The Value of Electroencephalogram (EEG) Findings in the Evaluation and Treatment Management of Pediatric Acute Liver Failure.

Background Pediatric acute liver failure (PALF) is still life-threatening and requires urgent care. The presence of encephalopathy is a clinical diagnosis, but it is more difficult to diagnose in children than in adults, and an electroencephalogram (EEG) can be invaluable. The role of EEG in managing the treatment of patients with PALF, other than the identification of encephalopathy, is unknown. This study aimed to investigate patients' EEGs, which may guide in choosing the most appropriate treatment in encephalopathy children. A further aim was to investigate a new score method, based on the laboratory results, which might indicate the presence of encephalopathy in cases with PALF. Methods Medical data of 33 PALF patients followed in our clinic were reviewed retrospectively. This study included 33 patients, whose EEG recording was taken on the first day of supportive treatment due to liver failure in the pediatric intensive care unit (PICU). The EEG findings were categorized into three classes: normal, epileptic and non-epileptic paroxysmal, and background encephalopathic patterns including widespread slowing and voltage suppression. Result This retrospective study included 13 male and 20 female patients with a mean age at presentation of 4.82±4.81 months whose EEG was performed on the first day of supportive therapy for liver failure in the PICU. The EEG findings were categorized into three groups: normal, epileptic and non-epileptic paroxysms, and encephalopathic patterns including diffuse background slowing and voltage suppression. Comparing EEG findings and treatments, we found that the normal EEG group responded well to liver-supporting therapy and the rate of plasmapheresis treatment was significantly higher in the diffuse slowing group. Patients with diffuse slowing of the EEG were 9.6 times more likely to receive plasmapheresis. We found that above a cut-off of ≥7.5 for the TAI (total bilirubin, albumin, and international normalized ratio (INR)) score used in our study, the risk of developing encephalopathy increased 14.4-fold. Conclusions In PALF, EEG findings can provide findings that will help clinicians in determining treatment selection and prognosis, as well as detecting epileptic focus and encephalopathy. The TAI score can be used to assess the risk of encephalopathy in cases of PALF, when it is challenging to identify encephalopathy or when an EEG is not possible.

Anxiety, depression, sleep disorders and quality of life in parents of children with first unprovoked seizure and epilepsy.

BACKGROUND: Parents of a child with neurological problems such as seizures and epilepsy experience significant mental distress. Little is known about the mental state of parents in such a stressful situation. This study aims to determine the prevalence of self-reported depression, anxiety, sleep disorders, and quality of life in parents of children with epilepsy and first unprovoked seizure. METHODS: This cross-sectional study was conducted among the parents of children diagnosed with first unprovoked seizure and epilepsy admitted to the Pediatric Neurology Department, Outpatient Unit of Inönü University Medical Faculty Hospital. Participants filled out a questionnaire investigating demographic variables, Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI), and 36- Item Short-Form Health Survey (SF-36). RESULTS: 113 parents participated in the study. Depression was found in 7%, anxiety in 14%, and sleep quality disorder in 33.3% of parents of children diagnosed with epilepsy on the basis of moderate or higher severity, while depression was found in 8.9%, anxiety in 14.3%, and sleep disorder in 21.4% of parents of children diagnosed with first unprovoked seizure. There was no statistically significant difference between the groups. Mothers were at higher risk for loss of physical function and social functionality. There was a positive correlation between BAI, BDI, and PSQI scores. Quality of life sub-dimension measured by SF-36 was associated with different levels of depression, anxiety, and sleep quality. CONCLUSION: Addressing parental psychiatric problems by professionals involved in the treatment of children with a history of seizures may have the potential to provide further support for the family and the care of patients.

Optic neuritis in Turkish children and adolescents: A multicenter retrospective study.

BACKGROUND: Various etiologies may underlie optic neuritis, including autoantibody-mediated disorders described in the last decade. We re-examined demographic, clinical, laboratory features and prognostic factors in pediatric patients with autoimmune optic neuritis according to current knowledge. METHODS: Cases of pediatric ON from 27 centers in Türkiye diagnosed between 2009 and 2022 were included for retrospective evaluation. RESULTS: The study included 279 patients, 174 females and 105 males, with a female-to-male ratio of 1.65. The average age at onset was 12.8 ± 3.4 years, and mean follow-up, 2.1 years (range: 1-12.1 years). Patients <10 years old were grouped as "prepubertal" and those ≥10 years old as "others". The diagnoses made at the end of follow-up were multiple sclerosis associated optic neuritis (n = 90, 32.3 %), single isolated optic neuritis (n = 86, 31 %), clinically isolated syndrome (n = 41, 14.7 %), myelin oligodendrocyte glycoprotein antibody associated optic neuritis (n = 22, 7.9 %), and relapsing isolated optic neuritis (n = 18, 6.5 %). Predominant diagnoses were myelin oligodendrocyte glycoprotein antibody associated optic neuritis and acute disseminated encephalomyelitis associated optic neuritis in the prepubertal group and multiple sclerosis associated optic neuritis in the older group. Recurrences were observed in 67 (24 %) patients, including 28 with multiple sclerosis associated optic neuritis, 18 with relapsing isolated optic neuritis, 11 with myelin oligodendrocyte glycoprotein antibody associated optic neuritis, 8 with aquaporin-4 antibody related optic neuritis, and 2 with chronic relapsing inflammatory optic neuropathy. Recurrences were more common among female patients. Findings supporting the diagnosis of multiple sclerosis included age of onset ≥ 10 years (OR=1.24, p = 0.027), the presence of cranial MRI lesions (OR=26.92, p<0.001), and oligoclonal bands (OR=9.7, p = 0.001). Treatment in the acute phase consisted of intravenous pulse methylprednisolone (n = 46, 16.5 %), pulse methylprednisolone with an oral taper (n = 212, 76 %), and combinations of pulse methylprednisolone, plasmapheresis, or intravenous immunoglobulin (n = 21, 7.5 %). Outcome at 12 months was satisfactory, with 247 out of 279 patients (88.5 %) demonstrating complete recovery. Thirty-two patients exhibited incomplete recovery and further combination treatments were applied. Specifically, patients with relapsing isolated optic neuritis and aquaporin-4 antibody related optic neuritis displayed a less favorable prognosis. CONCLUSION: Our results suggest optic neuritis is frequently bilateral in prepubertal and unilateral in peri­ or postpubertal patients. Age of onset 10 or older, presence of oligoclonal bands, and brain MRI findings reliably predict the development of multiple sclerosis. The risk of developing multiple sclerosis increases mostly during the second and third years of follow-up. Relapsing isolated optic neuritis remains a separate group where the pathogenesis and outcome remain unclear. Investigation of predisposing and diagnostic biomarkers and long follow-up could help to define this group.

Sleep quality and depression in mothers of children with epilepsy and its relation to their children's sleep.

OBJECTIVE: This study aimed to evaluate the relationship between sleep disturbances in children with epilepsy (CWE) and maternal sleep quality and depression severity. METHODS: A Cross-sectional study was conducted in pediatric sleep disturbances using questionnaires on mother-reported sleep of CWE [Children's Sleep Habits Questionnaire (CSHQ)], maternal sleep quality [Pittsburgh Sleep Quality Index (PSQI)], and maternal depression status [Self-Rating Depression Scale (SDS)]. 114 dyads consisting of CWE and their mothers were included in this study. RESULTS: Over three-quarters (78.9 %) of mothers reported poor sleep quality (total PSQI score ≥ 5), and nearly a third (29.8 %) met clinical criteria for moderate or severe depression levels. The mothers' total PSQI scores were between 5.93 ±â€¯2.44 (range: 2-16 points). The most affected PSQI subcomponents were sleep latency (AUC = 0.826p < 0.001) and daytime dysfunction (AUC = 0.800p < 0.001). The majority of children (88.6 %) were stated by their mothers to have sleep-related problems. The total CSHQ scores of the children were between 49.06 ±â€¯9.20 (range: 33-86 points). The most affected CSHQ subcomponents were detected sleep anxiety (AUC = 0.856, p < 0.001), bedtime resistance (AUC = 0.818, p < 0.001) and daytime sleepiness (AUC = 0.807, p < 0.001). There was a statistically significant positive correlation between maternal sleep quality and depression severity (rho = 0.842; p < 0.001). A statistically significant positive moderate correlation was detected between sleep problems in CWE and maternal sleep quality and depression severity (rho = 0.406; p < 0.001, rho = 0.399; p < 0.001, respectively). As a result of multiple stepwise logistic regression analysis, the presence of seizures during sleep and generalized epileptiform discharges on electroencephalography were associated risk factors with poor maternal sleep quality (OR:6.6, p = 0.014; OR:11.5, p = 0.018, respectively). A borderline insignificant relationship was observed between a less than 50 % decrease in seizure frequency and the poor maternal sleep quality (OR:20.59p = 0.059). Seizures during sleep was associated risk factor with children's sleep disturbances (OR:7.2, p = 0.02). CONCLUSIONS: Sleep problems in CWE may lead to negative consequences such as sleep quality and/or depression in mothers. Interventions planned to correct sleep disturbances in mothers suggest that children's sleep problems should be optimally managed.

Shared Biological Pathways and Processes in Patients with Intellectual Disability: A Multicenter Study.

BACKGROUND: Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses. METHODS: In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. RESULTS: Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage-gated ion channel activity/voltage-gated channel activity, respectively. CONCLUSION: Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.

Re-examining the characteristics of pediatric multiple sclerosis in the era of antibody-associated demyelinating syndromes.

BACKGROUND: The discovery of anti-myelin oligodendrocyte glycoprotein (MOG)-IgG and anti-aquaporin 4 (AQP4)-IgG and the observation on certain patients previously diagnosed with multiple sclerosis (MS) actually have an antibody-mediated disease mandated re-evaluation of pediatric MS series. AIM: To describe the characteristics of recent pediatric MS cases by age groups and compare with the cohort established before 2015. METHOD: Data of pediatric MS patients diagnosed between 2015 and 2021 were collected from 44 pediatric neurology centers across Türkiye. Clinical and paraclinical features were compared between patients with disease onset before 12 years (earlier onset) and ≥12 years (later onset) as well as between our current (2015-2021) and previous (<2015) cohorts. RESULTS: A total of 634 children (456 girls) were enrolled, 89 (14%) were of earlier onset. The earlier-onset group had lower female/male ratio, more frequent initial diagnosis of acute disseminated encephalomyelitis (ADEM), more frequent brainstem symptoms, longer interval between the first two attacks, less frequent spinal cord involvement on magnetic resonance imaging (MRI), and lower prevalence of cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCBs). The earlier-onset group was less likely to respond to initial disease-modifying treatments. Compared to our previous cohort, the current series had fewer patients with onset <12 years, initial presentation with ADEM-like features, brainstem or cerebellar symptoms, seizures, and spinal lesions on MRI. The female/male ratio, the frequency of sensorial symptoms, and CSF-restricted OCBs were higher than reported in our previous cohort. CONCLUSION: Pediatric MS starting before 12 years was less common than reported previously, likely due to exclusion of patients with antibody-mediated diseases. The results underline the importance of antibody testing and indicate pediatric MS may be a more homogeneous disorder and more similar to adult-onset MS than previously thought.

High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases.

Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms. We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two per cent of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations. This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%). We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialized bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity.

Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in TUBGCP2 encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans.

Acute Ataxia in Childhood: Clinical Presentation, Etiology, and Prognosis of Single-Center Experience.

BACKGROUND: Acute ataxia is a common reason for presentation to the pediatric emergency department and the pediatric neurology clinic in childhood. Its incidence is between 1/100,000 and 1/500,000. Its most common reason is infections. OBJECTIVE: The aim of this study was to examine the clinical presentation, etiological factors, and prognosis of patients presenting to our regional tertiary pediatric neurology clinic with a diagnosis of acute ataxia. METHODS: An evaluation was made of patients younger than 18 years diagnosed with acute ataxia in our tertiary pediatric neurology clinic between 2009 and 2016. RESULTS: Thirty-nine children were included in the analysis. Sex, age, diagnoses, treatment options, and clinical and radiological findings were evaluated. Acute postinfectious cerebellar ataxia was the most common diagnosis (21/39 [51.2%]). No agent could be identified in viral serological examination in 34 patients (87.2%). Rotavirus was identified in 2 (10.5%) of the acute postinfectious cerebellar ataxia cases, and varicella-zoster virus, herpes simplex virus, and hepatitis A positivities were each identified in 1 case. In 20 (51.2%) of 39 patients, varying treatments were applied according to the primary etiology. CONCLUSIONS: Acute ataxia is a significant neurological problem in childhood. In this study, Rotavirus was the most common infectious agent. It may be related to vaccination. This study can be considered of value as the most comprehensive study conducted to date on this subject in the eastern region of Turkey.

A Novel SCN1A Mutation: A Case Report.

INTRODUCTION: Dravet syndrome (DS) is characterized by severe infant-onset myoclonic epilepsy with delayed psychomotor development and increased premature mortality. The seizures triggered by fire have been gradually decreased over time, and finally they start to occur without fever at the age of 2-3 years. Along with its initiation of myoclonic seizures in the early period, other types such as atypical absence, versive, and complex partial seizures occur between 1 and 4 years of age. CASE REPORT: A 3-year-old male patient with refractory epilepsy and neuromotor developmental retardation was admitted to our clinic. The patient initially had seizures in the afebrile period, when he was 4 months old, and he had a total of five seizures by the age of 1 year. Neuromotor developmental retardation developed over time in patients with normal neuromotor development in the early stages of his life. His cranial magnetic resonance imaging and metabolic test findings were normal. The SCN1A mutation was investigated, and a new variant mutation of SCN1A, homozygous (p.Y1599Ffs*19-c.4796delA) was detected. The patient's family was also screened and this new mutation was detected as heterozygous mutation. The patient had hepatomegaly. The etiology of hepatomegaly was investigated but no cause was found. CONCLUSION: Variant mutations of DS should be kept in mind and diagnostic genetic testing should be done in patients with neuromotor developmental retardation starting with afebrile seizures. In DS, hepatomegaly is not an expected condition. Maybe this new mutation might have caused hepatomegaly.

Clinical, electrophysiological findings and evaluation of prognosis of patients with Guillain-Barré syndrome.

Kiliç B, Güngör S, Özgör B. Clinical, electrophysiological findings and evaluation of prognosis of patients with Guillain-Barré syndrome. Turk J Pediatr 2019; 61: 200-208. Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy characterized by frequent rapid progressive, ascending, symmetric weakness and areflexia. We aimed to evaluate the etiology, clinical and electrophysiological findings with treatment and prognosis of the patients with GBS in our clinic. Patients who were diagnosed with GBS in our clinic between 2009 and 2017 were evaluated retrospectively. The study included 20 female and 25 male patients. The most frequent symptom was the absence of walking (95.5%). All of the patients had muscle weakness on examination; in addition to that hyperesthesia (31%), autonomic symptoms (13.3%), sensory loss (11.1%), ataxia (11.1%), bilateral facial nerve palsy (6.6%), oculomotor nerve palsy (2.2%), and multiple cranial nerve involvement (2.2%) were the other detected findings. Ventilation support was required in 6 cases (13.3%). Acute motor axonal neuropathy (AMAN) was found in 20 patients (44.5%), acute inflammatory demyelinating polyradiculoneuropathy (AIDP) was found in 24 patients (53.3%), and acute motor and sensory axonal neuropathy (AMSAN) was only present in 1 patient (2.2%). Intravenous immunoglobulin (IVIG) was administered to 33 of the patients (73.3%). The mean hospital stay was 8.4±3.5 (2-17 days), and the relationship between the duration of hospital stay and the treatment given was statistically significant (p = 0.001). Complete remission was observed in 37 patients (82.3%) and the remaining 5 children (11.1%) experienced incomplete recovery. Three patients (6.7%) died of treatment-resistant hypotension, arrhythmia and severe pulmonary infection. The short duration of neurological deficit following infection, clinical stage of application, need for mechanical ventilation, dysautonomia, cranial nerve involvement, and current subtype were the negative prognostic factors. Although GBS is a self-limiting disease, early diagnosis and treatment are very important to reduce hospital stay with morbidity and mortality. Patients expected to be at high risk should be monitored closely.

Two siblings with metachromatic leukodystrophy caused by a novel identified homozygous mutation in the ARSA gene.

Background Metachromatic leukodystrophy (MLD) is an autosomal recessively (AR) inherited disease caused by the deficiency of the enzyme arylsulfatase A (ARSA). Although MLD is the most common form of hereditary leukoencephalopathy, it is still very rare. More than 200 gene mutations have been identified in the ARSA gene. The most frequently identified mutation is the one located on chromosome 22q13.33. In the present study, new mutations are reported in two siblings of different ages and with different clinical presentations. Case presentation A 9-year-old male patient, suffering from ataxia, attention deficit and perceptual difficulties, was first seen at the age of 7. While the findings of neurological examination and neuroradiological evaluation suggested MLD, the ARSA enzyme levels were analyzed and found to be at a lower limit. Genetic analysis revealed variant homozygous mutations of the ARSA gene at p.N352S/c.1055T>C in exon 6 and at p.E331K/c.991G>A in exon 7. In the genetic analysis of his three siblings and parents, a variant heterozygous mutation of the ARSA gene was detected at p.N352S/c.1055T>C in exon 6 and at p.E331K/c.991G>A in exon 7. Conclusions MLD is a rare disease; however, it is likely to find different variant forms in our population, in which the frequency of consanguineous marriages is high. Genetic diagnosis is important in symptomatic cases with enzyme levels within the normal ranges.

Prevalence of celiac disease in parents of preterm or low birthweight newborns.

AIM: Celiac disease (CD) may present with atypical symptoms, including poor pregnancy outcomes, such as preterm and low birthweight (LBW) deliveries, thus we aimed to investigate the frequency of CD in mothers and fathers of preterm or LBW newborns. MATERIALS AND METHODS: In this study, 316 parents of 164 preterm or LBW newborns and 246 parents of 123 healthy newborns were included. CD was screened using tissue transglutaminase immunoglobulin A. Endoscopic duodenal biopsy was provided in the seropositive cases. RESULTS: Positive tissue transglutaminase immunoglobulin A was found in six (1.1%; 1/94) individuals (three mothers and three fathers); five were from the study group (1.6%; 1/63) and one was from the control group (0.4%; 1/246). CD prevalence in mothers, fathers and parents of preterm newborns was 1/57 (1.8%), 1/57 (1.8%) and 1/29 (3.5%), respectively. In the LBW group, seropositivity in fathers was 1/50 (2%) with no seropositive mothers. Biopsy-proven CD was found in 1/159 mothers (0.6%) and 1/79 fathers (1.3%). Mean birthweights of the newborns of seropositive mothers and fathers were 214 g (P < 0.05) and 320 g lower than those of seronegative ones, respectively. However, in logistic regression analysis it was found that seropositivity of mothers or fathers did not affect gestational age or birthweight of the newborns. CONCLUSION: Because the prevalence of CD in parents of preterm or LBW newborns is not statistically higher than the healthy population, routine CD screening in that group cannot be recommended at the time being. For more definite conclusions further studies are needed.

Coeliac disease and reproductive disorders.

Reproductive problems, such as delayed menarche, amenorrhea, early menopause, infertility, impotence, hypogonadism, recurrent abortions, and low-birth-weight or preterm deliveries, are now known to be among the atypical symptoms of coeliac disease (CD). The pathogenesis of reproductive disorders in CD is unclear, but some hypotheses have been suggested, including autoimmunity and macro- and/or micronutrient deficiency. Recent investigations which have focused on tissue transglutaminase are promising with respect to the clarification of the mechanism of infertility and poor pregnancy outcomes in CD. In this review, the effects of CD on male and female reproductive disorders and pregnancy outcomes are discussed and the need for CD screening in the case of reproductive problems is emphasized.