Mitochondrial metabolism related markers GDF-15, FGF-21, and HIF-1α are elevated in pediatric migraine attacks.

OBJECTIVE: The purpose of this study was to investigate the serum levels of mitochondrial metabolism/reactive oxygen species (ROS)-related peptides (hypoxia inducible factor-1α [HIF-1α], fibroblast growth factor-21 [FGF-21], growth differentiation factor-15 [GDF-15]) and key migraine-related neuropeptides (calcitonin gene-related peptide [CGRP], pituitary adenylate cyclase-activating peptide-38 [PACAP-38], substance P [SP], and vasoactive intestinal peptide [VIP]) during migraine attacks and to evaluate their diagnostic value in pediatric migraine. BACKGROUND: There is increasing evidence for the important role of impairment in oxidative mitochondrial metabolism in the pathophysiology of migraine. Potential biomarkers that may reflect the relationship between migraine and mitochondrial dysfunction are unclear. METHODS: A total of 68 female pediatric migraine patients without aura and 20 female healthy controls aged 8-18 years, admitted to the hospital, were enrolled in this cross-sectional study. Serum concentrations of these molecules were determined by enzyme-linked immunosorbent assays, and clinical features and their possible diagnostic value were analyzed. RESULTS: Serum levels of HIF-1α (252.4 ± 51.9 [mean ± standard deviation]) pg/mL), GDF-15 (233.7 ± 24.7 pg/mL), FGF-21 (96.1 ± 13.1 pg/mL), CGRP (44.5 ± 11.3), and PACAP-38 (504.7 ± 128.9) were significantly higher in migraine patients compared to healthy controls (199.8 ± 26.8, 192.8 ± 20.7, 79.3 ± 4.1, 34.1 ± 3.5 and 361.2 ± 86.3 pg/mL, respectively). The serum levels of these peptides were also higher in patients with chronic migraine than in patients with episodic migraine, and higher in the ictal period than in the interictal period. A positive correlation was found between attack frequency and both HIF-1α and FGF-21 levels in migraine patients. Serum levels of VIP and SP were not different between the migraine patients and healthy controls. CONCLUSION: Migraine attacks are accompanied by elevated HIF-1α, FGF-21, GDF-15, CGRP, and PACAP-38 in medication-naive pediatric patients with migraine. Elevated circulating mitochondrial metabolism/ROS-related peptides suggest a mitochondrial stress in pediatric migraine attacks and may have potential diagnostic value in monitoring disease progression and treatment response in children. Novel approaches intervening with mitochondrial metabolism need to be investigated.

Esculetin alleviates pentylenetetrazole-induced seizures, cognitive impairment and pro-inflammatory cytokines and suppresses penicillin-induced epileptiform activity in rats.

AIMS: To investigate the effects of different doses of esculetin on epileptiform activity, behavioral seizures, memory impairment, and cortical and hippocampal NF-κB, as a mediator of pro-inflammatory gene induction, and pro-inflammatory cytokines in penicillin- and pentylenetetrazole(PTZ)-induced seizure models in rats. MAIN METHODS: Different doses of esculetin (5, 10, and 20 mg/kg), and diazepam (5 mg/kg) as a positive control, were tested in penicillin- and pentylenetetrazole(PTZ)-induced seizure models. In the PTZ model, cognitive function, behavioral seizures, and cortical and hippocampal pro-inflammatory biomarkers and survival factor was evaluated. In the penicillin model, the frequency and amplitude of electrophysiological epileptiform activity were assessed. KEY FINDINGS: In the PTZ model, the 10 mg/kg esculetin displayed anticonvulsant effects by extending onset-times of myoclonic-jerk and generalized tonic-clonic seizure, and by diminishing seizure severity and duration of generalized tonic-clonic seizure. It also ameliorated PTZ-induced cognitive impairment, and cortical and hippocampal activin-A, IL-1ß, IL-6 and NF-κB levels. In the penicillin model, the 10 mg/kg esculetin decreased the frequency of spikes without changing the amplitude of spikes. As a positive-control, diazepam reversed all changes induced by both PTZ and penicillin. SIGNIFICANCE: Esculetin exhibits anticonvulsant and memory-improving effects by alleviating the behavioral and electrophysiological characteristics of epileptic seizures. Additionally, esculetin exerts anti-neuroinflammatory actions in the PTZ-induced seizures model. Thus, esculetin may be a multi-targeted promising agent with anticonvulsant and anti-neuroinflammatory effects in the treatment of epilepsy.

Can hyperoxic stress cause susceptibility to acute seizure in the neonatal period?: a rat study.

Objective: Preterm neonates encounter hyperoxia relatively early, and are more exposed to hyperoxic stress due to their insufficient antioxidant defense mechanisms. This study was planned around the hypothesis that this hyperoxic effect may cause a disposition to future acute seizures. Methods: This study was composed of two main groups Hyperoxy and Control (Room air with normal O2 levels) Groups. Group 1 - hyperoxia (Study): The experimental group consisted of premature newborn rats exposed to hyperoxia with their dams from birth to postnatal day 5. Group 2 - room air (Control): The group was not exposed to hyperoxia and housed the same room air and temperature as their dams. Female, Acute Epilepsy Female, Male, Acute Epilepsy Male, and a total of eight subgroups were formed in both the control and hyperoxia groups. When the rats were two months old, intracranial electrodes were attached to obtain electrocorticography (ECoG) recordings. Pre-model recordings were taken, after which an acute pentylenetetrazole (PTZ) model of absence seizure was induced by the intraperitoneal administration of PTZ at 50 mg/kg. ECoG records were examined using the PowerLab system for 180 min. Spike wave number and duration, Spike wave frequency and amplitude data were evaluated.Results: Seven female and three male rats were exposed to hyperoxia, and a control group of five female and three male rats were included in the study. The median interquartile range for spike wave latency in the hyperoxia and control groups were 1112 (644-1545) and 654 (408-1152), frequency 4476 (3120-7421) and 3934 (2264-4704), and amplitude data 0.68 (0.59-0.79) and 0.52 (0.37-0.67), respectively. Although a difference was observed in median values capable of constituting susceptibility to epilepsy, the difference was not statistically significant (p > 0.05). In terms of gender, spike-wave counts were significantly higher in female rats (p < 0.05). Females exposed to hyperoxia were more susceptible to epilepsy than both males and females in the control group (p < 0.05).Conclusion: Exposure to hyperoxia in the first days of life of premature neonates due to their susceptibility to oxidative stress and insufficient antioxidant mechanisms, can cause a disposition to acute seizures. As a result, females exposed to hyperoxia during the neonatal period may be prone to epilepsy in maturity.

Risk factors affecting seizure recurrence in childhood epilepsy during short-term follow-up.

PURPOSE: The aim of this study is to examine the factors affecting seizure recurrence in pediatric patients diagnosed with epilepsy. METHODS: Three hundred patients presenting to the pediatric neurology clinic between 2015 and 2018 and diagnosed with epilepsy and treated with single antiseizure drug were included in the study. Medical histories and clinical and laboratory findings were retrieved retrospectively from the hospital data system. The combined and adjusted effects of risk factors on seizure recurrence were evaluated using multivariate binary logistic regression analysis. RESULTS: Boys had a higher rate of seizure recurrence than girls. Seizure recurrence was also higher in patients with abnormal neurological examinations at the time of diagnosis compared to those with normal neurological examinations. Seizure recurrence was significantly higher in patients with global growth retardation. Epilepsy patients with abnormal MRI findings also had a higher rate of seizure recurrence than patients with normal neuroimaging findings. In addition, seizure recurrence was significantly higher in epilepsy patients with comorbidities such as cerebral palsy and autism spectrum disorders compared to patients without comorbidities. No significant association was observed between seizure recurrence and the first drug, perinatal asphyxia history, localization of epileptiform discharges on EEG, family history of epilepsy, family history of febrile seizures, history of stay in the neonatal intensive care unit during the perinatal period, or preterm delivery. CONCLUSION: Abnormal neurological examination, abnormal neuroimaging and accompanying comorbidities, and global growth retardation at the time of diagnosis are important factors affecting seizure recurrence in pediatric patients with epilepsy.

Plasma levels of vasoactive neuropeptides in pediatric patients with migraine during attack and attack-free periods.

BACKGROUND: Increasing evidence suggests that vasoactive neuropeptides such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide are involved in the pathophysiology of migraine in adults, but their role in pediatric migraineurs remains unclear. We prospectively investigated plasma levels of these vasoactive neuropeptides in pediatric migraine patients without aura and compared the results with those of age-matched healthy controls. METHODS: Thirty-eight children aged 6-18 years with migraine without aura and 20 age-matched control subjects were included in the study. Neuropeptides in plasma samples from the controls, and in either the ictal or interictal periods in pediatric migraine without aura, were measured using ELISA. RESULTS: PACAP-38 and vasoactive intestinal peptide levels in both ictal and interictal plasma were higher in the patients with pediatric migraine without aura than in the controls (p < 0.001), although calcitonin gene-related peptide and substance P levels remained unchanged. Otherwise, no significant difference was determined between ictal and interictal periods in terms of all neuropeptide levels. CONCLUSIONS: This study demonstrates increased plasma PACAP-38 and vasoactive intestinal peptide levels, but not calcitonin gene-related peptide and substance P levels, in pediatric patients with migraine during both attack and attack-free periods. The study findings suggest that PACAP-38 and vasoactive intestinal peptide may be implicated in the pathophysiology of migraine, particularly in pediatric migraineurs.

The role of clinical signs in the diagnosis of papilledema: development of an algorithm.

PURPOSE: The aim of this study was not only to emphasize the role of clinical signs as well as ophthalmologic evaluation for accurate and differential diagnosis of papilledema (PE), but also to present an instructive algorithm that would help to eliminate unnecessary examinations and treatments. METHOD: The files of 43 patients (ages 0-18) diagnosed with PE were retrospectively reviewed. The study included 25 patients from our pediatric neurology outpatient clinic, who were thought to have PE, and 18 patients, who were referred from the external centers to our hospital with a pre-diagnosis of PE. RESULTS: Of the 43 patients, 28 had PE, 8 had pseudopapilledema (PPE), and 7 had optic nerve pathologies (ONP). For patients who applied directly to our pediatric neurology unit, a margin of error of 8% was detected based on only a simple ophthalmologic examination and an evaluation of clinical findings. For the patients who were forwarded to our pediatric neurology unit from the external centers without examining any clinical findings and with no details, the margin of error was 72%. CONCLUSION: For patients with suspected PE, advanced ophthalmologic opinion is a necessary requirement before invasive radiological examinations are used. When the ophthalmologic evaluation is properly elaborated, the distinction can be made more clearly by using noninvasive methods. In order to determine the gold standard in terms of the methods used in the evaluation of patients who are not clinically diagnosed, new prospective studies with more patients should be planned.

Epilepsy and drug-resistant epilepsy in children with cerebral palsy: A retrospective observational study.

PURPOSE: The objective of this study was to determine risk factors for epilepsy and drug-resistant epilepsy (DRE) development in children with cerebral palsy. METHOD: Two hundred twenty-nine patients presenting to the pediatric neurology clinic and diagnosed as having cerebral palsy between November 2016 and November 2019 were included in the study. Medical histories and clinical, laboratory, and radiological findings were examined retrospectively from patient records in the hospital data system. RESULTS: Girls represented 103 patients (45%) and boys 126 (55%). The patients' mean age was 8.39 ±â€¯4.54 years. Epileptic seizures were present in 120 (52.4%) patients and drug-resistant seizures in 64 (27.9%). The risk of epilepsy was significantly higher in patients with motor or speech impairment, with hearing impairment, or undergoing first seizure in the neonatal period. We also observed a higher risk of epilepsy in patients with psychiatric comorbidity, particularly autism spectrum disorder. The risk of epilepsy was also higher in patients with microcephaly or quadriplegic cerebral palsy and in patients with focal and generalized epileptiform abnormality on electroencephalograms (EEGs). However, no significant difference was identified when all these factors were evaluated in terms of the risk of developing DRE. CONCLUSION: Patients with cerebral palsy have high comorbid epilepsy rates. We think that the risk of epilepsy may be higher in patients undergoing first seizure in the neonatal period, with microcephaly, with quadriplegic type cerebral palsy, and with additional psychiatric comorbidity. The rate of DRE development was very low in patients with normal EEG findings or with only background rhythm abnormalities on first EEGs during neonatal seizures. This may be regarded as a good prognostic factor for nondevelopment of DRE.

Reflex Epilepsy with Hot Water: Clinical and EEG Findings, Treatment, and Prognosis in Childhood.

Hot water epilepsy (HWE) is a subtype of reflex epilepsy in which seizures are triggered by the head being immersed in hot water. Hot water or bathing epilepsy is the type of reflex epilepsy most frequently encountered in our clinic. We describe our patients with HWE and also discuss the clinical features, therapeutic approaches, and prognosis. Eleven patients (10 boys, 1 girl), aged 12 months to 13 years, admitted to the pediatric neurology clinic between January 2018 and August 2019, and diagnosed with HWE or bathing epilepsy based on International League Against Epilepsy (ILAE)-2017, were followed up prospectively for ∼18 months. Patients' clinical and electroencephalography (EEG) findings and treatment details were noted. All 11 patients' seizures were triggered by hot water. Age at first seizure was between 2 months and 12 years. Seizure types were generalized motor seizures, absence, and atonic. EEG was normal in two patients, but nine patients had epileptiform discharges. Magnetic resonance imaging of the brain was performed and reported as normal (except in one case). Histories of prematurity were present in two patients, unprovoked seizures in one, and low birth weight and depressed birth in the other. Patients with HWE have normal neuromuscular development and neurological examination results, together with prophylaxis or seizure control with a single antiepileptic drug, suggesting that it is a self-limited reflex epilepsy.

The role of obesity and vitamin D deficiency in primary headaches in childhood.

This study evaluates the role of obesity, overweight and vitamin D deficiency in primary headaches in childhood. This retrospective observational study included pediatric patients aged 5-17 years admitted to the pediatric neurology clinic with headaches between January 2015 and August 2018 and diagnosed with primary headache based on ICHD III-beta criteria. The control group consisted of healthy children without headache admitted to the pediatric outpatient clinic for check-ups before engaging in athletic or school activities. The control and patient groups were at the same risk of low 25(OH)D3 levels. The study population was divided into three groups-patients with migraine (group A), patients with tension-type headache (TTH) (group B) and the control group (group C). Participants' demographic data, medical histories, physical examination findings and laboratory results were retrieved retrospectively from the patient charts. BMI was significantly higher in patients with primary headache, the risk of primary headache increasing in patients with a BMI in excess of 25. Comparison of the patients with primary headache and the control group revealed lower 25(OH)D levels in the primary headache group, although the difference was not statistically significant. Girls with primary headache had significantly lower 25(OH)D levels than boys. A relationship may be present between overweight, obesity and primary headache, while female gender may be suggested as a negative factor for primary headache. Patients should be advised to lose weight if BMI indicates overweight or obesity.

Cause or Consequence: The Relationship Between Cerebral Venous Thrombosis and Idiopathic Intracranial Hypertension.

AIM: The aims of our study were to refer to the complex relationship between idiopathic intracranial hypertension (IIHT) and cerebral sinovenous thrombosis (CSVT), and to determine the differences and commonalities between the patients with and without CSVT in their etiology, along with documenting the uncertainties in concluding on the diagnosis and treatment of these patients. MATERIAL AND METHODS: IIHT was diagnosed according to Dandy criteria, while CSVT was screened for by way of a cranial magnetic resonance imaging for all patients and cranial magnetic resonance venography only if the magnetic resonance imaging was nebulous or there was a family history. RESULTS: We retrospectively evaluated a total of 26 patients (9 of whom had CSVT) diagnosed with IIHT between 2014 and 2018. A total of 9 patients with concurrent CSVT were described as suffering from vascular IIHT, while the remaining 17 were described as suffering from other IIHT. Demographic characteristics were similar in both groups (mean age: 12 vs. 11; male/female ratio: 2/7 vs. 5/12 in vascular IIHT and other IIHT, respectively). Clinical findings, cerebrospinal fluid-opening pressure values, and pathologies of etiology were also similar (vitamin D deficiency: 66% vs. 52%; vitamin B12 deficiency: 11% vs. none; iron deficiency: 22% vs. 11%; obesity: 22% vs. 23%). A mixture of acetazolamide, topiramate, anticoagulant therapy, and acetylsalicylic acid were given according to the diagnoses. CONCLUSION: CSVT is a common clinical entity among the causes of IIHT, and it should be taken into consideration in this patient group. However, there is a need for a common guideline for laboratory and imaging methods to understand the etiopathogenesis of childhood IIHT and determine the patients at risk.

Childhood Facial Palsy: Etiologic Factors and Clinical Findings, an Observational Retrospective Study.

The purpose of this study was to determine the etiologic factors, clinical characteristics, seasonal distributions, family history, response to corticosteroid therapy, recurrence and residual paralysis rates, and factors affecting these in pediatric facial palsy. Patients aged <18 years diagnosed with acute peripheral facial palsy were included in the study. Demographic data and clinical findings were retrieved from patients' records. The study was completed with 113 patients. Causes were idiopathic in 74 (65.4%) cases. Complete healing was not achieved in 6 (5.3%) patients, and recurrence was observed in 11 (9.7%). None of the patients with residual paralysis used corticosteroid, but all the patients with recurrence had employed them. We determined that young age may have an adverse impact on complication development and that corticosteroid therapy may be useful in the healing process in idiopathic facial nerve palsy. In conclusion, age may have an adverse impact in idiopathic facial nerve palsy, whereas corticosteroid therapy has a positive effect.