Effectiveness and Safety of Epilepsy Surgery for Pediatric Patients with Intractable Epilepsy: A Clinical Retrospective Study from a Single-Center Experience.

INTRODUCTION: Pediatric epilepsy surgery is an effective treatment modality for patients with drug-resistant epilepsy (DRE). Early pediatric surgery yields favorable results for DRE in terms of seizure control and neurophysiological outcome. In this study, pediatric patients were categorized based on their age (above 3 years old and below 3 years old) to demonstrate the effectiveness and safety of surgical procedures. METHODS: In this retrospective, single-center study, 60 pediatric patients who underwent epilepsy surgery at Istanbul Faculty of Medicine between 2002 and 2018 were evaluated. Overall morbidity and mortality rates, as well as seizure outcomes of the patients, were assessed and compared based on two age groups: those aged 3 years old or younger and those older than 3 years old. The effectiveness of invasive monitoring was also evaluated in relation to pathological results. The postoperative seizure outcome rates were evaluated using Engel's classification, with an average follow-up period of 8.7 years. RESULTS: Out of the total number of patients, 47 (78.4%) underwent resective surgery, while 13 (21.6%) had palliative surgery. Ten patients (16.6%) had invasive monitoring. Among all patients, 34 were classified as Engel I and II (56.6%), while 26 were classified as Engel III and IV (43.4%) postoperatively. 47% of patients who were under 3 years old, 60.4% of patients who were over 3 years old, and 50% of patients who underwent invasive monitoring had a favorable seizure outcome (Engel I-II). Postoperative morbidity and mortality rates were 35% (n = 21) and 1.6% (n = 1), respectively. CONCLUSION: Pediatric epilepsy surgery is an important treatment modality for preserving cognitive abilities and providing effective treatment for pediatric DRE. In our study, we claim that both invasive monitoring and epilepsy surgery lead to favorable seizure outcomes for all age groups. Further clinical studies should be conducted to provide more reliable data on the safety and effectiveness of the surgery, particularly in patients under the age of three.

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.

An overview of smell and taste problems in paediatric COVID-19 patients.

At the start of the COVID-19 pandemic in March 2020, fever and respiratory symptoms were the indications for virus testing in our hospital. As data have continued to accumulate worldwide, gastrointestinal, neurological, cardiovascular, cutaneous and ocular symptoms have been reported for confirmed COVID-19 cases. There have been few case reports on problems with taste and smell in paediatric COVID-19. However, new symptoms can provide diagnostic and testing criteria for patients with no other clinical presentation, especially in older children. CONCLUSION: This paper looks at the taste and smell problems reported in paediatric patients and shares insights from our hospital.

Are Interictal Discharges Associated with Neuronal Cell Loss in Electrical Status Epilepticus in Sleep?

OBJECTIVE: Neuron-specific enolase is an established biomarker of neuronal damage. This study aimed to reveal the relationship between serum neuron-specific enolase level and continuous interictal discharges in a group of encephalopathy with electrical status epilepticus in sleep patients for the first time and determine whether there is a neuronal cell loss or damage. MATERIALS AND METHODS: We analyzed serum neuron-specific enolase levels in patients with an electrical status epilepticus in sleep pattern on their electroencephalographs with age- and sex-matched control subjects. Patients with a spike-wave index of at least 50% and acquired neuropsychological regression were included in the study. Magnetic resonance imaging of all electrical status epilepticus in sleep patients and control subjects included in the study was within normal limits. Neuron-specific enolase is measured by the enzyme-linked immunosorbent assay kit based on the sandwich technique. RESULTS: In this study, 14 patients diagnosed with electrical status epilepticus in sleep and 21 healthy controls were included. The median age of electrical status epilepticus in sleep patients was 7.1 years (min-max: 4.5-10.7 years) and 7.7 years (min-max: 3.2-14 years) in the control subjects. According to the results of serum neuron-specific enolase measurements, the mean ± standard deviation level of neuron-specific enolase was 7.61 ± 3.19 ng/dL for the electrical status epilepticus in sleep group and 6.93 ± 2.55 ng/dL for the control group. Serum neuron-specific enolase levels between electrical status epilepticus in sleep patients and the control group were not statistically significant (P = .749). CONCLUSION: No significant difference was observed in serum neuron-specific enolase levels between electrical status epilepticus in sleep patients and control subjects. Our results may indicate that frequent interictal discharges do not result in neuronal cell loss or damage in electrical status epilepticus in sleep patients.

BEND4 as a Candidate Gene for an Infection-Induced Acute Encephalopathy Characterized by a Cyst and Calcification of the Pons and Cerebellar Atrophy.

Three siblings born to Turkish parents from the same village had normal brain development until acute neurological deterioration between 12 months and 8 years of age. Consequent loss of all acquired motor, social, and language functions following infections was associated with a pontine cyst, calcification, and cerebellar atrophy. Exome sequencing revealed a homozygous c.1297G>A (p.Gly433Ser) alteration in BEND4, which was predicted to be deleterious in in silico analysis tools and segregated in multiple affected individuals in the family. BEND4 has not been associated with any existing disease. Immunofluorescence microscopy analysis of wild-type and mutant BEND4 expressing Vero cells showed nuclear and cytoplasmic localization. Wild-type BEND4 displayed a network-like distribution, whereas mutant BEND4 showed a juxtanuclear distribution pattern. Differential proteome analysis of Vero cells expressing BEND4 revealed that mutant BEND4 expression caused selective increase in reticulocalbin-1 and endoplasmic reticulum resident protein-29. Both proteins are associated with the endoplasmic reticulum and are primarily involved in protein processing and folding pathways. Any defect or stress in protein folding creates stress on cells and may cause chronic damage. This is the first study showing that pathogenic BEND4 variants may lead to an infection-induced acute necrotizing encephalopathy as demonstrated in characteristic neuroimaging findings.

Proteomic Analysis of m.8296A>G Variation in the Mitochondrial tRNA Lys Gene.

Variation in the mitochondrial tRNA Lys gene at position 8296 was previously found to be associated with maternally inherited diabetes mellitus and deafness, hypertrophic cardiomyopathy, myoclonic epilepsy with ragged-red fibers and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The pathogenicity of the m.8296A>G variation is unclear. In this study, we aimed to analyze the mitochondrial proteome in a patient with m.8296A>G variation to elucidate the effects of this mutation at the protein level. Whole-exome sequencing and mitochondrial genome analysis were performed in a patient with sensorineural hearing impairment, cognitive impairment, leukodystrophy, migraine-like headaches, and gastrointestinal dysmotility. Mitochondrial genome analysis identified a homoplasmic m.8296A>G variation in the mitochondrial tRNA Lys gene in the proband and unaffected mother. Global mitochondrial proteome analysis was carried out in the muscle mitochondria of the index patient and a control subject. Comparative muscle mitochondrial proteome analysis revealed a total of 13 nuclear-encoded mitochondrial proteins differently expressed with respect to the control. Ten of the 13 proteins were downregulated. Most of the proteins were involved in ATP synthesis and Krebs cycle and have strong interactions with each other. We considered the m.8296A>G variation to be pathogenic with variable penetrance for our patient's phenotype, and this variation led to different expressions of nuclear-encoded proteins involved in energy metabolism.

Relationship Between Lactate Levels and Length of Hospital Stay in Infants with Lower Respiratory Tract Infection.

Background: Increased lactate concentrations are directly related to the severity of shock and mortality rates. There are limited data regarding the prognostic value of lactate among lower respiratory tract infections. We aimed to investigate the impact of lactate levels on admission on the clinical outcomes of children with lower respiratory tract infections. Methods: We performed a retrospective study of hospitalized patients aged 1-12 months. We recorded data on patient demographics, clinical, laboratory, treatment, and outcomes. The primary outcome measure was the length of hospital stay, and the secondary outcome was transfer to the pediatric intensive care unit (PICU) and/or mortality rates. Results: A total of 304 infants were included in the study. There were 198 infants with lactate levels of >2 mmol/L. Lactic acidosis was present in 6 infants, with a mean hospital stay of 8 ± 3 days. Only 1 (0.3%) patient required intubation, and 5 (1.6%) were transferred to the PICU. The overall mortality rate was 0%. Lactate levels (≤2 and >2 mmol/L) were not related to the length of hospital stay, transfer to PICU/discharge, and the need for intubation (P = 0.16, 0.8, and 0.46, respectively). The length of hospital stay was not correlated with lactate levels on admission (r = 0.01, P = 0.84), pCO2 (r = 0.03, P = 0.52), pH (r = 0.07, P = 0.19), C-reactive protein (r = 0.06, P = 0.28), and oxygen saturation (r = -0.02, P = 0.72). Conclusions: Lactate levels on admission did not predict the length of hospital stay in children with lower respiratory infections and were not related to the need for transfer to the intensive care unit. We suggest using lactate levels in combination with clinical, laboratory, and physical examination findings as predictors of disease severity.

Long-term clinical and radiologic follow-up of Schilder's disease.

BACKGROUND: Schilder's disease is a rare, subacute, or chronic demyelinating disorder that mainly affects children and generally shows a monophasic course. CASE: Here, we present three boys diagnosed with Schilder's disease, age at onset 10-14 years, and followed up for 4-8 years. All of them presented with headache, two with encephalopathy and vomiting, and one with diplopia and vertigo. Cranial magnetic resonance imaging (MRI) showed two large demyelinating lesions, asymmetric in two patients and symmetric in the other. They were treated with steroid therapy. There were no radiologic relapses after discontinuation of corticosteroid therapy in all patients, but clinical attack without objective clinical findings was observed in one patient. Mild memory deficits and decline in school performance were the only neurologic sequelae in two patients. Cranial MRI findings showed significant shrinkage, but persistent T2-weighted hyperintensity of white matter lesions and loss of ring contrast enhancement at the end of the steroid therapy. There were no differences between the radiologic findings at the end of the steroid therapy and subsequent follow-ups. CONCLUSION: Although Schilder's disease is considered to be a variant of MS, it behaves more like ADEM with its monophasic course, and low recurrence rates. Radiologic features include shrinkage of mass lesions after steroid therapy, but sequel lesions remain same at the subacute and chronic stage.

Pyruvate dehydrogenase-E1α deficiency presenting as recurrent acute proximal muscle weakness of upper and lower extremities in an 8-year-old boy.

The mitochondrial pyruvate dehydrogenase enzyme complex (PDHC) plays an important role in aerobic energy metabolism and acid-base equilibrium. PDHC contains of 5 enzymes, 3 catalytic (E1, E2, E3) and 2 regulatory, as well as 3 cofactors and an additional protein (E3-binding protein) encoded by nuclear genes. The clinical presentation of PDHC deficiency ranges from fatal neonatal lactic acidosis to chronic neurologic dysfunction without lactic acidosis. Paroxysmal neurologic problems such as intermittent ataxia, episodic weakness, exercise-induced dystonia and recurrent demyelination may also be seen although they are rare. Here, we present an 8-year-old boy complaining of acute proximal muscle weakness of upper and lower extremities with normal mental status. He had a history of Guillain-Barré-like syndrome at the age of 2 years. Electrophysiologic studies showed sensorial polyneuropathy findings in the first attack and sensorimotor axonal polyneuropathy findings in the last attack. The genetic analysis revealed a previously reported hemizygote novel mutation of the PDHA1 gene (p.A353T/c.1057G > A), which encodes the E1α subunit of PDHC. Thiamine was ordered (15 mg/kg/day), dietary carbohydrates were restricted and clinical findings improved in a few weeks. This rare phenotype of PDHC deficiency is discussed.

Clinical outcomes in children with herpes simplex encephalitis receiving steroid therapy.

BACKGROUND: Herpes simplex virus encephalitis (HSE) is a significant cause of morbidity and mortality. Neurologic sequelae are common even after early initiation of acyclovir treatment. The host immune response during HSE can also lead to brain damage. There are an increasing number of reports favoring steroid use in HSE. OBJECTIVES: We aimed to compare the prognosis of children with HSE with and without steroid therapy. STUDY DESIGN: We retrospectively screened our hospital archive from 2009 to 2014 for patients diagnosed with HSE with a positive result for herpes simplex virus polymerase chain reaction in cerebrospinal fluid. Patients ≥1 month and ≤18 years at diagnosis were included in the study. Clinical outcomes in terms of cognitive function, motor function, electroencephalographic findings, seizure frequency, and radiologic findings were compared in patients who received adjuvant steroid therapy with those who did not. RESULTS: Six patients (1 boy, 5 girls; aged 4 months to 10 years) were included. Overall symptom duration before hospital admission was ≤5days. Patients received acyclovir treatment for 21-28days. Three received steroid therapy early during the disease and three patients did not. No adverse effects related to steroids were observed. Follow-up duration was 6 months to 5 years. All patients had radiologic sequelae of encephalitis. Cognition, motor function, and seizure control were better in patients who received steroid therapy. CONCLUSIONS: Adjuvant steroid therapy seems to be effective in decreasing morbidity in children with HSE but the radiologic sequelae were the same in both groups.

Clinical and neuroradiologic variability of Aicardi-Goutiéres syndrome: Two siblings with RNASEH2C mutation and a boy with TREX1 mutation.

Aicardi-Goutières syndrome (AGS) is a rare, autosomal recessively inherited, immune-mediated neurodevelopmental disorder. The syndrome causes infantile-onset progressive encephalopathy characterized by the neuroradiologic features of basal ganglia and periventricular white matter calcification, leucodystrophy and cerebral atrophy. Lymphocytosis and elevated levels of interferon alpha (IFN-alpha) in the cerebrospinal fluid are supplementary findings of AGS. It is frequently misdiagnosed as sequelae of congenital infection (pseudo-TORCH) and mostly recognized later. We describe three AGS cases with different clinical presentation, two male siblings with RNASEH2C mutation and a boy with TREX1 mutation. These cases highlight the importance of considering AGS in the differential diagnosis of unexplained leukoencephalopathy and developmental delay. We suggest to search for intracranial calcification, especially if there are more than one affected cases in a family.

TSEN54 gene-related pontocerebellar hypoplasia type 2 presenting with exaggerated startle response: report of two cases in a family.

The pontocerebellar hypoplasias (PCHs) are a heterogeneous group of autosomal recessive disorders characterized by hypoplasia of the ventral pons and cerebellum, with variable cerebral involvement and severe psychomotor retardation. Eight different subtypes (PCH1-8) have been reported up to now. PCH2 is the most common type, generally caused by homozygous mutations in the TSEN54 gene and characterized by cerebellar hypoplasia that affects the hemispheres more severely than the vermis, progressive cerebral atrophy, microcephaly, dyskinesia, seizures and death in early childhood. We present two cousins with PCH2. Both patients presented with exaggerated startle response in the newborn period. Here we discuss the clinical and neuroradiological findings of PCH2, and its differentiation from familial startle disease or hereditary hyperekplexia.