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, because of their largely different connections and functions, are usually excluded.
Overview of the components of the basal ganglia in coronal view. The main nuclei of the basal ganglia are represented in blue, 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). This concept was based largely on the experimental work of Whittier and Mettler and of Carpenter, in the late 1940s. These investigators demonstrated, in monkeys, that a characteristic movement disorder, which they termed choreoid dyskinesia, could be brought about in the limbs of one side of the body by a lesion localized to 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.
Schematic illustration of major efferent and afferent connections of the basal ganglia. The blue lines indicate neurons with excitatory effects, whereas the black lines indicate inhibitory influences. (See text for details; also Fig. 4-2.) (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science, 5th ed. New York: McGraw-Hill, 2013.)
New observations have made it apparent that there are instead, a number of parallel circuits as detailed further on. However, 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 vital link, 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.
The foregoing view of basal ganglionic organization has been broadened considerably as a result of newer anatomic, physiologic, and pharmacologic data (see reviews of Gombart and colleagues, of DeLong, and of Penney and Young). Whereas earlier concepts emphasized the serial connectivity of the basal ganglionic structures as mentioned earlier, current evidence indicates an organization into several parallel basal ganglionic–cortical circuits. These circuits run parallel to the premotor pathway but remain separate anatomically and physiologically. At least five such anatomic circuits have been described, each projecting to a different portion of the frontal lobe: (1) the prototypical motor circuit, converging on the premotor cortex; (2) the oculomotor 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 one or another cell type is destroyed preferentially in degenerative diseases such as Huntington chorea.
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, and that the output nuclei of the basal ganglia consist of the medial (internal) pallidum and the pars reticulata (nonpigmented portion) of the substantia nigra (Fig. 4-3).
It has been proposed on the basis of physiologic, lesional, and pharmacologic studies, that there are two main efferent projections from the putamen; but these models are still in evolution. Nonetheless, 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 connections.
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 medial pallidum 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 lateral pallidum to the medial pallidonigral output nuclei. A complete account of this intricate connectivity cannot be given, but the main themes outlined here seem valid.
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.
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—e.g., 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 indicates that a balanced functional architecture, one excitatory and the other inhibitory, is operative 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 medial 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 lateral pallidum, which, in turn, disinhibits the subthalamic nucleus through GABA release, providing subthalamic drive to the medial pallidum and substantia nigra pars reticulata. The net effect is thalamic inhibition that 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.
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. In Parkinson disease, e.g., 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 has come from the discovery that the parkinsonian syndrome is reproduced in humans and primates by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This toxin was discovered accidentally in drug addicts who self-administered an analogue of meperidine. The toxin binds with high affinity to monoamine oxidase (MAO), an extraneural enzyme that transforms it to pyridinium, a toxic metabolite that is bound by melanin in the dopaminergic nigral neurons in sufficient quantities to destroy 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 medial globus pallidus and decreased activity in the lateral globus pallidus, as predicted from the above described models. This comes about because of the differential loss of activity of dopaminergic striatal neurons that project to each of these parts of the pallidum. The end result is increased inhibition of thalamocortical -neurons. It is, however, difficult to explain why medial pallidal lesions do not regularly cause parkinsonism. Perhaps it is because the subtle imbalance between the medial and lateral pallidal circuits that exists in Parkinson disease is not reproduced. This subtlety may also explain why crude lesions, such as infarcts, hemorrhages, and tumors, rarely produce the complete parkinsonian syndrome of tremor, bradykinesia, and rigidity. Indeed, striking improvements in parkinsonian symptoms are obtained, paradoxically, by placing lesions in the medial pallidum (pallidotomy) as discussed in Chap. 39.
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 of oscillations in other parts of the system, as well as bringing individual cells closer to firing. Another deficiency 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. Figure 4-4 summarizes their roles. 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.
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, i.e., they act as neuromodulators.
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.
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. 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 4–2 Properties and Localization of Dopamine Receptors ||Download (.pdf)
Table 4–2 Properties and Localization of Dopamine Receptors
CLASSES OF DOPAMINERGIC RECEPTORS
Within basal ganglia
Medial GP/SN pars reticulata
SN pars compacta
Outside basal ganglia
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.
Even these details do not capture the intricacy of neural transmission in the basal ganglia. In contrast to the almost instantaneous actions of glutamate and its antagonist, GABA, at synapses, the monoamines have more protracted effects, lasting for seconds or as long as several hours. Dopamine and related neurotransmitters have a slower influence through the "second messenger" cyclic adenosine monophosphate (cAMP), which, in turn, controls the phosphorylation or dephosphorylation of numerous intraneuronal 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 from exposure to high levels of the drug. Similarly, drugs that inhibit catechol O-methyltransferase (COMT), another enzyme that metabolizes dopamine, prolong the effects of administered L-dopa.
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. 39.
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 some 240 cases in which there were lesions in the caudate, putamen, and globus pallidus associated with movement abnormalities. Dystonia occurred in 36 percent, chorea in 8 percent, parkinsonism in only 6 percent, and dystonia-parkinsonism in 3 percent. Bilateral lesions of the lenticular nuclei resulted in parkinsonism in 19 percent and dystonia-parkinsonism in 6 percent. It is also notable that a common associated behavioral abnormality was abulia (apathy and loss of initiative, spontaneous thought, and emotional responsivity), in those with caudate lesions. The deficiencies of this type of case analysis (i.e., the crudeness of computed tomography studies and obtained without regard to the temporal aspects of the clinical disorder), conceded by the authors, are obvious. We 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 4–3 Clinicopathologic Correlations of Extrapyramidal Movement Disorders ||Download (.pdf)
Table 4–3 Clinicopathologic Correlations of Extrapyramidal Movement Disorders
PRINCIPAL LOCATION OF MORBID ANATOMY
Unilateral plastic rigidity with rest tremor (Parkinson disease)
Contralateral substantia nigra plus (?) other mesencephalic structures
Unilatral 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
Neuronal degeneration, usually diffuse or predominating in cerebral or cerebellar cortex and dentate nuclei
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 disorders is clearly a consequence of rigidity and postural disorders, whereas in others, where rigidity is slight or negligible, they seem to represent primary deficiencies. Psychological stress and anxiety generally worsen the abnormal movements in extrapyramidal syndromes, just as relaxation improves them.
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 memory of 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 not swallowed as quickly as it is produced, 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, which connotes slowness rather than lack of movement, is another aspect of the same physiologic difficulty. 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—i.e., increased reaction time), but the velocity of movement, or the time from onset to completion of movement, is slower than normal. Hallett distinguishes between akinesia and bradykinesia, equating akinesia with a prolonged reaction time and bradykinesia with a prolonged time of execution, but he has noted that if bradykinesia is severe, it results in akinesia. This is apparently not the result of slowness in formulating the plan of movement, which nonetheless seems at times to be another component of the parkinsonian syndromes. 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.
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. 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. 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.
In terms of pathologic anatomy and physiology, bradykinesia may be caused by any process or drug that interrupts some component of 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 diseases.
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 and limbs and of the neck. Anticipatory and compensatory righting reflexes 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 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, i.e., 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, e.g., 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 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 (all discussed in Chap. 39), exposure to neuroleptic drugs, and mineralization of the basal ganglia (Fahr disease). 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.
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, see Chap. 53).
Involuntary Movements (Chorea, Athetosis, Ballismus, Dystonia)
In deference to usual practice, these symptoms are described as though each represented a discrete clinical phenomenon, readily distinguishable from the others. 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, but 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 in Chaps. 6 and 43.
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, and giving rise to the "hung-up" reflex.
The hypotonia in chorea as well as the pendular reflexes may suggest a disturbance 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. 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.
Table 4-4 lists diseases characterized mainly by chorea. It is a major feature of Huntington disease, in which the movements tend more typically to be choreoathetotic. There may be subtle additional ataxia of gait, as noted by Breedveld and colleagues. 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 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. These are discussed in Chap. 39.
Table 4–4 Diseases Characterized by Chorea ||Download (.pdf)
Table 4–4 Diseases Characterized by Chorea
Benign hereditary chorea
Immune mediated chorea
Paraneoplastic, often with other movements
Neuroleptics (phenothiazines, haloperidol, metoclopramide, and others)
Phenytoin (occasionally other antiepileptic drugs)
Excess dosages of L-dopa and dopamine agonist medications
Chorea symptomatic of systemic disease
Hyperosmolar, nonketotic hyperglycemia
Toxoplasmosis in AIDS
Typical choreic movements are the dominant feature of Sydenham chorea and of the variety of that disease associated with pregnancy (chorea gravidarum), disorders that are strongly linked through some immune mechanism to streptococcal infection. 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. In these cases the neurologic problems are said to arise suddenly, subside, and return with future streptococcal infections, as discussed in Chap. 6. This seems unlikely to explain chorea in adults. 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 in Chap. 31, as reported by O'Toole and colleagues.
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 far less frequently associated with the problems. Excess dopamine administration in advanced Parkinson disease is perhaps the most common cause of a choreiform dyskinesia in practice, but the movements tend to be more complex and continuous than those seen in chorea.
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. Also, only about one-third of cases involve a stroke, and some have demonstrated hypermetabolism of the basal ganglia, as in Sydenham chorea. A connection between hemichorea and the antiphospholipid syndrome alone, without lupus, is more tenuous.
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 paraneoplastic variety may combine several aspects of chorea with athetosis, ballismus, or dystonia; inflammatory lesions are found in the striatum (Chap. 31).
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). A cerebral infarction is the usual cause. A number of rare paroxysmal kinesigenic disorders, discussed later in this chapter, may have a choreic component.
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 case proved to be Huntington disease.
The precise anatomic basis of chorea is often uncertain or at least inconsistent. 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 relate to disorders of the same system of neurons; however, the subthalamic nucleus, the region typically implicated in ballismus, is affected only slightly in Huntington chorea and, on the other hand, transient chorea or ballismus arises from infarctions in any part of the striatum on the side opposite to the movement, particularly in the caudate.
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, 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 to be 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 cocontraction of antagonistic muscles and a spread (overflow) of contraction to muscles not normally required in the movement (intention spasm). 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). In other forms, the spasms appear to occur spontaneously, i.e., they are involuntary and, if persistent, give rise to more or less fixed dystonic postures.
Athetosis may affect all four limbs or may be unilateral, especially in children who have suffered a hemiplegia at some previous time (posthemiplegic athetosis). Many athetotic patients exhibit variable degrees of rigidity and motor deficit as a result of associated corticospinal tract disease; these may account for the slower quality 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, which begins in childhood. Athetosis appearing in the first years of life is usually the result of a congenital or postnatal condition such as hypoxia (cerebral palsy) or, rarely, kernicterus. Postmortem examinations in some of the cases have disclosed a unique pathologic change of probable hypoxic etiology, status marmoratus, in the striatum (Chap. 38). In other cases, of probable kernicteric (hyperbilirubinemic) etiology, there has been 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. 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 medial 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 anticonvulsants. 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 an uncontrollable, 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, rarely 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 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).
(See Chap. 6 for a discussion of focal dystonias.)
Dystonia is an unnatural spasmodic movement of posture that puts the limb in a twisted posture. 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 central feature is involuntary cocontraction 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; see also Fig. 6-2).
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. 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 the illness, is the correct diagnosis made. 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.
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. 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 "double athetosis" caused by hypoxic damage to the fetal or neonatal brain, kernicterus, pantothenate kinase-associated neurodegeneration (formerly Hallevorden-Spatz disease), Huntington disease, Wilson disease, lysosomal storage diseases, striatopallidodentatal calcification (sometimes caused by hypoparathyroidism), thyroid disease, and exposure to neuroleptic drugs, as discussed below.
Widespread torsion spasm (another term for dystonia) may also be a prominent feature of certain rare heredodegenerative disorders, such as familial striatal necrosis with affection of the optic nerves and other parts of the nervous system (Marsden et al, Novotny et al). A distinct subset of patients with an idiopathic dystonia (described by Nygaard et al and discussed in Chap. 39) responds to extremely small doses of L-dopa. The disease 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. This process has a number of names, including L-dopa–responsive dystonia and Segawa disease, for which specific causative mutations have been discovered. Another rare hereditary dystonia that has its onset in adolescence or early adulthood 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, which may follow (Dobyns et al). A few cases have followed a febrile episode. The disorder is termed rapid-onset dystonia-parkinsonism. It is our understanding that the features of rapid-onset dystonia-parkinsonism are also mild and not responsive to L-dopa. Chapter 39 discusses these hereditary forms of dystonia.
A frequent cause of acute generalized dystonic reactions, more so in the past, has been from exposure to the class of neuroleptic drugs—phenothiazines, butyrophenones, or metoclopramide—and even with the newer agents such as olanzapine, which has the advantage of producing these side effects less frequently than the others. A characteristic, almost diagnostic, example of the 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 to some extent to diphenhydramine or benztropine given two or three times over 24 to 48 h. L-Dopa, calcium channel blockers, and a number of anticonvulsants and anxiolytics are among a long list of other medications that may on occasion induce dystonia, the various causes of which are listed in Table 4-5. The acute dystonic drug reactions are idiosyncratic and now, probably as common as the "tardive dyskinesias" that had followed long-standing use or the withdrawal of a medication.
Table 4–5 Diseases Characterized by Dystonia ||Download (.pdf)
Table 4–5 Diseases Characterized by Dystonia
Hereditary and degenerative dystonias
Dystonia musculorum deformans (recessive and autosomal dominant forms)
Juvenile dystonia—Parkinson syndrome (L-dopa–responsive)
Dystonia with other heredodegenerative disorders (neural deafness, striatal necrosis with optic nerve affection, paraplegic amyotrophy)
Focal dystonias and occupational spasms (see Chap. 6), 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
Symptomatic (secondary) dystonias
Double athetosis (cerebral palsy) caused by cerebral hypoxia
Acquired hepatocerebral degeneration
Lysosomal storage diseases
Multiple sclerosis with cord lesion
Paraneoplastic striatopallidodentatal calcification (Fahr disease)
Toxic necrosis of lenticular nuclei (e.g., methanol) can be delayed
Idiopathic focal dystonias
Writer's cramp and other occupational spasms
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 in Chaps. 6 and 39.
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 the former, 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.
Numerous drugs have been used to treat idiopathic chronic generalized dystonia, with a notable lack of success. However, Fahn has reported beneficial effects (more so in children than in adults) with the anticholinergic agents, trihexyphenidyl, benztropine, and ethopropazine given in massive amounts—which are achieved by increasing the dosage very gradually. The drug-induced tardive dyskinesias require specialized treatment, as described in Chaps. 6 and 42. Reinstitution of the offending drug or anticholinergic agents is often tried. Tetrabenazine, a centrally active monoamine-depleting agent, is effective but not readily available. The acute dystonic drug reactions are treated as noted above.
Stereotactic surgery on the pallidum and ventrolateral thalamus, a treatment introduced by Cooper in the middle of the last century, had reported generally positive but unpredictable results. In recent years there has been a renewed interest in a derivative of this form of treatment, deep brain stimulation (see Chap. 39). 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.
In the focal dystonias, the most effective treatment has proved to be the periodic injection of botulinum toxin into the affected muscles as discussed in Chap. 6.
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. One, which has an autosomal dominant (less often recessive) pattern of inheritance and a tendency to affect males, begins in adolescence or earlier. It is characterized by numerous brief (several minutes) attacks of choreoathetosis provoked by startle, sudden movement, or hyperventilation—hence the title paroxysmal kinesigenic choreoathetosis. There may be many dozens of attacks per day or occasional ones. This disorder responds well to anticonvulsant medication, particularly to phenytoin and carbamazepine.
In a second type, such as those originally 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 per se (nonkinesigenic type). The attacks may be predominantly one-sided or bilateral. 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. Each of these types has a different causative gene. 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).
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 and those secondary to focal brain lesions, such as the ones reported by Demirkirian and Jankovic. They classify 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 anticonvulsants; others respond better to clonazepam.
Some intermittent dyskinesias are an expression of a neurologic or metabolic disease. They may follow injuries such as stroke, trauma, encephalitis, perinatal anoxia, multiple sclerosis, hypoparathyroidism, or thyrotoxicosis, and particularly, nonketotic hyperosmolarity. The most severe instances in our experience have been related to multiple sclerosis (tetanoid spasms), and, in the setting of HIV infection, as a result of toxoplasmosis, lymphoma, or presumed encephalitis caused by the retrovirus itself. 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).
The Identity of Chorea, Athetosis, and Dystonia
It may be evident from the foregoing descriptions that the distinctions between chorea, athetosis, and dystonia are probably not fundamental. 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 practice, one finds that the patient with relatively slow movements also shows discrete, rapid ones, and vice versa, and that many patients with chorea and athetosis also exhibit a persistent disorder of movement and posture that is essentially dystonic.
In a similar way, no meaningful distinction except one of degree can be made between chorea, athetosis, and ballismus. Particularly forceful movements of large amplitude (ballismus) are observed in some cases of Sydenham and Huntington chorea which, according to traditional teaching, exemplify pure forms of chorea and athetosis. The close relationship between these involuntary movements is illustrated by the patient with hemiballismus who, upon recovery, shows only choreoathetotic flexion–extension movements.
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, but rather some 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.