Pathophysiology
Clinical meaning
Neuroleptic malignant syndrome (NMS) results from acute, profound dopamine D2 receptor blockade in the central nervous system, producing a life-threatening cascade affecting thermoregulation, motor control, autonomic stability, and skeletal muscle metabolism. Understanding the cellular mechanisms is essential for appreciating why dantrolene is a cornerstone of treatment. The pathophysiology begins with excessive dopamine D2 receptor antagonism. In the hypothalamus, D2 blockade disrupts the thermoregulatory center's ability to dissipate heat through vasodilation and sweating, while simultaneously the massive skeletal muscle contraction generates enormous metabolic heat (rigidity is essentially sustained involuntary isometric contraction). In the nigrostriatal pathway, dopamine depletion removes the normal inhibitory modulation of the extrapyramidal motor system, resulting in the characteristic lead-pipe rigidity -- sustained, velocity-independent resistance to passive movement throughout the full range of motion. In the mesocortical pathway, D2 blockade contributes to the altered mental status ranging from confusion to catatonia. The autonomic nervous system becomes unstable due to disrupted dopaminergic-sympathetic balance, producing labile blood pressure, tachycardia, and diaphoresis. The rigidity of NMS drives rhabdomyolysis: sustained skeletal muscle contraction depletes ATP stores, disrupts sarcolemmal integrity, and releases intracellular contents...