MOVEMENT DISORDERS FOCUS By Judith Blazer, Joy B. Leffler and Catherine Friederich Murray

How to Identify and Minimize Tardive Because this wide-ranging and multifaceted condition can be difficult to treat, prevention and early detection are essential.

ardive dyskinesia (TD) is an ing, finger flicking, and trunk twisting. inability to clear phenylalanine leads to umbrella term encompassing a TD symptoms can range from mild an increase of this chemical in the brain wide variety of involuntary, to severe, based on the frequency and and a decrease of other chemicals neces- repetitive, persistent, stereo- intensity of the movements. When sary for the to control Ttypic movements caused by the severe, abnormal movements of the smooth and accurate movements. use of drugs that block dopamine recep- tongue may occur up to 66 times per Antipsychotic agents, both typical tors, known as dopamine-receptor minute. The numbers of these move- and atypical, include DRAs that have antagonists or DRAs. Involuntary move- ments are often reduced when the been shown be associated with TD, ments such as those associated with dys- patient moves affected body parts. including phenothiazines, butyrophe- tonia, , tics and , rest- Movement may be increased when the nones, dibenzodiazepines, diphenyl- lessness with muscle quivering and the patient moves unaffected body parts. butyl-piperidines, indolones and thiox- urge to move () all may be man- The abnormal movements usually anthenes. Reports of TD incidence with ifestations of TD. When used in the decrease with emotional arousal, the use of newer atypical antipsychotic classic sense, TD refers to an iatrogenic increase with relaxation, and disappear agents such as clozapine (Clozaril), olan- disorder produced by the long-term use during sleep. zapine (Zyprexa), risperidone of drugs to treat schizophrenia that act TD and its various related conditions (Risperdal) and quetiapine (Seroquel) by blocking dopamine receptors. As part are also known as “hyperkinetic have varied greatly. Risperdal appears to of the ongoing educational efforts extrapyramidal syndromes” or EPS. The bring out the symptoms of TD more fre- offered by WE MOVE, this article will term EPS should be avoided, as it does quently compared to the other newer provide an overview of what’s currently not really “name” the disorder. Related atypical antipsychotic agents. known about TD’s causes and manage- conditions, which may also be caused by Drugs other than those used to treat ment. Additional resources on TD and use of a DRA, include drug-induced psychiatric illnesses can also block the other movement disorders are available ; immediate reactions to dopamine receptors, and their use has online at www.wemove.org. DRAs, such as acute and acute also been found to be linked to TD. akathisia; more delayed syndromes, These include drugs and Symptoms including tardive dystonia and tardive selective serotonin reuptake inhibitors TD is characterized by coordinated, akathisia; and either acute or tardive (SSRIs). Whether other antidepressants constant movements of the mouth, withdrawal “emergent syndromes” in such as monoamine oxidase inhibitors tongue, jaw and cheeks. Jaw movements which symptoms appear when treatment and tricyclics cause TD is not clear. An may be from side-to-side or may resem- with the drug is stopped; and neurolep- increased risk of TD may also be associ- ble chewing motions. The tongue move- tic malignant syndrome. ated with the use of certain antihista- ments may be squirming or twisting mines, decongestants, stimulants and (choreoathetoid). Trunk movements, if Pathophysiology and Etiology certain drugs used to treat gastrointesti- present, are typically in the form of Although the exact underlying cause of nal disorders, disorders, anxiety, rapid forward motions of the lower TD is unknown, several theories do and malaria. Evidence that these drugs abdomen and hips (pelvic thrusting) or exist. All point to an increased sensitivi- may be associated with TD is relatively twisting or flicking movements of the ty in people who take DRAs. One weak. Several populations have been arms and legs. potential cause that has been proposed is suggested to have an increased risk for The involuntary abnormal repeated related to a person’s decreased ability to developing TD, but further epidemio- movements of TD may also include lip metabolize phenylalanine. This theory logic studies are needed to confirm these smacking, cheek puffing, tongue thrust- maintains that, in people with TD, the observations.

56 Practical April 2007 tongue both inside and outside the Table 1. Strategies for Prevention of TD mouth. Because of the wide variety of movements that are associated with TD, Inform Weigh the risks of TD and benefits of treatment. Inform patients and their if the exam reveals only minimal or mild family members about these risks before instituting therapy with a DRA. movements in one body area, repeat the Restrict Restrict the use of DRAs to only those patients for whom no alternative visit within one week to confirm the treatment is available. presence of the movements. Limit Limit exposure by keeping the dose of DRA to the lowest possible level. The differential diagnosis of TD includes hereditary and acquired forms Assess Every three months, reassess the patient's need for continued treatment of , primary torsion dystonia, psy- with a DRA. chogenic , the stereo- Switch When possible, switch patients to a medication that has limited antagonism typic movements of schizophrenia, of dopamine receptors; for example, consider using an atypical antipsychot- Tourette syndrome, neuroacanthocyto- ic rather than a typical antipsychotic drug. sis, hyperthyroidism, attention- Examine Every three months, examine patients who are taking DRAs for symptoms of deficit/hyperactivity disorder, restless TD. legs syndrome, hypoparathyroidism, sys- Avoid Avoid the use of drug holidays; they have not been proven to be effective in temic lupus erythematosus, and ill-fit- reducing the risk of TD. ting dentures or edentulousness. Drug-induced parkinsonism mani- fests with the some of the same symp- Quantifying TD’s Prevalence sexes. Kane et al. found a cumulative toms as classic Parkinson’s disease: Identifying the exact number of people incidence of five percent at one year, 10 bradykinesia and rigidity. Tardive dysto- affected by TD is difficult because of percent at two years, 15 percent after nia may appear at any time in the course factors such as fluctuation in symptoms three years, and 19 percent after four of treatment with DRAs and up to years and the use of drugs that can mask or years of exposure to DRAs. afterward; acute dystonia may occur hide TD symptoms, thereby causing an within a few days of exposure. Backward underestimation of the true number of Exam and Diagnosis arching of the trunk is primarily seen in affected people. The estimated preva- The diagnosis of TD is based on the acute dystonia; , lence of TD varies greatly, from 0.5 per- findings of a physical examination and a retrocollis, and internal rotation of the cent to 65 percent, in accordance with thorough neuropsychiatric history. arms, elbow extension, and wrist flexing the population being studied. Factors However, tests to rule out other disor- are characteristic of tardive dystonia. affecting the rate include age of the pop- ders listed in the differential diagnosis Tardive akathisia usually exists along ulation, the DRA being used, the defini- may be warranted and include a com- with tardive dystonia. tion of TD being employed in the study, plete blood cell count; serum elec- The movements of withdrawal emer- and the design of the study. trolytes, copper, and ceruloplasmin; thy- gent syndromes are brief, jerky, and The rate of TD increases with age (50 roid function tests; screening for con- irregular (choreic). These movements percent in a group of elderly schizo- nective tissue disorders; and imaging typically flow from one body part to phrenic patients), as does the rate of studies of the head. another in a random manner and usual- spontaneous . In one study, The clinician should use standardized ly involve the arms, legs, trunk, and 19 percent of young adults were found exam procedures to investigate the neck. These are different than the to have TD after five cumulative years of nature and severity of the movements. unusual movements of the mouth and exposure to a neuroleptic drug. Because the symptoms of TD have a nat- tongue seen in classic TD. In adults, According to a review of more than ural ebb and flow and may not be evi- withdrawal dyskinesia may manifest as a 39,000 patients exposed to neuroleptic dent upon initial examination, the clini- transient TD, which typically resolves agents, Yassa and Jeste identified a mean cian may attempt to bring the symptoms within three months after removal of the prevalence of 24.2 percent, with a signif- out during an office visit by engaging neuroleptic agent. icantly higher prevalence in women the patient in conversation or distracting Neuroleptic malignant syndrome is (26.6 percent) than in men (21.6 per- the patient. Pay particular attention to an abrupt, life-threatening response that cent); however, Lauterbach et al. found the area around the patient’s mouth, occurs in approximately 0.2 percent of no difference in the incidence between including observing movements of the patients after they receive a therapeutic

April 2007 Practical Neurology 57 MOVEMENT DISORDERS FOCUS By Judith Blazer, Joy B. Leffler and Catherine Friederich Murray

dose of a neuroleptic drug. The symp- atric illness may then be left untreated cents as well as boys and girls with TD, toms include an alarming high body and become worse. When the use of a the abnormal movements decreased sig- temperature or hyperthermia (> 38°C), typical antipsychotic medication leads to nificantly after the consumption of muscle rigidity, and problems with a TD, switching to an atypical antipsy- Tarvil three times a day. This treatment part of the nervous system (autonomic chotic may prove to be the most effica- has few, if any, side effects. dysregulation) that helps to regulate cer- cious strategy. Vitamin E. A 2000 Cochrane data- tain involuntary body functions such as Amine-depleting Agents. Amine- base review, which included a large clin- sweating, blood pressure, etc. depleting drugs such as reserpine ical trial conducted by the Veterans (Serpalan, Serpasil) and Administration, found no or very limit- Management Options (Nitoman) work on dopamine, norepi- ed evidence to support the use of vita- The most important step in the treat- nephrine, and serotonin; these drugs min E in the treatment of TD. In 2002, ment of TD is prevention. Because TD deplete the availability in the brain of results of a 12-week clinical study were is caused only by the use published (Zhang et of DRAs, every effort al.) in which pa- should be made to limit tients treated with the use of these drugs to In treating TD, amine-depleting an alpha-tocopherol those patients for whom had decreased scores no other treatment agents seem to be most effective on the Abnormal options are available. Involuntary Move- Physicians will continual- when not used at the same ment Scale and ly review the patient’s higher levels of need for ongoing DRA time as neuroleptic therapy; superoxide dismu- therapy and examine tase, a measure of patients who are receiv- instead, they may be used after oxidative state. ing long-term treatment with DRAs at three- to the neuroleptic drug is stopped. Summary six-month intervals for TD manifests as evidence of TD. hyperkinetic move- The treatment of TD ments of primarily is challenging, as the symptoms vary the face, jaw and tongue, but also the greatly among patients and because most these neurotransmitters. Few studies limbs and trunk. It is caused by the use patients with TD also have an underly- have been undertaken to evaluate the of dopamine-receptor-blocking drugs. ing psychiatric illness, which necessitat- effectiveness of these drugs in the treat- Treatment is not universally effective, ed the initial use of DRAs that caused ment of TD, although they are in wide- although early recognition and removal the TD. This challenge is the delicate spread use in clinical practice. Tetra- of the offending agent are key factors in balance between the need for treatment benazine (Nitoman) appears to be the the outcome of patients with TD. Even of the essential psychiatric condition most effective drug for the treatment of in those patients who have long-stand- and the level of tolerable dyskinetic TD, although it is not currently avail- ing, apparently irreversible TD, symp- movements. able in the United States. Amine-deplet- toms may slowly subside over time, with No pharmacologic treatment has ing agents seem to be most effective younger patients having the best prog- been proven to be universally or even when not used at the same time as neu- nosis. PN typically effective in the treatment of roleptic therapy; instead, they may be TD in clinical practice. Therefore, the used after the neuroleptic drug is treatment of TD is instead aimed at pre- stopped. Significant side effects limit the Judith Blazer is Executive Director of WE MOVE. venting, recognizing and managing the use of these drugs. Joy B. Leffler is Director of Education & Informatics of movements. Strategies for prevention are Branched-chain Amino Acids. A WE MOVE. listed in Table 1. Discontinuing or medical food comprising branched- reducing the level of the drug that chain amino acids (Tarvil) seems to tar- Catherine Friederich Murray is a medical writer working with the WE MOVE staff. Patient and physician caused the TD may lead to a reduction get excess phenylalanine. In clinical tri- education resources are available at www.wemove.org. in the movements; however, the psychi- als that studied adult men and adoles-

58 Practical Neurology April 2007