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.

Independent home use of a brain-computer interface by people with amyotrophic lateral sclerosis.

OBJECTIVE: To assess the reliability and usefulness of an EEG-based brain-computer interface (BCI) for patients with advanced amyotrophic lateral sclerosis (ALS) who used it independently at home for up to 18 months. METHODS: Of 42 patients consented, 39 (93%) met the study criteria, and 37 (88%) were assessed for use of the Wadsworth BCI. Nine (21%) could not use the BCI. Of the other 28, 27 (men, age 28-79 years) (64%) had the BCI placed in their homes, and they and their caregivers were trained to use it. Use data were collected by Internet. Periodic visits evaluated BCI benefit and burden and quality of life. RESULTS: Over subsequent months, 12 (29% of the original 42) left the study because of death or rapid disease progression and 6 (14%) left because of decreased interest. Fourteen (33%) completed training and used the BCI independently, mainly for communication. Technical problems were rare. Patient and caregiver ratings indicated that BCI benefit exceeded burden. Quality of life remained stable. Of those not lost to the disease, half completed the study; all but 1 patient kept the BCI for further use. CONCLUSION: The Wadsworth BCI home system can function reliably and usefully when operated by patients in their homes. BCIs that support communication are at present most suitable for people who are severely disabled but are otherwise in stable health. Improvements in BCI convenience and performance, including some now underway, should increase the number of people who find them useful and the extent to which they are used.

Nature and Action of Antibodies in Myasthenia Gravis.

This article discusses antibodies associated with immune-mediated myasthenia gravis and the pathologic action of these antibodies at the neuromuscular junctions of skeletal muscle. To explain how these antibodies act, we consider the physiology of neuromuscular transmission with emphasis on 4 features: the structure of the neuromuscular junction; the roles of postsynaptic acetylcholine receptors and voltage-gated Na+ channels and in converting the chemical signal from the nerve terminal into a propagated action potential on the muscle fiber that triggers muscle contraction; the safety factor for neuromuscular transmission; and how the safety factor is reduced in different forms of autoimmune myasthenia gravis.

Pathophysiological links between traumatic brain injury and post-traumatic headaches.

This article reviews possible ways that traumatic brain injury (TBI) can induce migraine-type post-traumatic headaches (PTHs) in children, adults, civilians, and military personnel. Several cerebral alterations resulting from TBI can foster the development of PTH, including neuroinflammation that can activate neural systems associated with migraine. TBI can also compromise the intrinsic pain modulation system and this would increase the level of perceived pain associated with PTH. Depression and anxiety disorders, especially post-traumatic stress disorder (PTSD), are associated with TBI and these psychological conditions can directly intensify PTH. Additionally, depression and PTSD alter sleep and this will increase headache severity and foster the genesis of PTH. This article also reviews the anatomic loci of injury associated with TBI and notes the overlap between areas of injury associated with TBI and PTSD.

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.

Formation and function of acute stroke-ready hospitals within a stroke system of care recommendations from the brain attack coalition.

BACKGROUND AND PURPOSE: Many patients with an acute stroke live in areas without ready access to a Primary or Comprehensive Stroke Center. The formation of care facilities that meet the needs of these patients might improve their care and outcomes and guide them and emergency responders to such centers within a stroke system of care. METHODS: The Brain Attack Coalition conducted an electronic search of the English medical literature from January 2000 to December 2012 to identify care elements and processes shown to be beneficial for acute stroke care. We used evidence grading and consensus paradigms to synthesize recommendations for Acute Stroke-Ready Hospitals (ASRHs). RESULTS: Several key elements for an ASRH were identified, including acute stroke teams, written care protocols, involvement of emergency medical services and emergency department, and rapid laboratory and neuroimaging testing. Unique aspects include the use of telemedicine, hospital transfer protocols, and drip and ship therapies. Emergent therapies include the use of intravenous tissue-type plasminogen activator and the reversal of coagulopathies. Although many of the care elements are similar to those of a Primary Stroke Center, compliance rates of ≥67% are suggested in recognition of the staffing, logistical, and financial challenges faced by rural facilities. CONCLUSIONS: ASRHs will form the foundation for acute stroke care in many settings. Recommended elements of an ASRH build on those proven to improve care and outcomes at Primary Stroke Centers. The ASRH will be a key component for patient care within an evolving stroke system of care.

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.

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.

Neuromuscular transmission failure in myasthenia gravis: decrement of safety factor and susceptibility of extraocular muscles.

An appropriate density of acetylcholine receptors (AChRs) and Na(+) channels (NaChs) in the normal neuromuscular junction (NMJ) determines the magnitude of safety factor (SF) that guarantees fidelity of neuromuscular transmission. In myasthenia gravis (MG), an overall simplification of the postsynaptic folding secondary to NMJ destruction results in AChRs and NaChs depletion. Loss of AChRs and NaChs accounts, respectively, for 59% and 40% reduction of the SF at the endplate, which manifests as neuromuscular transmission failure. The extraocular muscles (EOM) have physiologically less developed postsynaptic folding, hence a lower baseline SF, which predisposes them to dysfunction in MG and development of fatigue during "high performance" eye movements, such as saccades. However, saccades in MG show stereotyped, conjugate initial components, similar to normal, which might reflect preserved neuromuscular transmission fidelity at the NMJ of the fast, pale global fibers, which have better developed postsynaptic folding than other extraocular fibers.

Abnormal leg muscle latencies and relationship to dyscoordination and walking disability after stroke.

The purpose was to determine timing characteristics of leg muscle latencies for patients following stroke (>12 months) who had persistent coordination and gait deficits, and to determine the relationships among abnormal latencies, dyscoordination, and gait deficits. We compared nine healthy controls and 27 stroke survivors. Surface electromyography measured activation and deactivation latencies of knee flexor and extensor muscles during a ballistic knee flexion task, consistency of latencies across repetitions, and close coupling between agonist and antagonist muscle latencies. We measured Fugl-Meyer (FM) coordination and the functional gait measure, six minute walk test (6MWT). For stroke subjects, there were significant delays of muscle activation and deactivation, abnormal inconsistency, and abnormal decoupled agonist and antagonist activations. There was good correlation between activation latencies and FM and 6MWT. Results suggest abnormal timing characteristics underlie coordination impairment and dysfunctional gait. These abnormal muscle activation and deactivation timing characteristics are important targets for rehabilitation.

Endplate contributions to the safety factor for neuromuscular transmission.

The neuromuscular junction (NMJ), for most extremity and axial skeletal muscle fibers, with the exception of extraocular, middle ear, and some facial and pharyngeal muscles, is a 'slave' synapse that is designed to activate the muscle fiber every time the nerve terminal is activated. The fidelity of the NMJ hinges upon the electrical depolarization produced by activation of acetylcholine receptors (AChRs), called the endplate potential (EPP), being larger than is needed to trigger an action potential (AP) in the skeletal muscle fiber. The safety factor (SF) is a measure of how much larger the EPP is than the depolarization needed to trigger an AP (EAP). The SF depends on the amount of transmitter released, AChR density, EAP, and the effectiveness of the EPP in stimulating the Na(+) channels that trigger the AP. This study focuses on the postsynaptic factors that influence the SF and how the SF is altered in myasthenia gravis.