Evaluation of seizure semiology, genetics, magnetic resonance imaging, and electroencephalogram findings in children with Rett syndrome: A multicenter retrospective study.

OBJECTIVES: This study aimed to evaluate seizure semiology, electroencephalogram (EEG), magnetic resonance imaging (MRI), and genetic findings, as well as treatment choices in Rett syndrome (RTT). METHODS: A retrospective analysis was conducted on one hundred and twenty cases diagnosed with RTT with a genetic mutation. Data were obtained from nine participating centers. RESULTS: In this study, 93.3 % of patients were female, with typical RTT found in 70 % of cases. Genetic etiology revealed MECP2, FoxG1, and CDKL5 in 93.8 %, 2.7 %, and 1.8 % of cases, respectively. Atypical RTT clinics were observed in 50 % of male cases, with the first EEG being normal in atypical RTT cases (p = 0.01). Generalized tonic-clonic and myoclonic epilepsy were the most common seizure semiologies, while absence and focal epilepsy were less prevalent. Valproate, levetiracetam, lamotrigine, and clobazam were the most commonly used antiepileptic drugs, affecting the severity and frequency of seizures (p = 0.015, p=<0.001, p = 0.022, and p=<0.001, respectively). No significant differences were observed in EEG findings. The initiation of anti-seizure medications significantly altered seizure characteristics (Table 4). A ketogenic diet and vagal nerve stimulation (VNS) correlated with a 50 % improvement in cognitive function, while steroid treatment showed a 60 % improvement. Remarkably, seizures were substantially reduced after VNS application. CONCLUSION: This study underscores the importance of genetic diagnosis in RTT cases with a clinical diagnosis. These preliminary results will be further validated with the inclusion of clinically diagnosed RTT cases in our ongoing study.

Autism in Turkey: demographics, behavior problems, and accompanying medical conditions in a sample of Turkish youth with autism spectrum disorder.

Autism spectrum disorder (ASD) is an etiologically heterogeneous neurodevelopmental condition that eludes a single explanation or cure. Epidemiological studies reveal risk factors, relevant comorbidities, and behavioral correlates to reach a better understanding of ASD. To contribute such data from an understudied ASD population, this paper presents epidemiological data from a Turkish sample of individuals with ASD (n = 911, 748 boys (82.1%) and 163 girls (17.9%) between 1 and 18 years of age). Average age at diagnosis was 31.06 ± 11.88 months, and the male-to-female ratio was 4.6:1. Three in 4 individuals with ASD had obsessive behaviors, and 1 in 4 had allergic conditions, inappropriate sexual behaviors, self-harming behaviors, and harmful behaviors towards others. One in 3 received a dietary treatment for at least 3 months; almost half received vitamin supplements; the majority (70%) did not experience constipation; and 2 in 3 were picky eaters. This paper presents data on the age of diagnosis, gender ratios, accompanying behaviors, and dietary interventions in Turkish individuals with ASD, which are topics of current research interest about ASD. Such data from non-Western populations may supplement epidemiological knowledge gained from Western populations to help reach a more comprehensive understanding of this condition with many unknowns.

Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome.

OBJECTIVE: Joubert syndrome is a neurodevelopmental disorder with a distinctive hindbrain malformation called molar tooth sign, causing motor and cognitive impairments. More than 40 genes have been associated with Joubert syndrome. We aim to describe a group of Joubert syndrome patients clinically and genetically emphasizing organ involvement. METHODS: We retrospectively collected clinical information and molecular diagnosis data of 22 patients with Joubert syndrome from multiple facilities. Clinical exome or whole-exome sequencing were performed to identify causal variations in genes. RESULTS: The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. Multi-systemic organ involvement was observed in nine (40%) patients, with the eye being the most common, including Leber's congenital amaurosis, ptosis, and optic nerve coloboma. Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. The HYLS1 gene, which commonly causes hydrolethalus syndrome 1, was also associated with Joubert syndrome in one of our patients. A mild phenotype with hypophyseal hormone deficiencies without the classical molar tooth sign was observed with compound heterozygous and likely pathogenic variants not reported before in the KATNIP gene. CONCLUSION: Some rare variants that display prominent genetic heterogeneity with variable severity are first reported in our patients. In our study of 22 Joubert syndrome patients, CPLANE1 is the most affected gene, and Joubert syndrome as a ciliopathy is possible without a classical molar tooth sign, like in the KATNIP gene-affected patients.

Changes in EEG complexity with neurofeedback and multi-sensory learning in children with dyslexia: A multiscale entropy analysis.

Multiscale entropy analysis (MSE) is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. MSE has been successfully applied in the literature when measuring autism traits, Alzheimer's, and schizophrenia. However, until now, there has been no research on MSE applied to children with dyslexia. In this study, we have applied MSE analysis to the EEG data of an experimental group consisting of children with dyslexia as well as a control group consisting of typically developing children and compared the results. The experimental group comprised 16 participants with dyslexia who visited Ankara University Medical Faculty Child Neurology Department, and the control group comprised 20 age-matched typically developing children with no reading or writing problems. MSE was calculated for one continuous 60-s epoch for each experimental and control group's EEG session data. The experimental group showed significantly lower complexity at the lowest temporal scale and the medium temporal scales than the typically developing group. Moreover, the experimental group received 60 neurofeedback and multi-sensory learning sessions, each lasting 30 min, with Auto Train Brain. Post-treatment, the experimental group's lower complexity increased to the typically developing group's levels at lower and medium temporal scales in all channels.

A mobile app that uses neurofeedback and multi-sensory learning methods improves reading abilities in dyslexia: A pilot study.

Reading comprehension is difficult to improve for children with dyslexia because of the continuing demands of orthographic decoding in combination with limited working memory capacity. Children with dyslexia get special education that improves spelling, phonemic and vocabulary awareness, however the latest research indicated that special education does not improve reading comprehension. With the aim of improving reading comprehension, reading speed and all other reading abilities of children with dyslexia, Auto Train Brain that is a novel mobile app using neurofeedback and multi-sensory learning methods was developed. With a clinical study, we wanted to demonstrate the effectiveness of Auto Train Brain on reading abilities. We compared the cognitive improvements obtained with Auto Train Brain with the improvements obtained with special dyslexia training. Auto Train Brain was applied to 16 children with dyslexia 60 times for 30 minutes. The control group consisted of 14 children with dyslexia who did not have remedial training with Auto Train Brain, but who did continue special education. The TILLS test was applied to both the experimental and the control group at the beginning of the experiment and after a 6-month duration from the first TILLS test. Comparison of the pre- and post- TILLS test results indicated that applying neurofeedback and multi-sensory learning method improved reading comprehension of the experimental group more than that of the control group statistically significantly. Both Auto Train Brain and special education improved phonemic awareness and nonword spelling.

CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature.

INTRODUCTION: Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors. Although more cases are being diagnosed, no drugs are approved to treat the core symptoms or cognitive and behavioral problems associated with autism. Therefore, there is an urgent need to develop an effective and safe treatment. OBJECTIVE: In this study, we aim to share our 2-year experience with CBD-enriched cannabis treatment in autism and review the latest studies. MATERIALS AND METHODS: The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The mean age was 7.7 ± 5.5 years. The average daily dosage of cannabidiol (CBD) was 0.7 mg/kg/day (0.3-2 mg/kg/day). The median duration of treatment was 6.5 months (3-28 months). The preparations used in this study contained full-spectrum CBD and trace elements tetrahydrocannabinol (THC) of less than 3%. RESULTS: The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to evaluate the effectiveness of the CBD-enriched cannabis treatment. According to the parents' reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12,9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition among patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses. Additionally, this study includes an extensive review of the literature regarding CBD treatment in autism spectrum disorder. According to recent studies, the average dose of CBD was 3.8±2.6 mg/kg/day. The ratio of CBD to THC in the used preparations was 20:1. The most significant improvements were seen in the behavioral problems reported in 20-70% of the patients. CONCLUSION: Using lower doses of CBD and trace THC seems to be promising in managing behavioral problems associated with autism. In addition, this treatment could be effective in managing the core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

A Rare Cause of Autistic Regression in a Boy with Down Syndrome: Hashimoto Encephalopathy.

BACKGROUND: Hashimoto encephalopathy (HE) is a rare condition associated with autoimmune thyroid disease. We aimed to report the youngest patient with Down syndrome and HE with an unusual presentation. CASE REPORT: Six years and six months old boy with Down syndrome admitted due to loss of speech. His physical development was appropriate for his age and had no goiter. Neurological examination revealed the absence of eye contact and stereotypic movements. Autism spectrum disorder was considered based on his result on Gilliam autism evaluation scale. He had subclinical hypothyroidism with markedly elevated anti-thyroid peroxidase antibody level, rare spikes in the frontocentral area were found in electroencephalography, and cranial magnetic resonance imaging was normal. Neurologic improvement was observed to a treatment with glucocorticoid and thyroid hormone. CONCLUSION: HE might be considered in patients with Down syndrome along with progressive cognitive decline and autistic regression.

Play interactions of parents toward children with autism spectrum disorder: NeuroPLAY parent play behavior assessment scale.

PROBLEM: The aim of this study is to analyze the changes that NeuroPLAY, which is an intensive early intervention method for children with autism spectrum disorder (ASD) and ages of 12-42 months, has created in the play skills of the parents of children with ASD by using method strategies. METHODS: The study cohort includes 91 children ages ranging from 18 to 42 months old. The study is designed for repetitive measurements performed pre- and post-intervention. Within the scope of the study, children's ASD symptoms were evaluated with the Childhood Autism Rating Scale (CARS) and changes in the play skills of parents were evaluated using NeuroPLAY Parental Play Behavior Assessment Scale (NPPBAS). RESULTS: The NPPBAS score at the beginning of the intervention was 12.55; repeated measurements (46.22 after 3 months, 45.95 after 6 months, and 48.53 after 12 months) were observed to increase core. The older age of the parents in the intervention program is associated with lower final NPPBAS scores. However, it was determined that the CARS score, which is an indicator of the autism spectrum, will decrease after intervention regardless of the parents' age. CONCLUSION: The results showed that NeuroPLAY led to significant improvement in play behaviors of the parents.

Impact of eating habits and nutritional status on children with autism spectrum disorder.

OBJECTIVES: Obesity is common among children with Autism Spectrum Disorder (ASD). They suffer more feeding problems than children with normal developmental milestones. Several kinds of diet are recommended for children with ASD. This study determines the frequency of eating disorders and obesity among such children. We investigate the predisposing factors of eating disorders and examine the effects of consumed food on autism scores. METHODS: In this single-centre, cross-sectional study, 46 children with ASD aged between 2 and 10 years were included. Anthropometric measurements were recorded and Brief Autism Mealtime Behavior Inventory (BAMBI), Autism Behavior Checklist (ABC), and Food Frequency Questionnaire (FFQ) forms were filled in by their parents. RESULTS: The rates of being overweight and obese were 10.9% and 28.3%, respectively. Food selectivity was observed in 84.8% of the children, and BAMBI food refusal scores were significantly higher for those aged between 2 and 5 years (p = 0.03). Autism scores and consumption of milk, yoghurt, oily seeds, rice/pasta, and fruits (p < 0.05) were significantly correlated. There were also significant differences between these scores and the frequency of consuming eggs, legumes, and other cereals (p < 0.05). CONCLUSION: Obesity was more common in children with ASD than typically developed children. Despite the high rate of food selectivity, our findings confirmed that food selectivity could be considered independent of obesity. Further, the diet of patients with ASD must include more fruits, yogurt, eggs, legumes, other cereals, less milk, and less rice/pasta.

Pontine Tegmentum Lesions Accompanying Myelitis During an Enterovirus Outbreak: Differential Diagnosis and Outcome.

AIM: To investigate etiology and prognostic significance of pontine tegmentum lesions accompanying a cluster of acute flaccid myelitis. METHOD: We retrospectively examined patients from 6 centers in Turkey who manifested encephalitis or myelitis associated with dorsal pontine lesions on magnetic resonance imaging (MRI) between July 2018 and February 2019. RESULTS: Twenty-two patients were evaluated. Ten of 22 (45%) presented with acute paralysis and 12 of 22 (55%) with brainstem symptoms only. Reverse transcription polymerase chain reaction for enterovirus was positive in 2 patients' respiratory tract. Other etiologic factors were detected in 10 cases. On follow-up, patients presenting with symptoms of myelitis developed motor sequalae although spinal cord lesions on MRI resolved in 5 of 9 (55%). Encephalitic symptoms, present in 17 cases, recovered in 13 (76%), and brain MRI showed complete or near-complete resolution in 11 of 14 (78%). CONCLUSION: Various etiologic agents can be detected in patients with pontine involvement, even in a series collected during an outbreak of EV-D68. Encephalitis has a fair outcome but clinical recovery is slow and motor sequalae are frequent in spinal involvement, irrespective of follow-up spinal MRI findings.

Neonatal hypoxic ischemic encephalopathy: an update on disease pathogenesis and treatment.

INTRODUCTION: Hypoxic ischemic encephalopathy (HIE) is the most important reason for morbidity and mortality in term-born infants. Understanding pathophysiology of the brain damage is essential for the early detection of patients with high risk for HIE and development of strategies for their treatments. Areas covered: This review discusses pathophysiology of the neonatal HIE and its treatment options, including hypothermia, melatonin, allopurinol, topiramate, erythropoietin, N-acetylcyctein, magnesium sulphate and xenon. Expert commentary: Several clinical studies have been performed in order to decrease the risk of brain injury due to difficulties in the early diagnosis and treatment, and to develop strategies for better long-term outcomes. Although currently standard treatment methods include therapeutic hypothermia for neonates with moderate to severe HIE, new supportive options are needed to enhance neuroprotective effects of the hypothermia, which should aim to reduce production of the free radicals and to have anti-inflammatory and anti-apoptotic actions.

Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly.

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.

Febrile seizures in children with familial Mediterranean fever: Coincidence or association?

BACKGROUND: Familial Mediterranean fever (FMF) is an inherited disease characterized by recurrent bouts of fever and polyserositis and caused by MEditerranean FeVer gene (MEFV) mutations. Given the febrile characteristics of the disease one would expect higher frequency of febrile seizure in this group of pediatric patients. OBJECTIVES: To evaluate the frequency of febrile seizure and related factors in patients with FMF. METHODS: The children with the diagnosis of FMF were enrolled in the study. Information including clinical features, type of mutation and the history of febrile seizure were all noted. RESULTS: A total of 97 patients, 43 (44.3%) girls with a median age of 7.93 ± 4.05 years (2-16) and a median follow-up period of 20.65 ± 24.33 months (6-135) were included in the study. The frequency of febrile seizure in children with FMF was found as 13.4%, which is higher than the general population [p = 0.04, OR: 2.9 (95% CI: 1.0-8.5)]. The allele frequency of exon 2 mutations in MEFV genes was higher in the patients with febrile seizure (p = 0.03). Frequency of FMF related clinical findings (fever, abdominal pain, arthralgia/myalgia, arthritis, chest pain and erysipelas-like erythema) was similar between the two groups. However, frequency of headache was higher in the patients with febrile seizure (p = 0.014). CONCLUSION: The frequency of febrile seizure in children with FMF was found to be higher than the general population. Although this finding may be related to high fever during FMF attacks in individuals with genetic propensity of febrile seizure, it may also be a neurologic complication of FMF.

Pediatric Guillain-Barré syndrome: Indicators for a severe course.

OBJECTIVES: This study aims to retrospectively evaluate pediatric Guillain-Barré syndrome cases in a tertiary center in Istanbul, Turkey. MATERIALS AND METHODS: The data of 40 patients with Guillain-Barré syndrome who had been admitted to the Department of Pediatrics at the Istanbul University Medical Faculty between 2005 and 2011 were collected. Mann-Whitney U, Kruskal-Wallis, chi-square, and Fisher's exact tests were used for statistical analysis. RESULTS: Mean patient age was 5.4 ± 3.0 years; 20 out of 40 patients (50%) were female and 20 (50%) were male. Preceding infection was detected in 32 cases (80%). Six patients had speech impairment. Out of eight patients with respiratory distress (20%), five required respiratory support (12.5%) of which three of them had speech impairment as well. According to nerve conduction studies, 21 patients (52.5%) had acute inflammatory demyelinating polyradiculoneuropathy, 14 (35%) had acute motor axonal neuropathy, and five (12.5%) had acute motor-sensory axonal neuropathy. Thirty-three patients (82.5%) received intravenous immunglobulin, 3 (7.5%) underwent plasmapheresis and 4 (10%) received both. Time until recovery (P = 0.022) and time until aided (P = 0.036) and unaided (P = 0.027) walking were longer in patients with acute gastrointestinal infection than in those with upper respiratory tract infection (P < 0.05). Time until response to treatment (P = 0.001), time until aided (P = 0.001) and unaided (P = 0.002) walking, and time until complete recovery (P = 0.002) were longer in acute motor axonal neuropathy cases as compared to acute inflammatory demyelinating polyradiculoneuropathy cases. CONCLUSION: Recovery was longer with acute gastrointestinal infection and acute motor axonal neuropathy. Speech impairment could be a clinical clue for the need of mechanical ventilation.

The debate on the link between subclinical hypothyroidism and childhood migraine: is initial endocrinological evaluation necessary for children with migraine?

Subclinical hypothyroidism (SH) is characterized by mildly elevated thyroid stimulating hormone (TSH) levels with normal serum-free thyroxine (fT4). While the prevalence of SH is 2 % in pediatric population, it has been reported much higher in children with migraine headache. In this study, the presence of subclinical hypothyroidism and associated endocrinological abnormalities in children with migraine naïve to treatment was investigated. Children with migraine who were diagnosed in Pediatric Neurology Clinic based on the second edition of the International Classification of Headache Disorders and who did not receive any medication were recruited in this cross-sectional study. All patients were examined by the same pediatric endocrinologist and anthropometric measurements, systemic blood pressure, pubertal stages were recorded. Fasting serum levels of thyroid function tests, lipids, glucose and insulin were obtained. Ninety-eight children (55 female) with a mean age of 11.45 ± 3.1 years were evaluated. Of those, 39 were prepubertal and 59 were pubertal. Subclinical hypothyroidism (TSH ≥ 5.0 mIU/L with normal fT4) was detected in five patients (5.1 %); none had positive thyroid antibodies. Other conditions were obesity (n = 6), hirsutism (n = 4), short stature (n = 3), polycystic ovaries (PCO, n = 3), precocious puberty (n = 2) and gynecomastia (n = 1). Of five patients with SH, only one had obesity. Our results revealed that the prevalence of SH in children with migraine is not as high as previously reported. Since no significant endocrinologic disturbance was found in those children, we suggest that the initial endocrinological evaluation or screening for SH is unnecessary.

The role of parental, school, and peer factors in adolescent bullying involvement: results from the Turkish HBSC 2005/2006 study.

The aim of this study was to explore the relationships between involvement in bullying behaviors and school, family, and peer factors. Health Behavior in School Age Children survey questionnaire was used. Of the students surveyed, 20% were both bully and victim, 11% were bully, and 21% were victim. Being male, poor parental support, and poor monitoring by the father were found to be risk factors for being both bully and victim. Poor academic achievement, having peers at different ages, poor quality of friendship, poor communication with parents, and not being isolated by peers were found to be risk factors for being bully. Not liking school, feeling pressured by school work, poor quality of friendship, poor monitoring by the father, close bonding with mother, and poor status of the peer group were found to be risk factors for being victim. These findings highlight the importance that bullying intervention programs should include country-specific and culture-specific influences for success.

Preliminary anatomical and neurodevelopmental outcomes of intravitreal bevacizumab as adjunctive treatment for retinopathy of prematurity.

PURPOSE: To evaluate the two-year follow-up of patients with type 1 retinopathy of prematurity (ROP) who received intravitreal bevacizumab (IVB) as adjunctive treatment. MATERIALS AND METHODS: We conducted a longitudinal follow-up study of premature infants who received 0.625 mg IVB therapy in addition to standard laser photocoagulation therapy. For comparison of the ophthalmological and neurological assessment outcomes of these infants, a control group was formed with 13 birth weight- and gestational age-matched infants who were treated with laser therapy alone for type 1 ROP. The neurological status of the study group and the control group was examined systematically, and neurodevelopmental evaluation was assessed by the Bayley Scales of Infant Development (BSID-III). RESULTS: A total of 18 eyes of 13 infants were included in the study. Anatomical success was obtained in 14 eyes (78%) and retinal detachment was observed in 4 eyes (22%). At two years of age, no significant difference was found in terms of spherical or cylindrical refractive errors compared to the control group. In control group, 2/13 patients' and in study group, 3/13 patients' neurological examinations were abnormal. No significant difference was found in the mean cognitive, language or motor BSID-III test scores of the groups. CONCLUSIONS: IVB appears to be useful for advanced ROP when laser treatment is precluded or not sufficient for preventing the progression of ROP. This pilot study indicates that IVB seems to contribute no further complications to the complications already present due to prematurity.