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Natural history of multiple sclerosis from the Indian perspective: Experience from a tertiary care hospital
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.170079
Context: Multiple sclerosis (MS) has a spectrum of heterogeneity, as seen in western and eastern hemispheres, in the clinical features, topography of involvement and differences in natural history. Keywords: Evoked potential; multiple sclerosis; neuromyelitis optica; oligoclonal band; optico-spinal multiple sclerosis
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, with a wide spectrum of clinical presentation. The long-term disability depends on the delicate balance between demyelination, remyelination, and axonal loss. The severity and natural history of MS depends on the disease course, impact of individual events and accumulating long-term disability. There is a considerable heterogeneity of the clinical spectrum, topography and natural history of MS observed in the western and eastern hemispheres. A recent study suggested that the prevalence rate of MS in India has increased consequent to the availability of modern investigative facilities and increased awareness.[1] The presentation of MS in patients in India as well as Asia is a little different from that seen in their western counterparts. They have greater optic nerve and spinal cord involvement.[1],[2],[3],[4],[5],[6] Various studies on MS from India have reported a higher incidence of visual dysfunction at the onset of the disease, recurrent acute transverse myelitis, more of optico-spinal involvement with greater functional disability, and less frequent involvement of the cerebellum. However, there is a paucity of reports regarding the natural history of MS from India. The objectives of this study were to assess the impact of clinical spectrum, imaging findings, electrophysiological evaluation, cerebrospinal fluid (CSF) characteristics as well as the influence of various prognostic factors on the long term outcome of the disease.
Patients with multiple sclerosis, selected during the period from January 1, 1993 to February 29, 2013 (a 20 year period), who were managed in the Department of Neurology, Christian Medical College, Vellore, India were included in this study. This study was a retrospective, clinical investigator driven one and has been approved by the institutional review board and ethics committee (No: 7521 dated July 5, 2011). The antecedent events, clinical symptoms and signs, magnetic resonance imaging (MRI) studies, evoked potentials, CSF patterns, treatment details, and the response to treatment and follow-up were entered into a detailed proforma. Information was obtained from the outpatient case records, discharge summaries and follow-up records. Steps were taken to obtain consent and to maintain confidentiality. The Kurtzke Expanded Disability Status Scale (EDSS) was recorded for every patient at presentation and at each follow-up.[7] Gadolinium – enhanced MRI of the brain and spine was done at the first visit and on subsequent visits, as required. Inclusion criteria
Exclusion criteria
Statistical analysis We performed descriptive analyses using the Chi-square and Fisher's exact tests for categorical variables. Statistical significance was taken to be at the two-tailed 0.05 level. Multiple binary logistic regression analysis was carried out to assess for significance. Kaplan–Meier curves were drawn to estimate the time to irreversible disability (EDSS ≥ 6). Log-rank test was used to compare the survival curves. All statistical analyses were performed by SPSS (Statistical Package for the Social Science) version 16.0 (SPSS Inc., Chicago, Illinois, USA) with the help from the Department of Biostatistics.
Demography In our study, 146 (93%) patients were adults and 11 (7%) were children below the age of 16 years. In this cohort, 71 (45.2%) were male and 86 (54.8%) were female patients. The female: male ratio was 1.21:1. There was no statistically significant predilection of a particular MS type amongst the two genders. The mean age was 29.38 ± 10.09 (range 8–58) years at the time of initial diagnosis of MS. The maximum number of patients {77, 49%} were in the 16–33 year age-group. At the last available follow-up, the mean age was 38.57 ± 11.7(range 15–70) years. There were a total of 157 patients who were evaluated during this period and follow-up details were available for 114 (72.6%) patients. The observed MS types were relapsing remitting (RR; 85, 54.1%), primary progressive (PP; 24, 5.3%), secondary progressive (SP; 47, 29.9%) and progressive relapsing (PR; 1, 0.6%). Fifty-nine (37.6%) patients had the presentation of opticospinal MS (OSMS) syndrome and the rest of the 98 (62.4%) patients had a non-OSMS (NOSMS) syndrome. NMO IgG (neuromyelitis optica immunoglobulin) was not routinely checked in the OS form of MS. There was no statistical difference between the ages, gender, and years of follow-up among the groups. For outcome analysis, the patients were divided into two groups based on the final follow-up EDSS. These included patients with a scale of ≥6 and those with a scale of <6 on the basis of requirement of support for ambulation [Figure 1].
Presentations The initial presentations were motor weakness (45.8%, paraparesis being the most common), followed by brainstem/cerebellar (32.5%) and visual (26.7%) dysfunction. The asymmetrical onset bilateral visual loss was seen in 6 patients [Table 1].
Monosymptomatic presentation was more common in the OSMS than in the NOSMS group [51 (86.4%) versus 56 (57.1%) (P ≤ 0.01)]. RRMS was more common in the OSMS group (P ≤ 0.01). Hemispheric, cerebellar and ophthalmoplegic presentations were more common in the NOSMS group, while myelopathy and optic neuropathy were more common in the OSMS group [Table 2].
Multimodal evoked potentials Visual evoked potentials (VEP), tibial somatosensory evoked potentials (SSEP) as well as median SSEP and brainstem auditory evoked response (BAER) were conducted in all the patients. VEP test had unilateral and bilateral (U/L and B/L) abnormalities in 30/157 (19.1%) and 91/157 (57.9%) patients, respectively. 101/157 (64.3%), 83/157 (52.8%) and 63/157 (40.1%) patients had tibial SSEP, median SSEP, and BAER abnormalities, respectively. Cerebrospinal fluid studies Cerebrospinal fluid (CSF) cell and protein values were within normal range in 87/157 (55.4%) patients. The oligoclonal band (OCB) was found to be positive in 57/157 (36.3%) patients. In the OSMS and NOSMS groups, the OCB was positive in 33.8% (20/59) and 37.7% (37/98) patients, respectively, and there was no statistical difference between the groups. Magnetic resonance imaging studies Magnetic resonance imaging of the brain showed abnormalities in all the patients. 85.3% of them had spinal cord abnormalities. In 140 (89.2%) patients, >15 lesions were found [Table 3].
Treatment received During the acute attack of MS, all the patients received pulse injections of methylprednisolone. The most common immunomodulatory agents used were mycophenolate (44.1%), followed by azathioprine (29.4%), and interferon β (8.3%). Course of the disease During the course of the disease, 16 (14%) had one episode, 23 (20.2%) had two episodes, 41 (36%) had three episodes and 20 (17.5%) had four episodes of the clinical attack. The mean number of episodes was 3 ± 1.36 (range 1–9) in our study. The second episode occurred 1.62 ± 1.51 (0.1–12) years after the first one. The recovery was complete in 109 (69.4%) patients after the first episode. Outcome analysis The patients presented to us after a mean duration of 0.8 ± 0.59 (range 0.1–1.3) years following the first episode. At presentation, the mean EDSS of the patients was 4.4 ± 1.31 (range 1–8). The median inter quartile range (IQR) of the duration of follow-up for 114 patients was 9.1 (8.2, 11) years. During the last follow-up, the mean EDSS was 4.1 ± 2.31 (range 0–10). One patient died following an accident and was not included in the final outcome analysis. One patient's death due to respiratory failure was attributable to the significant cervico-medullary lesion. The difference in outcome in OSMS and NOSMS was not statistically significant (P = 0.282). The model was designed to assess the prognostic factors responsible for a better outcome indicated by an EDSS <6 (not requiring support during ambulation) at the final visit [Table 4].
The relapsing-remitting form of MS had a significantly better outcome (odds ratio: 0.12, 95% confidence interval [CI]: 0.02–0.57, P = 0.008) compared to the progressive form of MS (PP, SP) after adjusting for other variables like recovery after the first episode, poly/monosymptomatic presentation, bladder symptoms and the initial EDSS at presentation [Figure 2]. Other risk factors were statistically significant in the univariate analysis but lose significance in the multivariate analysis. The odd's ratio and the 95% confidence intervals signified their prognostic role. Complete recovery after the first episode [Figure 3] was associated with a better outcome. The worst outcome on a long term basis was observed in patients with a poly-symptomatic presentation [Figure 4] and those with bladder symptoms [Figure 5]. EDSS at the first visit had a significant prognostic role [Figure 6]. The CSF analysis and evoked potentials had no role in predicting the outcome of the disease.
According to the Hosmer and Lameshow test for goodness of fit, the P value was 0.843. Evaluating the receiver operating characteristic curve, the area under the curve was 0.884 with P < 0.01 (0.79–0.973). The model building of multiple logistic regressions was done by using the stepwise method.
Over the last one decade, Indian hospital-based studies have shown that the total proportion of MS-related admissions have increased from 1.58% to 2.54%.[4] Our study depicts the admission rate of patients with MS as being 1.02% of the total admission during this period. Geographically, South India (below 15° N latitude) has 3.2 new cases of MS per year compared to 4.15 from North West India (above 15° N latitude).[10] Historically, the diagnosis of MS was based on clinical and electrophysiological findings as well as the CSF analysis but in the modern times, neuroimaging plays the maximum role in diagnosing the entity. In the present study, the age of onset was 29.38 (±10.09) years which is comparable to other Indian studies,[1],[2],[3],[4],[5],[6] the youngest and the oldest cases reported in the present study being 8 and 58 year old, respectively. The mean age in the PPMS group was 33.38 ± 8.18 years, which was higher compared to the other groups. This age difference has also been recognized in other studies.[11] Eleven (7%) patients were children below the age of 16 years at the time of inclusion in the study, which is in accordance with the previous studies.[12],[13] The female-to-male ratio was 1.21:1, which is in agreement with the other studies reported from India.[3],[4] Some of the previous Indian studies also reported a higher male ratio.[2],[5] Increase in literary status as well as increasing awareness of medical illnesses in India has been responsible for the detection of more female patients with MS. The annual relapse rate for RRMS was 0.35/year, which is comparable to the results found in the previous studies.[14],[15] In this study, motor weakness was the commonest initial presentation (45.8%), followed by visual impairment (26.7%) and sensory paresthesia (24.2%). These features correlate well with other studies from India [5],[16] and also the western literature.[17] Some Indian and Japanese studies have reported visual symptoms to be the predominant presenting complaints.[3],[18],[19] These demographic and clinical features correlate well with other studies from India [Table 5].
Indian MS has many similarities to the Western variety,[5],[20],[21] but an increased frequency of visual involvement is a common feature in the Asian variety.[3],[18] These subtle but important differences between different geographical regions within the same country and in different part of the world suggest that environmental and genetic factors play a crucial role in the varied symptomatology of MS. Our study showed that pyramidal (86.6%), sensory (68.2%) and bowel and bladder (66.2%) involvement predominate during the course of illness whereas optic nerve involvement was seen in 58.6% cases. A major difference in the Caucasian and Oriental series has been in the incidence of cerebellar involvement, which was found in over 80% of the former patients [22] and in only 30–58% of the latter patients.[2],[5],[6] In the present study, cerebellar involvement was seen in 36.9% of patients. Seizures are an uncommon presentation of MS and were noted in nine patients in our series (5.7%) and internuclear ophthalmoplegia was seen in nine of our patients (5.7%); this is in accordance with the findings of the series by Gangopadhyay et al., where seizures were present in 2.3–5% patients, and internuclear ophthalmolegia was observed in 6.66% patients.[3] The cerebrospinal fluid analysis showed the cells and protein being in the normal range in 55.4% (87/157) patients. In our series, OCB positivity was observed in 36.3% of patients and there was no statistically difference among the OSMS and NOSMS groups. OCBs were found in a higher number of cases (90%) in Caucasian patients [23] whereas in Asian studies, its incidence has been found to be between 33–45%.[24] It has been suggested that the finding of OCBs has a close association with the presence of HLA-DR2.[24] It may, therefore, be postulated that the absence of HLA-DR2 association in Indian patients is similar to that seen in other Asian series. The paucity of family history in our series also reflects the different disease triggering and genetic factors in our population compared to the Caucasian patients. Multimodal evoked potentials were performed to detect the subclinical sites of demyelination. In our series, VEP showed bilateral abnormality in 59.3% and unilateral abnormality in 18.6% patients. The results of this evoked potential analysis were similar to that seen in the previous studies.[25] The result of evoked potential studies were not predictive of a worse outcome. A high frequency of MRI abnormalities detected in the present series was because of the strict adherence to the recent McDonald's criteria.[8] The lesion load had no significant correlation with the eventual outcome. Previous studies have shown that brain atrophy had a stronger association with physical disability than the T1 hypointense (black hole) and T2 hyperintense lesion load.[26],[27] Gadolinium enhancing lesions were noted in 48 (30.6%) patients but did not predict a worse outcome. A meta-analysis has shown that the gadolinium-enhancing lesions may predict the occurrence of relapses of the disease; however, it is not a strong predictor of the development of disability or cumulative impairment.[28] The presence of cerebellar and basal ganglia lesions was associated with a worse outcome in our study. Optico-spinal presentation was observed in 37.6% (59/157) patients in our series. This is in concordance with the published literature on the high frequency of optico-spinal involvement in several Japanese [29] and Indian [18] studies. OSMS, with attacks restricted clinically to the optic nerve and spinal cord, was seen in 20–60% of cases reported from Japan.[30] The clinical attacks confined to the spinal cord and the optic nerve were seen in 47% of the MS cases in the series reported by Pandit and Shetty.[31] There is also a high prevalence of NMO in India, as suggested by Jain and Maheshwari.[10] The progression of the disease was dependent on the symptom characteristics at the onset of the disease and its severity. Patients with an acute onset of the disease and complete recovery from the first attack were significantly associated with a favorable long-term prognosis. In our study, the patients with polysymptomatic presentation with motor as well as sphincteric involvement at the onset had a poorer outcome. This natural history of the disease was comparable to other studies.[32] The relapse rate in our study was 3 ± 0.36, which did not correlate with the outcome, as has already been demonstrated in an earlier study.[33] In our study, the EDSS of patients at presentation was 4.4 ± 1.31; and, at final follow-up (with IQR) of 9.1 (8.2, 11) years was 4.1 ± 2.31. The EDSS at presentation had a significant prognostic role on a long-term basis. The median EDSS score was 2.1 in Iran at 5.5 years;[11] and, 3.7 in the series by Gangopadhyay et al., after 6 years of follow up.[3] The British Columbia Study [34] showed that the median time from disease-onset to the EDSS of 6 was 27.9 years, and the median age from birth to the EDSS of 6 was 59 years. Hence, a longitudinal epidemiological study is warranted on a long term basis for proper evaluation of the disability progression. Limitations of the study This was retrospective study with a short duration of follow-up. Future directions A long-term prospective study is suggested for the proper analysis of the natural history of MS. There is need for a biological marker, which could ideally predict the immunological disease activity and help in the clinical decision making. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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