Parkinson’s Disease

PARKINSON’S DISEASE

Parkinson’s disease is a slowly progressing neurologic movement disorder that eventually leads to disability. The degenerative or id-iopathic form is the most common; there is also a secondary form with a known or suspected cause. Although the cause of most cases is unknown, research suggests several causative factors, including ge-netics, atherosclerosis, excessive accumulation of oxygen free radi-cals, viral infections, head trauma, chronic antipsychotic medication use, and some environmental exposures. Parkinsonian symptoms usually first appear in the fifth decade of life; however, cases have been diagnosed at the age of 30 years. It is the fourth most common neurodegenerative disease. Parkinson’s disease affects men morefrequently than women and nearly 1% of the population older than 60 years of age (Gray & Hildebrand, 2000).

Pathophysiology

Parkinson’s disease is associated with decreased levels of dopamine due to destruction of pigmented neuronal cells in the substantia nigra in the basal ganglia of the brain (Fig. 65-4). The nuclei of the substantia nigra project fibers or neuronal pathways to the corpus striatum, where neurotransmitters are key to control of complex body movements. 

Through the neurotransmitters acetyl-choline (excitatory) and dopamine (inhibitory), striatal neurons relay messages to the higher motor centers that control and refine motor movements. The loss of dopamine stores in this area of the brain results in more excitatory neurotransmitters than inhibitory neurotransmitters, leading to an imbalance that affects voluntary movement.

Basic science research in the past two decades has revealed that more neurotransmitter pathways in the brain than just the dopaminergic system are involved. Parts of the glutamatergic, cholinergic, tryptaminergic, noradrenergic, adrenergic, seroton-ergic, and peptidergic pathways (responsible for cell metabolism, growth, nutrition, and so forth) show damage in Parkinson’s dis-ease (Chase, Oh & Konitsiotis, 2000; Przuntek, 2000; Rascol, 2000).

Clinical symptoms do not appear until 60% of the pigmented neurons are lost and the striatal dopamine level is decreased by 80%. Cellular degeneration impairs the extrapyramidal tracts that control semiautomatic functions and coordinated movements; motor cells of the motor cortex and the pyramidal tracts are not affected.

Clinical Manifestations

Parkinson’s disease has a gradual onset and symptoms progress slowly over a chronic, prolonged course. The three cardinal signs are tremor, rigidity, and bradykinesia (abnormally slow move-ments). Other features include hypokinesia, gait disturbances, and postural instability (Gray & Hildebrand, 2000).

TREMOR

Although symptoms are variable, a slow, unilateral, resting tremor is present in 70% of patients at the time of diagnosis. Resting tremor characteristically disappears with purposeful movement but is evident when the extremities are motionless. The tremor may present as a rhythmic, slow turning motion (pronation– supination) of the forearm and the hand and a motion of the thumb against the fingers as if rolling a pill (Fig. 65-5). Tremor is present while the patient is at rest; it increases when the patient is walking, concentrating, or feeling anxious.

RIGIDITY

Resistance to passive limb movement characterizes muscle rigidity. Passive movement of an extremity may cause the limb to move in jerky increments referred to as cogwheeling. Rigidity of the pas-sive extremity increases when another extremity is engaged in voluntary active movement. Stiffness of the neck, trunk, and shoul-ders is common. Early in the disease, the patient may complain of shoulder pain.

BRADYKINESIA

One of the most common features of Parkinson’s disease is brady-kinesia. Patients take longer to complete most activities and have difficulty initiating movement, such as rising from a sitting posi-tion or turning in bed.

Hypokinesia (abnormally diminished movement) is also com-mon and may appear after the tremor. The freezing phenomenon is a transient inability to perform active movement and is thought to be an extreme form of bradykinesia. Additionally, the patient tends to shuffle and exhibits a decreased arm swing. As dexterity declines, micrographia (shrinking, slow handwriting) develops. The face becomes increasingly masklike and expressionless and the frequency of blinking decreases. Dysphonia (soft, slurred, low-pitched, and less audible speech) may occur due to weakness and incoordination of the muscles responsible for speech. In many cases, the patient develops dysphagia, begins to drool, and is at risk for choking and aspiration.

The patient commonly develops postural and gait problems. There is a loss of postural reflexes, and the patient stands with the head bent forward and walks with a propulsive gait. The posture is caused by the forward flexion of the neck, hips, knees, and el-bows. The patient may walk faster and faster, trying to move the feet forward under the body’s center of gravity (shuffling gait). Difficulty in pivoting and loss of balance (either forward or back-ward) places the patient at risk for falls.

OTHER MANIFESTATIONS

The effect of Parkinson’s disease on the basal ganglia often pro-duces autonomic symptoms that include excessive and un-controlled sweating, paroxysmal flushing, orthostatic hypotension, gastric and urinary retention, constipation, and sexual distur-bances (Herndon et al., 2000).

Psychiatric changes are often interrelated and may be predictive of one another. They include depression, dementia (progressive mental deterioration), sleep disturbances, and hallucinations (Herndon et al., 2000). Depression is common; whether it is a reaction to the disorder or is related to a biochemical abnormal-ity remains a question. Mental changes may appear in the form of cognitive, perceptual, and memory deficits, although intellect is not usually affected. A number of psychiatric manifestations (personality changes, psychosis, dementia, and acute confusion) are common among the elderly. The prevalence of dementia is about 25% and the pattern is similar to that of patients with Alzheimer’s disease. Although there is no direct documented causal relationship, the rates of depression and dementia are highly cor-related in these patients (Herndon et al., 2000).Approximately 41% of women and 25% of men with Parkin-son’s disease experience sleep disturbances. This may be connected to depression, dementia, or medications. Auditory and visual hal-lucinations have been reported in approximately 37% of persons with Parkinson’s and may be associated with depression, demen-tia, lack of sleep, or adverse effects of medications (Herndon et al., 2000).

Complications associated with Parkinson’s disease are com-mon and are typically related to disorders of movement. As the disease progresses, patients are at risk for respiratory and urinary tract infection, skin breakdown, and injury from falls. The ad-verse effects of medications used to treat the symptoms are asso-ciated with numerous complications.

Assessment and Diagnostic Findings

Laboratory tests and imaging studies are not helpful in the diag-nosis of Parkinson’s disease, although PET scanning has been used in evaluating levodopa (precursor of dopamine) uptake and conversion to dopamine in the corpus striatum (Freed et al., 2001). Currently, the disease is diagnosed clinically from the pa-tient’s history and the presence of two of the three cardinal man-ifestations: tremor, muscle rigidity, and bradykinesia.

Early diagnosis can be difficult because the patient can rarely pinpoint when symptoms started. Often a family member notices a change such as stooped posture, a stiff arm, a slight limp, tremor, or slow, small handwriting. The medical history, presenting symp-toms, neurologic examination, and response to pharmacologic management are carefully evaluated when making the diagnosis.

Medical Management

Treatment is directed at controlling symptoms and maintaining functional independence because there are no medical or surgical approaches that prevent disease progression. Care is individual-ized for each patient based on presenting symptoms and social, occupational, and emotional needs. Pharmacologic management is the mainstay of treatment, although advances in research have led to increased interest in surgical interventions. Patients are usu-ally cared for at home and admitted to the hospital only for com-plications or to initiate new treatments.

PHARMACOLOGIC THERAPY

Antiparkinsonian medications act by 1) increasing striatal dopa-minergic activity, 2) reducing the excessive influence of excitatory cholinergic neurons on the extrapyramidal tract, thereby restor-ing a balance between dopaminergic and cholinergic activities, oracting on neurotransmitter pathways other than the dopami-nergic pathway.

Antiparkinsonian Medications.

Levodopa (Dopar, Larodopa) isthe most effective agent and the mainstay of treatment (Karch, 2002; Obeso et al., 2001). Because levodopa is thought to pre-cipitate oxidation, which further damages the substantia nigra and eventually speeds disease progression, physicians delay pre-scribing the medication or increasing the dosage for as long as possible (Karch, 2002). Levodopa is converted to dopamine in the basal ganglia, producing symptom relief. The beneficial ef-fects of levodopa are most pronounced in the first few years of treatment. Benefits begin to wane and adverse effects become more severe over time. Confusion, hallucinations, depression, and sleep alterations are associated with prolonged use. Levodopa is usually given in combination with carbidopa (Sinemet), an  amino acid decarboxylase inhibitor that helps to maximize the beneficial effects of levodopa by preventing its breakdown out-side the brain and reducing its adverse effects (Karch, 2002).

Within 5 to 10 years, most patients develop a response to the medication characterized by dyskinesia (abnormal involun-tary movements), including facial grimacing, rhythmic jerking movements of the hands, head bobbing, chewing and smacking movements, and involuntary movements of the trunk and extrem-ities. The patient may experience an on–off syndrome in which sudden periods of near immobility (“off effect”) are followed by a sudden return of effectiveness (“on effect”). Various adjunctive therapies are used to minimize dyskinesias (Przuntek, 2000; Rascol, 2000).

Budipine, available in Europe but not the United States, is a non-dopaminergic, antiparkinsonian medication that significantly reduces akinesia, rigidity, and tremor. It is non-dopaminergic be-cause the action appears to be on neurotransmitter pathways other than the dopaminergic pathway. It may be used as monotherapy or in conjunction with other available antiparkinsonian medica-tions (Przuntek, 2000; Przuntek et al., 2002). The usual dose of 40 to 60 mg is reached gradually. Nausea and dry mouth are the most common side effects, although 75% of patients experienced no side effects in clinical drug trials (Przuntek, 2000).

Anticholinergic Therapy.

Anticholinergic agents (trihexyphenidyl,cycrimine, procyclidine, biperiden, and benztropine mesylate) are effective in controlling tremor and rigidity. They may be used in combination with levodopa. They counteract the action of the neurotransmitter acetylcholine. Because the side effects include blurred vision, flushing, rash, constipation, urinary retention, and acute confusional states, these medications are often poorly tol-erated in elderly patients. Intraocular pressure must be closely monitored: these medications are contraindicated in patients with narrow-angle glaucoma. Patients with prostate hyperplasia are monitored for signs of urinary retention.

Antiviral Therapy.

Amantadine hydrochloride (Symmetrel) is anantiviral agent used in early Parkinson’s treatment to reduce rigidity, tremor, and bradykinesia. It is thought to act by releasing dopamine from neuronal storage sites. Studies suggest it may also have antiglutamatergic properties that affect the glutamatergic pathway, thus improving levodopa-induced dyskinesias (Rascol, 2000). Amantadine has a low incidence of side effects, which in-clude psychiatric disturbances (mood changes, confusion, depres-sion, hallucinations), lower extremity edema, nausea, epigastric distress, urinary retention, headache, and visual impairment.

Dopamine Agonists.

Bromocriptine mesylate and pergolide (ergotderivatives) are dopamine receptor agonists and are useful in postponing the initiation of carbidopa or levodopa therapy. Dopamine agonists are often added to the medication regimen when carbidopa or levodopa loses effectiveness. Pergolide (Permax) is 10 times more potent than bromocriptine mesylate (Parlodel), although this provides no therapeutic advantage. Adverse re-actions to these medications include nausea, vomiting, diar-rhea, lightheadedness, hypotension, impotence, and psychiatric effects.

Two new dopamine agonists, ropinirole hydrochloride (Requip) and pramipexole (Mirapex) (nonergot derivatives), are primarily for patients in the early stages of Parkinson’s disease and are not expected to have the potentially serious adverse effects of per-golide and bromocriptine mesylate. Pramipexole (Mirapex) canbe used without levodopa for treatment of early disease and with levodopa in advanced stages. Cabergoline (Dostinex), an ergot alkaloid with a long duration of action, has been approved for use.

Monoamine Oxidase Inhibitors (MAO Inhibitors).

Of the MAOinhibitors, selegiline (Eldepryl) is one of the most exciting and controversial developments in the pharmacotherapy of Parkin-son’s disease (Herndon et al., 2000). This medication inhibits dopamine breakdown and is thought to slow the progression of the disease. Researchers believe this medication may have a neuro-protective effect in the early stages of Parkinson’s disease, but this has not been shown in clinical trials. Selegiline is currently used in combination with a dopamine agonist to delay the use of car-bidopa or levodopa therapy. Adverse effects are similar to those of levodopa.

Catechol-O-methyltransferase (COMT) Inhibitors.

Clinical trialssuggest that the COMT inhibitors entacapone (Comtess) and tolcapone (Tasmar) have little effect on parkinsonian symptoms when given alone but can increase the duration of action of car-bidopa or levodopa when given in combination with them. COMT inhibitors block an enzyme that metabolizes levodopa, making more levodopa available for conversion to dopamine in the brain. Entacapone and tolcapone reduce motor fluctuations in patients with advanced Parkinson’s disease.

Antidepressants.

Tricyclic antidepressants may be prescribed toalleviate the depression that is so common in Parkinson’s disease. The usual dosage is one-third to one-half the dosage used in de-pressed patients without Parkinson’s disease. Amitriptyline is typ-ically prescribed because of its anticholinergic and antidepressant effect. Serotonin reuptake inhibitors, such as fluoxetine hydro-chloride (Prozac) and bupropion hydrochloride (Wellbutrin), are effective for treating depression but may aggravate parkinsonism.

Antihistamines.

Diphenhydramine hydrochloride (Benadryl),orphenadrine citrate (Banflex), and phenindamine hydrochloride (Neo-Synephrine) have mild central anticholinergic and sedative effects and may reduce tremors.

SURGICAL MANAGEMENT

The limitations of levodopa therapy, improvements in stereotac-tic surgery, and new approaches in transplantation have renewed interest in the surgical treatment of Parkinson’s disease. In pa-tients with disabling tremor, rigidity, or severe levodopa-induced dyskinesia, surgery may be considered. Although surgery provides some relief in selected patients, it has not been shown to alter the course of the disease or produce permanent improvement.

Stereotactic Procedures.

Thalamotomy and pallidotomy areeffective in relieving many of the symptoms of Parkinson’s dis-ease. Patients eligible for these procedures are those who have had an inadequate response to medical therapy; they must meet strict criteria to be eligible. Candidates eligible for these procedures are patients with idiopathic Parkinson’s disease who are taking max-imum doses of antiparkinsonian medications. Patients with de-mentia and atypical Parkinson’s disease are usually not considered for stereotactic procedures. Parkinson’s disease rating scales and specific neurologic testing are used to identify eligible patients.The intent of thalamotomy and pallidotomy is to interrupt the nerve pathways and thereby alleviate tremor or rigidity. During thalamotomy, a stereotactic electrical stimulator destroys part of the ventrolateral portion of the thalamus in an attempt to reduce tremor; the most common complications are ataxia and hemiparesis. Pallidotomy involves destroying part of the ventral aspect of the medial globus pallidus through electrical stimula-tion in patients with advanced disease. The procedure is effective in reducing rigidity, bradykinesia, and dyskinesia, thus improv-ing motor function and activities of daily living in the immediate postoperative course. In small studies, clinical improvements have been demonstrated over 3 to 4 years. The clinical benefit is greater in patients younger than 60 years (Freed et al., 2001). Complications include hemiparesis, stroke, and visual changes.

CT, x-rays, MRI, or angiography is used to localize the ap-propriate surgical site in the brain. Then the patient’s head is po-sitioned in a stereotactic frame (Fig. 65-6). The surgeon makes an incision in the skin and then a burr hole. Next, the surgeon passes an electrode through the burr hole to the target area in the thalamus or globus pallidum. The desired response of the patient to the electrical stimulation is the basis for the final site chosen by the neurosurgeon. Stereotactic procedures are completed on one side of the brain at a time. If rigidity or tremor is bilateral, a 6-month interval is suggested between procedures.

Neural Transplantation.

Surgical implantation of adrenal medul-lary tissue into the corpus striatum is performed in an effort to reestablish normal dopamine release. Preliminary evidence has shown high morbidity and mortality rates, and the implants ap-pear to improve parkinsonian symptoms for only 6 months. Re-searchers are conducting studies to determine if transplanting human fetal brain cells or genetically engineered cells into the ni-grostriatal region is effective (Aminoff, 2000). Legal and ethical issues surrounding the use of fetal brain cells have limited the im-plementation of this procedure. Recently, fetal pig neuronal cells survived transplantation into a patient with Parkinson’s dis-ease; this may provide an alternative to human cell transplants (Aminoff, 2000).

Deep Brain Stimulation.

Recently approved by the FDA,pacemaker-like brain implants show promising results in relieving tremors. The stimulation can be bilateral or unilateral, although bilateral stimulation of the subthalamic nucleus is thought to be of greater benefit to patients than results achieved with thala-motomy, pallidotomy, or fetal nigral transplantation (Obeso et al., 2001). 

In deep brain stimulation, an electrode is placed in the thalamus and connected to a pulse generator implanted in a subcutaneous subclavicular or abdominal pouch. The battery-powered pulse generator sends high-frequency electrical impulses through a wire placed under the skin to a lead anchored to the skull (Fig. 65-7). The electrode blocks nerve pathways in the brain that cause tremors. These devices are not without compli-cations, both from the surgical procedure needed for implanta-tion and from complications (such as lead leakage) of the device itself (Koller et al., 2001; Obeso et al., 2001).