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Extrapyramidal Symptoms
Introduction
Extrapyramidal side effects (EPS), commonly referred to as drug-induced movement disorders are among the most common adverse drug effects patients experience from dopamine-receptor blocking agents. It was first described in 1952 after chlorpromazine-induced symptoms resembling Parkinson disease.[1] A variety of movement phenotypes has since been described along the EPS spectrum, including dystonia, akathisia, and parkinsonism, which occur more acutely, as well as more chronic manifestations of tardive akathisia and tardive dyskinesia. The symptoms of EPS are debilitating, interfering with social functioning and communication, motor tasks, and activities of daily living. This is often associated with poor quality of life and abandonment of therapy, which may result in disease relapse and re-hospitalization, particularly in schizophrenic patients stopping pharmacologic therapy.[2]
Etiology
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Etiology
Centrally-acting, dopamine-receptor blocking agents, namely the first-generation antipsychotics haloperidol and phenothiazine neuroleptics, are the most common medications associated with EPS. While EPS occurs less frequently with atypical antipsychotics, the risk of EPS increases with dose escalation.[3] Other agents that block central dopaminergic receptors have also been identified as causative of EPS, including antiemetics (metoclopramide, droperidol, and prochlorperazine),[4][5] lithium,[6] serotonin reuptake inhibitors (SSRIs),[7] stimulants,[8] and tricyclic antidepressants (TCAs).[7] In rare situations, antivirals, antiarrhythmics, and valproic acid have also been implicated.[9]
Epidemiology
Rates of EPS are dependent on the class of medication administered. First-generation neuroleptics were associated with EPS in 61.6% of patients in a study of institutionalized patients with schizophrenia.[10] Rates of EPS have declined with atypical antipsychotics with clozapine having the lowest risk and risperidone the highest.[11] In terms of antiemetics with a dopamine D2 receptor antagonist effect, EPS incidence is cited to be between 4% to 25% with metoclopramide[12][13][14] and between 25% to 67% with prochlorperazine.[15][16]
Risks factors include a history of prior EPS and high medication dose.[17] Elderly females are more susceptible to drug-induced parkinsonism and tardive dyskinesia,[18][19] while young males manifest with more dystonic reactions.[20]
Pathophysiology
The mechanism of EPS is thought to be due to the antagonistic binding of dopaminergic D2 receptors within the mesolimbic and mesocortical pathways of the brain. However, the antidopaminergic action in the caudate nucleus and other basal ganglia may also contribute significantly to the occurrence of EPS.[21]
Toxicokinetics
Researchers previously hypothesized that the faster dissociation of atypical antipsychotics from the dopamine receptor, compared to typical antipsychotics, explained the reduced incidence of EPS. However, a recent study by Sykes utilized a novel time-resolved fluorescence energy transfer assay to demonstrate that binding kinetics and association rates, not dissociation, correlate more with EPS.[22]
History and Physical
There is a wide spectrum of EPS presentations. Dystonia most often occurs within 48 hours of drug exposure in 50% of cases, and within five days in 90% of cases.[23] On physical exam, dystonia manifests with involuntary muscle contractions resulting in abnormal posturing or repetitive movements. It may affect muscles in different body parts, including the back and extremities (opisthotonus), neck (torticollis), jaw (trismus), eyes (oculogyric crisis), abdominal wall, and pelvic muscles (tortipelvic crisis), and facial and tongue muscles (buccolingual crisis).[24] The provider must evaluate these patients for pain and particularly difficulty in breathing, swallowing, and speech.
Akathisia is characterized by a subjective feeling of internal restlessness and a compelling urge to move, leading to the objective observation of repetitive movements comprising leg crossing, swinging, or shifting from one foot to another.[19] The onset is usually within four weeks of starting or increasing the dosage of the offending medication. Due to its often vague and non-specific presentation of nervousness and discomfort, akathisia is often misdiagnosed as anxiety, restless leg syndrome, or agitation. In an attempt to treat these incorrect diagnoses, the provider may subsequently increase anti-psychotic or SSRI medications, further exacerbating akathisia.[19][25] This failure to correctly diagnose can be detrimental as the severity of akathisia is linked to suicidal ideation, aggression, and violence.[26] The provider must also note that withdrawal akathisia may occur with discontinuation or dose reduction of antipsychotic medication, and is typically self-limited lasting within six weeks.[19]
Drug-induced parkinsonism presents as tremor, rigidity, and slowing of motor function in the truncal region and extremities. The classic appearance is an individual with masked facies, stooped posture, and a slow shuffling gait. Gait imbalance and difficulty rising from a seated position are often noted.[9][27]
Finally, tardive dyskinesia manifests as involuntary choreoathetoid movements affecting orofacial and tongue muscles, and less commonly the truncal region and extremities. While symptoms are typically not painful, they may impede social interaction and cause difficulty in chewing, swallowing, and talking.[28]
Evaluation
In most cases, laboratory and imaging tests are not required. The diagnosis is apparent from an accurate history and physical exam, especially noting a history of medication exposure.
Treatment / Management
If a patient is experiencing acute onset of EPS, particularly dystonia, the provider must assess if an emergency airway intervention is necessary as laryngeal and pharyngeal dystonic reactions may increase the risk of imminent respiratory arrest. Dystonic reactions are rarely life-threatening, and the provider should discontinue the offending agent and manage pain if present. If the causative medication is a typical first-generation antipsychotic, switching to an atypical antipsychotic may be trialed. Administration of an antimuscarinic agent (benztropine, trihexyphenidyl) or diphenhydramine may relieve dystonia within minutes.[21] In cases of tardive dystonia, additional therapeutic strategies include administration of benzodiazepine,[21] injection of botulinum toxin for facial dystonia,[29][30] trial of muscle relaxant (e.g., baclofen),[30] trial of dopamine-depleting agents (e.g. tetrabenazine),[30] and consideration of deep-brain stimulation or pallidotomy for refractory cases.[30][31](A1)
For the treatment of akathisia, strategies similar to managing dystonia are employed, including stopping or reducing the dosage of the offending medication, switching to an atypical antipsychotic if a typical first-generation antipsychotic was the offending drug, and administering anti-muscarinic agents. Additional therapeutic strategies more specific to akathisia include administration of a beta-blocker (most commonly propranolol), amantadine, clonidine, benzodiazepines, mirtazapine, mianserin (tetracyclic antidepressant), cyproheptadine, and propoxyphene.[32][33]
Tardive dyskinesia is treated by withdrawal or dose reduction of the causative medication, switching to an atypical antipsychotic, withdrawal of concurrent antimuscarinic medications (although trihexyphenidyl has been reported to be therapeutic[34]), injection of botulinum toxin for facial dyskinesia,[35] benzodiazepines,[36] amantadine,[36] and trial of dopamine-depleting medications (e.g. tetrabenazine[37]). Interestingly, the trial of levetiracetam, zonisamide, pregabalin, vitamin B6, and vitamin E have also been reported as therapeutic.[28][38](A1)
Drug-induced parkinsonism is treated with discontinuation or dose reduction of the causative medication, switching to an atypical antipsychotic, and administration of medications used for Parkinson disease, including amantadine, antimuscarinic agents, dopamine agonists, and levodopa.[27]
Differential Diagnosis
EPS may be challenging to distinguish from other idiopathic movement disorders. Muscle rigidity and tension are nonspecific symptoms that may be observed in neuroleptic malignant syndrome, serotonin syndrome, and other movement disorders. Chorea and athetosis are also present in Huntington disease (distinguished based on family history and genetic testing), Sydenham chorea (identified with a history of streptococcal infection), Wilson disease (adolescent-onset with a defect in copper metabolism), and cerebrovascular lesions.[39][40] The flat facial expression, psychomotor slowing, and low energy level in akathisia may mimic the negative symptoms of schizophrenia. In addition, restlessness in akathisia may also appear similar to anxiety and psychotic agitation.[41] If dementia accompanies parkinsonian signs and other motor abnormalities, the provider should evaluate the patient for Parkinson disease, Lewy body dementia, vascular dementia, and frontotemporal dementia.[40] Interestingly, up to a third of new-onset schizophrenic patients who have never been medicated may present with parkinsonian signs.[42]
Prognosis
EPS typically resolve spontaneously or improve with pharmacologic interventions. Acute dystonic reactions are often transient, but late-onset and persistent tardive dystonia have been described in the literature where symptoms persisted for years.[43] A study of 107 cases of tardive dystonia reported that only 14% of patients achieved remission over a mean follow-up period of 8.5 years.[44] Similarly, while acute akathisia may spontaneously resolve or improve with appropriate medication, studies have reported cases of tardive akathisia persisting over many years.[45] Tardive dyskinesia also persists chronically with a cumulative persistence rate as high as 82% in a study of patients with schizophrenia.[46]
Complications
Antipsychotic-induced and metoclopramide-induced laryngeal dystonia has been reported predominantly in young males.[47] Rhabdomyolysis is a rare complication of drug-induced dystonia, especially if prolonged dystonia is present.[48] While dystonic storm typically occurs in patients with primary known dystonia (e.g., Wilson disease, DYT1 dystonia), triggers typically include infection and medication adjustment in a significant number of cases.[49] A dystonic storm is a life-threatening situation that manifests with fever, tachycardia, tachypnea, hypertensive crisis, diaphoresis, dysphagia, and respiratory failure.[49] The manifestation of EPS in schizophrenic patients is associated with poor compliance with other atypical antipsychotic medications, which may subsequently lead to a relapse of schizophrenia and hospitalization.[2] Failure to correctly diagnose and treat EPS is linked to suicidal ideation, aggression, and violence.[26]
Consultations
While some drug-induced movement disorders may last a few minutes, others may last long-term for weeks to years, and may potentially lead to contractures, bony deformities, or significant motor impairment. Physical medicine and rehabilitation consultation may provide useful treatment modalities that have shown efficacy in alleviating dystonia, including relaxation training, biofeedback, transcutaneous electrical nerve stimulation (TENS), and percutaneous dorsal column stimulation.[50] Physical and occupational therapy is paramount, leading to improvement in gait and mobility. In patients with oromandibular or laryngeal involvement, speech therapy may assist with dysphagia and communication barriers. In presentations of EPS refractory to pharmacologic management, neurosurgical consultation may be beneficial to explore deep brain stimulation, thalamotomy, and pallidotomy.
Enhancing Healthcare Team Outcomes
The spectrum of acute symptoms in EPS is distressing, especially with painful torticollis, oculogyric crisis, and bulbar type of speech. If left untreated, it may cause dehydration, infection, pulmonary embolism, rhabdomyolysis, respiratory stridor, and obstruction.[4][24][51][52] To this end, studies investigating the administration of prophylactic anticholinergic medications to prevent or reduce EPS have been performed. Authors have cautioned that prophylactic anticholinergic medications have distressing peripheral side-effects, including dry mouth, urinary disturbances, and constipation, as well as undesirable central effects comprising cognitive dysfunction and delirium.[53] This long-term prophylactic administration of anticholinergic medications in schizophrenia patients taking antipsychotics may worsen underlying cognitive impairment and subsequently worsen the quality of life.[53] Thus, while current guidelines generally do not recommend the prophylactic or long-term use of anticholinergics in schizophrenic patients taking antipsychotics, this decision should be made on a case-by-case basis with meticulous risk-benefit analysis. In the emergency medicine realm, a meta-analysis demonstrated that prophylactic diphenhydramine reduces EPS in patients receiving bolus administration of antiemetic (with a dopamine D2 antagonist effect), but not when the antiemetic was given as an infusion; thus, this meta-analysis concluded that the most effective strategy would be to administer the antiemetic as an infusion without anticholinergic prophylaxis.
While typical, first-generation antipsychotics are used less frequently today, the provider must also be cognizant that even second-generation atypical antipsychotics may lead to EPS, although at a lower incidence. Abouzaid and colleagues recently assessed the economic burden of EPS due to atypical antipsychotics in schizophrenia patients. During a 12-month follow-up period, 12.6% of patients experienced EPS. Compared to those without EPS, patients who did experience EPS had more schizophrenia-related and all-cause hospitalizations, schizophrenia-related emergency room visits, and higher schizophrenia-related and all-cause total healthcare, inpatient, and prescription medication costs.[54]
Psychiatric nurses and pharmacists should educate patients about EPS. Nurses monitor patients and consult with the team if issues persist. Pharmacists review acute and chronic medications for doses and interactions. [Level 5]
Media
(Click Video to Play)
Parkinson Gait, Involuntary Movement, Festinant Gait
Contributed by RS Kumar, MD
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(Click Image to Enlarge)
Shuffling gait in parkinson disease Image courtesy S Bhimji MD
References
Rifkin A. Extrapyramidal side effects: a historical perspective. The Journal of clinical psychiatry. 1987 Sep:48 Suppl():3-6 [PubMed PMID: 2887555]
Level 3 (low-level) evidenceFrances A, Weiden P. Promoting compliance with outpatient drug treatment. Hospital & community psychiatry. 1987 Nov:38(11):1158-60 [PubMed PMID: 3666712]
Level 3 (low-level) evidenceFarah A. Atypicality of atypical antipsychotics. Primary care companion to the Journal of clinical psychiatry. 2005:7(6):268-74 [PubMed PMID: 16498489]
D'Souza RS, Mercogliano C, Ojukwu E, D'Souza S, Singles A, Modi J, Short A, Donato A. Effects of prophylactic anticholinergic medications to decrease extrapyramidal side effects in patients taking acute antiemetic drugs: a systematic review and meta-analysis. Emergency medicine journal : EMJ. 2018 May:35(5):325-331. doi: 10.1136/emermed-2017-206944. Epub 2018 Feb 3 [PubMed PMID: 29431143]
Level 1 (high-level) evidenceMiller LG, Jankovic J. Metoclopramide-induced movement disorders. Clinical findings with a review of the literature. Archives of internal medicine. 1989 Nov:149(11):2486-92 [PubMed PMID: 2684075]
Kane J, Rifkin A, Quitkin F, Klein DF. Extrapyramidal side effects with lithium treatment. The American journal of psychiatry. 1978 Jul:135(7):851-3 [PubMed PMID: 665801]
Madhusoodanan S, Alexeenko L, Sanders R, Brenner R. Extrapyramidal symptoms associated with antidepressants--a review of the literature and an analysis of spontaneous reports. Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists. 2010 Aug:22(3):148-56 [PubMed PMID: 20680187]
Level 2 (mid-level) evidenceAsser A, Taba P. Psychostimulants and movement disorders. Frontiers in neurology. 2015:6():75. doi: 10.3389/fneur.2015.00075. Epub 2015 Apr 20 [PubMed PMID: 25941511]
Bohlega SA, Al-Foghom NB. Drug-induced Parkinson`s disease. A clinical review. Neurosciences (Riyadh, Saudi Arabia). 2013 Jul:18(3):215-21 [PubMed PMID: 23887211]
Janno S, Holi M, Tuisku K, Wahlbeck K. Prevalence of neuroleptic-induced movement disorders in chronic schizophrenia inpatients. The American journal of psychiatry. 2004 Jan:161(1):160-3 [PubMed PMID: 14702266]
Divac N, Prostran M, Jakovcevski I, Cerovac N. Second-generation antipsychotics and extrapyramidal adverse effects. BioMed research international. 2014:2014():656370. doi: 10.1155/2014/656370. Epub 2014 Jun 3 [PubMed PMID: 24995318]
Ganzini L, Casey DE, Hoffman WF, McCall AL. The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Archives of internal medicine. 1993 Jun 28:153(12):1469-75 [PubMed PMID: 8512437]
Level 3 (low-level) evidenceParlak I, Atilla R, Cicek M, Parlak M, Erdur B, Guryay M, Sever M, Karaduman S. Rate of metoclopramide infusion affects the severity and incidence of akathisia. Emergency medicine journal : EMJ. 2005 Sep:22(9):621-4 [PubMed PMID: 16113179]
Level 1 (high-level) evidenceParlak I, Erdur B, Parlak M, Ergin A, Turkcuer I, Tomruk O, Ayrik C, Ergin N. Intravenous administration of metoclopramide by 2 min bolus vs 15 min infusion: does it affect the improvement of headache while reducing the side effects? Postgraduate medical journal. 2007 Oct:83(984):664-8 [PubMed PMID: 17916877]
Level 1 (high-level) evidenceSaadah HA. Abortive headache therapy in the office with intravenous dihydroergotamine plus prochlorperazine. Headache. 1992 Mar:32(3):143-6 [PubMed PMID: 1563946]
Taylor WB, Bateman DN. Preliminary studies of the pharmacokinetics and pharmacodynamics of prochlorperazine in healthy volunteers. British journal of clinical pharmacology. 1987 Feb:23(2):137-42 [PubMed PMID: 3828192]
Level 1 (high-level) evidenceHedenmalm K, Güzey C, Dahl ML, Yue QY, Spigset O. Risk factors for extrapyramidal symptoms during treatment with selective serotonin reuptake inhibitors, including cytochrome P-450 enzyme, and serotonin and dopamine transporter and receptor polymorphisms. Journal of clinical psychopharmacology. 2006 Apr:26(2):192-7 [PubMed PMID: 16633151]
Level 2 (mid-level) evidenceJeste DV. Tardive dyskinesia rates with atypical antipsychotics in older adults. The Journal of clinical psychiatry. 2004:65 Suppl 9():21-4 [PubMed PMID: 15189108]
Salem H, Nagpal C, Pigott T, Teixeira AL. Revisiting Antipsychotic-induced Akathisia: Current Issues and Prospective Challenges. Current neuropharmacology. 2017:15(5):789-798. doi: 10.2174/1570159X14666161208153644. Epub [PubMed PMID: 27928948]
Kondo T, Otani K, Tokinaga N, Ishida M, Yasui N, Kaneko S. Characteristics and risk factors of acute dystonia in schizophrenic patients treated with nemonapride, a selective dopamine antagonist. Journal of clinical psychopharmacology. 1999 Feb:19(1):45-50 [PubMed PMID: 9934942]
Kamin J, Manwani S, Hughes D. Emergency psychiatry: extrapyramidal side effects in the psychiatric emergency service. Psychiatric services (Washington, D.C.). 2000 Mar:51(3):287-9 [PubMed PMID: 10686232]
Sykes DA, Moore H, Stott L, Holliday N, Javitch JA, Lane JR, Charlton SJ. Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D(2) receptors. Nature communications. 2017 Oct 2:8(1):763. doi: 10.1038/s41467-017-00716-z. Epub 2017 Oct 2 [PubMed PMID: 28970469]
Pasricha PJ, Pehlivanov N, Sugumar A, Jankovic J. Drug Insight: from disturbed motility to disordered movement--a review of the clinical benefits and medicolegal risks of metoclopramide. Nature clinical practice. Gastroenterology & hepatology. 2006 Mar:3(3):138-48 [PubMed PMID: 16511548]
Low LC, Goel KM. Metoclopramide poisoning in children. Archives of disease in childhood. 1980 Apr:55(4):310-2 [PubMed PMID: 7416782]
Peitl MV, Prološčić J, Blažević-Zelić S, Skarpa-Usmiani I, Peitl V. Symptoms of agitated depression and/or akathisia. Psychiatria Danubina. 2011 Mar:23(1):108-10 [PubMed PMID: 21448111]
Level 3 (low-level) evidenceLipinski JF Jr, Mallya G, Zimmerman P, Pope HG Jr. Fluoxetine-induced akathisia: clinical and theoretical implications. The Journal of clinical psychiatry. 1989 Sep:50(9):339-42 [PubMed PMID: 2549018]
Level 3 (low-level) evidenceShin HW, Chung SJ. Drug-induced parkinsonism. Journal of clinical neurology (Seoul, Korea). 2012 Mar:8(1):15-21. doi: 10.3988/jcn.2012.8.1.15. Epub 2012 Mar 31 [PubMed PMID: 22523509]
Cornett EM, Novitch M, Kaye AD, Kata V, Kaye AM. Medication-Induced Tardive Dyskinesia: A Review and Update. Ochsner journal. 2017 Summer:17(2):162-174 [PubMed PMID: 28638290]
Vogt T, Lüssi F, Paul A, Urban P. [Long-term therapy of focal dystonia and facial hemispasm with botulinum toxin A]. Der Nervenarzt. 2008 Aug:79(8):912-7. doi: 10.1007/s00115-008-2486-2. Epub [PubMed PMID: 18551268]
Cloud LJ, Jinnah HA. Treatment strategies for dystonia. Expert opinion on pharmacotherapy. 2010 Jan:11(1):5-15. doi: 10.1517/14656560903426171. Epub [PubMed PMID: 20001425]
Level 3 (low-level) evidenceVidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Benabid AL, Cornu P, Lagrange C, Tézenas du Montcel S, Dormont D, Grand S, Blond S, Detante O, Pillon B, Ardouin C, Agid Y, Destée A, Pollak P, French Stimulation du Pallidum Interne dans la Dystonie (SPIDY) Study Group. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. The New England journal of medicine. 2005 Feb 3:352(5):459-67 [PubMed PMID: 15689584]
Level 1 (high-level) evidenceMiller CH, Fleischhacker WW. Managing antipsychotic-induced acute and chronic akathisia. Drug safety. 2000 Jan:22(1):73-81 [PubMed PMID: 10647977]
Inada T. [Drug-Induced Akathisia]. Brain and nerve = Shinkei kenkyu no shinpo. 2017 Dec:69(12):1417-1424. doi: 10.11477/mf.1416200927. Epub [PubMed PMID: 29282345]
Kang UJ, Burke RE, Fahn S. Natural history and treatment of tardive dystonia. Movement disorders : official journal of the Movement Disorder Society. 1986:1(3):193-208 [PubMed PMID: 2904118]
Alabed S, Latifeh Y, Mohammad HA, Rifai A. Gamma-aminobutyric acid agonists for neuroleptic-induced tardive dyskinesia. The Cochrane database of systematic reviews. 2011 Apr 13:(4):CD000203. doi: 10.1002/14651858.CD000203.pub3. Epub 2011 Apr 13 [PubMed PMID: 21491376]
Level 1 (high-level) evidenceWaln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor and other hyperkinetic movements (New York, N.Y.). 2013:3():. pii: tre-03-161-4138-1. doi: 10.7916/D88P5Z71. Epub 2013 Jul 12 [PubMed PMID: 23858394]
Kenney C, Jankovic J. Tetrabenazine in the treatment of hyperkinetic movement disorders. Expert review of neurotherapeutics. 2006 Jan:6(1):7-17 [PubMed PMID: 16466307]
Cloud LJ, Zutshi D, Factor SA. Tardive dyskinesia: therapeutic options for an increasingly common disorder. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2014 Jan:11(1):166-76. doi: 10.1007/s13311-013-0222-5. Epub [PubMed PMID: 24310603]
Handley A, Medcalf P, Hellier K, Dutta D. Movement disorders after stroke. Age and ageing. 2009 May:38(3):260-6. doi: 10.1093/ageing/afp020. Epub 2009 Mar 10 [PubMed PMID: 19276093]
Sanders RD, Gillig PM. Extrapyramidal examinations in psychiatry. Innovations in clinical neuroscience. 2012 Jul:9(7-8):10-6 [PubMed PMID: 22984647]
Kane JM. Extrapyramidal side effects are unacceptable. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2001 Oct:11 Suppl 4():S397-403 [PubMed PMID: 11587887]
Peralta V, Basterra V, Campos MS, de Jalón EG, Moreno-Izco L, Cuesta MJ. Characterization of spontaneous Parkinsonism in drug-naive patients with nonaffective psychotic disorders. European archives of psychiatry and clinical neuroscience. 2012 Mar:262(2):131-8. doi: 10.1007/s00406-011-0219-1. Epub 2011 May 28 [PubMed PMID: 21626260]
Burke RE, Fahn S, Jankovic J, Marsden CD, Lang AE, Gollomp S, Ilson J. Tardive dystonia: late-onset and persistent dystonia caused by antipsychotic drugs. Neurology. 1982 Dec:32(12):1335-46 [PubMed PMID: 6128697]
Level 3 (low-level) evidenceKiriakakis V, Bhatia KP, Quinn NP, Marsden CD. The natural history of tardive dystonia. A long-term follow-up study of 107 cases. Brain : a journal of neurology. 1998 Nov:121 ( Pt 11)():2053-66 [PubMed PMID: 9827766]
Level 3 (low-level) evidenceBurke RE, Kang UJ, Jankovic J, Miller LG, Fahn S. Tardive akathisia: an analysis of clinical features and response to open therapeutic trials. Movement disorders : official journal of the Movement Disorder Society. 1989:4(2):157-75 [PubMed PMID: 2567492]
Level 2 (mid-level) evidenceTenback DE, van Harten PN, Slooff CJ, van Os J. Incidence and persistence of tardive dyskinesia and extrapyramidal symptoms in schizophrenia. Journal of psychopharmacology (Oxford, England). 2010 Jul:24(7):1031-5. doi: 10.1177/0269881109106306. Epub 2009 Jun 1 [PubMed PMID: 19487321]
Level 2 (mid-level) evidenceChristodoulou C, Kalaitzi C. Antipsychotic drug-induced acute laryngeal dystonia: two case reports and a mini review. Journal of psychopharmacology (Oxford, England). 2005 May:19(3):307-11 [PubMed PMID: 15888517]
Level 3 (low-level) evidenceCavanaugh JJ, Finlayson RE. Rhabdomyolysis due to acute dystonic reaction to antipsychotic drugs. The Journal of clinical psychiatry. 1984 Aug:45(8):356-7 [PubMed PMID: 6746581]
Level 3 (low-level) evidenceTermsarasab P, Frucht SJ. Dystonic storm: a practical clinical and video review. Journal of clinical movement disorders. 2017:4():10. doi: 10.1186/s40734-017-0057-z. Epub 2017 Apr 28 [PubMed PMID: 28461905]
Cho HJ, Hallett M. Non-Invasive Brain Stimulation for Treatment of Focal Hand Dystonia: Update and Future Direction. Journal of movement disorders. 2016 May:9(2):55-62. doi: 10.14802/jmd.16014. Epub 2016 May 25 [PubMed PMID: 27240806]
Level 3 (low-level) evidenceNovick D, Haro JM, Bertsch J, Haddad PM. Incidence of extrapyramidal symptoms and tardive dyskinesia in schizophrenia: thirty-six-month results from the European schizophrenia outpatient health outcomes study. Journal of clinical psychopharmacology. 2010 Oct:30(5):531-40. doi: 10.1097/JCP.0b013e3181f14098. Epub [PubMed PMID: 20814320]
Level 2 (mid-level) evidenceLevinson DF, Simpson GM. Neuroleptic-induced extrapyramidal symptoms with fever. Heterogeneity of the 'neuroleptic malignant syndrome'. Archives of general psychiatry. 1986 Sep:43(9):839-48 [PubMed PMID: 2875701]
Ogino S, Miyamoto S, Miyake N, Yamaguchi N. Benefits and limits of anticholinergic use in schizophrenia: focusing on its effect on cognitive function. Psychiatry and clinical neurosciences. 2014 Jan:68(1):37-49. doi: 10.1111/pcn.12088. Epub 2013 Sep 19 [PubMed PMID: 24102938]
Abouzaid S, Tian H, Zhou H, Kahler KH, Harris M, Kim E. Economic burden associated with extrapyramidal symptoms in a medicaid population with schizophrenia. Community mental health journal. 2014 Jan:50(1):51-8. doi: 10.1007/s10597-012-9561-7. Epub 2012 Nov 16 [PubMed PMID: 23229052]
Level 2 (mid-level) evidence