125. Verrips A, Hoefsloot LH, Steenbergen GCH, et al. Clinical and molecu- lar characterist ics of patients with cerebrotendinous xanthomatosis. Brain 2000; 123 : 908 \200\2231 9 . 143. Kamm C, Healy DG, Quinn NP, et al. Th e fragile X tremor ataxia syn- drome in the diff erential diagnosis of multiple system atrophy: data from the EMSA Study Group. Brain 2005; 128 : 1855 \200\2236 0 . 126. Gallus GN, Dotti MT, Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci 2006; 27 : 143 \200\2239 . 144. Li JY, Hsu CC, Tsai CR. Spinocerebellar variant of adrenoleukodystro- phy with a novel ABCD1 gene mutation. J Neurol Sci 2010; 290 : 163 \200\2235 . 145. Vianello M, Manara R, Betterle C, Tavolato B, Mariniello B, Giometto B. X-linke d adrenoleukodystrophy with olivo pontocerebellar atrophy. Eur J Neurol 2005; 12 : 912 \200\22314 . 127. Vanier MT. Niemann \200\223Pic k disease type C. 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Seattle, WA : University of Washington , 1993. Available online at http: //www.ncbi.nlm.nih.gov/ bookshelf/ (last updated 11 February 2011). 148. Milone M, Massie R. Polymerase gamma 1 mutations: clinical correla- tions. Neurologist 2010; 16 (2): 84 \200\2239 1 . 149. Manto M. Dominant ataxias. In: Manto M (ed.) Cerebellar disorders. A practical approac h to diagnosis and management , pp. 242 \200\22383 . Cambridge : Cambridge University Press . 132. Harding AE. Classifi cation of the hereditary ataxias and paraplegias. Lancet 1983; 1 : 1151 \200\2235 . This page intentionally left blank CHAPTER 28 Drug-Induced Movement Disorders Shyamal H. Mehta , John C. Morgan , and Kapil D. Sethi Movement disorders due to dopamine-receptor blocking agents (DBAs) Antipsychotic agents, al so commonly referred to as neuroleptics, are used not only to treat psychiatric disorders b ut also in neuro- logical diseases such as Tourette \200\231s syndrome, Huntington \200\231 s disease, and psychosis in advanced Parkinson \200\231s disease. Th e introduction of chlo rpromazine in the early 1950s was a great advance in the treatment of psychosis, but it was soon realized that signifi cant neurological side eff ects are associated with this class of drugs. In fact, in the 1950s when it was noted that both chlorpromazine and reserpine in duced extrapyramidal side eff ects (EPS), despite being distinct chemical entities, it was thought that induction of EPS was integral to their clinical antipsychotic effi cacy. Recen t advances in drug development have revealed that this is not true and evidence implicates D2 receptor antagonism and the speed of dissociation of the drug from the receptor in the d evelopment of these EPS (DBAs with less D2 affi nity and more rapid dissociation are less l ikely to produce EPS). Over the last several decades, cumulative experience with the older (typical) and newer (atypical) neuroleptics has high- lighted the wide range of acute to mo re delayed movement disor- ders that may be caused by these agents (Table 28.1) (1). also showed a 2.4-fold higher risk of DBA-induced EPS in AIDS patients compared with age-ma tched psychotic patients without AIDS (7). Cocaine abuse may predispose to acute dystonic r eac- tions (8). Also, in contrast with other antidepressant medications, selective serotoni n-reuptake inhibitors (SSRIs) have been known to induce acute dystonic reactions, mostly ea rly in the course of treatment or aft er a dose increase (2). Th ese reactions have also be en reported with the dopamine depletor tetrabenazine, perhaps because of its partial dopami ne blocking activity. Although the pathophysiology of acute dystonia due to DBAs is unclear, it is well known tha t the propensity of any DBA to cause acute dystonia strongly correlates with its ability to block the D2 receptor in the striatum. It is through this D2-receptor mediated sig- nallin g that the DBA infl uences the intricate neuronal circuitry and modulates the cholinergic, GABAergic, and NO-synthase-positive interneurons in the striatum (2). As far as modulation of cholin- ergic signaling is concerned, one hypothesis is that dopaminergic hypofunction r esults in a relative overactivity of cholinergic mecha- nisms (9). Th is hypothesis is supp orted by a consistent response of acute dystonia to anticholinergic drugs. Another hypothes is pro- poses that DBAs induce paradoxical dopaminergic hyperfunction by blockade of presyn aptic dopamine receptors. As the level of the DBA decreases, postsynaptic receptors are exp osed to the natural release of dopamine from presynaptic terminals (10) which may precipita te the dystonia. Acute dystonia Acute dystonia occurs shortly aft er the introduction of the DBA and occasio nally aft er a dose increase. Estimates of incidence of acute dystonia from DBAs depend on several factors, such as patient population being studied, type and dosage of DBA used, and concurrent medications (2). Studies in patients with a fi rst episode of psychosis treated with DBAs have reported a 34 \200\22360% risk of developing drug-induced acute dystonia (2 \200\2234) and 50% of patients experience the fi rst signs of dystonia within 48 hours of drug intake (5). Clinical features Drug-induced dystonia can aff ect various regions of the body and can be very painful. Based on several prospective studies, Mazurek and Rosebush (2) reported that 42% of acute dystonic reactions involved torticollis or retrocollis as a clinical feature. Involvement of the facial muscles, which may range from grimacing and tight- ness to masse ter spasm, is another common fi nding. Although rare, other facial muscles causing blepharo spasm or lip curling may also be involved. Similarly, the limb muscles may also be involved , although less frequently. Some of the risk factors for developing acute dystonia aft er expo- sure to DBAs are young age, male sex, previous dystonic reaction, higher dose and high potency of DBAs, familial p redisposition, underlying psychiatric illness, mental retardation, and a history of electro convulsive therapy (2, 6). Interestingly, a retrospective study Some of the more severe clinical manifestations involve the throat musculature ( 19%) causi ng swallowing diffi culties or Oxford Textbook of Movement Disorders 304 the objective manifestations of restlessness in the form of move- ments of the limbs, a ten dency to shift body position in the chair while sitting, or marching while standing. Table 28.1 Movement disorders induced by dopamine blocking agents I. Acute \227\206 Acute dystonia Recent studies using large databases clearly indicate that akathisia occurs with the newer DBAs, although the frequency is not as high as with conventional antipsychotics. Th ese sym ptoms have also been associated with the administration of SSRIs. Other drugs that can caus e acute akathisia are listed in Table 28.2. Acute akathisia Drug-induced parkinsonism II. Chronic Tardive dyskinesia/stereotypy Th e temporal association with drug administration is a very important feature in the diagn osis of acute akathisia. Acute aka- thisia usually starts within the fi rst 2 weeks and alm ost always within the fi rst 6 weeks (18, 19). Th e appearance of akathisia is also dose de pendent, with higher dosages of DBAs more likely to precipitate symptoms (18, 19). Other ri sk factors include use of conventional or higher-potency antipsychotics, bipolar depression , palliative care settings, and co-morbid substance abuse in psychosis (20). Tardive myoclonus Tardive tics Tardive tremor Tardive dystonia Tardive akathisia III. Miscellaneous Withdrawal emergent syndrome Th e reported prevalence of neuroleptic-induced akathisia varies widely depending on the DB As used. With older neuroleptics it is typically around 20% (18, 19). With the advent of ne wer atypical neuroleptics the incidence of akathisia has decreased, although has not comple tely disappeared. A study of quetiapine across a dose range 75 \200\223750 mg/day found an akathisia prevalence of 0 \200\2232% versus 8% and 15% for patients randomized to placebo a nd haloperidol, respectively (21). Neuroleptic malignant syndrome laryngospasm, which can be potentially life-threatening. Oculogyric crises (upward deviatio n of the eyes) and opisthotonus (back arch- ing) are a striking presentation of acute drug- induced dystonia. Th ese represent 6 \200\22315% and 3.5 \200\22312% of dystonic reaction s, respectively, and are seen in acute as well as tardive dystonia (2). A variety of conditions should be considered in the diff erential diagnosis of acute drug-i nduced akathisia. Agitation and restless- ness can be seen as a part of generalized anxiety disorder, mania, or depression, and patients with acute psychosis may have agitated pacing similar to akathisia (22). Movement disorders such as rest- less legs syndrome and pseudo- akathisia (movements as seen in akathisia without the subjective complaints of restlessness ) may also be diffi cult to distinguish from acute akathisia (22). Management Acute dystonia responds well to injectable anticholinergic drugs such as benztro pine (11) or antihistaminic agents such as diphen- hydramine (12). Benzodiazepines such as diazepam or lorazepam are equally effi cacious. Th e response to anticholinergics is so con - sistent that if a patient with suspected DBA-induced acute dystonia fails to respond, cli nicians should suspect phencyclidine-induced dystonia (13). If an episode of acute dystonia persists aft er an initial parenteral dose, another dose should be repeated in 30 minutes . At times, acute dystonic reactions such as laryngeal dystonia are severe enough to warran t life-saving measures (tracheostomy). Th e acute dystonic reaction may recur aft er an ini tial response even without exposure to a subsequent dose of DBA and repeated thera- peutic intervention may be necessary. Although the exact mechanism of drug-induced akathisia remains unknown, the increased frequ ency of acute akathisia with high-potency D2 blocking DBAs suggests that D2 receptor antago nism plays an integral role. Two studies using positron emis- sion tomography (PET) demonst rated an association between D2 occupancy in the striatum and the development of akathisia, with the authors suggesting a threshold for D2 receptor occupancy of 74 \200\22382% for th e production of EPS including akathisia (23, 24). Evidence also suggests that reduced activ ity of dopaminergic pro- jections from the midbrain to the ventral striatum may lead to the development of akathisia (25). In addition to the dopaminergic systems, the serotonergic s ystem may also be involved as SSRIs are a common cause of acute akathisia. A recent double- blind placebo-controlled study showed improvement of akathisia with trazodone, most likely through its property of serotonin 2A postsynaptic receptor antagonism (26). Th ere is some evidence to suggest that acute dystonic reactions may be prevented by the us e of anticholinergic drugs (14, 15). It is recommended that patients at high risk of acute dystonia (young patients, cocaine abusers, and AIDS patients) or in specifi c situa- tions (i.e. fi rst exposure to DBA) receive prophylactic anticholiner- gics (15). Since the incre ased risk of developing a dystonic reaction to DBAs is in the fi rst week of initiating tre atment, the prophylactic medication can be withdrawn thereaft er. Acute akathisia Th e term \200\230akathisia \200\231 (from Greek, literally \200\230inabi lity to sit \200\231) was introduced by Haskovec in 1902, who thought that the symp- toms h ad a psychological cause (16). Th e fi rst case report of drug- induced akathisia was by Si gwald in 1947, prior to the introduction of neuroleptics, who noticed it in association wit h promethazine (17). Th ere are two aspects of akathisia: Table 28.2 Other drugs that can cause acute akathisia Antiepileptics Carbamazepine, ethosuximide Antidepressants: Lithium SSRIs: \202 uoxetine, sertraline, citalopram, etc. Tricyclic and heterocyclic antidepressants Calcium-channel blockers Diltiazem, \202 unarizine, cinnarizine a subjective report of restlessness or inner tension, mostly in the legs, with a consequent inability to maintain a posture for several minutes and anxiety; \227\206 Dopamine depleters Tetrabenazine and reserpine 5-HT receptor ligands Buspirone, methysergide CHAPTER 28 Drug-Induced Movement Disorders 305 Management Th e drugs most commonly used to treat drug-induced aka- thisia include beta-blo ckers, anticholinergics, amantadine, ben- zodiazepines, and newer agents such as serotonerg ic (5-HT) antagonists (27). Table 28.3 Drugs that can cause or exacerbate drug-induced parkinsonism Neuroleptics Typical neuroleptics: Phenothiazines such as chlorpromazine, promethazine, etc. Propranolol (40 \200\22380 mg/day), a non-selective lipophilic beta- adrenergic antagonist, has been used as a fi rst-line anti-akathisia agent for decades. Studies with propranolol have shown signifi cant overall improvement in both subjective and objective measures of ak athisia (28, 29). Anticholinergics used to treat akathisia include biperiden (2 \200\2236 m g/day), benztropine (1.5 \200\2238 mg/day), or trihexy- phenidyl (2 \200\22310 mg/day). How ever, many clinicians feel that these are only partially eff ective and their use is limite d by anticholiner- gic side eff ects. It is recommended that these agents are only used in patients with akathisia who have associated parkinsonism (27). Butyrophenones such as haloperidol, droperidol, triperidol, etc. Th ioxanthenes such as thiothexene, zuclopenthixol, \202 upenthixol, etc. Atypical neuroleptics: Risperidone, olanzapine, clozapine, ziprasidone, etc. Dopamine depleters Tetrabenazine, reserpine Substituted benzamides M etoclopramide, cisapride, sulpiride, clebopride, etc. Commonly used benzodiazepines include lorazepam (1 \200\2232 mg/ day), clonazepam (0.5 \200 \2231 mg/day), and diazepam (5 \200\22315 mg/day). Placebo-controlled studies with clonazep am and diazepam showed benefi t in patients with akathisia (22). Improvements occurred aft er the fi rst week of treatment, with minimal additional benefi t aft er the second week of treatment (22). Vestibular sedatives Flunarizine, cinnarizine, etc. Calcium-channel blockers Amiodarone, verapamil, diltiazem, nifedipine, etc. Immunosuppressants Cyclophosphamide, cytosine arabinoside, cyclosporin, etc. Antidepressants SSRIs ( \202 uoxetine etc.), lithium, phenelzine, etc. Agents with marked 5-HT 2 A receptor antagonism such as mir- tazapine, mianserin, and cypro heptadine are anti-akathisia thera- pies based on their potential to counteract antipsychot ic-induced dopamine D2 receptor blockade by increasing dopaminergic neu- rotransmission (27 ). Clinical studies attest to the utility and effi - cacy of this class of compounds as an alternative to beta-adrenergic blockers for the treatment of acute akathisia. Others Valproic acid, amphotericin B, disul \201 ram, molindone, etc. all cases initially thought to have idiopathic PD were subsequently diagnosed as DIP (33). Numerous retrospective analyzes and epidemiologic studies have been performed to reliably i dentify risk factors for DIP. However, all studies have demonstrated one unambiguous fact \200\224there is enormous individual variation in susceptibility to develop move- ment diso rders secondary to the DBAs (34). Ayd (18) was the fi rst to identify female sex, old age, and high-potency neuroleptics as potential risk factors for DIP. Based on current research, only neuroleptic potency and dose are unequivocal risk factors for DIP. Others, such as in creasing age, female sex, pre-existing EPS, dementia, brain injury, family history of PD, a nd severe psychiatric illness, are best regarded as possible predisposing factors (34). Drug-induced parkinsonism Drug-induced parkinsonism (DIP) may result from a variety of pre- scribed medications. Drugs that either block the dopamine recep- tors or deplete dopamine stores produce a functional dopaminergic defi ciency and signs/symptoms akin to idiopathic Parkinson \200\231s dis- ease (PD). Th e most common off ending drugs are DBAs, such as neu roleptics; however, there are other non-neuroleptic drugs which may also cause DIP. From a review of 17 years \200\231 experience of 261 drugs suspected of causing DIP, most involved central dopaminergic antagonists (49%), followed by antidepressants (8%), calcium-channel blockers (5%), peripheral dopaminergic antago- nists (5%), and H1 antihistamines (5%). Case s with lithium, valp- roic acid, amiodarone, anticholinesterases, or trimetazidine were als o found (30). Table 28.3 lists the drugs that can cause or exacer- bate parkinsonism. DIP appears to develop in almost all patients given high doses of high-potency DBAs suffi c ient to block 80% of central dopamin- ergic receptors, especially D2 receptors (35). In ad dition, compara- tive ratios between antagonism of diff erent receptors may play an importa nt role: high acetylcholine/dopamine receptor antagonism, and a favorable ratio of 5-HT 2 t o D2 receptor antagonism have a lower propensity to result in movement disorders (36). Since the advent of atypical neuroleptics and increasing aware- ness (i.e. litigation) rega rding medications such as metoclopra- mide, the incidence of DIP has now decreased. However , clinically it remains a challenge as it is oft en missed and also misinterpreted as idiop athic PD. Clinical features Clinically, DIP may present with rest tremor, bradykinesia, and rigidity. Patients with DIP are less likely to have prominent gait freezing and postural instability . Other manifestations include speech disturbance, micrographia, and facial hypomimia. Th u s, DIP cannot be distinguished clinically from idiopathic PD as the features can be similar (34). Also, asymmetry is common in DIP and should not be misconstrued as a sign against th e diagnosis. In general, patients with DIP are less likely to exhibit tremor, but this is n ot helpful in the individual patient in diff erentiating DIP from IPD (37). Th e relative l ack of tremor may either refl ect a younger patient population affl icted with DIP or an in trinsic, as yet un realized, pathophysiological diff erence between the two Epidemiology and pathophysiology DIP is a common complication of antipsychotic drug use, oc cur- ring in 15 \200\22360% of patients treated with DBAs (18). In one study, 51% of 95 pat ients referred for evaluation had parkinsonism asso- ciated with prescribed drugs (31). Ano ther study found that in a general neurology practice, 56.8% of 306 cases with parkinson- i sm were either induced or aggravated by drugs (32). Frequently, these patients are misdiagn osed as idiopathic PD and treated with dopaminergic drugs without benefi t. In a community study, 18% of Oxford Textbook of Movement Disorders 306 conditions (34). Th e co-existence of a hyperkinetic movement disorder, such as oro-buccal- lingual dyskinesia, in the absence of levodopa treatment supports a diagnosis of DIP rather than idi- opathic PD. 44). Limited experience exists for other therapeutic modalities, such as dopamine agonists, levodopa, propranolol and electrocon- vulsive therapy (34). In a survey of 3775 patients, Ayd (18) found that DIP usually occurs later than akathisia a nd dystonia, and 90% of cases devel- oped within the fi rst 72 days. Another study reported that the time of onset of DIP from haloperidol was dose related, with higher doses produci ng symptoms within 2 weeks (38). Not much is known regarding the natural progression of DIP with continued neuroleptic exposure. Fernandez and colleagues (39) studied 53 patients who remained on neuroleptics over a 14-year period; these subjects experienced a decrease in t ardive dyskinesia symptoms but a signifi cant increase in DIP, suggesting that DIP progress es over time. Upon cessation of the off ending agent, DIP may ameliorate with time as patie nts with DIP who are treated with antiparkinso- nian drugs can oft en have these discontinu ed without a recurrence of symptoms (34). Even though data are limited, evidence suggests t hat severe long-term DIP is uncommon and chronic antiparkinso- nian therapy is rarely requi red (40). Chronic/delayed movement disorders caused by dopamine receptor blocking agents Tardive dysk inesia Tardive dyskinesia (TD) refers to abnormal excessive involuntary movements related t o exposure to at least one DBA. Th e onset of symptoms should be within 6 months of the las t DBA use and per- sist for at least a month aft er cessation of the off ending drug (45). In 1980 the American Psychiatric Association Task Force defi ned TD as an abnormal involunt ary movement following a minimum of 3 months of neuroleptic treatment in a patient with no other identifi able etiology for movement disorders (46). However, the DSM-IV criteria requ ire only one month of exposure to neurolep- tics in individuals aged 60 and older (47). Th e term dyskinesia refers to any abnormal, involuntary, repeti- tive, co-ordinated moveme nts, regardless of etiology. Stereotypy is the most common manifestation of classic TD. Oth er forms of tardive movements include tics, dystonia, akathisia, and myo- clonus, among oth ers. However, most oft en patients clinically manifest classic TD as a combination of orofa cial stereotypy with choreic movements of hands, fi ngers, and lower extremities or dystoni a (48). Rarely, when diaphragm and chest muscles are involved, these are called \200\230re spiratory dyskinesias \200\231 or referred to as \200\230copulatory dyskinesias \200\231 w hen the involvement of abdominal or pelvic muscles produces pelvic rocking type movements ( 49, 50). Sometimes hyperkinetic (stereotypy, chorea, etc.) and hypokinetic (parkinsonism) m ovements co-exist (51). Th e symptoms of TD may fi rst emerge upon a reduction in or cessat ion of a DBA. Th e term \200\230withdrawal-emergent dyskinesia \200\231 refers to emergenc e of dys- kinesia upon discontinuation of the DBA. It may manifest as gen- eralized chorea, especially in children, and resolves within 90 days. Persistence beyond this is called cov ert dyskinesia. In older patients and for those with more protracted and chronic symptoms it is possible th at DIP may unmask subclini- cal PD. Th is is supported by the persistence of parkinsonism i n some patients aft er discontinuing DBA. In addition, a patho- logical study revealed cell loss and Lewy bodies in the substantia nigra of two patients who died some time aft er the ir parkinson- ism had resolved following discontinuation of DBA. Clinically, it is diffi cu lt to distinguish DIP from idiopathic PD, and functional imaging has been used to clarify t his issue. One study examined 18 F-dopa PET scans in thirteen DIP patients. In four out of thir- teen DIP patients there was evidence of signifi cant reduction of 18 F-dopa uptake in the putamen within the PD range, and in three of these four patients there was continuing or worsening parkin- sonism. However, all nine patients with normal scans recovered from th eir DIP symptoms (41). In another study, twenty patients who developed parkinsonism while o n neuroleptics underwent a [ 123 I]-FP-CIT SPECT scan. Nine patients had normal scans and e leven showed signifi cantly diminished striatal binding, suggest- ing underlying nigrostria tal dysfunction. Notably, there were no diff erences in clinical features between patients with normal and abnormal scans (42). Epidemiology and risk factors It has been over 50 years since the fi rst reports of TD asso ciated with neuroleptic exposure. However, it was not until the 1970s that there was genera l acceptance of the association of TD with long-term neuroleptic use (52). Th e frequency o f TD has changed over the past several decades, driven by one important factor \200\224the transition from typical to atypical (second-generation) neurolep- tics. Th e pharmacologica l profi le of the newer atypical neuroleptics is shown in Table 28.4. Management Ideally, prevention of DIP would be best. Some authorities suggest using antipar kinsonian drugs at the onset of neuroleptic therapy. Since anticholinergics and amantadine also have side eff ects, a more prudent approach might be to institute prophylactic therapy to cover high-risk patients such as those with a family history of PD, elderly subjects, a nd female subjects (43). A detailed literature review by Smith and colleagues (53, 54) provides an insight into the prevalence of TD in an earlier neuroleptic era. In 56 studies involving nearly 35 000 typic al neuroleptic-treated patients, the overall prevalence of dyskinesia averaged 20%. Large-s cale prospective studies indicate an average rate of developing TD of 5% per year for the fi rst several years of treatment with typical neuroleptics and a cumulative 5-year inciden ce rate of 20 \200\22326% (54, 55). Glazer and colleagues (56) sug- gested risk increases i n a linear fashion with continued exposure (49% at 10 years and 25-year risk estimated at 6 8%). However, with the advent of second-generation neuroleptics, prevalence Th e treatment of clinically manifest DIP is diffi cult. In most cases, DIP is reversible o nce the off ending drug is withdrawn. However, in some cases this may not be possible; decr easing the dose of the neuroleptic or switching to an atypical neuroleptic such as clozap- ine or quetiapine may be benefi cial. Mild DIP can be left untreated. When symptoms of DIP are more troublesome, several studies have shown improvement with amantadine. Anticholinerg ics have also been used with some success in the treatment of DIP. However, the evidence fo r amantadine remains less confl icting than for anti- cholinergics, and this drug also seem s to be better tolerated (34, CHAPTER 28 Drug-Induced Movement Disorders 307 Table 28.4 Receptor binding pro \201 le of atypical neuroleptics Receptor binding Atypical neuroleptic Typical neuroleptic Haloperidol +++ Risperidone \200\223 Olanzapine +++ Quetiapine + Ziprasidone + Aripiprazole \200\223 Clozapine ++ D1 D2 5-HT 2 1 2 EPS +++ +++ ++ +++ +++ ++ ++++ ++++ ++++ +++ ++++ ++ ++++ + +++ +++ ++++ ++ + +++ ++ +++ \200\223 + \200\223 + +++ \200\223 +++ ++ + ++ + + ++++ Clinical features Tardive stereotypy/dyskinesias Th e term tardive dyskinesia denotes repet itive, co-ordinated, and seemingly purposeful movements, aff ecting mainly the oro facial a rea, which are induced by chronic exposure to neuroleptics. Classic TD is characterized by stereotypic movements aff ecting the orolinguobuccal muscles. Some prefer to use the term \200\230tardive stereotypy \200\231, since that is the predominant movement disorder. It ma nifests as repetitive movements of the tongue, lips, and mouth causing tongue protrusion an d retraction, lip smacking, and chew- ing movements. Th e diaphragm and chest muscles are f requently involved in respiratory dyskinesias, resulting in noisy and diffi cult breathing. Th e abdominal and pelvic muscles may also be involved producing truncal or pelvic movemen ts known as copulatory dys- kinesia (1). Most commonly, TD patients exhibit a combination o f movement disorders. Frequently, the stereotypy of classic TD is combined with choreic mov ements of the hands, fi ngers, arms, and feet or with akathisia, which involves restlessnes s, pacing, rubbing of hands together, etc. Other causes of orofacial dyskinesias should als o be considered in the diff erential diagnosis, and these are out- lined in Table 28.5. of both acute EPS and TD declined over months of treatment in patients changed from traditi onal to modern neuroleptics (57). In mid-2003, the Hillside Hospital group analyzed several clini- cal trials with 2700 patients on modern neuroleptics, with an average duration of exposure of 301 days. Th ey found the annual incidence of TD associated with second-generat ion neuroleptics (weighted by numbers of subjects exposed) averaged 2.1% overall: 0.8% in a dults aged <50 years versus 5.3% among patients aged >50 years (58). Th us the risk of TD i s signifi cantly lower (by two- to threefold) with most modern neuroleptics compared with o lder neuroleptics (57). However, TD risks associated with modern antipsychotics may be simi lar to those of older antipsychotics of low to moderate potency. Risperidone (and its activ e metabolite paliperidone), at high doses, may carry a high TD risk, whereas TD risk is int rinsically low with clozapine, and perhaps quetiapine and aripiprazole (59). Epidemiological studies have identifi ed several putative risk fac- tors which may increase the chance of developing TD. Demographic risk factors include increased age, diagnosis of mood disorders, and gender. Th e gender eff ect is complicated: earlier studies suggested a higher risk in the female population, whereas more recent con- trolled studies show a high er risk in females only over age 65 and increased severity in younger males (60). Other ris k factors include total cumulative drug exposure, diabetes, alcohol consumption, cocaine ab use, persistence of drug exposure aft er development of TD, and a history of electroconvuls ive therapy (60). Tardive tourettism Tardive tourettism is an acquired form of tourettism, with onset of abno rmal movements and vocalizations following chronic neu- roleptic exposure. Th e fi rst case was reported by Golden in 1974 (64) and was named \200\230tardive tourettism \200\231 by Stahl in 1980 (65). Clinically, the symptoms of tardive tourettism are indistinguishable Pathophysiology of tardive dyskinesia Th e pathophysiology of TD is complicated and poorly understood. Concisely put, most accepted theories suggest that chronic exposure to neurolep tics result in a combination of postsynaptic dopamine receptor hypersensitivity, abnormalit ies of striatal GABA-containing neurons, and degeneration of striatal cholinergic interneur ons (61). It seems plausible that dopamine receptor hypersensitivity may create a condition simulating dopaminergic excess in the striatum, leading to the development of TD. Observat ions which support this theory include reduction of DBA dose which can precipitate TD (with drawal-emergent syndrome or covert dyskinesia). Similarly, increasing the DBA dose can temp ora rily mask TD symptoms. Also, dyskinesias induced by levodopa in PD patients may closely resem- ble the movements seen in TD (1). Another hypothesis implicates GABA depletion as a cause. Th is is based on animal studies which showed decreased GABA turnover and upregulat ion of receptors in animals with signifi cant TD (62). A small human post-mortem study show ed signifi cantly decreased glutamic acid decarboxylase activity (the rate-limiting enzyme in GABA synthesis) in patients with TD compared with patients without (63). 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).