A Pediatric Case of B Cell Precursor ALL With Blinatumomab-associated Encephalopathy.

Blinatumomab is a CD3/CD19-directed bispecific T-cell engager used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Although blinatumomab has shown efficacy, it can cause serious adverse events, including cytokine release syndrome and neurological events. Among the neurological events, encephalopathy is rare, and knowledge is lacking. Herein, we present a pediatric case of blinatumomab-associated encephalopathy that initially presented with refractory convulsions and later developed into a cerebral infarction. The patient experienced prolonged paralysis and increased brain damage.

HFA analysis using scalp electroencephalograms in two cases of Rasmussen's syndrome.

OBJECTIVE: In recent years, wide-band EEGs have been used to assess brain activity, and their effectiveness in the pathological analysis of epilepsy has been demonstrated. This report describes two cases of Rasmussen's syndrome (RS) in which high-frequency scalp EEGs were retrospectively analyzed to assess the pathological condition of epilepsy in RS. METHODS: The two RS cases were divided into three periods: incipient, stable, and frequent seizure periods. Using the EEG record of each period, interictal epileptiform discharges (IEDs) were visually extracted. Subsequently, a time-frequency analysis was performed to calculate the rate of high-frequency activities (HFAs) (IED-HFA rate). Finally, differences between the three periods were examined. RESULTS: IED-HFA rates significantly increased in the frequent seizure period compared with the stable period in both cases(P < 0.05). CONCLUSION: there was a significant increase in HFAs superimposed over IEDs during the frequent seizure period compared to the stable period. HFAs are thought to be associated with epileptogenicity. Similarly, HFAs could be a useful biomarker for the pathological condition of epilepsy in RS.

Evaluation of cerebrospinal fluid biomarkers in pediatric patients with spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disorder characterised by muscle weakness and muscle atrophy and classified into five known subtypes based on clinical features. The recent development of novel drugs to treat SMA has been encouraging, and nusinersen is the first drug approved to treat SMA. OBJECTIVE: To explore cerebrospinal fluid (CSF) biomarkers of SMA and investigate their relationship with symptoms and the treatment response in pediatric patients. METHODS: We analyzed the CSF levels of chitotriosidase 1 (CHIT1) and inflammatory cytokines (tumor necrosis factor [TNF]-α and interferon [INF]-γ) using enzyme-linked immunosorbent assays in pediatric SMA patients treated at Hiroshima University Hospital over 2 years. RESULTS: This study analyzed pediatric SMA patients. While the CSF inflammatory cytokines (TNF-α and INF-γ) in these SMA children were unchanged, the CHIT1 levels decreased significantly from year 1 to 2 of treatment. We also found a trend toward an inverse correlation between the motor function score (HINE-2 scores) and CHIT1 level from year 1 to 2 of treatment. CONCLUSIONS: CHIT1 may be a CSF biomarker of the treatment response in pediatric SMA.

Effect of Lacosamide therapy on blood cells and IgA levels in children and adolescents with epilepsy in a clinical setting.

INTRODUCTION: Lacosamide (LCM) is a third-generation antiepileptic drug (AED) that affects sodium channel inactivation. AEDs can affect multiple organ systems and blood parameters. Carbamazepine (CBZ) reportedly affects blood sodium, lipid, and immunoglobulin levels and thyroid function. Despite multiple studies on the adverse effects of AEDs, few reports have discussed the impact of LCM on blood parameters. The purpose of this study was to clarify the effects of LCM on blood parameters. METHODS: We retrospectively examined the medical records of 15 children and adolescents in whom LCM was initiated between April 2017 and March 2021, 6 and 12 months after treatment initiation. Blood cell counts, biochemical and thyroid function, and immunoglobulin levels were investigated at baseline and 6 and 12 months after initiation of LCM. RESULTS: Neutrophil levels were significantly reduced 12 months after LCM initiation (p = 0.0046); however, the value was not abnormal. Immunoglobulin A was significantly elevated 6 and 12 months after LCM initiation (p = 0.0078 and 0.020, respectively). No significant difference was identified in the other parameters. Electrolyte and lipid levels and thyroid function remained unaffected, unlike with CBZ. CONCLUSIONS: LCM may affect the immune system, as well as hematological parameters. Further investigation with larger samples is required in the future to assess the clinical impact.

Clinical impact of the dose and blood concentration of lacosamide in Japanese pediatric patients with epilepsy: A cohort study.

PURPOSE: The relationship between treatment efficacy/tolerability and the dose/blood concentration of lacosamide (LCM) was investigated in a clinical cohort of Japanese pediatric patients with epilepsy. METHODS: This retrospective analysis reviewed the medical records of patients treated with LCM for >6 months at the Department of Pediatrics, Hiroshima University Hospital, from September 2017 to January 2021. The collected data included age, sex, epilepsy type, seizure type, seizure frequency before and after treatment initiation, adverse events leading to LCM discontinuation, dose at any evaluation point, serum concentration, and concomitant antiepileptic drugs (AEDs). RESULTS: The study included 51 patients (31 male patients) between the ages of 2 and 19 years. All patients were Japanese. Epilepsy was classified as focal in 44 patients, generalized in six patients, and combined generalized and focal in one patient. The 50% responder rate for LCM treatment was 56.9%. Seven patients experienced complete seizure control (absence of seizures for 6 months before the follow-up visit). A relationship between dose and blood concentration was identified. Although the blood LCM concentration was higher in the responders than in the nonresponders (7.86 vs. 6.16 µg/mL; p = 0.028), there was no significant difference in dose between the two groups. Lacosamide showed efficacy at a dose >5 mg/kg/day in more than half of the 50% responders. The treatment-emergent adverse events (TEAEs) included seizure aggravation in five patients, irritability in two patients, and somnolence and drug eruption in one patient each. In six patients with TEAEs, the TEAEs developed within 1 month after treatment initiation and led to LCM discontinuation. CONCLUSION: In Japanese pediatric patients with epilepsy, LCM treatment is effective, particularly at higher doses. The blood concentration may be related more to efficacy than to dose. Lacosamide is generally well-tolerated by pediatric patients, and should be used at the maximum tolerable dose (needed to be gradually increased) in patients with otherwise insufficient seizure control. As TEAEs leading to discontinue treatment likely occur in early phase, it is needed to monitor patients carefully if TEAEs would happen in that phase.

Effects of perampanel add-on therapy on immunoglobulin levels in pediatric patients with epilepsy.

BACKGROUND: Perampanel (PER) has a unique pharmacological mechanism and marked efficacy in both focal and generalized epilepsy, but may cause adverse events similar to those of other antiepileptic drugs (AEDs). AEDs can affect multiple organ systems, as well as thyroid function, lipid profiles, and immunoglobulin levels; the low free T4 levels, hyperlipidemia, and low immunoglobulin levels can be caused by AEDs. While many studies have examined conventional AEDs, little is known about the long-term effects of PER on blood parameters. METHODS: We retrospectively reviewed the medical records of 18 pediatric patients with epilepsy who were treated with PER added to >1 other AED. Blood parameters (e.g., blood cell counts, biochemical and thyroid function, and immunoglobulin levels) were investigated at baseline and at 6 and 12 months after initiation of PER. RESULTS: PER did not affect the blood counts, transaminase levels, lipid profile, or thyroid function at 12 months after initiation of PER. However, IgA levels significantly increased (p = 0.00319) without symptoms. IgM levels increased temporarily, but had returned to baseline by 12 months after initiation of PER. CONCLUSIONS: IgA levels were elevated at 12 months after initiation of PER in pediatric patients with intractable epilepsy, although no symptoms were observed. PER did not affect other parameters, including lipid profile and thyroid function.

Successful treatment of intractable life-threatening seizures with perampanel in the first case of early myoclonic encephalopathy with a novel de novo SCN1A mutation.

PURPOSE: Early myoclonic encephalopathy (EME) is a form of developmental and epileptic encephalopathy with myoclonic seizures and a suppression burst on electroencephalogram, which occurs during the neonatal or early infantile period and is characterized by highly intractable seizures and severe development impairment. Although multiple genetic aetiologies of EME have been identified, no SCN1A mutation has been reported. METHODS: We described a female patient with EME due to an SCN1A mutation. RESULTS: She developed frequent myoclonic and apnoeic seizures during the neonatal period. As her seizures were refractory to many antiepileptic drugs, she underwent a tracheotomy and has since been treated with continuous mechanical ventilation. Eventually, perampanel was added, which resulted in the cessation of the apnoeic seizures. Genetic analysis revealed a heterozygous de novo missense mutation in the SCN1A gene (c.2588 T > C:p.Leu863Ser). CONCLUSION: This is the first patient with EME due to anSCN1A mutation to be successfully treated with perampanel. Recently, perampanel was reported to be effective in treating Dravet syndrome, including cases with an SCN1A mutation. Perampanel may contribute to seizure reduction in patients with intractable epilepsy carrying the SCN1A mutation.

Clinical profiles associated with serum perampanel concentrations in children with refractory epilepsy.

BACKGROUND: Perampanel (PER) is a new antiepileptic drug (AED) with a novel mechanism of action. Investigations of the efficacy and safety of PER in pediatric and adult patients have increased recently. Although the clinical usefulness and pharmacokinetics of PER have been investigated in adolescent and adult populations, similar studies have not been performed in children. PATIENTS AND METHODS: We retrospectively reviewed the medical records of patients treated with PER for more than 6 months in the Department of Pediatrics, Hiroshima University Hospital, between September 2016 and November 2018. We obtained demographic and clinical data including age, sex, epilepsy type, seizure type, seizure frequency before and after treatment initiation, adverse events, reasons for discontinuing PER treatment, doses at evaluation points, serum concentrations, concomitant AEDs, intellectual status, and epilepsy etiology. Seizure types and epilepsy syndromes were classified according to the criteria of the International League Against Epilepsy. RESULTS: The study included 44 patients (22 males) between the ages of 6 months and 16 years. Of those, 10 patients discontinued PER therapy. The 50% response rate was 52.3% in patients treated with PER, and four patients achieved complete seizure control. Perampanel was highly effective in patients with generalized and focal epilepsy (50% responder rates, 52.9% and 50.0%, respectively). Favorable response rates were observed for tonic-clonic, focal nonmotor, and absence seizures with 50% response rates of 54.5%, 50.0%, and 66.7%, respectively. The 50% responder rate was 31.3 for epileptic spasms (ES). Treatment-emergent adverse events (TEAEs) included somnolence (n = 8), irritability (n = 2), ataxia (n = 2), and one case each of dizziness, compulsiveness, and enuresis. Serum concentrations of PER were compared in patients taking concomitant enzyme-inducing antiepileptic drugs (EIAEDs; carbamazepine, phenytoin, and phenobarbital) and those taking concomitant non-EIAEDs. Serum PER concentrations were correlated with dose per body weight in both groups (EIAED: r = 0.765, p = 0.00000212; non-EIAED: r = 0.71, p = 0.0000158). The mean concentration-to-dose (CD) ratio was 2398.4 ng mL-1 mg-1 kg-1 (range: 800-4524.7) in the non-EIAED group and 693.7 ng mL-1 mg-1 kg-1 (range: 344-1309.7) in the EIAED group. Serum PER levels were lower in the EIAED group than in the non-EIAED group. All patients with serum PER concentrations above 400 ng/mL experienced somnolence. CONCLUSIONS: Perampanel is effective against various types of seizures, including ES, in pediatric patients with refractory epilepsy. Furthermore, PER has good tolerability when the dose is adjusted based on serum concentrations. The PER CD ratio was lower in pediatric patients than in adolescents and adults; therefore, clinicians must consider the CD ratio when treating children with PER.

Producing Small Domain Features Using Miktoarm Block Copolymers with Large Interaction Parameters.

We demonstrate that small domain features (∼13 nm) can be obtained in a series of polystyrene (PS) and poly(lactic acid) (PLA) block copolymers, PS-(PLA)2 and (PS)2-(PLA)2, that combine miktoarm molecular architectures with large interaction parameters. To supplement the experimental work, we used self-consistent field theory in tandem with the random phase approximation to explore and contrast the phase behavior of ABn and AnBn types of miktoarm block copolymers. Specifically, AB2 and A2B2 were found to be effective molecular architectures for inducing strong shifts in phase boundaries with copolymer composition and to simultaneously tune domain feature sizes. The performance of these systems is markedly different from the corresponding linear diblock copolymers and indicates the potential of macromolecular architecture control for future applications in lithography.