Table 28.5 Di \200 erential diagnosis of orofacial dyskinesias 1. Spontaneous dyskinesia o f elderly (usually dystonic) 2. Neuroacanthocytosis 3. Hereditary chorea (Huntington \200\231s disease etc.) 4. Basal ganglia strokes 5. Edentulous dyskinesia 6. Drugs other than neuroleptics causing dyskinesias: levodopa amphetamines cocaine tricyclic antidepressants cimetidine \202 unarizine antihistamines phenytoin toxicity Oxford Textbook of Movement Disorders 308 from classic Tourette \200\231s syndrome, with most motor tics occurring in the craniocervi cal region and vocalizations involving bark- ing, sniffi ng, coprolalia, etc. (66). To make a diagnosis of tardive tourettism, it is imperative that the patient has no previous histo ry of tics (motor or vocal) prior to neuroleptic exposure (1). Usually patients also have o ther associated movements (such as orofacial dyskinesia etc.), and their presence strengthe ns the association between the occurrence of tics and neuroleptic exposure (66). Table 28.7 Major drugs known to cause postural, intention, and resting tremors Major catego ry Typical examples Postural Antiarrhythmics Amiodarone, mexiletine, procainamide Antidepressants/mood stabilizers Amitriptyline, lithium, SSRIs Antiepileptics Valproate Tardive myoclonus Myoclonus is characterized by abrupt, brisk, jerky, and repetitive involu ntary movements caused by asynchronous or synchronous contractions of muscles. Tardive myoc lonus with or without other associated movements has been reported as a complication of neu - roleptic exposure (67, 68). Other drugs that can worsen or cause myoclonus are listed in Table 28.6. Improvement of tardive myo- clonus with clonazepam has been reported. Bronchodilators Albuterol, salmeterol Chemotherapeutics Tamoxifen, Ara-C, ifosfamide Drugs of abuse Cocaine, ethanol, MDMA ( \200\230ecstasy \200\231), nicotine Gastrointestinal drugs Metoclopramide, cimetidine Hormones Th yroxine, calcitonin, medroxyprogesterone Immunosuppressants Tacrolimus, cyclosporine, -interferon Th eophylline, ca \200 eine Methylxanthines Neuroleptics/dopamine depleters Haloperidol, thioridazine, cinnarizine, reserpine, tetrabenazine Tardive tremor Tardive syndromes rarely manifest as a pure tremor. Stacy and Jankovic (69) reported a small series of patients who developed a 3 \200\2235 Hz rest and action tremor, which developed during the course of neuroleptic treatment and worsened aft er neuroleptic with- drawal (69). Th e symptoms improved aft er treatment with the dopamine-depleting agen t tetrabenazine. Th ese features, along with the absence of other parkinsonian symptoms and lack of response to traditional medications used to treat tremor, distinguish tardive trem or from other typical causes of tremor. Table 28.7 lists most of the common drugs and drugs of abuse which can cause resting, postural/action, and intention tremors. Intention Antibiotics/antivirals/ antimycotics Ara-A Antidepressants/mood stabilizers Lithium Bronchodilators Albuterol, salmeterol Chemotherapeutics Ara-C, ifosfamide Drugs of abuse Ethanol Hormones Adrenaline Immunosuppressants Tacrolimus, cyclosporin Resting Antibiotics/antivirals/ antimycotics Tardive dystonia Tardive dystonia (TDt) is defi ned as sustained muscle contractions causin g twisting and repetitive movements or abnormal postures in the setting of chronic DBA ther apy (70). Th e diagnostic cri- Trimethoprim/sulfa, amphotericin B Antidepressants/mood stabilizers SSRIs, lithium Antiepileptics Valproate Chemotherapeutics Th alidomide Table 28.6 Other drugs that worsen or cause myoclonus Drug class Anesthetics Drugs of abuse Cocaine, ethanol, MDMA, MPTP Examples Etomidate, en \202 urane, propofol Gastrointestinal drugs Metoclopramide Hormones Medroxyprogesterone Spinal anesthetics Neuroleptics/dopamine depleters Haloperidol, thioridazine, cinnarizine, reserpine, tetrabenazine Antibiotics/antimalarials Cephalosporins, \202 uoroquinolones, imipenem, me \202 oquine, penicillins MDMA, 3,4-methylenedioxymethamphetamine ( \200\230ecstasy \200\231); MPTP, 1-methyl-4-pheny l-1,2,3- tetrahydropyridine; SSRIs, selective serotonin reuptake inhibitors; Ara-A; vidarab ine; Ara-C, cytarabine. Reproduced with permission from Morgan JC, Sethi KD. Lancet Neurol 2005; 4: 866 \200\22376. Antiepileptics Carbamazepine, gabapentin, lamotrigine, phenytoin, valproate, vigabatrin Antidepressants MAOIs, SSRIs, tricyclics Antineoplastic drugs Chlorambucil, ifosfamide Calcium-channel antagonists Diltiazem, nifedipine, verapamil teria for TDt, fi rst outlined by Burke and colleagues (71), are as follows: Contrast agents Dopaminergics Levodopa, dopamine agonists and antagonists the dystonia must be present for more than a month and may occur during ongoing neuroleptic treatment or within 3 months of its discontinuation; \227\206 Drugs of abuse MDMA Gastrointestinal drugs Bismuth salts there must be a negative family history of dystonia; \227\206 Narcotics Methadone, meperidine, morphine, oxycodone other known causes of secondary dystonia must be excluded; \227\206 it is not necessary for other movements to be absent (i.e. tardive dyskinesia or tardive ak athisia), as long as dystonia is present and is the dominant movement disorder. \227\206 Other drugs -hydroxybutyrate, tranexamic acid MAOI, monoamine oxidase inhibitor; MDMA, 3,4-methylenedioxymethamphetamine ( \200\230ecstas y \200\231). CHAPTER 28 Drug-Induced Movement Disorders 309 Based on a review of eleven cross-sectional studies involving psy- chiatric patients, the p revalence of TDt ranged from 0.5 to 21.6% with a mean of 2.7% in a total of over 4000 patie nts exposed to DBAs (72). All classes of DBAs are implicated, and even atypical neuroleptic s can produce TDt. Clozapine appears to be the least likely to produce TDt. Children and yo ung adults are more likely to develop TDt, and increasing age decreases the likelihood of d evel- oping generalized dystonia (72). restlessness and there is a sense of relief when carrying out the movements. A study of pat ients with TA showed that the legs were the most frequently involved body part, with patien ts either march- ing in place while standing or crossing/uncrossing their legs while sittin g, etc. (80). Truncal movements with rocking back and forth were also commonly noted. A var iety of less common movements such as face rubbing, folding/unfolding arms, respiratory irr egu- larities (e.g. panting), and moaning have also been reported (80). As far as prognosis is concerned, a large proportion of TA patients continue to have sympto ms for years, even aft er the neu- roleptics have been discontinued. True remissions are in frequent, although they can occur. It seems that younger patients or early age of onset of TA may have a more reversible course and favor- able prognosis (66). Th e onset of TDt is oft en insidious, developing over weeks to months. It usually starts w ith one body part and can become seg- mental or even generalized. Craniocervical areas are the most com- mon sites of onset and are involved in 80% (72). Presentation with arm, trun k, or leg involvement is less common. Younger patients tended to have a more rapid spread t han older patients with TDt. In a study by Kiriakakis and colleagues (73) the mean age of o nset in TDt patients with rapid spread (<1 year) was 32 years compared with 42 years for pa tients in whom the dystonia spread more slowly (>1 year) (73). TDt may be diffi cult to dis tinguish from idiopathic dystonia, although Molho and colleagues (74) reported that tor- ti collis, laterocollis, and sensory tricks were less common in TDt than in idiopathic dystoni a. In a study of oromandibular dystonia (OMD), Tan and Jankovic (75) found that oro-buccal- lingual stere- otypies were more common in the tardive group when compared with idiopathic OMD (74). Also, lateral fl exion of the trunk and Pisa syndrome can occur in TDt and are le ss common in idiopathic dystonia (76). Management of tardive syndromes Tardive stereotypy/dyskinesias Th e optimal management of T D is to prevent it in the fi rst place by not using DBAs unless absolutely necessary or, if they have to be used, choosing an atypical neuroleptic at the lowest possible dose. Howeve r, when symptoms of TD fi rst appear an important decision involves whether to continue neu roleptic therapy or not. Data com- piled from multiple studies showed that 36% of patients improved aft er drug withdrawal (81). Ideally, the neuroleptic drug should be discontinued; however, if the risk for relapse of the psychiatric con- dition is high, other options suc h as dose reduction, switching to high-potency atypical neuroleptics, or adding other medic ations to treat the symptoms should be considered. TDt is a rather persistent disorder and remissions are uncom- mon. A review highlighted a l ow remission rate of 10% in TDt patients aft er a mean follow-up period of 6.6 years (73). However, our personal experience suggests that remission may occur if inter- vention is ea rly in the course of TDt. Prompt discontinuation of the off ending DBA seems to be the only factor relevant to infl u- encing remission. From a treatment perspective, it is important to distinguish TDt from tardive dyskinesia as anticholinergic drugs tend to worsen classic tardive dyskinesia but are benefi cial in tar- dive dystonia. Oft en, additional medications to treat the symptoms of TD are needed. Dopamine-depleting a gents such as tetrabenazine and reserpine are considered to be the most eff ective treatmen t for severe TD. Both of these medications should be introduced at low doses (tetrabenazine at 25 mg/day and reserpine at 0.25 mg/day) and then slowly titrated upwards at weekly inte rvals until adequate therapeutic benefi t or side eff ects occur. Th e dose of tetrabenazin e needed for adequate control of TD symptoms is 75 \200\223100 mg/day, and that for reserp ine is 3 \200\2236 mg/day. Reserpine has been used in combination with -methyl para-tyr osine, another dopamine- depleting agent, with signifi cant benefi t (82). Tardive akathisia Akathisia is characterized by a subjective aversion to remaining still wh ich is relieved by moving. Th e movements may be simple or complex and are stereotyped. Neu roleptic drug exposure is a com- mon cause of chronic akathisia; some of the other causes i nclude restless legs syndrome and parkinsonism. Tardive akathisia (TA) frequently seems to evolve from acute akathisia (which is clearly a complication of neuroleptic exposure). TA, rather than TDt, is more commonly associated with tardive dyskinesia (66). Multiple studies suggest a high prevalence of TA in patients with long-term neuroleptic exposure, ranging f rom 20 to 30% (66, 77). Like other tardive syndromes, TA has been reported with both typica l and atypical neuroleptics; case reports of TA induced by clozapine also exist, although t hey are rare (78). Drugs with GABAergic properties have also been used to treat TD. Among these, clonazepam ha s been successfully used to treat milder forms of TD. A common practice is to start with 0. 5 mg at bedtime and increase the dose by 0.5 mg every week until a therapeutic eff ect is a chieved. Caution needs to be exercised in combining clonazepam with antipsychotic medicatio n as it can lead to respiratory depression (83). Other GABAergic drugs such as sodium valpr oate and viga- batrin have been reported to have some effi cacy in a small number of patien ts (84) but, given their unfavorable risk \200\223benefi t profi le, they are not commonly used in clinical practice. For patients who must be treated with antipsychotics, an atypical neuroleptic such as cloza pine may be used. Clozapine has the low- est risk of causing TD and symptoms oft en improve once patients are switched to this drug. Th is may in part be due to the preferen- tial bl ockade of D4 over D2 receptors by clozapine (60). Treatment is initiated at 25 mg/day and s lowly titrated (range, 100 \200\223500 mg/ day) until therapeutic benefi t or side eff ects occur. With clozapine, weekly blood counts are required for 6 months to monitor for leu- c openia, and then every 2 weeks for the next 6 months, and then monthly, as it can cause agr anulocytosis (60). As mentioned above, clinically akathisia comprises both a sub- jective component of restles sness (which is oft en described as jit- teriness or nervousness) and an objective componen t of increased frequency of movement which may be complex and stereotyped. However, in TA t he subjective component becomes less severe and sometimes may evolve into a state of \200 \230pseudo-akathisia \200\231 (79). Patients with TA can temporarily suppress the abnormal move- ments, but it is associated with an increasing sense of tension or Oxford Textbook of Movement Disorders 310 Some other drugs that have shown limited success, either in a limited number of patients or small clinical trials, include the following. Amantadine showed effi cacy in a small study of 20 patients with TD when compared with placebo (85). Th is drug should be used careful ly in the elderly as it can cause or worsen confusion. Calcium-channel blockers have produc ed varying results, with nifedipine and verapamil demonstrating effi cacy (86), and diltiaz em being ineff ective (87). (66). Anticholinergics should be avoided in elderly patients prone to cognitive impairment, and patients with a history of depression should avoid dopamine-depleting agents. Benzodia zepines such as clonazepam may also be useful in treating TDt and they are oft en used in c ombination with the dopamine depleters or anticholiner- gics mentioned above. Other drugs, such as bromocriptine, cloni- dine, verapamil, amantadine, carbamazepine, and valproate, ma y be helpful in some patients (93). Clonidine, at doses ranging from 0.15 to 0.45 mg/day, has shown moderate improvement of sym ptoms in 75% of patients and com- plete resolution of abnormal movements in 50% of treated patients (88). Much attention has also been focused on vitamin E whose use is based on the belief that it may reverse the toxic eff ect of free radicals produced via DBAs (89). Th e doses employed range from 1200 to 1600 mg/day in three divided doses. Mixed results have be en reported, making its usefulness unclear. A Cochrane review of eight small studies with p oor randomization suggested that vitamin E does improve symptoms of TD (89), but a large pr ospective randomized 2-year trial of vitamin E versus matching placebo in patients with TD failed to show any benefi t (90). In addition to systemic pharmacological approaches to manage- ment, focal tardive dystonias aff ecting the craniocervical region have been successfully treated with botulinum toxin i njections (94, 95). Select patients with severe, irreversible tardive dystonia can show imp rovement aft er bilateral globus pallidus (GPi) deep brain stimulation (92). Other tardive phenomena Withdrawal emergent syndrome Th e withdrawal emergent syndrome is t ypically seen following the abrupt withdrawal of drugs from children who have been on long- standing DRBA (96). In contrast with classic TD, the move- ments in withdrawal emergent syn drome are choreic in nature and more generalized. Th ey tend to involve the neck, limbs, an d trunk, and seldom involve the orofacial region (unlike classic TD). Th ese movements have also been called \200\230withdrawal dyskinesias \200\231 and reported to occur rarely in adults with sudden cessation of an antipsychotic agent (60, 66). Th e withdrawal emergent s yndrome is usually self-limiting and typically disappears within 3 months. Another term enc ountered in the literature is \200\230covert dyskinesias \200\231. Th ese occur upon reduc tion of neuroleptic therapy and persist for longer periods. However, this distinction is ar bitrary, as some covert dyskinesias will disappear aft er prolonged follow-up (1). Another strategy to eliminate the abnormal movements is to reinstitute the off ending DRBA and then slowly taper it off (60, 66). Other drugs, such as propranolol, and antiepileptics such as leve- tiracetam have also been reported to have some benefi t in the treat- ment of TD based on anecdotal reports or smal l studies (89). Botulinum toxin injections have been used for the treatment of orofacial TD, with injection s into the lingual and mastica- tory muscles. Treatment should be initiated with low doses and then gradually increased as tolerated, as side effects such as dysphagia may occur (91) . Rarely, deep brain stimulation of the globus pallidus internus has been used with some be nefit to treat severe symptoms of orofacial TD, but more often in tardive dystonia (92). Tardive tourettism, myoclonus, and tremor In general, the principles of treatment of tardiv e tourettism, myo- clonus, and tremor are similar to those outlined in the section on tardi ve dyskinesias. Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS), fi rst recognized in 1 960 by Delay and colleagues (97), is an iatrogenic disorder associated with (but not limite d to) exposure to neuroleptics. Some of the other causes of NMS are listed in Table 28.8. T h e overall incidence of NMS is quite low, at around 0.2%, although other reports of Tardive akathisia Th e principles of treating tardive akathisia are similar to those for tr eating TD. Whenever possible, the off ending neuroleptic should be stopped. It is important to note that TA diff ers signifi cantly from acute akathisia. Opiates and propranolol, whi ch are eff ective in acute akathisia, are not useful in treating TA, whereas dopamine block ers, which worsen acute akathisia, have the opposite eff ect in TA (66). Table 28.8 C auses of neuroleptic malignant syndrome Use of neuroleptics Although there are few studies focused on treatments for tardive akathisia, evidence sugges ts that dopamine blockers (tetrabenazine and reserpine) are most eff ective in managing the se patients (66). At any time during its use (from initiation to being on stable dose) Withdrawal of dopaminergic therapy in PD Associated with stopping amantadine, levodopa, or dopamine agonists suddenly in PD patients Tardive dystonia As with other tardive syndromes, discontinuation of the off end- ing drug is the fi rst step. If the off ending DBA cannot be discon- tinued and the involuntary move ments are disabling, additional medications may have to be added. Th e dopamine-depleting a gents tetrabenazine and reserpine are the most eff ective drugs for the treatment of TDt. U nlike tardive dyskinesia, tardive dystonia responds well to anticholinergic therapies such as trihexyphenidyl. Since it is unclear which patients will respond to either of these clas ses of medications, the decision to use dopamine-depleting agents versus anticholinergics i s driven by their side-eff ect profi le Can occur during levodopa OFF periods Rarely, with dopaminergic medication dose adjustments Use of tetrabenazine Cocaine abuse Combining TCA + MAOI TCA, tricyclic antidepressant; MAO-I, monoamine oxidase inhibitor. Can lead to NMS-like syndrome. CHAPTER 28 Drug-Induced Movement Disorders 311 higher incidence exist (98, 99). Even though a uniform consensus regarding the defi nition and criteria are lacking, most experts agree that NMS is a clinical syndrome comprising fev er, rigidity, men- tal status changes, autonomic dysfunction, and other movement disorders (tremor, dystonia, and myoclonus) (100). Prominent laboratory abnormalities include leucocy tosis and elevated serum creatine kinase. Additionally, acute-phase reactants, including al bumin and serum iron levels, may be decreased (100). NMS typically occurs with exposure to DBAs, such as neuroleptics (both typical and atypical), and dopamine depleters, such as res erpine or tetrabenazine, and following withdrawal of dopaminergic agents in Parkinson \200 \231s disease (in the absence of neuroleptic exposure it has also been called parkinsonism \200\223hyperpyrexia syndrome) (60). NMS may occur within days to months of initiating neur oleptics, although only around 3% develop the syndrome aft er 6 months of stable neurolepti c medication (101). Risk factors include young age, male sex, potency of the neuroleptics, and rate of dose increase. Duration of NMS symptoms is signifi cantly shorter with atypical neuroleptics than with the older typical agents (102). 10. Marsden CD, Jenner P. the pathophysiology of extrapyramidal side eff ects of neuroleptic drugs. Psychol Med 1980; 10 : 55 \200\2237 2 . 11. 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Neuroleptic malignant syndrome in children and adol escents on atypical antipsychotic medication: a review. J Child Adolesc Psychopharmacol 200 9; 19 : 415 \200\2232 2 . 92. Welter ML, Grabli D, Vidailhet M. Deep brain stimulation for hyperki- netics disorders: dystonia, tardive dyskinesia, and tics. Curr Opin Neurol 2010; 23 : 420 \200\2235 . 103. Strawn JR, Keck PE, Jr, Caroff SN. Neuroleptic-malignan t syndrome. Am J Psychiatry 2007; 164 : 870 \200\2236 . 93. Fahn S. Th e tardive syndromes: phenomenology, concepts on patho- physiology and treatm ent. A comprehensive review of movement disor- ders for the clinical practitioner. 2003, 18 1 \200\22326 5 . This page intentionally left blank CHAPTER 29 Systemic Disease and Movement Disorders Leslie J. Cloud and Joseph Jankovic Summary Systemic illness is oft en complicated by the development of move- ment disorders, and the spectrum of movement disorders occur- ring in systemic diseases is as diverse as th e spectrum of diseases eliciting them. While movement disorders oft en develop in patients with a known systemic illness, they can sometimes be the present- ing feature of a systemic disease (1). Although pregnancy is not considered an \200\230illness \200\231, there are many movement disorders asso- ciated with this condition (2). Recognition and treatment of the underlying condition or a systemic disorder is essential for the opti- mal management o f associated abnormal movements. Th erefore, when evaluating patients with movement disorde