Guidelines of the International Headache Society for controlled trials of pharmacological preventive treatment for persistent post-traumatic headache attributed to mild traumatic brain injury.

BACKGROUND: Persistent headache attributed to traumatic injury to the head is divided into two subtypes, one attributed to moderate or severe traumatic injury and another attributed to mild traumatic injury (i.e., concussion). The latter is much more prevalent, in part because more than 90% of cases with traumatic brain injury are classified as mild. The pathophysiology of persistent post-traumatic headache is poorly understood and the underlying mechanisms are likely multifactorial. There is currently no approved treatment specifically for persistent post-traumatic headache, and management strategies rely on medications used for migraine or tension-type headache. Therefore, high-quality trials are urgently needed to support clinical decision-making and optimize management strategies. International guidelines can facilitate appropriate trial design and ensure the acquisition of high-quality data evaluating the efficacy, tolerability, and safety of available and novel pharmacological therapies for the preventive treatment of persistent post-traumatic headache. METHODS: The development of this guideline was based on a literature review of available studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, along with a review of previously published guidelines for controlled trials of preventive treatment for episodic and chronic migraine. The identified literature was critically appraised, and due to the scarcity of scientific evidence, recommendations were primarily based on the consensus of experts in the field. OBJECTIVE: To provide guidelines for designing state-of-the-art controlled clinical trials aimed at evaluating the effectiveness of preventive treatments for persistent post-traumatic headache attributed to mild traumatic brain injury.

Plasma calcitonin gene-related peptide and nerve growth factor as headache and pain biomarkers in recently deployed soldiers with and without a recent concussion.

OBJECTIVE: The objective of this study was to characterize the utility of calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) as potential biomarkers for headache and pain disorders in the post-military deployment setting. BACKGROUND: The need to improve recognition, assessment, and prognoses of individuals with posttraumatic headache or other pain has increased interest in the potential of CGRP and NGF as biomarkers. METHODS: The Warrior Strong Study (NCT01847040) is an observational longitudinal study of United States-based soldiers who had recently returned from deployment to Afghanistan or Iraq from 2009 to 2014. The present nested cross-sectional analysis uses baseline data collected from soldiers returning to Fort Bragg, North Carolina. RESULTS: In total, 264 soldiers (mean (standard deviation [SD] age 28.1 [6.4] years, 230/264 [87.1%] men, 171/263 [65.0%] White) were analyzed. Mean (SD) plasma levels of CGRP were 1.3 (1.1) pg/mL and mean levels of NGF were 1.4 (0.4) pg/mL. Age was negatively correlated with NGF (-0.01 pg/mL per year, p = 0.007) but was not associated with CGRP. Men had higher mean (SD) CGRP plasma levels than women (1.4 95% confidence interval [CI; 1.2] vs. 0.9 95% CI [0.5] pg/mL, p < 0.002, Kruskal-Wallis test). CGRP levels were lower in participants who had a headache at the time of the blood draw (1.0 [0.6] pg/mL vs. 1.4 [1.2] pg/mL, p = 0.024). NGF was lower in participants with continuous pain (all types; 1.2 [0.4] vs. 1.4 [0.4] pg/mL, p = 0.027) and was lower in participants with traumatic brain injury (TBI) + posttraumatic headache (PTH) versus TBI without PTH (1.3 [0.3] vs. 1.4 [0.4] pg/mL, p = 0.021). Otherwise, CGRP and NGF were not associated with migraine-like headache, TBI status, or headache burden as measured by the number of medical encounters in crude or adjusted models. CONCLUSION: In this exploratory study, plasma levels of NGF and CGRP showed promise as biomarkers for headache and other types of pain. These findings need to be replicated in other cohorts.

Post-traumatic headache attributed to traumatic brain injury: classification, clinical characteristics, and treatment.

Post-traumatic headache is a common sequela of traumatic brain injury and is classified as a secondary headache disorder. In the past 10 years, considerable progress has been made to better understand the clinical features of this disorder, generating momentum to identify effective therapies. Post-traumatic headache is increasingly being recognised as a heterogeneous headache disorder, with patients often classified into subphenotypes that might be more responsive to specific therapies. Such considerations are not accounted for in three iterations of diagnostic criteria published by the International Headache Society. The scarcity of evidence-based approaches has left clinicians to choose therapies on the basis of the primary headache phenotype (eg, migraine and tension-type headache) and that are most compatible with the clinical picture. A concerted effort is needed to address these shortcomings and should include large prospective cohort studies as well as randomised controlled trials. This approach, in turn, will result in better disease characterisation and availability of evidence-based treatment options.

Central Executive and Default Mode Network Intranet work Functional Connectivity Patterns in Chronic Migraine.

BACKGROUND: The neural mechanisms of chronic migraine remain largely unknown but linked to the decreased connectivity to intrinsic brain networks. OBJECTIVE: To characterize the intranetwork functional connectivity within the Central Executive Network (CEN) and Default Mode Network (DMN) in chronic migraine (CM), with and without medication overuse headache (MOH). METHODS: Using functional magnetic resonance imaging, we performed post-hoc analysis of a total of 136 pairs of nodes to node functional connectivity (NTNC) within the CEN and 6 pairs of NTNC within the DMN in CM (n=13) and CMMOH (n=16) as compared to controls, and between these two subgroups. RESULTS: Connectivity between right ventrolateral prefrontal cortex (PFC) to contralateral anterior thalamus and connectivity between left dorsal PFC/frontal eye field (FEF) to dorsomedial PFC were decreased within the CEN in both CM and CMMOH subgroups. In the CEN, there was more widespread disruption in the CMMOH (n=16) versus CM (n=13), when compared to healthy controls. Within the subgroups, connectivity between right inferior frontal gyrus to left dorsolateral PFC was decreased in CMMOH compared to CM. In the DMN, only one NTNC (left lateral parietal to precuneus/PCC) was disrupted in the CMMOH group when compared to controls. CONCLUSION: There are similar patterns of NTNC dysfunction within CEN in CM regardless of MOH status. We observed more extensive intranetwork disruption in CMMOH than CM. The decreased coherence between the right inferior frontal gyrus and the left dorsolateral PFC in CMMOH is likely associated with a significant disruption in the inhibitory control and a maladaptive response in risk aversion and reward; whereas the decreased coherence between right dorsolateral and ventrolateral PFC to contralateral dorsal PFC/FEF may be related to lack of cognitive control and top-down regulation of pain in both CM and CMMOH.

Painful Craniofacial/Cervical Surface Area and Continuous Headache After Military Concussion: A Morphometric Retrospective Cohort Study.

OBJECTIVE: In this retrospective study of active duty service members (ADSMs), possible relationships were examined between extent of headache pain depicted on head/neck diagrams and headache phenomenology. BACKGROUND: The signature injury of US military operations in Iraq and Afghanistan is mild traumatic brain injury (mTBI). Blast injury, especially from improvised explosive devices, was the most common cause during the height of the wars; the most persistent symptom remains posttraumatic headache (PTH). Neurologic patients were asked to draw pain diagrams/maps, a method of pain assessment in several clinical settings. METHODS: Thirty-four ADSMs attributing PTH to both blast and non-blast sources underwent clinical evaluations; diagnoses and headache characteristics were obtained. They completed 58 drawings depicting craniofacial/cervical headache pain on non-standardized templates. Drawings were of 29 continuous and 29 non-continuous headaches (CHA and NCHA, respectively). Surface area was calculated using a grid and expressed as a percentage. RESULTS: The sample was male (100%), primarily white (83%), with an average age of 30.3 years. Evidence for statistical independence of observations is provided (intra-class correlation = 0.004). Percent surface area was larger for CHA (median [mdn] = 35.2, interquartile range [IQR] = 9.0, 78.3) than NCHA (mdn = 9.1, IQR = 5.4, 34.1, P = .029). In those with blast injury, CHA percent surface areas (mdn = 45.9, IQR = 27.0, 100) were larger than NCHA (mdn = 11.6, IQR = 5.8, 28.9; P = .0012), a relationship not observed in patients with PTH from non-blasts (CHA: mdn = 26.8, IQR = 8.5, 52.0; NCHA: mdn = 9.1, IQR = 5.0, 47.6, P = .050). This pattern is observed after pooling at the median (blast, P < .012; non-blast: P = .264). CONCLUSION: Painful craniofacial/cervical surface area, as shown on patient drawings, is related to PTH phenomenology (continuous versus non-continuous headache). This relationship is stronger after blast injury.

Staying in service with posttraumatic headache: A retrospective cohort study of patient outcome.

OBJECTIVE: To predict the probability of a military outcome (medical discharge/retirement) in patients with mild traumatic brain injury from a clinical analysis of predetermined patient and headache characteristics. METHODS: This retrospective cohort study sampled all new patients referred for headache evaluation at the Brain Injury Clinic of the Womack Army Medical Center, Ft. Bragg, NC (August 2008-January 2010). Headache characteristics were extracted and analyzed. Multivariable binary logistic regressions were conducted to predict probability of medical discharge/retirement. RESULTS: Ninety-five soldiers (age 31.3 ± 7.4 years, male 93.7%) reported 166 headaches. The most common injury cited was a blast (53.7%). Patients with a continuous headache have almost 4 times the odds of a medically related discharge/retirement compared to patients without such a headache (continuous headache regression coefficient estimate: p < 0.042, odds ratio 3.98, 95% Wald confidence interval 1.05-15.07). Results suggest that, compared to service members who did not have a continuous headache, patients with headache histories with severe holocephalic pain who medicate to keep functioning had the highest probability of medical discharge/retirement. CONCLUSIONS: Certain headache characteristics may be predictive of military outcomes after mild traumatic brain injury, and we propose a profile that may be useful in that prediction. These data could be useful in future attempts to assess and treat patients with posttraumatic headache and to advise longer-term planning for return to duty or discharge.

Which Matters More? A Retrospective Cohort Study of Headache Characteristics and Diagnosis Type in Soldiers with mTBI/Concussion.

OBJECTIVE: To describe the diagnostic types and characteristics of headaches in soldiers with mild traumatic brain injury during the wars in Afghanistan and Iraq. BACKGROUND: Persistent post-traumatic headache interferes with returns to activity or duty. The most commonly cited headache diagnosis after concussion is migraine. We hypothesize that headache diagnosis type, eg, migraine, is not sufficient to predict relationships with occupational outcomes after concussion. METHODS: The study sample consisted of all new patients referred for headache evaluation at the Brain Injury Center at Womack Army Medical Center over a 1-year time period. The design was retrospective and observational. Clinical data reported included demographics, causes of injury, headache characteristics, and headache diagnosis type. After reviewing records for retention or severance from military service, the primary occupational outcome measure was departure from service due to medical cause as determined by a Medical Evaluation Board (MEB). The primary outcome measure was to test the strength of association between leaving service for MEB and headache characteristics or diagnosis. RESULTS: A total of 95 patients (94% male) with concussion described 166 distinct headache types, the most common being migraine (60%) and trigeminal autonomic cephalalgia (24%). A total of 25% of all patients remained on active duty. A continuous headache of any type was present in 75% of patients and of these, 23% remained on active duty. Of the 51% of patients who had both a continuous and non-continuous headache, 17% remained on active duty (P < .001). Therefore, we report that a continuous headache, regardless of diagnosis type was associated with negative occupational outcomes. Regardless of headache duration, headache diagnosis type alone was not associated with soldiers' separations from service. CONCLUSIONS: Persistent post-traumatic headache is most likely to present with continuous pain. Migraine is the most common primary diagnosis type. The presence of a continuous headache was strongly associated with negative occupational outcomes. Primary headache diagnosis type was not. Headache characteristics, therefore, may be more important than diagnosis type when determining active duty status. Further prospective research is indicated.

Headache in military service members with a history of mild traumatic brain injury: A cohort study of diagnosis and classification.

Introduction Headaches after concussion are highly prevalent, relatively persistent and are being treated like primary headaches, especially migraine. Methods We studied all new patients seen between August 2008 and December 2009 assessed by a civilian headache specialist at the TBI Center at Womack Army Medical Center, Fort Bragg, NC. We report sample demographics, injuries and headache characteristics, including time from injury to headache onset, detailed descriptions and International Classification of Headache Disorders second edition primary headache diagnosis type. Results A total of 95 soldiers reported 166 headaches. The most common injury cited was a blast (53.7%). Most subjects (76.8%) recalled the onset of any headache within 7 days of injury. The most commonly diagnosed headache was a continuous type with migraine features ( n = 31 (18.7%)), followed by chronic migraine (type 1.5.1, n = 14 (8.4%)), migraine with aura (type 1.2.1, n = 10 (6.0%)), hemicrania continua (type 4.7, n = 12 (7.2%)), chronic cluster (type 3.1.2, n = 6 (3.6%)) and headaches not otherwise classifiable (type 14.1, n = 5 (3.0%)) also present. The most clinically important was a continuous headache with migraine features. Conclusion We present a series of patients seen in a military treatment facility for headache diagnosis after concussion in whom we found migraine, as well as uncommon primary headache types, at frequencies that were much higher than expected.

Botulinum toxin and the treatment of headache: A clinical review.

Since its discovery, Onabotulinum toxins have been tried for the treatment of various head, neck and face pain syndromes. The end result of controlled clinical trials was that there was not clear evidence for use in many of the common primary and secondary headaches. In chronic migraine, affecting 1-2% of the population, a fixed site and fixed dose treatment approach was shown to be superior to placebo and was approved for use. In this review, evidence for that use and the history leading to it is described.

Onabotulinum toxin a for the treatment of headache in service members with a history of mild traumatic brain injury: a cohort study.

OBJECTIVE: Post-traumatic headache (PTH) of the migraine type is a common complication of mild traumatic brain injury (including blast injuries) in active duty service members. Persistent and near-daily headache occur. Usual preventive medications may have unacceptable side effects. Anecdotal reports suggest that onabotulinum toxin A (OBA) might be an effective treatment in these patients. METHODS: This study is a real-time retrospective consecutive case series of all patients treated with OBA at the Concussion Care Clinic of Womack Army Medical Center, Ft. Bragg, NC, between August 2008 and August 2012. Clinical treatment and pharmacy records were corroborated with the electronic medical records in the Armed Forces Health Longitudinal Technology Application to determine demographics, current headache and treatment characteristics, and clinical and occupational outcomes. RESULTS: Sixty-four subjects (63 male) with mean age of 31.3 + 7.5 (range 20-59) years were evaluated and treated. Blast injuries were most common (n = 36; 56.3%) and 7 patients (11%) reported a prior history of headache. Most patients (36; 56.3%) described more than 1 headache type and 48 (75%) patients had continuous pain. The most prevalent treating diagnosis was mixed continuous headache with migraine features on more than 15 days per month (n = 26; 40.6%). The mean time from injury to the first injections was 10.8 + 21.9 (1-96) months. Forty (62.5%) patients received the Food and Drug Administration-approved chronic migraine injection protocol. Forty-one (64%) patients reported being better. Two patients discontinued for side effects. Twenty-seven (41%) remained on active duty. CONCLUSIONS: We demonstrate that active duty military patients with headaches related to concussions may benefit from treatment with OBA. Further studies are indicated.

Dietary considerations in migraine management: does a consistent diet improve migraine?

The clinical expression of migraine is significantly impacted by dietary and gastrointestinal issues. This includes gut dysfunction during and between attacks, food triggers, increase in migraine with obesity, comorbid GI and systemic inflammation influenced by diet, and specific food allergies such as dairy and gluten. Practitioners often encourage migraineurs to seek consistency in their lifestyle behaviors, and environmental exposures, as a way of avoiding sudden changes that may precipitate attacks. However, rigorous evidence linking consistency of diet with improvement in migraine is very limited and is, at best, indirect, being based mainly on the consistency of avoiding suspected food triggers. A review of current data surrounding the issue of dietary consistency is presented from the perspective of migraine as an illness (vulnerable state), as a disease (symptom expression traits), and with a view toward the role of local and systemic inflammation in its genesis. Firm recommendations await further investigation.

Headaches in soldiers with mild traumatic brain injury: findings and phenomenologic descriptions.

OBJECTIVE: The primary goal of this study was to use headache criteria-based classification for headache types described by service members. BACKGROUND: Headache is common in soldiers returning from the wars in Afghanistan and Iraq. To date, few papers have provided detailed descriptions of these headaches. METHODS: The first 25 patients seen by a certified headache specialist at the Traumatic Brain Injury Center at Womack Army Medical Center, Fort Bragg, NC, between August 2008 and December 2009 are reported. RESULTS: Service members described a total of 55 headaches. Most, but not all, headaches began within 1 week after injury. Migraine type was most common. Aura occurred in 5 soldiers. Continuous headaches were described in 88%. Uncommon headache types including cluster type were diagnosed. Additional symptoms and service outcomes are described. CONCLUSIONS: We conclude that headaches occurring after various types of head injury, including explosions, can be assigned primary and secondary headache diagnoses using standard classifications not necessarily available to larger survey-based studies.

Patient characteristics associated with frequent calls to a headache specialty clinic.

OBJECTIVE: To identify characteristics of patients who frequently initiate contact with a headache specialty clinic outside of scheduled appointments. MATERIALS AND METHODS: We scanned records of all telephone calls received during 1 calendar year at an academic headache clinic to identify frequent callers. High-frequency (HF) callers were defined as established patients who initiated calls on ≥20 days during the year. We compared these patients with a cohort of established low-frequency (LF) callers who initiated no telephone calls during the same year. Clinic records were analyzed for demographic characteristics, diagnoses, and medication use. Additionally, we administered a questionnaire to clinic physicians and administrative staff querying their perception of each patient's demands on clinic resources. RESULTS: High-frequency (n=26) and LF (n=18) callers did not differ significantly in marital status, ethnicity, diagnosis, or age. There was a trend toward female gender among HF callers and toward being outside of a body mass index range of 19 to 30 kg/m2. The groups were similar in their use of triptans and botulinum toxin treatments, but HF callers were more likely to be opioid users (96% vs 11.1%) and more likely to be taking multiple opioids in substantially higher potency, dosage, and quantity (154.4 mg vs 1.4 mg morphine equivalents/day). More than 80% of each group were migraineurs, but HF callers were more likely to have comorbid psychiatric disorders (P<0.05). High-frequency callers were also more likely to be rated by administrative staff and physicians as demanding and time-consuming. CONCLUSIONS: In this university-based headache specialty clinic, HF callers were more likely to be opioid users on high morphine-equivalent doses. Compared with LF callers, HF callers placed a greater burden on health care resources as perceived by staff and physicians.

The prevalence of neck pain in migraine.

OBJECTIVE: To determine the prevalence of neck pain at the time of migraine treatment relative to the prevalence of nausea, a defining associated symptom of migraine. METHODS: This is a prospective, observational cross-sectional study of 113 migraineurs, ranging in attack frequency from episodic to chronic migraine. Subjects were examined by headache medicine specialists to confirm the diagnosis of migraine and exclude both cervicogenic headache and fibromyalgia. Details of all migraines were recorded over the course of at least 1 month and until 6 qualifying migraines had been treated. For each attack, subjects recorded the presence or absence of nausea as well as the intensity of headache and neck pain (graded as none, mild, moderate, or severe). RESULTS: Subjects recorded 2411 headache days, 786 of which were migraines. The majority of migraines were treated in the moderate pain stage. Regardless of the intensity of headache pain at time of treatment, neck pain was a more frequent accompaniment of migraine than was nausea (P< .0001). Prevalence of neck pain correlated with chronicity of headache as attacks moved from episodic to chronic daily headache. CONCLUSIONS: In this representative cross-section of migraineurs, neck pain was more commonly associated with migraine than was nausea, a defining characteristic of the disorder. Awareness of neck pain as a common associated feature of migraine may improve diagnostic accuracy and have a beneficial impact on time to treatment.

The legitimization of headache medicine.

Simultaneous with the drive to ensure the acceptance of headache disorders as "real diseases," the field of headache medicine has strived for recognition as a subspeciality with itself. Efforts to gain such recognition eventually came to fruition in 2005.