Cerebral vasoconstriction and stroke after use of serotonergic drugs

To the Editor:

I read with interest the report of three cases of the Call–Fleming syndrome associated with serotonergic drug use by Dr. Singhal and colleagues1 and respond with several observations. The case reports raise important questions regarding potential risks associated with the use of newer antidepressants and triptan antimigraine drugs, two drug categories heavily promoted through direct-to-consumer (DTC) advertisements.3 Specific prescription drugs with prominent DTC promotion include fluoxetine, paroxetine, sumatriptan, and zolmitriptan. Pharmaceutical companies spend more than $US 2.0 billion per year in DTC advertising. One assumes that Dr. Singhal reported these three rare events to the FDA as spontaneous reports of severe adverse events. Because the Call–Fleming syndrome is an uncommon adverse reaction, the FDA has stressed the importance of reporting events that may represent even modest increases in risk (2- to 3-fold relative risk) associated with drug exposure.4 Although the real increase in risk is as yet unknown, spontaneous reports such as these can be important in alerting the FDA to public health concerns.

In the 1990s, spontaneous reports of acute myocardial infarction, severe hypertension, and stroke in association with the use of drugs and dietary supplements5 led an FDA advisory committee to recommend the recall of over-the-counter products containing phenylpropanolamine (PPA). Unfortunately, because “dietary supplements” are not required to seek FDA approval before marketing and are sold under the much weaker provisions of the Dietary Supplement Health and Education Act of 1994, ephedrine alkaloids continue to be sold as athletic performance enhancing or weight loss supplements.6

Because epidemiologic studies of events such as the Call–Fleming syndrome have well-known limitations, neurologists should be diligent in the work-up of events such as reported by Dr. Singhal and colleagues and report all cases to the FDA.

Reply from the Authors:

Dr. Gilbert raises an important question—is Call–Fleming syndrome simply a severe attack of migraine with vasoconstriction and stroke? “Migrainous vasospasm” is often implicated in the pathophysiology of Call–Fleming syndrome.7 This is because headache is invariably present at the onset of this syndrome, many patients have a history of migraine, and because vasoconstriction is believed to play a role in migraine-associated neurologic deficits. The multiple serotonergic factors identified in our patients suggest that serotonergic mechanisms underlie the vasoconstriction in some cases of Call–Fleming syndrome.1 Because serotonin is also implicated in the pathophysiology of migraine, our cases seem to support a relationship between migraine, vasoconstriction, and Call–Fleming syndrome.

However, there are several important differences between these conditions that must be addressed before drawing any conclusions. Although strokes associated with Call–Fleming syndrome probably result from severe vasoconstriction, the neurologic deficits during an attack of migraine are believed to result from primary neuronal mechanisms as well as vascular mechanisms. Most patients with “complicated migraine” and “migraine-induced stroke” have normal cerebral angiograms, whereas the vasoconstriction in Call–Fleming syndrome is prolonged, and affects large and medium-sized arteries. The onset headache in Call–Fleming syndrome is usually acute and severe (“thunderclap”), quite unlike the patient’s prior migraine episodes. It is debatable whether the thunderclap headache is a primary headache disorder (a migraine variant?) that caused the vasoconstriction, or a secondary headache disorder that is symptomatic of the underlying vasoconstriction.8 Thunderclap headaches are usually symptomatic of conditions like subarachnoid hemorrhage and venous sinus thrombosis.8 Migraine tends to recur, however Call–Fleming syndrome is not known to recur. Lastly, not all patients with Call–Fleming syndrome have a prior history of migraine. Reversible cerebral arterial vasoconstriction, the defining feature of Call–Fleming syndrome, has been associated with numerous conditions that seem to be unrelated to migraine.9 Clearly, much work is needed to identify the etiology of vasoconstriction in Call–Fleming syndrome and to define the relationship of this syndrome with migraine.

Dr. Petro discusses important issues in his letter. We certainly agree that the FDA should be alerted about adverse events, and confirm that our cases have been voluntarily reported to the FDA via their user-friendly internet submission program (http://www. fda.gov/medwatch/report/hcp.htm).