Evaluating the Phenotypic Patterns of Post-Traumatic Headache: A Systematic Review of Military Personnel

ABSTRACT

Introduction

Mild traumatic brain injury (TBI) affects a significant number of military personnel, primarily because of physical impact, vehicle incidents, and blast exposure. Post-traumatic headache (PTH) is the most common symptom reported following mild TBI and can persist for several years. However, the current International Classification of Headache Disorders lacks phenotypic characterization for this specific headache disorder. It is important to appropriately classify the headache sub-phenotypes as it may enable more targeted management approaches. This systematic review seeks to identify the most common sub-phenotype of headaches in military personnel with PTH attributed to mild TBI.

Methods

We conducted a systematic search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines, focusing on the military population. PubMed, Web of Science, Cochrane, and Clinicaltrials.gov databases were searched. Abstracts and full texts were independently reviewed by two authors using predefined inclusion and exclusion criteria. Data extraction was performed using a standardized form. The risk of bias was assessed using the Newcastle-Ottawa Scale.

Results

Eight papers related to the military population were included in this review. Migraine was the most commonly reported headache sub-phenotype, with a prevalence ranging from 33 to 92%. Additionally, one military study identified tension-type headaches as the most prevalent headache phenotype. Although not the primary phenotype, one military cohort reported that approximately one-third of their cohort experienced trigeminal autonomic cephalalgias, which were associated with exposure to blast injuries and prior concussions.

Conclusion

This systematic review demonstrated that PTH in the military population frequently exhibit migraine-like features. Tension-type headache and trigeminal autonomic cephalalgias also occur, although less commonly reported. Sub-phenotyping PTH may be important for initiating effective treatment since different phenotypes may respond differently to medications. The study populations analyzed in this systematic review display heterogeneity, underscoring the necessity for additional research features, more stringent criteria and comprehensive recording of baseline characteristics. Characterizing headaches following injury is crucial for an accurate diagnosis to enable effective management and rehabilitation planning for our armed forces.

INTRODUCTION

Traumatic brain injury (TBI) refers to an alteration in brain function or other evidence of brain pathology caused by an external force.¹ In England and Wales, head injuries account for approximately 1.4 million hospital visits annually, with around 200,000 resulting in admissions.² The incidence of mTBI among military personnel is substantial. Within deployed UK military personnel, the estimated prevalence of mild traumatic brain injury (mTBI) is 4.4%, rising to 9.5% for those in combat roles.³ In comparison, the U.S. military reported a prevalence ranging between 12% and 23%.^4,5 Blast injuries, specifically, are the most frequent mechanism of injury, having been particularly prevalent in the wars in Iraq and Afghanistan.^3,6 The U.S. Government has acknowledged the significance of mTBI and established the Traumatic Brain Injury Center of Excellence, which has developed specific clinical recommendations and educational tools.⁷

Post-traumatic headache (PTH) is a common consequence of mTBI, and has been the subject of increasing investigation.^8,9 The reported incidence of PTH attributed to mTBI varies, ranging from 16% to 79% at three months,^8,10–12 and 15% to 58% at one year in both civilian and military cohorts.^8,10,13 In a large U.S. military study, the incidence of PTH was at the lower end of this range, at 16% to 27% at three months, and 20% to 28% at 12 months.¹⁰ Although studies vary in their methodology, it may be that the lower incidence in U.S. cohorts is that they observe participants of a younger age and have better access to protective equipment.^10,14,15 According to the International Classification of Headache Disorders, 3rd edition (ICHD-3), PTH is defined as a new or worsening headache attributed to head injury and occurring within seven days of trauma, after regaining consciousness or recovering the ability to sense and report pain.¹⁶ Post-traumatic headache can occur in isolation or as part of post-concussion syndrome, which can include dizziness, fatigue, sleep disturbances, mood changes, and impaired cognition.¹⁷ Post-traumatic headache can be classified as acute if the headache resolves within 3 months or persistent if it persists beyond three months.¹⁶

When examining the pathophysiology of mTBI and PTH, the impact of mechanical force on the brain disrupts cellular homeostasis, setting off a complex cascade of neurochemical and neurometabolic alterations.¹⁷ The pathophysiology of PTH involves several proposed theories, which are likely multifaceted and overlapping in nature. One such theory suggests impaired descending modulation, supported by findings from Schwedt et al., who observed structural differences in cortical thickness without changes in cerebral volume among PTH patients compared to healthy controls, potentially stemming from diffuse axonal injury following TBI.¹⁸ Additionally, cortical spreading depression, a phenomenon observed during migraine auras, has been linked to secondary injury mechanisms following TBI.¹⁹ Moreover, the neuroinflammatory response subsequent to TBI may activate the trigeminal sensory system, a key player in migraine pathogenesis, further implicating its role in the development of PTH.¹⁷

The clinical characteristics of PTH have been extensively studied and evidence has emerged that clinical features often resemble those of primary headache disorders.^16,20,21 It is important to appropriately classify the headache sub-phenotypes as it may enable more targeted management approaches.²² To date, a systematic review specifically focusing on phenotyping PTH in the military population has not been conducted. Thus, the aim of this review was to determine the most common headache sub-phenotype among individuals with PTH attributed to mTBI in the military population.

METHODS

Search Criteria

This systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines.²³ A systematic search was performed focusing on PTH phenotype following mTBI in military personnel. Two reviewers (H.S.L. and M.S.) from the University of Birmingham independently screened the abstracts retrieved from the above-mentioned searches using Rayyan software.²⁴ Any discrepancies were resolved through a third senior author (J.M.). The names of authors and journals were not masked from the reviewers. Following abstract review based on the inclusion criteria, selected articles underwent full-text review by two reviewers (H.S.L. and M.S.) working independently. Additionally, the reference lists of these selected articles were searched to identify additional articles that potentially met the inclusion criteria and were subject to the same review process.

Methods for Inclusion

The search criteria for this systematic review included peer-reviewed and published studies meeting the following criteria: (1) military population active personnel; (2) participants aged 18 years or older; (3) participants diagnosed with mTBI or concussion; (4) participants experiencing subsequent PTH; (5) studies published from inception until March 1, 2023; and (5) studies written in the English language. Searches were conducted in PubMed, Web of Science, Cochrane, and Clinicaltrials.gov. A complete list of the search terms for each database is provided in Supplemental Table S1.

Exclusion Criteria

Reviews, commentaries, editorials, conference proceedings, case reports, and case series (defined as studies involving fewer than four participants) were excluded. Studies in which PTH was not defined as an outcome or did not include PTH sub-phenotypes were also excluded.

Data Extraction and Outcome Results

Data extraction was independently performed by the two reviewers (H.S.L. and M.S.) using a standardized form (Supplemental Table S2). Any discrepancies were discussed and resolved between the two investigators, with a senior researcher (J.M.) serving as moderator. Mixed cohort studies were also included in the analysis.^25,26

Assessment of Strength of Evidence

Each selected study was independently assessed by two investigators (H.S.L. and M.S.) to determine the strength of evidence. The level of evidence was classified and scored based on a modified version of the Newcastle-Ottawa scale.²⁷ A quality assessment rating of “high” (corresponding to ≥7 scores), “medium” (score 6), or “low” (≤5 scores) was assigned to each study.

RESULTS

Resulting Articles and Risk of Bias

The military search initially yielded 719 articles (Figure 1). Following the screening of abstracts, 13 articles met the inclusion criteria and underwent a full-text review. Upon completion of full-text review, eight military studies^{25,26,28–33} satisfied the final criteria. The methodological risk of bias for each study is reported in Supplemental Table S3; The Newcastle-Ottawa scores ranged from five to seven (mean 6.1).²⁷

Figure 1.

PRISMA flow diagram.

Baseline Characteristics

An overview of the studies included is displayed in Supplemental Table S4. Half of the military studies had a prospective design,^25,26,31,33 while the other half were retrospective.^28–30,32 Two studies did not define their population as “military” but included a large proportion of blast injury, 43% to 44%,^25,26 and therefore given that blast injuries predominantly occur among military personnel, they have been included in the analysis. Six studies focused on soldiers in active duty, with three studies specifying that their cohorts had recently returned from deployment.^14,29,33 The duration of these deployments were typically one year, and two studies evaluated participants within seven days of injury.^31,32 The two mixed cohort studies observed those with persistent PTH, with a mean average time of assessment post-injury at 10.6 years.^25,26

In terms of sex distribution, female participants accounted for 0% to 10% of the exclusive military cohorts, with 32 to 35% reported in the mixed cohort studies.^25,26 Blast injuries were a unique aspect of military personnel, comprising 31% to 92% of the reported injuries.

Although most studies phenotype headache using the ICHD, the definition of mTBI, however, varied across the studies, with some employing the criteria set by the VA/DoD,³⁴ Centers for Disease Control and Prevention (CDC),³⁵ or no specific criteria. Regarding family history of primary headaches, it was reported in 28% to 32% of the studies,^30,32,36 with six studies including participants with previous concussions, which affected 18% to 79% of the cohorts.^{25,26,29,30,32,33} Three studies excluded participants with pre-existing headaches.^25,26,31

Headache Phenotype

The headache phenotypes are shown in Table 1.

Table 1.

Military Studies PTH Phenotypes

		Headache phenotypes N (%)
First author (year)	Mean time after injury	Migraine	Probable migraine	TTH	TAC	Other headaches
Chong (2021)	10.6  years	37 (77)	9 (19)	2 (4)	X	X
Metti (2020)a	Within 1 year	76 (33) total  18) with aura  34 (15) without aura	X	“other headaches” 148 (64.4)
Howard (2018)	10.56 years	49 (88)		6 (11)	X	Unclassified 1 (2)
Finkel (2017)b	27.6 months	55 (33) Mixed migraine-TTH 31 (19)	3 (12)	31 (19)	Hemicrania continua 12 (7) Cluster 6 (4) Probable TAC 4 (2)	Primary stabbing headache 3 (2) Primary exertional headache 1 (1) Secondary headaches 6 (4) Cranial neuralgia and central causes of facial pain 9 (5) Unclassifiable 5 (3)
Jouzdani (2014)	90 - 100 days	7 (39)	5 (28)	“Non-migraine” 6 (33)
Finkel (2012)b	25.3 months	23 (92)		14 (56)	Hemicrania continua 3 (12) Trigeminal neuralgia 2 (8) Cluster headache 2/55 (8) Paroxysmal hemicrania 1 (4) SUNA 1 (4)	Primary stabbing headache 4 (16) Headache attributed to disorder of the neck 2 (8) Supraorbital neuralgia 1 (4) Attributed to low CSF pressure 1 (4) Attribute to TMJ disorder 1 (4)
Theeler (2010)	Approx 1 year	210 (58)	113 (31)	Other headache 38 (10)
Theeler (2009)b	Approx 1 year	23 (69) 15 (45) migraine without aura 8 (24) migraine with aura	3 (9)	5 (15)	X	Occipital neuralgia 5 (15) MOH 4 (12) NOS 7 (21)

CSF, cerebrospinal fluid; MOH, medication overuse headache; NOS, headache not otherwise specified; SUNA, short-lasting unilateral neuralgiform headaches with cranial autonomic symptoms; TMJ, temporomandibular joint; X, not included in study.

Chronic daily headache defined as 15 or more headache days per month for the previous 3 months.

^aThe percentage values for Metti et al. do not add up to 100% as they had 2.6% with no headache but were later judged to have PTH.

^bTheeler et al. (2009), had a total of 57 headaches for 33 participants. Finkel et al. (2012) reported 55 headaches for 25 participants. Finkel et al. (2017) reported 166 headaches for 95 participants. Percentages are as a portion of the total participants so may not be equal to 100%.

In three studies, participants were allowed to report multiple headache types,^29,30,32 with up to 30% of participants reporting multiple headache types.²⁹ Migraine-like was the most common headache sub-phenotype in seven studies, ranging from 33% to 92% of participants.^14,29–32 However, one study reported lower numbers, with 33% of participants suffering from migraine-like and 64% classified as “other headaches.”³³ Different studies had varying approaches to categorizing migraine-like and probable migraine-like, with some treating them as distinct phenotypes,^{14,25,29,31,32} while others combined them,^26,30 or did not provide information on probable migraine-like at all.³³ Five of the included studies further separated “non-migrainous” headaches into other primary headache phenotypes.^{25,26,29,30,32} Tension-type headache (TTH)-like was the second most common headache sub-phenotype in four studies.^26,29,30,32 There were 13% to 36% of participants with trigeminal autonomic cephalalgias (TACs) in two studies (same cohort), with blast injuries and prior concussions being contributing factors.^30,32 A study comparing mTBI cohorts with healthy controls found that those with PTH had predominantly migrainous features, and specific symptoms strongly associated with PTH included visual or sensory aura, allodynia, and daily or continuous headaches.³³ The headache assessments in the eight studies involved a variety of professionals, including neurologist/headache specialist,^{25,26,29,30,32} and healthcare professionals in an emergency department.³¹ Self-administered questionnaires were also used in some studies.^14,33

Additional headache characteristics were reported in Table 2. In the seven military studies that reported monthly headache days (MHDs), the mean range was 9.9 to 26.7 MHD.^{14,25,26,29,30,32,33} Most headaches lasted more than four hours and had a moderate to severe severity.^{14,29,30,32,33}

Table 2.

Additional Headache Characteristics

Study	Headache onset	Mean headache days per month	Mean headache duration (hours)	Mean headache severity	Return to work outcomes
Chong (2021)	X	16.1 (SD 8.4)	X	X	X
Metti (2020)	X	15 (SD 10)	9.4 (SD 20.4)	6.8 (2.0) (0–10 pain scale)	X
Howard (2018)	X	16.2	X	X	X
Finkel (2017)a	≤7 days 73 (76.8%) 8-30 days 7 (7.4%) 1-3 months 2 (2.1%) 3-6 months 1 (1%) >3 months 3 (3.2%) Unknown 9 (9.5%)	26.7 (SD 6.8)	X	16.9 (SD 9.7) headache severe days	71 (74.7%) retired  52 (66.7%) had positive MEB and were discharged/retired 24 (25.3%) continued active duty
Finkel (2012)a	92% of soldiers <1 week 65.4% of all headache types <1 week 9% began after 1 month No headaches started after 3 months	15.7	31% lasted less than 4  hours	Moderate to severe	X
Theeler (2010)	<1 week 361 1–4 weeks 187 >1 month 409	9.9	4.5	5.7 (0–10 pain scale)	134 (37%) with decreased activity days. 16 (4%) with missed workdays 42 (11%) with sick call visits
Theeler (2009)	<1 week 12 (36%) 1–4 weeks 1 (3%) >1 month 3 (9%) Unspecified onset 5 (15%) Worsening of pre-existing headache 12 (36%)	14.5 ±11.7 during deployment 11.9 ±10.0 after deployment	8.8 ±7.3	7.1 ± 1.5 (0–10 pain scale)	Mean MIDAS 30.8 ± 44.3

MEB, medical evaluation board; MIDAS, migraine disability assessment score; X, not reported.

Table does not include studies that do not have this information i.e., Jouzdani (2014).

^aUsing data for headache onset within 1 week of trauma.

DISCUSSION

Migraine was found to be a common headache phenotype following mTBI; however, there was a wide range of reported prevalence rates. Tension type headache was also reported as a prevalent headache phenotype. Interestingly, a proportion of military personnel were diagnosed with TACs, which were associated with exposure to blast injuries and prior concussions. Trigeminal autonomic cephalalgias often have a delayed diagnosis because of a lack of expertise in the recognition of the phenotype, and this underlines the importance of involving neurological expertise in the management of TBI.³⁷

Most studies used the ICHD to phenotype headaches, either the second^14,29–32 or third^25,26,33 edition. Both editions define PTH as headache onset within seven days of injury, but there are slight differences in the diagnostic criteria for sub-phenotypes; i.e., migraine, TTH. Both editions omit any further headache characteristics and this is likely a consensus opinion rather than evidence-based.¹⁶ It is important to note that the ICHD acknowledge that delayed PTH may present up to three months after injury.¹⁶

In a large U.S.-based study of 3,952 U.S. Army personnel deployed in Iraq, 587 self-reported concussions, with 72.2% reported as blast-related.³⁸ Blast injury has unique physiological and biochemical effects, including primary blast (direct blast wave impact), secondary blast (penetrating/non-penetrating injuries caused by debris or fragments), tertiary blast (body displacement or impact with environment), and quaternary (effects on explosion; i.e., burns) blast effects.³⁹ Given that a migraine-like phenotype is also the main headache phenotype observed among civilians, it could be hypothesized that the modality of injury in mTBI may not play a predominant role in the phenotype of the headache.³⁶ Although there are differences, they share similar underlying mechanistic pathways, including central sensitization, neuroinflammation, and alterations in pain processing pathways.⁴⁰

There is a well-established sex disparity among the population of migraine sufferers, with migraine being three to four times more frequent in women than in men.⁴¹ Research has also suggested than women reported longer durations of migraine attacks than men.⁴¹ Outside of the mixed cohort studies, female participants only accounted for 0% to 10% of available military studies, although there is a 11.3% female representation of the UK Regular Forces (2022)⁴² and 17.3% Female Active Duty members in the United States (2021).⁴³ Females may be underrepresented in the current literature with studies having an overall average of 3% (44/1,406) mTBI compared to the regular forces representation of 11.3% which may, in part, be because of lower representation in frontline combat.

There is evidence that migraine and PTH are not pathophysiologically identical. Magnetic resonance imaging (MRI)-based studies have examined differences in the brain between persistent PTH and those with migraine, including cortical thickness, regional volumes, surface area, and both static and dynamic functional connectivity for regions involved in pain processing.^18,44 These studies indicate differing underlying pathophysiology between PTH and migraine, emphasizing the need for more specific characterization of PTH. However patients with persistent PTH, and no pre-existing headache, were shown to develop headache exacerbation with migraine-like features after intravenous infusion of calcitonin gene-related peptide (CGRP).⁴⁵ However, one study surprisingly found lower CGRP plasma levels in 100 participants with persistent PTH, compared with sex-matched healthy non-headache controls.⁴⁶ This opposes the consistent observations of elevated plasma and salivary CGRP levels in the interictal phase of those with migraine.^47–49

Sub-phenotyping PTH may be important for initiating effective treatment, since different phenotypes may respond differently to medications.²² Post-traumatic headache is often difficult to treat, which can be related to the heterogenous nature of PTH, and is mostly based on expert consensus.^22,50 Although there are effective treatments for chronic migraine in the general population (i.e., CGRP) for reducing monthly migraine days and acute medication use, it remains to be determined if these can be extrapolated to migraine-like PTH.⁵¹ Although management of PTH is not within the scope of this review, it is advised that all patients are offered an oral non-steroid anti-inflammatory, if tolerated, or paracetamol. Additionally, the advice is to not use opiates.⁵⁰ For those with a migraine-like phenotype they may benefit from a triptan or gepant.⁵⁰ A review by Ashina et al. (2022) recommended amitriptyline, mirtazapine, and venlafaxine for those with TTH-like phenotype; with amitriptyline, candesartan, or certain beta-blockers for migraine-like phenotype. A U.S. study demonstrated statistically significant improvement in headache frequency, reducing by 4.5 days per month, in a military cohort with chronic PTH after mTBI using Topiramate, when compared to tricyclic antidepressants, propranolol, and valproate.⁵² There has been increasing evidence highlighting the role of CGRP in PTH, as mentioned above.⁴⁵ A more recent open-label trial indicated that those with persistent PTH may benefit from erenumab (monoclonal antibody against CGRP receptor), with the mean MHDs of moderate-to-severe intensity reducing by 2.8 days from 15.7 days at baseline to week 9 through to 12, but was not compared to placebo or alternative treatment.⁵³

Limitations

We were unable to perform a meta-analysis of these results because of substantial heterogeneity highlighted above, and instead provided a narrative description of the findings. This review has highlighted that characterizing PTH in deployed military personnel faces several challenges. When looking at the variability in Newcastle-Ottawa scores, two studies received a score of five (high risk of bias),^25,26 which raises concerns regarding its methodological limitations and potential biases. Some of the included studies lacked documentation of participants’ baseline characteristics regarding pre-existing headache disorders, which are known to be associated with the development of PTH.^14,33 Notably, three studies explicitly excluded patients with pre-existing headaches before their head injury.^25,26,31 Since PTH can also be defined as the worsening of pre-existing headaches, excluding this sub-cohort of patients could introduce selection bias. This, in turn, can alter study outcomes, such as the sub-phenotype of PTH. Conversely, a review article argues that including those with pre-existing headaches is unlikely to represent the prevalence rates of the general population, thus limiting generalizability.⁵⁴ This discrepancy underscores the importance of careful study design to balance the accurate representation of PTH characteristics and the generalizability of findings to the broader population. Additionally, there is the risk of recall bias because of assessments being conducted after their return from operations, along with possible cognitive disturbances associated with wider post-concussion syndrome. This bias extends not only to the timing of headache onset but also to the accurate identification of the injury as a mTBI. It is important to note that the military participants were usually assessed within a year of injury, whereas the mixed cohorts included individuals up to 11 years post injury. Limited participation of females in military studies poses a potential limitation in generalizing the findings to the broader population. It is important to acknowledge there may be variability in blast injury severity within the category of mTBI. The use of different professionals for documenting headache phenotypes introduces variability in expertise, training, and consistency, highlighting the need for standardized criteria and protocols to minimize variability and potential bias in the classification of headache phenotypes. In addition, there is some symptom overlap with migraine and TTH, with photophobia, phonophobia and kinesiophobia also being experienced by those with TTH, and this can lead to discrepancy in results.⁵⁵ The exclusion of probable migraine-like as a phenotype in certain studies raises the possibility that some headaches categorized as “unclassified” may actually meet the criteria for this phenotype, leading to under-reporting of this phenotype. The 2 studies that reported higher numbers of TAC were from the same cohort at different time points and so may not be representative of the wider military cohort.^30,32 While using the term “military” as a population there are many different roles within a military population that may be more susceptible to PTH and mTBI, such as those involved in close combat roles versus those involved in shaping operational environments.

Future Directions

In future research, we would recommend appropriately recording baseline characteristics, including the presence of any pre-existing headache, family history of headache, and any previous concussion history. It would also be useful to investigate when the headaches started and observe any potential changes in phenotype over time i.e., prospective contemporaneous longitudinal studies. The study populations analyzed in this systematic review display heterogeneity, underscoring the necessity for additional research features, more stringent criteria, and comprehensive recording of baseline characteristics.

CONCLUSION

Post-traumatic headache among military personnel most commonly presents with migraine-like features, with TTH-like headache being the second most prevalent sub-phenotype. Of note, TACs were more prevalent among one military cohort—potentially because of the modality of injury, pre-existing characteristics, or the headache phenotyping interview itself. Characterization of PTH will allow for better identification of this type of headache. It will lead to targeted therapeutic trials and in turn enable the rehabilitation of our armed forces that suffer mTBI and subsequent PTH.

SUPPLEMENTARY MATERIAL

Supplementary material is available at Military Medicine online.

FUNDING

Funded by the UK mTBI Predict consortia grant from the Ministry of Defence.

M.S., NIHR Academic Clinical Fellow, is funded by the NIHR. The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS, or the UK Department of Health and Social Care.

A.Y. is funded by an Association of British Neurologists and Guarantors of the Brain fellowship.

A.J.S. is funded by a Sir Jules Thorn Award for Biomedical Science. H.L. is funded by the Ministry of Defence (MoD) as part of mTBI-PREDICT. J.L.M. and D.R.W. are employees of the MoD.

CONFLICT OF INTEREST STATEMENT

A.J.S. reports personal fees from Invex therapeutics in her role as Director with stock holdings, during the conduct of the study; other from Allergan, Novartis, Cheisi and Amgen outside the submitted work.

S.P.M. has received honoraria for speaker events from Heidelberg engineering; Chugai-Roche Ltd and Teva. Honoraria for advisory boards for Invex Therapeutics, Gensight and ocular therapeutix. Consultancy fees Neurodiem and Invex Therapeutics. Research funding from the UK Space Agency. All declared interested are outside the area of this submitted work.

A.Y. reports receiving speaker fees from Teva, UK outside the submitted work.

All other authors declare no competing interests.

Authors declare no other financial relationships with any organization that might have an interest in the submitted work; and no other relationships or activities that could appear to have influenced the submitted work.

DATA AVAILABILITY

No new data were generated or analyzed in support of this research.