In Focus Spotlight on the May 31 Issue Robert A. Gross, MD, PhD, FAAN Editor-in-Chief, Neurology®
Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis
Predicting survival in frontotemporal dementia with motor neuron disease
Clinical relapses of 1866 patients and gadolinium-enhanced (Gd⫹) lesions of 341 patients were analyzed over an 8-month period. This paper provides evidence that when you stop Tysabri in patients with multiple sclerosis, clinical and MRI activity gradually returns to pre-study baseline activity over 3–4 months.
The authors demonstrated that patients with frontotemporal dementia and motor neuron disease with prominent language impairment have shorter survival than patients with prominent behavioral impairment, in part due to bulbar onset symptoms. This finding has prognostic importance.
See p. 1858; Editorial, p. 1854
Stress and the risk of multiple sclerosis Several studies have shown that stressful life events are associated with an increased risk of multiple sclerosis (MS) exacerbations. This study found, in two cohorts of female nurses, that there was no increased risk of MS in those with severe stress at home, severe physical abuse during childhood or those forced into sexual activity in childhood. See p. 1866
Incident lacunes influence cognitive decline: The LADIS study This first paper investigated the contribution of lacunar infarcts in longitudinal cognitive change in 387 elderly subjects. Incident lacunes paralleled steeper decline of psychomotor speed and executive functions, thus determining progressive cognitive impairment in cerebral small vessel disease. See p. 1872; Editorial, p. 1856; see also p. 1879
Vascular risk factors and longitudinal changes on brain MRI: The ARIC study Epidemiological studies provide a broader view of vascular risk factors than overt strokes. This second paper showed that diabetes and hypertension in midlife were associated with infarcts and loss of brain volume in brain MR scans 10 years later. See p. 1879; Editorial, p. 1856; see also p. 1872
See p. 1886
Real-life driving outcomes in Parkinson disease This prospective cohort study ascertained the time until driving cessation, a crash or a traffic citation in 106 active drivers with Parkinson disease and in 130 controls. Severity of parkinsonism, visual and cognitive dysfunction, older age, worse road performance, and driving history at baseline were associated with driving cessation in this group. See p. 1894
Clinical and MRI characteristics of acute migrainous infarction The authors investigated clinical and MR imaging characteristics in 17 patients with migraine associated acute cerebral ischemia, from 8137 stroke patients over an 11 year period. Their findings support previous observations that migrainous infarction mostly occurs in the posterior circulation, and in younger women with a history of migraine with aura. See p. 1911
VIEWS & REVIEWS
Abbreviated report of the NIH/NINDS workshop on sudden unexpected death in epilepsy
From editorialists Filley and Brodtmann: “Using longitudinal designs requiring many years of follow-up, these articles provide evidence supporting the notion that lacunar strokes can negatively affect processing speed and executive function, and that hypertension and diabetes are of etiologic importance.”
Sudden unexpected death in epilepsy (SUDEP) is not rare. This multidisciplinary workshop was held to advance research into SUDEP and its prevention. Scientific sessions covered potential causes and education sessions covered when and how to discuss SUDEP. Suggestions for further research and prevention were outlined.
See p. 1856
See p. 1932
NB: “Resident & Fellow Clinical Reasoning: A young adult presents with focal weakness and hemorrhagic brain lesions,” see p. e106. To check out other Resident & Fellow submissions, point your browser to http://www.neurology.org and click on the link to the Resident and Fellow Section. Access the podcast at www.neurology.org.
Copyright © 2011 by AAN Enterprises, Inc.
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EDITORIAL
Interruption of natalizumab therapy for multiple sclerosis What are the risks?
Robert T. Naismith, MD Dennis Bourdette, MD
Address correspondence and reprint requests to Dr. Dennis Bourdette, Department of Neurology L226, Oregon Health & Science University, Portland, OR 97239
[email protected] Neurology® 2011;76:1854–1855
Thomas Huxley, the great 19th century British biologist, quipped that “many a beautiful theory was killed by an ugly fact.” In late 2004, the Food and Drug Administration approved natalizumab for relapsing-remitting multiple sclerosis (RRMS), a “magic bullet” that seemed to arrest multiple sclerosis (MS) disease activity. That beautiful idea died a few months later with the discovery of an ugly fact: natalizumab was associated with a risk of progressive multifocal leukoencephalopathy (PML). After removal from the market in early 2005, natalizumab was rereleased in 2006 to a cautious community of neurologists and patients. Since the rerelease of natalizumab for the treatment of RRMS, neurologists have struggled with some fundamental questions. Which patients are most appropriately treated with natalizumab? How long should treatment continue? Does the disease rebound when the medication is stopped? Is a drug holiday effective at reducing the risk of PML? How can we assess an individual patient’s risk of developing PML and mitigate that risk? In this issue of Neurology®, O’Connor et al.1 provide information on the kinetics of the return of MS disease activity after natalizumab cessation. When the risk of PML was discovered in 2005, study participants in natalizumab trials and open-label extension phases were followed for safety after the medicine was discontinued. This post hoc analysis assessed the temporal characteristics in relapse rates and gadolinium-enhancing lesions upon natalizumab withdrawal. Over 1,800 subjects from AFFIRM, SENTINEL, and GLANCE studies were included. Subjects were followed for 8 months after stopping natalizumab; most were not on a disease-modifying therapy during this time. MS disease activity began to increase 3 months after stopping natalizumab. The length of treatment with natalizumab varied depending upon whether the study participant was originally assigned to placebo (mean exposure time 4 months) or originally
allocated to the natalizumab study arm (mean time 28 months). Disease activity returned to pretreatment baseline by 4 months for the group treated ⬍6 months on average, and disease activity peaked at 7 months for the group treated an average ⬎2 years. Notably, relapses and gadolinium lesions were not observed to be elevated beyond pretreatment levels. Presently, natalizumab is often reserved for those deemed to have highly active disease, to offset the risks by providing the medication to patients with the greatest potential treatment benefit.2 Thus, a relevant additional analysis evaluated those with highly active disease, defined by ⱖ2 relapses in the year preceding study entry and ⱖ1 gadolinium lesion on the baseline MRI. Those with active disease at baseline had an increased risk for relapse between months 3 and 4, whereas those without active disease increased their relapse rate after month 6. Even for this highly active group, return of relapse rates did not exceed or rebound beyond the mean, prestudy, baseline rate. What are the clinical implications for this present study? The results suggest that risk of disease activity may remain relatively low for a 3-month window after cessation of natalizumab. Thus, switching a patient from natalizumab to any new therapy should consider this time frame, in addition to the onset for the replacement therapy to effectively treat the disease. A prolonged natalizumab washout period must be tempered with the possibility for a relapse. While this study did not indicate that cessation of natalizumab therapy was associated with heightened or rebound disease activity, patients nevertheless return to their baseline disease activity within 4 –7 months of stopping natalizumab. There is no evidence to indicate that drug holidays from natalizumab treatment can reduce the risk of developing PML, although neurologists discuss this possibility.3 While the present study did not address this issue, the study provides relevant pharmacodynamic data. The theory is that temporary cessation of natalizumab will allow for restoration of
See page 1858 e-Pub ahead of print on May 4, 2011, at www.neurology.org. From the Washington University School of Medicine (R.T.N.), Saint Louis, MO; and Oregon Health & Science University (D.B.), Portland. Disclosure: Author disclosures are provided at the end of the editorial. 1854
Copyright © 2011 by AAN Enterprises, Inc.
brain immunosurveillance, permitting the restored immune function to clear the JC virus and thereby substantially lower the risk of PML. If return of clinical and MRI activity is a sine qua non for immune surveillance, the data presented by O’Connor and colleagues suggests that any treatment cessation may need to last at least 7 months. Thus a drug holiday from natalizumab may necessarily carry the risk of reactivation of MS disease activity. Furthermore, placing a patient on an immune-modulating therapy that was ineffective before natalizumab may not provide adequate disease control during the holiday. While this current study provides compelling evidence that disease activity begins to return 3 months after stopping natalizumab, consistent with its known biological half-life, natalizumab may have more long-acting immunosuppressive properties, especially in patients receiving the drug for 2 years or longer.4 Whether this altered immune regulation conveys an increased risk of opportunistic infections for future years is unknown. Switching a patient from natalizumab to another therapy that also alters the immune system may be associated with risks that cannot be predicted at this time. Thomas Huxley’s admonishment to “Learn what is true in order to do what is right” is relevant to our care of patients with MS. Our knowledge about natalizumab continues to expand. We soon may have a JC virus antibody assay that can help define the risk of PML in individuals.5,6 We also are gaining more insight into the relationship between risk of PML, duration of treatment with natalizumab, and effects of prior immunosuppressive therapy. With new therapies on the horizon, each with a unique profile of efficacy, safety, and mechanism of action, under-
standing their pharmacokinetics, pharmacodynamics, and immunologic effects will be critical to doing what is right for our patients. DISCLOSURE Dr. Naismith has received travel expenses and/or honoraria for lectures, educational activities, and consulting from Acorda Therapeutics Inc., Bayer Schering Pharma, Biogen Idec, EMD Serono, Inc., Genzyme Corporation, and Teva Pharmaceutical Industries Ltd.; serves as an Associate Editor for Journal Watch; serves on speakers’ bureaus for Acorda Therapeutics Inc., Bayer Schering Pharma, Biogen Idec, EMD Serono, Inc., and Teva Pharmaceutical Industries Ltd.; and receives research support from Acorda Therapeutics Inc. and the NIH. Dr. Bourdette has received travel expenses and/or honoraria for lectures and educational activities from Teva Pharmaceutical Industries Ltd., Biogen Idec, and EMD Serono, Inc.; serves as an Associate Editor for Journal of Medicinal Medicine and Autoimmune Diseases and as Section Editor for Current Neurology and Neuroscience Reports; and has research support from the US Department of Veterans Affairs, the NIH, and the National Multiple Sclerosis Society.
REFERENCES 1. O’Connor PW, Goodman A, Kappos L, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 2011;76:1858 –1865. 2. Klawiter EC, Cross AH, Naismith RT. The present efficacy of multiple sclerosis therapeutics: is the new 66% just the old 33%? Neurology 2009;73:984 –990. 3. Hartung HP. New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab. Lancet Neurol 2009;8:28 –31. 4. Stuve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006;59:743–747. 5. Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010; 68:295–303. 6. Tyler KL. Progressive multifocal leukoencephalopathy: can we reduce risk in patients receiving biological immunomodulatory therapies? Ann Neurol 2010;68:271–274.
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EDITORIAL
Lacunes and cognitive decline Little things matter
Christopher M. Filley, MD Amy Brodtmann, MD, PhD
Address correspondence and reprint requests to Dr. Christopher M. Filley, Behavioral Neurology Section, 12631 East 17th Avenue, P.O. Box 6511, Aurora, CO 80045
[email protected] Neurology® 2011;76:1856–1857
Neurologists evaluating patients with cognitive impairment or dementia are regularly confronted with the task of determining the importance of lacunar infarcts on brain imaging scans. Best seen on MRI, these lesions occur in both deep gray and white matter (WM) and are most often commingled with varying degrees of WM hyperintensity (WMH), further complicating the matter. Subcortical lacunes and WMH have been linked with vascular cognitive impairment, a concept that is evolving1; further, when severe, these findings suggest the diagnosis of subcortical ischemic vascular dementia.2 However, the relative contribution of lacunes and WMHs to cognitive decline is controversial. Whereas the clinical relevance of lacunes to motor and sensory syndromes is widely accepted,3 the degree to which cerebral lacunes affect cognitive function has been less clear. Dementia associated with multiple lacunes—the e´tat lacunaire of Pierre Marie4— has been recognized for over a century, but the cognitive dysfunction resulting from one or a few lacunes is often considered negligible.3 Further consideration of this question is warranted, based on the evidence that even a single WM lacune can produce cognitive deficits.5 Yet when the relationship of lacunes and cognition has been examined in larger samples, both crosssectional6,7 and longitudinal8,9 studies have shown contradictory results. Uncertainty thus persists about the management of patients with lacunar disease that has produced no obvious cognitive sequelae. In this issue of Neurology®, 2 large longitudinal studies address these important questions anew. In the first, Jokinen and colleagues10 report 3-year interval findings in elders without dementia from the multinational Leukoaraiosis and Disability (LADIS) study in Europe, demonstrating that incident lacunes on MRI were associated with declines in processing speed and executive function but not memory or global cognition. Notably, people with frontal WM and basal ganglia lacunes did not differ cognitively from those with those with lacunes elsewhere, an un-
expected finding likely related to the relative infrequency of lacunes developing in other cerebral regions. Baseline WMH volume was the strongest predictor of future cognitive decline, but the deleterious impact of lacunes alone was still apparent. In a companion study, Knopman and colleagues11 provide longitudinal data, from a still larger cohort, on the effects of glycemic and blood pressure control on the development of lacunes. Over 1,100 subjects from 4 United States communities of the Atherosclerosis Risk in Communities (ARIC) study had MRI scans 10 years apart, and strokes during that time, mostly lacunes, were clearly related to elevated fasting blood glucose and blood pressure. In this study and the one discussed above, significant subject dropout occurred, and indeed, substantial attrition is unavoidable in longitudinal studies of aging. Nevertheless, the data clearly implicate 2 readily modifiable risk factors— diabetes and hypertension—in the etiology of lacunar infarction among the elderly. Taken together, these studies enhance our understanding of the cognitive sequelae of lacunar infarction, and how these lesions might be averted by medical intervention. Using longitudinal designs requiring many years of follow-up, these articles provide evidence supporting the notion that lacunar strokes can negatively affect processing speed and executive function, and that hypertension and diabetes are of etiologic importance. A factor not addressed in this work, of course, is the contribution of other disorders—most obviously Alzheimer disease (AD)—to cognitive decline, and indeed, a complex mixture of vascular and AD neuropathology is becoming increasingly apparent in many older people with dementia.1,2 Notwithstanding, the new evidence from these studies on the origin and cognitive outcome of lacunes is consistent and neurobiologically plausible. Hypertension and diabetes are risk factors that predispose to the ischemic small vessel disease underlying lacunes,12 and the cognitive dysfunction resulting from lacunar infarction results from selective damage
See pages 1872 and 1879 e-Pub ahead of print on May 4, 2011, at www.neurology.org. From the Departments of Neurology and Psychiatry (C.M.F.), University of Colorado School of Medicine, Aurora; Denver Veterans Affairs Medical Center (C.M.F.), Denver, CO; and Behavioural Neuroscience, Stroke, Florey Neuroscience Institutes (A.B.), University of Melbourne, Melbourne, Australia. Disclosure: Author disclosures are provided at the end of the editorial. 1856
Copyright © 2011 by AAN Enterprises, Inc.
to frontal-subcortical circuits subserving processing speed and executive function.13 While the importance of WMH cannot be ignored,14 lacunes by themselves exert an independent detrimental effect on cognitive function. The case for preventive care is further supported by the observation that both lacunes and WMH appear to produce advancing brain atrophy, noted by previous work15 and in the study of Knopman and colleagues. Neurologists can thus proceed with more confidence in appreciating not only the harmful effects of lacunes on cognition but also the potential benefit of preventive strategies involving assiduous control of hypertension and diabetes. Whereas it has long been clear that the e´tat lacunaire is to be vigorously avoided, increasing evidence suggests that any degree of lacunar infarction may be detrimental to cognition, and that efforts to prevent lacunar strokes are always indicated. Whether or not AD is present, lacunar disease offers a target for beneficial intervention in the quest to preserve cognition in older people. DISCLOSURE Dr. Filley has received funding for travel and speaker honoraria from the American Academy of Neurology, the International Neuropsychological Society, the American Neuropsychiatric Association, and Weill Medical College-Cornell University; receives publishing royalties for Neurobehavioral Anatomy (University Press of Colorado, 2nd ed, 2001) and The Behavioral Neurology of White Matter (Oxford University Press, 2001); has received/receives research support from the University of Colorado Alzheimer’s Disease and Cognition Center, the Alzheimer’s Association, and the NIH/NIAMS; and has given expert legal testimony. Dr. Brodtmann has received funding for travel, symposia organization and speaker honoraria from Novartis, Lundbeck Inc. and Pfizer Inc; and has received/ receives research support from the National Health and Medical Research Council, Ross Foundation, Telematics Trust, Brain Foundation and Wicking Trust.
REFERENCES 1. Pantoni L, Gorelick P. Advances in vascular cognitive impairment 2010. Stroke 2011;42:291–293. 2. Chui H. Subcortical ischemic vascular dementia. Neurol Clin 2007;25:717–740. 3. Fisher CM. Lacunar strokes and infarcts: a review. Neurology 1982;32:871– 876. 4. Marie P. Des foyers lacunaires de de´sinte´gration et de diffe´rentes autres e´tats cavitaires du cerveau. Rev Me´d 1901; 21:281–298. 5. van Zandvoort MJ, van der Grond J, Kapelle LJ, de Hann EH. Cognitive deficits and changes in neurometabolites after a lacunar infarct. J Neurol 2005;25:183–190. 6. Carey CL, Kramer JH, Josephson SA, et al. Subcortical lacunes are associated with executive dysfunction in cognitively normal elderly. Stroke 2008;39:397– 402. 7. Fein G, Di Sclafani V, Tanabe J, et al. Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease. Neurology 2000;55:1626 –1635. 8. Mungas D, Harvey D, Reed BR, et al. Longitudinal volumetric MRI change and rate of cognitive decline. Neurology 2005;65:565–571. 9. Kramer JH, Mungas D, Reed BR, et al. Longitudinal MRI and cognitive change in healthy elderly. Neuropsychology 2007;21:412– 418. 10. Jokinen H, Gouw AA, Madureira S, et al. Incident lacunes influence cognitive decline: the LADIS study. Neurology 2011;76:1872–1878. 11. Knopman DS, Penman AD, Catellier DJ, et al. Vascular risk factors and longitudinal changes on brain MRI: the ARIC study. Neurology 2011;76:1879 –1885. 12. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9:689 –701. 13. Bonelli RM, Cummings JL. Frontal-subcortical dementias. Neurologist 2008;14:100 –107. 14. Filley CM. White matter: beyond focal disconnection. Neurol Clin 2011;29:81–97. 15. Nitkunan A, Lanfranconi S, Charlton RA, Barrick TR, Markus HS. Brain atrophy and cerebral small vessel disease: a prospective follow-up study. Stroke 2011;42:133– 138.
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ARTICLES
Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis P.W. O’Connor, MD A. Goodman, MD L. Kappos, MD F.D. Lublin, MD D.H. Miller, MD C. Polman, MD R.A. Rudick, MD W. Aschenbach, PhD N. Lucas, PhD
Address correspondence and reprint requests to Dr. Paul W. O’Connor, St. Michael’s Hospital, 30 Bond St., Suite 3-007 Shuter Wing, Toronto, Ontario, Canada M5B 1W8
[email protected] ABSTRACT
Background: Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies. Objectives: To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS. Methods: Clinical relapses and gadolinium-enhanced (Gd⫹) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumab dosing that occurred in February 2005. Results: Relapses were analyzed in 1,866 patients, and Gd⫹ lesions were analyzed in 341 patients. Annualized relapse rates and Gd⫹ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd⫹ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted.
Conclusions: Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound. Neurology® 2011;76:1858–1865 GLOSSARY ARR ⫽ annualized relapse rates; CI ⫽ confidence interval; EDSS ⫽ Expanded Disability Status Scale; Gdⴙ ⫽ gadoliniumenhanced; MS ⫽ multiple sclerosis; PML ⫽ progressive multifocal leukoencephalopathy.
Editorial, page 1854 Supplemental data at www.neurology.org
Natalizumab, an ␣-4 integrin antagonist for treatment of relapsing multiple sclerosis (MS), is associated with progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the CNS that occurs in approximately 1:1,000 treated patients.1 Concerns over the heightened risk of PML with increased natalizumab exposure cause some physicians to temporarily interrupt, or stop treatment altogether, after 2–3 years of therapy.2,3 However, little evidence exists regarding the safety of natalizumab treatment interruption, the rate and magnitude of MS disease activity return, or alternative treatment strategies. Concerns about MS “rebound” (worsening of disease activity beyond pretreatment levels) arise from small placebo studies4 and single-center cohort observations.5 In contrast, larger phase 2b studies specifically designed to test for rebound6 and longitudinal analyses of patients from natalizumab pivotal MS trials7 provide strong evidence that while disease activity returns during natalizumab treatment interruption, rebound is unlikely to occur. While these reports e-Pub ahead of print on May 4, 2011, at www.neurology.org. From the St. Michael’s Hospital (P.W.O.), Toronto, Ontario, Canada; University of Rochester Medical Center (A.G.), Rochester, NY; University Hospital Basel (L.K.), Basel, Switzerland; Mt. Sinai School of Medicine (F.D.L.), New York, NY; Institute of Neurology (D.H.M.), London, UK; VU Medical Centre (C.P.), Free University Hospital, Amsterdam, the Netherlands; Cleveland Clinic Foundation (R.A.R.), Cleveland, OH; and Biogen Idec, Inc. (W.A., N.L.), Weston, MA. Study funding: Supported in part by Biogen Idec and Elan Corporation. Disclosure: Author disclosures are provided at the end of the article.
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provide insight regarding the duration of natalizumab’s therapeutic effect following interruption, and the concomitant return of MS disease activity, they are derived from patient samples that are either too small, or from uncontrolled settings, and do not provide sufficient clinical guidance. However, the voluntary suspension of natalizumab dosing that occurred in 2005 following the first 2 reported cases of PML from the pivotal MS trials8,9 provided an opportunity to evaluate natalizumab treatment interruption in a large cohort of patients. Here, we report MS disease activity, as measured by relapses and gadolinium-enhancing (Gd⫹) lesions on MRI, before and during natalizumab treatment interruption. METHODS Patients and treatments. This was a post hoc analysis of patients who received natalizumab in the AFFIRM (10; natalizumab monotherapy vs placebo), SENTINEL (11; natalizumab ⫹ IM interferon -1a vs placebo ⫹ IM interferon -1a), and GLANCE (12; natalizumab ⫹ glatiramer acetate vs
Figure 1
Sources of patients for evaluation
placebo ⫹ glatiramer acetate) studies, or who were enrolled in their respective open-label safety extensions, prior to the voluntary suspension of natalizumab dosing in 2005. Inclusion and exclusion criteria for these studies have been previously described.10-12 Since it has been suggested that MS disease activity return may be more pronounced in patients with shorter natalizumab exposures,5,13 patients who discontinued study drug early were included in this analysis.
Assessments and analyses. As soon as possible after natalizumab treatment interruption, patients were asked to participate in a safety evaluation to assess potential adverse events, and were subjected to cranial MRI scans (performed at least 2 months after the last natalizumab dose). Subsequent safety evaluations, and evaluations of clinical relapses, were performed every 3 months for up to 12 months. Unadjusted relapse rates were calculated for each treatment interruption evaluation period by recording the total number of relapses experienced by all patients, and annualized relapse rates (ARR) by dividing by the total number of person-years at each time period. On-study ARRs for AFFIRM and SENTINEL patients were adjusted for age (⬍40 vs ⱖ40 years), Expanded Disability Status Scale (EDSS) score (ⱕ3.5 vs ⬎3.5), the number of relapses in the previous year, and the presence or absence of Gd⫹ lesions at baseline. Since some patients were derived from a study of natalizumab monotherapy, and return of MS disease activity may be affected by both the severity of underlying disease and utilization of alternative medications, separate analyses were performed on patients who originated from the AFFIRM study, had highly active MS disease at study baseline (defined as ⱖ2 relapses in the year prior to study enrollment and ⱖ1 Gd⫹ lesion at study enrollment), and received alternative MS medications during the natalizumab treatment interruption period.
A total of 1,866 patients who received at least one dose of natalizumab either in the AFFIRM, SENTINEL, and GLANCE trials or during their respective extension studies were evaluated (figure 1). At the time of natalizumab treatment interruption, the overall population was a mean of 40.2 years old, most were female (72%), most were white (95%), and the mean EDSS score was 2.4 (table). Baseline characteristics did not differ between patients who were treated with either placebo or natalizumab prior to treatment interruption. The mean time on natalizumab treatment prior to discontinuation was 16.3 and 123.6 weeks for patients previously treated with placebo or natalizumab, respectively. Approximately 13% of patients (for whom relapse data were available) received alternative MS medications during the treatment interruption period, the most common being interferon -1a (9.9%) and glatiramer acetate (2.4%).
RESULTS Patient demographics.
Return of relapse activity. Relapse evaluations were
At the time of the dose suspension, a minority of patients (n ⫽ 251) from the AFFIRM, SENTINEL, and GLANCE studies who had received at least one dose of natalizumab elected not to enter into the safety extension study. A total of 1,615 patients did enter the study, divided between those originally on placebo (n ⫽ 666) and originally on natalizumab (n ⫽ 949).
performed on all 1,866 natalizumab-treated patients, of whom 1,517 were followed during treatment interruption for at least 8 months (figure 2A). Relapse activity, expressed as an ARR, increased shortly after natalizumab was stopped and peaked at 4 months (0.61; 95% confidence interval [CI] 0.41– 0.86) in Neurology 76
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Table
Demographics and natalizumab exposure prior to treatment interruption Originally placebo-treated (n ⴝ 666)
Originally natalizumab-treated (n ⴝ 1,200)
Total (n ⴝ 1,866)
Mean age, y (SD)
41.0 (7.8)
39.7 (8.3)
40.2 (8.2)
Gender, % female
69
74
72
Race, % white
94
96
95
Mean EDSS score (SD)
2.6 (1.5)
2.4 (1.4)
2.4 (1.4)
Mean time on natalizumab prior to treatment interruption, wk (SD)
16.3 (12.1)
123.6 (31.9)
85.3 (57.8)
Median no. of natalizumab infusions prior to treatment interruption (range)
5.0 (1.0–17.0)
34.0 (1.0–41.0)
30.0 (1.0–41.0)
Abbreviation: EDSS ⫽ Expanded Disability Status Scale.
patients who were originally placebo-treated in the clinical trials, and at 7 months (0.74; 95% CI 0.57– 0.94) in patients who were treated with natalizumab during both the clinical trials and safety extension studies. At no time during the treatment interruption period did ARR exceed the rates observed for placebo-treated patients in the AFFIRM (0.73; 95% CI 0.62– 0.87) or SENTINEL (0.75; 95% CI 0.67– 0.84) trials. Since natalizumab is typically administered as a monotherapy, relapses in the 866 AFFIRM patients were analyzed separately (figure 2B). Similar to what was observed in the overall population, ARR increased shortly after natalizumab was interrupted in both patient groups (natalizumab- and placebotreated), peaked at 7 months, and generally remained below the on-study placebo level of 0.73 (the only exception being observed in AFFIRM patients previously treated with natalizumab when the ARR peaked to 0.83) at 7 months. The overall proportion of patients who experienced relapses during natalizumab treatment interruption was 21% (20% for previous AFFIRM patients), which was substantially lower than the proportion of placebo-treated patients who experienced relapses in the first year of AFFIRM (40%). Relapse activity increased during natalizumab treatment interruption, regardless of whether patients were treated with alternative MS medications or not (figure 3A). Annualized relapse rate was 0.43 (95% CI 0.36 – 0.52) in 544 patients who received no alternative medications during treatment interruption, 0.63 (95% CI 0.37–1.01) in 56 patients who initiated alternative MS medication at the time natalizumab was interrupted, and 0.57 (95% CI 0.47– 0.70) in 346 patients who were continuously treated with alternative medications (interferon -1a from SENTINEL and glatiramer acetate from GLANCE). Further, sensitivity analyses of patients from the overall population (n ⫽ 1,623) and AFFIRM (n ⫽ 815) that excluded those receiving alternative MS medications 1860
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demonstrated a similar pattern of relapse return, with no differences being observed between patients who were either placebo- or natalizumab-treated in the clinical trials (figure e-1A on the Neurology® Web site at www.neurology.org). At no time did relapse rates in patients taking alternative MS medications exceed the onstudy placebo relapse rates observed in AFFIRM or SENTINEL. In order to assess the influence of MS severity on the pattern of disease activity return, relapses were separately analyzed in patients who had highly active disease at baseline in AFFIRM, SENTINEL, and GLANCE studies (n ⫽ 222), compared to those without highly active disease (n ⫽ 994). As shown in figure 3B, ARR increased in patients with highly active disease from an on-study baseline of 0.27 (95% CI 0.20 – 0.36) to 1.56 (95% CI 0.96 –2.38) at 4 months and a peak of 1.69 (95% CI 1.04 –2.58) at 6 months, compared to an increase in patients with non-highly active disease from 0.30 (95% CI 0.26 – 0.34) at baseline to a peak of 0.65 (95% CI 0.45– 0.90) at 6 months. At no time during natalizumab treatment interruption did relapse rates in either the highly active or non-highly active groups exceed their respective on-study placebo relapse rates from the clinical trials. Return of Gdⴙ lesions. Upon suspension of natali-
zumab dosing, a safety evaluation was conducted in which cranial MRI scans were obtained from all patients who received at least one dose in the clinical trials or extension studies. While most scans were obtained within the first 60 days of the safety evaluation, 341 were performed at least 60 days after the final dose, which represents a time when natalizumab should be cleared from the blood based on its pharmacokinetic profile.15 Therefore, these patient scans represent the first true “off-treatment” MRI evaluations available. As shown in figure 4A, the mean number of Gd⫹ lesions was reduced from 1.6 ⫾ 0.2 to 0.3 ⫾ 0.1 after 108 weeks of natalizumab treatment. Once treatment was interrupted, Gd⫹ lesions gradually increased over time to a peak of 1.2 ⫾ 0.4 after 6 months. When patients who took alternative MS medications during natalizumab treatment interruption were excluded from this analysis, there was no evidence of a rebound in Gd⫹ lesion activity (data not shown). In patients without highly active disease, Gd⫹ lesions increased from a mean of 0.0 on treatment to 0.6 after 6 months of interruption, whereas patients with highly active disease exhibited an increase from 0.0 Gd⫹ lesions at baseline to 3.0 lesions after 6 months. Despite this difference in the magnitude of lesion return between non-highly active and highly active disease, no evidence of rebound beyond baseline levels (0.9 and 4.9 lesions, respectively) was evident in either group. As shown in fig-
Figure 2
Clinical relapses return to baseline levels during natalizumab treatment interruption
Unadjusted annualized relapse rates (ARR) during natalizumab treatment interruption in all patients evaluated (A) and patients from AFFIRM (B).
ure 4B, while all patients had either 0 (97%) or 1 (3%) Gd⫹ lesions after 108 weeks of natalizumab, the percent of patients exhibiting between 2 and 4 Gd⫹ lesions progressively increased during the treatment interruption period, and was nearly identical to prestudy baseline levels at 6 months. The main finding of this analysis of over 1,800 patients was that MS disease activity, as assessed by clinical relapses and Gd⫹ enhanced lesions on MRI, started to return shortly after interruption of natalizumab treatment and reached baseline levels by 4–7 months. This pattern appeared to be unaffected by the duration of exposure to natalizumab prior to treatment interruption or whether or not patients were treated with alternative MS medications once natalizumab treatment was stopped. In patients with highly active
DISCUSSION
disease, the return of disease activity was more rapid and of greater magnitude than in patients without highly active disease, but the overall pattern of return was similar. And importantly, at no time did the level of disease activity during an 8-month natalizumab treatment interruption period exceed the levels that were observed in placebo-treated subjects in the clinical trials, thus providing no evidence of a rebound effect. The return of disease activity following natalizumab treatment interruption most likely reflects a resumption of lymphocyte migration across endothelial membranes as natalizumab is cleared from the circulation. Steady-state concentrations of natalizumab are achieved in the serum after approximately 6 months of repeated monthly infusions, and the elimination half-life is approximately 11 days.14 Neurology 76
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Figure 3
Return of clinical relapses in patients receiving alternative multiple sclerosis (MS) treatments and in those with high MS disease activity
Unadjusted annualized relapse rates (ARR) during natalizumab interruption in patients receiving alternative MS treatments (A) and patients with and without highly active MS disease (B).
Based on this pharmacokinetic profile, natalizumab should be fully cleared from circulation approximately 2 months (5 half-lives) following the last dose. A study of patients with MS receiving monthly infusions of natalizumab found that reductions in ␣4-integrin surface expression and inhibition of migratory capacity of peripheral blood mononuclear cells were not sustained for the entire 4-week dosing interval.15 Another study of patients with MS who were treated with between 1 and 41 doses of natalizumab found that lymphocyte counts in CSF remained suppressed up to 6 months following the last 1862
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dose.16 Taken together, these findings demonstrate that the effects of natalizumab wane shortly after dosing is stopped, while some residual effects persist for up to 6 months. This time course is consistent with the pattern of disease activity return reported here, and suggests that the 8-month observation period was sufficient to allow all biological effects of natalizumab to abate. However, the RESTORE study (ClinTrials.gov identifier: NCT01071083), which is currently underway, is designed to directly assess how quickly the immune effects of natalizumab disappear, when MS symptoms return, and if other
Figure 4
Gadolinium-enhanced (Gdⴙ) lesion activity returns to baseline levels during natalizumab treatment interruption
Mean (⫾ standard error) Gd⫹ lesion count (A), and percent of patients with 0 to ⱖ4 Gd⫹ lesions (B) during treatment interruption in patients who received at least one natalizumab infusion. A total of 341 patients were evaluated.
drugs (interferon-1a, methylprednisolone, glatiramer acetate) may help control MS symptoms during a 24-week natalizumab interruption period. Concerns over potential MS disease activity rebound after natalizumab treatment interruption were initially raised in a small (n ⫽ 70) placebo-controlled phase 2 study.4 In that study, 2 infusions of natalizumab significantly reduced the number of new or active lesions on MRI over 12 weeks, but significantly more natalizumab-treated patients experienced a
relapse during a second 12-week posttreatment observation period. This observation is difficult to interpret because a large number of placebo-treated patients experienced fewer relapses during the second 12-week observation period, and there was no evidence of rebound on MRI. An increased number of T2 lesions was observed in a small (n ⫽ 21) group of patients 15 months after discontinuation of natalizumab compared to lesion numbers prior to treatment.13 However, this increase in T2 lesion number during the postnatalizumab period was largely attributable to a subset of patients (n ⫽ 10) who had a short (median of 2 infusions) exposure to natalizumab, which is consistent with a recent report suggesting that MS disease activity (relapses) return during a 4-month treatment interruption seemed to be more likely in patients who received relatively shorter courses of natalizumab therapy.5 While the current analysis of 1,800 natalizumab-treated patients does not provide evidence that the intensity of MS disease activity return during interruption is related to the duration of prior exposure, it remains to be determined whether differences in the amount of activity return after short courses of treatment are of clinical significance. The results of this analysis are consistent with other reports that directly contradict the notion of disease activity rebound consequent to natalizumab treatment interruption. For example, in a larger (n ⫽ 213) phase 2b study that was specifically designed to test for MS disease activity rebound, return of Gd⫹ lesions and relapses after treatment interruption were not different between natalizumab and placebo-treated patients who were followed for a 12-month observation period.6 Similarly, a longitudinal analysis of 22 natalizumab-treated patients from the AFFIRM and SENTINEL trials demonstrated a return, but no rebound, of Gd⫹ lesions, T2 lesion volume, or relapses for the 14-month period after treatment was stopped.7 Recently, a small (n ⫽ 32), mixed cohort of patients with relapsing-remitting and secondary progressive MS was reported to exhibit relapses and severe inflammatory activity on MRI during a 4-month natalizumab interruption.5 While these observations are provocative, interpretation and extrapolation are difficult due to the few patients observed, and the fact that all were refractory to at least one disease-modifying treatment prior to initiating natalizumab, and 72% had failed more than one treatment. Thus, not only does this represent a cohort with severe MS disease, but a true baseline level of disease activity (e.g., prior to any treatment administration) is not known. Interestingly, the degree of inflammatory response during treatment interruption in this cohort was most notable in patients with secondary progressive MS, and those with greater MRI activity prior to natalizumab treatment, which is consistent with the more rapid, greater magnitude of disease activity return Neurology 76
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that occurred in the patients with highly active disease in this analysis. While the present analysis may be limited by an open-label design, post hoc nature, and absence of a control group, these results were derived from the largest sample of patients (⬎1,800) analyzed to date. Further, the voluntary suspension of natalizumab dosing in 2005 provided an 8-month observation period of natalizumab treatment interruption that was adequate to assess “off-treatment” disease course, based on the known pharmacokinetic and pharmacodynamic properties of natalizumab. These data demonstrate that MS disease activity resumes and reaches baseline levels in a time frame consistent with natalizumab elimination kinetics, and is apparently unaffected by the duration of prior natalizumab exposure or alternate MS treatments during treatment interruption. Importantly, while the magnitude of disease activity return was particularly evident in patients with highly active disease prior to starting natalizumab therapy, rebound of disease activity was not observed in any patient group analyzed (a possible effect of alternative medications in patients with highly active disease cannot be completely excluded). These data indicate that a return of disease activity to pretreatment levels should be anticipated soon after natalizumab treatment is interrupted, underscore that the consequences of recurrent MS disease activity should be weighed against potential benefits of PML risk reduction, and should motivate the search for suitable alternatives to a mere treatment interruption. AUTHOR CONTRIBUTIONS Statistical analysis was conducted by Dr. Nisha Lucas.
DISCLOSURE Dr. O’Connor serves on scientific advisory boards for Novartis, sanofiaventis, Bayer Schering Pharma, Genentech, Inc., and Roche; has received funding for travel and/or speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Novartis, and sanofi-aventis; serves/has served as a consultant for Biogen Idec, Actelion Pharmaceuticals Ltd, Bayer Schering Pharma, EMD Serono, Inc., Teva Pharmaceutical Industries Ltd., Genentech, Inc., and Warburg Pincus; and receives research support from Abbott, Bayer Schering Pharma, Daiichi Sankyo, Wyeth, Genmab A/S, Novartis, BioMS Medical, sanofi-aventis, Cognosci, Inc., and Roche; and serves as a National Scientific and Clinical Advisor to the MS Society of Canada. Dr. Goodman serves on a scientific advisory board and/or as a consultant for Biogen Idec; has received funding for travel and speaker honoraria from Acorda Therapeutics Inc., Actelion Pharmaceuticals Ltd, Avanir Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, EMD Serono, Inc., Genentech, Inc., Genzyme Corporation, Novartis, Pfizer Inc, and Teva Pharmaceutical Industries Ltd.; and receives research support from Acorda Therapeutics Inc., Bayer Schering Pharma, Biogen Idec, EMD Serono, Genentech, Inc., Genzyme Corporation, Novartis, Teva Pharmaceutical Industries Ltd., Takeda Pharmaceutical Company Limited, and Ono Pharmaceutical Co. Ltd., the NIH and the Montel Williams Foundation. Dr. Kappos serves on the editorial boards of the International MS Journal and Multiple Sclerosis; receives research support from the Swiss National Research Foundation, the Swiss MS Society, and the Gianni Rubatto Foundation (Zurich); and has served on scientific advisory boards and his Department at the University Hospital Basel has 1864
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received research support from Acorda Therapeutics Inc., Actelion Pharmaceuticals Ltd, Abbott, AstraZeneca, Bayhill Therapeutics, Bayer Schering Pharma, Biogen Idec, Boehringer Ingelheim, Centocor Ortho Biotech Inc., Eisai Inc., Genzyme Corporation, GlaxoSmithKline, The Immune Response Corporation, MediciNova, Inc., Neurocrine Biosciences, Novartis, sanofi-aventis, Merck Serono, Roche, Teva Pharmaceutical Industries Ltd., UCB, and Wyeth. Dr. Lublin has served on scientific advisory boards for and received funding for travel from BioMS Medical and Pfizer Inc; serves on the editorial boards of Multiple Sclerosis, Mount Sinai Medical Journal, and US Neurology; serves/has served as a consultant for and received funding for travel from Pfizer Inc, EMD Serono, Inc., Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, Biogen Idec, Genentech, Inc., Novartis, Genmab A/S, MediciNova, Inc., Actelion Pharmaceuticals Ltd, Allozyne, Inc., sanofi-aventis, Acorda Therapeutics Inc., Questcor Pharmaceuticals, Inc., Avanir Pharmaceuticals, Roche, Celgene, Abbott, and MorphoSys AG; serves on speakers’ bureaus for Pfizer Inc, EMD Serono, Inc., and Teva Pharmaceutical Industries Ltd.; receives research support from Acorda Therapeutics Inc., Biogen Idec, Teva Pharmaceutical Industries Ltd., Novartis, Genentech, Inc., Genzyme Corporation, sanofi-aventis, the NIH/NINDS, and the National Multiple Sclerosis Society; and has current stock ownership and/or financial interests in Cognition Pharmaceuticals. Dr. Miller serves on scientific advisory boards for Novartis, GlaxoSmithKline, Bayer Schering Pharma, Biogen Idec, and the NIH; has received funding for travel or speaker honoraria from Biogen Idec, Novartis, Bayer Schering Pharma, GlaxoSmithKline, the National MS Society and Cleveland Clinic; receives publishing royalties for McAlpines Multiple Sclerosis, fourth edition (Churchill Livingstone, 2005); serves as a consultant for GlaxoSmithKline and Biogen Idec; receives research support (through his institution) from Biogen Idec, GlaxoSmithKline, Schering-Plough Corp., and Novartis; and receives research support from the MS Society of Great Britain & Northern Ireland and the NIH. Dr. Polman serves on scientific advisory boards for and has received funding for travel and speaker honoraria from Actelion Pharmaceuticals Ltd, Biogen Idec, Bayer Schering Pharma, GlaxoSmithKline, Teva Pharmaceutical Industries Ltd., Merck Serono, Novartis, and UCB, Roche; serves on the editorial boards of Lancet Neurology and Multiple Sclerosis; and receives research support from Biogen Idec, Merck Serono, Novartis, UCB, European Community Brussels, and MS Research Foundation Netherlands. Dr. Rudick has served as a consultant for Wyeth, Genzyme Corporation/Bayer Schering Pharma, Bayhill Therapeutics, Pfizer Inc, Teva Pharmaceutical Industries Ltd., Biogen Idec, and Novartis; has received funding for travel or speaker honoraria from Biogen Idec, Genzyme Corporation, Wyeth, and Biogen Idec; receives royalties from the publication of Multiple Sclerosis Therapeutics, third edition (Informa Healthcare, 2007); and receives research support from Biogen Idec, Elan Corporation, and the NIH. Dr. Aschenbach is a full-time employee of and owns stock in Biogen Idec. Dr. Lucas is a full-time employee of and owns stock in Biogen Idec.
Received August 7, 2010. Accepted in final form December 27, 2010.
REFERENCES 1. Yousry TA, Habil M, Major EO, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924 –933. 2. Berger JR, Centonze D, Comi G, et al. Considerations on discontinuing natalizumab for the treatment of multiple sclerosis. Ann Neurol 2010;68:409 – 413. 3. Clifford DB, De Luca A, Simpson DM, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010;9:438 – 446. 4. Tubridy N, Behan PO, Capildeo R, et al. The effect of anti-␣4 integrin antibody on brain lesion activity in MS. Neurology 1999;53:466 – 472. 5. Miravalle A, Jensen R, Kinkel RP. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis
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following cessation of natalizumab therapy. Arch Neurol 2011;68:186 –191. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15–23. Stu¨ve O, Cravens P, Frohman E, et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 2009;72:396 – 401. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353:369 –374. Langer-Gould A, Atlas S, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375–381. Polman CH, O’Connor P, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899 –910.
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Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1 for relapsing multiple sclerosis. N Engl J Med 2006;354:911–923. 12. Goodman AD, Rossman HS, Bar-Or A, et al. GLANCE: results of a phase 2, randomized, doubleblind, placebo-controlled study. Neurology 2009;72: 806 – 812. 13. Vellinga MM, Castelijns JA, Barkhof F, et al. Postwithdrawal rebound increase in T2 lesional activity in natalizumabtreated patients. Neurology 2008;70:1150 –1151. 14. TYSABRI® (natalizumab) package insert. Cambridge, MA: Biogen Idec Inc.; 2008. 15. Niino M, Bodner C, Simard M-L, et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol 2006;59:748 –754. 16. Stu¨ve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006;59:743–747.
Historical Abstract: October 1, 1971 A DOUBLE-BLIND STUDY OF THE EFFECTS OF LEVODOPA IN PARKINSON’S DISEASE KK Nakano, HR Tyler Neurology 1971;21:1069-1074 There is considerable evidence suggesting that the symptoms of parkinsonism are related to a depletion of striatal dopamine.1-4 Since oral dopamine does not cross the blood-brain barrier, efforts have focused on the systemic administration of L-dopa, dopamine’s immediate precursor, which appears to pass through the barrier. Recent studies indicate that L-dopa is rapidly becoming the treatment of choice in parkinsonism.5-8 In the present study, a double-blind therapeutic trial has been used in the treatment of Parkinson’s syndrome. The purpose of the study is to compare L-dopa to a conventional antiparkinsonian medication (procyclidine hydrochloride) and a placebo (lactose). Additionally, this study has been designed to determine whether a two- to six-week period is an adequate length of time to see the benefits of L-dopa therapy in parkinsonian patients receiving no other medication. It was also designed so that a patient could continue to take any drug that brought about significant improvement; in such cases, he was not required to try the other drugs in the study. References can be found in the online article. Free Access to this article at www.neurology.org/content/21/10/1069 Comment from Ryan J. Uitti, MD, FAAN, Associate Editor: This was a landmark study documenting the monumental effects of the best treatment for the most common movement disorder.
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Stress and the risk of multiple sclerosis
T. Riise, PhD D.C. Mohr, PhD K.L. Munger, ScD J.W. Rich-Edwards, PhD I. Kawachi, MD A. Ascherio, MD
Address correspondence and reprint requests to Dr. T. Riise, Department of Public Health and Primary Health Care, University of Bergen, Kalfarveien 31, N-5018 Bergen, Norway
ABSTRACT
Objective: Several studies have shown that stressful life events are associated with a subsequent significant increase in risk of multiple sclerosis (MS) exacerbations. We wanted to study prospectively whether stress can increase the risk of developing the disease itself. Methods: We studied 2 cohorts of female nurses: the Nurses’ Health Study (NHS) (n ⫽ 121,700) followed from 1976 and the Nurses’ Health Study II (NHS II) (n ⫽ 116,671) followed from 1989. The risk of MS after self-report on general stress at home and at work in the NHS in 1982 was studied prospectively using Cox regression. Logistic regression was used to retrospectively estimate the effects of physical and sexual abuse in childhood and adolescence collected in the NHS II 2001. We identified 77 cases of MS in the NHS by 2005 and 292 in the NHS II by 2004. All analyses were adjusted for age, ethnicity, latitude of birth, body mass index at age 18, and smoking. Results: We found no increased risk of MS associated with severe stress at home in the NHS (hazard ratio 0.85 [95% confidence interval (CI)] 0.32–2.26). No significantly increased risk of MS was found among those who reported severe physical abuse during childhood (odds ratio [OR] 0.68, 95% CI 0.41–1.14) or adolescence (OR 0.77, 95% CI 0.46–1.28) or those having been repeatedly forced into sexual activity in childhood (OR 1.47, 95% CI 0.87–2.48) or adolescence (OR 1.21, 95% CI 0.68–2.17).
Conclusions: These results do not support a major role of stress in the development of the disease, but repeated and more focused measures of stress are needed to firmly exclude stress as a potential risk factor for MS. Neurology® 2011;76:1866–1871 GLOSSARY BMI ⫽ body mass index; CI ⫽ confidence interval; MS ⫽ multiple sclerosis; NHS ⫽ Nurses’ Health Study; OR ⫽ odds ratio.
Multiple sclerosis (MS) is a chronic autoimmune disease affecting the CNS with unknown causes. It appears that the etiology is multifactorial, including both genetic and environmental components.1-3 Exposure to stress has long been suspected as a factor that can aggravate MS. There are many studies showing that among people diagnosed with MS, stressful life events are associated with a significant increase in risk of MS exacerbation in the weeks or months following onset of the stressor.4 A number of mechanisms have been proposed, including mediation between stressful events and the immune system via the glucocorticoid and the -adrenergic pathways.5,6 But it is not known whether stressful life events could increase the risk of developing the disease itself. In spite of a general concern of such a relation particularly among many patients who report that they had been going through a stressful period prior to their first symptom of their disease, few studies have addressed this question. One prospective study found that among people without MS a traumatic stressor, the death of a child, significantly increased the risk of subsequent diagnosis with MS.7 Moreover, the effect was strongest for parents who lost their child From the Department of Public Health and Primary Health Care (T.R.), University of Bergen, Bergen; The Norwegian Multiple Sclerosis Competence Centre (T.R.), Haukeland University Hospital, Bergen, Norway; Department of Preventive Medicine (D.C.M.), Feinberg School of Medicine, Northwestern University, Chicago, IL; Departments of Nutrition (K.L.M., A.A.), Epidemiology (J.W.R.-E., A.A.), and Society, Human Development & Health (I.K.), Harvard School of Public Health, Boston; and Connors Center for Women’s Health and Gender Biology (J.W.R.-E.) and Channing Laboratory (A.A.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. Study funding: Supported by the NIH/NINDS (NS042194 and NS046635). Disclosure: Author disclosures are provided at the end of the article. 1866
Copyright © 2011 by AAN Enterprises, Inc.
suddenly, as compared with those who did not, suggesting a possible dose effect. This suggests that stress not only can affect pathogenic processes in patients with MS, but that traumatic stressors can affect the risk of ever developing clinically diagnosable MS. Therefore, we estimated the risk of developing MS related to major stress at work and at home and sexual and physical trauma in childhood in 2 large cohorts of US women. METHODS Study population. The study population comprised women participating in 2 prospective studies of female registered nurses living in the United States: the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHS II). The NHS was established in 1976 and recruited 121,700 nurses aged 30 to 55 years; the NHS II was established in 1989 and recruited 116,671 nurses aged 25 to 42 years. Every 2 years, women in these cohorts update lifestyle factors and are asked to report to us any major disease diagnoses, including MS. The procedure for ascertainment of the MS cases in these cohorts and the validity of this approach have previously been reported.8,9 Briefly, women reporting a new diagnosis of MS are asked for permission for study investigators to contact their neurologists. The neurologists completed a questionnaire regarding the diagnosis including the certainty of the diagnosis (definite, probable, possible, not MS, based on Poser criteria), clinical history (including date of MS diagnosis and date of the first symptoms of MS), and the results of laboratory tests including MRI. The diagnosis was supported by positive MRI findings in 76% (NHS) and 89% (NHS II) of the cases, reflecting a higher proportion of cases with recent onset in the NHS II. By June 2004, we documented 94 cases of definite and probable MS in the NHS with onset of symptoms after baseline in 1982 (when the exposure to stress was assessed). In the NHS II, there were 509 definite and probable cases by the end of 2005 with onset of symptoms during the study period, of whom 460 cases had had onset before the information on childhood trauma was ascertained in 2001.
Stress measurements. In 1982, a total of 110,282 of the participants of NHS were sent a questionnaire including questions on stress at home and at work. A total of 94,185 of the nurses responded to this questionnaire, including 77 nurses who later developed MS. They were asked “How would you rate the amount of stress in your daily life? i) at home ii) at work” with “minimal,” “light,” “moderate,” or “severe” as the response categories. This measure of stress has previously been shown to be a major predictor for suicide in this cohort.10 The 2001 questionnaire sent to the participants of the NHS II included 22 questions on physical and sexual abuse in childhood and adolescence. Such traumas can fundamentally alter systems that mediate the effect of stress (e.g., sensitization of neuroendocrine response), reduce neuroendocrine regulation of inflammation (e.g., glucocorticoid resistance), and increase inflammatory activity.11 These effects can extend into adulthood, suggesting that these systems are permanently altered by childhood trauma.12 Child and adolescent sexual abuse was measured by questions regarding unwanted sexual touching and forced sexual activity adapted from a national survey conducted in 1995,13,14
while the questions on physical abuse were adapted from the Revised Conflict Tactics Scale.15 A total of 68,505 women responded to this questionnaire (response rate of 75%) including 292 individuals who had developed MS between 1989 and 2001 or after the survey in 2001. Physical abuse was measured querying whether a participant’s parent, stepparent, or adult guardian ever did the following to them: pushed, grabbed, or shoved; kicked, bit, or punched; hit with something that hurt; choked or burned; or physically attacked in some other way. For each type of physical abuse, respondents were asked about the frequency of the event (never, once, a few times, more than a few times). Questions were asked separately for childhood (up to age 11 years) and adolescence (ages 11–17 years). As described elsewhere,6 a categorical physical abuse severity scale for childhood and adolescence was created ranging from a minimum score of 0 ⫽ no physical abuse, 1 ⫽ mild physical abuse, 2 ⫽ moderate physical abuse, and 3 ⫽ severe physical abuse. Those who had abuse experiences in several categories (e.g., those who experienced both mild and severe abuse) were classified as having the highest severity category. Items on sexual abuse in childhood and adolescence included a question on forced sexual touching: “Were you ever touched in a sexual way by an adult or an older child or were you forced to touch an adult or an older child in a sexual way when you did not want to?” and a question on forced sexual activity: “Did an adult or older child ever force you or attempt to force you into any sexual activity by threatening you, holding you down, or hurting you in some way when you did not want to?” Respondents could answer “no, this never happened”; “yes, this happened once”; or “yes, this happened more than once.” These questions on early physical and sexual abuse have previously been shown to be a predictor of diabetes and of an early start of smoking in the same study population.16,17 For both studies, information on smoking (never/past/current, pack-years: ⬍10 packs/y, 10 –24, 25⫹), body mass index (BMI) at age 18 (in kg/m2: ⬍18.5, 18.5–21, 21–23, 23–25, 25–27, 27–30, 30⫹), ethnicity (Scandinavian, Southern European, other Caucasians, others), and latitude at birth (south tier, middle tier, north tier) was available. The distribution of these covariates in the 2 cohorts has previously been reported.9,18,19 The marked difference in the number of MS cases in the 2 cohorts reflects the prospective design in the NHS compared to the use of all prevalent cases in the NHS II. Further, the NHS II is also a younger cohort of women—they were 25– 42 years old at baseline compared with 30 –55 in the NHS. Thus, the NHS women were largely past the age of peak MS incidence.
Standard protocol approvals and patient consents. Approval was received from the Brigham and Women’s Hospital institutional review board, and written informed consent was obtained from all patients participating in the study.
Statistical methods. Analyses in the NHS were completely prospective (i.e., women who already had developed MS at the time level of stress was assessed [1982] were excluded from the analysis) and Cox proportional hazards models, conditioned on age and follow-up cycle, were used to estimate the risk of MS in the subgroups of reported stress at home or at work. Logistic regression was used to conduct a bidirectional analysis (retrospective considering cases from 1989 to 2001 and prospective considering cases from 2001 to 2005) of the associations of physical and sexual abuse on the risk of MS in the NHS II. All analyses in both cohorts were adjusted for age, ethnicity, latitude of birth, BMI at age 18, and smoking. Neurology 76
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Table 1
Incidence rates and hazard ratios of multiple sclerosis by levels of home and work stress in the Nurses’ Health Study 1982–2003 (n ⴝ 94,185) Total cohort, n (%)
MS cases, n (%)
IRa
HRb
HRc (95% CI)
Minimal
17,498 (19)
13 (17)
3.6
1
1
Light
27,447 (29)
25 (32)
4.4
0.91
0.88 (0.44–1.73)
Moderate
40,856 (43)
32 (42)
3.8
0.78
0.75 (0.39–1.45)
Severe
7,309 (8)
6 (8)
4.0
0.87
0.85 (0.32–2.26)
Missing
1,075 (1)
1 (1)
4.6
1.18
1.23 (0.16–9.48)
7,862 (8)
6 (8)
3.7
1
1
Light
15,172 (16)
21 (27)
6.6
1.67
1.64 (0.66–4.07)
Moderate
40,967 (44)
30 (39)
3.5
0.91
0.90 (0.38–2.18)
Severe
10,296 (11)
4 (5)
1.9
0.52
0.52 (0.15–1.85)
Missing
19,888 (21)
16 (21)
4.0
1.33
1.38 (0.54–3.54)
Home stress
Work stress Minimal
Abbreviations: HR ⫽ hazard ratio; IR ⫽ incidence rate; MS ⫽ multiple sclerosis. a Crude incidence rates per 100,000 person-years of follow-up. b Hazard ratios adjusted for age in 5-year groups. c Hazard ratios adjusted for age, ethnicity, latitude of birth, body mass index at age 18, and smoking (never, ⬍10 packs/year, 10–24 packs/year, 25⫹ packs/year).
Based on the known distribution of the stress variables and the number of cases in the cohorts, we estimated a statistical power of 0.54 to detect a relative risk of 2.0 for comparing severe stress (prevalence ⫽ 10%) with little/no stress (90%) in the NHS and 0.90 for comparing severe physical/sexual abuse (7%) with less/no abuse (93%) in the NHS II.
Table 2
Odds ratios and 95% confidence intervals of risk of multiple sclerosis by severity of physical abuse in childhood (n ⴝ 68,321) and adolescence (n ⴝ 68,325)a No. (%) noncases
No. (%) MS cases
ORb
95% CI
Severity of physical abuse in childhood (3.0)
Tibial F-wave latency (normal for height)
1
0
0
5.0
42
6.4
53 (⬍55)
2
0
NR
6.5
43
3.2
61 (⬍56)
3
0
NR
7.0
38
6.4
57 (⬍53)
4
NR
0
4.5
50 (Median)
7.8 (Median)
27 (⬍ 26; median)
5
0
0
4.9
41
6.0
51 (⬍53)
6
0
0
5.1
42
8.5
50 (⬍53)
7
0
0
7.0
38
1.7
57 (⬍60)
8
0
0
4.8
45
7.4
53 (⬍54)
9
0
0
4.7
47
9.9
46 (HNR)
10
0
0
6.6
41
17
4.9 (HNR)
11
0
0
8.0
29
2.1
31 (HNR) (median)
12
0
0
4.6
51
5.7
52 (⬍57)
13
0
NR
6.9
31
0.5
NR
14
0
0 (Median)
5.3
34
2.9
73 (HNR)
15
NR
0
7.6
48 (Peroneal)
0.9
NR
16
NR
0
6.4
53 (Peroneal)
1.4 (Peroneal)
NR
17
0
0
4.4
50
17
NR
18
0
0
5.1
40
3.8
52 (HNR)
Abbreviations: 0 ⫽ absent; DML ⫽ distal motor latency; HNR ⫽ height not recorded; N ⫽ normal; NCV ⫽ nerve conduction velocity; NR ⫽ not recorded; SNAP ⫽ sensory nerve action potential. Neurology 76
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1907
Figure 2
T1-weighted MRI illustrating the spectrum of cerebellar atrophy found in the cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS)
(A) Sagittal view of very mild cerebellar atrophy; (B) parasagittal view of very mild cerebellar atrophy; (C) sagittal view of very mild cerebellar atrophy; (D) parasagittal view of very mild cerebellar atrophy; (E) sagittal view of mild cerebellar atrophy; (F) parasagittal view of mild cerebellar atrophy; (G) sagittal view of moderate cerebellar atrophy; (H) parasagittal view of moderate cerebellar atrophy; (I) sagittal view of non-CANVAS pattern cerebellar atrophy for comparison; (J) parasagittal view of non-CANVAS pattern cerebellar atrophy for comparison; (K) parasagittal view of the labeled cerebellar lobules, and crus I and II; (L) sagittal view of the labeled cerebellar lobules.
strated that enhancement of the cervico-ocular reflex, one mechanism thought to be responsible for functional adaptation in patients with isolated bilateral vestibular failure, is absent in patients with additional cerebellar involvement, a factor which may also contribute to the prominent disability in this group.1,13 1908
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Additionally, we have found that a consistent pattern of cerebellar atrophy is present on MRI scanning. However, while likely to be invariably demonstrable in the more advanced stages of the disorder, it should be noted that this configuration of atrophy is not pathognomonic for CANVAS and
can, for example, be seen in combination with pontine atrophy in patients with multiple system atrophy of cerebellar type. A similar pattern of crus I atrophy is also evident in a published case of SCA 12.14 Further, prospective, blinded neuroradiologic assessment would be required to establish the sensitivity and specificity of this pattern for clinically diagnosed CANVAS. The 2 MRI scans that demonstrated a radiologically normal cerebellar appearance were taken 4 and 5 years prior to the patients’ assessment for this study, and as such, likely indicate that the MRI scan may be normal in the earlier stages of the disease. A similar conclusion was reached by others,6 and it seems probable to us that their separation of those patients with ataxia and vestibulopathy but without cerebellar atrophy on MRI from those with the same constellation of clinical findings but with cerebellar atrophy on MRI is artificial. A longitudinal study with repeated MRI scanning will be required to settle this point conclusively, however. Whether apparently sporadic cerebellar ataxia plus vestibular failure but without sensory neuropathy, as described in some patients in 2 previous series,5,6 is the same condition as CANVAS is as yet unclear. Neuropathy might develop later in some patients, requiring careful longitudinal study for its exclusion, or it might be inapparent clinically, and escape attention unless NCS are done routinely, as in our patients 16 and 18. In at least one case, neuropathy preceded the other clinical features by a period of years. It is worth emphasizing that although all 18 of our patients had absent SNAPs, they were initially selected purely for the presence of cerebellar impairment with vestibular failure, regardless of the presence of neuropathy. This suggests, at least, that further series should include NCS routinely, and perhaps longitudinally, to determine the true frequency of neuropathy in CANVAS. On the basis of our series, NCS can at least be suggested as a useful adjunctive test in such patients. It is also clear from our series and from the original description of CABV that downbeating nystagmus is by no means a uniform feature of CANVAS,4 despite one previous series having originally selected the patients for their series on the basis of its presence.6 While the combination of late-onset recessive or sporadic progressive ataxia (usually with cerebellar atrophy), vestibular failure, and sensory neuropathy is distinctive, various aspects of the disorder may be mimicked by other conditions. Of the dominantly inherited ataxias, spinocerebellar ataxia type 3 (SCA 3; Machado-Joseph disease) may combine impairment of VOR gain,15–18 and neuropathy,19,20 with ataxia. Distinguishing features from CANVAS include a family history consistent with a dominant
disorder, and a pattern of MRI involvement resulting in enlargement of the fourth ventricle (presumably partly as a result of prominent dentate nucleus involvement) with atrophy of vermal lobules I, II, IV, VIIIb, and IX, but without cerebellar hemispheric atrophy.19 –21 The neuropathy in SCA 3 also typically affects motor as well as sensory neurons/fibers,20 in contrast to the severe sensory impairment with frequently normal motor studies in CANVAS. Other SCAs typically (SCA 4, 25)22,23 or sometimes (SCAs 1, 8, 27)24 –26 manifest sensory neuropathy, while a sensorimotor neuropathy was a feature of the only family described to date with SCA 18.27 Sensory loss is a typical although not universal feature of SCA 2, but the typically slow saccades and preserved VOR gain,15 obvious brainstem atrophy on MRI, and dominant inheritance help to exclude this disorder. Friedreich ataxia (FRDA) is characterized by loss of sural SNAPs with preserved motor conduction velocities,28,29 and, being a common recessively inherited disorder, may appear to be sporadic. While a severe vestibulopathy has been found to be a component of FRDA,30 the disease typically has an onset below 25 years, although rare late-onset cases may present even after age 60.28 Furthermore, the MRI appearance is not reminiscent of CANVAS: the cerebellar cortex is relatively spared until late in the disease course, and the spinal cord is typically atrophic.28 ACKNOWLEDGMENT The authors thank the following neurologists who referred subjects for this study: Peter J. Hand, John King, and Philip D. Thompson.
DISCLOSURE Dr. Szmulewicz and Dr. Waterston report no disclosures. Dr. Halmagyi serves on the scientific board for the Brain Foundation of Australia; serves on the editorial boards of Acta Otolaryngologica, Otology, Neurotology, Audiology, Neuro-otology, and the Italian Journal of Otolaryngology; has served as a consultant for GN Otometrics; and receives research support from the National Health and Medical Research Council. Dr. Mossman reports no disclosures. Dr. Chancellor has received funding for travel from Biogen Idec and sanofi-aventis and serves on the editorial board for Practical Neurology. Dr. McLean reports no disclosures. Dr. Storey has received funding for travel (and speaker honoraria payable to his institution) from Pfizer Inc; serves as Neurology Co-Editor for Journal of Clinical Neuroscience; and receives research support from National Health and Medical Research Council (Australia), the NIH, Alfred Hospital Research Foundation, Wicking Foundation, and Bethlehem-Griffiths Foundation.
Received December 24, 2010. Accepted in final form January 6, 2011.
REFERENCES 1. Bronstein AM, Mossman S, Luxon LM. The neck-eye reflex in patients with reduced vestibular and optokinetic function. Brain 1991;114:1–11. 2. Rinne T, Bronstein AM, Rudge P, et al. Bilateral loss of vestibular function. Acta Otolaryngol 1995;(suppl 520): 247–250. Neurology 76
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Rinne T, Bronstein AM, Rudge P, et al. Bilateral loss of vestibular function: clinical findings in 53 patients. J Neurol 1998;245:314 –321. Migliaccio AA, Halmagyi GM, McGarvie LA, et al. Cerebellar ataxia with bilateral vestibulopathy: description of a syndrome and its characteristic clinical sign. Brain 2004; 127:280 –293. Zingler VC, Cnyrim C, Jahn K, et al. Causative factors and epidemiology of bilateral vestibulopathy in 255 patients. Ann Neurol 2007;61:524 –532. Wagner JN, Glaser M, Brandt T, Strupp M. Downbeat nystagmus: aetiology and comorbidity in 117 patients. J Neurol Neurosurg Psychiatry 2008;79:672– 677. Palla A, Schmid-Priscoveanu A, Studer A, Hess K, Straumann D. Deficient high-acceleration vestibular function in patients with polyneuropathy. Neurology 2009;72: 2009 –2013. Halmagyi GM, Cuthroys IS. A clinical sign of canal paresis. Arch Neurol 1988;45:737–739. Baloh RW, Kerber KA. Clinical Neurophysiology of the Vestibular System, 4th ed. New York: Oxford University Press; 2011:155. Martina ISJ, van Koningsveld R, Schmitz PIM, et al. Measuring vibration threshold with a graduated tuning fork in normal aging and in patients with polyneuropathy. J Neurol Neurosurg Psychiatry 1998;65:743–747. Schmahmann JD, Doyon J, Petrides M, Evans et al. MRI Atlas of the Human Cerebellum. San Diego: Academic Press; 2000. Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP): report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology 1991;41:617– 618. Waterston JA, Barnes GR, Grealy MA, Luxon LM. Coordination of eye and head movements during smooth pursuit in patients with vestibular failure. J Neurol Neurosurg Psychiatry 1992;55:1125–1131. Holmes SE, Hearn EO, Ross CA, Margolis RL. SCA12: an unusual mutation leads to an unusual spinocerebellar ataxia. Brain Res Bull 2001;56:397– 403. Buttner N, Geschwind D, Jen JC, et al. Oculomotor phenotypes in autosomal dominant ataxias. Arch Neurol 1998;55:1353–1357. Burk K, Fetter M, Abele M, et al. Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2 and SCA3. J Neurol 1999;246: 789 –797.
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Takegosh H, Murofushi T. Vestibular evoked myogenic potentials in patients with spinocerebellar degeneration. Acta Otolaryngol 2000;120:821– 824. Gordon CR, Joffe V, Vainstein G, Gadoth N. Vestibuloocular areflexia in families with spinocerebellar ataxia type 3 (Machado-Joseph disease). J Neurol Neurosurg Psychiatry 2003;74:1403–1406. Schols L, Amoiridis G, Buttner T, et al. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol 1997;42:924 –932. Klockgether T, Schols L, Abele M, et al. Age related axonal neuropathy in spinocerebellar ataxia type 3/MachadoJoseph disease (SCA3/MJD). J Neurol Neurosurg Psychiatry 1999;66:222–224. Lukas C, Schols L, Bellenberg B, et al. Dissociation of grey and white matter reduction in spinocerebellar ataxia type 3 and 6: a voxel-based morphometry study. Neurosci Lett 2006;408:230 –235. Flanigan K, Gardner K, Alderson K, et al. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 1996;59: 392–399. Stevanin G, Bouslam N, Thobois S, et al. Spinocerebellar ataxia with sensory neuropathy (SCA25) maps to chromosome 2p. Ann Neurol 2004;55:97–104. Subramony SH, Vig PJS. Clinical aspects of spinocerebellar ataxia 1. In: Wells RD, Warren ST, eds. Genetic Instabilities and Hereditary Neurological Diseases. San Diego: Academic Press; 1998:231–239. Koob MD, Moseley ML, Schut LJ, et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet 1999;21:379 –384. Dalski A, Atici J, Kreuz FR, et al. Mutation analysis in the fibroblast growth factor 14 gene: frameshift mutation and polymorphisms in patients with inherited ataxias. Eur J Hum Genet 2005;13:118 –120. Brkanac Z, Fernandez M, Matsushita M, et al. Autosomal dominant sensory/motor neuropathy with ataxia (SMNA): linkage to chromosome 7q22-q32. Am J Med Genet 2002; 114:450 – 457. Pandolfo M. Friedreich ataxia. Semin Pediatr Neurol 2003;10:163–172. Alper G, Narayanan V. Friedreich’s ataxia. Pediatr Neurol 2003;28:335–341. Fahey MC, Cremer PD, Aw ST, et al. Vestibular, saccadic and fixation abnormalities in genetically confirmed Friedreich ataxia. Brain 2008;131:1035–1045.
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Clinical and MRI characteristics of acute migrainous infarction
M.E. Wolf, MD K. Szabo, MD M. Griebe, MD A. Fo¨rster, MD A. Gass, MD M.G. Hennerici, MD R. Kern, MD
Address correspondence and reprint requests to Dr. Marc E. Wolf, Department of Neurology, Universita¨tsMedizin Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
[email protected] ABSTRACT
Objective: Migrainous infarction is considered a rare complication of migraine. Although several studies reported silent brain lesions on neuroimaging in patients with migraine with aura, knowledge about lesion patterns in acute migrainous infarction is scarce. We investigated clinical and MRI characteristics in a series of patients with migraine-associated acute cerebral ischemia. Methods: Seventeen patients among 8,137 stroke patients over an 11-year period were included. All had undergone a dedicated stroke workup including diffusion-weighted imaging (DWI) and a detailed assessment of clinical features and of vascular risk factors.
Results: The majority of patients presented with prolonged aura symptoms (visual aura 82.3%, sensory dysfunction 41.2%, and aphasia 5.9%; median NIH Stroke Scale score 2). Presentation at hospital was significantly delayed after symptom onset (mean 33 hours). A total of 70.6% had acute ischemic lesions in the posterior circulation; the middle cerebral artery territory was affected in 29.4%. Small lesions were present in 64.7%; multiple lesions were found in 41.2%. No overlapping ischemic lesions of different vascular territories were found. The prevalence of a patent foramen ovale was high (64.7%).
Conclusions: This study supports previous observations that migrainous infarction mostly occurs in the posterior circulation, and in younger women with a history of migraine with aura. Acute ischemic lesions were often multiple and located in distinct arterial territories. As there were no overlapping ischemic lesions, hemodynamic compromise during the development of migraine is unlikely the cause of infarction. Differentiation between migrainous infarction and prolonged migraine aura is difficult and associated with delayed admission of patients. Neurology® 2011;76:1911–1917 GLOSSARY CADASIL ⫽ cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CSD ⫽ cortical spreading depression; DWI ⫽ diffusion-weighted imaging; FLAIR ⫽ fluid-attenuated inversion recovery; IHS ⫽ International Headache Society; MA ⫽ migraine with aura; MO ⫽ migraine without aura; MRA ⫽ magnetic resonance angiography; mRS ⫽ modified Rankin scale; NIHSS ⫽ NIH Stroke Scale; NSAID ⫽ nonsteroidal anti-inflammatory drug; PCA ⫽ posterior cerebral artery; PFO ⫽ patent foramen ovale; TCD ⫽ transcranial Doppler ultrasound; TOF ⫽ time-of-flight; TTP ⫽ time-to-peak.
Migrainous infarction is considered a rare complication of migraine. Epidemiologic studies have shown that 0.5%–1.5% of all ischemic strokes are migrainous infarctions.1-3 Among younger patients with unusual etiology, migrainous infarction was reported to account for 13% of first-ever ischemic strokes.4 Transient neurologic symptoms are typical for migraine with aura (MA), but differentiation among migrainous aura, transient ischemic attacks, and migrainous infarction can be very difficult or even impossible on clinical grounds alone. Brain imaging is essential for diagnosis of migrainous infarction according to the criteria of the International Headache Society (IHS): “a typical attack of MA in a patient with a history of MA and evidence of cerebral ischemia proven by neuroimaging.”5 This definition additionally requires precise details from medical history since true migrainous infarction is only one of several migraine-related stroke syndromes.6 Previous CT- and MRI-based studies have investigated the ischemic lesion patterns in patients with migraine. Silent infarctions were detected predominantly in the posterior circula-
From the Department of Neurology, Universita¨tsMedizin Mannheim, University of Heidelberg, Mannheim, Germany. Disclosure: Author disclosures are provided at the end of the article. Copyright © 2011 by AAN Enterprises, Inc.
1911
tion territory,7,8 especially in MA.9,10 The majority of these studies were designed to study patients in the asymptomatic phase; only few cases of acute migrainous infarction have been reported.11-14 The aim of this study was to describe ischemic lesion patterns on diffusion-weighted MRI (DWI) in patients with acute migrainous infarction with respect to the affected vascular territory and number and size of ischemic lesions. In addition, we sought to evaluate clinical features, relevant cardiovascular risk factors, prior migraine history, and outcome of this uncommon stroke etiology. METHODS Subjects. Prospectively collected data of 8,137 stroke patients admitted to the Stroke Unit of our institution between 1998 and 2009 were screened for subjects with acute migrainous infarction or migraine-associated cerebral ischemia. Inclusion criteria were 1) a history of MA or migraine without aura (MO), 2) presentation with neurologic symptoms and headache compatible with a migraine attack, 3) MRI including DWI performed no later than 24 hours after admission, and 4) presence of acute ischemic lesions on DWI. Patients were excluded if they had cerebral infarction of other cause coexisting with migraine, and if MRI including DWI was not performed or did not show acute ischemic lesions. Clinical data and technical investigations were collected and recorded according to a standardized acute stroke care protocol: physical and neurologic examination including the NIH Stroke Scale (NIHSS) score on admission and during hospitalization, the modified Rankin scale (mRS) at 3 months, cardiovascular risk factors, Doppler and duplex ultrasound of the extracranial vessels, transcranial Doppler ultrasound (TCD), transthoracic echocardiography, 24-hour ECG and blood pressure monitoring, oxygen saturation (pulse oximetry) and laboratory tests with tests of the coagulation system including D-dimer, and screening for vasculitis. All included patients had a screening for a patent foramen ovale (PFO) using TCD with the galactose-based microbubbles contrast agent Echovist® or transesophageal echocardiography. PFO grades were defined according to published criteria.15,16 Patients were further assigned to 2 groups depending on their migraine history. Patients of group 1 had a typical history of MA and evidence of acute cerebral ischemia on DWI, complying with the IHS criteria for acute migrainous infarction.5 Patients of group 2 had a history of MO (thus not fulfilling the IHS criteria in the strict sense) and presented with first-ever neurologic symptoms compatible with MA and concomitant migraine headaches.
MRI studies. According to our predefined institutional standard stroke protocols, all MRI datasets from a 1.5-Tesla scanner included T1-weighted and T2-weighted sequences, fluidattenuated inversion recovery (FLAIR), DWI (b ⫽ 0, 500, and 1,000 s/mm2 with sequential application of 3 separate diffusion sensitizing gradients in perpendicular directions), and 3-dimensional time-of-flight (TOF) magnetic resonance angiography (MRA). Structured visual analysis of DWI was performed to characterize the hyperintense acute lesions in their location and extent. Infarct pattern characteristics such as number of lesions, cortical or subcortical location, and the affected territory 1912
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were described in all subjects. T1-weighted, T2-weighted, and FLAIR images were analyzed visually for preexisting chronic tissue damage (e.g., white matter lesions, territorial stroke). On coronal and transverse views of 3-dimensional MRA reconstruction, the following MRA characteristics of the flow signal were recorded: 1) absence of flow signal indicating vessel occlusion, 2) flow signal reduction in the ipsilateral artery of the affected territory compared to contralateral side indicating reduced blood flow, 3) flow signal interruption as a sign of focal higher grade stenosis, 4) normal flow signal, and 5) asymmetrically stronger flow signal as potential sign for hyperperfusion. In order to define hemodynamic alterations due to vascular pathology, calculated time-to-peak (TTP) images demonstrating the arrival of the contrast agent bolus in the brain parenchyma were additionally employed in 8 subjects. TTP map lesions were identified visually as parenchymal areas of increased signal intensity. In conformity with these findings, perfusion MRI studies were classified as normal, hyperperfused, or hypoperfused in any areas of brain parenchyma.
Clinical presentation and history of migraine. Clinical features on admission such as clinical presentation, character of onset (abrupt, progressive, or fluctuating), duration, severity, and occurrence of headaches, and other neurologic symptoms were obtained from medical records. All patients were contacted by telephone for a structured interview. They were asked to recall their symptoms at the index event, reasons for seeking medical help, and whether there was a difference between symptoms of the index event and their previous migraine attacks. A detailed report on the history of migraine (with or without aura, frequency and duration of prior attacks, medication), on persisting neurologic deficits after the index event, and on migraine characteristics and severity after cerebral ischemia was obtained during this telephone interview. The mean time interval between the index event and the telephone interview was 41 ⫾ 27.6 months (range 4 –93 months). Standard protocol approvals and patient consents. Ethical approvals for collection and analysis of individuals’ data were obtained according to appropriate national regulations. Patients gave written consent for participation in this study.
Twenty-two eligible patients were identified from the database of whom 17 (4 male and 13 female, mean age 44.6 ⫾ 15.9 years, range 20 –71 years) were included and further assigned to 2 groups depending on their migraine history (group 1: n ⫽ 11 [64.7%], group 2: n ⫽ 6 [35.3%]). The remaining 5 patients were excluded from the study because a competing etiology was identified after complete stroke workup: one patient had a carotid artery dissection, one a mitral valve endocarditis, one a coronary angiography 3 days prior to symptom onset; in another patient, a heterozygote factor V Leiden mutation associated with a protein S deficiency was found. Finally, one patient had a positive diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
RESULTS
MRI findings. MRI studies were performed between 2
hours and 7 days after onset, depending on the time of
Figure 1
Diffusion-weighted imaging lesion patterns of 11 patients with migrainous infarction (group 1)
Patients 1–4 have multiple small lesions, patients 5–8 have isolated lesions in the posterior circulation territory, and patients 9–11 have isolated lesions in the middle cerebral artery territory.
admission. MRI was done within 24 hours after occurrence of initial symptoms in 58.8%. Analysis of all 17 patients showed DWI lesions in the posterior circulation in 70.6% (occipital lobe: n ⫽ 6, thalamus: n ⫽ 1, cerebellum: n ⫽ 1, multiple areas: n ⫽ 4); 29.4% had middle cerebral artery territory infarction (figures 1 and 2). Multiple lesions were found in 41.2%. Territorial infarction was found in 35.3%; 64.7% had small DWI lesions. Overlapping ischemic lesions in different vascular territories were not observed. In 6/8 patients with additional perfusion MRI, a hypoperfused area matching the DWI lesion was noted. There was no hypoperfusion overlapping different vascular territories. Hyperperfusion was not observed in any of the cases. Figure 2
Diffusion-weighted imaging lesion patterns of 6 patients with migraine attack preceding acute stroke (group 2)
Patients 12 and 13 have multiple small lesions, patients 14 and 15 have isolated lesions in the posterior circulation territory, and patients 16 and 17 have isolated lesions in the middle cerebral artery territory.
MRA was normal in 5 patients; in 4 patients the artery corresponding to the ischemic territory showed flow abnormalities with a reduced flow, whereas in 2 patients this vessel was more prominent. In 5 patients, abnormalities were found in arteries not corresponding to the symptomatic territory. Evaluation of T1-weighted, T2weighted, and FLAIR images showed chronic white matter lesions in 3 cases; one patient had a small chronic (T2-hyperintense and T1-hypointense) lesion in the right cerebellar hemisphere. Prevalence of PFO and other risk factors. A relevant
right-to-left shunt suggestive of a PFO was detected in 64.7%. Presence of a PFO was equally distributed among patients with cerebral ischemia in the anterior (66.6%) and posterior circulation (63.3%). Six of 7 cases with multiple DWI lesions had a PFO (table 1). Sixteen patients (94.1%) had at least one other risk factor for ischemic stroke. Arterial hypertension was the most common (47.1%), followed by use of oral contraceptives in 41.2%, nicotine abuse, and hyperlipidemia (35.2% each). Coagulation abnormalities were found in 2 patients. Clinical presentation and history of migraine. Presentation time at the emergency department due to persisting deficits after a migrainous attack varied between 30 minutes and 5 days after onset (41.2% within 4 hours, 41.2% within 2 days, and 17.6% later than 2 days; mean 33 hours), illustrating a significant delay for these patients with a long history of migraine, compared to “standard” stroke patients. Therefore, none of the patients of this study could be thrombolyzed. Eleven patients had already taken their regular medication (triptans: n ⫽ 3; nonsteroidal anti-inflammatory drugs [NSAID]: n ⫽ 8), reNeurology 76
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1913
Table 1
Patient no.
Clinical features, risk factors, and associated findings (PFO) in patients with migraine and stroke Time of presentation after onset
NIHSS score on admission
Symptoms at presentation
PFO screening (TEE/TCD results)a
Risk factors/associated conditions
None
Group 1 1
4h
0
VD, hypesthesia, imbalance
PFO III ⫹ ASA
2
30 min
2
VD
Normal
HT, hyperlipidemia
3
5d
2
VD
PFO II–III
HT, hyperlipidemia, OC
4
5d
0
VD, hypesthesia, imbalance, dysarthria
PFO III
OC
5
5h
2
VD, hypesthesia
PFO III ⫹ ASA
Smoking, OC
6
3d
2
VD
PFO III ⫹ ASA
HT
7
12 h
1
VD
PFO II–III
HT
8
2d
2
VD
Normal
Smoking, OC, factor V Leiden (heterozygote)
9
1h
4
VD, hypesthesia, imbalance
PFO II ⫹ ASA
Smoking
10
2d
2
VD, hypesthesia, imbalance, aphasia
PFO I
HT, hyperlipidemia, smoking, hyperhomocysteinemia
11
14 h
VD; later severe sensorimotor hemiparesis and aphasia
Normal
Estrogen therapy
17
Group 2 12
15 min
0
VD
PFO I
HT, smoking
13
2h
0
VD, imbalance
PFO III
HT, hyperlipidemia, lipoprotein (a) elevation
14
2d
2
VD, hemianopia
Normal
Positive family history for stroke at younger age
15
10 h
1
VD, imbalance
Normal
HT, hyperlipidemia, estrogen therapy
16
2d
4
Hemiparesis, hypesthesia
Normal
Hyperlipidemia, smoking, OC
17
1h
2
Hypesthesia
PFO III
OC, protein S deficiency
Abbreviations: ASA ⫽ atrial septum aneurysm; HT ⫽ hypertension; NIHSS ⫽ NIH Stroke Scale; OC ⫽ oral contraception; PFO ⫽ patent foramen ovale; TCD ⫽ transcranial Doppler ultrasound; TEE ⫽ transesophageal echocardiography; VD ⫽ visual disturbances. a PFO grades were defined according to published criteria.15,16 PFO I: ⬍10 microbubbles passed from the right to the left atrium on TEE/detected by TCD; PFO II: 10–30 microbubbles passed from the right to the left atrium on TEE/detected by TCD; PFO III: ⬎30 microbubbles passed from the right to the left atrium (opacified left atrium due to bright contrast)/ “curtain” pattern on TCD. The presence of ASA was defined as a protrusion of the atrial septum into the left or right atrium of greater than 11 mm on TEE.
flecting their initial suspicion of a “normal” migraine attack (table 2). All patients of group 1 perceived similar symptoms to those from previous migrainous aura; there were no additional or unusual symptoms reported. However, in all patients, the usually transient aura symptoms persisted beyond headache relief and 2 patients had more severe symptoms; this led to early presentation at the emergency department. All 6 patients of group 2 had a typical migraine attack, 4 of them presenting with visual sensations like oscillopsias, photopsias, fortification spectra, or scintillating scotomas, and 2 with sensory disturbances compatible with migraine aura. Overall, visual aura was the most common symptom (82.3%), followed by sensory dysfunction in 41.2%; aphasia was reported in only 5.9%. At neurologic examination on admission, the mean NIHSS score was 2.5 ⫾ 3.8 (median 2; range 0 –17). Patients had a longstanding 1914
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history of migraine lasting between 4 and 55 years (median 13 years). Frequency of attacks varied between once per month and several days per week (47.1% with 1–2 attacks/month, 17.6% with 5–10 attacks/month, and 35.3% with ⬎10 attacks/ month). Four patients had a positive family history for migraine. Three patients were on a prophylactic medication with metoprolol or propanolol. Outcome. At telephone interview, 6 patients (35.3%)
reported residual symptoms from the index event (median mRS 1.5). Two patients with middle cerebral artery infarction complained about persisting mild motor aphasia with word-finding difficulties and a moderate right hemiparesis. Three patients with posterior cerebral artery (PCA) infarction had persisting visual field deficits. Two patients had very mild residual hypesthesia that were not debilitating
Table 2
Migraine history: clinical characteristics and treatment
Patient no.
Migraine duration, y
Frequency of attacks/mo
Acute migraine treatment on index event
Migraine prophylaxis
1
23
⬎10
NSAID
None
2
55
1–2
None
None
3
Unknown (⬎15 y)
1–2
None
None
4
4
1–2
NSAID ⫹ caffeine
None
5
4
1–2
Unknown
None
6
25
5–10
NSAID ⫹ caffeine
None
7
15
⬎10
NSAID ⫹ caffeine
None
8
10
5–10
NSAID
Metoprolol
9
24
⬎10
NSAID ⫹ caffeine
None
10
15
1–2
NSAID
None
11
35
1–2
Triptans
None
12
30
5–10
None
Metoprolol
13
10
⬎10
Triptans
Propranolol
14
13
1–2
NSAID
None
15
10
⬎10
None
None
16
5
⬎10
Triptans
None
17
3.5
1–2
None
None
Group 1
Group 2
Abbreviation: NSAID ⫽ nonsteroidal anti-inflammatory drug.
in daily life. Interestingly, most patients reported that the frequency of migraine attacks had decreased since the index event, except for one who described more frequent attacks but with a milder intensity. Two patients in our study underwent PFO closure and both reported decreasing intensity and frequency of attacks. DISCUSSION A large variety of different terms and definitions are being used in the literature to describe the potential relationship between cerebral ischemia and migraine17; it is controversial whether the migrainous attack is the cause or the symptom of ischemic stroke in these patients.18 According to the IHS criteria, migrainous infarction in the strict sense is a typical attack of migrainous aura in a patient with previous history of MA and evidence of cerebral ischemia proven by neuroimaging. If a concomitant etiology is detected (e.g., cervical arterial dissection, cardiac arrhythmia, coagulation abnormalities, paradoxical embolism in presence of a PFO), or if a patient with a history of MO develops ischemic stroke after a migraine attack, the disease shall not be classified “migrainous infarction” but “ischemic stroke coexisting with migraine.” As reported in the literature, migraine mimics may occur occasionally in various acute cerebrovascular diseases.19 Interestingly, CADASIL was later diagnosed in one of our patients. However, we included 6 patients with MO and
stroke under the assumption of a mechanistic link between the migrainous attack and the ischemic insult, although it is difficult to rule out the possibility that such a headache is the consequence of cerebral ischemia. The IHS classification is rather strict and maybe too restrictive, since there is only one detail from medical history (history of aura or not) which constrains to divide patients with an identical clinical presentation in 2 completely different groups. Inclusion of patients with MO and stroke might help to obtain larger samples of patients, permitting more valuable epidemiologic studies investigating such an association. According to our data retrieved from a large stroke database, migrainous infarction is a rare disease with an estimated frequency of approximately 2 among 1,000 strokes per year. A total of 76% of our study population was female, most likely reflecting the higher prevalence of MA in women. All patients had a history of migraine for several years, which may suggest an increased risk for migrainous infarction in long disease duration. Analysis of our data, however, did not reveal any particular associations regarding frequency of attacks, risk factors, or medical treatment for migraine prophylaxis. Given the few patients included, it is not possible to judge whether prophylactic treatment may reduce the risk of migrainous stroke. Previous brain imaging studies describing infarct patterns of acute migrainous infarction have mostly been CT based. Conventional MRI has only been used in small case studies, e.g., in a series of 6 cases in which, similar to our findings, most patients were women and had ischemic lesions predominately located in the posterior circulation.14 Since differentiation between migrainous aura and cerebral ischemia can be difficult in the first hours using clinical criteria alone, DWI provides relevant additional information substantially influencing further management. Given the high sensitivity to detect acute ischemic lesions including even small lacunar or punctuate cortical infarcts, DWI is extremely valuable in the hyperacute phase for positive stroke diagnosis and exclusion of stroke mimics such as migrainous aura symptoms20-22 and should therefore be preferred in the acute setting. In contrast to the few studies on acute migrainous infarction, many data are available evaluating chronic brain lesions in patients with MA using MRI. Silent infarctions predominantly in the posterior circulation territory have been reported on T2-weighted and FLAIR images.7-10 In the Cerebral Abnormalities in Migraine, an Epidemiologic Risk Analysis (CAMERA) study, infarct-like lesions in the PCA territory were observed in 8.1% of patients with MA and in 2.2% of patients with MO.23 A meta-analysis Neurology 76
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from 2004 revealed a 4-fold higher risk to have white matter abnormalities in migraine compared to controls.7 There is still a debate on whether these chronic lesions on MRI reflect asymptomatic strokes.24,25 Despite a long history of migraine we found only one small chronic ischemic lesion in our cohort. Previous studies did not show any relationship between white matter lesions on brain imaging and presence of a PFO.26 We noted a high prevalence of PFO in our study (65%) which is much higher than expected in the normal population and in stroke patients (20%– 40%).27 The high prevalence of a PFO for patients with anterior and posterior circulation stroke might indicate a cardiogenic mechanism of ischemia in these patients. Two patients in our study underwent PFO closure and both reported decreasing intensity and frequency of attacks, as has been previously reported in other studies and case reports.28,29 To date, there is no convincing explanation for why the posterior circulation territory is predominately affected by acute and chronic ischemic lesions. Cortical spreading depression (CSD) with transient hypoperfusion and hyperperfusion, a relevant phenomenon in the pathophysiology of migraine, is also known to predominately occur in the posterior part of the brain.30 The visual aura as the most frequent aura symptom (82% in this study) likely reflects perfusion changes in the occipital cortex. Our previous findings of a disturbed vasomotor reactivity of the PCAs in MA also contribute to the concept of a particular vulnerability for perfusion disturbances in the posterior circulation.31 A link between CSD with excessive vasoconstriction and consequent cerebral ischemia may be postulated. However, we did not find any overlapping ischemic lesions or hypoperfusion/hyperperfusion of different vascular territories which might have been found if a pathophysiologic link between CSD and a secondary ischemic event would be relevant. In contrast, it could be hypothesized that an embolism causes ischemia-related CSD, which produces the typical aura symptoms but leaves in its wake the infarction. The concept of ischemiainduced migraine attacks18 has recently been supported by the observation that cerebral microemboli were able to trigger CSD in mice.32 According to our data, the overall outcome after migrainous infarction seems favorable. Only a few patients reported persisting symptoms; most of them had recovered completely. Recurrent events were not reported on telephone interview. In addition, the frequency of migraine attacks tended to decrease after the cerebrovascular event. However, clinical and outcome data should be interpreted with some caution given the limitations of this study. Since the outcome was assessed by telephone interview at a mean of 41 months after the ischemic 1916
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event a recall bias cannot be excluded. In addition, patients were not examined personally by the authors on admission and follow-up. This study supports previous observations that migrainous infarction mostly occurs in the posterior circulation and in younger women with a history of MA and additional cardiovascular risk factors. Differentiation among migrainous infarction, prolonged migraine aura, and other stroke etiologies can be very difficult in the acute setting, emphasizing the importance of MRI including DWI for these patients. Small and multiple lesions that may not have been detected using conventional imaging were common in our cohort. Visual disturbances were the most frequent symptoms similar to migrainous aura, consistent with the distribution of DWI lesions predominantly affecting the posterior circulation. Patients with MA, additional risk factors, and PFO should be informed about the potential risk of ischemic stroke. They should seek medical help in case of an unusually long persistence of neurologic symptoms. This might lead to a faster presentation at the hospital with a higher chance for thrombolytic treatment. DISCLOSURE Dr. Wolf, Dr. Szabo, Dr. Griebe, and Dr. Fo¨rster report no disclosures. Prof. Gass serves on the editorial board of Cerebrovascular Diseases. Prof. Hennerici serves on a scientific advisory board for SERVIER; serves as Editor-in-Chief of Cerebrovascular Diseases, on the editorial board of the Journal of Neuroimaging, and Consulting Editor for the International Journal of Stroke; receives publishing royalties for Vascular Diagnosis with Ultrasound: Clinical References With Case Studies (Thieme Medical Publishers, 1998) and Case Studies in Stroke: Common and Uncommon Presentations (Cambridge University Press, 2006); has received speaker honoraria from SERVIER, Otsuka Pharmaceutical Co., Ltd., and Boehringer Ingelheim; and receives research support from BMBF, DFG SFB, and the European Union. Dr. Kern received a speaker honorarium from Philips Medical Systems and has received research support from the Federal Ministry of Education and Research (BMBF), Germany.
Received September 6, 2010. Accepted in final form February 18, 2011.
REFERENCES 1. Kittner S, Stern B, Wozniak M, et al. Cerebral infarction in young adults: the Baltimore-Washington Cooperative Young Stroke Study. Neurology 1998;50:890 – 894. 2. Sacquegna T, Andreoli A, Baldrati A, et al. Ischemic stroke in young adults: the relevance of migrainous infarction. Cephalalgia 1989;9:255–258. 3. Sochurkova D, Moreau T, Lemesle M, Menassa M, Giroud M, Dumas R. Migraine history and migraine-induced stroke in the Dijon stroke registry. Neuroepidemiology 1999;18:85–91. 4. Arboix A, Massons J, Garcia-Eroles L, Oliveres M, Balcells M, Targa C. Migrainous cerebral infarction in the Sagrat Cor Hospital of Barcelona stroke registry. Cephalalgia 2003;23:389 –394. 5. Headache Classification Committee of the IHS. The International Classification of Headache Disorders. Cephalalgia 2004;24(suppl 1):1–152.
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Welch KM, Levine SR. Migraine-related stroke in the context of the International Headache Society Classification of Head Pain. Arch Neurol 1990;47:458 – 462. Swartz R, Kern R. Migraine is associated with MRI white matter abnormalities: a meta-analysis. Arch Neurol 2004; 61:1366 –1368. Kruit MC, Van Buchem MA, Hofman PAM. Migraine as a risk factor for subclinical brain lesions. JAMA 2004;291: 427– 434. Degirmenci B, Yaman M, Haktanir A, Albayrak R, Acar M, Yucel A. Cerebral and cerebellar ADC values during a migraine attack. Neuroradiology 2007;49:419 – 426. Ziegler D, Batnitzky S, Barter R, McMillan JH. Magnetic resonance abnormalities in migraine with aura. Cephalalgia 1991;11:147–150. Guest IA, Wolf AL. Fatal infarction of the brain. BMJ 1964;1:225–226. Lindboe CF, Dahl T, Rostad B. Fatal stroke in migraine: a case report with autopsy findings. Cephalalgia 1989;9: 277–280. Robion M, Benderitter T. De´ce`s au cours d’une crise de migraine. Rev Neurol 1992;148:631– 634. Frigerio R, Santoro P, Ferrarese C, Agostoni E. Migrainous cerebral infarction: case reports. Neurol Sci 2004; 25(suppl 3):S300 –S301. Jauss M, Zanette E. Detection of right-to-left shunt with ultrasound contrast agent and transcranial Doppler sonography. Cerebrovasc Dis 2000;10:490 – 496. Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septum aneurysm, or both. N Engl J Med 2001;13:1740 – 1746. Bousser MG, Welch KM. Relation between migraine and stroke. Lancet Neurol 2005;4:533–542. Olesen J, Friberg L, Olsen TS, et al. Ischaemia-induced (symptomatic) migraine attacks may be more frequent than migraine-induced ischaemic insults. Brain 1993;116: 187–202. Weinberger J. Stroke and migraine. Curr Cardiol Rep 2007;9:13–19.
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Gass A, Ay H, Szabo K, Koroshetz WJ. Diffusionweighted MRI for the “small stuff ”: the details of acute cerebral ischemia. Lancet Neurol 2004;3:39 – 45. Fiebach J, Jansen O, Schellinger P, et al. Comparison of CT with diffusion-weighted MRI in patients with hyperacute stroke. Neuroradiology 2001;43:628 – 632. Ay H, Buonanno FS, Rodorf G, et al. Normal diffusionweighted MRI during stroke-like deficits. Neurology 1999;52:1733–1736. Kruit MC, Launer LJ, Ferrari MD, van Buchem MA. Infarcts in the posterior circulation territory in migraine: the population-based MRI CAMERA study. Brain 2005;128: 2068 –2077. Goldberg M, Ransom B. New light on white matter. Stroke 2003;34:330 –332. Lipton R, Pan J. Is migraine a progressive brain disease? JAMA 2004;291:493– 494. Del Sette M, Dinia L, Bonzano L, et al. White matter lesions in migraine and right-to-left shunt: a conventional and diffusion MRI study. Cephalalgia 2008;28:376 –382. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318:1148 –1152. Morandi E, Anzola GP, Angeli S, Melzi G, Onorato E. Transcatheter closure of patent foramen ovale: a new migraine treatment? J Interv Cardiol 2003;16:39 – 42. Sztajzel R, Genoud D, Roth S, Mermillod B, Le FlochRohr J. Patent foramen ovale, a possible cause of symptomatic migraine: a study of 74 patients with acute ischemic stroke. Cerebrovasc Dis 2002;13:102–106. Lauritzen M, Olsen TS, Lassen NA, Paulson OB. Changes in regional cerebral blood flow during the course of classical migraine attacks. Ann Neurol 1983;13:633– 641. Wolf ME, Ja¨ger T, Ba¨zner H, Hennerici MG. Changes in functional vasomotor reactivity in migraine with aura. Cephalalgia 2009;2009:1156 –1164. Nozari A, Dilekoz E, Sukhotinsky I, et al. Microemboli may link spreading depression, migraine aura, and patent foramen ovale. Ann Neurol 2010;67:221–229.
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Potential utility of conventional MRI signs in diagnosing pseudoprogression in glioblastoma R.J. Young, MD A. Gupta, MD A.D. Shah, MD J.J. Graber, MD Z. Zhang, PhD W. Shi, MS A.I. Holodny, MD A.M.P. Omuro, MD
Address correspondence and reprint requests to Dr. Robert J. Young, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065
[email protected] ABSTRACT
Objective: To examine the potential utility of conventional MRI signs in differentiating pseudoprogression (PsP) from early progression (EP).
Methods: This retrospective study reviewed initial postradiotherapy MRI scans of 321 patients with glioblastoma undergoing chemotherapy and radiotherapy. A total of 93 patients were found to have new or increased enhancing mass lesions, raising the possibility of PsP. Final diagnosis of PsP or EP was established upon review of surgical specimens from a second resection or by clinical and radiologic follow-up. A total of 11 MRI signs potentially helpful in the differentiation between PsP and EP were examined on the initial post-RT MRI and were correlated with the final diagnosis through 2 or Fisher exact test. Results: Sixty-three (67.7%) of the 93 patients had EP, of which 22 (34.9%) were diagnosed by pathology. Thirty patients (32.3%) had PsP; 6 (16.7% of the 30) were diagnosed by pathology. Subependymal enhancement was predictive for EP (p ⫽ 0.001) with 38.1% sensitivity, 93.3% specificity, and 41.8% negative predictive value. The other 10 signs had no predictive value (p ⫽ 0.06–1.0).
Conclusions: Conventional MRI signs have limited utility in diagnosing PsP in patients with recently treated glioblastomas and worsening enhancing lesions. We did not find a sign with a high negative predictive value for PsP that would have been the most useful for the clinical physician. When present, subependymal spread of the enhancing lesion is a useful MRI marker in identifying EP rather than PsP. Neurology® 2011;76:1918–1924 GLOSSARY ADC ⫽ apparent diffusion coefficient; DWI ⫽ diffusion-weighted image; EP ⫽ early progression; FLAIR ⫽ fluid-attenuated inversion recovery; MGMT ⫽ O6-methylguanine-methyltransferase enzyme; OS ⫽ overall survival; poly-ICLC ⫽ polyriboinosinic-polyribocytidylic; PsP ⫽ pseudoprogression; RT ⫽ radiation therapy; TE ⫽ echo time; TI ⫽ inversion time; TMZ ⫽ temozolomide; TR ⫽ repetition time.
Radiation therapy (RT) plus concurrent and adjuvant chemotherapy with temozolomide (TMZ) is the standard of care for patients with newly diagnosed glioblastoma.1 Soon after completion of RT, patients may demonstrate pseudoprogression (PsP), defined as the transient worsening of enhancing abnormalities or mass effect on MRI. PsP may occur in 14%–31% of patients with treated malignant glioma,2-5 and up to 58% of patients with methylated O6methylguanine-methyltransferase enzyme (MGMT) promoter status.6 PsP is thought to be due to potentiated radiation-induced tissue injury with associated inflammatory reaction and necrosis. The worsening lesions, which reflect treatment effects rather than treatment failure, subsequently stabilize or improve and are not correlated with poorer outcomes.7 The increased or new enhancing lesions of PsP and early progression (EP) may both fulfill criteria for worsening disease when applying standard response criteria.8 There is therefore a need for improved imaging biomarkers to distinguish EP from PsP in order to optimize patient treatments and the study design of clinical trials. Identifying conventional MRI signs to determine PsP may spare these patients from unnecessary surgery or inappropriate and possibly From the Department of Radiology (R.J.Y., A.G., A.D.S., A.I.H.), Brain Tumor Center (R.J.Y., A.I.H., A.M.P.O.), Department of Neurology (J.J.G., A.M.P.O.), and Department of Epidemiology and Biostatistics (Z.Z., W.S.), Memorial Sloan-Kettering Cancer Center, New York, NY. Disclosure: Author disclosures are provided at the end of the article. 1918
Copyright © 2011 by AAN Enterprises, Inc.
Figure 1
STARD diagram
RT ⫽ radiation therapy.
more toxic chemotherapy, both of which may become necessary later in the course of the disease. The purpose of this article is to examine the potential utility of conventional MRI signs in differentiating PsP from EP. METHODS Standard protocol approvals, registrations, and patient consents. This retrospective study was granted a Waiver of Informed Consent by the Memorial SloanKettering Cancer Center Institutional Review Board. With the approval of the hospital Privacy Board and compliant with Health Insurance Portability and Accountability Act regulations, we retrospectively identified 321 consecutive patients with glioblastoma who were treated between January 2003 and November 2009 from the hospital database.
Patients. All patients had a pathologic diagnosis of glioblastoma according to revised World Health Organization criteria after biopsy, subtotal resection, or gross total resection. Selection of the main study cohort is summarized in figure 1. Only newly diagnosed patients with primary glioblastomas who underwent initial combination RT and chemotherapy treatment were included in this study. A total of 112 patients were excluded due to transformed low-grade or anaplastic glioma (n ⫽ 10), no RT (n ⫽ 5), Gliadel wafer implantation (n ⫽ 1), bevacizumab concomitant with RT (n ⫽ 10), incomplete clinical or imaging follow-up (n ⫽ 85), or uncertain diagnosis after pathology (n ⫽ 1). Upon review of initial post-RT MRI findings, a total of 93
patients with either EP or PsP were identified, as per the following inclusion criteria: 1) successfully completed RT with concurrent chemotherapy; 2) developed worsening (new or increased) enhancing mass lesions on the initial post-RT MRI (usually 2– 4 weeks after completion of RT) as compared to the pre-RT MRI (usually ⬍48 hours before beginning RT); and 3) diagnosis of the worsening lesions by either pathology after repeat resection, or, when pathology was not available, by clinical and imaging follow-up assessed every 1–2 months. These patients constituted the main study cohort and were reviewed as further described below. The remaining 116 patients who did not display worsening disease (stable, n ⫽ 70, or improved, n ⫽ 46) on the initial post-RT MRI did not undergo additional analysis, aside from collection of mortality/survival data. All 93 patients in the main study cohort underwent partial brain external beam RT using conventional or intensity modulated planning. As summarized in table 1, most patients (90%) received a standard course of RT with 5,940 or 6,000 cGy given over 6 –7 weeks. Some poorly functioning or elderly patients (10%) who were considered by the radiation oncologist as unlikely to complete the standard course received an abbreviated course of RT to 4,005 cGy given over 3 weeks, an acceptable alternative.9 Almost all patients (97.8%) received TMZ at standard doses (75 mg/m2) daily concomitant with RT. For adjuvant therapy after completion of RT, most patients (75.2%) received standard TMZ (150 –200 mg/m2 ⫻ 5/28 days), while others were included in a phase 2 trial10 randomizing patients to receive either Neurology 76
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Table 1
Characteristics of patients with worsening abnormalities on initial post-RT MRI Total
EP
PsP
Patients, n (%)
93
63 (68)
30 (32)
Mean age (range), y
59 (9–84)
59 (9–81)
57 (21–84)
Female
35 (38)
23 (36)
12 (40)
Male
58 (62)
40 (64)
18 (60)
Biopsy
12 (13)
8 (13)
4 (13)
Subtotal resection
50 (54)
38 (60)
12 (40)
Gross total resection
31 (33)
17 (27)
14 (47)
Standard (5,940 cGy ⴛ33 fractions or 6,000 cGy ⴛ30 fractions, given 5 d/wk ⴛ6–7 wk)
84 (90)
56 (89)
28 (93)
Abbreviated (4,005 cGy ⴛ15 fractions, 5 d/wk ⴛ3 wk)
9 (10)
was required for a minimum of 6 months from the end of RT. This definition allows for the continued mild increase of the worsening enhancing lesions, as compared to the usual decrease or stabilization, as long as no treatment change occurred during this time period. The diagnosis of EP was made if imaging or clinical worsening prompted a change in treatment. Diagnosis was made while blinded to the patient’s MGMT status.
Sex, n (%)
Extent of surgery, n (%)
Radiation therapy, n (%)
7 (11)
2 (7)
Concurrent chemotherapy Standard temozolomide (75 mg/m2 daily)
91 (98)
Poly-ICLCa
2 (2)
62 (98)
29 (97)
1 (2)
1 (3)
Adjuvant chemotherapy, n (%) Standard temozolomide (150–200 mg/m2 on days 1–5 of 28-day cycle)
68 (73)
45 (71)
23 (77)
Dose-dense temozolomide (150 mg/m2 days 1–7 and 15–21 of 28-day cycle)
13 (14)
8 (13)
5 (17)
Metronomic temozolomide (50 mg/m2 continuous daily)
10 (11)
9 (14)
1 (3)
Poly-ICLCa
2 (2)
1 (2)
1 (3)
Abbreviations: EP ⫽ early progression; PsP ⫽ pseudoprogression; RT ⫽ radiation therapy. a Polyriboinosinic-polyribocytidylic acid (poly-ICLC): the same 2 patients who received concomitant poly-ICLC continued on adjuvant poly-ICLC.
low-dose metronomic TMZ (14.0%) at 50 mg/m2/day or dosedense TMZ (10.8%) at 150 mg/m2/day 1 week on and 1 week off. Only 2 patients (2.2%) did not receive TMZ; they both received polyriboinosinic-polyribocytidylic (poly-ICLC) concomitant with RT followed by adjuvant poly-ICLC. When available, MGMT methylation status was obtained through chart review. The methylation of this DNA repair enzyme promoter was determined by methylation-specific PCR analysis. Decisions to perform MGMT assays were based on enrollment into a clinical trial requiring MGMT analysis for some patients, or as part of an emerging standard of practice for all patients with glioblastoma seen at Memorial Sloan-Kettering Cancer Center toward the end of the study.
Diagnosis of PsP and EP. The worsening lesions on the initial post-RT MRI was determined to represent either EP or PsP based on pathologic analysis after repeat biopsy or resection when available. PsP was characterized when necrotizing treatment effects were present with no to minimal identifiable tumor. The presence of residual or recurrent tumor established EP. If repeat pathology was not available, the clinical diagnosis of EP or PsP was made by consensus of 2 neuro-oncologists (with 3 and 10 years of experience) after complete chart and imaging review. The diagnosis of PsP was made if no change in treatment 1920
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MRI parameters. MRI was obtained using 1.5 T (Signa Excite) and 3 T magnets (Discovery 750, GE Healthcare, Waukesha, WI). All studies were acquired using 5-mm slice thickness and no interslice gap. For 1.5 T, axial fast spin-echo T2weighted (repetition time [TR]/echo time [TE] ⫽ 4,000/100 msec, matrix 256 ⫻ 256); axial fluid-attenuated inversion recovery (FLAIR; TR/TE/inversion time [TI] ⫽ 10,000/160/2,200 msec, matrix 256 ⫻ 256); sagittal and axial T1-weighted; and contrast coronal, sagittal, and axial T1-weighted images (TR/ TE ⫽ 500/10 msec, matrix 256 ⫻ 256) were obtained. For 3 T, axial fast spin-echo T2-weighted (TR/TE ⫽ 4,000/100 msec, matrix 512 ⫻ 512); axial FLAIR (TR/TE/TI ⫽ 9,000/125/ 2,250 msec, matrix 512 ⫻ 512); sagittal and axial T1-weighted/ FLAIR; and contrast coronal, sagittal, and axial T1-weighted/ FLAIR images (TR/TE/TI ⫽ 2,500/6/860 msec, matrix 512 ⫻ 512) were obtained. Gadopentetate dimeglumine (Magnevist, HealthCare Pharmaceuticals Inc. Wayne, NJ) was injected though a peripheral angiocatheter (18 –21 gauge) at a standard dose (0.2 mL/kg body weight, maximum 20 mL). The same dose of contrast was administered for both 1.5 T and 3 T scans. The mean ⫾ SD of the first, second, and third MRI scans obtained after completing RT were 20 ⫾ 9 days, 90 ⫾ 30 days, and 150 ⫾ 38 days, respectively. Conventional MRI signs. Two neuroradiologists (1 with 5 years experience and the other with 10 years experience and holding a Certificate of Added Qualification in Neuroradiology) blinded to the final diagnosis of EP or PsP described by consensus the worsening lesions on the initial post-RT MRI according to these signs: 1) new enhancement; 2) marginal enhancement around the surgical cavity; 3) nodular enhancement; 4) callosal enhancement; 5) subependymal enhancement; 6) spreading wavefront of enhancement; 7) cystic or necrotic change; 8) increased peritumoral T2 abnormality; and 9) diffusion restriction. Diffusion restriction was visually determined as hyperintense signal on diffusion-weighted images (DWI) and corresponding hypointense signal on the apparent diffusion coefficient (ADC) maps, while avoiding areas of hemorrhage and calcification. Two additional parameters were described by comparing the initial post-RT MRI to subsequent post-RT MRIs performed over the next 2–5 months to evaluate evolution of the enhancing lesions prior to any change in treatment; 10) decreasing enhancement intensity; and 11) increasing cystic or necrotic change. Statistical analysis. Univariate analysis using 2 or Fisher exact test was performed to determine the relative utility of the conventional MRI signs in predicting PsP vs EP. Univariate analyses were also performed to determine potential correlations with the degree of resection (gross total vs subtotal vs biopsy), dose of RT (dichotomized at 5,940 cGy), and different schedules for adjuvant TMZ administration. A Fisher exact test was used to test the potential correlation between diagnosis and MGMT status. Statistical significance was set at p ⫽ 0.05. Overall survival (OS) among the different groups was calculated from the date of RT completion to the date of death or last
Table 2
Distribution of conventional MRI signs PsP, n (%) (n ⴝ 30)
EP, n (%) (n ⴝ 63)
p Value
New enhancement
12 (40)
32 (51)
0.38
Marginal enhancement around cavity
21 (70)
49 (78)
0.45
Nodular enhancement
8 (27)
28 (44)
0.12
Callosal enhancement
6 (20)
22 (35)
0.16
Subependymal enhancement
2 (7)
24 (38)
0.001a
Spreading wavefront of enhancement
16 (53)
47 (75)
0.06
Cystic/necrotic changes
22 (73)
54 (86)
0.16
Increased peritumoral T2 hyperintensity
22 (73)
45 (71)
1.00
Diffusion restriction
16 (73)
32 (51)
0.83
Subsequent decreased enhancement
7 (23)
5 (8)
0.19
Subsequent cystic/necrotic change
5 (17)
9 (14)
1.00
in 9, slightly worsened (by ⬍25%) in 5, and worsened (by ⬎25%) then stabilized in 2. The diagnosis of EP or PsP in all cases was made prior to any change in treatment. Conventional MRI signs. The conventional MRI re-
sults are summarized in table 2. Only subependymal enhancement was found to be predictive for EP ( p ⫽ 0.001), with 38.1% sensitivity, 93.3% specificity, 92.3% positive predictive value, and 41.8% negative predictive value. A representative case is shown in figure 2. The other 10 signs had no predictive value ( p ⫽ 0.06 to 1.0). Among the patients who displayed new enhancement, all lesions occurred at or immediately adjacent to the primary tumor site; no patient developed remote enhancement (i.e., ⬎3 cm away). Clinical variables. Information on MGMT promoter
EP ⫽ early progression; PsP ⫽ pseudoprogression. a Significant.
follow-up using the Kaplan-Meier method. OS curves were compared using the log-rank test.
The characteristics and treatments received by the 93 main analysis patients are summarized in table 1. Sixty-three (67.7%) of the 93 patients were determined to have EP, of which 22 (34.9% of the 63 patients) were diagnosed by repeat pathology. Thirty patients (32.3%) were determined to have PsP, of which 6 (16.7% of the 30 patients) were diagnosed by repeat pathology. Of the other 24 patients diagnosed with PsP, follow-up showed that the enhancing disease had improved in 8, stabilized
RESULTS
Figure 2
methylation status was available in 22 patients. Among those, MGMT promoter methylation was detected in 5 patients, all of them in the EP group. Unmethylated MGMT promoter was found in 11 patients with EP and 6 patients with PsP. There was no association between EP/PsP status and MGMT status ( p ⫽ 0.27), nor with the degree of resection ( p ⫽ 0.14), dose of RT ( p ⫽ 0.49), or different schedules of adjuvant TMZ ( p ⫽ 0.27). Overall survival. Among the patients with worsening
initial post-RT MRI (n ⫽ 93), the median OS was 318 days (range, 70 –1,926 days) for the EP group and 440 days (206 –1,422 days) for the PsP group. Survival was longer for the PsP group as compared to the EP group ( p ⫽ 0.003). Median OS was 459 days (52–1,943 days) for patients with stable initial
Subependymal enhancement in a patient with early progression
Contrast T1-weighted images. Pre–radiation therapy (RT) and 1 day after resection (A), the patient shows a left pterional craniotomy with a blood/fluid-filled surgical cavity in the temporal lobe and minute enhancement in the mesial temporal lobe. One month post-RT (B), there is increased enhancement in the mesial temporal lobe and new enhancement along the subependymal margin of the temporal horn. Five months post-RT (C), the subependymal enhancement has extended posteriorly to the occipital horn, and there are 2 new sites of enhancement in the lateral temporal lobe. The patient continued to show clinical deterioration, and treatment was switched from adjuvant temozolomide to bevacizumab for tumor progression. Neurology 76
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Figure 3
Kaplan-Meier survival curves
(A) Overall survival of the pseudoprogression (PsP) group was longer than of the early progression (EP) group. (B) Overall survival of the EP group was shorter than the PsP, stable, and improved groups. The latter 3 groups had similar overall survival.
post-RT MRI, and 463 days (132–1,861 days) for patients with improved initial post-RT MRI. OS of the stable and improved groups was similar to that of the PsP group ( p ⫽ 0.75) and different from the EP group ( p ⫽ 0.0002). Kaplan-Meier curves are shown in figure 3. No differences in survival according to MGMT promoter methylation status could be detected ( p ⫽ 0.94; n ⫽ 22), although analysis was limited by the low number of patients with methylated MGMT promoter. Reliable imaging biomarkers are necessary to efficiently conduct clinical trials that compare the efficacy of new therapies. Nearly 75% of oncologic clinical trials rely on surrogate imaging endpoints rather than patient survival,11 with most clinical trials for malignant glioma treatment using modified Macdonald criteria to determine treatment response.8 A major limitation of the Macdonald criteria, which were developed 2 decades ago, is the reliance on changes in size of the enhancing tumor. PsP may be indistinguishable from EP using these response criteria. Recognizing this difficulty in diagnosis, many phase II trials for recurrent malignant gliomas exclude patients with worsening enhancing lesions within 3 months after RT.4,5,12 Although advanced imaging techniques such as MR perfusion, MR spectroscopy, and PET may have increased accuracy and sensitivity, these technologies are not as well-studied or ubiquitously available as conventional MRI. As a result, even the most recent attempts to establish new criteria by the Response Assessment by Neuro-Oncology13 group rely on conventional MRI characteristics (contrast enhancement and T2/FLAIR signal abnormality). Determining conventional MRI signs that would best determine DISCUSSION
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PsP would assist the management of these patients and potentially impact clinical decision-making processes. In this study, we report the largest cohort of patients systematically reviewed for MRI findings that could differentiate PsP from EP. We found that subependymal enhancement predicts the development of EP rather than PsP in worsening enhancing lesions that occur soon after completion of combination chemoradiation therapy. Although subependymal enhancement has high specificity for EP (93.3%), its low sensitivity (38.1%) and low negative predictive value (41.8%) suggest that it may have only limited utility in the majority of patients with suspected PsP. Subependymal spread of tumor is a known pattern of glioma failure, although it is less common than local progression.14,15 Infiltration of the margins of the ventricles may occur by direct spread of tumor cells in the subependymal space or by deposits transferred by the CSF.16 One study of 51 multifocal gliomas (of which 31 were glioblastoma) reported subependymal spread to be the second most common route for disseminated disease at 24%.17 Less frequent rates of subependymal or spinal spread have been described by other groups,14 ranging from 0% to 14%. Conventional MRI signs to distinguish radiation necrosis from tumor recurrence have been investigated in patients with malignant gliomas. One study of 27 patients did not find individual signs to be useful predictors for tumor recurrence, although combining 2 signs with involvement of the corpus callosum and multiple enhancing lesions was useful ( p ⫽ 0.02), as were combining 3 signs with involvement of the corpus callosum, multiple enhancing le-
sions, and crossing of the midline ( p ⫽ 0.04) or subependymal spread ( p ⫽ 0.01).18 The lack of significance for individual signs such as subependymal spread ( p ⫽ 0.26),18 in contrast to the findings in our study ( p ⫽ 0.001), may reflect the smaller number of patients or differing central distributions of lesions in that series. In addition, those patients all had new enhancing lesions that occurred more than 6 months after proton beam RT, which were more consistent with radiation necrosis than with PsP. The 2 entities are similar but not synonymous, with PsP showing earlier onset after completion of RT at 1–3 months that reflects an intermediate stage between subacute radiation reaction and later radiation necrosis at 6 –18 months or more.2 Treatment-related necrosis can also occur in the periventricular region and mimic subependymal spread of tumor.19 This is thought to reflect the relatively poor vascularity of the periventricular region, which is supplied by long medullary arteries without collateral supply that are vulnerable to radiationinduced vasculopathy.19 The low incidence of subependymal enhancement in PsP (6.7%) found in our study, however, suggests that this complication may be less frequent than direct spread to the subependymal region by centrally located tumors. Treatmentrelated necrosis becomes more common with increasing total doses, high fraction doses, hyperfractionation, and concurrent chemotherapy.2,20 The majority of our patients were treated with standard RT plans, with relatively equal small proportions of the EP and PsP groups instead receiving abbreviated RT plans that are acceptable alternatives.9 Although we did not detect a correlation with the RT dose, further examination of the potential relationship between RT dose and fields with subependymal enhancement may be useful. Survival has been reported as longer in patients with methylated MGMT promoter status who receive temozolomide.6,21 A study attempting to correlate MGMT status and PsP found that methylated MGMT promoter status is a strong predictor of PsP, occurring in 21/23 (91.3%) of methylated vs 11/27 (40.7%) of unmethylated patients ( p ⫽ 0.0002).6 Less than a quarter (23.7%) of our patients had known MGMT promoter status, with methylated MGMT promoter detected in 5 patients with EP, including 2 patients with pathologic confirmation of their EP status, and none of the patients with PsP. The low number of patients precludes further analysis, although this finding does highlight the unreliability of using MGMT status to predict PsP or EP in an individual patient. We are prospectively collecting molecular and genetic data in contemporary patients, and plan a separate project to specifically
examine the potential relationship between MRI and MGMT status. One potential limitation of our study relates to the lack of a widely accepted definition of PsP. Specific clinical, imaging, and pathologic criteria for the diagnosis of PsP were established for this study, including patients who did not require additional treatment for a minimum of 6 months. Although this may have underestimated the true incidence of PsP, the primary intent of the study was to determine clinically useful conventional MRI signs that could guide treatment decisions by confidently identifying the patients who would not have required a change in treatment. We recognize that this definition also potentially biased the survival analysis, since the condition of a 6-month interval was not imposed upon the EP group. Another limitation is that most but not all patients received standard RT and TMZ chemotherapy as established by Stupp et al.1 Since PsP or early treatment-related necrosis has been described with other RT and chemotherapy regimens,19,22 the heterogeneity of TMZ vs non-TMZ treatment and differing adjuvant TMZ schedules should have little effect on the analysis. In addition, the proportion of patients determined to have PsP (32.3%) is similar to previously published rates.2-5 The majority (75.2%) of patients in this study received adjuvant TMZ according to the standard 5/28 day cycle. We did not detect a correlation between PsP and TMZ schedule ( p ⫽ 0.27). It is possible that a more effective adjuvant dosing schedule could cause EP to remit and mimic PsP, although differential rates of PsP have not been described with dose-dense vs metronomic TMZ treatment.10 Conventional MRI signs have limited utility in the diagnosis of PsP in patients with recently treated glioblastomas and worsening enhancing lesions. The distinction is important for making treatment decisions, patient counseling, and establishing prognosis. We did not find a sign with a high negative predictive value for PsP, which would have provided the most useful information for treating clinicians. When present, direct subependymal spread of the enhancing lesion is a useful MRI marker in identifying EP rather than PsP. Additional research into advanced imaging modalities or biomarkers such as MRI perfusion, diffusion tensor, spectroscopy, and PET/CT is necessary. AUTHOR CONTRIBUTIONS Statistical analysis was conducted by Dr. Zhigang Zhang and Weiji Shi. Dr. Robert J. Young takes full responsibility for the data, analyses and interpretation, and the conduct of the research, and has full access to all of the data with the right to publish all data separate and apart from any sponsor. Neurology 76
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ACKNOWLEDGMENT The authors thank Judith A. Lampron for editorial advice.
DISCLOSURE Dr. Young, Dr. Gupta, Dr. Shah, Dr. Graber, Dr. Zhang, and W. Shi report no disclosures. Dr. Holodny has served on a scientific advisory board for Bayer Schering Pharma and serves on the editorial advisory board of the American Journal of Neuroradiology. Dr. Omuro served as a Section Editor for Current Opinion in Neurology and receives research support from Genentech, Inc., Schering-Plough Corp/Merck Serono, Exelixis Inc., the NIH/NCI, the BCured Foundation, and the Collaborative Ependymoma Research Network (CERN).
Received September 9, 2010. Accepted in final form February 14, 2011. REFERENCES 1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–996. 2. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 2008;9:453– 461. 3. Chamberlain MC, Glantz MJ, Chalmers L, Van Horn A, Sloan AE. Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. J Neurooncol 2007;82:81– 83. 4. de Wit MC, de Bruin HG, Eijkenboom W, Sillevis Smitt PA, van den Bent MJ. Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression. Neurology 2004;63:535–537. 5. Taal W, Brandsma D, de Bruin HG, et al. Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer 2008;113:405– 410. 6. Brandes AA, Franceschi E, Tosoni A, et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 2008;26:2192–2197. 7. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 2008;9:453– 461. 8. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277–1280. 9. Roa W, Brasher PM, Bauman G, et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 2004;22:1583–1588.
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Clarke JL, Iwamoto FM, Sul J, et al. Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol 2009;27:3861–3867. 11. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 2003;21:1404 –1411. 12. Chaskis C, Neyns B, Michotte A, De Ridder M, Everaert H. Pseudoprogression after radiotherapy with concurrent temozolomide for high-grade glioma: clinical observations and working recommendations. Surg Neurol 2009;72: 423– 428. 13. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010;28:1963–1972. 14. Sneed PK, Gutin PH, Larson DA, et al. Patterns of recurrence of glioblastoma multiforme after external irradiation followed by implant boost. Int J Radiat Oncol Biol Phys 1994;29:719 –727. 15. Garden AS, Maor MH, Yung WK, et al. Outcome and patterns of failure following limited-volume irradiation for malignant astrocytomas. Radiother Oncol 1991;20:99 – 110. 16. McGeachie RE, Gold LHA, Latchaw RE. Periventricular spread of tumor demonstrated by computed tomography. Radiology 1977;125:407– 410. 17. Kyritsis AP, Levin VA, Alfred Yung WK, Leeds NE. Imaging patterns of multifocal gliomas. Eur J Radiol 1993;16: 163–170. 18. Mullins ME, Barest GD, Schaefer PW, Hochberg FH, Gonzalez RG, Lev MH. Radiation necrosis versus glioma recurrence: conventional MR imaging clues to diagnosis. AJNR Am J Neuroradiol 2005;26:1967–1972. 19. Kumar AJ, Leeds NE, Fuller GN, et al. Malignant gliomas: MR imaging spectrum of radiation therapy- and chemotherapy-induced necrosis of the brain after treatment. Radiology 2000;217:377–384. 20. Ruben JD, Dally M, Bailey M, Smith R, McLean CA, Fedele P. Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys 2006;65: 499 –508. 21. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997–1003. 22. Watne K, Hager B, Heier M, Hirschberg H. Reversible oedema and necrosis after irradiation of the brain: diagnostic procedures and clinical manifestations. Acta Oncol 1990;29:891– 895.
Prognostic importance of serial postoperative EEGs after anterior temporal lobectomy Chaturbhuj Rathore, MD Sankara P. Sarma, PhD Kurupath Radhakrishnan, MD
Address correspondence and reprint requests to Dr. Kurupath Radhakrishnan, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum 695 011, Kerala, India
[email protected] ABSTRACT
Objective: To assess the value of postoperative EEG in predicting seizure outcome and seizure recurrence following antiepileptic drug (AED) withdrawal in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Methods: We studied 262 consecutive patients with MTLE-HS with serial EEGs at 3 months, and at 1, 2, and 3 years after anterior temporal lobectomy (ATL), and considered the presence of interictal epileptiform discharges (IED) as abnormal. We attempted AED withdrawal in all seizurefree patients. We defined favorable outcome as freedom from seizures/auras during the entire follow-up period (outcome 1) and during terminal 1-year follow-up (outcome 2). Results: During mean follow-up period of 7.6 (range 5–12) years, 129 (49.2%) patients had favorable outcome 1 and 218 (83.2%) had favorable outcome 2. Of 225 (85.9%) patients in whom AED withdrawal was attempted, 61 (27.1%) had seizure recurrence. Compared to patients with normal EEG, those with IED on 1-year post-ATL EEG had a 3-fold increased risk for unfavorable outcome 1 and 7-fold increased risk for unfavorable outcome 2. The patients in whom all the 4 EEGs were abnormal had 9-fold odds for unfavorable outcome 1 and 26-fold odds for unfavorable outcome 2. An abnormal EEG at 1 year increased the risk of seizure recurrence following AED withdrawal by 2.6-fold.
Conclusions: Post-ATL EEG predicts seizure outcome and seizure recurrence following AED withdrawal. Serial EEGs predict outcome better than single EEG. This information will be helpful in counseling of patients after ATL, and in making rational decisions on AED withdrawal. Neurology® 2011;76:1925–1931 GLOSSARY AED ⫽ antiepileptic drug; ATL ⫽ anterior temporal lobectomy; CI ⫽ confidence interval; IED ⫽ interictal epileptiform discharge; MTLE-HS ⫽ mesial temporal lobe epilepsy with hippocampal sclerosis; OR ⫽ odds ratio.
In a recent systematic analysis that had investigated the relationship between the presence of interictal epileptiform discharges (IED) on postoperative EEG and seizure outcome following resective epilepsy surgery, IED on postoperative EEG strongly predicted an unfavorable seizure outcome.1 However, the results of this analysis were limited by the marked heterogeneity between studies with regard to the number of patients, epilepsy surgery types, classification of seizure outcome, and methodology of performing and interpreting the EEGs.1 Whether serial postoperative EEG findings can enhance the predictive value for seizure recurrence compared to a single EEG is unknown. In patients who become seizure-free following epilepsy surgery, very little reliable information is available regarding the factors that predispose for seizure recurrence on attempted AED withdrawal. A recent review highlighted the following limitations of published studies2: few patients in individual studies, grouping of patients with disparate surgical procedures together, bias introduced by selection of patients for AED withdrawal due to factors other than seizure freedom, and short duration of follow-up. Whether an EEG undertaken before the attempted AED withdrawal can predict the risk of seizure recurrence in the postoperative period is uncertain. From the R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India. Disclosure: The authors report no disclosures. Copyright © 2011 by AAN Enterprises, Inc.
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This prompted us to investigate the value of EEGs following anterior temporal lobectomy (ATL) in predicting seizure outcome in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) to answer the following questions: Can performing serial EEGs enhance the information provided by single EEG? Can abnormal postoperative EEG predict seizure recurrence following attempted AED withdrawal? METHODS Patient selection and evaluation. From the elaborate database maintained at the R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Trivandrum, Kerala, India, we reviewed the records of consecutive patients who had undergone ATL from January 1996 to December 2002 and had completed a minimum of 5 years of postoperative follow-up. We included only patients with MTLE who had a minimum of 4 EEGs in the post-ATL period, i.e., at completion of 3 months, 1 year, 2 years, and 3 years. The preoperative diagnosis of MTLE-HS was based on a standard presurgical evaluation that included a detailed clinical history and examination, long-term video-EEG monitoring, 1.5 T MRI, and neuropsychological evaluation as described by us in detail previously.3–5 We made the decisions for ATL after a thorough discussion in the multidisciplinary patient management conference based upon the concordance between the electroclinical and MRI data.4 The standard ATL carried out under general anesthesia by the same neurosurgeon consisted of excision of neocortical structures, followed by microsurgical resection of the amygdala, and complete en bloc resection of the hippocampus and parahippocampal gyrus.3,6 The pathologic substrate was reviewed for this study and we defined hippocampal sclerosis as the loss of neuronal cell population of 30% or more in the CA1 sector of the hippocampal formation with or without neuronal loss and gliosis involving other mesial temporal structures.7 We excluded patients with MTLE associated with lesions like benign neoplasms or vascular malformations in order to assemble a uniform cohort of patients.
Postoperative AED management. All seizure-free patients were planned for gradual AED withdrawal during postoperative follow-ups. We also withdrew AED in patients who had early postoperative recurrence or those with persistent auras, provided they did not have any consciousness-impairing seizures for 2 consecutive years. In those patients with 2 or more AEDs, we started AED withdrawal at the end of the third post-ATL month, while it was started at 1 year in those on monotherapy. We did not take into account the findings of post-ATL EEG while deciding AED withdrawal. Reduction in AED doses was always done at every 2 months except in patients taking more than 2 AEDs, who underwent more rapid withdrawal of the third AED. Usual rate of withdrawal for different AEDs, at every 2 months, was as follows: carbamazepine 100 mg; oxcarbazepine 150 mg; phenytoin 50 mg; phenobarbital 15 mg; clobazam 2.5 mg; lamotrigine 25 mg; topiramate 25 mg; levetiracetam 250 mg; clonazepam 0.25 mg; and zonisamide 50 mg. Patients who had seizure recurrence due to some precipitating factor, other than noncompliance, were considered as true recurrence and managed on the standard lines. Standard protocol approvals, registrations, and patient consents. All patients or their guardians provided written informed consent to be treated and the data pertaining to the management to be stored in a database approved by the Institution’s Internal Review Board for experimental research. They also consented for utilization of the data for this study.
Statistical analysis. We summarized the quantitative data as
Postoperative EEG. We utilized the Mayo system of EEG
mean ⫾ SD and qualitative data as percentages. We calculated the sensitivity, specificity, and predictive values for presence of IED with respect to seizure outcome, and computed the odds for unfavorable seizure outcome in patients with IED compared to those without IED. We used Fisher exact tests to compare the patients with favorable and unfavorable seizure outcomes and those with and without AED withdrawal seizure recurrences, with respect to the presence of normal or abnormal EEG at each point of the follow-up period. All analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL). A p value of ⬍0.05 was considered significant.
classification and coding of EEG abnormalities.8 Our EEG protocol insists upon a partial sleep deprivation (not more than 3– 4 hours of sleep on the night before EEG study) and recording for at least 40 minutes, both during wakefulness and sleep.9 Natural sleep was obtained in the majority, but, if required, chloral hydrate (25 mg/kg, maximum dose 2 g) was used as a hypnotic agent. All EEG recordings were performed with 18- or 22channel EEG (Nicolet, Madison, WI) and with electrode placement according to the 10 –20 system. Anterior temporal (T1 and T2) electrodes were used routinely. We performed activation procedures including intermittent photic stimulation and hyperventilation for all the patients. The senior author (K.R.), who underwent training at the Mayo Clinic, Rochester, MN, reviewed all the recordings for this study. Only definite spikes or
During the study period, 327 patients underwent ATL for MTLE-HS. Seventeen patients did not have a minimum of 5 years post-ATL follow-up (6 died and 11 were lost to follow-up). Of the remaining 310 patients, 262 (84.5%) patients (150 male, 112 female) in whom all 4 serial post-ATL EEGs were available for review fulfilled our inclusion criteria. Their mean age at ATL was 27.4 ⫾ 9.2 years and mean duration of epilepsy prior to ATL was 18.2 ⫾ 8.8 years. Except for 4 patients who were selected for ATL after bilateral hippocampal depth electrode monitoring, all
Postoperative follow-up. Postoperatively, all patients were followed up at 3 months, at 1 year, and then at yearly intervals. We classified the outcome in 2 different manners: favorable outcome 1 was defined as complete freedom from seizures (including auras) during the entire follow-up period, while favorable outcome 2 was defined as similar outcome for the terminal 1-year follow-up period.
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sharp waves were considered as IED. We classified the IED according to the distribution as temporal and extratemporal IED. We defined IED in anterior and midtemporal electrodes (F7, F8, T1, T2, T3, and T4) as temporal IED. Temporal IED were further classified into unilateral (all IED confined to the side of surgery), contralateral (confined to the opposite side), or bilateral. As presence of slowing on postoperative EEG is confounded by the previous surgery and breach rhythm,10 we did not take into account the focal slowing. We tried to obtain a sleep record in every patient but did not exclude patients without a sleep record. For this study, we did not differentially quantify the IED on the EEG during wakefulness and sleep.
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RESULTS
Table 1
Prognostic importance of IED on postoperative EEG in patients who were seizure-free during the entire postoperative follow-up period (outcome 1) IED present
IED absent
EEG timing
Not SF
SF
3 mo
36
19
1y
31
2y
28
3y IED on any single EEG
Not SF
p Valuea
SF
Sensitivity
Specificity
PPV
NPV
97
110
27
85
65
53
0.01
2.1 (1.2–4.0)
Odds ratio (95% CI)
12
102
117
23
91
72
54
0.002
3.0 (1.5–6.1)
12
105
117
21
90
70
52
0.01
2.6 (1.3–5.4)
34
11
99
118
26
91
76
54
⬍0.0001
3.7 (1.8–7.7)
67
39
66
90
50
70
63
58
⬍0.001
2.6 (1.6–4.3)
IED on all 4 EEGs vs rest of patients
13
2
120
127
10
98
87
51
0.006
6.9 (1.5–31.1)
IED on all 4 EEGs vs patients with all 4 EEGs normal
13
2
66
90
—
—
—
—
⬍0.001
8.9 (1.9–40.6)
Abbreviations: CI ⫽ confidence interval; IED ⫽ interictal epileptiform discharge; NPV ⫽ negative predictive value; PPV ⫽ positive predictive value; SF ⫽ seizure-free. a By Fisher exact test.
the other patients were selected based upon the noninvasive investigations. We confirmed the diagnosis of HS pathologically in 252 patients. The hippocampal specimens from 10 patients (who had unequivocal evidence for HS on MRI) were considered insufficient to make a definite diagnosis. IED on postoperative EEG. Out of 1,048 EEGs, 821
(78.3%) comprised both awake and sleep recordings, while the remainder had only awake recordings. Numbers of patients with IED in the postoperative EEG at each follow-up period were as follows: 55 (21%) at 3 months, 43 (16.4%) at 1 year, 40 (15.3%) at 2 years, and 45 (17.2%) at 3 years. A total of 106 (40.5%) patients had at least one abnormal EEG: 65 patients had one abnormal EEG; 20 patients had 2 abnormal EEGs; 6 patients had 3 abnormal EEGs; and all 4 EEGs were abnormal in 15 patients. Although the proportion of patients with abnormal EEG at each follow-up was relatively constant, it did not represent the same group of patients. Thus, 21 (19.8%) patients had first abnormal EEG at 1 year while 15 (14.2%) patients had first abnormal EEG each at second and third years. In those patients with abnormal EEG, at each time point, the majority had ipsilateral temporal IED (⬃80%), and few had extratemporal (15%–20%) or bitemporal (4%–5%) IED. Seizure outcome and postoperative EEG. At a mean follow-up period of 7.6 ⫾ 1.8 (range 5–12) years, 129 patients (49.2%) had favorable outcome 1 while 218 patients (83.2%) had favorable outcome 2. For both the outcome measures, presence of IED on postoperative EEG, at each timepoint, was significantly associated with unfavorable seizure outcome. Compared to patients without IED, those with IED in post-ATL EEG at 1 year had 3-fold odds for unfavorable outcome 1 (odds ratio [OR] 3.0; 95% confi-
dence interval [CI] 1.5– 6.1) (table 1) and 7-fold odds for unfavorable outcome 2 (OR 7.1; 95% CI 3.4 –14.7) (table 2). Compared to those with normal EEGs, the patients in whom all the 4 EEGs were abnormal had 9-fold odds for unfavorable outcome 1 (OR 8.9; 95% CI 1.9 – 40.6) (table 1) and 26-fold odds for unfavorable outcome 2 (OR 25.9; 95% CI 7.3–91.3) (table 2). Presence of IED on all 4 EEG had 98% specificity for unfavorable outcomes. For outcome 1, IED on postoperative EEG at 1 year had a good positive predictive value (⬃70%) but rather modest negative predictive value (⬃50%) (table 1). For outcome 2, an abnormal EEG at 1 year showed relatively low positive predictive value (⬃45%) but a very good negative predictive value (⬃90%) (table 2). We also tried to correlate the seizure outcome with the number of abnormal EEGs in a given patient. For outcome 1, one abnormal EEG was associated with 55% risk of unfavorable outcome while 4 abnormal EEGs predicted 87% risk of unfavorable outcome (figure 1). For outcome 2, one abnormal EEG was associated with 11% risk of unfavorable outcome while 4 abnormal EEGs predicted 73% risk of unfavorable outcome (figure 2). Four normal post-ATL EEGs predicted 90% seizure-free longterm and terminal outcomes (figures 1 and 2). AED withdrawal, seizure recurrence, and postoperative EEG. In the immediate postoperative period, 71
patients were receiving monotherapy, 179 patients 2 AEDs, and 12 patients more than 2 AEDs. We attempted AED withdrawal in 225 (85.9%) patients during the course of follow-up. Rests of the patients were never seizure-free for a sufficient period to attempt AED withdrawal. During the mean follow-up period after last AED change of 4.8 (range 1–12) Neurology 76
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Table 2
Prognostic importance of IED on postoperative EEG in patients who were seizure-free during the terminal year of follow-up (outcome 2) IED present
IED absent
EEG timing
Not SF
SF
Not SF
SF
Sensitivity
Specificity
PPV
NPV
3 mo
17
38
27
180
39
83
31
87
p Valuea 0.002
Odds ratio (95% CI) 3.0 (1.5–6.0)
1y
20
23
24
195
45
89
46
89
⬍0.0001
7.1 (3.4–14.7)
2y
18
22
26
196
41
90
45
88
⬍0.0001
6.2 (2.9–13.0)
3y
21
24
23
194
48
89
47
89
⬍0.0001
IED on any single EEG
29
77
15
141
63
65
25
90
0.001
IED on all 4 EEGs vs rest of patients
11
4
33
214
25
98
73
87
0.0001
17.8 (5.4–59.3)
IED on all 4 EEGs vs patients with all 4 EEGs normal
11
4
15
141
—
—
—
—
0.0001
25.9 (7.3–91.3)
7.4 (3.6–15.3) 3.5 (1.8–7.0)
Abbreviations: CI ⫽ confidence interval; IED ⫽ interictal epileptiform discharge; NPV ⫽ negative predictive value; PPV ⫽ positive predictive value; SF ⫽ seizure-free. a By Fisher exact test.
years, seizure recurrence was noted in 61 (23.3%) patients. Seizure recurrence occurred while tapering AED in 37 patients, while in 24 patients it occurred after complete AED discontinuation. An abnormal postoperative EEG at 1 year increased the risk of seizure recurrence on attempted AED withdrawal by 2.6-fold (table 3). After excluding 5 patients who had seizure recurrence during the first post-ATL year, 12/56 (21.4%) with IED had seizure recurrence, while 15/162 (9.3%) without IED had a similar outcome ( p 0.03). Out of 13 patients with persistent auras at the end of first post-ATL year, 4 patients developed seizure recurrence on attempted AED withdrawal at a later date. We did not investigate the relationship between the presence of auras, IED, and seizure recurrence because of the few patients in this group. At last follow-up, AEDs could be completely discontinued in 141 (54.6%) patients. We wish to emphasize the following merits of our study. First, we assembled a uniform co-
DISCUSSION
Figure 1
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hort of 262 well-characterized patients with MTLEHS, who underwent identical ATL by the same neurosurgeon. Second, we maximized the yield of EEG by adhering to a uniform protocol of EEG recording and by obtaining sleep recording in the majority of our patients. At least 4 similarly spaced post-ATL EEGs were available for each of our patients. Third, we attempted a planned AED withdrawal in all the eligible seizure-free patients, thereby minimizing selection bias. In developed countries, the decision for AED withdrawal is often influenced by factors other than seizure freedom, such as fear of loss of driving privileges if seizure recurs. Thus, only 48% of adult patients included in a systematic review risked AED discontinuation trial after successful epilepsy surgery.2 Finally, a minimum of 5 years of post-ATL follow-up and 1 year follow-up after complete AED discontinuation was available for our patients. Our results are in agreement with the results of a recent systematic review of the studies that had assessed the prognostic importance of IED on EEG af-
Correlation between number of abnormal EEGs and seizure outcome during the entire follow-up period (outcome 1)
May 31, 2011
Figure 2
Correlation between number of abnormal EEGs and seizure outcome during the terminal 1-year follow-up period (outcome 2)
ter epilepsy surgery,1 and further underscore the value of post-ATL EEG in predicting seizure outcome. We wish to acknowledge the following limitations of our study. Although we collected the EEG data prospectively, the analysis was retrospective. We excluded 48 out of 310 (15.5%) eligible patients, as they did not have all 4 EEGs. We do not feel that exclusion of these few patients influenced our results. We did not differentially quantify the IEDs on the EEG during wakefulness and sleep. As the yield of IED is likely to be increased with a sleep recording,11 differential prognostic importance of awake only and awake plus sleep records merits interrogation in future studies. It should be emphasized that the seizure outcome after epilepsy surgery is influenced by multiple preoperative and postoperative factors, each with its own relative importance.12–14 Postoperative EEG is only one of the tools in the multimodality model of seizure outcome prediction and needs to be used in conjunction with other factors. It is well-known that, in a given patient, the diagnostic yield of EEG can be increased by performing serial
Table 3
EEGs.11,15 In our study, serial EEGs over a period of 3 years progressively increased the yield of abnormal EEG as well as its predictive ability. Risk of unfavorable outcome increased with increase in the number of abnormal EEGs in a given patient. In contrast, when 4 post-ATL EEGs (at 3 months, 1 year, 2 years, and 3 years) were all normal, our patients had a 90% chance for seizure-free and aura-free outcome. The increased yield of serial EEG may be related to increase in the recording time rather than repeating EEG at specific post-ATL time points. Would a single EEG of longer duration provide similar results? Would it be preferable to repeat EEG on different occasions but over a much shorter period of time to be able to predict seizure outcome very early on after ATL? We cannot answer these important questions based on our EEG study protocol. Our results also show that the predictive ability of EEG varies according the type of outcome being studied. When we defined favorable outcome as no seizures or aura during the entire post-ATL follow-up period (outcome 1), which is the best possible outcome following resective epilepsy surgery, abnormal post-ATL EEG at 1 year had a good posi-
Prognostic importance of interictal epileptiform discharges on postoperative EEG in relation to seizure recurrence following attempted antiepileptic drug withdrawal in 225 patients IED present
IED absent
EEG timing
Seizure recurrence
No recurrence
Seizure recurrence
No recurrence
Sensitivity
Specificity
PPV
NPV
p Valuea
Odds ratio (95% CI)
3 mo
14
27
47
137
22
83
34
74
0.3
1.5 (0.7–3.1)
1y
13
16
48
148
21
90
33
74
0.02
2.6 (1.0–7.1)
2y
8
16
53
148
13
90
33
74
0.47
1.4 (0.6–3.5)
3y
13
17
48
147
21
90
43
75
0.02
2.3 (1.1–5.2)
3 mo and 1 yb
22
36
39
128
36
78
38
77
0.04
2.0 (1.1–3.8)
c
29
52
32
112
48
68
36
78
0.03
2.0 (1.1–3.6)
All combined
Abbreviations: CI ⫽ confidence interval; IED ⫽ interictal epileptiform discharge; NPV ⫽ negative predictive value; PPV ⫽ positive predictive value. a By Fisher exact test. b Patients with IED on EEG at 3 months, 1 year, or at both timepoints. c All patients with IED on at least one EEG. Neurology 76
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tive predictive value, but a low negative predictive value. That means, although presence of IED on post-ATL EEG at 1 year predicts long-term unfavorable seizure outcome, a normal EEG at that point of time does not ensure seizure-free outcome for the entire follow-up period. Conversely, a single normal EEG has very good predictive value for seizure-free outcome during last 1 post-ATL year (outcome 2). Though an abnormal EEG at any time point in the post-ATL period increases the risk of seizure recurrence in a given patient, whether the seizures will be persistent in the long run can only be predicted with repeat EEG recordings. To our knowledge, no previous study, including 3 recently published studies of patients who had undergone temporal lobe resective epilepsy surgery,16 –18 has specifically inquired into the role of EEG in predicting postoperative seizure recurrence on AED withdrawal. Although the optimum timepoint in the postoperative period to begin AED withdrawal is unknown, AED withdrawal is usually considered after having had seizure freedom for at least 1 year.2 Our results suggest that patients with IED in the 1-year post-ATL EEG have higher chances of seizure recurrence following attempted AED withdrawal even after excluding patients who had seizure recurrence during the first post-ATL year. The studies that have investigated the role of EEG in medically treated patients undergoing AED withdrawal have shown that serial EEGs during AED withdrawal have more predictive value compared to prewithdrawal EEG.19 –21 However, it is possible that the presence of IED in those patients with seizure recurrence during AED withdrawal might be a consequence of seizure relapse rather than the presence of IED being a predictor of seizure recurrence following AED withdrawal. Due to the few patients who had seizure recurrence on AED withdrawal, we could reliably assess neither the role of serial EEG findings nor the cause and effect relationship. The majority of our patients with abnormal postoperative EEG and thus with unfavorable seizure outcome had IED on the same side of surgery. Our results are in agreement with the electroclinical evaluation findings on patients with failed temporal lobe resective epilepsy surgery that recurrent seizures originate at or adjacent to the site of resection in a majority of them.22 Those patients with persistent IEDs in the post-ATL EEG might have predominant temporal neocortical epileptogenic zone, where inadequate neocortical resection might result in abnormal EEG and continuing seizures.23,24 Received August 5, 2010. Accepted in final form February 18, 2011. 1930
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REFERENCES 1. Rathore C, Radhakrishnan K. Prognostic significance of interictal epileptiform discharges after epilepsy surgery. J Clin Neurophysiol 2010;27:255–262. 2. Schmidt D, Baumgartner C, Loscher W. Seizure recurrence after planned discontinuation of antiepileptic drugs in seizure-free patients after epilepsy surgery: a review of current clinical experience. Epilepsia 2004;45:179 –186. 3. Sylaja PN, Radhakrishnan K, Kesavadas C, Sarma PS. Seizure outcome after anterior temporal lobectomy and its predictors in patients with apparent temporal lobe epilepsy and normal MRI. Epilepsia 2004;45:803– 808. 4. Lachhwani DK, Radhakrishnan K. Epilepsy surgery in India. In: Lu¨ders HO, ed. Textbook of Epilepsy Surgery. Boca Raton, FL: Taylor & Francis; 2008:134 –144. 5. Chemmanam T, Radhakrishnan A, Sarma SP, Radhakrishnan K. A prospective study on the cost-effective utilization of long-term inpatient video-EEG monitoring in a developing country. J Clin Neurophysiol 2009;26:123–128. 6. Rao MB, Radhakrishnan K. Is epilepsy surgery possible in countries with limited resources? Epilepsia 2000;41(suppl 4):S31–S34. 7. Radhakrishnan A, Radhakrishnan K, Radhakrishnan VV, et al. Corpora amylacea in mesial temporal lobe epilepsy: clinico-pathological correlations. Epilepsy Res 2007;74:81–90. 8. Mayo Clinic and Mayo Foundation. Clinical Examinations in Neurology, 6th ed. Baltimore: Mosby; 1991:354 – 451. 9. Radhakrishnan K, Santoshkumar B, Venugopal A. Prevalence of benign epileptiform variants observed in an EEG laboratory from South India. Clin Neurophysiol 1999; 110:280 –285. 10. Radhakrishnan K, Chandy D, Menon G, Sarma S. Clinical and electroencephalographic correlates of breach activity. Am J Electroneurodiagnostic Technol 1999;39:138 –147. 11. Mendez OE, Brenner RP. Increasing the yield of EEG. J Clin Neurophysiol 2006;23:282–293. 12. McIntosh AM, Kalnins RM, Mitchell LA, Fabinyi CA, Briellmann RS, Berkovic SF. Temporal lobectomy: longterm seizure outcome, late recurrence and risks for seizure recurrence. Brain 2004;127:2018 –2030. 13. Spencer SS, Berg AT, Vickrey BG, et al, for The Multicenter Study of Epilepsy Surgery. Predicting long-term seizure outcome after resective epilepsy surgery: the multicenter study. Neurology 2005;65:912–918. 14. Te´llez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 2005;128:1188 –1198. 15. Salinsky M, Kanter R, Dasheiff RM. Effectiveness of multiple EEGs in supporting the diagnosis of epilepsy: an operational curve. Epilepsia 1987;28:331–334. 16. Kim YD, Heo K, Park SC, et al. Antiepileptic drug withdrawal after successful surgery for intractable temporal lobe epilepsy. Epilepsia 2005;46:251–257. 17. Al-Kaylani M, Konrad P, Lazenby B, Blumenkopf B, Abou-Khalil B. Seizure freedom off antiepileptic drugs after temporal lobe epilepsy surgery. Seizure 2007;16:95–98. 18. Lee S-Y, Lee J-Y, Kim DW, Lee SK, Chung CK. Factors related to successful antiepileptic drug withdrawal after anterior temporal lobectomy for medial temporal lobe epilepsy. Seizure 2008;17:11–18. 19. Tinuper P, Avoni P, Riva R, Provini F, Lugaresi E, Baruzzi
20.
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A. The prognostic value of the electroencephalogram in antiepileptic drug withdrawal in partial epilepsies. Neurology 1996;47:76 –78. Verrotti A, Morresi S, Cutarella R, Morgese G, Chiarelli F. Predictive value of EEG monitoring during drug withdrawal in children with cryptogenic partial epilepsy. Neurophysiol Clin 2000;30:240 –245. Uesugi H, Kojima T, Miyasaka M, et al. Discontinuation of antiepileptic drug treatment in controlled seizure patients. Jpn J Psychiatry Neurol 1994;48:255–258.
22.
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24.
Hennessy MJ, Elwes RD, Binnie CD, Polkey CE. Failed surgery for epilepsy: a study of persistence and recurrence of seizures following temporal resection. Brain 2000;123: 2445–2466. Ryvlin P, Kahane P. The hidden causes of surgery-resistant temporal lobe epilepsy: extratemporal or temporal plus? Curr Opin Neurol 2005;18:125–127. Chabarde`s S, Kahane P, Minotti L, et al. The temporopolar cortex plays a pivotal role in temporal lobe seizures. Brain 2005;128:1818 –1831.
Editor’s Note to Authors and Readers: Levels of Evidence coming to Neurology® Effective January 15, 2009, authors submitting Articles or Clinical/Scientific Notes to Neurology® that report on clinical therapeutic studies must state the study type, the primary research question(s), and the classification of level of evidence assigned to each question based on the classification scheme requirements shown below (left). While the authors will initially assign a level of evidence, the final level will be adjudicated by an independent team prior to publication. Ultimately, these levels can be translated into classes of recommendations for clinical care, as shown below (right). For more information, please access the articles and the editorial on the use of classification of levels of evidence published in Neurology.1-3 REFERENCES 1. French J, Gronseth G. Lost in a jungle of evidence: we need a compass. Neurology 2008;71:1634 –1638. 2. Gronseth G, French J. Practice parameters and technology assessments: what they are, what they are not, and why you should care. Neurology 2008;71:1639 –1643. 3. Gross RA, Johnston KC. Levels of evidence: taking Neurology® to the next level. Neurology 2009;72:8 –10.
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VIEWS & REVIEWS
Abbreviated report of the NIH/NINDS workshop on sudden unexpected death in epilepsy L.J. Hirsch, MD E.J. Donner, MD E.L. So, MD M. Jacobs, AB L. Nashef, MBChB, MD, FRCP J.L. Noebels, MD, PhD J.R. Buchhalter, MD, PhD
Address correspondence and reprint requests to Dr. Lawrence J. Hirsch, Comprehensive Epilepsy Center, Department of Neurology, Yale University, PO Box 208018, New Haven, CT 06520-8018
[email protected] ABSTRACT
Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy and is not rare. The NIH and National Institute of Neurological Disorders and Stroke sponsored a 3-day multidisciplinary workshop to advance research into SUDEP and its prevention. Parallel sessions were held: one with a focus on the science of SUDEP, and the other with a focus on issues related to the education of health care practitioners and people with epilepsy. This report summarizes the discussions and recommendations of the workshop, including lessons learned from investigations of sudden infant death syndrome (SIDS), sudden cardiac death, autonomic and respiratory physiology, medical devices, genetics, and animal models. Recommendations include educating all people with epilepsy about SUDEP as part of their general education on the potential harm of seizures, except in extenuating circumstances. Increasing awareness of SUDEP may facilitate improved seizure control, possibly decreasing SUDEP incidence. There have been significant advances in our understanding of the clinical and physiologic features of SIDS, sudden cardiac death, and SUDEP in both people and animals. Research should continue to focus on the cardiac, autonomic, respiratory, and genetic factors that likely contribute to the risk of SUDEP. Multicenter collaborative research should be encouraged, especially investigations with direct implications for the prevention of SUDEP. An ongoing SUDEP Coalition has been established to facilitate this effort. With the expansion of clinical, genetic, and basic science research, there is reasonable hope of advancing our understanding of SUDEP and ultimately our ability to prevent it. Neurology® 2011;76:1932–1938 GLOSSARY NINDS ⫽ National Institute of Neurological Disorders and Stroke; SIDS ⫽ sudden infant death syndrome; SUDEP ⫽ sudden unexpected death in epilepsy.
Throughout the world, approximately 0.5%–1% of the population has epilepsy. One-third of people with epilepsy have persistent seizures despite appropriate treatment. Each year, slightly less than one of every thousand people with epilepsy dies of sudden, unexpected, unexplained death. In those with refractory epilepsy, this occurs in 1 in 150 people each year. The risk is particularly high in those with uncontrolled tonic-clonic seizures. In 2007, the American Epilepsy Society and the Epilepsy Foundation formed a task force to address the research and educational issues concerning the phenomenon of sudden unexpected (unexplained) death in epilepsy (SUDEP). Among the published recommendations of the task force was that a multidisciplinary workshop on SUDEP be convened.1 The goal of the workshop was to bring together a multidisciplinary group of professionals and lay advocates with diverse expertise to further our understanding of SUDEP and our ability to prevent it. The depth and breadth of the participants included epileptologists and other neurologists, patient and professional educators, Supplemental data at www.neurology.org e-Pub ahead of print on May 4, 2011, at www.neurology.org. From the Comprehensive Epilepsy Center (L.J.H.), Department of Neurology, Columbia University, New York, NY; Division of Neurology (E.J.D.), Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada; Department of Neurology (E.L.S.), Mayo Clinic College of Medicine, Rochester, MN; Epilepsy Program (M.J.), NIH/NINDS, Bethesda, MD; Department of Neurology (L.N.), King’s College Hospital, London, UK; Departments of Neurology, Neuroscience, and Molecular and Human Genetics (J.L.N.), Baylor College of Medicine, Houston, TX; and Comprehensive Pediatric Epilepsy Program (J.R.B.), Phoenix Children’s Hospital, Phoenix, AZ. Study funding: This workshop was supported by NIH/NINDS. Disclosure: Author disclosures are provided at the end of the article. The NIH/NINDS workshop on sudden unexpected death in epilepsy was held November 12–14, 2008, Bethesda, MD. 1932
Copyright © 2011 by AAN Enterprises, Inc.
advocates from the bereaved community, and experts in guideline development as well as experts from related fields, such as sudden cardiac death (cardiology), neurocardiology, the autonomic nervous system, sudden infant death syndrome (SIDS), genetics, animal models of sudden death, respiratory physiology, and pathology (medical examiners/coroners). In November 2008, a unique, 3-day multidisciplinary SUDEP workshop was convened by the NIH and the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, MD. The workshop consisted of parallel sessions, one with a focus on the science of SUDEP, and the other with a focus on issues related to the education of health care practitioners and people with epilepsy. This report summarizes the discussions and recommendations from the workshop. For brevity, only a few select references are included. This report is a workshop summary, not a guideline, practice parameter, or evidencebased review. While some of the suggestions involve clinical practice, these recommendations only represent the views of the majority of the workshop participants at this time. Further study is required to develop future evidence-based guidelines. The definition of SUDEP used in this document is based on that of Nashef and Brown2: “Sudden, unexpected, witnessed or unwitnessed, nontraumatic and nondrowning death in a patient with epilepsy, with or without evidence of a seizure and excluding documented status epilepticus.” Definite SUDEP requires a postmortem examination showing no definite cause of death (such as high levels of illicit drugs or acute myocardial infarction). Probable SUDEP is used when postmortem examination is not performed, but the definition is otherwise fulfilled. Possible SUDEP is applied to less clear cases that might have been SUDEP, but where there is inadequate information to be certain or competing possible causes of death. For this workshop and summary, the term near-SUDEP is used to describe cases in which death was likely if resuscitation or other intervention had not been applied.
DEVELOPING A RESEARCH AGENDA TO UNDERSTAND AND PREVENT SUDEP Lessons
learned from SIDS. The prone sleep position is asso-
ciated with autonomic dysfunction, decreased arousability, heat trapping, rebreathing of exhaled gases, and higher risk of SIDS. Many patients with SUDEP are found prone. Exposure to cigarette smoke, especially in utero, is a risk factor for SIDS. In both animal and human infant studies, smoke exposure decreases ventilatory responses to hypoxia and decreases arousal from sleep. There appears to be a higher risk of SIDS with recent infection, autonomic dysfunction, and decreased sighs, gasps, spontaneous arousals, and arousability. Brainstem serotonin dysfunction appears to play a significant role in SIDS, possibly explaining up to half of cases. As many as 10% of SIDS cases appear to be associated with genetic variations known to be associated with cardiac arrhythmias and sudden death, or linked to regulation of CNS serotonin levels. In addition to genes associated with cardiac ion channelopathies (both sodium and potassium), genetic variants have been reported in genes relating to serotonin transport, autonomic nervous system and brainstem development, cytokines, and energy production (mitochondrial function). These factors that have been associated with SIDS have either not been investigated in SUDEP (cigarette smoke exposure, infection, arousability, brainstem physiology) or require additional investigation. Lessons learned from sudden cardiac death, neurocardiology, and studies of the autonomic nervous system.
In general, increases in sympathetic activity and decreases in parasympathetic activity are markers for increased risk of cardiac arrhythmia. Heart rate variability and baroreflex sensitivity are reasonable measures of autonomic system dysfunction that might predispose to sudden cardiac death. Baroreflex sensitivity may be more relevant to SUDEP, as it is a measure of an acute, reactive vagal response rather then chronic vagal tone as measured by heart rate variability. Inflammation, fever, and high C-reactive protein appear to be associated with an increased risk of sudden cardiac death. Genetic factors are clearly important in cardiac arrhythmias. Many of the known cardiac arrhythmia genes associated with either long or short QT syndromes, Brugada syndrome, or catecholaminergic polymorphic ventricular arrhythmia are dually expressed in heart and brain. Examples include KCNQ1, KCNH2, RyR2, and some sodium and calcium channel genes. SCN1A, a sodium channel gene known to be associated with generalized epilepsy with febrile seizures plus and severe myoclonic epiNeurology 76
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lepsy of infancy (Dravet syndrome), is also expressed in the heart. SUDEP may be particularly common in Dravet syndrome. There are several mechanisms of sudden cardiac death or myocardial injury that may be relevant to patients with epilepsy, especially during seizures. This includes a hyperadrenergic state, which is associated with coagulative myocytolysis (also known as contraction band necrosis), and can occur with subarachnoid hemorrhage and “scared-to-death” syndrome (also known as “voodoo death” or “broken heart” syndrome). This can be associated with apical ballooning or Takotsubo cardiomyopathy. Other acute autonomic changes that may occur in “voodoo death,” including hyperparasympathetic activity and possibly acute adrenal failure, may play a role as well. With some seizures in animals, brain discharges become directly linked to the activity of small intracardiac autonomic nerves (the “lock-step” phenomenon), which predisposes to arrhythmias in animal models. Intracardiac release of catecholamines is an important cause of cardiac injury. Cumulative injury may occur over time via this mechanism. Seizures can by associated with hyperactive parasympathetic activity, including asystole, and possibly hyperactive baroreflex activity. Cardiac ischemia due to coronary atherosclerosis can be exacerbated by seizures, which are a form of “stress test”; this cause of death is not typically considered SUDEP, but is still a potentially preventable cause of sudden seizure-related death in epilepsy patients. Other possible mechanisms include arrhythmias/channelopathies, conduction or autonomic effects of antiepileptic drugs or their withdrawal, and combinations of the above, with or without pulmonary mechanisms, especially hypoxia. Lessons learned from respiratory physiology. Serotonin plays a role in respiratory drive and the response to hypercapnia. In sheep and mouse models of SUDEP, seizures are associated with death due to respiratory arrest. In one strain of mice (DBA), pharmacologically increasing serotonin or its action can prevent death by preventing seizure-related respiratory arrest, and blocking serotonin activity increases seizure-related death. In other studies, increasing serotonin may decrease sleep apnea and death after stroke. In at least one animal model, administration of oxygen prevented seizure-related sudden death. Possible respiratory mechanisms contributing to SUDEP include central and obstructive apnea, pulmonary edema (especially neurogenic edema, as seen in a sheep model of SUDEP), ictal hypoxia, aspiration (not typically considered SUDEP, but another potential cause of sudden nontraumatic, nondrowning, seizure-related death), and laryngospasm. Central apnea may be most important, either related to serotonin as above, other substances released during 1934
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seizures such as adenosine or opiates, or to “cerebral shutdown” of all brain activity after a seizure. This “shutdown” may be due to ictal or postictal dysfunction of monoamine neurons, including serotonergic neurons. Inactivity of monoamine neurons could lead to simultaneous central apnea and decreased arousal, both thought to occur in SUDEP. Ictal hypoxia is frequently observed with seizures, including complex partial seizures without generalization. Hypoxia can be present without obvious respiratory distress or dysfunction. It typically involves a component of central apnea, but may also involve ventilation-perfusion mismatch or pulmonary edema. Life-threatening laryngospasm has been reported in relation to seizures, perhaps induced by aspiration. This may leave no obvious findings on autopsy, and therefore is likely to be classified as SUDEP. Recommendations to advance research in SUDEP. For details on recommendations to advance research in SUDEP, see table 1 and online report (appendix e-1 on the Neurology® Web site at www.neurology.org). We need to continue to develop animal models of SUDEP, including genetic ones. Sudden death, typically seizure-related, is known to occur in animal models of epilepsy. These deaths should be viewed as a research opportunity to learn more about their relevance to SUDEP. Ideally, investigators should simultaneously monitor cardiac, respiratory (including for central and obstructive components), cortical (EEG), brainstem, and autonomic function in these models. Clinical investigations should include the role of a screening EKG in all people with epilepsy, other methods to identify those at risk of arrhythmias, and the role of anti-arrhythmic medication or devices. Peri-ictal cardiac injury, autonomic dysfunction, and their prevention require further study. The role of respiratory drive, arousability, sleep position, serotonin, adenosine, sleep apnea, hypoxia, pulmonary edema, postictal EEG flattening, nocturnal supervision, tactile stimulation, and pulmonary edema all warrant further study. Further genetic investigation is needed to search for SUDEP-related genes, especially genes coding for the numerous channels that are dually expressed in heart and brain. Improved medical devices are needed, including reliable and convenient home oxygen and pulse monitors and seizure detectors. Implanted devices that can monitor respiratory, cardiac, and cerebral activity could define pathophysiology, identify highrisk patients, and be linked to specific treatment modalities such as cardiac defibrillators and pacemakers, alerting stimuli, and diaphragmatic pacing.
Table 1
Avenues of scientific research related to SUDEP and its preventiona
System
Avenues of research
Cardiac
Utility of obtaining an EKG in all patients with epilepsy Role of drugs known to prevent sudden cardiac death (unrelated to epilepsy), including use of existing large databases of epilepsy patients Peri-ictal cardiac function, including EKG, effects of AEDs, assessing for apical ballooning on echocardiography, and postictal cardiac injury markers such as troponin and brain natriuretic peptide Prolonged EKG monitoring (months–years) Cardiac MRI in high-risk patients
Autonomic
Measures of static and dynamic autonomic function, including in the peri-ictal setting
Respiratory
Role of prone sleep position, rebreathing, and partial obstruction Arousability and the rate of sighs and gasps at baseline while awake and asleep Postictal respiratory function, including role of tactile or other alerting stimuli in aborting central apnea and pathophysiology of postictal hypoxia, including ventilation/perfusion mismatch Role of serotonin, SSRIs, and peri-ictal respiration (including retrospective study of epilepsy patients in existing large databases that have SUDEP information) Physiology of postictal apnea, including role of “cerebral shutdown,” brainstem spreading depression, neurotransmitters (including serotonin, opiates, adenosine, acetylcholine, histamine, norepinephrine), and triggers to resume breathing Peri-ictal pulmonary edema Aspiration and laryngospasm Phrenic nerve monitoring in SUDEP models
Genetic
Role of genes known to be involved in sudden cardiac death or SIDS, and genes known to be involved in epilepsy but that are also expressed in the cardiac, autonomic, or respiratory systems Family history of sudden cardiac death Bank tissues/DNA of large cohort of high-risk individuals and persons with SUDEP
Medical devices
Development of better home monitors, including an oxygen saturation monitor Development of implanted device that can record and store EEG, EKG, oxygenation, respiratory effort, and body position or movement; include alarms and ability to activate treatment devices such as cardiac pacemakers, defibrillators, alerting stimuli, phrenic/diaphragmatic pacemakers, or even brainstem stimulators for cerebral shutdown with central apnea Study of existing home “seizure monitors,” preferably prior to commercial marketing and use Role of pacemakers once specific arrhythmias are found
Postmortem, including case identification
Education of, and collaboration with, medical examiners to increase recognition and documentation of SUDEP, and referral to central study sites Development of a standardized SUDEP protocol for autopsy and clinical data collection at time of death Role of establishing SUDEP as a reportable condition with requirements for autopsy and tissue banking Investigation of brainstem respiratory centers, including serotonergic system as in SIDS Investigation and banking of DNA and tissues for genetic studies Detailed cardiac studies, including thin slices for subtle fibrosis or other injury Postmortem examinations with specific protocol, including investigation of brain, heart, lungs, and autonomic system, preferably at centralized site or sites
Other
Effect of room sharing or special monitoring devices Effect of prenatal and postnatal tobacco smoke exposure, recent infection, fever, and inflammatory markers Rate of SUDEP in specific epilepsy syndromes, such as Dravet syndrome, and role of SCN1A mutations Effect of implanted deep brain and responsive brain stimulators on the rate of SUDEP and on peri-ictal respiration Effect of AEDs on all of the above measures, including interictal and peri-ictal cardiac, respiratory, and autonomic measures; also consider effect of withdrawal of AEDs Investigation of near-SUDEP cases, status epilepticus–related death, and seizure-related myocardial infarction Investigation of decreasing polytherapy, possibly via a randomized trial of reduction in number of AEDs
Abbreviations: AED ⫽ antiepileptic drug; SIDS ⫽ sudden infant death syndrome; SSRI ⫽ selective serotonin reuptake inhibitor; SUDEP ⫽ sudden unexpected death in epilepsy. a See text, plus full report (appendix e-1 on the Neurology® Web site at www.neurology.org) for details.
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Collaboration with coroners and medical examiners will be crucial to improve recognition, documentation, and investigation of SUDEP. Protocols for investigating deaths should be standardized. Creating a research consortium and SUDEP registry may be the most effective approach. A multicenter study of high-risk patients could be performed (e.g., those with refractory convulsions, especially in sleep), enrolling subjects and studying the following while in the epilepsy monitoring unit: 1. 12-lead EKG 2. Blood/DNA for banking. Blood for DNA can be banked via blood-spot cards that are easy to store and can be kept at room temperature 3. Baseline echocardiogram; cardiac monitoring, including ictal and postictal 4. Autonomic evaluation, including heart rate variability, baroreceptor sensitivity, and response to Valsalva 5. Respiratory evaluation, including oxygen saturation in the interictal, ictal, and postictal states; nasal airflow, chest and abdominal wall movement; sighs/yawns/arousability measures (as in SIDS studies); possibly full polysomnography 6. Standardized history including family history of sudden death, in utero and postnatal smoke exposure, sleep habits/environment, alcohol and drug use 7. Check C-reactive protein, postictal troponin, and postictal brain natriuretic peptide 8. Consider including a volunteer high-risk subgroup in whom a device would be implanted to obtain long-term recordings of the O2 level, EKG, EEG, and respiratory effort 9. Annual phone follow-up and questionnaire, including information about medications, illicit drugs, alcohol, compliance, sleep habits, SUDEP awareness 10. In the event of near-SUDEP or SUDEP, provide readily accessible information to first responders, emergency room staff, or medical examiner office on how to contact the study center (i.e., prior educational programs, medical alert ID or bracelet) 11. If probable or possible SUDEP occurs, perform a standardized autopsy, preferably with select tissues analyzed at a central or regional site. Of note, one should not rely on formalin-fixed, paraffinembedded tissue for genetic studies but rather blood-spot cards, blood in EDTA, or frozen tissue. In addition, detailed cardiopulmonary examination; specialized brainstem neuropathology, including serotonin evaluation; further genetic studies on tissue 12. Create a SUDEP registry and central tissue bank. It was estimated that there are about 1936
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2,000 SUDEP deaths per year in the United States, and perhaps 400 –500 per year in the United Kingdom. Include cases with and without known seizures at the time of death, and possibly include prolonged seizures/status epilepticus if no obvious cause of death EDUCATING PEOPLE WITH EPILEPSY AND THEIR FAMILIES ABOUT SUDEP Ethics: The
right to know vs the right not to know. To address
the issue of specific benefits and harms of discussing SUDEP with people with epilepsy and their families, primary bioethics principles were considered: respect for autonomy, nonmaleficence, beneficence, and justice.3 The potential benefits of health care providers discussing SUDEP with people with epilepsy and their families include the following: 1. Helps health care providers and people with epilepsy share in treatment goals 2. Helps to establish a “truth-telling” relationship 3. Avoids a false sense of security and resulting complacency regarding epilepsy and its treatment 4. Allows for expression of the natural anxiety regarding epilepsy and encourages it to be dealt with in a constructive fashion 5. Allows people with epilepsy to organize their lives with reasonable expectations 6. Allows people with epilepsy and their families to help reduce possible risk factors for SUDEP, e.g., by ensuring medical compliance and minimizing behavior that can exacerbate seizures 7. Significantly reduces the fear of SUDEP in lowrisk populations, especially in those who fear dying or fear the death of their loved one due to seizures, but have been afraid to inquire 8. If SUDEP does occur, the family’s pain, grief, and blame may be lessened by having been fully informed, knowing the patient was fully informed, and knowing how to get information and grief counseling, including discussing with other affected individuals’ families The potential risks of health care providers discussing SUDEP with people with epilepsy and their families include the following: 1. Precipitating anxiety, depression, or posttraumatic stress disorder in individuals with a predisposed psychological makeup 2. In certain cultures, the discussion could be interpreted as predisposing the individual to the event 3. Misunderstanding of “low risk” as “no risk” When and how to provide information to people with epilepsy and their families. At the time of the work-
shop, 2 published studies addressed the issue of prac-
Table 2
Avenues of research related to SUDEP education and awareness
3.
Determine if patients at low risk of SUDEP want to be educated Determine how patients/families learn best about SUDEP Determine readiness to learn so that information can be presented at the optimal time Determine the barriers providers have to discussing SUDEP
4.
Determine the best format for presenting information in the office and out Determine barriers to providers following guidelines for presentation of information regarding SUDEP Determine the effect of education on patients’ anxiety, quality of life, compliance, avoidance of high-risk behaviors, and the incidence of SUDEP
5.
Abbreviation: SUDEP ⫽ sudden unexpected death in epilepsy.
titioners’ communication with their patients about SUDEP. Lewis et al.4 conducted a survey of members of the UK Clinical Nurse Epilepsy Specialists association and other nurses with an interest in epilepsy. They found that 50% discuss SUDEP with most or all patients; improved adherence to treatment was reported in 62% of cases. Morton et al.5 conducted a survey of UK neurologists to determine compliance with the National Institute of Clinical Excellence guidelines, which recommend that SUDEP be discussed with people with epilepsy. A total of 26% of physicians surveyed reported that they discussed SUDEP with the majority of their patients, 61% with some, 7.5% with none, and 5% with all. Doctors who discussed SUDEP with most or all patients were significantly less likely to report negative reactions from their patients, and noted most patients received the information with equanimity or positively. There is no existing literature to guide the health care provider in assessing the readiness of a person with epilepsy or their family to learn about SUDEP, the timing and content of these discussions, or the appropriate cultural and social considerations. Recommendations. Along with the following, see ta-
ble 2 for a list of recommendations. 1. Except for patients with cultural or psychological circumstances which preclude safe discussion, it was the consensus of the discussants that the benefits of disclosing the risk of SUDEP to patients outweigh the harms. This is particularly (but not only) true in patients with generalized tonicclonic seizures. Further research is needed in this area. 2. The increased risk of sudden death, including SUDEP, associated with epilepsy should be disclosed as part of the overall education and coun-
6.
seling to patients about their condition and prognosis of living with epilepsy. A brief clinical tool should be designed and validated to assess readiness to learn about SUDEP. This could be used to determine how and when people with epilepsy and their families should receive information about SUDEP. Focus groups should be held for people recently diagnosed with epilepsy, people with medically intractable epilepsy, and families who have been affected by SUDEP to determine when and how much information should be presented. Research studies should be performed to determine the best methods of educating people with epilepsy and their families, the effects of discussing SUDEP on the patient and family, and the role of SUDEP disclosure on the reduction of identified risk factors and the incidence of SUDEP. Learning materials should include consistent, appropriate, widely available information for the public to ensure that SUDEP education is accurate and communicated appropriately.
EDUCATING HEALTH CARE PROVIDERS ABOUT SUDEP There is a paucity of data regarding health
care provider knowledge of SUDEP and attitudes toward disclosure of risk. Recommendations
1. Develop a survey aimed at identifying health professionals’ knowledge of SUDEP, expectations of patients’ and families’ reactions to information on SUDEP, comfort with and timing of discussion of SUDEP with patients and families, and perception of the utility of educational tools. 2. Develop and disseminate tailored but consistent information regarding SUDEP to professionals. 3. Develop evidence-based guidelines that provide recommendations for why, when, and how SUDEP should be discussed with people affected by epilepsy. Health care providers should be part of the guideline development. The intended and unintended consequences of guidelines should be considered based upon the experience of countries in which guidelines are in place. Specific consideration should be given to meeting the needs of the broad spectrum of individuals affected by epilepsy (as determined by future research) as well as the social and legal implications of the proposed guidelines. PREVENTION OF SUDEP WITH CURRENT KNOWLEDGE AND DATA Based on current knowledge, the
most effective means of SUDEP prevention is to reduce the frequency of seizures, especially but not Neurology 76
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only generalized tonic-clonic seizures, through optimized epilepsy care, including maximizing compliance with medications, avoiding seizure triggers such as sleep deprivation and heavy ethanol use, and consideration of epilepsy surgery in appropriate candidates in a timely fashion, as recommended in the prior AES/EF SUDEP Task Force report1; unnecessary polytherapy should be avoided as well. To this end, the measures discussed above regarding patient, family, and care provider education were endorsed. The recommendation to develop a research agenda in SUDEP will aid with prevention in the long term. Preliminary evidence suggests that nocturnal supervision or monitoring devices may be protective for SUDEP, but this requires further study. Additional recommendations to aid in SUDEP prevention include the following: 1. Educate patients about research promotion and participation. 2. Increase awareness of what constitutes good seizure management, both in care providers and patients. 3. Increase awareness of SUDEP in the public domain, including through the use of lay media. 4. Establish collaborations among support groups, funding sources, health care professionals, and others, both nationally and internationally, to advance the public discussion of SUDEP. 5. Consider developing a SUDEP practice guideline via the American Academy of Neurology. 6. For future clinical studies, consider using social science study designs to compare SUDEP rates before and after interventions in various regions, and following trends over time. Consider randomizing communities to “aggressive educational campaign” or standard care and following SUDEP rates. 7. Concentrate research on modifiable risk factors, both at the animal and human level. FUTURE DIRECTIONS
1. Create an ongoing SUDEP workgroup. This has already begun. The SUDEP Coalition has been formed jointly by the American Epilepsy Society, The Epilepsy Foundation, Citizens United for Research in Epilepsy, and NINDS. The goal is to promote and organize SUDEP research and other SUDEP-related activities, including the creation of a SUDEP registry and tissue banks. See www.aesnet.org/SUDEP for further information. 2. Encourage funding sources to solicit and fund proposals on SUDEP.
1938
Neurology 76
May 31, 2011
DISCLOSURE Dr. Hirsch has received speaker honoraria from UCB, GlaxoSmithKline, Pfizer Inc, and Lundbeck Inc.; serves on the editorial board of the Journal of Clinical Neurophysiology and as a contributing editor for Epilepsy Currents; receives publishing royalties for Atlas of EEG in Critical Care (WileyBlackwell, 2010) and UpToDate, Inc.; serves as a consultant for Lundbeck Inc. and Ikano Therapeutics Inc.; serves/has served on speakers’ bureaus for GlaxoSmithKline, UCB, Pfizer Inc, and Lundbeck Inc.; and receives research support from Eisai Inc., Pfizer Inc, UCB, Lundbeck Inc., Upsher-Smith, the American Epilepsy Society, and the Epilepsy Foundation. Dr. Donner serves on the editorial board of the Journal of Child Neurology; has received speaker honoraria from Nutrica, Inc. and the American Academy of Neurology; and has received research support from the Canadian Institutes of Health Research and C.U.R.E. Dr. So serves on the editorial board of Epilepsia, Epilepsy Research, and Journal of Clinical Neurophysiology. M. Jacobs reports no disclosures. Dr. Nashef is a trustee for Epilepsy Research UK and serves on the scientific advisory committee of Epilepsy Bereaved; receives publishing royalties for Oxford Specialist Handbooks in Neurology: Epilepsy (Oxford University Press, 2009); and has attended medical conferences as a guest of pharmaceutical companies and supervised staff funded by pharmaceutical companies carrying out audits (GlaxoSmithKline, UCB, Pfizer Inc, and Eisai Inc.). Dr. Noebels served on the editorial board of the Journal of Neuroscience and receives research support from the NIH/NINDS and the Blue Bird Circle Foundation for Pediatric Research. Dr. Buchhalter serves on scientific advisory boards for the NIH and the Charlie Foundation; serves on the editorial advisory board of Clinical Neurology News; and receives research support from Lundbeck Inc, Pfizer Inc, and the NIH/NINDS.
APPENDIX Participants. Scientific session cochairs: Elson So, Jeff Noebels. Subsection moderators: Clinical factors: Elizabeth J. Donner, Anne Berg. Cardiorespiratory and autonomic mechanisms: Lawrence Hirsch, Martin Samuels. Genetics: Alica Goldman, Michael Ackerman. Case identification: Nancy Temkin, Paul Schraeder. Prevention: Nina Graves, Lina Nashef. Education session cochairs: Jeffrey Buchhalter and Tess Sierzant. Subsection moderators: Ethics: Nancy Collins, Jane Hanna. Educating patients and families: Joan Austin, Fran London. Educating professionals: Andres Kanner, Jacci Bainbridge. Guidelines: Cynthia Harden, Susan Duncan. Prevention: Rosemary Panelli, David Thurman. Other participants are listed in appendix e-1 on the Neurology® Web site at www.neurology.org.
Received July 10, 2010. Accepted in final form February 14, 2011.
REFERENCES 1. So EL, Bainbridge J, Buchhalter JR, et al. Report of the American Epilepsy Society and the Epilepsy Foundation joint task force on sudden unexplained death in epilepsy. Epilepsia 2009;50:917–922. 2. Nashef L, Brown S. Epilepsy and sudden death. Lancet 1996;348:1324 –1325. 3. Jonsen AR, Siegler M, Winslade WJ. Clinical Ethics: A Practical Approach to Ethical Decisions in Clinical Medicine, 6th ed. New York: McGraw-Hill; 2006. 4. Lewis S, Higgins S, Goodwin M. Informing patients about sudden unexpected death in epilepsy: a survey of specialist nurses. Br J Neurosci Nursing 2008;41:30 –34. 5. Morton B, Richardson A, Duncan S. Sudden unexpected death in epilepsy (SUDEP): don’t ask, don’t tell? J Neurol Neurosurg Psychiatry 2006;77:199 –202.
Clinical/Scientific Notes
E. Thouvenot, MD, PhD C. Schmidt, MD C. He´roum, MD B. Carlander, MD A. Bonafe´, MD W. Camu, MD, PhD
DIABETES INSIPIDUS AS A FIRST MANIFESTATION IN MULTIPLE SCLEROSIS
Endocrine disturbance in multiple sclerosis (MS) is a rare condition and involvement of the hypothalamus is rarely described.1 The hypothalamus encompasses many nuclei where demyelinating lesions are hardly detectable using conventional MRI.2 Deficiency of antidiuretic hormone (ADH) can be encountered in inflammatory processes such as sarcoidosis, but may be idiopathic, possibly related to pathogenic antibodies. In MS, only 2 cases of ADH deficiency have been reported without overt hypothalamic lesions.3,4 Herein, we present the case of a 28-year-old man who developed diabetes insipidus (DI) 7 years before diagnosis of MS. MRI revealed the presence of bilateral MS lesions in the supraoptic nuclei, suggesting that DI was the first manifestation of MS. Case report. A 28-year-old man was referred after discovering cerebral white matter abnormalities on an MRI prescribed to explore DI. The patient had ingested ⬎10 L of water every day since the age of 21. He had neither familial history of DI nor personal antecedent head trauma or neurosurgery. Neurologic and general examinations were normal. The patient had no history of asthenia, fever, dyspnea, coughs, arthritis, parotitis, splenomegaly, hepatomegaly or adenopathies, erythema nodosum, or skin sarcoid. A low ADH level was found, while prolactin, growth hormone, insulin-like growth factor 1, adrenocorticotropic hormone, cortisol, and thyroid-stimulating hormone levels were within normal range. Biology revealed hypernatremia and hyponatruria, with inability to concentrate urine when deprived of water. Treatment with desmopressin (20 g nasal spray) completely suppressed polyuria/polydipsia. MRI failed to show enlargement of the pituitary stalk or gadolinium enhancement of the pituitary gland or hypothalamus. Unexpectedly, brain MRI showed periventricular and juxtacortical lesions, 2 of which were enhanced after gadolinium injection, suggesting MS. CSF analyses disclosed no white blood cells, normal CSF protein, 4 oligoclonal bands, and an increased immunoglobulin G (IgG)
index. Other investigations (antinuclear antibodies, antineutrophil cytoplasmic antibodies, neuromyelitis optica IgG, HIV, human T-cell lymphotrophic virus and syphilis testing, angiotensin converting enzymes, biopsy of a minor salivary gland, millimetric chest CT scan, EKG) were normal. Two months after the first brain MRI, the patient presented with left optic neuritis. Studies on visual evoked potential showed a bilateral demyelinating pattern. Ophthalmologic examination during optic neuritis ruled out uveitis. A further brain MRI 6 months later showed new T2 hyperintensities, one of which was enhanced after gadolinium injection and confirmed the diagnosis of MS through dissemination in time. Thin (2-mm) coronal T2-weighted sections of the hypothalamus revealed the presence of lesions in both supraoptic nuclei (figure). The patient received methylprednisolone infusions (1 g/day, 3 days) and glatiramer acetate treatment was started. ADH deficiency remained unchanged. Discussion. In 85% of cases, MS presents with an acute and classic clinically isolated syndrome (CIS) involving optic nerves, brain, or spinal cord. However, in this case, DI, a most unusual symptom, had started 7 years before. As DI is not a typical sign of MS, a comprehensive examination was performed. However, the time course would be unusual for neurosarcoidosis and there were no other clinical, biological, or radiologic abnormalities. The diagnosis of MS was done according to the 2005 revised McDonald criteria. Hypothalamic abnormalities are more common in neuromyelitis optica,5 but antiaquaporin antibodies were absent, and MRI aspects were more consistent with MS.1 Other acute neuroendocrine problems in MS such as hypothermia6 or the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have been associated with inflammation of the hypothalamus.7 It has also been suggested that MS-related fatigue could be related to hypothalamic dysfunctions.1 Only 2 authors have reported the occurrence of DI in the course of MS.3,4 However, in these cases, the cause of DI remained unclear and neither MRI nor CSF data were documented. In our case, exploration of other antehypophyseal hormones gave normal results and the theraNeurology 76
May 31, 2011
1939
Figure
Initial MRI scans
T2-weighted MRI coronal sections of the brain. (A) Bilateral lesions of the supraoptic nuclei (SO) and periventricular demyelinating lesions over the lateral ventricles (arrowheads). (B) Control MRI.
1940
peutic response to desmopressin was excellent. We then considered DI as the first manifestation of MS even though an association of idiopathic autoimmune DI and MS cannot be excluded. Brain MRIs revealed typical MS plaques fulfilling the Barkhof criteria for dissemination in space. Coronal MRI sections of the hypothalamic area showed periventricular plaques without enhancement after gadolinium injection. Bilateral lesions involving the supraoptic nuclei could account for the neuroendocrine problems in this patient, and thus may have been the first manifestation of MS in this case. MRI thin coronal T1 and T2 sections are useful in revealing the existence of lesions of the hypothalamus.2 DI, like SIADH, is a clinical manifestation that should be considered as a rare form of CIS. In this setting, brain MRI should screen for demyelinating lesions outside the hypothalamic area.
and Novartis; and has received research support from Biogen Idec, Bayer Schering Pharma, Merck Serono, and sanofi-aventis/Teva Pharmaceutical Industries Ltd.
From the Service de Neurologie (E.T., C.H., B.C., W.C.) and Service de Neuroradiologie (C.S., A.B.), Hoˆpital Gui de Chauliac, Montpellier, France. Disclosure: Dr. Thouvenot has received research support from Bayer Schering Pharma and ARSEP. Dr. Schmidt and Dr. He´roum report no disclosures. Dr. Carlander has received funding for travel from Merck Serono, Biogen Idec, Teva Pharmaceutical Industries Ltd./sanofi-aventis, and Bayer Schering Pharma; has received speaker honoraria from Merck Serono; and has received research support from Actelion Pharmaceuticals Ltd, Biogen Idec, Cephalon, Inc., BIOPROJET, Merck Serono, and sanofi-aventis. Prof. Bonafe´ has served as a consultant for ev3, Inc., Boston Scientific, and MicroVention. Prof. Camu has received speaker honoraria from Merck Serono; has served as a consultant for sanofi-aventis, Merck Serono,
4.
Neurology 76
May 31, 2011
Received September 28, 2010. Accepted in final form February 10, 2011. Address correspondence and reprint requests to Dr. E. Thouvenot, Service de Neurologie, Hoˆpital Gui de Chauliac, 80 Avenue Augustin Fliche, 34295 Montpellier Cedex 5, France;
[email protected] Copyright © 2011 by AAN Enterprises, Inc. 1.
2.
3.
5.
6.
7.
Zellini F, Niepel G, Tench CR, Constantinescu CS. Hypothalamic involvement assessed by T1 relaxation time in patients with relapsing-remitting multiple sclerosis. Mult Scler 2009;15:1442–1449. Miller MJ, Mark LP, Yetkin FZ, et al. Imaging white matter tracts and nuclei of the hypothalamus: an MRanatomic comparative study. AJNR Am J Neuroradiol 1994;15:117–121. Voiculescu V, Psatta DM. Diabetes insipidus in a patient with suspected multiple sclerosis. Rom J Neurol Psychiatry 1990;28:153–154. Weiler FG, Blumberg K, Liboni CS, Roque EA, Gois AF. [Diabetes insipidus in a patient with multiple sclerosis.] Arq Bras Endocrinol Metab 2008;52:134 –137. Carlander B, Vincent T, Le Floch A, Pageot N, Camu W, Dauvilliers Y. Hypocretinergic dysfunction in neuromyelitis optica with coma-like episodes. J Neurol Neurosurg Psychiatry 2008;79:333–334. Weiss N, Hasboun D, Demeret S, et al. Paroxysmal hypothermia as a clinical feature of multiple sclerosis. Neurology 2009;72:193–195. Sakai N, Miyajima H, Shimizu T, Arai K. Syndrome of inappropriate secretion of antidiuretic hormone associated with multiple sclerosis. Intern Med 1992;31:463– 466.
Tiesong Shang, MD, PhD Ana Delgado, MD David Adams, MD
JC VIRUS GRANULE CELL NEURONOPATHY AND HYPER-IgE IN HIV DISEASE
The polyomavirus JC (JCV) is the causative agent of progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients. JCV is a neurotropic virus that causes productive infection of oligodendrocytes and restrictive infection of astrocytes. The concept of narrow host cell selection of JCV has been challenged by recent case studies. It was reported that JCV can also cause productive infection of cerebellar granular neurons (CGN) independently of PML infection in the cerebral hemisphere. This novel syndrome was called JCV granule cell neuronopathy (JCV-GCN).1,2 Isolated cerebellar degeneration due to JCV infection restricted to the cerebellum in the absence of typical features of PML in HIV disease was only reported in one case.1 Hyperimmunoglobulinemia E (hyper-IgE) and eosinophilia have been described in some HIVinfected patients.3 The immunoglobulin E (IgE) level was correlated with immune status. Very high IgE level (20- to 100-fold above normal) usually occurred with significant decrease in CD4 cells. These patients usually presented with atopic dermatitis and recurrent soft tissue infection. Case report. A 58-year-old right-handed black woman had unremarkable past medical history and family history. In early January 2010, she initially developed slurred speech, followed by ataxia on her left side. In March 2010, she developed ataxia on her right side and lost the ability to walk. She developed episodic vertigo and diplopia. Physical examination in early July 2010 was remarkable for severe scanning dysarthria, ataxic pursuit eye movements, saccadic overshoot, and conjugate nystagmus on upgaze. She could not perform finger-nose or heel-knee-shin movements or sit up because of severe extremity and truncal ataxia. Deep tendon reflexes were normal and the plantar responses were flexor. Sensation and cognitive examinations were normal. Serologic studies for infection, hepatitis, toxoplasmosis, autoimmune, and paraneoplastic disease were negative. Stool study Figure
was negative for parasites. Blood cell count revealed eosinophilia with percentage of 39.5% (normal ⬍ 5%) and absolute count of 0.9 ⫻ 103/mL (normal ⬍ 0.5 ⫻ 103/mL). Serum proteinogram showed immunoglobulin A 575 mg/dL (normal ⬍400 mg/dL), immunoglobulin G 1,820 mg/dL (normal ⬍1,600 mg/dL), immunoglobulin M 137 mg/dL (normal ⬍230 mg/dL), and IgE 91,200 IU/mL (normal ⬍100 IU/mL), without monoclonal spike. AntiHIV1 antibodies were positive. CD4 cell count was 6/mm3. HIV1 RNA level was 154,180 copies/mL. CSF analysis showed erythrocytes 0/mm3, leukocytes 0/mm3, glucose 56 mg/dL, and protein 36.3 mg/dL. PCR for cytomegalovirus, herpes simplex virus 1 and 2, varicella zoster virus, Epstein-Barr virus, and HIV were negative in CSF. JCV PCR was positive in CSF. Brain MRI (figure) revealed severe cerebellar atrophy. Fluid-attenuated inversion recovery (FLAIR) images and T2 sequences showed areas of slight hyperintensity in bilateral middle cerebellar peduncles (MCP), which were restrictive on diffusion-weighted imaging but not on apparent diffusion coefficient. There was no hypointensity on T1 and no enhancement with gadolinium. The patient was treated with highly active antiretroviral therapy (HAART) (ritonavir/lopinavir, zidovudine, and lamivudine) and re-examined 10 weeks later. There was improvement of ataxia on her left side, but the rest of the examination was unchanged. Laboratory results showed serum IgE level of 49,900 IU/mL, eosinophils of 5.1% in percentage and 0.1 ⫻ 103/mL in absolute count, CD4 cell count of 39/ mm3, and HIV RNA level of 237 copies/mL. Discussion. Biopsy was not performed in this case so pathology was not available. But the clinical, laboratory, and radiologic features are consistent with JCV CGN. Typical clinical and radiologic features of PML were not present. The slight hyperintensity in bilateral MCP on MRI FLAIR and T2-weighted images is of uncertain meaning, although it is tempting
Diffuse cerebellar atrophy was demonstrated by MRI
ADC ⫽ apparent diffusion coefficient; DWI ⫽ diffusion-weighted imaging; FLAIR ⫽ fluid-attenuated inversion recovery. Neurology 76
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1941
to postulate that this is an extremely limited form of leukoencephalopathy associated with this particular type of JCV infection. It could be related to a cerebellar form of PML as it has been reported that cerebellar involvement was frequent in HIV-infected patients with PML.4 However, the MCP involvement was rare without typical PML and usually showed hypointensity on T1-weighted images.5 Furthermore, this MCP hyperintensity may simply be a nonspecific metabolic signal change due in some way to the effects of the infection, since the MCPs can be prominently involved in diverse and unrelated conditions such as the cerebellar form of multiple system atrophy, adult Alexander disease, and adult vanishing white matter disease.6 The significance of hyper-IgE is uncertain but may reflect impaired immune response. Her symptoms and laboratory results improved after HAART therapy, which has good CNS penetration.7 The eosinophilia resolved and IgE level was decreased by half after 10 weeks’ treatment. It is unlikely that her symptoms were due to parasite infection or other immunologic disorders. JCV CGN should be suspected in cerebellar degeneration in HIV-infected patients. This patient expands the spectrum of JCV-related CNS disease. From the Department of Neurology, Jackson Memorial Hospital, University of Miami, Miami, FL.
Disclosure: The authors report no disclosures. Received October 30, 2010. Accepted in final form January 11, 2011. Address correspondence and reprint requests to Dr. David Adams, General Neurology Division, Department of Neurology, Jackson Memorial Hospital, 1611 NW 12th Avenue, Miami, FL 33136;
[email protected] Copyright © 2011 by AAN Enterprises, Inc. 1.
2.
3. 4.
5.
6.
7.
Koralnik IJ, Wuthrich C, Dang X, et al. JC virus granule cell neuronopathy: a novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann Neurol 2005;57:576 –580. Du Pasquier RA, Corey S, Margolin DH, et al. Productive infection of cerebellar granule cell neurons by JC virus in an HIV⫹ individual. Neurology 2003;61:775–782. Lin RY, Smith JK Jr. Hyper-IgE and human immunodeficiency virus infection. Ann Allergy 1988;61:269 –272. Wu¨thrich C, Cheng YM, Joseph JT, et al. Frequent infection of cerebellar granule cell neurons by polyomavirus JC in progressive multifocal leukoencephalopathy. J Neuropathol Exp Neurol 2009;68:15–25. Woo HH, Rezai AR, Knopp EA, Weiner HL, Miller DC, Kelly PJ. Contrast-enhancing progressive multifocal leukoencephalopathy: radiological and pathological correlations: case report. Neurosurgery 1996;39:1031–1035. Schiffmann R, van der Knaap MS. Invited article: an MRIbased approach to the diagnosis of white matter disorders. Neurology 2009;72:750 –759. Tozzi V, Balestra P, Salvatori MF, et al. Changes in cognition during antiretroviral therapy: comparison of 2 different ranking systems to measure antiretroviral drug efficacy on HIV-associated neurocognitive. J Acquir Immune Defic Syndr 2009;52:56 – 63.
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Neurology 76
May 31, 2011
Clinical/Scientific Notes
E. Thouvenot, MD, PhD C. Schmidt, MD C. He´roum, MD B. Carlander, MD A. Bonafe´, MD W. Camu, MD, PhD
DIABETES INSIPIDUS AS A FIRST MANIFESTATION IN MULTIPLE SCLEROSIS
Endocrine disturbance in multiple sclerosis (MS) is a rare condition and involvement of the hypothalamus is rarely described.1 The hypothalamus encompasses many nuclei where demyelinating lesions are hardly detectable using conventional MRI.2 Deficiency of antidiuretic hormone (ADH) can be encountered in inflammatory processes such as sarcoidosis, but may be idiopathic, possibly related to pathogenic antibodies. In MS, only 2 cases of ADH deficiency have been reported without overt hypothalamic lesions.3,4 Herein, we present the case of a 28-year-old man who developed diabetes insipidus (DI) 7 years before diagnosis of MS. MRI revealed the presence of bilateral MS lesions in the supraoptic nuclei, suggesting that DI was the first manifestation of MS. Case report. A 28-year-old man was referred after discovering cerebral white matter abnormalities on an MRI prescribed to explore DI. The patient had ingested ⬎10 L of water every day since the age of 21. He had neither familial history of DI nor personal antecedent head trauma or neurosurgery. Neurologic and general examinations were normal. The patient had no history of asthenia, fever, dyspnea, coughs, arthritis, parotitis, splenomegaly, hepatomegaly or adenopathies, erythema nodosum, or skin sarcoid. A low ADH level was found, while prolactin, growth hormone, insulin-like growth factor 1, adrenocorticotropic hormone, cortisol, and thyroid-stimulating hormone levels were within normal range. Biology revealed hypernatremia and hyponatruria, with inability to concentrate urine when deprived of water. Treatment with desmopressin (20 g nasal spray) completely suppressed polyuria/polydipsia. MRI failed to show enlargement of the pituitary stalk or gadolinium enhancement of the pituitary gland or hypothalamus. Unexpectedly, brain MRI showed periventricular and juxtacortical lesions, 2 of which were enhanced after gadolinium injection, suggesting MS. CSF analyses disclosed no white blood cells, normal CSF protein, 4 oligoclonal bands, and an increased immunoglobulin G (IgG)
index. Other investigations (antinuclear antibodies, antineutrophil cytoplasmic antibodies, neuromyelitis optica IgG, HIV, human T-cell lymphotrophic virus and syphilis testing, angiotensin converting enzymes, biopsy of a minor salivary gland, millimetric chest CT scan, EKG) were normal. Two months after the first brain MRI, the patient presented with left optic neuritis. Studies on visual evoked potential showed a bilateral demyelinating pattern. Ophthalmologic examination during optic neuritis ruled out uveitis. A further brain MRI 6 months later showed new T2 hyperintensities, one of which was enhanced after gadolinium injection and confirmed the diagnosis of MS through dissemination in time. Thin (2-mm) coronal T2-weighted sections of the hypothalamus revealed the presence of lesions in both supraoptic nuclei (figure). The patient received methylprednisolone infusions (1 g/day, 3 days) and glatiramer acetate treatment was started. ADH deficiency remained unchanged. Discussion. In 85% of cases, MS presents with an acute and classic clinically isolated syndrome (CIS) involving optic nerves, brain, or spinal cord. However, in this case, DI, a most unusual symptom, had started 7 years before. As DI is not a typical sign of MS, a comprehensive examination was performed. However, the time course would be unusual for neurosarcoidosis and there were no other clinical, biological, or radiologic abnormalities. The diagnosis of MS was done according to the 2005 revised McDonald criteria. Hypothalamic abnormalities are more common in neuromyelitis optica,5 but antiaquaporin antibodies were absent, and MRI aspects were more consistent with MS.1 Other acute neuroendocrine problems in MS such as hypothermia6 or the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have been associated with inflammation of the hypothalamus.7 It has also been suggested that MS-related fatigue could be related to hypothalamic dysfunctions.1 Only 2 authors have reported the occurrence of DI in the course of MS.3,4 However, in these cases, the cause of DI remained unclear and neither MRI nor CSF data were documented. In our case, exploration of other antehypophyseal hormones gave normal results and the theraNeurology 76
May 31, 2011
1939
Figure
Initial MRI scans
T2-weighted MRI coronal sections of the brain. (A) Bilateral lesions of the supraoptic nuclei (SO) and periventricular demyelinating lesions over the lateral ventricles (arrowheads). (B) Control MRI.
1940
peutic response to desmopressin was excellent. We then considered DI as the first manifestation of MS even though an association of idiopathic autoimmune DI and MS cannot be excluded. Brain MRIs revealed typical MS plaques fulfilling the Barkhof criteria for dissemination in space. Coronal MRI sections of the hypothalamic area showed periventricular plaques without enhancement after gadolinium injection. Bilateral lesions involving the supraoptic nuclei could account for the neuroendocrine problems in this patient, and thus may have been the first manifestation of MS in this case. MRI thin coronal T1 and T2 sections are useful in revealing the existence of lesions of the hypothalamus.2 DI, like SIADH, is a clinical manifestation that should be considered as a rare form of CIS. In this setting, brain MRI should screen for demyelinating lesions outside the hypothalamic area.
and Novartis; and has received research support from Biogen Idec, Bayer Schering Pharma, Merck Serono, and sanofi-aventis/Teva Pharmaceutical Industries Ltd.
From the Service de Neurologie (E.T., C.H., B.C., W.C.) and Service de Neuroradiologie (C.S., A.B.), Hoˆpital Gui de Chauliac, Montpellier, France. Disclosure: Dr. Thouvenot has received research support from Bayer Schering Pharma and ARSEP. Dr. Schmidt and Dr. He´roum report no disclosures. Dr. Carlander has received funding for travel from Merck Serono, Biogen Idec, Teva Pharmaceutical Industries Ltd./sanofi-aventis, and Bayer Schering Pharma; has received speaker honoraria from Merck Serono; and has received research support from Actelion Pharmaceuticals Ltd, Biogen Idec, Cephalon, Inc., BIOPROJET, Merck Serono, and sanofi-aventis. Prof. Bonafe´ has served as a consultant for ev3, Inc., Boston Scientific, and MicroVention. Prof. Camu has received speaker honoraria from Merck Serono; has served as a consultant for sanofi-aventis, Merck Serono,
4.
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Received September 28, 2010. Accepted in final form February 10, 2011. Address correspondence and reprint requests to Dr. E. Thouvenot, Service de Neurologie, Hoˆpital Gui de Chauliac, 80 Avenue Augustin Fliche, 34295 Montpellier Cedex 5, France;
[email protected] Copyright © 2011 by AAN Enterprises, Inc. 1.
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Zellini F, Niepel G, Tench CR, Constantinescu CS. Hypothalamic involvement assessed by T1 relaxation time in patients with relapsing-remitting multiple sclerosis. Mult Scler 2009;15:1442–1449. Miller MJ, Mark LP, Yetkin FZ, et al. Imaging white matter tracts and nuclei of the hypothalamus: an MRanatomic comparative study. AJNR Am J Neuroradiol 1994;15:117–121. Voiculescu V, Psatta DM. Diabetes insipidus in a patient with suspected multiple sclerosis. Rom J Neurol Psychiatry 1990;28:153–154. Weiler FG, Blumberg K, Liboni CS, Roque EA, Gois AF. [Diabetes insipidus in a patient with multiple sclerosis.] Arq Bras Endocrinol Metab 2008;52:134 –137. Carlander B, Vincent T, Le Floch A, Pageot N, Camu W, Dauvilliers Y. Hypocretinergic dysfunction in neuromyelitis optica with coma-like episodes. J Neurol Neurosurg Psychiatry 2008;79:333–334. Weiss N, Hasboun D, Demeret S, et al. Paroxysmal hypothermia as a clinical feature of multiple sclerosis. Neurology 2009;72:193–195. Sakai N, Miyajima H, Shimizu T, Arai K. Syndrome of inappropriate secretion of antidiuretic hormone associated with multiple sclerosis. Intern Med 1992;31:463– 466.
Tiesong Shang, MD, PhD Ana Delgado, MD David Adams, MD
JC VIRUS GRANULE CELL NEURONOPATHY AND HYPER-IgE IN HIV DISEASE
The polyomavirus JC (JCV) is the causative agent of progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients. JCV is a neurotropic virus that causes productive infection of oligodendrocytes and restrictive infection of astrocytes. The concept of narrow host cell selection of JCV has been challenged by recent case studies. It was reported that JCV can also cause productive infection of cerebellar granular neurons (CGN) independently of PML infection in the cerebral hemisphere. This novel syndrome was called JCV granule cell neuronopathy (JCV-GCN).1,2 Isolated cerebellar degeneration due to JCV infection restricted to the cerebellum in the absence of typical features of PML in HIV disease was only reported in one case.1 Hyperimmunoglobulinemia E (hyper-IgE) and eosinophilia have been described in some HIVinfected patients.3 The immunoglobulin E (IgE) level was correlated with immune status. Very high IgE level (20- to 100-fold above normal) usually occurred with significant decrease in CD4 cells. These patients usually presented with atopic dermatitis and recurrent soft tissue infection. Case report. A 58-year-old right-handed black woman had unremarkable past medical history and family history. In early January 2010, she initially developed slurred speech, followed by ataxia on her left side. In March 2010, she developed ataxia on her right side and lost the ability to walk. She developed episodic vertigo and diplopia. Physical examination in early July 2010 was remarkable for severe scanning dysarthria, ataxic pursuit eye movements, saccadic overshoot, and conjugate nystagmus on upgaze. She could not perform finger-nose or heel-knee-shin movements or sit up because of severe extremity and truncal ataxia. Deep tendon reflexes were normal and the plantar responses were flexor. Sensation and cognitive examinations were normal. Serologic studies for infection, hepatitis, toxoplasmosis, autoimmune, and paraneoplastic disease were negative. Stool study Figure
was negative for parasites. Blood cell count revealed eosinophilia with percentage of 39.5% (normal ⬍ 5%) and absolute count of 0.9 ⫻ 103/mL (normal ⬍ 0.5 ⫻ 103/mL). Serum proteinogram showed immunoglobulin A 575 mg/dL (normal ⬍400 mg/dL), immunoglobulin G 1,820 mg/dL (normal ⬍1,600 mg/dL), immunoglobulin M 137 mg/dL (normal ⬍230 mg/dL), and IgE 91,200 IU/mL (normal ⬍100 IU/mL), without monoclonal spike. AntiHIV1 antibodies were positive. CD4 cell count was 6/mm3. HIV1 RNA level was 154,180 copies/mL. CSF analysis showed erythrocytes 0/mm3, leukocytes 0/mm3, glucose 56 mg/dL, and protein 36.3 mg/dL. PCR for cytomegalovirus, herpes simplex virus 1 and 2, varicella zoster virus, Epstein-Barr virus, and HIV were negative in CSF. JCV PCR was positive in CSF. Brain MRI (figure) revealed severe cerebellar atrophy. Fluid-attenuated inversion recovery (FLAIR) images and T2 sequences showed areas of slight hyperintensity in bilateral middle cerebellar peduncles (MCP), which were restrictive on diffusion-weighted imaging but not on apparent diffusion coefficient. There was no hypointensity on T1 and no enhancement with gadolinium. The patient was treated with highly active antiretroviral therapy (HAART) (ritonavir/lopinavir, zidovudine, and lamivudine) and re-examined 10 weeks later. There was improvement of ataxia on her left side, but the rest of the examination was unchanged. Laboratory results showed serum IgE level of 49,900 IU/mL, eosinophils of 5.1% in percentage and 0.1 ⫻ 103/mL in absolute count, CD4 cell count of 39/ mm3, and HIV RNA level of 237 copies/mL. Discussion. Biopsy was not performed in this case so pathology was not available. But the clinical, laboratory, and radiologic features are consistent with JCV CGN. Typical clinical and radiologic features of PML were not present. The slight hyperintensity in bilateral MCP on MRI FLAIR and T2-weighted images is of uncertain meaning, although it is tempting
Diffuse cerebellar atrophy was demonstrated by MRI
ADC ⫽ apparent diffusion coefficient; DWI ⫽ diffusion-weighted imaging; FLAIR ⫽ fluid-attenuated inversion recovery. Neurology 76
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to postulate that this is an extremely limited form of leukoencephalopathy associated with this particular type of JCV infection. It could be related to a cerebellar form of PML as it has been reported that cerebellar involvement was frequent in HIV-infected patients with PML.4 However, the MCP involvement was rare without typical PML and usually showed hypointensity on T1-weighted images.5 Furthermore, this MCP hyperintensity may simply be a nonspecific metabolic signal change due in some way to the effects of the infection, since the MCPs can be prominently involved in diverse and unrelated conditions such as the cerebellar form of multiple system atrophy, adult Alexander disease, and adult vanishing white matter disease.6 The significance of hyper-IgE is uncertain but may reflect impaired immune response. Her symptoms and laboratory results improved after HAART therapy, which has good CNS penetration.7 The eosinophilia resolved and IgE level was decreased by half after 10 weeks’ treatment. It is unlikely that her symptoms were due to parasite infection or other immunologic disorders. JCV CGN should be suspected in cerebellar degeneration in HIV-infected patients. This patient expands the spectrum of JCV-related CNS disease. From the Department of Neurology, Jackson Memorial Hospital, University of Miami, Miami, FL.
Disclosure: The authors report no disclosures. Received October 30, 2010. Accepted in final form January 11, 2011. Address correspondence and reprint requests to Dr. David Adams, General Neurology Division, Department of Neurology, Jackson Memorial Hospital, 1611 NW 12th Avenue, Miami, FL 33136;
[email protected] Copyright © 2011 by AAN Enterprises, Inc. 1.
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3. 4.
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Koralnik IJ, Wuthrich C, Dang X, et al. JC virus granule cell neuronopathy: a novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann Neurol 2005;57:576 –580. Du Pasquier RA, Corey S, Margolin DH, et al. Productive infection of cerebellar granule cell neurons by JC virus in an HIV⫹ individual. Neurology 2003;61:775–782. Lin RY, Smith JK Jr. Hyper-IgE and human immunodeficiency virus infection. Ann Allergy 1988;61:269 –272. Wu¨thrich C, Cheng YM, Joseph JT, et al. Frequent infection of cerebellar granule cell neurons by polyomavirus JC in progressive multifocal leukoencephalopathy. J Neuropathol Exp Neurol 2009;68:15–25. Woo HH, Rezai AR, Knopp EA, Weiner HL, Miller DC, Kelly PJ. Contrast-enhancing progressive multifocal leukoencephalopathy: radiological and pathological correlations: case report. Neurosurgery 1996;39:1031–1035. Schiffmann R, van der Knaap MS. Invited article: an MRIbased approach to the diagnosis of white matter disorders. Neurology 2009;72:750 –759. Tozzi V, Balestra P, Salvatori MF, et al. Changes in cognition during antiretroviral therapy: comparison of 2 different ranking systems to measure antiretroviral drug efficacy on HIV-associated neurocognitive. J Acquir Immune Defic Syndr 2009;52:56 – 63.
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NEUROIMAGES
Giant thoracic meningocele associated with neurofibromatosis 1
Figure
Giant thoracic meningocele
(A, C) Axial and sagittal T2-weighted MRI demonstrating a giant meningocele (star) at the left T8 vertebral level. (B) Postoperative MRI demonstrating complete resection of the meningocele with reexpansion of the spinal cord (arrows) and lung (asterisk). (D) Gross specimen of the resected meningocele.
A 48-year-old man with neurofibromatosis 1 presented with progressive shortness of breath over the course of 4 years. There was prominent kyphoscoliosis. Imaging revealed a large thoracic meningocele compressing the left lung (figure). He then developed progressive lower extremity weakness and a decline in pulmonary function. He underwent drainage, resection, and closure of his thoracic meningocele. In a second stage, he underwent spinal cord decompression and fusion. He is no longer requiring supplemental oxygen and is gaining strength. Thoracic meningoceles may occur in neurofibromatosis secondary to congenital mesodermal dysplasia and hypoplastic bone changes.1,2 Brian P. Walcott, MD, Kristopher T. Kahle, MD, PhD, John C. Wain, MD, Lawrence F. Borges, MD, Boston, MA Disclosure: The authors report no disclosures. Address correspondence and reprint requests to Dr. Lawrence F. Borges, Neurosurgical Spine Service, Neurosurgical Stereoscopic 3-dimensional Video Laboratory, Massachusetts General Hospital, White 1205, 55 Fruit Street, Boston, MA 02114;
[email protected] 1. 2.
Miles J, Pennybacker J, Sheldon P. Intrathoracic meningocele: its development and association with neurofibromatosis. J Neurol Neurosurg Psychiatry 1969;32:99 –110. Rainov NG, Heidecke V, Burkert W. Thoracic and lumbar meningocele in neurofibromatosis type 1: report of two cases and review of the literature. Neurosurg Rev 1995;18:127–134. Copyright © 2011 by AAN Enterprises, Inc.
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Historical Abstract: October 1, 1971 A DOUBLE-BLIND STUDY OF THE EFFECTS OF LEVODOPA IN PARKINSON’S DISEASE KK Nakano, HR Tyler Neurology 1971;21:1069-1074 There is considerable evidence suggesting that the symptoms of parkinsonism are related to a depletion of striatal dopamine.1-4 Since oral dopamine does not cross the blood-brain barrier, efforts have focused on the systemic administration of L-dopa, dopamine’s immediate precursor, which appears to pass through the barrier. Recent studies indicate that L-dopa is rapidly becoming the treatment of choice in parkinsonism.5-8 In the present study, a double-blind therapeutic trial has been used in the treatment of Parkinson’s syndrome. The purpose of the study is to compare L-dopa to a conventional antiparkinsonian medication (procyclidine hydrochloride) and a placebo (lactose). Additionally, this study has been designed to determine whether a two- to six-week period is an adequate length of time to see the benefits of L-dopa therapy in parkinsonian patients receiving no other medication. It was also designed so that a patient could continue to take any drug that brought about significant improvement; in such cases, he was not required to try the other drugs in the study. References can be found in the online article. Free Access to this article at www.neurology.org/content/21/10/1069 Comment from Ryan J. Uitti, MD, FAAN, Associate Editor: This was a landmark study documenting the monumental effects of the best treatment for the most common movement disorder.
Historical Abstract: November 1, 1999 USE OF THE BRAIN PARENCHYMAL FRACTION TO MEASURE WHOLE BRAIN ATROPHY IN RELAPSING-REMITTING MS R.A. Rudick, E. Fisher, J.-C. Lee, J. Simon, L. Jacobs, and the Multiple Sclerosis Collaborative Research Group Neurology 1999;53:1698 –1704 Background: Episodic inflammation in the CNS during the early stages of MS results in progressive disability years later, presumably due to myelin and axonal injury. MRI demonstrates ongoing disease activity during the early disease stage, even in some patients who are stable clinically. The optimal MRI measure for the destructive pathologic process is uncertain, however. Methods: In this post-hoc study, MRI scans were analyzed from patients with relapsing MS participating in a placebo-controlled trial of interferon -1a. The brain parenchymal fraction, defined as the ratio of brain parenchymal volume to the total volume within the brain surface contour, was used to measure whole brain atrophy. The relationship between disease features and brain atrophy and effect of interferon -1a were determined. Results: MS patients had significant brain atrophy that worsened during each of 2 years of observation. In many patients, brain atrophy worsened without clinical disease activity. Baseline clinical and MRI abnormalities were not strongly related to the rate of brain atrophy during the subsequent 2 years. Treatment with interferon -1a resulted in a reduction in brain atrophy progression during the second year of the clinical trial. Conclusions: Patients with relapsing-remitting MS have measurable amounts of whole brain atrophy that worsens yearly, in most cases without clinical manifestations. The brain parenchymal fraction is a marker for destructive pathologic processes ongoing in relapsing MS patients, and appears useful in demonstrating treatment effects in controlled clinical trials. Free Access to this article at www.neurology.org/content/53/8/1698 Comment from Richard M. Ransohoff, MD, Associate Editor: This study showed conclusively that MS is a neurodegenerative disorder from early phases of disease and also delineated a useful tool for monitoring therapeutic trials.
RESIDENT & FELLOW SECTION Section Editor Mitchell S.V. Elkind, MD, MS
Tuhin Virmani, MD, PhD Ashima Agarwal, MD Eric C. Klawiter, MD
Address correspondence and reprint requests to Dr. Tuhin Virmani, Neurology, Box 8111, 660 S. Euclid Ave., St. Louis, MO 63110
[email protected] Clinical Reasoning: A young adult presents with focal weakness and hemorrhagic brain lesions SECTION 1
A 25-year-old man who emigrated from Mexico 5 years ago presented with headache, altered mental status, and left hemiparesis. Initial history obtained from collateral sources indicated the patient had complained of a headache of increasing severity for the past 2 months. Two weeks prior to presentation, he experienced malaise, decreased appetite, nausea and vomiting, visual changes, and gait difficulties resulting in 2 falls. The day of presentation, he developed acute onset left upper and lower extremity weakness prompting emergency evaluation. On arrival he was lethargic, disoriented, and did not follow commands. Following intubation in the emergency department, he was transferred to the neurologic intensive care unit (ICU). He was febrile and tachycardic on arrival to the ICU. Upon cessation of sedation, the patient was ill-appearing but awake and able to cooperate with the neurologic examination. He was oriented to hospital name and year and was able to follow one-step commands. His pupils were equal, round, and reactive to light and accommodation. Bedside funduscopic examination showed normal discs and vessels. His extraocular movements were full except for the inability to adduct his right eye. He blinked to threat bilaterally but had left-sided visual neglect with a right gaze preference. He had left lower facial weakness. On motor examination, he had left flaccid paralysis as well as mild decreased strength in his right upper and lower extremities (4⫹/5) that might have
Figure 1
CT findings
Two foci of hemorrhage are seen in the right frontal and parietal lobes with surrounding vasogenic edema.
been attributable to incomplete cooperation. Sensation was intact to light touch on the right but only to noxious painful nail bed stimulation on the left. Reflexes were brisk on the right and diminished on the left. He had a left Babinski sign. Head CT revealed 2 foci of hemorrhage in the right frontal and parietal lobes with associated vasogenic edema (figure 1). Questions for consideration: 1. What is the differential diagnosis? 2. What would be the next step in your management of this patient?
GO TO SECTION 2
From the Departments of Neurology (T.V., E.C.K.) and Pathology (A.A.), Washington University, St. Louis, MO. Study funding: Supported by the NIH (UL1RR024992 to E.C.K.). E.C.K. was supported by an American Academy of Neurology Foundation Clinical Research Training Fellowship. Disclosure: Author disclosures are provided at the end of the article. e106
Copyright © 2011 by AAN Enterprises, Inc.
SECTION 2
The differential diagnosis for this presentation with multiple neurologic symptoms rapidly cumulative over time should initially be kept broad to avoid missing a treatable disease. Both the neurologic examination and initial imaging implicate a multifocal localization. Given the prolonged headache, malaise, and fever at presentation, one must first consider infectious processes such as viral and bacterial meningitis or encephalitis including tuberculous meningitis, cysticercosis, and aspergillosis. Infective endocarditis leading to multiple septic emboli could also account
Figure 2
MRI findings
for the clinical picture and the potential involvement of both anterior and posterior circulation territories. Other causes of multifocal stroke with hemorrhagic conversion include CNS vasculitis and moyamoya disease. Central demyelinating conditions such as acute hemorrhagic leukoencephalitis are possible given the patient’s age and presentation. Finally, neoplasms (primary CNS tumors, metastatic disease, or primary CNS lymphoma) could potentially cause multiple hemorrhagic lesions that become symptomatic with dissemination in time. Additional history revealed no prior illness. He had not visited Mexico since arrival to the United States. A brother presented with sudden onset of weakness at age 17 with a fluctuating course that resulted in death. His father died of renal failure. Initial studies showed normal serum chemistries except for low sodium (127 mmol/L). White blood cell (WBC) count was elevated at 18,000/mm3 with 90% neutrophils. Additional testing included negative antinuclear antibodies, antineutrophil cytoplasmic antibodies, and extractable nuclear antigen screens with a mildly elevated erythrocyte sedimentation rate at 16 mm/hour (0 –12). HIV testing was negative. Lumbar puncture was remarkable for mildly elevated protein (53 mg/dL), normal glucose, 1 WBC/mm3, 2 red blood cells (RBC)/mm3, negative bacterial culture, and negative varicella zoster virus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, and enterovirus PCRs. Brain MRI (figure 2) revealed multiple foci of hyperintensity in bilateral cerebral hemispheres, brainstem, and cerebellum on fluid-attenuated inversion recovery (FLAIR) images with associated enhancement on T1 postgadolinium sequences in a majority of lesions. Susceptibility-weighted images suggested hemorrhage in more locations than appreciated on head CT. There was no evidence of diffusion restriction. Questions for consideration:
Multiple scattered T2 hyperintensities are appreciated on fluid-attenuated inversion recovery images (A) with evidence of hemorrhage on susceptibility-weighted images (B), contrast enhancement on T1 postgadolinium images (C), and without diffusion restriction on diffusion-weighted imaging (D).
1. How does the presence of multiple foci of hemorrhage and enhancement on MRI narrow the differential diagnosis? 2. What additional testing would you request?
GO TO SECTION 3
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Figure 3
Pathology findings
Histology demonstrates inflammatory infiltrate on CD3 staining (A), relative preservation of axons on neurofilament staining (B), and a significant paucity of myelin on Luxol fast blue/periodic acid–Schiff staining in the region demarcated by the arrowhead (C).
SECTION 3
The MRI findings help narrow the differential diagnosis by excluding acute ischemic stroke. Infectious, demyelinating, inflammatory, and neoplastic processes should continue to be considered. The low serum sodium was likely secondary to the syndrome of inappropriate anti-diuretic hormone secretion from the multiple CNS lesions. Subsequent CSF testing demonstrated normal immunoglobulin G index and synthesis rate and no oligoclonal bands. Extensive infectious evaluation including CSF acid fast bacteria (AFB) stain and culture, CSF toxoplasma PCR, blood and urine histoplasma antigen, CSF and blood Cryptococcus antigen, Aspergillus galactomannan antigen, CSF and nasal Mycoplasma pneumoniae PCR, CSF ova and parasites screen, and CSF Acanthamoeba culture were all negative. The patient was still without a definitive diagnosis.
Ultimately, biopsy of an enhancing left frontal cortical lesion revealed an inflammatory process, consisting of CD3-positive T cells, numerous CD68positive histiocytes/macrophages, and only rare CD20-positive B cells (figure 3). There was no evidence of vasculitis. No atypical cells indicative of a neoplasm were identified. Tissue cultures from the biopsy were also negative for AFB, fungal, and bacterial elements. Neurofilament staining showed relative preservation of axons. Severe loss of myelin was demonstrated on Luxol fast blue/periodic acid-Schiff staining. Scattered macrophages with blue-staining material consistent with myelin in their cytoplasm were identified. Question for consideration: 1. Given the findings on brain biopsy, how would you diagnose this patient?
GO TO SECTION 4
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SECTION 4
This patient initially had a headache followed by rapid progression of neurologic symptoms resulting in decreased level of consciousness and left hemiparesis. MRI showed multiple T2 hyperintensities, some with hemorrhagic involvement. Brain biopsy showed patchy demyelination with axon preservation. Presence of CD3-positive T cells and CD68 histiocytes/ macrophages with rare B cells indicated a reactive process, less likely to be neoplastic. These findings are consistent with a diagnosis of acute hemorrhagic leukoencephalitis (AHLE). Interestingly, the cause of death of the patient’s brother is unknown, but he presented in a similar fashion. One could speculate that it is possible the 2 siblings had the same disorder. AHLE is a rare disorder on the spectrum of acute postinfectious leukoencephalopathies including acute disseminated encephalomyelitis and Bickerstaff brainstem encephalitis.1 AHLE typically presents with an abrupt onset of neurologic symptoms including encephalopathy, focal neurologic deficits, seizures, and coma up to 20 days after a nonspecific viral illness, similar to this case report.2 CSF typically shows a lymphocytic pleocytosis, elevated RBC count, and elevated protein. MRI may demonstrate white matter T2 hyperintensities with associated edema and often hemorrhage.3,4 Contrast enhancement is not typically present but was appreciated in this patient. Pathology shows fibrinoid vascular necrosis, widespread perivascular polymorphonuclear infiltrates, “ring and ball” hemorrhages, and loss of myelin with preservation of axons.5 The etiology of AHLE remains unclear, with a prevailing theory that infectious agents trigger the formation of T-cell clones, resulting in an inflammatory cascade targeting myelin basic protein. The perivascular infiltrate has been suggested to represent an acute vasculitis with occlusion of vessels eventually leading to vessel wall necrosis and subsequent hemorrhage.3,6,7 Treatment currently includes surgical decompression for increased intracranial pressure with craniectomy or ventriculostomy if necessary. Immunosuppressive agents such as IV steroids, IV immunoglobulins, and cyclophosphamide have also been employed with varying success, although morbidity and mortality remain high.8,9 This patient was treated with IV methylprednisolone (5 g) over 5 days. His symptoms improved
with in-patient physical, occupational, and speech therapy over his 3-week hospitalization. At the time of discharge to a specialized rehabilitation hospital, he still had a significant left hemiparesis. After a 1-month stay in the rehabilitation hospital, he continued to recover, improving to only a mild left hemiparesis. Although prognosis is variable in AHLE, further improvement in strength could be expected in this case. This case emphasizes that demyelinating conditions should be included in the differential diagnosis of a young adult presenting with multifocal complaints with a decreased level of consciousness and evidence of hemorrhage on neuroimaging. DISCLOSURE Dr. Virmani and Dr. Agarwal report no disclosures. Dr. Klawiter has served on a scientific advisory board and as a consultant for Teva Pharmaceutical Industries Ltd.; has served on speakers’ bureaus for and received speaker honoraria from Teva Pharmaceutical Industries Ltd. and Bayer Schering Pharma; and has received research support from the NIH and an American Academy of Neurology Foundation Clinical Research Training Fellowship.
REFERENCES 1. Sonneville R, Klein IF, Wolff M. Update on investigation and management of postinfectious encephalitis. Curr Opin Neurol 2010;23:300 –304. 2. Sonneville R, Klein I, de Broucker T, Wolff M. Postinfectious encephalitis in adults: diagnosis and management. J Infect 2009;58:321–328. 3. Mader I, Wolff M, Niemann G, Kuker W. Acute haemorrhagic encephalomyelitis (AHEM): MRI findings. Neuropediatrics 2004;35:143–146. 4. Kuperan S, Ostrow P, Landi MK, Bakshi R. Acute hemorrhagic leukoencephalitis vs ADEM: FLAIR MRI and neuropathology findings. Neurology 2003;60:721–722. 5. Lann MA, Lovell MA, Kleinschmidt-DeMasters BK. Acute hemorrhagic leukoencephalitis: a critical entity for forensic pathologists to recognize. Am J Forensic Med Pathol 2010;31:7–11. 6. Dale RC, de Sousa C, Chong WK, Cox TC, Harding B, Neville BG. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain 2000;123:2407–2422. 7. Stone MJ, Hawkins CP. A medical overview of encephalitis. Neuropsychol Rehabil 2007;17:429 – 449. 8. Payne ET, Rutka JT, Ho TK, Halliday WC, Banwell BL. Treatment leading to dramatic recovery in acute hemorrhagic leukoencephalitis. J Child Neurol 2007;22:109 – 113. 9. Markus R, Brew BJ, Turner J, Pell M. Successful outcome with aggressive treatment of acute haemorrhagic leukoencephalitis. J Neurol Neurosurg Psychiatry 1997;63:551.
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RESIDENT & FELLOW SECTION Section Editor Mitchell S.V. Elkind, MD, MS
J.-Y. Cho, MD, PhD S.Y. Moon, MD, PhD K.-S. Hong, MD, PhD Y.-J. Cho, MD S.-C. Kim, MD S.-I. Hwang, MD S.-Y. Seo, MD J.-E. Kim, MD H.K. Park, MD
Teaching NeuroImages: Unilateral prosopometamorphopsia as a dominant hemisphere-specific disconnection sign Figure
Drawings of facial features as described by the patients, along with the patients’ brain MRIs
Address correspondence and reprint requests to Dr. Hee Kyung Park, Department of Neurology, Ilsan Paik Hospital, Inje University, 2240 Daewhadong, Ilsanseo-gu, Goyang-city, Gyeonggi-do, 411-706, Korea
[email protected] (A) This figure was drawn based on the first patient’s statement. (B) Diffusion-weighted MRI of the first patient demonstrated infarction in the left splenium with a tiny focus on the right side. (C) This figure was drawn according to the second patient’s statement. (D) Brain MRI of the second patient showed infarction in the right splenium of the corpus callosum.
We report 2 patients who complained that the left half of faces appeared distorted. A 58-year-old right-handed woman explained that although the left side of the face
was clearly visible, it appeared distorted “like a monster.” The left eye looked elongated toward the left ear, while the nose appeared to be bent toward the left cheek, and the mouth toward the chin. She did not have any dyslexia in the left or right visual field. A 53year-old right-handed man described that the left eyelid of people looked swollen as if they had undergone “failed eyelid surgery,” while the nose appeared to be bent downward and the left facial outlines either bulged or writhed. This was the same with pictures of others, but was absent with objects. He did not show hemialexia, color anomia, or optic aphasia. Brain MRIs showed splenial infarctions (figure). The prosopometamorphopsia in the right hemifield was likely caused by the disruption of the pathway from the left occipital area to the right hemisphere. Unilateral prosopometamorphopsia could be a dominant hemisphere–specific disconnection sign in which neurologic abnormalities are observed in the ipsilateral side of the dominant hemisphere.1 Our cases provide additional evidence that the splenium of the corpus callosum interconnects visual cortices and the right hemisphere is dominant for integrating facial information.2 REFERENCES 1. Lee JI, Kim JH, Lee BH, et al. Dominance specific visual extinction associated with callosal disconnection. Neurocase 2010;16:7–14. 2. Minnebusch DA, Daum I. Neuropsychological mechanisms of visual face and body perception. Neurosci Biobehav Rev 2009;33:1133–1144.
From the Department of Neurology (J.-Y.C., K.-S.H., Y.-J.C., S.-C.K., S.-I.H., S.-Y.S., J.-E.K., H.K.P.), Ilsan Paik Hospital, Inje University College of Medicine, Gyeonggi-do; and Department of Neurology (S.Y.M.), Ajou University School of Medicine, Suwon, Korea. Disclosure: Dr. J.-Y. Cho receives research support from the Ministry of Health, Welfare and Family Affairs, Republic of Korea. Dr. Moon reports no disclosures. Dr. Hong serves on the speakers’ bureau of Pfizer Inc; and receives/has received research support from Otsuka Pharmaceutical Co., Ltd., Boryung Pharmaceutical Co., Ltd., Novartis, and the Ministry of Health, Welfare and Family Affairs, Republic of Korea. Dr. Y.-J. Cho receives research support from sanofi-aventis and Otsuka Pharmaceutical Co., Ltd. Dr. S.-C. Kim, Dr. Hwang, Dr. Seo, Dr. J.E. Kim, and Dr. Park report no disclosures. e110
Copyright © 2011 by AAN Enterprises, Inc.
PATIENT PAGE Section Editors David C. Spencer, MD Steven Karceski, MD
Raghav Tripathi Kevin Wang Priyanka Mysore David C. Spencer, MD
The influence of lacunes on cognitive function
Smallvessel disease (SVD) occurs when small yet vital arteries in the brain narrow. This process may block blood flow to certain parts of the brain, especially in the “white matter.” The white matter of the brain is made up of the connections— or wiring— between brain areas. Similar SVD can affect the “gray matter,” where the brain cells or neurons live. MRI scans of the brain in patients with SVD often show both white matter lesions (WML) and lacunar infarcts. WML are patchy areas in the brain where the white matter shows signs of being affected by SVD. Lacunar infarcts are areas where the blood flow to small parts of the brain has been blocked, resulting in a tiny stroke called a “lacune” or lacunar infarct.
WHAT IS SMALL-VESSEL DISEASE?
Previous studies have shown that WML affect brain function, but the role of lacunes has been less clear. It is possible that they are so small that they are not important. In their article (Neurology® 2011;76:1872–1878), Jokinen et al. ask: “What is the true medical significance of lacunes?” and “Why do they matter to you and me?” They examined how lacunes affect brain function and reviewed available literature on this topic. Their objective was to find a more definite answer.
WHY WAS THE STUDY CONDUCTED?
HOW DID THEY DO THE STUDY? The researchers studied 387 older adults who were all independently functioning, with no dementia, and who all had some evidence of SVD on their MRI scans. As mentioned before, the researchers looked for 2 different types of lesions, WML and lacunar infarcts, both of which may be present in MRI scans of patients with SVD. All adults had baseline MRI and cognitive testing done at the start of the study. The cognitive testing included measures of speed and motor control and “executive skills.” Executive skills are high-level abilities such as decision-making, planning, abstract thinking, and adapting to changing situations. All patients’ memory was also tested. All testing was repeated after 3 years. The researchers controlled for factors other than the lacunes that might affect
thinking ability. These factors included age, sex, education, baseline cognition, and the baseline level of SVD. The goal was to relate changes in brain MRI findings to changes in cognition over the 3-year period. They wanted to see what features were most closely related. WHAT DID THE RESEARCHERS FIND? Out of the 387 subjects, 72 developed one or more new lacunes over the 3-year time period. The most important result from the study was that lacunes were found to be related to a decline in speed and motor control, as well as a decline in executive skills. Those small lacunes did cause a change in function. However, new lacunes were not related to changes in memory function. In addition, the locations of lacunes did not seem to play a large role in determining their effect. The best predictor of cognitive function at the 3-year follow-up was actually the WML volume calculated in a subject’s first scan, not the number of lacunes. Still, they showed that the effect of lacunes was important.
Lacunes can happen in a moment’s time, but they may have long-lasting effects on cognition. It has been shown that WML cause cognitive decline; however, the contribution of lacunes to cognitive decline was unclear. Some past studies suggested that lacunes cause cognitive problems, while other research showed that they do not. Although this study showed that their effects are relatively small, lacunes found on MRIs do lead to measurable cognitive decline. Although WMLs and larger strokes may have greater effects on the brain, lacunes should not be ignored, because they can significantly affect cognitive functions. Patients with SVD should do as much as they can to prevent lacunes by controlling or preventing the risk factors for a stroke, especially high blood pressure and diabetes.
WHY WAS THE STUDY IMPORTANT?
FOR MORE INFORMATION American Academy of Neurology http://patients.aan.com
Copyright © 2011 by AAN Enterprises, Inc.
e111
Correspondence
THE MoCA: WELL-SUITED SCREEN FOR COGNITIVE IMPAIRMENT IN PARKINSON DISEASE
To the Editor: We read the article by DalrympleAlford et al.,1 who compared the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) with the standardized Mini-Mental State Examination (SMMSE) and the Scales for Outcomes in Parkinson disease–Cognition (SCOPA-COG) in healthy controls, patients with Parkinson disease without dementia (PD-N), patients with PD with mild cognitive impairment (PD-MCI), and patients with PD with dementia (PD-D). As developers of the SCOPA-COG,2 we were interested in the comparison between the SCOPA-COG and the MoCA. The authors concluded that “all 3 mental status tests produced excellent discrimination of PD-D from patients without dementia and PD-MCI from PD-N patients but [that] the MoCA was generally better suited across both assessments.” The S-MMSE and MoCA were administered to all patients allowing head-to-head comparisons between both scales. In addition, it permitted the transformation of the data to other prevalence rates (see footnote c in table 3). However, the SCOPA-COG was not administered in 38 out of the 114 patients with PD (37 PD-N and 1 PD-D). We were surprised that the diagnostic accuracy between the MoCA and SCOPACOG was directly compared. A direct comparison of these parameters is only justified if the populations are identical; the comparison should therefore have been restricted to subjects in whom both instruments were administered. Even at a constant specificity, a higher number of noncases within the sample—as in the case of the MoCA—would affect the negative predictive value (NPV) and positive predictive value (PPV). At higher specificity values, as in the current situation, this would have led to an increase of the NPV and a decrease of the PPV. The effect of these errors is likely to pertain to the comparison between patients with PD-MCI and PD-N in particular, since here the SCOPA-COG was administered in less than half the number of patients with PD-N compared to the MoCA. We ignored that a different specificity value could have been obtained for the SCOPA-COG, had 1944
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all patients with PD been assessed with this scale. This is very possible and would make the data even less comparable. The authors cannot draw valid conclusions regarding the difference in diagnostic accuracy between the MoCA and SCOPA-COG on the basis of the presented data. We encourage them to reanalyze the data while restricting the analysis to the population in whom both the MoCA and the SCOPACOG was administered. Johan Marinus, Dagmar Verbaan, Jacobus J. van Hilten, Leiden, the Netherlands Disclosure: Dr. van Hilten served on the scientific advisory board and as a consultant for Novartis and GSK; received funding from the Netherlands Ministry of Economic Affairs (TREND [Trauma RElated Neuronal Dysfunction]); and is an editorial board member of Movement Disorders. Drs. Marinus and Verbaan report no disclosures.
Reply from the Authors: On reading our study of screening instruments for cognitive impairment in PD,1 Marinus et al.2 suggested that we made an inappropriate comparison between the validity of the MoCA and their instrument, the SCOPA-COG. They correctly noted that these instruments were not administered to all patients. The critical issue is their relative value in discriminating patients with PD with relatively normal cognition (PD-N) from those meeting our criteria for mild cognitive impairment (PD-MCI). Although not explicitly stated in our article, comparisons between the area under the curve (AUC) of any 2 instruments requires restriction to those individuals tested on both measures and this comparison was reported. The 2 instruments were equivalent when assessing dementia (PD-D) relative to no dementia, but a difference emerged in favor of the MoCA when examining the separation between PD-N and PD-MCI. As we stated, the AUC difference in favor of the MoCA was 12% (95% confidence interval [CI] 0.3%–24.0%, p ⫽ 0.045).1(p1720) The AUC for the MoCA itself for those patients with PD-MCI and patients with PD-N tested on both MoCA and SCOPA-COG was 93% (95% CI 83%–98%). Therefore, the AUC was at least marginally better than when examining all patients tested on the
MoCA (90%; CI 82%–95%). It is unlikely that the specificity of the SCOPA-COG for the PD-N vs PD-MCI comparison would improve with a larger sample for a screening cutoff because this instrument is sensitive to minor impairments evident in the PD-N group (table 2).1 Relative to the values given for the whole sample in table 3,1 no diagnostic performance values worsened and some improved when the MoCA analysis was restricted to those patients with PD-N and patients with PD-MCI who were tested on both the MoCA and the SCOPA-COG. The cutoffs suggested for optimal screen, diagnostics, and maximum accuracy remained the same. However, specificity for the optimal screen cutoff increased from 75% to 86% while PPV increased from 61% to 73%; the PPV for the optimal diagnostic cutoff increased from 79% to 90%; and both specificity (75% to 86%) and PPV (61% to 73%) increased for the maximum accuracy cutoff. The base rates used to estimate PPV
and NPV were population base rates, not sample base rates, which will vary across different criteria especially in PD-MCI.3 This evidence suggests that our original conclusion of the value of MoCA regarding cognitive screening for PD is sound. J.C. Dalrymple-Alford, PhD, C.T. Nakas, PhD, M.R. MacAskill, PhD, L. Livingston, BA, T.J. Anderson, MD, Christchurch, New Zealand Disclosure: See original article for full disclosure list. Copyright © 2011 by AAN Enterprises, Inc. 1.
2.
3.
Dalrymple-Alford JC, MacAskill MR, Nakas CT, et al. The MoCA: well-suited screen for cognitive impairment in Parkinson disease. Neurology 2010;75:1717–1725. Marinus J, Visser M, Verwey NA, et al. Assessment of cognition in Parkinson’s disease. Neurology 2003;61: 1222–1228. Dalrymple-Alford JC, Livingston L, MacAskill MR, et al. Characterizing mild cognitive impairment in Parkinson’s disease. Mov Disord 2011;26:629 – 636.
CORRECTION Olfactory copy number association with age at onset of Alzheimer disease In the article “Olfactory copy number association with age at onset of Alzheimer disease” by C.A. Shaw et al. (Neurology® 2011;76:1302–1309), there is an error in the disclosure. Dr. Doody “… [receives] research support from Medivation Inc. and Sonexa Therapeutics, Inc.” should have read Dr. Doody “… holds stock options in Medivation Inc. and Sonexa Therapeutics, Inc.” The editorial staff regrets the error.
Neurology 76
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1945
Correspondence
THE MoCA: WELL-SUITED SCREEN FOR COGNITIVE IMPAIRMENT IN PARKINSON DISEASE
To the Editor: We read the article by DalrympleAlford et al.,1 who compared the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) with the standardized Mini-Mental State Examination (SMMSE) and the Scales for Outcomes in Parkinson disease–Cognition (SCOPA-COG) in healthy controls, patients with Parkinson disease without dementia (PD-N), patients with PD with mild cognitive impairment (PD-MCI), and patients with PD with dementia (PD-D). As developers of the SCOPA-COG,2 we were interested in the comparison between the SCOPA-COG and the MoCA. The authors concluded that “all 3 mental status tests produced excellent discrimination of PD-D from patients without dementia and PD-MCI from PD-N patients but [that] the MoCA was generally better suited across both assessments.” The S-MMSE and MoCA were administered to all patients allowing head-to-head comparisons between both scales. In addition, it permitted the transformation of the data to other prevalence rates (see footnote c in table 3). However, the SCOPA-COG was not administered in 38 out of the 114 patients with PD (37 PD-N and 1 PD-D). We were surprised that the diagnostic accuracy between the MoCA and SCOPACOG was directly compared. A direct comparison of these parameters is only justified if the populations are identical; the comparison should therefore have been restricted to subjects in whom both instruments were administered. Even at a constant specificity, a higher number of noncases within the sample—as in the case of the MoCA—would affect the negative predictive value (NPV) and positive predictive value (PPV). At higher specificity values, as in the current situation, this would have led to an increase of the NPV and a decrease of the PPV. The effect of these errors is likely to pertain to the comparison between patients with PD-MCI and PD-N in particular, since here the SCOPA-COG was administered in less than half the number of patients with PD-N compared to the MoCA. We ignored that a different specificity value could have been obtained for the SCOPA-COG, had 1944
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all patients with PD been assessed with this scale. This is very possible and would make the data even less comparable. The authors cannot draw valid conclusions regarding the difference in diagnostic accuracy between the MoCA and SCOPA-COG on the basis of the presented data. We encourage them to reanalyze the data while restricting the analysis to the population in whom both the MoCA and the SCOPACOG was administered. Johan Marinus, Dagmar Verbaan, Jacobus J. van Hilten, Leiden, the Netherlands Disclosure: Dr. van Hilten served on the scientific advisory board and as a consultant for Novartis and GSK; received funding from the Netherlands Ministry of Economic Affairs (TREND [Trauma RElated Neuronal Dysfunction]); and is an editorial board member of Movement Disorders. Drs. Marinus and Verbaan report no disclosures.
Reply from the Authors: On reading our study of screening instruments for cognitive impairment in PD,1 Marinus et al.2 suggested that we made an inappropriate comparison between the validity of the MoCA and their instrument, the SCOPA-COG. They correctly noted that these instruments were not administered to all patients. The critical issue is their relative value in discriminating patients with PD with relatively normal cognition (PD-N) from those meeting our criteria for mild cognitive impairment (PD-MCI). Although not explicitly stated in our article, comparisons between the area under the curve (AUC) of any 2 instruments requires restriction to those individuals tested on both measures and this comparison was reported. The 2 instruments were equivalent when assessing dementia (PD-D) relative to no dementia, but a difference emerged in favor of the MoCA when examining the separation between PD-N and PD-MCI. As we stated, the AUC difference in favor of the MoCA was 12% (95% confidence interval [CI] 0.3%–24.0%, p ⫽ 0.045).1(p1720) The AUC for the MoCA itself for those patients with PD-MCI and patients with PD-N tested on both MoCA and SCOPA-COG was 93% (95% CI 83%–98%). Therefore, the AUC was at least marginally better than when examining all patients tested on the
MoCA (90%; CI 82%–95%). It is unlikely that the specificity of the SCOPA-COG for the PD-N vs PD-MCI comparison would improve with a larger sample for a screening cutoff because this instrument is sensitive to minor impairments evident in the PD-N group (table 2).1 Relative to the values given for the whole sample in table 3,1 no diagnostic performance values worsened and some improved when the MoCA analysis was restricted to those patients with PD-N and patients with PD-MCI who were tested on both the MoCA and the SCOPA-COG. The cutoffs suggested for optimal screen, diagnostics, and maximum accuracy remained the same. However, specificity for the optimal screen cutoff increased from 75% to 86% while PPV increased from 61% to 73%; the PPV for the optimal diagnostic cutoff increased from 79% to 90%; and both specificity (75% to 86%) and PPV (61% to 73%) increased for the maximum accuracy cutoff. The base rates used to estimate PPV
and NPV were population base rates, not sample base rates, which will vary across different criteria especially in PD-MCI.3 This evidence suggests that our original conclusion of the value of MoCA regarding cognitive screening for PD is sound. J.C. Dalrymple-Alford, PhD, C.T. Nakas, PhD, M.R. MacAskill, PhD, L. Livingston, BA, T.J. Anderson, MD, Christchurch, New Zealand Disclosure: See original article for full disclosure list. Copyright © 2011 by AAN Enterprises, Inc. 1.
2.
3.
Dalrymple-Alford JC, MacAskill MR, Nakas CT, et al. The MoCA: well-suited screen for cognitive impairment in Parkinson disease. Neurology 2010;75:1717–1725. Marinus J, Visser M, Verwey NA, et al. Assessment of cognition in Parkinson’s disease. Neurology 2003;61: 1222–1228. Dalrymple-Alford JC, Livingston L, MacAskill MR, et al. Characterizing mild cognitive impairment in Parkinson’s disease. Mov Disord 2011;26:629 – 636.
CORRECTION Olfactory copy number association with age at onset of Alzheimer disease In the article “Olfactory copy number association with age at onset of Alzheimer disease” by C.A. Shaw et al. (Neurology® 2011;76:1302–1309), there is an error in the disclosure. Dr. Doody “… [receives] research support from Medivation Inc. and Sonexa Therapeutics, Inc.” should have read Dr. Doody “… holds stock options in Medivation Inc. and Sonexa Therapeutics, Inc.” The editorial staff regrets the error.
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Section Editors Christopher J. Boes, MD Kenneth J. Mack, MD, PhD
Book Review
PEDIATRIC NEUROLOGY
by Gregory L. Holmes, 176 pp., Oxford University Press, 2010, $26.95 In this book, Pediatric Neurology, in the What Do I Do Now? series, Dr. Holmes, a widely known epileptologist in laboratory research into the basic mechanisms of epilepsy, demonstrates his command of general pediatric neurology. Despite being a senior clinician, he has obviously retained a keen appreciation for the potential pitfalls and uncertainties faced by a trainee or beginning practitioner when he or she first encounters a clinical problem or when he or she encounters a clinical problem for the first time. Dr. Holmes organized his book along the same basic principles as used successfully in the many editions of Dr. Gerald Fenichel’s Clinical Pediatric Neurology. However, instead of this book being organized in terms of specific symptoms such as headache or developmental regression, Dr. Holmes devotes various chapters to some of the more common diagnoses in general pediatric neurologic practice. Attention is also directed to several less common conditions, for which early identification and prompt treatment are particularly relevant. Chapters are devoted to febrile
seizures, acute cerebellar ataxia, tethered spinal cord, and hydrocephalus as well as to Hashimoto encephalopathy, ornithine transcarbamylase deficiency, and opsoclonus myoclonus syndrome. The intent is not to produce an encyclopedic compendium of pediatric neurologic disease; this would not be possible in a volume of this size. Rather, Dr. Holmes imparts key facts about both common and medically crucial diagnoses and, at the same time, imparts a diagnostic approach that can serve as a sound basis for evaluation and management of a variety of disorders. The references are pertinent and insightful and provide maximum value. This thin volume (a total of 145 pages not counting the index) is well worth its price and is highly recommended for both general practitioners, adult neurologists, and those specializing in pediatric neurology as they begin their careers and hone their skills. Reviewed by David Neal Franz, MD Disclosure: Cincinnati Children’s Hospital has received financial support from Novartis Pharmaceuticals for research conducted by Dr. Franz. Dr. Franz has received honoraria from Novartis Pharmaceuticals and UCB Pharma and is a paid consultant for Novartis Pharmaceuticals. Copyright © 2011 by AAN Enterprises, Inc.
Note to Book Publishers: Neurology® provides reviews of books of interest to the clinical neurologist. Please send any books for possible review in the journal to: Robert A. Gross, MD, PhD, FAAN, Editor-in-Chief, Neurology, 1080 Montreal Ave, St. Paul, MN 55116. Inquiries can be directed to:
[email protected]. Please note that not all books received are chosen for review. We do not return books.
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Calendar
Neurology® publishes short announcements of meetings and courses related to the field. Items must be received at least 6 weeks before the first day of the month in which the initial notice is to appear. Send Calendar submissions to Calendar, Editorial Office, Neurology®, 1080 Montreal Ave., St. Paul, MN 55116
[email protected] 2011 JUN. 5-9 15th International Congress of Parkinson’s Disease and Movement Disorders will be held at the Metro Toronto Convention Centre, Toronto, ON, Canada. Info: http://www. movementdisorders.org/congress/congress11/. JUN. 6 Methodist Alzheimer’s Symposium, hosted by the Nantz National Alzheimer Center, will be held at the Methodist Neurological Institute, Houston, TX. Info: tel (713) 441-1150;
[email protected]; www.nantzfriends.org. JUN. 10–11 Florida Neurosurgical Society Annual Meeting will be held at the Ritz-Carlton, Sarasota, FL. Info: tel: (305) 325-4873; http://www.floridaneurosurgerysociety.com/. JUN. 16–23 International Society for the History of the Neurosciences and Cheiron Joint Meeting in Calgary (June 16–19) and Banff (June 19–23), Alberta, Canada. Info: e-mail:
[email protected] or
[email protected]; http://www.ishn.org/. JUN. 22–25 Computer Assisted Radiology and Surgery (CARS) 25th Annual International Congress and Exhibition will be held at the Estrel Hotel in Berlin, Germany. Info: www.cars-int.org. JUN. 24 Mellen Center Update in Multiple Sclerosis and Related Disorders will be held at the InterContinental Hotel and Bank of America Conference Center, Cleveland, OH. Info: www.ccfcme.org/ms11. JUN. 24–26 11th Annual TianTan International Stroke Conference in Beijing, China. Info: Dr. Liping Liu, e-mail:
[email protected]. JUN. 27–JUL. 1 Neuroradiology Review with the Experts (NRE) Summer Session will be held at Park Hyatt Aviara Resort, Carlsbad, CA. Info: www.nreconference.com. JUL. 6–8 UCLA Transcranial Doppler & Cerebral Blood Flow Monitoring Course will be held at Ronald Reagan UCLA Med. Ctr., Los Angeles, CA. Info: Karen Einstein, e-mail:
[email protected], tel: (310) 206-0626, fax: (310) 794-2147; http://neurosurgery.ucla.edu/tcdcourse.
AUG. 5–7 2011 Neurology Update - Comprehensive Review for the Clinician will be held at the Ritz-Carlton, Washington, DC. Info: www.ccfcme.org/NeuroUpdate11. AUG. 8–12 Gamma Knife Radiosurgery Course will be held at the Cleveland Clinic Gamma Knife Center, Cleveland, OH. Info: http://my.clevelandclinic.org/brain_tumor/education/ gamma_knife_radiosurgery/default.aspx. SEP. 9–10 Neuromuscular Update will be held in Cleveland, OH. Info: tel: (216) 983-1239 or (800) 274-8263; e-mail:
[email protected]; http://casemed.case.edu/cme (click on Activities & Events). SEP. 16 3rd Annual Practical Management of Acute Stroke Conference will be held at the Embassy Suites Hotel & Conference Center, Independence, OH. Info: www.ccfcme.org/ acutestroke11. SEP. 16-18 12th biennial Conference of the Indian Society for Stereotactic and Functional Neurosurgery, ISSFN 2011, will be held at The Raintree Hotel, Mount Road, Chennai, Tamil Nadu, India. Info: Dr. M. Balamurugan, e-mail:
[email protected]; www.issfn2011.co.in. SEP. 25–28 The American Neurological Association will hold its 136th Annual Meeting at the Manchester Grand Hyatt, San Diego, CA. Info: www.aneuroa.org. OCT. 13–16 5th World Congress on Controversies in Neurology (CONy) will take place in Beijing, China. Info: http:// comtecmed.com/cony/2011/. OCT. 21–22 Neurocritical Care 2011: Across the Universe comprises the 9th Annual Cleveland Neurocritical Care and Stroke Conference, the 4th Annual Critical Care Bioinformatics Workshop, the 3rd Annual Transcranial Doppler Ultrasound Workshop, and the 2nd Annual Cleveland Music and Medicine Symposium. At Case Western Reserve University, Cleveland, OH. Select components also available live via the internet. Info: tel: (216) 983-1239 or (800) 274-8263; e-mail:
[email protected]; http:// casemed.case.edu/cme (click on Activities & Events).
JUL. 13–19 Cleveland Spine Review Hand-on Course 2011 will be held at Cleveland Clinic Lutheran Hospital, Cleveland, OH. Info: www.ccfcme.org/spinereview11.
OCT. 21–23 2011 American Academy of Neurology Fall Conference will be held at Encore Wynn, Las Vegas, NV.
JUL. 14–17 Headache Update – 2011 will be held at Disney’s Grand Floridian, Lake Buena Vista, FL. Info: tel: (877) 706-6363 (toll free) or (773) 883-2062; e-mail:
[email protected]; www.dhc-fdn.org.
OCT. 24–25 Gamma Knife Radiosurgery Course will be held at the Cleveland Clinic Gamma Knife Center, Cleveland, OH. Info: http://my.clevelandclinic.org/brain_tumor/education/ gamma_knife_radiosurgery/default.aspx.
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NOV. 2–4 UCLA Transcranial Doppler & Cerebral Blood Flow Monitoring Course will be held at Ronald Reagan UCLA Med. Ctr., Los Angeles, CA. Info: Karen Einstein, e-mail:
[email protected], tel: (310) 206-0626, fax: (310) 794-2147; http://neurosurgery.ucla.edu/tcdcourse.
NOV. 28–DEC. 2 Gamma Knife Radiosurgery Course will be held at the Cleveland Clinic Gamma Knife Center, Cleveland, OH. Info: http://my.clevelandclinic.org/brain_tumor/ education/gamma_knife_radiosurgery/default.aspx.
NOV. 3–5 4th Conference Clinical Trials on Alzheimer’s Disease will be held in San Diego, CA. Info: http://www.ctad.fr.
DEC. 8–11 North American Neuromodulation Society 15th Annual Meeting will be held at the Wynn, Las Vegas, NV.
Retain a Permanent Record of the 2011 AAN Annual Meeting Watch webcasts, read syllabi, and listen to MP3s on the best programming at the 2011 Annual Meeting. Whether you made it to Hawaii or not, you’ll want these valuable products for future reference. Order today at www.aan.com/vam.
Save These Dates for AAN CME Opportunities! Mark these dates on your calendar for exciting continuing education opportunities, where you can catch up on the latest neurology information. Regional Conference ● October 21–23, 2011, Las Vegas, Nevada, Encore Wynn Hotel AAN Annual Meeting ● April 21–28, 2012, New Orleans, Louisiana, Morial Convention Center
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In the next issue of Neurology® Volume 76, Number 23, June 7, 2011 www.neurology.org THE MOST WIDELY READ AND HIGHLY CITED PEER-REVIEWED NEUROLOGY JOURNAL
IN FOCUS
1949
2002
Meta-analysis of the relationship between Parkinson disease and melanoma R. Liu, X. Gao, Y. Lu, and H. Chen
2010
Assessment of sympathetic index from the Valsalva maneuver Peter Novak
2017
Comparison of IVIg and PLEX in patients with myasthenia gravis D. Barth, M. Nabavi Nouri, E. Ng, et al.
2024
Small-fiber neuropathy in patients with ALS J. Weis, I. Katona, G. Mu ¨ller-Newen, et al.
Spotlight on the June 7 Issue
SPECIAL EDITORIAL
1950
On the 60th anniversary of Neurology姞 Robert B. Daroff
EDITORIALS
1952
Fluctuating concepts of childhood absence epilepsy John M. Zempel and Michael Ciliberto
1954
Adipocyte fatty acid–binding protein and ischemic stroke: Another brick in the wall? Michael R. Skilton and Gail J. Pyne-Geithman
1956
Stroke centers and quality of stroke care: How are we doing? Jason Mackey and Dawn Kleindorfer
CLINICAL/SCIENTIFIC NOTES
2030
ALS risk but not phenotype is affected by ataxin-2 intermediate length polyglutamine expansion G. Soraru `, M. Clementi, M. Forzan, V. Orsetti, et al.
2032
RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions C. Fratter, P. Raman, C.L. Alston, E.L. Blakely, et al.
IN MEMORIAM
1958
Clark H. Millikan, MD, FAAN (1915–2011) Jack P. Whisnant
ARTICLES
1960
1968
1976
Resting functional connectivity between the hemispheres in childhood absence epilepsy X. Bai, J. Guo, B. Killory, M. Vestal, et al.
NEUROIMAGES
Serum adipocyte fatty acid–binding protein associated with ischemic stroke and early death A.W.K. Tso, T.K.Y. Lam, A. Xu, K.H. Yiu, et al.
HISTORICAL ABSTRACTS
Outcomes after ischemic stroke for hospitals with and without Joint Commission–certified primary stroke centers J.H. Lichtman, S.B. Jones, Y. Wang, et al.
1983
Etiologic investigation of ischemic stroke in young adults V. Larrue, N. Berhoune, P. Massabuau, et al.
1989
Common viruses associated with lower pediatric multiple sclerosis risk E. Waubant, E.M. Mowry, L. Krupp, T. Chitnis, et al.
1996
Demographic and clinical characteristics of malignant multiple sclerosis T. Gholipour, B. Healy, N.F. Baruch, H.L. Weiner, et al.
Subject to change
2035
Whole-body imaging in schwannomatosis Avneesh Chhabra and Jaishri Blakely
1995
The risk of epilepsy following febrile convulsions
2009
Revised diagnostic criteria for neuromyelitis optica
RESIDENT & FELLOW SECTION
e112
Book Review: Pediatric Epilepsy Surgery Keith R. Ridel
e113
Teaching Video NeuroImages: Epilepsy with myoclonic absences: A distinct electroclinical syndrome R. Menon, N.N. Baheti, A. Cherian, et al.
CORRESPONDENCE
2036
MRI for the diagnosis of acute ischemic stroke
DEPARTMENTS
2039 2041
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