Parkinson Disease

Parkinson Disease: PD
Tremor 2. Rigidity 3. Bradykinesia 4. Characteristic abnormalities of gait and posture May occur with many disorders. PD is idiopathic parkinsonism without evidence of more widespread neurologic involvement. PD afflicts 1 million individuals in the United States (1% of those 55 years). Peak age of onset in the 60s (range is 35 to 85);
1.

Famous Faces of Parkinson

Michael J. Fox Muhammad Ali

Katharine Hepburn

Mao Tse Tung Pope John Paul II Johnny Cash

Clinical Features
Tremor (pill rolling of hands) At rest (46 Hz); Worsens with stress. Tremor stops when person attempts to grab something A faster (78 Hz) action tremor if hands are held against gravity. Unilateral tremor is common.

Rigidity
Cogwheeling increased ratchet-like resistance to passive limb movements Lead pipe: increased resistance to passive limb movements all through

DD spasticity: UMNL: clasp- knife

Bradykinesia
Slow voluntary movements. Mask face Reduced frequency of blinking Hypophonic voice Drooling: Impaired rapid alternating movements, Micrographia (small handwriting)

Gait
Reduced arm swing while walking, Flexed stooped posture with walking Shuffling gait, Difficulty initiating or stopping walking En-bloc turning (multiple small steps required to turn) Retropulsion (tendency to fall backwards).

Non-motor aspects
Depression and anxiety, Cognitive impairment, sleep disturbances, Sensation of inner restlessness, Loss of smell (anosmia) Autonomic dysfunction. Severe: intellectual and behavioral deterioration Aspiration pneumonia, Bedsores.

Neurological examination
Normal muscular strength, Normal deep tendon reflexes Normal sensory exam. Diagnosis based upon history and examination Neuroimaging EEG, CSF studies Usually normal for age.

Etiology
Degeneration of substantia nigra in midbrain dopaminergic input to striatum eosinophilic intraneural inclusion granules (Lewy bodies). free radicals and oxidative stress. cell death Early age of onset suggests a genetic cause of PD: mutations in alpha synuclein or parkin genes.

Differential Diagnosis
Features of parkinsonism may occur with: 1. Depression (paucity of vocal inflection and facial movement); 2. Essential tremor
High-frequency tremor with limbs held against gravity, Head tremor Improves with alcohol)
3.

Normal-pressure hydrocephalus
Apraxic gait Urinary incontinence Dementia)

4.

Wilsons disease
Early age of onset Kayser-Fleischer rings, low serum copper low ceruloplasmin

Differential Diagnosis
1. 2.

3.

4.

Huntingtons disease (family history, chorea, dementia) Multiple system atrophy (early urinary incontinence, orthostatic hypotension, dysarthria) Dementia with Lewy bodies (early hallucinations, behavioral disturbances) Progressive supranuclear palsy (early imbalance and falls, downgaze

TREATMENT
Goals are to maintain function and avoid drug-induced complications. Bradykinesia, tremor, rigidity, and abnormal posture respond early in illness cognitive symptoms, hypophonia, autonomic dysfunction, and balance difficulties respond poorly.

Medical Treatment
Anticholinergic Artane, Akineton, Cogentin Levodopa Sinemet, Sinemet CR, Madopar, Madopar HBS, Dopamine Agonists D1: Apomorphine D2: Bromocriptine, Pergolide, Pramipexole, Ropinirole, Cabergoline D3: Pramipexole, Ropinirole D4: MAO-B Inhibitor Selegiline COMT Inhibitors Tocapone, Entacapone Amantadine, Remacemide

Agents that Increase Dopamine functions

Increasing the synthesis of dopamine - lDopa Inhibiting the catabolism of dopamine selegiline Stimulating the release of dopamine amphetamine Stimulating the dopamine receptor sites directly - bromocriptine & pramipexole Blocking the uptake and enhancing the release of dopamine - amantadine

Initiation of Therapy Dopaminomimetic therapy

initiated when symptoms interfere with quality of life. In early PD, dopamine agonist monotherapy well tolerated and reduces risk of later treatment-related complications such as motor fluctuations and dyskinesias (50% of pts treated over 5 years with levodopa). Motor fluctuations are the exaggerated ebb and flow of parkinsonian signs between doses of medications. Dyskinesias refer to choreiform and dystonic movements that can occur as a peak dose effect or at the beginning or end of the dose.

Dopamine agonist monotherapy requires higher doses than needed when agonist is used to supplement levodopa Slow titration necessary to avoid side effects. Most pts require addition of levodopa or another agent within 1 to 3 years of initiating dopamine agonist monotherapy. Levodopa, the metabolic precurser of dopamine, remains most effective treatment for PD.

Dopamine Agonists
longer acting > levodopa more uniform stimulation of dopamine R. Used as monotherapeutic agents Used as adjuncts to carbidopa/levodopa Used with anticholinergics and amantadine. Effective against bradykinesia, disturbed gait Less effective against tremor. SE: nausea, postural hypotension,

Carbidopa/Levodopa Formulations

Immediate release: IR: Sinemet, Atamet

10/100 mg, 25/100 mg, and 25/250 mg

Controlled release (CR) :Sinemet CR

25/100 mg, 50/200 mg

Stalevo: IR carbidopa/levodopa + 200 mg entacapone Carbidopa blocks peripheral levodopa decarboxylation into dopamine and thus symptoms of nausea and orthostasis often associated with the initiation of levodopa. Gradual dose escalation recommended Initiation of dosing at mealtimes will reduce nausea.

Levodopa Augmentation: Selegiline

Selective and irreversible MAO inhibitor Weak symptomatic effect For Older and cardiac pts Monotherapy or with carbidopa/levodopa. Initial therapy or added for tremor or levodopa associated wearing off; 5 mg with breakfast and lunch. SE: insomnia.

Levodopa Augmentation:
catechol O-methyltransferase (COMT) inhibitors entacapone and tolcapone

block enzymatic degradation of levodopa and dopamine. Entacapone is preferred to tolcapone (hepatic and hematologic side effects). used with carbidopa/levodopa, to alleviate wearing-off and increase time a pt remains on during the day. SE: GIT & increased dyskinesias. Entacapone 200 mg with each dose of carbidopa/levodopa. Tolcapone is 50 to 200 mg tid.

Adjuncts: Anticholinergics and Amantadine

Anticholinergics Useful for controlling rest tremor and dystonia
Trihexyphenidyl, 25 mg tid Benztropine, 0.52 mg tid

Amantadine Reduce drug induced dyskinesias by up to 70%. 100 mg bid Anticholinergic, dopaminomimetic, glutamate antagonist Aggravate confusion and psychosis in elderly.

Surgical Treatments
OLD: ablation (e.g., pallidotomy or thalamotomy) Deep-brain stimulation. Indications (1) a diagnosis of idiopathic PD, (2) a clear response to levodopa (3) significant intractable symptoms of PD (4) Drug induced dyskinesias and wearing off. Contraindications to surgery include Atypical PD Cognitive impairment Major psychiatric illness Substantial medical comorbidities Advanced age (a relative factor). Symptoms not responding to levodopa are unlikely to benefit

Deep Brain Stimulation

An electrode is placed in one of several parts of the brain (thalamus, globus palladus, or subthalamic nucleus). The electrode is attached to a computerized pulse-generator which is put under this skin in the chest. Symptoms are relieved through the regulation of electrical impulses from those three areas of the brain.

Deep Brain Stimulation

Current Research
Neural grafting, or transplantation of nerve cells, is an experimental technique proposed for treating the disease. Investigators have shown in animal models that implanting fetal brain tissue from the substantia nigra into a parkinsonian brain causes damaged nerve cells to regenerate. Gene Therapy Scientists are also working to develop new protective drugs that can delay, prevent, or reverse the disease.

HUNTINGTONS DISEASE

Frontal/ executive disorder Chorea. behavioral disturbance fourth to fifth decade can present at almost any age. family history, Autosomal dominant I Expanded trinucleotide Repeat in gene encoding the protein huntingtin. Diagnosis Genetic testing coupled with genetic counseling. Symptomatic treatment of movements and behaviors; SSRIs may help depression.