Shared Biological Foundations of Post-traumatic Headache and Migraine

Håkan Ashina; Michael A. Moskowitz

Disclosures

Headache. 2021;61(3):558-559. 

Post-traumatic headache (PTH) is a common sequela of traumatic brain injury (TBI). The most common headache phenotype is migraine-like followed by tension-type-like headache. Indeed, one clinic-based study found that about 90% of patients with persistent PTH experience recurrent migraine-like headaches.[1] Among patients with PTH expressing this phenotype, two-thirds experienced at least eight monthly headache days with migraine-like features.[1] These observations as well as those listed below raise questions about whether PTH and migraine share similar mechanisms, perhaps within the framework of a final common pathway implicated in headache pathogenesis.[2]

The trigeminovascular system (TVS) is an important player in migraine pathophysiology and treatment and has been thought of as a final common pathway in headache pathogenesis. Axonal projections arise from trigeminal ganglion cells to innervate pain-sensitive intracranial structures (e.g., meninges—dura mater [the inner periosteum of the skull] and pial arteries).[2] These innervating nerve fibers contain vasoactive peptides that, upon release, modulate nociceptive transmission and promote vasodilation, leakage of plasma proteins as well as activation of resident macrophages within meningeal tissues.[2] With its role in cephalic pain transmission plus its content of neuropeptides and receptors, we believe the TVS is poised to become a foundational player in PTH pathophysiology and pharmacology, just as in migraine.

There are at least six lines of emerging evidence to support this perspective. First, calcitonin gene-related peptide (CGRP) has been implicated as a key molecule in pathogenesis and treatment. Intravenous infusion of CGRP induces migraine attacks in patients with migraine, whereas patients with persistent PTH (and no pre-existing migraine) develop headache exacerbation with migraine-like features.[4] In a randomized, placebo-controlled, double-blind, two-way crossover study, 30 patients with persistent PTH were allocated to receive intravenous infusion of CGRP or placebo (isotonic saline) on two separate study days.[4] Following the start of the infusion, patients were instructed to fill out a headache diary during the subsequent 12-hour observational period. CGRP infusion caused headache exacerbation with migraine-like features in 70% of patients with persistent PTH, compared with 20% after placebo.

Second, monoclonal antibodies (mAbs) against CGRP or its receptor have proven effective in migraine prevention. More recently, an open-label study reported therapeutic benefits of targeting CGRP signaling in prevention of persistent PTH.[5] Indeed, 28% of patients with persistent PTH (and no personal history of migraine) experienced at least 50% reduction in their monthly headache days of moderate to severe intensity after receiving a mAb against the CGRP receptor.[5] The therapeutic benefit seems higher in patients with migraine, but this point requires further research. Nevertheless, the evidence that CGRP infusion mimics the effects of released neuropeptide from trigeminovascular afferents and that receptor blockade by mAbs ameliorates the impact of both PTH and migraine, underscores the importance of shared biological mechanisms. For example, these shared mechanisms are likely to include sensitization of perivascular afferents and upregulation of inflammatory pathways that sensitize or discharge trigeminovascular afferents along with release of CGRP and other neuromediators. In fact, a growing body of evidence suggests CGRP involvement across headache disorders, including migraine, post-traumatic headache, cluster headache, and idiopathic intracranial hypertension.[2,4–6]

Third, some patients with persistent PTH experience aura symptoms along with migraine-like headaches.[1] Cortical spreading depression (CSD), the biological substrate of migraine aura, erupts in some patients following TBI.[7] Interestingly, CSD evoked in animal models is noxious, pro-inflammatory, and sufficient to activate trigeminovascular nociceptive pathways.[8] Like migraine more than a single explanation is probably responsible for triggering headaches.

Fourth, and potentially important to all the above, are newly identified microvascular channels that course between skull bone marrow and dura mater.[3] The human skull bone marrow contains numerous microvascular channels that serve in animals as conduits for inflammatory cell migration into the meninges and possibly to other intracranial structures related to headache,[3] as documented in experimental stroke and chemical meningitis. Interestingly, most nerve fibers in the bone marrow are nociceptive and CGRP-containing.[9] The same study also reported that CGRP is involved in mobilization of myeloid cells from the bone marrow.[9] It could therefore be speculated that calvarial bone marrow provides a source of inflammatory cells and proinflammatory molecules in meninges and overlying bone following trauma to the calvarium.

Fifth, a study using positron emission/magnetic resonance imaging published this year provided evidence that these skull bone marrow channels may be functional in patients with migraine.[10] In all, 11 well-characterized patients with multiple episodes of migraine with visual auras recorded their migraine episodes in a diary for a 4-week period before imaging. A persisting inflammatory signal was detected at least 18 days after the last attack not only appearing in the meninges but also within the calvarium (primarily, bone marrow) specifically overlying the occipital cortex in patients with migraine but not controls.

Based on extensive preclinical data, it seems reasonable to propose that events within cortex or brain injury itself initiate a sequence of events that cause meningeal inflammation in humans and trigeminovascular activation. The evidence in TBI is sufficient to posit that a signal from injured bone may recruit cells that augment meningeal inflammation and promote trigeminovascular activation and sensitization leading to headache exacerbation and persistence. The signal(s) to bone, albeit unknown, may also migrate from injured cortex in patients with TBI. Additional studies are required to clarify these relationships.

Lastly, the process of headache chronification, although complex and poorly understood, may also reflect an overlapping biology between PTH and migraine. For instance, cutaneous allodynia, suggestive of central sensitization, is common in patients with migraine, and more so in those with chronic migraine. A recent clinic-based study found cutaneous allodynia in 46% of patients with persistent PTH.[1] In addition to central sensitization, it is also possible that chronification of headache is mediated, at least in part, by impaired descending pain modulation. Interestingly, chronification develops, not infrequently, within weeks or months in PTH, whereas it usually takes years to develop in patients with migraine. It seems accelerated in PTH even in patients with no migraine history. Susceptibility to it may depend upon intensity, number, and duration of attacks, responsiveness to therapy, history of migraine, comorbidities as well as genetic predisposition. Based on the above, it can also be posited that mechanism-based therapies in the early phase of PTH (within a few weeks of its onset) might prevent chronification as well as persistence.

In summary, typical headache features plus available experimental data seem to suggest that the headache in PTH and migraine share certain similar underlying mechanisms such as a final common pathway of headache pathogenesis, namely the TVS. Despite this knowledge, the cellular mechanisms by which head trauma evokes persistent headache with migraine-like features warrant further investigation, such as by the use of animal models of closed head injury, functional imaging, and human provocation models. Future efforts should also address whether tools of personalized medicine (e.g., clinical phenotyping) can better inform and predict treatment responses in individual patients with PTH. Armed with this knowledge, patients with PTH will be better served by a more thorough understanding of headache pathogenesis and by efforts to develop mechanism-based therapies.

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