Demyelinating & Degenerative Disorders Flashcards
Enzyme defect in myelin metabolic pathway
- Dysmyelination
- Hypomyelination
Demyelination
Destruction of normally constituted myelin
Primary: Immunologic destruction of myelin with relative axonal preservation (MS)
Secondary: Myelin loss resulting from another CNS pathology, usually with neuronal/axonal destruction
Multiple Sclerosis
- autoimmune destruction of CNS myelin and oligodendrocytes (vs. Schwann cells)
- Epidemiology: White Women in 20-30’s
- presents with relapsing neurologic deficits with periods of remission (MULTIPLE LESIONS IN TIME AND SPACE)
- Gross: periventricular/perivascular plaques
- Micro: loss of myelin w/ preservation of axons; perivascular lymphcytic/plasma cell infiltrate; Lipid-laden macrophages; reactive astrocytes
Clinical features of Multiple Sclerosis
- stresses (infection, heat, trauma) precipitate exacerbations
Charcot’s Classic Triad (SIN):
- Scanning speech
- Intention Tremor
- Nystagmus
- Optic Neuritis: Blurred vision in one eye
- Vertigo
- Internuclear ophthalmoplegia: Medial Longitudinal Fasciculus Syndrome
- Hemiparesis
- Hemisensory symptoms
- Bladder/Bowel Incontinence
- Medial Longitudinal Fasciculus Syndrome
- Internuclear Ophthalmoplegia
CN6 (Lateral rectus muscle innervation) sends signal via MLF to CN3 of opposite eye to innervate Medial Rectus Muscle
- If damage to MLF: CN6 eye can look lateral, but opposite eye (CN3) cannot look medially
Multiple Sclerosis Etiologies
Genetic: HLA-DR2 genetically more susceptible
Viral: PERFORM LUMBAR PUNCTURE TO EVALUATE CSF
- IgG molecules of narrow specificities –> will see oligoclonal bands in CSF
- abnormal immune response to measles
- Retroviral (HTLV-1 Virus) demyelination
Multiple Sclerosis Plaques
- areas of oligodendrocyte loss and reactive gliosis, found in multiple CNS sites
- MRI IS GOLD STANDARD for MS plaque detection
White matter: periventricular
Gray matter: basal ganglia, thalamus, hypothalamus, brainstem
- stains normal myelin blue
- MS plaques won’t stain
Luxol Fast Blue Stain
Charcot Variant of MS
- Long course of alternating relapses and
remissions with increasing functional limitations
Marburg Variant of MS
- acute form with involvement of
vital brainstem centers - fatal at first presentation
Acute Disseminated Encephalomyelitis
- Acute mulitfocal perivenular inflammation and demyelination after infection (commonly measles or VZV) or certain vaccinations (rabies, smallpox)
- Pathologically resembles acute MS (Marburg Variant)
Primary/Endogenous Encephalopathies
- Defective enzyme iin metabolliic pathway related to neurolipids, carbohydrates, amino acids, nucleic acids, pigments, or metals
- Non-catabolized metabolite accumulates and destroys neurons and/or glia
- Leukodystrophy = white matter most severely affected, e.g., Canavan Disease
– Poliodystrophy = gray matter most severely affected - Rare diseases off infancy and childhood
– Insidious onset, relentlessly progressive
Secondary/Exogenous Encephalopathies
CNS metabolism perturbed by extra-CNS disease - Metabolic substrate deprivation - Metabolic cofactor deficiency - Major organ failure - Chemical imbalances - Intoxications - Stress: heat, trauma, sepsis
- Common diseases of any stage of life
– Acute/subacute onset
– Amenable to treatment
Thiamine B1 Deficiency (Metabolic CNS disease)
- Affects malnourished, especially alcoholics
Presentation:
1. CNS: Wernicke’’s encephalopathy/Korsakoff’s syndrome: Hemorrhage and necrosis in mammillary bodies and periventricular gray matter
2. PNS: Peripheral neuropathy
3. Heart failure
Cobalamin B12 Deficiency (Metabolic CNS Disease)
- Seen in malnourished and pernicious anemia
patients
– Interferes with hematopoeisis and CNS myelin
- Megaloblastic anemia- Subacute combined degeneration: Myelin destruction in POSTERIOR and LATERAL columns of spinal cord
Hepatic Encephalopathy (Metabolic CNS Disease)
Elevated ammonia levels are toxic to CNS metabolism
- Neuronal membrane depolarization and neuronal hyperexcitability
- Perturbed neurotransmitter metabolism and imbalance among neurotransmitters
– Alzheimer type 2 astrocytes: Gray matter astrocytes with swollen clear nuclei and
no visible cytoplasm
Hypoxia//hypoglycemia (Metabolic CNS Disease)
– Cerebral cortical necrosis
– Neuronal necrosis in hippocampus (CA1 region), Purkinje cells of cerebellum
– Necrosis in watershed zones of major vascular territories
Central Pontine Myelinolysis (Metabolic CNS Disease)
- Patient with abnormal serum Na+ corrected too rapidly
- Alcoholics; other debilitated chronically ill patients
– Diamond-shaped area of myelin destruction in central pons
Common Factors of Degenerative CNS Diseases
- Etiology unknown
- Insidious onset and relentless progression
- Neurons//axons primary disease target, resulting in neuronal death with reactive glosses
– Often involves groups of functionally related neurons (systems) - Clinical: Presents with dementia, movement disorders, or both
- Named after the affected gene
Huntington’s Disease
- Presents with Chorea (sudden, jerky, purposeless movements
- Autosomal dominant (AD)
- Chromosome 4 has repeating trinucleotide units (CAG)
• Normal: < 34 CAG repeats in huntingtin gene
• HD: > 36 CAG repeats in huntingtin gene - Loss off GABAergic neurons (inhibitory neurotransmitter) in caudate nucleus, putamen, thalamus, cerebral cortex results in Extrapyramidal movement diisorder ± dementia
- suicide is common cause of death
Friedreich’s Ataxia
- AR trinculeotide repeat disorder of GAA in frataxin gene in Chromosome 9
- leads to impairment of mitochondrial functioning
– Spinocerebellar degeneration: Loss of axons/neurons in spinal cord, cerebellum - Gait ataxia (staggering gait), followed by other cerebellar, posterior column, and pyramidal tract signs and symptoms (frequent falling)
Charcot-Marie-Tooth Disease
Hereditary Peroneal Muscular Atrophy
- Autosomal dominant (AD)
– Segmental repeat in PMP 22 gene (of chromosome 17) for myelin structural
protein - results in Myelin damage and axonal loss in peripheral nerves
- Distal leg weakness and muscle atrophy ± sensory loss
Duchenne muscular dystrophy
- X-linked recessiive (XLR)
- Loss of DNA in X chromosome: Deletion in dystrophin gene coding for structural protein in skeletal muscle
- results in slow progressive wasting of skeletal and cardiac muscle
- Progressive loss of muscle function–> immobility –> respiratory paralysis
Prion Disease
Transmission of a non-nucleic-acid-containing protein inducing structural change in normal neuronal protein
– Creutzfeldt-Jakob disease (CJD): rapidly progressive dementia with myoclonus (twitching of group of muscles)
– Kuru
– Bovine spongiform encephalopathy (mad cow disease)
Alzheimer’s Disease
- Most common dementia
–Widespread neuronal loss and gliosis affecting the Cerebral cortex, brainstem, basal ganglia, resulting in Decrease in brain weight and volume, and Increase in ventricular volume (hydrocephalus ex vacuo) - Symptoms: slow-onset memory loss and progressive loss of everyday function
- will see loss of Ach (cholinergic) neurons in the nucleus basalis of Meynert
Histological findings for Alzheimer’s Disease
Neuritic/Senile Plaques: EXTRACELLULAR core comprised of AB amyloid with entangled neuritic processes
- AB amyloid is derived from APP (coded on Chromosome 21 - Hence Down Syndrome have early onset)
- Normal APP undergoes alpha cleavage
- In AD: undergoes Beta cleavage
- Cerebral Amyloid Angiopathy: AB amyloid that deposits around blood vessels of brain, increasing risk of hemorrhage
Neurofibrillary Tangles: INTRACELLULAR aggregates of hyperphosphorylated tau protein
- Tau is a microtubule-associated protein
- Hirano Bodies: insoluble cytoskeletal elements
- Granulovacuolar degeneration: Lysosomes with altered cytoskeletal proteins
Etiology of Alzheimer’s Disease
Sporadic:
- age
- ApoE4: increases risk
- ApoE2: protective
Early-onset AD:
- Presenilin 1 & 2 mutation
- Down Syndrome (Trisomy 21)
- APP on Chromosome 21
Pick’s Disease
- Frontotemporal Dementia
- similar clinically to Alzheimer’s disease, but different in Gross and microscopic findings:
– Marked atrophy of frontal lobe and anterior 2/3 of superior temporal gyrus; sparing of parietal lobe, occipital lobe and posterior superior temporal gyrus
– ROUND/SPHERICAL Tau protein aggregates/silver-positive neuronal inclusions (Pick bodies) - behavioral (frontal) and language (temporal) symptoms arise early
Multi-infarct dementia
- Dementia secondary to vascular disease, which is the cumulative consequence of many small strokes, or moderate global cerebral ischemia
- 2nd most common cause of dementia in elderly
- results in memory loss and cognitive dysfunction
Binswanger’s Encephalopathy
- Diffuse damage to CNS white matter from arteriolar disease (usually hypertensive)
Normal Pressure Hydrocephalus
- Increased CSF/decreased absorption of CSF into arachnoid granulations, resulting in dilated ventricles (stretching of the corona radiate)
- b/c of stretching, there is only intermittent increase in ICP
- Classic Triad: Urinary incontinence, Gait Instability and Dementia (Wet, Wobbly & Wacky)
- Tx: Lumbar puncture, or Ventriculoperitoneal Shunt
Parkinson Disease
- Degenerative loss of dopaminergic neurons in the SUBSTANTIA NIGRA of the basal ganglia (pallor), resulting in EXTRAPYRAMIDAL movement disorder
- Lewy Bodies: round, pink, target-like inclusions in surviving neurons of substantial nigra
Clinical features (TRAP):
- Tremor: pill rolling tremor at rest
- Rigidity: cogwheel rigidity in extremities
- Akinesia/Bradykinesia: slowing of voluntary movement; mask fasce
- Postural instability & shuffling gait
Lewy Body Dementia
Parkinson Disease + Dementia
- Lewy bodies accumulate in the cerebral cortex in addition to the substantia nigra
Motor Neuron Disease
- Idiopathic degeneration of lower motor
neurons in spinal cord and cranial nerve
nuclei (spinal ventral horn neurons), plus degeneration of axons of upper
motor neurons (corticospinal tract)
– Clinical: Combined upper and lower motor neuron signs
Histo:
– Neuronal loss and gliosis of the ventral horns of spinal cord and lower cranial nerve motor nuclei (XII)
– Neurogenic atrophy in denervated skeletal
muscle
Spinal Muscular Atrophy
- Idiopathic fetal and infantile degeneration of
lower motor neurons (spinal cord, cranial
nerve motor nuclei) WITHOUT corticospinal tract signs
– SMA type I (Werdnig-Hoffmann disease)
important and fatal cause of neonatal hypotonia
– Autosomal recessive disease carried on
chromosome 5
