Epilepsia最新文献

Objective

POLR3B encodes the second largest subunit of RNA polymerase III, which is essential for transcription of small non-coding RNAs. Biallelic pathogenic variants in POLR3B are associated with an inherited hypomyelinating leukodystrophy. Recently, de novo heterozygous variants in POLR3B were reported in six individuals with ataxia, spasticity, and demyelinating peripheral neuropathy. Three of these individuals had epileptic seizures.

The aim of this article is to precisely define the epilepsy phenotype associated with de novo heterozygous POLR3B variants.

Methods

We used online gene-matching tools to identify 13 patients with de novo POLR3B variants. We systematically collected genotype and phenotype data from clinicians using two standardized proformas.

Results

All 13 patients had novel POLR3B variants. Twelve of 13 variants were classified as pathogenic or likely pathogenic as per American College of Medical Genetics (ACMG) criteria. Patients presented with generalized myoclonic, myoclonic-atonic, atypical absence, or tonic-clonic seizures between the ages of six months and 4 years. Epilepsy was classified as epilepsy with myoclonic-atonic seizures (EMAtS) in seven patients and “probable EMAtS” in two more.

Seizures were treatment resistant in all cases. Three patients became seizure-free. All patients had some degree of developmental delay or intellectual disability. In most cases developmental delay was apparent before the onset of seizures. Three of 13 cases were reported to have developmental stagnation or regression in association with seizure onset.

Treatments for epilepsy that were reported by clinicians to be effective were: sodium valproate, which was effective in five of nine patients (5/9) who tried it; rufinamide (2/3); and ketogenic diet (2/3).

Additional features were ataxia/incoordination (8/13); microcephaly (7/13); peripheral neuropathy (4/13), and spasticity/hypertonia (6/13).

Significance

POLR3B is a novel genetic developmental and epileptic encephalopathy (DEE) in which EMAtS is the predominant epilepsy phenotype. Ataxia, neuropathy, and hypertonia may be variously observed in these patients.

Objective

This study was undertaken to assess the clinical utility, safety, and tolerability in epilepsy patients of ultra long-term monitoring with a novel subcutaneous electroencephalographic (EEG) device (sqEEG).

Methods

Five patients with drug-resistant focal epilepsy were implanted (one patient bilaterally) with sqEEG. In phase 1, we assessed sqEEG sensitivity for seizure recording by recording seizures simultaneously with scalp EEG in the epilepsy monitoring unit (EMU). sqEEG was scored either visually (v-sqEEG) or by using a semiautomatic algorithm (EpiSight; E-sqEEG). In phase 2, the patients were monitored as outpatients for 3–6 months. sqEEG data were analyzed monthly, evaluating concordance of data obtained by v-sqEEG, E-sqEEG, and patients' diaries. v-sqEEG data were used to guide treatment adjustments. sqEEG-related side effects were assessed throughout the study.

Results

In phase 1, v-sqEEG detected all seizures recorded in the EMU in all patients, whereas E-sqEEG was as effective in three patients. In the other two patients, E-sqEEG detected only a proportion or none of the seizures, respectively. Sensitivity of E-sqEEG depended on the ictal EEG features. In phase 2, a 100% concordance between E-sqEEG and v-sqEEG in seizure detection was observed for the same three patients as in phase 1. In the other two patients (one implanted bilaterally), effectiveness of E-sqEEG in detecting seizure as compared to v-sqEEG ranged from 0% to 83%. v-sqEEG showed that all patients reported in their diaries fewer seizures than they actually suffered. In four of five patients, v-sqEEG showed that the treatment adjustments had been ineffective or associated with a seizure increment. The only side effect was an infection at the implantation site in one patient.

Significance

The sqEEG system could collect reliable information on seizure activity, thus providing clinically relevant information. Sensitivity of EpiSight in detecting seizures varied across patients, depending on the ictal EEG features. sqEEG ultra long-term monitoring was feasible and well tolerated.

Objective

Epilepsy is primarily treated with antiseizure medications (ASMs). The recommendations for first ASM in newly diagnosed epilepsy are inconsistently followed, and we sought to examine whether nonrecommended first ASM was associated with acute care utilization.

Methods

We conducted a retrospective cohort study of adults (≥18 years old) with newly diagnosed epilepsy (identified using validated epilepsy/convulsion International Classification of Diseases, Clinical Modification codes) in 2015–2019, sampled from Marketscan's Commercial and Medicare Databases. Exposure of interest was receipt of a non-guideline-recommended ASM, and the primary outcome was acute care utilization (an emergency department visit or hospitalization after the first ASM claim). Descriptive statistics characterized covariates, and multivariable negative binominal regression models were built adjusting for age, sex, Elixhauser Comorbidity Index, comorbid neurologic disease (e.g., stroke), and ASM polypharmacy.

Results

Approximately 14 681 people with new epilepsy were prescribed an ASM within 1 year. The three most prescribed medications were levetiracetam (54%, n = 7912), gabapentin (10%, n = 1462), and topiramate (7%, n = 1022). Approximately 4% (n = 648) were prescribed an ASM that should be avoided, and ~74% of people with new epilepsy had an acute care visit during the follow-up period. Mean number of acute care visits during follow-up was 3.34 for “recommended” ASMs and 4.42 for ASMs that “should be avoided.” Prescription of a recommended/neutral ASM as compared to an ASM that should be avoided was associated with reduced likelihood of acute care utilization (incidence rate ratio [IRR] = .85, 95% confidence interval [CI] = .77–.94). The recommended/neutral category of ASMs was not statistically significantly associated with seizure- or epilepsy-specific acute care utilization (IRR = .93, 95% CI = .79–1.09).

Significance

Adults with new epilepsy are frequent users of acute care. There remain a proportion of persons with epilepsy prescribed ASMs that guidelines suggest avoiding, and these ASMs are associated with increased likelihood of emergency department visit or hospitalization. These findings reinforce the importance of optimizing the choice of first ASM in epilepsy.

Objective

In adult anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, corticosteroids are commonly used as first-line treatment. However, the optimal oral prednisone tapering (OPT) following intravenous methylprednisolone pulse therapy remains unclear. We aim to compare the efficacy and safety of different OPT courses in anti-NMDAR encephalitis.

Methods

The CHASE study, a multicenter prospective observational cohort study, enrolled patients with autoimmune encephalitis from October 2011 to March 2023. Patients were grouped based on oral prednisone tapering course: ≤3 months (Group ≤3 month), 3–6 months (Group 3–6 months, including 3 months), and >6 months (Group > 6 months). Kaplan–Meier plots were used to analyze time to relapse and time to total recovery within 2 years.

Results

Among 666 screened patients, 171 (median [IQR] age 27 [21.0–36.5] years, 55.0% female) met selection criteria. Responders at 3 months were prevalent in Group ≤3 months (OR 7.251 [95% CI 2.252 to 23.344] and Group 3–6 months (OR, 3.857 [95% CI 1.107 to 13.440] than in Group >6 months. Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores at 12 months were higher in Group >6 months than in Group ≤3 months and Group 3–6 months (β, −2.329 [95% CI −3.784 to −.875]; β, −2.871 [95% CI −4.490, −1.253]). CASE seizures subscore was higher in Group >6 months than in Group 3–6 months (β, −.452 [95% CI −.788 to −.116]). No significant difference in seizure freedom rates among the groups. Adverse events were higher in Group 3–6 months and Group >6 months than in Group ≤3 months (OR 6.045 [95% CI 2.352 to 15.538]; OR 6.782 [95% CI 1.911 to 24.073]).

Significance

Longer oral prednisone courses for adult patients with anti-NMDAR encephalitis did not show superior effects compared to shorter courses in improving modified Rankin Scale (mRS) scores and CASE scores, reducing the risk of relapse within 2 years, or achieving seizure freedom. Instead, extended prednisone courses may lead to more side effects— particularly weight gain. This outcome recommends evaluating the possibility of shortening the duration of oral prednisone after a thorough patient assessment.

Objective

The incidence of late-onset epilepsy (LOE) is rising, and these patients may use an excess of health care resources. This study aimed to measure pre-/post-diagnostic health care use (HCU) for patients with LOE compared to controls.

Methods

This was an observational open cohort study covering years 1998–2019 using UK population-based linked primary care (Clinical Practice Research Datalink [CPRD]) and hospital (HES) electronic health records. The participants included patients with incident LOE enrolled in CPRD and 1:10 age-, sex-, and general practice–matched controls. The exposure was incident LOE (diagnosed at age ≥65) using a 5-year washout. The main outcome was all HCU (primary care [PC], accident and emergency [A&E], admitted patient and outpatient care) using inverse proportional weighting to PC use and HCU by setting. An interrupted time-series analysis was used to examine pre-/post-diagnostic HCU between patients with LOE and controls over 4 years either side of diagnosis/matching date. An adjusted mixed-effects negative binomial regression was used for post-diagnosis HCU interactions.

Results

Of 2 569 874 people ≥65 years of age, 1048 (4%) developed incident LOE. Mean weighted total HCU increased by 32 visits per patient-year (95% confidence interval [95% CI]: 13–50, p = .003) until LOE diagnosis, and then dropped by a mean of 60 visits per patient-year (95% CI: −81 to −40). There was an acute rise and fall over the 1–2 years immediately pre-/post-diagnosis. Incident HCU remained higher for LOE compared to controls post-diagnosis (adjusted incidence rate ratio: 1.72; 95% CI: 1.65–1.70; p < .001), including A&E, outpatient, and admitted care.

Significance

Health care use demonstrates an acute on chronic rise over the 4 years before diagnosis of LOE. To what extent the partial reversal of the acute pre-diagnosis rise, and the mediators of the accelerated increase compared to controls are attributed to epilepsy, comorbid and bidirectional disease states, or a combination of both warrants further exploration.

Objective

E2730, an uncompetitive γ-aminobutyric acid (GABA) transporter-1 (GAT-1) inhibitor, has potent anti-seizure effects in a rodent model of chronic temporal lobe epilepsy, the kainic acid status epilepticus (KASE) rat model. In this study, we examined purported neuroimaging and physiological surrogate biomarkers of the effect of E2730 on brain GABAergic function.

Methods

We conducted a randomized cross-over study, incorporating 1-week treatments with E2730 (100 mg/kg/day subcutaneous infusion) or vehicle in epileptic post-KASE rats. KASE rats underwent serial 9.4 T magnetic resonance spectroscopy (MRS) measuring GABA and other brain metabolites, [¹⁸F]Flumazenil positron emission tomography (PET) quantifying GABA_A receptor availability, quantitative electroencephalography (qEEG) and transcranial magnetic stimulation (TMS)–mediated motor activity, as well as continuous video-EEG recording to measure spontaneous seizures during each treatment. Age-matched, healthy control animals treated with E2730 or vehicle were also studied.

Results

E2730 treatment significantly reduced spontaneous seizures, with 8 of 11 animals becoming seizure-free. MRS revealed that E2730-treated animals had significantly reduced taurine levels. [¹⁸F]Flumazenil PET imaging revealed no changes in GABA receptor affinity or density during E2730 treatment. The power of gamma frequency oscillations in the EEG was decreased significantly in the auditory cortex and hippocampus of KASE and control rats during E2730 treatment. Auditory evoked gamma frequency power was enhanced by E2730 treatment in the auditory cortex of KASE and healthy controls, but only in the hippocampus of KASE rats. E2730 did not influence motor evoked potentials triggered by TMS.

Significance

This study identified clinically relevant changes in multimodality imaging and functional purported biomarkers of GABAergic activity during E2730 treatment in epileptic and healthy control animals. These biomarkers could be utilized in clinical trials of E2730 and potentially other GABAergic drugs to provide surrogate endpoints, thereby reducing the cost of such trials.

Objective

Phenotypic heterogeneity presents challenges in providing clinical care to patients with pathogenic SCN8A variants, which underly a wide disease spectrum ranging from neurodevelopmental delays without seizures to a continuum of mild to severe developmental and epileptic encephalopathies (DEEs). An important unanswered question is whether there are clinically important subgroups within this wide spectrum. Using both supervised and unsupervised machine learning (ML) approaches, we previously found statistical support for two and three subgroups associated with loss- and gain- of- function vari-ants, respectively. Here, we test the hypothesis that the unsupervised subgroups (U1–U3) are distinguished by differential contributions of developmental and epileptic components.

Methods

We predicted that patients in the U1 and U2 subgroups would differ in timing of developmental delay and seizure onset, with earlier and concurrent onset of both features for the U3 subgroup. Standard statistical procedures were used to test these predictions, as well as to investigate clinically relevant associations among all five subgroups.

Results

Two-population proportion and Kruskal–Wallis tests supported the hypothesis of a reversed order of developmental delay and seizure onset for patients in U1 and U2, and nearly synchronous developmental delay/seizure onset for the U3 (termed DEE) subgroup. Association testing identified subgroup variation in treatment response, frequency of initial seizure type, and comorbidities, as well as different median ages of developmental delay onset for all five subgroups.

Significance

Unsupervised ML approaches discern differential developmental and epileptic components among patients with SCN8A-related epilepsy. Patients in U1 (termed developmental encephalopathy) typically gain seizure control yet rarely experience improvements in development, whereas those in U2 (termed epileptic encephalopathy) have fewer if any developmental impairments despite difficulty in achieving seizure control. This understanding improves prognosis and clinical management and provides a framework to discover mechanisms underlying variability in clinical outcome of patients with SCN8A-related disorders.