Clinical and radiological spectrum of acquired inflammatory demyelinating diseases of the central nervous system in a tertiary care center

INTRODUCTION

Central demyelinating diseases are a group of heterogeneous conditions with autoimmune mechanism directed against central nervous system (CNS) myelin. The spectrum of primary inflammatory demyelinating disorders is broad including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), idiopathic optic neuritis (ON), acute disseminated encephalomyelitis (ADEM), myelin oligodendrocyte glycoprotein antibody disease (MOGAD), and clinically isolated syndrome (CIS). There has been an increase in the overall prevalence of demyelinating disorders in the past decade. Available data suggest a rise in the prevalence of MS to 2.8 million in 2020 from 2.3 million in 2013 worldwide.^[1] The non-white population has a higher prevalence of NMOSD compared to the white population.^[2] With the advent of reliable antibody assays like anti-aquaporin-4, the diagnosis of primary CNS demyelinating diseases has improved. Another significant development is the availability of live cell based assays for anti-MOG antibodies detection in the past decade enabling the reclassification of patients with myelitis and ON who were previously labeled as seronegative NMOSD.^[3] In India, the availability of magnetic resonance imaging (MRI) has become widespread in the past decade which has led to better diagnosis and management. However, there is still a dearth of data regarding primary CNS demyelinating disorders in India compared to its western counterparts. In particular, there are only a few studies that comprehensively include all the categories of primary CNS demyelinating disorders put together, as the majority of currently available studies have taken individual diagnostic category into consideration. It is important to understand the clinical spectrum and differentiate among various categories of CNS demyelinating diseases as their treatments can be different. In a resource limited country like ours, it is imperative to perform a proper clinical evaluation and neuroimaging to make decisions regarding further serological workup. Furthermore, in the seronegative cases, careful history, examination, and imaging guide the diagnosis, management, prognostication, and long-term immunomodulatory treatment strategies. The objective of this study was to determine the clinical presentation, cerebrospinal fluid (CSF) analysis findings, imaging findings, serology results, diagnosis, and treatment outcome of primary inflammatory demyelinating disorders of the CNS.

MATERIALS AND METHODS

RESULTS

DISCUSSION

In this study, we profiled patients with primary CNS demyelinating disease presenting to our tertiary care hospital into different diagnostic categories. NMOSD (n = 20) was found to be the most common group constituting about 45.5% followed by MS (n = 10) accounting for 22.7% of the cases. Manisha et al. in a single-center Indian study similarly reported preponderance of NMOSD over MS.^[4] This is also similar to data from other Asian counterparts, which showed a higher prevalence of NMOSD compared to the western population.^[2]

Overall, the mean age of presentation in our study was 30.5 ± 11.15, which is similar to results from other Indian and western population studies.^[4-6] Among all the groups, patients with ADEM showed a younger age of onset (22.33 ± 9.07), which might be due to the usual common occurrence of ADEM in children and younger adults compared to older adults.^[7] In our study, the NMOSD group showed younger (30.90 ± 11.74) mean age of onset compared to patients with MS (32 ± 11.30). A similar trend was seen in an Indian study by Manisha et al. and another multicenter cross-sectional South American study.^[4,6] However, Indian studies by Nayak et al. and Pandit and Kundapur showed a higher age of onset in the NMOSD group compared to MS.^[5,8] Likewise, other major hospital-based studies from Asia and worldwide prevalence studies also showed younger clinical disease onset in MS compared to NMOSD in contrast to our study.^[9-11]

Overall, female preponderance (n = 34, 77.3%) observed in our study is a usual finding for the primary CNS demyelinating disorders. The female preponderance in immune-mediated CNS inflammatory diseases is likely due to a complex interplay of factors like genetic, epigenetic effects, hormonal, and indirect modulation of microbiome.^[12] The female-to-male ratio in the NMOSD patient group was 4:1 which was in acceptance with the results from other Indian studies.^[13,14] All the ten MS patients in our study cohort were female (100%) which was very high compared to gender ratios seen in other MS epidemiology studies from India.^[15,16] Unlike other categories, there is a slight male preponderance (57%) in the MOGAD group. Data from multicenter studies by Jarius et al. and Ramanathan et al. showed slight female preponderance in MOGAD patients.^[17,18] However, the appropriate conclusion could not be drawn regarding the male majority in our MOGAD group, keeping in mind the small number (n = 7) of patients in this group.

In our study, an infectious prodrome was reported in 11 (25%) patients. Compared to other categories, a significant proportion of patients with MOGAD (n = 5, 71.4%) had a preceding infection. Several other studies also showed a similar higher occurrence of infection preceding the demyelinating episode in MOGAD patients ranging from 30–70% compared to 15–30% in NMOSD patients.^[19-21] The underlying mechanism is the infectious prodrome leading to the stimulation of autoimmune pathology by molecular mimicry, bystander activation, and epitope spreading.^[22] In MOGAD, there is also an additional activation of Toll-like receptor by viruses, converting the MOG-specific B-cells into plasmablasts that secrete MOG antibodies.^[23]

Overall, the most common presentation was myelitis (52.3%) followed by ON (45.5%) similar to results from other studies.^[4,5] In both males and females, the most common presentations were ON and myelitis. Many of the patients were polysymptomatic especially ON and myelitis together seen in 9 (20.5%). Among the nine patients with such opticospinal syndrome, the majority (n = 7) belonged to the NMOSD group.

In the NMOSD group, myelitis was seen in 16 (80%) patients, ON in 11 (55%) patients, and both together in 7 (35%) patients. These results were very much similar to another Indian hospital-based cohort.^[24] One of the NMOSD patients, who presented with altered sensorium, was a known Aquaporin 4 positive NMOSD patient with three relapses in the past, and she was on rituximab therapy. She had a history of gradually worsening cognitive disturbances over a period of two years, and this patient ultimately did not survive after being bedridden for two months. Her MRI brain showed progressive (compared to previous images) cortical and subcortical atrophy of the cerebral cortex predominantly involving temporal lobes. She was extensively evaluated for other treatable causes of dementia including screening for malignancies, autoimmune encephalitis profile, CNS, and systemic infections which all came out negative. Cognitive impairment in NMOSD is not as well described as in MS. The unique dynamics shown by AQP4-IgG may cause significant diffuse cortical neuronal loss resulting in neurodegeneration independent of clinical attacks.^[25] Disruption of glutamate and water homeostasis lead to excitotoxicity with subsequent release of several neurotoxic factors triggering neurodegeneration. According to a meta-analysis done by Meng et al., NMOSD patients performed significantly poorly on various cognitive tests.^[26]

Out of the 20 patients who met the criteria for NMOSD, 15 (75%) patients showed aquaporin 4 seropositivity only 5 (25%) were double seronegative. This detection rate was higher compared to other Indian studies probably due to the increased awareness and widespread availability of aquaporin 4 and MOG antibody assays.^[27] Comparatively, aquaporin 4 positive patients showed higher female preponderance and more disability than seronegative patients, which is in acceptance with observations from studies by Pandit et al. and Kunadison et al.^[28,29]

Most of the MS patients (80%) were of relapsing remitting MS type similar to other Indian studies.^[30] None of the MS patients had features of myelitis at present, although they showed evidence of spinal cord involvement on imaging. In the MS group, 90% of the patients showed cerebral white matter lesions, and in a few of these patients, coexistent MS typical spinal cord lesions helped in differentiating from other radiological mimics of MS-like stroke.^[31] The majority of NMOSD patients have been suspected to show longitudinally extensive spinal cord involvement on MRI, particularly cervicodorsal cord with rostral extension into the medulla. In three cases, this rostral extension characteristic of NMOSD was helpful in differentiating from other causes of longitudinally extensive myelitis.^[32] The majority (85.7%) of patients with MOGAD showed spinal cord involvement on MRI but unlike the previous studies which showed prominent thoracolumbar and conus medullaris involvement; our patients showed predominant cervicodorsal cord involvement.^[33,34]

CONCLUSION

In this article, we have given an overview on CNS inflammatory demyelinating diseases in Southern India, particularly for MS and NMOSD. The NMOSDs are a common cause of demyelinating illnesses in this region like other Asian counterparts but with a younger age of onset compared to MS, unlike other previous studies. Seropositive NMOSD patients showed higher disability compared to aquaporin-negative patients warranting the need to treat these patients with a more aggressive approach even during the first attack. A higher proportion of MOGAD patients having preceding viral infection helps in identifying such patients to undergo MOG antibody testing. Most of the patients in our cohort showed good outcome, and this is likely due to the ready availability of serological assays and also the treatment with aggressive immunomodulation from the beginning. Further studies with long-term follow-up would help contrast and compare outcomes.