June 2019 By PsychDB.com

Extrapyramidal Symptoms (EPS)

Extrapyramidal Symptoms (EPS) are drug-induced movement disorders that occur due to antipsychotic blockade of the nigrostriatal dopamine tracts. These blockades can lead to increased cholinergic activity, resulting in acute dystonia, acute akathisia, antipsychotic-induced parkinsonism, tardive dyskinesia (TD), tardive dystonia, and tardive akathisia.

Acute dystonia is an acute movement disorder that can result from antipsychotic use. It occurs more commonly with typical antipsychotics, and can affect 3 to 10% of individuals. It can occur either immediately or within days of starting an antipsychotic. Acute dystonia is characterized by sustained contractions of the neck, orofacial muscles, or tongue (i.e. - opisthotonos, torticollis). When identified, it can be easily treated with an anticholingeric such as benztropine and will resolve. The pathophysiology of acute dystonia is thought to be due to postsynaptic striatal dopamine blockade.[1] Acute dystonia is less common in the elderly due to overall lower levels of dopamine (D2) receptor activity.[2]

Pathophysiology
Airway Impairment

In rare cases, the diaphragm can also be involved, and there can be breathing compromise. Patients may also report a tense tongue or throat, another moderate sign of acute dystonia. If untreated, acute dystonia can progress to dysphagia, laryngospasm/pharyngospasm, leading to dyspnea. In rare, but severe cases, there can be asphyxia or choking.

Oculogyric Crisis

Other rare presentations of acute dystonia include oculogyric crises, which can lead to permanent injury. On physical exam, patients in an oculogyric crisis have prolonged involuntary upwards deviation of the eyes bilaterally.

Confusing Terminology Alert!

Dystonia can be both acute or tardive, therefore, you can have both acute and tardive dystonia (tardive dystonia is less common and much rarer). However, tardive dystonia is NOT the same as tardive dyskinesia. The difference is that there are sustained muscular contractions in tardive dystonia. An individual's posture is also abnormal in tardive dystonia.

Treatment

The offending antipsychotic should first be stopped. After, an intramuscular or oral anticholinergic like benztropine can given. In theory, any drug that block cholinergic activity (e.g., antiparkinsonian agents) or drugs that increase striatal dopamine function (e.g., various atypical antipsychotics) can correct this postsynaptic striatal dopamine blockade. The long-term benefits of chronic anticholinergic for EPS use are questionable and there are adverse effects, including cognitive impairment and worsening of tardive dyskinesia.[3]

Treatment for Acute Dystonia

Dose Daily max Onset of action
Benztropine 1-2 mg PO/IM q4h PRN for EPS 6 mg < 1 hour
Diphenhydramine 25-50 mg po/IM/IV q4h PRN for EPS 200 mg 1-3 hours

Akathisia is the subjective feeling of anxiety and restlessness. Individuals may feel compelled to pace and do tasks. For certain individuals, this can cause severe agitation, irritability, outbursts, and may place individuals at higher suicide risk.[4] Akathisia is an acute reaction, and occurs in days to weeks of starting the offending agent.

A Medical Student's Experience of Akathisia

“[Akathisia] was a diffuse, slowly increasing anxiety. My uneasiness soon began to focus on the idea that I could not possibly sit for the rest of the experiment. I imagined walking outside; the idea of walking was particularly attractive. I could not concentrate on what I had been reading. As soon as I could move, I found myself pacing up and down the lab, shaking and wringing my hands. Whenever I stopped moving, the anxiety increased. I imagined bicycling home rapidly - the thought of rapid motion was again appealing. I gladly washed a large pile of dishes that were not mine–normally not my favorite activity. Two features of this akathisia reaction impressed me. First, the intensity of the dysphoria was striking. Second, the sense of a foreign influence forcing me to move was dramatic. Long before I thought of akathisia, or even discovered that moving made me less anxious, I was pacing and wringing my hands. Had I been asked why I was behaving this way, I can imagine I would have looked at my hands and feet and responded “I don't know.” The sense of a foreign force driving one to move, with the concomitant anxiety, might be extremely disconcerting to an uninformed patient who is already struggling with psychosis.”

Kenneth S. Kendler, 1976 (after receiving 1mg IM haloperidol in an experiment)

Treatment

Treatment of akathisia includes reducing the dose of the offending agent, or treatment with benzodiazepines. Benzodiazepines can also be given prophylactically to reduce the incidence of akathisia. Other treatments include propranolol or mirtazapine.[5][6][7]

Pathophysiology

Treatment for Akathisia

Dose Daily max Onset of action
Lorazepam 1-2 mg PO/SL/IM 8 mg 15-30 mins
Propranolol 10-20mg PO 120 mg 1-2 hours

Parkinsonism is a clinical syndrome comprised primarily of rigidity, tremor, and bradykinesia. The most common cause of parkinsonism is Parkinson disease, but parkinsonism also can occur because of the use of antipsychotics (more accurately referred to as medication-induced Parkinsonism, or pseudoparkinsonism, since the symptoms are not from a true Parkinson's Disease). It usually appears within a few days of starting treatment, or may evolve slowly over several weeks. Other causes of parkinsonism include Lewy Body Dementia, Wilson's disease, substance abuse, or Huntington disease, and must be ruled out.

Symptoms are similar to Parkinson's Disease, including bradykinesia, mask-like face, cogwheel rigidity, and tremors. Tremors are considered a cardinal sign of antipsychotic-induced Parkinsonism.[8] Other features of drug-induced parkinsonism include increased salivation, drooling, seborrhea, and postural instability. Approximately 40% of older patients treated with typical antipsychotics can develop drug-induced parkinsonism even at low doses.[9] Atypical antipsychotics have a lower incidence of causing parkinsonism.

Pathophysiology

Treatment

Benztropine is commonly prescribed, but its use should be limited to short-term use, as there are significant adverse effect associated with long-term anticholinergic use, including: tachycardia, memory loss, blurred vision, urinary retention, and constipation. This is especially common in older patients.

Tardive dyskinesias (TD) are involuntary movements of the muscles of the face, mouth, and tongue that are referred to as orofacial dyskinesias. These are repetitive oral, facial, and tongue movements that can resemble grimacing, chewing, lip smacking, tongue protrusion. Tardive dyskinesia movements can often be revealed or amplified by an activation technique since many patients need to be distracted before the disorder will visually manifest. For example, ask the patient to keep their mouth open for 20 to 30 seconds, then ask them hold up their hand while tapping each finger to the thumb in sequence. Another clinical exam is to ask the patient to open and close each hand while the mouth is open. This allows one to observe any curling or writhing movements of the tongue.[10] TD can persist even after discontinuing treatment, hence, it is very important to monitor for early signs of TD using the Abnormal Involuntary Movement Scale (AIMS).

Pathophysiology

TD is thought to occur due to a supersensitivity response to chronic dopamine blockade (in the nigrostriatal pathway), which causes a proliferation of dopamine receptors on the postsynaptic side of the nigrostriatal tract. This is clinically manifested as tardive dyskinesia.[11] Of note, this remains a theory and research is still ongoing. However it remains a useful pathophysiological explanation for the development of tardive dyskinesias.

Treatment

Do not use benztropine to treat TD!

Benztropine should only be used for treatment of acute dystonia and Parkinsonism. Using benztropine for tardive dyskinesia can worsen/aggravate symptoms of TD.[12]

Treatment of tardive dyskinesia is either to stop the offending antipsychotic, reduce the dose, or to switch to clozapine. Adjunctive treatments can be added, such as tetrabenazine,[13] and with newer agents like the VMAT-2 inhibitor valbenazine.[14] See also: Cochrane: Miscellaneous treatments for antipsychotic-induced tardive dyskinesia

Abnormal Involuntary Movement Scale (AIMS)

The Abnormal Involuntary Movement Scale (AIMS) is a rating scale that was designed in the 1970s to measure involuntary movements known as tardive dyskinesia (TD).

EPS (Tardive Dyskinesia) Monitoring

Abnormal Involuntary Movement Scale (AIMS)
Rater Clinician
Description The AIMS is a 12-item clinician-rated scale to assess severity of dyskinesias (specifically, orofacial movements and extremity and truncal movements)
Download AIMS Download
Name Rater Description Download
Abnormal Involuntary Movement Scale (AIMS) Clinician The AIMS is a 12-item clinician-rated scale to assess severity of dyskinesias (specifically, orofacial movements and extremity and truncal movements) AIMS Download

Extrapyramidal Symptoms

Symptoms Onset Risk Factors Symptoms Treatment
Acute dystonia Within 5 days Young Asian or Black males Sustained abnormal posture, contraction of muscle groups, muscle spasms (e.g. - oculogyric crisis, laryngospasm, torticollis) Benztropine, diphenhydramine, stop offending antipsychotic
Akathisia Within 10 days Elderly females Motor restlessness, crawling sensation in legs, distressing, increased risk of suicide and medication non-adherence Lorazepam, propranolol, reduce dose of antipsychotic
Parkinsonism Within 30 days Elderly females Cogwheel rigidity, tremors, postural instability, stooped posture, shuffling gait, en bloc turning Benztropine, reduce dose of antipsychotic
Tardive dyskinesia (TD) After 3 months Chronic antipsychotic use Purposeless, constant writhing movements involving facial muscles, less commonly limbs Reduce antipsychotic dose, switch to clozapine, or treatment with valbenazine or tetrabenazine

Time of Symptom Onset

Figure 1 shows the timeline of EPS over time.

Timeline of Antipsychotic Side Effects Figure 1