Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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 (the above mentioned hypokinesia), and the fingers straighten and assume a flexed and adducted posture at the metacarpophalangeal joints.


Neurology_Adams

Neurology_Adams. 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 1 finger or 1 hand. The tremor of the fully developed case takes several forms, as was remarked in Chap. 4. The approximately 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 repose is 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


Neurology_Adams

Neurology_Adams. tremor in repose is 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) and sometimes palpable by the examiner; 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 but there has been a dissociation of these two signs in many of our patients). 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.


Neurology_Adams

Neurology_Adams. Lance and associates called attention to the high incidence of a second, essential type of tremor in Parkinson disease—a fine, 7to 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 4-1). 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.


Neurology_Adams

Neurology_Adams. Rigidity of the extrapyramidal type 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,


Neurology_Adams

Neurology_Adams. 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 Chap. 4. There should be no pyramidal signs in Parkinson disease unless they are due to an alternate disorder such as stroke or cervical spondylosis.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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 after a second or more to generate normal or near-normal peak power, especially in the large muscles; however, in the small ones, strength is slightly diminished.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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 or with REM sleep behavior disorder. Shaving or applying lipstick becomes difficult, as the facial muscles become more immobile and rigid.


Neurology_Adams

Neurology_Adams. 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. 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 not dystonic but instead, due to axial posterior muscular wasting or weakness. We have not been impressed that this very troubling symptom is ameliorated by l-dopa. Why some patients with Parkinson disease are extremely bent over and others are not at all is unknown.


Neurology_Adams

Neurology_Adams. 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 (e.g., as escaping from a fire), the patient with all but the most advanced disease is capable of brief but remarkably effective movement (kinesis paradoxica).


Neurology_Adams

Neurology_Adams. Regarding other elicitable neurologic signs, there is an inability to inhibit blinking in response to a tap over the bridge of the nose or glabella (Myerson sign) but grasp and suck reflexes are not present 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.


Neurology_Adams

Neurology_Adams. 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 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 or back 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


Neurology_Adams

Neurology_Adams. 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, as well as REM sleep behavior disorder (Chap 18) are not as frequent as in multiple system atrophy (Shy-Drager syndrome) or in Lewy body dementia. Several of our younger Parkinson patients with recurrent syncope proved to have cardiac arrhythmias; hence, other causes of fainting must be considered. Any relationship to cardiac denervation, which is detectable by special testing, is not clear.


Neurology_Adams

Neurology_Adams. Postural instability is a core feature of the advancing 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 2 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).


Neurology_Adams

Neurology_Adams. 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 but it has been higher in some series. 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.


Neurology_Adams

Neurology_Adams. 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 by modern therapies.


Neurology_Adams

Neurology_Adams. Hemiparkinson–hemiatrophy syndrome 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’ 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.


Neurology_Adams

Neurology_Adams. 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 but the accuracy of diagnosis, especially early in the course of disease has been poor when compared with pathologic verification as noted just below. Much of this discrepancy in our view has been due simply to inadequate examination and follow up. 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. A response of the main symptoms to dopaminergic medication (as noted below and see further on) has been the most


Neurology_Adams

Neurology_Adams. an early sign of “resting” alternating tremor that is more prominent in one arm. A response of the main symptoms to dopaminergic medication (as noted below and see further on) has been the most dependable feature for accurate diagnosis in several series.


Neurology_Adams

Neurology_Adams. 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, in our experience, few. Yet in a series of 100 cases, studied clinically and pathologically by Hughes and associates, the diagnosis was inaccurate in 25 percent (see also Adler et al). 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.


Neurology_Adams

Neurology_Adams. 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 but quantifying how much asymmetry is too much is not possible. Also, the constellation of features termed “lower half parkinsonism” consisting of difficulty purely with gait and stability, as discussed below and in Chap. 6, suggest a process other than Parkinson disease.


Neurology_Adams

Neurology_Adams. 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 complete absence of this sign after approximately 3 to 5 years of use of the drug also brings the diagnosis into question.


Neurology_Adams

Neurology_Adams. Disorders simulating Parkinson disease 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


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Essential tremor may cause difficulty in diagnosis as already mentioned but it 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. 4.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 two 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. 38-5). 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


Neurology_Adams

Neurology_Adams. 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, non parkinsonian 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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 but has been challenged by Burke and colleagues (2008) and by others. An epidemiologic study of individuals who underwent vagotomy and reduced rates of Parkinson disease compared to the general population has been brought to bear on the argument, suggesting that the procedure blocks entry of synuclein into the brainstem (Svensson et al). Lang has suggested that this distribution of cell loss explains some of the nondopaminergic features of the disease and offers other


Neurology_Adams

Neurology_Adams. blocks entry of synuclein into the brainstem (Svensson et al). Lang has suggested that this distribution of cell loss explains some of the nondopaminergic features of the disease and offers other avenues for therapy.


Neurology_Adams

Neurology_Adams. 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 two diseases may be 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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, in some epidemiologic studies 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


Neurology_Adams

Neurology_Adams. 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).


Neurology_Adams

Neurology_Adams. Considering its frequency, coincidence in a family on the basis of chance occurrence might be as high as 5 percent, however, 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.


Neurology_Adams

Neurology_Adams. Mutations in at least 10 genes (the most important being SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and others) that have been related to typical or “classical” forms of Parkinson disease but only 5 percent of patients have monogenic forms of disease. Some of these and several others have been only tentatively identified or are risk factors rather than being obligate markers of disease. More importantly for the clinician, the majority of typical cases is tied to the combined effects of fairly common sequence variants, too numerous to list here. Several of these have stood out as being more common than others or offering biological insights into the nature of Parkinson disease (see the review by Lill and Klein for a more extensive listing and explanation of these genes).


Neurology_Adams

Neurology_Adams. These main genetic associations are summarized in Table 38-3 and the pathophysiologic significance of the more outstanding ones are discussed below. The former nomenclature of PARK genes followed by numerals has been updated and qualified based on the gene responsible in accord with the approach proposed by the Task Force on the Definition of Parkinson’s Disease (Berg et al). It is clear that many other genes are related to disorders that have parkinsonian features embedded in them, for example, a number of spinocerebellar ataxias, but are not Parkinson disease per se and they are not in this compilation. Several genetic variants have also been tentatively linked to particular nonmotor features of the disease.


Neurology_Adams

Neurology_Adams. As already emphasized, 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Parkin is a ubiquitin protein ligase that participates in the removal of unnecessary proteins from cells through the proteasomal system (Fig. 38-6). 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 38-3). Figure 38-6 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. A mutation noted above that has received attention has been in LRRK2 (leucine-rich repeat kinase 2) because 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 an obvious 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,


Neurology_Adams

Neurology_Adams. 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, have been reviewed by Brice.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 38-3). 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 a common genetic factor for the disease, particularly in this ethnographic population.


Neurology_Adams

Neurology_Adams. 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 38-4). 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.


Neurology_Adams

Neurology_Adams. l-dopa and l-dopa–modifying drugs At present, l-dihydroxyphenylalanine (l-dopa) is the most effective agent for the treatment of Parkinson disease and the therapeutic results, even in those with far advanced disease, are consistently better than have been obtained with other drugs. 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.


Neurology_Adams

Neurology_Adams. 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 effective 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. The once-held 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. This was tentatively taken to endorse the opposite notion, that l-dopa was somehow protective for the progress of disease but the alternative explanation was that the drug had a symptomatic carry over effect after it was stopped. This was addressed further in a trial


Neurology_Adams

Neurology_Adams. was somehow protective for the progress of disease but the alternative explanation was that the drug had a symptomatic carry over effect after it was stopped. This was addressed further in a trial conducted by


Neurology_Adams

Neurology_Adams. Verschuur and colleagues, who compared patients receiving l-dopa for 80 weeks to those in whom the start of treatment was delayed for the first 40 weeks and found no difference in outcomes or in the rates of progression of symptoms. Taken together, these results suggest the drug has no effect on the underlying disease in either direction, beyond the expected symptomatic improvement.


Neurology_Adams

Neurology_Adams. Neuropathologic study of the substantia nigra in the brains of Parkinson patients and their medication histories failed to corroborate a reduction in the number of pigmented neurons in relation to l-dopa (Parkkinen et al). Also, the 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. The comparative effectiveness of l-dopa compared to the dopamine agonists is discussed below.


Neurology_Adams

Neurology_Adams. Dopamine agonists 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 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 development of some interest is the 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.


Neurology_Adams

Neurology_Adams. The relative merits of dopamine agonists and l-dopa are difficult to contrast. One insight was given by the PD Med trial (PD Med Collaborative Group), which compared, in an open-label fashion, l-dopa, dopamine agonists and monoamine oxidase-B inhibitors (see further on). Rather than the metric of the UPDRS scale or similar instruments, this trial used a patient’s quality of life questionnaire and found that after a median of 3 years l-dopa received slightly higher scores. What was more telling was that there were far higher rates of discontinuation of the other 2 medications, mainly due to psychological side effects.


Neurology_Adams

Neurology_Adams. Even small doses of dopaminergic drugs, when first introduced, may induce orthostatic hypotension, but most patients are, or become, 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). Excessive and dysfunctional behaviors particularly gambling (including on line gambling in some of our patients) and hypersexuality have been serious problems in a few individuals (also see further on).


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Adjunctive medications 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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-B 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


Neurology_Adams

Neurology_Adams. 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 (2000 and 2005).


Neurology_Adams

Neurology_Adams. Neuroprotective agents An additional approach 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 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 often institute one


Neurology_Adams

Neurology_Adams. (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 often institute one of these MAO-B inhibitors in many patients.


Neurology_Adams

Neurology_Adams. Following this same line of reasoning, several studies, some still disputed or unconfirmed, have suggested that ropinirole, pramipexole, and even l-dopa have “neuroprotective” effects in Parkinson disease. The issues relating to l-dopa are addressed above. 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 in 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.


Neurology_Adams

Neurology_Adams. 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. Finally, attempts to slow the disease by vitamin antioxidants such as vitamin E have met with 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 functions, but not on most neurologic scales.


Neurology_Adams

Neurology_Adams. Side effects of dopamine treatments 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 (see Verhagen et al), 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 in the following text). 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 as mentioned earlier (the same has been seen in treatment of restless


Neurology_Adams

Neurology_Adams. to sexual assertiveness. Other curious effects of excessive drive from l-dopa and dopamine agonists have been pathologic gambling as mentioned earlier (the same has been seen in treatment of restless legs syndrome) and odd behaviors such as cross-dressing (Quinn et al, 1983).


Neurology_Adams

Neurology_Adams. Anticholinergic agents or l-dopa should not generally 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.


Neurology_Adams

Neurology_Adams. 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 may 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Until recently, success with l-dopa had entirely 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. These remain the most resistant symptoms with modern surgical techniques as well.


Neurology_Adams

Neurology_Adams. Through the work of Leskell and others as described by Laitinen, this mode of therapy has evolved into stereotactically guided procedures and advanced by the technique of implanted electrodes with an electrical stimulator implanted in the chest wall (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 most features of the disease, including in bradykinesia, that is lost after several years, but as mentioned, 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. The ideal candidates for DBS are those in whom, after several years, there is a failure of medications to adequately relieve symptoms but especially if there are unmanageable dyskinesias that result from l-dopa. Restated, the typical patient who will derive benefit from deep-brain stimulation is 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. 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. The effect on nonmotor symptoms such as pain are less predictable but our


Neurology_Adams

Neurology_Adams. native disease or as a result of medication, may also benefit from this treatment, perhaps more so with pallidal stimulation. The effect on nonmotor symptoms such as pain are less predictable but our patients have not noticed much improvement unless the pain was due to dystonia. A small series reported by Cury and coworkers came to essentially the same conclusion.


Neurology_Adams

Neurology_Adams. 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 compared to subthalamic stimulation. Hemorrhage into the basal ganglia and local infection near the stimulator has occurred in a small number of patients after surgery. Depression and suicides also appear as adverse events in some trials. One remarkable case had a severe depressive emotional state and affect that could be turned on and off with stimulation; the electrode tip had migrated from the intended site at the subthalamic nucleus into the mesencephalon but the mechanism of depression is obscure (Bejjani et al). We have encountered a few instances of serious delirium after electrode implantation as in the series reported by Carlson and colleagues (and rarely during the procedure if the patient is awake).


Neurology_Adams

Neurology_Adams. Recently, DBS has been introduced early 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.


Neurology_Adams

Neurology_Adams. 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. 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 stimulator 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.


Neurology_Adams

Neurology_Adams. Presumably, the mechanism of DBS is that high- frequency electrical impulses disrupt local neuronal activity, producing the functional equivalent of an ablative lesion, but the effects of deep brain stimulation may be more complex by way of stimulating neurotransmitter release.


Neurology_Adams

Neurology_Adams. The cerebral implantation of fetal dopaminergic tissue provided a modest improvement in motor function for a limited period (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. The effect has not been satisfactorily reproduced. 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 two trials have failed to show benefit. Similarly, the implantation of stem cells is being explored but has several obstacles.


Neurology_Adams

Neurology_Adams. 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 et al with thalamic lesions (ventral intermediate nucleus).


Neurology_Adams

Neurology_Adams. Ancillary treatments 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 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Hypotensive episodes respond to fludrocortisone, droxidopa, pyridostigmine, or midodrine given each morning. Compression stockings and increased water and salt intake have also been recommended but have not been not well studied. The subject is reviewed by Wu and Hohler. 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. Multiple System Atrophy (Striatonigral Degeneration, Shy-Drager Syndrome, Olivopontocerebellar Degeneration)


Neurology_Adams

Neurology_Adams. As the name multiple system atrophy indicates, this depicts a group of disorders characterized by neuronal degeneration mainly in the substantia nigra, striatum, autonomic nervous system, and cerebellum. Following a report in 1964 by Adams and colleagues of what was then called striatonigral degeneration, many patients were recognized in whom the changes of striatonigral and olivopontocerebellar degeneration were combined and who had symptoms and signs of cerebellar ataxia and parkinsonian manifestations. The pathologic changes were found by chance in 4 middle-aged patients, in 3 of whom a parkinsonian syndrome had been described clinically, none with a family history of similar disease. Rigidity, stiffness, and akinesia had begun on one side of the body, then spread to the other, and progressed over a 5-year period but with minimal characteristic tremor of idiopathic Parkinson disease. A flexed posture of the trunk and limbs, slowness of all movements, poor balance, mumbling speech,


Neurology_Adams

Neurology_Adams. over a 5-year period but with minimal characteristic tremor of idiopathic Parkinson disease. A flexed posture of the trunk and limbs, slowness of all movements, poor balance, mumbling speech, and a tendency to faint when standing were other elements. There was an early-onset cerebellar ataxia in the fourth patient that was later obscured by a Parkinson syndrome.


Neurology_Adams

Neurology_Adams. The postmortem examinations disclosed extensive loss of neurons in the zona compacta of the substantia nigra, but notably, there were no Lewy bodies or neurofibrillary tangles in the remaining cells. Even more striking were the degenerative changes in the putamina and to a lesser extent in the caudate. Secondary pallidal atrophy (loss of striatopallidal fibers) was present. In the patient with ataxia there was, in addition, advanced degeneration of the pons, olives, and cerebellum (see below). Bannister and Oppenheimer astutely named the broad syndrome “multiple system atrophy.” Recognizing that the clinical and pathologic features of striatonigral degeneration, with or without autonomic failure, can coexist with olivopontocerebellar atrophy,


Neurology_Adams

Neurology_Adams. Graham and Oppenheimer proposed the term multiple system atrophy (MSA), which has gained wide acceptance. Several large series of cases of this complex syndrome have been published, providing a perspective on the frequency and nature of its component syndromes. Either parkinsonism or cerebellar ataxia may predominate. They are designated as MSA-P and MSA-C, respectively, depending on whether they display predominantly parkinsonism or cerebellar ataxia. More than half of the patients with striatonigral degeneration have orthostatic hypotension, which proves at autopsy to be associated with loss of intermediolateral horn cells and pigmented nuclei of the brainstem. This combined parkinsonian and autonomic disorder, formerly referred to as the Shy-Drager syndrome, was alluded to in Chaps. 17 and 25 and is now termed MSA-A, for multiple system atrophy with autonomic changes. The frequency of MSA-P is higher than for MSA-C and much higher than isolated MSA-A. The exception seems to be in


Neurology_Adams

Neurology_Adams. and 25 and is now termed MSA-A, for multiple system atrophy with autonomic changes. The frequency of MSA-P is higher than for MSA-C and much higher than isolated MSA-A. The exception seems to be in Japan, where the cerebellar type is more frequent than MSA-P and more frequent than in other areas of the world.


Neurology_Adams

Neurology_Adams. Despite the overlap of clinical features in striatonigral degeneration, olivopontocerebellar degeneration, and the Shy-Drager syndrome, each of these disorders can occur in almost isolated clinical form; we therefore remind readers of their original designations. However, experienced clinicians will suspect that an adult onset slowly progressive ataxia is due to MSA-C, or that an unusual parkinsonian syndrome could be MSA-P but will make the diagnosis only confidently when the autonomic features appear some time later.


Neurology_Adams

Neurology_Adams. In addition to orthostatic hypotension, other features of autonomic failure in any of the variants include erectile dysfunction, loss of sweating, dry mouth, miosis, and urinary retention or incontinence. Vocal cord palsy is sometimes an initial manifestation of the disorder; it may cause dysphonia or stridor and airway obstruction requiring tracheostomy. A dusky discoloration of the hands as a sign of this disorder was ascribed to poor control of cutaneous blood flow by Klein and colleagues. Constipation, loss of sweating and sleep apnea occur in many patients as the disease progresses. A diagnostic problem arises in that orthostatic hypotension is also observed in at least 15 percent of patients with Parkinson disease and perhaps a larger proportion in Lewy body disease, a feature that may be exaggerated by medications, but the degree of drop in blood pressure is typically greater and more frequent in patients with this form of multiple system atrophy. These nonmotor aspects have


Neurology_Adams

Neurology_Adams. may be exaggerated by medications, but the degree of drop in blood pressure is typically greater and more frequent in patients with this form of multiple system atrophy. These nonmotor aspects have been referred as “prodromal” but are simply initial manifestations of the disease.


Neurology_Adams

Neurology_Adams. In the Brain Tissue Bank of the Parkinson Disease Society of Great Britain, MSA accounted for 13 percent of patients who had been identified during life as having idiopathic Parkinson disease. These cases represent advanced forms of the disease, however, at that stage, all the patients with MSA had one or more symptoms of autonomic failure (postural hypotension, urinary urgency or retention, urinary or fecal incontinence, erectile dysfunction) and dysphonia or stridor. Babinski signs were present in half the patients and cerebellar ataxia in one-third. Tremor was rare. Males were affected more often than females. In a comparable series of 100 patients (67 men and 33 women) studied by Wenning and coworkers (1994), the disease began with a striatonigral-parkinsonian syndrome in approximately half; often it was asymmetrical at the onset. Mild tremor was detected in some but in only a few was it of the “resting” or “pill rolling” Parkinson type. In nearly half, the illness began with


Neurology_Adams

Neurology_Adams. half; often it was asymmetrical at the onset. Mild tremor was detected in some but in only a few was it of the “resting” or “pill rolling” Parkinson type. In nearly half, the illness began with autonomic manifestations; orthostatic hypotension occurred eventually in almost all patients, but it was disabling in only a few. Cerebellar features dominated the initial stages of the disease in only 5 percent, but ataxia was eventually obvious in half the larger group. This ataxic clinical presentation of multiple system atrophy will be elaborated further in the section on the degenerative cerebellar ataxias.


Neurology_Adams

Neurology_Adams. The extrapyramidal illness, on the whole, is eventually more severe than in Parkinson disease, as more than 40 percent of patients are confined to a wheelchair or otherwise severely disabled within 5 years. These observations generally match the findings in the group described by Quinn and colleagues, but they emphasized that pyramidal signs were present in 60 percent. Features that are considered not supportive of the diagnosis of MSA include the typical “pill rolling” tremor of Parkinson disease, hallucinations not induced by medications (more compatible with Lewy body or Parkinson disease), dementia, or family history of ataxia or parkinsonism.


Neurology_Adams

Neurology_Adams. Colosimo and colleagues reviewed the clinical findings in 16 pathologically verified cases of MSA and found that several signs, namely, relative symmetry of the signs and rapid course, the lack of response to l-dopa, absence or minimal amount of tremor, and the early presence of autonomic disorders, reliably distinguished this syndrome from Parkinson disease. These observations are in keeping with our own and we would add that abnormalities of eye movement are not prominent in MSA. Additional features occurring occasionally in MSA are remarked upon in other series; anterocollis or dystonia of the lower facial muscles, for example, is striking in a few cases. It is noteworthy that levodopa has had little or no effect or has made these patients worse early in the disease but we have seen exceptions. The lack of l-dopa effect is probably attributable to the loss of striatal dopamine receptors.


Neurology_Adams

Neurology_Adams. The diagnosis of MSA, especially the form with ataxia, has been aided by imaging techniques. Both MRI and CT scanning frequently show atrophy of the cerebellum and pons in those with cerebellar features. The putamina are hypointense on T2-weighted MRI and may show an increased deposition of iron in the parkinsonian form. In the cerebellar form, a “hot cross bun” sign has been emphasized on MRI; it reflects atrophy of the pontocerebellar fibers that manifest high T2 signal intensity in an atrophic pons. Studies with PET have disclosed impairment of glucose metabolism in the striatum and to a lesser extent in the frontal cortex, a reflection, no doubt, of the loss of functioning neuronal elements in these parts.


Neurology_Adams

Neurology_Adams. Although the cause of this process is not known, and the majority of cases is sporadic, The Multiple-System Atrophy Research Collaboration identified a mutation in COQ2 in a Japanese cohort, coding for a protein involved in the synthesis of coenzyme Q10, in both familial cases and a very small proportion of sporadic ones. The mutation has not been found in European or North American families.


Neurology_Adams

Neurology_Adams. Pathology In recent years, attention has been drawn to the presence of abnormal staining material in the cytoplasm of astroglia and oligodendrocytes and in some neurons as well. These cytoplasmic aggregates have been referred to as glial cytoplasmic inclusions (Papp et al). Although they bear little resemblance morphologically to other discrete inclusions that have come to be accepted as characteristic of certain degenerative CNS diseases (e.g., Lewy bodies), they are composed of α-synuclein (the main component of Lewy bodies). These have become the histopathologic hallmark of MSA as suggested by Chin and Goldman and by Lantos, but their presence is not specific; they have been identified in practically every degenerative disease that has been subjected to sensitive silver impregnation stains. Many types of inclusions are, of course, nonspecific, as, for example, α-synuclein–positive inclusions have been detected in several neurodegenerative syndromes. Appropriate control studies to


Neurology_Adams

Neurology_Adams. Many types of inclusions are, of course, nonspecific, as, for example, α-synuclein–positive inclusions have been detected in several neurodegenerative syndromes. Appropriate control studies to determine whether the glial inclusions are found in nondegenerative lesions in brain (e.g., at the edge of an infarct) are needed. Also lacking is information about the frequency of these cytoplasmic inclusions in relation to the aging brain.


Neurology_Adams

Neurology_Adams. 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 previously. The condition is not rare and examples are seen in every neurologic practice. By 1972, when Steele reviewed the subject, 73 cases (22 with postmortem examinations) had been described in the medical literature. Most cases are sporadic but 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.


Neurology_Adams

Neurology_Adams. 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. The falls are frequently backward. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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 again 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