can exacerbate the injury; and control swelling by applying Ice, applying Compression, and Elevating the injured limb.

Evidence regarding the efficacy of a surgical versus a conservative approach to ligament tears is inconclusive.

Figure 14. Ottawa ankle and foot rules. An ankle radiographic series is indicated if a patient has pain in the malleolar zone and any of these findings: bone tenderness at A, bone tenderness at B, or inability to bear weight immediately and in the emergency department (or physician’s office). A foot radiographic series is indicated if a patient has pain in the midfoot zone and any of these findings: bone tenderness at C, bone tenderness at D, or inability to bear weight immediately and in the emergency department (or physician’s office). Reproduced with permission from Davis MF, Davis PF, Ross DS. ACP Expert Guide to Sports Medicine. Philadelphia, PA: American College of Physicians, 2005:404. Copyright 2009, American College of Physicians.

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Hind Foot Pain Plantar fasciitis is the most common cause of heel pain and is a major source of concern for runners. Symptoms are worse in the mornings. Diagnosis is based on demonstrating palpable tenderness at the anterior base of the calcaneus. Pain that is more posterior on the calcaneus may indicate a calcaneal stress fracture. The windlass test looks for pain in the plantar fascia by simulating the motion of a step. With the patient’s foot in a weight-bearing position, the toes are dorsiflexed by the examiner, maximally stretching the plantar fascia. When the windlass test

produces the foot pain, the diagnosis is almost certainly plantar fasciitis. Radiography adds little to the evaluation for plantar fasciitis (15% of foot radiographs for heel pain find a heel spur that is unrelated to the pain) unless alternative sources for the pain are being sought. Conservative treatment of plantar fasciitis includes arch supports, ice after exercise, morning massage, fascia stretching (rolling the foot over a tennis ball while sitting), and orthotic devices, although most patients improve eventually regardless of the therapy. Corticosteroid injection has been used with some efficacy; however, rupture of the plantar fascia may occur after injection in a small number (7%) of patients. Fat pad syndrome is a condition seen in older runners in which the natural fat pad overlying the calcaneus becomes thinned. Pain increases with prolonged exercise, distinguishing it from plantar fasciitis. Shoe inserts may cushion the impact of the foot. Achilles tendinitis presents with tenderness in runners. NSAIDs and rest are the first-line treatment. Achilles tendinitis usually resolves with conservative treatment within 2 weeks. Corticosteroid injections should be avoided so as not to precipitate Achilles tendon rupture. Fluoroquinolone antibiotics may also precipitate Achilles tendon ruptures, probably by potentiating the production of matrix metalloproteinases in tendons. While it is unusual for this tendon to rupture without heavy exertional stress, patients on corticosteroids and those who have been on fluoroquinolones can rupture an Achilles tendon with no more than low-level walking. Patients who undergo percutaneous surgical repair have less chance of re-rupture than patients with nonoperative treatment. However, in patients at higher surgical risks, a nonoperative approach with a cast or a functional brace is reasonable.

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Midfoot Pain The tarsal tunnel syndrome is a nerve entrapment condition that causes foot pain and paresthesias. Stretching the posterior tibial nerve by dorsiflexion of the toes and simultaneous eversion of the foot may replicate the pain. Treatment measures are similar to those for carpal tunnel syndrome. Tarsal and metatarsal bone fractures are rare, but do occur in high-impact sports. They require a high index of suspicion to diagnose and should be considered when presumed diagnoses are not responding to standard therapies.

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Forefoot Pain

Metatarsalgia is a painful condition, more frequent in athletes, in which the distal head of the metatarsal is tender and painful. It may be caused by poorly fitting footwear and usually responds to improved shoeware. Morton neuroma is an entrapment syndrome of the interdigital nerve, characterized by tenderness between the third and fourth metatarsals. Unilateral presentation is most common in patients with this condition, and women, usually in their fifth decade, are affected more often than men. Lateral compression of the forefoot can reproduce symptoms. Wider shoes and corticosteroid injection may help, but severe cases may only respond to surgery.

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Aldridge T. Diagnosing heel pain in adults [erratum in Am Fam Physician. 2006;73(5):776]. Am Fam Physician, 2004;70(2):332-338. [PMID:15291091]. See PubMed Bachmann LM, Kolb E, Koller MT, Steurer J, ter Riet G. Accuracy of Ottawa ankle rules to exclude fractures of the ankle and mid-foot: systematic review. BMJ. 2003;326(7386):417. [PMID:12595378]. See PubMed Childs JD, Fritz JM, Flynn TW, et al. A clinical prediction rule to identify patients with low back pain most likely to benefit from spinal manipulation: a validation study. Ann Intern Med. 2004;141(12): 920-928. [PMID:15611489]. See PubMed Chou R, Qaseem A, Snow V, et al; Clinical Efficacy Assessment Subcommittee of the American College of Physicians; American College of Physicians; American Pain Society Low Back Pain Guidelines Panel. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society [erratum in Ann Intern Med. 2008;148(3):247-248]. Ann Intern Med. 2007;147(7):478-491. [PMID:17909209]. See PubMed Gerritsen AA, de Vet HC, Scholten RJ, Bertelsmann FW, de Krom MC, Bouter LM. Splinting vs. surgery in the treatment of carpal tunnel syndrome: a randomized controlled trial. JAMA, 2002;288(10): 1245-1251. [PMID:12215131]. See PubMed Gross AR, Goldsmith C, Hoving JL, et al; Cervical Overview Group. Conservative management of mechanical neck disorders: a systematic review. J Rheumatol. 2007;34(5):1083-1102. [PMID:17295434]. See PubMed Hunt D, Clohisy J, Prather H. Acetabular labral tears of the hip in women. Phys Med Rehabil Clin N Am. 2007;18(3):497-520, ix-x. [PMID:17678764]. See PubMed Peat G, Thomas E, Duncan R, Wood L, Hay E, Croft P. Clinical classification criteria for knee osteoarthritis: performance in the general population and primary care. Ann Rheum Dis. 2006;65(10):1363-1367. [PMID:16627539]. See PubMed Sherman KJ, Cherkin DC, Erro J, Miglioretti DL, Deyo RA. Comparing yoga, exercise, and a self-care book for chronic low back pain: a randomized, controlled trial. Ann Intern Med 2005;143(120:849-856. [PMID:16365466]. See PubMed Trinh KV, Phillips SD, Ho E, Damasma K. Acupuncture for the alleviation of lateral epicondyle pain: a systematic review. Rheumatology (Oxford). 2004;43(9):1085-1090. [PMID:15213328]. See PubMed

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Hyperlipidemia • • •

Screening for Lipid Disorders Evaluation of Lipid Levels Management of Dyslipidemias


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Dietary intervention is always indicated for patients with dyslipidemia, with total fat limited to 25% to 35% of total calories and saturated fat to less than 7% of total calories. LDL cholesterol–lowering therapy is twice as effective for secondary prevention of cardiovascular disease compared with primary prevention. Statins are usually well tolerated but may cause myositis or rhabdomyolysis in elderly patients, those with comorbid illnesses, or those taking certain other medications, including fibrates and nicotinic acid. If initial therapy to lower LDL cholesterol fails to achieve lipid goals, combination therapy using moderate doses of statins and another drug is an alternative option to using maximum doses of statins. Treatment for hypertriglyceridemia is indicated for patients with non–HDL cholesterol that is 30 mg/dL (0.78 mmol/L) above the patient’s LDL cholesterol goal or with a triglyceride level above 500 mg/dL (5.65 mmol/L). Pharmacologic treatment for low HDL cholesterol is only indicated for patients with established coronary artery disease. Treating the elderly for hyperlipidemia requires an individualized approach; both primary and secondary prevention of cardiovascular disease should be considered in those with reasonable life expectancy and few comorbid illnesses.

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Screening for Lipid Disorders The standard screening test for lipid disorders is a lipid panel obtained after a 12-hour fast. Abnormal results are interpreted according to the number of risk factors present in the patient (see Routine Care of the Healthy Patient). Two samples should be obtained at least 1 week apart before making treatment decisions.

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Evaluation of Lipid Levels •

LDL Cholesterol

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Triglycerides HDL Cholesterol Nonstandard Lipid Risk Factors Metabolic Syndrome

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LDL Cholesterol Dyslipidemia (hyperlipidemia and/or low HDL cholesterol) is diagnosed when there are one or more lipid abnormalities found on a whole blood lipid panel after a 12-hour fast. Although a total cholesterol level above 200 mg/dL (5.18 mmol/L) is considered abnormal, therapy is targeted at the individual components of total cholesterol. LDL cholesterol is the major atherogenic lipoprotein and is the primary target for therapy. Elevations are primarily related to dietary and genetic factors. Secondary causes include hypothyroidism, obstructive liver disease, nephrotic syndrome, estrogen use, antipsychotic medications, and protease inhibitors (used to treat HIV disease). Individual LDL cholesterol goals are determined by the presence or absence of five major risk factors (Table 28). LDL cholesterol goals and therapy are provided in Table 29. The Adult Treatment Panel of the National Cholesterol Education Program (ATP III) recommends that patients with two or more risk factors whose LDL cholesterol is above 130 mg/dL (3.37 mmol/L) should be further stratified using the Framingham risk equation, which predicts the 10-year absolute risk of a major cardiovascular event, to determine treatment goals and options. (See http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof for an on-line Framingham risk calculator.) For patients at greatest risk (those with at least two major risk factors, such as coronary artery disease [CAD] and smoking, or CAD and diabetes mellitus), achieving an LDL cholesterol of less than 70 mg/dL (1.81 mmol/L) is considered an optional goal. Total cholesterol/HDL cholesterol ratio is a predictor of CAD risk but should not replace LDL cholesterol as the primary target of therapy.

Table 28. Major Risk Factors (Exclusive of LDL Cholesterol) Used To Individualize LDL Cholesterol Goals Cigarette smoking Hypertension (blood pressure ≥140/90 mm Hg or taking antihypertensive medication) Older age (men ≥45 y; women ≥55 y) Low HDL cholesterol (2 mg/dL [152.6 µmol/L]) Anemia (hemoglobin 30% High M protein (IgG >3.5 g/dL [35 g/L], IgA >2.0 g/dL [20 g/L], Bence-Jones proteinuria >1.0 g/24 h) Minor Criteria Bone marrow clonal plasma cells 10%-30% M-protein less than above

Lytic bone lesions Reduced normal immunoglobulins to 10 days per month) of acute headache medications, including analgesics, ergots, triptans, and opioids. In addition, more than half of all patients with chronic daily headache have sleep disturbance and mood disorders, such as depression and anxiety. The clinical features of the common disorders causing chronic daily headache are shown in Table 13. These disorders are classified (on the basis of the usual length of each headache episode) as long-lasting (4 hours or longer) and short-lasting (less than 4 hours) disorders. Chronic migraine and medication overuse headache overwhelmingly represent the most common and challenging of the chronic daily headache disorders in clinical practice. Chronic migraine (previously referred to as transformed migraine) is defined as headaches that occur on more than 15 days per month of which at least 8 headache days must meet the diagnosis of migraine without aura and/or respond to migraine-specific drugs (ergots or triptans). In general, patients with chronic migraine have headache 20 to 25 days per month, and almost all headaches meet the ICHD criteria for migraine without aura. The diagnoses of chronic migraine and medication overuse headache can be missed because patients may report only their most severe headaches. In addition, they may not report use of over-the-counter analgesics for headache that they do not consider to be migraine. Therefore, patients with migraine should be asked how many days in an average month they have a headache of any type and how many days in an average month they use any acute medication for headache. Medication overuse headache (previously referred to as rebound headache) is defined as daily or near-daily headache (at least 15 days per month) that occurs in patients with a primary headache disorder who frequently and regularly use symptomatic or acute medications, often in excessive amounts. Overuse is defined as the use of acute headache medications on more than 10 days per month (more than 15 days for simple analgesics, such as acetaminophen, or the use of two or more acute medications [for example, 7 days of a triptan and 9 days of a simple analgesic agent]). The most frequently overused acute headache medications include analgesics, opioids, ergotamine, and triptans. Patients who overuse triptans develop overuse headache faster but respond more quickly and more completely to withdrawal than do patients who overuse opioids or combination analgesics, especially those that contain butalbital, caffeine, and acetaminophen. Moreover, the relapse rate in patients who overuse triptans is significantly lower than that of patients overusing opioids and combination analgesics. Patients with migraine, especially those with several attacks per month, should be cautioned about the risk of medication overuse headache and advised to limit acute medication use to no more than 2 days per week. Although it is often difficult to be certain whether the overuse of

acute headache medication is the cause or the consequence of the daily headache disorder, accurate diagnosis and management require the withdrawal of overused headache medications in all patients. Medication overuse headache and chronic migraine are managed similarly, with the obvious exception of the need to discontinue the overuse of acute medications in medication overuse headache (Table 14). Most patients can be managed as outpatients, except for those in whom the overuse of opioids or butalbital-containing analgesics is excessive, which makes outpatient withdrawal unsafe because of the risk of withdrawal syndromes and seizures. Patients in this population should, in general, be referred to a headache medicine specialist.

Table 13. Primary Chronic Daily Headache Disorders Disorder

Clinical Features

Recommended Treatments Chronic Migraine with or without aura on >15 days per month Approved medications for migraine for >3 months episodic migraine (propranolol, topiramate, valproic acid) Mild to moderate severity; no migraine symptoms; Amitriptyline Chronic tension-type bilateral headache New daily Bilateral, persistent, moderately severe; may be Amitriptyline persistent preceded by viral infection; may resemble migraine or headache tension-type headache Indomethacin Hemicrania Rare, unilaterally constant exacerbations of severe continua headache, cranial autonomic symptoms, and “ice-pick” pain; completely responsive to indomethacin Cluster Cluster periods of 4-8 weeks, 1-3 times per year; daily Verapamil, prednisone, headache headaches, frequently nocturnal, occurring 1-8 times gabapentin; acute: per day, each lasting about 1 hour on average; sumatriptan by NS or SC extremely severe, mostly periorbital/temporal, and injection; zolmitriptan by associated with motor restlessness and autonomic NS; 100% oxygen symptoms (tearing, rhinorrhea) Hypnic Occurs daily but only during sleep; moderately severe; Caffeine; lithium; headache often bilateral; lasts about 1 hour; not associated with indomethacin autonomic symptoms Paroxysmal Headaches identical to cluster headache except that Indomethacin hemicrania attacks occur more frequently (>5 and up to 24 per day) and are shorter in duration (8-25 min); usually completely responsive to indomethacin SUNCT Headaches resemble cluster and paroxysmal Lamotrigine, gabapentin, syndrome hemicranias except that attacks occur more frequently topiramate, (30-100 per day) and are much shorter in duration (20- carbamazepine

120 seconds). These headaches may be mistaken for trigeminal neuralgia except that patients have strictly periorbital (cranial nerve V1) pain and cranial autonomic symptoms. Note: Secondary causes require careful consideration and exclusion. These include medication overuse headache, cervicogenic headache, intracranial hypertension or hypotension, intracranial infection (meningitis or sinusitis), space-occupying lesions, posttraumatic headache, arterial dissection, venous sinus thrombosis, and giant-cell arteritis. NS = nasal spray; SC = subcutaneous; SUNCT = short lasting unilateral neuralgiform pain with conjunctival injection and tearing. Source: Dodick DW. Clinical practice. Chronic daily headache [erratum in N Engl J Med. 2006;354(8):884]. N Engl J Med. 2006;354(2):160. [PMID: 16407511]

Table 14. Treatment of Chronic Migraine and Medication Overuse Headache Education, support, and close follow-up for 8 to 12 weeks Lifestyle modifications (quitting smoking, eliminating caffeine, exercising, eating regular meals, and establishing a regular sleep schedule) Behavioral therapy (relaxation therapy, biofeedback, cognitive behavioral therapy) Abrupt withdrawal of overused medications for acute headache, except barbiturates or opioidsa Standard acute headache treatment (for moderate or severe headache; such therapy is generally not associated with medication overuse headache) NSAIDs (such as naproxen sodium, 550 mg) Dihydroergotamine (1 mg intranasally, subcutaneously, or intramuscularly) Antiemetics (metoclopramide, 10-20 mg; prochlorperazine, 10 mg) Preventive therapy Topiramate, 50-100 mg twice daily Valproic acid, 250-500 mg twice daily Amitriptyline, 50-100 mg at bedtime a

For butalbital overuse, taper the drug over a period of 2 to 4 weeks; if there is concern about the possibility of withdrawal syndrome, provide a tapering course of phenobarbital (30 mg twice daily for 2 weeks, followed by 15 mg twice daily for 2 weeks). For opioid overuse, taper the drug over a period of 2 to 4 weeks; if there is concern about the possibility of withdrawal syndrome, provide clonidine (transdermal therapeutic system patch for 1 to 2 weeks). Source: Dodick DW. Clinical practice. Chronic daily headache [erratum in N Engl J Med. 2006;354(8):884]. N Engl J Med. 2006;354(2):163. [PMID: 16407511]

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Cluster Headache and Other Trigeminal Autonomic Cephalalgias The trigeminal autonomic cephalalgias are a group of primary headache disorders characterized by excruciating unilateral headache that occurs in association with prominent cranial autonomic features such as lacrimation, nasal congestion, rhinorrhea, and conjunctival injection. These disorders include cluster headache, paroxysmal hemicrania, and Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT) syndrome. The trigeminal autonomic cephalalgias differ in duration and frequency of episodes and in their response to therapy. Cluster headache lasts longest (mean duration, 1 hour), has relatively low episode frequency (one to three per day), and responds best to verapamil. Paroxysmal hemicrania has an intermediate duration (mean, 15 minutes), has an intermediate episode frequency (mean, 11 per day), and responds best to indomethacin. SUNCT syndrome has the shortest duration (mean, 60 seconds), has the highest frequency (30 to 200 per day), and may respond best to lamotrigine (although controlled trials are lacking). It is important to recognize these syndromes because of their highly selective response to treatment. Cluster headache is the most common trigeminal cephalalgia and is three times more common in men than in women. Guidelines for the treatment of cluster headache and other trigeminal autonomic cephalalgias have been recently developed (Table 15). Treatment usually consists of a transitional therapy for 1 or 2 weeks to rapidly suppress episodes and preventive treatment, which may take 1 to 2 weeks to become effective but is then usually maintained for at least 2 weeks beyond the usual duration of a cluster episode. Cluster episodes usually last 6 to 8 weeks and remission periods usually last 2 to 6 months, but the duration of episodes and remission varies greatly among patients. In patients with chronic cluster headache, which occurs in up to 20% of patients, remission does not last more than 1 month. Typically, a brief course of oral corticosteroids (1 to 3 weeks) or an occipital nerve block is started in conjunction with verapamil as the preventive drug of choice. Oxygen delivered by face mask at 7 to 15 L/min or subcutaneous sumatriptan are first-line acute treatments for breakthrough attacks.

Table 15. Treatment Guidelines for the Trigeminal Autonomic Cephalalgias Cluster Headache Therapy Acute 100% oxygen, 15 L/min (A)

Treatment of Choice Paroxysmal Hemicrania SUNCT Syndrome None None

Sumatriptan, 6 mg subcutaneously (A) Sumatriptan, 20 mg nasally (A) Zolmitriptan, 5 mg nasally (A/B) Zolmitriptan, 10 mg nasally (A/B) Zolmitriptan, 5 mg orally (B) Zolmitriptan, 10 mg orally (B) Lidocaine intranasally (B) Octreotide (B) Preventive Verapamil (A)

Indomethacin (A)

Corticosteroids (A)

Verapamil (C)

Lithium carbonate (B)

NSAIDs (C)

Lamotrigine (C)

Methysergide (B) Topiramate (B) Ergotamine tartrate (B) Valproic acid (C) Melatonin (C) Baclofen (C) A = effective; B = probably effective; C = possibly effective; SUNCT = short lasting unilateral neuralgiform pain with conjunctival injection and tearing.

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Trigeminal Neuralgia Trigeminal neuralgia is a unilateral condition characterized by brief episodes of lancinating pain in the distribution of one or more divisions of the trigeminal nerve, invariably V2 and/or V3. The pain is excruciating and often described as sudden, sharp, superficial, and stabbing or burning in

quality. The pain is paroxysmal and usually lasts 2 to 3 seconds and may occur in volleys of jabs or stabs of pain. The paroxysms are often punctuated by pain-free periods lasting seconds to hours. Characteristically, the painful episodes are associated with trigger zones, particularly around the mouth and nostrils, and the pain may be triggered by trivial stimuli, such as wind on the face, brushing the teeth, shaving, chewing, or even talking. Although most cases are idiopathic, there are features that may suggest a secondary cause. Pain that spreads to involve the ear, occiput, neck, or chest is likely the result of another cause. Bilateral pain is invariably associated with a secondary cause, such as nasopharyngeal carcinoma, leptomeningeal carcinomatosis, brainstem lesion, or connective tissue disease (such as Sjögren syndrome). Although a dull aching discomfort may persist for several hours following an especially long or intense episode of pain, suspicion of a secondary cause should arise when chronic continuous pain is present or when sensory symptoms, such as paresthesia or numbness, are present. Because more than 90% of patients present after age 40 years, a diagnosis in a younger patient should prompt an extensive evaluation for secondary causes, such as multiple sclerosis, posterior fossa tumors, and vascular or aneurysmal compression of the trigeminal nerve. Up to 10% of patients with trigeminal neuralgia may harbor an intracranial lesion; therefore, an MRI should be obtained for every patient with trigeminal neuralgia, even those who respond to medication and whose examination findings are normal. Spontaneous remissions are the rule in trigeminal neuralgia. More than 50% of affected patients have a remission of at least 6 months. Therefore, after approximately 8 weeks of successful therapy with complete remission of pain, a slow drug taper over a similar time period may be considered. All medications should be started at a low dosage and titrated slowly until the desired effect is achieved or dose-limiting side effects occur. Monotherapy is a treatment goal, but in some patients, combination therapy with two drugs used in smaller dosages may be more effective and better tolerated. The drug of first choice is carbamazepine or oxcarbazepine, but caution must be exercised in the use of these drugs in patients of Asian origin. Oxcarbazepine may be preferred because carbamazepine may cause hematologic and hepatic toxicity, although both drugs may cause symptomatic hyponatremia. Serum sodium concentration should be monitored during treatment with either of these medications. Other potentially useful medications include gabapentin, clonazepam, lamotrigine, baclofen, valproic acid, and phenytoin. Approximately 30% of patients with trigeminal neuralgia do not respond to medical therapy and may require a surgical or ablative procedure. Microvascular decompression is the definitive procedure for idiopathic trigeminal neuralgia, but it is often reserved for intractable cases because of the need for a craniotomy. MRI of the head with high-resolution images of the posterior fossa obtained to evaluate for vascular compression of the trigeminal nerve is recommended before surgery. The procedure involves an occipital craniotomy and separation of the trigeminal nerve from a juxtaposed or adherent vessel using a synthetic material. The success rate is approximately 90%. Other procedures involve ablation of the trigeminal nerve or root with either radiation (gamma knife) or a percutaneous radiofrequency lesion; balloon

compression; or glycerol injection of the trigeminal ganglion at the skull base. Each procedure has similar long-term success rates (60% to 85%), but facial sensory loss may occur; corneal anesthesia, anesthesia dolorosa (severe spontaneous pain occurring in an anesthetic zone), dysesthesias, and masseter muscle weakness can also occur.

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Headaches Due to Disorders of Intracranial Pressure or Volume • •

Orthostatic Headache Idiopathic Intracranial Hypertension (Pseudotumor Cerebri)

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Orthostatic Headache Spontaneous leak of cerebrospinal fluid (CSF) may cause orthostatic headache, which mimics the headache that occurs after a traumatic lumbar puncture. Many patients report a history of trivial trauma, which might have started a leak, especially in patients with an inherited connective tissue disorder or weakened and attenuated dura or meningeal diverticula. Headache is the main clinical feature of a CSF leak. It is typically an orthostatic headache that is present when the patient is upright and relieved when the patient is supine. In some patients, the orthostatic features may diminish over weeks or months, and the headache may become chronic, daily, and continuous. Muffled hearing is common, and some patients may experience cranial nerve palsies, stupor, encephalopathy, parkinsonism, ataxia, and bulbar weakness, most likely due to sagging of the brain within the cranial vault. Although most patients with CSF leak have reduced pressure on lumbar puncture, the opening pressure may be normal in up to one third of these patients. The CSF protein concentration is often normal or less than 100 mg/dL (1000 mg/L), but it may be as high as 1000 mg/dL (10,000 mg/L). The erythrocyte and leukocyte counts may be normal or as high as 200/µL (200 × 106/L). An MRI with gadolinium may show diffuse, homogeneous, pachymeningeal thickening and enhancement; engorgement of the dural venous sinuses; enlargement and enhancement of the pituitary gland; and evidence of “brain sag,” including subdural fluid collections, buckling of the optic chiasm, compression of the midbrain, crowding of the posterior fossa, and descent of the cerebellar tonsils, mimicking a Chiari malformation (Figure 13). In patients in whom the disorder is suspected but the imaging and CSF findings are absent, indium-111–labeled isotope cisternography may show the presence of a leak. CT myelography is the most sensitive diagnostic test for determining the location of the leak.

Conservative treatment, including bed rest and hydration, is effective for many patients. If symptoms persist, an autologous epidural blood patch is the treatment of choice, which involves withdrawing a 15- to 40-mL sample of the patient’s own blood, inserting a spinal needle into the epidural space, and injecting the blood slowly over minutes because some patients may develop radicular or back pain with more rapid injections. In the few patients who do not respond to the first epidural blood patch, a second blood patch is usually effective. Some patients may require up to six blood patches before complete relief is obtained. Autologous blood patches may be effective when delivered at the lumbar epidural space, even when the leak is at the level of the thoracic or cervical spine. In unusually refractory cases, an autologous blood patch and/or CTguided injections of fibrin glue at the site of the leak may be effective. In rare cases, open surgical repair may be necessary.

Figure 13. Coronal gadolinium-enhanced MRI of the brain. Coronal T1-weighted MRI with gadolinium showing the smooth and continuous enhancement of the dura mater over the supratentorial pachymeninges (A arrow) and tentorium cerebelli (B arrow) in a patient with low cerebrospinal fluid (CSF) pressure secondary to a spinal CSF leak.

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Idiopathic Intracranial Hypertension (Pseudotumor Cerebri) Idiopathic intracranial hypertension is primarily a disorder of young obese women. The diagnosis rests on documenting elevated CSF opening pressure (>250 mm H2O) during lumbar puncture measured in the lateral decubitus position, normal CSF composition, and normal mental status, as well as on evidence from MRI and venography of the brain and dural venous sinuses. Other factors associated with increased intracranial pressure include systemic retinoid therapy, tetracyclines, a subdermal implant of levonorgestrel (Norplant®), corticosteroid withdrawal, human growth hormone, cerebral venous sinus thrombosis, mastoiditis, Behçet disease, renal failure, and obstructive sleep apnea. Intracranial hypertension may develop during pregnancy, although pregnancy is not an independent risk factor for the disorder. The onset of idiopathic intracranial hypertension in the peripartum period or after fetal loss should prompt an evaluation for cerebral venous sinus thrombosis. The most common presenting symptom of idiopathic intracranial hypertension is headache, which occurs in more than 90% of patients. Photophobia, blurred vision, diplopia, and visual field loss commonly accompany the headache. Transient visual obscurations are also common and are described as partial or complete episodes of visual loss lasting seconds to minutes, are often precipitated by rising from a stooped position or rolling the eyes, and reflect brief episodes of optic nerve head ischemia caused by papilledema. Visual loss may be acute and dramatic, leading to profound visual loss or blindness. Pulsatile tinnitus occurs in 60% of patients and is often described as “hearing my heartbeat in my head” or a whooshing sound in one or both ears. The hallmark of idiopathic intracranial hypertension is papilledema that may be asymmetric and, rarely, unilateral. Mild papilledema may be difficult to discern with the direct ophthalmoscope; stereoscopic viewing with indirect ophthalmoscopy or slit lamp bimicroscopy is helpful to detect subtle disc edema. The treatment of idiopathic intracranial hypertension is generally coordinated by a neurologist (or neuro-ophthalmologist) and an ophthalmologist. The goals of treatment are to preserve vision and to alleviate symptoms. All treatment recommendations are based on case series and clinical experience. Asymptomatic patients with mild papilledema may be followed closely without specific treatment. Weight loss is generally advised for obese patients but is not always successful in reducing intracranial pressure or alleviating symptoms. Acetazolamide is the most common medication used; side effects include paresthesias, taste perversion, somnolence, and depression. Rare but serious side effects are hypersensitivity reaction, renal stones, and aplastic

anemia. Furosemide therapy may also lower intracranial pressure, but the patient must be monitored to prevent dehydration and hypokalemia. Topiramate, which is commonly used for migraine prevention, is associated with weight loss and may be useful as treatment of idiopathic intracranial hypertension, especially because migraine and tension-type headaches commonly occur in such patients. Corticosteroid therapy should be avoided because it causes weight gain and fluid retention and may cause rebound intracranial hypertension as therapy is withdrawn. Surgery may be indicated when severe optic neuropathy is present early in the course of the illness, when there is rapid deterioration of vision, or when other forms of therapy fail to prevent visual loss. Surgery is not recommended for the treatment of headaches alone. Optic nerve sheath fenestration generally stabilizes or improves vision and sometimes relieves headaches; risks include transient or permanent visual loss, diplopia, and infection. Shunts (ventriculoperitoneal or lumboperitoneal) lower intracranial pressure and may spare vision and relieve headache, but they have a very high failure rate, with over half of patients ultimately requiring one or more revisions. Other complications of shunting include low CSF pressure, infection, obstruction, and migration of the shunt catheter. Patients with a sudden decline in vision often have an ischemic component to their visual loss and may fail to improve even after aggressive medical and surgical intervention.

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Thunderclap Headache A thunderclap headache is a severe and explosive headache that is maximal in intensity at or within 60 seconds of onset. Every thunderclap headache must be immediately evaluated to detect potentially catastrophic conditions, especially subarachnoid hemorrhage. An underlying disorder, most commonly vascular, is detected in 30% to 80% of patients. Thunderclap headache may occur in isolation, may be recurrent over days to weeks, and may begin spontaneously or be triggered by Valsalva maneuvers, physical effort, or sexual intercourse. CT of the head without enhancement is the most sensitive test for subarachnoid hemorrhage. A lumbar puncture is necessary if CT scan results are normal. If results of both the CT scan and lumbar puncture are normal, the patient still requires urgent investigation for other serious neurologic causes of thunderclap headache, including cerebral venous sinus thrombosis, arterial dissection, unruptured intracranial aneurysm, and reversible cerebral vasoconstriction. Therefore, neurovascular imaging is indicated in these patients and should include magnetic resonance or CT angiography (or venography). If all investigations are negative, the patient may have primary (idiopathic) thunderclap headache or another primary headache disorder, such as primary sexual headache.

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Boes CJ, Swanson JW. Paroxysmal hemicrania, SUNCT, and hemicrania continua. Semin Neurol. 2006;26(2):260-270. [PMID:16628536]. See PubMed

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Dodick DW. Clinical practice. Chronic daily headache [erratum in N Engl J Med. 2006;354(8):884]. N Engl J Med. 2006;354(2):158-165. [PMID:16407511]. See PubMed Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004(24 Suppl 1):9-160. [PMID:14979299]. See PubMed Kurth T, Slomke MA, Kase CS, et al. Migraine, headache, and the risk of stroke in women: a prospective study. Neurology. 2005; 64(6):1020-1026. [PMID:15781820]. See PubMed May A, Leone M, Afra J, et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol. 2006;13(10):1066-1077. [PMID:16987158]. See PubMed Practice parameter: the utility of neuroimaging in the evaluation of headache in patients with normal neurologic examinations (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1994;44(7):1353-1354. [PMID:8035948]. See PubMed Schwedt TJ, Matharu MS, Dodick DW. Thunderclap headache. Lancet Neurol. 2006;5(7):621-631. [PMID:16781992]. See PubMed

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Head Injury • • • • •

Concussive Head Injury Subdural Hematomas Imaging in Traumatic Brain Injury Concussive Head Injury and Traumatic Brain Injury in an Elderly Population Concussive Head Injury and Traumatic Brain Injury in the Military

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All athletes with a grade-2 or grade-3 concussion should not return to play during the sporting event. For athletes with a grade-2 or grade-3 concussion, the American Academy of Neurology recommends a neurologic evaluation and a minimum of 1 week away from competitive play. For athletes with a grade-2 or grade-3 concussion, the American College of Sports Medicine states that return to play on the same day is contraindicated if any loss of consciousness, posttraumatic amnesia, or retrograde amnesia has occurred. All patients with traumatic head injury who have a hemorrhagic diathesis or are on anticoagulation should undergo noncontrast CT of the head. Noncontrast CT head imaging should be performed in persons who experience traumatic head injury if they have a persistent headache (>72 hours); if there is a change in their level of consciousness, awareness, or behavior; or if focal or lateralizing neurologic symptoms or signs develop.

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Concussive Head Injury A concussion is a trauma-induced alteration in mental status that is sometimes associated with a loss of consciousness. Confusion and amnesia, the hallmarks of concussion, can occur immediately after a blow to the head or several minutes later. The most frequently observed symptoms of patients with concussion are listed in Table 16.

Table 16. Symptoms of Concussion Onset of Concussion Symptoms After Injury Early (Minutes and Hours Later) Late (Days to Weeks Later) Headache Persistent low-grade headache Dizziness or vertigo Light-headedness Lack of awareness of surroundings Poor attention and concentration Nausea or vomiting Memory dysfunction Easy fatigability Irritability and low tolerance of frustration Intolerance of bright lights or difficulty focusing vision Intolerance of loud noises, sometimes with ringing in the ears Anxiety and/or depressed mood Sleep disturbance

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Grades of Concussion Because internists may frequently encounter symptoms of concussive head injury in patients (for example, in young athletes), they must be able to determine the seriousness of the injury. The usefulness of a grading scale to determine concussion severity has been well established in sports medicine, and several groups have developed guidelines. For example, the American Academy of Neurology has established a practice parameter for the management of concussion in sports that uses the following grading scale:

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Grade 1: The most common yet most difficult form of concussion to recognize. An affected athlete is not rendered unconscious and has only momentary confusion (for example, inattention, poor concentration, or an inability to process information or sequence tasks) or mental status alterations (colloquially referred to as having been “dinged” or having one’s “bell rung”). Grade 2: No loss of consciousness, but an affected athlete experiences symptoms or exhibits signs of concussion or mental status abnormalities (such as poor concentration or posttraumatic amnesia) on examination that last longer than 15 minutes. Any persistent grade-2 symptoms (lasting longer than 1 hour) warrant medical observation. Grade 3: Any loss of consciousness, either brief (seconds) or prolonged (minutes).

Although originally designed for subjects with sports-related injuries, this scale can and is used to grade all concussive head injuries, regardless of how the trauma occurred.

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Returning to Play or Work in Patients with Concussive Head Injury There is general agreement that all athletes who sustain a concussion, regardless of grade, require an on-site evaluation and should not return to play during the sporting event. The American Academy of Neurology further states that all athletes with grade-2 or grade-3 concussions also require a neurologic evaluation and recommends a period away from competitive play for a minimum of 1 week. Multidisciplinary consensus recommendations from the American College of Sports Medicine similarly indicate that the athlete be asymptomatic at rest before resuming any exertional activity and complete a progressive aerobic and resistance exercise challenge before full return to play; return to play on the same day is contraindicated if any loss of consciousness, posttraumatic amnesia, or retrograde amnesia has occurred. Although some controversy and a lack of evidence exist about same-day return to play in athletes with lesserseverity grade-2 injuries whose symptoms have fully resolved or are persistently mild, the American College of Sports Medicine indicates that the duration and severity of symptoms are the determining factors and that the safest course of action is to disallow same-day return to play when in doubt about subjects with a grade-2 concussion. Guidelines for determining when an athlete may return to play after a concussive headache injury are based on the grade of the concussion (Table 17). These guidelines should be closely followed in practice and can be applied in nonathletes as return-to-work recommendations, especially because one of the most frequent and disabling symptoms after a concussive head injury is cognitive impairment.

Table 17. American Academy of Neurology Guidelines on When to Return to Play or Work After a Concussion

Grade of Concussion Single or multiple grade-1 concussions Grade-2 concussion Multiple grade-2 concussions Grade-3 concussion with brief (seconds) loss of consciousness Grade-3 concussion with prolonged (minutes) loss of consciousness Multiple grade-3 concussions

a

Time Until Return to Play or Worka 1 week 1 week 2 weeks 1 week 2 weeks 1 month or longer, based on the clinical determination of the evaluating physician

Only if asymptomatic, with a normal neurologic assessment at rest and with exercise.

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Subdural Hematomas Acute subdural hematomas usually occur after severe, high-impact head trauma and may be associated with contusions of adjacent brain tissue. At presentation, patients with subdural hematomas typically have symptoms of headache, an altered level of awareness or consciousness, and/or focal neurologic symptoms and signs, which may be transient or persistent. Neurosurgical consultation should be available in the event of an acute intracranial hemorrhage. Chronic subdural hematomas may occur as a result of the gradual accumulation of liquefied hematoma over weeks or months. Chronic subdural hematomas occur after mild or seemingly trivial head trauma, which the patient may not even recall. Affected patients have the same symptoms as those with acute subdural hematoma, but the symptoms are more gradual in onset and more indolent in their progression. Neurosurgical drainage of the hematoma may be required because the hemorrhage, which has collected over weeks, behaves as a mass with displacement and mass effect on adjacent brain structures.

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Imaging in Traumatic Brain Injury The imaging modality of choice in patients who have experienced a traumatic brain injury is CT of the head. CT scans are very sensitive for detecting acute intracranial hemorrhage and skull fractures. Patients with symptoms of a subdural hematoma must undergo urgent imaging with noncontrast CT. All patients with traumatic brain injury who are on anticoagulation or have a

hemorrhagic diathesis (such as those with severe hepatic disease) should undergo imaging. In addition, patients who experience persistent headache (>72 hours); a change in the level of behavior, consciousness, or alertness; or focal or lateralizing neurologic symptoms or signs should undergo emergent CT without contrast.

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Concussive Head Injury and Traumatic Brain Injury in an Elderly Population Concussive head injury and mild traumatic brain injury are common in elderly patients because of the dysequilibrium that occurs as a result of age and because of other diseases that affect spatial orientation and gait. Such diseases are more common in elderly persons, particularly vestibular disorders (such as benign paroxysmal positional vertigo) and neurodegenerative diseases. Because of age-related brain atrophy, subdural hematomas can occur more commonly in elderly persons with a head injury, most likely because of traction on bridging dural veins. Additionally, anticoagulation with warfarin or antiplatelet therapy, which is very common in elderly persons because of the increasing prevalence of cardiovascular risk factors and disease, increases the risk of intracranial hemorrhage, particularly subdural hematomas.

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Concussive Head Injury and Traumatic Brain Injury in the Military Head and neck injuries, including severe brain trauma, have been reported in one quarter of service members who have been evacuated from Iraq and Afghanistan, and traumatic brain injury has been labeled a signature injury of these wars. Nearly 15% of these soldiers have reported an injury during deployment that involved loss of consciousness or altered mental status. Soldiers with mild traumatic brain injury are significantly more likely to experience physical and mental health problems and to report poor general health, headache, missed days at work, medical visits, and more somatic and postconcussive symptoms, including mood alteration and cognitive impairment. Those with more serious traumatic brain injury with loss of consciousness are more likely to have symptoms of posttraumatic stress disorder and depression. The high prevalence of traumatic brain injury, somatic symptoms, affective disorders, and significant disability emphasizes the need for aggressive, multidisciplinary care of these patients.

Bibliography •

Concussion (mild traumatic brain injury) and the team physician: a consensus statement. Med Sci Sports Exerc. 2006;38(2):395-399. [PMID:16531912]. See PubMed

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Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med. 2008;358(5):453-463. [PMID:18234750]. See PubMed Practice parameter: the management of concussion in sports (summary statement). Report of the Quality Standards Subcommittee. Neurology. 1997;48(3):581-585. [PMID:9065530]. See PubMed

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Movement Disorders • • • • • • • • •

Approach to the Patient with a Movement Disorder Evaluation of the Patient with Gait Unsteadiness Cerebellar Ataxia Parkinson Disease Other Parkinsonism Disorders Essential Tremor Dystonia Chorea Restless Legs Syndrome and Periodic Limb Movements of Sleep

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Ischemic or hemorrhagic stroke in the brain stem, cerebellum, or thalamus can cause a cerebellar ataxia that affects the extremities, speech, and gait. Wernicke encephalopathy can occur in persons who have alcoholism, have undergone bariatric surgery, had a prolonged period of fasting, had repeated episodes of vomiting, or have been on prolonged parenteral nutrition without adequate vitamin supplementation Immediate treatment with parenteral thiamine can prevent irreversible neurologic dysfunction in persons with Wernicke encephalopathy. The cardinal clinical features of Parkinson disease are a resting tremor, bradykinesia, rigidity, and postural instability; early falls, rapid progression, poor or waning response to levodopa, dementia, early autonomic failure, and ataxia suggest other disorders. The tremor, bradykinesia, and rigidity of Parkinson disease are characteristically asymmetric. Levodopa is the drug of choice to treat Parkinson disease in older patients, whereas dopamine agonists are often used first in patients younger than 65 years. Patients with Parkinson disease who have disabling dyskinesias on levodopa monotherapy may benefit from the addition of a dopamine agonist. Approximately 60% of patients with Parkinson disease develop psychiatric symptoms, and more than 60% develop a sleep disorder. Neuroleptic medications are frequently associated with drug-induced parkinsonism. Multiple system atrophy is a heterogeneous degenerative disorder that can be associated with parkinsonism, ataxia, and autonomic nervous system impairment.

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Essential tremor is distinguished from Parkinson disease by the lack of rigidity, bradykinesia, postural instability, and resting tremor; approximately 50% to 70% of patients have a family history of the disorder. Propranolol and primidone are first-line agents when essential tremor interferes with activities of daily living or causes psychological distress. Botulinum toxin therapy has been reported to be beneficial in 60% to 85% of patients with cervical dystonia and is the treatment of choice. Restless legs syndrome may be familial or associated with pregnancy, end-stage renal disease, iron deficiency anemia, or peripheral neuropathy. Dopamine agonists, such as ropinirole and pramipexole, are first-line agents used to treat daily symptoms of restless legs syndrome.

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Approach to the Patient with a Movement Disorder A careful neurologic history and thorough neurologic examination are essential in the correct identification of a movement disorder. These disorders are diagnosed primarily by their clinical features. General categories of abnormal movements include tremor, dystonia, chorea, ataxia, myoclonus, and parkinsonism. Recognition of the presence (and absence) of these movements allows the practitioner to arrive at a specific clinical diagnosis. Tremor refers to the rhythmic oscillation of a body part. Tremor frequency, distribution, and presence at rest, with movement, or with sustained posture should be noted. A unilateral, lowfrequency resting tremor is typical of Parkinson disease, whereas a bilateral, high-frequency, kinetic, and postural tremor (with both limb movement and sustained posture) is typical of essential tremor. Dystonia is characterized by the sustained contraction of agonist and antagonist muscles; can be generalized, focal, or segmental; and can involve virtually any body part. Chorea refers to brief, irregular, nonstereotypical, nonrhythmic movements and can involve the extremities, head, trunk, and face. Cerebellar ataxia is characterized by impaired initiation and coordination of movements and can involve speech, gait, and the extremities. Myoclonus refers to abnormal lightning-like jerking extremity movements. Parkinsonism refers to a set of clinical features that include rigidity, resting tremor, bradykinesia, and postural instability. This term is generally used to describe such clinical features in either a patient with an established secondary cause (such as drug-induced parkinsonism) or a patient with an unknown condition causing the symptoms. Many of the diseases discussed in this section can be associated with parkinsonism. Parkinson disease is a specific clinical parkinsonian disorder characterized by its distinct clinical and pathologic features and by its robust therapeutic response to dopaminergic medication.

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Evaluation of the Patient with Gait Unsteadiness Gait unsteadiness is a common symptom, particularly in elderly persons. Because many conditions affect gait in characteristic patterns, careful observation can permit the identification of an underlying neurologic disorder. Gait analysis should ideally occur over a distance of 20 or more feet. Many different systems are involved in the control of posture and ambulation. The musculoskeletal system provides mechanical stability and, if perturbed, can cause pain, weakness, and gait unsteadiness. Maintenance of an upright posture is dependent on postural reflexes and a dynamic interplay of visual, vestibular, and somatosensory systems. Impairment in any of these systems can result in postural and gait instability. Impairment in proprioception (joint position sense) or a positive Romberg sign suggests somatosensory impairment. A history of vertigo (the illusion of self- or environmental motion) can suggest vestibular impairment. Recognition of the clinical features of the major gait disorders is helpful. The spastic gait pattern found in patients with corticospinal tract problems is characterized by circumduction of the involved leg such that the stiffly extended knee is swung laterally and forward from the hip, which often results in dragging the foot on the ground. Cerebellar ataxia is recognized by a widebased stance and lurching, irregular steps that are worse with turning. Patients with a sensory ataxia adopt a wide-based stance and may have a foot slap. The akinetic rigid (parkinsonian) gait is characterized by poor initiation of gait, freezing or complete cessation of gait, postural instability, and a slow, shuffling gait pattern.

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Cerebellar Ataxia • • •

Approach to the Patient with Ataxia Acquired Ataxic Disorders Inherited Ataxias

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Approach to the Patient with Ataxia Ataxic disorders can affect posture, gait, the extremities, and speech and can manifest as gait unsteadiness, extremity incoordination, and slurred speech. Because many acquired and hereditary disorders can cause cerebellar ataxia, a thoughtful approach based on the mode and timing of symptom onset is necessary to guide diagnostic evaluation (Table 18). Symptom distribution is also an important consideration. Unilateral ataxia suggests a structural cause due to stroke, tumor, or demyelinating disease. Chronic alcohol abuse can result in gait

unsteadiness due to truncal and leg ataxia, with the arms left unaffected. Identification of involvement of other neurologic systems can suggest particular conditions. A history of rapidly progressive ataxia in conjunction with signs of progressive cognitive dysfunction most typically indicates Creutzfeldt-Jakob disease or a paraneoplastic disorder. The presence of parkinsonism or dysautonomia in a patient with chronic, progressive cerebellar ataxia suggests multiple system atrophy. The primary inherited cerebellar ataxic disorders in adults include spinocerebellar ataxia, Friedreich ataxia, and fragile X tremor ataxia syndrome.

Table 18. Approach to Ataxia Based on Mode of Onset Acute Onset Ischemic stroke of the cerebellum, brain stem Hemorrhagic stroke of the cerebellum, brain stem Medication induced Subacute Onset Thiamine deficiency Multiple sclerosis Hydrocephalus Posterior fossa tumor Posterior fossa abscess Paraneoplastic disorder Toxins Miller-Fisher form of Guillain-Barré syndrome Chronic Progressive Primary progressive multiple sclerosis Alcoholic cerebellar degeneration Paraneoplastic disorder Hydrocephalus Vitamin E deficiency Hypothyroidism Celiac disease Creutzfeldt-Jakob disease Posterior fossa tumor Inherited ataxias Multiple system atrophy

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Acquired Ataxic Disorders

In general clinical practice, ataxia is more likely to be due to an acquired disorder. Ischemic or hemorrhagic stroke in the brain stem, cerebellum, or thalamus can cause cerebellar ataxia. Patients with the disorder report abrupt symptom onset, with ataxia that typically affects the extremities, speech, and gait. Cerebellar ataxia is a frequent manifestation of multiple sclerosis lesions involving the spinal cord or brainstem. Primary brain tumors or metastatic brain tumors can also involve the cerebellar pathways and cause chronic progressive cerebellar ataxia. In addition to chronic alcohol abuse, cerebellar ataxia may also occur in association with phenytoin, 5-fluorouracil, and cytosine arabinoside administration. Wernicke encephalopathy characteristically results in ataxia but is also associated with ophthalmoplegia (paresis of eye muscles), confusion, peripheral neuropathy, and even seizures. Wernicke encephalopathy is caused by thiamine (vitamin B1) deficiency; it most commonly occurs in persons with alcoholism but has also been reported in patients who have undergone bariatric surgery, have had a prolonged period of fasting, have had repeated episodes of vomiting, or have been on prolonged parenteral nutrition without adequate vitamin supplementation. Immediate treatment with parenteral thiamine is necessary, or a chronic amnestic state (Korsakoff psychosis) may develop. Acquired vitamin E deficiency may also result in gait ataxia and sensory neuropathy, most typically in patients with a history of malabsorption due to gastrointestinal disease. A severe, rapidly progressive cerebellar ataxia may occur as a paraneoplastic manifestation in a patient with a known or occult cancer. Patients with paraneoplastic ataxia often have other neurologic manifestations, including peripheral neuropathy or encephalomyelitis. For further discussion, see Neuro-oncology. Hypothyroidism is a very rare cause of ataxia. The ataxia resolves completely with thyroid hormone replacement. Celiac disease can (rarely) be associated with ataxia, and most patients will have concomitant sensory peripheral neuropathy.

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Inherited Ataxias The hereditary ataxic disorders are a heterogeneous group of diseases that manifest primarily as chronic, progressive ataxia. Degeneration occurs in the cerebellum and, in many of these disorders, also in the spinal cord. These conditions are typically either autosomal dominant or autosomal recessive. Although the responsible genetic defect is known in several of these disorders, the only treatable conditions are Refsum disease, cerebrotendinous xanthomatosis, and ataxia with isolated vitamin E deficiency. In the other disorders, treatment is supportive.

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Fragile X Tremor Ataxia Syndrome

Fragile X tremor ataxia syndrome is a recently recognized disorder that develops in later life, primarily with symptoms of ataxia and intention tremor. Other reported symptoms include dementia, psychiatric symptoms, peripheral neuropathy, and dysautonomia. Diagnosis is established by demonstrating allele expansion of the FMR1 gene.

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Friedreich Ataxia Friedreich ataxia is the most common autosomal recessive ataxic disorder, with an estimated prevalence of 2 to 3 per 100,000 persons. The mean age of onset is approximately 15 years, but onset into the sixth decade of life is seen. Typical symptoms include ataxia involving gait, limbs, and speech. Neurologic examination shows absent deep tendon reflexes in the lower limbs and impaired proprioception. Cardiomyopathy develops in most patients, and diabetes mellitus is present in some. Diagnosis is established by demonstrating a trinucleotide (GAA) repeat in the X25 gene. Treatment is supportive.

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Spinocerebellar Ataxias The spinocerebellar ataxias are a clinically and genetically heterogeneous group of disorders. Estimated prevalence of the spinocerebellar ataxias is approximately 1 per 100,000 persons. The spinocerebellar ataxias have an autosomal dominant pattern of inheritance and are associated with chronic, progressive cerebellar ataxia, with a mean age of onset in the fourth and fifth decades.

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Parkinson Disease • • •

Epidemiology and Genetics Clinical Features and Diagnosis Treatment of Parkinson Disease

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Epidemiology and Genetics

One of the more common neurodegenerative disorders, Parkinson disease is estimated to affect 1% of persons older than 65 years and 2.5% of persons older than 80 years. Estimated prevalence is 100 to 200 per 100,000 persons. Peak onset is in the sixth and seventh decades of life. The disease is more prevalent in men, with a ratio of 1.5-2:1. A chronic, progressive disease course is expected, with significant disability approximately 10 to 15 years after onset. It is now thought that as many as 10% to 15% of cases may be familial, although genetic testing is currently performed only for research purposes.

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Clinical Features and Diagnosis Parkinson disease remains a clinical diagnosis that is based on a cardinal set of clinical features, including resting tremor, bradykinesia, rigidity, and postural instability; the tremor, bradykinesia, and rigidity are asymmetric. Sustained levodopa responsiveness is expected in Parkinson disease and helps confirm the clinical diagnosis. Signs suggesting an alternative condition include symmetric symptoms or signs, early falls, rapid progression, poor or waning response to levodopa, dementia, early autonomic failure, and ataxia. Parkinsonism can be a presenting feature of a number of other conditions (Table 19). The diagnostic evaluation of suspected Parkinson disease should include a careful review of a patient’s medication history to exclude drug-induced parkinsonism. A history of repeated head trauma or toxin exposure should also be explored. Although findings are normal in Parkinson disease, MRI is indicated to exclude other disease processes, such as vascular disease, hydrocephalus, and other degenerative diseases.

Table 19. Differential Diagnosis of Parkinsonism Disorder Parkinson Diseasea Degenerative parkinsonism Multiple system atrophy Progressive supranuclear palsy Corticobasal degeneration Dementia with Lewy bodies Secondary parkinsonism Drugs (antipsychotics, antiemetics, metoclopramide, reserpine, lithium, tetrabenazine, flunarizine) Toxins (manganese, MPTP, mercury, methanol, ethanol, carbon monoxide)

Notes

Ataxia, dysautonomia Early falls, impaired vertical eye movement Asymmetric spasticity and rigidity, alien limb movement, myoclonus Dementia and hallucinations Exposure history

Exposure history

Vascular Trauma (including pugilistic encephalopathy) Hydrocephalus Creutzfeldt-Jakob disease Paraneoplastic syndrome Hepatocerebral degeneration Hypothyroidism Hereditary Disorders Associated with Parkinsonismb Wilson disease

Familial amyotrophy-dementiaparkinsonism Spinocerebellar ataxias Huntington disease Fragile X tremor ataxia syndrome

History and MRI showing stroke History of head trauma MRI suggestive of contusion, lower body parkinsonism Rapidly progressive; signs and symptoms of ataxia, dementia, myoclonus, and dystonia Rapidly progressive; signs and symptoms of ataxia, encephalopathy, and myoclonus History of liver disease; MRI changes in basal ganglia Rare; resolves with treatment

Must be ruled out in patients less than age 50 years; Hepatic and psychiatric disease; tremor; dystonia; ataxia Cognitive/behavioral change; extremity weakness, atrophy; rigidity, bradykinesia Autosomal dominant; begin in early life; Ataxia predominates Chorea, dystonia, psychiatric symptoms, dementia, ataxia Ataxia, tremor, dementia

MPTP = methylphenyltetrahydropyridine. a

Characterized by asymmetric tremor, rigidity, and brandykinesia.

b

Not a complete list.

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Treatment of Parkinson Disease To date, no treatment exists to slow the loss of dopamine-producing neurons in Parkinson disease. Both pharmacologic therapy and nonpharmacologic therapy are tailored to patient age, the nature of the symptoms, and symptom severity.

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General Pharmacotherapy The mainstay of drug therapy is targeted toward dopamine replacement with levodopa or dopamine agonists. Drug treatment can be delayed until the patient’s symptoms interfere with employment or social activities. The choice of pharmacotherapy in early Parkinson disease remains somewhat controversial because of concerns about levodopa-induced motor complications. Levodopa is the most effective medication used in the treatment of Parkinson disease but is associated with motor fluctuations, such as dyskinesias and a “wearing-off” effect, which refers to enhanced parkinsonian symptoms due to ineffective dopamine therapy. These motor fluctuations develop at a rate of 10% annually in patients older than 60 years but seem to develop more rapidly and are more severe in younger patients. Therefore, most clinicians will initiate therapy with a dopamine agonist in patients younger than 65 years. At some point, however, all patients will require the addition of levodopa therapy. Levodopa is the drug of choice in older patients. Levodopa is administered in conjunction with carbidopa, which prevents the peripheral conversion of levodopa to dopamine, in a three-times daily dosing regimen at least 1 hour before meals. The dopamine agonists ropinirole and pramipexole are also administered in a three-times daily dosing regimen, starting at a low dose and titrating up on the basis of treatment effect. Involvement of physical therapists can benefit patients with significant gait freezing and postural instability.

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Management of Motor Fluctuations in Parkinson Disease At some point, most patients with Parkinson disease develop motor complications, such as dyskinesias and “wearing off” (also called “off-time”). Dyskinesias are recognized as choreiform and dystonic movements, which are involuntary and related to dopamine therapy. If these are mild and do not disturb the patient, they should not be treated. Risk factors for motor fluctuations include younger age of onset, increasing disease severity, higher levodopa dosage, and longer disease duration. Patients with disabling dyskinesias on levodopa monotherapy may benefit from the addition of a dopamine agonist. Amantadine can also be used to reduce dyskinesias. In patients with wearingoff phenomena, the initial strategy is to increase either individual levodopa dosage or the frequency of levodopa administration. If dyskinesias then become problematic or the duration of levodopa effect becomes too short, coadministration of a dopamine agonist is often beneficial. Administration of entacapone or rasagiline has also been shown to reduce the wearing-off effect. Additionally, deep brain stimulation has been shown to improve motor function, reduce the wearing-off effect, and reduce dyskinesias. Patients with severe motor fluctuations despite optimal pharmacotherapy should be referred for consideration of deep brain stimulation.

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Treatment of Neuropsychiatric and Sleep Disturbances in Parkinson Disease Approximately 60% of patients with Parkinson disease develop psychiatric symptoms during the course of their disease. Depression and anxiety are common manifestations and can occur at any stage of the disease. The first step in such patients is to optimize dopaminergic therapy. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are first-line agents for those requiring drug treatment. Other patients may benefit from a subset of these medications that also have antianxiolytic properties (paroxetine, sertraline, venlaflaxine). A number of controlled trials have demonstrated the efficacy of antidepressant agents, including paroxetine, sertraline, bupropion, and the tricyclic nortriptyline, for the treatment of depression in Parkinson disease. Neuropsychiatric symptoms, including psychosis, commonly occur in patients with advanced Parkinson disease. Before initiation of neuroleptic therapy for treatment of psychosis in such patients, medical conditions—such as urinary tract and pulmonary infections, metabolic disturbances, and adverse effects of medications—must be excluded. Polypharmacy, in particular, has been shown to be an independent risk factor for the development of psychosis in Parkinson disease. Therefore, in patients with persistent psychosis, reduction or elimination of medications should be considered, including parkinsonian medications. Such changes are usually best made in consultation with a neurologist. Psychological approaches to the management of psychosis, such as cognitive-behavioral therapy, supportive therapy, and psychoeducation, should also be considered. Pharmacotherapy is occasionally necessary in the treatment of psychosis. Cholinesterase inhibitors may be beneficial in some patients and are usually well tolerated. Quetiapine, an atypical antipsychotic medication that typically does not worsen motor function, is used by many experts as first-line therapy. Sleep disorders affect 60% to 98% of patients with Parkinson disease. Motor manifestations of these disorders are common causes of sleep disturbance and can manifest as stiffness, inability to move, dystonia, cramps, or pain. Therapy with an extended-release carbidopa-levodopa preparation should be considered. Restless legs syndrome and periodic limb movements of sleep are also common and may require additional dopaminergic medication before bedtime. Rapid eye movement sleep behavior disorder may occur in up to one third of patients with Parkinson disease, manifesting as kicking, grabbing, yelling, and falling or even jumping out of bed. A sleep study may facilitate the recognition of these disorders. Clonazepam before bedtime may be indicated if these events disrupt sleep or are dangerous to the patient (or their sleeping partner).

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Other Parkinsonism Disorders

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Drug-Induced Parkinsonism Multiple System Atrophy Progressive Supranuclear Palsy Corticobasal Degeneration

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Drug-Induced Parkinsonism Parkinsonism is an established side effect of many medications, particularly those that interfere with the storage, synthesis, and release of dopamine or cause blockade of dopaminergic receptors. Neuroleptic medications are frequently associated with parkinsonian side effects; however, many others have been associated with the development of drug-induced parkinsonism (see Table 19). The parkinsonism is bilateral, with evident bradykinesia, rigidity, and tremor. Tremor in drug-induced parkinsonism is often postural and may be higher in frequency than in Parkinson disease.

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Multiple System Atrophy Multiple system atrophy is a heterogeneous degenerative disorder that can be associated with parkinsonism, ataxia, and autonomic nervous system impairment. It has an estimated prevalence of 4.4 per 100,000 persons and seems to affect men and women equally. Multiple system atrophy is generally considered to be a sporadic disease of unknown cause. Mean age of onset is in the sixth decade of life, and median survival is 9.5 years. There are different forms of multiple system atrophy, and its classification has historically been based on the predominant neurologic system involved. However, most patients will have a combination of symptoms, reflecting degeneration of multiple neurologic systems. Parkinsonian symptoms, such as rigidity, bradykinesia, and postural instability, occur in conjunction with ataxia or symptoms of dysautonomia. Signs and symptoms of dysautonomia include erectile dysfunction, constipation, diarrhea, urinary incontinence, and orthostatic hypotension. A history of voice change or breathing difficulties should prompt ear, nose and throat evaluation to look for vocal cord abnormalities. Treatment of multiple system atrophy is symptomatic only. Carbidopa-levodopa should be administered to affected patients with significant parkinsonism; 25% of these patients will have an initial beneficial response to this drug. Orthostatic hypotension is treated with a combination of conservative and pharmacologic measures. Patients should be instructed to elevate the head of

the bed, increase their salt intake, and use compression stockings. Medications used to treat orthostatic hypotension include midodrine, fludrocortisone, and pyridostigmine.

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Progressive Supranuclear Palsy Progressive supranuclear palsy is a progressive neurodegenerative disorder with an estimated prevalence of 6.5 per 100,000 persons. Occurring equally in men and women, it is a sporadic condition. Patients typically present in their sixties with symptoms of gait impairment, falls, and bulbar abnormalities, including slurred speech and dysphagia. Examination shows parkinsonism, impaired vertical eye movements, dysarthria, and a reduction in facial expression and blink frequency. The presence of symmetric bradykinesia and axial muscle rigidity, the lack of a significant resting tremor, and the restriction of vertical saccades help distinguish progressive supranuclear palsy from Parkinson disease. Treatment of progressive supranuclear palsy is limited. A levodopa trial can be considered in patients with significant parkinsonism, although the effects are typically modest and are not sustained. Involvement of physical and occupational therapists can help to prevent contractures and provide gait aid.

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Corticobasal Degeneration Corticobasal degeneration is a rare, sporadic, degenerative condition. Clinical manifestations include gait impairment, dystonia, myoclonus, tremor, and slurred speech. Neurologic examination shows asymmetric rigidity, bradykinesia, and dystonia in most patients. The presence of alien limb phenomenon, by which an extremity moves independent of conscious voluntary control, in conjunction with these signs suggests corticobasal degeneration. Tremor is less frequently seen than in patients with Parkinson disease. Diagnosis is based on clinical features, and therapy is symptomatic, similar to that for progressive supranuclear palsy.

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Essential Tremor Essential tremor affects between 1% and 6% of the population and has a bimodal age of onset, peaking in the third and sixth decades. Both sexes are affected equally. Although there is no evidence of increased mortality in patients with essential tremor, the tremor can become disabling. Approximately 50% to 70% of patients with essential tremor have a family history of such tremor. A person with a first-degree relative with essential tremor is five times more likely to develop the disorder.

Essential tremor is characterized by an upper extremity high-frequency tremor, which is present with both limb movement and sustained posture of the involved extremities. The tremor is characteristically bilateral, but there can be mild to moderate asymmetry. Tremor amplitude over time typically increases and can be so severe as to interfere with writing, drinking, and other activities requiring smooth, coordinated upper limb movements. Head tremor is seen in 50% of patients, voice tremor in 30%, and a tremor involving the legs or chin in 15%. Many patients report improvement in the tremor with ingestion of alcohol. Diagnosis of essential tremor is based on clinical features. It is distinguished from Parkinson disease by the lack of rigidity, bradykinesia, postural instability, and resting tremor. Medication history should be reviewed to exclude medication-induced (such as corticosteroid-, valproate-, and lithium-induced) tremor. Enhanced physiologic tremor due to anxiety, stress, and metabolic disturbances, such as hypoglycemia and hyperthyroidism, should be considered and excluded. Wilson disease should be considered in a patient younger than 40 years who has a kinetic or postural tremor. Patients with mild tremor may not require treatment. For more serious tremors, propranolol and primidone are first-line agents (Table 20). Either drug may be initiated when tremor interferes with activities of daily living or causes psychological distress. Alternative medication options include gabapentin, topiramate, alprazolam, and sotalol. Injection of botulinum toxin can be considered in patients with head tremor because oral medications are less effective in treating this type of tremor. Botulinum toxin has also been used in some patients with severe extremity tremor. The 15% of patients with severe, disabling essential tremor should be considered for deep brain stimulation, which is generally safe, results in 60% to 90% improvement, and has been reported to improve quality of life.

Table 20. Treatment of Essential Tremor Treatment Propranolol Primidone Gabapentin Topiramate Atenolol Nadolol Sotalol Botulinum toxin Deep brain stimulation

Potential Adverse Effects Reduced blood pressure and/or heart rate, impotence, drowsiness, dyspnea Drowsiness, fatigue, ataxia, vertigo, vomiting, nausea Lethargy, fatigue, dizziness, depression, cognitive impairment Weight loss, paresthesias, cognitive impairment, glaucoma Lightheadedness, nausea, sleepiness Hypotension, dizziness Drowsiness, arrhythmia, palpitations, fatigue, nausea, vomiting Hand/neck weakness Infection, hematoma, seizures, visual disturbances

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Dystonia • • •

Drug-Induced Dystonia Cervical Dystonia Spasmodic Dysphonia

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Drug-Induced Dystonia All medications that block D2 dopamine receptors can cause acute dystonic reactions. Dystonic movements are due to sustained contraction of agonist and antagonist muscles, which results in twisting and repetitive movements or sustained abnormal postures. These movements most frequently affect the ocular muscles (oculogyric crisis) and the face, jaw, tongue, neck, and trunk. The limbs are rarely affected. Neuroleptic, antiemetic, and serotoninergic agents have been implicated. Treatment consists of parenteral diphenhydramine, benztropine mesylate, or biperiden.

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Cervical Dystonia Cervical dystonia, formerly known as torticollis, is a focal dystonia that involves the cervical musculature and causes abnormal postures of the head, neck, and shoulders. Quick, nonrhythmic, repetitive movements can also occur and can be mistaken for tremor. The prevalence of cervical dystonia is approximately 33 per 100,000 persons. The diagnosis is based on clinical features. MRI of the brain and cervical spine to rule out structural disease is indicated in those with cervical dystonia that is acute in onset and is associated with restricted range of motion about the neck. Mild, nondisabling symptoms of cervical dystonia may not require therapy. However dystonic movements that interfere with social or occupational functioning should be considered for pharmacotherapy or botulinum toxin therapy. Botulinum toxin therapy, which has been reported to be beneficial in 60% to 85% of patients with cervical dystonia, is the treatment of choice. Therapy with anticholinergic medications results in improvement in 39% of patients with this disorder.

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Spasmodic Dysphonia Characterized by spasmodic interruptions in the voice, spasmodic dysphonia is classified as a task-specific focal dystonia of the voice caused by inappropriate vocal cord spasm. Diagnosis is based on the presence of appropriate clinical features. Other disorders, such as vocal cord paralysis, gastroesophageal reflux, and vocal fold polyps, nodules, and cysts, should be excluded by laryngeal evaluation. Botulinum toxin injection, typically into the thyroarytenoid muscles, is the treatment of choice.

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Chorea • •

Acquired Causes of Chorea Huntington Disease

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Acquired Causes of Chorea Chorea may result from medications, systemic metabolic disorders, immunologic disease, brain tumor, or cerebrovascular disease. Substances associated with chorea include oral contraceptive agents, lithium, digoxin, tricyclic medications, anticonvulsant agents, amphetamines, cocaine, and dopaminergic medications. Hyper- and hypoparathyroidism, hyper- and hypoglycemia, and pregnancy have been associated with chorea. Systemic lupus erythematosus and primary antiphospholipid antibody syndrome should be excluded by checking serum levels of antinuclear and anticardiolipin antibodies. Children and adolescents with chorea should be checked for recent streptococcal infection (Sydenham chorea).

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Huntington Disease Huntington disease is a hereditary, progressive, neurodegenerative disorder characterized by increasingly severe motor impairment, cognitive decline, and psychiatric symptoms. In addition to chorea, other motor symptoms include ataxia, dystonia, slurred speech, swallowing impairment, and myoclonus. Various psychiatric symptoms, such as dysphoria, agitation, irritability, anxiety, apathy, disinhibition, delusions, and hallucinations, are commonly seen. Symptoms typically begin in the fourth and fifth decade, but 10% of patients have symptoms in the second decade. Average illness duration (diagnosis to death) is approximately 15 years but is shorter in patients younger than 20 years and older than 50 years.

Huntington disease is an autosomal dominant disorder caused by a CAG repeat within the gene on chromosome 4. Genetic testing is commercially available and should always be offered with genetic counseling. There is, however, no definitive therapy, and treatment is symptomatic. Quetiapine, olanzapine, or risperidone can be considered in the treatment of severe chorea. Speech, physical, and occupational therapy can be helpful for some of the other motor manifestations of the disease. Selective serotonin reuptake inhibitors can be used to treat depression, and quetiapine, risperidone, or olanzapine can be used to treat psychotic symptoms.

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Restless Legs Syndrome and Periodic Limb Movements of Sleep Restless legs syndrome is a common condition, with an estimated prevalence between 6% and 12%. A positive family history is present in at least 50% of patients with the disorder. Genetic studies in familial restless leg syndrome have suggested linkage to chromosomes 12 and 14, typically with an autosomal dominant pattern of inheritance. Restless legs syndrome can be divided into primary and secondary forms. The primary form refers to patients without another condition known to be associated with restless legs syndrome. Well-established conditions that can be labeled as secondary restless legs syndrome include pregnancy, end-stage renal disease, and iron deficiency. Symptoms resolve with resolution of these conditions. Restless legs syndrome remains a clinical diagnosis. Besides an urge to move the legs, there are four other criteria for making the diagnosis: (1) an uncomfortable or unpleasant sensation in the legs; (2) an unpleasant sensation in the legs that begins or worsens during periods of rest or inactivity; (3) an unpleasant sensation in the legs that is partially or totally relieved by movement, as long as activity continues; and (4) an unpleasant sensation that is worse in the evening or night or is present only at night. Physical examination typically shows normal findings in affected patients, although associated peripheral neuropathy is common in patients with late-onset restless legs syndrome. Evaluation for iron deficiency anemia by measurement of serum ferritin levels and percent iron saturation should be performed in all patients suspected of having the disease. Periodic limb movements of sleep occur in 85% of patients with restless legs syndrome and, when present, help confirm the diagnosis; they are described as involuntary jerking (clonic) movements of the legs during sleep. A positive family history of restless legs syndrome and response to dopaminergic therapy also help confirm the diagnosis. Both pharmacologic and nonpharmacologic therapies should be considered in the treatment of restless legs syndrome and are tailored to symptom severity (Table 21). Dopamine agonists, such as ropinirole and pramipexole, are first-line agents used to treat daily symptoms. Gabapentin, clonazepam, and opioid medications can also be helpful either as combination

therapy with a dopamine agonist or as monotherapy. Changing to a different dopamine agonist, switching to an opioid or gabapentin, combining therapies, and using high-dose opioid therapy with another medication (such as methadone) are all treatment options in patients with refractory restless legs syndrome.

Table 21. Management of Restless Legs Syndrome Nonpharmacologic Management Avoiding medications/substances that exacerbate restless legs syndrome Antidepressant medications (selective serotonin reuptake inhibitors, tricyclic antidepressants Neuroleptic medications Antihistamine medications Antinausea medications, promotility agents (metoclopramide, chlorpromethazine) Caffeine Alcohol Sleep hygiene Regular sleep and wake times Restricting bed to sleep and intimacy Avoiding perturbing activities before sleep Behavioral interventions Brief walks before bedtime Hot baths or cold showers Massaging of limbs Pharmacotherapy For daily symptoms Dopamine agonists Ropinirole Pramipexole Anticonvulsant agents Gabapentin Clonazepam Opioids (low potency) Tramadol Hydrocodone Oxycodone For refractory symptoms Switch to a different dopamine agonist. Switch to a low-potency opioid or gabapentin if currently using a dopamine agonist. Add a second medication.

Use a high-potency opioid (such as methadone).

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Benito-León J, Louis ED. Clinical update: diagnosis and treatment of essential tremor. Lancet. 2007;369(9580):1152-1154. [PMID:17416247]. See PubMed Chen H, O’Reilly E, McCullough ML, et al. Consumption of dairy products and risk of Parkinson’s disease. Am J Epidemiol. 2007; 165(9):998-1006. [PMID:17272289]. See PubMed Diamond A, Jankovic J. The effect of deep brain stimulation on quality of life in movement disorders. J Neurol Neurosurg Psychiatry. 2005; 76(9):1188-1193. [PMID:16107348]. See PubMed Ferreri F, Agbokou C, Gauthier S. Recognition and management of neuropsychiatric complications in Parkinson’s disease. CMAJ. 2006; 175 (12):1545-1552. [PMID:17146092]. See PubMed Haehner A, Hummel T, Hummel C, Sommer U, Junghanns S, Reichmann H. Olfactory loss may be a first sign of idiopathic Parkinson’s disease. Mov Disord. 2007;22(6):839842. [PMID:17357143]. See PubMed Hauser RA, Zesiewicz TA. Advances in the pharmacologic management of early Parkinson disease. Neurologist. 2007;13(3):126-132. [PMID:17495756]. See PubMed Pahwa R, Factor SA, Lyons KE, et al. Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66(7):983-995. [PMID:16606909]. See PubMed

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Demyelinating Diseases • • • • • •

Spectrum, Pathophysiology, and Epidemiology of Demyelinating Diseases Presenting Signs and Symptoms of Multiple Sclerosis Diagnosis of Multiple Sclerosis Differential Diagnosis of Multiple Sclerosis Clinical Course in Multiple Sclerosis Treatment of Multiple Sclerosis

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Genetic and environmental factors contribute to multiple sclerosis susceptibility. The cause of multiple sclerosis (MS) is unknown, but approximately 15% of people with MS have a family history of the disease.

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Moving before adulthood from a low- to a high-prevalence geographic region of multiple sclerosis increases risk of the disease. Optic neuritis, Lhermitte sign, diurnal fatigue, heat sensitivity, and internuclear ophthalmoplegia are characteristic features of multiple sclerosis. In multiple sclerosis, brain MRI reveals ovoid lesions in the periventricular white matter that sometimes enhance with gadolinium; misinterpretation of brain MRI white matter abnormalities discovered in patients with nonspecific symptoms is a leading cause of misdiagnosis of multiple sclerosis. Cerebrospinal fluid analysis is useful when the clinical setting is suspicious for multiple sclerosis but neuroimaging is inconclusive because approximately 85% of patients with MS have abnormal findings. Multiple sclerosis begins with a clinical attack in 85% of patients; if the brain MRI at presentation shows lesions consistent with demyelination, the risk of experiencing a second attack (confirmed multiple sclerosis) approaches 90% over the next 10 to 15 years. At least two thirds of patients with relapsing-remitting multiple sclerosis develop a secondary progressive disease course; the median time from onset until such progression ranges from 10 to 15 years. Multiple sclerosis begins as a primary progressive disorder in 15% of patients. Immunizations should be delayed for 4 to 6 weeks after an acute attack of multiple sclerosis, and live vaccines should not be administered to patients on immunosuppressive therapies, such as mitoxantrone. Pseudorelapses (worsening of neurologic symptoms due to another cause, such as systemic infection, that requires antibiotic treatment or supportive care) should be differentiated from true multiple sclerosis relapses (which may require corticosteroid treatment). Intravenous methylprednisolone, 1 g/d for 3 to 5 days, may be used to speed recovery from multiple sclerosis relapses that impair vision, strength, balance, or coordination, and severe corticosteroid-refractory relapses may respond to rescue therapy with plasmapheresis. Three interferons, glatiramer acetate, and natalizumab are approved for reducing the relapse rate in relapsing-remitting multiple sclerosis. Natalizumab is associated with a small risk of developing progressive multifocal leukoencephalopathy, and treatment requires participation in a safety surveillance program. No therapies have had convincing effects on the neurodegenerative processes that underlie progressive forms of multiple sclerosis. Adequate rest and regular physical exercise may reduce fatigue related to multiple sclerosis, but many patients require treatment with stimulants, such as amantadine or modafinil. Multiple sclerosis is associated with a high prevalence of depression and an elevated risk of suicide, so mood should be assessed regularly. Spasticity in patients with multiple sclerosis is best managed by physical therapy interventions that include stretching, with or without antispasticity medications.

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Spectrum, Pathophysiology, and Epidemiology of Demyelinating Diseases The idiopathic inflammatory demyelinating diseases of the central nervous system (CNS) are defined by their distribution, clinical symptoms, severity, and tendency to relapse (Table 22). Multiple sclerosis (MS), the most common of these disorders, is a putative autoimmune disease characterized by episodic neurologic symptoms and signs caused by focal demyelinating lesions (plaques) involving the white matter of the brain, spinal cord, and optic nerves. The pathologic hallmarks of MS plaques are inflammation and demyelination, with relative sparing of nerve axons. However, axonal loss and degenerative processes, major contributors to neurologic disability, may begin early in this disease. Moreover, contemporary immunopathologic studies show that MS is heterogeneous. Four different pathologic patterns have been described, each with distinctive characteristics, such as complement activation and immunoglobulin deposition, loss of oligodendrocytes (myelin-supporting cells), or apoptosis. Lesions from individual patients with MS appear restricted to one pattern, suggesting that the term “multiple sclerosis” encompasses several distinct disorders that follow different mechanisms toward the final common pathway of inflammatory demyelination. Each mechanism may require a specific therapeutic strategy; this is an area of active research. MS is the most common cause of nontraumatic neurologic disability in young and middle-aged adults in the United States; it affects 0.1% to 0.2% of the population or 400,000 people. Disease onset is usually between age 20 and 40 years; however, MS may occur at virtually any age, including during childhood. Epidemiologic studies demonstrate a female-to-male predominance of approximately 2:1, and recent data indicate that the female preponderance has increased over the past several decades, nearing 3:1. The cause of MS is unknown, but genetic and environmental factors each contribute to individual risk. Approximately 15% of people with MS have a family history of the disease. There are strong racial and ethnic predilections; the highest rates occur in Northern Europeans, whereas in other groups, such as North American aboriginal people and black Africans, typical MS is virtually unknown. Environmental factors are also necessary to allow disease expression in a genetically susceptible individual. These as yet unidentified factors are postulated to act early in life. Migration studies show that moving prior to adulthood from a low-prevalence (30 cases per 100,000 population) region increases MS risk. However, migration during adulthood from a low-prevalence to a high-prevalence region does not increase risk. These findings, together with evidence of possible MS “outbreaks” in certain areas, suggest that an infective agent or agents might be involved. The “molecular mimicry” concept hypothesizes that sequence similarities between foreign peptides (from viruses or other infective agents) and self-peptides (such as myelin) are sufficient to activate autoreactive T or B cells that trigger autoimmune disease. No single agent has been proved responsible, but serologic evidence

indicates that an immune response against Epstein-Barr virus early in life is a risk factor for later development of MS. The prevalence of MS escalates with increasing geographic latitude, a fact only partially explained by genetic factors and population migration patterns. Additional influences might include climate, sunlight exposure, or other factors. Vitamin D has been implicated in MS pathogenesis because many patients with the disease are vitamin D deficient, and dietary supplementation with vitamins, including vitamin D, is associated with a lower future risk of MS; vitamin D also has immunologic effects. Reduced sunlight exposure during winter months in high-latitude regions may result in vitamin D deficiency and subsequent MS risk. A notable recent advance is the discovery of an autoantibody marker, NMO-IgG, which distinguishes neuromyelitis optica (Devic disease) from MS. Neuromyelitis optica is now recognized as a distinct demyelinating disease with a predilection for the optic nerves and spinal cord. NMO-IgG targets the water channel aquaporin-4, and growing evidence suggests it may be the primary cause of neuromyelitis optica.

Table 22. Spectrum of Inflammatory Demyelinating Diseases of the Central Nervous System Disorder Distribution Course Relapse Severity Multiple sclerosis Multifocal Relapsing or progressive Mild to moderate Neuromyelitis optica Optic nerve and spinal cord Relapsing Severe ADEM Multifocal Monophasic Moderate to severe Transverse myelitis Focal Monophasic or relapsing Moderate to severe ADEM = acute disseminated encephalomyelitis.

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Presenting Signs and Symptoms of Multiple Sclerosis Symptoms of MS typically emerge as discrete events called attacks (also known as relapses, flare-ups, or exacerbations). Attacks are subacute episodes of neurologic dysfunction that progress over days to weeks, plateau, and then improve partially or completely over subsequent days to months. Demyelinating plaques are the pathologic basis for attacks and cause symptoms by interrupting electrical conduction along neural pathways. Virtually any CNS symptom can occur in MS. Sensory symptoms, such as paresthesias of the limbs or face, are particularly common. Typical sensory patterns include ascending numbness of the distal limb with gradual proximal spread to involve the trunk with a sensory level, a “useless

hand” syndrome in which impaired dexterity occurs with reduced proprioceptive function, or a “tight band” sensation around the trunk or limb. Optic neuritis is common and consists of monocular loss of vision (partial or complete) associated with orbital pain, pain with eye movement, and impaired color vision. Examination usually reveals a scotoma and a relative afferent pupillary defect in which the affected pupil fails to constrict normally with direct light stimulation but shows a normal “indirect” constrictive response when the contralateral eye is illuminated. Oculomotor dysfunction causes diplopia or oscillopsia (perception of involuntary eye movements), and internuclear ophthalmoplegia (one eye fails to adduct normally with contralateral gaze) on examination is strongly suggestive of MS. Motor weakness, imbalance, bladder or bowel dysfunction (especially urinary urgency, frequency, and incontinence and constipation), and facial pain (trigeminal neuralgia) are other common symptoms. Characteristic symptoms include Lhermitte sign (spinal or limb paresthesias elicited by neck flexion), diurnal fatigue (typically worst in the early afternoon), and sensitivity to heat exposure or exercise (which may cause temporary worsening of fatigue or neurologic symptoms). Memory loss or other cognitive symptoms, chronic neuropathic pain, and mood disorders are also prevalent but usually develop gradually rather than as a relapse.

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Diagnosis of Multiple Sclerosis Brain MRI is the most useful test for diagnosing MS. In addition to excluding other structural causes of a patient’s symptoms and signs, brain MRI reveals white matter lesions supportive of a diagnosis of MS (Figure 14). Such lesions are characteristically ovoid in shape, are distributed in periventricular regions and in the posterior fossa, and are oriented perpendicular to the lateral ventricles and corpus callosum. Recent lesions (50 years, hypertension, smoking, diabetes mellitus, hyperlipidemia), and head trauma, are also associated with white matter abnormalities on brain MRI. The morphology of the white matter lesions associated with these conditions differs from that of typical MS; the lesions are usually small or punctate, somewhat irregular, and subcortical (nearer to the cortex or brain surface). Misinterpretation of white matter abnormalities discovered incidentally in a patient with nonspecific symptoms is a leading cause of MS misdiagnosis. Additional neuroimaging may be used to establish the presence of subclinical lesions that confirm involvement of multiple CNS regions (dissemination in space). Lesions detected by spinal cord MRI have high specificity for MS and do not occur in association with migraine or

cerebrovascular disease. Orbital MRI with gadolinium obtained during an attack of optic neuritis may reveal optic nerve enhancement, which confirms an inflammatory process. Cerebrospinal fluid (CSF) analysis is useful if the clinical features are suggestive of MS but neuroimaging is inconclusive. About 85% of patients with MS have abnormal CSF findings. A mild lymphocytic pleocytosis, generally 10 to 30 cells/µL, may be present, although in most patients the cell count is normal. More specific findings include the presence of CSF oligoclonal bands not detectable in serum samples collected at the time of lumbar puncture and indices that show intrathecal immunoglobulin production (elevation of the IgG index and synthesis rate). Neurophysiologic studies can detect subclinical lesions in visual pathways (visual evoked potentials) or sensory tracts (somatosensory evoked potentials) and therefore demonstrate dissemination of lesions in space when results of MRI studies are normal.

Figure 14. Brain MRI of a patient with multiple sclerosis. Right, axial brain MRI, fluid-attenuated inversion recovery sequence, shows numerous typical ovoid lesions of MS (long arrows), many in a periventricular location (short arrow). Right, axial T1-weighted brain MRI with gadolinium reveals multiple enhancing lesions (arrows) that indicate active MS.

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Differential Diagnosis of Multiple Sclerosis

Patients referred to MS clinics may be categorized as having MS, another CNS demyelinating disease, a different neurologic disease, a medical or psychiatric disorder, or no disease. More than half of patients referred to tertiary MS clinics for diagnostic purposes receive a final diagnosis other than MS. The primary reasons for this include the overlap of MS symptomatology with that of other disorders and the strong suspicion of MS in patients with vague neurologic symptoms who have nonspecific brain MRI results. The emergence of new disease-modifying therapies for MS, which are becoming increasingly powerful and are associated with uncommon but serious toxicities, mandates accurate and early diagnosis, preferably by an experienced neurologist. Although MS is the most common sporadic inflammatory demyelinating CNS disease, there are others. Neuromyelitis optica causes attacks of recurrent optic neuritis and myelitis with relative sparing of the brain and is associated with severe disability early in the disease course. Neuromyelitis optica comprises a greater proportion of demyelinating disease in non-white populations (blacks, Hispanics, Asians), has a 9:1 female-to-male predominance, and is associated with coexisting systemic autoimmunity, such as thyroid or connective tissue disorders or serum autoantibodies, including antinuclear antibody. Early detection is paramount because the treatment strategy differs from that of MS, as explained later. In addition, the monophasic disorder acute disseminated encephalomyelitis is more common in childhood but can occur as a postinfectious disorder in adults, typically presenting as a meningoencephalitic syndrome with multifocal neurologic symptoms and signs, numerous enhancing brain lesions, and inflammatory CSF. Caution is warranted in applying this diagnosis because many patients ultimately relapse and follow a course typical for MS. A partial list of other neurologic diseases that can mimic features of MS is provided in Table 23. Finally, some patients have nonspecific (but numerous) neurologic symptoms in the setting of major depression, anxiety or panic disorder, or other psychiatric disorders that, after excluding other causes, seem to best explain their syndrome (see MKSAP 15 General Internal Medicine).

Table 23. Differential Diagnosis of Multiple Sclerosis Disorder Structural or compressive lesions of the brain or spinal cord Spinal cord compression by cervical spondylosis or compressive disk disease Durally based arteriovenous fistula Meningioma Primary CNS neoplasm (glioma, lymphoma) Paraneoplastic syndrome

Notes These disorders typically progress subacutely and do not remit. They can usually be differentiated from MS with an MRI.

This manifests as a progressive, severe ataxia or myelopathy in

Metabolic disorders Vitamin B12 deficiency Vitamin E deficiency Copper deficiency Vascular diseases Sporadic and genetic stroke syndromes CNS vasculitis Multisystem inflammatory diseases Systemic lupus erythematosus Sjögren syndrome Sarcoidosis Behçet syndrome Infections HIV Lyme disease Human T-lymphotropic virus type 1 Syphilis Migraine Medical disorders that cause transient neurologic dysfunction (diabetes mellitus, thyroid disorders)

the setting of cancer, especially lung or breast carcinoma. Spasticity, weakness, and dorsal column dysfunction (vibratory and proprioception loss) in the setting of malabsorption suggest vitamin B12 or copper deficiency; vitamin E deficiency causes ataxia. Nonspecific white matter lesions are associated with increased age and vascular risk factors. Family history of migraine, early stroke, dementia, and mood disorders suggests CADASIL, which can be detected with skin biopsy or genetic analysis. Known coexisting disease or systemic clues (arthritis, rash, sicca syndrome, lymphadenopathy, orogenital ulceration) are evident.

These infections are associated with myelopathy and can be excluded with appropriate laboratory and CSF testing.

This is associated with nonspecific brain MRI white matter abnormalities, which sometimes lead to concern about MS. Such diseases cause symptoms (fatigue, paresthesias) that sometimes lead to investigations for MS.

CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CNS = central nervous system; CSF = cerebrospinal fluid; MS = multiple sclerosis.

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Clinical Course in Multiple Sclerosis The clinical course of MS is used to describe its behavior over time but also to establish prognosis and treatment options. Multiple sclerosis begins with a clinical attack in 85% of patients. Patients presenting at this stage are diagnosed with a “clinically isolated syndrome,”

which implies that if their brain MRI shows lesions consistent with demyelination, they have a risk of experiencing another attack over the next 10 to 15 years (and, therefore, of having confirmed MS) that approaches 90%. If their brain MRI is normal and no other cause is found, the risk of future confirmed MS is low but still approaches 20%. Therefore, neurologic follow-up is required for all such patients. Once there is evidence of “dissemination in time,” either by occurrence of a second clinical attack or by development of new demyelinating lesions on serial brain MRIs, a diagnosis of relapsing-remitting MS is confirmed (Figure 15). Individual relapses tend to be mild to moderate in severity and recover completely (or nearly so) with or without acute therapies. Relapses may be triggered by viral or bacterial infections but most occur without an obvious precipitant. Women experience a reduced relapse rate during pregnancy and a transient increased rate in the first several postpartum months. Over time, relapse frequency declines but so does the degree of recovery from individual relapses. Therefore, the risk of residual neurologic impairment from attacks increases with disease duration. The course of relapsing-remitting MS is notoriously heterogeneous; early in the disease, the mean relapse frequency is one event every 12 to 14 months. However, some patients will experience a series of severe relapses during the first year despite aggressive treatment, whereas others will maintain clinical remission for several years without preventive therapy. Unfortunately, there is no validated method to predict outcome for an individual patient at an early disease stage. From a population standpoint, adverse prognostic factors include the involvement of more than one neurologic system at onset and a relatively high attack frequency in the first few years after onset. Disability rating at 5 years after clinical onset is an independent predictor of the future disability accrual. Other long-held negative prognostic factors, such as male sex and older age at disease onset, have recently been challenged. More than two thirds of patients with relapsing-remitting MS eventually develop a secondary progressive course, which is defined as the development of gradual neurologic worsening without remission. Typically, this manifests as a gradually worsening gait disorder. Documentation of objective decline for more than 1 year is required to confidently declare the onset of secondary progressive MS. This is an important turning point in the disease because once the secondary progressive phase is established, the risk of accumulating permanent disability increases markedly, and the effectiveness of current preventive therapies is minimal. The rate of progression varies enormously between patients, but important changes are usually noted over years rather than weeks or months. Fifteen percent of patients with MS experience a gradually progressive disorder, rather than an attack, at disease onset (see Figure 15). They are classified as having primary progressive MS. This diagnosis may be more difficult to make because the lack of clinical relapses and relative paucity of MRI lesions make it harder to establish dissemination in time and space. However, diagnostic criteria address this problem by using serial MRI studies and ancillary laboratory studies, including CSF analysis and evoked potentials, to provide supportive evidence and exclude other disorders. Primary progressive MS develops at a later age (fifth to sixth decade) and follows an unremitting course that is remarkably similar to secondary progressive disease in pace and clinical phenotype.

Permanent neurologic disability in progressive MS can take many forms, including dementia, visual loss, or ataxia, but in most instances manifests as a gait disorder with weakness and ataxia. Most patients who require gait assistance or a wheelchair reach those points as a result of progressive disease. The median time from MS onset until conversion to the secondary progressive phase ranges from 10 to 15 years, and to reach the point that unilateral gait assistance (cane) is required, 15 to 25 years. However, many patients are able to walk with some type of assistance for more than 20 years after the progressive phase begins. Multiple sclerosis has a minimal effect on expected life-span, but, notably, the risk of suicide is approximately 7 times higher in those with MS than in control populations. Those patients with a diagnosis of MS who do not experience progressive disease have a greater chance of being categorized as having “benign MS.” This category, which is defined loosely as no or minimal neurologic impairment 15 or more years after MS onset, may encompass as many as 20% of all patients. The definition of benign MS is controversial because continued follow-up of such patients often uncovers late progressive disease and disability accrual. However, there is little doubt that a small minority of patients with MS live a long and essentially unrestricted life.

Figure 15. Clinical course of multiple sclerosis. Top, course of relapsing-remitting multiple sclerosis (MS). A representation of the intermittent, unpredictable, self-limited attacks or exacerbations of neurologic dysfunction lasting days to

weeks is shown by the darkly shaded areas. Recovery is usually complete (or nearly so) early in the course of the disease, as illustrated by the initially slight rise in the lightly shaded (“Residual disabilities”) area; repeated attacks (“Acute exacerbations”) typically result in accrual of permanent neurologic dysfunction, but the remission phase between attacks is defined by clinical stability. About two thirds of patients go on to develop secondary progressive MS, defined by a transition to a gradually progressive (unremitting) course of increasing disability (steeper rise in the lightly shaded area). Acute relapses may still be superimposed on progression but are less frequent than during the relapsing-remitting phase. Bottom, course of primary progressive MS. There is a later age of onset of the disease, which begins, by definition, as a progressive disorder rather than with a clinical attack. The course of the disease is remarkably similar to that of secondary progressive MS.

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Treatment of Multiple Sclerosis • • • •

Lifestyle Modifications and General Health Care Treatment of Acute Exacerbations Disease-Modifying Therapies Symptomatic Management

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Lifestyle Modifications and General Health Care Because many people with MS are deficient in vitamin D and may be at risk for bone loss because of reduced mobility, encouragement of dietary supplementation with vitamin D (the optimal dose is not established, but 800 U daily is safe) and calcium (1500 mg daily) is reasonable. Physical activity, including cardiovascular exercise, strengthening, and stretching, is to be encouraged because it increases aerobic fitness and health self-perception and reduces fatigue. Temporary re-emergence or worsening of neurologic symptoms with exercise (Uhthoff phenomenon) is common, and patients should be told that this physiologic phenomenon does not worsen nerve injury or trigger exacerbations. Cooling vests or collars may reduce heat-related symptoms in patients who are particularly sensitive to temperature. Planned rest or nap periods may assist in fatigue management. Patients with MS should follow Centers for Disease Control and Prevention indications for routine immunizations, including those for influenza, hepatitis B, varicella, and tetanus; there is insufficient evidence for other vaccinations, but clinical experience suggests that they are also safe. It is advised to delay immunization for 4 to 6 weeks after an acute MS attack, and live vaccines should not be administered to patients with MS who are on immunosuppressive therapies, such as mitoxantrone.

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Treatment of Acute Exacerbations Patients should be educated about the typical symptoms and temporal profile of relapses. Pseudorelapses, or temporary worsening of neurologic symptoms, may occur in the setting of systemic infection, possibly because of the effects of fever. If there is uncertainty about whether new symptoms represent a true MS relapse or a pseudorelapse, investigation for occult infection is warranted with evaluation for urinary tract infection and history- and examination-directed laboratory tests, if deemed necessary. Successful treatment of the infection or supportive care, such as antipyretics for a viral upper respiratory tract infection, will be followed by neurologic improvement. True MS relapses that have no or minimal impact on function may simply be observed. If functional status (vision, strength, balance, or coordination) is impaired, intravenous methylprednisolone, 1 g/d for 3 to 5 days, may be used to speed recovery, although it does not alter the ultimate degree of recovery. A 10- to 14-day oral prednisone taper is optional after completion of intravenous therapy. Severe corticosteroid-refractory relapses of demyelinating disease (MS or neuromyelitis optica) may respond to rescue therapy with plasmapheresis. Physical, occupational, or speech therapy may be necessary to enhance adaptation during the recovery period, depending on the type, severity, and therapeutic responsiveness of the relapse.

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Disease-Modifying Therapies There are currently six disease-modifying MS therapies approved by the U.S. Food and Drug Administration (Table 24). All have immunomodulatory or immunosuppressive properties and reduce relapse rate, relapse severity, and the accumulation of lesions as determined by MRI. These therapies vary substantially regarding route and frequency of administration and potential toxicity, factors which influence patients' preferences and initial choice of therapy. There are no predefined treatment durations, except for mitoxantrone, which is limited by cumulative doserelated cardiotoxicity. Therefore, most patients continue on a preventive therapy as long as they tolerate it well and experience little or no breakthrough disease activity. Three of the drugs are interferon preparations that, among other effects, appear to protect the blood-brain barrier. Interferon beta-1a is administered intramuscularly once weekly (Avonex®) or subcutaneously three times weekly (Rebif®), whereas interferon beta-1b (Betaseron®) is administered subcutaneously every other day. More frequently administered preparations may have somewhat greater efficacy, according to MRI findings. Each of the drugs reduces the risk of relapse by about one third and modestly slows disability progression. Interferon beta-1a and interferon beta-1b are also indicated for delay of a second clinical attack in patients with a clinically isolated syndrome and brain lesions on MRI. The development of persistent neutralizing antibodies likely interferes with interferon efficacy, but there is not yet consensus regarding use of this information in clinical decision-making.

Glatiramer acetate (Copaxone®) is administered by daily subcutaneous injection; it consists of the acetate salts of four amino acids and is thought to modulate immune responses relevant to MS pathophysiology. Glatiramer acetate is well tolerated and reduces the relapse rate by approximately one third. Mitoxantrone, a general immunosuppressant, is approved for worsening relapsing-remitting or secondary progressive MS. There is a risk of cumulative dose-dependent cardiotoxicity, limiting treatment to 2 years with the standard protocol of quarterly infusions. Mitoxantrone should not be used in patients with a baseline ejection fraction of less than 50% and should be discontinued if cardiac symptoms or signs emerge during therapy or if the ejection fraction decreases by more than 10% or goes below 50%. Posttherapy leukemia risk has been reported to be as high as 0.4%. Mitoxantrone is typically used for rapidly worsening disease that has not responded to other therapies. Natalizumab (Tysabri®) is a monoclonal antibody that targets α4 integrin and interferes with the transendothelial migration of lymphocytes into the CNS. Administered intravenously every 4 weeks, natalizumab is associated with a two-thirds reduction in relapse rate and a 40% reduction in disability progression rate. However, the emergence of three cases of progressive multifocal leukoencephalopathy, an often fatal opportunistic JC-virus CNS infection, in MS and Crohn disease trials that included approximately 3000 patients (risk of one case of progressive multifocal leukoencephalopathy per 1000 treated patients over 18 months of treatment) led to brief market withdrawal of the drug. It was reapproved in 2006 with a rigorous surveillance plan and guidelines for use, including restriction to relapsing-remitting disease and avoidance of concomitant immunosuppressive therapies. Natalizumab is generally used as a second-line agent for significant breakthrough disease despite use of other therapies or when there is an inability to tolerate such therapies. Treatments for progressive forms of MS have limited or no efficacy. Interferon drugs appear to influence the course of secondary progressive MS for patients who continue to have superimposed relapses, but trials of interferons and glatiramer acetate for primary progressive MS have shown no benefit. These progressive forms of MS require different therapeutic strategies aimed at slowing neurodegenerative mechanisms. Preventive therapy for neuromyelitis optica involves immunosuppression with agents such as azathioprine or rituximab.

Table 24. Drug Treatment for Multiple Sclerosis Agent Interferon beta-1a and interferon beta1b

Notes Immunomodulatory Reduction in relapse rate and accrual of neurologic disability Flu-like symptoms, fatigue, injection site reactions, liver chemistry abnormalities, depression Dosing depends on specific agent used Pre- and postinjection acetaminophen or NSAIDs may reduce flu-like symptoms.

Glatiramer acetate

Natalizumab

Mitoxantrone

Corticosteroid

Monitoring of CBC and liver chemistry is required every 6 months FDA class C drug—should not be used during pregnancy or lactation Immunomodulatory Reduction in relapse rate Injection site reactions Rare systemic symptoms (dyspnea/panic attack–like syndrome) No laboratory monitoring is required FDA class B drug—safety in pregnancy or lactation is not established Selective adhesion molecule inhibitor Reduction in relapse rate Boxed warning: indeterminate risk of progressive multifocal leukoencephalopathy Headache, back pain, 1.3% incidence of infusion reaction, 0.8% incidence of anaphylactoid reaction Only patients, treating physicians, infusion centers, and pharmacies that are enrolled in a restricted distribution prescribing program known as TOUCH™ are authorized to prescribe, distribute, or infuse natalizumab FDA class C drug—should not be used during pregnancy or lactation Immunosuppression Reduction in relapse rate; disease stabilization in rapidly progressive disease Boxed warnings: cardiotoxicity and secondary acute myeloid leukemia Immunosuppression risks, infection, nausea, mouth sores, mild alopecia, menstrual irregularities; urine may temporarily be colored blue Monitoring of cardiac ejection fraction (with echocardiography or multigated radionuclide angiography) is required before each dose FDA class D drug—has well-documented fetal risk Immunomodulatory Speeds recovery from MS exacerbations Insomnia, flushing, metallic taste, fluid retention, electrolyte abnormalities, hyperglycemia

CBC = complete blood (cell) count; FDA = U.S. Food and Drug Administration; MS = multiple sclerosis. Adapted from Wingerchuk DM. Multiple sclerosis. pier.acponline.org/physicians/diseases/d468/drug.tx/d468-s7.html (login required). In PIER (online database). Philadelphia: American College of Physicians, 2008. Accessed January 15, 2009.

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Symptomatic Management At all stages of MS, effective symptom management can provide improved quality of life. Specific drugs used to treat disease-associated symptoms are generally empiric and not based on randomized controlled studies, except in a few cases. Fatigue is a common but nonspecific symptom. Exclusion of anemia, sleep disorders, hypothyroidism, and other medical conditions is required. Adequate rest, regular physical exercise, and treatment with stimulant drugs, such as amantadine or modafinil, can be helpful. Depression commonly coexists with MS, and the risk of suicide is elevated compared with the general population. Mood should be regularly assessed with a standard screening instrument, and contributing factors (such as medications) should be eliminated, if possible. Psychological support and pharmacologic therapy may be required. Neuropathic pain, especially involving the lower extremities, is very common and may require tricyclic antidepressants, gabapentin, pregabalin, duloxetine, analgesics, or other agents. Trigeminal neuralgia responds to carbamazepine or gabapentin, but patients with refractory pain may require surgical intervention, such as glycerol or radiofrequency rhizotomy. Spasticity, spasms, and cramping usually respond to a combination of physical therapy (stretching) and oral antispasticity drugs, such as baclofen, tizanidine, or clonazepam. Patients with severe and refractory symptoms may require trials of botulinum toxin injections or an intrathecal baclofen pump. Urinary urgency and frequency with occasional incontinence may be managed with timed voiding, avoidance of caffeine, and judicious use of anticholinergic drugs, such as oxybutynin or tolterodine, as long as the postvoid residual urine volume is less than 100 mL. Patients with mixed symptoms (urgency and incomplete bladder emptying), pelvic or bladder pain, or hematuria should be referred to a urologist.


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Frohman EM, Racke MK, Raine CS. Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med. 2006;354(9):942-955. [PMID:16510748]. See PubMed Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines [erratum in Neurology. 2002;59(3):480]. Neurology. 2002;58(2):169-178. [PMID:11805241]. See PubMed Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of

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Neurology [erratum in Neurology. 2007;69(7):712]. Neurology. 2007:68(13): 977-984. [PMID:17389300]. See PubMed Kappos L, Bates D, Hartung HP, et al. Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol. 2007;6(5):431441. [PMID:17434098]. See PubMed Munger KL, Leven LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006:296(23):2832-2838. [PMID:17179460]. See PubMed Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343(13):938-952. [PMID:11006371]. See PubMed Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005;58(6):840-846. [PMID:16283615]. See PubMed Rolak LA, Fleming JO. The differential diagnosis of multiple sclerosis. Neurologist. 2007;13(2):57-72. [PMID:17351525]. See PubMed Sayao AL, Devonshire V, Tremlett H. Longitudinal follow-up of “benign” multiple sclerosis at 20 years. Neurology. 2007;68(7):496-500. [PMID:17296915]. See PubMed Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol. 2007; 6(9):805-815. [PMID:17706564]. See PubMed

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Neuromuscular Disorders • • • •

Peripheral Neuropathies Amyotrophic Lateral Sclerosis Neuromuscular Junction Disorders Myopathy

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Typical findings on neurologic examination in patients with a peripheral neuropathy include sensory loss, muscle weakness, and reduced or absent deep tendon reflexes in the distal extremities. Small-fiber nerves cannot be detected by routine electromyography and may be best assessed with skin biopsy or autonomic nerve studies. In patients with suspected median and ulnar neuropathy, electromyographic studies are necessary to establish the diagnosis, determine severity, and diagnose other diseases (such as cervical radiculopathy) that may be subclinical. Ulnar neuropathy causes numbness of the fourth and fifth fingers and, occasionally, weakness of the hand. Treatment of Bell palsy should include corneal protection and, if the patient is seen within 72 hours of symptom onset, oral prednisone.

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Distal sensorimotor peripheral neuropathy is the most common type of neuropathy in patients with diabetes mellitus. All patients with small-fiber peripheral neuropathy should be screened for diabetes mellitus by measurement of their fasting plasma glucose level and, if normal or minimally elevated, a 2-hour glucose tolerance test. Patients with Guillain-Barré syndrome, characterized by limb weakness, sensory loss, and reduced or absent deep tendon reflexes on neurologic examination, require treatment with either intravenous immune globulin or plasma exchange; corticosteroids are not effective. Patients with chronic inflammatory demyelinating polyradiculoneuropathy have chronic symptoms and signs similar to the acute ones of Guillain-Bathé syndrome and require long-term immune-modulating therapy. Corticosteroids and neuromuscular junction–blocking agents should be avoided in patients with critical illness neuropathy. Neuropathic pain, which is common in patients with peripheral neuropathy, typically affects the distal extremities and is often worse at night. Both upper and lower motoneuron findings are present in patients with amyotrophic lateral sclerosis. Bilevel positive airway pressure and percutaneous endoscopic gastrostomy tube placement, when indicated, have been shown to prolong survival and improve quality of life in patients with amyotrophic lateral sclerosis. Approximately 85% of patients with myasthenia gravis have antibodies directed against the acetylcholine receptor. CT scan of the chest should be performed in patients with myasthenia gravis to exclude the presence of a thymoma. Treatment of patients with myasthenia gravis is based on symptom distribution and severity and includes pyridostigmine and usually the addition of immune-modulating agents. At least 50% of patients diagnosed with Lambert-Eaton myasthenic syndrome ultimately develop a malignancy, most commonly small cell lung cancer. Corticosteroid-induced myopathy is the most common endocrine-related muscle disorder. Electromyography findings and serum creatine kinase levels are normal in patients with corticosteroid-induced myopathy. Proximal limb weakness is a common but correctable finding in patients with myopathy and hyperthyroidism, hypothyroidism, hyperparathyroidism, or vitamin D deficiency.

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Peripheral Neuropathies Peripheral neuropathies are common disorders that may involve a single nerve (mononeuropathy), two or more nerves in different sites (mononeuropathy multiplex), or many nerves over a wide area, which causes a more generalized disorder (polyneuropathy).

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General Findings and Diagnosis At presentation, patients with a peripheral neuropathy typically have sensory symptoms, such as numbness and tingling, burning or lancinating pain, weakness, and unsteady gait. Symptoms most commonly involve the distal extremities, particularly the feet. With increasing disease severity, signs and symptoms may become more profound and progress to involve the proximal extremities. The most common categories of peripheral neuropathies are listed in Table 25. Evaluation requires a review of symptom distribution; time course; medical, medication, and family history; and any associated autonomic symptoms, such as orthostatic hypotension, constipation, and early satiety. Typical findings on neurologic examination include sensory loss, muscle weakness, and reduced or absent deep tendon reflexes in the distal extremities. The history and neurologic examination help determine the cause of a suspected peripheral neuropathy and guide the diagnostic evaluation. Routine laboratory studies include a complete blood count, measurement of erythrocyte sedimentation rate and serum vitamin B12 and fasting plasma glucose levels, and serum immunofixation. Electromyography (EMG) helps confirm the diagnosis and characterize the type (axonal or demyelinating), severity, and distribution of the neuropathy. Additional laboratory studies, such as cerebrospinal fluid (CSF) examination and nerve or skin biopsies, may be necessary. CSF examination should be considered in patients with acute, severe, or rapidly progressive neuropathy and in those with a demyelinating neuropathy. Sural nerve biopsy is most typically performed in patients with suspected vasculitis or amyloidosis. Skin biopsy may be necessary to diagnose a small-fiber neuropathy, given that EMG is often normal in this condition. Small fiber neuropathies often present with painful sensory symptoms, such as burning, dysesthesias, paresthesias, and autonomic symptoms and signs, without significant motor weakness. Autonomic testing may also be performed in patients with a suspected smallfiber neuropathy or in patients with symptoms suggestive of dysautonomia. This testing typically includes tests of sudomotor (sweating), cardiovagal (heart rate change with Valsalva or deep breathing), and cardiovascular adrenergic (blood pressure response with tilt-table testing) function.

Table 25. Clinical Correlates of Peripheral Neuropathy Classification Signs and Symptoms Major Diagnostic Considerations Mononeuropathy multiplex Subacute asymmetric motor Vasculitis and sensory impairment Diabetes mellitus Sensory neuropathy Severe pansensory loss Sjögren syndrome (sensory ataxia) Paraneoplastic syndrome Copper deficiency

Autonomic neuropathy

Small-fiber neuropathy

Orthostatic hypotension

Celiac disease Amyloidosis

Constipation

Diabetes mellitus

Early satiety

Paraneoplastic syndrome

Erectile dysfunction Burning extremity pain without weakness

Diabetes mellitus Impaired glucose tolerance

Normal reflexes Sjögren syndrome

Acquired sensorimotor neuropathy

Distal sensory loss and diminished reflexes

Familial burning feet syndrome Diabetes mellitus Monoclonal gammopathy

Distal extremity weakness Hereditary sensorimotor neuropathy

Polyradiculoneuropathy

High arches

Toxic (chemotherapy) Charcot-Marie-Tooth disease

Hammer toes

Familial amyloidosis

Family history Severe weakness

Guillain-Barré syndrome

Sensory loss

Chronic inflammatory demyelinating polyradiculoneuropathy

Areflexia Motor neuropathy

Asymmetric weakness

Amyloidosis Multifocal motor neuropathy

Muscle atrophy

Motoneuron disease

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Mononeuropathies

Median and ulnar neuropathies are the most common mononeuropathies and are typically due to compression of these nerves at the wrist and elbow, respectively. Carpal tunnel syndrome, for example, refers to median nerve compression at the wrist in the carpal tunnel. This syndrome is associated with paresthesias and occasionally with pain or weakness involving the fingers. Examination may show sensory loss over the palmar surface of the first three digits and weakness of abduction and opposition of the thumb. The paresthesias are often worse at night or when holding a book or steering a car. EMG is essential to confirm the diagnosis, to exclude other subclinical disorders, and to establish disease severity. Conservative treatment options include wrist splints and corticosteroid injections. Surgery should be considered in patients with severe sensory loss, hand weakness, moderate to severe EMG findings, or failure to respond to conservative therapy. Ulnar neuropathy causes numbness of the fourth and fifth fingers and, when severe, may cause weakness of interosseous muscles. EMG should be performed to localize the site of ulnar nerve impairment and to document severity. The elbow is the most frequent site of compression. Patients are initially managed conservatively with a splint that can be used during sleep and instructions to avoid resting the elbow on furniture and other objects or to use an elbow pad. When conservative measures fail, surgical options include either decompression or translocation of the ulnar nerve. Bell palsy refers to paralysis of the facial nerve causing weakness of ipsilateral facial muscles. Mounting evidence implicates human herpesvirus 1 in the pathogenesis of this condition. Symptoms typically begin suddenly and peak over 1 to 2 days. Paralysis of the upper and lower face distinguishes Bell palsy from stroke, which affects only lower facial muscles (sparing the forehead and eye) when associated with facial paralysis. Most patients experience excellent recovery, although as many as 30% of patients may have poor recovery. Treatment involves eye patching and lubrication to protect the cornea. A recently reported randomized, double-blind, placebo-controlled trial showed improved outcome in patients treated with prednisone within 72 hours of symptom onset. Evidence-based studies have not clearly demonstrated benefit with antiviral therapy.

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Brachial Plexopathy The brachial plexus is responsible for sensory and motor innervation of the entire upper limb. Conditions that can impair brachial plexus function include trauma, radiation, carcinomatous infiltration, and neuralgic amyotrophy. Neuralgic amyotrophy, or Parsonage-Turner syndrome, is a self-limited, idiopathic, inflammatory disorder of the brachial plexus. Severe shoulder and arm pain is typically followed by sensory loss and weakness of the upper limb. EMG studies confirm the diagnosis. Corticosteroid therapy can be helpful for pain.

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Polyneuropathies • • • •

Neuropathies of Diabetes Mellitus and Impaired Glucose Tolerance Hereditary Neuropathies Polyradiculoneuropathies Critical Illness Neuropathy

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Neuropathies of Diabetes Mellitus and Impaired Glucose Tolerance Diabetes mellitus is associated with several different neuropathies (Table 26). More than one type may exist in the same patient. The most common is a distal sensorimotor peripheral neuropathy. Patients may be asymptomatic but typically report numbness, tingling, and often lancinating or burning foot pain. Median and ulnar mononeuropathies are also common in patients with diabetes. Involvement of autonomic nerves can occur in patients with long-standing diabetes. Diabetic lumbosacral radiculoplexus neuropathy (diabetic amyotrophy) is a severe form of neuropathy in patients with mild or early diabetes and may even occur in those with previously undiagnosed diabetes. Patients typically present with weight loss, unilateral leg pain (often severe), numbness, proximal weakness, and atrophy. Signs and symptoms develop over weeks, may progress over several months, and may later involve the contralateral leg or even the arms. Small-fiber peripheral neuropathy frequently develops in patients with diabetes and in those with impaired glucose tolerance. Symptoms include numbness, tingling, and burning or lancinating foot pain. All patients with a small-fiber peripheral neuropathy should be screened for diabetes. This should include measurement of fasting plasma glucose level, hemoglobin A1c determination, and (if these values are normal or only minimally elevated) a 2-hour glucose tolerance test.

Table 26. Peripheral Nerve Manifestations of Diabetes Mellitus Classification Sensorimotor peripheral neuropathy

Signs and Symptoms Distal sensory loss and weakness May cause pain

Radiculopathy

May be asymptomatic Sensory loss

Mononeuropathy

Weakness in distribution of nerve root(s) Sensory loss

Autonomic neuropathy

Weakness in distribution of single nerve, most often the median or ulnar nerve Orthostatic hypotension Constipation Early satiety

Diabetic lumbosacral radiculoplexus neuropathy (diabetic amyotrophy)

Erectile dysfunction Severe pain, weakness, and sensory loss Weight loss

Small-fiber neuropathy

Autonomic symptoms common Burning extremity pain without weakness

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Hereditary Neuropathies Although hereditary neuropathies are a common cause of peripheral neuropathy, establishing a diagnosis is often challenging. Patients are frequently unaware of their family medical history; neuropathy in family members may have been misdiagnosed, or family members may have died before a hereditary neuropathy was recognized. De novo mutations are also common. The hereditary neuropathies can be broadly categorized as hereditary small-fiber neuropathies, Charcot-Marie-Tooth disease, and familial amyloidosis. Patients with hereditary small-fiber neuropathy typically have burning or lancinating pain in the feet, which can progress to involve the legs and hands. They may also have signs and symptoms of dysautonomia. EMG findings are often normal. Conditions to consider include autosomal dominant burning feet syndrome, hereditary sensory autonomic neuropathies, and Fabry disease. Patients with Charcot-Marie-Tooth disease typically present with distal extremity weakness, an unsteady gait, and numbness. These patients do not develop neuropathic pain symptoms and typically have high arches, hammer toes, and distal leg atrophy (Figure 16). EMG is important to determine whether axonal or demyelinating neuropathy is present because genetic testing is generally commercially available for the demyelinating but not the axonal forms of Charcot-

Marie-Tooth disease. Treatment is supportive, including bracing (for example, an ankle-foot orthosis) when indicated.

Figure 16. Inherited neuropathy. Distal leg atrophy (left) and a high arch and hammer toe (right) in a patient with an inherited neuropathy, in this case Charcot-Marie-Tooth disease, are shown.

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Polyradiculoneuropathies Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) involve an inflammatory process directed against both nerve roots and peripheral nerves. Guillain-Barré syndrome is an acute disorder (symptoms peak within 4 weeks), and CIDP is more chronic (symptoms must be present for at least 8 weeks for a diagnosis). The distinction between acute and chronic forms is important because Guillain-Barré syndrome is a self-limited disorder, whereas patients with CIDP require ongoing immune-modulating therapy.

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Guillain-Barré Syndrome At presentation, patients with Guillain-Barré syndrome have numbness, weakness, unsteady gait, and often neuropathic pain in the extremities. Most patients have a preceding history of infection, trauma, or surgery. The most frequent precipitating factor is Campylobacter jejuni infection that

causes a diarrheal syndrome. Findings on neurologic examination typically include limb weakness, sensory loss, and reduced or absent deep tendon reflexes. Bulbar and respiratory muscle weakness may impair speaking and swallowing functions and result in respiratory failure. Dysautonomia develops in 20% of patients, most often in those with severe, generalized weakness and respiratory failure. Signs and symptoms of dysautonomia include cardiac arrhythmias, marked blood pressure instability, and constipation. All patients with suspected Guillain-Barré syndrome should be hospitalized for urgent evaluation and ongoing observation. Initial evaluation requires EMG, CSF examination, and pulmonary function testing (including measurement of maximal inspiratory and expiratory pressures). The EMG typically shows a predominantly demyelinating process. Typical CSF findings include a normal glucose level and cell count and an elevated protein concentration; presence of CSF pleocytosis in patients with suspected Guillain-Barré syndrome should prompt consideration of other diagnoses, such as HIV, cytomegalovirus, West Nile virus infection, or other infectious or inflammatory processes. Treatment of Guillain-Barré syndrome includes either intravenous immune globulin or plasma exchange. Intravenous immune globulin, 0.4 g/kg, is given once daily for 5 consecutive days, and plasma exchange involves five exchanges of 200 mL/kg over 10 days. Both treatments are equally effective. Corticosteroids are not effective. Supportive therapies are crucial, including respiratory and cardiovascular monitoring, venous thrombosis prophylaxis, physical and occupational therapy, and bowel care. The overall prognosis in patients with Guillain-Barré syndrome is good, with 80% of patients achieving recovery with little or no disability. Poor prognostic features include the need for mechanical ventilation, axonal findings on EMG, and rapidly progressive weakness.

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Chronic Inflammatory Demyelinating Polyradiculoneuropathy At presentation, patients with CIDP have symptoms similar to those of patients with GuillainBarré syndrome, but the symptoms are chronic (of at least 8 weeks in duration). Symptoms may be progressive or relapsing-remitting. Diagnostic evaluation includes EMG, CSF examination, and, occasionally, nerve biopsy. Patients require long-term immune-modulating therapy with prednisone, mycophenolate mofetil, azathioprine, or cyclosporine. A brief or ongoing course of intravenous immune globulin may also be helpful. Plasma exchange may be tried in patients with severe CIDP to attempt to induce or sustain remission.

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Critical Illness Neuropathy Neuropathy develops in as many as 50% to 70% of patients with sepsis. Critical illness neuropathy is typically recognized when a patient is unable to be weaned from mechanical ventilation or when severe, generalized weakness of the extremities develops during or after recovery from a critical illness. A complete history, neurologic examination, and EMG are required to exclude other disorders that can present similarly, particularly given that the neurologic examination in these critically ill, often encephalopathic patients may be limited. The specific EMG finding in critical illness neuropathy is an axonal sensorimotor peripheral neuropathy. There is growing consensus that most patients with critical illness neuropathy also have a myopathy of critical illness or a critical illness neuromyopathy. Once the diagnosis of critical illness neuropathy is suspected, corticosteroids and neuromuscular junction–blocking agents are contraindicated because they may play a role in pathogenesis. Treatment is supportive and includes ongoing physical and occupational therapy. The severity of critical illness neuropathy is associated with length of stay in the intensive care unit, elevated plasma glucose levels, and decreased serum albumin levels. Prognostic data are limited, but at least one third of patients may have significant residual weakness.

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Treatment of Neuropathic Pain Neuropathic pain is common in patients with peripheral neuropathy. It is usually described as a burning or lancinating pain that typically affects the distal extremities and is often worse at night. Physical measures, such as soaking the affected area in warm or cold water, may be helpful. Many different medications are used to treat neuropathic pain. Topical agents, such as lidocaine patches and capsaicin cream, may be helpful and do not cause systemic side effects. Tricyclic antidepressants, such as amitriptyline and nortriptyline, are first-line agents but can cause excessive sedation, orthostatic hypotension, and weight gain. Gabapentin, pregabalin, and duloxetine are newer agents that may be helpful and are now considered first-line agents. Tramadol is a nonnarcotic, centrally acting, second-line agent that is often used adjunctively to decrease pain. Mexiletine, carbamazepine, and lamotrigine are third-line agents. Some patients may require more than one drug for pain control. Although somewhat controversial, opioid medications may be needed to treat some patients. Patients with refractory pain may benefit from oral medications that have a different mechanism of action (such as a tricyclic antidepressant in conjunction with an anticonvulsant agent).

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Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive motoneuron disorder with an estimated incidence of two cases per 100,000 persons. Most cases are acquired or sporadic, but some (about 10%) are inherited. Approximately 20% of patients with inherited ALS have a mutation in the superoxide dismutase gene. Superoxide dismutase is an important mediator in free-radical pathways, and mutations in this gene may lead to excessive free-radical damage to anterior horn cells. Patients with ALS typically report progressive painless weakness, atrophy, and fasciculations beginning in an arm or leg. Patients do not have sensory loss, pain, or impairment in bowel and bladder function. In addition to lower motoneuron signs of atrophy and fasciculations, upper motoneuron signs, such as hyperreflexia and extensor plantar responses, are also typically seen. Approximately 20% of patients have bulbar-onset ALS, characterized by slurred speech, difficulty swallowing, and emotional lability. As ALS progresses, patients develop weight loss and respiratory insufficiency. The presence of cognitive impairment, specifically frontotemporal dementia, is being increasingly recognized in some patients (see Dementia). Findings on neurologic examination include limb weakness, fasciculations, atrophy, brisk deep tendon reflexes, and extensor plantar responses. Signs of bulbar impairment (such as slurred speech), tongue atrophy, and fasciculations may also be evident. MRI of the brain and spinal cord should be performed to exclude a structural lesion. EMG is essential to rule out other disorders and to establish the extent and severity of denervation. Pulmonary function tests and overnight pulse oximetry studies can establish the presence of respiratory insufficiency. Patients with bulbar signs or symptoms require evaluation of swallowing function. Management is symptom based, and referral to a multidisciplinary ALS clinic for ongoing care and support is beneficial. Riluzole, a glutamate antagonist, is the only medication approved by the U.S. Food and Drug Administration for treatment of ALS and has been shown in clinical trials to slow the decline of muscle weakness and prolong survival by a median of 83 days. Use of noninvasive positive-pressure ventilation with bilevel positive airway pressure has also been shown to prolong survival and improve quality of life. In addition to symptoms of nocturnal hypoventilation, indications for ventilatory support include a forced vital capacity of less than 50%, nocturnal oxygen saturation of less than 90% for more than 1 minute, maximal inspiratory pressure of less than 60 cm H2O, and maximal expiratory pressure of less than 30 cm H2O. Placement of a percutaneous endoscopic gastrostomy tube has also been shown to improve the quality of life in patients with ALS. Such tube placement should be considered when patients experience a 10% or greater weight loss, require 30 minutes or more to finish a meal, or have episodes of coughing and choking when eating. Excessive salivation can be treated symptomatically with anticholinergic agents, such as glycopyrrolate, amitriptyline, and benztropine. When oral medications are ineffective, injection of botulinum toxin into the parotid or submandibular glands can be considered. Excessive

emotional lability can be treated with either tricyclic antidepressants or selective serotonin reuptake inhibitors. Augmentative and alternative communication devices can help preserve communication when speech becomes unintelligible.

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Neuromuscular Junction Disorders Disorders of neuromuscular junction transmission should be considered in patients with painless proximal limb weakness and in those with bulbar symptoms, such as diplopia, ptosis, dysarthria, and dysphagia. Myasthenia gravis and Lambert-Eaton myasthenic syndrome are the primary neuromuscular junction disorders.

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Myasthenia Gravis Myasthenia gravis is caused by an immune-mediated attack on postsynaptic neuromuscular junctions. Approximately 85% of patients have antibodies directed against the acetylcholine receptor. Among patients without acetylcholine receptor antibodies, approximately 50% have antibodies directed against muscle-specific kinase receptors. Patients with the disease but without detectable antibodies against any of these receptors are considered to have seronegative myasthenia gravis. Myasthenia gravis is estimated to occur in 140 per million persons in the United States. There are two recognized forms: ocular and generalized. The ocular disorder is less common and occurs in approximately 10% of patients. Some patients who initially have only ocular symptoms ultimately develop the generalized disorder. Generalized myasthenia gravis can affect either sex at any age but typically begins in the third and fourth decades in women and after age 50 in men. Signs and symptoms in patients with ocular myasthenia gravis include fatigable blurring of vision, binocular diplopia, and ptosis. Patients with generalized myasthenia gravis typically report limb weakness, diplopia, slurred speech, dysphagia, and dyspnea. Findings on neurologic examination include ptosis, impaired ocular motility, and limb weakness that increases with repeated testing (fatigable weakness). Deep tendon reflexes and the sensory examination are normal. Diagnostic evaluation includes screening assays for acetylcholine antibodies and, if negative, testing for muscle-specific kinase antibodies. Serum thyroid-stimulating hormone levels should also be measured because of the association of myasthenia gravis with autoimmune thyroid disorders. EMG studies, including repetitive nerve stimulation studies, help to exclude other conditions and confirm the diagnosis. Single-fiber EMG is the most sensitive diagnostic test.

Once the diagnosis is confirmed, a CT scan of the chest should be performed to exclude a thymoma, which is present in up to 15% of patients. Treatment of myasthenia gravis is based on symptom distribution and severity. Pyridostigmine, an acetylcholinesterase inhibitor, is usually given as first-line therapy (Table 27). Patients with mild ocular or generalized myasthenia gravis may not require additional immune-modulating agents, at least initially. Some patients may experience a transient worsening of myasthenic symptoms when first placed on corticosteroids. Prednisone plus mycophenolate mofetil, azathioprine, cyclosporine, or rituximab is used to induce or sustain remission. Those with significant bulbar dysfunction, respiratory impairment, or severe limb weakness may benefit from plasma exchange, given as five exchanges over 10 days. Thymectomy is indicated in patients with CT evidence of thymoma and may be considered in patients younger than 50 years of age without thymoma.

Table 27. Treatment of Myasthenia Gravis Drug Classificationa Medication or Procedure Immediate Pyridostigmine Intermediate Plasma exchange Intravenous immune globulin Prednisone Long-term Mycophenolate mofetil Azathioprine Rituximab Cyclosporine Thymectomy a

Medications are classified on the basis of the time to clinical effect.

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Lambert-Eaton Myasthenic Syndrome Lambert-Eaton myasthenic syndrome is a rare neuromuscular junction transmission disorder caused by antibodies directed against presynaptic voltage-gated P/Q-type calcium channels. This syndrome occurs in 5% of patients who have small cell lung cancer and also in patients with other cancers. The diagnosis of a cancer frequently follows the diagnosis of Lambert-Eaton myasthenic syndrome.

Patients typically report progressive proximal limb weakness, and most have symptoms of dysautonomia, such as dry eyes, dry mouth, constipation, and erectile dysfunction. LambertEaton myasthenic syndrome should be considered in any patient with findings of proximal limb weakness and absent deep tendon reflexes on neurologic examination. Facilitation (improvement of deep tendon reflexes and muscle strength after brief isometric exercise) may also be noted on neurologic examination. EMG testing and positive assays for P/Q-type calcium channel antibodies establish the diagnosis. Patients with newly diagnosed Lambert-Eaton myasthenic syndrome but without a known malignancy should undergo evaluation for occult cancer, because at least 50% will ultimately develop a malignancy (mostly small cell lung cancer). CT scans of the chest, abdomen, and pelvis should be performed in all patients, and if results are normal, whole-body positron emission tomography should be performed. Treatment consists of pyridostigmine and 3,4diaminopyridine; the latter is available on a compassionate-use basis at some institutions in the United States.

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Myopathy Myopathy should be suspected in patients with a history of progressive limb weakness but without signs or symptoms of sensory loss. Most myopathies primarily affect proximal limb muscles, but some myopathic disorders may severely affect specific muscle groups (for example, finger flexor and quadriceps muscle weakness in inclusion-body myositis). Whereas motoneuron disorders typically begin asymmetrically, most myopathies cause symmetric limb weakness. Although many patients with a myopathy report fatigue, the presence of markedly fluctuating, fatigue-induced weakness is not typical and should suggest a neuromuscular junction disorder. Muscle pain is not typical in most myopathic disorders and should prompt consideration of other conditions. However, specific myopathic disorders that may be associated with muscle pain include toxic myopathies, myotonic dystrophy, metabolic myopathies, infectious myositis, and infiltrative myopathies, such as amyloidosis and sarcoidosis. Because acquired myopathies do not typically cause significant facial muscle dysfunction, a neuromuscular junction disorder should be considered in a patient with a history of ocular symptoms or facial muscle weakness. Certain inherited myopathic disorders, including oculopharyngeal muscular dystrophy, facioscapulohumeral dystrophy, and certain mitochondrial myopathies, can prominently affect ocular or facial muscles. Age of symptom onset and rate of progression are important historical features. A rapidly progressive myopathic disorder suggests an inflammatory myopathy, such as polymyositis or dermatomyositis, whereas a chronic, slowly progressive disorder is typical of an inherited myopathy. Myopathic disorders are frequently associated with involvement of other organ systems. For example, the presence of a typical rash in conjunction with proximal limb weakness suggests

dermatomyositis. Cardiac disease, including arrhythmias and cardiomyopathy, is also common in many types of muscular dystrophy, and patients with a myopathy known to cause cardiac disease require screening. Cataracts and frontal balding are common features in patients with myotonic dystrophy. EMG is necessary to help confirm the presence of a myopathy, exclude neuromuscular junction disorders, and establish the distribution and severity of disease. EMG is helpful to guide the selection of a site for muscle biopsy and can be used to monitor response to treatment. Muscle biopsy should be performed in patients with significant muscle weakness or elevated serum creatine kinase levels and in those with EMG findings of significant myopathy. Genetic testing should be considered in patients with a suspected inherited myopathy and can obviate the need for muscle biopsy in many of them.

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Inflammatory Myopathies The inflammatory myopathic disorders, which include polymyositis, dermatomyositis, and inclusion-body myositis, are discussed in detail in MKSAP 15 Rheumatology.

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Endocrine-Related Myopathies • • • •

Corticosteroid-Induced Myopathy Thyrotoxic Myopathy Hypothyroid Myopathy Myopathy Associated with Hyperparathyroidism and Vitamin D Deficiency

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Corticosteroid-Induced Myopathy Corticosteroid-induced myopathy is the most common endocrine-related muscle disorder. Patients report proximal limb weakness, most often in the lower limbs. Most patients have a cushingoid appearance. Ocular, facial, and distal extremity muscle strength and deep tendon reflexes are normal. Women are affected nearly twice as often as men. Prednisone dosages of 30 mg/d or higher seem to confer the greatest risk. Pulsed and alternate-day corticosteroid regimens are less likely to induce myopathy.

Although EMG findings and serum creatine kinase levels are normal in patients with corticosteroid-induced myopathy, these studies should be obtained to rule out other conditions, such as neuromuscular junction disorders or other neurogenic processes. Muscle biopsy results show only atrophy of type IIb muscle fibers. Treatment involves discontinuing or tapering corticosteroid therapy.

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Thyrotoxic Myopathy Although most patients with hyperthyroidism do not report limb weakness as a presenting symptom, symmetric proximal limb weakness is typically found on examination. Other signs and symptoms of hyperthyroidism are present, including anxiety, tremor, heat intolerance, insomnia, and weight loss. Myalgia and fatigue are also commonly reported. Serum creatine kinase measurement and EMG findings are typically normal. After treatment of the thyrotoxic state, the myopathy usually resolves over several months.

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Hypothyroid Myopathy Proximal limb weakness develops in one third of patients with hypothyroidism. Myalgia, cramps, and muscle hypertrophy are also common. Neurologic examination findings show proximal limb weakness and delayed relaxation of deep tendon reflexes. Serum creatine kinase levels may be normal or slightly elevated. EMG findings are usually normal, although minor myopathic changes are occasionally seen. Gradual improvement in myopathic symptoms occurs with correction of the hypothyroidism.

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Myopathy Associated with Hyperparathyroidism and Vitamin D Deficiency Myopathy occurs in patients with both primary and secondary hyperparathyroidism and causes proximal limb weakness, particularly of the lower extremities. Serum parathyroid hormone levels are elevated, and serum calcium levels are also usually increased. Serum creatine kinase measurement and EMG findings are typically normal, although minor myopathic changes may be seen on EMG. Myopathy improves or resolves following medical or surgical treatment of the hyperparathyroidism.

Vitamin D deficiency has been associated with osteomalacia and proximal muscle weakness. There is strong evidence that vitamin D deficiency, even in the absence of osteomalacia, is associated with myalgia and proximal limb weakness. Low serum 25-hydroxyvitamin D levels suggest the diagnosis. Serum creatine kinase measurement and EMG findings are usually normal, and myopathic symptoms typically improve following vitamin D supplementation.

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Inherited Myopathies The inherited myopathies are a diverse group of disorders that include congenital myopathies, muscular dystrophies, myotonic disorders, and metabolic myopathies (Table 28). Inheritance patterns are autosomal dominant, autosomal recessive, or, rarely, X-linked or maternal. Age of onset, rate of disease progression, and severity of disease are often quite variable. The genetic and molecular abnormalities have been identified in some disorders and are unknown in others.

Table 28. Inherited Myopathies Myopathy Type Congenital Central core disease

Nemaline myopathy Centronuclear myopathy Myofibrillar myopathy Congenital fiber-type disproportion myopathy Muscular Dystrophiesa Limb-girdle muscular dystrophy Duchenne muscular dystrophy Becker muscular dystrophy Emery-Dreifuss muscular dystrophy

Notes Allelic with malignant hyperthermia Mutation of ryanodine receptor gene Can present in infancy, childhood, or adulthood May have elongated face, high-arched palate, and scoliosis In addition to proximal myopathy, may have polyneuropathy and cardiomyopathy May have dysmorphic facial and skeletal features

Proximal greater than distal weakness X-linked Limb-girdle weakness with cardiomyopathy X-linked Proximal greater than distal weakness

Facioscapulohumeral muscular dystrophy Distal myopathy

Cardiac conduction defects and muscle contractures Asymmetric facial, scapular and proximal upper limb weakness Asymmetric distal extremity weakness

Myotonic dystrophy

Myotonia and weakness of the forearm and peroneal muscular groups Balding Cataracts

Proximal myotonic myopathy

Cardiac dysrhythmia Myotonia Proximal weakness and pain

Oculopharyngeal muscular dystrophy

Cardiac dysrhythmia Ptosis Dysphagia Proximal limb weakness

Metabolic Myopathies Glycogen metabolism disorders Lipid metabolism disorders Mitochondrial myopathies

Cramping, stiffness, and pain shortly after exertion Cramping, stiffness, and pain shortly after exertion Exercise intolerance Various other neurologic and systemic symptoms

a

Not a comprehensive list.

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Critical Illness Myopathy Myopathy is a common complication of critical illness and most likely occurs more frequently than does critical illness neuropathy (see Critical Illness Neuropathy). As in critical illness neuropathy, critical illness myopathy should be suspected in patients who cannot be weaned from mechanical ventilation. Diffuse, flaccid weakness involving the limb, neck, diaphragm, and even facial muscles is noted on examination. Serum creatine kinase levels are often normal but may be elevated in patients with acute necrotizing myopathy. Muscle biopsy is generally not needed for diagnosis. The prognosis is favorable in patients without an elevated serum creatine kinase level or necrosis on muscle biopsy.

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Toxic Myopathies Prompt recognition of toxic myopathies is essential because of the potential for reversibility. Statin medications may cause an acute or subacute painful proximal myopathy with rhabdomyolysis. Myalgia, with or without a slight increase in the serum creatine kinase level, is more commonly reported. Other substances with established myotoxic potential include corticosteroids (see Corticosteroid-Induced Myopathy), alcohol, chloroquine, hydroxychloroquine, interferon alfa, colchicine, and procainamide.


•

• • •

•

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Bolton CF. Neuromuscular manifestations of critical illness. Muscle Nerve. 2005;32(2):140-163. [PMID:15825186]. See PubMed Dyck PJB, Windebank AJ. Diabetic and nondiabetic radiculoplexus neuropathies: new insights into pathophysiology and treatment. Muscle Nerve. 2002;25(4):477-491. [PMID:11932965]. See PubMed Hoffman-Snyder C, Smith BE, Ross MA, Hernandez J, Bosch EP. Value of the oral glucose tolerance test in the evaluation of chronic idiopathic axonal polyneuropathy. Arch Neurol. 2006;63(8):1075-1079. [PMID:16769858]. See PubMed Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81(3):353-373. [PMID:16529140]. See PubMed Hughes RAC, Wijdicks EFM, Benson E, et al. Supportive care for patients with GuillainBarré syndrome. Arch Neurol. 2005;62(8): 1194-1198. [PMID:16087757]. See PubMed Oh SJ, Kurokawa K, de Almeida DF, Ryan HF Jr, Claussen GC. Subacute inflammatory demyelinating polyneuropathy. Neurology. 2003;61(11):1507-1512. [PMID:14663033]. See PubMed Simmons Z. Management strategies for patients with amyotrophic lateral sclerosis from diagnosis through death. Neurologist. 2005; 11(5):257-270. [PMID:16148733]. See PubMed Sullivan FM, Swan IR, Donnan PT, et al. Early treatment with prednisolone or acyclovir in Bell’s palsy. N Engl J Med. 2007;357(16): 1598-1607. [PMID:17942873]. See PubMed

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Neuro-oncology • • • • •

Introduction Primary Central Nervous System Tumors Primary Central Nervous System Lymphoma Metastatic Brain Tumors Paraneoplastic Syndromes of the Nervous System

Key Points

• • • • • • • •

• • • •

Common presenting symptoms of brain malignancy include seizures, headaches, behavioral changes, and subacute progressive focal neurologic deficits. Gliomas account for 50% of all primary brain tumors. Surgical resection is curative in patients with grade-1 gliomas; median survival is 9 years for grade-2 lesions, 3 years for grade-3 lesions, and 1 year for glioblastoma multiforme. Meningiomas appear on CT scans and MRIs as well-delineated, partially calcified, durabased masses with strong homogeneous contrast enhancement. Small, asymptomatic meningiomas in older adults can be managed by serial clinical evaluations and radiographic follow-up studies. Surgical resection is the treatment of choice for meningiomas in younger patients with and without symptoms and in symptomatic older adults and is curative when complete. Primary central nervous system lymphoma is diagnosed by detection of a clonal B-cell population in serum or cerebrospinal fluid or by brain biopsy. Treatment for most patients with primary central nervous system lymphoma involves high-dose systemic or intrathecal methotrexate followed by whole-brain radiation therapy. In adults, the malignant tumors most likely to spread to the brain are lung cancer (50%), breast cancer (10% to 20%), and melanoma (10%). Patients with a single brain metastasis may be treated surgically; those with multiple metastases require palliative therapy. A paraneoplastic syndrome should be suspected in any patient with an otherwise unexplained subacute progressive neurologic disorder. The cause of paraneoplastic syndromes is most likely autoimmune, and the diagnosis is made by detecting antibodies in either serum or cerebrospinal fluid.

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Introduction Neuro-oncologic disorders are classified as primary tumors, metastatic tumors, and paraneoplastic syndromes. Patients with primary and metastatic brain lesions typically present with seizures, nonfocal neurologic findings (such as headache and behavioral and cognitive changes), or subacute progression of a focal neurologic deficit (such as hemiparesis). Neurologic deficits result from edema, compression, or infiltration of the brain and spinal cord and vary according to tumor location. Definitive treatment depends on tumor type and may include resection, radiation therapy, and chemotherapy. Corticosteroids can provide symptomatic relief when tumor-associated edema is present. Seizures should be treated with anticonvulsant agents. However, primary prophylaxis for seizures is not of proven benefit.

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Primary Central Nervous System Tumors

Primary central nervous system (CNS) tumors develop from nervous system cells or their embryonic precursors. The most common of these neoplasms are gliomas and meningiomas, followed by CNS lymphomas.

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Gliomas Gliomas account for 50% of all primary brain tumors. The most common subtypes are astrocytomas, oligodendrogliomas, mixed gliomas, and ependymomas. In the World Health Organization histopathologic classification system, gliomas are classified from grade 1 to 4, with higher grades correlating with more aggressive behavior and poorer prognosis. The most common glial tumor, the grade-4 glioblastoma multiforme, is also the most malignant. Low-grade gliomas (grades 1 and 2) occur most often in the fourth to sixth decade of life. Seizures are the most common presenting symptom. Although grade-2 gliomas grow slowly, they almost inevitably transform into a higher grade if left untreated. High-grade gliomas (grades 3 and 4) are most often diagnosed in patients in their forties to sixties. On an MRI, which is the imaging modality of choice for detecting gliomas, low-grade gliomas appear as poorly marginated lesions with minimal contrast enhancement and little or no edema (Figure 17). Ninety percent of oligodendrogliomas are calcified. Higher-grade tumors are more likely to show irregular contrast enhancement and surrounding edema. Glioblastoma multiforme is further characterized by areas of necrosis and hemorrhage (Figure 18). Tissue diagnosis by brain biopsy or craniotomy resection is required. Specialized genetic testing is sometimes used for additional classification and prognosis. For example, loss of heterozygosity at chromosomes 1p and 19q in patients with an oligodendroglioma correlates with improved response to chemotherapy and prolonged survival. Surgical resection is curative for grade-1 gliomas. Grade-2 and -3 gliomas require maximally safe surgical resection followed by radiation therapy or chemotherapy, or both. Glioblastoma multiforme is refractory to treatment; however, radiation therapy and chemotherapy with temozolomide have a small, proved therapeutic benefit. Median survival is 9 years for grade-2 lesions, 3 years for grade-3 lesions, and 1 year for glioblastoma multiforme.

Figure 17. Low-grade glioma. Coronal flair MRI showing an infiltrating lesion (arrow) enlarging the postcentral gyrus.

Figure 18. Glioblastoma multiforme. Axial (left) and coronal (right) postcontrast T1-weighted MRI showing a large right temporal mass (arrows) with central necrosis and peripheral nodular enhancement.

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Meningiomas Meningiomas are benign, slow-growing, dura-based tumors. The second most common primary brain tumor in adults (after gliomas), meningiomas account for 20% of all primary brain tumors. Incidence increases with age and female sex. Most meningiomas are estrogen receptor– and progesterone receptor–positive, and approximately 50% are positive for androgen receptors. Exposure to exogenous hormones may be a risk factor for the development of meningioma. Meningiomas are often found incidentally during neuroimaging studies. At diagnosis, patients may be asymptomatic or have subtle signs and symptoms. Seizure is the most common presentation and is reported in greater than 50% of symptomatic patients. Meningiomas characteristically appear on CT scans and MRIs as a well-delineated, partially calcified, durabased mass with strong homogeneous contrast enhancement (Figure 19). Treatment depends on tumor size and location and age of the patient. Older adults with small, asymptomatic tumors can be managed conservatively with observation and serial neuroimaging studies. Surgical resection is the treatment of choice for younger patients with and without symptoms and for symptomatic older adults and is curative when complete. Radiation therapy or stereotactic radiosurgery may benefit patients with unresectable or rare aggressive meningiomas.

Figure 19. Meningiomas. Left, axial postcontrast T1-weighted MRI showing a meningioma arising from the falx cerebri. Right, coronal postcontrast T1-weighted MRI demonstrating a larger parafalcine meningioma with associated edema and mass effect. Note the homogeneous enhancement and “dural tail” (arrow) in both images.

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Primary Central Nervous System Lymphoma Primary central nervous system lymphoma is a rare form of non-Hodgkin lymphoma that is limited to the brain, meninges, spinal cord, and eyes; 90% of such tumors are large B-cell lymphomas. The prevalence has increased in recent decades but appears to be stabilizing at 3% to 4% of newly diagnosed primary CNS tumors. Severe immunosuppression is a risk factor, and the incidence is significantly increased in patients with congenital immunodeficiency and in patients who have received transplants. In immunocompromised patients, primary central nervous system lymphoma is associated with Epstein-Barr virus infection. Primary central nervous system lymphoma can occur at any age but peaks at ages 60 to 70 years in immunocompetent patients. Unlike patients with systemic lymphoma, those with primary central nervous system lymphoma present with neurologic deficits or seizures rather than “B” symptoms (fever and chills, drenching night sweats, fatigue, pruritus, and weight loss). Twenty percent of these patients have ocular involvement and report floaters, blurred vision, or eye pain.

MRI with contrast is the recommended diagnostic imaging study. The classic finding is a single, rounded, contrast-enhancing lesion involving the deep white matter or basal ganglia (Figure 20). Meningeal spread is the rule but may be difficult to detect on imaging studies. It is best assessed by cerebrospinal fluid examination, including cytology and flow cytometry studies that look for a monoclonal B-cell population. When cerebrospinal fluid analysis is nondiagnostic, stereotactic biopsy of the brain lesion is generally required to establish the diagnosis. Ocular involvement may be seen on slit lamp examination, and vitreal biopsy may also be used for diagnosis. Corticosteroid administration may cause primary central nervous system lymphoma to “vanish” temporarily and reduce the yield of tissue diagnosis. Withholding corticosteroids is therefore recommended, when feasible, until after tissue diagnosis. In severely immunosuppressed patients, the differential diagnosis of primary central nervous system lymphoma includes toxoplasmosis and progressive multifocal leukoencephalopathy. Polymerase chain reaction of the cerebrospinal fluid to detect Eptein-Barr virus and JC virus (causing progressive multifocal leukoencephalopathy) and serologic studies for toxoplasmosis may help distinguish between these causes, but tissue diagnosis is still the gold standard. Because primary central nervous system lymphoma is rare, determining the optimal treatment has been difficult. Surgery is seldom indicated and does not improve survival. Treatment for most patients involves high-dose systemic or intrathecal methotrexate followed by whole-brain radiation therapy. Chemotherapy alone is often recommended for patients over age 60 years because of the excessive neurotoxicity from radiation therapy in this age group. The 5-year survival rate after combined therapy is 25% to 40%. Even with treatment, however, local recurrence or progression is common.

Figure 20. Primary central nervous system lymphoma.

Axial (left) and coronal (right) T1-weighted MRI of the head with gadolinium enhancement in a patient with a primary central nervous system lymphoma. Note the homogeneous enhancement and periventricular location.

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Metastatic Brain Tumors Metastases to the central nervous system are more common than primary brain tumors and occur in 10% to 30% of all patients with cancer. In adults, the malignant tumors most likely to spread to the brain are lung cancer (50%), breast cancer (10% to 20%), and melanoma (10%). Signs and symptoms depend on the size and location of the metastases, which can develop in the brain, leptomeninges, and spinal cord. Symptoms may be subtle, so a high level of suspicion is justified in patients with known underlying primary tumors. MRI with contrast is the diagnostic study of choice and typically shows rounded, contrast-enhancing lesions at the gray-white junction with surrounding edema (Figure 21). Brain metastases may sometimes be the first manifestation of cancer elsewhere in the body, necessitating workup for the underlying primary malignancy. Tissue diagnosis is required and is generally best obtained from the primary lesion. When the primary lesion cannot be identified or is inaccessible, stereotactic brain biopsy can be considered. The prognosis for patients with brain metastases is poor. Treatment focuses on improving quality of life. For patients with a single metastatic lesion and otherwise limited systemic disease, standard treatment is surgical resection followed by whole-brain radiation therapy. Median survival is 10 to 16 months. For patients with multiple metastases, radiation therapy can be administered for palliation. Median survival is 3 to 6 months.

Figure 21. Central nervous system metastases. Left, axial postcontrast T1-weighted MRI showing a strongly enhancing nodular lesion in the left parietal lobe with marked surrounding edema and mass effect causing a left-to-right shift. Right, axial postcontrast T1-weighted MRI showing leptomeningeal enhancement from metastasis (arrows) that is seen most prominently over the right hemisphere and posteriorly along the falx cerebri.

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Paraneoplastic Syndromes of the Nervous System Paraneoplastic syndromes involve signs and symptoms of organ dysfunction in a patient with cancer that are unexplained by the direct effect of the tumor, metastatic disease, or treatment side effects. Although any organ system can be involved, deficits of the central and peripheral nervous systems are most commonly encountered. Paraneoplastic syndromes are rare and affect less than 1% of all cancer patients. Early recognition is important because the neurologic disorder often causes significant, irreversible morbidity. In addition, paraneoplastic symptoms are often the first sign of an underlying malignant tumor, which may still be focal and potentially curable. The most frequently identified primary tumors associated with paraneoplastic syndromes are small cell lung cancer; breast, ovarian, and testicular cancer; Hodgkin lymphoma; and thymoma. Although paraneoplastic syndromes occur at any age, they most often develop in older adults (median age, 65 years). A paraneoplastic syndrome should be suspected in any patient with an otherwise unexplained, subacute, progressive neurologic disorder. Any part of the neuraxis may be affected, and involvement is often multifocal. Signs and symptoms include sensory or motor neuropathy, muscle weakness, cranial nerve palsies, ataxia, memory loss, psychiatric changes, and seizures. The cause is most likely autoimmune, and the diagnosis is made by detecting antibodies in either serum or cerebrospinal fluid (Table 29). Although individual antibodies were once believed to correlate with specific clinical patterns, syndrome overlap is increasingly recognized. Therefore, diagnostic testing should evaluate a broad panel of known antibodies. Once detected, however, an individual antibody may guide further evaluation toward a specific underlying tumor. Diagnostic studies to identify the underlying tumor include CT or MRI of the chest, abdomen, and pelvis, as well as testicular ultrasonography or mammography when appropriate. If these studies are unrevealing, whole-body [18F]fluorodeoxyglucose positron emission tomography may improve detection of small tumors. Primary treatment is aimed at the underlying tumor. If the neoplastic process can be cured, the paraneoplastic syndrome will remit. Neurologic deficits may not be reversible, but further progression can possibly be avoided. If the cancer is incurable, immune-modifying therapies (such as plasma exchange or intravenous immune globulin) and immunosuppressive agents (such as corticosteroids) are used. However, these treatments have had only variable success in

alleviating neurologic symptoms. (For specific treatment options for Lambert-Eaton myasthenic syndrome, see Neuromuscular Disorders.)

Table 29. Selected Neuronal Paraneoplastic Antibodies Antibody Tumor ANNA-1 (anti-Hu) SCLC

Associated Syndromes Encephalomyelitis Cerebellar degeneration Sensory neuropathy

ANNA-2 (anti-Ri) SCLC

MA

Autonomic neuropathy Ataxia neuropathy

Breast cancer SCLC

Opsoclonus-myoclonus Encephalomyelitis

Breast cancer

Cerebellar degeneration

PCA-1 (anti-Yo)

Testicular cancer Breast cancer Cerebellar degeneration

PCA-2

Ovarian cancer SCLC

Encephalomyelitis

SCLC

Cerebellar degeneration Encephalomyelitis

Thymoma

Cerebellar degeneration

CRMP-5

Neuropathy

Amphiphysin

VGCC

SCLC

Chorea Encephalomyelitis

Breast cancer

Neuropathy

SCLC

Stiff-man syndrome Lambert-Eaton myasthenic syndrome Encephalomyelitis Cerebellar degeneration

VGKC

SCLC

Neuropathy Limbic encephalitis

Thymoma ANNA = antineuronal nuclear antibody; CRMP = collapsin response mediator protein; MA = monoclonal antibody; PCA = Purkinje cell antibody; SCLC = small cell lung cancer; VGCC = voltage-gated calcium channel; VGKC = voltage-gated potassium channel.

Bibliography •

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Buckner JC, Brown PD, O’Neill BP, Meyer FB, Wetmore CJ, Uhm JH. Central nervous system tumors. Mayo Clin Proc. 2007;82(10):1271-1286. [PMID:17908533]. See PubMed Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med. 2003;349(16):1543-1554. [PMID:14561798]. See PubMed Ferreri AJ, Reni M. Primary central nervous system lymphoma. Crit Rev Oncol Hematol. 2007;63(3):257-268. [PMID:17590348]. See PubMed Hoffman S, Propp JM, McCarthy BJ. Temporal trends in incidence of primary brain tumors in the United States, 1985-1999. Neuro Oncol. 2006;8(1):27-37. [PMID:16443945]. See PubMed

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Epilepsy • • • • • • •

Approach to the Patient with a Suspected Seizure Epidemiology, Pathophysiology, and Classification of Seizures Epilepsy Syndromes and Their Diagnosis Risk Factors Differential Diagnosis and Diagnostic Evaluation Treatment of Epilepsy Status Epilepticus


Appropriate treatment of acute symptomatic seizures is correction of the underlying cause, rather than initiation of antiepileptic medication. The incidence of epilepsy is greatest in patients older than 60 years. Generalized seizures are those that involve both hemispheres diffusely from the onset, whereas partial seizures arise in a focal area of the cortex.

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Partial seizures with maintained consciousness are subclassified as simple partial, whereas those with altered awareness are called complex partial. Patients with juvenile myoclonic epilepsy require lifelong antiepileptic drug therapy. Approximately 30% to 40% of patients with epilepsy do not respond to treatment with currently available anticonvulsant drugs. Failure to attain seizure control in patients despite adequate trials of two appropriate antiepileptic drugs has been shown to correlate with a less than 10% likelihood of achieving seizure freedom with subsequent medication trials in those patients. Risk factors for the development of epilepsy include meningoencephalitis, childhood febrile convulsions, a history of head trauma, and a family history of epilepsy. Among diagnosed cases of epilepsy, 70% have no identifiable cause. Normal findings on an electroencephalogram do not rule out a diagnosis of epilepsy, especially because interictal epileptiform discharges are found on the first electroencephalogram in only 25% to 50% of patients with epilepsy. An MRI of the brain is superior to a CT scan for detection of epileptogenic lesions with the exception of acute blood products, such as those associated with subarachnoid hemorrhage or hemorrhagic stroke. After a single unprovoked seizure, a greater risk of recurrence is predicted by a partial seizure, Todd paralysis, a family history of epilepsy, age greater than 65 years, and abnormal findings on neurologic examination. For adult patients, the reported rate of relapse after stopping antiepileptic medication is 25% to 60% over 2 years. Monotherapy antiepileptic drug regimens are preferred over polytherapy regimens. Chronic use of older antiepileptic drugs has been associated with an increased risk of osteoporosis. Exposure to antiepileptic drugs during pregnancy results in a 4% to 6% risk of major congenital malformation in newborns, which is twice the rate seen in the general population. Patients with disabling partial seizures that have not responded to treatment with two anticonvulsant drugs should be considered for epilepsy surgery. Vagus nerve stimulation is a reasonable treatment option for medically refractory seizures in patients who are not candidates for traditional epilepsy surgery. Treatment of status epilepticus should commence after 5 minutes of continuous seizure activity because of an overall mortality rate of approximately 20% and neurologic sequelae, including future seizures, cognitive impairment, aphasia, and motor deficits. Benzodiazepines are the first-line treatment for status epilepticus. In patients who are unresponsive or somnolent after status epilepticus, continuous EEG monitoring is strongly advocated to distinguish between ongoing nonconvulsive status epilepticus and postictal states.

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Approach to the Patient with a Suspected Seizure

Patients may experience many types of spells, faints, and other episodic attacks that resemble epileptic seizures. The first step in evaluating a patient with a suspected seizure is to rule out other conditions, such as syncope or transient ischemic attack, by taking a careful history, performing a physical examination, and obtaining appropriate diagnostic testing. If the event is in fact determined to have been a seizure, the next step is to distinguish between an acute symptomatic seizure and one that was unprovoked. Acute symptomatic seizures are directly attributable to an acute insult to the central nervous system or to a systemic metabolic derangement (Table 30). Appropriate treatment of acute symptomatic seizures involves correcting the underlying cause, rather than initiating an antiepileptic medication. Epilepsy, on the other hand, is a condition of repeated unprovoked seizures and is diagnosed only when two or more such seizures have occurred.

Table 30. Common Causes of Acute Symptomatic Seizures Head trauma (immediate—seizure occurs at impact) Intoxication Prescription drugs Alcohol Illicit drugs (cocaine, amphetamines) Drug withdrawal Alcohol Benzodiazepines, barbiturates Metabolic Hypo- or hyperglycemia Hyponatremia Hypocalcemia Cardiovascular Acute stroke Acute intracerebral hemorrhage Infectious

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Epidemiology, Pathophysiology, and Classification of Seizures Approximately 10% of the population worldwide will experience a single seizure in their lifetime. Epilepsy affects 3 million people in the United States, with a lifetime cumulative incidence of 3%. Although seizures can occur in patients of any age, the most common times are during childhood and after age 60 years, with the greatest incidence in the latter group. In 60% to

70% of patients with epilepsy, no cause of the seizures is identified. Elderly patients are more likely to have an identified remote symptomatic etiology, with one third of epilepsy cases in this age group attributed to cerebrovascular disease. Seizures represent abnormal bursts of synchronous electrical activity arising from cortical neurons. These abnormal bursts can result from excess excitatory neuronal activity, failure of inhibitory pathways, or changes in ion channels that control neuronal membrane potential. The clinical manifestations vary depending on the cortical area involved and can include motor, sensory, psychic, and autonomic phenomena and changes in the level of consciousness. Seizures are divided into two types—partial and generalized—on the basis of the region of the cortex involved in seizure initiation. Generalized seizures involve both hemispheres diffusely from the onset. The most familiar form of generalized seizure is the generalized tonic-clonic or grand-mal seizure. The initial tonic phase manifests as a sustained muscular contraction that results in stiffening of the jaw, trunk, and limbs. Tonic contraction of the diaphragm may result in a characteristic vocal cry and in cyanosis. The clonic phase follows, with symmetric rhythmic jerking of the extremities. There can be urinary and occasionally bowel incontinence. The seizure typically stops spontaneously in 1 to 2 minutes and may be followed by a period of lethargy, confusion, or agitation lasting minutes to hours. Prolonged postictal confusion must be differentiated from ongoing subtle seizure activity. Other types of generalized seizures include absence, myoclonic, and atonic seizures. Absence seizures are typified by staring and unresponsiveness lasting several seconds. Myoclonic seizures are sudden, brief, shock-like muscle contractions, which may be focal, multifocal, or generalized in distribution. Atonic seizures consist of a sudden loss of muscle tone that causes a drop to the ground and carries a high risk of injury. With the exception of myoclonus, generalized seizures are all characterized by loss of consciousness. In contrast, partial seizures arise in a focal area of the cortex. The manifestation of a partial seizure depends on the area of cortical involvement. The larger the area involved, the greater the likelihood of impaired consciousness. Partial seizures with fully maintained consciousness are subclassified as simple partial, and those with altered awareness are called complex partial. Partial seizures may spread to involve the cortex diffusely, a state referred to as secondary generalization. The temporal lobe is the most common site of origin for partial seizures. Simple partial seizures in this area may manifest as an “indescribable feeling,” a rising epigastric sensation, an unpleasant olfactory or gustatory sensation, a psychic phenomenon (such as déjà vu), or autonomic disturbances (such as flushing, diaphoresis, or lightheadedness). Some patients may report auditory distortion or vertigo. These symptoms typically last less than 1 minute and are often referred to as an aura. Complex partial seizures arising in the temporal lobe classically manifest with behavioral and speech arrest lasting less than 2 minutes. Automatisms (nonpurposeful stereotyped motor behaviors) are often exhibited and may include repetitive lip smacking, chewing, swallowing, or fumbling or picking behaviors with the ipsilateral hand. A period of postictal confusion lasting minutes to hours is common.

In contrast, frontal lobe seizures tend to be brief, nocturnal events that are less likely to be followed by postictal confusion. Seizures arising in frontal lobe structures outside the motor cortex can present with bizarre motor phenomena, including violent thrashing, bicycling movements, or clapping. Patients may experience intense fear or other emotions and significant autonomic changes. Such unusual motor activity and emotional features commonly lead to frontal lobe seizures being misdiagnosed as psychogenic events. Frontal lobe seizures may tend to cluster or to generalize secondarily. Simple partial seizures arising in the primary motor cortex will present as localized tonic or clonic activity in the contralateral body. Seizure activity can spread to adjacent regions of the motor strip, a phenomenon called jacksonian march. The most common clinical manifestation of a jacksonian seizure is twitching of the thumb, which then spreads up the arm and into the ipsilateral face. Transient weakness of the involved limbs after the seizure has ended is common and is referred to as Todd paralysis, which usually lasts minutes but can persist for hours. When weakness is prolonged, it is important to rule out continued subtle seizure activity or, if it occurs after a first seizure, an underlying structural lesion or stroke. Parietal and occipital lobe seizures are rare. Parietal seizures usually involve sensory phenomena, such as electric sensations, pain, or a feeling of pins and needles. Like seizures arising in the motor strip, jacksonian spread can be described by patients who experience it. Poorly formed visual hallucinations consisting of vague shapes and shadows may also be reported. Occipital lobe seizures usually manifest as unformed visual phenomena, such as flashes of light or loss of vision.

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Epilepsy Syndromes and Their Diagnosis Epilepsy is defined as a predilection for recurrent, unprovoked seizures and is typically diagnosed when two such seizures have occurred. Epilepsy is not a single disease but, rather, a group of disorders that share seizures as one manifestation. Epilepsy syndromes are defined by type of seizure, associated neurologic or systemic symptoms, age of onset, findings on an electroencephalogram (EEG), and family/genetic history. Appropriate identification of the epilepsy syndrome can be helpful in determining prognosis and appropriate treatment.

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Classification of Epilepsy Syndromes In the International League Against Epilepsy (ILAE) system, epilepsy syndromes are divided according to cause. Epilepsy attributable to a known brain abnormality is called symptomatic, whereas the term cryptogenic is used when an underlying brain disorder is suspected but unidentified. Epilepsies unrelated to a structural lesion or disorder are classified as idiopathic and are generally presumed to have a genetic cause. Like single seizures, epilepsy syndromes are also

classified as generalized and partial. Generalized epilepsies typically manifest in childhood or adolescence, whereas new-onset epilepsy in adults (of all ages) is almost always partial.

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Commonly Encountered Epilepsy Syndromes • • •

Juvenile Myoclonic Epilepsy Lennox-Gastaut Syndrome Intractable Epilepsy

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Juvenile Myoclonic Epilepsy Juvenile myoclonic epilepsy is an idiopathic generalized epilepsy syndrome characterized by both myoclonic seizures on awakening and generalized tonic-clonic seizures. These seizure types occur independently, but a flurry of myoclonic seizures may presage a generalized tonic-clonic seizure. Onset is usually in adolescence. Seizures may be provoked by sleep deprivation, alcohol, or flickering lights. The EEG demonstrates generalized spike and wave discharges of 4 to 6 Hz. Most patients with juvenile myoclonic epilepsy have an excellent response to medication, with lamotrigine and valproic acid considered first-line treatments. Although juvenile myoclonic epilepsy can usually be successfully controlled with treatment, the susceptibility to seizure persists over the patient’s lifetime, and 75% to 100% of patients will relapse if medication is withdrawn. Juvenile myoclonic epilepsy is thought to be a multigene disorder, with familial studies demonstrating a strong but complex inheritance pattern.

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Lennox-Gastaut Syndrome Lennox-Gastaut syndrome is characterized by mental retardation and intractable seizures. Onset is usually by age 5, and the disorder is lifelong. A unique finding is the presence of multiple seizure types in the same patient, including atonic, atypical absence, myoclonic, and generalized tonic-clonic seizures. Status epilepticus (discussed later) is common. The EEG shows a characteristic pattern of generalized slow spike and wave discharges superimposed on a slow background. In about 60% of patients with the disorder, Lennox-Gastaut syndrome is attributable to a known symptomatic cause, such as tuberous sclerosis, meningoencephalitis, or hypoxicischemic injury.

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Intractable Epilepsy Medically refractory, or intractable, epilepsy is a clinically useful categorization, although not formally part of the ILAE classification system. Approximately 30% to 40% of patients with epilepsy do not respond to treatment with currently available anticonvulsant drugs. There is no single accepted criterion by which refractory epilepsy is defined. However, failure to attain seizure control despite adequate trials of two appropriate antiepileptic drugs is a commonly used indicator of intractability. Patients whose seizures persist despite such treatment have a less than 10% likelihood of achieving seizure freedom with subsequent medication trials. The consequences of uncontrolled seizures include increased mortality, greater adverse medication effects, cognitive decline, and impairment of psychosocial functioning, including mood, interpersonal relationships, and employment. It is important, therefore, to recognize patients with intractable epilepsy early in their disease course. Referral to a comprehensive epilepsy care center to explore nonmedical management is appropriate.

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Risk Factors Risk factors for the development of epilepsy include meningoencephalitis, childhood febrile convulsions, a history of head trauma, and a family history of epilepsy. Among diagnosed cases of epilepsy, 70% have no identifiable cause. For the 30% with a known etiology, leading causes are cerebrovascular disease, developmental brain disorders, remote head trauma, brain tumor, and neurodegenerative conditions. For patients with epilepsy, commonly cited seizure triggers include sleep deprivation, alcohol, flickering lights, and menstruation. Many prescription medications, including quinolone antibiotics, antipsychotic agents, and antidepressants, may also lower seizure threshold. When these medications are necessary, adjustment in antiepileptic therapy may be needed to maintain seizure control.

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Differential Diagnosis and Diagnostic Evaluation Diagnosis of seizures and epilepsy requires obtaining a detailed and accurate history. Because patients who have experienced a seizure are often unaware of what occurred, obtaining an eyewitness account is invaluable. Many physiologic events can mimic seizures and should be part of the differential diagnosis. In adults, cardiac syncope, arrhythmia, transient ischemic attack, migraine, metabolic derangements, intoxication, and vertigo are among the common conditions that can present similarly to seizures (Table 31). Psychiatric conditions must also be considered. Psychogenic nonepileptic spells are seizure-like events that occur in patients with a conversion or somatoform disorder. Such spells occur with an estimated prevalence of 1.5 per 100,000 persons and are

commonly misdiagnosed as epilepsy. Because psychogenic spells can also occur in 10% to 20% of patients with epilepsy, care must be taken in patients with suspected psychogenic spells to definitively exclude the diagnosis of epilepsy. Panic attacks should also be considered in the differential diagnosis of seizure. Carefully detailed questions about the episodes and about risk factors for epilepsy, including minor or major head trauma and concomitant medications, must be asked. Further diagnostic testing is often needed to confirm or clarify the cause of a seizure-like episode. Depending on the history, evaluation of metabolic derangements, cardiac disease, cerebrovascular disorders, or vestibular dysfunction may be appropriate. A general laboratory survey should include a complete blood count, measurement of serum electrolyte and plasma glucose levels, and a toxicology screen, if appropriate. A lumbar puncture is generally only indicated if there are signs or symptoms suggesting an underlying infection of the central nervous system or if the patient is immunocompromised. Electroencephalography and neuroimaging should be standard components of the diagnostic work-up of patients suspected to have epilepsy.

Table 31. Characteristics That Distinguish Between Common Mimics of Seizure in Adults Characteristic Seizure Warning/aura Variable

Duration

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