Module 6 - Parkinson's Disease: Causes, Symptoms, and Mechanisms

Parkinson's Disease and Movement Disorders

• Movement disorders can be hypokinetic (decreased movement, e.g., Parkinson's) or hyperkinetic (increased movement, e.g., myoclonus, tremor).
• Parkinson's is classified as a hypokinetic disorder due to bradykinesia, despite the presence of tremors.
• Voluntary movement involves corticospinal tracts running from the motor cortex to the spinal cord, coordinating delicate movements and interacting with the basal ganglia and cerebellum.
• The extrapyramidal system coordinates involuntary actions, reflexes, gross movements, and postural control, modulated by the basal ganglia, cerebellum, and cerebral cortex.
• Parkinson's disease is a degenerative disorder characterized by resting tremor, stiffness, rigidity, bradykinesia, and postural instability.
• Parkinson's is caused by the progressive degeneration of dopaminergic neurons in the basal ganglia.
• Parkinson's is usually idiopathic but can have a genetic predisposition, with a mean onset age of 57, and early-onset occurring between 21 and 40.
• Parkinson's pathophysiology involves synuclein, an insoluble neuronal protein that forms aggregates called Lewy bodies.
• Accumulation of Lewy bodies in the basal ganglia leads to cellular death and dopamine depletion.
• Normal movement requires a balance between inhibitory dopamine and excitatory acetylcholine.
• In Parkinson's, loss of dopamine's inhibitory action causes overactivity of excitatory acetylcholine, resulting in tremors, rigidity, bradykinesia, and postural disturbances.
• The majority (80%) of the brain's dopamine is in the basal ganglia which can be reduced to as low as 10% of normal in Parkinson's patients.

Treatment of Parkinson's Disease

• Pharmacological treatment aims to restore dopaminergic function.
• Levodopa is a dopamine precursor that crosses the blood-brain barrier and is converted to dopamine in the basal ganglia by dopa decarboxylase.
• Approximately 95% of orally ingested levodopa is broken down in the periphery before reaching the brain.
• Levodopa metabolites can be further metabolized to norepinephrine and epinephrine, requiring COMT for breakdown.
• Levodopa/Carbidopa (e.g., Sinemet) includes carbidopa, which inhibits dopa decarboxylase in the periphery, allowing more levodopa to reach the central nervous system.
• Levodopa/Carbidopa maximizes levodopa delivery to the brain and allows for a lower levodopa dose.
• Adverse effects of levodopa include gastrointestinal issues, endocrine effects, cardiovascular effects, neuromuscular issues, and psychiatric effects.
• Parkinsonism-Hyperpyrexia Syndrome, a life-threatening emergency, can occur with abrupt withdrawal or dose reduction of levodopa, presenting with rigidity, pyrexia, and autonomic instability.
• Levodopa has drug interactions, including antagonism by antipsychotic drugs, potentiation of catecholamine effects with MAOIs, synergism with anticholinergic drugs, and enhanced peripheral metabolism with vitamin B6.
• Dopamine agonists (e.g., bromocriptine, pramipexole, ropinirole, rotigotine) directly mimic dopamine at dopamine receptors, bypassing the need for conversion or transport across the BBB.
• Dopamine agonists can cause hallucinations, hypotension, dyskinesia, pulmonary fibrosis, vertigo, and nausea.
• Amantadine, an antiviral drug, can improve Parkinson's symptoms by increasing dopamine release and delaying reuptake in the basal ganglia, or through anticholinergic or glutamate antagonist effects.
• Amantadine can cause anticholinergic effects, peripheral edema, confusion, and psychosis.
• MAO-B inhibitors (e.g., selegiline, rasagiline) inhibit the breakdown of dopamine in the CNS, increasing its availability.
• Selegiline is highly selective for MAO-B and does not significantly affect peripheral norepinephrine metabolism.
• MAO-B inhibitors can cause insomnia, confusion, and hallucinations.
• COMT inhibitors (e.g., tolcapone, entacapone) block the peripheral breakdown of levodopa, enhancing its delivery to the CNS, when used in combination with levodopa/carbidopa.
• COMT inhibitors can worsen dyskinesias and cause nausea, and in rare cases, hepatotoxicity or rhabdomyolysis.
• Anticholinergics (e.g., benztropine, trihexyphenidyl) block the excitatory effects of acetylcholine, helping to restore the dopamine-acetylcholine balance, primarily controlling tremor and reducing excess salivation.
• Anticholinergics have minimal effect on muscle rigidity and bradykinesia.
• Anticholinergic adverse effects include confusion, hallucinations, sedation, mydriasis, ileus, and urinary retention.
• Diphenhydramine, an H1 receptor antagonist with anticholinergic effects, can be used for symptom management and acute Parkinsonian crisis.
• Surgical treatment includes stereotactic deep brain stimulation (DBS), which involves stimulating specific areas of the brain to help manage disabling symptoms in patients without dementia.
• Lesional surgery is another surgical option, though less commonly performed for Parkinson's.

Anesthetic Considerations for Patients with Parkinson's Disease

• Patients with Parkinson's disease are at risk for autonomic dysfunction, including orthostatic hypotension, which can be challenging to manage during anesthesia.
• Patients with Parkinson's may have poor temperature control, sialorrhea, and pulmonary dysfunction due to bradykinesia and rigidity of respiratory muscles, increasing the risk of aspiration due to swallowing impairments.
• Cognitive impairment in Parkinson's patients increases the risk of postoperative delirium.
• For DBS surgery, patients are often awake or very lightly sedated to allow for symptom monitoring and microelectrode recordings (MER).
• General anesthesia that causes GABA inhibition in the basal ganglia can worsen or abolish MER.
• Drugs like dexmedetomidine, propofol, fentanyl, remifentanil, and benzodiazepines can interfere with MER or worsen symptoms.
• Beta-blockers should be avoided if tremors are being tested during DBS.
• Maintaining stable blood pressure is crucial to prevent hemorrhage during DBS.
• Anti-parkinsonian drugs should not be held preoperatively to avoid symptom exacerbation, but are usually held the morning of surgery for DBS procedures under the guidance of the neurologist or neurosurgeon.
• For postoperative nausea and vomiting (PONV), dopamine antagonist antiemetics (e.g., promethazine, metoclopramide, haloperidol, droperidol) should be avoided as they can worsen Parkinson's symptoms.
• Ondansetron is the preferred antiemetic for Parkinson's patients.
• Diphenhydramine can be given during anesthesia to treat extrapyramidal motor symptoms.
• It's important to assess the patient's baseline motor function preoperatively to monitor for changes postoperatively.

Seizure Disorders and Anti-Epileptic Drugs

• A seizure is an abnormal, unregulated electrical discharge from cortical gray matter that transiently interrupts normal brain function.
• Epilepsy is a chronic brain disorder characterized by recurrent (two or more) seizures not related to reversible stressors, occurring more than 24 hours apart.
• Seizures can manifest with altered awareness, loss of consciousness, abnormal sensations, focal involuntary movements, or generalized violent involuntary muscle contractions (convulsions).
• Some patients experience an aura (sensory, autonomic, or psychic sensation or motor activity) preceding the seizure.
• The postictal state following a seizure is often characterized by deep sleep, headache, confusion, and muscle soreness, lasting from minutes to hours.
• Most seizures end spontaneously within 1-2 minutes.
• Status epilepticus is defined as a seizure lasting longer than 5-10 minutes or serial seizures without a return to baseline.
• Perioperatively, major seizures can increase morbidity and mortality.
• It's important to identify and treat any known causes of seizures, such as metabolic disturbances or alcohol withdrawal.
• If there is no known cause or it's an acute breakthrough seizure, antiseizure medication should be administered.
• Commonly used perioperative antiseizure drugs include fosphenytoin, levetiracetam, valproic acid, and benzodiazepines.
• Factors that can increase seizure risk in the perioperative period include sleep-wake pattern changes, certain anesthetic drugs (older ones like enflurane), electrolyte abnormalities, hypoglycemia, medication withdrawal, extremes of age, and hyperventilation.
• Factors that can promote the spread of seizure foci include low serum glucose, tissue hypoxia, electrolyte/metabolic imbalances (hypernatremia, hypercalcemia, potassium channel blockade), endocrine changes, stress, and fatigue.
• Hypoalbuminemia can increase the free concentration of antiseizure drugs.
• Many antiseizure drugs are hepatic enzyme inducers, which can increase the metabolism of various anesthetic drugs, often requiring higher doses of propofol, thiopental, midazolam, opioids, and non-depolarizing muscle relaxants (NDMRs).
• The mechanism of antiseizure drugs is to decrease neuronal excitability or enhance inhibition, often by affecting ion currents (sodium, potassium, calcium) or the synaptic activity of inhibitory neurotransmitters like GABA.
• Benzodiazepines (e.g., diazepam, lorazepam, midazolam) are used for short-term treatment of acute seizures, status epilepticus, and alcohol withdrawal.
• Diazepam (IV) and nasal midazolam are particularly effective for status epilepticus, and diazepam is the preferred benzodiazepine for local anesthetic systemic toxicity (LAST).
• The mechanism of Benzodiazepines involves positive allosteric modulation of GABA inhibition.
• Adverse effects of Benzodiazepines include sedation, irritability/hyperactivity (especially in pediatrics), ataxia, skeletal muscle incoordination, tolerance, and withdrawal seizures with abrupt discontinuation.
• Phenobarbital, a long-acting barbiturate, is effective for most seizure types by increasing GABA inhibition and decreasing glutamate excitation.
• Cognitive and behavioral side effects limit the use of Phenobarbital.
• Gabapentinoids (gabapentin, pregabalin) have a mechanism that is not fully understood but involves binding to the alpha-2-delta subunit on calcium channels, inhibiting excitatory neurotransmitter release (e.g., glutamate).
• Gabapentinoids are typically used as adjunct medications.
• Adverse effects of Gabapentinoids include sedation, drowsiness, ataxia, dizziness, and vertigo.
• Gabapentinoids do not affect GABA binding, uptake, or metabolism.
• Levetiracetam (Keppra) is used for myoclonic epilepsy, partial, and generalized seizures.
• The mechanism of Levetiracetam is not fully understood but may involve inhibition of calcium channels, decreased neurotransmitter release, and increased GABA inhibition.
• The typical IV dose of Levetiracetam for seizure prophylaxis in neurosurgery is 500 to 1000 mg infused over 15 minutes.
• Levetiracetam does not require serum level monitoring.
• Adverse effects of Levetiracetam include headache, increased blood pressure, somnolence, and sedation.
• Valproic acid (Depakene) is used for all generalized and convulsive epilepsies, potentially by increasing GABA levels, mimicking GABA, and inhibiting sodium and calcium channels.
• Valproic acid has a black box warning for fatal hepatotoxicity, especially in children under 2 years old, and is teratogenic.
• Other adverse effects of Valproic acid include gastrointestinal symptoms, increased bleeding time, thrombocytopenia, sedation, and enzyme inhibition.
• Phenytoin (Dilantin) is used for partial and generalized seizures by regulating sodium membrane transport, promoting efflux and decreasing influx in motor cortex neurons, thus stabilizing the neuronal membrane.
• The therapeutic plasma range of Phenytoin is 10-20 mcg/mL.
• Phenytoin should be administered by slow IV infusion (< 50 mg/min) due to the risk of hypotension and arrhythmias (black box warning).
• Adverse effects of Phenytoin include CNS toxicity (nystagmus, double vision, vertigo), peripheral neuropathy, gingival hyperplasia, inhibition of insulin secretion (hyperglycemia), hepatotoxicity, skin reactions, and increased metabolism of NDMRs.
• Carbamazepine (Tegretol) stabilizes sodium channels in an inactivated state, making neurons less excitable.
• Adverse effects of Carbamazepine include liver dysfunction, thrombocytopenia, dizziness, vertigo, and nausea/vomiting.
• Carbamazepine has a black box warning for fatal dermatologic reactions and aplastic anemia.
• Lamotrigine (Lamictal) inhibits glutamate release and voltage-gated sodium channels.
• Lamotrigine also carries a black box warning for severe, life-threatening rashes.
• Other adverse effects of Lamotrigine include dizziness, vision symptoms, headache, sedation, and ataxia.
• Ethosuximide (Zarontin) is the drug of choice for absence (petit mal) epilepsy, blocking voltage-gated calcium channels in thalamic neurons.
• Adverse effects of Ethosuximide include gastrointestinal intolerance, lethargy, dizziness, ataxia, hyponatremia, and bone marrow suppression.
• Antiepileptic drugs should generally not be held prior to surgery.

CNS Stimulants

• Analeptic drugs stimulate the CNS, potentially by blocking inhibition or enhancing excitation, to treat conditions with CNS depression.
• Amphetamine and methylphenidate are used to treat ADHD, narcolepsy, and obesity.
• The mechanism of Amphetamine and methylphenidate involves the release of norepinephrine from central and peripheral nerve terminals, leading to stimulation of respiratory centers, increased alertness/concentration, and increased muscle strength.
• In acute intoxication, Amphetamine and methylphenidate increase MAC.
• Chronic exposure Amphetamine and methylphenidate can lead to catecholamine depletion and decrease MAC.
• In patients with chronic amphetamine use, direct-acting vasopressors (e.g., epinephrine, phenylephrine, vasopressin) should be used for hypotension instead of indirect-acting ones like ephedrine.
• Doxapram is used to treat COPD-related acute hypercapnia, postoperative respiratory depression, and drug-induced CNS depression by stimulating the medulla through peripheral carotid chemoreceptors, increasing tidal volume and ventilation.
• Adverse effects of Doxapram are related to SNS outflow (hypertension, tachycardia, arrhythmias) and CNS stimulation (increased body temperature, vomiting).
• Methylxanthines (caffeine, theophylline, theobromine) have multiple mechanisms, including antagonism at adenosine receptors and phosphodiesterase inhibition.
• Physiologic effects of Methylxanthines include CNS stimulation, diuresis, increased myocardial contractility, and smooth muscle relaxation.
• Methylxanthines can be used for apnea related to prematurity, bronchospasm related to asthma, and postdural puncture headache (caffeine).
• Methylxanthines promote wakefulness.
• Acidic urine promotes the excretion of basic drugs by causing them to become ionized and trapped in the tubules.