Paul S. Fishman
Tremor and Other Abnormal Movements
Definition and Classification of Tremor
Tremor is defined as the involuntary rhythmic or oscillatory movement of a body part, resulting from alternating contractions of antagonistic muscle groups. Tremor is conveniently classified by its relationship to the conditions of rest, postural maintenance, and movement (kinetic or intention tremor). Accurate classification of tremor type is important because each points to a group of specific underlying conditions (Table 90.1), with specific therapy. Several conditions will have tremor that is related to more than one state (resting/action) so that it is useful to note the state where the tremor is most prominent.
Other Abnormal Movements
Tremor can usually be distinguished by its rhythmicity, but can be confused with other abnormal movements. The most basic abnormal movement is myoclonus. This is a brief twitch or jerk of a single muscle or muscle group. Such a movement can be normal, such as the myoclonic jerk associated with the early stages of sleep. When occurring repetitively throughout many muscle groups, they are frequently a sign of an underlying metabolic encephalopathy. In this setting myoclonus usually coexists with asterixis (sometimes referred to as negative myoclonus). During asterixis, there is a sudden pause in muscle activity with a brief loss of posture. Myoclonus may be repetitive but is usually not rhythmic. The rare forms of repetitive
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myoclonus are more commonly confused with focal motor seizures than tremor because of their twitch-like quality. Patients who survive hypoxic/ischemic brain injury can later develop myoclonic jerks with action or intention movements of the limb. This form of action, myoclonus, can be confused with an intention type tremor (1). In patients with metabolic encephalopathy or degenerative diseases of the brain myoclonus and tremor can coexist.
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TABLE 90.1 Conditions Associated with the Three Major Types of Tremor |
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Chorea refers to brief rapid distal movements. These jerky movements are more complex than myoclonus, usually involving a small group of muscles in rapid succession rather than simultaneous activation. The speed and duration of chorea is variable, and these movements usually coexist with slower proximal writhing movements called athetosis. The best descriptions of choreoathetosis come from patients with Huntington disease, but these movements can occur with injury to the basal ganglia associated with other conditions such as stroke, acquired immunodeficiency syndrome, systemic lupus erythematosus (SLE), after streptococcal infection (Sydenham chorea) and chronic neuroleptic exposure (tardive dyskinesia). Dramatic, vigorous, flinging movements are termed ballism and can be viewed as an extreme form of chorea and are seen particularly after injury to a small basal ganglia center called the subthalamic nucleus (2).
Sustained abnormal posture is referred to as dystonia. Dystonia can occur throughout the body (generalized) commonly on an inherited basis, but is usually restricted to a specific body part (focal dystonia). Cervical dystonia, also called spasmodic torticollis or wry neck, is the most common focal dystonia characterized by intermittent or constant abnormal twisting of the neck (3). Tremor is commonly observed superimposed on a dystonic posture. Focal dystonia can also be provoked by specific movements (action dystonia). The involuntary muscle contraction of writer's cramp is the most common action dystonia (4). Other common focal dystonias include blepharospasm (involuntary spasm of the eyelids), hemifacial spasm, and spasmodic dysphonia with involuntary laryngeal spasms that interrupt speech (5, 6, 7).
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TABLE 90.2 Principal Features of Different Tremor Types |
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Tics are repetitive rapid movements distinguished from chorea by their stereotyped pattern. They can be distinguished from tremor by their lack of rhythmicity, erratic appearance in different body parts, complexity of movement, and onset in childhood or adolescence. Persistent multiple tics with vocalizations are the features of Tourette syndrome (8). Tics are often preceded by a buildup of inner tension that subsides after the tic. Patients may be able to temporarily suppress a tic, whereas most other abnormal movements usually lack such a degree of voluntary control. Complex repetitive movements that can be clearly voluntarily suppressed or interrupted are referred to as mannerisms.
Evaluation of the Patient with Tremor
The history and physical examination are fundamental in the diagnosis of tremor (Table 90.2), and in almost all cases no further workup is necessary. The differential diagnosis, in general practice, is almost always between Parkinson disease (PD) and essential tremor (ET). Most patients with tremor and other movement disorders do not have any specific abnormality on laboratory investigation (including imaging).
History
Important historical information includes the temporal onset of the tremor, associated neurologic symptoms, family history, a survey of medications and other medical illnesses, and whether the tremor is suppressed by alcohol. Almost all varieties of tremor increase in amplitude under stress, diminish with relaxation, and disappear during
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sleep. The impact of the tremor on the patient determines whether treatment is indicated. Some patients do not find their tremor disabling and seek medical attention only for diagnostic purposes. Young patients with ET may need only reassurance that they do not have PD or another degenerative disorder. However, most patients find the tremor physically or emotionally problematic.
Emphasis should be placed on the activities of daily living (ADLs). Patients with tremor typically have trouble with tasks requiring fine motor control such as buttoning, feeding, shaving, brushing their teeth, writing, and cooking. Embarrassment is often an unvoiced source of disability, and patients should be questioned about social isolation caused by the tremor. The ADLs also provide objective parameters for judging the effectiveness of therapy.
Physical Examination
The objectives of the physical examination are to determine the frequency, severity, and conditions of maximal activation of the tremor and to search for associated neurologic signs. Patients should be examined with their hands resting on their laps, with their arms held outstretched, and while performing finger-to-nose maneuvers. Samples of handwriting and a drawing of a spiral should also be obtained as an objective means of following response to therapy. Observations while the patient is drinking from a cup or using a fork or spoon are also helpful in assessing functional impairment.
The resting tremor of parkinsonism is characterized by 3- to 6-Hz flexion–extension at the metacarpophalangeal joints, abduction–adduction of the thumb, and pronation–supination of the forearm; these produce the so-called pill-rolling tremor. Resting tremor is often brought out by having the patient walk or by distracting the patient with conversation or mental arithmetic. Early in its course, the parkinsonian tremor is almost always unilateral, which is one of the most helpful signs distinguishing it from ET. ET almost always begins bilaterally, although it may be asymmetric.
Postural tremor is characteristic of ET and consists of 6- to 12-Hz symmetric flexion–extension at the wrists and shoulders. It is brought on by having the patient assume an antigravity posture of the upper extremities (e.g., outstretched arms), and it is not present when the arms are resting against the body or on a surface. ET may persist during finger-to-nose testing, leading to the misdiagnosis of a cerebellar tremor.
Kinetic tremor (also called intention tremor) is encountered most commonly in cerebellar disease and is characterized by 3- to 5-Hz irregular oscillations as the limb approaches a target. This type of tremor is often accompanied by inaccuracies in direction (dysmetria). In acquired cerebellar diseases, such as stroke and multiple sclerosis, kinetic tremors are often asymmetric, whereas degenerative diseases involving the cerebellum usually produce bilateral symmetric tremor. Conditions that may mimic this aspect of cerebellar disease include severe ET (which may impair purposeful movements) and conditions producing severe proprioceptive loss. Unlike patients with PD or ET, patients with cerebellar impairment rarely present complaining only of tremor. Additional signs pointing toward the cerebellum include gait ataxia, dysarthria, and nystagmus (9).
Generally, it is difficult to estimate the rhythmic frequency of a tremor in a clinical setting. Tremors are commonly described as “fine” or “coarse”—a nonuseful composite of frequency and amplitude. Particularly for ET, it is useful to attempt to rate the severity of tremor by its peak to peak amplitude (severe, greater than 1 to 2 cm). This aspect is most clearly related to both disability and response to treatment. Tremor frequency can be accurately assessed using electromyography (EMG), but can also be assessed with an office form of accelerometry. Using an electrocardiogram solely as a calibrated paper recorder, the patient attempts to make a straight line with a marker pen on the moving paper. The number of oscillations drawn in each marked second gives the tremor frequency.
Physiologic and Exaggerated Physiologic Tremor
Most people have a barely perceptible postural tremor, so-called physiologic tremor, that may be best appreciated by placing a piece of paper over the outstretched hands. Although asymptomatic, this tremor may be transiently exacerbated during systemic illness, metabolic derangements, stress, and by the use or withdrawal of certain drugs or alcohol (Table 90.1). The most important step in management is identification and removal of the offending cause; resolution of the tremor confirms the diagnosis of exaggerated physiologic tremor. Although discontinuation of tremorogenic drugs usually leads to prompt resolution of the tremor, it may take 1 to 2 weeks for the tremor to resolve after resolution of a systemic illness or a severe metabolic abnormality. It is difficult to distinguish an enhanced physiologic tremor from mild ET. The proof of this diagnosis rests on the resolution of the tremor. If the underlying condition cannot be eliminated (e.g., in patients requiring lithium for manic-depressive illness), the tremor can often be suppressed using medications for ET. For patients subject to situational anxiety manifested by exaggerated physiologic tremor, prophylactic treatment with propranolol (20 to 40 mg) taken 1 hour before an anxiety-producing situation (e.g., public speaking) may be helpful (10).
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Essential Tremor
Characteristics
ET is the most common form of postural or kinetic tremor with prevalence of 4% to 6% (11). Estimates of the prevalence of ET are limited by the fact that most patients do not seek treatment for their condition and remain undiagnosed. Although it has been assumed that these undiagnosed patients are only mildly affected, there is recent evidence that the majority of these patients suffer both distress and disability from ET (12). ET is synonymous with familial tremor, benign ET, and senile tremor when it occurs in the elderly. No neuropathologic abnormalities have been identified in ET, but physiologic evidence suggests that both the central and peripheral nervous systems are involved. The onset is insidious and may begin as early as childhood, but ET characteristically presents in adulthood, usually after age 50 years with both incidence and prevalence rising with age. Unlike the tremor of PD, which typically makes the patient seek medical attention within months of its onset, patients with ET often give a history of tremor going back many years. At least 50% of patients with ET give a positive family history; the inheritance is autosomal dominant. Patients with a positive family history are more likely to have a younger age at onset. Genetic linkage studies have identified at least two susceptibility loci with recent identification of a mutation in a neuronal protein (13).
In its prototypical form, ET is characterized by a bilateral and symmetric tremor of the hands, but it may also affect other body parts either in isolation (commonly the head or voice) or combined with a hand tremor. At least half of patients with ET notice a beneficial effect from small amounts of alcohol (14). Although its regular use to suppress tremor should be discouraged, when used sparingly alcohol is an effective treatment for ET, particularly when exacerbated by situational stress. There does not seem to be an increased prevalence of alcoholism among patients with ET (15). ET is a progressively worsening disorder with the tremor gradually increasing in severity, spreading to other body regions (usually hands to head) and occurring at rest along with movement.
Treatment
When ET begins to interfere with the ADLs or causes significant embarrassment, treatment is indicated. Before starting medication, patients should be told that the goal of treatment is not to abolish the tremor, which is rarely possible, but instead to reduce its severity and allow them to function better. The patient's ADLs should be used as a gauge to determine the effectiveness of treatment. As with exaggerated physiologic tremor, treatment begins with elimination of potentially exacerbating factors, including stimulant drugs and medication. ET also has a consistent relationship to exercise where education may help in its control (16). The tremor is worsened directly after vigorous physical exercise of the involved limb due to fatigue, but is also more problematic if exercise is entirely avoided and the involved muscles become deconditioned. Some prosthetic devices, such as handwriting aids, are useful in reducing the disability of ET, particularly for patients who tolerate medications poorly (17).
The two medications most effective for ET are propranolol and primidone. The drugs are equally effective and may be synergistic, but only propranolol is U.S. Food and Drug Administration (FDA)-approved for this indication (18).
Propranolol is started at 10 mg twice per day in elderly patients and gradually increased, depending on the beneficial response and appearance of side effects, to a maximum of 320 mg/day. Once a stable dosage has been reached, patients can be converted to a long-acting form. In younger patients, treatment can be started with the controlled release form (60 mg) with a gradual escalation of the dosage. Although other β-blockers have also been shown to be effective for ET, none is superior to propranolol (19,20). Newer β-blockers have the advantage of being β1 selective and therefore safer to use in patients with ET and asthma, but at the higher dosages usually needed, β1selectivity is diminished. In general, β-blockers should be avoided in the presence of bronchospastic disease, second- or third-degree heart block, or insulin-dependent diabetes.
Primidone, a barbiturate-like anticonvulsant, was found by serendipity to improve ET. The mechanism of action of primidone is unknown, but its effect does not appear to result from either of its metabolites, phenylethylmalonamide and phenobarbital (21). Primidone is available as scored tablets in two strengths, 50 and 250 mg. The starting dosage must be very low (e.g., 25 milligrams per day) because occasional patients (5% to 10%, especially the elderly) develop severe side effects after even a single small dose, known as the first-dose phenomenon. Symptoms include dizziness, lethargy, confusion, nausea, sedation, and ataxia, which usually diminish with continued use. The dose is initially given at bedtime and then gradually escalated to a maximum of 250 mg three times per day as tolerated. In general, if patients show no response to low dosages (250 mg/day), it is rare for higher dosages to be effective. If patients tolerate primidone initially, long-term use is well tolerated and may be superior to propanolol (22).
If there is a beneficial but suboptimal response to either propranolol or primidone used alone, the two should be combined beginning at low dosages and increasing in small increments, watching carefully for side effects,
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particularly in elderly patients. Blood levels of primidone or phenobarbital are not helpful (unless toxicity or noncompliance is suspected) because they do not correlate with its tremor-suppressing effect.
Generally, patients who fail to respond to propanolol or primidone have a poor chance of success with other drugs. Although benzodiazepines have been widely prescribed for ET, the clinical trial experience with these drugs has been mixed at best. It has been difficult to assign an anti-tremor affect to these agents independent of their anxiolytic effect (23).
The most useful of the benzodiazepines is alprazolam, which has been shown to be effective in the treatment of ET (24). The maintenance dosage is 0.75 to 3.0 mg/day, in divided doses. Its rapid onset of action and intermediate half-life, in comparison with other benzodiazepines, allow for its intermittent use when situational stress temporarily exacerbates ET. Several of the newer anticonvulsant medications have been evaluated for ET and can be viewed as second-line medical therapy. Although gabapentin has been most extensively studied, the experience has been mixed (25,26). Topiramate has shown efficacy in small placebo controlled trials, while there is some promising open-label data using levetiracetam, an anticonvulsant that is useful to suppress some forms of myoclonus (27, 28, 29).
Intramuscular injection of botulinum toxin, the standard treatment of focal dystonia, has been used to treat ET as well. Treatment of ET involving the hands is difficult to achieve without causing perceptible weakness (30,31). Botulinum neurotoxin has been of greatest use in suppression of tremor of the head, a condition that is both socially distressing and frequently medication resistant (32).
Stereotactic ablation of the ventralis intermedius (VIM) nucleus of the thalamus has long been accepted as the most effective treatment of severe or disabling ET (33). Effective to dramatic reduction of ET (80% to 90% decrease in amplitude) has also been demonstrated after VIM implantation of a high-frequency stimulation device (34). These devices, which cause deep brain stimulation (DBS), are FDA-approved for implantation into the thalamus for control of tremor associated with either ET or PD. Implantation of a thalamic deep brain stimulator has a slightly lower risk of neurologic deficit than thalamotomy but is a more extensive procedure requiring surgical placement of the pacemaker-like device in the chest and a continuing risk of device or lead malfunction (35,36). Deep brain stimulator placement is generally preferred over standard thalamotomy, although the older procedure may be more suitable for specific patients. Although the risk of serious morbidity is relatively low (less than 5%), patients referred for stereotactic surgery should first have an adequate trial of medication to control ET.
The atypical neuroleptic clozapine has also shown efficacy in refractory cases of ET. This drug is worth considering despite its potential to cause agranulocytosis, because its risk is lower than that of surgery for treatment of ET (37,38).
Tremor Caused by Cerebellar Dysfunction (Kinetic or Intention Tremor)
Tremor is rarely the sole presenting sign of cerebellar dysfunction, and most often the underlying disease is already known or readily apparent (multiple sclerosis, stroke, drug intoxication, long-standing alcoholism, head trauma, inherited disease, or paraneoplastic syndrome). Paraneoplastic syndromes involving the cerebellum are of particular concern with the presentation of tremor and ataxia over a few weeks or months, since brain imaging is frequently unremarkable and these systemic malignancies (usually breast, ovarian, small cell, or lymphoma) are usually occult (39). Occasionally, severe ET may be exacerbated with action, giving the impression of cerebellar disease, but the faster frequency, prominent postural component, and lack of associated cerebellar signs usually suffice to distinguish the ET from cerebellar dysfunction (40).
With the exception of drug-induced cerebellar tremor (Table 90.1), which should be managed by discontinuation or reduction of the dosage of the offending drug, a patient with newly diagnosed cerebellar tremor should be referred to a neurologist. Cerebellar tremors in general respond poorly to medication, which may also reflect the fact the tremor is intimately related to poor control of ballistic movements. Relatively small trials of clonazepam, carbamazepine, and isoniazid have shown some efficacy for cerebellar tremor (41). As with severe ET, there is a role for an occupational therapist. Weighted bracelets have had some benefit in dampening the tremor, and specialized devices to aid in writing and feeding are useful. Computer-controlled tremor damping gloves are under investigation to control severe ataxic tremor. As is the case with severe ET, stereotactic thalamotomy is a viable option for disabling cerebellar tremor (42).
Primary Writing Tremor and Orthostatic Tremor
Two uncommon but distinct types of tremor are primary writing tremor (43) and orthostatic tremor (44). Primary writing tremor is one variant of a group of task-specific tremors. These are characterized by maximal activation during a specific task. Primary writing tremor occurs exclusively when patients attempt to write. It probably is related to ET but may share some features in common with focal action dystonias, such as writer's cramp. Writing tremor may respond to drugs used to treat ET
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(see Essential Tremor, Treatment) or treatments of action dystonias such as anticholinergics, clonazepam, or botulinum therapy. Primary orthostatic tremor is characterized by rapid shaking of the legs, only with standing, and may respond to clonazepam (0.5 to 3.0 mg/day). Recent studies suggest that many patients with this syndrome have other extrapyramidal findings as well.
Parkinson Disease and “Parkinsonism”
Epidemiology
PD is one of the most common neurologic diseases in the ambulatory setting. Approximately 1 million persons are affected in the United States, with an annual incidence of 18 per 100,000. In general, PD increases in incidence with age, with an average age at onset of 60. The incidence of PD appears to decline in the very old. This observation, along with the increasing incidence of essential (senile) tremor and other extrapyramidal symptoms in the elderly, makes the diagnosis of new-onset PD older than age 80 both difficult and somewhat suspect. Recently, there has been heightened awareness of young-onset PD; up to 5% of PD patients have an age at onset younger than 40 (45).
Pathogenesis
Premature dysfunction and death of dopamine-producing (and neuromelanin-containing) neurons of the substantia nigra is the basis for both the major motor symptoms of PD and its treatment. Along with neuronal loss, the pathologic hallmark of PD is an eosinophilic cytoplasmic inclusion called a Lewy body. Although the cause of PD in most cases is unknown, PD is emerging as the proving ground for theories of the interaction of environmental and genetic factors in neuronal aging and death. The evidence for an environmental basis of PD comes from two sources. In 1983, it was discovered that an impurity in the illegal production of meperidine, called MPTP (methyl-phenyl-tetrahydropyridine), was capable of causing irreversible Parkinson symptoms in abusers who injected the drug (46). MPTP injection can cause similar symptoms in animals along with the death of dopaminergic nigral neurons. The final steps in MPTP toxicity involve impairment of mitochondrial energy generation, suggesting a role for oxidative injury. Epidemiologic studies also support a role for environmental factors in PD. An increased incidence of PD is found in farm workers with long-standing exposure to herbicides and pesticides (47).
Genetic factors also play a role in the development of PD. Five to ten percent of PD patients have an affected first-degree relative. In the last 10 years the first five genes have been identified that are clearly associated with inherited forms of PD. Mutations in the gene for the protein α-synuclein lead to a form of PD, inherited on an autosomal dominant basis (48). Although families carrying these mutations are extremely rare, the role of α-synuclein in both inherited and sporadic PD is first suggested by the observation that α-synuclein is the major component of Lewy bodies (49). Up to 50% of patients with inherited young-onset PD have recessively inherited mutations in the gene for the enzyme parkin involved in the ubiquitin-proteasome pathway for degradation of aberrant cellular proteins (50). DJ1 is a multifunctional protein where mutations also cause recessively inherited young onset PD (51). PINK-1 is a mitochondrial protein mutated in inherited PD, while LRRK2 (Dardarin) mutations are the most common cause of inherited, typical late adult onset PD discovered at this time (52,53). Animal model and cellular studies suggest that cell death in PD is the result of interactions of production of abnormal toxic proteins, proteasomal dysfunction and inadequate elimination of these proteins, and mitochondrial dysfunction with resulting oxidative injury (54).
Differential Diagnosis
The cardinal signs of PD include tremor at rest, bradykinesia, muscular rigidity, and postural instability. Common symptoms along with tremor include impaired handwriting (micrographia); difficulty walking; falling; poor coordination; difficulty arising from a deep chair, couch, or the toilet; drooling; and difficulty turning in bed. When the syndrome is fully developed, the diagnosis is straightforward. Patients where tremor dominates the clinical picture can be confused with ET, whereas patients without a resting tremor are difficult to distinguish from the other atypical parkinsonian syndromes described below.
Four of the parkinsonian syndromes in Table 90.3 deserve special mention because their treatment and prognosis differ. Other clinical clues to these syndromes include the following: early onset dementia, rapid progress, early onset dysarthria or dysphagia, prominent and early dysautonomia, early falling, impaired ocular motility, lower motor neuron, cerebellar or pyramidal signs, and bilaterally symmetrical involvement. A positive family history and little or no response to L-dopa are also suggestive of a parkinsonian syndrome rather than Parkinson disease. Neuroleptic-induced parkinsonism, may be clinically indistinguishable from idiopathic PD and can be diagnosed only retrospectively when parkinsonian signs resolve after discontinuation of the offending drug. In some patients signs may take as long as 1 year to resolve completely, emphasizing the periodic need to reassess antiparkinsonian therapy. In patients whose signs never resolve, it is likely that the neuroleptic simply uncovered a case of latent PD (55).
Progressive supranuclear palsy (PSP) is the most common nonpharmacologic mimic of PD. It is distinguished by impaired vertical eye movements, although early in its
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course ocular motility may be full with the only clinical clue being slow vertical saccades. Other distinguishing features include neck extension as opposed to the flexion seen in PD, early dysarthria and dysphagia, early and prominent balance and gait impairment with associated falls, greater axial than appendicular rigidity (axial dystonia), progression to severe disability in 5 to 10 years, and limited response to antiparkinsonian medications (56,57).
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TABLE 90.3 Differential Diagnosis of Parkinsonism |
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Multiple system atrophy (MSA) is another more widespread neurodegenerative disease with autonomic, cerebellar, and cortical pathology that can mimic PD. A common form of MSA is parkinsonism signs associated with significant autonomic dysfunction (formerly referred to as the Shy-Drager syndrome). Early identification of these patients is important since treatment of their motor features with dopaminergic drugs will commonly worsen their prominent and symptomatic orthostatic hypotension (58).
Wilson disease (hepatolenticular degeneration) is an autosomal-recessive condition characterized by copper accumulation throughout the body. Parkinsonian features in a young patient should prompt an investigation for this condition. Liver disease may be present at the onset of neurologic disease, but normal liver studies should not deter one from pursuing the diagnosis. The diagnosis is confirmed by demonstrating Kayser-Fleischer rings (green or golden deposits of copper in the Descemet membrane of the cornea), low blood ceruloplasmin, and elevated urinary copper excretion. Although a rare cause of abnormal movements, Wilson disease is noteworthy as a potentially reversible cause of parkinsonism. Timely diagnosis and treatment with copper chelating agents such as penicillamine (1 to 2 g/day) can prevent progression and to some extent reverse neurologic signs and symptoms (59).
Manifestations
Resting Tremor
Tremor is the presenting complaint in at least 70% of patients with PD. The tremor is maximal when the limb is at rest and has a frequency of 3 to 6 Hz. It consists of flexion–extension at the metacarpophalangeal joints, abduction–adduction of the thumb, and pronation–supination of the forearm, producing the typical pill-rolling appearance. The tremor may affect the legs, lips, tongue, or chin but virtually never affects the head (a tremor of the head suggests ET). The parkinsonian tremor is accentuated by stress and distraction, diminishes with relaxation, and disappears during sleep. Although there may be an associated postural tremor in PD, typically the resting tremor suppresses with posture and movement, which helps to distinguish it from ET. Classic resting tremor, which abates transiently with movement, is almost never seen with structural damage to the brain such as stroke (60).
Rigidity
Rigidity is a form of abnormal muscular tone or resistance to passive movement. This feeling of resistance is present and unchanged when moving a patient's limb in flexion or extension, regardless of the speed of the movement, and is described as having a “lead pipe” quality. In this manner, rigidity can be distinguished from spasticity, the other major form of abnormal muscle tone. In spasticity, resistance is greater to extension than flexion and is particularly prominent at the onset of a rapid attempt to flex the arm or leg. This quality gives rise to descriptions of spasticity as “clasp knife” or having a “catch.” When the limb of a PD patient is moved passively, there is also a regular ratchet-like quality to the resistance, which gives rise to the term cogwheel rigidity. Deep tendon reflexes are increased in patients with spasticity while they are normal or decreased in parkinsonism rigidity. Patients rarely complain of rigidity per se and instead notice stiffness or describe the abnormal tone as weakness. Cogwheel rigidity is best felt at the elbow, wrist, or neck and may be demonstrated or enhanced by having the patient perform a maneuver with the contralateral limb such as opening and closing the fist or
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drawing a circle in the air. The cogwheeling phenomenon can also be misleading, since patients with nonparkinsonian tremor such as ET may have a similar ratchet-like quality to passive movement, but without the increased resistance in rigidity.
Bradykinesia and Akinesia
Patients with PD have difficulty initiating movements, and their movements are slow and performed with much greater conscious effort. Speech gradually becomes soft, slow, and monotonal (hypophonia). The blink rate is diminished, as is facial expression (hypomimia), producing the so-called masked face. Movements of PD patients are not only slowed but are reduced in amplitude. This is most prominent with repeated activity, where the movements appear to collapse into a barely visible quiver.
Gait and Postural Abnormalities
Patients with moderate to severe PD are flexed at multiple joints (neck, hips, knees, elbows, and fingers), producing the typical stooped posture. Arising from a chair is often accomplished only with difficulty; patients may need to rock back and forth several times and eventually push off from arm rests. Early changes in gait include a reduction in stride length and diminished associated movements such as arm swing changes usually associated with the very old. The gait later becomes slow and shuffling. Turning is done en bloc, with the entire body moving as the feet slowly rotate. There is a tendency to progress involuntarily from walking to running (festination), seemingly in an attempt to catch up with the body's center of gravity thrown forward by the flexed posture. A patient may describe festination as like chasing your shadow. Patients have difficulty maintaining balance and are often unable to correct for a rapid postural displacement, particularly backward. The combination of the flexed posture, bradykinesia, freezing, festination, and impaired postural righting reflexes leads to one of the major problems in the latter stages of PD—falling.
Other Associated Symptoms or Signs
Seborrhea and excessive perspiration and facial oiliness are both common, and although often attributed to inadequate hygiene caused by physical impairment, they are an intrinsic part of the disease process.
Dysphagia often surfaces in the latter stages of the disease where it contributes significantly to morbidity and mortality caused by inanition and aspiration pneumonia. Although not completely understood, swallowing abnormalities have been demonstrated at various levels, including the voluntary muscles of the oral cavity and the involuntary muscles of the pharynx and esophagus. Solids are usually more of a problem than liquids. If patients with advanced PD are unable to maintain sufficient caloric intake, a discussion of the pros and cons of tube feeding should be held with the patient and family.
Sialorrhea is probably the result of decreased initiation of swallowing rather than overproduction of saliva. This can be treated with a low dosage of an anticholinergic, but there is growing experience in the use of injection of the salivary glands with botulinum toxin in the treatment of sialorrhea (61).
Autonomic dysfunction may occur in PD itself and as a side effect of antiparkinsonian medication. Orthostatic hypotension and constipation are the most common autonomic signs in PD, but bladder dysfunction and impotence are also encountered. In each case, medications may be at fault, and a search for other causes should be carried out before the defects are ascribed to PD.
Natural History
PD patients can be viewed as having one of three forms of the disease with implications for both natural history and treatment:
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neurodegenerative diseases than PD. Expert consultation is essential in evaluation in this group, looking for ocular movement abnormalities, behavioral and cognitive abnormalities, and autonomic and cerebellar dysfunction seen in the atypical parkinsonian syndromes. Not only do these conditions have these other abnormalities, they have more rapidly progressive and disabling disease. Difficulties with speech, swallowing, and posture (with frequent falling) as well as dementia are seen relatively early in the course for many of these patients.
Treatment Overview
The problems facing PD patients vary throughout the course of this disease, which progresses over many years. Treatment strategies that consider both short- and long-term aspects of PD are useful in helping patients, families, and physicians in anticipating and preparing for new problems and maximizing functionality and quality of life.
Treatment of Early Parkinson Disease
Nonmedication Strategies
Education and counseling play a major role in newly diagnosed patients. Fear of disability and death are common but frequently are not voiced. Reassurance is needed that disease progression is in general slow and disability can be forestalled for many years. Patients also need to be reminded that both understanding and treatment of PD are among the most rapidly changing aspects of all of neurology. There is not only reason to be optimistic regarding treatment with current therapy, but therapy will clearly be improving over the patient's lifetime. Patient-oriented books and support groups are often helpful for both patient and families. However, support groups should not be allowed to become the sole source of information for newly diagnosed patients, because they tend to focus on the most severely affected patients. Exercise programs are useful both to reduce physical signs of PD but also in encouraging an active lifestyle (63). Restrictions in activity are only appropriate when activities pose a safety hazard (e.g., working at a height, with heavy machinery, bicycle riding, rollerblading) in early PD.
For tremor predominant patients, declining symptomatic medications remains a viable option. A resting tremor can be quite pronounced and still cause little or no functional impairment. Frequently, embarrassment caused by tremor is the major drive for seeking treatment.
Depression is common in PD (40% to 50% of patients) and frequently is present at the time of diagnosis (64). In general it is not closely related to physical disability (or fear of it), because the incidence of depression in PD is higher than in other disabling conditions. The diagnosis of depression is made more difficult by the presence of facial masking where outward expression of emotion may not be an accurate reflection of mood state. Treatment of depression is accomplished with standard antidepressants (such as the selective serotonin reuptake inhibitor [SSRI] group; see Chapter 24) rather than with purely antiParkinson drugs.
Medications
Table 90.4 lists the medications used for the treatment of early PD.
Anticholinergics
Patients with early PD, in whom tremor is the major aspect, can benefit from anticholinergics. Generally, poor patient tolerance limits their use. Dry mouth (which may help sialorrhea), dry eyes, and mild visual blurring are common and dose related. Urinary retention, constipation, memory loss, and confusion are more serious problems, particularly in the elderly with a high prevalence of pre-existing dementia. Narrow angle glaucoma is a contraindication to these agents. Trihexyphenidyl and benztropine are the two most widely used of this class. Trihexyphenidyl is sometimes preferred because of its short duration of action (3 to 5 hours), because it allows a patient to target tremor control to desired situations. The recommended dose for trihexyphenidyl is 2 to 12 mg/day.
Amantadine
Although originally developed as an anti-influenzal drug, amantadine is an FDA-approved antiparkinsonian agent. Its effects are in general modest, but it is better tolerated than anticholinergic drugs. It is useful for mild bradykinesia and rigidity as well as tremor. It has a stimulant effect in many patients, which may account for its use in the treatment of fatigue in multiple sclerosis and chronic fatigue syndrome (65). Dry mouth and insomnia are usually mild. Livedo reticularis on the legs with associated edema occurs in 5% to 10% of patients, leading to discontinuation of amantadine. Exacerbation of congestive heart failure has also been reported with amantadine use. A dose of 100 mg twice daily is usual in early PD.
Carbidopa/Levodopa (L-dopa)
Although the introduction of L-dopa for PD is one of the therapeutic highlights of neurology, its use in early PD remains controversial. Despite the introduction of new medications, L-dopa remains the most effective drug for overall relief of motor symptoms of PD. The controversy surrounding L-dopa use has both theoretical and clinical basis. As mentioned earlier, there is evidence that metabolism of dopamine generates oxidative injury, which may play a role in the progressive cell death in PD. This evidence comes mostly from cell culture studies with relatively
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little animal data, and no clinical studies support the concept that levels of L-dopa used in treatment of PD are toxic. Results of an early clinical study are in direct conflict with the belief that L-dopa treatment accelerates neuronal death in PD. Patients who had L-dopa treatment begun early in the course of their disease had less overall morbidity and mortality than patients where therapy was initiated at a later stage (66). A recent clinical study of initial L-dopa treatment of PD which attempted to resolve the issue of L-dopa's potential neurotoxicity, gave a puzzling result. Patients initiated on L-dopa showed greater signs of degeneration of dopaminergic neurons on imaging studies than placebo treated patients after one year. However, the L-dopa initiated patients not only had greater relief of their PD symptoms than placebo patients, but remained the more improved group even after the placebo patients began on L-dopa. This suggests that early initiation with L-dopa had long lasting benefits in spite of enhanced brain imaging signs of neurodegeneration (67). L-Dopa therapy is however, associated with a major complication of moderate to severe PD—fluctuating motor response (68). Dose fluctuations take two forms:
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TABLE 90.4 Drugs Used for Parkinson Disease |
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A practical approach is to defer initiating L-dopa until the patient's motor symptoms interfere with daily activities or cannot be adequately treated with another drug. L-Dopa therapy in early PD is initiated as carbidopa/L-dopa at a dose one 25/100 tablet twice a day, although half of this dose is suggested for elderly patients.
The addition of carbidopa to L-dopa as a combination medication (formerly marketed as Sinemet) dramatically improves its tolerability. Carbidopa inhibits the enzyme dopa-decarboxylase, preventing the conversion of L-dopa to dopamine outside of brain. This leads to marked reduction (10-fold) of the effective L-dopa dose with reduction in so-called peripheral side effects of nausea, gastrointestinal (GI) intolerance (cramps/diarrhea), and hypotension. Patients with refractory nausea on 25/100 combination
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tablets may benefit from additional carbidopa, available as 25-mg tablets (Lodosyn). Although L-dopa is absorbed best on an empty stomach, this also usually leads to an increased incidence of nausea, so that it is initially prescribed with meals and, once tolerated, can be taken half an hour earlier. Although some patients have an immediate beneficial effect, it may take several weeks before a change is noticed. After that time, if there is no improvement, the dosage is gradually increased every few days to three to four times daily, using full or half-tablet increments, until the patient has shown significant improvement or a total daily dosage of 400 to 600 mg of L-dopa per day has been reached.
Although most patients tolerate carbidopa/L-dopa well, side effects are common, particularly in the elderly or in patients with dementia (seeDementia subsection). These include confusion, hallucinations, hypersexuality, and fluid retention. Orthostatic hypotension is common particularly in patients with autonomic dysfunction related to their untreated PD. Standing and supine blood pressure measurements should be checked before and after initiating treatment.
Dopamine Agonists: Bromocriptine (Parlodel), Pergolide (Permax), Pramipexole (Mirapex), and Ropinirole (Requip)
Medications from this group have been used as adjuvants to L-dopa for patients in the later stages of PD for many years. Recently there has been growing clinical experience with these agents as initial therapy of PD, particularly as an alternatives to L-dopa. All four dopamine agonists have been shown to be safe and effective as monotherapy for PD. The three newer agents appear to be somewhat more effective than bromocriptine, the first dopamine agonist introduced. The two newest agonists (pramipexole and ropinirole) have been shown to be virtually as effective as L-dopa in the treatment of mild PD patients (69,70). The major rationale for their use as initial therapy of PD is the significantly lower level of dose fluctuations—particularly dyskinesias—compared to L-dopa over at least the first 5 years of treatment (71,72). As many as half of PD patients can be adequately treated with an agonist without L-dopa for 3 to 5 years. The metabolism of these agents does not produce oxidative injury, so that it has been suggested that they may be less likely to accelerate the underlying neurodegeneration of PD. Both ropinirole and pramipexole initiated patients show fewer signs of dopaminergic degeneration compared to L-dopa–initiated patients with dopamine terminal imaging studies mentioned earlier. Unlike L-dopa, dopamine agonists are not available as a combination pill with an agent to prevent dopamine-related side effects. Dopamine agonists have a higher incidence of nausea and GI disturbances than carbidopa/L-dopa combinations. These side effects can be minimized by a very gradual titration schedule, allowing for tolerance to the drug to occur. The mantra for use of dopamine agonists is “start low, go slow, aim high,” because starting doses are typically one tenth of the therapeutic dose (Table 90.4). Patients need to understand both the schedule of dose escalation and its rationale. Overly slow escalation can lead to discontinuation by the patient because of a perceived lack of efficacy, whereas overly rapid escalation leads to discontinuation because of side effects (usually nausea). However, the cost of dopamine agonists is significantly higher than equivalent amounts of carbidopa/L-dopa, particularly in its immediate release generic form.
Domperidone is a useful medication to relieve nausea caused by dopamine agonists (or levodopa) (73). Domperidone is a dopamine antagonist that does not cross the blood–brain barrier and, in contrast to the typical neuroleptics and related antinausea drugs, does not worsen symptoms of PD. It is currently available through Canadian pharmacies as a stimulant for GI motility (its indication worldwide). The two newer agonists ropinirole and pramipexole differ from bromocriptine and pergolide chemically as nonergot derivatives. Fibrotic complications of ergot-based drugs, although rare, are well described. There have been recent reports of valvular abnormalities with long-term pergolide treatment, leading to the recommendation of transthoracic echocardiographic evaluation for patients remaining on this medication (74).
There are no proven neuroprotectants for Parkinson disease. Current data supports the use of either L-dopa or a dopamine agonist as initial therapy for symptomatic PD. Although initial studies suggested that the selective monoamine oxidase type B (MAO-B) inhibitor selegiline may have neuroprotective qualities, it remains uncertain to what extent its unanticipated symptomatic effects contributed to this conclusion (75).
Treatment of Moderate Parkinson Disease
Patients usually experience worsening motor symptoms of PD, requiring increasing amounts of medications (particular L-dopa) within the first 5 years after diagnosis. The most common new problem for patients with moderate stage PD is a reduction in the duration of benefit of each dose of L-dopa, known as wearing off. Although patients with early PD may have uninterrupted benefit from taking L-dopa twice a day, patients with moderate PD may find that their symptoms may worsen at the end of a dose taken three or four times a day. Disease severity plays a major role in this change. L-Dopa has a very short serum half-life (90 minutes), but early PD patients appear to have a capacity for a sustained benefit well beyond its pharmacokinetic effect. As PD worsens, the duration of action of L-dopa approaches its short serum lifetime.
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Addressing “Wearing Off” of L-Dopa
Several useful strategies reduce the wearing off of L-dopa. L-Dopa is available in a controlled-release form extending its duration of action by approximately 10% (76). Selegiline inhibits the degradation of dopamine and extends the duration of action of L-dopa by approximately 10% to 15% (77). Selegiline is a virtually irreversible MAO inhibitor and is dosed twice a day regardless of a patient's L-dopa dose schedule. Selegiline is so long acting that when signs of dopamine excess occur with its use, L-dopa dose must be reduced along with discontinuation of selegiline. Inhibitors of the major dopamine degrading enzyme, catechol-O-methyltransferase (COMT), are also available. Tolcapone (Tasmar) was the first COMT inhibitor released, and it remains the most potent drug to prolong the duration of action of carbidopa/L-dopa. Mild elevations of liver function tests were observed in its pivotal clinical trials. After its release, reports of fatal hepatotoxicity mandated regular assessment of alanine aminotransferase (ALT) levels, which has greatly limited its use. Entacapone (Comtan) has not been associated with hepatotoxicity. This COMT inhibitor is more effective than selegiline in prolonging the duration of action of L-dopa and is used in a very different fashion (78). Entacapone is a short-acting medication that is given as a fixed dose (200 mg) along with each dose of L-dopa. Entacapone is available in a preparation combined with carbidopa and L-dopa (Stalevo) (79). For patients requiring frequent doses, L-dopa is also available as a rapidly dissolving tablet that can be taken without water (Parcopa) (80).
Use of the longer acting dopamine agonists along with L-dopa is another proven strategy to reduce wearing off and improve the duration of daily “on” time. All the dopamine agonists have shown significant improvement of PD symptoms when used along with L-dopa (81,82). For patients with severe wearing off, a combination of strategies to increase L-dopa action as well as the addition of agonist therapy is commonly used.
Management of dose fluctuations becomes more problematic when patients develop both wearing off and clinically significant dyskinesias. The overall strategy is to reduce the total amount of short-acting L-dopa and supplement therapy with a longer acting agent, usually a dopamine agonist. This strategy is based on the observation that most dyskinesias occur at the time of peak action of L-dopa (peak dose dyskinesia), although some dyskinesias may occur during rapid drop in L-dopa levels (wearing off dyskinesias). All forms of L-dopa extension therapy and agonist adjuvant therapy are associated with an increase in dyskinesias, particularly when these treatments are initiated. It is only through the reduction of the daily L-dopa dose that these dyskinesias can be controlled while maintaining an improved duration of “on” time.
Treatment of Severe Parkinson Disease
Drug Treatment of Motor Fluctuations
As PD worsens (usually at least 10 years after diagnosis), patients develop both wearing off and dyskinesias with increasing frequency and severity. The regimens of L-dopa extension drugs and dopamine agonists frequently make such motor fluctuations more unpredictable. Conflict between patients and their physicians over therapy are common in this period. Physicians view dyskinesias as the most medically refractory symptom and aim to reduce them by reducing total daily L-dopa. However, most PD patients do not view dyskinesias as their most significant problem and may even be unaware of mild dyskinesias. Patients usually view the intrusion of PD symptoms during a sudden “off period” as more distressing and functionally more important and may seek increases in their L-dopa daily dose. Direct discussions about both short- and long-term goals of therapy are needed to maximize both patient satisfaction and medication compliance.
Bioavailability of L-dopa is influenced by dietary protein so that a protein restriction/redistribution diet is appropriate for patients with severe fluctuation in motor function (83). Consultation with a nutritionist is needed, because weight loss can occur in this population of patients that is already below their ideal weight. Although daytime wearing off usually improves, evening dyskinesias may develop with protein redistribution. Attempts at controlling daytime wearing off with drug therapy may also increase evening dyskinesias as L-dopa levels gradually rise over the day. For sudden unexpected wearing off, injectable apomorphine (Apokyn) has been shown to be effective (84). This short-acting dopamine agonist is self-administered using a subcutaneous injector system. Relief of PD “off” symptoms begins within minutes, much more rapidly attained than with the use of an additional dose of oral L-dopa as a rescue medication. The short half-life of apomorphine allows it to be used along with the patient's usual schedule of medication. Because of the risk of hypotension and the high incidence of nausea and vomiting, initial test use of subcutaneous apomorphine should be done in a physician's office.
Long-term prevention of dyskinesias, as well as optimal dosing to reduce dyskinesia are particularly important since the medical treatment of dyskinesias is extremely limited. The only agent that can be practically used is amantadine. At doses of up to 400 mg/day, this drug has been shown to significantly reduce L-dopa–induced dyskinesias (85).
Surgery
Severe motor fluctuations despite optimal medical therapy is the strongest indication for surgical treatment of PD. Stereotactic thalamotomy and thalamic DBS are
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effective for parkinsonian tremor, but are now infrequently performed in PD patients (86). Since thalamotomy has little effect on PD signs other than tremor, if a PD patient with thalamotomy develops other PD symptoms years later, he may require a second surgical procedure at a different brain location.
Two other brain regions are targets of stereotactic surgery for relief of not only tremor, but rigidity and bradykinesia as well. The subthalamic nucleus (STN) is currently the most popular target for PD surgery. This small deep brain nucleus was only rarely targeted prior to the introduction of the adjustable/programmable DBS systems. The major benefit of STN DBS is a significant reduction in severity and duration of L-dopa “off” motor symptoms. Many of these patients are able to achieve substantial (30%) reduction in dopaminergic medications with resulting reduction in dyskinesia (87). The globus pallidus interna is also targeted for relief of motor symptoms of PD. Stereotactic lesioning of the globus pallidus interna has been extensively studied and still remains an option for patients who wish to avoid an implanted device and its potential complications. DBS of the globus pallidus interna appears to provide slightly less symptomatic relief than STN DBS. However, like pallidotomy and in contrast to STN surgery, globus pallidus interna DBS directly reduces dyskinesias and can improve patient benefit from medication (88). Careful patient selection is a key to attaining good outcome from DBS surgery. Good surgical candidates have severe motor fluctuation on optimal medical management, but still have good quality (but not duration) L-dopa “on” states.
There is a window of opportunity for PD surgery that cannot be reclaimed once it has passed. Stereotactic surgery for PD is very demanding on patients. For most of the hours of surgery the patient is awake and is an active participant as the target brain region is identified physiologically and test stimulation of the DBS unit is performed. Transient confusion can occur after surgery even in cognitively intact patients. Dementia (see Dementia subsection), a common problem in severe PD, is a clear contraindication to this form of surgery. Poor postural stability, another problem of advanced PD, usually does not improve with surgery. Generally, younger patients (younger than 65 years of age) tolerate PD surgery better and have better outcomes (89). Complications of DBS include not only perioperative bleeding and infection associated with brain lesioning, but device specific problems. A second surgical procedure is needed to implant the pacemaker-like pulse generator in the chest. The generator's battery must be changed on average every 3 years and complications such as device failure, lead fracture, or infection need surgical intervention. After implantation the device must be programmed to attain maximal relief of PD systems without stimulation-related side effects, which include unpleasant sensations, dysarthria, emotional changes, and diplopia. DBS currently is the standard of care for surgical approaches to PD. Fetal brain tissue transplantation has not shown significant benefit in a placebo controlled trial with a patient population resembling optimal DBS candidates (90). These relatively young, L-dopa–responsive PD patients are also the target population for experimental surgical therapies including growth factor infusion, gene therapy, and stem cell transplantation (91,92).
Psychosis
Psychosis, including hallucinosis, can occur in any PD patient receiving dopaminergic therapy. Psychotic symptoms become more prevalent and serious in advanced cases. Age, presence of dementia, and dose of antiparkinsonian drugs are the major risk factors for psychosis in PD patients. Although all forms of PD therapy can cause psychotic symptoms, L-dopa appears to have a superior ratio of relief of motor symptoms of PD to induction of psychosis compared with the dopamine agonists, adjunctive therapy with amantadine or anticholinergics. Psychosis is particularly problematic in demented patients with severe PD. The most common useful strategy to combat psychosis is to lower or simplify the dose of PD therapy. However, many advanced PD patients may not be able to tolerate lowering the dose of their PD medications. In the past, little could be done for these patients because the use of typical neuroleptics worsened motor symptoms to the same extent as reducing a PD medication. The introduction of clozapine (Clozaril) has significantly improved the treatment of these patients. Relatively low doses (12.5 to 50 mg) of clozapine can successfully suppress hallucinations and delusions without worsening motor symptoms (93). Unfortunately, the most common serious side effect of clozapine (agranulocytosis) is an idiosyncratic event, so that regular monitoring of leukocyte count is needed even at these low doses. The newer atypical neuroleptics are also useful to treat psychotic symptoms in PD. At this time quetiapine (Seroquel) appears to be the most useful (25 to 75 mg/day) (94). Risperidone (Risperdal) appears to have a greater propensity to worsen motor symptoms in PD than other atypical neuroleptics.
Dementia
Dementia eventually occurs in at least 30% of PD patients. It is most strongly associated with age (as with virtually all dementing illnesses) but is also associated with duration and severity of motor signs of PD (95). Because dementia is not an invariable part of PD, an evaluation for a reversible cause is needed. The underlying basis for dementia in PD is controversial. Some of these patients have concomitant Alzheimer disease (see Chapter 26). Another group of demented PD patients may have predominantly frontal lobe related abnormalities with loss of spontaneity, poor decision making and planning with less prominent loss of short-term memory (96). A third group of patients
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have another of the more widespread neurodegenerative diseases known as dementia with Lewy bodies (DLB) or diffuse Lewy body disease. This form of atypical parkinsonism not only shows motor signs, but patients have psychosis and hallucinosis early in the course of their disease even without PD drug therapy. Significant day-to-day fluctuation in behavior, cognition, and motor symptoms are also commonly observed in this condition (97). Clinical and pathologic criteria for DLB have been established relatively recently, but it is clear that it has been underdiagnosed in the past and represents a major form of non-Alzheimer type dementia (98). The anticholinesterase (AchE) that are FDA-approved for Alzheimer disease do provide comparable benefit for patients with PD and dementia (99,100). Worsening of motor signs of PD usually does not occur, and is generally restricted to worsening of resting tremor. Improvement in psychiatric symptoms has also been shown with these medications in patients with DLB, where extremely low levels of acetylcholine synthetic capacity as well as dramatic improvement with AchE treatment has been reported (101,102). Although the antidementia drug memantine has been investigated as an anti-PD medication, it has not been studied in PD with dementia (103,104). Because of its structural similarity to amantadine (contraindicated in PD dementia) this N-methyl-D-aspartate (NMDA) antagonist should be avoided in these patients until further information is available.
Autonomic Dysfunction
The most common serious form of autonomic dysfunction in PD is orthostatic hypotension, and it is usually worsened by dopaminergic therapy. Added dietary salt along with the mineralocorticoid fludrocortisone (Florinef) are useful to expand plasma volume. The limitations to this therapy are worsening of congestive heart failure and supine hypertension. Midodrine (ProAmatine) is an α-adrenergic agonist that is FDA-approved for orthostatic hypotension because of autonomic failure (105). This short-acting agent can be dosed during the day (2.5 to 5 mg) every 4 hours to minimize recumbent hypertension. Poor esophageal and intestinal motility are also seen in advanced PD. Domperidone (see Dopamine Agonists) may also be used in this setting since metoclopramide (Reglan) is relatively contraindicated in PD because of its tendency to worsen motor symptoms.
Patient Support Organizations
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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