Multiple Sclerosis

General Characteristics

Multiple sclerosis is a multifocal demyelinating disease – the disease causes the destruction of the myelin sheath of nerve fibers – scar-like lesions called sclerotic plaques form in the areas where the demyelination has occurred and block or distort the normal transmission of nerve impulses.

• Incidence and prevalence vary geographically
  • fewer cases near the equator and larger numbers in the northern and southern latitudes
    • between 250,000 to 350,000 people with MS in the United States, with three times more cases among residents in the northern (versus southern) half of the country.
      • this distribution suggests an environmental contribution to the disease
  • MS is twice as likely to affect women than men

• Two severity outcomes defined
  • Benign outcome: Full functioning for 15 years post onset
  • Malignant outcome: rapidly progressive course with significant disability or death soon after onset

Diagnosis

• Can be difficult to diagnose in early stages b/c of its presentation
• Diagnosis requires the occurrence of 2 or more attacks each lasting a minimum of 24 hours and separated by at least a month.
• The attacks must also be caused by lesions in 2 distinct areas of the CNS
• Diagnosis rests on clinical grounds
• MRI’s can be used to detect demyelinating plaques in the brain
  • BUT other disease can cause similar imaging patterns – e.g., AIDS and Lyme disease
  • Plaques have predilection for periventricular white matter of brain (L/R hemisphere equally affected)
  • Extent of plaques and total lesion area is related to cognitive fxing, but in general location of plaques is not predictive
• CSF analyses – can be used to detect oligoclonal abnormalities

Etiology

• Actual etiology is unknown, but data implicates:
  • Genetic variables – 1st degree relatives of affected individuals are 6-8 times more at risk than the general population, with siblings being most at risk; women:men = 2:1
  • Environmental variables – siblings who develop MS do so in the same calendar year rather than at the same age
    • prevalence rates of MS decreases systematically as latitude of habitation nears the equator
    • those who move from high-risk latitude to a low-risk latitude (e.g. Europeans moving to South Africa) or vice-versa carry with them some of the risk from their place of origin if their movement occurs after the age of 15 — disease acquisition is believed to occur before puberty
  • immunologic variables
  • Proposed explanations include a slow acting virus, a delayed reaction to a common virus, or an autoimmune reaction in which the body attacks its own tissues

Treatment

• Corticosteriods, adrenocorticotropic hormone (ACTH) and other anti-inflammatory agents may be used during exacerbation to hasten remission
  • These drugs are known to produce mood changes and should be considered when assessing affective changes in patients with MS
• Now introducing immunomodulators (e.g., interferon B-1-a) to treat, but even these still can’t arrest or cure

Disease Course

• Deficits partially resolve as inflammation subsides; also can be suppressed with steroids, but with more attacks more plaques develop and permanent deficits occur
• Approximately 50% have a mixed or generalized type, which involves the optic nerve, the brain, the cerebellum, and the spinal cord
• 2/3 of people are diagnosed between the ages of 20-40 (average 30); although the transient and variable nature of MS symptoms make it difficult to diagnose (mean delay of 3.5 – 4 years from time of onset to diagnosis has been documented)
  • likely acquired before puberty however
    • onset before 15 rare
  • onset after 40 typically characterized by quicker progression and shorter length of survival
• Typical lifespan following MS onset about 30 years, but this varies

Disease Categories

(Categories imprecise at best)

1. Relapsing/Remitting (most common in early years – about 90%)
2. Primary progressive
3. Secondary progressive – initially relapsing-remitting course followed by progression with or without occasional relapses, minor remissions and plateaus
4. Progressive relapsing (rarest) – progressive disease from onset with clear acute relapses, periods between relapses characterized by continuing progression

General Symptoms

• Early symptoms commonly include:
  • Weakness in one or more limbs
  • Bladder dysfunction – includes urinary urgency, frequency, dysuria, nocturia, and incontinence
  • Optic neuritis (i.e., inflammation, demyelination or degeneration of the optic nerve)
    • results in temporary or total loss of vision, usually occurring over several hours or days
    • retrobulbar neuritis – optic neuritis that occurs far enough behind the optic disk that no early changes of the optic disk are visible by opthalmascope (MS is the most common cause for this)
  • Acute Myelitis (Transverse Myelitis) – common designation for an acutely evolving inflammatory-demyelinative lesion of the spinal cord, which often is expression of MS
  • Other neurological signs
    • e.g., vertigo, seizures, nystagmus, ataxia, diplopia, hemiplegia, deafness, neuropathy, aphasia and emotional changes
    • Charcot’s Triad: nystagmus, dysarthria, and tremor
    • Spinal Cord (3 I’s): incontinence, impotence, impairment of gait

• Other common symptoms
  • spasticity
  • fatigue – one of the most common and debilitating complaints, affecting upto 90% of patients
  • psychiatric changes – including affective disturbances, psychoses and personality changes
    • believed to be due to the disease process rather than (only) a psychological response to the illness

Cognitive Symptoms

Cognitive symptoms have been reported in the early stages of the disease, but they become more evident as more white matter is affected

• Overall prevalence of cognitive symptoms between 40-70%
  • Of the people with cognitive impairment, 80% of these folks have mild impairments
  • Even mild cognitive problems in MS are enough to interfere with day-to-day activities
• Pattern of impairments more likely to resemble patients with frontal and subcortical lesions
• Receptive and expressive language skills are generally spared (although mild deficits in naming and word generation are common)
• Cognitive symptoms result from demyelination rather than gray matter lesions
• Most common deficits are in memory, complex attention/speed of information processing and executive functions
• basic cognitive profile (consistent with subcortical dementia, although because procedural memory spared might be considered White Matter Dementia):
  • little or no language deficit
  • impairment in retrieval from long-term memory, but normal recognition, immediate recall, and rates of forgetting
  • impaired abstract and conceptual reasoning, slowed rates of information processing
  • impaired attention

• Intellectual Functioning
  • VIQ>PIQ (likely reflects motor impairments)

• Memory Functioning
  • Some research suggests that memory impairments represent difficulties in retrieval, with storage, encoding, and recognition are generally spared (although this is a somewhat controversial finding)

• Speed of Information Processing
  • While exaggerated by physical impairment, it also appears to cause an overall slowed speed of processing
  • May contribute to verbal memory impairments
  • commonly manifest as difficulty keeping up with conversations, work tasks

• Attention
  • may be reflected as reduced span, impaired mental tracking, or slowed complex visuomotor tracking
• Working memory deficits common

• Executive Functions
  • Impairments similar to frontal lobe patients (e.g., problems with conceptual flexibility, abstraction, planning and problem solving)
  • Most common w/ chronic-progressive form
  • clinically evident in disinhibition and tangential speech, difficulty planning day-to-day activities, and problems organizing ideas in conversation and speech

• Motor Slowing
  • Often seen early in course of disease

• Visual Spatial Functions
  • Generally intact visual spatial skills but 10% to 20% of people with MS show higher order visual spatial processing problems(variable – impairments more related to exec. fxns and motor speed)
  • May be seen clinically as problems running into things while walking (e.g., walls, doors) or driving (e.g., curbs, posts) due to miscalculations

• Typical areas of preserved functioning (again, may be variable): Memory storage, encoding, recogniton, simple auditory span; motor skill and implicit learing, language skills (aside from fluency), basic visual spatial functions

Affective and Behavioral Functioning

• Depression is a common finding in people with MS
  • It is sometimes the first or most prominent symptom
  • People with MS have 50% lifetime risk of depression
    • May be exacerbated by high levels of perceived stress, low levels of perceived instrumental and emotional support, disease exacerbation and pharmocological treatment of disease associated with greater distress and depression
    • Notassociated with severity of neurological disability
• Personality changes – also (rarely) includes euphoria
• Anxiety also common, and found in about 25% of people with MS, but not well studied
  • May be prominent in early stages of disease when diagnosis and prognosis are unclear
  • comorbidity of anxiety and depression is more associated with somatic complaints and social dysfunction than either anxiety or depression alone
• Emotional changes may be related to periventricular and frontal white matter lesions
  • Assocations between impairments in complex attention, information processing speed, and perhaps, executive functions and depression have been found
    • may have common neuroanatomical substrate

Differential Diagnosis

• Dysmyelination
• Number of conditions that can mimic MS
  • Guillain-Barre Syndrome – demyelinating disease of PNS
    • characterized by monophasic attack, lasting several weeks to months; no cog impairment
  • Leukodystrophies
    • Group of genetically transmitted illnesses
    • Usually manifest in children or adolescents, but sometimes later
    • Cause unremitting physical and mental deterioration
    • Two well-known: adrenoleukodystrophy (ALD) and metachromatic leukodystrophy (MLD)
  • Infections
  • Toxins – numerous toxins preferentially attack CNS myelin
    • Marchiafava-Bignami: possibly caused by substance in homemade red wine and results degeneration of CC
    • Chronic Toluene exposure
  • Lupus: produces CNS changes in only about 5% of cases