Parkinson Disease

Maurice Victor, Allan H. Ropper, Raymond D. Adams


This common disease, known since ancient times, was first cogently described by James Parkinson in 1817. In his words, it is characterized by “involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace, the senses and intellect being uninjured.” Strangely, his essay contains no reference to rigidity or to slowness of movement, and it stresses unduly the reduction in muscular power. The same criticism can be leveled against the term paralysis agitans, which appeared for the first time in 1841, in Marshall Hall's textbook Diseases and Derangements of the Nervous System.
Certain aspects of the natural history of the disease are of interest. As a rule, it begins between 40 and 70 years of age, with the peak age of onset in the sixth decade. It is infrequent before 30 years of age (only 4 of 380 cases in one series), and most series contain a somewhat larger proportion of men. Trauma, emotional upset, overwork, exposure to cold, “rigid personality,” and so on, among many other factors, have been suggested as predisposing to the disease, but there is no convincing evidence to support any such claims. The possible relationship to repeated cerebral trauma and to the “punch-drunk” syndrome (dementia pugilistica, page 944) has been particularly problematic and is unresolved despite the documentation provided by several celebrated cases (Lees). Idiopathic Parkinson disease is observed in all countries, all ethnic groups, and all socioeconomic classes, although the incidence in blacks is only one-quarter that in whites; in Asians, the incidence is one-third to one-half that in whites. A lack of concordance of Parkinson disease in twins appears to negate the role of genetic factors, but a study of dopamine metabolism utilizing PET scanning has shown that 75 percent of asymptomatic twins of Parkinson patients had evidence of striatal dysfunction and only a small portion of dizygotic twins showed these changes (Piccini et al). These data suggest a more substantial role for an inherited trait in cases of ostensibly sporadic disease. Also, Krüger and colleagues have reported a 13-fold increased susceptibility to the disease in patients who harbor a combination of a-synuclein and apolipoprotein E genotypes (see below).
While familial cases are decidedly rare, Golbe and colleagues have described two large kindreds (probably related and originating from a small town in southern Italy) in which 41 patients in four generations were affected. The illness in their cases was characteristic of Parkinson disease both clinically and pathologically, the only unusual features being a somewhat earlier onset (mean age 46 years), a relatively rapid course (10 years from onset to death), and a reported incidence of tremor in only 8 of the 41 patients. The dominantly inherited parkinsonism described by Dwork and others also differed clinically (onset in third decade, prominence of dystonia) and pathologically (absence of Lewy bodies) from classic Parkinson disease. It was in the latter kindred and in three Greek families that Polymeropoulos et al identified a locus on chromosome 4q that contained a mutation for a-synuclein, a main component of the Lewy body. Other families in which there have been mendelian patterns of inheritance are associated with gene defects at other sites (but still mostly on chromosome 4). These genetic data have been reviewed by Dunnett and Björklund.
The disease is common. In North America there are approximately 1 million patients, constituting about 1 percent of the population over the age of 65 years. The incidence in all countries where vital statistics are kept is similar. Considering its frequency, coincidence in a family on the basis of chance occurrence might be as high as 5 percent.
Clinical Features The core syndrome of expressionless face, poverty and slowness of voluntary movement, “resting” tremor, stooped posture, axial instability, rigidity, and festinating gait has been fully described in Chap. 4, and only certain diagnostic problems and variants in the clinical picture need to be considered here. The early symptoms may be difficult to perceive and are often overlooked. Advancing years have a way of rendering the spine and limbs less pliable and elastic, and in the senium the gait may become short-stepped and then reduced to a shuffle. The voice tends to become soft and monotonous. Hence it is all too easy to attribute the early symptoms of Parkinson disease to the effects of aging. For a long time the patient may not be conscious of the inroads of the disease; at first the only complaints may be of aching of the back, neck, shoulders, or hips and of vague weakness. A slight stiffness and slowness of movement or a reduction in the natural swing of one arm during walking are ignored, until one day it occurs to the physician or to a member of the family that the patient has Parkinson disease. Infrequency of blinking, as pointed out originally by Pierre Marie, is often a helpful early sign. The usual rate (12 to 20 blinks per minute) is reduced in the parkinsonian patient to 5 to 10. And with it there is a slight widening of the palpebral fissures, creating a stare (Stellwag sign). A reduction in movements of the small facial muscles imparts the characteristic expressionless (“masked”) appearance (hypomimia). When seated, the patient makes fewer small shifts and adjustments of position than the normal person (hypokinesia), and the fingers straighten and assume a flexed and adducted posture at the metacarpophalangeal joints.
The characteristic tremor, which usually involves a hand, is often listed as the initial sign; but in at least half the cases, observant family members will have remarked earlier on the patient's relative immobility and poverty of movement. Moreover, in 20 to 25 percent of cases the tremor is mild and intermittent or evident in only one finger or one hand. The tremor of the fully developed case takes several forms, as was remarked in Chap. 6. The 4-per-second “pill-rolling” tremor of the thumb and fingers is seen in only a small proportion of patients and is typically present when the hand is motionless, i.e., not used in voluntary movement (hence the term resting tremor). Complete relaxation, however, greatly reduces or abolishes the tremor, and a volitional movement usually but not always dampens it momentarily. The rhythmic beat coincides with an alternating burst of activity in agonists and antagonists in the electromyogram (EMG). The arm, jaw, tongue, eyelids, and foot are less often involved. The least degree of tremor is felt during passive movement of a rigid part (cogwheel phenomenon or Negro's sign). The tremor shows surprising fluctuations in severity and is aggravated by walking and excitement, but tremor frequency remains constant (Hunker and Abbs). One side of the body is typically involved before the other, and the tremor then remains asymmetrical as the illness advances.
Lance and associates have called attention to another common type of tremor in Parkinson disease—a fine, 7- to 8-per-second, slightly irregular action tremor of the outstretched fingers and hands. This tremor, unlike the slower one, persists throughout voluntary movement, is not evident with the limb in a resting position, and is more easily suppressed by relaxation. Electromyographically, it lacks the alternating bursts of action potentials seen in the more typical tremor. The patient may have either type of tremor or both.
We have been less impressed with rigidity and hypertonus as important early findings. They tend to appear in the more advanced stages of the disease. Once rigidity develops, it is constantly present; it can be felt by the palpating finger and seen as a salience of muscle groups even when the patient relaxes. When the examiner passively moves the limb, a mild resistance appears from the start (without the short free interval that characterizes spasticity), and it continues evenly throughout the movement, in both flexor and extensor groups, being interrupted only by the cogwheel phenomenon. Both the rigidity and its cogwheel feature can be elicited by having the patient occupy the opposite limb with a motor task requiring some degree of concentration, such as tracing circles in the air or touching each finger to the thumb. Postural hypertonus predominates in the flexor muscles of trunk and limbs and confers upon the patient the characteristic flexed posture. Particulars of the parkinsonian disorders of muscle tone, stance, and gait are discussed further in Chap. 4 and Chap. 7.
Regarding the quality of volitional and postural movements, a few additional points should be made. The patient is slow and ineffective in attempts to deliver a quick hard blow; he cannot complete a quick (ballistic) movement by a single burst of agonist-antagonist-agonist sequence of energizing activity, like the normal person; several bursts are needed (Hallett and Khoshbin). Alternating movements, at first successful, become progressively impeded and finally are blocked completely or adopt the rhythm of the patient's tremor. Also, the patient has difficulty in executing two motor acts simultaneously. Originally the impaired facility of movement was attributed to rigidity, but the observation that appropriately placed surgical lesions can abolish rigidity without affecting the disorder of movement refutes this interpretation. Thus the difficulty is not one of rigidity but one of bradykinesia (slowness in both the initiation and execution of movement), the extreme degree of which is akinesia. The latter deficits underlie the characteristic poverty of movement, shown by infrequency of swallowing, slowness of chewing, a limited capacity to make postural adjustments of the body and limbs in response to displacement of these parts, a lack of small “movements of cooperation” (as in arising from a chair without first adjusting the feet), absence of arm swing in walking, etc. Despite a perception of muscle weakness, the patient is able to generate normal or near-normal power, especially in the large muscles; however, in the small ones, strength is slightly diminished.
As the disorder of movement worsens, all customary activities show the effects. Handwriting becomes small (micrographia), tremulous, and cramped, as first noted by Charcot. The voice softens and the speech seems hurried and monotonous; the voice becomes less audible and finally the patient only whispers. Exceptionally, “mumbling” is an early complaint. Caekebeke and coworkers refer to the speech disorder as a “hypokinetic dysarthria”; they attribute it to respiratory, phonatory, and articulatory dysfunction. The consumption of a meal takes an inordinately long time. Each morsel of food must be swallowed before the next bite is taken. Walking becomes reduced to a shuffle; the patient frequently loses his balance, and in walking forward or backward must “chase the body's center of gravity” with a series of short steps in order to avoid falling (festination). Defense and righting reactions are faulty. Falls do occur, but surprisingly infrequently given the degree of postural instability. Gait is typically improved by sensory guidance, as by holding the patient at the elbow, whereas obstacles have the opposite effect, at times causing the patient to “freeze” in place. Difficulty in turning over in bed is a characteristic feature as the illness advances, but the patient rarely volunteers this information. Shaving or applying lipstick becomes difficult, as the facial muscles become more immobile and rigid.
Persistent extension or clawing of the toes, jaw clenching, and other fragments of dystonia may enter the picture but rarely are early findings.
As noted above, these various motor impediments and tremor characteristically begin in one limb (more often the left) and spread to one side and later to both sides, until the patient is quite helpless. Yet in the excitement of some unusual circumstance (a fire, for example), the patient is capable of brief but remarkably effective movement (kinesis paradoxica).
Regarding other elicitable neurologic signs, there is an inability to inhibit blinking in response to a tap over the bridge of the nose or glabella (Myerson sign), but grasp and suck reflexes are not present and buccal and jaw jerks are rarely enhanced. Commonly there is an impairment of upward gaze and convergence; if noted early in the disease, this raises the possibility of progressive supranuclear palsy. The bradykinesia may extend to eye movements, in that patients may show a delay in the initiation of gaze to one side, slowing of conjugate movements (decreased maximal saccadic velocity), hypometric saccades, and breakdown of pursuit movements into small saccades. There are no sensory changes. Drooling is troublesome; an excess flow of saliva has been assumed, but actually the problem is one of failure to swallow with normal frequency. Seborrhea and excessive sweating are probably secondary as well, the former due to failure to cleanse the face sufficiently, the latter to the effects of the constant motor activity. Postural instability can be elicited by tugging at the patient's shoulders from behind and noting the lack of a small step backward to maintain balance. The tendon reflexes vary, as they do in normal individuals, from being barely elicitable to brisk. Even when parkinsonian symptoms are confined to one side of the body, the reflexes are usually equal on the two sides, and the plantar responses are flexor. Exceptionally, the reflexes on the affected side are slightly more brisk, which raises the question of corticospinal involvement; but the plantar reflex remains flexor. In these respects, the clinical picture differs from that of corticobasal ganglionic degeneration, in which rigidity, hyperactive tendon reflexes, and Babinski signs are combined with apraxia (see further on). There is a tendency to syncope in some cases; this was found by Rajput and Rozdilsky to be related to cell loss in the sympathetic ganglia. However, syncope is never as prominent as in striatonigral degeneration.
At times, Parkinson disease is complicated by a dementia, a feature that had been commented upon by Charcot. The reported frequency of this combination varies considerably, based on the selection of patients and type of testing. An estimate of 10 to 15 percent (Mayeux et al) is generally accepted and matches our experience. The incidence increases with advancing age, approaching 65 percent in Parkinson patients above 80 years of age. In some instances of Parkinson disease with dementia, MRI reveals lesions in the cerebral white matter (in T1-weighted images) not seen in parkinsonians without dementia. The pathologic basis of the dementia in Parkinson disease is discussed below.
The overall course of the disease is quite variable. In the majority of patients, the mean period of time from inception of the disease to a chairbound state is 7.5 years (Hoehn and Yahr; Martilla and Rinne). On the other hand, as many as one-third of cases are relatively mild and remain stable for 10 years or more.
Diagnosis Early in the course of Parkinson disease, when only a slight asymmetry of stride or an ineptitude of one hand is present and tremor has yet to appear and impart the unmistakable stamp of the disease, a number of small signs already alluded to may be helpful in diagnosis. These include a reduced blink rate, the Myerson glabellar sign, a lack of arm swing, digital impedance (a tendency for rapid alternating movements to be slowed, to assume a tremor rhythm, or to be blocked altogether) and perceptible rigidity of one arm when the opposite limb is occupied in a motor task such as tracing circles in the air. Lack of a Babinski sign or of increased tendon reflexes in the affected limbs eliminates a corticospinal lesion as the cause of slowed movements, and lack of a grasp reflex helps to exclude a premotor cerebral disorder.
The main difficulty in diagnosis is to distinguish Parkinson disease from the many parkinsonian syndromes, some caused by other degenerative diseases and some by medications or toxins. Parkinson disease is far more common than any of the syndromes that resemble it. Bradykinesia and rigidity of the limbs and axial musculature are shared symptoms, but only in Parkinson disease is “resting” tremor an early sign, and it remains prominent even late in the illness.
The typical signs of Parkinson disease, when present in their entirety, impart an unmistakable clinical picture. When not all the signs are evident, there is no alternative but to re-examine the patient at several-month intervals until it is clear that Parkinson disease is present or until the signature of another degenerative process becomes evident (e.g., vertical gaze impairment in progressive supranuclear palsy; dysautonomia with fainting, bladder, or vocal cord signs in striatonigral degeneration; early and rapidly evolving dementia or psychosis in Lewy body disease, or apraxia in corticobasal ganglionic degeneration). If the patient's symptoms warrant, a beneficial response to levodopa also gives a reasonably secure although not entirely conclusive indication of the presence of Parkinson disease. The other parkinsonian syndromes are for the most part unchanged by the drug.
As pointed out on page 813, the epidemic of encephalitis lethargica (von Economo encephalitis) that spread over western Europe and the United States after the First World War left great numbers of parkinsonian cases in its wake. No definite instance of this form of encephalitis had been recorded before the period 1914–1918, and virtually none has been seen since 1930; hence postencephalitic parkinsonism is no longer a diagnostic consideration. Rarely, a Parkinson-like syndrome has been described with other forms of encephalitis (particularly with Japanese B virus and eastern equine encephalitis).
In England and Europe an “arteriopathic” or “arteriosclerotic” form of Parkinson disease was at one time much diagnosed, but we have never been convinced of its reality. Pseudobulbar palsy from a series of lacunar infarcts or from Binswanger disease (page 878) can cause a clinical picture simulating certain aspects of Parkinson disease, but unilateral and bilateral corticospinal tract signs, hyperactive facial reflexes, spasmodic crying and laughing, and other characteristic features distinguish spastic bulbar palsy from Parkinson disease. Of course, the parkinsonian patient in advancing years is not impervious to cerebrovascular disease, and the two conditions then overlap.
Normal-pressure hydrocephalus can create a syndrome that resembles Parkinson disease, particularly in regard to gait and postural instability and at times to bradykinesia; but rigid postures, slowness of alternating movements, hypokinetic ballistic movements, and resting tremor are not part of the clinical picture.
Senile (familial or essential) tremor is distinguished by its fine, quick quality, its tendency to become manifest during volitional movement and to disappear when the limb is in a position of repose, and the lack of associated slowness of movement, flexed postures, etc. The head is more often involved in senile tremor than in Parkinson disease. Some of the slower, alternating forms of essential tremor are difficult to distinguish from parkinsonian tremor, and one can only wait to see whether it is the first manifestation of Parkinson disease.
Progressive supranuclear palsy (see further on) is characterized by rigidity and dystonic postures of the neck and shoulders, a staring and immobile countenance, and a tendency to topple when walking—all of which are suggestive of Parkinson disease. Inability to produce vertical saccades and, later, paralysis of upward and downward gaze and eventually of lateral gaze with retention of reflex eye movements establish the diagnosis in most cases. Strict adherence to the diagnostic criteria for Parkinson disease also permits its differentiation from corticostriatospinal, striatonigral, and corticobasal ganglionic degeneration and Machado-Joseph disease—all of which are discussed in other parts of this chapter.
Paucity of movement, unchanging attitudes and postural sets, and a slightly stiff and unbalanced gait may be observed in patients with an anergic or hypokinetic (“retarded”) type of depression. Since as many as 25 to 30 percent of parkinsonian patients are depressed, the separation of these two conditions may then be difficult (see page 1612). The authors have seen patients who were called parkinsonian by competent neurologists but whose movements became normal when antidepressant medication or electroconvulsive therapy was given.
The rapid onset of the Parkinson syndrome, especially in conjunction with other medical diseases, should always raise the suspicion of drug effects; phenothiazines, haloperidol, and the neuroleptics pimozide and metoclopramide, used at times as antiemetics, all cause a slight masking of the face, stiffness of the trunk and limbs, lack of arm swing, fine tremor of the hands, and mumbling speech. They may also evoke an inner restlessness, a “muscular impatience,” an inability to sit still, and a compulsion to move about much like that which occurs at times in the parkinsonian patient (akathisia; page 118). Spasms of the neck, face, and jaw muscles (open mouth, protruded tongue, retrocollis or torticollis, grimacing) may also be provoked by such drugs. A mild, localized rigidity of an arm due to local tetanus was studied by R. D. Adams) in a patient who had been referred as a case of acute parkinsonism.
All in all, if one adheres to the strict definition of Parkinson disease—bradykinesia, “resting” tremor, postural changes and instability, cogwheel rigidity, and response to L-dopa—errors in diagnosis are few. Yet in a series of 100 cases, studied clinically and pathologically by Hughes and associates, the diagnosis was inaccurate in 25 percent. The reasons are that about this number of Parkinson patients do not have the characteristic tremor and about 10 percent do not respond to L-dopa. These authors noted that early dementia and autonomic disorder and the presence of ataxia and corticospinal signs were reliable exclusion criteria.
Pathology and Pathogenesis It is now accepted that a loss of pigmented cells in the substantia nigra and other pigmented nuclei (locus ceruleus, dorsal motor nucleus of the vagus) is the most constant finding in both idiopathic and postencephalitic Parkinson disease. The substantia nigra is visibly pale to the naked eye; microscopically, the pigmented nuclei show a marked depletion of cells and replacement gliosis, findings that enable one to state with confidence that the patient must have suffered from Parkinson disease. Also, many of the remaining cells of the pigmented nuclei contain eosinophilic cytoplasmic inclusions with a faint halo, called Lewy bodies. These are seen in practically all cases of idiopathic Parkinson disease. They were present in a few postencephalitic cases as well, but in the latter neurofibrillary tangles were more usual. However, both of these cellular abnormalities appear occasionally in the substantia nigra of aging, nonparkinsonian individuals. Possibly the individuals with Lewy bodies would have developed Parkinson disease if they had lived a few more years. Noteworthy is the finding by McGeer et al that nigral cells normally diminish with age, from a maximal complement of about 425,000 to 200,000 at age 80. Tyrosine-hydroxylase, the rate-limiting enzyme for dopamine, diminishes correspondingly. These authors found that in patients with Parkinson disease, the number of pigmented neurons was reduced to about 30 percent of that in age-matched controls. Using more refined counting techniques, Pakkenberg and coworkers estimated the average total number of pigmented neurons to be 550,000 and to be reduced by 66 percent in Parkinson patients. The number of nonpigmented neurons in their control subjects was 260,000 and again was reduced in patients by 24 percent. Thus, aging contributes importantly to nigral cell loss, but the cell depletion is so much more marked in Parkinson disease that some factor other than aging must also be operative.
Other depletions of cells are widespread, but they have not been quantitatively evaluated and their significance is less clear. There is neuronal loss in the mesencephalic reticular formation, near the substantia nigra. These cells project to the thalamus and limbic lobes. In the sympathetic ganglia, there is slight neuronal loss and Lewy bodies are seen; this is also true of the pigmented nuclei of the lower brainstem as well as of the putamen, caudatum, pallidum, and substantia innominata. Dopaminergic neurons that project to cortical and limbic structures, to caudate nucleus and nucleus accumbens, and to periaqueductal gray matter and spinal cord are affected little or not at all. The lack of a consistent lesion in either the striatum or the pallidum is noteworthy in view of the reciprocal connections between the striatum and the substantia nigra and the depletion of striatal dopamine that characterizes the parkinsonian state.
The statistical data relating Parkinson and Alzheimer diseases are difficult to assess because of different methods of examination from one reported series to another (Quinn et al). Nevertheless, the overlap of the two diseases is more than fortuitous, as indicated in an earlier part of this chapter. In our own pathologic material, the majority of the demented Parkinson patients showed Alzheimer-type changes, but there were several in whom few plaques or neurofibrillary changes could be found or in whom the cortical neuronal loss was accompanied by a widespread distribution of Lewy bodies (Lewy body dementia, discussed earlier, on page 1120).
Of great interest in recent years has been the observation, both in human opiate addicts and in monkeys, that a neurotoxin (known as MPTP) can produce irreversible signs of parkinsonism and selective destruction of cells in the substantia nigra (as described on page 105). The toxin, ingested by persons who self-administered an analogue of meperidine, was shown to bind with high affinity to an extraneural enzyme, monoamine oxidase, which transformed it to a toxic metabolite, pyridinium MPP+. The latter is bound by the melanin in the dopaminergic nigral neurons in sufficient concentration to destroy the cells. The precise mechanism by which MPTP produces the Parkinson syndrome is unsettled. One hypothesis is that the inner segment of the globus pallidus is rendered hyperactive because of reduction of the GABA influence of the subthalamic nucleus. The theory of an environmental toxin as a cause of Parkinson disease has been greatly stimulated by the MPTP findings. (Uhl et al; see also the review by Snyder and D'Amato). The disease is more frequent in industrialized countries and agrarian areas in which toxins are commonly used, but its universal occurrence would militate against any one toxin. To date, no chemical toxin, heavy metal, etc., has been incriminated in the causation of Parkinson disease.
Provocative recent discoveries have involved the synaptic protein alpha-synuclein, the main component of Lewy bodies in both the sporadic and inherited forms of Parkinson disease as well as in Lewy body disease. Synuclein normally exists in a soluble unfolded form, but in high concentrations it forms aggregates of neurofilaments to form the Lewy body. Immunostaining techniques have also disclosed less specific proteins, such as ubiquitin and tau, within the Lewy bodies. Furthermore, as noted earlier, in four unrelated families with the rare autosomal dominant form of Parkinson disease, a mutation on chromosome 4 has been found that codes for an aberrant form of synuclein (Polymeropoulos et al). However, no gene error relating to synuclein has been found in patients with sporadic Parkinson disease and the misfolding of synuclein as a cause of the common sporadic disease is only a speculation.
Treatment Although there is no known treatment that will halt or reverse the neuronal degeneration that presumably underlies Parkinson disease, methods are now available that afford considerable relief from symptoms. Treatment can be medical or surgical, although reliance is placed mainly on drugs, particularly on L-dopa.
At present, L-dihydroxyphenylalanine (L-dopa) is unquestionably the most effective agent for the treatment of Parkinson disease, and the therapeutic results, even in those with far-advanced disease, are much better than have been obtained with other drugs, even newer ones that act as dopamine agonists. As mentioned earlier, some degree of response is so nearly universal that many neurologists use it as a diagnostic criterion. The theoretical basis for the use of this compound rests on the observation that striatal dopamine is depleted in patients with Parkinson disease but that the remaining nigral cells are capable of producing dopamine by taking up its precursor, L-dopa. The neurons of the striatum that are targets of nigral projections are not depleted and remain receptive to any dopamine released by nigral cells. Over time, however, the number of remaining nigral neurons that convert L-dopa to dopamine becomes inadequate and the receptivity to dopamine of the striatal target neurons becomes excessive, possibly as a result of denervation hypersensitivity; this results in both a reduced response to L-dopa and to paradoxical and excessive movements (dyskinesias) with each dose.
By combining a decarboxylase inhibitor (carbidopa or benserizide), which is unable to penetrate the central nervous system (CNS), with L-dopa, the decarboxylation of L-dopa to dopamine is greatly diminished in peripheral tissues. This permits a greater proportion of L-dopa to reach nigral neurons and, at the same time, a reduction in the peripheral side effects of L-dopa and dopamine (nausea, hypotension, etc.). Combinations of levodopa-carbidopa are available in a 10:1 or 4:1 ratio and the benserizide combination in a 4:1 ratio. The initial dose of levodopa-carbidopa is typically one-half of a 100-mg/25-mg tablet given two or three times daily and increased slowly until optimum improvement is achieved, usually up to a maximum of two tablets administered four times daily, or a similar dose of the 250-mg/25-mg combination. A newer class of catechol-O-methyltransferase (COMT) inhibitors, typified by tolcapone, extends the plasma half-life and the duration of L-dopa effect by preventing its breakdown (as opposed to increasing its bioavailability as with carbidopa). But these drugs require further study, for there have been several complications and rare unexplained deaths after their use.
Long-acting preparations of levodopa-carbidopa may reduce dyskinesias in some patients (Hutton and Morris) in the advanced stages of disease, but our experience with these drugs given earlier in the course has been less impressive. In transferring a patient from conventional L-dopa/carbidopa preparations to the long-acting formulation, the frequency of administration can be roughly halved while the total amount of L-dopa initially remains unchanged. The absorption of the long-acting drug, however, is approximately 70 percent, often necessitating a slight increase in total dose. To facilitate the treatment of morning rigidity and tremor, the long-acting tablet can be broken in half to speed absorption or a small dose of conventional medication can be given at the same time. Often some degree of dyskinesia must be accepted as the price to be paid for the therapeutic effect.
Bromocriptine, pergolide, and lisuride are synthetic ergot derivatives whose action in Parkinson disease is explained by their direct stimulating effect on dopamine (D2) receptors, which are located on corticostriate neurons, thus bypassing the depleted nigral neurons. The newer nonergot dopamine agonists ropinirole and pramipexole seem to be tolerated well and have a duration of effectiveness similar to that of other D2 agonists; these agents are very helpful in supplementing L-dopa and are now increasingly popular as the sole therapeutic agent before L-dopa is instituted. Rascol and colleagues have reported that the use of ropinirole during the first 5 years of the parkinsonian illness controlled the symptoms satisfactorily and, in addition, reduced the incidence of dyskinesias, compared to treatment with L-dopa. Why dyskinesias are less frequent with ropinirole than with L-dopa is not known. Bromocriptine should be introduced cautiously, 7.5 to 10 mg daily in three to four divided doses, and the dosage increased very slowly to an optimal level of 40 to 60 mg daily; levodopa-carbidopa should be reduced concomitantly by 50 percent. A dose of 5 to 10 mg of bromocriptine has about the equivalent effect of 100/25 mg levodopa/carbidopa. It has a longer duration of action than L-dopa and causes nausea and vomiting less often, but otherwise the action and side effects of the two drugs are much the same. Even small doses of these drugs, when first introduced, may induce a prolonged episode of hypotension. Our observations are in agreement with those of Marsden, who found that of 263 patients, all but 82 had abandoned one of the ergot dopamine agonists after 6 months because of lack of effect or adverse reactions. Nevertheless, a proportion of patients continue to benefit for up to 3 years. Ropinirole and pramipexole are useful in smoothing the effects of L-dopa and allowing a reduction in its dose. As with the ergot-based dopamine agonists, they can be utilized in some patients as the sole treatment for a limited time. They may produce sudden and unpredictable sleepiness, similar to narcolepsy, and patients should be warned of this possibility in relation to driving. More data are required to judge the efficacy of initiating therapy with a dopamine agonist rather than with L-dopa combinations.
Because of the side effects of levodopa and of dopaminergic agents, particularly in older patients, some neurologists avoid all types of pharmacotherapy if the patient is in the early phase of the disease and the parkinsonian symptoms are not troublesome. When the symptoms become more annoying, initial therapy with either amantadine 100 mg bid or an anticholinergic medication may be advised. Only when the symptoms begin to interfere with work and social life or falling becomes a threat is a carbidopa/levodopa preparation introduced, and then at the lowest possible dose—10/100 mg bid or tid. This dose is slowly increased until maximal benefit is achieved.
Another approach, now controversial, has been to initiate the treatment of new cases of Parkinson disease with the monoamine oxidase inhibitor selegiline, 5 mg bid, and to continue its use until symptoms become disabling, at which point L-dopa or a dopamine agonist is introduced. Selegiline inhibits the intracerebral metabolic degradation of dopamine, and clinical trials conducted by the Parkinson Study Group have suggested that it slows progression of the disease in its early stages. Subsequent observations, however, have not confirmed the view that selegiline markedly alters the natural course of the disease, and we use it infrequently.
As already mentioned, L-dopa is not without significant side effects, so that its use is limited in some circumstances. Approximately two-thirds of patients tolerate the drug initially and experience few serious adverse effects; one-third will show dramatic improvement, especially in hypokinesia and tremor. Many patients are at first troubled by nausea, especially if the medication is not taken with meals, and a few have orthostatic hypotensive episodes. Nausea usually disappears after several weeks of continued use or can be allayed by the specific dopaminergic chemoreceptor antagonist domperidone. Coincident psychiatric symptoms may also present problems and are to be expected in 15 to 25 percent of patients, particularly in the elderly. Depression is occasionally a serious problem, even to the point of suicide; delusional thinking may occur in these circumstances. This combination of movement and psychiatric disorders is difficult to treat, and one must institute an antidepressant regimen or one of the newer class of antipsychotic medications that are associated with few extrapyramidal side effects, as described below and in Chap. 50. Trazodone has been helpful in treating depression and insomnia, which may be a major problem. The selective serotonin reuptake inhibitors are useful in apathetic depressions, but some patients report worsening of parkinsonian symptoms. Excitement and aggressiveness appear in a few. A return of libido may lead to sexual assertiveness.
Confusion and outright psychosis (hallucinations and delusions), seen in advanced cases of Parkinson disease when high doses of L-dopa are required, is first treated by attempting to reduce the dose of the drug. If this is not possible, the atypical neuroleptics olanzapine, clozapine, risperidone, or quetiapine in low doses are often successful (Friedman and Lannon). The side effects of these drugs include sleepiness, orthostatic hypotension, sialorrhea, and the most serious, agranulocytosis, requiring regular monitoring of the blood count. Clozapine has been said to provide an additional benefit of suppressing dyskinesias in advanced Parkinson disease (Bennett et al), but it requires weekly surveillance of the blood count because of the idiosyncratic occurrence of agranulocytosis in up to 2 percent of patients. Although useful in the treatment of frankly psychotic patients, these drugs tend to be far less effective once dementia has supervened. The anticonvulsant valproate is also said to be useful in this circumstance, but our experience with this drug has not been as favorable as with clozapine. Despite their lesser tendency to produce rigidity, olanzapine and probably the other similar agents in high doses eventually worsen motor disability.
The most common and troublesome effects of L-dopa, requiring individualization of therapy, are end-of-dose failure, the “on-off” phenomenon, and the induction of involuntary movements—restlessness, head wagging, grimacing, lingual-labial dyskinesia, and choreoathetosis and dystonia of the limbs, neck, and trunk. The on-off phenomenon refers to an unpredictable change in the patient, in a matter of minutes or from one hour to the next, from a state of relative mobility to one of complete or nearly complete immobility. These disorders eventually appear in about 75 percent of patients within 5 years. Above a certain daily dose, which varies from patient to patient, very few patients escape these effects, forcing a reduction in dosage.
If involuntary movements are induced by relatively small doses of L-dopa, the therapeutic effect may be enhanced to some extent by the addition of other dopaminergic agents, such as pergolide, bromocriptine, or the newer nonergot preparations, such as ropinirole and pramipexole (see below) and, to some extent, amantadine. The use of long-acting preparations of L-dopa may also be helpful in reducing dyskinesias, as mentioned above. Amantadine, an antiviral agent, is thought to act by releasing dopamine from striatal neurons; it also has an anticholinergic property. It is given in doses of 50 to 100 mg three times daily. Its benefit appears almost immediately but tends to be slight. In addition to anticholinergic symptoms (dry mouth, etc.), the side effects are similar to those of L-dopa but are much milder. Edema of the legs has been troublesome in some patients. However, amantadine is effective in combination with L-dopa and may reduce the dyskinesias and motor fluctuations associated with advanced disease (Verhagen Metman et al). Given alone or in combination with L-dopa, it offers a modest alternative treatment for patients with early Parkinson disease or those who are having untoward effects with standard doses of L-dopa.
The notion that the administration of L-dopa early in the disease might reduce the period over which it remains effective has been largely dispelled, but some experts continue to adhere to this idea. Cedarbaum et al, who reviewed the course of the illness in 307 patients over a 7-year period, found no evidence that the early initiation of L-dopa treatment predisposes to the development of motor response fluctuations, dyskinesia, and dementia. Also, the large multicenter study reported by Diamond et al indicated that patients who were given L-dopa early in the disease actually survived longer and with less disability than those who were started late.
Anticholinergic agents have long been in use and are still given occasionally, either in conjunction with L-dopa or to patients who cannot tolerate the latter drug. Several synthetic preparations are available, the most widely used being trihexyphenidyl (Artane) and benztropine mesylate (Cogentin) and amantadine (see above). When tremor is the most prominent symptom, we have had success with the related drug ethopropazine (Parsidol, Parsitan in Canada). In order to obtain maximum benefit from the use of these drugs, they should be given in gradually increasing dosage to the point where toxic effects appear: dryness of the mouth (which can be beneficial when drooling of saliva is a problem), blurring of vision from pupillary mydriasis (for which corrective glasses may be indicated), constipation, and sometimes urinary retention (especially with prostatism). Unfortunately, mental slowing, confusional states, hallucinations, and impairment of memory—especially in patients with already impaired mental function—are frequent side effects of these drugs and sharply limit their usefulness. Ethopropazine, 50 to 200 mg daily, is given in divided doses. We have effectively managed cases of isolated parkinsonian tremor in young patients using anticholinergic drugs alone. The optimum dosage level is the point at which the greatest relief from tremor is achieved within the limits of tolerable side effects. Occasionally, further benefit may accrue from the addition of one of the antihistaminic drugs, such as diphenhydramine or phenindamine. An important note of warning: anticholinergic agents or L-dopa should not be discontinued abruptly in advanced cases. If this is done, the patient may become totally immobilized by a sudden and severe increase of tremor and rigidity; rarely, a neuroleptic syndrome has been induced by such withdrawal.
Long-term treatment with L-dopa or dopamine receptor agonists has not prevented the slow advance of the disease. With progressive loss of nigral cells, there is an increasing inability to store L-dopa and periods of drug effectiveness become shorter. In some instances, the patient becomes so sensitive to L-dopa that as slight an excess as 50 to 100 mg will precipitate choreoathetosis; if the dose is lowered by the same amount, the patient may develop disabling rigidity. With the end-of-dose loss of effectiveness and on-off phenomenon, which with time become increasingly frequent and unpredictable, the patient may experience pain, respiratory distress, akathisia, depression, anxiety, and even hallucinations. Some patients function quite well in the morning and much less well in the afternoon, or vice versa. In such cases, and for end-of-dose and on-off phenomena, one must titrate the dose of L-dopa and utilize more frequent doses during the 24-h day; combining it with a dopamine agonist or use of the long-acting preparations may be helpful. Sometimes temporarily withdrawing L-dopa and at the same time substituting other medications will control the on-off phenomenon.
Based on the hypothesis that alimentary-derived amino acids antagonize the clinical effects of L-dopa, the use of a low-protein diet has been advocated as a means of controlling the motor fluctuations described above (Pincus and Barry). Symptoms can often be reduced by the simple expedient of eliminating dietary protein from breakfast and lunch. Moreover, this dietary regimen may permit the patient to reduce the total daily dose of L-dopa. Such dietary manipulation is worth trying in appropriate patients; it is not harmful, and most of our patients who have persisted with this diet have reported improvement in their symptoms or an enhanced effect of L-dopa.
Surgical Measures Until recently, success with L-dopa had practically replaced the use of ablative surgical therapy. The latter involves the stereotactic placement of lesions in either the globus pallidus, ventrolateral thalamus, or subthalamic nucleus, contralateral to the side of the body chiefly affected. The best results have been obtained in relatively young patients, in whom unilateral tremor or rigidity, rather than akinesia, are the predominant symptoms. The symptoms that have responded least well to operation (or to treatment with L-dopa) are postural imbalance and instability, paroxysmal akinesia, bladder and bowel disturbances, dystonia, and speech difficulties.
In the last decade, through the work of Laitinen and others, this mode of therapy has been revived and expanded. Under precise stereotactic control and with placement of a lesion in the posterior and ventral (medial) part of the globus pallidus, improvement of contralateral parkinsonian symptoms has been effected more reliably than in the past. Also, postoperatively, there is an enhanced responsiveness to L-dopa and a reduction of drug-induced dyskinesias, To what extent the improvement will be sustained remains to be determined, since the disease process continues to advance. In patients who have been studied for more than a few years, the beneficial effects on dyskinesias contralateral to the operation are sustained to some extent, but not in the ipsilateral limbs. The improvement in “off-state” bradykinesia is lost after 2 or so years and any betterment in axial rigidity and imbalance is lost in many patients within a year of operation, as summarized by Gregory and by Lang et al. In the only randomized trial to date that has compared pallidotomy to continued medical treatment of patients with dyskinesias, bradykinesia, or severe fluctuations in response to L-dopa, de Bie and colleagues demonstrated a clear improvement in motor function after surgery, while the group treated with medication continued to worsen. Using patient diaries, they estimated that dyskinesias were reduced 50 percent contralateral to the operated side and that parkinsonian symptoms during the “off phase” were improved by 30 to 50 percent. These improvements do not persist indefinitely and are in part due to the ability to reduce the dose of L-dopa. It should be mentioned that most groups have abandoned the pallidum as a surgical target in favor of the subthalamic nucleus.
Recently, through the use of implanted electrodes, the sites that are the targets of ablative procedures have been subjected to high-frequency stimulation—with virtually identical if not better results. In particular, high-frequency stimulation of the subthalamic nucleus has produced impressive improvement in all features of the disease (Limousin et al). Long-term studies are in progress to determine the persistence of these effects and their merits in comparison to ablative lesions.
The cerebral implantation of adrenal medullary tissue from 8- to 10-week-old human fetuses has provided a modest but undeniable improvement in motor function (Spencer et al), and some patients also appear to have benefited from the striatal implantation of human fetal and porcine nigral cells and autologous adrenal cells. These procedures are hampered by many difficulties, mainly in obtaining tissue and the failure of grafts to survive. Much of the original enthusiasm for these procedures has subsided, and it seems unlikely that they will have wide applicability in the treatment of Parkinson disease in the near future. Investigation into their possible usefulness continues.
Finally, in the management of the patient with Parkinson disease, one must not neglect the maintenance of optimum general health and neuromuscular efficiency by a planned program of exercise, activity, and rest; expert physical therapy and exercises such as those performed in yoga may be of help in achieving these ends. Sleep may be aided by the soporific antidepressants. Postural imbalance can be greatly mitigated by the use of a cane or walking frame. Hypotensive episodes respond to 0.5 mg of fludrocortisone (Florinef) each morning. In addition, the patient often needs much emotional support in dealing with the stress of the illness, in comprehending its nature, and in carrying on courageously in spite of it.