This common disease, known since ancient times, was first cogently described by James Parkinson in 1817. In his words, it was 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 contained no reference to rigidity or to slowness of movement and it stressed 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 and has fallen out of use, but was such a common term in the literature that it is included here.
The natural history of the disease is of interest. As a rule, it begins between 45 and 70 years of age, with the peak age of onset in the sixth decade. It is infrequent before 30 years of age, and most series contain a somewhat larger proportion of men. Trauma, emotional upset, overwork, exposure to cold, "rigid personality," and so on, were among many factors that had been suggested over the years as predisposing to the disease, but there is no evidence to support any such claims. Idiopathic Parkinson disease is observed in all countries, all ethnic groups, and all socioeconomic classes, although the incidence in African Americans is only one-quarter that in whites. There may be an increased incidence in rural compared to urban areas. In Asians, the incidence is one-third to one-half that in whites. The disease is frequent in North America, where there are approximately 1 million affected patients, constituting about 1 percent of the population over the age of 65 years. The incidence in European countries where vital statistics are kept is similar. A possible relationship to repeated cerebral trauma and to the "punch-drunk" syndrome (dementia pugilistica; chronic traumatic encephalopathy) has been particularly problematic and is unresolved despite several celebrated cases (Lees). A protective effect of smoking and coffee drinking has emerged in some epidemiologic studies but is marginal.
A tetrad of hypo- and bradykinesia, resting tremor, postural instability, and rigidity are the core features of Parkinson disease. These are evident as an expressionless face, poverty and slowness of voluntary movement, "resting" tremor, stooped posture, axial instability, rigidity, and festinating gait. Much can still be gained from perusal of the often-cited study by Hoehn and Yahr, published in 1967 before the widespread use of L-dopa. Table 39-2 is reproduced from that paper. The manifestations of basal ganglionic disease are fully described in Chap. 4, and only certain diagnostic problems and variations of the clinical picture need be considered here.
Table 39-2 Initial Symptoms in Patients with Parkinson Disease ||Download (.pdf)
Table 39-2 Initial Symptoms in Patients with Parkinson Disease
Loss of dexterity
Depression, nervousness, other psychiatric disturbance
The early symptoms may be difficult to appreciate and are often overlooked by family members because they evolve slowly and tend to be attributed to the natural changes of aging. Speech becomes soft, monotonous, and cluttered. 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. 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 the overall cast of Parkinson disease. Infrequency of blinking, as originally pointed out by Pierre Marie, is an early sign. The usual blink rate (12 to 20/min) is reduced in the parkinsonian patient to 5 to 10/min, and with it there is a slight widening of the palpebral fissures, creating a stare. 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 already have remarked on the patient's relative slowness of movement. In about one-quarter 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, although most characteristic, is seen in only about half the patients. It is typically present when the hand is motionless, that is not used in voluntary movement (hence the commonly used term resting tremor). Complete relaxation, however, reduces or abolishes the tremor, so that the term tremor in the position of repose is actually a more accurate description. Volitional movement dampens it momentarily. The rhythmic beat coincides with an alternating burst of activity in agonist and antagonist muscles in the electromyogram (EMG); hence the description alternating tremor is applied. The arm, jaw, tongue, eyelids, and foot are less often involved. Even the least degree of tremor is felt during passive movement of a rigid part (cogwheel phenomenon, or Negro sign, or at least this is the ostensible explanation for cogwheeling). The tremor shows surprising fluctuations in severity and is aggravated by walking and excitement, but its frequency remains constant (Hunker and Abbs). It bears repetition that one side of the body is typically involved before the other with tremor and rigidity, and the tremor in particular remains asymmetrical as the illness advances.
Lance and associates have called attention to the high incidence of a second essential 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 typical tremor and resembles, if not equates with, essential tremor (see Table 6-1). It is subject to modulation by different medications than those used for the alternating Parkinson tremor. The patient may have either type of tremor or both.
Rigidity is less often an early finding. Once rigidity develops, it is constantly present and can be felt by the palpating fingers and 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 movement in both flexor and extensor groups, being interrupted to a variable degree only by the cogwheel phenomenon. Rigidity and its cogwheel component are elicited or enhanced by having the patient engage the opposite limb in a motor task requiring some degree of concentration, such as tracing circles in the air (termed Froment sign, or Noïka-Froment sign when the patient is asked to raise the other arm as high as possible, but this maneuver was actually utilized first to bring out cogwheeling in essential tremor) or touching each finger to the thumb. In the muscles of the trunk, postural hypertonus predominates in the flexor groups and confers on the patient the characteristic flexed posture. Other particulars of the parkinsonian appearance of muscle tone, stance, and gait are discussed in detail in Chaps. 4 and 7. There should be no pyramidal signs in Parkinson disease.
Here, a few additional points should be made regarding the quality of volitional and postural movements. The patient is slow and ineffective in attempts to deliver a quick hard blow; he cannot complete a rapid (ballistic) movement. On the EMG, the normal single burst of agonist–antagonist–agonist sequence of energizing activity is replaced by several sequential brief bursts, according to Hallett and Khoshbin. Alternating movements, at first successful, become progressively impeded if performed repetitively and, finally, they are blocked completely or adopt the rhythm of the patient's alternating tremor. The patient has great difficulty in executing 2 motor acts simultaneously. In the past the impaired facility of movement had been attributed to rigidity, but the observation that certain surgical lesions in the brain abolished rigidity without affecting movement refuted this interpretation. Thus slowness and lack of natural movements (bradykinesia and hypokinesia, respectively) are not derived from rigidity but are independent manifestations of the disease. The bradykinetic deficits underlie the characteristic poverty of movement, reflected also 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, and most of the other aspects of the parkinsonian countenance. 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. Speech softens and seems hurried, monotonous, and mumbling (cluttered): The voice becomes less audible and, finally, the patient only whispers. Caekebeke and coworkers refer to the speech disorder as a hypokinetic dysarthria and attribute it to combined respiratory, phonatory, and articulatory dysfunctions. There is a failure to fully close the mouth. 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 balance, and in walking forward or backward seems to be "chasing" the body's center of gravity with a series of increasingly rapid 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 improved by sensory guidance, as by holding the patient at the elbow. Obstacles such as door thresholds have the opposite effect, at times causing the patient to "freeze" in place. Getting in and out of a car or elevator or walking into a room or in a hall becomes particularly difficult. Difficulty in turning over in bed is a similarly characteristic feature as the illness advances, but the patient rarely volunteers this information. Several of our patients have fallen out of bed at a frequency that suggests a connection to their reduced mobility combined with slowed corrective or defensive postural movements. 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, often quite painful, may enter the picture and are sometimes early findings. (These are particularly resistant to treatment.) A special problem of camptocormia occurs in some Parkinson patients wherein an extreme forward flexion of the spine and correspondingly severe stooping occur. It appears to be a type of axial dystonia when it occurs with Parkinson disease. The deformity resolves when the patient is supine or pushes upward on the handles of a walker. This symptom is associated with a variety of other diseases, some of them muscular. We have not been impressed that it is ameliorated by L-dopa. Why some patients with Parkinson disease are extremely bent over and others are not at all affected is unknown.
As noted above, these various motor impediments and tremors 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 (as escaping from a fire, for example), the patient with all but the most advanced disease is capable of brief but remarkably effective movement (kinesis paradoxica).
Regarding 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 unless dementia supervenes and buccal and jaw jerks are rarely enhanced. Commonly there is an impairment of upward gaze and convergence; if prominent or noted early in the disease, this sign suggests more the possibility of progressive supranuclear palsy. Bradykinesia may extend to eye movements, in that there is 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 findings, but a wide variety of paresthetic and other sensory complaints and discomforts are common. These affect mainly the calves and abdomen and are among the most distressing of the nonmotor parkinsonian symptoms. Drooling is troublesome; an excess flow of saliva has been assumed, but actually the problem is probably one of failure to swallow with normal frequency. Seborrhea and excessive sweating are claimed to be secondary as well, the former due to failure to cleanse the face sufficiently, the latter to the effects of the constant motor activity but this explanation seems lacking to us; an autonomic disturbance is more plausible. Other nonmotor features are mostly in the category of autonomic disturbances and include most prominently constipation, abdominal pains and cramps, erectile dysfunction, joint aches, and various other sensory experiences that may be difficult for the patient to describe. There is a tendency in some patients to have orthostatic hypotension and sometimes syncope; this has been attributed by Rajput and Rozdilsky to cell loss in the sympathetic ganglia. However, these features are not as prominent as in multiple system atrophy (Shy-Drager syndrome). It is worth mentioning that several of our younger Parkinson patients with recurrent syncope proved to have cardiac arrhythmias; hence other causes of fainting must be considered.
Postural instability is a core feature of the illness; it can be elicited by tugging at the patient's shoulders from behind and noting the lack of a small step backward to maintain balance often with a fall or the initiation of backward festination. 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 brisker, 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).
As mentioned earlier, Parkinson disease may be complicated by dementia, a feature described 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 the generally accepted figure and matches our experience. The incidence increases with advancing age and duration of disease, approaching 65 percent in Parkinson patients older than 80 years of age, but mental decline may become apparent in patients in their late fifties. The pathologic basis of the dementia 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, but with a wide range (Hoehn and Yahr; Martilla and Rinne). As much as 10 percent of cases remain relatively mild and only very gradually progressive, and such patients may remain almost stable for 10 years or more. These trajectories have been altered somewhat by modern therapies.
Mentioned here is a rare syndrome described by Klawans and elaborated in a series of 30 patients by Wijemanne and Jankovic. The typical case shows atrophy in one or more body parts, including at times the face, often since childhood, and usually quite subtle. Signs of progressive parkinsonism or dystonia begin in midlife on the atrophic side and, for the most part, are responsive to L-dopa, but some, such as Klawans' original patients, are resistant. Several types of early life cerebral injury underlie the syndrome, but half of patients have no such lesion evident. Understanding of the idiopathic cases is limited. Those with deep brain lesions may be experiencing a slow degeneration of basal ganglia pathways.
The 2 main difficulties are to distinguish typical Parkinson disease from the many parkinsonian syndromes caused by other degenerative conditions and by medications or toxins, and to distinguish the Parkinson tremor from other types, especially essential tremor. It is worth noting that Parkinson disease is far more common than any of the degenerative syndromes that resemble it. Bradykinesia and rigidity of the limbs and axial musculature are symptoms shared with other forms of parkinsonism, but it is mainly in Parkinson disease that one observes an early sign of "resting" alternating tremor that is more prominent in one arm.
When not all the typical signs are evident, there is no alternative but to reexamine the patient at several-month intervals until it is clear that Parkinson disease is present or until the characteristic features of another degenerative process become evident; these include early falls and vertical gaze impairment in progressive supranuclear palsy; dysautonomia with fainting, bladder, or vocal cord dysfunction in multiple system atrophy; early and rapidly evolving dementia or intermittent psychosis in Lewy-body disease; or apraxia in corticobasal ganglionic degeneration. Very symmetrical findings, particularly tremor, suggest an alternative to idiopathic Parkinson disease. Also, the constellation of features termed "lower half parkinsonism" consisting of difficulty purely with gait and stability, as discussed below and in Chap. 7, suggest a process other than Parkinson disease.
If the symptoms warrant, a beneficial and sustained response to levodopa or a dopamine agonist also gives a reasonably secure, although not entirely conclusive, indication of the presence of Parkinson disease (see further on). The other parkinsonian syndromes are for the most part changed only slightly or only for a few weeks or months by the drug. Conversely, although some experts disagree, we have adhered to the notion that complete resistance of the symptoms to L-dopa early in the illness makes the diagnosis unlikely. Furthermore, almost all patients with idiopathic Parkinson disease eventually acquire dyskinesias in response to L-dopa and the absence of this sign after approximately 3 to 5 years of use of the drug brings the diagnosis into question.
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 to 1918, and very few have been seen since 1930; hence, this type of postencephalitic parkinsonism is no longer a diagnostic consideration. However, a Parkinson-like syndrome has been described following other forms of encephalitis, particularly with Japanese B virus, West Nile virus, and eastern equine encephalitis. In the few cases caused by these viruses that we have observed, there has been fairly symmetrical rigidity, hypokinesia, and little or no tremor.
An "arteriopathic" or "arteriosclerotic" form of Parkinson disease was at one time much diagnosed but we have never been entirely convinced of its reality, referring to damage to the substantia nigra as a result of vascular disease or to a syndrome that closely resembles Parkinson disease as a result of atherosclerotic white matter damage. Nonetheless, a number of authoritative clinicians are of the opinion that patients with a vascular cause have a predominantly "lower half" parkinsonism in which shuffling gait, stickiness on turning, and falling are disproportionate to other features. There is no tremor, and little or no response to L-dopa (see Winikates and Jankovic). MRI in such cases has shown substantial white matter changes in both cerebral hemispheres. In the few cases attributable to vascular parkinsonism that have come to our attention with autopsy material, there have been Lewy bodies in the appropriate locations. Pseudobulbar palsy from a series of lacunar infarcts or from Binswanger disease can cause a clinical picture that simulates 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 elderly parkinsonian patient is not impervious to cerebrovascular disease, and the 2 conditions overlap, but differentiating the predominantly gait or dementing disorders of widespread vascular brain damage from idiopathic Parkinson disease is not difficult.
Normal-pressure hydrocephalus can undoubtedly produce a syndrome resembling Parkinson disease, particularly in regard to gait and postural instability, and at times extending to bradykinesia; but rigid postures, slowness of alternating movements, hypokinetic ballistic movements, and resting tremor are not part of the clinical picture. The gait tends to be short-stepped but not shuffling and there is more of a tendency to retropulsion than there is in Parkinson disease. Sometimes a lumbar puncture gives surprising benefit, indicating hydrocephalus as the cause of the motor slowing and gait disorder.
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 or of flexed postures. Cogwheeling of minor degree may be associated. The head and voice are more often truly tremulous in essential tremor than in Parkinson disease. Some of the slower, alternating forms of essential tremor are difficult to distinguish from parkinsonian tremor; one can only wait to see whether it is the first manifestation of Parkinson disease. A markedly asymmetrical or unilateral tremor favors Parkinson disease. Also as noted, a faster oscillation is often mixed with the slow alternating Parkinson tremor, but the fast-frequency tremor is only occasionally an opening feature of the disease as discussed in Chap. 6.
Progressive supranuclear palsy (discussed in a section 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 vaguely suggestive of Parkinson disease. Early and frequent falls are particularly suggestive of this disease, not being atypical of Parkinson disease until its late stages. Inability to produce vertical saccades and, later, paralysis of upward and downward gaze and eventual loss of lateral gaze with retention of reflex eye movements establish the diagnosis of PSP in most cases.
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 type of depression. Because a fair proportion of parkinsonian patients are depressed, the separation of these 2 conditions is at times difficult. 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. Several such patients have nonetheless insisted that levodopa helps them in some nondescript way.
The rapid onset of parkinsonism should suggest exposure to neuroleptic medications (used at times as antiemetics and gastric motility agents [metoclopramide]), a variant of Creutzfeldt-Jakob disease, an unusual postinfectious or paraneoplastic illness, or viral encephalitis. The implicated drugs 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). Even the newer antipsychosis medications, favored specifically because of a putative lack of extrapyramidal effects, may be at fault.
Strict adherence to the diagnostic criteria for Parkinson disease also permits its differentiation from corticostriatospinal, striatonigral, and corticobasal ganglionic degeneration, calcification of the basal ganglia, Wilson disease, the acquired hepatolenticular degeneration of repeated hepatic coma, manganese poisoning, as well as Machado-Joseph disease, all of which are discussed in other parts of this chapter.
All in all, if one adheres to the standard definition of Parkinson disease—bradykinesia, hypokinesia "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 ostensible explanation for this difficulty is that approximately one-quarter of Parkinson patients fail to display the characteristic tremor and approximately 10 percent are said to not respond to L-dopa. These authors noted that early dementia and autonomic disorder and the presence of ataxia or corticospinal signs were reliable guides to an alternate diagnosis.
Pathology and Pathogenesis
The most constant and pertinent finding in both idiopathic and postencephalitic Parkinson disease is a loss of pigmented cells in the substantia nigra and other pigmented nuclei (locus ceruleus, dorsal motor nucleus of the vagus). The substantia nigra is visibly pale to the naked eye; microscopically, the pigmented nuclei show a marked depletion of cells and replacement gliosis, and some of the remaining cells have reduced quantities of melanin, 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, surrounded by a faint halo, called Lewy bodies (Fig. 39-5). These are seen in practically all cases of idiopathic Parkinson disease. They were generally absent in postencephalitic cases, but there were neurofibrillary tangles within nigral cell in that disorder. Both these cellular abnormalities appear occasionally in the substantia nigra of aged, nonparkinsonian individuals. Possibly the individuals with Lewy bodies would have developed Parkinson disease had they lived a few more years. Many of the inherited forms of Parkinson disease also lack Lewy bodies.
Photomicrograph of a round Lewy-body inclusion in the cytoplasm of a nigral neuron. (Hematoxylin and eosin [H&E] staining.) (Courtesy of Matthew Frosch, MD, PhD.)
Noteworthy is the finding by McGeer and colleagues that nigral cells normally diminish with age, from a maximal complement of about 425,000 to 200,000 at age 80 years. Tyrosine-hydroxylase, the rate-limiting enzyme for the synthesis of dopamine, diminishes correspondingly. However, these authors and others have found that in patients with Parkinson disease the number of pigmented neurons is reduced to 30 percent or less 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 in absolute numbers by 66 percent in Parkinson patients. (The number of nonpigmented neurons was reduced in Parkinson cases by only 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 regions of neuronal loss are widespread as mentioned, but 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 neuronal populations in the putamen, caudatum, pallidum, and substantia innominata. On the other hand, 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. An alternative hypothesis offered by Braak and Tredici, mentioned in an earlier section of this chapter and attributed to Braak and Braak, is that the substantia nigra compacta is affected only late in the pathobiology of Parkinson disease. Their study found that the earliest changes in the brain occur in the dorsal glossopharyngeal-vagal and anterior olfactory nuclei, and only later did they appear in the midbrain nuclei. This theory accommodates a variety of clinical features and potential environmental triggers to the disease. Lang has suggested that this distribution of cell loss explains some of the nondopaminergic features of the disease and offers other avenues for therapy.
Statistical data relating Parkinson and Alzheimer diseases are difficult to assess because of different methods of examination from one series to another. Nevertheless, the overlap of the 2 diseases is more than fortuitous, as indicated earlier in this chapter. The majority of the demented Parkinson patients show some Alzheimer-type changes but there are some in whom few plaques or neurofibrillary changes can be found and instead display cortical neuronal loss accompanied by widespread distribution of Lewy bodies, marking the process as Lewy-body dementia and not Parkinson disease.
Of interest had been the observation, both in humans and in monkeys, that a neurotoxin (known as MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]) produces irreversible signs of parkinsonism and selective destruction of cells in the substantia nigra. The toxin, an analogue of meperidine, which was self-administered by addicts, binds with high affinity to monoamine oxidase, an extraneural enzyme that transforms MPTP to a toxic metabolite, pyridinium MPP (1-methyl-4-phenylpyridinium). The latter is bound by the melanin in the dopaminergic nigral neurons in sufficient concentration to destroy the cells. The mechanism by which MPTP produces the clinical aspects of the Parkinson syndrome is unsettled. One hypothesis is that the inner segment of the globus pallidus is rendered hyperactive because of reduction of the influence of gamma-aminobutyric acid (GABA) of the subthalamic nucleus. The notion of some other environmental toxin as a cause of Parkinson disease has been stimulated by the MPTP findings (see Uhl et al; also the review by Snyder and D'Amato). For example, Parkinson disease is slightly more frequent in industrialized countries and in agrarian regions where organophosphates are commonly used, but its universal occurrence would argue against this hypothesis. Despite extensive study, no chemical toxin, heavy metal, or infection has been causally related to the disease. Some plausible theories hold that a toxin might be implicated only on a genetic background predisposing to the disease. The MPTP disease serves as a model for the neurophysiologic and neurochemical changes of Parkinson disease because of destruction of the substantia nigra, but in most other respects it does not reflect the naturally occurring disorder (including the absence of Lewy bodies).
Considering its frequency, coincidence in a family on the basis of chance occurrence might be as high as 5 percent. However, careful epidemiologic studies suggest that a familial occurrence may be as high as 15 percent. A lack of concordance of Parkinson disease in twins was at first thought to negate the role of genetic factors, but a study of dopamine metabolism using PET scanning showed that 75 percent of asymptomatic twins of Parkinson patients had evidence of striatal dysfunction, whereas only a small portion of dizygotic twins showed these changes (Piccini et al). These data indicate a substantial role for inherited traits, even in cases of ostensibly sporadic Parkinson disease (see below regarding the better defined inherited forms). Some mutations and polymorphisms are more clearly modifying factors in producing the disease, but others act as dominant disease genes. These are summarized in Table 39-3. We have chosen to retain the nomenclature of the PARK genes for ease of exposition but, as the genes are sequenced, their names have replaced this generic notation in many summaries of the genetics of the disease.
Table 39-3 Main Genetic Defects Associated with Parkinson Disease ||Download (.pdf)
Table 39-3 Main Genetic Defects Associated with Parkinson Disease
AGE OF ONSET
Park1 & Park4
Two main mutations—A53T, A30P—promote oligomerization of α-synuclein.
Accounts for 50% of early-onset inherited PD; 20% of "sporadic" early-onset cases.
Resembles idiopathic PD.
UCHL-1 (ubiquitin esterase)
Two different polymorphisms confer risk of PD.
Mutations decreased recycling of ubiquitin monomers.
PINK1 (PTEN-induced putative kinase 1)
Slow progression; gene plays role in cellular response to oxidative stress.
LRRK2 (leucine-rich repeat kinase 2)
Ashkenazic Jews. Protein also called dardarin; related to Gaucher disease.
PLA2G6 (phospholipase A2)
Dystonia-parkinsonism; late onset; other mutations cause neuroaxonal dystrophy.
NURR1 (nuclear receptor related protein 1)
Confers susceptibility to PD
Gene is implicated in the formation and identity of dopaminergic neurons.
Numerous observations have implicated the nuclear and synaptic protein α-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, a normal component of the synapse, exists in a soluble unfolded form, but in high concentrations it aggregates into filaments, which are the main (but not the only) constituent of the Lewy body. Immunostaining techniques disclose additional less-specific proteins, such as ubiquitin and tau within the Lewy bodies. Furthermore, in families with a rare autosomal dominant form of Parkinson disease, several different mutations on chromosome 4 code for an aberrant form of synuclein that decreases its stability and promotes its aggregation (Polymeropoulos et al). A family has also been described in which the cause of Parkinson disease is an extra nonmutant copy of the α-synuclein gene (Singleton et al), comparable to the circumstance or triplication of chromosome 21 in the Alzheimer disease of Down syndrome. Additionally, some cases of familial parkinsonism result from mutations that control the removal of α-synuclein from the cell via proteasomal pathways. Together, these findings indicate that instability or misfolding of α-synuclein or its deficient removal may be a primary defect in the disease. The protofibrillary form of the protein (i.e., a soluble protein in the cytosol) is also toxic to dopaminergic neurons. These processes are accelerated by defects in heat shock proteins that chaperone α-synuclein into and out of the cell. Curiously, Lewy bodies are not found in patients with most of the parkin mutations.
Parkin is a ubiquitin protein ligase that participates in the removal of unnecessary proteins from cells through the proteasomal system (Fig. 39-6). Attachment of parkin and ubiquitin to cytosolic proteins is understood to be an obligatory step in the disposal of proteins by proteasomes. Mutations in the parkin gene lead either to an inadequacy or misfolding of synuclein, resulting in its accumulation, or to the disruption of disposal of proteins in dopamine-producing cells. The importance of the ubiquitination pathway in this disease is further highlighted by the report that parkinsonian features are present in a family with mutations in ubiquitin carboxyterminal hydrolase L1 (Park5, UCHL-1; Table 39-3). Figure 39-6 illustrates these relationships and the processing of synuclein in the cell. It must be emphasized that most of the mechanisms illustrated are speculative or are derived from the molecular study of familial Parkinson disease and therefore may not apply to the sporadic process.
Schematic diagram of proposed mechanisms of α-synuclein toxicity in Parkinson disease. In this model, α-synuclein levels are elevated by (a) duplication of one copy of the α-synuclein gene; (b) point mutations in the α-synuclein gene that generate excessive accumulations of synuclein; or (c) mutations in parkin and UCH-L1 genes that reduce normal removal of synuclein by the proteosomes. The excess of synuclein polymerizes to form protofibrils, a process that is enhanced by defects in heat shock proteins (Hsps) or by the action of dopamine, which binds to synuclein. In turn, this leads to formation of Lewy bodies. This model attributes the neurotoxicity to either the protofibrils or the Lewy bodies. (Adapted by permission from Eriksen JL, Dawson TM, Dickson DW, Petrucelli L: Caught in the act: α-Synuclein is the culprit in Parkinson's disease. Neuron 40:453–456, 2003.)
A mutation that has received much attention has been at the LRRK2 (leucine-rich repeat kinase 2) site. It is implicated in both genetic and sporadic forms of the disease, particularly among those of Ashkenazic Jewish or North African origin. The LRRK2 protein (dardarin) is a cytoplasmic component that is widely distributed in the brain and peripheral nerves. It has been estimated that mutations in the gene (mainly one common one, G20195) are responsible for 1 percent of sporadic cases and are found in 5 to 8 percent of individuals with a first-degree relative who has the disease. The gene acts as a dominant trait but penetrance of the defect increases with age, being 85 percent at 70 years. Therefore, there may not be a family history. The clinical syndrome in most respects simulates the sporadic form of the disease according to Papapetropoulos and colleagues, but several other series have noted the absence of tremor. The genetics of this disorder, also called Park8, are reviewed by Brice.
Several other gene defects are of interest in familial parkinsonism. One is a dominantly inherited mutation in the gene Nurr1, whose normal function is to specify the identity of dopaminergic neurons. Another is in recessively inherited parkinsonism caused by defects in the gene DJ-1, a protein that is essential for the normal neuronal response to oxidative stress. Also, a disease-causing mutation in the gene termed PINK, corresponding to Park6, codes for a mitochondrial kinase, therefore implicating this cellular structure in some forms of Parkinson disease (Valente et al). Presumably, dopaminergic neurons are compromised in some manner by these defects.
There has also been emphasis on mutations on 1 of 12 exons in the so-called Park2 gene, which codes for the protein parkin (see Table 39-3). The most common types are point mutations or deletions in exon 7, but abnormalities of the other exons evince similar syndromes. Homozygous mutations generally give rise to early-onset disease, but certain hemizygous changes (in exon 7) are associated with a later onset. The resultant syndromes have been termed parkin disease to distinguish them from the idiopathic variety. It has been estimated by Khan and colleagues that 50 percent of families that display an early onset of Parkinson disease and 18 percent of sporadic cases with early onset (before age 40 years) harbor mutations in this gene. Perhaps of greater clinical interest is finding that up to 2 percent of late-onset cases are associated with parkin mutations, and 1 percent due to changes in the aforementioned LRRK2 gene. Sequencing of these genes is now available in commercial laboratories for the purposes of detecting mutations and polymorphisms.
From a clinical perspective, the presentation of the late-onset cases with parkin mutations has been quite variable. Collectively, they can often be identified by an extreme sensitivity to L-dopa, maintaining an almost complete suppression of symptoms over decades with only small doses of medication; also, they have a low threshold for dyskinesias induced by L-dopa. We can also corroborate from experience with our own patients an excellent response of tremor, postural changes, and bradykinesia to anticholinergic drugs. A second feature has been that most of these patients may enjoy a remarkable restorative benefit from sleep, which creates a diurnal pattern of symptoms. Several series, particularly those of Lohmann and associates and of Khan and colleagues, have indicated that there may be a wide variety of additional features: hyperreflexia, cervical, foot, or other focal dystonias, sometimes induced by exercise; and, less often, autonomic dysfunction, peripheral neuropathy, and psychiatric symptoms. The sensitivity to medication and sleep benefit have long been known as the distinguishing components of juvenile-onset parkinsonism with dopa-responsive dystonia (Segawa disease), which is discussed later in the chapter.
Of similar interest as a modulating factor in the development of the disease is strong association between mutations in the glucocerebrosidase gene (other mutations of which causes Gaucher disease) among Ashkenazi Jews (Sidransky et al), the same population predominantly affected by polymorphisms of LRRK2. Although population studies allow only limited conclusions about clinical correlations, the glucocerebrosidase mutation is present more often in patients with a family history of the disease, have an earlier onset that in patients with a normal gene and a lower incidence of resting tremor. Mutations have been present in 7 percent of Parkinson patients who had their genes fully sequenced, making it so far the most common genetic factor for the disease, and certainly in this ethnographic population.
It is hoped that the genetic mutations that give rise to Parkinson disease will expose the molecular pathophysiology of the disease. As discussed earlier, several sites are implicated in the familial forms of Parkinson disease, some related to the gene that codes for synuclein, the main component of the Lewy body.
Although there is no current treatment that clearly halts or reverses the neuronal degeneration underlying 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 (Table 39-4). The following sections are necessarily detailed so as to give the clinician a full comprehension of the use and side effects and interactions of these drugs.
Table 39-4 Drugs Commonly Used in the Treatment of Parkinson Disease ||Download (.pdf)
Table 39-4 Drugs Commonly Used in the Treatment of Parkinson Disease
25/100 mg tid
Up to 50/250 mg q3h
Reduction of tremor and bradykinesia; less effect on postural difficulties
Nausea, dyskinesias, orthostatic hypotension, hallucinations, confusion
Controlled release carbidopa-L-dopa
25/100 mg tid
Up to 50/200 mg q4h
May prolong L-dopa effects
0.25 mg tid
9 to 24 mg/d
Moderate effects on all aspects; reduced motor fluctuations of L-dopa
Orthostatic hypotension, excessive and abrupt sleepiness, confusion, hallucinations
0.125 mg tid
0.75 to 3 mg/d
100 mg bid–tid
Smoothing of motor fluctuations
Leg swelling, congestive heart failure, prostatic outlet obstruction, confusion, hallucinations, insomnia
Up to 4 mg/d
Tremor reduction, less effect on other features
Atropinic effects: dry mouth, urinary outlet obstruction, confusion, and psychosis
0.5 mg bid
Up to 2 mg tid
200 mg with L-dopa
Prolonged effect of L-dopa
Urine discoloration, diarrhea, increased dyskinesias
1 mg daily
Reduced "off" time, Potential neuroprotection
Hypertensive crisis with tyramine-rich foods and sympathomimetics
5 mg bid
L-Dopa and L-Dopa–Modifying Drugs
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. The levodopa, or a dopamine agonist preparation as described below, is introduced when the symptoms begin to interfere with work and social life or falling becomes a threat, and then these drugs are used at the lowest possible dose. 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 diseased nigral cells are still capable of producing some dopamine by taking up its precursor, L-dopa. The number of neurons in the striatum is not diminished and they remain receptive to ingested dopamine acting through the residual nigral neurons. Over time, however, the number of remaining nigral neurons 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. The drug has an interesting history that includes many early trials that failed to persuade neurologists of its effectiveness; Barbeau's paper on this historical subject may be consulted by the interested reader.
Most patients tolerate the drug initially, experiencing few serious adverse effects and showing various degrees of improvement, sometimes dramatic, especially in hypokinesia and tremor after several days or sooner. However, the side effects and limitations of L-dopa become considerable as the drug therapy continues and the disease progresses, as discussed below.
By combining L-dopa with a decarboxylase inhibitor (carbidopa or benserazide), which is unable to penetrate the central nervous system (CNS), 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, reduces the peripheral side effects of L-dopa and dopamine (nausea, hypotension, confusion). Combinations of carbidopa-levodopa are available in a 1:10 or 1:4 ratio and the benserazide-levodopa combination is available in a 1:4 ratio. The initial dose of carbidopa-levodopa is typically one-half to one of a 25/100-mg tablet given bid or tid and increased slowly until optimum improvement is achieved, usually up to 4 tablets administered 5 or more times daily as the disease advances, or a similar dose of the 25/250-mg combination.
A class of catechol-O-methyltransferase (COMT) inhibitors, typified by entacapone, extends the plasma half-life and the duration of L-dopa effect by preventing its breakdown (as opposed to increasing its bioavailability, as in the case of carbidopa). A combination of L-dopa, carbidopa, and a COMT inhibitor is available in a single pill.
Long-acting preparations of levodopa-carbidopa may provide slightly longer effect and 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 of disease has given less-predictable results. The absorption of the long-acting drug, however, is approximately 70 percent and may be inconsistent, often necessitating a slight increase in total dose. To facilitate the treatment of morning rigidity and tremor, the long-acting tablet can be given late in the previous evening.
For patients who require very frequent but small doses of the drug because of severe motor fluctuations and dyskinesias, an oral suspension may be formulated that allows precisely measured doses to be delivered orally or through a nasogastric tube. The typical composition is 500 mg L-dopa (of carbidopa-L-dopa 10/100 or 25/100), 500 mg of ascorbic acid to stabilize the drug, and 250 mL of water, resulting in a concentration of L-dopa of 2 mg/mL, which is administered in small amounts. A gel preparation is also available for delivery through a duodenal tube.
Each patient requires empirical adjustment of the dose and timing of medication and then generally does well by maintaining a relatively regular medication schedule, supplemented by small intercalated doses when needed. The effect of L-dopa may be virtually immediate (i.e., after absorption, which occurs over 30 to 40 min) but there is a further cumulative effect over several days of consistent dosing. The principles that guide the adjustment of dosing (end-of-dose wearing off, dyskinesias, freezing, confusion) are discussed further on.
These drugs have a direct dopaminergic effect on striatal neurons, thereby partially bypassing the depleted nigral neurons. They have found a place both as the initial treatment, replacing L-dopa in this role, and in modulating the effects of L-dopa later in the illness. However, dopamine agonists are consistently less potent than L-dopa in managing the main features of Parkinson disease and, in higher doses and in older individuals, they produce undesirable motor and cognitive side effects (see further on). They are favored because they are associated with fewer dyskinetic motor complications, or at least, delay the need for L-dopa and its dyskinetic effects. Bromocriptine and lisuride are synthetic ergot derivatives whose action in Parkinson disease is explained by their direct stimulating effect on dopamine (D2) receptors located on striate neurons. The nonergot dopamine agonists ropinirole and pramipexole have a similar type and duration of effectiveness and are used more widely because of their minimal ergot-like effects. Pergolide and the related drug cabergoline are no longer used because of the risk of cardiac valvular damage, particularly at higher dose levels.
The dopamine agonists are introduced gradually. For example, the initial dose of pramipexole is 0.125 mg tid, following which the dosage is doubled weekly to a total of 3 to 4.5 mg/d if the medication is used without L-dopa. If an individual is already taking L-dopa, these drugs usually permit a gradual reduction in levodopa-carbidopa dose by approximately 50 percent. Their duration of action is slightly longer than that of L-dopa and they cause less nausea. These medications may be also useful in reducing the motor fluctuations of L-dopa.
Our experience is in general agreement with that of Marsden, who found that of 263 patients given dopamine agonists as the sole treatment, 181 had abandoned medication after 6 months because of lack of effect or adverse reactions. Nevertheless, the fact that a large enough proportion of patients continue to benefit for up to 3 to 5 years indicates that the initial use of dopamine agonists has merit (see also Rascol et al). A recent development of some interest is a transdermally absorbed dopamine agonist such as rotigotine. Several trials suggest that the transdermal system can maintain a stable plasma level of the drug. In the study by LeWitt and associates, the main effect was a doubling of "on" time without unwanted dyskinesias. The effects on the quality of life in Parkinson patients appear to be positive but minor in degree. Skin reactions are common and the sulfites used in the patch formulation can cause severe systemic reactions in sensitive individuals.
Even small doses of dopaminergic drugs, when first introduced, may induce orthostatic hypotension, but most patients are tolerant of them. They may also produce abrupt and unpredictable sleepiness, and patients should be warned of this possibility in relation to driving. In some individuals, particularly the elderly, dopamine agonists may produce hallucinosis or confusion; these problems are most profound in patients who are later determined to have Lewy-body disease (see further on). More data are required to judge the efficacy of the current trend of initiating therapy with a dopamine agonist rather than with L-dopa.
Many clinicians initiate treatment with small amounts of a dopamine agonist, at least as much for the putative delay of dyskinesias that they offer in comparison to starting L-dopa. Alternatively, carbidopa/L-dopa tid can be initiated and supplemented over a month with a dopamine agonist. The side effects and subtleties of dosing are explained in the sections above on each of these classes of drug. The issue of also starting an MAO inhibitor such as rasagiline early in the illness is discussed below.
Because of the side effects of levodopa and of dopaminergic agents, some neurologists avoid pharmacotherapies if the patient is in the early phase of the disease and the parkinsonian symptoms are not troublesome. When the predominant manifestation is tremor, very satisfactory results can be obtained in some patients for up to several years with anticholinergic agents alone. The anticholinergic drugs have limited effect on the postural, hypokinetic, and other manifestations of disease. Koller's study, which quantified the effect of anticholinergic medication on tremor and compared it to L-dopa, concluded that there was considerable variability in response between patients but that L-dopa was on average more effective. Nonetheless, anticholinergic agents have long been in use for the treatment of tremor in younger patients and we still use them occasionally, either in conjunction with L-dopa or in patients who cannot tolerate the latter drug. The optimum dosage level is the point at which the greatest relief from tremor is achieved within the limits of tolerable side effects, mainly dry mouth. In older patients, one must be alert to changes in cognitive function, hallucinations, and urinary outflow obstruction.
Several synthetic preparations of anticholinergic drugs are available, the most widely used ones being trihexyphenidyl (beginning with 1 to 2 mg/d and increased up to 6 to 8 mg over several weeks) and benztropine mesylate (1 to 4 mg/d in divided doses). When it has been available, we have also had success with the related agent ethopropazine (50 to 200 mg daily in divided doses; but it has become difficult to obtain). The effects on tremor are cumulative and may not be evident for several days. 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, constipation, and urinary retention as mentioned (especially with prostatism). The presence of angle closure glaucoma is a contraindication to its use. Tremor abates in several days and most of our patients have become tolerant to the dry mouth after several weeks. Pyridostigmine, propantheline, or glycopyrrolate can be given to reduce the oral dryness.
With higher dose ranges, mental slowing, confusional states, hallucinations, and impairment of memory in elderly patients—specifically if there is already some degree of forgetfulness—are side effects that limit usefulness. Occasionally, further benefit may accrue from the addition of another antihistaminic drug, such as diphenhydramine or phenindamine.
The antiviral agent amantadine (100 mg bid) has mild or moderate benefit for tremor, hypokinesia, and postural symptoms. In some patients, it reduces L-dopa–induced dyskinesias (see further on). Its mechanism of action is unknown but antagonism of NMDA or release of stored dopamine has been proposed. It should be noted that amantadine commonly causes leg swelling, may worsen congestive heart failure, and can have an adverse effect on glaucoma, as well as exaggerate the cognitive changes associated with anticholinergic medications. The use of the centrally acting anticholinesterase, donepezil, is being explored for a possible effect on improving gait stability but requires further study. Finally, the monoamine oxidase inhibitors, described just below as putative neuroprotective agents, have a beneficial effect on motor fluctuations induced by L-dopa and may have a slight beneficial effect on the main Parkinson symptoms as described in several trials, such as the one reported by Rascol and colleagues.
An additional approach, still somewhat controversial, has been to initiate treatment early in the course of the disease with a monoamine oxidase-B inhibitor (MAO-B inhibitor), with the aim of reducing oxidative stress in dopaminergic neurons. The DTAATOP trial conducted by The Parkinson Study Group (1989) reported a slowing of disease progression but later followup showed little difference between treated and untreated groups. Other agents in this class, notably rasagiline, have given similar mixed results in brief studies including the ADAGIO trial reported by Olanow and coworker. The difficulty in assessing the benefit of these agents has to do with their mild but definite symptomatic benefit on motor function. A credible long-term study has reported that early initiation of treatment with bromocriptine (now little used) did not reduce mortality or motor disability over 14 years and that any reduction in motor complications was unsustained (Katzenschlager et al). Nonetheless, we institute one of these MAO-B inhibitors in many patients.
Following this same line of reasoning, several studies, most still disputed or unconfirmed, have suggested that ropinirole, pramipexole, and even L-dopa have "neuroprotective" effects in Parkinson disease. However, slowing of the progression of symptoms, as measured by a variety of scales, has not been corroborated. Technical problems in interpreting these results are discussed at length in the reviews by Wooten and by Clarke and Guttman. The uncertainties have to do with clinical grading systems, functional imaging techniques, and points of comparison to treatment with 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 neurologists continue to adhere to this idea. Cedarbaum and colleagues, 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 predisposed to the development of fluctuations in motor response or to dyskinesia and dementia. In fact, the findings of the "Elldopa" trial by The Parkinson Study Group (2004) were that functional and other measures were better in patients who had taken L-dopa for 40 weeks and then stopped the medications than in those who received no medication. Neuropathologic study of the substantia nigra in the brains of Parkinson patients and their medication histories also failed to corroborate a reduction in the number of pigmented neurons (Parkkinen et al). Also, the large multicenter study reported by Diamond and colleagues indicated that patients who were given L-dopa early in the disease actually survived longer and with less disability than those who began the medication late in the course; that is, L-dopa may have itself been neuroprotective. However, there have been many alternative interpretations of these data.
Finally, attempts to slow the disease by vitamin antioxidants such as vitamin E have met with mixed, but generally negative, results. A possible exception was the trial of coenzyme Q10 by Shults and colleagues. Massive doses of this agent, 1,200 mg/d, were found to offer marginal advantages on the progression over 6 to 18 months as measured by certain scores of overall daily function but not on most neurologic scales. Further study of this approach is advised.
Side Effects of Dopamine Treatment and Their Management
The side effects of L-dopa are at times significant to the degree that its continuation cannot be tolerated. Some patients are at first troubled by nausea, although this can be mitigated by taking the medication with meals. Nausea usually disappears after several weeks of continued use or can be allayed by the specific dopaminergic chemoreceptor antagonist domperidone. A few have mild orthostatic hypotensive episodes.
The most troublesome effects of L-dopa as the disease advances, usually after several years of treatment, are end-of-dose reduction in efficacy and the induction of involuntary "dyskinetic" movements—restlessness, head wagging, grimacing, lingual-labial dyskinesia, blepharospasm, and especially, choreoathetosis and dystonia of the limbs, neck, and trunk. A decline in efficacy at the end of the dose interval, typically 2 to 4 h, may be treated by more frequent dosing, the addition of dopaminergic agonist, or a COMT inhibitor.
The on–off or off phenomenon is a rapid and sometimes unpredictable change—in a matter of minutes or from 1 h to the next—from a state of relative freedom from symptoms to one of nearly complete immobility. Both dyskinesias and severe "off" periods appear in approximately 75 percent of patients within 5 years. Few patients escape these opposing effects, forcing an increased frequency of administration and usually a reduction in dosage.
If involuntary dyskinetic movements are induced by relatively small doses of L-dopa, the problem may be suppressed to some extent by the addition of direct-acting dopaminergic agents or by the concurrent administration of amantadine, or by the use of an oral suspension of L-dopa as mentioned earlier. The use of lower doses of long-acting preparations of L-dopa may be helpful in reducing dyskinesias and the atypical antipsychotic medications have been said to be useful for this purpose but carry their own risks.
The onset of psychiatric symptoms coincident with the use of L-dopa or dopamine agonists may also present problems and is to be expected eventually in 15 to 25 percent of patients, particularly in the elderly. Confusion and outright psychosis (hallucinations and delusions) are seen in advanced cases of Parkinson disease when high doses of L-dopa are required and the disease has been present for many years. This may first be treated by reducing the dose of the drug. If this is not tolerated, the atypical neuroleptics olanzapine, clozapine, risperidone, or quetiapine may be given in low doses. The side effects of these drugs include sleepiness, orthostatic hypotension, and sialorrhea. As noted above, clozapine has been said to provide an additional benefit of suppressing dyskinesias in advanced Parkinson disease, but its hematologic risks have led to limited use. Although useful in the treatment of frankly psychotic patients, these drugs tend to be far less effective once dementia has supervened. The antiepileptic drug, valproate is also said to be useful in this circumstance, but it has not been as effective as clozapine and related drugs. Despite its lesser tendency to produce rigidity, olanzapine, and probably the other similar agents, in high doses may slightly worsen motor disability.
Depression, although frequent, is only occasionally a serious problem, even to the point of suicide. Delusional thinking may also occur in these circumstances. This combination of movement and psychiatric disorders is difficult to treat, and one is faced with instituting an antidepressant regimen or perhaps using one of the newer classes of antipsychotic medications that have the least extrapyramidal side effects (see below). While the selective serotonin reuptake inhibitors have been useful in cases of apathetic depression, they may cause slight worsening of parkinsonian symptoms. Trazodone has been helpful in treating depression and insomnia, the latter also being a major problem in some patients. Excitement and aggressiveness appear in a few. A return of libido may lead to sexual assertiveness. Other curious effects of excessive drive from L-dopa and dopamine agonists have been pathologic gambling (the same has been seen in treatment of restless legs syndrome) and cross-dressing (Quinn et al, 1983).
Anticholinergic agents or L-dopa should not be discontinued abruptly in advanced Parkinson disease. If abruptly discontinued, the patient may become totally immobilized by a sudden and severe increase of tremor and rigidity; rarely, a neuroleptic syndrome, sometimes fatal, has been induced by such withdrawal. Reducing the medication dose over a week or so is usually adequate.
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 50 to 100 mg will precipitate dyskinesias; if the dose is lowered by the same amount, the patient may develop disabling rigidity. With the end-of-dose loss of effectiveness and the 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 use more frequent dosing during the 24-h day; combining it with a dopamine agonist or a long-acting preparation may be helpful. Sometimes temporarily withdrawing L-dopa and at the same time substituting other medications may reduce the on–off phenomenon.
Based on the principle that alimentary-derived amino acids compete for absorption of L-dopa, the use of a low-protein diet has been advocated as a means of controlling the motor fluctuations (Pincus and Barry). Symptoms can sometimes be reduced by the simple expedient of eliminating dietary protein from breakfast and lunch. Moreover, this dietary regimen may permit the patient to reduce slightly 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 with advanced disease who have persisted with this diet have reported improvement in their symptoms or an enhanced effect of L-dopa. A novel observation by Pierantozzi and colleagues has been that the absorption of L-dopa may be influenced by the presence of gastric Helicobacter pylori infection and that eradication of the organism was associated with longer "on" time.
Until recently, success with L-dopa had replaced the use of the ablative surgical therapy pioneered by Cooper 50 years ago. The surgical approaches involved the placement of lesions in the globus pallidus, ventrolateral thalamus, or subthalamic nucleus, contralateral to the side of the body chiefly affected. The best results were obtained in relatively young patients, in whom unilateral tremor or rigidity rather than akinesia were predominant. The symptoms that responded least well to surgical therapy in Cooper's patients were postural imbalance and instability, paroxysmal akinesia, bladder and bowel disturbances, dystonia, and speech difficulties.
More recently, through the work of Laitinen, Leksell, and others, this mode of therapy has been revived as a stereotactically guided procedure and advanced by the newer technique of implanted electrodes (deep brain stimulation, DBS). For the treatment of Parkinson disease, the electrodes are placed in the posterior and ventral (medial) parts of the subthalamic nucleus or in the internal segment of the globus pallidus. Most patients who have DBS experience enhanced responsiveness to L-dopa and a reduction of drug-induced dyskinesias. Bilateral stimulation of the subthalamic nucleus has produced improvement in all features of the disease, including in bradykinesia, that is lost after several years, but there is generally little benefit for impaired gait and balance (Limousin et al; Weaver et al, who conducted a more extensive study but for only 6 months). A study by the Deep-Brain Stimulation for Parkinson's Disease Group demonstrated at least short-term benefit in motor fluctuations after the bilateral implantation of stimulating electrodes in the subthalamic nuclei and the durability of this effect with continued DBS in subsequent studies ranged from 2 to 7 years.
The ideal candidates for DBS are considered to be those in whom, after several years, there is a failure of medications to relieve symptoms but especially because of unmanageable dyskinesias that result from L-dopa. A randomized, blinded trial by Deuschl and colleagues confirmed this effect and demonstrated an overall improvement in the quality of life at 6 months. The benefit with bilateral stimulation of the globus pallidus has been essentially equivalent to results from subthalamic stimulation (Follett et al). Dystonia, when present as part of the native disease or as a result of medication, may also benefit from this treatment, perhaps more so with pallidal stimulation. Several groups have pointed out that cognitive function may decline slightly with DBS, but deterioration is not as prominent in some spheres of performance, such as speed of processing, with stimulation of the globus pallidus. Hemorrhage into the basal ganglia and local infection near the stimulator has occurred in a small number of patients so treated. Depression and suicides also appear as adverse events in some stimulation trials.
The typical patient who will derive benefit from deep-brain stimulation is considered to be one who, to maintain mobility, requires a dose of L-dopa that produces unacceptable dyskinesias and who is constantly cycling between on and off periods. More recently, DBS has been introduced earlier in the course of illness, when the patient is still largely responsive to L-dopa and before severe motor complications such as dyskinesias arise. These patients are, of course, younger and have had a shorter duration of disease. In a trial conducted by Schuepbach and coworkers, in patients with mean durations of illness of 7.5 years and 52 years of age, there was a significant and sustained benefit in quality of life measures, motor complications and on time, for subthalamic DBS.
The stimulator is inserted in a pouch that is created near the rostral pectoral muscle and inferior to the clavicle. An external controller allows the stimulator to be adjusted for which 4 electrodes on either side are activated and their polarity, voltage applied, frequency of pulses, and pulse duration are manipulated. All patients with implanted electrodes require frequent initial contact with a physician experienced in programming the stimulator. Some patients can make minor adjustments or even turn off the stimulator on their own with a small control device that has preset limits. The battery must be exchanged periodically, the duration of service depending on the voltage used over time and other parameters of use. A comprehensive review of the subject has been given by Okun, including comments on the controversies regarding the differences in cognitive disturbance and the reduction in L-dopa doses comparing stimulation of the globus pallidus with the subthalamic nucleus.
Presumably, the high-frequency electrical impulses cause a disruption of local neuronal activity that is the functional equivalent of an ablative lesion, but the effects of deep brain stimulation may be more complex by way of stimulating neurotransmitter release.
The cerebral implantation of fetal dopaminergic tissue provided a modest improvement in motor function for a limited period of time (Spencer et al; Freed et al). The study by Freed and colleagues found a small improvement on a global scale that measured functional, psychologic, and neurologic aspects only in younger patients but the effect waned by 1 year. These procedures are hampered by many difficulties, mainly in obtaining tissue and the failure of grafts to survive but also the problem of uncontrollable dyskinesias in some patients. Another provocative approach has been the delivery of neural trophic factors directly or in a viral vector through a small catheter; at least 2 trials have failed to show benefit. Similarly, the implantation of stem cells is being explored but has several obstacles.
Techniques of focused ultrasound energy to produce ablative lesions in deep nuclei are being developed. So far, they have found use for the treatment of essential tremor, such as in the trial conducted by Elias with thalamic lesions (ventral intermediate nucleus).
In the management of the patient with Parkinson disease, one must not neglect the maintenance of general health and neuromuscular efficiency by a program of exercise, activity, and rest; physical therapy and exercises such as those performed in yoga may be of help in achieving these ends. Sleep may be aided by soporific antidepressants. Postural imbalance and falls can be greatly mitigated by the use of a cane or walking frame. A number of excellent exercise programs have been devised specifically for patients with Parkinson disease, and measures such as massage and yoga have their advocates. Among these mechanical therapies that have been studied systematically, tai chi has been found to improve balance and reduce falls as measured by objective criteria (Li et al), indicating that these approaches are of substantial value. Several of our patients have taken up dancing and report that their balance in daily circumstances is improved. Our position has been that any activity that keeps the patient moving and committed is of great value. Speech exercises help the motivated patient.
Hypotensive episodes respond to fludrocortisone or midodrine given each morning. Focal dystonias of the foot are partially treatable with local injections of botulinum toxin. In addition, the patient often needs emotional support in dealing with the stress of the illness, with the anxiety that seems to be an integral part of the disease in some patients, in comprehending the future, and in carrying on courageously in spite of it.
Progressive Supranuclear Palsy
In 1963, Richardson, Steele, and Olszewski crystallized medical thought about a clinicopathologic entity—progressive supranuclear palsy (PSP)—to which there had been only ambiguous reference in the past. The condition is not rare. By 1972, when Steele reviewed the subject, 73 cases (22 with postmortem examinations) had been described in the medical literature. Rare familial clusters have been described in which the pattern of inheritance is compatible with autosomal dominant transmission (Brown et al; de Yébenes et al). Rojo and coworkers described 12 pathologically confirmed pedigrees and made note of the variable phenotypical expression of the disease even within a single pedigree. No toxic, encephalitic, racial, or geographic factor has been incriminated.
The disease has its onset typically in the sixth decade (range: 45 to 75 years), with some combination of difficulty in balance, abrupt falls, visual and ocular disturbances (giving the syndrome its name), slurred speech, dysphagia, and sometimes vague changes in personality, including apprehensiveness and fretfulness suggestive of an agitated depression. The most common early complaint is unsteadiness of gait and unexplained falling without loss of consciousness. The patient has difficulty in describing his imbalance, using terms such as "dizziness," "toppling," or an ambiguous problem with walking. At first, the neurologic and ophthalmologic examinations may be unrevealing, and it may take a year or longer for the characteristic syndrome comprising supranuclear ophthalmoplegia, pseudobulbar palsy, and axial dystonia to develop fully.
Difficulty in voluntary vertical movement of the eyes, often downward but sometimes only upward, and later impairment of voluntary saccades in all directions are characteristic. A related but more subtle sign has been the finding of hypometric saccades in response to an optokinetic drum or striped cloth moving vertically in one direction (usually best seen with stripes moving downward). Later, both ocular pursuit and refixation movements are delayed and diminished in amplitude and eventually all voluntary eye movements are lost, first the vertical ones and then the horizontal ones as well. However, if the eyes are fixated on a target and the head is turned slowly, full movements can be obtained, demonstrating the supranuclear, nonparalytic character of paralysis of ocular pursuit. Other prominent oculomotor signs are sudden jerks of the eyes during fixation, "cogwheel" or saccadic choppiness of pursuit movements, and hypometric saccades of long duration (Troost and Daroff). The Bell phenomenon (reflexive upturning of eyes upon forced closure of the eyelids) and the ability to converge are also lost eventually, and the pupils become small but remain round and reactive to both light and to accommodative stimuli. The upper eyelids may be retracted, and the wide-eyed, unblinking stare imparts an expression of perpetual surprise. Blepharospasm and involuntary eye closure are prominent in some cases. In the late stages, the eyes may be fixed centrally and all oculocephalic and vestibular reflexes are lost. It should be emphasized, however, that a proportion of patients do not demonstrate these eye signs for a year or more after the onset of the illness. We have also followed several patients who had no disorder of eye movement during life but in whom the typical pathologic changes of PSP were nonetheless found. In one such patient, there was a subcortical type of dementia; in another, focal limb dystonia and parkinsonism. Furthermore, other degenerative conditions can manifest a supranuclear vertical gaze disorder, although never to the extent seen in PSP; these include corticobasal-ganglionic degeneration, Lewy-body disease, Parkinson disease, and Whipple disease.
The gait disturbance and repeated falling have proved difficult to analyze, as discussed in Chap. 7. Walking becomes increasingly awkward and tentative; the patient has a tendency to totter and fall repeatedly, but has no ataxia of gait or of the limbs and does not manifest a Romberg sign or orthostatic tremor. Some patients tend to lean and fall backward (retropulsion). One of our patients, a large man, fell repeatedly, wrecking household furniture as he went down, yet careful examination provided no clue as to the basic defect in this "toppling" phenomenon. Along with the oculomotor and balance disorders, there is a gradual stiffening and extension of the neck (in one of our patients it was sharply flexed in a manner consistent with camptocormia) but this is not an invariable finding. The face acquires a staring, "worried" expression with a furrowed brow (a result of the tonic contraction of the procerus muscle), made more striking by the paucity of eye movements. A number of our patients have displayed mild dystonic postures of a hand or foot, especially as the illness advanced but occasionally early on. The limbs may be slightly stiff and there are Babinski signs in a few cases.
The stiffness, slowness of movement, difficulty in turning and sitting down, and hypomimia may suggest a diagnosis of Parkinson disease. However, the facial expression of the PSP patient is more a matter of tonic grimace than of lack of movement, and the lack of tremor, the erect rather than stooped posture, and prominence of oculomotor abnormalities serve to distinguish the 2 disorders. The signs of pseudobulbar palsy are eventually prominent, and this feature, along with the eye movements, distinguishes the process most conspicuously from other degenerative conditions. The face becomes less expressive ("masked"), speech is slurred in a slowed spastic fashion, the mouth tends to be held open, and swallowing is difficult. Forced laughing and crying, said to be infrequent, have been present in about half of our cases late in the course. Many patients complain of sleep disturbances. The total sleep time and REM sleep are reduced, and spontaneous awakenings during the night are more frequent and longer than in normal individuals of the same age. Complaints of urinary frequency and urgency have also been frequent in advanced cases under our care.
The diagnosis often proves difficult to make if the main features are not outstanding. Other features, such as tremor, palilalia, myoclonus, chorea, orofacial dyskinesias, and disturbances of vestibular function, are observed in some cases. Finally the patient becomes anarthric, immobile, and quite helpless. Dementia of some degree is probably present in many cases, but is mild in most. Some patients do become forgetful and appear apathetic and slow in thinking; many others are irritable or at times euphoric. Dubois and colleagues proposed an "applause sign" as distinctive to this disease; the patient fails to stop clapping after being asked to do so only 3 times, but we are unable to corroborate this.
By MRI one can, in advanced cases, appreciate atrophy of the dorsal mesencephalon (superior colliculi, red nuclei) giving rise to a "mouse ears" configuration (Fig. 39-7), but these changes may not be evident early in the illness when diagnosis is most difficult. Several measurements of midbrain atrophy have been proposed as aiding diagnosis; for example, there is little overlap between PSP, multiple system atrophy, and Parkinson disease in the ratio of midbrain-to-pons cross-sagittal area, according to Oba and colleagues. The CSF remains normal. Nonetheless, the diagnosis continues to rest on the clinical features, mainly affecting eye movements.
Progressive supranuclear palsy. T2-weighted axial MRI showing the atrophic dorsal midbrain that gives rise to the "mouse ears" (also "Mickey mouse") appearance.
Postmortem examinations have disclosed a bilateral loss of neurons and gliosis in the periaqueductal gray matter, superior colliculus, subthalamic nucleus, red nucleus, pallidum, dentate nucleus, and pretectal and vestibular nuclei, and to some extent in the oculomotor nucleus. The expected loss of the myelinated fiber bundles arising from these nuclear structures has also been commented upon. The remarkable finding has been the neurofibrillary degeneration of many of the residual neurons. The neurofibrillary tangles are thick and often composed of single strands, either twisted or in parallel arrangement. The neurons of the cerebral cortex have been involved in some cases (shown by staining of tau protein), but these changes do not correlate with dementia. The cerebellar cortex is usually spared.
The cause and nature of this disease remain obscure. Though some clinical and pathologic heterogeneity is seen, the majority of cases of PSP conform to the typical pattern as we have just described. These interesting diagnostic and clinicopathologic aspects are summarized by Williams and Lees. Studies with PET demonstrate a decrease in blood flow, most marked in the frontal lobes, and a lesser extent of oxygen utilization in central structures (Leenders et al). Striatal dopamine formation and storage are significantly decreased when compared with control values. Much current interest has been directed to the neurofibrillary tangles and tau deposition in PSP and a potential link to the tau pathology displayed in frontotemporal dementia and in corticobasalganglionic degeneration (see below). As summarized by Golbe, certain tau gene haplotypes on chromosome 17p (the same site implicated in familial frontotemporal dementia) are more often associated with PSP than in unaffected individuals, but other factors, environmental or genetic, must also be involved. It is intriguing that the tau-gene haplotype of frontotemporal dementia is not found in PSP. A recent investigation into the mechanism of postural instability using functional imaging, showed a correlation between gait instability and decreased thalamic glucose metabolism and activation (Zwergal).
PSP should be suspected whenever an older adult inexplicably develops a state of imbalance, frequent falls with preserved consciousness, and variable extrapyramidal symptoms, particularly dystonia of the neck, ocular palsies, or a picture resembling pseudobulbar palsy. If the typical abnormalities of eye movements are present, the diagnosis is not difficult. When only a parkinsonian syndrome without tremor is apparent the main diagnostic consideration is striatonigral degeneration or the corticobasalganglionic syndrome, described below.
L-Dopa has been of slight and unsustained benefit in some of our patients, and combinations of L-dopa and anticholinergic drugs have been entirely ineffective in others. A marked response to these drugs should, of course, suggest the diagnosis of Parkinson disease. Recently, the drug zolpidem, a gabanergic agonist of benzodiazepine receptors, has been reported to ameliorate the akinesia and rigidity of PSP (Daniele et al); however, these observations require corroboration. Benztropine or trihexyphenidyl has been somewhat helpful in reducing dystonia but botulinum injections may be a better alternative if there are focal signs. Treatments of the sleep difficulties and urinary incontinence are of great assistance to the patient and family. A feeding tube becomes necessary in advanced cases. Observing the decline of these patients and the limitations of treatment is a frustrating ordeal for all involved.
Dystonia Musculorum Deformans (Torsion Dystonia)
Dystonia as a symptom was discussed in Chaps. 4 and 6. Here we are concerned with a disease or diseases of which dystonia is the major manifestation. Schwalbe's account, in 1908, of 3 siblings of a Jewish family who were afflicted with progressive involuntary movements of trunk and limbs probably represents the first description of a disease in which severe and progressive dystonia was the sole manifestation. In 1911, Oppenheim contributed other cases and coined the term dystonia musculorum deformans in the mistaken belief that the disorder was primarily one of muscle and always associated with deformity. Flatau and Sterling, in the same year, first suggested that the disease might have a hereditary basis and gave it the more accurate name torsion dystonia of childhood. At first the condition was considered by some to be a manifestation of hysteria; only later was it recognized as a neurologic entity with a predilection for individuals of Eastern European Jewish origin. Soon thereafter, a second hereditary form of torsion dystonia, affecting non-Jews, was observed. The recessive form begins in early childhood, is progressive over a few years, and is restricted to Jewish patients. The dominant form begins later, usually in late childhood and adolescence, progresses more slowly, and is not limited to any ethnic group.
As indicated in Chap. 6, most instances of idiopathic (primary) dystonias that come to our attention, particularly the segmental or restricted types, do not conform to the classic hereditary disorders as defined above, although some may represent limited variants of the disease. In general, these more restricted types have a later onset and a relatively milder, more slowly progressive course, with a tendency to involve an axial or a distal region alone. Only the paravertebral, cervical, or cranial muscles may be involved (focal dystonia including torticollis and writer's cramp), with little change from year to year. The clinical classification of the predominantly adult-onset dystonias is made more complex by the fact that both the restricted and generalized forms may be sporadic or genetic. Molecular genetic studies, although still incomplete, hold the promise of clarifying the classification of the heritable dystonias. More than 10 types have been distinguished by genetic mapping, as summarized by Németh. The most important of these is an abnormal gene (DYT1, also known as TOR1A) on chromosome 9q, which codes for the protein, torsin A in both Jewish and non-Jewish families. The most common DYT1 mutation, causing deletion of a single glutamate from the torsin A peptide, is found in most cases of dystonia musculorum deformans. This disease is inherited in an autosomal dominant pattern. Although the penetrance of the clinical trait in these families is low, PET demonstrates hypermetabolism in the cerebellum, lenticular nuclei, and supplementary motor cortex in all carriers of the mutated gene.
The function of torsin A is not fully defined. It is present in neurons throughout the brain and has adenosine triphosphate (ATP) binding and nuclear localization. It may function as a chaperone protein that shuttles other proteins in and out of cells. A current speculation, shared with other degenerative disease, is that the absence of torsin A renders neurons unduly sensitive to oxidative stress (Walker and Shashidharan).
Although DYT1 mutations account for the majority of inherited cases of generalized dystonia, they are also implicated in a small proportion of the more restricted dystonias, particularly blepharospasm (see further on). Some individuals in families affected with generalized dystonia will demonstrate only localized forms (e.g., writer's cramp or torticollis). The general rule stated above still holds, namely, that the inherited variety (dystonia musculorum deformans) related to DYT1 manifests early in life and begins in one limb and then spreads to most muscles of the body, while in the common dystonias (mostly sporadic but some heritable) the disease remains confined to the craniocervical or another region, does not generalize, and has an adult onset.
The first manifestations of the generalized disease may be rather subtle. Intermittently, and usually after activity (late in the day), the patient (usually a child between 6 and 14 years of age, less often an adolescent) begins to invert one foot, to extend one leg and foot in an unnatural way, or to hunch one shoulder, raising the question of a nervous tic. As time passes, the motor disturbance becomes more persistent and interferes increasingly with the patient's activities. Soon the muscles of the spine and shoulder or pelvic girdle become implicated in involuntary spasmodic twisting movements. The cardinal feature of these severe dystonic muscle contractions is the simultaneous contraction of both agonists and antagonists at a joint. These cocontraction spasms are intermittent at first; in intervals that are free of the dystonia, muscular tone and volitional movements are normal. In some instances, the muscles are hypotonic. Gradually, the spasms become more frequent; finally, they are continuous and the body may become grotesquely contorted, as shown in Fig. 4-5A. Lateral and rotatory scoliosis uniformly results as secondary deformities. For a time, recumbency relieves the spasms, but later on position has no influence. The hands are seldom involved, although at times they may be held in a fisted posture. Cranial muscles do not escape, and in a few instances a slurring, staccato-type speech was the initial manifestation. Uncontrollable blepharospasm was the initial disorder in one of our patients; in two others, severe dysarthria and dysphagia were the first signs, caused by dystonia of the tongue, pharyngeal, and laryngeal muscles.
Other manifestations include torticollis, tortipelvis, dromedary gait, propulsive gait, action tremor, myoclonic jerks during voluntary movement, and mild choreoathetosis of the limbs. Excitement worsens the dystonia and sleep abolishes it. As the years pass the postural distortion may become fixed to the point where it does not disappear even in sleep. Tendon reflexes are normal, corticospinal signs are absent, and there is no ataxia, sensory abnormality, convulsive disorder, or dementia.
No agreement has been reached concerning the pathologic substrate of the disease. None of the features of symptomatic dystonia are found, such as the ferrocalcinosis of PKAN, the lesions of Wilson disease, kernicterus, état marbré of neonatal hypoxia, or the cavitation of familial striatal necrosis, lesions have been observed in the basal ganglia. However, in the hereditary forms of dystonia, which are the subject of this section, one cannot be certain of any specific lesions that would account for the clinical manifestations. The brain is grossly normal and ventricular size is not increased. According to Zeman, who reviewed all the reported autopsy studies up to 1970, there were no significant changes in the striatum, pallidum, or elsewhere. This means only that the techniques being used (qualitative analysis of random sections by light microscopy) are inadequate or the problem is subcellular. The report by McNaught and colleagues of perinuclear inclusions in periaqueductal neurons by the use of special immunostaining methods is provocative. There had been tentative interest in elevations of dopamine β-hydroxylase in patients with the autosomal dominant form of the disease, but the meaning of these findings is not clear.
Early in the course of the illness, several drugs including L-dopa, bromocriptine, carbamazepine, diazepam, and tetrabenazine seem to be helpful, but only in a few patients, and the benefit is not lasting. Intrathecal baclofen has been somewhat more successful in children. The rare hereditary form of dystonia-parkinsonism (described below) responds well to small doses of L-dopa and dopamine agonists and is exceptional in this respect. Burke and coworkers advocate the use of very high doses (up to 30 mg daily or more) of trihexyphenidyl (Artane). Apparently, dystonic children can tolerate these high doses if the medication is raised gradually, by 5-mg increments weekly. In adults, high-dose anticholinergic treatment is less successful but worthy of a trial. Clonazepam is beneficial in some patients with segmental myoclonus.
Impressive results were obtained in the past by the use of stereotactic techniques that made lesions in the ventrolateral nuclei of the thalamus or in the pallidum-ansa lenticularis region. Some frightfully disabled children, unable to sit or stand, were restored to near normalcy for a time. Approximately 70 percent of the patients in Cooper's series in the 1950s were moderately to markedly improved by unilateral or bilateral operations and, based on a 20-year followup study, the improvement was usually sustained. More recent studies report a somewhat less favorable but nonetheless clear improvement (see Tasker et al; Andrew et al). The main risk of the operation was a corticospinal tract lesion, produced inadvertently by damaging the internal capsule. Bilateral lesions have sometimes been disastrous, causing pseudobulbar palsy. The production of lesions has been supplanted, with success over long periods, by bilateral stimulation of the internal segments of the globus pallidus (Vidailhet and colleagues).
Hereditary Dystonia-Parkinsonism (Segawa Syndrome, Juvenile Dopa-Responsive Dystonia)
This process is discussed here because its main characteristic is a dystonia that is responsive to L-dopa, but most cases also have features of parkinsonism, which is why it was also mentioned in the earlier discussion of hereditary forms of Parkinson disease, especially in young patients. Following the description of the syndrome by Segawa and colleagues in 1976, others drew attention to this unique form of hereditary dystonia (Allen and Knopp; Deonna; Nygaard and Duvoisin). The pattern of inheritance is autosomal dominant and there is no ethnic predilection. Nygaard and colleagues found a linkage to the gene on chromosome 14q for the protein GTP cyclohydrolase 1 (GCH1 gene) that is implicated in the synthesis of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase. It is likely that the mutation impairs the generation of dopamine, a prediction that accords with responsiveness of the parkinsonian and dystonic features to L-dopa. In one autopsied case (an accidental death), there was a reduction in the amount of tyrosine hydroxylase in the striatum and depigmentation but no cell loss in the substantia nigra (Rajput et al). The affected enzyme was reduced in the striatum, as was the level of dopamine.
The dystonic manifestations usually become evident in childhood, usually between 4 and 8 years of age; females outnumber males in a ratio of 3:2. Often the legs are first affected by intermittent stiffening, with frequent falls and peculiar posturing, sometimes the feet assuming an equinovarus position. The arms become involved as well as the truncal muscles; retrocollis or torticollis may appear. Within 4 to 5 years, all parts of the body, including the bulbar muscles, are involved. Mild parkinsonian features (rigidity, bradykinesia, postural instability) can usually be detected early in the course of the illness, but more characteristically they are added to the clinical picture several years later. In our own patients, and in several of those of Deonna, there was rigidity of the limbs as well as slowness of movement and a tremor at rest, all aspects more parkinsonian than dystonic. In still others, the clinical picture has been one of cerebral spastic diplegia.
A remarkable feature is the disappearance or marked subsidence of the symptoms after a period of sleep and worsening as the day progresses. This diurnal variation is shared with many of the inherited forms of Parkinson disease listed in Table 39-3. Fluctuations of symptoms with exercise and menses and in the first month of pregnancy have been observed in some cases.
The special feature of this juvenile dystonia-parkinsonism syndrome is the dramatic response of both the dystonic and parkinsonian symptoms to treatment with L-dopa. As little as 10 mg/kg/d may eliminate the movement disorder and permit normal functioning. Unlike idiopathic Parkinson disease, the medication can be continued indefinitely without the development of tolerance, wearing-off effects, or dyskinesias. Segawa disease accounts for some cases that had in the past been reported as juvenile Parkinson disease.
Torticollis and Other Restricted Dyskinesias and Dystonias (see Chap. 6)
With advancing age, a large variety of focal or regional movement disorders come to light. Various neurophysiologic abnormalities, summarized in Chap. 6, have been implicated. In the common restricted dystonias, localized groups of adjacent muscles manifest arrhythmic cocontracting spasms (i.e., agonist and antagonist muscles are activated simultaneously). The patient's inability to suppress the dystonia and the recognition that it is for the most part beyond voluntary control distinguishes it from tics, habit spasms, and mannerisms described in Chap. 6. If the muscle contraction is frequent and prolonged, it is accompanied by an aching pain that may mistakenly be blamed for the spasm and the involved muscles may gradually undergo hypertrophy. Worsening under conditions of excitement and stress and improvement during quiet and relaxation are typical of this group of disorders and contributed in the past to the mistaken notion that the spasms had a psychogenic origin.
The most frequent and familiar type is torticollis, wherein an adult, more often a woman, becomes aware of a turning of the head to one side while walking. Usually this condition worsens gradually to a point where it may be more or less continuous, but in some patients it remains mild or intermittent for years on end. When followed over the years, the condition is observed to remain limited to the same muscles (mainly the scalene, sternocleidomastoid, and upper trapezius). Rarely, the torticollis is combined with dystonia of the shoulder, arm, and trunk; tremor; facial spasms; or dystonic writer's cramp.
Other restricted dyskinesias involve the neck in combination with facial muscles, the orbicularis oculi (blepharospasm and blepharoclonus), the throat and respiratory muscles (spastic dysphonia, orofacial dyskinesia, and respiratory and phonatory spasms), the hand in writer's cramp (graphospasm) or musician and other performing artist's dystonia, and proximal leg and pelvic-girdle muscles, where dyskinesia is elicited by walking. All these conditions and their treatments are discussed fully in Chap. 6.
Other Forms of Hereditary Dystonia
Several familial movement-induced (kinesogenic) dystonic syndromes and a type that is not kinesogenic and arises suddenly in adolescence, at times with parkinsonian features, have been described. There are other degenerative diseases that combine hereditary dystonia with neural deafness and intellectual impairment (Scribanu and Kennedy) and with amyotrophy in a paraplegic distribution (Gilman and Romanul). These are discussed in greater detail in Chap. 6.
Other important symptomatic dystonias that fall into the category of hereditary dystonia were described in Chap. 37. These are PKAN and calcification of the basal ganglia; of course, Wilson disease may have dystonia as a central feature. Many extrapyramidal diseases, including idiopathic Parkinson disease and progressive supranuclear palsy, may include fragmentary dystonias of the hand, foot, face, or periorbital muscles.