Brain tumor-related epilepsy management: A Society for Neuro-oncology (SNO) consensus review on current management.

Tumor-related epilepsy (TRE) is a frequent and major consequence of brain tumors. Management of TRE is required throughout the course of disease and a deep understanding of diagnosis and treatment is key to improving quality of life. Gross total resection is favored from both an oncologic and epilepsy perspective. Shared mechanisms of tumor growth and epilepsy exist, and emerging data will provide better targeted therapy options. Initial treatment with antiseizure medications (ASM) in conjunction with surgery and/or chemoradiotherapy is typical. The first choice of ASM is critical to optimize seizure control and tolerability considering the effects of the tumor itself. These agents carry a potential for drug-drug interactions and therefore knowledge of mechanisms of action and interactions is needed. A review of adverse effects is necessary to guide ASM adjustments and decision-making. This review highlights the essential aspects of diagnosis and treatment of TRE with ASMs, surgery, chemotherapy, and radiotherapy while indicating areas of uncertainty. Future studies should consider the use of a standardized method of seizure tracking and incorporating seizure outcomes as a primary endpoint of tumor treatment trials.

Incidence of Seizure and Associated Risk Factors in Patients in the Medical Intensive Care Unit (ICU) at Memorial Sloan Kettering Cancer Center (MSK) from 2016-2017.

Background: Seizures and status epilepticus are common neurologic complications in the intensive care unit (ICU) but the incidence in a cancer ICU is unknown. It is important to understand seizure risk factors in cancer patients to properly diagnose the seizure type to ensure appropriate therapy. Methods: We identified patients admitted to the medical ICU at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to December 2017 who had continuous or routine electroencephalography (EEG) and identified clinical and electrographic seizures by chart review. Results: Of the 1059 patients admitted to the ICU between 2016 and 2017, 50 patients had clinical and/or electrographic seizures (incidence of 4.7%, 95% CI: 3.4-6.0). The incidences of clinical and electrographic seizure were 4.1% and 1.1%, respectively. In a multivariable stepwise regression model, history of seizure (OR: 2.9, 95% CI: 1.1-7.8, P: .03), brain metastasis (OR: 2.5, 95% CI: 1.1-5.8, P: .03), vasopressor requirement (OR: 2.2, 95% CI: 1.0-4.9, P: .05), and age < 65 (2.4, 95% CI: 1.2-5.0, P: .02) were associated with increased risk of seizure (either clinical or electrographic). Obtaining continuous EEG instead of routine EEG increased the yield of seizure detection significantly (OR: 3.9, 95% CI: 1.3-11.1, P: .01). No chemotherapy in the past 30 days, no antibiotic use, vasopressor requirement, and having a brain tumor increased risk of electrographic seizure. Length of continuous EEG > 24 h significantly increased the chances of both clinical and electrographic seizure detection, (OR: 2.6 [95% CI: 1.2-5.7] and 15.0 [95% CI: 2.7-82.5], respectively). Conclusions: We identified known and cancer-related risk factors which can aid clinicians in diagnosing seizures in cancer ICUs. Long-term video EEG monitoring should be considered, particularly given the treatable and reversible nature of seizures.

Pharmacoresistant seizures and IDH mutation in low-grade gliomas.

BACKGROUND: Many low-grade gliomas (LGG) harbor isocitrate dehydrogenase (IDH) mutations. Although IDH mutation is known to be epileptogenic, the rate of refractory seizures in LGG with IDH mutation vs wild-type had not been previously compared. We therefore compared seizure pharmacoresistance in IDH-mutated and wild-type LGGs. METHODS: Single-institution retrospective study of patients with histologic proven LGG, known IDH mutation status, seizures, and ≥2 neurology clinic encounters. Seizure history was followed until histological high-grade transformation or death. Seizures requiring ≥2 changes in anti-epileptic drugs were considered pharmacoresistant. Incidence rates of pharmacoresistant seizures were estimated using competing risks methodology. RESULTS: Of 135 patients, 25 patients (19%) had LGGs classified as IDH wild-type. Of those with IDH mutation, 104 (94.5%) were IDH1 R132H; only 6 were IDH2 R172K. 120 patients (89%) had tumor resection, and 14 (10%) had biopsy. Initial post-surgical management included observation (64%), concurrent chemoradiation (23%), chemotherapy alone (9%), and radiotherapy alone (4%). Seizures became pharmacoresistant in 24 IDH-mutated patients (22%) and in 3 IDH wild-type patients (12%). The 4-year cumulative incidence of intractable seizures was 17.6% (95% CI: 10.6%-25.9%) in IDH-mutated and 11% (95% CI: 1.3%-32.6%) in IDH wild-type LGG (Gray's P-value = .26). CONCLUSIONS: 22% of the IDH-mutated patients developed pharmacoresistant seizures, compared to 12% of the IDH wild-type tumors. The likelihood of developing pharmacoresistant seizures in patients with LGG-related epilepsy is independent to IDH mutation status, however, IDH-mutated tumors were approximately twice as likely to experience LGG-related pharmacoresistant seizures.

SNO and EANO practice guideline update: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors.

OBJECTIVE: To update the 2000 American Academy of Neurology (AAN) practice parameter on anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. METHODS: Following the 2017 AAN methodologies, a systematic literature review utilizing PubMed, EMBASE Library, Cochrane, and Web of Science databases was performed. The studies were rated based on the AAN therapeutic or causation classification of evidence (class I-IV). RESULTS: Thirty-seven articles were selected for final analysis. There were limited high-level, class I studies and mostly class II and III studies. The AAN affirmed the value of these guidelines. RECOMMENDATIONS: In patients with newly diagnosed brain tumors who have not had a seizure, clinicians should not prescribe antiepileptic drugs (AEDs) to reduce the risk of seizures (level A). In brain tumor patients undergoing surgery, there is insufficient evidence to recommend prescribing AEDs to reduce the risk of seizures in the peri- or postoperative period (level C). There is insufficient evidence to support prescribing valproic acid or levetiracetam with the intent to prolong progression-free or overall survival (level C). Physicians may consider the use of levetiracetam over older AEDs to reduce side effects (level C). There is insufficient evidence to support using tumor location, histology, grade, molecular/imaging features when deciding whether or not to prescribe prophylactic AEDs (level U).

Inflammatory Leptomeningeal Cytokines Mediate COVID-19 Neurologic Symptoms in Cancer Patients.

SARS-CoV-2 infection induces a wide spectrum of neurologic dysfunction that emerges weeks after the acute respiratory infection. To better understand this pathology, we prospectively analyzed of a cohort of cancer patients with neurologic manifestations of COVID-19, including a targeted proteomics analysis of the cerebrospinal fluid. We find that cancer patients with neurologic sequelae of COVID-19 harbor leptomeningeal inflammatory cytokines in the absence of viral neuroinvasion. The majority of these inflammatory mediators are driven by type II interferon and are known to induce neuronal injury in other disease states. In these patients, levels of matrix metalloproteinase-10 within the spinal fluid correlate with the degree of neurologic dysfunction. Furthermore, this neuroinflammatory process persists weeks after convalescence from acute respiratory infection. These prolonged neurologic sequelae following systemic cytokine release syndrome lead to long-term neurocognitive dysfunction. Our findings suggest a role for anti-inflammatory treatment(s) in the management of neurologic complications of COVID-19 infection.

Sugar-Mediated Green Synthesis of Silver Selenide Semiconductor Nanocrystals under Ultrasound Irradiation.

Silver selenide (Ag2Se) is a promising nanomaterial due to its outstanding optoelectronic properties and countless bio-applications. To the best of our knowledge, we report, for the first time, a simple and easy method for the ultrasound-assisted synthesis of Ag2Se nanoparticles (NPs) by mixing aqueous solutions of silver nitrate (AgNO3) and selenous acid (H2SeO3) that act as Ag and Se sources, respectively, in the presence of dissolved fructose and starch that act as reducing and stabilizing agents, respectively. The concentrations of mono- and polysaccharides were screened to determine their effect on the size, shape and colloidal stability of the as-synthesized Ag2Se NPs which, in turn, impact the optical properties of these NPs. The morphology of the as-synthesized Ag2Se NPs was characterized by transmission electron microscopy (TEM) and both α- and ß-phases of Ag2Se were determined by X-ray diffraction (XRD). The optical properties of Ag2Se were studied using UV-Vis spectroscopy and its elemental composition was determined non-destructively using scanning electron microscopy-energy-dispersive spectroscopy (SEM-EDS). The biological activity of the Ag2Se NPs was assessed using cytotoxic and bactericidal approaches. Our findings pave the way to the cost-effective, fast and scalable production of valuable Ag2Se NPs that may be utilized in numerous fields.

Inflammatory leptomeningeal cytokines mediate delayed COVID-19 encephalopathy.

SARS-CoV-2 infection induces a wide spectrum of neurologic dysfunction. Here we show that a particularly vulnerable population with neurologic manifestations of COVID-19 harbor an influx of inflammatory cytokines within the cerebrospinal fluid in the absence of viral neuro-invasion. The majority of these inflammatory mediators are driven by type 2 interferon and are known to induce neuronal injury in other disease models. Levels of matrix metalloproteinase-10 within the spinal fluid correlate with the degree of neurologic dysfunction. Furthermore, this neuroinflammatory process persists weeks following convalescence from the acute respiratory infection. These prolonged neurologic sequelae following a systemic cytokine release syndrome lead to long-term neurocognitive dysfunction with a wide range of phenotypes.

Seizure response to temozolomide chemotherapy in patients with WHO grade II oligodendroglioma: a single-institution descriptive study.

BACKGROUND: Tumor-related epilepsy (TRE) is common in patients with low-grade oligodendrogliomas. TRE is difficult to control despite multiple antiepileptic drugs (AEDs) in up to 30% of patients. Chemotherapy has been used for treatment to avoid potential radiotherapy-related neurotoxicity. This study evaluates the effect of temozolomide on seizure frequency in a homogeneous group with World Health Organization (WHO) grade II oligodendrogliomas. METHODS: A retrospective analysis was conducted of adult patients with WHO grade II oligodendrogliomas and TRE followed at Memorial Sloan Kettering between 2005 and 2015 who were treated with temozolomide alone either as initial treatment or for disease progression. All had seizures 3 months prior to starting temozolomide. Seizure frequency was reviewed every 2 cycles and at the end of temozolomide treatment. Seizure reduction of ≥50% compared to baseline was defined as improvement. RESULTS: Thirty-nine individuals met inclusion criteria. Median follow-up since starting temozolomide was 6 years (0.8-13 years). Reduction in seizure frequency occurred in 35 patients (89.7%). Improvement was independent of AED regimen adjustments or prior antitumor treatment in 16 (41%); of these, AED dosage was successfully reduced or completely eliminated in 10 (25.6%). Twenty-five patients (64.1%) remained on a stable AED regimen. The majority (n = 32, 82%) had radiographically stable disease, 5 (12.8%) had objective radiographic response, and 2 (5.2%) had disease progression. CONCLUSIONS: Temozolomide may result in reduced seizure frequency, and permit discontinuation of AEDs in patients with WHO II oligodendroglioma. Improvement was observed irrespective of objective tumor response on MRI, emphasizing the importance of incorporating seizure control in assessing response to tumor-directed therapy.

Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials.

Patients with low-grade glioma frequently have brain tumor-related epilepsy, which is more common than in patients with high-grade glioma. Treatment for tumor-associated epilepsy usually comprises a combination of surgery, anti-epileptic drugs (AEDs), chemotherapy, and radiotherapy. Response to tumor-directed treatment is measured primarily by overall survival and progression-free survival. However, seizure frequency has been observed to respond to tumor-directed treatment with chemotherapy or radiotherapy. A review of the current literature regarding seizure assessment for low-grade glioma patients reveals a heterogeneous manner in which seizure response has been reported. There is a need for a systematic approach to seizure assessment and its influence on health-related quality-of-life outcomes in patients enrolled in low-grade glioma therapeutic trials. In view of the need to have an adjunctive metric of tumor response in these patients, a method of seizure assessment as a metric in brain tumor treatment trials is proposed.

Neurologic Emergencies in the Patients With Cancer.

Neurologic complications of cancer are common and are frequently life-threatening events. Certain neurologic emergencies occur more frequently in the cancer population, specifically elevated intracranial pressure, epidural cord compression, status epilepticus, ischemic and hemorrhagic stroke, central nervous system infection, and treatment-associated neurologic dysfunction. These emergencies require early diagnosis and prompt treatment to ensure the best possible outcome and are best managed in the intensive care unit. This article reviews the presentation, pathophysiology, and management of the most common causes of acute neurologic decompensation in the patient with cancer.

Feasibility of Intraoperative Nerve Monitoring in Preventing Thermal Damage to the "Nerve at Risk" During Image-Guided Ablation of Tumors.

PURPOSE: To assess feasibility of intraoperative neurophysiologic monitoring (IONM) during image-guided, percutaneous thermal ablation of tumors. MATERIALS AND METHODS: From February 2009 to October 2013, a retrospective review of all image-guided percutaneous thermal ablation interventions using IONM was performed and data was compiled using electronic medical records and imaging studies. RESULTS: Twelve patients were treated in 13 ablation interventions. In 4 patients, real-time feedback from the monitoring neurologist was used to adjust applicator placement and ablation settings. IONM was technically feasible in all procedures and there were no complications related to monitoring or ablation. All nerves at risk remained intact and of the 11 patients who could be followed, none developed new nerve deficit up to a minimum of 2 months after ablation. CONCLUSION: IONM is safe and feasible for use during image-guided thermal ablation of tumors in the vicinity of nerves. Outcomes in this study demonstrate its potential utility in image-guided ablation interventions.

Peripheral neuropathy associated with ipilimumab: a report of 2 cases.

Ipilimumab, a monoclonal antibody targeting human cytotoxic T-lymphocyte-associated antigen 4, was approved by the FDA and European Medicines Agency for the treatment of metastatic melanoma. Immune-related adverse effects can occur with the use of this agent, but peripheral nervous system problems are rare. We report 2 cases of ipilimumab-induced polyneuropathy.

"Trap-door" and "clamshell" surgical approaches for the management of pediatric tumors of the cervicothoracic junction and mediastinum.

BACKGROUND/PURPOSE: For pediatric tumors of the cervicothoracic junction, an isolated cervical or thoracic surgical approach provides insufficient exposure for achieving complete resection. We retrospectively examined "trap-door" and "clamshell" pediatric thoracotomies as a surgical approach to these tumors. METHODS: We searched our database for pediatric patients with cervicothoracic tumors who underwent clamshell or trap-door thoracotomy between 1991 and 2013, reviewing tumor characteristics, surgical technique, completeness of resection, morbidity, and outcome. RESULTS: Trap-door (n=13) and clamshell (n=4) thoracotomies were performed for neuroblastoma (n=9), non-rhabdomyosarcoma soft tissue sarcoma (n=4), germ cell tumor (n=2), rhabdomyosarcoma (n=1), and neuroendocrine small cell carcinoma (n=1). Fourteen of these cervicothoracic tumors were primary, and three were metastatic. Gross total resection was achieved in 15 patients (94%). Operative complications included vocal cord paralysis (n=2), mild upper-extremity neuropraxia (n=2), and hemidiaphragm paralysis (n=1), All but one involved encased nerves. Overall survival was 61% for the series and 80% for patients with primary tumors. Eleven (73%) of 15 patients who underwent gross total resection had no evidence of recurrence. Three patients with metastatic disease died of distant progression within 1.3years. CONCLUSIONS: Gross total resection of primary cervicothoracic tumors can be accomplished with specialized exposure in pediatric patients with minimal morbidity.

Thorascopic resection of an apical paraspinal schwannoma using the da Vinci surgical system.

BACKGROUND: Posterior mediastinal neurogenic tumors have traditionally been resected via an open posterolateral thoracotomy. Video-assisted thorascopic surgery has emerged as an alternative technique allowing for improved morbidity with decreased blood loss, less postoperative pain, and a shorter recovery period, among others. The da Vinci surgical system, as first described for urologic procedures, has recently been reported for lung lobectomy. This technique provides the advantages of instrumentation with 6 degrees of freedom, stable operating arms, and improved visualization with the three-dimensional high-definition camera. METHODS: We describe the technique for thorascopic resection of an apical paraspinal schwannoma of the T1 nerve root with the da Vinci surgical system. This technique used a specialized intraoperative neuromonitoring probe for free-running electromyography (EMG) and triggered EMG. RESULTS: We demonstrate successful resection of a posterior paraspinal schwannoma with the da Vinci surgical system while preserving neurologic function. The patient displayed stable intraoperative monitoring of the T1 nerve root and full intrinsic hand strength postoperatively. CONCLUSION: The technique described in this article introduces robotic system accuracy and precludes the need for an open thoracotomy. In addition, this approach demonstrates the ability of the da Vinci surgical system to safely dissect tumors from their neural attachments and is applicable to other such lesions of similar size and location.

Intraoperative neurophysiologic monitoring and neurologic outcomes in patients with epidural spine tumors.

PURPOSE: Multimodal intraoperative neurophysiologic monitoring (IOM) provides assessment of spinal cord pathways during neurosurgery. Despite widespread use, few data exist regarding sensitivity and specificity of IOM in predicting neurologic outcome during decompression and instrumentation for epidural spine tumors. METHODS: Retrospective analysis evaluated consecutive spine procedures involving IOM modalities (somatosensory evoked potentials [SSEP], motor evoked potentials [MEP], and electromyography [(EMG]) from 2007 to 2009. Demographic and surgical information, intraoperative neurophysiologic data, and pre- and postoperative neurologic status were collected. All cases involved neoplastic epidural spinal cord compression by a primary or metastatic tumor and included posterolateral decompression and instrumented fusion. RESULTS: Two-hundred and eight consecutive patients had spine surgery during this time period and one hundred and fifty-two met inclusion criteria. All patients had SSEP monitoring, with 4 having transient changes and 7 persistent changes. One hundred and twenty-two patients had combined SSEP and MEP monitoring, with 3 having transient changes and 4 persistent changes in MEP signals. Two patients had neurophysiologic changes associated with hypotension and correction led to normalization. One developed new neurologic deficits after surgery. Two from the total cohort had new postoperative neurologic deficits. One had a transient decrease in MEP amplitude while the other had no intraoperative changes. DISCUSSION: These cases are often long with significant blood loss, and stability of multiple IOM modalities provides reassurance that spinal cord function remains intact. Signal changes should result in scrutiny of blood pressure, surgical technique and anesthesia. Preserved IOM signals are suggestive of preserved neurologic outcome.

Spectrum of nonconvulsive status epilepticus in patients with cancer.

PURPOSE: Determine incidence, clinical presentation, electrographic correlates, and outcome of nonconvulsive status epilepticus (NCSE) in cancer patients on whom an EEG was performed. METHODS: Retrospective review of 947 EEG reports on 658 patients in whom any type of EEG was performed at Memorial Sloan-Kettering Cancer Center (July 2006 to March 2008). Using the Epilepsy Research Foundation criteria, patients were classified as definite or probable NCSE. Medical records were reviewed for diagnosis, causes of NCSE, response to treatment, and outcome. Mortality was determined for patients with NCSE. RESULTS: Twenty-six episodes of NCSE were identified in 25 patients (25/658, 4%). Eleven patients had primary brain tumor, 12 patients systemic cancer, and two had both. At diagnostic EEG, 18 were awake, 3 were lethargic, and 5 patients were comatose. EEG revealed a seizure in 62% of the patients, periodic lateralized epileptiform discharges in 42%, and periodic epileptiform discharges in 7.7%. Neuroimaging revealed new intracranial pathology in 54% of the patients. Seventy-seven percent of the patients achieved control; 65% required ≥3 antiepileptic drugs, and 33% required intubation. Three patients died from NCSE. DISCUSSION: In our cohort, awake NCSE was more common than comatose NCSE. Treatment was successful in patients with heterogeneous central nervous system disease. EEG evaluation should be considered in patients with cancer because NCSE is treatable despite a high prevalence of structural brain disease. Nonconvulsive status epilepticus control did not always require intubation and burst suppression, but frequently required three or more antiepileptic drugs.