Serotonin syndrome: a rare undiagnosed cause of hyperpyrexia

Abstract

Serotonin syndrome (SS) is a rare but potentially life-threatening condition, and it is caused by increasing serotonergic activities. It is an underdiagnosed and under-reported condition. Clinical manifestations can range from mild to moderate to severe symptoms. The intensity of symptoms reflects the degree of serotonin toxicity, and mild serotonin syndrome is easily overlooked by physicians.

Severe serotonin toxicity typically occurs to a combination of serotonergic agents.

Herein, we describe a case of severe serotonin toxicity in a 38-year-old Egyptian male with a history of generalized anxiety disorder and depression. With increased depressive symptoms, he received 20 mg of fluoxetine daily, and the symptoms developed 1 month after starting fluoxetine, which is the uncommon onset of presentation. The patient was already on tramadol for chronic low backache. The aim is to increase awareness of the syndrome among physicians and neuropsychiatrists.

Background

A 38-year-old male was presented to the emergency department of Embaba Fever Hospital (Giza, Egypt) in an acute confusional state associated with hyperpyrexia and severe agitation, and he is known to have had a psychic depression for which he had been prescribed fluoxetine 20 mg once daily. He had a history of chronic low back pain for which he was receiving tramadol. The symptoms started 1 month after fluoxetine treatment, and he was observed to have myoclonic jerks, marked tremors, and inducible patellar and ankle clonus. According to the presence of hyperpyrexia, inducible clonus, marked tremors, severe agitation, and a history of concurrently using two serotonergic medications (fluoxetine and tramadol), a diagnosis of serotonin syndrome was made. The purpose is to highlight the clinical manifestation of serotonin syndrome in its severest form and also to alert emergency physicians and neuropsychiatrists to be aware of the syndrome even in mild cases as they are likely to be missed as the patient on a serotonergic agent presents with only tremors and hyperreflexia. Every patient with mild SS is a potential candidate for developing life-threatening severe serotonin syndrome [1].

Case presentation

A 38-year-old male was referred from a private hospital to the emergency department of Embaba Fever Hospital (Giza, Egypt), with an ambulance he was referred in a delirious state and severe agitation. There was no history of head trauma, and he convulsed once in the ER. He is on regular use of tramadol because of chronic low backache. He had suffered an attack of depression and anxiety 1 month before admission, for which he received fluoxetine 20 mg single daily dose.

Examination

The temperature on admission was 41 °C for which he had been managed in the ER as non-exertional heat hyperpyrexia. He was admitted to the intensive care unit, sedated, intubated, and mechanically ventilated. The patient was tremulous. Restless with marked spasticity in both lower limbs to the degree that both knee joints appeared to be locked, he had hyperreflexia and induced clonus in both ankles and patellae.

Investigation

Complete blood count, Biochemical investigation, Arterial blood gases, and CSF analysis are shown in table 1.

Table 1 Complete blood count, biochemical investigation, arterial blood gases and CSF analysis

Chest X-ray: normal

The patient was diagnosed clinically with serotonin syndrome according to Hunter’s toxicity criteria [2] after the exclusion of other causes in the differential diagnosis.

Discussion

Serotonin syndrome is an under-reported and under-diagnosed condition [1]. The diagnosis of SS is easily missed as many physicians (up to 85%) might not be aware of this syndrome as a clinical entity and hence the importance of this case to increase its awareness [3, 4].

The assessment of serotonin syndrome requires determining first whether the clinical features are consistent with serotonin toxicity, and second the severity of the toxicity, the clinical assessment should include observation for myoclonus jerks, diaphoresis, ocular clonus (slow continuous horizontal eye movements), and agitation. The presence of hyperreflexia with tremors is suggestive of SS if the patient has taken serotonergic agents in the past 5 weeks [5]. Tremor is a well-known recognized symptom of SS. Severe SS may develop after the addition of the second serotonergic drug in patients who already have some mild SS because of the first serotonergic drug [6,7,8]. The onset of mild SS may have an indolent course or symptoms may go unnoticed by patients [5], while the onset of severe serotonin toxicity usually rapidly follows the administration of the offending agent [4]. Unlike this patient, symptoms’ onset may be rapid and may occur within minutes [3], mostly within 24 h of taking a serotonergic agent, with an estimated 60% of patients experiencing symptoms within 6 h [9, 10]. However approximately 7% of patients may experience delayed symptoms up to 6 weeks after the initial dose [9], like this patient.

Severe serotonin toxicity typically occurs to a combination of serotonergic agents, examination findings can include hyperthermia, agitation, ocular clonus, tremors, akathisia, deep tendon hyperreflexia, inducible or spontaneous clonus, muscle rigidity, dilated pupils, dry mucous membranes, increased bowel sounds, flushed skin and diaphoresis, neuromuscular finding are typically more pronounced in the lower extremities, Hunter’s Criteria is a measure commonly used to diagnose serotonin syndrome.

There is no specific test for serotonin syndrome and measurement of serotonin levels has not been shown to be helpful [11]. Laboratory abnormalities are non-specific but include elevated creatine phosphokinase, leukocytosis, transaminitis, and low serum bicarbonate [12].

The differential diagnosis includes anxiety, neuroleptic malignant syndrome (NMS), anticholinergic toxicity, malignant hyperthermia, sympathomimetic intoxication, encephalitis, and serotonin syndrome is often misdiagnosed with NMS [13].

NMS is distinguished on the basis of history, examination findings, and clinical course. NMS develops over days to weeks, whereas serotonin syndrome mostly develops over 24 h [14]. Approximately 7% of patients with serotonin syndrome may experience delayed symptoms like this patient (serotonin syndrome is characterized by neuromuscular hyperactivity (tremors, hyperreflexia, myoclonus), while NMS develops sluggish neuromuscular response (rigidity, hyporeflexia). Anticholinergic toxicity classically presents with hyperthermia and agitation, altered mental status, mydriasis, dry mucous membranes, urinary retention, and decreased bowel sounds but the muscular tone and reflexes are normal, malignant hyperthermia occurs in susceptible individuals exposed to halogenated volatile anesthetics and depolarizing muscle relaxants (e.g., succinylcholine) [15]. Serotonin syndrome is distinguished from other causes of agitated delirium on the basis of neuromuscular findings, whereas patients with serotonin syndrome show signs of neuromuscular activation, patients with sympathomimetic activity or infections of the CNS lack these findings [6].

The Hunter serotonin toxicity criteria decision rules in the presence of a serotonergic agent are the following:

• 1 If spontaneous clonus = yes, then serotonin toxicity = yes

• 2 If inducible clonus = yes, and agitation = yes or diaphoresis = yes, then serotonin toxicity = yes

• 3 If ocular clonus = yes and agitation = yes or diaphoresis = yes, then serotonin toxicity = yes

• 4 If tremor = yes, and hyperreflexia = yes, then serotonin toxicity = yes

• 5 If hypertonia = yes, and temperature > 38 °C, and ocular clonus = yes, or inducible clonus = yes, then serotonin toxicity = yes

According to the presence of Hunter’s criteria [2] for serotonin toxicity, (hyperthermia, marked agitation, hyperreflexia, muscle rigidity, inducible clonus, and the medical history of combined serotonergic drug intake), the diagnosis of serotonin syndrome was made, and both the analgesic medicine tramadol and the selective serotonin reuptake inhibitor ‘fluoxetine’ inhibit serotonin reuptake, thus increasing serotonin activity and causing serotonin toxicity. There is no specific antidote for serotonin toxicity. Although cyproheptadine is considered a drug of choice for SS, cyproheptadine is an antihistamine with antimuscarinic properties [16, 17]. To date, there are no specific treatment guidelines for the treatment of serotonin syndrome; the most important course of treatment is to discontinue the offending drugs [1, 3,4,5]. It should be noted that linezolid is a reversible, non-selective monoamine oxidase inhibitor. Serotonin syndrome with linezolid plus either an SSRI or venlafaxine is a progressive process. When recognized, however, serotonin syndrome is readily reversible on discontinuation or a decrease of the dosage of serotonergic agents, if the clinical situation warrants the use of linezolid in a patient receiving an SSRI, linezolid may be used concomitantly with SSRI with careful monitoring for signs and symptoms of serotonin syndrome [18].

The patient was sedated and mechanically ventilated based on the hypoxemia and severe metabolic acidosis, and the management included treatment of hyperthermia, IV fluids, muscle relaxants, and cyproheptadine 8 mg initial dose by the Ryle tube, followed by 2 mg every 2 h with no physical restraint in order not to increase hyperthermia. Evaporative and convective cooling is the method used most often to treat non-exertional (classic) heat stroke because it is effective, non-invasive, and easily performed; and does not interfere with other aspects of patient care, hyperpyrexia was managed by placing the patient in an air-conditioned room with a current airway (fan) behind the bed with the removal of restrictive clothing and spraying water on the body, alternating with soaked sheets and placing ice packs in the axillae and groins. Rapid cooling is a key determinant of a favorable outcome. When used to treat older adult patients with non-exertional heat stroke, evaporative and convective cooling is associated with decreased morbidity and mortality [19,20,21].

Special beds called body cooling units have been made for this purpose [20]. In spite of every effort that was done to save the life of the patient, he was ultimately arrested and failed all trials for his resuscitation.

Conclusion

Serotonin syndrome is a rare cause of hyperpyrexia, it should be suspected in all patients receiving serotonergic medicine, a single serotonergic agent usually causes mild or moderate serotonin toxicity while severe serotonin syndrome may develop after the addition of a second serotonergic drug.

Early diagnosis of mild serotonin syndrome prevents the development of severe life-threatening serotonin syndrome so it is suggested that every patient on the serotonergic drug should be examined for the presence of hyperreflexia, tremor, and clonus.