Our findings challenge four commonly made assumptions about SS, which over time have become accepted textbook knowledge. There is only little agreement between current criteria systems for the diagnosis of SS so that clinicians need to keep an open mind about the diagnosis, even if diagnostic criteria not are met.

Hypothesis 1

HC may clinically be less sensitive than hitherto assumed. We acknowledge that our case note collection is inevitably subject to selection bias, but this does not invalidate our arguments. Understanding uncommon or emergent conditions that cannot be captured through randomized controlled trials often depends on pattern recognition from few cases. This way, for instance, the acquired immune deficiency syndrome (AIDS) was discovered [13]. It is unlikely that all cases missed by HC were false positives. The HC originators themselves have reported 96 % specificity for SC (compared to 97 % for HC). This means we would only have expected 4 % false positive cases when applying SC. Neither is the trend towards reporting according to HC over time automatically a proof a HC superiority. This trend may simply reflect that it has become increasingly difficult to publish cases that do not fulfil HC.

History of the three classification systems

SC was the first classification system published in 1999, derived from 38 psychiatric inpatients [5]. SC was criticized for being too unspecific and relying too much on mental status changes. For instance, SC could indicate SS without any neuromuscular symptom, if a patient presented with confusion, agitation and elevated temperature.

In 2001, Radomski refined SC based on a review of 62 cases, including Sternbach’s original 38 cases [6]. RC differentiated between major and minor symptoms of SS and added rigidity to the neuromuscular symptoms.

In 2003, Dunkley et al. released the HC based on a review of 2222 cases of overdoses with selective serotonin reuptake inhibitors (SSRIs) [7]. This classification focused on neuromuscular symptoms to a far greater extent than the other two classification systems. HC introduced clonus in its various forms (spontaneous, inducible and ocular). At the same time, HC removed myoclonus from the symptom list. The HC originators reported their classification system as more sensitive and specific than the other two classification systems.

Is there a gold standard for diagnosing SS?

Rather than being a tangible physical quantity such as body temperature or blood glucose, SS is an abstract construct made up of various conceptual, elements (items). In this way, the three classification systems are similar to a psychometric scale that might measure a construct such as quality of life. As any psychometric measurement tool, all three classification systems have tried in various ways to identify symptoms or symptom constellations that capture best “the nature of what is being measured” and “the relationship of that variable to its purported cause” [14]. In the case of SS, we measure CNS hyperexcitability and try to relate this to a purported drug-induced serotonin excess.

As CNS hyperexcitability can manifest itself in many ways, it may be difficult to establish a “true” gold standard for the diagnosis of SS. HC, the latest classification system in use, has reported superior sensitivity and specificity though. In these terms, HC should be best at both picking up cases and not picking up false positive cases. This has led to wide-spread endorsement of HC as the gold standard for the diagnosis of SS [1, 11]. It has also been suggested that reports of cases of SS that have not met HC are of poor scientific value [15]. Yet, the purported HC superiority is based on one study only. This may not be sufficient to underpin HC superior validity since “the burden of evidence in testing construct validity arises not from a single powerful experiment, but from a series of converging experiments” [14].

One concern regarding validity is that HC was derived exclusively from SSRI overdoses. Although HC is based on many more cases than SC and RC, the confinement to overdose cases suggests that HC may not automatically be generalizable to non-overdose states of serotonin excess, where symptoms may be less clear-cut than in acute poisonings. A second concern is that a proportion of the cases used to derive HC was then also used to validate HC. Verifying a construct, in this case SS, by including the same data, which was used to derive the construct in the first place, will lead to an overestimate of its validity [16]. Thirdly, HC may not perform well in patients with other underlying neurological pathologies. Hyperreflexia or clonus, two essential HC symptoms, may not occur in patients with peripheral neuropathy where nerve damage “masks upper motor neuron signs” [17]. Equally, reflexes or clonus may not be elicitable in patients with severe SS who have developed substantial muscle rigidity [1].

Clinically, particularly when a condition is life threatening, it may be better to err on the side of caution and temporarily withdraw a purported offending agent, until the differential diagnosis is clarified and appropriate action can be taken. The alternative of refusing to take into account symptoms because they do not meet HC and continuing a potentially harmful agent seems less safe. In many such cases, it may be possible to reinstate treatment with serotonergic drugs, once the SS has resolved and measures are taken to prevent the precipitating event in the future. Such measures include avoiding future overdoses, discontinuing opiates with serotonergic properties or withdrawing serotonergic antidepressants in good time prior to administration of methylene blue and linezolid.

Hypothesis 2

The claim that contrary to neuroleptic malignant syndrome (NMS), the onset of SS is usually rapid is based on one review of 41 cases with SS published between 1995 and 1999 [18]. In this case collection, 61.5 % presented with six hours of ingestion of the causative agent and only 25.6 % later than 24 h. Thus, SS may develop quickly or slowly, depending on the context in which it occurs. Our results fit with the observation that the onset of linezolid-associated SS may be delayed in elderly [19]. Whether SS develops quickly or slowly, may to a large extent depend on pharmacokinetic factors. Although polypharmacy is an important etiological factor in the development of SS per se, dose and speed of distribution may determine its severity. It remains also uncertain whether SS typically resolves much faster than NMS [20]. Rather, time to SS resolution may depend on the half-lives of the implicated agents.

Hypothesis 3

Fever is considered a hallmark of SS and hyperthermia. To be more precise, a temperature > 41.1 °C, a hallmark of severe SS [1]. Elevated temperature in SS is thought to arise from a loss of physiologic control of temperature regulation (leading to hyperthermia) rather than pyrogen mediated upregulation of the hypothalamic thermostat (pyrexia/hyperpyrexia) [20]. It is unclear, why some SS cases develop hyperthermia and others do not. In the context of SS, hyperthermia is linked to increased muscle activity as consequence of hyperexcitability and direct serotonergic effects on the muscle [1, 21, 22]. Naturally, these factors are subject to biological variability. Psychological and environmental factors such as exercise, heating, apprehension and excitement have shown to precipitate serotonin-mediated hyperthermia in susceptible animals [22].

Hypothesis 4