Neurology_Adams

Neurology_Adams. Myoclonus specifies the very rapid, shock-like contractions of a group of muscles, irregular in rhythm and amplitude, and, with few exceptions, asynchronous and asymmetrical in distribution. If such contractions occur singly or are repeated in a restricted group of muscles, such as those of an arm or leg, the phenomenon is termed segmental myoclonus, whereas widespread, lightning-like, arrhythmic repeated contractions are referred to as polymyoclonus. In all forms of myoclonus, the muscle contraction is brief (20 to 50 ms)—that is, faster than that of chorea, with which it may be confused. The speed of the myoclonic contraction is the same whether it involves a part of a muscle, a whole muscle, or a group of muscles. The discussion that follows makes evident that each of the three phenomena has a distinctive pathophysiology and clinical implications.


Neurology_Adams

Neurology_Adams. A common and benign example of myoclonus, familiar to many persons, is the “sleep-start” that consists of a jerking of the body, particularly the torso, while falling asleep or occasionally, just prior to waking. Several other sleep-related syndromes involve repetitive leg movements that include an element of myoclonus. Rarely, the movements may extend to daytime behavior (Walters and colleagues). These sleep disorders are discussed in Chap. 18.


Neurology_Adams

Neurology_Adams. Several rapid movements of the limb or a part of a limb simulate myoclonus but have entirely different mechanisms and implications. For example, epilepsia partialis continua is a special type of epileptic activity in which one group of muscles—usually of the face, arm, or leg—is continuously (day and night) involved in a series of rhythmic monophasic contractions. These may continue for weeks, months, or years. The disorder appears to be cerebral in origin, but in most cases its precise anatomic and physiologic basis cannot be determined (see Chap. 15 for further discussion). The related term clonus designates another rapid rhythmic contraction and relaxation of a group of muscles. Reference has already been made in Chap. 3 to relationship of clonus to spasticity and heightened tendon reflexes in diseases affecting the corticospinal tract. It is most easily elicited by forcefully dorsiflexing the ankle; a series of rhythmic jerks of small to moderate amplitude result.


Neurology_Adams

Neurology_Adams. Focal, Segmental, and Regional Myoclonus Patients with idiopathic epilepsy may complain of a localized myoclonic jerk or a short burst of myoclonic jerks, occurring particularly on awakening and on the day or two preceding a major generalized seizure, after which these movements cease. One-sided or focal myoclonic jerks are the dominant feature of a particular form of childhood epilepsy—the so-called benign epilepsy with rolandic spikes (see Chap. 15).


Neurology_Adams

Neurology_Adams. The notion that monophasic-restricted myoclonus always emanates from the cerebral cortex, cerebellum, or brainstem cannot be sustained, as there are forms that are traceable to a purely spinal cause. The problem takes the form of an almost continuous arrhythmic jerking of a restricted group of muscles, often on one side of the body. Such a subacute spinal myoclonus of obscure origin was described many years ago by Campbell and Garland, and similar cases continue to be cited in the literature. We have seen several in which myoclonus was isolated to the musculature of the abdominal or thoracic wall on one side, or to the legs; only rarely were we able to establish a cause, and the spinal fluid has been normal. This form has been referred to as “propriospinal” when it involves repetitive flexion or extension myoclonus of the torso that is aggravated by stretching or action.


Neurology_Adams

Neurology_Adams. Examples of myelitis with irregular and strictly segmental myoclonic jerks (either rhythmic or arrhythmic) have been reported in humans and have been induced in animals by the Newcastle virus. Many such myelitic cases involve the legs or a few muscles of one leg. In our experience, this type of myoclonus has occurred following zoster myelitis, postinfectious transverse myelitis, and rarely with multiple sclerosis, epidural cord compression, or after traumatic spinal injury. A paraneoplastic form has also been described, usually associated with breast cancer (see Chap. 30). When highly ionic contrast media was in the past used for myelography, painful spasms and myoclonus sometimes occurred in segments where the dye was concentrated by a block to the flow of spinal fluid.


Neurology_Adams

Neurology_Adams. Treatment is difficult and one resorts to a combination of antiepileptic drugs and benzodiazepines, just as in cerebral myoclonus. Levetiracetam reportedly has been successful when other drugs have failed (Keswani et al). Focal myoclonus is also one of the notable features of degenerative neurologic conditions, particularly corticobasal ganglionic degeneration; it is generally seen in a limb that is made rigid by this process. Under the title paramyoclonus multiplex, Friedreich, in 1881, described a sporadic instance of idiopathic widespread muscle jerking in an adult. It was probably in the course of this description that the term myoclonus was used for the first time. No other neurologic abnormalities accompanied the movement abnormality and its nature is obscure. We are not familiar with this process occurring in modern practice. Yet, there are many diseases in which multifocal or widespread asynchronous myoclonus is a manifestation, appropriately called polymyoclonus.


Neurology_Adams

Neurology_Adams. Several disparate disorders give rise to diffuse myoclonus. It may occur in pure or “essential” form as a benign, often familial, nonprogressive disease. A second broad category is allied with special forms of childhood epilepsy and there are several types that are associated with acquired neurologic diseases as discussed below, some quite serious in nature.


Neurology_Adams

Neurology_Adams. Symptoms may begin at any period of life but usually appear first in childhood. This disorder may be of the same nature as the one described by Friedreich, as mentioned above. An autosomal dominant mode of inheritance is evident in some families. The myoclonus takes the form of irregular twitches of one or another part of the body, involving groups of muscles, single muscles, or even a portion of a muscle. As a result, an arm may suddenly flex, the head may jerk backward or forward, or the trunk may curve or straighten. The face, neck, jaw, tongue, ocular muscles, and diaphragm may twitch. According to Wilson, even fascicles of the platysma may twitch. Some muscle contractions cause no visible displacement of a limb. Some patients register little complaint, accepting the constant intrusions of motor activity with stoicism; they generally lead relatively normal, active lives. Seizures, dementia, and other neurologic deficits are notably absent but several rare forms have been


Neurology_Adams

Neurology_Adams. intrusions of motor activity with stoicism; they generally lead relatively normal, active lives. Seizures, dementia, and other neurologic deficits are notably absent but several rare forms have been associated with axial dystonias. In a Mayo Clinic series reported by Aigner and Mulder, 19 of 94 cases of polymyoclonus were considered to be of this “essential” type.


Neurology_Adams

Neurology_Adams. Myoclonus in Epilepsy (See Also Myoclonic Seizures in Chap. 15)


Neurology_Adams

Neurology_Adams. Myoclonus may be a direct reflection of seizures but is also a separate nonepileptic manifestation in several neurodegenerative and storage diseases, of which seizures are an important component. For example, a relatively benign idiopathic condition, juvenile myoclonic epilepsy, is accompanied by myoclonic jerks when the patient is tired or has ingested alcohol. A more serious type of myoclonic epilepsy, identified with the names Unverricht and Lundborg, in the beginning is marked by polymyoclonus as an isolated phenomenon, but later is associated with dementia and other signs of progressive neurologic disease. An outstanding feature of the latter is a remarkable sensitivity of the myoclonus to stimuli of all sorts. If a limb is passively or actively displaced, the resulting myoclonic jerk may lead, through a series of progressively larger and more or less synchronous jerks, to a generalized convulsive seizure. In late childhood this type of stimulus-sensitive myoclonus is usually a


Neurology_Adams

Neurology_Adams. may lead, through a series of progressively larger and more or less synchronous jerks, to a generalized convulsive seizure. In late childhood this type of stimulus-sensitive myoclonus is usually a manifestation of the juvenile form of lipid storage disease, which, in addition to myoclonus, is characterized by seizures, retinal degeneration, dementia, rigidity, pseudobulbar paralysis, and, in the late stages, by spastic quadriplegia.


Neurology_Adams

Neurology_Adams. Myoclonus may be associated with atypical petit mal and akinetic seizures in the Lennox-Gastaut syndrome (absence or petit mal variants); the patient often falls during the brief lapse of postural mechanisms that follows a single myoclonic contraction. Similarly, in the West syndrome of infantile spasms, the arms and trunk are suddenly flexed or extended in a single massive myoclonic jerk (“jackknife” or “salaam” seizures); mental regression occurs in 80 to 90 percent of these cases, even when the seizures are successfully treated. These types of special “myoclonic epilepsies” are discussed further below and in Chap. 15 in relation to epilepsy.


Neurology_Adams

Neurology_Adams. Another form of stimulus-sensitive (reflex) myoclonus, inherited as an autosomal recessive trait, begins in late childhood or adolescence and is associated with neuronal inclusions (Lafora bodies thus Lafora-body disease) in the cerebral and cerebellar cortex and in brainstem nuclei. In yet another familial type (described under the title of Baltic myoclonus by Eldridge and associates), autopsy has disclosed a loss of Purkinje cells but no inclusion bodies. Unlike Lafora-body disease, the Baltic variety of myoclonic epilepsy has a favorable prognosis, particularly if the seizures are treated with valproic acid.


Neurology_Adams

Neurology_Adams. Under the title of cherry-red-spot myoclonus syndrome, Rapin and associates have drawn attention to a familial (autosomal recessive) form of diffuse, incapacitating intention myoclonus associated with visual loss and ataxia. This disorder develops insidiously in adolescence. The earliest sign is a cherry-red spot in the macula that may fade in the chronic stages of the illness. The intellect is relatively unimpaired. A similar clinical syndrome of myoclonic epilepsy is seen in a variant form of neuroaxonal dystrophy and in the late childhood–early adult neuronopathic form of Gaucher disease, in which it is associated with supranuclear gaze palsies and cerebellar ataxia (see Chap. 36). Diffuse Myoclonus with Acquired Neurologic Disease


Neurology_Adams

Neurology_Adams. The clinical settings in which one observes widespread random myoclonic jerks as a transient or persistent phenomenon in adults is most often an acquired metabolic disorder (prototypically uremic and anoxic encephalopathy) and in certain drug intoxications, notably with haloperidol, lithium, and amphetamines. For example, an acute onset of polymyoclonus with confusion occurs with lithium intoxication; once ingestion is discontinued, there is improvement (slowly over days to weeks) and the myoclonus is replaced by diffuse action tremors, which later subside. A second broad category of acquired myoclonus consists of structural brain diseases such as viral encephalitis, Creutzfeldt-Jakob disease, syphilitic general paresis, advanced Alzheimer and Lewy body disease, corticobasal ganglionic degeneration, and occasionally Wilson disease. Table 4-7 lists these and others. A subacute encephalopathy with diffuse myoclonus may occur in association with the autoantibodies that characterize


Neurology_Adams

Neurology_Adams. degeneration, and occasionally Wilson disease. Table 4-7 lists these and others. A subacute encephalopathy with diffuse myoclonus may occur in association with the autoantibodies that characterize Hashimoto thyroiditis and also in Whipple disease. Diffuse, severe myoclonus may be a prominent feature of early tetanus and strychnine poisoning. Polymyoclonus that occurs in the acute stages of anoxic encephalopathy should be distinguished from postanoxic action or intention myoclonus that emerges with recovery from cardiac arrest or asphyxiation (it is discussed below). The factor common to all these disorders, with the exception of acquired metabolic disorders and intoxications, is the presence of diffuse neuronal disease.


Neurology_Adams

Neurology_Adams. Myoclonus in association with signs of cerebellar incoordination and opsoclonus (rapid, irregular conjugate eye movements in all directions as described in Chap. 13) is another syndrome of both children and adults. Most cases run a chronic course, waxing and waning in severity. Many of the childhood cases are associated with occult neuroblastoma, and some have responded to the administration of corticosteroids. In adults, a similar syndrome is well known as an effect of specific circulating antibodies that are elaborated in response to the presence of some tumors (“paraneoplastic,” mainly breast, and ovary as discussed in Chap. 30). The conduction also occurs as a self-limited manifestation of a postinfectious (usually viral) illness as described by Baringer and colleagues.


Neurology_Adams

Neurology_Adams. As mentioned above, diffuse myoclonus is a prominent and often early feature of the prion illness, Creutzfeldt-Jakob disease, characterized by rapidly progressive dementia, disturbances of gait and coordination, and all manner of mental and visual aberrations (see Chap. 32). Initially the jerks are random but late in the disease they may attain an almost rhythmic and symmetric character. In addition there is an exaggerated startle response, and violent myoclonus may be elicited by tactile, auditory, or visual stimuli in advanced stages of the disease. In yet another group of myoclonic dementias, the most prominent associated abnormality is a progressive deterioration of intellect. The myoclonic dementias may be sporadic or familial and may affect children or adults. A rare childhood type is subacute sclerosing panencephalitis (SSPE), which is an acquired subacute or chronic (occasionally remitting) disease related to a latent infection with the measles virus (see Chap. 32).


Neurology_Adams

Neurology_Adams. This type of myoclonus was described by Lance and Adams in a group of patients who were recovering from hypoxic encephalopathy. When the patient is relaxed, the limb and other skeletal muscles are quiet (except in the most severe cases); only seldom does the myoclonus appear during slow, smooth (ramp) movements. Fast (ballistic) movements, however, especially when directed to a target elicit a series of irregular myoclonic jerks that differ from intention tremor. Only the limb that is moving is involved; hence it is a localized, stimulus-evoked myoclonus. Speech may be fragmented by the myoclonic jerks, and a syllable or word may be almost compulsively repeated, as in palilalia. Myoclonus of the axial muscles may make walking impossible.


Neurology_Adams

Neurology_Adams. Action myoclonus is almost always associated with cerebellar ataxia. The pathologic anatomy has not been entirely ascertained. Lance and Adams found the irregular discharges to be transmitted via the corticospinal tracts, preceded in some cases by a discharge from the motor cortex. Chadwick and coworkers postulated a reticular loop reflex mechanism, while Hallett and colleagues (1977) found that a cortical reflex mechanism was operative in some cases and a reticular reflex mechanism in others. Whether these are two aspects of one mechanism could not be decided. Barbiturates and valproic acid have been helpful in some cases. Several clinical trials and case reports have suggested that the antiepileptic levetiracetam may be useful (Krauss et al, 2001). The use of 5-hydroxytryptophan alone or in combination with tryptophan or other drugs had been recommended in the past (van Woert et al). A combination of several of these medications is usually required to make the patient functional.


Neurology_Adams

Neurology_Adams. Pathophysiology of Myoclonus It seems logical to assume that myoclonus is caused by abnormal discharges of aggregates of motor neurons or interneurons because of the enhanced excitability of these cells or the removal of some inhibitory mechanism. Sensory provocation may be a prominent feature of polymyoclonus, particularly those related to metabolic disorders. Flickering light, a loud sound, or an unexpected tactile stimulus to some part of the body initiates a jerk so quickly and consistently that it must utilize a direct sensorimotor pathway or the mechanism involved in the startle reaction. Repeated stimuli may recruit a series of incremental myoclonic jerks that culminate in a generalized convulsion, as often happens in the familial myoclonic syndrome of Unverricht-Lundborg.


Neurology_Adams

Neurology_Adams. Evidence implicating cortical hyperexcitability in myoclonus is indirect, being based mainly on the finding that the cortical components of the somatosensory evoked potential are exceedingly large and that in some instances, the myoclonic jerks have a strict time relationship (“time-locked”) to preceding spikes in the contralateral rolandic area (Marsden et al; Brown et al). It is possible that these potentials originate from subcortical structures that project both to the descending motor pathways and upward to the cortex. There is an indication, for example, that postanoxic action myoclonus has its basis in reflex hyperactivity of the reticular formation. Furthermore, the only consistent damage in some disorders such as postanoxic myoclonus is in the cerebellum rather than in the cerebral cortex. As already noted, several types of myoclonus are closely coupled with other cerebellar degenerations.


Neurology_Adams

Neurology_Adams. Pathologic examinations have been of little help in determining the essential sites of this unstable neuronal discharge because in most cases, the disease is diffuse. Nonetheless, the most restricted lesions associated with myoclonus are located in the cerebellum and rostral brainstem. Removal of the modulating influence of the cerebellum on the thalamocortical system of neurons has been postulated as a mechanism, but it is uncertain whether the disinhibited motor activity is then expressed through corticospinal or reticulospinal pathways. For example, pentylenetetrazol injections evoke myoclonus in animals, and the myoclonus persists despite transection of corticospinal and other descending tracts of the hemispheres and upper brainstem until the lower brainstem reticular structures are destroyed.


Neurology_Adams

Neurology_Adams. To some degree, everyone startles or jumps in reaction to a totally unanticipated, potentially threatening stimulus. This normal startle reflex is probably a protective reaction, being seen also in animals, and its purpose seemingly is to prepare the organism for escape. In most ways, startle cannot be separated from myoclonus except for its generalized nature and an obligatory evocation by various stimuli. Any stimulus—most often an auditory one but also a flash of light, a tap on the neck, back, or nose, or even the presence of someone behind the patient—can normally evince a sudden contraction of the orbicularis, neck, and spinal musculature and even the legs. However, in the abnormal startle response that occurs in the diseases discussed below, the contraction is of greater amplitude and is more widespread, with less tendency to habituate. There may even be a jump and occasionally an involuntary shout and fall to the ground. It is these characteristics that distinguish pathologic


Neurology_Adams

Neurology_Adams. and is more widespread, with less tendency to habituate. There may even be a jump and occasionally an involuntary shout and fall to the ground. It is these characteristics that distinguish pathologic startle.


Neurology_Adams

Neurology_Adams. Aside from exaggerated forms of the normal startle reflex, the commonest isolated syndrome is so-called startle disease, referred to as hyperexplexia or hyperekplexia (Gastaut and Villeneuve). This is a familial disease (e.g., the “jumping Frenchmen of Maine,” and others, as described further on). The nature of the phenomenon displayed by the “jumping Frenchmen of Maine” has been disputed. The syndrome was described originally by James Beard in 1868 among small pockets of French-speaking lumberjacks in northern Maine. The subjects displayed a greatly exaggerated response to minimal stimuli, to which there was no adaptation. The reaction consisted of jumping, raising the arms, screaming, and flailing of limbs, sometimes with echolalia, echopraxia, and a forced obedience to commands, even if this entailed a risk of serious injury. A similar syndrome in Malaysia and Indonesia is known as latah and in Siberia as miryachit. This syndrome has been framed in psychologic terms as conditioned


Neurology_Adams

Neurology_Adams. this entailed a risk of serious injury. A similar syndrome in Malaysia and Indonesia is known as latah and in Siberia as miryachit. This syndrome has been framed in psychologic terms as conditioned responses (Saint-Hilaire et al) or as culturally determined behavior (Simons). Possibly some of the complex secondary phenomena can be explained in this way, but the stereotyped onset with an uncontrollable startle and the familial occurrence attest to a biologic basis. The most common mutation is in the 1-subunit of the inhibitory glycine receptor GLRA1 (Shiang et al) but other glycine receptor–related genes have been implicated in other cases. As pointed out by Suhren and associates and by Kurczynski, the condition is transmitted in some families as an autosomal dominant trait. The subject has been reviewed by Wilkins and colleagues and by Ryan and associates.


Neurology_Adams

Neurology_Adams. Later in life, excessive startle must be distinguished from normal sleep starts, epileptic seizures, which may begin with a startle or massive myoclonic jerk (startle epilepsy), from the multiple tic disorder, Gilles de la Tourette syndrome, of which startle may be a prominent manifestation, and from cataplexy. With idiopathic startle disease, even with a fall, there is no loss of consciousness, and the manifestations of tic and other neurologic abnormalities are absent. Reflecting the clinical proximity to myoclonus, a stimulus-evoked startle response may be a manifestation of several myoclonic neurologic diseases including Tay-Sachs disease, SSPE, “stiff-man” syndrome, lipid storage diseases and, Creutzfeldt-Jakob disease.


Neurology_Adams

Neurology_Adams. The mechanism of the startle response has been a matter of speculation. In animals, the origin of the phenomenon has been localized in the pontine reticular nuclei, with transmission to the lower brainstem and spinal motor neurons via the reticulospinal tracts. During the startle, the EEG may show a vertex or frontal spike–slow-wave complex, followed by a general desynchronization of the cortical rhythms; between startles the EEG is normal. Some authors have postulated a disinhibition of certain brainstem centers. Others, on the basis of testing by somatosensory evoked potentials, have suggested that hyperactive long-loop reflexes constitute the physiologic basis of startle disease (Markand et al). Wilkins and coworkers consider hyperexplexia to be an independent phenomenon (different from the normal startle reflex) and to fall within the spectrum of stimulus-sensitive myoclonic disorders. Presumably, the altered glycine receptor in startle disease is the source of some form of


Neurology_Adams

Neurology_Adams. from the normal startle reflex) and to fall within the spectrum of stimulus-sensitive myoclonic disorders. Presumably, the altered glycine receptor in startle disease is the source of some form of hyperexcitability in one or another of the motor or reticular alerting systems.


Neurology_Adams

Neurology_Adams. Clonazepam controls the startle disorders to varying degrees. Levetiracetam has reportedly been helpful in some patients. Also, the act of flexing the neck and bringing the arms close to the torso may reduce the intensity of an attack (Vigevano maneuver).


Neurology_Adams

Neurology_Adams. The focal or segmental dystonias, in contrast to the generalized dystonic disorders, are intermittent, brief or prolonged spasms or contractions of a group of adjacent muscles that places the body part in a forced and unnatural position. The most common type of focal dystonia is torticollis, a spasm that is limited to the neck muscles as detailed below. Other dystonias restricted to craniocervical muscle groups are spasms of the orbicularis oculi, causing forced closure of the eyelids (blepharospasm) and contraction of the muscles of the mouth and jaw, which may cause forceful opening or closure of the jaw and retraction or pursing of the lips (oromandibular dystonia). With the last of these conditions, the tongue may undergo forceful involuntary protrusion; the throat and neck muscles may be thrown into spasm when the patient attempts to speak or the facial muscles may contract in a grimace. Another form of dystonia that occurs independently or in association with orofacial movements


Neurology_Adams

Neurology_Adams. be thrown into spasm when the patient attempts to speak or the facial muscles may contract in a grimace. Another form of dystonia that occurs independently or in association with orofacial movements is spasmodic dysphonia, a dystonia of the laryngeal muscles that imparts a high-pitched, strained quality to the voice (sometimes incorrectly termed “spastic” dysphonia) as discussed in Chap. 22. Yet a different group of focal dystonias affects the limbs, particularly the hand in relation to overuse of a small skilled movement such as writing.


Neurology_Adams

Neurology_Adams. To give a perspective of the relative frequencies of these disorders, of the focal dystonias seen in the movement disorder clinic of Columbia Presbyterian Hospital, 44 percent were classified as torticollis, 26 percent as spasmodic dysphonia, 14 percent as blepharospasm, 10 percent as focal dystonia of the hand (writer’s cramp), and 3 percent as oromandibular dystonia.


Neurology_Adams

Neurology_Adams. These movement disorders are involuntary and cannot be inhibited, thereby differing from habit spasms or tics. At one time, torticollis was thought to be a psychological disorder but all now agree that it is a localized form of dystonia. It is characteristic of focal dystonias to display a simultaneous activation of agonist and antagonist muscles (co-contraction) and to have a tendency for the spasm to spread to adjacent muscle groups that are not normally activated in the movement (overflow), but these features tend not to be as prominent in focal dystonias as in the generalized varieties described earlier. Sometimes, focal dystonias include an arrhythmic intermixed tremor, which may be the prominent incipient feature. The tremor in particular may cause difficulty in diagnosis if the slight degree of underlying dystonia is not appreciated by careful observation and by palpation of the involved muscles.


Neurology_Adams

Neurology_Adams. The pathogenesis of the idiopathic focal dystonias is uncertain, although there is evidence that some of them, like the generalized dystonias, are genetically determined. Authoritative commentators, including Marsden, classified the apparently idiopathic adult-onset focal dystonias with genetically determined generalized torsion dystonia. This view is based on several lines of evidence: the recognition that each of the focal dystonias may appear as an early component of generalized syndrome in children, the occurrence of focal and segmental dystonias in family members of these children, as well as a tendency of the dystonia in some adult patients to spread to other body parts. Perhaps the most compelling observation in this regard has been the finding that there are families in which the only manifestation of the DYT1 mutation (the gene associated with generalized torsion dystonia) is a late-onset writer’s cramp or other focal dystonia. Whether this explains most or even many of the


Neurology_Adams

Neurology_Adams. only manifestation of the DYT1 mutation (the gene associated with generalized torsion dystonia) is a late-onset writer’s cramp or other focal dystonia. Whether this explains most or even many of the cases of adult onset focal dystonia is unclear but it does emphasize the phenotypic variability associated with the DYT1 mutation. The genetics of primary torsion dystonia is more complex than portrayed here, and is reviewed in Chap. 38.


Neurology_Adams

Neurology_Adams. It is noteworthy that no consistent pathologic changes have been demonstrated in any of the idiopathic or genetically determined dystonias (see Zeman). Most physiologists cast the disorder in terms of reduced cortical inhibition of unwanted muscle contractions, as summarized by Berardelli and colleagues. Moreover, physiologic changes in the cortical sensory areas that are pertinent to the dystonias associated with overuse of body parts (occupational dystonias) are described further on.


Neurology_Adams

Neurology_Adams. A focal dystonia rarely emerges transiently after a stroke that involves the striatopallidal system, mainly the internal segment of the pallidum or the thalamus, but the varied locations of these infarctions makes it difficult to draw conclusions about the mechanism of dystonia. It will be noticed that the same disturbances that cause chorea, as discussed in an earlier section, may produce focal dystonias (see Table 4-4). Focal dystonias may also occur in metabolic diseases such as Wilson disease and nonwilsonian hepatolenticular degeneration. Any of the typical forms of restricted dystonia may represent a tardive dyskinesia; that is, they complicate treatment with high-potency dopamine antagonists and other medications that are used primarily for the treatment of psychosis and nausea (see further on under “Drug-Induced Dyskinesias”). Dystonias of the hand or foot often emerge as components of a number of degenerative diseases—Parkinson disease in particular but also corticobasal


Neurology_Adams

Neurology_Adams. (see further on under “Drug-Induced Dyskinesias”). Dystonias of the hand or foot often emerge as components of a number of degenerative diseases—Parkinson disease in particular but also corticobasal ganglionic degeneration, and progressive supranuclear palsy (described in Chap. 38). Such cases that fall into the category of symptomatic or secondary dystonias are described by Krystkowiak and colleagues and by Munchau and colleagues. Janavs and Aminoff have summarized several focal dystonias that are caused by acquired systemic disorders, such as drugs, and by autoantibodies, including from systemic lupus erythematosus. It is the last of these that we have encountered most often in clinical practice.


Neurology_Adams

Neurology_Adams. Torticollis, the most frequent form of restricted dystonia, is localized to the neck and adjacent muscles. It usually begins as a subtle tilting or turning of the head that tends to worsen slowly, first evident in early to middle adult life, somewhat more commonly in women (peak incidence in the fifth decade) (extreme form shown in Fig. 4-8A). With the exception of the finding of DYT1 gene abnormality in a few patients, it is idiopathic. The quality of the neck and head movements varies greatly. Intermittent turning or tilting of the head may be deliberate and smooth, or jerky, but more typically there is a sustained deviation or tilting of the head to one side. Sometimes brief bursts of twitching or an irregular, high-frequency tremor accompanies deviation of the head, beating in the direction of the dystonic movement. At times the tremor is more dominant than is the dystonia, causing difficulty in diagnosis. The spasms are often worse when the patient stands or walks and are


Neurology_Adams

Neurology_Adams. the direction of the dystonic movement. At times the tremor is more dominant than is the dystonia, causing difficulty in diagnosis. The spasms are often worse when the patient stands or walks and are characteristically reduced or abolished by a contactual stimulus, such as placing a hand on the chin or neck; exerting mild but steady counterpressure on the side of the deviation or less often on the opposite side; or bringing the occiput in contact with the back of a high chair. These maneuvers, termed gestes, or “sensory tricks” become less effective as the disease progresses. In many cases, the spasms are reduced when the patient lies down. In chronic cases, as the dystonic position typically becomes increasingly fixed in position, the affected muscles undergo hypertrophy. At that late stage, pain in the contracting muscles is common.


Neurology_Adams

Neurology_Adams. In a few of our patients, the condition disappeared without therapy, an occurrence observed in 10 to 20 percent in the series of Dauer et al. In their experience, remissions usually occurred during the first few years after onset in patients whose disease began relatively early in life; however, nearly all these patients relapsed within 5 years.


Neurology_Adams

Neurology_Adams. The most prominently affected muscles are the sternocleidomastoid, levator scapulae, and trapezius. EMG studies also show sustained or intermittent activity in the posterior cervical muscles on both sides of the neck. The levator spasm lifts the affected shoulder slightly, and tautness in this muscle is sometimes the earliest feature. As a general observation, we have been impressed with information gained from palpating the muscles of the neck and shoulder in order to establish which muscles are the predominant causes of the spasm and to direct treatment to them as noted further on. In most patients the spasms remain confined to the neck muscles and persist in unmodified form, but in some the spasms spread, involving muscles of the shoulder girdle and back or the face and limbs. The distinction between these patterns is not fundamental. About 15 percent of patients with torticollis also have oral, mandibular, or hand dystonia, 10 percent have blepharospasm, and a similarly small


Neurology_Adams

Neurology_Adams. distinction between these patterns is not fundamental. About 15 percent of patients with torticollis also have oral, mandibular, or hand dystonia, 10 percent have blepharospasm, and a similarly small number have a family history of dystonia or tremor (Chan et al). As already noted, no neuropathologic changes have been found in case studies, for example, those reported by Tarlov and by Zweig and colleagues.


Neurology_Adams

Neurology_Adams. Spasmodic torticollis is resistant to treatment with L-dopa and other antiparkinsonian agents, although occasionally they give slight relief. The drugs are, however, effective in those few instances in which dystonia is a prelude to Parkinson disease. Trihexyphenidyl or benztropine, used in the past in high doses for dystonia, may allow some amelioration but they are difficult to tolerate.


Neurology_Adams

Neurology_Adams. The most widely used form of treatment is the periodic (every 3 to 6 months) injection of small amounts of botulinum toxin directly into several sites in the affected muscles. The injections are best guided by palpation of muscles in spasm and by EMG analysis to determine which of the tonically contracted muscles are most responsible for the aberrant posture. All but 10 percent of patients with torticollis have had some degree of relief from symptoms with this treatment. Adverse effects (excessive weakness of injected muscles, local pain, and dysphagia—the latter from a systemic effect of the toxin) are usually mild and transitory. Five to 10 percent of patients eventually become resistant to repeated injections because of the development of neutralizing antibodies to the toxin (Dauer et al).


Neurology_Adams

Neurology_Adams. More recently, the use of deep brain stimulation has found some success in the treatment of cases of idiopathic cervical dystonia that have been refractory to medications and botulinum injection. The internal segments of the globus pallidus and the subthalamic nuclei have been used as targets. This approach is certainly preferable to the former use of ablative lesions in these areas and in the thalami but, as in the randomized trial conducted by Volkmann and colleagues, adverse effects such as dysarthria, dyskinesias and worsening of dystonia occur in a proportion of cases. In the most severe cases of torticollis, a combined sectioning of the spinal accessory nerve and of the first three cervical motor roots bilaterally has been successful in reducing spasm of the muscles without totally paralyzing them. Considerable relief has been achieved for as long as 6 years in one-third to one-half of cases treated in this way (Krauss et al; Ford et al).


Neurology_Adams

Neurology_Adams. Patients in mid and late adult life, predominantly women, may present with the complaint of excessive blinking and involuntary forced closure of the eyes, which is due to spasm of the orbicularis oculi muscles. Any attempt to look at a person or object is associated with a persistent tonic, symmetric spasm of the eyelids (see Fig. 4-8B). During conversation, the patient struggles to overcome the spasms and is distracted by them. Reading and watching television are impossible at some times but surprisingly easy at others. Jankovic and Orman in a survey of 250 such patients found that in the past, before effective treatment, 75 percent progressed in severity over the years to the point, in about 15 percent of cases, of making the patients functionally blind. Some instances of blepharospasm are a component of the Meige syndrome that includes jaw spasms (see next section) or are associated with spasmodic dysphonia, torticollis, and other dystonic fragments. Blepharospasm may also be a


Neurology_Adams

Neurology_Adams. are a component of the Meige syndrome that includes jaw spasms (see next section) or are associated with spasmodic dysphonia, torticollis, and other dystonic fragments. Blepharospasm may also be a result of drug-induced tardive dyskinesia.


Neurology_Adams

Neurology_Adams. One’s first inclination is to attribute this disorder to photophobia or a response to an ocular irritation or corneal dryness, and indeed, the patient may state that bright light is annoying. For example, ocular inflammation, especially of the iris, may produce severe reflex blepharospasm. However, the spasms persist in dim light and even after anesthesia of the corneas. Patients may hold the lid open with a finger and the eyebrow is seen to be displaced downward; in some forms, there is tonic contraction of the frontalis muscles in an apparent attempt to aid lid opening.


Neurology_Adams

Neurology_Adams. In the past, a psychiatric causation was proposed but, with the exception of a depressive reaction in some patients, psychiatric symptoms are lacking, and the use of psychotherapy, biofeedback, acupuncture, behavior modification therapy, and hypnosis has failed to cure the spasms. No neuropathologic lesion or neurochemical profile has been established in any of these disorders (Marsden et al; see also Hallett). A genetic basis is possible although few cases seem to be inherited and there has been no association with the known dystonia genes.


Neurology_Adams

Neurology_Adams. The most effective treatment consists of the injection of botulinum toxin into several sites in the orbicularis oculi and adjacent facial muscles. The benefit lasts for 3 to 6 months and repeated cycles of treatment are usually required. There appear to be few adverse systemic effects because of the low doses used. In the treatment of blepharospasm, a variety of antiparkinsonian, anticholinergic, and tranquilizing medications may be tried, but one should not be optimistic about the chances of success. A few of our patients in the past had temporary and partial relief from L-dopa. Sometimes the blepharospasm disappears spontaneously (in 13 percent of the cases in the series of Jankovic and Orman). Thermolytic destruction of part of the fibers in the branches of the facial nerves that innervate the orbicularis oculi muscles is reserved for the most resistant and disabling cases. Other Causes of Blepharospasm


Neurology_Adams

Neurology_Adams. Other Causes of Blepharospasm There are several clinical settings other than the one described above in which blepharospasm or a condition that simulates it may be observed. In the days following cerebral infarction or hemorrhage, the stimulus of lifting the patient’s eyelids may lead to strong involuntary closure of the lids. Reflex blepharospasm, as Fisher has called this phenomenon, takes liberty with the term as it more in the character of an apraxia of opening of the lids. It is more commonly associated with a left than a right hemiplegia. A homolateral blepharospasm has also been observed with a small thalamomesencephalic infarct. In patients with Parkinson disease, progressive supranuclear palsy, or Wilson disease and with other lesions in the rostral brainstem, light closure of the eyelids may induce blepharospasm and an inability to open the eyelids voluntarily.


Neurology_Adams

Neurology_Adams. We have seen an instance of blepharospasm as part of paraneoplastic midbrain encephalitis, and there have been several reports of it with autoimmune disease such as systemic lupus but the mechanism in these cases is as obscure as for the idiopathic variety. Also among our patients have been two with myasthenia gravis and blepharospasm of the type described by Roberts and colleagues, but we have been unable to ascertain if this represented a second disturbance or simply an exaggerated response to keeping the lids open. Finally, eye closure with fluttering of the lids in patients with a high degree of suggestibility is usually indicative of a psychological disorder. Blepharospasm induced by pain from ocular conditions such as iritis and rosacea of the eyelids has already been mentioned. Lingual, Facial, and Oromandibular Spasms (Meige Syndrome)


Neurology_Adams

Neurology_Adams. These special varieties of involuntary movements appear in later adult life, with a peak age of onset in the sixth decade. Women are affected more frequently than men. The most common type is characterized by forceful opening of the jaw, retraction of the lips, spasm of the platysma, and protrusion of the tongue; or the jaw may be clamped shut and the lips may purse (Fig. 4-8B). Other patterns include lateral jaw deviation and bruxism. Common terms for this condition are Meige syndrome, after the French neurologist who gave an early description of it, and Brueghel syndrome, because of the similarity of the grotesque grimace to that of a subject in a Brueghel painting called De Gaper. Difficulty in speaking and swallowing (due in part to spasmodic dysphonia) and blepharospasm are also frequently conjoined, and occasionally patients with these disorders develop torticollis or dystonia of the trunk and limbs. A number have tremor of affected muscles or of the hands as well. All these


Neurology_Adams

Neurology_Adams. conjoined, and occasionally patients with these disorders develop torticollis or dystonia of the trunk and limbs. A number have tremor of affected muscles or of the hands as well. All these prolonged, forceful spasms of facial, tongue, and neck muscles had in the past followed the administration of phenothiazine and butyrophenone drugs (tardive dyskinesia). More often, however, the dyskinetic disorder induced by neuroleptics is somewhat different, consisting of choreoathetotic chewing, lip smacking, and licking movements (tardive orofacial dyskinesia, rabbit-mouth syndrome; see later).


Neurology_Adams

Neurology_Adams. Very few cases of the Meige syndrome have been studied neuropathologically. In most of them no lesions were found. In one patient there were foci of neuronal loss in the striatum (Altrocchi and Forno); another patient showed a loss of nerve cells and the presence of Lewy bodies in the substantia nigra and related nuclei (Kulisevsky et al); both are of uncertain significance.


Neurology_Adams

Neurology_Adams. A form of focal dystonia that affects only the jaw muscles has been described (masticatory spasm of Romberg); a similar dystonia may be a component of orofacial and generalized dystonias. In the cases described by Thompson and colleagues, the problem began with brief periods of spasm of the pterygoid or masseter muscle on one side. Early on, the differential diagnosis includes bruxism, hemifacial spasm, the odd rhythmic jaw movements associated with Whipple disease, and tetanus. As the illness progresses, forced opening of the mouth and lateral deviation of the jaw may last for days and adventitious lingual movements may be added. A form that occurs with hemifacial atrophy has been described by Kaufman. An intermittent spasm that is confined to one side of the face (hemifacial spasm) is not, strictly speaking, a dystonia and is considered with disorders of the facial nerve in Chap. 44.


Neurology_Adams

Neurology_Adams. As with the other focal and regional dystonias, substantial success has been obtained with injections of botulinum toxin into the masseter, temporal, and medial pterygoid muscles. High doses of benztropine and related anticholinergic drugs may be helpful, but are not as effective as botulinum toxin treatment. Many other drugs have been used in the treatment of these craniocervical spasms, but none has effected persistent benefit.


Neurology_Adams

Neurology_Adams. Occupational cramps or spasms are included in this chapter because the prevailing opinion is that they are acquired forms of regional or focal “task-specific” dystonias. In the most common form, writer’s cramp, the patient experiences, upon attempting to write, that all the muscles of the thumb and fingers either go into spasm or are inhibited by a feeling of stiffness and pain or hampered in some other inexplicable way. The clinical descriptions of writer’s cramp by Sheehy and Marsden are worth consulting. Men and women are equally affected, most often between the ages of 20 and 50 years. The spasm may be painful and can spread into the forearm or even the upper arm and shoulder. Sometimes the spasm fragments into a tremor that interferes with the execution of fluid, cursive movements. Immediately upon cessation of writing, the spasm disappears. At all other times and in the execution of grosser movements, the hand is normal, and there are no other neurologic abnormalities. Many


Neurology_Adams

Neurology_Adams. Immediately upon cessation of writing, the spasm disappears. At all other times and in the execution of grosser movements, the hand is normal, and there are no other neurologic abnormalities. Many patients learn to write in new ways or to use the other hand, though that, too, may become involved.


Neurology_Adams

Neurology_Adams. Other highly skilled motor acts performed over long periods of time, such as playing the piano or fingering the violin, may induce a similar highly task-dependent spasm (“musician’s cramp,” “musician’s dystonia”) or in the past, telegrapher’s palsy. The “loss of lip” in trombonists and other brass and wind instrumentalists (embouchure dystonia) represents an analogous phenomenon, seen only in experienced musicians. In each case a delicate motor skill, perfected by years of practice and performed almost automatically, suddenly comes to require a conscious and labored effort for its execution. Discrete movements are impaired by a spreading recruitment of unneeded muscles (intention spasm). Once developed, the disability persists in varying degrees of severity, even after long periods of inactivity of the affected part.


Neurology_Adams

Neurology_Adams. Regarding pathogenesis, Byl and colleagues, found that sustained, rapid, and repetitive highly stereotypical movements of the hand in monkeys greatly expand the area of hand cortical representation. These authors have hypothesized that degradation of sensory feedback to the motor cortex was responsible for excessive and persistent motor activity, including dystonia. Many patients with focal acquired dystonia demonstrate minor sensory abnormalities by way of impaired temporal and spatial detection of stimuli on careful examination. A similar enlargement of the area of cortical response to magnetic stimulation has been found by a number of investigators in patients with writer’s cramp and the volume of gray matter was decreased in the sensorimotor cortex, thalamus, and cerebellum corresponding to the affected hand in the report by Delmaire and coworkers. There is a special category of dystonia following nerve injury, often with severe burning pain and autonomic changes that conforms to


Neurology_Adams

Neurology_Adams. to the affected hand in the report by Delmaire and coworkers. There is a special category of dystonia following nerve injury, often with severe burning pain and autonomic changes that conforms to reflex sympathetic dystrophy. In these cases, it may be the injury that causes a reconfiguration of the sensory receptive fields. Berardelli et al have reviewed other theories pertaining to the physiology of the focal dystonias. More recent notions have included changes in synaptic plasticity as a result of overuse.


Neurology_Adams

Neurology_Adams. A high degree of success has been obtained by injections of botulinum toxin into specifically involved muscles, such as those of the hand and forearm in cases of writer’s cramp (Cohen et al; Rivest et al), and this is now widely used. The best results are obtained by guiding the injection from both palpation and EMG detection of the specific muscles that are active in the dystonic posture. Various forms of hand retraining are also said to be useful. Transcutaneous electrical stimulation (TENS) of the forearm in 20-minute sessions has a modest effect according to a study by Tinazzi and colleagues. It had been claimed that the patient can be helped by a deconditioning procedure that delivers an electric shock whenever the spasm occurs or by biofeedback, but these forms of treatment have been largely abandoned in favor of botulinum treatments. There have been some preliminary investigations of thalamotomy and deep brain stimulation for resistant cases.


Neurology_Adams

Neurology_Adams. Dyskinesia is a broadly encompassing term that is applied to many hyperkinetic involuntary movements including those taking the conventional forms of dystonia, chorea, athetosis, and tremor and the less well-defined ones that are produced by L-dopa therapy in Parkinson disease. When modified by the adjective tardive, it refers specifically to movements induced by the use of neuroleptic drugs, often but not always phenothiazines, that are delayed in onset from the initiation of drug therapy and persist after the drugs are withdrawn. These movements are distinguished from acute dystonic reactions that occur in the first few days of exposure to medications, are aborted by anticholinergic drugs, and do not persist. At one time, tardive dyskinesia was a common problem in psychiatric and general medical practice but it has been less prevalent with the newer classes of antipsychosis drugs. The problem is still easily recognized and familiar to physicians who treat psychiatric patients. The


Neurology_Adams

Neurology_Adams. medical practice but it has been less prevalent with the newer classes of antipsychosis drugs. The problem is still easily recognized and familiar to physicians who treat psychiatric patients. The movements tend to lessen over a period of months or years and mild cases abate on their own or leave little residual effect; rarely have the symptoms worsened.


Neurology_Adams

Neurology_Adams. Tardive dyskinesias are intermittent or persistent and not subject to the will of the patient. The facial, lingual, eyelid, and bulbar muscles are most often involved but neck, shoulder, and spine muscles with arching of the back may be implicated in individual cases as noted below. There may be added blepharospasm and truncal, hand, or neck movements and akathisia of the legs, but these are not nearly so prominent as the orofacial and lingual dyskinesias. Longer exposure is more likely to cause the movements. If the drug is discontinued immediately after the movements appear, the problem may not persist. Oromandibular spasm and blepharospasm (Meige syndrome) and Huntington disease may cause difficulty in diagnosis.


Neurology_Adams

Neurology_Adams. In addition to the typical neuroleptic drugs, less familiar ones such as metoclopramide, pimozide, amoxapine, and clebopride, some of which are used for disorders other than psychosis, and newer agents such as risperidone may also be causative. Less often, the movements arise soon after cessation of one of these same drugs.


Neurology_Adams

Neurology_Adams. There are a number of other drug-induced tardive movement syndromes, mainly varieties of dystonias, some of which have been mentioned earlier, and akathisia (see further on). Often they begin focally in the neck and spread over time to the limbs. One highly characteristic pattern combines retrocollis, backward arching of the trunk, internal rotation of the arms, extension of the elbows, and flexion of the wrists simulating an opisthotonic posture. Other patients may have both orofacial and cervical dyskinesias. Many patients report that the dystonia abates during walking and other activities, quite unlike idiopathic torsion dystonia. These drug-induced dyskinesias are viewed as the result of changes in the concentration of dopamine receptors, five of which are currently known, as discussed earlier. Blockade and subsequent unmasking of the D2 receptor have been particularly linked to the development of the tardive syndromes.


Neurology_Adams

Neurology_Adams. Little has been found to be consistently effective. If the movements follow withdrawal of one of the offending drugs, reinstitution of the medication in small doses often reduces the dyskinesias but may have the undesired side effects of causing parkinsonism and drowsiness. For this reason most clinicians who are experienced in this field avoid using the known offending drugs if possible and choose one of the newer agents for the treatment of the underlying psychiatric condition. The newer “atypical” neuroleptic drugs have less of a propensity to cause tardive dyskinesia. Dopamine and noradrenergic-depleting drugs such as reserpine and tetrabenazine have also been successful if used carefully but the more effective of the two, tetrabenazine, may be difficult to obtain. The dystonias also respond to anticholinergic drugs (trihexyphenidyl 2.5 mg once or twice daily, increased by small increments weekly up to 12.5 mg) if high enough doses can be tolerated.


Neurology_Adams

Neurology_Adams. Further discussion of the side effects of the antipsychosis drugs is found in later chapters.


Neurology_Adams

Neurology_Adams. When idle, almost all individuals display a variety of fidgeting types of small amplitude movement, gestures, and mannerisms. They are slower and more complex than tics and spasms. Others, throughout their lives are given to odder and more intrusive but benign habitual movements. These range from simple, highly idiosyncratic mannerisms (e.g., of the lips and tongue) to repetitive actions such as sniffing, clearing the throat, protruding the chin, or blinking whenever these individuals become tense. Stereotypy and irresistibility are the main identifying features of these phenomena. The patient admits to making the movements and feels compelled to do so in order to relieve perceived tension. Such movements can be suppressed for a short time by an effort of will, but they reappear as soon as the subject’s attention is diverted. In certain cases the tics become so ingrained that the person is unaware of them and seems unable to control them. An interesting feature of many tics is that


Neurology_Adams

Neurology_Adams. as the subject’s attention is diverted. In certain cases the tics become so ingrained that the person is unaware of them and seems unable to control them. An interesting feature of many tics is that they correspond to coordinated acts that normally serve some purpose to the organism. It is only their incessant repetition when uncalled for that marks them as habit spasms or tics. The condition varies widely in its expression from a single isolated movement (e.g., blinking, sniffing, throat clearing, tongue clicking, or stretching the neck) to a complex of movements.


Neurology_Adams

Neurology_Adams. Children between 5 and 10 years of age are especially likely to develop these habit spasms. These consist of blinking, hitching up one shoulder, sniffing, throat clearing, jerking the head or eyes to one side, grimacing, etc. If ignored, such spasms seldom persist for longer than a few weeks or months and tend to diminish on their own. In adults, relief of nervous tension by sedative or tranquilizing drugs may be helpful, but the disposition to tics persists. A putative relationship to streptococcal infection is discussed below.


Neurology_Adams

Neurology_Adams. Special types of rocking, head bobbing, hand waving (in autism) or hand wringing (typical of Rett syndrome), and other movements, particularly self-stimulating movements, are disorders of motility frequent in the developmentally delayed child or adult. These “rhythmias” have no known pathologic anatomy in the basal ganglia or elsewhere in the brain. Apparently they represent a persistence of some of the rhythmic, repetitive movements of normal infants. In some cases of impaired vision and photic epilepsy, eye rubbing or moving the fingers rhythmically across the field of vision is observed, especially again in developmentally delayed children.


Neurology_Adams

Neurology_Adams. Multiple tics—sniffing, snorting, involuntary vocalization, and troublesome compulsive and aggressive impulses—constitute the rarest and most severe tic syndrome—Gilles de la Tourette syndrome (his complete surname). The problem begins in childhood, in boys three times more often than in girls, usually as a simple tic. As the condition progresses, new tics are added to the repertoire. It is the multiplicity of tics and the combination of motor and vocal tics that distinguish the disorder from the more benign, restricted tic disorders. The modern definition has expanded to include an attention deficit disorder that may not reach a severity appropriate for that diagnosis independently as summarized by Kurlan.


Neurology_Adams

Neurology_Adams. Vocal tics, sometimes loud and irritating in pitch, are characteristic. Some patients display repetitive motor behavior, such as jumping, squatting, or turning in a circle. Other common types of repetitive behavior include the touching of other persons and repeating one’s own words (palilalia) and the words or movements of others. Explosive and involuntary cursing and the compulsive utterance of obscenities (coprolalia) are perhaps the most dramatic manifestations. Interestingly, the latter phenomenon is reportedly uncommon in Japanese patients, whose decorous culture and language contain few obscenities. The full repertoire of tics and compulsions comprised by Gilles de la Tourette syndrome has been described by Tolosa and Bayes and in the reviews by Jankovic and by Leckman, which are recommended.


Neurology_Adams

Neurology_Adams. Stone and Jankovic have noted the occurrence of blepharospasm, torticollis, and other dystonic fragments in a small number of patients. Isometric contractions of isolated muscle groups (tonic tics) may also occur. As in other tic disorders, there is a premonitory sensation of tightness, discomfort or paresthesia, or a psychic sensation or urge that is relieved by the movement. A fair proportion stutters or displays a mild dysfluency of speech. So-called soft neurologic signs are noted in half of the patients. Feinberg and associates have described four patients with arrhythmic myoclonus and vocalization, but it is not clear whether these symptoms represent an unusual variant of the disease or a new syndrome. A degree of cyclicality of symptoms has been noted by several authors; tics tend to happen in groups over minutes or hours and they are clustered over weeks and months. This gives the appearance of a waxing and waning process.


Neurology_Adams

Neurology_Adams. The course of the illness is unpredictable. In half of adolescents the tics subside spontaneously by early adulthood and those that persist become milder with time. Others undergo long remissions only to have tics recur, but in other patients the motor disorder persists throughout life. This variability emphasizes the difficulty in separating transient habit spasms from the Gilles de la Tourette chronic multiple tic syndrome. Isolated and mild but lifelong motor tics probably represent a variant of Tourette syndrome insofar as they display the same predominantly male heredofamilial pattern and similar responses to medication.


Neurology_Adams

Neurology_Adams. An attention-deficit hyperactivity disorder, obsessive-compulsive traits, or both are said to be evident at some time in the course of the illness, and these interfere with progress in school to a greater degree than do the tics. Poor control of temper, impulsiveness, self-injurious behavior, and certain sociopathic traits are seen in a few but by no means all affected children. Evidence of cognitive impairment by psychometric tests was found in 40 to 60 percent of patients in the series reported by Shapiro and colleagues, but intelligence did not deteriorate. Nonspecific abnormalities of the EEG have occurred in more than half of the patients but are not consistent enough to be considered a feature of the disease.


Neurology_Adams

Neurology_Adams. In one-third of the cases reported by Shapiro and colleagues, isolated tics were observed in other members of the family. Several other studies have reported a familial clustering of cases in which the pattern of transmission appears to be autosomal dominant with incomplete penetrance (Pauls and Leckman) but this has been disputed and several predisposing genes have been found. In any biologic explanation, the marked predominance of males must be accounted for. At the moment, Tourette syndrome cannot be attributed to a single genetic locus. Nonetheless, support for a primary genetic nature of Tourette syndrome derives from twin studies, which have revealed higher concordance rates in monozygotic twin pairs than in dizygotic pairs. An ethnic propensity has been reported in Ashkenazi Jews but this has not been borne out in other large series (Lees et al).


Neurology_Adams

Neurology_Adams. As to causation, little is known. There is no consistent association with infection, trauma, or other disease except the putative connection to streptococcal infections discussed further on. Hyperactive children who have been treated with stimulants appear to be at increased risk of developing or exacerbating tics (Price et al) but a causal relationship has not been established beyond doubt (see comments regarding treatment below). MRI has shown no uniform abnormalities; functional imaging has demonstrated numerous but inconsistent abnormalities. Histopathologic changes have not been discerned in the few brains examined by the usual methods. However, Singer and coworkers (1991), who analyzed preand postsynaptic dopamine markers in postmortem striatal tissue, found a significant alteration of dopamine uptake mechanisms; more recently, Wolf and colleagues, have found that differences in D2 dopamine receptor binding in the head of the caudate nucleus reflected differences in the


Neurology_Adams

Neurology_Adams. of dopamine uptake mechanisms; more recently, Wolf and colleagues, have found that differences in D2 dopamine receptor binding in the head of the caudate nucleus reflected differences in the phenotypic severity of Gilles de la Tourette syndrome. These observations, coupled with the facts that L-dopa exacerbates the symptoms of the syndrome and that haloperidol, which blocks dopamine (particularly D2) receptors, is an effective treatment, support a dopaminergic abnormality in the basal ganglia, more specifically in the caudate. In this respect, instances of compulsive behavior in relation to lesions in the head of the caudate nucleus and its projections from orbitofrontal and cingulate cortices may be pertinent.


Neurology_Adams

Neurology_Adams. For delimited and benign tics, treatment is generally not necessary. Reassurance of the parents can be very helpful. Isolated or infrequent nonintrusive, motor tics in males beyond adolescence, generally an inherited trait, is often aided by clonazepam but may require some of the more potent medications named above.


Neurology_Adams

Neurology_Adams. Two classes of drugs are used in treatment of intractable and multiple tics; alpha agonists and antipsychosis medications. The alpha2-adrenergic agonists clonidine and guanfacine have been useful in several studies. These are not as potent as treatment with neuroleptic drugs, but their side effects are less severe and they are recommended as the first treatment. Guanfacine has the advantage over clonidine of daily dosing and less sedating effect. The initial dose is 0.5 to 1 mg given at bedtime and gradually increased as needed to a total dose of 4 mg. Clonidine is started as a bedtime dose of 0.05 mg and increased every several days by 0.05 mg until a total dose of about 0.1 mg three times daily. The neuroleptics haloperidol and pimozide, (and less frequently used sulpiride and tiapride) have proved to be effective therapeutic agents but should be used only in severely affected patients and usually after the adrenergic agents have been tried. Haloperidol is instituted in small doses


Neurology_Adams

Neurology_Adams. have proved to be effective therapeutic agents but should be used only in severely affected patients and usually after the adrenergic agents have been tried. Haloperidol is instituted in small doses (0.25 mg initially, increasing the dosage gradually to 2 to 10 mg daily). The atypical neuroleptics, such as risperidone, have also been used with some success. Pimozide, which has a more specific antidopaminergic action than haloperidol, may be more effective than haloperidol; it should be given in small amounts (0.5 mg daily) to begin with and increased gradually to 8 to 9 mg daily. The addition of benztropine mesylate (0.5 mg daily) at the outset of treatment may help to prevent the adverse motor effects of haloperidol. The potent agent tetrabenazine, a drug that depletes monoamines and blocks dopamine receptors, may be useful if high doses can be tolerated. Further details of the use of these drugs can be found in the reviews by Leckman and by Kurlan. According to a trial conducted by


Neurology_Adams

Neurology_Adams. dopamine receptors, may be useful if high doses can be tolerated. Further details of the use of these drugs can be found in the reviews by Leckman and by Kurlan. According to a trial conducted by the Tourette’s Syndrome Study Group, the hyperactivity component of the Tourette syndrome can be treated safely with methylphenidate or clonidine without fear of worsening the tics.


Neurology_Adams

Neurology_Adams. Another interesting approach has been to inject botulinum toxin in muscles affected by prominent focal tics, including the vocal ones as described by Scott and colleagues; curiously, this treatment is said to relieve the premonitory sensory urge. Deep brain stimulation of thalamic and other nuclei has shown promise in a few small series of drug resistant cases.


Neurology_Adams

Neurology_Adams. Using the model of Sydenham chorea, a recent line of investigation has implicated streptococcal infection in the genesis of abruptly appearing Tourette syndrome and of less-generalized tics in children. This association has been extended by some authors to explain obsessive-compulsive behavior of sudden and unexplained onset. These putative poststreptococcal disorders were summarized by Swedo and colleagues under the acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection). In a few cases there has been a relapsing course that is similar to that seen in Sydenham chorea. Two health database studies have suggested a modest association between tic disorder, obsessive-compulsive disorder, and streptococcal infection. These observations taken together are intriguing but not confirmed and several groups have been unable to differentiate patients with PANDAS and Gilles de la Tourette syndrome from controls on the basis of epidemiologic factors


Neurology_Adams

Neurology_Adams. are intriguing but not confirmed and several groups have been unable to differentiate patients with PANDAS and Gilles de la Tourette syndrome from controls on the basis of epidemiologic factors or serum autoantibodies to streptococcus (Singer et al, 2005; Schrag and coworkers).


Neurology_Adams

Neurology_Adams. This term was coined by Haskovec in 1904 to describe an inner feeling of restlessness, an inability to sit still, and a compulsion to move about. When sitting, the patient constantly shifts his body and legs, crosses and uncrosses his legs, and swings the free leg. Running in place and persistent pacing are also characteristic. This abnormality of movement is most prominent in the lower extremities and may not be accompanied, at least in mild forms of akathisia, by perceptible rigidity or other neurologic abnormalities. In its advanced form, patients complain of difficulty in concentration, distracted, no doubt, by the constant urge to move.


Neurology_Adams

Neurology_Adams. First noted in patients with Parkinson disease and Alzheimer disease, akathisia is now observed most often in patients receiving neuroleptic drugs as a component of tardive dyskinesia or independently. However, this disorder may be observed in psychiatric patients who are receiving no medication. It occurs in both medicated and unmedicated patients with Parkinson disease. The main diagnostic considerations are an agitated depression, particularly in patients already on neuroleptic medications, and the “restless legs” syndrome—a sleep disorder that may be evident during wakefulness in severe cases (see Chap. 18). Patients with the restless leg syndrome describe a crawling or drawing sensation in the legs rather than an inner restlessness, although both disorders create an irresistible desire for movement. At times these distinctions are blurred.


Neurology_Adams

Neurology_Adams. Many of the medications used for the restless legs syndrome, such as clonazepam, may be tried for akathisia or, if the symptom is a component tardive dyskinesia, selecting a less potent neuroleptic, an anticholinergic medication, amantadine, or a beta-adrenergic–blocking drug. Adams RD, Foley JM: The neurological disorder associated with liver disease. Res Publ Assoc Nerv Ment Dis 32:198, 1953. Adams RD, Shahani B, Young RR: Tremor in association with polyneuropathy. Trans Am Neurol Assoc 97:44, 1972. Adler CH, Bansberg SF, Hentz JG, et al: Botulinum toxin type A for treating voice tremor. Arch Neurol 61:1416, 2004. Aigner BR, Mulder DW: Myoclonus: Clinical significance and an approach to classification. Arch Neurol 2:600, 1960. Albin RL, Young AB, Penney JB: The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366, 1989.


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