Randomized controlled pilot trial of prazosin for prophylaxis of posttraumatic headaches in active-duty service members and veterans.

OBJECTIVE: Evaluate the efficacy and tolerability of prazosin for prophylaxis of headaches following mild traumatic brain injury in active-duty service members and military veterans. BACKGROUND: Prazosin is an alpha-1 adrenoreceptor antagonist that reduces noradrenergic signaling. An open-label trial in which prazosin reduced headache frequency in veterans following mild traumatic brain injury provided the rationale for this pilot study. METHODS: A 22-week parallel-group randomized controlled trial  which included 48 military veterans and active-duty service members with mild traumatic brain injury-related headaches was performed. The study design was based on International Headache Society consensus guidelines for randomized controlled trials for chronic migraine. Following a pre-treatment baseline phase, participants with at least eight qualifying headache days per 4 weeks were randomized 2:1 to prazosin or placebo. After a 5-week titration to a maximum possible dose of 5 mg (morning) and 20 mg (evening), participants were maintained on the achieved dose for 12 weeks. Outcome measures were evaluated in 4-week blocks during the maintenance dose phase. The primary outcome measure was change in 4-week frequency of qualifying headache days. Secondary outcome measures were percent participants achieving at least 50% reduction in qualifying headache days and change in Headache Impact Test-6 scores. RESULTS: Intent-to-treat analysis of randomized study participants (prazosin N = 32; placebo N = 16) demonstrated greater benefit over time in the prazosin group for all three outcome measures. In prazosin versus placebo participants, reductions from baseline to the final rating period for 4-week headache frequency were -11.9 ± 1.0 (mean ± standard error) versus -6.7 ± 1.5, a prazosin minus placebo difference of -5.2 (-8.8, -1.6 [95% confidence interval]), p = 0.005 and for Headache Impact Test-6 scores were -6.0 ± 1.3 versus +0.6 ± 1.8, a difference of -6.6 (-11.0, -2.2), p = 0.004. The mean predicted percent of participants at 12 weeks with ≥50% reduction in headache days/4 weeks, baseline to final rating, was 70 ± 8% for prazosin (21/30) versus 29 ± 12% for placebo (4/14), odds ratio 5.8 (1.44, 23.6), p = 0.013. The trial completion rate of 94% in the prazosin group (30/32) and 88% in the placebo group (14/16) indicated that prazosin was generally well tolerated at the administered dose regimen. Morning drowsiness/lethargy was the only adverse effect that differed significantly between groups, affecting 69% of the prazosin group (22/32) versus 19% of the placebo group (3/16), p = 0.002. CONCLUSIONS: This pilot study provides a clinically meaningful efficacy signal for prazosin prophylaxis of posttraumatic headaches. A larger randomized controlled trial is needed to confirm and extend these promising results.

Post-traumatic headaches in civilians and military personnel: a comparative, clinical review.

Post-traumatic headache (PTH) is the most frequent symptom after traumatic brain injury (TBI). We review the epidemiology and characterization of PTH in military and civilian settings. PTH appears to be more likely to develop following mild TBI (concussion) compared with moderate or severe TBI. PTH often clinically resembles primary headache disorders, usually migraine. For migraine-like PTH, individuals who had the most severe headache pain had the highest headache frequencies. Based on studies to date in both civilian and military settings, we recommend changes to the current definition of PTH. Anxiety disorders such as post-traumatic stress disorder (PTSD) are frequently associated with TBI, especially in military populations and in combat settings. PTSD can complicate treatment of PTH as a comorbid condition of post-concussion syndrome. PTH should not be treated as an isolated condition. Comorbid conditions such as PTSD and sleep disturbances also need to be treated. Double-blind placebo-controlled trials in PTH population are necessary to see whether similar phenotypes in the primary headache disorders and PTH will respond similarly to treatment. Until blinded treatment trials are completed, we suggest that, when possible, PTH be treated as one would treat the primary headache disorder(s) that the PTH most closely resembles.

Diagnosis and management of moderate and severe traumatic brain injury sustained in combat.

Traumatic brain injury exists in a spectrum of severity among wounded personnel. The evaluation and clinical presentation, initial management, and treatment interventions to prevent secondary injury processes for combat-associated moderate and severe traumatic brain injury are reviewed. Promising therapies are discussed, and a current review of the literature is provided.

Physician knowledge of the Glasgow Coma Scale.

Appropriate triage is critical to optimizing outcome from battle related injuries. The Glasgow Coma Scale (GCS) is the primary means by which combat casualties, who have suffered head injury, are triaged. For the GCS to be reliable in this critical role, it must be applied accurately. To determine the level of knowledge of the GCS among military physicians with exposure and/or training in the scale we administered a prospective, voluntary, and anonymous survey to physicians of all levels of training at military medical centers with significant patient referral base. The main outcome measures were correct identification of title and categories of the GCS along with appropriate scoring of each category. Overall performance on the survey was marginal. Many were able to identify what "GCS" stands for, but far fewer were able to identify the titles of the specific categories, let alone identify the specific scoring of each category. When evaluated based on medical specialties, those in surgical specialties outperformed those in the medical specialties. When comparing the different levels of training, residents and fellows performed better than attending staff or interns. Finally, those with Advanced Trauma Life Support (ATLS) certification performed significantly better than those without the training. Physician knowledge of the GCS, as demonstrated in this study, is poor, even in a population of individuals with specific training in the use of the scale. It is concluded that, to optimize outcome from combat related head injury, methods for improving accurate quantitation of neurologic state need to be explored.

Post-traumatic headaches.

Chronic pain, especially headache, is an exceedingly common complication of traumatic brain injury (TBI). In fact, paradoxically, the milder the TBI, the more likely one is to develop headaches. The environment of injury and the associated comorbidities can have a significant impact on the frequency and severity of headaches and commonly serve to direct management of the headaches. Trauma likely contributes to the development of headaches via alterations in neuronal signaling, inflammation, and musculoskeletal changes. The clinical picture of the patient with post-traumatic headaches is often that of a mixed headache disorder with features of tension-type headaches as well as migrainous headaches. Treatment of these headaches is thus often guided by the predominant characteristics of the headaches and can include pharmacologic and nonpharmacologic strategies. Pharmacologic therapies include both abortive and prophylactic agents with prophylaxis targeting comorbidities, primarily impaired sleep. Nonpharmacologic interventions for post-traumatic headaches include thermal and physical modalities as well as cognitive behavioral approaches. As with many postconcussive symptoms, headaches can lessen with time but in up to 25% of patients, chronic headaches are long-term residua.

Prior housing conditions and sleep loss may affect recovery from brain injury in rats: a pilot study.

The purpose of this study is to understand the effect of combat-associated conditions such as sleep deprivation (SD) on subsequent traumatic brain injury (TBI). Prior to TBI (or sham surgery) induced by controlled cortical impact (CCI), rats were housed singly in chambers that prevented rapid eye movement sleep or allowed unrestricted sleep (no SD). Sensorimotor function was tested pre-SD and retested on postoperative days (PDs) 4, 7, and 14. Two additional control groups were housed socially prior to either CCI or sham surgery. CCI resulted in immediate performance deficits on sensorimotor tasks. The PD on which performance returned to baseline depended on preinjury conditions. Overall, preinjury SD+CCI resulted in an earlier recovery than no SD+CCI, and the no SD+CCI group (housed singly under conditions comparable with the SD group) recovered slower than all other groups. These data are the first to raise the possibility that recovery of sensorimotor function following TBI is affected by preinjury conditions. The data suggest that preinjury SD 24 h in duration may result in faster recovery and that novel or social isolation conditions may impede recovery. Thus, the combat environment may contribute to complexities associated with TBIs common in U.S. servicemembers.

For veterans with mild traumatic brain injury, improved posttraumatic stress disorder severity and sleep correlated with symptomatic improvement.

This was an observational study of a cohort of 63 Operation Iraqi Freedom/Operation Enduring Freedom veterans with mild traumatic brain injury (mTBI) associated with an explosion. They had headaches, residual neurological deficits (NDs) on neurological examination, and posttraumatic stress disorder (PTSD) and were seen on average 2.5 years after their last mTBI. We treated them with sleep hygiene counseling and oral prazosin. We monitored headache severity, daytime sleepiness using the Epworth Sleepiness Scale, cognitive performance using the Montreal Cognitive Assessment test, and the presence of NDs. We quantitatively measured olfaction and assessed PTSD severity using the PTSD Checklist-Military Version. Nine weeks after starting sleep counseling and bedtime prazosin, the veterans' headache severity decreased, cognitive function as assayed with a brief screening tool improved, and daytime sleepiness diminished. Six months after completing treatment, the veterans demonstrated additional improvement in headache severity and daytime sleepiness and their improvements in cognitive function persisted. There were no changes in the prevalence of NDs or olfaction scores. Clinical improvements correlated with reduced PTSD severity and daytime sleepiness. The data suggested that reduced clinical manifestations following mTBI correlated with PTSD severity and improvement in sleep, but not the presence of NDs or olfaction impairment.

Rehabilitation in the patient with mild traumatic brain injury.

Traumatic brain injury (TBI) has garnered increased public attention in the past several years because of high-profile athletes with possible long-term effects of their injuries as well as large numbers of returning combat veterans injured by blast explosions. Most of these injuries are mild in nature and require no specific surgical treatment but may benefit from brief rehabilitation interventions. To appropriately rehabilitate patients with mild traumatic brain injury (mTBI), one must fully understand its clinical course and the factors that accelerate or delay recovery. Education is the centerpiece of mTBI treatment and should be included in the rehabilitation plan. When devising the rehabilitation plan, the neurologist should take into account the goals of the patient and establish a reasonable time frame for treatment paralleling the expected recovery course. Cognitive and vestibular functions are commonly affected after mTBI and are particularly responsive to rehabilitation interventions. Vocational rehabilitation and community reentry planning are aspects of the global rehabilitation plan that should not be neglected. Combat-injured veterans with mTBI present unique challenges to the rehabilitation team, and assessment of these patients often needs to include assessment of psychological function.

Relationships between mild traumatic brain injury sustained in combat and post-traumatic stress disorder.

The setting of the trauma is a distinguishing feature between mild traumatic brain injury (mTBI; also called concussion) that occurs in civilian settings compared with that occurring in combat. Combat mTBI is frequently associated with a prolonged stress reaction, post-traumatic stress disorder (PTSD). Individuals with mTBI and PTSD from combat in Operations Iraqi Freedom and Enduring Freedom often develop prolonged post-concussion symptoms (PCSs) such as headache. Both mTBI and PTSD may contribute to PCSs. PTSD may worsen and prolong the PCSs following mTBI by disrupting sleep. It is not known how mTBI predisposes an individual to develop PTSD.

Damage to sensory fibers in a martin-gruber anomaly after biceps tendon repair.

A patient with a distal biceps tendon rupture developed ulnar distribution sensory loss after surgical repair using the modified two-incision Boyd and Anderson technique. Electrodiagnosis demonstrated an absent ulnar sensory response but no clinical or electrodiagnostic evidence of ulnar neuropathy at the elbow. Nerve conduction studies demonstrated an anastomosis between the median and ulnar nerves (Martin-Gruber anomaly). Ulnar sensory fibers were probably damaged as they coursed with the median nerve at the elbow as a component of the innervation anomaly. This case documents the presence of ulnar sensory fibers as part of a Martin-Gruber anomaly.