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SHOULD
HEADACHE BE VIEWED AS PART OF A LARGER BIORHYTHMIC DISORDER?
STOWE, VT—A genetic link between headache and a familial sleep disorder was employed as a key example of why clinicians are urged to routinely consider the possibility that a headache is part of a larger syndrome. While neurologists are skilled at considering headache as a primary or secondary expression of a clinical disorder, there is a growing body of evidence suggesting that headaches are frequently inextricable manifestations of a broader syndrome, such as a disturbed biorhythm, that may be best managed when understood in this context.
"In many cases, it does not appear to be a chicken-or-egg phenomenon. Trying to isolate headache from other complaints risks missing the syndrome," reported Robert E. Shapiro, MD, PhD, Associate Professor of Neurology, University of Vermont, Burlington. Speaking at the Headache Cooperative of New England’s 16th Annual Headache Symposium, Dr. Shapiro indicated that the advantage of recognizing headaches in the context of their syndrome is that it may allow episodes to become more predictable, and it may suggest appropriate steps to intervene.
HEADACHE WITHIN SYNDROMES
The concept that headaches often occur in the context of some disturbed biorhythm, such as menstrual cycles or circadian sleep patterns, is not new, but Dr. Shapiro argued that there is insufficient attention to the fact that headaches may be just one clinical sign of a larger syndrome. He suggested that current data make it clear that "headache and biorhythmic disorders are joined at the hip."
Among several examples, Dr. Shapiro pointed to relatively recent data that linked familial advanced sleep phase syndrome (FASPS)—a disorder of shortened endogenous circadian rhythm—and migraine in one extended family unit. In a study for which Dr. Shapiro was a coauthor, a mutation in the casein kinase Id gene present in affected members of this family was linked to multiple traits, including FASPS, migraine with aura, flushing spells, and myalgias. In animal studies looking at the same genetic mutation, disturbances in sleep-wake patterns consistent with FASPS were replicated, and the genetic defect was linked to altered phosphorylation of enzyme substrates that are implicated in biologic functions that affect circadian rhythms. Finding this link is the first step in ongoing research that would suggest that headache in these patients is not caused by altered sleep patterns but is instead another manifestation of the same shared molecular pathophysiology.
"The next step is to prove that this specific mutation is also responsible for migraine in these patients. We have not proven that yet, but we believe that we are near it," Dr. Shapiro said. If this is achieved, "we can look at the biochemical functions controlled by this mutation, which might have promise as targets for therapy."
PARTS OF A BIOLOGIC WHOLE
In patients with a chief complaint of headache, symptoms described as secondary—such as disturbed sleep patterns—are often and understandably evaluated in the context of the symptom that brought the patient to the physician, but Dr. Shapiro suggested that the opposite is also true. When the chief complaint is a disturbed sleep pattern, concomitant headaches are likely to be viewed as subordinate. The change suggested by Dr. Shapiro is to increase the focus on the possibility that a broad array of symptoms may be better understood as part of a syndrome than as independent phenomena.
In particular, Dr. Shapiro proposed that many of these syndromes are driven by disturbances in biorhythms, a term referring to time-dependent biologic cycles. They may occur over 24 hours, as in circadian sleep-wake cycles, over several weeks, as in menstrual cycles, or even seasonally. He suggested that there is substantial potential for the existence of a variety of biorhythms affecting hormone levels, enzyme activity, or other biochemical changes that have not yet been isolated. While recurrent headache in the context of the menstrual cycle is a well-documented example of biorhythms and headache, the syndrome of menstrual headache may be more complex than a simple cause-and-effect from reproductive hormones. Dr. Shapiro noted that even women with headaches strongly linked to fluxes in hormone levels do not necessarily respond to hormone replacement therapy.
"The etiology may be complex even if the recurrent pattern of headache onset helps us to consider prophylactic therapeutic strategies," reported Dr. Shapiro, citing successful controlled clinical trials of preemptive triptan therapies in women with predictable menstrual cycle–related headache patterns.
FROM ONSET TO TREATMENT
Looking for patterns in the onset of headache has clear implications for identifying new targets of therapy. Dr. Shapiro provided several examples of where the timing of headache may generate clues of how to intervene. One example is the rising interest in adenosine as a potential endogenous mediator of headache in the early waking hours. Upon awakening, circulating adenosine levels rise precipitously. Although this is not the only neuromodulator that changes in the early waking hours, other evidence further supports this connection. For instance, caffeine, which is often effective for acute headache control and which may produce headaches upon its withdrawal, antagonizes adenosine receptors.
In hypnic "alarm clock headaches," which are most commonly observed in elderly women and produce bilateral pain and nausea, evidence of the benefit of lithium has produced interest in the pathways of neurologic signaling on which this drug acts to identify etiologic events. "Mutations at the presumptive site of action of lithium are associated with disrupted circadian rhythmicity in animal models," Dr. Shapiro observed. He indicated that these may also have a relation to the often-observed circadian regularity of cluster headache attacks and that they may also respond to lithium therapy. Moreover, cluster headache periods often have a perisolstitial pattern, signifying greater activity near solstices, which are times in the year of "maximum discordance between internal and external clocks."
As one last example, Dr. Shapiro identified a relationship between cluster headaches and narcolepsy. Evidence that both are mediated by hypocretin, an orexin precursor, provides an important potential link that may explain both.
"I would propose that narcolepsy and cluster headache are reciprocal disorders," Dr. Shapiro said. He listed several parallels, including the fact that orexinergic neurons and CSF orexin A are diminished in human narcolepsy while orexinergic neurons are located in brain regions of increased metabolic activity and tissue density in cluster headache patients. Also, some mutations in the gene for the orexin-2 receptor increase the susceptibility to cluster headache. Dr. Shapiro speculates that orexin B may be increased in the brain during cluster headache attacks. If this is the case, he suggests that this disorder may be a result of hyperactivity of orexinergic systems and that there may be a potential for the therapeutic use of selective orexin-2 receptor antagonists in cluster headache, an approach that requires testing.
While much of the support for the importance of biorhythms in defining the risk of migraine and headache has been drawn from disparate sources, the point emphasized by Dr. Shapiro is that a reorientation might be warranted to reconsider headache in a broader context. While the risk of headache in any given individual may be mediated by some combination of environmental factors, genetics, and disturbances in biorhythms, headache may not be best evaluated in many patients as an isolated phenomenon but as just one manifestation of a syndrome in which symptoms share an etiology.
NR
—Ted Bosworth
Suggested Reading
Xu Y, Padiath QS, Shapiro RE, et al. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature. 2005;434:640-644.
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