Epilepsy-related clinical factors and psychosocial functions in pediatric epilepsy.

PURPOSE: The aim of this study was to identify the different influencing patterns of demographic and epilepsy-related variables on various aspects of psychosocial function in pediatric epilepsy. METHOD: Five hundred ninety-eight patients with pediatric epilepsy between the ages of 4 and 18 years (boys=360, 60% and girls=238, 40%) and their parents participated in the study. Parents completed the Social Maturity Scale (SMS), the Korean version of the Child Behavior Checklist (K-CBCL), and the Korean version of the Quality of Life in Childhood Epilepsy Questionnaire (K-QOLCE) to assess daily living function, behavior, and quality of life. The Children's Global Assessment Scale (CGAS) was completed by clinicians to assess general adaptive function. Demographic variables, such as age and sex of child, and epilepsy-related clinical variables, including seizure type, seizure frequency, duration of epilepsy, and number of medications, were obtained from medical records. RESULTS: Demographic and epilepsy-related clinical variables had a strong influence (22-32%) on the cognition-related domain such as general adaptive function, school/total competence, and quality of life for cognitive function while a comparatively smaller effect (2-16%) on the more psychological domain including behavioral, emotional, and social variables. Younger age, shorter duration of illness, and smaller number of medications showed a strong positive impact on psychosocial function in pediatric epilepsy, particularly for adaptive function, competence, and quality-of-life aspects. CONCLUSION: Given the wide range of impact of demographic and clinical variables on various facets of psychosocial functions, more specific understanding of the various aspects of factors and their particular pattern of influence may enable more effective therapeutic approaches that address both the medical and psychological needs in pediatric epilepsy.

Therapeutic effects of exon skipping and losartan on skeletal muscle of mdx mice.

Various attempts have been made to find treatments for Duchenne muscular dystrophy (DMD) patients. Exon skipping is one of the promising technologies for DMD treatment by restoring dystropin protein, which is one of the muscle components. It is well known that losartan, an angiotensin II type1 receptor blocker, promotes muscle regeneration and differentiation by lowering the level of transforming growth factor-beta1 signaling. In this study, we illustrated the combined effects of exon skipping and losartan on skeletal muscle of mdx mice. We supplied mdx mice with losartan for 2 weeks before exon skipping treatment. The losartan with the exon skipping group showed less expression of myf5 than the losartan treated group. Also the losartan with exon skipping group recovered normal muscle architecture, in contrast to the losartan group which still showed many central nuclei. However, the exon skipping efficiency and the restoration of dystrophin protein were lower in the losartan with exon skipping group compared to the exon skipping group. We reveal that losartan promotes muscle regeneration and shortens the time taken to restore normal muscle structure when combined with exon skipping. However, combined treatment of exon skipping and losartan decreases the restoration of dystrophin protein meaning decrease of exon skipping efficiency.

Intracranial hemorrhage in infants with cephalohematoma.

BACKGROUND: Intracranial hemorrhage (ICH) is a rare birth injury in term infants. Newborn infants with cephalohematoma (CH) associated with ICH, however, have frequently been found incidentally at Kyungpook National University Hospital; many of them had no neurological symptoms. The aim of this study was to evaluate the clinical manifestations of ICH in newborn infants with CH. METHODS: Newborn infants with CH in the neonatal intensive care unit were retrospectively evaluated. During period I (5 years), neuroimaging (brain computed tomography and magnetic resonance imaging) was performed when intracranial abnormalities were suspected. During period II (36 months) neuroimaging was performed when CH > 5 cm in diameter was present. RESULTS: During period I, seven out of 19 infants who underwent neuroimaging had ICH (36.8%) including two epidural hemorrhages (EDH). During period II, 18 out of 27 infants who underwent neuroimaging had ICH (66.7%), including two EDH. There was no significant difference in the clinical manifestations between infants with and without ICH. In 10 cases of CH accompanied with a linear skull fracture, nine had ICH, including all cases of ICH that needed intervention. CONCLUSIONS: The association of ICH appears to be common in newborn infants with CH; particularly in infants with CH accompanied with a skull fracture, the rate of ICH was very high, and all cases of EDH requiring intervention were associated with skull fracture. Therefore, evaluation of accompanying skull fracture should be required in infants with CH, and, in cases of skull fracture, neuroimaging should be considered.

Differential effects of seizure control and affective symptoms on quality of life in people with epilepsy.

OBJECTIVE: The purpose of the study was to delineate how affective symptoms (AS) influence quality of life (QOL) for individuals with drug-refractory epilepsy (DRE) and those with well-controlled epilepsy (WCE) independently. METHODS: All subjects participating in the study were asked to complete reliable and validated self-report health questionnaires, including AS, measured with the Korean versions of the Beck Depression Inventory, Beck Anxiety Inventory, and Quality of Life in Epilepsy Inventory-31 (QOLIE-31). We examined predictors of QOLIE-31 scores among the various demographic and clinical factors. We compared the effects of AS on QOL between patients with DRE and those with WCE and investigated the differential effects of seizure control and AS on QOL. RESULTS: Two hundred forty-nine patients with DRE or WCE were included in the study. The strongest predictor of QOL was AS, followed by seizure control and MRI abnormality. Affective symptoms had almost two times the effect of seizure control and six times the effect of MRI abnormality. Poorest QOL was noted in patients with DRE with AS, followed by those with WCE with AS, DRE without AS, and WCE without AS. CONCLUSION: The major determinant of QOL in patients with epilepsy is AS rather than DRE or WCE status.

Neuropsychological effects of levetiracetam and carbamazepine in children with focal epilepsy.

OBJECTIVE: To prospectively evaluate the neuropsychological effect of levetiracetam (LVT) in comparison with carbamazepine (CBZ) and its efficacy and tolerability as a monotherapy in children with focal epilepsy. METHODS: A total of 121 out of 135 screened children (4-16 years) were randomly assigned to LVT or CBZ groups in a multicenter, parallel-group, open-label trial. The study's primary endpoints were defined as the end of 52 weeks of treatment, followed by analysis of changes observed in a series of follow-up neurocognitive, behavioral, and emotional function tests performed during treatment in the per protocol population. Drug efficacy and tolerability were also analyzed among the intention-to-treat (ITT) population (ClinicalTrials.gov, number NCT02208492). RESULTS: Eighty-one patients (41 LVT, 40 CBZ) from the randomly assigned ITT population of 121 children (57 LVT, 64 CBZ) were followed up to their last visit. No significant worsening or differences were noted between groups in neuropsychological tests, except for the Children's Depression Inventory (LVT -1.97 vs CBZ +1.43, p = 0.027, [+] improvement of function). LVT-treated patients showed an improvement (p = 0.004) in internalizing behavioral problems on the Korean Child Behavior Checklist. Seizure-free outcomes were not different between the 2 groups (CBZ 57.8% vs LVT 66.7%, p = 0.317). CONCLUSIONS: Neither LVT nor CBZ adversely affected neuropsychological function in pediatric patients. Both medications were considered equally safe and effective as monotherapy in children with focal epilepsy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with pediatric focal epilepsy, LVT and CBZ exhibit equivalent effects on neuropsychological function.

Detection and characterization of 45 kDa platelet activating factor acetylhydrolase in cerebrospinal fluid of children with meningitis.

Platelet activating factor acetylhydrolase (PAF-AH) activity has been identified in cerebrospinal fluid (CSF) samples taken from children with meningitis. We reported that PAF-AH activity is significantly increased, by about 3 fold, in patients with meningitis compared to control subjects. Because of limited knowledge about this enzyme in CSF, we examined the biochemical properties of CSF PAF-AH. PAF-AH of CSF was calcium independent, showed a broad pH spectrum and was relatively heat stable. In addition, this enzyme activity was strongly inhibited by phenylmethanesulfonyl fluoride (PMSF), partially inhibited by p-bromophenacylbromide (p-BPB), uninhibited by iodoacetamide, and moderately stimulated by dithiothreitol (DTT). PAF-AH of CSF did not degrade phospholipid with a long chain fatty acyl group at sn-2 position. This enzyme hydrolyzed PAF and oxidatively modified phosphatidylcholine. Furthermore, we identified a monomeric polypeptide with a molecular weight of approximately 45 kDa by Western blot using human plasma PAF-AH antibody. These results suggested that plasma type PAF-AH activity exist in CSF taken from children with meningitis.

Losartan improves adipose tissue-derived stem cell niche by inhibiting transforming growth factor-ß and fibrosis in skeletal muscle injury.

Recently, adipose tissue-derived stem cells (ASCs) were emerged as an alternative, abundant, and easily accessible source of stem cell therapy. Previous studies revealed losartan (an angiotensin II type I receptor blocker) treatment promoted the healing of skeletal muscle by attenuation of the TGF-ß signaling pathway, which inhibits muscle differentiation. Therefore, we hypothesized that a combined therapy using ASCs and losartan might dramatically improve the muscle remodeling after muscle injury. To determine the combined effect of losartan with ASC transplantation, we created a muscle laceration mouse model. EGFP-labeled ASCs were locally transplanted to the injured gastrocnemius muscle after muscle laceration. The dramatic muscle regeneration and the remarkably inhibited muscular fibrosis were observed by combined treatment. Transplanted ASCs fused with the injured or differentiating myofibers. Myotube formation was also enhanced by ASC(+) satellite coculture and losartan treatment. Thus, the present study indicated that ASC transplantation effect for skeletal muscle injury can be dramatically improved by losartan treatment inducing better niche.

Intraparenchymal pericatheter cyst as a complication of a ventriculo-peritoneal shunt in a premature infant.

A ventriculo-peritoneal shunt is a standard surgical management for hydrocephalus, but complications may impede the management of this disease. Obstruction of the catheter is one of the most common complications and manifests clinically in various ways. Intraparenchymal cyst development after shunt malfunction has been reported by several authors, but the underlying mechanism and optimal treatment methods are debatable. The authors report a case of intraparenchymal cyst formation around a proximal catheter in a premature infant after a ventriculo-peritoneal shunt and discuss its pathogenesis and management.

Predictors of suicidal ideation in people with epilepsy living in Korea.

BACKGROUND AND PURPOSE: The risk of suicide or suicide attempts is reported higher in people with epilepsy (PWE) than in the general population. Although epileptic, psychiatric, and psychosocial factors are known risk factors for suicide or suicide attempt, no studies have evaluated the predictors of the severity of suicidal ideation-which is a warning sign for suicide attempts-in PWE. Therefore, we measured the severity of suicidal ideation and its risk factors. METHODS: Consecutive PWE who were medicated with antiepileptic drugs (AEDs) and attended epilepsy clinic were included in the study. The subjects completed self-reported questionnaires, which included the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Symptom Checklist-90-Revised (SCL-90-R), and Scale for Suicide Ideation-Beck (SSI-Beck). We compared the patients' demographic and clinical variables, and BDI, BAI, and SCL-90-R scores with their SSI-Beck score, and used our findings to determine the predictors for suicidal ideation. RESULTS: In total, 257 PWE were enrolled in the study. SSI-Beck scores correlated strongly with several seizure-related variables, duration of education, IQ, BDI and BAI scores, and nine domains of the SCL-90-R questionnaire. However, the strongest predictor for suicidal ideation was BDI score (beta=0.41, p<0.001), followed by several SCL-90-R domains, such as obsessive-compulsive (beta=-0.39, p<0.001), depression (beta=0.38, p<0.001), hostility (beta=0.22, p=0.002), paranoid ideation (beta=0.17, p=0.01), and IQ (beta=-0.10, p=0.017). These variables explained 59% of the variance in the SSI-Beck score. The seizure-related variables that influenced the BDI score were seizure frequency, duration of education, MRI abnormality, and number of AEDs. However, these variables explained only 18% of the variance in the BDI score. CONCLUSIONS: Major risk factors for suicidal ideation in PWE were depressive and psychiatric symptoms rather than seizure-related variables. Therefore, clinicians should focus on screening for depression and other psychiatric problems and treat them appropriately in order to reduce suicidal behavior in PWE. Since seizure-related variables also exhibited a minor role in determining depressive symptoms, stronger seizure-related risk factors for depression should be sought, such as seizure severity or psychosocial factors, to minimize suicidal behavior.

Cognitive effects of antiepileptic drugs.

Antiepileptic drugs (AEDs) can adversely affect cognitive function by suppressing neuronal excitability or enhancing inhibitory neurotransmission. The main cognitive effects of AEDs are impaired attention, vigilance, and psychomotor speed, but secondary effects can manifest on other cognitive functions. Although the long-term use of AEDs can obviously elicit cognitive dysfunction in epilepsy patients, their cognitive effects over short periods of up to a year are inconclusive due to methodological problems. In general, the effects on cognition are worse for older AEDs (e.g., phenobarbital) than for placebo, nondrug condition, and newer AEDs. However, topiramate is the newer AED that has the greatest risk cognitive impairment irrespective of the comparator group. Since the cognitive impact of AEDs can be serious, clinicians should be alert to adverse events by evaluating cognitive function using screening tests. Adverse cognitive events of AEDs can be avoided by slow titration to the lowest effective dosage and by avoiding polytherapy.

Long-term cognitive and mood effects of zonisamide monotherapy in epilepsy patients.

This study was a prospective, randomized, open-label investigation of the long-term effects of zonisamide (ZNS) monotherapy on cognition and mood of patients with epilepsy. Forty-three patients with epilepsy received ZNS, with final dose groups of 100, 200, 300, and 400mg/day. Cognitive and mood tests were done twice, at baseline and 1 year after starting medication. Nine patients were withdrawn prior to their follow-up tests. Three patients (33%) dropped out during the titration period because of cognitive and mood problems. Thirty-four patients completed follow-up neuropsychological tests. After 1 year of treatment, 16 patients (47%) complained of cognitive deficits. Only 5 patients (15%) experienced mood changes. Although ZNS decreased seizure frequency and EEG abnormalities and did not elicit significant mood changes, it had negative effects on several cognitive tests. Worse performance on delayed word recall, Trail Making Test Part B, and verbal fluency was related to dose. In conclusion, ZNS has adverse effects on cognition even after 1 year of treatment.

Long-term efficacy and safety of zonisamide monotherapy in epilepsy patients.

BACKGROUND AND PURPOSE: Zonisamide (ZNS) is a useful antiepileptic drug with a broad therapeutic spectrum. However, there is limited information on the long-term use of ZNS as a monotherapy. This study investigated the long-term effects of ZNS as a monotherapy for the treatment of epilepsy. METHODS: We retrospectively analyzed the records of epilepsy patients treated with ZNS monotherapy at our clinic. We identified outcomes for patients treated with ZNS monotherapy for a minimum of 6 months. Efficacy was quantified as the percentage change in seizure frequency, and safety was assessed by the frequency and types of adverse events. RESULTS: Sixty patients who received ZNS for a minimum of 6 months were included. The mean duration of treatment was 19.8 months (range, 6-37 months), and the mean ZNS dosage was 255 mg/day (range, 100-500 mg/day). Twenty-seven patients (45%) were seizure-free, and an additional 20 patients (33%) had above 50% seizure frequency reduction at the last follow-up visit. Partial seizures with or without secondary generalization and generalized seizures were well controlled by ZNS, whereas complex partial seizures were not. Forty-eight patients (80%) reported mild-to-moderate adverse events, including memory loss (35%), attention deficit (27%), and weight loss (20%). CONCLUSIONS: Long-term ZNS monotherapy is effective at treating a broad spectrum of seizure disorders, except complex partial seizures. However, a specific adverse event, such as cognitive impairment, is common and long-lasting.

Cognitive impairment in juvenile myoclonic epilepsy.

BACKGROUND AND PURPOSE: Cognitive impairments are frequent consequences of epilepsy, with intellectual ability reportedly being lower in patients with idiopathic generalized epilepsies than in the general population. However, neuropsychological investigations have been rarely performed in patients with juvenile myoclonic epilepsy (JME). We aimed to quantify the cognitive function in JME patients using various neuropsychological tests. METHODS: We compared cognitive function in 27 JME patients with that in 27 healthy volunteers using tests examining cognitive performance, such as the verbal and visual memory, frontal function, attention, IQ score, and mood. In the JME group, we examined risk factors for cognitive function such as age, sex, family history, education level, age at seizure onset, seizure frequency, EEG abnormality, disease duration, and previous intake of antiepileptic drugs. RESULTS: Verbal learning was significantly lower in JME patients than in controls, and attention and verbal fluency were impaired in JME patients compared with controls. However, general intellectual ability and mood did not differ between the groups. Early onset of seizure and long duration of disease were closely related to impaired cognitive function. CONCLUSIONS: JME patients may exhibit impaired cognitive function, in terms of memory and execution, despite having normal intelligence and mood.

Comparison of cognitive effects of lamotrigine and oxcarbazepine in epilepsy patients.

BACKGROUND AND PURPOSE: This study compared the cognitive effects of 1 year of treatment with lamotrigine (LTG) and oxcarbazepine (OXC) in epilepsy patients. METHODS: This retrospective study investigated 60 epilepsy patients undergoing neuropsychological tests who were either newly diagnosed or untreated in the preceding 6 months. The cognitive function in 30 patients receiving LTG monotherapy and 30 age-matched patients receiving OXC monotherapy was compared after 1 year. The neuropsychological scores at baseline and all of the epilepsy-relevant variables except seizure type did not differ between the groups. The mean daily dosages of LTG and OXC at 1 year were 93 mg and 825 mg, respectively. RESULTS: The posttreatment list-learning performance was better in the LTG group than in the OXC group (p<0.05). The incidence of cognitive complaints did not differ between the two groups. The list-learning performance and Trail Making Test scores were better in each group after treatment. CONCLUSIONS: LTG and OXC monotherapies have similar, slightly beneficial effects on cognitive function, and are probably not harmful.

Cognitive effects of low-dose topiramate monotherapy in epilepsy patients: A 1-year follow-up.

The present study was conducted to evaluate the long-term effects of low-dose topiramate (TPM) monotherapy on the cognitive function of epilepsy patients. Forty-seven epilepsy patients received TPM, with target doses of 50, 75, and 100 mg/day. Cognitive tests were performed twice, at baseline and 1 year after starting medication. Thirty-six patients completed the follow-up neuropsychological tests. After a year of treatment, 16 patients (44%) complained of cognitive problems. Although it improved seizure frequency and EEG abnormalities, TPM had significantly negative effects on the digit span and verbal fluency tests. These cognitive effects were dose-related and significantly improved after withdrawal from TPM and substitution with older antiepileptic drugs. In conclusion, even at a low dose, TPM has long-term, negative effects on working memory and verbal fluency.

Molecular analysis of HLA class II-associated susceptibility to neuroinflammatory diseases in Korean children.

The work was done to study immunogenetic peculiarities of neuroinflammatory diseases among Korean children. A total of 13 children with neuroinflammatory diseases (8 males and 5 females; mean age 4.6 +/-2.6 yr) were consecutively recruited. Geno-mic typing was performed on their HLA DRB/HLA DQB genes using PCR-SSOP/SSP techniques with gel immunoelectrophoresis. The frequencies of HLA-DR1 *15 in children with acute disseminated encephalomyelitis (ADEM) (31%) and DQB1 *06 in other neuroinflammatory diseases (38%) were significantly increased compared with control subjects. The frequencies of HLA-DRB3 * 0202 (100%), HLA-DRB1 * 1302 (67%), HLA-DRB3 * 0301 (67%), and HLA-DQB1 * 0301 (67%) were significantly increased in children with multiple sclerosis and the frequencies of HLA-DRB1 * 1501 (40%) and HLA-DRB5 * 0101 (40%) were significantly increased in children with ADEM. HLA-DRB1 * 1401, HLA- DRB3 * 0202, and HLA-DQB1 * 0502 were found in children with acute necrotizing encephalopathy. In conclusion, HLA-DR1 * 15 and DQB1 * 06 may be involved in susceptibility to inflammation in Korean children. The frequencies of HLA-DRB1 * 1501, HLA-DRB5 * 0101, HLA-DRB3 * 0301, and HLA-DQB1* 0602 were not as high in Korean children with multiple sclerosis as in western children. However, HLA-DRB3 * 0202 was seen in all children with multiple sclerosis. Our data may provide further evidence that the immunogenetic background of neuroinflammatory diseases in Korean is distinctly different from the ones in western countries. Further studies are necessary to confirm this finding.

Interleukin-8 and tumor necrosis factor-alpha are increased in minimal change disease but do not alter albumin permeability.

AIMS: Minimal change disease (MCD) is the most common primary nephrotic syndrome in children. Some suggested that interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) are involved in the pathogenesis of MCD. This study was done to see changes of plasma and urinary IL-8, TNF-alpha, and their effects on determination of permeability of glomerular basement membrane (BM) contributed by heparan sulfate proteoglycan (HSPG). METHODS: Study patients consisted of 19 biopsy-proven MCD children aged 2-15 years old. Both plasma, urinary IL-8 and TNF-alpha were measured. Employing the Millicell system, IL-8 and TNF-alpha were screened for the permeability factors. We examined whether IL-8 and TNF-alpha regulated BM HSPG gene expression and HS synthesis in the glomerular epithelial cells (GECs). RESULTS: Urinary IL-8 during relapse was significantly increased when compared with that of during remission or controls (13,996 +/- 2,811 vs. 2,941 +/- 373, 5,331 +/- 640 ng/mg.cr) (p < 0.05). Urinary TNF-alpha during relapse was also significantly increased (364.4 +/- 51.2 vs. 155.3 +/- 20.8, 36.0 +/- 4.5 ng/mg.cr) (p < 0.05). Plasma IL-8 during relapse was significantly increased compared to that during remission(1.19 +/- 0.62 vs. 0.51 +/- 0.42 ng/ml) (p < 0.05). However, the negative results were obtained in the permeability assay using the Millicell system. No difference was seen in BM HSPG gene expression and HS synthesis in the GECs. CONCLUSION: Therefore, it seems that both IL-8 and TNF-alpha may not play a disease-specific role in the pathogenesis of MCD.