Exploring naturally occurring clinical subgroups of post-traumatic headache

Headache attributed to traumatic injury to the head [1] also known as post-traumatic headache (PTH) is a common condition following injury to the head and/or neck. The prognosis is generally favorable with most cases resolving within 3–6 months of the inciting injury [2]. However, it is reported that 18–22% of PTH last for more than 1 year [3].

PTH is a poorly understood entity. According to the International Classification of Headache Disorders-3 (ICHD-3): It is defined as any headache related to a traumatic injury to the head and/or neck with headache being reported within 7 days [1]. Little is known about the pathophysiology of PTH: A number of factors have been suggested including microglial activation in the brain parenchyma, dural inflammation related to mast cell degranulation with sensitization of pain pathways, injury to the extracranial tissues and direct damage to neuronal and brain structures [4].

The diagnosis of acute versus persistent PTH is based on an arbitrary cutoff selection of 3 months of headache duration, greater than 3 months for persistent PTH and lesser than 3 months for acute PTH [1]. Limited evidence has looked into the factors associated with the transformation of acute to persistent PTH. A prior population-based study identified that history of traumatic brain injury, being injured under the influence of alcohol, and history of acute PTH were predictors for persistent PTH [5]. PTH is also associated with somatic, cognitive and psychological symptoms [6]. It is known that there is a bidirectional association between headache and psychiatric disorders [7, 8]. Anxiety, depression, affective temperamental dysregulation and suicidal behavior may be seen in patients with chronic headache disorders [6, 8, 9]. In the diagnosis of PTH, the possibility of co-occurring medication overuse headache (MOH) is an important consideration as well [10]. Based on this information, we wanted to test the hypothesis that exposure to clinical predictors, such as medication overuse and psychological symptoms are associated with persistent PTH compared to acute PTH. In addition, we hypothesized that there exists naturally occurring heterogeneous clusters within the persistent PTH group of patients.

In this hospital-based study, we explored the clinical predictors that may be more likely associated with persistent versus acute PTH. Identifying potential clinical predictors may have treatment implications and provide a plausible explanation as to why some patients develop persistent headaches after an injury to the head and/or neck. In addition, we conducted clustering analysis to identify naturally-occurring subgroups of PTH and compare them with ICHD-3 classification of acute versus persistent.

In this study, pre-existing psychological history, history of migraine, new PTH-associated comorbidities and medication overuse predicted the occurrence of persistent PTH. Previous studies have suggested that a previous history of headache, less severe injury, female gender and the presence of comorbid psychiatric disorders are associated with PTH [5, 7, 13‐16].

However, these studies did not specify who made the diagnosis and the details on their previous headache history, including their headache diagnosis, duration, frequency and/or intensity. In our study, the diagnostic accuracy for the persistent PTH group was high since 58% of them were made by neurologists and headache specialists (Table 2). Our study reflects the real word setting where acute PTH is often seen and managed by primary care physicians including family medicine, internal medicine and emergency room physicians. When PTH becomes persistent and refractory to treatment, they are referred to specialty clinics. Based on the ICHD diagnostic criteria, PTH can only be diagnosed in the setting of migraine if patients have at least 2 fold increase in frequency and/or intensity of their headaches after their injury [1]. This information was documented within the persistent PTH group. Our study found that the duration of persistent PTH did not impact other clinical variables. This may be related to trigeminal neuroplasticity and central sensitization seen in prolonged PTH [17‐19].

Our clustering analysis revealed two naturally occurring PTH clusters which highly correlated with ICHD-based acute versus persistent PTH classification. Cluster 1 represented the majority of persistent PTH while Cluster 2 represented the majority of acute PTH patients. A history of migraine, medication overuse, pre-existing psychological history, new PTH-associated comorbidities ranked as the top 4 classifying clinical variables in descending order. Cluster 1 phenotype was burdened with high levels of these 4 clinical variables compared to Cluster 2. That our clustering results mostly corroborated with ICHD-based classification provides evidence base for acute versus persistent PTH subgroups.

Our findings of four naturally occurring clusters within the persistent PTH group shows the presence of distinct persistent PTH profiles. This proves that not all persistent PTH patients are similar, and thus cannot be placed under an umbrella classification of “persistent PTH”. Some persistent PTH patients may have resolution within 2 years (i.e., Cluster 3) while others may have longer duration, higher psychological burden, and medication overuse (i.e., Cluster 2). Identifying these naturally occurring PTH clusters is important for providing personalized clinical management as well as for conducting precise clinical trials, since different patients may respond differently as per their baseline distinct cluster characteristics. There are a few possible pathophysiological mechanisms to explain the development of the four different clusters of persistent PTH: Cluster 1, in contrast to Cluster 2 was found to have the lowest migraine prevalence with low levels of psychological comorbidity and medication overuse while featuring moderate levels of new PTH-associated comorbidities may indicate uncontaminated phenotype of persistent PTH. Studying this phenotype may reveal distinct PTH-specific neuroanatomic regions involved e.g. dysfunctional inhibitory pathways which follow pericranial tissue injury [20]. Cluster 1 persistent PTH phenotype may explain whether PTH has a different mechanism compared to perturbed sensory processing and subcortical aminergic modulatory pathways described in migraine [21, 22]. Cluster 2 PTH patients may be exhibiting pronounced neuroinflammation, and increased peripheral and central sensitization, as shown by protracted migraine history and psychological comorbidities. Studies have shown that patients recovering from unconscious states can have long term chronic pain experiences due to aberrant limbic and trigemino-amygdalar pathways [23‐27]. This may explain our finding of Cluster 3 patients featuring the shortest PTH duration along with the lowest prevalence of loss of consciousness. Likewise, Cluster 2 patients having correlation of higher prevalence of loss of consciousness and longer PTH duration supports this speculation. Cluster 4 patients seemed to signify the direct relationship between frequency of head injuries and new PTH-associated comorbidities. Cluster 4 persistent PTH patients may also be having increased natural tolerance to pain behavior as evidenced by the cluster’s relatively lower prevalence of psychological comorbidity, medication overuse, and migraine history.

The overuse of abortive headache medications may contribute to the chronicity of headache after a head injury. 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 [10]. This may suggest a percentage of patients with persistent PTH may have MOH rather than true persistent PTH and refractory headache in persistent PTH may be partly caused by MOH. Prospective studies are required to explore if medication overuse is a confounding factor and/or play a role in promoting chronicity in patients with PTH. A previous published study demonstrated that migraine patients are more prone to develop MOH compared to patients with other headache types such as cluster headache [28]. This increased susceptibility may explain why migraine and medication overuse predicted the occurrence of persistent PTH in our study. Furthermore, continuous intake of acute headache medications may alter descending inhibitory pathways that are thought to be important mechanisms in PTH [20].

A previous published study showed that individuals with a history of headache, such as migraine were significantly more likely to report headaches both acutely and chronically after a traumatic head injury compared to those without a history of headaches [29]. This suggests that a history of headache may predispose patients in developing persistent PTH after a head injury. Although the pathophysiology of PTH is not completely understood, the proposed mechanism of impaired descending neuromodulation, activation of trigeminal and cervical afferents, neurometabolic changes, cortical spreading depression, calcitonin gene-related peptide dependent mechanisms and neuroinflammation overlap with the migraine entity [30]. One would suspect after further injury to the head and/or neck, the underlying process would be intensified.

Previous report has suggested that the occurrence of PTH after mild brain injury was not related to the type of injury [14]. However, in our study, motor vehicle accidents are associated with the persistent PTH group (Table 1). This may suggest the development of other comorbidities from a motor vehicle accident, such as post-traumatic stress disorder, vestibular dysfunction and neck injury. Patients within the two PTH groups had mild traumatic brain injury. Headache prevalence and severity have been reported to be greater in those with mild head injury compared to those with more severe head injury 13 . it is unclear why this inverse dose response relationship is seen, and further investigation is warranted.

Rarely does headache occur in isolation in closed head injury and other comorbidities are often seen. From our study, patients in the persistent PTH group suffered from multiple new PTH-associated comorbidities, including neck pain, vertigo, back pain, autonomic disturbance, anxiety, depression and cognitive impairment. Neck pain is one of the most common associated symptoms/comorbidities in the persistent PTH group: 70 out of the 150 patients (46%) had neck pain. The injured cervical structures could, in addition to causing neck pain, refer pain to the head due to a close relationship between the upper cervical inputs and the trigeminal system [31]. Hooten et al. has demonstrated significant reduction in headache frequency, intensity and neck pain after 12 months of exercise therapy for patients with a history of cervicogenic headaches, which may be part of the phenotype seen in PTH [32]. Thus, treatment on the neck, such as neck physical therapy may benefit PTH.

A pre-existing psychological history, including depression, anxiety, bipolar disease, post-traumatic stress orders were associated with the development of persistent PTH. Epidemiological and functional imaging studies suggest that a directional relationship exists between chronic pain and mental health disorders [32]. Stilling et al. has shown a significant reduction in depression rating and headache frequency after 1 month of repetitive transcranial magnetic stimulation (rTMS), and rTMS is an FDA approved treatment for depression [33]. The alteration of neurotransmitters such as serotonin and dopamine have a major role in pain modulation [32]. With better mental health, one would be able to be more active and practice good lifestyle routines. These measures can lead to a good clinical outcome in patients with headache [34, 35].

To note, two hundred patients were excluded in this study suggesting the diagnostic criteria of PTH may be an unfamiliar entity amongst healthcare providers. In addition, this may indicate STARR tool may give rise to false positive PTH identifications. The STARR identification was 60% accurate (300 out of 500 patients), which is an acceptable percentage based on a simple word-based patient search. Further education is required for providers who manage PTH, because a misdiagnosis may alter the management plan and have litigation implications.

Strengths of this study include application of robust statistical tests, with adequate goodness-of-fit regression models, adjustment for confounders, examination of multiple headache-related variables. More than 58% of the persistent PTH patients were diagnosed by neurologists or headache specialists (Table 2).

Our limitations included the following: The precise time of headache resolution or improvement was unavailable within the acute PTH group. Acute PTH results were based on patients not reporting headaches at their next physician visit (less than 3 months). Some information was not available including lifestyle routine changes, and details on allied health involvement and this was inherent to the retrospective study. Acute PTH was diagnosed mainly by general practitioners or emergency room physicians who may not be familiar with the diagnostic criteria of PTH. Assessment of pre-injury headache suffering may be influenced by recall problems. Our hospital-based study may not be representative of the general PTH population. Our results may not be valid for all age groups since we only studied participants from age greater than 18 years old. A causation could not be established from our results, rather association only. Although a previous clinical-based study in PTH patients reported higher prevalence of tension-type headache than migraine [10], tension-type headache was rarely documented or labeled as a pre-existing diagnosis in our study. Our speculation is that tension-type headache may not be a common referral to our center. Besides, tension-type headache is thought to be more common in community-based studies than in clinical-based studies [36, 37]. Hence, our clinical-based study setting may not give the true population burden of pre-existing tension-type headache in PTH patients.

A pre-existing psychological history, history of migraine, new PTH-associated comorbidities and medication overuse predicted the occurrence of persistent PTH. Our study has raised a few interesting questions: Would there be a difference in clinical outcome between patients who have medication overuse versus no medication overuse in the development of PTH. Pre-existing psychological history, history of migraine, new PTH-associated comorbidities and medication overuse were found to be associated with persistent PTH. These clinical variables should be targeted as part of early treatment plan since managing these variables may impact PTH prognosis and recovery. Future prospective studies are needed to further validate our results. In addition, our study showed that data-driven classification can perform accurately correlating to ICHD-based PTH subclasses - hence providing evidence based for ICHD classification. In the future, machine learning tools can be developed based on our clustering results using clinical variables such as pre-existing psychological history, history of migraine, new PTH-associated comorbidities and medication overuse. Also, it could be useful to develop a specific score for predicting patients at risk of developing persistent PTH, instead of using non-specific assessment tools such as the Sports Concussion Assessment Tool (SCAT3) [38].