Acute disseminated encephalomyelitis: A clinical and neuroradiological profile of pediatric patients
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.193808
Source of Support: None, Conflict of Interest: None
Objectives: To discuss the clinical and neuroradiological profile of pediatric patients with acute disseminated encephalomyelitis (ADEM).
Keywords: Acute disseminated encephalomyelitis; corticosteroids; encephalopathy; magnetic resonance imaging; multiple sclerosis; neurological deficit
Acute disseminated encephalomyelitis (ADEM) is a monophasic inflammatory demyelinating disorder with pleotropic clinical manifestations, which presents with encephalopathy with or without other focal or multifocal symptoms suggestive of a central nervous system (CNS) inflammatory disorder., ADEM should be suspected when one or more of the following features are present such as a multifocal and polysymptomatic initial presentation, an age younger than 10 years, the presence of signs and symptoms suggestive of meningoencephalitis, encephalopathy, bilateral optic neuritis, cerebrospinal fluid (CSF) fluid pleocytosis along with the typical magnetic resonance imaging (MRI) picture., Although it is monophasic by definition, relapsing forms of ADEM has also been recognized. In the present study, we present a cohort of 36 children, diagnosed as having ADEM, who despite their varied presentations, shared some common characteristics. The study also includeed a few relapsing and resistant cases of ADEM. An early suspicion and a confirmatory MRI facilitated an early initiation of steroid therapy in most of the cases and a survival of approximately 88% could be achieved.
This prospective study included children with ADEM registered between July 2009 and September 2014 in the Department of Pediatrics, the Institute of Child Health, Kolkata. Only those patients who had at least 4 months of follow-up were included in the study after obtaining a written informed consent from the parents. These patients were followed up regularly in our Pediatric Neurology Clinic with documentation of all relevant clinical and laboratory data in a detailed proforma. The diagnosis of ADEM was based on the typical clinical findings supported by relevant laboratory investigations and by exclusion of other diseases. The data collected include details of history of the illness, clinical and laboratory features, treatment details with outcome, and MRI findings. Clinical records of these patients were analyzed for clinical events since the time of registration until the last available follow-up to identify any possibile episodes of relapse or recurrence.
This prospective study included a total of 36 patients in a period from July 2009 to September 2014. The age at presentation ranged from 16 months to 15 years with the mean age being 6.86 years. The male:female ratio was 11:4.
In 18 patients (50%), there was a history of preceding viral infection, usually in the form of a mild cough and cold with fever. In one child, there was a history of chickenpox and in three other cases, there was preceeding history of acute gastroenteritis. The mean duration from the onset of prodromal symptoms to the onset of ADEM was 17 days. In two cases (5.55%), a history of administration of vaccination was present; one child was vaccinated with a varicella vaccine and the other with the measles, mumps, and rubella vaccine. Fever was present at the onset in 16 (44.44%) cases, while features of changing mental status or encephalopathy were almost universally present (91.66%). Most of the cases (91.66%) were associated with some neurological deficit. Seizure was present in 41.66%, cases, visual disturbances in 30.55%, and gait disturbance and bladder symptoms in 41.66%, and 36.11% patients, respectively. Neck pain as an early sign was present in a significant number of patients [Table 1]. The detailed neurological examination revealed neck rigidity in 18 (50%) patients. Cranial nerve involvement was present in 14 (38.88%), limb weakness in 19 (52.77%), and ataxia in 13 (36.11%) patients. Signs of involvement of the basal ganglia were detected in 6 (22.22%) of the patients. Increased deep tendon reflexes and an extensor planter response were found in 66.66% and 75% of the patients, respectively [Table 2].
Most of the findings on laboratory investigations were nonspecific. Markers of acute inflammation such as raised total leucocyte count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were present in 30–40% of the cases. The CSF study conducted in 32 patients revealed a normal CSF in 16 patients, an increased protein content in 6 patients, pleocytosis in 10 patients, and both pleocytosis and increased protein in 2 patients. An electroencephalograph (EEG), done in 23 patients, showed an abnormality in 9 patients, especially in those who presented with a seizure. The visual evoked potential was abnormal in 7 patients [Table 3].
Neuroimaging, especially the MRI, is the diagnostic test of choice, especially to differentiate ADEM from other CNS disorders such as meningitis or meningoencephalitis. MRI on a 1.5 Tesla machine was done in all 36 patients. In 24 children, the lesions were asymmetric (66.66%), and in the rest 12 (33.33%) patients, the lesions appeared to be symmetric. In addition to the predominantly white matter involvement, especially the periventricular white matter in the majority of the cases, in 6 cases, deep gray matter nuclei, like the thalamic nuclei, were also involved [Table 4]. It was observed that those patients with ADEM who presented with gray matter involvement frequently had seizures and were often associated with a poor outcome. The few patients with brain stem and cervical spinal affliction usually needed mechanical ventilatory support to tide over their respiratory manifestations [Table 4].
Treatment and outcome
All 36 children in this cohort were treated with corticosteroids. Thirty-two of them (88.88%) were administered intravenous (IV) methylprednisolone (30 mg/kg/day) for 3–5 days depending on the severity of illness. This was followed by oral prednisolone at a dose of 2 mg/kg/day during the initiation and then the medication was tapered over the next 6–8 weeks. In 4 children, only oral prednisolone was tried at a dose of 2 mg/kg/day as they had a relatively milder form of the disease. All of them responded well to the steroid therapy. IV immunoglobulin (IVIg) was used in 2 refractory cases. Azathioprine was needed in 2 patients, and cyclophosphamide and rituximab were tried in 1 patients with a relapsing disease [Table 5].
An excellent outcome with complete recovery without any relapse or recurrence was achieved in 27 (75%) patients. The disease relapsed in 3 (8.33%) patients. Among them, one patient presently remains well after the first recurrence and did not need administration of any immunosuppressive drugs other than steroids. The other 2 patients have had a multiphasic ADEM with frequent relapses and are now being treated with steroid sparing immunosuppressive agents such as azathioprine and cyclophosphamide. One of them was also treated with IV rituximab and is still having intermittent relapses, needing treatment with steroids. Four of our patients did not survive; and, 2 survived after being placed on a prolonged ventilation and are persisting with severe neurological sequelae [Table 6].
ADEM, also known as postinfectious encephalomyelitis, is a demyelinating CNS disorder that usually follows the occurrence of infection, or more infrequently, after the administration of a vaccination.,, ADEM is an immune-mediated disease. Although traditionally, it has been believed that there is an immunological reaction following a viral infection or administration of vaccination which causes the brain damage, the occurrence of these events has not been included in the definition of ADEM in most studies, including the new consensus clinical criteria.,,,,,, Only four series have described patients with a clear antecedent history of infection or vaccination.,,, The preceding history of infection or vaccination may be just a mere co-incidence. In our study, half of the patients had a history suggestive of a preceeding viral infection and 5.55% had a history of vaccination. We were unable to isolate any organism from any of our cases. Mikaeloff et al., found an association of an antecedent infection or vaccination administration in around 64% of their patients; and, Dale et al., found this history in 69% of their study population. Jayakrishnan et al., have reported that an acute febrile illness preceded the onset of neurological symptoms in 64% of their children. The definition of ADEM is consistent with the currently proposed clinical criteria , and assumes that there is a unique immune-mediated CNS process with a distinct pathophysiology. This process may be independent of the immunological trigger, which is often not apparent from the clinical history. Consequently, a strict requirement of an antecedent infection or vaccination is neither specific nor sensitive for the diagnosis of ADEM.,
ADEM is typically a polysymptomatic, multifocal, and monophasic disease. There may be a mild fever at the onset of symptoms. The predominant features are encephalopathy in the form of irritability, drowsiness and often frank obtundation, coupled with features of focal neurological deficits. In our case series, almost 92% patients had encephalopathy and some form of neurological deficits at the time of presentation. Limb weakness was found to be more specific than cranial nerve weakness. Though encephalopathy and neurological deficits were almost universally found in the patients included in the study by Mikaeloff et al., this observation was not supported by other studies. Jayakrishnan et al., found motor deficits in 71% of the cases and cranial nerve palsies in 36% of the cases. ADEM is typically a white matter disease and the presence of seizures, therefore, seems to be quite uncommon. However, after improvements have occurred in diagnostic imaging, more patients of ADEM with deep gray matter involvement are being seen, and these cases often present with seizures. Our study documents 42% of the patients presenting with seizures, although this incidence is quite less when compared with literature reporting on seizures. Features of meningoencephalitis in the form of neck pain, neck rigidity, or neck stiffness often leads to an initial diagnostic confusion between ADEM and meningoencephalitis. The presence of meningism (50%) in our series was higher than that seen in other series. Approximately one-third (30.55%) of our patients had a complaint of decreased visual acuity during their illness. We found that optic neuritis (ON) rather than papilledema was the cause of visual blurring, and it was often bilateral in nature. Dale et al., found that 23% of the patients diagnosed with ADEM presented with bilateral ON. However, none of our patients had permanent eye damage, and the neuritis recovered completely after steroid therapy.
In our cohort, neck rigidity was found in half of the cases. These were cases where we initially suspected the presence of meningoencephalitis. Dale et al., found meningism in 31% of the cases whereas Anlar et al., found it in 24% of cases. The cause of this neck rigidity or neck stiffness is not very well defined, but many cases of fatal ADEM have evidence of lymphocytic meningitis on histopathologic examination. Features of neurological deficits are almost universal in ADEM. A detailed examination to assess for cranial nerve paresis, muscle power deterioration, or changes in deep and superficial tendon reflexes, therefore, appears mandatory. Sometimes, it may happen that initially, the mother only complains that her child is not moving a limb properly or that the child is a bit drowsy. However, subsequently, these symptoms may progress to the development of frank ADEM.,,, Rarely ADEM may present with signs of basal ganglia involvement in the form of chorea or athetosis. Autonomic involvement in the form of swings of blood pressure and arrhythmias may also occur.,,
The laboratory investigations, especially the hematological investigations, are usually nonspecific and may vary from case to case. However, in general, there are no features of active infection such as a neutrophilic leukocytosis or a very high ESR or CRP. This helps to differentiate it from infective meningoencephalitis in the initial evaluation before MRI report is available.,, The CSF study is noncontributory in the majority of the cases, but before diagnosing ADEM, infection needs to be excluded by CSF analysis. As we have an in house MRI, we stressed upon performing the MRI before the CSF study in the cases suspected of having ADEM. The CSF study was done only where diagnostic confusion persisted even after the MRI. CSF may be normal in ADEM or may reveal a lymphocytic pleocytosis, in contrast to the cases with multiple sclerosis, which rarely showed pleocytosis. The CSF may reveal an increased protein concentration, and sometimes both pleocytosis and raised protein may be present., Jayakrisnan et al., in their study, did not find any CSF pleocytosis. The detection of oligoclonal bands (OCBs) may be helpful in predicting a subsequent diagnosis of MS but its true utility is unknown because as many as 58% of adult and 29% of pediatric cases with ADEM have OCBs. Anecdotally, the bands should resolve in ADEM but are expected to persist in MS.,
The utility of an electroencephalography (EEG) is limited in the evaluation of this disease. However, in those patients, who present predominantly with seizures, an EEG should be done because it may help to prognosticate the disease and may help in the choice of anticonvulsant therapy. An abnormal EEG was found in 9 among 23 of our patients where this investigation was carried out.
MRI is the investigation of choice in ADEM. Although MRI neuroimaging is useful for the diagnosis of ADEM and exclusion of other diagnoses, the consensus ADEM criterion emphasizes on the clinical criteria more and underplays the role of MRI. In clinically defined cases of ADEM, the MRI will often demonstrate multifocal areas of increased T2-weighted signal abnormalities in the CNS white matter, with or without gray matter involvement. These multiple foci of demyelinating lesions may be seen in the cerebrum, midbrain, brain stem, and cerebellum. These lesions are rather extensive and may be symmetric or asymmetric. They are more often located in the peripheral subcortical cerebral white matter. Lesions may be present in the thalami, hypothalamus and basal ganglia as well. In our series, we had approximately 17% cases with thalamic involvement. In many the other studies, this figure is quite high and may even be as high as 60%. As the name suggests, the manifestation is in the form of an encephalomyelitis, and some evidence of spinal cord involvement is always present. Cervical cord is the most often involved location. In our series, 27.7% children had an evidence of cervical cord involvement. MRI documented brain stem lesions, and cervical cord involvement resulted in more chances of respiratory compromise and the need for mechanical ventilation. Hence, it seems wise to always include the screening of at least the cervical spine while performing MRI of the brain as it can also show evidence of myelitis. Although ADEM lesions (of similar duration) are supposed to enhance with gadolinium, this finding is rarely seen, and gadolinium enhancement may even be absent. We performed a non-contrast MRI in our patients as the diagnosis could easily be established from noncontrast studies in most of the cases as well. The recently published consensus criteria require an abnormal MRI and state that the lesions should be larger than 1 to 2 cm to be compatible with ADEM. The current consensus criteria for ADEM also suggest that rarely, a large focal lesion may be compatible with ADEM even though some may regard this as a tumefactive presentation of MS.,,,,,,,,
Once the presence of an acute and severe infection has been reasonably excluded, IV methylprednisolone, 25–30 mg/kg/day for 3–5 days, is the most common therapeutic medication administered in clinical practice, based on anecdotal evidence from case reports and clinical series. However, if the patient is relatively stable and there is a confusion between the presence of a clinically isolated syndrome and ADEM, and there is a very scanty evidence of encephalopathy, one can even try oral prednisolone. In our series, we gave prednisolone to four children who were relatively stable with minimal encephalopathy and all of them responded well. However, whatever be the type of steroids used, it is mandatory to continue them for at least 6–8 weeks in a tapering dosage schedule to prevent future recurrences.,,,,, IVIg may be an effective alternative, especially in refractory or relapsing cases of ADEM. The often fatal hemorrhagic ADEM (hemorrhagic leukoencephalopathy) also often responds to IVIg. It should be given in a total dose of 2 g/kg administered over 2–5 days., Two of our patients received IVIg as a rescue measure. Plasmapheresis is another alternative for the steroid nonresponders. Typically 5–7 exchanges, administered every other day, is effective. In relapsing ADEM, immunosuppressive agents other than steroids are used, as is often also used in patients suffering from MS. One of our patients with multiphasic ADEM showed a good response to pulse cyclophosphamide, while another one had frequent relapses even on azathioprine and cyclophosphamide but responded to 4 doses of rituximab. In a few studies, a promising role of rituximab in refractory relapsing ADEM or MS has been seen. However, a large multicentric studies should be undertaken before we can unequivocally substantiate the role of rituximab in refractory relapsing ADEM.
The prognosis, after an acute attack of ADEM, is usually excellent if timely treatment with steroids is instituted. Most of the children experienced a full recovery after ADEM, but some were left with residual motor or cognitive deficits. 75% of our patients recovered completely after an acute attack of ADEM without any neurological sequelae. The hemorrhagic variant of ADEM (hemorrhagic leukoencephalopathy) is usually fatal and needs an early aggressive treatment with steroids as well as IVIg or plasma exchange. We found that those patients presenting with refractory seizure or respiratory abnormality at the time of admission (indicating brain stem involvement) had a poor prognosis. As discussed earlier, though traditionally believed as a monophasic illness, the demyelinating symptoms may fluctuate over the years and may be termed as recurrent ADEM or multiphasic ADEM, depending upon the MRI characteristics. 10–15% of ADEM are relapsing. In our study, relapsing ADEM was evident in three patients (8.33%), and among them, one is now being treated on the line of treatment for MS. A close follow-up, repeated MRI and an expert opinion are needed to differentiate the lesion from MS and for the institution of appropriate immunosuppressive agents.
ADEM in childhood is not as uncommon as was thought previously. In children, who present with sudden onset encephalopathy, along with neurological deficits, with a preceeding history of viral infection, ADEM should initially be suspected. Though predominantly monophasic, relapses may occur in ADEM; and, relapsing ADEM is not synonymous with multiple sclerosis. Maintaining a high index of suspicion and conducting an early neuroimaging helps in initiating an early steroid therapy, which may lead to a good prognosis.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]