Intra- and inter-hemispheric network dynamics supporting object recognition and speech production.

We built normative brain atlases that animate millisecond-scale intra- and inter-hemispheric white matter-level connectivity dynamics supporting object recognition and speech production. We quantified electrocorticographic modulations during three naming tasks using event-related high-gamma activity from 1,114 nonepileptogenic intracranial electrodes (i.e., non-lesional areas unaffected by epileptiform discharges). Using this electrocorticography data, we visualized functional connectivity modulations defined as significant naming-related high-gamma modulations occurring simultaneously at two sites connected by direct white matter streamlines on diffusion-weighted imaging tractography. Immediately after stimulus onset, intra- and inter-hemispheric functional connectivity enhancements were confined mainly across modality-specific perceptual regions. During response preparation, left intra-hemispheric connectivity enhancements propagated in a posterior-to-anterior direction, involving the left precentral and prefrontal areas. After overt response onset, inter- and intra-hemispheric connectivity enhancements mainly encompassed precentral, postcentral, and superior-temporal (STG) gyri. We found task-specific connectivity enhancements during response preparation as follows. Picture naming enhanced activity along the left arcuate fasciculus between the inferior-temporal and precentral/posterior inferior-frontal (pIFG) gyri. Nonspeech environmental sound naming augmented functional connectivity via the left inferior longitudinal and fronto-occipital fasciculi between the medial-occipital and STG/pIFG. Auditory descriptive naming task enhanced usage of the left frontal U-fibers, involving the middle-frontal gyrus. Taken together, the commonly observed network enhancements include inter-hemispheric connectivity optimizing perceptual processing exerted in each hemisphere, left intra-hemispheric connectivity supporting semantic and lexical processing, and inter-hemispheric connectivity for symmetric oral movements during overt speech. Our atlases improve the currently available models of object recognition and speech production by adding neural dynamics via direct intra- and inter-hemispheric white matter tracts.

Clinical profile of reading ability and reading and writing achievement of children with borderline full-scale intellectual quotient: a prospective study.

BACKGROUND: Poor reading ability is one of the common causes of low academic performance. In previous studies, children with dyslexia were found to demonstrate poor academic achievement due to poor reading ability. However, the relationship between academic achievement and reading ability in children with a borderline full-scale intellectual quotient (FSIQ) is unknown. This study aimed to clarify the clinical characteristics of children with borderline FSIQ and poor reading ability, and differentiate these characteristics from those of children with higher FSIQ and poor reading ability. METHODS: A total of 126 children (aged 6-15 years) identified as having low academic performance were enrolled. The reading ability of children was assessed through their performance on the hiragana (Japanese syllabary) reading task, while their reading and writing achievement was assessed through their reading and writing score on the Kaufman Assessment Battery for Children, Second Edition. Children were categorized into two groups based on their FSIQ score (FSIQ > 85 and 85 ≥ FSIQ ≥ 70). Reading ability in children was evaluated by referring to the linear relationship between FSIQ and the standard deviation value of reading tasks in typically developing children. A one-way analysis of variance (ANOVA) was performed to examine clinical characteristics between higher and lower FSIQ groups. Associations between reading and writing achievement, reading ability, and ages of children were assessed using Pearson's product-moment correlation coefficients for the higher and lower FSIQ groups. RESULTS: Poorer reading and writing achievement was associated with poorer reading ability in the higher FSIQ group. Conversely, poorer reading and writing achievement and poor reading ability were associated with older age in the lower FSIQ group. CONCLUSIONS: Poor reading and writing achievement were associated with older age, not with poor reading ability in the lower FSIQ group. Children with lower FSIQ need appropriate educational interventions based on independent assessments to further their academic achievement and reading ability. Moreover, they need more frequent evaluations of their academic achievement than do children with higher FSIQ and poor reading ability since they are more likely to be at a lower academic achievement level at an older age.

Association between lack of functional connectivity of the frontal brain region and poor response inhibition in children with frontal lobe epilepsy.

PURPOSE: We investigated the relationship between electroencephalographic (EEG) functional connectivity and executive function in children with frontal lobe epilepsy (FLE). METHODS: We enrolled 24 children with FLE (mean age, 11.0 years; 13 boys) and 22 sex-, age-, and intelligence-matched typically developing children (TDC) to undergo 19-channel EEG during light sleep. We estimated functional connectivity using the phase lag index (PLI) that captures the synchronization of EEG. We also performed continuous performance tests (CPTs) on the children and obtained questionnaire responses on attention deficit hyperactivity disorder and oppositional defiant disorder (ODD). RESULTS: The average gamma PLI was lower in the FLE group than in the TDC group, especially between long-distance frontoparietal pairs, between interhemispheric frontal pairs, and between interhemispheric parietotemporal pairs. Gamma PLIs with long-distance frontoparietal and interhemispheric frontal pairs were positively associated with inattention, ODD scores, omission error, and reaction time in the FLE group but not in the TDC group. Conversely, they were negatively associated with age, hyperactivity score, and commission error. CONCLUSIONS: A lack of functional connectivity of the frontal brain regions in children with FLE was associated with poor response inhibition.

Adaptive behavior and its related factors in children with focal epilepsy.

OBJECTIVE: We aimed to clarify the strengths and weaknesses in adaptive behavior in children with focal epilepsy and show children-associated factors related to adaptive behavior. MATERIALS AND METHODS: Sixty-three children with focal epilepsy aged 5-18 years with intellectual quotient (IQ) ranging from 67 to 135 were enrolled in this study. Adaptive behavior was evaluated using the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II). The children performed continuous performance test and tests of reading, writing, and IQ; parents answered questionnaires regarding attention-deficit hyperactivity disorder and autism spectrum disorder (ASD). Participants were categorized into four groups based on IQ and adaptive behavior scores for statistical comparisons. RESULTS AND DISCUSSION: Children with low adaptive behavior were more likely to show a reduction in daily living skills, and those with both low adaptive behavior and IQ were more likely to show a reduction in daily living skills and communication. Lower adaptive behavior was related to more severe autistic symptoms, lower academic achievement in children with IQ > 85, and lower executive function in children with IQ ≤ 85. There was a qualitative difference of cognitive dysfunction in adaptive behavior between both groups. CONCLUSIONS: There were differences in VABS-II domain and subdomain characteristics between children with focal epilepsy and those with ASD; however, it was more difficult for children with more severe ASD and coexisting focal epilepsy to show age-equivalent adaptive behavior.

Seizure imitators monitored using video-EEG in children with intellectual disabilities.

Diagnosis of seizure imitators in children is often challenging, and individuals with intellectual disability (ID) could be at additional risk of seizure imitator misdiagnosis. We aimed to elucidate distinct features of clinical semiology among children of different intellectual levels, which may help in distinguishing seizure imitators from epilepsy in such individuals. We retrospectively compared semiological features of seizure imitators in children with and without ID captured using video-electroencephalography (video-EEG). Seizure imitators were classified based on the definition of the International League Against Epilepsy (ILAE). A total of 67 individuals (mean age: 8.4 years, SD: 4.2 years) with seizure imitators documented using long-term video-EEG were identified, in which 27 patients had normal IQ/DQ, 20 had moderate ID, and 20 had severe ID. There was no statistically significant difference in the semiological features of seizure imitators between individuals with ID and those without ID; similarly, no difference was found between those with moderate ID and severe ID compared with individuals with normal IQ/DQ. Among all the patients, altered responsiveness mimicking cognitive or absence seizures was most frequently observed (36%), followed by jerks mimicking myoclonic seizures (22%). The most common seizure imitators among all the patients were unclassifiable nonepileptic seizures per the ILAE definition (28 cases, 42%), followed by day dreaming (24 cases, 36%) and physiological myoclonus (14 cases, 21%). In summary, the present study found no marked difference in semiological features of seizure imitators between patients with ID and those without ID regardless of ID severity, suggesting the necessity of early video-EEG for correct diagnosis.

Independent risk factors for recurrence of apparent life-threatening events in infants.

The risk factors for recurrent apparent life-threatening event (ALTE) are unclear although the risk of recurrent ALTE is an important consideration for the management of ALTE patients. This study aimed to identify the risk factors for recurrent ALTE. We conducted a secondary analysis of the data from a single center retrospective cohort study in Japan conducted from March 2002 to January 2012, which included children diagnosed with ALTE at a pediatric emergency department (ED) in Tokyo. Among 112 ALTE patients, 18 (16%) had recurrences and 94 (84%) did not. Symptoms of respiratory tract infection (RTI) were more frequent in the recurrent group than in the non-recurrent group (44 vs. 14% p = 0.0055), and the proportion of patients triaged as level 1 was larger in the recurrent group than in the non-recurrent group (31 vs. 7%, p = 0.0312). Pallor was observed more frequently in the recurrent group than in the non-recurrent group (100 vs. 76%, p = 0.0216). Multivariate analysis demonstrated that the independent risk factors of recurrent ALTE were respiratory tract infection symptoms (OR, 5.02; 95% CI, 1.48-16.98). CONCLUSION: ALTE patients who had RTI symptoms at the ED visit for first ALTE should be admitted for close observation of potential recurrences. What is Known: • Approximately 10% of ALTE patients experienced recurrence of ALTE episodes. • The risk of recurrent ALTE is one of the major consideration for the management of ALTE patients at the ED because these patients have higher rates of serious underlying diseases which require interventions. What is New: • Respiratory infection symptoms at ED presentation can be independent risk factors for recurrent ALTE.

Cortical and white matter substrates supporting visuospatial working memory.

OBJECTIVE: In tasks involving new visuospatial information, we rely on working memory, supported by a distributed brain network. We investigated the dynamic interplay between brain regions, including cortical and white matter structures, to understand how neural interactions change with different memory loads and trials, and their subsequent impact on working memory performance. METHODS: Patients undertook a task of immediate spatial recall during intracranial EEG monitoring. We charted the dynamics of cortical high-gamma activity and associated functional connectivity modulations in white matter tracts. RESULTS: Elevated memory loads were linked to enhanced functional connectivity via occipital longitudinal tracts, yet decreased through arcuate, uncinate, and superior-longitudinal fasciculi. As task familiarity grew, there was increased high-gamma activity in the posterior inferior-frontal gyrus (pIFG) and diminished functional connectivity across a network encompassing frontal, parietal, and temporal lobes. Early pIFG high-gamma activity was predictive of successful recall. Including this metric in a logistic regression model yielded an accuracy of 0.76. CONCLUSIONS: Optimizing visuospatial working memory through practice is tied to early pIFG activation and decreased dependence on irrelevant neural pathways. SIGNIFICANCE: This study expands our knowledge of human adaptation for visuospatial working memory, showing the spatiotemporal dynamics of cortical network modulations through white matter tracts.

Quality of life of children with neurodevelopmental disorders and their parents during the COVID-19 pandemic: a 1-year follow-up study.

This study aimed to reveal changes in the quality of life (QOL) of children with neurodevelopmental disorders and their parents, and the interaction between their QOL and parental mental state during the coronavirus 2019 (COVID-19) pandemic. Eighty-nine school-aged children and parents participated in surveys in May 2020 (T1) and May 2021 (T2). The parents completed questionnaires that assessed their QOL, depression, parenting stress, and living conditions. Children's temporary mood status was evaluated using the self-reported visual analog scale (VAS). Children's QOL and VAS at T2 were higher than their QOL at T1. Parents' QOL at T2 was lower than their QOL at T1. Severe parental depression at T1 had a synergistic effect on severe parenting stress and severe depressive state at T2. Additionally, children's high QOL at T1 had a synergistic effect on low parenting stress and children's high QOL at T2. Furthermore, children's low VAS scores and parents' low QOL at T2 were associated with deterioration of family economic status. Children and parents' QOL changed during the prolonged COVID-19 pandemic. Improvement in children's QOL was influenced by reduced maternal depressive symptoms. Public support for parental mental health is important to avoid decreasing QOL.

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.

Psychological Status Associated With Low Quality of Life in School-Age Children With Neurodevelopmental Disorders During COVID-19 Stay-At-Home Period.

Background: This study seeks to ascertain how the COVID-19 stay-at-home period has affected the quality of life (QOL) of children with neurodevelopmental disorders (NDDs) who had experienced sleep schedules alteration and clarify what psychological status predicted low QOL in children with and without altered sleep patterns. Materials and Methods: Study participants were 86 children between 8 and 17 years of age (mean age, 11.7 years; 70 boys, 16 girls; mean intellectual quotient, 83.6). QOL was evaluated using the self-assessment KINDLR. Participants answered questions regarding depression and anxiety on a visual analog scale (VAS) for temporary mood. Their parents answered questionnaires regarding their maladaptive behaviors and differences in sleep patterns before and during the COVID-19 pandemic. The student's t-test was performed to examine the presence or absence of sleep changes in the children, which affected QOL, temporary mood, and maladaptive behaviors. Multiple or simple linear regression analyses were also performed to identify the psychogenic factors that significantly affected decreased QOL for each group with and without changes in sleep schedule. Results: During the COVID-19 stay-at-home period, 46.5% of participants experienced changes in sleep patterns. These changes were associated with decreased QOL as well as internalized symptoms. The decreased QOL of children with sleep patterns changed was predicted by a high level of depression. In addition, low QOL in children with unchanged sleep patterns was predicted by a high level of depression and low current mood status. Conclusions: Almost half of the participants experienced a poor sleep schedule during the stay-at-home period. These alterations in sleep patterns were associated with a low QOL. The QOL of children with a stable life schedule was affected not only by depressive tendencies but also temporary moods. Therefore, they need to live a fulfilling life to maintain their QOL. However, the QOL of children with poor sleep patterns was affected only by depressive tendencies. Hence, clinicians need to ensure that children with NDDs are well-diagnosed with depression and treated for sleep problems.

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.

The quality of life of children with neurodevelopmental disorders and their parents during the Coronavirus disease 19 emergency in Japan.

This study aimed to reveal how the COVID-19 stay-at-home period has affected the quality of life (QOL) of children with neurodevelopmental disorders and their parents and to identify possible factors that enabled them to maintain their QOL. We enrolled 136 school-aged children (intellectual quotient ≥ 50) and their parents and administered QOL questionnaires to assess the maladaptive behavior of the children; depression, anxiety, and stress of the parents; and activities of their daily lives. The relationship between their QOL and clinical features was examined. The decrease in QOL of children and parents was associated with the mother's limited job flexibility. Decreased QOL was also associated with changes in the sleep rhythms of the children. Maladaptive behaviors in children were associated with parental stress. However, maintained QOL of some families who faced these same conditions of job stress and sleep disorders was associated with less parental stress, less parental depression and anxiety, and milder maladaptive behavior in children. Both mothers with limited job flexibility and changes in the sleep rhythm of children were associated with reduced QOL of children and their parents. Low parental stress was associated with decreased maladaptive behavior in children and with maintained QOL of the family.

Atypical gamma functional connectivity pattern during light sleep in children with attention deficit hyperactivity disorder.

INTRODUCTION: We examined functional connectivity analyses in electroencephalograms (EEGs) of patients with attention deficit hyperactivitydisorder (ADHD) and in those of typically developing children (TDC) to uncover neurobiological abnormalities. METHODOLOGY: We enrolled 31 children with ADHD (mean age 11.1 years; 23 boys) and 17 sex-, age-, and intelligence-matched TDC to undergo 19-channel EEGs during light sleep. We estimated functional connectivity using the phase lag index (PLI) and coherence measurements that capture the synchronization of EEG signals and graphed metrics with GRETNA. We also performed continuous performance tests (CPTs) on the children and obtained answered questionnaires on ADHD and autism spectrum disorder. RESULTS: The central-to-posterior gamma PLI was lower in children with ADHD than that in TDC. The other PLI frequency bands and all coherence frequency bands were not statistically different between both groups. Individuals with high hyperactivity scores on questionnaires and low reaction times (SDs) on CPT had low motor and occipital pairs of gamma PLIs. Graph metrics showed no differences between the groups. CONCLUSIONS: The difference in averaged gamma PLI (especially with motor and occipital pairs) between groups was more suitable for diagnosis than the averaged coherence. Lower averaged gamma PLIs reflected more severe ADHD symptoms. A prospective study with more controlled conditions is warranted to determine if gamma-band PLI can be used as an auxiliary tool for ADHD diagnosis.

Executive dysfunction in medication-naïve children with ADHD: A multi-modal fNIRS and EEG study.

OBJECTIVE: Children with attention deficit hyperactivity disorder (ADHD) exhibit deficits in executive function. Since there are no clear biomarkers for the disorder, this study aimed to investigate the neurophysiological biomarkers for deficits in executive function in children with ADHD using functional near-infrared spectroscopy (fNIRS) and electroencephalography. METHODS: Twenty patients diagnosed with ADHD and 19 typically developing children (TDC; 8-11 years old) were included. Event related potentials (ERPs) were recorded using an electroencephalogram (EEG) and oxygenated hemoglobin concentrations (Oxy-Hb) were recorded using fNIRS during a colored Go/NoGo task, simultaneously. Latencies and amplitudes of NoGo-N2 and NoGo/Go-P3 tasks were measured using EEG. RESULTS: Children with ADHD showed significantly decreased Oxy-Hb in the right frontal cortex as well as longer NoGo-P3 latencies and a decreased NoGo/Go-P3 amplitude. There was a significant positive correlation between the Oxy-Hb and NoGo/Go-P3 amplitude. CONCLUSIONS: These results suggest that children with ADHD experience executive dysfunction. Hemodynamic and electrophysiological findings during the Go/NoGo task might be useful as a biomarker of executive function. SIGNIFICANCE: These findings have key implications for understanding the pathophysiology of deficits in executive function in ADHD.

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.

Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders.

BACKGROUND: Recently, many genes related to neurodevelopmental disorders have been identified by high-throughput genomic analysis; however, a comprehensive understanding of the mechanism underlying neurodevelopmental disorders remains to be established. To further understand these underlying mechanisms, we performed a comprehensive genomic analysis of patients with undiagnosed neurodevelopmental disorders. METHODS: Genomic analysis using next-generation sequencing with a targeted panel was performed for a total of 133 Japanese patients (male/female, 81/52) with previously undiagnosed neurodevelopmental disorders, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. Genomic copy numbers were also analyzed using the eXome Hidden Markov Model (XHMM). RESULTS: Thirty-nine patients (29.3%) exhibited pathogenic or likely pathogenic findings with single-gene variants or chromosomal aberrations. Among them, 20 patients were presented here. Pathogenic or likely pathogenic variants were identified in 18 genes, including ACTG1, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANK3, SMARCA2, STXBP1, SYNGAP1, and TBL1XR1. CONCLUSION: A diagnostic yield of 29.3% in this study was nearly the same as that previously reported from other countries. Thus, we suggest that there is no difference in genomic backgrounds in Japanese patients with undiagnosed neurodevelopmental disabilities. Although most of the patients possessed de novo variants, one of the patients showed an X-linked inheritance pattern. As X-linked recessive disorders exhibit the possibility of recurrent occurrence in the family, comprehensive molecular diagnosis is important for genetic counseling.

Epileptic phenotype of FGFR3-related bilateral medial temporal lobe dysgenesis.

Hypochondroplasia (HCH) is a skeletal dysplasia, characterized by short stature and macrocephaly. Clinical symptoms and radiological and histopathological features of HCH are similar, but milder than those seen in achondroplasia. Particularly, HCH patients with Asn540Lys mutation in the FGFR3 gene are reported to have medial temporal lobe dysgenesis and epilepsy. We report a 3-year-old girl who developed recurrent epileptic apnea, which started immediately after birth. The apneic seizures were refractory to antiepileptic medications; ictal electroencephalography showed rhythmic activity originating from the left or right temporal areas and rarely from the right frontal area. Macrocephaly was noted since birth. Neuroimaging revealed bilateral dysgenesis and hypometabolism of the medial temporal structures as well as perfusion changes in the left lateral temporofrontal areas during the ictal period. Clonazepam was initiated and acetazolamide dosage was increased at 6months, resulting in complete seizure control after 8months of age. Genetic analysis identified an Asn540Lys (c.1620 C>A) mutation in the FGFR3 gene. Characteristic bone findings on the lumbar spine, iliac bone, and femur were retrospectively confirmed on X-rays during infancy. This was the first report that delineated the epilepsy phenotype in FGFR3-related bilateral medial temporal lobe dysgenesis; such findings would lead to an early diagnosis and better epilepsy management.

Effect of Serotonin 1A Agonists and Selective Serotonin Reuptake Inhibitors on Behavioral and Nighttime Respiratory Symptoms in Rett Syndrome.

BACKGROUND: Rett syndrome is characterized by psychomotor regression during early childhood, autistic-like behaviors, and aberrant breathing patterns. Dysfunction of the serotonergic system has been postulated to play a role in the pathophysiology of these symptoms. PATIENT DESCRIPTION: We present an 11-year-old girl with Rett syndrome who exhibited marked respiratory symptoms, including frequent apneic events during sleep. She had been treated for these respiratory symptoms using noninvasive positive pressure ventilation since age six years. Treatment with serotonin 1A receptor agonist was initiated at age eight years, whereas treatment using a selective serotonin reuptake inhibitor began at age nine years. Noninvasive positive pressure ventilation therapy was effective in reducing symptoms of sleep apnea, and administration of serotonergic agents resulted in amelioration of sleep apneic events even in the absence of noninvasive positive pressure ventilation. In addition, improvements in hand stereotypy and social skills were observed after initiation of serotonin-based therapy. DISCUSSION: The respiratory difficulties our patient experienced during non-rapid eye movement (REM) sleep are characteristic of post-sigh central apnea. Exaggerated activity of expiratory neurons during such apneic events has been observed in mouse models of Rett syndrome. We suggest that prescribed serotonergic agents might serve to inhibit such activity, attenuating the imbalance between inspiratory and expiratory neurons. These agents might also be useful in the treatment of autistic-like behaviors caused by impaired serotonergic transmission in the brain.

Effects of donepezil and serotonin reuptake inhibitor on acute regression during adolescence in Down syndrome.

A 14-year-old boy with Down syndrome (DS) showed a gradual decline in his daily activities and feeding capacities, and a marked deterioration triggered by a streptococcal infection was observed at the age of 15 years. He became bedridden, accompanied by sleep disturbance, sustained upward gaze, and generalized rigidity. Magnetic resonance imaging showed unremarkable findings, but antiglutamate receptor autoantibodies were positive in his cerebrospinal fluid. Treatment with thiamine infusion and steroid pulse therapy showed little effect, but gross motor dysfunction and appetite loss were ameliorated by the administration of l-DOPA and serotonin reuptake inhibitors. Thereafter, autistic behaviors predominated, including loss of social interaction, oral tendency, water phobia, and aggressiveness. Initiation of donepezil, an acetylcholinesterase inhibitor, resulted in the disappearance of these symptoms and total recovery of the patient to his previous psychosocial levels. We hypothesize that the acute regression in adolescence represents a process closely related to the defects of serotonergic and cholinergic systems that are innate to DS brains and not just a nonspecific comorbidity of depression or limbic encephalitis.

Effect of Intrathecal Baclofen on Delayed-Onset Paroxysmal Dystonia due to Compression Injury Resulting From Congenital and Progressive Spinal Bone Deformities in Chondrodysplasia Punctata.

BACKGROUND: Dystonia due to spinal lesions in adult patients is characterized by the provocation and/or amelioration of the spasm by somatosensory stimulation with a sensory trick. PATIENT DESCRIPTION: An infant with brachytelephalangic chondrodysplasia punctata developed flaccid tetraplegia due to cervical cord compression resulting from congenital atlantoaxial dislocation. Episodic, tonic extension of the extremities, neck, and trunk had appeared daily since age two years and was often provoked by tactile stimulation. Although decompression surgery was performed at age three years, progressive spinal deformity resulted in the aggravation of episodic dystonia thereafter, lasting for hours. Foot dorsiflexion and wearing a truncal brace for scoliosis inhibited these spasms. Intrathecal baclofen bolus injection transiently ameliorated the paroxysmal dystonia and detrusor-sphincter dyssynergia in the lower urinary tract. CONCLUSION: Paroxysmal dystonia is unusual in children with spinal cord lesions; however, it should be recognized for appropriate individualized clinical management.