Eye tracker outcomes in a randomized trial of 40 sessions of hyperbaric oxygen or sham in participants with persistent post concussive symptoms.

PURPOSE: Eye movements may offer a sensitive method to measure response to intervention in mild traumatic brain injury (mTBI). METHODS: The Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury Study (BIMA) randomized 71 participants to 40 sessions of hyperbaric oxygen or sham. A companion normative study (Normal) enrolled 75 participants. An eye tracking system measured left and right eye movements for saccadic and smooth pursuit. At baseline two smooth pursuit tasks, circular and horizontal ramp, and four saccadic tasks, horizontal and vertical step, reading, and memory guided-on tasks differentiated BIMA from Normal participants. The change from baseline in these tasks were measured and compared between interventions and against Normal participants at 13 weeks and six-month follow-up using the two-sample t-test. The Holm-Bonferroni procedure was used to adjust for multiple testing. RESULTS: Change from baseline in eyetracker measures for participants assigned to the hyperbaric oxygen arm did not significantly differ from those assigned to the sham arm at post-randomization time points 13 weeks and six months. Consistent shifts of BIMA participant values toward Normal values at 13 weeks and six months were observed for overall fixation duration, forward saccadic duration, and number of lines read for the reading task, number of misses on the memory guided-on task, and absolute intersaccadic interval velocity and absolute saccadic amplitude on the circular task. The distributions between Normal and BIMA participants were no longer statistically significantly different at 13 weeks and six months post enrollment for these measures. CONCLUSION: The baseline differences between BIMA and Normal suggest potential vulnerability of the smooth pursuit system and the saccadic system. During the six-month follow-up period, improvement toward Normal was seen on some measures in both the hyperbaric oxygen and sham intervention arms without difference between intervention groups. IDS: clinicaltrials.gov Identifiers NCT01611194 and NCT01925963.

Adverse events and blinding in two randomized trials of hyperbaric oxygen for persistent post-concussive symptoms.

Safety monitoring and successful blinding are important features of randomized, blinded clinical trials. We report chamber- and protocol-related adverse events (AEs) for participants enrolled in two randomized, double-blind clinical trials of hyperbaric oxygen (HBO2) for persistent post-concussive symptoms clinicaltrials.gov identifiers NCT01306968, HOPPS, and NCT01611194, BIMA), as well as the success of maintaining the blind with a low-pressure sham control arm. In both studies, participants were randomized to receive HBO2 (1.5 atmospheres absolute, >99% oxygen) or sham chamber sessions (1.2 atmospheres absolute, room air). In 143 participants undergoing 4,245 chamber sessions, chamber-related adverse events were rare (1.1% in the HOPPS study, 2.2% in the BIMA study). Minor, non-limiting barotrauma was the most frequently reported. Rarely, some participants experienced headache with chamber sessions. No serious adverse events were associated with chamber sessions. An allocation questionnaire completed after intervention revealed that the sham control arm adequately protected the blind in both trials. Participants based allocation assumptions on symptom improvement or lack of symptom improvement and could not discern intervention arm by pressure, smell, taste, or gas flow.

A composite outcome for mild traumatic brain injury in trials of hyperbaric oxygen.

INTRODUCTION: Global outcomes can strengthen inferences from clinical trials. We evaluate global outcomes for persistent post-concussive symptoms (PCS) after mild traumatic brain injury (mTBI) in two clinical trials of hyperbaric oxygen (HBO2) in United States service members. METHODS: During study design, outcomes of symptom, cognitive, and functional impairments planned for a trial of HBO2 for PCS (HOPPS) were weighted and grouped into different domains to formulate the composite outcome total score. The composite outcome was compared between the intervention groups in HOPPS and those in a subsequent HBO2 trial (BIMA) for validation. Additionally, two post hoc global outcome measures were explored, including one composed of components that demonstrated favorable characteristics in both studies and another via components used in another TBI randomized trial (COBRIT). RESULTS: In total, 143 active-duty or veteran military personnel were randomized across the two studies. Composite total scores improved from baseline for HBO2 (mean ± SD -2.9±9.0) and sham (-2.9±6.6) groups in HOPPS but did not differ significantly between groups (p=0.33). In BIMA, 13-week changes from baseline favored the HBO2 group (-3.6±6.4) versus sham (-0.3±5.2; p=0.02). No between-group differences were found when COBRIT composite scoring was applied to BIMA. Overall, HBO2 effects were maximized when the post hoc global measure derived from both studies was applied to the data. CONCLUSIONS: Composite total scores in HOPPS and BIMA were consistent with primary study results. The global measures considered may offer utility as endpoints to achieve maximal HBO2 effect in future trials of the mTBI population. IDS: clinicaltrials.gov Identifiers NCT01611194 (BIMA) and NCT01306968 (HOPPS).

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.

Sleep assessment in a randomized trial of hyperbaric oxygen in U.S. service members with post concussive mild traumatic brain injury compared to normal controls.

STUDY OBJECTIVE: In this exploratory, double-blind, longitudinal sham-controlled trial of hyperbaric oxygen (HBO2) for military personnel with post concussive mild traumatic brain injury (mTBI), self-reports and objective measures of sleep-wake disturbances were assessed and compared to normals. METHODS: Self-reports consisting of Pittsburg Sleep Quality Index (PSQI), sleep diary, screening for obstructive sleep apnea (OSA) risk, restless legs syndrome (RLS), cataplexy, and objective actigraphic measures of sleep-wake were obtained on 71 military personnel with mTBI [baseline, 13 weeks and six months post-randomization (post-intervention)], of which 35 met post-traumatic stress disorder (PTSD) criteria, and 75 healthy volunteers (baseline). Baseline between-group and follow-up changes from baseline overall and within subgroups were evaluated. Mild TBI was defined as consisting of head injury associated loss of consciousness (<24 h), post-traumatic amnesia, and neurological deficits. RESULTS: Sleep quality by self-reports was markedly degraded in the mTBI group at baseline compared to a normative cohort; insomnia 87.3 versus 2.8%, OSA risk 70% versus 1.3%, RLS 32.4% versus and 2.7%. (all p-values <0.001), but actigraphy measures did not differentiate between groups. HBO2 compared to sham treatment improved self-reports of PSQI sleep measures, reports (five out of eight at 13-weeks and two out of eight at six-months). However, other sleep-wake measures were not different. CONCLUSIONS: Perceived sleep quality was markedly disrupted in mTBI military personnel and sleep-wake disturbances were prevalent compared to a normative cohort. HBO2 relative to sham improved some measures of sleep quality on the PSQI, but other measures of sleep were not significantly different.

Hyperbaric oxygen for post-concussive symptoms in United States military service members: a randomized clinical trial.

BACKGROUND: In prior military randomized trials, participants with persistent symptoms after mild traumatic brain injury (TBI) reported improvement regardless of receiving hyperbaric oxygen (HBO2) or sham intervention. This study's objectives were to identify outcomes for future efficacy trials and describe changes by intervention. METHODS: This Phase II, randomized, double-blind, sham-controlled trial enrolled military personnel with mild TBI and persistent post-concussive symptoms. Participants were randomized to receive 40 HBO2 (1.5 atmospheres absolute (ATA), ⟩99% oxygen, 60 minutes) or sham chamber sessions (1.2 ATA, room air, 60 minutes) over 12 weeks. Participants and evaluators were blinded to allocation. Outcomes assessed at baseline, 13 weeks and six months included symptoms, quality of life, neuropsychological, neurological, electroencephalography, sleep, auditory, vestibular, autonomic, visual, neuroimaging, and laboratory testing. Participants completed 12-month questionnaires. Intention-to-treat results are reported. RESULTS: From 9/11/2012 to 5/19/2014, 71 randomized participants received HBO2 (n=36) or sham (n=35). At baseline, 35 participants (49%) met post-traumatic stress disorder (PTSD) criteria. By the Neurobehavioral Symptom Inventory, the HBO2 group had improved 13-week scores (mean change -3.6 points, P=0.03) compared to sham (+3.9 points). In participants with PTSD, change with HBO2 was more pronounced (-8.6 vs. +4.8 points with sham, P=0.02). PTSD symptoms also improved in the HBO2 group, and more so in the subgroup with PTSD. Improvements regressed at six and 12 months. Hyperbaric oxygen improved some cognitive processing speed and sleep measures. Participants with PTSD receiving HBO2 had improved functional balance and reduced vestibular complaints at 13 weeks. CONCLUSIONS: By 13 weeks, HBO2 improved post-concussive and PTSD symptoms, cognitive processing speed, sleep quality, and balance function, most dramatically in those with PTSD. Changes did not persist beyond six months. Several outcomes appeared sensitive to change; additional studies are warranted.

Executive summary: The Brain Injury and Mechanism of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) Study.

The Brain Injury and Mechanism of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) study, sponsored by the Department of Defense and held under an investigational new drug application by the Office of the Army Surgeon General, is one of the largest and most complex clinical trials of hyperbaric oxygen (HBO2) for post-concussive symptoms (PCS) in U.S. military service members.

Hyperbaric oxygen for mild traumatic brain injury: Design and baseline summary.

The Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (mTBI) (BIMA) study, sponsored by the Department of Defense, is a randomized double-blind, sham-controlled clinical trial that has a longer duration of follow-up and more comprehensive assessment battery compared to recent HBO2 studies. BIMA randomized 71 participants from September 2012 to May 2014. Primary results are expected in 2017. Randomized military personnel received hyperbaric oxygen (HBO2) at 1.5 atmospheres absolute (ATA) or sham chamber sessions at 1.2 ATA, air, for 60 minutes daily for 40 sessions. Outcomes include neuropsychological, neuroimaging, neurological, vestibular, autonomic function, electroencephalography, and visual systems evaluated at baseline, immediately following intervention at 13 weeks and six months with self-report symptom and quality of life questionnaires at 12 months, 24 months and 36 months. Characteristics include: median age 33 years (range 21-53); 99% male; 82% Caucasian; 49% diagnosed post-traumatic stress disorder; 28% with most recent injury three months to one year prior to enrollment; 32% blast injuries; and 73% multiple injuries. This manuscript describes the study design, outcome assessment battery, and baseline characteristics. Independent of a therapeutic role of HBO2, results of BIMA will aid understanding of mTBI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Baseline neurological evaluations in a hyperbaric trial of post-concussive syndrome.

Standard neurologic examinations may not detect abnormalities in U.S. military service members with persistent post-concussive symptoms following mild traumatic brain injury. The Brain Injury and Mechanisms of Action of Hyperbaric Oxygen for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury Study (BIMA) enrolled 71 participants September 2012-May 2014. Participants received: comprehensive neurological and oculomotor exam; balance testing (Berg Balance Scale-BBS; Romberg Test-RT, Sharpened Romberg Test-SRT); olfactory function (Brief Smell Identification Test-BSIT). Two trained neurologists conducted the examinations at a central facility in Colorado Springs. Median age was 32 years (range 21-53), 99% male, 82% Caucasian, 49% PTSD, 28% most recent qualifying injury three months to one year prior to enrollment, 32% blast injuries only, and 73% multiple injuries. Some participants presented with abnormal facial sensation (15%), abnormal tandem gait (13%), and tremor (11%). 54% had abnormal near point of convergence (abnormal range 13-80 cm). 86% scored ≥ 55 on the BBS, with no participant scoring ⟨ 50. 49% scored ⟨ 30 seconds on the best trial of the SRT. RT was abnormal in 10%. 15% of participants scored ≤ 9 (out of 12) on BSIT, about twice what is expected in a normal population. The neurological examination found abnormalities across a range of testing, with convergence insufficiency and SRT having the most sensitivity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Baseline EEG abnormalities in mild traumatic brain injury from the BIMA study.

The Brain Injury and Mechanisms of Action of HBO2 for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (BIMA), sponsored by the Department of Defense, is a randomized, double-blind, sham-controlled trial of hyperbaric oxygen (HBO2) in service members with persistent post-concussive symptoms following mild TBI, undergoing comprehensive assessments. The clinical EEG was assessed by neurologists for slow wave activity, ictal/interictal epileptiform abnormalities, and background periodic discharges. There is scant literature about EEG findings in this population, so we report baseline clinical EEG results and explore associations with other evaluations, including demographics, medication, neurological assessments, and clinical MRI outcomes. Seventy-one participants were enrolled: median age 32 years, 99% male, 49% comorbid PTSD, 28% with mTBI in the previous year, 32% blast injuries only, and 73% multiple injuries. All participants reported medication use (mean medications = 8, SD = 5). Slowing was present in 39%: generalized 37%, localized 8%, both 6%. No other abnormalities were identified. Slowing was not significantly associated with demographics, medication or neurological evaluation. Participants without EEG abnormalities paradoxically had significantly higher number of white matter hyperintensities as identified on MRI (p = 0.003). EEG slowing is present in more than one-third of participants in this study without evidence of associations with demographics, medications or neurological findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Neuropsychological assessments in a hyperbaric trial of post-concussive symptoms.

Results of studies addressing the effect of mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) on symptoms and neuropsychological assessments are mixed regarding cognitive deficits in these populations. Neuropsychological assessments were compared between U.S. military service members with mTBI only (n=36) vs. those with mTBI÷ PTSD (n=35) from a randomized interventional study of mTBI participants with persistent post-concussive symptoms (PCS). The mTBI group endorsed worse symptoms than published norms on PCS, PTSD and pain scales (⟩50% abnormal on Neurobehavioral Symptom Inventory (NSI), PTSD Checklist-Civilian, McGill Pain Questionnaire-Short Form) and some quality of life domains. Worse symptom reporting was found in the mTBI÷ PTSD group compared to mTBI (e.g., mean NSI total score in mTBI 27.5 (SD=12.7), mTBI÷ PTSD 39.9 (SD=13.6), p⟨0.001). The mTBI÷PTSD group performed worse than mTBI on the Weschler Adult Intelligence Scale digit span (mean difference -1.5, 95% CI[-2.9,-0.1], p=0.04) and symbol search (mean difference -1.5, 95% CI[-2.7,-0.2], p=0.03) and Grooved Pegboard (dominant hand mean difference -7.0, 95% CI[-11.5,-2.4], p=0.003; non-dominant mean difference -9.8, 95% CI[-14.9,-4.7], p⟨0.001). Differences were detected in ANAM simple reaction time (p=0.04) and mathematical processing (p=0.03) but not verbal fluency or visuospatial memory assessments. Results indicate increased symptom severity and some cognitive deficits in mTBI÷ PTSD compared to mTBI alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

The relationship of dietary omega-3 long-chain polyunsaturated fatty acid intake with incident age-related macular degeneration: AREDS report no. 23.

OBJECTIVE: To examine the association of dietary omega-3 long-chain polyunsaturated fatty acid and fish intake with incident neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA). METHODS: Multicenter clinic-based prospective cohort study from a clinical trial including Age-Related Eye Disease Study (AREDS) participants with bilateral drusen at enrollment. Main outcome measures were incident neovascular AMD and CGA, ascertained from annual stereoscopic color fundus photographs (median follow-up, 6.3 years). We estimated nutrient and food intake from a validated food frequency questionnaire (FFQ) at baseline, with intake of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), combined EPA and DHA, and fish as primary exposures. RESULTS: After controlling for known covariates, we observed a reduced likelihood of progression from bilateral drusen to CGA among people who reported the highest levels of EPA (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.87) and EPA+DHA (OR, 0.45; 95% CI, 0.23-0.90) consumption. Levels of DHA were associated with CGA in age-, sex-, and calorie-adjusted models (OR, 0.51; 95% CI, 0.26-1.00); however, this statistical relationship did not persist in multivariable models. CONCLUSIONS: Dietary lipid intake is a modifiable factor that may influence the likelihood of developing sight-threatening forms of AMD. Our findings suggest that dietary omega-3 long-chain polyunsaturated fatty acid intake is associated with a decreased risk of progression from bilateral drusen to CGA.

Cataract classification using serial examinations in the age-related eye disease study: age-related eye disease study report no. 24.

PURPOSE: To describe use of serial lens examinations to assign cataract phenotype in the Age-Related Eye Disease Study (AREDS). DESIGN: Cohort study. METHODS: Lens photographs were graded annually using the AREDS system for classifying cataracts. Nuclear grades (0.9 to 6.1) were assigned using standard photographs. Percentage of pupillary involvement was used to assign cortical and posterior subcapsular grades. Cutpoints were established for the presence or absence of each type of opacity (absent<4.0 for nuclear, <10% for cortical, and <5% of central 5 mm for posterior subcapsular). An algorithm weighted for grades at the last three examinations was used to assign cataract phenotype. Separately, cataract phenotype was assigned as grade predicted at final visit by linear regression of serial grades. Results from the two approaches were compared and final person phenotypes were established. These person cataract phenotype assignments were compared with phenotype assignments based on the last serial grade alone. RESULTS: Four thousand six hundred and twenty-eight AREDS participants aged 55 to 80 years at baseline had median follow-up of 10.6 years. Person phenotype assignments agreed for the two approaches in 4,557 (98.5%) participants after some algorithmic adjudication. Phenotypes were no cataract (n=1,418), nuclear (n=1,287), cortical (n=1,396), posterior subcapsular (n=541), cataract surgery and no specific opacity type (n=335), and questionable (n=426). Phenotype assignments based on serial grades and on last examination alone were in good agreement. CONCLUSIONS: Serial lens photographs obtained over a 10-year period were used to provide a robust assignment of cataract phenotype. Well-characterized cataract phenotypes are of importance as genetic studies of the AREDS cohort are considered.

The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20.

OBJECTIVE: To evaluate the association of lipid intake with baseline severity of age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). METHODS: Age-Related Eye Disease Study participants aged 60 to 80 years at enrollment (N = 4519) provided estimates of habitual nutrient intake through a self-administered semiquantitative food frequency questionnaire. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with <15 small drusen). RESULTS: Dietary total omega-3 long-chain polyunsaturated fatty acid (LCPUFA) intake was inversely associated with neovascular (NV) AMD (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.41-0.90), as was docosahexaenoic acid, a retinal omega-3 LCPUFA (OR, 0.54; 95% CI, 0.36-0.80), comparing highest vs lowest quintile of intake, after adjustment for total energy intake and covariates. Higher fish consumption, both total and broiled/baked, was also inversely associated with NV AMD (OR, 0.61; 95% CI, 0.37-1.00 and OR, 0.65; 95% CI, 0.45-0.93, respectively). Dietary arachidonic acid was directly associated with NV AMD prevalence (OR, 1.54; 95% CI, 1.04-2.29). No statistically significant relationships existed for the other lipids or AMD groups. CONCLUSION: Higher intake of omega-3 LCPUFAs and fish was associated with decreased likelihood of having NV AMD.

Potential public health impact of Age-Related Eye Disease Study results: AREDS report no. 11.

OBJECTIVE: To estimate the potential public health impact of the findings of the Age-Related Eye Disease Study (AREDS) on reducing the number of persons developing advanced age-related macular degeneration (AMD) during the next 5 years in the United States. METHODS: The AREDS clinical trial provides estimates of AMD progression rates and of reduction in risk of developing advanced AMD when a high-dose nutritional supplement of antioxidants and zinc is used. These results are applied to estimates of the US population at risk, to estimate the number of people who would potentially avoid advanced AMD during 5 years if those at risk were to take a supplement such as that used in AREDS. RESULTS: An estimated 8 million persons at least 55 years old in the United States have monocular or binocular intermediate AMD or monocular advanced AMD. They are considered to be at high risk for advanced AMD and are those for whom the AREDS formulation should be considered. Of these people, 1.3 million would develop advanced AMD if no treatment were given to reduce their risk. If all of these people at risk received supplements such as those used in AREDS, more than 300,000 (95% confidence interval, 158,000-487,000) of them would avoid advanced AMD and any associated vision loss during the next 5 years. CONCLUSION: If people at high risk for advanced AMD received supplements such as those suggested by AREDS results, the potential impact on public health in the United States would be considerable during the next 5 years.

Who should receive oral supplement treatment for age-related macular degeneration?

Oxidative damage to the retina has been proposed as a risk factor for age-related macular degeneration (AMD). Dietary or supplemental antioxidants may play a protective role. The Age-Related Eye Disease Study (AREDS), a randomized, multicenter, placebo-controlled clinical trial designed to test the effect of pharmacologic doses of antioxidants and zinc on the incidence and progression of AMD, reported a beneficial effect of high-dose supplements, taken for approximately 6 years, in delaying the progression of intermediate AMD to advanced AMD. AREDS and subsequent research on dietary intake or supplement use have not indicated a protective role of antioxidant or zinc intake or supplement use in the incidence or prevalence of early AMD. Numbers of cases were insufficient to investigate effects on late AMD. Persons with intermediate AMD and without contraindications should consider using antioxidant and zinc supplements. There is no evidence to date that earlier use conveys benefit.