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Summary Table

Domain	Detail
Risk Factors	Age 40 to 70 years (mean onset above 55), male sex (M:F ratio 3:2), family history, environmental exposures (lead, iron, copper), head trauma, NSAID use
Etiology	Degenerative loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and corpus striatum, with cytoplasmic Lewy body inclusions; exact cause remains unclear but linked to genetic and environmental factors
Patient Presentation	Gradual onset of unilateral resting tremor, slowness of movement, stiffness, shuffling gait, difficulty initiating movement; prodromal non-motor symptoms may include hyposmia, constipation, sleep disturbance, and depression
Classic Physical Exam	Resting "pill-rolling" tremor (4 to 6 Hz), cogwheel rigidity, bradykinesia (decrement in amplitude and speed of repetitive movements), postural instability, masked facies, stooped posture, festinating gait
Key Diagnostic Results	Clinical diagnosis; no confirmatory biomarker or imaging finding; good and sustained response to levodopa supports the diagnosis; re-diagnosis recommended every 6 to 12 months
Management	Levodopa (gold standard, Grade A), dopamine agonists (pramipexole, rotigotine), MAO-B inhibitors (rasagiline, selegiline, safinamide), COMT inhibitors (entacapone), amantadine for dyskinesia; advanced therapies include STN-DBS, LCIG, and apomorphine infusion
Keywords	Resting tremor, bradykinesia, rigidity, postural instability, Lewy bodies, substantia nigra, wearing off, on-off fluctuation, peak-dose dyskinesia, pill-rolling tremor, cogwheel rigidity, masked facies, festinating gait

1. Pathophysiology

Parkinson's Disease (PD) is a chronic, progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). These neurons project to the corpus striatum via the nigrostriatal pathway, and their degeneration leads to a profound deficit of dopamine in the striatum. The hallmark histopathological finding is the presence of Lewy bodies, which are intracytoplasmic eosinophilic inclusions composed primarily of aggregated alpha-synuclein protein.

The basal ganglia circuit relies on a balance between dopaminergic (excitatory via the direct pathway, inhibitory via the indirect pathway) and cholinergic neurotransmission. When dopamine levels fall, the indirect pathway becomes overactive and the direct pathway becomes underactive. The net result is excessive inhibitory output from the globus pallidus internus (GPi) to the thalamus, which in turn reduces thalamocortical excitation. This is why patients develop bradykinesia and rigidity: the motor cortex receives less facilitatory input and voluntary movement becomes slow and difficult to initiate.

Resting tremor arises from oscillatory activity within the basal ganglia-thalamocortical loop. It is characteristically present at rest and diminishes with voluntary movement, which distinguishes it from the action/intention tremor of cerebellar disease. The tremor is typically asymmetric and described as "pill-rolling."

Postural instability tends to appear later in the disease course and reflects involvement of non-dopaminergic pathways (cholinergic, serotonergic, noradrenergic). It responds less well to levodopa than bradykinesia or rigidity.

The non-motor symptoms of PD, including constipation, hyposmia, REM sleep behavior disorder, depression, and autonomic dysfunction, are explained by the widespread nature of alpha-synuclein deposition beyond the substantia nigra. According to the Braak staging hypothesis, Lewy body pathology begins in the lower brainstem and olfactory bulb before ascending to the midbrain, which is why non-motor prodromal symptoms can precede motor manifestations by years.

The PERDOSNI guideline emphasizes that PD remains a clinical diagnosis. There is currently no biomarker with sufficient sensitivity and specificity, and imaging findings on routine CT or MRI are not pathognomonic. Up to 20% of patients diagnosed clinically with PD during life are found to have an alternative diagnosis at autopsy.

2. Classification and Clinical Manifestation

Motor Symptoms

Feature	Description
Bradykinesia	Slowness of movement with progressive reduction in speed and amplitude of repetitive actions; the cardinal and obligatory feature for diagnosis
Resting Tremor	4 to 6 Hz "pill-rolling" tremor, typically asymmetric, present at rest, diminishes with action
Rigidity	Increased resistance to passive movement throughout the range of motion ("lead-pipe"); superimposed tremor produces "cogwheel" rigidity
Postural Instability	Impaired postural reflexes leading to falls; typically a later feature; poor response to dopaminergic therapy

Non-Motor Symptoms

Category	Examples
Autonomic	Constipation, orthostatic hypotension, urinary dysfunction, erectile dysfunction, excessive salivation (drooling)
Neuropsychiatric	Depression, anxiety, apathy, psychosis (hallucinations), dementia, impulse control disorders
Sleep	Insomnia, REM sleep behavior disorder, excessive daytime sleepiness
Sensory	Hyposmia, pain (musculoskeletal/dystonic), paresthesia
Other	Fatigue, seborrheic dermatitis

MDS Clinical Diagnostic Criteria (2015)

The International Parkinson and Movement Disorders Society (MDS) published two tiers of clinical certainty in 2015, adopted by the PERDOSNI guideline:

Category	Criteria
Clinically Established PD	Bradykinesia plus at least one of tremor or rigidity; presence of multiple supportive criteria; absence of absolute exclusion criteria; no red flags
Clinically Probable PD	Same motor criteria; supportive features outnumber red flags; no absolute exclusion criteria present

The guideline recommends that diagnosis be reviewed every 6 to 12 months, especially when new atypical features arise, given the known risk of early misdiagnosis.

Key Differentiating "Red Flags" Suggesting an Alternative Diagnosis

Red Flag	Implication
Early severe autonomic failure	Consider Multiple System Atrophy (MSA)
Early dementia preceding or concurrent with motor onset	Consider Dementia with Lewy Bodies (DLB)
Supranuclear vertical gaze palsy with early falls	Consider Progressive Supranuclear Palsy (PSP)
Poor or absent levodopa response	Consider atypical parkinsonism
Symmetric onset, rapid progression	Consider MSA, PSP, or vascular parkinsonism
History of neuroleptic exposure	Consider drug-induced parkinsonism

3. Diagnostic Workup

Test	Role	Notes
Clinical examination (bradykinesia + tremor/rigidity)	Best Initial and Primary Diagnostic Method	PD is a clinical diagnosis; no single test confirms it
Levodopa trial (chronic, not acute challenge)	Supportive diagnostic tool	A sustained good response to levodopa supports PD; acute levodopa or apomorphine challenge alone should NOT be the sole diagnostic method
CT/MRI Brain	Exclusion of structural causes	Not routinely recommended for PD diagnosis; used when red flags suggest vascular parkinsonism, NPH, or tumor
I-FP-CIT SPECT (DaTSCAN)	Aid in uncertain cases	Considered when there is clinical uncertainty between PD/parkinsonism and essential tremor or other tremor disorders
PET Scan	Not recommended	Not part of routine parkinsonian syndrome workup
Olfactory testing	Not recommended	Not sufficiently accurate for diagnosis
Genetic testing	Not routinely recommended	May be considered on a voluntary basis in early-onset PD; should be done by a movement disorder consultant

The PERDOSNI guideline makes clear that PD should be suspected in any patient presenting with tremor, rigidity, slowness of movement, balance difficulty, or gait disturbance. The best initial step is a thorough neurological examination by a neurologist (or movement disorder specialist), looking for the combination of bradykinesia plus at least one of resting tremor or rigidity.

There is no single laboratory or imaging biomarker that can reliably diagnose PD at the first visit. Routine CT or MRI of the brain is not indicated for diagnosis of PD itself but should be performed when atypical features ("red flags") raise suspicion for structural pathology such as normal pressure hydrocephalus, multiple lacunar infarcts (vascular parkinsonism), or a space-occupying lesion.

A long-term levodopa trial is a critical step. The guideline explicitly states that an acute levodopa or apomorphine challenge test should not be used as the sole diagnostic method. Rather, patients with suspected PD should be started on a therapeutic course of levodopa, and their sustained clinical response over weeks to months supports the diagnosis. If a patient shows no meaningful response to adequately dosed levodopa, the diagnosis should be reconsidered.

Functional imaging with I-FP-CIT SPECT (DaTSCAN) should be reserved for cases where genuine diagnostic uncertainty exists between PD and a non-degenerative tremor disorder (such as essential tremor). It is not indicated for routine screening or for differentiating PD from other neurodegenerative parkinsonisms (MSA, PSP), as dopaminergic deficit is present in all of those conditions.

4. Management and Treatment

The PERDOSNI guideline states that current treatment of PD is purely symptomatic; no pharmacological therapy has been shown to modify disease progression.

Drug Class	Drug	Monotherapy Grade	Adjuvant Grade	Key Notes
Levodopa + DDC inhibitor	Levodopa/carbidopa or levodopa/benserazid	A	A	Gold standard; start at lowest effective dose; first-line for patients above 60 years
Dopamine Agonist (non-ergot)	Pramipexole	A	--	First-line option for patients below 60 years; lower risk of motor fluctuations than levodopa
	Rotigotine (patch)	A	--	Transdermal; rotate application site every 24 hours; same 14-day skin cycle
	Bromocriptin (ergot)	C (not effective)	--	Not recommended; risk of fibrosis (peritoneal, pleural, pericardial) and valvular heart disease
MAO-B Inhibitor	Rasagiline	A	B	Can be first-line for mild symptoms; once daily dosing
	Selegiline	B	B	Metabolized to amphetamine derivatives; avoid combining with fluoxetine/fluvoxamine
	Safinamide	--	C	Reversible MAO-B inhibitor plus sodium channel blocker; approved as add-on to levodopa or DA in advanced PD
COMT Inhibitor	Entacapone	--	A (with levodopa)	Must always be co-administered with levodopa; reduces OFF time by 1 to 2 hours
Amantadine	Amantadine	C	C	NMDA antagonist; useful for dyskinesia; avoid evening dosing (insomnia risk); caution in renal impairment
Anticholinergic	Trihexyphenidyl	B	B	NOT first-line; restricted to select cases below 70 years with dominant resting tremor; high side-effect burden (cognitive impairment, urinary retention, dry mouth)

Principles of Early-Stage Management

No single drug is universally recommended as the first choice. The decision is individualized based on symptom severity, impact on the dominant hand, social and occupational needs, cost, and patient preference.

Levodopa is considered the treatment of choice and the most effective oral agent for motor symptom control. The guideline recommends starting at the lowest effective dose (Grade A), because higher levodopa doses correlate with a higher risk of motor complications (dyskinesia, wearing off). Clinical benefit has been demonstrated at 150 to 300 mg per day of levodopa, and dyskinesia risk is lower when the total daily dose stays below 400 mg. Taking levodopa with meals can reduce nausea in early disease but may impair absorption in advanced disease due to competition with dietary amino acids.

Dopamine agonists (pramipexole, rotigotine) may be used as initial dopaminergic therapy in patients below 60 years to delay levodopa initiation and postpone motor fluctuations. They carry a lower dyskinesia risk but are less effective than levodopa. They should be avoided in patients above 70 years and in those with a history of impulse control disorders (pathological gambling, hypersexuality, compulsive shopping/eating), excessive daytime sleepiness, hallucinations, or cognitive impairment.

MAO-B inhibitors (rasagiline, selegiline) can serve as first-line monotherapy for mild symptoms. Most patients on MAO-B inhibitor monotherapy will need additional therapy within 2 to 3 years.

Anticholinergics (trihexyphenidyl) must never be first-line. They are reserved for younger patients (below 70) with dominant resting tremor refractory to other agents, and only after weighing the risk of cognitive side effects.

Advanced-Stage PD: Motor Complications

Over time, response to levodopa becomes less predictable. The guideline identifies the following motor complications:

Wearing off: the therapeutic effect of each levodopa dose becomes shorter, and symptoms re-emerge before the next dose is due. Management begins with adjusting levodopa dosing (shortening the interval between doses without increasing the total daily dose, and separating intake from meals by at least 1 hour). If this is insufficient, adding an adjuvant agent is the next step:

Adjuvant for Wearing Off	Grade
COMT inhibitor (entacapone)	A
MAO-B inhibitor (rasagiline, safinamide)	A
Dopamine agonist (pramipexole, rotigotine)	A
Levodopa controlled release	C

Dyskinesia: involuntary movements related to levodopa use. Peak-dose dyskinesia is managed by reducing individual levodopa doses and increasing dosing frequency. Amantadine (200 to 400 mg/day) is the only oral agent with proven efficacy in reducing dyskinesia without worsening parkinsonism (Grade A). It should be given in the morning to avoid insomnia. Clozapine is an alternative (Grade U) for patients who cannot tolerate amantadine.

Device-Aided Therapy for Refractory Motor Complications

When oral medications fail to control motor fluctuations and dyskinesia, the guideline recommends considering:

Therapy	Indication	Key Details
STN-DBS (subthalamic nucleus deep brain stimulation)	PD with medication-refractory motor fluctuations or tremor	Grade A; produces 50 to 70% improvement in fluctuations and dyskinesia; candidates should be below 70, cognitively intact, and show at least 33% improvement on levodopa challenge (UPDRS); contraindicated in dementia, uncontrolled psychiatric comorbidity
LCIG (levodopa-carbidopa intestinal gel via PEG-J)	Severe fluctuations uncontrolled by oral therapy	Continuous jejunal infusion; reduces OFF time and increases ON time by about 2 hours vs oral levodopa; high rate of device-related adverse events
Apomorphine infusion (subcutaneous pump)	Severe fluctuations when oral therapy and DBS are not options	Continuous subcutaneous infusion; effective for motor fluctuations; antiemetic premedication recommended; Grade C

Non-Motor Symptom Management Highlights

Non-Motor Domain	Recommended Treatment	Evidence Level
Depression	Venlafaxine (clinically beneficial), pramipexole (effective), SSRIs (possibly beneficial)	Variable
Psychosis	Clozapine (effective, requires monitoring), pimavanserin (effective), quetiapine (possibly beneficial); olanzapine is NOT effective and NOT recommended	Variable
Dementia	Rivastigmine (effective, clinically beneficial); donepezil and galantamine (possibly beneficial)	Variable
Orthostatic hypotension	Midodrine, fludrocortisone, droxidopa (all possibly beneficial)	Insufficient
Constipation	Probiotics/prebiotic fiber (effective), lubiprostone, macrogol (possibly beneficial)	Variable
Drooling/sialorrhea	Botulinum toxin A or B injection (effective, requires trained personnel)	Effective
Erectile dysfunction	Sildenafil (effective, clinically beneficial)	Effective
Fatigue	Rasagiline (effective, possibly beneficial)	Limited
Pain	Safinamide (possibly effective for muscle cramp/stiffness in motor fluctuations)	Limited

5. Differential Diagnosis and Distractors

Differential	Why It Looks Similar	Key Discriminator
Essential Tremor	Tremor is the dominant feature	Essential tremor is an action/postural tremor that improves at rest and worsens with sustained posture or movement; it is bilateral and symmetric; no bradykinesia or rigidity; often positive family history; may improve with alcohol
Drug-Induced Parkinsonism	Bradykinesia, rigidity, tremor indistinguishable from PD	History of neuroleptic/antiemetic use (haloperidol, metoclopramide); typically bilateral and symmetric from onset; resolves weeks to months after drug withdrawal
Vascular Parkinsonism	Gait difficulty, rigidity, bradykinesia	Predominantly lower-body involvement ("lower-body parkinsonism"); stepwise progression; history of cerebrovascular risk factors; MRI shows multiple lacunar infarcts in basal ganglia/white matter; poor levodopa response
Normal Pressure Hydrocephalus (NPH)	Gait disturbance resembling parkinsonian gait	Classic triad of gait apraxia (magnetic gait), urinary incontinence, and dementia; CT/MRI shows ventriculomegaly out of proportion to cortical atrophy; improvement with CSF tap test
Progressive Supranuclear Palsy (PSP)	Rigidity, bradykinesia, postural instability, falls	Early and prominent falls (within first year), especially backwards; supranuclear vertical gaze palsy (difficulty looking down); axial more than appendicular rigidity; poor levodopa response
Multiple System Atrophy (MSA)	Parkinsonism, autonomic failure	Early severe autonomic dysfunction (orthostatic hypotension, urinary retention); cerebellar ataxia (MSA-C subtype); symmetric onset; poor levodopa response; "hot cross bun" sign on pontine MRI
Corticobasal Syndrome (CBS)	Asymmetric rigidity and bradykinesia	Alien limb phenomenon; cortical sensory loss (agraphesthesia, astereognosis); myoclonus; apraxia; markedly asymmetric cortical atrophy on imaging
Dementia with Lewy Bodies (DLB)	Parkinsonism, hallucinations, cognitive decline	Dementia precedes or occurs within one year of motor onset (the "1-year rule"); prominent visual hallucinations; fluctuating cognition and alertness; REM sleep behavior disorder

6. Traps and High-Yield Pearls

The most common way students lose points on PD questions is by confusing the initial drug choice based on patient age and symptom severity. The guideline draws a clear line: for patients above 60 years, levodopa at a low dose is the preferred starting agent; for patients below 60 years with mild to moderate symptoms, dopamine agonists (pramipexole or rotigotine) or MAO-B inhibitors may be used first to delay levodopa-associated motor complications. Anticholinergics are never first-line.

A second frequent trap involves the management of dyskinesia. Students often select "reduce levodopa" as the answer and stop there. While dose adjustment is the initial approach, the guideline emphasizes that amantadine is the only proven pharmacological agent that reduces dyskinesia without worsening parkinsonism, and it should be the answer when a question asks about persistent dyskinesia despite dose optimization.

Third, remember that PD is a clinical diagnosis. There is no role for routine DaTSCAN, PET, or MRI in confirming PD. Imaging is indicated only to exclude structural causes when red flags are present or when there is genuine diagnostic uncertainty between PD and a non-degenerative tremor disorder.

Fourth, students sometimes forget that dopamine agonists carry a meaningful risk of impulse control disorders (gambling, hypersexuality, compulsive shopping and eating), excessive daytime sleepiness, and sudden-onset sleep. The guideline recommends screening with the QUIP questionnaire and Epworth Sleepiness Scale before and during dopamine agonist therapy.

Finally, be alert to the wearing off versus dyskinesia distinction. Wearing off is a loss of motor benefit before the next dose, and the strategy centers on smoothing out dopaminergic stimulation (shortening intervals, adding COMT or MAO-B inhibitors). Dyskinesia is an excess of involuntary movement during the peak effect of levodopa, and the strategy centers on reducing peak dopamine levels (smaller, more frequent doses) plus amantadine. Questions will test whether you can identify which complication is occurring and match it to the correct management approach.

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