Treatment odyssey to epilepsy surgery in children with focal cortical dysplasia: Risk factors for delayed surgical intervention.

OBJECTIVE: To elucidate the patient's journey to epilepsy surgery and identify the risk factors contributing to surgical delay in pediatric patients with drug-resistant epilepsy (DRE) due to focal cortical dysplasia (FCD). METHODS: A retrospective review was conducted of 93 pediatric patients who underwent curative epilepsy surgery for FCD between January 2012 and March 2023 at a tertiary epilepsy center. The Odyssey plot demonstrated the treatment process before epilepsy surgery, including key milestones of epilepsy onset, first hospital visit, epilepsy diagnosis, MRI diagnosis, DRE diagnosis, and surgery. The primary outcome was surgical delay; the duration from DRE to surgery. Multivariate linear regression models were used to examine the association between surgical delay and clinical, investigative, and treatment characteristics. RESULTS: The median age at seizure onset was 1.3 years (interquartile range [IQR] 0.14-3.1), and at the time of surgery, it was 6 years (range 1-11). Notably, 46% experienced surgical delays exceeding two years. The Odyssey plot visually highlighted that surgical delay comprised a significant portion of the patient journey. Although most patients underwent MRI before referral, MRI abnormalities were identified before referral only in 39% of the prolonged group, compared to 70% of the non-prolonged group. Multivariate analyses showed that delayed notification of MRI abnormalities, longer duration from epilepsy onset to DRE, older age at onset, number of antiseizure medications tried, and moderate to severe intellectual disability were significantly associated with prolonged surgical delay. CONCLUSION: Pediatric DRE patients with FCD experienced a long journey until surgery. Early and accurate identification of MRI abnormalities is important to minimize surgical delays.

Intraventricular hemorrhage volume and younger age at surgery may be risk factors for postoperative hydrocephalus after hemispherotomy in children.

OBJECTIVE: Hemispherotomy is an effective treatment for intractable hemispheric epilepsy; however, hydrocephalus remains a common complication of the procedure. The causes of hydrocephalus following hemispherotomy have not been fully elucidated; therefore, the purpose of this study was to identify the risk factors associated with the condition. METHODS: The authors investigated the records of all patients aged < 18 years who underwent hemispherotomy at their institution between 2003 and 2020 and were monitored for hydrocephalus for at least 1 year after the procedure. To identify the risk factors for hydrocephalus, the following information about each patient was collected: sex, corrected age at surgery, body weight at surgery, previous intracranial surgery, etiology of epilepsy, results of PET for hypermetabolism, side of surgery, type of operation (vertical or horizontal approach), operation time, blood loss during surgery, use of intraventricular drainage, occurrence of intraventricular hemorrhage (IVH) on the 1st postoperative day, duration of postoperative fever of > 38°C, and maximum C-reactive protein level after the operation. Multivariate logistic regression analyses were performed. RESULTS: This study included 51 children who underwent hemispherotomies for drug-resistant epilepsy at our hospital. Seven patients (13.7%) experienced hydrocephalus and were treated with ventricular or subdural peritoneal shunts or fenestration. Multivariate logistic analysis using the Bayesian information criterion revealed that 3 factors were associated with the occurrence of hydrocephalus: age at surgery, postoperative IVH volume, and duration of postoperative fever of > 38°C. CONCLUSIONS: This study showed that younger age at surgery, postoperative IVH volume, and duration of postoperative fever of > 38°C might be risk factors for hydrocephalus after hemispherotomy. The risk of hydrocephalus should be considered in cases of early surgical indication in children. Intraoperative hemostasis and postoperative use of anti-inflammatory measures may reduce the risk of hydrocephalus.

Duplication within two regions distal to MECP2: clinical similarity with MECP2 duplication syndrome.

BACKGROUND: X-linked methyl-CpG-binding protein 2 (MECP2) duplication syndrome is prevalent in approximately 1% of X-linked intellectual disabilities. Accumulating evidence has suggested that MECP2 is the causative gene of MECP2 duplication syndrome. We report a case of a 17-year-old boy with a 1.2 Mb duplication distal to MECP2 on chromosome Xq28. Although this region does not contain MECP2, the clinical features and course of the boy are remarkably similar to those observed in MECP2 duplication syndrome. Recently, case reports have described duplication in the region distal to, and not containing, MECP2. These regions have been classified as the K/L-mediated Xq28 duplication region and int22h1/int22h2-mediated Xq28 duplication region. The case reports also described signs similar to those of MECP2 duplication syndrome. To the best of our knowledge, ours is the first case to include these two regions. CASE PRESENTATION: The boy presented with a mild to moderate regressive intellectual disability and progressive neurological disorder. He developed epilepsy at the age of 6 years and underwent a bilateral equinus foot surgery at 14 years of age because of the increasing spasticity in lower extremities since the age of 11. Intracranial findings showed hypoplasia of the corpus callosum, cerebellum, and brain stem; linear hyperintensity in the deep white matter; and decreased white matter capacity. During his childhood, he suffered from recurrent infection. However, genital problems, skin abnormalities and gastrointestinal manifestations (gastroesophageal reflux) were not observed. CONCLUSIONS: Cases in which duplication was observed in the region of Xq28 that does not include MECP2 also showed symptoms similar to those of MECP2 duplication syndrome. We compared four pathologies: MECP2 duplication syndrome with minimal regions, duplication within the two distal regions without MECP2, and our case including both regions. Our results suggest that MECP2 alone may not explain all symptoms of duplication in the distal part of Xq28.

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.

Low EEG Gamma Entropy and Glucose Hypometabolism After Corpus Callosotomy Predicts Seizure Outcome After Subsequent Surgery.

Background: Patients with generalized epilepsy who had lateralized EEG abnormalities after corpus callosotomy (CC) occasionally undergo subsequent surgeries to control intractable epilepsy. Objectives: This study evaluated retrospectively the combination of EEG multiscale entropy (MSE) and FDG-PET for identifying lateralization of the epileptogenic zone after CC. Methods: This study included 14 patients with pharmacoresistant epilepsy who underwent curative epilepsy surgery after CC. Interictal scalp EEG and FDG-PET obtained after CC were investigated to determine (1) whether the MSE calculated from the EEG and FDG-PET findings was lateralized to the surgical side, and (2) whether the lateralization was associated with seizure outcomes. Results: Seizure reduction rate was higher in patients with lateralized findings to the surgical side than those without (MSE: p < 0.05, FDG-PET: p < 0.05, both: p < 0.01). Seizure free rate was higher in patients with lateralized findings in both MSE and FDG-PET than in those without (p < 0.05). Conclusions: This study demonstrated that patients with lateralization of MSE and FDG-PET to the surgical side had better seizure outcomes. The combination of MSE and conventional FDG-PET may help to select surgical candidates for additional surgery after CC with good postoperative seizure outcomes.

Sirolimus for epileptic seizures associated with focal cortical dysplasia type II.

OBJECTIVE: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II. METHODS: Sixteen patients (aged 6-57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5-15 ng/mL, followed by a 12-week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES-FCD) in which 60 patients with FCD type II were included as an external control group. RESULTS: The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1-4-, 5-8-, and 9-12-week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus-treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL-6 level was elevated over time. INTERPRETATION: The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations.

Epilepsy surgery in children under 3 years of age: surgical and developmental outcomes.

OBJECTIVE: Pediatric epilepsy surgery is known to be effective, but early surgery in infancy is not well characterized. Extensive cortical dysplasia, such as hemimegalencephaly, can cause refractory epilepsy shortly after birth, and early surgical intervention is indicated. However, the complication rate of early pediatric surgery is significant. In this study, the authors assessed the risk-benefit balance of early pediatric epilepsy surgery as relates to developmental outcomes. METHODS: This is a retrospective descriptive study of 75 patients who underwent their first curative epilepsy surgery at an age under 3 years at the authors' institution between 2006 and 2019 and had a minimum 1-year follow-up of seizure and developmental outcomes. Clinical information including surgical complications, seizure outcomes, and developmental quotient (DQ) was collected from medical records. The effects of clinical factors on DQ at 1 year after surgery were evaluated. RESULTS: The median age at surgery was 6 months, peaking at between 3 and 4 months. Operative procedures included 27 cases of hemispherotomy, 19 cases of multilobar surgery, and 29 cases of unilobar surgery. Seizure freedom was achieved in 82.7% of patients at 1 year and in 71.0% of patients at a mean follow-up of 62.8 months. The number of antiseizure medications (ASMs) decreased significantly after surgery, and 19 patients (30.6%) had discontinued their ASMs by the last follow-up. Postoperative complications requiring cerebrospinal fluid (CSF) diversion surgery, such as hydrocephalus and cyst formation, were observed in 13 patients (17.3%). The mean DQ values were 74.2 ± 34.3 preoperatively, 60.3 ± 23.3 at 1 year after surgery, and 53.4 ± 25.1 at the last follow-up. Multiple regression analysis revealed that the 1-year postoperative DQ was significantly influenced by preoperative DQ and postoperative seizure freedom but not by the occurrence of any surgical complication requiring CSF diversion surgery. CONCLUSIONS: Early pediatric epilepsy surgery has an acceptable risk-benefit balance. Seizure control after surgery is important for postoperative development.

Corpus callosotomy in pediatric patients with non-lesional epileptic encephalopathy with electrical status epilepticus during sleep.

Epileptic encephalopathy with electrical status epilepticus during sleep (ESES) is often refractory to medical treatment and leads to poor cognitive outcomes. Corpus callosotomy may be an effective treatment option for drug-resistant ESES with no focal etiology. We retrospectively identified three patients who underwent corpus callosotomy for drug-resistant ESES in our institution. Electroencephalography (EEG) findings and cognitive functions were evaluated before surgery, at 3 months, 6 months, 1 year, and 2 years after surgery. Age at surgery was 6 years 10 months, 7 years 9 months, and 8 years 4 months, respectively. Period between the diagnosis of ESES and surgery ranged from 7 to 25 months. All patients had no obvious structural abnormalities and presented with cognitive decline despite multiple antiseizure medications and steroid therapies. One patient showed complete resolution of ESES and an improvement of intelligence quotient after surgery. Epileptiform EEG was lateralized to one hemisphere after surgery and spike wave index (SWI) was decreased with moderate improvement in development and seizures in the other 2 patients. SWI re-exacerbated from 6 months after surgery, but without subsequent developmental regression in these 2 patients. Corpus callosotomy may become an important treatment option for drug-resistant ESES in patients with no structural abnormalities.

A Single-Arm Open-Label Clinical Trial on the Efficacy and Safety of Sirolimus for Epileptic Seizures Associated with Focal Cortical Dysplasia Type II: A Study Protocol.

Epileptic seizures are core symptoms in focal cortical dysplasia (FCD), a disease that often develops in infancy. Such seizures are refractory to conventional antiepileptic drugs (AED) and temporarily disappear in response to AED in only 17% of patients. Currently, surgical resection is an important option for the treatment of epileptic seizures in FCD. In 2015, Korean and Japanese groups independently reported that FCD is caused by somatic mosaic mutation of the MTOR gene in the brain tissue. Based on these results we decided to test a novel treatment using sirolimus, an mTOR inhibitor, for epileptic seizures in patients with FCD type II. A single arm open-label clinical trial for FCD type II patients is being conducted in order to evaluate the efficacy and safety of sirolimus. The dose of sirolimus is fixed for the first 4 weeks and dose adjustment is achieved to maintain a blood level of 5 to 15 ng/mL during 8 to 24 weeks after initiation of administration, and it is kept within this level during a maintenance therapy period of 12 weeks. Primary endpoint is a reduction in the rate of incidence of focal seizures (including focal to bilateral tonic-clonic seizures) per 28 days during the maintenance therapy period from the observation period. To evaluate the frequency of epileptic seizures, registry data will be used as an external control group. We hope that the results of this trial will lead to future innovative treatments for FCD type II patients.

Improvement of brain function after surgery in infants with posterior quadrant cortical dysplasia.

OBJECTIVE: To reveal whether neurodevelopmental outcome of infants after epilepsy surgery can be quantitatively assessed by electroencephalography (EEG) functional connectivity analysis. METHODS: We enrolled 13 infants with posterior quadrant dysplasia aged <2 years who were treated using posterior quadrantectomy and 21 age-matched infants. EEG was performed both before and one year after surgery. Developmental quotient (DQ) was assessed both before and 3 years after surgery. The phase lag index (PLI) of three different pairs of electrodes in the nonsurgical hemisphere, i.e., the anterior short distance (ASD), posterior short distance (PSD), and long distance (LD) pairs, were calculated as indices of brain connectivity. The relationship between the PLI and DQ was evaluated. RESULTS: Overall, 77% infants experienced seizure freedom after surgery. The beta- and gamma- range PLI of PSD pairs increased preoperatively. All these pairs normalized postoperatively. Simple linear regression analysis revealed a significant relationship between the postoperative DQ and the postoperative beta-band PLI of ASD pairs. CONCLUSION: Preoperative abnormal hyper-connectivity was normalized to the control level after surgery. The postoperative hyperconnectivity was associated with long-term neurodevelopmental improvement. SIGNIFICANCE: PLI quantifies neurodevelopmental improvements after posterior quadrantectomy.

Postoperative improvement of executive function and adaptive behavior in children with intractable epilepsy.

INTRODUCTION: An alteration in postoperative cognitive function varies according to the patients' background characteristics, such as etiology, focus, and seizure duration. Accurate prediction and assessment of postoperative cognitive function is difficult in each patient. Adaptive behavior could describe the typical performance of daily activities and represents the ability to translate cognitive potential into real-world skills. We examined the relationship between alterations of executive function (EF) and adaptive behavior in school children undergoing surgery for intractable epilepsy. METHODOLOGY: We enrolled 31 children with focal resection or corpus callosotomy for intractable epilepsy [mean age at surgery, 12.5 years; 16 boys; mean intellectual quotient, 73.3]. We surveyed answered questionnaires on attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and adaptive behavior using the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II), and performed continuous performance tests (CPTs) on children pre- and postoperatively. RESULT: ADHD and ASD symptoms improved after epilepsy surgery. The omission error (OE) in the CPT variable improved after epilepsy surgery, especially in children with a shorter preoperative period. Improved ASD symptoms led to an increased score of the coping skills subdomain. The reduced OE observed after surgery also increased the score of the community skills subdomain. CONCLUSION: Improvement in EF and ASD symptoms resulted in better adaptive behavior postoperatively. These results were important for the pre- and postoperative evaluation and re-evaluation of children with epilepsy requiring special education and related services.

Hyperglycemic Crisis in Patients With Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS).

BACKGROUND: Diabetes mellitus is the most commonly encountered endocrinopathy in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which manifests as multisystemic organ failure. Whether the management of diabetes mellitus in MELAS requires special consideration is not fully clarified. METHODS: In this single-center study, we retrospectively reviewed the medical records of patients with MELAS to elucidate the clinical characteristics of MELAS-associated diabetes mellitus. RESULTS: Four patients among a total of 25 individuals with MELAS who were treated in the study institution developed diabetes mellitus. One patient had well-controlled diabetes mellitus, whereas the remaining three patients experienced hyperglycemic crisis as the first manifestation of diabetes mellitus. Two of the three patients were children aged four and six years. The hyperglycemic events occurred after surgery, infection, and status epilepticus, respectively. None of the three patients had diabetes mellitus previously based on randomly measured serum glucose levels that were within the normal range before the hyperglycemic crisis. Glycated hemoglobin levels measured during the hyperglycemic crisis indicated prediabetes in two patients and diabetes mellitus in one patient. Two patients recovered, whereas one patient died after developing multiorgan failure. CONCLUSIONS: Fulminant-onset diabetes mellitus occurring in patients with MELAS underscore the importance of routine measurement for glycated hemoglobin and more intense evaluation of glucose intolerance regardless of the patient age and lack of symptoms. Clinicians should be aware of the potential acute onset of hyperglycemic crisis in patients with MELAS, especially in individuals with aggravating factors.

Cognitive and developmental outcomes after pediatric insular epilepsy surgery for focal cortical dysplasia.

OBJECTIVE: Cognitive risk associated with insular cortex resection is not well understood. The authors reviewed cognitive and developmental outcomes in pediatric patients who underwent resection of the epileptogenic zone involving the insula. METHODS: A review was conducted of 15 patients who underwent resective epilepsy surgery involving the insular cortex for focal cortical dysplasia, with a minimum follow-up of 12 months. The median age at surgery was 5.6 years (range 0.3-13.6 years). Developmental/intelligence quotient (DQ/IQ) scores were evaluated before surgery, within 4 months after surgery, and at 12 months or more after surgery. Repeated measures multivariate ANOVA was used to evaluate the effects on outcomes of the within-subject factor (time) and between-subject factors (resection side, anterior insular resection, seizure control, and antiepileptic drug [AED] reduction). RESULTS: The mean preoperative DQ/IQ score was 60.7 ± 22.8. Left-side resection and anterior insular resection were performed in 9 patients each. Favorable seizure control (International League Against Epilepsy class 1-3) was achieved in 8 patients. Postoperative motor deficits were observed in 9 patients (permanent in 6, transient in 3). Within-subject changes in DQ/IQ were not significantly affected by insular resection (p = 0.13). Postoperative changes in DQ/IQ were not significantly affected by surgical side, anterior insular resection, AED reduction, or seizure outcome. Only verbal function showed no significant changes before and after surgery and no significant effects of within-subject factors. CONCLUSIONS: Resection involving the insula in children with impaired development or intelligence can be performed without significant reduction in DQ/IQ, but carries the risk of postoperative motor deficits.

Bipolar disorder in megalencephalic leukoencephalopathy with subcortical cysts: a case report.

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC), or Van der Knaap disease, is a rare spongiform leukodystrophy that is characterized by macrocephaly, progressive motor dysfunction, and mild mental retardation. It is very rare for mental illness such as psychotic disorders, affective disorders and anxiety disorders to occur in MLC. CASE PRESENTATION: A 17-year-old boy was admitted to our hospital after he developed symptoms of depressive state with catatonia after being diagnosed as having MLC with confirmed MLC1 mutation. His catatonic symptoms were improved with administration of olanzapine and sertraline and he was discharged after 4 months. Several months later, he became hypomanic. He was diagnosed with bipolar II disorder. Mood swings were controlled with the administration of carbamazepine. CONCLUSIONS: This case is the first report of bipolar disorder during the clinical course of MLC. This case indicate the possibility that MLC influences the development of bipolar disorder in MLC, however, further studies involving more patients are required to clarify this.

Transient water-electrolyte disturbance after hemispherotomy in young infants with epileptic encephalopathy.

PURPOSE: This study aimed to elucidate the clinical features of water-electrolyte disturbance (WED) as a sequela of hemispherotomy. METHODS: We performed a retrospective chart review to identify the clinical features of diabetes insipidus (DI) as a complication in < 12-month-old patients who underwent hemispherectomy or hemispherotomy for severe epilepsy between 2007 and 2018. Central DI was diagnosed if a patient developed polyuria (urine output > 5 mL/kg/h), abnormally high serum osmolality (> 300 mOsm/kg), high serum sodium level (> 150 mEq/L), either abnormally low urine specific gravity (< 1.005) or low urine osmolality (< 300 mOsm/kg) or both, and effective control of polyuria with arginine vasopressin (AVP). The clinical course of post-hemispherotomy WED, complications other than WED, and seizure outcomes were analyzed. RESULTS: The review identified that 3 of 23 infants developed WED. All patients developed polyuria within 2 days after surgery, with high serum osmolality and hypotonic urine; AVP was effective in treating these symptoms. The clinical course was compatible with central DI. Two patients subsequently developed hyponatremia in a biphasic or triphasic manner. All patients had multiple seizures that were probably related to WED. Two patients developed asymptomatic cerebral sinovenous thrombosis, possibly because of the surgical procedure and dehydration; anticoagulant treatment was provided. All patients were treated for WED for up to 2 months and had no residual pituitary dysfunction. CONCLUSION: Systemic complications other than intracranial ones can occur in patients who have undergone hemispherotomy. Perioperative systemic management of young infants undergoing this procedure should include careful water and electrolyte balance monitoring.

Alteration of the anatomical covariance network after corpus callosotomy in pediatric intractable epilepsy.

PURPOSE: This study aimed to use graph theoretical analysis of anatomical covariance derived from structural MRI to reveal how the gray matter connectivity pattern is altered after corpus callosotomy (CC). MATERIALS AND METHODS: We recruited 21 patients with epilepsy who had undergone CC. Enrollment criteria were applied: (1) no lesion identified on brain MRI; (2) no history of other brain surgery; and (3) age not younger than 3 years and not older than 18 years at preoperative MRI evaluation. The most common epilepsy syndrome was Lennox-Gastaut syndrome (11 patients). For voxel-based morphometry, the normalized gray matter images of pre-CC and post-CC patients were analyzed with SPM12 (voxel-level threshold of p<0.05 [familywise error-corrected]). Secondly, the images of both groups were subjected to graph theoretical analysis using the Graph Analysis Toolbox with SPM8. Each group was also compared with 32 age- and sex-matched control patients without brain diseases. RESULTS: Comparisons between the pre- and post-CC groups revealed a significant reduction in seizure frequency with no change in mean intelligence quotient/developmental quotient levels. There was no relationship among the three groups in global network metrics or in targeted attack. A regional comparison of betweenness centrality revealed decreased connectivity to and from the right middle cingulate gyri and medial side of the right superior frontal gyrus and a partial shift in the distribution of betweenness centrality hubs to the normal location. Significantly lower resilience to random failure was found after versus before CC and versus controls (p = 0.0450 and p = 0.0200, respectively). CONCLUSION: Graph theoretical analysis of anatomical covariance derived from structural imaging revealed two neural network effects of resection associated with seizure reduction: the reappearance of a structural network comparable to that in healthy children and reduced connectivity along the median line, including the middle cingulate gyrus.

Static Leukoencephalopathy Associated with 17p13.3 Microdeletion Syndrome: A Case Report.

BACKGROUND: Leukoencephalopathy associated with dysmorphic features may be attributed to chromosomal abnormalities such as 17p13.3 microdeletion syndrome. CASE: A 19-year-old female patient was referred to our hospital for diagnostic evaluation of her leukoencephalopathy. She demonstrated moderate intellectual disability, minor dysmorphic features, and short stature. Serial brain magnetic resonance images obtained within a 16-year interval revealed prolonged T2 signals in the deep cerebral white matter with enlarged Virchow-Robin spaces. A nonsymptomatic atlas anomaly was also noted. Using microarray-based comparative genomic hybridization, we identified a 2.2-Mb terminal deletion at 17p13.3, encompassing YWHAE, CRK, and RTN4RL1 but not PAFAH1B1. CONCLUSION: Except for atlas anomaly, the patient's clinical and imaging findings were compatible with the diagnosis of 17p13.3 microdeletion syndrome. The white matter abnormality was static and nonprogressive. The association between the atlas abnormality and this deletion remains elusive. We note the importance of exploring submicroscopic chromosomal imbalance when patients show prominent but static white matter abnormalities with discrepantly mild and stable neurological signs.

A novel PAK3 pathogenic variant identified in two siblings from a Japanese family with X-linked intellectual disability: case report and review of the literature.

Intellectual disability (ID) is a clinically and genetically heterogeneous developmental brain disorder. The present study describes two male siblings, aged 7 and 1 yr old, with severe ID, spastic quadriplegia, nystagmus, and brain atrophy with acquired microcephaly. We used the exome sequencing to identify the causative gene in the patients and identified a hemizygous missense variant, c.1282T>A (p.W428R), in the p21-activated serine/threonine kinase 3 gene (PAK3), which is associated with X-linked ID. p.W428R is located within the highly conserved kinase domain and was predicted to induce loss of enzymatic function by three mutation prediction tools (SIFT, PolyPhen-2, and MutationTaster). In addition, this variant has not been reported in public databases (as of the middle of December 2018) or in the data from 3275 individuals of the Japanese general population analyzed using high-depth whole-genome sequencing. To date, only 13 point mutations and deletions in PAK3 in ID have been reported. The literature review illustrated a phenotypic spectrum of PAK3 pathogenic variant, and our cases represented the most severe form of the PAK3-associated phenotypes. This is the first report of a PAK3 pathogenic variant in Japanese patients with X-linked ID.

Childhood-onset cerebellar ataxia in Japan: A questionnaire-based survey.

OBJECTIVE: The diagnosis of childhood-onset cerebellar ataxia (CA) is often challenging due to variations in symptoms and etiologies. Despite the known regional differences in the prevalence of etiologies underlying CA, the frequency and characteristics of CA in Japan remain unclear. We conducted a questionnaire-based survey to identify the clinical characteristics of childhood-onset CA in the Japanese population. MATERIALS AND METHODS: Questionnaires were sent to 1,103 board-certified pediatric neurologists in Japan from 2016 to 2017. The primary survey requested the number of patients with CA under care, and the follow-up secondary questionnaire requested additional clinical characteristics of the patients. RESULTS: The primary survey obtained 578 responses (response rate, 52.4%) on 385 patients with CA, including 171 diagnosed and 214 undiagnosed cases (diagnostic rate, 44.4%). The most frequent etiology was dentatorubropallidoluysian atrophy (DRPLA), followed by mitochondrial disorders and encephalitis. The secondary survey obtained the clinical characteristics of 252 cases (119 diagnosed and 133 undiagnosed cases). Multiple logistic regression analysis revealed that a younger age at onset, hearing issues, and short stature were associated with a higher risk of remaining undiagnosed with CA in Japan. CONCLUSIONS: The diagnostic rate of childhood-onset CA in the current study was comparable to those reported in other countries. The high prevalence of autosomal dominant ataxia, especially DRPLA, was a signature of CA in Japan. These data offer insights into the characteristics of childhood-onset CA in the Japanese population.

Postoperative changes in the brain: Assessment with serial T2WI/FLAIR MR images in non-neoplastic patients.

The aim of the current study was to investigate the postoperative changes of high-signal lesions at the surgical margin on serial T2WI/FLAIR images in non-neoplastic patients. Seventy-one postoperative MR images in 27 patients (17 focal cortical dysplasia and 10 hippocampal sclerosis) who underwent surgery for intractable epilepsy were evaluated. T2WI/FLAIR-high-signal lesions in size and shape were visually assessed using a 3-point grading system. Associations of postoperative seizures or electroencephalography(EEG)spikes with advancing grade were also evaluated. As a result, follow-up showed enlarged T2WI/FLAIR-high-signal lesions in 6 of 27 patients (22%). The presence of post-operative seizures or EEG spikes was significantly associated with enlargement of the T2WI/FLAIR-high-signal lesion. Enlargement of the T2WI/FLAIR-high-signal lesion was observed in some non-neoplastic patients, and this finding might be correlated with remnant epileptogenesis.