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Stage Sites affected by Lewy bodies Major symptoms I Dorsal motor nucleus of the vagus nerve and olfactory tract Constipation, anosmia II Locus coeruleus and subcoeruleus complex Sleep and mood dysfunction III Substantia nigra Motor symptoms of Parkinson disease IV–VI Cortical involvement Dementia, psychosis Nonmodifiable risk factors (14)– (16) Modifiable risk factors Increased risk Possible decreased risk Age (mean age 65 yr)
Sex (M:F = 1.5:1.0)
Genetics (10% of cases)
LRRK2 mutation (most common)
Glucocerebrosidase gene mutation
Parkin mutation (juvenile onset)
Industrial exposure (17)
Heavy metals (i.e., manganese, lead, copper) (16), (19)
Pesticides (i.e., rotenone, paraquat) (15), (21)
Obstructive sleep apnea (maybe in women) (22)
Smoking (may be protective) (18)
Caffeine (may lower risk, relative risk 0.69; does not imply causality) (20)
Note: F = female, M = male.
Early motor features (30), (31) Early nonmotor features (may precede the diagnosis) Late features (usually develop 5–10 yr after disease onset) (31)– (34) Late nonmotor features (31)– (34) Difficulty turning in bed
Frozen shoulder
Stiffness, numbness or pain in limb
Micrographia (35)
Difficulty with fine finger movements (bradykinesia)
Tremor of hand, jaw, foot
Decreased facial expression
Decreased arm swing, dragging a leg
Soft voice (“Do people ask you to repeat yourself over the phone?”)
Constipation (30%) (34)
REM sleep behaviour disorder* (50%, often preceding the diagnosis by median of 14 yr) (36)– (38)
Depression occurs with a prevalence of 35% in Parkinson disease, and 10%–15% will have depression at the time of diagnosis (39)
Olfaction impairment (most consistent nonmotor feature predicting Parkinson disease); up to 97% of patients (34), (40), (41)
Motor fluctuations
Dyskinesia (complication of dopaminergic treatment, more so with levodopa); typically choreiform, involving the neck, head, limbs and trunk
Gait freezing
Falls
Dysphagia (50% at 15 yr) (42)
Neuropsychiatric symptoms (50% at 15 yr), (42) including hallucinations, sleep disturbance and dementia
Autonomic disturbances (70%–80%), (43), (44) including sweating, orthostasis, sialorrhea and urinary dysfunction
Seborrheic dermatitis (usually involving the forehead, with flaky oily skin)
Note: HR = hazard ratio, REM = rapid eye movement.
↵* The risk of synucleinopathy (i.e., Parkinson disease, multiple system atrophy, Lewy body dementia) in patients with REM sleep behaviour disorder was reported to be 30% at 3 years, rising to 66% at 7.5 years. (45) Advanced age (HR 1.07), olfactory loss (HR 2.8), abnormal colour vision (HR 3.1), subtle motor dysfunction (HR 3.9) and nonuse of antidepressants (HR 3.5) identified higher risk of disease conversion. (45)
Predictors of a more benign course Predictors of a more rapid course Early onset (24)
Tremor-predominant
Female sex (118)
Late onset (24)
Male sex (118)
Postural instability (predominant gait difficulty)
Rigidity or bradykinesia as first symptom
Dementia
Poor response to levodopa
Associated comorbidities (e.g., stroke)
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