MS has no unique clinical signs and symptoms, but some are highly characteristic of the disease. Sign and symptoms of MS may vary depending on the part of the central nervous system affected. The onset is often polysymptomatic where patients usually manifest heterogeneous group of signs and symptoms. The most common symptoms of MS include
11 sensory symptoms in limbs or face, vision loss (unilateral visual loss, diplopia), ataxia (difficulties with coordination and balance), and acute or subacute muscle weakness and spasms. Additional signs and symptoms that may develop with the disease course include fatigue, pain, gait disturbance and balance problems, Lhermitte’s sign (electric shock-like sensations that run down the back and/or limbs upon flexion of the neck), dysarthria (problems in speech), vertigo, bladder and bowel dysfunction, acute transverse myelopathy, dysphagia (problems in swallowing), tremor and seizures.93, 94
Progression of the disease after onset may eventually lead to accumulation of disability. A number of measures have been created to clinically assess disability progression and symptom severity. Some of these include the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Score (MSSS) and Scripps Neurologic Rating Scale (NRS). The EDSS is the gold standard in assessing physical disability in MS, which utilises a ten-point disease severity scale from 0 (normal) to 10 (death due to MS).95 The EDSS is limited, in that it has a limited sensitivity and non-linear scale. MSSS is a useful measure of MS severity, which partially corrects for the limitation of the EDSS. The MSSS is a cross-sectional measure of disability progression, as it uses the EDSS and takes disease duration into account.96
1.4.2 Clinical course of MS
In 1996, a unified categorisation of MS clinical course was published.97 In that publication, the clinical course of MS was characterized as: relapsing-remitting, secondary progressive, primary progressive and progressive-relapsing MS. Since then, an increased understanding of MS and its pathology prompted a re-examination and revision of the disease phenotypes in 2013.97-99 The newer characterization of MS phenotypes was dependent on consideration of clinical relapse rate, imaging findings and disease progression. Progressive relapsing MS has been eliminated from the clinical course descriptions and clinically isolated syndrome has
12 been added.98 This is to provide objective criteria and to ensure accurate separation or description of the phenotypes.98, 99 This is particularly crucial for the purpose of design and recruitment of clinical trials, management and treatment decision-making, prognostication and communication.98, 99
The clinical course of MS has been categorized into four clinical subtypes based on the core phenotype characteristics of relapsing and progressive disease. The clinical subtypes now include clinically isolated syndromes (CIS), relapsing-remitting MS (RRMS), secondary- progressive MS (SPMS) and primary-progressive MS (PPMS).
1.4.2.1 Clinically isolated syndromes (CIS)
CIS is the first clinical presentation of a disease that demonstrates characteristics of inflammatory demyelination isolated in time that could possibly convert to definite MS, but has yet to meet the diagnostic criteria for MS.99, 100 Common presentations of CIS include optic neuritis, a brainstem and/or cerebellar syndrome and spinal cord syndrome.100
The core requirement for the diagnosis of MS is the objective demonstration of dissemination of lesions in the CNS in both space and time, based upon either clinical findings alone or a combination of clinical and MRI findings. Also, for individuals with CIS to become definite MS patients, they may have to develop a second exacerbation or relapse.100, 101
For patients with CIS who have MRI lesions at baseline, the chance of developing definite MS is about 60% to 80% by 10 years, and CIS patients who have a normal baseline MRI have a 20% chance of developing MS within 10 years.100
1.4.2.2 Relapsing-remitting MS (RRMS)
RRMS is the most predominant form of the disease, accounting for more than 80% of cases. The relapsing-remitting form is characterised by unpredictable relapses followed by remissions.94, 102 A relapse is defined as the acute or subacute appearance or reappearance of
13 a neurological abnormality typical of an acute inflammatory demyelinating event in the central nervous system (lasting at least 24 hours), immediately preceded by a stable, improving, or slowly progressive neurological state for 30 days, in the absence of fever, known infection, concurrent steroid withdrawal, or externally derived increases in body temperature.102, 103 Most patients with RRMS will eventually enter a secondary-progressive phase.
1.4.2.3 Secondary progressive MS (SPMS)
A subset of persons with RRMS will after some amount of time convert to a progressive form of disease, featuring a steady accrual or progression to increased disability and worsening of function. Relapses can be seen during the early stages of SPMS, but are uncommon as the disease further progresses. Because there are no established criteria or predictors to determine when RRMS converts to SPMS, the diagnosis of SPMS is made retrospectively.99, 104 The conversion from RRMS to SPMS usually takes 10 to 20 years after disease onset. In one study, the median time from CIS to the development of SPMS was 19 years, while the median time from MS diagnosis to SPMS was 12 years.105
1.4.2.4 Primary progressive MS (PPMS)
PPMS is characterized by progressive accumulation of disability from disease onset without any relapses or remission.104 The PPMS form of the disease may account for about 10-15% of MS cases at disease onset.104, 106 A common clinical presentation of PPMS is a spinal cord syndrome with spastic paraparesis. PPMS patients have a more even sex distribution than RRMS and tend to have a worse prognosis for ultimate disability in comparison with patients who have RRMS.107
1.5 Environmental, lifestyle, genetic factors in MS onset and progression