Cross-sectional examination of current and future trends and attributes of the presidents of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons societies.

Objective: The present study aimed to analyze the academic attributes of the presidents of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS) over the past four decades to elucidate the trajectories of these societies' leaderships. Methods: Forty-three AANS and 43 CNS presidents of the past four decades were identified. Demographic and research productivity data were collected from publicly available sources. Results: Compared to AANS presidents, CNS presidents were younger (median = 48 years vs. 59.5 years; p < 0.001), had fewer years of practice prior to their election (15 years vs. 28 years; p < 0.001), had higher NIH funding rate (37.2% vs. 11.6%; p = 0.01), and higher rate of practicing at academic institutions (93% vs. 74.4%; p = 0.04). The CNS presidents had a comparable median number of publications at election (AANS: 72 vs. CNS: 94 publications, p = 0.78) but a higher median h-index scores (AANS: 28 vs. CNS: 59; p = 0.04). In the multiple linear regression analysis, vascular subspecialty (ß = 0.21 [95% CI: 0.09-0.34]; p = 0.002) and practicing in a non-academic institution (ß = 0.23 [95% CI: 0.08-0.39]; p = 0.007) were predictors for later election for AANS presidency. Conclusions: We characterized the attributes of AANS and CNS presidents to serve as useful references for career trajectories for junior neurosurgeons and trainees. Research and academic presence seem to be associated with early election to both societies.

Glutathione Depletion and Concomitant Elevation of Susceptibility in Patients with Parkinson's Disease: State-of-the-Art MR Spectroscopy and Neuropsychological Study.

Parkinson's disease (PD) is characterized by extrapyramidal motor disturbances and nonmotor cognitive impairments which impact activities of daily living. Although the etiology of PD is still obscure, autopsy reports suggest that oxidative stress (OS) is one of the important factors in the pathophysiology of PD. In the current study, we have investigated the impact of OS in PD by measuring the antioxidant glutathione (GSH) levels from the substantia nigra (SN), left hippocampus (LH) and neurotransmitter γ-amino butyric acid (GABA) levels from SN region. Concomitant quantitative susceptibility mapping (QSM) from SN and LH was also acquired from thirty-eight PD patients and 30 age-matched healthy controls (HC). Glutathione levels in the SN region decreased significantly and susceptibility increased significantly in PD compared to HC. Nonsignificant depletion of GABA was observed in the SN region. GSH levels in the LH region were depleted significantly, but LH susceptibility did not alter in the PD cohort compared to HC. Neuropsychological and physical assessment demonstrated significant impairment of cognitive functioning in PD patients compared to HC. GSH depletion was negatively correlated to motor function performance. Multivariate receiver operating characteristic (ROC) curve analysis on the combined effect of GSH, GABA, and susceptibility in the SN region yielded an improved diagnostic accuracy of 86.1% compared to individual diagnostic accuracy based on GSH (65.8%), GABA (57.5%), and susceptibility (69.6%). This is the first comprehensive report in PD demonstrating significant GSH depletion as well as concomitant iron enhancement in the SN region.

SWADESH: a multimodal multi-disease brain imaging and neuropsychological database and data analytics platform.

Multimodal neuroimaging data of various brain disorders provides valuable information to understand brain function in health and disease. Various neuroimaging-based databases have been developed that mainly consist of volumetric magnetic resonance imaging (MRI) data. We present the comprehensive web-based neuroimaging platform "SWADESH" for hosting multi-disease, multimodal neuroimaging, and neuropsychological data along with analytical pipelines. This novel initiative includes neurochemical and magnetic susceptibility data for healthy and diseased conditions, acquired using MR spectroscopy (MRS) and quantitative susceptibility mapping (QSM) respectively. The SWADESH architecture also provides a neuroimaging database which includes MRI, MRS, functional MRI (fMRI), diffusion weighted imaging (DWI), QSM, neuropsychological data and associated data analysis pipelines. Our final objective is to provide a master database of major brain disease states (neurodegenerative, neuropsychiatric, neurodevelopmental, and others) and to identify characteristic features and biomarkers associated with such disorders.

Blood Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. The characteristic pathological manifestation of AD includes the deposition of extracellular insoluble ß amyloid plaques and intracellular neurofibrillary tangles formed from hyperphosphorylated tau protein. Cost effective and minimally invasive peripheral blood-based biomarkers are critical for early AD diagnosis. Currently, the plasma based two fraction of ß amyloid peptide ratio (Aß42/40) and phosphorylated tau (p-tau) are considered as blood-based biomarkers for AD diagnosis. Recent research indicates that oxidative stress (OS) occurs prior to amyloid plaque (Aß) formation and abnormal tau phosphorylation in AD. The imbalance of the master antioxidant, glutathione (GSH), and prooxidants (iron, zinc, and copper)─plays a crucial role in AD neurodegeneration. We present peripheral blood-based OS related biomarkers that are mechanistically involved in the disease process and may serve as a novel screening tool for early detection of AD onset. This OS based approach may also provide a quick and cost efficient method to monitor the effects of disease-modifying therapies in AD clinical trials.

Oxidative Stress Occurs Prior to Amyloid Aß Plaque Formation and Tau Phosphorylation in Alzheimer's Disease: Role of Glutathione and Metal Ions.

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disorder that affects millions of people worldwide. Although the pathogenesis remains obscure, there are two dominant causal hypotheses. Since last three decades, amyloid beta (Aß) deposition was the most prominent hypothesis, and the other is the tau hyperphosphorylation hypothesis. The confirmed diagnostic criterion for AD is the presence of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and the deposition of toxic oligomeric Aß in the autopsied brain. Consistent with these hypotheses, oxidative stress (OS) is garnering major attention in AD research. OS results from an imbalance of pro-oxidants and antioxidants. There is a considerable debate in the scientific community on which process occurs first, OS or plaque deposition/tau hyperphosphorylation. Based on recent scientific observations of various laboratories including ours along with critical analysis of those information, we believe that OS is the early event that leads to oligomeric Aß deposition as well as dimerization of tau protein and its subsequent hyperphosphorylation. This OS hypothesis immediately suggests the consideration of novel therapeutic approaches to include antioxidants involving glutathione enrichment in the brain by supplementation with or without an iron chelator.

Brain Imaging Databases.

The availability of neuroimaging-based databases is helping immensely to understand the brain function in healthy and diseased conditions. This viewpoint highlights the objectives, commonalities, and differences within these existing databases and pointers for researchers to choose a particular database. We introduce a multimodal multidisease database, SWADESH, and its comparison with the existing databases. A futuristic database blueprint is proposed for housing multidisease, multimodal, and longitudinal brain imaging data systematically organized in a matrix form along with neuropsychological assessment scores for the identification of causal disease processes. The information-rich databases will ultimately assist with the systematic identification of prime features linked to causal disease processes, leading to the design of appropriate clinical trials for successful therapeutic interventions.

Quantitation of Brain and Blood Glutathione and Iron in Healthy Age Groups Using Biophysical and In Vivo MR Spectroscopy: Potential Clinical Application.

The antioxidant glutathione (GSH) and pro-oxidant iron levels play a balancing role in the modulation of oxidative stress (OS). There is a significant depletion of GSH in the left hippocampus (LH) in patients with Alzheimer's disease (AD) with concomitant elevation of iron level. However, the correlation of GSH and iron distribution patterns between the brain and the peripheral system (blood) is not yet known. We measured GSH and magnetic susceptibility (e.g., iron) in the LH region along with GSH in plasma and iron in serum across four age groups consisting of healthy volunteers (age range 18-72 y, n = 70). We report non-variability of the mean GSH in the plasma and LH region across mentioned age groups. The mean iron level in the LH region does not change, but the iron level in the serum in the 51-72 y age group increases non-significantly. Regression analysis of our data indicated that GSH and iron levels (both in blood and in brain) are not related to age. This research pave the way for the identification of a risk/susceptibility biomarker for AD and Parkinson's disease from the evaluation of GSH (in plasma) and iron (in serum) levels concomitantly.

A Proprietary Herbal Blend Containing Extracts of Punica granatum Fruit Rind and Theobroma cocoa Seeds Increases Serum Testosterone Level in Healthy Young Males: A Randomized, Double-Blind Placebo-Controlled Study.

LN18178 is a proprietary herbal blend containing extracts of Punica granatum fruit rind and Theobroma cocoa seeds. The objective of the present study was to evaluate the effect of LN18178 on serum testosterone levels in healthy young adults in a randomized, double-blind, placebo-controlled study. One hundred and twenty male volunteers (age 21-35 years) were randomized into three groups. Each group (n = 40) received a daily dose of either placebo or 200 or 400 mg LN18178 for fifty-six days. An increase in serum testosterone (free and total) was the primary efficacy measure of the study. The secondary measures included dihydrotestosterone (DHT), cortisol, Luteinizing hormone (LH), 17ß-Estradiol (E2), hand grip strength, and the mid-upper arm circumferences (MUAC). The vital signs and clinical chemistry parameters in blood and urine were performed to determine product safety. Post-intervention, both doses of LN18178 significantly increased free testosterone (p < 0.0001 vs. baseline; p = 0.0268 and p < 0.0001, respectively vs. placebo). The high dose group showed significant increases in total testosterone (p < 0.0001 vs. baseline; p = 0.0184 vs. placebo) and luteinizing hormone (p < 0.0007 vs. baseline; p = 0.0470 vs. placebo). The changes in other hormones were not significant. At post-trial, the LN18178-400 group showed significant improvements in the hand grip strength and mid-upper arm circumference. The hemato-biochemical parameters, urinalysis, and vital signs of the participants were within the normal range. Together, these observations suggest that LN18178 is a safe and tolerable herbal blend; it increases testosterone level and increases muscle strength and MUAC in young, healthy males.Supplemental data for this article is available online at https://doi.org/10.1080/19390211.2022.2035037 .

Hippocampal glutathione depletion with enhanced iron level in patients with mild cognitive impairment and Alzheimer's disease compared with healthy elderly participants.

Oxidative stress has been implicated in Alzheimer's disease, and it is potentially driven by the depletion of primary antioxidant, glutathione, as well as elevation of the pro-oxidant, iron. Present study evaluates glutathione level by magnetic resonance spectroscopy, iron deposition by quantitative susceptibility mapping in left hippocampus, as well as the neuropsychological scores of healthy old participants (N = 25), mild cognitive impairment (N = 16) and Alzheimer's disease patients (N = 31). Glutathione was found to be significantly depleted in mild cognitive impaired (P < 0.05) and Alzheimer's disease patients (P < 0.001) as compared with healthy old participants. A significant higher level of iron was observed in left hippocampus region for Alzheimer's disease patients as compared with healthy old (P < 0.05) and mild cognitive impairment (P < 0.05). Multivariate receiver-operating curve analysis for combined glutathione and iron in left hippocampus region provided diagnostic accuracy of 82.1%, with 81.8% sensitivity and 82.4% specificity for diagnosing Alzheimer's disease patients from healthy old participants. We conclude that tandem glutathione and iron provides novel avenue to investigate further research in Alzheimer's disease.

Metabolic management of microenvironment acidity in glioblastoma.

Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic heterogeneity seen within the tumor. The transition from respiration to fermentation arises from the documented defects in the number, the structure, and the function of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and glutamine are the major fermentable fuels that drive GBM growth. The major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis. Besides surgical debulking, therapies used for GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification and, although often providing a time-limited disease control, will thus favor tumor recurrence and complications. The simultaneous restriction of glucose and glutamine, while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore the pH balance of the microenvironment while, at the same time, providing a non-toxic therapeutic strategy for killing most of the neoplastic cells.

The effect of hyperbaric oxygen therapy on cognition, performance, proteomics, and telomere length-The difference between zero and one: A case report.

Introduction: Hyperbaric oxygen (HBO2) therapy has recently been suggested for the treatment of different brain injuries as well as for physical and cognitive enhancement. The author recently carried out a self-experiment to obtain objective information on the effects of HBO2 therapy on neurocognition, cardiopulmonary function, neuroimaging and its effect on novel biomarkers such as telomere length and proteomics. In the following case report, the author will present and discuss the results and the differences between zero and one. Methods: This is a personal case report on a single subject, myself, who underwent a protocol of 60 daily HBO2 therapy sessions within 3 months. Pre- and post-therapy objective evaluation measured included computerized cognitive assessment, brain imaging, cardiopulmonary exercise test, physical assessments and blood tests including telomere length and proteomics. Results: Neurocognitive results showed a 3.1-3.8% improvements in global cognitive function as well as all other cognitive function domains. In the perfusion MRI, there was a relative increase ranging from 43.3 to 52.3% in cerebral perfusion in various areas subserving memory, coordination, and visual motor cortex function. Similar improvements in cerebral perfusion were seen in the SPECT scans, which ranged from 8.79 to 16.12% increased perfusion in the temporal pole and entorhinal cortex subserving memory, as well as in the subcallosal area and lingual gyrus. MRI-DTI showed prominent increases in fractional anisotropy in several white matter areas including 9% in the body of the corpus callosum, 16.85% in for the fornix and 22.06% in the tapetum. In the physical domains, there were improvements in both anaerobic threshold, exercise endurance, muscle strength, gait speed and grip strength in the 7-15% range. The telomeres length was doubled and clusters of inflammatory proteins dropped around the 40th session and remained low at the 60th session. Conclusion: The difference between zero and one in this single case study of HBO2 therapy confirmed improvement in objective biomarkers which measured cognition, memory, brain processing speed, athletic performance and neuroimaging modalities measuring cerebral perfusion, blood flow and tractography. Additional studies with larger sample size and randomized clinical trials using similar biomarkers are needed to confirm the results and to delineate the longevity of these improvements.

In Vivo 13C Magnetic Resonance Spectroscopy for Assessing Brain Biochemistry in Health and Disease.

Magnetic resonance spectroscopy (MRS) is a non-invasive technique that contributes to the elucidation of brain biochemistry. 13C MRS enables the detection of specific neurochemicals and their neuroenergetic correlation with neuronal function. The synergistic outcome of 13C MRS and the infusion of 13C-labeled substrates provide an understanding of neurometabolism and the role of glutamate/gamma-aminobutyric acid (GABA) neurotransmission in diseases, such as Alzheimer's disease, schizophrenia, and bipolar disorder. Moreover, 13C MRS provides a window into the altered flux rate of different pathways, including the tricarboxylic acid cycle (TCA) and the glutamate/glutamine/GABA cycle, in health and in various diseases. Notably, the metabolic flux rate of the TCA cycle often decreases in neurodegenerative diseases. Additionally, 13C MRS can be used to investigate several psychiatric and neurological disorders as it directly reflects the real-time production and alterations of key brain metabolites. This review aims to highlight the chronology, the technological advancements, and the applications of 13C MRS in various brain diseases.

AD Hypotheses and Suggested Clinical Trials.

Alzheimer's disease (AD) is a major neurodegenerative disorder that impairs cognitive reserve impacting activities of daily living. The prime pathological characteristics of AD include the deposition of neurofibrillary tangles of hyperphosphorylated tau (τ) proteins, accumulation of amyloid-ß (Aß), and neuronal loss. Expanding literature suggests that oxidative stress (OS) is a vital factor contributing to the pathogenesis of AD such that biometals (e.g., iron, zinc, copper) are believed to play a crucial role in Aß formation and neurodegeneration. Growing evidence indicates the impact of OS in AD, and clinical trials with antioxidative therapeutic interventions are in the frontline of AD research. We discuss various AD hypotheses and associated clinical trials. We present a case for future therapeutic intervention for AD by putting forth postulated hypotheses and trials.

Return to Play Guidelines After Cervical Spine Injuries in American Football Athletes: A Literature-Based Review.

STUDY DESIGN: Literature-based review. OBJECTIVE: We sought to evaluate clinical and case studies related to return to play (RTP) after cervical spine injuries in elite American football athletes and to formulate guidelines to help health care practitioners manage these conditions. SUMMARY OF BACKGROUND DATA: American football athletes are at unique risk of cervical spine injury and appropriate case-by-case management of cervical spine injuries is necessary for these athletes. Despite this need, no standardized guidelines exist for RTP after cervical spine injury. METHODS: Observational or case-based articles relating to RTP after cervical spine injury in American football athletes were curated from PubMed/EMBASE databases. Primary literature published before December 1, 2019 involving National Football League (NFL) or National Collegiate Athletic Association (NCAA) athletes met inclusion criteria. RESULTS: The data acquisition process yielded 28 studies addressing cervical spine injuries and RTP in American football athletes. Stingers/burners were the most common injury and placed athletes at higher risk of a more severe re-injury. Transient quadriplegia, cervical stenosis, cervical disc herniation (CDH), and cervical fractures have a more significant impact on the long-term health and career longevity of the American football athlete. As such, the literature offers some guidance for management of these athletes, including average time for RTP in patients treated nonoperatively, thresholds involving cervical stenosis, and postoperative recommendations after spinal decompression and/or fusion surgery. CONCLUSION: Elite American football athletes are at high risk for cervical spine injury due to the nature of their sport. The decision to allow these athletes to return to play should involve an understanding of the average RTP time, the potential risks of recurrence or re-injury, and individual characteristics such as position played and pathology on imaging.Level of Evidence: 3.

Ketogenic Metabolic Therapy, Without Chemo or Radiation, for the Long-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report.

Background: Successful treatment of glioblastoma (GBM) remains futile despite decades of intense research. GBM is similar to most other malignant cancers in requiring glucose and glutamine for growth, regardless of histological or genetic heterogeneity. Ketogenic metabolic therapy (KMT) is a non-toxic nutritional intervention for cancer management. We report the case of a 32-year-old man who presented in 2014 with seizures and a right frontal lobe tumor on MRI. The tumor cells were immunoreactive with antibodies to the IDH1 (R132H) mutation, P53 (patchy), MIB-1 index (4-6%), and absent ATRX protein expression. DNA analysis showed no evidence of methylation of the MGMT gene promoter. The presence of prominent microvascular proliferation and areas of necrosis were consistent with an IDH-mutant glioblastoma (WHO Grade 4). Methods: The patient refused standard of care (SOC) and steroid medication after initial diagnosis, but was knowledgeable and self-motivated enough to consume a low-carbohydrate ketogenic diet consisting mostly of saturated fats, minimal vegetables, and a variety of meats. The patient used the glucose ketone index calculator to maintain his Glucose Ketone Index (GKI) near 2.0 without body weight loss. Results: The tumor continued to grow slowly without expected vasogenic edema until 2017, when the patient opted for surgical debulking. The enhancing area, centered in the inferior frontal gyrus, was surgically excised. The pathology specimen confirmed IDH1-mutant GBM. Following surgery, the patient continued with a self-administered ketogenic diet to maintain low GKI values, indicative of therapeutic ketosis. At the time of this report (May 2021), the patient remains alive with a good quality of life, except for occasional seizures. MRI continues to show slow interval progression of the tumor. Conclusion: This is the first report of confirmed IDH1-mutant GBM treated with KMT and surgical debulking without chemo- or radiotherapy. The long-term survival of this patient, now at 80 months, could be due in part to a therapeutic metabolic synergy between KMT and the IDH1 mutation that simultaneously target the glycolysis and glutaminolysis pathways that are essential for GBM growth. Further studies are needed to determine if this non-toxic therapeutic strategy could be effective in providing long-term management for other GBM patients with or without IDH mutations.

Sport-Related Structural Brain Injury and Return to Play: Systematic Review and Expert Insight.

BACKGROUND: Sport-related structural brain injury (SRSBI) is intracranial pathology incurred during sport. Management mirrors that of non-sport-related brain injury. An empirical vacuum exists regarding return to play (RTP) following SRSBI. OBJECTIVE: To provide key insight for operative management and RTP following SRSBI using a (1) focused systematic review and (2) survey of expert opinions. METHODS: A systematic literature review of SRSBI from 2012 to present in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a cross-sectional survey of RTP in SRSBI by 31 international neurosurgeons was conducted. RESULTS: Of 27 included articles out of 241 systematically reviewed, 9 (33.0%) case reports provided RTP information for 12 athletes. To assess expert opinion, 31 of 32 neurosurgeons (96.9%) provided survey responses. For acute, asymptomatic SRSBI, 12 (38.7%) would not operate. Of the 19 (61.3%) who would operate, midline shift (63.2%) and hemorrhage size > 10 mm (52.6%) were the most common indications. Following SRSBI with resolved hemorrhage, with or without burr holes, the majority of experts (>75%) allowed RTP to high-contact/collision sports at 6 to 12 mo. Approximately 80% of experts did not endorse RTP to high-contact/collision sports for athletes with persistent hemorrhage. Following craniotomy for SRSBI, 40% to 50% of experts considered RTP at 6 to 12 mo. Linear regression revealed that experts allowed earlier RTP at higher levels of play (ß = -0.58, 95% CI -0.111, -0.005, P = .033). CONCLUSION: RTP decisions following structural brain injury in athletes are markedly heterogeneous. While individualized RTP decisions are critical, aggregated expert opinions from 31 international sports neurosurgeons provide key insight. Level of play was found to be an important consideration in RTP determinations.

Management of thoracic spinal cord injury in a professional American football athlete: illustrative case.

BACKGROUND: A case of catastrophic thoracic spinal cord injury (SCI) sustained by a professional American football player with severe scoliosis is presented. OBSERVATIONS: A 25-year-old professional football player sustained an axial loading injury while tackling. Examination revealed a T8 American Spinal Injury Association Impairment Scale grade A complete SCI. Methylprednisolone and hypothermia protocols were initiated. Computed tomography scan of the thoracic spine demonstrated T8 and T9 facet fractures on the left at the apex of a 42° idiopathic scoliotic deformity. Magnetic resonance imaging (MRI) demonstrated T2 spinal cord hyperintensity at T9. He regained trace movement of his right lower extremity over 12 hours, which was absent on posttrauma day 2. Repeat MRI revealed interval cord compression and worsening of T2 signal change at T7-T8 secondary to hematoma. Urgent decompression and fusion from T8 to T10 were performed. Additional treatment included high-dose omega-3 fatty acids and hyperbaric oxygen therapy. A 2-month inpatient spinal cord rehabilitation program was followed by prolonged outpatient physical therapy. He currently can run and jump with minimal residual distal left lower limb spasticity. LESSONS: This is the first known football-related thoracic SCI with idiopathic scoliosis. Aggressive medical and surgical intervention with intensive rehabilitation formed the treatment protocol, with a favorable outcome achieved.

Treatment of glioblastoma multiforme with "classic" 4:1 ketogenic diet total meal replacement.

INTRODUCTION: Glioblastoma (GBM) has poor survival with standard treatment. Experimental data suggest potential for metabolic treatment with low carbohydrate ketogenic diet (KD). Few human studies of KD in GBM have been done, limited by difficulty and variability of the diet, compliance, and feasibility issues. We have developed a novel KD approach of total meal replacement (TMR) program using standardized recipes with ready-made meals. This pilot study evaluated feasibility, safety, tolerability, and efficacy of GBM treatment using TMR program with "classic" 4:1 KD. METHOD: GBM patients were treated in an open-label study for 6 months with 4:1 [fat]:[protein + carbohydrate] ratio by weight, 10 g CH/day, 1600 kcal/day TMR. Patients were either newly diagnosed (group 1) and treated adjunctively to radiation and temozolomide or had recurrent GBM (group 2). Patients checked blood glucose and blood and urine ketone levels twice daily and had regular MRIs. Primary outcome measures included retention, treatment-emergent adverse events (TEAEs), and TEAE-related discontinuation. Secondary outcome measures were survival time from treatment initiation and time to MRI progression. RESULTS: Recruitment was slow, resulting in early termination of the study. Eight patients participated, 4 in group 1 and 4 in group 2. Five (62.5%) subjects completed the 6 months of treatment, 4/4 subjects in group 1 and 1/4 in group 2. Three subjects stopped KD early: 2 (25%) because of GBM progression and one (12.5%) because of diet restrictiveness. Four subjects, all group 1, continued KD on their own, three until shortly before death, for total of 26, 19.3, and 7 months, one ongoing. The diet was well tolerated. TEAEs, all mild and transient, included weight loss and hunger (n = 6) which resolved with caloric increase, nausea (n = 2), dizziness (n = 2), fatigue, and constipation (n = 1 each). No one discontinued KD because of TEAEs. Seven patients died. For these, mean (range) survival time from diet initiation was 20 months for group 1 (9.5-27) and 12.8 months for group 2 (6.3-19.9). Mean survival time from diagnosis was 21.8 months for group 1 (11-29.2) and 25.4 months for group 2 ( 13.9-38.7). One patient with recurrent GBM and progression on bevacizumab experienced a remarkable symptom reversal, tumor shrinkage, and edema resolution 6-8 weeks after KD initiation and survival for 20 months after starting KD. CONCLUSION: Treatment of GBM patients with 4:1 KD using total meal replacement program with standardized recipes was well tolerated. The small sample size limits efficacy conclusions. TRIAL REGISTRATION: NCT01865162 registered 30 May 2013, and NCT02302235 registered 26 November 2014, https://clinicaltrials.gov/.