Parkinson's Disease

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Contents 1 More Specific Terms 2 Introduction 3 Etiology 4 Epidemiology 5 Pathology 6 Genetics 7 Clinical-manifestations 8 Laboratory 9 Radiology 10 Complications 11 Differential-diagnosis 12 Management 13 More General Terms 14 Additional Terms 15 Internet Database 16 References

More Specific Terms

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

Introduction

• 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

• idiopathic
• viral encephalitis (rare)
• focal lesions of the substantia nigra (rare)
• Parkinson's disease may occur as a result of single event rather than a chronic process:

• progressive neurodegeneration after exposure to a neurotoxin earlier in life
• delayed onset of parkinsonism after encephalitis lethargica

• risk factors include pesticides, welding, trichloroethylene, milk (men) [21,28], oophorectomy before menopause ( RR 1.8) [32]
• reduced risk associated with coffee & caffeine consumption [8] higher serum uric acid [22], NSAIDs not protective [23,44], calcium channel blockers [33]
• lowering serum cholesterol may reduce risk [47]

Epidemiology

• Incidence: 13-20 cases/100,000, Prevalence: 187 cases/100,000 [15,42]
• lifetime risk 1-2% [15]
• usual age of onset: 50-70 years; can occur after age 20
• more common in males, M:F ratio 3:2 [15]
• rare familial forms with autosomal dominant inheritance
• increased incidence in rural areas, drinking well water

Pathology

• selective neuronal loss

• pars compacta of substantia nigra ( dopaminergic neurons)

• neuronal loss greatest in ventrolateral tier, followed by medial ventral tier & dorsal tier
• 60-70% loss at onset of symptoms
• pattern of neuronal loss opposite that in normal aging
• loss of striatal dopaminergic projections most prominent in dorsal & intermediate subdivisions of putamen
• down-regulation of dopamine transporters in part compensates for loss of dopaminergic terminals [36]
• cholinergic hypersensitivity within the striatum [15]
• results in excessive inhibitory output of the globus pallidus interna to the thalamus [15]

• locus ceruleus
• raphe nuclei
• hypothalamic neurons
• small cortical neurons

• cingulate gyrus
• entorhinal cortex

• nucleus basalis of Meynert
• olfactory bulb
• sympathetic ganglia
• parasympathetic neurons in gut
• projection cells that generate long, unmyelinated or sparsely myelinated axons [29]

• Lewy bodies
• Lewy neurites

• degenerating neurites containing

• ubiquitin
• alpha-synuclein

• found in affected brainstem regions
• especially prominent in dorsal nucleus of vagus
• cognitive impairment correlates with Lewy neurites in CA2 region of hippocampus

Genetics

• autosomal dominant forms [31]

• alpha-synuclein gene (SNCA) mutations
• UCH-L1 mutations ( ubiquitin carboxyl-terminal hydrolase)
• chromosome 2q
• LRRK2 (along with parkin, most common genetic form)

• autosomal recessive

• parkin ( PARK2) (no Lewy bodies)
• DJ-1
• PINK1

• up-regulation of DDIT4, CPLX1 in substantia nigra neurons
• twin studies:

• if < 55 years of age, relative risk = 6.0
• if > 55 years of age, no increased risk

• other implicated genes:

• SNCAIP, ( cyt P450s?), MAPT, HLA-DRB5, BST1, GAK
• ACMSD, STK39, MCCC1/ LAMP3, SYT11, CCDC62/ HIP1R) [44], kallikrein-6

Clinical-manifestations

• onset: between ages 40 & 70
• preclinical symptoms [24]

• constipation
• loss of smell
• slow reaction time
• excessive daytime sleepiness

• presenting symptoms:

• classic triad of: tremor, rigidity, bradykinesia
• loss of dexterity, deterioration of handwriting, difficulties in getting up from a chair or out of bed, a shuffling gait, changes in posture
• asymmetry of symptoms at presentation, often with persistance of asymmetry [6]
• leg motor restlessness

• not restless legs syndrome [48]

• tremor at rest* (4-5 Hz)

• first noted in the hands & fingers "pin rolling"
• later may involve legs, face & tongue
• may be unilateral at the onset (asymmetry is the rule)
• exacerbated by anxiety
• absent during sleep

• a faster (7-8 Hz) "action tremor" may be present
• superimposition of tremor on passive movements creates a sense of "cogwheel rigidity" best demonstrated at the wrist
• postural abnormalities:

• flexion of the head, trunk, elbows, & knees, & positional deformities of the hands

• infrequent eye blinking
• a fixed, expressionless "masked" face
• decreased arm movements while walking
• bradykinesia* (difficulty in initiating movement)
• frequent falls may occur, but are generally a late feature
• additional signs may include:

• autonomic dysfunction:

• orthostatic hypotension (advanced disease)
• constipation, diarrhea
• urinary frequency, urinary urgency
• hyperhidrosis ( excessive sweating)
• sialorrhea (diminished swallowing of saliva)
• dyspnea ( shortness of breath)

• sensory symptoms

• pain
• hyposmia [42]

• micrographia
• dysarthria & hypophonia
• hypometric saccades
• seborrhea
• subtle dementia (25-30%) (see Parkinson's dementia)

• rarely the presenting symptom; tends to occur late [15]
• generally reflects subcortical pattern

• depression# [21]
• excessive daytime sleepiness# (51%) [12]

• tendon reflexes & sensory pathways are normal
• 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
• early falls, rapid progression, poor response to Sinemet, dementia, early autonomic failure, ataxia suggest other disorders (see differential diagnosis) [6]

• * either resting tremor or bradykinesia (or both) must be present for diagnosis (see diagnostic criteria for Parkinson's disease)
• # not L-dopa/ carbidopa responsive [15]

Laboratory

• CSF & EEG typically normal

Radiology

• CT & MRI typically normal
• MRI for exclusionary criteria [15]

• NO lacunar infarcts, normal pressure hydrocephalus, cerebellar atrophy, brainstem atrophy

Complications

• aspiration pneumonia
• decubitus ulcers & other problems associated with inanition occur in advanced cases
• hallucinations

• dopamine agonists & cognitive impairment contribute
• serotonin 2A receptors may be involved [40]

• excessive sleep & sleep attacks may be associated with dopaminergic agonists [13,20]
• disordered sleep (85%) [16]

• sleep fragmentation most common
• periodic limb movements
• nocturnal myoclonus
• nocturnal immobility
• sleep-related respiratory dysrhythmias
• nocturnal psychiatric disturbance
• NOT responsive to L-dopa [15]

• falls may result in fracture or subdural hematoma
• increased risk of melanoma (HR = 2.2) [39]
  
• disease interaction(s) of Parkinson's disease with urinary incontinence
• disease interaction(s) of rapid eye movement behavioral disorder with synucleinopathy

Differential-diagnosis

• depression
• essential tremor
• Parkinson plus syndromes

• progressive supranuclear palsy
• olivopontocerebellar degeneration
• Shy Drager syndrome

• diffuse Lewy body disease ( LBD)

• hallucination plus REM-sleep disorder suggest LBD [26]

• secondary parkinsonism

• head trauma (professional boxing)
• metabolic disorders - hypoparathyroidism
• cerebrovascular disease [15]
• normal pressure hydrocephalus [15]
• post- viral encephalitis
• toxins

• carbon tetrachloride
• carbon monoxide
• carbon disulfide
• cyanide
• manganese
• methanol
• MPTP

• pharmacologic agents:

• neuroleptics:

• haloperidol ( Haldol)
• fluphenazine ( Prolixin)

• antiemetics

• prochlorperazine ( Compazine)
• metoclopramide ( Reglan)

• reserpine
• alpha-methyldopa (rare)
• lithium carbonate (rare)

• cerebrovascular disease ( CVD)

• CVD also with shuffling gait & retropulsion
• multistep turning & increased muscle tone of CVD may be confused with PD
• tremor, cogwheel rigidity & festination of PD absent in CVD

Management

• drug-induced parkinsonism is treated by stopping or diminishing the dose of offending drug
• pharmaceutical treatment of symptoms when disability becomes apparent
• suppression of resting tremor in mild cases

• anticholinergics ( trihexyphenidyl or benztropine)

• antagonize striatal cholinergic hypersensitivity
• anticholinergics associated with worsened cognitive function in Parkinson patients [41]

• amantadine ( Symmetrel)

• more useful late in the disease
• treatment of Sinemet induced dyskinesias

• primidone may also be of value

• Sinemet (carbidopa/levodopa)

• mainstay of therapy in elderly & in most other cases
• TID or more frequent dosing to minimize motor fluctuations
• combinations of CR TID & regular every 3-4 hours
• therapeutic window narrows with more advanced disease
• amantadine ( Symmetrel) for treatment of Sinemet induced dyskinesias

• dopamine receptor agonists

• useful in younger patients [15] (< 50 years of age)
• not useful in treating early stages to delay the need for Sinemet [34]
• may have neuroprotective effects [10,15]
• less likely than Sinemet to cause extrapyramidal effects
• agents

• bromocryptine
• pergolide
• amantadine
• pramipexole ( Mirapex)
• ropinirole ( Requip)
• rotigotine ( Neupro) patch

• MAO inhibitors

• L-deprenyl ( Selegiline)

• appears not to slow disease progression [15]
• the combination of L-deprenyl & Sinemet may produce an undesired outcome

• rasagiline

• dose of 1 mg QD may have favorable disease-modifying effects [37]
• may be used at lower dose (0.5 mg QD) with Sinemet

• COMT* inhibitors inhibit L-dopa catabolism

• tolcapone ( Tasmar)
• entacapone ( Comtan)
• Stalevo combines carbidopa/levodopa & entacapone [18]

• anticonvulsants - zonisamide may be of benefit[ 30]
• hallucinations/ psychosis

• quetiapine ( Seroquel) helps control hallucinations without worsening Parkinson's disease (start 2.5 mg QHS)
• clozapine is the most effective for controlling hallucinations without worsening motor function, but weekly CBC is required (start 12.5 mg QHS)
• serotonin 2A receptor ( HTR2A) antagonists may be of benefit [40]

• quetiapine & clozapine have some HTR2A antagonism
• cyproheptadine, trazodone

• avoid antipsychotics with anticholinergic activity [41]
• cholinesterase inhibitors may be of benefit [14]

• 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

• unilateral pallidotomy for patients not responding to medication
• transplants of adrenal medullary & fetal tissue to the striatum ( investigational treatment of Parkinson's disease)
• deep brain stimulation of benefit to treatment- refractory cases [35]
• assistive devices:

• patients with Parkinson's disease often have a tendency to fall backwards & do best with front wheel walkers

• treat constipation with isosmotic polyethylene glycol [38]
• treat depression [21] see depression & Parkinson's disease

• avoid antidepressants with anticholinergic activity ( tricyclic antidpressants)

• CoQ10 300-1200 mg/day; 100 mg/day might slow progression of Parkinson's disease [15,17]
• regular exercise with attention to posture [15]

• Tai chi may be of benefit
• resistance training may be of benefit
• stretching is recommended [46]

• excessive daytime somnolence, sleep attacks

• disease may impair ability to operate motor vehicle [27]
• modafinil may improve patient's perception of excessive daytime sleepiness, but objective measures may be lacking
• methylphenidate may be useful for fatigue, but abuse is potentially a problem [38]

• sildenafil for erectile dysfunction [38]
• annual skin examination [39]
• prognosis:

• most symptoms can be effectly managed for years
• mortality similar to patients without Parkinson's disease [15]

• * catechol O-methyltransferase ( COMT)

More General Terms

• synucleinopathy
• basal ganglia disease
• geriatric disease

Additional Terms

• deep brain stimulation (DBS)
• depression & Parkinson's disease
• diagnostic criteria for Parkinson's disease
• investigational treatment of Parkinson's disease
• parkinson plus syndrome
• Parkinson's dementia
• Parkinson's disease 2, juvenile, autosomal recessive
• parkinsonism
• pharmacologic agents for treatment of Parkinson's disease
• staging of Parkinson's disease (Hoehn-Yahr scale)

Internet Database

OMIM: 168600
OMIM: 556500
Kegg: [1]

References

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Parkinson's disease (paralysis agitans)