Approach
Diagnosis of serotonin toxicity is primarily clinical, and diagnostic tests are rarely required. Toxicity is characterized by a triad of clinical features (neuromuscular excitation, autonomic effects, and altered mental status) in combination with a history of exposure to a serotonergic drug.[1][2] It is important to establish whether serotonin toxicity is mild, moderate, or severe, as this guides treatment.[3] A number of clinical diagnostic criteria have been used for serotonin toxicity, but those currently recommended are the Hunter Serotonin Toxicity Criteria (HSTC) (see below).[4][21]
History
Ascertaining whether the patient has been exposed to serotonergic drugs is an essential part of the diagnosis, and should include over the counter medications and complementary medicines. It is important to establish an accurate history of exposure from either the patient or a reliable source (e.g., if patient is unconscious), which includes when the agent was started or taken, whether the agent was prescribed for the patient or belongs to someone else, how much of the agent was taken, and the name of the agent if known.[1][3][4][9] Absence of exposure excludes serotonin toxicity as a diagnosis. Combinations of serotonergic drugs that act via different pharmacologic mechanisms (most commonly a selective serotonin-reuptake inhibitor plus a monoamine oxidase inhibitor) is the most likely cause of severe serotonin toxicity.[2]
Symptoms of altered mental status include anxiety and agitation, and occur most commonly in moderate toxicity. Confusion is uncommon but may be present in cases of severe toxicity. Although these symptoms are nonspecific, in the presence of other features they are often the most distressing for the patient. Other nonspecific symptoms include generalized sweating and headache.
Symptoms of neuromuscular excitation (e.g., tremor, shivering, or muscle jerks) are common. Tremor and shivering are abnormal regular shaking movements of the muscles that differ in frequency. Muscle jerking is sudden involuntary movements of the muscles.
Physical exam
A general exam looking for autonomic signs and mental status, and a focused neurologic exam, should be conducted.[1][2] Patient may appear agitated, anxious, or confused on initial exam.
Autonomic signs include tachycardia, diaphoresis, flushing, dilated pupils, and hyperthermia. Tachycardia is a nonspecific sign but occurs commonly in moderate toxicity and is a reasonable indicator of deterioration or improvement in the patient. Blood pressure is not a diagnostic factor in serotonin toxicity but is usually normal or mildly elevated in most cases. Diaphoresis and flushing are also nonspecific signs, but they can occur in all severities of serotonin toxicity. Dilated pupils may be seen, but this is more diagnostic of other toxidromes such as anticholinergic syndrome.[22] A mild elevation in temperature (i.e., >100.4°F [>38°C]) may occur, but this is neither diagnostic nor contributory on its own. Hyperthermia (temperature >101.3°F [>38.5°C] or rapidly rising) is a diagnostic feature of severe toxicity and its presence necessitates urgent treatment.[4][8] In the absence of neuromuscular features, other causes of hyperthermia should be considered.[11]
Signs of neuromuscular excitation include clonus, hyperreflexia, tremor, myoclonus, and hypertonia/rigidity. Clonus is the single most common diagnostic feature of serotonin toxicity. It ranges in severity from inducible clonus (>3 beats) to spontaneous clonus and is best elicited at the ankle. It can also be elicited in other muscular groups in the upper and lower limbs but is more difficult to induce. In more severe cases, clonus will be sustained or will become spontaneous and may be difficult to distinguish from hypertonia. Ocular clonus is a diagnostic sign and is rarely seen in other clinical conditions. It is manifested by rapid and equal movements of the eyes and is best elicited by getting the patient to fix on a finger moved rapidly to the midline. It should be distinguished from nystagmus, in which there is a fast and slow component. Hyperreflexia occurs almost universally with serotonin toxicity and in the majority of patients on serotonergic drugs therapeutically. It is usually more pronounced in the lower limbs. Hypertonia is most likely due to sustained spontaneous clonus in severe toxicity. It usually occurs in association with hyperthermia and should be considered to be diagnostic of severe toxicity requiring immediate treatment.
In moderate serotonin toxicity, patients will startle easily (e.g., at sudden sounds or changes in the environment), although this should not be elicited on exam.[23]
In clinical practice overdose patients may have taken multiple medications, with patients who have overdosed on multiple neuro-active medications, it is common to have features of multiple toxidromes in one patient. For more information, see Cocaine toxicity, Benzodiazepine overdose, Opioid overdose and Tricyclic antidepressant overdose.
Hunter Serotonin Toxicity Criteria (HSTC)
In the presence of a serotonergic agent, serotonin toxicity exists:
If spontaneous clonus is present OR
If inducible clonus AND agitation or diaphoresis are present OR
If ocular clonus AND agitation or diaphoresis are present OR
If tremor AND hyperreflexia are present OR
If hypertonia AND pyrexia (temperature >100.4°F [>38°C]) AND ocular clonus or inducible clonus are present.
[Figure caption and citation for the preceding image starts]: Hunter Serotonin Toxicity Criteria (HSTC) algorithmFrom the collection of Dr Geoffrey Isbister [Citation ends].
Investigations
Diagnosis of serotonin toxicity is primarily clinical, and diagnostic tests are rarely required unless other differential diagnoses are being considered (e.g., complete blood count to exclude infection, creatine phosphokinase to assess for rhabdomyolysis in patients presenting with clonus). An ECG may be performed in patients with suspected serotonin toxicity because some agents also cause cardiac toxicity (QT prolongation), importantly citalopram and escitalopram. It is likely to demonstrate tachycardia. Blood cultures, lumbar puncture, and/or brain imaging may be considered to help exclude central nervous system infection as a cause for the patient’s symptoms.
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