Parkinson Disease and Parkinsonism

Dopamine Depletion in Basal Ganglia Circuits

• Selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) leads to striatal dopamine deficiency of >50% before motor symptoms manifest
• Loss of dopaminergic input disrupts the balance between direct (facilitatory) and indirect (inhibitory) motor pathways within basal ganglia circuits
• The indirect pathway becomes hyperactive relative to the direct pathway, increasing inhibition of thalamic output to motor cortex and resulting in hypokinesia
• Remaining dopamine neurons undergo compensatory upregulation of dopamine synthesis and release, explaining initial treatment responsiveness

Lewy Body Pathology and Neuroinflammation

• α-synuclein accumulates in intracytoplasmic inclusions called Lewy bodies, which are the pathological hallmark of idiopathic PD
• Abnormal α-synuclein undergoes prion-like propagation in a rostral-to-caudal manner, beginning in dorsal motor nucleus of vagus and olfactory bulb before reaching substantia nigra (explaining early non-motor symptoms)
• Lewy body formation disrupts cellular proteasomal and autophagy-lysosomal degradation pathways, leading to protein accumulation and cellular dysfunction
• Neuroinflammation with microglial activation and pro-inflammatory cytokine production contributes to ongoing neuronal loss and disease progression

Mitochondrial Dysfunction and Oxidative Stress

• Impaired mitochondrial complex I function in dopaminergic neurons leads to reduced ATP production and accumulation of reactive oxygen species (ROS)
• Oxidative stress overwhelms cellular antioxidant defenses (reduced glutathione, decreased catalase), causing lipid peroxidation and protein oxidation
• Iron accumulation in the substantia nigra catalyzes formation of free radicals via Fenton chemistry, further damaging dopaminergic neurons
• Environmental toxins (MPTP, pesticides) exacerbate this process by directly inhibiting complex I

Loss of Non-Motor Neurotransmitter Systems

• Degeneration extends beyond dopaminergic neurons to serotonergic, noradrenergic, and cholinergic systems, explaining non-motor manifestations
• Disruption of serotonin signaling contributes to depression, anxiety, and impulse control disorders
• Loss of noradrenergic neurons in locus coeruleus correlates with orthostatic hypotension and sleep dysfunction
• Cholinergic deficiency in pedunculopontine tegmentum contributes to postural instability and gait freezing

Idiopathic Parkinson Disease (85-90% of cases)

• No identifiable secondary cause; likely involves interplay of genetic susceptibility and environmental exposures
• Pathological hallmark of Lewy body pathology with selective nigrostriatal dopaminergic neurodegeneration

Genetic Forms of Parkinsonism (10-15% of cases; often younger onset)

• LRRK2 mutations (most common genetic cause): autosomal dominant; clinically similar to idiopathic PD but may present with atypical features
• PARKIN mutations (parkin gene): autosomal recessive; early-onset PD with slower progression and excellent dopaminergic response
• PINK1 mutations: autosomal recessive early-onset parkinsonism with prominent dystonia
• DJ-1 mutations: autosomal recessive early-onset disease
• α-synuclein duplications/multiplications and glucocerebrosidase (GBA) mutations: influence disease penetrance and phenotype

Environmental Risk Factors

• Pesticide and herbicide exposure (paraquat, rotenone): inhibit mitochondrial complex I
• Head trauma with loss of consciousness: may accelerate dopaminergic neurodegeneration
• Well water consumption and rural living: associated with increased pesticide exposure
• Smoking (paradoxically protective in observational studies, likely detection bias)

Secondary Parkinsonism: Drug-Induced

• Antipsychotics (both typical and atypical): dopamine D2 receptor antagonism most common medication cause
• Metoclopramide and prochlorperazine: common antiemetics causing parkinsonism
• Lithium, valproate, SSRIs (rarely)

Secondary Parkinsonism: Structural/Vascular

• Subdural hematoma: can present with parkinsonian features; treatable with neurosurgery
• Normal pressure hydrocephalus: classic triad of gait disturbance ("magnetic gait"), dementia, and urinary incontinence with parkinsonism
• Stroke: particularly basal ganglia infarcts

Secondary Parkinsonism: Metabolic/Toxic

• Wilson disease: ceruloplasmin deficiency with copper accumulation; presents with parkinsonian features, Kayser-Fleischer rings, and hepatic dysfunction
• MPTP toxicity: synthetic opioid contaminant causing selective nigrostriatal destruction in young users
• Carbon monoxide poisoning: delayed parkinsonism possible months after acute exposure
• Hypoxia, hypercalcemia, hypothyroidism

Secondary Parkinsonism: Neurodegenerative (Atypical Parkinsonian Syndromes)

• Progressive supranuclear palsy (PSP): vertical supranuclear gaze palsy, early postural instability, poor levodopa response
• Corticobasal degeneration (CBD): asymmetric cortical signs (apraxia, alien hand), cortical sensory loss, poor levodopa response
• Multiple system atrophy (MSA): prominent autonomic dysfunction (orthostatic hypotension, urinary retention), cerebellar features, poor levodopa response
• Dementia with Lewy bodies (DLB): cognitive decline preceding or concurrent with motor features, visual hallucinations, REM sleep behavior disorder

Cardinal Motor Features (Bradykinesia REQUIRED for diagnosis)

• Bradykinesia (slowed movement): most specific feature; manifests as slow, effortful voluntary movements with reduced amplitude; present in virtually all patients; can be subtle (slow rapid alternating movements, loss of arm swing with gait)
• Resting tremor ("pill-rolling"): low-frequency (4-6 Hz) tremor of hands and occasionally lips/jaw at rest, suppressed by voluntary movement; present in ~70% of patients; may be absent in akinetic-rigid variant
• Muscular rigidity ("lead-pipe" or "cogwheel"): increased tone throughout range of motion; cogwheel rigidity (superimposed tremor on sustained resistance) highly suggestive of PD
• Postural instability: impaired righting reflexes leading to falls, typically appearing later in disease course (if present early, suggests atypical parkinsonian syndrome)

Gait and Motor Features

• Gait disturbance: shuffling gait with reduced stride length, loss of arm swing, forward-flexed posture; "freezing of gait" (sudden inability to initiate or continue walking) common in advanced disease
• Speech abnormalities: hypophonia (soft, breathy voice), dysarthria with reduced prosody
• Micrographia: handwriting becomes progressively smaller
• Masked facies: reduced facial expressiveness due to facial muscle rigidity

Non-Motor Features (Present in Majority of Patients)

• Olfactory dysfunction: hyposmia or anosmia present in 70-90% of PD patients; often precedes motor symptoms
• Sleep disturbances: REM sleep behavior disorder (RBD) with vivid dreams and acting out during sleep; insomnia; excessive daytime somnolence; restless leg syndrome
• Autonomic dysfunction: orthostatic hypotension (blood pressure drop >20 mmHg systolic upon standing), constipation (slowed GI motility), urinary urgency/frequency, erectile dysfunction
• Neuropsychiatric symptoms: depression (occurs in 30-40%; may precede motor symptoms); anxiety; impulse control disorders with dopaminergic therapy; hallucinations (typically visual, non-threatening)
• Cognitive changes: mild cognitive impairment (MCI) or dementia in 24-31% of patients; executive dysfunction more prominent than memory loss early

Physical Examination Findings

• Bradykinesia assessment: slow speed on rapid alternating hand movements, fine motor tasks; reduced arm swing with gait; slow eye closure/blinking
• Tremor characteristics: observe at rest with hands supported; ask patient to perform mental arithmetic or count backward to elicit tremor if not immediately apparent
• Rigidity assessment: passively move limbs through full range of motion (gentle examination important as patients may guard due to pain)
• Postural reflexes: pull test (examiner stands behind patient, pulls backward at shoulders; normal response is quick step backward; abnormal is falling backward); assess ability to rise from chair without use of arms
• Tandem walking: assess gait stability and balance

Clinical Diagnosis Criteria (UK Parkinson's Disease Society Brain Bank)

• Required: Bradykinesia AND at least one of the following:
• Muscular rigidity
• 4-6 Hz rest tremor
• Loss of postural reflexes
• Supportive criteria: Unilateral onset, asymmetry of signs, progression over 10 years, excellent (70-100%) response to levodopa
• Features suggestive of alternative diagnosis: early cognitive decline (dementia within 1 year of motor onset suggests DLB), early vertical supranuclear gaze palsy (PSP), early speech/voice changes

Diagnostic Laboratory Testing

• No definitive biomarker available for clinical diagnosis; diagnosis remains clinical
• Ceruloplasmin and serum copper levels if age <40 or atypical features suggestive of Wilson disease
• Basic metabolic panel, TSH, calcium, liver function: screen for metabolic causes of secondary parkinsonism
• Biomarkers under investigation: CSF α-synuclein (decreased in PD), phosphorylated tau, amyloid-β; serum phosphorylated α-synuclein; these not yet clinically applicable

Neuroimaging

• MRI brain (structural imaging):
• Rule out secondary causes (subdural hematoma, normal pressure hydrocephalus, stroke)
• Assess for swallow tail sign (preservation of T2 signal intensity in dorsolateral substantia nigra on axial MRI at level of red nucleus); preserved swallow tail favors PD, loss suggests atypical parkinsonian syndrome
• Putaminal atrophy or middle cerebellar peduncle atrophy suggest MSA; midbrain atrophy with hummingbird sign suggests PSP
• MRI not required for routine diagnosis but important to exclude structural pathology

• Dopaminergic Imaging (DAT scan, F-DOPA PET):
• Demonstrates reduced striatal dopamine transporter uptake in PD and atypical parkinsonian syndromes
• Normal DAT scan argues against parkinsonism (helpful in distinguishing essential tremor or drug-induced parkinsonism from true PD)
• Not required for clinical diagnosis but useful when diagnosis uncertain or to differentiate from mimics
• Pattern of uptake may help distinguish PD (bilateral symmetric posterior putaminal loss) from atypical syndromes

• CT head: if acute presentation or acute deterioration (evaluate for stroke, hemorrhage)

Genetic Testing

• Not recommended for screening asymptomatic relatives or routine diagnosis
• Consider in patients with:
• Early-onset PD (<40 years): PARKIN, PINK1, DJ-1, LRRK2
• Family history of PD: LRRK2, GBA
• Consult genetics for counseling given complex inheritance patterns

Differential Diagnostic Approach

• Essential tremor vs. PD: essential tremor is postural/kinetic (worse with action), bilateral symmetric; PD tremor is at rest, often asymmetric; essential tremor responsive to alcohol, beta-blockers; excellent response to levodopa argues for PD
• Drug-induced parkinsonism: temporal relationship to antipsychotic or metoclopramide initiation; DAT scan normal; symptoms may resolve with drug discontinuation (though tardive dyskinesia may develop)
• Atypical parkinsonian syndromes: see detailed features below under complications/differential

General Principles

• Dopaminergic replacement therapy forms the foundation of PD treatment
• Treatment decisions individualized based on age at onset, functional status, disease severity, comorbidities, and medication tolerance
• Avoid dopamine antagonists (antipsychotics, metoclopramide) which worsen PD; use quetiapine or pimaverin if antipsychotic needed
• Nausea management: peripheral dopamine antagonist domperidone preferred over metoclopramide; or combine levodopa with carbidopa/benserazide

Levodopa-Based Therapy (Gold Standard for Motor Symptom Control)

• Mechanism: levodopa is decarboxylated to dopamine in striatum; combined with carbidopa or benserazide (peripheral decarboxylase inhibitors preventing peripheral conversion and reducing nausea)
• Dosing: start low (carbidopa/levodopa 25/100 mg three times daily) and titrate gradually based on response and tolerability
• Advantages: most potent and fastest-acting dopaminergic agent; excellent efficacy for bradykinesia and rigidity
• Disadvantages: long-term therapy complicated by motor fluctuations (wearing-off) and dyskinesias (involuntary movements); more problematic in younger patients given longer disease duration
• Motor complications:
• Wearing-off: return of symptoms before next dose; managed by increasing dose frequency, adding long-acting formulations, or adjunctive agents
• Dyskinesias: involuntary choreiform or dystonic movements; peak-dose dyskinesias most common; diphasic dyskinesias occur at dose onset and offset; off-period dystonia occurs when medication wears off
• On-off fluctuations: abrupt, unpredictable switches between on (controlled) and off (symptomatic) states; managed by more frequent, smaller doses or long-acting agents

Dopamine Agonists (First-Line Monotherapy in Younger Patients)

• Mechanism: direct D2/D3 dopamine receptor agonists at postsynaptic receptors
• Agents: pramipexole, ropinirole (non-ergot, preferred due to ergot-related complications); rotigotine (transdermal patch)
• Advantages: lower risk of motor fluctuations and dyskinesias compared to levodopa when used as monotherapy; may slow PD progression
• Disadvantages: less potent than levodopa; impulsivity and impulse control disorders (gambling, hypersexuality, compulsive eating) occur in 10-15% of patients; somnolence; orthostatic hypotension
• Typical approach: start pramipexole 0.125 mg three times daily or ropinirole 0.5 mg three times daily; titrate gradually over weeks; add levodopa if dopamine agonist monotherapy insufficient

Monoamine Oxidase B (MAO-B) Inhibitors

• Mechanism: inhibit dopamine catabolism in striatum, prolonging dopamine action
• Agents: selegiline (irreversible inhibitor), rasagiline (reversible inhibitor; appears more potent), safinamide
• Efficacy: modest symptom relief when used alone; additive benefit when combined with other

Complications of the disease itself

• Aspiration pneumonia: pharyngeal bradykinesia and impaired cough produce silent aspiration; it is the most common terminal event in advanced PD. New fever, hypoxia, or a wet voice after swallowing should prompt a formal swallow evaluation. Acute aspiration is an emergency.
• Falls, hip fracture, and subdural hematoma: loss of postural reflexes plus orthostatic hypotension. Any unexplained cognitive or motor decline after a fall warrants noncontrast head CT — an expanding subdural is an emergency.
• Parkinson disease dementia and psychosis: cortical Lewy body spread; hallmark is well-formed visual hallucinations, often with preserved insight early. Abrupt confusion instead suggests delirium from infection or drugs, not disease progression.
• Autonomic failure: locus coeruleus and peripheral sympathetic degeneration cause neurogenic orthostatic hypotension (fall in BP without compensatory tachycardia), constipation that can progress to ileus or megacolon, and urinary retention.
• Freezing of gait and camptocormia: cholinergic/pedunculopontine dysfunction; freezing responds poorly to levodopa, distinguishing it from wearing-off.

Complications of treatment

• Parkinsonism-hyperpyrexia (acute akinesia) syndrome: abrupt withdrawal of levodopa — missed doses when a patient is made NPO, or an unrecognized malfunctioning pump — causes rigidity, fever, autonomic instability, and rhabdomyolysis clinically identical to neuroleptic malignant syndrome. This is an emergency: restore dopaminergic therapy (enteral or transdermal rotigotine), cool, and hydrate.
• Impulse control disorders: D3 receptor stimulation in mesolimbic pathways by dopamine agonists causes pathological gambling, hypersexuality, and compulsive shopping or eating. Patients rarely volunteer this — ask directly.
• Sudden-onset sleep attacks: dopamine agonists; counsel about driving.
• Serotonin syndrome: MAO-B inhibitors combined with serotonergic agents (classically meperidine, also tramadol and some antidepressants); clonus, hyperthermia, agitation — an emergency.
• Tolcapone hepatotoxicity: FDA boxed warning for fulminant hepatic failure; requires serial transaminase monitoring. Entacapone instead causes diarrhea and harmless orange urine.
• Amantadine and anticholinergics: livedo reticularis and ankle edema with amantadine; trihexyphenidyl precipitates confusion, urinary retention, and glaucoma in the elderly.

• **The TRAP mnemonic is only half the answer**: Tremor, Rigidity, Akinesia/bradykinesia, Postural instability — but bradykinesia is required, and asymmetric onset with an excellent levodopa response is what makes the stem idiopathic PD rather than a mimic.
• The prodrome is the favorite association: REM sleep behavior disorder (dream enactment, loss of REM atonia) plus hyposmia and constipation may precede motor signs by years, reflecting the caudal-to-rostral α-synuclein spread described in Braak staging. An older man who punches his wife in his sleep is being set up for a synucleinopathy.
• Drug-induced parkinsonism is the most common reversible mimic: think metoclopramide, prochlorperazine, or an antipsychotic; features are typically symmetric, tremor is less prominent, and the DAT scan is normal. The single best next step is to stop the offending drug, not to start levodopa — improvement can take weeks to months.
• Never give haloperidol or metoclopramide to a PD patient. For hallucinations, first reduce the polypharmacy in reverse order of benefit (anticholinergics, amantadine, MAO-B inhibitor, dopamine agonist) before adding quetiapine, clozapine, or pimavanserin, the only antipsychotics that do not worsen motor function; note the FDA boxed warning on increased mortality with antipsychotics in elderly patients with dementia.
• Never abruptly hold levodopa, including in the perioperative or NPO patient — this triggers parkinsonism-hyperpyrexia syndrome.
• Carbidopa's job is peripheral: it blocks DOPA decarboxylase outside the CNS, reducing nausea and orthostasis and allowing more levodopa to cross the blood–brain barrier. High-protein meals compete with levodopa for the large neutral amino acid transporter and can blunt a dose.
• Timing separates the atypicals: dementia within about a year of motor onset points to dementia with Lewy bodies; early falls plus vertical supranuclear gaze palsy to PSP; early autonomic failure or cerebellar signs to MSA; alien limb and apraxia to corticobasal degeneration — all respond poorly to levodopa.
• Common distractor: essential tremor. It is bilateral, action/postural rather than at rest, improves with alcohol, and responds to propranolol or primidone.
• Any parkinsonism under age 40 gets a Wilson disease workup — ceruloplasmin, slit-lamp for Kayser-Fleischer rings.