Clinical and Radiological Profiles, Treatment, and Outcome of Pediatric Acquired Demyelinating Disorders of Central Nervous System.

INTRODUCTION: Demyelinating disorders of central nervous system are rare childhood disorders that cause significant physical and cognitive disabilities. Early diagnosis and appropriate treatment determines prognosis and outcome.
OBJECTIVE: The objective of this work was to study clinical profile, investigative and radiological features, treatment, and outcome of children with demyelinating disorders.
MATERIALS AND METHODS: A retrospective chart review of 32 children with demyelinating disorders admitted in a tertiary-care pediatric hospital from Bangalore between November 2013 and October 2017 was conducted. Sociodemographic data, clinical features, cerebrospinal fluid (CSF) findings, radiological features, treatment received, and outcome were collected and results were analyzed.
RESULTS: Among 32 patients of demyelinating disorders, majority were acute disseminated encephalomyelitis (ADEM) (15, 46.9%), followed by transverse myelitis (9, 28.1%), multiple sclerosis (MS) (3, 9.4%), optic neuritis (3, 9.4%), and neuromyelitis optica (NMO) (2, 6.2%). Mean age of presentation was 7.8 years. Among 32 patients, 15 were male (47%). In patients with ADEM, the mean age of presentation was 5.5 years. Two patients had tumefactive ADEM and 10 recovered after steroid therapy. In patients with MS, the mean age of presentation was 10.6 years; one patient died and the condition of two patients improved. In patients with transverse myelitis, the mean age of presentation was 8.9 years and seven patients recovered. In a patient with NMO, CSF was positive for antibody to aquaporin-4. The child improved with steroids and intravenous immunoglobulin. Three patients with optic neuritis were treated with steroids and they recovered.
CONCLUSION: Even though demyelinating disorders are rare in pediatric age group, one should be aware of this entity as early diagnosis and treatment improves outcome. Most common among them is ADEM.

Introduction

Acquired demyelinating disorders of central nervous system (CNS) are rare childhood disorders and cause significant physical and cognitive disabilities.[1] These disorders are caused by immune-mediated destruction of the white matter of brain, optic nerve, and spinal cord. This group of disorders includes acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), clinically isolated syndrome (CIS), transverse myelitis, optic neuritis, and neuromyelitis optica (NMO).[2] Diagnosis of these disorders mainly depends on clinical findings and neuroimaging features.[3] Early institution of steroid therapy improves the outcome because of the autoimmune nature of this group of disorders.[2] Exact knowledge about the incidence, clinical features, diagnosis, and treatment outcome is not known in pediatric age group. International Pediatric MS Study Group (IPMSSG) has proposed consensus definitions for this group of disorders for proper diagnosis and management and to facilitate uniformity in research.[4] Hence, the objective of this study was to determine the clinical profile, cerebrospinal fluid (CSF) picture, neuroimaging findings, and treatment outcome of pediatric acquired demyelinating disorders of the CNS.

Materials and Methods

A retrospective chart review was conducted in 32 children up to 18 years of age who were diagnosed with demyelinating disorders on outpatient or inpatient basis in a tertiary-care pediatric hospital from Bangalore between November 2013 and October 2017. The cases were included based on IPMSSG definitions. Details such as sociodemographic data, clinical features, neurological findings, CSF picture, CT and MRI findings, treatment received, and outcome were collected and results were analyzed. Ethical clearance was obtained from the institutional ethics committee.

Results

A total of 32 cases diagnosed with demyelinating disorders were included in the study. Of these, there were 15 (46.9%) cases of ADEM, 9 (28.1%) of transverse myelitis, 3 (9.4%) of optic neuritis, 2 (6.2%) of NMO, and 3 (9.4%) of MS. The mean age of presentation was 7.8 years (range: 9 months–17 years). Of 32 cases, 15 (47%) were male and 17 (53%) female with female/male ratio of 1.1:1; i.e., there is no sex predominance. The common presenting features are described in Table 1.

Table 1

Common presenting features of pediatric demyelinating disorders

Clinical feature	ADEM (n = 15)	MS (n = 3)	Transverse myelitis (n = 9)	Optic neuritis (n = 3)	Neuromyelitis optica (n = 2)
Fever	12 (80%)	3 (100%)	2 (22.2%)	–	–
Encephalopathy	8 (53.3%)	3 (100%)	1 (11.1%)	–	–
Convulsions	6 (40%)	2 (66.7%)	1 (11.1%)	–	–
Quadriparesis	4 (26.7%)	1 (33.3%)	3 (33.3%)	–	–
Paraparesis	3 (20%)	–	6 (66.7%)	–	–
Hemiparesis	6 (40%)	2 (66.7%)	–	–	–
Weakness of both upper limbs	1 (6.7%)	–	–	–	–
Cranial nerve involvement	4 (26.7%)	–	–	–	–
Extrapyramidal features	2 (13.3%)	–	–	–	–
Visual disturbances	1 (6.7%)	1 (33.3%)	–	3 (100%)	2 (100%)
Bilateral	1	1		1	2
Unilateral	–	–		2	–
Cerebellar involvement	1 (6.7%)	–	–	–	–
Sensory disturbances	3 (20%)	1 (33.3%)	6 (66.7%)	–	–
Headache	1 (6.7%)	1 (33.3%)	–	–	1 (50%)
Meningism	1 (6.7%)	2 (66.7%)	–	–	–
Bowel and bladder involvement	4 (26.7%)	1 (33.3%)	9 (100%)	–	–
Recurrent history	1 (6.7%)	3 (100%)	–	–	1 (50%)

ADEM = acute disseminated encephalomyelitis, MS = multiple sclerosis

In patients with ADEM, the mean age of presentation was 5.5 years (range: 9 months–15 years). Of 15 patients, 8 (53.3%) were male and 7 (46.7%) female. Most common presenting features were fever (80%), encephalopathy (53.3%), and convulsions (40%). During hospital stay, all patients developed encephalopathy. Of six cases with convulsions, four had generalized tonic clonic seizure convulsions and two had focal seizures. Of 15 cases, hemiparesis was observed in six cases, quadriparesis in four, and paraparesis in three cases. One case had weakness in both upper limbs. Cranial nerve involvement in the form of facial nerve palsy and involvement of sixth nerve were observed in four cases. Sensory disturbances were observed in three cases, bowel and bladder involvement in three, extrapyramidal features in two, cerebellar involvement in one, and headache and meningism in one case. One child had relative apparent papillary defect with sluggishly reactive pupils. Of 15 cases, 2 cases were diagnosed with tumefactive ADEM.

In patients with MS, the mean age of presentation was 10.6 years (range: 6–17 years). Of three cases, two (66.7%) were females and one (33.3%) was male. Recurrent history was present in all three cases. Common presenting features were fever, altered sensorium, convulsions, hemiparesis, and quadriparesis. Sensory disturbances were found in one case, headache in one, meningism in two, and bowel and bladder involvement in one case.

In patients with transverse myelitis, the mean age of presentation was 8.9 years (range: 4–15 years). Of nine cases, four (44.4%) were male and five (55.6%) were female. The most common presenting features were paraparesis (66.7%), quadriparesis (33.3%), sensory disturbances (66.7%), and bowel and bladder disturbances (100%) (incontinence in five cases, retention in four cases). History of fever was present in two (22.2%) cases.

In patients with optic neuritis, the mean age of presentation was 8.6 years (range: 8–12 years). Of three cases, two were male and one was female. All presented with sudden loss of vision that was unilateral in two cases and bilateral in one case.

In patients with NMO, the mean age of presentation was 14 years. Both the cases were females. Both of them presented with sudden loss of vision in both eyes. Headache was present in one case and a history of similar illness with weakness of right lower limb was present in the other.

Of nine ADEM cases, CSF analysis showed pleocytosis in three cases and increased protein level in two cases. One case of transverse myelitis, one case of optic neuritis, and one case of MS were found to be positive for CSF oligoclonal bands. One case of NMO was positive for NMO antibodies in CSF.

CT scan of the brain conducted in most of the patients was normal except in two cases that showed a hypodense lesion in cerebrum and cerebellum. MRI of the brain conducted in ADEM cases showed hyperintensities in subcortical white matter of supratentorial region, basal ganglia, thalamus, cerebellum, corpus callosum, and cervical–thoracic cord. Basal ganglia involvement was found in five (34%) patients and spinal cord involvement in two (11.6%) patients. Two patients were found to have tumefactive ADEM with MRI of the brain showing chronic hemorrhagic infarcts, and follow-up imaging done in these patients showed cystic encephalomalacic changes and gliosis. MRI of the brain conducted in ADEM cases showed multiple bilateral asymmetrical T2 hyperintense signal changes in white matter, middle cerebellar peduncles and adjacent cerebellar white matter, mid pons, and right side of splenium of corpus callosum [Figure 1].

Figure 1

MRI of brain. (A) Axial T2-weighted image shows multiple bilateral asymmetrical T2 hyper intense signal changes in subcortical white matter. (B) Axial T2-weighted image shows multiple bilateral asymmetrical T2 hyper intense signal changes in deep white matter. (C) Axial T2-weighted image shows bilateral asymmetrical hyper intense signal changes at middle cerebellar peduncles and adjacent cerebellar white matter, few small hyperintense foci in the mid pons. (D) Coronal FLAIR image, shows bilateral multiple asymmetrical hyper intense signal changes at subcortical, periventricular white matter, right side of splenium of corpus callosum, and cerebellar white matter along with adjacent cerebellar peduncles

MRI scan of the brain conducted in MS cases showed multiple demyelinating plaques involving supratentorial, infratentorial, corpus callosum, cerebellum, brainstem, and cervical cord with new lesions in repeat MRI. In transverse myelitis cases, MRI of the spine showed hyperintensities in cervical and dorsal cords. Atrophy of spine was observed in one case and MRI was normal in one case. In NMO cases, MRI of the brain and spine showed hyperintensities in periventricular, frontoparietal lobe, thalami, cerebral peduncle, pons, periaqueductal region, cervicomedullary junction, cervical and dorsal cords with mild thickening, and enhancement in retro-orbital and intraconal segments of optic nerve, as shown in Figure 2. MRI of the orbit conducted in optic neuritis cases showed mild thickening and altered signals with enhancement in retro-orbital segment of the optic nerve.

Figure 2

MRI of brain, Axial T2-weighted sequence: (A), showing ill-defined white mater hyperintense lesion involving the left cerebral peduncle. (B)Sagittal T2-weighted sequence of cervical spine showing T2 hyperintense cord signal changes involving C1 to C5 vertebral levels

All patients were treated with pulse dose of methyl prednisolone followed by a short course of oral steroids. Intravenous immunoglobulin was administered in one patient with ADEM, one patient with transverse myelitis, and one patient with NMO. The patient with NMO was started on rituximab and azathioprine.

Recovery was observed in 10 (66.7%) cases with ADEM with residual disability in five cases; seven (77.8%) cases of transverse myelitis recovered with death in one case (cause not related to transverse myelitis) and residual disability in one case. One (50%) case with NMO and all three cases with optic neuritis recovered. Of the three patients with MS, one patient died and two were healthy in between episodes.

Discussion

This study describes the clinical features, CSF findings, neuroimaging findings, and treatment and outcome of children with demyelinating disorders of the CNS. The mean age of presentation was 5.5 years (range: 9 months–15 years) in ADEM and 10.6 years (range: 6–17 years) in MS; i.e., the age of presentation was late in patients with MS compared to those with ADEM, which is similar to the study conducted by Alper et al.[5] No sex predilection was found in the present study compared to previous studies.[6]

The most common presenting features of ADEM in this study were encephalopathy (53%), hemiparesis (40%), convulsions (40%), quadriparesis (27%), and paraparesis (20%). One important criterion for diagnosis of ADEM is the presence of encephalopathy, which was found in 53% patients in this study. This is similar to study conducted by Alper et al.[5] where 47% patients had encephalopathy. As reports of encephalopathy vary from 45% to 69% in various studies,[78] so ADEM should be considered even in the absence of encephalopathy if patients have other supporting features. Preceding febrile illness was found in 80% of patients, as observed in the study conducted by Hynson et al.[8]

The most common presenting features of MS were hemiparesis, quadriparesis, and convulsions followed by sensory disturbances, bowel and bladder disturbances, and visual disturbances as observed in other studies.[2] Preceding febrile illness was observed in all three patients. All three patients with MS presented with encephalopathy in contrast to other studies where encephalopathy was not the presenting feature.[25] In patients with transverse myelitis, presenting features are paraparesis/quadriparesis (paraparesis > quadriparesis), neurogenic bladder, and sensory involvement. Patients with NMO presented with visual impairment in contrast to other studies.[25]

CSF autoantibodies and oligoclonal bands are described in relation to demyelinating disorders. Among these, anti-aquaporin-4 antibodies are more reliably associated with NMO[9] and are related to the pathogenesis of this condition as the aquaporin channels are located in the periventricular region.[10] One patient with NMO had positive NMO antibodies. CSF oligoclonal bands were positive in one patient with MS but none of the patient with ADEM had positive CSF oligoclonal bands as seen in other studies.[5]

Radiologically, patients with ADEM showed predominant involvement of deep and subcortical white matter and supratentorial lesions with occasional involvement of gray matter and spinal cord. Basal ganglia and thalamic involvement were also observed in five patients with ADEM, as seen in other studies, which is a typical finding in ADEM.[6] In patients with MS, demyelinating plaques involving supratentorium, infratentorium, and juxtacortical region were seen as in other studies.[26] In patients with NMO, hyperintensities were observed in periventricular, subcortical white matter, spine, and optic nerve, as seen in other studies.[2] In patients with transverse myelitis, MRI showed patchy involvement of cervical and thoracic cords. Tumefactive demyelinating lesions most commonly found in MS[11] were observed in two cases with ADEM.

Most of the patients (69%) responded well to steroids, making recovery over weeks to months with no residual deficits as seen in other studies.[26] Residual deficits, which ranged from mild to severe, were seen in 25% of the patients. Rituximab and azathioprine, used in a patient with NMO with recurrent history, helped in preventing recurrences as seen in other studies.[12]

Limitations of this study include retrospective design and exact outcome of the patients, i.e., the degree of impairment, amount of recovery, and time for recovery, is not elicited. However, this study shows that demyelinating disorders can occur even at a younger age, i.e., as early as 9 months and MS can occur in pediatric age group with encephalopathy as the presenting feature and they respond well to steroids.

Conclusion

Even though demyelinating disorders are rare in pediatric age group, one should be aware of this entity as early diagnosis and treatment with steroids improves outcome. Most common among them is ADEM. MS is not rare in pediatric age group, accounting for 9.4% in this study. MRI is more sensitive than CT in the diagnosis of demyelinating disorders. Mortality is rare in these groups of disorders.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.