What is the pathophysiology of Extrapyramidal Symptoms (EPS)?

Pathophysiology of Extrapyramidal Symptoms (EPS)

Core Mechanism: Dopamine Blockade in the Basal Ganglia

Extrapyramidal symptoms result from dopamine blockade or depletion in the basal ganglia, specifically through antagonism of dopamine D2 receptors in the nigrostriatal pathway, which disrupts normal movement control. 1, 2, 3

Primary Pathophysiological Pathway

• Dopamine D2 receptor blockade in the substantia nigra and striatum is the fundamental mechanism underlying most drug-induced EPS 1, 2
• The degree of dopamine receptor antagonism directly correlates with EPS risk—high-potency antipsychotics like haloperidol produce more severe extrapyramidal symptoms due to stronger D2 blockade 1, 2
• This dopaminergic disruption occurs in the nigrostriatal pathways and spinal cord, mimicking idiopathic pathologies of the extrapyramidal system 2, 3

Neuroanatomical Substrate

• The basal ganglia contains medium-sized spiny projection neurons that are normally modulated by dopaminergic input from the substantia nigra 4
• Sudden, non-selective disinhibition of indirect pathway medium-sized spiny projection neurons occurs when D2 receptors are blocked, distorting normal motor program execution 4
• Tonically active giant cholinergic interneurons in the striatum play a critical role—these neurons integrate cerebellar input with cortical output and are directly targeted by dopaminergic fibers 4

Cholinergic-Dopaminergic Imbalance

The pathophysiology involves a critical imbalance between dopaminergic and cholinergic systems in the basal ganglia. 1, 4

Mechanism of Cholinergic Involvement

• When dopamine D2 receptors are blocked, there is relative cholinergic hyperactivity in the striatum, explaining why anticholinergic medications effectively treat acute dystonia and parkinsonism 1, 2
• Striatal cholinergic interneurons have widespread influence on all medium-sized spiny projection neurons through muscarinic receptors 4
• Blocking muscarinic receptors with anticholinergics reduces the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation, thereby alleviating symptoms 4

Specific EPS Subtypes and Their Pathophysiology

Acute Dystonia

• Results from sudden spastic contraction of distinct muscle groups due to abrupt dopamine D2 blockade 1, 5, 2
• Young males are at highest risk, suggesting additional hormonal or developmental factors in susceptibility 1, 2
• Typically occurs within the first few days of treatment when dopaminergic transmission is most acutely disrupted 2

Drug-Induced Parkinsonism

• Caused by progressive dopamine depletion in the substantia nigra projecting to the striatum, producing bradykinesia, tremors, and rigidity 1, 5, 2
• This mechanism directly parallels idiopathic Parkinson's disease, where approximately 40-50% of dopaminergic neurons must be lost before symptoms appear 1
• The pathophysiology involves the same nigrostriatal pathway affected in primary Parkinson's disease 1

Akathisia

• Represents a subjective sense of severe restlessness with physical agitation, likely involving disruption of mesocortical and mesolimbic dopamine pathways in addition to nigrostriatal effects 1, 5, 2
• The pathophysiology is less well understood than other EPS, explaining why anticholinergics are inconsistently helpful and beta-blockers or benzodiazepines may be needed 1, 2

Tardive Dyskinesia

• Develops through long-term neuroplastic changes in response to chronic dopamine receptor blockade 1, 5, 2
• Involves faulty processing of somatosensory input leading to inappropriate execution of motor programs 4
• Neuroplastic alterations in the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation occur with chronic dopamine blockade 4
• The mechanism involves dopamine receptor upregulation and supersensitivity after prolonged blockade, explaining why symptoms may worsen when antipsychotics are discontinued 1

Receptor Subtype Specificity

• While D2 receptor antagonism is central, receptor subtype specificity and brain region selectivity play important roles in determining which patients develop EPS 6
• The ratio of different receptor subtype antagonism (D2 vs. serotonin 5-HT2A, for example) explains why atypical antipsychotics cause fewer EPS 6
• Medications with lower D2 affinity or higher serotonin receptor antagonism (like olanzapine, quetiapine, clozapine) produce less nigrostriatal dopamine blockade 2

Non-Antipsychotic Causes

• Antiemetics (metoclopramide, prochlorperazine) cause EPS through the same dopamine D2 blockade mechanism in the basal ganglia 2, 3, 7
• Certain antidepressants, lithium, and anticonvulsants can produce extrapyramidal symptoms through dopamine depletion or blockade, though less commonly 3, 7
• These non-antipsychotic causes produce symptoms indistinguishable from neuroleptic-induced EPS because they affect the same dopaminergic pathways 3, 7

Clinical Pitfalls in Understanding EPS Pathophysiology

• Distinguishing drug-induced parkinsonism from negative symptoms of schizophrenia or catatonia can be difficult, as both involve bradykinesia and reduced motor activity 1
• In Huntington's disease patients, differentiating drug-induced parkinsonism from disease progression is challenging because rigidity develops as part of the underlying disease process 8
• The pathophysiology of akathisia remains incompletely understood, making it the most difficult EPS to treat effectively 1, 6