Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children

Methods.

The records of children diagnosed with ADEM at the Royal Children’s Hospital, Melbourne between January 1993 and December 1998 were retrospectively reviewed. Chart review was performed according to the Royal Children’s Institutional Review Board policy. Potential cases were identified using radiologic reports containing the terms “Acute Disseminated Encephalomyelitis” or “ADEM,” codes applied to patients with this diagnosis by the Department of Information Services and a database held in the Department of Neurology. Patients were included in the study if they had experienced the acute onset of neurologic disturbance and had MRI changes involving the white matter in a distribution consistent with ADEM. Those with indeterminate clinical histories, features more in keeping with alternative diagnoses, or who did not undergo MRI were excluded.

Clinical information was obtained from the medical record. Follow-up information was obtained either from medical records or, if the child had been discharged from the neurology clinic, by telephone from their primary practitioner.

Where available, the results of serologic testing, CSF examination, and EEG were obtained. Oligoclonal bands were only regarded as significant if they were present in the CSF and not in a paired serum sample.

MRI scans (GE Echospeed LX 1.5 T, General Electric Medical Systems, Milwaukee, WI) were reviewed with a pediatric neuroradiologist (L.C.), who was blinded to the patient’s identity, clinical presentation, and original MRI report. Information was recorded according to the following categories: 1) areas of involvement: white matter, gray matter, corpus callosum, deep gray matter (basal ganglia, thalami), brainstem, spinal cord; 2) presence of mass effect; and 3) enhancement following administration of gadolinium.

Results.

Discussion.

ADEM most commonly affects young adults and children5,7⇓ and presents with signs of encephalopathy that may vary in severity from irritability to coma, and with multifocal neurologic abnormalities such as ataxia, hemiparesis, optic neuritis, and cranial nerve palsies.2 ADEM has been described following a variety of infections including measles, varicella, infectious mononucleosis, Mycoplasma pneumoniae infection, and nonspecific febrile illnesses.8 In our series, ataxia was the most common presenting feature, followed by cranial nerve palsies and hemiparesis. This is consistent with the findings of three recent smaller series.5,8,9⇓⇓ Impaired consciousness was less frequent than in previous reports, with 10 patients (32%) unaffected. Mutism has not been previously reported as a feature of ADEM, but was noted in four patients in this series. There was no correlation between this symptom and the location of lesions on MRI scans. Only four of our patients had serologic evidence of recent infection and no pathogen was identified in the CSF of any patient, including one child who had evidence of recent infection with EBV.

Although regarded as a monophasic condition, a characteristic feature of ADEM is the evolution of symptoms and signs over time. Ten children in this series deteriorated after admission to the hospital, with many developing new neurologic signs. Ataxia was usually present at the outset and did not develop later in the illness. Similarly, enhancement of MRI lesions was variable in individuals, suggesting lesions of different ages, as the breakdown of the blood–brain barrier in the acute inflammatory phase is the pathologic correlate of this appearance.

Although ADEM is typically described as a monophasic illness lasting from 2 to 4 weeks, relapses have been reported.1,2,6,10⇓⇓⇓ Four children had relapses in this series, and three of these had involvement of the corpus callosum on MRI. In two of these children, relapse occurred relatively early and may have represented a protracted clinical course or treatment failure rather than a new episode. It is our belief that these children did not have MS because the lesion load on MRI was high, deep gray matter involvement was evident, oligoclonal bands were absent, and there has since been a long symptom-free interval (up to 4 years). The third child may have had Schilder’s myelinoclastic diffuse sclerosis, a subacute demyelinating disorder characterised by bilateral, large and vaguely symmetrical lesions of the cerebral white matter.11 The fourth child also presented with a tumorlike mass and on repeated MRI during a vomiting illness was noted to have new lesions. No clinical relapse has occurred in this child in the subsequent year of follow-up. This subgroup of children may represent an intermediate entity between ADEM and MS.12,13⇓ The relationship between hepatitis B vaccination and ADEM or its variants requires further study.

MRI is highly sensitive in detecting white matter abnormalities and is the investigation of choice in ADEM.4,5⇓ In previous reports, high-intensity lesions were seen on T2-weighted images, most commonly in the subcortical white matter, brain stem, middle cerebellar peduncle, and periventricular white matter.5,8⇓ The lesions are bilateral, asymmetrical, and highly variable in size and number,3,7⇓ which is in accordance with our findings. Although ADEM is typically described as affecting white matter, gray matter involvement is not unusual5,7⇓ because it also contains myelin. We found a significant number of cases with involvement of the deep gray matter (61%), particularly the basal ganglia. This finding may prove useful in distinguishing ADEM from MS, particularly in cases in which there is involvement of the corpus callosum.

Mass effect and enhancement, which result from swelling and disruption of the blood–brain barrier,4,7⇓ are generally seen during the acute phase of ADEM. In theory, all new lesions should enhance with gadolinium, but in practice, this is not a uniform finding, as our results show. In previous studies, large lesions were commonly seen, but did not produce mass effect.5 In this series however, mass effect was identified in 26% of cases. In patients who had repeat imaging, enhancement (four patients) and mass effect (five patients) were seen only on the initial examination, suggesting resolution of the acute disease process. Lesions may remain on MRI,4,7,8⇓⇓ however, and although they usually decrease in size as the patient recovers,5 extensive involvement may persist without clinical deficits.7,8⇓ In the children who underwent follow-up MRI, six demonstrated diminution in the size of the original lesions, but not complete resolution. Only two of these children had not completely recovered, indicating that the persistence of neuroradiologic findings is not necessarily a poor prognostic sign. Importantly, no new lesions were identified unless a clinical relapse had occurred.

Discrimination between ADEM and the first presentation of MS has important prognostic and therapeutic implications. Patients with ADEM generally recover completely, whereas those with MS may have recurrent relapses or progressive deterioration over time. No clinical feature is exclusive to either condition, but some characteristics are more commonly seen in one than the other. MS is rarely associated with a viral prodrome,2,14⇓ whereas the majority of patients with ADEM will describe a preceding viral infection,2,9⇓ as our study confirms. ADEM is more typically a monophasic illness, whereas the course of MS is usually multiphasic and characterized by relapses and remissions.15 Relapse can be seen in ADEM but in our series tended to occur early and may have represented a protracted single phase rather than a new episode. Ataxia, a common feature of ADEM, is an uncommon presenting feature in children with MS, with sensory symptoms being frequent.16

In MS the lesions are usually less extensive and involve the periventricular white matter in up to 98% of cases.2,17,18⇓⇓ Lesions were demonstrated in this region in 29% of our patients, which is in keeping with the findings of a previous smaller series.5 The corpus callosum is usually not involved in ADEM,10 although we identified lesions in nine patients (29%), including the two patients with tumorlike lesions. This finding, together with the relatively high incidence of periventricular involvement in this series, may be a reflection of the higher lesion load in ADEM. Thalamic involvement is exceedingly rare in MS, but may be seen in up to 40% of patients with ADEM,7 making this finding a potentially useful discriminator. Involvement of the deep gray matter may help in distinguishing between ADEM and MS, particularly in those patients who have the corpus callosal changes more typical of the latter condition. Of the nine patients in this series who had lesions in the corpus callosum without tumorlike lesions, only two did not have deep gray matter involvement. It has been said, however, that distinguishing MS from ADEM on any single MRI examination is impossible.3,7⇓ Serial studies performed at least 6 months apart may prove more helpful.3,4⇓ The finding of new lesions is highly suggestive of MS.14 In ADEM, new lesions should not appear unless a clinical relapse has occurred.

Steroids are now used in the treatment of ADEM despite the lack of case-controlled studies to prove their efficacy. Anecdotal evidence of their benefit is now strong.7,19⇓ Although we are unable to provide statistical evidence for the efficacy of steroids in ADEM, we believe our study supports their use. Firstly, 14 of the 23 patients who received IV high-dose methylprednisolone improved within 24 hours of the first dose. This figure includes three children who had been ill for 14 days before treatment and another two who had been ill for at least 25 days. None of these five patients were showing signs of improvement and two were deteriorating. A number of children who were not given steroids improved with similar rapidity, but most of these were showing signs of recovery soon after admission. Secondly, there were two occasions in which patients treated with a short course of methylprednisolone or not treated at all had progression of their disease until they were treated. Steroid therapy may improve the patient’s condition, but withdrawal of treatment while the disease is still active may result in the return of original symptoms or the development of new ones. The role of steroid therapy in ADEM is an obvious area for further research.