Multiple Sclerosis

 

• Background

  Chronic autoimmune disease of the CNS.

  Time course

  • 85% start as an episodic, 'relapsing-remitting' disease (RRMS). 80% eventually become progressive (secondary progressive MS, SPMS), 50% in the first 10 years.
  • The remainder are progressive from the outset – primary progressive MS (PPMS) – with a small minority (2%) featuring progressive disease plus exacerbations (progressive-relapsing MS).

  Pathophysiology

  • Relapsing-remitting phase is characterised by T-cell mediated autoimmune damage, causing discreet plaques of demyelination throughout the CNS.
  • Some degree of healing occurs following damage.
  • Eventual progression to a neurodegenerative process involving axonal loss.

  Epidemiology

  • Mean onset: RRMS age 30, PPMS age 40.
  • 3 times commoner in women.
  • 1 in 300 lifetime risk in UK.

• Presentation

  Relapses

  Symptomatic episodes lasting >24 hours.

  Clinical features:

  • Symptoms peak within hours-days, and resolve within days-weeks-months.
  • Usually present with 1 neurological deficit at a time.
  • Stress may trigger relapses.
  • On average, around 1 relapse occurs per year, though there is considerable variation between patients.
  • The first MS-like episode is known as clinically isolated syndrome (CIS). 90% will have a second attack, meeting the criteria for MS.
  • Relapses decrease during pregnancy, then increase post-partum.

  Common presentations

  Optic neuritis (ON):

  • Impaired central vision, ranging from mild blurring and reduced colour vision, to complete loss of vision. Phosphenes (flashes) may also occur.
  • Periorbital and retro-ocular pain, worse on movement.
  • Signs: relative afferent pupillary defect, disc swelling, optic atrophy, delayed visual evoked potentials.
  • Onset in hours-days, and resolution in days-weeks.
  • Usually unilateral.

  Transverse myelitis (TM):

  • UMN symptoms below the lesion, a numb sensory level, and altered sphincter function.
  • More atypical presentations include a Brown-Sequard lesion.
  • Full resolution may take months.

  Brainstem attacks. Presentations include:

  • Eyes: bilateral intranuclear ophthalmoplegia (INO), diplopia, nystagmus.
  • Balance: vertigo, ataxia.
  • Weakness: face palsy, dysarthria.

  Other presentations

  Focal lesions can happen anywhere in the CNS:

  • Sensory: dysaesthesia (feels like water trickling or electric shock), pins and needles, ↓vibration sensation, trigeminal neuralgia. Distribution is non-dermatomal.
  • Motor: spastic weakness.
  • Eyes: hemianopia, pupillary defects.
  • Cerebellar symptoms.
  • GI: dysphagia, constipation.
  • GU: erectile dysfunction, anorgasmia, urinary retention, incontinence, frequency.
  • Rare: epilepsy, psychosis.

  Non-focal features:

  • Fatigue
  • Cognitive impairment (>50%) including memory problems.
  • Autonomic dysfunction: bladder and bowel problems, orthostatic hypotension, postural tachycardia, sweating.
  • Personality changes including irritability.

  Uhthoff's phenomenon:

  • Worsening of MS symptoms with increased temperature e.g. from exercise, hot food, hot bath, warm weather.

  Paroxysmal symptoms

  • Brief symptoms lasting from seconds to minutes, possibly repeated.
  • Do not constitute a full attack.
  • Possible features: trigeminal neuralgia, epilepsy, tonic spasms, Lhermitte's sign (electrical sensation down back and into limbs, worse on bending neck).

  Progressive disease

  • During the relapsing-remitting phase, there may be a gradual accumulation of disability.
  • In the progressive phase, there is a steady decline in function as opposed to episodic flare-ups.
  • By age 60, 50% require a cane for walking, and 10% a wheelchair.
  • End-stage symptoms: spastic tetraparesis, optic atrophy, brainstem signs, pseudobulbar palsy, urinary incontinence, dementia.

• Risk factors

  • Low sunlight exposure and/or vitamin D deficiency.
  • Family history. 10x risk in first-degree relatives with MS.
  • Infectious mononucleosis.
  • Lifestyle and demographic: female, smoking, obesity.

• Differential diagnosis

  Focal neurological episode:

  • Isolated optic neuritis. 30% of ON progresses to MS within 5 years, and 50% within 15 years, but the rest remain isolated.
  • Transverse myelitis can be due to infection or other inflammatory disease e.g. NMO, SLE, Sjogren's.
  • Acute disseminated encephalomyelitis (ADEM).
  • Stroke
  • Epilepsy

  Episodic neurological disease:

  • Sarcoidosis
  • Neuro-Behcet's
  • Cerebral vasculitis e.g. due to SLE.
  • Multiple strokes.
  • Neuromyelitis optica.

  Progressive neurological decline:

  • Hypothyroidism
  • ↓B12
  • Mitochondrial disease.
  • Infection: HIV, Lyme, syphilis.

  Signs suggesting non-MS cause:

  • Fever, nausea and vomiting, meningism.
  • Malaise
  • Seizures
  • Aphasia
  • Bilateral optic neuritis.

• Investigations

  Diagnosis

  MRI brain and spinal cord:

  • Plaques: hyperintense lesions on T2-weighted MRI, or enhancement of active lesions with gadolinium-enhanced T1 MRI. Periventricular lesions are common.
  • Axonal loss: appear as black holes on T1 MRI.
  • High sensitivity but low specificity.

  CSF:

  • Oligoclonal IgG bands on electrophoresis which are not found in serum (80% sensitive).
  • Less commonly: ↑protein, ↑WBC.

  McDonald criteria

  • ≥2 CNS attacks, disseminated in time (>30 days) and place (≥2 areas of CNS), not explained by anything else.
  • Diagnosis can be purely clinical, provided there are objective neurological findings for at least 1 attack, and attacks last >24 hours.
  • Radiological diagnosis requires 2 lesions. Dissemination in time can be shown with 1 lesion gadolinium-enhancing and the other not.
  • Can be a combination of clinical and radiological 'attacks'.
  • After clinically isolated syndrome, arrange MRI at 6 months to look for evidence of second lesion.
  • PPMS criteria: {>1 year of progressive symptoms} plus {dissemination in space on MRI and/or +ve CSF}.

  Other investigations

  Tests to rule out other causes (NICE recommends before referral to neurology):

  • FBC and CRP for signs of inflammatory disease.
  • B12 as a cause of neurological disease.
  • TSH for eye disease.
  • U&E for electrolyte abnormalities and vasculitis. Ca2+ too.
  • Glucose for diabetes, which can cause neuropathy and eye disease.
  • HIV, which can have various neurological manifestations.
  • Anti-AQP4 Ab for NMO may be done in secondary care.

  Evoked potentials (EP, aka evoked response) may be delayed:

  • Visual, auditory, somatosensory.
  • Not usually needed.

• Management

  General measures

  • MDT approach: neurologist, specialist nurse, GP, physio, OT.
  • Should be reviewed by specialist at least annually.
  • Psychosocial and lifestyle: refer to support groups, exercise (may help symptoms), stop smoking (reduces progression), contact DVLA.

  Disease modifying therapy (DMT)

  Options:

  • Initial therapy: interferon beta, glatiramer acetate, dimethyl fumarate.
  • For resistant disease or initial therapy in highly-active disease: natalizumab, alemtuzumab, ocrelizumab, fingolimod.

  Benefits and indications:

  • RRMS: reduces relapses and short-term disability progression, but does not slow decline during progressive disease. There is some evidence that early treatment slows long-term disability progression and reduces mortality.
  • Can also be used for CIS. Risk of unnecessary side effect exposure (if they don't have MS), but some evidence that early intervention slows progression.
  • Treatment should stop 3 months before attempting pregnancy.
  • Generally no benefit in PPMS, except small benefit with ocrelizumab.

  Symptomatic relief

  • Fatigue: amantadine, physiotherapy, or psychotherapy (mindfulness-based training or CBT). Physiotherapy with progressive resistance training helps reduce fatigue and improve mobility and balance.
  • Spasticity: baclofen or gabapentin are 1st line. Baclofen can be given intrathecally for wheelchair or bedbound patients.
  • Psychological problems: amitriptyline for emotional lability. Also monitor for and treat depression and anxiety, which are common in MS.
  • Neuropathic pain: amitriptyline, duloxetine, gabapentin, or pregabalin.
  • Urinary symptoms: oxybutynin, or intermittent self-catheterisation if there is significant residual volume.

  Attacks

  • Methylprednisolone if symptoms interfere with normal functioning. Reduces relapse severity and duration, but doesn't prevent any long-term damage. Similar efficacy for PO and IV.
  • IVIg is 2nd line.
  • Don't use >3 times/year, due to side effects.
  • Infection/illness (e.g. UTI) may trigger a flare up of symptoms due to a pre-existing lesion. This is not a genuine relapse and there is no role for steroids, so rule out infection whenever a relapse is suspected.

• Prognosis

  Recent research suggests a similar prognosis for young vs. old onset, and RRMS vs. PPMS. Although disease progress is quicker in late onset and PPMS, the absolute age at which disability milestones are reached is similar.

  Poor prognostic signs at diagnosis:

  • Motor signs.
  • Severe disease: frequent relapses, many MRI lesions, axonal loss.

  Mortality:

  • Around 10 years earlier vs. the general population.
  • Respiratory failure or infection are common causes of early death.

• Multiple sclerosis drugs

  Subcutaenous therapies

  Interferon beta (also IM) and glatiramer acetate:

  • Mechanisms unclear, but may shift immune response from Th1 to Th2 and increase regulatory T cells.
  • Reduce relapses by ⅓.
  • Side effects: flu-like reaction (especially interferon), depression, injection site reactions. These reactions become milder over time.
  • Glatiramer has a slow onset (6-9 months).

  Oral therapies

  Dimethyl fumarate:

  • Mechanism unclear, but may reduce neuronal damage from oxidative stress.
  • Reduces relapses by ½.
  • Side effects: flushing, GI symptoms, ↓lymphocytes.

  Fingolimod:

  • Sphingosine-1-phosphate-receptor modulator, preventing lymphocyte migration from lymph nodes.
  • Reduces relapses by ½.
  • Side effects: bradycardia, macular oedema.

  Intravenous monoclonal antibodies

  Natalizumab:

  • Monoclonal antibody to the adhesion molecule α4-integrin, preventing lymphocyte migration into the CNS.
  • Reduces relapses by ⅔.
  • Side effects: progressive multifocal leukoencephalopathy (PML) among those who are JC virus +ve. Screen first and monitor.

  Alemtuzumab:

  • Monoclonal antibody to CD52, a marker of mature lymphocytes.
  • Reduces relapses by ⅔.
  • Side effects: autoimmune reaction (thyroid disease, ITP), ↓WBC.

  Ocrelizumab:

  • Monoclonal antibody to CD20, a B-cell marker.
  • Reduces relapses by ⅔.
  • Side effects: infusion-related reactions, infections (usually mild).

• Neuromyelitis optica (NMO)

  Aka Devic's disease.

  Pathophysiology

  • Autoimmune destruction of myelin.
  • Features antibodies against aquaporin 4 proteins in astrocyte membranes, though mechanism of demyelination is unclear.

  Signs and symptoms

  • Severe attacks of optic neuritis (ON) and transverse myelitis.
  • ON may be bilateral and cause blindness.
  • No progressive phase per se, though attacks lead to long-term disability from paraplegia and blindness.

  Investigations

  • MRI: longitudinal spinal lesions, but rarely brain lesions.
  • AQP4-Ab (aka NMO-IgG) present in 70%.

  Management

  • Methylprednisolone IV or plasmapheresis for attacks.
  • Eculizumab, azathioprine, mitoxantrone, or rituximab for relapse prevention.