Neurology -- Correspondence for Singhal et al., 58 (1) 130-133

Correspondence published:

Re: Serotonergic drugs and stroke: Aneesh B. Singhal (29 April 2002)

Reply to Letter to the Editor: Aneesh Singhal (29 April 2002)

Cerebral vasoconstriction and stroke after use of serotonergic drugs: Gordon J Gilbert (29 April 2002)

Serotonergic drugs and stroke: Denis J Petro, none (9 April 2002)

Re: Serotonergic drugs and stroke 29 April 2002

Aneesh B. Singhal,
Neurologist
Massachusetts General Hospital
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Re: Re: Serotonergic drugs and stroke

asinghal{at}partners.org Aneesh B. Singhal

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).

Reply to Letter to the Editor 29 April 2002

Aneesh Singhal
Massachusetts General Hospital Boston MA
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Re: Reply to Letter to the Editor

asinghal{at}partners.org Aneesh Singhal

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. [2] This is because headache is invariably present at the onset of this syndrome, many patients have a past 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] Since 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 addressed before drawing any conclusions. While 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. [3] Thunderclap headaches are usually symptomatic of conditions like subarachnoid hemorrhage and venous sinus thrombosis. [3] 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. [4] 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.
References:
1.Singhal AB, Caviness VS, Degleiter AF et al. Cerebral vasoconstriction and stroke after use of serotonergic drugs. Neurology 2002;58:130-132.
2.Serdaru M, Chiras J, Cujas M, Lhermitte F. Isolated benign cerebral vasculities or migrainous vasospasm? J Neurol Neurosurg Psychiatry 1984;47:73.76.
3.Dodick DW. Thunderclap headache. J Neurol Neurosurg Psychiatry 2002:72:6-11.
4.Singhal AB, Koroshetz W, Caplan LR. Cerebral vasoconstriction syndromes. In: Bogousslavsky J, Caplan LR, eds. Uncommon causes of stroke. Cambridge, UK: Cambridge Universtiy Press;2001:114-123.

Cerebral vasoconstriction and stroke after use of serotonergic drugs 29 April 2002

Gordon J Gilbert
Neurology and Electroencephalography St Petersburg FL
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Re: Cerebral vasoconstriction and stroke after use of serotonergic drugs

sandi_moriarity{at}urmc.rochester.edu Gordon J Gilbert

I suspect that Singhal et al. [1] have reported three cases of �complicated migraine.� The Call-Fleming syndrome seems to entail a specification of certain pathogenic mechanisms whereby complicated migraines can be induced. The three cases analyzed by Singhal et al had a background of migraine and thunderclap headaches, while in each case a serotonergic mechanism could be adduced. This is a highly useful article to the clinician trying to deal effectively with a rare but often difficult disorder. In many cases of complicated migraine it is not clear why the particular attack became �complicated�, and the Call-Fleming syndrome offers an important approach that both clarifies mechanism and can lead to appropriate therapy. In patients prone to disabling vasoconstrictive migraine, verapamil seems an effective prophylaxis. The first case reported by Singhal et al can be regarded as one of complicated basilar artery migraine precipitated by elevated serotonergic activity. I have also seen two cases of complicated migraine that seemed induced by a hemodynamic mechanism as one patient, taking propranolol for hypertension, stood in a hot shower during a migraine attack, [2] and as another stood up after a heavy meal, presumably inducing a hemodynamic crisis in an already constricted artery.
References:
1)Singhal AB, Caviness VS, Degleiter AF et al. Cerebral vasoconstiction and stroke after use of serotonergic drugs. Neurology 2002;58:130-132.
2)Gilbert GJ. An occurrence of complicated migraine during propranolol therapy. Headache 1982;22:81-83.

Serotonergic drugs and stroke 9 April 2002

Denis J Petro,
neurologist
private practice,
none
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Re: Serotonergic drugs and stroke

djpmsmd{at}aol.com Denis J Petro, et al.

I read with interest the report of three cases of the Call-Fleming syndrome associated with serotonergic drug use by Dr. Singhal and colleagues(1) 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(2). Specific prescription drugs with prominent DTC promotion include fluoxetine, paroxetine, sumatriptan and zolmitriptan, Pharmaceutical companies spend over $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. Since the Call-Fleming syndrome is an uncommon adverse reaction, the FDA has stressed the importance of reporting events which may represent even modest increases in risk (two- to three-fold relative risk) associated with drug exposure(3). While 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 decade of the 1990's, spontaneous reports of acute myocardial infarction, severe hypertension, and stroke in association with the use of drugs and dietary supplements(4) led an FDA advisory committee to recommend the recall of OTC products containing phenylpropanolamine (PPA). Unfortunately , since "dietary supplements" are not required to seek FDA approval prior to 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(5).
Since 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.
1 Singhal AB, Caviness VS, Begleiter AF, Mark EJ, Rordorf G, Koroshetz WJ. Cerebral vasoconstriction and stroke after use of serotonergic drugs. Neurology 2002;58:130-133.
2 Woloshin S, Schwartz LM, Tremmel J, Welch HG. Direct-to-consumer advertisements for prescription drugs:What are Americans being sold? Lancet 2001;358:1141-1146
3 Temple R. Meta-analysis and epidemiologic studies in drug development and postmarketing surveillance. JAMA 1999;281:841-844.
4 Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000;343:1833-1838.
5 Lindsay BD. Are serious adverse cardiovascular events an unintended consequence of the Dietary Supplement Health and Education Act of 1994? Mayo Clin Proc 2002;77:7-9.