CAR T-cell therapy for gliomas.

PURPOSE OF REVIEW: To review the landscape of chimeric antigen receptor T-cell (CAR T) therapy for gliomas as seen in recently published trials and discuss on-going challenges with new cancer immunotherapy treatments. RECENT FINDINGS: Given how CAR T therapy has revolutionized the treatment of several hematologic malignancies, there has been increasing interest in using immunotherapy, and particularly CAR T therapy for gliomas. Within the past decade, several first in human trials have published early patient experiences showing treatment is generally well tolerated but with limited efficacy, which may be improving with newer evolutions in CAR T design to overcome known resistance mechanisms in glioma treatment. SUMMARY: CAR T therapy is a promising avenue of treatment for high-grade gliomas, which have a universally poor prognosis as well as limited therapeutics. There are a growing number of CAR T clinical trials for CNS tumors and thus, an understanding of their treatment strategies, toxicity management, and overcoming resistance mechanisms will be important for both clinical practice and to identify areas for future research.

Neurotoxicity of Cancer Immunotherapies Including CAR T Cell Therapy.

PURPOSE OF REVIEW: To outline the spectrum of neurotoxicity seen with approved immunotherapies and in pivotal clinical trials including immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy, vaccine therapy, and oncolytic viruses. RECENT FINDINGS: There has been an exponential growth in new immunotherapies, which has transformed the landscape of oncology treatment. With more widespread use of cancer immunotherapies, there have also been advances in characterization of its associated neurotoxicity, research into potential underlying mechanisms, and development of management guidelines. Increasingly, there is also mounting interest in long-term neurologic sequelae. Neurologic complications of immunotherapy can impact every aspect of the central and peripheral nervous system. Early recognition and treatment are critical. Expanding indications for immunotherapy to solid and CNS tumors has led to new challenges, such as how to reliably distinguish neurotoxicity from disease progression. Our evolving understanding of immunotherapy neurotoxicity highlights important areas for future research and the need for novel immunomodulatory therapeutics.

A rare neuromyelitis optica mimic: Primary CNS histiocytic sarcoma.

Primary central nervous system (CNS) histiocytic sarcoma is a rare hematolymphoid malignancy with features of mature histiocytes and carries a poor prognosis. We describe a unique case in which a 50-year-old woman presented with recurrent acute brainstem syndrome, area postrema syndrome, and myelitis with corresponding magnetic resonance imaging (MRI) lesions meeting diagnostic criteria for seronegative neuromyelitis optica spectrum disorder (NMOSD). Despite initial improvement with steroids and plasma exchange, she experienced recurrent symptoms over 10 months referable to new and persistently enhancing lesions. At autopsy, neuropathology revealed a diffusely infiltrative primary CNS histiocytic sarcoma. This case represents a rare clinicoradiologic mimic of NMOSD, underscoring the importance of evaluation for infiltrative diseases in cases of atypical seronegative NMOSD.

Raccoon Roundworm Infection Associated with Central Nervous System Disease and Ocular Disease - Six States, 2013-2015.

Baylisascaris procyonis, predominantly found in raccoons, is a ubiquitous roundworm found throughout North America. Although raccoons are typically asymptomatic when infected with the parasite, the larval form of Baylisascaris procyonis can result in fatal human disease or severe neurologic outcomes if not treated rapidly. In the United States, Baylisascaris procyonis is more commonly enzootic in raccoons in the midwestern and northeastern regions and along the West Coast (1). However, since 2002, infections have been documented in other states (Florida and Georgia) and regions (2). Baylisascariasis is not a nationally notifiable disease in the United States, and little is known about how commonly it occurs or the range of clinical disease in humans. Case reports of seven human baylisascariasis cases in the United States diagnosed by Baylisascaris procyonis immunoblot testing at CDC are described, including review of clinical history and laboratory data. Although all seven patients survived, approximately half were left with severe neurologic deficits. Prevention through close monitoring of children at play, frequent handwashing, and clearing of raccoon latrines (communal sites where raccoons defecate) are critical interventions in curbing Baylisascaris infections. Early treatment of suspected cases is critical to prevent permanent sequelae.

Neuro-Oncologic Emergencies.

Cancer can have diverse and widespread effects on the nervous system. Knowledge of the most common characteristic mechanisms by which cancer impacts the nervous system enables prompt diagnosis and appropriate management. Here, a variety of neuro-oncologic emergencies are reviewed. Mass effect, status epilepticus, pituitary apoplexy, and metastatic epidural spinal cord compression are emergencies that arise from direct effects of central nervous system neoplasms. Limbic encephalitis may result in hospitalization and at times critical illness, and is usually caused by antibody-mediated reactions to neoplasms. Treatment-related neuro-oncologic emergencies from the effects of radiation and chemotherapy in severe cases may also result in medical emergencies.

Concurrent intrathecal methotrexate and liposomal cytarabine for leptomeningeal metastasis from solid tumors: a retrospective cohort study.

Leptomeningeal metastasis (LM) from solid tumors is typically a late manifestation of systemic cancer with limited survival. Randomized trials comparing single agent intrathecal methotrexate to liposomal cytarabine have shown similar efficacy and tolerability. We hypothesized that combination intrathecal chemotherapy would be a safe and tolerable option in solid tumor LM. We conducted a retrospective cohort study of combination IT chemotherapy in solid tumor LM at a single institution between April 2010 and July 2012. In addition to therapies directed at active systemic disease, each subject received IT liposomal cytarabine plus IT methotrexate with dexamethasone premedication. Patient characteristics, survival outcomes and toxicities were determined by systematic chart review. Thirty subjects were treated during the study period. The most common cancer types were breast 15 (50 %), glioblastoma 6 (20 %), and lung 5 (17 %). Cytologic clearance was achieved in 6 (33 %). Median non-glioblastoma overall survival was 30.2 weeks (n = 18; range 3.9-73.4), and did not differ significantly by tumor type. Median time to neurologic progression was 7 weeks (n = 8; range 0.9-57), with 10 subjects (56 %) experiencing death from systemic disease without progression of LM. Age less than 60 was associated with longer overall survival (p = 0.01). Six (21 %) experienced grade III toxicities during treatment, most commonly meningitis 2 (7 %). Combination IT chemotherapy was feasible in this small retrospective cohort. Prospective evaluation is necessary to determine tolerability, the impact on quality of life and neurocognitive outcomes or any survival benefit when compared to single agent IT chemotherapy.

Education Research: Sustained Implementation of Quality Improvement Practices Is Observed in Early Career Physicians Following a Neurology Resident QI Curriculum.

Background and Objectives: The Accreditation Council for Graduate Medical Education and American Board of Psychiatry and Neurology expect engagement in quality improvement (QI) activities for all residents and practicing neurologists. Our neurology residency program instituted an experiential Neurology Residency QI Curriculum in 2015 for all residents. In this study, we aimed to characterize the role of QI engagement in the early-career paths of program graduates. Methods: We distributed an online survey evaluating QI training, scholarship, and leadership (before, during, and after residency training) to all individuals who graduated from our residency program (graduation years 2017-2021). Primary outcomes were QI project leadership or mentorship and QI scholarship (projects, posters, and publications) after residency. Predictors of these outcomes were also evaluated using Fisher exact test. Results: Twenty-nine of 50 graduates (58%) completed the survey. Median time from residency graduation was 3 years. Of the respondents, 14% actively participated in a QI project before residency, 83% during residency, and 48% after graduating. In addition, 41% had led or mentored a QI project and 34% had performed QI scholarship since residency. Fourteen percent of participants held formal roles in QI or patient safety, while 24% received formal full-time equivalents for QI work. Significant predictors (p < 0.05) of QI leadership included older age, time since graduation, rank, and participation in Clinical Effectiveness Leadership Training (CELT-an institutional QI faculty development course). Significant predictors (p < 0.05) of QI scholarship included older age, time since graduation, participation in CELT, and participation in QI scholarship during residency. QI training, participation, and/or project leadership before residency did not predict either QI leadership or scholarship after residency. Discussion: Many neurology residency graduates continued to lead QI projects and produce QI scholarship in the early years after graduation. However, receiving protected time for leadership and academic work in this area is uncommon. Our findings suggest that more infrastructure, including training, career development, and mentorship, can foster neurologists interested in leading in quality and patient safety. In academic models, promotion pathways that support academic advancement for faculty leading in QI are needed.

Education Research: Educational Outcomes Associated With the Introduction of a Neurohospitalist Program.

Background and Objectives: As the prevalence of the neurohospitalist (NH) practice model grows, understanding its effect on trainee education is imperative. We sought to determine the impact of an academic NH program on neurology resident evaluations of faculty teaching. Methods: We performed a retrospective study of faculty teaching evaluations before and after the implementation of a full-time NH service. Primary outcomes were neurology resident evaluations of faculty teaching, which were compared in the pre-NH period (August 2010-July 2014) vs the post-NH period (August 2016-July 2018). In a secondary analysis, we used the difference-in-difference approach to analyze the effect of introducing the NH service on resident evaluation of faculty teaching compared with stroke and neurocritical care faculty controls. We performed an additional descriptive analysis of medical student evaluation of faculty teaching and described Residency In-service Training Exam scores and Accreditation Council for Graduate Medical Education (ACGME) resident survey data before and after the intervention. Results: There were 368 resident and 360 medical student evaluations of faculty teaching during the study period. Compared to the pre-NH period, the post-NH period had significantly higher resident evaluations of faculty teaching in 19 of 27 questions of faculty teaching, across 5 of the 6 ACGME core competencies. Within the competencies of patient care, practice-based learning and improvement, and systems-based practice, the NH teaching faculty were rated significantly higher across all questions. In the difference-in-difference model, resident evaluations of faculty teaching following the implementation of the NH service remained significantly improved compared with controls in teaching evidence-based medicine, teaching diagnostic algorithms, and explaining rationale for clinical decisions. Medical student ratings of faculty teaching were unchanged in the pre-NH and the post-NH period. Discussion: Neurology residents may benefit from the clinical expertise of NHs and their ability to teach evidence-based practice and role model systems-based practice. Given the central role NHs may play in trainee education, additional focus on both the local and national levels should be dedicated to further developing the teaching skills of NHs.

Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma.

ABSTRACT: CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development after CD19 CAR T-cell therapy in patients with MCL. All patients (N = 26) who received standard-of-care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (grade ≥3) ICANS. All patients with ICANS had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. Overall, 92% of EEGs revealed interictal changes; no patients experienced frank seizures because of ICANS. In total, 86% of patients with severe ICANS with postinfusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of postinfusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in patients with severe ICANS, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

Prolonged ventilatory failure and flaccid quadriparesis after ingestion of poison hemlock.

INTRODUCTION: A 28-year-old man presented with acute flaccid paralysis and respiratory failure that persisted for 2 weeks after suicidal ingestion of unknown substances. METHODS: Extensive clinical, nerve, laboratory, and neuroimaging testing excluded alternative causes of this neuromuscular syndrome. Prompted by clues provided by family members, liquid chromatography time-of-flight mass spectrometry was used to investigate for the presence of poison hemlock. RESULTS: Testing of the residue in a jar used for the ingestion of a poisonous concoction confirmed the presence of the nicotinic alkaloid coniine. Analysis of patient serum suggested the presence of conhydrine. Concentrations of amitriptyline and diazepam were also found to be supratherapeutic, but only through the first few days of hospitalization. CONCLUSIONS: Herein we describe a case of reversible coma, flaccid quadriparesis, and neuromuscular respiratory failure caused by intentional ingestion of poison hemlock.

Single institution experience with death by neurological criteria/brain death guideline adherence.

OBJECTIVE: To determine the effect on adherence to an institutional death by neurological criteria/brain death (DNC/BD) policy of implementation of a standardized DNC/BD checklist in the electronic medical record (EMR). METHODS: The retrospective study cohort included all patients admitted to our institution who were declared dead by neurologic criteria determined by ICD code (G93.82) between June 2015 and October 2019. Two investigators independently reviewed each case for adherence with institutional policy, and agreement was assessed using unweighted kappa statistics. Patient data and adherence to institutional policy before and after implementation of a standardized DNC/BD checklist were compared. RESULTS: There were 66 patients identified by the initial search and 38 were included in the final analysis, with 19 cases in both the pre- and post- checklist periods. There were no significant differences in age, cause of DNC/BD, time to DNC/BD determination, potential toxic, metabolic, physiologic confounders, or use of ancillary testing. The pre-checklist period adherence was 47.4% (n = 9/19) versus 94.6% (n = 18/19; p = 0.001) in the post-checklist EMR DNC/BD period. CONCLUSION: Implementation of a standardized EMR checklist substantially improved DNC/BD policy adherence in our institution. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence on the use of standardized EMR checklist to improve death by neurologic criteria/brain death policy adherence.

Continuous EEG monitoring detects nonconvulsive seizure and Ictal-Interictal Continuum abnormalities in moderate to severe ICANS following systemic CAR-T therapy.

Background and Purpose: Immune Cell Effector Associated Neurotoxicity Syndrome (ICANS) is common amongst patients receiving CD19 targeted Chimeric Antigen Receptor T-cell (CAR-T) therapy. The purpose of this study is to characterize the incidence of seizures and ictal-interictal continuum (IIC) abnormalities in patients with ICANS. Methods: Retrospective review of consecutive patients treated with axicabtagene ciloleucel (axi-cel) for recurrent high-grade systemic lymphoma at Stanford Medical Center between 2/2016-6/2019. Electronic medical records (EMR) were reviewed for clinical features, treatment information, EEG data, CRS (cytokine release syndrome)/ICANS severity, and clinical outcomes. Results: Fifty-six patients met inclusion criteria. 85.7% of patients developed CRS, and 58.9% developed ICANS. Twenty-eight patients had EEG monitoring, of whom 26 had ICANS. Median duration of EEG monitoring was 30 hours (range .5-126 hours). Four patients (7.1%) had seizures (1 patient had a clinical generalized seizure, 2 patients had clinical and nonconvulsive seizures, and 1 patient had an isolated non-convulsive seizure). Ictal-interictal continuum abnormalities were common, of which generalized periodic discharges (GPDs) with triphasic morphology and GPDs with epileptiform morphology were most frequently seen. Generalized periodic discharges with triphasic wave morphology were found across Grade 2-3 peak ICANS severity, however the majority (86%) of patients with epileptiform GPDs had Grade 3 peak ICANS severity. Conclusions: Among patients receiving axi-cel, seizure occurred in 7.1% of the total cohort, representing 12% of patients with ICANS. Ictal-interictal continuum abnormalities are also seen in patients with ICANS, most commonly GPDs. 75% of patients with seizures had nonconvulsive seizures supporting the use of continuous video EEG monitoring in this population.

Multifocal demyelinating leukoencephalopathy and oligodendroglial lineage cell loss with immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19 CAR T-cell therapy for mantle cell lymphoma.

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a prevalent condition seen after treatment with chimeric antigen receptor T-cell (CAR T) therapy and other cancer cell therapies. The underlying pathophysiology and neuropathology of the clinical syndrome are incompletely understood due to the limited availability of brain tissue evaluation from patient cases, and a lack of high-fidelity preclinical animal models for translational research. Here, we present the cellular and tissue neuropathologic analysis of a patient who experienced grade 4 ICANS after treatment with anti-CD19 CAR T therapy for mantle cell lymphoma. Our pathologic evaluation reveals a pattern of multifocal demyelinating leukoencephalopathy associated with a clinical course of severe ICANS. A focused analysis of glial subtypes further suggests region-specific oligodendrocyte lineage cell loss as a potential cellular and pathophysiologic correlate in severe ICANS. We propose a framework for the continuum of neuropathologic changes thus far reported across ICANS cases. Future elucidation of the mechanistic processes underlying ICANS will be critical in minimizing neurotoxicity following CAR T-cell and related immunotherapy treatments across oncologic and autoimmune diseases.

Tumor inflammation-associated neurotoxicity.

Cancer immunotherapies have unique toxicities. Establishment of grading scales and standardized grade-based treatment algorithms for toxicity syndromes can improve the safety of these treatments, as observed for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in patients with B cell malignancies treated with chimeric antigen receptor (CAR) T cell therapy. We have observed a toxicity syndrome, distinct from CRS and ICANS, in patients treated with cell therapies for tumors in the central nervous system (CNS), which we term tumor inflammation-associated neurotoxicity (TIAN). Encompassing the concept of 'pseudoprogression,' but broader than inflammation-induced edema alone, TIAN is relevant not only to cellular therapies, but also to other immunotherapies for CNS tumors. To facilitate the safe administration of cell therapies for patients with CNS tumors, we define TIAN, propose a toxicity grading scale for TIAN syndrome and discuss the potential management of this entity, with the goal of standardizing both reporting and management.

Outcomes of a Neurohospitalist Program at an Academic Medical Center.

Background and Purpose: The purpose is to determine the impact of an academic neurohospitalist service on clinical outcomes. Methods: We performed a retrospective, quasi-experimental study of patients discharged from the general neurology service before (August 2010-July 2014) and after implementation of a full-time neurohospitalist service (August 2016-July 2018) compared to a control group of stroke patients. Primary outcomes were length of stay and 30-day readmission. Using the difference-in-difference approach, the impact of introducing a neurohospitalist service compared to controls was assessed with adjustment of patients' characteristics. Secondary outcomes included mortality, in-hospital complications, and cost. Results: There were 2706 neurology admissions (1648 general; 1058 stroke) over the study period. The neurohospitalist service was associated with a trend in reduced 30-day readmissions (ratio of ORs: .52 [.27, .98], P = .088), while length of stay was not incrementally changed in the difference-in-difference model (-.3 [-.7, .1], P = .18). However, descriptive results demonstrated a significant reduction in mean adjusted LOS of .7 days (4.5 to 3.8 days, P < .001) and a trend toward reduced readmissions (8.9% to 7.6%, P = .42) in the post-neurohospitalist cohort despite a significant increase in patient complexity, shift to higher acuity diagnoses, more emergent admissions, and near quadrupling of observation status patients. Mortality and in-hospital complications remained low, patient satisfaction was stable, and cost was not incrementally changed in the post-neurohospitalist cohort. Conclusions: Implementation of a neurohospitalist service at an academic medical center is feasible and associated with a significant increase in patient complexity and acuity and a trend toward reduced readmissions.

Recurrent Status Epilepticus in the Setting of Chimeric Antigen Receptor (CAR)-T Cell Therapy.

Axicabtagene ciloleucel (AC) is an FDA-approved anti-CD19 autologous chimeric antigen receptor T-cell (CAR-T) therapy for refractory diffuse large B cell lymphoma (DLBCL). While its efficacy in DLBCL has been promising, neurotoxicity remains a significant concern. We present a case of a 22-year-old woman with chemotherapy-refractory DLBCL who exhibited Grade IV neurotoxicity in the setting of sepsis, after undergoing AC infusion. Despite prophylactic levetiracetam given per guidelines,1,2 she experienced a precipitous mental status decline on post-infusion day 8 (D8) followed by hypoxic respiratory failure in the setting of clinical status epilepticus on D11 and nonconvulsive status epilepticus (NCSE) on D18. While neuroimaging was unremarkable, EEG demonstrated diffuse slowing and 2.5-3 Hz generalized periodic discharges consistent with NCSE. Seizures were initially refractory to lorazepam, increasing doses of levetiracetam, and phenobarbital, requiring a midazolam drip titrated to 50-70% burst suppression for resolution. Methylprednisolone and tocilizumab were used to treat neurotoxicity and cytokine release syndrome, respectively. Empiric antibiotics were used for sepsis. After cessation of sedatives on D19, mental status improved to near baseline. PET/CT just prior to discharge showed a complete response of the DLBCL (Deauville 3). She was discharged on D37 with no further seizure activity. Unfortunately, a 3-month interval PET/CT demonstrated disease progression which continued through salvage pembrolizumab eventually leading to death 1.2 years post-CAR-T infusion. This case illustrates the clinical management challenges of a complex and rare neurotoxic side effect of CAR-T cell therapy, namely NCSE following status epilepticus.

Neuro-Oncologic Emergencies.

Cancer and cancer therapies have the potential to affect the nervous system in a host of different ways. Cerebral edema, increased intracranial pressure, cerebrovascular events, status epilepticus, and epidural spinal cord compression are among those most often presenting as emergencies. Neurologic side-effects of cancer therapies are often mild, but occasionally result in serious illness. Immunotherapies cause autoimmune-related neurologic side-effects that are generally responsive to immunosuppressive therapies. Emergency management of neuro-oncologic problems benefits from early identification and close collaboration among interdisciplinary team members and patients or surrogate decision-makers.

Leptomeningeal metastasis in breast cancer - a systematic review.

BACKGROUND: There is limited data on the impact of specific patient characteristics, tumor subtypes or treatment interventions on survival in breast cancer LM. METHODS: A systematic review was conducted to assess the impact of hormone receptor and HER-2 status on survival in breast cancer LM. A search for clinical studies published between 1/1/2007 and 7/1/2012 and all randomized-controlled trials was performed. Survival data from all studies are reported by study design (prospective trials, retrospective cohort studies, case studies). RESULTS: A total of 36 studies with 851 LM breast cancer subjects were identified. The majority (87%) were treated with intrathecal chemotherapy. Pooled median overall survival ranged from 14.9-18.1 weeks depending on study type. Breast cancer LM survival (15 weeks) was longer than other solid tumor LM 8.3 weeks and lung cancer LM 8.7 weeks, but shorter than LM lymphoma (15.4 versus 24.2 weeks). The impact of hormone receptor and HER-2 status on survival could not be determined. CONCLUSIONS: A median overall survival of 15 weeks in prospective studies of breast cancer LM provides a historical comparison for future LM breast cancer trials. Other outcomes including the impact of molecular status on survival could not be determined based on available studies.

Leptomeningeal metastases in breast cancer.

Central nervous system (CNS) metastasis from breast cancer may be characterized as either parenchymal brain metastasis (BM) or leptomeningeal (LM) metastasis. BM are much more common (about 80% of all CNS metastases), and have been more extensively studied than LM. CNS metastasis in breast cancer has been associated with reduced overall survival, with the shortest survival generally observed in cases of LM. Here, we review the epidemiology, prognostic factors, diagnostic tools, currently available treatments, and potential future therapies for LM from breast cancer.

Headache and focal neurologic deficits in a 37-year-old woman.

A 37-year-old woman presented with progressively worsening headache. She had no headache history, and initial evaluation revealed hydrocephalus of unclear etiology. A ventriculoperitoneal shunt was placed with improvement. However, her headache returned and she developed neurologic deficits. Imaging studies demonstrated multiple cystic lesions in the posterior fossa. Serum and cerebrospinal fluid studies were unrevealing and a biopsy of the cystic lesions was performed. The clinical approach, differential diagnosis, and neuropathological findings are discussed.