Danger in plain sight: determining who is at highest risk for cefepime induced neurotoxicity and its associated morbidity and mortality.

Cefepime is a fourth-generation cephalosporin that is widely used to treat sepsis but is associated with a potentially dangerous neurotoxicity syndrome, cefepime-induced neurotoxicity (CIN). As a result, patients treated with cefepime may be at higher risk for morbidity, including seizures, and mortality. Though the recent ACORN trial concluded that cefepime does not increase the risk of mortality, most of these patients were not critically ill or elderly, two of the most at risk populations for CIN. Further, diagnosis may be difficult in the critical care setting as patients may have multiple reasons for encephalopathy. Therefore, this population in particular should be studied and monitored closely for CIN. Importantly, there are not well defined diagnostic criteria for CIN to guide evaluation and management. Defining the risk factors for CIN and using laboratory and EEG to help support the clinical diagnosis could be helpful in early recognition of CIN to help institute treatment and to rule out seizures. In this mini review, we highlight risk factors for CIN, discuss the possible value of EEG, and propose a diagnostic and management approach in the evaluation and management of CIN.

Radiologic Classification of Hippocampal Sclerosis in Epilepsy.

Temporal lobe epilepsy is a common form of epilepsy that is often associated with hippocampal sclerosis (HS). Although HS is commonly considered a binary assessment in radiological evaluation, it is known that histopathological changes occur in distinct clusters. Some subtypes of HS only affect certain subfields, resulting in minimal changes to the overall volume of the hippocampus. This is likely a major reason why whole hippocampal volumetrics have underperformed versus expert readers. With recent advancements in MRI technology, it is now possible to characterize the substructure of the hippocampus more accurately. However, this is not consistently addressed in radiographic evaluations. The histological subtype of HS is critical for prognosis and treatment decision making, necessitating improved radiological classification of HS. The International League Against Epilepsy (ILAE) has issued a consensus classification scheme for subtyping HS histopathological changes. This review aims to explore how the ILAE subtypes of HS correlate with radiographic findings, introduce a grading system that integrates radiological and pathological reporting in HS, and outline an approach to detecting HS subtypes using MRI. This framework will not only benefit current clinical evaluations, but also enhance future studies involving high-resolution MRI in temporal lobe epilepsy.ABBREVIATIONS: CA = cornu ammonis; DG = dentate gyrus; HS = hippocampal sclerosis; ILAE = International League Against Epilepsy; SRLM = strata radiatum, lacunosum, and moleculare layers; TLE = temporal lobe epilepsy.

Early Postoperative Seizures Following Awake Craniotomy and Functional Brain Mapping for Lesionectomy.

OBJECTIVE: Awake craniotomy with electrocorticography (ECoG) and direct electrical stimulation (DES) facilitates lesionectomy while avoiding adverse effects. Early postoperative seizures (EPS), occurring within 7 days following surgery, can lead to morbidity. However, risk factors for EPS after awake craniotomy including clinical and ECoG data are not well defined. METHODS: We retrospectively studied the incidence and risk factors of EPS following awake craniotomy for lesionectomy, and report short-term outcomes between January 1, 2020, and December 31, 2022. RESULTS: We included 138 patients (56 female) who underwent 142 awake craniotomies, average age was 50.78 ± 15.97 years. Eighty-eight (63.7%) patients had a preoperative history of tumor-related epilepsy treated with antiseizure medication (ASM), 12 (13.6%) with drug-resistance. All others (36.3%) received ASM prophylaxis with levetiracetam perioperatively and continued for 14 days. An equal number of cases (71) each utilized a novel circle grid or strip electrodes for ECoG. There were 31 (21.8%) cases of intraoperative seizures, 16 with EPS (11.3%). Acute abnormality on early postoperative neuroimaging (P = 0.01), subarachnoid hemorrhage (P = 0.01), young age (P = 0.01), and persistent postoperative neurologic deficits (P = 0.013) were associated with EPS. Acute abnormality on neuroimaging remained significant in multivariate analysis. Outcomes during hospitalization and early outpatient follow up were worse with EPS. CONCLUSIONS: We report novel findings using ECoG and clinical features to predict EPS, including acute perioperative brain injury, persistent postoperative deficits and young age. Given worse outcomes with EPS, clinical indicators for EPS should alert clinicians of potential need for early postoperative EEG monitoring and perioperative ASM adjustment.

Enhanced sensitivity of electrocorticography during awake craniotomy using a novel circular grid electrode.

PURPOSE: Awake craniotomy with intraoperative functional brain mapping (FBM) bedside neurological testing is an important technique used to optimize resective brain surgeries near eloquent cortex. Awake craniotomy performed with electrocorticography (ECoG) and direct electrical stimulation (DES) for FBM can delineate eloquent cortex from lesions and epileptogenic regions. However, current electrode technology demonstrates spatial limitations. Our group has developed a novel circular grid with the goal of improving spatial recording of ECoG to enhance detection of ictal and interictal activity. METHODS: This retrospective study was approved by the institutional review board at Mayo Clinic Florida. We analyzed patients undergoing awake craniotomy with ECoG and DES and compared ECoG data obtained using the 22 contact circular grid to standard 6 contact strip electrode. RESULTS: We included 144 cases of awake craniotomy with ECoG, 73 using circular grid and 71 with strip electrode. No significant differences were seen regarding preoperative clinical and demographic data, duration of ECoG recording (p = 0.676) and use of DES (p = 0.926). Circular grid was more sensitive in detecting periodic focal epileptiform discharges (PFEDs) (p = 0.004), PFEDs plus (p = 0.032), afterdischarges (ADs) per case (p = 0.022) at lower minimum (p = 0.012) and maximum (p < 0.0012) intensity stimulation, and seizures (p = 0.048). PFEDs (p < 0.001), PFEDs plus (p < 0.001), and HFOs (p < 0.001) but not ADs (p = 0.255) predicted electrographic seizures. CONCLUSION: We demonstrate higher sensitivity in detecting ictal and interictal activity on ECoG during awake craniotomy with a novel circular grid compared to strip electrode, likely due to better spatial sampling during ECoG. We also found association between PFEDs and intraoperative seizures.

Can we improve electrocorticography using a circular grid array in brain tumor surgery?

Intraoperative electrocorticography (iECoG) is used as an adjunct to localize the epileptogenic zone during surgical resection of brain tumors in patients with focal epilepsies. It also enables monitoring of after-discharges and seizures with EEG during functional brain mapping with electrical stimulation. When seizures or after-discharges are present, they complicate accurate interpretation of the mapping strategy to outline the brain's eloquent function and can affect the surgical procedure. Recurrent seizures during surgery requires urgent treatment and, when occurring during awake craniotomy, often leads to premature termination of brain mapping due to post-ictal confusion or sedation from acute rescue therapy. There are mixed results in studies on efficacy with iECoG in patients with epilepsy and brain tumors influencing survival and functional outcomes following surgery. Commercially available electrode arrays have inherent limitations. These could be improved with customization potentially leading to greater precision in safe and maximal resection of brain tumors. Few studies have assessed customized electrode grid designs as an alternative to commercially available products. Higher density electrode grids with intercontact distances less than 1 cm improve spatial delineation of electrophysiologic sources, including epileptiform activity, electrographic seizures, and afterdischarges on iECoG during functional brain mapping. In response to the shortcomings of current iECoG grid technologies, we designed and developed a novel higher-density hollow circular electrode grid array. The 360-degree iECoG monitoring capability allows continuous EEG recording during surgical intervention through the aperture with and without electrical stimulation mapping. Compared with linear strip electrodes that are commonly used for iECoG during surgery, the circular grid demonstrates significant benefits in brain tumor surgery. This includes quicker recovery of post-operative motor deficits (2.4 days versus 9 days, p = 0.05), more extensive tumor resection (92.0% versus 77.6%, p = 0.003), lesser reduction in Karnofsky Performance scale postoperatively (-2 versus -11.6, p = 0.007), and more sensitivity to recording afterdischarges. In this narrative review, we discuss the advantages and disadvantages of commercially available recording devices in the operating room and focus on the usefulness of the higher-density circular grid.

Risk factors for preoperative and postoperative seizures in patients with glioblastoma according to the 2021 World Health Organization classification.

OBJECTIVE: To identify risk factors for developing glioblastoma (GBM) related preoperative (PRS) and postoperative seizures (POS). Also, we aimed to analyze the impact of PRS and POS on survival in a GBM cohort according to the revised 2021 WHO glioma classification. METHODS: We performed a single-center retrospective cohort study of patients with GBM (according to the 2021 World Health Organization Classification) treated at Mayo Clinic Florida between January 2018 and July 2022. Seizures were stratified into preoperative seizures (PRS) and postoperative seizures (POS, >7 days after surgery). Associations between patients' characteristics and overall survival with PRS and POS were assessed. RESULTS: One hundred nineteen adults (mean =60.9 years), 49 (41.2 %) females, were identified. The rates of PRS and POS in the cohort were 35.3 % (n = 42) and 37.8 % (n = 45), respectively. Patients with PRS were younger (p = 0.035) and were likely to undergo intraoperative electrocorticography. The incidence of PRS (p = 0.049) and POS (p<0.001) was lower among patients with tumors located in the occipital location. PRS increased the risk of POS after adjusting for age and sex (RR: 2.59, CI = 1.44-4.65, p = 0.001). There was no association between PRS or POS and other patient-related factors, including several tumor molecular markers (TMMs) examined. PRS (p = 0.036), POS (p<0.001), and O6-Methylguanine-DNA Methyltransferase (MGMT) promotor methylation status (p = 0.032) were associated with longer survival time. CONCLUSIONS: PRS and POS are associated with non-occipital tumor location and longer survival time in patients with GBM. While younger ages predicted PRS, PRS predicted POS. Well-designed prospective studies with larger sample sizes are needed to clarify the influence of TMMs in the genesis of epileptic seizures in patients with GBM.

Incidence and risk factors associated with seizures in cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) is a common cause of intracranial hemorrhage (ICH), which is a risk factor for seizures. The incidence and risk factors of seizures associated with a heterogeneous cohort of CAA patients have not been studied. METHODS: We conducted a retrospective study of patients with CAA treated at Mayo Clinic Florida between 1 January 2015 and 1 January 2021. CAA was defined using the modified Boston criteria version 2.0. We analyzed electrophysiological and clinical features, and comorbidities including lobar ICH, nontraumatic cortical/convexity subarachnoid hemorrhage (cSAH), superficial siderosis, and inflammation (CAA with inflammation [CAA-ri]). Cognition and mortality were secondary outcomes. Univariate and multivariate analyses were performed to determine risk of seizures relative to clinical presentation. RESULTS: Two hundred eighty-four patients with CAA were identified, with median follow-up of 35.7 months (interquartile range = 13.5-61.3 months). Fifty-six patients (19.7%) had seizures; in 21 (37.5%) patients, seizures were the index feature leading to CAA diagnosis. Seizures were more frequent in females (p = 0.032) and patients with lobar ICH (p = 0.002), cSAH (p = 0.030), superficial siderosis (p < 0.001), and CAA-ri (p = 0.005), and less common in patients with microhemorrhage (p = 0.006). After controlling for age and sex, lobar ICH (odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.1-4.2), CAA-ri (OR = 3.8, 95% CI = 1.4-10.3), and superficial siderosis (OR = 3.7, 95% CI = 1.9-7.0) were independently associated with higher odds of incident seizures. CONCLUSIONS: Seizures are common in patients with CAA and are independently associated with lobar ICH, CAA-ri, and superficial siderosis. Our results may be applied to optimize clinical monitoring and management for patients with CAA.

From Alpha to Zeta: A Systematic Review of Zeta Waves.

PURPOSE: Electroencephalogram is used for prognostication and diagnosis in critically ill patients and is vital in developing clinical management algorithms. Unique waveforms on EEG may distinguish neurological disorders and define a potential for seizures. To better characterize zeta waves, we sought to define their electroclinical spectrum. METHODS: We performed a systematic review using MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Review [through Ovid], Scopus, Science Citation Index Expanded and Emerging Sources Citation Index [through the Web of Science], and Epistemonikos. Grey literature resources were searched. RESULTS: Five hundred thirty-seven articles were identified. After excluding duplicates and reviewing titles, abstracts, and bodies and bibliographies of articles, four studies reported 64 cases describing data from patients with zeta waves, with a prevalence of 3 to 4%. Various and often incomplete clinical, neuroimaging, and EEG data were available. 57 patients (89.1%) had a focal cerebral lesion concordant with the location of zeta waves on EEG. 26 patients (40.6%) had clinical seizures, all but one being focal onset. Thirteen patients (20%) had epileptiform activity on EEG. Typically, zeta waves were located in the frontal head regions, often with generalized, frontal, predominant, rhythmic delta activity and associated with focal EEG suppression. CONCLUSIONS: Zeta waves frequently represent an underlying focal structural lesion. Their presence suggests a heightened risk for seizures. The small number of retrospective cases series in the literature reporting zeta waves might be an underrepresentation. We suggest a need for prospective studies of cEEG in critically ill patients to determine their clinical significance.

Intraoperative electrocorticography during laser-interstitial thermal therapy predicts seizure outcome in mesial temporal lobe epilepsy.

OBJECTIVE: Magnetic resonance-guided laser interstitial thermal therapy (MRLiTT) for treating temporal lobe epilepsy has recently gained popularity. We aimed to investigate the predictive value of pre-and post-MRLiTT epileptiform discharges (EDs) on intraoperative electrocorticography (iECoG) in seizure outcomes for patients with mesial temporal lobe epilepsy (mTLE). METHODS: We conducted a pilot, prospective single-center cohort study on seven consecutive patients with mTLE that underwent MRLiTT. Pre- and post-MRLiTT iECoG was performed using a 1x8 contact depth electrode along the same trajectory used for the laser catheter. RESULTS: The responders had a robust reduction in ED frequency compared to pre-MRLiTT iECoG (86% vs 13%, p < 0.01). Clinical characteristics, including risk factors for epilepsy, duration of epilepsy, presence of mesial temporal lobe sclerosis, prior intracranial monitoring, the absolute frequency of pre- or post-MRLiTT EDs, and ablation volume were not significantly associated with responder status. CONCLUSIONS: This is the first demonstration that intraoperative reduction in EDs during mesial temporal lobe MRLiTT may potentially predict seizure outcomes and may serve as an intraoperative biomarker for satisfactory ablation. However, larger prospective studies are needed to confirm our findings and evaluate the utility of iECoG during MRLiTT. SIGNIFICANCE: iECoG during mesial temporal lobe MRLiTT may help assess seizure outcomes.

Neurophysiological and Clinical Correlates of Acute Posthypoxic Myoclonus.

SUMMARY: Prognostication following cardiorespiratory arrest relies on the neurological examination, which is supported by neuroimaging and neurophysiological testing. Acute posthypoxic myoclonus (PHM) is a clinical entity that has prognostic significance and historically has been considered an indicator of poor outcome, but this is not invariably the case. "Malignant" and more "benign" forms of acute PHM have been described and differentiating them is key in understanding their meaning in prognosis. Neurophysiological tests, electroencephalogram in particular, and clinical phenotyping are crucial in defining subtypes of acute PHM. This review describes the neurophysiological and phenotypic markers of malignant and benign forms of acute PHM, a clinical approach to evaluating acute PHM following cardiorespiratory arrest in determining prognosis, and gaps in our understanding of acute PHM that require further study.

Clinical outcome of imaging-based programming for anterior thalamic nucleus deep brain stimulation.

OBJECTIVE: The authors hypothesized that the proximity of deep brain stimulator contacts to the anterior thalamic nucleus-mammillothalamic tract (ANT-MMT) junction determines responsiveness to treatment with ANT deep brain stimulation (DBS) in drug-resistant epilepsy and conducted this study to test that hypothesis. METHODS: This retrospective study evaluated patients who had undergone ANT DBS electrode implantation and whose devices were programmed to stimulate nearest the ANT-MMT junction based on direct MRI visualization. The proximity of the active electrode to the ANT and the ANT-MMT junction was compared between responders (≥ 50% reduction in seizure frequency) and nonresponders. Linear regression was performed to assess the percentage of seizure reduction and distance to both the ANT and the ANT-MMT junction. RESULTS: Four (57.1%) of 7 patients had ≥ 50% reduction in seizures. All 4 responders had at least one contact within 1 mm of the ANT-MMT junction, whereas the 3 patients with < 50% seizure improvement did not have a contact within 1 mm of the ANT-MMT junction. Additionally, the 4 responders demonstrated contact positioning closer to the ANT-MMT junction than the 3 nonresponders (mean distance from MMT: 0.7 mm on the left and 0.6 mm on the right in responders vs 3.0 mm on the left and 2.3 mm on the right in nonresponders). However, proximity of the electrode contact to any point in the ANT nucleus did not correlate with seizure reduction. Greater seizure improvement was correlated with a contact position closer to the ANT-MMT junction (R2 = 0.62, p = 0.04). Seizure improvement was not significantly correlated with proximity of the contact to any ANT border (R2 = 0.24, p = 0.26). CONCLUSIONS: Obtained using a combination of direct visualization and targeted programming of the ANT-MMT junction, data in this study support the hypothesis that proximity to the ANT alone does not correlate with seizure reduction in ANT DBS, whereas proximity to the ANT-MMT junction does. These findings support the importance of direct targeting in ANT DBS, as well as imaging-informed programming. Additionally, the authors provide supportive evidence for future prospective trials using ANT-MMT junction for direct surgical targeting.

Case Report: "Aggressive" perioperative antiseizure medication prophylaxis in patients with glioma-related epilepsy at high risk of early postoperative seizures following awake craniotomy.

Early postoperative seizures (EPS) are a common complication of brain tumor surgery. EPS can lead to hemorrhage, cerebral hypoxia, increased intracranial pressure, longer hospitalization, reduced quality of life, decreased overall survival, and increased morbidity. However, there are no formal guidelines on perioperative antiseizure medication (ASM) management in patients with tumor-related epilepsy who are deemed high risk for EPS. In this study, we describe the case of a 38-year-old man with isocitrate dehydrogenase-mutant mixed glioma and two episodes of EPS manifesting with status epilepticus during prior tumor surgeries and who presented with tumor progression. The Tumor Board recommended awake craniotomy with direct electrical stimulation (DES). The patient was administered aggressive preoperative "prophylactic" ASMs by increasing the maintenance doses of lacosamide and levetiracetam by 25% 48 h before surgery. An intravenous load of fosphenytoin (20 mg/kg) was administered in the operating room before DES, followed by a maintenance dosing of 300 mg/day for 14 days. EPS did not occur, and he was discharged home on postoperative day 4. Our case illustrates that aggressive perioperative prophylactic ASM therapy beyond the maintenance ASM regimen can be considered in patients with tumor-related epilepsy at risk of EPS.

EEG as an indispensable tool during and after the COVID-19 pandemic: A review of tribulations and successes.

During the coronavirus disease 2019 (COVID-19) pandemic, elective and non-emergent tests and procedures were delayed or suspended in lieu of diverting resources to more emergent treatment of critically ill patients and to avoid the spread and contraction of COVID-19. Further, the workforce was stretched thin, and healthcare facilities saw high turnover rates for full-time and contract employees, which strained the system and reduced the ability to provide clinical services. One of the casualties of these changes was electroencephalography (EEG) procedures, which have been performed less frequently throughout the world since the pandemic. Whether considered routine or emergent, the deferral of EEG studies can cause downstream effects, including a delay in diagnosis and initiation of treatment for epilepsy and non-epileptic seizures resulting in a higher risk of morbidity and mortality. Despite these limitations, the importance and utility of EEG and EEG technologists have been reinforced with the development of COVID-related neurological complications, including encephalopathy and seizures, which require EEG for diagnosis and treatment. Since the pandemic, reliance on remote telemonitoring has further highlighted the value and ease of using EEG. There has also been a heightened interest in rapid EEG devices that non-technologist professionals can attach quickly, allowing minimum patient contact to avoid exposure to COVID-19 and taking advantage of remote EEG monitoring. This review discusses the acute and potential long-term effects of the COVID-19 pandemic on the use and performance of EEG.

Association of intracranial abnormalities with the development of epilepsy and drug-resistant epilepsy in patients with Parry-Romberg syndrome.

BACKGROUND: Epilepsy represents an essential component of Parry Romberg syndrome (PRS). This study aimed to identify clinical factors that influence the development of epilepsy and drug-resistant epilepsy (DRE) in PRS. METHODS: We retrospectively reviewed the medical records of eighty patients with PRS. Data including the age of onset for PRS, history of seizures, use and timing of immunotherapy, antiseizure medication use, and EEG and brain imaging findings were reviewed. For comparison with the patients with epilepsy (PRSe+) group, we selected 18 age and sex-matched controls from the patient without epilepsy (PRSe-) cohort using propensity score matching. RESULTS: Eighteen (22.5%) had epilepsy: 12 were female, and the median age was 14.5 years (range = 6-48 years). Eleven patients developed DRE. The median latency between the onset of cutaneous manifestations and diagnosis and timing and use of immunotherapy was similar between the PRSe + and PRSe- groups. Intracranial abnormalities were commonly seen in the PRSe + group (16 vs. 2, p < 0.01). White matter disease and ipsilateral atrophy were common among the PRSe + group. Timing and use of immunotherapy, epileptiform discharges, and brain imaging abnormalities did not differ between those with DRE and without. CONCLUSIONS: The presence and degree of severity of ipsilateral brain abnormalities are risk factors for the development of epilepsy in PRS but not factors in predicting drug resistance. The timing of immunotherapy did not influence the development of PRSe + or DRE. Prospective studies are needed to identify biomarkers for epilepsy and assess the role of immunotherapy on seizure outcomes in PRSe + .

"Temporal" intermittent rhythmic delta activity: the true localizing nature of TIRDA

Temporal lobe epilepsy is the most common form of focal epilepsy and is frequently resistant to antiseizure medication. Non-invasive biomarkers are crucial when resective epilepsy surgery is considered in order to guide diagnostic work-up and management. Interictal epileptiform discharges, when concordant with ictal EEG recording and a focal abnormality on functional imaging or anatomic MRI in patients with temporal lobe epilepsy, portend a favorable outcome with resective or ablative surgery. An interictal non-epileptiform feature on EEG believed to have the same localizing potential as epileptiform discharges is temporal intermittent rhythmic delta activity (TIRDA). The precise localization of TIRDA has been a subject of debate, but has been associated with seizures that arise from the temporal region. We report a 64-year-old female who underwent unsuccessful right anterior temporal lobectomy for drug-resistant focal epilepsy, suspected to originate from the right temporal lobe. Subsequent video-EEG monitoring revealed right, greater than left, TIRDA and interictal epileptiform discharges arising from the temporal regions bilaterally, despite a generous temporal lobectomy demonstrated by brain MRI. Further, using EEG source localization, we identified TIRDA using scalp EEG in sensor space, localized to the ipsilateral orbitofrontal region. We discuss the proposed localization of TIRDA in this case and address the importance of characterizing TIRDA in the presurgical evaluation of patients with epilepsy.