This is an extra blog post in my usual series on emergency toxicology. The last post was about acute behavioural disturbances and can be found here.
As emergency clinicians, we often have to deal with adverse reactions to drugs. In some cases, these reactions can be severe. Most of us will have come across one of the dreaded “hyperthermic drug syndromes” in our practice. The most famous of these are serotonin syndrome, neuroleptic malignant syndrome (NMS), and malignant hyperthermia. More common in practice are anticholinergic and sympathomimetic syndromes, which are often associated with behavioural emergencies.
A few weeks ago, a fantastic set of podcasts went out on EMCRIT covering this topic. I recommend everyone give these a listen in full. They contain pretty much everything you need to know about serotonergic and dopalytic syndromes, with some expert perspectives from neuro-intensivist Eelco Wijdicks, author of a recent review for JAMA.
I wanted to write a quick response to one of the points made on the podcast about the clinical diagnosis of serotonin syndrome.
Scott Weingart explains that the serotonergic “toxidrome” can be differentiated from other drug reactions by examining for neuromuscular excitation, which is emphasized in the Hunter criteria and manifests as tremor, hyperreflexia, and clonus. He explains that the other characteristic signs – hyperthermia, altered mental status, and autonomic instability – are seen, for example, in abuse of stimulants, or NMS.
I agree with this point overall, and I think it is an important one to make. We cannot rely solely on drug history to make diagnoses like these. Sometimes the exposures are unknown, or equivocal. Plenty of patients take both antidepressants and antipsychotics and there are some antipsychotics, such as ariprazole, that have serotonergic properties or shared metabolic enzymes with serotonergic agents. Initiation of these newer antipsychotics can precipitate serotonin syndrome while giving clinicians a drug history more suggestive of NMS. Neurological examination is vital to confirm the toxidrome.
To add a little bit more more to the podcast, I went on a deep dive into the actual performance of examination in this context. This was inspired, in part, by conversations we have had here in Virchester about how difficult it can be to make these diagnoses. Sadly, we have had quite a few cases in recent years.
If we look at the movement disorder literature, it would seem that motor abnormalities are difficult to assess. Inter-rater reliability for the examination of clonus has been found to be highly variable among psychiatrists (n=47; κ 0.854) and physiotherapists (n=9; κ 0.40-0.60), as well as between neurosurgeons and physiotherapists (n=51; κ 0.66). Similar findings have been reported with rigidity – the hallmark of NMS – among general neurologists (n=30; κ 0.51) and movement disorder specialists (n=404; ICC = 0.84), and between neurologists and specialist nurses (n=50; ICC = 0.81). It is unsurprising to me that emergency clinicians have faced uncertainty in so many cases of suspected serotonin syndrome and NMS despite a thorough neurological examination.
It is worth adding that it is possible for patients to present with both serotonin syndrome and NMS if they have taken a polydrug overdose, or have had multiple changes made to their long-term medications. In these cases the neurological examination is likely to be equivocal.
The reason all of this matters is because there are potentially severe consequences to over-calling serotonin syndrome. The treatment recommended by TOXBASE® includes antipsychotics — which can dramatically worsen NMS and anticholinergic syndromes.
What do you think? Drop a comment below. And again: go listen to the EMCRIT podcast.
vb
Greg
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