High-Dose Intravenous Ascorbic Acid: Ready for Prime Time in Traumatic Brain Injury?

Traumatic brain injury (TBI) is one of the leading public health problems in the USA and worldwide. It is the number one cause of death and disability in children and adults between ages 1-44. Despite efforts to prevent TBIs, the incidence continues to rise. Secondary brain injury occurs in the first hours and days after the initial impact and is the most effective target for intervention. Inflammatory processes and oxidative stress play an important role in the pathomechanism of TBI and are exacerbated by impaired endogenous defense mechanisms, including depletion of antioxidants. As a reducing agent, free radical scavenger, and co-factor in numerous biosynthetic reactions, ascorbic acid (AA, vitamin C) is an essential nutrient that rapidly becomes depleted in states of critical illness. The administration of high-dose intravenous (IV) AA has demonstrated benefits in numerous preclinical models in the areas of trauma, critical care, wound healing, and hematology. A safe and inexpensive treatment, high-dose IV AA administration gained recent attention in studies demonstrating an associated mortality reduction in septic shock patients. High-quality data on the effects of high-dose IV AA on TBI are lacking. Historic data in a small number of patients demonstrate acute and profound AA deficiency in patients with central nervous system pathology, particularly TBI, and a strong correlation between low AA concentrations and poor outcomes. While replenishing deficient AA stores in TBI patients should improve the brain's ability to tolerate oxidative stress, high-dose IV AA may prove an effective strategy to prevent or mitigate secondary brain injury due to its ability to impede lipid peroxidation, scavenge reactive oxygen species, suppress inflammatory mediators, stabilize the endothelium, and reduce brain edema. The existing preclinical data and limited clinical data suggest that high-dose IV AA may be effective in lowering oxidative stress and decreasing cerebral edema. Whether this translates into improved clinical outcomes will depend on identifying the ideal target patient population and possible treatment combinations, factors that need to be evaluated in future clinical studies. With its excellent safety profile and low cost, high-dose IV AA is ready to be evaluated in the early treatment of TBI patients to mitigate secondary brain injury and improve outcomes.

Traumatic Brain Injury in Select Low- and Middle-Income Countries: A Narrative Review of the Literature.

Low- and middle-income countries (LMICs) experience the majority of traumatic brain injuries (TBIs), yet few studies have examined the epidemiology and management strategies of TBI in LMICs. The objective of this narrative review is to discuss the epidemiology of TBI within LMICs, describe the adherence to Brain Trauma Foundation (BTF) guidelines for the management of severe TBI in LMICs, and document TBI management strategies currently used in LMICs. Articles from January 1, 2009 to September 30, 2021 that included patients with TBI greater than 18 years of age in low-, low middle-, and high middle-income countries were queried in PubMed. Search results demonstrated that TBI in LMICs mostly impacts young males involved in road traffic accidents. Within LMICs there are a myriad of approaches to managing TBI with few randomized controlled trials performed within LMICs to evaluate those interventions. More studies are needed in LMICs to establish the effectiveness and appropriateness of BTF guidelines for managing TBI and to help identify methods for managing TBI that are appropriate in low-resource settings. The problem of limited pre- and post-hospital care is a bigger challenge that needs to be considered while addressing management of TBI in LMICs.

A standardized test battery for the study of synesthesia.

Synesthesia is an unusual condition in which stimulation of one modality evokes sensation or experience in another modality. Although discussed in the literature well over a century ago, synesthesia slipped out of the scientific spotlight for decades because of the difficulty in verifying and quantifying private perceptual experiences. In recent years, the study of synesthesia has enjoyed a renaissance due to the introduction of tests that demonstrate the reality of the condition, its automatic and involuntary nature, and its measurable perceptual consequences. However, while several research groups now study synesthesia, there is no single protocol for comparing, contrasting and pooling synesthetic subjects across these groups. There is no standard battery of tests, no quantifiable scoring system, and no standard phrasing of questions. Additionally, the tests that exist offer no means for data comparison. To remedy this deficit we have devised the Synesthesia Battery. This unified collection of tests is freely accessible online (http://www.synesthete.org). It consists of a questionnaire and several online software programs, and test results are immediately available for use by synesthetes and invited researchers. Performance on the tests is quantified with a standard scoring system. We introduce several novel tests here, and offer the software for running the tests. By presenting standardized procedures for testing and comparing subjects, this endeavor hopes to speed scientific progress in synesthesia research.

Medical management of epileptic seizures: challenges and solutions.

Epilepsy is one of the most common neurologic illnesses. This condition afflicts 2.9 million adults and children in the US, leading to an economic impact amounting to $15.5 billion. Despite the significant burden epilepsy places on the population, it is not very well understood. As this understanding continues to evolve, it is important for clinicians to stay up to date with the latest advances to provide the best care for patients. In the last 20 years, the US Food and Drug Administration has approved 15 new antiepileptic drugs (AEDs), with many more currently in development. Other advances have been achieved in terms of diagnostic modalities like electroencephalography technology, treatment devices like vagal nerve and deep-brain stimulators, novel alternate routes of drug administration, and improvement in surgical techniques. Specific patient populations, such as the pregnant, elderly, those with HIV/AIDS, and those with psychiatric illness, present their own unique challenges, with AED side effects, drug interactions, and medical-psychiatric comorbidities adding to the conundrum. The purpose of this article is to review the latest literature guiding the management of acute epileptic seizures, focusing on the current challenges across different practice settings, and it discusses studies in various patient populations, including the pregnant, geriatric, those with HIV/AIDS, comatose, psychiatric, and "pseudoseizure" patients, and offers possible evidence-based solutions or the expert opinion of the authors. Also included is information on newer AEDs, routes of administration, and significant AED-related drug-interaction tables. This review has tried to address only some of these issues that any practitioner who deals with the acute management of seizures may encounter. The document also highlights the numerous avenues for new research that would help practitioners optimize epilepsy management.

An Outcome Model for Intravenous rt-PA in Acute Ischemic Stroke.

Most early phase trials in stroke and brain trauma have failed in phase 3, including efforts to improve acute ischemic stroke outcomes beyond that achieved by intravenous recombinant tissue plasminogen activator (t-PA) (IVT). With the exception of more recent stent retriever trials, most subsequent phase 3 trials failed. We previously showed that baseline imbalances, non-linear relationships of these factors to outcome, and unrepresentative control populations invalidate traditional statistical analysis in early trials of heterogeneous diseases such as stroke. We developed an alternative approach using a pooled outcome model derived from control arms of randomized clinical trial (RCTs). This model then permits comparing treatment trials to an expected outcome of a pooled population. Here, we hypothesized we could develop such a model for IVT and tested it against outcomes without IVT. We surveyed literature for all trials involving one arm with IVT reporting baseline National Institute Stroke Scale (NIHSS), age, and outcome. A non-linear fit was performed including multi-dimensional statistical intervals (±95 %) permitting visual comparison of outcomes at their own baselines. We compared models derived from non-IVT control arms. Models from 24 IVT RCTs representing 3195 subjects were successfully generated for functional outcome, modified Rankin Scale (mRS) 0-2 (r(2) = 0. 83, p < 0.001), and mortality (r(2) = 0.54; p = 0.001). We confirmed better outcomes compared to no IVT and mixed use IVT models across the range of baseline factors. It was possible to generate an expected outcome model for IVT from existing literature. We confirmed benefit compared to placebo. This model should be useful to compare to new agents without the need for statistical manipulation.

Primary Sjogren's syndrome presenting as acute cerebellitis.

A 64-year-old previously healthy man presented with acute ataxia. He was diagnosed with acute cerebellitis on the basis of clinical features, negative MRI of the head and lymphocytic pleocytosis in cerebrospinal fluid. A detailed work up for etiology revealed auto-antibodies for Sjogren's syndrome. He responded well to cyclophosphamide and steroids.

Hyperglycemia worsens outcome after rt-PA primarily in the large-vessel occlusive stroke subtype.

Hyperglycemia at the time of ischemic stroke has been associated with poorer outcomes. Preclinical literature suggests that hyperglycemia is an independent prognostic factor and the vasculature is more vulnerable to reperfusion injury. We applied a method to match subjects on important baseline factors to test whether, independent of stroke severity, stroke subtype influences the effect of hyperglycemia on outcome after recombinant tissue plasminogen activator (rt-PA). We reanalyzed the NINDS rt-PA dataset with respect to matching variables baseline NIHSS, age, and investigator-determined stroke subtypes small-vessel occlusive stroke (SVS), large-vessel occlusive stroke (LVS), and cardioembolic stroke (CES), above and below a glucose threshold of 150 mg/dl. Ninety-day outcomes were compared. Post hoc baseline matching was excellent in most cases. Hyperglycemia was associated with worsened functional outcome mostly in the LVS subtype with increased mortality in the placebo arm (15.3% mortality normoglycemia vs. 30.6% hyperglycemia; p = .046), worse functional outcome in the rt-PA arm (modified Rankin Score (mRS) 0-1; 46.3 vs. 22.0%; p = .034), and no improvement in functional outcome with rt-PA compared to placebo (mRS 0-1; 25% in both groups). Among hyperglycemic subjects, CES subjects showed significant improvement following rt-PA (p = .027). After matching for baseline severity, the influence of hyperglycemia on outcome was primarily in the LVS subtype, especially after rt-PA. This finding is consistent with a deleterious effect of hyperglycemia on ischemia/reperfusion of symptomatic large arteries. If confirmed, the particular vulnerability of the LVS subtype is important in understanding the role of stroke subtype in the mechanism of worsening and potential treatment of hyperglycemic stroke patients.

The genetics of colored sequence synesthesia: suggestive evidence of linkage to 16q and genetic heterogeneity for the condition.

Synesthesia is a perceptual condition in which sensory stimulation triggers anomalous sensory experiences. In colored sequence synesthesia (CSS), color experiences are triggered by sequences such as letters or numbers. We performed a family based linkage analysis to identify genetic loci responsible for the increased neural crosstalk underlying CSS. Our results implicate a 23 MB region at 16q12.2-23.1, providing the first step in understanding the molecular basis of CSS.