Neuro News Roundup: TBI Awareness Month

In recent months, the NeurologyLive® team has been covering the news on the latest updates in the clinical care of individuals with neuromuscular disorders, multiple sclerosis, movement disorders, sleep disorders, and more.

For Traumatic Brain Injury Month — March 2023 —the team has culminated some of the biggest pieces of news to offer updates on new developments in literature in brain injury to spread awareness on the prevention and treatment of concussions.

Click here for more coverage of the latest news from NeurologyLive®.

Latest Literature

Day-of-injury Plasma GFAP and UCH-L1 Predict Functional Recovery After Traumatic Brain Injury

In a recent observational cohort study, Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI; NCT02119182), a significant increase in the prognostic accuracy of the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) models was displayed for patients with traumatic brain injury, demonstated by Glasgow Coma Scale (GCS) score of 3 to 12.¹

From the participants with brain injury (n = 1696) at baseline and 6 months, 7.1% died (n = 120), 13.9% had an unfavorable outcome (n= 235), 66.9% had an incomplete recovery (n = 1135), and 33.1% had recovered fully (n = 561).¹ The corresponding area under the curve (ACU) for ubiquitin C-terminal hydrolase L1 (UCH-L1) were 0.89 (95% CI, 0.86-0.92) for predicting death, 0.86 (95% CI, 0.84-0.89) for unfavorable outcome, and 0.61 (95% CI, 0.59-0.64) for incomplete recovery at 6 months.

The study enrolled 2552 patients from the TRACK-TBI observational cohort study from Feb 26, 2014, to Aug 8, 2018, who were 17 years and older and evaluated for TBI at a US level 1 trauma centers. The analysis included participants who had day-of-injury plasma samples for measurement of GFAP and UCH-L1 and completed 6-month assessments with the Glasgow Outcomes Scale-Extended (GOSE-TBI) because of traumatic brain injury.

All told, the AUC of GFAP for predicting death at 6 months in all patients was 0.87 (95% CI, 0.83-0.91), for unfavorable outcome was 0.86 (95% CI, 0.83-0.89), and for incomplete recovery was 0.62 (95% CI, 0.59-0.64). AUCs were higher for participants with traumatic brain injury and GCS score of 3–12 than for those with GCS score of 13-15. Among participants with GCS score of 3 to 12 (n = 353), added with the GFAP and/or UCH-L1 to each of the 2 IMPACT in traumatic brain injury models significantly increased AUCs for predicting death (range, 0.90-0.94) and unfavorable outcome (range, 0.83-0.89).

Concussion Treatment PRV-002 Demonstrates Safe, Tolerable Profile in Phase 1 Trial

According to a recent announcement, Odyssey Health’s investigational agent PRV-002, a fully synthetic nonnaturally occurring neurosteroid intended to treat concussion, was safe and tolerated in a small cohort of healthy volunteers. The company is currently selecting clinical sites and developing the Investigator’s Brochure for an upcoming phase 2 trial.²

In total, the phase 1 trial was designed with 6 cohorts comprised of 8 individuals each, with data expected to be reported after each cohort is completed. In cohort 1 of the multiday ascending dose (MAD) trial, 8 healthy human volunteers were randomly assigned 1:1 to ether 1 dose of PRV-003 or placebo for 5 consecutive days. Evaluated by the Safety Review Committee, no serious adverse events were recorded, and all patients demonstrated normal vital signs, electrocardiogram readings, and breathing function.

Conducted at Nucleus Network for each of the 5 days of dosing, pharmacokinetic analysis showed a direct relationship between drug dosing concentration and blood plasma levels. Additionally, blood levels of the active drug were significantly lower on average with intranasal administration than what would be expected with other routes of delivery. Furthermore, there was no appreciable accumulation of PRV-003 with consecutive day treatments, as well as no alterations in blood samples using multiday treatment.

No Evidence of Connection Between Traumatic Brain Injury, PTSD and Elevated Alzheimer-Related Biomarkers

Data from a recently published study in Alzheimer’s & Dementia showed no association between increased levels of Alzheimer disease (AD)-related biomarkers and veterans exposed to traumatic brain injury (TBI) and/or posttraumatic stress disorder (PSTD). Patients with TBI, PTSD, and/or both demonstrated poorer cognitive status; however, investigators believed that may have been attributable to other comorbid pathologies.³

The study included 289 nondemented veterans with either PSTD (n = 81), TBI (n = 43), or TBI and PTSD (n = 93), as well as controls (n = 71) who were followed up for up to 5.2 years. Each patient underwent clinical evaluation, cerebrospinal fluid (CSF) collection, MRI, amyloid-ß and tau PET, and apolipoprotein ε testing.

Controls were demographically comparable and service-connected for conditions other than TBI-related injuries or PTSD, and had no record of TBI or PTSD before, during, or after the Vietnam War (1955-1975). Demographically, there was a difference in frequency of mild cognitive impairment (MCI) among the groups, with each of the exposure groups associated with higher frequency of MCI than of controls (P <.001). Additionally, the number of errors on the Mini-Mental State Examination (MMSE) differed between the groups (P = .03), with PTSD (P = .008) and both TBI and PTSD (P = .009) groups having more errors than control group, both of which remained significant after Tukey-Kramer adjustment for multiple comparisons.

Decompressive Craniectomy Shows Greater Improvements in Traumatic Intracranial Hypertension Than Standard Treatment

Results from a secondary analysis of the RESCUEicp randomized clinical trial (ISRCTN66202560) showed better sustained reductions in mortality and higher rates of vegetative state, severe disability, and moderate disability at 24 months in those with traumatic intracranial hypertension treated with decompressive craniectomy over standard medical care.⁴

For every 100 patients treated with surgical rather than medical intent, 21 additional patients survived at 24 months (4 were in vegetative state, 2 had lower and 7 had upper severe disability, and 5 had lower and 3 had upper moderate disability). The study investigators concluded that these findings support the use and potential benefit of decompressive craniectomy in long-term follow-up for traumatic brain injury (TBI) clinical trials.

Investigators randomly assigned 408 patients with traumatic intracranial hypertension (>25 mm Hg) to either decompressive craniectomy with standard care or to ongoing medical treatment with the option to add barbiturate infusion. At 6 and 24 months, investigators assessed patients using the 8-point Extended Glasgow Outcome Scale (GOS-E), with 1 indicating death and 8 denoting upper good recovery.

In comparison, 45.1% of those in the surgical group vs 31.0% of those in the medical group had a GOS-E outcome of upper severe disability or better (X2 = 7.41; P = .006), according to sensitivity analyses. Using Dunn-Bonferroni post-hoc testing, investigators found significant differences between the 6- and 24-month GOS-E outcomes in the surgical group (P = .004), but no other between-group significant differences at any other time points.

Risk Factors Identified in TBI for Early Posttraumatic Seizures, Posttraumatic Epilepsy

Newly published data from a large cohort study identified multiple clinical risk factors of traumatic brain injury (TBI) that may be used to predict early posttraumatic seizures (EPS), specifically the presence of prior medical comorbidities, subarachnoid hemorrhage (SAH) and subdural hemorrhage (SDH), and injury severity.⁵

In addition to these risk factors, investigators concluded that EPS were associated with significant in-hospital mortality, poorer outcomes, and subsequent risk of mortality at 24 months on follow-up Glasgow Outcome Scale-Extended (GOS-E) score. In total, the long-term mortality rate was 14% (n = 1658) for the group of patients without EPS and 24% (n = 76) for patients who had EPS (P <.001).

The final sample pulled from an Australian statewide registry included 15,152 patients with moderate to severe TBI, defined as Abbreviated Injury Scale (AIS) head severity score of 3 to 6. Of that cohort, 2.7% (n = 416) of patients had EPS, identified via International Statistical Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM)codes. The gathered cohort was used to evaluate risk factors for EPS, associated morbidity and mortality, and contribution to posttraumatic epilepsy (PTE). Conducted using patients from 2005 to 2019, the incidence of EPS decreased each year (incidence rate ratio, 0.94; 95% CI, 0.92-0.96; P <.001). Of patients with EPS, 6.5% experienced status epilepticus (0.2% of all cases).

Demographically, patients who experienced EPS were older than those who did not (median, 69 years [IQR, 44-81] vs 60 years [IQR, 35-79]). Factors such as sex, service accessibility and rurality, preexisting mental health conditions and drug misuse, or socioeconomic status had no association with EPS. Individuals with EPS demonstrated a higher Clinical Global Impression (CGI) score and had associations with preexisting alcohol misuse.

REFERENCES
1. Korley FK, Jain S, Sun X, et al. Prognostic value of day-of-injury plasma GFAP and UCH-L1 concentrations for predicting functional recovery after traumatic brain injury in patients from the US TRACK-TBI cohort: an observational cohort study. Lancet Neurol. 2022;21(9):803-813. doi:10.1016/S1474-4422(22)00256-3
2. dyssey Health achieves positive safety outcomes for concussion drug in multiple ascending dosing trial. Odyssey Health. August 18, 2022. Accessed March 30, 2023. https://www.globenewswire.com/news-release/2022/08/18/2500777/0/en/Odyssey-Health-Achieves-Positive-Safety-Outcomes-for-Concussion-Drug-in-Multiple-Ascending-Dosing-Trial.html
3. Weiner MW, Harvey D, Landau SM, et al. Traumatic brain injury and post-traumatic stress disorder are not associated with Alzheimer’s disease pathology measured with biomarkers. Alzheimers Dement. Published online June 29, 2022. doi:10.1002/alz.12712
4. Kolias AG, Adams H, Timofeev IS, et al. Evaluation of outcomes among patients with traumatic intracranial hypertension treated with decompressive craniectomy vs standard medical care at 24 months: a secondary analysis of the RESCUEicp randomized clinical trial. JAMA Neurol. Published online June 6, 2022. doi:10.1001/jamaneurol.2022.1070.
5. Laing J, Gabbe B, Chen Z, et al. Risk factors and prognosis of early posttruamtic seizures in moderate to severe traumatic brain injury. JAMA Neurol. 2022;79(4):334-341. doi:10.1001/jamaneurol.2021.5420