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Movement Disorders Caused by Medical Disease Brandon Barton, M.D.,1 S. Elizabeth Zauber, M.D.,1 and Christopher G. Goetz, M.D.1 ABSTRACT Movement disorders often occur in the context of medical illness, whether as the presenting sign of the illness, as a related feature of the underlying disease process, or as a complication of treatment. Early recognition of an underlying medical cause for movement disorders is essential because the treatment and prognosis differ significantly depending on the underlying pathophysiology. Parkinsonism, nonparkinsonian tremor, dystonia, and chorea have a wide variety of etiologies, requiring a careful medical history in the evaluation of new-onset movement disorders. The spectrum of medical diseases associated with these four syndromes is reviewed in this article. KEYWORDS: Systemic disease, parkinsonism, dystonia, chorea, tremor M ovement disorders occur in a variety of medical illnesses and can be a complication of medications used to treat medical illnesses. In some cases, the movement disorder can be the presenting sign of a general medical condition, and accurate recognition of the movements is helpful in establishing the medical diagnosis. In other cases, the general medical diagnosis will suggest the risk for either a single type of disorder or a mixed form of several movement disorders, so that the clinician can be vigilant to look for their appearance. Drug-related movement disorders are especially important to recognize because often the disorder will clear completely with medication adjustment. Of the many movement disorders, the four prototypic conditions are parkinsonism, nonparkinsonian tremor, dystonia, and chorea. An understanding of the common systemic diseases associated with these disorders and the common drugs used in internal medicine that can precipitate these four syndromes will facilitate rapid diagnosis and intervention strategies. PARKINSONISM The term parkinsonism describes a clinical syndrome with the cardinal motor features of rest tremor, rigidity, bradykinesia, and postural instability. Parkinsonism occurs due to disruption of the structure, physiology, or neurochemical function of the dopaminergic pathway traveling from the substantia nigra to the subcortical nuclei, including the putamen and caudate nucleus (striatum), thalami, and cortical circuits. This primary cell system can be influenced by involvement of the brainstem or other basal ganglia nuclei. Although the most common cause of parkinsonism is Parkinson’s disease, a wide range of medical conditions and treatments may be associated with parkinsonian signs. Given that these secondary causes of parkinsonism may involve a different prognosis or treatment than Parkinson’s disease, an individual patient presenting with parkinsonism requires a thorough medical history. In general, presentations of parkinsonism with rapid or subacute onset, mild or absent rest tremor, symmetric akinesia and rigidity, and early-onset gait disorder 1 The Neurological Complications of Medical Disease; Guest Editor, Steven L. Lewis, M.D. Semin Neurol 2009;29:97–110. Copyright # 2009 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-0029-1213731. ISSN 0271-8235. Department of Neurological Sciences, Movement Disorders Section, Rush University Medical Center, Chicago, Illinois. Address for correspondence and reprint requests: Christopher G. Goetz, M.D., Department of Neurological Sciences, Movement Disorders Section, Rush University Medical Center, 1725 West Harrison Street, Suite 755, Chicago, IL 60612 (e-mail: [email protected]). 97 98 SEMINARS IN NEUROLOGY/VOLUME 29, NUMBER 2 2009 with postural instability suggest secondary causes of parkinsonism. hyperkinetic movements including chorea, tremor, and dystonia.10 IRON METABOLISM Disorders of Metabolism Many kinds of metabolic disorders may cause parkinsonism. THYROID DISEASE Hypothyroidism shares many features in common with parkinsonism—including rigidity, fatigue, masked facial expression, constipation, depression, and slowed movements, speech, and gait—but can be distinguished from Parkinson’s disease by other medical features and diagnostic studies of endocrine dysfunction. The development of hypothyroidism in the setting of Parkinson’s disease may be mistaken for worsening parkinsonism, but the symptoms can improve with thyroid hormone replacement.1 Conversely, hyperthyroidism may mimic the weight loss or increased sweating seen with Parkinson’s disease or may exaggerate parkinsonian tremor, and improvement occurs with antithyroid treatment.2 RENAL FAILURE Parkinsonism has been reported in patients with uremia due to end-stage renal disease, particularly in patients with concomitant diabetes.3 Typical features include acute or subacute onset of parkinsonian symptoms and additional clinical features of altered consciousness, myoclonus, dysarthria, and ataxia. Neuroimaging findings include bilateral, symmetric, and reversible basal ganglia lesions with evidence of vasogenic edema.4 CALCIUM DISORDERS Disorders of calcium metabolism may occur in association with parkinsonism. Hypoparathyroidism has been reported to cause parkinsonism both in the presence and absence of basal ganglia calcifications. It may occur as a late complication after thyroidectomy5 and may be responsive to levodopa in some cases.6 Pseudohypoparathyroidism, characterized by end-organ resistance to normal endogenous parathyroid hormone, may be associated with parkinsonism in up to 4 to 12% of patients, either with or without evidence of basal ganglia calcifications,7 and may respond partly to normalization of serum calcium.8 Hyperparathyroidism due to parathyroid adenomas can rarely cause parkinsonism, which is reversible after surgical removal of the tumor.9 Bilateral subcortical calcification involving the basal ganglia and cerebellum, often labeled as Fahr’s disease, represents a heterogeneous collection of disorders that are not associated with a known disorder of calcium metabolism. Movement disorders in Fahr’s disease most commonly present as parkinsonism (55%), often in association with dementia, cerebellar signs, or other Hereditary hemochromatosis is an autosomal-recessive disorder characterized by abnormal iron accumulation in several organs, including the heart, liver, pituitary gland, and pancreas. Concurrent movement disorders in patients with hereditary hemochromatosis have rarely been reported, including eight cases of parkinsonism,11 as well as other movement disorders such as dystonia and tremor. There is debate, however, as to whether hereditary hemochromatosis is a cause of movement disorders or whether the association is only coincidental.12 LIVER FAILURE Non-Wilsonian liver disease may be associated with parkinsonian syndromes. Acquired hepatocerebral degeneration is a syndrome of neuropsychiatric and motor abnormalities associated with chronic liver failure. Multiple clinical phenotypes have been described, including isolated parkinsonism, cognitive impairment with psychiatric features, and gait ataxia associated with cognitive impairment and other motor signs, such as tremor and dystonia. Magnetic resonance imaging (MRI) demonstrates T1 basal ganglia hyperintensities, which are believed to correlate with brain manganese deposition (Fig. 1).13 A prospective evaluation of 51 liver transplant candidates documented 11 patients with parkinsonism who had postural tremor, lack of rest tremor, rapid progression, symmetric bradykinesia and rigidity, and early gait and postural impairment. These patients had T1 hyperintensities in the substantia nigra and globus pallidus, elevated serum and cerebrospinal fluid manganese levels, and variable response to levodopa therapy.14 Although ideal treatment of this disorder is unclear, the parkinsonism has been reported to improve after liver transplantation.15 ELECTROLYTE DISTURBANCE Extrapontine and central pontine myelinolysis syndromes can occur in the setting of chronic alcohol use, liver disease, rapid correction of sodium electrolyte imbalance, or malnutrition. Rarely, these syndromes may be associated with a subacute course of parkinsonism, often with neuropsychiatric symptoms and dystonia, which may respond to levodopa treatment.16 MITOCHONDRIAL DISEASE Parkinsonism may be observed in up to 12% of adult patients with respiratory chain disorders associated with mitochondrial dysfunction, including Leber hereditary optic neuropathy. Additional features usually include myopathy, polyneuropathy, progressive external ophthalmoplegia, and premature menopause. In this context, MOVEMENT DISORDERS CAUSED BY MEDICAL DISEASE/BARTON ET AL Figure 1 T1-weighted magnetic resonance imaging of the brain in a patient with chronic liver disease (cirrhosis) and parkinsonism. Bilateral, symmetric hyperintensities of the globus pallidus are demonstrated on sagittal (A) and axial (B) images. Hyperintensity of the substantia nigra and hypothalamus are also noted (C). levodopa may improve parkinsonism and cause druginduced dyskinesias.17 INBORN ERRORS OF METABOLISM Gaucher’s disease is caused by an autosomal recessively inherited deficiency of glucocerebrosidase (GBA) secondary to a mutation in the GBA gene, leading to accumulation of intracellular glucosylceramide. The disease manifests itself in a wide range of organ systems, with signs of hepatosplenomegaly, osteopenia, anemia, cardiopulmonary disease, or neurodegenerative syndromes. Neurological signs include ataxia, pyramidal signs, myoclonic epilepsy, or supranuclear ophthalmoplegia. A syndrome resembling Parkinson’s disease occurs in patients with Gaucher’s disease or carriers of GBA mutations, with relatively mild Gaucher’s symp- toms. Unlike typical Parkinson’s disease, these patients have an earlier onset and more aggressive disease course, with more prominent cognitive decline and less responsiveness to anti-Parkinson’s medications, although classic levodopa response has been described.18 Mutations in the GBA gene have been shown to increase the risk for developing Parkinson’s disease up to 13-fold compared with controls.19 Phenylketonuria, an autosomal-recessive disorder caused by deficiency of enzymatic conversion of phenylalanine to tyrosine, may result in severe neurological disability with seizures, mental retardation, and microcephaly unless treated by a strict diet in early infancy. Parkinsonism may occur in adult phenylketonuria patients after relaxation of dietary restrictions, and can be responsive to reinstitution of dietary therapy and levodopa.20 99 100 SEMINARS IN NEUROLOGY/VOLUME 29, NUMBER 2 2009 Infectious Disease Multiple types of movement disorders, including parkinsonism, may occur as a consequence of central nervous system infections, either as an acute or chronic manifestation.21 Infectious diseases with parkinsonism as their most frequent manifestation include Japanese encephalitis, encephalitis lethargica, influenza A encephalitis (as a long-term complication), and neurocysticercosis; the last disease is related to both focal basal ganglia lesions and secondary hydrocephalus. Other infections associated with parkinsonism include other forms of viral encephalitis (arbovirus, enterovirus, varicella-zoster virus, measles virus/subacute sclerosing panencephalitis), Mycobacterium tuberculosis meningitis or tuberculomas, Mycoplasma pneumoniae, Salmonella typhi, Plasmodium falciparum, prion disease, and African trypanosomiasis. As a special case, a variety of movement disorders may occur in the context of infection with HIV through several proposed mechanisms, including drug-induced parkinsonism, focal lesions of the basal ganglia from opportunistic infections or other secondary etiologies, or pathological changes related to HIV-associated dementia (HAD). In comparison with Parkinson’s disease, parkinsonism with HAD presents with more symmetric symptoms, less frequent occurrence of rest tremor, and earlier presentation of postural instability and gait disorders. Parkinsonism is a common feature of HAD, supported by documented pathological and radiological abnormalities of the basal ganglia in patients with this disorder.22 Parkinsonism may, although rarely, be the presenting feature of HIV infection and can respond to therapy with levodopa and highly active antiretroviral therapy (HAART).23 In addition, HIVinfected patients are more susceptible to the extrapyramidal side effects of dopamine receptor-blocking medications than HIV-negative patients, and drug interactions between HIV medications and other classes of medications may also predispose these patients to parkinsonism.22 Autoimmune Disease SJÖGREN’S SYNDROME Sjögren’s syndrome is an autoimmune disorder associated with exocrine gland dysfunction, with symptoms of dry eyes or dry mouth and evidence of lymphocytic infiltration of the salivary and lacrimal glands. Sjögren’s syndrome can be associated with a wide variety of central and peripheral neurological symptoms. Parkinsonism has been reported in eight patients with Sjögren’s syndrome, some with abnormal white matter lesions on neuroimaging, all lacking significant response to levodopa, and with variable improvement with immunosuppressive therapy.24 SYSTEMIC LUPUS ERYTHEMATOSUS Systemic lupus erythematosus is associated with neuropsychiatric symptoms, which occur in 30 to 60% of patients. Movement disorders are rarely reported, and chorea is seen more often than parkinsonism or myoclonus.25 Recent literature reviews and case reports identify 29 cases of systemic lupus erythematosusassociated parkinsonism,26 10 with juvenile onset.27 Most cases were young women under 30 years of age. Rigidity and akinesia were more common signs than tremor, and one third of the cases had hyperreflexia and Babinski signs. Additional associated features included mutism, anorexia, seizures, psychiatric symptoms, and altered consciousness, suggesting more widespread brain involvement. All patients who were treated with immunomodulatory therapy and/or antiparkinsonian medications improved. The mechanisms of extrapyramidal symptoms in systemic lupus erythematosus are unclear, with possible direct or indirect contributions from the disease: only a minority of patients had focal basal ganglia lesions on neuroimaging, one case demonstrated serum antidopaminergic antibodies,28 and neuroimaging in one case noted basal ganglia hyperperfusion.29 ANTIPHOSPHOLIPID ANTIBODY SYNDROME Antiphospholipid antibody syndrome is rarely associated with parkinsonism, with a probable main mechanism of thrombo-occlusive vasculopathy, and is associated with periventricular white matter changes on MRI, cerebral infarctions, and poor response to levodopa treatment.30 NEURO-BECHET’S DISEASE Behçet’s disease may cause parkinsonism in the setting of oral ulcerations, recurrent monoarthritis, and skin papules and pustules, with abnormal MRI findings in the basal ganglia.31 NONVASCULITIC AUTOIMMUNE INFLAMMATORY MENINGOENCEPHALITIS Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM) is a syndrome involving encephalopathy, evidence of inflammatory disease on tissue biopsy, and responsiveness to steroids. It may present in a similar manner to prion disease, with rapidly progressive parkinsonism, dementia, and myoclonus associated with periodic sharp wave complexes on electroencephalogram (EEG), but responds dramatically to high-dose corticosteroids.32 Paraneoplastic Paraneoplastic parkinsonism is rare. Two cases were associated with breast cancer, one described as a syndrome of parkinsonism and painful dystonia, with progression to death 5 months after onset. On autopsy, there was MOVEMENT DISORDERS CAUSED BY MEDICAL DISEASE/BARTON ET AL degeneration of the substantia nigra without Lewy bodies or inflammation.33 Another case described a patient with multiple myeloma and rapidly progressive parkinsonism with incontinence, impotence, and levodopa-induced moaning. Pathological findings included loss of pigmented neurons from the substantia nigra without Lewy bodies. In addition, there are two reports of progressive supranuclear palsy-like syndromes in association with B-cell lymphoma and bronchial carcinoma.34 No immunological markers had been discovered for the above cases. More recent reports have documented associations with specific antibodies. The collapsin response-mediator protein (CRMP)-5 antibody has been reported with a few cases of parkinsonism,35 and antineuronal nuclear antibody type 2/Anti-Ri has been reported with two cases of parkinsonism and breast cancer.36 Anti-Ma2associated encephalitis has been associated with atypical parkinsonism in three patients, with a syndrome of severe hypokinesia and rigidity associated with dystonia, hyperreflexia, excessive sleepiness, hypophonia, and poor verbal output.37 Parkinsonism was reported in 11% of a series of 72 patients with voltage-gated potassium channel autoimmunity, in addition to tremor (7%) and chorea (3%).38 Toxins Exposure to a variety of exogenous environmental toxins may play a role in the development of parkinsonism, and may be risk factors for Parkinson’s disease based on current models of the molecular pathogenesis of the disease.39 Reported agents include organophosphates, methanol, cyanide, mercury, carbon disulphide, aliphatic hydrocarbons, manganese, and addictive drugs (MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]), heroin pyrolysate, inhaled solvents such as toluene, and ecstasy).40 Exposure history, improvement after removal from the putative toxic environmental source, and, in some cases, biochemical assays may help solidify the diagnosis. drugs are not effective, but spontaneous recovery occurs in the majority of patients after 6 months. TOTAL PARENTERAL NUTRITION Patients on long-term total parenteral nutrition (TPN) may have high-signal abnormalities in the basal ganglia, but the relationship of these imaging abnormalities, presumably due to manganese deposition, to neurological symptoms is unclear, because they may occur in asymptomatic patients.43 Drugs A variety of drugs commonly used in the treatment of medical disease may cause drug-induced parkinsonism, and may account for up to 20% of cases of parkinsonism in a community setting.44 In contrast to Parkinson’s disease, women are affected more commonly than men. DOPAMINE RECEPTOR-BLOCKING MEDICATIONS Drug-induced parkinsonism can occur in patients treated with dopamine receptor blockers, such as antipsychotics (haloperidol, risperidone, perphenazine), antiemetic agents (prochlorperazine, promethazine), and prokinetic agents (metoclopramide). A history of dopamine receptor-blocking medication use may not be offered up front, requiring specific questioning about their use in the evaluation of new-onset parkinsonism. Metoclopramide, a frequently used drug in the treatment of gastroparesis, esophagitis, nausea, and vomiting, may account for up to 29% of drug-induced parkinsonism in the elderly (with average age of 69), second only to antipsychotics.45 Although drug-induced parkinsonism may be less prevalent in patients treated with atypical, newer generation antipsychotics compared with traditional neuroleptics, the risk is still clinically pertinent. Discontinuation of the offending agent usually leads to recovery in several weeks or months. OTHER MEDICATIONS EPHEDRONIC ENCEPHALOPATHY A distinct syndrome of parkinsonism, severe hypophonia, and gait abnormality in association with manganese-related hyperintense signal on T1-weighted MRI in the globus pallidus and substantia nigra has recently been reported in Eastern European methcathinone users; these patients also had hepatitis C and/or HIV.41 CARBON MONOXIDE POISONING Carbon monoxide poisoning may lead to delayed-onset postanoxic parkinsonism in up to 10% of patients, typically within 4 weeks but occurring up to 6 months after initial encephalopathy, associated with changes in the pallidum on neuroimaging.42 Antiparkinsonian Among the other medications used to treat medical diseases that are reported to cause reversible parkinsonism or exacerbate Parkinson’s disease in small series or single case histories are calcium channel blockers (diltiazem, nifedipine, verapamil), monoamine depleters (reserpine, tetrabenazine), antiarrhythmic drugs (amiodarone), anticonvulsants (phenytoin, sodium valproate), immunosuppressants or chemotherapeutic agents (cyclosporine, vincristine, busulfan, cytosine arabinoside, doxorubicin), lithium, procaine, a-methyldopa, chloroquine, buspirone, and high doses of diazepam.40 When the drug is stopped, parkinsonism improves; in those cases where parkinsonism persists, it is probable that the patient had early Parkinson’s disease unmasked by the drug. 101 102 SEMINARS IN NEUROLOGY/VOLUME 29, NUMBER 2 2009 NONPARKINSONIAN TREMOR As opposed to parkinsonian tremor, which most often occurs at rest, tremor induced by drugs and metabolic disorders typically causes postural and/or action tremor. Most postural tremor is due to enhanced physiological tremor. Disorders of Metabolism Conditions associated with increased catecholamine levels are common causes of enhanced physiological tremor, such as pheochromocytoma, stress, anxiety, fever, and amphetamine use. Metabolic derangements such as hypoglycemia, hyperthyroidism, and renal and hepatic dysfunction also cause tremor. Of special note, Wilson’s disease is an autosomalrecessive disorder caused by a mutation in the ATP7B gene, which encodes a copper transport protein. Although the gene is known and genetic testing can be used to identify affected family members, gene testing is not useful as a screening test for the disease because the gene is large and there are many different diseasecausing mutations. Expression of the defective ATP7B protein results in the failure of the biliary excretion of excess copper, leading to progressive accumulation of copper in liver hepatocytes and other organs and tissues. Symptoms usually appear in the second or third decade of life and may include hepatic, neurological, and psychiatric symptoms. Patients who present with neurological symptoms tend to be older than those presenting with hepatic symptoms.46 Neurological features can be the presenting signs of Wilson’s disease in 40 to 60% of patients, with tremor being the most frequent initial finding; the proximal ‘‘wing-beating’’ tremor is common, but other types of tremor may also occur, including rest, posture, and action tremor.47 A wide variety of other neurological symptoms may occur, including dystonia, gait abnormalities, dysarthria, ataxia, and parkinsonism as well as cognitive or behavioral changes such as depression, anxiety, and psychosis. Dystonia can occur in 40% of cases and can be generalized, segmental, or multifocal, but the ‘‘sardonic smile’’ is most characteristic of the disorder.48 Other systemic findings include renal dysfunction, cardiac involvement, pancreatic disease, hemolytic anemia, hypoparathyroidism, osteoporosis, and skin abnormalities. Workup for Wilson’s disease should be considered in any patient with a new-onset movement disorder and liver abnormalities of uncertain cause. Patients with Wilson’s disease have low serum ceruloplasmin, although this finding is not sensitive or specific enough to be used alone as a screening tool. Additional workup should include measurement of 24-hour urine copper, which is increased (> 100 mg) in Wilson’s disease, and slit-lamp examination to look for Kaiser-Fleischer rings because these are present in the majority of patients with neurological symptoms. Liver biopsy is usually not required but can be diagnostic. Brain MRI shows increased T2 and decreased T1 signal in the basal ganglia. Treatment consists of either copper chelation to promote copper excretion or treatment with zinc to reduce copper absorption. Trientine is recommended as first-line treatment because of its effectiveness and fewer side effects than penicillamine.46 Drugs Drugs are a common cause of acquired tremor. In general, patients with advanced age, impaired renal and hepatic function, or underlying medical or neurological disease are more susceptible to drug-induced tremor. Amiodarone causes tremor in one third of exposed patients. The tremor is usually postural and increases with intention, closely resembling essential tremor. Dose reduction usually leads to improvement in 2 weeks. Cyclosporin frequently causes a postural tremor with rates as high as 40% reported, but the tremor is usually mild and does not require dose reduction.49 Tacrolimus causes a more disabling tremor: most frequent reports are in liver transplant patients, although it has also been described in patients with rheumatoid arthritis.50 Antidepressants are a common cause of tremor, which occurs in 20% of patients treated with selective serotonin reuptake inhibitors (SSRIs), and even more frequently in patients treated with tricyclic antidepressants. Tremor usually develops 1 to 2 months after starting therapy and resolves 1 month after discontinuation. Lithium causes tremor frequently: at least 30% of patients develop tremor at therapeutic levels, and at toxic levels nearly all patients have tremor. Concomitant treatment with SSRIs increases the likelihood of developing tremor with lithium use. Valproic acid is the most common antiepileptic drug to cause tremor: tremor occurs in 25% of patients, usually after 3 months of treatment. Tremor severity does not necessarily correlate with serum level, although dose reduction and longacting preparations may reduce the tremor.50 Other types of drugs used to treat medical diseases that can cause tremor are antiviral agents (acyclovir, vidarabine) and chemotherapy drugs (thalidomide, cytarabine). In general, the approach to treating drug-induced tremor is to taper the drug or substitute another drug with a lower risk of tremor. Propranolol can be added if tapering or changing the medicine is not feasible. DYSTONIA Dystonia is a movement disorder characterized by involuntary, sustained, patterned, and repetitive muscle MOVEMENT DISORDERS CAUSED BY MEDICAL DISEASE/BARTON ET AL contractions leading to twisting movements or abnormal postures.51 Dystonic movements may be classified by their anatomical distribution or by their clinical characteristics, and can be further categorized as primary (idiopathic) or secondary (symptomatic) in regard to etiology. Primary dystonia, by definition, is unaccompanied by other neurological deficits, and may be associated with several known genetic mutations.52 Secondary dystonia should be suspected when dystonia occurs in association with the following: Other neurological abnormalities, other movement disorders, or other abnormalities on general medical examination Rapid presentation Presentation in a location or pattern atypical for demographics Medical history that includes a known medical condition or treatment associated with dystonia In all instances, dystonia is thought to involve the neuroanatomic circuitry that includes the basal ganglia nuclei, sensorimotor system, brainstem, and cerebellum.53 Secondary dystonia is associated with a very wide range of etiologies, each of which has a different prognosis and some of which are treatable; therefore, every effort should be made to identify secondary causes by obtaining a careful medical history. Heredodegenerative Diseases A large number of heredodegenerative diseases can cause secondary dystonia, often in the setting of other multisystemic abnormalities and other movement disorders.54 Most of these disorders are rare and inherited as autosomal-recessive diseases; present at a younger age; are associated with abnormal neuroimaging; and may have other features more prominent than the dystonia, such as mental retardation, seizures, peripheral neuropathy, and ophthalmological abnormalities.48 However, some disorders are autosomal-dominant, X-linked, or mitochondrially inherited, and they may present in adolescence or adulthood. A specific diagnosis should be sought because some conditions have therapeutic interventions. Clues to diagnosis can include concomitant involvement of other organ systems. Table 1 summarizes those disorders that may present in adulthood. Some of the diseases seen in the table are discussed in the text that follows. ACERULOPLASMINEMIA Aceruloplasminemia is an autosomal-recessive disorder of iron metabolism caused by mutations in the CP gene, which encodes ceruloplasmin. This mutation results in iron accumulation in the brain and viscera and may be associated with anemia, diabetes mellitus, and retinal Table 1 Heredodegenerative Dystonias Associated with Medical Disease Autosomal-Recessive X-linked Recessive Wilson’s disease Lesch-Nyhan syndrome Aceruloplasminemia Neuroacanthocytosis Hartnup disease Mitochondrial GMI/GM2 gangliosidosis Leigh’s disease Niemann-Pick Type C Homocystinuria Leber’s disease MELAS Ataxia-telangiectasia Kearns-Sayre syndrome Cockayne’s syndrome Gaucher’s disease MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. degeneration. Neurological symptoms may start in the fifth decade and include dystonia (60%, particularly craniocervical), parkinsonism (41%), ataxia, dysarthria, and progressive dementia. Brain MRI may be abnormal, with low intensities on T1- and T2-weighted images of the striatum, thalamus, and dentate nuclei representative of iron deposition.55 NEUROACANTHOCYTOSIS Neuroacanthocytosis is a heterogeneous group of disorders in which abnormally spiculated red blood cells are found in association with a neurological syndrome. Chorea-acanthocytosis is an autosomal-recessive disorder caused by a mutation in the VPS13A gene, which encodes the protein chorein. Patients most characteristically present with involuntary movements of the face, mouth, and tongue, which may have a choreic or dystonic component, most dramatically with a tongue protrusion dystonia that interferes with eating. Dystonia occurs in 50% of patients and parkinsonism in one third.56 Dystonia and chorea may also be prominent features in McLeod’s syndrome, an X-linked mutation of the XK gene.57 NIEMANN-PICK DISEASE Niemann-Pick Type C is an autosomal-recessive lipid storage disease caused by a mutation in the NPC1 or NPC2 gene. Patients can present over a wide age range, with the classic presentation in middle-to-late childhood with dementia, vertical supranuclear gaze palsy, and ataxia. Dystonia is common and can start in one limb, gradually involving all limbs as well as axial muscles; patients may also have myoclonus, chorea, or parkinsonism. Speech is affected with findings of dysphonia, dysarthria, and eventual dysphagia. Clues to NiemannPick C include hepatosplenomegaly, particularly in early childhood. Bone marrow, spleen, and liver contain characteristic foamy cells.58 103 104 SEMINARS IN NEUROLOGY/VOLUME 29, NUMBER 2 2009 HOMOCYSTINURIA Homocystinuria is an autosomal-recessive inherited disease caused by cystathionine-b-synthase deficiency, with multiple systemic, ophthalmological, and neuropsychiatric manifestations. Dystonia, chorea, tremor, and (rarely) parkinsonism have been reported in association with the disorder.59 Disorders of Metabolism MITOCHONDRIAL DISEASE Mitochondrial/respiratory chain disorders may cause dystonia, typically presenting in childhood and associated with bilateral basal ganglia lesions on brain imaging. Dystonia may occur with Leigh syndrome, a heterogeneous disorder associated with multiple respiratory chain defects and pyruvate dehydrogenase deficiency. Dystonia is also reported in association with Leber hereditary optic neuropathy; mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); and Kearns-Sayre syndrome.17 HYPOXIA Hypoxic brain injury, particularly in the perinatal period, may cause any pattern of dystonia, typically more generalized, in 1% of survivors of perinatal asphyxia, starting even up to 32 years after the initial insult.60 In a review of 12 patients recovering from hypoxic injury due to various causes, dystonia developed between 1 week and 36 months after the injury, was gradually progressive, and was most often associated with evidence of putamenal damage on neuroimaging. An older age at time of insult and lesions involving the globus pallidum predicted the development of an akinetic-rigid motor syndrome, which frequently later developed dystonic features.61 CALCIUM METABOLISM Hypocalcemia from idiopathic hypoparathyroidism may cause paroxysmal dystonia and choreoathetosis, which, rarely, may be kinesigenic. It is associated with basal ganglia calcification on neuroimaging.62 THYROID DISEASE Hyperthyroidism has been associated with the onset of segmental and task-specific dystonia that improved after treatment with antithyroid medications, with postulated alteration of the dopaminergic system by elevated thyroid hormone.63 Pseudohypoparathyroidism was discovered in one case of an 11-year-old girl presenting with paroxysmal, exercise-induced facial and upper extremity dystonic movements in association with hypocalcemia, which ceased with normalization of calcium levels.64 Infectious Disease Infectious agents associated with dystonia are numerous.21 Dystonia as a prominent symptom has been reported with viral encephalitis (Japanese encephalitis, influenza A, cytomegalovirus), tuberculous meningitis, cerebral malaria, and M. pneumoniae infection. Although reported less frequently in HIV infection, dystonia can occur in patients with HAD treated with dopamine receptor antagonists, who may have increased susceptibility due to underlying basal ganglia dysfunction.22 Dystonia may also occur in association with opportunistic infections related to HIV (particularly toxoplasmosis). Autoimmune Disease The relationship of dystonia to autoimmune disease has been demonstrated in a small number of case reports and case series. In a series of 100 patients with blepharospasm and orofacial-cervical dystonia (Meige syndrome), a high antinuclear antibody (ANA) titer (> 1:80) was found in 26%, and specific autoimmune disease was diagnosed in 7%.65 Antibasal ganglia antibodies were found in 63% of a series of 46 patients with atypical dystonia (adult onset generalized dystonia or fixed limb dystonia), suggesting an underlying autoimmune pathophysiology.66 A group of patients with dystonia and antibasal ganglia antibodies responded favorably to immunomodulatory therapy.67 SYSTEMIC LUPUS ERYTHEMATOSUS Individual cases of blepharospasm and torticollis have been reported in the setting of systemic lupus erythematosus or myasthenia gravis. The dystonic movements in these cases responded to immunomodulatory therapies and, in the case of systemic lupus erythematosus, correlated in severity with autoimmune titers.68 NEURO-BEHÇET’S DISEASE One case of Neuro-Behçet’s disease presented as a jawopening dystonia in association with chorea as part of generalized cerebral, meningeal, and brainstem involvement, with good response to immunomodulatory treatment.69 CELIAC DISEASE Celiac disease, a gluten-sensitive enteropathy associated with malabsorption and development of autoantibodies, may be associated with neurological syndromes, including ataxia, myoclonus, and dementia. Unilateral dystonic limb posturing, in association with cortical tremor, has been reported as the presenting neurological sign in a case of untreated celiac disease.70 Paraneoplastic Case reports of paraneoplastic dystonia are rare, with dystonia occurring mostly in association with other MOVEMENT DISORDERS CAUSED BY MEDICAL DISEASE/BARTON ET AL movement disorders, as referenced in the section on parkinsonism. Two additional cases with dystonia predominance were reported in association with nonHodgkin’s lymphoma—one case of camptocormia that began 3 years before the development of the malignancy,71 and another case associated with the CRMP5 antibody manifesting as cervical dystonia, blepharospasm, dysphonia, bradykinesia, and choreodystonic limb movements. Anti-Ri (ANNA-2) antibodies were identified in four patients with laryngospasm and four patients with jaw opening dystonia (two of the latter with additional cervical dystonia and one with parkinsonism) in association with breast, cervix, and lung malignancies.36 Toxins Many of the same toxins predisposing to parkinsonism may cause dystonia due to injury to the basal ganglia. Methanol, cyanide, carbon monoxide, manganese, mercury, carbon disulfide, and mycotoxin are examples.72 As discussed earlier, treatment involves removal of the offending agent in addition to the use of dopaminergic drugs or anticholinergic agents in cases of residual dystonia. Drugs Drug-induced dystonia may appear otherwise similar to primary dystonia because it most commonly manifests only as dystonic movements. Therefore, careful questioning for the typically implicated medications during the medical history is crucial.48 Many of the drugs previously mentioned as causing drug-induced parkinsonism are also implicated in drug-induced dystonia, but, unlike parkinsonism, dystonia usually occurs either acutely or late in treatment. Drugs can be grouped by their tendency to cause acute or late (tardive) dystonic syndromes, although many cause both. Classes of drugs that may cause acute dystonia include dopaminergic agents, antidepressants, neuroleptics, anxiolytics, antiepileptic drugs, and antihistamines. Acute dystonic reactions usually occur in axial, cranial, cervical, or pharyngeal muscles, but can be variable in location. Effective treatment of acute dystonic reactions includes discontinuation of the causative agent and intravenous diphenhydramine or anticholinergic medications.73 Tardive dystonia is most often associated with dopamine receptor-blocking antipsychotic drugs such as neuroleptics, antiemetics, and prokinetic gastrointestinal agents.51,72 Next to haloperidol, metoclopramide is the second most common drug reported to cause tardive dystonia and tardive dyskinesia.74 Patients with HIV-associated dementia are particularly sensitive to dopamine receptor-blocking medications.22 Pseudodystonia Some medical conditions can themselves mimic dystonia, and may be termed ‘‘pseudodystonia.’’ Examples include tetany-related carpopedal spasm due to alkalosis, hypocalcemia, or hypermagnesemia; abnormal postures secondary to bone, joint, or ligamental pathology from orthopedic or rheumatologic conditions; torticollis associated with retropharyngeal abscess; or the head tilt associated with hiatal hernia and gastroesophageal reflux with Sandifer’s syndrome.48 CHOREA Chorea is associated with a large number of hereditary or systemic diseases. This discussion focuses on chorea that arises secondary to medical diseases. Chorea consists of involuntary, irregular movements that may either take on a ‘‘worm-like’’ appearance called athetosis or a more proximal flinging movement called ballismus. Vascular STROKE Chorea is the most common movement disorder to occur as a result of stroke. In a series of 1500 patients with stroke, 4% developed movement disorders; of that 4%, chorea accounted for a third. There are several interesting features of the patients who developed chorea following stroke: compared with patients who developed other movement disorders, patients with stroke-induced chorea were older and had the shortest time interval between stroke and development of the movement disorder. Chorea caused by stroke is usually unilateral, called hemichorea, and occurs contralateral to the side of the stroke. Thalamic lesions are the most common localization of stroke-induced chorea. The majority of patients (75%) improve partially or fully by 1 year.75 POSTPUMP CHOREA Chorea can occur in children after cardiac surgery, often called postpump chorea. Most cases are mild and resolve; however, more severe forms can be life-threatening. These severe cases are associated with older age and preoperative cyanosis. It is not known whether chorea results from hypoxia, hypothermia, or the combination of both factors.76 POLYCYTHEMIA VERA Polycythemia vera is often categorized as a vascular cause of chorea, although the exact mechanism of action is not known. Chorea usually occurs acutely or subacutely and may often precede the hematologic changes.77 It is most common in elderly females, even though polycythemia vera is more common in men. This discrepancy suggests that multiple factors underlie the pathophysiology of 105 106 SEMINARS IN NEUROLOGY/VOLUME 29, NUMBER 2 2009 chorea in these patients. Chorea occurs in only 1 to 5% of patients with polycythemia vera and improves with phlebotomy.78 Autoimmune Autoimmune mechanisms account for several types of acquired chorea. estrogen enhances central dopaminergic sensitivity. However, it is not known whether OCPs alone are sufficient to cause chorea because many patients with chorea on OCPs had coexisting antiphospholipid antibody syndrome, lupus, or prior rheumatic fever.85 Positron emission tomography (PET) imaging of a patient with OCP-associated chorea showed contralateral caudate hypermetabolism, suggesting that in this condition chorea is not due to a lesional effect.86 SYDENHAM’S CHOREA Sydenham’s chorea occurs in 25% of cases of acute rheumatic fever. Chorea develops weeks to months after infection with group A b-hemolytic streptococcus. The onset of chorea can be delayed by up to 6 months after infection. Chorea can be accompanied by facial grimacing, dysarthria, gait disturbance, and hypometric saccades. The average age of onset is 9 years. Girls are more often affected than boys. Remission occurs in half the patients by 6 months, but mild chorea may persist for years.79 It has also been suggested that changes in attention and behavior such as learning disabilities, obsessive compulsive disorder, and tics are more common in patients with a history of Sydenham’s disease, although this is controversial.80 The mechanism of action of chorea in Sydenham’s chorea is thought to be cross-reactivity between antibodies to group A b-hemolytic streptococcus and the basal ganglia. In fact, antibasal ganglia antibodies have been identified as sensitive and specific markers of Sydenham’s chorea.81 Volumetric MRI shows enlargement of the basal ganglia in affected patients without other abnormalities. Pathology shows inflammation and neuronal loss in the basal ganglia.80 Patients with Sydenham’s chorea and rheumatic fever require treatment with penicillin for acute pharyngitis followed by chronic penicillin prophylaxis for 10 years. A randomized controlled trial of prednisone 2 mg/kg/d for 4 weeks followed by a taper showed that treatment with steroids improved chorea and shortened the time to remission.82 If symptomatic, chorea can be treated with valproic acid, carbamazepine, or haloperidol; however, some suggest that patients with Sydenham’s chorea may be more susceptible to drug-induced parkinsonism.83 SYSTEMIC LUPUS ERYTHEMATOSUS Other systemic autoimmune diseases are rare causes of chorea. Chorea occurs in 1% of patients with systemic lupus erythematosus and usually is associated with the antiphospholipid antibody syndrome.84 Antibody-related pathophysiology may underlie these conditions. CHOREA GRAVIDARUM Chorea gravidarum may share a similar mechanism of action to that of OCP-associated chorea. It usually begins in the first trimester of pregnancy and improves later in pregnancy or after delivery.87 Paraneoplastic Paraneoplastic chorea is most often associated with antiCRMP-5 antibodies in small-cell lung cancer. The majority of these patients have other paraneoplastic neurological signs, including vision loss, neuropathy, ataxia, limbic encephalitis, elevated cells and protein concentration in cerebrospinal fluid (CSF), and T2 and fluid-attenuated inversion recovery (FLAIR) lesions on MRI. Chorea improves with cancer treatment and steroids.88 Paraneoplastic chorea has been reported in several other malignancies and in some cases can be refractory to medical treatment.89 Disorders of Metabolism GLUCOSE METABOLISM Nonketotic hyperglycemia-induced chorea has several interesting features. It occurs more often in women and usually is associated with very high blood glucose (average 481 mg/dL).90 Nearly all patients recover fully by 6 months. All cases have MRI changes in the putamen with high signal intensity on T1-weighted imaging (Fig. 2). The etiology of the MRI changes is not fully understood, but most resolve on follow-up, suggesting a reversible process such as petechial hemorrhage (not calcification); however, rare pathological reports show gliosis without hemorrhage. A study evaluating singlephoton emission computed tomography (SPECT) scans in patients with nonketotic hyperglycemia-induced chorea documented striatal hypometabolism compared with patients without chorea who had the same level of hyperglycemia.91 Hypoglycemia-induced chorea has also been reported.92 THYROID DISEASE ORAL CONTRACEPTIVES Chorea has been attributed to use of oral contraceptive pills (OCPs). Several lines of evidence suggest that Hyperthyroidism is a rare metabolic cause of chorea. It is thought to result from enhanced catecholamine effects in the striatum,93 and can occur with thyroid replacement MOVEMENT DISORDERS CAUSED BY MEDICAL DISEASE/BARTON ET AL clopramide, a dopamine antagonist, can cause tardive syndromes. OTHER DRUGS A variety of drugs have been reported to cause chorea. Those of special importance in internal medicine include cimetidine, digoxin, isoniazid, verapamil, and theophylline. Others include baclofen, tricyclic antidepressants, steroids, and antiepileptics.100 Chorea can also develop from abuse of cocaine and amphetamines. Figure 2 T1-weighted magnetic resonance imaging of the brain in a patient with left-sided hemichorea and nonketotic hyperglycemia demonstrates right putaminal hyperintensity. therapy. When chorea occurs with Hashimoto’s thyroiditis, it is usually in the setting of Hashimoto’s encephalopathy.94 Chorea due to hyperthyroidism improves with treatment of hyperthyroidism, although it may persist for weeks after thyroid levels are normalized.95 Symptomatic treatment with propranolol is also effective.93 RENAL FAILURE Uremia has been associated with the sudden onset of chorea. Patients with diabetes and end-stage renal disease who develop chorea have MRI changes in basal ganglia consistent with vasogenic edema.96 Treatment with more frequent dialysis leads to resolution of the chorea.97 CALCIUM METABOLISM Hypocalcemia, most frequently in the setting of hypoparathyroidism, can cause chorea, which improves when calcium is corrected.98,99 INBORN ERRORS OF METABOLISM Several inborn errors of metabolism can cause chorea but usually include a mix of different movement disorders.17 Drugs DOPAMINE RECEPTOR ANTAGONISTS Tardive dyskinesia occurs after exposure to dopamine receptor antagonists.74 Most characteristically, patients develop oral-lingual-buccal movements, although chorea may affect the limbs and the trunk as well. 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