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.

Focal ictal direct current shifts by a time constant of 2 seconds were clinically useful for resective epilepsy surgery.

OBJECTIVE: Ictal direct current shifts (icDCs) and ictal high-frequency oscillations (icHFOs) have been reported as surrogate markers for better surgical outcomes in epilepsy surgery. icDCs have been classified into two types: rapid and slow development. icDCs have been investigated with a time constant of 10 s (TC10s); however, many institutes use electroencephalography with a time constant of 2 s (TC2s). This study aimed to evaluate whether icDCs can be observed adequately with TC2s; moreover, it examined the relationship between the resected core area of icDCs or icHFOs and surgical outcomes, occurrence rate of each type of icDCs, and relationship between each type of icDCs and pathology. METHODS: Twenty-five patients with intractable focal epilepsy were analyzed retrospectively. icDCs and icHFOs were defined according to common metrics. The amplitude of icDCs was defined at >200 µV and even <200 µV. The two electrodes producing the most prominent icDCs and icHFOs were defined as core electrodes. The correlation between the resected core electrode area and degree of seizure control after surgery was analyzed. icDCs were classified into two types based on a peak latency value cutoff of 8.9 s, and the occurrence rates of both patterns were investigated. RESULTS: icDCs (142/147 seizures [96.6%]) and icHFOs (135/147 seizures [91.8%]) occurred in all patients (100%). Compared with the amplitude of icDCs with TC10s reported in previous studies, the amplitude of icDCs with TC2s was attenuated in the current study. A significant positive correlation was observed between the resected core electrode area and degree of seizure control in both icDCs and icHFOs. A rapid development pattern was observed in 202 of 264 electrodes (76.5%). SIGNIFICANCE: Similar to icDCs with TC10s, those with TC2s were observed adequately. Furthermore, favorable outcomes are expected using TC2s, which is currently available worldwide.

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.

Ictal direct current shifts contribute to defining the core ictal focus in epilepsy surgery.

Identifying the minimal and optimal epileptogenic area to resect and cure is the goal of epilepsy surgery. To achieve this, EEG analysis is recognized as the most direct way to detect epileptogenic lesions from spatiotemporal perspectives. Although ictal direct-current shifts (below 1 Hz) and ictal high-frequency oscillations (above 80 Hz) have received increasing attention as good indicators that can add more specific information to the conventionally defined seizure-onset zone, large cohort studies on postoperative outcomes are still lacking. This work aimed to clarify whether this additional information, particularly ictal direct-current shifts which is assumed to reflect extracellular potassium concentration, really improve postoperative outcomes. To assess the usefulness in epilepsy surgery, we collected unique EEG data sets recorded with a longer time constant of 10 s using an alternate current amplifier. Sixty-one patients (15 with mesial temporal lobe epilepsy and 46 with neocortical epilepsy) who had undergone invasive presurgical evaluation for medically refractory seizures at five institutes in Japan were retrospectively enrolled in this study. Among intracranially implanted electrodes, the two core electrodes of both ictal direct-current shifts and ictal high-frequency oscillations were independently identified by board-certified clinicians based on unified methods. The occurrence patterns, such as their onset time, duration, and amplitude (power) were evaluated to extract the features of both ictal direct-current shifts and ictal high-frequency oscillations. Additionally, we examined whether the resection ratio of the core electrodes of ictal direct-current shifts and ictal high-frequency oscillations independently correlated with favourable outcomes. A total of 53 patients with 327 seizures were analyzed for wide-band EEG analysis, and 49 patients were analyzed for outcome analysis. Ictal direct-current shifts were detected in the seizure-onset zone more frequently than ictal high-frequency oscillations among both patients (92% versus 71%) and seizures (86% versus 62%). Additionally, ictal direct-current shifts significantly preceded ictal high-frequency oscillations in patients exhibiting both biomarkers, and ictal direct-current shifts occurred more frequently in neocortical epilepsy patients than in mesial temporal lobe epilepsy patients. Finally, although a low corresponding rate was observed for ictal direct-current shifts and ictal high-frequency oscillations (39%) at the electrode level, complete resection of the core area of ictal direct-current shifts significantly correlated with favourable outcomes, similar to ictal high-frequency oscillation outcomes. Our results provide a proof of concept that the independent significance of ictal direct-current shifts from ictal high-frequency oscillations should be considered as reliable biomarkers to achieve favourable outcomes in epilepsy surgery. Moreover, the different distribution of the core areas of ictal direct-current shifts and ictal high-frequency oscillations may provide new insights into the underlying mechanisms of epilepsy, in which not only neurons but also glial cells may be actively involved via extracellular potassium levels.

Two types of clinical ictal direct current shifts in invasive EEG of intractable focal epilepsy identified by waveform cluster analysis.

OBJECTIVE: To determine clinically ictal direct current (DC) shifts that can be identified by a time constant (TC) of 2 s and to delineate different types of DC shifts by different attenuation patterns between TC of 10 s and 2 s. METHODS: Twenty-one patients who underwent subdural electrode implantation for epilepsy surgery were investigated. For habitual seizures, we compared (1) the peak amplitude and (2) peak latency of the earliest ictal DC shifts between TC of 10 s and 2 s. Cluster and logistic regression analyses were performed based on the attenuation rate of amplitude and peak latency with TC 10 s. RESULTS: Ictal DC shifts in 120 seizures were analyzed; 89.1% of which were appropriately depicted even by a TC of 2 s. Cluster and logistic regression analyses revealed two types of ictal DC shift. Namely, a rapid development pattern was defined as the ictal DC shifts with a shorter peak latency and they also showed smaller attenuation rate of amplitude (73/120 seizures). Slow development pattern was defined as the ictal DC shifts with crosscurrent of a rapid development pattern, i.e., a longer peak latency and larger attenuation rate of amplitude (47/120 seizures). Focal cortical dysplasia (FCD) 1A tended to show a rapid development pattern (22/29 seizures) and FCD2A tended to show a slow development pattern (13 /18 seizures), indicating there might be some correlations between two types of ictal DC shift and certain pathologies. CONCLUSIONS: Ictal DC shifts, especially rapid development pattern, can be recorded and identified by the AC amplifiers of TC of 2 s which is widely used in many institutes compared to that of TC of 10 s. Two types of ictal DC shifts were identified with possibility of corresponding pathology. SIGNIFICANCE: Ictal DC shifts can be distinguished by their attenuation patterns.

[Migraine with multiple visual symptoms and out-of-body experience may mimic epilepsy].

The patient was an 18-year-old man who had suffered from various visual symptoms as follows since he was 17 years old: 1) a diagonal line appeared in his visual field, shifting his upper field of view to the right and his lower field of view to the left; 2) his whole vision seemed distorted with ripples; and 3) black spots covered parts of his visual field and moved up and down. These visual symptoms were followed by out-of-body experience (OBE), which he felt as seeing his own body apart from his left back. Headache attacks followed these symptoms. On brain MRI, bilateral occipital atrophy was suspected. An electroencephalogram showed intermittent irregular delta in the bilateral occipital area. No epileptiform discharges were observed. We finally diagnosed him as having migraine with multiple visual auras and OBE. He was very well treated with a small dose of valproic acid which he tolerated well. OBE rarely occurs in migraine and should be distinguished from epilepsy.

[Non-convulsive status epilepticus manifesting as ictal catatonia: a case report].

A 66 year-old right-handed female was admitted to our hospital presenting with recurrent episodes of catatonic symptoms consisting of stupor, waxy flexibility, and catalepsy lasting about 5-20 minutes. A brain MRI showed no significant abnormalities. An scalp-electroencephalography (EEG) concurrent with the symptoms showed ictal EEG activities arising from the left fronto-central area, which evolved into the bilateral frontal and bilateral parietal areas together. An 18F-fluorodeoxy glucose positron emission tomography (18F-FDG-PET) 4 days after improvement of the symptoms showed hypermetabolism in the bilateral frontal and parietal lobes. Her catatonic symptoms are assumed to be due to non-convulsive status epilepticus (NCSE), namely ictal catatonia. The introduction of several anti-epileptic drugs improved the symptoms and normalized the EEG and FDG-PET findings. NCSE must be considered as one of the underlying state of catatonic symptoms because the treatment plan for acute and chronic state is different from that of catatonic syndrome due to psychiatric disorders.

Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation.

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory disease caused by loss-of-function mutations in both alleles of the ADA2 gene. Most patients with DADA2 exhibit systemic vasculopathy consistent with polyarteritis nodosa, but large phenotypic variability has been reported, and the pathogenesis of DADA2 remains unclear. OBJECTIVES: This study sought to assess the clinical and genetic characteristics of Japanese patients with DADA2 and to gain insight into the pathogenesis of DADA2 by multi-omics analysis. METHODS: Clinical and genetic data were collected from 8 Japanese patients with DADA2 diagnosed between 2016 and 2019. ADA2 variants in this cohort were functionally analyzed by in vitro overexpression analysis. PBMCs from 4 patients with DADA2 were subjected to transcriptome and proteome analyses. Patient samples were collected before and after introduction of anti- TNF-α therapies. Transcriptome data were compared with those of normal controls and patients with other autoinflammatory diseases. RESULTS: Five novel ADA2 variants were identified in these 8 patients and were confirmed pathogenic by in vitro analysis. Anti-TNF-α therapy controlled inflammation in all 8 patients. Transcriptome and proteome analyses showed that upregulation of type II interferon signaling was characteristic of DADA2. Network analysis identified STAT1 as a key regulator and a hub molecule in DADA2 pathogenesis, a finding supported by the hyperactivation of STAT1 in patients' monocytes and B cells after IFN-γ stimulation. CONCLUSIONS: Type II interferon signaling and STAT1 are associated with the pathogenesis of DADA2.

[Scalp-recorded cortical spreading depolarizations (CSDs) of EEG with time constant of 2 seconds in a patient with acute traumatic brain injury].

An 82-year-old female suffered from head trauma, and developed acute consciousness disturbance 6 days after the event. Head CT showed the acute subdural hematoma in the left temporooccipital area and the patient underwent emergency hematoma evacuation and decompression. However, her consciousness disturbance became worse after surgery. Intermittent large negative infraslow shifts (lasting longer than 40 seconds) were recorded in the right posterior quadrant by scalp EEG with TC of 2 sec, that was defined as cortical spreading depolarizations (CSDs). Clinically consciousness disturbance sustained poor until 1 month after surgery in spite of treatment by anti-epileptic drugs. CSDs were observed on the right side where head injury most likely occurred. It may explain the sustained consciousness disturbance associated with significant prolonged ischemia. Once scalp EEG could record CSDs in this particular patient, the degree and its prognosis of traumatic head injury were estimated.

Mathematical structures for epilepsy: High-frequency oscillation and interictal epileptic slow (red slow).

In the present study, we attempted to characterize two characteristic features within the dynamic behavior of wideband electrocorticography data, which were recorded as the brain waves of epilepsy, comprising high-frequency oscillations (HFOs) and interictal epileptic slow (red slow). The results of power spectrum and nonlinear time series analysis indicate that, on one hand, HFOs at epileptic focus are characterized by one-dimensional dynamical systems in ictal onset time segments at an epileptic focus for two patients' datasets; on the other hand, an interictal epileptic slow is characterized by the residue of power spectrum. The results suggest that the degree of freedom of the brain dynamics during epileptic seizure with HFO degenerates to low-dimensional dynamics; hence, the interictal epileptic slow as the precursors of the seizure onset can be detected simply from interictal brain wave data for the dataset of one patient. Therefore, our results are essential to understand the brain dynamics in epilepsy.

[A case series of 4 epilepsy patients with promnesia].

Promnesia is a feeling of familiarity and foreknowledge and is a manifestation of simple partial seizures (focal aware seizures). It is similar to déjà vu and has been reported to be a rare symptom in patients with temporal lobe epilepsy. Here, we investigated the clinical characteristics in 4 patients with partial epilepsy presenting promnesia. Three out of 4 patients showed abnormal electroencephalography (EEG) and/or MRI findings in the temporal lobe. Furthermore, in 2 patients, promnesia was the only aura. It is important to actively obtain medical history of patients about promnesia because this is useful for identifying the epileptic focus. Further cases need to be analyzed to evaluate the sensitivity and specificity of promnesia for diagnosis and therapy of partial epilepsy.

[A case of subarachnoid hemorrhage due to infective endocarditis by methicillin-resistant coagulase-negative staphylococcus].

A 77-year-old man visited our hospital with unstable gait following 2 months of anorexia. Brain MRI showed multiple infarcts; cardiac echocardiography revealed mitral-valve vegetation; and blood culture revealed methicillin-resistant coagulase-negative staphylococci. The patient was diagnosed with infective endocarditis (IE). Subarachnoid hemorrhage (SAH) developed ten days after antibiotic treatment. Intracranial aneurysm was not found. We speculated that chronic inflammation of the cerebral arterial walls by bacteria of low virulence was associated with SAH complication. The vegetation disappeared following additional gentamicin administration and the patient recovered to walk.

Posterior Reversible Encephalopathy Syndrome with Extensive Deep White Matter Lesions Including the Temporal Pole.

Posterior reversible encephalopathy syndrome (PRES) typically affects the posterior subcortical white matter. We report the case of a 55-year-old man with atypical PRES, who had malignant hypertension and renal dysfunction. Magnetic resonance imaging of the brain revealed extensive vasogenic edema in the deep white matter including the temporal pole, as well as in the brainstem and cerebellum. Antihypertensive therapy and hemodialysis contributed to both clinical and radiological improvement. Involvement of the deep white matter including the temporal pole, which is rarely affected in an ischemic stroke, should be recognized as a potential sign of PRES.

[A Case of Anti-GQ1b Antibody Syndrome Associated with Pure Bilateral Adie's Pupils].

A 37 year-old Japanese male felt photophobia of both eyes one week following the onset of the common cold. His neurological examination revealed bilateral Adie's tonic pupils, no extraocular movement disorder, normal deep tendon reflexes, and no cerebellar signs. Based on markedly increased blood levels of anti-GQ1b IgG and anti-GT1a IgG antibodies, we diagnosed him as anti-GQ1b antibody syndrome. Bilateral Adie's tonic pupils were improved by IVIg drip infusion and methylprednisolone pulse therapy. This case suggests that we need to investigate anti ganglioside antibody when a patient presents with bilateral Adie's tonic pupils.