In this chapter, disorders of the automatic, static, postural, and other less-modifiable motor activities of the nervous system are discussed. Many of them are an expression of what has come to be called the extrapyramidal motor system, meaning—according to S.A.K. Wilson, who introduced this term—the motor structures of the basal ganglia and certain related thalamic and brainstem nuclei. However, others such as myoclonus and various tremors have obscure or multiple causes. These are discussed together because they are often combined and because of their inclusion in the clinical specialty of movement disorders.
THE BASAL GANGLIA (STRIATOPALLIDONIGRAL SYSTEM)
The activities of the basal ganglia and the cerebellum are blended with and modulate the corticospinal system and the postural influence of the extrapyramidal system is indispensable to voluntary corticospinal movements. This close association of the basal ganglia and corticospinal systems becomes evident in the course of many forms of neurologic disease. In many aberrant motor patterns, one sees evidence not only of the activity of the basal ganglia but also of labyrinthine, tonic neck, and other postural reflexes that are mediated through nonpyramidal brainstem motor systems, including the vestibulospinal, rubrospinal, and reticulospinal tracts. Observations such as these have blurred the original distinctions between pyramidal and extrapyramidal motor systems. Nevertheless, this division remains a useful concept in clinical work because it informs a distinction among several motor syndromes—one that is characterized by a loss of volitional movement accompanied by spasticity—the corticospinal syndrome; a second by bradykinesia, rigidity, and tremor without loss of voluntary movement—the hypokinetic basal ganglionic syndrome; a third by involuntary movements (choreoathetosis and dystonia)—the hyperkinetic basal ganglionic syndrome; and yet another by incoordination (ataxia)—the cerebellar syndrome. Table 4-1 summarizes the main clinical differences between corticospinal and extrapyramidal syndromes.
Table 4-1CLINICAL DIFFERENCES BETWEEN CORTICOSPINAL AND EXTRAPYRAMIDAL SYNDROMES ||Download (.pdf) Table 4-1CLINICAL DIFFERENCES BETWEEN CORTICOSPINAL AND EXTRAPYRAMIDAL SYNDROMES
| ||CORTICOSPINAL ||EXTRAPYRAMIDAL |
|Character of the alteration of muscle tone ||Clasp-knife effect (spasticity) ||Plastic, equal throughout passive movement (rigidity), or intermittent (cogwheel rigidity) |
|Distribution of hypertonus ||Flexors of arms, extensors of legs ||Generalized but predominates in flexors of limbs and of trunk |
|Involuntary movements ||Absent ||Presence of tremor, chorea, athetosis, dystonia |
|Tendon reflexes ||Increased ||Normal or slightly increased |
|Babinski sign ||Present ||Absent |
|Paralysis of voluntary movement ||Present ||Absent or slight |
As an anatomic entity, the basal ganglia have no precise definition. Principally they include the caudate nucleus and the lentiform (lenticular, from its lens-like shape) nucleus with its two subdivisions—the putamen and globus pallidus. Insofar as the caudate nucleus and putamen are really a continuous structure (separated only incompletely by fibers of the internal capsule) and are cytologically and functionally distinct from the pallidum, it is more meaningful to divide these nuclear masses into the striatum (or neostriatum), comprising the caudate nucleus and putamen, and the paleostriatum or pallidum, which has a medial (internal) and a lateral (external) portion. The putamen and pallidum lie on the lateral aspect of the internal capsule, which separates them from the caudate nucleus, thalamus, subthalamic nucleus, and substantia nigra on its medial side (Figs. 4-1 and 4-2). By virtue of their close connections with the caudate and lenticular nuclei, the subthalamic nucleus (nucleus of Luys) and the substantia nigra are included as parts of the basal ganglia. The claustrum and amygdaloid nuclear complex, despite their largely different connections and functions, are sometimes included although they do not participate in any direct way in the modulation of movement.
Overview of the components of the basal ganglia in coronal view. The main nuclei of the basal ganglia are represented in light brown, as labeled on the right.
Diagram of the basal ganglia in the coronal plane, illustrating the main interconnections (see text for details). The pallidothalamic connections are illustrated in Fig. 4-3.
For reasons indicated further on, some physiologists have expanded the list of basal ganglionic structures to include the red nucleus, the intralaminar thalamic nuclei, and the reticular formations of the upper brainstem. These structures receive direct cortical projections and give rise to rubrospinal and reticulospinal tracts that run parallel to the corticospinal (pyramidal) ones; hence they also were once referred to as extrapyramidal. However, these nonpyramidal linkages are structurally independent of the major extrapyramidal circuits and are better termed parapyramidal systems. As the final links in this circuit—the premotor and supplementary motor cortices—ultimately project onto the motor cortex, they are more aptly referred to as prepyramidal (Thach and Montgomery).
Earlier views of basal ganglionic organization emphasized serial connectivity and the funneling of efferent projections to the ventrolateral thalamus and thence to the motor cortex (Fig. 4-3). The most important basal ganglionic connections and circuitry are indicated in Figs. 4-1, 4-2, and 4-3. The striatum, mainly the putamen, is the receptive part of the basal ganglia, receiving topographically organized fibers from all parts of the cerebral cortex and from the pars compacta (pigmented neurons) of the substantia nigra. The output nuclei of the basal ganglia consist of the medial (internal) pallidum and the pars reticulata (nonpigmented portion) of the substantia nigra (see Fig. 4-3). Further explication of basal ganglionic function can be found in the excellent book by Watts and Koller.
Schematic illustration of major efferent and afferent connections of the basal ganglia. The green lines indicate neurons with excitatory effects, whereas the red lines indicate inhibitory influences. (See text for details and Fig. 4-2.) (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science, 5th ed. New York: McGraw-Hill, 2013.)
These concepts were based largely on the experimental work of Whittier and Mettler and of Carpenter, in the late 1940s. These investigators demonstrated, in monkeys, that a disorder, which they termed choreoid dyskinesia, could be brought about in the limbs of one side of the body by a lesion localized to in the opposite subthalamic nucleus. They also showed that for such a lesion to provoke dyskinesia, the adjacent pallidum and pallidofugal fibers had to be preserved; that is, a second lesion—placed in the medial segment of the pallidum, in the fasciculus lenticularis, or in the ventrolateral thalamus—abolished the dyskinesia. This experimental hyperkinesia could also be abolished by interruption of the lateral corticospinal tract but not by sectioning of the other motor or sensory pathways in the spinal cord. These observations were interpreted to mean that the subthalamic nucleus exerts an inhibitory or regulating influence on the globus pallidus and ventral thalamus. Removal of this influence by selective destruction of the subthalamic nucleus is expressed physiologically by an irregular activity that is now identified as chorea, presumably arising from the intact pallidum and conveyed to the ventrolateral thalamic nuclei, thence by thalamocortical fibers to the ipsilateral premotor cortex, and from there, to the motor cortex, all in a serial manner.
A general principle that has withstood the test of time is the central role of the ventrolateral and ventroanterior nuclei of the thalamus. Together, these nuclei form a nexus, not only from the basal ganglia but also from the cerebellum, to the motor and premotor cortex. Thus, both basal ganglionic and cerebellar influences are brought to bear, via thalamocortical fibers, on the corticospinal system and on other descending pathways from the cortex. Direct descending pathways from the basal ganglia to the spinal cord are relatively insignificant.
It is currently proposed on the basis of physiologic, lesional, and pharmacologic studies that there are two main efferent projections from the putamen. There are reasons to conceptualize: (1) a direct efferent system from the putamen to the medial (internal) pallidum and then to the substantia nigra, particularly to the pars reticulata, and (2) an indirect system originating in the putamen that traverses the lateral (external) pallidum and continues to the subthalamic nucleus, with which it has strong reciprocal connection. To these, has been added (3) a hyperdirect pathway that activates the subthalamic nucleus directly from the motor cortex, without the necessity of the intervening striatum.
In most ways, the subthalamic nucleus and lateral pallidum operate as a single functional unit, (at least in terms of the effects of lesions in those locations on parkinsonian symptoms and the neurotransmitters involved. The internal (medial) pallidum (GPi) and reticular part of the substantia nigra can be viewed in a similar unitary way, sharing the same input and output patterns. Within the indirect pathway, an internal loop is created by projections from the subthalamic nucleus to the medial segment of the pallidum and pars reticulata. A second offshoot of the indirect pathway consists of projections from the external (lateral) pallidum (GPe) to the medial pallidonigral output nuclei. A complete account of this intricate connectivity cannot be given, but the main themes outlined here seem valid and are to be found in the review by Obeso and colleagues.
From the internal pallidum, two bundles of fibers reach the thalamus—the ansa lenticularis and the fasciculus lenticularis. The ansa sweeps around the internal capsule; the fasciculus traverses the internal capsule in a number of small fascicles and then continues medially and caudally to join the ansa in the prerubral field. Both of these fiber bundles join the thalamic fasciculus, which then contains not only the pallidothalamic projections but also mesothalamic, rubrothalamic, and dentatothalamic ones. These projections are directed to separate targets in the ventrolateral nucleus of the thalamus and to a lesser extent in the ventral anterior and intralaminar thalamic nuclei. The centromedian nucleus of the intralaminar group projects back to the putamen and, via the parafascicular nucleus, to the caudate. A major projection from the ventral thalamic nuclei to the ipsilateral premotor cortex completes the large cortical–striatal–pallidal–thalamic–cortical motor loop, with conservation of the somatotopic arrangement of motor fibers, again emphasizing the nexus of motor control at the thalamic nuclei.
Newer observations have made it apparent that there are a number of parallel basal ganglionic–cortical circuits. These circuits run parallel to the premotor pathway but remain separate anatomically and physiologically. At least five such anatomic connections have been described, each projecting to different portions of the frontal lobe: (1) the prototypical motor circuit, converging on the premotor cortex; (2) the ocular motor circuit, projecting onto the frontal eye fields; two prefrontal circuits: (3) one ending in the dorsolateral prefrontal and (4) the other on the lateral orbitofrontal cortex; and (5) a limbic circuit that projects to the anterior cingulate and medial orbitofrontal cortex.
An additional and essential feature of basal ganglionic structure is the nonequivalence of all parts of the striatum. Particular cell types and zones of cells within this structure appear to mediate different aspects of motor control and to utilize specific neurochemical transmitters, as detailed below under “Pharmacologic Considerations” (see also Albin et al and DeLong). This specialization has taken on further importance with the observation that specific cell types are destroyed preferentially in degenerative diseases such as Huntington chorea.
In simplest physiologic terms, Denny-Brown and Yanagisawa, who studied the effects of ablation of individual extrapyramidal structures in monkeys, concluded that the basal ganglia function as a kind of clearinghouse where, during an intended or projected movement, one set of activities is facilitated and all other unnecessary ones are suppressed. They used the analogy of the basal ganglia as a brake or switch, the tonic inhibitory (“brake”) action preventing target structures from generating unwanted motor activity and the “switch” function referring to the capacity of the basal ganglia to select which of many available motor programs will be active at any given time. Still other theoretical constructs focus on the role of the basal ganglia in the initiation, sequencing, and modulation of motor activity (“motor programming”). Also, it appears that the basal ganglia participate in the constant priming of the motor system, enabling the rapid execution of motor acts without premeditation—for example, hitting a baseball. In most ways, these conceptualizations restate the same notions of balance and selectivity imparted to all motor actions by the basal ganglia.
Physiologic evidence reflects this balanced architecture, one excitatory and the other inhibitory within the individual circuits. The direct striatomedial pallidonigral pathway is activated by glutaminergic projections from the sensorimotor cortex and by dopaminergic nigral (pars compacta)—striatal projections. Activation of this direct pathway inhibits the internal pallidum, which, in turn, disinhibits the ventrolateral and ventroanterior nuclei of the thalamus. As a consequence, thalamocortical drive is enhanced and cortically initiated movements are facilitated. The indirect circuit arises from putaminal neurons that contain gamma-aminobutyric acid (GABA) and smaller amounts of enkephalin. These striatal projections have an inhibitory effect on the medial pallidum, which, in turn, disinhibits the subthalamic nucleus through GABA release, providing subthalamic drive to the internal pallidum and substantia nigra pars reticulata. The net effect is thalamic inhibition, which reduces thalamocortical input to the precentral motor fields and impedes voluntary movement. These complex anatomic and physiologic relationships have been summarized in numerous schematic diagrams similar to Fig. 4-4 and those by Lang and Lozano and by Standaert and Young.
A. Schematic diagram of the cortical–basal ganglia–thalamic circuits showing the main neurotransmitter pathways and their effects. Dopaminergic neurons arising in the pars compacta of the substantia nigra have an excitatory influence on the direct pathway (via D1 receptors) and an inhibitory effect on the indirect pathway (via D2 receptors). B. In Parkinson disease, hypokinesia is thought to result from reduced dopamine input from the substantia nigra to the striatum. As a result, decreased inhibition of the globus pallidus interna by the direct pathway, and increased excitation of the globus pallidus interna by the indirect pathway, leads to increased inhibitory drive of the thalamus and therefore decreased excitation of the cortex. C. In Huntington disease, there is degeneration of the striatum. For the direct pathway, there is overall a net inhibition of the globus pallidus interna (due to decreased inhibition from the striatum, increased inhibition from the globus pallidus externa, and decreased excitation from the subthalamic nucleus). For the indirect pathway, there is less inhibition of the globus pallidus externa, leading to more inhibition of the subthalamic nucleus, less excitation of globus pallidus interna. In sum, there is less inhibition of the thalamus, and increased excitation of the cortex, leading to hyperkinetic movements.
Restated, the current view is that enhanced conduction through the indirect pathway leads to hypokinesia by increasing pallidothalamic inhibition, whereas enhanced conduction through the direct pathway results in hyperkinesia by reducing pallidothalamic inhibition. The direct pathway has been conceived by Marsden and Obeso as facilitating cortically initiated movements and the indirect pathway as suppressing potentially conflicting and unwanted motor patterns. Dopamine released by the pars reticulata of the substantia nigra helps maintain the normal balance between the direct and indirect pathways. In Parkinson disease a loss of dopaminergic input from the substantia nigra diminishes activity in the direct pathway and increases activity in the indirect pathway; the net effect is to increase inhibition of the thalamic nuclei and to reduce excitation of the cortical motor system.
Further insight into these systems and into the mechanism of Parkinson disease came from the discovery that the parkinsonian syndrome is largely reproduced in humans and primates by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This toxin was discovered when drug abusers self-administered an analogue of meperidine. The molecule binds with high affinity to monoamine oxidase (MAO), an extraneural enzyme that transforms it to pyridinium, a metabolite that is bound by melanin in the dopaminergic nigral neurons and destroys the cells, probably by interfering with mitochondrial function. In monkeys made parkinsonian by the administration of MPTP, electrophysiologic studies have shown increased activity in the internal globus pallidus and decreased activity in the external globus pallidus, as predicted from the above described models. The end result is increased inhibition of thalamocortical neurons.
However, crude lesions of either or both parts of the pallidum, such as infarcts, hemorrhages, and tumors, even beyond their unilateral location, do not cause the full parkinsonian syndrome. Perhaps it is because the subtle imbalance is not reproduced between the internal and external pallidal circuits that exist in Parkinson disease. More specifically, the internal segment is part of the direct and indirect pathway, one excitatory and the other inhibitory, whereas the external segment is only influenced by the indirect pathway. Indeed, striking improvements in parkinsonian symptoms are obtained, paradoxically, by placing lesions in the internal pallidum (pallidotomy) as discussed in Chap. 38.
It is likely that the static model of inhibitory and excitatory pathways and the parsing of a direct and an indirect pathway, as useful as it is as a mnemonic, does not account well for the dynamic activities of the basal ganglia. In particular, the electrical activity of the neurons in these systems oscillate and influence the frequency pattern of firing in other parts of the system, as well as bringing individual cells closer to firing. Another limitation of currently conceived models is that they do not account for the tremor of Parkinson disease. To further complicate matters, the various subtypes of dopamine receptors act in both excitatory and inhibitory ways under different circumstances depending on their location as discussed below.
The manner in which excessive or reduced activity of various components of the basal ganglia gives rise to hypokinetic and hyperkinetic movement disorders is discussed further on, under “Symptoms of Basal Ganglia Disease.”
A series of pharmacologic observations have considerably enhanced our understanding of basal ganglionic function and led to a rational treatment of Parkinson disease and other extrapyramidal syndromes. Whereas physiologists had for years failed to discover the functions of the basal ganglia by stimulation and crude ablation experiments, clinicians became aware that certain drugs, such as reserpine and the phenothiazines, could produce extrapyramidal syndromes (e.g., parkinsonism, choreoathetosis, dystonia). These observations stimulated the study of central nervous system (CNS) transmitter substances in general. The current view is that the integrated basal ganglionic control of movement can be best understood by considering, in the context of the anatomy described above, the physiologic effects of neurotransmitters that convey the signals between cortex, striatum, globus pallidus, subthalamic nucleus, substantia nigra, and thalamus.
The most important neurotransmitter substances from the point of view of basal ganglionic function are glutamate, GABA, dopamine, acetylcholine, and serotonin. A more complete account of this subject may be found in the reviews of Penney and Young, of Alexander and Crutcher, and of Rao.
The following is what is known with a fair degree of certainty. Glutamate is the neurotransmitter of the excitatory projections from the cortex to the striatum and of the excitatory neurons of the subthalamic nucleus. GABA is the inhibitory neurotransmitter of striatal, pallidal, and substantia nigra (pars reticulata) projection neurons.
Of the catecholamines, dopamine has the most pervasive role but its influence can be excitatory or inhibitory depending on the site of action and the subtype of dopamine receptor. Disturbances of dopamine signaling are essential abnormalities of several CNS disorders including parkinsonism, schizophrenia, attention deficit hyperactivity disorder, and drug abuse. Within the basal ganglia, the areas richest in dopamine are the substantia nigra, where it is synthesized in the nerve cell bodies of the pars compacta, and the termination of these fibers in the striatum. In the most simplified models, stimulation of the dopaminergic neurons of the substantia nigra induces a specific response in the striatum—namely, an inhibitory effect on the already low firing rate of neostriatal neurons.
However, the effects of dopamine have proved even more difficult to resolve, in large part because there are now five known types of postsynaptic dopamine receptors (D1 to D5), each with a particular anatomic distribution and pharmacologic action. This heterogeneity is exemplified in the excitatory effect of dopamine on the small spiny neurons of the putamen and an inhibitory effect on others. Viewed from the perspective of the direct and indirect pathways, dopamine enhances the activity of the former and inhibits the latter, resulting in a net disinhibition of thalamic nuclei and a release of cortical motor function.
The five types of dopamine receptors are found in differing concentration throughout various parts of the brain, each displaying differing affinities for dopamine itself and for various drugs and other agents (Table 4-2; also see Jenner). The D1 and D2 receptors are highly concentrated in the striatum and are the ones most often implicated in diseases of the basal ganglia; D3 in the nucleus accumbens, D4 in the frontal cortex and certain limbic structures, and D5 in the hippocampus and limbic system. In the striatum, the effects of dopamine act as a class of “D1-like” (D1 and D5 subtypes) and “D2-like” (D2, D3, and D4 subtypes) receptors. Activation of the D1 class stimulates adenyl cyclase, whereas D2 receptor binding inhibits this enzyme. Whether dopamine functions in an excitatory or inhibitory manner at a particular synapse is determined by the local receptor. As mentioned earlier, excitatory D1 receptors predominate on the small spiny putaminal neurons that are the origin of the direct striatopallidal output pathway, whereas D2 receptors mediate the inhibitory influence of dopamine on the indirect striatopallidal output, as indicated in Fig. 4-4.
Table 4-2PROPERTIES AND LOCALIZATION OF DOPAMINE RECEPTORS ||Download (.pdf) Table 4-2PROPERTIES AND LOCALIZATION OF DOPAMINE RECEPTORS
|CLASSES OF DOPAMINERGIC RECEPTORS |
| ||D1 ||D2 ||D3 ||D4 ||D5 |
|Within basal ganglia |
| Striatum ||+a ||+b ||+ ||+ ||+ |
| Lateral GP || ||+ || ||+ || |
| Subthalamic nucleus ||+ ||+ ||+ || || |
| Medial GP/SN pars reticulata ||+ || || || || |
| SN pars compacta ||+ ||+ ||+ || || |
|Outside basal ganglia |
| Nucleus accumbens ||+ || ||+ || || |
| Frontal cortex ||+ || || ||+ || |
| Limbic structures || || || ||+ || |
| Hippocampus || || || ||+ || |
| Hypothalamus || || ||+ || ||+ |
| Olfactory tubercle || || ||+ || || |
| Pituitary ||+ || || || || |
| Brainstem || || || ||+ || |
|Drug affinities |
| Dopamine ||++ ||+++ ||++++ ||N/A ||N/A |
| Bromocriptine ||– ||++ ||++ ||N/A ||N/A |
| Pergolide ||+ ||++++ ||+++ ||N/A ||N/A |
| Ropinirole ||0 ||+++ ||++++ ||N/A ||N/A |
| Pramipexole ||0 ||+++ ||++++ ||N/A ||N/A |
Some of the clinical and pharmacologic effects of dopamine are made clear by considering both the anatomic sites of various receptors and their physiologic effects. For example, it appears that drug-induced parkinsonian syndromes and tardive dyskinesias (described further on) are prone to occur when drugs are administered that competitively bind to the D2 receptor, but that the newer antipsychosis drugs, which produce fewer of these effects, have a stronger affinity for the D4 receptor. However, the situation is actually far more complex, in part because of the synergistic activities of D1 and D2 receptors, each potentiating the other at some sites of convergence, and the presence on the presynaptic terminals of nigrostriatal neurons of D2 receptors, which inhibit dopamine synthesis and release.
In contrast to the almost instantaneous actions of glutamate and its antagonist, GABA, the monoamines may have more protracted effects, lasting for seconds or up to several hours. Dopamine and related neurotransmitters therefore have a slower influence through the “second messenger” cyclic adenosine monophosphate (cAMP), which, in turn, controls the phosphorylation or dephosphorylation of numerous intraneuronal G-proteins. These intracellular effects have been summarized by Greengard.
The effects of certain drugs, some no longer in use, are also best comprehended by understanding the manner in which they alter neurotransmitter function. Several drugs—namely reserpine, the phenothiazines, and the butyrophenones (notably haloperidol)—induce prominent parkinsonian syndromes in humans. Reserpine, for example, depletes the striatum and other parts of the brain of dopamine; haloperidol and the phenothiazines work by a different mechanism, probably by blocking dopamine receptors within the striatum.
The basic validity of the physiologic-pharmacologic model outlined here is supported by the observation that excess doses of L-dopa or of a direct-acting dopamine receptor agonist lead to excessive motor activity. Furthermore, the therapeutic effects of the main drugs used in the treatment of Parkinson disease are understandable in the context of neurotransmitter function. To correct the basic dopamine deficiency from a loss of nigral cells that underlies Parkinson disease, attempts were at first made to administer dopamine directly. However, dopamine as such cannot cross the blood–brain barrier and therefore has no therapeutic effect. But its immediate precursor, L-dopa, does cross the blood–barrier and is effective in decreasing the symptoms of Parkinson disease as well as of the above-described MPTP-induced parkinsonism. This effect is enhanced by the addition of an inhibitor of dopadecarboxylase, an important enzyme in the catabolism of dopamine. The addition of an enzyme inhibitor of this type (carbidopa or benserazide) to L-dopa results in an increase of dopamine concentration in the brain, while sparing other organs. The benefit of combining L-dopa with carbidopa is to minimize the systemic side effects of peripheral dopamine, such as nausea, vomiting, and hypotension. Similarly, drugs that inhibit catechol O-methyltransferase (COMT), another enzyme that metabolizes dopamine, prolong the effects of administered L-dopa.
Acetylcholine (ACh), long established as the neurotransmitter at the neuromuscular junction and the autonomic ganglia, is also physiologically active in the basal ganglia. The highest concentration of ACh, as well as of the enzymes necessary for its synthesis and degradation (choline acetyl transferase and acetylcholinesterase), is in the striatum. Acetylcholine is synthesized and released by the large but sparse (Golgi type 2) nonspiny striatal neurons. It has a mixed but mainly excitatory effect on the more numerous spiny neurons within the putamen that constitute the main origin of the direct and indirect pathways described above. It is likely that the effectiveness of atropinic agents—which have been used empirically for many years in the treatment of Parkinson disease and dystonia—depends on their capacity to antagonize ACh at sites within the basal ganglia and in projections from the pedunculopontine nuclei. Acetylcholine also appears to act on the presynaptic membrane of striatal cells and to influence their release of neurotransmitters, as discussed below. In addition, the basal ganglia contain other biologically active substances—substance P, enkephalin, cholecystokinin, somatostatin, and neuropeptide Y—which enhance or diminish the effects of other neurotransmitters, that is, they act as neuromodulators.
Because of the pharmacologic effects of ACh and dopamine, it was originally postulated by Ehringer and Hornykiewicz (the latter originated the idea) that a functional equilibrium exists in the striatum between the excitatory activity of ACh and the inhibitory activity of dopamine. In Parkinson disease, the decreased release of dopamine by the substantia nigra onto the striatum disinhibits neurons that synthesize ACh, resulting in a predominance of cholinergic activity—a notion supported by the observation that parkinsonian symptoms are aggravated by centrally acting cholinergic drugs and improved by anticholinergic drugs. According to this theory, administration of anticholinergic drugs restores the ratio between dopamine and ACh, with the new equilibrium being set at a lower-than-normal level because the striatal levels of dopamine are low to begin with. This view has been validated in clinical practice in that one observes a beneficial effect on parkinsonian symptoms after the administration of anticholinergic agents. The use of drugs that enhance dopamine synthesis or its release, or that directly stimulate dopaminergic receptors in the striatum (e.g., pramipexole), represents another more direct method of treating Parkinson disease as outlined in Chap. 38.
The Pathology of Basal Ganglionic Disease
The extrapyramidal motor syndrome as we know it today was first delineated on clinical grounds and so named by S.A.K. Wilson in 1912. In the disease that now bears his name and that he called hepatolenticular degeneration, the most striking abnormality was a bilaterally symmetrical degeneration of the putamen, sometimes to the point of cavitation. To these lesions Wilson correctly attributed the characteristic symptoms of rigidity and tremor. Shortly thereafter, van Woerkom described a similar clinical syndrome in a patient with acquired liver disease (Wilson’s cases were familial), the most prominent lesions again consisting of foci of neuronal degeneration in the striatum. Clinicopathologic studies of Huntington chorea—beginning with those of Meynert (1871) and followed by those of Jelgersma (1908) and Alzheimer (1911)—related the excessive movements and rigidity characteristic of the disease to a loss of nerve cells in the striatum. In 1920, Oskar and Cecile Vogt gave a detailed account of the neuropathologic changes in several patients who had been afflicted with choreoathetosis since early infancy; the changes, which they described as a “status fibrosus” or “status dysmyelinatus,” were confined to the caudate and lenticular nuclei. Surprisingly, it was not until 1919 that Tretiakoff demonstrated the underlying cell loss of the substantia nigra in cases of what was then called paralysis agitans and is now known as Parkinson disease. Finally, a series of observations, culminating with those of J. Purdon Martin and later of Mitchell and colleagues, related hemiballismus to lesions in the subthalamic nucleus of Luys and its immediate connections. While these observations have been invaluable, it has become apparent from clinical work that none of the relationships between anatomic loci and movement disorders are exclusive and the same movement disorder can result from lesions at one of several sites.
Another broad perspective on the result of focal damage in the basal ganglia was afforded by Bhatia and Marsden, who reviewed 240 cases based on CT and MRI in which there were lesions in the caudate, putamen, and globus pallidus associated with movement abnormalities. Dystonia was the most common finding, and chorea and parkinsonism were infrequent. It was also notable that a common associated behavioral abnormality was abulia (apathy and loss of initiative), in those with caudate lesions. The deficiencies of this type of case analysis (i.e., the crudeness of early imaging studies obtained without regard to the temporal aspects of the clinical disorder), conceded by the authors, are obvious. We nonetheless find it surprising that choreoathetosis was not more frequent. Needed are detailed anatomic (postmortem) studies of cases in which the disturbances of function were stable for many months or years. However, restating the comments above, there is no consistent association between any type of movement disorder and a particular location in the basal ganglia.
As a prelude to the next section, Table 4-3 summarizes the clinicopathologic correlations of extrapyramidal movement disorders that are accepted by most neurologists; it must be emphasized, however, that there is still some uncertainty as to the finer details.
Table 4-3CLINICOPATHOLOGIC CORRELATIONS OF EXTRAPYRAMIDAL MOVEMENT DISORDERS ||Download (.pdf) Table 4-3CLINICOPATHOLOGIC CORRELATIONS OF EXTRAPYRAMIDAL MOVEMENT DISORDERS
|SYMPTOMS ||PRINCIPAL LOCATION OF MORBID ANATOMY |
|Unilateral plastic rigidity with rest tremor (Parkinson disease) ||Contralateral substantia nigra plus (?) other mesencephalic structures |
|Unilateral hemiballismus and hemichorea ||Contralateral subthalamic nucleus of Luys or luysial–pallidal connections |
|Chronic chorea of Huntington type ||Caudate nucleus and putamen |
|Athetosis and dystonia ||Contralateral striatum (pathology of dystonia musculorum deformans unknown) |
|Cerebellar incoordination, intention tremor, and hypotonia ||Ipsilateral cerebellar hemisphere; ipsilateral middle or inferior cerebellar peduncle; brachium conjunctivum (ipsilateral if below decussation, contralateral if above) |
|Decerebrate rigidity, i.e., extension of arms and legs, opisthotonos ||Usually bilateral in tegmentum of upper brainstem at level of red nucleus or between red and vestibular nuclei |
|Palatal and facial myoclonus (rhythmic) ||Ipsilateral central tegmental tract with denervation of inferior olivary nucleus and nucleus ambiguus |
|Diffuse myoclonus ||Neuronal degeneration, usually diffuse or predominating in cerebral or cerebellar cortex and dentate nuclei |
SYMPTOMS OF BASAL GANGLIA DISEASE
In broad terms, all motor disorders consist of functional deficits (or negative symptoms) and conversely, excessive motor activity (positive symptoms), the latter being ascribed to the release or disinhibition of the activity of undamaged parts of the motor system. When diseases of the basal ganglia are analyzed along these lines, bradykinesia, hypokinesia, and loss of normal postural reflexes stand out as the primary negative symptoms, and tremor, rigidity, and the involuntary dyskinetic movements of chorea, athetosis, ballismus and dystonia, as the positive ones. Disorders of phonation, articulation, and locomotion due to basal ganglia disease are more difficult to classify. In some instances this group of signs is clearly a consequence of rigidity and postural disorders, whereas in others, where rigidity is slight or negligible, they seem to represent primary deficiencies. The changes in gait related to diseases of the basal ganglia are the result of both fundamental alterations in tone and posture as well as disruption of the more inherent control of walking by the extrapyramidal system. Psychological stress and anxiety generally worsen the abnormal movements in extrapyramidal syndromes, just as relaxation improves them. A role for the basal ganglia in cognitive function and abnormal behavior is hinted at provocatively in Parkinson disease, progressive supranuclear palsy, Tourette syndrome, and other processes, as summarized by Ring and Serra-Mestres. Slowness in thinking (bradyphrenia) in some of these disorders was alluded to earlier, but is inconsistent. Again, it would be an oversimplification to assign primary importance to the presence of depression, dementia, psychosis, and other disturbances in disease of the basal ganglia or to view changes in these structures as proximate causes of obsessive-compulsive and other behavioral disorders; rather, a role as part of a larger circuitry is likely. All that can be stated is that the basal ganglia modulate complex behavior, but the precise nature of their effect is not known at this time.
Hypokinesia and Bradykinesia
The terms hypokinesia and akinesia (the extreme form of hypokinesia) refer to a reduction in the spontaneous movements of an affected part and a failure to engage it freely in the natural actions of the body. In contrast to what occurs in paralysis (the primary symptom of corticospinal tract lesions), strength is not significantly diminished. Also, hypokinesia is unlike apraxia, in which a lesion erases the pattern of movements necessary for an intended act, leaving other actions intact. Hypokinesia is expressed most clearly in the parkinsonian patient where it takes the form of an extreme underactivity (“poverty”) of movement. The frequent automatic, habitual movements observed in the normal individual—such as putting the hand to the face, folding the arms, or crossing the legs—are absent or greatly reduced. In looking to one side, the eyes move, but not the head. In arising from a chair, there is a failure to make the usual small preliminary adjustments, such as pulling the feet back, putting the hands on the arms of the chair, and so forth. Blinking is infrequent. Saliva is swallowed less frequently and drooling results. The face lacks expressive mobility (“masked facies,” or hypomimia). Speech is rapid, mumbling (or “cluttered”), and monotonic, and the voice is soft.
Bradykinesia connotes slowness of movement, another aspect of the same physiologic difficulty as reflected in hypokinesia. Not only is the parkinsonian patient slightly “slow off the mark” (displaying a longer-than-normal interval between a command and the first contraction of muscle—that is, increased reaction time), but the velocity of movement, or the time from onset to completion of movement, is slower than normal. The extremes of hypokinesia or of bradykinesia can result in a complete impediment of movement, akinesia, a sign that may also result from several other disorders of motor function and volitional motor initiation. Hallett equates akinesia with a prolonged reaction time and bradykinesia with a prolonged time of execution. For a time, bradykinesia was attributed to the frequently associated rigidity, which could reasonably hamper all movements, but the limitation of this explanation became apparent when it was discovered that an appropriately placed stereotactic lesion in a patient with Parkinson disease may abolish rigidity while leaving the hypokinesia unaltered. Thus it appears that apart from their contribution to the maintenance of posture, the basal ganglia provide an essential element for the performance of the large variety of voluntary and semiautomatic actions required for the full repertoire of natural human motility. That cells in the basal ganglia participate in the initiation of movement is also evident from the fact that the firing rates in these neurons increase before movement is detected clinically.
Hallett and Khoshbin, in an analysis of ballistic (rapid) movements in the parkinsonian patient, found that the normal triphasic sequence of agonist–antagonist–agonist activation, as described in the next chapter, is intact but lacks the amplitude (number of activated motor units) to complete the movement normally. Several smaller triphasic sequences are then needed, which slow the movement. The patient experiences these phenomena as not only slowness but also a perceived weakness.
In terms of pathologic anatomy and physiology, bradykinesia may be caused by any process or drug that interrupts the cortico-striato-pallido-thalamic circuit. Clinical examples include reduced dopaminergic input from the substantia nigra to the striatum, as in Parkinson disease; dopamine receptor blockade by neuroleptic drugs; extensive degeneration of striatal neurons, as in striatonigral degeneration and the rigid form of Huntington chorea; and destruction of the medial pallidum, as in Wilson disease. As illustrated in Fig. 4-4B, which gives a schematic representation of the hypokinetic state of Parkinson disease, changes in the cortico-striato-pallido-thalamic circuit (in this case mainly the direct striatopallidal pathway) can be interpreted in terms of altered neurochemical and resultant physiologic connectivity within the basal ganglia. The reciprocal situation, enhanced motor activity, is summarized in the analogous diagram for Huntington disease (Fig. 4-4C), in which a reduction in the activity of the indirect striatopallidal pathway leads to enhanced excitatory motor drive in the thalamocortical motor pathway.
A number of other disorders of voluntary movement may also be observed in patients with diseases of the basal ganglia. A persistent voluntary contraction of hand muscles, as in holding a pencil, may fail to be inhibited, so that there is interference with the next willed movement. This has been termed tonic innervation, or blocking, and may be brought out by asking the patient to repetitively open and close a fist or tap a finger. Attempts to perform an alternating sequence of movements may be blocked at one point, or there may be a tendency for the voluntary movement to adopt the frequency of a coexistent tremor (entrainment).
Disorders of Postural Fixation, Equilibrium, and Righting
These deficits are also demonstrated most clearly in the parkinsonian patient. The prevailing posture is one of involuntary flexion of the trunk, limbs and the neck, which gives the parkinsonian individual a characteristic appearance, even at a distance from the observer, as described by Parkinson, “A propensity to bend the trunk forwards, and to pass from a walking to a running pace.” Anticipatory and compensatory righting reflexes, referring to mechanisms that maintain upright posture, are also manifestly impaired. This occurs early in the course of progressive supranuclear palsy and later in Parkinson disease. The inability of the patient to make appropriate postural adjustments to tilting or falling and his inability to move from the reclining to the standing position are closely related phenomena. A gentle push on the patient’s sternum or a tug on the shoulders may cause a fall or start a series of small corrective steps that the patient cannot control (festination). These basal ganglionic postural abnormalities are not attributable to weakness or to defects in proprioceptive, labyrinthine, or visual function, the principal forces that control the normal posture of the head and trunk.
Rigidity and Alterations in Muscle Tone
In the form of altered muscle tone known as rigidity, the muscles are continuously or intermittently firm and tense. Although brief periods of electromyographic silence can be obtained in selected muscles by persistent attempts to relax the limb, there is obviously a low threshold for involuntary sustained muscle contraction, and this is present during most of the waking state, even when the patient appears quiet and relaxed. In contrast to spasticity, the increased resistance on passive movement that characterizes rigidity is not preceded by an initial “free interval” and has an even or uniform quality throughout the range of movement of the limb, like that experienced in bending a lead pipe or pulling a strand of toffee. The contrasting terms clasp-knife for spasticity and lead-pipe for rigidity have been applied to the examiner’s physical perception on attempting to smoothly manipulate the patient’s limb through an arc of movement. Moreover, the rigidity of extrapyramidal disorder is not velocity dependent, as it is in spasticity. The tendon reflexes are not enhanced in the rigid limb as they are in spasticity and, when released, the limb does not resume its original position, as happens in spasticity.
Rigidity usually involves both flexor and extensor muscle groups, but it tends to be more prominent in muscles that maintain a flexed posture, that is, in the flexor muscles of trunk and limbs. It appears to be somewhat greater in the large muscle groups, but this may be merely a matter of muscle mass. Certainly the small muscles of the face and tongue and even those of the larynx are often affected by rigidity. Concordant with the physical examination, in the electromyographic tracing, motor-unit activity is more continuous in rigidity than in spasticity, persisting even after apparent relaxation.
A special feature that may accompany rigidity, first noted by Negro in 1901, is the cogwheel phenomenon. When the hypertonic muscle is passively stretched, for example, when the hand is dorsiflexed, one encounters a rhythmically interrupted, ratchet-like resistance. Many believe that this phenomenon represents an underlying tremor that, if not manifestly present, emerges faintly during manipulation. In that case it would not be a fundamental property of rigidity and would be found in many tremulous states. However, numerous instances of severe tremor with minimally perceptible cogwheeling, and the opposite, suggest to us on clinical grounds that the phenomenon may be more complex.
Rigidity is characteristically variable in severity at different times; in some patients with involuntary movements, particularly in those with chorea or dystonia, the limbs may actually be intermittently or persistently hypotonic. Rigidity is a prominent feature of many basal ganglionic diseases, such as Parkinson disease, Wilson disease, striatonigral degeneration (multiple system atrophy), progressive supranuclear palsy, dystonia musculorum deformans (discussed further on and in Chap. 38), exposure to neuroleptic drugs, and mineralization of the basal ganglia (Fahr disease).
Another distinctive type of variable resistance to passive movement is one in which the patient seems unable to relax a group of muscles on request. When the limb muscles are passively stretched, the patient appears to actively resist the movement (gegenhalten, paratonia, or oppositional resistance). Natural relaxation normally requires concentration on the part of the patient. If there is inattentiveness—as happens with diseases of the frontal lobes, dementia, or other confusional states—this type of oppositional resistance may raise a question of parkinsonian rigidity. This is not a manifestation of basal ganglia disorder per se but may indicate that the connections of the basal ganglia to the frontal lobes are impaired. A similar difficulty in relaxation is observed normally in small children. Also not to be mistaken for rigidity or paratonia is the “waxy flexibility” displayed by the psychotic-catatonic patient when a limb placed in a suspended position is maintained for minutes in the identical posture (flexibilitas cerea).
Chorea, Athetosis, Ballismus, Dystonia
These involuntary hyperkinetic symptoms are described as discrete clinical phenomenon, readily distinguishable from the others. Although distinctions are made between chorea, athetosis, and dystonia, even their most prominent differences—the discreteness and rapidity of choreic movements and the slowness of athetotic ones—are more apparent than real. As pointed out by S.A. Kinnier Wilson, involuntary movements may follow one another in such rapid succession that they become confluent and therefore appear to be slow. In reality, they usually occur together or blend imperceptibly into each other and have many points of clinical similarity. There are reasons to believe that they have a common anatomic and physiologic basis although distinct sites in the brain have been tentatively implicated for each. One must be mindful that chorea, athetosis, and dystonia are symptoms and are not to be equated with disease entities that happen to incorporate one of these terms in their names (e.g., Huntington chorea, dystonia musculorum deformans). Here the discussion is limited to the symptoms. The diseases of which these symptoms are a part are considered mainly in Chap. 39.
Somewhat more ambiguous but in common clinical use is the term dyskinesia. It encompasses all the active movement phenomena that are a consequence of disease of the basal ganglia, usually implying an element of dystonia. It has also been used to refer more specifically to the undifferentiated excessive movements that are induced in Parkinson patients at the peak of L-dopa effect and to numerous dystonic and athetotic movements that may follow the use of neuroleptic drugs (“tardive dyskinesias”) that are discussed further on.
Derived from the Greek word meaning “dance,” chorea refers to involuntary arrhythmic movements of a forcible, rapid, jerky type. These movements may be simple or quite elaborate and of variable distribution. Although the movements are purposeless, the patient may incorporate them into a deliberate act, as if to make them less noticeable. When superimposed on voluntary actions, they may assume an exaggerated and bizarre character. Grimacing and peculiar respiratory sounds may be other expressions of the disorder. Usually the movements are discrete, but if very numerous, they become confluent and then resemble athetosis, as described below. In moments when the involuntary movements are held in abeyance, volitional movements of normal strength are possible; but they also tend to be excessively quick and poorly sustained. The limbs are often slack or hypotonic and because of this, the knee jerks tend to be pendular; in other words, with the patient sitting on the edge of the examining table and the foot free of the floor, the leg swings back and forth several times in response to a tap on the patellar tendon, rather than once or twice, as it does normally. A choreic movement may be superimposed on the reflex movement, checking it in flight, so to speak.
Chorea differs from myoclonus mainly with respect to the speed of the movements; the myoclonic jerk is much faster and may involve single muscles or part of a muscle as well as groups of muscles. Failure to appreciate these differences often results in an incorrect diagnosis. The hypotonia as well as the pendular reflexes that accompany chorea may also occur in disturbances of cerebellar function. Lacking, however, are “intention” tremor and true incoordination or ataxia. In some circumstances, it may be necessary to distinguish chorea from myoclonus.
Table 4-4 lists diseases characterized mainly by chorea or localized lesions that may at times cause chorea. Of the degenerative conditions, chorea is a major feature of Huntington disease, in which the movements tend more typically to be a merging of choreiform and the below-described athetotic (choreoathetotic) motions. Not infrequently, chorea has its onset in late life without the other identifying features of Huntington disease. It is then referred to as senile chorea, a term that is hardly helpful in understanding the process. Its relation to Huntington chorea in any individual case is settled by genetic testing. A number of less common degenerative conditions are associated with chorea, among them dentatorubropallidoluysian atrophy (DRPLA) and a form of chorea associated with acanthocytosis of red blood cells. Also, there is an inherited form of chorea of childhood onset without dementia that has been referred to as benign hereditary chorea. There may be subtle additional ataxia of gait, as noted by Breedveld and colleagues. These are discussed in Chap. 38.
Table 4-4DISEASES ASSOCIATED WITH CHOREA ||Download (.pdf) Table 4-4DISEASES ASSOCIATED WITH CHOREA
Immune mediated chorea
Chorea symptomatic of systemic disease
Typical choreic movements are the dominant feature of several immune-related conditions, perhaps the best characterized being Sydenham chorea that is strongly linked to streptococcal infection, mainly in women. Striatal abnormalities, usually transient and rarely persistent, have been demonstrated by MRI (Emery and Vieco). It is perhaps not surprising that antibodies directed against cells of the basal ganglia have been detected in both acute and late Sydenham chorea (Church et al). Following from the connection to streptococcal infection and the detection of these antibodies, it has been suggested in recent years that the spectrum of poststreptococcal disorders can be extended to tic and obsessive-compulsive behavior in children (PANDAS syndrome discussed in a later section). In these cases the neurologic problems are said to arise suddenly, subside, and return with future streptococcal infections, as discussed further on. This seems unlikely to explain chorea in adults. There also exists a variety of chorea associated with pregnancy (chorea gravidarum), which in the past had a close linkage to prior episodes of Sydenham chorea. Alternatively, pregnancy may expose lupus-related chorea or be concordant with the onset of Huntington chorea. However, the elicitation of chorea by oral contraceptives in the modern era, as noted below, suggests a hormonal rather than immune causation in many cases. There have been instances of paraneoplastic chorea associated in a very few cases with lung cancer and anti-CRMP or anti-Hu antibodies of the type described as reported by O’Toole and colleagues and by Vernino et al. The paraneoplastic variety may combine several aspects of chorea with athetosis, ballismus, or dystonia; inflammatory lesions are found in the striatum (see Chap. 30).
The use of oral contraceptives sometimes elicits chorea in an otherwise healthy young woman, but many such patients have underlying systemic lupus erythematosus and antiphospholipid antibodies. Whether the chorea (usually unilateral) is the result of a small infarction (as suggested by a mild hemiparesis on the affected side) or is an immunologic condition is not settled. The reemergence of chorea in these circumstances as steroids are withdrawn or birth control pills are introduced suggests a more complex process than simply a small, deep infarction—perhaps something akin to Sydenham chorea as discussed above. A connection between hemichorea and the antiphospholipid syndrome alone, without lupus, is more tenuous.
The chronic administration of phenothiazine drugs or haloperidol (or an idiosyncratic reaction to these drugs) is a common cause of extrapyramidal movement disorders of all types, including chorea; these may become manifest during use of the drug or in a delayed “tardive” fashion, as already mentioned. The newer antipsychosis drugs (the atypical neuroleptics) have been less frequently associated with the problems. Excess dopamine administration in advanced Parkinson disease is perhaps the most common cause of a choreiform dyskinesia in neurologic practice, but the movements tend to be more complex and continuous than those seen in chorea. The use of phenytoin or other anticonvulsant drugs may cause chorea in sensitive individuals. A transitory chorea may occur in the course of an acute metabolic derangement, mainly with hyperosmolar hyperglycemia, hypoglycemia, or hyponatremia, and with the inhalation of crack cocaine.
Rarely, chorea complicates hyperthyroidism, polycythemia vera, lupus erythematosus or some forms of cerebral arteritis. AIDS has emerged as a cause of a few cases of subacute progressive movement disorders that are initially asymmetrical. The usual associations in AIDS have been with focal lesions in or near basal ganglionic structures such as toxoplasmosis, progressive multifocal leukoencephalopathy, and lymphoma, but a number of instances of chorea are not explained by any of these focal lesions. A number of rare paroxysmal kinesigenic disorders, discussed later in this chapter, may have a choreic component.
Chorea may be limited to one side of the body (hemichorea). When the involuntary movements involve proximal limb muscles and are of wide range and flinging in nature, the condition is called hemiballismus (see further on under that heading). A cerebral infarction is the usual cause of both of these disorders.
The review by Piccolo and colleagues puts the frequency of the various causes of chorea in perspective. Of consecutive neurologic admissions to two general hospitals they identified 23 cases of chorea, of which 5 were drug induced, 5 were AIDS related, and 6 were caused by stroke. Sydenham chorea and arteritis were each found in 1 case. In 4 cases no cause could be determined, and 1 proved to be Huntington disease.
The precise anatomic basis of chorea is often uncertain or at least inconsistent. Transient chorea or ballismus arises from infarctions in any part of the striatum, particularly in the caudate, on the side opposite to the movement. In Huntington chorea, there are obvious lesions in the caudate nucleus and putamen. Yet one often observes vascular lesions in these parts without chorea. The localization of lesions in Sydenham chorea and other choreic diseases has not been determined beyond a generalized disturbance in the striatum, which is evident on some imaging studies. It is of interest that in instances of chorea related to acute metabolic disturbances, there are sometimes small infarctions in the basal ganglia or metabolic changes in the lenticular nucleus, as shown by imaging studies. One suspects from their close clinical similarity that chorea and hemiballismus (see below) relate to disorders of the same system of neurons.
This term stems from a Greek word meaning “unfixed” or “changeable.” The condition is characterized by an inability to sustain the fingers and toes, tongue, or any other part of the body in one position. The maintained posture is interrupted by relatively slow, writhing or twisting, sinuous, purposeless movements that have a tendency to flow into one another. As a rule, the abnormal movements are most pronounced in the digits and hands, face, tongue, and throat, but no group of muscles is spared. One can detect as the basic patterns of movement an alternation between extension–pronation and flexion–supination of the arm and between flexion and extension of the fingers, the flexed and adducted thumb being trapped by the flexed fingers as the hand closes. Other characteristic movements are eversion–inversion of the foot, retraction and pursing of the lips, twisting of the neck and torso, and alternate wrinkling and relaxation of the forehead or forceful opening and closing of the eyelids. The movements appear as slower than those of chorea, but all gradations between the two are seen; in some cases, it is impossible to distinguish between them, hence the term choreoathetosis. An apt description could be of a moving dystonia (see below). Discrete voluntary movements of the hand are executed more slowly than normal, and attempts to perform them may result in a co-contraction of antagonistic muscles and a spread (overflow) of contraction to muscles not normally required in the movement. The overflow appears related to a failure of the striatum to suppress the activity of unwanted muscle groups. Some forms of athetosis occur only during the performance of projected movement (intention or action athetosis).
Athetosis may affect all four limbs or may be unilateral, especially in children who have suffered a hemiplegia at an early time in life (posthemiplegic athetosis). Many athetotic patients with destructive focal brain lesions exhibit variable degrees of rigidity and motor deficit as a result of associated corticospinal tract disease; these may account for the slower quality in these patients of athetosis compared to chorea. In other patients with generalized choreoathetosis, as pointed out above, the limbs may be intermittently hypotonic.
The combination of athetosis and chorea of all four limbs is a cardinal feature of Huntington disease and of a state known as double athetosis, a form of cerebral palsy that begins in childhood. Athetosis appearing in the first years of life is usually the result of a congenital or postnatal condition such as hypoxia or, now rarely, kernicterus. Postmortem examinations in some of the cases have disclosed a unique pathologic change, status marmoratus, of probable hypoxic etiology in the striatum (see Chap. 37). In other cases, of probable kernicteric (hyperbilirubinemic) etiology, there is a loss of nerve cells and myelinated fibers—a status dysmyelinatus—in the same regions. In adults, athetosis may occur as an episodic or persistent disorder in hepatic encephalopathy, as a manifestation of chronic intoxication with phenothiazines or haloperidol, and as a feature of certain degenerative diseases, most notably Huntington chorea but also Wilson disease, Leigh disease, and other mitochondrial disease variants; less frequently athetosis may be seen with Niemann-Pick (type C) disease, Kufs disease, neuroacanthocytosis, and ataxia telangiectasia, all of which are described in later chapters. It may also occur as an effect of excessive L-dopa in the treatment of Parkinson disease, in which case it appears to be caused by a decrease in the activity of the subthalamic nucleus and the internal segment of the globus pallidus (Mitchell et al). Athetosis, usually in combination with chorea, may occur rarely in patients with AIDS and in those taking antiepileptic drugs. Localized forms of athetosis may occasionally follow vascular lesions of the lenticular nucleus or thalamus, as in the cases described by Dooling and Adams.
This term designates uncontrollable, large amplitude, poorly patterned flinging movement of an entire limb. As remarked earlier, it is closely related to chorea and athetosis, indicated by the frequent coexistence of these movement abnormalities and the tendency for ballismus to blend into a less-obtrusive choreoathetosis of the distal parts of the affected limb. Ballistic movements are usually unilateral (hemiballismus) and the result of an acute lesion of or near the contralateral subthalamic nucleus or immediately surrounding structures (infarction or hemorrhage, less often a demyelinative or other lesion). Rarely, a transitory form is linked to a subdural hematoma or thalamic or parietal lesion. The flinging movements may be almost continuous or intermittent, occurring several times a minute, and of such dramatic appearance that it is not unusual for them to be regarded as hysterical in nature.
Bilateral ballismus is infrequent and usually asymmetrical; here a metabolic disturbance, particularly nonketotic hyperosmolar coma, is the usual cause. In combination with choreoathetosis, a paraneoplastic process is another rare cause. When ballismus persists for weeks on end, as it often did before effective treatment became available, the continuous forceful movements resulted in exhaustion, weight loss, and even death. In most cases, medication with haloperidol or phenothiazine suppresses the violent movements. In extreme cases, stereotactic lesions or implanted stimulating electrodes placed in the ventrolateral thalamus and zona incerta have proved effective (Krauss and Mundinger).
Dystonia is an unnatural spasmodic movement or posture that puts the limb in a twisted position. It is often patterned, repetitive or tremulous and can be initiated or worsened by attempted movement. There is unwanted overflow contraction of adjacent muscles and a common feature is involuntary co-contraction of agonist and antagonist muscles. Dystonia may take the form of an overextension or overflexion of the hand, inversion of the foot, lateral flexion or retroflexion of the head, torsion of the spine with arching and twisting of the back, forceful closure of the eyes, or a fixed grimace (Fig. 4-5).
A. Characteristic dystonic deformities in a young boy with dystonia musculorum deformans. B. Sporadic instance of severe axial dystonia with onset in adult life. C. Incapacitating postural deformity in a young man with dystonia. (Photos courtesy of Dr. I. S. Cooper and Dr. Joseph M. Waltz.)
Dystonia, like athetosis, may vary considerably in severity and may show striking fluctuations in individual patients. Dystonia may be limited to the facial, cervical, or trunk muscles or to those of one limb, and it may cease when the body is in repose and during sleep. Severe instances result in grotesque movements and distorted positions of the body; sometimes the whole musculature seems to be thrown into spasm by an effort to move an arm or to speak. In its early stages it may be interpreted as an annoying mannerism or hysteria, and only later, in the face of persisting postural abnormality, lack of the usual psychologic features of hysteria, and the emerging character of other aspects of an underlying illness, is the correct diagnosis made.
Causes of generalized dystonia
Generalized dystonia is seen in its most pronounced form as an uncommon heritable disease, dystonia musculorum deformans, which is associated with a mutation in the DYT gene (see Table 4-5). It was in relation to this disease that Oppenheim and Vogt in 1911 introduced the term dystonia. Dystonia also occurs as a manifestation of many other diseases, each of which is characteristic of a certain age group. These include the aforementioned double athetosis caused by hypoxic damage to the fetal or neonatal brain (a form of cerebral palsy), kernicterus, pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz disease), Huntington disease, Wilson disease, lysosomal storage diseases, striatopallidodentatal calcification (Fahr disease, sometimes caused by hypoparathyroidism), certain forms of thyroid disease, and exposure to neuroleptic drugs, as discussed below.
Table 4-5DISEASES ASSOCIATED WITH DYSTONIA ||Download (.pdf) Table 4-5DISEASES ASSOCIATED WITH DYSTONIA
Dystonia musculorum deformans (recessive and autosomaldominant forms)
Juvenile dystonia—Parkinson syndrome (Ldopa–responsive)
Dystonia with other heredodegenerative disorders (neural deafness, striatal necrosis with optic nerve affection, paraplegic amyotrophy)
Focal dystonias and occupational spasms, some of which are allied with hereditary torsion dystonia
Parkinson disease (occasional)
Progressive supranuclear palsy
Acute and chronic phenothiazine, haloperidol, metoclopramide, and other neuroleptic intoxications
L-Dopa excess in Parkinson disease
Antiepileptic, anxiolytic and other drugs
Symptomatic (secondary) dystonias
Double athetosis (cerebral palsy) caused by cerebral hypoxia
Acquired hepatocerebral degeneration
HIV infection and related focal brain lesions
Lysosomal storage diseases
Multiple sclerosis with cord lesion
Paraneoplastic striatopallidodentatal calcification (Fahr disease)
Toxic necrosis of lenticular nuclei (e.g., methanol) can be delayed
Dystonia with reflex sympathetic dystrophy
Idiopathic focal dystonias
A distinct subset of patients with an idiopathic dystonia (Segawa disease, described also by Nygaard et al and discussed in Chap. 38) responds to extremely small doses of L-dopa. This disorder is familial, usually autosomal dominant, and the dystonia-athetosis may be combined with elements of parkinsonism. Marked diurnal fluctuation of symptoms is characteristic, with the movement disorder worsening as the day wears on and improving with sleep. Another rare hereditary dystonia, termed rapid-onset dystonia-parkinsonism, has its onset in adolescence or early adulthood and is of interest because of the rapid evolution, at times within an hour but more often over days, of severe dystonic spasms, dysarthria, dysphagia, and postural instability with bradykinesia (Dobyns et al). Dystonia is a component of a number of obscure multisystem degenerations that may include diverse features such as optic neuropathy and striatal necrosis.
A frequent cause of acute generalized dystonic reactions, more so in the past, had been from exposure to the class of neuroleptic drugs—phenothiazines, butyrophenones, or metoclopramide—and even with the newer agents such as olanzapine, which have the advantage of producing these side effects less frequently. A characteristic, almost diagnostic, example of the acute drug-induced dystonias consists of retrocollis (forced extension of the neck), arching of the back, internal rotation of the arms, and extension of the elbows and wrists—together simulating opisthotonos. These reactions respond relatively predictably to diphenhydramine or benztropine. L-Dopa, calcium channel blockers, and a number of antiepileptic drugs and anxiolytics are among a long list of other medications may on occasion induce dystonia, as listed in Table 4-5. The acute dystonic drug reactions are idiosyncratic and probably now as common as the tardive dyskinesias that had in the past followed long-standing use of a medication.
In the literature, there have been reported numerous cases of limb injury and subsequent reflex sympathetic dystrophy (see Chap. 10) that were accompanied by a variety of movement disorders, particularly dystonia. The nature and mechanism of this association are uncertain. Finally, a peculiar and dramatic spasm of a limb or the entire body may be seen in patients with multiple sclerosis. The movements have aspects of dystonia and may be provoked by hyperventilation but they may not be, strictly speaking, dystonic. They are most likely to occur in patients with large demyelinative lesions of the cervical spinal cord.
Restricted or fragmentary forms of dystonia are the types most commonly encountered in clinical practice. Characteristically the spasms involve only the orbicularis oculi and face or mandibular muscles (blepharospasm-oromandibular dystonia), tongue, cervical muscles (torticollis), hand (writer’s cramp), or foot. There may be an associated tremor, or tremor may be the only manifestation of an early dystonia. These are described further on and in Chap. 38.
Hemidystonia represents an unusual form of acquired movement that, in our experience, is rarely pure. In an analysis of 33 of their own cases and 157 previously published ones, Chuang and colleagues found stroke, mainly in the contralateral putamen, to be most often responsible. Traumatic and perinatal damage accounted for several cases and a large proportion had no lesions found by imaging tests. In traumatic cases, there was a delay of several years between the injury and the start of the movements; these authors also commented on the resistance of this syndrome to drug treatment.
In the focal dystonias, the most effective treatment has proved to be the periodic injection of botulinum toxin into the affected muscles as discussed earlier and emphasized later in the chapter. The acute dystonic drug reactions are treated as noted above. Numerous drugs have been used to treat idiopathic chronic generalized dystonia, with a notable lack of success. Fahn reported beneficial effects (more so in children than in adults) with the anticholinergic agents, trihexyphenidyl, benztropine, and ethopropazine given in large doses—which are achieved by increasing the medications very gradually.
The drug-induced tardive dyskinesias require specialized treatment, as described in later chapters and further on. Tetrabenazine and reserpine, centrally active monoamine-depleting agents, are effective. The offending drug may be at first stopped in patients who have not already ceased taking it, but this often leads to worsening of the movements. Reinstitution of the offending drug or high doses of anticholinergic agents is then sometimes necessary but is only partially effective, and requires that the patient tolerate the other effects of the medication such as sedation and parkinsonism. The problem has become less frequent with the introduction of the newer classes of antipsychosis drugs.
Stereotactic surgery on the pallidum and ventrolateral thalamus, a treatment introduced by Cooper in the middle of the last century, had generally positive but unpredictable results in generalized dystonia. In recent years there has been a renewed interest in a modern derivative of this form of treatment, deep brain stimulation. In a controlled trial, Vidailhet and colleagues demonstrated the effectiveness of this approach by stimulating the posteroventral globus pallidus bilaterally. Their patients had an average improvement of 50 percent on most scores of dystonic movement over 1 year. Increasingly, this is the method resorted to in cases of severe generalized dystonia.
Paroxysmal Choreoathetosis and Dystonia
Under the names paroxysmal kinesigenic dyskinesia, familial paroxysmal choreoathetosis, and periodic dystonia, among others, are a number of uncommon sporadic or familial disorders characterized by paroxysmal attacks of choreoathetotic movements or dystonic spasms of the limbs and trunk. Both children and young adults are affected.
There are three main forms of familial paroxysmal choreoathetosis and dystonia. Various genes and mutations have been implicated, some of which involve ion channels. One clinical type, which has an autosomal dominant (less often recessive) pattern of inheritance and a tendency to affect males, begins in adolescence or earlier and abates later in life. It is characterized by numerous brief (several minutes) attacks of dystonia or choreoathetosis provoked by sudden movement, startle, or hyperventilation—hence the name paroxysmal kinesigenic choreoathetosis. There may be many dozens of attacks per day or occasional ones. This disorder responds well to antiepileptic medication, particularly to phenytoin and carbamazepine. Mutations of PRRT2, the proline-rich transmembrane protein, have been identified as the cause in some families and link the disease to a variety of infantile convulsions as summarized by Gardiner and colleagues.
In a second nonkinesigenic type, such as described by Mount and Reback and subsequently by Lance and by Plant et al, the attacks take the form of persistent (5 min to 4 h) dystonic spasms and reportedly have been precipitated by the ingestion of alcohol or coffee or by fatigue but not by movement. The attacks may be predominantly one sided or bilateral. Attacks may occur every several days or be separated by years. A favorable response to benzodiazepines (clonazepam) has been reported, even when the drug is given on alternate days (Kurlan and Shoulson). This form of the disease is inherited as an autosomal dominant trait; a few families have displayed diplopia and spasticity and others have shown a familial tendency to infantile convulsions. There are several variations of this nonkinesigenic illness, each with a different implicated gene mutation.
A third type, formerly thought to be a variant of the Mount-Reback type mentioned above, is precipitated by prolonged exercise. In addition to a response to benzodiazepines, it has the unique characteristic of improving with acetazolamide.
More common than these familial dyskinesias are sporadic cases secondary to focal brain lesions such as stroke, trauma, encephalitis, perinatal anoxia, multiple sclerosis, HIV encephalitis or as a result of associated toxoplasmosis, lymphoma; and also generalized metabolic disorders such as hypoparathyroidism, thyrotoxicosis, and particularly, nonketotic hyperosmolarity. Demirkirian and Jankovic classified the acquired paroxysmal dyskinesias according to the duration of each attack and the event or activity that precipitates the abnormal movements (kinesigenic, nonkinesigenic, exertional, or hypnagogic). As with the familial cases, the acquired kinesigenically induced movements often improve with antiepileptic drugs; some cases respond particularly to clonazepam.
The most severe instances of paroxysmal dyskinesia in our experience have been related to the previously mentioned multiple sclerosis (“tetanoid spasms”), and from the secondary brain lesions of HIV. These patients were relatively unresponsive to medications. Also, it should be recalled that oculogyric crises and other nonepileptic spasms have occurred episodically in patients with postencephalitic parkinsonism; these phenomena are now rarely seen with acute and chronic phenothiazine intoxication and with Niemann-Pick disease (type C).
Tremor may be defined as involuntary rhythmic oscillatory movement produced by alternating or irregularly synchronous contractions of reciprocally innervated muscles. Its rhythmic quality distinguishes tremor from the other involuntary movements described earlier, and its oscillatory nature distinguishes it from myoclonus and asterixis. The many varieties of tremor can be considered in terms of their frequency, amplitude, location, and positional activation, and the enhancement or attenuation of the tremor by certain drugs. In some processes, such as Parkinson disease, more than one tremor may be displayed and tremor may be a component of other movement disorders such as dystonia and cerebellar ataxia. The characteristics of the main tremors seen in practice are summarized in Table 4-6.
Table 4-6MAIN TYPES OF TREMOR ||Download (.pdf) Table 4-6MAIN TYPES OF TREMOR
|TYPE OF TREMOR ||FREQUENCY, HZ ||PREDOMINANT LOCATION ||ENHANCING AGENTS ||ATTENUATING AGENTS |
|Physiologic (enhanced) ||8–13 ||Hands ||Epinephrine, β-adrenergics ||Alcohol, β-adrenergic antagonists |
|Parkinson (rest) ||3–5 ||Hands and forearms, fingers, feet, lips, tongue ||Emotional stress ||L-Dopa, anticholinergics |
|Cerebellar (intention, ataxic, “rubral”) ||2–4 ||Limbs, trunk, head ||Emotional stress ||— |
|Postural, or action ||5–8 ||Hands ||Anxiety, fright, β-adrenergics, alcohol withdrawal, xanthines, lithium, exercise, fatigue ||β-Adrenergic antagonists in some cases |
|Essential (familial, senile) ||4–8 ||Hands, head, vocal cords ||Same as above ||Alcohol, propranolol, primidone |
|Alternate beat ||3.5–6 ||Hands, head ||Same as above ||Clonazepam, alcohol, β-adrenergic antagonists |
|Orthostatic ||14-16, irregular ||Legs ||Quiet standing ||Repose, walking, clonazepam, valproate |
|Tremor of neuropathy ||4–7 ||Hands ||— ||— |
|Palatal tremor ||1–2 (60–100/min) ||Palate, sometimes facial, pharyngeal, proximal limb muscles ||— ||Clonazepam, valproate |
|Dystonic ||Irregular ||Concordant with focal dystonia ||— ||Local botulinum toxin, gestes |
A normal, or physiologic, tremor is embedded in the motor system. The movement is so fine that it can barely be seen by the naked eye, and then only if the fingers are firmly outstretched; asking the patient to aim a laser pointer at a distant target will often expose the tremor. It is present in all contracting muscle groups and persists throughout the waking state and even in certain phases of sleep. It ranges in frequency between 8 and 13 Hz, the dominant rate being 10 Hz in adulthood and somewhat less in childhood and old age. Several hypotheses have been proposed to explain physiologic tremor, a traditional one being that it reflects the passive vibration of body tissues produced by mechanical activity of cardiac origin, but this cannot be the whole explanation. As Marsden has pointed out, several additional factors—such as spindle input, the unfused grouped firing rates of motor neurons, and the natural resonating frequencies and inertia of the muscles and other structures—are probably of greater importance. Certain abnormal tremors, namely, the metabolic varieties of postural or action tremor and at least one type of familial tremor, are considered by some to be variants or exaggerations of physiologic tremor—that is, “enhanced physiologic tremor,” as discussed further on.
In patients with pathologic tremor of almost any type, Narabayashi has recorded rhythmic burst discharges of unitary cellular activity in the nucleus intermedius ventralis of the thalamus (as well as in the medial pallidum and subthalamic nucleus) synchronous with the beat of the tremor. Neurons that exhibit the synchronous bursts are arranged somatotopically and respond to kinesthetic impulses from the muscles and joints involved in the tremor but that is not to say that there is a causal relationship between this activity and the tremor. A stereotaxic lesion in this region of the thalamus abolishes the tremor. The effectiveness of a thalamic lesion may be a result of interruption of pallidothalamic and dentatothalamic projections or, more likely, of projections from the ventrolateral thalamus to the premotor cortex, as the impulses responsible for tremor are ultimately transmitted by the lateral corticospinal tract. Some of what is known about the physiology of specific tremors is noted in the following paragraphs.
Action tremors are evident during use of the affected body part, as opposed to tremor that is apparent in a position of rest or repose. Action tremors can be roughly divided into two categories: goal directed action tremor of the ataxic type related to cerebellar disorders (discussed in Chap. 5) and postural tremors, which are either the enhanced physiologic variety or essential tremor (Fig. 4-6). A postural tremor occurs with the limbs and trunk actively maintained in certain positions (such as holding the arms outstretched) and may persist throughout active movement. More particularly, the tremor is absent when the limbs are relaxed but becomes evident when the muscles are activated. The tremor is accentuated as greater precision of movement is demanded, but it does not approach the degree of augmentation seen with cerebellar intention tremor. Most cases of action tremor are characterized by relatively rhythmic bursts of grouped motor neuron discharges that occur not quite synchronously in opposing muscle groups as shown in Fig. 4-7. Slight inequalities in the strength and timing of contraction of opposing muscle groups account for the tremor. In contrast, rest (parkinsonian) tremor, is characterized by alternating activity in agonist and antagonist muscles.
Types of tremor. In each, the lowest trace is an accelerometric recording from the outstretched hand; the upper two traces are surface EMG from the wrist extensor (upper) and flexor (middle) muscle groups. A. A physiologic tremor; there is no evidence of synchronization of EMG activity. B. Essential (familial) tremor; the movements are very regular and EMG bursts occur simultaneously in antagonistic muscle groups. C. Neuropathic tremor; movements are irregular and EMG bursts vary in timing between the two groups. D. Parkinsonian (“rest”) tremor; EMG bursts alternate between antagonistic muscle groups. Calibration is 1 s. (Courtesy of Dr. Robert R. Young.)
Enhanced physiologic tremor
The type of action tremor that seems merely to be an exaggeration of the above-described physiologic tremor, can be brought out in most normal persons. It has the same fast frequency as physiologic tremor (about 10 Hz; see Fig. 4-7) but with greater amplitude. Such a tremor, best elicited by holding the arms outstretched with fingers spread apart, is characteristic of intense fright and anxiety (hyperadrenergic states), certain metabolic disturbances (hyperthyroidism, hypercortisolism, hypoglycemia), pheochromocytoma, intense physical exertion, withdrawal from alcohol and other sedative drugs, and the toxic effects of several drugs—lithium, nicotinic acid, xanthines (coffee, tea, aminophylline), cocaine, methylphenidate, other stimulant drugs, and corticosteroids. Young and colleagues have determined that the enhancement of physiologic tremor that occurs in metabolic and toxic states is not a function of the central nervous system but is instead a consequence of stimulation of muscular beta-adrenergic receptors by increased levels of circulating catecholamines.
A special type of postural action tremor, closely related to the enhanced physiologic tremor, occurs as the most prominent feature of the early stages of withdrawal from alcohol or other sedative (benzodiazepines, barbiturates) following a sustained period of use. LeFebvre-D’Amour and colleagues have described two tremors of slightly different frequency, one of which is indistinguishable from essential tremor. Either of these may occur as the individual emerges from a relatively short period of intoxication (“morning shakes”). A number of alcoholics, on recovery from the withdrawal state, exhibit a persistent tremor of essential (familial) type, described below. The mechanisms involved in alcohol withdrawal symptoms are discussed in the chapter on Disorders of the Nervous System Caused by Alcohol, Drugs, Toxins, and Chemical Agents.
Action tremors are seen in a number of other clinical settings. A large number of drugs can cause tremor either as direct or an idiosyncratic effect. At times it is difficult to determine if the drug is simply exaggerating a preexisting tremor, but most often the tremor is only evident with the drug and ceases when the drug is withdrawn. The main examples are antiepileptic medications, particularly valproate; bronchodilators and adrenergic drugs such as aminophylline, cocaine, thyroxine; gastrointestinal drugs such as metoclopramide and cimetidine; psychiatric drugs, mainly lithium but also amitriptyline, the selective serotonin reuptake inhibitors and haloperidol; and immunosuppressants such as tamoxifen, tacrolimus, cyclosporine, and interferon-alpha. A more complete discussion of drug-induced tremors can be found in the review by Morgan and Sethi. A coarse action tremor, sometimes combined with myoclonus, accompanies various types of meningoencephalitis (e.g., in the past it was quite common with syphilitic general paresis) and certain intoxications (methyl bromide and bismuth).
Essential (Familial) Tremor
This, the commonest type of tremor, is of lower frequency (4 to 8 Hz) than physiologic tremor and is unassociated with other neurologic changes; thus it is called “essential.” It is usually at the lower end of this frequency range and of variable amplitude. Aside from its rate, the identifying feature is its appearance or enhancement with attempts to maintain a static limb posture or to produce a smooth trajectory of movement. Like many other tremors, essential tremor is worsened by emotion, exercise, and fatigue. One infrequent type of essential tremor is faster and of the same frequency (6 to 8 Hz) as enhanced physiologic tremor. Essential tremor may increase in severity to a point where the patient’s handwriting becomes illegible and he cannot bring a spoon or glass to his lips without spilling its contents. Eventually, all tasks that require manual dexterity become difficult or impossible. The pathophysiology of this tremor and its treatment are discussed further on.
Typical essential tremor occurs in several members of a family, for which reason it has been called familial or hereditary essential tremor. Inheritance is in an autosomal dominant pattern with high penetrance. The idiopathic and familial types cannot be distinguished on the basis of their physiologic and pharmacologic properties and probably should not be considered as separate entities. This condition had been referred to as “benign essential tremor,” but this is hardly so in many patients in whom it worsens with age and interferes with normal activities.
Essential tremor most often makes its appearance late in the second decade, but it may begin in childhood and then persist. A second peak of increased incidence occurs in adults older than 35 years of age. It is a relatively common disorder, with an estimated prevalence of 415 per 100,000 persons older than the age of 40 years (Haerer et al). As described by Elble, the tremor frequency diminishes slightly with age while its amplitude increases. The tremor practically always begins in the hands and is said to be symmetrical; in approximately 15 percent of patients, however, it appears first in the dominant hand and an emerging concept has been that it is more often asymmetric than stated in older descriptions. It is also possible, of course, that the patient does not find a mild bilateral tremor troublesome until it affects activities that are dependent on the dominant hand. However, a severe isolated arm or leg tremor, or a predominant finger tremor, should still suggest another disease (Parkinson disease or focal dystonia, as described further on).
The tremor may remain limited to the upper limbs or to a side-to-side or nodding movement of the head; tremor of the chin may be added or may occur independently. In certain cases of essential tremor, there is additional involvement of the jaw, lips, tongue, and larynx, the latter imparting a severe quaver to the voice (voice tremor). Infrequently, the tremor of the head or voice precedes that of the hands. The head tremor is also postural in nature and disappears when the head is supported. It has also been noted that the limb and head tremors tend to be muted when the patient walks, in contrast to most parkinsonian tremors. In some of our patients whose tremor remained isolated to the head for a decade or more, there has been little if any progression to the arms and almost no increase of the amplitude of movement.
The lower limbs are usually spared or only minimally affected. In the large series of familial tremor cases by Bain and colleagues, solitary jaw or head tremor was not found but we have observed isolated head tremor, as noted. Most patients with essential tremor will have identified the amplifying effects of anxiety and the ameliorating effects of alcohol on their tremor. We have also observed the tremor to become greatly exaggerated during emergence from anesthesia in a few patients.
Electromyographic studies reveal that the tremor is generated by more or less rhythmic and almost simultaneous bursts of activity in pairs of agonist and antagonist muscles (Fig. 4-7B). Less often, especially in the tremors at the lower range of frequency, the activity in agonist and antagonist muscles alternates (“alternate beat tremor”), a feature more characteristic of Parkinson disease, which the tremor then superficially resembles (see below). Tremor of either pattern may be disabling, but the less common, slower, alternate-beat tremor tends to be of higher amplitude, is more of a handicap, and is usually more resistant to treatment.
To date, only a few cases of essential tremor have been examined postmortem, and these have disclosed no consistent lesion to which the tremor could indisputably be attributed (Herskovits and Blackwood; Cerosimo and Koller). A singular case of a 90-year-old woman studied by Louis and colleagues demonstrated more extensive cerebellar cortical and dentate nucleus cell loss and reactive changes than had been previously reported.
The question of the existence and locus of a generator for essential tremor as opposed to the unbalancing of a feedback loop system, is unresolved. As indicated by McAuley, various studies demonstrate that rhythmic tremor activity is not primarily generated in the cortex. Based on electrophysiologic recordings in patients, two likely origins of oscillatory activity are the olivocerebellar circuits and the thalamus. Whether a particular structure possesses intrinsic rhythmicity or, as currently favored, the tremor is an expression of reciprocal oscillations in circuits of the dentato–brainstem–cerebellar or thalamic–tegmental systems is not at all clear. Studies of blood flow in patients with essential tremor by Colebatch and coworkers affirm that the cerebellum is rhythmically activated; on this basis they argue that there is a release of an oscillatory mechanism in the olivocerebellar pathway. Dubinsky and Hallett demonstrated that the inferior olives also become hypermetabolic when essential tremor is activated, but this has been questioned by Wills and colleagues who recorded increased blood flow in the cerebellum and red nuclei, but not in the olive. These proposed mechanisms of tremor are reviewed by Elble and also by Hallett.
Although this disorder is familial, almost always autosomal dominant, a single genetic site has not yet been established; several candidate polymorphisms have been tentatively proposed.
A curious fact about essential tremor of the typical (non–alternate-beat) type is that it can be suppressed by a small amount of alcohol in more than 75 percent of patients; but once the effects of the alcohol have worn off, the tremor returns and may even worsen for a time. Of more therapeutic interest, essential tremor is inhibited by the beta-adrenergic antagonist propranolol (between 80 and 200 mg per day in divided doses or as a sustained-release preparation) taken orally, usually remaining effective over a long period of time. Often it takes several days or weeks for the effect to be evident. The benefit is variable and often incomplete; most studies indicate that 50 to 70 percent of patients have some symptomatic relief but may complain of side effects such as fatigue, erectile dysfunction, and bronchospasm (see Young and colleagues). Several but not all of the other beta-blocking drugs are similarly effective: metoprolol and nadolol, which may be better tolerated than propranolol, are the ones most extensively studied, but they have yielded less consistent results compared to propranolol. The relative merits of different drugs in this class are discussed by Louis and by Koller et al.
The mechanism and site of action of beta-blocking agents is not known with certainty. It is blockade of the beta-2 adrenergic receptor that is most closely aligned with reduction of the tremor. Young and associates have shown that neither propranolol nor ethanol, when injected intraarterially into a limb, decreases the amplitude of essential tremor. These findings, and the delay in action of medications, suggest that their therapeutic effect is due less to blockade of the peripheral beta-adrenergic receptors than to their action on structures within the central nervous system. This is in contrast to the earlier mentioned muscle receptor-mediated effect of adrenergic compounds in physiologic tremor. It is possible that ambiguity regarding the action of beta-blocking drugs is the result of their effect on physiological tremor that is superimposed on essential tremor.
The barbiturate drug primidone has also been effective in controlling essential tremor and may be tried in patients for whom beta-blocking medications and not effective or tolerated. The side effects may be drowsiness, nausea, and slight ataxia. Treatment should be initiated at 25 mg twice or three times per day and increased slowly in order to minimize these effects. Gabapentin, topiramate (see Connor), mirtazapine, a variety of benzodiazepines and a large number of other drugs have been used generally without success, and should be considered second-line therapies; these alternatives are discussed by Louis. Amantadine also has a modest effect on tremor and may be used as an adjunct.
The alternate-beat, slow, high-amplitude, kinetic-predominant type of essential tremor is more difficult to suppress but has reportedly responded to clonazepam (Biary and Koller); in our experience, however, this approach has not been as successful. Alcohol and primidone have less effect than they do in typical essential tremor. Indeed, the tremor has often been resistant to most attempts at suppression, for which reason surgical approaches are now being used (see further on).
Injections of botulinum toxin into a portion of a limb can reduce the severity of essential tremor locally, but the accompanying weakness of arm and hand muscles often proves unacceptable to the patient. The same medication injected into the vocal cords can suppress severe voice tremor as described in a series of cases by Adler and colleagues as well as by others, but caution must be exercised to avoid paralyzing the cords. Doses as low as 1 U of toxin injected into each cord may be effective, with a latency of several days. The long-term repeated use of this treatment has not been adequately studied for essential-type limb or voice tremor.
In resistant cases of essential tremor of the fast or slow variety, stimulation by electrodes implanted or ablative lesions in the ventral medial nucleus of the thalamus or the internal segment of the globus pallidus (of the same type used to treat Parkinson disease) has produced a response over many years; details can be found in the small study reported by Sydow and colleagues.
Adams and coworkers described a disabling action tremor in patients with chronic demyelinating and paraproteinemic polyneuropathies. It is a particularly prominent feature of the polyneuropathy caused by immunoglobulin M (IgM) antibodies to myelin-associated glycoprotein (MAG). The movements simulate a coarse essential, or ataxic, tremor and typically worsen if the patient is asked to hold his finger near a target. The EMG pattern is more irregular than that in essential (familial) tremor (Fig. 4-7C). Pedersen and colleagues have found it to vary greatly in amplitude with considerable side-to-side oscillation, which is induced by co-contracting muscle activity; they also found little suppression of the tremor with loading of the limb, unlike most other organic tremors. It is hypothesized that there is a disturbance of muscle spindle afferents.
Some cases of acute or chronic inflammatory neuropathy or ganglionopathy may be marked by a similar and prominent ataxic tremor and a faster action tremor. A special type of Guillain-Barré syndrome (Fisher variant) is characterized by a tremor that is indistinguishable from the ataxic type but probably has a peripheral basis. Also, the inherited disease, peroneal muscular atrophy (Charcot-Marie-Tooth disease), may be associated with tremor of the essential type but the two may be coincident rather than directly related; this combination of symptoms was the basis on which Roussy and Levy incorrectly set it apart as a distinct disease. Chapter 43 discusses these polyneuropathies.
Parkinsonian (Repose, Rest) Tremor
This is a coarse, rhythmic tremor with a frequency of 3 to 5 Hz, characterized by bursts of activity that alternate between opposing muscle groups. The tremor is most often localized in one or both hands and forearms and less frequently in the feet, jaw, lips, or tongue (Fig. 4-7D). It occurs when the limb is in an attitude of repose and is suppressed or diminished by willed movement, at least momentarily, only to reassert itself once the limb assumes a new position. Even though it is termed a “resting” tremor, maintaining the arm in an attitude of repose requires a certain degree of muscular contraction, albeit slight. If the tremulous hand is completely relaxed, as it is when the arm is fully supported at the wrist and elbow, the tremor usually disappears. It is difficult, however, for the parkinsonian patient to relax and instead it is typical to maintain a state of slight tonic contraction of the trunk and proximal muscles.
Parkinsonian tremor is “alternating” in the sense that it takes the form of flexion–extension or abduction–adduction of the fingers or the hand; pronation–supination of the hand and forearm is also a common presentation. Flexion–extension of the fingers in combination with adduction–abduction of the thumb yields the characteristic “pill-rolling” tremor of Parkinson disease. The tremor continues and may worsen while the patient walks, unlike essential tremor; indeed, it may first become apparent to the patient during walking. When the legs are affected, the tremor takes the form of a flexion–extension movement of the foot, sometimes the knee. In the jaw and lips, it is seen as up-and-down and pursing movements, respectively. The eyelids, if they are closed lightly, tend to flutter rhythmically (blepharoclonus), and the tongue, when protruded, may move in and out of the mouth at about the same tempo as the tremor elsewhere.
The cogwheel effect is a ratchet-like interruption perceived by the examiner on passive movement of an extremity (the Negro sign) as mentioned earlier. It is said by many authors to be no more than a palpable tremor superimposed on rigidity and as such, is not specific for Parkinson disease although it is most often recognized in that condition. This explanation is called into question by the numerous cases in which Parkinson patients display minimal or no resting tremor but nonetheless have the cogwheel phenomenon. Cogwheeling can be brought out by having the patient engage the opposite limb, such as tracing circles in the air; called the Froment sign, this finding was originally described in essential tremor.
The parkinsonian tremor frequency is surprisingly constant over long periods, but the amplitude is variable. Emotional stress augments the amplitude and may add to the effects of an enhanced physiologic or essential tremor. With advance of the disease, increasing rigidity of the limbs obscures or reduces it. It is curious how little the tremor interferes with voluntary movement; for example, it is possible for a tremulous patient to raise a full glass of water to his lips and drain its contents without spilling a drop; this is not always the case with “benign” essential tremor, as already emphasized.
Almost always in Parkinson disease, the tremor is asymmetric and at the outset may be entirely unilateral. There is not a close correspondence between the degree of tremor and the degree of rigidity or akinesia. A bilateral parkinsonian type of tremor may also be seen in elderly persons without akinesia, rigidity, or mask-like facies. In some of these patients, the tremor is followed years later by the other manifestations of Parkinson disease, but in others it is not, remaining unchanged or progressing very slowly, unaffected by anti-Parkinson drugs. This entity probably equates with the earlier mentioned alternate-beat type of essential tremor. Patients with Wilson disease or an acquired form of hepatocerebral degeneration may also show a tremor of parkinsonian type, usually mixed with ataxic tremor and other extrapyramidal motor abnormalities. An alternating tremor may be seen in toxin and drug-induced parkinsonism but it is relatively symmetric and tends not to be a prominent feature. The tremor of postencephalitic parkinsonism (which is now virtually extinct) often had greater amplitude than typical parkinsonian tremor and involved proximal muscles.
Parkinsonian tremor is suppressed to some extent by the anticholinergic drugs benztropine and trihexyphenidyl; it is also suppressed less consistently but sometimes impressively by L-dopa and dopaminergic agonist drugs.
Parkinsonian tremor is often associated with an additional tremor of faster frequency; the latter is of essential type and responds better to beta-blocking drugs than to anti-Parkinson medications. Stereotactic lesions or electrical stimulation in the basal ventrolateral nucleus of the thalamus diminishes or abolishes tremor contralaterally; other stimulation sites such as the internal segment of the globus pallidus and the subthalamic nucleus are also effective but possibly to a lesser degree. Chapter 38 discusses treatment of Parkinson disease in greater detail.
The anatomic basis of parkinsonian tremor is not known. In Parkinson disease, the visible lesions predominate in the substantia nigra, and this was true also of the postencephalitic form of the disease. In animals, however, experimental lesions confined to the substantia nigra or striatopallidum do not result in tremor. Moreover, not all patients with lesions of the substantia nigra have tremor; in some there is only bradykinesia and rigidity. In a group of patients poisoned with the toxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a meperidine analogue that destroys the neurons of the substantia nigra pars compacta, only half developed a tremor, which had more of the characteristics of a proximal action or postural tremor than of a rest tremor as discussed by Burns and colleagues. In all likelihood, these inconsistencies reflect the complex influence of dopamine on a number of basal ganglionic structures.
Ward and others have produced a Parkinson-like tremor in monkeys by placing a lesion in the ventromedial tegmentum of the midbrain, just caudal to the red nucleus and dorsal to the substantia nigra. He postulated that interruption of the descending fibers at this site liberates an oscillating mechanism in the lower brainstem; this presumably involves limb innervation via the reticulospinal pathway. Alternative possibilities are that the lesion in the ventromedial tegmentum interrupts the brachium conjunctivum, a tegmental-thalamic projection, or the descending limb of the superior cerebellar peduncle, which functions as a link in a dentatoreticular-cerebellar feedback mechanism (see Fig. 5-3). The differential effect of drugs on tremor and bradykinesia suggest that they must have separate mechanisms.
Intention (Ataxic, Cerebellar, Goal-Directed Action) Tremor
As will be discussed in Chap. 5, the word intention is ambiguous in this context because the tremor itself is not intentional and occurs not when the patient intends to make a movement but only during the most demanding phases of active performance. In this sense it is a kinetic or action tremor, but the latter term has connotations of the essential tremor to neurologists, as described earlier. The term ataxic is a suitable substitute for intention, because this tremor is always combined with cerebellar ataxia and adds to it. Its salient feature is that it requires for its full expression the performance of an exacting, precise, projected movement. The tremor is absent both when the limbs are inactive and during the first part of a voluntary movement, but as the action continues and fine adjustments of the movement are demanded (e.g., in touching the tip of the nose or the examiner’s finger), an irregular interruption of forward progression appears. These side-to-side oscillations are more or less rhythmic and may continue for several beats after the target has been reached. Unlike essential and parkinsonian tremors, the oscillations occur in more than one plane but are mainly horizontal and perpendicular to the trajectory of movement. The tremor and ataxia may seriously interfere with the patient’s performance of skilled acts. In some patients there is a rhythmic oscillation of the head on the trunk (titubation), or of the trunk itself, at approximately the same rate. As already indicated, this type of tremor points to disease of the cerebellum or its outflow connections, but certain peripheral nerve diseases may simulate it.
Ataxic tremor has been produced in monkeys by inactivating the deep cerebellar nuclei or by sectioning the superior cerebellar peduncle or the brachium conjunctivum below its decussation. A lesion of the nucleus interpositus or dentate nucleus causes an ipsilateral tremor of ataxic type, as one might expect, associated with other manifestations of cerebellar ataxia. In addition, such a lesion gives rise to a “simple tremor,” which is the term that Carpenter applied to a “resting” or parkinsonian tremor. He found that the latter was most prominent during the early postoperative period and was less enduring than ataxic tremor. Nevertheless, the concurrence of the two types of tremor and the fact that both can be abolished by ablation of the contralateral ventrolateral thalamic nucleus suggest that they have related neural mechanisms, at least in monkeys.
There is another, higher amplitude tremor associated with cerebellar ataxia, in which every movement, even lifting the arm slightly or maintaining a static posture with the arms held out, results in a wide-ranging, rhythmic 2- to 5-Hz “wing-beating” movement. This tremor can be of sufficient force to throw the patient off balance. In such cases, the lesion is usually in the midbrain, involving the rostral projections of the dentatorubrothalamic fibers and the medial part of the ventral tegmental reticular nucleus. Because of the location of the lesion in the region of the red nucleus, Holmes originally called this a rubral tremor. However, experimental evidence in monkeys indicates that the tremor is produced not by a lesion of the red nucleus per se but by interruption of fibers that traverse this nucleus—that is, the cerebellar efferent fibers that form the superior cerebellar peduncle (Carpenter). This type of tremor is seen most often in patients with multiple sclerosis or Wilson disease, occasionally with vascular and other lesions of the tegmentum of the midbrain and subthalamus, and rarely as an effect of antipsychosis medications. Beta-adrenergic blocking agents, anticholinergic drugs, and L-dopa have little therapeutic effect. It is abolished by a surgical lesion in the opposite ventrolateral nucleus of the thalamus. Thalamic stimulation may be particularly helpful in severe cases that are the result of demyelinating lesions in the cerebellar peduncles.
This is a strongly familial episodic tremor disorder of the chin and lower lip that begins in childhood and may worsen with age. Psychic stress and concentration are known to precipitate the movements, which are described by Danek as “trembling.” Rare instances involve other facial muscles. The disorder must be distinguished from a similar tremor of the chin that is part of essential tremor, facial myokymia or fasciculations, and palatal tremor. The disorder results from a mutation on chromosome 9.
Primary Orthostatic Tremor
This is a rare but striking tremor isolated to the legs that is remarkable by its occurrence only during quiet standing and its cessation almost immediately on walking. It is difficult to classify and more relevant to disorders of gait than it is to tremors of other types. The frequency of the tremor has been recorded as approximately 14 to 16 Hz, making it difficult to observe and more easily palpable. An important accompanying feature is the sensation of severe imbalance, which causes the patient to assume a widened stance while standing; these patients are unable to walk a straight line (tandem gait). We have observed prominent tonic contraction of the legs during standing, seemingly in an attempt to overcome imbalance (see Heilman; Thompson, Rothwell, Day et al). The arms are affected little or not at all. Often the first step or two when the patient begins to walk are halting, but thereafter, the gait is entirely normal. Because falls are infrequent, the symptoms are often attributed to hysteria. Tremulousness is not present when the patient is seated or reclining, but in the latter positions it can be evoked by strong contraction of the leg muscles against resistance.
Electromyographic recordings demonstrate rhythmic co-contraction of the gastrocnemius and anterior tibialis muscles. Although some authors, such as Wee and colleagues, have classified the disorder as a type of essential tremor, most of its characteristics suggest otherwise. Sharott and coworkers consider it an exaggerated physiologic tremor in response to imbalance; others have suggested a spinal origin for the tremor because of an intrinsic rhythm at approximately 16 Hz that is generated by damaged spinal cord in patients with myelopathy.
Some cases have responded to the administration of clonazepam, gabapentin, primidone, or sodium valproate alone or in combination but it often proves difficult to treat. A few intractable cases have been treated with an implanted spinal cord stimulator (Krauss et al, 2005).
Tremors may be a feature of incipient dystonia as mentioned earlier. When the underlying dystonic posturing is not overt, the tremor may be ascribed to the essential variety or to hysteria. Dystonic tremor is focal, for example superimposed on torticollis, or a dystonic hand. The movement is not entirely rhythmic, sometimes jerky, and often intermittent. These cases are also discussed further on in the section on focal dystonia. In addition, a fair number of patients with dystonia have an essential tremor.
Tremor may be a dramatic manifestation of hysteria. It simulates many types of organic tremor, often causing some difficulty in diagnosis. Psychogenic tremors are usually restricted to a single limb, often in the dominant hand; they are gross in nature and are less regular than the common static or action tremors. Importantly, they often diminish in amplitude or disappear if the patient is distracted as, for example, when asked to make a complex movement with the opposite hand. If the examiner restrains the affected hand and arm, the tremor may move to a more proximal part of the limb or to another part of the body (“chasing the tremor”). Other useful features in identifying hysterical tremor are paradoxical exaggeration of the tremor by loading the limb—for example, by having the patient hold a book or other heavy object—which reduces almost all other tremors with exception of those produced by polyneuropathy. Hysterical tremor often acquires the frequency of a willed movement in a different limb.
Not all tremors correspond exactly with those described above and several of them may coexist. It is common for one type of tremor to show a feature ordinarily considered characteristic of another. In some parkinsonian patients, for example, the tremor is accentuated rather than dampened by active movement; in others, the tremor may be very mild or absent in repose and become obvious only with movement of the limbs. As mentioned above, a patient with a typical parkinsonian tremor may, in addition, show a fine essential tremor of the outstretched hands and occasionally even an element of ataxic tremor as well. In a similar way, essential or familial tremor may, in its advanced stages, assume the aspects of a cerebellar tremor. Further examples include patients with essential tremor or ataxic tremor who also display a rhythmic parkinsonian tremor in relation to sustained postures.
Palatal Tremor (“Palatal Myoclonus”)
This is a rare disorder consisting of rapid, rhythmic, involuntary movements of the soft palate. For many years it was considered to be a form of uniphasic myoclonus (hence the terms palatal myoclonus and palatal nystagmus). Because of the persistent rhythmicity, it is now classified as a tremor. There are two forms of this movement, according to Deuschl and colleagues. One is essential palatal tremor that reflects the rhythmic activation of the tensor veli palatini muscles; it has no known pathologic basis. The palatal movement may impart a repetitive audible click, which ceases during sleep. The second, more common form is a symptomatic palatal tremor caused by a diverse group of brainstem lesions that interrupt the central tegmental tract(s); (Fig. 5-3). There is a latency of many months after the focal injury before the tremor becomes evident. It has been reported by Deuschl and coauthors (1990) that the experience of clicking is reported by patients with the essential, but not the symptomatic, variety. The frequency of the tremor varies greatly between patients and tends to be higher and remain fixed in the symptomatic variety.
Palatal tremor, in contrast to the essential type and all other tremors, persists during sleep and is sometimes associated with pendular nystagmus that is synchronized with the palatal movements. In some cases, the pharynx as well as the facial muscles, diaphragm, vocal cords, and even the muscles of the neck and shoulders partake of the persistent rhythmic movements. A similar phenomenon, in which contraction of the masseters occurs concurrently with pendular ocular convergence, has been observed in Whipple disease (oculomasticatory myorhythmia).
Magnetic resonance imaging (MRI) reveals no lesions to account for essential palatal tremor; in the symptomatic form, however, there are tegmental brainstem lesions accompanied by conspicuous enlargement of the inferior olivary nucleus unilaterally or bilaterally. With unilateral palatal tremor, it is the contralateral olive that becomes enlarged. It has been proposed that the lesions in the symptomatic form interrupt the circuit (dentate nucleus–brachium conjunctivum–red nucleus-central tegmental tract–olivary nucleus–dentate nucleus) that Lapresle and Ben Hamida called the triangle of Guillain-Mollaret (see Fig. 5-3). The lesions have been vascular, neoplastic, demyelinating, or traumatic, and have been found mainly in midbrain or pontine portions of the central tegmental fasciculus.
The physiologic basis of palatal tremor remains conjectural. Matsuo and Ajax postulated a denervation hypersensitivity of the inferior olivary nucleus and its dentate connections, but others have suggested that the critical event is denervation not of the olive but of the nucleus ambiguus and the dorsolateral reticular formation adjacent to it. Dubinsky and colleagues have suggested that palatal tremor may be based on the same mechanism as postural tremor—that is, presumably a disinhibition and rhythmic coupling of neurons in the olive induced by a lesion of the dentato-olivary pathway.
The use of drugs in treating this movement disorder has met with variable success. Clonazepam (0.25 to 0.5 mg/d, increasing gradually to 3.0 to 6.0 mg/d), sodium valproate (250 mg/d, increasing to 1000 mg/d), and gabapentin (up to 2100 mg) have suppressed the movement in some cases, particularly the last of these drugs, which reportedly has had a dramatic effect in some patients. Also, tetrabenazine and haloperidol have been helpful on occasion. Selective injection of the palatal muscles with botulinum toxin, while technically demanding, affords modest relief; it is particularly helpful in eliminating the bothersome ear clicking.
The movement disorder known as asterixis was described by Adams and Foley in patients with hepatic encephalopathy but it occurs with a variety of systemic metabolic disorders as mentioned below. It consists of arrhythmic lapses of sustained posture that allow gravity or the inherent elasticity of muscles to produce a sudden movement, which the patient then corrects, sometimes with overshoot. Later, Leavitt and Tyler and then Young and Shahani demonstrated that the initial interruption or lapse in posture is associated with EMG silence for a period of 35 to 200 ms. By interlocking EMG and electroencephalogram (EEG) recordings, Ugawa et al found that a sharp wave, probably generated in the motor cortex, immediately precedes the period of EMG silence. This confirmed that asterixis differs physiologically from both tremor and myoclonus, with which it was formerly confused; it had incorrectly been referred to as a “negative tremor” or “negative myoclonus.”
Asterixis is most readily evoked by asking the patient to hold his arms outstretched with hands dorsiflexed or to dorsiflex the hands and extend the fingers while resting the forearms on the bed or the arms of a chair. Flexion movements of the hands may then occur arrhythmically once or several times a minute. The same lapses in sustained muscle contraction can be provoked in any muscle group—including, for example, the protruded tongue, the closed eyelids, or the flexed trunk muscles. Sometimes, asterixis can be elicited best by asking the patient to place his hand flat on a table and raise the index finger.
Asterixis was first observed in patients with hepatic encephalopathy but was later noted to occur with hypercapnia, uremia, and other metabolic and toxic encephalopathies including those caused by phenytoin and other antiepileptics, usually indicating that these drugs are present in excessive concentrations. Medications in classes other than the antiepileptics, particularly some antibiotics, cause the disorder from time to time, also usually when they are present at toxic levels.
Unilateral asterixis occurs in an arm and leg on the side opposite an anterior thalamic infarction or small hemorrhage, after stereotaxic thalamotomy, and with an upper midbrain lesion, usually as a transient phenomenon after stroke. In two series, Kim and Montalban and colleagues came to a similar conclusion, namely, that unilateral asterixis is usually attributable to an acute thalamic stroke on the contralateral side, but there was an interesting variety of other localizations including the frontal lobe (anterior cerebral artery infarction), midbrain, and cerebellum in a few cases each. Our experience is limited to those arising from thalamic and overlying parietal vascular lesions. Many drugs may unmask unilateral asterixis that has its basis in an underlying lesion of the anterior thalamus. Of course, an individual with a metabolic encephalopathy and a hemiparesis, new or old, will only manifest asterixis on the normal side.
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.
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.
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.
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).
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.
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.
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.
Diffuse Myoclonus (Polymyoclonus)
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.
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.
Essential (Familial) Myoclonus
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 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.
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 (See Also Myoclonic Seizures in Chap. 15). 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 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.
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.
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.
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
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 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.
Table 4-7CAUSES OF GENERALIZED AND REGIONAL MYOCLONUS ||Download (.pdf) Table 4-7CAUSES OF GENERALIZED AND REGIONAL MYOCLONUS
Benign epilepsy with rolandic spikes
Juvenile myoclonic epilepsy
Infantile spasms (West syndrome)
Cherry-red-spot myoclonus (sialidase deficiency)
Myoclonus epilepsy with ragged red fibers (MERRF)
Ceroid lipofuscinosis (Kufs disease)
Epilepsia partialis continua
|Essential forms |
Subacute sclerosing panencephalitis
Familial progressive poliodystrophy
Alzheimer, Lewy-body, and Wilson diseases (occasional in late stages)
Whipple disease of the central nervous system
Corticobasal ganglionic degeneration
Myoclonus with cerebellar disease (myoclonic ataxia)
Opsoclonus-myoclonus syndrome (paraneoplastic [anti-Ri], neuroblastoma, post- and parainfectious)
Postanoxic myoclonus (Lance Adams type)
Ramsay-Hunt dyssynergia cerebellaris myoclonica (see Hunt JR)
Metabolic, immune, and toxic disorders
Cerebral hypoxia (acute and severe)
Haloperidol and sometimes phenothiazine intoxication
Hepatic encephalopathy (rare)
Nicotinic acid deficiency encephalopathy
Other drug toxicities
Focal and spinal forms of myoclonus
Herpes zoster myelitis
Other unspecified viral myelitis
Traumatic spinal cord injury
Arteriovenous malformation of spinal cord
Subacute myoclonic spinal neuronitis
Paraneoplastic spinal myoclonus
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.
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).
Postanoxic Intention (or Action) Myoclonus
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.
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.
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.
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.
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.
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 startle.
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 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.
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.
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 hyperexcitability in one or another of the motor or reticular alerting systems.
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).
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 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.
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.
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.
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 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.
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.
Symptomatic Restricted Dystonias
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 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.
Spasmodic Torticollis (Idiopathic Cervical Dystonia)
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 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.
Dystonic movement disorders. A. Young man with severe spasmodic retrocollis. Note hypertrophy of sternocleidomastoid muscles. B. Meige syndrome of severe blepharospasm and facial-cervical dystonia. C. Characteristic athetoid-dystonic deformities of the hand in a patient with tardive dyskinesia. (Photographs courtesy of Dr. Joseph M. Waltz.)
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.
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 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.
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.
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).
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).
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 result of drug-induced tardive dyskinesia.
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.
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.
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
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.
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)
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 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).
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.
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.
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.
Task-Specific Dystonias Including Writer’s Cramp and Musician’s Spasm
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 patients learn to write in new ways or to use the other hand, though that, too, may become involved.
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.
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 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.
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.
Drug-Induced Tardive (Delayed) Dyskinesias
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 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.
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.
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.
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.
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.
Further discussion of the side effects of the antipsychosis drugs is found in later chapters.
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 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.
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.
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.
Gilles de la Tourette Syndrome
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.
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.
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.
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.
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.
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).
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 pre- and 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 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.
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.
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 (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 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.
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.
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 or serum autoantibodies to streptococcus (Singer et al, 2005; Schrag and coworkers).
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.
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.
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.
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