Electrocorticography Analysis in Patients With Dual Neurostimulators Supports Desynchronization as a Mechanism of Action for Acute Vagal Nerve Stimulator Stimulation.

PURPOSE: Both vagal nerve stimulation (VNS) and responsive neurostimulation (RNS System) are treatment options for medically refractory focal epilepsy. The mechanism of action of both devices remains poorly understood. Limited prior evidence suggests that acute VNS stimulation may reduce epileptiform activity and cause EEG desynchronization on electrocorticography (ECoG). Our study aims to isolate effects of VNS on ECoG as recorded by RNS System in patients who have both devices, by comparing ECoG samples with and without acute VNS stimulation. METHODS: Ten 60-second ECoGs each from 22 individuals at 3 epilepsy centers were obtained-5 ECoGs with VNS "off" and 5 ECoGs with VNS "on." Electrocorticograps containing seizures or loss of telemetry connection artifact were excluded from analysis (total of 169 ECoGs were included). Electrocorticographs were analyzed for differences in spectral content by generating average spectrograms for "on" and "off" states and using a linear mixed-effects model to isolate effects of VNS stimulation. RESULTS: Acute VNS stimulation reduced average power in the theta band by 4.9%, beta band by 3.8%, and alpha band by 2.5%. The reduction in theta power reached statistical significance with a P value of <0.05. CONCLUSIONS: Our results provide evidence that acute VNS stimulation results in desynchronization of specific frequency bands (salient decrease in theta and beta bands, smaller decrease in alpha band) in ECoGs recorded by the RNS device in patients with dual (VNS and RNS) neurostimulators. This finding offers support for desynchronization as a theorized mechanism of action of VNS. Further research may lead to future improved neurostimulator efficacy by informing optimal stimulation programming parameters.

Concurrent brain-responsive and vagus nerve stimulation for treatment of drug-resistant focal epilepsy.

OBJECTIVE: Clinical trials of a brain-responsive neurostimulator, RNS® System (RNS), excluded patients with a vagus nerve stimulator, VNS® System (VNS). The goal of this study was to evaluate seizure outcomes and safety of concurrent RNS and VNS stimulation in adults with drug-resistant focal-onset seizures. METHODS: A retrospective multicenter chart review was performed on all patients with an active VNS and RNS who were treated for a minimum of 6 months with both systems concurrently. Frequency of disabling seizures at baseline before RNS, at 1 year after RNS placement, and at last follow-up were used to calculate the change in seizure frequency after treatment. Data on adverse events and complications related to each device were collected. RESULTS: Sixty-four patients from 10 epilepsy centers met inclusion criteria. All but one patient received RNS after VNS. The median follow-up time after RNS implantation was 28 months. Analysis of the entire population of patients with active VNS and RNS systems revealed a median reduction in seizure frequency at 1 year post-RNS placement of 43% with a responder rate of 49%, and at last follow-up a 64% median reduction with a 67% responder rate. No negative interactions were reported from the concurrent use of VNS and RNS. Stimulation-related side-effects were reported more frequently in association with VNS (30%) than with RNS (2%). SIGNIFICANCE: Our findings suggest that concurrent treatment with VNS and RNS is safe and that the addition of RNS to VNS can further reduce seizure frequency.

Transcranial magnetic stimulation for the treatment of epilepsy.

BACKGROUND: Epilepsy is a highly prevalent neurological condition characterised by repeated unprovoked seizures with various aetiologies. Although antiepileptic medications produce clinical improvement in many individuals, nearly a third of individuals have drug-resistant epilepsy that carries significant morbidity and mortality, and even individuals who have clinical improvement from antiepileptic medications often report iatrogenic symptoms. There remains a need for non-invasive and more effective therapies for this population. Transcranial magnetic stimulation (TMS) uses electromagnetic coils to excite or inhibit neurons, with repetitive pulses at low-frequency producing an inhibitory effect that could conceivably reduce cortical excitability associated with epilepsy. This is an updated version of the original Cochrane Review published in 2016. OBJECTIVES: To assess the evidence for the use of TMS in individuals with drug-resistant epilepsy compared with other available treatments in reducing seizure frequency, improving quality of life, reducing epileptiform discharges, antiepileptic medication use, and side effects. SEARCH METHODS: For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid 1946 to 2 June 2020). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including Epilepsy. SELECTION CRITERIA: We included randomised controlled trials that were double-blinded, single-blinded, or unblinded, and placebo controlled, no treatment, or active controlled, which used repetitive transcranial magnetic stimulation (rTMS) without restriction of frequency, coil, duration or intensity on participants with drug-resistant epilepsy. DATA COLLECTION AND ANALYSIS: We extracted information from each trial including methodological data; participant demographics including baseline seizure frequency, type of epileptic drugs taken; intervention details and intervention groups for comparison; potential biases; and outcomes and time points, primarily change in seizure frequency or responder rates, as well as quality of life and epileptiform discharges, adverse effects, and changes in medication use. MAIN RESULTS: The original search revealed 274 records from the databases that after selection provided seven full-text relevant studies for inclusion. The latest search identified 179 new records from the databases that after evaluation against the inclusion and exclusion criteria provided one additional full-text relevant study. The eight included studies (241 participants) were all randomised trials; seven of the studies were blinded. Methodological and design information in the included studies was unclear, particularly relating to randomisation and allocation concealment methods. We were not able to combine the results of the trials in analysis due to differences in the studies' designs. For the current update, two of the eight studies analysed showed a statistically significant reduction in seizure rate from baseline (72% and 78.9% reduction of seizures per week from the baseline rate, respectively), whilst the other six studies showed no statistically significant difference in seizure frequency following rTMS treatment compared with controls (low-certainty evidence). One study assessed quality of life and found that more participants showed improvement in quality of life scores with active treatments compared to the sham treatment, but this only involved seven participants (very low-certainty evidence). Four studies evaluated our secondary endpoint of mean number of epileptic discharges, three of which showed a statistically significant reduction in discharges after active rTMS treatment. Adverse effects were uncommon in the studies and typically involved headache, dizziness, and tinnitus; however increased seizure frequency did occur in a small number of individuals. The included trials reported no significant changes in medication use. Overall the risk of bias was either low or unclear, and the certainty of the evidence was low to very low. AUTHORS' CONCLUSIONS: Overall, we judged the certainty of evidence for the primary outcomes of this review to be low to very low. We found some evidence to suggest that rTMS is safe but some adverse events were experienced. The variability in technique and outcome reporting prevented meta-analysis, and the evidence for efficacy of rTMS for seizure reduction is still lacking, despite reasonable evidence that it is effective at reducing epileptiform discharges.

Safety and efficacy of midazolam nasal spray for the treatment of intermittent bouts of increased seizure activity in the epilepsy monitoring unit: A double-blind, randomized, placebo-controlled trial.

OBJECTIVE: Midazolam nasal spray (MDZ-NS) is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern, in patients 12 years of age and older with epilepsy. This trial evaluated safety and efficacy of MDZ-NS in patients with epilepsy who were admitted to the epilepsy monitoring unit for seizure characterization/presurgical evaluation. METHODS: In this randomized, double-blind, placebo-controlled phase 3 trial (P261-301; NCT01999777), eligible patients with ≥2 seizures in the 6-hour window preceding trial medication administration for whom treatment was appropriate based on investigator's judgment were randomized (1:1) to MDZ-NS 5 mg or placebo. Efficacy outcomes were proportion of patients seizure-free for 6 hours after treatment and time to first seizure within 6 hours. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). RESULTS: Sixty-two patients were randomized (MDZ-NS n = 31; placebo n = 31), received trial medication, and completed the trial. A higher proportion of patients on MDZ-NS than placebo were seizure-free for 6 hours following treatment (54.8% vs 38.7%); however, the 16.1% difference was not statistically significant (P = .1972). The Kaplan-Meier curve of time to first seizure showed separation of both groups in favor of MDZ-NS from ~1.5 hours post-dose and throughout the 6-hour Treatment phase. Median time to first seizure was not estimable for MDZ-NS (>50% of patients had no seizure) and 3.9 hours for placebo (P = .1388). TEAEs with MDZ-NS were generally comparable to those with placebo. There were no deaths, serious TEAEs, or discontinuations due to TEAEs. SIGNIFICANCE: Although the observed treatment difference may be clinically meaningful, statistical significance was not demonstrated. Results suggest that MDZ-NS 5 mg may provide improvement over placebo, with efficacy maintained for ≥6 hours post-dose. MDZ-NS was well tolerated in this population.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Electrocorticographic events from long-term ambulatory brain recordings can potentially supplement seizure diaries.

PURPOSE: To determine the feasibility of using epileptiform events detected by continuous electrocorticographic monitoring via a brain-responsive neurostimulation system to supplement patient-maintained seizure diaries. METHODS: Data were retrospectively analyzed from a randomized controlled trial of brain-responsive neurostimulation (RNS® System) for adjunctive treatment of medically intractable focal onset seizures in 191 subjects. The long-term (≥3 months) correspondence between daily counts of diary-reported seizures and device-recorded "long epileptiform events" (LEs), a proxy for electrographic seizures (ESs), was assessed using cross-correlation and logistic generalized estimating equation models. RESULTS: Diary-reported seizures and LEs significantly co-varied across days in 124 patients whose detection settings were held constant, with a significantly higher correlation in 54 patients (44 %) whose LEs were usually ESs (high concordance patients). There were more days in which LEs were detected than days in which patients reported a seizure (positive predictive value (PPV): 34 %). On days when there were no LEs, there were typically no diary-reported seizures (negative predictive value (NPV): 90 %). In patients with a high concordance between LEs and ESs, the PPV and NPV were both slightly higher, 43 % (35-52 %) and 93 % (95 % CI: 86-97 %) respectively. CONCLUSION: Although LEs can substantially outnumber diary reported seizures, the high across-day correlation and strong NPV between LEs and diary seizures suggests that LEs recorded by the RNS® System could potentially supplement seizure diaries by providing an objective biomarker for relative seizure burden.

Infectious disease consultations at a South African academic hospital: A 6-month assessment of inpatient consultations.

BACKGROUND: Infectious diseases (IDs) dominate the disease profile in South Africa (SA) and the ID department is increasingly valuable. There has been little evaluation of the IDs consultation services in SA hospitals. METHODS: A qualitative review of ID inpatient consultations was performed over 6 months at a SA tertiary hospital. Prospectively entered data from each consultation were recorded on a computerised database and retrospectively analysed. RESULTS: 749 ID consultations were analysed, 4.8% of hospital admissions. Most consultations included initiation of antiretroviral therapy (ART) (27.8%), lipoarabinomannan antigen testing (24.8%) and change of ART (21.6%). Of patients reviewed, 93.3% were human immunodeficiency virus (HIV) positive and the median CD4 count was 52 cells/mm3. The infectious diagnoses (excluding HIV) most frequently encountered were pulmonary and abdominal tuberculosis (TB) and acute gastroenteritis. When all subcategories of TB infection were combined, 42.9% were found to have TB. Patients had predominantly one (45.4%) or two (30.2%) infectious diagnoses in addition to HIV. Some (12%) had three infectious diagnoses during their admission. The number of diagnoses, both infectious (odds ratio [OR] 2.00; 95% confidence interval [CI] 1.11-3.60) and non-infectious (OR 2.27; 95% CI 1.25-4.11), was associated with increased odds of death. CONCLUSION: The IDs department sees a high volume of patients compared to most developed countries. HIV, TB and their management dominate the workload. This study shows that HIV patients still have significant morbidity and mortality. The complexity of these patients indicates that specific expertise is required beyond that of the general physician.

Novel Use of Responsive Neurostimulation (RNS System) in the Treatment of Super Refractory Status Epilepticus.

There are very few randomized controlled trials studying treatment of super refractory status epilepticus (SE), despite estimated occurrence in about 15% of SE cases and its association with high morbidity and mortality rates. Small case series and case reports have described use of neurostimulation, including vagal nerve stimulation, transcranial magnetic stimulation, and deep brain stimulation, to treat super refractory SE when medical interventions have failed. To our knowledge, this is the first reported case of responsive neurostimulation being used to successfully treat a case of super refractory SE. A 37-year-old man with refractory focal epilepsy and a known focal cortical dysplasia involving motor cortex was implanted with an RNS System device after being in super refractory SE for 20 days. Responsive neurostimulation strip and depth electrodes were placed targeting the cortical dysplasia. Detection and stimulation parameters were adjusted over a 14-day period, as medications were gradually weaned. Seizures abated 15 days after implant, 24 hours after stimulation parameters were configured to mimic seizure offset pattern. Seizure remission was sustained, allowing the patient to be weaned off sedating medications and discharged to a rehabilitation facility. At 6 weeks of follow-up, the patient was near his neurologic baseline with no focal deficits.

High Cryptococcal Antigen Titers in Blood Are Predictive of Subclinical Cryptococcal Meningitis Among Human Immunodeficiency Virus-Infected Patients.

Background: High mortality rates among asymptomatic cryptococcal antigen (CrAg)-positive patients identified through CrAg screening, despite preemptive fluconazole treatment, may be due to undiagnosed cryptococcal meningitis. Methods: Symptoms were reviewed in CrAg-positive patients identified by screening 19233 individuals with human immunodeficiency virus infection and CD4 cell counts <100/µL at 17 clinics and 3 hospitals in Johannesburg from September 2012 until September 2015, and at 2 hospitals until June 2016. Cerebrospinal fluid samples from 90 of 254 asymptomatic patients (35%) and 78 of 173 (45%) with headache only were analyzed for cryptococcal meningitis, considered present if Cryptococcus was identified by means of India ink microscopy, culture, or CrAg test. CrAg titers were determined with stored blood samples from 62 of these patients. The associations between blood CrAg titer, concurrent cryptococcal meningitis, and mortality rate were assessed. Results: Cryptococcal meningitis was confirmed in 34% (95% confidence interval, 25%-43%; 31 of 90) of asymptomatic CrAg-positive patients and 90% (81%-96%; 70 of 78) with headache only. Blood CrAg titer was significantly associated with concurrent cryptococcal meningitis in asymptomatic patients (P < .001) and patients with headache only (P = .003). The optimal titer for predicting cryptococcal meningitis was >160 (sensitivity, 88.2%; specificity, 82.1%); the odds ratio for concurrent cryptococcal meningitis was 34.5 (95% confidence interval, 8.3-143.1; P < .001). Conclusions: About a third of asymptomatic CrAg-positive patients have concurrent cryptococcal meningitis. More effective clinical assessment strategies and antifungal regimens are required for CrAg-positive patients, including investigation for cryptococcal meningitis irrespective of symptoms. Where it is not possible to perform lumbar punctures in all CrAg-positive patients, blood CrAg titers should be used to target those most at risk of cryptococcal meningitis.

Does Disseminated Nontuberculous Mycobacterial Disease Cause False-Positive Determine TB-LAM Lateral Flow Assay Results? A Retrospective Review.

We retrospectively reviewed the Determine TB-LAM lateral flow assay (LF-LAM) results among human immunodeficiency virus-infected patients with disseminated nontuberculous mycobacterial (NTM) disease. LF-LAM was positive in 19 of 21 patients without evidence of tuberculosis (TB) coinfection. Although TB-NTM coinfection may have been underdiagnosed, our results suggest that disseminated NTM disease may cause false-positive LF-LAM results.

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.

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.

Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

OBJECTIVE: To assess the diagnostic accuracy and prognostic value of functional MRI (fMRI) in determining lateralization and predicting postsurgical language and memory outcomes. METHODS: An 11-member panel evaluated and rated available evidence according to the 2004 American Academy of Neurology process. At least 2 panelists reviewed the full text of 172 articles and selected 37 for data extraction. Case reports, reports with <15 cases, meta-analyses, and editorials were excluded. RESULTS AND RECOMMENDATIONS: The use of fMRI may be considered an option for lateralizing language functions in place of intracarotid amobarbital procedure (IAP) in patients with medial temporal lobe epilepsy (MTLE; Level C), temporal epilepsy in general (Level C), or extratemporal epilepsy (Level C). For patients with temporal neocortical epilepsy or temporal tumors, the evidence is insufficient (Level U). fMRI may be considered to predict postsurgical language deficits after anterior temporal lobe resection (Level C). The use of fMRI may be considered for lateralizing memory functions in place of IAP in patients with MTLE (Level C) but is of unclear utility in other epilepsy types (Level U). fMRI of verbal memory or language encoding should be considered for predicting verbal memory outcome (Level B). fMRI using nonverbal memory encoding may be considered for predicting visuospatial memory outcomes (Level C). Presurgical fMRI could be an adequate alternative to IAP memory testing for predicting verbal memory outcome (Level C). Clinicians should carefully advise patients of the risks and benefits of fMRI vs IAP during discussions concerning choice of specific modality in each case.