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.

Role of serostatus in pediatric neuromyelitis optica spectrum disorders: A nationwide multicentric study.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are immune-mediated inflammatory disorders of the central nervous system (CNS) mostly presenting as optic neuritis and acute myelitis. NMOSD can be associated with seropositivity for aquaporin 4 antibody (AQP4 IgG), myelin oligodendrocyte glycoprotein antibody (MOG IgG), or can be seronegative for both. In this study, we retrospectively examined our seropositive and seronegative pediatric NMOSD patients. METHOD: Data were collected from all participating centres nationwide. Patients diagnosed with NMOSD were divided into three subgroups according to serology: AQP4 IgG NMOSD, MOG IgG NMOSD, and double seronegative (DN) NMOSD. Patients with at least six months of follow-up were compared statistically. RESULTS: The study included 45 patients, 29 female and 16 male (ratio:1.8), mean age 15.16 ± 4.93 (range 5.5-27) years. Age at onset, clinical manifestations, and cerebrospinal fluid findings were similar between AQP4 IgG NMOSD (n = 17), MOG IgG NMOSD (n = 10), and DN NMOSD (n = 18) groups. A polyphasic course was more frequent in the AQP4 IgG and MOG IgG NMOSD groups than DN NMOSD (p = 0.007). The annualized relapse rate and rate of disability were similar between groups. Most common types of disability were related to optic pathway and spinal cord involvement. Rituximab in AQP4 IgG NMOSD, intravenous immunoglobulin in MOG IgG NMOSD, and azathioprine in DN NMOSD were usually preferred for maintenance treatment. CONCLUSION: In our series with a considerable number of double seronegatives, the three major serological groups of NMOSD were indistinguishable based on clinical and laboratory findings at initial presentation. Their outcome is similar in terms of disability, but seropositive patients should be more closely followed-up for relapses.

Postnatal surgery for myelomeningocele in neonates: neurodevelopmental outcomes.

BACKGROUND: The study aims to evaluate the neurodevelopmental outcomes of neonates with myelomeningocele (MMC) operated in the postnatal period. METHODS: This is a prospective follow-up study in a tertiary neonatal intensive care unit. Neurodevelopmental outcomes of term neonates operated for MMC and healthy term newborns were compared with the Bayley Scales of Infant and Toddler Development -Third Edition (BSID III) at 12-18 months. RESULTS: A total of 57 cases were included in the study (patient group = 27; control group = 30). Demographic data between the groups were similar. Cognitive, linguistic, and motor composite scores of the patient group were lower than those of the control group (p < 0.001). In the patient group, those who underwent ventriculoperitoneal shunt had lower cognitive, language and motor scores than those without shunt (p < 0.05). The cognitive, linguistic, and motor composite scores in the patient group who underwent surgery before 72 h were better than those who underwent surgery after 72 h. DISCUSSION: In our study, it was found that the neurodevelopmental prognosis of MMC cases requiring ventriculoperitoneal shunt in the postnatal period was significantly worse than those without shunt. It is the first study in which the neurodevelopment of patients with MMC who were operated in the postnatal period was evaluated with BSID III evaluated and delays in all areas were shown in cases with MMC compared to normal cases. Better neurodevelopmental outcomes in patients operated in the first 72 h suggest that early surgery will improve neurodevelopmental outcomes in patients with MMC.

A female case of 5,10-methenyltetrahydrofolate synthetase deficiency with novel neuro-imaging abnormalities.

BACKGROUND: Folate metabolism disorders can affect various organ systems, including the nervous system. 5,10-methenyltetrahydrofolate synthetase deficiency is a rare cerebral folate deficiency in which MTHFS activity is disrupted with low-normal cerebrospinal fluid (CSF) 5,10-methenyltetrahydrofolate levels, while peripheral folate levels are normal. CASE REPORT: We present here a female patient with developmental delay, microcephaly, hypotonia, nystagmus, and seizure in which a distinct brain MRI and CT showed restricted diffusion in the bilateral parietal and occipital lobes, and calcifications of the bilateral putamen, globus pallidus, and caudate nucleus, and the bilateral parietal and occipital lobes. Laboratory tests revealed macrocytic anemia, increased homocysteine, low-normal CSF 5,10-methenyltetrahydrofolate, and low CSF folate, but normal serum vitamin B12 and folate levels. A whole exome sequencing analysis verified the diagnosis of 5,10-methenyltetrahydrofolate synthetase deficiency. CONCLUSIONS: We have added novel knowledge which is nystagmus and hypotonia in the clinical findings, the involvement and restriction of bilateral putamen, globus pallidus, parietal and occipital lobes, and calcification of the bilateral putamen, globus pallidus, caudate nucleus, and parietal and occipital lobes in neuroimaging images and also low CSF folate in the metabolic investigation with the patient in 5,10-methenyltetrahydrofolate synthetase deficiency.

The effectiveness and tolerability of clobazam in the pediatric population: Adjunctive therapy and monotherapy in a large-cohort multicenter study.

OBJECTIVE: To evaluate the effectiveness and tolerability of clobazam therapy in the pediatric population in terms of seizure semiology, epileptic syndromes, and etiological subgroups. METHODS: A retrospective cohort study was conducted consisting of 1710 epileptic children from eight centers in seven geographic regions of Turkey. The initial efficacy of clobazam therapy was evaluated after three months of treatment. The long-term effectiveness of the drug, overall seizure outcomes, and overall therapeutic outcomes were evaluated during 12 months of therapy. RESULTS: Analysis of initial efficacy after the first three months of clobazam therapy showed that 320 (18.7 %) patients were seizure-free, 683 (39.9 %) had > 50 % seizure reductions, and 297 (17.4 %) had < 50 % seizure reductions. A positive response (seizure-free and >50 % seizure reduction) was determined for focal-onset (62.3 %) seizures, epileptic spasms (61.5 %), and generalized onset seisures (57.4). The highest positive response rate among the epileptic syndromes was for self-limited epilepsy with centrotemporal spikes (SeLECTS). The highest negative response rate was for developmental and/or epileptic encephalopathies (DEEs). Magnetic resonance imaging (MRI) revealed a structural etiological diagnosis in 25.8 % of the cohort. A higher positive response rate was observed at MRI in patients with sequelae lesions than in those with congenital lesions. The seizure recurrence rate was higher in the patient group with epilepsy with genetic and metabolic causes, in individuals with more than one seizure type, and in those using three or more antiseizure drugs. CONCLUSIONS: This cohort study provides additional evidence that clobazam is an effective and well-tolerable drug with a high seizure-free rate (18.7 %), a significant seizure reduction rate (57.3 %), and with excellent overall therapeutic outcomes with a low seizure relapse rate and considerable reversible benefits in the pediatric population.

Evaluation of micronutrient levels in children with cerebral palsy.

BACKGROUND: Many studies evaluating the nutritional status of children with cerebral palsy (CP) have focused on energy requirements and protein intake. The present work aimed to assess nutritional status and micronutrient levels of children with (CP). METHODS: This multicenter, cross-sectional and observational study was conducted in 10 different cities in Turkey. Data were available for 398 participants. Anthropometric measurements, feeding mode, nutritional status, and micronutrient levels were evaluated. RESULTS: The study was conducted with 398 participants (303 patients and 95 healthy controls). Statistical analysis showed that according to the Gomez Classification, weight-for-age (WFA) revealed malnutrition in 92.6% of children with CP, based on Centers for Disease Control and Prevention percentiles. Measurements of micronutrient levels showed that zinc levels were low in patients, whereas vitamin A levels were low in controls. Phosphorous and manganese levels were significantly lower in malnourished children than in typical children. The results revealed that children consuming enteral nutrition solutions had higher selenium and lower zinc levels than non-consumers. CONCLUSIONS: Malnutrition is not only a protein- or calorie-based problem; micronutrient deficiencies might cause severe health problems. Children with chronic neurological disabilities must be carefully evaluated for these issues. Therefore, nutritional interventions should be adapted to nutrition.

Clinical profile and long-term outcome of the first seizures in children.

BACKGROUND: Seizures are one of the most common causes of pediatric admissions to hospitals in children. This study aims to identify the clinical profile and outcome of first seizures in children. METHODS: Children who presented to the pediatric neurology outpatient clinic and pediatric emergency service with a first-time seizure and aged one month through 18 years old were enrolled to the study. At the time of the study, enrolled children were categorized into three study groups according to seizure characteristics: febrile seizure, nonfebrile-provoked seizure and, unprovoked seizure. RESULTS: The study group consisted of 138 children. Of the 138 patients, 60 (43%) had febrile first seizures, 23 (17%) had nonfebrile-provoked first seizures, and 55 (40%) had unprovoked first seizures. The patients did not experience the recurrence of a seizure by the treatment of underlying cause at the eighteenth month and the eighth year follow-up in the nonfebrile-provoked seizure group. Among the children admitted for unprovoked first seizures, 33 (60%) patients had seizure recurrence during 18 month follow-up and 36 (82%) patients had seizure recurrence during eight year follow-up. Seizure recurrence rate was statistically higher in patients with abnormal EEG and cranial MRI findings in the unprovoked seizure group (p < .05). CONCLUSIONS: The patients with provoked first seizure did not develop epilepsy during eight year follow-up. However, 36 patients with unprovoked seizures were diagnosed with epilepsy during eight year follow-up. It is essential to determine the causes of the seizures and treat the condition.

An Unexpected Cause of Ptosis: 22q11.2 Duplication Syndrome.

The chromosome 22q11.2 region is highly susceptible to both microdeletions and microduplications that have been known to be responsible for multiple congenital anomaly disorders. We describe a patient of 22q11.2 duplication syndrome presenting with bilateral ptosis who has normal psychomotor development. Cranial magnetic resonance imaging and electromyography with repetitive nerve stimulation were normal. Chromosome microarray analysis was performed, and the patient was found to have a de novo 2.8 Mb duplication at 22q11.21. To our knowledge, bilateral ptosis and normal psychomotor development with 22q11.2 duplication syndrome has not been described. The 22q11.2 duplication syndrome should be considered in the differential diagnosis of ptosis. This case report contributes to an expanding clinical spectrum of patients with 22q11.2 duplication syndrome.

Treatment Outcomes of Pediatric Status Epilepticus in a Tertiary Pediatric Intensive Care Unit.

OBJECTIVE: Status epilepticus is associated with high rates of morbidity and mortality; thus, early diagnosis and proper treatment are crucial. We aimed to study the etiology, clinical features, and treatment among pediatric patients with convulsive status epilepticus. METHODS: The medical records of 100 patients were retrospectively obtained from pediatric intensive care unit. Etiology, clinical features, and treatment were interpreted by using Fisher exact test, χ2 test, and Spearman ρ correlation coefficient. RESULTS: Seizures had stopped with the first-, second-, and third-line treatment in 29%, 36%, and 35% of the patients, respectively. Only phenytoin treatment was efficient; it has 32.3% rate in second-line treatment. Whereas mortality rate was 10%, morbidity rate was 14% during the follow-up. Epilepsy, hemiparesis, spastic tetraparesis, and mental retardation developed. Mortality was significantly much more in the patients with refractory seizure and cerebral palsy. Development of mental retardation was much higher in the male sex. CONCLUSIONS: Phenytoin is still one of the most efficient antiepileptic drugs. If the duration of status epilepticus can be shortened by prompt treatment, neurological complications may be prevented.

Acute flaccid myelitis outbreak through 2016-2018: A multicenter experience from Turkey.

AIM: We aim to describe the demographic characteristics, etiology, neurophysiology, imaging findings, treatment, prognosis, and prognostic factors of acute flaccid myelitis. METHODS: The clinical data, laboratory test and, magnetic resonance imaging (MRI) results of pediatric patients diagnosed with acute flaccid myelitis according to the Centers for Disease Control criteria between August 1, 2016, and December 31, 2018, from 13 centers in Turkey were reviewed. RESULTS: Of the 34 cases identified, 31 were confirmed (91.2%). Eighteen patients (55.9%) were boys. The median patient age was 4 years (interquartile range 2.5-6.9 years). Most of the patients were admitted in 2018 (n = 27). A preceding history of a febrile illness was reported in all patients, with a median of 4 days (interquartile range 3-7 days) before symptom onset. Thirty-one patients had T2 hyperintensity on spinal MRI, and 18 patients had cerebrospinal fluid pleocytosis. The most common infectious agents were entero/rhinoviruses (n = 5) in respiratory specimens. All patients except one received immunotherapy either alone or in combination. Among 27 patients with follow-up data 24 had persistent weakness. Involvement of four limbs together with an abnormal brain MRI at onset were associated with a poor prognosis. CONCLUSION: The number of patients with acute flaccid myelitis increased since 2012, spiking with every 2-year interval, largely in the pediatric population. The median age decreases with every outbreak. Clinicians should be aware of the clinical picture for early collection of specimens and early start of rehabilitation programs. Further studies are needed to better characterize the etiology, pathogenesis, risk factors, and treatment of this rare condition.

A Case with Neonatal-onset Type 2 Neuronal Ceroid Lipofuscinosis: A Novel Mutation.

Neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder that causes progressive neurodegenerative disease as a result of storage in neurons and other cells. Late infantile type (NCL Type 2) of NCL, which is the most common neurodegenerative disease in childhood, is characterised by a homozygous mutation in the tripeptidyl peptidase-1 (TPP-1) gene. A male infant was referred to our neonatal intensive care unit (NICU) on 26th day of life with a diagnosis of metabolic disease. He was intubated. He was hypotonic and newborn reflexes were not present. Cranial magnetic resonance (MR) imaging revealed severe atrophy and delayed myelination of cerebellum and cerebral hemispheres. A novel homozygous pathological mutation was detected in exon 9 of the TPP-1 gene. With this case, it should be kept in mind that NCL may rarely start early in neonatal period and should be suspected in newborns with cerebral and cerebellar atrophy for early diagnosis. Key Words: Hypotonia, Lysosomal storage diseases, Metabolic disease, Neuronal ceroid lipofuscinosis, Newborn.

Variant ataxia-telangiectasia in a child presenting with laryngeal dystonia.

BACKGROUND: Dystonia is a common hyperkinetic movement disorder in children; however, making an early and definitive diagnosis of dystonia can sometimes be challenging for clinicians. CASE: Herein, we report a case of a 16 years-old girl presenting with laryngeal dystonia due to compound heterozygosity of a known pathogenic and a novel variant in the ATM gene. Serum alpha-fetoprotein level was elevated. Serum IgG, IgA, IgM and IgE levels were within normal range. Treatment with L-DOPA had no benefit. Her symptoms were dramatically improved by localized botulinum toxin injections. CONCLUSION: Mutations in the ATM gene show a wide phenotypic spectrum from severe classical early-onset ataxia-telangiectasia (A-T) to late-onset milder variant A-T. Our findings highlight the importance of recognizing laryngeal dystonia as one of the clinical signs of A-T.

Pediatric case of persistent hiccups associated with hypertrophic olivary degeneration.

BACKGROUND: Hypertrophic olivary degeneration (HOD) is a rare degenerative disorder that is thought to occur subsequent to a disruption of the dentate-rubro-olivary pathway. CASE: We report a pediatric case of unilateral HOD presented with persistent hiccups and palatal tremor. Radiological examination of diaphragm was normal considering ultrasound and chest x-ray. On T2WI (weighted images) and Fluid Attenuated Inversion Recovery (FLAIR) images, hyperintense enlargement of the right inferior olivary nucleus was seen. No abnormal enhancement was detected on post-contrast scans and no evidence of restricted diffusion was seen. Susceptibility weighted imaging (SWI) sequences revealed a chronic hemorrhage involving the medulla oblongata and cerebellum. Cranial magnetic resonance imaging (MRI) findings were consistent with unilateral HOD. Palatal tremor and dentate-rubral tremor are frequent presentation of HOD, however to our knowledge persistent hiccups had not yet been reported in children with HOD. CONCLUSION: We highlight a pediatric case of unilateral HOD, which presented with persistent hiccups. Awareness of clinical and radiological findings of HOD is important to avoid misinterpretation as a mass lesion, an ischemic event, or a demyelinating disease and provide adequate management.

Identification of PCDH19 Gene Mutations/Deletions in Patients with Early Onset Epilepsy.

BACKGROUND AND AIMS: PCDH19 gene, which encodes protocadherin 19, is associated with epilepsy and intellectual disability, mainly in affected females. The clinical manifestations are heterogeneous and the main features include early onset seizure, generalized or focal seizures sensitive to fever, and brief seizures occurring in clusters. The disorders exhibit a unique and unusual X-linked pattern of expression. We aimed to investigate PCDH19 mutations/deletions in patients with epilepsy and describe the clinical/molecular features. METHODS: PCDH19 gene was analyzed in 35 Turkish female patients from 34 families with early-onset epilepsy via direct sequencing and multiplex ligation-dependent probe amplification analysis. Additionally, array comparative genomic hybridization analysis was performed in patients with whole gene deletion. RESULTS: We identified 2 different heterozygous mutations in 2 unrelated probands (5. 7%) which were located in exon 1. Additionally, whole gene deletions were detected in dizygotic twin girls (5. 7%), who had distinct clinical features and the deletion was inherited from the unaffected father. The second twin suffered more severe clinical manifestations including autistic features, behavioral problems, mild-moderate mental retardation and seizures, which were under control with multidrug regimen when compared with the first twin. CONCLUSION: PCDH19 is a major causative gene in patients with epilepsy and further data is required to gain a better understanding of phenotype-genotype correlation. In addition to gene sequencing, deletion/duplication analysis will improve the molecular diagnosis in patients with clinical findings.

A case of spastic paraplegia-15 with a novel pathogenic variant in ZFYVE26 gene.

Hereditary spastic paraplegia (HSP) is a group of rare neurodegenerative disorder with genetic and clinical heterogeneity. It has autosomal dominant (AD), autosomal recessive (AR) and X-linked forms. HSPs are clinically classified into 'pure' and 'complicated' (complex) forms. SPG11 (KIAA1840) and SPG15 (ZFYVE26) are the most common ARHSPs with thin corpus callosum (TCC). They typically present with early cognitive impairment in childhood followed by gait impairment and spasticity in the second and third decades of life. Here, we present a patient girl, born to a couple who were first cousins, was admitted to the pediatric neurology outpatient clinic at 14 years of age because of walking with help, dysarthria and forgetfulness. Her examination revealed a motor mental retardation, bilateral leg spasticity, increased deep tendon reflexes in lower limbs, bilateral pigmentary retinopathy; TCC and white matter hyperintensities on brain MRI, sensorimotor axonal polyneuropathy findings in lower limbs on electromyography. Based on the clinical features and the imaging studies, the diagnosis of HSP was suspected. Targeted next generation sequencing (NGS) was performed using Inherited NGS Panel that consists of 579 gene associated with Mendelian disorders. Analysis of the patient revealed a c.6398_6401delGGGA(p.Arg2133Asnfs*15)(Exon35) homozygous novel change in ZFYVE26 gene. Genotype-phenotype correlation of HSP is complicated due to heterogeneity. The clinical similarity of HSP types increases the importance of genetic diagnosis. There are few reports about pathogenic variants in ZFYVE26 gene in the literature. This case report is one of the few studies that revealed a novel pathogenic variant in ZFYVE26 gene using NGS.

Impact of next-generation sequencing panels in the evaluation of limb-girdle muscular dystrophies.

INTRODUCTION: Limb-girdle muscular dystrophy (LGMD) is the fourth most common muscular dystrophy, with progressive proximal muscle weakness. However, a large number of neuromuscular conditions are similarly presented. Because of this, the use of high-throughput methods such as next-generation sequencing (NGS) is important in the evaluation of LGMD. METHODS: In this report, we applied a custom target capture-based NGS panel covering 31 LGMD-associated genes (MYOT, LMNA, CAV3, DES, DNAJB6, FLNC, CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TCAP, TRIM32, FRKP, TTN, POMT1, ANO5, FKTN, POMT2, POMGnT1, DAG1, PLEC, GAA, GMPPB, HNRNPDL, TNPO3, LIMS2, POMK, TRAPPC11, ISPD) in 74 patients suspected of LGMD. RESULTS: In 25 (33.8%) out of 74 patients analyzed, one or more pathogenic/likely pathogenic variants in 13 different genes were detected. Six of the patients had the variants that were not found in databases and literature; thus, they were interpreted as novel pathogenic variants. DISCUSSION: The diagnosis rate achieved (33.8%) is consistent with previous literature reports and underlines the efficiency and importance of NGS technology in the molecular genetic evaluation of LGMD.

An Option to Consider for Alternating Hemiplegia of Childhood: Aripiprazole.

Alternating hemiplegia of childhood (AHC) is an infrequent neurological disorder characterized by recurrent transient attacks of hemiplegia that last minutes to days and impress either side of the body, dystonic or tonic attacks, and nystagmus. Cognitive or neurological deficits with progressive course are another findings. Epileptic seizures may occur in some patients. We report the medical treatment in a case of AHC in a-12-year-old male patient with convulsions. The patient did not respond to available therapies for AHC, except for aripiprazole. After the initiation of aripiprazole therapy, duration and frequency of hemiplegia episodes were decreased. Also, he is currently seizure-free with topiramate treatment for 3 months. On follow-up, a compound heterozygous ATP1A3 mutation c.868C > T (p.R290C)/c.684 + 1G > A was determined. Aripiprazole may reduce the attacks of AHC, which are resistant to other available therapies.