PARKINSON DISEASE

PARKINSON DISEASE

A 56-year-old man is brought to the office by his wife for evaluation of a resting tremor that she noticed recently. She also states that her husband has been moving “very slowly” as of late. When questioned, the patient states that he feels fine and does not know why his wife is dragging him from doctor to doctor. His past medical history is significant for mild hypertension that has been treated with a thiazide diuretic.

Physical examination is significant for a resting tremor noted in his right hand. When walking, the patient is stooped forward, taking small steps. You note cogwheel rigidity in his right upper extremity with a positive Myerson sign.

Definition. Parkinson disease is defined as a neurologic syndrome resulting from the deficiency of the neurotransmitter dopamine as a consequence of degenerative, vascular, or inflammatory changes in the basal ganglia.

Etiology. There are numerous causes of Parkinsonism. Many drugs can cause Parkinsonism, including neuroleptic agents (haloperidol, chlorpromazine), antiemetics (metoclopramide), alpha-methyldopa, and reserpine. Poisoning from MPTP, carbon monoxide, cyanide, and manganese are also causes of Parkinsonism. Any structural lesion around the basal ganglia (trauma, tumor, abscess, infarct) can produce clinical Parkinson disease. Patients who have survived an episode of encephalitis can develop postencephalitic Parkinsonism.

Clinical Presentation. The cardinal manifestations of Parkinson disease are bradykinesia (manifested by slow movements, mask facies, reduction of automatic movements), cog- wheel rigidity, postural instability, and resting tremor. A useful mnemonic is to think of Mr. Parkinson as a fine BRITish gentleman.

Bradykinesia Rigidity (cogwheel) Instability (postural) Tremor (resting)

There are a number of “Parkinson plus” syndromes, which are characterized by their relative lack of response to therapy with levodopa/carbidopa.

Parkinsonism + vertical gaze palsy = supranuclear palsy Parkinsonism + prominent ataxia = olivopontocerebellar  atrophy

Parkinsonism + prominent orthostatic hypotension = Shy-Drager syndrome (now called multiple-system atrophy)

Several other diseases can imitate Parkinsonism. Severe depression can cause a paucity of spontaneous movement that can mimic Parkinsonism.   Essential tremor can be mistaken   for the tremor of Parkinson disease, but the lack of other neurologic symptoms and a posi- tive family history of tremor and its amelioration with alcohol distinguish the two entities.   A normal pressure hydrocephalus can present with ataxia and gait disturbances, which can also be mistaken for Parkinson disease. The presence of dementia and urinary incontinence with dilated ventricles on a CT scan of the head can help identify this disorder. Huntington disease can present with akinesia and chorea. The positive family history and dementia usu- ally suggest the correct diagnosis.

Diagnosis. The diagnosis of Parkinson disease is a clinical one. It is important to identify any secondary causes of a patient’s Parkinsonism that are potentially reversible. There is no diagnostic test of choice that can identify patients with Parkinson disease.

Treatment. There are many medications available for the treatment of Parkinson disease. The underlying pathophysiology that causes Parkinson disease is the imbalance of dopaminergic (too little) and cholinergic (too much) tone on the basal ganglia. Thus, medical treatment revolves around increasing dopaminergic tone or decreasing cholinergic tone on the basal ganglia.

Not surprisingly, the medications available for the medical treatment of Parkinson disease directly stimulate dopamine receptors (carbidopa/levodopa, dopamine agonists), indirectly increase the amount of dopamine available (COMT inhibitors, selegiline, amantadine), or block acetylcholine stimulation of the basal ganglia (benztropine, trihexyphenidyl).

Direct-acting dopamine agonists such as pramipexole or ropinirole can be used alone as ini- tial therapy or in combination with small doses of levodopa/carbidopa. Two other dopamine agonists are bromocriptine and cabergoline. All of them are less efficacious than levodopa. Dopamine agonists do, however, have less dyskinetic side effects. Bromocriptine and per- golide are ergot derivatives and can cause cardiac toxicity.

The first step when considering what medication to start with is evaluating the patient’s func- tional status. Patients with an intact functional status are managed differently from patients with a compromised functional status.

Patients with intact functional status (less bradykinesia) are not generally given carbidopa/ levodopa as initial therapy. Such patients are started on anticholinergic medication when they are age <60. This is particularly true for those in whom tremor is the predominant symp- tom. When age >60, the treatment of choice is amantadine. The reason why anticholinergics are relatively contraindicated in elderly patients is because the side effects (dry mouth, uri- nary retention, constipation, confusion/hallucinations) occur more frequently and severely. Anticholinergics such as benztropine and trihexyphenidyl are used mostly to relieve tremor and rigidity. Avoid with BPH and glaucoma.

For patients with compromised functional status (more significant bradykinesia), the best initial therapy is carbidopa/levodopa. Carbidopa inhibits extracerebral dopa-decarboxylase, allowing more of the levodopa to reach the central nervous system, where it is needed. Levodopa is the precursor to dopamine. Carbidopa protects the levodopa from breakdown  in the periphery, ensuring its secure delivery to the central nervous system. There are sev- eral late complications to carbidopa/levodopa therapy: Dyskinesia (abnormal movements), akathisia (restlessness), and “on-off” phenomena are all disconcerting to the patient. All of these late side effects are termed “response fluctuations” and can be managed by using a sustained release form of  carbidopa/levodopa, adding a dopamine agonist, selegiline, or   a COMT inhibitor, or restricting the main protein meal to the night. COMT inhibitors        are tolcapone and entacapone. They are always used in conjunction with levodopa to help reduce the dose or modify response fluctuations. COMT inhibitors have no effect alone;  they decrease the metabolism of the levodopa. They are an adjunct to the use of levodopa to reduce adverse effects.

Selegiline was once thought to slow the progression of the disease. Selegiline can be used in those with a declining or fluctuating response to levodopa. Selegiline offers mild symptom- atic benefit in early disease. Rasagiline is a newer version.

Surgery should only be considered for patients who cannot tolerate or respond adequately to medical therapy. The procedures usually performed are pallidotomy or thalamotomy. The placement of deep brain stimulators is also effective when placed in the globus pallidus or subthalamic nuclei. Surgical therapy is a last resort.