Efficacy and safety of perampanel as early add-on therapy in Chinese patients with focal-onset seizures: a multicenter, open-label, single-arm study.

Background: No interventional study has been conducted in China to assess efficacy and safety of perampanel in treating Chinese patients with epilepsy, nor has there been any study on perampanel early add-on therapy in China. This interventional study aimed to assess efficacy and safety of perampanel as an early add-on treatment of focal-onset seizures (FOS) with or without focal-to-bilateral tonic-clonic seizures (FBTCS) in Chinese patients. Methods: In this multicenter, open-label, single-arm, phase 4 interventional study, Chinese patients ≥ 12 years old with FOS with or without FBTCS who failed anti-seizure medication (ASM) monotherapy from 15 hospitals in China were enrolled and treated with perampanel add-on therapy (8-week titration followed by 24-week maintenance). The primary endpoint was 50% responder rate. Secondary endpoints included seizure-freedom rate and changes in seizure frequency from baseline. Treatment-emergent adverse events (TEAEs) and drug-related TEAEs were recorded. Results: The full analysis set included 150 patients. The mean maintenance perampanel dose was 5.9 ± 1.5 mg/day and the 8-month retention rate was 72%. The 50% responder rate and seizure-freedom rate for all patients during maintenance were 67.9 and 30.5%, respectively. Patients with FBTCS had higher 50% responder rate (96.0%) and seizure-freedom rate (76.0%) during maintenance. Patients on concomitant sodium valproate had a significantly higher seizure-freedom rate than those on concomitant oxcarbazepine. Eight-six (55.1%) patients experienced treatment-related TEAEs, and the most common TEAEs were dizziness (36.5%), hypersomnia (11.5%), headache (3.9%), somnolence (3.2%), and irritability (3.2%). Withdrawal due to TEAEs occurred to 14.7% of the patients. Conclusion: Perampanel early add-on was effective and safe in treating Chinese patients≥12 years old with FOS with or without FBTCS.Clinical trial registrationwww.chictr.org.cn, Identifier ChiCTR2000039510.

Multidisciplinary molecular consultation increases the diagnosis of pediatric epileptic encephalopathy and neurodevelopmental disorders.

BACKGROUND: Epilepsy (EP) is a common neurological disease in which 70-80% are thought to have a genetic cause. In patients with epilepsy, neurodevelopmental delay (NDD) was prevalent. Next generation of sequencing has been widely used in diagnosing EP/NDD. However, the diagnostic yield remains to be 40%-50%. Many reanalysis pipelines and software have been developed for automated reanalysis and decision making for the diseases. Nevertheless, it is a highly challenging task for smaller genetic centers or a routine pediatric practice. To address the clinical and genetic "diagnostic odyssey," we organized a Multidisciplinary Molecular Consultation (MMC) team for molecular consultation for 202 children with EP/NDD patients referred by lower level hospitals. METHODS: All the patients had undergone an aligned and sequential consultations and discussions by a "triple reanalysis" procedure by clinical, genetic specialists, and researchers. RESULTS: Among the 202 cases for MMC, we totally identified 47 cases (23%) harboring causative variants in 24 genes and 15 chromosomal regions after the MMC. In the 15 cases with positive CNVs, 3 cases harbor the deletions or duplications in 16p11.2, and 2 cases for 1p36. The bioinformatical reanalysis revealed 47 positive cases, in which 12 (26%) were reported to be negative, VUS or incorrectly positive in pre-MMC reports. Additionally, among 87 cases with negative cases, 4 (5%) were reported to be positive in pre-MMC reports. CONCLUSION: We established a workflow allowing for a "one-stop" collaborative assessments by experts of multiple fields and helps for correct the diagnosis of cases with falsenegative and -positive and VUS genetic reports and may have significant influences for intervention, prevention and genetic counseling of pediatric epilepsy and neurodevelopmental disorders.

Reference values for trans-laminar cribrosa pressure difference and its association with systemic biometric factors.

OBJECTIVES: To provide reference values of trans-laminar cribrosa pressure difference (TLCPD) and reveal the association of TLCPD with systemic biometric factors. METHODS: In this cross-sectional study, 526 quasi-healthy subjects (including 776 eyes) who required lumbar puncture for medical reasons were selected from 4915 neurology inpatients from 2019 to 2022. Patients with any diseases affecting intraocular pressure (IOP) or intracranial pressure (ICP) were excluded. The ICPs of all subjects were obtained by lumbar puncture in the left lateral decubitus position. IOP was measured in the seated position by a handheld iCare tonometer prior to lumbar puncture. TLCPD was calculated by subtracting ICP from IOP. Systemic biometric factors were assessed within 1 h prior to TLCPD measurement. RESULTS: The TLCPD (mean ± standard deviation) was 4.4 ± 3.6 mmHg, and the 95% reference interval (defined as the 2.5th-97.5th percentiles) of TLCPD was -2.27 to 11.94 mmHg. The 95% reference intervals for IOP and ICP were 10-21 and 6.25-15.44 mmHg, respectively. IOP was correlated with ICP (r = 0.126, p < 0.001). TLCPD was significantly negatively correlated with body mass index (r = -0.086, p = 0.049), whereas it was not associated with age, gender, height, weight, blood pressure, pulse, or waist and hip circumference. CONCLUSIONS: This study provides reference values of TLCPD and establishes clinically applicable reference intervals for normal TLCPD. Based on association analysis, TLCPD is higher in people with lower BMI.

SCN1A-Related Epilepsy: Novel Mutations and Rare Phenotypes.

Objectives: To expand the genotypes and phenotypes of sodium voltage-gated channel alpha subunit 1 (SCN1A)-related epilepsy. Methods: We retrospectively collected the clinical and genetic information of 22 epilepsy patients (10 males, 12 females; mean: 9.2 ± 3.9 years; 3.9-20.3 years) carrying 22 variants of SCN1A. SCN1A mutations were identified by next-generation sequencing. Results: Twenty-two variants were identified, among which 12 have not yet been reported. The median age at seizure onset was 6 months. Sixteen patients were diagnosed with Dravet syndrome (DS), two with genetic epilepsy with febrile seizures plus [one evolved into benign epilepsy with centrotemporal spikes (BECTS)], one with focal epilepsy, one with atypical childhood epilepsy with centrotemporal spikes (ABECTS) and two with unclassified epilepsy. Fourteen patients showed a global developmental delay/intellectual disability (GDD/ID). Slow background activities were observed in one patient and epileptiform discharges were observed in 11 patients during the interictal phase. Significance: This study enriches the genotypes and phenotypes of SCN1A-related epilepsy. The clinical characteristics of patients with 12 previously unreported variants were described.

A Prognostic Analysis of the Outcomes in Patients With Anti-γ-Aminobutyric Acid B Receptor Encephalitis.

Objective: To evaluate neurological function and its influencing factors in patients with anti-γ -aminobutyric acid B receptor (GABABR) encephalitis. Methods: This was a clinical cohort study of patients diagnosed with anti-GABABR encephalitis; long-term follow-up was performed by telephone. Clinical factors associated with prognosis were analyzed, including clinical manifestations, laboratory examinations, imaging features, tumor comorbidities and therapeutic responses. Results: Twenty-two patients with anti-GABABR encephalitis were evaluated (median age: 55 years). Lung cancer was detected in eight patients. All were with serum tumor markers (mainly NSE), and three of them had additional onconeuronal antibodies. The patients with tumors were older than the patients without tumors and more likely to develop status epilepticus (62.5% vs. 14.3%; p = 0.052), central hypoventilation (50% vs. 7.1%; p = 0.039), and hyponatremia (87.5% vs. 14.3%; p = 0.001). The patients with tumors had higher mortality (87.5% vs. 0%; p < 0.05). Although 92.9% of the patients without tumors became functionally independent (mRS ≤2), sequelae of symptomatic seizures, neuropsychiatric symptoms, and cognitive impairment were still observed in 14.3%, 21.4%, and 21.4% of patients, respectively. Conclusions: (1) Elderly patients with anti-GABABR antibodies, especially those with severe symptoms, serum tumor markers, and additional onconeuronal antibodies, should be screened for lung cancer. (2) Anti-GABABR encephalitis with tumors has a poor prognosis. (3) Most patients without tumors achieve self-care, but some still experience remaining neurological deficits.

Case Report: A Novel Missense Mutation c.517G>C in the UMPS Gene Associated With Mild Orotic Aciduria.

Background: Hereditary orotic aciduria (HOA) is a rare genetic disorder of pyrimidine metabolism caused by variations in the uridine monophosphate synthetase (UMPS) gene and inheritance are autosomal recessive. Heterozygous UMPS mutations can also lead to orotic aciduria without clinical consequence. Methods: We conducted molecular genetic analyses on proband using whole-exome sequencing (WES) and on 12 family members using Sanger sequencing for UMPS mutation. We analyzed the urine metabolites of family members carrying UMPS heterozygous variants with standard gas chromatography-mass spectrometry (GC-MS). Results: We identified a novel UMPS mutation (c.517G>C) in a Chinese-origin of orotic aciduria pedigree. The proband presented with epilepsy and intellectual disability (ID). Other mutation carriers in our pedigree presented with mild orotic aciduria without relevant medical complaints except for the proband. Conclusion: Our study further expanded the genotype of orotic aciduria and highlighted the probability of misdiagnosis in clinical practice.

Clinical Features, Immunotherapy, and Outcomes of Anti-Leucine-Rich Glioma-Inactivated-1 Encephalitis.

OBJECTIVE: The investigators aimed to explore the clinical characteristics, immunotherapy, and outcomes of patients with antileucine-rich glioma-inactivated-1 (anti-LGI1) encephalitis. METHODS: Data on participants' clinical characteristics, laboratory findings, radiological and electroencephalogram (EEG) features, treatment, and outcomes from January 2012 to December 2016 were collected. Statistical analysis was conducted to assess the factors associated with patient functional outcome. Forty-three patients were enrolled in the study, with a predominance of males (65.1%). The median age at onset was 57 years (interquartile range [IQR]: 44.0-65.0). The median time from onset to diagnosis was 60 days (IQR: 37.0-127.0). RESULTS: The main clinical manifestations included epilepsy (100%), faciobrachial dystonic seizures (FBDS; 44.2%), cognitive dysfunction (95.3%), neuropsychiatric disturbances (76.7%), sleep disorders (58.1%), and disturbance of consciousness (48.8%). Twenty-two patients (51.2%) had hyponatremia, 31 (72.1%) had abnormal EEG results, and 30 (69.8%) had abnormal brain MRI scans, mainly involving the hippocampus (76.7%) or temporal lobe (40%). Twenty of 34 patients (58.8%) in a follow-up MRI examination exhibited hippocampal atrophy. Twenty-five patients (58.2%) were administered corticosteroids and intravenous immunoglobulin, whereas 17 patients were treated only with corticosteroids. Forty-one patients (95.3%) had favorable outcomes after a median of 21.5 months (IQR: 7-43) of follow-up. Serum sodium level was a factor associated with a disabled status (odds ratio=0.81, 95% CI=0.66, 0.98, p=0.03). Anti-LGI1 encephalitis patients were characterized by seizures, FBDS, cognitive deficits, neuropsychiatric disturbances, and hyponatremia. CONCLUSIONS: Most patients with anti-LGI1 encephalitis are nonparaneoplastic, have low recurrence rates, and have favorable prognostic outcomes. Rapid evaluation, prompt immunotherapy, and long-term follow-up are essential in the care of anti-LGI1 encephalitis patients.

Clinical and Imaging Features of Patients With Encephalitic Symptoms and Myelin Oligodendrocyte Glycoprotein Antibodies.

Background: Myelin oligodendrocyte glycoprotein-antibody (MOG-ab)-associated disease (MOGAD) has highly heterogenous clinical and imaging presentations, in which encephalitis is an important phenotype. In recent years, some atypical presentations in MOG-ab-associated encephalitis (MOG-E) have been increasingly reported but have not yet been described well. The aim of the study was to describe the clinical and imaging features of patients with MOG-E in our center. Atypical phenotypes would be reported, which is expected to expand the spectrum of MOGAD. Methods: We reviewed medical records of 59 patients with MOGAD diagnosed in our center and identified cases who had ever experienced encephalitic symptoms. Three hundred ten patients with autoimmune encephalitis (AE) were also reviewed, and cases with positive MOG-ab were identified. Besides, patients with chronically progressive encephalitis were identified from 13 MOG-E and 310 AE patients. We collected demographic, clinical, laboratory, radiological, and outcome data to explore clinical and imaging characteristics in MOG-E, especially in the atypical phenotype of chronically progressive encephalitis. Results: We identified 13 patients (7 males, 6 females) with MOG-E. The median age at onset was 33 years (range 13~62 years). Most (9/13, 69.2%) of patients showed acute or subacute onset of encephalitic symptoms. Brain MRI abnormalities were observed in all patients. The most common lesion locations on MRI were cortical/subcortical (11/13, 84.6%), deep/periventricular white matter (10/13, 76.9%) and corpus callosum (4/13, 30.8%). Brain MRI patterns were categorized into four phenotypes. The most common pattern was cortical encephalitis with leptomeningeal enhancement/brain atrophy (10/13, 76.9%). Eight (8/13, 61.5%) patients had a good response to immunotherapy. Four (4/13, 30.8%) patients with chronically progressive course were identified from MOG-E cohort. They showed leukodystrophy-like pattern, multifocal hazy lesions, or cortical encephalitis on MRI. With immunotherapy, they only showed mild or no improvement. We also identified four (4/310, 1.3%) patients with chronically progressive course from AE cohort. They had better outcomes than counterparts in MOG-E. Conclusions: This study demonstrates that encephalitic presentations in MOGAD had complex clinical patterns. Chronically progressive encephalitis may be a new phenotype of MOGAD. We recommend to test MOG-ab in subacute and chronic progressive dementia with leukodystrophy-like MRI lesions.

Neurofunctional outcomes in patients with anti-leucine-rich glioma inactivated 1 encephalitis.

OBJECTIVE: To evaluate the cognitive and neurofunctional outcomes in patients with anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis. METHODS: A cohort follow-up study was performed after a median of 33 months (range 6-78) from disease onset to the last follow-up in patients diagnosed with anti-LGI1 encephalitis, to assess the neurofunctional outcomes using modified Rankin Scale (mRS), activities of daily living (ADL), neuropsychiatric inventory (NPI) and modified telephone interview for cognitive status (TICS-M). Remote symptomatic seizure and clinical relapses were also recorded. The clinical, laboratory features, and treatment responses that characterize the disability were analyzed. RESULTS: The results showed that 81 of 86 (94.2%) patients with anti-LGI1 encephalitis were successfully followed up, while eight (9.9%) died after discharge. Among the 73 survivors, clinical relapses occurred in 18 (24.7%) patients, and those with relapses were at a higher risk of developing remote symptomatic seizure (p = .019). Although 85.2% of the patients became functionally independent (mRS ≤2), the sequelae of symptomatic seizure, neuropsychiatric symptoms, and cognitive deficits were found in 11.0%, 21.9%, and 39.7% of the patients, respectively. Residual cognitive deficits primarily occurred in the elderly subjects as well as those with symptoms of memory deficit, psychiatric disorders, sleep disturbance, disturbance of consciousness at diagnosis, and higher CSF protein levels. CONCLUSIONS: Although most patients survived and became functionally independent, a subset of patients could not return to all premorbid activities. They may have clinical relapses or suffer from remote symptomatic seizure, neuropsychiatric symptoms, and cognitive impairment.

Overlapping syndrome of anti-N-methyl-D-aspartate receptor encephalitis and anti-myelin oligodendrocyte glycoprotein inflammatory demyelinating diseases: A distinct clinical entity?

BACKGROUND: The co-existence of anti-N-methyl-D-aspartate receptor encephalitis (NMDARe) and anti-myelin oligodendrocyte glycoprotein (MOG) antibody disease has sparsely been reported, which needs to be investigated. METHOD: Among the patients with NMDARe in Xuanwu Hospital, MOG antibody disease and NMDARe overlapping syndrome (MNOS) were retrospectively identified. We combined our data with those from previously reported cases to characterize this new entity. RESULT: There were 45 patients with MNOS with a median onset age of 20. A total of 97.8% of the patients had symptoms of encephalitis; 68.9% of the patients had symptoms of demyelination, including optic neuritis (ON) (37.9%), longitudinally extensive transverse myelitis (LETM) (31.0%) and acute disseminated encephalomyelitis (ADEM) (27.6%). Abnormal signals on magnetic resonance imaging (MRI) usually involved cortical (46.7%), subcortical (31.1%) and basal ganglia (26.7%) lesions, as well as infratentorial (48.9%) and spinal cord (28.9%) lesions. No tumours were found. A total of 62.2% of the patients relapsed, with recurrence rates of 66.7% and 50.0% for those treated with first-line therapy alone and in combination with second-line immunotherapy, respectively. The pathological changes from the biopsy indicated immune-mediated inflammatory demyelination. Although some patients may have residual deficits, 93.3% of the patients became functionally independent. CONCLUSION: The possibility of MNOS should be considered when patients diagnosed with anti-NMDARe simultaneously or sequentially develop ON, LETM or ADEM. MNOS occurred without tumour association, and inflammatory demyelination may be the pathological change. Steroids combined with second-line immunotherapy can help to reduce high recurrence rates, and most patients will have substantial recovery.

Comprehensive genetic, clinical and electrophysiological studies of familial cortical myoclonic tremor with epilepsy 1 highlight the role of gene configurations.

OBJECTIVES: Two configurations of TTTTA/TTTCA expansion in SAMD12 have been identified in familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1). This study investigated the clinical and neurophysiological features of FCMTE1 and their association with TTTTA/TTTCA expansion patterns. METHODS: In total, 76 patients from 20 Chinese pedigrees were enrolled. Genetic (TTTTA/TTTCA configuration), clinical (e.g., onset, medication, prognosis, and anticipation) and neurophysiological examination (e.g., electroencephalogram and magnetoencephalography) data were evaluated, and associations between these parameters were analyzed. RESULTS: All patients carried the TTTTA/TTTCA expansion mutation, 19 displayed the (TTTTA)exp(TTTCA)exp (type I) configuration and 1 displayed the (TTTTA)exp (TTTCA)exp(TTTTA)exp (type II) configuration. All patients manifested as progressive tremor, but symptoms of patients carrying type II expansion were more severe. The onset of tremor but not generalized tonic and clonic seizures displayed clinical anticipation between generations of 7 pedigrees, but the pedigree carrying the type II mutation did not show anticipation. Nanopore sequencing showed that the repeats expanded during maternal/offspring transmission (pedigree #7) but shrank during paternal/offspring transmission (pedigree #9). Magnetoencephalographic dipoles were localized in the right frontal lobe near the central sulcus in 4 patients carrying the type I mutation and on the left side in one patient carrying the type II mutation. SIGNIFICANCE: We confirmed the causative roles played by TTTTA/TTTCA repeat expansion in the SAMD12 gene in FCTME1. Both the length and the configuration of the repeats contribute to the clinical and neurophysiological characteristics of the disease.

[Simultaneous determination of twelve antiepileptic drugs in serum by ultra high performance liquid chromatography-tandem mass spectrometry].

A sensitive, high-throughput method was established for the simultaneous determination of 12 antiepileptics in serum by ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The antiepileptics were gabapentin, lamotrigine, pregabalin, lacosamide, levetiracetam, topiramate, oxcarbazepine, clonazepam, sodium valproate, carbamazepine, phenobarbital and phenytoin sodium. Phenacetin and chlorzoxazone were used as internal standards. The antiepileptics and internal standards were extracted from serum by protein precipitation using acetonitrile as the precipitant. Chromatographic separation was achieved on an ACQUITY UPLC BEH C18 column with a gradient mobile phase comprising 10 mmol/L ammonium formate aqueous solution and methanol (containing 10 mmol/L ammonium formate) at a flow rate of 0.4 mL/min. Detection was performed in multiple reaction monitoring mode with ion mode switching. The results showed good linear trends in their respective concentration ranges and the correlation coefficients (r2) were greater than 0.992. The spiked recoveries of the 12 antiepileptics in serum were 90.80%-114.0% at the three spiked levels. The intra-assay (n=6) and inter-assay (n=3) precisions were less than 13.2% and 14.8%, respectively. The method has high specificity and sensitivity, and it can be used for clinical blood concentration monitoring and pharmacokinetic studies of the 12 antiepileptics.

Levetiracetam-induced a new seizure type in a girl with a novel SV2A gene mutation.

The target brain binding site of levetiracetam (LEV) is synaptic vesicle glycoprotein 2A (SV2A). Up to now, only a homozygous pathogenic SV2A gene mutation was reported in human. We now report a novel heterozygous pathogenic SV2A gene mutation both in a girl and her mother result in epilepsy and poor response to LEV. Furthermore, the girl developed a new seizure type after using LEV. Our report had a clinical relevance that LEV could potentially produce contradictory efficacy in patients with SV2A gene mutation. If patients' seizures became exacerbated while using LEV, SV2A gene testing is recommended.

Identification of a novel mutation in PLA2G6 gene in a Chinese pedigree with familial cortical myoclonic tremor with epilepsy.

PURPOSE: Familial cortical myoclonic tremor with epilepsy (FCMTE) is an epileptic syndrome with autosomal dominant inheritance, of which four genetic subtypes (FCMTE1-4) have been reported. In the present study, we described the clinical and neurophysiologic features of a newly diagnosed Chinese FCMTE family, and investigated the genetic cause for this disease. METHODS: Clinical information was obtained from affected and normal individuals of an FCMTE family comprising 41 members. Electroencephalographies were analyzed in five of six affected members (including the proband). Brain magnetic resonance imaging, somatosensory evoked potential with C-reflex analysis and magnetoencephalography was performed in the proband. Genomic DNA of three affected and two unaffected individuals was analyzed to detect the genetic mutations by using whole-exome sequencing. RESULTS: The inheritance pattern of the pedigree was autosomal dominant. A novel missense mutation c.475C>T (p.Ala159Thr) of PLA2G6 were identified in this family. The mutated locus is highly conserved among other species. The mutation is predicted to have a functional impact, and completely co-segregated with the phenotype. CONCLUSION: This study identifies a novel PLA2G6 mutation that is the possible genetic cause of FCMTE in this family. This mutation and associated clinical features expand the spectrum and phenotypes of PLA2G6-related disorders including neurodegenerative diseases.

Clinical characterization of autoimmune LGI1 antibody limbic encephalitis.

OBJECTIVE: Autoimmune encephalitis associated with antibodies to leucine-rich glioma inactivated 1 (LGI1) has recently been identified and is characterized by an acute to subacute onset of cognitive impairment and convulsion, faciobrachial dystonic seizures (FBDSs), and psychiatric disturbances. This study analyzed the clinical characteristics and outcomes of 10 patients with LGI1 antibody encephalitis in order to further understand this disease and to improve its therapeutic strategies. METHODS: Between January 2013 and March 2015, we identified 10 patients with LGI1 antibody encephalitis. We retrospectively analyzed the clinical details, laboratory results, electrophysiological and imaging findings, and the treatment outcomes. RESULTS: All patients tested had LGI1 antibodies. Immunotherapy was effective in all patients. Seizures in patients with FBDS showed a poor response to antiepileptic drugs. Two patients examined by magnetoencephalogram (MEG) during the acute disease phase showed a small quantity of spike-wave dipoles in the temporal lobe close to the lateral fissure and insular lobe. CONCLUSION: Patients with LGI1 antibody encephalitis responded well to immunotherapy. We speculate that FBDS is likely a form of insular epilepsy.

Elevated plasma S100B concentration is associated with mesial temporal lobe epilepsy in Han Chinese: a case-control study.

Mesial temporal lobe epilepsy (MTLE) is a common type of intractable epilepsy characterized by astroglial gliosis. The S100B was viewed as an astrocyte marker and experimental studies indicated that S100B might be involved in the pathophysiology of temporal lobe epilepsy. In this study, we measured plasma S100B levels by ELISA in 28 patients with MTLE and 28 healthy controls and found that patients showed significantly elevated S100B levels compared with healthy controls (P=0.018). Moreover, S100B levels were significantly higher in female patients than those in male patients (P=0.027). These results suggest that S100B may be a biomarker of MTLE.