Extrapyramidal symptoms

Extrapyramidal symptoms (EPS) are symptoms that are archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they are also known as extrapyramidal side effects (EPSE). The symptoms can be acute (short-term) or chronic (long-term). They include movement dysfunction such as dystonia (continuous spasms and muscle contractions), akathisia (may manifest as motor restlessness),^[1] parkinsonism characteristic symptoms such as rigidity, bradykinesia (slowness of movement), tremor, and tardive dyskinesia (irregular, jerky movements).^[2] Extrapyramidal symptoms are a reason why subjects drop out of clinical trials of antipsychotics; of the 213 (14.6%) subjects that dropped out of one of the largest clinical trials of antipsychotics (the CATIE trial [Clinical Antipsychotic Trials for Intervention Effectiveness], which included 1460 randomized subjects), 58 (27.2%) of those discontinuations were due to EPS.^[3]

Extrapyramidal symptoms
Other names	extrapyramidal manifestations; extrapyramidal side effects (EPSE) (when caused by drugs)
Specialty	Neurology

Causes

Medications

Extrapyramidal symptoms are most commonly caused by typical antipsychotic drugs that antagonize dopamine D2 receptors.^[2] The most common typical antipsychotics associated with EPS are haloperidol and fluphenazine.^[4] Atypical antipsychotics have lower D2 receptor affinity or higher serotonin 5-HT2A receptor affinity which lead to lower rates of EPS.^[5]

Other anti-dopaminergic drugs, like the antiemetic metoclopramide, can also result in extrapyramidal side effects.^[6] Short and long-term use of antidepressants such as selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), and norepinephrine-dopamine reuptake inhibitors (NDRI) have also resulted in EPS.^[7] Specifically, duloxetine, sertraline, escitalopram, fluoxetine, and bupropion have been linked to the induction of EPS.^[7]

Non-medication-related

Other causes of extrapyramidal symptoms can include brain damage and meningitis.^[8] However, the term "extrapyramidal symptoms" generally refers to medication-induced causes in the field of psychiatry.^[9]

Diagnosis

Since it is difficult to measure extrapyramidal symptoms, rating scales are commonly used to assess the severity of movement disorders. The Simpson-Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), and Extrapyramidal Symptom Rating Scale (ESRS) are rating scales frequently used for such assessment and are not weighted for diagnostic purposes;^[2] these scales can help clinicians weigh the benefit/expected benefit of a medication against the degree of distress which the side effects are causing the patient, aiding in the decision to maintain, reduce, or discontinue the causative medication(s).^{[citation needed]}

Classification

• Acute dystonic reactions: painful, muscular spasms of neck, jaw, back, extremities, eyes, throat, and tongue; highest risk in young men.^[2][10]
  • Oculogyric crisis is a kind of acute dystonic reaction that involves the prolonged involuntary upward deviation of the eyes.
• Akathisia: A feeling of internal motor restlessness that can present as tension, nervousness, or anxiety.^[2] Clinical manifestations include pacing and an inability to sit still.^[10]
• Pseudoparkinsonism: drug-induced parkinsonism (rigidity, bradykinesia, tremor, masked facies, shuffling gait, stooped posture, sialorrhoea, and seborrhoea; greater risk in the elderly).^[2] Although Parkinson's disease is primarily a disease of the nigrostriatal pathway and not the extrapyramidal system, loss of dopaminergic neurons in the substantia nigra leads to dysregulation of the extrapyramidal system. Since this system regulates posture and skeletal muscle tone, a result is the characteristic bradykinesia of Parkinson's.
• Tardive dyskinesia: involuntary muscle movements in the lower face and distal extremities; this can be a chronic condition associated with long-term use of antipsychotics.^[2]

Treatment

Medications are used to reverse the symptoms of extrapyramidal side effects caused by antipsychotics or other drugs, by either directly or indirectly increasing dopaminergic neurotransmission. The treatment varies by the type of the EPS, but may involve anticholinergic agents such as procyclidine, benztropine, diphenhydramine, and trihexyphenidyl. Certain medications such as dopamine agonists are not used, as they may worsen psychotic symptoms to those taking neuroleptic drugs.

If the EPS are induced by an antipsychotic, EPS may be reduced by decreasing the dose of the antipsychotic or by switching from a typical antipsychotic to an (or to a different) atypical antipsychotic, such as aripiprazole, ziprasidone, quetiapine, olanzapine, risperidone, or clozapine. These medications possess an additional mode of action that is believed to mitigate their effect on the nigrostriatal pathway, which means they are associated with fewer extrapyramidal side-effects than "conventional" antipsychotics (chlorpromazine, haloperidol, etc.)^[11]

Dystonia

Anticholinergic medications are used to reverse acute dystonia. If the symptoms are particularly severe, the anticholinergic medication may be administered by injection into a muscle to rapidly reverse the dystonia.^[9]

Akathisia

Certain second-generation antipsychotics, such as lurasidone and the partial D2-agonist aripiprazole, are more likely to cause akathisia compared to other second-generation antipsychotics.^[12] If akathisia occurs, switching to an antipsychotic with a lower risk of akathisia may improve symptoms.^[13] Beta blockers (like propranolol) are frequently used to treat akathisia. Other medications that are sometimes used include clonidine, mirtazapine, or even benzodiazepines. Anticholinergic medications are not helpful for treating akathisia.^[9]

Pseudoparkinsonism

Medication interventions are generally reserved for cases in which withdrawing the medication that caused the pseudoparkinsonism is either ineffective or infeasible. Anticholinergic medications are sometimes used to treat pseudoparkinsonism, but they can be difficult to tolerate when given chronically. Amantadine is sometimes used as well. It is rare for dopamine agonists to be used for antipsychotic-induced EPS, as they may exacerbate psychosis.^[9]

Tardive dyskinesia

When other measures fail or are not feasible, medications are used to treat tardive dyskinesia. These include the vesicular monoamine transporter 2 inhibitors tetrabenazine and deutetrabenazine.^[9]

History

Extrapyramidal symptoms (also called extrapyramidal side effects) get their name because they are symptoms of disorders in the extrapyramidal system, which regulates posture and skeletal muscle tone. This is in contrast to symptoms originating from the pyramidal tracts.^{[citation needed]}

See also

• Neuroleptic malignant syndrome
• Rabbit syndrome

References

1. Akagi, Hiroko; Kumar, T Manoj (2002-06-22). "Akathisia: overlooked at a cost". BMJ: British Medical Journal. 324 (7352): 1506–1507. doi:10.1136/bmj.324.7352.1506. ISSN 0959-8138. PMC 1123446. PMID 12077042.
2. Pierre, JM (2005). "Extrapyramidal symptoms with atypical antipsychotics: incidence, prevention and management". Drug Safety. 28 (3): 191–208. doi:10.2165/00002018-200528030-00002. PMID 15733025. S2CID 41268164.
3. Jeffrey A. Lieberman; T. Scott Stroup; Joseph P. McEvoy; Marvin S. Swartz; Robert A. Rosenheck; Diana O. Perkins; Richard S.E. Keefe; Sonia M. Davis; Clarence E. Davis; Barry D. Lebowitz; Joanne Severe; John K. Hsiao & for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators (September 22, 2005). "Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia". N Engl J Med. 353 (12): 1209–1223. doi:10.1056/NEJMoa051688. PMID 16172203.
4. Nevena Divac; Milica Prostran; Igor Jakovcevski & Natasa Cerovac (2014). "Second-Generation Antipsychotics and Extrapyramidal Adverse Effects". BioMed Research International. 2014: 6 pages. doi:10.1155/2014/656370. PMC 4065707. PMID 24995318.
5. Correll C (2014). "Mechanism of Action of Antipsychotic Medications". J Clin Psychiatry. 75 (9): e23. doi:10.4088/jcp.13078tx4c.
6. Moos, DD.; Hansen, DJ. (October 2008). "Metoclopramide and Extrapyramidal Symptoms: A Case Report". Journal of PeriAnesthesia Nursing. 23 (5): 292–299. doi:10.1016/j.jopan.2008.07.006. PMID 18926476.
7. Madhusoodanan S, Alexeenko L, Sanders R, Brenner R (2010). (PDF). Annals of Clinical Psychiatry. 22 (3): 148–156. PMID 20680187. Archived from the original (PDF) on 2013-11-27. Retrieved 2016-05-03.
8. Ori Scott; Simona Hasal & Helly R. Goez (November 2013) [September 10, 2012]. "Basal Ganglia Injury With Extrapyramidal Presentation: A Complication of Meningococcal Meningitis". J Child Neurol. 28 (11): 1489–1492. doi:10.1177/0883073812457463. PMID 22965562. S2CID 30536341.
9. "Involuntary Movement Disorders (Ch. 18)". Kaufman's Clinical Neurology for Psychiatrists (8th ed.). Elsevier Inc.
10. "Be Drug Wise: Psychotherapeutic Meds". Educational Global Technologies, Inc. Retrieved 10 September 2020.
11. Michael J. Peluso; Shôn W. Lewis; Thomas R. E. Barnes; Peter B. Jones (2012). "Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs". The British Journal of Psychiatry. 200 (5): 387–92. doi:10.1192/bjp.bp.111.101485. PMID 22442101.
12. E. Thomas, Jennifer; Caballero, Joshua; A. Harrington, Catherine (13 October 2015). "The Incidence of Akathisia in the Treatment of Schizophrenia with Aripiprazole, Asenapine and Lurasidone: A Meta-Analysis". Current Neuropharmacology. 13 (5): 681–691. doi:10.2174/1570159X13666150115220221. PMC 4761637. PMID 26467415.
13. Salem, Haitham; Nagpal, Caesa; Pigott, Teresa; Teixeira, Antonio Lucio (15 June 2017). "Revisiting Antipsychotic-induced Akathisia: Current Issues and Prospective Challenges". Current Neuropharmacology. 15 (5): 789–798. doi:10.2174/1570159X14666161208153644. PMC 5771055. PMID 27928948.

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