14th February 2025

Diagnosis of SS

The single most important diagnostic factor is the presence of serotonergic drugs, particularly if started or increased in the past 24 hours. This might be in the form of:

• Serotonergic drug therapy
  • Selective serotonin reuptake inhibitors (SSRI), e.g. fluoxetine, paroxetine, sertraline, citalopram
  • Serotonin and norepinephrine reuptake inhibitors (SNRI), e.g. duloxetine, venlafaxine
  • Other antidepressants: imipramine
  • Opioids: tramadol, fentanyl
  • Monoamine oxidase inhibitors (MAO-I)
  • Others: lithium, lamotrigine, tryptophan
  • Drug interactions: multiple serotonergic drug therapy increases the likelihood of SS
• Illicit drug use, e.g. amphetamines, methamphetamine, ecstasy, cocaine
• Deliberate or accidental overdose of the above

Examination in SS

Typical features may include the following, but anywhere along the spectrum of severity:

• Altered conscious level: anxiety, agitation, confusion, coma
• Autonomic instability: hyperthermia, tachycardia, hyper/hypotension, sweating, mydriasis*
• Respiratory distress
• Neuromuscular excitability*: clonus, progression to spontaneous clonus (can appear similar to muscle rigidity or a generalised tonic-clonic seizure), tremor, hyperreflexia

Presentation of SS is very similar to NMS, and some drugs can cause both SS and NMS. The main discriminators are the shorter onset time in SS from drug initiation or dose change and features marked with *.

Investigations in SS

NMS is a clinical diagnosis with no specific test, although the below support diagnosis and screen for complications.

Bedside tests:

• ECG: autonomic instability can trigger cardiac issues
• Urine toxicology screen: for illicit drug causes of SS

Blood tests:

• FBC, U&Es, LFTs, clotting, blood cultures: screen for infection
• Blood glucose: rule out hypoglycaemia
• Consider CK if NMS is a differential diagnosis

Tests to rule out infection or other causes of confusion should be considered, e.g. CXR, CT head, LP.