Parkinson s Disease Sirilak yimcharoen
EPIDEMIOLOGY ~1% of people over 55 years Age range 35 85 years peak age of onset is in the early 60s ~5% of cases characterized by an earlier age of onset (typically before age 45 years)
PATHOGENESIS Microscopic presence of Lewy bodies in the remaining neurons Genetic :earlier age onset
Etiology Degradation of dopaminergic neurons in the substantia nigra
CLINICAL FEATURES Symptoms Motor symptoms Non motor symptoms cardinal signs rest tremor rigidity bradykinesia
Motor symptoms Tremor, bradykinesia, rigidity, postural instability Hypominia, dysarthria, dysphagia, Decreased arm swing, difficult arising from chair micrographia Glabellar reflex, blebphalospasm, dystonia, camptocormia, scoliosis
Bradykinesia most characteristic clinical feature manifestations of bradykinesia slowness of movement loss of spontaneous movements and gesturing drooling monotonic and hypophonic dysarthria loss of facial expression Freezing(motor blocks) is a form of akinesia
Bradykinesia correlate best with degree of dopamine deficiency Assessment of bradykinesia rapid, repetitive, alternating movements of the hand observing not only slowness but also decrementing amplitude
Tremor Rest tremor is the most common unilateral, frequency between 4 and 6 Hz Hand tremors are described as supination pronation ( pill-rolling ) involve :lips, chin, jaw and legs rarely involve: the neck/head responsive to dopaminergic therapy
Rigidity increased resistance cogwheel Postural deformities Camptocormia
Non-motor symptoms Mental problem : dementia, depression, apathy Autonomic disturbance : postural hypotension, constipation, bladder dysfunction Sensory symptom : anosmia, ageusia, paresthesia Sleep disturbance
Diagnostic criteria UK Parkinson s Disease Society Brain Bank s clinical criteria for the diagnosis of probable Parkinson s disease Step 1 Bradykinesia At least one of the following criteria: Rigidity 4 6 Hz rest tremor Postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction Step 2 Exclude other causes of parkinsonism Step 3 At least three of the following supportive (prospective) criteria: Unilateral onset Rest tremor Progressive disorder Persistent asymmetry primarily affecting side of onset Excellent response (70 100%) to levodopa Severe levodopa induced chorea (dyskinesia) Levodopa response for 5 years or more Clinical course of 10 years or more
National Institute of Neurological Disorders and Stroke (NINDS) diagnostic criteria for Parkinson s disease Group A features (characteristic of PD) Resting tremor Bradykinesia Rigidity Asymmetric onset Group B features (suggestive of alternative diagnoses) Features unusual early in the clinical course Prominent postural instability in the first 3 years after symptom onset Freezing phenomenon in the first 3 years Hallucinations unrelated to medications in the first 3 years Dementia preceding motor symptoms or in the first year Supranuclear gaze palsy (other than restriction of upward gaze) or slowing of vertical saccades Severe, symptomatic dysautonomia unrelated to medications Documentation of condition known to produce parkinsonism and plausibly connected to the patient s symptoms (such as suitably located focal brain lesions or neuroleptic use within the past 6 months)
National Institute of Neurological Disorders and Stroke (NINDS) diagnostic criteria for Parkinson s disease Criteria for definite PD All criteria for probable Parkinson s are met and Histopathological confirmation of the diagnosis is obtained at autopsy Criteria for probable PD At least three of the four features in group A are present and None of the features in group B is present (note: symptom duration 3 years is necessary to meet this requirement) and Substantial and sustained response to levodopa or a dopamine agonist has been documented Criteria for possible PD At least two of the four features in group A are present; at least one of these is tremor or bradykinesia and Either none of the features in group B is present or symptoms have been present 3 years and none of the features in group B is present and Either substantial and sustained response to levodopa or a dopamine agonist has been documented or the patient has not had an adequate trial of levodopa or a dopamine agonist
Disease staging and assessment Hoehn and Yahr Staging UPDRS 0 No signs of disease. There are 6 major parts; 1 Unilateral disease. 1. Mentation, behavior and mood Bilateral disease, without impairment 2 2. Activities of daily living of balance. 3. Motor examination 3 Mild to moderate bilateral disease; some postural instability; physically independent. 4. Complication of therapy 5. Modified Hoehn and Yahr staging 6. Schwab and England Severe disability; still able to walk or 4 activites of daily living scale stand unassisted. 5 Wheelchair bound or bedridden unless aided.
Differential diagnosis of parkinsonism 1. Primary parkinsonism parkinson s disease Juvenile parkinsonism 3. Parkinson plus disorder Multiple system atrophy Cortico-basal ganglionic degeneration Progressive supranuclear palsy 5. Secondary parkinsonism Drug-induced Vascular parkinsonism
Differential diagnosis of parkinsonism 3. Secondary parkinsonism Normal pressure hydrocephalus Toxin-induced Infectious 4. Heredodegenerative parkinsonism Dementia with Lewy Bodies Huntington disease Wilson disease
Treatment Algorithm
Treatment Algorithm Anticholinergics (Tremor) Dopamine agonists Pharmacologic 65 yrs >65 yrs Add COMT inh., MAO-B inh., or others Dopamine replacement Clinical pearls in drug selection Age Cognitive function Severity of motor features Response to previous PD treatment
3OMD Peripheral organ COM T 3OMD Alphasynuclein COM T NMDA R
Peripheral organ 3OMD COM T Entacapon e Tolcapone Benserazid e Carbidopa 3OMD Alphasynuclein COM T Amantadin e NMDA R Selegiline Rasagiline Dopamin e agonists
Dopamine Replacement L-dopa/Benserazide (4:1), L-dopa/Carbidopa (10:1) Start with low dose (prefer regular release) Select appropriate preparation Beware of motor complications (later disease)
Complications from levodopa Motor complications Wearing off effect On-off effect Peak-dose dyskinesia Non-motor complications Psychosis Hallucination Autonomic symptoms e.g. constipation
Motor Complications from Levodopa Level of levodopa in the body Wearing off Time Peak dose dyskinesia On 3me Off 3me Dose Dose Dose Dose Dose http://www.mypdinfo.com/en/treatment_of_pd/ treating_pd_with_medications/what_is_wearing_off/
Management of Motor Wearing off Complications On-off Peak dose Symptom deterioration Random deterioration Too much movement Predictable Unpredictable dose ± frequency, add an3dykine3cs frequency, controlled release DT, add other drugs
CNS Drugs 2010; 24 (11): 941-968 Ergot Dopamine agonists e.g. Caution: Fibrosis e.g. heart valve, lung (dose and time of exposure related) Fibrosis: stimulation of 5- HT2B that may potentiate inflammation Nonergot e.g. pramiprexol, ropinirole Benefit when use in early disease Bromocriptine (delays the use of levodopa) Start low, go slow (better tolerate with evening dose) Caution: Sleep attack was first reported in pt treated with ropinirole and pramiprexol Use in management of motor complications e.g. dyskinesia esp. long acting
COMT Inhibitors Entacapone and Tolcapone (not available in Thailand) Benefit Reduce dose of levodopa Use to treat motor complications Cautions Autonomic symptoms e.g. diarrhea levodopa Hepatotoxic esp. tolcapone Monitor liver function closely in first 6 mons. European Handbook of Neurological Management (2 nd Ed), 2011
MAO-B Inhibitors Selegiline and Rasagiline Benefit Neuroprotective Cautions Drug interaction CYP2B6, CYP2C19 SSRI, lithium, imipramine à risk of serotonin syndrome Selegiline metabolite is amphetamine derivatives Minimal effects e.g. insomnia, hallucination European Handbook of Neurological Management (2 nd Ed), 2011
Brain and Cogni3on 68 (2008) 415 435, Pharmacology & Therapeu3cs 117 (2008) 232 243 Anticholinergics Trihexylphenidyl, benztropine Benefit Tremor predominant Cautions Anticholinergic side effects (start low, go slow) Cognitive impairment (due to M1 machr)
NMDA-receptor antagonist
European Handbook of Neurological Management (2 nd Ed), 2011 NMDA-receptor antagonist Amantadine Benefit Inhibit excitatory pathway (glutamic pathway) Management of motor complication esp. dyskinesia Caution Dose adjustment in renal impairment
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