A Successful Infliximab Treatment of a Pediatric Case of Severe Polyarteritis Nodosa With a Cerebral Infarction and a Decreased Adenosine Deaminase 2 Activity.

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis common in males over 50 years of age that causes various organ symptoms. In recent years, it has become important to distinguish deficiency of adenosine deaminase 2 (DADA2) from childhood-onset PAN. A 13-year-old girl was urgently transferred to our hospital with sudden weakness in her right upper and lower limbs. The National Institutes of Health Stroke Scale (NIHSS) was 8. Plain MRI of the brain indicated high-signal areas in the right caudate nucleus, internal capsule, and left basal ganglia when applying T2-weighted, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI); and low signals in the same regions in an apparent diffusion coefficient (ADC) map. It demonstrated inflammatory demyelinating disease of the central nervous system or multiple cerebral infarctions attributable to vasculitis, and it is difficult to differentiate between them based on image findings alone, and cannot be determined without following the clinical course. Hence, we treated with steroid therapy, which is effective for both conditions. Although the paralysis was alleviated, an MRI of the brain reperformed on day 7 revealed expansion of the lesion with contrast enhancement in the feeding area of the left lateral striatal artery, a high signal in DWI, and a low signal in an ADC map. Based on the clinical and radiological findings, we diagnosed a cerebral infarction attributable to vasculitis. Contrast computed tomography (CT) of her chest and abdominal CT angiography revealed that she met the diagnostic criteria for PAN, and adenosine deaminase 2 (AD2) activity level was low. The patient was treated with steroids combined with azathioprine and cyclophosphamide but three weeks after discharge developed a new cerebral infarction in the right basal ganglia. We commenced infliximab; no recurrence of cerebral infarction has been noted. The low AD2 activity may explain the intractable atypical course of this case. Further studies are needed to reveal the role of AD2 in patients with residual enzyme activity and reevaluation of the PAN diagnostic criteria is essential.

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.

Impact of COVID-19 pandemic on epilepsy care in Japan: A national-level multicenter retrospective cohort study.

OBJECTIVE: The impact of the coronavirus disease 2019 (COVID-19) pandemic on epilepsy care across Japan was investigated by conducting a multicenter retrospective cohort study. METHODS: This study included monthly data on the frequency of (1) visits by outpatients with epilepsy, (2) outpatient electroencephalography (EEG) studies, (3) telemedicine for epilepsy, (4) admissions for epilepsy, (5) EEG monitoring, and (6) epilepsy surgery in epilepsy centers and clinics across Japan between January 2019 and December 2020. We defined the primary outcome as epilepsy-center-specific monthly data divided by the 12-month average in 2019 for each facility. We determined whether the COVID-19 pandemic-related factors (such as year [2019 or 2020], COVID-19 cases in each prefecture in the previous month, and the state of emergency) were independently associated with these outcomes. RESULTS: In 2020, the frequency of outpatient EEG studies (-10.7%, p<0.001) and cases with telemedicine (+2,608%, p=0.031) were affected. The number of COVID-19 cases was an independent associated factor for epilepsy admission (-3.75*10-3 % per case, p<0.001) and EEG monitoring (-3.81*10-3 % per case, p = 0.004). Further, the state of emergency was an independent factor associated with outpatient with epilepsy (-11.9%, p<0.001), outpatient EEG (-32.3%, p<0.001), telemedicine for epilepsy (+12,915%, p<0.001), epilepsy admissions (-35.3%; p<0.001), EEG monitoring (-24.7%: p<0.001), and epilepsy surgery (-50.3%, p<0.001). SIGNIFICANCE: We demonstrated the significant impact that the COVID-19 pandemic had on epilepsy care. These results support those of previous studies and clarify the effect size of each pandemic-related factor on epilepsy care.

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.

IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation.

IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis.

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.

Clinical and genetic characteristics of patients with Doose syndrome.

OBJECTIVE: To elucidate the genetic background and genotype-phenotype correlations for epilepsy with myoclonic-atonic seizures, also known as myoclonic-astatic epilepsy (MAE) or Doose syndrome. METHODS: We collected clinical information and blood samples from 29 patients with MAE. We performed whole-exome sequencing for all except one MAE case in whom custom capture sequencing identified a variant. RESULTS: We newly identified four variants: SLC6A1 and HNRNPU missense variants and microdeletions at 2q24.2 involving SCN1A and Xp22.31 involving STS. Febrile seizures preceded epileptic or afebrile seizures in four patients, of which two patients had gene variants. Myoclonic-atonic seizures occurred at onset in four patients, of which two had variants, and during the course of disease in three patients. Variants were more commonly identified in patients with a developmental delay or intellectual disability (DD/ID), but genetic status was not associated with the severity of DD/ID. Attention-deficit/hyperactivity disorder and autistic spectrum disorder were less frequently observed in patients with variants than in those with unknown etiology. SIGNIFICANCE: MAE patients had genetic heterogeneity, and HNRNPU and STS emerged as possible candidate causative genes. Febrile seizures prior to epileptic seizures and myoclonic-atonic seizure at onset indicate a genetic predisposition to MAE. Comorbid conditions were not related to genetic predisposition to MAE.

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.

High Incidence of Renal Stones in Severely Disabled Children with Epilepsy Treated with Topiramate.

PURPOSE: This study was aimed to assess the accurate incidence of renal stones in severely disabled children treated with topiramate (TPM). METHOD: We reviewed the medical records of severely disabled children with epilepsy under 15 years old who underwent radiological examinations to investigate urinary stones. The study enrolled 26 patients who were divided into two groups. One group had been treated with TPM for at least 1 year and the other had not been treated with TPM, zonisamide, acetazolamide, or other diuretic drugs. We collected parameters from the medical records and compared the groups. RESULTS: All participants were evaluated radiologically, with computed tomography (CT) in two patients, ultrasonography in 22 patients, and both in two. No patient had any morphological abnormality of the kidneys and history of urinary tract infection. There were no significant differences in sex, age, body weight, or feeding manner between the groups, while the incidence of renal stones or calcifications was significantly higher in the TPM-treated group (60 vs. 0%; p = 0.00241). CONCLUSION: There is a high incidence of renal stone formation in severely disabled children treated with TPM.

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.

Anti-MOG antibody encephalitis mimicking neurological deterioration in a case of Rett syndrome with MECP2 mutation.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, resulting in developmental regression after normal development during infancy. Transient presentation of many autistic features is also commonly seen in RTT. Anti-myelin oligodendrocyte glycoprotein (MOG)-antibody encephalitis is an acquired relapsing demyelinating syndrome characterized by a variety of neuroinflammatory symptoms. Here, we report a case of anti-MOG antibody encephalitis in a patient with genetically confirmed RTT, which mimicked many of the features of RTT. CASE REPORT: A three-year-old girl presented with subacute verbal and motor dysfunction, along with involuntary movements and marked irritability. Magnetic resonance imaging (MRI) revealed extensive white matter lesions, with anti-MOG antibodies detected in the serum and cerebrospinal fluid, resulting in an initial diagnosis of anti-MOG antibody encephalitis. However, additional testing of the MECP2 gene was performed in response to persistent involuntary hand movements in combination with progressive verbal and motor deterioration. Sequencing analysis revealed a known pathogenic mutation in MEPC2, indicating a concurrent diagnosis of RTT. CONCLUSION: Both RTT and anti-MOG antibody encephalitis are rare conditions. Similarities in disease presentation suggest that anti-MOG antibody encephalitis may mimic many of the symptoms of RTT.

Recurrence of Epileptic Spasms as Reflex Seizures Induced by Eating: A Case Report and Literature Review.

Background Eating epilepsy (EE) is a rare form of reflex epilepsy in which seizures are induced by eating. It is known that most patients with eating seizures, in fact, suffer from symptomatic temporal lobe epilepsy (TLE), whereas only a few patients with epileptic spasms induced by eating (E-ES) have been reported. Patient Description The patient was an 8-year-old girl whose magnetic resonance imaging (MRI) of the head detected dysgenesis of the corpus callosum, cerebellar hypogenesis, marked cerebral asymmetry, broad polymicrogyria, periventricular heterotopia, and closed lip-type schizencephaly. She experienced E-ES as the second form of recurrent seizures after the first recurrence of spontaneous ES. After E-ES occurred, the EEG findings in the right hemisphere, predominantly over the right centrotemporal region, were clearly exacerbated, although the interictal EEG originally showed left-side-dominant asymmetric hypsarrhythmia. The ictal EEG of the E-ES showed diffuse large triphasic (negative-positive-negative) potentials, predominantly over the right centrotemporoparietal region. Conclusions This is a unique case because the E-ES were recurrent ES, although the previous ES were spontaneous, which may provide insight into the mechanism of E-ES.

Combined surgical intervention with vagus nerve stimulation following corpus callosotomy in patients with Lennox-Gastaut syndrome.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is a drug-resistant pediatric epilepsy characterized by multiple seizure types, including drop attacks (DAs). Palliative procedures such as corpus callosotomy (CC) and vagus nerve stimulation (VNS) may be effective for adequate seizure control in LGS patients who are not candidates for resective surgery. We evaluated the efficacy of the combination of these two procedures for LGS-related seizures. METHOD: Ten patients with LGS (age 3-30 years at VNS implantation) underwent CC and subsequent VNS. We evaluated surgical outcomes, particularly with respect to the efficacy of VNS on seizure reduction rates for different residual seizure types after CC. We compared clinical parameters, including sex, age, seizure duration, history, MRI findings, extent of CC, number of antiepileptic drugs, and neuropsychological states, between VNS responders and non-responders to predict satisfactory seizure outcomes with respect to residual seizures after CC. FINDINGS: VNS was effective for residual seizures regardless of seizure type (except for DAs) after CC in patients with LGS. Six of ten (60%) patients had a satisfactory seizure outcome (≥50% seizure reduction) for all residual seizure types after VNS. Two of ten (20%) patients were seizure-free at 12 months post-VNS. Even those patients that were non-responders, with respect to all seizures including DAs, after prior CC showed favorable responses to subsequent VNS. Compared to VNS, excellent seizure outcomes for DAs were achieved after CC in seven of nine (77.8%) patients with DAs. Among the clinical parameters, only conversation ability before VNS was significantly different between responders and non-responders (p = 0.033). CONCLUSION: Combined VNS and prior CC produced satisfactory seizure outcomes in LGS patients with different seizure types, including DAs. Even non-responders to prior CC responded to subsequent VNS for residual seizures, except for DAs. There is a greater likelihood that these procedures may be more feasible in patients who possess conversation ability prior to VNS.

Late-onset epileptic spasms in a patient with 22q13.3 deletion syndrome.

Patients with 22q13.3 deletion syndrome present with diverse neurological problems such as global developmental delays, hypotonia, delayed or absent speech, autistic behavior, and epilepsy. Seizures occur in up to one-third of patients with 22q13.3 deletion syndrome; however, only a few reports have provided details regarding the seizure manifestations. The present report describes a patient with 22q13.3 deletion syndrome who presented with late-onset epileptic spasms (ES) and electroencephalography features like Lennox-Gastaut syndrome. An array comparative genomic hybridization analysis revealed that a chromosomal deletion of this patient included SHANK3. To the best of our knowledge, this is the first confirmed case of late-onset ES occur in patients with 22q13.3 deletion syndrome with a SHANK3 deletion.

A pediatric case of peripheral polyneuropathy with IgM anti-GM1 antibody associated with A group a beta-hemolytic Streptococcus infection.

INTRODUCTION: Postinfectious peripheral neuropathy can be associated with various viral or bacterial infections. Group A beta-hemolytic Streptococcus infection can lead to neurological disorders, which involve predominantly the central nervous system, whereas peripheral neuropathy during childhood is rare. PATIENT DESCRIPTION: We describe a 12-year-old boy who presented with peripheral polyneuropathy associated with Group A beta-hemolytic Streptococcus infection. Anti-GM1 IgM was significantly elevated in his serum during the acute phase, which suggested that it was related with the pathophysiology in this patient. CONCLUSION: Group A beta-hemolytic Streptococcus infection may cause peripheral neuropathy via the autoimmune system and glycolipids.