Paradoxical effects of levetiracetam in people with epilepsy with rhythmic epileptiform discharges.

OBJECTIVE: To elucidate the incidence and risk factors for paradoxical effects (i.e., increased seizure frequency, increased seizure severity, or onset of new seizure types) of levetiracetam (LEV) in people with epilepsy (PWE) and identify the usefulness of electroencephalography (EEG) in predicting these effects. METHODS: We examined data for consecutive PWE treated with LEV. All PWE underwent EEG and magnetic resonance imaging (MRI) before LEV administration. We also evaluated the incidence of paradoxical LEV effects and conducted multivariate logistic regression analyses to identify the associated factors. RESULTS: In total, 210 (66.2%) of 317 PWEs treated in our department had a history of LEV use. The incidence of paradoxical LEV effects was 5.2% (n = 11) and was significantly associated with a high LEV dose (p = 0.029), high seizure frequency (p = 0.005), temporal lobe epilepsy (p = 0.004), focal awareness seizure (p = 0.004), focal impaired awareness seizure (p = 0.007), spike (p = 0.015), rhythmic epileptiform discharges (REDs; p = 0.003), and MRI-identified focal cortical dysplasia (FCD; p < 0.0001). Multivariate analyses revealed that REDs (odds ratio [OR] = 5.35, p = 0.048, 95% confidence interval [CI]: 1.01-28.21) were independently associated with paradoxical LEV effects. CONCLUSIONS: Paradoxical LEV effects occurred in PWE, particularly in those with drug-resistant focal epilepsy. Furthermore, the occurrence of REDs in EEG was an independent factor associated with the paradoxical effects of LEV in PWE.

Immediate and 6-month seizure outcomes following first and second SARS-CoV2 mRNA vaccinations: A multicenter study with a nationwide survey.

OBJECTIVE: This study aimed to identify seizure outcomes in people with epilepsy (PWE) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) messenger RNA vaccination. METHODS: We examined PWE (n = 332, age ≥ 14 years) treated in four tertiary hospitals between 2021 and 2022 to assess the incidence of seizure worsening following vaccination using closed questions. We identified the clinical factors associated with worsening and 6-month vaccination outcomes. We also conducted a nationwide survey on self-reported seizure worsening using open questions, to which 261 general practitioners from 99 institutes contributed. RESULTS: Of the 282 PWE vaccinated in the four hospitals, 16 (5.7%) exhibited seizure worsening; most of them emerged within 48 h of vaccination and were not sustained. Thus, all PWE were at baseline condition 6 months after their vaccination. PWE with seizure worsening were more significantly associated with focal impaired awareness seizures (p < 0.001), high seizure frequency (p = 0.025), and drug-resistant epilepsy (p = 0.007) at baseline compared to PWE without worsening. Multivariate logistic regression analysis revealed that focal impaired awareness seizures were independently associated with worsening (odds ratio, 7.0; 95% confidence interval, 1.50-32.77). A nationwide survey of 5156 PWE data (real-world data) confirmed an extremely low incidence rate of self-reported seizure worsening (0.43%). SIGNIFICANCE: Some PWE, particularly refractory focal epilepsy, exhibit seizure worsening. However, the worsening events were infrequent, non-sustainable, and probably under-reported by PWE, suggesting that there is little evidence that worsening seizures discourage current and future vaccinations.

Knockdown of optineurin controls C2C12 myoblast differentiation via regulating myogenin and MyoD expressions.

Mutations in optineurin (OPTN) have been identified in a small proportion of sporadic and familial amyotrophic lateral sclerosis (ALS) cases. Recent evidences suggest that OPTN would be involved in not only the pathophysiological mechanisms of motor neuron death of ALS but also myofiber degeneration of sporadic inclusion body myositis. However, the detailed role of OPTN in muscle remains unclear. Initially, we showed that OPTN expression levels were significantly increased in the denervated muscles of mice, suggesting that OPTN may be involved in muscle homeostasis. To reveal the molecular role of OPTN in muscle atrophy, we used cultured C2C12 myotubes treated with tumor necrosis factor-like inducer of apoptosis (TWEAK) as an in vitro model of muscle atrophy. Our data showed that OPTN had no effect on the process of muscle atrophy in this model. On the other hand, we found that myogenic differentiation was affected by OPTN. Immunoblotting analysis showed that OPTN protein levels gradually decreased during C2C12 differentiation. Furthermore, OPTN knockdown inhibited C2C12 differentiation, accompanied by reduction of mRNA and protein expression levels of myogenin and MyoD. These findings suggested that OPTN may have a novel function in muscle homeostasis and play a role in the pathogenesis of neuromuscular diseases.

Seizure Deterioration with Increased Levetiracetam Blood Concentration during the Postpartum Period in Refractory Temporal Lobe Epilepsy.

We evaluated a 39-year-old pregnant woman with right temporal lobe epilepsy. During the second trimester, seizure deterioration was responsive to an increased daily dose of levetiracetam (LEV). However, immediately after delivery, new non-habitual seizures emerged along with a sharply increased LEV concentration. The frequency of habitual seizures also slightly increased. The non-habitual seizures completely disappeared, and the frequency of the habitual seizures improved to the baseline level after the LEV dosage was reduced. Thus, a paradoxical effect of an increased LEV blood concentration was assumed to be a potential cause of these events. Peripartum pharmacokinetic fluctuations in LEV levels should be monitored carefully.

A longitudinal seizure outcome following the COVID-19 pandemic in 2020 and 2021: Transient exacerbation or sustainable mitigation.

OBJECTIVE: To study the longitudinal seizure outcomes of people with epilepsy (PWE) following the acute and chronic phases of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Consecutive PWE who were treated at the epilepsy center of Hiroshima University Hospital between 2018 and 2021 were enrolled. We evaluated the incidence of seizure frequency increase or decrease following the pandemic during observational periods in 2020 and 2021. Data between 2018 and 2019 were used as a control set. The sustainability of the altered seizure frequency condition was evaluated throughout the study period. We analyzed the clinical, psychological, and social factors associated with PWE with seizure exacerbation or amelioration. RESULTS: Among the 223 PWE who were evaluated (mean age 37.8 ± 16.3 years), seizure frequency increased for 40 (16.8%) and decreased for 34 (15.2%) after the pandemic began. While seizure exacerbation tended to be a transient episode during 2020, seizure amelioration was likely to maintain excellent status over the observation periods; the sustainability of the altered seizure frequency condition was more prominent for amelioration than exacerbation (p < 0.001). Seizure exacerbation was significantly associated with "no housemate" (odds ratio [OR] 3.37; p = 0.045) and "comorbidity of insomnia" (OR 5.80; p = 0.004). Conversely, "structural abnormality of MRI" (OR 2.57; p = 0.039) and "two-generation householding" (OR 3.70; p = 0.004) were independently associated with seizure amelioration. CONCLUSION: This longitudinal observation confirmed that seizure exacerbation and amelioration emerged during the COVID-19 pandemic. The COVID-19 pandemic has shed light on the stark difference that social support systems can make on outcomes for PWE.

Efficacy of Lacosamide in a Patient with Refractory Generalized Epilepsy Based on Video Electroencephalography.

A 20-year-old man with drug-resistant generalized epilepsy (GE) was admitted for video electroencephalography (vEEG) monitoring under treatment with multiple antiepileptic drugs, including levetiracetam (3,000 mg/day), valproic acid (800 mg/day), and lacosamide (LCM) (100 mg/day). No seizures were noted after the withdrawal of levetiracetam. However, after the withdrawal of LCM, atypical absence seizures with a 2- to 2.5-Hz generalized spike and wave complex frequently appeared, followed by subsequent generalized-onset tonic-clonic seizures. After re-administration of LCM, the seizures and epileptic discharges clearly disappeared. Subsequent LCM titration was successful in achieving a seizure-free status. Our vEEG results suggest that LCM may be a worthwhile antiepileptic drug adjunct in refractory GE patients without a risk of worsening absence seizures.

Socio-economic impact on epilepsy outside of the nation-wide COVID-19 pandemic area.

OBJECTIVE: To identify people with epilepsy (PWE) who required extensive care before the novel coronavirus disease 2019 (COVID-19) pandemic that had world-wide impacts on medical care and on socio-economic conditions. METHODS: Consecutive PWE who were treated at the epilepsy center of Hiroshima University Hospital, which was located in the COVID-19 non-pandemic area, between March 2019 and August 2020 were enrolled. We evaluated clinical and socioeconomic factors that were associated with seizure exacerbation (an increase in seizure frequency) during the first 6 months after the COVID-19 pandemic started compared with the previous 6 months. RESULTS: Among the 196 PWE who were evaluated (mean age was 37.8 ±â€¯16.2 years), there were 33 PWE (16.8%) whose seizure frequency had increased after the pandemic began. People with epilepsy with a seizure increase showed a significant association with living alone (p < 0.001), a higher seizure frequency (p < 0.001), negative findings on MRI (p = 0.020), history of dissociative seizure (p < 0.001), mood disorders (p < 0.001), insomnia (p < 0.001), and high psychological stress levels (p = 0.024) at baseline compared with PWE without seizure exacerbation. Multivariate logistic regression analysis revealed that "living alone" (odds ratio (OR) 3.69; 95%CI 1.29-10.52), "high seizure frequency at baseline" (OR 4.53; 95%CI 1.63-12.57), and "comorbidity of insomnia" (OR 9.55; 95%CI 3.71-24.55) were independently associated with seizure exacerbation. CONCLUSIONS: Even in the non-pandemic area, PWE had seizure exacerbation, suggesting that clinicians should screen patients' mental health before the outbreak to provide care, reduce the burden, and prevent social isolation in PWE. This should be addressed particularly in patients with medically refractory seizures with insomnia who live alone.

[Valproic acid-induced hyperammonemic encephalopathy in a patient receiving valproic acid monotherapy].

A 79-year-old female was diagnosed with epilepsy because she experienced loss of consciousness twice in January and February and then had a seizure in June 2016. She was treated with 800 mg sodium valproate (sustained release). After 3 days, she experienced loss of appetite, and more than 3 days later, disturbance of consciousness. Serum valproic acid (VPA) concentration was 128.3 µg/ml and serum ammonia was 404 µmol/l. Cerebral edema and status epilepticus occurred. Severe neurological dysfunction remained, even after treatment with continuous hemodiafiltration and levocarnitine. VPA is widely used for the treatment of generalized epilepsy. VPA-induced hyperammonemic encephalopathy is a rare but serious adverse event of VPA. Thus, we must pay attention to serum ammonia levels when using VPA, even VPA monotherapy.

Abscess Formation in Metastatic Brain Tumor with History of Immune Checkpoint Inhibitor: A Case Report.

We present the case of a 68-year-old man with brain metastasis from lung cancer and a history of immune checkpoint inhibitor administration, with overlapping abscess within the metastatic lesion. He initially received antibiotic treatment under a diagnosis of brain abscess because of a hyper-intense area on diffusion-weighted imaging inside the gadolinium-enhanced wall. The size of the enhanced lesion did not change much, but the extent of perifocal edema decreased after antibiotic treatment. After 2-4 months, the lesion gradually enlarged, and imaging characteristics changed from single cyst to multiple cysts. Surgical resection was performed and pathological examination revealed the lesion as metastasis from the lung tumor. Smear preparation of the tumor contents detected Gram-positive bacilli, confirming the dual pathology of metastasis and brain abscess. Discussing the pathogenesis, we speculated that therapy with durvalumab (MEDI4736), an anti-PD-L1 antibody, induced immune status modification including immunosuppressive regulation, which might have promoted abscess formation.

Synphilin-1 has neuroprotective effects on MPP+-induced Parkinson's disease model cells by inhibiting ROS production and apoptosis.

Synphilin-1, a cytoplasmic protein, interacts with α-synuclein which is one of the main constituents of Lewy bodies and plays an important role in the pathology of Parkinson's disease (PD), in neurons. This interaction indicates that synphilin-1 may also play a central role in PD. However, the biological functions of synphilin-1 are not fully understood, and whether synphilin-1 is neurotoxic or neuroprotective remains controversial. This study examined the function of synphilin-1 in a PD model in vitro. We used an inhibitor of mitochondrial complex I, 1-methyl-4-phenylpyridinium (MPP+). We established human neuroblastoma SH-SY5Y cell lines that stably expressed human synphilin-1. We found that overexpression of synphilin-1 increased SH-SY5Y cell viability after MPP+ treatment. We further found that synphilin-1 significantly suppressed apoptotic changes in nuclei, including nuclear condensation and fragmentation, after MPP+ treatment. We showed that synphilin-1 significantly decreased MPP+-induced cleaved caspase-3 and cleaved poly-ADP-ribose polymerase levels by using western blotting. Production of reactive oxygen species (ROS) induced by MPP+ was significantly reduced in cells expressing synphilin-1 compared to those expressing empty vector. Synphilin-1 inhibited MPP+-induced cytochrome c release from mitochondria into the cytosol. These data suggested that synphilin-1 may function to protect against dopaminergic cell death by preserving mitochondrial function and inhibiting early steps in the intrinsic apoptotic pathway. Taken together, our results indicated that synphilin-1 may play neuroprotective roles in PD pathogenesis by inhibiting ROS production and apoptosis.

Prediction of Pneumonia in Acute Stroke Patients Using Tongue Pressure Measurements.

Swallowing dysfunction caused by stroke is a risk factor for aspiration pneumonia. Tongue pressure measurement is a simple and noninvasive method for evaluating swallowing dysfunction. We have hypothesized that low tongue pressure may be able to predict pneumonia occurrence in acute stroke patients. Tongue pressure was measured using balloon-type equipment in 220 acute stroke patients. The modified Mann Assessment of Swallowing Ability (MASA) score was evaluated independently on the same day. Tongue pressure was measured every week thereafter. An improvement in tongue pressure was observed within the first 2 weeks. Receiver operating curve analysis was performed to determine the ability of tongue pressure to predict modified MASA score <95, which suggests swallowing dysfunction. The optimal cutoff for tongue pressure was 21.6 kPa (χ2 = 45.82, p<0.001, sensitivity 95.9%, specificity 91.8%, area under the curve = 0.97). The tongue pressure was significantly lower in patients with pneumonia than in those without pneumonia. Using a Cox proportional hazard model for pneumonia onset with a cutoff tongue pressure value of 21.6 kPa and adjustment for age, sex, and National Institutes of Health Stroke Scale score at admission, the tongue pressure had additional predictive power for pneumonia onset (hazard ratio, 7.95; 95% confidence interval, 2.09 to 52.11; p = 0.0013). In the group with low tongue pressure, 27 of 95 patients showed improvement of tongue pressure within 2 weeks. Pneumonia occurred frequently in patients without improvement of tongue pressure, but not in patients with improvement (31/68 and 2/27, p<0.001). Tongue pressure is a sensitive indicator for predicting pneumonia occurrence in acute stroke patients.

Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains.

TDP-43 is the major disease-associated protein involved in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions linked to TDP-43 pathology (FTLD-TDP). Abnormal phosphorylation, truncation and cytoplasmic mis-localization are known to be the characteristics for the aggregated forms of TDP-43, and gain of toxic abnormal TDP-43 or loss of function of physiological TDP-43 have been suggested as the cause of neurodegeneration. However, most of the post-translational modifications or truncation sites in the abnormal TDP-43 in brains of patients remain to be identified by protein chemical analysis. In this study, we carried out a highly sensitive liquid chromatography-mass spectrometry analysis of Sarkosyl-insoluble pathological TDP-43 from brains of ALS patients and identified several novel phosphorylation sites, deamidation sites, and cleavage sites. Almost all modifications were localized in the Gly-rich C-terminal half. Most of the cleavage sites identified in this study are novel and are located in N-terminal half, suggesting that these sites may be more accessible to proteolytic enzymes. The data obtained in this study provide a foundation for the molecular mechanisms of TDP-43 aggregation and ALS pathogenesis.

Lamotrigine is favourable for startle-induced seizures.

Falling due to startle-induced seizures (SISs) often leads to injury. The triggers of SIS are mostly unexpected auditory stimuli, which are too common to avoid in daily life. As SISs are often refractory to conventional medications, effective therapeutic options have to be established. We report a small series of six patients treated with lamotrigine (LTG) as add-on therapy. Seizure control was improved greatly in three of the six patients, resulting in less restricted daily life, but no effect was observed in two and a skin rash developed in one. Patient 1 was a 19-year-old man. His seizure comprised of a sudden tonic extension of the extremities induced by auditory or visual stimulus. He fell down due to SISs, five to ten times a day, with frequent injuries. After adding LTG to treatment with valproate (VPA) and clobazam (CLB), SISs were reduced to once a month. Patient 2 was a 51-year-old woman. Sudden tonic extension of all limbs induced by unexpected sounds frequently threw her down onto the floor. Addition of LTG to treatment with CLB, zonisamide and phenytoin reduced her SISs from several to less than once a day. Patient 3 was a seven-year-old girl with post-encephalitic epilepsy. After adjunctive treatment of LTG to VPA, the severity of SISs became milder thus avoiding injury, although seizure frequency did not decrease. LTG is potentially effective for the treatment of SISs and may prevent falling. The addition of LTG treatment dramatically improved the lives of the patients presented here and should be considered as an option for startle-induced seizures.