CHAPTER 33 PARKINSON’S DISEASE AND PARKINSONIAN SYNDROMES
Practice of Geriatrics
CHAPTER 33 PARKINSON’S DISEASE AND PARKINSONIAN SYNDROMES
David Gordon Lichter, M.B., Ch.B., F.R.A.C.P.
Differential Diagnosis of Parkinson’s Disease
Management of Parkinson’s Disease
Institutionalization in Parkinson’s Disease
Life Expectancy in Parkinson’s Disease
Parkinson’s disease (PD) currently affects approximately 1 million people in North America and is particularly common in those over age 60, of whom 1% to 2% are afflicted. Prevalence ratios increase steeply with advancing age, and the disorder is expected to become correspondingly more common as human life is prolonged. Despite major advances in our understanding of PD, the diagnosis is still made solely on clinical criteria. In the elderly, as in other age groups, attempts must be made to differentiate idiopathic PD (defined by the cardinal features of rest tremor, rigidity, bradykinesia, and postural instability) from other (secondary) causes of parkinsonism. Therapy for PD must be prescribed on an individual basis, taking into account the expectations and needs of the patient, the projected life span, and the presence of co-existing medical conditions. The heightened susceptibility of the elderly to the toxic effects of drugs, particularly anticholinergics, and age-related changes in pharmacokinetics must also be considered when drug therapy for patients with PD is chosen.
Degeneration of Dopaminergic Neurons
Central to the pathology of PD is the degeneration of dopamine-generating neurons, located in the pars compacta of the substantia nigra and ventral tegmental area of the midbrain. These neurons project to the striatum (caudate and putamen) and frontal and limbic brain regions. Clinicopathologic correlations have indicated that clinical deficits emerge when approximately 80% of the nigral cells have been lost, and the course of clinical decline then parallels the degeneration of the remaining nigral neurons.
Differences Between Parkinson’s Disease and Normal Aging
Although certain “parkinsonian” features of aging have been attributed to a decline in dopaminergic function, it is clear that PD is not just an exaggeration of “normal” aging. Aging in humans is associated with a slow attrition of nigrostriatal dopaminergic neurons that results in a significant drop in dopamine concentrations in the putamen after the age of 60 years. However, the striatal dopamine loss that occurs with normal aging does not mimic the typical subregional pattern of striatal dopamine loss found in idiopathic PD. Correspondingly, the lateral ventral tier of the substantia nigra is relatively spared in normal aging but is specifically involved in PD. There is evidence, also, of active cell breakdown, phagocytosis, and gliosis in PD but not in age-matched controls or in postencephalitic parkinsonism after years of subsequent “normal aging.” These observations, together with the failure of levodopa to affect the mild extrapyramidal impairment of normal elderly subjects,1 have suggested that PD has a distinct pathobiology.2
The Oxidant Stress Hypothesis of Parkinson’s Disease
Although the cause of PD remains obscure and may be multifactorial (e.g., toxins, reduced primordial population of nigral dopaminergic neurons, infections, genetic predisposition), toxicity from endogenous and exogenous oxidative mechanisms has been implicated as a fundamental process in the progressive nigral cell loss. In this conceptualization, normal age-related changes may aggravate oxidative stresses on dopaminergic neurons.
In preclinical disease, it has been suggested that the efforts of surviving neurons to compensate with increasing dopamine output may result in enhanced generation of hydroxyl radicals and other potentially toxic by-products of oxidative deamination of dopamine. This process is compounded by a reduced concentration of a number of free radical scavengers, including glutathione, in the substantia nigra and basal ganglia in PD. In mice, experimental glutathione depletion produces morphologic changes in nigral neurons that resemble those seen in both normal aging and the MPTP neurotoxicity model of PD. MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine) is highly toxic to neurons in the pars compacta of the substantia nigra and produces clinical and neuropathologic features that closely resemble those of PD in both nonhuman primates and humans. Oxidative biotransformation of MPTP by the enzyme monoamine oxidase B is required for its neurotoxic effect, which is mediated via disruption of mitochondrial functions. Monoamine oxidase B is increased in concentration in the aged brain, and aged animals are more susceptible to the neurotoxic effects of MPTP than younger animals. Such observations have suggested that oxidation of both endogenous and exogenous compounds may predispose to the senescence of dopaminergic neurons in patients with PD, with the further implication that aging may increase their vulnerability to this process.
The Role of Aging in Parkinson’s Disease
Despite their appeal and apparent coherence, both the oxidant stress hypothesis of PD and the argument that aging may contribute to dopaminergic cell loss in PD have been challenged.3,4 Not all studies have indicated a continuing increase in frequency of PD with age, and some have suggested a decrease in frequency after age 75 to 80. The rate of loss of dopaminergic innervation in the caudate nucleus appears to be similar whether the disease begins before or after 60 years of age. Similarly, neuronal loss in the substantia nigra appears to be no greater and may be less severe in late-onset patients than in early-onset patients despite comparable disease durations. Thus, although aging may contribute an additional risk factor in the development of PD and may clearly alter the expression of symptoms (see later discussion), it may not have a major effect on the degeneration of dopaminergic neurons in this disorder.
The typical presentation of parkinsonism, with initially asymmetrical resting tremor, bradykinesia, and rigidity, may be seen in patients of any age. However, patients with late-onset disease are more likely to present with relatively symmetrical signs, and display at an earlier stage, or to a greater degree, signs of postural instability, gait disorders, frontal lobe symptoms or dementia, and autonomic dysfunction.5 In addition, more than a third of patients whose parkinsonian symptoms first appear at the age of 75 or older appear to be unresponsive to levodopa despite clinical features that may be otherwise typical. Patients with late-onset disease are also less likely to develop significant “on-off” motor fluctuations,6 which usually complicate therapy with levodopa in the middle and late stages of the disease. Although use of lower doses of levodopa in older patients may partially account for this observation, age-related changes in the brain (including loss of striatal dopamine receptors), different pathology in some late-onset cases, and other unknown factors may modify the disease course in the elderly.
DIFFERENTIAL DIAGNOSIS OF PARKINSON’S DISEASE
Parkinson’s Disease Versus Parkinsonism
In the absence of any available confirmatory diagnostic tests, the diagnosis of idiopathic PD remains a clinical judgment based on a typical history and characteristic neurologic examination. All four of the cardinal clinical signs (see first paragraph of this chapter) need not be present to make the diagnosis, particularly if the patient presents with a characteristic unilateral rest tremor. However, if akinesia and rigidity (even if unilateral) are present in the absence of a rest tremor, the diagnosis of PD is less certain, and other possible causes of parkinsonism must be considered.
After a diagnosis of PD or parkinsonism has been made, attention should be directed toward (1) excluding specific etiologic factors, including drugs (see later discussion), toxins (e.g., manganese, carbon monoxide, carbon disulfide, methanol, and ethanol), anoxic brain injury, and encephalitis (including that due to syphilis and acquired immunodeficiency syndrome (AIDS), and (2) identifying any “unusual” or distinguishing clinical features. These “red flags” include initial bilateral presentation, subacute onset (suggestive of drug-induced or other secondary causes of parkinsonism), lack of response to levodopa, absence of rest tremor, and the presence of nonparkinsonian neurologic deficits, which may suggest a “parkinsonism plus” syndrome.
The “Parkinsonism Plus” Syndromes
“Parkinsonism plus” syndromes are disorders in which the classic features of parkinsonism are combined with other neurologic deficits, particularly autonomic, cerebellar, oculomotor, cortical, and pyramidal dysfunction. The prognosis of these conditions is generally considerably worse than that of idiopathic PD. Although they may be impossible to distinguish from PD early in the course, an absent, limited, or transient response to levodopa, caused by degeneration of striatal or pallidal neurons, should alert the physician to the presence of an atypical syndrome.
The combination of parkinsonism and visual symptoms (unusual in PD), associated with a markedly decreased blink rate and impairment of conjugate eye movements, should suggest the diagnosis of progressive supranuclear palsy (PSP). Early slowing and later limitation of voluntary downgaze may result in difficulties with reading, eating, tying shoes, and walking downstairs. These problems are followed by progressive loss of all voluntary vertical and horizontal eye movements, but oculocephalic reflexes are preserved. There is disproportionate axial rigidity and dystonia, the neck often being held stiffly in extension, as opposed to the flexed posture characteristic of PD. A prominent feature is an early loss of the postural reflexes, which predisposes the person to “log-like” falls, often backward. Pseudobulbar palsy, characterized by dysphagia, dysarthria, and emotional incontinence, may be an early or late finding.
The disorders known as multiple system atrophy (MSA) overlap clinically and pathologically and are best distinguished by their presenting clinical signs. Among these, the Shy-Drager syndrome is notable for prominent dysautonomia, which may be present for up to 3 years before parkinsonian signs appear. Common early features include orthostatic hypotension, syncope, impotence, anhidrosis, and symptoms of neurogenic bladder disturbance (urinary frequency, nocturia, retention, and overflow incontinence). Laryngeal stridor may occur late in the course of the Shy-Drager syndrome and in striatonigral degeneration, a disorder that may be suspected initially on the basis of a levodopa-resistant akinetic-rigid syndrome. In the olivopontocerebellar atrophies (OPCA), parkinsonism is typically associated with cerebellar signs (such as ataxia, intention tremor, and nystagmus), bulbar deficits (dysarthria and dysphagia), and corticospinal signs. Magnetic resonance imaging (MRI) frequently shows atrophy of the brain stem and cerebellum.
Corticobasal ganglionic degeneration is an unusual but readily differentiated syndrome that usually presents in the seventh decade of life and is characterized by extreme rigidity and apraxia, which starts in one limb, often the nondominant upper extremity, and then spreads over a period of a few years to the ipsilateral limb and then to the contralateral limbs. As opposed to the rest tremor characteristic of PD, there is a 6- to 8- Hz action or intention tremor that differs from essential tremor by its myoclonic jerkiness. Associated findings include the “alien limb” syndrome, cortical sensory loss, constructional apraxia, frontal release signs, and, later in the course, cognitive dysfunction or dementia, reflecting the characteristic frontal and parietal cortical pathology.
Because drug-induced parkinsonism is reversible when the offending agent is stopped, it should never be overlooked. Drugs that act presynaptically by inhibiting dopamine synthesis (e.g., alpha-methylparatyrosine), disrupting vesicular storage of dopamine (e.g., reserpine), or producing false neurotransmitters (e.g., alpha-methyldopa) are, fortunately, now relatively uncommon causes of parkinsonism. On the other hand, parkinsonism is still a common complication of drugs that block the central D2 dopamine receptors. Of these, neuroleptic agents such as the phenothiazines (e.g., chlorpromazine) and butyrophenones (e.g., haloperidol) are the most frequently recognized offenders. Parkinsonism may also be a side effect of the tricyclic antidepressant dibenzoxazepine (amoxapine), which has an antipsychotic metabolite, loxapine. However, the most common drug-induced form of parkinsonism seen in the elderly in outpatient settings, and one that is frequently overlooked, is that produced by antiemetics, particularly metoclopramide (Reglan) and prochlorperazine (Compazine).7,8 These drugs have the potential to block central as well as peripheral D2 dopamine receptors.
The calcium channel blockers flunarizine and cinnarizine have structural similarities to neuroleptics and are well documented as causes of parkinsonism. Although these drugs are not available in the United States, other commonly used calcium channel blockers, including verapamil and diltiazem, may occasionally cause this complication. The mechanism of this effect is unclear, but blockade of calcium entry into the nigrostriatal neurons and alteration of dopamine release may contribute to it.
Recently, it has been recognized that selective serotonin reuptake inhibitors such as fluoxetine (Prozac), which may be prescribed for depression or obsessive compulsive symptoms, may occasionally induce or aggravate parkinsonism in susceptible individuals. This effect is thought to be mediated by serotonin-induced inhibition of central dopamine systems. Both phenytoin and valproate may rarely produce parkinsonism. Other, less clearly documented causes include lithium (which more commonly causes a postural and action tremor) and captopril.
In general, advanced age predisposes to druginduced parkinsonism. Age-related loss of nigral dopaminergic neurons or “preclinical” PD in elderly patients could account for this added risk. Female sex is also a predisposing factor. This may be explained by the influence of estrogens and, in the case of neuroleptics, by a higher average per kilogram prescribed dosage in female patients.
The clinical appearance of the aging process itself bears some resemblance to PD, normal elderly subjects often showing weakness of the voice, motoric slowing, variable increases in muscle tone, particularly in the legs, and a characteristic alteration of posture and gait. The main features of this syndrome are a slightly flexed posture, diminished arm swing, slowness and stiffness in walking, usually on a slightly widened base, and a shortened step (marche a petit pas). Turns are achieved by multiple short steps rather than by a single, fluid movement. Most older individuals adopt this “senile” or “cautious” gait9 to a greater or lesser degree. In the individual case, it may be a compensation for arthritis, pain, weakness, vestibular inaccuracy, or sensory impairments, including mild proprioceptive loss and age-related visual impairment. Other factors differentiate this condition from PD. Thus, rest tremor is absent in normal aging; there is no festination of gait (a tendency to advance increasingly rapidly, with short steps) and no propulsion or freezing occurs. Furthermore, facial masking is seldom present, micrographia is absent, and slowing of movement is not accompanied by the prominent fatigability (progressive fade and collapse of sequential or repetitive movements) that characterizes true bradykinesia.
Higher-Level Gait Disorders in the Elderly
Adding to the diagnostic difficulties encountered in the elderly, senile gait may be compounded by both fear of falling and other nonparkinsonian neurologic conditions that may produce gait apraxias and “freezing” of various types. The resulting disorder may vary widely in severity and includes sudden “motor blocks” only when the patient is confronted with obstacles, difficulty in initiating gait, with shuffling on the spot (“the slipped clutch”), and, in its most severe form, a total inability to start walking, the feet appearing glued to the floor (“magnetic response”). In the syndrome of “isolated gait ignition failure,” the gait has some elements of parkinsonism, with hesitation in starts and turns, shuffling, and freezing, but it is relatively unremarkable once entrained and is marked by upright posture and normal or near-normal equilibrium. The cause of this levodopa-resistant syndrome is unclear, but it may include focal degeneration of the frontal lobes or frontal lobe vascular disease.
A more typical gait in patients with cerebrovascular disease, including those with Binswanger’s disease (subcortical arteriosclerotic encephalopathy) combines elements of start and turn hesitation, short steps, and freezing with progressive dysequilibrium and falls. This condition has been termed lower-half or lower-body parkinsonism.9 Unlike patients with PD, these patients typically walk on a widened base, have an upright trunk and leg posture, and usually do not show festination, propulsion, or retropulsion. Associated findings often include cognitive impairment, pseudobulbar palsy, frontal release signs, paratonia, pyramidal signs, and urinary disturbances. Vascular risk factors, including hypertension, diabetes mellitus, hyperlipidemia, elevated fibrinogen levels, and cardiomyopathy, are often present and should be addressed in an effort to slow the progression of disease. The pathophysiology of this condition may be linked to damage to the reciprocal connections between the frontal lobes and the basal ganglia secondary to subcortical white matter disease. Similar abnormalities of equilibrium and gait have been described in patients with normal pressure hydrocephalus.
Benign Essential (Senile) Tremor
Although rest tremor is absent in normal aging, older persons not uncommonly have a posturalaction tremor (a “senile” variant of benign essential tremor), which may be mistaken for a parkinsonian tremor. Essential tremor is frequently a familial condition and is generally inherited as an autosomal dominant trait. It presents as an alcohol-responsive postural and action tremor, affecting the upper limbs, head (as a “no-no” or “yes-yes” movement), and voice, the legs being infrequently affected. This tremor tends to be more symmetrical than the rest tremor of PD. Parkinsonian tremor may involve the lips, tongue, or jaw but usually spares the head and is never associated with vocal tremor. Although other parkinsonian features are absent in essential tremor, between 40% and 50% of patients with PD manifest some postural and action tremor as well as rest tremor. More significantly, a postural-action tremor that is indistinguishable from essential tremor may precede by several years the development of PD in some patients. Elderly patients with apparent essential tremor should therefore be followed closely for emergence of symptoms or signs of PD.
Arthritis and Other Musculoskeletal Conditions
Osteoarthritis of the hips and knees or an old hip fracture may add to postural and gait difficulties in the elderly and sometimes suggests parkinsonism. Conversely, early signs of PD may be missed in elderly arthritic patients in whom painful joints or fixed deformities may hinder accurate assessment of muscle tone, bradykinesia, dexterity, handwriting, or walking. Adding to possible diagnostic confusion, the onset of PD is insidious, and symptoms of stiffness, slow movement, and (occasionally) aching pain may be overlooked or attributed incorrectly to “arthritis” in the elderly. Frozen shoulder may be the first symptom of PD in at least 8% of patients and may occur up to 2 years prior to the onset of more commonly recognized features of parkinsonism. Sciatic-like pain may also occur as an early sign of PD and may lead to unnecessary surgery.
Stroke is common in the elderly, and unilateral parkinsonism may sometimes be confused initially with hemiparesis. Attention to certain features of the examination should help in differentiating these conditions. In PD, the patient’s increased tone has the characteristics of rigidity (“lead-pipe” resistance throughout the range of movement or “cogwheel”-type resistance when tremor is also present) rather than spasticity (hypertonicity that is direction- and velocity-dependent). A pyramidal tract pattern of weakness should not be present in uncomplicated PD. Similarly, a true Babinski’s sign is not a feature of PD, in which even the tonically extended great toe (“striatal toe”) should show the normal flexor response to plantar stimulation. Associated findings, including hypophonia, hypomimia (reduced facial expression), and flexed posture on standing, may suggest the correct diagnosis.
The psychomotor retardation of depression may be mistaken for the bradykinesia and hypomimia of PD, and vice versa. Distinguishing features suggestive of uncomplicated depression are a lack of tremor and rigidity and the presence of vegetative symptoms, such as reduced appetite, weight loss, and insomnia. However, vegetative symptoms and signs are frequently absent in the normal elderly population with depressive symptoms, the majority of whom present with dysphoria rather than major depression. In contrast, symptomatic dysphoria is rare in patients with PD, who are more likely to present with dysthymic disorder, agitated depression (with associated anxiety and panic symptoms), or major depression.
Diagnostic difficulties commonly arise when parkinsonism is accompanied by dementia. The prevalence of dementia in patients with PD varies from 20% to 40%, depending on the criteria for diagnosis of dementia and the population surveyed. This figure indicates a risk of dementia that is up to four times greater for parkinsonian subjects than for age-matched controls. Older age, more severe disease, and depression have been found to be predictive of incident dementia in a community population sample of PD patients. In addition to the influences of PD and aging, causes of dementia in a parkinsonian patient include the presence of a parkinsonian plus syndrome (see earlier section), other neurologic conditions, metabolic disorders, and drugs.
Most levodopa-responsive parkinsonian patients who develop dementia have a predominantly “subcortical” dementia syndrome, characterized by cognitive slowing (bradyphrenia), disproportionate impairment in executive skills (including the ability to sustain attention, plan, monitor, and modify behavior appropriately to achieve a particular goal), impaired memory function, and perceptual motor dysfunction. Although there is a relative sparing of language, praxis, and other “higher” cortical functions, a majority of such individuals manifest one or more pathologic correlates of Alzheimer’s disease, such as degeneration of cholinergic neurons of the nucleus basalis of Meynert, senile neuritic plaques, and neurofibrillary tangles. Because these patients may experience a worsening of parkinsonism if they are treated with an anticho-linesterase drug such as tacrine (Cognex) or donepezil HCl (Aricept), they need to be distinguished from subjects with senile dementia of the Alzheimer’s type. The latter patients have a course that is characterized from the onset by a progressive “cortical”-type dementia (typified by such features as aphasia, apraxia, and agnosia, as well as substantial memory impairment), with later development of extrapyramidal signs. In such cases, rigidity may be accompanied by bradykinesia, but true rest tremor should not be present, and there is usually no response to levodopa.
A history of psychosis, vulnerability to levodopa-induced psychosis, sensitivity to neuroleptics, and, occasionally, a positive family history, may suggest a diagnosis of “diffuse Lewy body disease,” a pathologic variant of PD in which abundant Lewy bodies (the hallmark of PD) are present throughout the cortex, not just in the substantia nigra compacta. Alternatively, an abrupt onset, stepwise deterioration, or fluctuating course of dementia, presence of vascular risk factors, focal neurologic symptoms or signs, or a history of previous strokes suggests the presence of a vascular dementia, which is likely to be associated with levodopa-resistant “lower-body” parkinsonism (see earlier discussion).
A routine complete blood count, chemistry screen, thyroxine (T4) and thyroid-stimulating hormone levels, vitamin B12 level, and computed tomographic (CT) or MRI scan should exclude common treatable causes of dementia, such as metabolic encephalopathy, normal pressure hydrocephalus, intracranial masses, and multi-infarct state. Finally, even in patients who do not manifest hallucinations or delusions (usually signs of a dopaminergic psychosis) or frank delirium, reduction of unnecessary drugs, particularly those with anticholinergic properties, may improve memory and cognition in the elderly parkinsonian patient.
MANAGEMENT OF PARKINSON’S DISEASE
The first step in pharmacologic management of the patient with PD is for the patient and physician to agree on therapeutic goals. Attempts to treat symptoms or signs that are of no importance to the patient will not be useful and may carry the risk of significant adverse effects. Second, it is important in the elderly, who may be very sensitive to drugs, to “start low and go slow” when introducing and titrating medications. Finally, one should explore the effect of dose changes in only one drug at a time.
Management of Parkinsonian Motor Dysfunction
ANTICHOLINERGIC DRUGS AND AMANTADINE
Centrally acting anticholinergic drugs such as trihexyphenidyl (Artane) and benztropine (Cogentin) may be useful for the early treatment of PD in patients 60 years of age or younger in whom resting tremor is the predominant symptom. However, their use is not recommended in older patients or in those with dementia in view of a high incidence of peripheral and central side effects (see later discussion of Psychotoxicity and Its Management).
Amantadine hydrochloride (Symmetrel, Symadine) is an antiviral agent discovered by chance to have antiparkinsonian activity. In addition to possible mild peripheral anticholinergic actions, it is an N-methyl D-aspartate (NMDA) receptor antagonist with possible neuroprotective properties (see Psychotoxicity and Its Management), and it promotes release of dopamine from presynaptic terminals, blocks dopamine reuptake, and stimulates dopamine receptors. Amantadine may be used as an initial short-term (1 to 2 years) monotherapy for mild to moderate parkinsonian symptoms. Peripheral side effects include livedo reticularis (a reddish-purple reticular mottling, usually limited to the skin of the ankles and lower legs), ankle edema, dry mouth, constipation, and blurred vision, which are rarely severe enough to limit treatment. However, when amantadine is used in doses of up to 300 mg daily, with or without levodopa, confusion and hallucinations have been found to occur twice as often (47% incidence) in patients over age 65 than in younger patients. The reduced glomerular filtration rate in older patients may account for this phenomenon because amantadine is excreted unchanged from the kidney. In view of the greater risk of toxicity, amantadine should generally be avoided in patients with impaired renal function. In older patients, it is best to titrate amantadine over a 2-week period, preferably using the liquid formulation (50 mg/5 mL), to a maximum of 100 mg bid. If this dose is well tolerated, the capsules (100 mg) can then be substituted. Thereafter, it is necessary to remain vigilant for any emerging adverse effects, which may occur most commonly after 3 to 9 months of treatment.
The decision about the timing of the introduction of levodopa, now routinely combined with the peripheral decarboxylase inhibitor carbidopa (in the United States) or benserazide (in other countries), is based entirely on the needs, expectations, and age of the individual patient. In addition, the observed or anticipated response to and the side effects of alternative antiparkinsonian therapies should factor into this judgment and are particularly important considerations in the elderly. Although levodopa remains the most effective treatment for PD, end-of-dose fluctuations (reemergence of parkinsonian signs and symptoms as each levodopa dose wears off) and dyskinesias (abnormal involuntary movements) complicate the course in up to 50% of patients within 5 to 7 years of initiating therapy. However, the available evidence suggests that fluctuations and dyskinesias are likely to take longer to develop after starting levodopa in elderly patients, and when they do develop, they are less likely to be disabling.6,10 The elderly patient is more likely to die of unrelated causes before these problems are encountered. When one considers also the heightened susceptibility of the elderly to the toxic effects of alternative medications, such as anticholinergic drugs and amantadine, one can make a strong case for early rather than late introduction of levodopa in this population.
Quality of life and functional status should be the primary factors guiding the decision for initiation of levodopa therapy. Mild bradykinesia or rest tremor, which may produce significant disability for younger patients who are still employed, often does not have the same import for elderly retired individuals. On the other hand, the importance of hobbies or social activities to the psychological well-being of the older patient should not be underestimated. Limitations in these areas, even if there is no significant impact on other activities of daily living, may warrant the introduction of levodopa. Rigidity and bradykinesia that have progressed to the point where social independence is compromised (for example, when difficulties are encountered in such domains as maintenance of personal hygiene, feeding or dressing oneself, getting in and out of bed and chairs, walking, and driving) represent clear indications for levodopa therapy.
In general, plasma concentrations of levodopa are substantially higher in elderly subjects than in younger patients following a given oral dose.11 Slower gastric emptying in the elderly, with subsequent increased duodenal levodopa absorption, contributes to this phenomenon. In addition, an age-related decrease in first-pass metabolic decarboxylation in the gastrointestinal tract results in levodopa bioavailability in elderly patients that may be as much as 20% greater than that in younger patients. This difference is abolished by the peripheral decarboxylase inhibitor carbidopa. The systemic clearance and volume of distribution of levodopa, with or without carbidopa, are also reduced in the elderly, probably because of an age-related decline in lean body mass. Regardless of concomitant decarboxylase inhibitor therapy, elderly subjects may therefore require a smaller dose of levodopa than younger patients.12
Levodopa is usually best initiated at a dose of half of a 25/100 carbidopa-levodopa (Sinemet) tablet, two or three times daily after a meal and is increased by half a tablet every 4 to 7 days using tid or qid dosing until a satisfactory response occurs. The goal of such therapy should be to eliminate disability rather than to abolish all symptoms or signs of the disease. For the patient with early emerging disability related to PD, an average of 300 to 400 mg of levodopa daily is required to accomplish this goal. With the 25/100 Sinemet tablet, this dose also provides 75 to 100 mg/day of carbidopa, which is normally sufficient to block the peripheral dopamine decarboxylase enzyme, thereby minimizing nausea and other adverse effects of levodopa.
An alternative initial strategy is to begin levodopa with controlled-release (CR) Sinemet at an initial dose of one 25/100 tablet twice a day and then switching to CR 50/200 bid, if this is tolerated. This formulation offers convenience of dosing but is more likely to be associated with confusion or psychosis in patients with preexisting cognitive dysfunction. Other common shortcomings of the CR preparation include inadequate antiparkinsonian effect and a delay in onset of action of the day’s first dose. The latter problem can usually be overcome by increasing the first CR dose by half of a 50/200 tablet or supplementing the first CR dose by a tablet of regular Sinemet, 25/100.
The psychiatric complications of levodopa (see section on Psychotoxicity and Its Management) are typically more troublesome in the evening and at night and can often be ameliorated or abolished by discontinuing the evening or bedtime dose. In other cases, however, use of a long-acting dopaminergic drug at bedtime (e.g., Sinemet CR, or a direct dopamine agonist such as bromocriptine or pergolide) may improve not only nocturnal parkinsonian symptoms but also early morning akinesia. The latter symptom is often the first sign of “end-of-dose” deterioration or the “wearing-off” effect of Sinemet.
Wearing-off fluctuations during the day develop later in the course of PD and, similarly, may be effectively managed by switching from regular to controlled-release Sinemet. It is important to realize that the bioavailability of CR averages approximately 70% of that of regular Sinemet. A useful rule of thumb in converting patients to the controlled-release drug is to double each dose of regular Sinemet and administer CR at twice the previous wearing-off interval minus 1 hour. For example, for a patient taking Sinemet 25/100 with wearing-off beginning 3 hours after each dose, the initial CR conversion dose would be 50/200 at twice the wearing-off interval (2 × 3 = 6) minus 1, i.e., every 5 hours.
Alternatively, wearing-off fluctuations can be managed by supplementing regular Sinemet with either a direct dopamine agonist or deprenyl (see next section). In some older patients, however, the resulting prolonged dopaminergic agonism may aggravate side effects, particularly dyskinesias, confusion, and psychosis, and a better overall therapeutic response may be achieved by using monotherapy with smaller, more frequent doses of regular Sinemet.
Deprenyl (selegiline, Eldepryl) is an irreversible (“suicide”) inhibitor of the type B isoenzyme of monoamine oxidase, which reduces catabolism of brain dopamine. Although some studies have continued to reinforce the earlier hopes of finding a neuroprotective effect of deprenyl, an extension of the DATATOP (deprenyl and tocopherol antioxidant therapy of parkinsonism) study failed to show an enduring benefit of this drug for patients with newly diagnosed disease after 18 months of therapy.13 Similarly, deprenyl at a dose of 10 mg daily provided no advantage in preventing or postponing complications from levodopa therapy in DATATOP patients.14
Disadvantages of deprenyl include its high cost and a generally less favorable risk-benefit ratio in the elderly, especially when it is combined with levodopa. Surprisingly, a recent open randomized study of patients with early PD showed a 60% increase in mortality after 3 to 5 years in patients who received levodopa plus deprenyl compared with those who received levodopa alone.15 There were several limitations in this study, particularly in regard to accuracy of diagnosis, cause of death, compliance with treatment assignment, and statistical methodology, and “on-treatment” analysis of mortality failed to show a significant difference between treatment groups. The mortality was excessively high, inconsistent with clinical experience, and at variance with findings of 10 previous controlled long-term trials of deprenyl in PD. Nevertheless, the continued use of deprenyl, especially in older patients, merits further study because it has been suggested that we may be using too high a dose for too long.16
The combination of deprenyl and selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants may precipitate a potentially serious toxic reaction, the serotonin syndrome. This is characterized by mental status changes (e.g., confusion, altered level of consciousness), motor dysfunction (e.g., rigidity, myoclonus), autonomic disturbance (e.g., fever and tachycardia), and, occasionally, rhabdomyolysis, thus closely resembling the neuroleptic malignant syndrome. Recent evidence suggests that this is a rare reaction and probably complicates combination therapy in less than 0.5% of PD patients. Nevertheless, deprenyl should be used with caution in elderly PD patients and may be best avoided in the presence of concomitant SSRI therapy.
DIRECT DOPAMINE RECEPTOR AGONISTS
Currently, two direct dopamine receptor agonists, both ergot derivatives, are available in the United States: (1) pergolide mesylate (Permax), an agonist at both D1 and D2 dopamine receptors, and (2) bromocriptine mesylate (Parlodel), an agonist at D2 receptors and a mild antagonist at D1 sites. Action at both D1 and D2 receptors appears to be necessary for optimal control of parkinsonism, which perhaps explains the slightly better results obtained with pergolide in studies that have compared the efficacies of the two drugs (see later in this section). Neither drug is as effective as carbidopa-levodopa (Sinemet), and although agonist monotherapy may be sufficient to control emerging symptoms for short periods of time in selected patients with newly diagnosed PD, in general this is not an optimal therapeutic strategy, particularly for elderly subjects.
Later in the course, however, dopamine agonists may be useful as adjunctive medications to prolong the antiparkinsonian effects of levodopa and thereby alleviate end-of-dose deterioration (the “wearing-off” effect). This is particularly true of pergolide, which has a longer duration of action than bromocriptine. At the same time, the addition of pergolide or bromocriptine usually permits a reduction in levodopa dosage, thereby reducing the frequency and severity of peak dose dyskinesias and other adverse effects. Pergolide, often in small doses, may also be effective in reducing pain or dystonia during “off” periods in patients with motor fluctuations and may be similarly effective for painful dystonic cramping that occurs during exercise.
As a general rule, it is recommended that bromocriptine be started at a dose of 1.25 mg at bedtime for several days and then increased by 1.25 mg, in divided doses, every 3 to 7 days until optimal results are achieved. However, a simple three-step method of dose titration (2.5 mg qd for 3 weeks, followed by 2.5 mg tid for 3 weeks and then 5 mg tid) may achieve similar results. No significant difference was noted in efficacy or side effects when this regimen was compared with a more gradual dose titration in elderly subjects.17 Doses in excess of 15 mg qd in the elderly tend to result in more significant side effects and more frequent drug withdrawal and have marginal if any therapeutic advantage over lower doses.18
Pergolide is available in three tablet sizes (0.05 mg, 0.25 mg, and 1.0 mg), 1.0 mg being approximately equivalent to bromocriptine 10 mg. The dose should be increased slowly over several weeks, starting with 0.05 mg qd, advancing to a tid schedule, and then switching to the 0.25-mg tablet once the total daily dose reaches about 0.75 mg. Occasionally, patients may experience a transient worsening of PD symptoms when therapy is initiated; this is attributed to preferential D2 autoreceptor stimulation at low agonist doses. Although the average daily dose of pergolide is 3.0 mg, older patients are more likely to experience adverse effects at doses above 1.5 mg/day. These complications, noted also with bromocriptine, include both hypotension and central effects such as restlessness, hypomania, anxiety, panic attacks, and psychosis, and may be seen even in cognitively intact patients.
Pergolide may be more effective than bromocriptine for longer periods of time19 and may be effective in ameliorating disability in patients who have experienced a waning response to bromocriptine. While some improvement in antiparkinsonian efficacy relative to bromocriptine may be seen when switches are made, this may be purchased at a cost of increased dyskinesias, which may necessitate a reduction in the dose of levodopa. Two recent reports have suggested that pergolide may slow progression of Parkinson’s disease.19 However, sample bias, ceiling effects, and symptomatic effects of the drug may have contributed to the more benign course observed in these subjects, and further studies are required before firm conclusions can be drawn. A theoretical rationale for considering pergolide in elderly patients is provided by the finding of Felton and colleagues that chronic dietary pergolide administered to aged rats resulted in a reduction in the expected age-related loss of both dopamine cell bodies in the substantia nigra compacta and dopaminergic terminals in the striatum.19 This effect was attributed to a reduction in the baseline release of dopamine in response to the D2 agonist effect of pergolide at presynaptic autoreceptors (an action shared by bromocriptine), with resulting reduction in toxic metabolites formed by oxidative deamination of dopamine.
Psychotoxicity and Its Management
There is a broad spectrum of psychiatric complications of levodopa, including depression, euphoria, hypomania, hypersexuality, personality changes, confusion, delirium, night terrors, vivid dreams, nightmares, delusions, and paranoid psychosis and hallucinations. Delusions and hallucinations in PD occur more frequently in the elderly, particularly in patients with dementia, and are almost invariably drug-related. The recent observation that hallucinations substantially increase the need for nursing home placement (see later discussion) emphasizes the importance of addressing this complication adequately. Hallucinations associated with levodopa therapy are typically formed, visual, nonfrightening, and stable for each patient, whereas those associated with anticholinergic medications tend to be less formed, multimodal, and threatening and are frequently accompanied by delirium. Both delirium and visual hallucinations have also been observed as side effects of amantadine.
In managing confusion and psychosis in patients with PD, anticholinergics and amantadine should be withdrawn first, followed by selegiline, which potentiates many of the side effects of other dopaminergic drugs. Direct dopamine agonists should then be tapered and if necessary discontinued over a period of several days to avoid the withdrawal hallucinations that may accompany abrupt withdrawal of these drugs. Finally, the dose of levodopa, the most effective antiparkinsonian agent, may have to be cautiously reduced. If troublesome hallucinations persist, or if there is an unacceptable increase in parkinsonism, treatment with clozapine should be considered.20
Clozapine is an atypical neuroleptic that acts primarily to block limbic D4 dopamine receptors, its lack of significant D2 receptor blockade accounting for its low incidence of antiparkinsonian side effects. A low starting dose (6.25 mg qd) should be used in older patients, who are more prone to initial sedation. The dose is increased over several weeks according to response, 50 to 75 mg qd usually being sufficient to control symptoms. In view of a small risk of agranulocytosis, weekly white blood cell counts are mandatory for all patients receiving clozapine. This cost, while high, is nevertheless small compared with that of nursing home care.
Olanzapine is another atypical antipsychotic drug, with a high affinity for dopaminergic and serotonergic receptors, that appears promising as a treatment of dopaminergic psychosis in patients with PD, at doses between 1 and 15 mg/day.21 The clinical profile of olanzapine is comparable to that of clozapine, but it does not produce granulocytopenia.
A variety of anticholinergic drugs may contribute to psychotoxicity in PD, including the tricyclic antidepressants. In selected patients, amitriptyline or imipramine may be useful in low doses at bedtime to improve sleep and anticholinergic-responsive parkinsonian symptoms, such as tremor and dystonic cramping. In older patients with cognitive impairment, an alternative tricyclic with less anticholinergic activity, such as nortriptyline or desipramine, may be preferable. Caution should be used with “peripherally” acting anticholinergics such as oxybutynin and propantheline, which are often prescribed for urinary frequency and urgency in patients with PD (see later section, Urinary Symptoms).
Autonomic Dysfunction and Its Management
Constipation, described by James Parkinson in his original paper, remains one of the most frequent autonomic-related symptoms in patients with PD. The cause is likely to be multifactorial, possible factors including lack of dietary fiber, inadequate fluid intake, diminished physical activity, aging, and the effect of antiparkinsonian medications, particularly anticholinergic agents and amantadine. In addition, primary degeneration of colonic neurons in the myenteric plexus occurs in PD, which results in impaired colonic muscle contraction and slowed stool transit time. Megacolon and sigmoid volvulus may also occur.
In a separate syndrome, some parkinsonian patients, particularly those with more advanced disease, suffer a dyssynergy of pelvic floor muscle contractions (anismus), which prevents rectal emptying. In these patients, attempts to defecate produce contraction rather than relaxation of the striated anal sphincter. The prevalence of this condition is unknown. The powerful dopamine receptor agonist apomorphine (not available in the United States) has been shown to alleviate anismus in some PD patients. Botulinum toxin injection into the anal sphincter has also been suggested as a possible treatment for refractory cases.
In the initial management of constipation, a high-fiber diet (40 to 70 g of fiber per day, contained in raw vegetables such as carrots, cauliflower, and broccoli and in cereals such as oat bran), hydration (drinking at least eight glasses of water each day), an exercise program, and regularly scheduled toileting should be encouraged. Anticholinergics, amantadine, and narcotic analgesics should be avoided. Bulk-forming agents, such as bran and psyllium, with or without stool softeners such as docusates, are effective within 1 to 3 days of intake and should be continued daily. Lactulose, 10 to 20 g/day, may benefit some patients. Glycerin suppositories stimulate defecation by causing retention of fluid in the rectum. They are more effective if given before periods of increased gut motility.
Osmotic laxatives such as milk of magnesia and Fleet enemas can be used on an “as needed” basis to manage constipation, with the awareness that chronic use of magnesium and phosphate salts may induce fluid and electrolyte disturbances. Contact-stimulant laxatives—those containing senna (Senokot), cascara, bisacodyl (Dulcolax), and phenolphthalein (Modane)—should also be used judiciously because regular use of such agents over many years may result in a dilated, atonic “cathartic colon.” Mineral oil should probably be avoided in patients with PD, particularly those with more advanced disease, in whom there may be a risk of aspiration.
Cisapride is a relatively new parasympathomimetic agent that has relatively few side effects and may be effective for both gastroparesis (delayed gastric emptying) and constipation in patients with PD. The dose is 10 to 20 mg three times a day before meals.
Up to 70% of patients with PD experience urinary symptoms. Nocturia, frequency, and urge incontinence are often symptomatic of the autonomic disturbance associated with PD, while more pervasive urinary symptoms, particularly obstructive ones (hesitancy, retention, slowing of stream, postvoid dribbling) require exclusion of prostatic hypertrophy and other neurogenic conditions. It is therefore important for PD patients with urinary dysfunction to have an adequate urologic evaluation. In the individual case, this may require recording of bladder and sphincter pressures, sphincter electromyography, and fluoroscopy.
Urodynamic studies in parkinsonian patients with urinary complaints reveal that 60% to 90% have detrusor hyperreflexia, which is manifested by inappropriate bladder contractions at low bladder volumes. Nocturia is the most common and usually the earliest symptom and can often be alleviated by simply eliminating the intake of liquids after the evening meal. If this intervention is ineffective, peripherally acting anticholinergic agents such as oxybutynin (5 to 10 mg) or propantheline (7.5 to 15 mg) at bedtime can be tried. Similar doses may also be effective on a tid basis for daytime frequency but carry a high risk of side effects in the elderly. If anticholinergics prove ineffective, the parasympatholytic drug hyoscyamine is worth a trial, using a dose of 0.15 to 0.30 mg at night or on a qid schedule. Refractory symptoms may respond to desmopressin, administered as an intranasal spray (DDAVP) at night in incremental doses (usually 10 to 20 µg).
Less commonly, urinary frequency and incomplete bladder emptying occur in patients with PD as a result of weak or absent bladder contraction due to detrusor areflexia or hyporeflexia. Anticholinergic medications may precipitate or aggravate this condition. Non-drug-related detrusor hypoactivity, documented by cystometric studies, may respond to alpha-adrenergic blocking agents such as prazosin or doxazosin, which decrease tone in the bladder neck. Such drugs commonly exacerbate or induce orthostatic hypotension and should be initiated in low doses at bedtime, and blood pressure should be closely monitored. In other patients, urinary hesitancy or retention coincide with motor fluctuations, which usually occur during “off” periods and improve during “on” periods. Treatment with the cholinergic agent bethanechol (at a starting dose of 25 mg every 6 hours) has been recommended for this condition, although evidence of its benefit in controlled studies in PD is lacking. A bedside commode should be provided and a voiding schedule designed to coincide with periods of improved motor function.
There is a subgroup of patients with documented hyperreflexia of the external sphincter for whom drugs that relax striated muscle, such as diazepam, baclofen, or dantrolene, can occasionally be effective. For PD patients with both obstructive symptoms and clinical evidence of prostatic hypertrophy, surgery should be considered only if bladder outlet obstruction can be demonstrated with urodynamic studies because there is a relatively high risk of postsurgical incontinence. Patients with deficient voluntary control of the external urinary sphincter are at especially high risk for this complication.22 Therapeutic options for incontinence include an external collection device, incontinence pads, or an indwelling catheter.
Patients with PD tend to have a lower resting blood pressure than the general population and a greater tendency toward orthostatic hypotension. This is likely to be due to a combination of dopaminergic therapy and disease-related factors. Relevant pathologic changes in PD involve the hypothalamus as well as lower levels of the autonomic nervous system, with loss of the preganglionic sympathetic neurons in the intermediolateral column of the spinal cord and Lewy body inclusions in the autonomic ganglia. Prior to the advent of levodopa, however, patients with PD rarely developed orthostatic symptoms. Severe orthostatic hypotension, particularly early in the disease course and in those with relatively mild parkinsonism, should suggest the Shy-Drager syndrome (see earlier section, The “Parkinsonism Plus” Syndromes).
Orthostatic hypotension may be dramatic when dopaminergic therapy is initiated in the parkinsonian patient, particularly in the elderly. This complication can generally be avoided by administering low doses of dopamine agonists at bedtime and then slowly titrating the dose upward. In patients with more advanced PD, symptoms of orthostatic hypotension may be alleviated by reducing the dose of levodopa, dopamine agonists, or selegiline, or by using supplemental carbidopa (Lodosyn, obtained directly from the manufacturer, Merck, Sharpe and Dohme).
In the patient who has an exaggerated increase in pulse with standing, hypovolemia should be suspected and reversible medical causes, such as dehydration, anemia, medication effect (e.g., from diuretics and other antihypertensive agents), and hypoadrenalism excluded. Nonpharmacologic approaches to the management of orthostatic hypotension should include avoidance of hot weather, hot baths, and alcohol, which produce peripheral vasodilatation, and avoidance of large meals, which may redirect blood flow to the splanchnic circulation. It is important to offer advice to patients about techniques of using an adjustment period prior to standing, consisting of sitting up and contracting the muscles of the legs for a few minutes. Regular isotonic exercises and graded physical activity may improve orthostatic tolerance as well as overall fitness. Elastic hip-high stockings prevent pooling of blood in the lower extremities and have been shown to increase venous return but frequently must be applied by a caregiver and may be poorly tolerated, especially in the summer months. Elevation of the head of the bed by 8 to 12 inches at night induces a mild hypotensive stress when the patient is recumbent, reducing renal perfusion and thereby promoting renin release and retention of sodium and water. Dietary salt may have to be liberalized, and this maneuver may be augmented by the use of salt tablets, up to 2 g/day.
When these measures are insufficient, the potent mineralocorticoid fludrocortisone is often helpful for managing orthostatic hypotension. At low doses (0.1 mg qd), fludrocortisone enhances the vasoconstrictor response to norepinephrine, and at higher doses (0.2 to 1.0 mg qd) it promotes retention of sodium, thereby expanding extracellular volume. Potential adverse effects, which necessitate close monitoring, include supine hypertension, congestive heart failure, peripheral edema, and hypokalemia. The prostaglandin inhibitor, indomethacin, at a dose of 25 mg tid, is not as effective as fludrocortisone but is better tolerated.
Management of Sialorrhea
Most common in the later stages of the disease, sialorrhea (drooling) is caused not by an excessive production of saliva but by a reduction in automatic or conscious swallowing, thus representing a hypokinetic phenomenon. Despite their potent effect on other akinetic symptoms, dopaminergic agents are frequently only partially effective in managing sialorrhea. In this situation, low doses of a centrally acting anticholinergic agent may serve the dual purpose of reducing saliva production and ameliorating other parkinsonian symptoms. Benztropine (Cogentin) or trihexyphenidyl (Artane) should be started at doses of 0.5 mg and 1 mg, respectively, at bedtime and gradually increased, using a bid or tid dosing schedule, to a total dose that should generally not exceed 2 and 4 mg, respectively, in older subjects. If these drugs produce unacceptable central side effects, peripherally acting anticholinergic agents such as oxybutynin (5 mg every 8 hours) or propantheline (7.5 to 15 mg every 6 hours) may be tried. The usefulness of these drugs may also be limited, however, by such side effects as constipation, urinary hesitancy or retention, visual blurring (due to impaired pupillary constriction), and tachycardia. In comparison, methscopolamine bromide (Pamine) at a dose of 2.5 mg bid or tid has fewer anticholinergic side effects and may be a useful alternative for some patients. Papaya extract from a health food store may also be tried to decrease saliva production. For extreme cases of sialorrhea that do not respond to drug therapy, a portable suction catheter apparatus may have to be considered.
Management of Seborrhea
Excessive secretion of oil by the sebaceous glands is common in PD. Coal tar or selenium-based shampoos used up to once or twice weekly, may be effective for dandruff as well as for seborrhea affecting the eyebrows and forehead. Daily topical hydrocortisone is also effective, particularly for the face, but its use should be monitored by a dermatologist.
Management of Balance and Gait Difficulties
Just as a variety of strategies other than drugs must be considered in the management of orthostatic hypotension, nonpharmacologic aids are central to the management of certain balance and gait difficulties that emerge later in the course of PD and are poorly responsive or nonresponsive to dopaminergic therapies. Strategically placed rails, particularly in bathrooms and showers, provide support as well as assistance with standing. Physical therapy and gait training may be beneficial and can be aided by certain motor and sensory tricks. Start hesitation, for example, can be ameliorated by encouraging the patient to rock or march in place to initiate gait. The use of another person’s foot or an inverted or adapted walking stick23 (fitted with a low projecting arm) can reduce start hesitation or sudden transient freezing by providing the patient with a visual target over which to step. Parallel stripes marked on the floor provide a similar target and may be particularly useful in frequently traveled areas such as the bedroom and bathroom. In some cases, the mere imagining of a line to step over may be sufficient to interrupt freezing. For patients who experience freezing or balance impairment when turning, the strategy of walking around turns may significantly improve gait and reduce falling. The use of a quadrapod or walker may also help to compensate for postural instability but will not protect against spontaneous retropulsion in the later stages of the disease. The assistance of a caregiver or use of a wheelchair will then be necessary to aid mobility and prevent injury from falls.
INSTITUTIONALIZATION IN PARKINSON’S DISEASE
Based on 1985 utilization statistics in the United States and a survey of 40 Norwegian nursing homes, 2% to 5% of nursing home residents have PD.24 Neither motor disability nor cognitive impairment are significant risks for nursing home placement, suggesting that these impairments may be managed adequately by community caregivers and other support systems. In contrast, hallucinations represent a significant risk factor for permanent nursing home placement, highlighting the importance of this challenging but potentially treatable complication of advanced PD.24
LIFE EXPECTANCY IN PARKINSON’S DISEASE
Epidemiologic studies in both Italy and the United States have shown a change in age-specific mortality for patients with PD in recent decades. There has been a substantial decline in mortality among the middle-aged and a notable increase in mortality in the geriatric age groups (75 years and older). Several factors may contribute to these changes, including a possible reduction in the prevalence of PD in middle life or an increase in the incidence of PD among the elderly, better case ascertainment in the elderly, a decrease in earlier deaths from other competing causes, and improved treatment of PD.
The survival rate of patients with PD improved considerably following the introduction of levodopa in 1967. Indeed, it has been estimated that the median duration of illness, at each stage of the disease, is 3 to 5 years longer in levodopatreated patients than in those not receiving this medication. Nevertheless, survival of PD patients in the levodopa era is still significantly poorer than that of the general population. After adjusting for age and sex, parkinsonism is associated with a twofold increase in the risk of death, and this risk is strongly related to the presence of a gait disturbance.25 An important difference from the general population is the higher incidence of death due to bronchopneumonia in PD patients. Other common causes of death in PD patients are atherosclerotic heart disease, malignant neoplasms, stroke, and urinary tract infections.
Improved survival in PD is associated with a higher 10-year expected survival (based on age, gender, and birth year), absence of dementia, diagnosis of idiopathic PD as opposed to other causes of parkinsonism (e.g., progressive supranuclear palsy or multiple system atrophy), and less severe parkinsonism (Hoehn and Yahr stage 1 or 2) at the initial neurologic visit. In addition, a retrospective study has suggested that treatment with amantadine, an antagonist of the N-methyl D-aspartate (NMDA) receptor (see earlier section), may be an independent predictor of improved survival in PD.26 A prospective controlled randomized trial of the effect of amantadine or an alternative NMDA antagonist on PD progression will be required to address this finding definitively.
Newman RP, LeWitt PA, Jaffe N, Calne DB, Larsen TA: Motor function in the normal aging population: Treatment with levodopa. Neurology 1985;35:571–573.
Langston JW, Koller WC, Giron LT: Etiology of Parkinson’s disease. In Olanow CW, Lieberman AN (eds): The Scientific Basis for the Treatment of Parkinson’s Disease. Park Ridge, NJ, The Parthenon Publishing Group, 1992, pp. 33–58.
Agid Y: Parkinson’s disease: Pathophysiology. Lancet 1991;337:1321–1324.
Calne DB: The free radical hypothesis in idiopathic parkinsonism: Evidence against it. Ann Neurol 1992;32:799–803.
Broe GA: Antiparkinsonian drugs. In Swift C (ed): Clinical Pharmacology in the Elderly. New York, Marcel Dekker, 1987, pp. 473–509.
Gibb WR, Lees AJ: A comparison of clinical and pathological features of young and old onset Parkinson’s disease. Neurology 1988;38:1402–1406.
Friedman JH: Drug-induced parkinsonism. In Lang AE, Weiner WJ (eds): Drug-Induced Movement Disorders. Mount Kisco, NY, Futura Publishing, 1992, pp. 41–83.
Avorn J, Gurwitz JH, Bohn RL, et al: Increased incidence of levodopa therapy following metoclopramide use. JAMA 1995;274:1780–1782.
Nutt JG, Marsden CD, Thompson PD: Human walking and higher-level gait disorders, particularly in the elderly. Neurology 1993;43:268–279.
Hoehn MM: Result of chronic levodopa therapy and its modification by bromocriptine in Parkinson’s disease. Acta Neurol Scand 1985;71:97–106.
Robertson DRC, George CF: Drug therapy for Parkinson’s disease in the elderly. Br Med Bull 1990;46:124–146.
Yeh KC, August TF, Bush DF, et al: Pharmacokinetics and bioavailability of Sinemet CR: A summary of human studies. Neurology 1989;39 (Suppl 2):25–38.
Parkinson Study Group: Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP subjects not requiring levodopa. Ann Neurol 1996;39:29–36.
Parkinson Study Group: Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa. Ann Neurol 1996;39:37–45.
Lees AJ, on behalf of the Parkinson’s Disease Research Group of the United Kingdom: Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson’s disease. Br Med J 1995;311:1602–1607.
MacMahon DG: The use of selegiline in elderly patients: Current indications and future potential. Rev Contemp Pharmacother 1992;3:77–85.
MacMahon DG, Overstall PW, Marshall T: Simplification of the initiation of bromocriptine in elderly patients with advanced Parkinson’s disease. Age Ageing 1991;20:146–151.
The Bromocriptine Multicenter Trial Group: Bromocriptine as initial therapy in elderly parkinsonian patients. Age Ageing 1990;19:62–67.
Sage JI, Duvoisin RC: Pergolide. In Koller WC, Paulson G (eds): Therapy of Parkinson’s Disease, 2nd ed. New York, Marcel Dekker, 1995, pp. 249–259.
Friedman JH, Lannon MC: Clozapine in the treatment of psychosis in Parkinson’s disease. Neurology 1989;39:1219–1221.
Wolters ECh, Jansen ENH, Tuynman-Qua HG, Bergmans PLM: Olanzapine in the treatment of dopaminomimetic psychosis in patients with Parkinson’s disease. Neurology 1996;47:1085–1087.
Staskin DS, Vardi Y, Siroky MB: Post-prostatectomy continence in the parkinsonian patient: The significance of poor voluntary sphincter control. J Urol 1988;140:117–118.
Dietz MA, Goetz CG, Stebbins GT: Evaluation of a modified inverted walking stick as a treatment for parkinsonian freezing episodes. Mov Disord 1990;5:243–247.