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Case 22.2 – Multiple Sclerosis

Category: Medicine | Discipline: Neurology | Setting: Neurology Outpatient Clinic

Case

Ellen Tweedle is a 34 year old woman who you first meet in the neurology outpatient clinic. She has presented with an episode of visual loss which has gradually recovered. This had occurred out of the blue, without any preceding headaches or other symptoms that she could think of. The visual loss had occurred in the right eye only and initially she had not been able to see anything through that eye. The visual loss had been extremely frightening but over a few days had spontaneously recovered. When you examine her you find weakness in the right hand with brisk reflexes down the right arm. This appears to be pyramidal (i.e. the finger and wrist extensors are much weaker than the flexors). Ellen tells you that she had put the weakness down to a lot of work as an osteopath. On visual field testing she has a central scotoma (loss of vision) through the right eye, which she seems to have accommodated to. When examined for her eyes' response to light, her right pupil constricts less when a direct light is shone in that eye than when the light is shone in her left eye. This is called a relative afferent pupillary defect (RAPD). As part of the thorough neurological examination, you pick up decreased sensation to pin prick over the left side of her body, extending from her jaw down her left arm, trunk and leg, stopping at the midline.

Questions

1. What is the most likely diagnosis? Discuss your rationale including the application of the revised McDonald criteria for the diagnosis of multiple sclerosis. What neurological levels might be affected in order to explain Ellen's neurological signs?

Most Likely Diagnosis: Multiple Sclerosis (MS)

Rationale:

  • Ellen is a young woman (34 years old) - MS typically presents between ages 20-40 and is more common in women (F:M ratio ~3:1)
  • She has clinical evidence of lesions affecting multiple parts of the CNS:
    • Optic nerve: Episode of visual loss with RAPD and central scotoma (consistent with optic neuritis)
    • Right corticospinal tract: Right hand weakness with brisk reflexes (pyramidal pattern)
    • Left spinothalamic pathway: Left-sided pin prick loss from jaw to leg
  • Dissemination in space: multiple CNS lesions
  • Dissemination in time: the visual loss occurred and recovered; the hand weakness appears to be from an earlier episode; these suggest attacks separated in time

McDonald Criteria (2017 Revision) for MS Diagnosis:

The McDonald criteria require evidence of dissemination in space (DIS) and dissemination in time (DIT) of CNS lesions:

Dissemination in Space (DIS) requires ≥1 T2 lesion in at least 2 of 4 CNS areas:

  • Periventricular
  • Cortical or juxtacortical
  • Infratentorial
  • Spinal cord

Dissemination in Time (DIT) can be demonstrated by:

  • Simultaneous presence of gadolinium-enhancing and non-enhancing lesions at any time, OR
  • A new T2 and/or gadolinium-enhancing lesion on follow-up MRI compared with baseline, OR
  • Clinical: a second clinical attack involving a different CNS site

Application to Ellen:

  • She has clinical evidence of lesions in multiple areas (optic nerve, corticospinal tract, spinothalamic pathway)
  • Her presentation suggests at least two separate episodes (visual loss that recovered, plus existing weakness)
  • MRI will be essential to confirm DIS and potentially DIT
  • CSF analysis may show oligoclonal bands (present in ~95% of MS patients)

Neurological Levels Affected:

  • Right optic nerve: Optic neuritis causing unilateral visual loss, RAPD, and central scotoma
  • Right corticospinal tract: Likely cervical cord or brainstem lesion causing right arm pyramidal weakness
  • Left spinothalamic pathway: Likely right-sided brainstem or cervical cord lesion affecting sensory pathways (spinothalamic tract crosses at the level of entry, so left body sensation is affected by right-sided lesion)
2. What investigations would help confirm the diagnosis?

Essential Investigations:

1. MRI Brain and Spinal Cord (with and without gadolinium contrast):

  • Most important investigation for MS diagnosis
  • Look for T2 hyperintense lesions (bright on T2/FLAIR sequences)
  • Typical MS lesions are:
    • Periventricular (Dawson's fingers - perpendicular to ventricles)
    • Juxtacortical or cortical
    • Infratentorial (brainstem, cerebellum)
    • Spinal cord (typically partial lesions extending over 1-2 vertebral segments)
  • Gadolinium enhancement indicates acute/active inflammation (breakdown of blood-brain barrier)
  • Helps establish dissemination in space and time per McDonald criteria

2. Lumbar Puncture and CSF Analysis:

  • Oligoclonal bands (OCBs): Present in CSF but not serum in ~95% of MS patients
  • Elevated IgG index: Indicates intrathecal IgG synthesis
  • Cell count: Mild lymphocytic pleocytosis (usually <50 cells/mm³); higher counts suggest alternative diagnosis
  • Protein: Normal or mildly elevated
  • CSF analysis helps exclude MS mimics (infection, malignancy, inflammatory conditions)

3. Visual Evoked Potentials (VEPs):

  • Assess optic nerve function
  • Delayed P100 latency indicates optic nerve demyelination (even if subclinical)
  • Useful if clinical history suggests optic neuritis
  • Can demonstrate subclinical lesions

4. Blood Tests (to exclude MS mimics):

  • Full blood count, ESR, CRP
  • Vitamin B12 and folate (deficiency can mimic MS)
  • Thyroid function tests
  • ANA, anti-dsDNA, ANCA (to exclude SLE, vasculitis)
  • Anti-aquaporin-4 (AQP4) antibodies (to exclude neuromyelitis optica spectrum disorder - NMOSD)
  • Anti-MOG antibodies (MOG-antibody disease can mimic MS)
  • ACE level (sarcoidosis)
  • Syphilis and HIV serology (in appropriate clinical context)
  • Lyme serology (if relevant exposure history)

Other Tests to Consider:

  • Optical Coherence Tomography (OCT): Can detect retinal nerve fiber layer thinning in optic neuritis
  • Somatosensory Evoked Potentials: May show delayed conduction in sensory pathways
3. What are the clinical phenotypes (presentations) of MS?

There are four main clinical phenotypes of MS:

1. Relapsing-Remitting MS (RRMS) - ~85% at onset:

  • Most common initial presentation
  • Characterized by clearly defined relapses (acute attacks) with full or partial recovery
  • Relapses are followed by periods of remission with no disease progression
  • Neurological disability may accumulate with incomplete recovery from relapses
  • Between relapses, there is no progression of disability
  • Average relapse rate: ~1 per year (but highly variable)

2. Secondary Progressive MS (SPMS):

  • Develops in ~50-80% of people with RRMS over 10-20 years
  • Initial relapsing-remitting course is followed by gradual neurological deterioration
  • Progression occurs with or without occasional relapses, minor remissions, or plateaus
  • Characterized by steady worsening of disability independent of relapses
  • Transition from RRMS to SPMS can be difficult to identify in real-time

3. Primary Progressive MS (PPMS) - ~10-15% at onset:

  • Disease progression from onset without relapses or remissions
  • Steady worsening of neurological function from the beginning
  • Occasional plateaus or temporary minor improvements may occur
  • Tends to present later (mean age ~40 years, compared to ~30 for RRMS)
  • Equal gender ratio (unlike RRMS which is more common in women)
  • Often presents with progressive myelopathy (spinal cord involvement)

4. Progressive-Relapsing MS (PRMS) - Rare (~5%):

  • Progressive disease from onset with clear acute relapses superimposed
  • May or may not have recovery from relapses
  • Continues to progress between relapses
  • Some classification systems have merged this with PPMS

Clinical Features to Define a Relapse:

  • New or worsening neurological symptoms lasting >24 hours
  • Occurs in the absence of fever or infection
  • Separated from previous relapse by at least 30 days
4. What types of symptoms may present in MS?

MS can affect any part of the CNS, leading to a wide variety of symptoms:

Visual Symptoms:

  • Optic neuritis: Painful unilateral vision loss, typically recovering over weeks; RAPD; central scotoma
  • Diplopia: Double vision from internuclear ophthalmoplegia (INO) or VI nerve palsy
  • Nystagmus: Often associated with brainstem/cerebellar lesions

Motor Symptoms:

  • Weakness: Pyramidal pattern (extensors weaker than flexors in arms; opposite in legs)
  • Spasticity: Increased tone, velocity-dependent
  • Fatigue: One of most common and disabling symptoms (~80% of patients)

Sensory Symptoms:

  • Numbness, tingling, paresthesias: Can affect any part of body
  • Lhermitte's sign: Electric shock sensation down spine/limbs with neck flexion (suggests cervical cord lesion)
  • Pain: Neuropathic pain, trigeminal neuralgia
  • Loss of proprioception/vibration sense

Coordination and Balance:

  • Ataxia: Cerebellar involvement causing incoordination, tremor, dysmetria
  • Vertigo: Brainstem/cerebellar lesions
  • Gait disturbance: May be due to weakness, spasticity, ataxia, or sensory loss

Bladder, Bowel, and Sexual Dysfunction:

  • Urinary urgency, frequency, incontinence: Very common (~80%)
  • Urinary retention: Can lead to infections
  • Constipation: Common
  • Erectile dysfunction, reduced libido, anorgasmia

Cognitive and Psychiatric:

  • Cognitive impairment: Affects ~40-65%; includes problems with memory, attention, processing speed, executive function
  • Depression: Very common (~50% lifetime prevalence)
  • Anxiety
  • Emotional lability (pseudobulbar affect)

Other Symptoms:

  • Uhthoff's phenomenon: Worsening of symptoms with heat/exercise (due to temperature-sensitive conduction block in demyelinated axons)
  • Dysarthria: Slurred speech
  • Dysphagia: Difficulty swallowing (brainstem involvement)
  • Facial weakness or pain
  • Seizures: Occur in ~2-5% (higher than general population)

Common MS Presenting Syndromes:

  • Optic neuritis (20-30%)
  • Brainstem/cerebellar syndrome (25%)
  • Transverse myelitis/partial cord syndrome (30-40%)
  • Sensory symptoms
  • Mixed presentations
5. Describe the management of MS including acute attack management, disease modifying therapies, and symptomatic management

1. ACUTE RELAPSE MANAGEMENT:

High-dose corticosteroids:

  • Methylprednisolone 1g IV daily for 3-5 days (or oral prednisolone 500mg daily)
  • Shortens duration and severity of acute relapses
  • Does NOT affect long-term disability or relapse rate
  • Usually well tolerated; side effects include insomnia, mood changes, hyperglycemia, GI upset
  • Consider gastric protection (PPI) if needed

Plasma exchange (plasmapheresis):

  • Reserved for severe relapses not responding to steroids
  • Evidence of benefit in fulminant demyelinating attacks

2. DISEASE-MODIFYING THERAPIES (DMTs):

Goal: reduce relapse rate, slow disability accumulation, reduce MRI lesion activity

First-line DMTs (Moderate efficacy, better safety profile):

  • Injectable therapies:
    • Interferon beta-1a/1b (subcutaneous or intramuscular): Reduce relapse rate by ~30%; side effects include flu-like symptoms, injection site reactions, hepatotoxicity
    • Glatiramer acetate (subcutaneous daily): Reduce relapse rate by ~30%; generally well tolerated; injection site reactions
  • Oral therapies:
    • Teriflunomide: Once daily; similar efficacy to injectables; monitor LFTs
    • Dimethyl fumarate: Twice daily; reduce relapse rate ~40-50%; side effects include flushing, GI upset; monitor lymphocyte count

Second-line/Higher efficacy DMTs (More effective but higher risk):

  • Fingolimod (oral): First-dose monitoring required (bradycardia risk); macular edema, infections; very effective
  • Natalizumab (IV infusion monthly): Very effective (~68% relapse reduction); risk of PML (progressive multifocal leukoencephalopathy) especially if JC virus positive; requires monitoring
  • Ocrelizumab (IV infusion every 6 months): Anti-CD20 monoclonal antibody; very effective; approved for RRMS and PPMS; infusion reactions, infections
  • Alemtuzumab (IV infusion): Very effective but significant autoimmune side effects (thyroid, ITP); requires intensive monitoring
  • Cladribine (oral): Short course therapy; very effective; lymphopenia

For Primary Progressive MS:

  • Ocrelizumab: First DMT approved for PPMS; modestly slows progression

3. SYMPTOMATIC MANAGEMENT:

Spasticity:

  • Physiotherapy, stretching exercises
  • Baclofen (GABA agonist)
  • Tizanidine (alpha-2 agonist)
  • Gabapentin
  • Botulinum toxin for focal spasticity
  • Intrathecal baclofen pump for severe cases
  • Cannabis-based medicine (nabiximols) in some countries

Fatigue:

  • Exclude and treat other causes (depression, sleep disorders, anemia, thyroid dysfunction)
  • Energy conservation strategies, exercise programs
  • Amantadine (modest benefit)
  • Modafinil (off-label use)

Bladder Dysfunction:

  • Urinary urgency/frequency: Anticholinergics (oxybutynin, solifenacin, tolterodine)
  • Urinary retention: Intermittent self-catheterization
  • Treat UTIs promptly

Neuropathic Pain:

  • Gabapentin or pregabalin
  • Amitriptyline or duloxetine
  • Carbamazepine (especially for trigeminal neuralgia)

Depression and Anxiety:

  • Psychological support, CBT
  • SSRIs (sertraline, citalopram)
  • SNRIs (venlafaxine, duloxetine)

Tremor and Ataxia:

  • Physiotherapy and occupational therapy
  • Medications often ineffective but can try: propranolol, primidone, gabapentin
  • Weighted devices, adaptive equipment

4. MULTIDISCIPLINARY CARE:

  • Neurology: Diagnosis, DMT initiation and monitoring
  • MS nurse specialist: Crucial for education, support, symptom management
  • Physiotherapy: Mobility, spasticity, exercise programs
  • Occupational therapy: ADL support, adaptive equipment, fatigue management
  • Speech and language therapy: Dysarthria, dysphagia
  • Neuropsychology: Cognitive assessment and rehabilitation
  • Urology: Bladder dysfunction
  • Psychiatry/Psychology: Depression, anxiety, adjustment
  • Social work: Benefits, social support

5. LIFESTYLE AND GENERAL MEASURES:

  • Vitamin D supplementation: Some evidence for benefit; most MS patients are deficient
  • Smoking cessation: Smoking associated with faster progression
  • Exercise: Beneficial for symptoms and general health
  • Vaccinations: Keep up to date (avoid live vaccines if on immunosuppression)
  • Avoid triggers: Heat, stress, infections can worsen symptoms temporarily