Pharmacological and nonpharmacological interventions in the treatment of Parkinson's disease.

Key Words: Neuromuscular disorders, Parkinson's disease, Pharmacology, Physical therapy.

Parkinson's disease is a progressive neurodegenerative disease affecting every 100 to 150 per 100,000 individuals, or about 1% of those over 60 years of age, in the US population.[1,2] Parkinson's disease affects men and women equally.[2] The disease is characterized by the cardinal signs of tremor, bradykinesia, rigidity, and postural instability, which ultimately lead to functional disability. Management is lifelong, including pharmacologic and nonpharmacologic (physical and psychosocial) interventions. The management plan should be tailored to the stage of the disease.

Description of Parkinson's Disease

There are many parkinsonian syndromes. Primary parkinsonism or Parkinson's disease is characterized clinically by tremor, bradykinesia, rigidity, and postural instability and pathologically by the loss of pigmented neurons in the substantia nigra and eosinophilic cytoplasmic inclusions (Lewy bodies). Parkinsonism may, however, result from injury to the basal ganglia by cerebrovascular disease, infections, and toxins; this form of the disease is known as secondary parkinsonism. Further, parkinsonian syndromes include inherited neurodegenerative disorders and acquired multiple-system degenerations (Tab. 1). These disorders usually can be differentiated from Parkinson's disease by the presence of additional neurologic abnormalities, such as supranuclear ophthalmoparesis, and ataxia. In addition, early gait abnormalities, the absence of tremor, and poor response to levodopa suggest diagnoses other than Parkinson's disease.[3,4]

Parkinson's disease is primarily characterized by disorders of movement resulting from a deficiency of dopamine in the central nervous system's motor control pathways.[2,5(p655)] There is a degeneration of the neurons in the substantia nigra that produce dopamine. There are other neurotransmitter deficiencies in Parkinson's disease, such as serotonin or norepinephrine, but the effects are less well known than that of dopamine.[5(p655),6] The lack of the neurotransmitter, dopamine, in the basal ganglia results in Parkinson's disease.[7]

The basal ganglia consists of five subcortical nuclei: caudate nucleus, putamen, globus pallidus (internal and external portions), subthalamic nucleus, and substantia nigra (reticula and compacta regions).[5(p648)] Together, the caudate nucleus and putamen constitute the striatum. There are many neurotransmitter connections among the nuclei of the basal ganglia. They receive input from various cortical areas and project to the thalamus, which then projects to the cortex. There are two major types of pathways within the basal ganglia: direct and indirect (Figure).

In the direct pathway, various cortical areas send input to the striatum. The striatum then projects to the globus pallidus (internal portion) and the substantia nigra (reticulum) via inhibitory GABA (gamma-aminobutyric acid) and substance P. The globus pallidus and substantia nigra project to the thalamus via GABA. The thalamus then provides excitatory input to the cortex via glutamine. Physical movement occurs in part due to the phasic disinhibition of the thalamus by excitatory input to the striatum, allowing increased activity from the thalamus to the cortex.[8-10]

In the indirect pathway, the striatum projects to the globus pallidus (external portion) via inhibitory GABA and enkephalin. The globus pallidus then projects to the subthalamic nucleus via GABA, and the subthalamic nucleus in turn projects to the internal portion of the globus pallidus and substantia nigra via the excitatory neurotransmitter glutamine. This excitatory input stimulates inhibitory GABA neurons that then project to the thalamus, thereby reducing thalamic firing to the cortex.[8-10] Thus, the direct and indirect striatal efferent systems have opposite effects on the output basal ganglia (globus pallidus [internal portion] and substantia nigra [reticulum]) and ultimately on the thalamic input to the cortex.

Dopamine is produced in the substantia nigra (compacta) of the brain stem. Through nigrostriatal pathways, dopamine influences both the direct and the indirect loops within the basal ganglia. Dopaminergic axons exert both excitatory and inhibitory input to the striatum. It appears that dopamine has a net excitatory effect on the striatum via the direct pathway and a net inhibitory effect via the indirect pathway. With loss of dopamine (ie, Parkinson's disease), the striatal input via the indirect pathway to the globus pallidus is increased and disinhibits the subthalamic nucleus. The subthalamic nucleus excites the globus pallidus internal portion), which inhibits the thalamus by inhibitory GABA fibers from the substantia nigra (reticulum), thus reducing thalamic excitatory projections to the motor cortex.[8,9] By the direct pathway, the dopamine deficiency effectively causes a disinhibition of the globus pallidus, allowing inhibitory GABA influence on the thalamus and cortical stimulation. These relationships are summarized in the Figure. The clinical presentation of parkinsonism may vary due to the complexity of the neurochemical connections among the various pathways. In some patients, the dopaminergic as well as the nondopaminergic systems may be involved to a variable degree, producing unique clinical presentations.[1]

The initial presentation of Parkinson's disease may be quite variable, but tremor is present in 70% of patients at initial diagnosis.[1] Usually, the tremor begins unilaterally, affecting the hand and upper extremity. The tremor is described as a slow (4-7 Hz), pill-rolling, resting tremor. With action or intention and sleep, the tremor generally disappears, although stress and anxiety will accentuate it.[11] Tremor is disturbing to patients, as it is visible in public and may be embarrassing or physically disabling.

Muscular rigidity (ie, the resistance to passive movement) is a disabling symptom of Parkinson's disease and appears to affect proximal appendicular musculature early, with subsequent spread to most muscles including the axial structures.[1,11] Rigidity results in decreased range of movement and slowness, as well as the fatigue many patients with Parkinson's disease describe. With involvement of the facial muscles, expression is diminished, leading to the characteristic masked faces or "poker stare."

Bradykinesia, or the slowness of movement, is a common symptom and usually develops along with rigidity.[11] In Parkinson's disease, the ability to initiate and execute a movement is impaired. The slowness and reduction in movement lead to prolonged time to complete physical movements and ultimately tasks (eg, activities of daily living such as grooming, dressing, eating), precluding independence. Akinesia ("without movement") is the extreme of bradykinesia.[9,10]

Motor planning deficits also affect many people with this disease. Motor planning is involved in the ability to execute simultaneous or sequential motor programs (simple learned movements). Motor planning may be impaired so that reflex movements that usually occur with little to no conscious effort (eg, blinking, facial movements) now require a concentrated volitional effort.[12,13] Some patients experience sudden cessation of movement called "freezing episodes," which are an extreme form of bradykinesia (akinesia) and may, in part, be a result of motor plan access deficits.[8]

Postural instability may also be a direct consequence of the neurotransmitter imbalances of Parkinson's disease. In this context, postural instability refers to the loss of balance or lack of recovery of balance when perturbed that some patients with Parkinson's disease experience.[8,11] The inability to recover balance is probably related to bradykinesia secondary to dopamine deficiency. True impairments of postural stability are differentiated from generalized balance dysfunction, which may be caused by a number of other impairments (eg, sensory loss, motor planning dysfunction, or loss of range of motion and flexibility). Patients with Parkinson's disease may have abnormal gait with retropulsion, leading to backward falls. The rapid festinating gait in combination with the stooped posture may lead to forward fars.[8,14]

Tremor, rigidity, bradykinesia, and postural instability all occur as "direct effects" of Parkinson's disease.[15] These direct effects may lead to the indirect or secondary musculoskeletal effects of the disease--stooped posture, kyphosis, head flexion, shoulder protraction, and knee or elbow contractures--that further impair physical performance.[15,16] Other symptoms and signs of Parkinson's disease include muscle aches or cramps, depression, dementia, dysarthria, dysphagia, orthostatic hypotension, bladder problems, and sexual problems.[1,8]

The direct and indirect impairments of Parkinson's disease contribute to functional limitations that are particularly apparent in tasks such as getting in and out of bed, dressing, bathing, and walking. Cognitive deficits, such as memory loss, and psychological problems, such as depression and emotional lability, add confounding dimensions to the patient's functional status and quality of life. The process of Parkinson's disease affects the entire family, because loss of independence has an impact on the lives of the caregivers as well.

Idiopathic Parkinson's disease can be further differentiated into two subgroups, which have been identified by Zetusky et al[17] as the "tremor predominant" and the "postural instability and gait disturbed" (or PIGD). Patients who are tremor predominant usually have little bradykinesia or postural instability. The course of deterioration appears slower, with an earlier age of onset. The PIGD group, however, has a poorer prognosis and more rapid decline and disability, with bradykinesia and postural instability. The PIGD group may have more neurobehavioral disturbances and dementia. A clear demarcation between the two groups is not seen because there is overlap in clinical symptoms.[1] The subgroups, however, may illustrate the variation of degree of neurochemical transmitter involvement. The apparent difference in the course of the disease between the subgroups may provide a basis for counseling patients.

Parkinson's disease is insidious, and the diagnosis is based not on neuro-imaging studies and blood tests but on clinical examination and patient report. Accurate diagnosis is based on careful assessment with a high index of suspicion. Common criteria include the following: akinesia/bradykinesia, rigidity, and tremor.[3] Usually by the time a diagnosis is made, the disease has been present for several years.[18] Many patients will have noticed a tremor, disturbed gait, or change. in the quality of movements. Currently, there are no available markers for disease onset that would serve as screening for the disease.

Pharmacologic Management of Parkinson's Disease

When antiparkinsonian medications became available during the 1960s, they had a tremendous impact on the management of Parkinson's disease. Prior to the use of levodopa, anticholinergics and stereotaxic surgery were used to treat individuals with Parkinson's disease.[19] The disabling symptoms of akinesia and bradykinesia, which had not responded to anticholinergics, did respond to levodopa. Severely disabled patients became more mobile.[19,20] Although motor and central nervous system (CNS) problems are associated with levodopa, it has been the mainstay of pharmacologic treatment of individuals with Parkinson's disease. Drugs have been very effective in treating some of the direct effects of the disease (including bradykinesia, rigidity, and tremor), but it is not clear to what extent, if any, drugs can affect postural instability and impaired motor planning.[21] Also, along with the many positive results, came unwanted side effects such as dyskinesia, hallucinations, and the "on-off" syndrome.[19] Medications, therefore, must be used carefully in order to balance their benefits with possible problems associated with long-term use.

After initiating any type of treatment, patients should be assessed clinically to determine their response to treatment. Most assessments may be based on self-report of functional limitations by the patient, physical performance measures, or qualitative or quantitative clinical examination for the impairments (eg, rigidity, bradykinesia and tremor, musculoskeletal impairments, speech dysfunction).

A number of Parkinson's disease rating scales are available, such as the Northwestern University Disability Scale,[22] the New York University Scale,[23] and the United Parkinson's Disease Rating Scale.[24] These scales are based on subjective reporting of symptoms and functional ability. They vary in their sensitivity to change (due to the different gradations of items scored) as well as the aspects of disease that are measured.[25] The rating scales range from very short (5-6 items in the Northwestern University Disability Scale) to very long. For example, the United Parkinson's Disease Rating Scale evaluates 42 items and includes a modified disease staging scale (Hoehn and Yahr[26]) and activities of daily living (eg, bathing, eating, transferring). Although symptoms and performance may vary greatly in this disease, one recent report[27] indicates that impairment and physical performance measures can be reliably obtained by direct clinical examination for patients in early stages of the disease.

Treatment consists of dopamine replacement, dopaminergic drugs (which act at the postsynaptic site), or anticholinergics. In the last several years, an additional level to drug therapy has been added--neuroprotective therapy, with seligiline, which is thought to retard the progression of the disease (Tab. 2).

L-dopa

The mainstay of treatment is dopamine replacement. Dopamine will not cross the blood-brain barrier, so the levo-isomer levodopa (L-dopa) is given, which will enter the CNS and undergo enzymatic conversion to dopamine.[28] Almost 99% of the ingested L-dopa, however, is metabolized peripherally before it can cross into the brain, which necessitates larger amounts of levodopa to achieve the effective CNS dosing. Such large doses of levodopa can cause nausea and vomiting, and orthostasis. The most commonly used form today is a combination of carbidopa and levodopa (Sinemet). The carbidopa is a peripheral decarboxylase inhibitor preventing the peripheral conversion of the levodopa to dopamine, which allows more available levodopa to enter the CNS and ultimately smaller doses to be used.[6,28,29]

Sinemet is composed of carbidopa and levodopa in a 1:10 or 1:4 ratio. The plasma half-life of levodopa is about 1.3 hours, which dictates multiple dosing throughout the day. A controlled-release preparation is available containing 50 mg of carbidopa and 200 mg of levodopa for a 1:10 ratio or 25 mg of carbidopa and 100 mg of levodopa for a 1:4 ratio (Sinemet CR). The controlled-release preparation has been shown to produce fewer fluctuations in the plasma concentration, resulting in a smoother therapeutic response.[30] The onset is slower, and bioavailability is only about 70% as compared with 99% for the standard preparation.[28] The relative cost (average wholesale cost [AWC]) of 1 month's supply of Sinemet 25/100 three times a day is $65 compared with Sinemet CR 50/200 two times a day at $83.[31] About one third of patients treated with levodopa will continue to respond for most of their lives, one third will respond for about 5 to 7 years of treatment, and another third will respond for only 4 to 5 years of treatment.[1]

Side effects of levodopa therapy include nausea and vomiting (usually reduced with carbidopa), orthostatic hypotension, and cardiac dysrhythmias. Among the elderly especially, starting at a lower dose and titrating judiciously to the desired effect is prudent. Central nervous system side effects include confusion, delirium, and behavioral changes.[32] The suggestion has been made that a metabolite of levodopa has deleterious effects on surviving dopaminergic neurons,[33,34] but there is no conclusive evidence to support such an effect on mortality or disability among treated patients with Parkinson's disease.[35]

Later complications of levodopa include dyskinesias, clinical fluctuations, and psychiatric disturbances as the disease progresses. Clinical fluctuations include the "wearing off" or the "on-off" syndrome. Wearing off is the end of dose deterioration that occurs as the effective period of levodopa grows shorter over time. The on-off syndrome is the phenomenon of swings in the response to drug therapy. There may be an abrupt loss of drug effectiveness, resulting in akinesia ("off"). The akinesia may be followed by a sudden return of effectiveness, which may include dyskinesias ("on").[8,36] The dyskinesias and clinical fluctuations may be managed by lowering the dosage of levodopa and increasing the frequency of administration, changing over to the controlled-release formulation, or addition of dopamine agonists. Drug "holidays" were used in the past because it was thought that a "holiday" from the drug by the receptors would increase efficacy when reintroduced. Many patients did not tolerate weaning and discontinuance of the levodopa due to an abrupt return of the rigidity, bradykinesia, and immobility, and in some cases, even death resulted. At present, drug holidays are not usually recommended.[29,37]

Levodopa therapy has had a tremendous impact on patients with Parkinson's disease and has increased survival among these patients about 5 years.[38] Prior to levodopa, the mortality rate among this population was three times that of the "normal" population. Now the observed rate of mortality is dose to normal. Prior to levodopa therapy, Hoehn and Yahr[26] found that 28% of patients with idiopathic Parkinson's disease became severely disabled (dependent) or died within 5 years, 61% became severely disabled or died within 10 years, and 83% became severely disabled or died within 15 years. This finding is in contrast to results of studies carried out after the introduction of levodopa: 90/o of patients with the disease for 1 to 5 years were disabled or dead, 21% of patients with the disease for 6 to 10 years were disabled or dead, and 37.5% of patients with the disease for 11 to 15 years were disabled or dead.39 Although the drug does not alter the overall rate of progression of the disease, the time at lower disability levels is increased, improving the quality of life over the course of the disease. The majority of patients do not die from parkinsonism, but from complications such as cardiac disease, pneumonia, or thromboembolic disorders. Hip fractures are common among patients with Parkinson's disease, and those who sustain a fracture have greater mortality and morbidity rates than does the population at large.[40] Falling is caused by postural instability, which is not reversed by levodopa.[14] Falling is reported by more than one third of patients with Parkinson's disease.[8,14]

Table 1. Classification of
Parkinsonism[3]
Primary parkinsonism, Parkinson's disease
  (78%)
Secondary parkinsonism (8%)
  Vascular: multiple infarctions
  Drugs: reserpine, lithium, phenothiazines
  Infections: postencephalitic
  Toxins: manganese, carbon dioxide, MPTP(a)
  Trauma: pugilistic encephalopathy (boxing)
Hereditary parkinsonism (1%)
  Huntington's disease
  Olivopontocerebellar and spinocerebellar
    degenerations
  Hallervorden-Spatz disease
  Wilson's disease
Parkinsonism-plus syndromes (multiple
  systems degeneration) (12%)
  Progressive supranuclear palsy
  Shy-Drager syndrome
  Striatonigral degeneration
  Lewy body disease
(a) MPTP=1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

[TABULAR DATA 2 OMITTED]

TM Cutson, MD, MHS, is Assistant Professor, Department of Community and Family Medicine, and Associate, Department of Medicine, Claude D Pepper Older Americans Independence Center, Duke University Medical Center, Box 3003, Durham, NC 27710 (USA). Dr Cutson is also associated with the Geriatric Research, Education, and Clinical Center, Durham Veterans' affairs Medical Center, 508 Fulton St, Durham, NC 27705. Address all correspondence to Dr Cutson at the first address.

KC Laub, PT, is Research Physical Therapist, Department of Physical Therapy, Claude D Pepper Older Americans Independence Center, Duke University Medical Center.

M Schenkman, PhD, PT, is Associate Professor, Graduate Program of Physical Therapy, and Co-Director, Claude D Pepper Older Americans Independence Center, Duke University Medical Center.

This work was supported by the National Institutes of Health, National Institute on Aging, Claude D Pepper Older Americans independence Center Grant

Dopamine Agonists

Dopamine agonists have been examined as adjunctive or replacement treatment in patients with Parkinson's disease. Currently available dopamine agonists are ergot alkaloids, which act directly on the postsynaptic receptors, requiring no endogenous enzymatic activation.[36,41] This effectively bypasses the degenerating presynaptic neuron. Dopamine agonists have most effect on rigidity and bradykinesia, but perhaps little effect on postural impairment. Bromocriptine (Parlodel) and pergolide (Permax) are the only dopamine agonists available in the United States, When these agonists were used as initial monotherapy, symptoms improved but recurred, necessitating addition of levodopa after 1 or 2 years. Early adjunctive therapy (ie, added to levodopa) resulted in fewer clinical fluctuations; fluctuations later in the course of the disease responded to the addition of a dopamine agonist.[41]

Central nervous system side effects of agonists are similar to those of levodopa, ranging from insomnia to delusions and confusion. The risk of adverse CNS effects increase in elderly patients with cognitive impairment.[6,36] These side effects may be more severe and persistent than those induced by levodopa.[6,41] Other side effects include erythromelalgia (reddish edema of the lower extremities), pulmonary and retroperitoneal fibrosis (usually with bromocriptine), postural hypotension, nausea, and vomiting.[6] A dosage of 5 to 20 mg per day in divided doses of bromocriptine and 3 to 5 mg per day in divided doses of pergolide is usually effective. Pergolide has a longer duration of action. There is no evidence that either one of the dopamine agonists is superior to the other.[29,42] Response to one agonist may not be predictive of response to another. The varying responses may reflect differences in the number and type of dopamine receptors.[29,43] Dopamine agonists are very expensive. A month's supply of bromocriptine at 5 mg twice daily is $140 (AWC); pergolide at 1 mg three times daily is $240.31

Anticholinergies

Anticholinergic drugs ameliorate the symptoms of Parkinson's disease by rectifying the imbalance between dopamine and acetylcholine in the striatum. Anticholinergic drugs were the first drugs used to treat patients with Parkinson's disease. The symptom most improved by anticholinergic agents is tremor. There is little to no corrective effect on rigidity or bradykinesia, the more disabling symptoms.[28,29] Agents used include trihexyphenidyl (Artane) and benztropine (Cogentin). Diphenhydramine (Benadryl) is an antihistamine with anticholinergic properties that may be helpful. Adverse side effects of anti-cholinergics include memory impairment, hallucinations, dry mouth, constipation, urinary retention, and blurred vision. These side effects are especially problematic among elderly patients. The anticholinergic medications are relatively inexpensive, with an average month's supply costing about $20.[31]

Amantadine

Amantadine is a drug used for influenza prophylaxis; its efficacy for Parkinson's disease was discovered serendipitously.[44] The drug is thought to have both dopaminergic and anticholinergic properties. It appears to stimulate release of dopamine from surviving presynaptic terminals in the striatum.[37,44] The effects are short-lived (weeks), but this drug can be useful for testing purposes in suspected cases of Parkinson's disease. Patients are instructed to take 100 mg twice daily; amelioration of rigidity and bradykinesia within a few days is supportive of the diagnosis. Side effects include livedo reticularis and ankle edema. The cost of amantadine for about 1 month at 100 mg twice daily is about $20 for the generic formulation.[31]

Seligiline

Until recently, drug therapy for Parkinson's disease included only symptomatic treatment. A recent addition to the therapy choices in the United States is seligiline (Eldepryl), an inhibitor of monoamine oxidase, type B (MAO-B), which may slow the progression of the disease.[44,46] This drug was designed as an antidepressant and "energizer" in Hungary in 1960. In the mid-1980s, it was found that seligiline prevented the development of parkinsonian symptoms induced by the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). MPTP is a protoxin that was discovered as a contaminant in synthetic heroin in San Jose, Calif, in the early 1980s. MPTP is oxidized by MAO-B into a 1-methyl-4-phenyl-pyridinium ion (free radical), the actual neural toxin that destroyed the dopamine-producing neurons. Seligiline selectively inhibits MAO-B, which inactivates dopamine in the brain.[37] Based on the effects of seligiline on Parkinson's disease induced by the drug contaminant MPTP, it is theorized (but not yet proven) that death of cells in the substantia nigra may be due to other oxidative mechanisms via MAO-B with free radical production.

Seligiline may protect neurons via a decrease in the generation of free radicals by reducing the oxidative metabolism of dopamine. This drug may possibly rescue damaged neurons through activation of tropic mechanisms. Salo and Tatton[47] demonstrated an increased number of surviving rat motoneurons after axotomy when treated with seligiline and contended that seligiline compensated by some mechanism for the loss of target-derived trophic support caused by the axotomy.[47] Although the exact role (symptomatic versus protective) and mechanism are not yet understood, several clinical trials have shown that seligiline significantly delays the need for levodopa.[45,48] The usual dose is 5 mg in the morning and at noon. Doses greater than 20 mg per day may cause loss of the MAO selectivity; MAO inhibition, type A, results in the increased risk of hypertensive crisis with certain foods and drugs.49 Metabolic by-products include methamphetamine, so to reduce the risk of insomnia, the drug should not be taken late in the day. Methamphetamine may aggravate peptic ulcer disease. In patients already taking levodopa, a reduction of 10% to 30% of the levodopa dosage may be necessary to avoid side effects. The cost of 1 month's therapeutic supply of seligiline is $128.[31]

Surgery for Parkinson's Disease

Prior to the introduction of efficacious pharmacologic therapy, unilateral thalamotomies were performed to reduce disabling tremor.[19] Such procedures, however, carried a high risk of hemiparesis. Since pharmacologic agents have become available, these neurosurgical procedures are not commonly performed. There have, however, been favorable reports recently about posteroventral pallidotomies.[50,51]

More recently, autologous adrenal transplants have been reported with modest and unfortunately transient results. Theoretically, the adrenal chromaffin cells transplanted into the striatum would produce epinephrine and precursors, including dopamine. Dramatic results were initially reported in Sweden[52] and Mexico,[53] but these results have not been replicated and this technique has fallen from favor. By mid-1988, fetal nigral cells were used with some promise in several countries, including the United States.[54,55] This area of research is growing to include the future use of cultured cells for implantation and research.[29]

Therapeutic interventions

Drug and surgical therapies do not cure or shorten the duration of the disease. Rather, they may reduce some of the direct effects of the disease and prolong the time until the onset of disability.[18] Almost all patients with Parkinson's disease will experience at least some functional limitations. Optimal management of Parkinson's disease includes physical, speech, and psychosocial intervention--involving both the patient and the family/caregivers--in addition to pharmacologic intervention.

Physical, speech, and psychological interventions may be the key to maximizing quality of life in the face of this potentially devastating disease. Decisions regarding physical and psychosocial intervention depend on whether the goal of treatment is prevention, correction, or compensation for deficits, and whether treatment is directed at impairments or performance.

Early physical intervention should focus on preventing the general effects of deconditioning including losses of range of motion, aerobic capacity, and strength. Many possible approaches exist such as aerobic exercise, strengthening program, and water exercise.[56,57] Written programs are available through the American Parkinson's Disease Association[58] and the United Parkinson's Foundation.[59] An axial mobility exercise program for patients in the early stages of Parkinson's disease is currently under investigation via a randomized control trial at the Claude D Pepper Older Americans Independence Center at Duke University's Center for the Study of Aging and Human Development.[60]

In addition to deconditioning, common indirect effects of Parkinson's disease include various musculoskeletal changes.[57] Physical therapy intervention can help improve aerobic capacity and general fitness through cardiovascular, strengthening, and flexibility exercises. Physical therapy is perhaps most crucial in treating musculoskeletal changes that occur as a result of rigidity, bradykinesia, loss of mobility, and inactivity. These problems should respond well to therapy before they become fixed deficits.

Speech therapy can be used to improve language problems associated with low volume, poor enunciation, and faulty speed, as well as to improve inspiratory muscle strength. Swallowing difficulty can also be addressed.[61,62]

It is not always possible or appropriate to correct problems associated with Parkinson's disease for several reasons. First, caregivers and health professionals must remember that the disease is progressive, and, unfortunately, existing therapies are effective only in managing the symptoms of the disease. As the disease progresses, both direct and indirect effects can become so severe that they are refractory to treatment. Second, if a patient cannot benefit from improvement in a particular area because of other more overwhelming deficits, it is of little use to the patient to invest time working on such problems. When correction is not feasible, compensatory techniques or adaptive equipment become necessary. The use of rails, a headboard or hospital bed, or satin sheets, for example, can keep a patient independent in bed mobility. The use of a cane, walker, or other assistive devices such as a button aid, Velcro[R],(*) or a reacher can also reduce a patient's dependence on others.

Although data are inconclusive, some studies[63,64] have shown modest gains or improvement in physical performance activities with exercise. Comella et al[65] recently found that repetitive exercises for range of motion, endurance, balance and gait, and fine motor dexterity demonstrated benefit in areas of rigidity and bradykinesia, as measured by the United Parkinson's Disease Rating Scale. This was a single-blind, crossover study with 16 subjects in the moderate stage of Parkinson's disease. Although there was improvement in physical disability, this improvement did not persist beyond 6 months with return to normal activity.

Palmer et al[63] Compared 14 patients randomly assigned to exercises of the United Parkinson's Foundation or karate training. Both groups demonstrated improvement in gait, arm tremor, grip strength, and fine motor coordination.

In summary, medications have been shown to reduce rigidity and bradykinesia as well as tremor. Although these direct effects may be ameliorated by drugs, the secondary effects are best addressed by physical intervention. Currently, pharmacologic and nonpharmacologic modalities of treatment are important and complimentary to provide optimal improvement for the patient with Parkinson's disease.

Specific Management Considerations Throughout the Stages of Parkinson's Disease

Parkinson's disease is chronic and progressive; the clinician may treat patients throughout different stages of the disease. Management of Parkinson's disease is a challenge including treatment of the progressive manifestations of the disease, complications of therapy, and the attendant psychosocial issues. Effective management should be tailored to the phase or stage of disease and should involve multiple professionals as well as the family. In order to better describe the different facets of treatment, we can divide Parkinson's disease into three stages: early, middle, and late (Tab. 3).

Early Stage

In the very early stages, the patient may complain of specific symptoms (eg, shaking in one hand, weakness in a leg) yet remain fully functional and independent. The diagnosis of Parkinson's disease is usually considered in an individual when symptoms are yet relatively minor. Traditionally, clinicians would have delayed pharmacologic intervention in the early stage of the disease. The decision is, however, dependent on the personal preference of the patient. Choices of symptomatic therapy as well as neuroprotective therapy are now available. Although not conclusively proven to slow the progression of the disease, seligiline does stay the need for levodopa.[46] Many physicians believe the early use of levodopa increases the likelihood of management problems such dyskinesias and mobility fluctuations (wearing off or "on-off" phenomena) so that delaying institution of levodopa as long as possible is beneficial. Thus, many clinicians institute seligiline with the initial diagnosis of Parkinson's disease.[66,67]

Education about Parkinson's disease, including close clinical follow-up and institution of an exercise program to prevent or reverse musculoskeletal changes, is advised in the early stage of the disease. Adoption of an exercise routine at this point in the course of the disease may be much more successful than later in the disease when it may be difficult for the patient to learn the appropriate exercises and fixed deformities may have occurred. In the early stage of Parkinson's disease, the exercise program may be fairly general, including flexibility, strength, and endurance training. The program should also include specific exercises directed at correcting any impairments that are apparent at this stage (eg, excessive thoracic kyphosis, tight hamstring muscles).

Support groups can be helpful from the beginning by giving patients and families the opportunity to meet other people in similar situations as themselves, and by providing educational material. Depression is a common problem in Parkinson's disease at all stages.[17,68] Early education can help families recognize depression and seek help before the depression becomes overwhelming.

Middle Stage

The middle stage can be characterized by increasingly apparent symptoms, yet the patient remains functional, with some limitations. The patient is independently ambulatory. Early in this stage, the patient is essentially independent with ADLs. Toward the end of this stage, the patient experiences difficulty and slowness and may require assistance with many functional activities.

Medications are important in this stage to help control or alleviate some of the symptoms, including rigidity, bradykinesia, and certainly tremor. Increasing dosages of medication or addition of adjunctive agents are usually necessary for optimal management. Clinical fluctuations (eg, wearing of, "on-off") may be emerging, requiring further adjustment of the medications.

Physical intervention for range of motion, posture, and function is also important in this phase of the disease. Losses of lower-extremity, upper-extremity, and axial range of motion can directly affect how patients move, regardless of whether or not Parkinson's disease is present.[57] For example, loss of musculoskeletal range of motion and flexibility may contribute to loss of balance control even in the absence of Parkinson's disease.[69] Older persons with restricted spinal range of motion often are limited in their choice of movements because of an inability to rotate, laterally flex, and extend the spine. (The types of movement used by older patients during gait and bed mobility have caused Parkinson's disease to be mistaken for "old age.") Musculoskeletal impairments can be even more functionally limiting in the presence of the disease. In the middle stage of Parkinson's disease, the goals of physical intervention are to correct musculoskeletal impairment where possible and to prevent worsening of those refractory to treatment.

In addition to range of motion impairments, patients with Parkinson's disease frequently have motor planning problems, which further limit their freedom of movement. Patterns of movement become increasingly "parkinsonian" (ie, stooped posture with flexed upper extremities, minimal trunk rotation, shuffling gait with a narrow base of support, use of hands and knees to get in and out of bed as opposed to rolling and sitting up). Therefore, to influence a patient's level of function, physical therapy should address both range of motion impairments and physical performance. Effective functional training of bed mobility, transfers, and gait is best achieved by incorporating improved range of motion into more efficient movement patterns.

Gait disturbances, difficulties with balance control, and falls may be present in this stage. These deficits become a major issue and a barrier to independence. Whether levodopa replacement has an important effect on these impairments is questionable. These difficulties may arise because of musculoskeletal limitations, as a result of primary postural instability, or some combination of the two. Difficulties with balance and gait resulting from musculoskeletal impairments can be improved through appropriate physical intervention. Loss of balance control due to postural instability is unlikely to respond to physical intervention; the patient should be assisted to use appropriate compensatory strategies (eg, learning to avoid precarious positions, to use appropriate assistive devices, and to rely on contact guarding from a family member or caregiver when needed). A sudden change in balance or in frequency of falls may warrant a head computed tomographic or magnetic resonance imaging scan to rule out other pathology such as a subdural hematoma.[67]

Physical therapists and occupational therapists can help with the general problems of physical function by teaching appropriate compensatory techniques and energy-conserving strategies to enable the patient with Parkinson's disease to continue to perform ADLs successfully. Occupational therapists can determine appropriate adaptive equipment for activities of bathing, dressing, and eating. These interventions must be appropriate for the patient's needs and stage of disease. For example, a physical therapist may have success in correcting a deficit in range of motion attributable to decreased hamstring muscle length or limited thoracic rotation. If cognitive and motor planning problems, however, prevent the patient from learning new movement patterns, then the newly gained motion may be of little use to the patient. The same principle can apply to physical performance training. A physical therapist may be able to teach a patient how to transfer independently during therapy sessions. Due to increased rigidity and fatigue caused by effortful movement, however, the patient may not be successful each time at home and may experience more stress when attempting to perform the transfer independently. In this situation, it is more effective for the physical therapist to teach the patient and caregiver how to perform the transfer together. The patient needs to remain an active participant in the process, to use what functional mobility he or she has, and to maintain a sense of control instead of dependency.

Decisions regarding compensating for deficits can become very complicated. The needs for safety and independence are often weighed against a patient's own need for control and self-worth. Denial in some patients is very strong, and compensating for deficits seems to represent "giving up" or, at the very last, admitting that there is a problem. These types of situations can be even more difficult on the family than on the patient. Emotional support, as well as technical advice from physicians and therapists, is invaluable to families coping with these types of problems.

It is in this stage of the disease that speech impairments occur. These impairments may result as a direct effect of the disease and may be exacerbated by musculoskeletal impairments. Speech therapy can be instrumental for teaching the patient compensatory strategies, such as appropriate pacing (prosody) and volume support, to maintain effective communication.[11,61,62] Swallowing may be problematic due to tremor, rigidity, or abnormal oral musculature. Speech therapy can be helpful to teach safety and compensatory techniques such as taking small bites of food and head positioning.[11]

Psychosocial issues are more prevalent with increased manifestation of the disease. Depression and perhaps even early cognitive impairment may be present. Treatment of depression is important and can be managed with medications. If the depression is severe or refractory to a trial of antidepressants, electroconvulsive therapy should be considered. Electroconvulsive therapy has been shown to transiently improve motor symptoms associated with Parkinson's disease.[69] The mechanism is not known. Participation in a support group may be particularly beneficial during this stage of the disease.

Late Stage

During the late stage of Parkinson's disease, the progression of the disease has led to multiple, fixed, indirect effects such as kyphoscoliosis and contractures of the spine and extremities. The rigidity and bradykinesia may be severe, leading to immobility. Pulmonary function and swallowing are compromised, which contributes to more fatigue and even malnutrition. Bladder dysfunction with resulting incontinence becomes an issue. The patient with severe Parkinson's disease is essentially dependent in mobility and self-care. Self-expression may be severely compromised.

By this stage of the disease, clinical fluctuations may be common. Ultimately, very few of the drugs are efficacious, and compensatory approaches to intervention are essential. Skin care (to avoid breakdown), pulmonary toilet (to avoid pneumonia), and nutrition become important areas of concern. Education of the patient and caregivers may now center on prevention of secondary complications (malnutrition, aspiration, pressure wounds, and pneumonia) and compensatory strategies to ease the burden of caregiving (bed mobility, transfers, wheelchair use). Patients usually succumb not to Parkinson's disease, but to the resulting medical complications.

Conclusions

Parkinson's disease is a chronic progressive neurologic disorder. The management of Parkinson's disease requires multiple professionals to address not only the patient's needs, but also those of the family and caregiver. Pharmacologic interventions are important and the mainstay of treatment, but appropriate interventions from other disciplines are also necessary throughout the stages of the disease. Physical techniques are needed to prevent or correct musculoskeletal impairments, to improve physical performance, and to assist the patient and family toward appropriate compensatory strategies of function as the disease progresses. Psychosocial support and intervention may be instrumental in assisting the patient and family to adjust to the disease. Patients must be continuously monitored and reassessed for appropriate treatment strategies.

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