Ictal Direct Current Shifts Preceded Much Earlier Than High Frequency Oscillations After Status: Is It the Effect of Status or Antiseizure Medication?

PURPOSE: While spikes and sharp waves are considered as markers of epilepsy in conventional electroencephalography, ictal direct current (DC) shifts and high-frequency oscillations (HFOs) appear to be useful biomarkers for epileptogenicity. We analyzed how ictal DC shifts and HFOs were affected by focal status epilepticus and antiseizure medications (ASMs). METHODS: A 20-year-old female patient who underwent long-term intracranial electrode implantation for epilepsy surgery presented with 72 habitual seizures and a focal status epilepticus episode lasting for 4 h. Ten, 3, and 10 consecutive habitual seizures were analyzed before the status, after the status, and after ASM (valproate) loading, respectively. RESULTS: Before and immediately after the status, ictal DC shifts remained the same in terms of the amplitude, duration, and slope of DC shifts. High-frequency oscillations also remained the same in terms of the duration, frequency, and power except for the power of the lower frequency band. After ASM loading, the duration, amplitude, and slope of the ictal DC shift were significantly attenuated. The duration, frequency, and power of the HFOs were significantly attenuated. Furthermore, the interval between the DC onset and HFO onset was significantly longer and the interval between the HFO onset and ictal DC shift peak was significantly shorter. CONCLUSIONS: The attenuation of ictal DC shifts and HFOs after ASM loading implies that astrocyte and neuronal activity may be both attenuated by ASMs. This finding may help with our understanding of the pathophysiology of epilepsy and can aid with the discovery of new approaches for epilepsy management.

End-stage ADPKD with a low-frequency PKD1 mosaic variant accelerated by chemoradiotherapy.

Autosomal dominant polycystic kidney disease (ADPKD) is commonly caused by PKD1, and mosaic PKD1 variants result in milder phenotypes. We present the case of a 32 year-old male with chronic active Epstein-Barr virus who underwent bone marrow transplantation with chemoradiotherapy at age 9. Despite a low-frequency mosaic splicing PKD1 variant, he developed severe renal cysts and end-stage renal disease in his 30 s. This case highlights how environmental factors may contribute to the genetic predisposition to ADPKD.

Corrigendum: Sensory nerve action potential in patients with functional neurological disorders with sensory manifestations.

[This corrects the article DOI: 10.3389/fneur.2023.1259887.].

Efficacy and safety of mycophenolate mofetil for steroid reduction in neuromyelitis optica spectrum disorder: a prospective cohort study.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disease that can affect multiple generations and cause complications with long-term prednisolone treatment. This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) in preventing NMOSD relapse while reducing prednisolone dosage. The trial involved nine patients with NMOSD who received MMF along with prednisolone dose reduction. MMF was effective in achieving prednisolone dose reduction without relapse in 77.8% of patients, with a significant decrease in mean annualized relapse rate. All adverse events were mild. The findings suggest that MMF could be a viable treatment option for middle-aged and older patients who require steroid reduction.Clinical trial registration number: jRCT, jRCTs051180080. Registered February 27th, 2019-retrospectively registered, https://jrct.niph.go.jp/en-latest-detail/jRCTs051180080.

Nerve enlargement differs among chronic inflammatory demyelinating polyradiculoneuropathy subtypes and multifocal motor neuropathy.

Objective: We aimed to evaluate differences in ultrasonographic nerve enlargement sites among typical chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), distal CIDP, multifocal CIDP and multifocal motor neuropathy (MMN) in a Japanese population. Methods: We retrospectively reviewed medical records and selected 39 patients (14 with typical CIDP, 7 with multifocal CIDP, 4 with distal CIDP, and 14 with MMN) who underwent ultrasonography. Median and ulnar nerve cross-sectional areas (CSAs) were measured at the wrist, forearm, elbow, and upper arm. CSA ratios for each nerve were calculated as: wrist-to-forearm index (WFI) = wrist CSA/forearm CSA; elbow-to-upper arm index (EUI) = elbow CSA/upper arm CSA; and intranerve CSA variability (INCV) = maximal CSA/minimal CSA. Results: Significant differences were observed among typical CIDP, multifocal CIDP, distal CIDP, and MMN in CSA at the forearm and upper arm in the median nerves (p < 0.05). Patients with multifocal CIDP had lower WFI and EUI and higher INCV than the other groups (p < 0.05). Conclusions: Regardless of the untreated period, compared with other CIDP subtypes and MMN, multifocal CIDP showed a focal and marked nerve enlargement in the Japanese population. Significance: Differences in nerve enlargement site may be an underlying feature of multifocal CIDP.

Sensory nerve action potential in patients with functional neurological disorders with sensory manifestations.

Introduction: Functional neurological disorder (FND) has various clinical manifestations. Even though diagnostic criteria for FND have been proposed, FND characteristics with sensory manifestations have not been elucidated. Therefore, we aimed to investigate the association between sensory nerve action potential (SNAP) amplitudes and FND with sensory manifestations. Methods: We included 76 outpatients with FND with sensory manifestations whose nerve conduction studies were performed retrospectively. Additionally, we defined 121 patients with other neurological diseases who did not have peripheral neuropathy as disease controls. The SNAP amplitudes were compared between the two groups. We also explored the relationship between SNAP amplitudes and FND-specific clinical symptoms in patients with FND. Results: No differences were observed in SNAP amplitudes adjusted for age between patients with FND who had sensory manifestations and disease control patients. Additionally, no differences were observed between patients with FND who had and did not have FND-specific clinical symptoms. Conclusion: The SNAP amplitude in patients with FND who had sensory manifestations was equivalent to that in controls.

Periodic discharges plus fast activity on electroencephalogram predict worse outcomes in poststroke epilepsy.

OBJECTIVE: Postseizure functional decline is a concern in poststroke epilepsy (PSE). However, data on electroencephalogram (EEG) markers associated with functional decline are scarce. Thus, we investigated whether periodic discharges (PDs) and their specific characteristics are associated with functional decline in patients with PSE. METHODS: In this observational study, patients admitted with seizures of PSE and who had scalp EEGs were included. The association between the presence or absence of PDs and postseizure short-term functional decline lasting 7 days after admission was investigated. In patients with PD, EEG markers were explored for risk stratification of short-term functional decline, according to the American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology. The association between EEG markers and imaging findings and long-term functional decline at discharge and 6 months after discharge, defined as an increase in the modified Rankin Scale score compared with the baseline, was evaluated. RESULTS: In this study, 307 patients with PSE (median age = 75 years, range = 35-97 years, 64% males; hemorrhagic stroke, 47%) were enrolled. Compared with 247 patients without PDs, 60 patients with PDs were more likely to have short-term functional decline (12 [20%] vs. 8 [3.2%], p < .001), with an adjusted odds ratio (OR) of 4.26 (95% confidence interval [CI] = 1.44-12.6, p = .009). Patients with superimposed fast-activity PDs (PDs+F) had significantly more localized (rather than widespread) lesions (87% vs. 58%, p = .003), prolonged hyperperfusion (100% vs. 62%, p = .023), and a significantly higher risk of short-term functional decline than those with PDs without fast activity (adjusted OR = 22.0, 95% CI = 1.87-259.4, p = .014). Six months after discharge, PDs+F were significantly associated with long-term functional decline (adjusted OR = 4.21, 95% CI = 1.27-13.88, p = .018). SIGNIFICANCE: In PSE, PDs+F are associated with sustained neuronal excitation and hyperperfusion, which may be a predictor of postseizure short- and long-term functional decline.

[Cingulate seizure as a clinical manifestation of anti-myelin oligodendrocyte glycoprotein antibody-positive cerebral cortical encephalitis of two cases].

We report two male patients who had a sensory seizure, which evolved into a focal impaired awareness tonic seizure, and after that, focal to bilateral tonic-clonic seizure. The first case, a 20-year-old man had been treated with steroids for anti-myelin oligodendrocyte glycoprotein (MOG) antibody-positive optic neuritis. His seizure started with abnormal sensation in the little finger of the left hand, which spread to the left upper and then to the left lower limb. The seizure then evolved into tonic seizures of the upper and lower limbs and he finally lost awareness. The second case, a 19-year-old man experienced floating dizziness while walking, followed by numbness and a pain-like electrical shock in the right upper limb. The right arm somatosensory seizure evolved into a right upper and lower limb tonic seizure, which spread to the bilateral limbs, and finally he lost awareness. Symptoms of both patients improved after the treatment with steroids. Both patients shared a similar high-intensity FLAIR lesion in the posterior midcingulate cortex. Both patients were diagnosed with MOG antibody-positive cerebral cortical encephalitis because of a positive titer of anti-MOG antibody in the serum. Several reports showed involvement of the cingulate gyrus in MOG antibody-positive cerebral cortical encephalitis, but only a few reported seizure semiology in detail. The semiology reported here is consistent with that of cingulate epilepsy or the findings of electrical stimulation of the cingulate cortex, namely, somatosensory (electric shock or heat sensation), motor (tonic posture), and vestibular symptoms (dizziness). Cingulate seizures should be suspected when patients show somatosensory seizures or focal tonic seizures. MOG antibody-positive cerebral cortical encephalitis should be considered as one of the differential diagnoses when the young patient shows the unique symptoms of an acute symptomatic cingulate seizure.

Short-range axono-cortical evoked-potentials in brain tumor surgery: Waveform characteristics as markers of direct connectivity.

OBJECTIVE: Intraoperative measurement of axono-cortical evoked potentials (ACEP) has emerged as a promising tool for studying neural connectivity. However, it is often difficult to determine if the activity recorded by cortical grids is generated by stimulated tracts or by spurious phenomena. This study aimed to identify criteria that would indicate a direct neurophysiological connection between a recording contact and a stimulated pathway. METHODS: Electrical stimulation was applied to white matter fascicles within the resection cavity, while the evoked response was recorded at the cortical level in seven patients. RESULTS: By analyzing the ACEP recordings, we identified a main epicenter characterized by a very early positive (or negative) evoked response occurring just after the stimulation artifact (<5 ms, |Amplitude| > 100 µV) followed by an early and large negative (or positive) monophasic evoked response (<40 ms; |Amplitude| > 300 µV). The neighboring activity had a different waveform and was attenuated compared to the hot-spot activity. CONCLUSIONS: It is possible to distinguish the hotspot with direct connectivity to the stimulated site from neighboring activity using the identified criteria. SIGNIFICANCE: The electrogenesis of the ACEP at the hotspot and neighboring activity is discussed.

[Intraoperative Cortico-Cortical Evoked Potential].

In the surgery management of lesions in areas of the eloquent cortices the preservation of brain functions is required. Intraoperative electrophysiological methods are necessary to preserve the integrity of the functional network, such as motor or language areas. Cortico-cortical evoked potentials(CCEPs)have recently developed as a new intraoperative monitoring method because of advantages of a recording time of approximately 1-2 min, no requirement of patient cooperation, and high reproducibility and reliability of the data. The recent intraoperative CCEP studies have shown that CCEP can map the eloquent areas and white matter pathway, such as the dorsal language pathway, frontal aslant tract, supplementary motor area, and optic radiation. To establish intraoperative electrophysiological monitoring even under general anesthesia, further studies are required.

Mesial temporal lobe epilepsy with amygdalar hamartoma-like lesion: Is it a distinct syndrome?

INTRODUCTION: We examined the clinical, semiological, scalp electroencephalographic (EEG), and neuropsychological features of patients with amygdalar hamartoma-like lesion (AHL) without hippocampal sclerosis (HS). METHODS: This retrospective study included 9 patients with mesial temporal lobe epilepsy (MTLE) who had an amygdalar lesion on preoperative MRI; underwent mesial temporal resection; were diagnosed with amygdalar hamartoma-like lesion (AHL) without hippocampal sclerosis (HS); were followed up for at least 2 years after surgery; and had a favourable postoperative seizure outcome (Engel Class I). There were 5 women and 4 men, and age at surgery ranged from 19 to 54 (mean, 36.6) years. Clinical characteristics, auras, video-recorded seizure semiology, interictal and ictal EEG, and preoperative neuropsychological data were reviewed. Twenty patients with MTLE with HS who had favourable postoperative seizure outcomes (Engel Class I) were selected as controls. RESULTS: Age at seizure onset was significantly higher in patients with AHL without HS than in those with HS. Fear was more frequently seen in patients with AHL (44 %) than in those with HS (5 %) (P = 0.022). There were no significant differences in interictal epileptiform discharges or ictal EEG pattern. Preoperative full-scale IQ score was significantly higher in the AHL group than in the HS group (mean, 92.9 v. 74.8, P = 0.004), as was preoperative memory quotient score (mean 100.7 v. 85.1, P = 0.028). CONCLUSION: We clarified the clinical, semiological, and neuropsychological features of patients with MTLE-AHL. These findings may be useful for preoperative evaluation, especially of patients with suspected MTLE but without apparent HS on preoperative MRI.

Dynamics of AMPA receptors regulate epileptogenesis in patients with epilepsy.

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.

The dynamics of cortical interactions in visual recognition of object category: living versus nonliving.

Noninvasive brain imaging studies have shown that higher visual processing of objects occurs in neural populations that are separable along broad semantic categories, particularly living versus nonliving objects. However, because of their limited temporal resolution, these studies have not been able to determine whether broad semantic categories are also reflected in the dynamics of neural interactions within cortical networks. We investigated the time course of neural propagation among cortical areas activated during object naming in 12 patients implanted with subdural electrode grids prior to epilepsy surgery, with a special focus on the visual recognition phase of the task. Analysis of event-related causality revealed significantly stronger neural propagation among sites within ventral temporal lobe (VTL) at early latencies, around 250 ms, for living objects compared to nonliving objects. Differences in other features, including familiarity, visual complexity, and age of acquisition, did not significantly change the patterns of neural propagation. Our findings suggest that the visual processing of living objects relies on stronger causal interactions among sites within VTL, perhaps reflecting greater integration of visual feature processing. In turn, this may help explain the fragility of naming living objects in neurological diseases affecting VTL.

Association of Cortical Superficial Siderosis with Post-Stroke Epilepsy.

OBJECTIVE: To assess whether post-stroke epilepsy (PSE) is associated with neuroimaging findings of hemosiderin in a case-control study, and whether the addition of hemosiderin markers improves the risk stratification models of PSE. METHODS: We performed a post-hoc analysis of the PROgnosis of POST-Stroke Epilepsy study enrolling PSE patients at National Cerebral and Cardiovascular Center, Osaka, Japan, from November 2014 to September 2019. PSE was diagnosed when one unprovoked seizure was experienced >7 days after the index stroke, as proposed by the International League Against Epilepsy. As controls, consecutive acute stroke patients with no history or absence of any late seizure or continuing antiseizure medications at least 3 months after stroke were retrospectively enrolled during the same study period. We examined cortical microbleeds and cortical superficial siderosis (cSS) using gradient-echo T2*-weighted images. A logistic regression model with ridge penalties was tuned using 10-fold cross-validation. We added the item of cSS to the existing models (SeLECT and CAVE) for predicting PSE and evaluated performance of new models. RESULTS: The study included 180 patients with PSE (67 women; median age 74 years) and 1,183 controls (440 women; median age 74 years). The cSS frequency was higher in PSE than control groups (48.9% vs 5.7%, p < 0.0001). Compared with the existing models, the new models with cSS (SeLECT-S and CAVE-S) demonstrated significantly better predictive performance of PSE (net reclassification improvement 0.63 [p = 0.004] for SeLECT-S and 0.88 [p = 0.001] for CAVE-S at the testing data). INTERPRETATION: Cortical superficial siderosis was associated with PSE, stratifying stroke survivors at high risk of PSE. ANN NEUROL 2023;93:357-370.

Circulating plasmablasts and follicular helper T-cell subsets are associated with antibody-positive autoimmune epilepsy.

Autoimmune epilepsy (AE) is an inflammatory disease of the central nervous system with symptoms that have seizures that are refractory to antiepileptic drugs. Since the diagnosis of AE tends to rely on a limited number of anti-neuronal antibody tests, a more comprehensive analysis of the immune background could achieve better diagnostic accuracy. This study aimed to compare the characteristics of anti-neuronal antibody-positive autoimmune epilepsy (AE/Ab(+)) and antibody-negative suspected autoimmune epilepsy (AE/Ab(-)) groups. A total of 23 patients who met the diagnostic criteria for autoimmune encephalitis with seizures and 11 healthy controls (HC) were enrolled. All patients were comprehensively analyzed for anti-neuronal antibodies; 13 patients were identified in the AE/Ab(+) group and 10 in the AE/Ab(-) group. Differences in clinical characteristics, including laboratory and imaging findings, were evaluated between the groups. In addition, the immunophenotype of peripheral blood mononuclear cells (PBMCs) and CSF mononuclear cells, particularly B cells and circulating Tfh (cTfh) subsets, and multiplex assays of serum and CSF were analyzed using flow cytometry. Patients with AE/Ab(+) did not show any differences in clinical parameters compared to patients with AE/Ab(-). However, the frequency of plasmablasts within PBMCs and CSF in patients with AE/Ab(+) was higher than that in patients with AE/Ab(-) and HC, and the frequency of cTfh17 cells and inducible T-cell co-stimulator (ICOS) expressing cTfh17 cells within cTfh subsets was higher than that in patients with AE/Ab(-). Furthermore, the frequency of ICOShighcTfh17 cells was positively correlated with that of the unswitched memory B cells. We also found that IL-12, IL-23, IL-6, IL-17A, and IFN-γ levels were elevated in the serum and IL-17A and IL-6 levels were elevated in the CSF of patients with AE/Ab(+). Our findings indicate that patients with AE/Ab(+) showed increased differentiation of B cells and cTfh subsets associated with antibody production. The elevated frequency of plasmablasts and ICOS expressing cTfh17 shift in PBMCs may be indicative of the presence of antibodies in patients with AE.

Interictal epileptiform discharges as a predictive biomarker for recurrence of poststroke epilepsy.

Poststroke epilepsy is a major ischaemic/haemorrhagic stroke complication. Seizure recurrence risk estimation and early therapeutic intervention are critical, given the association of poststroke epilepsy with worse functional outcomes, quality of life and greater mortality. Several studies have reported risk factors for seizure recurrence; however, in poststroke epilepsy, the role of EEG in predicting the risk of seizures remains unclear. This multicentre observational study aimed to clarify whether EEG findings constitute a risk factor for seizure recurrence in patients with poststroke epilepsy. Patients with poststroke epilepsy were recruited from the PROgnosis of POst-Stroke Epilepsy study, an observational multicentre cohort study. The enrolled patients with poststroke epilepsy were those admitted at selected hospitals between November 2014 and June 2017. All patients underwent EEG during the interictal period during admission to each hospital and were monitored for seizure recurrence over 1 year. Board-certified neurologists or epileptologists evaluated all EEG findings. We investigated the relationship between EEG findings and seizure recurrence. Among 187 patients with poststroke epilepsy (65 were women with a median age of 75 years) admitted to the lead hospital, 48 (25.7%) had interictal epileptiform discharges on EEG. During the follow-up period (median, 397 days; interquartile range, 337-450 days), interictal epileptiform discharges were positively correlated with seizure recurrence (hazard ratio, 3.82; 95% confidence interval, 2.09-6.97; P < 0.01). The correlation remained significant even after adjusting for age, sex, severity of stroke, type of stroke and generation of antiseizure medications. We detected periodic discharges in 39 patients (20.9%), and spiky/sharp periodic discharges were marginally associated with seizure recurrence (hazard ratio, 1.85; 95% confidence interval, 0.93-3.69; P = 0.08). Analysis of a validation cohort comprising 187 patients with poststroke epilepsy from seven other hospitals corroborated the association between interictal epileptiform discharges and seizure recurrence. We verified that interictal epileptiform discharges are a risk factor for seizure recurrence in patients with poststroke epilepsy. Routine EEG may facilitate the estimation of seizure recurrence risk and the development of therapeutic regimens for poststroke epilepsy.

[...First Do No Harm: Drug-Resistant Epilepsy].

Although currently it is known that neuronal hyperexcitability is the mechanism underlying epilepsy, this condition was previously associated with spiritual factors. Epilepsy surgery is considered in patients in whom administration of anti-seizure drugs is infeasible. Functional mapping of the brain and intraoperative monitoring have improved safety of epilepsy surgery. A ketogenic diet is considered in patients in whom surgery is not adaptive. The American made-for-television movie ...First Do No Harm (1997) highlights the usefulness of the ketogenic diet for intractable epilepsy. Notably, ketogenic diet therapy was approved for public health insurance coverage in Japan in 2016.

Diagnostic value of an algorithm for autoimmune epilepsy in a retrospective cohort.

Purpose: This study aims to propose a diagnostic algorithm for autoimmune epilepsy in a retrospective cohort and investigate its clinical utility. Methods: We reviewed 60 patients with focal epilepsy with a suspected autoimmune etiology according to board-certified neurologists and epileptologists. To assess the involvement of the autoimmune etiology, we used the patients' sera or cerebrospinal fluid (CSF) samples to screen for antineuronal antibodies using rat brain immunohistochemistry. Positive samples were analyzed for known antineuronal antibodies. The algorithm applied to assess the data of all patients consisted of two steps: evaluation of clinical features suggesting autoimmune epilepsy and evaluation using laboratory and imaging findings (abnormal CSF findings, hypermetabolism on fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging abnormalities, and bilateral epileptiform discharges on electroencephalography). Patients were screened during the first step and classified into five groups according to the number of abnormal laboratory findings. The significant cutoff point of the algorithm was assessed using a receiver-operating characteristic curve analysis. Results: Fourteen of the 60 patients (23.3%) were seropositive for antineuronal antibodies using rat brain immunohistochemistry. Ten patients had antibodies related to autoimmune epilepsy/encephalitis. The cutoff analysis of the number of abnormal laboratory and imaging findings showed that the best cutoff point was two abnormal findings, which yielded a sensitivity of 78.6%, a specificity of 76.1%, and an area under the curve of 0.81. Conclusion: The proposed algorithm could help predict the underlying autoimmune etiology of epilepsy before antineuronal antibody test results are available.