Pathophysiology

The mechanism for each type of reaction is varied and in some cases remains uncertain:

Serotonin syndrome

Serotonin syndrome is a potentially life-threatening condition caused by serotonin toxicity as a result of excessive serotonin activity in both the central and peripheral nervous systems. This can arise following an overdose, an interaction between drugs or an adverse drug effect [6]. According to Perry et al, case reports mostly indicate that serotonin syndrome occurs as a result of serotonin agonist drug combination therapy [7].

Serotonin syndrome presents with a classical triad of:

• Mental status changes e.g. agitation, confusion, hypomania, hyperactivity
• Autonomic hyperactivity e.g. hyperthermia, hypertension, tachycardia, diaphoresis, mydriasis, flushing
• Neuromuscular manifestations e.g. muscle rigidity, hyperreflexia, hypertonia, induced clonus, ocular clonus, tremor

Onset of symptoms is usually within minutes to hours of the ingestion and may range from mild to severe. Mild cases of serotonin syndrome tend to improve within 72 hours with supportive treatment and discontinuation of causative drugs [5]. Severe cases with a rapidly increasing temperature can, however, progress to multi-organ failure [6].

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is a potentially life-threatening emergency associated with the use of neuroleptic agents including the newer atypical antipsychotics such as clozapine [9]. The cause of neuroleptic malignant syndrome is not yet known but is thought to be associated with dopamine receptor blockade [7,9]. The incidence of neuroleptic malignant syndrome in patients taking such agents ranged between 0.02 to 3 percent with an onset typically over 1 to 3 days [9]. Development of neuroleptic malignant syndrome is not related to either the dose or duration of the causative medication [2].

Neuroleptic malignant syndrome patients present with four main symptoms:

• Mental status alteration eg delirium, agitation, confusion, catatonia
• Muscular rigidity – typically lead pipe rigidity
• Hyperthermia – temperatures >38°C are typical
• Autonomic instability e.g. tachycardia, labile BP, tachypnoea, diaphoresis

Symptoms of neuroleptic malignant syndrome have been divided into major and minor categories. According to Levenson’s criteria, the presence of all three major features or two major plus four minor features indicates a high probability of the diagnosis of neuroleptic malignant syndrome [10]:

Category	Feature
Major	Fever Rigidity Elevated CK
Minor	Tachycardia Abnormal arterial pressure Altered consciousness Diaphoresis Leucocytosis

Anticholinergic syndrome

Anticholinergic agents are associated with hyperthermia at both therapeutic and toxic doses [2,3]. Symptoms arise as result of the blockade of both the central and peripheral muscarinic acetylcholine receptors [2,3,11].

Symptoms resulting from central muscarinic receptor blockade:

• Altered mental status, confusion, restlessness, seizures, coma
• Symptoms resulting from peripheral muscarinic receptor blockade:
• Impaired sweat gland function
• Dry mouth
• Dry axillae
• Mydriasis
• Tachycardia
• Flushing
• Urinary retention

The combination of increased muscle activity causing increased heat production and the impaired ability to sweat leads to hyperthermia [2].

The onset of anticholinergic symptoms depends upon the drug but usually occurs within a couple of hours of ingestion [11].

Sympathomimetic syndrome

Sympathomimetic agents can cause life-threatening hyperthermia although the exact mechanism is unknown [2,3].

Sympathomimetics cause a central increase in the concentrations of norepinephrine, dopamine and serotonin whilst peripherally causing a vasoconstriction, increased muscle activity and impaired behavioural responses [2]. The degree of hyperthermia is not directly related to drug, mode of administration or duration [2]. The agents which are most commonly associated with hyperthermia are amphetamine, metamphetamine, MDMA and cocaine [3].

Symptoms of sympathomimetic syndrome include agitation, altered mental status, hallucinations, coma, seizures. Hyperthermia caused by sympathomimetics can also exacerbate these symptoms [2].

Malignant hyperthermia syndrome

This is a rare autosomal dominant skeletal muscle disorder that results in a hypermetabolic crisis [3]. The hypermetabolic state occurs in response to exposure to inhalational agents (eg halothane, sevoflurane, desflurane), suxamethonium and in rare cases stressors such as vigorous exercise or heat [3,12,13].

Symptoms of malignant hyperthermia typically occur within minutes to hours of administration of the causative agent [3].

Early signs: tachycardia, tachypnoea, muscle rigidity (especially masseter), ventricular dysrhythmias, unexplained hypercarbia [2,3,12].

Late clinical findings:  muscle rigidity, acidosis, hyperthermia [2,3,12].