Position Paper on Post-Traumatic Headache: The Relationship Between Head Trauma, Stress Disorder, and Migraine

DOI: https://doi.org/10.1007/s40122- 020- 00220- 1

Abstract-Summary Post-traumatic headache (PTH) is one of the most frequent symptoms that follow a mTBI, occurring in isolation with a tension-type or migraine phenotype, or more often as part of a complex neurobehavioural array of symptoms.

Classification issues and a lack of methodologically robust epidemiological and clinical studies have made it difficult to elucidate the mechanisms underlying acute and even more persistent PTH (PPTH).

Psychiatric comorbidities such as post-traumatic stress disorder (PTSD), previ- ous history of migraine, and legal issues often reported by PPTH patients have com- plicated the understanding of this condition, hence treatment approaches for PTH remain problematic.

The broad overlap between PTH, migraine, and PTSD suggests that research in this field should start with a re-appraisal of the diagnostic criteria, followed by methodologically sound epidemiological and clinical studies.

Preclinical research should strive to create more reliable PTH models to support human neuroimaging, neurochemical, and neurogenetic studies, aiming to underpin new pathophysiological hypotheses that may expand treatment targets and improve the management of PTH patients.

Extended: Post-traumatic headache (PTH) is one of the most frequent physical symptoms that follow a mTBI, which can occur in isolation, or more often as part of a complex neurobehavioural clinical spectrum that encompasses cognitive defi- cits, psychiatric symptoms and the so-called post-traumatic syndrome [1, 2].

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Introduction In view of the frequent expression of a migraine phenotype after a mTBI, a line of research hypothesizes that PTH may only constitute an exacerbation of pre-existing primary headache disorders.

Complex clinical picture, a mTBI would act as a mere trigger, similarly to any other chronic headache precipitating/worsening factors including family/work stressors, which are often reported by migraine patients at the start of their chronic daily symptoms, which then become more frequently persistent and difficult to treat in the subgroup of patients with pre-existing psycho-pathological conditions or other sleep and/or pain comorbidities.

5.1

Post-concussion Syndrome

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Persistent PTH with a migraine phenotype, often diagnosed as post-traumatic syndrome, seems clinically very similar to chronic migraine (CM) or new daily persistent headache (NDPH) migraine variant, which are also often associated by behavioural, psychiatric, sleep, vestibular, and pain comorbidities [3, 4].

Basic Science Preclinical Models Since no biochemical or genetic markers are available that would enable in vitro models to predict pain occurrence and evolution, as well as response to drugs, ani- mal models are still essential in pain studies, including the study of post-traumatic headache.

Animal models of post-traumatic brain injury are often non-standardized and classified as mild, moderate, and severe depending on the alleged severity of injury. Studies on PTH in animals have been based on the induction of mild traumatic

brain injury.

A few studies have attempted to quantitate the presence of CGRP in these mod- els, and concluded that, similarly to migraine, CGRP is increased in the trigeminal system following traumatic brain injury.

Whereas basic science studies indicate that there may be common pathways in migraine and post-traumatic headache, especially those involving CGRP, the lack of specific animal models makes it difficult to unambiguously interpret the experimen- tal results.

Clinical Models and Overlap The most frequent pre-existing headache disorder in PTH patients is migraine, it is possible to postulate that head trauma is a trigger/worsening factor of a pre-existing headache disorder, which is daily and causes severe disability in a subgroup of patients with a pre-existing psychiatric history and other comorbidities typically associated with chronic migraine (CM) [5, 6].

These findings may be biased by factors like different patient selection (differ- ence in the duration of the condition in years, number of monthly migraine as opposed to headache days, and the presence of a daily continuous pattern as opposed to a non-daily pattern), presence of co-morbidities (psychiatric, sleep, non-cephalic pain), and level of treatment refractoriness (naïve to preventive treatments vs. difficult- to-treat patients).

Diffusion tensor imaging evidence in subjects with PTH and PPTH with a migraine phenotype versus subjects with mild TBI and no subsequent headache showed MRI changes which overlap with the ones found in migraine, suggesting common underlying mechanisms between PPTH and migraine [7].

Treatment The PPTH phenotype shares clinical and management strategies with NDPH and CM, which are also frequently difficult to treat and associated with psychopatho- logical comorbidities, shared mechanisms may account for the treatment refractori- ness of these disorders, the elucidation of which would lead to a major advancement in the field.

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5 Future Directions

Noninvasive and invasive neuromodulation approaches may also have a role in

PPTH treatment.

Initial open-label short-term evidence on the effectiveness of erenumab in PPTH with a predominant CM phenotype showed a meaningful response in 28% of the patients, which is lower than the responder rate that emerged from the CM studies in difficult-to-treat populations [8–10].

Fremanezumab is being studied for the treatment for PTH in a phase 2 multicen-

tre randomized controlled study (ClinicalTrials.gov Identifier: NCT03347188).

These treatments may well be effective in ultimately improving patients’ quality of life, and hopefully stimulating further clinical, biochemical, and neuroimaging research in the field.

Conclusion It is unclear whether a head trauma triggers a biologically unique headache condi- tion or whether the head pain mechanisms share migraine or tension-type pathways. In the absence of any study confirming whether PPTH is a separate entity or merely an exacerbation of pre-existing migraine, tension-type headache, or a sub- form of NDPH, neuroimaging research has been the first attempt to objectively differentiate between PPTH and migraine, though data are still preliminary and somewhat conflicting.

Basic scientists and clinicians should collaborate towards the development of specific animal models of PTH along with biochemical and neuroimaging studies in humans to confirm the existence of PTH as a separate entity.

Once established, then prospective population-based epidemiological studies, along with studies assessing headache persistency and refractoriness mechanisms, may set the scene for the development of mechanism-specific novel treatments, for which a vast unmet need exists at present.

Acknowledgement A machine generated summary based on the work of Lambru, Giorgio; Benemei, Silvia; Andreou, Anna P.; Luciani, Michelangelo; Serafini, Gianluca; van den Brink, Antoinette Maassen; Martelletti, Paolo 2020 in Pain and Therapy.

Post-traumatic headache: epidemiology and pathophysiological insights