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Table of Contents
ORIGINAL ARTICLE
Year : 2015  |  Volume : 18  |  Issue : 5  |  Page : 48-55
 

Acquired demyelinating disorders of central nervous system: A pediatric cohort


1 Department of Pediatrics, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi, India
2 Department of Radio-Diagnosis, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi, India

Date of Submission06-Oct-2014
Date of Decision19-Nov-2014
Date of Acceptance18-Feb-2015
Date of Web Publication11-Sep-2015

Correspondence Address:
Sheffali Gulati
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-2327.164829

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   Abstract 

Objective : This is a retrospective chart review of consecutive children with acquired demyelinating disorders presenting to a north Indian tertiary care hospital over 4 years. The aim of this review is to describe all the patients (with single event as well as those with recurrences) with detailed description of those who recurred. Materials and Methods: Overall 35 cases were reviewed and their clinical presentations, diagnosis, management, and follow-up are being presented. Results : Out of 35 cases, 24 did not show any recurrences (seven acute disseminated encephalomyelitis (ADEM) and 17 clinically isolated syndromes). Amongst the 11 patients with recurrent demyelination, majority were multiple sclerosis (8/11, 72.7%) followed by neuromyelitis optica (NMO; 2/11), and multiphasic ADEM (1/11). The median disease duration and follow-up since onset for those with recurrent episodes is 4 years (2.5-4.5 years). Steroids caused significant improvement in acute episodes of demyelination. However, recurrent demyelinating disorders like multiple sclerosis and NMO required long-term immunomodulation. Azathioprine currently is the most favored long-term immunomodulator used in NMO. Interferon-β and glatiramer acetate are currently recommended for multiple sclerosis. However, azathioprine may be a suitable alternative in a resource-limited setting. Conclusion : The consensus definitions for these groups of disorders need further validation in the pediatric age group. Studies with larger population size are required to characterize features that predict future recurrences.


Keywords: Acquired demyelination, azathioprine, central nervous system, multiple sclerosis, neuromyelitis optica


How to cite this article:
Gulati S, Chakrabarty B, Kumar A, Jain P, Patel H, Saini L. Acquired demyelinating disorders of central nervous system: A pediatric cohort. Ann Indian Acad Neurol 2015;18, Suppl S1:48-55

How to cite this URL:
Gulati S, Chakrabarty B, Kumar A, Jain P, Patel H, Saini L. Acquired demyelinating disorders of central nervous system: A pediatric cohort. Ann Indian Acad Neurol [serial online] 2015 [cited 2019 Oct 22];18, Suppl S1:48-55. Available from: http://www.annalsofian.org/text.asp?2015/18/5/48/164829



   Introduction Top


Inflammatory demyelinating diseases of the central nervous system comprise of monofocal or polyfocal, monophasic, multiphasic, or progressive group of disorders of autoimmune origin. These include Acute Disseminated Encephalomyelitis (ADEM), Multiple Sclerosis (MS), Clinically Isolated Syndrome (CIS) and Neuromyelitis Optica (NMO). [1],[2] Although these disorders are associated with significant morbidity, early diagnosis results in improved functional and neurological outcome. [3]

The definitions for pediatric demyelinating disorders are evolving. [4],[5] Individual attacks are managed acutely by immunotherapy (primarily parenteral steroids followed by short course of oral steroids). However, disease modifying therapies in the form of long-term immunomodulators and steroid sparing agents are required for recurring entities, viz., MS and NMO. [6],[7] Timely diagnosis and institution of appropriate therapy determines prognosis and outcome. [8]

One aspect of these groups of disorders that have always intrigued researchers is predicting the recurrence risk after the first attack. Interestingly, patients can be labeled as MS or NMO even after the first clinical attack [Table 1] and [Table 2]; current consensus guidelines for diagnosis of MS and NMO, respectively]. [4],[5] It is crucial to pick up these cases early for institution of disease modifying therapy. However, clinical and radiological criteria are still evolving for the pediatric age group. [9]
Table 1: Current consensus diagnostic criteria for multiple sclerosis (based on 2010 McDonald criteria)

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Table 2: Current consensus diagnostic criteria for pediatric neuromyelitis optica

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This is a retrospective chart review of pediatric patients with central nervous system demyelinating disorders.


   Materials and Methods Top


This is a retrospective chart review of pediatric case records of demyelinating events presenting to a tertiary care teaching center in north India. Overall 35 cases of acquired, acute onset, first episode of central nervous system demyelination presented over a 4-year period (July 2009-April 2013), out of which 11 patients showed recurrence. The final diagnoses of the subtype of demyelination in 35 cases were established in concordance with the definition proposed by International MS Study Group and revised McDonald criteria.

All the cases after they presented to the current center were subjected to magnetic resonance imaging (MRI) brain, orbit and spine with contrast, brainstem-evoked response audiometry, and visually-evoked response evaluation in the presenting as well as recurrent episodes. In the 11 recurrent cases, two patients presented to the current center in their first episodes. Cerebrospinal fluid (CSF) oligoclonal bands (OCBs) were assayed (isoelectric focusing using gel electrophoresis) in all patients when they presented with a recurrent episode and also in first episodes with clinically isolated syndromes (other than acute transverse myelitis (ATM)). Serum anti-NMO antibodies (enzyme-linked immunosorbent assay) were done if patients presented with isolated transverse myelitis or optic neuritis or both or in ADEM-like presentation with MRI brain lesions characteristic of NMO. The cases with isolated transverse myelitis or optic neuritis were also subjected to antibody testing as the current consensus guideline for diagnosing pediatric NMO does not mention longitudinally extensive transverse myelitis (LETM) as an obligatory criteria. [5] Moreover in NMO, optic neuritis and transverse myelitis can occur in isolation and follow each other sequentially even after years. Cases which were being followed-up prior to availability of serum anti-NMO antibody assay in the current center, were subjected to it (after it was available) only if they had any recurrence in a relevant clinicoradiological scenario. Demyelinating events which happen as a part of infection rather than parainfectious etiology were not ruled out. This was because most of the events presented clinically in a classical parainfectious manner; and moreover, appropriate microbial tests to rule out infections were not available in the current setup.

In appropriate clinicoradiological scenarios, neurometabolic (arterial and CSF lactate, arterial pH, blood sugar, serum ammonia, blood tandem mass spectrometry, urine gas chromatography mass spectrophotometry, serum ceruloplasmin, and 24-h urinary copper) and autoimmune work up (antinuclear antibody, antithyroid antibodies, and antineutrophilic cytoplasmic antibodies) were done.


   Results Top


All cases presented till December 2010 were classified according to the consensus definition proposed by International MS Study Group, from January 2011, the 2010 revised McDonald criteria was used. Subsequently, all cases were reclassified using the 2010 revised McDonald criteria.

Out of 35 cases, 24 did not show any recurrences (seven ADEM and 17 CIS (isolated ATM, eight; optic neuritis with myelitis, three; isolated optic neuritis, two; basal ganglia syndrome, two; and hemispheric syndrome, two)). The median age at initial presentation for those who did not have recurrent events (n = 24) was 7 years (range: 1-12 years).

Amongst the 11 patients with recurrent demyelination, majority were multiple sclerosis (8/11, 72.7%) followed by NMO (2/11, both seropositive) and multiphasic ADEM (1/11). The median age at initial presentation for those with recurrences (n = 11) was 5 years (range: 3-12 years). The clinical, salient laboratory, and radiological investigations of all patients with recurrent demyelination have been detailed in [Table 3] and [Table 4].
Table 3: Clinical and laboratory features of recurrent demyelinating cases with final diagnosis

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Table 4: Radiological features of recurrent demyelinating cases

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All patients with multiple sclerosis fulfilled the revised McDonald diagnostic criteria. The median time interval between first and second episodes in MS patients was12 months (4-36 months). Overall 23 events of demyelination were noted in eight patients with MS, out of which only three (13%) were polyfocal, rest being monofocal (20/23,86.9%). Of the 20 monofocal MS events, predominant clinical manifestations were hemispheric syndrome in six (30%) followed by encephalopathy (5,25%) and visual symptoms in four (20%). Hemispheric syndrome with pancerebellar features was present in two polyfocal events, the other event being a paraparesis with visual manifestations.

Of the patients with an isolated episode of optic neuritis and/or myelitis who presented after the availability of anti-NMO antibody assay in the current center, only one showed antibody positivity. Of the two patients with anti-NMO antibody positivity in the recurrent group, one (patient 7) fulfilled the current consensus diagnostic criteria. The other patient (patient 2) had three episodes of encephalopathy with subclinical cervical myelopathy without any evidence of visual involvement.

Only one patient had multiphasic ADEM who presented with recurrent episodes of encephalopathy.

All the patients who presented with visual complaints had impaired visually-evoked responses; subclinical responses were present in none. None of the patients had abnormal brainstem-evoked audiometric responses. Routine CSF microscopy and biochemistry were normal in all; however, positive OCBs were seen in four patients (patient 4, 5, 8, and 11) [Table 3] with multiple sclerosis.

None of the patients had abnormality in neurometabolic or autoimmune work up in relevant clinicoradiological scenarios.

In those patients with single demyelination events, radiologically ADEM cases showed predominantly asymmetric involvement of deep and subcortical white matter with occasional involvement of deep grey matter, brainstem, and spinal cord. Patients with isolated ATM-like presentation had patchy involvement mainly of cervical and dorsal cord. Other patients of CIS had radiological picture corresponding to their clinical presentation.

The radiological features of recurrent demyelinating disorders are elaborated in [Table 4]. In multiple sclerosis, lesions were present predominantly in juxtacortical and periventricular locations [Figure 1] followed by infratentorial (brainstem and cerebellum) sites and spinal cord. In anti-NMO antibody positive patients, lesions were present in cervical cord and deep and subcortical white and grey matter with optic nerve involvement seen in only one of the three patients. The classical LETM described in NMO was seen in the patient (anti-NMO antibody positive) with an isolated event of myelitis [Figure 2].
Figure 1: Axial MRI brain show a focal lesion in left occipital lobe which is hypointense on T1W (a) and hyperintense on T2W (b) images. Axial FLAIR image (c) at a higher level shows multiple other bilateral lesions in white matter, some of which are oriented perpendicular to the lateral ventricle (arrow). T2W sagittal image (d) shows the involvement of anterior part of the corpus callosum (arrow). MRI = Magnetic resonance imaging, FLAIR = Fluid-attenuated inversion recovery, T1W = T1-weighted, T2W = T2-weighted

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Figure 2: Sagittal MRI whole spine in an 8-year-old child showing hyperintense signal on T2 in the spinal cord extending from C2 vertebral level till the conus with patchy areas of contrast enhancement consistent with transverse myelitis

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Thalamic and basal ganglia lesions were present in both MS and NMO patients.

The multiphasic ADEM patient had lesions spread over deep and subcortical white matter, thalamus, dorsal cord, and brainstem.

Individual episodes were treated with intravenous pulse methylprednisolone therapy followed by oral steroids for 2-3 weeks. Those with active infection were given intravenous immunoglobulin instead of steroids. In all patients with isolated single episode of demyelination, except for three patients with ATM, complete clinicoradiolgical recovery was observed. The three ATM patients showed radiological evidence of myelomalacia with clinical evidence of paraparesis as sequelae. One patient, who tested positive for serum anti-NMO antibody in the first event with ATM, has been started on oral azathioprine (2 mg/kg/day) without any recurrence for 1 year.

All patients with NMO and MS are being continued on azathioprine in a dosage of 2-3 mg/kg/day without any side effects. Except for two patients (patient 7 with NMO and 11 with MS) none of them have had a radiological or clinical recurrence after starting azathioprine, although sequelae are present in 50% patients (5/10). The patient with multiphasic ADEM is in remission and not on any long term immunomodulation. The median disease duration and follow-up since onset for those with recurrent episodes is 4 years (2.5-4.5years).


   Discussion Top


The current cohort describes clinical and diagnostic features, treatment, and follow-up in children with demyelinating disorders with emphasis on those with recurrences. In the first event it may be difficult to identify the ones that are going to recur, but every effort should be made to identify the ones that are at risk of recurrence. The pediatric clinicoradiological characteristics of NMO and MS are different from adults to some extent. The adult characteristics are better validated and more studies are required to delineate the pediatric features. [10],[11]

Clinically, the predominant presentation in MS is polyfocal in children compared to monofocal in adolescents and adults. [12] Interestingly in the current cohort, the predominant presentation was monofocal, although the median age at onset was 5 years. The most frequent monofocal presentations reported in pediatric MS are motor and brainstem dysfunction followed by sensory features and ataxia. [13],[14] In the current cohort although motor manifestations were the predominant finding, the next common presentation was encephalopathy. An ADEM-like presentation has been described in pediatric MS patients to the tune of 2-18%. [5],[9],[15-17] Thus, this cohort reinforces the fact that an ADEM-like presentation does not preclude a diagnosis of MS. Moreover, it seems that the concept of waiting for two non-ADEM events to occur for labeling MS and starting long-term immunomodulation [18] needs reevaluation and modification, particularly in the pediatric age group. The fact that the predominant pattern of pediatric MS is relapsing remitting and is supported by the current cohort. [9],[19] The two recurrent NMO cases also had atypical clinical presentations. One presented with three ADEM-like events; whereas, the other one presented with monoparesis and impaired vision. Upto 16% pediatric NMO patients present with isolated cerebral syndrome; whereas in adults, brain lesions are mostly asymptomatic. [18]

CSF OCB positivity is not mandatory for the diagnosis of MS. Moreover, they can be negative initially in the course of illness. However, they are useful in scenarios like primary progressive MS and in unusual clinical situations (ADEM-like presentations) as exemplified in the current cohort by patient 8 and 11, respectively. [4],[6] Similarly in NMO, the pediatric consensus diagnostic criteria does not have serum anti-NMO positivity as an essential feature. [20] Upto 78% children with NMO demonstrate anti-NMO seropositivity. [21] In the current cohort, patient 6 although clinically fits into an NMO-like picture, was seronegative and has been labeled as opticospinal MS. [22] However, those patients who have presented with isolated episode of optic neuritis and/or myelitis (including long segment), not all have been tested for anti-NMO antibody positivity, as the test has been made available in the current center only in recent past. Evidence shows that anti-NMO antibody positivity is to the tune of 40-50% in patients with LETM. It is negligible in patients with smaller lesions. Moreover in patients with seropositive LETM, recurrence in terms of myelitis or neuritis is around 50%. [23],[24]

Another immunological assay of interest is myelin oligodendrocyte glycoprotein (MOG). It is particularly useful in pediatric ADEM and MS. However in recent times, it has also been found to be positive in seronegative NMO. In the current cohort, none of the cases were subjected to this assay because of nonavailability. The therapeutic implications of this assay is that seropositive patients are more likely to benefit from plasmapheresis and/or B-cell directed therapy. [25],[26]

Clinicoradiologically, all patients with MS in the current cohort fulfilled the criteria of dissemination of space and time according to the revised McDonald criteria. [4] Multifocal extensive bilateral diffuse white matter involvement has been classically described in ADEM and it is usually one of its differentiating features from MS. Rarely this has been described in pediatric MS and has been documented in patient 6 in the current cohort [Figure 3]. [27] However, one has to keep a very high index of suspicion in view of close radiological mimickers like leukodystrophies and mitochondrial disorders. Patient 2 with NMO who presented with recurrent cerebral syndrome, radiologically demonstrated predominant periventricular and subcortical white matter involvement [Figure 4], which is in concordance with existing literature. This is because these regions are densely populated with aquaporin-4 channels. [18],[28] Interestingly, patient 7 with NMO showed callososeptal interface signal changes [Figure 5] which are characteristic of MS. [11]
Figure 3: T2-weighted axial MRIbrain at multiple levels showing multifocal bilateral hyperintense lesions involving bilateral brachium pontis (arrows in a), left cerebral peduncle (arrow in b), corpus callosum (long arrow in c), left internal capsule (short arrow in c), and deep periventricular white matter (arrows in d)

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Figure 4: Axial FLAIR MRI brain showing bilateral asymmetrical multiple hyperintense focal lesions involving right brachium pontis (a), basal ganglia (b), corpus callosum, and subcortical and deep white matter(c)

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Figure 5: MRI showing bilateral multiple focal hypointense lesions on T1W axial (a) and bilateral multiple focal hyperintense lesions on T2W axial (b) and sagittal (c) involving centrum semiovale with predominant periventricular distribution. The perpendicular orientation of few lesions to the ventricles (arrows in b) represents the 'periventricular perpendicularly oriented lesions(PVPOLs)'. Note the characteristic involvement of the callososeptal interface (arrow in c)

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Researchers have tried to predict future risk of MS on the basis of features of the first demyelinating event. Before the international consensus definitions were developed, in a large prospective study with 296 French children, age more than 10 years and optic neuritis were predictive of increased risk of relapse, whereas encephalopathy and myelitis were associated with low risk of further attacks. [14] Dale et al., in their review mentioned that patients with a CIS presentation (except ATM) in their first episode are more likely to have recurrent episodes. [6] Recently, Banwell et al., prospectively followed 302 Canadian children and proposed that in the presence of T2 lesions on MRI brain, age >11.85 years, and absence of encephalopathy predict a higher risk of developing MS later in life. [15]

In the current cohort, the median age was lower for those with recurrent episodes as compared to those with single episode. However, there was a definite trend showing that an initial isolated ATM-like event was unlikely to recur. The factors in first episode of demyelination which has been stated to favor recurrence and their distribution in the current cohort have been enumerated in [Table 5].
Table 5: Distribution of factors favoring recurrence in the first episode of demyelination in those with recurrent episodes in the current cohort

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Radiologically, presence of periventricular perpendicular ovoid lesions (PVPOLs) in an initial demyelinating event should be considered strongly for future development of MS even in the presence of encephalopathy. [29] In the current cohort, these were seen in patient 10 with MS in one of the recurring episodes [Figure 1]. Interestingly, patient 7 who was finally diagnosed as seropositive NMO had PVPOLs in first episode of demyelination. Tumefactive lesions which are classically seen with ADEM [10] have been demonstrated in the current cohort in a primary progressive OCB positive MS patient (patient 11) [Figure 6].
Figure 6: Axial T1W (a), FLAIR (b), and post-contrast T1W (c) images showing bilateral large tumefactive lesions appearing hypointense on T1, hyperintense on FLAIR, and peripheral rim enhancement on post gad images. Follow-up MRI axial T2W image (d) done 1 year later shows marked regression in the size of the lesions

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Azathioprine is one of the commonly used long-term immunomodulators in patients with NMO [11] which also has been followed for current cohort with encouraging results. Current recommendation for treating pediatric MS suggests glatiramer acetate and interferon-β as the first-line drugs. Second line includes immunomodulators like azathioprine. [30],[31] The current status of azathioprine in MS is one of a promising disease modifying agent with favorable risk-benefit ratio, which should be evaluated in randomized trials with interferon, as inferred by the Cochrane systematic review group. [31] In a developing country like ours, factors like cost of the drugs, transportation expenses for coming to the hospital, and awareness for the requirement of repeated parenteral therapy are significant barriers for treatment of chronic conditions like MS. In the current cohort, all patients of MS have been started on azathioprine only. Except one, none of the patients had a clinical or radiological recurrence after starting azathioprine and the sequelae of previous episodes were improving in all. In view of the logistic reasons described above, none of them had been started on glatiramer acetate and interferon-β.

The current study has certain limitations, viz., retrospective design and limited sample size. However, it still highlights certain important aspects of these disorders. Strong clinical suspicion along with radiological support can help diagnose pediatric central nervous system demyelinating disorders. Currently proposed diagnostic criteria require validation in pediatric population. Factors that predict recurrence in the adult population may not be extrapolated to the pediatric population (particularly in < 10 years age), further studies are required in larger population size. Steroids have a well-established role in the management of an acute demyelinating event. Immunomodulators like interferons and glatiramer acetate are usually recommended for long-term management of MS to prevent relapses. However, in a resource-limited setting, drugs like azathioprine may be useful.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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