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Parkinson's disease (paralysis agitans, PD)

In 1817 James Parkinson, a London physician, described the motor disorder that now bears his name: '... involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported, with a propensity to bend the trunk forwards, and to pass from a walking to a running pace, the senses and intellects being uninjured.' Etiology: 1) idiopathic 2) viral encephalitis (rare) 3) focal lesions of the substantia nigra (rare) 4) Parkinson's disease may occur as a result of single event rather than a chronic process: a) progressive neurodegeneration after exposure to a neurotoxin earlier in life b) delayed onset of parkinsonism after encephalitis lethargica 5) traumatic brain injury in older adults increases risk of Parkinson's disease [80] 6) parasopmnias including REM sleep behavior disorder may play a role [115. 172] 7) risk factors include: - alcohol misuse (RR=1.32) [172] - hypertension (RR=1.29) [172] - anosmia, primarily white men (RR=2.16) [103,172] & sensory impairments beyond anosmia - hearing loss (RR=1.14) [172] - hearing loss is an independent dose-dependent risk factor for later development of Parkinson's disease - hearing aids attenuate risk [201] - changes of skin sensation (RR=1.31) [172] - restless legs syndrome (RR=4.19)* [172] - tremor (RR=4.49)* [172] - sleep apnea (RR=1.45) [172] - epilepsy (RR=2.26) [172] - migraine (RR=1.21) [172] - bipolar disorder (RR=3.81)* [172] - schizophrenia (RR=4.48)* [172] - skin disorders - seborrheic dermatitis (RR=1.30) [172] - psoriasis (RR=1.13) [172] - rosacea (RR=1.71, 2.03 if ocular rosacea) - risk normalized by treatment with tetracycline [89] - gastrointestinal disorders - gastroesophageal reflux (RR=1.29) [172] - gastritis (RR=1.28) [172] - ulcerative colitis, 0.37 vs 0.22 per 1000 person-years [112] - gastroparesis, dysphagia, constipation: > 2-fold risk within 5 years [180] - nearly all patients with Parkinson's disease experience digestive problems & lesions in intrinsic & extrinsic innervation of the GI tract [187] - seronegative osteoarthritis (RR=1.21) [172] - diabetes mellitus type-1 (RR=1.32) [172] - diabetes mellitus type-2 (RR=1.24-1.3) [114,172] - pesticides - air pollution: nitrogen dioxide (NO2) [148] - higher levels of PM2.5 & NO2 exposure are associated with increased risk of Parkinson's disease [198] - higher levels of PM2.5 exposure are associated with increased risk of akinetic rigid Parkinson's disease & dyskinesia vs exposure to lower levels [198] - welding - volatile organic compounds [178] - trichloroethylene [175,178] - copper ? [161] - milk (men) [21,28] - oophorectomy before menopause (RR 1.8) [32] 8) statin use may increase risk (RR=1.6-1.7) [92] - lower HDL cholesterol & increased HDL cholesterol variability may increase risk [146] - statin use associated with worse baseline nigrostriatal dopamine degeneration [152] - statin use prior to diagnosis associated with increased risk of dementia [152] 9) anticonvulsants including lamotrigine, levetiracetam, & sodium valproate with weaker evidence for carbamazepine may increase risk of Parkinson's disease (RR ~1.8) [171] - evidence is stronges for sodium valproate [171] 10) depression ? [81] 11) intestinal flora may play a role [113] - decrease in Lactococcus, Streptococcus, & Lactobacillus - lytic bacteriophages in the fecal microbiome may play a role in regulation of intestinal flora [113] * symptoms may be present 5-10 years prior to diagnosis of Parkinson's disease [172] * reduced risk associated with: - coffee & caffeine consumption [8] - plasma caffeine, paraxanthine & theophylline metabolites of caffeine are inversely associated with risk of Parkinson's disease (RR=0.80, 0.82, & 0.78) [190] - higher serum uric acid [22] * calcium channel blockers [33] - NSAIDs not protective [23,44] * truncal vagotomy may decrease risk of PD [95] * beta-2 adrenergic receptor agonists may reduce expression of alpha-synuclein & risk of Parkinson's disease [101] * increased physical activity (RR=0.79) [118,135] * high serum cholesterol & LDL cholesterol has a protective effect [92,97] (RR ~0.9 cited) * maybe vitamin E & vitamin C [147] * maybe vitamin B12 [176] - not folate of vitamin B6 [176] Epidemiology: 1) Incidence: 13-20 cases/100,000 - incidence rate ~90,000 cases annually for people >= 65 years [169] - Prevalence: 187 cases/100,000 [15,42] 2) lifetime risk 1-2% [15] 3) usual age of onset: 50-70 years; can occur after age 20 4) more common in males, M:F ratio 3:2 [15] 5) rare familial forms with autosomal dominant inheritance 6) increased incidence in rural areas, drinking well water 7) a cluster of counties with higher Parkinson's incidence in Midwestern & Southern regions of the country [169] - incidence also were elevated in southern California, southeastern Texas, central Pennsylvania, and Florida [169] 8) between 1975 & 1985, water supplies at Camp Lejeune were contaminated with several volatile organic compounds [178] - levels were highest for trichloroethylene, with median values > 70-fold permissible levels [178] Pathology: 1) selective neuronal loss a) pars compacta of substantia nigra (dopaminergic neurons) 1] neuronal loss greatest in ventrolateral tier, followed by medial ventral tier & dorsal tier 2] 60-70% loss at onset of symptoms 3] pattern of neuronal loss opposite that in normal aging 4] loss of striatal dopaminergic projections most prominent in dorsal & intermediate subdivisions of putamen 5] deficit in dopamine release 6] down-regulation of dopamine transporters in part compensates for loss of dopaminergic terminals [36] 7] cholinergic hypersensitivity within the striatum [15] 8] results in excessive inhibitory output of the globus pallidus interna to the thalamus [15] 9] retinal thinning may be linked to dopaminergic neuronal atrophy [117] b) locus ceruleus - deficit in norepinephrine release c) raphe nuclei d) hypothalamic neurons e) small cortical neurons 1] cingulate gyrus 2] entorhinal cortex f) nucleus basalis of Meynert g) olfactory bulb h) sympathetic ganglia i) parasympathetic neurons in gut j) projection cells that generate long, unmyelinated or sparsely myelinated axons [29] k) peripheral autonomic nerves may be affected before the brainstem [115] l) serotonergic pathology in premotor A53T SNCA carriers may precede development of dopaminergic pathology & motor symptoms [132] 2) Lewy bodies 3) Lewy neurites a) degenerating neurites containing 1] ubiquitin 2] alpha-synuclein - copper modifies & accelerates alpha synuclein aggregation [161] b) found in affected brainstem regions c) especially prominent in dorsal nucleus of vagus d) cognitive impairment correlates with Lewy neurites in CA2 region of hippocampus 4) diminished glucocerebrosidase activity appears to be an early step in degeneration of dopaminergic neurons [94] 5) possible preventive effect of truncal vagotomy on incidence of PD provides support for Braak hypothesis that PD begins in the gut & spreads to the brain [95] 6) early caudate dysfunction may increase risk for later cognitive impairment & depression [128] 7) alterations in gut microbiome - alterations in intestinal permeability [113] - Lactococcus & Lactobacillus regulate intestinal permeability & are diminished in intestinal flora of PD patients [113] - lytic bacteriophages may play a role in diminished intestinal Lactococcus [113] - vermiform appendix may play a role [121] - 46 of 48 healthy human appendixes with insoluble alpha-synuclein, similar to alpha-synuclein found in brains of patients with Parkinson's disease [121] - appendectomy lowers risk of Parkinson's disease [121] - reduced abundance Roseburia faecis, Eubacterium rectale, and E. ramulus (known for flavonoid degradation), Oscillibacter_sp_57_20, Bacteroides xylanisolvens, E. siraeum [184] - increased abundance of Bifidobacterium dentium, B. longum, E. tayi, C. leptum, R. lactatiformans [184] - findings of mucosal damage on upper endoscopy associated with a 76% greater risk of developing Parkinson's disease [196] 8) reduced retinal ganglion cell-inner plexiform layer thickness & reduced retinal inner nuclear layer thickness as determined by optical coherence tomography [179] Genetics: 1) autosomal dominant forms [31] a) alpha-synuclein gene (SNCA) mutations b) UCH-L1 mutations (ubiquitin carboxyl-terminal hydrolase) c) chromosome 2q d) LRRK2 (along with parkin, most common genetic form) - p.G2019S 2) autosomal recessive a) parkin (PARK2) (no Lewy bodies) b) DJ-1 c) PINK1 3) up-regulation of DDIT4, CPLX1 in substantia nigra neurons 4) twin studies: a) if < 55 years of age, relative risk = 6.0 b) if > 55 years of age, no increased risk 5) variants in the GBA1 gene are associated with faster disease progression [183] 6) other implicated genes: - SNCAIP, (cyt P450s?), MAPT, HLA-DRB5, BST1, GAK - ACMSD, STK39, MCCC1/LAMP3, SYT11, CCDC62/HIP1R) [44], kallikrein-6 7) associated with cholinergic & monoaminergic neurons (including dopaminergic neurons) & with enteric neurons & oligodendrocytes [140] 8) > 2000 specific bacteriophages infecting gut bacteria are associated human chronic diseases, particularly Parkinson disease & obesity [149] - many of the viral sequences are integrated into human chromosomal DNA or in circular episomes [149] History: - review diagnosis, psychiatric symptoms, autonomic symptoms - ask about cognitive impairment, sleep disturbance, adverse drug effects [91] Clinical manifestations: 1) onset: between ages 40 & 70 2) preclinical symptoms [24,76,131,170] a) tremor within 2 years of diagnosis (41%) [76] b) within 2-5 years of diagnosis - tremor, constipation, balance problems, hypotension, erectile dysfunction, urinary dysfunction, dizziness, fatigue, depression, anxiety [76] c) within 5-10 years of diagnosis - tremor, constipation d) 3 years prior to diagnosis - problems with walking, balance, lifting heavy objects [170] e) other - anosmia (loss of smell) - slow reaction time - excessive daytime sleepiness - REM sleep behavior disorder [131,135] (wild dreams) - impaired color vision [135] f) anosmia, constipation, REM sleep behavior disorder may precede movement disorder in a subgroup of patients [3] g) depression may precede movement disorder in a subgroup of patients [70,81] 3) presenting symptoms: a) classic triad of: tremor, rigidity, bradykinesia* b) cerebellar signs normal: finger-to-nose & heel-to-shin intact [6] c) postural reflex abnormality (falling)* d) shuffling gait & changes in posture e) loss of dexterity, deterioration of handwriting, difficulties in getting up from a chair or out of bed, f) asymmetry of symptoms at presentation, often with persistence of asymmetry [6] g) leg motor restlessness - not restless legs syndrome [48] 4) tremor at rest* (4-5 Hz) [111] a) first noted in the hands & fingers "pin rolling" b) later may involve legs, face & tongue c) may be unilateral at the onset (asymmetry is the rule) d) exacerbated by anxiety e) absent during sleep 5) a faster (7-8 Hz) "action tremor" may be present 6) superimposition of tremor on passive movements creates a sense of "cogwheel rigidity" best demonstrated at the wrist 7) postural abnormalities: - flexion of the head, trunk, elbows, & knees, & positional deformities of the hands - postural tremor [110] 8) infrequent eye blinking 9) a fixed, expressionless "masked" face 10) decreased arm movements while walking 11) bradykinesia* - difficulty in initiating movement - decrements in speed & amplitude of repetitive movements [182] 12) frequent falls may occur, but are generally a late feature a) backward falls b) pull test predicts likelihood of backward falls c) early falls suggests parkinson plus syndrome 13) additional signs may include: a) autonomic dysfunction: 1] orthostatic hypotension (advanced disease) 2] constipation, diarrhea 3] urinary frequency, urinary urgency 4] hyperhidrosis (excessive sweating) 5] sialorrhea (diminished swallowing of saliva) 6] dyspnea (shortness of breath) 7] seborrhea 8] hyposmia b) sensory symptoms 1] pain 2] hyposmia [42] c) micrographia d) dysarthria & hypophonia - hypokinetic dysarthria common [195] e) dysphagia - choking or coughing with eating - regurgitation is uncommon [16] f) hypometric saccades g) seborrhea h) subtle dementia (25-30%) (see Parkinson's dementia) 1] rarely the presenting symptom; tends to occur late [15] 2] generally reflects subcortical pattern 3] cognitive dysfunction can be a prodromal sign [108] i) depression# [21], anxiety, apathy [6] j) excessive daytime sleepiness# (51%) [12] 13) tendon reflexes & sensory pathways are normal 14) any of the signs/symptoms may occur alone making the diagnosis of Parkinson's disease difficult without the passage of time & progession of signs/symptoms 15) early falls, rapid progression, poor response to Sinemet, dementia, early autonomic failure, cerebellar ataxia suggest other disorders (see differential diagnosis & parkinsonism) [6] * major criteria for diagnosis, bradykinesia + at least one other [6] (see diagnostic criteria for Parkinson's disease) # not L-dopa/carbidopa responsive [15] Diagnostic criteria: - bradykinesia - at least one other feature of Parkinson's disease - resting tremor - cogwheel rigidity - gait disorder or balance disorder - absence of sign/symptoms of parkinson plus syndrome Laboratory: - CSF typically normal - alpha synuclein aggregates in CSF - neuronally derived extracellular vesicle alpha-synuclein Ag in serum - specificity for alpha-synucleinopathy of 80% within 12 years [189] - alpha synuclein aggregates in skin cells may identify pre-symptomatic Parkinson's disease [197] - damaged nerve fibers within skin are enriched with phosphorylated- alpha synuclein aggregates [197] - higher levels of neurofilament light chain in serum in multiple system atrophy or progressive supranuclear palsy than in Parkinson's disease & healthy controls - L-dopa decarboxylase in CSF [185] - HDL cholesterol in serum - targeted multiplexed mass spectrometry identify biomarkers predicting Parkinson's disease up to 7 years before onset of symptoms - granulin precursor - mannan-binding-lectin-serine-peptidase-2 - endoplasmatic-reticulum-chaperone-BiP - prostaglaindin-H2-D-isomaerase - interceullular-adhesion-molecule-1 - complement C3 - Dickkopf-WNT-signalling pathway-inhibitor-3 - plasma-protease-C1-inhibitor Special laboratory: - EEG typically normal - tilt-table testing may reveal orthostatic hypotension resulting from autonomic dysfunction as a cause of syncope - polysomnography may be useful in the treatment of a comorbid sleep disorder [50] - ophthalmoscopy & retinal optical coherence tomography for retinal thinning* may suggest early cognitive changes in Parkinson's disease [117,144,179] * reduced retinal ganglion cell-inner plexiform layer thickness & reduced retinal inner nuclear layer thickness may be seen by optical coherence tomography years before diagnosis of Parkinson's disease [179] Radiology: 1) neuroimaging (CT &/or MRI) typically normal - neuroimaging not routinely required for diagnosis [6,85] - utility is to exclude other diagnoses [6] 2) MRI for exclusionary criteria [15] - NO lacunar infarcts, normal pressure hydrocephalus, cerebellar atrophy, brainstem atrophy - pixel-based analysis of MRI neuroimaging to analyze micro- & macro- structural changes in white-matter tracts may identify PD patients with visual hallucination, visual dysfunction or both [137] 3) SPECT* of brain reserved for differentiating Parkinson's disease from drug-induced parkinsonism & in difficult cases of essential tremor [6] 4) [11]C-DASB PET scan to assess serotonergic neurotransmitter system prior to diagnosis of Parkinson's disease (investigational) * detects dopamine transporter (DAT scan) [6] Complications: 1) oropharyngeal dysphagia [71] - aspiration pneumonia - dysphagia for medications is common (67-70%) [168] - capsules swallowed more efficiently than tablets, regardless of size [168] 2) decubitus ulcers & other problems associated with inanition occur in advanced cases 3) hallucinations a) dopamine agonists & cognitive impairment contribute b) serotonin 2A receptors may be involved [40] c) visual hallucinations & visual-processing abnormalities may be harbingers of Parkinson's dementia [137] 4) excessive sleep & sleep attacks may be associated with dopaminergic agonists [13,20] 5) disordered sleep (85%) [16] a) sleep fragmentation most common b) diminished slow-wave sleep may be associated with loss of working memory [50] c) rapid eye movement sleep behavioral disorder - periodic limb movements d) nocturnal myoclonus e) nocturnal immobility f) sleep-related respiratory dysrhythmias g) nocturnal psychiatric disturbance h) oxygen-desaturation may be associated with loss of working memory [50] i) NOT responsive to L-dopa [15] 6) other sleep-related disorders [6] a) restless legs syndrome b) sleep-wake reversal c) distressing dreams are associated with faster cognitive decline & increased risk of dementia [166] 7) autonomic disorders [6] a) postural hypotension - common, RR=3.at baseline & 5 at 7 years - prevalence: 64% with 29% clinically significant - cause of syncope - cognition worsens when sitting or standing in PD patients with orthostatic hypotension [93] b) urinary incontinence c) sexual dysfunction d) constipation e) sialorrhea f) seborrhea g) excessive sweating 8) falls may result in fracture or subdural hematoma - document falls (an outcome measure) [91] 9) increased risk of melanoma (HR = 2.2) [39] 10) behavioral disorders [6] a) impulse control disorder* (impulsive behavior) [55] b) craving for dopaminergic agonists [6] c) hypersexuality 11) cognitive impairment [6] - bradyphrenia, confusion, Parkinson's dementia - may be an early sign of impending parkinsonism & Parkinson's disease [108] - likelihood of dementia 9-27% within 10 years [199] - may be lower than previously thought [199] 12) depression, anxiety, apathy [6,71] - apathy disrupts white-matter networks & executive function [141] 13) delusions, psychosis [6] 14) musculoskeletal [6] a) truncal & neck flexion b) dystonic joint deformities: flexion of metacarpal joints, extension of proximal interphalangeal joints [6] c) frozen shoulder [6] d) osteoarthritis 153] 15) pain-related [6] a) painful dystonia, painful rigidity b) visceral painful sensations c) primary central pain 16) neuroleptic malignant syndrome caused by withdrawal of dopaminergic agent, carbodopa/levodopa or dopaminergic receptor agonist [6] 17) weight loss in Parkinson's disease is associated with dementia, dependency & mortality [106] 18) frailty is common leading to increased morbidity & mortality [153] * impulse control disorder may be drug-related [6] Differential diagnosis: 1) depression 2) essential tremor 3) Parkinson plus syndromes a) progressive supranuclear palsy b) multiple system atrophy - olivopontocerebellar degeneration - inability to move eyes vertically - Shy Drager syndrome - nigrostiatal degeneration 4) diffuse Lewy body disease (LBD) - early dementia within 1st year of parkinsonism suggests LBD [6] - hallucination plus REM-sleep disorder suggests LBD [26] 5) secondary parkinsonism a) head trauma (professional boxing) b) metabolic disorders - hypoparathyroidism c) cerebrovascular disease [15] d) normal pressure hydrocephalus [15] e) post-viral encephalitis f) toxins 1] carbon tetrachloride 2] carbon monoxide 3] carbon disulfide 4] cyanide 5] manganese 6] methanol 7] MPTP g) pharmacologic agents produce symmetric motor effects* 1] neuroleptics: a] haloperidol (Haldol) b] fluphenazine (Prolixin) 2] antiemetics a] prochlorperazine (Compazine) b] metoclopramide (Reglan) 3] reserpine 4] alpha-methyldopa (rare) 5] lithium carbonate (rare) 6) cerebrovascular disease (CVD) a) CVD also with shuffling gait & retropulsion b) multistep turning & increased muscle tone of CVD maybe confused with PD c) tremor, cogwheel rigidity & festination of PD absent in CVD * absence of a response to high-dose L-dopa/carbidopa is the strongest predictor of an atypical parkinsonism syndrome [6] * early symmetric signs/symptoms, early falls, early autonomic disorder, early dementia, rapid progression, cerebellar signs (ataxia) or poor response to Simemet suggest other diagnosis [6] * gaze palsy (PSP), recent neuroleptic use suggest other diagnosis [6] * non-motor features of Parkinson's disease are not elicited by pharmaceuticals [6] Management: 1) drug-induced parkinsonism is treated by stopping or diminishing the dose of offending drug 2) pharmaceutical treatment of symptoms when disability becomes apparent, i.e. when symtoms begin to interfere with function [6] 3) suppression of resting tremor in mild cases a) anticholinergics (trihexyphenidyl or benztropine) 1] antagonize striatal cholinergic hypersensitivity 2] anticholinergics associated with worsened cognitive function in Parkinson patients [41] 3] trihexyphenidyl, benztropine, biperiden [6] b) amantadine (Symmetrel) 1] more useful late in the disease 2] treatment of Sinemet induced dyskinesias c) primidone may also be of value 4) Sinemet (carbidopa/levodopa) a) first line drug for initial therapy for elderly [6,72] - 7 years outcomes better & adverse effects & discontinuation rates lower relative to initiation of therapy with MAO-B inhibitor or dopamine agonist [72] b) mainstay of therapy in elderly & in most other cases c) TID or more frequent dosing to minimize motor fluctuations d) combinations of sustained-release TID & regular every 3-4 hours e) therapeutic window narrows with more advanced disease f) amantadine (Gocovri) for treatment of Sinemet-induced dyskinesias [99] g) for levodopa-induced orthostasis (new onset orthostasis with Sinemet therapy) increase dose of carbidopa [11] (also see orthostatic hypotension) [6] h) continuous delivery of levodopa-carbidopa with an intestinal gel delivered through a percutaneous gastrojenunal tube may be of benefit for patients with advanced Parkinson's disease [62] i) early Sinemet neither neuroprotective nor harmful [124] - a 40 week delay initiating Sinemet does not effect 5-year outcome [191] j) quality of life among PD patients with motor complications uncontrolled by levodopa superior when MAO-B inhibitors or dopamine agonists were used as adjuvant treatment compared with COMT inhibitors [159] k) foscarbidopa/foslevodopa by continuous subcutaneous infusion (Vyalev) FDA-approved Oct 2024 5) dopamine receptor agonists a) 1st line for patients < 65 years of age [6] - useful in patients < 50 years of age [15] - used to delay the need for Sinemet (MKSAP19) [6] - replace with Sinemet if adverse effects (hallucinations, worsening motor function) become problematic [124,142] b) not useful in treating early stages to delay the need for Sinemet [34] c) may have neuroprotective effects [10,15] d) less likely than Sinemet to cause extrapyramidal effects e) agents 1] bromocryptine 2] pergolide 3] amantadine 4] pramipexole (Mirapex) 5] ropinirole (Requip) 6] rotigotine (Neupro) patch 7] apomorphine a] parenteral b] sublingual form may be useful for off episodes [136] 8] cabergoline 9] lisuride 10] piribedil f) associated with impulse control disorders [116] g) avoid dopamine receptor antagonists [91] 6) MAO inhibitors a) L-deprenyl (Selegiline) 1] appears not to slow disease progression [15] 2] the combination of L-deprenyl & Sinemet may produce an undesired outcome b) rasagiline 1] dose of 1 mg QD may have favorable disease-modifying effects [37] 2] may be used at lower dose (0.5 mg QD) with Sinemet c) safinamide (Xadago) FDA-approved for treatment of "off" episodes with levodopa/carbidopa d) MAO-B inhibitors may be underused as adjuvant therapy to levodopa [159] 7) COMT* inhibitors inhibit L-dopa catabolism a) tolcapone (Tasmar) b) entacapone (Comtan) c) Stalevo combines carbidopa/levodopa & entacapone [18] 8) dopaminergic therapy may increase creativity in patients with Parkinson's disease 9) potential therapies - adding carbidopa to Sinemet + entacapone may reduce "off" time [125] - 105 mg carbidopa vs 65 mg with 75, 100, 125, or 150 mg of levodopa + 200 mg of entacapone - exenatide may have symptomatic benefit [100] - anticonvulsants - zonisamide may be of benefit [30] - anticonvulsants associated with diminishes quality of life [151] - CoQ10 300-1200 mg/day; 100 mg/day might slow progression of Parkinson's disease [15,17] - rivastigmine may improve gait stability & reduce risk of falls (RR=0.58) [87] - prasinezumab, a monoclonal antibody targeting alpha-synuclein aggregates of no benefit for early Parkinson's disease [163] - venglustat of no benefit in GBA1-associated Parkinson's disease [183] - continuous subcutaneous levodopa-carbidopa infusion for patients with motor fluctuations [192] - gene therapy [60,127] - other investigational treatments - see investigational treatment of Parkinson's disease 10) hallucinations/psychosis [61] a) clozapine is effective for controlling psychosis & hallucinations without worsening motor function [174] - weekly CBC is required (start 12.5 mg QHS) b) pimavanserin (Nuplazid) - FDA-approved to treat hallucinations & delusions in patients with Parkinson's disease - improves psychosis without affecting motor function [174] c) quetiapine (Seroquel) - helps control hallucinations without worsening motor function - associated with a decline in cognitive function d) serotonin 2A receptor (HTR2A) antagonists may be of benefit [40] 1] quetiapine & clozapine have some HTR2A antagonism 2] cyproheptadine, trazodone e) avoid using high-affinity dopamine receptor antagonists (haloperidol, risperidone ..) in patients with Parkinson's disease [119] 1] may worsen cognition 2] may result in neuroleptic malignant syndrome 3] quetiapine preferred agent for patients with Parkinson's disease [119] e) avoid antipsychotics with anticholinergic activity [41] f) cholinesterase inhibitors may be of benefit [14] g) antipsychotic use in Parkinson's disease associated with increased risk of mortality (RR=2.35) [90] 11) neurosurgery a) stereotactic surgery to place lesions in the ventral lateral thalamus may be beneficial in cases of severe tremor - also electrical implant into thalamus for severe tremor b) unilateral pallidotomy for patients not responding to medication - focused ultrasound ablation of the posteroventral globus pallidus internus opposite the most symptomatic Parkinson's disease side [173] c) MRI-guided unilateral ultrasound subthalamotomy may benefit patients with asymmetric Parkinson's disease [107] d) deep brain stimulation - benefit for patients with sustained response to Sinemet, but use limited by adverse effects [6] - wearing off of Sinemet not responsive to optimizing medication management [6] - benefit to treatment-refractory cases [35] - subthalamic nucleus stimulation may be superior to globus pallidus pars interna stimulation [53] - may benefit selected patients early in the course of Parkinson's disease [54] - may be of benefit in 'off state' central pain [79] - adaptive deep brain stimulation may improve symptoms of Parkinson's disease [109] - worse quality-of-life score before deep brain stimulation associated with greater improvement at 2 years [126] e) transcranial image-guided focused ultrasound 12) assistive devices for fall prevention - patients with Parkinson's disease often have a tendency to fall backwards & do best with front wheel walkers [16,69] - 4 wheel walkers also decrease risk of falling due to fenistation - GRS11 states 4 wheeled walker increases stability & promotes a forward position that would prevent a backward fall [16] - standard walkers (without wheels) tend to increase freezing & may increase risk of backward fall when lifted [16] - straight canes & 4-prong canes provide less stability than walkerds & can increase fall risk by tripping & promoting a wide-based gait [16] 13) treat constipation with isosmotic polyethylene glycol [38] 14) treat depression [21] - rasagiline added to an SSRI may improve mood & cognition [77] - avoid antidepressants with anticholinergic activity (tricyclic antidpressants) - telephone-based cognitive behavioral therapy effective for treatment of depression [139] 15) nabilone may improve anxiety & sleep disorders [3] 16) cognitive therapy may improve functional disability [75] - cognitive behavioral therapy may benefit patients with impulse control disorder (impulsive behavior) [55] - does not improve depressive symptoms or apathy [75] - beneficial effects of cognitive training are small but statistically significant [86] - working memory, processing speed, & executive function improve - global cognition, overall memory, visuospatial skills, & depressive symptoms do not 17) regular exercise with attention to posture [15] a) encourage physical activity for all patients [6] - a healthy diet & physical activity may improve outcomes [162] b) Tai chi may be of benefit [46] - subtle structural brain changes occur after gait & balance training [157] c) resistance training may be of benefit d) stretching is recommended [46] e) low-intensity aerobic exercise (treadmill) improves gait instability & cardiovascular fitness [51] f) walking (70-80% of maximum heart rate) 3 times/week for 45 minutes improves aerobic fitness, motor function, cognition, & quality of life [74] g) early exercise & other regular physical activity both associated with slower clinical decline [160] h) exercise recommendations should be individualized [16] i) weekly dance training slows progression of motor & non-motor symptoms [150] j) timed get-up & go test may be preferred functional assessment tool [16] 18) rehabilitation & palliative care - offer rehabilative therapy options [91] - physical therapy of benefit [49]; may be of benefit [16,56] - combination of physical therapy & occupational therapy of no benefit [88] - outpatient multidisciplinary palliative care program associated with short-term improvements in quality of life [138] 19) excessive daytime somnolence, sleep attacks a) disease may impair ability to operate motor vehicle [27] b) modafinil 200-400 mg/day - modestly effective [66] - not useful [68] - GRS8 says modafinil improves daytime hypersomnolence [16] & cites refs [66,68] (SOE = B) c) methylphenidate may be useful for fatigue [38] - abuse is potentially a problem [38] - no evidence of effectiveness for hypersomnolence due to sleep disturbance [16] d) melatonin 50 mg QHS shows statistically significant improvement in total sleep time, but small improvement may not be clinically significant [67] 20) sildenafil for erectile dysfunction [38] 21) alternative therapy - moving to music rather than a metronome better supports entrainment & control [133] - acupuncture may improve gait in Parkinson disease patients [156] - diet high in flavonoid-rich foods linked to lower mortality risk in persons with Parkinson's disease [158] 22) unproven therapies - creatine does not slow progression of Parkinson's disease [78] - caffeine of no benefit for tremor motor symptoms [96,105] - monoclonal antibodies targeting alpha-synuclein (Cinpanemab & Prasinezumab) of no benefit [164,165] - simvastatin of no benefit as Parkinson's disease-modifying agent [167] - nicotine patches do not slow progression of early Parkinson's disease [186] 23) annual skin examination [39] 24) neurology consult: - care provided by a neurologist reduces hospitalizations, results in shorter hospitalizations, & reduces overall care costs [52] 25) telemedicine for virtual house calls for Parkinson disease is feasible & with similar quality-of-life outcomes to those of traditional office-visit approach [98] 26) surgery in patients with Parkinson's disease - withholding Parkinson agents for surgery (Sinemet &/or dopaminergic receptor agonists) may result in parkinsonism-hyperpyrexia syndrome - management includes restarting Parkinson agents [6] 27) Lee Silverman voice treatment (speech therapy) for Parkinson's patients with dysarthria [195] 28) prognosis: a) most symptoms can be effectly managed for years - within 5 years of Sinemet or dopamine agonist treatment, 50% of patients will develop motor fluctuations or dyskinesias [6] b) timed get-up & go test may be preferred functional assessment tool [16] c) mortality similar to patients without Parkinson's disease [15] - Parkinson patients without early dementia do not have a reduced lifespan [123] 29) compensation strategies for patients with Parkinson's disease 30) advance directives discussion [91] 31) prevention: - MIND diet & Mediterranean diet may delay onset of Parkinson's disease [145] - a healthful plant-based diet with the inclusion of vegetables, nuts & tea may be associated with a lower risk of Parkinson's disease [181] - tetanus vaccination is associated with reduced occurrence & slower progression of Parkinson's disease [193] * catechol O-methyltransferase (COMT) 32) investigational therapy - continuous intracerebroventricular administration of an anaerobic dopamine formulation (A-dopamine) [200] - A-dopamine is infused with a telemetry-controlled intra-abdominal pump connected to a subcutaneous catheter implanted through the right frontal horn into the third ventricle close to the caudate where dopamine is needed [200] - implantation surgery takes 4 hours Comparative biology: - induced pluripotent stem cell-derived dopaminergic progenitors functioned as midbrain dopaminergic neurons in Macaca fascicularis treated with the neurotoxin MPTP [102] - the mature dopaminergic neurons extended dense neurites into the striatum - an increase in spontaneous movement of the monkeys after transplantation observed - no neoplasms noted within 2 years - in mice, Parkinson's disease can begin with formation of pathological alpha-synuclein in the gut, which travels up the vagus nerve to the brain [130] Notes: - health care providers diagnosing or providing treatment to Parkinson's disease patients are now required to report each case of Parkinson's disease to the California Department of Public Health [128]

Interactions

disease interactions

Related

deep brain stimulation (DBS) diagnostic criteria for Parkinson's disease investigational treatment of Parkinson's disease orthostatic hypotension in Parkinson's disease parkinson plus syndrome Parkinson's dementia; Parkinson's psychosis-dementia complex Parkinson's disease 2, juvenile, autosomal recessive staging of Parkinson's disease (Hoehn-Yahr scale)

Useful

pharmacologic agents for treatment of Parkinson's disease

Specific

familial Parkinson's disease Kufor-Rakeb syndrome (Parkinson disease-9)

General

basal ganglia disease parkinsonism synucleinopathy (includes alpha-synucleinopathy)

Properties

PATHOLOGY: Lewy body

References

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OMIM correlations Kegg hsa/hsa05020 Figures/diagrams/slides/tables related to Parkinson's disease image related to Parkinson's disease