Guidelines for Seizure Prophylaxis in Adults Hospitalized with Moderate-Severe Traumatic Brain Injury: A Clinical Practice Guideline for Health Care Professionals from the Neurocritical Care Society.

BACKGROUND: There is practice heterogeneity in the use, type, and duration of prophylactic antiseizure medications (ASMs) in patients with moderate-severe traumatic brain injury (TBI). METHODS: We conducted a systematic review and meta-analysis of articles assessing ASM prophylaxis in adults with moderate-severe TBI (acute radiographic findings and requiring hospitalization). The population, intervention, comparator, and outcome (PICO) questions were as follows: (1) Should ASM versus no ASM be used in patients with moderate-severe TBI and no history of clinical or electrographic seizures? (2) If an ASM is used, should levetiracetam (LEV) or phenytoin/fosphenytoin (PHT/fPHT) be preferentially used? (3) If an ASM is used, should a long versus short (> 7 vs. ≤ 7 days) duration of prophylaxis be used? The main outcomes were early seizure, late seizure, adverse events, mortality, and functional outcomes. We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to generate recommendations. RESULTS: The initial literature search yielded 1998 articles, of which 33 formed the basis of the recommendations: PICO 1: We did not detect any significant positive or negative effect of ASM compared to no ASM on the outcomes of early seizure, late seizure, adverse events, or mortality. PICO 2: We did not detect any significant positive or negative effect of PHT/fPHT compared to LEV for early seizures or mortality, though point estimates suggest fewer late seizures and fewer adverse events with LEV. PICO 3: There were no significant differences in early or late seizures with longer versus shorter ASM use, though cognitive outcomes and adverse events appear worse with protracted use. CONCLUSIONS: Based on GRADE criteria, we suggest that ASM or no ASM may be used in patients hospitalized with moderate-severe TBI (weak recommendation, low quality of evidence). If used, we suggest LEV over PHT/fPHT (weak recommendation, very low quality of evidence) for a short duration (≤ 7 days, weak recommendation, low quality of evidence).

Targeted Therapy for BRAF Mutant Brain Tumors.

OPINION STATEMENT: Molecular heterogeneity has confounded attempts to target individual pathways in brain tumors. However, gliomas with BRAF mutations have been identified as being uniquely vulnerable to targeted therapies. Such mutations are predominantly seen in brain tumors of the adolescent and young adult population. Given that accurate and timely identification of such mutations is essential for offering appropriate treatment, treatment centers should offer both immunohistochemical and sequencing methods for detection of these mutations to guide treatment. Additional studies of these tumors at recurrence would also allow identification of breakthrough resistance mechanisms that may also be targetable for treatment. Due to the relative rarity of these tumors, multicenter collaborative studies will be essential in achieving long term control of these tumors.

Association of dietary insulinaemic potential and odds of non-alcoholic fatty liver disease among adults: A case-control study.

BACKGROUND: Hyperinsulinaemia is considered as a major risk factor for the development of a myriad of chronic diseases. We examined the association between the dietary insulinaemic potential and the odds of non-alcoholic fatty liver disease (NAFLD) among Iranian adults. METHODS: After being subjected to a liver ultrasound, 166 patients with NAFLD and 200 controls were included in the study. The dietary intakes and the physical activity levels of the participants were evaluated using a validated semi-quantitative food frequency questionnaire and the International Physical Activity Questionnaire (short IPAQ), respectively. The insulinaemic potential of the diet was assessed by computing the scores of the Empirical Dietary Index for Hyperinsulinemia (EDIH) and the Empirical Dietary Index for Insulin Resistance (EDIR). RESULTS: Compared with the control subjects, patients with NAFLD were significantly older; had higher values for body mass index, fasting blood sugar, triglycerides, low-density lipoprotein cholesterol, total cholesterol and alanine transaminase; and were more likely to smoke. Moreover, NAFLD patients had significant lower levels of high-density lipoprotein cholesterol and were less likely to perform physical activity. The risk of NAFLD was higher in the individuals in the highest tertile of the EDIH (odds ratio [OR] = 2.79; 95% confidence interval [CI] = 1.32-5.90; p value for trend < 0.05) and EDIR (OR = 2.42; 95% CI = 1.22-4.79; p value for trend < 0.05) compared to those in the lowest tertile of these scores. CONCLUSIONS: Our study indicates that a higher dietary insulinaemic potential is associated with an increased risk of NAFLD.

What information about sudden unexpected death in epilepsy (SUDEP) is available on YouTube?

OBJECTIVE: We sought to assess and analyze the information available about sudden unexpected death in epilepsy (SUDEP) and the general perception of this condition by the public on YouTube. METHODS: We evaluated all consecutive videos containing references to 'sudden unexpected death in epilepsy' and 'SUDEP' on YouTube. Data were extracted after applying the inclusion and exclusion criteria. Various characteristics of the videos including the type of content, uploading source, likes, dislikes, and comments received were classified and analyzed. RESULTS: A total of 113 videos were included, with the majority uploaded by individual users (51.3%) followed by activist groups (40.7%). The primary content from individual users created videos were tribute to family members who died because of SUDEP (43.1%) and personal narration (36.2%), whereas educational/scientific information (55%) and advertisements (45%) to raise SUDEP awareness comprised the videos from professional societies and activist groups. More than three-fourths of the comments to the videos were in response to individual user uploaded videos, and mainly comprised of positive statement conveying empathy or describing personal encounters. CONCLUSION: Substantial information is available regarding SUDEP on YouTube; however, the viewer engagement remains limited. Individual user-created videos about SUDEP are the most popular and viewer engaging. Incorporating personal/anecdotal experiences in addition to scientific information in the video content might further improve the viewer engagement.

Reporting Compliance of Stroke Trials: Cross-Sectional Analysis.

BACKGROUND: The FDA mandates timely reporting of all clinical trials conducted in the United States. However, often the results are not reported in a timely manner, resulting in wastage of finite resources. We assessed the reporting of results of completed stroke trials and compared the reporting trends between U.S. and non-U.S. stroke trials. METHODS: We assessed consecutive clinical stroke trials registered as completed in ClinicalTrials.gov between January 1, 2008 and January 1, 2015. Descriptive data collected included study phase, study type, participant age, number of enrolled patients, study locations, start and primary completion dates, result availability, time to reporting (months), sponsorship, funding sources, and publication status. We also performed manual search for stroke trials in Pubmed, Web of Science, and Google scholar. RESULTS: Out of a total 140 completed trials, 39 trials (35,359 patients) involved at least 1 U.S. center and 101 trials (58,542 patients) were conducted in non-U.S. centers. Of the trials involving at least a single U.S. center, 31 of 39 (79%) reported their results, whereas only 6 of 31 (19%) reported their results within 1 year. Of the trials conducted at non-U.S. centers, 72 of 101 (71%) reported their results, whereas results for 24 of 72 (33%) trials were available within a year of completion. The time to reporting of results was significantly lower for all the included clinical trials in the 2012-2014 period (P < .001, Cohen's d = .726) as compared to the 2008-2011 period. CONCLUSION: Only one-fifth of completed stroke trials involving at least a single U.S. center report their results within 1 year. Additionally, every fifth completed trial involving stroke patients at U.S. centers remain unreported.

A Rare Association of Hypomagnesemia and Posterior Reversible Encephalopathy Syndrome (PRES).

Posterior reversible encephalopathy syndrome (PRES) is a rare neurologic disorder that presents with variable symptoms and symmetrical abnormal white matter signaling most commonly of the occipital and parietal lobes on magnetic resonance imaging (MRI). PRES, also known as reversible posterior leukoencephalopathy syndrome (RPLS) is commonly associated with hypertension. Hypomagnesemia's association with PRES has been rarely reported. Here, we report a patient with severe hypomagnesemia that presented with PRES syndrome that improved with magnesium replacement. Hypomagnesemia should be considered an underlying etiology in patients presenting with PRES syndrome and should be promptly treated. The presentation can often be concerning for acute cerebrovascular accidents with symptoms of dysarthria and upper motor neuron symptoms, such as facial droop, dysarthria, and gait instability. Differential diagnosis of PRES often includes rostral brainstem infarction, transient ischemic attack, infectious encephalopathy, and metabolic/toxic encephalopathy, which is evaluated in the description of the case. The most common presentation of RPLS/PRES includes altered mental status, drowsiness, seizure, vomiting, alterations in speech including dysarthria, and visual disturbance. The first signs noted are commonly lethargy and somnolence. In this case, the patient presented notably with initial symptoms of dysarthria of speech and facial droop, with serum hypomagnesemia in which symptoms corrected rapidly with the administration of intravenous magnesium sulfate.

The association between food insulin index and odds of non-alcoholic fatty liver disease (NAFLD) in adults: a case-control study.

AIM: This research aimed to study the association of food insulin index and biochemical parameters with the odds of developing NAFLD in adult Iranians. BACKGROUND: Hyperinsulinemia may play an important role in the development of non-alcoholic fatty liver disease (NAFLD) because of the relationship between insulin response and body fat accumulation. METHODS: A case-control study of 169 NAFLD patients and 200 healthy adults aged 18-55 years was conducted. Dietary data was collected using a validated 168-item quantitative food frequency questionnaire (FFQ). Food insulin index (FII) was calculated by dividing the total insulin load by total energy intake (kcal/day). Total insulin load (ILoverall) was also calculated using a standard formula. RESULTS: Mean participant age was 43.9 ± 5.9 years. Patients with NAFLD were significantly associated with higher body mass index, levels of liver enzymes, triglyceride, low density lipoprotein-cholesterol (LDL), total cholesterol, and fasting blood sugar (FBS) compared to the healthy subjects (p < 0.05). The highest tertiles of FII were associated with higher odds of NAFLD (OR=1.4, 95% CI: 0.88-2.48, p for trend <0.001) and obesity (OR=2.33, 95% CI: 0.97-5.75) compared to the lowest tertiles. Potential confounders for the association were controlled. CONCLUSION: This study found that adherence to a diet with high FII was associated with greater odds of NAFLD and overweight or obesity. Additional studies are required to better understand this association.

Predictors of Nonconvulsive Seizure and Their Effect on Short-term Outcome.

INTRODUCTION: Nonconvulsive seizures (NCSs) are common in critically ill adult patients with acute neurologic conditions. However, the effect of NCSs on patient outcome remains unclear. In this study, we aimed to determine the effect of NCSs on short-term outcome and to assess the clinical and EEG factors associated with NCSs. METHODS: We retrospectively identified 219 adult patients from the EEG reporting system who underwent continuous EEG (cEEG) monitoring between January 2018 and June 2018. Patients with anoxic brain injury were excluded from the study. Clinical, laboratory, and EEG data were reviewed to determine potentially predictive factors of NCSs. The impact of NCSs on in-hospital mortality, length of stay, and disability on discharge was measured; an modified Rankin scale of three or greater was considered disabled. RESULTS: Of the 219 patients included in our study, a total of 14% (n = 31) had NCSs on continuous EEG, of which 42% (n = 13) had their first seizure discharge recorded during the first hour of continuous EEG monitoring. The presence of clinical seizures before continuous EEG (odds ratio = 1.787; 95% confidence interval = 1.197-2.667, P = 0.0045), history of epilepsy (odds ratio = 1.508; 95% confidence interval = 1.027-2.215, P = 0.035), and comatose state (29 vs. 16%; P = 0.0006) were associated with NCSs. Among EEG characteristics, the presence of interictal epileptiform discharges (P < 0.0001), lateralized rhythmic delta activity (P = 0.02), and lateralized periodic discharges (P < 0.0001) were associated with NCSs. Nonconvulsive seizures were significantly associated with longer in-hospital stay (23.68 ± 24.84 vs. 17.14 ± 20.52; P = 0.036) and disability on discharge (87% [n = 27] vs. 13% [n = 4], P = 0.02). However, there was no significant association between NCS and in-hospital mortality (9.6% [n = 3] vs. 10.6% [n = 20]; P = 0.1). CONCLUSIONS: Nonconvulsive seizures are associated with longer in-hospital stay and disability on discharge but not with in-hospital mortality in adult patients.

Prognostic implications of epidermal and platelet-derived growth factor receptor alterations in 2 cohorts of IDHwt glioblastoma.

BACKGROUND: Glioblastoma remains a deadly brain cancer with dismal prognosis. Genetic alterations, including IDH mutations, 1p19q co-deletion status and MGMT promoter methylation have been proven to be prognostic and predictive to response to treatment in gliomas. In this manuscript, we aimed to correlate other mutations and genetic alterations with various clinical endpoints in patients with IDH-wild-type (IDHwt) glioblastoma. METHODS: We compiled a comprehensive clinically annotated database of IDHwt GBM patients treated at the Ohio State University Wexner Medical Center for whom we had mutational data through a CLIA-certified genomic laboratory. We then added data that is publicly available from Memorial Sloan Kettering Cancer Center through cBioPortal. Each of the genetic alterations (mutations, deletions, and amplifications) served as a variable in univariate and multivariate Cox proportional hazard models. RESULTS: A total of 175 IDHwt GBM patients with available MGMT promoter methylation data from both cohorts were included in the analysis. As expected, MGMT promoter methylation was significantly associated with improved overall survival (OS). Median OS for MGMT promoter methylated and unmethylated GBM was 26.5 and 18 months, respectively (HR 0.45; P = .003). Moreover, EGFR/ERBB alterations were associated with favorable outcome (HR of 0.37 (P = .003), but only in MGMT promoter unmethylated GBM. We further found that patients with EGFR/ERBB alterations who also harbored PDGFRA amplification had a significantly worse outcome (HR 7.89; P = .025). CONCLUSIONS: Our data provide further insight into the impact of genetic alterations on various clinical outcomes in IDHwt GBM in 2 cohorts of patients with detailed clinical information and inspire new therapeutic strategies for IDHwt GBM.

Erratum to: Characterizing Benefit from Temozolomide in MGMT Promoter Unmethylated and Methylated Glioblastoma: A Systematic Review and Meta-analysis.

[This corrects the article DOI: 10.1093/noajnl/vdaa082.].

The role of VEGF receptor inhibitors in preventing cerebral radiation necrosis: a retrospective cohort study.

BACKGROUND: Radiation necrosis (RN) is a potential complication after radiation therapy for brain tumors. It is hypothesized that VEGF plays an important role in the pathophysiology of RN. Bevacizumab, a monoclonal antibody against VEGF-A, is often successful in the management of RN. The objective of this study is to assess whether VEGF receptor (VEGFR) inhibitors, a group of oral tyrosine kinase inhibitors (TKIs), can prevent or reverse RN. METHODS: We retrospectively studied a cohort of 102 patients with renal cell carcinoma and brain metastases seen at The Ohio State University James Cancer Center between January 1, 2011 and April 30, 2019. We identified those who developed RN and analyzed the temporal relationship between the use of VEGFR TKIs and the development of RN. RESULTS: The cumulative incidence of RN is 13.7% after radiation treatments that included LINAC-based stereotactic radiosurgery, fractionated stereotactic radiotherapy, or Gamma Knife radiosurgery. There was no statistically significant difference in the cumulative incidence of RN between patients taking TKIs and patients who were off TKIs (9.9% and 11.5% respectively, P = .741). The median time to development of RN was only numerically shorter in patients taking TKIs (151 vs 315 days, P = .315). One patient developed RN after stopping cabozantinib. Eight patients developed RN while on cabozantinib, pazopanib, or sunitinib. One patient was started on axitinib during active RN without significant improvement subsequently. CONCLUSIONS: VEGFR TKIs do not consistently prevent RN. The therapeutic effects of VEGFR TKIs against RN warrant further research.

How Are Residents Trained in Neuropathology? A Survey of Neurology Program Directors in the United States.

To understand the current state of neurology residents training in neuropathology, we electronically distributed a 16-item survey to 150 adult and 70 child neurology program directors (PDs). The survey inquired about their program characteristics, neuropathology curriculum and assessment methods, trainee performance, and attitudes. Descriptive analysis was used to summarize categorical variables as frequencies and percentages and continuous as means and standard deviations. We conducted a series of Mann-Whitney U and Fisher's exact tests to evaluate differences between various program characteristics. Sixty-four (29%) PDs responded to the survey, including 45 (30%) adult and 19 (27%) child neurology PDs. Thirty-one programs required a dedicated neuropathology rotation. The majority (92%) used the Residency In-Service Training Examination (RITE) to assess trainee's knowledge. Approximately 86% of the PDs agreed that neuropathology is essential and a defined curriculum is necessary during residency training. There was no difference in the RITE scores between programs. We conclude that a neuropathology rotation was felt to be essential even though the RITE scores did not differ between programs with and without a dedicated rotation. Alternative evaluation and training methods may need consideration. A future survey of all the stakeholders may be required to thoroughly understand and disseminate the neuropathology education well.

False-positive 1p/19q Testing Results in Gliomas: Clinical and Research Consequences.

BACKGROUND: The revised fourth edition of the World Health Organization Classification of Tumors of the Central Nervous System-published in 2016-established 1p19q codeletion as the molecular hallmark for the diagnosis of oligodendrogliomas. Fluorescence in situ hybridization (FISH) is currently the most commonly used modality for 1p19q testing. However, as with most laboratory testing, 1p19q FISH testing has a false-positive rate, potentially resulting in an erroneous diagnosis of oligodendroglioma with significant implications for the choice of therapy and prognosis. METHODS: The authors describe a case series of 5 patients treated at the Ohio State University James Cancer Center to illustrate the problem of false-positive 1p19q FISH results. RESULTS: In our case series, the authors present a spectrum of possibilities for conflicting 1p19q testing results and the clinical consequences. The authors present 4 cases that, in retrospect, are believed to have had a false 1p19q FISH results. One other case may represent a true transformation of oligodendroglioma to glioblastoma or a second malignancy. Neuro-oncologists should pay attention to additional molecular markers, namely ATRX, TP53, and MGMT methylation status, before discussing the pathology with the patient and formulating a treatment plan. CONCLUSIONS: Pathologists and neuro-oncologists should be aware of false-positive 1p19q FISH results as they can significantly change treatment and prognosis for glioma patients. Moreover, this issue should be taken into account when designing clinical trials specific to this disease cohort.

Characterizing benefit from temozolomide in MGMT promoter unmethylated and methylated glioblastoma: a systematic review and meta-analysis.

BACKGROUND: The current standard of care for the management of patients with newly diagnosed glioblastoma (GBM) includes maximal safe resection followed by radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). While it is well established that TMZ has better efficacy in patients with MGMT promoter methylation, it remains an area of debate whether TMZ should be omitted when treating GBM patients with unmethylated MGMT. METHODS: We conducted a systematic review and meta-analysis to provide separate estimates of median overall survival (OS) and progression-free survival (PFS) for patients with methylated and unmethylated GBM treated with RT with or without TMZ. We searched multiple databases from inception to January 13, 2020. RESULTS: The median OS for patients with unmethylated GBM treated with RT/TMZ pooled from 5 phase III studies (N = 655) was 14.11 months (95% confidence interval [CI], 13.18-15.04) with a median PFS of 4.99 months (95% CI, 4.25-5.72). In contrast, the median OS for patients with methylated GBM pooled from 6 studies (N = 753) was 24.59 months (95% CI, 22.19-26.99) with a median PFS pooled from 7 studies (N = 805) of 9.51 months (95% CI, 7.41-11.61). There is a paucity of prospective data pertaining to OS/PFS in unmethylated patients treated with RT only and therefore a direct comparison was not possible. CONCLUSIONS: This meta-analysis provides estimates of survival for patients with MGMT methylated or unmethylated GBM treated with RT/TMZ. Further research is needed to delineate whether TMZ should be withheld for patients with unmethylated GBM outside of the setting of clinical trials.

Reporting bias in completed epilepsy intervention trials: A cross-sectional analysis.

OBJECTIVE: To explore the evidence of reporting bias among completed epilepsy intervention trials (EITs) and compliance of applicable EITs to Food and Drug Administration Amendments Act (FDAAA). METHODS: We included consecutive EITs registered as completed on ClinicalTrials.gov from 2008 to 2015. Descriptive data was collected including study type, study phase, funding source, primary completion date, and result reporting date. Time to result reporting was analyzed using Kaplan-Meier estimates for two time periods (2008-2011 and 2012-2015). PubMed, Web of Science, and Google scholar databases were manually searched for publication details. RESULTS: Overall, 95/126 EITs (75%) reported, while remaining 31/126 (25%) did not report their results. Time to reporting was significantly lower for trials completed during 2012-2015 (16.5 months; 95% CI: 13.60-19.40; p = .002; Cohen's d = 0.68) as compared to the trials completed during 2008-2011 (25.9 months; 95% CI: 21.56-30.22). 72/126 trials were conducted in at least one U.S. center. 56/72 (78%) of the trials met the FDAAA criteria, while only 19/56 (34%) reported within the mandated one-year time frame. CONCLUSION: The lack of reporting of nearly one-quarter of completed epilepsy intervention trials suggests existence of reporting bias. As such, it should be considered an important criterion for determining risk of bias in epilepsy systematic reviews.

Gyriform Infarction in Cerebral Air Embolism: Imaging Mimicker of Status Epilepticus.

Cerebral air embolism (CAE) is a potentially fatal iatrogenic complication related to common procedures including central venous catheter (CVC) removal. We report an interesting case of CAE related to CVC removal that was further complicated with status epilepticus. Neuroimaging of CAE and status epilepticus could pose diagnostic dilemmas and require consideration of wide diagnostic differentials. We discuss the clinical presentation, mechanism, and diagnostic approach, especially neuroimaging to differentiate various etiologies in CAE patients.

Stroke after Initiating IV Penicillin for Neurosyphilis: A Possible Jarisch-Herxheimer Reaction.

Introduction. Syphilis incidence has increased in the US in the last decade. Jarisch-Herxheimer reaction (JHR) is a well-documented adverse effect of penicillin treatment in syphilis. Stroke has not been reported as part of its phenomenology. Case Report. A 57-year-old man presented with worsening memory. His minimental status examination score was 14/30. Serum RPR test was positive and VDRL test in the CSF was reactive. Within six hours of first dose of IV crystalline penicillin G, he was found to have hemineglect and difficulty moving the left leg. MRI of the brain showed multiple acute ischemic strokes. Immediate MRA ruled out vascular occlusion. Penicillin treatment was stopped. Four hours later, he was found to be febrile and had two episodes of generalized tonic-clonic seizures. Conclusions. We report a case of confirmed neurosyphilis with no known modifiable stroke risk factors, who developed acute ischemic stroke and other constitutional symptoms consistent with JHR after IV penicillin. This is the first reported case in literature where an acute ischemic stroke can be attributed to Jarisch-Herxheimer reaction. Given an increase in incidence of syphilis in recent years, our case underlies the importance of keeping in mind potential catastrophic drug adverse reactions in neurosyphilis patients.