Evaluation of the Patients with the Diagnosis of Pontocerebellar Hypoplasia: A Multicenter National Study.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of neurodegenerative disorders characterized by hypoplasia and degeneration of the cerebellum and pons. We aimed to identify the clinical, laboratory, and imaging findings of the patients with diagnosed PCH with confirmed genetic analysis. We collected available clinical data, laboratory, and imaging findings in our retrospective multicenter national study of 64 patients with PCH in Turkey. The genetic analysis included the whole-exome sequencing (WES), targeted next-generation sequencing (NGS), or single gene analysis. Sixty-four patients with PCH were 28 female (43.8%) and 36 (56.3%) male. The patients revealed homozygous mutation in 89.1%, consanguinity in 79.7%, pregnancy at term in 85.2%, microcephaly in 91.3%, psychomotor retardation in 98.4%, abnormal neurological findings in 100%, seizure in 63.8%, normal biochemistry and metabolic investigations in 92.2%, and dysmorphic findings in 51.2%. The missense mutation was found to be the most common variant type in all patients with PCH. It was detected as CLP1 (n = 17) was the most common PCH related gene. The homozygous missense variant c.419G > A (p.Arg140His) was identified in all patients with CLP1. Moreover, all patients showed the same homozygous missense variant c.919G > T (p.A307S) in TSEN54 group (n = 6). In Turkey, CLP1 was identified as the most common causative gene with the identical variant c.419G > A; p.Arg140His. The current study supports that genotype data on PCH leads to phenotypic variability over a wide phenotypic spectrum.

Vincristine-Induced Peripheral Neuropathy in Children With Malignancy and the Effect of Missed Doses on Treatment Success.

INTRODUCTION: Recognizing the symptoms of vincristine-induced peripheral neuropathy (VIPN) earlier is crucial to preventing the persistent neurological sequelae. The treatment of neuropathy is to discontinue the drug, and the effect of a missed dose of vincristine on treatment success is unclear. This study aims to evaluate VIPN in children with malignancy and the effect of skipping vincristine doses on the treatment success of patients at a single center, retrospectively. METHODS: Medical records of the children with cancer who received vincristine in our institution between 2013 and 2020 were analyzed retrospectively. RESULTS: Vincristine neuropathy was found in 42 (7%) of 598 pediatric patients who received at least one dose of vincristine during the study period. Neuropathy developed at a statistically significantly lower cumulative dose in patients younger than seven years of age (p=0.04). The mean neuropathy duration of the cases was 8.5 months, and the findings of 40 (95.2%) cases improved. The mean cumulative dose was higher in patients with diffuse nerve involvement. The missed dose of vincristine was lower in the cases in complete remission compared to the other cases and higher doses of vincristine were missed in the stable disease group than in the remission group (p=0.03). CONCLUSION: VIPN can be encountered in less cumulative doses, mainly in the younger age group. Missed doses of vincristine may affect treatment success, and more comprehensive studies are needed to show this effect more clearly.

Retracted: Clinical and genetic evaluations of rare childhood epilepsies in Turkey's national cohort.

Aycan Ünalp, Yigithan Güzin, Bülent Ünay, Ayse Tosun, Dilek Çavusoglu, Hande Gazeteci Tekin, Semra Hiz Kurul, Ebru Arhan, Selvinaz Edizer, Gülten Öztürk, Uluç Yis, Ünsal Yilmaz, Turkish Rare Epilepsies Study Group, Clinical and genetic evaluations of rare childhood epilepsies in Turkey's national cohort, Epileptic Disorders, 2023, (https://doi.org/10.1002/epd2.20150) The above article, published online on 16 August 2023 on Wiley Online Library (www.onlinelibrary.wiley.com), has been retracted by agreement between the authors, the Editor-in-Chief, Sándor Beniczky, and John Wiley & Sons Ltd. The authors asked for a retraction based on an experimental error which would alter the results of the study if corrected.

Management of acute metabolic crisis in TANGO2 deficiency: a case report.

OBJECTIVES: TANGO2 deficiency is a rare inborn error of metabolism, with distinct clinical features. The clinical presentations of TANGO2 deficiency are developmental delay, speech difficulties, intellectual disability, non-life-threatening paroxysmal neurologic episodes (TANGO2 spells), acute metabolic crises, cardiac crises, seizures and hypothyroidism. Patients may die in acute metabolic crises. Here we report our experience in the management of an acute metabolic crisis in TANGO2 deficiency. CASE PRESENTATION: A 9-year-old patient diagnosed with TANGO2 deficiency was admitted with fever, fatigue, unable to walk. In follow up, encephalopathy, rhabdomyolysis and arrhythmia were detected. Vitamin B-complex was started. Our patient's mental status and rhabdomyolysis improved dramatically, and cardiac crises ended without Torsades de pointes, ventricular tachycardia and/or fibrillation or myocardial dysfunction. CONCLUSIONS: With this report, we aimed to show the effectiveness of vitamin B-complex in the management of acute metabolic crises.

Depression, anxiety, and sleep quality of caregivers of children with spinal muscular atrophy.

BACKGROUND: The aim of this study was to evaluate the prevalence of anxiety, depression, sleep, and associated factors in caregivers of children with spinal muscular atrophy (SMA). MATERIALS AND METHODS: Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory-State (STAI-S), the State-Trait Anxiety Inventory-Trait (STAI-T), and Pittsburgh Sleep Quality Index (PSQI) were used to assess the anxiety, depression, and sleep quality of the caregivers of children with SMA. Higher scores indicated worse outcome for all three questionnaires. RESULTS: Fifty-six caregivers of children with SMA were included in the study. Median age of children was 6 (3.2-10) years and mean age of the caregivers was 37.0 ± 6.5 years. Median scores of the BDI, STAI-S, STAI-T, and PSQI were 12 (7.2-17), 35.5 (31-44), 40.5 (35-48), and 7.0 (5.0-10.0), respectively. There was a positive correlation between BDI and PSQI scores (p < 0.05). There was a negative correlation between the age of the caregivers and PSQI, BDI, STAI-T scores (p = 0.01, r = -0.341; p = 0.006, r = -0.364; p = 0.003, r = -0.395, respectively). There was a negative correlation between the age of the patients and the PSQI scores of the caregivers (p = 0.01, r = -0.33). There was a negative correlation between BDI scores and household income (p = 0.01, r = -0.34). CONCLUSION: Caregivers of children with SMA had elevated depression and anxiety levels and they also had decreased sleep quality. Economic and social support resources are needed to help caregivers of those children.

Chromosomal microarray and exome sequencing in unexplained early infantile epileptic encephalopathies in a highly consanguineous population.

AIM: To identify genetic causes for early infantile epileptic encephalopathies (EIEE) in Turkish children with mostly consanguineous parents. METHODS: In a selected EIEE group (N = 59) based on results of nongenetic and initial genetic testing with unexplained etiology, 49 patients underwent array-based comparative genomic hybridization (aCGH) and 49 patients underwent whole exome sequencing (WES) including 39 with negative aCGH results and 10 with WES-only. RESULTS: Diagnostic yield of aCGH and WES for pathogenic or likely pathogenic variants was 14.3% and 38.8%, respectively. Including de novo variants of uncertain significance linked to compatible phenotypes, increased the diagnostic yield of WES to 61.2%. Out of 38 positive variants, 18 (47.4%) were novel and 16 (42.1%) were de novo. Twenty-one (56.8%) patients had recessive variants inherited from mostly consanguineous healthy parents (85.7%). Fourteen (37.8%) of patients with diagnostic results had positive variants in established EIEE genes. Seizures started during neonatal period in 32.4% patients. Posture or movement disorders were comorbid with EIEE in 40.5% of diagnosed patients. We identified treatable metabolic disorders in 8.1% of patients and pathogenic variants in genes which support using targeted medicine in 19% of patients. CONCLUSIONS: Detailed electro-clinical phenotyping led to expansion of some of the known phenotypes with non-neurological and neurological findings in addition to seizures, as well as suggestion of candidate genes (SEC24B, SLC16A2 and PRICKLE2) and a copy number variant (microduplication of Xp21.1p11.4). The high ratio of recessive inheritance could be important for family counseling.

Permanent Impairment of Language Functions in an Adolescent Case of Autoimmune Encephalitis.

Introduction: In pediatric and adolescent population, autoimmune encephalitis (AE) may present with a wide variety of symptoms including cognitive regression accompanied with loss of language skills. Despite its high prevalence in AE, linguistic functions have not been investigated in extensive detail. Case: A 12-year-old girl with no significant premorbid history and normal school performance presented with fever, hypersomnia, nocturnal myoclonus and behavioral changes. Although neurological examination was normal, psychiatric evaluation revealed euphoria, mild irritability and visual hallucinations. Cranial MRI was normal, whereas cerebrospinal fluid (CSF) analysis showed elevated protein concentration and lymphocyte count, electroencephalogram (EEG) showed diffuse slow waves. A panel for anti-neuronal antibodies demonstrated glutamic acid decarboxylase (GAD) antibodies in the serum. Following immunotherapy, all neurological and behavioral symptoms vanished. However, the patient suffered from significant worsening of school performance. Psychiatric evaluation revealed severe depression. Assessment of intelligence done on the 10th and 18th month of follow-up yielded significantly low scores at mental retardation level. Linguistic assessment showed significant impairment in all domains but especially in semantics. Conclusion: Our case emphasizes the fact that AE may cause permanent cognitive dysfunction and language impairment even in patients with normal MRI/neurological examination findings and relatively mild treatment-responsive disease course.

The outcome of two SMA cases treated with nusinersen at seven hours and at three days of life: the earliest ever.

New molecular therapies are available for the treatment of spinal muscular atrophy (SMA) but early intervention is required. We report two cases that were diagnosed prenatally, where treatment with nusinersen was initiated within 7 h and three days respectively. The children were followed up for 13 months and almost six years respectively. Both children have developed within entirely normal centiles, indicating that initiating treatment immediately after birth, as in these cases, is essential for a good outcome.

Comparison of telerehabilitation versus home-based video exercise in patients with Duchenne muscular dystrophy: a single-blind randomized study.

INTRODUCTION: Patients with Duchenne muscular dystrophy (DMD) have lost their access to on-site rehabilitation due to the COVID-19 pandemic. Telerehabilitation can be a viable approach for these patients to protect their muscle strength and functional status. The aim of this study is to compare telerehabilitation with home-based video exercises. PATIENTS AND METHODS: Male, ambulatory DMD patients were randomized into telerehabilitation and video-exercise groups. Nineteen patients were included in the final analyses. Telerehabilitation consisted of live online exercises, while video exercise implemented a pre-recorded video as a home-based program. Both programs spanned 8 weeks, three times a week. Patients' muscle strength with a hand-held dynamometer, Quick Motor Function Test, North-Star Ambulatory Assessment (NSAA), 6-Minute Walk Test (6MWT) and Caregiver Burden were recorded before and after treatment. RESULTS: The 6MWT of the telerehabilitation group was391.26 ± 95.08 m before and387.75 ± 210.93 after treatment (p = 0.94) and 327.46 ± 103.88 m before treatment and313.77 ± 114.55 after treatment in video group (p = 0.63). The mean NSAA score of the telerehabilitation group were26.70 ± 8.04 before treatment and 25.20 ± 11.33 after treatment (p = 0.24). In the video group scores were 21.66 ± 6.65 before to 22.00 ± 8.61 after treatment (p = 0.87). There were no significant changes between groups at the end of the treatments. The telerehabilitation group's neck extension, bilateral shoulder abduction, and left shoulder flexion, bilateral knee flexion and extension, bilateral ankle dorsiflexion, and left ankle plantar flexion strength improved significantly and were better than the video group (p < 0.05 for all measurements). CONCLUSION: A telerehabilitation approach is superior in improving muscle strength than a video-based home exercise, but none of the programs improved functional outcomes in ambulatory patients with DMD.

Respiratory outcome of spinal muscular atrophy type 1 patients treated with nusinersen.

BACKGROUND: Respiratory failure is the leading cause of mortality in spinal muscular atrophy type 1 (SMA1) children. The current study aims to evaluate the effect of nusinersen treatment on respiratory outcome of the patients with SMA1. METHODS: In this retrospective, single-center study, 52 SMA1 patients treated with nusinersen were included in the analysis. Patients were divided into two groups based on their age at the time of their first nusinersen treatment (Group 1: ≤6 months, Group 2: >6 months). Respiratory outcome on the 180th day of treatment is defined as the type of ventilation support (spontaneous breathing, noninvasive ventilation (NIV), and tracheostomized or intubated on invasive mechanical ventilation). Demographic data, respiratory outcome, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores were obtained from medical records. RESULTS: On the 180th day of treatment, 46 of the 52 (88.4%) children were alive. Prevalence of the mortality was similar in both groups (P = 0.65). The comparison of respiratory outcome in patients between group 1 and group 2 was as follows: spontaneous breathing, 7 (43.7%) versus 4 (13.3%) (P = 0.03); NIV <16 h/day, 3 (18.7%) versus 4 (13.3%) (P = 0.68); invasive mechanical ventilation, 6 (37.5%) versus 22 (73.3%) (P = 0.01). There were no patients using NIV ≥16 h/day. There were significant improvements in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores of the patients at day 180 in comparison with the baseline (P < 0.001). CONCLUSIONS: Early initiation of nusinersen treatment in SMA1 patients may alter the disease's natural course.

The Effects of Neurodevelopmental Therapy on Feeding and Swallowing Activities in Children with Cerebral Palsy.

This study investigated the effect of the structured Neurodevelopmental Therapy Method-Bobath (NDT-B) approach on the feeding and swallowing activity of patients with cerebral palsy (CP) and feeding difficulties. In addition to feeding and oral motor intervention strategies (OMIS), and nutrition-related caregiver training (NRCT), and the NDT-B, which was structured to increase trunk and postural control, was added to the therapy program. Forty patients with CP, with a mean age of 3.25 ± 0.927 years, were classified using the Gross Motor Function Classification System, Eating and Drinking Ability Classification System, and Mini-Manual Ability Classification System. The patients were randomly assigned into two groups as OMIS + NRCT (n = 20) and OMIS + NRCT + NDT-B (n = 20). The program was applied for 6 weeks, 2 days/week, for 45 min. The patients were evaluated using the Trunk Impairment Scale, Schedule for Oral Motor Assessment, and the Pediatric Quality of Life Inventory before and after 6 weeks. The trunk control of the OMIS + NRCT + NDT-B group was superior to the other group (P = 0.026). Although there was an improvement in the groups according to the subcategories of SOMA, the OMIS + NRCT + NDT-B group was superior in the trainer cup and puree subcategories of SOMA (P = 0.05). A significant correlation was observed between trunk control and oral motor functions in children with CP, and the eating function of children in the OMIS + NRCT + NDT-B group further improved. NDT-B-based neck and trunk stabilization exercises should be added to the treatment programs.Trial Registration NCT04403113.

CLB add-on treatment in patients with epileptic encephalopathy: a single center experience with long-term follow-up.

Clobazam (CLB) is an effective anticonvulsant used as an adjunctive treatment for several seizures and epilepsy syndromes. Data are limited on efficacy and safety of CLB as add-on therapy for epileptic encephalopaties (EEs) other than Lennox-Gastaut syndrome (LGS). This retrospective study aimed to assess efficacy and safety of long-term CLB add-on therapy for various EE syndromes. Data on CLB add-on therapy were assessed in 74 children (60.8% male) after 3 months (early) and 12 months (late) follow-up as well as in 57 (77%) patients who had been on CLB therapy longer than 12 months (mean:39.11 ± 30.29; range:12-129 months) (very late) were reported. Data on CLB add-on therapy were assessed in 74 children (60.8% male) after 3 months (early) and 12 months (late) follow-up as well as in 57 (77%) patients who had been on CLB therapy longer than 12 months (mean:39.11 ± 30.29; range:12-129 months) (very late) were reported. Good response rate (> 50%) for seizures was achieved in 24% at early follow-up, 30% at late follow-up, and 35% during very late follow-up. Complete seizure remission was achieved for 15% seizures; 72.7% occurred at very late follow-up. Myoclonic seizures were the most responsive (35%); this response increased during late follow-up (46%), whereas 27.3% of myoclonic-atonic/atonic seizures had good response at early and very late follow-up. At late follow-up, comparison of mean effective doses of CLB did not show significant difference among types of seizures with good response. Adverse effects reported in 15% of patients did not require stopping CLB therapy. Generalized epileptogenic potentials significantly decreased while focal epileptogenic potentials significantly increased at first year of treatment in comparison to basal EEG findings (p < 0.001). CLB should be considered as an optional antiepileptic that is well tolerated, particularly in EEs with myoclonic and myoclonic-atonic/atonic seizures.

How do presentation age and CSF opening pressure level affect long-term prognosis of pseudotumor cerebri syndrome in children? Experience of a single tertiary clinic.

BACKGROUND: Diagnosis and treatment of pseudotumor cerebri syndrome in children is still a challenge for clinicians. The aim of this study is to reveal the influence of presentation age and CSF opening pressure on long-term prognosis of pseudotumor cerebri and share our clinical data of the very young age (≤ 5-year) group. METHOD: This retrospective study includes the patients followed by the Marmara University Pediatric Neurology Clinic between years 2012 and 2020 diagnosed with definite, probable, or suggestive pseudotumor cerebri syndrome according to modified Friedman criteria. Patients were classified into three groups according to presentation age: group 1: ≤ 5 years old; group 2: 6-10 years; and group 3 > 10 years old. CSF opening pressure was also categorized into three groups as CSF < 20 cmH20; CSF 20-30 cmH20; and CSF > 30 cmH20. RESULTS: One hundred three patients, 62.1% female (n = 64), were enrolled in the study. Group 1 consisted of 16 patients (60% male), group 2 consisted of 30 patients (63.3% female), and group 3 consisted of 57 patients (66.7% female). The mean CSF opening pressure did not differ between the three age groups in our study (p > 0.05). Treatment response was not correlated with CSF opening pressure. Papilledema presence and level of CSF opening pressure were independent of age (p > 0.05). CONCLUSIONS: Age at presentation and CSF opening pressure at diagnosis are not any predictive factors that influence long-term prognosis of pseudotumor cerebri syndrome in children. Evaluation and follow-up of children should be done in personalized approach.

Neurodevelopmental Findings and Epilepsy in Malformations of Cortical Development.

AIM: The purpose of this study is to classify the malformations of cortical development in children according to the embryological formation, localization, and neurodevelopmental findings. Seizure/epilepsy and electrophysiological findings have also been compared. MATERIAL AND METHODS: Seventy-five children (age: 1 month-16.5 years; 56% male) followed with the diagnosis of malformation of cortical development, in Marmara University Pendik Research and Educational Hospital Department of Pediatric Neurology, were included in the study. Their epilepsy characteristics, electroencephalogram (EEG) findings, and prognosis were reported. Neurodevelopmental characteristics were evaluated by the Bayley Scales of Infant and Toddler Development (Bayley-III) for the ages of 0-42 months (n = 30); the Denver Developmental Screening Test-II (DDST-II) for ages 42 months-6 years (n = 11); and the Wechsler Intelligence Scales for Children (WISC-R), used for children 6 years and older (n = 34). RESULTS: The patients were classified as 44% premigrational (14.6% microcephaly, 24% tuberous sclerosis, 2.7% focal cortical dysplasia, 1.3% hemimegalencephaly, and 1.3% diffuse cortical dysgenesis); 17.3% migrational (14.6% lissencephaly, 2.7% heterotopia); and 38.6% postmigrational (14.6% schizencephaly, 24% polymicrogyria) developmentally. According to involved area, the classification was 34.7% hemispheric/multilobar, 33.3% diffuse, and 32% focal. Seventy-five percent of the patients had a history of epilepsy, and 92% were resistant to treatment. The seizures started before the age of 12 months in diffuse malformations, and epileptic encephalopathy was more common in microcephaly with a rate of 80% and lissencephaly with a rate of 54.5% in the first EEGs. Ninety-five percent of patients had at least one level of neurodevelopmental delay detected by DDST/Bayley-III; this was more common in patients with accompanying epilepsy (P < .05). As seen more commonly in patients with diffuse pathologies and intractable frequent seizures, mental retardation was detected by WISC-R in 64.5% of patients (P < .05). CONCLUSION: In cases with cortical developmental malformation, epilepsy/EEG features and neurodevelopmental prognosis can be predicted depending on the developmental process and type and extent of involvement. Patients should be followed up closely with EEG.

The Burden of Primary Caregivers of Spinal Muscular Atrophy Patients and Their Needs.

AIM: This study aims to reveal the problems faced by families of children with spinal muscular atrophy (SMA), by evaluating their care burden, needs, and expectations. MATERIALS AND METHODS: The participants were the primary caregivers of 34 children between the ages of 0 and 18 years diagnosed with SMA. Thirteen children were diagnosed with type 1, 13 children with type 2 and 8 children with type 3 SMA. Data on the medical history, functional levels of the participants, and the characteristics of families were collected. The childrens' parents completed the Family Needs Survey and the Zarit Caregiver Burden Scale. RESULTS: According to the results of the Family Needs Survey, it was found that information was the most common requirement, and this was independent of the level of education. According to the Caregiver Burden Scale, it was recorded that 64.7% of the caregivers were under mild/moderate burden. While there was a moderate correlation (r = 0.574; P < .001) between the Caregiver Burden Scale and the Family Needs Survey, it was observed that the functional level of the child was not associated with family needs and caregiver burden. CONCLUSIONS: Our study suggests that the needs of families of SMA patients, especially related to income level, have changed. The caregivers' burden is not directly related to the income level or the functional level of the child. Families' need for information should also be prioritized within the rehabilitation program.

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.