Multiple Sclerosis vs Acute Disseminated Encephalomyelitis in Childhood

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1 Multiple Sclerosis vs Acute Disseminated Encephalomyelitis in Childhood Steven David Brass, MD, Zografos Caramanos, BA, Carlos Santos, MD, Marie-Emmanuelle Dilenge, MD, Yves Lapierre, MD, and Bernard Rosenblatt, MD The initial presenting clinical and laboratory findings of either acute disseminated encephalomyelitis or the first attack of multiple sclerosis in the pediatric population were compared and contrasted. A retrospective review of the medical records was conducted of all children younger than 17 years who presented with either the diagnosis of acute disseminated encephalomyelitis or multiple sclerosis between 1987 and Seventeen cases of clinically definite multiple sclerosis (seven female, mean age years) and seven cases of acute disseminated encephalomyelitis (three female; mean age years) were reviewed. Systemic and nonfocal neurologic symptoms were more commonly evident in acute disseminated encephalomyelitis than in multiple sclerosis: fever (43% vs 6%), headache (57% vs 24%), fatigue (71% vs 29%), vomiting (57% vs 0%), and encephalopathy (71% vs 6%). In multiple sclerosis patients, T 2 -weighted white matter magnetic resonance imaging lesions were more commonly located in the corpus callosum (64% vs 17%) and the periventricular area (91% vs 50%) compared with those in patients with acute disseminated encephalomyelitis. These results suggest that acute disseminated encephalomyelitis and multiple sclerosis can be differentiated to some degree according to clinical and radiologic data at initial presentation, which is important because the long-term prognosis for childhood multiple sclerosis appears to be less favorable by Elsevier Inc. All rights reserved. Brass SD, Caramanos Z, Santos C, Dilenge M-E, Lapierre Y, Rosenblatt B. Multiple sclerosis vs acute disseminated encephalomyelitis in childhood. Pediatr Neurol 2003;29: Introduction Similarities exist between the clinical and neuroradiologic features of acute disseminated encephalomyelitis and multiple sclerosis. Both diseases have been reported in children, and recently the question of whether acute disseminated encephalomyelitis is a distinct disease or part of the multiple sclerosis spectrum has again resurfaced [1]. Acute disseminated encephalomyelitis is defined as a multifocal monophasic inflammatory disease involving the central nervous system. It tends to affect primarily children and young adults. It may be preceded by an infection or can follow a vaccination. The typical finding is a sudden onset of encephalopathy, with bilateral optic neuritis, visual field deficits, aphasia, tetraparesis, ataxia, and meningismus evident on examination. Magnetic resonance imaging (MRI) demonstrates evidence of diffuse white matter changes, although involvement of the subcortical gray matter, including the thalami and basal ganglia, has also been reported in acute disseminated encephalomyelitis. Although no established treatments based on randomized control trials exist, high-dose steroids, plasma exchange, and intravenous immunoglobulin (IVIG) have all been used with various success [2]. In large series of acute disseminated encephalomyelitis patients, the outcomes have been varied, with most reporting a favorable outcome, whereas other series demonstrate a mortality rate of 20% and a great burden of neurologic sequelae in the survivors [2-5]. Relapses may occur immediately after acute disseminated encephalomyelitis. If these relapses are thought to represent part of the same acute monophasic immune process, the term multiphasic disseminated encephalomyeltis is used. The criteria of Poser et al. [6] for the diagnosis of multiple sclerosis require at least a month between typical neurologic events to establish temporal dissemination to make the diagnosis of multiple sclerosis, but in cases in which the clinical From the Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. Communications should be addressed to: Dr. Rosenblatt; Montreal Children s Hospital; 2300 Tupper Street; Montreal, Quebec, Canada, H3H 1P3. Received January 9, 2003; accepted March 17, by Elsevier Inc. All rights reserved. Brass et al: Pediatric and doi: /s (03) /03/$ see front matter 227

2 finding is apparently acute disseminated encephalomyelitis, Kesserling et al. have suggested a more conservative requirement of separation by 6 months [7]. Childhood multiple sclerosis is a rare entity, composing 0.3% to 5.6% of all multiple sclerosis cases [2,8,9]. Duquette et al. reported on a cohort of 125 patients with onset of multiple sclerosis before age 16 years [9]. The disease course was relapsing-remitting in 56% and initially progressive in 22% of cases. The study demonstrated that multiple sclerosis occurred more often in females and presented with initially sensory or visual symptomatology as the first episode. The pace of the disease was demonstrated to be slow in these children than in older children (older than 15 years). After the first clinical episode, it is not always certain that the process represents a monophasic inflammatory event that is ending or the first attack of multiple sclerosis, which has critical importance for prognosis because multiple sclerosis is a chronic disease with the potential for further relapses and eventual disability. Studies in adult multiple sclerosis patients have emphasized that early use of disease-modifying agents, as early as the first episode, have been demonstrated to be beneficial in preventing disability, relapses, brain atrophy, and new T 2 -weighted lesions [10,11]. Therefore, given the high cost of these medications and their potential efficacy, knowing whether the patient is manifesting acute disseminated encephalomyelitis or multiple sclerosis has clinical and economic implications. The objective of this study was to compare children who remained monophasic with those who had developed clinically definite multiple sclerosis to determine criteria at onset that can be used to discriminate between the two entities. Patients and Methods All medical records of patients treated at the Montreal Neurological Hospital or the Montreal Children s Hospital for either multiple sclerosis or acute disseminated encephalomyelitis between 1987 and 2001 were reviewed. Patients records were reviewed for age at onset, race, place of birth, initial symptoms and signs on examination by the attending neurologist, family history of multiple sclerosis in first-degree relatives, clinical course, disease duration, recurrent episodes, Expanded Disability Status Scale Score (EDSS) at the last observation, and disease-modifying therapy. When possible, patients whose follow-up was incomplete were contacted by telephone. We used the criteria of Poser et al. [6] to define patients as clinically definite multiple sclerosis, with the exception of the first general consideration listed in the criteria (age at onset between 20 and 59 years inclusive). The diagnosis of acute disseminated encephalomyelitis was made according to an acute onset of neurologic disturbance with polysymptomatic presentation and MRI changes involving the white matter in the distribution manifesting a diffuse disseminated demyelinating disease. We excluded patients with evidence of central nervous system infection, vasculitis, or history of previous neurologic deficit. Laboratory studies consisted of electroencephalography (EEG), visual evoked potentials, brainstem auditory-evoked potentials, somatosensory evoked potentials, and cranial MRI. All neuroimaging was reviewed with a neuroradiologist (C.S.) who was unaware of the patient s identity, Table 1. Demographics of multiple sclerosis and acute disseminated encephalomyelitis patients clinical presentation, and original radiology report. The presence of cerebrospinal fluid oligoclonal bands was determined by agarose gel electrophoresis and subsequent immunofixation. Results No. of Patients (n 17) (n 7) Mean age (years) Male : female ratio 10:7 1.4:1 4:3 1.3:1 Caucasian, n (%) 12 (71) 5 (71) First-degree relative with, n (%) 3 (18) 0 (0) Abbreviations: Acute disseminated encephalomyelitis Multiple sclerosis Among the 24 cases analyzed were 17 cases of multiple sclerosis and seven cases of acute disseminated encephalomyelitis. See Table 1 for demographics of the multiple sclerosis and acute disseminated encephalomyelitis cohorts. All 17 multiple sclerosis cases initially correctly labeled as first attack of multiple sclerosis by the treating neurologist did ultimately meet the diagnostic criteria of Poser et al. [6] on follow-up by demonstrating evidence of the disease s being disseminated in space and time. The age range in the multiple sclerosis group was from 1.7 years to 16.9 years and from 2.1 to 12.8 years in the acute disseminated encephalomyelitis group. The per- Table 2. Clinical presentation of multiple sclerosis and acute disseminated encephalomyelitis patients (n 17) (n 7) Infectious prodrome 3/17 (18) 4/7 (57) Nonfocal and systemic findings Seizure 0/17 (0) 0/7 (0) Encephalopathy 1/17 (6) 5/7 (71) Meningismus 0/17 (0) 4/7 (57) Vomiting 4/17 (24) 5/7 (71) Fatigue 5/17 (29) 5/7 (71) Headache 4/17 (24) 4/7 (57) Fever 1/17 (6) 3/7 (43) Cranial nerve findings Facial plegia 3/17 (18) 2/7 (29) Facial numbness 3/17 (18) 2/7 (29) Hearing loss 1/17 (6) 0/7 (0) Dysphagia 2/17 (12) 3/7 (43) Dysarthria 4/17 (24) 3/7 (43) Diplopia 4/17 (24) 1/7 (14) Optic neuritis 6/17 (35) 1/7 (14) Ptosis 1/17 (6) 0/7 (0) Nystagmus 5/17 (29) 0/7 (0) Other central nervous system findings Pyramidal 11/17 (65) 7/7 (100) Sensory 10/17 (59) 1/7 (14) Ataxia 6/17 (35) 2/7 (29) Myelopathy 1/17 (6) 1/7 (14) 228 PEDIATRIC NEUROLOGY Vol. 29 No. 3

3 Table 3. Number of T 2 -weighted cerebral MRI lesions Table 5. Electrophysiologic studies Number of Cerebral T 2 - Weighted MRI Lesions on Presentation 9 3/11 (27) 3/6 (50) 4 8 5/11 (45) 2/6 (33) 2 3 2/11 (18) 1/6 (17) 1 1/11 (9) 0/6 (0) centage of Caucasians was equal in both groups. A family history positive for a first-degree relative with multiple sclerosis was present in 18% of multiple sclerosis cases vs 0% of acute disseminated encephalomyelitis cases. The initial clinical presentations of both groups are summarized in Table 2. An infectious prodrome was more commonly observed in the acute disseminated encephalomyelitis group 28 days before symptom onset than in the multiple sclerosis group. All infections were documented as viral respiratory tract infections; however, there was no supportive laboratory evidence for the diagnoses. Nonfocal systemic signs and symptoms were more commonly observed in the acute disseminated encephalomyelitis group than the multiple sclerosis group. Bulbar symptoms of dysphagia and dysarthria were also more commonly evident in the acute disseminated encephalomyelitis group than the multiple sclerosis group. Tables 3 and 4 summarize the MRI findings with respect to number of lesions and location of lesions in both groups of patients, respectively. The cerebral T 2 -weighted MRIs were available for review from the radiology archives in 11 of 17 multiple sclerosis cases and in six of seven acute disseminated encephalomyelitis cases. The entire spinal cord MRI was performed and available for review in eight multiple sclerosis patients and four acute disseminated encephalomyelitis patients. Both groups demonstrated multiple T 2 -weighted hyperintense lesions. For six multiple sclerosis patients whose MRIs were not available, radiology reports documented demyelination consistent with multiple sclerosis. One isolated acute disseminated encephalomyelitis patient died of brainstem Table 4. Location of T 2 -weighted magnetic resonance imaging lesions in the neuroaxis Location of MRI Lesions Spinal cord 2/8 (25) 0/4 (0) Cerebellum 4/11 (36) 1/6 (17) Medulla 2/11 (18) 0/6 (0) Pons 3/11 (27) 2/6 (33) Midbrain 2/11 (18) 2/6 (33) Internal capsule 4/11 (36) 0/6 (0) Thalamus 2/11 (18) 2/6 (33) Basal ganglia 1/11 (9) 2/6 (33) Corpus callosum 7/11 (64) 1/6 (17) Subcortical white matter 6/11 (55) 4/6 (67) Periventricular 10/11 (91) 3/6 (50) Cortical gray matter 1/11 (9) 2/6 (33) Abnormal EEG 2/7 (29) 4/5 (80) Abnormal BAEP 6/14 (43) 1/2 (50) Abnormal VEP 10/13 (77) 2/2 (100) Abnormal SSEP 8/14 (57) 2/2 (100) Abbreviations: BAEP Brainstem auditory-evoked potential SSEP Somatosensory evoked potential VEP Visual evoked potential herniation before the MRI; however, autopsy did confirm acute disseminated encephalomyelitis as the diagnosis. T 2 -weighted white matter MRI lesions were more commonly in the corpus callosum (64% vs 17%) and the periventricular area (91% vs 50%) in multiple sclerosis vs acute disseminated encephalomyelitis patients. The cerebrospinal fluid of only three of seven acute disseminated encephalomyelitis and 12 of 17 multiple sclerosis patients was examined for oligoclonal bands, which were present in eight of 12 multiple sclerosis patients tested vs none of three acute disseminated encephalomyelitis patients. Electrophysiologic studies, including EEG, brainstem auditory evoked potentials, visual evoked potentials, and somatosensory evoked potentials, were performed in select cases (Table 5). Mild to moderate EEG background electrical activity changes, which qualified the EEGs as abnormal, were evident in a greater percentage of acute disseminated encephalomyelitis than multiple sclerosis patients (80% vs 29%, respectively). All multiple sclerosis patients underwent follow-up examination between 0.1 to 3.9 years after the initial episode. Three acute disseminated encephalomyelitis patients underwent follow-up examination between 0.6 and 10.9 years after the initial episode. Multiple sclerosis patients manifested at least one subsequent episode at a mean time of 9.5 months between first and second episode. All 17 multiple sclerosis patients were classified as manifesting the relapsing-remitting subtype of multiple sclerosis. One acute disseminated encephalomyelitis patient died of brainstem herniation and underwent autopsy, which confirmed the diagnosis. None of the three acute disseminated encephalomyelitis patients who underwent follow-up exhibited a second episode. Disease-modifying therapies were used in five patients: two multiple sclerosis patients began receiving intramuscular interferon -1a (Avonex) and three began receiving subcutaneous interferon -1a (Rebiff) at one point in their illness. Whereas all acute disseminated encephalomyelitis patients manifested normal neurologic examination results at follow-up, 13 of 17 (81%) of multiple sclerosis patients exhibited EDSS scores less than 4: one of 17 (6%) manifested EDSS Brass et al: Pediatric and 229

4 scores between 4 and 6; and three of 17 (13%), higher than 6. Discussion In this study, to compare and contrast the features of the first demyelinating episode, clinical data are presented from 17 multiple sclerosis patients and seven patients with acute disseminated encephalomyelitis who had onset of disease before 17 years of age. The objective was to determine which criteria at onset can be used to discriminate between these two entities according to demographics, clinical presentation, laboratory investigations, and outcome. The demographics between these two cohorts of patients differed. Patients presenting with acute disseminated encephalomyelitis were typically younger than those with multiple sclerosis (mean age, years vs years, respectively). A history of a viral respiratory infection was present in 57% of acute disseminated encephalomyelitis patients vs 18% of multiple sclerosis patients 1 month before presentation. Although no serologic evidence of virus was documented in either group, a viral infection may serve as an antigenic trigger for the development of immune-mediated central nervous system demyelination, as has been evidenced in experimental allergic encephalomyelitis models in animals. The literature reports that there is often a history of infection or vaccine preceding acute disseminated encephalomyelitis patients up to 6 weeks before symptoms develop [1]. In multiple sclerosis, a viral antigenic trigger has also been reported to affect those predisposed to the development of multiple sclerosis; however, the gap between the onset of symptoms in multiple sclerosis and antigenic triggers may be months, years, or decades [1,2,12]. The notion of being genetically predisposed to multiple sclerosis is interesting because three of 17 (18%) multiple sclerosis patients in our cohort had a first-degree relative with multiple sclerosis, as compared with none in the acute disseminated encephalomyelitis group. The sex ratio showed a slightly higher predominance of males compared with females for multiple sclerosis (10 to seven) and acute disseminated encephalomyelitis (four to three) cohorts, which supports the findings of Ghezzi et al. [8], who reported a cohort of 149 pediatric multiple sclerosis patients and demonstrated that the female to male ratio increases with age: 0.8 before 12 years, with a slightly higher number of males, and then increasing to 3.0 after the age of 12 years. The sex ratio in acute disseminated encephalomyelitis studies is conflicting, with two of three large acute disseminated encephalomyelitis studies reporting a female predominance [2-4]. The differentiation of multiple sclerosis from acute disseminated encephalomyelitis is difficult because, with respect to acute disseminated encephalomyelitis, there exist no consensus or diagnostic criteria. On initial presentation, there was much overlap between all signs and symptoms in both cohorts. There were, however, notable trends toward differences in the acute disseminated encephalomyelitis group with respect to the higher percentage of systemic and nonfocal neurologic findings, including meningismus, encephalopathy, vomiting, fatigue, headache, and fever. Hynson et al. retrospectively examined 31 pediatric patients diagnosed with acute disseminated encephalomyelitis and concluded that they were unable to distinguish between multiple sclerosis and acute disseminated encephalomyelitis with certainty, but features such as a preceding viral prodrome, early onset ataxia, high lesion load on MRI, and lack of oligoclonal bands were more indicative of acute disseminated encephalomyelitis [4]. Dale et al. retrospectively reviewed 35 children with acute disseminated encephalomyelitis compared with 13 with multiple sclerosis and found that in the acute disseminated encephalomyelitis group, predemyelinating infectious disease, polysymptomatic presentation, pyramidal signs, encephalopathy, bilateral optic neuritis, and seizures were more commonly present [2]. This constellation of systemic and nonfocal findings may help guide the physician toward a diagnosis of acute disseminated encephalomyelitis rather than multiple sclerosis. Laboratory investigations have been reported in the literature to be somewhat helpful in discriminating multiple sclerosis from acute disseminated encephalomyelitis. It is difficult to make any conclusive statement with respect to the present series, given the small numbers and the lack of uniformity in which patients were evaluated with laboratory investigations. Gout reported the presence of oligoclonal bands in acute disseminated encephalomyelitis as a rare and transitory occurrence, whereas multiple sclerosis oligoclonal bands are present in 50% of patients at the initial episode [12]. This trend is similar to that evident in three acute disseminated encephalomyelitis and 12 multiple sclerosis patients who were tested: no acute disseminated encephalomyelitis and eight multiple sclerosis patients manifested cerebrospinal fluid positive for oligoclonal bands. The MRI in acute disseminated encephalomyelitis and multiple sclerosis may look similar in terms of diffuse T 2 -weighted hyperintensities, but the location of lesions in multiple sclerosis compared with those in acute disseminated encephalomyelitis may help differentiate these two entities [2,7,13-15]. The location of T 2 -weighted hyperintensities in the present multiple sclerosis patients supports what has been described, given the preferential periventricular (91% vs 50%) and corpus callosum (64% vs 17%) involvement with a greater tendency to spare the cortical gray matter (9% vs 33%) and thalami (18% vs 33%) when compared with acute disseminated encephalomyelitis. The use of EEG and evoked responses as diagnostic tools in this study supports what has been described: abnormalities can be present in both modalities and in both groups and thus are not helpful in the discrimination process between acute disseminated encephalomyelitis and multiple sclerosis [4]. Noteworthy is that the electroencephalograms revealed mild to moderate background abnormalities in 80% of acute dissemi- 230 PEDIATRIC NEUROLOGY Vol. 29 No. 3

5 nated encephalomyelitis patients examined vs 29% of multiple sclerosis patients, which may correlate with the greater encephalopathy observed in acute disseminated encephalomyelitis (71%) compared with multiple sclerosis (6%). The outcome for the multiple sclerosis patients appeared to be less favorable compared with that of the acute disseminated encephalomyelitis patients. Among the 17 multiple sclerosis patients, 6% manifested moderate disability (EDSS score 4-6), and 13% were graded as manifesting severe disability (EDSS 6). One of the acute disseminated encephalomyelitis patients died in the acute phase, and three patients recovered, with normal neurologic examination results and no further episodes. Follow-up on three acute disseminated encephalomyelitis patients was unobtainable, which is a limitation of the study. The present findings seem to support other outcome studies with respect to the more benign outcome of acute disseminated encephalomyelitis compared with multiple sclerosis. Tenembaum et al. reported the outcome of 84 acute disseminated encephalomyelitis patients and found that 89% manifested an EDSS of 0 to 2.5 and 11% exhibited an EDSS of 3 to 6.5 at a mean follow-up of 6.6 years [5]. Ghezzi et al. [8] divided the follow-up on 86 patients with pediatric multiple sclerosis by those with disease duration less than and greater than 8 years. Of the 44 patients with disease duration less than 8 years, 72.7% presented an EDSS score less than 4, 6.8% between 4 and 6, and 20.5% higher than 6. For the 42 children who manifested disease duration longer than 8 years, 40% presented an EDSS score less than 4, 33.3% between 4 and 6, and 26.7% higher than 6. Hahn et al. examined long-term neurocognitive outcome using neuropsychologic testing in pediatric acute disseminated encephalomyelitis patients and concluded that cognitive deficits in the acute disseminated encephalomyelitis group are milder than in the pediatric multiple sclerosis patients [16], which provides evidence for the notion of the more favorable outcome of acute disseminated encephalomyelitis compared with multiple sclerosis. It also reveals that even a monophasic insult may have long-term consequences with important implications that may be missed on routine neurologic examination. Although final diagnosis can be established only at follow-up, these results suggest that acute disseminated encephalomyelitis and multiple sclerosis can be differentiated to some degree according to clinical and investigational data at initial presentation. Identification of children who will develop multiple sclerosis is important because a proportion will develop a significant burden of disease before their third decade compared with the acute disseminated encephalomyelitis patients and thus should be studied more intensively in light of evolving therapies. The diagnosis of multiple sclerosis is crucial, given the Controlled High Risk Avonex Multiple Sclerosis Prevention Study (CHAMPS) [10] and Early Treatment of Multiple Sclerosis [11] studies clearly demonstrating support for early initiation of disease-modifying therapies after the first demyelinating episode in adults. The answer to the multiple sclerosis vs acute disseminated encephalomyelitis question relies on the basic foundation of medicine with respect to astute clinical observation and diligent follow-up until better diagnostic criteria exist. References [1] Hartnug HP, Grossman RI. : Distinct disease or part of the spectrum? Neurology 2001;56: [2] Dale RC, De Sousa C, Chong WK, et al. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain 2000;123: [3] Schwartz S, Mohr A, Knauth M, et al. Acute disseminated encephalomyelitis: A follow-up study of 40 adult patients. Neurology 2001;56: [4] Hynson JL, Kornberg AJ, Coleman LT, et al. Clinical and neuroradiological features of acute disseminated encephalomyelitis in children. Neurology 2001;56: [5] Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis: A long-term follow-up study of 84 pediatric patients. Neurology 2002;59: [6] Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Ann Neurol 1983;13: [7] Kesserling J, Miller DH, Robb SA, et al. Acute disseminated encephalomyelitis: MRI findings and distinction from multiple sclerosis. Brain 1990;113: [8] Ghezzi A, Deplano V, Faroni J, et al. Multiple sclerosis in childhood: Clinical features of 149 cases. Multiple Sclerosis 1997;3: [9] Duquette P, Murray TJ, Pleines GC, et al. Multiple sclerosis in childhood: Clinical profile in 125 patients. J Pediatr 1987;111: [10] Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1-a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000;343: [11] Comi G, Filippi M, Barkhof F, et al. Early Treatment of Multiple Sclerosis Study Group: Effect of early interferon treatment on conversion to definite multiple sclerosis: A randomised study. Lancet 2001;357: [12] Gout O. Mise au point encephalomyelite aigue disseminée. Rev Neurol 2002;158: [13] Boutin B, Esquivel E, Mayer M, et al. Multiple sclerosis in children: Report of clinical and paraclinical features of 19 cases. Neuropediatrics 1988;19: [14] Sindern E, Hans J, Stark E, et al. Early onset under the age of 16: Clinical and paraclinical features. Acta Neurol Scand 1992;86: [15] Tintore M, Rovira A, Brieva L, et al. Isolated demyelinating syndromes: Comparison of different MR imaging criteria to predict conversion to clinically definite multiple sclerosis. Am J Neuroradiol 2000;21: [16] Hahn CD, Miles B, MacGregor DL, et al. Long-term neurocognitive outcome following acute disseminated encephalomyelitis in childhood [abstract]. CJNS 2002;29:S6. Brass et al: Pediatric and 231