Abstract
Serotonin syndrome is a potentially life-threatening condition manifesting with a broad range of neurological features due to serotonergic hyperstimulation of the central nervous system (1, 2). Typical clinical manifestations include mental status and behavioural changes, motor symptoms such as restlessness, tremor, incoordination, myoclonus and autonomic symptoms. Convulsive seizures rarely occur in the early phase of serotonin syndrome and are often associated with hyperthermia (1, 2). Early recognition and treatment are important because this condition is potentially fatal (2).
Serotonin syndrome is usually caused by therapeutic drug use, intentional self-poisoning or drug interactions that increase serotonergic modulation. Many drugs and drug combinations have been associated with serotonin syndrome: monoamine oxidase inhibitors, selective serotonin re-uptake inhibitors (SSRIs), carbamazepine, lithium, opiate analgesics, weight-reduction agents, antiemetics, triptans and herbal products (2, 3). Serotonin syndrome is thought to occur as a result of excessive stimulation of the 5-HT1A and 5-HT2 receptors in the brainstem and spinal cord. Moreover, other neurotransmitters (dopamine, catecholamines, tryptamine) have been implicated (4).
We report on a patient who developed seizures as the presenting symptom of serotonin syndrome followed by acute rhabdomyolysis. The condition was precipitated by triptans use in a patient with long-lasting use of fluoxetine and hypericum.
Case report
A 28-year-old woman complained of frequent migraine attacks beginning in adolescence and occurring at a frequency of four episodes per month, each lasting 1–2 days. It was a pulsating migraine in the frontotemporal region with bilateral radiation of the pain. The pain was usually acute, associated with severe phono-, photophobia and nausea, worsening with physical exercise. Aura was never reported. The type of headache met International Classification of Headache Disorders-2 criteria for migraine without aura (5). The patient used to take eletriptan 40 mg/day at the beginning of the attack with good response, whereas non-steroidal anti-inflammatory drugs did not show the same efficacy. She had had only a brief course of prophylactic treatment with amitriptyline that had been discontinued 3 months earlier. During the last 6 months she had been on eletriptan at three to four administrations each month. She had also been in psychotherapy and on drug therapy with fluoxetine 60 mg/day for 1 year for an eating disorder with binge–purge behaviour. At the time of admission to the hospital the eating disorder was in remission and she had not experienced bulimic attacks for a few months.
The patient was admitted to hospital for sudden head deviation with loss of consciousness. In the emergency room she had an epileptic fit with tonic-clonic convulsions and tongue bite followed by mental confusion. She underwent a computed tomographic scan that revealed absence of brain focal lesions and was treated with lorazepam i.v. infusion. On admission she had been taking fluoxetine 60 mg/day for 1 year and self-prescribed St. John's wort pills, a herbal medication containing hypericum, for 1 month. In the previous 3 days before admission to hospital she had taken eletriptan 40 mg/day to treat recurrent migraine. Each time triptan administration prevented the development of full-blown migraine attack and symptoms such as nausea and vomiting were not experienced.
Clinical and neurological examinations were normal except for the presence of mental slowness and subtle postural tremor of the fingers. Body temperature was mildly elevated at 37.5°C and normal blood pressure and pulse rate values were recorded. No signs of autonomic dysfunction were present. Routine blood analysis was performed and besides a mild increase of myoglobin, with normal creatine kinase (CK) and a modest increase of
Time course of serum creatine kinase (CK) and
After admission to hospital, the patient complained of diffuse myalgias that worsened a few days later. Indices of acute rhabdomyolysis were detected: CK 13.660 U/l (normal 0–180 U/l), myoglobin 965 µg/l (normal <70), aldolase 80 U/l (normal 1–7.7 U/l). Serum aminotransferase and
Discussion
Serotonin syndrome is a clinical condition manifesting with the triad of mental status change, autonomic hyperactivity and neuromuscular abnormalities. Epileptic seizures occur in severe cases, often in association with other cognitive/behavioural alterations, fever and myoclonus. In a case series of 41 patients with serotonin syndrome, seizures were reported among the presenting symptoms in only 5% of cases (6). Although chronic treatment with fluoxetine has an anticonvulsant effect, generalized tonic-clonic seizures have been occasionally described associated with exposure to an overdose or an increase in dose. In our patient the dose of fluoxetine had been stable in the last months, with no overdose documented. In the literature there is no evidence that triptan use alone could have influenced the epileptic threshold. Electrolytes imbalance or dehydration following a severe migraine attack associated with vomiting may act as predisposing factors for the development of convulsive seizures. However, in our patient blood analysis was unremarkable for electrolyte abnormalities and signs of dehydration were not present on admission to hospital, making it unlikely that metabolic changes could have been responsible for convulsive seizures.
This patient presented with epileptic seizures, mild fever and mental slowness followed by severe, acute rhabdomyolysis with mild renal failure and increase in serum liver enzymes and
The diagnosis of serotonin syndrome was suggested by the history of multidrug use with potential interaction able to increase serotonergic neurotransmission, the abrupt onset of symptoms after a course with triptans, and rapid recovery after reduction and withdrawal of the medications. In this case the combination of hypericum and fluoxetine probably predisposed the patient to develop serotonin syndrome precipitated by subsequent use of eletriptan. Since eletriptan administration had been used occasionally by the patient for migraine attacks in the last year in association with SSRIs, without any side-effects, it is conceivable that the concomitant use of hypericum with SSRIs and triptans precipitated the condition by potentiating the pharmacodynamic interaction of serotonin neurotransmission.
St John's wort, containing hypericum, has been shown specifically to inhibit synaptosomal uptake of serotonin, norepinephrine and dopamine (8). This mechanism of action creates the potential for a pharmacodynamic interaction between the herbal and pharmaceutical drugs that share this mechanism of action, in particular SSRIs, which, like St John's wort, are used for mood disorders (9). The avoidance of multidrug regimens is critical to the prevention of serotonin syndrome. When a combination therapy is needed, it is important to study the drug setting to avoid the association with different serotonergic agents. In particular, before prescribing triptans the physician should analyse carefully the patient's drug setting, often including self-prescribed herbal medications, that interfere with the serotonergic modulation. This case highlights the interaction between migraine therapy and psychotropic medications, often prescribed to treat conditions in comorbidity with migraine. Besides polypharmacy, patients add over-the-counter self-prescribed herbal medicines, which have the potential to interact with pharmaceutical drugs. The adverse events resulting from these drug–drug and drug–homeopathic medicine interactions are rare, but potentially life threatening, as in severe serotonin syndrome. This possibility should always be considered and discussed with the patient when prescribing an antimigraine drug in association with other psychotropic medications and/or homeopathic medicines.