Movement Disorders Associated With General Medical Diseases

Hypoxic-Ischemic Disorders

Chorea and dystonia due to hypoxia-ischemia may result from global or focal cerebral hypoperfusion as well as cellular hypoxia, such as in mitochondrial toxicity.

Toxins

Exposure to certain gases and heavy metals is a rare cause of encephalopathy, parkinsonism, and dystonia, probably as a result of cellular hypoxia from mitochondrial dysfunction or the generation of free radicals. Carbon monoxide toxicity appears to result from a combination of tissue hypoxia and direct cellular toxicity. After initial recovery, about 10 percent of survivors will develop parkinsonism several weeks to months later; approximately 80 percent recover within 6 months. Imaging often reveals focal injury particularly to the pallidum and diffuse white matter changes, and the findings on magnetic resonance spectroscopy of white matter lesions are consistent with demyelination. Treatment with levodopa and anticholinergic agents usually is unhelpful.

Parkinsonism and dystonia are common among survivors of cyanide poisoning . The movement abnormalities may initially improve, only to worsen days to months later, followed by stabilization and gradual but incomplete recovery. Cyanide reacts with cytochrome- c oxidase, causing cellular hypoxia. Imaging studies show lesions in the caudate and lentiform nuclei, precentral cortex, and cerebellum. Functional imaging shows reduced dopamine transporter uptake suggestive of nigral neuronal loss.

Ingestion of methanol results in the production of formaldehyde by the liver; the liver and erythrocytes synthesize formic acid, which inhibits cytochrome- c oxidase and, thus, mitochondrial electron transport and tissue adenosine triphosphate production. Metabolic acidosis injures the retina and optic nerves and leads to necrosis of the putamen, subcortical white matter, cerebellum, brainstem, and spinal cord, resulting in parkinsonism, dystonia, tremor, and blindness. Initial treatment relies on correction of the metabolic acidosis with ethanol and elimination of methanol with hemodialysis. Gradual improvement may occur with time, and treatment with amantadine and dopaminergic medications sometimes helps.

Manganese toxicity may occur as an occupational exposure (e.g., in miners of the ore or with chronic exposure to metal alloys, batteries, paint, varnish, enamel, or colored glass), or as a consequence of liver failure. Manganese increases free radical formation, inhibits antioxidant function, may reduce mitochondrial energy production, and perhaps increases glutamate neurotoxicity. In addition to foot dystonia, parkinsonism, early freezing of gait, a distinct gait disturbance (cock gait), hyperreflexia, and Babinski signs may occur. Remission may occur in mild cases if further exposure is prevented, but the course is otherwise progressive. There are reports of improvement after chelation. Pathologic examination reveals damage to the globus pallidus and substantia nigra pars reticulata (which are downstream from the nigrostriatal dopaminergic pathway), consistent with the failure to respond to levodopa. Magnetic resonance imaging (MRI) may show hyperintensity of the putamen on T1-weighted images. A similar syndrome (with elevated serum manganese and putamen T1 hyperintensity) has been described in methcathinone users when the drug was produced using potassium permanganate oxidation of ephedrine or pseudoephedrine.

Organic mercury poisoning, as seen formerly with the ingestion of certain fungicides and shellfish (Minamata disease), causes visual loss, ataxia, paresthesias, and cognitive dysfunction. Choreoathetosis, parkinsonism, and tremor also occur, and dystonic posturing is occasionally seen. Inorganic mercury poisoning, seen in glass blowers, hatters, and battery workers, produces a psychotic encephalopathy and tremor.

Dystonia secondary to copper accumulation occurs in Wilson disease . If hepatic damage is mild, significant improvement follows chelation therapy with penicillamine or trientine and zinc, which reduces dietary absorption of copper. Liver transplantation may be required for nonresponders and patients with severe liver dysfunction. The movement disorder may respond to trihexyphenidyl, levodopa, dopamine agonists, or amantadine.

Cellular and global hypoxia-ischemia have been implicated in disulfiram overdose. In one such case, psychomotor slowing and parkinsonism were evident several days after awakening from coma, and over 10 years progressed to include dystonia of a lower limb, the eyelids, and speech. Brain computed tomography (CT) shows hypodense lesions, and MRI shows hyperintense lesions in the pallidum and inferior putamen. Chorea has also been described as a consequence of toluene (glue sniffing) and thallium exposures.

Drug-Induced Dystonia and Chorea

Medications may cause dystonia ( Chapter 32 ) and chorea ( Table 58-1 ). Acute iatrogenic dystonic reactions are idiosyncratic, reversible, and common. They may occur almost immediately (minutes to hours) after the first dose of a medication, or days to weeks later. For dystonia, the most common offenders include antipsychotics (both typical and atypical), benzodiazepines, anticonvulsants, dopamine agonists, and tricyclic antidepressants. Reactions have been encountered less often with calcium-channel blockers, propranolol, histamine-blocking drugs (cimetidine, ranitidine, cetirizine), and substituted benzamides (metoclopramide, sulpiride, clebopride, and domperidone). Patients with AIDS dementia complex are particularly sensitive to neuroleptic-related acute dystonic reactions because of underlying dopaminergic dysfunction. Dystonia may occur soon after starting antidepressants or develop after chronic use. Many agents (and medication classes) may be responsible including tetracyclics (trazodone and amoxipine), tricyclics (clomipramine, amitriptyline, and imipramine), selective serotonin reuptake inhibitors (including fluoxetine, paroxetine, fluvoxamine, escalopram, citalopram, and sertraline), and serotonin-norepinephine reuptake inhibitor (duloxetine).

If dystonia develops acutely, treatment involves discontinuation of the offending agent and administration of an anticholinergic drug or benzodiazepine. Diphenhydramine, benztropine mesylate, chlorpheniramine, diazepam, or lorazepam may be given orally or intravenously; treatment for several days is sometimes necessary, especially if the causal agent was taken regularly or in depot form. If dystonia is mild or develops slowly, gradual down-titration of the medication is appropriate.

Chorea has been reported secondary to a variety of medications including anticonvulsants (phenytoin, carbamazepine, valproate, and gabapentin), stimulants (amphetamine, cocaine, methylphenidate, pemoline), benzodiazepines, estrogens, lithium, levodopa (with or without catechol- O -methyltransferase inhibitors), dopamine agonists, tricyclic antidepressants, and antihistamines, as well as other agents such as baclofen, cimetidine, thyroxine, cyclosporine, and aminophylline. Chorea and encephalopathy has been associated with ciprofloxacin use and also with 4-aminopyridine overdose. Disulfiram overdose or poisoning (discussed earlier) may present clinically with encephalopathy, ketotic hyperglycemia, and dystonia.

Tardive syndromes develop after the introduction of the provoking medication, usually a dopamine receptor blocking drug. Most patients have been on the medication for at least 3 months; the disorder may first manifest after the causal agent has been discontinued, but typically does so within 6 months of withdrawal. The syndrome may involve dyskinesias, typically repetitive orolingual facial movements or repetitive movements of the head, trunk, and extremities. Older patients seem more susceptible than young persons. A tardive syndrome also may take the form of dystonia, chorea, akathisia, tremor, or myoclonus.

A number of medications have been associated with the development of tardive dyskinesia. It occurs most commonly with haloperidol or typical antipsychotics, but it is also common with the atypical antipsychotic drugs and with prolonged use (i.e., for more than 3 months) of metoclopramide. Other dopamine-blocking agents such as the antiemetics prochlorperazine and promethazine may cause tardive syndromes. Less commonly, certain calcium-channel blockers (especially cinnarizine and flunarizine) and rarely serotonin reuptake inhibitors have been associated with its development. The causal agent should be discontinued if feasible; otherwise, patients requiring antipsychotic medication should be switched to an atypical antipsychotic drug such as quetiapine. The withdrawal of dopamine-blocking agents may initially exacerbate the dyskinesia, but the movement disorder ultimately decreases or disappears in up to 50 percent of patients, persisting unchanged in the remainder. Dopamine-depleting agents (valbenazine, tetrabenazine, reserpine) are the most useful adjunctive treatments, followed by benzodiazepines such as clonazepam; GABA agonists such as baclofen and sodium valproate also have been used, but evidence of benefit is sparse. Anticholinergic drugs may exacerbate the syndrome.

Tardive dystonia may be indistinguishable from idiopathic dystonia and may respond to sensory tricks. It may be focal, segmental, or generalized; however, the head and neck region are most commonly affected, resulting in torticollis, blepharospasm, or oromandibular dystonia. Orobuccal-lingual dyskinesia or other tardive movements may occur in tardive dystonia, unlike in idiopathic dystonia. The onset is insidious, typically after several years of antipsychotic use, but may occur with exposures shorter than 1 year. Tapering the antipsychotic occasionally produces gradual or partial remission of tardive dystonia, often after an initial worsening. An increase in dose of the antipsychotic or its continuation may lead to temporary benefit, but probably worsens the long-term outlook. If treatment with an antipsychotic is necessary, replacement of the original neuroleptic with clozapine or quetiapine has been helpful. Approximately 50 percent of patients benefit from dopamine-depleting or -blocking agents and anticholinergic treatment. For patients with focal or segmental dystonia, botulinum toxin injections are beneficial. Stereotactic surgery, including pallidotomy and pallidal deep brain stimulation, has been successful for severe tardive dystonia unresponsive to other measures.

Some medications appear to cause chorea in the setting of pre-existing basal ganglia injury. For example, dose-related dyskinesias develop in a large proportion of parkinsonian patients taking carbidopa-levodopa. Similarly, many patients who develop chorea while taking oral contraceptives have had striatal abnormalities on imaging studies or have a past history of Sydenham chorea, chorea gravidarum, or chorea with Henoch–Schönlein purpura.

Among illicit drugs, cocaine and amphetamines have been most frequently associated with dyskinesias. Both influence central dopaminergic mechanisms, and cocaine also decreases serotonin turnover and degradation. Both may lead to choreoathetoid movements of the extremities, less often the head or trunk, or buccolingual dyskinesias within 24 hours of use; these typically resolve without treatment in 2 to 6 days. However, in chronic users, chorea persisting for more than 1 year after discontinuation of these stimulants has been described.

Infectious Disorders

Infections may cause the full spectrum of movement disorders ( Table 58-2 ). Movement abnormalities usually develop during the acute illness and are transient, but abnormal movements sometimes begin or persist after the infection has cleared. One mechanism is vasculitic ischemia of the basal ganglia, although direct neuronal injury by the organism or a toxin, and autoimmune cross-reactivity with basal ganglia epitopes are also postulated to play a role.

Autoimmune, Inflammatory, and Paraneoplastic Disorders

In systemic lupus erythematosus (SLE), choreoathetosis develops in 1 to 2 percent of patients and may be the presenting feature. Women are affected more commonly than men. The chorea typically occurs before the age of 30 years and tends to manifest during a lupus flare, often accompanied by behavioral disorders. It may be generalized or lateralized and is usually transient, lasting for a few days up to 3 years; recurrence occurs in approximately 25 percent of cases. Rarely, the chorea is permanent. The chorea may be self-limited or respond to corticosteroid or symptomatic treatment. Imaging studies may be abnormal, but the location of lesions does not usually explain the chorea.

Patients with SLE and chorea may possess antiphospholipid antibodies (lupus anticoagulant or anticardiolipin antibody) that predispose to endovascular thrombosis and cerebral infarction. Approximately 30 percent of patients with SLE and these antibodies have thrombotic events. Laboratory studies reveal that whole-blood clotting time is prolonged, and the prothrombin time and the Russell viper venom time may be abnormal. Chorea in several patients with SLE and antiphospholipid antibodies has improved within days on aspirin therapy or warfarin, consistent with a vascular mechanism. Thus, chorea in SLE may result from autoimmune vasculopathy or direct antibody-mediated basal ganglia dysfunction, or both.

The antiphospholipid syndrome may occur in the absence of SLE or other autoimmune conditions, the so-called primary antiphospholipid syndrome. Clinically and pathophysiologically, this condition is indistinguishable from that associated with SLE. In addition to lupus anticoagulant and an IgG anticardiolipin antibody, many patients have a low titer of antinuclear antibody, 30 percent have a false-positive Venereal Disease Research Laboratory test, and some have antithyroid antibodies. Chorea (either lateralized or generalized) has been the most frequently reported movement disorder, occurring in 1 to 4 percent of patients with primary or secondary antiphospholipid syndrome, although tics, dystonia, myoclonus, and corticobasal syndrome may occur. Brain MRI shows lesions of the basal ganglia in 6 to 16 percent of patients; labeled glucose PET imaging has revealed increased uptake contralateral to the hemichorea. For patients with no vascular events, treatment may consist of discontinuation of estrogen or progesterone (if applicable) and immunosuppressant treatment. For patients who have had a vascular event, anticoagulation may reduce the risk of recurrent thrombosis.

Chorea is a rare complication of polyarteritis nodosa and isolated angiitis of the CNS, and athetoid movements have been noted as the initial manifestation of primary Sjögren syndrome. Patients with Behçet syndrome (recurrent oral and genital ulcers, uveitis, and skin lesions) may present with chorea, jaw-opening dystonia, or paroxysmal dystonia. Typically, these patients have had an increased CSF protein concentration and lymphocytosis. They respond to immunosuppression but may require other agents to control abnormal movements. Chorea may also develop in Churg–Strauss syndrome.

Chorea sometimes occurs in Hashimoto encephalopathy. The CSF protein concentration is usually elevated, and some samples have oligoclonal bands or a mononuclear pleocytosis. Characteristically, the electroencephalogram (EEG) shows epileptiform activity, and transient or permanent areas of increased T2 signal are seen on brain MRI, particularly in the frontal and temporal lobes. Patients respond to prednisone, with a slow taper once improvement is stable. Complete remissions can be anticipated, although relapses sometimes occur or a deficit remains. Spontaneous remissions are rare.

Dystonia and tremor or chorea may be part of a movement disorder associated with celiac disease. Abdominal pain, ataxia, diarrhea, and myoclonus may also occur. Diagnosis is supported by demonstration of gliadin antibodies and characteristic findings on small bowel biopsy. The condition may respond to a gluten-free diet.

Chorea and dystonia are rare complications of paraneoplastic syndromes. In a series of 979 patients with paraneoplastic diseases, 9 presented with chorea and 3 had dystonia or dyskinesia. Most had small-cell cancer of the lung, and one each had nonsmall cell lung cancer, renal cancer, and colon cancer. Most of these patients had CV2/collapsing response-mediator protein (CRMP)-5 antibodies, but ANNA-1 (anti-Hu) antibodies were found in four. In many patients, chorea was the initial symptom. CSF was abnormal in some patients. Brain imaging was abnormal in four of the nine patients, with diffuse hyperintensity of the white matter in T2-weighted MRI; two showed basal ganglia hyperintensity. Improvement may occur with cancer treatment or symptomatic medications (dopamine-blocking or -depleting medications or benzodiazepines). Laryngospasm, jaw-opening dystonia, and cervical dystonia have been described in paraneoplastic syndromes associated with antineuronal nuclear antibody type 2 (ANNA-2, also known as anti-Ri antibodies, associated most commonly with breast or lung cancer).

Patients with anti– N -methyl- d -aspartate receptor encephalitis are usually women and many have ovarian cancers; various other cancers have also been reported. Patients commonly present with behavioral changes and seizures, and have dyskinesias (chorea, dystonia) involving the face, trunk, abdomen, and extremities in 80 percent of cases; orobuccolingual dyskinesias are most common. The dyskinesias usually respond to tetrabenazine, deutetrabenazine, or valbenazine.

Metabolic Disorders

The association between thyrotoxicosis and choreoathetosis or dystonic posturing was recognized by Gowers in 1893, particularly in young women, but patients of either sex may be affected. Chorea occurs in about 1 to 2 percent of those with hyperthyroidism and its course usually parallels that of the thyroid disorder. Abnormal movements typically involve the limbs, sometimes unilaterally, and are most conspicuous distally; the neck and face may also be affected. Paroxysmal (rather than more continuous) choreoathetosis may occur in rare instances; paroxysmal and kinesigenic choreoathetosis have also been reported with iatrogenic hyperthyroidism. No cerebral lesions have been noted on MRI or at autopsy. Treatment consists primarily in normalization of thyroid function (antithyroid drugs, radioiodine, or thyroidectomy). Chorea may respond to dopamine receptor blockers or propranolol even before hyperthyroidism has resolved. Altered dopamine turnover or increased dopamine receptor sensitivity may be responsible for the dyskinesia. Since chorea may occur in both hyperthyroidism secondary to Graves disease and iatrogenic thyrotoxicosis, it is hypothesized that the disorder results from a direct effect of thyroxine on the basal ganglia, perhaps by increasing dopamine receptor sensitivity.

Hypocalcemia from idiopathic hypoparathyroidism rarely may cause dystonia or choreoathetosis. The abnormal movements may be the presenting complaint, may be asymmetric, are usually paroxysmal, and rarely are kinesigenic. Patients are usually younger than 30 years, with calcium levels of 4 to 6 mg/dL, elevated serum phosphorus levels (5 to 12 mg/dL), and low serum magnesium. Brain imaging frequently reveals basal ganglia calcification that persists after treatment of hypocalcemia and resolution of chorea or dystonia.

Generalized chorea or hemiballism-hemichorea may occur in nonketotic hyperosmolar hyperglycemia . Brain CT may show high-density lesions, and MRI often shows high T1 signal and hypoperfusion in the caudate or putamen contralateral to the side involved clinically. These imaging findings are considered to be a consequence of hyperviscosity and cytotoxic edema, not petechial hemorrhage. The chorea may resolve with correction of hyperglycemia; however, dopamine-depleting or -blocking agents may be useful treatments until the condition resolves. Severe hypoglycemia may be accompanied by either generalized chorea or hemichorea that resolves as blood glucose normalizes.

Dystonia or chorea has rarely been noted in hypernatremic dehydration, hyponatremia, and hypomagnesemia and also after central pontine myelinolysis. In addition, many inherited metabolic disorders or inborn errors of metabolism can cause chorea or dystonia, as is reviewed elsewhere.

Other Causes

Post-traumatic focal and hemidystonia may occur rarely as a long-term consequence of severe head injury or following peripheral injury. Chorea-ballism may also follow head injury, as may functional movement disorders.

Approach to Diagnosis

The evaluation of patients with involuntary movements or postures requires a detailed history, as outlined earlier. Characterization of the movement disorder and its distribution, together with findings such as organomegaly, skin lesions, retinal or optic nerve disease, or neurologic deficits, narrows the differential diagnosis. The relaxed patient must be observed carefully while lying, sitting, standing, and walking to determine whether any abnormality is exacerbated by movement or rest. The patient should perform tasks that are particularly impaired because certain movement disorders are solely task specific.

The age of onset and the pattern of involvement and progression vary with the etiology. Focal or task-specific dystonias, often associated with a dystonic or essential-type tremor, onset in adulthood, a benign history, and no other abnormalities on examination are usually idiopathic. Limb dystonia beginning as action dystonia is usually idiopathic, whereas dystonia beginning at rest is sometimes symptomatic. Dystonia with onset in the legs is usually idiopathic in children but symptomatic in adults. Chorea or dystonia of acute or subacute onset or having a rapidly progressive course is more likely to be symptomatic. Hemidystonia at any age suggests a secondary etiology, and approximately 75 percent of patients have contralateral basal ganglia abnormalities on imaging, a history of hemiparesis, or both. One-third of hemidystonic patients have infarction or hemorrhage of the contralateral basal ganglia, especially the putamen. Generalized dystonia beginning at an early age may be idiopathic or symptomatic, but it is more often symptomatic when onset is in adulthood. Childhood-onset dystonias tend to become generalized, whereas those commencing in adulthood often remain focal or segmental. Similarly, tardive dystonia may be generalized in children, but it usually remains focal or multifocal in adults. Thus, dystonia of sudden onset, rapid progression, onset in infancy, cranial onset in children, lower-extremity onset in adults, or hemidystonia at any age is more likely symptomatic and requires full evaluation.

A large number of factors contribute to decision-making in the evaluation of chorea and dystonia. Brain MRI has a high yield, and basic laboratory studies include a complete blood count and blood electrolytes, calcium, phosphorus, uric acid, and liver and thyroid function tests. Any patient with chorea or dystonia younger than 40 years must be evaluated for Wilson disease. Evaluation for vascular disease, a hypercoagulable state, connective tissue disorders, and antiphospholipid antibodies may be required. Serum antistreptolysin O or antihyaluronidase titers and an electrocardiogram are useful when Sydenham chorea is suspected. Neurodegenerative and hereditary metabolic disorders require a separate battery of studies, which are described elsewhere.

Treatment

The treatment of secondary dystonia or chorea is difficult. In symptomatic cases, the underlying pathologic process should be treated first, as discussed earlier. General therapeutic measures may provide symptomatic benefit when specific treatments of the underlying lesion have failed to temper the movement disorder satisfactorily. Anticholinergics, dopaminergics, antidopaminergics, benzodiazepines, anticonvulsants, and certain other medications (discussed later) are used, based on patient age, tolerance, co-existing medical illnesses, and interactions with other medications taken concomitantly. All of these medications are disappointingly variable in their efficacy. Unfortunately, there is a paucity of adequate trials demonstrating therapeutic benefit or comparative efficacy because patient numbers are small, common side effects make double-blinding difficult, and nonspecific effects such as sedation can diminish abnormal movements. Moreover, spontaneous remissions, partial or complete, and transient or permanent, may occur unpredictably.

Anticholinergic medication, of which trihexyphenidyl is the best studied, is more effective in mild dystonia and in younger patients. Approximately one-third of patients with secondary dystonia benefit, and up to 50 percent of those with perinatal hypoxic injury improve. The selected agent is started at a low dose, which is increased slowly, depending on response and tolerance. (A particular daily dose may take several weeks to produce maximal benefit.) Side effects can be dose-limiting, particularly with advancing age. Tricyclic antidepressants and diphenhydramine are also sometimes used for their anticholinergic effects.

The useful antidopaminergic medications include dopamine depleters (reserpine, tetrabenazine, deutetrabenazine, valbenazine) or dopamine receptor antagonists. Valbenazine is particularly helpful for tardive dyskinesia.

Dopaminergic supplementation using levodopa is singularly effective in patients with dopamine-responsive dystonia, which may be present in 5 to 10 percent of patients with childhood-onset hereditary dystonia beginning in the legs, with or without diurnal fluctuations. It is less useful in treating symptomatic dystonias. In some instances, levodopa actually worsens symptomatic dystonia, whereas improvement may occur with dopamine agonists or amantadine.

Anticonvulsants have been tried and sometimes help, but usually the results are disappointing. Baclofen, a presynaptic γ-aminobutyric acid agonist, is also frequently tried and occasionally is effective, either orally or intrathecally. Other medications that have been tried alone or in combination, with variable benefit, include benzodiazepines, particularly clonazepam (which helps perhaps one-quarter of patients with secondary dystonia), muscle relaxants, cyproheptadine, and lithium. Adult-onset cranial or focal limb dystonias are best treated with intramuscular botulinum toxin.

Surgical approaches are sometimes warranted. Deep brain stimulation of the globus pallidus is effective for primary dystonia, myoclonus dystonia, and tardive dystonia. Selective peripheral denervation is sometimes successful for blepharospasm and cervical dystonia, but is now generally reserved for cases refractory to botulinum toxin. The use of deep brain stimulation for refractory chorea is being explored.