Parkinson s Disease

Sirilak yimcharoen

EPIDEMIOLOGY
~1% of people over 55 years Age range 3585 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 supinationpronation ( 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 Parkinsons Disease Society Brain Banks clinical criteria for the diagnosis of probable Parkinsons disease Step 1 Bradykinesia At least one of the following criteria: Rigidity 46 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 (70100%) 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 Parkinsons 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 Parkinsons disease
Criteria for definite PD All criteria for probable Parkinsons 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
0 No signs of disease. 1 2

UPDRS

4 5

There are 6 major parts; 1.Mentation, behavior and Unilateral disease. mood Bilateral disease, without impairment 2.Activities of daily living of balance. 3.Motor examination 4.Complication of therapy Mild to moderate bilateral disease; some postural instability; physically 5.Modified Hoehn and Yahr independent. staging 6.Schwab and England Severe disability; still able to walk or activites of daily living scale stand unassisted. Wheelchair bound or bedridden unless aided.

Differential diagnosis of parkinsonism

1. Primary parkinsonism
parkinsons disease Juvenile parkinsonism Multiple system atrophy Cortico-basal ganglionic degeneration Progressive supranuclear palsy Drug-induced Vascular parkinsonism

3. Parkinson plus disorder

5. Secondary 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
Pharmacologic
Anticholinergics
(Tremor)

Clinical pearls in drug selection

Age Cognitive function Severity of motor features Response to previous PD treatment

65 yrs

>65 yrs

Dopamine agonists

Dopamine replacement

Add COMT inh., MAO-B inh., or others

Peripheral organ
3OMD 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 Dopamin e agonists

Selegiline Rasagiline

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 o

Peak dose dyskinesia On 3me O 3me

Time

Dose

Dose

Dose

Dose

Dose

http://www.mypdinfo.com/en/treatment_of_pd/ treating_pd_with_medications/what_is_wearing_off/

Management of Motor Complications

Wearing off
Symptom deterioration

On-off
Random deterioration

Peak dose
Too much movement

Predictable

Unpredictable

dose frequency, add an3dykine3cs

frequency, controlled release

DT, add other drugs

Dopamine agonists
Ergot
e.g. e.g. pramiprexol Benefit when use in early disease Bromocriptine , ropinirole (delays the use of levodopa)
Caution: Start low, go slow Fibrosis e.g. heart valve, (better tolerate with evening lung (dose and time of exposure related) Fibrosis: stimulation of 5HT2B that may potentiate inflammation
CNS Drugs 2010; 24 (11): 941-968

Nonergot

Use in management of motor complications e.g. dyskinesia esp. long acting

Caution: Sleep attack was first dose) in pt reported treated with ropinirole and pramiprexol

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 (2nd Ed), 2011

MAO-B Inhibitors
Selegiline and Rasagiline Benefit
Neuroprotective

Cautions
Drug interaction
CYP2B6, CYP2C19 SSRI, lithium, imipramine risk of serotonin syndrome

Selegiline metabolite is amphetamine derivatives

European Handbook of Neurological Management (2

Minimal effects e.g. insomnia, nd hallucination

Ed), 2011

Anticholinergics
Trihexylphenidyl, benztropine Benefit
Tremor predominant

Cautions
Anticholinergic side effects (start low, go slow) Cognitive impairment (due to M1 mAChR)

Brain and Cogni3on 68 (2008) 415435, Pharmacology & Therapeu3cs 117 (2008) 232243

NMDA-receptor antagonist

NMDA-receptor antagonist
Amantadine Benefit
Inhibit excitatory pathway (glutamic pathway) Management of motor complication esp. dyskinesia

Caution
Dose adjustment in renal impairment

European Handbook of Neurological Management (2nd Ed), 2011

The end