A developing story in the pathophysiology and etiology of headaches is the relationship to organ transplantation and its management. In this article, the author outlines the epidemiology, causative pharmacotherapies, infective causes, vascular associations, and miscellaneous causes of headache in this patient population. Suggestions for management and possible pathophysiological mechanisms for this emerging disorder are discussed.
• Headache, which can significantly affect quality of life, is common in patients who have received transplants.
• The best characterized secondary cause of headache in patients who have received transplants is the usage of immunosuppressants such as cyclosporin.
• The most important differential diagnoses are infection and intracerebral hemorrhage.
Historical note and terminology
Organ transplantation may have been the greatest therapeutic advancement of the second half of the 20th century. The history of organ transplantation is long, beginning in India with skin autografting during the 6th century BC. In 1906 Mathieu Jaboulay attempted the first human kidney transplant using pig and goat kidneys anastomosed to blood vessels of a patient's arm; unfortunately, this only functioned for 1 hour. In 1911 Hammond and Sutton in Philadelphia had transient success with the first human-to-human kidney transplant. The techniques of vascular anastomosis were improved by Alexis Carrel, Jaboulay's student, who also introduced cooling for organ preservation while working in Chicago. Carrel first introduced the “principle of immunity" after noting continual failure of allografts of dog kidneys, whereas autografts functioned. Later work with skin allografts by Gibson and Medawar during World War II helped establish the immunologic concept of self and nonself.
The first successful human transplant took place on December 23, 1954, in Boston, Massachusetts; this was a kidney transplant between identical twins, as performed by Joseph Murray. In 1962 investigations began for the use of azathioprine as a sole immunosuppressive agent. This monotherapy was associated with few long-term survivors, and it became recognized that organ transplantation would require more immunotherapy than just azathioprine monotherapy. A year later, in 1963, the introduction of combination azathioprine and steroid therapy became the main agent of immunosuppression for renal transplants. This combination therapy approach was soon adopted in several transplant centers, becoming the standard of immunotherapy in organ transplantation by 1964. Despite this advancement, this immunotherapy regime seemed only adequate for living-related donor transplants, as the mortality and morbidity rates associated with cadaveric transplants were excessive. The addition of antilymphocyte globulin as an adjunct improved survival in only a limited fashion due to inability to standardize this drug and its excessive side effects. In 1976, a new immunosuppressive agent called cyclosporine was introduced. By 1979, prolonged graft survival was reported with cyclosporine used as monotherapy. By 1983, the triple therapy of cyclosporine, azathioprine, and corticosteroids became the preferred therapy for allograft transplantation. In the early 1980s, monoclonal antibodies against mature T lymphocytes were noted to reverse intractable rejection of renal grafts, and by 1987, the monoclonal antibody CD-3 (OKT-3) was approved by the Food and Drug Administration. Since that time, further innovations in immunosuppression have included agents such as tacrolimus, mycophenolate, sirolimus, and others.
In the 21st century, not only do transplants of kidneys and skin take place, but also transplants of liver, pancreas, pancreatic islet cells, intestine, heart, heart valves, lungs, corneas, bone marrow, and limbs.
The concept of headache in transplant patients does not have such a clear history. In fact, the nature of headaches reported after organ transplantation is poorly documented in terms of specific clinical features and pathogenesis. Although headaches are only infrequently mentioned as a clinically significant problem in transplant patients, they can have a significant effect on quality of life. When occurring as migraines, headaches can be severe enough to prevent ingestion of immunomodulatory drugs, thus, endangering graft survival. In renal transplant recipients, headaches were identified as having a greater impact on quality of life than more common adverse effects, such as changes in body and facial morphology, hirsutism, and tremor (Hricik et al 2001). The development of headaches in transplant patients is not well understood, and more clinical studies using newer investigational techniques are needed.
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