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This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article.

The tenets of neurosurgery worldwide, whether in the civilian or military sector, espouse vigilance, the ability to adapt, extreme ownership, and, of course, an innate drive for developing a unique set of technical skills. At a time in history when the complexity of battlefield neurotrauma climaxed coupled with a chronic shortage of military neurosurgeons, modernized solutions were mandated in order to deliver world-class neurological care to our servicemen and servicewomen. Complex blast injuries, as caused by an increased incidence of improvised explosive devices, yielded widespread systemic inflammatory responses with multiorgan damage. In response to these challenges, the "NeuroTeam," originally a unit of two neurosurgeons as deployed during Operation Desert Storm, was redesigned to instead pair a neurosurgeon with a neurointensivist and launched itself during two specialized missions in Operations Iraqi Freedom and Enduring Freedom. Representing a hybridized version of present-day neurocritical care teams, the purpose of this unit was to optimize neurosurgical care by focusing on interdisciplinary collaboration in an Echelon III combat support hospital. The NeuroTeam provided unique workflow capabilities never seen collectively on the battlefield: downrange neurosurgical capability by a board-certified neurological surgeon within 60 minutes from the point of injury paired with a neurocritical care–trained intensivist. This also set the stage for intraoperative telemedicine infrastructure for neurosurgery and optimized the ability to evaluate, triage, and stabilize patients prior to medical evacuation. This novel military partnership ultimately allowed the neurosurgeon to focus on the tenets of the craft and thereby the dynamic needs of the patient first and foremost. Since the success of these missions, the NeuroTeam has evolved into a detachable unit, the "Head and Neck Team," comprising neurosurgeons, otolaryngologists, and ophthalmologists, supported by a postinjury hospital unit, which includes an embedded neurocritical care physician. The creation and evolution of the NeuroTeam, necessitated by a shortage of military neurosurgeons and the dangerous shift in military wartime tactics, best exemplifies multidisciplinary collaboration and military medicine agility. As neurocritical care continues to evolve into a highly complex, distinct specialty, the lessons learned by the NeuroTeam ultimately serve as a reminder for civilian and military physicians alike. Despite the conditions and despite one’s professional ego, patients with highly complex morbid neurological disease deserve expert, multidisciplinary management for survival.

Operation Desert Storm (ODS) was an astounding success for combat arms and logistical units of the US Military. In contrast, Department of Defense (DOD) medical units struggled to keep pace with combat operations and were fortunate that casualty estimates for a Cold War–era battle failed to materialize. The medical support plan included a large contingent of active-duty and reserve neurosurgeons in anticipation of care requirements for more than 500,000 deploying service members engaged in a large-scale combat operation. Here, the authors review the clinical experience and operational challenges encountered by neurosurgeons deployed in support of this conflict and discuss legacies of ODS for both surgeons and the military medical system.

Traumatic brain injury (TBI) is a common casualty of war. In Operation Iraqi Freedom and Operation Enduring Freedom in Afghanistan, TBI was described as the “signature injury of these wars.” As in civilian practice, severe TBI is a serious life-threatening medical condition requiring treatment by expert medical providers. Military providers adapt existing civilian clinical practice guidelines (CPG) to manage these patients. Where civilian CPG are nonexistent or inadequate for war theater use, the DoD creates new ones. These CPG are published to enable critique and improvement. Two CPG for TBI to come from the war are the “Guidelines for the Field Management of Combat-Related Head Trauma” and the “VA/DoD Clinical Practice Guidelines for Management of Concussion/Mild TBI.” From these efforts, a new type of TBI, explosive blast TBI, was elucidated. Intracranial vasospasm was identified as a sequelae to this TBI. Treatments used by military healthcare providers include hemicraniectomy and endovascular techniques.

Military medical providers rely on civilian medical research to advanced care. The clinical practice guidelines developed for civilian practice is used by the military. Similarly, the same journals, expert panel reviews, and so on are all used by military medicine. However, due largely to limited civilian interest, there are specific medical conditions for which the Department of Defense (DoD) must itself conduct or sponsor. Examples of these conditions are hemorrhagic shock, explosive blast traumatic brain, malaria, and others. For many military patients, the highest level of care will be a medic, who may be required to render care for prolonged periods when evacuation is not possible. For these, the DoD will develop research programs that are conducted either by funding civilian medical scientists or engaging intramural DoD scientists. Importantly, the ethics and other rules of conduct regulating civilian medical research apply equally to the military scientists. These include all the typical human subject informed consent, animal use protocols, and review board approvals. For any human subject work done on behalf of the DoD, a second level of Human Use approval is required. DoD supported medical research, whether conducted on behalf of military or civilian patients, is meant to benefit everyone.

The potential relationship between chronic traumatic encephalopathy (CTE) and head injuries such as blast-related traumatic brain injury (TBI) is an important area of study, particularly for military and contact sports populations, yet little is known about this relationship. To address this topic, the Department of Defense (DoD) Blast Injury Research Program Coordinating Office organized the 2015 International State-of-The-Science Meeting, which brought together subject matter experts from the DoD, other federal agencies, academia, industry, foreign allies, and the sports community. Over the course of the meeting, this community of experts reached a consensus regarding the current body of knowledge and the future of the field. The overarching finding was that there is insufficient existing scientific evidence to link blast-related TBI with CTE. The meeting's Expert Panel also agreed on 13 additional findings describing research and knowledge gaps, clinical gaps, and research opportunities that, if addressed with focused effort, would further the understanding of the relationship between blast-related TBI and CTE. To this end, the Expert Panel also developed six recommendations for advancing research, each with short-and long-Term goals. Among the six recommendations, the Expert Panel identified the first four as highest priority for addressing pressing research needs. These four high-priority recommendations include, in order of priority: (1) more collection and study of clinical neuropathology samples, (2) standardization of clinical diagnostic criteria, (3) development of clinically appropriate and standardized animal models, and (4) development of noninvasive serial assessment strategies (i.e., imaging or biospecimen biomarkers). © Copyright 2017, Mary Ann Liebert, Inc. 2017.

Up to 19% of veterans returning from the wars in Iraq and Afghanistan have a history of mild traumatic brain injury with 70% associated with blast exposure. Tragically, 20-50% of this group reports persistent symptoms, including memory loss. Unfortunately, routine clinical imaging is typically normal, making diagnosis and clinical management difficult. The goal of this work was to develop methods to acquire hippocampal MRSI at 7 T and evaluate their sensitivity to detect injury in veterans with mild traumatic brain injury.At 7 T, hippocampal MRSI measurements are limited by: (1) poor B(0) homogeneity; (2) insufficient B(1)(+) strength and homogeneity; and (3) chemical shift dispersion artifacts. To overcofme these limitations we: (1) used third degree B(0) shimming; (2) an inductively decoupled transceiver array with radiofrequency shimming; and (3) a volume localized single slice sequence using radiofrequency shimming-based outer volume suppression.In 20 controls and 25 veterans with mild traumatic brain injury due to blast exposure with memory impairment, hippocampal N-acetyl aspartate to choline (P0.001) and N-acetyl aspartate to creatine (P0.001) were decreased in comparison to control subjects.With the appropriate methods robust spectroscopic imaging of the hippocampus can be carried out at 7 T. MRSI at 7 T can detect hippocampal injury in veterans with mild traumatic brain injury.

Time-dependent changes of protein biomarkers in the cerebrospinal fluid (CSF) can be used to identify the pathological processes in traumatic brain injury (TBI) as well as to follow the progression of the disease. We obtained CSF from a large animal model (swine) of blast-induced traumatic brain injury prior to and at 6, 24, 72 h, and 2 wk after a single exposure to blast overpressure, and determined changes in the CSF levels of neurofilament-heavy chain, neuron-specific enolase, brain-specific creatine kinase, glial fibrillary acidic protein, calcium-binding protein β (S100β), Claudin-5, vascular endothelial growth factor, and von Willebrand factor using reverse phase protein microarray. We detected biphasic temporal patterns in the CSF concentrations of all tested protein markers except S100β. The CSF levels of all markers were significantly increased 6 h after the injury compared to preinjury levels. Values were then decreased at 24 h, prior to a second increase in all markers but S100β at 72 h. At 2 wk postinjury, the CSF concentrations of all biomarkers were decreased once again; brain-specific creatine kinase, Claudin-5, von Willebrand factor, and S100β levels were no longer significantly higher than their preinjury values while neurofilament-heavy chain, neuron-specific enolase, vascular endothelial growth factor, and glial fibrillary acidic protein levels remained significantly elevated compared to baseline. Our findings implicate neuronal and glial cell damage, compromised vascular permeability, and inflammation in blast-induced traumatic brain injury, as well as demonstrate the value of determining the temporal pattern of biomarker changes that may be of diagnostic value.

PURPOSE: Rituximab has been reported to have little activity in small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) and to be associated with significant infusion-related toxicity. This study sought to decrease the initial toxicity and optimize the pharmacokinetics with an alternative treatment schedule. PATIENTS AND METHODS: Thirty three patients with SLL/CLL received dose 1 of rituximab (100 mg) over 4 hours. In cohort I (n = 3; 250 mg/m2) and cohort II (n = 7; 375 mg/m2) rituximab was administered on day 3 and thereafter three times weekly for 4 weeks using a standard administration schedule. Cohort III (n = 23; 375 mg/m2) administered rituximab similar to cohort II for the first two treatments and then over 1 hour thereafter. RESULTS: A total of 33 CLL/SLL patients were enrolled; only one patient discontinued therapy because of infusion-related toxicity. Thirteen patients developed transient hypoxemia, hypotension, or dyspnea that were associated with significant changes in baseline interleukin-6, interleukin-8, tumor necrosis factor alpha, and interferon gamma compared with those not experiencing such reactions. Infusion-related toxicity occurred more commonly in older (median age 73 v 62 years; P = .02) patients with no other pretreatment clinical or laboratory features predicting occurrence of these events. The overall response rate was 45% (3% CR, 42% PR; 95% CI 28% to 64%). Median response duration for these 15 patients was 10 months (95% CI, 6.8-13.2; range, 3 to 17+). CONCLUSION: Rituximab administered thrice weekly for 4 weeks demonstrates clinical efficacy and acceptable toxicity. Initial infusion-related events seem to be cytokine mediated and resolve by the third infusion making rapid administration possible. Future combination studies of rituximab with other therapies in CLL seem warranted.