N -acetylcysteine is associated with reduction of postconcussive symptoms in elderly patients: A pilot study.

INTRODUCTION: N -acetylcysteine (NAC) may be neuroprotective by minimizing postconcussion symptoms after mild traumatic brain injury (TBI), but limited data exist. This study evaluated the effects of NAC on postconcussion symptoms in elderly patients diagnosed with mild TBI. METHODS: This prospective, quasirandomized, controlled trial enrolled patients 60 years or older who suffered mild TBI. Patients were excluded if cognitive function could not be assessed within 3-hours postinjury. Patients were allocated to receive NAC plus standard care, or standard care alone, based on the trauma center where they presented. The primary study outcome was the severity of concussive symptoms measured using the Rivermeade Postconcussion Symptoms Questionnaire (RPQ). Symptoms were evaluated on days 0, 7, and 30. The RPQ scores were compared both within and between treatment groups. RESULTS: There were 65 patients analyzed (NAC, n = 34; control, n = 31) with an average age of 76 ± 10 years. Baseline demographics and clinical variables were similar. No group differences in head Abbreviated Injury Scale score or Glasgow Coma Scale score were observed. Baseline RPQ scores (6 [0-20] vs. 11 [4-20], p = 0.300) were indistinguishable. The RPQ scores on day 7 (2 [0-8] vs. 10 [3-18], p = 0.004) and 30 (0 [0-4] vs. 4 [0-13], p = 0.021) were significantly lower in the NAC group. Within-group differences were significantly lower in the NAC ( p < 0.001) but not control group ( p = 0.319). CONCLUSION: N -acetylcysteine was associated with significant improvements in concussion symptoms in elderly patients with mild TBI. These results justify further research into using NAC to treat TBI. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Effects of phytocannabinoids on heart rate variability and blood pressure variability in female post-concussion syndrome patients: case series.

Cannabidiol (CBD) can exert neuroprotective effects without being intoxicating, and in combination with Δ9-tetrahydrocannabinol (THC) CBD has shown to protect against THC psychosis. Acute concussion and post-concussion syndrome (PCS) can result in autonomic dysfunction in heart rate variability (HRV), but less information is available on blood pressure variability (BPV). Furthermore, the effects of phytocannabinoids on HRV and BPV in PCS are unknown. The purpose of this study was to observe the influence of daily administration of CBD or a combination of CBD and THC on HRV and BPV parameters in four female PCS participants. Participants completed a seated 5-min rest followed by six breaths-per-minute paced breathing protocol. Data was collected prior to phytocannabinoid intake and continued over 54 to 70 days. High frequency systolic BPV parameter increased every assessment period, unless altered due to external circumstances and symptoms. HRV parameters showed less consistent and varying responses. These results suggest that CBD can help to improve the altered autonomic dysfunction in those with PCS, and that responses to the drug administration was individualized. Double blinded, randomized controlled trials with greater sample sizes are required to better understand the influences of the varying dosages on human physiology and in PCS.

Efficacy of Melatonin for Sleep Disturbance in Children with Persistent Post-Concussion Symptoms: Secondary Analysis of a Randomized Controlled Trial.

Sleep disturbances are commonly reported in children with persistent post-concussion symptoms (PPCS). Melatonin treatment is often recommended, yet supporting evidence is scarce. We aimed to evaluate the efficacy of treatment with melatonin for sleep disturbance in youth with PPCS following mild traumatic brain injury (mTBI). This article is a secondary analysis of a clinical trial of melatonin compared with placebo to treat PPCS. Youth (8-18 years of age) with PPCS and significant sleep-related problems (SRPs) at 4-6 weeks post-injury were eligible. Exclusion criteria: significant medical/psychiatric history; previous concussion/mTBI within 3 months. Treatment groups were: placebo, melatonin 3 mg, or melatonin 10 mg. Primary outcome was change in SRPs measured using the Post-Concussion Symptom Inventory (PCSI) after 2 weeks of treatment. Secondary outcomes included change in actigraphy sleep efficiency, duration, onset latency, and wake-after-sleep-onset. Behavior was measured using Behaviour Assessment for Children (2nd edition). Seventy-two participants (mean age 14.0, standard deviation [SD] = 2.6) years; 60% female) with PPCS and significant sleep disturbance were included in the secondary analysis: placebo (n = 22); melatonin 3 mg (n = 25); melatonin 10 mg (n = 25). Sixty-four participants had actigraphy data. SRPs decreased across all groups over time with a significant effect of melatonin 3 mg (3.7; 95% confidence interval [CI]: 2.1, 5.4) compared with placebo (7.4; 95% CI: 4.2, 10.6) and melatonin 10 mg (6.4; 95% CI: 3.6, 9.2). Sleep duration increased in the melatonin 3 mg (43 min; 95% CI: 6, 93) and melatonin 10 mg groups (55 min; 95% CI: 5, 104) compared with placebo. A per protocol analysis demonstrated improved sleep efficiency in the melatonin 10 mg group (p = 0.029). No serious adverse events were reported. Depressive symptoms significantly decreased with melatonin 3 mg (-4.7; 95% CI: -9.2, -.2) but not with melatonin 10 mg (-1.4, 95% CI: -5.9, 3.2) treatment compared with placebo. Changes in cognition or behavior were otherwise not significantly different between treatment groups. Short-term melatonin is a well-tolerated treatment for sleep disturbance in youth with PPCS following mTBI. In this context, it may also be associated with a reduction in depressive symptoms.

Sleep Problems and Melatonin Prescription After Concussion Among Youth Athletes.

OBJECTIVES: To examine the effect of sleep disturbances on concussion symptom recovery and to examine the effect of melatonin prescription on symptom improvement among concussed adolescents with sleep problems. DESIGN: Longitudinal test-retest. SETTING: Sports medicine clinic. PARTICIPANTS: Patients aged 8 to 18 years, diagnosed with a concussion, evaluated within 14 days after injury, and evaluated again 15 to 35 days after injury. INDEPENDENT VARIABLES: We grouped patients based on whether they reported sleep disturbances within 14 days of injury. MAIN OUTCOME MEASURES: Outcome measures included symptom severity, headache severity, melatonin prescription, and the change in symptom severity between visits. RESULTS: Two hundred twenty-five patients were included: 36% who reported sleep problems (44% female; age = 14.4 ± 2.0 years; evaluated 7.3 ± 3.8 and 23.2 ± 5.4 days after injury) and 64% who did not (32% female; age = 14.6 ± 2.3 years; evaluated 7.2 ± 3.4 and 23.0 ± 5.3 days after injury). Those with sleep problems reported higher symptom severity than those without across the 2 visits (22.1 ± 14.3 vs 14.6 ± 12.5; P < 0.001). There was no significant difference in the change in symptom severity between visits among those who received [median = 9-point improvement; interquartile range (IQR) = 1-14] and did not (median = 9, IQR = 2-18) receive a melatonin prescription (P = 0.80). CONCLUSIONS: Sleep problems among pediatric patients within 2 weeks of concussion are associated with more severe symptoms. Melatonin prescription was not associated with faster symptom recovery.

Medical Therapies for Concussion.

The medications used in postconcussion syndrome are typically used to help manage or minimize disruptive symptoms while recovery proceeds. These medications are not routinely used in most concussions that recover within days to weeks. However, it is beneficial to be aware of medication options that may be used in athletes with prolonged concussion symptoms or for those that have symptom burdens that preclude entry into basic concussion protocols. Medications and supplements remain a small part of the concussion treatment plan, which may include temporary academic adjustments, physical therapy, vestibular and ocular therapy, psychological support, and graded noncontact exercise.

Neural Correlates of Sleep Recovery following Melatonin Treatment for Pediatric Concussion: A Randomized Controlled Trial.

Evidence-based treatments for children with persistent post-concussion symptoms (PPCS) are few and limited. Common PPCS complaints such as sleep disturbance and fatigue could be ameliorated via the supplementation of melatonin, which has significant neuroprotective and anti-inflammatory properties. This study aims to identify neural correlates of melatonin treatment with changes in sleep disturbances and clinical recovery in a pediatric cohort with PPCS. We examined structural and functional neuroimaging (fMRI) in 62 children with PPCS in a randomized, double-blind, placebo-controlled trial of 3 mg or 10 mg of melatonin (NCT01874847). The primary outcome was the total youth self-report Post-Concussion Symptom Inventory (PCSI) score after 28 days of treatment. Secondary outcomes included the change in the sleep domain PCSI score and sleep-wake behavior (assessed using wrist-worn actigraphy). Whole-brain analyses of (1) functional connectivity (FC) of resting-state fMRI, and (2) structural gray matter volumes via voxel-based morphometry were assessed immediately before and after melatonin treatment and compared with placebo to identify neural effects of melatonin treatment. Increased FC of posterior default mode network (DMN) regions with visual, somatosensory, and dorsal networks was detected in the melatonin groups over time. The FC increases also corresponded with reduced wake periods (r = -0.27, p = 0.01). Children who did not recover (n = 39) demonstrated significant FC increases within anterior DMN and limbic regions compared with those who did recover (i.e., PCSI scores returned to pre-injury level, n = 23) over time, (p = 0.026). Increases in GM volume within the posterior cingulate cortex were found to correlate with reduced wakefulness after sleep onset (r = -0.32, p = 0.001) and sleep symptom improvement (r = 0.29, p = 0.02). Although the melatonin treatment trial was negative and did not result in PPCS recovery (with or without sleep problems), the relationship between melatonin and improvement in sleep parameters was linked to changes in function-structure within and between brain regions interacting with the DMN.

Efficacy of Melatonin in Children With Postconcussive Symptoms: A Randomized Clinical Trial.

BACKGROUND: Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo. METHODS: We conducted a randomized, double-blind trial of 3 or 10 mg of melatonin compared with a placebo (NCT01874847). We included youth (ages 8-18 years) with PPCS at 4 to 6 weeks after mild traumatic brain injury. Those with significant medical or psychiatric histories or a previous concussion within the last 3 months were excluded. The primary outcome was change in the total youth self-reported Post-Concussion Symptom Inventory score measured after 28 days of treatment. Secondary outcomes included change in health-related quality of life, cognition, and sleep. RESULTS: Ninety-nine children (mean age: 13.8 years; SD = 2.6 years; 58% girls) were randomly assigned. Symptoms improved over time with a median Post-Concussion Symptom Inventory change score of -21 (95% confidence interval [CI]: -16 to -27). There was no significant effect of melatonin when compared with a placebo in the intention-to-treat analysis (3 mg melatonin, -2 [95% CI: -13 to 6]; 10 mg melatonin, 4 [95% CI: -7 to 14]). No significant group differences in secondary outcomes were observed. Side effects were mild and similar to the placebo. CONCLUSIONS: Children with PPCS had significant impairment in their quality of life. Seventy-eight percent demonstrated significant recovery between 1 and 3 months postinjury. This clinical trial does not support the use of melatonin for the treatment of pediatric PPCS.

Effect of Patient Compliance With Treatment Recommendations on Clinical Outcomes in Chronic mTBI: A TEAM-TBI Study.

INTRODUCTION: Treatment approaches for mild traumatic brain injury (mTBI) have evolved to focus on active and targeted therapies, but the effect of compliance with therapy has not been investigated. The purpose of this study was to examine the role of patient compliance with prescribed therapies on clinical outcomes following mTBI. MATERIALS AND METHODS: Participants were aged 18-60 years with chronic (ie, 6+ months) mTBI symptoms who were previously recalcitrant (n = 66). Participants were diagnosed with a vestibular disorder and were prescribed vestibular and exertion therapies. Participants were instructed to continue the exercise regimen during the 6-month treatment phase at home. Participant compliance was evaluated by clinicians at patients' follow up visit as: (1) high, (2) moderate, or (3) low compliance based on patient report and clinician interview. High-compliance was compared to a combined low- and moderate-compliance group on the outcomes using a 2 (group) × 2 (time) analysis of variance. RESULTS: 39 of the 66 (59%) participants with vestibular disorder returned for a 6-month evaluation and were included in the analyses. Of these 39 participants, 16 (41%) were high-compliance (36.7 ± 10.9 years, 18.8% female), 17 (44%) were moderate-compliance (32.5 ± 5.5 years, 23.5% female), and 6 (15%) were low-compliance (32.7 ± 3.3 years, 0% female). CONCLUSION: High compliance significantly reduced total Vestibular/Ocular Motor Screening scores compared to low/middle compliance (P = .005). Post-Concussion Symptom Scale was reduced by 48% and dizziness symptoms reduced by 31% in the high-compliance cohort. High compliance with prescribed exertion/vestibular rehabilitation therapies enhanced clinical outcomes for previously recalcitrant patients with chronic mTBI-related vestibular disorders.

Neuroprotection Following Concussion: The Potential Role for Cannabidiol.

Cannabidiol (CBD) has been generating increasing interest in medicine due to its therapeutic properties and an apparent lack of negative side effects. Research has suggested that high dosages of CBD can be taken acutely and chronically with little to no risk. This review focuses on the neuroprotective effects of a CBD, with an emphasis on its implications for recovering from a mild traumatic brain injury (TBI) or concussion. CBD has been shown to influence the endocannabinoid system, both by affecting cannabinoid receptors and other receptors involved in the endocannabinoid system such as vanilloid receptor 1, adenosine receptors, and 5-hydroxytryptamine via cannabinoid receptor-independent mechanisms. Concussions can result in many physiological consequences, potentially resulting in post-concussion syndrome. While impairments in cerebrovascular and cardiovascular physiology following concussion have been shown, there is unfortunately still no single treatment available to enhance recovery. CBD has been shown to influence the blood brain barrier, brain-derived neurotrophic factors, cognitive capacity, the cerebrovasculature, cardiovascular physiology, and neurogenesis, all of which have been shown to be altered by concussion. CBD can therefore potentially provide treatment to enhance neuroprotection by reducing inflammation, regulating cerebral blood flow, enhancing neurogenesis, and protecting the brain against reactive oxygen species. Double-blind randomized controlled trials are still required to validate the use of CBD as medication following mild TBIs, such as concussion.

Extended follow-up in a randomized trial of hyperbaric oxygen for persistent post-concussive symptoms.

To date, several Department of Defense (DoD) and civilian studies have evaluated hyperbaric oxygen for mild forms of traumatic brain injury. Prior to the DoD-sponsored "Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA)" trial, none included post-intervention follow-up beyond three to six months. Post-hoc attempts at long-term follow-up were complicated by low participation and potential self-selection bias. BIMA planned for follow-up through 12 months but was amended to add post-concussive and post-traumatic stress disorder, quality of life, pain, depression, anxiety, and alcohol use assessments at 24 and 36 months. A total of 42 of 71 BIMA participants consented to extendedfollow-up, and 40 and 14 completed a 24- or 36-month visit, respectively, representing an overall response rate of 59% and 20%. Participants who completed extended follow-up were similar to the study group that did not in terms of demographics, perceived intervention allocation, and initial response to intervention. There were no significant differences at 24 or 36 months between intervention groups, and group mean scores were near pre-intervention values. This return to baseline could be due to waning treatment effect, selection bias, or participant or perception effects. Though BIMA implemented several participant retention strategies, more frequent participant contact and increased compensation might improve long-term retention in future studies. clinicaltrials.gov Identifier NCT01611194.

Survey of Child Neurologists on Management of Pediatric Post-traumatic Headache.

Traumatic brain injury causes significant morbidity in youth, and headache is the most common postconcussive symptom. No established guidelines exist for pediatric post-traumatic headache management. We aimed to characterize common clinical practices of child neurologists. Of 95 practitioners who completed our survey, most evaluate <50 pediatric concussion patients per year, and 38.9% of practitioners consistently use International Classification of Headache Disorders criteria to diagnose post-traumatic headache. Most recommend nonsteroidal anti-inflammatory drugs as abortive therapy, though timing after injury and frequency of use varies, as does the time when providers begin prophylactic medications. Amitriptyline, topiramate, and vitamins/supplements are most commonly used for prophylaxis. Approach to rest and return to activities varies; one-third recommend rest for 1 to 3 days and then progressive return, consistent with current best practice. With no established guidelines for pediatric post-traumatic headache management, it is not surprising that practices vary considerably. Further studies are needed to define the best, evidence-based management for pediatric post-traumatic headache.

Amantadine Use for Postconcussion Syndrome.

The development of postconcussion syndrome after traumatic brain injury can result in a wide range of potentially debilitating symptoms that includes headaches, cognitive dysfunction, and mood disorders. Unfortunately, data on helpful medications are quite limited, particularly on the treatment of persistent headaches attributed to trauma. This retrospective medical record review used data collected from patients with a diagnosis of postconcussion syndrome in Mayo Clinic's Neurology and Physical Medicine and Rehabilitation outpatient clinics to evaluate the response of postconcussive symptoms to amantadine. A complete trial of amantadine was defined as 100 mg twice per day for 2 months. Thirty-three patients were prescribed amantadine for postconcussive syndrome after traumatic brain injury. One-third of patients discontinued the medication because of adverse effects. However, posttraumatic headaches were improved in 80% of patients who completed a full trial of amantadine. Surprisingly, patients had improvement in headaches even if the medication was prescribed years after the initial trauma. Little improvement was noted in other symptoms such as poor memory, dizziness, and personality changes. Although additional research is certainly needed, amantadine may be a reasonable medication to consider for the treatment of persistent headaches attributed to trauma, even if the initial injury is remote.

Posttraumatic Headache.

Posttraumatic headaches are among the most challenging complaints after mild traumatic brain injury (mTBI). They are a debilitating problem experienced by patients after TBI of all severities. Up to 90% of mild TBI patients experience headache, particularly if female and with a premorbid history of primary headache. Tension headache has classically been the most common subtype, but in military populations migraine has dominated. Posttraumatic headache encompasses a spectrum of headache types that overlap heavily with common primary headache disorders, but also autonomic cephalgias as well as several secondary headache conditions. It is important to understand the evolution of postconcussion syndrome as a concept, and the challenges associated with diagnosing and treating multidomain drivers effectively. The first-line treatments for posttraumatic headache are typically the same as those used in nontraumatic headache, with additional considerations for cognitive side effects, posttraumatic epilepsy, and coexisting injuries resulting in neuropathic pain or medication overuse.

Efficacy and Harms of Pharmacological Interventions for Neurobehavioral Symptoms in Post-Traumatic Amnesia after Traumatic Brain Injury: A Systematic Review.

Many individuals in post-traumatic amnesia (PTA) following traumatic brain injury (TBI) experience neurobehavioral symptoms (NBS) in addition to disorientation and amnesia. These symptoms are associated with low rehabilitation engagement, self-inflicted harm, and risk of violence. The aim of this systematic review was to evaluate the efficacy and harms of pharmacological interventions for NBS in PTA following TBI in adults. Studies in English published before December 2017 were reviewed. Six databases were searched, with additional hand searching of key journals, clinical trials registries, and international drug regulators. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. Thirteen studies were identified: three randomized controlled trials (RCTs), three cohort studies, and seven case series. In the RCTs, neither amantadine nor sertraline reduced NBS. Less rigorous studies reported reduced NBS in patients administered haloperidol, ziprasidone, carbamazepine, amitriptyline, desipramine, and varied neuroleptics. There is a paucity of well-designed, adequately powered and controlled studies of pharmacological interventions for NBS in PTA. More research is needed to provide evidence-based treatment recommendations and improve care.

Growing literature but limited evidence: A systematic review regarding prebiotic and probiotic interventions for those with traumatic brain injury and/or posttraumatic stress disorder.

Traumatic brain injury (TBI) is highly prevalent among a wide range of populations, including civilians, military personnel, and Veterans. TBI sequelae may be further exacerbated by symptoms associated with frequently occurring comorbid psychiatric conditions, including posttraumatic stress disorder (PTSD). This is particularly true among the population of military personnel from recent conflicts in Iraq and Afghanistan, with a history of mild TBI (mTBI) and PTSD. The need for efficacious treatments for TBI and comorbid PTSD is significant, and evidence-based interventions for these frequently co-occurring conditions are limited. Based on findings suggesting that inflammation may be an underlying mechanism of both conditions, anti-inflammatory/immunoregulatory agents, including probiotics, may represent a novel strategy to treat TBI and/or PTSD-related symptoms. The focus of this systematic review was to identify and evaluate existing research regarding prebiotic and probiotic interventions for the populations of individuals with a history of TBI and/or PTSD. Only 4 studies were identified (3 severe TBI, 1 PTSD, 0 co-occurring TBI and PTSD). Although findings suggested some promise, work in this area is nascent and results to date do not support some claims within the extensive coverage of probiotics in the popular press.

Predictors of Pharmacological Intervention in Adolescents With Protracted Symptoms After Sports-Related Concussion.

BACKGROUND: Although recovery after concussion is spontaneous and typically occurs within 2-3 weeks, a subset of adolescents develop persistent symptoms after a sports-related concussion. Medications are frequently prescribed as part of a comprehensive treatment approach to alleviate these symptoms; however, there are no guidelines for prescription of pharmacologic therapy after concussion. OBJECTIVE: To investigate common factors that are associated with the use of medications (antiepileptic, antidepressant, neurostimulant, or sleeping medication) during recovery from a sports-related concussion. DESIGN: Retrospective observational study. SETTING: Single-center specialty concussion center. PARTICIPANTS: A total of 100 adolescents, between the ages of 12 and 18 years, who sustained concussion due to sports. ASSESSMENT OF RISK FACTORS: Independent variables collected included age at the time of concussion, gender, sports played, personal history of prior concussion or mental health disorder, and personal or family history of headache (eg, migraines) or seizure disorder. MAIN OUTCOME MEASURE: Prescription of medications for treatment of concussion. RESULTS: Twenty-four patients (24%) were prescribed medications in this study, all of whom reported headache at the time of medication prescription. Amantadine was the most commonly prescribed medication, with amitriptyline and melatonin also being prescribed. Among the demographic information collected, only age and gender met criteria for inclusion in the regression model. Logistic regression analysis demonstrated that the odds that female participants were prescribed medications was 3.790 (95% confidence interval = 1.262-11.380) higher than male participants. A higher symptom score on the initial Post Concussion Symptom Scale (PCSS) was associated with increased odds of being prescribed medications (odds ratio = 1.031, 95% CI = 1.009-1.052). CONCLUSIONS: The current study found that initial symptom severity and female gender were associated with use of medication in recovery from sports-related concussion among variables available for study. LEVEL OF EVIDENCE: II.

Long-term treatment with methylphenidate for fatigue after traumatic brain injury.

OBJECTIVES: Traumatic brain injury (TBI) may cause long-lasting post-concussive symptoms, such as mental fatigue and concentration difficulties, and this may become the main hindrance for returning to work and studies. There is currently no effective treatment for long-lasting mental fatigue. In this hypothesis generating study, the long-term effects of methylphenidate on mental fatigue, cognitive function, and safety were assessed. MATERIALS & METHODS: Thirty participants who suffered from long-term post-concussion symptoms after a mild TBI or moderate TBI and who had reported positive effects with methylphenidate during an initial phase of this follow-up study were treated with methylphenidate for a further six months. RESULTS: After six-month follow-up, effects on Mental Fatigue Scale (MFS), depression, anxiety, and cognitive function (processing speed, attention, working memory) were significantly improved compared to baseline data (P < 0.001, respectively). Heart rate was significantly increased (P = 0.01), while blood pressure was not changed. CONCLUSIONS: Individuals suffering from prolonged symptoms after TBI reported reduced mental fatigue and improved cognitive functions with long-term methylphenidate treatment. It is suggested that methylphenidate can be a treatment option for long-term mental fatigue and cognitive impairment after a TBI, but further randomized control research is warranted.