Armando Hasudungan
Biology and Medicine videos

Multiple Sclerosis

“Each patient ought to feel somewhat the better after the physician’s visit irrespective of the nature of the illness.”

-Warfield Theobald Longcope

Overview

Multiple sclerosis (MS) is defined as an inflammatory demyelinating disease characterised by the presence of episodic neurological dysfunction in at least 2 areas of the CNS (brain, spinal cord, and optic nerves) separated in time and space.

Overview

MS is the most common cause of neurological disability among young adults. MS is most commonly diagnosed between 20 to 40 years old. Irreversible disability can occur, but life expectancy is generally not affected.

Defintion
Multiple Sclerosis: Incurable disease of the central nervous system that can affect the brain, spinal cord and optic nerves.
Guillain–Barré syndrome: Rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system.
Motor Neuron Disease: Motor neurone disease is largely a sporadic disease of middle and elderly life presenting in the sixth and seventh decades. The classic form of the disease is also referred to as amyotrophic lateral sclerosis and presents with a mixture of upper and lower motor neurone features, such as wasted fasciculating biceps with a brisk or easily obtained biceps deep tendon reflex. The rarer variants of the disease can have a pure upper motor neurone presentation, primary lateral sclerosis, or a pure lower motor neurone presentation, progressive muscular atrophy.
Myasthenia Graves: Autoimmune disease characterized by muscle weakness that fluctuates, worsening with exertion, and improving with rest. In about two-thirds of the patients, the involvement of extrinsic ocular muscle presents as the initial symptom, usually progressing to involve other bulbar muscles and limb musculature, resulting in generalized myasthenia gravis.

Anatomy and Physiology

Neuron Anatomy

Neurology - Neurons

Watch Neurology – Neuron structure and function

Spinal Cord

Neurology - Spinal cord and Glial cells

Watch Neurology – Spinal cord and Glial cells

Motor Pathways

Screen Shot 2016-08-27 at 11.30.52 AM

Watch Motor Pathway

Clinical Classification of MS

TYPES OF MULTIPLE SCLEROSIS BASED ON DISEASE ONSET
Relapsing remitting (85% of onset) Discrete attacks that evolve over days to weeks, followed by some degree of recovery over weeks to months; the patient has no worsening of neurologic function between attacks
Primary progressive (10% of onset) Gradual progression without acute attacks or improvements
Relapsing progressive (5% of onset) Like primary progressive, but with some superimposed relapses
TYPES OF MULTIPLE SCLEROSIS BASED ON DISEASE COURSE
Clinically isolated syndrome (commonest first presentation of multiple sclerosis) Probable first episode of relapsing-remitting multiple sclerosis (eg optic neuritis, transverse myelitis or brainstem episode). If two or more white matter lesions on MRI then about 80% chance of eventual multiple sclerosis; if MRI is normal then only about 20% chance
Secondary progressive (50% of Relapsing remitting may evolve to secondary progressive) Initial relapsing remitting disease, followed by gradual neurologic deterioration not associated with acute attacks
Benign Minimal or no disability after 15 years. Infrequent attacks with excellent recovery
Malignant (rare) Severe attacks with poor recovery and rapid progression leading to death or profound disability within 2 years

Risk Factors

  • Female sex
  • Northern latitude
  • Smoking
  • Vitamin D deficiency
  • Autoimmune disease

Signs and Symptoms

Common symptoms

  • Numbness and tingling
  • Weakness of limb(s)
  • Incoordination and dizziness
  • Visual loss, blurring and diplopia
  • Bladder urgency
  • Constipation
  • Sexual difficulties
  • Anxiety and depression
  • Fatigue and heat sensitivity

Signs and SymptomsSigns and Symptoms

Less common

  • Leg spasticity
  • Pain
  • Tremor
  • Slurred speech (dysarthria)
  • Major mood disorders
  • Bladder incontinence
  • Bowel incontinence
  • Cognitive disturbance
COMMON SIGNS AND SYMPTOMS SUGGESTIVE OF CNS DEMYLELINATION
Site Condition Symptoms Sign
Optic nerve  Optic neuritis Pain on eye movement, blurred vision Reduced monocular visual acuity, colour desaturation
Cerebellum Cerebellar disease Unsteadiness Limb or gait ataxia; horizontal or torsional gaze evoked nystagmus
Spinal cord (usually multifocal and asymmetric) Partial myelitis affecting pyramidal tracts Upper or lower limb weakness Pyramidal distribution weakness
Partial myelitis affecting spinothalamic tract and posterior columns Unilateral or bilateral limb numbness or paraesthesias L’Hermitte’s phenomenon (short electric shock-like sensation on neck movement) Sensory level
Brainstem
Medial longitudinal fasciculus
Pyramidal tracts
Spinothalamic tract and posterior columns
Internuclear ophthalmoplegia (Similar to conditions described in spinal cord) (Similar to conditions described in spinal cord) Blurred or double vision Internuclear ophthalmoplegia
Bowel/bladder Loss of upper motor neuron control Constipation, urinary frequency, urge incontinence, erectile dysfunction

Differential Diagnosis

  • Fibromyalgia
  • Sjogren’s Syndrome
  • Vitamin B12 deficiency
  • Stroke
  • Gullain-Barre Syndrome
  • Amyotrophic lateral sclerosis (ALS) also known as Motor Neuron Disease
  • Systemic  lupus erythematosus
  • Recurrent infarcts
  • Paraneoplastic syndromes
  • Psychiatric disease/functional symptoms.

Investigations

  • MRI – Brain and Spinal cord
  • FBC – Infection, inflammation, neoplasm
  • ESR – infection/inflammation
  • Rapid plasma reagin – Syphilis
  • Thyroid function test – Hypothyroidism
  • Serum vitamin B12
  • Antinuclear antibody titers – Rheumatologic disease, systemic lupus erythematosus
  • Borrelia titers – Lyme disease
  • Angiotensin-converting enzyme level – Sarcoidosis
  • HIV screening
Brain MRI of normal and person with MS

Brain MRI of normal and person with MS

 

Typical sites of lesions on MRI
Periventricular white matter (if at right angles to the corpus callosum, these are referred to as ‘Dawson fingers’)
Juxtacortical white matter
Corpus callosum
Optic nerve (with gadolinium enhancement in acute neuritis)
Infratentorial structures (pons, cerebellar peduncles and cerebellum)
Spinal cord

Spine MRI


Diagnosis Multiple sclerosis remains a clinical diagnosis supported by:

  • Magnetic resonance imaging (MRI)
  • Evoked potential studies (delayed evoked response with preserved waveform)
  • Cerebrospinal fluid examination (oligoclonal bands and raised IgG index)

Diagnosis

  • Clinical Two neurologic deficits (e.g., focal weakness, sensory disturbances) separated in time and space, in the absence of fever, infection, or competing etiologies, are considered diagnostic
Remember Attacks may be patient-reported or objectively observed, and must last for a minimum of 24 hours
  • MRI – Diagnosing MS in cases not meeting the threshold for clinical diagnosis
  • Evoked potentials (visual, auditory, and somatosensory) may provide objective evidence of deficits consistent with MS
  • Cerebrospinal fluid – demonstrates oligoclonal bands and an increased immunoglobulin G concentration

Pathophysiology

  • An immune mechanism is suggested by increased levels of activated T-lymphocytes in the CSF and increased Ig synthesis within the CNS
  • An attack CNS inflammation starts with the entry of activated T-lymphocytes across the BBB
  • T cells seek entry into the CNS via attachment to a receptor on endothelial cells
  • This interaction allows a breach in the BBB, leading to further upregulation of endothelial adhesion molecules and addition influx of inflammatory cells
  • These recognise myelin-derived antigens on the surface of nervous system’s APCs (the migroglia) and undergo clonal proliferation
  • The resulting inflammatory cascade releases cytokines and initiated destruction of oligodendrocyte-myelin unit by macrophages (oligodendrocytes try and repair the myelin but overtime as the myelin keeps getting destroyed, they become less effective at doing so)
  • The degernative component of MS is believed to reflect axonal degeneration and loss
  • Demyelination disrupts axonal support and leads to destabilisation of axonal membrane potentials which causes distal and retrograde degeneration over time (+ injury of the inflammatory cells to axons)

Course of disease

  • 85% present with relapsing/remitting disease (RRMS)
    • Subacute evolution of symptoms over days; symptoms reach a plateau and resolve over days or weeks
  • After 10–15 years, 50% enter the secondary progressive phase some with relapses (SPMS).
  • 10% have primary progressive disease (PPMS) with gradual accumulation of disability

Management

Side note With symptoms of relapse, it is vital to establish whether the symptoms are definitely neurological. Intercurrent infection, fever, increased environmental temperature, heightened body awareness and depression can all produce ‘pseudorelapses’. Many ‘attacks’ simply reflect heightened body awareness and anxiety, particularly in the first year after diagnosis

Acute Relapse

  • Mild – rest reassurance
  • Moderate – Oral corticosteroids 4days
  • Severe
    • IV Corticosteroids (methylprednisolone) 3 days
    • Intravenous immunoglobulins (if corticosteroids are ineffective)
    • Anticonvulsants (if sensory symptoms present)
    • Physiotherapy
    • Review

Prevention of relapse

  • Education
  • Immunomodulators (first line)
    • Interferon beta
    • Glatiramer acetate
    • Natalizumab
  • Immunosuppressants and newer therapies (second line)
  • Life style modifications (for urinary frequency and motor problems)
    • Avoid caffeine and vitamin waters
    • Yoga and relaxation
    • Physiotherapy excercise
Pharmacology Interferon beta is a naturally occurring antiviral and immunomodulatory substance. It can reduce the frequency of attacks by over 1/3, the severity of attacks, the number and size of lesion seen on MRI, and the rate of disease progression. Side effects: influenza-like reactions, local skin reactions and depression
Pharmacology Natalizumab Monoclonal antibody that works by selective inhibition of adhesion molecules, slowing entry of T cells through cerebral capillaries. Used in patients intolerant of/not responding to other immunomodulators. Side effects: fatigue, hypersensitivity hepatotoxicity and has been associated with progressive multifocal leukoencephalopathy

Treatment of Complication of MS

  • Spasticity
    • Physiotherapy
    • Baclofen, Botox IM
  • Ataxia, tremors –  Isoniasid, Clonazepam
  • Dysaesthesia – Carbamazepine
  • Bladder symptoms – Oxybutynin
  • Fatigue – Amantadine
  • Impotence – Sildenafil
  • Psychiatric symptoms

Lifestyle modification

  • Diet and weight
  • Smoking cessation
  • Substance use disorder screening

Complications and Prognosis

Complications

  • UTI
  • Osteoporosis/osteoporosis
  • Depression
  • Visual impairment
  • Erectile Dysfunction
  • Cognitive impairment
  • Impaired mobility
Complications

Complications of MS

Prognosis

  • Prognosis varies between patients
  • ~25% of patients with multiple sclerosis have a benign course throughout, with minimal or no disability after many years.
  • The majority of patients have a relapsing-remitting course of disease at the time of initial diagnosis
    • After 10 years, about half of the patients with relapsing-remitting disease will have changed to a progressive form (secondary progressive); this transition worsens the prognosis.

References

UpToDate
Best Practice
BMJ
AAFP – Multiple Sclerosis: A Primary Care Perspective
RACGP – Multiple Sclerosis: Diagnosis, management and prognosis