Serotonin syndrome unmasking thyrotoxicosis

Abstract

A 26-year-old cachectic man presented with an altered mental status. He was agitated, tremulous, hyperthermic and diaphoretic with largely dilated pupils. Collateral history revealed acute ingestion of 3,4-methylenedioxymethamphetamine on a background of chronic drug abuse. His condition deteriorated requiring sedation and intubation with transfer to the intensive care unit. A diagnosis of serotonin syndrome was made, based on his findings in keeping with the Hunter criteria, and he was treated with supportive management during a resultant and briefly sustained delirium. With gradual resolution of his agitated state, further questioning and blood work a concurrent, and potentially contributory, thyrotoxicosis was revealed. The patient was commenced on treatment for this with urgent outpatient follow-up with both a local otolaryngologist and endocrinologist for consideration of further treatment.

Background

Serotonin syndrome (SS), or serotonin toxicity, is a sometimes fatal condition associated with increased serotonergic activity of the Central Nervous System. SS can be induced accidentally, iatrogenically or in an intentional overdose. SS is a spectrum of clinical findings ranging from benign to lethal that encompasses, though is not limited to, a triad of mental status changes, increased autonomic activity and neuromuscular abnormalities.¹ SS is common in all age groups. Increasing medical usage of serotonergic agents and their usage in drug abuse and/or intentional overdose has lead to an increase in the incidence.¹ The diagnosis of SS is made on a purely clinical basis. Thorough history, particularly a collateral as evidenced in this case, and physical examination are essential. Mental status changes can include anxiety, agitations, delirium and disorientation.¹ Various signs can manifest from SS including tremor, muscle rigidity, myoclonus, hyper-reflexia and bilateral Babinski sign. These occur due to the neuromuscular effects of serotonin. Common findings, particularly in the lower extremities, include hyper-reflexia and clonus.¹ Though no laboratory tests specifically confirm SS, an elevated white cell count and creatine kinase with decreased serum bicarbonate can point towards the diagnosis. Severe disease can lead to rhabdomyolysis, disseminated intravascular coagulation, metabolic acidosis, renal failure and acute respiratory distress syndrome.² Many sets of diagnostic criteria can be utilised to confirm the diagnosis, though the Hunter criteria are generally accepted as the most accurate of these with 97% specificity when compared with gold standard in the evaluation of SS, diagnosis by medical toxicologist.³

This case is an important example of the complexity of the above diagnosis, the important differentials it can mimic and, as evidenced through our own learning, potential concurrent and influential pathologies.

Case presentation

A 26-year-old man presented acutely to the emergency department of an inner-city hospital via ambulance. He was brought in emergently following an accidental 3,4-methylenedioxymethamphetamine (MDMA) overdose with a symptom complex consisting of fever, agitation, tremor, diaphoresis and dilated pupils. The young man was cachectic looking with mild exophthalmus and a history of previous drug abuse and hepatitis C for which he was never fully treated due to poor compliance. Initial point of care testing revealed a positive urinary toxicology screen for the use of MDMA. Further confirmation with gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry was not followed as the facility unfortunately was not available in our service. In the absence of this confirmatory test, this does leave the potential for a false positive point of care result, though a retrospective history obtained did confirm the ingestion of MDMA by the patient. Blood results demonstrated hyperkalaemia, hypoglycaemia and leucocytosis (table 1). Liver function tests were stable from a prior baseline and an ultrasound of abdomen revealed no appreciable ascites. Chest X-ray showed no obvious consolidation. He was treated accordingly with 5% dextrose and covered with broad spectrum antimicrobials given his risk of both meningoencephalitis and bacterial endocarditis with septic embolisation. A diagnosis of SS was made using the Hunter criteria. The patient exhibited generalised hypertonia, a fever of 39.4°C, hyper-reflexia and inducible clonus on examination. Treatment with benzodiazepines acutely failed to control his symptoms or the patient’s hyperthermia and thus he was sedated, intubated and transferred to the intensive care unit (ICU) given his agitation and general deterioration. The patient remained in the ICU, intubated for 48 hours. During this period of time, his hypoglycaemia and hyperkalaemia were treated and followed with daily blood panels. He was closely monitored, via telemetry, for arrythmia given his heightened risk with the aforementioned hyperkalaemia in combination with his concurrent SS. Weaning of sedation was deliberately slow given the agitation and aggression preceding his ICU admission. Extubation was successful and uneventful. Post extubating, he remained in the ICU for an observation period of 24 hours. On day 4, he was transferred to the medical ward for further management. As sedation was weaned, an acute delirium followed for which he was linked with psychiatric services and treated with orientation and sedation as required. A CT brain was performed to exclude any other intracranial pathology. This study was normal as were a repeated full blood count, urea and electrolytes (U&E) and C-reactive proteint (CRP). Results of thyroid function tests performed revealed a Thyroid stimulating hormone (TSH) of <0.01 mIU/L (0.35–4.94), Free T-4 of 28.9 pmol/L (9.0–19.1) and total T3 of 4.78 nmol/L (0.8–3.0). Propranolol 80 mg LA was commenced to treat his symptomatic tachycardia and tremor. carbimazole 20 mg three times daily was also commenced. This was presumed a new diagnosis or consequence of his acute presentation as outlined in the discussion section. On day 10, he had returned to his baseline with hallucinations and paranoia settling without medical intervention. Once the patient was verbalising appropriately post delirium, he confirmed that he had previously been diagnosed with hyperthyroidism at a different hospital and prescribed this medication, though he did not take it as directed (carbimazole 10 mg once daily maintenance). This diagnosis was made 4 months prior to admission under our care on the basis of a Free T4 of 32.9 pmol/L (9.0–19.1) and TSH of <0.01 mIU/L (0.35–4.94). An ultrasound of thyroid revealed a mildly heterogeneous thyroid gland demonstrating mild hyperaemia with no focal nodules. The patient was referred for urgent outpatient review with both the local otolaryngologist and endocrinologist for consideration of further management, be it with radioiodine or thyroidectomy, as deemed appropriate. He was also re-referred to a gastroenterological department for management of his active hepatitis C, a concurrent ultrasound of his liver thankfully demonstrating no obvious cirrhosis. The patient was discharged well and linked with social work for cessation of his ongoing drug abuse and also with addiction services.

Table 1.

Admission blood work

WCC	25.3×109/L (4.4–11.3)	Troponin I	14 ng/L (0–34)	Urea	7.8 mmol/L (2.8–8.4)
Neutrophils	19.4×10.9/L (1.4–6.6)	Glucose	0.5 mmol/L	Creatinine	110 μmol/L (64-104)
Hb	158 g/L (130–170)	Potassium	6.0 mmol/L (3.5–4.9)	Creatine kinase	132 U/L (30–200)
International Normalised Ratio (INR)	1.13 (0.9–1.1)	Sodium	143 mmol/L (132-144)	ALT	181 U/L (0–55)
Prothrombin Time (PT)	12.6 seconds (9.6–11.8)	Paracetamol	<10 mg/dL	AST	128 U/L (5–34)
Activated Partial Thromboplastin Time (APTT)	23.3 seconds (20.5–28.4)	Salicylate	<7 mg/dL	GGT	72 U/L (12–64)
PLT	260×10.9/L (140–440)	Bilirubin	15.2 μmol/L (3.4–20.5)	CRP	1 mg/L (0–5)

Hb, haemoglobin; PLT, platelet; WCC, white cell count.

Differential diagnosis

Though a broad list of differentials exist for SS, including neuroleptic malignant syndrome, intoxication, encephalitis, meningitis and malignant hyperthermia, in this particular case the events surrounding the presenting complaint focused this list considerably.

Acute intoxication, SS, meningitis, hepatic encephalopathy, addisonian crisis and thyrotoxicosis formed our main differentials. The patient had multiple risk factors for each of these. His past history of heroin use and active hepatitis C predisposed him to multiple drug overdose or intoxication as well as potential endocarditis with septic embolisation and meningoencephalitis. Deranged hepatic function associated with his active hepatitis C and alcoholism were both risk factors for hepatic encephalopathy. The history of poorly controlled hyperthyroidism, though not initially known, of course predisposes him to a thyrotoxic crisis.

Although SS is a clinical diagnosis, it is imperative to exclude the other diagnoses mentioned as part of a thorough work-up. In the acute scenario, this is not always as straight forward and a low threshold is required to cover, for example with antimicrobials, for alternative diagnoses in the initial stage and be aware of the possibility of concurrent pathologies.

Outcome and follow-up

The patient was discharged on propranolol LA 80 mg and carbimazole 20 mg three times a day with an urgent arrangement for outpatient review with otolaryngology and endocrinology to follow. Given his prior non-compliance with medical management of his hyperthyroidism, definitive treatment with radioiodine or thyroidectomy and thyroxine supplementation thereafter were deemed most appropriate to avoid future complications.

Discussion

Differentiating SS and thyrotoxicosis is a diagnostic dilemma as during an acute SS a non-thyroidal illness syndrome is a distinct possibility and differential.⁴ Furthermore, were the elevated levels of total T3 and free T4 to trend downwards following treatment of SS alone, then in the absence of thyroid-specific treatment the diagnostic picture could be in keeping with a resolving thyroiditis. Fortunately, in the above case, we have the added advantage of a prior history of hyperthyroidism and non-compliance with same as a causative factor for his deranged thyroid function tests. In cases where no prior history is known, close monitoring of these values after the acute presentation is imperative to narrow this differential and treat accordingly.

The relationship between thyroid hormones and serotonin is of a rather complex nature and not yet fully understood. A review of literature performed by Bauer et al highlights the potential sensitising nature of thyroid hormones for cortical 5-HT2 receptors. This paper also demonstrates the increased cortical concentration of 5-HT associated with experimentally induced hypothyroid states that were corrected with thyroxine. These studies highlight an altered serotonin metabolism in the hyperthyroid patient which is suggested to remain still above that of normal control subjects even after successful treatment.⁵

The relationship between MDMA and thyroid hormones is equally complex. Animal models have shown that the thermoregulatory effects exhibited by MDMA are mediated via an increase in thyroxine levels. This was shown by administering MDMA to animals with both hypophysectomies and thyroparathyroidectomies both of which failed to produce the same hyperthermic responses without thyroxine replacement.⁶

The aforementioned studies suggest that our patient’s ingestion of MDMA would have likely resulted in a further deterioration in his thyroid status which in turn would preclude a heightened 5-HT concentration cortically and the observed SS.

Learning points.

• The importance of a collateral history.

• In acutely altered mental status this cannot be stressed enough. Certainly, in this case a prompt diagnosis was vital and reached with relative ease due to the aforementioned.

• The risk of concurrent diagnoses.

• As mentioned in our differentials section, certainly this man’s risks for multiple causative aetiologies is evidence in and of itself that exclusion of these diagnoses is imperative in the acute scenario. A missed concurrent diagnosis of endocarditis, encephalitis or meningitis can be devastating if not even fatal.

• Beware stereotyping clinical signs.

• Drug abuse brings with its poor self-care and weight loss. However, on reflection the level of cachexia seen in this man was even still out of keeping and more appropriately explained by his thyroid status.