Most movement disorders result from diseases that affect the basal ganglia. Clinically, movement disorders can be divided into hypokinetic and hyperkinetic disorders: hypokinetic disorders are characterized by slow, impaired voluntary movements typified by parkinsonism; hyperkinetic disorders are characterized by involuntary movements, including chorea, ballismus, dystonia, tremor, tic, and myoclonus. Because of shared neural mechanisms, movement disorders with different etiologies may have similar motor manifestations. This clinical overlap, together with the lack of biologic markers for many of these disorders, can make etiologic diagnosis a challenging exercise. Nevertheless, major advances in the understanding of the genetics, molecular biology, and pathophysiology of these disorders have led to the availability of genetic testing for a selected few and to the development of effective pharmacologic and surgical treatments for others. Furthermore, the symptomatic therapies used today are often effective irrespective of etiology.
Movement disorders usually coexist with psychiatric, cognitive, and sleep disturbances that can contribute significantly to disability and that may even dominate the clinical picture. For example, depression can impair the response to otherwise adequate treatment of motor symptoms. In many instances, treatment of these comorbid conditions is an important aspect of management.
Pathophysiology
Movement disorders may arise from dysfunction in the basal ganglia, the thalamocortical motor circuits, or brain stem connections [see Figure 1].1 Alterations of basal ganglia output at the level of the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) can lead both to impairment of voluntary movements and to involuntary movements.2
A pathophysiologic model of parkinsonism has been developed on the basis of animal studies [see Figure 2]. The biochemical hallmark of this syndrome is dopamine deficiency in the putamen and the caudate nucleus, which promotes excessive excitatory drive from the STN to the GPi and, in turn, abnormal output from the GPi.2 Although initially, attention was focused on the increased inhibitory output from the GPi, it now appears that changes in the pattern of GPi output play a major role as well. That impairment of movement results from the excessive and abnormal GPi output is supported by studies demonstrating that treatment directed toward the GPi or STN (either surgery or deep brain stimulation) greatly improves the motor signs of Parkinson disease (PD).3 Moreover, in patients with PD, the restoration of cortical activation during a movement task has been demonstrated by comparing positron emission tomography (PET) scans taken before and after treatment with pallidoto-my (a procedure that surgically destroys the motor segment of the GPi) or with electrical stimulation of the STN.4
In contrast to hypokinetic disorders, hyperkinetic disorders appear to result from abnormally low and altered GPi output [see Figure 2].5,6 Reduced STN output leads to a reduction in the thalamic inhibition by GPi. In hemiballismus, this stems from damage to the STN or its connections. In Huntington disease, it is the result of selective loss of striatal neurons that project to the external portion of the GPi or the substantia nigra.7 Just as the same patho-physiologic changes in GPi and STN output are responsible for the disturbances of eye movements that occur in PD and Hunt-ington disease, it is tempting to speculate that changes in the other basal ganglia-thalamocortical circuits contribute to behavioral, cognitive, and limbic signs and symptoms that parallel many of the motor symptoms and signs of these disorders.8
Hypokinetic Disorders
Parkinsonism is a clinical syndrome with multiple etiologies that is characterized by varying degrees of bradykinesia, tremor, rigidity, and postural instability.9 The common denominator of all forms of parkinsonism is the reduction of striatal dopaminer-gic transmission in the nigrostriatal pathways. Parkinsonism may be subdivided into PD, which accounts for approximately 75% of cases, and atypical forms of parkinsonism, which account for the rest [see Table 1]. It is important to distinguish PD from these other forms of parkinsonism because prognosis and treatment differ significantly in each. Early etiologic diagnosis will become increasingly important in the coming years, with the emergence of therapies that may be specific to subtypes of PD.
Parkinson disease
Epidemiology, Etiology, and Genetics
PD is a progressive neurodegenerative disorder that afflicts more than one million persons in the United States, including 1% of the population older than 55 years.10 A genetic contribution to familial forms of PD has now been firmly established; thus, these forms should be considered primary rather than idiopathic PD. Accordingly, PD is now considered a syndrome with many genetic and nongenetic causes. Genetic forms are associated with at least eight identified autosomal dominant and autosomal recessive mutations.11 PD resulting from these mutations often has an earlier onset (occurring in patients younger than 50 years) and a severely progressive course compared with the typical sporadic form of PD, which has a mean age of onset of 60 years. In some of these disorders, signs of parkinsonism develop before age 20; these are termed juvenile parkinsonism. The genetic basis of most cases of early-onset disease is further supported by epidemiolog-ic studies in monozygotic and dizygotic twins.
One line of PD research has addressed the possible causative role of environmental factors (e.g., head injury, rural living, exposure to pesticides). Current thinking, which is influenced by evidence from animal models of PD, is that any role of environmental factors is almost exclusively limited to persons with a genetic predisposition.13,14
Autosomal dominant cases of PD are linked to two independent mutations in the a-synuclein gene.11,15 The first a-synuclein mutation, PARK1, was found in a large Italian kindred and in three unrelated families of Greek origin.15 This gene is located on chromosome 4q21 and codes for a-synuclein, the precursor protein of the non-|-amyloid component of Alzheimer disease found in neuritic plaques. The protein is found in presynaptic terminals, and its distribution in the brain is identical to that of Lewy bodies. Its normal function is still unclear. For PD from the PARK1 mutation, disease onset occurs before age 50; the disease generally has a rapid course and is often accompanied by dementia.
Figure 1 Functional anatomy of the basal ganglia. (a) The basal ganglia are appropriately viewed as components of larger cortical-subcortical reentrant pathways that also include portions of the thalamus. These form a family of functionally segregated circuits that subserve and ultimately target the skeletomotor, oculomotor, associative (cognitive), and limbic cortices of the frontal lobes. (b) The basal ganglia comprise the corpus striatum (caudate nucleus and putamen), the globus pallidus, the subthalamic nucleus, and the two parts (pars compacta and pars reticularis) of the substantia nigra. These components are found deep in the cerebral hemispheres and nearby parts of the diencephalon and midbrain. The figure illustrates a simplified schema of the motor circuit. The segregated organization of the cortical-subcortical circuits permits simultaneous and independent parallel processing of diverse motor and nonmotor inputs (e.g., representation of face, arm, and leg). For each circuit, output (i.e., cortical impulses) from a specific cortical area passes through a unique portion of the striatum (e.g., putamen), the external and internal segments of the globus pallidus, the substantia nigra pars reticularis (not shown in this figure), the subthalamic nucleus, and the ventrolateral thalamus and returns to the specific frontal cortical area—in this case, the area related to motor function (i.e., premotor cortex, primary motor cortex, and supplementary motor cortex). The motor circuit originates from the precentral and postcentral sensorimotor fields, engages specific portions of the basal ganglia and motor thalamus, and ends back in the precentral motor fields of the frontal lobe. For example, voluntary movements are normally initiated in cortical areas that provide input to the basal ganglia and thalamus, which in turn modify these same cortical areas via the return projection through the motor circuit.
A second form of autosomal dominant, Lewy body-positive PD has been linked to the PARK3 mutation on chromosome 2p13. PARK3 may also play a role in sporadic PD, given that PD develops in only 40% of persons with this mutation and that the age of onset and response to levodopa therapy in these cases are indistinguishable from those in sporadic cases.
There are at least six other rare autosomal dominant mutations that can cause parkinsonian syndromes similar to idiopathic PD. Clinically, these conditions resemble autosomal recessive juvenile parkinsonism (AR-JP), but they are often also associated with ataxia and amyotrophy.16,17
One form of AR-JP is linked to the parkin gene, which has been mapped to a large region of chromosome 6 (PARK2) and is found in Japanese and some European families.18-20 In these patients, an initially robust response to levodopa is soon complicated by severe motor fluctuations. Pathologically, these patients do not have Lewy bodies but instead express Lewy fibrils and neu-rites that are immunohistochemically positive for a-synuclein. Two autosomal recessive forms, involving the PARK2 and PARK7 mutations, have atypical features and very early (juvenile) onset.
In the vast majority of patients with sporadic PD, no strong genetic determinant appears to play a role. It is believed, however, that these patients may share an as yet undefined genetic vulnerability that results in clinical illness only when the individual is exposed to as yet uncertain internal or external environmental factors.12 Genetic vulnerability may be attributed to deficits in mitochondrial oxidative phosphorylation genes (OXPHOS complex I), cytochrome P-450, and other polymorphisms, as well as to deficits in oxidative radical scavenging enzyme activity (e.g., glutathione transferases).
Certain epidemiologic factors have been linked to a reduced incidence of PD. These include coffee drinking, cigarette smoking, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and estrogen replacement in postmenopausal women.
Pathophysiology and Pathogenesis
The classic pathologic hallmarks of PD are degeneration of the dopaminergic cells of the substantia nigra pars compacta (SNc) and the presence of Lewy bodies in pigmented brain stem neurons, including the locus coeruleus, the pontine raphe nuclei, and the dorsal motor nucleus of the vagus nerve. The earliest pathologic changes may occur in the mesenteric plexus of the intestine and in the anterior olfactory nuclei.24 The process spreads rostral-ly to the dorsal motor nucleus of the vagus and glossopharyngeal Disturbances of the proper balance between the two circuits result in a variety of clinical syndromes. For example, in Parkinson disease, which is a hypokinetic disorder, dopamine deficiency increases the activity of the indirect pathway and thus the excitatory drive from STN to GPi/SNr. This condition stimulates inhibitory output from GPi and results in the increased inhibition of thalamocortical neurons, which renders cortical projection areas less responsive to inputs normally involved in the initiation and execution of movement. This process is illustrated by the reduced thickness of the excitatory arrows from the thalamus to the cortex and from the cortex to the brain stem and spinal cord. Changes in the pattern of GPi discharge are also a major factor in Parkinson disease.
Figure 2 This figure gives a more detailed illustration of striatal outflow and its functional significance in movement disorders. The corpus striatum serves as the input or receptive stage of the basal ganglia portion of the circuit, whereas the internal segment of the globus pallidus (GPi) and the substantia nigra reticularis (SNr) serve as output stages. The output nuclei of the basal ganglia are linked to the corpus striatum by a direct pathway between the corpus striatum and the GPi and the SNr and an indirect projection to the GPi via the external segment of the globus pallidus (GPe) and the subthalamic nucleus (STN). Other than the excitatory (glutamatergic) STN-GPi pathway (blue arrows), all projections of the direct and indirect pathways are inhibitory, or GABAergic (black arrows). (Note that the pathways from the cortex to the putamen, from the thalamus to the cortex, and from the cortex to the brain stem are also excitatory.) Considering the polarity of these connections and the fact that GPi/SNr output is tonic and inhibitory on thalamic neurons, it follows that activation of the direct pathway by cortical input (or dopamine stimulation) will reduce the activity of the output nuclei GPi and SNr and, thereby, disinhibit (by removal of inhibitory input) thalamocortical projection neurons, which will in turn facilitate movement. In contrast, activation of the indirect pathway, which has a net excitatory effect on GPi/SNr activity, will act to inhibit thalamocortical neurons or inhibit movements that may conflict with the intended movement. Too much activity of this pathway leads to movement inhibition in general and thus to parkinsonism. Dopamine is released by the terminals of the substantia nigra pars compacta (SNc) projections to the corpus striatum (putamen) and acts to modulate the activity in these circuits. Dopamine differentially influences the balance between the two pathways by inhibiting transmission in the indirect pathway via D2 dopamine receptors on striatal neurons projecting to GPe and by facilitating transmission in the direct pathway via D1 dopamine receptors on striatal neurons projecting to GPi. Thus, release of dopamine in the corpus striatum reduces basal ganglia output to the thalamus (Thal), whereas loss of dopamine increases output.
In the hyperkinetic disorder hemiballismus, a lesion in the STN knocks out the excitatory drive from the STN to the GPi, which leads to loss of inhibition, or stimulation of the thalamocortical neurons, rendering cortical projection areas highly responsive to inputs involved in the initiation and execution of movement (illustrated by the thick excitatory arrows from the thalamus to the cortex and from the cortex to the brain stem and spinal cord). In the case of chorea, early selective loss of striatal neurons projecting to GPe via the indirect pathway (e.g., Huntington disease or proposed neuroleptic-induced toxicity in tardive dyskinesia) leads to the disinhibition of the GPe and thus excessive inhibition of striatal outflow (GPi/SNr). The result is a loss of inhibition of the excitatory thalamocortical pathway that consequently leads to the multiple, poorly synchronized movements of chorea.
Table 1 Differential Diagnosis of Parkinsonism
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Idiopathic (sporadic) Parkinson disease |
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Most common form; clinical expression may be influenced by so-called vulnerability genes |
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Genetically mediated (primary) Parkinson disease |
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Identified mutations (rare) |
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PARK1 (a-synuclein; two mutations) |
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PARK2 (Parkin gene mutation) with multiple polymorphisms |
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PARK3 |
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Primary |
Other neurodegenerative disorders |
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a-Synuclein disorders |
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Multiple-system atrophies (glial and neuronal inclusions) |
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Striatonigral degeneration |
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Olivopontocerebellar atrophy |
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Shy-Drager syndrome |
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Motor neuron disease with parkinsonian features |
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Lewy body dementia (cortical and brain stem neuronal inclusions) T1 il • / 1 • 1 ‘(1 • i ill \ |
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Tauopathies (disorders with primary tau pathology) Progressive supranuclear palsy |
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Corticobasal degeneration |
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Frontotemporal dementia |
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Amyloidopathies (disorders with primary amyloid pathology and secondary tau pathology and dementia) |
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Alzheimer disease with parkinsonism (sporadic, amyloid precursor protein-related, presenilin 1- and presenilin 2- related) |
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Genetically mediated disorders with occasional parkin-sonian features |
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Wilson disease |
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Hallervorden-Spatz disease |
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Chediack-Higashi syndrome |
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Spinocerebellar ataxia type 3 |
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X-linked dystonia parkinsonism (DYT3) |
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Huntington disease (Westphal variant) |
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Prion disease |
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Miscellaneous acquired conditions |
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Vascular parkinsonism |
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Normal-pressure hydrocephalus |
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Catatonia |
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Cerebral palsy |
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Repeated head trauma (dementia pugilistica) |
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Infectious and postinfectious diseases |
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Postencephalitic Parkinson disease |
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Neurosyphilis |
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Secondary |
Toxins |
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Carbon disulfide |
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Carbon monoxide |
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Cyanide |
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Manganese |
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Methanol |
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MPTP (1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine) |
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n-Hexane? |
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Drugs |
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Neuroleptics (typical antipsychotics) |
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Selected atypical antipsychotics [see text] |
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Antiemetics (e.g., prochlorperazine, metoclopramide) |
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Dopamine-depleting agents (e.g., reserpine, tetrabenazine) |
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a-Methyldopa |
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Lithium carbonate |
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Valproic acid |
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Fluoxetine |
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Metabolic Conditions |
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Hypoparathyroidism or pseudohypoparathyroidism with basal ganglia calcifications |
Ultimately, cell depletion occurs gradually in the SNc and other areas; parkinsonian signs begin to develop after 50% to 80% of midbrain dopamine neurons are lost and compensatory mechanisms fail [see Figure 3]. Involvement of the other pathologically involved nuclei may play a major role in the development of associated nonmotor aspects of PD (e.g., autonomic dysfunction, sleep disorders, depression).
Considerable attention has focused on the role of oxidative stress in PD and the damage that may be caused by free radicals produced by the metabolism of dopamine.25,26 Mitochondrial dysfunction is another possible factor that may contribute to vulnerability to oxidative stresses. There is now solid evidence of mitochondrial dysfunction in the brain and platelets of patients with PD.27,28 Defects in energy metabolism may interact with the protein products of mutations, leading to protein aggregation, low-grade inflammation, microglial activation, and further escalation of oxidative stress.29 Other factors, such as accumulation of protein aggregates as a result of proteosomal dysfunction, may play a role as well in some cases of PD.30,31
For example, it has been postulated that the mutated a-synu-clein protein of PARK1 has an abnormal tertiary structure that makes it prone to self-aggregation and thus formation of the amyloidlike cores of Lewy bodies.15 Mice that hyperexpress this gene develop granular intracytoplasmic inclusions similar to Lewy bodies.15 In vitro, low concentrations of aggregated fibrillo-genic fragments of a-synuclein are toxic to dopamine neurons,32 and mutations that alter the expression of the a-synuclein protein make dopamine neurons highly vulnerable to oxidative stress.
