Post-traumatic headache: epidemiology and pathophysiological insights

DOI: https://doi.org/10.1038/s41582- 019- 0243- 8

Abstract-Summary Post-traumatic headache (PTH) is a highly disabling secondary headache disorder and one of the most common sequelae of mild traumatic brain injury, also known as concussion.

5.1

Post-concussion Syndrome

887

Considerable overlap exists between PTH and common primary headache

disorders.

A better understanding of the pathophysiological similarities and differences between primary headache disorders and PTH could uncover unique treatment tar- gets for PTH.

In this Review, we describe the evidence from animal and human studies that indicates involvement of several potential mechanisms in the development and per- sistence of PTH.

Extended: Post-traumatic headache (PTH) accounts for ~4% of all symptomatic headache disorders [11] and is one of the most common sequelae of mild traumatic brain injury (mTBI) [12, 13], also known as concussion.

In this Review, we present the current knowledge about the epidemiology of

PTH and the underlying pathophysiological mechanisms.

We outline future research opportunities to advance our understanding of the

disease mechanisms, and treatment options for PTH.

The emphasis of future studies should be the establishment of biomarkers that are involved in progression to persistent PTH and the identification of potential treatment targets to enable randomized controlled trials to be conducted in this patient population.

Introduction Much remains unknown about the underlying pathophysiological mechanisms of PTH, and no evidence-based, PTH-specific treatment currently exists [14].

Novel, mechanism-based treatment options are needed from human and socio-

economic perspectives.

In this Review, we present the current knowledge about the epidemiology of

PTH and the underlying pathophysiological mechanisms.

We outline future research opportunities to advance our understanding of the

disease mechanisms, and treatment options for PTH.

Classification and Terminology PTH is further subdivided into ‘acute headache attributed to traumatic injury to the head’ and ‘persistent headache attributed to traumatic injury to the head’ [15].

The original ICHD-1 criteria for PTH required that patients report the onset of

headache within 14 days of a TBI [16].

The diagnostic criteria for PTH attributed to mild traumatic injury to the head include the criteria for mTBI [17], and those for PTH attributed to moderate to severe traumatic injury to the head include the criteria for moderate and severe TBI [17].

The term PTH also includes headache attributed to whiplash or craniotomy [15].

Epidemiology and Characteristics Forty percent of patients with TBI who reported acute PTH in one study later devel- oped persistent PTH [18].

888

5 Future Directions

Some studies have found that most people with PTH have tension-type-like headaches [19, 20], whereas others have found a higher prevalence of migraine-like headache [1, 21].

In one study, 97% of patients with de novo headache after mTBI and persistent

PTH had a tension-type-like headache phenotype [20].

Thirty-six percent of the patients with persistent PTH reported more than one

headache phenotype, and migraine was the most prevalent overall.

Another study showed that 49% of people with persistent PTH at 1 year after mTBI had either a migraine-like headache or a probable migraine-like headache [1], whereas only 32% had a tension-type-like headache.

A study conducted at the Danish Headache Center showed that 42% of patients who fulfilled the criteria for PTH at the time of referral also fulfilled the criteria for MOH [19].

Genetics and Pre-existing Headache One study found that patients with concussion who had a family history of migraine were more likely to exhibit a migraine-like headache phenotype than those without a family history of migraine [22].

In a study of US collegiate athletes, a history of concussion was associated with

an increased risk of a post-traumatic migraine-like headache phenotype [23].

An increased risk of post-traumatic migraine-like headache was seen in patients

with a history of migraine [24].

Pathophysiology In one retrospective MRI study of patients with PTH [25], DTI was used to compare 58 patients with mTBI and a migraine-like headache phenotype with 16 controls who had mTBI but either no PTH or PTH without a migraine-like headache phenotype.

In one MRI study [26], regional brain volumes and cortical thickness, surface area and curvature in 28 patients with persistent PTH (75% of whom had a migraine- like phenotype) were compared with those in 28 patients with migraine and 28 healthy controls.

This study also showed that lower cortical thickness in bilateral superior frontal regions correlates with a higher frequency of headache in patients with persis- tent PTH.

One study [27] found more pronounced generalized cephalic cutaneous allo- dynia in patients with persistent PTH compared with patients with traumatic head injury without persistent PTH, indicating damage to central nociceptive and thermal systems.

Future Directions Future animal studies should be conducted symptomatology.

to

investigate PTH-specific

Interpretation of the findings from such studies should be done while keeping in mind that inference of disease mechanisms of PTH from animal models of TBI is challenging, mainly because PTH is a disorder of unknown aetiology, making disease- specific modelling complicated.

5.1

Post-concussion Syndrome

889

Future animal studies could also aid with development of novel PTH-specific

treatments.

The integration of headache-inducing molecules and their respective inhibitors into animal models of PTH would greatly increase our understanding of the signal- ling pathways involved in PTH pathogenesis.

These models would demonstrate whether intravenous infusion of nociceptive signalling molecules, such as CGRP, induces headache attacks in patients with per- sistent PTH.

If so, a novel model for the provocation of headache attacks in PTH could be established, and this model could be used to examine whether the efficacy of anti- CGRP antibody treatment in patients with persistent PTH can be predicted on the basis of their hypersensitivity to CGRP.

Conclusions Some progress has been made in understanding the underlying mechanisms, but more targeted animal and human studies are needed.

The emphasis of future studies should be the establishment of biomarkers that are involved in progression to persistent PTH and the identification of potential treatment targets to enable randomized controlled trials to be conducted in this patient population.

Acknowledgement A machine generated summary based on the work of Ashina, Håkan; Porreca, Frank; Anderson, Trent; Amin, Faisal Mohammad; Ashina, Messoud; Schytz, Henrik Winther; Dodick, David W. 2019 in Nature Reviews Neurology.

Persistent post-traumatic headache: a migrainous loop or not? The preclinical evidence