Brandon Foreman

Intravenous ketamine for the treatment of refractory status epilepticus: A retrospective multicenter study

To examine patterns of use, efficacy, and safety of intravenous ketamine for the treatment of refractory status epilepticus (RSE).

Generalized periodic discharges in the critically ill: A case-control study of 200 patients

Objective: Generalized periodic discharges are increasingly recognized on continuous EEG monitoring, but their relationship to seizures and prognosis remains unclear. Methods: All adults with generalized periodic discharges from 1996 to 2006 were matched 1:1 to controls by age, etiology, and level of consciousness. Overall, 200 patients with generalized periodic discharges were matched to 200 controls. Results: Mean age was 66 years (range 18–96); 56% were comatose. Presenting illnesses included acute brain injury (44%), acute systemic illness (38%), cardiac arrest (15%), and epilepsy (3%). A total of 46% of patients with generalized periodic discharges had a seizure during their hospital stay (almost half were focal), vs 34% of controls (p = 0.014). Convulsive seizures were seen in a third of both groups. A total of 27% of patients with generalized periodic discharges had nonconvulsive seizures, vs 8% of controls (p < 0.001); 22% of patients with generalized periodic discharges had nonconvulsive status epilepticus, vs 7% of controls (p < 0.001). In both groups, approximately half died or were in a vegetative state, one-third had severe disability, and one-fifth had moderate to no disability. Excluding cardiac arrest patients, generalized periodic discharges were associated with increased mortality on univariate analysis (36.8% vs 26.9%; p = 0.049). Multivariate predictors of worse outcome were cardiac arrest, coma, nonconvulsive status epilepticus, and sepsis, but not generalized periodic discharges. Conclusion: Generalized periodic discharges were strongly associated with nonconvulsive seizures and nonconvulsive status epilepticus. While nonconvulsive status epilepticus was independently associated with worse outcome, generalized periodic discharges were not after matching for age, etiology, and level of consciousness.

New-onset refractory status epilepticus Etiology, clinical features, and outcome

Objectives: The aims of this study were to determine the etiology, clinical features, and predictors of outcome of new-onset refractory status epilepticus. Methods: Retrospective review of patients with refractory status epilepticus without etiology identified within 48 hours of admission between January 1, 2008, and December 31, 2013, in 13 academic medical centers. The primary outcome measure was poor functional outcome at discharge (defined as a score >3 on the modified Rankin Scale). Results: Of 130 cases, 67 (52%) remained cryptogenic. The most common identified etiologies were autoimmune (19%) and paraneoplastic (18%) encephalitis. Full data were available in 125 cases (62 cryptogenic). Poor outcome occurred in 77 of 125 cases (62%), and 28 (22%) died. Predictors of poor outcome included duration of status epilepticus, use of anesthetics, and medical complications. Among the 63 patients with available follow-up data (median 9 months), functional status improved in 36 (57%); 79% had good or fair outcome at last follow-up, but epilepsy developed in 37% with most survivors (92%) remaining on antiseizure medications. Immune therapies were used less frequently in cryptogenic cases, despite a comparable prevalence of inflammatory CSF changes. Conclusions: Autoimmune encephalitis is the most commonly identified cause of new-onset refractory status epilepticus, but half remain cryptogenic. Outcome at discharge is poor but improves during follow-up. Epilepsy develops in most cases. The role of anesthetics and immune therapies warrants further investigation.

Quantitative EEG for the detection of brain ischemia

Monitoring in most intensive care units (ICUs) is limited to continuous assessments of cardiopulmonary function, whereas brain monitoring has traditionally been limited to serial neurological examinations and infrequent imaging studies. Increasingly it is becoming clear that secondary neurological complications, such as seizures and brain ischemia, are also seen in the medical-surgical ICU population and are not limited to patients with primarily neurological injury. Electroencephalography (EEG) offers a continuous, real-time, non-invasive measure of brain function. Originally developed for the characterization of seizures and epilepsy, continuous EEG monitoring (cEEG) has been used for seizure detection in the ICU. Additionally, cEEG has been used as a method of identifying subclinical brain injury during neurosurgical procedures, such as carotid endarterectomy, and for ischemia detection, global function assessment, medication titration, and prognostication [1].

The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy.

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão’s historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

High-dose midazolam infusion for refractory status epilepticus

Objective: This study compares 2 treatment protocols allowing low vs high continuous IV midazolam (cIV-MDZ) doses. Methods: We compared adults with refractory status epilepticus treated with a protocol allowing for high-dose cIV-MDZ (n = 100; 2002–2011) with those treated with the previous lower-dose cIV-MDZ (n = 29; 1996–2000). We collected data on baseline characteristics, cIV-MDZ doses, seizure control, hospital course, and outcome. Results: Median maximum cIV-MDZ dose was 0.4 mg/kg/h (interquartile range [IQR] 0.2, 1.0) for the high-dose group and 0.2 mg/kg/h (IQR 0.1, 0.3) for the low-dose group (p < 0.001) with similar duration of infusion. Median time from status epilepticus onset to cIV-MDZ start was 1 day (IQR 1, 3) for the high-dose group and 2 days (IQR 1, 5) for the low-dose group (p = 0.016). “Withdrawal seizures” (occurring within 48 hours of discontinuation of cIV-MDZ) were less frequent in the high-dose group (15% vs 64%, odds ratio 0.10, 95% confidence interval 0.03–0.27). “Ultimate cIV-MDZ failure” (patients requiring change to a different cIV antiepileptic medication) and hospital complications were not different between groups. Hypotension was more frequent with higher cIV-MDZ doses but was not associated with worse outcome. Discharge mortality was lower in the high-dose group (40% vs 62%, odds ratio 0.34, 95% confidence interval 0.13–0.92 in multivariate analysis). Conclusions: High-dose cIV-MDZ treatment of refractory status epilepticus can be performed safely, is associated with a lower seizure rate after cIV-MDZ discontinuation, and may be associated with lower mortality than traditional lower-dose protocols. Classification of evidence: This study provides Class III evidence that midazolam at higher infusion rates is associated with a reduction in seizure recurrence within 48 hours after discontinuation and may be associated with lower mortality.

Epilepsy Emergencies: Diagnosis and Management

Seizures and status epilepticus are epilepsy emergencies with high morbidity and mortality. Early treatment is crucial, and the identification of an underlying etiology informs both continued treatment and prognosis. Many patients have underdiagnosed nonconvulsive seizures or nonconvulsive status epilepticus, particularly the comatose or critically ill. Timely EEG can be useful for diagnosis, management, optimizing treatment response, and determining prognosis in these patients. Refractory conditions can be quite complicated with limited evidence-based guidance, but treatment should not be restricted by nihilism even in the most prolonged cases, especially if there is not widespread irreversible brain injury.

Sensitivity of quantitative EEG for seizure identification in the intensive care unit

Objective: To evaluate the sensitivity of quantitative EEG (QEEG) for electrographic seizure identification in the intensive care unit (ICU). Methods: Six-hour EEG epochs chosen from 15 patients underwent transformation into QEEG displays. Each epoch was reviewed in 3 formats: raw EEG, QEEG + raw, and QEEG-only. Epochs were also analyzed by a proprietary seizure detection algorithm. Nine neurophysiologists reviewed raw EEGs to identify seizures to serve as the gold standard. Nine other neurophysiologists with experience in QEEG evaluated the epochs in QEEG formats, with and without concomitant raw EEG. Sensitivity and false-positive rates (FPRs) for seizure identification were calculated and median review time assessed. Results: Mean sensitivity for seizure identification ranged from 51% to 67% for QEEG-only and 63%–68% for QEEG + raw. FPRs averaged 1/h for QEEG-only and 0.5/h for QEEG + raw. Mean sensitivity of seizure probability software was 26.2%–26.7%, with FPR of 0.07/h. Epochs with the highest sensitivities contained frequent, intermittent seizures. Lower sensitivities were seen with slow-frequency, low-amplitude seizures and epochs with rhythmic or periodic patterns. Median review times were shorter for QEEG (6 minutes) and QEEG + raw analysis (14.5 minutes) vs raw EEG (19 minutes; p = 0.00003). Conclusions: A panel of QEEG trends can be used by experts to shorten EEG review time for seizure identification with reasonable sensitivity and low FPRs. The prevalence of false detections confirms that raw EEG review must be used in conjunction with QEEG. Studies are needed to identify optimal QEEG trend configurations and the utility of QEEG as a screening tool for non-EEG personnel. Classification of evidence review: This study provides Class II evidence that QEEG + raw interpreted by experts identifies seizures in patients in the ICU with a sensitivity of 63%–68% and FPR of 0.5 seizures per hour.

The Pathophysiology of Delayed Cerebral Ischemia.

Summary: Subarachnoid hemorrhage (SAH) affects 30,000 people in the Unites States alone each year. Delayed cerebral ischemia occurs days after subarachnoid hemorrhage and represents a potentially treatable cause of morbidity for approximately one-third of those who survive the initial hemorrhage. While vasospasm has been traditionally linked to the development of cerebral ischemia several days after subarachnoid hemorrhage, emerging evidence reveals that delayed cerebral ischemia is part of a much more complicated post–subarachnoid hemorrhage syndrome. The development of delayed cerebral ischemia involves early arteriolar vasospasm with microthrombosis, perfusion mismatch and neurovascular uncoupling, spreading depolarizations, and inflammatory responses that begin at the time of the hemorrhage and evolve over time, culminating in cortical infarction. Large-vessel vasospasm is likely a late contributor to ongoing injury, and effective treatment for delayed cerebral ischemia will require improved detection of critical early pathophysiologic changes as well as therapeutic options that target multiple related pathways.