Clinical outcomes among initial survivors of cryptogenic new-onset refractory status epilepsy (NORSE).

OBJECTIVE: New-onset refractory status epilepticus (NORSE) is a rare but severe clinical syndrome. Despite rigorous evaluation, the underlying cause is unknown in 30%-50% of patients and treatment strategies are largely empirical. The aim of this study was to describe clinical outcomes in a cohort of well-phenotyped, thoroughly investigated patients who survived the initial phase of cryptogenic NORSE managed in specialist centers. METHODS: Well-characterized cases of cryptogenic NORSE were identified through the EPIGEN and Critical Care EEG Monitoring Research Consortia (CCEMRC) during the period 2005-2019. Treating epileptologists reported on post-NORSE survival rates and sequelae in patients after discharge from hospital. Among survivors >6 months post-discharge, we report the rates and severity of active epilepsy, global disability, vocational, and global cognitive and mental health outcomes. We attempt to identify determinants of outcome. RESULTS: Among 48 patients who survived the acute phase of NORSE to the point of discharge from hospital, 9 had died at last follow-up, of whom 7 died within 6 months of discharge from the tertiary care center. The remaining 39 patients had high rates of active epilepsy as well as vocational, cognitive, and psychiatric comorbidities. The epilepsy was usually multifocal and typically drug resistant. Only a minority of patients had a good functional outcome. Therapeutic interventions were heterogenous during the acute phase of the illness. There was no clear relationship between the nature of treatment and clinical outcomes. SIGNIFICANCE: Among survivors of cryptogenic NORSE, longer-term outcomes in most patients were life altering and often catastrophic. Treatment remains empirical and variable. There is a pressing need to understand the etiology of cryptogenic NORSE and to develop tailored treatment strategies.

Closed system production of serum eye drops using dockable saline.

BACKGROUND AND OBJECTIVES: A fully closed system solution to manufacture serum eye drops using diluted serum has remained elusive, necessitating production steps to mitigate bacterial contamination risks in a clean suite environment, hampering production efficiency amid growing demand. We describe our recent implementation of a fully closed manufacturing process at New Zealand Blood Service. MATERIALS AND METHODS: A dockable format for sterile saline manufactured to custom specifications configured with a 15-cm tubing to enable sterile connections was sourced from a local pharmaceutical manufacturer. RESULTS: From a total of 30,168 eye drop vials manufactured since implementation, the average production time was reduced by up to 45% performed in the general laboratory environment, attributed to eliminating processes performed in a clean suite. No bacterial contamination was observed, demonstrating robust sterile connections. CONCLUSION: Dockable saline takes serum eye drops manufactured from a functionally closed system to a fully closed system, thereby enhancing patient safety, significantly reducing manufacturing time and cost and transforming production from a highly restrictive process into a portable workflow that is simple, practical and effective.

Long-term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open-label extension trial.

OBJECTIVE: To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label extension (OLE) of the randomized, placebo-controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported. METHODS: Patients who completed the randomized trial enrolled to receive CBD (Epidiolex® in the United States; Epidyolex® in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC-associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC). RESULTS: Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1-57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One-year retention rate was 79%. Median treatment time was 267 days (range, 18-910) at a 27 mg/kg/day mean modal dose. Most patients (92%) had an adverse event (AE). Most common AEs were diarrhea (42%), seizure (22%), and decreased appetite (20%). AEs led to permanent discontinuation in 6% of patients. There was one death that was deemed treatment unrelated by the investigator. Elevated liver transaminases occurred in 17 patients (9%) patients; 12 were taking valproate. Median percentage reductions in seizure frequency (12-week windows across 48 weeks) were 54%-68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%-61%, 29%-45%, and 6%-11% across 12-week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks. SIGNIFICANCE: In patients with TSC, long-term add-on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement.

Machine learning approaches for imaging-based prognostication of the outcome of surgery for mesial temporal lobe epilepsy.

OBJECTIVES: Around 30% of patients undergoing surgical resection for drug-resistant mesial temporal lobe epilepsy (MTLE) do not obtain seizure freedom. Success of anterior temporal lobe resection (ATLR) critically depends on the careful selection of surgical candidates, aiming at optimizing seizure freedom while minimizing postoperative morbidity. Structural MRI and FDG-PET neuroimaging are routinely used in presurgical assessment and guide the decision to proceed to surgery. In this study, we evaluate the potential of machine learning techniques applied to standard presurgical MRI and PET imaging features to provide enhanced prognostic value relative to current practice. METHODS: Eighty two patients with drug resistant MTLE were scanned with FDG-PET pre-surgery and T1-weighted MRI pre- and postsurgery. From these images the following features of interest were derived: volume of temporal lobe (TL) hypometabolism, % of extratemporal hypometabolism, presence of contralateral TL hypometabolism, presence of hippocampal sclerosis, laterality of seizure onset volume of tissue resected and % of temporal lobe hypometabolism resected. These measures were used as predictor variables in logistic regression, support vector machines, random forests and artificial neural networks. RESULTS: In the study cohort, 24 of 82 (28.3%) who underwent an ATLR for drug-resistant MTLE did not achieve Engel Class I (i.e., free of disabling seizures) outcome at a minimum of 2 years of postoperative follow-up. We found that machine learning approaches were able to predict up to 73% of the 24 ATLR surgical patients who did not achieve a Class I outcome, at the expense of incorrect prediction for up to 31% of patients who did achieve a Class I outcome. Overall accuracies ranged from 70% to 80%, with an area under the receiver operating characteristic curve (AUC) of .75-.81. We additionally found that information regarding overall extent of both total and significantly hypometabolic tissue resected was crucial to predictive performance, with AUC dropping to .59-.62 using presurgical information alone. Incorporating the laterality of seizure onset and the choice of machine learning algorithm did not significantly change predictive performance. SIGNIFICANCE: Collectively, these results indicate that "acceptable" to "good" patient-specific prognostication for drug-resistant MTLE surgery is feasible with machine learning approaches utilizing commonly collected imaging modalities, but that information on the surgical resection region is critical for optimal prognostication.

Impact of COVID-19 on seizure-related emergency attendances and hospital admissions - A territory-wide observational study.

This is a territory-wide study to investigate the impact of coronavirus disease 2019 (COVID-19) pandemic on Accident and Emergency Department (A&E) attendances and acute ward admissions for seizures. Adult patients who presented to the A&E with seizures from January 23, 2020 to March 24, 2020 (study period) were included and compared with parallel intervals from 2015 to 2019 (control periods). Preexisting time trend in control periods and potential changes during COVID-19 were analyzed by Poisson, negative and logistic regression models. Accident and Emergency Department attendances and ward admissions for seizures decreased significantly during the COVID-19 pandemic. A total of 319 and 230 recorded ward admissions and A&E attendances for seizures were identified during the study period in 2020, compared with 494 and 343 per annum, respectively in the control periods. The ratio of acute ward admission per A&E attendance for seizures did not change significantly. Intensive care utility and mortality rates remained stable. For some patients, delaying medical attention due to fear of nosocomial COVID-19 cross-infection may lead to severe or even life-threatening consequences. This change in medical help-seeking behavior calls for new medical care models to meet the service gap. Education to patients with epilepsy and their caregivers is of utmost importance during this pandemic.

30 years of second-generation antiseizure medications: impact and future perspectives.

Since 1989, 18 second-generation antiseizure medications have reached the market, resulting in a greatly increased range of treatment options for patients and prescribers. 30 years have passed and now is the time for an appraisal of the effect of these medications on clinical outcomes. Every antiseizure medication needs to be assessed individually, but overall second-generation drugs are less likely to cause pharmacokinetic interactions than their older counterparts. Some second-generation antiseizure medications have shown advantages in tolerability and safety, particularly in the treatment of older patients and women of childbearing potential. Disappointingly, however, none of these medications appear to be more efficacious than first-generation antiseizure medications, highlighting the need for novel strategies in epilepsy drug development. Although second-generation antiseizure medications have not substantially reduced the proportion of patients with pharmacoresistant epilepsy, their availability has enabled more opportunities to tailor treatment choice to the characteristics of the individual.

Simple partial status epilepticus in Chinese adults.

Simple partial status epilepticus (SPSE) is uncommon compared with generalized tonic-clonic status epilepticus. We evaluated the clinical profile and predictors of poor outcome in a group of Chinese patients with this condition. We identified 32 patients above the age of 14 years with SPSE from a large urban hospital over an eleven-year period. Factors for poor outcome, defined as death or morbidity, were analyzed. The most common underlying causes were due to cerebrovascular disease (46.9%), CNS infection (15.6%), metabolic derangement (12.5%) and tumor (12.5%). At 30 days from the onset of seizures, 13(40.5%) patients had recovered fully and seven (21.9%) had died. Poor outcome was associated with the presence of an acute symptomatic injury.

Refractory epilepsy: a progressive, intractable but preventable condition?

Intractable seizures are just one manifestation of 'refractory epilepsy', which can be recognized as a distinct condition with multifaceted dimensions, including neurobiochemical plastic changes, cognitive decline and psychosocial dysfunction, leading to dependent behaviour and a restricted lifestyle. The biological basis of 'refractoriness' is likely to be multifactorial, and may include the severity of the syndrome and/or underlying neuropathology, abnormal reorganization of neuronal circuitry, alteration in neurotransmitter receptors, ion channelopathies, reactive autoimmunity, and impaired antiepileptic drug (AED) penetration to the seizure focus. Some of these deleterious changes may be a consequence of recurrent seizures. We hypothesize that 'refractory epilepsy' may be prevented by interrupting this self-perpetuating progression. There is increasing evidence that these patients can be identified early in the clinical course and, thus, be targeted early for effective therapeutic intervention. Failure of two first-line AEDs due to lack of efficacy or poor tolerability should prompt consideration of epilepsy surgery in a patient with a resectable brain abnormality. For the majority not suitable for 'curative' surgery, AEDs should be combined with the aim of achieving 'synergism'. This strategy has the potential to improve outcome by preventing the insidious progression to intractable 'refractoriness' and a downward spiraling quality of life.