What is Multiple Sclerosis (MS) and how is it managed?

Multiple Sclerosis: Overview and Management

What is Multiple Sclerosis?

Multiple sclerosis is a chronic autoimmune inflammatory disease of the central nervous system characterized by demyelination, axonal damage, and neurodegeneration that typically affects young adults (mean age 20-30 years) and presents with relapsing neurological symptoms or progressive disability. 1, 2

Pathophysiology

• MS results from complex interactions between genetic susceptibility and environmental factors (particularly Epstein-Barr virus infection) that trigger immune dysregulation 1
• The disease involves activation of pro-inflammatory B cells and T cells that cross the blood-brain barrier and attack myelin sheaths in the CNS 1, 3
• Pathological hallmarks include widespread focal myelin degradation, variable axonal and neuronal injury, and activation of innate immune responses (microglia, astrocytes) leading to chronic inflammation 1, 4

Epidemiology and Risk Factors

• MS affects approximately 900,000 people in the United States with worldwide prevalence ranging from 5 to 300 per 100,000 people, increasing at higher latitudes 2
• The disease affects women more than men (nearly 3:1 female-to-male ratio) 2
• Environmental risk factors include vitamin D deficiency, low sunlight exposure, and possibly dietary factors (lower saturated fat, higher polyunsaturated fatty acids) 1
• Life expectancy is reduced compared to the general population (75.9 vs 83.4 years) 2

Clinical Presentation

Typical Symptoms at Onset

• Unilateral optic neuritis (vision loss, eye pain with movement) 2
• Partial myelitis (sensory disturbances, motor weakness affecting limbs) 2
• Brainstem syndromes such as internuclear ophthalmoplegia (diplopia, impaired eye movements) 2
• Sensory disturbances (numbness, tingling, decreased sensation) 5, 2

Symptoms typically develop over several days rather than suddenly 2

Disease Subtypes

• Relapsing-Remitting MS (RRMS): Affects approximately 85% of patients; characterized by discrete relapses with stable disability between episodes 1, 2
• Primary Progressive MS (PPMS): Affects approximately 15% of patients; characterized by steadily increasing neurological disability from onset without clear relapses 1
• Secondary Progressive MS: Develops after initial relapsing-remitting course with steadily increasing disability 2

Common Long-term Manifestations

• Balance dysfunction, gait abnormalities, and falls occur in 50-80% of patients 6
• Cognitive impairment and executive function deficits 3
• Spasticity, fatigue, bladder dysfunction 6
• Vision problems, coordination difficulties 6

Diagnosis

Diagnostic Criteria

Diagnosis requires demonstration of CNS lesions disseminated in both space and time, with exclusion of alternative diagnoses, using the McDonald criteria which integrate clinical presentation with MRI and laboratory findings. 7, 5

Key Diagnostic Components

Clinical Assessment:

• At least one clinical event consistent with acute demyelination is required; diagnosis cannot be made on MRI alone 5
• Diagnosis applies best to individuals aged 10-59 years with typical presentations 5
• Must be made by a specialist familiar with MS and its differential diagnoses 5

MRI Findings:

• MRI is the most important paraclinical tool and preferred imaging modality 7, 5
• Look for T2-weighted hyperintense lesions and gadolinium-enhancing lesions indicating active inflammation 2
• Dissemination in space requires lesions in at least 2 of 4 CNS areas: periventricular, cortical/juxtacortical, infratentorial, and spinal cord 7
• Dissemination in time can be demonstrated by simultaneous gadolinium-enhancing and non-enhancing lesions, or new T2 lesions on follow-up MRI 7

Laboratory Studies:

• Cerebrospinal fluid analysis showing oligoclonal bands supports diagnosis 2
• Visual evoked potentials may provide additional evidence in atypical cases 5

Critical Differential Diagnoses to Exclude

• Cerebrovascular disease (multifocal cerebral ischemia/infarction in young adults) 5
• Neuromyelitis optica spectrum disorder (NMOSD) - must be distinguished from MS 5
• Infectious diseases (HTLV-1, Lyme disease) 5
• Paraneoplastic disorders 5
• Monophasic demyelinating diseases 5
• Genetic disorders of myelin 5

Red Flags Suggesting Alternative Diagnoses

• Bilateral sudden hearing loss suggests a condition other than MS 5
• Sudden onset of focal symptoms (headache, confusion, diplopia, dysarthria, focal weakness) may indicate stroke 5
• Age over 50 years or presence of vascular risk factors requires more stringent diagnostic criteria 5

Management

Disease-Modifying Therapies (DMTs)

Nine classes of DMTs are available for relapsing-remitting MS and secondary progressive MS with activity, reducing annualized relapse rates by 29-68% compared to placebo or active comparators. 2, 8

Available DMT Classes:

1. Interferons (injectable) 2, 8
2. Glatiramer acetate (injectable) 2, 8
3. Teriflunomide (oral) - reduces new inflammatory lesion formation 9, 2
4. Sphingosine 1-phosphate receptor modulators (oral, e.g., fingolimod) 2, 8
5. Fumarates (oral, e.g., dimethyl fumarate) 2, 8
6. Cladribine (oral) 2
7. Monoclonal antibodies:
   • Natalizumab (IV every 4 weeks) - indicated for relapsing forms of MS including clinically isolated syndrome, RRMS, and active secondary progressive disease 10
   • Alemtuzumab 8
   • Ocrelizumab - approved for both relapsing MS and primary progressive MS 2

Critical Safety Considerations for DMTs

Natalizumab carries a black box warning for progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection that usually leads to death or severe disability. 10

• Risk factors for PML include: anti-JCV antibody positivity, duration of therapy, and prior immunosuppressant use 10
• Natalizumab is only available through the TOUCH® Prescribing Program REMS 10
• Monitor patients for any new neurological signs/symptoms; withhold dosing immediately if PML suspected 10
• Diagnostic evaluation for suspected PML includes gadolinium-enhanced brain MRI and CSF analysis for JC viral DNA 10

Other DMT Adverse Effects:

• Infections, bradycardia, heart blocks 2
• Macular edema, infusion reactions, injection-site reactions 2
• Secondary autoimmune effects (e.g., autoimmune thyroid disease) 2

Treatment Strategy Approaches

Sequential Monotherapy:

• Start with one DMT and switch if inadequate response or intolerance 8

Escalation Therapy:

• Begin with lower-risk DMTs (interferons, glatiramer acetate) and escalate to higher-efficacy agents (natalizumab, alemtuzumab, ocrelizumab) if disease activity continues 8

Induction and Maintenance:

• Use high-efficacy therapy upfront (alemtuzumab, cladribine) followed by maintenance with lower-intensity agents 8

Important Limitations of Current Therapies

• Current DMTs primarily target inflammatory mechanisms and do not promote remyelination or reverse existing neurological damage 1, 9
• DMTs reduce relapses and new MRI lesions but long-term benefits on disability progression remain unclear 8
• No effective treatments exist yet for the neurodegenerative component driving secondary progression 4

Monitoring and Follow-up

• Regular MRI monitoring is essential to assess disease activity and treatment response 5
• Look for new T2 lesions and gadolinium-enhancing lesions indicating breakthrough disease activity 2
• Clinical assessment for new relapses or progression of disability 2

Rehabilitation and Supportive Care

Rehabilitation plays a crucial role in managing symptoms and maintaining function, including physical therapy, occupational therapy, and cognitive rehabilitation. 5

• Physical therapy addresses balance dysfunction, gait abnormalities, and fall prevention 6
• Occupational therapy helps maintain independence in daily activities 5
• Cognitive rehabilitation addresses executive function and memory deficits 5
• Symptomatic treatments for spasticity, fatigue, bladder dysfunction, and pain 6

Special Populations

Pediatric MS (under age 11):

• Requires special diagnostic care 5
• Presence of at least one black hole (T1 hypointense lesion) and one periventricular lesion helps distinguish MS from monophasic demyelination 5

Older Adults (over 50 years):

• Apply more stringent diagnostic criteria (higher number of periventricular lesions required) 5
• Consider vascular risk factors more carefully in differential diagnosis 5