Multiple Sclerosis (MS) is an uncommon disease with an estimated prevalence of one to two per 100,000 population in multiracial Malaysia with its Malay, Chinese, Indian, and indigenous racial groups [
There have been a number of revisions to the diagnostic criteria for MS over the last 15 years (2001, 2005, and 2010) while the revised Wingerchuk criteria (2006) incorporates the anti-aquaporin 4 antibody (anti-AQP4 Ab) in the diagnosis of neuromyelitis optica (NMO) and its spectrum disorders (NMOSD) [
The primary objective of this study was to characterize patients with multiple sclerosis in Malaysia in terms of demographics, clinical features, laboratory characteristics and neuroimaging of the brain and the spine.
In order to achieve this, every effort was made by incorporating clinical and paraclinical evidence such as oligoclonal bands, the anti-AQP4 antibody test and neuroimaging in excluding patients with neuromyelitis optica (NMO) and its spectrum disorders (NMOSD) as well as other idiopathic inflammatory demyelinating disorders (IIDDs). A comparison was drawn between these two groups (MS and NMO/NMOSD) with regard to demographics and MRI of the spine.
This was a retrospective, observational study with longitudinal follow-up of patients who had presented to the Neurology Department, Kuala Lumpur Hospital (Kuala Lumpur, Malaysia) from 2008 to 2013. Consecutive patients presenting to the Neurology department with IIDDs (all who consented were tested for Anti- AQP4 antibody) were identified from the Demyelinating Diseases’ Registry(MREC 10503) and included in this study.
These patients were diagnosed with clinically definite multiple sclerosis [
Showing the anti-AQP4 antibody, oligoclonal band, and spinal MRI results for patients with idiopathic inflammatory demyelinating disease.
Diagnosis (after incorporating |
Anti-AQP4 antibody |
Cerebrospinal fluid |
Spine MRI | |||
---|---|---|---|---|---|---|
Positive | Negative | Positive | Negative | Cord lesion |
Cord lesion | |
Clinical Diagnosis | ||||||
MS | ||||||
CIS (MRI brain CDMS) | 0 | 7 | 5 | 2 | 5 (in two no lesions) | 0 |
CDMS | 0 | 91 | 30 | 16 | 55 | 22 |
Opticospinal recurrent type of |
8** | 2 | 0 | 10 | 4 | 6* |
Spinal multiple sclerosis | 1# | 4 | 3 | 2 | 5 | 0 |
NMO | 31 | 4 | 1 | 43 | 2 | 33 |
NMOSD | ||||||
Single episode optic neuritis/relapsing |
3 | 1 | 0 | 0 | 0 | 0 |
Single episode transverse |
7 | 2 | 0 | 9 | 1 | 8 |
Brain lesions typical of NMOSD | 6 | 3 | 1 | 8 | 4 | 5 |
| ||||||
Other IIDDs | ||||||
ADEM | 0 | 26 | 1 | 25 | 8 | 18 |
Single episode optic neuritis |
0 | 7 | 0 | 7 | 0 | 0 |
Single episode transverse myelitis |
0 | 20 | 0 | 10 | 8 | 12 |
Unclassified single episode |
0 | 8 | 0 | 8 | 0 | 0 |
Unclassified relapsing optic neuritis |
0 | 3 | 0 | 3 | 0 | 0 |
MS: multiple sclerosis; NMO: neuromyelitis optica; NMOSD: neuromyelitis optica spectrum disorder; VS: vertebral segments.
*Six patients initially diagnosed with opticospinal variants of Multiple sclerosis upon reviewing first MRI at onset of disease were found to have longitudinally extensive cord lesions.
**Eight patients reclassified as NMO.
#Reclassified as NMOSD.
The remaining patients were diagnosed with neuromyelitis optica spectrum disorder and included those patients with single episode or recurrent optic neuritis, single episode or recurrent longitudinally extensive transverse myelitis with cord lengths of more than 3 vertebral segments and patients with brain involvement at onset of disease with demyelinating lesions not typical of multiple sclerosis who were anti-AQP4 antibody positive.
Patients with relapsing short cord myelitis (<3 vertebral segments VS) with brain MRI undeclared as MS with or without oligoclonal band positivity and anti-AQP4 antibody negativity were diagnosed initially with spinal multiple sclerosis until they developed anti-AQP4 positivity or brain MRI declared itself as NMOSD-like on follow-up.
Patients with opticospinal presentation with cord lesions less than 3 VS with normal brain MRI or few nonspecific small subcortical brain lesions not in keeping with MS were diagnosed with opticospinal multiple sclerosis (OSMS) [
Those patients with IIDDs with brain involvement at onset of disease as described by Kim et al. [
All other IIDDs not meeting the above criteria including patients with ADEM, single episode optic neuritis or transverse myelitis undeclared as MS or NMO/NMOSD (with MRI_brain negative, anti-AQP4 negative), unclassifiable recurrent optic neuritis, idiopathic or post infective transverse myelitis and non-IIDDs were not included. All these latter patients were anti-AQP4 antibody negative. Furthermore, in this group the cerebrospinal fluid oligoclonal bands were negative and where positive there were bands in the corresponding serum.
The racial distribution, sexual preponderance, clinical features with expanded disability status scale at onset of disease, and neuroimaging features (MRI of brain as well as the distribution, type and, length of spinal cord segment involved) in patients with MS were analysed.
All patients’ case notes and neuroimaging, both at onset of disease and on follow-up (when available), were reviewed by a single neurologist (SV). The initial diagnosis of all patients was reviewed and when necessary re-evaluated based on current criteria.
Brain and spine MRIs were done at onset and on follow-up using a 1.5 Tesla machine. When patients were referred from another hospital for an opinion, every effort was made to obtain the first MRI of the brain and spine done when the patient presented with the first symptom or symptoms or the first MRI brain and spine done when the patient first presented to that particular referring hospital. Axial and sagittal views of T1- and T2-weighted images (WI), fluid-attenuated inversion recovery (FLAIR) images, and T1 pre- and postgadolinium WI were obtained. These were carried out at first presentation, within 3 months and annually, or if there were relapses. These brain and spine MRIs were reviewed by a single neuroradiologist (NR) in consultation with the single neurologist, SV.
Data was analysed using SPSS version 16 software, (SPSS Inc, Chicago, IL, USA) looking at descriptive data, means, medians, percentages, and standard deviations. Nonparametric data was evaluated using the Wilcoxon signed rank test.
The anti-AQP4 test was conducted on a cell line at the Autoimmune Unit, Allergy and Immunology Research Centre, Institute for Medical Research, Kuala Lumpur. Anti-AQP4 antibodies (AQP-4) were determined in the serum of the patients by cell based indirect immunofluorescence assay (EUROIMMUN AG, Lubeck, Germany) which utilizes fixed, AQP4-transfected human embryonic kidney (HEK) cells on slides as an antigenic substrate.
Biochip slides containing AQP-4 transfected cells and nontransfected cells (EU-90) were incubated with diluted patient samples. In the case of positive reactions, specific antibodies of the classes of IgA, IgG, and IgM will bind to the antigens. In a second step, the attached antibodies are stained with fluorescein-labelled anti-human antibodies and made visible with the fluorescence microscope.
A total of 245 patients with idiopathic demyelinating disease were identified with 104 patients categorized as MS and 77 patients as NMO/NMOSD. 26 patients were identified with acute demyelinating encephalomyelitis (ADEM) and undeclared as NMO or MS were, 7 patients with a single episode of optic neuritis, and 20 patients with single episode, transverse myelitis (all of whom had MRI of brain and or spine negative for MS or NMOSD). Eight patients had unclassified, single episode demyelinating brain disease while 3 other patients had relapsing optic neuritis of unclassified type (MRI of brain and spine negative for MS,NMO, or non-IIDDs).
Out of 104 patients, females made up 83% and males 17%, giving a female to male ratio of 5 : 1. Mean age at onset was
Malays were the predominant racial group affected with 55/104 (52.9%), followed by the Chinese, 19/104 (18.3%) and Indians, 28/104 (26.9%), all of whom were from West Malaysia as well as 2/104 (1.9%) subjects of indigenous origin from Sabah and Sarawak in East Malaysia (Table
Showing the clinical features of multiple sclerosis patients in Malaysia. (A subgroup analysis of demographics in NMO/NMOSD patients was also included.)
|
|
---|---|
Female : male/% | 87 : 17 (83% : 17%) ( ratio: 5 : 1) |
In the MS group: |
|
In the NMO/NMOSD group: |
|
Mean age at onset/years |
|
Mean duration of illness/years |
|
Site of involvement | At onset At first relapse |
Optic nerve | 37/104 (35.6%) 20/104 (19.2%) |
Spinal cord | 26/104 (25.0%) 33/104 (31.7%) |
Subcortical | 23/104 (22.1%) 32/104 (30.7%) |
Brainstem and cerebellum | 18/104 (17.3%) 19/104 (18.4%) |
Mean number of exacerbations |
|
Annualized relapse rates/year |
|
Mean EDSS at onset |
|
Familial involvement | 5/104 (5%) |
Clinical course | |
RRMS | 93/104 (89.4%) |
SPMS | 6/104 (5.8%) |
PPMS | 5/104 (2.9%) |
CSF (OCB %) | 38/66 (57.6%) |
Ambulating independently (current status) | 78/104 (75%) |
Visual acuity (20/30 and above) in one/both eyes | 94/104 (90.4%) |
ANA positivity (1 : 40 to 1 : 80) | 4/104 (3.8%) |
Initial brain MRI fulfills |
|
Spinal multiple sclerosis | 4/104 (3.8%) |
MS: multiple sclerosis; ANA: antinuclear factor, RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; PPMS: primary progressive multiple sclerosis; OCB: oligoclonal bands; EDSS: expanded disability status scale.
At the onset of disease, 64/104 (61.5%) and 69/104 (66.4%) fulfilled McDonald’s criteria (2005, 2010) [
Five patients had relapsing myelitis with short cord segments less than 3 VS but only 4/104 (3.8%) were included in the final analysis as one tested positive for anti-AQP4 antibody. These four patients’ brain MRIs did not fulfil Swanton’s [
Of the 10 patients initially diagnosed with optico-spinal recurrents based on clinical criteria [
The optic nerve (37/104, 35.6%) and the spinal cord (26/104, 25.0%) were the commonest sites of involvement at onset. However, this did not imply that patients had pure opticospinal presentation at onset as their MRI of brain fulfilled criteria for MS. This was followed by symptoms localized in the subcortical white matter (22.1%), brainstem (9.6%), and cerebellum (7.7%). At first relapse, cord presentation 33/104 (31.7%) appeared more common than optic nerve involvement (20/104), followed by symptoms localized to the subcortical white matter, brainstem and cerebellum. One patient presented with seizure at first relapse.
At onset, the common presenting complaints were monoparesis (6/104, 5.8%), hemiparesis (7/104, 6.7%), paraparesis (15/104, 14.4%), sensory complaints (21/104, 20.1%), blurring of vision, scotomas or loss of vision with or without pain around the eye (37/104, 35.6%), unsteady gait (7/104, 6.7%), vertigo(3/104, 2.9%), double vision(3/104, 2.9%), internuclear ophthalmoplegia (3/104, 2.9%), facial pain(1/104, 0.96%) due to trigeminal neuralgia, and cognitive impairment (1/104, 0.96%). A disseminated onset was seen in 15.4% of patients. Paroxysmal tonic spasms were uncommonly seen in only 17.3% of patients.
Out of the 104 patients with MS, the relapsing-remitting course of disease was seen in 89.4%, secondary progressive multiple sclerosis in 5.8%, and primary progressive disease in 2.9%. After 10 years of disease nineteen patients had become secondary progressive with mean expanded disability status scale (EDSS) of 6.59.
The mean number of relapses was
The majority of the patients in our series are still ambulating independently, that is, 75.0%, and 13.5% are walking with support, 3.8% are wheelchair-bound, and only 7.7% are nonambulatory and bedbound. In terms of visual acuity in the best eye, 90.4% had visual acuity of above 20/30 and 5.8% between 20/30 and 20/200, and the remainder reported visual acuity of less than 20/200 to no perception of light.
MRI’s of brain and spine were carried out at disease onset, on follow-up (once or twice a year), at relapse, or if the disease had a more aggressive course, in order to assess the lesion load. At disease onset 13/104 (12.5%) had cord lesions of one vertebral segment (VS) or less, 40/104 (38.5%) had cord lesions of more than one vertebral segment but ≤3 VS. Twenty two subjects (21.2%) presented with multiple, ill defined, patchy, short segments between 1 and 3 VS which when added up came up to >3 VS and were located sometimes close together, almost coalescing or separated along the cord (all these patients were anti-AQP4 negative) and 1.9% (2/104) presented with multiple well-defined short segments which when added up were <3 VS. No lesion was found in 19.2% (20/104) of patients, and MRI spine was not carried out in 7 patients.
The mean cord lesion length was
Neuroimaging of the spine in patients with multiple sclerosis and neuromyelitis optica and its spectrum disorders in Malaysia.
Spinal cord findings | MS |
NMO/NMOSD |
---|---|---|
Mean cord lesion length at onset for all clinical types/VS |
|
|
Mean cord lesion length in RRMS patients |
|
— |
Commonest site for cord involvement | ||
Cervical | 42/104 (40.4) | 28/77 (36.4) |
Cervicothoracic | 24/104 (23.1) | 33/77 (42.9) |
Thoracic | 6/104 (5.8) | 8/77 (10.4) |
Thoracic and lumbar cord | 1/104 (1.0) | 1/77 (1.3) |
Cervical/thoracic/lumbar cord (interrupted segments) | 4/104 (3.8) | — |
Whole spine | 3/77 (3.9) | |
Location of the lesion | ||
Periphery of cord (lateral/posterolateral) | 68/104 (65.4) | 3/77 (3.9) |
Central gray matter | 9/104 (8.6) | 36/77 (46.8) |
Holocord | — | 34/77 (44.2) |
Length of cord lesions (vertebral segments-VS) | ||
1 VS or less | 13/104 (12.5) | 1/77 (1.3) |
>1 VS to ≤3 VS (Single patchy/well defined lesion) | 40/104 (38.5) |
9/77 (11.7) |
>3 VS (multiple ill-defined patchy short segments between 1 to 3 VS) | 22/104 (21.2) |
63/77 (81.8) |
Multiple well-defined short segments, <3 VS | 2/104 (1.9) | 0/77 (0) |
No lesion | 20/104 (19.2) | 4/77 (5.2) |
No scan done | 7/104 (6.7) | — |
Cord atrophy | ||
Yes | 3/104/(2.8) |
26/77 (33.8) |
No | 74/104/(71.2) | 47/77 (61.0) |
T1 hypointensity | ||
Yes | 2/104 (1.9) | 17/77 (22.0) |
No | 75/104 (74.0) | 56/77 (72.7) |
Cord edema | ||
Yes | 0/104 (0) | 24/77 (31.2) |
No | 77/104 (74.0) | 49/77 (63.6) |
MS: multiple sclerosis; VS: vertebral-segments; RRMS: relapsing-remitting multiple sclerosis; NMO: neuromyelitis optica; NMOSD: neuromyelitis optica spectrum disorder.
The commonest site for cord involvement was the cervical cord in 42/104, 40.4%, and cervicothoracic cord in 24/104, 23.1%. The thoracolumbar and the cervicothoracic, and lumbar cord were also involved. None of these patients had longitudinal contiguous or longitudinal linear lesions at disease onset. Twelve out of 25 patients with MS in the secondary progressive stage of disease and four with aggressive disease tended to have longer cord lesions of more than 3 VS on follow-up which was not there at disease onset (Figures
(a) Sagittal T2WI of the spine showing coalescing of multiple short segment lesions in a patient with relapsing-remitting multiple sclerosis at onset of disease and on follow-up once she entered the progressive phase of disease. (b) Sagittal T2WI of the spine showing a relapsing-remitting patient with multiple sclerosis with a short segment lesion superimposed on a longer patchy lesion at onset of disease. (c) Sagittal T2WI of the spine showing patchy ill-defined lesions more than 3 vertebral segments involving the entire cervicothoracic cord and axial T2WI of MRI brain with clinically definite multiple sclerosis in a patient with secondary progressive disease. (d) Sagittal T2WI (left) of the cervical spine showing a longitudinally extensive cord lesion with edema and corresponding T1WI (right) with T1 hypointensity within the cervical cord in a patient with neuromyelitis optica.
Cerebrospinal fluid studies for oligoclonal bands (OCB) (isoelectric focusing method) were obtained in 66 patients of which 38 (57.6%) were positive. CSF pleocytosis was rare and ranged between 5 and 10 lymphocytes/mm [
All patients with multiple sclerosis were tested for anti-AQP4 antibody. All were negative except for 8 patients who prior to recategorization by the neurologist SV had pure optic nerve and spinal cord presentation. Of these 8 patients, 4 had unilateral blindness and severe myelitis which was relapsing in nature. MRI of brain showed nonspecific white matter lesions not fulfilling Swanton’s criteria.
Retrospective analysis of records obtained during the first presentation revealed the MRI spine at presentation from a neighbouring hospital to have cord lesions between 2.5 and 3.0 VS in 2 of them, 4 and 5 VS in 4 of them and in the remaining 2 patients to have longitudinally extensive contiguous cord lesions involving the entire cervico-thoracic cord. All of them tested positive for anti-AQP4 antibody on longitudinal follow-up and were excluded from the final 104 patients. The misdiagnosis happened as the MRI of the spine at time of referral to our tertiary institution was not the first MRI at onset of disease. With time the cord lesion had become patchy and interrupted, and so initially they were diagnosed as multiple sclerosis. With reevaluation, these patients were included in the NMO cohort.
Out of the 77 NMO/NMOSD patients, the commonest initial presentation was that of myelitis followed by optic neuritis. In terms of demographics it was interesting to see more Chinese having NMO/NMOSD than MS, with a ratio of nearly 2 : 1 (NMO: MS) (
Patients with NMO and relapsing myelitis and NMOSD patients with brain involvement at onset had cord lesions which were longitudinally contiguous or linear, with cord atrophy, majority in the cervicothoracic region which predominantly involved the central gray matter or had holocord appearance. These changes were not seen or were rare in MS patients at onset of disease. Longer cord lesions in MS patient were seen if there was a more aggressive disease or later on in the course of the disease. Edema and T1 hypointensities were more commonly seen in the NMO/NMOSD groups but rare in MS patients at onset of disease; see Table
In our study, the clinical spectrum of MS in Malaysia was found to have changed since the late 80s. The findings in this study also highlighted the similarities that still hold true over time such as the high female preponderance in MS. This female preponderance has been described in other parts of Asia, for instance, in northern Japan where the female to male ratio is 3.38 : 1, and in the west where the ratio has now increased to more than 2 [
The young remained the commonest age group affected with a mean age at onset of 29 years, similar to Caucasian patients [
Malaysia has a multiracial population where Malays and indigenous people (67.4%) are the predominant ethnic group followed by the Chinese (24.6%) and Indians (7.3%) [
Rapid urbanization (71% in 2010 compared to 26.8% in 1970) and the increase in rural to urban migration by Malays may account for this change in demographics of MS in Malaysia [
The relapsing-remitting course of disease remains the commonest type of clinical presentation. Progressive disease, primary or secondary, was seen in 8.7%. Ten years later 18.3% had become secondary progressive. This is unusual in Asia. Here the progressive course of disease has been reported to be rare [
Mean EDSS at onset and on long term follow-up was much lower than previous reports [
A large proportion of patients fulfilled DIS brain criteria by McDonald’s 2005/2010 [
It was interesting to see how the MRI spine and its descriptions had changed over time. In the past, longitudinally extensive contiguous spinal cord lesions had been reported as a feature of MS and, this was thought to reflect severe cord involvement in Asia [
Some patients who went into the progressive phase had patchy longer cord lesions which initially were well-demarcated short segments but later on became longish when these short segments coalesced. Again it cannot be overemphasized how important the timing of the MRI and MRI at onset of disease is in evaluating these patients as cord lesions increase in number, fragment and coalesce with time [
The mean cord lesion length was 2.06 VS. This is shorter than earlier reports in Asia, that is,
In our series we had four patients presenting with cord lesions of between 1 and 3 VS with disease restricted to the spinal cord so-called “spinal multiple sclerosis” all of whom were anti-AQP4 antibody negative. Three were oligoclonal band positive. Since disease onset, these patients have not shown any lesions in the brain. Therefore they remain outside the current Swanton’s criteria for MS and only longitudinal prospective follow-up will show whether these patients are true “pure spinal” entity within the MS spectrum as described by Malaysian authors before or otherwise [
Oligoclonal band positivity too (>50%) was much higher than previously described though still less than the western series. CSF pleocytosis was rare [
In conclusion, this study shows that the type of multiple sclerosis we are seeing in Malaysia is constantly changing with regard to racial distribution, clinical presentation, severity of disease, neuroimaging, and laboratory findings. With access to earlier MRI, better use of available diagnostic criteria and ancillary laboratory testing we were able to categorize patients a little better as it has tremendous impact on therapy. We acknowledge the limitations to the study such as small sample size, retrospective descriptive design, possible exclusion of true CIS cases, and short study follow-up and hope to address these issues in the future. We also hope to look closely at the differentiating features between different types of IIDDs especially NMO/NMOSD and the MS groups.
Multiple sclerosis
Neuromyelitis optica
Neuromyelitis optica spectrum disorder
Idiopathic inflammatory demyelinating diseases
Vertebral segments
Oligoclonal bands
Anti-aquaporin 4 antibody
Clinically definite MS
Dissemination in space
Cerebrospinal fluid
Dissemination in time
Expanded disability status scale
Clinically isolated syndrome.
All authors did not have any conflict of interests.
Study concept and design and analysis and interpretation were made by Dr. Shanthi Viswanathan. Drafting of paper was done by Dr. Shanthi Viswanathan, Dr. Norzaini Rose, Dr. Jasbir Dhaliwal, Dr. Masita Arip, Dr. Santhi Datuk Puvanarajah, and Dr. Sobri Muda. Critical revision of paper for intellectual content was done by Dr. Santhi Datuk Puvanarajah, Dr. Jasbir Dhaliwal, and Dr. Sobri Muda and study supervision by Dr. Mohd. Hanip Rafia.
This research did not receive any specific funding from any agency, public, governmental, or nongovernmental organizations (NGOs). NR refers to Norzaini Rose, a neuro-radiologist. SV refers to Shanthi Viswanathan, a neurologist.
The authors would like to thank the Director-General of Health of Malaysia for allowing them to publish this study. The authors would also like to thank the patients who contributed their data to this registry.