Extrapyramidal symptoms

Extrapyramidal symptoms also known as extrapyramidal side effects, include acute dyskinesias, dystonia, tardive dyskinesia, parkinsonism, akinesia, akathisia, and neuroleptic malignant syndrome ¹. Extrapyramidal symptoms are commonly referred to as drug-induced movement disorders are among the most common drug side effects from dopamine-receptor blocking agents ². Less recognized is that extrapyramidal symptoms are also associated with certain non-antipsychotic agents, including some antidepressants, lithium, various anticonvulsants, antiemetics and rarely, oral-contraceptive agents ¹. Extrapyramidal symptoms caused by these agents are indistinguishable from neuroleptic-induced extrapyramidal symptoms. Clinicians must be able to recognize these side effects and be able to determine the antipsychotic-induced and non-antipsychotic causes of extrapyramidal symptoms.

Extrapyramidal symptoms was first described in 1952 after chlorpromazine-induced symptoms resembling Parkinson disease ³. A variety of movement phenotypes has since been described along the extrapyramidal side effects 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 extrapyramidal side effects 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 ⁴.

Rates of extrapyramidal side effects are dependent on the class of medication administered. First-generation neuroleptics were associated with extrapyramidal side effects in 61.6% of patients in a study of institutionalized patients with schizophrenia ⁵. Rates of extrapyramidal side effects have declined with atypical antipsychotics with clozapine having the lowest risk and risperidone the highest ⁶. In terms of antiemetics with a dopamine D2 receptor antagonist effect, extrapyramidal side effects incidence is cited to be between 4% to 25% with metoclopramide ⁷ and between 25% to 67% with prochlorperazine ⁸.

Extrapyramidal symptoms causes

Centrally-acting, dopamine-receptor blocking agents, namely the first-generation antipsychotics haloperidol and phenothiazine neuroleptics, are the most common medications associated with extrapyramidal side effects ². While extrapyramidal side effects occurs less frequently with atypical antipsychotics, the risk of extrapyramidal side effects increases with dose escalation ⁹. Other agents that block central dopaminergic receptors have also been identified as causative of extrapyramidal side effects, including antiemetics (metoclopramide, droperidol, and prochlorperazine) ¹⁰, lithium ¹¹, serotonin reuptake inhibitors (SSRIs) ¹², stimulants ¹³ and tricyclic antidepressants (TCAs) ¹². In rare situations, antivirals, antiarrhythmics, and valproic acid have also been implicated ¹⁴.

Risks factors include a history of prior extrapyramidal side effects and high medication dose ¹⁵. Elderly females are more susceptible to drug-induced parkinsonism and tardive dyskinesia ¹⁶, while young males manifest with more dystonic reactions ¹⁷.

The mechanism of extrapyramidal side effects 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 extrapyramidal side effects ¹⁸.

Researchers previously hypothesized that the faster dissociation of atypical antipsychotics from the dopamine receptor, compared to typical antipsychotics, explained the reduced incidence of extrapyramidal side effects. 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 extrapyramidal side effects ¹⁹.

Extrapyramidal side effects prevention

Studies investigating the administration of prophylactic anticholinergic medications to prevent or reduce extrapyramidal side effects have been performed. Authors ²⁰ 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. 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 ²⁰. 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 extrapyramidal side effects 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.

Extrapyramidal side effects symptoms

There is a wide spectrum of extrapyramidal side effects presentations, some extrapyramidal side effects 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 ¹⁰.

Dystonia most often occurs within 48 hours of drug exposure in 50% of cases, and within five days in 90% of cases ²¹. 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) ²². 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 ¹⁶. 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 ¹⁶. This failure to correctly diagnose can be detrimental as the severity of akathisia is linked to suicidal ideation, aggression, and violence ²³. Healthcare 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 ¹⁶.

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 ¹⁴.

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 ²⁴.

Extrapyramidal side effects complications

Antipsychotic-induced and metoclopramide-induced laryngeal dystonia has been reported predominantly in young males ²⁵. Rhabdomyolysis is a rare complication of drug-induced dystonia, especially if prolonged dystonia is present ²⁶. 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 ²⁷. A dystonic storm is a life-threatening situation that manifests with fever, tachycardia, tachypnea, hypertensive crisis, diaphoresis, dysphagia, and respiratory failure ²⁷. The manifestation of extrapyramidal side effects in schizophrenic patients is associated with poor compliance with other atypical antipsychotic medications, which may subsequently lead to a relapse of schizophrenia and hospitalization ⁴. Failure to correctly diagnose and treat extrapyramidal side effects is linked to suicidal ideation, aggression, and violence ²³.

Extrapyramidal symptoms diagnosis

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.

Extrapyramidal symptoms differential diagnosis

Extrapyramidal side effects 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 ²⁸. 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 ²⁹. 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 ²⁸. Interestingly, up to a third of new-onset schizophrenic patients who have never been medicated may present with parkinsonian signs ³⁰.

Extrapyramidal symptoms treatment

If a patient is experiencing acute onset of extrapyramidal side effects, particularly dystonia, healthcare provider must assess if an emergency airway intervention is necessary as laryngeal and pharyngeal dystonic reactions may increase the risk of imminent respiratory arrest ². Dystonic reactions are rarely life-threatening, and healthcare 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 ¹⁸. In cases of tardive dystonia, additional therapeutic strategies include administration of benzodiazepine ¹⁸, injection of botulinum toxin for facial dystonia ³¹, trial of muscle relaxant (e.g., baclofen) ³¹, trial of dopamine-depleting agents (e.g. tetrabenazine),[30] and consideration of deep-brain stimulation or pallidotomy for refractory cases ³¹.

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.

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) ³³, injection of botulinum toxin for facial dyskinesia ³⁴, benzodiazepines ³⁵, amantadine ³⁵, and trial of dopamine-depleting medications (e.g. tetrabenazine) ³⁶. Interestingly, the trial of levetiracetam, zonisamide, pregabalin, vitamin B6, and vitamin E have also been reported as therapeutic ²⁴.

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 ³⁷.

Extrapyramidal symptoms prognosis

Extrapyramidal side effects 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 ³⁸. 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 ³⁹. Similarly, while acute akathisia may spontaneously resolve or improve with appropriate medication, studies have reported cases of tardive akathisia persisting over many years ⁴⁰. Tardive dyskinesia also persists chronically with a cumulative persistence rate as high as 82% in a study of patients with schizophrenia ⁴¹.

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 ⁴². 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 extrapyramidal side effects refractory to pharmacologic management, neurosurgical consultation may be beneficial to explore deep brain stimulation, thalamotomy, and pallidotomy.

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