Transcranial Doppler cerebrovascular reactivity: Thresholds for clinical significance in cerebrovascular disease.

BACKGROUND AND PURPOSE: Thresholds for abnormal transcranial Doppler cerebrovascular reactivity (CVR) studies are poorly understood, especially for patients with cerebrovascular disease. Using a real-world cohort with cerebral arterial stenosis, we sought to describe a clinically significant threshold for carbon dioxide reactivity (CO2R) and vasomotor range (VMR). METHODS: CVR studies were performed during conditions of breathing room air normally, breathing 8% carbon dioxide air mixture, and hyperventilation. The mean and standard deviation (SD) of CO2R and VMR were calculated for the unaffected side in patients with unilateral stenosis; a deviation of 2 SDs below the mean was chosen as the threshold for abnormal. Receiver operating characteristic (ROC) curves for both sides for patients with unilateral and bilateral stenosis were evaluated for sensitivity (Sn) and specificity (Sp). RESULTS: A total of 133 consecutive CVR studies were performed on 62 patients with stenosis with mean±SD age 55±16 years. Comorbidities included hypertension (60%), diabetes (15%), stroke (40%), and smoking (35%). In patients with unilateral stenosis, mean±SD CO2R for the unaffected side was 1.86±0.53%, defining abnormal CO2R as <0.80%. Mean±SD CO2R for the affected side was 1.27±0.90%. The CO2R threshold predicted abnormal acetazolamide single-photon emission computed tomography (SPECT) (Sn = .73, Sp = .79), CT/MRI perfusion abnormality (Sn = .42, Sp = .77), infarction on MRI (Sn = .45, Sp = .76), and pressure-dependent exam (Sn = .50, Sp = .76). For the unaffected side, mean±SD VMR was 39.5±15.8%, defining abnormal VMR as <7.9%. For the affected side, mean±SD VMR was 26.5±17.8%. The VMR threshold predicted abnormal acetazolamide SPECT (Sn = .46, Sp = .94), infarction on MRI (Sn = .27, Sp = .94), and pressure-dependent exam (Sn = .31, Sp = .90). CONCLUSIONS: In patients with multiple vascular risk factors, a reasonable threshold for clinically significant abnormal CO2R is <0.80% and VMR is <7.9%. Noninvasive CVR may aid in diagnosing and risk stratifying patients with stenosis.

Disparities in Decompressive Cranial Surgery Utilization in Severe Traumatic Brain Injury Patients without a Primary Extra-Axial Hematoma: A U.S. Nationwide Study.

OBJECTIVE: Decompressive craniectomy is recommended to reduce mortality in severe traumatic brain injury (TBI). Disparities exist in TBI treatment outcomes; however, data on disparities pertaining to decompressive craniectomy utilization is lacking. We investigated these disparities, focusing on race, insurance, sex, and age. METHODS: Hospitalizations (2004-2014) were retrospectively extracted from the Nationwide Inpatient Sample. The criteria included are as follows: age ≥18 years and indicators of severe TBI diagnosis. Poor outcomes were defined as discharge to institutional care and death. Multivariable logistic regression models were used to assess the effects of race, insurance, age, and sex, on craniectomy utilization and outcomes. RESULTS: Of 349,164 hospitalized patients, 6.8% (n = 23,743) underwent craniectomy. White (odds ratio [OR] = 0.50, 95% confidence interval [CI] = 0.44-0.57; P < 0.001) and Black (OR = 0.45, 95% CI = 0.32-0.64; P = 0.003) Medicare beneficiaries were less likely to undergo craniectomy. Medicare (P < 0.0001) and Medicaid beneficiaries (P < 0.0001) of all race categories had poorer outcomes than privately insured White patients. Black (OR = 1.2, 95% CI = 1.08-2.34; P = 0.001) patients with private insurance and Black (OR = 1.39, 95% CI = 1.22-1.58; P < 0.0001) Medicaid beneficiaries had poorer outcomes than privately insured White patients (P < 0.0001). Older patients (OR = 0.74, 95%, CI = 0.71-0.76; P < 0.001) were less likely to undergo craniectomy and were more likely to have poorer outcomes. Females (OR = 0.82, 95% CI = 0.76-0.88; P < 0.001) were less likely to undergo craniectomy. CONCLUSIONS: There are disparities in race, insurance status, sex, and age in craniectomy utilization and outcome. This data highlights the necessity to appropriately address these disparities, especially race and sex, and actively incorporate these factors in clinical trial design and enrollment.

Use of Transcranial Doppler as a Biomarker of CAR T Cell-Related Neurotoxicity.

Background and Objectives: To examine the relationship between transcranial Doppler (TCD) mean flow velocity (MFV) and the severity and temporal onset of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed lymphoma. Methods: We identified a cohort of 165 patients with relapsed or refractory B-cell lymphoma who received CAR T-cell therapy. TCDs were performed at baseline, treatment day 5, and throughout hospitalization based on development of neurologic symptoms. We assessed the percent change in velocity from baseline in each of the 6 major supratentorial arteries and the relationship of these values to development and timing of neurotoxicity. Results: Our cohort was 30% female with an average age of 60 years. Of patients with TCDs performed, 63% developed neurotoxicity, and 32% had severe neurotoxicity. The median time of neurotoxicity onset was day 7. Higher maximum percent change in MFV across all vessels was significantly associated with likelihood of developing neurotoxicity (p = 0.0002) and associated with severe neurotoxicity (p = 0.0421). We found that with increased percent change in MFV, the strength of correlation between day of TCD velocity change and day of neurotoxicity onset increased. There was no single vessel in which increase in MFV was associated with neurotoxicity. Discussion: Our study demonstrates an association between increase in TCD MFV and the development of neurotoxicity, as well as timing of neurotoxicity onset. We believe that TCD ultrasound may be used as a bedside functional biomarker in CAR T-cell patients and may guide immunologic interventions to manage toxicity in this complex patient group.

Multiple high-grade and rare immune-related adverse events in a colon cancer patient with genomic and cytokine profiling.

We report a case of multiple high-grade and rare immune-related adverse events (irAEs) in a patient with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A middle-aged MSI-H mCRC patient with metastases to the lungs and lymph nodes received several lines of chemotherapy and immunotherapy and developed five different high-grade irAEs during immunotherapy, including lymphadenitis, pneumonitis, hypophysitis, thyroiditis and transverse myelitis. Genomic profiling revealed high tumor mutational burden of 43 Muts/Mb. Cytokine profiling showed a threefold increase in MMP-9 shortly prior to the onset of lymphadenitis and a fourfold increase of Ang-1 1 week after the resolution of lymphadenitis. Further studies are warranted to investigate the association of MSI-H mCRC with irAEs and the role of cytokines in predicting irAEs.

Immune-related adverse events (irAEs) are a potential side effect of taking immunotherapy treatment for cancer. We report a case of a patient with a highly mutated form of metastatic colon cancer who developed five unique and severe irAEs while receiving immunotherapy. The patient developed inflammation of the lymph nodes, lungs, pituitary gland, thyroid and spinal cord. Genetic testing showed that the tumor was highly mutated (43 Muts/Mb). Analysis of cell signaling proteins called cytokines revealed that MMP-9 sharply increased before the onset of lymphadenitis and Ang-1 sharply increased after its resolution. Further research is needed to understand the relationship between highly mutated colon cancer and irAEs as well as the role of cytokines in predicting the onset and resolution of irAEs.

EEG findings in CAR T-cell-associated neurotoxicity: Clinical and radiological correlations.

BACKGROUND: While EEG is frequently reported as abnormal after chimeric antigen receptor (CAR) T-cell therapy, its clinical significance remains unclear. We aim to systematically describe EEG features in a large single-center cohort and correlate them with clinical and radiological findings. METHODS: We retrospectively identified patients undergoing CAR T-cell therapy who had continuous EEG. Neurotoxicity grades, detailed neurological symptoms, and brain MRI or FDG-PET were obtained. Correlation between clinical and radiological findings and EEG features was assessed. RESULTS: In 81 patients with median neurotoxicity grade 3 (IQR 2-3), diffuse EEG background slowing was the most common finding and correlated with neurotoxicity severity (P <.001). A total of 42 patients had rhythmic or periodic patterns, 16 of them within the ictal-interictal-continuum (IIC), 5 with clinical seizures, and 3 with only electrographic seizures. Focal EEG abnormalities, consisting of lateralized periodic discharges (LPD, n = 1), lateralized rhythmic delta activity (LRDA, n = 6), or focal slowing (n = 19), were found in 22 patients. All patients with LRDA, LPD, and 10/19 patients with focal slowing had focal clinical symptoms concordant with these EEG abnormalities. In addition, these focal EEG changes are often correlated with PET hypometabolism or MRI hypoperfusion, in absence of a structural lesion. CONCLUSION: In adult patients experiencing neurotoxicity after CAR T-cell infusion, EEG degree of background disorganization correlated with neurotoxicity severity. IIC patterns and focal EEG abnormalities are frequent and often correlate with focal clinical symptoms and with PET-hypometabolism/MRI-hypoperfusion, without structural lesion. The etiology of these findings remains to be elucidated.

Neurologic Complications in Patients with Cancer.

Neurologic symptoms are commonly seen in patients with cancer and can be among the most challenging to diagnose and manage. It is often difficult to determine if new neurologic symptoms are secondary to direct effects of a malignant lesion, systemic complications of disease, paraneoplastic disorders, or side effects of cancer treatment itself. However, early diagnosis and treatment of each of these conditions can improve patients' quality of life and long-term functional outcomes. In this review, we describe a systematic approach to the diagnosis of new neurologic symptoms in patients with known malignancy. We have categorized the neurologic complications of cancer through a mechanistic approach, with an emphasis on ascertaining underlying pathophysiology to guide treatment choice. This review focuses on the acute neurologic complications of cancer that require hospital admission.

Neurological complications of cancer immunotherapy (CAR T cells).

Chimeric antigen receptor (CAR) T cell therapy has become an indispensable tool in the treatment of advanced malignancy, however, it is associated with significant neurologic toxicity. The pathophysiology of CAR T-cell associated neurotoxicity is incompletely understood, and the specific risk factors have only recently begun to be characterized. Despite a growing clinical experience with CAR T cell therapy, the unpredictability of neurologic symptoms remains a source of great anxiety for patients and practitioners alike, and a major limitation for more widespread adoption of this important treatment modality. The purpose of this review is to familiarize clinicians with the typical clinical manifestations and salient features of CAR T cell associated neurotoxicity. We place an emphasis on highlighting the clinical and laboratory markers that may be helpful for predicting clinical course, allowing teams to anticipate necessary supportive measures. We will also review the appropriate diagnostic workup for CAR T cell neurotoxicity and current treatment recommendations.

Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy.

Importance: Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion. Objective: To identify clinical and laboratory parameters predictive of neurotoxicity and to develop a prognostic score associated with its risk. Design, Setting, and Participants: This single-center diagnostic/prognostic accuracy study was conducted at Brigham and Women's Hospital/Dana Farber Cancer Institute from April 2015 to February 2020. A consecutive sample of all patients undergoing CAR T-cell therapy with axicabtagene ciloleucel for relapsed or refractory lymphoma were assessed for inclusion (n = 213). Patients who had previously received CAR T cells or who were treated for mantle cell lymphoma were excluded (n = 9). Patients were followed up for a minimum of 30 days from the date of CAR T-cell infusion. Main Outcomes and Measures: The primary outcomes were measures of performance (accuracy, sensitivity, specificity, area under the curve) of a diagnostic tool to predict the occurrence of CAR-associated neurotoxicity, as graded by the Common Terminology Criteria for Adverse Events criteria. Results: Two hundred four patients (127 men [62.2%]; mean [SD] age, 60.0 [12.1] years) were included in the analysis, of which 126 (61.8%) comprised a derivation cohort and 78 (38.2%), an internal validation cohort. Seventy-three patients (57.9%) in the derivation cohort and 45 patients (57.7%) in the validation cohort experienced neurotoxicity. Clinical and laboratory values obtained early in admission were used to develop a multivariable score that can predict the subsequent development of neurotoxicity; when tested on an internal validation cohort, this score had an area under the curve of 74%, an accuracy of 77%, a sensitivity of 82%, and a specificity of 70% (positive:negative likelihood ratio, 2.71:0.26). Conclusions and Relevance: The score developed in this study may help predict which patients are likely to experience CAR T-cell-associated neurotoxicity. The score can be used for triaging and resource allocation and may allow a large proportion of patients to be discharged from the hospital early.

The PET Sandwich: Using Serial FDG-PET Scans with Interval Burst Suppression to Assess Ictal Components of Disease.

BACKGROUND: Determining the cause of refractory seizures and/or interictal continuum (IIC) findings in the critically ill patient remains a challenge. These electrographic abnormalities may represent primary ictal pathology or may instead be driven by an underlying infectious, inflammatory, or neoplastic pathology that requires targeted therapy. In these cases, it is unclear whether escalating antiepileptic therapy will be helpful or harmful. Herein, we report the use of serial [F-18] fluorodeoxyglucose positron emission tomography (FDG-PET) coupled with induced electrographic burst suppression to distinguish between primary and secondary ictal pathologies. We propose that anesthetic suppression of hypermetabolic foci suggests clinical responsiveness to escalating antiepileptic therapy, whereas non-suppressible hypermetabolic foci are suggestive of non-ictal pathologies that likely require multimodal therapy. METHODS: We describe 6 patients who presented with electrographic findings of seizure or IIC abnormalities, severe neurologic injury, and clinical concern for confounding pathologies. All patients were continuously monitored on video electroencephalography (cvEEG). Five patients underwent at least two sequential FDG-PET scans of the brain: one in a baseline state and the second while under electrographic burst suppression. FDG-avid loci and EEG tracings were compared pre- and post-burst suppression. One patient underwent a single FDG-PET scan while burst-suppressed. RESULTS: Four patients had initially FDG-avid foci that subsequently resolved with burst suppression. Escalation of antiepileptic therapy in these patients resulted in clinical improvement, suggesting that the foci were related to primary ictal pathology. These included clinical diagnoses of electroclinical status epilepticus, new-onset refractory status epilepticus, stroke-like migraine attacks after radiotherapy, and epilepsy secondary to inflammatory cerebral amyloid angiopathy. Conversely, two patients with high-grade EEG abnormalities had FDG-avid foci that persisted despite burst suppression. The first presented with a poor examination, fever, and concern for encephalitis. Postmortem pathology confirmed suspicion of herpes simplex virus encephalitis. The second patient presented with concern for checkpoint inhibitor-induced autoimmune encephalitis. The persistence of the FDG-avid focus, despite electrographic burst suppression, guided successful treatment through escalation of immunosuppressive therapy. CONCLUSIONS: In appropriately selected patients, FDG-PET scans while in burst suppression may help dissect the underlying pathophysiologic cause of IIC findings observed on EEG and guide tailored therapy.

Neurological toxicities associated with chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor T cell therapy has become an important tool in the treatment of relapsed and refractory malignancy; however, it is associated with significant neurological toxicity. We characterized the neurological toxicity associated with chimeric antigen receptor T-cell therapy in a consecutive series of 100 patients up to 2 months post transfusion, 28 of whom were obtained from chart review and the others by prospective observation. The underlying neoplasms were lymphoma (74%), myeloma (14%), leukaemia (10%), and sarcoma (2%). The median age of the cohort was 64.5 years old and 39% of patients were female. The most commonly occurring neurological symptoms were encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%) and focal weakness (11%). Focal neurological deficits are frequently observed after chimeric antigen receptor T-cell therapy and are associated with regional EEG abnormalities, FDG-PET hypometabolism, and elevated velocities on transcranial Doppler ultrasound. In contrast, structural imaging was typically normal. As this form of treatment is more widely adopted, recognition of the frequently encountered symptoms will be of increasing importance for the neurologists and oncologists caring for this growing patient population.

Neuropathology of a Case With Fatal CAR T-Cell-Associated Cerebral Edema.

Chimeric antigen receptor (CAR) T cells are a new and powerful class of cancer immunotherapeutics that have shown potential for the treatment of hematopoietic malignancies. The tremendous promise of this approach is tempered by safety concerns, including potentially fatal neurotoxicity, sometimes but not universally associated with cytokine release syndrome. We describe the postmortem examination of a brain from a 21-year-old patient with relapsed pre-B cell acute lymphoblastic leukemia (ALL) who died from fulminant cerebral edema following CAR T-cell infusion. We found a range of changes that included activation of microglia, expansion of perivascular spaces by proteinaceous exudate, and clasmatodendrosis-a beading of glial fibrillary acidic protein consistent with astrocyte injury. Notably, within the brain parenchyma, we identified only infrequent T cells and did not identify ALL cells or CAR T cells. The overall findings are nonspecific but raise the possibility of astrocyte and blood-brain barrier dysfunction as a potential etiology of fatal CAR T-cell neurotoxicity in this patient.

Fatal Powassan Encephalitis (Deer Tick Virus, Lineage II) in a Patient With Fever and Orchitis Receiving Rituximab.

Importance: Powassan virus is a rare but increasingly recognized cause of severe neurological disease. Objective: To highlight the diagnostic challenges and neuropathological findings in a fatal case of Powassan encephalitis caused by deer tick virus (lineage II) in a patient with follicular lymphoma receiving rituximab, with nonspecific anti-GAD65 antibodies, who was initially seen with fever and orchiepididymitis. Design, Setting, and Participants: Comparison of clinical, radiological, histological, and laboratory findings, including immunohistochemistry, real-time polymerase chain reaction, antibody detection, and unbiased sequencing assays, in a single case report (first seen in December 2016) at an academic medical center. Exposure: Infection with Powassan virus. Main Outcomes and Measures: Results of individual assays compared retrospectively. Results: In a 63-year-old man with fatal Powassan encephalitis, serum and cerebrospinal fluid IgM antibodies were not detected via standard methods, likely because of rituximab exposure. Neuropathological findings were extensive, including diffuse leptomeningeal and parenchymal lymphohistiocytic infiltration, microglial proliferation, marked neuronal loss, and white matter microinfarctions most severely involving the cerebellum, thalamus, and basal ganglia. Diagnosis was made after death by 3 independent methods, including demonstration of Powassan virus antigen in brain biopsy and autopsy tissue, detection of viral RNA in serum and cerebrospinal fluid by targeted real-time polymerase chain reaction, and detection of viral RNA in cerebrospinal fluid by unbiased sequencing. Extensive testing for other etiologies yielded negative results, including mumps virus owing to prodromal orchiepididymitis. Low-titer anti-GAD65 antibodies identified in serum, suggestive of limbic encephalitis, were not detected in cerebrospinal fluid. Conclusions and Relevance: Owing to the rarity of Powassan encephalitis, a high degree of suspicion is required to make the diagnosis, particularly in an immunocompromised patient, in whom antibody-based assays may be falsely negative. Unbiased sequencing assays have the potential to detect uncommon infectious agents and may prove useful in similar scenarios.

Autoimmune Neurologic Disorders.

The practice of autoimmune neurology focuses on the diagnosis and treatment of a wide spectrum of neurological conditions driven by abnormal immune responses directed against neural tissues. These include autoimmune, paraneoplastic, postinfectious, and iatrogenic conditions. Symptoms of autoimmune neurologic disorders can be diverse and often difficult to recognize in their early stages, complicating the diagnosis. This review discusses the classification and management of common autoimmune neurological conditions, placing an emphasis on the rapid identification of autoimmune etiology and mechanism of immune dysfunction to allow for the timely institution of appropriate treatment.

Autoimmune Encephalitis in Critical Care: Optimizing Immunosuppression.

Autoimmune diseases affecting the nervous systems are a common cause of admission to the intensive care unit (ICU). Although there exist several well-described clinical syndromes, patients more commonly present with progressive neurologic dysfunction and laboratory and radiographic evidence of central nervous system (CNS) inflammation. In the critical care setting, the urgency to intervene to prevent permanent damage to the nervous system and secondary injury from the systemic manifestations of these syndromes often conflicts with diagnostic uncertainty. Furthermore, treatment is limited by current therapeutic agents that remain non-specific for individual diseases, especially for those whose pathophysiology remains unclear. Primary autoimmune, paraneoplastic, parainfectious, and iatrogenic neurologic disorders all share the common underlying pathophysiology of an adaptive immune response directed against an antigen within the nervous system. Several different mechanisms of immune dysfunction are responsible for pathogenesis within each of these categories of disease, and it is at this level of pathophysiology that the most effective and appropriate therapeutic decisions are made. In this review, we outline the basic diagnostic and therapeutic principles in the management of autoimmune diseases of the nervous system in the ICU. We approach these disorders not as lists of distinct clinical syndromes or molecular targets of autoimmunity but rather as clusters of syndromes based on these common underlying mechanisms of immune dysfunction. This approach emphasizes early intervention over precise diagnosis. As our understanding of the immune system continues to grow, this framework will allow for a more sophisticated approach to the management of patients with these complex, often devastating but frequently reversible, neurologic illnesses.

Timing of Decompressive Hemicraniectomy for Stroke: A Nationwide Inpatient Sample Analysis.

BACKGROUND AND PURPOSE: Previous clinical trials were not designed to discern the optimal timing of decompressive craniectomy for stroke, and the ideal surgical timing in patients with space-occupying infarction who do not exhibit deterioration within 48 hours is debated. METHODS: Patients undergoing decompressive craniectomy for stroke were extracted from the Nationwide Inpatient Sample (2002-2011). Multivariable logistic regression evaluated the association of surgical timing with mortality, discharge to institutional care, and poor outcome (a composite end point including death, tracheostomy and gastrostomy, or discharge to institutional care). Covariates included patient demographics, comorbidities, year of admission, and hospital characteristics. However, standard stroke severity scales and infarct volume were not available. RESULTS: Among 1301 admissions, 55.8% (n=726) underwent surgery within 48 hours. Teaching hospital admission was associated with earlier surgery (P=0.02). The timing of intervention was not associated with in-hospital mortality. However, when evaluated continuously, later surgery was associated with increased odds of discharge to institutional care (odds ratio, 1.17; 95% confidence interval, 1.05-1.31, P=0.005) and of a poor outcome (odds ratio, 1.12; 95% confidence interval, 1.02-1.23; P=0.02). When evaluated dichotomously, the odds of discharge to institutional care and of a poor outcome did not differ at 48 hours after hospital admission, but increased when surgery was pursued after 72 hours. Subgroup analyses found no association of surgical timing with outcomes among patients who had not sustained herniation. CONCLUSION: s-In this nationwide analysis, early decompressive craniectomy was associated with superior outcomes. However, performing decompression before herniation may be the most important temporal consideration.

Brainstem and limbic encephalitis with paraneoplastic neuromyelitis optica.

The spectrum of disorders associated with anti-neuromyelitis optica (NMO) antibody is being extended to include infrequent instances associated with cancer. We describe a patient with brainstem and limbic encephalitis from NMO-immunoglobulin G in serum and cerebrospinal fluid in the context of newly diagnosed breast cancer. The neurological features markedly improved with excision of her breast cancer and immune suppressive therapy. This case further broadens the NMO spectrum disorders (NMOSD) by an association between NMOSD and cancer and raises the question of coincidental occurrence and the appropriate circumstances to search for a tumor in certain instances of NMO.