Posttraumatic Seizures Research Articles

178 Multicenter Prospective Trial of Anti-Epileptics for Early Seizure Prevention in Mild Traumatic Brain Injury with a Positive CT Scan

INTRODUCTION: Post-traumatic seizures (PTS) are a major source of disability after traumatic brain injury (TBI). The Brain Trauma Foundation Guidelines recommend prophylactic anti-epileptics (AEDs) for early PTS in severe TBI, but high-quality evidence is lacking in mild or moderate TBI. METHODS: We performed a prospective, multicenter study evaluating consecutive patients who presented to a level 1 trauma center from January 2017 through December 2020. Patients were excluded for previous seizure history, current AED use, or a neurosurgical procedure. Patients were given a 7-day course of prophylactic AEDs on a week-by-week basis and followed with in-person clinic visits, in-hospital evaluation, or a validated phone questionnaire. RESULTS: 490 patients were enrolled, 349 (71.2%) had follow-up, and 139 (39.8%) were given prophylactic AEDs. There was no difference between seizure rates for the prophylactic AED group (0.7%) and those without (2.9%; p = 0.25). Patients who had a PTS were on average older (81.4 years) than patients without a seizure (64.8 years; p = 0.02). Seizure rate increased linearly by age groups: <60 years-old (0%); 60-70 years-old (1.7%); 70-80 years-old (2.3%); and >80 years-old (4.6%). CONCLUSION: Prophylactic AEDs did not provide a benefit for PTS reduction in mild TBI patients with a positive CT head scan. Future studies should be appropriately powered for the small effect size of AEDs in mild TBI and evaluate the effects between age and prophylactic AED use.

440 Have We Made Temporal Advancements in Optimizing Surgical Outcomes and Recovery for High Risk Spinal Deformity Patients?

INTRODUCTION: Surgical correction of adult spinal deformity (ASD) has high rates of complication. However, patients often derive significant benefits in functional status and quality of life from surgery despite high-risk status. It has yet to be investigated whether spine surgeons are improving surgery for high risk patients and minimizing poor outcomes. METHODS: Included: operative ASD pts =18 yrs with pre-(BL) and 2-year (2Y) postop radiographic/HRQL data. Pts were categorized as having undergone surgery from 2009 to 2013[Early] or 2014 to 2018[Late]. High risk [HR] pts were defined as meeting =2 of the following BL criteria: 1) ++PILL or SVA by SRS-Schwab, 2) elderly [=70yrs], 3) severe frailty[Miller index], 4) high CCI [=1 SD above cohort mean], 5) three column osteotomy, and 6) fusion of >12 levels, or >7 levels for elderly pts. Differences in Smith et al. best/worst clinical outcomes, radiographic alignment targets(SRS-Schwab, age-adjusted, GAP score), and complication rates were assessed by time of surgery(Early/Late) for HR pts. RESULTS: 725 ASD pts included (61yrs, 77%F, CCI: 1.82±1.74, levels fused 11.0±4.4). 18.5% underwent 3CO. SRS-Schwab modifiers at BL: 41.4% ++PI-LL, 30.3% ++SVA, 28.8% ++PT. 47% of pts (n=338) had surgery prior to 2014[Early], and 53% (n=387) underwent surgery in 2014 or later[Late]. Overall, 52% of pts (n=377) were deemed high risk[HR]. There was a higher proportion of HR pts in the Late group (p=0.028). In terms of individual HR criteria: Late pts were older, more likely to be ++PI-LL at BL, had higher CCI, and were less likely to undergo 3CO (all p<0.05). Analysis of HR pts by Early/Late status showed no significant differences in radiographic alignment by SRS-Schwab, age-adjusted target, or GAP score by 2Y (all p>0.05). Late/HR pts were less likely to have a poor outcome by Smith et al. definition for SRS and ODI (both p<0.01). Late/HR pts had lower rates of complication, reoperation, deep surgical infection, early PJK (before 6 months), and PJF by 2Y (p<0.05). CONCLUSION: Over time in our data set, spine surgeons have both increased and optimized operating on high risk patients, while minimizing the occurrence of poor clinical outcomes and reducing complication rates.

Associations between Electroencephalographic Variables, Early Post-Traumatic Seizure Risk, and Outcomes following Pediatric Severe Traumatic Brain Injury

AbstractEarly post-traumatic seizures (PTS) are associated with worse outcomes in children with traumatic brain injury (TBI). Our aim was to identify the association between continuous electroencephalogram (cEEG) characteristics and early PTS risk following pediatric severe TBI. We also evaluated the relationship between cEEG background features and outcomes. A single-center retrospective cohort study was performed on children between 0 and 18 years of age admitted to the pediatric intensive care unit from 2016 to 2019 with severe TBI and cEEG monitoring within 7 days of injury. Raw cEEG tracings were reviewed by an epileptologist in accordance with American Clinical Neurophysiology Society (ACNS) Critical Care EEG terminology. Univariate comparisons were made between children with and without early PTS, as well as between those with and without varying cEEG background features. Eighteen children (31%) of the 59 included had early PTS. Interictal abnormalities, inclusive of sporadic spikes and sharp waves, rhythmic delta activity, or lateralized periodic discharges (LPDs) were more common among children with seizures (100 vs. 22%; p < 0.01). LPDs were also more common in the seizure group (44 vs. 2%; p < 0.01). Background discontinuity was associated with worse Glasgow Outcome Scale—Extended Pediatric Version (GOS-E Peds) scores at discharge and 3-, 6-, and 12-month post-discharge (p < 0.01). Lack of reactivity was also associated with worse GOS-E Peds scores at 3-, 6-, and 12-month post-discharge (p < 0.01). Interictal abnormalities and LPDs were each associated with early PTS following pediatric severe TBI. Larger studies should evaluate if high-risk patients would benefit from prolonged cEEG monitoring and/or more aggressive anti-seizure prophylaxis. Discontinuity and lack of variability were associated with worse outcomes. Future studies should attempt to clarify their role as potential early markers of prognosis.

Risk Factors and Prognosis of Early Posttraumatic Seizures in Moderate to Severe Traumatic Brain Injury

Early posttraumatic seizures (EPS) that may occur following a traumatic brain injury (TBI) are associated with poorer outcomes and development of posttraumatic epilepsy (PTE). To evaluate risk factors for EPS, associated morbidity and mortality, and contribution to PTE. Data were collected from an Australian registry-based cohort study of adults (age ≥18 years) with moderate to severe TBI from January 2005 to December 2019, with 2-year follow-up. The statewide trauma registry, conducted on an opt-out basis in Victoria (population 6.5 million), had 15 152 patients with moderate to severe TBI identified via Abbreviated Injury Scale (AIS) head severity score, with an opt-out rate less than 0.5% (opt-out n = 136). EPS were identified via International Statistical Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM) codes recorded after the acute admission. Outcome measures also included in-hospital metrics, 2-year outcomes including PTE, and post-discharge mortality. Adaptive least absolute shrinkage and selection operator (LASSO) regression was used to build a prediction model for risk factors of EPS. Among the 15 152 participants (10 457 [69%] male; median [IQR] age, 60 [35-79] y), 416 (2.7%) were identified with EPS, including 27 (0.2%) with status epilepticus. Significant risk factors on multivariable analysis for developing EPS were younger age, higher Charlson Comorbidity Index, TBI sustained from a low fall, subdural hemorrhage, subarachnoid hemorrhage, higher Injury Severity Score, and greater head injury severity, measured using the AIS and Glasgow Coma Score. After adjustment for confounders, EPS were associated with increased ICU admission and ICU length of stay, ventilation and duration, hospital length of stay, and discharge to inpatient rehabilitation rather than home, but not in-hospital mortality. Outcomes in TBI admission survivors at 24 months, including mortality (relative risk [RR] = 2.14; 95% CI, 1.32-3.46; P = .002), development of PTE (RR = 2.91; 95% CI, 2.22-3.81; P < .001), and use of antiseizure medications (RR = 2.44; 95% CI, 1.98-3.02; P < .001), were poorer for cases with EPS after adjustment for confounders. The prediction model for EPS had an area under the receiver operating characteristic curve of 0.72 (95% CI, 0.66-0.79), sensitivity of 66%, and specificity of 73% in the validation set. We identified important risk factors for EPS following moderate to severe TBI. Early posttraumatic seizures were associated with longer ICU and hospital admissions, ICU ventilation, and poorer 24-month outcomes including mortality and development of PTE.

Abstract P4-04-11: Dysregulation of immune checkpoint proteins in newly- diagnosed early breast cancer patients

Abstract Background: Checkpoint proteins regulate the immune system. Breast cancer (BC) cells can up-regulate or down-regulate these proteins to evade anti-tumor immune responses. Soluble forms of immune checkpoint molecules (ICMs) can be measured in human plasma. The study aimed to measure the systemic levels of a series of positive and negative ICMs at diagnosis, post-neo-adjuvant chemotherapy (NAC) and post-surgery in newly- diagnosed BC patients (pts) relative to those of a healthy control group. Method: Soluble ICMs were measured using Multiplex® bead array technology in plasma from 72 BC patients and 45 healthy controls. Data was prospectively obtained and levels compared between pre-treatment, post-NAC, and post-surgery using non-parametric tests (Mann-Whitney &amp; Kruskal-Wallis). Results: Pre-treatment, soluble stimulatory molecules viz. GITR (p&amp;lt;0.0000), GITRL (p&amp;lt; 0.0199), CD27 (p&amp;lt; 0.0243), CD40 (p&amp;lt; 0.0209), ICOS (p&amp;lt; 0.0087), as well as the inhibitory molecules PD-L1 (p&amp;lt; 0.0000), CTLA-4 (p&amp;lt; 0.005), TIM-3 (p&amp;lt; 0.0004), HVEM (p&amp;lt; 0.0004) levels were significantly lower in early BC pts compared to controls. Post treatment, there were significant increases in most ICM levels (Table 1), with the exception of CTLA-4 which decreased significantly following treatment. A pCR was documented in 65% of patients (mostly TNBC). There was no correlation between pre-treatment ICM levels and pCR. Conclusion: We identified low levels of stimulatory and inhibitory ICMs in newly-diagnosed, non-metastatic BC patients compared to healthy controls. Following treatment, with the exception of CTLA-4, most of these pre-treatment abnormalities of systemic ICM levels corrected. NAC is associated with upregulation of sPD-L1 and most other ICMs. These results indicate that early BC is associated with down-regulation of soluble stimulatory and inhibitory ICMs. Newly-diagnosed early BC patients appear to have generalized immune-suppression independent of subtype and stage. To our knowledge, this is the first study to describe the effect of treatment on systemic ICMs in early BC patients. Table 1.The effect of treatment on soluble, systemic ICMsICMControlDiagnosis (Group A)Post-NAC (Group B)Post-surgery (Group C) Group A vs Group BComparing pre-treatment levels vs post-treatment levelsMedian (pg/ml)p-valueBTLA18147130229987127770,0366CD8023291678304836110,0000CD8614297115859922124390,2789CTLA-4261815665986870,0000LAG31504161312754648805001330,0000PD-L133421647479452150,0000PD-1149171230513350150760,8888TIM350473897997596150,0000CD2745773342535154270,0000CD28461353291444277500580,0415CD4019771523203020540,0002GITR37971497403544340,0000GITRL71515886533959270,4938ICOS265061512326586297460,0001HVEM22901865404739500,0000TLR2304772683133837370420,0257 Citation Format: Bernardo Leon Rapoport, Helen C Steel, Carol Ann Benn, Simon Nayler, Teresa Smit, Liezl Heyman, Annette Theron, Nomsa Hlatswayo, Luyanda Kwofie, Pieter Meyer, Ronald Anderson. Dysregulation of immune checkpoint proteins in newly- diagnosed early breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-11.

Abstract P3-12-20: Outcomes of patients with pathologic complete response following neoadjuvant HER2-targeted therapy in patients with HER2+ early stage breast cancer

Abstract BACKGROUND: Contemporary clinical trials of HER2-targeted therapies have shown benefits regarding recurrence and survival in patients (pts) with HER2+ early stage breast cancer. The outcomes of pts treated in community practice settings who had a pathologic complete response (pCR) to neoadjuvant therapy or who had residual disease at definitive surgery (non-pCR) have not been well characterized. This preliminary study aimed to describe the patient characteristics, disease-free survival (DFS) and overall survival (OS) in patients with and without pCR following neaoadjuvant HER2-targeted therapy in The US Oncology Network. METHODS: This retrospective cohort study identified pts diagnosed with stage I-III HER2+ breast cancer who initiated neoadjuvant HER2-targeted therapy in the community setting between April 1, 2014 - March 31, 2019. Pts were followed through the date of last visit, death, or study end (March 31, 2021), whichever occurred first. Data were collected from the US Oncology Network’s electronic medical record database, iKnowMed. Natural language processing/artificial intelligence was used to identify pts with pCR status and pts with disease recurrence during the study period. Patient profiles, risk of recurrence (RR), and time to recurrence (TTR) were assessed descriptively. Kaplan-Meier methods were used to evaluate DFS and OS from the start of neoadjuvant therapy. Results were stratified by pCR status. RESULTS: The study included 641 pts (median age, 55 years), 71% had non-pCR and 29% had pCR. The majority of pts were Caucasian (79%) or black (8%). At diagnosis, 78% of pts had stage I/II disease, and 21% stage III. Nearly 74% were HR+. With a median follow-up of 33 months, pts who had non-pCR had a higher risk of disease recurrence (10.3% vs 8.1%) and a shorter median TTR (18.6 vs 21.1 months) compared to pts with pCR. Three-year DFS (87.5% vs 92.2%) and OS (96.0% vs 98.8%) were lower in pts with non-pCR than with pCR. CONCLUSIONS:Findings from this real-world study of HER2+ early stage breast cancer pts who received neoadjuvant HER2-targeted therapy in the community setting suggested that pts with non-pCR had shorter DFS and OS outcomes than pts with pCR. Pts with non-pCR had a risk of recurrence of nearly 10% over approximately a 3-year time period . This residual risk of recurrence among non-pCR pts suggested a potential opportunity to improve long-term outcomes in this group. Future analyses, including HR subgroups, are planned as data mature and longer follow-up time is available. Results on additional pts with known pCR/non-pCR data, with longer follow-up, and outcomes by HR+ vs HR- status will be presented. Disclosure DeclarationThis study was funded by Puma Biotechnology, Inc. Outcomes of pts with pCR or non-pCR following neoadjuvant HER2-targeted therapyNon-pCRpCROverall CohortN=429N=185N=641Follow-up time, months, median (range)30.8 (0.0,81.6)38.4 (2.8,83.3)33.0 (0.0,83.3)Patients with recurrence, n (%)44 (10.3%)15 (8.1%)59 (9.6%)Time to recurrence, median (range)18.6 (0.0,42.4)21.1 (0.0,60.3)18.8 (0.0,60.3)Disease-free survival at 36 months87.5% (83.4,90.7)%92.2% (86.8,95.4)%89.0% (85.9,91.5)%Overall survival at 36 months96.0% (92.8,97.8)%98.8% (95.2,99.7)%97.0% (94.9,98.3)% Citation Format: Joyce O'Shaughnessy, Nina Oestreicher, Nicole Fulcher, Wan-Yu Tseng, April Beeks, Julia Moore, Deepa Lalla. Outcomes of patients with pathologic complete response following neoadjuvant HER2-targeted therapy in patients with HER2+ early stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-20.

Abstract OT1-12-07: A phase 2 study of chemotherapy de-escalation using a pathological response-guided strategy in patients with HER2-positive, low-risk early breast cancer: PHERGain-2

Abstract Background: The introduction of trastuzumab (H) and pertuzumab (P) and ado-trastuzumab emtansine (T-DM1) has drastically improved clinical outcomes in patients (pts) with HER2-positive early breast cancer, allowing to explore chemotherapy-sparing approaches in this population. PHERGain trial is evaluating the efficacy of dual HER2-blockade with HP as both neoadjuvant and adjuvant treatment using an 18F-fluorodeoxyglucose-PET-based and a pathological response-adapted strategy [Pérez-García JM et al., Lancet Oncol. 2021;22:858-871]. PHERGain-2 study is an additional step forward and aims to assess the feasibility of chemotherapy de-escalation with neoadjuvant HP followed by adjuvant HP or T-DM1 using a pathological response-adapted strategy in low-risk HER2-positive early breast cancer pts. Trial Design: PHERGain-2 is a multicenter, open-label, non-comparative, phase 2 trial. Eligible participants are patients aged ≥18 years with previously untreated, centrally confirmed, HER2-positive (immunohistochemical score 3+), invasive, node-negative breast cancer (&amp;gt;0.5 and &amp;lt;2.5 cm in tumor size). Eastern Cooperative Oncology Group performance status of 0 or 1, left ventricular ejection fraction of at least 55%, and adequate organ function are also required. Pts will receive the fixed-dose combination of HP for subcutaneous injection (1200 mg P plus 600 mg H loading dose, followed by 600 mg P plus 600 mg H maintenance doses) administered every 3 weeks for 8 cycles as neoadjuvant treatment. Hormone receptor-positive pts will be additionally given letrozole (2.5 mg/day orally) if postmenopausal or tamoxifen (20 mg/day orally) plus gonadotropin-releasing hormone analogue if pre-/peri-menopausal or men. Centrally reviewed MRI will be performed at screening and within 2 weeks prior to surgery. Surgery will be done within 4 weeks after the last dose of study treatment. After surgery, pts who achieve a pathologic complete response in breast and axilla (ypT0/is, ypN0) will continue HP for a total of 18 cycles; pts with residual invasive breast disease and/or ypN0(i+/mol+), ypN1mi will receive T-DM1 for 10 cycles; and pts with ypN1-3 will receive T-DM1 for 10 cycles and, at investigator’s discretion, chemotherapy before starting T-DM1. Adjuvant endocrine therapy and radiotherapy will be administered as per hormone receptor status and institutional practices. The primary efficacy and safety endpoints are 3-year recurrence-free interval (RFI) as per STEEP criteria and patient-reported outcomes after 1 year from neoadjuvant treatment initiation as measured by the EORTC-QLQ-C30 scale in the overall population. Key secondary endpoints include pathologic complete response, residual cancer burden, breast-conserving surgery rate; 3-year and 5-year event-free survival, relapse-free survival, distant relapse-free survival, disease-free survival, invasive disease-free survival, breast cancer-specific survival, overall survival; and safety and tolerability as per CTCAE 5.0. A total of 393 pts will be enrolled. The sample size was calculated with the log-minus-log Kaplan-Meier method. The analysis will test the null hypothesis that the 3-year RFI rate is ≤94% and the alternative hypothesis that 3-year RFI rate is ≥98%. With the expectation a 20% dropout rate, a sample size of 393 pts is necessary to attain 80% power at nominal level of two-sided alpha of 0.05. The analysis for the primary efficacy and safety endpoints will be conducted with 95% confidence intervals based on Kaplan-Meier estimator. This trial was opened to accrual in May 2021. Citation Format: José Manuel Pérez-García, Ángel Guerrero-Zotano, Jacques Medioni, Andreas Schneeweiss, Marco Colleoni, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac. A phase 2 study of chemotherapy de-escalation using a pathological response-guided strategy in patients with HER2-positive, low-risk early breast cancer: PHERGain-2 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-07.

Abstract PD5-05: Impact of anti-HER2 therapy alone and in association with weekly paclitaxel on the ovarian reserve of young women with HER2-positive early breast cancer: Biomarker analysis of the NeoALTTO trial

Abstract Background: Knowledge regarding risk of treatment-induced premature ovarian insufficiency (POI) is crucial for appropriate oncofertility counseling. While the gonadotoxicity of anthracycline- and cyclophosphamide-based chemotherapy (CT) in young breast cancer (BC) patients (pts) is well established, the impact of anti-HER2 agents remains largely unknown and limited conflicting evidence exists for taxanes. Anti-Mullerian hormone (AMH) is an established biomarker of ovarian reserve; its measurements during systemic therapies may aid in diagnosis and prediction of POI. The NeoALTTO trial represented a unique setting to explore the acute gonadotoxicity of anti-HER2 therapy alone and in combination with weekly paclitaxel in pts not previously exposed to any other potentially gonadotoxic anticancer treatment. Methods: NeoALTTO (NCT00553358) is a multicenter, open-label, randomized phase III neoadjuvant trial in HER2-positive early BC pts randomized to receive lapatinib (L), trastuzumab (T), or their combination (L+T) alone for 6 weeks followed by the addition of paclitaxel for 12 weeks before surgery.The present analysis included only premenopausal women aged ≤45 years with available frozen serum samples at baseline (i.e. before administering any anticancer treatment), at week 2 (i.e. “biological window” of anti-HER2 therapy alone) and/or at surgery (i.e. after completion of paclitaxel plus anti-HER2 therapy). Central AMH testing was performed at Erasme Hospital (Brussels, Belgium) with the Roche Elecsys® AMH Plus assay (LoD=0.010 ng/ml). AMH levels during anti-HER2 therapy alone and then combined with paclitaxel were assessed as a measure of treatment impact on ovarian reserve. The impact of different anti-HER2 agents (T and/or L), pts’ age and baseline AMH levels on treatment gonadotoxicity were also investigated. Results: The present analysis included 130 pts with a median age of 38 years (IQR: 33-42 years), of whom 86 (66.2%) were ≤40 years. At baseline, median AMH levels were 1.29 ng/mL (IQR 0.56 - 2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median value: 1.10 ng/mL, IQR 0.45 - 2.09 ng/mL, p&amp;lt;0.001; median cumulative decrease: -12.5%, IQR -37.6% - 12.4%). At surgery, there was a large significant decline in AMH levels (median value: 0.01 ng/mL, IQR 0.01 - 0.03 ng/mL, p&amp;lt;0.001; median cumulative decrease: -99.9%, IQR -100.0% - -98.7%). Type of anti-HER2 treatment (L vs. L vs. T+L) did not impact the results: there was no significant difference between treatment arms in degree of reduction in AMH levels at week 2 (p=0.763) or at surgery (p=0.700). Age and pre-treatment ovarian reserve had a major impact on treatment-induced gonadotoxicity risk, with a more profound decrease in AMH levels observed for older pts (p&amp;lt;0.001) and those with lower baseline AMH levels (p&amp;lt;0.001). Among pts aged &amp;lt;35 years, there was no significant difference in AMH levels between those with (n=7) or without (n=35) a subsequent pregnancy at baseline (p=0.316), week 2 (p=0.463) or at surgery (p=0.610). Conclusions: This biomarker analysis of the NeoALTTO trial showed for the first time the potential acute gonadal damage induced by anti-HER2 therapies alone and with the addition of weekly paclitaxel. We observed a small but significant reduction in AMH levels during T and/or L alone and then a profound reduction to almost undetectable levels following the addition of weekly paclitaxel, without differences by specific anti-HER2 regimen. Age and pre-treatment AMH levels strongly impacted gonadotoxicity risk. While this analysis is limited by lack of AMH measurement in longer term follow-up, findings have important implications for future research and oncofertility counseling of premenopausal women with HER2-positive BC. Citation Format: Matteo Lambertini, Marcello Ceppi, Richard A. Anderson, David A. Cameron, Marco Bruzzone, Maria Alice Franzoi, Claudia Massarotti, Sarra El-Abed, Yingbo Wang, Christophe Lecocq, Paolo Nuciforo, Rebecca Rolyance, Lajos Pusztai, Joohyuk Sohn, Jacopo Ligato, Maria Maddalena Latocca, Luca Arecco, Barbara Pistilli, Kathryn J. Ruddy, Alberto Ballestrero, Lucia Del Mastro, Fedro A. Peccatori, Ann H. Partridge, Cristina Saura, Michael Untch, Martine Piccart, Serena Di Cosimo, Evandro de Azambuja, Isabelle Demeestere. Impact of anti-HER2 therapy alone and in association with weekly paclitaxel on the ovarian reserve of young women with HER2-positive early breast cancer: Biomarker analysis of the NeoALTTO trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-05.

Occurrence of early epilepsy in children with traumatic brain injury: a retrospective study.

Early post-traumatic seizures (EPTS) refer to epileptic seizures occurring within one week after brain injury. This study aimed to define the risk factors of EPTS and the protective factors that could prevent its occurrence. This is a single-center retrospective study in thePICU, Beijing Children's Hospital. Patients diagnosed with traumatic brain injury (TBI), admitted with and without EPTS between January 2016 and December 2020 were included in the study. We included 108 patients diagnosed with TBI.The overall EPTS incidence was 33.98% (35/108). The correlation between EPTS and depressed fractures is positive (P = 0.023). Positive correlations between EPTS and intracranial hemorrhage and subarachnoid hemorrhage had been established (P = 0.011and P = 0.004, respectively). The detection rates of EPTS in the electroencephalogram (EEG) monitoring was 80.00%. There was a significant difference in the EEG monitoring rate between the two groups (P = 0.041). Forty-one (37.86%, 41/108) post-neurosurgical patients were treated with prophylactic antiepileptic drugs (AEDs), and eight (19.51%, 8/41) still had seizures. No statistical significance was noted between the two groups in terms of prophylactic AEDs use (P = 0.519). Logistic regression analysis revealed that open craniocerebral injury and fever on admission were risk factors for EPTS, whereas, surgical intervention and use of hypertonic saline were associated with not developing EPTS. Breakthrough EPTS occurred after severe TBI in 33.98% of pediatric cases in our cohort. This is a higher seizure incidence than that reported previously. Patients withfever on admission and open craniocerebral injuries are more likely to develop EPTS.

Early posttraumatic seizures in pediatric traumatic brain injury: a multicenter analysis.

Early posttraumatic seizures (EPTSs) in children after traumatic brain injury (TBI) increase metabolic stress on the injured brain. The authors sought to study the demographic and radiographic predictors for EPTS, and to investigate the association between EPTS and death, and between EPTS and poor functional outcomes among children with moderate to severe TBI in Asia. A secondary analysis of a retrospective TBI cohort among participating centers of the Pediatric Acute & Critical Care Medicine Asian Network was performed. Children < 16 years of age with a Glasgow Coma Scale (GCS) score ≤ 13 who were admitted to pediatric intensive care units between January 2014 and October 2017 were included. Logistic regression analysis was performed to study risk factors for EPTS and to investigate the association between EPTS and death, and between EPTS and poor functional outcomes. Poor functional outcomes were defined as moderate disability, severe disability, and coma as defined by the Pediatric Cerebral Performance Category scale. Overall, 313 children were analyzed, with a median age of 4.3 years (IQR 1.8-8.9 years); 162 children (51.8%) had severe TBI (GCS score < 8), and 76 children (24.3%) had EPTS. After adjusting for age, sex, and the presence of nonaccidental trauma (NAT), only younger age was significantly associated with EPTS (adjusted odds ratio [aOR] 0.85, 95% CI 0.78-0.92; p < 0.001). Forty-nine children (15.6%) in the cohort died, and 87 (32.9%) of the 264 surviving patients had poor functional outcomes. EPTS did not increase the risk of death. After adjusting for age, sex, TBI due to NAT, multiple traumas, and a GCS score < 8, the presence of EPTS was associated with poor functional outcomes (aOR 2.08, 95% CI 1.05-4.10; p = 0.036). EPTSs were common among children with moderate to severe TBI in Asia and were associated with poor functional outcomes among children who survived TBI.

Short- and Long-Range Connections Differentially Modulate the Dynamics and State of Small-World Networks.

The human brain contains billions of neurons that flexibly interconnect to support local and global computational spans. As neuronal activity propagates through the neural medium, it approaches a critical state hedged between ordered and disordered system regimes. Recent work demonstrates that this criticality coincides with the small-world topology, a network arrangement that accommodates both local (subcritical) and global (supercritical) system properties. On one hand, operating near criticality is thought to offer several neurocomputational advantages, e.g., high-dynamic range, efficient information capacity, and information transfer fidelity. On the other hand, aberrations from the critical state have been linked to diverse pathologies of the brain, such as post-traumatic epileptiform seizures and disorders of consciousness. Modulation of brain activity, through neuromodulation, presents an attractive mode of treatment to alleviate such neurological disorders, but a tractable neural framework is needed to facilitate clinical progress. Using a variation on the generative small-world model of Watts and Strogatz and Kuramoto's model of coupled oscillators, we show that the topological and dynamical properties of the small-world network are divided into two functional domains based on the range of connectivity, and that these domains play distinct roles in shaping the behavior of the critical state. We demonstrate that short-range network connections shape the dynamics of the system, e.g., its volatility and metastability, whereas long-range connections drive the system state, e.g., a seizure. Together, these findings lend support to combinatorial neuromodulation approaches that synergistically normalize the system dynamic while mobilizing the system state.

Late-onset Seizure and Left Hemiparesis after Unusual Craniocerebral Penetrating Injury by a Rusty Sickle: A Case Report

BACKGROUND: Penetrating head injuries are a significant public health problem in worldwide, with an estimated 35.000 civilian deaths annually. Patients that survive to reach the hospital require rapid triage and imaging evaluation. This case report describes a patient with late-onset seizures and left hemiparesis after unusual craniocerebral penetrating injury by a rusty sickle. CASE PRESENTATION: A 26-year-old man reported that he had a sickle stabbed into the right-side parietal area. On admission, he had no neurological deficits. The rusty sickle was broken off just above the skull and did not protrude from the scalp. Computed tomography showed that the knife blade was in the parenchyma without underlying tract hematoma. Surgery was performed after 2 h of admission. Post-operatively, he recovered with no neurological deficit. After 16th days postoperatively, he was complaining of seizure and left hemiparesis. CT scan with contras showed edema and hypodense lesion at the right side of hemisphere. A course of intravenous phenytoin 100 mg/8 h and ceftriaxone 2 g/day was initiated. Physical therapy was done on the patient for 2 weeks. CONCLUSION: Traumatic brain injury (TBI) is the result of energy being transferred from an object to the human skull and underlying brain. Post-traumatic epilepsy is a common complication and can occur as early or late manifestations related to penetrating TBI. Prophylactic treatment of post-traumatic seizures (PTS) is currently not routinely recommended beyond 1 week following head injury (role of antiseizure prophylaxis). Phenytoin is the most rigorously tested AED for PTS.

Penggunaan Antikejang Pada Cedera Kepala: Tinjauan Sistematis

Brain injury can occur due to direct head impact and injury due to brain tissue damage such as hypotension, hypoxia, acidosis and edema. Brain injury will trigger an inflammatory process that can lead to post-trauma seizures. The use of anti- epileptic drugs is intended as a seizure prophylaxis so that it can reduce the incidence of seizures in the early phase of injury. Quantify the effectivity of anti seizure usage on post traumatic seizure accident. The method used in this paper is a relevant systematic review from various references and focuses on the use of analgesics for the management of seizures due to brain injury. The literature search used PubMed and found 7 literature that met the criteria. Consists of 1 RCT study and 6 observational studies. Prophylactic therapy in the incidence of head injury is effective in preventing PTS. The use of anti seizure can be given to patients with moderate or severe TBI and can be given less than 12 hours after injury to prevent seizures. Prophylactic therapy is only recommended for 7 days after head injury. Anti seizure drug which is often used as a prophylactic agent are phenytoin and levetiracetam. Lacosamide is recommended for users with refractory status epilepticus. Levetiracetam has fewer side effects than phenytoin and lacosamide, so the use of this drug is preferable to use.Using Anti seizure in cases of post-traumatic brain injury (TBI) or post traumatic seizure (PTS) is behoof as a seizure prophylactic attempt by using recommendation less than eight days because OAE has been shown several side effects, include increasing mortality. Especially for using phenytoin and lacosamide, it is necessary to monitor

Efficacy of phenytoin for 7 days versus 21 days as prophylactic anticonvulsant in traumatic brain injury patients - A comparative study.

Post traumatic seizures (PTS) are very common after traumatic brain injury and occur more common in severe form of injury. Prophylactic treatment with phenytoin has been found to be effective however till now no uniform internationally agreed guideline is available for the duration of anticonvulsant prophylaxis for traumatic brain injury patients. 100 patients of either sex between age group of 18-65 years who have suffered intracranial injury identified by CT scan, admitted in Trauma ICU were enrolled in this prospective randomized single blinded clinical study. Group 1 (n = 50) received 7 days prophylactic anticonvulsant therapy with phenytoin and Group 2 (n = 50) received for 21 days. The primary end point was the occurrence of seizures, which were classified as early (occurring from time of drug loading to day 7) or late (occurring on day 8 or later after loading of drug). Patients were also assessed for the possible adverse side effects of phenytoin. Out of 100 patients, 90 completed the study successfully as 5 patients from each group expired during the duration of the study. On comparing the frequency of seizure from 1st to 7th day after loading dose of phenytoin between two groups, out of 45 patient, 2 (4.4%) developed seizure in group 1 and 3 (6.7%) developed seizure in group 2 and found to be statistically insignificant (P = 0.645). On comparing the frequency of seizure from 1st to 21st day after loading dose of phenytoin between two groups, out of 45 patient, 4 (8.9%) developed seizure in groups 1 and 3 (11.1%) developed seizure in group 2 and found to be statistically insignificant (P = 0.725). A 21-day prophylactic anticonvulsant therapy with phenytoin was not more effective than a 7-day prophylactic therapy with phenytoin to reduce the frequency of seizure in a TBI patient in trauma ICU and was also associated with more adverse side effects that were insignificant.

Endoscopic characteristics and management of Subepithelial Lesions in Video-Gastascopie

The basic concept of Neuroanesthesia &amp; Neuro Critical Care is referred to as the ABCDE of neuroanesthesia. Early Brain Injury (EBI) was formerly known as primary brain injury. In EBI there is a loss of autoregulation and loss of blood-brain barrier integrity. The presence of Cushing's triad indicates the presence of intracranial hypertension. The target of blood pressure in traumatic brain injury (TBI) is to avoid blood pressure systolic &lt;110 mmHg, maintain cerebral perfusion pressure (CPP) 60-70 mmHg, target PaCO2 regulation is normocarbia, PaCO2 35–40 mmHg, prophylactic use of phenytoin or valproate is not recommended to prevent late post-traumatic seizures (late PTS). There is still a need to analyse decompressive craniectomy (DECRA) therapy compared with continued medical therapy for refractory intracranial pressure (ICP) elevations after TBI. General anesthesia for patients with severe TBI is preferable to total intravenous anesthesia (TIVA), the administration of fluids should consider the osmolarity of these fluids. In the new concept, in patients with elevated ICP, the volatile anesthetic concentration should be limited to 0.5 MAC. The target blood sugar is normoglycemia. Prophylactic or therapeutic hypo

Role of pericytes in the development of late-onset posttraumatic seizure.

Role of pericytes in the development of late-onset posttraumatic seizure.

Prophylactic Activation of Shh Signaling Attenuates TBI-Induced Seizures in Zebrafish by Modulating Glutamate Excitotoxicity through Eaat2a.

Approximately 2 million individuals experience a traumatic brain injury (TBI) every year in the United States. Secondary injury begins within minutes after TBI, with alterations in cellular function and chemical signaling that contribute to excitotoxicity. Post-traumatic seizures (PTS) are experienced in an increasing number of TBI individuals that also display resistance to traditional anti-seizure medications (ASMs). Sonic hedgehog (Shh) is a signaling pathway that is upregulated following central nervous system damage in zebrafish and aids injury-induced regeneration. Using a modified Marmarou weight drop on adult zebrafish, we examined PTS following TBI and Shh modulation. We found that inhibiting Shh signaling by cyclopamine significantly increased PTS in TBI fish, prolonged the timeframe PTS was observed, and decreased survival across all TBI severities. Shh-inhibited TBI fish failed to respond to traditional ASMs, but were attenuated when treated with CNQX, which blocks ionotropic glutamate receptors. We found that the Smoothened agonist, purmorphamine, increased Eaat2a expression in undamaged brains compared to untreated controls, and purmorphamine treatment reduced glutamate excitotoxicity following TBI. Similarly, purmorphamine reduced PTS, edema, and cognitive deficits in TBI fish, while these pathologies were increased and/or prolonged in cyclopamine-treated TBI fish. However, the increased severity of TBI phenotypes with cyclopamine was reduced by cotreating fish with ceftriaxone, which induces Eaat2a expression. Collectively, these data suggest that Shh signaling induces Eaat2a expression and plays a role in regulating TBI-induced glutamate excitotoxicity and TBI sequelae.

To determine the effectiveness of antiepileptic drugs in treatment of acute traumatic brain injury for preventing seizure.

Objectives: To determine the effectiveness of antiepileptic drugs in treatment of acute traumatic brain injury for preventing seizure. Study Design: Cross Sectional Study. Setting: Ziauddin Hospital, North Campus, Karachi. Period: 2014 to 2016. Material &amp; Methods: Eighty diagnosed cases of traumatic brain injury were included in this study. Patients were examined physically and neurological assessment, with mental status was assessed by Glasgow Coma scoring. A blood sample was taken and Computed tomography was performed. Antiepileptic therapy was given for a period of one week minimally or 10 days maximally and patients were assessed clinically for seizures. All information was collected in the predesign proforma. Results: The patients median age was 25[16-43]. There were 70% male and 30% female. Rate of seizure was 6.3% (5/80) cases mortality was observed 5% (4/80) cases. Rate of seizure was significantly high in patients who had moderate TBI as compare to mild TBI (p=0.016). It was also significantly high in those cases who had diabetes and IHD. Rate of mortality was significantly high in seizure cases (p=0.0005). Conclusion: Prophylactic antiepileptic drugs are effective in decreasing the risk of early post-traumatic seizures in acute traumatic brain injury.These drug may provide an important and alternative treatment option for seizure prevention in acute TBI patients and prevent further brain damage.

In Reply: Recommendation to Create New Neuropathological Guidelines for the Postmortem Diagnosis of Chronic Traumatic Encephalopathy

In Reply: Recommendation to Create New Neuropathological Guidelines for the Postmortem Diagnosis of Chronic Traumatic Encephalopathy

Abstract 11616: Seizures in Infants with Congenital Heart Disease

Background: Infants with congenital heart disease (CHD) may have an increased risk to develop seizures during hospitalization. Objectives: to examine the association of CHD with non-epileptic, non-traumatic seizures in hospitalized infants up to one year of age. Methods: We conducted a retrospective analysis of the U.S. National Inpatient Sample dataset (2015-2018). We used the international classification of disease-10 th version to identify infants with different types of CHD. We included infants up to one year of age. We excluded infants &lt;35 week gestational age, infants with central nervous system or with major congenital anomalies, common trisomy or genetic disorders. We used chi square testing to examine the association of subtypes of CHD with seizures excluding post traumatic and epileptic seizures. We calculated mortality in infants with CHD who developed seizures versus those who did not have seizures. Results: There was 12,023,781 infants in the weighted sample who met our inclusion criteria. Of them, 48.7% were females, 46.7% were Caucasians, 195,685 (1.63%) were identified with a CHD and 20,565 (0.17%) suffered at least one episode of seizure during hospitalization. Seizures occurred in 4225 (2.2%) of infants with any type of CHD compared to 16,340 (0.14%) in infants with no CHD, odds ratios for seizures is 15.6 (CI: 15.2-16.5, p &lt;0.001). The association of seizures with subtypes of CHD is shown in table-1. Among infants with CHD, 2205 infants expired during hospitalization. Mortality was higher in infants with CHD who suffered seizures (8.5%) vs. those who did not have seizures (1.0%), OR 9.6 (8.5-10.8, p &lt;0.001). Conclusion: Infants with CHD have a higher chance to experience seizure episodes during their hospitalization and those who have seizures have higher chances of mortality during hospitalization. Further analysis is required to understand the pathological correlation between seizures and CHD and its impact on long term developmental outcomes.