Patho Exam #3: Neurodegenerative Diseases

Patho Exam #3: Neurodegenerative Diseases

• Neurodegenerative disorders involve a loss of functional neurons, often multifactorial.
• Basal ganglia are subcortical areas responsible for integrating and fine-tuning nerve fibers for movement. They don't directly cause movement.

Basal Ganglia Pathways

• Indirect Pathway (inhibition): Dopamine binding to D2 receptors inhibits the striatum; this decreases GABA release onto the Globus Pallidus External (GPe). Less inhibited GPe releases more GABA onto the Subthalamic Nuclei, decreasing glutamate release onto the Globus Pallidus Internal (GPi). Reduced glutamate to GPi means less GABA release onto the thalamus, increasing thalamic activity and resulting in decreased motor coordination.
• Indirect Pathway (without dopamine): Striatum releases GABA to the GPe, decreasing GPe-mediated GABA release onto subthalamic nuclei. Less GABA means increased glutamate release from the Subthalamic Nuclei to the GPi, increasing GABA release onto the thalamus, leading to decreased motor coordination.
• Direct Pathway (with dopamine): Dopamine binding to D1 receptors in the striatum increases GABA release onto the GPi. This decreases GABA release from the GPi to the thalamus, resulting in increased thalamic activity and fluidity of movement.

Parkinson's Disease

• Characterized by Bradykinesia (slow movements), tremors (initially with voluntary movement, later at rest), gait abnormalities (shuffling gait), and late-stage cognitive difficulties.
• Lesions are in pars compacta (most highly affected).
• Management:
  • Levodopa + Carbidopa (dopamine precursor, peripheral inhibitor).
  • Dopaminergic agonists (pramipexole, ropinirole, bromocriptine).
  • MAO-B inhibitors (selegiline, rasagiline).

Huntington's Disease

• Mutation in CAG trinucleotide repeats on chromosome 4, leading to Huntington protein accumulation.
• Early stages: Hyperkinetic phenotypes (chorea, athetosis).
• Late stages: Bradykinesia, rigidity, tremors, similar to Parkinson's. Non-motor symptoms:
  • Visuospatial deficits/behavioral issues due to specific striatal neuron projections.
  • Neuropsychiatric deficits/dementia.
• Subcortical and striatal degeneration leads to disease progression(mainly in striatum).

Amyotrophic Lateral Sclerosis (ALS)

• Glutamate toxicity damages mitochondria, leading to neuronal death.
• Symptoms:
  • Upper motor neuron symptoms: Hyperreflexia, spasticity, uncontrollable laughing/crying.
  • Lower motor neuron symptoms: Muscle atrophy, muscle twitches, weakness, loss of reflexes, speech issues, facial/tongue atrophy.
• Management:
  • Riluzole (blocks glutamate transmission).
  • Edaravone (free radical scavenger, adjunct).

Seizures

• Focal seizures: Abnormal hyperexcitability in one area, may or may not spread to other areas, may or may not have loss of awareness.
• Generalized seizures: Involve both hemispheres, loss of consciousness, post-ictal state.
• Infectious causes: Meningitis (Streptococcus pneumoniae, Neisseria meningitidis, Cryptococcal Meningitis), encephalitis (Borrelia burgdorferi, herpesviruses, mosquito-borne infections), demyelination.
• Pathophysiology: Excessive glutamate activation, decreased GABA inhibition. Abnormal neuronal firing synchronization.
• Management:
  • IV benzodiazepines (Ativan, Midazolam, Diazepam)
  • Long-acting anticonvulsants (Phenytoin, Valproic Acid, Levetiracetam).
  • Phenobarbital or similar barbiturates (if needed,Phenytoin not available).
  • General anesthesia (propofol)

Seizure-Promoting Medications

• Bupropion (sodium blockade, increased excitability).
• Flumazenil (benzodiazepine reversal agent, GABA antagonist).
• Isoniazid (pyridoxine deficiency, decreased GABA production, increased glutamate toxicity).
• Clozapine (increased glutamatergic transmission, possible granulocytopenia).
• Illicit drugs (increased glutamate release).

Withdrawal Syndromes (Seizures)

• Benzodiazepine withdrawal: CNS hyper-excitability.
• Alcohol withdrawal: Decreased GABA transmission, increased glutamatergic activity. Delirium Tremens (severe) symptoms include agitation, hallucinations, autonomic instability.
• Management: IV Lorazepam, long-acting benzodiazepines, general anesthesia (severe cases).