CASE REPORT Serotonin Syndrome Presenting With Migrainelike Stroke Majid Molaie, MD From Seton Hall University, South Orange, NJ. Address all correspondence to Dr. Majid Molaie, 1360 W. Sixth Street, #220, San Pedro, CA 90732. Accepted for publication October 27, 1996. Serotonin syndrome is the result of the drug interaction that enhances serotonergic tone in the central nervous system. The neurological manifestations are transient in most of the reported cases with rare fatality. Case Description.—A 30-year-old woman developed ischemic infarction of the right temporoparietal and cerebellar hemispheres 48 hours after administration of a large dose of clomipramine. This drug was given within 24 hours of discontinuation of high-dose fluoxetine, both of which are known to enhance serotonergic tone in the central nervous system. The distribution of the ischemic infarction in this case did not respect the major territorial arteries and was similar to spreading oligemia/ischemia that is described in migraine. A similar pathogenesis may exist for stroke in serotonin syndrome and in migraine. Key words: serotonin, migraine, stroke, clomipramine, fluoxetine, obsessive-compulsive Abbreviations: CNS central nervous system, CSD cortical spreading depression (Headache 1997;37:519–521) The concept of the "serotonin syndrome" is based on enhancement of serotonergic tone at receptor sites within the central nervous system (CNS).1,2 The syndrome has been described in patients who have been exposed to two or more psychotropic agents, such as monoamine oxidase (MAO) inhibitors and clomipramine,3 moclobemide and clomipramine,4 trazodone and buspirone,5 fluoxetine and sertraline, fluoxetine and L-tryptophan, bromocriptine and L-dihydroxyphenylalanine,2,6 and tranylcypromine and sertraline and clonazepam.7 The described clinical manifestations include acute mental status changes (agitation, confusion, seizure, and coma); involuntary movements (myoclonus, tremor); altered muscle tone (rigidity or spasticity); and autonomic instability (hypertension or hypotension, tachycardia, diaphoresis, hyperpyrexia, and diarrhea).1–7 Autonomic disturbances and alteration of muscle tone have been observed mainly in those interactions involving MAO inhibitors,1–3 and a lethal outcome has been mainly restricted to this group of patients.8,9 To my knowledge, stroke has not been reported with this syndrome. This case highlights the contribution of acute enhancement of serotonergic tone to ischemic infarction with permanent sequelae in a patient with a history of migraine. CASE HISTORY The patient, a 30-year-old, right-handed Caucasian woman with history of an intractable obsessive-compulsive disorder and migraine headaches, was seen for the first time in the emergency department in February of 1990 with a single episode of convulsion and altered mental status. She had been receiving fluoxetine 100 mg/day for several months when it was abruptly switched to clomipramine 200 mg/day 48 hours prior to the ictus. A head CT scan performed within 2 hours of arrival revealed no abnormality. Lumbar puncture revealed bloody CSF that was thought to be the result of a traumatic puncture. The initial neurologic exam revealed a confused and combative woman who was unable to follow simple verbal commands. Both pupils were 4 mm in diameter and symmetrically reactive to light. The funduscopic exam revealed sharp optic disc margins and a normal vascular pattern. She was able to move all extremities only in response to painful stimuli, more vigorous on the right than on the left. There was hyperreflexia of the lower extremities, with a bilateral plantar extensor sign. The following day, the patient was more awake and was able to follow simple commands. Incoordination of both hands and truncal ataxia were prominent findings. On the second day of admission, an MRI of the head revealed abnormal signal intensity on T1- and T2-weighted images in the right temporoparietal and cerebellar hemispheres suggestive of recent ischemic infarction (Figures 1, 2, and 3). Electroencephalography revealed focal slow activity in the right temporal and occipital areas with isolated epileptiform discharges in these regions. Cerebral angiogram revealed no abnormality. Extensive laboratory studies for detection of coagulopathy, inflammatory vasculopathy, antiphospholipid antibody syndrome, and infectious disease including HIV were negative. Cardiac evaluation, including echocardiogram and 24-hour Holter monitoring, revealed no abnormality. During the subsequent days, her mental status improved to some extent. However, her cognitive function remained impaired and she was left with constructional apraxia and right cerebellar ataxia at the time of discharge. During the 5 years of close follow-up, she has shown a slow steady improvement of neurologic status. However, her cognitive function has remained moderately impaired, and she has experienced occasional complex partial seizures despite adequate levels of antiepileptic medication. Several follow-up MRIs have revealed no new lesions. Repeated panels for vasculitis and antiphospholipid antibody were negative. The patient's obsessive-compulsive disorder improved after the stroke without psychotropic drugs. However, intermittent headaches associated with photophobia and nausea have persisted with less intensity. COMMENTS A number of differential diagnoses were initially entertained, particularly those with predilection for [Fig. 1.] [Fig. 2.] [Fig. 3.] small vessel disease of the CNS. The extensive laboratory evaluation and a 5-year nonprogressive course of the disorder ruled out vasculopathy or any source of cerebral embolism. The patient's clinical manifestations, particularly in regard to the interval between the ictus and the administration of combined high-dose serotonergic drugs, support the diagnosis of serotonin syndrome.2 Premature initiation of a serotomimetic drug after discontinuation of a serotonin- enhancing drug with a long half-life such as fluoxetine and its metabolites has already been reported as the cause of serotonin syndrome.10–20 The multiple ischemic lesions predominantly cortical in location and not respecting major arterial territories suggest the pattern of infarctions similar to spreading oligemia in cases of migraine with aura.13-19 The data from cerebral blood flow studies in patients with induced or spontaneous attacks of migraine indicates decreased regional cerebral blood flow in the posterior part of the brain initially, spreading to parietal and temporal lobes at a rate of 2 to 3 mm per minute; so called "spreading oligemia." A similar phenomenon (cortical spreading depression [CSD]) was first identified in rabbit cerebral cortex by Leão in 1944.20,21 There is no satisfactory explanation for the spreading mechanism of oligemia, but the spread probably involves the diffusion of one or more chemical mediators, possibly serotonin and glutamate into the extracellular compartment.22 In many respects, the ionic disequilibrium during CSD resembles transient ischemia, but there is usually no shortage of energy supply during CSD, thus cellular death and infarction are uncommon.23 Considering the transient neurological manifestations in most of the reported cases of serotonin syndrome, it is possible that most with this syndrome suffer from diffuse cerebral oligemia without ischemia and thus, do not manifest permanent neurological sequelae. 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