Parkinson's Disease¶
Chapter 446 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 446
Key Clinical Points¶
- Cardinal motor features of PD are bradykinesia, rest tremor, rigidity, and postural instability.
- Pathologic hallmark is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the presence of α-synuclein inclusions (Lewy bodies and Lewy neurites).
- α-synuclein pathology may follow a 'Braak hypothesis' progression from the periphery/gut via the vagus nerve to the brainstem and finally to the SNc.
- Genetic factors (e.g., SNCA, LRRK2, GBA1) influence age of onset and severity; the 'double-hit' hypothesis suggests an interaction between genetic susceptibility and environmental triggers.
- Nonmotor features (anosmia, sleep disorders like RBD, autonomic dysfunction) often precede motor symptoms by years or even decades.
- Atypical parkinsonisms (MSA, PSP, CBS) are characterized by early falls, poor levodopa response, and additional neurological signs (e.g., orthostatic hypotension in MSA, slow saccades in PSP).
- Secondary parkinsonism results from external factors such as drugs (neuroleptics), toxins (MPTP, manganese), or other conditions like Wilson's disease.
- Pimavenserin (34 mg daily) is FDA-approved for psychosis in Parkinson's Disease; clozapine is an alternative.
- Orthostatic hypotension is common and requires nonpharmacologic management as a first step.
- Levodopa-induced complications include 'wearing off' and dyskinesias, which typically progress over time during chronic treatment.
DEFINITION & OVERVIEW¶
• Definition: Parkinson's disease (PD) is the second most common age-related neurodegenerative disease, exceeded only by Alzheimer's disease (AD). • Cardinal Motor Features: ◦ Bradykinesia (slowing) ◦ Rest tremor ◦ Rigidity (stiffness) ◦ Gait dysfunction with postural instability • Pathologic Hallmarks: ◦ Degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) ◦ Reduced striatal dopamine ◦ Intraneuronal proteinaceous inclusions (Lewy bodies and Lewy neurites) that stain for α-synuclein. • Systemic Involvement: ◦ Neuronal degeneration with Lewy pathology can also affect: ◦ Cholinergic neurons of the nucleus basalis of Meynert (NBM) ◦ Norepinephrine neurons of the locus coeruleus (LC) ◦ Serotonin neurons in the raphe nuclei ◦ Olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous system.
EPIDEMIOLOGY¶
• Global Burden: ◦ Approximately 10.8 million people currently affected. ◦ Expected to double within 20 years due to the aging population. • Demographics: ◦ Mean age of onset: ~60 years. ◦ Lifetime risk: ~3% for men, ~2% for women. ◦ Early-onset cases (even in the 20s) are often associated with pathogenic gene mutations.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Genetic Factors: ◦ ~15% of cases are familial. ◦ Key genes: SNCA, LRRK2, MAPT, GBA1. ◦ 'Double-hit' hypothesis: Interaction between (1) genetic risk factors inducing susceptibility and (2) exposure to toxic environmental factors. Note: No direct evidence currently supports this theory for clinical use. • Environmental Factors: ◦ Potential risks: Pesticides, solvents, rural living, farming, and drinking well water (results are inconsistent). ◦ Protective factors: Caffeine, cigarette smoking, NSAIDs, and calcium channel blockers. • α-Synuclein Pathology: ◦ SNCA gene is the first linked to PD; mutations or duplications/triplications of wild-type SNCA cause PD. ◦ Prion-like model: α-synuclein misfolds → forms toxic oligomers → aggregates into Lewy bodies → spreads to adjacent neurons. ◦ Braak hypothesis: Pathology may begin in the GI tract → travel via vagus nerve → lower brainstem (dorsal motor nucleus of the vagus) → SNc.
CLINICAL FEATURES¶
• Cardinal Motor Features: ◦ Bradykinesia, rest tremor, rigidity, and postural instability. • Other Motor Features: ◦ Micrographia, masked facies (hypomimia), reduced eye blinking, drooling, soft voice (hypophonia), dysphagia, freezing, and falling. • Nonmotor Features: ◦ Sensory: Anosmia, pain, hyposmia. ◦ Mood/Sleep: Depression, anxiety, apathy; fragmented sleep, REM sleep behavior disorder (RBD). ◦ Autonomic: Orthostatic hypotension, gastrointestinal disturbances, genitourinal/sexual dysfunction. • Pre-motor Phase: ◦ Nonmotor symptoms and specific pathologies (e.g., in the olfactory system or autonomic nervous system) may precede motor features by years.
DIFFERENTIAL DIAGNOSIS¶
• Atypical Parkinsonism: ◦ Multiple-system atrophy (MSA): Characterized by prominent orthostatic hypotension. ◦ Progressive supranuclear palsy (PSP): Characterized by slow saccades with impaired downgaze. ◦ Corticobasal syndrome (CBS). ◦ Features: Early speech/gait impairment, lack of tremor, no motor asymmetry, poor levodopa response. • Secondary Parkinsonism: ◦ Drug-induced (e.g., neuroleptics). ◦ Toxins (e.g., MPTP, manganese, carbon monoxide). ◦ Other: Tumor, infection, vascular, Wilson's disease, NPH. • Clinical Indicators for Differentiation: ◦ Early speech/gait impairment → Atypical parkinsonism ◦ Onset <40 years → Genetic form, Wilson's, or DRD ◦ Hallucinations/dementia preceding motor features → Dementia with Lewy bodies (DLB) ◦ Poor response to levodopa → Atypical or secondary parkinsonism.
INVESTIGATIONS & DIAGNOSIS¶
- Clinical Assessment: ◦ Identify core features: Bradykinesia, rigidity, tremor. ◦ Assess for 'Red Flags': Early falls, lack of asymmetry, and rapid progression.
- MDS Clinical Diagnostic Criteria: ◦ Step 1: Confirm motor parkinsonism. ◦ Step 2: Evaluate supporting criteria (e.g., levodopa response, specific nonmotor features). ◦ Step 3: Rule out exclusion criteria (drug-induced, secondary causes). ◦ Step 4: Determine if condition is 'clinically established' or 'clinically probable'.
- Imaging & Biomarkers: ◦ [11C]Dihydrotetrabenazine PET: Used as a marker of VMAT2 density to assess presynaptic dopaminergic nerve terminals. ◦ Clinical observation of levodopa response: Key for distinguishing PD from atypical forms.
MANAGEMENT & TREATMENT¶
- Pharmacologic Treatment for Psychosis: ◦ First-line: Pimavenserin (34 mg daily). ◦ Alternative: Clozapine.
- Management of Autonomic Dysfunction: ◦ Orthostatic hypotension → prioritize nonpharmacologic measures first.
- Cognitive Symptoms in DLB: ◦ Use Cholinesterase inhibitors (rivastigmine, donepezil).
- Levodopa Therapy & Monitoring: ◦ Initial: Carbidopa/levodopa (200–1000 mg levodopa/day). ◦ Add-on for 'off' periods: Entacapone (200 mg with each dose), Tolcapone (100–200 mg tid), or Opicapone (50 mg HS). ◦ On-demand therapy: Apomorphine sublingual strip (5–40 mg, up to 5 doses per day).
- Supportive Care: ◦ Physical therapy and safety measures for gait/falling.
GENETIC SUBTYPES¶
• Dominantly Inherited PD: ◦ SNCA: Median AAO 46y (19–77); features include early-onset, severe parkinsonism with cognitive dysfunction. ◦ LRRK2: Median AAO 56y (20–95); clinically typical PD with slightly slower progression. ◦ VPS35: Median AAO 52y (26–75); very rare form of PD. ◦ CHCHD2: Likely clinically typical PD; predominantly found in Asia. ◦ RAB32: Likely clinically typical, possibly more frequent dementia. ◦ GBA1: Clinically overall typical; however, faster progression and greater risk of cognitive impairment. • Recessively Inherited PD: ◦ PRKN: Median AAO 31y (3–81); often presents with dystonia in a leg. ◦ PINK1: Median AAO 32y (9–67); prominent psychiatric features reported. ◦ PARK7: Median AAO 27y (15–40); clinically similar to PRKN and PINK1.
KEY PEARLS & CLINICAL TRAPS¶
• Diagnostic Clues: ◦ Lack of tremor + early falls → suspect Atypical Parkinsonism. ◦ Presence of orthostatic hypotension → suggests MSA. ◦ Slow saccades/impaired downgaze → suggest PSP. ◦ REM sleep behavior disorder (RBD) → prodromal marker for synucleinopathies. • Treatment Pitfalls: ◦ Avoid neuroleptics in patients with parkinsonism to prevent worsening of motor symptoms. ◦ Recognize that 'wearing off' and dyskinesias are expected complications of long-term levodopa use.
Reference Tables¶
TABLE 446-1 Clinical Features of Parkinson’s Disease¶
Harrison's 22e, p.3494
| CARDINAL MOTOR FEATURES |
OTHER MOTOR FEATURES |
NONMOTOR FEATURES |
|---|---|---|
| Bradykinesia Rest tremor Rigidity Postural instability |
Micrographia Masked facies (hypomimia) Reduced eye blinking Drooling Soft voice (hypophonia) Dysphagia Freezing Falling |
Anosmia Sensory disturbances (e.g., pain, hyposmia) Mood disorders (e.g., depression, anxiety, apathy) Sleep disturbances (e.g., fragmented sleep, RBD) Autonomic disturbances Orthostatic hypotension Gastrointestinal disturbances Genitourinal disturbances Sexual dysfunction Cognitive impairment/dementia |
TABLE 446-2 Differential Diagnosis of Parkinsonism Parkinson’s disease¶
Harrison's 22e, p.3495
| Parkinson’s disease Sporadic Genetic PD with dementia/dementia with Lewy bodies |
Atypical parkinsonism Multiple-system atrophy (MSA) Cerebellar type (MSA-c) Parkinson type (MSA-p) Progressive supranuclear palsy Parkinsonian variant Richardson variant Corticobasal syndrome |
Secondary parkinsonism Drug-induced Tumor Infection Vascular Normal-pressure hydrocephalus Trauma Liver failure Toxins (e.g., carbon monoxide, manganese, MPTP, cyanide, hexane, methanol, carbon disulfide) |
Other neurodegenerative disorders associated with parkinsonism Wilson’s disease Huntington’s disease Neurodegeneration with brain iron accumulation SCA 3 (spinocerebellar ataxia) Fragile X–associated ataxia-tremor-parkinsonism Prion diseases X-linked dystonia-parkinsonism Alzheimer’s disease with parkinsonism Dopa-responsive dystonia |
|---|---|---|---|
TABLE 446-3 Features Suggesting an Atypical or Secondary Cause of Parkinsonism SYMPTOMS/SIGNS History Early speech and…¶
Harrison's 22e, p.3497
| SYMPTOMS/SIGNS | ALTERNATIVE DIAGNOSIS TO CONSIDER |
|---|---|
| History | |
| Early speech and gait impairment (lack of tremor, lack of motor asymmetry, early falls) |
Atypical parkinsonism |
| Onset prior to age 40 years | Genetic form of PD, Wilson’s disease, DRD |
| Hallucinations and dementia which precede the development of PD features |
Dementia with Lewy bodies |
| Poor or no response to an adequate trial of levodopa |
Atypical or secondary parkinsonism |
| Physical Examination | |
| Prominent orthostatic hypotension | MSA |
| Slow saccades with impaired downgaze | PSP |
TABLE 446-4 Confirmed Genetic Causes of Parkinson’s Disease (PD) with a Clinical Presentation Similar to Idiopathic PD…¶
Harrison's 22e, p.3498
| DESIGNATIONa AND REFERENCE |
GENEREVIEWS AND OMIM REFERENCE | CLINICAL CLUESB | COMMENTS |
|---|---|---|---|
| Dominantly Inherited PD | |||
| PARK-SNCA | GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1223/ OMIM 168601 |
Median AAO: 46 years (range 19–77 years); 25th/75th percentile: 36/54 years. Gene duplications cause classical PD. Most missense mutations and triplications cause early-onset, severe parkinsonism with prominent cognitive dysfunction |
Very rare form of PD, α-synuclein protein main component of Lewy bodies, the pathological hallmark of PD |
| GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1208/ OMIM 607060 |
Median AAO: 56 years (range 20–95 years); 25th/75th percentile: 47/64 years. Clinically typical PD with slightly slower progression |
||
| PARK-VPS35 | GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1223/ OMIM 616710 |
Median AAO: 52 years (range 26–75 years); 25th/75th percentile: 45/61 years. Clinically typical PD |
Very rare form of PD |
| GeneReviews N/A OMIM 614203 |
Likely clinically typical PD. Systematic MDSGene review not yet available |
||
| PARK-RAB32 | GeneReviews N/A OMIM 612906 (disease link not yet included) |
Likely clinically typical PD, possibly more frequent dementia. Systematic MDSGene review not yet available |
Most recently found form of PD. All currently identified patients and families carry the same founder pathogenic variant |
| GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1223/ OMIM 168600/606463 |
Clinically overall typical PD; however, faster progression and greater risk of cognitive impairment. Systematic MDSGene review not yet available |
||
| Recessively Inherited PD | |||
| PARK-PRKN | GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1155/ OMIM 600116 |
Median AAO: 31 years (range 3–81 years); 25th/75th percentile: 23/38 years. Often presents with dystonia, typically in a leg |
Most common early-onset form of genetic PD. Protein name: Parkin |
| GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1223/ OMIM 605909 |
Median AAO: 32 years (range 9–67 years); 25th/75th percentile: 24/40 years. Prominent psychiatric features have been described in several families |
||
| PARK-PARK7 | GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1223/ OMIM 606324 |
Median AAO: 27 years (range 15–40 years); 25th/75th percentile: 22/34 |
Clinically very similar to PARK-PRKN and PARK-PINK1, but rarest of all forms. Protein name: DJ-1 |
TABLE 446-5 Drugs Commonly Used for Treatment of Parkinson’s Disease a AGENT Levodopa a¶
Harrison's 22e, p.3504
| AGENT | AVAILABLE DOSAGES | TYPICAL DOSING |
|---|---|---|
| Levodopaa | ||
| Carbidopa/levodopa | 10/100, 25/100, 25/250 mg | 200–1000 mg levodopa/day |
| Benserazide/levodopa | 25/100, 50/200 mg | |
| Carbidopa/levodopa CR | 25/100, 50/200 mg | |
| Benserazide/levodopa MDS |
25/200, 25/250 mg | |
| Parcopa | 10/100, 25/100, 25/250 mg | |
| Rytary (carbidopa/ levodopa) Carbidopa/levodopa/ entacapone |
23.75/95, 36.25/145, 48.75/195, 61.25/245 12.5/50/200, 18.75/75/200, 25/100/200, 31.25/125/200, 37.5/150/200, 50/200/200 mg |
See conversion tables |
| 0.125, 0.25, 0.5, 1.0, 1.5 mg 0.375, 0.75, 1.5. 3.0, 4.5 mg 0.25, 0.5, 1.0, 3.0 mg 2, 4, 6, 8 mg 2-, 4-, 6-, 8-mg patches 2–8 mg |
||
| COMT inhibitors | ||
| Entacapone | 200 mg | 200 mg with each levodopa dose |
| Tolcapone Opicapone |
100, 200 mg 50 mg |
100–200 mg tid 50 mg HS |
| 5 mg 0.5, 1.0 mg 100 mg |
||
| On-demand therapy for off periods Inhaled levodopa Apomorphine sublingual strip |
5–40 mg | Up to 5 doses per day Up to 5 doses per day |
| 20, 40 mg 100–400 mg |