Harrison's Neurology in Clinical Medicine, 3rd Edition

CHAPTER 30. PARKINSON’S DISEASE AND OTHER EXTRAPYRAMIDAL MOVEMENT DISORDERS

C. Warren Olanow Image Anthony H.V. Schapira

PARKINSON’S DISEASE AND RELATED DISORDERS

Parkinson’s disease (PD) is the second commonest neurodegenerative disease, exceeded only by Alzheimer’s disease (AD). It is estimated that approximately 1 million persons in the United States and 5 million persons in the world suffer from this disorder. PD affects men and women of all races, all occupations, and all countries. The mean age of onset is about 60 years, but cases can be seen in patients in their 20s, and even younger. The frequency of PD increases with aging, and based on projected population demographics, it is estimated that the prevalence will dramatically increase in future decades.

Clinically, PD is characterized by rest tremor, rigidity, bradykinesia, and gait impairment, known as the “cardinal features” of the disease. Additional features can include freezing of gait, postural instability, speech difficulty, autonomic disturbances, sensory alterations, mood disorders, sleep dysfunction, cognitive impairment, and dementia (Table 30-1), all known as nondopaminergic features because they do not fully respond to dopaminergic therapy.

TABLE 30-1

CLINICAL FEATURES OF PARKINSON’S DISEASE

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Pathologically, the hallmark features of PD are degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), reduced striatal dopamine, and intracytoplasmic proteinaceous inclusions known as Lewy bodies (Fig. 30-1). While interest has primarily focused on the dopamine system, neuronal degeneration with inclusion body formation can also affect cholinergic neurons of the nucleus basalis of Meynert (NBM), norepinephrine neurons of the locus coeruleus (LC), serotonin neurons in the raphe nuclei of the brainstem, and neurons of the olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous system. This “nondopaminergic” pathology is likely responsible for the nondopaminergic clinical features listed in Table 30-1. Indeed, there is evidence that pathology begins in the peripheral autonomic nervous system, olfactory system, and dorsal motor nucleus of the vagus nerve in the lower brainstem, and then spreads in a sequential manner to affect the upper brainstem and cerebral hemispheres. These studies suggest that dopamine neurons are affected in midstage disease. Indeed, several studies suggest that symptoms reflecting nondopaminergic degeneration such as constipation, anosmia, rapid eye movement (REM) behavior sleep disorder, and cardiac denervation precede the onset of the classic motor features of the illness.

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FIGURE 30-1

Pathologic specimens from a patient with Parkinson’s disease (PD) compared to a normal control demonstrating (A) reduction of pigment in SNc in PD (right) vs control (left), (B) reduced numbers of cells in SNc in PD (right) compared to control (left), and (C) Lewy bodies (arrows) within melanized dopamine neurons in PD. SNc, substantia nigra pars compacta.

DIFFERENTIAL DIAGNOSIS

Parkinsonism is a general term that is used to define a symptom complex manifest by bradykinesia with rigidity and/or tremor. It has a wide differential diagnosis (Table 30-2) and can reflect damage to different components of the basal ganglia. The basal ganglia comprise a group of subcortical nuclei that include the striatum (putamen and caudate nucleus), subthalamic nucleus (STN), globus pallidus pars externa (GPe), globus pallidus pars interna (GPi), and the SNc (Fig. 30-2). The basal ganglia play an important role in regulating normal motor behavior. It is now appreciated that basal ganglia also play a role in modulating emotional and cognitive functions. Among the different forms of parkinsonism, PD is the most common (approximately 75% of cases). Historically, PD was diagnosed based on the presence of two of three parkinsonian features (tremor, rigidity, bradykinesia). However, postmortem studies found a 24% error rate when these criteria were used. Clinicopathologic correlation studies subsequently determined that parkinsonism associated with rest tremor, asymmetry, and a good response to levodopa was more likely to predict the correct pathologic diagnosis. With these revised criteria (known as the U.K. brain bank criteria), the clinical diagnosis of PD is confirmed pathologically in 99% of cases.

TABLE 30-2

DIFFERENTIAL DIAGNOSIS OF PARKINSONISM

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FIGURE 30-2

Basal ganglia nuclei. Schematic (A) and postmortem (B) coronal sections illustrating the various components of the basal ganglia. SNc, substantia nigra pars compacta; STN, subthalamic nucleus.

Imaging of the brain dopamine system in PD with positron emission tomography (PET) or single-photon emission computed tomography (SPECT) shows reduced uptake of striatal dopaminergic markers, particularly in the posterior putamen (Fig. 30-3). Imaging can be useful in difficult cases or research studies but is rarely necessary in routine practice, as the diagnosis can usually be established on clinical criteria alone. This may change in the future when there is a disease-modifying therapy and it is important to make the diagnosis at as early a time point as possible. Genetic testing is not generally employed at present, but it can be helpful for identifying at-risk individuals in a research setting. Mutations of the LRRK2 gene (see later) have attracted particular interest as they are the commonest cause of familial PD and are responsible for approximately 1% of typical sporadic cases of the disease. Mutations in LRRK2 are particularly common causes of PD in Ashkenazi Jews and North African Berber Arabs. The penetrance of the most common LRRK2 mutation ranges from 28 to 74%, depending on age. Mutations in the parkin gene should be considered in patients with disease onset prior to 40 years.

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FIGURE 30-3

[11C]dihydrotetrabenazine PET (a marker of VMAT2) in healthy control (A) and PD (B) patient. Note the reduced striatal uptake of tracer which is most pronounced in the posterior putamen and tends to be asymmetric. (Courtesy of Dr. Jon Stoessl.)

Atypical and secondary parkinsonism

Atypical parkinsonism refers to a group of neurodegenerative conditions that usually are associated with more widespread neurodegeneration than is found in PD (often involvement of SNc and striatum and/or pallidum). As a group, they present with a parkinsonism (rigidity and bradykinesia) but typically have a slightly different clinical picture than PD, reflecting differences in underlying pathology. Parkinsonism in these conditions is often characterized by early speech and gait impairment, absence of rest tremor, no asymmetry, poor or no response to levodopa, and an aggressive clinical course. In the early stages, they may show some modest benefit from levodopa and be difficult to distinguish from PD. Neuroimaging of the dopamine system is usually not helpful, as several atypical parkinsonisms also have degeneration of dopamine neurons. Pathologically, neurodegeneration occurs without Lewy bodies (see later for individual conditions). Metabolic imaging of the basal ganglia/thalamus network may be helpful, reflecting a pattern of decreased activity in the GPi with increased activity in the thalamus, the reverse of what is seen in PD.

Multiple-system atrophy (MSA) manifests as a combination of parkinsonian, cerebellar, and autonomic features and can be divided into a predominant parkinsonian (MSA-p) or cerebellar (MSA-c) form. Clinically, MSA is suspected when a patient presents with atypical parkinsonism in conjunction with cerebellar signs and/or early and prominent autonomic dysfunction, usually orthostatic hypotension (Chap. 33). Pathologically, MSA is characterized by degeneration of the SNc, striatum, cerebellum, and inferior olivary nuclei coupled with characteristic glial cytoplasmic inclusions (GCIs) that stain for α-synuclein. MRI can show pathologic iron accumulation in the striatum on T2-weighted scans, high signal change in the region of the external surface of the putamen (putaminal rim) in MSA-p, or cerebellar and brainstem atrophy (the pontine “hot cross buns” sign [Fig. 33-2]) in MSA-c.

Progressive supranuclear palsy (PSP) is a form of atypical parkinsonism that is characterized by slow ocular saccades, eyelid apraxia, and restricted eye movements with particular impairment of downward gaze. Patients frequently experience hyperextension of the neck with early gait disturbance and falls. In later stages, speech and swallowing difficulty and dementia become evident. MRI may reveal a characteristic atrophy of the midbrain with relative preservation of the pons (the “hummingbird sign” on midsagittal images). Pathologically, PSP is characterized by degeneration of the SNc and pallidum along with neurofibrillary tangles and GCIs that stain for tau.

Corticobasal ganglionic degeneration is less common and is usually manifest by asymmetric dystonic contractions and clumsiness of one hand coupled with cortical sensory disturbances manifest as apraxia, agnosia, focal myoclonus, or alien limb phenomenon (where the limb assumes a position in space without the patient being aware of it). Dementia may occur at any stage of the disease. MRI frequently shows asymmetric cortical atrophy. Pathologic findings include achromatic neuronal degeneration with tau deposits similar to those found in PSP.

Secondary parkinsonism can be associated with drugs, stroke, tumor, infection, or exposure to toxins such as carbon monoxide or manganese. Dopamine-blocking agents such as the neuroleptics are the commonest cause of secondary parkinsonism. These drugs are most widely used in psychiatry, but physicians should be aware that drugs such as metoclopramide and chlorperazine, which are primarily used to treat gastrointestinal problems, are also neuroleptic agents and common causes of secondary parkinsonism and tardive dyskinesia. Other drugs that can cause secondary parkinsonism include tetrabenazine, amiodarone, and lithium.

Finally, parkinsonism can be seen as a feature of other degenerative disorders such as Wilson’s disease, Huntington’s disease (especially the juvenile form known as Westphal variant), dopa-responsive dystonia, and neurodegenerative disorders with brain iron accumulation such as pantothenate kinase (PANK)–associated neurodegeneration (formerly known as HallervordenSpatz disease).

Some features that suggest parkinsonism might be due to a condition other than PD are shown in Table 30-3.

TABLE 30-3

FEATURES SUGGESTING ALTERNATE DIAGNOSIS THAN PD

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ETIOLOGY AND PATHOGENESIS

Most PD cases occur sporadically (~85–90%) and are of unknown cause. Twin studies suggest that environmental factors likely play the more important role in patients older than 50 years, with genetic factors being more important in younger patients. Epidemiologic studies suggest increased risk with exposure to pesticides, rural living, and drinking well water and reduced risk with cigarette smoking and caffeine. However, no environmental factor has yet been determined to cause PD. The environmental hypothesis received a boost with the demonstration in the 1980s that MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine), a byproduct of the illicit manufacture of a heroin-like drug, caused a PD-like syndrome in addicts in northern California. MPTP is transported to the central nervous system, where it is metabolized to form MPP+, a mitochondrial toxin that is selectively taken up by, and damages, dopamine neurons. However, MPTP or MPTP-like compounds have not been linked to sporadic PD. MPTP has, however, proved useful for generating an animal model of the disease. About 10–15% of cases are familial in origin, and multiple specific mutations and gene associations have been identified (Table 30-4). It has been proposed that most cases of PD are due to a “double hit” involving an interaction between a gene mutation that induces susceptibility coupled with exposure to a toxic environmental factor. In this scenario, both factors are required for PD to ensue, while the presence of either one alone is not sufficient to cause the disease.

TABLE 30-4

GENETIC CAUSES OF PD

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Factors that have been implicated in the pathogenesis of cell death include oxidative stress, intracellular calcium accumulation with excitotoxicity, inflammation, mitochondrial dysfunction, and proteolytic stress. Whatever the pathogenic mechanism, cell death appears to occur, at least in part, by way of a signalmediated apoptotic or “suicidal” process. Each of these mechanisms offer potential targets for neuroprotective drugs. However, it is not clear which of these factors is primary, if the cause is the same in each case, or if one or all merely represent epiphenomena unrelated to the true cause of cell death that remains undiscovered (Fig. 30-4).

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FIGURE 30-4

Schematic representation of how pathogenetic factors implicated in PD interact in a network manner, ultimately leading to cell death. This figure illustrates how interference with any one of these factors may not necessarily stop the cell death cascade. (Adapted from CW Olanow: Movement Disorders 22:S-335, 2007.)

Gene mutations discovered to date have been helpful in pointing to specific pathogenic mechanisms as being central to the neurodegenerative process. The most significant of these mechanisms appear to be protein mis-folding and accumulation and mitochondrial dysfunction. The idea that proteins are involved in the pathogenesis of PD is not surprising, given that PD is characterized by Lewy bodies and Lewy neurites, which are composed of misfolded and aggregated proteins (Fig. 30-1). Protein accumulation could result from either increased formation or impaired clearance of proteins. Mutations in α-synuclein promote misfolding of the protein and the formation of oligomers and aggregates thought to be involved in the cell death process. Importantly, duplication or triplication of the wild-type α-synuclein gene can itself cause PD, indicating that increased production of even the normal protein can cause PD. Increased levels of unwanted proteins could also result from impaired clearance. Proteins are normally cleared by the ubiquitin proteasome system or the autophagy/lysosome pathway. These pathways are defective in patients with sporadic PD, and interestingly α-synuclein is a prominent component of Lewy bodies in these cases. Further, mutations in parkin (a ubiquitin ligase that attaches ubiquitin to misfolded proteins to promote their transport to the proteasome for degradation) and UCH-L1 (which cleaves ubiquitin from misfolded proteins to permit their entry into the proteasome) are causative in other cases of familial PD. Collectively, these findings implicate abnormal protein accumulation in the etiology of PD. Indeed, in laboratory models both overexpression of α-synuclein or impairment of proteasomal clearance mechanisms leads to degeneration of dopamine neurons with inclusion body formation.

Mitochondrial dysfunction has also been implicated in familial PD. Several causative genes (parkinPINK1, and DJ1) either localize to mitochondria and/or cause mitochondrial dysfunction in transgenic animals. Postmortem studies have also shown a defect in complex I of the respiratory chain in the SNc of patients with sporadic PD.

Six different LRRK2 mutations have been linked to PD, with the Gly2019Ser being the commonest. The mechanism responsible for cell death with this mutation is not known but is thought to involve altered kinase activity.

Mutations in the glucocerebrosidase (GBA) gene associated with Gaucher’s disease are also associated with an increased risk of idiopathic PD. Again the mechanism is not precisely known, but it is noteworthy that it is associated with altered autophagy and lysosomal function, suggesting that mutations in this gene might also impair protein clearance leading to PD.

Whole-genome association studies have provided conflicting results. Most recently, linkage to mutations in human leukocyte antigen (HLA) genes were identified in PD patients, suggesting that altered immunity or inflammation may be a causative or contributory factor.

While gene mutations account for only a small percentage of cases of PD, it is hoped that better understanding of the mechanisms whereby they cause cell death will provide insight into the nature of the cell death process in the more common sporadic form of the disease. These mutations could also permit the development of more relevant animal models of PD in which to test putative neuroprotective drugs.

PATHOPHYSIOLOGY OF PD

The classic model of basal ganglia functional organization in the normal and PD states is provided in Fig. 30-5. A series of neuronal loops link the basal ganglia nuclei with corresponding cortical motor regions in a somatotopic manner to help regulate motor function. The striatum is the major input region of the basal ganglia, while the GPi and SNr are the major output regions. The input and output regions are connected via direct and indirect pathways that have reciprocal effects on the output pathway. The output of the basal ganglia provides inhibitory tone to thalamic and brainstem neurons that in turn connect to motor systems in the cerebral cortex and spinal cord to regulate motor function. Dopaminergic projections from SNc neurons serve to modulate neuronal firing and to stabilize the basal ganglia network.

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FIGURE 30-5

Basal ganglia organization. Classic model of the organization of the basal ganglia in the normal, PD, and levodopa-induced dyskinesia state. Inhibitory connections are shown as blue arrows and excitatory connections as red arrows. The striatum is the major input region and receives its major input from the cortex. The GPi and SNr are the major output regions and they project to the thalamocortical and brainstem motor regions. The striatum and GPi/SNr are connected by direct and indirect pathways. This model predicts that parkinsonism results from increased neuronal firing in the STN and GPi and that lesions or DBS of these targets might provide benefit. This concept led to the rationale for surgical therapies for PD. The model also predicts that dyskinesia results from decreased firing of the output regions, resulting in excessive cortical activation by the thalamus. This component of the model is not completely correct as lesions of the GPi ameliorate rather than increase dyskinesia in PD, suggesting that firing frequency is just one of the components that lead to the development of dyskinesia. DBS, deep brain stimulation; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; SNr, substantia nigra, pars reticulata; SNc, substantia nigra, pars compacta; STN, subthalamic nucleus; VL, ventrolateral thalamus; PPN, pedunculopontine nucleus. (Derived from JA Obeso et al: Trends Neurosci 23:S8, 2000.)

In PD, dopamine denervation leads to increased firing of neurons in the STN and GPi, resulting in excessive inhibition of the thalamus, reduced activation of cortical motor systems, and the development of parkinsonian features (Fig. 30-5). The current role of surgery in the treatment of PD is based upon this model, which predicted that lesions or high-frequency stimulation of the STN or GPi might reduce this neuronal overactivity and improve PD features.


TREATMENT Parkinson’s Disease

LEVODOPA Since its introduction in the late 1960s, levodopa has been the mainstay of therapy for PD. Experiments in the late 1950s by Carlsson demonstrated that blocking dopamine uptake with reserpine caused rabbits to become parkinsonian; this could be reversed with the dopamine precursor, levodopa. Subsequently, Hornykiewicz demonstrated a dopamine deficiency in the striatum of PD patients and suggested the potential benefit of dopaminergic replacement therapy. Dopamine does not cross the blood-brain barrier (BBB), so clinical trials were initiated with levodopa, a precursor of dopamine. Studies over the course of the next decade confirmed the value of levodopa and revolutionized the treatment of PD.

Levodopa is routinely administered in combination with a peripheral decarboxylase inhibitor to prevent its peripheral metabolism to dopamine and the development of nausea and vomiting due to activation of dopamine receptors in the area postrema that are not protected by the BBB. In the United States, levodopa is combined with the decarboxylase inhibitor carbidopa (Sinemet), while in many other countries it is combined with benserazide (Madopar). Levodopa is also available in controlled-release formulations as well as in combination with a COMT inhibitor (see later). Levodopa remains the most effective symptomatic treatment for PD and the gold standard against which new therapies are compared. No current medical or surgical treatment provides antiparkinsonian benefits superior to what can be achieved with levodopa. Levodopa benefits the classic motor features of PD, prolongs independence and employability, improves quality of life, and increases life span. Almost all PD patients experience improvement, and failure to respond to an adequate trial should cause the diagnosis to be questioned.

There are, however, important limitations of levodopa therapy. Acute dopaminergic side effects include nausea, vomiting, and orthostatic hypotension. These are usually transient and can generally be avoided by gradual titration. If they persist, they can be treated with additional doses of a peripheral decarboxylase inhibitor (e.g., carbidopa) or a peripheral dopamine-blocking agent such as domperidone (not available in the United States). More important are motor complications (see later) that develop in the majority of patients treated long-term with levodopa therapy. In addition, features such as falling, freezing, autonomic dysfunction, sleep disorders, and dementia may emerge that are not adequately controlled by levodopa. Indeed, these nondopaminergic features are the primary source of disability and main reason for nursing home placement for patients with advanced PD.

Levodopa-induced motor complications consist of fluctuations in motor response and involuntary movements known as dyskinesias (Fig. 30-6). When patients initially take levodopa, benefits are long-lasting (many hours) even though the drug has a relatively short half-life (60–90 min). With continued treatment, however, the duration of benefit following an individual dose becomes progressively shorter until it approaches the half-life of the drug. This loss of benefit is known as the wearing-off effect. At the same time, many patients develop dyskinesias. These tend to occur at the time of maximal clinical benefit and peak plasma concentration (peak-dose dyskinesia). They are usually choreiform in nature but can manifest as dystonia, myoclonus, or other movement disorders. They are not troublesome when mild, but can be disabling when severe and can limit the ability to fully utilize levodopa to control PD features. In more advanced states, patients may cycle between “on” periods complicated by disabling dyskinesias and “off” periods in which they suffer severe parkinsonism. Patients may also experience “diphasic dyskinesias,” which occur as the levodopa dose begins to take effect and again as it wears off. These dyskinesias typically consist of transient, stereotypic, rhythmic movements that predominantly involve the lower extremities and are frequently associated with parkinsonism in other body regions. They can be relieved by increasing the dose of levodopa, although higher doses may induce more severe peak-dose dyskinesia.

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FIGURE 30-6

Changes in motor response associated with chronic levodopa treatment. Levodopa-induced motor complications. Schematic illustration of the gradual shortening of the duration of a beneficial motor response to levodopa (wearing off) and the appearance of dyskinesias complicating “on” time.

The cause of levodopa-induced motor complications is not precisely known. They are more likely to occur in young individuals with severe disease and with higher doses of levodopa. The classic model of the basal ganglia has been useful for understanding the origin of motor features in PD, but has proved less valuable for understanding levodopa-induced dyskinesias (Fig. 30-5). The model predicts that dopamine replacement might excessively inhibit the pallidal output system, thereby leading to increased thalamocortical activity, enhanced stimulation of cortical motor regions, and the development of dyskinesia. However, lesions of the pallidum that completely destroy its output are associated with amelioration rather than induction of dyskinesia as suggested by the classic model. It is now thought that dyskinesia results from levodopa-induced alterations in the GPi neuronal firing pattern (pauses, bursts, synchrony, etc.) and not simply the firing frequency alone. This in turn leads to the transmission of misinformation from pallidum to thalamus/cortex, resulting in dyskinesia. Pallidotomy might thus ameliorate dyskinesia by blocking this abnormal firing pattern and preventing the transfer of misinformation to motor systems.

Current information suggests that altered neuronal firing patterns and motor complications relate to nonphysiologic levodopa replacement. Striatal dopamine levels are normally maintained at a relatively constant level. In the PD state, dopamine neurons degenerate and striatal dopamine is dependent on peripheral availability of levodopa. Intermittent doses of short-acting levodopa do not restore dopamine in a physiologic manner and cause dopamine receptors to be exposed to alternating high and low concentrations of dopamine. This intermittent or pulsatile stimulation of dopamine receptors induces molecular changes in striatal neurons and neurophysiologic changes in pallidal neurons, leading to the development of motor complications. It has been hypothesized that more continuous delivery of levodopa might prevent the development of motor complications. Indeed, continuous levodopa infusion is associated with improvement in both “off” time and dyskinesia in advanced PD patients, but this approach has not yet been proved to prevent dyskinesia in clinical trials.

Behavioral alterations can be encountered in levodopa-treated patients. A dopamine dysregulation syndrome has been described where patients have a craving for levodopa and take frequent and unnecessary doses of the drug in an addictive manner. PD patients taking high doses of levodopa can also have purposeless, stereotyped behaviors such as the meaningless assembly and disassembly or collection and sorting of objects. This is known as punding, a term taken from the Swedish description of the meaningless behaviors seen in chronic amphetamine users. Hypersexuality and other impulse-control disorders are occasionally encountered with levodopa, although these are more commonly seen with dopamine agonists.

DOPAMINE AGONISTS Dopamine agonists are a diverse group of drugs that act directly on dopamine receptors. Unlike levodopa, they do not require metabolism to an active product and do not undergo oxidative metabolism. Initial dopamine agonists were ergot derivatives (e.g., bromocriptine, pergolide, cabergoline) and were associated with ergot-related side effects, including cardiac valvular damage. They have largely been replaced by a second generation of non-ergot dopamine agonists (e.g., pramipexole, ropinirole, rotigotine). In general, dopamine agonists do not have comparable efficacy to levodopa. They were initially introduced as adjuncts to levodopa to enhance motor function and reduce “off” time in fluctuating patients. Subsequently, it was shown that dopamine agonists, possibly because they are relatively long-acting, are less prone than levodopa to induce dyskinesia. For this reason, many physicians initiate therapy with a dopamine agonist, although supplemental levodopa is eventually required in virtually all patients. Both ropinirole and pramipexole are available as orally administered immediate (tid) and extended-release (qd) formulations. Rotigotine is administered as a once-daily transdermal patch. Apomorphine is a dopamine agonist with efficacy comparable to levodopa, but it must be administered parenterally and has a very short half-life and duration of activity (45 min). It is generally administered SC as a rescue agent for the treatment of severe “off” episodes. Apomorphine can also be administered by continuous infusion and has been demonstrated to reduce both “off” time and dyskinesia in advanced patients. However, infusions are cumbersome, and this approach has not been approved in the United States.

Acute side effects of dopamine agonists include nausea, vomiting, and orthostatic hypotension. As with levodopa, these can usually be avoided by slow titration. Hallucinations and cognitive impairment are more common with dopamine agonists than with levodopa. Sedation with sudden unintended episodes of falling asleep while driving a motor vehicle have been reported. Patients should be informed about this potential problem and should not drive when tired. Injections of apomorphine and patch delivery of rotigotine can be complicated by development of skin lesions at sites of administration. Recently, it has become appreciated that dopamine agonists are associated with impulse-control disorders, including pathologic gambling, hypersexuality, and compulsive eating and shopping. The precise cause of these problems, and why they appear to occur more frequently with dopamine agonists than levodopa, remains to be resolved, but reward systems associated with dopamine and alterations in the ventral striatum have been implicated.

MAO-B INHIBITORS Inhibitors of monoamine oxidase type B (MAO-B) block central dopamine metabolism and increase synaptic concentrations of the neurotransmitter. Selegiline and rasagiline are relatively selective suicide inhibitors of the MAO-B enzyme. Clinically, MAO-B inhibitors provide modest antiparkinsonian benefits when used as monotherapy in early disease, and reduced “off” time when used as an adjunct to levodopa in patients with motor fluctuations. MAO-B inhibitors are generally safe and well tolerated. They may increase dyskinesia in levodopa-treated patients but this can usually be controlled by down-titrating the dose of levodopa. Inhibition of the MAO-A isoform prevents metabolism of tyramine in the gut, leading to a potentially fatal hypertensive reaction known as a “cheese effect” as it can be precipitated by foods rich in tyramine such as some cheeses, aged meats, and red wine. Selegiline and rasagiline do not functionally inhibit MAO-A in doses employed in clinical practice and are not associated with a cheese effect. There are theoretical risks of a serotonin reaction in patients receiving concomitant SSRI antidepressants, but these are rarely encountered.

Interest in MAO-B inhibitors has also focused on their potential to have disease-modifying effects. MPTP toxicity can be prevented by coadministration of a MAO-B inhibitor that blocks its conversion to the toxic pyridinium ion MPP+. MAO-B inhibitors also have the potential to block the oxidative metabolism of dopamine and prevent oxidative stress. In addition, both selegiline and rasagiline incorporate a propargyl ring within their molecular structure that provides antiapoptotic effects in laboratory models. The DATATOP study showed that selegiline significantly delayed the time until the emergence of disability, necessitating the introduction of levodopa in untreated PD patients. However, it could not be determined whether this was due to a neuro-protective effect that slowed disease progression or a symptomatic effect that merely masked ongoing neurodegeneration. More recently, the ADAGIO study demonstrated that early treatment with rasagiline 1 mg/d but not 2 mg/d provided benefits that could not be achieved with delayed treatment with the same drug, consistent with a disease-modifying effect; however, the long-term significance of these findings is uncertain.

COMT INHIBITORS When levodopa is administered with a decarboxylase inhibitor, it is primarily metabolized by catechol-O-methyltransferase (COMT). Inhibitors of COMT increase the elimination half-life of levodopa and enhance its brain availability. Combining levodopa with a COMT inhibitor reduces “off” time and prolongs “on” time in fluctuating patients while enhancing motor scores. Two COMT inhibitors have been approved, tolcapone and entacapone. There is also a combination tablet of levodopa, carbidopa, and entacapone (Stalevo).

Side effects of COMT inhibitors are primarily dopaminergic (nausea, vomiting, increased dyskinesia) and can usually be controlled by down-titrating the dose of levodopa by 20–30%. Severe diarrhea has been described with tolcapone, and to a lesser degree with entacapone, and necessitates stopping the medication in 5–10% of individuals. Cases of fatal hepatic toxicity have been reported with tolcapone, and periodic monitoring of liver function is required. This problem has not been encountered with entacapone. Discoloration of urine can be seen with both COMT inhibitors due to accumulation of a metabolite, but it is of no clinical concern.

It has been proposed that initiating levodopa in combination with a COMT inhibitor to enhance its elimination half-life will provide more continuous levodopa delivery and reduce the risk of motor complications. While this result has been demonstrated in parkinsonian monkeys, and continuous infusion reduces “off” time and dyskinesia in advanced patients, no benefit of initiating levodopa with a COMT inhibitor compared to levodopa alone was detected in early PD patients in the STRIDE-PD study, and the main value of COMT inhibitors for now continues to be in patients who experience motor fluctuations.

OTHER MEDICAL THERAPIES Central-acting anticholinergic drugs such as trihexyphenidyl and benztropine were used historically for the treatment for PD, but they lost favor with the introduction of dopaminergic agents. Their major clinical effect is on tremor, although it is not certain that this is superior to what can be obtained with agents such as levodopa and dopamine agonists. Still, they can be helpful in individual patients. Their use is limited particularly in the elderly, due to their propensity to induce a variety of side effects including urinary dysfunction, glaucoma, and particularly cognitive impairment.

Amantadine also has historical importance. Originally introduced as an antiviral agent, it was appreciated to also have antiparkinsonian effects that are now thought to be due to NMDA-receptor antagonism. While some physicians use amantadine in patients with early disease for its mild symptomatic effects, it is most widely used as an antidyskinesia agent in patients with advanced PD. Indeed, it is the only oral agent that has been demonstrated in controlled studies to reduce dyskinesia while improving parkinsonian features, although benefits may be relatively transient. Side effects include livido reticularis, weight gain, and impaired cognitive function. Amantadine should always be discontinued gradually as patients can experience withdrawal symptoms.

A list of the major drugs and available dosage strengths is provided in Table 30-5.

TABLE 30-5

DRUGS COMMONLY USED FOR TREATMENT OF PDa

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NEUROPROTECTION Despite the many therapeutic agents available for the treatment of PD, patients can still experience intolerable disability due to disease progression and the emergence of features such as falling and dementia that are not controlled with dopaminergic therapies. Trials of several promising agents such as rasagiline, selegiline, coenzyme Q10, pramipexole, and ropinirole have had positive results in clinical trials consistent with disease-modifying effects. However, it is not possible to determine if the positive results are due to neuroprotection with slowed disease progression or confounding symptomatic or pharmacologic effects that mask ongoing progression. If it could be determined that a drug slowed disease progression, this would be a major advance in the treatment of PD.

SURGICAL TREATMENT Surgical treatments for PD have been employed for more than a century. Lesions placed in the motor cortex improved tremor, but were associated with motor deficits and this approach was abandoned. Subsequently, it was appreciated that lesions placed into the VIM nucleus of the thalamus reduced contralateral tremor without inducing hemiparesis, but these lesions did not meaningfully help other more disabling features of PD. Lesions placed in the GPi improved rigidity and bradykinesia as well as tremor, particularly if placed in the posteroventral portion of the nucleus. Importantly, pallidotomy was also associated with marked improvement in contralateral dyskinesia. This procedure gained favor with greater understanding of the pathophysiology of PD (see earlier). However, this procedure is not optimal for patients with bilateral disease, as bilateral lesions are associated with side effects such as dysphagia, dysarthria, and impaired cognition.

Most surgical procedures for PD performed today utilize deep brain stimulation (DBS). Here, an electrode is placed into the target area and connected to a stimulator inserted SC over the chest wall. DBS simulates the effects of a lesion without necessitating a brain lesion. The stimulation variables can be adjusted with respect to electrode configuration, voltage, frequency, and pulse duration in order to maximize benefit and minimize adverse side effects. In cases with intolerable side effects, stimulation can be stopped and the system removed. The procedure has the advantage that it does not require making a lesion in the brain and is thus suitable for performing bilateral procedures with relative safety.

DBS for PD primarily targets the STN or the GPi. It provides dramatic results, particularly with respect to “off” time and dyskinesias, but does not improve features that fail to respond to levodopa and does not prevent the development or progression of nondopaminergic features such as freezing, falling, and dementia. The procedure is thus primarily indicated for patients who suffer disability resulting from levodopa-induced motor complications that cannot be satisfactorily controlled with drug manipulation. Side effects can be seen with respect to the surgical procedure (hemorrhage, infarction, infection), the DBS system (infection, lead break, lead displacement, skin ulceration), or stimulation (ocular and speech abnormalities, muscle twitches, paresthesias, depression, and rarely suicide). Recent studies indicate that benefits following DBS of the STN and GPi are comparable, but that GPi stimulation may be associated with a reduced frequency of depression. While not all PD patients are candidates, the procedure is profoundly beneficial for many. Research studies are currently examining additional targets that might benefit gait dysfunction, depression, and cognitive impairment in PD patients.

EXPERIMENTAL SURGICAL THERAPIES FOR PD There has been considerable scientific and public interest in a number of novel therapies as possible treatments for PD. These include cell-based therapies (such as transplantation of fetal nigral dopamine cells or dopamine neurons derived from stem cells), gene therapies, and trophic factors. Transplant strategies are based on implanting dopaminergic cells into the striatum to replace degenerating SNc dopamine neurons. Fetal nigral mesencephalic cells have been demonstrated to survive implantation, reinnervate the striatum in an organotypic manner, and restore motor function in PD models. Several open-label studies reported positive results. However, two double-blind, sham surgery–controlled studies failed to show significant benefit of fetal nigral transplantation in comparison to a sham operation with respect to their primary endpoints. Post hoc analyses showed possible benefits in patients aged <60 years and in those with milder disease. It is now appreciated that grafting of fetal nigral cells is associated with a previously unrecognized form of dyskinesia that persists even after lowering or stopping levodopa. In addition, there is evidence that after many years, transplanted healthy embryonic dopamine neurons from unrelated donors can develop PD pathology, suggesting that they somehow became affected by the disease process. Most importantly, it is not clear how replacing dopamine cells alone will improve nondopaminergic features such as falling and dementia, which are the major sources of disability for patients with advanced disease. These same concerns apply to dopamine neurons derived from stem cells, which have not yet been tested in PD patients, and bear the additional theoretical concern of unanticipated side effects such as tumors. The short-term future for this technology as a treatment for PD, at least in its current state, is therefore not promising.

Gene therapy involves viral vector delivery of the DNA of a therapeutic protein to specific target regions. The DNA of the therapeutic protein can then be incorporated into the genome of host cells and thereby, in principle, provide continuous and long-lasting delivery of the therapeutic molecule. The AAV2 virus has been most often used as the viral vector because it does not promote an inflammatory response, is not incorporated into the host genome, and is associated with long-lasting transgene expression. Studies performed to date in PD have delivered aromatic amino acid decarboxylase with or without tyrosine hydroxylase to the striatum to facilitate dopamine production; glutamic acid decarboxylase to the STN to inhibit overactive neuronal firing in this nucleus; and trophic factors such as GDNF (glialderived neurotrophic factor) and neurturin to the striatum to enhance and protect residual dopamine neurons in the SNc by way of retrograde transmission. Positive results have been reported with open-label studies, but these have not yet been confirmed in double-blind trials. While gene delivery technology has great potential, this approach also carries the risk of possible unanticipated side effects, and current approaches also do not address the nondopaminergic features of the illness.

MANAGEMENT OF THE NONMOTOR AND NONDOPAMINERGIC FEATURES OF PD While most attention has focused on the dopaminergic features of PD, management of the nondopaminergic features of the illness should not be ignored. Some nonmotor features, while not thought to reflect dopaminergic pathology, nonetheless benefit from dopaminergic drugs. For example, problems such as anxiety, panic attacks, depression, sweating, sensory problems, freezing, and constipation all tend to be worse during “off” periods, and they improve with better dopaminergic control of the underlying PD state. Approximately 50% of PD patients suffer depression during the course of the disease that is frequently underdiagnosed and undertreated. Antiparkinsonian agents can help, but antidepressants should not be withheld, particularly for patients with major depression. Serotonin syndromes have been a theoretical concern with the combined use of selective serotonin reuptake inhibitors (SSRIs) and MAO-B inhibitors, but are rarely encountered. Anxiety can be treated with short-acting benzodiazepines.

Psychosis can be a major problem in PD. In contrast to AD, hallucinations are typically visual, formed, and nonthreatening and can limit the use of dopaminergic agents to adequately control PD features. Psychosis in PD often responds to low doses of atypical neuroleptics. Clozapine is the most effective, but it can be associated with agranulocytosis, and regular monitoring is required. For this reason, many physicians start with quetiapine even though it is not as effective as clozapine in controlled trials. Hallucinations in PD patients are often a harbinger of a developing dementia.

Dementia in PD (PDD) is common, affecting as many as 80% of patients. Its frequency increases with aging and, in contrast to AD, primarily affects executive functions and attention, with relative sparing of language, memory, and calculations. PDD is the commonest cause of nursing home placement for PD patients. When dementia precedes, or develops within 1 year after, the onset of motor dysfunction, it is by convention referred to as dementia with Lewy bodies (DLB; Chap. 29). These patients are particularly prone to have hallucinations and diurnal fluctuations. Pathologically, DLB is characterized by Lewy bodies distributed throughout the cerebral cortex (especially the hippocampus and amygdala). It is likely that DLB and PDD represent a PD spectrum rather than separate disease entities. Levodopa and other dopaminergic drugs can aggravate cognitive function in demented patients and should be stopped or reduced to try and provide a compromise between antiparkinsonian benefit and preserved cognitive function. Drugs are usually discontinued in the following sequence: anticholinergics, amantadine, dopamine agonists, COMT inhibitors, and MAO-B inhibitors. Eventually, patients with cognitive impairment should be managed with the lowest dose of standard levodopa that provides meaningful antiparkinsonian effects and does not aggravate mental function. Anticholinesterase agents such as rivastigmine and donepezil reduce the rate of deterioration of measures of cognitive function in controlled studies and can improve attention. Memantine, an antiglutamatergic agent, may also provide benefit for some PDD patients.

Autonomic disturbances are common and frequently require attention. Orthostatic hypotension can be problematic and contribute to falling. Initial treatment should include adding salt to the diet and elevating the head of the bed to prevent overnight sodium natriuresis. Low doses of fludrocortisol (Florinef) or midodrine control most cases. Vasopressin, erythropoietin, and the norepinephrine precursor 3-0-methylDOPS can be used in severe cases. If orthostatic hypotension is prominent in early disease, MSA should be considered. Sexual dysfunction can be helped with sildenafil or tadalafil. Urinary problems, especially in males, should be treated in consultation with a urologist to exclude prostate problems. Anticholinergic agents, such as Ditropan, may be helpful. Constipation can be a very important problem for PD patients. Mild laxatives can be useful, but physicians should first ensure that patients are drinking adequate amounts of fluid and consuming a diet rich in bulk with green leafy vegetables and bran. Agents that promote GI motility can also be helpful.

Sleep disturbances are common in PD patients, with many experiencing fragmented sleep with excess daytime sleepiness. Restless leg syndrome, sleep apnea, and other sleep disorders should be treated as appropriate. REM behavior disorder (RBD) may precede the onset of motor features. This syndrome is composed of violent movements and vocalizations during REM sleep, possibly representing acting out of dreams due to a failure of the normal inhibition of motor movements that typically accompanies REM sleep. Low doses of clonazepam are usually effective in controlling this problem. Consultation with a sleep specialist and polysomnography may be necessary to identify and optimally treat sleep problems.

NONPHARMACOLOGIC THERAPY Gait dysfunction with falling is an important cause of disability in PD. Dopaminergic therapies can help patients whose gait is worse in “off” time, but there are currently no specific therapies available. Canes and walkers may become necessary.

Freezing episodes, where patients freeze in place for seconds to minutes, are another cause of falling. Freezing during “off” periods may respond to dopaminergic therapies, but there are no specific treatments for “on” period freezing. Some patients will respond to sensory cues such as marching in place, singing a song, or stepping over an imaginary line.

Exercise, with a full range of active and passive movements, has been shown to improve and maintain function for PD patients. It is less clear that formal physical therapy is necessary, unless there is a specific indication. It is important for patients to maintain social and intellectual activities to the extent possible. Education, assistance with financial planning, social services, and attention to home safety are important elements of the overall care plan. Information is available through numerous PD foundations and on the web, but should be reviewed with physicians to ensure accuracy. The needs of the caregiver should not be neglected. Caring for a person with PD involves a substantial work effort and there is an increased incidence of depression among caregivers. Support groups for patients and caregivers may be useful.

CURRENT MANAGEMENT OF PD The management of PD should be tailored to the needs of the individual patient, and there is no single treatment approach that is universally accepted. Clearly, if an agent could be demonstrated to have disease-modifying effects, it should be initiated at the time of diagnosis. Indeed, constipation, REM behavior disorder, and anosmia may represent pre-motor features of PD and could permit the initiation of a disease-modifying therapy even prior to onset of the classical motor features of the disease. However, no therapy has yet been proved to be disease-modifying. For now, physicians must use their judgment in deciding whether or not to introduce rasagiline (see earlier) or other drugs for their possible disease-modifying effects.

The next important issue to address is when to initiate symptomatic therapy. Several studies now suggest that it may be best to start therapy at the time of diagnosis in order to preserve beneficial compensatory mechanisms and possibly provide functional benefits even in the early stage of the disease. Levodopa remains the most effective symptomatic therapy for PD, and some recommend starting it immediately using relatively low doses, but many others prefer to delay levodopa treatment, particularly in younger patients, in order to reduce the risk of motor complications. Another approach is to begin with an MAO-B inhibitor and/or a dopamine agonist, and reserve levodopa for later stages when these drugs can no longer provide satisfactory control. In making this decision, the age, degree of disability, and side-effect profile of the drug must all be considered. In patients with more severe disability, the elderly, those with cognitive impairment, or where the diagnosis is uncertain, most physicians would initiate therapy with levodopa. Regardless of initial choice, it is important not to deny patients levodopa when they cannot be adequately controlled with alternative medications.

If motor complications develop, they can initially be treated by manipulating the frequency and dose of levodopa or by combining lower doses of levodopa with a dopamine agonist, a COMT inhibitor, or an MAO-B inhibitor. Amantadine is the only drug that has been demonstrated to treat dyskinesia without worsening parkinsonism, but benefits may be short-lasting and there are important side effects. In severe cases, it is usually necessary to consider a surgical therapy such as DBS if the patient is a suitable candidate, but as described above, these procedures have their own set of complications. There are ongoing efforts aimed at developing a long-acting oral or transdermal formulation of levodopa that mirrors the pharmacokinetic properties of a levodopa infusion. Such a formulation might provide all of the benefits of levodopa without motor complications and avoid the need for polypharmacy and surgical intervention.

A decision tree that considers the various treatment options and decision points for the management of PD is provided in Fig. 30-7.

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FIGURE 30-7

Treatment options for the management of PD. Decision points include:

a. Introduction of a neuroprotective therapy: No drug has been established to have or is currently approved for neuroprotection or disease modification, but there are several agents that have this potential based on laboratory and preliminary clinical studies (e.g., rasagiline 1 mg/d, coenzyme Q10 1200 mg/d, the dopamine agonists ropinirole and pramipexole).

b. When to initiate symptomatic therapy: There is a trend toward initiating therapy at the time of diagnosis or early in the course of the disease because patients may have some disability even at an early stage, and there is the possibility that early treatment may preserve beneficial compensatory mechanisms; however, some experts recommend waiting until there is functional disability before initiating therapy.

c. What therapy to initiate: Many experts favor starting with an MAO-B inhibitor in mildly affected patients because of the potential for a disease-modifying effect; dopamine agonists for younger patients with functionally significant disability to reduce the risk of motor complications; and levodopa for patients with more advanced disease, the elderly, or those with cognitive impairment.

d. Management of motor complications: Motor complications are typically approached with combination therapy to try and reduce dyskinesia and enhance the “on” time. When medical therapies cannot provide satisfactory control, surgical therapies can be considered.

e. Nonpharmacologic approaches: Interventions such as exercise, education, and support should be considered throughout the course of the disease.

Source: Adapted from CW Olanow et al: Neurology 72:S1, 2009.


HYPERKINETIC MOVEMENT DISORDERS

Hyperkinetic movement disorders are characterized by involuntary movements that may occur in isolation or in combination (Table 30-6). The major hyperkinetic movement disorders and the diseases with which they are associated are considered in this section.

TABLE 30-6

HYPERKINETIC MOVEMENT DISORDERS

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TREMOR

CLINICAL FEATURES

Tremor consists of alternating contractions of agonist and antagonist muscles in an oscillating, rhythmic manner. It can be most prominent at rest (rest tremor), on assuming a posture (postural tremor), or on actively reaching for a target (kinetic tremor). Tremor is also assessed based on distribution, frequency, and related neurologic dysfunction.

PD is characterized by a resting tremor, essential tremor (ET) by a postural tremor, and cerebellar disease by an intention or kinetic tremor. Normal individuals can have a physiologic tremor that typically manifests as a mild, high-frequency, postural or action tremor that is usually of no clinical consequence and often is only appreciated with an accelerometer. An enhanced physiologic tremor (EPT) can be seen in up to 10% of the population, often in association with anxiety, fatigue, underlying metabolic disturbance (e.g., hyperthyroidism, electrolyte abnormalities), drugs (e.g., valproate, lithium), or toxins (e.g., alcohol). Treatment is initially directed to the control of any underlying disorder and, if necessary, can often be improved with a β blocker.

ET is the commonest movement disorder, affecting approximately 5–10 million persons in the United States. It can present in childhood, but dramatically increases in prevalence over the age of 70 years. ET is characterized by a high-frequency tremor (up to 11 Hz) that predominantly affects the upper extremities. The tremor is most often manifest as a postural or kinetic tremor. It is typically bilateral and symmetric, but may begin on one side and remain asymmetric. Patients with severe ET can have an intention tremor with overshoot and slowness of movement. Tremor involves the head in ~30% of cases, voice in ~20%, tongue in ~20%, face/jaw in ~10%, and lower limbs in ~10%. The tremor is characteristically improved by alcohol and worsened by stress. Subtle impairment of coordination or tandem walking may be present. Disturbances of hearing, cognition, and even olfaction have been described, but usually the neurologic examination is normal aside from tremor. The major differential is a dystonic tremor (see later) or PD. PD can usually be differentiated from ET based on the presence of brady-kinesia, rigidity, micrographia, and other parkinsonian features. However, the examiner should be aware that PD patients may have a postural tremor and ET patients may develop a rest tremor. These typically begin after a latency of a few seconds (emergent tremor). The examiner must take care to differentiate the effect of tremor on measurement of tone in ET from the cog-wheel rigidity found in PD.

ETIOLOGY AND PATHOPHYSIOLOGY

The etiology and pathophysiology of ET are not known. Approximately 50% of cases have a positive family history with an autosomal dominant pattern of inheritance. Linkage studies have detected loci at chromosomes 3q13 (ETM-1), 2p22-25 (ETM-2), and 6p23 (ETM-3). Recent genomewide studies demonstrate an association with the LINGO1 gene, particularly in patients with young-onset ET, and it is likely that there are many other undiscovered loci. Candidate genes include the dopamine D3 receptor and proteins that map to the cerebellum. The cerebellum and inferior olives have been implicated as possible sites of a “tremor pacemaker” based on the presence of cerebellar signs and increased metabolic activity and blood flow in these regions in some patients. Recent pathologic studies have described cerebellar pathology with a loss of Purkinje’s cells and axonal torpedoes. However, the precise pathologic correlate of ET remains to be defined.

TREATMENT

Many cases are mild and require no treatment other than reassurance. Occasionally, tremor can be severe and interfere with eating, writing, and activities of daily living. This is more likely to occur as the patient ages and is often associated with a reduction in tremor frequency. β Blockers or primidone are the standard drug therapies for ET and help in about 50% of cases. Propranolol (20–80 mg daily, given in divided doses) is usually effective at relatively low doses, but higher doses may be effective in some patients. The drug is contra-indicated in patients with bradycardia or asthma. Hand tremor tends to be most improved, while head tremor is often refractory. Primidone can be helpful, but should be started at low doses (12.5 mg) and gradually increased (125–250 tid) to avoid sedation. Benefits have been reported with gabapentin and topiramate. Botulinum toxin injections may be helpful for limb or voice tremor, but treatment can be associated with secondary muscle weakness. Surgical therapies targeting the VIM nucleus of the thalamus can be very effective for severe and drug-resistant cases.

DYSTONIA

CLINICAL FEATURES

Dystonia is a disorder characterized by sustained or repetitive involuntary muscle contractions frequently associated with twisting or repetitive movements and abnormal postures. Dystonia can range from minor contractions in an individual muscle group to severe and disabling involvement of multiple muscle groups. The frequency is estimated at 300,000 cases in the United States, but is likely much higher as many cases may not be recognized. Dystonia is often brought out by voluntary movements (action dystonia) and can become sustained and extend to involve other body regions. It can be aggravated by stress and fatigue, and attenuated by relaxation and sensory tricks such as touching the affected body part (geste antagoniste). Dystonia can be classified according to age of onset (childhood vs adult), distribution (focal, multifocal, segmental, or generalized), or etiology (primary or secondary).

PRIMARY DYSTONIAS

Several gene mutations are associated with dystonia. Idiopathic torsion dystonia (ITD) or Oppenheim’s dystonia is predominantly a childhood-onset form of dystonia with an autosomal dominant pattern of inheritance that primarily affects Ashkenazi Jewish families. The majority of patients have an age of onset younger than 26 years (mean 14 years). In young-onset patients, dystonia typically begins in the foot or the arm and in 60–70% progresses to involve other limbs as well as the head and neck. In severe cases, patients can suffer disabling postural deformities that compromise mobility. Severity can vary within a family, with some affected relatives having severe disability and others a mild dystonia that may not even be appreciated. Most childhood-onset cases are linked to a mutation in the DYT1 gene located on chromosome 9q34 resulting in a trinucleotide GAG deletion with loss of one of a pair of glutamic acid residues in the protein torsin A. DYT1 mutations are found in 90% of Ashkenazi Jewish patients with ITD and probably relate to a founder effect that occurred about 350 years ago. There is variable penetrance, with only about 30% of gene carriers expressing a clinical phenotype. Why some gene carriers express dystonia and others do not is not known. The function of torsin A is unknown, but it is a member of the AAA+ (ATPase) family that resembles heat-shock proteins and may be related to protein regulation. The precise pathology responsible for dystonia is not known.

Dopa responsive dystonia (DRD) or the Segawa variant (DYT5) is a dominantly inherited form of childhood-onset dystonia due to a mutation in the gene that encodes for GTP cyclohydrolase-I, the rate-limiting enzyme for the synthesis of tetrahydrobiopterin. This mutation leads to a defect in the biochemical synthesis of tyrosine hydroxylase, the rate-limiting enzyme in the formation of dopamine. DRD typically presents in early childhood (1–12 years), and is characterized by foot dystonia that interferes with walking. Patients often experience diurnal fluctuations, with worsening of gait as the day progresses and improvement with sleep. DRD is typified by an excellent and sustained response to small doses of levodopa. Some patients may present with parkinsonian features, but can be differentiated from juvenile PD by normal striatal fluorodopa uptake on positron emission tomography and the absence of levodopa-induced dyskinesias. DRD may occasionally be confused with cerebral palsy because patients appear to have spasticity, increased reflexes, and Babinski responses (which likely reflect a dystonic contraction rather than an upper motor neuron lesion). Any patient suspected of having a childhood-onset dystonia should receive a trial of levodopa to exclude this condition.

Mutations in the THAP1 gene (DYT6) on chromosome 8p21q22 have been identified in Amish families and are the cause of as many as 25% of cases of non-DYT1 young-onset primary torsion dystonia. Patients are more likely to have dystonia beginning in the brachial and cervical muscles, which later can become generalized and associated with speech impairment. Myoclonic dystonia (DYT11) results from a mutation in the epsilon-sarcoglycan gene on chromosome 7q21. It typically manifests as a combination of dystonia and myoclonic jerks, frequently accompanied by psychiatric disturbances.

FOCAL DYSTONIAS

These are the most common forms of dystonia. They typically present in the fourth to sixth decades and affect women more than men. The major types are (1) blepharospasm—dystonic contractions of the eyelids with increased blinking that can interfere with reading, watching TV, and driving. This can sometimes be so severe as to cause functional blindness. (2) Oromandibular dystonia (OMD)—contractions of muscles of the lower face, lips, tongue, and jaw (opening or closing). Meige syndrome is a combination of OMD and blepharospasm that predominantly affects women older than age 60 years. (3) Spasmodic dysphonia—dystonic contractions of the vocal cords during phonation, causing impaired speech. Most cases affect the adductor muscles and cause speech to have a choking or strained quality. Less commonly, the abductors are affected, leading to speech with a breathy or whispering quality. (4) Cervical dystonia—dystonic contractions of neck muscles causing the head to deviate to one side (torticollis), in a forward direction (anterocollis), or in a backward direction (retrocollis). Muscle contractions can be painful, and associated with a secondary cervical radiculopathy. (5) Limb dystonias—These can be present in either arms or legs and are often brought out by task-specific activities such as handwriting (writer’s cramp), playing a musical instrument (musician’s cramp), or putting (the yips). Focal dystonias can extend to involve other body regions (about 30% of cases), and are frequently misdiagnosed as psychiatric or orthopedic in origin. Their cause is not known, but genetic factors, autoimmunity, and trauma have been suggested. Focal dystonias are often associated with a high-frequency tremor that resembles ET. Dystonic tremor can usually be distinguished from ET because it tends to occur in conjunction with the dystonic contraction and disappears when the dystonia is relieved.

SECONDARY DYSTONIAS

These develop as a consequence of drugs or other neurologic disorders. Drug-induced dystonia is most commonly seen with neuroleptic drugs or after chronic levodopa treatment in PD patients. Secondary dystonia can also be observed following discrete lesions in the striatum, pallidum, thalamus, cortex, and brainstem due to infarction, anoxia, trauma, tumor, infection, or toxins such as manganese or carbon monoxide. In these cases, dystonia often assumes a segmental distribution. More rarely, dystonia can develop following peripheral nerve injury and be associated with features of chronic regional pain syndrome.

DYSTONIA PLUS SYNDROMES

Dystonia may occur as a part of neurodegenerative conditions such as HD, PD, Wilson’s disease, CBGD, PSP, the Lubag form of dystonia-parkinsonism (DYT3), and mitochondrial encephalopathies. In contrast to the primary dystonias, dystonia is usually not the dominant neurologic feature in these conditions.

PATHOPHYSIOLOGY OF DYSTONIA

The pathophysiologic basis of dystonia is not known. The phenomenon is characterized by co-contracting synchronous bursts of agonist and antagonist muscle groups. This is associated with a loss of inhibition at multiple levels of the nervous system as well as increased cortical excitability and reorganization. Attention has focused on the basal ganglia as the site of origin of at least some types of dystonia as there are alterations in blood flow and metabolism in basal ganglia structures. Further, ablation or stimulation of the globus pallidus can both induce and ameliorate dystonia. The dopamine system has also been implicated, as dopaminergic therapies can both induce and treat some forms of dystonia.


TREATMENT Dystonia

Treatment of dystonia is for the most part symptomatic except in rare cases where treatment of a primary underlying condition is available. Wilson’s disease should be ruled out in young patients with dystonia. Levodopa should be tried in all cases of childhood-onset dystonia to rule out DRD. High-dose anticholinergics (e.g., trihexyphenidyl 20–120 mg/d) may be beneficial in children, but adults can rarely tolerate high doses because of cognitive impairment with hallucinations. Oral baclofen (20–120 mg) may be helpful, but benefits if present are usually modest and side effects of sedation, weakness, and memory loss can be problematic. Intrathecal infusion of baclofen is more likely to be helpful particularly with leg and trunk dystonia, but benefits are frequently not sustained and complications can be serious and include infection, seizures, and coma. Tetrabenazine (the usual starting dose is 12.5 mg/d and the average treating dose is 25–75 mg/d) may be helpful in some patients, but use may be limited by sedation and the development of parkinsonism. Neuroleptics can improve as well as induce dystonia, but they are typically not recommended because of their potential to induce extrapyramidal side effects, including tardive dystonia. Clonazepam and diazepam are rarely effective.

Botulinum toxin has become the preferred treatment for patients with focal dystonia, particularly where involvement is limited to small muscle groups such as in blepharospasm, torticollis, and spasmodic dysphonia. Botulinum toxin acts by blocking the release of acetylcholine at the neuromuscular junction, leading to muscle weakness and reduced dystonia, but excessive weakness may ensue and can be troublesome particularly if it involves neck and swallowing muscles. Two serotypes of botulinum toxin are available (A and B). Both are effective, and it is not clear that there are advantages of one over the other. No systemic side effects are encountered with the doses typically employed, but benefits are transient and repeat injections are required at 2- to 5-month intervals. Some patients fail to respond after having experienced an initial benefit. This has been attributed to antibody formation, but improper muscle selection, injection technique, and inadequate dose should be excluded.

Surgical therapy is an alternative for patients with severe dystonia who are not responsive to other treatments. Peripheral procedures such as rhizotomy and myotomy were used in the past to treat cervical dystonia, but are now rarely employed. DBS of the pallidum can provide dramatic benefits for patients with primary DYT1 dystonia. This represents a major therapeutic advance as previously there was no consistently effective therapy, especially for these patients who had severe disability. Benefits tend to be obtained with a lower frequency of stimulation and often occur after a relatively long latency (weeks) in comparison to PD. Better results are typically obtained in younger patients. Recent studies suggest that DBS may also be valuable for patients with focal and secondary dystonias, although results are less consistent. Supportive treatments such as physical therapy and education are important and should be a part of the treatment regimen.

Physicians should be aware of dystonic storm, a rare but potentially fatal condition that can occur in response to a stress situation such as surgery in patients with preexisting dystonia. It consists of the acute onset of generalized and persistent dystonic contractions that can involve the vocal cords or laryngeal muscles, leading to airway obstruction. Patients may experience rhabdomyolysis with renal failure. Patients should be managed in an ICU with protection of airway if required. Treatment can be instituted with one or a combination of anticholinergics, diphenhydramine, baclofen, benzodiazepines, and dopamine agonists/antagonists. Spasms may be difficult to control, and anesthesia with muscle paralysis may be required.


CHOREAS

HUNTINGTON’S DISEASE (HD)

HD is a progressive, fatal, highly penetrant autosomal dominant disorder characterized by motor, behavioral, and cognitive dysfunction. The disease is named for George Huntington, a family physician who described cases on Long Island, New York, in the nineteenth century. Onset is typically between the ages of 25 and 45 years (range, 3–70 years) with a prevalence of 2–8 cases per 100,000 and an average age at death of 60 years. It is prevalent in Europe, North and South America, and Australia but is rare in African blacks and Asians. HD is characterized by rapid, nonpatterned, semipurposeful, involuntary choreiform movements. In the early stages, the chorea tends to be focal or segmental, but progresses over time to involve multiple body regions. Dysarthria, gait disturbance, and oculomotor abnormalities are common features. With advancing disease, there may be a reduction in chorea and emergence of dystonia, rigidity, bradykinesia, myoclonus, and spasticity. Functional decline is often predicted by progressive weight loss despite adequate calorie intake. In younger patients (about 10% of cases), HD can present as an akinetic-rigid or parkinsonian syndrome (Westphal variant). HD patients eventually develop behavioral and cognitive disturbances, and the majority progress to dementia. Depression with suicidal tendencies, aggressive behavior, and psychosis can be prominent features. HD patients may also develop non-insulin-dependent diabetes mellitus and neuroendocrine abnormalities, e.g., hypothalamic dysfunction. A clinical diagnosis of HD can be strongly suspected in cases of chorea with a positive family history. The disease predominantly strikes the striatum. Progressive atrophy of the caudate nuclei, which form the lateral margins of the lateral ventricles, can be visualized by MRI (Fig. 30-8). More diffuse cortical atrophy is seen in the middle and late stages of the disease. Supportive studies include reduced metabolic activity in the caudate nucleus and putamen. Genetic testing can be used to confirm the diagnosis and to detect at-risk individuals in the family, but this must be performed with caution and in conjunction with trained counselors, as positive results can worsen depression and generate suicidal reactions. The neuropathology of HD consists of prominent neuronal loss and gliosis in the caudate nucleus and putamen; similar changes are also widespread in the cerebral cortex. Intraneuronal inclusions containing aggregates of ubiquitin and the mutant protein hunting-tin are found in the nuclei of affected neurons.

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FIGURE 30-8

Huntington’s disease. A. Coronal FLAIR MRI shows enlargement of the lateral ventricles reflecting typical atrophy (arrows). B. Axial FLAIR image demonstrates abnormal high signal in the caudate and putamen (arrows).

ETIOLOGY

HD is caused by an increase in the number of polyglutamine (CAG) repeats (>40) in the coding sequence of the huntingtin gene located on the short arm of chromosome 4. The larger the number of repeats, the earlier the disease is manifest. Acceleration of the process tends to occur, particularly in males, with subsequent generations having larger numbers of repeats and earlier age of disease onset, a phenomenon referred to as anticipation. The gene encodes the highly conserved cytoplasmic protein huntingtin, which is widely distributed clean in neurons throughout the CNS, but whose function is not known. Models of HD with striatal pathology can be induced by excitotoxic agents such as kainic acid and 3-nitropoprionic acid, which promote calcium entry into the cell and cytotoxicity. Mitochondrial dysfunction has been demonstrated in the striatum and skeletal muscle of symptomatic and presymptomatic individuals. Fragments of the mutant huntingtin protein can be toxic, possibly by translocating into the nucleus and interfering with transcriptional upregulation of regulatory proteins. Neuronal inclusions found in affected regions in HD may represent a protective mechanism aimed at segregating and facilitating the clearance of these toxic proteins.


TREATMENT Huntington’s Disease

Treatment involves a multidisciplinary approach, with medical, neuropsychiatric, social, and genetic counseling for patients and their families. Dopamine-blocking agents may control the chorea. Tetrabenazine has recently been approved for the treatment of chorea in the United States, but it may cause secondary parkinsonism. Neuroleptics are generally not recommended because of their potential to induce other more troubling movement disorders and because HD chorea tends to be self-limited and is usually not disabling. Depression and anxiety can be greater problems, and patients should be treated with appropriate antidepressant and antianxiety drugs and monitored for mania and suicidal ideations. Psychosis can be treated with atypical neuroleptics such as clozapine (50–600 mg/d), quetiapine (50–600 mg/d), and risperidone (2–8 mg/d). There is no adequate treatment for the cognitive or motor decline. A neuroprotective therapy that slows or stops disease progression is the major unmet medical need in HD. Promitochondrial agents such as ubiqui-none and creatine are being tested as possible disease-modifying therapies. Antiglutamate agents, caspase inhibitors, inhibitors of protein aggregation, neurotrophic factors, and transplantation of fetal striatal cells are areas of active research, but none has as yet been demonstrated to have a disease-modifying effect.


HUNTINGTON’S DISEASE–LIKE 1 (HDL1), HUNTINGTON’S DISEASE–LIKE 2 (HDL2)

HDL1 is a rare inherited disorder due to mutations of the protein located at 20p12. Patients exhibit onset of personality change in the third or fourth decade, followed by chorea, rigidity, myoclonus, ataxia, and epilepsy. HDL2 is an autosomal dominantly inherited disorder manifesting in the third or fourth decade with a variety of movement disorders, including chorea, dystonia, or parkinsonism and dementia. Most patients are of African descent. Acanthocytosis can sometimes be seen in these patients, and they must be differentiated from neuroacanthocytosis. HDL2 is caused by an abnormally expanded CTG/CAG trinucleotide repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.3. The pathology of HDL2 also demonstrates intranuclear inclusions immunoreactive for ubiquitin and expanded polyglutamine repeats. Chorea can be seen in a number of disorders.

OTHER CHOREAS

Sydenham’s chorea (originally called St. Vitus’ dance) is more common in females and is typically seen in childhood (5–15 years). It often develops in association with prior exposure to group A streptococcal infection and is thought to be autoimmune in nature. With the reduction in the incidence of rheumatic fever, the incidence of Sydenham’s chorea has fallen, but it can still be seen in developing countries. It is characterized by the acute onset of choreiform movements, behavioral disturbances, and occasionally other motor dysfunctions. Chorea generally responds to dopamine-blocking agents, valproic acid, and carbamazepine, but is self-limited and treatment is generally restricted to those with severe chorea. Chorea may recur in later life, particularly in association with pregnancy (chorea gravidarum) or treatment with sex hormones.

Chorea-acanthocytosis (neuroacanthocytosis) is a progressive and typically fatal autosomal recessive disorder that is characterized by chorea coupled with red cell abnormalities on peripheral blood smear (acanthocytes). The chorea can be severe and associated with self-mutilating behavior, dystonia, tics, seizures, and a polyneuropathy. Mutations in the VPS13A gene on chromosome 9q21 encoding chorein have been described. A phenotypically similar X-linked form of the disorder has been described in older individuals who have reactivity with Kell blood group antigens (McLeod syndrome). A benign hereditary chorea of childhood (BHC1) due to mutations in the gene for thyroid transcription factor 1 and a late-onset benign senile chorea (BHC2) have also been described. It is important to ensure that patients with these types of choreas do not have HD.

A range of neurodegenerative diseases with brain iron accumulation (NBIA) manifesting with chorea and dystonia have been described including autosomal dominant neuroferritinopathy, autosomal recessive pantothenate-kinase-associated neurodegeneration (PKAN; Hallervorden-Spatz disease), and aceruloplasminemia. These disorders have excess iron accumulation on MRI and a characteristic “eye of the tiger” appearance in the globus pallidus due to iron accumulation.

Chorea may also occur in association with vascular diseases, hypo- and hyperglycemia, and a variety of infections and degenerative disorders. Systemic lupus erythematosus is the most common systemic disorder that causes chorea; the chorea can last for days to years. Choreas can also be seen with hyperthyroidism, autoimmune disorders including Sjögren’s syndrome, infectious disorders including HIV disease, metabolic alterations, polycythemia rubra vera (following open-heart surgery in the pediatric population), and in association with many medications (especially anticonvulsants, cocaine, CNS stimulants, estrogens, lithium). Chorea can also be seen in paraneoplastic syndromes associated with anti-CRMP-5 or anti-Hu antibodies.

Paroxysmal dyskinesias are a group of rare disorders characterized by episodic, brief involuntary movements that can include chorea, dystonia, and ballismus. Paroxysmal kinesigenic dyskinesia (PKD) is a familial childhood-onset disorder in which chorea or chorea-dystonia is precipitated by sudden movement or running. Attacks may affect one side of the body, last seconds to minutes at a time, and recur several times a day. Prognosis is usually good, with spontaneous remission in later life. Low-dose anticonvulsant therapy (e.g., carbamazepine) is usually effective if required. Paroxysmal nonkinesigenic dyskinesia (PNKD) involves attacks of dyskinesia precipitated by alcohol, caffeine, stress, or fatigue. Like PKD, it is familial and childhood in onset and the episodes are often choreic or dystonic, but have longer duration (minutes to hours) and are less frequent (1–3/d).


TREATMENT Paroxysmal Nonkinesigenic Dyskinesia

Diagnosis and treatment of the underlying condition, where possible, are the first priority. Tetrabenazine, neuroleptics, dopamine-blocking agents, propranolol, clonazepam, and baclofen may be helpful. Treatment is not indicated if the condition is mild and self-limited. Most patients with PKND do not benefit from anticonvulsant drugs but some may respond to clonazepam.


HEMIBALLISMUS

Hemiballismus is a violent form of chorea composed of wild, flinging, large-amplitude movements on one side of the body. Proximal limb muscles tend to be predominantly affected. The movements may be so severe as to cause exhaustion, dehydration, local injury, and in extreme cases, death. The most common cause is a partial lesion (infarct or hemorrhage) in the subthalamic nucleus (STN), but rare cases can also be seen with lesions in the putamen. Fortunately, hemiballismus is usually self-limiting and tends to resolve spontaneously after weeks or months. Dopamine-blocking drugs can be helpful but can themselves lead to movement disorders. In extreme cases, pallidotomy can be very effective. Interestingly, surgically induced lesions or DBS of the STN in PD are usually not associated with hemiballismus.

TICS

TOURETTE’S SYNDROME (TS)

TS is a neurobehavioral disorder named after the French neurologist Georges Gilles de la Tourette. It predominantly affects males, and prevalence is estimated to be 0.03–1.6%, but it is likely that many mild cases do not come to medical attention. TS is characterized by multiple motor tics often accompanied by vocalizations (phonic tics). A tic is a brief, rapid, recurrent, and seemingly purposeless stereotyped motor contraction. Motor tics can be simple, with movement only affecting an individual muscle group (e.g., blinking, twitching of the nose, jerking of the neck), or complex, with coordinated involvement of multiple muscle groups (e.g., jumping, sniffing, head banging, and echopraxia [mimicking movements]). Vocal tics can also be simple (e.g., grunting) or complex (e.g., echo-lalia [repeating other people’s words], palilalia [repeating one’s own words], and coprolalia [expression of obscene words]). Patients may also experience sensory tics, composed of unpleasant focal sensations in the face, head, or neck. Patients characteristically can voluntarily suppress tics for short periods of time, but then experience an irresistible urge to express them. Tics vary in intensity and may be absent for days or weeks only to recur, occasionally in a different pattern. Tics tend to present between ages 2 and 15 years (mean 7 years) and often lessen or even disappear in adulthood. Associated behavioral disturbances include anxiety, depression, attention deficit hyperactivity disorder, and obsessive-compulsive disorder. Patients may experience personality disorders, self-destructive behaviors, difficulties in school, and impaired interpersonal relationships. Tics may present in adulthood and can be seen in association with a variety of other disorders, including PD, HD, trauma, dystonia, drugs (e.g., levodopa, neuroleptics), and toxins.

ETIOLOGY AND PATHOPHYSIOLOGY

TS is thought to be a genetic disorder, but no specific gene mutation has been identified. Current evidence supports a complex inheritance pattern, with one or more major genes, multiple loci, low penetrance, and environmental influences. The risk of a family with one affected child having a second is about 25%. The pathophysiology of TS is not known, but alterations in dopamine neurotransmission, opioids, and second-messenger systems have been proposed. Some cases of TS may be the consequence of an autoimmune response to β-hemolytic streptococcal infection (pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection [PANDAS]); however, this remains controversial.


TREATMENT Tourette’s Syndrome

Patients with mild disease often only require education and counseling (for themselves and family members). Drug treatment is indicated when the tics are disabling and interfere with quality of life. Therapy is generally initiated with the α-agonist clonidine, starting at low doses and gradually increasing the dose and frequency until satisfactory control is achieved. Guanfacine (0.5–2 mg/d) is an α-agonist that is preferred by many clinicians because it only requires once-a-day dosing. If these agents are not effective, antipsychotics can be employed. Atypical neuroleptics (risperidone, olanzapine, ziprasidone) are preferred as they are thought to be associated with a reduced risk of extrapyramidal side effects. If they are not effective, low doses of classical neuroleptics such as haloperidol, fluphenazine, or pimozide can be tried. Botulinum toxin injections can be effective in controlling focal tics that involve small muscle groups. Behavioral features, and particularly anxiety and compulsions, can be a disabling feature of TS and should be treated. The potential value of DBS targeting the anterior portion of the internal capsule is currently being explored.


MYOCLONUS

Myoclonus is a brief, rapid (<100 ms) shock-like, jerky movement consisting of single or repetitive muscle discharges. Myoclonic jerks can be focal, multifocal, segmental, or generalized and can occur spontaneously, in association with voluntary movement (action myoclonus) or in response to an external stimulus (reflex or startle myoclonus). Negative myoclonus consists of a twitch due to a brief loss of muscle activity (e.g., asterixis in hepatic failure). Myoclonic jerks differ from tics in that they interfere with normal movement and are not suppressible. They can be seen in association with pathology in cortical, subcortical, or spinal cord regions and associated with hypoxemic damage (especially following cardiac arrest), encephalopathy, and neurodegeneration. Reversible myoclonus can be seen with metabolic disturbances (renal failure, electrolyte imbalance, hypocalcemia), toxins, and many medications. Essential myoclonus is a relatively benign familial condition characterized by multifocal lightning-like movements. Myoclonic jerks can be disabling when they interfere with normal movement. They can also be innocent and are commonly observed in normal people when waking up or falling asleep (hypnogogic jerks).


TREATMENT Myoclonus

Treatment primarily consists of treating the underlying condition or removing an offending agent. Pharmacologic therapy involves one or a combination of GABAergic agents such as valproic acid (800–3000 mg/d), piracetam (8–20 g/d), clonazepam (2–15 mg/d), or prim-idone (500–1000 mg/d). Recent studies suggest that levetiracetam may be particularly effective.


DRUG-INDUCED MOVEMENT DISORDERS

This important group of movement disorders is primarily associated with drugs that block dopamine receptors (neuroleptics) or central dopaminergic transmission. These drugs are primarily used in psychiatry, but it is important to appreciate that drugs used in the treatment of nausea or vomiting (e.g., Compazine) or gastroesophageal disorders (e.g., metoclopramide) are neuroleptic agents. Hyperkinetic movement disorders secondary to neuroleptic drugs can be divided into those that present acutely, subacutely, or after prolonged exposure (tardive syndromes). Dopamine-blocking drugs can also be associated with a reversible parkinsonian syndrome for which anticholinergics are often concomitantly prescribed, but there is concern that this may increase the risk of developing a tardive syndrome.

ACUTE

Dystonia is the most common acute hyperkinetic drug reaction. It is typically generalized in children and focal in adults (e.g., blepharospasm, torticollis, or oromandibular dystonia). The reaction can develop within minutes of exposure, and can be successfully treated in most cases with parenteral administration of anticholinergics (benztropine or diphenhydramine) or benzodiazepines (lorazepam or diazepam). Choreas, stereotypic behaviors, and tics may also be seen, particularly following acute exposure to CNS stimulants such as methylpheni-date, cocaine, or amphetamines.

SUBACUTE

Akathisia is the commonest reaction in this category. It consists of motor restlessness with a need to move that is alleviated by movement. Therapy consists of removing the offending agent. When this is not possible, symptoms may be ameliorated with benzodiazepines, anticholinergics, β blockers, or dopamine agonists.

TARDIVE SYNDROMES

These disorders develop months to years after initiation of neuroleptic treatment. Tardive dyskinesia (TD) is the commonest and is typically composed of choreiform movements involving the mouth, lips, and tongue. In severe cases, the trunk, limbs, and respiratory muscles may also be affected. In approximately one-third of patients, TD remits within 3 months of stopping the drug, and most patients gradually improve over the course of several years. In contrast, abnormal movements may develop after stopping the offending agent. The movements are often mild and more upsetting to the family than to the patient, but they can be severe and disabling, particularly in the context of an underlying psychiatric disorder. Atypical antipsychotics (e.g., clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) are associated with a significantly lower risk of TD in comparison to traditional antipsychotics. Younger patients have a lower risk of developing neuroleptic-induced TD, whereas the elderly, females, and those with underlying organic cerebral dysfunction have been reported to be at greater risk. In addition, chronic use is associated with increased risk, and specifically, the FDA has warned that use of metoclopramide for more than 12 weeks increases the risk of TD. Since TD can be permanent and resistant to treatment, antipsychotics should be used judiciously, atypical neuroleptics should be the preferred agent whenever possible, and the need for their continued use should be regularly monitored.

Treatment primarily consists of stopping the offending agent. If the patient is receiving a traditional anti-psychotic and withdrawal is not possible, replacement with an atypical antipsychotic should be tried. Abrupt cessation of a neuroleptic should be avoided as acute withdrawal can induce worsening. TD can persist after withdrawal of antipsychotics and can be difficult to treat. Benefits may be achieved with valproic acid, anti-cholinergics, or botulinum toxin injections. In refractory cases, catecholamine depleters such as tetrabenazine may be helpful. Tetrabenazine can be associated with dose-dependent sedation and orthostatic hypotension. Other approaches include baclofen (40–80 mg/d), clonazepam (1–8 mg/d), or valproic acid (750–3000 mg/d).

Chronic neuroleptic exposure can also be associated with tardive dystonia with preferential involvement of axial muscles and characteristic rocking movements of the trunk and pelvis. Tardive dystonia frequently persists despite stopping medication and patients are often refractory to medical therapy. Valproic acid, anticholinergics, and botulinum toxin may occasionally be beneficial. Tardive akathisia, tardive Tourette, and tardive tremor syndromes are rare but may also occur after chronic neuroleptic exposure.

Neuroleptic medications can also be associated with a neuroleptic malignant syndrome (NMS). NMS is characterized by muscle rigidity, elevated temperature, altered mental status, hyperthermia, tachycardia, labile blood pressure, renal failure, and markedly elevated creatine kinase levels. Symptoms typically evolve within days or weeks after initiating the drug. NMS can also be precipitated by the abrupt withdrawal of antiparkinsonian medications in PD patients. Treatment involves immediate cessation of the offending antipsychotic drug and the introduction of a dopaminergic agent (e.g., a dopamine agonist or levodopa), dantrolene, or a benzodiazepine. Treatment may need to be undertaken in an intensive care setting and includes supportive measures such as control of body temperature (antipyretics and cooling blankets), hydration, electrolyte replacement, and control of renal function and blood pressure.

Drugs that have serotonin-like activity (tryptophan, MDMA or “ecstasy,” meperidine) or that block serotonin reuptake can induce a rare, but potentially fatal, serotonin syndrome that is characterized by confusion, hyperthermia, tachycardia, and coma as well as rigidity, ataxia, and tremor. Myoclonus is often a prominent feature, in contrast to NMS, which it resembles. Patients can be managed with propranolol, diazepam, diphenhydramine, chlorpromazine, or cyproheptadine as well as supportive measures.

A variety of drugs can also be associated with parkinsonism (see earlier) and hyperkinetic movement disorders. Some examples include phenytoin (chorea, dystonia, tremor, myoclonus), carbamazepine (tics and dystonia), tricyclic antidepressants (dyskinesias, tremor, myoclonus), fluoxetine (myoclonus, chorea, dystonia), oral contraceptives (dyskinesia), β adrenergics (tremor), buspirone (akathisia, dyskinesias, myoclonus), and digoxin, cimetidine, diazoxide, lithium, methadone, and fentanyl (dyskinesias).

RESTLESS LEGS SYNDROME

Restless legs syndrome (RLS) is a neurologic disorder that affects approximately 10% of the adult population (it is rare in Asians) and can cause significant morbidity in some. It was first described in the seventeenth century by an English physician (Thomas Willis), but has only recently been recognized as being a bona fide movement disorder. The four core symptoms required for diagnosis are as follows: an urge to move the legs, usually caused or accompanied by an unpleasant sensation in the legs; symptoms begin or worsen with rest; partial or complete relief by movement; and worsening during the evening or night.

Symptoms most commonly begin in the legs, but can spread to or even begin in the upper limbs. The unpleasant sensation is often described as a creepy-crawly feeling, paresthesia, or burning. In about 80% of patients, RLS is associated with periodic leg movements (PLMs) during sleep and occasionally while awake. These involuntary movements are usually brief, lasting no more than a few seconds, and recur every 5–90 s. The restlessness and PLMs are a major cause of sleep disturbance in patients, leading to poor-quality sleep and daytime sleepiness.

RLS is a heterogeneous condition. Primary RLS is genetic, and several loci have been found with an autosomal dominant pattern of inheritance, although penetrance may be variable. The mean age of onset in genetic forms is 27 years, although pediatric cases are recognized. The severity of symptoms is variable. Secondary RLS may be associated with pregnancy or a range of underlying disorders, including anemia, ferritin deficiency, renal failure, and peripheral neuropathy. The pathogenesis probably involves disordered dopamine function, which may be peripheral or central, in association with an abnormality of iron metabolism. Diagnosis is made on clinical grounds but can be supported by polysomnography and the demonstration of PLMs. The neurologic examination is normal. Secondary RLS should be excluded and ferritin levels, glucose, and renal function should be measured.

Most RLS sufferers have mild symptoms that do not require specific treatment. General measures to improve sleep hygiene and quality should be attempted first. If symptoms remain intrusive, low doses of dopamine agonists, e.g., pramipexole (0.25–0.5 mg) and ropinirole (1–2 mg), are given 1–2 h before bedtime. Levodopa can be effective but is frequently associated with augmentation (spread and worsening of restlessness and its appearance earlier in the day) or rebound (reappearance sometimes with worsening of symptoms at a time compatible with the drug’s short half-life). Other drugs that can be effective include anticonvulsants, analgesics, and even opiates. Management of secondary RLS should be directed to correcting the underlying disorder; for example, iron replacement for anemia. Iron infusion may also be helpful for severe primary RLS but requires expert supervision.

DISORDERS THAT PRESENT WITH PARKINSONISM AND HYPERKINETIC MOVEMENTS

WILSON’S DISEASE

Wilson’s disease (WD) is an autosomal recessive inherited disorder of copper metabolism that may manifest with neurologic, psychiatric, and liver disorders, alone or in combination. It is caused by mutations in the gene encoding a P-type ATPase. The disease was first comprehensively described by the English neurologist Kin-near Wilson at the beginning of the twentieth century, although at around the same time the German physicians Kayser and Fleischer separately noted the characteristic association of corneal pigmentation with hepatic and neurologic features. WD has a worldwide prevalence of approximately 1 in 30,000, with a gene carrier frequency of 1 in 90. About half of WD patients (especially younger patients) manifest with liver abnormalities. The remainder present with neurologic disease (with or without underlying liver abnormalities), and a small proportion have hematologic or psychiatric problems at disease onset.

Neurologic onset usually manifests in the second decade with tremor and rigidity. The tremor is usually in the upper limbs, bilateral, and asymmetric. Tremor can be on intention or occasionally resting and, in advanced disease, can take on a wing-beating characteristic. Other features include parkinsonism with bradykinesia, dystonia (particularly facial grimacing), dysarthria, and dysphagia. More than half of those with neurologic features have a history of psychiatric disturbances, including depression, mood swings, and overt psychosis. Kayser-Fleischer (KF) rings are seen in 80% of those with hepatic presentations and virtually all with neurologic features. KF rings represent the deposition of copper in Descemet’s membrane around the cornea. They consist of a characteristic grayish rim or circle at the limbus of the cornea and are best detected by slit-lamp examination. Neuropathologic examination is characterized by neurodegeneration and astrogliosis, particularly in the basal ganglia.

WD should always be considered in the differential diagnosis of a movement disorder in a child. Low levels of blood copper and ceruloplasmin and high levels of urinary copper may be present, but normal levels do not exclude the diagnosis. CT brain scan usually reveals generalized atrophy in established cases and ~50% have hypointensity in the caudate head, globus pallidum, substantia nigra, and red nucleus. MRI shows symmetric hyperintensity on T2-weighted images in the putamen, caudate, and pallidum. However, correlation of imaging changes with clinical features is not good. It is very rare for WD patients with neurologic features not to have KF rings. Nevertheless, liver biopsy with demonstration of high copper levels remains the gold standard for the diagnosis.

In the absence of treatment, the course is progressive and leads to severe neurologic dysfunction and early death. Treatment is directed at reducing tissue copper levels and maintenance therapy to prevent reaccumulation. There is no clear consensus on treatment and all patients should be managed in a unit with expertise in WD. Penicillamine is frequently used to increase copper excretion, but it may lead to a worsening of symptoms in the initial stages of therapy. Side effects are common and can to some degree be attenuated by coadministration of pyridoxine. Tetrathiomolybdate blocks the absorption of copper and is used instead of penicillamine in many centers. Trientine and zinc are useful drugs for maintenance therapy. Effective treatment can reverse the neurologic features in most patients, particularly when started early. Some patients stabilize and a few may still progress, especially those with hepatocerebral disease. KF rings tend to decrease after 3–6 months and disappear by 2 years. Adherence to maintenance therapy is a major challenge in long-term care.

OTHER DISORDERS

Pantothenate kinase (PANK)-associated neurodegeneration, acanthocytosis, and Huntington’s disease can also present with parkinsonism associated with involuntary movements.

PSYCHOGENIC DISORDERS

Virtually all movement disorders including tremor, tics, dystonia, myoclonus, chorea, ballism, and parkinsonism can be psychogenic in origin. Tremor affecting the upper limbs is the most common psychogenic movement disorder. Psychogenic movements can result from a somatoform or conversion disorder, malingering (e.g., seeking financial gain), or a factitious disorder (e.g., seeking psychological gain). Psychogenic movement disorders are common (estimated 2–3% of patients in a movement disorder clinic), more frequent in women, disabling for the patient and family, and expensive for society (estimated $20 billion annually). Clinical features suggesting a psychogenic movement disorder include an acute onset and a pattern of abnormal movement that is inconsistent with a known movement disorder. Diagnosis is based on the nonorganic quality of the movement, the absence of findings of an organic disease process, and positive features that specifically point to a psychogenic illness such as variability and distractibility. For example, the magnitude of a psychogenic tremor is increased with attention and diminishes or even disappears when the patient is distracted by being asked to perform a different task or is unaware that he or she is being observed. Other positive features suggesting a psychogenic problem include a tremor frequency that is variable or that entrains with the frequency of movement in the contralateral limb, and a positive response to placebo medication. Associated features can include nonanatomic sensory findings, give-way weakness, and astasia-abasia (an odd, gyrating gait; Chap. 13). Comorbid psychiatric problems such as anxiety, depression, and emotional trauma may be present, but are not necessary for the diagnosis of a psychogenic movement disorder to be made. Psychogenic movement disorders can occur as an isolated entity or in association with an underlying organic problem. The diagnosis can often be made based on clinical features alone and unnecessary tests or medications avoided. Underlying psychiatric problems may be present and should be identified and treated, but many patients with psychogenic movement disorders have no obvious psychiatric pathology. Psychotherapy and hypnosis may be of value for patients with conversion reaction, and cognitive behavioral therapy may be helpful for patients with somatoform disorders. Patients with hypochondriasis, factitious disorders, and malingering have a poor prognosis.