Brainstem Disorders
Peter P. Urban • Louis R. Caplan (Editors)
Brainstem Disorders
Editors Peter P. Urban Abteilung für Neurologie Asklepios Klinik Barmbek Rübenkamp 220 22291 Hamburg Germany
[email protected] Louis R. Caplan Beth Israel Deaconess Medical Center 330 Brookline Ave Boston, MA 02215 USA
[email protected] ISBN 978-3-642-04202-7 e-ISBN 978-3-642-04203-4 DOI 10.1007/978-3-642-04203-4 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2011921399 Authorized translation of the 1st German language edition: Urban, Peter P. Erkrankungen des Hirnstamms, © 2009 by Schattauer GmbH, Stuttgart/Germany © Springer-Verlag Berlin Heidelberg 2011 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudioCalamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)
Preface
Brainstem disorders may result in a broad spectrum of clinical signs and symptoms ranging from isolated signs, including vertigo, gait unsteadiness, and double vision, to complex clinical syndromes and life-threatening situations, such as basilar artery thrombosis. The complex topography of the brainstem represents a challenge even for experienced neurologists in localizing brainstem lesions and diagnosing brainstem disorders. Modern magnetic resonance imaging and electrophysiological techniques have significantly improved understanding of brainstem function. However, the clinical examination continues to be the cornerstone of topodiagnosis, and careful matching of clinical and technical findings is a prerequisite for the correct diagnosis. This comprehensive clinical handbook presents a review of all brainstem disorders and provides the relevant clinical knowledge required for the diagnosis. In addition to a detailed outline of the basic brainstem neuroanatomy the work discusses the state-of-the-art diagnostic imaging procedures for brainstem lesions. The topodiagnostic analysis of neurological findings is explained in detail and brainstem disorders are illustrated by a large number of magnetic resonance images and brief reports. Twenty-five contributors and two editors participated in the writing of this text. One of the most appealing features of this book is the vast experience of our authors evidenced by the many important contributions they made to the understanding of brainstem function in recent years. The editors want to thank and acknowledge all those who participated in the development of this text. We are profoundly aware of their genuine personal commitment and extensive time devoted to writing these chapters. It is our hope that this publication will be useful in clinical practice and enrich knowledge of brainstem disorders. Hamburg, Germany Boston, MA, USA
Peter P. Urban Louis R. Caplan
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Contents
1 Neuroanatomy of the Brainstem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anja K.E. Horn-Bochtler and Jean A. Büttner-Ennever
1
1.1 General Architecture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.2 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
1.3 External Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
1.4 Internal Architecture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
1.5 Pathways in the Brainstem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
1.6 Brain Stem Vascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
2 Diagnostic Imaging, Interventional Treatment of Brainstem Lesions and Electrophysiologic Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
2.1 Neuroradiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peter Stoeter and Stephan Boor
38
2.2 Ultrasound diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Martin Eicke and Uwe Walter
54
2.3 Electrophysiologic diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jürgen Marx, Frank Thömke, Peter P. Urban, Sandra Bense, and Marianne Dieterich
61
Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
3 Diagnostic Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
3.1 Disorders of ocular motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Frank Thömke
3.2 Horner’s syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Jürgen Marx
3.3 Central vestibular disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Marianne Dieterich and Sandra Bense
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3.4 Tinnitus and auditory disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Marianne Dieterich and Sandra Bense
3.5 Intra-axial Cranial Nerve Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 Frank Thömke and Peter P. Urban
3.6 Speech disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Peter P. Urban
3.7 Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Peter P. Urban
3.8 Ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Peter P. Urban
3.9 Pareses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Peter P. Urban and Jürgen Marx
3.10 Sensory disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Peter P. Urban
3.11 Bladder disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Peter P. Urban
3.12 Drop attacks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Peter P. Urban
3.13 Respiratory disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Peter P. Urban
3.14 Disturbances of consciousness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 Frank Thömke
3.15 Brain death diagnosis in primary brainstem injury . . . . . . . . . . . . . . . . 168 Frank Thömke
3.16 Clinical brainstem reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 Peter P. Urban
3.17 Rare findings/symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Peter P. Urban Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
4 Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
4.1 Vascular brainstem diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Jürgen Marx, Peter P. Urban, Frank Thömke, Wibke Müller-Forell, Sandra Bense, and Marianne Dieterich
4.2 Inflammatory brainstem diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Uta Meyding-Lamadé and André Grabowski
4.3 Brainstem involvement in demyelinating diseases . . . . . . . . . . . . . . . . . . . 243 Oliver Kastrup
4.4 Paraneoplastic brainstem syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Heidrun Golla and Raymond Voltz
Contents
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4.5 Brainstem tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 Thomas Hundsberger and Dorothee Wiewrodt
4.6 Traumatic brainstem lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Raimund Firsching, Dieter-Heinrich Woischneck, and Stefan Schreiber
4.7 Degenerative Brainstem Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Andres Ceballos-Baumann
4.8 Abnormalities of brainstem development . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Wolfgang Wagner
4.9 Metabolic brainstem diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Joachim Wolf and Armin Grau
4.10 Vascular cranial nerve and brainstem compressions . . . . . . . . . . . . . . . 326 Frank Thömke and Peter P. Urban
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Contributors
PD Dr. Sandra Bense Neurologische Klinik, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 München, Germany
[email protected] Dr. Stephan Boor Institut für Neuroradiologie, Universitätskliniken Mainz, Langenbeckstr. 1, 55101 Mainz, Germany
[email protected] Prof. Dr. Jean A. Büttner-Ennever Anatomische Anstalt, Lehrstuhl III, LMU München, Pettenkoferstrr. 11, 80336 München, Germany
[email protected] Prof. Dr. Andres Ceballos-Baumann Neurologisches Krankenhaus München, Tristanstr. 20, 80804 München, Germany
[email protected] Prof. Dr. Marianne Dieterich Neurologische Klinik, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377 München, Germany
[email protected] PD Dr. Martin Eicke Neurologische Abteilung, Klinikum Idar-Oberstein GmbH, Dr.-Ottmar-Kohler-Str. 2, 55743 Idar-Oberstein, Germany
[email protected] Prof. Dr. Raimund Firsching Klinik für Neurochirurgie, Universitätskliniken Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
[email protected] Dr. Heidrun Golla Klinik und Poliklinik für Palliativmedizin, Klinikum der Universität zu Köln, Kerpener Str. 62, 50924 Köln, Germany
[email protected] Dr. André Grabowski Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
[email protected] Prof. Dr. Armin Grau Neurologische Klinik, Städtisches Klinikum, Bremserstr. 79, 67073 Ludwigshafen, Germany
[email protected] PD Dr. Anja K.E. Horn-Bochtler Anatomische Anstalt, Lehrstuhl III, LMU München, Pettenkoferstr. 11, 80336 München, Germany
[email protected] xi
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Dr. Thomas Hundsberger Klinik für Neurologie, Kantonsspital St. Gallen, Rorschacher Str. 95, 9007 St. Gallen, Switzerland
[email protected] Dr. Oliver Kastrup Neurologische Klinik, Universitätsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany
[email protected] PD Dr. Jürgen Marx Praxis für Neurologie, Holzhofstr. 5, 55116 Mainz, Germany
[email protected] Prof. Dr. Uta Meyding-Lamadé Neurologische Klinik, Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany
[email protected] Prof. Dr. Wibke Müller-Forell Institut für Neuroradiologie, Universitätskliniken Mainz, Langenbeckstr. 1, 55101 Mainz, Germany
[email protected] Dr. Stefan Schreiber Klinik für Neurochirurgie, Universitätskliniken Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
[email protected] Prof. Dr. Peter Stoeter Institut für Neuroradiologie, Universitätskliniken Mainz, Langenbeckstr. 1, 55101 Mainz, Germany
[email protected] Prof. Dr. Frank Thömke Institut für Neuroradiologie, Universitätskliniken Mainz, Langenbeckstr. 1, 55101 Mainz, Germany
[email protected] Prof. Dr. Peter P. Urban Abteilung für Neurologie, Asklepios Klinik Barmbek, Rübenkamp 220, 22291 Hamburg, Germany
[email protected] Prof. Dr. Raymond Voltz Klinik und Poliklinik für Palliativmedizin, Klinikum der Universität zu Köln, Kerpener Str. 62, 50924 Köln, Germany
[email protected] Prof. Dr. Wolfgang Wagner Klinik und Poliklinik für Neurochirurgie, Universitätskliniken Mainz, Langenbeckstr. 1, 55101 Mainz, Germany
[email protected] Prof. Dr. Uwe Walter Neurologische Universitätsklinik Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany
[email protected] PD Dr. Dorothee Wiewrodt Neurochirurgie der Universitätsklinik Münster (UKM), Albert-Schweitzer-Str. 33, 49149 Münster, Germany
[email protected] Dr. Dieter-Heinrich Woischneck Klinik für Neurochirurgie, Universitätsklinikum Ulm, Steinhövelstr. 9, 89075 Ulm, Germany
[email protected] Dr. Joachim Wolf Neurologische Klinik, Städtisches Klinikum, Bremserstr. 79, 67073 Ludwigshafen, Germany
[email protected] Contributors
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Neuroanatomy of the Brainstem Anja K.E. Horn-Bochtler and Jean A. Büttner-Ennever
Contents 1.1 General Architecture . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.3 External Characteristics . . . . . . . . . . . . . . . . . . . . . . 1.3.1 Mesencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.2 Pons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.3 Medulla Oblongata . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.4 Retinal Inputs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.5 Cranial Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3 3 4 4 4 4
1.4 Internal Architecture . . . . . . . . . . . . . . . . . . . . . . . . . 8 1.4.1 Cranial Nerve Nuclei of the Brainstem . . . . . . . . . . . . 8 1.4.1.1 Oculomotor Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Edinger-Westphal Nucleus . . . . . . . . . . . . . . . . . . . . . 9 Light Reaction and Near Response . . . . . . . . . . . . . . . 9 1.4.1.2 Trochlear Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 1.4.1.3 Abducens Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 1.4.1.4 Trigeminal Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Trigeminal Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 1.4.1.5 The Facial Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Facial Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 1.4.1.6 Vestibular Nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 1.4.1.7 Cochlear Nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 1.4.1.8 Nuclear Groups of the Vagal System . . . . . . . . . . . . . . 14 Glossopharyngeal Nerve . . . . . . . . . . . . . . . . . . . . . . . 14 Solitary (Tract) Nucleus . . . . . . . . . . . . . . . . . . . . . . . 15 Vagus Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Dorsal Motor Vagal Nucleus (Dorsal Nucleus of the Vagal Nerve) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Nucleus Ambiguus . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 1.4.1.9 Nuclear Groups of the Accessory Nerve . . . . . . . . . . . 16 1.4.1.10 Nucleus Hypoglossus . . . . . . . . . . . . . . . . . . . . . . . . . 16 1.4.2 Reticular Formation: A Coordination Center for Complex Movement . . . . . . . . . . . . . . . . . . . . . . . . 16 1.4.3 Ascending Activating System: Attention, Wake–Sleep Rhythm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 1.4.4 Limbic Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 1.4.5 Premotor Control of Eye Movements . . . . . . . . . . . . . 18 1.4.5.1 Saccades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 1.4.5.2 Vestibulo-ocular Reflex . . . . . . . . . . . . . . . . . . . . . . . . 19 1.4.5.3 Optokinetic Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 1.4.5.4 Smooth Pursuit Eye Movements . . . . . . . . . . . . . . . . . 20 1.4.5.5 Convergence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.4.5.6 Gaze Stabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.4.6 Parasympathetic and Sympathetic Pathways . . . . . . . . 21 1.4.7 Nuclear Regions of the Mesencephalon . . . . . . . . . . . 23 1.4.7.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 1.4.7.2 Pretectum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
1.4.7.3 Superior and Inferior Colliculi . . . . . . . . . . . . . . . . . . 1.4.7.4 Red Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.7.5 Substantia Nigra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.7.6 Periaqueductal Gray . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.8 Nuclear Regions of the Pons . . . . . . . . . . . . . . . . . . . . 1.4.8.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.8.2 Pontine Nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.8.3 Parabrachial Nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.8.4 Pontine Micturition Center . . . . . . . . . . . . . . . . . . . . . 1.4.9 Nuclear Regions of the Medulla Oblongata . . . . . . . . 1.4.9.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.9.2 Inferior Olive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.9.3 Ventrolateral Cell Groups of the Medulla . . . . . . . . . . Cardiovascular Reflexes . . . . . . . . . . . . . . . . . . . . . . . Respiratory Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . Swallowing, Vomiting, and Sneeze Reflexes . . . . . . . . 1.4.9.4 Area Postrema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24 25 25 27 27 27 27 28 28 28 28 29 29 29 29 29 30
1.5 Pathways in the Brainstem . . . . . . . . . . . . . . . . . . . . 1.5.1 Descending Pathways . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2 Ascending Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2.1 Lemniscal Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2.2 Spinothalamic Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2.3 Spinocerebellar Tracts . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2.4 Auditory Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30 30 31 31 31 31 32
1.6 Brain Stem Vascularization . . . . . . . . . . . . . . . . . . . 1.6.1 Mesencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6.2 Pons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6.3 Medulla Oblongata . . . . . . . . . . . . . . . . . . . . . . . . . . .
32 32 34 34
Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
1.1 General Architecture The brainstem (truncus cerebri) comprises the medulla oblongata, the pons and the mesencephalon (midbrain) (Fig. 1.1). The brain develops from the neural tube and can be traced back to the primary blueprint in all its components. The brainstem contains. the fourth ventricle in the region of the medulla oblongata and the pons, as well as the aqueduct in the midbrain. These represent the cerebrospinal fluid reservoirs within the brainstem. A simplified description of the basic architecture of the brainstem divided into four longitudinal sections is presented in Fig. 1.1b, c (from dorsal to ventral).
P.P. Urban and L.R. Caplan (eds.), Brainstem Disorders, DOI: 10.1007/978-3-642-04203-4_1, © Springer-Verlag Berlin Heidelberg 2011
1
2 Fig. 1.1 Diagrammatic representation of the lateral aspect of the brain, showing all six parts including the intracerebral fluid containing spaces. The brain stem shown here includes the mesencephalon and the rhombencephalon (a). Depiction of the longitudinal zones (b) extending throughout the entire brainstem at varying degrees of expression (c)
1 Neuroanatomy of the Brainstem
a
Telencephalon
DiMesencephalon encephalon
Rhombencephalon
Pons
b
Medulla oblongata
Liquor spaces
Spinal cord
Brainstem Roof/roof plate lCSF spaces Tegmentum Floor
c Superior colliculus
Inferior colliculus Plexus choroideus Roof/roof plate
Aqueduct Liquor spaces Tegmentum
Cerebral peduncle
Pyramids
Base of pons Mesencephalon
1. Roof plate: A thick quadrigeminal plate (superior and inferior colliculus; tectum) in the mesencephalon, a thin velum (superior medullary velum) in the pons, and a singlelayer lamina (inferior medullary velum) with the choroid plexus in the medulla oblongata 2. Cerebrospinal fluid spaces: Fourth ventricle and mesencephalic aqueduct 3. Mesencephalic tegmentum: Contains all brainstem nuclei, including the reticular formation 4. Floor: Fibrous layer consisting of the cerebral peduncles, the base of the pons, and the pyramids The assignment of lesions to one of these four components can be readily achieved based on MRI-images, whereby the majority of clinical symptoms – with the exception of paralyses – can be attributed to injuries to the brain nuclei and to nerve tracts in the tegmentum.
Pons
Medulla oblongata
1.2 Development The neuroectoderm is induced in the epiblast by the mesodermal notochord and its head. The neuroectoderm forms the neural tube, neural crest, and placodes (congregation of specialized cells of ectodermal origin in the head region). The central nervous system develops from the neural tube, while the neural crest and the placodes give rise to the peripheral nervous system and parts of the large sense organs among other structures. The neural crest is divided into a cranial and a trunk part. While the cranial neural crest contributes to the development of the sensory and the parasympathetic nerve ganglia, it also forms the mesenchymal basis for the development of non-neuronal tissues, including the cranial bones (primarily skeletal bones of the face), cartilage, dentine, and the smooth musculature of vessels.
1.3 External Characteristics
3
1.3 External Characteristics
The complex morphogenic cell migrations during brain development are controlled by cell-intrinsic control genes and extrinsic signals (signal molecules) that mutually influence one another. Control genes, e.g. genes of the Hox family, transcription factors, e.g. Krox-20, and signal molecules like the Sonic Hedgehog (Shh) have a crucial role in brain stem and spinal cord development (Hofmann 2004). Around the 6th week of embryonic development eight transversal swellings, the rhombomeres (Fig. 1.2) become transiently visible at the floor of the fourth ventricle. This lends a segmented structure (rhombomere) to the brainstem, that is reflected in the organization of the cranial nerves and their nuclei. Each rhombomere is characterized by a specific gene expression pattern of the control gene, as well as by morphogenetic molecular factors. The absence of a control gene can lead to the loss of an entire rhombomere or prevent its merging with another rhombomere. The resulting damages would not only have an effect on the structures of the respective brain segments, but also on the tissue developing from the neural crest cells and placodes of the affected rhombomere (e.g. sensory cranial nerves and parasympathetic head ganglia, as well as parts of the cranial skeleton) (Kiernan et al. 2002).
1.3.1 Mesencephalon The dorsal surface of the mesencephalon is characterized by the quadrigeminal plate (Figs. 1.1c and 1.3b), which consists of the superior colliculi with visuomotor functions and the inferior colliculi as part of the auditory pathway (p. 32). The trochlear nerve (N. IV) exits the dorsal surface of the brain stem from behind the inferior colliculus. The dorsal view of the mesencephalon shows the broad exit pathway of the inferior colliculus, the brachium of the inferior colliculus, and its rostrolateral course towards the medial geniculate body. The posterior commissure forms the rostral border between the mesencephalon and the diencephalon and marks the opening of the mesencephalic aqueduct in the third ventricle. Located immediately dorsally to this is the epiphysis, or pineal body, a diencephalic structure with an important role in the regulation of circadian rhythms. The robust cerebral crura constitute the key feature of the basal aspect of the mesencephalon. They comprise fiber bundles of axons that descend from the cerebral cortex to
Pharyngeal arch 1–4
Cranial nerves III-XII Mesencephalon III IV Rhombencephalon R1
1 Trigeminal placodes Krox-20
Fig. 1.2 Diagram depicting the development of the brain stem and cranial nerves. Somatoefferent and visceroefferent neurons originate from the floor plate of the rhombomeres (R1-8) and the mesencephalon. They send their axons to the respective cranial nerves. Correspondingly, the peripheral and central axons are formed from ganglia of the somatoafferent and visceroafferent neurons. The vertical bars illustrate the expression of morphogenetic factors (Hox gene, transcription factor Krox-20, Kreisler) and demonstrate that each rhombomere is characterized by a specific gene expression pattern. (Modified from Neuhuber 2004)
Geniculate ganglion Ear placodes
V
R2
Hox b-1 2
R3 VII
R4
VIII R5 VI
Inferior ganglion N.IX Inferior ganglion N.X
3
Kreisler
R6
IX
R7
4
X, XI
R8
XII
Hox a,b,d-4
Hox a-2
Hox a,b,d-3
Hox b-2
4
the pons, where the majority of the axons terminate in the pontine nuclei. The cerebral crus with the adjacent tegmentum is also referred to as the cerebral peduncle. At the midline between the cerebral crura lies the interpeduncular fossa, from where the oculomotor nerves (N. III) emerge. On removal of the leptomeninx, the small arteries (interpeduncular perforating arteries) are avulsed and leave small holes in the brain substance, which lead this area to be described as the posterior perforated substance. The basis of the mesencephalon is bounded rostrally by the mammillary bodies.
1.3.2 Pons The ventral surface of the pons (“bridge”) is formed by a broad band of horizontally arranged fibers that run laterally by way of the medial cerebellar peduncle to the cerebellum (Fig. 1.3b). The corticopontine fibers from the ipsilateral cerebral peduncle synapse with a second neuron in the pons and form the large rounded eminence of the pontine nuclei. All efferents from the pontine nuclei form pontocerebellar fibers and decussate contralaterally. The chief cranial nerve, the trigeminal nerve (N. V), emerges laterally from the brainstem through the pontine fibers. On its dorsal surface the pons forms the floor of the fourth ventricle and the floor of the rhomboid fossa caudally. Two lateral recesses are viewed in the fourth ventricle at the level of the caudal pons. Through an aperture at the extremity of each lateral recess, the foramina of Luschka, cerebrospinal fluid from the fourth ventricle can drain into the subarachnoid space.
1.3.3 Medulla Oblongata The transition from the medulla to the spinal cord is located at approximately the level of the foramen magnum, superior to the ventral roots of the first cervical segment. The junction of the medulla and the spinal cord is formed ventrally by the decussation of the pyramids and dorsally by the tubercle of gracile, cuneate, and trigeminal (or cinereum) nuclei (Fig. 1.3). In the dorsal view the obex forms the caudal border of the medulla, the site at which the fourth ventricle continues the central canal. At this location an unpaired median aperture (the foramen of Magendie) is viewed in the inferior medullary velum, which connects the fourth ventricle with the subarachnoid space. The most prominent external landmark is the inferior olive, which forms a 14 mm long and 7 mm wide bulge on the ventral side of the medulla (Fig. 1.3a, b). The roots of the hypoglossal nerve (N. XII) leave the brainstem between the pyramids and the inferior olive; the roots of the glossopharyngeal (N. IX), the vagus (N. X) and
1 Neuroanatomy of the Brainstem
the accessory (N. XI) nerves emerge lateral to the inferior olive. More rostrally, at the junction of the medulla and the pons, the facial nerve emerges together with the intermediate nerve (N. VII), and the vestibulocochlear nerve (N. VIII) exits the brainstem at the cerebellopontine angle more laterally. The abducens nerve (N. VI) emerges from the brainstem at the upper border of the pyramid and the lower margin of the pons (Fig. 1.3).
1.3.4 Retinal Inputs Proceeding from the optic chiasm, the optic tract runs across the ventral surface of the cerebral peduncle and travels to the lateral geniculate nucleus in the diencephalon, the main projection area (Fig. 1.3b). Medially and parallel to the optic tract an additional small bundle of fibers exiting the retina follows a similar route across the cerebral peduncle. While they were originally described by Bernhard von Gudden (1881) as the transverse peduncular tract, today they are referred to as the inferior and superior fascicles of the accessory optic tract. Both the fibers of the optic tract and the accessory optic tract exit the retina, decussate in the optic chiasm and proceed as self-contained bundles to a number of small nuclei, the accessory optic nuclei in the mesencephalon: the dorsal terminal nucleus, the lateral terminal nucleus, the interstitial terminal nucleus and the various components of the medial terminal nucleus. The accessory optic system constitutes a phylogenetically old system and plays – together with the proximally located pretectal nucleus of the optic tract – an important role in evoking optokinetic reflexes (Büttner and Büttner-Ennever 2006; Gamlin 2006; Giolli et al. 2006). The accessory optic nuclei are located on the surface of the mesencephalon and are therefore vulnerable to potential external injury. Thus far no clinical picture has, however, been associated with damage to these structures.
1.3.5 Cranial Nerves Comparable to the spinal nerves with sensory dorsal and motor ventral roots connecting the spinal cord to the periphery, the brainstem is similarly connected to the periphery of the head by “cerebral,” or alternatively named, “cranial,” nerves. These serve to transmit information between the highly specialized head region (e.g. tongue, ears, eyes, facial muscles) and the brain. Among the 12 cranial nerves the first two, the olfactory and the optic nerve, do not constitute peripheral nerves in the true sense of the word, but form protuberances in the anterior portion of the brain that are ensheathed by the meninges and contain cells found exclusively in the CNS.
1.3 External Characteristics
5
a
b Geniculate body Pineal body – medial – lateral Pretectum
Cerebral crus
Roof of the third ventricle Colliculus – superior – inferior
N. III N. IV N. V
Mesencephalon
N. IV Superior medullary velum
Pons N. VI N. VII N. VIII N. IX
Pyramid N. XII
N. X
Inferior olive
Tubercle of cuneate Medulla nuclei Roots oblongata Tubercle of – cranial gracile accessory nerves nuclei – spinal Spinal accessory nerves cord N. XI
C1 ventral root Decussation of the pyramids
Cerebellar peduncle – medial – superior – inferior
Pons
Medullary striae Obex Median sulcus Trigeminal tubercle
c Superior colliculi Inferior colliculi
Cerebral crus
N. IV N. V N. VIII N. VII N. VI
N. IX N. XII
N. X
N. XI
C1 C2
Fig. 1.3 Brainstem and cranial nerves viewed from ventral (a), dorsal (b), and lateral (c)
The true cranial nerves may contain both efferent and afferent fibers of all modalities (Table 1.1). The pseudounipolar or bipolar nerve cell bodies of the sensory afferents are found outside the central nervous system within compact ganglia. In some instances they may, however, also be dispersed as cell groups within the nerve fascicle. The ganglia are components of the peripheral nervous system and constitute, with a view to embryonic development, a derivative of the neural crest (in contrast to the central nervous system which is a neural tube derivative). The peripheral
nervous system thus contains nerve and glial cells different from those of the central nervous system, and may therefore represent an entry zone for specific diseases (e.g. neuropathies) which are different from those of the central nervous system. In the region of the point of passage through the pia mater into the brainstem, the cranial nerves are characterized by a transition zone (up to 8 mm wide), the Obersteiner–Redlich line, where the peripheral Schwann cell myelination is replaced by central oligodendrocyte myelination (Carlstedt et al. 2004). Here the displacement
SVE SA SE SA? SVE VE SVA SSA SVE
Superior orbital fissure Round foramen Oval foramen Superior orbital fissure Internal acoustic meatus
Vestibulocochlear nerve (VIII) Internal acoustic meatus Jugular foramen Glossopharyngeal nerve (IX) Third pharyngeal arch nerve
Medulla oblongata
Abducens nerve (VI) Facial nerve (VII) (Intermediate nerve) Second pharyngeal arch nerve
Trigeminal nerve (V) First pharyngeal arch nerve - Ophthalmic branch (V1) - Maxillary branch (V2) - Mandibular branch (V3)
Pons
SA? SE
Superior orbital fissure
VE SA SVA VA
Cochlear nuclei Nucleus ambiguus Inferior salivary nucleus Spinal trigeminal nerve nucleus Solitary tract nucleus Solitary tract nucleus (caudal part)
Vestibular nuclei
Mesencephalic nucleus of trigeminal n. Chief sensory nucleus of trigeminal n. Spinal nucleus of trigeminal nerve Abducens nerve nucleus Facial nerve nucleus Superior salivary nucleus Solitary tract nucleus
Vestibular ganglion (Scarpa) Spiral ganglion Otic ganglion Superior ganglion Inferior (petrosal) ganglion
Geniculate ganglion
Pterygopalatine ganglion Submandibular ganglion
Trigeminal ganglion (Semilunar ganglion; Gasserion ganglion)
Motor nucleus of trigeminal nerve
Ciliary ganglion
Êdinger-Westphal nucleus Trochlear nerve nucleus
VE
Trochlear nerve (IV)
Sensitive and vegetative ganglia
Nucleus of the oculomotor nerve
Oculomotor nerve (III)
Mesencephalon
Optic canal
Area of nuclei of origin or termination
SE
Superior orbital fissure
Optic nerve (II)
Diencephalon
Lamina cribrosa, Ethmoidal orifice
Olfactory nerve (I) (olfactory filaments)
Quality
TelencePhalon
Point of passage in the cranium
Description
Brain segment
Tabl. 1.3 The Cranial Nerves
Sensory cells in semicircular canals, sacculus, utriculus Sensory cells in organ of Corti Pharyngeal constrictors (with N.X), stylopharyngeal muscle Parotid, buccal, labial gland Tongue (posterior 1/3; touch, temperature, pain) soft palate, pharynx, mucosa of the tympanic cavity Tongue (posterior 1/3; fibers of taste sensation) Chemoreceptors (Carotid glomus), pressoreceptors in the carotid sinus
Muscles of mastication (proprioceptive); facial skin, mucosa of the rhinopharyngeal space, tongue, anterior 2/3s, - mechanoreception) Lateral rectus muscle Proprioception? Muscles of facial expression, stylohyoid muscle, posterior belly of digastric muscle, stapedius muscle Lacrimal, nasal, palatine glands Submandibular, sublingual, anterior lingual glands Taste buds (anterior 2/3s of the tongue)
Muscles of mastication, floor of the mouth, tensor tympani muscle, tensor veli palatini muscle via V3
Superior, medial, inferior rectus muscles; inferior oblique muscle; levator palpebrae muscle Pupillary sphincter muscle, ciliary muscle Proprioception Superior oblique muscle
Retina
Olfactory mucosa
Area of distribution
6 1 Neuroanatomy of the Brainstem
Vagus nerve (X) Fourth pharyngeal arch nerve
Jugular foramen
Nucleus ambiguus Dorsal vagal nucleus Spinal trigeminal nerve nucleus
SVE VE SA
Pharyngeal muscles, soft palate (partially with N. IX), Laryngeal muscles Thoracic and abdominal organs to Cannon’s point Meninges (posterior cranial fossa, external auditory canal Taste buds on epiglottis
Prevertebral and intramural ganglia Superior ganglion (jugular) Solitary tract nucleus (rostral part) Inferior ganglion SVA (nodosal) Mucosa of pharynx and larynx, Solitary tract nucleus (caudal part) Inferior ganglion VA pressoreceptors in the aortic arch, chemoreceptors (aortic glomus), thoracic and abdominal organs Trapezius muscle, sternocleidomas Spinal nucleus of accessory nerve SE Jugular foramen Accessory nerve (XI) toid muscle Tongue muscles Nucleus of hypoglossal nerve SE Hypoglossal canal Hypoglossal nerve (XII) SA = somatic afferences, SE = somatic efferences, SSA = special somatic afferences, SVA = special visceral afferences, SVE = special visceral efferences, VA = visceral afferences, VE = visceral efferences
Medulla oblongata
1.3 External Characteristics 7
8
of a vascular loop can lead to the compression of a cranial nerve and thus be a cause of neuralgia (Fig. 1.17, p. 31) (Duus et al. 2003).
1.4 Internal Architecture
1 Neuroanatomy of the Brainstem
a posterior
Alar plate (sensory)
Sulcus limitans
Basal plate (motor)
1.4.1 Cranial Nerve Nuclei of the Brainstem Spinal nerves comprise four functionally different categories of nerve fibers: 1. Somatoefferent (SE) or somatomotor fibers which innervate the striated muscles 2. Visceroefferent (VE) or visceromotor fibers which supply the smooth muscles or glands 3. Visceroafferent (VA) or viscerosensory fibers and 4. Somatoafferent (SA) or somatosensory fibers The neurons of the SE-fibers are derivatives of the basal plate and form an anterior column ventrally in the spinal cord. SA-fibers from the periphery terminate posteriorly in the posterior horn, a derivative of the alar plate. Located between these are a general-visceroafferent and a generalvisceroefferent central column (Fig. 1.4). Three additional fiber components are found in the cranial nerves which innervate the sense organs and the striated pharyngeal arch musculature in the head and cervical region: 1. Special-somatoafferent (SSA-) fibers innervate the cochlea and the labyrinth via N. VIII. 2. Special-visceroafferent (SVA-) fibers of the taste buds course in nerves N. VII, N. IX and N. X. 3. Special-visceroefferent (SVE-) fibers innervate the striated muscles that derive from the pharyngeal arch mesoderm. These include motor fibers in N. V, which innervate the muscles of mastication as well as the tensor tympani, the tensor veli palatini, the mylohyoid and the anterior belly of the digastric muscles; motor fibers in N. VII for the pharyngeal levator muscles (the stylopharyngeus, palatopharyngeus, salpingopharyngeus muscles), as well as motor fibers in N. X (in part together with N. IX) to the pharynx constrictors, all inner larynx muscles, the cricothyroid muscle, the striated musculature of the upper twothirds of the esophagus and the muscles of the soft palate (excepting the tensor veli palatine muscle) (Neuhuber 2004). The organization of the functional nuclei of origin and termination of the cranial nerves in the brainstem follows in principle that of the spinal cord. As a result of the “bursting” of the cerebrospinal fluid containing spaces in the region of the medulla and the pons, the sensory (dorsal horn-) regions are shifted laterally, while the motor (anterior horn-) regions are moved to a near-midline location. The view of the dorsal
anterior
b
Sulcus limitans
Motor sensory
Vestibuloacoustic organ, SSA
Pharyngeal arch muscles SVE
Skin, SA Taste, blood pressure, SVA, VA
Viscera VE Brainstem
Muscles of myotomal origin, SE
Fig. 1.4 Schematic cross-section of the spinal cord and brain stem. In the early developmental stage of the spinal cord a sensory alar lamina (gray) can be differentiated from a motor basal lamina (red). (a). The “opened up” diagrammatic view of the brain (b) shows the sensory and motor cerebral nuclei. SSA special somatic afferents, SVA special visceral afferents, VA visceral afferents, SA somatic afferents, SVE special visceral efferences, VE visceral efferences, SE somatic efferences
brain stem showing the cranial nerve nuclei (Fig. 1.5) confirms that the described organization applies to the entire brainstem: the motor nuclei are located medially, sensory nuclei are found laterally, while the visceral nuclei are located between these. In the cross-section, the boundary between the afferent and efferent columns, both in the spinal cord and the brain stem, are marked by the sulcus limitans (Fig. 1.4). 1.4.1.1 Oculomotor Nucleus The oculomotor nerve nucleus is a compact paired nucleus situated in the tegmentum of the mesencephalon, inferior to the mesencephalic aqueduct and superior to the fibers of the medial longitudinal fascicle. It contains the motor neurons that supply the ipsilateral inferior rectus muscle, the inferior oblique muscle, the medial rectus muscle, and the contralateral superior rectus muscle. The motor neurons of the individual eye muscles are topographically arranged in the oculomotor nucleus. The central caudal nucleus is an unpaired nucleus located at the caudal end of the oculomotor nucleus and contains motor neurons of the levator palpebrae muscle which elevates the eyelid. The motor neurons of the levator palpebrae muscles of both sides are intermixed, while the premotor projections to the motor neurons most likely are present on separate sides, an assumption that is supported
1.4 Internal Architecture
9 Sensory nuclei
Motonuclei Edinger-Westphal nucleus
Mesencephalic trigeminal nucleus
III
Oculomotor nucleus
IV
Principal trigeminal nucleus
Trochlear nucleus
V
Motor trigeminal nucleus V
V
Abducens nucleus
Vestibular nuclei VIII
Cochlear nucleus
Facial nucleus VI
Superior and inferior salivary nucleus
VII N. VII
N. IX N. X
N. VII N. VI
XII IX X
N. VIII
N. XI V
Solitary nucleus Spinal trigeminal tract and nucleus XI
Nucleus ambiguus
N. IX N. X Cuneate nucleus Dorsal nucleus of the vagus nerve Gracile nucleus Hypoglossal nucleus Nucleus accessorius
Fig. 1.5 Dorsal view of cranial nerve nuclei. The sensory cranial nerves containing projections of sensitive fibers of cranial nerves are shown on the left side. Depicted on the right side are the somatomotor (dark red)
nuclei, motonuclei of the original pharyngeal arch musculature (pink), and the visceromotor or parasympathetic (red) nuclei
by the occurrence of unilateral supranuclear eye movement disorders. Three separate groups of motor neurons of the medial rectus muscle have been identified within the oculomotor nucleus and are referred to as the A-, B-, and C-group. The C-group contains motor neurons supplying multiple innervated muscle fibers of the medial rectus muscle. Two main categories of muscle fibers can be differentiated in the eye muscle:
Edinger-Westphal Nucleus
1. Twitch muscle fibers with a central endplate zone, similar to those in skeletal muscles, respond to activation with a twitch, according to the all-or-nothing principle and 2. Multiple innervated, or non-twitch muscle fibers that react with a gradual contraction to a stimulus The motor neurons of non-twitch muscle fibers are located in the periphery of the classic oculomotor nucleus (Fig. 1.6) and receive different premotor projections from the classic motoneurons within the oculomotor nucleus. It is assumed that the non-twitch motoneurons and non-twitch muscle fibers serve eye alignment during gaze fixation, while the larger twitch motoneurons within the nucleus together with the twitch muscle fibers promote the actual eye movement (phasic components) (Büttner-Ennever 2006b).
Today the Edinger-Westphal nucleus is usually described as the nucleus that contains the parasympathetic preganglionic cells, whose efferent axons in the oculomotor nerve travel to the ciliary ganglion in the orbits where they are relayed to postganglionic neurons, whose fibers innervate the pupillary sphincter in the anterior eye. The nucleus is located posterior to the oculomotor nucleus and is also known as the accessory oculomotor nucleus. More recent findings suggest that, in humans, parasympathetic preganglionic neurons are not located within the boundaries of the traditional EdingerWestphal nucleus, but dispersed dorsal to it (Olszewski and Baxter 1982; Horn et al., 2008).
Light Reaction and Near Response The pupils normally act as an aperture diaphragm and ensure sufficient depth of focus in near viewing. Luminance in the retina is also regulated by pupillary size, whereby adaptive circuits in the retina have a significantly greater influence on the retinal response than pupillary width. The light reflex, i.e. constriction of the pupil on exposure to light, is mediated via the following pathway: ganglionic cells of the retina, optic
10
1 Neuroanatomy of the Brainstem Oculomotor nerve (N. III)
Trochlear nerve (N. IV)
Abducens nerve (N. VI)
N. IV
Facial nucleus N. VII N. III
Nucleus ruber N. VI
Oculomotor nucleus
Abducens nucleus
Trochlear nucleus
C-Group
Salivary nucleus superior and inferior
N. VII
IV IR VI
IO III SR
MLF
MLF N. VI
MR
Fig. 1.6 Schematic representation of the eye muscle nuclei and nerves. The top row shows a schematic cross-sections of the brainstem to illustrate the location of the eye muscle nuclei (oculomotor, trochlear, abducens nuclei) in the tegmentum and the course of their nerves from the brain stem. See also the course of the facial nerve around the abducens nucleus (genu of facial nerve) and the neurons of origin of the superior and inferior salivary nucleus circling the facial nucleus.
The bottom row shows detailed schematic depictions of the eye muscle nuclei and illustrates the location of non-twitch motoneurons (black dots). The twitch motoneurons are located within the nuclei (red). The location of the individual motor neuron groups for each muscle is illustrated in the oculomotor nucleus. MLF medial longitudinal fasciculus, IO inferior oblique muscle, IR inferior rectus muscle, MR medial rectus muscle, SR superior rectus muscle
nerve and optic tract, pretectal region (see p. 24), (bilateral pretectal olivary nucleus), parasympathetic preganglionic cells of the Edinger-Westphal nucleus (bilaterally), synapse on postganglionic neurons in the ciliary ganglion whose fibres activate the pupillary sphincter muscle. The consensual light response of both pupils to ipsilateral illumination is ensured by the bilateral connections of retinal afferents to the pretectal area and its bilateral influence on the EdingerWestphal nucleus via the posterior commissure.
96–98%) motor neurons of the contralateral superior oblique muscle, whereas the motor neurons of the multiple innervated fibers are found immediately above (Fig. 1.6). The trochlear nerve is the only cranial nerve that exits from the dorsal aspect of the brainstem (Fig. 1.3b, c).
1.4.1.2 Trochlear Nucleus The trochlear nucleus forms a compact, somewhat rounded paired nucleus (divided into a rostral and a dorsal group, respectively) located just caudal to the oculomotor nucleus in the mesencephalic tegmentum. The neurons are partially embedded in the fibers of the medial longitudinal fasciculus. The trochlear nucleus contains almost exclusively (up to
1.4.1.3 Abducens Nucleus The abducens nucleus is located beneath the floor of the fourth ventricle inferior to the genu of the facial nerve (Fig. 1.6). It contains both the motor neurons that innervate the ipsilateral lateral rectus muscle and internuclear neurons (INT), whose axons cross at the level of the abducens nucleus, ascend in the contralateral medial longitudinal fasciculus, and end monosynaptically on motor neurons of the medial rectus muscle in the contralateral oculomotor nucleus (Fig. 1.12a, p. 20). Both groups of neurons receive the same premotor signals from the reticular formation for horizontal saccades, as well as
1.4 Internal Architecture
11
bilaterally from the vestibular nuclei for vestibuloocular reflexes, and so form the anatomical basis for conjugate horizontal eye movements (pp. 18–20). Although these two nerve groups are not separated from each other in the nucleus of the abducens nerve, internuclear neurons tend to be located more laterally and caudally. In contrast to cholinergic motor neurons, internuclear neurons use glutamate as a transmitter. In addition to motor neurons and internuclear neurons, a “rostral cap” of the abducens nucleus comprises neurons that project to the floccular region of the cerebellum; functionally these can be allocated to the so-called paramedian tract cell groups (PMT cells). These cells may have an important role in gaze stabilization (p. 20; Büttner-Ennever 2006).
and the mandibular nerve (jaw region V3) are important in the differentiation between peripheral and central trigeminal syndromes. The trigeminal nerve is a “mixed” nerve with primarily sensory and a smaller part of motor functions for the muscles of mastication and the tensor tympani muscle in the middle ear. As the spinal ganglia, the trigeminal ganglion contains pseudounipolar ganglion cells whose central projections transmit information, e.g. touch and pressure (thick axons) as well as pain and temperature (thin axons) to the sensory trigeminal nuclei (Figs. 1.5 and 1.7). The trigeminal nucleus is the largest of all cranial nerve nuclei and extends throughout the entire brainstem to the cervical region of the spinal cord. It is divided into three sensory and one motor part:
1.4.1.4 Trigeminal Nucleus
1. The mesencephalic trigeminal nucleus forms a slender cell column at the lateral border of the periaqueductal gray. It consists of pseudounipolar nerve cells (which are otherwise found only in spinal or cranial nerve ganglia), whose peripheral projections enter via the small motor root of the mandibular nerve and transmit proprioceptive signals from the muscles of mastication to the mesencephalic trigeminal nucleus. The central
The trigeminal nerve (N. V) is the principal somatosensory nerve for the head and serves as a sensor for pain, temperature, and strong touch as well as gentle touch and jaw proprioception. Knowledge of the distribution of the innervation patterns of the three trigeminal branches, the ophthalmic nerve (upper face, V1) maxillary nerve (middle face V2)
Mesencephalic trigeminal nucleus
Motor trigeminal nucleus
Trigeminal ganglion (Gasseri)
Principal trigeminal nucleus Ophthalmic nerve
Fig. 1.7 Depiction of the relationships between the trigeminal nerve and the trigeminal nuclear complex. The sensory nuclei (light gray) of the principal trigeminal nucleus and the spinal trigeminal spinal nucleus receive thick fibers for touch sensation and thin pain sensation fibers, respectively. Their pseudounipolar nerve cell bodies lie in the trigeminal ganglion. Descending, primarily thin fibers, form the spinal tract of the trigeminal nerve. The cell bodies of the proprioceptive afferents of the masseter muscle lie in the mesencephalic trigeminal nucleus (dark gray). They constitute the afferent limb of the masseter reflex; the motor fibers of the masseter muscle in the trigeminal nerve originating from the motor trigeminal nucleus (light red) form the efferent limb
Maxillary nerve Mandibular nerve
Spinal trigeminal tract Masseter reflex Spinal trigeminal nucleus
12
axons of the neurons of mesencephalic trigeminal nucleus terminate on the motor trigeminal nuclei in the pons and mediate the masseter reflex (Fig. 1.7). To elicit the masseter reflex, the chin of the patient is lightly tapped, which causes the masseter muscle to stretch, resulting in activation of the spindle afferents. Via direct synapses onto neurons of the motor trigeminal nucleus these then elicit a monosynaptic reflex, which can be observed on both sides. An abnormally pronounced masseter reflex serves as an indication of a central disturbance of muscle tone. 2. The Principal trigeminal nucleus lies in the pons rostral to the abducens nucleus and lateral to the motor trigeminal nucleus. It is the primary termination target for the thickly myelinated axons conveying touch and pressure (Fig. 1.7). In the older literature this nucleus is also described as the “relay nucleus of epicritic sensitivity.” The efferents decussate and ascend as the trigeminal lemniscus (Fig. 1.4a, b) dorsomedial to the medial lemniscus and so correspond to the tracts of the posterior white column in the spinal cord (Fig. 1.16b). 3. The spinal trigeminal nucleus and tract extend to the cervical spinal cord as a continuation of Lissauer’s tract and the substantia gelatinosa (Rexed layers I-III) of the dorsal horn. There the termination site of the afferents for pain and temperature in topographic order (mouth and nose are in a rostral location, concentric skin areas around mouth and nose are located more caudally). 4. The motor trigeminal nucleus is located in the lateral tegmentum of the pontine brainstem. It contains motor neurons of the mylohyoid muscle, the anterior belly of the digastric muscle, as well as the masseter, temporal, tensor veli palatini and tensor tympani muscles. A large number of thin axons of all three branches enter the caudal medulla where they form the “concentric-ring-topography” in the spinal trigeminal nucleus. The axons form the spinal trigeminal tract lateral to the nucleus region and represent a relay station of the “protopathic” pain system (Figs. 1.7 and 1.14). The ascending fibres of the spinal trigeminal nucleus cross in the medulla oblongata to the other side and join the spinothalamic tract to the contralateral ventroposterior thalamus (also termed the anterolateral tract). Based on the somatotopic organisation of the spinal trigeminal nucleus, caudal part, a small central lesion results in the selective loss of protopathic sensitivity (e.g. in the perioral region or the respective onion skin distribution of the side of the face). A lesion in the principal trigeminal nucleus leads to the selective loss of the epicritic sensitivity of the face, which would not occur in the presence of a peripheral lesion. The motor trigeminal nucleus and therefore the muscles of mastication and, the tensor tympani in the middle
1 Neuroanatomy of the Brainstem
ear receive bilateral central ipnuts via the corticonuclear tract, primarily from the contralateral side. Therefore a unilateral lesion of the supranuclear pathways does not result in a severe paralysis because of the presence of ipsilateral projections. The tensor tympani muscle modulates the mobility of the small bones in the middle ear to prevent sensory overload of the Corti organ as a result of loud noise. Supranuclear projections to the motor neurons of the tensor tympani provide protection from one’s own voice. Trigeminal Reflexes The sensory fibers of the trigeminal nerve are involved in several important reflex arcs: tactile stimulation of the cornea (ophthalmic nerve) activates neurons of the trigeminal nerve; these, in turn, have bilateral projections to the facial nucleus via intermediate neurons, whereby the blink reflex is elicited. For the sucking reflex, tactile stimulation of the lips (mandibular nerve) causes afferent signals to be transmitted to the principal trigeminal nucleus. The orbicularis oris muscle is activated via polysynaptic bilateral projections to the facial nucleus. Eliciting the sucking or nasal reflex the stimulation of trigeminal afferents results in the excitation of several muscle groups, and the reticular formation assumes an important role in coordinating activation of the different motor nuclei (pp. 16, 18 and 28). The masseter reflex has already been discussed above.
1.4.1.5 The Facial Nucleus The facial nucleus is located in the ventrolateral pontine tegmentum. Although the neurons are analogous to the motor anterior horn cells, they are developmentally derived from the second pharyngeal arch. During development the facial nerve is pushed dorsally by the abducens nucleus which grows in a posterior direction and loops around it, forming the internal genu of the facial nerve (Fig. 1.6). In its course from the anterolateral pons to the periphery, the facial nerve converges with fibers from the superior salivary nucleus as well as with fibers for taste sensation from the anterior third of the tongue (Fig. 1.5). In contrast to earlier assumptions, systematic investigation of the location of the salivary nuclei has not shown any differences between the distribution of the neurons of the superior and inferior salivary nucleus surrounding the facial nucleus (Blessing 2004). While the fibers of the intermediate and the facial nerve are intermingled in the pons, they leave the brainstem as two separate nerves – a thicker motor facial nerve and a thinner intermediate nerve, which contains visceroafferent and somatoafferent as well as visceroefferent fibers.
1.4 Internal Architecture
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The motor neurons of the facial nucleus innervate the facial mimetic muscles and are located in different subnuclei. The ventrolateral cell group supplies the perioral musculature, motor neurons in intermediate and dorsomedial locations innervate the orbicularis oculi and the forehead muscles. The stapedius muscle in the middle ear, the posterior belly of the digastric muscle and the stylohyoid muscle are innervated by cells outside the classic facial nucleus in the adjacent reticular formation. Corticonuclear (corticobulbar) connections for voluntary movement of facial muscles project bilaterally to facial motor neurons of the upper part of the face, but only contralaterally to those of the lower part of the face. These fibers cross in the caudal pons. Unilateral lesions of the corticonuclear pathway are associated with contralateral paresis of the facial muscles (sagging corners of the mouth), except the muscles of the forehead, which can be moved on both sides because of their bilateral innervation. The patient cannot produce a smile on the affected side on demand, whereas a spontaneous smile is possible. This phenomenon is accounted for by direct bilateral limbic influences on the facial nucleus. In contrast, the ipsilateral facial musculature is completely paralysed after a nuclear or peripheral injury (Holstege et al. 2004).
colliculus, whose efferents can also elicit a blink reflex via the facial motoneurons. Auditory projections via the cochlear nucleus activate the periolivary nucleus in the rostral pole of the superior olivary nucleus bilaterally and thereby also activating the motor neurons of the stapedius muscle, which increase the acoustic impedance of the auditory ossicles in the middle ear.
1.4.1.6 Vestibular Nuclei Primary afferents from the three semicircular canals and both otolith organs (utricle and saccule) are activated by angular or linear acceleration of the head, and effect compensatory movements of the eye, head, and cervical musculature via their connections in the brainstem (Fig. 1.8). Without these compensatory reflexes the visual perception of spontaneous movement would significantly be impaired. The primary afferents end in the vestibular nuclei as the first relay station (Figs. 1.5, 1.11 and 1.12). Four vestibular nuclei can be differentiated anatomically: • • • •
Facial Reflexes The facial nucleus is a component of different reflex arcs: corneal reflex, blink reflex and stapedius reflex. Sensory impulses from the conjunctiva reach the spinal trigeminal nucleus via the ophthalmic nerve, and are locally relayed via oligosynaptic and polysynaptic pathways of the reticular formation to motoneurons of the orbicularis oculi muscle in the facial nucleus. An intense light stimulus activates the superior
The superior vestibular nucleus (Bechterew) The lateral vestibular nucleus (Deiters) The medial vestibular nucleus (Schwalbe) The inferior vestibular nucleus (or descending vestibular nucleus)
At the border to the lateral vestibular nucleus a magnocellular part can be defined in the medial vestibular nucleus that represents a relay station for the vestibuloocular pathways (Fig. 1.12). The magnocellular part is also referred to as the ventral lateral vestibular nucleus and is differentiated from the dorsal part of the lateral vestibular nucleus which contains large “Deiters” cells projecting to the spinal cord. The inferior vestibular nucleus can cytoarchitectonically be Cerebral cortex Spatial orientation
Cerebellum Fine control of movements
Fig. 1.8 Block diagram showing the primary connections of the vestibular nuclei. The vestibular nuclei receive sensory input from the vestibular nerve and are connected to different regions of the brain where they are predominantly involved in the control of movements. PCI inferior cerebellar peduncle, MLF medial longitudinal fascicle, MVST medial vestibulospinal tract, LVST lateral vestibulospinal tract
Thalamus PCI
MLF
Ocular muscle nuclei Vestibuloocular reflexes
Vestibular nuclei Vestibular nerve Sensory input
MVST LVST
Spinal cord Control of body posture
Vegetative centers Cardiovascular, visceral and respiratory control
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differentiated from the other vestibular nuclei by their plaqueshaped pattern of the fiber bundles coursing through it. At the caudal end, superior to the inferior cerebellar peduncle (restiform body) lies the y-group, which forms a part of the bridge between the fourth ventricle and the lateral aspect of the brain stem. Upon entry of the vestibular nerve, each vestibular fiber divides as follows: one branch descends to the medial and the inferior vestibular nucleus, an ascending branch sends collaterals to the superior vestibular nucleus before continuing to the cerebellum, predominantly to the nodular lobe (lobule X) and the uvula (lobule IXd) (Voogd 2004). These pathways serve for fine control of movements (Fig. 1.8). Analogous to cerebellar nuclei, the vestibular nuclei receive direct projections from the Purkinje cell fibers of the cerebellar cortex. In this sense the vestibular nuclei may be regarded as externally located cerebellar nuclei. The lateral vestibular nucleus receives direct projections from the cerebellum but only very few from the periphery, predominantly from the saccule. Primary afferents from the saccule also terminate in the ventral part of the y-group, while those of the utricle terminate predominantly in the rostral part of the inferior vestibular nucleus and in the ventral aspect of the lateral vestibular nucleus. Descending pathways from these regions are important for compensatory body posture during head movements. Lesions in the vestibular system result in vestibular vertigo with nystagmus and disturbance of spatial orientation (Fig. 1.8). Acoustic neuromas do not arise – as the name suggests – from the acoustic, but from the vestibular nerves. The slow growing tumor can cause increased excitability of the vestibular system. Because this disturbance continues to be centrally compensated by the vestibular nuclei, the patient does usually not feel vertigo. The pathways of the vestibuloocular reflex are shown in Fig. 1.12a on page 20.
1 Neuroanatomy of the Brainstem
and whose axons cross in the medullary stria or in the reticular formation before projecting via the lateral lemniscus directly to the contralateral inferior colliculus (p. 31 and Fig. 1.16b, d).
1.4.1.8 Nuclear Groups of the Vagal System Due to various common functions of the glossopharyngeal, vagus, accessory (cranial part) and intermediate nerves and their nuclear regions, including the solitary tract nucleus, the ambiguus and trigeminal nuclei, the system is often described as the vagal system (Figs. 1.5, 1.9, 1.14, 1.15 and p. 29; Holstege 1991; Neuhuber 2004).
Glossopharyngeal Nerve In addition to motor fibers the glossopharyngeal nerve comprises predominantly sensory, visceral afferent fibers (Table 1.1, p. 6; Figs. 1.5, p. 9 and 1.9). Tactile stimulation of the somatosensory afferent fibers projecting to the principal trigeminal nucleus will elicit the gag reflex, a constriction of the pharyngeal musculature. The swallow reflex is a response to stimulation of the oropharynx, mediated by visceroafferent fibers of the glossopharyngeal nerve projecting to the caudal solitary tract nucleus – also named the commissural nucleus – which, in turn, has connections to the adjacent swallowing center in the reticular formation. Cerebral cortex, thalamus Parabrachial complex
1.4.1.7 Cochlear Nuclei Within the cochlear nerve (N. VIII) afferent nerve fibers of the bipolar cells of the spiral ganglion traverse the internal acoustic meatus and enter the brainstem at the cerebellopontine angle. The fibers divide in a t-shaped fashion and form short ascending and descending branches before terminating in the ipsilateral posterior and anterior cochlear nucleus, respectively (Fig. 1.5). The anterior cochlear nucleus comprises several parts that process various aspects of auditory signals, e.g. tonotopy, tone intensity, and the determination of the interaural time difference of a sound source, which are important for directional hearing. The axons leave the anterior cochlear nucleus via the dorsal intermediary or ventral acoustic stria and cross in the trapezoid body of the pons to the contralateral side. The posterior cochlear nucleus contains neurons (pyramid cells) that process complex acoustic processes,
N. VII Gustatory Respiratory Cardiovascular Visceral Respiratory Cardiovascular Visceral
N. X N. IX
Gustatory nucleus Cardiorespiratory part Commissural nucleus Solitary tract nucleus
Fig. 1.9 Subnuclei of the solitary tract nucleus and representation of the primary afferents. Based on afferent termination sites, the solitary tract nucleus (light gray) can be divided into different subnuclei: afferents carrying taste information reach the rostral gustatory nucleus via the intermediate nerve (N. VII), respiratory and cardiovascular afferents terminate predominantly in middle cardiorespiratory part, visceral afferents end in the posterior commissural nucleus. The information is conducted via the glossopharyngeal (N. IX) and the vagus nerve (N. X)
1.4 Internal Architecture
The functions of the glossopharyngeal nerve can be divided into a number of different categories: • Afferent somatosensory fibers from the mucosa of the oropharynx and nasopharynx, the soft palate, the pharyngopalatine arch, the tympanic cavity, as well as the Eustachian tube project to the principal trigeminal nucleus (touch), or to the spinal trigeminal nucleus (pain and temperature) (p. 11). • Special visceroafferent fibres from the taste buds of the posterior third of the tongue project to the solitary tract nucleus (also described as the gustatory nucleus). • Visceroafferent pathways from the carotid sinus (arterial pressure, baroreflex) and the carotid body (fall in pO2 or a rise in pCO2) project to the middle part of the solitary tract nucleus. • Visceroafferent fibers from the viscera terminate in the caudal solitary tract nucleus (commissural nucleus) (Fig. 1.9). • Visceroefferent fibers from the inferior salivary nucleus course within the glossopharyngeal nerve and innervate the parotid gland. • Somatosensory fibers with origin in the nucleus ambiguus supply the striated musculature of the pharynx and stylopharyngeal muscle. A detailed description of the reflex pathways in the medulla is found elsewhere in the literature (Blessing 2004). Solitary (Tract) Nucleus The solitary nucleus is a sensory nucleus and receives afferents via the facial (middle part), the glossopharyngeal, and the vagus nerves (Figs. 1.5, 1.9, 1.14a, e). It stands out anatomically because it is accompanied along its entire length by compact myelinated axons of the solitary tract. Functionally the solitary (tract) nucleus can be divided into four regions (Fig. 1.9): 1. The rostral part, as the gustatory nucleus, receives afferent taste information from the taste buds of the tongue and the pharynx. 2. The dorsal respiratory nucleus is situated in the middle and lateral part. 3. The baroreceptor nucleus, cardiorespiratory part, is located in the middle and medial part. 4. Caudally the solitary tracts of both sides converge to form the commissural nucleus. This part receives visceroafferent signals from the intestinal and the respiratory tract (p. 29).
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“vagus” is “wandering” and the name serves as an indication of its complicated peripheral course. The vagus nerve is an important visceromotor nerve for the heart, lung and viscera, although it also contains a fourfold greater share of sensory fibers. The visceromotor fibers originate in the dorsal nucleus of the vagus nerve, while the somatomotor fibers originate in the nucleus ambiguus. The viscerosensory afferents with ganglia cells in the superior or inferior ganglion (Table 1.1, p. 6) project to the spinal trigeminal nucleus. Somatomotor fibers from the nucleus ambiguus innervate the striated musculature of the pharyngeal arch derivatives, the pharynx, soft palate, larynx (vocal nerve), and the esophagus. Visceromotor fibers from the dorsal nucleus of the vagus nerve innervate the smooth musculature and the glands of the digestive and respiratory tract. The axons of these motor fibers are relayed to intramural ganglion cells in the periphery. Visceromotor fibers of the vagus nerve also regulate cardiac action. Visceral sensory afferents of the vagus nerve from the heart, lung and viscera located in the ganglion cells of the larger nodose ganglion (inferior) terminate in the caudal solitary tract nucleus, the commissural nucleus (Fig. 1.9) These visceral afferents mediate important reflexes, e.g. the Bainbridge reflex (increase in heart rate due to stretching of right atrium), the cough reflex (after stimulation of the tracheobronchial system) and the Hering-Breuer reflex (inhibition of the dorsal respiratory center after stimulation of the stretch receptors in the lung) (see Fig. 1.15 and p. 29) (Holstege 1991; Blessing 2004). Somatosensory afferents from the external auditory meatus as well as from the meninges of the posterior cranial fossa also course in the vagus nerve and terminate in the spinal trigeminal nucleus.
orsal Motor Vagal Nucleus (Dorsal Nucleus D of the Vagal Nerve) The dorsal motor vagal nucleus represents the largest collections of preganglionic parasympathetic neurons in the brainstem. The name of this nucleus emphasizes its primary function as a visceral motor nucleus. Together with the solitary tract nucleus it extends from the rostral medulla to the level of the decussation of the pyramids (Fig. 1.5). Because of the described close relationship between the solitary tract nucleus and the dorsal motor vagal nucleus the structure is frequently referred to as the “vagus-solitary complex.”
Nucleus Ambiguus Vagus Nerve The vagus nerve (N. X) is the largest nerve of the parasympathetic system. The literal translation of the Latin word
The nucleus ambiguus is a cytoarchitectonically inconspicuous nucleus insofar as it contains motor neurons, interneurons and preganglionic neurons in relatively widely scattered locations. The axons of the motor neurons travel
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together with the glossopharyngeal, vagus and accessory (cranial part) nerves to the musculature of the soft palate, the pharynx and the larynx, as well as to the striated musculature in the superior esophagus. The nucleus ambiguus lies within the reticular formation on the level of the middle part of the spinal trigeminal nucleus interpolaris part, (Figs. 1.5, 1.14d, e, 1.15). In this central location it receives afferents from structures in the immediate vicinity via reflexes elicited by, retching, coughing and swallowing. The nucleus retroambiguus forms the caudal extension of the nucleus ambiguus and plays a role in expiration via its projections to the respective motoneurons in the spinal cord (Holstege et al. 2004).
1.4.1.9 Nuclear Groups of the Accessory Nerve The accessory nerve (N. XI) comprises two roots: the spinal and the cranial root. The spinal portion is purely motor: the alpha and gamma motor neurons lie in the anterior horn of C2–C6 in the nucleus of the accessory nerve (Fig. 1.5). The roots pass laterally between the dorsal and ventral roots into the subarachnoidal space, before ascending and joining the roots of successive, higher segments (Fig. 1.3, not shown). The spinal root enters the skull via the foramen magnum (for this reason the accessory nerve is also described as a “false cranial nerve”) and joins the cranial root along a short path to the jugular foramen, the exit site of the accessory nerve. The spinal portion exits the accessory nerve as the external ramus and passes at the level of the neck to the pharyngeal arch derivatives, the sternocleidomastoid muscle and the trapezius (upper part) muscle. In the cervical plexus the accessory nerve is joined by additional motor (C2–C4) as well as sensory (proprioceptive) fibers. Activation of the trapezius muscle results in lifting of the shoulder, activation of the sternocleidomastoid muscle causes a head turn the contralateral side. The neurons of origin of the N.XI cranial root are located in the nucleus ambiguus (Fig. 1.5). The axons exit the spinal portion already in the jugular foramen, join the vagus nerve, and innervate the muscles of the larynx, except the cricothyroid muscle. Modern classifications of the cranial nerves have assigned the cranial root to the vagus nerve and not to the accessory nerve proper (Table 1.1).
1.4.1.10 Nucleus Hypoglossus The nucleus hypoglossus consists of several groups of motoneurons that innervate the extrinsic and intrinsic muscles of the tongue. The extrinsic muscles move the tongue as a whole, while the interior musculature alters the shape of the tongue. The majority of studies have shown that both muscle groups are innervated by motor neurons of the same
1 Neuroanatomy of the Brainstem
side. A lesion in the nuclear region is generally associated with a bilateral flaccid paresis that may be accounted for by the medial location of both hypoglossal nuclei. After exiting the cranium via the hypoglossal nerve canal, the hypoglossal nerve (N. XII) descends along the internal carotid artery. It forms anastomoses with the vagus nerve, the superior cervical ganglion and the lingual nerve. The hypoglossal nerve also carries fibers of proprioceptive afferents from C1 for innervation of the numerous muscle spindles in the tongue. The nucleus hypoglossus receives bilateral premotor afferents from the adjacent reticular formation as well as from the trigeminal nuclei and the solitary tract nucleus conveying sensory information from the oral cavity as well as from the masticatory and tongue musculature. These inputs are important for reflex movements of the tongue (swallowing, chewing, sucking, licking). Since the supranuclear control of the nucleus hypglossus is exerted predominantly, but not exclusively, by the contralateral cortex, unilateral cortical injury is not associated with major impairments of tongue mobility.
1.4.2 Reticular Formation: A Coordination Center for Complex Movement Fifty years ago an ascending system was identified in the brainstem that regulates attention processes in the forebrain. In animals, stimulation of large regions of the brainstem evokes an awakening reaction, causing the sleeping animal to wake up. Based on the diffuse cytoarchitecture of these attention pathways within the “core” of the brainstem (i.e. the reticular formation), this system was unfortunately described as the ascending reticular activating system (ARAS). Today the exact origin of the diffuse ascending and descending nerve tracts of the brainstem that regulate the wake-sleep rhythm is well known. These regions are not part of the unstructured reticular formation, but are embedded in compact nuclei as, e.g. the locus caeruleus or the raphe nuclei that are described below (see Figs. 1.10 and 1.14). The term ascending activating system is therefore a more appropriate scientific name to describe this system. There are a number of definitions for the reticular formation; some descriptions also include the raphe nuclei and the locus caeruleus in the term. In the light of more recent findings on the origin of the ascending activating system it is more appropriate to define the discrete reticular formation as “cell groups of the tegmentum with a characteristic cytoarchitecture” between well defined cranial nuclei as, e.g. the red nucleus and the cranial nerve nuclei. In the past century Forel was the first researcher to identify the reticular formation as a cytoarchitectonic unity that extends throughout the
1.4 Internal Architecture Fig. 1.10 Dorsal view of the reticular formation and neuromodulatory brainstem nuclei. Shown on the left side is a schematic representation of the cytoarchitecture of the reticular formation whereby a medial magnocellular part can be differentiated from a lateral parvocellular part. Shown against a gray background is the region of the paramedian pontine reticular formation (PPRF), which is important in the generation of horizontal saccades. The right side shows brainstem nuclear groups with neuromodulatory function. The asterisks mark the locus caeruleus. The parabrachial nuclei are found on both sides of superior cerebellar peduncle (S). M medial cerebellar peduncle, I inferior cerebellar peduncle
17 Reticular formation
Neuromodulatory brainstem nuclei Dorsal raphe nucleus
Mesencephalic cuneiform nucleus
Dorsal tegmental nucleus
Nucleus reticularis pontis oralis Nucleus reticularis pontis caudalis Gigantocellular nucleus Paramedian reticular nucleus
Pedunculopontine tegmental nucleus
S S
M I
Lateral parabrachial nucleus Medial parabrachial nucleus Locus caeruleus and subcaeruleus Superior central nucleus
Parvocellular reticular nucleus
Nucleus raphe magnus Nucleus raphe obscurus Nucleus raphe pallidus
entire brainstem (Fig. 1.10, left side). The reticular formation forms a long column of discrete multipolar neurons, while the medial longitudinal zone contains larger neurons from which bilateral reticulospinal tracts branch off; posture and orienting movements are modulated via these pathways (Nieuwenhuys et al. 1991; Büttner-Ennever and Horn 2004). The lateral parvocellular zone contains interneurons with short ipsilateral axons that coordinate the activity of motor neurons in the facial and ambiguus nuclei, as well as the hypoglossal and trigeminal nerves during activities such as breathing, vomiting, swallowing, chewing, licking and calling (Holstege 1991). The lateral parvocellular zone extends rostrally to the parabrachial nuclei (Fig. 1.10) as well as to the Kölliker-Fuse nucleus and continues in the spinal cord as the intermediate zone (Rexed layers V–VIII). In contrast to the ascending activating system (raphe nuclei and locus caeruleus), the reticular formation functions as a coordination center where information is very specifically conveyed (see pp. 18 and 27); small areas of the reticular formation in the pons relay signals, e.g. premotor signals for the motor neurons of the external eye muscles, and generate exact saccadic eye movements.
1.4.3 Ascending Activating System: Attention, Wake–Sleep Rhythm A number of brainstem nuclei have particularly long efferent axons, whose fine and diffuse terminal fields cover huge projection areas as, e.g. the entire cerebral cortex, the cerebellum, and the spinal cord, and transport transmitters to these areas.
Examples of these include the noradrenergic locus caeruleus, the serotoninergic raphe nuclei, the cholinergic cells in the pedunculopontine tegmental nucleus, the dorsolateral tegmental nucleus, and dopaminergic cell groups in the ventral tegmental area of the mesencephalon (Fig. 1.10), as well as the cholinergic basal nucleus of Meynert in the basal forebrain. These networks exert a modulating effect that intensifes specific signals (Saper et al. 2001; Halliday 2004). The neurons of the cholinergic pedunculopontine tegmental and the dorsolateral tegmental nucleus project topographically to the thalamus and are assumed to be indispensable for thalamocortical transmission. These neurons are particularly active during REM sleep. The monoaminergic cell groups (locus caeruleus, dopaminergic neurons of the ventral periaqueductal central gray substance, raphe nuclei) project to the nonspecific thalamus, but also extend via a fiber tract running through the basal forebrain into the entire cerebral cortex. The firing frequency of monoaminergic neurons is strongly correlated with wakefulness: the neurons are most active during the state of attention, less active in sleep, and completely inactive during REM sleep. The ascending activating system is accompanied by histaminergic axons of the tuberomammillary nucleus and orexincontaining neurons of the lateral hypothalamus (Sakurai 2005). Current hypotheses assume that the different activities of the cholinergic and monoaminergic ascending activating systems regulate the state of attention or sleep and REM sleep, and thus emphasize the close relationship between these states and eating behaviour, thermoregulation and circadian rhythms (Saper 2006). The locus caeruleus is characterized by descending axons that terminate throughout the entire spinal cord as well as in the
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nucleus raphe magnus and the nucleus raphe pallidus. From the nucleus raphe magnus these fibers descend bilaterally in Lissauer’s tract and terminate almost exclusively in the dorsal horn, primarily in the substantia gelatinosa (Rexed layer I). By way of their transmitter serotonin, these diffusely distributed terminals cause inhibition of the enkephalinergic interneurons of the dorsal horn. They are therefore able to control the sensory input to the spinal cord and effect stimulus- or stress-induced analgesia (Holstege 1991). Conversely, descending fibers of the nucleus raphe pallidus terminate primarily in the ventral horn and thus have a vital influence on the entire motor system. It is of importance that the control of the spinal cord by raphe nuclei or the locus caeruleus is not organized topographically and is therefore effective throughout the system. The raphe nuclei are subject to rigorous control by the periaqueductal gray matter. However, in a life-threatening situation endorphin influences from the hypothalamus can disinhibit the periaqueductal gray matter, and thus gain supraspinal control of pain afferents.
1.4.4 Limbic Control The anatomic organization of the brainstem provides evidence of an emotional or ‘limbic’ motor system (Holstege et al. 2004). The limbic premotor pathways which proceed separately from the somatomotor system terminate on motoneurons in the caudal brainstem, and are concerned with generating motor activity patterns during micturition, swallowing, vomiting, vocalization, sexual behavior, and with respiratory and cardiovascular reactions. The descending limbic pathways originate in the preoptic region of the lateral hypothalamus, the central nucleus of the amygdala, and the lateral aspect with the nucleus of the stria terminalis. Loosely packed projections pass from these telencephalic regions to the periaqueductal gray substance (p. 25) and to the lateral tegmentum of the caudal brain stem, which contains the respective premotor and preganglionic neurons (Figs. 1.10 and 1.13). The periaqueductal gray substance also provides important input to these limbic cell groups. The limbic pathways can be divided into medial and a lateral components. The medial part projects to the raphe nuclei and the pedunculopontine tegmental nucleus via diffuse pathways, modulates both motor and sensory activity, and thereby serves as a way to determine threshold values. The lateral part activates specific motor behavior patterns that have a role in emotional behavior.
1.4.5 Premotor Control of Eye Movements Five different eye movement types – saccades, vestibulo-ocular reflex, optokinetic reflex, smooth pursuit eye movements,
1 Neuroanatomy of the Brainstem
convergence – and gaze stabilization can be differentiated in humans. They are generated in different neuronal networks and their efferent premotor pathways converge on motor neurons of the eye muscles and continue to the orbit as a short common pathway before terminating (Fig. 1.11). Consequently, damage to one premotor pathway or to an individual premotor region of the brain can lead to a relatively selective loss of one eye movement type, while the others remain intact (Leigh and Zee 2006).
1.4.5.1 Saccades Information about a gaze target is transmitted via different rostral regions of the brain to the superior colliculus, and then these neurons in the deep layers of the colliculus project to premotor centers in the reticular formation, which in turn activate motor neurons of the eye muscles, thus generating a rapid eye movement (saccade) (Fig. 1.11). This results in the generation of horizontal saccades in the paramedian pontine reticular formation (PPRF), while vertical and torsional saccades are generated in the mesencephalic reticular formation. The paramedian pontine reticular formation comprises anatomically the nucleus reticularis pontis caudalis and contains the premotor neurons for horizontal saccades to both sides, as well as inhibiting glycinergic omnipause neurons located near the midline and control the triggering of saccades in all directions (Fig. 1.10; Büttner-Ennever and Horn 2004). Efferent connections from the PPRF exist to the abducens nerve nucleus, the prepositus hypoglossal nucleus, the medial vestibular nucleus, and to motor neurons of the cervical muscles that are activated on changes in gaze direction. Unilateral damage to the paramedian pontine reticular formation therefore leads to horizontal gaze paresis to one side, while a lesion located in proximity to the midline is associated with complete gaze paresis (Leigh and Zee 2006). Premotor neurons for vertical and torsional saccades are located in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and in the interstitial nucleus of Cajal (INC) (Fig. 1.4a and p. 19). The riMLF and adjacent INC are embedded in the fibers of the medial longitudinal fasciculus, inferior to the thalamus and dorsolateral to the rostral pole of the oculomotor nucleus (Büttner-Ennever and Horn 2004). In addition to projections to motoneurons of the vertically moving eye muscles in the oculomotor and trochlear nuclei, the riMLF and INC have efferent connections to cell groups of the paramedian tract in the pons and medulla, as well as to vestibular nuclei and the spinal cord via the medial longitudinal fasciculus. Bilateral lesions of the riMLF lead to vertical gaze paresis, mostly upward or downward and – in rare cases – to isolated down gaze paresis due to the presence of very small lesions (Leigh and Zee 2006).
1.4 Internal Architecture
19 PPRF riMLF
Frontal eye fields
SC
1 Saccades
Basal ganglia
Vestibular nuclei Motor neurons
2 Vestibulo-ocular reflex (VOR)
Accessory optic nuclei Nucleus of the optic tract
Eye muscle
3 Optokinetic reflex (OKN)
Retina
Visual cortex
Vestibular nuclei
Floccular region
Pretectum MRF
?
Interstitial nucleus of Cajal Prepositus hypoglossal nucleus
4 Smooth pursuit Eye movements
Pontine nuclei
5 Vergence
Vestibular nuclei
Floccular region
6 Gaze stabilization
Fig. 1.11 Block diagram illustrating the premotor pathways of eye movements. Five eye movement types and gaze stabilization can be differentiated. They are generated via separate premotor pathways that converge, on motoneurons in the eye muscle nuclei. Some of the same premotor
pathways are used by different eye movement types (vestibulo-ocular and optokinetic reflexes). riMLF rostral interstitial nucleus of the medial longitudinal fasciculus, PPRF paramedian pontine reticular formation, SC superior colliculus, MRF mesencephalic reticular formation
1.4.5.2 Vestibulo-ocular Reflex
the prepositus nucleus via collaterals, cell groups of the paramedian tracts, the interstitial nucleus of Cajal, and the rostral interstitial nucleus of the medial longitudinal fasciculus. Furthermore, a group of vestibulo-ocular secondary neurons in the medial and inferior vestibular nuclei send collaterals via the contralateral medial vestibulospinal tract to the spinal cord ending on motor neurons of the cervical muscles. Purely vestibulospinal pathways project from the lateral vestibular nucleus ipsilaterally in the lateral vestibulospinal tract and innervate the cervical musculature (Fig. 1.8 and p. 13) (Shinoda et al. 2006).
The vestibulo-ocular reflex occurs in the form of a slow compensatory eye movement in response to excitation of the semicircular canals (rotation of the head), interrupted by rapid return saccades of the eyes (Fig. 1.11). Repeatedly occurring compensatory and saccadic eye movements are described as “nystagmus”; the direction is defined by the direction of the fast (saccadic) phase of the nystagmus. While return saccades are generated via premotor pathways of the saccadic system, the compensatory movement is generated via a short and therefore very rapidly reacting three neuron arc: primary afferents from the semicircular canals activate secondary neurons in the rostral third of the vestibular nuclei monosynaptically, which then directly activate the motor neurons of one eye muscle pair (superior oblique muscle and inferior rectus muscle; superior rectus muscle and inferior oblique muscle; lateral rectus muscle and the internuclear neurons in the abducens nerve nucleus, the medial rectus muscle motoneurons). In this process excitatory vestibular pathways cross to contralateral, while inhibitory pathways remain ipsilateral (Fig. 1.12). Nearly all of these neuronal connections project via the medial longitudinal fasciculus. The inhibiting vestibuloocular connections of the horizontal system use glycine as transmitter, while GABA is used by the vertical systems (BüttnerEnnever and Gerrits 2004; Highstein and Holstein 2006). The vertical vestibulo-ocular pathways further innervate
1.4.5.3 Optokinetic Reflex The vestibulo-ocular reflex is complemented by the optokinetic system, which is activated by large-field visual stimuli moving across the retina, e.g. movement from the surrounding world (Fig. 1.11). Two anatomic systems play an important role in the generation of the resulting compensatory eye movement, the optokinetic reflex: the accessory optic system (see ‘Retinal Inputs’ p. 5) and the pretectum with the nucleus of the optic tract (see p. 24). Retinal signals are transmitted to the vestibular nuclei via the nucleus of the optic and the accessory optic nuclei via different parallel pathways and with involvement of the prepositus nucleus. From the vestibular nuclei the same premotor pathways as those for the vestibulo-ocular reflex are used for optokinetic responses (Fig. 1.11).
20
1 Neuroanatomy of the Brainstem
a
b
c
IO+ MR
LR
+SR
IO
SR
LR
–SO
–IR
SO +
IR +
III
MLF INT
III
III
IV
IV MLF
MLF
VI –
HC +
MLF
Vestibular nuclei
–
AC +
Vestibular nuclei
MLF
–
PC
+ Vestibular nuclei
Fig. 1.12 Representation of pathways for the vestibulo-ocular reflex. Primary afferents of the semicircular canals are relayed to excitatory (red) and inhibitory secondary neurons (black axons) in the vestibular nuclei; these in turn travel to the motor neurons of the respective eye muscles, which they activate (red, with red arrow) while inhibiting their antagonists (gray, dotted line arrow). Shown here is the pulling direction of eye muscle, not the muscles themselves. On excitation of the horizontal canal (a) internuclear neurons (INT) in addition to lateral rectus muscle (LR) motoneurons are activated in the abducens nucleus
(VI), which then excite the medial rectus muscle (MR) neurons in the contralateral oculomotor nucleus (III). The result of bilateral activation of the anterior semicircular canal (b) is an upward eye movement, while activation of the posterior canal (c) leads to a downward movement. IV trochlear nerve nucleus, VI abducens nerve nucleus, IO inferior oblique muscle, SO superior oblique muscle, IR inferior rectus muscle, SR superior rectus muscle, AC anterior canal, HC horizontal canal, MLF medial longitudinal fasciculus, PC posterior canal
1.4.5.4 Smooth Pursuit Eye Movements
1.4.5.5 Convergence
Signal processing for smooth pursuit eye movements, which permit the constant representation of a small moving gaze target on the fovea, is initiated via corticopontine-cerebellar pathways. In this process visual information is transmitted from the retina through the lateral geniculate nucleus to the primary visual cortex to be transformed into the respective smooth pursuit eye movements via activated parietotemporal visual cortex areas, the frontal eye fields, pontine nuclei, cerebellum and vestibular nuclei (other areas than those for the vestibulo-ocular reflex) (Fig. 1.11). In addition, parallel pathways project through the nucleus of the optic tract to the pontine nuclei and the nucleus reticularis tegmenti pontis (Fig. 1.14c), which corresponds in humans to the nucleus papilliformis together with the pontine gray supralemniscal process (Olszewski and Baxter 1982). Cell groups of the pons around the corticopontine and the descending fiber bundles of the corticospinal tract are described as pontine nuclei. Based on their anatomic location they are divided into different subnuclei, these subnuclei do not represent functional unities. The dorsolateral and adjacent dorsomedial pontine nuclei constitute the primary components of the pathways for smooth pursuit eye movements (Thier and Möck 2006).
In convergence, the only type of normally occurring disconjugate eye movements, motor neurons of the medial and inferior rectus muscles of both eyes are activated simultaneously. The premotor connections for convergence have not been extensively investigated thus far. Premotor neurons are assumed to be located in an area dorsomedial to the oculomotor nerve nucleus and in the pretectum (Fig. 1.11). Additional premotor pathways for convergence are found in the vestibular nuclei. Activation of the otoliths as a result of linear acceleration (e.g. on a toboggan) automatically produces compensatory convergence eye movements whose amplitude is dependent upon the distance from the point of visual fixation. In this connection an independent monosynaptic activation of medial rectus motor neurons also occurs from the ipsilateral ventrolateral vestibular nucleus via the ascending tract of Deiters.
1.4.5.6 Gaze Stabilization On completion of an eye movement, velocity signals in the motor neurons must be converted into a position signal to maintain the eyes in a stable position. An important role regarding this integrator function is assumed by the
1.4 Internal Architecture
21
Fig. 1.13 Overview of the vegetative nervous system. The central sympathetic pathway from the hypothalamus activates the neurons of origin of the visceral efferent pathways of the sympathetic nervous system in the lateral horn of the spinal cord segments T1-L2 (black). These are relayed in different ganglia of the sympathetic nerve trunk to postganglionic neurons with relatively long axons projecting to the effector organ, whereby the sympathetic pathway for the orbital region (broken black line) takes a particularly long and thus vulnerable course. The central parasympathetic pathway from the hypothalamus (red) activates the visceral efferent motor neurons in the parasympathetic brainstem nuclei and in the sacral region of the spinal cord
• Superior tarsal muscle • Dilatator of the pupil • Orbital muscle • Sweat glands vessels of the face
Hypothalamus
Central sympathetic pathway Central parasympathetic pathway
Internal carotid artery Brainstem Pupillary constrictor muscle ciliary muscle
Oculomotor nerve Facial nerve
Lacrimal and salivary glands
Vagus nerve Thoracoabdominal cavity Superior cervical ganglion
Proximal ganglia
T1
• Head region • Thoracoabdominal cavity • Extremities Sympathetic nerve trunk L2
Pelvic cavity Pelvic nerves
prepositus nucleus for horizontal (McCrea and Horn 2006), and by the interstitial nucleus of Cajal for vertical and torsional eye movements (Horn 2006). The prepositus nucleus is located medially on the floor of the fourth ventricle between the abducens nucleus and the hypoglossal nucleus, and the interstitial nucleus of Cajal lies dorsolateral to the oculomotor nerve nucleus. Both nuclei have reciprocal connections to the respective premotor neurons of the horizontal and vertical/torsional saccadic and vestibular system, as well as to the cerebellar flocculus (Fig. 1.11). The eye position signal is presumed to be transmitted via their projections to the respective motor neurons in the abducens nucleus or the oculomotor and trochlear nuclei. It is further assumed that the recently described paramedian tract neurons near the midline in close proximity to the raphe
nuclei in the pons and medulla, play a key role in the feedback control for maintaining gaze position, because they also receive input from all premotor areas and in turn project to the cerebellar flocculus. An injury to these neurons may serve in some cases to explain gaze stability disturbances (Büttner-Ennever and Horn 1996).
1.4.6 Parasympathetic and Sympathetic Pathways The function of internal organs of importance for respiration, circulation, metabolism, body temperature, water balance, digestion, secretion, procreation, etc. is dependent on the interaction of visceral efferents of the parasympathetic
22 Fig. 1.14 Schematic cross-sections at different levels of the brainstem. Shown are cross-sections at the level of the mesencephalon (a), the pons (b, c) and the medulla oblongata (d, e). The most important nuclear regions and fiber tracts are represented in all of the cross-sections
1 Neuroanatomy of the Brainstem
a
Aqueduct
III
Periaqueductal gray
Central sympathetic pathway Inferior brachium of the midbrain
Interstitial nucleus of Cajal Spinothalamic tract Lemniscus – trigeminal – medial
Mesencephalic tract of the trigeminal nerve
Corticopontine tract Red nucleus
Mesencephalic reticular formation
Corticospinal/nuclear tract
Medial longitudinal fasciculus Tegmental decussation
b
Medial longitudinal fasciculus
Ventral tegmental area
Substantia nigra
Fourth ventricle
Locus caeruleus Lateral lemniscus Reticular formation Superior central nucleus
Corticopontine tract
Central sympathetic pathway Mesencephalic tract of the trigeminal nerve Superior cerebellar peduncle Spinothalamic tract Rubrospinal tract
Tegmental decussation
Medial lemniscus Trigeminal lemniscus
Pontine nuclei
Corticospinal/nuclear tract Tectospinal tract
c
Superior cerebellar peduncle Locus caeruleus Nucleus reticularis pontis oralis Lateral lemniscus Central tegmental tract Medial lemniscus Nucleus reticularis tegmenti pontis
Anterior medullary velum
Medial longitudinal fasciculus Central sympathetic pathway Motor trigeminal nucleus Principal trigeminal nucleus Spinal trigeminal nucleus
Spinothalamic tract Rubrospinal tract Tectospinal tract Pyramidal tract
Pontine base
1.4 Internal Architecture Fig. 1.14 (continued)
23
d
Nucleus raphe obscurus Hypoglossal nucleus
Prepositus nucleus Vestibular nuclei
Solitary tract Dorsal motor vagal nucleus Inferior cerebellar peduncle
Spinal trigeminal nucleus Central sympathetic pathway Medial longitudinal fasciculus
Rubrospinal tract Spinothalamic tract Nucleus ambiguus Hypoglossal nerve
Tectospinal tract Inferior olivary nucleus Medial lemniscus Pyramidal tract
e
Commissural nucleus Spinal tract nucleus of the trigeminal nerve Medial longitudinal fasciculus Central sympathetic pathway Spinothalamic tract Tectospinal tract Medial lemniscus
and sympathetic nervous systems. In contrast to visceral efferents, visceral afferents cannot be subdivided into parasympathetic or sympathetic. The parasympathetic or sympathetic systems are controlled either by the hypothalamus as the higher control center for descending pathways through the brainstem, or via the hormonal path with use of the hypothalamic-hypophyseal system (Fig. 1.13). The most important efferent connections of the hypothalamus to the brainstem comprise the medial forebrain bundle (medial telencephalic fasciculus) and the mammillotegmental tract. The dorsal longitudinal fasciculus (bundle of Schütz) takes a periventricular position in its course, immediately dorsal to the medial longitudinal fasciculus (Figs. 1.13 and 1.14). Signals from the rostral hypothalamus are transmitted along the descending pathways and are relayed at several sites before reaching the parasympathetic preganglionic neurons in the brainstem tegmentum, the Edinger-Westphal nucleus, the superior and inferior salivary nuclei (Figs. 1.5 and 1.13), and the dorsal motor vagal nucleus. Further parasympathetic preganglionic neurons are located in the lateral horns of the sacral region of the spinal cord (pelvic parasympatheticus, S2, S3 and S4). On stimulation of the caudal hypothalamus the sympathetic pathways are more likely to be activated. Sympathetic fibers from the hypothalamus decussate in the mesencephalon and travel in the central tegmental tract of the reticular formation through the pons and medulla to the intermediolateral cell column of the upper thoracic region of the spinal cord (Fig. 1.13, central sympathetic pathway, Fig. 1.14). Similar to the descending pathways of the parasympathetic system, the path is discrete and does not form a compact fiber tract.
Gracile nucleus
Dorsal motor vagal nucleus Cuneate nucleus External cuneate nucleus Solitary tract Hypoglossal nerve nucleus Nucleus ambiguus Pyramidal tract
The parasympathetic innervation of the eye (pupil) is discussed in Sect. 1.4.1. Sympathetic innervation to the eye is controlled by the sympathetic tract through activation of preganglionic neurons in the lateral horn of the spinal cord (C8-T2), in the so-called ciliospinal center. The preganglionic sympathetic fibers in the cervical sympathetic trunk project from there and are relayed in the superior cervical ganglion onto postganglionic neurons. The postganglionic fibers travel along the internal carotid artery, continue without synapsing through the ciliary ganglion and innervate the pupil dilatator muscle (Fig. 1.13, black dotted line). Lesions in the course of central or peripheral sympathetic pathways on their way to the eye are associated with loss of pupil dilator muscle function and lead to ptosis (Horner’s syndrome). A particularly frequent example of damage to the descending sympathetic tract is found in the presence of a circulatory disturbance of the lateral medulla oblongata after an infarct in the region of the posterior inferior cerebellar artery (Wallenberg’s syndrome) (Figs. 1.13, 1.14d, e, 1.18c, and p. 33).
1.4.7 Nuclear Regions of the Mesencephalon 1.4.7.1 Overview The nucleus of the posterior commissure is closely associated with the fibers of the posterior commissure in the medial pole of the mesencephalon. It can be divided into at least five different subgroups. One subgroup, the subcommissural nucleus, contains virtually no neurons and comprises the
24
1 Neuroanatomy of the Brainstem
a
b XII
Parabrachial nuclei (“pneumotaxic center”)
Solitary nucleus Medial vestibular nucleus
Bötzinger complex
Dorsomedial respiratory complex
Pre-Bötzinger complex Dorsomedial respiratory complex
Nucleus ambiguus
Rostral respiratory complex Ventrolateral respiratory complex
Diaphragm motoneurons C3-C7
Ventrolateral respiratory complex Caudal respiratory complex
Fig. 1.15 Representation of premotor brainstem respiratory areas involved in the regulation of respiratory activity. (a) The crosses within the ventrolateral respiratory complex represent the excitatory premotor neurons of the sympathetic system in the rostral ventrolateral medulla for the baroreceptor-vasomotor reflex. The dotted line in the dorsal
view of b marks the plane of section for a. (b) The parabrachial nuclei form a pneumotaxic center and modulate the dorsomedial and ventrolateral premotor respiratory complex in the rostral medulla, which in turn activate the motoneurons of the respiratory muscles in the nucleus ambiguus. XII hypoglossal nerve nucleus
circumventricular subcommissural organ, a neurohumoral region (McKinley et al. 2004). In neurohumoral regions hormones are produced in the neurons and released into the bloodstream. Lesions in the posterior commissural nucleus or the posterior commissure are frequently caused by tumours of the nearby pineal body and can lead to vertical upward gaze paresis (Leigh and Zee 2006; Horn 2006). In primates premotor neurons for vertical and torsional saccades are located in the rostral interstitial nucleus of the medial longitudinal fasciculus as well as in the interstitial nucleus of Cajal (Fig. 1.14a and p. 18-22), and in the fibers of the medial longitudinal fasciculus at the anterior end of the mesencephalon. The nucleus of Darkschewitsch is situated immediately above the interstitial nucleus of Cajal (INC) in the periaqueductal gray. Both the INC and the red nucleus receive and project to the inferior olive. Contrary to various older descriptions, the nucleus of Darkschewitsch does not constitute part of the premotor pathways for eye movements (Büttner-Ennever 2006). The area medial to the substantia nigra is named the ventral tegmental area; like the adjacent pigmented parabrachial nucleus it contains dopaminergic neurons and possesses strong connections to the limbic structures (Fig. 1.14a; Holstege et al. 2004).
Baldauf and Herczeg 2002); a number of them have specialized visual motor functions, while others are involved, e.g. in the processing of pain stimuli (Gamlin 2006). • Pretectal olivary nucleus: this nucleus has an important role in the mediation of the pupillary light reflex. • Nucleus of the optic tract: it corresponds to the region which was formerly also described as the lentiform nucleus. In primates, the pretectal olivary nucleus is completely enveloped by cells of the nucleus of the optic tract, which suggests increasing cooperation between these nuclei. The nuclei of the optic tract on both sides are connected by commissural fibers via the posterior commissure. They have an important function in the generation of optokinetic nystagmus, smooth pursuit eye movements, and gain adaptation of the horizontal vestibuloocular reflex (Fig. 1.11 and p. 19). • Posterior pretectal nucleus: the nucleus has traditionally been described as the sublentiform nucleus. • Medial pretectal nucleus: this nucleus corresponds to the pretectal area involved in accommodation. • Anterior pretectal nucleus: the findings of recent studies provide evidence that this nucleus has an inhibitory influence on afferent pathways in the dorsal horn of the spinal cord.
1.4.7.2 Pretectum 1.4.7.3 Superior and Inferior Colliculi The pretectum is located just rostral to the superior colliculus below the brachium of the superior colliculus, where it forms the transition region between the brainstem and the diencephalon (Fig. 1.3). It contains several small nuclei (Borostyankoi-
The superior colliculus acts as a central relay station for fast orientation movements, which are also described as the ‘visual grasp reflex’. Histologically it consists of several layers
1.4 Internal Architecture
(I–VII). The superficial layers (I–III) receive exclusively sensory input from the retina and the visual cortex, while the intermediate (IV) and deep (V–VII) layers receive multimodal input from the trigeminal, auditory, somatosensory and vestibular systems (May 2006). The superior colliculus has an important function in the transformation of visual and auditory stimuli to motor signals. Electrical stimulation of the superior colliculus is followed by a saccade to the contralateral side, whose amplitude and direction depends upon the site of stimulation. The topographic representation of the visual field in the superficial layers correlates with motor map contained in the deeper layers. In the caudal superior colliculus larger saccades are induced by electrical stimulation and are frequently combined with movements of the head; small saccades are induced by electrical stimulation in the rostral aspect. Stimulation in the rostral area of foveal representation leads to fixation of the eyes (Fig. 1.11 and p. 18). The deeper layers also receive input from the cerebral cortex (frontal eye fields), the basal ganglia, including the substantia nigra (reticular part), cerebellar nuclei and the prepositus nucleus. The descending efferents of the deeper layers cross in the dorsal tegmental decussation (Meynert); at this level it gives rise to a bundle ascending to the thalamus, the basal ganglia, and the rostral interstitial nucleus of the medial longitudinal fasciculus, while another branch travels just below the medial longitudinal fasciculus in the tectoreticulospinal tract (predorsal bundle) and innervates via collaterals, among other structures, the paramedian pontine reticular formation, the abducens nucleus, and the inferior olive. The tectoreticulospinal tract terminates on motor neurons in the rostral spinal cord that supply the cervical musculature. The inferior colliculus is subdivided into the central nucleus, a laminar nucleus for ascending fibers of the auditory pathway (Fig. 1.16b, e and p. 31), the pericentral nucleus for descending fibers of the auditory pathway from the auditory cortex, and the external nucleus for descending fibers from the cortex and thalamus, as well as for afferents from the contralateral inferior colliculus, the trigeminal nucleus, and the solitary tract nucleus. The external nucleus forms a zone between the superior and the inferior nucleus. The multisensory afferents of this nucleus and its connection to the superior colliculus support the hypothesis that it has an important role in orienting responses to auditory stimuli. The afferent axons from the inferior colliculus converge in the lateral zone and form the brachium of the inferior colliculus. From here the fibers ascend to the medial geniculate body (Moore and Linthicum 2004).
1.4.7.4 Red Nucleus Like the pyramidal pathway, the red nucleus controls fine movements of the distal extremities (hand and finger), although
25
this applies mainly to automatically performed and not to newly learned movements. It represents the largest nucleus of the midbrain, is topographically organized (face dorsal, upper extremities medial, lower extremities ventrolateral), and interspersed with numerous bundles of medullated fibers of the brachium conjunctivum, some of which terminate in this nucleus. In addition, roots of the oculomotor nerve on their way to the interpeduncular fossa, as well as the tractus retroflexus, travel through the red nucleus without terminating there. Within the red nucleus a caudal magnocellular part can be differentiated from a rostral parvocellular one. The nucleus receives its main inputs from the cerebral cortex and the cerebellum, and sends efferent axons to the inferior olive and the spinal cord; the cells in the magnocellular part are the origin of the rubrospinal tract. Compared to the situation in monkeys and cats, the rubrospinal tract in humans is only rudimentary (Holstege 1991, Holstege et al., 2004). This topographically organized fiber pathway exits the nucleus medially, crosses in the ventral part of the important ventral tegmental decussation (tegmental decussation of Forel, Fig. 1.14a, b), descends initially in the ventrolateral pons and medulla and from there travels in the dorsolateral funiculus of the spinal cord (Fig. 1.16). Here the areas with representation of the hand and wrist receive the largest number of terminals. The magnocellular part of the red nucleus receives inputs from the motor cortex and is connected via reciprocal projections with the emboliform and globosus nuclei of the spinocerebellum. The size of the parvocellular part of the red nucleus is related to development of the cerebellar hemispheres (neocerebellum). It receives inputs primarily from the cerebral cortex that originate from larger areas than those to the magnocellular part. The corticorubral tract descends in the ipsilateral internal capsule to the parvocellular part of the red nucleus. The efferents from the parvocellular part also cross in the ventral tegmental decussation and project via several adjacent mesencephalic structures (nucleus of Darkschewitsch, medial accessory nucleus of Bechterew, interstitial nucleus of Cajal and mesencephalic reticular formation) to the inferior olive. From there crossed fibers pass as climbing fibers via the inferior cerebellar peduncle to the cerebellum. These pathways form important neural loops for motor learning.
1.4.7.5 Substantia Nigra The substantia nigra contains a mixed population of neurons located in the ventral mesencephalon and constitutes the major tissue between the cerebral crus and the red nucleus (Halliday 2004). At approximately the age from 15 to 18 years it becomes strongly pigmented due to the presence of neuromelanin, a metabolic product of dopamine. The dopaminergic part of the substantia nigra is described as
26
1 Neuroanatomy of the Brainstem
a
Internal capsule
b
Thalamus
III
IV
V
VI VII XII X
Lateral lemniscus Gracile nucleus
Red nucleus XII
Medial lemniscus
XI
Corticospinal tract Anterior corticospinal tract
Spinothalamic tract
Lateral corticospinal tract
Cuneate nucleus
c Parietopontine tract
Inferior colliculus
Medial longitudinal fasciculus
Red nucleus Corticonuclear tract Rubrospinal tract
To cerebral cortex
d Occipitopontine Superior tract cerebellar peduncle
Frontopontine tract
Corticonuclear tract Middle cerebellar peduncle Inferior cerebellar peduncle
Temporopontine tract Red nucleus
Cerebral crus Corticospinal tract
III Red nucleus IV
Rubrospinal tract Medial longitudinal fasciculus
Vestibulocerebellar tract
Corticopontine tract
V VI VII Lateral corticospinal tract (crossed)
Pontine nuclei
XII XI
Inferior olive Anterior corticospinal tract (uncrossed)
Anterior spinocerebellar tract Posterior spinocerebellar tract
e Red nucleus Central tegmental tract
Medial lemniscus Inferior colliculus Lateral lemniscus
f Red nucleus Decussation
Corticopontine tract
Superior cerebellar peduncle
Pontine nuclei
Medial cerebellar peduncle
Spinothalamic tract
Cuneate nucleus Gracile nucleus
Trapezoid body
Dentate nucleus Inferior olive
Inferior olive Anterior spinocerebellar tract
Fig. 1.16 Connections of pathways in the brainstem. (a–c) Lateral view of brainstem connections; (d–f) dorsal view with descending (red) and ascending pathways (dark gray). Pathways descending from the cortex are
Inferior cerebellar peduncle
Olivocerebellar tract Posterior spinocerebellar tract
shown in (a) and (d), pathways of the spinothalamic tract and the lemniscal system ascending to the cortex are shown in (b) and (e); and connections to the cerebellum in (c) and (f) (modified from Bähr and Frotscher, 2003)
1.4 Internal Architecture
the pars compacta and can be divided into a dorsal and a ventral layer. Located ventral to the pars compacta is a third layer, the pars reticulata, a group of unpigmented neurons. The three layers of the substantia nigra can be further divided into columnar cell groups that have a close topographic relationship to the basal ganglia, the thalamus and the brainstem. The cells of the pars reticulata contain GABA and are frequently described as the caudal extension of the internal part of the globus pallidus. The lateral part of the substantia nigra has a visual motor function (Harting and Updyke 2006). Functionally, the substantia nigra forms an integral part of the basal ganglia, which play a role in the modulation or generation of movement. The striatum (caudate nucleus and putamen) is a central part of the basal ganglia and has reciprocal connections to the dopaminergic pars compacta, and is controlled by striatal activity. The GABAergic cells of the pars reticulata form (via the superior colliculus) the second most important output of the basal ganglia. The substantia nigra is separated from the red nucleus by the nucleus parabrachialis pigmentosus, a loosely packed dopaminergic cell group, which is referred to as A10 or the dorsal part of the substantia nigra. All Parkinson disease types, not only the classical form, are characterized by progressive death of dopaminergic cells in the pars compacta of the substantia nigra. Three of the types, progressive supranuclear palsy, corticobasal degeneration, and postencephalitic Parkinson’s disease are also characterized by the loss of non-dopaminergic cells of the pars reticulata (Hardmann et al. 1997).
1.4.7.6 Periaqueductal Gray Owing to the fact that staining of cells or fibers does not enable the identification of individual cell groups within the periaqueductal gray, staining with neurochemical markers (NADPH diaphorase, NO synthetase, acetylcholine) and examination of their connections are used for this purpose. The functional mapping studies show that the periaqueductal gray can be divided into quadrants consisting of a dorsomedial, dorsolateral, lateral and ventrolateral column. From a neuroanatomical point of view, the subdivisions of the periaqueductal gray represent a relay station for ascending sensory pathways, responsible for the transmission of pain stimuli, as well as for the descending limbic pathways; both of these interact with the ventrolateral column, while the dorsomedial column transmits information to the thalamus and receives afferents from the limbic regions of the cerebral cortex. Conversely, the dorsolateral part is associated with the neighboring intermediate and deeper layers of the superior colliculus, and thereby serves to support the orientation of the body in response to alarm stimuli. Functionally, the periaqueductal gray is involved in a wide range of coordinated emotional behavior, including the modulation of pain, cardiovascular regulation,
27
vocalization, micturition, defence reactions and sexual behavior (Holstege et al. 2004).
1.4.8 Nuclear Regions of the Pons 1.4.8.1 Overview The term pontine nuclei refers to the clusters of neurons embedded among the fiber bundles of the pontine base, while all other cell groups of the pons are located in the dorsal tegmentum (Fig. 1.1). The mesencephalic trigeminal nucleus, the proprioceptive nucleus of the muscles of mastication (Fig. 1.7 and p. 11), is situated in the rostral part, in addition to the locus caeruleus which is located at the border of the central gray substance (Fig. 1.14c). Both nuclei extend further caudally through the entire pons. The reticular formation is penetrated by the caudal part of the decussation of the superior cerebellar peduncles (brachium conjunctivum). The parabrachial nuclei lateral to the brachium conjunctivum are particularly developed at this level (Fig. 1.10 and p. 16). The lateral lemniscus proceeds along the outer limit to the inferior colliculi. Several smaller nuclei are embedded in its course, which constitute relay nuclei of the auditory pathway. The raphe nuclei are found at the midline of the medial pons and both the motor nucleus and principal nucleus of the trigeminal nerve are situated laterally (Figs. 1.7, 1.14c and p. 11). Located in the caudal pons are the abducens nucleus, the facial nucleus, as well as the spinal trigeminal nucleus. Located ventrolaterally to these structures is the lateral lemniscus with the medially adjacent complex of the superior olivary nucleus, which is essential for directional hearing (p. 31). Figure 1.10 shows the location of the paramedian pontine reticular formation, comprising the nuclei reticularis pontis caudalis and oralis.
1.4.8.2 Pontine Nuclei Numerous neuronal islets, the pontine nuclei, are found in the pontine base; these can be divided into groups on the basis of their location, but not with regard to functional relationships. The corticopontine fibers, which run in the crura of the cerebrum lateral to the corticospinal and the corticonuclear tract terminate on these pontine nuclei. After synapsing in the pontine nuclei, and maintaining the same topography (Thier and Möck 2006), the majority of axons of the pontine nuclei (90% in monkeys) cross to the contralateral side and travel in the medial cerebellar peduncle before reaching the nuclei and the medial cerebellar cortex as mossy fibers. The nucleus reticularis tegmenti pontis (nucleus papilliformis and the pontine gray supralemniscal process – Olszewski and Baxter 1982) is situated just dorsal
28
1 Neuroanatomy of the Brainstem
1.4.8.4 Pontine Micturition Center
Internal carotid artery Middle cerebral artery
Anterior cerebral artery Anterior communicating artery
Posterior communicating artery Basilar artery N. V Anterior inferior cerebellar artery (AICA)
Posterior cerebral artery Superior cerebellar artery N. VI
N. VIII N. VII N. IX N. X
Vertebral artery Posterior inferior cerebellar artery (PICA)
Anterior spinal artery
Posterior spinal artery
Fig. 1.17 Ventral view of the brainstem arteries. The arterial system forms an anastomotic ring (“arterial circle of Willis” ventrally). The posterior communicating artery connects the middle cerebral artery with the posterior cerebral artery; the anterior communicating artery connects the anterior cerebral artery with the contralateral anterior cerebral artery. There is a close spatial relationship between some of the vessels and the cranial nerves, whose sensory transition zone (Redlich-Obersteiner zone) is marked in black here. The vascular loops of the superior cerebellar artery pose a particular threat to N. V; the loops of the anterior inferior cerebellar artery represent a threat to N. VIII
to the pontine nuclei and, like these, projects only to the cerebellum. Although the pontine nuclei and nucleus reticularis tegmenti pontis are similar with a view to afferents and function, they cannot be equated.
Micturition describes the sequence of coordinated muscle activations needed for urination. This action is mediated by contraction of the smooth muscle of the urinary bladder with simultaneous relaxation of the striated external urethral sphincter (Holstege et al. 2004). The muscle of the urinary bladder is innervated by parasympathetic motor neurons of the intermediolateral column of the sacral region of the spinal cord and by sympathetic motor neurons of the intermediolateral column of the thoracic and lumbar regions of the spinal cord (T11-L2); the external urethral sphincter receives innervation from the motor neurons of the nucleus of Onuf (anterior horn of the sacral region of the spinal cord, S1–S3; Fig. 1.13, p. 21). The parasympathetic motoneurons receive direct excitatory input from the pontine micturition center (M-region or Barrington’s nucleus). There is experimental evidence that activation of the M-center can be stimulated by the preoptic region, which terminates in the periaqueductal gray substance and projects to the parabrachial area. The M-region in turn projects to the inhibitory interneurons in the sacral region of the spinal cord that inhibit the motor neurons in Onuf’s nucleus locally and thereby induce relaxation of the sphincter, thus enabling urine flow simultaneously with contraction of the bladder. There are also indications of the presence of a lateral L-region in the lateral pontine tegmentum, which activates Onuf’s nucleus – and thus sphincter activity. The exact relationship between parabrachial nuclei and the M- and L-region is still unknown (Holstege et al. 2004).
1.4.9 Nuclear Regions of the Medulla Oblongata 1.4.9.1 Overview
1.4.8.3 Parabrachial Nuclei The medial and lateral parabrachial nuclei surround the superior cerebellar peduncle and consist of a number of subnuclei (Fig. 1.10). While this complex was previously classified as being part of the lateral zone of the reticular formation, today it is viewed as an independent nuclear complex. Due to reciprocal connections with the vagalsolitary-complex, the ventrolateral medulla (Fig. 1.15), the limbic system, the hypothalamus, the insular and prefrontal cortex, the thalamus and the spinal cord, the parabrachial nuclei can be regarded as an ‘integration center’ for brainstem reflexes, forebrain behavior and central-autonomous systems. Of importance is the transmission of visceral information, pain and taste sensation. Located in the same region as the parabrachial nuclei are the pneumotaxic and the micturition center.
Approximately 90% of the corticospinal tract fibers cross at the caudal border of the medulla oblongata and form the lateral corticospinal tract of the spinal cord. Both dorsal column nuclei lie at this level: the gracile nucleus (lower extremities) is located medially, and the cuneate nucleus (upper extremities) laterally. The sensory relay nuclei contain the second neuron of the lemniscal system for touch and proprioception. Their efferent axons cross via the internal arcuate fibers into the medial lemniscus and continue from there to the contralateral thalamus. Laterally, the cuneate nucleus is joined by the external cuneate nucleus, whose neurons carry information from the spinal afferents of the upper extremities to the cerebellum. Further rostral, the inferior cerebellar peduncle (restiform body) and the posterior or dorsal spinocerebellar tract (from the lower extremities) are joined by these ascending fibers. However, the reciprocal connections between the
1.4 Internal Architecture
nuclear complex of the inferior olive and the cerebellum constitute the main part of the inferior cerebellar peduncle. The spinal trigeminal nucleus extends throughout the entire length of the medulla oblongata; running more lateral is the spinal tract of the trigeminal nerve as well as the ascending fibers of the spinothalamic tract (also known as the anterolateral system), which are responsible for the conduction of pain and temperature in the contralateral part of the body, the rubrospinal tract, and the descending central sympathetic pathway (Figs. 1.14 and 1.16). The fourth ventricle opens at the level of the obex; the area postrema in the wall of the ventricle is also found at this site. The other medullary nuclei, including the hypoglossal nucleus and the prepositus nucleus, the nucleus ambiguus, the solitary tract nucleus and the dorsal nucleus of the vagus nerve have been discussed elsewhere in this chapter (see p. 14).
1.4.9.2 Inferior Olive The nuclear complex of the inferior olive consists of the principal olivary nucleus and its subnuclei, the dorsal and the medial accessory olivary nuclei. The olivocerebellar tract exists through the hilum, crosses the midline, travels in the inferior cerebellar peduncle to the cerebellum, and projects there as climbing fibers exclusively to the cerebellar nuclei and the cerebellar cortex. On its way topographically organized longitudinal zones are formed in the cerebellar cortex. The inferior olive is the only source of climbing fibers, and modulates the activity of the cerebellum in its function as coordinator of precise voluntary movements via these glutaminergic projections (Barmack 2006). The climbing fibers define spatial coordinates for Purkinje cells of the entire cerebellar cortex and determine the output from the cerebellum via their inhibitory GABAergic axons projecting onto the cerebellar and vestibular nuclei. The major afferents of the inferior olive emerge from the red nucleus, the nucleus of Darkschewitsch, the pretectum, and the superior colliculus.
1.4.9.3 Ventrolateral Cell Groups of the Medulla
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the ‘rostral ventrolateral cell complex’ in the rostral medulla, including the adrenergic group C1, then via descending sympathetic pathways, effect a reduction in peripheral vasoconstriction and bradycardia (Fig. 1.5). In a similar manner, an incipient fall in blood pressure would lead to reflexive vasoconstriction via the solitary tract nucleus. The parasympathetic control of blood pressure via the vagus nerve efferents may possibly be exerted via a direct projection from the solitary tract nucleus to the dorsal vagus nerve nucleus.
Respiratory Reflexes Inspiration and the final phase of expiration are active motor activities and are controlled by cervical and thoracic motor neurons (C3–C5; phrenic nerve, T6–T12; intercostal nerve). The respective relay circuit is located in the caudal brainstem. There the inspiratory premotor neurons are situated in the lateral solitary tract nucleus and form a dorsomedial respiratory group. Their axons project, among others, to the motoneurons of the diaphragm (C3–C7) in the spinal cord. Expiratory and inspiratory premotor neurons constitute a rostral respiratory group in the ventrolateral medullary reticular formation, dorsal to the nucleus ambiguus and project to the spinal cord (Fig. 1.15). Other neighboring structures to the ventrolateral and dorsomedial respiratory group are the premotor neurons of the sympathetic control of the baroreceptor-vasomotor reflex (crosses in Fig. 1.15a). The respiratory centers form a vertical column consisting of different cell groups, and extends from the level of the area postrema to the parabrachial nuclei of the pons, which function as a pneumotaxic center. A circumscribed area of this column constitutes the pre-Bötzinger complex, a center for respiratory rhythm generation (Blessing 2004). Sensory signals from the periphery of importance for respiratory activity are transmitted via the glossopharyngeal and vagus nerves from stretch receptors in the lung, chemoreceptors, or several glomera located in the cervical zone along the trunk and the branches of the two cranial nerves, the largest of which represents the carotid body.
Cardiovascular Reflexes Stretch receptors (baroreceptors) in the carotid sinus and the aortic arch are activated by a sudden rise in blood pressure. This information is transmitted via afferent nerve fibers in the glossopharyngeal and vagus nerves, whose cell bodies are located in the neighborhood of the jugular foramen in the petrosal or nodose ganglion, and activate neurons in the caudal part of the solitary tract nucleus (commissural nucleus) (Blessing 2004). It is currently hypothesized that efferents from the solitary tract nucleus activate a group of GABAergic neurons in the ‘caudal ventrolateral medulla’ which relays to
Swallowing, Vomiting, and Sneeze Reflexes Motor neurons of the tongue (hypoglossal nucleus), the floor of the mouth, the pharynx and larynx (nucleus ambiguus), as well as of the face (facial nucleus) are involved in a number of reflexes, e.g. swallowing, vomiting, or sneezing. Coordination of the correct sequence of activity in the individual muscle nuclei is the responsibility of the immediately adjacent reticular formation in the medulla. The reticular formation distributes from here the afferent sensory stimuli
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from the solitary tract nucleus, the spinal, or the principal trigeminal nucleus, as well as inputs from more rostral centers to the appropriate motoneurons to trigger the respective reflex. In parallel, the premotor neurons coordinate the respiratory network.
1.4.9.4 Area Postrema Immediately rostral to the obex, appearing as a paired bulge on each side of the floor of the fourth ventricle lies the area postrema, one of the circumventricular organs. These are characterized by a close contact to the blood and cerebrospinal fluid spaces. To perform this function, they possess a modified ependyma, a pronounced glial network, as well as a dense vascularisation with wide perivascular spaces and fenestrated blood capillaries, which cause the blood– brain barrier to be broken down at these sites. Neurons of the circumventricular organs are therefore able to gain access to the circulating humoral mediators in blood (McKinley et al. 2004). Neurons of the area postrema are very small and difficult to differentiate under a microscope from astroglia. Efferent nerve fibers emanating from the area postrema terminate in the nearby dorsal motor vagal nucleus and the solitary tract nucleus, in the noradrenergic neurons of the caudal ventrolateral medulla, the nucleus ambiguus, the parabrachial nuclei, as well as in the cerebellar nuclei (nucleus fastigii). The majority of these connections are reciprocal; additional afferents to the area postrema originate from the hypothalamus. The area postrema serves as a chemical trigger for the vomiting reflex.
1.5 Pathways in the Brainstem 1.5.1 Descending Pathways The corticospinal pathways cross in the pyramidal decussation to the contralateral side (Fig. 1.16d); damage to these pathways in the brainstem therefore leads to contralateral function disturbances. The corticospinal pathways arise from the pyramidal cells in the cortical lamina V of the frontal lobe (60%) and the parietal lobe (40%). The fibers course in the corona radiata to the posterior crus of the internal capsule in the following topographic order: the rostral half terminates on motor neurons of the highest levels of the spinal cord, the caudal half innervates increasingly lower spinal cord levels. The topographic order is sustained in the cerebral crus and the more caudal pyramidal
1 Neuroanatomy of the Brainstem
pathway, whereby the parts for the upper extremities are found in a medial and those for the lower extremities in a lateral location. Eighty-five to ninety percent of the corticospinal fibers decussate at the transition from the medulla to the spinal cord and form the also topographically ordered lateral corticospinal tract, while the uncrossed fibers course in the anterior corticospinal tract. Parallel to the corticospinal pathways, the corticonuclear connections travel in the corticonuclear tract, which has also been described as the corticobulbar tract (“bulbus” = former term of the medulla oblongata). The corticonuclear fibers run through the genu of the internal capsule and congregate in the medial cerebral crus, along with the corticospinal fibers. The mesencephalic, pontine and bulbar corticonuclear fibers exert an influence on the cranial nerve nuclei, which control the skeletal musculature (Neuhuber 2004). While some of these projections may be direct, the majority terminate initially near the respective motor brainstem nuclei on interneurons of the reticular formation. Nuclei of the ocular muscle nerves (N. III, N. IV, N. VI) are thus controlled indirectly by frontal and parietal eye fields of the cortex via gaze control centers in the midbrain (e.g. superior colliculus) and the pons (e.g. omnipause neurons). Both the motor trigeminal and the facial nuclei are innervated bilaterally, while the activation of motoneurons for the lower part of the face is initiated almost exclusively by the contralateral cerebral cortex. The medial longitudinal fasciculus (MLF) runs from the rostral end of the reticular formation to the spinal cord. It contains heavily myelinated fibers of the rostral interstitial nucleus of the medial longitudinal fasciculus, the interstitial nucleus of Cajal, as well as of the oculomotor and vestibular nuclei, which form important ascending and descending connections for the coordination of eye movements (Fig. 1.12 and p. 9). The dorsal longitudinal fasciculus (Schütz-bundle) is located dorsal to the medial longitudinal fascicle in the central gray substance and, in contrast to the MLF, can be seen only with difficulty, due to its fine, weakly myelinated fibers. The dorsal longitudinal fascicle carries information from the medial hypothalamus primarily to the periaqueductal gray substance and therefore has an indirect influence on the autonomic nuclei of the brain stem. The corticopontine component of the fiber systems descending from the cortex is strongly pronounced in humans (Fig. 1.16c, f). Corticopontine fibers originate in both motor and non motor areas and terminate in the pontine nuclei of the pontine base. The neurons of the pontine nuclei, in turn, send their fibers via the medial cerebellar peduncle (pontine brachium) to the contralateral side, but with collaterals also projecting to the ipsilateral side. The function of this pontocerebellar system consists of the control of motor processes. The cerebellum is connected on both sides to the brainstem via three cerebellar peduncles (Fig. 1.16c, f); the superior cerebellar peduncle (brachium conjunctivum) represents the
1.5 Pathways in the Brainstem
output pathway for information from the cerebellar nuclei to the thalamus and the red nucleus. Alone the anterior spinocerebellar tract uses the superior cerebellar peduncle as an entrance pathway to the cerebellum. The middle cerebellar peduncle (brachium pontis) projects fibers only from the pons to the cerebellum. The inferior cerebellar peduncle (restiform body) contains reciprocal vestibulocerebellar and spinocerebellar fibers, in addition to the fibers emanating from the inferior olive. The most important function of the cerebellum is the coordination of movements: structures near the midline (vermis and nucleus fastigii) participate in processing vestibular information, the adjacent intermediate regions receive input from the spinal cord, while the cerebellar hemispheres process information from the cerebral cortex. MRI images illustrate this impressively when they show that the contralateral cerebral cortex but the ipsilateral cerebellar hemisphere are activated during movements of the hand or finger. These images show that a decussation between the cerebellar efferents to the cortex is indispensable; decussation for afferents to the cerebellum occurs in the pontine nuclei and the crossing for efferents from the cerebellum ascending to the thalamus (dentate nucleus) takes place in the massive decussation of the superior cerebellar peduncle (Figs. 1.14b, 1.16f).
1.5.2 Ascending Pathways 1.5.2.1 Lemniscal Systems The ascending pathways coursing within the medial lemniscus of the brainstem are referred to using the term the lemniscal system (Fig. 1.16c, c). Central processes of the spinal ganglia cells transmit information regarding light touch, vibration and pressure ipsilaterally via the dorsal columns of the spinal cord to the dorsal column nuclei, the medially located gracile nucleus and the laterally situated cuneate nucleus (Kaas 2004). At this relay station, descending pathways like the corticospinal tract and the fiber systems of the reticular formation have an influence on information transmission. The topographic organization of the dorsal column is preserved after decussation in the dorsal column nuclei. In the caudal medulla oblongata the axons of the secondary neurons immediately decussate to the contralateral side and course from there as the medial lemniscus through the brainstem. At the level of the rostral medulla oblongata, the medial lemniscus is joined at its dorsolateral aspect by the decussated fibers of the trigeminal lemniscus, which forms the respective conduction pathway for mechanoreceptors from the head region. The spinothalamic tract approaches the lateral pole of the medial lemniscus in the mesencephalon. Both fiber bundles terminate together in the thalamus, primarily in the
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ventral posterolateral nucleus; the fibers of the trigeminal lemniscus reach the ventral posteromedial nucleus. 1.5.2.2 Spinothalamic Tract The pain fiber system is composed of primary afferent nociceptors, the ascending pain pathways in the spinal cord and trigeminal system, as well as of descending modulating pathways, and a number of different areas of the brain that process pain information. The lateral spinothalamic tract and the anterior spinothalamic tract transmit signals for pain, temperature and coarse pressure sensations, and are often termed the “anterolateral system” or “spinothalamic tract.” The cells of origin are located in lamina I and V of the spinal cord where the majority of fibers cross over in the spinal commissure and ascend in the contralateral half of the spinal cord to the thalamus. The spinothalamic tract is organized somatotopically. Recent studies have shown that a further visceral pain pathway courses in the dorsal columns and follows the lemniscal pathways to the ventral posterolateral nucleus of the thalamus. The cells of origin of this pain pathway are located near the central canal and form the dorsal funiculus in the midline. Unilateral injury to a spinal cord segment (unilateral lesion according to Brown-Séquard) is associated with a loss of pain and temperature sensation caudally and contralaterally to the lesion, due to the fact that the spinothalamic tract crosses over in the spinal cord to the other side. Conversely, the modalities subserving discrimination, vibration and depth sensitivity that are conducted via the lemniscal system, are disturbed on the side of the body affected by the lesion. This is described as dissociated sensory loss. 1.5.2.3 Spinocerebellar Tracts There are four major connections between the spinal cord and the cerebellum on each side (Fig. 1.16c, f). The dorsal horn cells transmit information from the lower extremities via the posterior spinocerebellar tact, and from the upper extremities via the cuneocerebellar tract. The somatotopically arranged pathways project to the ipsilateral spinocerebellum via the inferior cerebellar peduncle. The other two pathways originate in the cells of the intermediate zone and transmit information on the activity of interneurons in the spinal cord and on spinal reflex activity. Information from the lower half of the body, decussate and travel in the contralateral anterior spinocerebellar tract through the medulla oblongata to the pons, and from there back to the ipsilateral cerebellum via the decussation of the superior cerebellar peduncles. Proprioceptive information from muscles of the upper extremities is transmitted ipsilaterally directly into the inferior cerebellar peduncle and directly into the cerebellum.
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1.5.2.4 Auditory Pathway Acoustic signals are transmitted to the ventral and dorsal cochlear nuclei in the brainstem via the cochlear nerve, and from there in several ascending pathways to the thalamus and the cerebral cortex. During this process tonotopy, the spatial location of sound sources, as well as feature extraction of complete sound patterns (e.g. language) are preserved. The massive trapezoid body is only one of the commissural pathways which characterize the auditory system (Fig. 1.1b,e). Because information from both ears is represented on both sides of the brain, brainstem lesions rarely lead to severe neurologic disturbances. At the superior olive, a medial nucleus can be distinguished from a lateral nucleus and the periolivary region. The neuronal relay for directional hearing is accomplished via the medial and lateral nucleus of the superior olivary nucleus. The main projection from the superior olive extends from the lateral lemniscus to the inferior colliculus. The periolivary region further represents the only source of efferents projecting within the olivocochlear bundle to the ipsilateral and contralateral cochlea. These efferents course initially in the vestibular part of N. VIII and cross in the internal acoustic meatus to the cochlear nerve before reaching the outer (thick axons) and inner (thin axons) hair cells of the cochlea. The olivocochlear bundle controls otoacoustic emission and improves the signal-noise-relationship, i.e. selective auditory attention.
1.6 Brain Stem Vascularization Blood supply to the brain is carried by four large arteries: two internal carotid arteries supply the anterior brain segments and two vertebral arteries carry blood to the posterior segments of the brain, including the occipital lobes, parts of the temporal lobe, splenium of the corpus callosum, caudal parts of the thalamus, caudal parts of the internal capsule, cerebellum, and the brainstem (Nieuwenhuys et al. 1991). At the base of the brain these four arteries form an arterial ring, the arterial circle of Willis that interconnects the two supply territories (Fig. 1.17). The anterior, middle and posterior cerebral arteries are divided into four segments: segment A1, for the anterior cerebral artery, is located anterior to the anterior communicating artery, A2 lies posteriorly; segment M1, for the middle cerebral artery, forms the horizontal segment, and M2 is located on the insula. Segment P1, for the posterior cerebral artery, is situated between the bifurcation of the basilar artery and the posterior communicating artery, and P2 between the posterior communicating artery and the anterior temporal artery; located posteriorly are segments P3 and P4, which supply the lateral and medial occipital lobes. The spatial relationship of the cranial nerve roots to the arteries is shown in Fig. 1.17, including the vulnerable
1 Neuroanatomy of the Brainstem
‘transition zone’, the transition from the peripheral myelin of Schwann cells to the central myelin of oligodendrocytes. It becomes apparent that the vascular loops of the superior cerebellar artery can be a threat to the roots of the trigeminal nerve, vascular loops of the anterior inferior cerebellar artery (= AICA) can affect the facial, vestibulocochlear and abducens nerves, and loops of the posterior inferior cerebellar artery (= PICA) can represent a threat to the glossopharyngeal and vagus nerves. While the surface of the vascular network is characterized by considerable variability, the internal organization of the branches in the brainstem is relatively constant and similar at all levels. Three different vascular territories can be differentiated: • A ventral vascular territory • A lateral vascular territory and • A dorsal vascular territory (Fig. 1.18) The spinal cord veins represent an extension of the brainstem veins, which form a vascular net around the brainstem, consisting of interconnected longitudinal veins and horizontally branches, in addition to branches connecting them with the basal cerebral vessels.
1.6.1 Mesencephalon The mesencephalon is enveloped on both sides by several arterial arches that give rise to the radially arranged inner vessels. The short arterial arches emerge from the arcuate branches of the posterior cerebral artery, while the longer arterial arches emerge from the posterior cerebral, the quadrigeminal, superior cerebellar, and posterior choroidal arteries. The ventral vascular territory comprises the nuclei of the oculomotor and trochlear nerves, the medial longitudinal fasciculus, the Edinger-Westphal nucleus, and paramedian regions of the ventral tegmental area up to the mesencephalic aqueduct, as well as the red nucleus and medial parts of the substantia nigra and the cerebral peduncle. This territory is supplied by a number of paramedian branches, the interpeduncular perforating arteries (from the P1 segment of the posterior cerebral artery), the posterior communicating artery, as well as the short and long circumferential arteries. Some of the paramedian vessels emerge from the anterior choroidal artery branch of the internal carotid artery. The lateral vascular territory comprises lateral parts of the tegmentum (cerebral peduncle and medial lemniscus), the substantia nigra, as well as the medial and lateral geniculate body. It is supplied by the radial vessels from the long and short circumferential arteries.
1.6 Brain Stem Vascularization Fig. 1.18 The arterial blood supply to the brainstem in cross-sections. Three crosssections are shown at the level of the mesencephalon (a), the pons (b), and the medulla (c); the arteries are shown on the right and their supply territories are indicated on the left. P1 and P2 represent sections of the posterior cerebral artery
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a
Posterior cerebral artery
Superior cerebellar artery Quadrigeminal artery
Posterior cerebral artery
Superior cerebellar artery
Posterior choroidal artery
Posterior choroidal arteries
Interpeduncular perforating arteries (PI)
P2 posterior cerebellar artery
Superior cerebellar artery N. III Basilar artery
Posterior communicating P1 artery posterior cerebral artery
b Pontine branches
Pontine branches
Lateral branches
Lateral branches Medial branches
Medial branches
Basilar artery
c
Posterior spinal artery
Posterior inferior cerebellar artery (PICA)
Posterior inferior cerebellar artery (PICA)
Vertebral artery Anterior spinal artery Anterior spinal artery
Vertebral artery
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The dorsal vascular territory, the tectum or the superior colliculus, receives blood from the quadrigeminal artery (usually a branch from the P1 segment of the posterior cerebral artery) and – more caudal at the level of N. IV and the inferior colliculus – from the superior cerebellar artery (Fig. 1.18a).
1.6.2 Pons Blood supply to the pons is carried via three groups of arteries arising from the basilar artery. The ventral group of arteries arises from the medial branches, the lateral group from the lateral branches, and the dorsal group from pontine branches. The paramedian branches can extend to the floor of the ventricle where they supply the medial tegmentum, the pontine nuclei, including the corticospinal fibers passing through this structure, and the roots of the abducens nerve emerging from the brainstem. The short circumferential branches are found only in the lateral part of the pontine base, while the long circumferential branches supply the entire pontine tegmentum, including the facial nucleus, vestibulocochlear and trigeminal nerves, as well as a segment of the middle cerebellar peduncle. An additional blood supply is carried by the branches of the anterior inferior cerebellar artery (AICA) to the caudal pons, and by branches of the superior cerebellar artery to the rostral pons (Fig. 1.18b).
1.6.3 Medulla Oblongata The medulla oblongata is supplied via two to three branches of the vertebral artery: the anterior spinal artery, posterior inferior cerebellar artery (PICA), and the spinal artery (a branch of the PICA) (Fig. 1.18c). Similar to the pons and the mesencephalon, a lateral and a dorsal vascular group can be differentiated. The medial medulla is supplied by branches of the anterior spinal artery which ascends in the midline, (frequently to the left or right side), to the floor of the fourth ventricle. They supply the hypoglossal nerve and the nucleus of the hypoglossal nerve, the nucleus of the dorsal vagus nerve, the corticospinal tract, the medial lemniscus, the medial longitudinal fasciculus, and the medial accessory olivary nucleus. An occlusion occurring in the ventral vascular group leads to the medial medullary syndrome (Déjerine). Branches of the lateral vascular group can emerge from PICA or from the vertebral artery and enter the medulla oblongata lateral to the inferior olive. They supply parts of the tegmentum, including the solitary tract nucleus, dorsal motor vagal nucleus, spinal trigeminal nucleus and ambiguus nucleus, a part of the vestibular and dorsal column nuclei
1 Neuroanatomy of the Brainstem
with the ascending spinothalamic tract (anterolateral pathways for pain), spinal trigeminal tract, the central descending sympathetic pathway, and a part of the inferior cerebellar peduncle. Obstructions in this lateral vascular group result in lateral medullary syndromes (Wallenberg syndrome inclusive of Horner syndrome). The branches of the dorsal vascular group emerge at the level of the obex from the PICA and the ascending branch of the posterior spinal artery. They supply the dorsal column nuclei as well as the spinal trigeminal tract and nucleus. Lesions of these vessels are rare. In a more rostral location blood supply to the entire dorsal medulla is carried exclusively via the PICA; branches of the AICA are involved in blood supply at the rostral border with the pons only.
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35 Neuhuber W (2004) Hirnstamm. In: Drenckhahn D (Hrsg) Benninghoff/Drenckhahn. Anatomie – Makroskopische Anatomie, Histologie, Embryologie, Zellbiologie. Elsevier, Urban & Fischer, München, pp 326–383 Nieuwenhuys R, Voogd J, Van Huijzen C (1991) Das Zentralnervensystem des Menschen: ein Atlas mit Begleittext, 2 Aufl. Springer, Berlin, Heidelberg, New York Olszewski J, Baxter D (1982) Cytoarchitecture of the human brain stem. Karger, Basel/München/Paris/London/New York/Sydney Sakurai T (2005) Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med Rev 9: 231–241 Saper CB (2006) Staying awake for dinner: hypothalamic integration of sleep, feeding, and circadian rhythms. Prog Brain Res 14: 243–252 Saper CB, Chou TC, Scammell TE (2001) The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 24: 726–731 Shinoda Y, Sugiuchi Y, Izawa Y, Hata Y (2006) Long descending motor tract axons and their control of neck and axial muscles. Prog Brain Res 151:527–563 Thier P, Möck M (2006) The oculomotor role of the pontine nuclei and the nucleus reticularis tegmenti pontis. Prog Brain Res 151: 293–320 Voogd J (1995) Nervous system – cerebellum. In: Berry MM, Standring SM, Bannister LH (eds) Gray’s anatomy. Churchhill Livingstone, London/New York, pp 1027–1065 Voogd J (2004) Cerebellum and precerebellar nuclei. In: Paxinos G, Mai JK (eds) The human nervous system. Elsevier Academic, San Diego, pp 321–392 Wilhelm H (1998) Störungen der Pupillomotorik. In: Huber A, Kömpf D (Hrsg) Klinische Neuroophthalmologie. Thieme, Stuttgart/New York, pp 622–630 Wilhelm H (2002) Pupillenstörungen. In: Lund O-E, Waubke TN (Hrsg) Neuroophthalmologie. Thieme, Stuttgart, pp 78–96
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Diagnostic Imaging, Interventional Treatment of Brainstem Lesions and Electrophysiologic Diagnostics
Contents 2.1 Neuroradiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1 Conventional Native Diagnostics . . . . . . . . . . . . . . . . . . 2.1.2 Computed Tomography . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2.1 Principles and Techniques . . . . . . . . . . . . . . . . . . . . . . . 2.1.2.2 CT in Investigations of the Brainstem . . . . . . . . . . . . . . 2.1.2.3 Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3 Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . 2.1.3.1 Principles and Techniques . . . . . . . . . . . . . . . . . . . . . . . 2.1.3.2 MRI Investigations of the Brainstem . . . . . . . . . . . . . . . 2.1.3.3 Specialized Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3.4 Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4 Angiography and Endovascular Interventions . . . . . . . . 2.1.4.1 Diagnostic Angiography . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4.2 Endovascular Interventions . . . . . . . . . . . . . . . . . . . . . . . Recanalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embolization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38 38 39 39 39 40 40 40 42 45 46 47 47 49 49 51
2.2 Ultrasound Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1 Vascular Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.1 Anatomic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.2 Principles and Techniques . . . . . . . . . . . . . . . . . . . . . . . Continuous Wave (cw) Doppler . . . . . . . . . . . . . . . . . . . Pulsed Doppler Sonography (Pulsed Wave Doppler, pw Doppler) . . . . . . . . . . . . . . . Color Duplex Sonography . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.3 Ultrasound Signal Enhancers . . . . . . . . . . . . . . . . . . . . . 2.2.1.4 Reference Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.5 Stenosis Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.6 Clinical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brainstem Infarction/TIA . . . . . . . . . . . . . . . . . . . . . . . . Basilar Artery Thrombosis . . . . . . . . . . . . . . . . . . . . . . . Subclavian Steal Syndrome or Subclavian Steal Phenomenon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rotational Vertebral Artery Occlusion . . . . . . . . . . . . . . 2.2.2 B-Mode Sonography of the Brainstem . . . . . . . . . . . . . . 2.2.2.1 Principles and Techniques . . . . . . . . . . . . . . . . . . . . . . . 2.2.2.2 Clinical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . Early Diagnosis of Idiopathic Parkinson’s Disease . . . . Differential Diagnosis of Parkinson Syndromes . . . . . . . Diagnosis of Affective Disturbances . . . . . . . . . . . . . . .
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2.3 Electrophysiologic Diagnostics . . . . . . . . . . . . . . . . . . 2.3.1 Blink Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.1.2 Clinical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1.3 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2 Masseter Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2.1 Anatomic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2.2 Clinical Application and Normal Values . . . . . . . . . . . .
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2.3.2.3 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3 Early Acoustic Evoked Potentials . . . . . . . . . . . . . . . . . . 2.3.3.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.3.2 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recording . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3.3 Physiologic Variability of EAEP and Abnormal Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3.4 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Central Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brainstem Ischemia/Bleeding . . . . . . . . . . . . . . . . . . . . . Brain Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4 Vestibulocollic Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.4.2 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4.3 Evaluation and Reference Values . . . . . . . . . . . . . . . . . . 2.3.4.4 Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5 Exteroceptive Suppression of Masticatory Muscle Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . Afferences of Exteroceptive Suppression . . . . . . . . . . . . Interconnection of ES1 . . . . . . . . . . . . . . . . . . . . . . . . . . Interconnection of ES2 . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5.2 Clinical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recording . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5.3 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5.4 Reference Values/Normal Variants and Pathologic ES Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.5.5 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . 2.3.6 Somatosensory Evoked Potentials . . . . . . . . . . . . . . . . . 2.3.6.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.6.2 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recording . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.6.3 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Generator Question and the Interconnection of SEPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Far-Field Potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.6.4 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . 2.3.6.5 Brainstem Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.7 Transcranial Magnetic Stimulation . . . . . . . . . . . . . . . . . 2.3.7.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.7.2 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Corticofacial Projections . . . . . . . . . . . . . . . . . . . . . . . . . Corticolingual Projections . . . . . . . . . . . . . . . . . . . . . . . 2.3.7.3 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TMS of Corticofacial Projections . . . . . . . . . . . . . . . . . . TMS of Corticolingual Projections . . . . . . . . . . . . . . . . .
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2.3.7.4 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . . Brainstem Ischemia Prognostic Significance of MEPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Topodiagnostic Significance of MEPs . . . . . . . . . . . . . . Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . Hereditary Spastic Spinal Paralysis . . . . . . . . . . . . . . . . 2.3.8 Laser Evoked Potentials . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.8.1 Anatomic and Physiologic Principles . . . . . . . . . . . . . . . 2.3.8.2 Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recording . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.8.3 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.8.4 Interpretation of Findings . . . . . . . . . . . . . . . . . . . . . . . .
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Central Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brainstem Ischemia/Hemorrhage . . . . . . . . . . . . . . . . . . 2.3.9 Recording of Eye Movements . . . . . . . . . . . . . . . . . . . . 2.3.9.1 Direct Current Recording . . . . . . . . . . . . . . . . . . . . . . . . 2.3.9.2 Infrared Reflective Oculography . . . . . . . . . . . . . . . . . . . 2.3.9.3 Videooculography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.9.4 Scleral Search Coil Technique . . . . . . . . . . . . . . . . . . . . 2.3.10 Other Electrophysiologic Methods for the Investigation of Brainstem Reflexes . . . . . . . . . . . . . . . . 2.3.10.1 Stapedius Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.10.2 Trigemino-Cervical Reflex . . . . . . . . . . . . . . . . . . . . . . . 2.3.10.3 Trigemino-Hypoglossal Silent Period . . . . . . . . . . . . . . .
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Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2.1 Neuroradiology Peter Stoeter and Stephan Boor
2.1.1 Conventional Native Diagnostics Conventional native diagnostics of the skull no longer has an important role in disorders of the brainstem today, and conventional tomography has been completely abandoned for reasons of radiation protection. A similar situation exists with a view to special images of the skull base and the petrous bones (in projections according to Schüller and Stenvers), which have been replaced with thin section computed tomography (CT) scans that have a significantly higher detail resolution. Survey radiographs of the skull in two planes and a radiograph of the back of the head obtained in half-axial projection with the tube tilted toward the vertex are occasionally recommended after craniocerebral trauma and shotgun wounds, or for the detection of other metallic foreign bodies. The finding of fractures of the skull cap or skull base can serve as an indicator of violent assault. If not done at the time of the primary diagnosis, a CT scan is indicated at the latest on detection of a fracture on the plain radiograph, in particular in the presence of space-occupying bleeding. At the craniocervical junction, the search for a fracture of the upper cervical spine is important in trauma patients; in particular unstable fractures of the atlas or dens and luxations with ligament lesions after injury to the spinal cord and the caudal part of the medulla oblongata have to be identified, while a secondary lesion in these structures as a result of incautious manipulation must be prevented. This also applies to instabilities due to other causes, e.g. odontoid bone or rheumatoid arthritis. Radiographic functional studies in forward and backward tilt under fluoroscopy have to be carried out for the assessment of cervical spine stability (Fig. 2.1), whereby the differentiation from the physiologic mobility of the upper cervical vertebrae is not readily achieved, particularly in children.
Fig. 2.1 Craniocervical dysplasia. Plain radiograph in backward (a) and forward tilt (b) CT in sagittal reconstruction (c) T2-weighted MRI (d) shortening of the clivus, separate disposition of the dens process as odontoid bone with pseudoarthrosis and anterolisthesis (including atlas and occiput) vis-à-vis the dens, resulting in severe stenosis between the upwardly displaced posterior arch of the atlas and the posterior border of the second cervical vertebral body and dens with malacia (bright signal on T2-weighting) in the caudal part of the medulla oblongata. Only slight increase in forward slippage on forward tilt (comp. a and b). Synostosis C2–5
2.1 Neuroradiology
Further indications for plain radiographs are cranial anomalies (premature suture synostosis), general disorders of the skull cap and skull base as, e.g. Paget’s disease, or suspected metastases. Constrictions of the foramina of the skull base can lead to cranial nerve lesions. Constitutional or acquired constrictions at the craniocervical junction, like a basilar impression (upward displacement of the dens into the foramen magnum with resulting depression of the medulla oblongata), or achondroplasia (shortening of clivus with constriction of foramen magnum) can already be identified on the survey radiograph. Overall, however, the information provided by native diagnostics regarding brainstem involvement is limited compared to multislice diagnostic modalities.
2.1.2 Computed Tomography 2.1.2.1 Principles and Techniques In computed tomography (CT), which – like conventional native diagnostics – is based on x-ray absorption, the x-ray film is replaced by a detector system for the measurement of x-ray absorption. The patient is positioned on the examination table and moved longitudinally, i.e. in very precise small steps or nowadays continuously, through the measurement unit (gantry). The x-ray tube and detector ring are mounted opposite each other in the gantry. In units of the third and fourth generation they rotate continuously around the part of the body to be imaged at a speed of 0.3–3 revolutions per second. The emitted radiation beam is pulsed and collimated in a fanshaped fashion onto the slice of interest. Modern units enable the measurement of slice thicknesses from 0.5 to 10 mm. The individual detectors transform – as scintillation crystals or ionization chambers – the received radiation into electric signals, from which the image processor calculates the attenuation values of the x-rayed volume elements (voxels). In newer CT units with continuous rotation, the tube voltage is provided by slip rings, which obviates the need for repositioning of the cables. The examination table moves continuously through the gantry while a spiral scan of the object to be examined is conducted and a volume data set is acquired. The resulting data set can be used to reconstruct single slices of varying thickness. Multidetector systems enable the simultaneous acquisition of multiple (currently up to 640) slices of a specified width. By means of “folded rear projection” relative x-ray attenuation values of the individual voxels can be calculated from the measured detector voltage and correlated to the absorption values of water (0) and air (−1,000) as Hounsfield units (HU). The “density” of gray matter thus ranges at 45 HU, and that of white matter at 35 HU. Because the human eye can differentiate only approximately 20 grayscales, the width and
39
position of the viewing window have to be accurately adjusted to the contrast area to be differentiated. Conversely, all values above or below the window width are shown as “white” or “black” without further differentiation. Spatial resolution is also low in the presence of slight density differences, ranging only from about 2 to 3 mm, so that pathways and nuclei in the brainstem are poorly differentiated from each other, even when a narrow window width is used. However, in high contrast areas as, e.g. in the visualization of bony petrosal structures, spatial resolutions of up to 0.35 mm can be achieved with special reconstruction algorithms. Further section planes can be reconstructed from the data sets. With the commonly used 512 matrix the slice thickness is substantially greater than the edge length of the image elements (pixels), the resolution of secondary sections in the reconstruction direction has thus far been lower than for direct measurements. With the introduction collimation, units of the latest generation permit the measurement – or at least the calculation – of isotope voxels, which enables multiplanar reconstruction without quality loss. A further advantage of multiplanar systems, in addition to shorter measurement times, is reduction of partial volume effects and therefore an improved sharpness, resulting from the presence of structures with different densities in one voxel, and their visualization as one unit with proportional weighting. After intravenous bolus administration of iodized x-ray contrast medium, reconstruction of image elements with maximum intensities, e.g. of vessels using maximum intensity projection (MIP), as well as three-dimensional reconstructions with, e.g. shaded surface display (SSD) or volume rendering technique (VR), are also possible. In CT angiography it is important to ensure that the examination of the region of interest is carried out at exactly the moment when the injected contrast medium passes through the arteries or veins.
2.1.2.2 CT in Investigations of the Brainstem Due to the low spatial resolution in the low contrast area, the diagnostic value of CT in investigations of the brainstem is relatively limited. The primary indication – also in view of the short examination time – is emergency diagnostic imaging, particularly for the demonstration of skull base fractures after trauma, and bleeding in the brainstem or cisterns. Furthermore, calcifications of cavernomas (Fig. 2.2), other vascular malformations or various neoplasms, e.g. ependymomas, can be accurately identified. The majority of brainstem lesions like infarctions or patches of demyelinization are rare and can be conclusively shown primarily above the middle of the pons. In addition to low contrast resolution, this is due to the occurrence of streak artefacts (Hounsfield artefacts) that develop as the result of energetically different x-ray absorption in the bones of the skull base, primarily the petrous bones,
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• Vascular stenoses or vascular occlusions – particularly when a basilar artery occlusion is suspected • Arterial aneurysms (demonstration at 90% sensitivity as of a diameter of 5 mm) (Dammert et al. 2004) • Central cerebral veins or sinus thromboses The availability of modern units has rendered CT angiography coequal to MR angiography. As in MR angiography, the use of multislice CT scanners enables visualization of the entire supra-aortal vascular region.
Fig. 2.2 Cavernoma of the lamina quadrigemina. Axial CT at the time of diagnosis (a) and after 8 months (b). Calcifications in the right superior colliculus (a) and enlargement of the hyperdense region due to bleeding with compression of the aqueduct and CSF accumulation (b)
and mask the lower parts of the brainstem. The artifacts can be eliminated only partially with special programs using artefact filters and secondary slice reconstruction from consolidated thin sections. CT perfusion measurements for the differentiation between a nuclear infarct and an undersupplied penumbra do not yet play an important role in brainstem investigations. However, larger intracerebral and extracerebral tumors as well as other infratentorial space occupying masses like cysts and malformations at the craniocervical junction which may lead to CSF accumulation, can also be visualized on CT. The indication for the investigation may be valid in emergency patients with a suspected increase in intracranial pressure. When magnetic resonance imaging (MRI) can, for different reasons, not be done in patients with a suspected tumor, intravenous contrast medium has to be administered to visualize some intrinsic tumors, e.g. astrocytomas and medulloblastomas – blood–brain barrier disorders and conditions that have high vascular density (e.g. von Hippel-Lindau tumor/Hemangioblastoma or vascular malformations) can be better differentiated from the surrounding structures by contrast enhancement. This also applies to abscesses originating from the petrous bone, which may lead to clouding of pneumatisation cells and osteolytic destructions. Other destructions of the skull base, e.g. metastases, chordomas, chondromas or sarcomas, which may be a cause of brainstem compression are also well visualized on CT scans. Enlargements of the internal acoustic meatus (IAC) are indicators of schwannomas, although a negative CT finding alone is not sufficient for the exclusion of this lesion. In cases where MRI is contraindicated, CT cisternography after intrathecal contrast medium injection should be carried out, comparable to the application of this procedure for a suspected cyst, to clarify communication with the subarachnoidal space. CT angiography for brainstem imaging is further used to visualize
2.1.2.3 Risks In accordance with the X-Ray Ordinance for Radiation Protection, any x-ray application must be approved by specialists and is subject to strict regulations, in particular with regard to pregnant women. In the region of the head, the eye lens is especially sensitive to x-ray exposure and should, whenever possible, be protected from the beam path by tilting of the gantry. In spiral technique applications, an x-ray exposure of the eye lens to 70 mGy simulated petrousal bone investigation; (Giacomuzzi et al. 2001) may be assumed when multislice spiral CT is used; the required dose of 0.5–2 Gy (Maclennan and Hadley 1995) for cataract induction is therefore highly unlikely to be exceeded, even after repeated CT scans. The use of x-ray contrast media is also subject to specific requirements: special care has to be taken in the presence of known allergies (possible administration of H1 and H2 blockers), disturbance of kidney function with creatinine levels above 1.5 mg/dL (sufficient water intake and administration of acetylcysteine), increased thyroid hormone levels, or decreased basal TSH (poss. perchlorate blockade), and pathologic serum proteins, as in multiple myeloma. The occurrence of allergic reactions is expected in up to 3% of patients, even in those without a prior history of allergies. However, the allergic reactions only rarely (below 0.04%) lead to a severe circulatory shock if non-ionic contrast media are used. Where indicated, and in the absence of a kidney function disturbance, an iodine-containing contrast medium can be replaced with a gadolinium- containing contrast medium. Patients with cardiac insufficiency have to be monitored for a short-term increase in intravascular blood volume after contrast medium injection.
2.1.3 Magnetic Resonance Imaging 2.1.3.1 Principles and Techniques Magnetic resonance imaging (MRI) is based on electromagnetic waves generated by rotation of the positive proton load (spins). The MRI scanner uses a powerful magnetic field
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(0.2–3 T in clinical applications) to align the spins parallel and antiparallel to the main magnetic field. The rotation speed or Larmor frequency is dependent upon the strength of the magnetic field and ranges at 42.5 MHz for 1 T. There is a slight surplus of parallel aligned spins due to ambient heat, which leads to the generation of a magnetic moment in the direction of the main magnetic field, although this can not yet be measured in itself. The additionally applied energy in the form of a high frequency pulse, which has to be in resonance with the Larmor frequency, causes additional spins to be tilted in the antiparallel direction, while the rotation (precession) of the spins about the direction of the main field is synchronized or brought “in sync.” This leads to the brief generation of a magnetic moment, which rotates in a plane perpendicular to the main field and generates the initially mentioned electromagnetic waves. These are received by a coil, which functions like an antenna and can be used for image calculation (Lauterbur 1973). The energy exchange with the surrounding protons and minute local differences in magnetic field strength lead to rapid dephasing of precession of the individual spins and therefore to signal loss. This spin–spin relaxation is characterized by T2-time and occurs at a significantly slower rate in pure water than in the presence of macromolecules. The image signal from tissues with a high water content is therefore maintained also after a longer latency of above 100 ms, while tissues with a low water content do not emit a signal at this time point due to spin dephasing (T2-weighting: CSF bright, cortex gray, spinal cord dark gray). However, dephasing caused by inhomogeneous magnetic field effects can be reverted with the application of an additional high frequency pulse, which effects a reversal in the rotational direction of the spin, and an “echo” of the initial signal is formed. The described pulse consisting of an excitation and inversion (180°-) pulse sequence is described as spin echo- (SE-) sequence. The energy release to the surrounding protons, the “lattice,” causes the direction of additional spins generated by the high frequency pulse to be switched into the antiparallel direction, and the magnetic moment rotating in the perpendicular plane will decay with time. Concurrently, the original moment is restored parallel to the main field. This spin-lattice rela xation is described by the T1-time and is markedly (up to tenfold) slower than the spin-spin relaxation. If a second excitation pulse is applied at an earlier time point, the more slowly relaxing tissues with a high water content will not yet have recovered full “longitudinal magnetization” oriented toward the field, and only a small surplus of foldable parallel aligned spins is available. As a result, the signal received from these tissues is weaker than that from tissues with shorter T1 time (T1 weighting: CSF dark, cortex gray, spinal cord light grey). If the influence of both T1- and T2-times on the image signal (short echo and long repetition times) is suppressed by means of the selection of respective sequence parameters,
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the number of available protons is the decisive factor regarding the image signal (proton weighting: cortex brighter than spinal cord, CSF dark). Spatial encoding is achieved with MRI by superimposing three gradient fields above the main field. This enables the modification of the local magnetic fields in all three spatial dimensions, so that each voxel receives a specific field and therefore also a specific resonance condition. Special, time limited connections between these fields further permits variation of the rotation frequency of the spins at the time of the echo, to change their phase, and to enable their application for spatial encoding. Due to the small size of the brainstem, the images should have the highest spatial resolution possible, i.e. maximal matrix and thin slice thicknesses. Since the image signal of a voxel depends upon its size, imaging of the brainstem requires either a greater number of measurements (repetitions) or greater field strengths. With the application of several parallel-connected coils the measurement times are shortened and the threat of motion artifacts can be significantly reduced. Spatial resolution can be enhanced with the use of threedimensional techniques. Particularly suitable for T2 weighting is the constructive interference in steady state (CISS) sequence, which allows measurement of slice thicknesses below 1 mm. As a result of the especially long echo times virtually all structures outside the CSF-containing cisterns are visualized as dark areas. The vessels and cranial nerves coursing in the cisterns can be viewed in high resolution images, as can virtual endoscopy procedures (Boor et al. 2000; Fig. 2.3) and the labyrinth in the petrous bone, while intensity differences in the brainstem as, e.g. patches of demyelinization or fresh infarcts versus normal structures are almost impossible to differentiate. The CISS sequence is therefore used mostly to differentiate between a neurovascular compression or a cisternal space-occupying or for petrous bone diagnostic imaging. Epidermoids, which are also almost impossible to differentiate from the CSF-signal, can be shown as mildly (in comparison with CSF) hypointensive space-occupying masses with this modality. T1 weighted sequences are also capable of further enhancing spatial resolution with the measurement of a three-dimensional volume data set, which provides a high signal-to-noise ratio. For reasons of time, the refocusing pulse is not applied here and a (weaker) echo is generated with the application of gradient fields, although this reacts with considerably higher sensitivity to magnetic field inhomogeneities (gradient echo sequence). At the concurrent prolongation of echo time (T2* weighting), the demonstration of fresh bleedings and paramagnetic blood degradation products (ferritin), e.g. older bleedings and cavernomas, becomes possible (Fig. 2.4). The described effect of signal attenuation due to magnetic field disturbances can be used advantageously in imaging perfusion measurements, where
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Fig. 2.3 Acoustic neurinoma. Highresolution MRI (CISS) in T2-weighting (a) and respective calculation of virtual endoscopy (b). Mass at the entrance to the internal acoustic meatus right, and normal course of the statoacoustic nerve left in cerebellopontine angle cistern. View of the lower surface of the tumor and the AICA, viewed as if through an endoscope located more caudally in the parapontine cistern
Fig. 2.4 Pontine cavernoma. MRI in T2 weighting (a) and T2* weighting (b). Signal reduction due to iron deposit (old bleeding) is markedly greater in the T2* weighted sequence, which is substantially more sensitive to susceptibility disturbances
signal degradation as a result of repeated measurements can be observed during the passage of the contrast agent bolus. However, this technique, which has an important role in the diagnosis of supratentorial infarcts and tumors, is not as frequently used in brainstem imaging. The T1 weighted signal of stationary spins can be suppressed by reducing the time interval between two excitations (repetition time), so that in particular successive spins flowing into the excited slice produce a signal (time-of-flight [TOF] angiography for imaging of vessels). Venous overlay can be reduced by presaturation of the sinus above the convexity. Contrast agent infusion enables both suppression of artifacts due to turbulent flow and contrasting of veins (contrast enhanced MRA [CE-MRA]). Comparable to CT-angiography (CTA), the reconstruction of the course of the vessels can be accomplished with postprocessing programs in MRA. Both methods of MR angiography are used to show vascular stenoses and malformations (angiomas, aneurysms; Fig. 2.5), in addition to imaging of neurovascular compressions. For special questions regarding the venous system, the use of TOF-MRA has proven to be of advantage, primarily for intracranial segments, due to the higher spatial resolution, while the examination of a large area is enabled by CE-MRA, making this the more suitable method for the extracranial segments.
A further method for MR tomographic flow measurement – used in particular in investigating CSF-flow at the craniocervical junction, in the cisterns and in the aqueduct – consists of imaging with phase contrast images by means of a two-dimensional steady state free precession sequence at velocity encoding of 7–10 cm/s in the direction of the z axis. The CSF flow leads to a phase shift that is proportional to the flow velocity and therefore quantifiable (Fig. 2.6). However, these investigations are time consuming due to required synchronization with cardiac movements (ECG triggering). Diffusion imaging employs brief applications of strong gradients before and after a 180° pulse, causing only signals of stationary spins to be completely rephased, while spins of diffusing protons produce a weaker signal due to their exposure to gradients of varying strengths as a result of a change in their spatial orientation before and after reversal of the rotational direction. Areas with diffusion disturbances like infarcts and occasionally also fresh patches of demyelinization are therefore viewed with high signal in these images (Fig. 2.7). These lesions are characterized by high signal in both diffusion weighting and T2 weighting sequences, therefore the T2 effect has to be calculated as well as the apparent diffusion coefficient (ADC). Diffusion disturbances are viewed as dark areas on these ADC maps. 2.1.3.2 MRI Investigations of the Brainstem MRI is superior to other imaging modalities in imaging the form and tissue structure of the brainstem, and thus makes a major contribution to differential diagnosis. To be discussed in this chapter are primarily the technique used for the investigation and the brainstem anatomy, while examples of pathologic findings are presented in the respective specialized chapters. All cranial nerves in the cisterns can be shown and differentiated from adjacent vessels on both T1 and T2 weighted sequences. While the robust trigeminal nerve can also be
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Fig. 2.5 Aneurysm of the basilar artery tip. MR angiography (TOF sequence) (a) with MIP reconstruction (b) conventional vertebral DSA left (c) and 3D rotational angiography (d). The aneurysmal sack exits from the basilar artery tip and both P1 segments of the posterior cerebral arteries. The branches supplying the thalamus are visualized on DSA only
Fig. 2.6 Chiari-II (Arnold–Chiari) malformation. MRI in T1 weighting (a), phase contrast image of CSF flow during systole (b), and diastole (c). Descent of the entire brainstem and cerebellar vermis, which extends together with the cerebellar tonsils through the foramen magnum into the spinal canal, with compression of the medulla oblongata and blockade of retromedullary CSF flow. Premedullary CSF flow is still demonstrable, systolic in caudal (dark), and diastolic in cranial (bright) direction
Fig. 2.7 Fresh midbrain infarction. MRI in T2 weighting (a) diffusion weighting (b) and CE MRA (c). While the paramedian infarction (arrows) is visualized primarily as a bright diffusion barrier in DWI, the T2 image shows only slight signal enhancement. CE MRA of the supratentorial vessels does not demonstrate any relevant stenosis
identified on survey scans, this is the case for more delicate nerves like the trochlear or abducens nerve only when a sufficiently high spatial resolution is achieved with CISS or gradient echo sequences. Regarding the vestibulocochlear nerve and the facial nerve, the four bundles of the superior and inferior vestibular nerves, the auditory nerve and the facial nerve in the internal auditory meatus can be differentiated in sagittal sections, while conclusive differentiation between the glossopharyngeal nerve and the vagus is generally not possible. Form, location and size of the individual brainstem segments can be assessed without difficulty. This also applies to the fourth ventricle, and here in particular to the rhomboid fossa, the aqueduct, and the cerebellar peduncles. The internal structure of the brainstem is characterized by close interweavement of pathways and nuclei, which can be very well differentiated with the use of proton weighted sequences and diffusion tensor imaging (see Specialized methods) (Fig. 2.8). In proton weighted images the pathways and nuclei display varying degrees of brightness, depending on their proton content. Diffusion weighting visualizes the different courses of pathways by giving preference to the diffusion parallel to the pathway (signal reduction) or by reducing the diffusion perpendicular to it (signal enhancement).
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Fig. 2.8 Normal MRI anatomy of brainstem pathways. T2 weighting (a, b), proton density weighting (b, e, f) color coded DTI maps (c, f). Axial sections through the lower part of the pons (a, c, e) and the midbrain (b, d, f). 1 Pontine base with corticospinal tract (pyramidal pathway) and 2 pontocerebellar tract (middle cerebellar peduncle), 3 pontine tegmentum with tegmental tract, 4 medial longitudinal fascicle, 5 spinocerebellar tract (lower cerebellar peduncle), asterisk: lateral part of the reticular formation with vestibular nuclei, 6 substantia nigra, 7 crossing of cerebellar efferents (cerebellorubrothalamic tract), 8 medial lemniscus, color coding on DTI color maps, red: trajectories in right-left direction, green: trajectories in AP direction, blue: ascending and descending trajectories
Sections through the upper part of the medulla oblongata permit identification of the long pathways, e.g. the pyramidal pathway ventrally, the medial lemniscus in the center, and the olive and the ascending pain and cerebellar pathways laterally. Located in the dorsal part of the medulla, i.e. in the floor or exit of the fourth ventricle, is the medial longitudinal fascicle, as well as the primary nuclei of the cranial nerves IX–XII. The corticospinal tracts and the cerebellar afferents coursing in a lateral direction are visualized in the base of the pons and can be differentiated from the more dorsally located pontine tegmentum with the medial and lateral lemnisci, the central tegmental tract, and the medial longitudinal fascicle. Visualized in the sections through the midbrain are the descending pathways in the cerebral crus, as well as the substantia nigra with several markedly enlarged Virchow–Robin spaces in the T2 image, where the relatively bright crossing of the cerebellar efferents, and the more rostrally located red nucleus, the lamina quadrigemina and the periaqueductal gray can also be identified. Pathologic processes of the
brainstem associated with severe morphological changes as, e.g. complex malformations (Chiari malformation, Dandy– Walker complex, Joubert syndrome), tumors of the brainstem and adjacent structures, as well as obstructions of the CSF passage with resulting hydrocephalus can be identified without difficulty. Pronounced stenoses or occlusions of the aqueduct, e.g. after inflammations, typically appear as a trumpet-shaped enlargement of the rostral segment of the aqueduct, which is located anterior to the occlusion. These can often already be identified in T2 weighted images due to the absence of a flow signal (no flow-related signal decay). Under these conditions the phase-weighted sequences described above are particularly suitable for flow imaging. Furthermore, atrophies due to system degeneration, i.e. olivopontocerebellar atrophy (OPCA) or pseudobulbar paralysis can be identified based on apparent loss of substance in the medulla, pons and/or midbrain (mesencephalic sagittal diameter below 14 mm). Intracerebral lesions of the brain substance like infarcts and patches of demyelinization require the use of at least T2 weighted sequences with high resolution (512 MB matrix or a narrow field of view) and thin slicing (slice thickness 2–3 mm). Wallerian degeneration of brainstem pathways can also be shown with this procedure, as well as toxic or metabolic damage to pathways, as in pontine myelinolysis, or the rare occurrence of olivary pseudohypertrophy following central tegmental tract lesions. The evaluation of proton weighted images is not readily accomplished in the brainstem, due to the close anatomic relationship of the gray matter to the white matter; this is in contrast to the cerebrum where edemas and gliomas can be well identified using this weighting. As mentioned above, exact anatomic knowledge of brainstem structures is a prerequisite for the differentiation of circumscribed lesions of pathways and nuclei in proton weighted images. Furthermore, fluid attenuated inversion recovery (FLAIR) sequence, which provides valuable supratentorial information, also does not yield a contrast-rich image of small brainstem lesions. In the presence of acute vascular processes, in particular of ischemic infarctions, diffusion weighted sequences should be taken to ensure that small lesions are not missed, and can be differentiated from possibly existing older ones (Fitzek et al. 1998). Infarcts lead to the breakdown of cell metabolism and ion pumps. This results in development of intracellular edema with compression of the extracellular space, the location with the most prolonged and therefore MRI-relevant water diffusion. A diffusion obstacle is created as a result of cellular swelling and the interruption of the active proton transport through the membrane. As diffusion leads to signal loss in MRI images, the nuclear infarcts with diminished diffusion appear early and are characterized by high signal intensity, while signal enhancement in the T2 weighted image, which is dependent on the water content, occurs after several hours or days. MRI is therefore superior by far to CT,
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particularly for the early diagnosis of brainstem infarcts. Although brainstem bleedings are also visualized on MRI in the acute stage as space-occupying masses – and with signal inhomogeneities in the diffusion image – they can be better shown with a latency of several days, due to the pronounced increase in signal intensity on T1 and T2 weighting over time. Ferritin deposits can be identified even later but particularly well in T2* weighted images, whereby cavernomas exhibit a typical “mulberry-shaped” arrangement of dark borders and a bright center. These deposits are absent in teleangiectasies and in developmental venous anomalies (DVA). For the investigation of space-occupying masses, a gadolinium-containing MR contrast medium is generally administered to display disturbances of the blood brain barrier as, e.g. gliomas or abscesses. A contrast material should also be injected for lesions whose origin can not be conclusively identified (ischemic, traumatic, or degenerative) in order to detect the presence of a blood–brain-barrier disturbance and thus to enable the diagnosis of an acute occurrence and/or spread of a process. This is of particular importance in multiple sclerosis when a acute episode of the disease is suspected, as well in the also well localized acute disseminated encephalomyelitis (ADEM), where all lesions are at a similar stage of development and therefore capable of uniform contrast medium uptake in the acute stage. Other inflammatory processes – sarcoidosis, borreliosis, tuberculomas and other encephalitides (e.g. listeriosis) – as well as neoplastic infiltrations in the cisterns and the substance of the brainstem are further visualized as circumscribed areas with enhancement (Fig. 2.9). Acute Wernicke’s encephalopathy due to vitamin B1 deficiency is also characterized by blood–brain-barrier disturbances, typically in the central gray matter of the midbrain and the hypothalamus. Contrast medium is also given to detect the above- mentioned vascular malformations, although primarily for the
Fig. 2.9 Infiltration of basal cisterns and brainstem in lymphatic leukaemia. Sagittal section in T2 weighting (a) and T1 weighting following contrast medium application (b). Marked signal (T2) enhancement (edema) in the medulla oblongata with circumscribed barrier disturbance (contrast agent leakage), extra- and intracerebral
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performance of MR angiography. While the contrast medium free TOF method provides better spatial resolution, it occasionally is rendered less diagnostic by turbulence caused by artifacts and is dependent upon flow velocity. Contrast medium is given in patients with arteriovenous malformations mostly to image venous drainage, while the arterial feeders are better captured on TOF angiography. This also applies to showing neurovascular compressions like trigeminal neuralgia, as well as to other cranial nerve disturbances, e.g. vascular compression of the vestibulocochlear nerve with concomitant attacks of vertigo. In addition to the abovementioned CISS sequences, TOF angiographies before and after contrast medium application are used here, to enable the differentiation between arterial and venous vessels in close proximity to the nerves. Contrast enhanced MR angiography (CE-MRA) is used to show the entire supraaortal region. Compared with contrast medium free angiography, which provides a higher resolution, CE MRA offers the advantage, that turbulence artifacts can be reliably differentiated from genuine constrictions. The demonstration of therapy relevant stenoses and occlusions on CE-MRA can be accomplished with a high degree of certainty, so that conventional digital subtracted angiography in the vertebrobasilar region is used in exceptional circumstances and exclusively for diagnostic reasons. This also applies to TOF-MR angiography for the detection of aneurysms. A high reliability rate can be achieved with this modality for aneurysms of 3 mm in diameter and above (Hirai et al. 2005).
2.1.3.3 Specialized Methods The following specialized methods are used for investigations by MRI imaging: • Cerebral activation • Diffusion tensor imaging (DTI) • Spectroscopy During cerebral activation the linkage of neuronal activity and brain perfusion leads to vasodilation with a latency of a few seconds. This produces both an increase in perfusion and oxygenated and therefore diamagnetic hemoglobin content. Both effects lead to a small increase in signal intensity, although this is only slightly higher than the basic noise of the image signals. The statistic significance therefore has to be demonstrated based on the correlation between repeated activations and signal development. Brainstem activations can thus be demonstrated with horizontal and vertical gaze direction nystagmus at different levels (pons or mesencephalon). In patients, this method has so far been applied for the preoperative diagnosis of cerebral processes (motor and speech activation). Diffusion tensor imaging (DTI) represents a further development of diffusion weighting. Since the diffusion of
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water molecules is always isotropic in water, but restricted in tissue by cell borders, and particularly by axon sheaths (anisotropic diffusion), the degree of anisotropy and the principal diffusion direction can be determined with gradient applications in different directions, and the measurement of a nine component diffusion tensor. The degree of the averaged diffusion direction and anisotropy serves as a parameter for intact nerve tract function. The courses of the main nerve tracts can be reconstructed from the principal characteristic vector of the tensors in the form of direction-coded color maps (Fig. 2.10). In clinical practice this method is used primarily for preoperative imaging of cerebral tumors and vascular malformations. The purpose of
the depiction of pyramidal pathways or optic radiation, and transfer of the trajectories to neuronavigation systems is to avoid injury of these pathways in the course of surgical interventions. This method can also show the corticospinal projections that traverse the pontine base. The signal of protons from water molecules used for imaging is suppressed during spectroscopy, which causes signals of protons from other substances to be visualized. Depending on their molecular environment, these show a slight substance-specific shift in Larmor frequency compared to water. The described frequency shift permits differentiation of three major peaks (choline [CHO] as a marker for membrane reconstruction, creatinin [Cr] as an indicator of energy metabolism, and N-acetyl aspartate [NAA] as an osmolyte). In the presence of tumors and depending on the tumor grade, there is an increase in the choline level compared with the creatinin level, and a decrease in the level of N-acetyl aspartate (Fig. 2.11). A lactate peak might be observed in acute inflammations and demyelinizations. Other products of metabolism as, e.g. amino acids or acetates in abscesses may, in some instances, be shown on spectroscopy. This method is nevertheless rarely used in clinical brainstem diagnostic tests, because the small measurement volume required here necessitates a long examination time.
2.1.3.4 Risks
Fig. 2.10 Trajectories of the right medial longitudinal fasciculus calculated from DTI data sets in axial (a, b) and sagittal cross-section (c)
Apart from slight tissue warming and the occurrence of photopsias at high magnetic field strengths (3 T), no MR- specific side effects have been shown in tissue, on condition that specific absorption rates (SAR) are given consideration. The indication for MRI examinations should, however, be particularly strict in pregnant women – especially in the second part of pregnancy – because the fetus reacts with increased movement to the acoustic noise due to the rapid switching on and off of the magnetic field gradients. 1 12 10
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Fig. 2.11 Thalamus and brainstem glioma: T2 weighted section through the lamina quadrigemina (a) and proton spectroscopy (b). Right-paramedian, in T2 signal-intensive space-occupying lesion in medial part of the thalamus and the superior quadrigeminal bodies, with pronounced increase in the choline peak (1), a slightly decreased creatinin (2) and markedly decreased N-acetyl-aspartate (NAA) peak (3)
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4 2 0 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
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While MRI does not generally represent a health hazard, the situation is completely reversed in the presence of ferromagnetic foreign material in the body, e.g. iron or steel remnants (shell fragments, splinters after accidents, old implants), that may heat up and cause injury to the vessels or nerves as a result of displacement. This applies in particular to old aneurysm clips and intraorbital metal fragments. Metallic paints used in tattoos can also cause burns. Damage may further result from the antenna effect of metal wires inside and outside the body that are used as electrophysiologic leads (e.g. ECG cables and electrodes). Whenever possible, these should be replaced with light guides. Especially patients with pacemakers are at a high risk for burns and subsequent scarring, as well as for arrhythmias. In this context MRI is rarely indicated only in patients with specially designed pacemaker devices or with a vital indication, and under adherence to appropriate safety precautions (among others the presence of a reanimation team with cardiologic competence) (Loewy et al.2004). Although other metals, including platinum or tantalum are not paramagnetic, artifacts frequently appear. Substantial signal loss and major image distortions are also caused by dental braces. To a lesser degree these events may also result from body piercing and make-up, especially from eye shadow containing active magnetic substances. Another, not insignificant risk is posed by the presence of ferromagnetic objects (gurneys, wheelchairs, surgical instruments, gas bottles) in the examination unit, if these are pulled into the scanner with a great expenditure of energy and transported while being exposed to increasing magnetic field strength in the vicinity of the magnet. Monitoring of the patient in the scanner is also difficult. A MR compatible device for the measurement of vital parameters is not always available, so that particular attention must be paid to the occurrence of epileptic episodes, or cardiovascular and respiratory disturbances as well as sudden emesis, which may develop in brainstem processes. A similar problem may arise during chemical sedation which may be indicated in agitated patients, e.g. small children. Gadoliniumcontaining contrast agents are better tolerated than the contrast media used in x-ray radiography, since the volumes are smaller and no iodine is injected. Although allergic reactions are also rarer, they may nevertheless be life-threatening. The use of unbound gadolinium may lead to nephrogenic systemic fibrosis in patients with severe renal impairment, and an accurate diagnosis is imperative in these cases.
2.1.4 Angiography and Endovascular Interventions 2.1.4.1 Diagnostic Angiography Conventional angiography requires technical skill as well as experience and is, as an invasive procedure, associated with
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a complication rate. In the presence of an exclusively diagnostic indication it is therefore increasingly replaced by Doppler sonography and CT or MR angiography. Conven tional angiography provides a high spatial resolution and enables the depiction of blood flow phases in chronological order, therefore this “gold standard” cannot be completely abolished. Selective vertebral angiography is required for visualization of the vertebrobasilar vascular system and can, especially in younger patients, be performed without technical difficulties. The Seldinger technique with insertion of the catheter via the femoral artery is employed for this procedure. The use of the subtraction technique permits the elimination of bone densities and leads to a significant improvement in image quality, especially in the posterior cranial fossa where the overlying petrous bones can be dispersed. It is carried out in form of digital subtracted angiography (DSA), if possible with a biplane x-ray unit. By the use of selective catheter placement in a vertebral artery, this procedure enables reduction of the contrast medium volume to a few milliliters, at an iodine content of 250 mg/mL compared to injection into the subclavian artery. A 3D-technique for angiography has become available, equipped with a C-arm unit that rotates around the head of the patient placed in the isocenter. With this procedure, complete angiograms at intervals of only few angular degrees are possible. The obtained data sets are used for three-dimensional reconstructions of the cervical and intracranial vessels which provide details of particular value in the diagnosis and therapy of aneurysms (free projections of the aneurysm head, exact measurement). Indirect techniques like countercurrent angiography of the brachial artery with the injection of 30 mL of contrast medium using high pressure, and contrast medium injection via a central venous catheter have been largely abandoned, as they do not offer any advantages over sectional image angiography with regard to image quality. Direct puncture of the vertebral artery is contraindicated due to the high risk of complications associated with intramural contrast medium injection. In the arterial phase of angiography, the origin of the vertebral artery from the subclavian artery is slightly constricted, also under normal conditions. Visualized in the further path of the vessel are the V1-segment up to its entry into the transverse foramen of the sixth cervical vertebra, the V2-segment in the homonymous “canal,” the arch of the atlas (V3-segment) between the second cervical vertebra and the foramen magnum, and finally the V4-segment until it unites with the contralateral vessel. From its cervical part, the vertebral artery sends muscle branches which anastomose with the other cervical arteries, principally with the external occipital artery. In the presence of embolizations in this region, these anastomoses have to be regarded as possibly “dangerous.” From the V4 section two meningeal branches supplying the dura mater originate extracranially, while the posterior inferior cerebellar artery (PICA) originates at a different level from an intradural location and divides, after a variable, loop-shaped course along the
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medulla oblongata, into two branches which supply blood to the basal parts of the vermis of the cerebellum and the cerebellar hemispheres. Small branches originating from the intracranial vertebral artery cross the lateral medullary fossa to supply the lateral medullary tegmentum and dorsal lateral base. The anterior spinal artery also originates from the V4 segment in a mostly asymmetrical fashion. Conversely, the anterior inferior cerebellar artery (AICA) branches off the proximal section of the basilar artery in the prepontine cistern and supplies the medial portions of the cerebellum; it also characterized by a vicarious relationship with the PICA and the more distally arising middle cerebellar artery. Angiographic depiction of the latter, as well as of the pontine branches, is possible only if the vessels are dilated due to the abnormally rapid rate of blood flow associated with arteriovenous malformations or fistulae, otherwise the vessels are too small to demonstrate. The superior cerebellar artery (SCA) arises in the distal segment of the basilar artery, frequently divided into two branches on one side. The cisternal segment of the artery winds around the midbrain and supplies the surface of the cerebellum, sending one branch to the superior vermis, one marginal hemispheric branch to the lateral fissure, and additional branches to the cerebellar convexity. At its tip, the basilar artery divides into the posterior cerebral arteries which proceed parallel to the superior cerebellar artery in the ambient cistern, i.e. rostral to the oculomotor nerve that travels in an anterior direction between these two arteries. The cisternal posterior segments (P1 and P2) are individually variably connected with the carotid siphon via the posterior communicating arteries and are therefore of critical importance for the basal collateral circulation (cerebral arterial circle [circle of Willis]). The thalamic perforating branches, as well as the medial posterior choroidal artery which proceeds to the plexus of the third ventricle, arise from the cisternal segment and require particular attention in the presence of basilar tip aneurysms. Increased vascular filling in the posterior cranial fossa occurs after an arterial phase of approximately 3 s and a long capillary phase of 2 s, a period during which vascular staining is observed only in pathological cases. The anterior and posterior veins of the cerebellar surface draining into the great cerebral vein (vein of Galen) and the tentorial sinus can be differentiated, as well as, in some instances, the veins draining into the transverse and sigmoid sinuses. Perimesencephalic and prepontine veins are further visualized, and parapontine imaging of the vein of Dandy draining into the superior petrosal sinus is accomplished. In addition to the blood flowing through the jugular foramen into the bulb of the internal jugular vein, which also receives blood from the inferior petrosal sinuses and occasionally from the occipital sinus, the occipital emissaries participate, as a variation, in the drainage of the intracranial space. Vascular drainage is further achieved via
the basilar plexus located intradurally on the clivus, and via veins in the neighborhood of the foramen magnum travelling to the internal vertebral venous plexus. The basilar venous plexus may also be responsible for prognostically benign perimesencephalic subarachnoid hemorrhage (SAH), in this case an aneurysm is generally not detected. The indication for diagnostic angiography of the vessels of the posterior cranial fossa is currently made in compliance with strict guidelines. While patients with malformations and tumors of the posterior cranial fossa previously also underwent angiography for the visualization of tumor vessels, or to at least enable the identification of the tumor location on the basis of the demonstrated arterial or venous displacement, today these examinations are carried out primarily in preparation for endovascular interventions. They become possible under certain prerequisites in the presence of vascular processes with stenoses and occlusions of the vertebral or basilar arteries. An investigation of the subclavian artery is further indicated when subclavian steal syndrome is suspected, as well as in cases of vascular malformations, primarily aneurysms, arteriovenous angiomas and dural AV fistulas. On occasion, conventional angiography is required for the preoperative identification of venous anomalies in the neighborhood of brainstem cavernomas, or of venous or sinus occlusions if CT angiography does not provide conclusive findings. Further indications include the confirmation of vasculitis, a disease which, comparable to degenerative vascular processes, is associated with arterial stenoses, although these may appear to be less punched out and can be accompanied by vascular dilatation. Angiography is also performed when intra-arterial treatment (thrombolysis or mechanical extraction of thrombi is considered as is discussed further below). Safety measures to be considered regarding the application of contrast media, especially in patients with a history of allergic reactions, have already been discussed in the section on computed tomography. The specific risk for neurologic complications associated with diagnostic cranial vessel angiography remains unchanged and ranges from 0.5% to 1%, despite the use of modern non-ionic contrast media with reduced osmolality and the technological improvements of catheters and guide wires (Willinsky et al. 2003). In addition to pareses, ataxias and eye movement disturbances represent the most severe complications in the vertebrobasilar system. The causes of these events may be small infarctions induced by embolic mechanisms that can be shown with diffusion weighted MRI in up to 20% of purely diagnostic angiographies, but remain in most cases clinically silent. The incidence of these lesions can be markedly reduced by using air bubble filters and heparinization of the contrast medium, as well as flush solution (Bendszus et al. 2004). Transient amnesia and cortical blindness may develop following infusion of larger contrast agent volumes in patients with the respective disposition, although these events
2.1 Neuroradiology
usually occur only after one or two successive injections. These complications have been interpreted as posterior encephalopathy on the basis of typical MR findings (Saigal et al. 2004). Radiation exposure is dependent upon the duration of angiography, and particularly on the screening time during cerebral interventions. The effective dose value for single interventions varies from 1.5 to 16 mSv, and may be in excess of 40 mSv for multiple procedures (Livingstone et al. 2003).
2.1.4.2 Endovascular Interventions Recanalization Recanalization is performed for vertebrobasilar stenoses and occlusions. These usually develop either as the result of a vascular wall lesion of atheromatous or inflammatory origin with localized thrombosis, or can be of atrial origin emboli due to dysrhythmia, septum defect, or generalized clotting disorders. The most common sites include the already relatively narrow origin of the vertebral artery from the subclavian artery, the intracranial V4 segment, as well as the entire course of the artery. The cervical vertebral segment may also very rarely be constricted from outside by osteophytes of the cervical vertebral joints. The symptoms, e.g. vertigo, can be provoked by certain neck or head positions. Vascular compression may also be caused by tumors like meningeomas or tumors of the base of the skull at the craniocervical junction. Further causes involving both the vertebral and carotid arteries include dissections with bleeding within the vascular wall, e.g. following whiplash injury or chiropractic maneuvers; they may also occur spontaneously in vascular wall disorders, e.g. fibromuscular dysplasia. A distinctive feature of this distribution area is the subclavian steal syndrome. It develops as a result of retrograde vertebral artery blood flow in response to high-grade proximal subclavian artery stenosis or occlusion. For the detection of vascular stenoses or occlusions, including those in the vertebrobasilar region, Doppler sonography represents the method of choice, followed by CTA or MRA techniques. Only when these do not provide a satisfactory confirmation of the tentative diagnosis, or if conflicting clinical findings are reported, can invasive conventional angiography be applied for diagnostic purposes. In the presence of proximal vascular processes, the origins of the vertebral arteries on both sides may be so severely narrowed that even short-term occlusions resulting from catheter insertion on one side are not tolerated. With a view to the possible development of brainstem ischemia, selective catheterization should be dispensed with for safety reasons, and the depiction of the vertebral artery should be attempted by means of a survey angiography of the subclavian artery, a
49
possibility to improve the quality in these cases is the simultaneous compression of the respective brachial artery manually or during blood pressure reading. Although this does not provide a high-contrast image, it is generally satisfactory to permit a conclusive diagnosis. In the setting of proximal vertebral artery occlusion, the depiction of the collateral supply via cervical branches of the subclavian artery – the ascending or the deep cervical artery – as well as of superior cervical anastomoses with the occipital artery may be required. Endovascular therapy for stenoses of the vessels responsible for blood supply to the brain was introduced in the 1980s. While this initially involved widening of stenoses at the carotid bifurcation and in the proximal section of the subclavian artery in the presence of a steal syndrome (Kachel et al. 1991), these interventions were later also successfully performed at the origin of the vertebral arteries and, more recently, also along the extracranial and intracranial course of the vertebral and basilar arteries. The therapeutic intervention is initiated by introducing a guide catheter over which a micro guidewire and a microcatheter can be advanced through the stenosis. After a exchange-maneuver, a balloon catheter is then passed over the microwire and inflated to dilate the stenosis. Subclavian artery occlusions can also be recanalized in this manner, provided a guidewire is successfully advanced through the occluded passage from the proximal or distal lumen of the vessel (after puncture of the brachial artery). The inflated balloon does, however, not only push atheromatous plaque into the vascular wall, but may also cause dissections and thus the risk of distal emboli affecting the entire vertebrobasilar system if they develop in the subclavian artery. Acute thrombosis of the dilated vascular segments represents a further, albeit rare complication. The administration of platelet aggregation inhibitors (acetylsalicylic acid, clopidogrel) before and after the intervention is therefore indispensable. With the use of these agents, subclavian artery interventions, also without additional stent applications, were reportedly associated with the recurrence of vascular occlusions in only 10% of cases over a 5-year postinterventional period. The prognosis for vertebral artery origin stenoses and intracranial artery stenoses after dilatation alone was less favorable, so that stenting was increasingly required to provide vascular wall support. In contrast to coil closure of aneurysms, where the stent serves to prevent coil loop prolapse into the parent vessel and wall stress in the artery is lower, stenoses have to be widened and patency of the lumen must be maintained. For this reason, primarily balloon-tipped models are mainly used for stenosis dilatation (Fig. 2.12). Vascular dilatation can be carried out after predilatation or concurrently with stent placement. Stents with a great radial force have to be employed in vertebral artery origin stenoses, similar to those used for renal artery origin stenoses, in order to ensure sustainable success. In the further course of the vertebral artery, specifically in the intracranial segment,
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Fig. 2.12 Dilatation/stenting for intracranial vertebral artery stenosis persisting under anticoagulation therapy. Vertebral artery angiography (a) before and (b) after stent application in the subtracted image, native image (c) with stent (arrows)
high-flexibility stents have to be used to avoid injury to the vascular wall during placement. Self-expanding stents for use in the intracranial territory are available today, although in some instances redilatation may be required. The risk for occlusion of the small arteries arising from intracranial segments of the vertebral and basilar arteries is apparently less high than initially assumed, due to the rare occurrence of ischemic complications in the area adjacent to the stent. This also applies to “overstenting” at the origin of larger vessels like the cerebellar arteries, which remain patent in the vast majority. The risk for complications associated with the intervention itself (ischemia, stent thromboses, bleeding) has been shown to range 9–15% (Weber et al. 2005; Kurre et al. 2010). Recurrences observed for coronary arteries unfortunately also occur in the cerebrovascular system. Six months after dilatation and stent therapy the incidence rate of intracranial residual stenoses ranged at 30%, while a rate of more than 40% was reported for extracranial residual stenoses, which were most frequently observed at the origin of the vertebral artery. These lesions were resymptomatic in more than a third of cases (SSYLVIA Study Investigators 2004). The therapy of vertebral artery origin stenoses may therefore be started by dilatation without stent placement and the intervention can be repeated should restenosis occur. A staged procedure has recently been proposed for therapy of intracranial stenoses where dilatation and stenting is performed at intervals of several weeks. Overall, stent-assisted dilatation for arteries supplying blood to the brain is an area undergoing continuing development of materials and application techniques, and therefore does not enable a concluding statement at this time. An evidence-based advantage of invasive therapy over conservative treatment has not been demonstrated in the available literature. The indication for stent-assisted dilatation of stenoses must thus be carefully considered. With respect to subclavian artery interventions it should be limited to patients with symptomatic steal syndrome, and in the presence of vertebral artery origin stenoses to patients with bilateral constrictions and ischemic symptoms persisting under anticoagulation therapy. The latter also applies to intracranial vertebral and basilar artery stenoses where collateralization via the posterior communicating artery does not infrequently occur.
Regarding the performance of acute dissections, reserve is also essential in judging the indication for interventional vessel dilatation, to prevent vascular wall bleeding from being pressed out with the subsequent danger of embolizations into distal regions. The thorough pre- and postinterventional therapy with thrombocyte aggregation inhibitors is indispensable for any stent application. A different situation is encountered in patients with acute occlusion of both vertebral arteries, or of the basilar artery due to the very poor prognosis for the spontaneous course, where the omission of lysis is known to result in a mortality rate of 40%, as well as in the need for constant care in two thirds of survivors (Schonewille et al. 2005, 2009). While embolism represents the most common cause in the distal basilar segment, in the proximal segment pre-existing stenosis with subsequent thrombosis may be the causative factor. The occlusion should be removed as early as possible due to the otherwise poor prognosis, whereby the local procedure has been the preferred measure for over 20 years compared with systemic lysis. Similar to supratentorial acute infarction, basilar or vertebral artery occlusions always represent a medical emergency. In the absence of a conclusive Doppler sonography finding, the diagnosis of vascular occlusion can be confirmed by CT or MR angiography. In contrast to middle cerebral artery trunk occlusion, the time limit to fibrinolysis has not been definitely defined and depends on the clinical condition: a rapid, invasive procedure in the presence of progressing symptoms, but reserve in patients with symptoms of several hours or prolonged infarctions. All other contraindications to lysis therapy, comprising bleedings, injuries, or prior surgical interventions, must self-evidently be observed. The optimal therapeutic procedure for this entity is still under intense discussion (Schonewille et al. 2009; SchulteAltedorneburg et al. 2009), the BASICS registry opened that field again. The intravenous versus the intraarterial use (with or without a bridging concept) of thrombolytic drugs is recommendable, the superiority of one of the concepts has not been thoroughly investigated. Intra-arterial lysis is performed via microcatheter with the infusion of urokinase (upto 1,000,000 IU) or recombinant tissue plasminogen activator (rT-PA upto 100 mg). Alternatively,
2.1 Neuroradiology
glycoprotein IIb–IIIa inhibitors can be used. In thrombolytic therapy, the tip of a microcatheter is either advanced to the proximal end of the thrombus or the embolus, or moved past this within the vascular lumen with the help of a guiding catheter; lysis is then achieved on slow catheter withdrawal. Despite the application of high doses, recanalization of the arteries can be expected in only 44–80% of cases, depending upon the volume of the thrombus and the time interval to onset of lysis. In addition, there is the danger of embolizations into the superior cerebellar and the posterior cerebral arteries. Mechanical thrombus removal is therefore frequently attempted, although with unpredictable success. Applied are wire loops, wire spirals and wire baskets for the retraction of an embolus, mechanical destruction using ultrasound or negative pressure (water jet pump effect), as well as “simple” aspiration via microcatheter, which is considered to be relatively effective, in particular in combination with preceding partial lysis (Fig. 2.13). The effectiveness of recent developments like mechanical thrombus fragmentation, brush-type microwires, and temporary stent insertion for acute therapy remains to be shown. Because proximal occlusions frequently occur in combination with stenoses, additional dilatation with stent application is recommended in these patients. A similar procedure is also possible for distal occlusions if lysis or mechanical thrombectomy is unsuccessful after a period of time. However, the paucity of currently available data does not permit a definitive statement on the success of this procedure. Critical prognostic factors include the patient’s clinical condition, and the latency to vascular recanalization (Eckert et al. 2002). For each intervention, additional bridging to the onset of therapy is possible with systemic administration of r-TPA or eventually glycoprotein IIb–IIIa inhibitors, and additional postinterventional heparinization over a minimum period of 24 h is requisite. Since platelet aggregation inhibitors further have to be given when stents are used, the anticoagulation regimen needs to be tailored to individual needs, to avoid provocation of intracranial bleeding. The reported survival rates for these invasive procedures currently range from 30% to 60%, while comparative independence was found in more than 50% of survivors (Pfefferkorn et al. 2005). The results of additional studies have to become available to ascertain if the results obtained
Fig. 2.13 Recanalization of an acute distal basilar artery occlusion. CTA (a) and DSA before (b) and after (c) recanalization. After only partially successful lysis with 10 mg rTPA, the residual (suspected embolic) material was aspirated via vertebral artery catheter. Residual posterior cerebral artery stenosis, right, and occlusion due to floated off emboli, left
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with this procedure are also improved according to evidencebased criteria over those obtained in patients undergoing conservative therapy or systemic lysis.
Embolization Embolization is a therapeutic option for the treatment of vertebrobasilar aneurysms, arteriovenous angiomas and dural arteriovenous fistulas comparable to conditions in the “anterior” circulation. two different types of aneurysms are observed in the posterior cranial fossa: berryshaped aneurysms that classically develop at the junction of vessels where they form a saccular pouch, and fusiform aneurysms formed along the wall of the vessel as the result of a vascular wall disorder (degenerative, inflammatory, or after dissection). In the majority of cases, the first type leads to typical subarachnoid hemorrhage (SAH), or may be an incidental finding, while the second type is more frequently associated with symptoms of brain stem or cranial nerve compression and potential SAH. Berry aneurysms of the vertebrobasilar system occur primarily at the tip of the basilar artery, with the aneurysm neck being located between the two posterior cerebral arteries, or between the posterior cerebral artery and the superior cerebellar artery, but less frequently at the origin of the PICA. They are rarely found at the origin of the AICA, or along the course of the basilar artery, the posterior cerebral artery, or the cerebellar arteries. Although they may occur in conjunction with arteriovenous angiomas. The incidence of vertebrobasilar aneurysm bleeding is markedly higher (1.8% p.a.) than in the anterior circulation, so that their therapy, including that of incidentally found aneurysms, is indicated for all sizes (Vindlacheruvu et al. 2005). After the occurrence of bleeding, emergency treatment should be commenced, due to the possibility of rebleeding, which places the patient at increased risk. Out of two competing therapeutic options, i.e. neurosurgical clipping of the aneurysm neck and endovascular coiling of the aneurysm sack, endovascular intervention in the posterior circulation has gained a certain advantage over clipping, because of the difficult surgical access to the principal
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locations. In the absence of very pronounced atherosclerotic changes in the vertebral artery, an aneurysm at the origin of the PICA, or at the tip of the basilar artery can be accessed via the endoscvascular route without major difficulties by experienced hands. Provided the aneurysm neck is small, a microcatheter is advanced to the site of the aneurysm and the aneurysm sack is occluded with detachable spiral coils (Fig. 2.14). Differently shaped coils consisting of platinum wires formed in the shape of a double helix are available for this procedure. The coils may be made of untreated metal, be coated with a hydrogel matrix, Dacron threads, or vasoactive substances. Separation of the coil from the delivery wire, which is retrieved later, can be achieved by electrolytic, thermic, or mechanical means. Coil occlusion is, however, more difficult to accomplish in wide-necked aneurysms, where the aneurysm neck can be occluded with a temporary balloon during coiling to avoid coil protrusion into the parent vessel (remodeling technique). An assistive stent can also be used for this purpose, and is a suitable device with great flexibility but relatively low thrust force that has been available for a number of years. The disadvantage of this method in an acute patient is the need for anticoagulation, which is mandatory after stent application but requires complete aneurysmal occlusion and leads to difficulties in
Fig. 2.14 Coil occlusion of a distal posterior inferior cerebellar artery aneurysm following acute subarachnoidal bleeding. DSA and 3D angiography (a, b) prior to and after (c) coiling of the aneurysm with visualization of the coil packet in the unsubtracted image (d)
the performance of subsequent procedures, e.g. the insertion of intraventricular drainage. The choice of the appropriate treatment option therefore needs to be agreed on in each individual patient by the neurosurgeon and the neuroradiologist. Reliable data on the benefit of one of these approaches over the other in the posterior fossa, in contast to the vessels in the anterior circulation, was not shown by the results of the ISAT study (Molyneux et al. 2002), due to the small number of patients with vertebrobasilar aneurysms included in the study. The decisive factor for the success of aneurysm coiling is the size, shape of the aneurysm sack and the configuration of the aneurysm neck. On average, therapeutic effective (sub) total occlusion can be expected in 80% of cases. The periprocedural complication rate of incidental aneurysms, without consideration of sequelae after bleeding, ranges below 5%. Coil compaction or widening of the aneurysm neck may lead to recurrence (~15%). Angiographic follow-up studies are therefore recommended after 6 months and 2 years; at these time points a re-coiling (Fig. 2.15) may be performed (Berkefeld et al. 2004). Recurrent bleeding occurred in 1% of
Fig. 2.15 Coil occlusion of a fusiform vertebral artery aneurysm left with brainstem compression. MRI with partially thrombosed aneurysm before intervention (a), vertebral DSA left before coil occlusion (b) and vertebral DSA right before a second intervention with recanalization and widening of aneurysm (c). After stent application via the vertebral artery right, and repeat coil occlusion of the distal aneurysmal segment (d)
2.1 Neuroradiology
cases during the first 12 months after coil occlusion, but developed less often after clipping. The findings of the ISAT study (Molyneux et al. 2002) showed a significant and durable better clinical result – at least in the anterior circulation – after the endovascular procedure than after neurosurgical clipping. Fusiform aneurysms of the vertebral or basilar arteries can lead to life-threatening brainstem compressions. The prognosis is also very poor in patients with vasodilatation developing after a dissection with intracranial bleeding. If an additional circumscribed saccular dilatation is present in the fusiform dilated segment, this can be treated with a neurosurgical or endovascular approach (using stenting and coils as in saccular aneurysms). Although coiling does not remove the space-occupying mass, it can reduce pulsations and thus lead to an improvement of symptoms. Occlusion of the entire dilated segment with clipping or coiling (trapping) represents a therapeutic alternative. In this setting, a balloon occlusion test has to be carried out prior to clipping/ coiling to ensure that the described occlusion will be tolerated. Another alternative is occlusion of one or even both vertebral arteries in the V4 segment to achieve a change in flow dynamics (although its form can not be accurately predicted) in an attempt to effect (partial) embolization of the aneurysmal lumen. The prerequisite for this procedure is, once again, adequate collateralization of the basilar artery via the cerebral arterial circle. Closed-wall stents (covered stents), very fine-meshed stents (flow-remodelling stents) and multiple telescoped intracranial stents are capable of blood flow modelling that enables extensive reconstruction of the original vascular lumen and thus offers further therapeutic options. Techniques like that were previously limited by the unsatisfactory flexibility of previously available stents (Saatci et al. 2004). Only 5–20% of cerebral arteriovenous angiomas or malformations (AVM) are found at an infratentorial location, with only 25% of these being situated in the brainstem. They may occur as part of a general “angiomatosis,” e.g. Osler’s disease, or Wyburn-Mason syndrome. They can become manifest most frequently in the form of bleedings and less often with neurologic deficits. Whether the tendency to hemorrhages is increased compared to the supratentorial location is controversially discussed. The precarious location renders both neurosurgical and endovascular interventions difficult, because not only misembolization into non-target arteries, but also perinidal edema and hemorrhages may occur after successful embolization. If an occlusion of the respective segment is nevertheless indicated in patients with rebleeding or progression of symptoms, and in view of the fact that the size of brainstem AVMs is generally in the favorable range of below 10 mm,
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stereotactic radiation represents the therapy of choice. However, the finding that post-therapeutic perinidal gliosis and rebleeding may occur until the time of definitive obliteration of the vessel after a period of up to 3 years has to be accepted. Successful embolization of brainstem AVMs has been reported in a small series of patients, in whom the usual procedure (injection of a N-butyl-cyanoacrylate [NBCA]lipiodol mixture into the nidus via microcatheter) was performed without significant complications, although complete obliteration was achieved in only one out of six patients (Liu et al. 2003). On principle, embolization is a factor which requires consideration in the decision on the therapeutic concept for brainstem AVMs. Comparable to pial AVMs, dural arteriovenous fistulae (DAVF) can cause bleeding and neurologic deficits, the latter developing as a result of venous reflux leading to edema and subsequent gliosis. DAVFs of the posterior cranial fossa are supplied by branches of the external occipital artery, the ascending pharyngeal artery, the medial and posterior meningeal arteries, as well as by the internal carotid artery (tentorial artery), that drain primarily into the sigmoid and transverse sinuses. In uncomplicated cases they may cause pulse-synchronous bruits in the ear. In cases of orthograde drainage (Borden Type I) there is no absolute need for therapy. In the presence of additional sinus stenoses, retrograde drainage into the cranial veins may develop (Borden Type II); this may further be observed in lesions located on the border of the tentorium. There may also be direct shunt drainage into the leptomeningeal veins (Borden Type III), which are then frequently characterized by circumscribed stenoses and widening (Szikora 2004). As space-occupying masses, the latter can cause brainstem and cranial nerve compression. Involvement of the cranial nerves is often associated with subarachnoidal or intracerebral bleedings, so that shunt occlusion must always be attempted when cranial nerves are involved. While a short-term improvement may be observed following transarterial embolization with particles, NBCA or OnyxR, the ramified vascular network can only less often be completely occluded with this therapeutic measure. Because the actual fistula points are mostly confined to a circumscribed region of the drainage vein, this region can be coil occluded via a transvenous approach, which enables complete obliteration of the fistula. Prior to this intervention it has to be angiographically confirmed that no other cranial veins drain into the segment designated for occlusion. This is of particular importance for fistula drainage into the transverse or sigmoid sinuses, whose occlusion could otherwise lead to bleeding due to passive hyperemia. Available alternatives to the endovascular approach in the therapy of DAVFs or incomplete fistula obliteration include neurosurgical interventions, e.g. “skeletization” of a sinus, or stereotactic radiation.
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2.2 Ultrasound Diagnostics Martin Eicke and Uwe Walter Ultrasonic diagnostic procedures of the brainstem have undergone continuous development over the past 20 years. The possibility of non-invasive identification of intracranial vertebrobasilar stenoses was first opened with the introduction of transcranial Doppler sonography in the mid-1980s. The advent of color duplex systems in the early 1990s saw the beginning of the age of accurate anatomic localization of intracranial vessels. The further development of duplex systems finally enabled transcending the boundaries of “classical” vascular ultrasound and placing image-morphologic aspects in the foreground of scientific research. The potential of this method has not yet been exhausted, in particular with regard to the therapeutic possibilities for extrapyramidal system diseases. The following chapter therefore discusses both the aspects of vascular ultrasound as the currently well established standard procedure and the possibilities of intracranial morphologic B-mode image diagnostics.
2.2.1 Vascular Ultrasound 2.2.1.1 Anatomic Principles Extracranial course: The origin of the vertebral artery (V0) is the preferred site of atherosclerotic plaque formation in this vessel and the entire posterior circulation. Endothelial rupture due to the physiologic presence of shearing forces and turbulences develops particularly frequently in this region and may lead to emboligenic stenoses in the further course. The hemodynamic risk of proximal stenosis or occlusion is relatively low, as extensive anastomoses usually provide sufficient distal vessel refilling via the contralateral vertebral artery or branches of the external carotid artery. The vertebral artery then travels craniad, anterior to the scalene muscle (prevertebral segment, V1) and enters the costotransverse foramen at the level of the sixth vertebra (transverse segment, V2). Distal to the foramen of the axis it initially curves at a 90° angle lateralward and runs again upward; after issuing from the foramen in the transverse process of the atlas the vessel bends backward at a right angle (V3). It finally curves medially and crosses the atlas via the vertebral artery sulcus (atlas segment, atlas loop); in this region the vessel is also predisposed to atherosclerotic changes and trauma, due to its pronounced tortuosity. The vertebral artery then pierces the posterior atlantooccipital membrane as well as the dura mater and continues in a rostral direction in the intracranial subarachnoidal space (intracranial segment, V4).
Intracranial course: The intracranial location of the vertebral arteries varies considerably, as significant side shifting may develop. The basilar artery arises at the confluence of the vertebral arteries and is approximately 30 mm long and 3 mm in diameter. In the majority of individuals the vessel courses rostrally in the midline, but in 10–20% of individuals extensive deviations to the right or left may be observed.
2.2.1.2 Principles and Techniques Three different system types are used in vertebrobasilar diagnostics: • Continuous wave (cw) doppler • Pulsed doppler sonography • Color duplex sonography
Continuous Wave (cw) Doppler This instrument evaluates the so-called Doppler shift, the frequency differences between the emitted and the reflected signal. According to the Doppler equation, this frequency difference is dependent on the relative speed of the reflector in relation to the probe on the one hand, and the emitted output frequency on the other hand. Frequency shifts resulting at the usual output frequency of 4 MHz and physiologic flow velocities of 10–200 cm/s, extend from 0.2 to 16 kHz, and are therefore within the audible frequency range of the human ear. The advantages offered by these instruments are that they are easy to handle, reasonably priced, and offer excellent sensitivity. Depth localization is not possible. Conversion of the frequency shift (kHz) to velocity values is not admissible in the presence of an unknown insonation angle. Examination technique: In particular segments V0 and V3 are amenable to examination with cw Doppler sonography. With the transducer held medial and caudal, V0 is imaged approximately 3 cm above the clavicle. The vertebral artery can be differentiated from other vessels in this region (particularly the common carotid artery, thyrocervical trunk) by the strong reverse Doppler effect on intermittent compression in the region of the atlas loop. Optimal visualization of V3 below the mastoid can be achieved with the patient’s head turned slightly to the contralateral side. In contrast to the internal carotid artery, the vertebral artery can typically be depicted with the flow towards the transducer as well as, with slight tilting of the transducer, away from it. While extracranial vessels like the occipital artery can be compressed by applying pressure to the vessel with the transducer tip, which leads to the loss of the Doppler signal, this is generally not possible (except in very slim patients) on insonation of the vertebral artery.
2.2 Ultrasound Diagnostics
Pulsed Wave Doppler Sonography (pw Doppler) Pw Doppler devices offer the additional option of depth allocation. Selective presetting of a time window of interest between transmission and reception enables analysis of the reflected signal from a specified depth window. One advantage among others is that a vessel can be followed along its course deep into the tissue. In vertebrobasilar ultrasound this procedure is particularly appropriate for V4/basilar artery examinations with the use of a low frequency 2 MHz transducer capable of deep penetration. Examination technique: The patient should be in a sitting (or supine) position and lower the chin as far as possible to the chest. The transducer is placed in the midline, approximately 3 cm below the occipital tubercle. On slight turning of the transducer, the right and left vertebral arteries can generally be differentiated at a depth of 60–70 mm, due to the availability of different spectral frequencies and pulsatilities. The vessels can frequently be imaged with bidirectional flow to a depth of 65 mm (atlas loop), and at greater depths only with flow away from the transducer. The vertebral arteries can serve as guide vessels to the basilar artery. In the evaluation, consideration must be given to the fact that the identification of the exact transition zone of the vertebral arteries and the basilar artery by means of pw Doppler can be made only with great reservations. Findings reported in the literature vary, depending on the application pressure, from 70 to 110 mm (!) (von Büdingen and Staudachet 1987; Ringelstein et al. 1990). It is therefore indispensable that a minimum depth of 100 mm is reached for secure identification of the proximal basilar artery. Complete visualization of the basilar artery to its division into the posterior cerebral arteries (tip of basilar artery) is possible in maximally 70% of cases, owing to deterioration of the signal-to-noise ratio. (von Büdingen and Staudachet 1987). A conversion of the frequency shift (Hz) into flow velocity is usually preferred by most sonographers on insonation of V4/basilar artery. The basis for this is the assumption that the insonation angle may be 10 mm) Normal situation
+
(+)
+
(+)
Idiopathic Parkinson’s disease
+++
+
+
(+)
Multiple system atrophy
(+)
–
+++
–
Progressive supranuclear gaze paresis
+
–
+++
+++
Corticobasilar degeneration
+++
+++
+++
–
Lewy body dementia
+++
+++
+
(+)
Frequency of abnormal findings in previous studies: – not found in any patient; (+) very rare; + low incidence; ++ frequent finding; +++ demonstrated in the majority of cases
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2 Diagnostic Imaging, Interventional Treatment of Brainstem Lesions and Electrophysiologic Diagnostics
Fig. 2.21 Electromyographic recording of a normal blink reflex obtained separately on either side after the respective supraorbital stimulation R1
0
R2
50 (ms) 100 Stimulation left, recording left
R2c
0
R1
R2c
0
(ms) 100 50 Stimulation right, recording left
ipsilateral region of the facial nucleus, in particular to the intermediate subnucleus (Marx et al. 2001). The exact course of the R1 reflex arc in the brainstem has been investigated by only a small number of experimental studies (Cruccu et al. 2005). The findings of clinical correlations and electrocoagulation studies in an animal model suggest a strictly ipsilateral dorsomedial pontine course with a close relationship to the principal trigeminal nerve nucleus (Ongerboer de Visser 1983). In humans, the frequent conjoint occurrence of R1-abnormalities and internuclear ophthalmoplegia is in favor of an anatomic proximity of the reflex arc to the medial longitudinal fasciculus. The bilaterally occurring late R2 response follows a polysynaptic reflex arc. After entry of the trigeminal afferents into the pons, the central fibers are assumed to descend together with the spinal tract of V from the dorsolateral pons to the level of the caudal pole of the hypoglossal nucleus in the medulla oblongata. After partial crossing at
50 (ms) 100 Stimulation left, recording right
0
R2
50 (ms) 100 Stimulation right, recording right
this level, they reascend through the propriobulbar segment of the reticular formation, medial to the spinal nucleus of the trigeminal nerve, bilaterally to the facial nucleus region (Cruccu et al. 2005. The fibers ascending to the ipsilateral facial nucleus may be located more laterally than those coursing to the contralateral nucleus (Tackmann et al. 1982). The central R2 reflex arc is subject to suprasegmental hemispheric and mesencephalic control. Both a supratentorial lesion and a disturbance of consciousness can influence the occurrence of the R2 response. The R2 response further habituates after multiple stimulations.
2.3.1.2 Clinical Application The supraorbital nerve is usually stimulated separately on both sides by means of surface electrodes placed on the
2.3 Electrophysiologic Diagnostics
63 Table 2.4 Upper limits of normal of blink reflex components published for different patient collectives Investigator Component Absolute Side differences latencies (ms) (ms)
Fig. 2.22 Technique for eliciting the blink reflex on supraorbital stimulation
supraorbital foramen (Fig. 2.22). The stimulation cathode should be positioned above the foramen, with the stimulation anode approximately 2 cm above it and rotated slightly laterally, to avoid transfer of the stimulation current to the contralateral side. If the infraorbital segment of the trigeminal nerve is to be examined, the stimulation cathode is placed on the infraorbital foramen above the exit point of the nerve, and the stimulation anode is positioned about 2 cm below. Stimulation is applied with supramaximal rectangular impulses of 0.1 ms, at an intensity of 3–20 mA. The stimulation strength can be increased until a stable maximal electromyographic response is obtained. The patient’s eyes should be closed lightly. The stimuli are applied at interstimulus intervals of at least 10–20 s to avoid habituation of the R2 response (Kimura 1989). The stimulus responses of each orbicular muscle are recorded separately on either side using surface electrodes. The different lead electrode is positioned directly below the lower eyelid, at an approximate mid-position between the inner and outer orbital border, the indifferent electrode is placed in the temporal region at the lateral orbital border. An additional ground electrode can be affixed submentally or to one forearm. Filter limits are usually set at 20 and 3,000 Hz. Measured are latencies from the trigger signal to initiation of the evoked reflex response. A minimum of five successive reflexes are recorded and evaluated for this purpose. Applying this technique, supraorbital stimulation evokes an ipsilateral R1 response and bilateral R2 responses in all healthy subjects. Defined as pathologic are • The absence of individual reflex components • Absolute latency prolongations above the upper limits of normal • Side to side latency differences above the upper limits of normal Pronounced intra- and interindividual amplitude fluctuations are usually not considered in the evaluation.
Kimura (1975)
R1 R2 R2c
1,000/mL, lactate ↑ and glucose ↓: bacterial infection likely – Cell count 0.7
↓
Normal
Normal
Lactate (in mmol/L)
3.5
Normal
Normal
Cell count per mL
1,000
10–1,000
Normal to mild
Granulocytic
Lymphocytic
Pleocytosis Cell picture
The use of the appropriate analytical method usually enables confirmation of the diagnosis. Cerebrospinal fluid analysis is also a valuable tool in monitoring the course of disease and the efficacy of therapy. Normal cerebrospinal fluid findings are contrasted with findings in inflammatory and infectious diseases in Table 4.9. Cytologic evaluation of cerebrospinal fluid enables differentiation of cells after staining. Neutrophilic granulocytosis is an indication of acute bacterial inflammation (although it may also occur in the initial phase of a viral infection). A lymphocytic cell picture (lymphocytes and plasma cells) is commonly found in viral inflammations. A mononuclear transformation (monocytes and macrophages) usually occurs in the postacute phase. In a suspected acute bacterial infection (meningococci, pneumococci, staphylococci), a gram stain standard or bacterial quick-test (for meningococci, pneumococci and Haemophilus influenzae) should be attempted. While eosinophilic granulocytes are normally not found in cerebrospinal fluid, they are frequently identified in parasitic infections. Although the use of Ziehl-Neelsen staining is expedient in the demonstration of tuberculous meningitis, it is nevertheless strongly dependent on the total number of pathogenic organisms and therefore often has only a low sensitivity. If opportunistic infections are suspected, the possibility of mycotic infection has to be considered. Cryptococci are readily confirmed by using the India ink method (sensitivity 80–90%). The microscopic detection of candidiasis and aspergillosis can usually be accomplished with methylene blue staining. Confirmation of the diagnosis is, however, frequently achieved only by culture of the organisms. With regard to differential diagnosis, the cerebrospinal fluid sample should always be tested for the presence of malignant cells (tumor cells, lymphoma cells; detection rate 50–70% at the initial examination). In analogy to blood cultures in infectious diseases, a cerebrospinal fluid culture (approx. 5 mL in aerobic blood culture bottle) should routinely be performed in conditions involving the CNS. Today, the majority of pathogenic organisms can be shown based on the formation of specific antibodies (IgM and IgG)
(immunological detection of causative organisms). The so-called Reiber’s graph shows the cerebrospinal fluidserum-ratio and reflects the relationship between the bloodbrain barrier disturbance and intrathecal antibody synthesis (IgG, IgM, IgA). The diagnosis of a CNS infection can only be established based on demonstration of specific intrathecal antibody production. The antibody specific index (AI) according to Reiber has become widely used in cerebrospinal fluid analysis. Concurrent serum sampling is required to determine the AI. The antibody index is a mathematical value calculated – in the presence of a normal cerebrospinal fluid-serum IgG ratio – from the cerebrospinal fluid-serum ratio of specific antibodies and the cerebrospinal fluid-serum ratio of the total IgG. Pathogen-specific intrathecal antibody production is demonstrable at an AI > 1.5. Antigen detection using polymerase chain reaction (PCR) represents a rapid, reliable (sensitivity 75–95%), and relatively cost-effective method, that is particularly useful in viral CNS diseases. The humoral antibody response may be inadequate in the acute phase of a viral disease, so that only the direct DNA or RNA finding enables establishment of the diagnosis. PCR is indicated without exception when • Microscopy, culture and serology are imprecise or inadequate • The results of the culture are incompatible with the clinical symptoms and do not match the expected spectrum of causative agents • Immunosuppressed patients are affected by viral disease Table 4.10 contains information on the practical application of cerebrospinal fluid analysis.
4.2.1.6 Diagnostic Imaging Brain imaging represents the second most important diagnostic tool after cerebrospinal fluid analysis in patients with inflammatory brainstem processes. The method of choice in
4.2 Inflammatory Brainstem Diseases Table 4.10 Information on the practical application of cerebrospinal fluid (CSF) analysis • CSF sampling prior to onset of therapy; ensure aseptic sampling conditions (to avoid contamination). • Sufficiently large sample should be taken for CSF chemistry + cytology + serology + culture (poss. consultation with laboratory!) • No “untargeted” centrifugation → cell destruction! • CSF analysis as close as possible to sampling (90%); HSV-2 is more often responsible for the occurrence of benign lymphocytic meningitis (e.g. Mollaret’s meningitis). CNS infection with HSV-1 involves primarily the temporobasal and frontobasal cerebral parenchyma and causes focal encephalitis. Isolated HSV-associated brainstem encephalitides are rare. Clinical symptoms depend chiefly on the location of the inflammation. The most prevalent anamnestic and clinical primary symptoms include fever, headache, and an impaired level of consciousness. The classic temporal HSV encephalitides are frequently associated with personality changes. Various focal neurologic deficits, cranial nerve deficits, seizures, and increased cranial pressure may be present. Hemorrhagic parenchymal necrosis can be observed.
Primary varicella zoster virus infection can occur in the form of a systemic infection (chickenpox, or herpes zoster), or manifest as a secondary infection due to reactivation of the virus. Immunosuppressed and chronically ill individuals, as well as children are at a particular risk for infection. The clinical picture and the course of the encephalitis are similar to that observed in other encephalitides. In addition to focal neurologic deficits and disturbances of consciousness, an acute cerebellar ataxia may be present in cerebellitis, as well as signs of myelitis and zoster radiculopathies and zoster neuralgias. Of importance from a differential diagnostic point of view is the VZV-associated unifocal vasculopathy (large-vessel granulomatous arteritis), which may clinically mimic an encephalitis, but is commonly characterized by a more subacute course.
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The diagnosis of VZV infection is made using PCR and the specific Antibody Index. The therapy is similar to that of HSV encephalitis.
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The diagnosis is established based on the clinical picture with vesicular skin alterations and mucosal ulcerations, and demonstration of antibodies or DNA in the cerebrospinal fluid using PCR assays.
Cytomegaly Virus (CMV) In addition to severe prenatal and perinatal encephalitides, CMV infection represents one of the most common opportunistic infections (after organ transplants and, most importantly, in advanced HIV disease) in immunosuppressed patients. The disease is characterized by an acute to subacute course. Neurologic complications manifest predominantly as severe encephalitis with a lethal outcome, or chorioretinitis, myelitis, and polyradiculitis. Focal neurologic deficits and signs of isolated brainstem inflammations are rare, more frequently observed are psychiatric complaints (DD: AIDS dementia complex), including confusion, apathy, and slowing of mental processing (Griffiths 2004). The diagnosis is established by means of antibody antigen identification (PCR) from cerebrospinal fluid. For the treatment of CMV, ganciclovir (2 × 5 mg/kg BW i.v.) can be used, alternatively or in combination also foscarnet (initially 2 × 90 mg/kg BW/day i.v., maintenance therapy 90–120 mg/kg BW/day i.v.) or cidofovir (5 mg/kg BW i.v. 1 × per week).
Poliomyelitis Virus Although the infection does not now play a major role in European countries, where it was brought under control with the use of effective vaccines, an emerging vaccine fatigue gives rise to fear of a possible resurgence of the disease. The incidence of poliomyelitis is particularly high in children and young adults in developing countries. More than 90% of the infections have an asymptomatic clinical course, or are associated with only minor gastrointestinal or respiratory symptoms. CNS involvement can manifest as aseptic meningitis, encephalitis or rapidly progressing myelitis or radiculitis. Most infected individuals develop flaccid paralysis of the extremities (legs > arms). Complicated clinical courses may be associated with respiratory insufficiency and involvement of the cranial nerve motor nuclei, so that approximately 10% of patients require intensive care management. The diagnosis of acute anterior poliomyelitis is supported by the typical course of disease and a fourfold increase in anti-polio antibodies. The direct culture of virus from cerebrospinal fluid is expensive and time-consuming, and therefore represents a diagnostic method of second choice.
Enterovirus Infections Myxovirus Infections Coxsackie and ECHO virus Clinically, these infections frequently manifest as an “influenzal infection”. In Central Europe the Coxsackie and ECHO viruses are the most common causative organisms of meningitis with a mild course (“cold of the brain”, herpangina, gastroenteritis, meningeal irritation). A polio-like clinical course is occasionally observed. Meningoencephalitides or isolated encephalitides are rare. The diagnosis can be made following the detection of specific antibodies or virus DNA (PCR) in cerebrospinal fluid. The therapy with pleconaril still lacks regulatory approval. Enterovirus 71 In 1998, this virus last caused endemic hand, foot and mouth disease in several thousand children in Taiwan. Neurologic involvement, primarily in the form of brainstem or rhombic encephalitides, was reported and described as being associated with a poor prognosis and a mortality rate of approximately 15% (Huang et al. 1999).
easles Virus, Mumps Virus, Influenza A and B Virus, M Parainfluenza Virus These viruses frequently cause parainfectious encephalitis with a benign clinical course and generally very good prognosis. Measles encephalitis may, however, have a severe course with coma and extended parenchymal defects (in up to 50% of patients), and be associated with a mortality rate from 10–20% in patients with a fulminant clinical course. In the discussion of measles infections consideration has to be given to the very rare condition of subacute scleroting panencephalitis (SSPE; synonym: Van Bogaert’s leucoencephalitis; incidence 1: 1,000,000). Affected are primarily children and adolescents after measles infection. SSPE has a progressive clinical course leading to death. The diagnosis is established based on the positive measles antibody index in the cerebrospinal fluid. Serologic diagnostic methods are available for all described myxoviruses (IgM and IgG antibodies, including the antibody-specific index). Definitive diagnosis can be made using PCR with demonstration of the virus DNA.
4.2 Inflammatory Brainstem Diseases
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Nipah Virus
Togaviridae Virus
The Nipah virus was discovered in 1999 during the investigation of a severe encephalitis epidemic among pig farmers in Malaysia and Singapore. The infection is caused by contact with the affected animals. It usually manifests with general symptoms (fever, headache, vomiting); patients with CNS involvement also show disturbance of consciousness, myoclonas, areflexia, cranial nerve deficits, while circulatory dysregulation (hypotension, hypertension, tachycardia) occurs in patients with brainstem involvement. The detection of antibody in cerebrospinal fluid can be used to make the diagnosis. The mortality rate is about 30% in patients with a complicated clinical course (Goh et al. 2000).
The West Nile virus is mosquito-borne; the encephalitis caused by the virus is mostly endemic (USA, Africa, Europe). The St. Louis encephalitis virus is found primarily in regions of North, Central and South America; it is spread through mosquitoes, and affects mainly older adults. The Japanese encephalitis virus is responsible for several thousand encephalitides in children from different Asian countries every year. Clinically, nonspecific general symptoms are initially observed in the three viral infections. Encephalitis with brainstem involvement occurs in approximately 60–70% of patients. The CNS disturbance can be associated with disturbances of consciousness, seizures, poliomyelitis-like paralyses, and parkinsonoid motor disturbances. Diagnosis is based on demonstration of virus-specific antibodies (IgM using ELISA) and detection of the virus in the cerebrospinal fluid by using PCR. The prognosis is significantly dependent on the localization of the lesion. Courses with a fatal outcome have been described in 10–30% of patients. Rubella virus encephalitis frequently manifests as a parainfectious disease and is usually characterized by a mild course. Comparable to measles encephalitis, complicated clinical courses may be accompanied by parenchymal defects and severe neurologic deficits (coma, cranial nerve deficits, seizures). The diagnosis of rubella virus encephalitis is established with the demonstration of antibodies in cerebrospinal fluid. A specific therapy is lacking. The reported mortality rate ranges at approximately 10%. The California virus is endemic in the USA. The infections affect mostly children and are frequently associated with seizures, although the prognosis is generally good. The Eastern equine encephalitis virus is endemic in East and Central American regions and is mosquito-borne. The disease is characterized by a mortality rate from 30–80%. The Western equine encephalitis virus occurs in Western Pacific regions, and is also spread through mosquitoes. At a mortality rate of 30 mmHg systolic or 15 mmHg diastolic after 3 min) • Urinary incontinence or incomplete bladder voiding, alone or in combination with erectile dysfunction in males Domain 2: Parkinson syndrome (parkinsonism) • Bradykinesia • Rigor • Postural instability (not caused by a disturbance of visual, vestibular, cerebellar, or proprioceptive function) • Tremor (resting tremor, postural tremor, or both) The criterion for the presence of parkinsonism is fulfilled, when bradykinesia and a minimum of one of the features 2-4 is identified.
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Onuf’s nucleus in the spinal cord and to neuronal death in the pontine micturition center. The essential neuropathologic criterion for the diagnosis of MSA is the demonstration of glial cytoplasmic inclusions. These comprise a-synuclein, ubiquitin, and tau-positive inclusions identified in the oligodendrocytic cytoplasm and nucleus, as well as in the neuronal nucleus, cytoplasm, and axon. The demonstration of a-synuclein has led to classification of MSA as an a-synucleinopathy. Lewy bodies are, however, not found in this clinical picture. The death of central or preganglionic autonomic neurons is responsible for the autonomic dysfunction in MSA, while the autonomic disturbances in Parkinson disease are mediated by damage to postganglionic nerve cells (Oertel and Möller 2005).
Domain 3: cerebellar disturbances • Gait ataxia • Dysarthria (ataxic) • Limb ataxia • Sustained gaze-evoked nystagmus The criterion for the presence of cerebellar dysfunction is fulfilled, when gait ataxia and a minimum of one of the features 2-4 is identified. Domain 4: corticospinal tract disturbance • Positive Babinski’s sign combined with pathologically increased muscular proprioceptive reflexes Pyramidal tract signs do not constitute a criterion for the diagnosis of MSA Evaluation Possible MSA • One criterion plus two features from two separate other domains; in parkinsonism a poor response to levodopa qualifies as one feature, so that only a second feature is required Probable MSA • Criterion for autonomic disturbance plus poorly levodopa responsive parkinsonism or cerebellar disturbance Definite MSA • Only on pathologically confirmed high density of glial cytoplasmic inclusion bodies in association with a combination of degenerative changes in the nigrostriatal olivopontocerebellar pathways Exclusion criteria for the diagnosis of MSA • Onset of symptoms under 30 years of age • Positive family history • Systemic diseases or other identifiable causes for symptoms according to domains 1-4 • Hallucinations unrelated to medication • Diagnostic-Statistic-Manual (DSM) criteria for dementia • Prominent slowing of vertical saccades or vertical supranuclear gaze palsy • Signs of a focal cortical dysfunction such as – Aphasia – Alien limb sign – Parietal dysfunction • Metabolic, molecular genetic or imaging confirmation of an alternative causes for symptoms according to domains 1-4
4.7.4.3 Clinical Findings Up to 41% of MSA patients have autonomic nervous system disturbances in the initial stage of the disease. A determining factor for the diagnosis in males is impotence, which may have been present for a number of years prior to the diagnosis, or urinary incontinence in both males and females. Other important questions relating to the patient history include orthostatic hypotension which may, e.g. manifest as extreme dizziness and/or syncope after sudden standing. Other characteristic features of MSA are atypical irregular resting, postural and/or kinetic tremor (60% of patients), as well as stimulus sensitive myoclonus and dystonias (46% of patients, 25% of whom have antecollis; Quinn 2005). Suggestive of brainstem dysfunction is the diagnosis of REM sleep disturbance in almost 90% of MSA patients, which can precede the manifestation of MSA by several years (Iranzo et al. 2005). The chiefly nocturnal inspiratory stridor in MSA may be a further indication of brainstem dysfunction (Vetrugno et al. 2007). Patients with MSA-P usually do not show a long-term response to L-dopa therapy. In the early stage, up to 30% of patients may show a favorable response to dopaminergic substances, while a positive L-dopa response is observed in 10% of patients in the advanced stage. It is therefore recommended to determine the response to L-dopa with the use of a standardized protocol. According to UPDRS part III (Unified Parkinson’s Disease Rating Scale = motor part) criteria, a positive reaction to L-dopa is defined as a 30% improvement following a 3-month course of therapy with a minimum dose of 1,000 mg L-dopa.
4.7.4.4 Diagnosis The diagnosis of MSA can be made clinically based on consensus criteria, but a number of these criteria can be clarified only in the course of the disease (Table 4.26). Available data records documenting the sensitivity and specificity of individual, or a combination of additional
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investigations are insufficient for the differential diagnosis of possible MSA, i.e. early parkinsonism. MRI may be regarded as the most useful examination in clinical practice. It often enables detection of basal ganglia and brainstem disturbances in vivo. Possible changes visualized on T2-weighted cranial MRI are in particular hyperintensities and hypointensities of the putamen, a hyperintense margin on the border between the putamen and the claustrum, in addition to the so-called hot cross bun sign within the pons. In addition to routine MRI examinations, MRI-based volumetry of the striatum and brainstem, diffusion-weighted MRI, as well as MIBG scintigraphy and sonographic imaging of the brain parenchyma may be helpful in the differential diagnosis of a parkinsonian syndrome (Wenning et al. 2004). The extent to which these techniques will become established routine diagnostic procedures remains to be seen. Electromyography with the demonstration of external anal sphincter muscle denervation has been proposed as a diagnostic measure for the differentiation of MSA from other parkinsonian syndromes. Pathologic spontaneous activity has, however, also been reported for PSP and advanced Parkinson’s disease. Positive results may also be observed, e.g. after transabdominal prostatectomy, other surgical interventions in the pelvic region, and in multiparous women, so that this examination must be viewed critically (Giladi et al. 2000). 4.7.4.5 Differential Diagnosis MSA is most frequently confused with Parkinson’s disease or progressive supranuclear palsy (PSP). A mild limitation of upward gaze is non-specific and may also be observed in MSA-P. In addition to the classic signs defined in the consensus criteria (Table 4.26), such as autonomic disturbances, cerebellar and pyramidal tract signs, as well as a poor response to dopaminergic stimulation, the following symptoms are important criteria for the diagnosis of MSA-P: • Early gait ataxia in the absence of dementia (in contrast to PSP) • Frequent falls • Early need for wheelchair use • Rapid disease progression • Prominent hypophonic dysarthria • Pain unresponsive to L-dopa • Arterial hypertension (supine position) • Contractures • Affective incontinence • Violaceous or cold extremities unrelated to the intake of medication Sporadic and familial late onset ataxias constitute the most important differential diagnosis of MSA-C. Patients within
4 Diseases
the group of autosomal dominantly inherited spinocerebellar ataxias are also part of the differential diagnosis. (Wenning et al. 2004; Oertel and Möller 2005).
4.7.4.6 Therapy In contrast to patients with Parkinson’s disease, approximately two thirds of MSA-P patients show no, or only a poor response to L-dopa therapy. A slight effect is generally more readily observed when the substance is discontinued. The remaining third showed a moderate to good response to L-dopa. Comparable to patients with Parkinson’s disease, about 10% of all patients with MSA report an improvement in symptoms. Up to 13% of patients with advanced stage MSA continue to show a favorable response to L-dopa. As a rule, all types of responses to L-dopa are diminished over a period of 1–2 years. The favorable response to L-dopa in up to one third of all MSA-P patients justifies a therapeutic attempt with a sufficiently large daily dose (1,000 mg). In very rare cases, MSA patients who do not show any response to an adequate dose of L-dopa report improvement following the administration of dopamine agonists. In order to prevent worsening of the orthostatic hypotension, domperidone cover should be considered in determining the appropriate dose of L-dopa or dopamine agonists. Amantadine represents a therapeutic option in the absence of a clinical response to either L-dopa, or dopamine agonists. Even low dose dopaminergics (e.g. 50 mgL-dopa) can produce severe craniocervical dystonias in patients with MSA. The therapeutic challenge in these patients consists of giving a dopaminergic dose sufficiently large to alleviate limb akinesia without compromising the speech and swallowing disturbances due to dystonia. An option in the presence of focal dystonias is the injection of botulinum toxin. The therapy of inspiratory stridor with botulinum toxin is difficult. Good results have been reported for long-term therapy with CPAP (Iranzo et al. 2004). Initial measures in the treatment of orthostatic hypotension include elastic compression stockings, increased salt intake, and elevating the head of the patient’s bed. Drug therapy with appropriate doses of midrodrine (Gutron®) and/or long-term therapy with fludrocortisone (Astonin-H®) may be helpful in patients who remain symptomatic. Desmopressin (Minirin®) can be effective in patients with nocturnal polyuria (Suchowersky et al. 1995). Exacerbation of orthostatic hypotension is known to occur in MSA patients receiving sildenafil (Viagra®) for erectile dysfunction (Hussain et al. 2001). Peripherally acting anticholinergics as, e.g. oxybutynin can be useful in the treatment of urinary incontinence, but are a frequent cause of increased urinary retention.
4.7 Degenerative Brainstem Diseases
4.7.4.7 Prognosis The median survival time from symptom onset is approximately 9 years (range: 2–17 years). Pneumonia is the most common cause of death in MSA patients. The median age at death reported for 48 out of 100 patients originally included in the study was 65 years (Wenning et al. 2004).
4.7.5 Tremors Tremor represents a common and complex clinical problem with either direct (Holmes’ tremor, palatal tremor) or indirect (pathophysiology of essential tremor) brainstem involvement. Tremor therefore represents either a characteristic psychophysiological phenomenon (e.g. fear), or can manifest as a symptom of a large number of neurologic and medical diseases (e.g. thyroid disorders). Tremor can also be an undesirable effect of a great number of medications (e.g. lithium, virtually all psychopharmaceuticals, betasympathomimetics). Diagnostic classification is crucial in the selection of effective therapy. In particular in patients with tremor, the decision on further therapeutic procedures often has to be made based alone on the results of both a thorough medical history and neurologic examination. Nevertheless, misdiagnoses with farreaching consequences are not uncommon. Essential tremor is often misdiagnosed as Parkinson’s disease and the patients may occasionally be subjected over a number of years to an ineffective, expensive treatment, or even to antiparkinsonian therapy leading to the development of serious side effects. 4.7.5.1 Epidemiology The incidence rate of tremor, independent of etiology, is about 20% in patients older than 65 years (Bennett et al. 1996). Depending on the results reported by different studies, 0.31–1.7% of the population suffer from essential tremor. The prevalence increases significantly with age (5.5% after age 40; 12.5% in patients older than 70 years). Tremor can be seriously debilitating and lead to complete social withdrawal. Many affected individual do not seek professional advice, because “shaking” is frequently regarded as part of the “normal” aging process. Tremor does, however, not only affect older individuals. In addition to a peak incidence for the onset of essential tremor in the 6th decade of life, a further peak in incidence occurs in the 2nd decade of life. 4.7.5.2 Etiology The neuropathology of Parkinson’s disease is well described in the literature. In contrast to hypokinesia as the cardinal
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symptom, tremor is considerably less well understood. No abnormal neuropathologic findings have thus far been reported for essential tremor, the most common type of tremor. A dysfunction in the pathways between the cerebellum, basal ganglia, thalamus, and the sensomotor cortex, in particular between the olive, red nucleus, and the cerebellum, has been hypothesized. Symptomatic tremor types, such as Holmes’s tremor, or secondary palatal tremor with olivary hypertrophy are suggestive of involvement of many different structures from the thalamus to the basal ganglia and the brainstem. Holmes’s tremor, the prototype of tremor conditions according to the pathophysiologic understanding of tremor will be discussed briefly. Holmes’s tremor combines a parkinsonian resting tremor with an action and postural tremor that may occur as the result of a cerebellar lesion and in severe cases of essential tremor. Several of its aspects correspond to findings in animal models of tremor. It has been shown that a resting and intention tremor in monkeys can be induced only by the concurrent occurrence of a lesion to the cerebellothalamic pathways and an injury to the nigrostriatal pathways in the brainstem. An additional prerequisite is a lesion to parts of the red nucleus. Indications of an involvement of both the cerebellothalamic and nigrostriatal systems have further been noted in humans. In most cases tremor is classified as symptomatic. The most frequent causal factors include brainstem/cerebellar injuries (Benedikt’s syndrome), olivopontocerebellar atrophies, and injuries to the brainstem, the midbrain, or the thalamus. In Parkinson’s disease it can occur if additional brainstem lesions are present. The majority of all posttraumatic tremors after midbrain compression also fall into this category, or can be classified as cerebellar tremors. 4.7.5.3 Clinical Findings Tremor is by definition a movement disorder, characterized by rhythmic, oscillating (sinusoidal) muscle movements of similar amplitude. The movements are attributable to either reciprocal alternating or synchronous contractions of antagonistic muscles. Tremor can be classified according to its etiology, activation conditions, and topologic distribution. Of particular clinical importance is the differentiation between the activation conditions for resting and action tremor (postural and kinetic tremor), since a resting tremor (with 4–6 Hz) is characteristic of parkinsonism and requires a fundamentally different therapy from essential tremor treatment, one of whose cardinal symptoms is a postural tremor. The discrete fine postural and action tremor found in the extremities of healthy individuals is described as physiologic tremor. It is heightened under conditions of physical exhaustion, anxiety and strong emotions. Caffeine, asthma medications, such as theophylline and betasympathomimetics as, e.g.
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salbutamol, are classic examples of pharmacologic enhancers of physiologic tremor. According to current knowledge, physiologic tremor may also be enhanced by lithium, amphetamines, caffeine and steroids, making the phenomenologic differentiation from essential tremor impossible. This tremor is a rapid small amplitude flexion/extension motion of the outstretched fingers. Essential tremor is a generally monosymptomatic, slowly progressive clinical picture without additional neurologic findings. Psychosocial stress exacerbates the symptoms. The arms are most frequently affected (90%), followed by the head (50%), the voice (30%), the legs and the chin (15%). The handwriting becomes illegible and activities like drinking from a cup are increasingly difficult. The patient may be forced to hold the cup in both hands, or use a straw as a drinking aid. This tremor is best seen by holding the arms outstretched and flexed in a so-called bat wing posture. The tremor usually has a rotatory motion. The tremor often increases on intention movements for example touching the finger and then the nose. Patients with an unfavorable course may find it impossible to eat soup with a spoon, or sign a document. Individuals with certain occupations (e.g. dentists, surgeons, precision mechanics) have to undergo occupational retraining or take early retirement. Familial tremor occurs in roughly 50% of patients. Individually different amounts of alcohol may lead to a substantial transient decrease in shaking in approximately 50–70% of patients with essential tremor. The tremor regularly rebounds, however, when the alcohol has been metabolized after 3–4 h. Sensitivity to alcohol serves as a differential diagnostic indicator of essential tremor. Essential tremor in the elderly is often described as “senile tremor”. This description is both obsolete and misleading, as it is suggestive of an independent tremor entity. A detailed examination enables the differential diagnosis of a resting and/or postural tremor also in elderly patients. In patients with mixed syndromes, atypical variants of essential tremor, or an early parkinsonism may be assumed if a preexisting essential tremor is suspected. Neuroleptics are often identified as causal factors. The so-called dystonic tremor affects primarily the head or the hand, manifesting as a tremorous spasmodic torticollis or writer’s cramp. It usually arises more irregularly than essential tremor and shows a similar favorable response to botulinum toxin as essential head tremor. In addition to rare tremors occurring in neuropathies, a number of additional tremor forms, e.g. resting tremor, exist in the context of parkinsonism. Holmes’s tremor is often referred to by a number of different names (midbrain tremor, myorhythmia, rubral tremor, brachium conjunctivum tremor, Benedict’s syndrome). The new nomenclature avoids inappropriate topographic definitions and is reminiscent of the scientist who
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first described this tremor, Gordon Holmes. The tremor is characterized by • A combination of resting, action, and postural tremors • Low tremor frequency (2.5–5 Hz) and • A typical latency period from the underlying brainstem and cerebellar injury to the occurrence of the tremor, provided the time of the injury can be defined (e.g. brainstem insult) The latency period may be from days to years. The clinical symptoms of this tremor can be subsumed under the combination of a parkinsonian-like resting tremor and cerebellar intention tremor. The patients often exhibit additional signs of brainstem and cerebellar damage. In particular the proximal sections of the arms are affected. The very lowfrequency Holmes’ tremor is frequently irregular and less rhythmic than other forms of tremor. The patients are seriously disabled by the tremor. The affected extremities generally become unusable. Both sides may be involved depending on the extent of the damage. Palatal tremor was formerly called palatal myoclonus or palatal nystagmus, although it meets all criteria for tremor. With consideration of the pathophysiologic mechanisms it may even be defined as the prototype of a tremor per se. It has since been shown that two variants can be differentiated: • Symptomatic palatal tremor occurs after damage to the dentate-olivary pathways, it is associated with typical pseudohypertrophy of the inferior olive; the responsible muscle is the levator veli palatini muscle. The patient complaints are generally attributable to brainstem and cerebellar injuries, while the tremor is often an accidental finding of the clinical examination. Only if additional muscles are involved in the hyperkinesia, tremor-related complications arise as a result of oscillopsy, when pendular nystagmus develops synchronously with the tremor, or when the extremity muscles are involved in the form of a resting, postural or intention tremor. • Essential palatal tremor, which is apparently not associated with olivary hypertrophy (Deuschl et al. 1994), is characterized by one, yet extremely irritating complaint of an objectively audible clicking sound occurring synchronously with the tremor. The clicking sound is made by spasmodic contractions of the tensor veli palatini muscle. Rhythmic myoclonus may correspond to the original definition of the tremor. They manifest as slow, rhythmic hyperkinesias, commonly accompanied by signs of an additional brainstem and/or cerebellar function disturbance. Further possible rhythmic segmental hyperkinesias without other function disturbances may be indicative of spinal myoclonus. They can, for example, affect one of the extremities. In these
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cases, nerve lesions or spinal affections (tumor, myelitis) are occasionally found.
4.7.5.4 Diagnosis and Differential Diagnosis The diagnosis can generally be established clinically. The report in the medical history of tremor occurring only while eating (soup!) or writing, generally speaks against the presence of parkinsonism. Resting tremor in Parkinson’s disease involves distal extremity segments, but not the head, the chin or the voice. Tremor involving these regions serves as an indication of essential tremor. It is essential to exclude causes of enhanced physiologic tremor and conditions with the phenomenologic resemblance of an essential tremor syndrome (e.g. Wilsons’s disease in patient under age 50) with the use of appropriate examinations. Further differential diagnoses which usually do not represent a serious problem include partial continuous epilepsy, rhythmic myoclonus, and clonus as a result of increased muscle extension reflexes. Patients with early stage parkinsonism who have a postural and intention component in addition to resting tremor pose a differential diagnostic problem. This also applies to patients with monosymptomatic intention tremor, dystonic and psychogenic tremor.
4.7.5.5 Therapy The decision regarding initiation of medical therapy has to be made on an individual basis and depends on the subjective degree of incapacity. A low-grade postural tremor can be extremely embarrassing for a sales person with customer contact, while a mason with the same symptoms may not consult a physician. Differentiation must be made between intention and resting tremor. Regardless of the etiology, the attempt to treat intention tremors should be made with the use of the same medical therapy recommended for essential tremor. A patient with resting tremor should receive probative drug therapy with similar medications used for the treatment of Parkinson’s disease. Many patients with essential tremor do not require longterm medical therapy. The patients may be afraid of developing Parkinson’s disease or multiple sclerosis. In these cases counselling is required. If further symptomatic therapy is indicated, it may be assumed that about half of the patients with essential tremor will benefit from medical therapy. Propranolol and primidone are the most extensively investigated substances. While the titration of primidone is difficult in 30% of patients, chronic undesirable effects of propranolol lead to the discontinuation of therapy in 20% of patients. More than 10% of patients developed a tolerance to both medications within a
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period of 1 year (Ceballos-Baumann and Boecker 2000). It is essential to avoid the abrupt discontinuation of long-term therapy with beta-receptor blockers or primidone. Therapeutic attempts in patients with Holmes’ tremor should consist of a combination of sufficiently large doses of L-dopa and a decarboxylase inhibitor (approx. 1,000 mg).
4.8 Abnormalities of Brainstem Development Wolfgang Wagner The most important abnormalities of brainstem development comprise the different Chiari malformations and DandyWalker malformation, as well as several very rare disease entities as, e.g. Joubert syndrome and rhombencephalosynapsis. Congenital aqueduct stenosis (aqueduct atresia) also falls into this category. Indirectly, impairments of the brainstem due to developmental abnormalities of neighboring structures can also be included among this group of conditions (e.g. arachnoid cysts of the posterior cranial fossa, craniocervical junction constriction in achondroplasia and basilar impression).
4.8.1 Chiari Malformations In two reports published at the end of the nineteenth century, the pathologist Hans Chiari described four forms of pathologic changes in the cerebellum, the pons, and the medulla oblongata, which he characterized as follows: • Type I due to cerebellar tonsillar herniation (to caudal beyond the level of the foramen magnum) • Type II due to caudal displacement of the cerebellum/ cerebellar vermis, lower brainstem, and fourth ventricle, into the cervical spinal canal • Type III due to herniation of the cerebellum into an occipitocervical encephalocele • Type IV due to cerebellar hypoplasia without caudal displacement (Koehler 1991) The described malformations were originally regarded as an embryologic-pathoanatomic continuum, a view that had to be revised on the basis of study results published in the past few decades (Milhorat et al. 1999). The by far most important of these malformations (Type I and II) will be discussed below, Type III is extremely rare (Chiari himself described only a single case). Strictly speaking, Type IV does not belong to this group and was only later added to the above classification scheme by Chiari.
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common symptom is pain in the back of the head and the neck area followed by feelings of retroorbital pressure, visual disturbances, vertigo, balance and hearing abnormalities, disturbances of the caudal cranial nerves, as well as other brainstem and cerebellar signs. A common feature of these symptoms is that they are increased on exertion and Valsalva maneuvers. Spinal symptoms as, e.g. weakness, paresthesias, and joint pain are seen in almost all patients with accompanying syringomyelia, although they occur (also somewhat less often) in the absence of syringomyelia.
4.8.1.1 Chiari Malformation Type I This malformation is characterized by a developmental unproportional relationship between a very small volume of the posterior cranial fossa and a normal metencephalon (not malformed) volume. This regularly leads to displacement of the outer cerebrospinal fluid spaces above, or behind and below the cerebellum with subsequent chronic tonsillar herniation, compression of neural structures, as well as abnormal cerebrospinal fluid dynamics (Milhorat et al. 1999). 4.8.1.2 Epidemiology
4.8.1.5 Diagnosis
The condition is rare, precise figures of incidence are not available. Women are significantly more often affected than men (women : men approx. 3:1). The results obtained by an analysis of past family medical histories of the patients strongly support the hypothesis of a genetic influence (Milhorat et al. 1999).
The disturbance of the embryologic development underlying the primary forms has been attributed to an aberrant development of the paraxial mesoderm. In the so-called secondary or acquired form, a Chiari I malformation may also be found in craniosynostoses, achondroplasia, and other disorders leading to compression within the posterior cranial fossa.
The diagnosis is usually made with magnetic resonance imaging (MRI). MRI shows an obliteration of the outer cerebrospinal fluid spaces above the cerebellum, and typically tonsillar herniation (caudal to the foramen magnum). Flow sensitive sequences also show restricted or abolished cerebrospinal fluid flow in the cisterna magna or the retrocerebellar subarachnoidal space (Fig. 4.60a). Syringomyelia was detected in 65% and scoliosis in 42% of patients among a large, clinically symptomatic population (Milhorat et al. 1999). In some cases, the cerebrospinal fluid obstruction may lead to the development of obstructive hydrocephalus (Decq et al. 2001). Displacement of the odontoid process with dorsal inclination and subsequent brainstem compression has also been described (Grabb et al. 1999; Tubbs et al. 2003).
4.8.1.4 Clinical Findings
4.8.1.6 Differential Diagnosis
The initial symptoms most often manifest between the ages of 10 and 40 years (Milhorat et al. 1999). By far the most
In making the differential diagnosis of the so-called acquired forms, consideration must be given to other diseases
4.8.1.3 Etiology
a
Fig. 4.60 Images obtained in a 15-year-old girl with sudden onset of severe neck pain, hemiparesis left, and pathologic somatosensory evoked potentials. (a) MRI identifies pronounced tonsillar herniation with compression in the posterior cranial fossa. Compression of the lower brainstem is increased due to dorsal displacement of the dens
b
axis. In the mid-cervical spinal cord, pronounced syringomyelia with spinal cord distension. (b) At the time of examination – 3 months after cerebellar tonsil resection – improvement of the clinical symptoms. MRI does not demonstrate any (dorsal) lower brainstem compression. Partial retrogression of the cervical syringomyelia
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associated with compression (e.g. tumors) in the posterior cranial fossa, even though MRI findings are generally typical in these cases.
4.8.1.7 Therapy Surgical therapy consists of decompression in the region of the craniocervical junction (bony decompression), possible dural enlargement, resection or “shrinking” of the cerebellar tonsils using electrocoagulation (Alden et al. 2001; Weprin and Oakes 2001; Yeh et al. 2006), and hydrocephalus therapy if indicated (Decq et al. 2001). Ventral decompression via a transoral approach may be required in rare cases of an associated pronounced displacement of the odontoid process (Grabb et al. 1999).
4.8.1.8 Prognosis The prognosis after Chiari I decompression is usually favorable; in some patients a possibly associated syringomyelia may resolve after craniocervical junction decompression, obviating the need for additional surgical intervention (Fig. 4.60b).
4.8.1.9 Chiari Malformation Type II This malformation, against its historical background also described as Arnold-Chiari malformation, is nearly always associated with open spina bifida; conversely, virtually all patients with this dysrhaphic disturbance have a Chiari type II malformation. The cerebellum (particularly the vermis), brainstem and the fourth ventricle are displaced caudally into the cervical spinal canal, the neural structures show inner and outer dysplasias. Caudal displacement of the medulla oblongata with spinal cord adhesion in the cervical spinal canal leads to cervicomedullary kinking. In some cases the anterior cerebellar surface also covers the lateral and ventral brainstem (cerebellar inversion). The mesencephalic tectum often shows tectal beaking. An accompanying hydrocephalus occurs in more than 80% of patients. Also present are cerebral malformations (e.g. corpus callosum hypoplasia, enlarged massa intermedia, aqueductal stenosis) of varying degree. The volume of the bony posterior cranial fossa is reduced, while the foramen magnum is enlarged (McLone and Dias 2003; Weprin and Oakes 2001).
4.8.1.10 Epidemiology Because the Chiari type II malformation is almost always associated with open spina bifida (and vice versa), the
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incidence or prevalence of neural tube defects serves as an indicator of the frequency of Chiari II malformations. The incidence ranges from 0.1:1,000 live births in Africa to 12.5:1,000 live births in Ireland. The significant difference in these rates remains unchanged when members of different ethnic groups emigrate to other geographic regions (Cohen and Robinson 2001). A correlation has been shown between (preconceptional) folic acid prophylaxis and reduction in the prevalence of Chiari type II malformations.
4.8.1.11 Etiology The primary cause of the neural tube defect (dysrhaphia) present in open spina bifida (commonly as lumbosacral myelomeningocele) and Chiari II malformation is attributed to a disturbance of the embryonic process of primary neurulation at the end of the fourth week after conception. A number of etiologic factors also play an important role. The prophylactic effect of (preconceptional) folic acid intake is in support of exogenous factors, and the varying prevalence of the disease in different populations, as well as familial clustering are suggestive of genetic influences.
4.8.1.12 Clinical Findings Apart from the typical stigmata of open spina bifida (or hydrocephalus if applicable), the most common symptoms in infancy comprise signs of brainstem dysfunction, such as swallowing and respiratory abnormalities, paralysis of the vocal cords with stridor, loss of the gag reflex, additional cranial nerve deficits, as well as opisthotonus. Prominent symptoms in older children include neck pain, sensory symptoms, pareses, increasing upper extremity spasticity, scoliosis, trunk and extremity ataxia, as well as cerebellar nystagmus (Weprin and Oakes 2001; McLone and Dias 2003). Intellectual development is usually not or only slightly impaired. Important in the therapy of these patients is to be aware of a shunt in place for an associated hydrocephalus, and consideration of the fact that the abovementioned Chiari II symptoms (in particular in acute or subacute phases) can be triggered or enhanced as a result of increased intracranial pressure due to shunt insufficiency.
4.8.1.13 Diagnosis An adequate imaging diagnosis requires cranial MRI including the craniospinal junction (Fig. 4.61), as well as of the complete vertebral column to enable assessment of all CNS segments. In addition to the clinical examination, electrophysiological techniques can be used to quantify brainstem function disturbances (Koehler et al. 2000).
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degree of neurologic recovery after neurosurgical decompression depends on the severity of the preoperative deficits, and apparently also on the age of the patient: the earlier the Chiari II malformation becomes symptomatic, the poorer the prognosis. A mortality rate of 50% has been reported in infants up to 6 months of age, while older children have significantly better chances of recovery (Weprin and Oakes 2001).
4.8.2 Dandy-Walker Malformation Fig. 4.61 Images obtained in an 8-month-old infant with lumbosacral myelomeningocele (surgical care immediately after birth) and associated hydrocephalus (ventriculo-peritoneal shunt). (a) Median sagittal MRI: Chiari II malformation with severe cerebellar herniation, mesencephalic tectal beaking, corpus callosum hypoplasia, extensive interthalamic adhesion and cervical syrinx. (b) Axial MRI at the level of the pontobulbar junction: posterior cranial fossa “filled” with cerebellar tissue, the ventral cerebellar surface also covers the lateroventral surface of the brainstem (cerebellar inversion). Neither the Chiari II malformation nor syringomyelia is clinically symptomatic at the time of examination
4.8.1.14 Differential Diagnosis The possibility of shunt failure needs to be considered, in particular in the presence of acute or subacute clinical symptoms of Chiari II malformation (always think first: it’s the shunt) (McLone and Dias 2003). The differential diagnosis of a Chiari I malformation should be excluded in the rare occurrence of an only mild Chiari II malformation in patients with open spina bifida, as both entities are fundamentally different embryologically and clinically.
4.8.1.15 Therapy Surgical intervention is required in the presence of brainstem compression (dorsal decompression of the craniocervical junction; possibly caudal opening of the fourth ventricle). This procedure does not permit elimination of intrinsic brainstem dysplasias (which may be the cause of the symptoms in the absence of extrinsic pressure). In cases of shunt insufficiency as the trigger of Chiari II symptoms, shunt revision or, alternatively, endoscopic ventriculostomy (compare section “Aqueductal stenosis”) is required (Wagner et al. 2002).
The Dandy-Walker malformation represents a fetal developmental disturbance of the cerebellum or the roof of the fourth ventricle with absent fusion of the cerebellar hemispheres (absence of vermis formation), and possible atresia of the foramina at the fourth ventricle exit. Anatomically it is characterized by aplasia or hypoplasia of the vermis, enlargement of the posterior cranial fossa with upward displacement of the tentorium and confluence of the sinuses, as well as cystic enlargement of the fourth ventricle filling almost the entire posterior cranial fossa. In this setting, associated malformations are found in the remaining CNS (e.g. absent corpus callosum, occipital encephalocele, dysplasias of pontine/bulbar nuclear regions, with embryological origin, comparable to the cerebellum, from the rhombic lip (Roessmann 1995)). Hydrocephalus is present in 90% of patients and is partly due to accompanying aqueductal stenosis. Systemic (e.g. cardiac) abnormalities have been reported in one fourth of patients by autopsy studies (Arai and Sato 2001).
4.8.2.1 Epidemiology The estimated incidence ranges from 1:25,000 to 1:30,000 births, girls appear to be more commonly affected than boys. Dandy-Walker malformation is the causal factor of perinatal hydrocephalus in 1–4% of cases (Arai and Sato 2001; Cinalli et al. 2004a).
4.8.2.2 Etiology The etiology of the malformation in the early fetal period is not fully understood. A number of exogenous and genetic influences appear to play a role in this context (Cinalli et al. 2004a).
4.8.1.16 Prognosis
4.8.2.3 Clinical Findings
Chiari II malformation is the leading cause of death in lethal courses of open spina bifida in the first 2 years of life. The
The most prominent clinical symptoms are caused by the accompanying hydrocephalus (compare section “Aqueductal
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stenosis”); possible additional symptoms include eye movement disturbances, spasticity, ataxia, hemiparesis and tetraparesis. Also present is mental retardation, whose severity correlates with the degree of hyperplasia or aplasia of the cerebellar vermis (Klein et al. 2003). In 70–90% the symptoms manifest as early as within the 1st year of life (primarily hydrocephalus associated); motor retardation, cerebellar signs and cranial nerve deficits are in the foreground in older children. 4.8.2.4 Diagnosis Magnetic resonance imaging (MRI) is the diagnostic procedure of choice; it is capable of showing the described anatomic characteristics, and enables planning of the neurosurgical therapy suitable for the individual patient (Fig. 4.62). 4.8.2.5 Differential Diagnosis Dandy-Walker malformation in the strict sense has to be differentiated from cerebellar hypoplasia with fourth ventricle enlargement, but without an enlarged posterior cerebral fossa (sometimes and terminologically non-uniformly also defined as Dandy-Walker variant), as well as from mega cisterna magna (enlargement of the cerebellomedullary cistern without cerebellar malformation) (Barkovich 2000; Cinalli et al. 2004a). The presence of an arachnoid cyst in the posterior cranial fossa, as well as an isolated fourth ventricle has to further be excluded. In these cases, MRI visualizes a normal (albeit compressed) vermis, a normal location for the confluence of the
Fig. 4.63 (a) Images obtained in a (pre-term) 2.5-year-old girl with post-hemorrhagic hydrocephalus treated with a ventriculoperitoneal shunt. Median-sagittal MRI with ballooned isolated fourth ventricle, membrane-shaped aqueduct closure, substantial compression of the cerebellum dorsal and of the brainstem ventral. Normal cerebral vermis. Clinical findings: delayed psychomotor development, strabismus, impaired movement, particularly of the right upper extremity. Pathologic somatosensory evoked potentials. (b) Situation 4 months after aqueductal plasty with stenting. The fourth ventricle is markedly smaller (although still large), unfolding of both the cerebellum and the brainstem. Clinical evidence of progress of psychomotor development, incomplete resolution of strabismus
sinuses, and permits differentiation, for example, of a retrocerebellar arachnoidal cyst from the (normal sized) fourth ventricle (Barkovich 2000). The so-called isolated fourth ventricle typically occurs in the context of an early childhood (primarily post-hemorrhagic) hydrocephalus with relative supratentorial ventricular system shunt overdrainage; other characteristic Dandy-Walker malformations are absent (Fig. 4.63).
4.8.2.6 Therapy Neurosurgical therapy is aimed at eliminating increased pressure both in the posterior cranial fossa and in the supratentorial space with the use of intracranial or extracranial cerebrospinal fluid drainage. Under ideal conditions, neuroendoscopic fenestration is sufficient; drainage of the fourth ventricle as well as of the supratentorial ventricle via a ventriculoperitoneal or cystoperitoneal shunt (or a combination of both) is required in most patients.
4.8.2.7 Prognosis Fig. 4.62 Images obtained in a 6-month-old girl with Dandy-Walker malformation. (a) Median-sagittal MRI: substantial enlargement of the posterior cranial fossa with cystic enlargement of the fourth ventricle, marked hypoplasia of the cerebellar vermis, upward displacement of confluence of the sinuses, absent corpus callosum. (b) Axial MRI on the level of the posterior cranial fossa: absent fusion of cerebellar hemispheres, broad junction from the fourth ventricle to the Dandy-Walker cyst, as well as supratentorial enlargement of the temporal horns of the lateral ventricle as a sign of hydrocephalus. The child received a ventriculoperitoneal shunt and currently has (aged 3 years) only minor neurologic abnormalities
The prognosis for survival is determined by the effectiveness of hydrocephalus therapy; success rates of more than 80% have been reported in this context (Arai and Sato 2001). Mental retardation, however, is not (only) determined by the degree of the cerebrospinal fluid circulation disturbance; the favorable influence of neurosurgical therapy is therefore limited. Patients with “isolated” forms of Dandy-Walker malformation, only moderate malformation of the vermis, no
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additional CNS malformations, and early effective hydrocephalus therapy have the best prognosis.
4.8.3 Aqueductal Stenosis Perinatal aqueductal stenosis (or atresia of the aqueduct) is one of the most common causes of congenital hydrocephalus. Based on pathoanatomic findings as well as on embryologic considerations it may be regarded as a prenatally acquired condition rather than a genuine developmental disturbance (“idiopathic aqueductal stenosis”) (Roessmann 1995). An exception is the rare hereditary form of aqueductal stenosis – the so-called X-linked hydrocephalus (BickersAdams-Edwards syndrome); this is associated with additional malformations such as corpus callosum agenesis, or bilateral absence of the pyramids in the medulla oblongata, and agenesis of the corticospinal fiber systems (Costa and Hauw 1995; Roessmann 1995). Further findings include aqueductal stenosis in the context of other CNS malformations (Chiari II malformation, Dandy-Walker malformation). The cerebrospinal fluid flow disturbance via the aqueduct is causal in the development of a triventricular occlusive hydrocephalus (enlargement of the supratentorial ventricles 1–3 upstream of the passage obstruction; normal size of the fourth ventricle below the obstruction).
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gaping cranial sutures, increasing head circumference, sunset phenomenon of the eyes, and possibly venous stasis in the region of the galea. Other neurologic and mental functions (with early therapy of hydrocephalus) are essentially normal. In contrast, thumb position defects (adduction position), spasticity, as well as severe motor and mental retardation are found in X-linked hydrocephalus.
4.8.3.4 Diagnosis Triventricular hydrocephalus can already be demonstrated in the unborn child with the use of ultrasound (possibly also MRI), in newborns and infants with ultrasonography, MRI and CT scans. Ultrasonographic depiction becomes difficult after fontanelle closure in early childhood. MRI is the modality of choice capable of showing typical triventricular hydrocephalus, displacement of the floor of the fourth ventricle to basal, as well as the absence of a flow signal within the aqueduct.
4.8.3.5 Differential Diagnosis In idiopathic aqueduct stenosis consideration has to be given to other causes, such as tectal tumors or secondary aqueduct occlusions due to adhesions after hemorrhages or meningitides.
4.8.3.1 Epidemiology
4.8.3.6 Therapy
Aqueductal stenosis is the cause of a hydrocephalus in 6–66% of cases in children and 5–49% in adults; there are significant differences in reports of the annual incidence (3.7:1,000,000 to 0.5:1,000) (Cinalli et al. 2004b). The X-linked hydrocephalus is very rare (1:30,000 male births) (Dirks 2004).
The therapy of choice in idiopathic aqueductal stenosis consists of endoscopic third ventriculostomy (ETV) with endoscopic fenestration of the floor of the third ventricle. This permits the cerebrospinal fluid to bypass the passage obstruction within the aqueduct and drain directly into the basal cisterns and thus into the outer cerebrospinal fluid spaces where it can be resorbed (Wagner and Koch 2006; Fig. 4.64b). In cases of insufficient effectiveness of the ETV (e.g. in the presence of an additional cerebrospinal fluid absorption disturbance, or repeated closure of the ventriculostoma (Wagner and Koch 2005)), placement of a ventriculoperitoneal shunt for cerebrospinal fluid drainage from the lateral ventricle into the peritoneal cavity is required. Among other factors, the success rate of ETV is dependent upon the age, and is highest (up to 80%) in children older than 1 year (Cinalli et al. 2004b; Koch-Wiewrodt and Wagner 2006).
4.8.3.2 Etiology The etiology of congenital “idiopathic” aqueductal stenosis is unknown. Secondary, acquired aqueductal stenoses occur after hemorrhages, infections, or in connection with neoplasias. 4.8.3.3 Clinical Findings The so-called idiopathic aqueductal stenoses are characterized by typical signs of increased intracranial pressure in hydrocephalus as, e.g. vomiting, disturbance of consciousness and convulsions, as well as tight fontanelles in infants,
4.8.3.7 Prognosis The prognostic outcome in idiopathic aqueductal stenosis is – providing therapy starts early enough – favorable,
4.9 Metabolic Brainstem Diseases
Fig. 4.64 (a) Images obtained in a 4-month-old infant with prepartal demonstration of triventricular hydrocephalus and significant progression of findings postpartum. Median sagittal MRI: enlargement of the third ventricle, normal size fourth ventricle, absent flow signal within the aqueduct (atresia). No hemorrhage, no meningitis, no other malformations. With the exception of a macrocephalus, essentially normal clinical findings. (b) Situation 10 months after endoscopic third ventricular cisternostomy: severe flow phenomenon (signal extinction) on the floor of the third ventricle as sign of a functional ventriculostoma. In the further course: persistent decrease in ventricle size and normalization of the head circumference; since the operation 5 years ago, the child has been without a shunt
although limited intellectual abilities (these were lower, the later aqueductal stenosis was clinically manifest) were found in larger series of patients. In X-linked hydrocephalus the motor and, in particular, the intellectual development of the child are notably poorer, despite adequate therapy. The prognosis in the secondary forms depends essentially on the underlying disease.
4.8.4 Rare Disturbances in Brainstem Development A number of very rare conditions are characterized by agenesis or hypoplasia of the vermis associated with other CNS malformations, including developmental abnormalities in the brainstem region. These comprise Joubert syndrome, the COACH syndrome, rhombencephalosynapsis, or tectocerebellar dysrhaphia. Very rare are syndromes associated with unilateral or bilateral aplasia, or hypoplasia of the cerebellar hemispheres, which are accompanied by developmental abnormalities of the lower brainstem (e.g. pontocerebellar hypoplasia), as well as olivopontocerebellar atrophy, Moebius’s syndrome, or developmental abnormalities in the context of chromosomal aberrations (Costa and Hauw 1995). Severe mental retardation is generally present in these cases and life expectancy is significantly shortened. The (neurosurgical) therapy is limited to the therapy of the associated hydrocephalus.
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Fig. 4.65 (a) Images obtained in a 6-month-old infant with achondroplasia. Clinical findings: respiratory disturbances, substantially reduced spontaneous motor function, spasticity of the upper extremities, markedly delayed psychomotor development. Median sagittal MRI: extensive lower brainstem compression mediated by a significantly constricted foramen magnum. (b) Findings 6 months after bony decompression (from dorsal): no brainstem compression, anatomically unfolded medulla oblongata, and marked improvement of the neurologic symptoms
4.8.5 Brainstem Impairment due to Pathologic Neighboring Structures The brainstem (even without intrinsic malformations) can be impaired due to compression from variously malformed neighboring structures. These comprise, e.g. arachnoidal cysts in the posterior cranial fossa, craniocervical junction constriction in achondroplasia (Fig. 4.65a), and basilar impressions. Diagnostic imaging is supported by MRI and (especially in bony processes) CT scanning. The clinical symptoms are the result of local brainstem compression and, in some instances, to the underlying disease. The aim of (neurosurgical) therapy is decompression of the brainstem (Fig. 4.65b).
4.9 Metabolic Brainstem Diseases Joachim Wolf and Armin Grau Metabolic diseases of the central nervous system constitute an etiologically highly heterogeneous group. They are often causal factors of more comprehensive disease patterns, that affect not only individual regions of the central nervous system as, for example the brainstem. A number of these diseases represent exceptions and become symptomatic exclusively or primarily in the brainstem. In addition to signs of cortical or cerebellar injury, various metabolic diseases are also associated with cardinal symptoms typical of the brainstem. The following chapter is limited specifically to discussion of the latter disease groups, without, however, making the claim of completeness.
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4.9.1 Central Pontine Myelinolysis
4 Diseases
after about 1 week, the brain is particularly vulnerable to osmotic trauma. The processes occurring under conditions of rapid hyponaCentral pontine myelinolysis (CPM) was first described in tremia correction are not merely a reversal of the initial pro1959 by Adams and co-workers as a distinct disease entity, cess, in particular since the intracellular reaccumulation of occurring in alcoholic and malnourished patients. The exisorganic molecules is decelerated. Shrinking of brain cells tence of extra pontine myelinolysis (EPM) was reported in occurs when the inorganic ionic processes within the cell are later studies. The disease is associated with symmetrical exhausted and the rise in serum osmolarity is faster than the demyelinations and often manifests following rapid correcintracellular synthesis or transport of organic substances into tion of hyponatremia. the cell (Martin 2004). Oligodendrocytes appear to be particularly vulnerable in this context; detachment of the myelin sheaths from the axons thus occurs. The osmotic changes cause 4.9.1.1 Epidemiology further injury to the endothelium, leading to the development The exact incidence rate of the disease is not known. In a of vasogenic edema and extravasation of myelin- damaging series of about 3,500 autopsies, typical changes for CPM were substances, which represents an additional mechanism of identified in 0.25% of cases (Lampl and Yazdi 2002). Fifteen demyelination. Animal studies have shown that an injury to the cases of an asymptomatic CPM were found in 3,000 routine blood-brain barrier during correction of hyponatremia is assoautopsies. It is estimated that the prevalence of asymptomatic ciated with high risk for CPM/EPM (Lampl and Yazdi 2002). The determining factor for the occurrence of CPM/EPM is CPM is at least as high as the incidence of the clinically diagnosed form (Newell and Kleinschmidt-Demasters 1996). The not the initial sodium concentration, but the rate and extent of disease is found slightly more often in men than in women, the blood sodium level correction. Preexisting alterations in the and usually occurs between 30 and 50 years; it has, however, brain due to malnutrition or prior medical conditions lead to an exacerbation of the disease. Patients with CPM/EPM often also been described in children (Lampl and Yazdi 2002). exhibit hypokalemia in addition to hyponatremia (Martin 2004). The disease can, however, also occur in patients with elevated or normal blood sodium levels or when hyponatremia is corrected 4.9.1.2 Etiopathogenesis at a rate that is considered safe. This underlines that still only Results of the majority of available studies support the incompletely known other osmotically active processes or other hypothesis that CPM and EPM are attributable to an overly pathomechanisms are involved in the pathogenesis. CPM is a disease which affects primarily the central segrapid correction of severe hyponatremia. The conditions manifest most commonly in patients with chronic hypona- ment of the pontine base with possible extension to the midtremia and complete intracellular adaptation to serum brain, very rarely also to the medulla oblongata (Martin hypoosmolarity, while only insufficient counter-regulatory 2004). Neuropathology shows a symmetrical, sharply defined mechanisms in response to rapid increase in serum osmolar- lesion of the myelin sheath, which involves all of the long ity are available. Rapid correction of the serum sodium con- pathways and is associated with a lesion as well as the loss of centration has become possible only with the introduction of oligodendrocytes. Axons and neurons are spared, inflammaintravenous fluid therapy; CPM and EPM are therefore often tory or vascular alterations do not exist (Adams et al. 1959). A particular predisposition in the pathogenesis, especially regarded as iatrogenic diseases (Brown 2000). Patients with a disturbed osmotic balance are at an of the pons, may be due to the close vicinity of oligodendroincreased risk for CPM/EPM. The formula to calculate cytes and the strongly vascularized gray matter; and thus, the serum osmolarity (serum osmolarity = 2 [Na+ + K+] + [glu- vasogenic edema and release of myelinotoxic substances cose/18] + [urea/3] mmol) emphasizes the important role may have markedly pronounced effects in this region (Lampl of sodium levels. Hyponatremia is present at levels of and Yazdi 2002). The lesion is not limited exclusively to the
