A study on acute disseminated encephalomyelitis in children

Introduction: Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of central nervous system characterized by scattered focal / multifocal inflammation of brain & spinal cord that usually follows an apparently benign infection in otherwise healthy children & young adults. It represents 30% of all childhood encephalitic illnesses. Material & Method: The study was conducted over a period of two years from October 2016 to September 2018 at S C B Medical College, Cuttack. The patient fulfilling the inclusion criteria were taken into study. Result: Early institution of with immunosuppressive drugs hastens recovery and reduces morbidity. Despite the serious neuropsychiatric manifestations ADEM in children generally has good outcome. Children with ADEM need long term follow up for cognitive impairments and emotional problems. Conclusion: ADEM most commonly presently as an acute polysymptomatic encephalopathy and initially diagnosis may not be clear. Clinical evaluation, MRI & CSF study are most useful to establish the diagnosis and rule out important differential diagnosis. Early institution of therapy with immunosuppressive therapy hasten recovery and reduces mortality.


Background
Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of central nervous system characterized by scattered focal / multifocal inflammation of brain & spinal cord that usually follows an apparently benign infection in otherwise healthy children & young adults. It represents 30% of all childhood encephalitic illnesses [1]. It is considered as an autoimmune disorder that is triggered by environment stimulus in genetically susceptible individuals.
It is usually presenting as a monophasic disorder associated with multifocal neurological symptoms & encephalopathy. In the past, ADEM commonly followed common childhood infection like measles, chickenpox & smallpox. Because of significant advances in infectious disease control & extensive immunisation coverage, nonspecific upper respiratory illness are the most common triggering event in developing countries, but the exact aetiological agent In the past in the development countries, the incidence rate of post infectious demyelinating disease was 1 in 10,000 out of which 1 out of 1000 followed measles infection. Post vaccination encephalomyelitis incidence rate was 1 in 25000 especially following duck embryo anti rabies vaccination & following live measles vaccination was 1to 2 per one million³. The incidence of ADEM is estimated to be 0.4 per 100,000 per year [1].  All these patients selected were first stabilised. Detailed history and clinical examination special reference to central nervous system was done.
The level of consciousness was assessed using Glassgow coma scale. Motor or sensory deficits were classified as partial or complete.
The presence of aphasia, hemi paresis and visual defect was evaluated whenever possible according to child's age. All associated symptoms like seizure, headache, fever, altered level of consciousness were recorded.
Relevant investigations were performed to exclude infective or inflammatory aetiologies which included complete blood count and measurement of serum electrolytes, erythrocyte sedimentation rate and Cerebrospinal fluid analysis (CSF). were obtained using gadopentetate dimeglumine (0.1mmol/kg). CT (Computed Tomography) was done in third generation scanner and contrast enhanced images were obtained in the selected few cases. Scans were reviewed by neurologist who was blinded to the clinical findings.
The images were assessed for lesion site, size, number, distribution, symmetry, any midline shift, haemorrhage and pattern of contrast enhancement. Standard 30minute interictal surface electroencephalo-phalogram (EEG) was recorded in patients with impaired consciousness or seizures.
These differential levels of investigations are the standard protocol in the diagnostic work up of patient with a neurological catastrophe and do not influence the etiologic diagnosis.
The incidence was defined as number of new cases of ADEM admitted to the hospital which came into existence within certain period of time per 100 patients admitted to the hospital.
All those cases then segregated as per age and gender.
The mean age at onset is calculated and sex predilection determined.
The incidence of prodermal period and history of recent vaccination was assessed. After neuroimaging study, the incidence of abnormal findings on MRI/CT was calculated.
Mode of onset mode of presentation i.e. the type of deficit, cranial nerve involvement, and level of consciousness, seizures, headache, and all the features then correlated with the immediate outcome. Thorough history and a formal neurological examination to evaluate the outcome in terms of full recovery, motor deficit, cognitive defect, visual field defect, recurrent seizure, learning disorder, personality changes, psychiatric manifestations, death etc.
Repeat brain imaging was arranged if there was suggestion of progression or recurrence of neurological deficits. After ADEM was diagnosed, all cases were treated with high dose intravenous corticosteroids, either methyl prednisolone (10-30mg/kg) or dexamethasone (1mg/kg) daily for 3-5days.
Subsequently prednisolone (1mg/kg orally) was started and continued for six weeks with gradual tapper. Plasma exchange, intravenous immunoglobulin (IVIG) (2mg/kg divided dose over 5days) or repeat high dose intravenous methyl prednisolone were given for patient who continued to detoriate. Data thus computed were analyzed and inferences drawn.

Analysis of data:
Results were expressed as mean ± standard deviation for continuous variables and as number (%) for categorical data. Since all data were normally distributed, the parametric tests were used for statistical analyses.
The data was analyzed by SPSS version 21 software along with below mentioned appropriate statistical tests at 5% level of significance. p value is calculated using Chi-Square Test given by the formulaWhere Oi is Observed frequency and Ei is Expected frequency.
Significance was interpreted as: 0.05<p<0.10 Suggestive of significance, 0.01<p<0.05 moderately significant, p<0.01 strongly significant.  Maximum cases were seen in the month of January. The variety of symptoms presented by the study sample at the onset was analyzed here. Seizures were documented to occur in highest no. Ofcases (64.9%). Next fever (59.5%) & altered sensorium (56.8%) followed.     Steroid were given in only 29 number of patient, steroid plus IVIG were given in 2 patient, only supportive treatment were given in 6 out of 37 patients. Out of 17 children with sequelae, epilepsy was predominantly seen 52.9% of cases.Motor deficit is seen in 47% of cases. Although the prevalence of predisposing factor seems to be higher in 0-4years age group, it is not confirmed statistically. It seems that 0-4 years had mostly moderate to severe presentation and 5-9 year age group had mostly severe presentation. Statistically significant association could not be established. There is no statistically significance as seen with outcome at discharge. ADEM was found in all age group of children with early childhood predominance. The youngest was 45 days old infant and oldest was 14 years old. The peak incidence was observed in 5-9 years age group with mean age presentation being 5.2 years ± 3.44. Studies in the past have reported comparable findings [3,5,8].

Observation
Boys constituted 65% of the children in the present study and girls constituted 35%. Studies from India and abroad have reported that ADEM is more common in boys, while multiple sclerosis is more common in girls [4,5]. Cases occurred throughout the year with predominance in the month of January which were comparable to the western data where predominance during winter and spring is reported [3,4].
MRI is of central importance in the diagnosis of acute CNS white matter disorder. CT is frequently normal in ADEM (Dunn et al 1986 [11], caldemeyer et al 1994 [12]). About 05 patient in our study had CT scan done that showed features suggestive of demyelination in 4 patients.
Abnormalities of brain MRI have been shown to be predictive of the development of multiple sclerosis in adults. In clinically isolated syndromes an abnormal MRI brainon presentation was associated with progression of multiple sclerosis in 83% of patients during last10years of follow up (O'Riordan et al 1998) [13].
Normal MRI was associated with progression to multiple sclerosis in our only patient during the study period. 33 out of 37 children in this study group had MRI done which was abnormal in presentation in all except one. T1 hypointensity was noted in 52% cases and T2 & FLAIR hyper intensity was noted in 76% cases.
Temporal shrinkage was noted in 05 patient (15%), contrast enhancement in 2(6%) & gyral thickening in 2(6%) Lobes of the brain were the most common area to be involved out of which fontal is the most frequent (56%). T2 hyperintensity of spinal cord was noted in three of our patients who had a screening MRI spine  [14]. Cortical grey lesions were infrequent.
Involvement of deep grey matter was also seen occurring in 32% cases of our study which may be the only imaging finding in ADEM (Baum et al 1994[15], Kimura et al 1996[16]). The asymmetry found in the white matter lesions are characteristics of acquired demyelinating lesion. Symmetrical white matter abnormalities should prompt consideration of leucody strophy. In contrast the deep grey matter abnormalities in ADEM are frequently symmetrical. Thalamic involvement was seen in 18% of cases, which can be up to 40% as per previous studies [3,4,12,17].
Evidence of CSF inflammations in the form of pleocytosis (43%) and elevated protein (71%) was seen which was described in 28-65% of studied cases of ADEM [3,4,18]. CSF opening pressure was normal in almost all cases baring a few. Cells were moderately elevated with mean cell countbeing 14/cumm ranging from 0-100/ cumm which were predominantly mononuclear.
Current opinion supports the use of intravenous methyl prednisolone followed by oral prednisolone therapy when infective encephalitis has been excluded and acute post infectious demyelination is suspected. Notably, however some children appear to recover fully without any therapeutic intervention, but recovery is usually incomplete [19,20]. No therapy (only supportive) was given in 6 patients in our study, some due to fulminant presentation that hardly give any time for intervention. Out of 31 patients who were treated only steroid was given in 29 of them and combined therapy of steroid &IVIG was given in 2.Therapeutic intervention was random, but previous studies have shown efficacy of various therapeutic modalities in specific area of involvement [21].
On follow up, complete recovery was seen in 11 subjects (38%); sequelae were found in 17 subjects (59%); 1 succumbed. 3 patients were lost to follow up. Out of 12 patient who had recovered completely at the time of discharge, 2 had sequelae in the form of behavioural problem and need for anti-epileptic drugs. Out of 20 patients who had partial or no recovery at the time of discharge ,1 succumbed,2 had complete recovery, residual neurological deficit were seen in rest others in the form of cognitive dysfunction, recurrent seizures, motor deficit, behavioural problem, dysphasia & dysphagia. Predominant sequelae observed were recurrent seizures (53%) & moor deficit (47%). In patient who had complete recovery, the recovery period ranged from 8days to maximum 3 months, recovery may continue from weeks to months as per previous studies [22].
The preceding illness were described as upper respiratory tract infection (8), nonspecific fever (4), GI infection (2), UTI (2), CNS infection (2), measles (1), mumps (1) and appendicitis (1), the majority of patient had a preceding history of upper respiratory tract(38%) as per previous studies [23,24]. The prevalenceof antecedent illness was mostly observed below 10 years of age (81%) with predominance of 0-4 years age group, the association could not be held statistically significant (p=0.084), this study needs with larger sample to comment on a definite association. In previous studies,the lack of prodrome has been observed >30% of adolescent cases [12]. The prevalence of preceding illness is usually less described in multiple sclerosis (R C Dale et al 2000) [4]. The association of age with severity of presentation do not have statistically significant value, need a larger sample. Also the outcome at discharge do not have any statistical significance.
The cases with severity of presentation had lower proportion of complete recovery (21.43%) & higher proportion of mortality (35.71%) than the cases with mild and moderate presentation. Similarly, the cases with moderate degree of presentation had lower rate of complete recovery (28.57%) than those with mild presentation (55.56%), this indicates that the severity of presentation was inversely proportional to recovery at discharge. It was proved to be statistically significant through chi-square test of association with p value =0.021.

Conclusion
ADEM most commonly present as a polysymptomatic encephalopathy and initially diagnosis may not be clear. Clinical evaluation, MRI & CSF studies are most useful to establish the diagnosis and rule out important differential diagnosis. There is presence of antecedent illness in case of severe presentation. The age, gender, predisposing factor do not influence the outcome, but the severity of presentation influence the outcome at discharge. Early institution of therapy with immunosuppressive drugs hasten recovery and reduces morbidity as evidence by the study done by Rust RS et al [19], Francis GS et al [20], Ravaglia S [21].
Pediatric Review: International Journal of Pediatric Research Available online at: www.medresearch.in 215|P a g e The two largest reviews found that disabilities was mild (defined as extended disability score of <4) in 40 and 60% of patients in 8 to10 years of follow up respectively (Dequet et al 1987 [25], Ghezee et al 1997 [26]) Children with ADEM need long term follow up for cognitive impairment and emotional problems as described by Boutin et al 1988 [27].
More than half of ADEM case had preceding illness including some vaccine preventable disease which could be prevented by proper vaccination.
What this study adds to existing knowledge?: Inadvertent short course use of steroid therapy is responsible for relapse and subsequent appearance of new symptoms. This study high lights the importance that malaria should be added to the list of infections able to precipitate ADEM. However, large prospective studies are required to address the aetio-pathogenesis.
Funding: Nil, Conflict of interest: None initiated, Perission from IRB: Yes