Association of hypercalciuria with vitamin D supplementation in patients undergoing ketogenic dietary therapy.

Background: Ketogenic dietary therapy (KDT) is used as an effective treatment for epilepsy. However, KDT carries the risk of bone health deterioration; therefore, vitamin D supplementation is required. Vitamin D replacement therapy in KDT has not been established because it may be related to hypercalciuria/urolithiasis, which are common adverse effects of KDT. Hence, this study aimed to evaluate the dose-dependent association between vitamin D3 and hypercalciuria/urolithiasis in patients undergoing KDT and dose optimization for renal complications. Materials and methods: Overall, 140 patients with intractable childhood epilepsy started 3:1 KDT (lipid to non-lipid ratio) at the Severance Children's Hospital from January 2016 to December 2019. Regular visits were recommended after KDT initiation. Participants were assessed for height, weight, serum 25-hydroxyvitamin D (25-OH-D3) level, parathyroid hormone level, and ratio of urinary excretion of calcium and creatinine (Uca/Ucr). Kidney sonography was conducted annually. Patients who already had urolithiasis and were taking hydrochlorothiazide before KDT, failed to maintain KDT for 3 months, did not visit the pediatric endocrine department regularly, did not take prescribed calcium and vitamin D3 properly, or needed hospitalization for > 1°month because of serious medical illness were excluded. Data from patients who started diuretic agents, e.g., hydrochlorothiazide, were excluded from that point because the excretion of calcium in the urine may be altered in these patients. Result: In total, 49 patients were included in this study. Uca/Ucr ratio significantly decreased with increasing levels of 25-OH-D3 (p = 0.027). The odds ratio for hypercalciuria was 0.945 (95% confidence interval, 0.912-0.979; p = 0.002) per 1.0 ng/mL increment in 25-OH-D3 level. Based on findings of receiver operating characteristic curve analysis and Youden's J statistic, the cut-off 25-OH-D3 level for preventing hypercalciuria was > 39.1 ng/mL at 6 months. Furthermore, the vitamin D3 supplementation dose cut-off was > 49.5 IU/kg for hypercalciuria prevention. Conclusion: An inverse relationship between Uca/Ucr ratio and 25-OH-D3 level was noted, which means that vitamin D supplementation is helpful for preventing hypercalciuria related to KDT. We suggest that the recommended 25-OH-D3 level is > 40 ng/mL for hypercalciuria prevention and that KDT for children with epilepsy can be optimized by vitamin D3 supplementation at 50 IU/kg.

Modification of electrophysiological activity pattern after anterior thalamic deep brain stimulation for intractable epilepsy: report of 3 cases.

OBJECTIVE Thalamic stimulation can provoke electroencephalography (EEG) synchronization or desynchronization, which can help to reduce the occurrence of seizures in intractable epilepsy, though the underlying mechanism is not fully understood. Therefore, the authors investigated changes in EEG electrical activity to better understand the seizure-reducing effects of deep brain stimulation (DBS) in patients with intractable epilepsy. METHODS Electrical activation patterns in the epileptogenic brains of 3 patients were analyzed using classical low-resolution electromagnetic tomography analysis recursively applied (CLARA). Electrical activity recorded during thalamic stimulation was compared with that recorded during the preoperative and postoperative off-stimulation states in patients who underwent anterior thalamic nucleus DBS for intractable epilepsy. RESULTS Interictal EEG was fully synchronized to the ß frequency in the postoperative on-stimulation period. The CLARA showed that electrical activity during preoperative and postoperative off-stimulation states was localized in cortical and subcortical areas, including the insular, middle frontal, mesial temporal, and precentral areas. No electrical activity was localized in deep nucleus structures. However, with CLARA, electrical activity in the postoperative on-stimulation period was localized in the anterior cingulate area, basal ganglia, and midbrain. CONCLUSIONS Anterior thalamic stimulation could spread electrical current to the underlying neuronal networks that connect with the thalamus, which functions as a cortical pacemaker. Consequently, the thalamus could modify electrical activity within these neuronal networks and influence cortical EEG activity by inducing neuronal synchronization between the thalamus and cortical structures.

Managing tuberous sclerosis in the Asia-Pacific region: refining practice and the role of targeted therapy.

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder, with heterogeneous manifestations that pose major diagnostic and management challenges and incur considerable chronic disease burden on patients, their caregivers and healthcare systems. This survey of clinical practice in the Asia-Pacific region highlights priorities for improving TSC management in the region. The prevalence of TSC in non-Caucasians is uncertain and more data are needed to assess its impact and health-economic burden. There are unmet needs for access to genetic testing and earlier diagnosis and intervention. TSC management is multidisciplinary and largely based on experience, backed by international guidelines; however, physicians in the Asia-Pacific region feel isolated and lack local or regional guidance and support structures to implement best-practice. Raising awareness of TSC and increasing trans-regional collaboration are particular priorities. Understanding of TSC pathophysiology has enabled the development of targeted therapies. Encouraging data indicate that mammalian target of rapamycin (mTOR) inhibitors can ameliorate TSC-related lesions and may potentially change the treatment paradigm. Ultimately, improving outcomes for TSC patients in the region requires greater collaboration and a holistic, patient-focused, continuum of care that is maintained through the transition from pediatric to adult care.

Polyunsaturated fatty acid-enriched diet therapy for a child with epilepsy.

The ketogenic diet (KD) is a high-fat, low-carbohydrate diet with an established efficacy for treating medically refractory epilepsy in children. Fatty acids are the most important constituent of the KD in all aspects of efficacy and complications. Among fatty acids, polyunsaturated fatty acids (PUFAs) increase anticonvulsant properties and reduce the complications associated with the high-fat diet. Here, we report a 7-year-old boy with Lennox-Gastaut syndrome combined with mitochondrial respiratory chain complex I deficiency, whose medically intractable seizures have been successfully controlled with a PUFA-enriched modified Atkins diet without any significant adverse events. The diet consists of canola oil and diverse menu items like fish and nuts instead of olive oil and has an ideal 1:2.8 ratio of omega-3 to omega-6. In addition, fractionation of this boy's plasma showed normal levels of fatty acids, including omega-3 (alpha-linoleic acid, eicosapentaenoic acid) and omega-6 (linoleic acid, arachidonic acid) as well as monounsaturated fatty acids (oleic acid). Plasma docosahexanoic acid remained low after PUFA-enriched diet therapy. PUFA-enriched diet therapy is likely to increase the efficacy of diet therapy and reduce complications of a high-fat diet in children with refractory epilepsy.

Wernicke's encephalopathy in a child with high dose thiamine therapy.

Wernicke's encephalopathy is an acute neurological disorder characterized by mental confusion, oculomotor dysfunction, and ataxia. It has been reported in individuals with alcohol dependence, hyperemesis gravidarum, and prolonged parenteral nutrition without vitamin supplementation. Here we present the case of a 13-year-old male patient with neuroblastoma and a history of poor oral intake and nausea for 3 months. After admission, he showed gait disturbances, nystagmus, and excessive dizziness; his mental state, however, indicated he was alert, which did not fit the classical triad of Wernicke's encephalopathy. A diagnosis of Wernicke's encephalopathy was made only after brain magnetic resonance imaging and serum thiamine level analyses were performed. The patient's symptoms remained after 5 days of treatment with 100-mg thiamine once daily; thus, we increased the dosage to 500 mg 3 times daily, 1,500 mg per day. His symptoms then improved after 20 days of replacement therapy. This case report describes a pediatric patient who was promptly diagnosed with Wernicke's encephalopathy, despite only 2 suspicious symptoms, and who completely recovered after high doses of thiamine were given intravenously.

Mitochondrial disease and epilepsy.

Mitochondrial diseases are a group of diseases caused by dysfunctional mitochondria, organelles that generate energy for the cell. Mitochondrial diseases are often caused by mutations, acquired, or inherited in the mitochondrial DNA or nuclear genes that code for respiratory chain complexes in the mitochondrion. Mitochondrial diseases involve multiple organs and show heterogeneous and unpredictable progression. The most common clinical presentation of mitochondrial diseases is encephalomyopathy, and epileptic seizures can frequently occur as a presenting sign of mitochondrial encephalopathy. While whether mitochondrial dysfunction or epilepsy is the cause or consequence is still debatable, they may be interrelated to create a vicious cycle. Epileptic phenotypes vary in different mitochondrial diseases. At present, there are no curative treatments for mitochondrial diseases, and the efficacy of many anticonvulsants, vitamins, nutritional supplements, and the ketogenic diet remain to be proven. Understanding the pathophysiology of mitochondrial diseases may further facilitate effective diagnostic and therapeutic approaches to these diseases.

Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group.

The ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research.

Newly observed thalamic involvement and mutations of the HEXA gene in a Korean patient with juvenile GM2 gangliosidosis.

Neuroimaging studies of patients with GM2 gangliosidosis are rare. The thalamus and basal ganglia are principally involved in patients affected by the infantile form of GM2 gangliosidosis. Unlike in the infantile form, in juvenile or adult type GM2 gangliosidosis, progressive cortical and cerebellar atrophy is the main abnormality seen on conventional magnetic resonance imaging (MRI); no basal ganglial or thalamic impairment were observed. This report is of a Korean girl with subacute onset, severe deficiency of hexosaminidase A activity and mutations (Arg137Term, Ala246Thr) of the HEXA gene. A 3.5-year-old girl who was previously in good health was evaluated for hypotonia and ataxia 3 months ago and showed progressive developmental deterioration, including cognitive decline. Serial brain MRI showed progressive overall volume decrease of the entire brain and thalamic atrophy. Fluorine-18 FDG PET scan showed severe decreased uptake in bilateral thalamus and diffuse cerebral cortex. We suggest, through our experience, that the thalamic involvement in MR imaging and FDG-PET can be observed in the juvenile form of GM2 gangliosidosis, and we suspect the association of mutations in the HEXA gene.

Comparison of corpus callosotomy and vagus nerve stimulation in children with Lennox-Gastaut syndrome.

PURPOSE: To compare the efficacy of corpus callosotomy and vagus nerve stimulation (VNS) for long-term adjunctive therapy in children with Lennox-Gastaut syndrome (LGS). METHOD: Fourteen patients underwent a total corpus callosotomy and 10 patients received VNS implantation. The patients were monitored for more than 12 months after treatment, and seizure rates and complications were retrospectively evaluated. RESULTS: Seizure types among the 24 patients included atonic or tonic seizures with head-drops in 17 patients, generalized tonic seizures in two patients, atypical absence seizures in one patient, generalized tonic-clonic seizures in one patient, and myoclonic seizures in three patients. Of the 14 patients who underwent a corpus callosotomy, nine (64.3%) had a greater than 50% reduction in seizure frequency and five (35.7%) had a greater than 75% reduction. Of the 10 patients who underwent VNS implantation, seven (70.0%) had a greater than 50% reduction in seizure frequency and two (20.0%) had a greater than 75% reduction. There was no significant difference between the two procedures in terms of final efficacy. Complications of corpus callosotomy included aphasia in one patient, ataxia in another, and paresis in a third. Among patients receiving VNS, one patient experienced dyspnea while sleeping and one patient suffered from drooling. These complications were transient and tolerable, and were controlled by simple adjustments of VNS treatment parameters. CONCLUSION: The efficacy and safety of corpus callosotomy and VNS were comparable in children with LGS.

Vagus nerve stimulation in intractable childhood epilepsy: a Korean multicenter experience.

We evaluated the long-term outcome of vagus nerve stimulation (VNS) in 28 children with refractory epilepsy. Of these 28 children, 15 (53.6%) showed a >50% reduction in seizure frequency and 9 (32.1%) had a >75% reduction. When we compared seizure reduction rates according to seizure types (generalized vs. partial) and etiologies (symptomatic vs. cryptogenic), we found no significant differences. In addition, there was no correlation between the length of the stimulation period and treatment effect. The seizure reduction rate, however, tended to be inversely related to the seizure duration before VNS implantation and age at the time of VNS therapy. VNS also improved quality of life in this group of patients, including improved memory in 9 (32.1%), improved mood in 12 (42.9%), improved behavior in 11 (39.3%), improved alertness in 12 (42.9%), improved achievement in 6 (21.4%), and improved verbal skills in 8 (28.6%). Adverse events included hoarseness in 7 patients, dyspnea at sleep in 2 patients, and wound infection in 1 patient, but all were transient and successfully managed by careful follow-up and adjustment of parameters. These results indicate that VNS is a safe and effective alternative therapy for pediatric refractory epilepsy, without significant adverse events.

Landau-Kleffner syndrome with mitochondrial respiratory chain-complex I deficiency.

Landau-Kleffner syndrome is characterized by epileptic aphasia associated with electrical status epilepticus of slow wave sleep. A 5-year-old female, who had manifested normal developmental progress, was referred with principal complaints of fluctuating sensory aphasia and bizarre behavior during the preceding 4 months. Landau-Kleffner syndrome was confirmed by clinical and electroencephalographic features; in addition, the patient's mitochondrial respiratory chain-complex I deficiency was confirmed by fibroblast culture with the evidence of energy metabolism disorder. This patient's seizures were intractable to many antiepileptic drugs, adrenocorticotrophic hormone, and intravenous immunoglobulin, with catastrophic cognitive and behavioral decline, but the seizures were successfully controlled by ketogenic diet with supplementary mitochondrial cocktail including coenzyme Q10, riboflavin, L-carnitine, and high-dose multivitamins. The patient finally regained fully normal cognitive functioning. Landau-Kleffner syndrome with mitochondrial respiratory chain-complex I deficiency was controlled in this case by ketogenic diet and supplementary mitochondrial cocktail therapy.