What are the extrapyramidal symptoms and their pathophysiology?

Extrapyramidal Symptoms: Definition and Pathophysiology

Extrapyramidal symptoms (EPS) are drug-induced movement disorders caused by dopamine D2 receptor blockade in the nigrostriatal pathways, manifesting as acute dystonia, drug-induced parkinsonism, akathisia, and tardive dyskinesia. 1

Core Pathophysiological Mechanism

The fundamental mechanism underlying EPS involves dopamine receptor blockade in the nigrostriatal pathways and spinal cord, which disrupts normal movement control. 1 This dopamine depletion or blockade in the basal ganglia produces the characteristic motor symptoms that define this syndrome. 2, 3

• The nigrostriatal dopaminergic pathway normally maintains smooth, coordinated voluntary movement through balanced neurotransmitter activity in the basal ganglia 1
• When antipsychotics or other dopamine-blocking agents interfere with D2 receptors, the resulting dopamine deficiency creates an imbalance between dopaminergic and cholinergic systems 2, 3
• This neurochemical imbalance manifests as the various movement disorders collectively termed EPS 1

Four Distinct Clinical Presentations

1. Acute Dystonia

Acute dystonia presents as sudden spastic contractions of muscle groups, typically occurring within the first few days of treatment. 1, 4

• Most commonly affects the neck (torticollis), eyes (oculogyric crisis), or torso 1, 4
• Young males face the highest risk for this presentation 1
• Can be life-threatening when laryngospasm occurs 4
• Improvement often occurs within minutes after intramuscular or intravenous anticholinergic administration 1

2. Drug-Induced Parkinsonism

Drug-induced parkinsonism results directly from dopamine receptor blockade and mimics idiopathic Parkinson's disease. 1, 4

• Characterized by the classic triad: bradykinesia (slowed movements), tremors, and rigidity 1, 4
• Symptoms are indistinguishable from naturally occurring Parkinson's disease 2, 3
• Responds well to anticholinergic medications 1

3. Akathisia

Akathisia manifests as a subjective feeling of severe restlessness with physical agitation, frequently misinterpreted as anxiety or psychotic agitation. 1, 4

• Patients typically pace constantly or demonstrate other motor manifestations of inner restlessness 1, 4
• This misinterpretation often leads to inappropriate dose escalation rather than recognition as a medication side effect 1
• Carries high risk of medication non-compliance due to the distressing subjective experience 1
• Less consistently responsive to anticholinergics compared to dystonia or parkinsonism 1

4. Tardive Dyskinesia

Tardive dyskinesia consists of involuntary choreiform or athetoid movements, typically affecting the orofacial region but potentially involving any body part. 1, 4

• Associated with long-term antipsychotic exposure 1
• Risk approximates 5% per year in young patients 1
• Can be potentially irreversible, particularly with prolonged exposure 1
• Requires regular monitoring every 3-6 months using standardized scales 1, 4

Causative Medications Beyond Antipsychotics

While high-potency typical antipsychotics (especially haloperidol) carry the highest EPS risk through strong D2 receptor blockade 1, multiple other medication classes can produce identical symptoms:

• Antiemetics: Metoclopramide and prochlorperazine block dopamine receptors and commonly cause EPS 1, 5
• Antidepressants: Tricyclic antidepressants, MAOIs, and SSRIs can induce EPS through complex interactions involving dopamine, serotonin, and norepinephrine between cortical structures and basal ganglia 6
• Other agents: Lithium, certain anticonvulsants, and rarely oral contraceptives have been associated with EPS 2, 3

Risk Stratification by Antipsychotic Agent

High-potency typical antipsychotics carry the greatest EPS risk, while atypical antipsychotics demonstrate variable risk profiles. 1

Highest Risk:

• Haloperidol and other high-potency typical antipsychotics 1
• Droperidol 4

Moderate Risk:

• Risperidone (dose-dependent, increasing significantly above 2 mg/day) 1, 4

Lower Risk:

• Olanzapine 1
• Aripiprazole 1

Minimal Risk:

• Quetiapine 1
• Clozapine (lowest EPS risk, may even alleviate parkinsonian symptoms) 1

Critical Risk Factors

Age represents the most significant risk factor, with children, adolescents, and elderly patients at substantially elevated risk. 1, 4

• Male gender increases risk, particularly for acute dystonic reactions 1
• Medication properties matter: high-potency agents and rapid dose escalation amplify risk 1
• Concurrent use of multiple dopamine-blocking agents compounds risk 1

Important Clinical Pitfall

A common error involves misinterpreting akathisia as worsening psychosis or anxiety, leading to inappropriate antipsychotic dose escalation rather than recognition as a medication side effect. 1, 4 This misidentification perpetuates and worsens the underlying problem, emphasizing the critical importance of recognizing akathisia's characteristic presentation of severe inner restlessness with motor agitation.