John P. Betjemann

Status epilepticus in adults

Status epilepticus is a common neurological emergency with considerable associated health-care costs, morbidity, and mortality. The definition of status epilepticus as a prolonged seizure or a series of seizures with incomplete return to baseline is under reconsideration in an effort to establish a more practical definition to guide management. Clinical research has focused on early seizure termination in the prehospital setting. The approach of early escalation to anaesthetic agents for refractory generalised convulsive status epilepticus, rather than additional trials of second-line anti-epileptic drugs, to avoid neuronal injury and pharmaco-resistance associated with prolonged seizures is gaining momentum. Status epilepticus is also increasingly identified in the inpatient setting as the use of extended electroencephalography monitoring becomes more commonplace. Substantial further research to enable early identification of status epilepticus and efficacy of anti-epileptic drugs will be important to improve outcomes.

Trends in Status Epilepticus—Related Hospitalizations and Mortality: Redefined in US Practice Over Time

IMPORTANCE Status epilepticus is a common neurologic emergency with significant associated morbidity, mortality, and health care costs, yet limited data exist detailing trends in status epilepticus-related hospitalizations and mortality. OBJECTIVE To examine trends in status epilepticus-related hospitalizations and mortality. DESIGN, SETTING, AND PARTICIPANTS We performed 2 retrospective serial cross-sectional studies including 408 304 status epilepticus-related hospital visits using generalizable national data from January 1, 1999, to December 31, 2010, from the Centers for Disease Control and Prevention and the Nationwide Inpatient Sample. Centers for Disease Control and Prevention death certificate data, using International Statistical Classification of Diseases, Tenth Revision, codes, were used to determine nonstandardized and age-standardized rates of status epilepticus as the underlying cause of death in the United States. Data from the Nationwide Inpatient Sample were used to estimate population-standardized status epilepticus-related hospitalization rates using International Statistical Classification of Diseases, Ninth Revision, codes. MAIN OUTCOMES AND MEASURES Status epilepticus-related hospitalizations were categorized by whether status epilepticus was the principal diagnosis, whether the patient was intubated, and by primary insurance type. Temporal trends were tested using Poisson regression and summarized with quarterly incident rate ratios. RESULTS In 2010, status epilepticus was the reported underlying cause of death in 613 deaths (approximately 2 per 1 000 000 persons). Age-standardized status epilepticus-related mortality per 1 000 000 persons increased by only 5.6% (incident rate ratio, 1.004; 95% CI, 1.002-1.006) from 1.79 in 1999 to 1.89 in 2010, while population-standardized hospitalizations for status epilepticus per 100 000 persons increased by 56.4% (incident rate ratio, 1.013; 95% CI, 1.012-1.013) from 8.86 in 1999 to 13.86 in 2010. The largest increase (181.6%; incident rate ratio, 1.030; 95% CI, 1.029-1.030) was seen among intubated patients with nonprincipal diagnoses of status epilepticus. Among varied insurance providers, the largest increase (81.3%) was seen in Medicare patients. CONCLUSIONS AND RELEVANCE A disconnect exists between the relatively stable status epilepticus-related mortality and the marked increase in status epilepticus hospitalizations, likely reflecting an increase in status epilepticus diagnoses through improved diagnostic sensitivity and changes in billing and coding. The definition and general approach to status epilepticus, including resource use, should evolve with these changing epidemiologic trends.

Diagnostic Yield of Electroencephalography in a General Inpatient Population

OBJECTIVE To determine the frequency and clinical predictors of seizures and markers of epileptiform activity in a non-critically ill general inpatient population. PATIENTS AND METHODS We performed a retrospective cohort study of patients 18 years and older who underwent inpatient electroencephalography (EEG) between January 1, 2005, and December 31, 2010, for an indication of spells or altered mental status. The EEGs and reports were reviewed for ictal activity, interictal epileptiform abnormalities, and nonepileptiform abnormalities. Demographic and clinical data were gathered from the electronic medical record to determine seizure predictors. RESULTS Of 2235 patients screened, 1048 met the inclusion criteria, of which 825 (78.7%) had an abnormal EEG finding. Seizures occurred in 78 of 1048 patients (7.4%), and interictal epileptiform discharges were noted in 194 of 1048 patients (18.5%). An intracranial mass and spells as the indication for the EEG were independently associated with the group of patients experiencing seizures in a multivariate logistic regression model (adjusted for age, sex, EEG indication, intracranial mass, stroke, and history of epilepsy). Ninety-seven percent of patients (69 of 71) experienced their first seizure within 24 hours of monitoring, and the presence of seizures was associated with a lower likelihood of being discharged (odds ratio, 0.45; 95% CI, 0.27-0.76). CONCLUSION Seizures occurred at a high frequency in hospitalized patients with spells and altered mental status. The EEG may be an underused investigative tool in the hospital with the potential to identify treatable causes of these common disorders.

Distinguishing language and race disparities in epilepsy surgery

This study aimed to identify whether race/ethnicity and limited English proficiency impact the likelihood of pursuing surgical treatment for medically refractory epilepsy. We conducted a retrospective cohort study of 213 patients with medically refractory epilepsy and mesial temporal sclerosis who were being considered for temporal lobectomy between January 1, 1993 and December 31, 2010 with follow-up through December 31, 2012. Demographic and clinical factors potentially associated with surgical utilization, including self-reported race/ethnicity and preferred language, were gathered from the medical record. Patients of Asian/Pacific Islander or African American race were significantly less likely to pursue surgical treatment of epilepsy compared with non-Hispanic whites in a multivariate logistic regression model (adjusted for nonconcordant ictal EEG, age, and limited English proficiency) (OR 0.20, p=0.003; OR 0.15, p=0.001, respectively). Limited English proficiency was also significantly associated with lower odds of surgery (OR 0.38, p=0.034). Both race and limited English proficiency contribute to disparities in the surgical management of medically refractory epilepsy, especially among Asian/Pacific Islanders and African Americans. Culturally sensitive patient-physician communication and patient education materials might aid in surgical decision-making among minority groups.

Delays in time to surgery for minorities with temporal lobe epilepsy

To determine whether adult minority patients with medically refractory temporal lobe epilepsy (TLE) experience significantly longer times to anterior temporal lobectomy (ATL) following presurgical evaluation.

Chronic Meningitis Investigated via Metagenomic Next-Generation Sequencing

Importance Identifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. Objective To present a case series of patients with diagnostically challenging subacute or chronic meningitis using metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) supported by a statistical framework generated from mNGS of control samples from the environment and from patients who were noninfectious. Design, Setting, and Participants In this case series, mNGS data obtained from the CSF of 94 patients with noninfectious neuroinflammatory disorders and from 24 water and reagent control samples were used to develop and implement a weighted scoring metric based on z scores at the species and genus levels for both nucleotide and protein alignments to prioritize and rank the mNGS results. Total RNA was extracted for mNGS from the CSF of 7 participants with subacute or chronic meningitis who were recruited between September 2013 and March 2017 as part of a multicenter study of mNGS pathogen discovery among patients with suspected neuroinflammatory conditions. The neurologic infections identified by mNGS in these 7 participants represented a diverse array of pathogens. The patients were referred from the University of California, San Francisco Medical Center (n = 2), Zuckerberg San Francisco General Hospital and Trauma Center (n = 2), Cleveland Clinic (n = 1), University of Washington (n = 1), and Kaiser Permanente (n = 1). A weighted z score was used to filter out environmental contaminants and facilitate efficient data triage and analysis. Main Outcomes and Measures Pathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results. Results The 7 participants ranged in age from 10 to 55 years, and 3 (43%) were female. A parasitic worm (Taenia solium, in 2 participants), a virus (HIV-1), and 4 fungi (Cryptococcus neoformans, Aspergillus oryzae, Histoplasma capsulatum, and Candida dubliniensis) were identified among the 7 participants by using mNGS. Evaluating mNGS data with a weighted z score–based scoring algorithm reduced the reported microbial taxa by a mean of 87% (range, 41%-99%) when taxa with a combined score of 0 or less were removed, effectively separating bona fide pathogen sequences from spurious environmental sequences so that, in each case, the causative pathogen was found within the top 2 scoring microbes identified using the algorithm. Conclusions and Relevance Diverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for 1 year, the first reported case of CNS vasculitis caused by Aspergillus oryzae, and the fourth reported case of C dubliniensis meningitis. Prioritizing metagenomic data with a scoring algorithm greatly clarified data interpretation and highlighted the problem of attributing biological significance to organisms present in control samples used for metagenomic sequencing studies.

Diagnostic yield of electroencephalography in a general inpatient population.

Objective: To determine the frequency and clinical predictors of seizures and markers of epileptiform activity in a non-critically ill general inpatient population. Patients and Methods: We performed a retrospective cohort study of patients 18 years and older who underwent inpatient electroencephalography (EEG) between January 1, 2005, and December 31, 2010, for an indication of spells or altered mental status. The EEGs and reports were reviewed for ictal activity, interictal epileptiform abnormalities, and nonepileptiform abnormalities. Demographie and clinical data were gathered from the electronic medical record to determine seizure predictors. Results: Of 2235 patients screened, 1048 met the inclusion criteria, of which 825 (78.7%) had an abnormal EEG finding. Seizures occurred in 78 of 1048 patients (7.4%), and interictal epileptiform discharges were noted in 194 of 1048 patients (18.5%). An intracranial mass and spells as the indication for the EEG were independently associated with the group of patients experiencing seizures in a multivariate logistic regression model (adjusted for age, sex, EEG indication, intracranial mass, stroke, and history of epilepsy). Ninety-seven percent of patients (69 of 71) experienced their first seizure within 24 hours of monitoring, and the presence of seizures was associated with a lower likelihood of being discharged (odds ratio, 0.45; 95% CI, 0.27–0.76). Conclusion: Seizures occurred at a high frequency in hospitalized patients with spells and altered mental status. The EEG may be an underused investigative tool in the hospital with the potential to identify treatable causes of these common disoreders.

Current Trends in Treatment of Status Epilepticus and Refractory Status Epilepticus.

Status epilepticus is a heterogeneous disorder with varied definitions and presentations. Taken together, all forms of status epilepticus carry significant morbidity and mortality, much of which is dictated by the underlying etiology. Generalized convulsive status epilepticus, which represents a common form, is a true neurologic emergency that requires emergent management. Treatment focuses on stabilizing the patient and aggressive medical management to achieve the timely termination of seizures. For other forms of status epilepticus including nonconvulsive and focal status epilepticus, the goal remains early seizure termination, but the use of intravenous medications should be weighed against the risks associated with these therapies. The diagnostic evaluation of status epilepticus is guided by the patients history and should be broad, including a screen for toxins, electrolytes, structural abnormalities, and central nervous system infectious and autoimmune/inflammatory etiologies. Considerable research is still needed to improve our understanding of the mechanisms, consequences, and therapy of status epilepticus.

Metagenomics for chronic meningitis: clarifying interpretation and diagnosis

Importance Identifying infectious causes of subacute and chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. Objective To present a case series of patients with diagnostically challenging subacute and chronic meningitis in whom metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF), supported by a statistical framework generated from mNGS sequencing of non-infectious patients and environmental controls, identified a pathogen. Design Case series. Using mNGS data from the CSF of 94 non-infectious neuroinflammatory cases and 24 water and reagent controls, we developed and implemented a weighted scoring metric based on z-scores at the species and genus level for both nucleotide and protein databases to prioritize and rank mNGS results. We performed mNGS on total RNA extracted from CSF of patients with subacute or chronic meningitis and highlight seven cases representing a diverse array of pathogens. Setting A multi-center study of mNGS pathogen discovery in patients with suspected neuroinflammatory conditions. Participants Patients with diagnostically challenging subacute or chronic meningitis enrolled in a research study of mNGS performed on CSF. Intervention mNGS was performed on total RNA extracted from CSF (0.25-0.5 mL). A weighted z-score was used to filter out environmental contaminants and facilitate efficient data triage and analysis. Main Outcomes 1) Pathogens identified by mNGS and 2) ability of a statistical model to prioritize, rank, and simplify mNGS results. Results mNGS identified parasitic worms, fungi and viruses in seven subjects: Taenia solium (n=2), Cryptococcus neoformans, human immunodeficiency virus-1, Aspergillus oryzae, Histoplasma capsulatum, and Candida dubliniensis. Evaluating mNGS data with a weighted z-score based scoring algorithm effectively separated bona fide pathogen sequences from spurious environmental sequences. Conclusions and Relevance mNGS of CSF identified a diversity of microbial pathogens in patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for one year, the first case of CNS vasculitis caused by Aspergillus oryzae, and the fourth reported case of Candida dubliniensis meningitis. Filtering metagenomic data with a scoring algorithm greatly clarified data interpretation and highlights the difficulties attributing biological significance to organisms that may be present in control samples used for metagenomic sequencing studies. Key Points Question: How can metagenomic next-generation sequencing of cerebrospinal fluid be leveraged to aid in the diagnosis of patients with subacute or chronic meningitis? Findings: Metagenomic next-generation sequencing identified parasitic worms, fungi and viruses in a case series of seven subjects. A database of water-only and healthy patient controls enabled application of a z-score based scoring algorithm to effectively separate bona fide pathogen sequences from spurious environmental sequences. Meaning: Our scoring algorithm greatly simplified data interpretation in a series of patients with a wide range of challenging infectious causes of subacute or chronic meningitis identified by metagenomic next-generation sequencing.

Preoperative and Postoperative Care of Patients with Neurologic Disorders

Patients with preexisting neurologic disease may pose particular problems in the perioperative period. It is crucial to identify the extent of neurologic disease and baseline preoperatively to aid in risk stratification and counseling of patients and family members. There are a number of medications used specifically in the treatment of neurologic diseases, and their continued use or discontinuation during the perioperative period requires careful consideration. These medications as well as certain aspects of neurologic disease impact anesthetic technique, choice of anesthetics, and neuromuscular blockade. Finally, preexisting neurologic diseases are associated with a range of perioperative complications that can have a profound impact on postoperative recovery and discharge disposition.