Depressed Level Of Consciousness Research Articles

A Drive Interrupted: Stroke of the Anterior Choroidal Artery – A Case Report

The anterior choroidal artery (AChA) is the most distal branch of the internal carotid artery (ICA) The ACHA is significant because it supplies important structures in the brain, including the optic tract, anterior portion of cerebral peduncle, lateral geniculate body, uncus, globus pallidus, posterior and superficial areas of the thalamus, and the retrolenticular and posterior portions of the internal capsule on the same side as the artery. Isolated strokes involving the AChA are rare and can result in HHH Syndrome, consisting of contralateral hemiplegia, hemisensory loss, and homonymous hemianopia. Features which distinguish an AChA infarction from larger arterial pathology are lack of headache and lack of depressed level of consciousness in subacute infarction, and usually lack of aphasia acutely. The etiology remains controversial, with proposed mechanisms including cardioembolic, large-vessel atherosclerosis, dissection of the ICA, small-vessel occlusion, and cryptogenic causes. Herein, the authors report a case of an isolated AChA infarction resulting in a right-sided, pure motor hemiparesis with no sensory or vision loss, highly suggestive of cardioembolic origin, with the evaluation of the patient, and eventual treatment strategy.

A Real-World Pharmacovigilance Study of Ceftazidime/Avibactam: Data Mining of the Food and Drug Administration Adverse Event Reporting System Database.

Ceftazidime/avibactam (CAZ/AVI) is a combination of a well-known third-generation, broad-spectrum cephalosporin with a new beta-lactamase inhibitor that has been approved for the treatment of various infectious diseases (especially multidrug-resistant Gram-negative bacterial infections) by the Food and Drug Administration (FDA). The current study extensively assessed CAZ/AVI-related adverse events (AEs) in the real world through data mining of the FDA Adverse Event Reporting System (FAERS) database to better understand toxicities. The signals of CAZ/AVI-related AEs were quantified using disproportionality analyses, including the reporting odds ratio, the proportional reporting ratio, the Bayesian confidence propagation neural network, and the multi-item gamma Poisson shrinker algorithms. Out of 10,114,815 records retrieved from the FAERS database, 628 cases were identified, where CAZ/AVI was implicated as the primary suspect drug. A total of 61 preferred terms with significant disproportionality that simultaneously met the criteria of all four algorithms were retained. Several unexpected safety signals may also occur, including melena, hypernatremia, depressed level of consciousness, brain edema, petechiae, delirium, and shock hemorrhagic. The median onset time for AEs associated with CAZ/AVI was 4 days, with most cases occurring within 3 days after CAZ/AVI initiation.

Occipital condyle fracture in the pediatric population: A management algorithm and systematic review.

This study aims to develop an accessible stepwise management algorithm for pediatric presentations of occipital condyle fractures (OCFs) based on a systematic review of the published literature regarding diagnostic evaluation, treatment, and outcomes. A systematic review of the literature was conducted on PubMed to locate English language studies reporting on the management of pediatric OCFs. Data extraction of clinical presentation, management strategies, imaging, and treatment outcome was performed. A total of 15 studies reporting on 38 patients aged 18 years and younger presenting with OCFs were identified. Loss of consciousness (LOC), depressed level of consciousness, neck pain, decreased neck range of motion (ROM), and cranial nerve injury were the most common presenting symptoms. Diagnostic imaging included radiographs, computed tomography (CT) scans, magnetic resonance imaging (MRI), and functional radiographs to assess cervical stability. Treatment options varied and included soft collar, hard collar, and halo vest. All studies resulted in a complete healing of the OCF, with resolution of associated pain. The proposed treatment algorithm suggests a framework for the management of pediatric OCFs based on the available evidence (levels of evidence: 3, 4). This review of the literature indicated that a stepwise approach should be utilized in the management of isolated pediatric OCFs.

Central Nervous System Adverse Reactions to Amantadine Intoxication: A Case Report and Analysis of JADER.

A few case reports of central nervous system (CNS) symptoms caused by amantadine intoxication have been published, detailing various types of symptoms and differing times to onset. We encountered a patient who developed CNS symptoms with amantadine. This prompted us to investigate the types, time to onset, and outcome of CNS adverse reactions to amantadine by analyzing data from a pharmacovigilance database. The patient was evaluated at Chutoen General Hospital, Shizuoka, Japan. Analysis was performed using the Japanese Adverse Drug Event Report (JADER) database. In our case, the amantadine blood concentration was 4,042 ng/ml, i.e., in the toxic range. The time to onset was 26 days for dyskinesia and 90 days for depressed level of consciousness. Symptoms resolved when amantadine was discontinued. The JADER database contained 974 cases of adverse reactions to amantadine. The most frequently reported CNS adverse reaction was hallucination, with a reporting odds ratio of 64.28 (95% confidence interval=52.67-78.46). Positive signals were detected for all CNS adverse reactions. For all CNS reactions, clinical outcomes were poor in a comparatively low percentage of cases. Most CNS reactions occurred soon after administration of amantadine, usually within approximately one month. Because most CNS adverse reactions to amantadine usually occur within approximately one month of initiating treatment, healthcare providers should exercise heightened vigilance in monitoring patients for such reactions during this period.

Clinical Experience with Cranial Nerve Impairment in the CARTITUDE-1, CARTITUDE-2 Cohorts A, B, and C, and Cartitude-4 Studies of Ciltacabtagene Autoleucel (Cilta-cel)

Introduction: Cilta-cel is a dual-binding, BCMA-targeting CAR-T cell therapy that has shown high rates of deep and durable response in patients (pts) with relapsed/refractory multiple myeloma (RRMM), and significantly prolonged PFS vs SOC in pts with lenalidomide-refractory MM after 1-3 prior lines of therapy (LOT; HR, 0.26) in the phase 3 CARTITUDE-4 trial. CAR-T therapies are associated with AEs related to immune activation, including neurologic toxicities (Gonzalez Castro. Neuro-Oncol Pract. 2020). Here, we describe the clinical experience with presentation and management of cranial neuropathy (CNP) in pts treated with cilta-cel in the CARTITUDE-1, CARTITUDE-2 Cohorts A, B, and C, and CARTITUDE-4 studies. Methods: CARTITUDE-1 and CARTITUDE-2 Cohort C pts had ≥3 prior LOT, incl PIs, IMiDs, and anti-CD38 mAbs, or were double-refractory to PI and IMiD; CARTITUDE-2 Cohort C pts also had non-cellular anti-BCMA therapy. CARTITUDE-2 Cohort B pts relapsed within 12 months of initial therapy. CARTITUDE-2 Cohort A and CARTITUDE-4 pts had 1-3 prior LOT, incl PI and IMiD, and were lenalidomide-refractory. After apheresis, pts received bridging therapy, then 1 cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) 5-7 days (d) after lymphodepletion. Pts presenting with signs/symptoms of cranial nerve impairment commonly underwent a diagnostic workup that included CSF analysis and brain MRI at investigator discretion. Correlative data were available for pts in CARTITUDE-4: cilta-cel levels and T cell memory phenotypes in peripheral blood were assessed by flow cytometry, and serum cytokines were measured using multiplex sandwich immunoassays on the Meso Scale Discovery platform. Results: Of the 332 pts infused with cilta-cel as study treatment in CARTITUDE-1, CARTITUDE-2 (Cohorts A, B, and C), and CARTITUDE-4, 21 (6.3%) developed CNP (TABLE); most cases were grade (gr) 2 (n=3 gr 3). 6 pts had CNP that affected both sides; most unilateral impairments were left-sided. Median time to onset was 22 d (range 17-101; 81% had onset on d 22 +/- 5). Cranial nerve (CN) VII was involved in all pts; 2 pts had additional CNs involved (1 CN III [gr 3], 2 CN V [gr 3]). Twelve pts had concurrent neurologic symptoms/neurotoxicities (headache, n=7; n=1 each for dysgeusia, parosmia, restlessness, peripheral sensory neuropathy, polyneuropathy, amnesia, aphasia, agitation, depressed level of consciousness). Clinical characteristics of pts with or without CNP were comparable. In the 21 pts with CNP, median age was 64 years; 81% were male; at baseline, 1 pt had high disease burden (BM 95% plasma cells), 4 had plasmacytomas (1 bone-based); 1 pt had ISS stage III. Most pts responded to bridging therapy. Six pts had an infection after cilta-cel infusion and prior to CNP onset (bacterial, n=5; CMV, n=2; both, n=1). CRS rate was comparable between pts with vs without CNP. 90% of pts with CNP had preceding CRS (all gr 1/2; median onset, d 7; median duration, 3 d); 13 received tocilizumab for CRS. One pt had preceding gr 2 ICANS; no pts had movement/neurocognitive TEAEs (MNT) at any time. CSF analysis and brain MRI were performed in 14 and 17 pts, respectively. No evidence of infectious or malignant etiology was identified in any of these cases; MRI showed facial nerve enhancement in 7 pts, in whom there were no other significant findings. Most CNP cases were treated with corticosteroids for median 13 d. CNP resolved in 19/21 pts within median 66 d, including the 3 pts with gr 3 CNP. In CARTITUDE-4, pts with CNP had significantly higher levels of CAR+ T cell expansion (C max) and greater exposure to CAR+ T cells (AUC 0-CNP onset) than those without CNP (FIGURE). Pts with CNP had a trend toward higher peak concentration and exposure level (AUC 0-CNP onset) of IL-6, IL-10, and IL-2Rα, but not in IFNγ. The differentiation pattern of memory T cells from apheresis to the time of peak CAR+ T expansion (T max) was comparable in pts with vs without CNP; CAR+ T cells at T max were dominant with central memory T cells in both groups. Conclusions:Ptstreated with CAR-T cells, including cilta-cel, may experience CNP.The pathogenesis of the events in these 3 studies was unknown/idiopathic, but it is important to rule out etiology of infection or MM progression. Most cases were low-grade and resolved with a limited course of corticosteroids. CNP in CARTITUDE-4 was associated with higher exposure to CAR-T cells before onset, but no predictive clinical factors have been established.

Study of Organophosphorus Poisoning at a Tertiary Care Teaching Hospital

Introduction: Organophosphate (OP) insecticides inhibit both cholinesterase and pseudo-cholinesterase activities. The inhibition of acetylcholinesterase causes accumulation of acetylcholine at synapses, and overstimulation of neurotransmission occurs as a result of this accumulation. The mortality rate of OP poisoning is high. Early diagnosis and appropriate treatment is often life saving. Treatment of OP poisoning consists of intravenous atropine and oximes. The clinical course of OP poisoning may be quite severe and may need intensive care management. Methods: A retrospective study was performed on the patients with OP poisoning. Fifty patients were included. Diagnosis was performed from the history taken either from the patient or from the patient's relatives about the agent involved in the exposure. Diagnosis could was confirmed with serum and red blood cell anticholinesterase levels. Intravenous atropine and pralidoxime was administered as soon as possible. Other measures for the treatment were gastric lavage and administration of activated charcoal via nasogastric tube, and cleansing the patient's body with soap and water. The patients were intubated and mechanically ventilated if the patients had respiratory failure, a depressed level of consciousness, which causes an inability to protect the airway, and hemodynamic instability. Mechanical ventilation was performed as synchronized intermittent mandatory ventilation + pressure support mode, either as volume or pressure control. Positive end expiratory pressure was titrated to keep SaO2 above 94% with 40% FIO2. Weaning was performed using either T-tube trials or pressure support weaning. The chi-square test was used for statistical analysis. Data are presented as mean ± standard deviation. Results: There were 26 female and 24 male patients. Thirty-five were suicide attempts and 15 were accidental exposure. The gastrointestinal route was the main route in 44 patients. The most frequent signs were meiosis, change in mental status, hypersalivation and fasciculations. Ten patients (20.0%) required mechanical ventilation. Complications were observed in 35 patients. These complications were respiratory failure (14 patients), aspiration pneumonia (10 patients), urinary system infection (6 patients), convulsion (4 patients) and septic shock (1 patient). The duration of the intensive care stay was 5.2 ± 3.0 days. Discussion: Ingestion of OP compounds for suicidal purposes is a major problem, especially in developing countries. Thirty-five of our patients used the OP insecticide for suicide. The average respiratory rate of these patients increased from 22 to 38 breaths/min, which is an important sign of respiratory distress. The nurse to patient ratio was increased after these events. Early recognition of respiratory failure resulting in intubation and mechanical ventilation is a life-saving intervention for patients with OP poisoning. Respiratory failure is the most troublesome complication, which was observed in 35 patients. Patients with OP poisoning may have respiratory failure for many reasons, including aspiration of the gastric content, excessive secretions, pneumonia and septicemia complicating acute respiratory distress syndrome. Conclusions: OP insecticide poisoning is a serious condition that needs rapid diagnosis and treatment. Since respiratory failure is the major reason for mortality, careful monitoring, appropriate management and early recognition of this complication may decrease the mortality rate among these patients.

Comparison of Propofol versus Midazolam Infusion for Conscious Sedation during Spinal Anaesthesia in Patients Undergoing Inguinal Hernia Repair

Abstract Background The operating room is an anxiety provoking environment. Supplemental sedation with an intravenous agent is often required to allay fear and anxiety in patients subjected to spinal anaesthesia. Sedation is a valuable tool to make surgery under regional anaesthesia convenient for the patient, the anaesthetist and the surgeon. Conscious sedation is a minimally depressed level of consciousness that retains the patient’s ability to maintain his or her airway independently and continuously and to respond appropriately to physical stimulation and verbal commands, produced by pharmacologic or non-pharmacologic methods alone or in combination. Aim of the Work This study will be designed to compare Propofol and Midazolam with regard to their suitability as sedative agents during spinal anaesthesia in terms of onset & recovery from sedation, haemodynamic stability, dosage and side effects of both the drugs. Patients and Methods This Interventional clinical study (Randomized double blinded study was conducted in Ain Shams University Hospital’s operating rooms through 3 months on 50 patients. After obtaining approval from the medical ethical committee in Ain Shams University Hospital’s operating rooms, a written informed consent was obtained from every patient after explaining the procedure. Results Based on this study the following conclusions have been made: Cardiovascular parameters and respiration were well maintained in both the study groups, no incidence of apnea was noticed in both the study groups, pain during the injection of propofol was a side effect noticed, onset of action was faster in the propofol group, propofol group was less co-operative than midazolam group but this was clinically insignificant, midazolam group showed slower recovery than propofol group restricting and wasting the productive time of the patient, qualities such as short plasma half-life period, absence of postoperative nausea and vomiting, make propofol a better choice for sedation and thus propofol is a fast acting, safe and easily controllable sedative with rapid recovery. This offered the advantage of early patient discharge and better patient compliance. Conclusion When given as a sedative adjunct to spinal I, both propofol and midazolam in equisedative infusions offer good anxiolysis and good cardio respiratory stability. Propofol has the advantage of providing faster onset of sedation, a rapid clear headed recovery from the same and lesser postoperative impairment of recall while midazolam offers better intraoperative amnesia.

Concomitant West Nile Virus Encephalitis and Ischemic Strokes – A Case Report and Review of the Literature. (P8-10.004)

<h3>Objective:</h3> We report a case of concomitant West Nile virus (WNV) encephalitis and acute ischemic strokes and review the literature documenting cases of WNV encephalitis with associated cerebrovascular disease. <h3>Background:</h3> Cases of WNV have risen since 2002, but neuroinvasive disease in uncommon, occurring in 1 in 150. The most common presentation of neuroinvasive WNV is a meningo-encephalitis. Cerebrovascular presentations are exceedingly rare. <h3>Design/Methods:</h3> We report a case of concomitant neuro-invasive WNV infection and acute stroke. We include magnetic resonance imaging (MRI), serologic and cerebrospinal fluid (CSF) laboratory data, and electroencephalogram (EEG) findings. We also present a review of PubMed, Embase, and Web of Science databases for cases of WNV encephalitis associated with cerebral infarctions. <h3>Results:</h3> A 70-year-old woman without significant cardiovascular history was admitted with depressed level of consciousness, hypophonia, and inability to participate in examination. MRI and computed tomography angiography demonstrated bilateral corona radiata strokes without obvious large vessel occlusion. Transthoracic echocardiogram demonstrated a patent foramen ovale; lower extremity ultrasound did not reveal any venous thrombosis. Low-density lipoprotein was elevated. Urine toxicology screen was positive for cocaine. Poor mental status could not be explained by the infarcts alone thus further testing was pursued. Testing for toxic and metabolic abnormalities was unrevealing. EEG demonstrated mild generalized delta slowing. CSF testing showed elevated WNV IgM and IgG. Upon discharged to a rehabilitation facility, her examination was unchanged from presentation. A review of the literature yielded 28 cases of WNV encephalitis complicated by cerebrovascular disease. Most cases were multi-territorial ischemic strokes but etiology of infarction appears varied. <h3>Conclusions:</h3> Pursuit of uncommon etiologies is imperative when presenting symptoms and imaging are not explained by routine testing. The association of neurotropic viruses and strokes may be underappreciated, and possible pathophysiologic connections remain unexplained. <b>Disclosure:</b> Dr. Hingorani has nothing to disclose. Dr. Feske has received publishing royalties from a publication relating to health care. Dr. Cervantes-Arslanian has nothing to disclose.

CTIM-23. DOSE ESCALATION TRIAL OF FC-ENGINEERED ANTI-CD40 MONOCLONAL ANTIBODY (2141-V11) ADMINISTERED INTRATUMORALLY WITH D2C7-IT VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMAS (RMGS)

Abstract BACKGROUND D2C7-IT, a novel immunotoxin-based cytotoxic therapy, targets epidermal growth factor receptor (EGFR) and mutant EGFR variant III. In preclinical studies, D2C7-IT kills tumor cells and prolongs survival, but is unable to generate cures in all animals. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. Eliminating glioblastoma immunosuppression via CD40 co-stimulation is anticipated to enhance D2C7-IT-induced antitumor responses. In murine glioma models, CED of D2C7-IT+αCD40 generated cures and long-term tumor-specific adaptive immunity. Hence, we are conducting a phase 1 trial of D2C7-IT+2141-V11 (αhuman-CD40) administered via CED in rMG patients. METHODS Eligibility includes adult patients with solitary supratentorial rMG (WHO grade 3/4); ≥ 4 weeks after chemotherapy, bevacizumab, or study drug; adequate organ function; and KPS ≥ 70%. Cohorts of 3 patients are treated with increasing doses of 2141-V11 to determine the maximum tolerated dose when administered sequentially following D2C7-IT (166,075 ng) via CED at 0.5 mL/hr. Five dose levels (DLs) are evaluated (2141-V11 at: #1: 0.70 mg; #2: 2.0 mg; #2**: 3.0 mg #2*: 4.0 mg; #3: 7.0 mg). RESULTS As of May 29, 2022, 13 patients were treated (3 patients on DL1, DL2, and DL2**; 2 patients on DL3 and DL2*). No dose-limiting toxicities were observed; however, lower DLs were added due to higher frequency of adverse events (AEs) expected with D2C7-IT+2141-V11 with DL3 and DL2* (fever, neurologic symptoms). All patients remain alive 0.7-10.6 months after therapy. Grade ≥ 2 AEs due to D2C7-IT+2141-V11 include: headache (grade 3, n = 1; grade 2, n = 4); pyramidal tract disorder (grade 3, n = 1; grade 2, n = 2); paresthesia (grade 3, n = 1); dysphasia (grade 3, n = 1); seizures (grade 2; n = 2); fever (grade 2; n = 2); and one each of grade 2 depressed level of consciousness, fatigue, and concentration impairment. Enrollment is ongoing. CONCLUSIONS Intratumoral administration of D2C7-IT+2141-V11 via CED is safe, encouraging efficacy results are observed.

Drugs used for sedation in gastrointestinal endoscopy

Background: Sedation, defined as the depressed level of consciousness induced by the administration of drugs, is used widely for gastrointestinal endoscopy to relieve the patient’s anxiety and discomfort. In addition, a successful procedure can be anticipated with the control of unintended movements. Therefore, sedation has become an essential element of gastrointestinal endoscopy.Current Concepts: Sedation is classified into the following four stages according to the level of consciousness: minimal sedation or anxiolysis, moderate sedation or conscious sedation, deep sedation, and general anesthesia. The degree of response to sedation varies from person to person, depending on the age, underlying diseases, alcohol or medication intake, anxiety level, sensitivity to pain, and pharmacogenetic characteristics. In particular, certain situations require special attention not only during preoperative evaluation but also during the procedure and recovery, such as old age, obesity, pregnancy, lactation, and liver cirrhosis. Therefore, the same procedure may require different levels of sedation in different patients, and some patients may even experience changing levels of sedation during a single procedure.Discussion and Conclusion: Although most patients undergoing gastrointestinal endoscopy under sedation recover without any problem, various types of adverse events related to sedation may occur occasionally. In rare cases, serious complications may occur that threaten the patient’s life. Therefore, basic principles governing the facilities and equipment as well as performance of sedation itself should be followed to prevent unfavorable accidents. Moreover, every medical personnel should be familiar with the pharmacological properties of the drugs used for sedation and trained for emergencies.

In-Hospital Depressed Level of Consciousness and Long-Term Functional Outcomes in ICU Survivors.

Among critically ill patients, acutely depressed level of consciousness is associated with mortality, but its relationship to long-term outcomes such as disability and physical function is unknown. We investigated the relationship of level of consciousness during hospitalization with long-term disability and physical function in ICU survivors. Multi-center observational cohort study. Medical or surgical ICUs at five U.S. centers. Adult survivors of respiratory failure or shock. None. Depressed level of consciousness during hospitalization was defined using the Richmond Agitation Sedation Scale (RASS) score (including all negative scores) by calculating the area under the curve using linear interpolation. Sedative-associated level of consciousness was similarly defined for all hospital days that sedation was received. We measured disability in basic activities of daily living (BADLs), instrumental activities of daily living (IADLs), discharge destination, and self-reported physical function. In separate models, we evaluated associations between these measures of level of consciousness and outcomes using multivariable regression, adjusted for age, sex, race, body mass index, education level, comorbidities, baseline frailty, baseline IADLs and BADLs, hospital type (civilian vs veteran), modified mean daily Sequential Organ Failure Assessment score, duration of severe sepsis, duration of mechanical ventilation, and hospital length of stay. Of the 1,040 patients enrolled in the ICU, 781 survived to hospital discharge. We assessed outcomes in 624 patients at 3 months and 527 patients at 12 months. After adjusting for covariates, there was no association between depressed level of consciousness (total or sedation-associated) with BADLs or IADLs at either 3- or 12-month follow-up. There was also no association with self-reported physical function at 3 or 12 months or with discharge destination. Depressed level of consciousness, as defined by the RASS, was not associated with disability or self-reported physical function. Future studies should investigate additional modifiable in-hospital risk factors for disability and poor physical function following critical illness.

Hepatic Encephalopathy and Treatment Modalities: A Review Article.

Hepatic encephalopathy (HE) is a condition that is commonly seen in individuals suffering from liver cirrhosis. After excluding brain illness, HE is described as a range of neuropsychiatric disorders in individuals with liver impairment. It is characterized by personality changes, intellectual impairment, and a depressed level of consciousness. Toxins that are typically eliminated from the body by the liver build up in the blood and eventually reach the brain, causing HE. Many signs and symptoms of HE may often be treated if caught early and treated properly. It is important to remember that not everyone who is affected may experience every symptom mentioned below. Affected individuals should speak with their doctor and medical staff about their specific disease, associated symptoms, and general prognosis. Many people only have minor symptoms, known as minimal HE. The exact pathophysiology of HE is still being debated, with the primary theories focusing on neurotoxins, reduced neurotransmission caused by alterations in brain energy metabolism, systemic inflammatory response, and blood-brain barrier (BBB) disturbances in liver failure, as well as metabolic irregularities.

A phase 1 trial of D2C7-it in combination with an Fc-engineered anti-CD40 monoclonal antibody (2141-V11) administered intratumorally via convection-enhanced delivery for adult patients with recurrent malignant glioma (MG).

e14015 Background: D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin comprising an EGFR wild-type and mutant-specific (EGFRvIII) monoclonal antibody (Ab) fragment and a genetically engineered form of the Pseudomonas exotoxin. When injected directly into the tumor by convection enhanced delivery (CED), immunotoxins induce both direct tumor killing and secondary immune responses by activation of CD4+ and CD8+ T-cells. Tumor-associated macrophages (TAMs) are the most prominent glioma-infiltrating immune cells and constitute up to 40% of the tumor mass. Upon binding of D2C7-IT to EGFR and cellular internalization, the Pseudomonas exotoxin moiety of the D2C7-IT kills residual GBM cells, upregulates proinflammatory CD40, and induces pattern recognition receptor pathway transcriptome expression. This potentially creates a proinflammatory glioma microenvironment where TAM activation may be further stimulated by sequential CED of 2141-V11, an Fc engineered anti-human CD40 agonist antibody developed at Rockefeller University. We are conducting a first in human trial of the combination of D2C7-IT + 2141-V11 administered via CED in recurrent MG patients. Methods: Eligibility includes adult patients with recurrence of a solitary supratentorial WHO grade 3 or 4 MG; ≥ 4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS ≥ 70%. Cohorts of 3 patients are treated with increasing levels of 2141-V11 to determine the maximum tolerated dose (MTD) of the compound administered intratumorally in conjunction with D2C7-IT. Dose escalation and de-escalation are managed using a modified Bayesian optimal interval (BOIN) design to identify the MTD. Intratumoral administration of D2C7-IT via CED (4612 ng/mL over 72 hours) is followed by a 7-hour infusion of 2141-V11, both infused at 0.5 mL/hr. 2141-V11 is dose-escalated to determine the MTD when combined with D2C7-IT. Four dose levels (DL) are planned: #1: 0.70 mg; #2: 2.0 mg; #3: 7.0 mg; #4: 21.0 mg. Results: As of February 7, 2022, three patients were treated at DL1 and DL2, and two patients at DL3. No DLTs have been observed, and all eight patients remain alive and in observation on study after 7.0, 6.5, 6.0, 4.4, 2.8, 2.4, 0.9 and 0.5 months. Early signs of tumor response have been observed, with one patient at DL1 and 2 patients at DL2 without radiographic evidence of active tumor. Grade 2 or higher AEs due to D2C7-IT and/or 2141-V11 include: headache (grade 3, n = 1; grade 2, n = 2); paresthesia (grade 3, n = 1; grade 2, n = 1); dysphasia (grade 3, n = 1); pyramidal tract disorder (grade 3, n = 1; grade 2, n = 1); and depressed level of consciousness (grade 2, n = 1). Enrollment is ongoing. Conclusions: Intratumoral administration of D2C7-IT + 2141-V11 via CED is safe, and encouraging efficacy results have been observed. Clinical trial information: NCT04547777.

Ketoacidosis and otitis media as a potencial cause of cerebral venous thrombosis in a 7-year-old boy

Cerebral venous sinus thrombosis (CVST) in childhood is a rare disorder, occurring most often in the neonatal period, with mortality approaching 10%. This condition has multifactorial etiology including common childhood illnesses such as fever, infection, dehydration, and anemia, as well as acute and chronic medical conditions such as congenital heart disease, nephrotic syndrome, and malignancy. Thrombosis can also develop and propagate in response to local venous stasis. A large number of children have coincident local head or neck pathology, including head trauma, brain tumors, or recent intracranial surgery. Clinical symptoms are frequently nonspecific and include seizures, depressed level of consciousness, coma, lethargy, nausea, vomiting, headache, visual impairment, papilledema, and hemiparesis, which may often obscure the diagnosis and delay treatment. In the case of patients with neurological symptoms, imaging studies such as computed tomography (CT) and magnetic resonance imaging (MRI) are invaluable in diagnostics of various pathologies of the nervous system, because of their non-invasiveness, high sensitivity, and specificity. Early diagnosis with management along with a plan for secondary prevention can save from catastrophic consequences.

An Uncommon Presentation of Cryptococcal Meningoencephalitis

Cryptococcal meningoencephalitis (CM) remains a common cause of central nervous system infections. Patients usually present with headache, fever, malaise, and altered mental status over several weeks. Signs are often absent, but they may include meningism, papilledema, cranial nerve palsies, and depressed level of consciousness. Individuals with CM can occasionally present with small vessel vasculitis causing cerebral lesions. The literature regarding patterns of cerebrovascular injury in CM is scarce.We describe a case of CM in which an unusual presentation was observed: transient focal neurological symptoms initially with absence of fever that led to a misleading primary diagnosis of transient ischemic attack. Since neurological symptoms may be a manifestation of a cryptococcal infection, it is necessary to have a high degree of suspicion for this pathology in the presence of focal neurological deficits, even in patients with vascular risk factors, requiring a thorough etiological investigation.

Associated Factors and Prognostic Implications of Non-convulsive Status Epilepticus in Ischemic Stroke Patients With Impaired Consciousness.

Background and Purpose: Non-convulsive status epilepticus (NCSE) is common in patients with disorders of consciousness and can cause secondary brain injury. Our study aimed to explore the determinants and prognostic significance of NCSE in stroke patients with impaired consciousness.Method: Consecutive ischemic stroke patients with impaired consciousness who were admitted to a neuro intensive care unit were enrolled for this study. Univariate and multivariable logistic regression were used to identify factors associated with NCSE and their correlation with prognosis.Results: Among the 80 patients studied, 20 (25%) died during hospitalization, and 51 (63.75%) had unfavorable outcomes at the 3-month follow-up. A total of 31 patients (38.75%) developed NCSE during 24-h electroencephalogram (EEG) monitoring. Logistic regression revealed that NCSE was significantly associated with an increased risk of death during hospital stay and adverse outcomes at the 3-month follow-up. Patients with stroke involving the cerebral cortex or those who had a severely depressed level of consciousness were more prone to epileptogenesis after stroke.Conclusion: Our results suggest that NCSE is a common complication of ischemic stroke, and is associated with both in-hospital mortality and dependency at the 3-month follow-up. Long-term video EEG monitoring of stroke patients is, therefore required, especially for those with severe consciousness disorders (stupor or coma) or cortical injury.

Pyridoxamine 5’-Phosphate Oxidase Deficiency: A Potentially Treatable Epileptic Encephalopathy

Pyridoxal phosphate-responsive neonatal epileptic encephalopathy due to pyridoxamine-5-primephosphate oxidase deficiency is a rare cause of epileptic encephalopathy. A neonate with this condition presents early in life with refractory seizures which does not respond to conventional anti-epileptic medications, depressed level of consciousness, and severe psychomotor retardation if left untreated. Early initiation of active cofactor pyridoxal-5’-phophate can be curative. We are describing a rare neurometabolic condition; the first case in the Kingdom of Bahrain to the best of our knowledge. Keywords: Pyridoxal-5’-phosphate, pyridoxamine 5’-phosphate oxidase, pyridoxine dependent epilepsy, epileptic encephalopathy, neonatal seizure

Phase I trial of sargramostim/pelareorep therapy in pediatric patients with recurrent or refractory high-grade brain tumors.

BackgroundBrain tumors are the leading cause of cancer death for pediatric patients. Pelareorep, an immunomodulatory oncolytic reovirus, has intravenous efficacy in preclinical glioma models when preconditioned with GM-CSF (sargramostim). We report a phase I trial with the primary goal of evaluating the safety of sargramostim/pelareorep in pediatric patients with recurrent or refractory high-grade brain tumors and a secondary goal of characterizing immunologic responses.MethodsThe trial was open to pediatric patients with recurrent or refractory high-grade brain tumors (3 + 3 cohort design). Each cycle included 3 days of subcutaneous sargramostim followed by 2 days of intravenous pelareorep. Laboratory studies and imaging were acquired upon recruitment and periodically thereafter.ResultsSix patients participated, including three glioblastoma, two diffuse intrinsic pontine glioma, and one medulloblastoma. Two pelareorep dose levels of 3 × 108 and 5 × 108 tissue culture infectious dose 50 (TCID50) were assessed. One patient experienced a dose limiting toxicity of persistent hyponatremia. Common low-grade (1 or 2) adverse events included transient fatigue, hypocalcemia, fever, flu-like symptoms, thrombocytopenia, and leukopenia. High-grade (3 or 4) adverse events included neutropenia, lymphopenia, leukopenia, hypophosphatemia, depressed level of consciousness, and confusion. All patients progressed on therapy after a median of 32.5 days and died a median of 108 days after recruitment. Imaging at progression did not show evidence of pseudoprogression or inflammation. Correlative assays revealed transient but consistent changes in immune cells across patients.ConclusionsSargramostim/pelareorep was administered to pediatric patients with recurrent or refractory high-grade brain tumors. Hyponatremia was the only dose limiting toxicity (DLT), though maximum tolerated dose (MTD) was not determined.

Neurologic Complications in Adult and Pediatric Patients with SARS-CoV-2 Infection

SARS-CoV-2 has an impact on the nervous system as a result of pathological cellular and molecular events at the level of vascular and neural tissue. Severe neurologic manifestations including stroke, ataxia, seizure, and depressed level of consciousness are prevalent in patients with SARS-CoV-2 infection. Although the mechanism is still unclear, SARS-CoV-2 has been associated with the pathogenesis of intravascular coagulation and angiotensin-converting enzyme-I, both exacerbating systemic inflammation and contributing to hypercoagulation or blood–brain barrier leakage, resulting in ischemic or hemorrhagic stroke. On the other hand, the SARS-CoV-2 spike protein in neural tissue and within the cerebrospinal fluid may induce neural dysfunction, resulting in neuroinflammation, which is exacerbated by peripheral and neural hypercytokinemia that can lead to neuronal damage and subsequent neuroinflammation. A deeper understanding of the fundamental biological mechanisms of neurologic manifestations in SARS-CoV-2 infection can pave the way to identifying a single biomarker or network of biomarkers to help target neuroprotective therapy in patients at risk for developing neurological complications.

Cortical Acetylcholine Levels Correlate With Neurophysiologic Complexity During Subanesthetic Ketamine and Nitrous Oxide Exposure in Rats.

BACKGROUND:Neurophysiologic complexity has been shown to decrease during states characterized by a depressed level of consciousness, such as sleep or anesthesia. Conversely, neurophysiologic complexity is increased during exposure to serotonergic psychedelics or subanesthetic doses of dissociative anesthetics. However, the neurochemical substrates underlying changes in neurophysiologic complexity are poorly characterized. Cortical acetylcholine appears to relate to cortical activation and changes in states of consciousness, but the relationship between cortical acetylcholine and complexity has not been formally studied. We addressed this gap by analyzing simultaneous changes in cortical acetylcholine (prefrontal and parietal) and neurophysiologic complexity before, during, and after subanesthetic ketamine (10 mg/kg/h) or 50% nitrous oxide.METHODS:Under isoflurane anesthesia, adult Sprague Dawley rats (n = 24, 12 male and 12 female) were implanted with stainless-steel electrodes across the cortex to record monopolar electroencephalogram (0.5–175 Hz; 30 channels) and guide canulae in prefrontal and parietal cortices for local microdialysis quantification of acetylcholine levels. One subgroup of these rats was instrumented with a chronic catheter in jugular vein for ketamine infusion (n = 12, 6 male and 6 female). The electroencephalographic data were analyzed to determine subanesthetic ketamine or nitrous oxide–induced changes in Lempel-Ziv complexity and directed frontoparietal connectivity. Changes in complexity and connectivity were analyzed for correlation with concurrent changes in prefrontal and parietal acetylcholine.RESULTS:Subanesthetic ketamine produced sustained increases in normalized Lempel-Ziv complexity (0.5–175 Hz; P < .001) and high gamma frontoparietal connectivity (125–175 Hz; P < .001). This was accompanied by progressive increases in prefrontal (104%; P < .001) and parietal (159%; P < .001) acetylcholine levels that peaked after 50 minutes of infusion. Nitrous oxide induction produced a transient increase in complexity (P < .05) and high gamma connectivity (P < .001), which was accompanied by increases (P < .001) in prefrontal (56%) and parietal (43%) acetylcholine levels. In contrast, the final 50 minutes of nitrous oxide administration were characterized by a decrease in prefrontal (38%; P < .001) and parietal (45%; P < .001) acetylcholine levels, reduced complexity (P < .001), and comparatively weaker frontoparietal high gamma connectivity (P < .001). Cortical acetylcholine and complexity were correlated with both subanesthetic ketamine (prefrontal: cluster-weighted marginal correlation [CW r] [144] = 0.42, P < .001; parietal: CW r[144] = 0.42, P < .001) and nitrous oxide (prefrontal: CW r[156] = 0.46, P < .001; parietal: CW r[156] = 0.56, P < .001) cohorts.CONCLUSIONS:These data bridge changes in cortical acetylcholine with concurrent changes in neurophysiologic complexity, frontoparietal connectivity, and the level of consciousness.