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Calcineurin Inhibitor-Induced Headache: Clinical Characteristics and Possible Mechanisms


  • Uta Ferrari,

  • Monika Empl,

  • Kwang Sik Kim,

  • Petra Sostak,

  • Stefanie Förderreuther,

  • Andreas Straube

  • Klinikum Grosshadern, Department of Neurology, Munich, Germany (Drs. Uta Ferrari, Monika Empl, Petra Sostak, Stefanie Förderreuther, and Andreas Straube); Johns Hopkins University, Division of Pediatric Infectious Diseases, Baltimore, Maryland, USA (Dr. Kwang Sik Kim).

Address all correspondence to Dr. Uta Ferrari, Klinikum Grosshadern, Department of Neurology, Munich, Germany.


Objective.—To classify the headache syndromes under treatment with calcineurin inhibitors and to investigate whether the latter influence the nitric oxide production of human brain microvascular cells (HBMEC).

Background.—Single cases of cyclosporine-induced headaches have been reported. Since calcineurin inhibitors are known to influence the renal metabolism of NO, a key molecule in tension-type headache and migraine, we were interested whether calcineurin inhibitors might change NO metabolism in HBMEC as well.

Design and Methods.—Headache symptoms of 74 patients receiving cyclosporine and/or tacrolimus for organ transplantation were retrospectively assessed. Furthermore, the effect of cyclosporine and tacrolimus on nitric oxide production in human brain microvascular endothelial cells was investigated after incubation.

Results.—Only 18 of the 74 patients reported no headache 1–36 months after liver, lung, or bone-marrow transplantation, 28 reported a new headache, and 17 an increase in the frequency or intensity of a pre-existing headache. The headache was generally classified as migraine without aura (IHS 1.1) or migraine-like headache (IHS 1.6). Furthermore, we found significantly increased NO production after co-incubation of calcineurin inhibitors with human brain microvascular endothelial cells.

Conclusion.—The pathophysiological mechanism of these headaches may be connected with an endothelial dysfunction in terms of increased production of NO.