Demyelinating & Degenerative Disorders

Question 1

Enzyme defect in myelin metabolic pathway

Answer 1

• Dysmyelination

- Hypomyelination

Question 2

Demyelination

Answer 2

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

Question 3

Multiple Sclerosis

Answer 3

• 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

Question 4

Clinical features of Multiple Sclerosis

Answer 4

• stresses (infection, heat, trauma) precipitate exacerbations

Charcot’s Classic Triad (SIN):

1. Scanning speech
2. Intention Tremor
3. Nystagmus

• Optic Neuritis: Blurred vision in one eye
• Vertigo
• Internuclear ophthalmoplegia: Medial Longitudinal Fasciculus Syndrome
• Hemiparesis
• Hemisensory symptoms
• Bladder/Bowel Incontinence

Question 5

• Medial Longitudinal Fasciculus Syndrome

- Internuclear Ophthalmoplegia

Answer 5

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

Question 6

Multiple Sclerosis Etiologies

Answer 6

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

Question 7

Multiple Sclerosis Plaques

Answer 7

• 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

Question 8

• stains normal myelin blue

- MS plaques won’t stain

Answer 8

Luxol Fast Blue Stain

Question 9

Charcot Variant of MS

Answer 9

• Long course of alternating relapses and

remissions with increasing functional limitations

Question 10

Marburg Variant of MS

Answer 10

• acute form with involvement of
  vital brainstem centers
• fatal at first presentation

Question 11

Acute Disseminated Encephalomyelitis

Answer 11

• Acute mulitfocal perivenular inflammation and demyelination after infection (commonly measles or VZV) or certain vaccinations (rabies, smallpox)
• Pathologically resembles acute MS (Marburg Variant)

Question 12

Primary/Endogenous Encephalopathies

Answer 12

• 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

Question 13

Secondary/Exogenous Encephalopathies

Answer 13

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

Question 14

Thiamine B1 Deficiency (Metabolic CNS disease)

Answer 14

• 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

Question 15

Cobalamin B12 Deficiency (Metabolic CNS Disease)

Answer 15

• 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

Question 16

Hepatic Encephalopathy (Metabolic CNS Disease)

Answer 16

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

Question 17

Hypoxia//hypoglycemia (Metabolic CNS Disease)

Answer 17

– Cerebral cortical necrosis
– Neuronal necrosis in hippocampus (CA1 region), Purkinje cells of cerebellum
– Necrosis in watershed zones of major vascular territories

Question 18

Central Pontine Myelinolysis (Metabolic CNS Disease)

Answer 18

• Patient with abnormal serum Na+ corrected too rapidly
  - Alcoholics; other debilitated chronically ill patients
  – Diamond-shaped area of myelin destruction in central pons

Question 19

Common Factors of Degenerative CNS Diseases

Answer 19

• 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

Question 20

Huntington’s Disease

Answer 20

• 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

Question 21

Friedreich’s Ataxia

Answer 21

• 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)

Question 22

Charcot-Marie-Tooth Disease

Hereditary Peroneal Muscular Atrophy

Answer 22

• 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

Question 23

Duchenne muscular dystrophy

Answer 23

• 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

Question 24

Prion Disease

Answer 24

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)

Question 25

Alzheimer's Disease

Answer 25

- 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

Question 26

Histological findings for Alzheimer's Disease

Answer 26

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

Question 27

Etiology of Alzheimer's Disease

Answer 27

Sporadic: - age - ApoE4: increases risk - ApoE2: protective Early-onset AD: - Presenilin 1 & 2 mutation - Down Syndrome (Trisomy 21) - APP on Chromosome 21

Question 28

Pick's Disease

Answer 28

- 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

Question 29

Multi-infarct dementia

Answer 29

- 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

Question 30

Binswanger’s Encephalopathy

Answer 30

``` - Diffuse damage to CNS white matter from arteriolar disease (usually hypertensive) ```

Question 31

Normal Pressure Hydrocephalus

Answer 31

- 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

Question 32

Parkinson Disease

Answer 32

- 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

Question 33

Lewy Body Dementia

Answer 33

Parkinson Disease + Dementia | - Lewy bodies accumulate in the cerebral cortex in addition to the substantia nigra

Question 34

Motor Neuron Disease

Answer 34

- 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

Question 35

Spinal Muscular Atrophy

Answer 35

- 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