Posttraumatic Headache: Basic Mechanisms and Therapeutic Targets

Joshua Kamins, MD; Andrew Charles, MD

Disclosures

Headache. 2018;58(6):811-826. 

In This Article

Genetic and Phenotypic Background

The responses to head/neck trauma are heterogeneous and variable from individual to individual. As discussed above, this may be in part due to variability in the traumatic event, but genetic background, previous history of headache, and preexiting comorbid conditions may also play an important role.

Genetic Influences

A study of adolescents found that those with a family history of migraine were significantly more likely to have posttraumatic headache with a migraine phenotype following sport–related concussion compared with those without a family history.[24] This suggests that head trauma may trigger migraine in those with a genetic predisposition. Although migraine is clearly familial in many cases, the genetic basis of migraine remains poorly understood. Meta–analysis of population genetic studies has revealed at least 38 gene polymorphisms that are associated with migraine.[25] None of these has a large effect size, so the potential contribution of any polymorphism to a given individual is uncertain. Posttraumatic headache is not particularly amenable to population genetic studies, and it seems unlikely that such studies would be productive. Further, the obvious genetic complexity of migraine indicates that identifying specific genes underlying a genetic predisposition to PTH based upon population studies is also likely to be highly challenging. It may, however, be worth considering genetic studies of well phenotyped subgroups of PTH patients – comparing, for example, genetic polymorphisms in patients whose headache is transient vs long–lasting, or responsive vs unresponsive to specific therapies. Also, while familial posttraumatic headache is rarely encountered, any family that is identified as having a predisposition to posttraumatic headache may be worthy of more detailed genetic analysis using whole–genome sequencing.

Another situation where genetic studies may be revealing is families in which mutations of single genes are associated with both familial migraine as well as an exaggerated response to head trauma. Mutations in genes associated with both familial hemiplegic migraine type 1 (FHM1 –CACNA1A gene encoding P/Q type calcium channel) and FHM2 (ATP1A2 gene encoding Na+/K+ ATPase) have been associated with exaggerated neurological responses to minor head trauma.[26–28] In some cases, hemiplegic migraine attacks may be triggered by mild head trauma. This indicates that genetically mediated alterations in the P/Q type calcium channel or the Na+/K+ pump could lead to severe migraine attacks in response to mild trauma, raising the possibility that similar mechanisms could be involved in the susceptibility to posttraumatic headache in patients who do not have FHM. Moreover, the P/Q type calcium channel and Na+/K+ ATPase could represent therapeutic targets in PTH.

Previous History of Migraine

It is clear that PTH commonly has features of migraine. What is less clear is how a previous history of migraine influences the clinical features and course of symptoms following concussion including PTH. A study of college athletes found that there was an increased prevalence of migraine among those with a previous history of concussion.[29] A previous history of migraine is, not unexpectedly, associated with an increased risk of posttraumatic migraine.[11] It is possible that migraine mechanisms could amplify the neurovascular response to trauma, leading to more severe and prolonged symptoms following concussion. Another possibility is that concussion activates underlying migraine mechanisms, particularly in those with a predisposition to migraine. A better understanding of the bidirectional relationship between mechanisms of response to trauma and those causing migraine is critical to the development of more specific and more effective therapies for posttraumatic headache.

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