Parkinson’s Disease

AIMGP Seminar

Prepared by: Ilan Lenga and Nicolas Szecket

References

• NEJM Review Articles– Parkinson’s Disease Part One October 8, 1998

– Parkinson’s Disease Part Two October 15, 1998

• UpToDate Vol 10.2

• Treatment Guidelines by the American Academy of Neurology. Neurology 50(3) Suppl3. 1998.

• Principles of Neural Science, Third edition

Case• Mr JP is a 63 yo male, school teacher• Gradual development of right hand

resting tremor over last 6 months• Also describes “difficulty getting going”,

and feeling “unsteady on my feet”• He has had no falls• His symptoms are not interfering with his

job or ADL’s

Case

• No sensory or motor symptoms

• No cognitive symptoms

• No bowel/bladder symptoms

• No significant past medical Hx

• No EtOH or other drugs

Case• O/E:

– Vitals normal, no postural change

– General physical exam unremarkable

– Neuro:• asymmetrical right handed tremor 4-6 Hz• Normal CN exam• Normal bulk, strength, DTR’s• Mild increased tone, cogwheeling of R wrist• Normal sensory and cerebellar exam• Gait unremarkable• Folstein 30/30

Question

• Does this man have Parkinson’s Disease?

“….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.”

James Parkinson, 1817

Features of PDT Tremor

• Classic pill-rolling or pronation/supination tremor is 4 - 6 Hz, usually upper limb (75% of pts). Brought out by distraction. Decreased with movement of limbs

R Rigidity• Lead-pipe or cogwheel, tone usually slightly more in flexors than extensors

A Akinesia• slowness of movement (bradykinesia), poverty of movement (facial

amimia, arm swing),difficulty initiating movement

P Postural Instability• impaired corrective postural reflexes(early), progresses to more upper

trunk instability with fall risk

Most Distinctive Signs of Idiopathic Parkinson’s Disease

• Asymmetrical Resting Tremor

• Dementia not an early feature

• Normal Strength

• Excellent initial response to L-dopa

DDx

• Parkinsonism Plus– Diffuse Lewy Body Dementia– Progressive Supranuclear Palsy– Multi-System Atrophy

• Shy-Drager• Striatonigral Degeneration• Olivopontocerebellar atrophy

– Corticobasal Degeneration

DDx• Drug-induced

• Vascular

• Toxins– CO, methanol, manganese, MPTP

• Post-infectious (Postencephalitis lethargica)

• Paraneoplastic/tumour

• Trauma

Question

• His symptoms are relatively mild, what measures would you institute now?

Non-Pharmacological&

?Neuroprotection?

Non-Pharmacological• Group Support for Patient & Family• Education

• Parkinson’s Foundation of Canada; www.wemove.org

• Physiotherapy• Exercise is critical to maintaining health

• Occupational Therapy• Patients acquire numerous disabilities & require assistance

with many ADLs

• Speech-Language Pathology• Speech and swallowing difficulties develop/intensify over

course of disease

Neuroprotection?• Selegiline • MAO-B inhibitor• Blocks formation of free radicals derived from the oxidative

metabolism of Dopamine• Able to protect mice from the effects of MPTP (drug-

induced PD)• RCT’s have shown that selegiline delays disability and

appears to slow the progression of symptoms in previously untreated PD.

• Whether this means it is truly “neuroprotective” is still being clarified

Case• JP and his wife join a support group, and you

start him on Selegiline 5mg BID

• You follow him in clinic

• Over the next 6 months, his symptoms are stable, but then his akinesia and rigidity begin to progress. He has almost fallen once.

• His symptoms are now interfering significantly with his job

Questions

• Would you initiate therapy now?

• What are the options?

Goals of Therapy

• Symptomatic improvement

• Maximizing quality of life

• Possibly prolonging survival

Symptomatic Pharmacological Rx

• Levodopa

• Dopamine Agonists

• Anticholinergics

• Amantadine

Levodopa• The cornerstone of PD therapy• Most effective agent available• Precursor to Dopamine• Can cross blood brain barrier (dopamine can’t)• Peripheral metabolism leads to side-effects -

nausea, vomiting, orthostasis• Carbidopa, a peripheral decarboxylase

inhibitor, decreases peripheral metabolism

Levodopa• Sinemet

100/25

200/25

200/50

250/50

• Goal is lowest dose required - at start, usually 300-600mg/day, titrate up to 1g/d

• Take on empty stomach, because absorption competes with amino acids

L-Dopa Carbidopa

Levodopa

• Disadvantages– 50% of patients within 5 years of Rx develop

L-dopa induced motor complications (stay tuned to the case)

– Neuropsychiatric problems - confusion, psychosis

– Theoretical concerns about accelerating disease due to oxidative damage to neurons

Dopamine Agonists• Act directly on striatal dopamine receptors without

synaptic uptake/release or metabolic conversion• Used as an L-dopa sparing strategy• Bromocriptine and Pergolide most common• Start slowly and increase gradually• Side effects include orthostasis, nausea,

vomiting, hallucinations, peripheral vasoconstriction, and rarely pleuro/retroperitoneal fibrosis

Anticholinergics

Dopamine Acetylcholine

Normal

Dopamine

Acetylcholine

Parkinson’s

Anticholinergics• Restores balance between Dopamine and

ACh in the brain• Benztropine and trihexyphenidyl (Artane)

most common• Not well tolerated due to side effects

– mydriasis, dry mouth, impaired sweating, urinary retention, constipation, delirium

• Used primarily for refractory tremor and sialorrhea

Amantadine• Mechanism of action unclear• Short term benefit, not sustained beyond

6 - 12 months• Side effects include ankle edema,

insomnia, nightmares, confusion, hallucinations, and anticholinergic effects

• Most effective for tremor, some activity against akinesia and rigidity

Summary of Main EffectsDrug

L-dopa

Dopamine Agonist

Anticholinergic

Amantadine

Tremor

poor

poor

good

good

Rigidity/Akinesia

excellent

good

poor

poor

A excellent, detailed, table of A excellent, detailed, table of drugs, dosages and side drugs, dosages and side effects. A recommended effects. A recommended reference. NEJM Oct 15, reference. NEJM Oct 15, 19981998

Case

• You elect to start him on Sinemet, on a dose of 100/25 TID

• His symptoms markedly improve

• He is left with a mild R hand tremor, but otherwise returns to excellent function

Case

• You follow Mr. JP over the next 4 years

• He requires gradual titration of his Sinemet up to a current dose of 250/50 TID

• He now comes in complaining that he is developing rigidity and “freezing” 30-60 minutes before each dose

Questions

• What’s going on?

• What can you do for him?

“Wearing Off” Effect

• As PD progresses dopaminergic nerve terminals degenerate and cannot store and release dopamine well

• The result is more dependence on plasma L-dopa levels

• L-dopa has a T1/2 of 1.3hrs, thus adequate levels are only maintained for up to 4 hours

Treatment Options

• Shorten dosing interval

• Sinemet CR (requires 30% increase in dose due to lower absorption)

• Add Dopamine Agonist

• Catechol-O-methyl transferase (COMT) inhibitor

COMT Inhibitor

• Tolcapone and entacapone

• prevent metabolism of L-dopa

• increase T1/2 of L-dopa, stabilizing plasma levels

• Side-effects: due to increased L-dopa, diarrhea (severe in 5%), rare hepatotoxicity

Case

• You switch Mr. JP to Sinemet CR with only modest improvement

• Ultimately he responses to tolcapone 100mg TID

Case

• 4 months later he begins to describe fluctuations between being “on” (responding to meds) and “off” (parkinsonian)

• Also he notes occasional involuntary movements during “on” periods and painful leg muscle “spasms” during off periods particularly in the early morning

Questions

• What is happening?

• Can anything be done?

Complications of L-dopa Rx• Motor Fluctuations

– wearing off effect– on-off phenomenon, rapid/unpredictable

• Dyskinesias– Peak dose dyskinesias (chorea, athetosis,

ballismus, myoclonus)– Off-period dystonias– diphasic dyskinesias (beginning & end dose)

• Psychiatric disturbances

Management

• Important to determine relationship to time of dose

• Peak-dose effects managed by:– smaller frequent doses of L-dopa

• risk more off periods

– lower L-dopa & add dopamine agonist– atypical neuroleptics (esp. clozapine)– ? Propanolol, fluoxetine, buspirone

Management

• Trough effects managed by:– managed as per the wearing-off strategies– Off-period dystonias managed with:

• night time or early am dosing• baclofen, botulinum, lithium

– a “delayed on” problem may be due to poor gastric emptying

• managed with domperidone

Management

• Psychiatric disturbances– Depression - treated as in non-PD patients– Psychotic symptoms

• favour atypical antipsychotics. Clozapine has least deletirious effect on PD, but risk of agranulocytosis

• Ondansetron may be effective

– Dementia• no effective treatment

Management

• Manifestations of advanced Parkinson’s and chronic levodopa therapy are notoriously difficult to manage

• Trial-and-error strategy required

• Seek advice from a movement disorder specialist in difficult cases

Case

• Mr. JP initially responds to lowering his L-dopa dose and adding bromocriptine

• Eventually he develops unpredictable “on-off” periods and diphasic dyskinesias

• You refer him to a movement disorder neurologist for ongoing management

The End