Multiple sclerosis

Background

• CNS myelin destruction causes variable motor, sensory, visual and cerebellar dysfunction
• Peak onset age 20-40 years, F:M ratio ~3:1
• More common in populations of Northern European descent and at higher latitudes

Types

• Clinically isolated syndrome (CIS)
  • Single first episode of neurologic symptoms lasting ≥24 hours, caused by CNS demyelination
  • May or may not progress to MS
• Radiologically isolated syndrome (RIS)
  • Incidental MRI findings suggestive of MS in asymptomatic patients
• Relapsing/remitting (most common)
  • Relapse (days-months) followed by remission
• Secondary progressive
  • Relapses and partial recoveries occur, but disability does not fade away between cycles
• Primary progressive
  • Symptoms progress slowly and steadily without remission
• Progressive relapsing
  • Similar to primary progressive but with superimposed flares

Clinical Features

• Classic patient has multiple presentations for neuro symptoms of different areas of pathology
  • Patient often has resolution of the earlier symptoms
• Symptoms worsen with increases in body temperature, classically after hot showers (Uhthoff's phenomenon)
• Muscle/sensory signs:
  • Lower extremity weakness usually worse than upper extremity
  • Upper motor neuron signs:
    • Hyperreflexia
    • Positive Babinski
  • Decrease in proprioception/pain/temperature sensation
  • Lhermitte sign
    • Electric shock sensation radiating down back into arms/legs from neck flexion
    • If the discomfort is severe, carbamazepine or gabapentin may be beneficial for some patients.
  • Partial transverse myelitis
    • Asymmetric motor/sensory deficits at a spinal cord level
    • One of the most common acute presenting syndromes
  • Trigeminal neuralgia
    • Bilateral trigeminal neuralgia in a young patient should raise suspicion for MS
• Optic neuritis
  • Initial sign in 30% of patients
  • Vision loss (usually unilateral) often preceded by retrobulbar pain
  • Blurred vision
  • Afferent pupillary defect is suggestive of optic neuritis
  • Nystagmus
  • Diplopia
• Internuclear ophthalmoplegia
  • Impaired adduction of the adducting eye with nystagmus of the abducting eye
  • Bilateral INO is classic for MS
  • Convergence (both eyes center medially) is preserved
• Dysautonomia
  • Urinary retention (increased risk of UTI/pyelo)
  • Constipation or incontinence
  • Sexual dysfunction (males)
• Other common symptoms
  • Fatigue — most common symptom overall; frequent reason for ED presentation
  • Cognitive dysfunction (up to 50% of patients)

Differential Diagnosis

Weakness

• Neuromuscular weakness
  • Upper motor neuron:
    • CVA
    • Hemorrhagic stroke
    • Multiple sclerosis
    • Amyotrophic Lateral Sclerosis (ALS) (upper and lower motor neuron)
  • Lower motor neuron:
    • Spinal and bulbar muscular atrophy (Kennedy's syndrome)
  • Spinal cord disease:
    • Infection (Epidural abscess)
    • Infarction/ischemia
    • Trauma (Spinal Cord Syndromes)
    • Inflammation (Transverse Myelitis)
      • Acute flaccid myelitis
    • Degenerative (Spinal muscular atrophy)
    • Tumor
  • Peripheral nerve disease:
    • Guillain-Barre syndrome
    • Toxins (Ciguatera)
    • Tick paralysis
    • Diabetic peripheral neuropathy
  • Neuromuscular junction disease:
    • Myasthenia gravis crisis
    • Botulism
    • Organophosphate toxicity
    • Lambert-Eaton myasthenic syndrome
  • Muscle disease:
    • Rhabdomyolysis
    • Dermatomyositis
    • Polymyositis
    • Alcoholic myopathy
• Non-neuromuscular weakness
  • Can't miss diagnoses:
    • ACS
    • Arrhythmia/Syncope
    • Severe infection/Sepsis
    • Hypoglycemia
    • Periodic paralysis (electrolyte disturbance, K, Mg, Ca)
      • Hypokalemic periodic paralysis
      • Thyrotoxic periodic paralysis
    • Respiratory failure
  • Emergent Diagnoses:
    • Symptomatic Anemia
    • Severe dehydration
    • Hypothyroidism
    • Polypharmacy
    • Malignancy
    • Aortic disease - occlusion, stenosis, dissection
  • Other causes of weakness and paralysis
    • Acute intermittent porphyria (ascending weakness)

Evaluation

MRI brain with contrast of a patient in her mid-20s with new onset MS. Large lesion in left parietal area.

MRI brain with contrast of same patient with new onset MS with another lesion in the left cerebellum.

Known MS Patient with Exacerbation

• Urinalysis — rule out occult UTI as pseudorelapse trigger (very common in MS)
• CBC, Chemistry
• Consider CXR or other infectious workup based on presentation
• Temperature — fever suggests pseudorelapse or infection
• MRI with GAD generally not needed emergently unless diagnostic uncertainty or concern for PML
• LP is generally not needed for exacerbation of known MS — defer to neurology

Suspected New Diagnosis

• MRI with GAD of brain (+/- spine) and orbits (if optic neuritis suspected)
  • Multiple lesions in supratentorial white matter, paraventricular area, spinal cord
• CSF
  • Elevated protein and gamma-globulin (increased oligoclonal bands)
  • Generally can be deferred to neurology
• CBC, Chemistry
• Urinalysis
• TSH, B12, RPR/VDRL — rule out MS mimics
• Consider NMO/aquaporin-4 antibody testing (especially if longitudinally extensive transverse myelitis or bilateral optic neuritis)

Management

Pseudorelapse vs True Relapse

	True Relapse	Pseudorelapse
Definition	New inflammatory demyelinating event	Temporary worsening of old symptoms from an external trigger
Duration	>24 hours, evolves over hours to days, persists days to weeks	Typically <24 hours; resolves when trigger is removed
Triggers	None (not explained by fever or infection)	Infection (especially UTI), fever, heat, stress, dehydration, medication changes
Symptoms	New neurologic symptoms OR worsening in a new distribution	Recurrence of prior/known deficits; symptoms may fluctuate
MRI	Often shows new gadolinium-enhancing lesion	No new lesion
Treatment	High-dose corticosteroids	Treat the underlying trigger; steroids are not indicated

• Always check UA and infectious workup before initiating steroids — occult UTI is a very common pseudorelapse trigger in MS patients
• If symptoms are identical to a prior relapse, pseudorelapse is more likely (MS rarely causes repeated inflammation in the same CNS location)
• Symptoms that fluctuate or resolve completely and then return favor pseudorelapse

Fever and Infection

• Fever must be reduced to minimize weakness associated with elevated temperature
• Antibiotics or surgical control of any infectious sources

Steroids

• High-dose steroid therapy for true relapses in the form of oral or intravenous methylprednisolone (1000 mg daily x 3-5 days)
  • Oral methylprednisolone at equivalent doses is non-inferior to IV and allows for outpatient treatment
• Do not initiate steroids until infection has been ruled out as the cause of symptom worsening

Plasma Exchange (PLEX)

• Second-line treatment for severe relapses refractory to high-dose corticosteroids
• ~20-35% of patients may not fully respond to steroids alone
• Typically 5-7 sessions over 10-14 days
• Consult neurology early if relapse is severe or not responding to steroids

Disease-Modifying Therapies (DMTs)

• Suppression therapies (IFN-β, Glatiramer, etc.) — initiation is generally not in ED
• However, ED physicians should be aware of complications of DMTs in patients already on treatment:

DMT	ED-Relevant Complications
Natalizumab (Tysabri)	Risk of PML (progressive multifocal leukoencephalopathy) — any new neurologic worsening warrants urgent MRI and JC virus testing
Fingolimod / Siponimod	Bradycardia, cardiac conduction abnormalities, macular edema
Ocrelizumab, Rituximab (anti-CD20)	Increased infection risk, infusion reactions, reactivation of hepatitis B
Interferons (Avonex, Rebif)	Flu-like symptoms (may mimic infection), hepatotoxicity, cytopenias
Dimethyl fumarate (Tecfidera)	Lymphopenia (increased infection risk); rare PML risk

Disposition

Discharge

• Mild relapse in a patient who can ambulate safely
• Able to tolerate oral medications (oral methylprednisolone non-inferior to IV)
• Has reliable follow-up with neurology (ideally within 1-3 days)
• No untreated infection
• Adequate social support

Admission

• Any disease exacerbation associated with significant morbidity or functional impairment
• IV antibiotics or steroid therapy required
• Inability to ambulate safely or care for self
• Urinary retention requiring catheterization
• Concern for PML or other serious DMT complication
• Depression and significant risk of suicide
• Need for plasma exchange

Neurology Consultation

• New suspected MS diagnosis
• Severe relapse with significant functional impairment
• Steroid-refractory symptoms (discuss PLEX)
• Concern for PML or other DMT-related complication
• Diagnostic uncertainty

Return Precautions

• Worsening weakness or new weakness
• New or worsening visual symptoms
• Inability to urinate or new incontinence
• Difficulty breathing or swallowing
• Fever

See Also

• Optic Neuritis
• Transverse myelitis
• Internuclear ophthalmoplegia