The role of cranial magnetic resonance imaging findings in pediatric epilepsy: A single-center experience.

OBJECTIVE: The aim of this study was to investigate cranial magnetic resonance imaging (MRI) findings in different age groups and genders in pediatric epilepsy, to determine the percentages of etiologic factors, and to evaluate the association between MRI positivity and treatment resistance. METHODS: Cranial MRIs of 359 patients with epilepsy aged 1 month to 18 years were retrospectively evaluated. Etiologic factors as an underlying cause of epilepsy were classified as previous parenchymal damage, hippocampal sclerosis, malformations of cortical development, tumor, neurocutaneous syndrome, myelination disorder, vascular anomaly, metabolic/genetic/neurodegenerative diseases, encephalitis, and an uncategorized "other" group. Data were transferred to IBM SPSS Statistics 25.0 (SPSS Inc., Chicago, IL, USA), and descriptive statistics, correlation analyses, chi-square, and t-tests were performed. RESULTS: Among the patients included in the study, 141 (39.3%) had pathological findings on MRI related to the etiology. Previous parenchymal damage (39.7%) was the most common etiologic cause in all age groups. Regarding the relationship between drug resistance and MRI positivity, MRI positivity was observed in 72% of drug-resistant cases, while a complete response to therapy was found in 67.6% of MRI-negative cases. CONCLUSION: MRI guides clinicians to determine the presence of an etiologic factor as the underlying cause of childhood epilepsy before treatment planning. MRI positivity is a remarkable indicator of response to antiseizure drug treatment and drug resistance.

A very early onset MNGIE-like syndrome with POLG1 mutation and accompanying leukoencephalopathy.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a well-known mitochondrial depletion syndrome. Since Van Goethem et al. described MNGIE syndrome with pathogenic POLG1 mutations in 2003, POLG1 gene became a target for MNGIE patients. Cases with POLG1 mutations strikingly differ from classic MNGIE patients due to a lack of leukoencephalopathy. Here we present a female patient with very early onset disease and leukoencephalopathy compatible with classic MNGIE disease who turned out to have homozygous POLG1 mutation compatible with MNGIE-like syndrome, mitochondrial depletion syndrome type 4b.

Evaluation of neuropathic pain with diverse pathophysiologies in childhood cancers.

OBJECTIVE: Neuropathic pain (NP) is caused by damage or disease affecting the somatosensory nervous system. The aim of this study was to evaluate the clinical characteristics, pathophysiologies, and treatments applied in pediatric cancer patients with NP. METHODS: Patients with cancer having NP between 5 and 18 years of age who were followed up in the pediatric oncology clinic of Okmeydani Training and Research Hospital between January 2015 and April 2019 were included in this study. NP was described as tingling, burning, and stinging. Patients with acute lymphoblastic leukemia and brain tumors were excluded from the study. A number of pediatric cancer patients were also recorded. Patients' age, gender, cancer diagnosis, NP characteristics and causes, treatments, and response to those treatments were investigated retrospectively and groups of NP according to their pathophysiological mechanism were established. RESULTS: NP was found in 26 (16%) of 160 patients followed up for childhood cancers. The average age was 11.8±4 years. Ten of the patients (38.4%) were female, and 16 (61.5%) were male. Osteosarcoma was the most common diagnosis in 10 (38%) patients. The most common cause of NP was compression of a nerve/root/spinal cord in 9 (35%) patients and the second most common was related with limb-sparing surgery. NP was found to be associated with chemotherapy (CT) in 5 (19%) patients, mostly with vincristine. Gabapentin was administered in a total of 22 (85%) patients for treatment. Opioid administration was more common as the disease stage progressed (p<0.05). A good or partial response to treatment was achieved in 19 (73%) patients. CONCLUSION: NP can occur in childhood cancers and is related to the cancer itself, CT, surgical treatment, and disseminated disease. Although there is no standard protocol, gabapentin and, for advanced-stage patients, opioids are the most commonly used treatment options.

Interacting with AP1 complex mutated synergin gamma (SYNRG) reveals a novel coatopathy in the form of complicated hereditary spastic paraplegia.

BACKGROUND: Today, it is known that about 80 genes are involved in the etiology of hereditary spastic paraplegia. However, there are many cases whose etiology could not be determined by extensive genetic tests such as whole-exome sequencing, clinical exome. METHODS: Candidate genes were determined, since no clinically illuminating variant was detected in the whole-exome sequencing analysis of three patients, two of whom were siblings, with a complex hereditary spastic paraplegia phenotype. RESULTS: The p.Leu1202Pro variant in the SYNRG gene in the 1st and 2nd cases, and the p.Gly533* variant in the 3rd case were homozygous. DISCUSSION: We suggest that the SYNRG gene interacting with AP-1 (adaptor-related protein) from the AP complex family may cause the complex hereditary spastic paraplegia phenotype with extensive clinical spectrum. It may be important to evaluate SYNRG gene variants in patients with hereditary spastic paraplegia whose etiology has not been clarified.

A genetic mimic of cerebral palsy: Homozygous NFU1 mutation with marked intrafamilial phenotypic variation.

BACKGROUND: Genetic defects in the NFU1, an iron-sulfur cluster scaffold protein coding gene, which is vital in the final stage of assembly for iron sulfur proteins, have been defined as multiple mitochondrial dysfunctions syndrome I. This disorder is a severe autosomal recessive disease with onset in early infancy. It is characterized by disruption of the energy metabolism, resulting in weakness, neurological regression, hyperglycinemia, lactic acidosis, and early death. PATIENT DESCRIPTION: This report documents the case of a 27-month-old girl, who showed clinical signs and symptoms of spastic paraparesis with a relapsing-remitting course. The patient had a sister with a severe phenotype who died at the age of 16 months. RESULTS: Magnetic resonance imaging revealed hyperintensity of the cerebral white matter that was more prominent in the frontal regions, with milder involvement in the posterior periventricular regions. There was also evidence of partial cystic degeneration and cavitation in the frontal regions. In addition, she had hyperglycinemia. Homozygous NM_001002755.4:c.565G>A (p.Gly189Arg) mutation was identified in the NFU1 gene; this had not previously been reported as homozygous. CONCLUSION: Hyperglycinemia and cavitating leukodystrophy are suggestive of an NFU1 mutation diagnosis. An intrafamilial phenotypic variation has not been published in NFU1-associated disorders before. Presenting with spasticity as a rare phenotype, NFU1 mutations could be considered a genetic mimic of cerebral palsy.

Efficacy and Side Effect Profile of Clobazam in Children with Different Etiologies of Epilepsy from a Single Center.

OBJECTIVES: Clobazam is a long-acting antiepileptic drug that belongs to benzodiazepines used in the polytherapy of childhood epilepsy. In this study, our aim is to retrospectively evaluate the effectiveness and side effect profile of clobazam in children with different etiologies of epilepsy, mostly drug resistant. METHODS: Forty patients aged 0-18 years that were admitted to Okmeydani Training and Research Hospital pediatric neurology outpatient clinic between January 2017-January 2019 and prescribed clobazam were included in this study. The data of the patients who gave informed consent were extracted retrospectively from the outpatient clinic files. The patients with no seizures over 50% reduction in seizures were classified as clobazam-responsive, whereas the patients with less than 50% reductions in seizures, patients who had no response, and who manifested side effects and stopped using the drug were classified as clobazam-unresponsive. RESULTS: Twenty-three of the patients (57.5%) were male, 17 were (42.5%) were female. The average onset age of epilepsy was 31.8±37.2 months, while the average age for the prescription of clobazam was 70.6±48.9 months. The types of seizures were focal in 23 patients (57.5%) and generalized in 17 (42.5%) patients. Thirty-three (82.5%) patients had been using double or triple combinations of eight different antiepileptic drugs when clobazam was added to their treatment and accepted as drug-resistant epilepsy. The etiology of twenty one patients (52.5%) was unknown. In the remaining 19 patients (47.5%), the most common cause was structural and others were genetic, infectious and metabolic. Thirty one of the patients (77.5%) were responsive to clobazam. Of them, fifteen (37.5%) had no seizures, and 16 had a reduction in seizures (>50%). Nine (22.5%) patients were accepted as unresponsive to clobazam. The mean dose per kg was 0.7±0.3 mg/kg/day with a median of 0.63 mg/kg/day. Side effects of clobazam were encountered in 18 patients (45%); these resulted in the cessation of administration in only six (15%) patients. The side effects that cause the cessation of clobazam were sedation, refusal to take the drug due to the taste, irritability, hypersalivation, and malaise. Four patients (10%) had their doses reduced, seven patients (17.5%) responsive to clobazam although with side effects continued taking the drug as prescribed. The most common side effects of all were hyperactivity and sedation consecutively. CONCLUSION: Clobazam is an effective treatment for ensuring seizure freedom in pediatric epilepsy, mostly drug-resistant. The side effects are at tolerable levels in patients who are responsive to the drug.

Clinically isolated syndrome and multiple sclerosis in children: a single center study.

BACKGROUND AND OBJECTIVES: This study was conducted to determine the differences in clinical and radiological features at the first demyelinating event in children with clinically isolated syndrome (CIS) and multiple sclerosis (MS). METHODS: This was a single center retrospective cohort study of the children with CIS followed-up at Istanbul University Faculty of Medicine, Department of Pediatric Neurology, between 2010 and 2018. Children with CIS who were assessed at 3, 6, 12 and 24 months following their first identified demyelinating event were included. Demographic data, mode of presentation and the presence of the oligoclonal band in the cerebrospinal fluid (CSF) were abstracted from the medical records. Magnetic resonance imaging of the brain and spinal cord was analyzed for the location, number, size and gadolinium enhancement of the lesions. RESULTS: A total of 51 patients` data was assessed, 38 patients at a mean age of 12.3 years were enrolled in the study. Twenty-seven children (71%) evolved into clinically definite MS after a mean follow-up of 11 months. Older age at first demyelinating event and the presence of the oligoclonal band in CSF were tended to be more common in patients with MS than patients with CIS (p < 0.05). The increased number of T2-hyperintense lesion and the presence of the lesion in periventricular, infratentorial and corpus callosum were associated with a tendency for development of MS (p < 0.05). CONCLUSION: Older age at first demyelinating event, the presence of the oligoclonal band in CSF, the number and localization of T2-hyperintense lesion were associated with a tendency for development of MS.

Short-term neurological outcomes in ischemic and hemorrhagic pediatric stroke.

BACKGROUND: The aim of this study was to retrospectively assess short-term neurological outcomes in pediatric stroke with regard to patient characteristics. METHODS: Children aged 28 days-18 years with arterial ischemic stroke (AIS), cerebral sinovenous thrombosis (CSVT), and hemorrhagic stroke (HS) between 2007 and 2013 were evaluated. Neurological findings in the first 3 months were accepted as short-term prognosis, and modified Rankin scale was used. RESULTS: A total of 33 patients (62%) with AIS, 12 (23%) with HS, and eight (15%) with CSVT were included. Moya moya syndrome was the most common new diagnosis in AIS. Stroke recurred in five (15%); and one AIS patient with posterior circulation infarct died (3%). Prognosis in AIS was favorable for 20 patients (61%) and poor for 13 patients (39%). Forty-two percent of HS were of vascular origin. Seven patients (70%) with HS had good prognosis and three (30%) had poor prognosis with no death. Homocysteine-related hypercoagulability was most frequently noted in the etiology of CSVT. Synchronous systemic thrombosis was observed in three CSVT patients (37.5%) and death occurred in two (25%). Prognosis was evaluated as favorable for three CSVT patients (37.5%) and poor for five (62.5%). For thrombophilia, thrombosis panel was performed fully in 83% of AIS and CSVT patients. CONCLUSIONS: Pediatric stroke is associated with a poor prognosis in a substantial number of patients in the short term, with CSVT having the worst prognosis. Detailed patient characteristics are listed not only for ischemic but also for hemorrhagic stroke; and a full thrombosis panel was achieved for most ischemic stroke patients.

Efficacy of Stiripentol and the Clinical Outcome in Dravet Syndrome.

Dravet syndrome is a rare and progressive epileptic encephalopathy of infancy. Stiripentol reduces the seizure frequency in patients with Dravet syndrome. We evaluated the clinical characteristics of patients with Dravet syndrome and their response to stiripentol. We retrospectively collected the data of 21 patients (11 females; mean age, 8.2 years, range: 5.4-15 years) with Dravet syndrome who were treated with stiripentol in our outpatient clinic between June 2016 and June 2017. Patients with seizure reduction ≥50% were considered responders. Most of our patients had severe (47%) or moderate (33%) cognitive disabilities, although 14% had mild cognitive disability. There was a significant difference in both status epilepticus and age between the groups with normal/mild versus severe/moderate neurocognitive prognoses. Of the patients, 85.7% were using stiripentol. The mean duration of stiripentol use was 41.2 months (range: 24-64 months). In 12 patients (57%), the seizure frequency decreased by more than 50%, and 2 of them were seizure-free. Status epilepticus was not recorded after stiripentol treatment in 8 of 11 patients with status epilepticus. Despite the small sample size, our results suggest that stiripentol has a favorable efficacy. In addition, considering the absence of status epilepticus after treatment and the negative effects of status epilepticus on cognitive development, early treatment should be initiated in SD patients, for whom disease control is difficult.

Vanishing white matter disease with a novel EIF2B5 mutation: A 10-year follow-up.

BACKGROUND: Vanishing white matter disease is a heterogeneous disorder caused by mutation in one of the five genes encoding subunits of the eukaryotic initiation factor eIF2B. It is a heterogeneous disorder due to phenotypic variation and a clear genotype-phenotype correlation could not be established so far. We describe a novel mutation in the EIF2B5 gene by analyzing the clinical phenotype and the progression of brain lesions for 10 years. CASE: A novel mutation in the EIF2B5 gene was detected in the heterozygous state; c.1688G > A (p. Arg563Gln) mutation in exon 12, accompanied by a previously detected c.806G > A (p. Arg269Gln) mutation in exon 6, leading to substitution of arginine for a glutamine. This compound heterozygous mutation was associated with disease onset at early childhood and relatively slow progression of neurological deterioration. In contrast to previous findings indicated the association of c.806G > A mutation and peripheral neuropathy in patients with vanishing white matter disease, electromyography of our case was normal. The corpus callosum inner rim was the affected area at early stages, which may be remarkable for early diagnosis of vanishing white matter disease. Serial follow-up magnetic resonance imaging revealed the white matter signal abnormality, subsequently cystic degeneration and decrease in white matter volume. CONCLUSION: The novel mutation c.1688G > A in compound heterozygous state leads to intermediate phenotype of the vanishing white matter disease. In the early stages of the disease the signal abnormality in the corpus callosum inner rim might be remarkable.

Lacosamide treatment of childhood refractory focal epilepsy: the first reported side effect in paediatric patients.

PURPOSE: Lacosamide (LCM) is an effective antiepileptic drug (AED) approved for the treatment of focal epilepsy in both children and adults. The aim of this observational study was to review our centre's experience with LCM and to characterise its efficacy and tolerability as an adjunct therapy in children with refractory focal epilepsy. METHODS: We retrospectively reviewed the medical records of 12 paediatric patients who underwent treatment with LCM from January 2014 to December 2015. We recorded the treatment response at three time points: at 3 and 6 months after LCM therapy and at the final follow-up visit. Children showing seizure reduction ≥ 50% were considered responders. RESULTS: We included 12 patients (five boys), and their mean age was 13.8 years (range: 6.2-17.6 years) at the end of LCM treatment. The average length of follow-up after starting LCM was 23 months (11-37 months). Eight patients (66%) had > 50% reduction in seizures at the 3-month follow-up visit, and seven (58%) had > 50% reduction at the 6-month follow-up visit. Six patients (50%) maintained ≥ 50% reduction in seizures at the final follow-up visit. Two patients (16.6%) were seizure free at the 6-month and final follow-up visits. Common adverse side effects included dizziness, ataxia, nausea, and vomiting. Two patients developed status epilepticus (SE), one each at 3 and 11 days after the first LCM dose; they both discontinued treatment. CONCLUSIONS: Our study points to the efficacy of LCM in a small paediatric group. Furthermore, it was important to report status epilepticus after LCM administration in the paediatric population for the first time.

Psychosocial and behavioral functioning and their relationship to seizure timing in children with benign epilepsy with centrotemporal spikes.

BACKGROUND: Psychosocial and behavioral problems have been reported in children with benign epilepsy with centrotemporal spikes (BECTS). Distinctive features of typical BECTS associated with cognitive and behavioral problems have not clearly been defined. PURPOSE: We aimed to identify psychosocial and behavioral functioning and their relationship to seizure timing in BECTS. METHODS: Consecutive patients with BECTS were recruited from the pediatric neurology outpatient clinic between May 2015 and May 2016. The patients were divided into two subgroups in according to seizure timing; group 1 consisted of patients with seizures only in the morning short before awakening, and group 2 consisted of patients with seizure shortly after falling asleep or in both time periods. Neuropsychological and behavioral evaluation in patients and healthy controls were examined using the Wechsler Intelligence Scale for Children-Revised test and the Turkish version of Strengths and Difficulties Questionnaire (SDQ). RESULTS: The participants comprised 46 children with BECTS and 49 healthy controls aged 7-16years. There was no significant difference between group 1, group 2, and control group regarding intelligence quantity in full-scale or verbal and performance subscales. Behavioral scores for overall stress significantly differed between group 2 and controls on the SDQ test, while group 1 and control group had no difference on the SDQ scores. CONCLUSION: Patients with BECTS who have seizure shortly after falling asleep may have a tendency towards behavior difficulties.

Coexisting neuronal autoantibodies among children with demyelinating syndromes.

OBJECTIVES: To determine the incidence and clinical relevance of neuronal autoantibodies in children with demyelinating syndromes. METHODS: We conducted a prospective study including 31 consecutive children with demyelinating syndromes. Four patients with N-Methyl-D-aspartate receptor (NMDAR) encephalitis, 32 patients with Guillain-Barre syndrome, 13 children with benign childhood epilepsy, and 28 healthy children were used as controls. Prior to initiating immunomodulatory therapy, serum samples were tested for antibodies against NMDAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) 1, AMPAR2, leucine-rich glioma-activated protein 1, contactin-associated protein 2, gamma-aminobutyric acid B receptors, paraneoplastic ma antigen 2 (PNMA2/Ta), Yo, Ri, Hu, CV2, amphiphysin, and aquaporin-4 by indirect immunofluorescence assays. RESULTS: Three anti-neuronal antibodies were detected; NMDAR antibody in one with multiple sclerosis, PNMA2/Ta antibody in one with multiple sclerosis, and Yo antibody in one with clinically isolated syndrome. The positivity rate of neuronal autoantibodies in demyelinating syndrome was 10%. All seropositive patients were found to be negative for tumor screening. None of these patients exhibited symptoms of encephalitis. CONCLUSION: Children with demyelinating syndromes without symptoms of encephalitis can be positive for anti-neuronal antibodies.

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.

Effects of oral motor therapy in children with cerebral palsy.

AIM: Oral motor dysfunction is a common issue in children with cerebral palsy (CP). Drooling, difficulties with sucking, swallowing, and chewing are some of the problems often seen. In this study, we aimed to research the effect of oral motor therapy on pediatric CP patients with feeding problems. MATERIALS AND METHODS: Included in this single centered, randomized, prospective study were 81 children aged 12-42 months who had been diagnosed with CP, had oral motor dysfunction and were observed at the Pediatric Neurology outpatient clinic of the Children's Health and Diseases Department, Istanbul Medical Faculty, Istanbul University. Patients were randomized into two groups: The training group and the control group. One patient from the training group dropped out of the study because of not participating regularly. Following initial evaluation of all patients by a blinded physiotherapist and pedagogue, patients in the training group participated in 1 h oral motor training sessions with a different physiotherapist once a week for 6 months. All patients kept on routine physiotherapy by their own physiotherapists. Oral motor assessment form, functional feeding assessment (FFA) subscale of the multidisciplinary feeding profile (MFP) and the Bayley scales of infant development (BSID-II) were used to evaluate oral motor function, swallowing, chewing, the gag reflex, the asymmetrical tonic neck reflex, tongue, jaw, and mouth function, severity of drooling, aspiration, choking, independent feeding and tolerated food texture during the initial examination and 6 months later. RESULTS: When the initial and post-therapy FFA and BSID-II scores received by patients in the training and the study group were compared, the training group showed a statistically significant improvement (P < 0.05). CONCLUSION: Oral motor therapy has a beneficial effect on feeding problems in children with CP.