Abstract
Background: Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the CNS. Few pediatric series have been published, with retrospective and short-term follow-up studies. Objectives: To describe a cohort of pediatric patients with ADEM and to determine whether clinical and neuroimaging findings predict outcome.
Methods: A prospective study was conducted between March 1988 and July 2000 on 84 consecutive children with ADEM at the National Pediatric Hospital “Dr. J. P. Garrahan.”
Results: Mean age at onset was 5.3 ± 3.9 years, with a significant male predominance. Sixty-two patients (74%) had a preceding viral illness or vaccination. Acute hemiparesis (76%), unilateral or bilateral long tract signs (85%), and changes in mental state (69%) were the most prominent presenting features. Four MRI groups were identified: ADEM with small lesions (62%), with large lesions (24%), with additional bithalamic involvement (12%), and acute hemorrhagic encephalomyelitis (2%). Of the 54 children whose CSF samples were analyzed, none showed intrathecal oligoclonal bands. The use of high-dose corticosteroid treatment, particularly IV methylprednisolone, was associated with good recovery and resolution of MRI lesions. After a mean follow-up of 6.6 ± 3.8 years, 90% of children showed a monophasic course, and 10% a biphasic disease. Eighty-nine percent of patients show at present Expanded Disability Status Scale scores of 0 to 2.5. Eleven percent have disability scores of 3 to 6.5.
Conclusions: Childhood acute disseminated encephalomyelitis is a benign condition, affecting boys more frequently. No association was found between MRI groups and disability. Disability was related to optic nerve involvement at presentation. Even in relapsing cases, the distinction between acute disseminated encephalomyelitis and MS was possible on the basis of long-term clinical and neuroimaging follow-up and the absence of oligoclonal bands in CSF.
Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the CNS that often follows a viral illness or vaccination. It is clinically characterized by the acute or subacute onset of multifocal neurologic disturbances that typically follow a monophasic course.1-4⇓⇓⇓ Nevertheless relapses have been reported,2,5,6⇓⇓ making it difficult to distinguish from MS.6-8⇓⇓ ADEM affects predominantly children and young adults.9
We describe a cohort of consecutive pediatric patients with ADEM with a long-term follow-up. Clinical features at presentation and MRI findings were used to identify subgroups and evaluate outcomes.
Methods and patients.
Patients.
From March 1988, we evaluated all patients admitted with ADEM at the National Pediatric Hospital “Dr. J. P. Garrahan” of Buenos Aires, where a representative population of Argentina is treated.
Inclusion criteria for ADEM diagnosis included the occurrence of a presumed inflammatory demyelinating event of acute or subacute onset affecting multifocal areas of the CNS with a polysymptomatic presentation, in an individual who had no history of neurologic symptoms suggestive of an earlier demyelinating episode. The patient had to show white matter changes on brain–spinal imaging studies, without radiologic evidence of a previous destructive white matter process. Patients with acute isolated monosymptomatic syndromes such as optic neuritis or transverse myelitis were excluded.
Methods.
All patients were evaluated by the senior author at presentation, at 3, 6, and 12 months after the onset, and again once per year up to the present time.
We analyzed gender, age at onset, preceding infection or immunization, neurologic syndromes at presentation, neuroimaging findings at onset, therapeutic response, clinical course, and final neurologic and neuroimaging outcome. MRI examinations were conducted using different machines, on 0.5- or 1.5-Tesla MRI scanners (Picker, Philips Medical System, Gyroscan ACS).
Quantitative and qualitative immunologic investigations were simultaneously performed in CSF and serum samples, which were sent in a blind way. The presence of oligoclonal bands of IgG in CSF and serum was evaluated by agarose isoelectric focusing, followed by passive protein transfer to a nitrocellulose membrane with immunodetection of IgG by a double antibody method: goat antihuman IgGFc, followed by horseradish peroxidase–conjugated rabbit antigoat serum. Local synthesis of IgG could be defined when at least two bands were present in CSF but absent from serum (“intrathecal oligoclonal bands”).10 An extensive workup for bacterial and viral infections was performed in all patients. Specific serum and CSF studies for influenza A and B, herpes simplex virus (HSV), cytomegalovirus, varicella zoster, measles, enterovirus, Epstein-Barr virus, hepatitis A and B, mycoplasma, mumps, and HIV as well as CSF, nested PCR, and bacterial cultures were performed.
The functional degree of neurologic disability was assessed using the Kurtzke functional systems and Expanded Disability Status Scale (EDSS)11 during hospitalization and was repeated at every visit upon discharge. The neuroimaging follow-up was assessed through serial brain and spinal MRI studies at 3, 6, or 12 months after onset depending on time of lesion resolution. After the first normal MRI, patients were reassessed with at least two MRI during the following 5 years, in order to rule out persistence of inflammatory white matter activity.
Analysis.
We compared the neuroimaging subgroups, neurologic involvement at presentation, and final disability scores by using the Kruskal-Wallis test and multiple-comparisons Dunn test. The Mann-Whitney test was used to compare differences between two groups of patients receiving different IV corticosteroid treatments. The level of significance was set at p < 0.05.
One patient whose condition was diagnosed in 1982 and 83 consecutive children examined between March 1988 and July 2000 met the inclusion criteria and have been followed up to the present time.
Results.
Patients and gender.
Eighty-four children met the inclusion criteria for ADEM. The male:female ratio was 1.8:1, against the ratio of 1.16:1 of children with different pathologies either admitted or treated on an outpatient basis at the hospital. The statistical analysis of proportions between both groups was p = 0.045. Age at presentation ranged from 0.4 to 16 years, with a mean age of 5.3 ± 3.9 years and a median of 4.5 years. Most children were neurologically normal at baseline, with the exception of two patients having ADEM shortly after herpes simplex encephalitis and one boy with Down syndrome.
Preceding events.
A clear infectious event or vaccination preceded the onset of illness in 74% of patients. The mean interval between the febrile prodrome and the beginning of neurologic disturbance was 12.1 days (range, 2 to 30 days). Table 1 shows the recognizable prodromes. Twenty-six percent of patients had no clear previous illness and could be considered as having cryptogenic ADEM.
Table 1 Precedent events in children with acute disseminated encephalomyelitis
Clinical findings.
Table 2 lists the frequency of presenting features in this group of children. The polysymptomatic picture of presentation showed a combination of multifocal deficits. Unilateral or bilateral long tract signs (85%), acute hemiparesis (76%), changes in mental status (69%), and ataxia (50%), isolated or in combination, were the most prominent initial findings.
Table 2 Frequency of presenting features in children with acute disseminated encephalomyelitis
Consciousness impairment (n = 58) evolved into coma in 16 cases. Seizures were mainly present as partial motor status epilepticus. The neurologic picture of presentation developed over a period of 1 to 45 days (mean, 4.5 days).
Neuroimaging findings.
Multifocal or diffuse white matter damage, the radiologic hallmark of the disease, was assessed in every patient at onset.
Brain CT scanning was performed in 69 patients and revealed abnormal findings in 54 scans (78%), after a mean interval of 6.5 days from initial symptoms. CT showed discrete hypodense areas in cerebral white matter, particularly evident in patients with large demyelinating lesions, but failed to show small and subtle lesions.
MRI studies have been available in our country since 1988 and were performed in every patient for diagnosis since then, with or without previous CT. MRI was performed during the acute stage in 79 patients and showed focal or multifocal areas of increased signal intensity on T2-weighted, proton density, and fast fluid-attenuated inversion-recovery images, in the cerebral white matter, basal ganglia, brainstem, cerebellum, or spinal cord. These lesions were bilateral and asymmetric, with variable extension to the subcortical white matter.
According to the pattern and frequency of abnormalities observed on MRI during the acute stage of the disease, patients were classified into four groups. In Group A, ADEM with small lesions (<5 mm) was diagnosed in 52 of 84 patients (62%) (figure 1). In Group B, ADEM with large confluent white matter lesions was observed in 20 patients (24%). These plaques showed asymmetric distribution with tumorlike appearance in some studies (figure 2). In Group C, ADEM with additional symmetric bithalamic involvement was observed in 10 patients (12%), with small white matter lesions in five cases (figure 3) and large lesions in the other five patients. In Group D, acute hemorrhagic encephalomyelitis (AHEM), two patients (2%) showed some degree of hemorrhage into the large demyelinating lesions (figure 4).
Figure 1. Group A: Acute disseminated encephalomyelitis with small lesions on MRI. A 9-year-old-boy developed acute left hemiparesis, bilateral ophthalmoplegia, drowsiness, and meningeal reaction 15 days after an upper respiratory disease. Axial T2-weighted images showed bilateral small hyperintense lesions in subcortical white matter.
Figure 2. Group B: Acute disseminated encephalomyelitis with large lesions. (A) Axial T2-weighted image with bilateral large demyelinating lesions that involved basal temporal lobe white matter and mesencephalon. (B) Complete resolution of lesions 3 months after receiving IV methylprednisolone treatment.
Figure 3. Group C: Acute disseminated encephalomyelitis with bithalamic involvement. (A) Coronal T2-weighted image shows hyperintense signal in both thalamic and insular regions, in a young boy 3 weeks after having mumps. (B) Marked resolution 8 months after IV methylprednisolone treatment.
Figure 4. Group D: Acute hemorrhagic encephalomyelitis. (A) Large bilateral hyperintense lesions with areas of very low signal intensity (breakdown products of hemoglobin) in axial T2-weighted MRI in a 5-month-old boy, 2 weeks after pertussis vaccination. (B) Axial T1-weighted image of the same case.
The 10 children with symmetric bithalamic involvement did not exhibit any extrapyramidal sign, particularly tremor, dystonia, or athetosis. Extrapyramidal signs were instead present in four of 12 children who showed asymmetric basal ganglia or thalamic signal abnormalities.
Among the 27 MRI studies performed after IV administration of gadolinium diethylene triamine penta-acetic acid during the acute stage, an open-ring gadolinium enhancement pattern was observed in eight patients (30%). In two cases (7%), enhancement was observed in some but not in all lesions.
Additional neuroimaging studies with normal results included cerebral MR angiography performed in 15 patients and digital angiography performed in one child in Group C.
Neurophysiologic studies.
Interictal EEG records were assessed during the acute stage of the disease in 51 patients. Diffuse slow background activity was observed in 40 (78%), focal slow activities in five (10%), and focal (temporal) spikes in one (2%). Five EEG records (10%) were normal.
Laboratory investigations.
CSF abnormalities were found in 24 children (28%) with either lymphocyte pleocytosis (<180 cells/mm3) or mildly elevated protein (<1 g/dL). Fourteen children (17%) revealed evidence of recent infection: seven patients with ADEM following measles vaccination showed high serum antibody titers for measles with negative CSF; one patient had positive serum titers with negative CSF for mumps; two patients had ADEM following HSV encephalitis and already had positive PCR and serum titers during the encephalitis, but no viral reactivation could be demonstrated 4 weeks later during the demyelinating disease. Four children with chicken pox as prodrome had positive serum titers for varicella zoster with negative PCR findings in CSF. Isoelectric focusing of IgG in CSF and serum could be assessed in 54 children. We found negative oligoclonal bands in CSF and serum in 52 patients (96%). Only two children (4%) showed positive oligoclonal bands in both CSF and serum, and they were the two patients with ADEM following HSV encephalitis. These two children also showed abnormal IgG index against HSV. Of the 54 children in whom CSF and serum isoelectric focusing of IgG were performed, none had intrathecal oligoclonal bands. Seven of 54 patients (13%) showed elevated IgG in CSF (>4.5 mg/dL) with normal IgG/total protein ratio (<12%). Increased myelin basic protein in CSF samples (>4 ng/mL) was found in 11% of patients.
Additional laboratory evaluations with normal results included antinuclear antibody, serum complement (C3-C4), LE cell test, C-reactive protein, IgM and IgG anticardiolipin antibodies, lupus anticoagulant, creatine kinase, lactate (in serum and CSF), acylcarnitines, and liver function tests. Erythrocyte sedimentation rate was elevated in six children. Very-long-chain fatty acid levels were assessed in eight children showing posterior bilateral large demyelinating lesions on MRI and were normal.
Brain biopsies were performed in one child with large lesions with mass effect and in another patient with atypical complete ring enhancement. They revealed diffuse and extensive demyelination with axonal sparing in white matter and cortical-subcortical junction, abundant macrophages containing myelin lipid-degradation products, reactive astrocyte hyperplasia, and perivascular cuffing with lymphocytes.
Treatment.
All patients received supportive care and symptomatic treatment during the acute stage of the disease. Antiepileptic drugs were administered to 29 patients (35%). Acyclovir was prescribed in 58 children (69%) for possible HSV infection. Thirty-six children (43%) required intensive pediatric care and 14 patients (16%) required artificial ventilation due to respiratory failure.
A high-dose, short-course corticosteroid treatment was administered to 80 children (95%). IV dexamethasone (1 mg/kg/day) was used in 43 patients over a 10-day period; IV methylprednisolone (30 mg/kg/day for <30 kg of body weight, and 1 g/day for >30 kg of body weight) was used over 3 to 5 consecutive days in 21 patients, followed by PO prednisolone (1 mg/kg/day) for 10 days; 10 patients received PO prednisolone (2 mg/kg/day) over 10 days, and six children received PO deflazacort (3 mg/kg/day). Steroid therapy was discontinued by slow tapering over 4 to 6 weeks in every patient treated. No patient showed steroid dependency.
We compared the clinical outcome (EDSS) in 25 patients seen earlier with a severe presenting picture including coma or optic nerve or spinal cord involvement who were treated with IV dexamethasone and 21 patients with similar involvement treated with pulsed IV methylprednisolone. The current median EDSS score for patients treated with IV dexamethasone was 3 (0 to 6.5) compared with a median EDSS score of 1 (0 to 3) for those treated with IV methylprednisolone (p = 0.029).
Neurologic outcome.
The follow-up period ranged from 1 to 19 years (mean, 6.6 ± 3.8 years; median 6.7 years). Table 3 summarizes the relation between the EDSS at last visit and neuroimaging subgroups.
Table 3 Neurologic outcome related to radiologic subgroups in children with acute disseminated encephalomyelitis (ADEM)
Eighty-nine percent of patients (n = 75) had either complete recovery with normal neurologic examination findings in most of them or abnormal signs without disability (EDSS of 0 to 2.5). They corresponded to 96% of patients with small lesions on MRI (Group A), 80% of those showing large lesions on MRI (Group B), 80% of those with bithalamic involvement (Group C), and one of the two patients with AHEM (Group D).
Eleven percent of children (n = 9) disclosed disability scores >3. They were four patients (20%) with large-lesion ADEM, 20% of those showing bithalamic involvement, 4% of those with small lesions on MRI, and one patient with AHEM. The residual deficits and neurologic syndromes detected in these patients are summarized in table 4.
Table 4 Residual deficits and neurologic syndromes in children with acute disseminated encephalomyelitis
There was no significant association between neuroimaging subgroups and disability scores. We also compared the neurologic involvement at presentation and final outcome, and the association between optic neuritis (n = 19) and final disability was p = 0.034.
Neuroimaging outcome.
Cranial MRI follow-up showed complete or almost complete resolution of demyelinating lesions between 3 and 24 months after steroid treatment (mean, 7.2 months). The complete resolution could be assessed in all patients with small lesions on MRI studies (Group A) but also in most patients with large lesions (Group B, see figure 2) and additional bithalamic involvement (group C, see figure 3).
Serial MRI studies assessed up to 5 years after diagnosis disclosed no new asymptomatic lesion formation in any patient, particularly no new T2-weighted or contrast-enhancing lesions.
Clinical evolution.
Seventy-six children (90%) showed a monophasic course during the follow-up period, with no further clinical relapse or new subclinical MRI lesion.
However, eight children (10%) showed a biphasic disease, with only one relapse in all of them between 2 months and 8 years (mean, 2.9 years; median, 2 years) following the initial attack (figure 5). CSF and serum samples were reassessed for oligoclonal bands in four children during relapse and were negative. Table 5 summarizes the main features of this particular subgroup of patients with a biphasic disseminated encephalomyelitis. After a follow-up of 3 to 16 years, these eight children remain relapse-free. Patients were followed with one brain–spinal MRI per year during the first 5 years from onset and showed no evidence of new lesions. The eight patients have complete neurologic recovery with EDSS scores of 0 to 2.5 at present.
Figure 5. Biphasic acute disseminated encephalomyelitis. (A and B) Axial T2-weighted MRI showing focal areas of high signal intensity in bilateral white matter. (C and D) Three months after corticosteroid treatment, axial T2-weighted MRI disclosed bilateral large posterior white matter lesions, with partial resolution of previous lesions in a 6-year-old boy during a second demyelinating event.
Table 5 Biphasic disseminated encephalomyelitis in children
Discussion.
In our series of 84 children with ADEM, the onset of neurologic disturbance was preceded by an infectious event or vaccination in 74%.
Acute hemiparesis with bilateral pyramidal tract signs was the most frequent presenting feature, followed by impaired consciousness and ataxia, often with other neurologic signs. Partial motor status epilepticus at onset was observed in 35% of patients, as in previous reports.12 Although aphasia has been considered uncommon in ADEM, it was noted in 21% of our patients.
We identified four MRI subgroups at presentation: ADEM with small white matter lesions; ADEM with large and confluent lesions; ADEM with additional bithalamic involvement; and AHEM. No prodromal event predicted the radiologic subgroups.
The large cerebral mass lesions observed in 31% of our patients strongly resembled Schilder myelinoclastic diffuse sclerosis.13,14⇓ This term has been applied to various white matter diseases. Although some authors consider that myelinoclastic diffuse sclerosis is a variant or a “transitional” form of MS,13 we consider our cases as ADEM examples.15 We believe that ADEM is not a progressive disease, even in cases mimicking the questioned Schilder disease. The monophasic clinical course observed in 20 of our patients with large white matter lesions, and the biphasic course in another six patients without further new clinical relapses and without new enhanced demyelinating lesions during the long-term follow-up, were distinguishing features to assess ADEM diagnosis.
We noted a distinctive symmetric bithalamic involvement in 10 children. The term acute necrotizing encephalopathy of childhood (ANE) has been proposed based on clinical and pathologic findings.16,17⇓ The cases studied were acute noninflammatory encephalopathies with a fulminant clinical course, associated with hyperintense and symmetric brain lesions, affecting particularly the thalamus, with high incidence between 6 and 18 months of age. Even when the imaging features in our patients resembled ANE showing brighter lesions in thalami than in other brain areas, there were differences. The mean age at onset was 2.8 years (range, 0.4 to 6 years), no patient showed abnormalities in liver function, and all patients improved following corticosteroid treatment. After a follow-up of 2 to 16 years (mean, 7 years), eight of 10 children had EDSS scores of 0 to 2.5, in contrast with the severe neurologic sequelae described in patients with ANE. A complete resolution of the bithalamic lesions without brain atrophy or gliosis was noted in all patients, in contrast to the multiple cavities observed in patients with ANE. Moreover, three of our 10 patients had a biphasic course of disease, with the bithalamic involvement assessed on MRI at onset but not during the relapse.18 Few similar cases with selective reversible bithalamic involvement following a febrile illness have been reported.19,20⇓ A similar neuroimaging pattern may be seen in patients with deep cerebral venous thrombosis (DCVT).20,21⇓ The diagnosis of DCVT was ruled out through the revision of brain MRI, particularly midsagittal T1- and T2-weighted images that showed no evidence of signal changes in the deep cerebral veins and the straight sinus. Metabolic and coagulation test results were normal in these patients. Moreover, brain MR angiography performed on admission in six of these patients and digital subtraction angiography in one patient showed no sign of vessel occlusion.
Of the 54 children whose CSF and serum samples were analyzed, none had intrathecal oligoclonal bands. Few patients with intrathecal oligoclonal IgG production have been reported,2,4,6,22⇓⇓⇓ but the follow-up period was not long enough to rule out the subsequent development of MS.
Although ADEM is a monophasic disease, relapses have been described mainly as case reports.2,18,23-26⇓⇓⇓⇓⇓ Eight children in our cohort (10%) developed a biphasic disease presenting one definite relapse each. To qualify as definite relapse, the new clinical episode required at least an interval of 1 month from the initial symptom,27 in addition to different symptoms and radiologic evidence of new lesions at a different site.24,27⇓ The concept of definite relapse was considered to differentiate biphasic ADEM5,23-25,28⇓⇓⇓⇓ from patients with steroid dependence who show reactivation of the same lesions.26,28,29⇓⇓ The mean age at disease onset (4.6 years) for these eight children was slightly lower than that of the series. The second attack was observed after a mean interval of 2.9 years from the first event, with an infectious prodrome in only one case. All relapses were polysymptomatic, with optic neuritis as part of the encephalopathy in two children. Because we saw only one definite relapse during the long-term follow-up, we propose that it be named biphasic disseminated encephalomyelitis (BDEM) instead of multiphasic DEM. Although BDEM is often difficult to differentiate from MS, long-term clinical and neuroimaging follow-up plays a prominent role in clarifying diagnosis.5 The lack of dissemination in time, the absence of further clinical relapses, and what was more relevant, the absence of new lesions on MRI scans repeated during the mean follow-up of 8.2 years, plus the lack of oligoclonal bands in CSF on presentation and during relapse, allowed us to differentiate BDEM from MS.30
Although ADEM treatment has not been subjected to controlled trials, corticosteroids are the most frequently reported therapy, improving recovery in most patients.2,31⇓ Clinical response is usually evident within hours of initiation of treatment, particularly after pulsed IV corticosteroids.32 Children in our study group were treated with either PO or IV corticosteroid therapy, depending on severity of neurologic involvement. Patients seen earlier were more frequently treated with IV dexamethasone. We now consider IV methylprednisolone the treatment of choice in any child with ADEM and severe consciousness impairment or optic nerve or spinal cord involvement and in those showing large lesions with mass effect on MRI studies.
No patient died or was lost from follow-up in our cohort. Nevertheless, some reports addressed high mortality frequencies (10 to 30%) in patients with ADEM during the first week of the illness, particularly in postmeasles ADEM.1,33,34⇓⇓ By extension, in catastrophic demyelinating AHEM, death has frequently been reported from brain edema within 1 week of onset.35 Nevertheless, increasing evidence has been published about survival when patients were treated with corticosteroids, without obvious neurologic sequelae in some of them.36-38⇓⇓
Based on our pediatric cohort results, ADEM is a benign condition, despite the usual dramatic clinical and radiologic presentation. Extended disability scores <2.5 were observed in 89% of patients. However, 11% disclosed residual deficits and neurologic syndromes, with disability scores between 3 and 6.5 at present. No significant association could be found between MRI subgroups and disability, probably due to the resolution of demyelinating lesions on follow-up in most patients. Nevertheless, optic nerve involvement at presentation may be related to more disability.
Our data support the existence of a monophasic and biphasic pattern in acute demyelinating encephalomyelitis (ADEM, BDEM) in children and suggest that ADEM is more frequent than previously reported. Even in cases with a relapsing course (BDEM), the disease may be distinguished from childhood MS on the basis of clinical, biochemical, and neuroimaging long-term follow-up.
Acknowledgments
Acknowledgment
The authors thank Ulises Questa, MD, for performing the statistical analysis and Gustavo Saposnik, MD, for helpful suggestions.
Footnotes
-
Presented in part at the 52nd annual meeting of the American Academy of Neurology, San Diego, CA, April 29 to May 6, 2000.
- Received October 24, 2001.
- Accepted July 1, 2002.
References
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