Chapter 428: Tremor, Chorea, and Other Movement Disorders

Hyperkinetic movement disorders are characterized by involuntary movements unaccompanied by weakness (Table 428-1). This term is somewhat arbitrary and potentially misleading as hypokinetic disorders such as Parkinson’s disease (PD) are often accompanied by tremor which is a hyperkinetic feature, and hyperkinetic disorders such as dystonia may manifest slow movements because of the severe muscle contractions. Nonetheless, the terms continue to be used because of convention. The major hyperkinetic movement disorders and the diseases with which they are associated are considered in this section.

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), on actively reaching for a target (kinetic tremor), or on carrying out a movement (action tremor). Tremor may also be characterized based on distribution, frequency, amplitude, and related neurologic dysfunction.

PD (Chap. 427) is characterized by a resting tremor, essential tremor (ET) by a tremor that typically occurs while trying to sustain a posture coupled with an action tremor, and cerebellar dysfunction by a kinetic tremor and is usually associated with hypotonia and past pointing. Normal individuals can have a physiologic tremor that typically manifests as a mild, high-frequency (10–12 Hz), postural or action tremor typically affecting the upper extremities. This tremor is usually of no clinical consequence and often is only appreciated with an accelerometer or under stress. An enhanced physiologic tremor (EPT) can be seen in up to 10% of the population, and tends to occur in association with anxiety, fatigue, a metabolic disturbance (e.g., hyperthyroidism, electrolyte abnormalities), drugs (e.g., valproate, lithium), or toxins (e.g., caffeine, smoking, alcohol). Treatment is initially directed at control of any underlying disorder and, if necessary, can often be improved with a beta blocker.

ESSENTIAL TREMOR

ET is the most common movement disorder, affecting ~5% of the population (an estimated 5–10 million persons in the United States or Western Europe). It can present in childhood but dramatically increases in prevalence in those aged >70 years. ET is characterized by a high-frequency tremor (6–10 Hz) that predominantly affects the upper extremities. The tremor is most often manifest as a postural or action tremor and, in severe cases, can interfere with functions such as eating and drinking. 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 suggesting the possibility of a cerebellar origin. Tremor involves the head in ~30% of cases, voice in ~20%, tongue in ~20%, face/jaw in ~10%, and lower limbs in ~10%. Multiple body parts are involved in at least 50% of cases. The tremor is characteristically improved by alcohol and worsened by stress. Subtle impairment of coordination or tandem walking may be present, and disturbances of hearing, cognition, personality, mood, and olfaction have been described, but usually the neurologic examination is normal aside from tremor. The differential diagnosis includes dystonic tremor (see below) or PD. PD can usually be differentiated from ET because the former stops at the onset of a voluntary action and is typically associated with bradykinesia with progressive slowing of sequential movements (sequence effect), rigidity, gait and postural instability, 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, and that these typically begin after a latency of a few seconds (emergent tremor). In contrast to the micrographia of PD, ET patients have relatively large handwriting with evidence of the effect of tremor. The examiner must also differentiate the effect of tremor when assessing tone in ET to distinguish this from the cogwheel 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 possibly linked loci in large ET families, but no independently confirmed causative genes have been identified to date. It is likely, however, that there are undiscovered genes for ET that have escaped detection to date because of the heterogeneity of the syndrome and the high population frequency of ET likely resulting in a large number of phenocopies, (i.e., family members with a similar clinical syndrome, but not carrying the causative mutation). The cerebellum and inferior olives have been implicated as possible sites of a “tremor pacemaker” based on the presence of cerebellar signs in about 10% of ET patients, and increased metabolic activity and blood flow in these regions in some patients. Some pathologic studies have described cerebellar pathology with a loss of Purkinje cells and axonal torpedoes, but these findings are controversial, and the precise pathologic correlate of ET remains to be defined. It is likely that multiple causes of ET will ultimately be identified.

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. Beta blockers and primidone are the standard drug therapies for ET and help in about 50% of cases. Propranolol (20–120 mg daily, given in divided doses) is usually effective at relatively low doses, but higher doses may be needed in some patients. The drug is contraindicated 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 mg tid) to avoid sedation, nausea, and dizziness. Benefits have also been reported with gabapentin and topiramate, but these drugs have not been widely employed. Botulinum toxin injections may be helpful for limb or voice tremor, but treatment can be associated with muscle weakness. Surgical therapies targeting the ventro-intermediate (VIM) nucleus of the thalamus can be very effective for severe and drug-resistant cases. Recently, focal ultrasound (which is a procedure that does not require surgery) has also been shown to be an effective therapy against tremor in ET.

CLINICAL FEATURES

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions of antagonist muscles causing abnormal often repetitive movements and postures. Dystonic movements are typically patterned and twisting and may be associated with a “dystonic tremor”. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia can range from focal minor contractions affecting only an individual muscle group to severe and disabling involvement of multiple muscle groups. The frequency is estimated to be 16 per 100,000 (~50,000 cases in the United States) but is likely to be much higher because many cases are not recognized. Dystonia is often brought out by voluntary movements (action dystonia) and can extend to involve other muscle groups and body regions not required for a given action (overflow). It can be aggravated by stress and fatigue and attenuated by relaxation and sensory tricks such as touching the affected body part (geste antagoniste).

Historically, dystonia has been described as primary or secondary. However, because of a confusing and not always congruent combination of phenotypic and etiologic features, the older terms are no longer recommended. A Movement Disorder Society Task Force charged with redefining dystonia recommends classifying dystonia along two main axes: clinical and etiologic. On clinical grounds, dystonia can be categorized by age of onset (infancy, childhood, adolescence, early and late adulthood), body distribution (focal, segmental, multifocal, and generalized), temporal pattern (static or progressive, action-specific [diurnal and paroxysmal]), and association with additional features. Clinical description along these lines enables formulating specific dystonia syndromes (e.g., early-onset generalized isolated dystonia).

Etiology of dystonia primarily reflects genetic abnormalities, although occasionally there may be other causes such as trauma and stroke. Genetic features used for classification include mode of inheritance or identification of a specific genetic defect. In the past three decades, more than 200 genes have been linked to different, mainly childhood-onset and generalized forms of dystonia. These include forms in which dystonia is the only disease manifestation with the exception of tremor (“isolated dystonia”), forms in which dystonia co-occurs with another movement disorder such as parkinsonism or myoclonus (“combined dystonia”) and disorders in which dystonia is only one of several clinical manifestations and may be a less prominent or even inconsistent feature (“complex dystonia”). Most of the genetic forms belong to the latter phenotypic group, which also represents the most heterogeneous class in terms of clinical expression.

ISOLATED DYSTONIAS

Focal (Multifocal, Segmental) Dystonia

Adult-onset, focal dystonia is by far the most frequent form of isolated dystonia, with women being affected about twice as often as men. Focal dystonia typically presents in the fourth to sixth decade and can be focal, multifocal, or segmental. The major clinical phenotypes are as follows: (1) Cervical dystonia—dystonic contractions of neck muscles causing the head to deviate to one side (laterocollis), twist (torticollis), move in a forward direction (anterocollis), or move in a backward direction (retrocollis). Muscle contractions can be painful and occasionally can be complicated with a secondary cervical radiculopathy. (2) Blepharospasm—dystonic contractions of the eyelids with increased blinking that can interfere with reading, watching television, working on a computer, and driving. This can sometimes be so severe as to cause functional blindness. (3) Oromandibular dystonia (OMD)—contractions of muscles of the lower face, lips, tongue, and jaw (opening or closing). Meige’s syndrome is a combination of OMD and blepharospasm that predominantly affects women aged >60 years. (4) 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. (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 in golf (the yips). The vast majority of patients have dystonia of the neck (cervical dystonia; ~50%) or the eye lid (blepharospasm; ~20%). Focal hand or leg dystonia (~5%), spasmodic dysphonia (~2%), musician’s dystonia (~3%), or OMD (~1%) are much less common. 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 usually not known, but genetic factors, autoimmunity, and trauma have been suggested. Focal dystonias are often associated with a high-frequency tremor that can resemble 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 (e.g., turning the head in the opposite direction of the dystonia).

GENERALIZED DYSTONIA

Generalized dystonia is often hereditary in nature and, unlike focal dystonia, generally has an age of onset in childhood or adolescence. There are currently at least four well established genes for isolated dystonia; TOR1A, THAP1, ANO3, and GNAL. According to the recommendations of the International Parkinson’s Disease and Movement Disorder Society, confirmed monogenic forms are classified according to absence or presence of accompanying clinical features and preceded by a “DYT” prefix, e.g., DYT-TOR1A. These genetic forms are all inherited in an autosomal dominant fashion and found in <5% of dystonia patients. Not all mutation carriers develop generalized dystonia; about 35% remain unaffected despite harboring a pathogenic mutation (reduced penetrance), and rarely they present with dystonia that remains focal or segmental in nature.

Mutations in the TOR1A gene (torsin family 1 member A—formerly known as the DYT1 gene) are the most common cause of early-onset generalized dystonia. The first, and currently the only clearly established mutation, is a 3-base pair deletion in the TOR1A gene. The mutation is frequently found among Ashkenazi Jewish patients due to a founder effect. Mutation carriers usually present with dystonia in an extremity in childhood that later progress to other body parts, but typically spare the face and neck.

THAP1 gene (THAP domain containing, apoptosis associated protein 1) mutations have been linked to adolescent-onset dystonia with mixed phenotype. About 100 different mutations have been reported in THAP1. Mutations typically manifest with dysphonia or writer’s cramp beginning in late childhood or adolescence. Over the course of the disease, dystonia spreads to other body parts with prominent craniocervical involvement.

Mutations in the ANO3 gene (anoctamin 3) were first reported in patients with predominantly craniocervical dystonia with a broad range of ages of onset. While a large number of missense variants can be found in healthy individuals, a pathogenic role of ANO3 mutations has recently been supported by the description of additional families with dystonia and myoclonic jerks.

Mutations in the GNAL gene (guanine nucleotide-binding protein subunit alpha L) are a rare cause of cervical or cranial dystonia with a mean age of onset in the thirties. About 30 different GNAL mutations have been reported in dystonia patients.

In addition to the above, missense mutations in KMT2B (lysine methyltransferase 2B) have recently been identified, and confirmed to be a cause of an early-onset generalized dystonia which may be accompanied by other syndromic features including intellectual disability, microcephaly, psychiatric features, dysmorphia, or skin lesions. The majority of the mutations occurred de novo. KMT2B mutations may account for up to 10% of early-onset generalized dystonia but further validation is warranted and placement into the group of isolated vs complex dystonias is currently under debate.

Combined Dystonia

A number of other well-established genes have been described for combined forms of dystonia in which dystonia occurs in conjunction with a different movement disorder, such as parkinsonism or myoclonus.

Dopa-responsive dystonia (DRD; also known as Segawa syndrome) is caused by mutations in the GCH1 gene (GTP cyclohydrolase-1) that encodes for the rate-limiting enzyme in the biosynthesis of dopamine via the biopterin pathway. It is manifest as a childhood-onset form of dystonia with diurnal fluctuations and is important to recognize as the condition dramatically responds to low doses of levodopa. Parkinsonism can be a major, or even the only finding, and there may be a presynaptic dopaminergic deficit as evidenced by SPECT. To date, more than 100 different mutations have been reported with a penetrance of around 50% which is considerably higher in women compared to men. Recessively inherited (biallelic) mutations in GCH1 result in a much more severe clinical phenotype with developmental delay and infantile onset. Due to the enzymatic defect in the levodopa biosynthesis, there is a lifelong and dramatic response to levodopa therapy. Indeed, all young onset forms of dystonia should be tested with levodopa to exclude the possibility of DRD.

X-linked dystonia-parkinsonism (Lubag) is a combined form of dystonia and parkinsonism that is found exclusively in patients of Filipino origin due to a founder effect and seems to be fully penetrant. Patients usually develop focal (cranial) dystonia first that rapidly generalizes and, after 5–10 years, is gradually replaced by a form of L-dopa-unresponsive parkinsonism. The exact mutation causing X-linked dystonia-parkinsonism (Lubag) is not yet known but several variants in a disease haplotype segregate with the disease and a retrotransposon insertion in the TAF1 (TATA-Box Binding Protein Associated Factor 1) gene has been suggested as the most likely disease cause.

Biallelic mutations in the PRKRA (protein activator of interferon-induced protein kinase EIF2AK2) gene are linked to a dystonia-parkinsonism syndrome and mostly due to the same missense mutation that seems to result from a shared founder. The phenotype includes early-onset generalized dystonia, often with laryngeal dystonia, tongue protrusion, prominent oromandibular involvement, dysphagia, and retrocollis. Parkinsonian features are mild (or even absent) and do not respond to levodopa therapy.

Mutations in the ATP1A3 (ATPase Na⁺/K⁺ transporting subunit alpha 3) gene present with a characteristic, sudden onset usually in adolescence or young adulthood, often triggered by high fever, physical exertion, or emotional stress. Dystonic symptoms frequently show a rostrocaudal gradient with a strong involvement of the bulbar region and are often accompanied by bradykinesia as a parkinsonian feature. In addition, mutations in ATP1A3 have also been linked to a variety of clinical syndromes (pleiotropy) including epileptic or hemiplegic attacks, ataxia, cognitive decline, and other neurological disorders, often with a more severe course and an earlier age at onset.

Myoclonic-dystonia is characterized by action-induced, alcohol-responsive myoclonic jerks predominantly involving the upper body half. Onset is usually in childhood or adolescence. Additionally, many individuals develop psychiatric features such as depression, anxiety-related disorders, and alcohol dependence. The disorder is primarily related to mutations in the SGCE gene (sarcoglycan epsilon) which codes for the ε member of the sarcoglycan family. About 80 different mutations have been reported in SGCE including deletions of the entire gene. The latter type of mutation often also involves loss of adjacent genes leading to additional clinical features such as joint problems. SGCE mutations are incompletely penetrant and only manifest when inherited from the father due to the epigenetic effect of maternal imprinting of SGCE.

A number of additional monogenic causes have been suggested for isolated and combined forms of dystonia but still await independent confirmation. Table 428-2 provides a list of the confirmed Monogenic Forms of Isolated and Combined Dystonias.

COMPLEX DYSTONIAS

In the complex dystonias, dystonia is one part of a syndrome with multiple different disease manifestations. Most frequently, they are hereditary such as Wilson’s disease (WD), Huntington’s disease (HD), Lesh Nyhan syndrome, corticobasal ganglionic disorders, and a variety of other neurologic, neurometabolic, and mitochondrial disorders. Complex dystonias may also develop as a consequence of drugs or toxins (previously referred to as secondary dystonias). Drug-induced dystonia may be acute or chronic, and is most commonly seen with neuroleptic drugs or after chronic levodopa treatment in PD patients. Dystonia can also be observed following discrete lesions in the striatum, and occasionally in the pallidum, thalamus, cortex, and brainstem due to infarction, hemorrhage anoxia, trauma, tumor, infection, or toxins such as manganese or carbon monoxide. In these cases, dystonia often assumes a segmental distribution, but may be generalized when lesions are bilateral or widespread. More rarely, dystonia can develop following peripheral nerve injury and be associated with features of complex regional pain syndrome (Chap. 432). A psychogenic origin is responsible for some cases of dystonia; these typically present with fixed, immobile dystonic postures (see below).

PATHOPHYSIOLOGY OF DYSTONIA

The pathophysiologic basis of dystonia is not completely known. The phenomenon is characterized by co-contracting synchronous bursts of agonist and antagonist muscle groups with recruitment of muscle groups that are not required for a given movement (overflow). Dystonia is characterized by derangement of the basic physiological principle of action-selection, leading to abnormal recruitment of inappropriate muscles for a given action with inadequate inhibition of this undesired motor activity. Physiologically, loss of surround inhibition is observed at multiple levels of the motor system (e.g., cortex, brainstem, spinal cord) accompanied by increased cortical excitability and reorganization. Attention has focused on the basal ganglia as the site of origin of at least some types of dystonia because there are alterations in blood flow and metabolism in these structures. Further, lesions of the basal ganglia (particularly the putamen) can induce dystonia, and surgical ablation or deep brain stimulation (DBS) of specific regions of the globus pallidus may ameliorate dystonia. The dopamine system has also been implicated, because dopaminergic therapies can both induce and treat some forms of dystonia in different circumstances. Interestingly, no specific pathology has been consistently identified in dystonia.

TREATMENT

HUNTINGTON’S DISEASE

HD is a progressive, fatal, highly penetrant autosomal dominant disorder characterized by motor, behavioral, oculomotor, 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 America, South America, and Australia but is rare in African blacks and Asians. HD is characterized by rapid, nonpatterned, semi-purposeful, involuntary choreiform movements, and for this reason was formerly referred to as Huntington’s chorea. However, dysarthria, gait disturbance, oculomotor abnormalities, behavioral disturbance, and cognitive impairment with dementia are also common features, thus the condition is currently referred to as HD. In the early stages, chorea tends to be focal or segmental, but progresses over time to involve multiple body regions. With advancing disease, there tends to be a reduction in chorea and the emergence of dystonia, rigidity, bradykinesia, and myoclonus. Functional decline is often predicted by progressive weight loss despite adequate calorie intake. In younger patients (~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 noninsulin-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, but genetic testing provides the ultimate confirmation of the diagnosis. The disease predominantly affects the striatum but progresses to involve the cerebral cortex and other brain regions. Progressive atrophy of the head of the caudate nucleus, which form the lateral margin of the lateral ventricle, can be visualized by MRI (Fig. 428-1), but the putamen can be equally or even more severely affected. More diffuse cortical atrophy can be seen in the middle and late stages of the disease. Supportive studies include reduced metabolic activity in the caudate nucleus and putamen, and reduced brain metabolites on MR spectroscopy. Genetic testing can be used to confirm the diagnosis and to detect at-risk individuals in the family, but must be performed with caution and in conjunction with trained counselors, because 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 huntingtin are found in the nuclei of affected neurons.

In anticipation of developing neuroprotective therapies, there has been an intensive effort to define the premanifest stage of HD. Subtle motor impairment, cognitive alterations, and imaging changes can be detected in at-risk individuals who later go on to develop the manifest form of the disease. Defining the rate of progression of these features is paramount for future studies of putative disease-modifying therapies designed to slow the rate of disease progression and the development of cumulative disability.

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 and the faster the rate of clinical decline. Intermediate forms of the disease with 36–39 repeats are described in some patients, typically with less severe clinical involvement. 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 in neurons throughout the central nervous system (CNS), but whose function is largely unknown. 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 regulation of 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. There is also interest in the possibility that protein accumulation and aggregation in HD, like Alzheimer’s disease (Chap. 423) and PD (Chap. 427), may be critical to the disease process and reflect a prion-like disorder (Chap. 430). Models of HD with striatal pathology can be induced in transgenic animals that express the mutant gene and by excitotoxic agents such as kainic acid and 3-nitropropionic acid which promote calcium entry into the cell and cytotoxicity.

TREATMENT

A group of rare inherited conditions that can mimic HD, designated HD-like (HDL) disorders, have also been identified. HDL-1, 2, and 4 are autosomal dominant conditions that typically present in adulthood. HDL-1 is due to expansion of an octapeptide repeat in PRNP, the gene encoding the prion protein (Chap. 430). Thus HDL-1 is properly considered a prion disease. Patients exhibit onset of personality change in the third or fourth decade, followed by chorea, rigidity, myoclonus, ataxia, and epilepsy. HDL-2 manifests 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 this condition must be distinguished from neuroacanthocytosis (below). HDL-2 is caused by an abnormally expanded CTG/CAG trinucleotide repeat expansion in the junctophilin-3 (JPH3) gene. The pathology of HDL-2 consists of intranuclear inclusions immunoreactive for ubiquitin and expanded polyglutamine repeats. HDL-4, the most common condition in this group, is caused by expansion of trinucleotide repeats in TBP, the gene that encodes the TATA box-binding protein involved in regulating transcription; this condition is identical to spinocerebellar ataxia (SCA) 17 (Chap. S10), and most patients present primarily with ataxia rather than chorea. Mutations of the C9Orf72 gene associated with amyotrophic lateral sclerosis (Chap. 429) have also been reported in some individuals with an HDL phenotype.

OTHER CHOREAS

Chorea can be seen in a number of additional disorders related to genetic mutations or other disease states.

Among the hereditary forms of childhood-onset chorea, mutations in the ADCY5 (adenylate cyclase 5) gene are an increasingly recognized and probably relatively common cause of childhood-onset chorea, often in combination with dystonia and developmental delay in some cases. Characteristic perioral movements are a hallmark of the disorder.

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 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.

Chorea may also occur in association with a variety of infections and degenerative disorders as well as vascular diseases and hypo- and hyperglycemia. Sydenham’s chorea (originally called St. Vitus’s 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 (Chap. 143) and is thought to be autoimmune in nature. It is characterized by the acute onset of choreiform movements and behavioral disturbances. 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. The 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. Several reports have documented cases of chorea associated with N-methyl-D-aspartate (NMDA) receptor antibody–positive encephalitis (Chap. 90) following herpes simplex virus encephalitis. Systemic lupus erythematosus (Chap. 349) is the most common systemic disorder that is associated with chorea. The chorea can last for days to years. Chorea can also be seen with hyperthyroidism, autoimmune disorders including Sjögren’s syndrome, infectious disorders including HIV disease, metabolic alterations, and polycythemia rubra vera. Chorea has also been described following open-heart surgery in the pediatric population and in association with many medications (especially anticonvulsants, cocaine, CNS stimulants, estrogens, and lithium). Chorea is commonly seen in association with chronic levodopa treatment (Parkinson’s Disease, Chap. 427). Chorea may also be encountered in paraneoplastic syndromes associated with anti-CRMP-5 or anti-Hu antibodies (Chap. 90).

HEMIBALLISMUS

Ballism is a violent form of choreiform movement composed of wild, flinging, large-amplitude movements most frequently affecting proximal limb muscles on one side of the body (hemiballism). The movements may only affect one limb (monoballism) or, more exceptionally, both upper or lower limbs (paraballism). The movements may be so severe as to cause exhaustion, dehydration, local injury, and, in extreme cases, death. Fortunately, dopamine-blocking drugs can be very helpful, and importantly, hemiballismus is usually self-limiting and tends to resolve spontaneously after weeks or months. The most common cause is a partial lesion (infarct or hemorrhage) in the subthalamic nucleus (STN), but in 30–40% of cases the lesion is found in the putamen, thalamus, or parietal cortex. Hemiballismus is also a common feature of the paroxysmal dyskinesias (see below). In extreme cases, pallidotomy or DBS of the GPi can be effective and abolish the involuntary movements. Interestingly, surgically induced lesions and DBS of the STN in PD patients are usually not associated with hemiballismus.

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]). Phonic (or vocal) tics can also be simple (e.g., grunting) or complex (e.g., echolalia [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. These can be mild and of little clinical consequence or severe and disabling to the patient. Tics may present in adulthood and can be seen in association with a variety of disorders, including PD, HD, trauma, dystonia, drugs (e.g., levodopa, neuroleptics), and toxins.

TOURETTE’S SYNDROME (TS)

TS is a neurobehavioral disorder named after the French neurologist Georges Gilles de la Tourette. It predominantly affects males, and the 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). 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, particularly in males. 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.

Etiology and Pathophysiology

TS is thought to be a genetic disorder, but no specific monogenic cause has yet been identified. Current evidence supports a complex inheritance pattern with an important contribution of de-novo, likely gene-disrupting variants. Four likely risk genes with multiple de novo damaging variants in unrelated probands include WWC1, CELSR3, NIPBL, and FN1. 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 entity remains controversial.

TREATMENT

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 myoclonus). Negative myoclonus consists of a brief loss of muscle activity (e.g., asterixis in hepatic failure). Myoclonic jerks can be severe and interfere with normal movement or benign and of no clinical consequence as is commonly observed in normal people when waking up or falling asleep (hypnagogic jerks).

Myoclonic jerks differ from tics in that they are not typically repetitive, can severely interfere with normal voluntary movement, and are not suppressible. They can arise in association with abnormal neuronal discharges in cortical, subcortical, brainstem, or spinal cord regions, particularly in association with hypoxemia (especially following cardiac arrest), encephalopathy, and neurodegeneration. Reversible myoclonus can be seen with metabolic disturbances (renal failure, electrolyte imbalance, hypocalcemia), toxins, and many medications. The combination of action myoclonus (cortical origin) with ataxia and generalized epilepsy is associated with several recognized causes. The most common is myoclonic epilepsy or Unverricht-Lundborg disease (EPM-1) which can have a variable but often progressive course. This is an autosomal recessive disease caused by mutations in the CSBT gene. Other causes are Lafora body epilepsy or progressive myoclonic epilepsy (PME-2) caused by mutations in in the EPM2A gene or the NHLRC1 gene and ceroid lipofuscinosis. In patients with less severe or absent epilepsy, mitochondrial disorders and neurodegenerative disorders affecting the cerebellum (i.e., SCAs) should be considered. Essential myoclonus is a relatively benign familial condition characterized by multifocal, very brief, lightning-like movements that are frequently alcohol-sensitive. Mutations in the epsilon-sarcoglycan gene have been associated with myoclonus seen in association with dystonia (myoclonic-dystonia).

TREATMENT

This important group of movement disorders is primarily associated with drugs that block dopamine receptors (neuroleptics) or central dopaminergic transmission. These drugs are widely used in psychiatry, but it is important to appreciate that drugs used in the treatment of nausea or vomiting (e.g., prochlorperazine [Compazine]) or gastroesophageal disorders (e.g., metoclopramide) are neuroleptic agents and can also cause these disorders. 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 and an underlying subclinical PD syndrome should be considered.

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 OMD). The reaction can develop within minutes of exposure and can be successfully treated in most cases with parenteral administration of anticholinergics (benztropine or diphenhydramine), benzodiazepines (lorazepam, clonazepam, or diazepam), or dopamine agonists. The abrupt onset of severe spasms may occasionally be confused with a seizure; however, there is no loss of consciousness, automatisms, or postictal features typical of epilepsy. The acute onset of chorea, stereotypic behavior, and tics may also be seen, particularly following exposure to CNS stimulants such as methylphenidate, cocaine, or amphetamines.

SUBACUTE

Akathisia is the most common 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, beta blockers, or dopamine agonists.

TARDIVE SYNDROMES

These disorders develop months to years after initiation of the neuroleptic agent. Tardive dyskinesias (TD) are most common, and typically present with choreiform and/or dystonic 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 remit within 3 months of stopping the drug, and most patients gradually improve over the course of several years. However, abnormal movements may also develop or worsen 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 lower risk of causing TD in comparison to traditional antipsychotics. Younger patients have a lower risk of developing neuroleptic-induced TD, whereas elderly, females, and those with underlying organic cerebral dysfunction have been reported to be at greater risk. Chronic use is associated with increased risk, and specifically, the U.S. Food and Drug Administration has warned that use of metoclopramide for more than 12 weeks increases the risk of TD. Because TD can be permanent and resistant to treatment, antipsychotics should be used judiciously, atypical neuroleptics should be the preferred agent when possible, and the need for continued use should be regularly monitored.

Treatment primarily consists of stopping the offending agent. If the patient is receiving a traditional antipsychotic, and withdrawal is not possible, replacement with an atypical antipsychotic should be tried. Abrupt cessation of a neuroleptic should be avoided because acute withdrawal can induce worsening. TD can persist after withdrawal of antipsychotics and can be difficult to treat. Valbenazine (Ingrezza™) is an ester of tetrabenazine that has recently been approved for the treatment of tardive dyskinesia based on results of efficacy in double blind trials, but it is associated with sleepiness and QT prolongation. It acts as a vesicular monoamine transporter type 2 (VMAT-2) inhibitor and blocks storage of dopamine. Deuterated tetrabenazine is also being studied for this indication. Benefits in open label studies have been reported with valproic acid (750–3000 mg/d), anticholinergics, or botulinum toxin injections. Other approaches that have been tried include baclofen (40–80 mg/d) or clonazepam (1–8 mg/d). In some cases, the abnormal movement is refractory to therapy.

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 can be more troublesome than tardive dyskinesia and frequently persists despite stopping medication. Valproic acid, anticholinergics, and botulinum toxin may occasionally be beneficial, but patients are frequently refractory to medical therapy. Tardive akathisia, tardive TS, 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 the acute or subacute onset of 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 dopaminergic 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. In very severe cases, when oral intake is not possible, a patch (delivering rotigotine subcutaneously) or an infusion pump (delivering apomorphine subcutaneously) may be the best approach to provide dopaminergic treatment. Treatment may need to be undertaken in an intensive care setting and include 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 in other respects. 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 and other 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).

Paroxysmal dyskinesias are a group of rare disorders characterized by episodic, brief involuntary movements that can manifest as various types of hyperkinetic movements, including chorea, dystonia, tremor, myoclonus, and ballism. There are three main types: (1) paroxysmal kinesigenic dyskinesia (PKD), where the involuntary movements are triggered by sudden movement, (2) paroxysmal nonkinesigenic dyskinesias (PNKD), where the attacks are not induced by movement, and (3) rare cases of exertion-induced dyskinesia (PED), where attacks are induced by prolonged exercise.

PKD are characterized by brief, self-limited attacks induced by movement onset such as running but also occasionally by unexpected sound or photic stimulation. Attacks may affect one side of the body, last seconds to minutes at a time, and recur several times a day. They usually manifest as a mixed hyperkinetic movement disorder with dystonic posturing of a limb, ballismus, and chorea, which may also become generalized. PKD is most commonly familial with an autosomal dominant pattern of inheritance and mutations in the proline-rich transmembrane protein 2 (PRRT2) gene, but may also occur secondary to various brain disorders such as multiple sclerosis or hyperglycemia. PKD is more frequent in males (4:1), and the onset is typically in the first or second decade of life. About 70% report sensory symptoms such as tingling or numbness of the affected limb preceding the attack by a few milliseconds. The evolution is relatively benign, and there is a trend toward resolution of the attacks over time. Treatment with low-dose anticonvulsant therapy such as carbamazepine or phenytoin is advised when the attacks are frequent and interfere with daily life activities, and is effective in about 80% of patients. Some clinical features of PKD (abrupt and short-lasting attacks preceded by an “aura”), the association with true seizure episodes, and its favorable response to anticonvulsant drugs have led to speculation that it is epileptic in origin, but this has not been established.

PNKD involve attacks of generalized dyskinesias precipitated by alcohol, caffeine, stress, or fatigue. In comparison to PKD, the episodes have a relatively longer duration (minutes to hours) and are less frequent (one to three per day). PNKD is inherited as an autosomal dominant condition with high (~80%) but incomplete penetrance. A missense mutation in the myofibrillogenesis regulator (PNKD) gene has been identified in several families. Recognition of the condition and elimination of the underlying precipitating factors, where possible, are the first priorities. Tetrabenazine, neuroleptics, dopamine-blocking agents, propranolol, clonazepam, and baclofen may be helpful. Treatment may not be required if the condition is mild and self-limited. Most patients with PNKD do not benefit from anticonvulsant drugs, but some may respond to clonazepam or other benzodiazepines.

The SLC2A1 (solute carrier family 2 member 1) gene, previously linked to GLUT1 (glucose transporter of the blood brain barrier) deficiency syndrome, has been identified to also cause paroxysmal PED. The attacks in this disorder are characterized by a combination of chorea, athetosis, and dystonia in excessively exercised body regions with the legs being most frequently affected. A single attack lasts from a few minutes to an hour and occurs after prolonged physical exercise. In addition to the movement disorder, several patients have other disease manifestations such as epilepsy, hemolytic anemia, and migraine. A ketogenic diet is an effective therapeutic option.

RLS is a neurologic disorder that affects ~10% of the adult population (it is rare in Asians) and can cause significant morbidity in some individuals. It was first described in the seventeenth century by the 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 that 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.

Primary RLS has a strong genetic component, and several loci have been associated with an autosomal dominant pattern of inheritance, although penetrance may be variable and no specifically causative gene has been identified to date. The mean age of onset in familial 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, possibly 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 causes of 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), ropinirole (1–2 mg), or patch rotigotine (2–3 mg), taken 1–2 h before bedtime are generally effective. Levodopa may also be effective but is more likely to be 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 related to the drug’s short half-life). Augmentation can also be seen with dopamine agonists, particularly if higher doses are employed. Other drugs that can be effective include anticonvulsants, analgesics, and opiates. Management of secondary RLS should be directed to correcting the underlying disorder; for example, iron replacement for anemia.

WILSON’S DISEASE

WD is an autosomal recessive inherited disorder of copper metabolism that manifests with neurologic, psychiatric, and liver disorders, alone or in combination. It is caused by mutations in the ATP7B gene encoding a P-type ATPase. The disease was first described by the English neurologist Kinnier 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 ~1 in 30,000, with a mutation 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, rigidity, and dystonia. The tremor is usually in the upper limbs, bilateral, and asymmetric. Tremor can be on intention or occasionally at rest and, in advanced disease, can take on a wing-beating characteristic (a flapping movement when the arms are held outstretched with the fingers opposed). Other features can 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 virtually in all patients with neurologic features and 80% of those with hepatic presentations. 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 in the basal ganglia, particularly in the striatum.

WD should always be considered in the differential diagnosis of a movement disorder in the first decades of life. Low levels of blood copper and ceruloplasmin and high levels of urinary copper may be present, but normal levels do not exclude the diagnosis. Brain imaging usually reveals generalized brain atrophy in established cases, and ~50% have signal hypointensity in the caudate head, putamen, globus pallidus, substantia nigra, and red nucleus on T2-weighted MRI scans. However, correlation of imaging changes with clinical features is not good. Liver biopsy with demonstration of high copper levels and genetic testing remain the gold standard for the diagnosis.

In the absence of treatment, the course is progressive and leads to severe neurologic dysfunction and early death in the majority of patients, although a small proportion experience a relatively benign course. Treatment is directed at reducing tissue copper levels and maintenance therapy to prevent reaccumulation. There is no clear consensus on optimal treatment, and patients should be managed in a unit with expertise in WD. Penicillamine is frequently used to increase copper excretion, but 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 can be used instead of penicillamine. Trientine and zinc are useful drugs for maintenance therapy. Effective treatment can reverse the neurologic features in most patients, particularly when started early. However, some patients 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. Patients with advanced hepatic disease may require a liver transplant, and research is looking into the potential role of organ-specific chelators.

NEURODEGENERATION WITH BRAIN IRON ACCUMULATION (NBIA)

NBIA represents a group of inherited disorders characterized by iron accumulation in the basal ganglia. Clinically, they can manifest as a progressive neurologic disorder with a variety of clinical features including parkinsonism, dystonia, neuropsychiatric abnormalities, and retinal degeneration. Cognitive disorders and cerebellar dysfunction may also be seen. Presentation is usually in childhood, but adult cases have been described. Multiple genes have been identified to date. Pantothenate kinase–associated neurodegeneration (PKAN) formerly known as Hallervorden-Spatz disease is caused by a mutation in the PANK2 gene, and is the most common form of NBIA accounting for about 50% of cases. Onset is usually in early childhood and is manifest as a combination of dystonia, parkinsonism, and spasticity. MRI shows a characteristic low signal abnormality in the center of the globus pallidus on T2-weighted scans caused by iron accumulation known as the “eye of the tiger” sign. Numerous other gene mutations have been described associated with iron accumulation including mutations in PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17. Iron chelation with the compound deferiprone reduces brain iron accumulation and may slow progression of the disease. One must be cautious, however, not to assume that all cases with iron accumulation in the basal ganglia represent an NBIA, because iron accumulation in specific basal ganglia regions is normal, and excess iron accumulation may occur in the basal ganglia region as a consequence of neurodegeneration associated with multiple causes unrelated to a defect in iron metabolism.

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 relatively common (estimated to be 2–3% of patients seen in a movement disorder clinic), more frequent in women, disabling for the patient and family, and expensive for society. Clinical features suggesting a psychogenic movement disorder include an acute onset with 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. This is the opposite of an organic tremor where the magnitude is increased with distraction and tends to be reduced when observed. Other positive features suggesting a psychogenic problem include a tremor frequency that is variable or that entrains with the frequency of a designated movement in the contralateral limb, or a response to placebo interventions. Associated features can include nonanatomic sensory findings, give-way weakness, astasia-abasia (an odd, gyrating gait or posture); (Chap. 23), and multiple somatic complaints with no underlying pathology (somatoform disorder). 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 can be 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.

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