HSS 460 MS & Parkinson's (Neuro pt. 1)

Oligodendrocytes

Glial cells responsible for myelinating & insulating CNS axons; allows faster action potential propagation along axons in the CNS

Multiple sclerosis (MS)

An inflammatory, autoimmune disease that causes demyelination of CNS axons; autoimmune-mediated destruction produces typical lesions called sclerotic “plaques” that scar and harden, resulting in impaired nerve transmission

• Effects females more than males

• Involves a genetic susceptibility, often related to MHC/HLA genes

• Onset is associated with environmental triggers

• Chronic course, with acute exacerbations occurring with certain triggers

MS etiology

Includes a combination of genetic susceptibility + infections and environmental factors…

• Genetic susceptibility: several genes associated with disease course & severity (e.g., HLA class II; mutation often results in abnormal antigen presentation)

  • About 20% of people with MS have a close relative with the disease

  • More common in those of Northern European ancestry

• Infections & environmental factors: infection may trigger an abnormal immune response and loving in northern latitudes is associated with earlier onset and severity of the disease

  • Possibly explained by migration patterns of Northern Europeans

  • Northern latitudes → less UVB exposure → lower serum vitamin D levels → altered immune system regulation

MS pathophysiology

Unknown if the immune response is initially directed toward myelin proteins of oligodendrocytes (the CNS cells that produce myelin)

• Autoreactive T cells cross blood-brain barrier → proliferate & release cytokines → recruit/activate microglia, macrophages, & other lymphocytes → immune response against myelin

• MHC/HLA class II molecules are used to present antigen to CD4+ T lymphocytes (helper T cells); abnormal presentation → destruction

MS lesions

Hardened, demyelinated sclerotic “plaques,” mostly in white matter; commonly found on optic nerves (CN II), periventricular WM, brainstem, cerebellum, and spinal cord WM

• Initial lesions contain reduced myelin basic protein (MBP) and increased proteolytic enzymes, macrophages, lymphocytes, and antibody-producing plasma cells

• Mature lesions show reduced or absent oligodendrocytes

Clinical courses of MS

1. Relapsing-remitting (RRMS)

2. Secondary progressive

3. Primary progressive

4. Progressive-relapsing

Relapsing-remitting MS (RRMS)

Characterized by disease relapses with either a full recovery or a deficit after recover; no progression of disease symptoms in recovery stage

• Acute exacerbations → recovery or deficit → stable course between relapses

• “Triggers” of relapse include stress, fatigue, infection, temperature extremes

• ~80% of people with MS are diagnosed with RRMS; ~50% of these progress over the course of years to secondary progressive

Secondary progressive MS

Disease progression from onset with infrequency plateaus and only temporary, small improvements; clinical status continuously worsens with no distinctive remissions

• Involves gradual deterioration in symptoms, with or without relapses

• Occurs in someone previously diagnosed with RRMS

Primary progressive MS

Begins as relapsing-remitting (RRMS) but progresses with with or without infrequent relapses, plateaus, and remissions

• Characterized by nearly continuous deterioration form onset of symptoms

Progressive-relapsing MS

Progressive from onset with short, definite relapses or without full recovery

Common early indicators of MS

• Visual impairments (e.g., clouding of vision with paint in eye [optic neuritis of CN II], diplopia, and nystagmus [involvement of CNs controlling eye position])

• Motor function difficulties

• Paresthesia (e.g., numbness, tingling, burning pain, “pins and needles”)

Motor dysfunction manifestations of MS

• Speech/swallowing

• Bladder and sexual dysfunction

• Gait changes (walking impairment), loss of coordination and balance (ataxia)

• Muscle weakness and spasticity

• Autonomic involvement may impair normal HR & BP responses

Cognitive manifestations of MS

• Fatigue is common and reported as one of the worst symptoms

• Depression

• Mood swings

• Forgetfulness, memory loss

Diagnostic testing for MS

• Medical history and neurological exam — symptom evaluation; establishes patterns of exacerbations, recovery/remission, & progression

• MRI — important in evaluating lesions (showing “multiple scleroses”)

• Cerebrospinal fluid (CSF) evaluation — large percentage of people with MS have elevated IgG levels in CSF

• Blood test — no specific blood test for MS, but useful for ruling out other diseases

Electrophoresis of CSF for MS diagnosis

90% of people with MS show “oligoclonal bands” on electrophoresis of CSF — represent IgG antibodies in the CSF but NOT in blood serum

• Demonstrates inflammation occuring specifically within the CNS

• Multiple bands show multiple lesions (or multiple, myelin-related targets of antibodies)

Parkinson’s disease (PD)

A progressive neurological disorder caused by loss of dopaminergic neurons in the substantia nigra of the midbrain (part of a collection of “deep nuclei” [basal ganglia] in the brain that control motor function)

• Classic PD is considered “idiopathic”, but numerous genes and some environmental toxins are linked

• Average age of diagnoses is 56 years

Parkinsonism

Clinical syndrome including progressive deterioration of motor skills and development of nonmotor symptoms such as cognitive dysfunction and depression

• Motor and nonmotor symptoms often lead to decreased independence and QOL

Motor functions of the basal ganglia/deep nuclei

• Starting, stopping, and monitoring movements initiated by the cortex, especially stereotyped motions (e.g., repetitive arm “swing” in walking)

• Inhibits antagonistic and unwanted movements

• Enhances movements in transition, efficiency, gracefulness

Role of the substantia nigra

Supplies inhibitory dopamine to other areas of the deep nuclei — prevents unwanted motor stimulation & balances the excitatory circuits between the cortex & thalamus

• Appears dark grey/black due to melanin pigment

• Dopaminergic neurons are selectively destroyed in PD

Manifestations of PD

Bradykinesia and at least one of the following…

• Muscle rigidity (resistance to flexion and extension through full ROM)

• Resting tremor (usually in hand or foot)

• Postural instability not caused by visual, vestibular, cerebellar, or proprioceptive dysfunction

What leads to a definitive diagnosis of PD?

The supportive criteria of 3+ of the following symptoms lead to a definitive diagnosis:

• Unilateral onset of symptoms

• Resting tremor present

• Progressive change in symptoms

• Persistent asymmetry of symptoms, with onset side having greater severity

• Response (decrease in symptoms) to levodopa (L-DOPA)

• Presence of levodopa-induced dyskinesia (involuntary movements)

  • A later adverse effect of L-DOPA treatment is the on-off phenomenon: abrupt changes in motor function that alternate between dyskinesia (on) and bradykinesia (off)

• Levodopa response ≥5 years

• Clinical course ≥10 years

L-DOPA

Aka levodopa; drug used in PD treatment

• L-DOPA can cross the BBB, whereas dopamine cannot

• Within neurons of substantia nigra, dopa-decarboxylase converts L-DOPA to dopamine

• L-DOPA is often given with Carbidopa, which blocks the action of dopa-decarboxylase in the peripheral blood so that more L-DOPA is available to enter the brain (it is not converted to dopamine until after passing the BBB)

Nonmotor signs & symptoms of PD

• Cognitive deficits — estimated that 75% of individuals who survive more than 10 years from diagnosis will develop dementia

• Depression — a significant barrier to therapies targeting QOL (e.g., exercise)

• Anxiety

• Sleep disorders

• Autonomic dysfunction — uncontrolled sweating, salivation, orthostatic hypotension, thermal regulation

• Sensory deficits