Clinical Features of Multiple Sclerosis
Typical Clinical Presentations
MS typically presents in young adults aged 20-30 years with unilateral optic neuritis, partial myelitis, sensory disturbances, or brainstem syndromes such as internuclear ophthalmoplegia developing over several days. 1
Sensory symptoms are the predominant presenting feature in approximately 52% of patients with clinically isolated syndrome, compared to 27% in relapsing-remitting MS 2
Motor symptoms are more common in primary progressive MS patients at presentation 2
Common symptoms include discrete episodes of numbness, tingling, weakness, vision loss, gait impairment, incoordination, imbalance, and bladder dysfunction 3
Between attacks, patients tend to be stable but may experience fatigue and heat sensitivity 3
MS affects women disproportionately with a female-to-male ratio of nearly 3:1 1
Diagnostic Tests for Multiple Sclerosis
Core Diagnostic Principle
The diagnosis requires demonstrating inflammatory-demyelinating injury within the CNS that is disseminated in both time and space, with no better explanation for the clinical presentation. 4, 3
MRI Criteria (Most Important Test)
MRI is the most sensitive and specific paraclinical test for MS diagnosis and should be the primary imaging modality. 5
Dissemination in Space (DIS)
- Requires three of the following four criteria: 4
- One gadolinium-enhancing lesion OR nine T2-hyperintense lesions (if no gadolinium enhancement)
- At least one infratentorial lesion
- At least one juxtacortical lesion
- At least three periventricular lesions
Dissemination in Time (DIT)
- Demonstrated by either: 5, 4
- Simultaneous presence of gadolinium-enhancing and non-enhancing lesions on a single MRI
- A new T2 or gadolinium-enhancing lesion on follow-up MRI (≥3 months after clinical event) compared with baseline
Cerebrospinal Fluid Analysis
CSF analysis showing oligoclonal bands provides evidence of inflammation and is particularly valuable when imaging findings are atypical or insufficient. 5
Positive CSF is defined as: 4
- Oligoclonal IgG bands detected by isoelectric focusing that differ from serum bands, OR
- Elevated IgG index
Oligoclonal bands are found in 89% of all MS patients without significant differences between disease subtypes 2
Lymphocytic pleocytosis should be less than 50/mm³ 4
Patients with clinically isolated syndrome have higher CSF cell counts than those diagnosed in later disease stages 2
CSF is especially helpful when: 4
- Imaging criteria fall short
- Clinical presentation is atypical
- Patients are older (where MRI findings may lack specificity due to microvascular disease)
Visual Evoked Potentials (VEP)
VEPs showing delay with well-preserved waveform provide additional diagnostic support 5
Particularly useful when: 5
- MRI abnormalities are few (especially in primary progressive MS with progressive myelopathy)
- MRI findings have less specificity (older individuals with vascular risk factors)
Prolonged VEP latencies are found in only 29% of patients with clinically isolated syndrome, compared to 66% in relapsing-remitting MS, 75% in secondary progressive MS, and 65% in primary progressive MS 2
Diagnostic Algorithm Based on Clinical Presentation
Two or more attacks + objective evidence of two or more lesions
- No additional tests required for diagnosis (though MRI, CSF would typically be abnormal if performed) 4
Two or more attacks + objective evidence of one lesion
- Requires demonstration of dissemination in space through MRI or positive CSF 4
One attack + objective evidence of two or more lesions
- Requires demonstration of dissemination in time through MRI or a second clinical attack 4
One attack + objective evidence of one lesion
- Requires demonstration of both dissemination in space AND time 4
Insidious neurological progression suggestive of MS
- Requires demonstration of dissemination in space and time OR continued progression for one year 4
Important Diagnostic Considerations
An attack must last at least 24 hours and represent true neurological dysfunction, not pseudoattacks from fever or infection 5
Separate attacks must be separated by at least 30 days from onset of the first event to onset of the second 5
Single paroxysmal episodes do not constitute a relapse, but multiple episodes over 24 hours do 5
Diagnostic Pitfalls and Differential Diagnosis
Critical Cautions
Special care must be taken in patients younger than 10 or older than 59 years, those with progressive onset, and those with unusual presentations such as dementia, epilepsy, or aphasia. 6, 4
In older individuals, MRI findings may have less specificity due to microvascular ischemic disease 5
Quality of paraclinical testing varies worldwide—ensure state-of-the-art technology for MRI, CSF analysis, and evoked potentials 6, 4
Always exclude alternative diagnoses before confirming MS 4
Key Differential Diagnoses to Consider
Vascular disorders: Multifocal cerebral ischemia/infarction from phospholipid antibody syndrome, lupus, CADASIL, Takayasu's disease, meningovascular syphilis, carotid dissection 6, 4
Paraneoplastic disorders: Cerebellar ataxia (elevated CSF IgG can occur) 6
Monophasic demyelinating diseases: Acute disseminated encephalomyelitis, Devic's syndrome (neuromyelitis optica), acute transverse myelitis 6, 4
Genetic disorders: Leukodystrophies, particularly in children and teenagers 6, 4
Additional Testing When Needed
Consider antiphospholipid antibodies, lupus serologies, HTLV-1, Lyme serology, and syphilis testing based on clinical context 4
Consider genetic testing for leukodystrophies in children and teenagers 4
Biopsy can confirm inflammatory demyelination when diagnosis remains uncertain despite comprehensive workup, but cannot alone establish MS diagnosis 4
MS Subtypes
Four Main Clinical Phenotypes
MS is classified into four main clinical phenotypes: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and clinically isolated syndrome (CIS). 7
Relapsing-Remitting MS (RRMS)
Characterized by clearly defined relapses with full or partial recovery, without disease progression between attacks 7
Typically presents in younger patients 7
Shows higher inflammatory activity on MRI with approximately 80% of new lesions showing gadolinium enhancement 7
Represents the most common initial presentation of MS 1
Secondary Progressive MS (SPMS)
Follows an initial relapsing-remitting course with subsequent progressive deterioration for at least six months, with or without superimposed relapses 7
Progression accounts for most long-term disability in MS 3
Primary Progressive MS (PPMS)
Characterized by progressive deterioration from disease onset without relapses or remissions 7
Affects approximately 10-15% of MS patients 7
Shows less inflammatory activity on MRI, with only about 5% of new lesions showing gadolinium enhancement 7
Clinically Isolated Syndrome (CIS)
The first clinical episode with features suggestive of MS but not yet meeting full criteria for MS diagnosis 7
May or may not progress to definite MS 7
Approximately 56% of CIS patients fulfill modified Barkhof MRI criteria at diagnosis 2
Important Classification Notes
The term "benign MS" should be used with caution as disease course can worsen at any time 7
Older terms like "clinically definite," "laboratory-supported definite MS," "clinically probable MS," and "laboratory-supported probable MS" are no longer recommended 5
Treatment of Multiple Sclerosis
FDA-Approved Disease-Modifying Therapies
Nine classes of disease-modifying therapies (DMTs) are available for relapsing-remitting MS and secondary progressive MS with activity, with efficacy rates ranging from 29-68% reduction in annualized relapse rates. 1
Available DMT Classes for Relapsing Forms of MS
Interferons (e.g., interferon beta-1a): Indicated for relapsing forms of MS including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease 8
Sphingosine 1-phosphate receptor modulators (e.g., fingolimod) 1, 9
Cladribine 1
Monoclonal antibodies (three types): 1
Treatment for Primary Progressive MS
Ocrelizumab is the only DMT approved specifically for primary progressive MS. 1
Treatment Efficacy and Adverse Effects
DMTs reduce clinical relapses and MRI lesions (new T2 lesions, gadolinium-enhancing lesions) 1
Common adverse effects include: 1
- Infections
- Bradycardia and heart blocks
- Macular edema
- Infusion reactions
- Injection-site reactions
- Secondary autoimmune effects (e.g., autoimmune thyroid disease)
Treatment Strategy Considerations
Sequential Monotherapy
- Traditional approach using one DMT at a time 9
Escalation Therapy
- Starting with lower-risk agents and escalating to higher-efficacy therapies if needed 9
Induction and Maintenance Therapy
- Using high-efficacy agents early to induce remission 9
Critical Treatment Warnings
Natalizumab should not be used in combination with immunosuppressants or TNF-α inhibitors due to increased PML risk. 10
When initiating natalizumab, physicians must consider whether expected benefit is sufficient to offset PML risk 10
If PML is suspected in natalizumab-treated patients, further dosing should be delayed and the patient carefully monitored 6
A negative CSF does not exclude PML, and clinical judgment is required for optimal management 6