A data-driven quality-score system for rating drug products and its implications for the health care industry.

The quality of drug products in the United States has been a matter of growing concern. Buyers and payers of pharmaceuticals have limited insight into measures of drug-product quality. Therefore, a quality-score system driven by data collection is proposed to differentiate between the qualities of drug products produced by different manufacturers. The quality scores derived using this proposed system would be based upon public regulatory data and independently-derived chemical data. A workflow for integrating the system into procurement decisions within health care organizations is also suggested. The implementation of such a quality-score system would benefit health care organizations by including the consideration of the quality of products while also considering price as a part of the drug procurement process. Such a system would also benefit the U.S. health care industry by bringing accountability and transparency into the drug supply chain and incentivizing manufacturers to place an increased emphasis on the quality and safety of their drug products.

Tracking Multisite Seizure Propagation Using Ictal High-Gamma Activity.

PURPOSE: Spatial patterns of long-range seizure propagation in epileptic networks have not been well characterized. Here, we use ictal high-gamma activity (HGA) as a proxy of intense neuronal population firing to map the spatial evolution of seizure recruitment. METHODS: Ictal HGA (80-150 Hz) was analyzed in 13 patients with 72 seizures recorded by stereotactic depth electrodes, using previously validated methods. Distinct spatial clusters of channels with the ictal high-gamma signature were identified, and seizure hubs were defined as stereotypically recruited nonoverlapping clusters. Clusters correlated with asynchronous seizure terminations to provide supportive evidence for independent seizure activity at these sites. The spatial overlap between seizure hubs and interictal ripples was compared. RESULTS: Ictal HGA was detected in 71% of seizures and 10% of implanted contacts, enabling tracking of contiguous and noncontiguous seizure recruitment. Multiple seizure hubs were identified in 54% of cases, including 43% of patients thought preoperatively to have unifocal epilepsy. Noncontiguous recruitment was associated with asynchronous seizure termination (odds ratio = 19.7; p = 0.029). Interictal ripples demonstrated greater spatial overlap with ictal HGA in cases with single seizure hubs compared with those with multiple hubs (100% vs. 66% per patient; p = 0.03). CONCLUSIONS: Ictal HGA may serve as a useful adjunctive biomarker to distinguish contiguous seizure spread from propagation to remote seizure sites. High-gamma sites were found to cluster in stereotyped seizure hubs rather than being broadly distributed. Multiple hubs were common even in cases that were considered unifocal.

Proceedings of the Sleep and Epilepsy Workshop: Section 1 Decreasing Seizures-Improving Sleep and Seizures, Themes for Future Research.

Epileptic seizures, sleep, and circadian timing share bilateral interactions, but concerted work to characterize these interactions and to leverage them to the advantage of patients with epilepsy remains in beginning stages. To further the field, a multidisciplinary group of sleep physicians, epileptologists, circadian timing experts, and others met to outline the state of the art, gaps of knowledge, and suggest ways forward in clinical, translational, and basic research. A multidisciplinary panel of experts discussed these interactions, centered on whether improvements in sleep or circadian rhythms improve decrease seizure frequency. In addition, education about sleep was lacking in among patients, their families, and physicians, and that focus on education was an extremely important "low hanging fruit" to harvest. Improvements in monitoring technology, experimental designs sensitive to the rigor required to dissect sleep versus circadian influences, and clinical trials in seizure reduction with sleep improvements were appropriate.

All-cause mortality and SUDEP in a surgical epilepsy population.

Epilepsy surgery is considered to reduce the risk of epilepsy-related mortality, including sudden unexpected death in epilepsy (SUDEP), though data from existing surgical series are conflicting. We retrospectively examined all-cause mortality and SUDEP in a population of 590 epilepsy surgery patients and a comparison group of 122 patients with pharmacoresistant focal epilepsy who did not undergo surgery, treated at Columbia University Medical Center between 1977 and 2014. There were 34 deaths in the surgery group, including 14 cases of SUDEP. Standardized mortality ratio (SMR) for the surgery group was 1.6, and SUDEP rate was 1.9 per 1000 patient-years. There were 13 deaths in the comparison group, including 5 cases of SUDEP. Standardized mortality ratio for the comparison group was 3.6, and SUDEP rate was 4.6 per 1000 patient-years. Both were significantly greater than in the surgery group (p < 0.05). All but one of the surgical SUDEP cases, and all of the comparison group SUDEP cases, had a history of bilateral tonic-clonic seizures (BTCS). Of postoperative SUDEP cases, one was seizure-free, and two were free of BTCS at last clinical follow-up. Time to SUDEP in the surgery group was longer than in the comparison group (10.1 vs 5.9 years, p = 0.013), with 10 of the 14 cases occurring >10 years after surgery. All-cause mortality was reduced after epilepsy surgery relative to the comparison group. There was an early benefit of surgery on the occurrence of SUDEP, which was reduced after 10 years. A larger, multicenter study is needed to further investigate the time course of postsurgical SUDEP.

Emergency Management of Epilepsy and Seizures.

Seizure- and epilepsy-related complications are a common cause of emergency medical evaluation, accounting for 5% of 911 calls and 1% of emergency department visits. Emergency physicians and neurologists must be able to recognize and treat seizure- and epilepsy-related emergencies. This review describes the emergency evaluation and management of new onset seizures, breakthrough seizures in patients with known epilepsy, status epilepticus, acute symptomatic seizures, and acute adverse effects of antiepileptic drugs.

Seizure modulation by sleep and sleep state.

Sleep is a dynamic process, during which the electrical rhythms of the brain orchestrate a complicated progression of changing frequencies, patterns and connectivity. Each stage of sleep is different electrophysiologically from wakefulness, and from other sleep stages. It should be no surprise, then, that the various sleep states influence the origin, suppression, and spread of seizures, and that different seizure types are affected in individual (and sometimes contradictory) ways. While much of the electrical symphony that occurs in both normal and epileptic brains is incompletely understood, at the basic level some interesting and often clinically important influences of the various sleep states have been identified. While interictal epileptiform activity is not a seizure, these markers of epilepsy are affected by sleep. Both initiation and propagation of various seizure types are affected by sleep, and these are discussed separately. Finally, the relationship between sleep and epilepsy is clearly reciprocal, and the final sections will explore the changes in sleep that seizures and antiepileptic drugs can induce.

Postictal clinical and electroencephalographic activity following intracranially recorded bilateral tonic-clonic seizures.

OBJECTIVE: The dynamics of the postictal period, which may demonstrate such dramatic clinical phenomena as focal neurological deficits, prolonged coma and immobility, and even sudden death, are poorly understood. We sought to classify and characterize postictal phases of bilateral tonic-clonic seizures based on electroencephalographic (EEG) criteria and associated clinical features. METHODS: We performed a detailed electroclinical evaluation of the postictal period in a series of 31 bilateral tonic-clonic seizures in 16 patients undergoing epilepsy surgery evaluations for focal pharmacoresistant epilepsy with intracranial electrodes and time-locked video. RESULTS: The postictal EEG demonstrated three clearly differentiated phases as follows: attenuation, a burst-attenuation pattern, and a return to continuous background, with abrupt, synchronized transitions between phases. Postictal attenuation was common, occurring in 84% of seizures in 94% of patients in this study. There was increased power in gamma frequencies (>25 Hz) during postictal attenuation periods relative to preictal baseline in 88% of seizures demonstrating the attenuation pattern (n = 25 seizures, P < 0.002). Such increases were seen in >90% of channels in 13 seizures (52%) and <10% of channels in three seizures (12%). Postictal immobility was seen in 87% of seizures, with either a flaccid (58%) or rigid/dystonic (29%) appearance. Clinical motor manifestations, including focal dystonic posturing, automatisms, head and eye deviation, and myoclonic jerking, continued or emerged within the first minute following seizure termination in 48% of seizures, regardless of EEG appearance. SIGNIFICANCE: Intracranial postictal attenuation, which may be diffuse or focal, is so common that it should be regarded as a ubiquitous feature of bilateral tonic-clonic seizures, rather than an unusual event. The prominence of high-frequency activity coupled with emerging clinical features, including rigid immobility and semiologies such as automatisms, during the postictal period supports the presence of ongoing seizure-related neuronal activity in unrecorded brain regions.

Presurgical depression and anxiety are not associated with worse epilepsy surgery outcome five years postoperatively.

PURPOSE: Anxiety and depression have been associated with poor seizure control after epilepsy surgery. This study explored the effect of presurgical anxiety or depression on two- and five-year seizure control outcomes. METHODS: Adult subjects were enrolled between 1996 and 2001 in a multicenter prospective study to evaluate outcomes of resective epilepsy surgery. A Poisson regression was used to analyze the association of depression and anxiety with surgical outcome, while adjusting for gender, age, ethnicity, number of years with seizures, and presence of mesial temporal sclerosis. RESULTS: The relative risk (RR) of presurgical depression on two-year seizure-free outcome in this cohort is 1.12 (95% confidence interval (CI), 0.84-1.49) and 1.06 (CI, 0.73-1.55) on five-year seizure free outcome. The RR of presurgical anxiety on two-year seizure outcome is 0.73 (CI, 0.50-1.07) and 0.70 (CI, 0.43-1.17) on five-year seizure outcome. When including Engel classes I and II, the RRs of presurgical depression, anxiety, or both two years after surgery were 0.96 (p=0.59), 0.73 (p<0.05), and 0.97 (p=0.70), respectively, and they were 0.97 (p=0.82), 0.84 (p=0.32), and 0.89 (p=0.15), respectively, five years after surgery. Only presurgical anxiety was associated with worse epilepsy surgery outcome two year after surgery but not at five years postsurgery. Depression was not a risk factor for poor epilepsy surgical outcome in the long term. CONCLUSION: These findings from a prospective study that utilized a standardized protocol for psychiatric and seizure outcome assessment suggest that presurgical mood disorders have no substantial impact on postsurgical seizure outcome for up to five years after surgery.

Laser ablation is effective for temporal lobe epilepsy with and without mesial temporal sclerosis if hippocampal seizure onsets are localized by stereoelectroencephalography.

OBJECTIVE: Selective laser amygdalohippocampotomy (SLAH) using magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is emerging as a treatment option for drug-resistant mesial temporal lobe epilepsy (MTLE). SLAH is less invasive than open resection, but there are limited series reporting its safety and efficacy, particularly in patients without clear evidence of mesial temporal sclerosis (MTS). METHODS: We report seizure outcomes and complications in our first 30 patients who underwent SLAH for drug-resistant MTLE between January 2013 and December 2016. We compare patients who required stereoelectroencephalography (SEEG) to confirm mesial temporal onset with those treated based on imaging evidence of MTS. RESULTS: Twelve patients with SEEG-confirmed, non-MTS MTLE and 18 patients with MRI-confirmed MTS underwent SLAH. MTS patients were older (median age 50 vs 30 years) and had longer standing epilepsy (median 40.5 vs 5.5 years) than non-MTS patients. Engel class I seizure freedom was achieved in 7 of 12 non-MTS patients (58%, 95% confidence interval [CI] 30%-86%) and 10 of 18 MTS patients (56%, 95% CI 33%-79%), with no significant difference between groups (odds ratio [OR] 1.12, 95% CI 0.26-4.91, P = .88). Length of stay was 1 day for most patients (range 0-3 days). Procedural complications were rare and without long-term sequelae. SIGNIFICANCE: We report similar rates of seizure freedom following SLAH in patients with MTS and SEEG-confirmed, non-MTS MTLE. Consistent with early literature, these rates are slightly lower than typically observed with surgical resection (60%-80%). However, SLAH is less invasive than open surgery, with shorter hospital stays and recovery, and severe procedural complications are rare. SLAH may be a reasonable first-line surgical option for patients with both MTS and SEEG confirmed, non-MTS MTLE.

Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Drug-resistant epilepsy in adults: Outcome trajectories after failure of two medications.

OBJECTIVE: To examine the seizure trajectories of adults with epilepsy developing drug-resistant epilepsy (DRE) and to identify the predictors of seizure trajectory outcome. METHODS: Adult patients failing two antiepileptic drugs (AEDs) due to inefficacy and starting their third AED at a tertiary epilepsy center were followed for seizure trajectory outcome during medical management. Seizure trajectories were categorized into one of four patterns: (1) course with constant seizures; (2) fluctuating course; (3) delayed attainment of seizure freedom (seizure freedom delayed for >12 months after start of the study, but patient stayed in seizure freedom); and (4) early attainment of seizure freedom (within 12 months of starting study). Multiple ordinal logistic regression models were used to estimate the association between trajectory categories and clinical factors. RESULTS: Four hundred three adult patients met the eligibility criteria. Of these, 212 (53%) never achieved a seizure-free period of a year or more. The trajectories of 63 patients (16%) had a complex fluctuating trajectory, 62 (15%) had delayed onset of seizure freedom, and 66 (16%) had an early seizure freedom. Independent predictors associated with more favorable outcome trajectories were epilepsy type and length of follow-up. Specifically, compared to patients with focal epilepsy of temporal lobe, patients with focal epilepsy of occipital lobe (OR 3.80, 95% confidence interval [CI] 1.00-14.51, p = 0.04), generalized genetic (OR 3.23, 95% CI 1.88-5.57, p < 0.0001), unclear epilepsy type (OR 3.82, 95% CI 1.53-9.52, p < 0.005), and both focal and generalized epilepsy(OR 11.73, 95% CI 1.69-81.34, p = 0.01) were significantly more likely to experience a better trajectory pattern. SIGNIFICANCE: Examination of patterns of seizure trajectory of patients with incident DRE showed that 31% were in continuous seizure freedom at the end of the observation period.

Safety and tolerability of an oral zonisamide loading dose.

PURPOSE: There are a limited number of anticonvulsant medications that can be administered with an oral loading dose in order to rapidly achieve an effective serum level, and most of these have associated adverse effects. Zonisamide is approved for the treatment of partial onset epilepsy, and is used in practice for both generalized and partial onset epilepsy. It is generally well-tolerated, has a long half-life, and can be administered once daily. Unfortunately, the recommended titration schedule for initiating therapy takes several weeks to reach target dose and therapeutic serum levels. METHODS: We initiated zonisamide therapy using a large initial dose of zonisamide in 32 patients in our epilepsy monitoring unit over the past four years. RESULTS: Adverse effects were rare and involved nausea/vomiting (9.4%) or drowsiness (6.3%). In patients where serum levels were available for review, therapeutic or near-therapeutic levels were achieved after an oral load of 600-900 mg given as divided doses over a 6-12h period. CONCLUSION: This report is the first to suggest a method of rapidly initiating zonisamide therapy, achieving therapeutic serum levels in a shorter time frame, with an adverse effect profile similar to the recommended titration schedule.

Sleep in the neurological intensive care unit: feasibility of quantifying sleep after melatonin supplementation with environmental light and noise reduction.

PURPOSE: Sleep deprivation may be particularly detrimental to intensive care unit (ICU) patients. Polysomnography has demonstrated abnormal sleep in medical and surgical ICU populations. Both environmental factors and circadian disruption have been implicated. We hypothesized that patients in a neurologic ICU would demonstrate similar sleep disturbances and that a combination of sleep-promoting interventions would increase sleep time. METHODS: Twelve patients were enrolled in this pilot-randomized, controlled, study in a neurologic ICU. For adult patients undergoing continuous EEG for clinical purposes, noise-cancelling headphones and eye masks were worn, and an oral dose of melatonin was administered for 3 days, or until EEG was stopped. Sleep was scored according to standard criteria; EEG was characterized and analyzed quantitatively. RESULTS: Sixty-five percent of the patients' recordings were unscorable based on accepted standardized criteria; therefore, sleep measures could not be compared. For those with sleep that could be scored, total sleep time was normal, although sleep was fragmented and time spent in slow-wave or rapid eye movement sleep was notably decreased. Patients with unscorable recordings had worse injury severity measures, absent or significantly slower posterior dominant rhythm, and less coherence of posterior faster frequencies. Clinical outcomes were similar between intervention and control groups. CONCLUSIONS: Although sleep-promoting interventions were feasible, sleep quantification based on currently accepted criteria limited the ability to score sleep. Similar to other ICUs, sleep in the neurologic ICU is abnormal; patients with unscorable sleep-like states have greater injury severity. This study was limited by strict enrollment criteria. A reliable method to quantify sleep and sleep-like states in the ICU is needed.

Quantitative EEG is an objective, sensitive, and reliable indicator of transient anesthetic effects during Wada tests.

The intracarotid amobarbital or Wada procedure is a component of the presurgical evaluation for refractory epilepsy, during which monitoring the onset and offset of transient anesthetic effects is critical. In this study, the authors characterized changes of 8 quantitative measures during 26 Wada tests, which included alpha, beta, theta, and delta powers, alpha/delta power ratio, beta/delta power ratio, median amplitude-integrated EEG, and 90% spectral edge frequency (SEF90), and correlated them with contralateral hemiplegia. The authors found that on the side of injection, delta and theta powers, alpha/delta power ratio, beta/delta power ratio, and SEF90 peaked within 1 minute after injection of 70 to 150 mg amobarbital or 4 to 7 mg methohexital. When contralateral arm strength returned to 3/5, delta power and amplitude-integrated EEG decayed on average 24% and 19%, respectively, for amobarbital, similar to that of methohexital (27% and 18%). Because delta power resolution most closely mirrored that of the hemiplegia and amplitude-integrated EEG had the highest signal/noise ratio, these quantitative values appear to be the best measures for decay of anesthetic effects. Increase in alpha power persisted longest, and therefore may be the best measure of late residual anesthetic effects.

Mood, anxiety, and incomplete seizure control affect quality of life after epilepsy surgery.

OBJECTIVE: We examined the complex relationship between depression, anxiety, and seizure control and quality of life (QOL) outcomes after epilepsy surgery. METHODS: Seven epilepsy centers enrolled 373 patients and completed a comprehensive diagnostic workup and psychiatric and follow-up QOL evaluation. Subjects were evaluated before surgery and then at 3, 6, 12, 24, 48, and 60 months after surgery. Standardized assessments included the Quality of Life in Epilepsy Inventory-89, Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). A mixed-model repeated-measures analysis was used to analyze associations of depression, anxiety, seizure outcome, and seizure history with overall QOL score and QOL subscores (cognitive distress, physical health, mental health, epilepsy-targeted) prospectively. RESULTS: The groups with excellent and good seizure control showed a significant positive effect on the overall QOL compared to the groups with fair and poor seizure control. The BDI and BAI scores were both highly and negatively associated with overall QOL; increases in BDI and BAI scores were associated with decreased overall QOL score. CONCLUSIONS: Depression and anxiety are strongly and independently associated with worse QOL after epilepsy surgery. Interestingly, even partial seizure control, controlling for depression and anxiety levels, improved QOL. Management of mood and anxiety is a critical component to postsurgical care.

Influence of anxiety on memory performance in temporal lobe epilepsy.

This study examined the degree to which anxiety contributed to inconsistent material-specific memory difficulties among 243 patients with temporal lobe epilepsy from the Multisite Epilepsy Study. Visual memory performance on the Rey Complex Figure Test (RCFT) was poorer for those with high versus low levels of anxiety but was not found to be related to the TLE side. The verbal memory score on the California Verbal Learning Test (CVLT) was significantly lower for patients with left-sided TLE than for patients with right-sided TLE with low anxiety levels but equally impaired for those with high anxiety levels. These results suggest that we can place more confidence in the ability of verbal memory tests like the CVLT to lateralize to left-sided TLE for those with low anxiety levels, but that verbal memory will be less likely to produce lateralizing information for those with high anxiety levels. This suggests that more caution is needed when interpreting verbal memory tests for those with high anxiety levels. These results indicated that RCFT performance was significantly affected by anxiety and did not lateralize to either side, regardless of anxiety levels. This study adds to the existing literature which suggests that drawing-based visual memory tests do not lateralize among patients with TLE, regardless of anxiety levels.