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Multiple Sclerosis (MS) - Unit 17 Complete Notes

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1. Definition & Historical Background

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2. Epidemiology

• Most common cause of non-traumatic neurological disability in young adults
• Peak onset: 20-40 years; can present from adolescence to late middle age
• Female:Male ratio = 2:1 (females predominate)
• Higher prevalence at greater distances from the equator (latitude gradient)
• Leading to unemployment within 10 years of disease in 50-80% of patients
• Prevalence of major depression: ~50% lifetime; bipolar disorder: 2x general population

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3. Etiology

Genetic Factors

• Concordance in identical twins: 25-30% (confirming a genetic, not purely genetic etiology)
• Dizygotic twins: ~5% - similar to other siblings
• HLA-DR2 (DRB1*1501) is the strongest genetic association
• Other susceptibility loci: IL-7R, IL-2R alpha chain genes

Environmental Factors

• Vitamin D deficiency - low sun exposure in northern latitudes
• Epstein-Barr virus (EBV) infection - near-universal prior EBV infection in MS patients
• Cigarette smoking increases risk 1.5x
• Childhood obesity
• Migration studies: people who migrate before age 15 acquire the risk of their new country; those who migrate after 15 retain original country risk - suggesting a critical exposure period in childhood/adolescence

Immunological Mechanism

• T-cell mediated autoimmunity is central
• Autoreactive CD4+ Th1 and Th17 cells breach the blood-brain barrier
• These attack myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG)
• Results in oligodendrocyte destruction → demyelination
• B cells and antibodies also contribute (especially anti-MOG, anti-AQP4 variants)
• Inflammation → demyelination → axonal injury (in progressive stages)

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4. Pathology / Pathophysiology

The MS Plaque

• Characteristic lesion = demyelinated plaque (sclerosis = scar)
• Predilection sites: periventricular white matter, optic nerves, brainstem, spinal cord (lateral and posterior columns), cerebellum
• Dawson's fingers - periventricular plaques oriented perpendicular to ventricles along medullary veins (classic on MRI)

Stages of a Plaque

Why Symptoms Occur

• Demyelination → slowed/blocked conduction along axons
• During attacks: inflammation and edema worsen conduction block
• Recovery: remyelination (thin myelin) restores partial function
• Uhthoff's phenomenon: worsening of symptoms with rise in body temperature (fever, exercise, hot bath) - because heat further impairs conduction in demyelinated axons
• Progression: axonal transection and neurodegeneration cause permanent disability

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5. Classification of MS

A. Relapsing-Remitting MS (RRMS) - Most common (~85% at onset)

• Episodes ("relapses/attacks") of acute neurological dysfunction lasting days to weeks
• Followed by partial or complete recovery ("remissions")
• Between attacks, no disease progression

B. Secondary Progressive MS (SPMS)

• After years of RRMS, the course transitions to gradual progressive worsening with or without occasional relapses
• Approximately 50% of untreated RRMS converts to SPMS within 10 years; 90% within 25 years

C. Primary Progressive MS (PPMS) - ~10-15% of cases

• Gradual neurological decline from onset, without distinct relapses or remissions
• More common in males; older age of onset (~40s)
• Typically manifests as progressive myelopathy (spastic paraparesis)

D. Progressive-Relapsing MS (PRMS)

• Progressive from onset but WITH clear acute relapses superimposed

E. Acute MS Variants

• Marburg disease: fulminant, rapidly progressive, fatal variant
• Tumefactive MS: large (>2 cm) pseudotumoral lesions mimicking brain tumor
• Balo's concentric sclerosis: alternating rings of demyelination and preserved myelin
• Schilder disease (Diffuse cerebral sclerosis): large bilateral hemispheric lesions

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6. Clinical Signs and Symptoms

Motor

• Spastic paraparesis/weakness (most common in spinal cord involvement)
• Upper motor neuron signs: hyperreflexia, extensor plantar response (Babinski sign), spasticity
• Fatigue (most common and disabling symptom overall)

Sensory

• Paresthesias (tingling, numbness) - often an early symptom
• Loss of vibration and joint position sense (dorsal column involvement)
• Lhermitte's sign: electric shock sensation radiating down the spine/limbs on neck flexion - indicates cervical cord involvement (highly suggestive of MS but not pathognomonic)

Visual

• Optic neuritis - most common first manifestation
  • Unilateral painful loss of vision
  • Central scotoma
  • Relative afferent pupillary defect (Marcus Gunn pupil)
  • Recovery is typical but recurrence is common
• Internuclear ophthalmoplegia (INO): impaired adduction of one eye with nystagmus of the abducting eye (due to MLF lesion) - bilateral INO is virtually pathognomonic of MS in a young adult
• Diplopia (CN VI or MLF lesion)
• Nystagmus

Cerebellar/Brainstem

• Charcot's triad: Intention tremor + Nystagmus + Scanning (staccato) speech - classic (though not commonly seen together)
• Ataxia, dysmetria, dysarthria
• Vertigo (due to brainstem lesions)

Bladder/Bowel/Sexual

• Bladder dysfunction (very common): urgency, frequency, hesitancy, incontinence
• Constipation
• Erectile dysfunction in males

Cognitive and Psychiatric

• Cognitive impairment in ~40-50% of patients (attention, memory, processing speed)
• Depression (25-50%)
• Emotional lability, pseudobulbar affect
• Fatigue (present in >80%)

Paroxysmal Symptoms

• Trigeminal neuralgia (facial pain)
• Paroxysmal dysarthria and ataxia
• Tonic spasms (painful, brief muscle contractions)
• Paresthesias - episodic

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7. Investigations

MRI Brain and Spine (most important diagnostic tool)

• T2/FLAIR: hyperintense white matter lesions
  • Periventricular ("Dawson's fingers")
  • Juxtacortical
  • Infratentorial (brainstem, cerebellum)
  • Spinal cord
• T1 gadolinium enhancement: active lesions (BBB breakdown) - indicates acute inflammation
• T1 hypointense "black holes": chronic axonal loss
• Fulfills McDonald 2017 criteria for Dissemination in Space (DIS) and Dissemination in Time (DIT)

Cerebrospinal Fluid (CSF)

• Oligoclonal IgG bands (OCBs) - present in >90% of MS patients (absent in serum = intrathecal synthesis)
• Elevated IgG index
• Mild pleocytosis (lymphocytes, typically <50 cells/mm³)
• Mildly elevated protein
• Normal glucose

Evoked Potentials

• Visual Evoked Potentials (VEP): prolonged P100 latency - indicates demyelination of optic nerve even subclinically
• Somatosensory evoked potentials (SSEP): delayed
• Brainstem Auditory Evoked Potentials (BAEP)
• Useful to detect subclinical lesions and confirm DIS

Blood Tests (to exclude differentials)

• ANA, anti-dsDNA, APS antibodies (to exclude SLE/lupus sclerosis)
• Anti-AQP4 (NMO-IgG) and anti-MOG antibodies - to exclude NMOSD
• B12, folate, HIV, VDRL
• Thyroid function

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8. McDonald Diagnostic Criteria (2017)

• DIS: Lesions in ≥2 of 4 characteristic CNS regions (periventricular, juxtacortical, infratentorial, spinal cord)
• DIT: New T2 lesion on follow-up MRI, OR simultaneous presence of enhancing and non-enhancing lesions, OR CSF-specific OCBs

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9. Differential Diagnosis

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10. Medical Management

A. Treatment of Acute Relapses

• IV Methylprednisolone 1g/day for 3-5 days - shortens relapse duration but does not affect long-term outcome
• Oral prednisolone is an alternative
• Plasmapheresis for severe steroid-unresponsive attacks

B. Disease-Modifying Therapies (DMTs)

1st Line / Moderate Efficacy

High Efficacy

C. Symptomatic Treatment

D. Rehabilitation (important for Physiotherapy students)

• Physiotherapy: exercise programs, stretching for spasticity, balance/gait training, fall prevention
• Occupational therapy: adaptive equipment, energy conservation techniques
• Speech therapy: dysarthria, dysphagia management
• Psychological support: CBT for depression, fatigue management programs
• Multidisciplinary MS care team

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11. Complications

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Quick Summary Table

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CASE STUDY: Multiple Sclerosis

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PATIENT PROFILE

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CHIEF COMPLAINTS

1. Sudden painless blurring of vision in the right eye - 3 weeks ago (resolved spontaneously)
2. Tingling and numbness in both legs - present for 2 weeks
3. Weakness in both lower limbs - progressive over 10 days
4. Electric shock sensation down the spine on bending the neck - 1 week
5. Urinary urgency and occasional incontinence - 5 days

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HISTORY OF PRESENT ILLNESS

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PAST HISTORY

• 5 years ago: An episode of transient diplopia (double vision) lasting 3 weeks that resolved spontaneously - never investigated
• No history of diabetes, hypertension, tuberculosis, epilepsy
• No prior hospitalizations

Clinical Note: The history of transient diplopia 5 years ago represents a prior demyelinating episode - highly significant in retrospect.

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FAMILY HISTORY

• No first-degree relative with MS or autoimmune disease
• Mother has Hashimoto's thyroiditis (autoimmune background in family)

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PERSONAL HISTORY

• Non-smoker, non-alcoholic
• Diet: predominantly vegetarian, limited sun exposure (lives in high-latitude, frequently cloudy Kashmir)
• No recent travel
• Menstrual history: regular; symptoms worsened after a hot bath last week

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DRUG HISTORY

• No current medications
• No history of drug allergy

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GENERAL EXAMINATION

• Conscious, cooperative, well-oriented to time, place, and person
• Vitals: BP 118/76 mmHg, Pulse 78/min, Temp 37°C, SpO2 98%
• No pallor, icterus, cyanosis, clubbing, lymphadenopathy, or edema
• No skin rash, oral ulcers, or joint swelling

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NEUROLOGICAL EXAMINATION

Higher Mental Functions

• Mini-Mental State Examination (MMSE): 27/30 (mild inattention, slightly slow processing)
• Mood: mildly anxious, appropriate affect

Cranial Nerve Examination

Key Finding: Unilateral optic neuritis + INO in a young woman = MS until proven otherwise

Motor Examination (Lower Limbs)

Sensory Examination

Cerebellar Examination

• Mild bilateral dysmetria on finger-nose test
• Heel-shin test mildly impaired bilaterally
• Tandem gait impossible (falls to sides)
• No dysarthria at this stage

Special Signs

• Lhermitte's sign: POSITIVE - electric shock sensation down the spine on neck flexion
• Uhthoff's phenomenon: POSITIVE - symptoms worsened after hot bath (history)
• Romberg's test: POSITIVE - sways markedly, near-fall

Bladder

• Palpable bladder on lower abdominal examination
• Post-void residual urine on bladder scan: 120 mL (neurogenic bladder)

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PROVISIONAL DIAGNOSIS

• Young female, episodic CNS attacks with recovery
• Current attack: spinal cord + optic nerve + brainstem involvement
• Previous attacks: diplopia (5 yrs ago) + optic neuritis (3 wks ago)
• Dissemination in SPACE: optic nerve + brainstem (INO) + spinal cord
• Dissemination in TIME: prior episode (5 yrs) + current attack

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INVESTIGATIONS

1. MRI Brain with Gadolinium (MOST IMPORTANT)

• Multiple T2/FLAIR hyperintense lesions in periventricular white matter, oriented perpendicular to ventricles (Dawson's fingers)
• Juxtacortical lesions in right frontal and parietal regions
• Infratentorial lesion in dorsal pons (explains INO)
• Gadolinium-enhancing lesion in right pericallosal region (active, current attack)
• Non-enhancing chronic lesions in left periventricular region (prior attack)

2. MRI Cervical Spine

• T2 hyperintense intramedullary lesion at C3-C5 level (right lateral column)
• Lesion < 3 vertebral segments in length
• No cord expansion or swelling

3. Cerebrospinal Fluid (CSF) Analysis

OCBs in CSF absent in serum = intrathecal IgG synthesis = highly supportive of MS

4. Visual Evoked Potentials (VEP)

• Right eye: P100 latency = 128 ms (prolonged; normal <115 ms) - confirms subclinical right optic nerve demyelination
• Left eye: P100 latency = 109 ms (borderline) - suggests subclinical prior involvement

5. Blood Investigations (to exclude differentials)

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DIAGNOSIS CONFIRMED

Relapsing-Remitting Multiple Sclerosis (RRMS)

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DIFFERENTIAL DIAGNOSES (Considered and Excluded)

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MANAGEMENT

Phase 1: Acute Relapse Treatment

• Shortens duration and severity of current relapse
• Does NOT improve long-term disability
• Followed by oral prednisolone taper (optional)

Phase 2: Disease-Modifying Therapy (DMT)

• Reduces relapse rate by ~30%
• Slows MRI lesion accumulation
• Counsel about: flu-like side effects (pre-treat with paracetamol), injection site reactions, liver function monitoring every 6 months, thyroid function (important here given autoimmune thyroid disease)

Phase 3: Symptomatic Management

Phase 4: Rehabilitation (Physiotherapy - Key for BPT students)

• Improve functional mobility and independence
• Reduce spasticity and prevent contractures
• Improve balance and reduce fall risk
• Manage fatigue

• Adaptive devices (grab rails, raised toilet seat, non-slip mats)
• Home modification advice
• Return-to-work planning

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COUNSELLING

1. MS is not curable, but is manageable - majority of RRMS patients remain ambulatory for decades
2. DMT reduces relapse rate and slows disability progression - must be taken regularly
3. Avoid heat - no hot baths, manage fever promptly (Uhthoff's phenomenon)
4. Pregnancy - MS relapses decrease during pregnancy (especially 3rd trimester) but increase post-partum; interferon beta must be stopped before conception
5. Importance of vitamin D supplementation and maintaining active lifestyle
6. Regular follow-up: MRI every 6-12 months, neurologist review every 3-6 months
7. MS Society support group referral
8. Psychological support offered

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FOLLOW-UP at 4 Weeks

• Patient reports significant improvement in leg strength (power improved to 4+/5 bilaterally)
• Urinary urgency reduced with oxybutynin
• Tingling partially resolved
• Lhermitte's sign still present but less intense
• Started walking with minimal support
• Commenced physiotherapy 5 days/week

• Gadolinium-enhancing lesion resolved (inactive)
• No new lesions (treatment response)

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COMPLICATIONS NOTED / ANTICIPATED

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LEARNING POINTS FROM THIS CASE

1. Optic neuritis in a young woman is MS until proven otherwise - 50% develop MS within 15 years
2. Bilateral INO in a young adult = pathognomonic of MS (virtually no other cause)
3. Lhermitte's sign + Uhthoff's phenomenon are hallmark clinical features
4. Dissemination in space AND time is the diagnostic cornerstone (McDonald criteria)
5. A prior undiagnosed episode (diplopia 5 years ago) is frequently identified retrospectively - thorough history is essential
6. CSF oligoclonal bands support diagnosis and allow earlier treatment initiation
7. Anti-AQP4 and anti-MOG must always be checked to exclude NMOSD/MOGAD before labeling MS
8. Physiotherapy is a core pillar of MS management - not supplementary
9. Avoid heat during physiotherapy sessions - use cool environments
10. MS is a lifelong condition requiring multidisciplinary care: Neurologist + Physiotherapist + Occupational Therapist + Urologist + Psychologist + Ophthalmologist

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