Concomitant treatment with topiramate and ketogenic diet in pediatric epilepsy

PURPOSE: Topiramate (TPM) is widely used as add-on therapy for epilepsy. TPM inhibits carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate. The ketogenic diet (KGD) predisposes patients to metabolic acidosis, especially during induction. In children with refractory epilepsy, cotreatment with TPM and KGD may be considered, but special attention should be paid to the combined risks for metabolic acidosis and nephrolithiasis. We report our experience in 14 children cotreated with TPM and the KGD. METHODS: Medical records of 14 children cotreated with the KGD and TPM for medically refractory epilepsy were reviewed retrospectively. Bicarbonate levels were analyzed and correlated with clinical profiles, including duration of cotreatment, TPM dose, KGD ratio, and seizure control. RESULTS: Nine children had a <20% decrease in bicarbonate levels, from 5.3 to 12.3 mEq/L (mean, 7.6 mEq/L). Cotreatment was continued in all patients for duration of 33 to 544 days (seven had remained on cotreatment at the end of the study period), although two children required bicarbonate supplements to continue the KGD. No patient had nephrolithiasis. CONCLUSIONS: Although a large decrease in bicarbonate level occurred in the majority of children, the decrease appeared mostly at the time of KGD induction when added to prior TPM therapy. Bicarbonate levels should be monitored carefully with TPM and KGD cotreatment, and bicarbonate supplements given when symptomatic.     

The ketogenic diet inhibits epileptogenesis in EL mice: a genetic model for idiopathic epilepsy

PURPOSE: The ketogenic diet (KD) is a high-fat, low-carbohydrate and -protein diet that has been used to treat refractory seizures in children for more than 75 years. However, little is known about how the KD inhibits seizures or its effects on epileptogenesis. Several animal models of epilepsy have responded favorably to KD treatment, but the KD has not been studied in animals with a genetic predisposition to seizures. Here we studied the antiepileptogenic effect of the KD in EL mice, an animal model for human idiopathic epilepsy. METHODS: Young male EL mice (postnatal day 30) were randomly separated into two groups fed ad libitum with either the KD (treated, n = 21) or Agway chow (control, n = 19). The mice were weighed and tested for seizures once per week for a total of 10 weeks. The effects of the KD on plasma levels of ketone bodies and glucose were analyzed at several time points throughout the study. Associative learning was compared between treated and control animals using a water maze. RESULTS: KD treatment delayed seizure onset in young male EL mice by 1 month; however, seizure protection was transient, inasmuch as the treated and control mice experienced a similar number and intensity of seizures after 6 weeks on the diet. Plasma glucose levels and associative learning were similar in the treated and control groups, but the plasma beta-hydroxybutyrate levels were significantly higher in mice on the KD. The level of ketosis, however, was not predictive of seizure protection in EL mice. CONCLUSION: The KD delayed seizure onset in EL mice, suggesting a transient protection against epileptogenesis. The KD did not influence plasma glucose levels or associative learning. Therefore, the EL mouse may serve as a good model to study the antiepileptogenic mechanisms of the KD.     

The metabolic consequences of experimental intraventricular hemorrhage

Experimental intraventricular hemorrhage was produced by injection of autologous fresh blood (0.25 ml/kg) or artificial CSF into the right lateral ventricle of 24 dogs. A transient ventricular fluid acidosis (pH drop to 7.09) was accompanied by increased lactate, pyruvate, ammonia, and Pco2, and decreased bicarbonate and glucose. High lactate/pyruvate ratios were the most persistent abnormality. The control group, which received intraventricular artificial CSF, developed minimal ventricular fluid acidosis (pH 7.26). Lumbar CSF and venous blood acid-base parameters did not change. Simultaneous cisternal samples obtained from some of the animals reflected similar metabolic abnormalities of lesser magnitude. Intraventricular injection of sodium bicarbonate normalized the pH in four animals.     

Propofol Infusion Associated Metabolic Acidosis in Patients Undergoing Neurosurgical Anesthesia: A Retrospective Study

Objective

Propofol and volatile anesthesia have been associated with metabolic acidosis induced by increased lactate. This study was designed to evaluate changes in pH, base excess (BE), and lactate in response to different anesthetic agents and to characterize propofol infusion-associated lactic acidosis.

Methods

The medical records of patients undergoing neurosurgical anesthesia between January 2005 and September 2012 were examined. Patients were divided into 2 groups : those who received propofol (total intravenous anesthesia, TIVA) and those who received sevoflurane (balanced inhalation anesthesia, BIA) anesthesia. Propensity analysis was performed (1 : 1 match, n=47), and the characteristics of the patients who developed severe acidosis were recorded.

Results

In the matched TIVA and BIA groups, the incidence of metabolic acidosis (11% vs. 13%, p=1) and base excess (p>0.05) were similar. All patients in the TIVA group who developed severe acidosis did so within 4 hours of the initiation of propofol infusion, and these patients improved when propofol was discontinued.

Conclusions

The incidence of metabolic acidosis was similar during neurosurgical anesthesia with propofol or sevoflurane. In addition, severe acidosis associated with propofol infusion appears to be reversible when propofol is discontinued.     

Topiramate and Metabolic Acidosis in Pediatric Epilepsy

PURPOSE: Topiramate (TPM) has been widely used as an adjunctive therapy for treating epilepsy. TPM is reported to have multiple mechanisms of action, including inhibition of carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate (HCO3-). METHODS: Clinical data from 30 children who received TPM as adjunctive therapy for medically refractory epilepsy were reviewed at Children's Hospital, Boston. Serum HCO3- levels were assessed before, during, and after discontinuing TPM (n = 9). When multiple data were available, mean values were used for analysis. RESULTS: Of the 30 patients, 21 had a >10% decrease in HCO3- levels. The mean decrease in HCO3- among the 21 patients was 4.7 mEq/L, and maximum was 10 mEq/L. No clinical symptoms occurred, and HCO3- supplement was not needed, except for one patient who developed tachypnea from worsened acidosis after prolonged status epilepticus during a suspected viral illness. Among the 21 patients, TPM was discontinued in seven children because of a lack of efficacy, and in two because of anorexia. After discontinuing TPM, the serum HCO3- returned to the previous level before starting TPM in all nine. CONCLUSIONS: Decreased HCO3- levels occurred in the majority of patients reviewed, usually only to a small to moderate extent, but by 8 and 10 mEq/L in two cases. In patients at risk for acidosis, the decrease in HCO3- may cause significant consequences, such as severe acidosis or renal calculi. Monitoring HCO3- levels before and during TPM therapy may be indicated, especially with conditions that predispose to acidosis.     

Elevated polyunsaturated fatty acids in blood serum obtained from children on the ketogenic diet

The authors analyzed blood metabolites in nine children with epilepsy prior to starting the ketogenic diet (KD) and 3 to 4 weeks after KD therapy. Elevated beta-hydroxybutyrate and cortisol levels were observed in all children on the KD. Free fatty acids increased 2.2-fold on the KD, with significant elevations in most polyunsaturated fatty acids (PUFA; arachidonate increased 1.6- to 2.9-fold and docosahexaenoate increased 1.5- to 4.0-fold). The rise in total serum arachidonate correlated with improved seizure control. Elevated PUFA may represent a key anticonvulsant mechanism of the KD.     

Vitamin D status in children with intractable epilepsy, and impact of the ketogenic diet

PURPOSE: The aim of this study was to describe vitamin D status in children with intractable epilepsy prescribed newer antiepileptic drugs (AEDs) before initiation of and during 15-month treatment with the ketogenic diet (KD). METHODS: Serum vitamin D (25-OHD and 1,25-OHD) and parathyroid hormone (PTH) were assessed in prepubertal children with intractable epilepsy before initiation of and during KD therapy. Three-day weighed dietary records including KD and vitamin and mineral supplementation were obtained at baseline and at 1 month. RESULTS: Forty-five children (aged 5.1 +/- 2.7 years) were enrolled. Before KD therapy, 4% had deficient and 51% had insufficient serum 25-OHD levels. Vitamin D intake was less than recommended in 47%. Adequate vitamin D intake, fewer AEDs, and generalized seizures were associated with higher serum 25-OHD levels (p < 0.01). After 3 months on the KD, 25-OHD levels increased (p < 0.001), and PTH declined (p < 0.001). Over the next 12-month period, 25-OHD levels steadily declined (p < 0.001), and PTH did not significantly change. CONCLUSIONS: Children with intractable epilepsy treated with newer AEDs had poor vitamin D status. Their status improved over the first 3 months of KD therapy with vitamin D supplementation and slowly declined thereafter.     

Growth dependence on insulin-like growth factor-1 during the ketogenic diet

Purpose:   To examine the influence of the ketogenic diet (KD) on linear growth and insulin-like growth factor I (IGF-I) levels in children with pharmacotherapy-resistant epilepsy.
Methods:   A prospective study was designed to evaluate growth, serum IGF-I levels, blood β-hydroxybutyric acid (β-OHB), and seizure frequency before and during KD in 22 children (median age 5.5 years). Growth was assessed by measurements of weight, height, body mass index (BMI), and height velocity. Standard deviation scores (SDS) were calculated for all measured parameters as well as for serum IGF-I to eliminate the influence of age- and sex-related differences among patients.
Results:   Fourteen of the 22 patients responded to the KD. Weight, height, BMI, and height velocity decreased significantly during the KD. We found that the KD had profound influence on growth and IGF-I levels. No correlation was found between seizure response and growth alterations. Height velocity correlated negatively with β-OHB during the KD. The slope of the regression of height velocity against IGF-I decreased significantly during the KD.
Conclusions:   Height velocity was most affected in those with pronounced ketosis, which implies that, in clinical practice, the level of ketosis should be related to outcomes in seizure response and growth. Our data indicate that growth disturbances and the decreased sensitivity of growth to similar IGF-I levels during KD are independent of seizure reduction. The metabolic status induced by KD may be the mechanism underlying both alterations of linear growth and seizure reduction.     

Carnitine levels and the ketogenic diet

PURPOSE: To determine the long-term effect of the ketogenic diet (KD) on carnitine levels and whether carnitine depletion is a significant cause of clinical complications during KD initiation or treatment. METHODS: Carnitine levels at 0, 1, 6, 12, and 24 months of diet treatment, carnitine antiepileptic drug (AED) history, lowest blood glucose and time to achieve ketosis during diet initiation, and diet complications were analyzed for 38 consecutive patients who initiated the KD from May 1997 to March 2000. Carnitine levels at follow-up were analyzed for eight patients started on the diet before to May 1997. RESULTS: Total carnitine (TC) at diet initiation correlated negatively with the number of AEDs at diet initiation but not with number of past AEDs, lowest blood glucose, or time to ketosis. TC decreased in the first months of diet treatment and then stabilized or increased slightly with long term treatment. Only 19% of patients were supplemented with carnitine for low TC. No patient showed clinical signs of carnitine deficiency. CONCLUSIONS: Multiple AED exposure lowers TC, but actual TC deficiency in patients initiating the KD is not common, and TC levels do not appear to predict hypoglycemia or problems achieving ketosis. Mild carnitine depletion may occur early in KD treatment and occasionally TC decreases out of the normal range, without clinical symptoms. TC stabilizes or increases back toward baseline with long-term treatment, and most patients do not require carnitine supplementation.     

Comparison of seizure reduction and serum fatty acid levels after receiving the ketogenic and modified Atkins diet

The ketogenic diet (KD) and the modified Atkins diet are effective therapies for intractable epilepsy. We compared retrospectively the KD and modified Atkins diet in 27 children and also assessed serum long chain fatty acid profiles. After 3 months, using an intent-to-treat analysis, the KD was more successful, with >50% seizure reduction in 11/17 (65%) vs. 2/10 (20%) with the modified Atkins diet, p = 0.03. After 6 months, however, the difference was no longer significant: 7/17 (41%) vs. 2/10 (20%) (p = 0.24). We observed a preventive effect of both diets on the occurrence of status epilepticus. After 1 and 3 months of either diet, responders experienced a significant decrease in serum arachidonic acid concentration compared to non-responders. The KD and modified Atkins diet led to seizure reduction in this small pilot series, with slightly better results after 3 months with the KD, but not after 6 months. The decrease of serum arachidonic acid levels might be involved in the anticonvulsive effects of KD or modified Atkins diet.     

Selenium deficiency associated with cardiomyopathy: a complication of the ketogenic diet

PURPOSE: The ketogenic diet (KD) is an efficacious treatment for intractable epilepsy, associated with infrequent side effects. The KD is known to be deficient in most vitamins and minerals and may be deficient in trace minerals. We report biochemical selenium deficiency in nine patients on the KD, including one who developed cardiomyopathy. METHODS: A whole-blood selenium level was obtained on the symptomatic patient after noting the patient's poor appearance on physical examination. Children already treated and children beginning the KD were then evaluated prospectively for selenium status by measuring whole-blood or serum selenium as part of routine laboratory evaluation every 3 months. RESULTS: The index case had no detectable whole-blood selenium. Cardiac physical examination and ECG were normal, but the echocardiogram revealed cardiomyopathy. Thirty-nine additional children had the selenium status evaluated. Eight had selenium levels below the normal range (six initially, and two developed low selenium levels on serial testing). They were referred for cardiology evaluations, which were normal. Selenium supplementation improved levels in all children. Low levels were seen in some children after only a few months of treatment. CONCLUSIONS: The nutrient adequacy of the currently used KD has not been fully evaluated. The nutrient content of KD with usual supplements may not meet Recommended Dietary Allowances (RDA) for selenium and may not provide other trace minerals in adequate amounts. At our center, selenium deficiency was found in 20% of the patients evaluated. Screening for selenium deficiency is suggested if the patient KD regimen does not meet > or =75% of the RDA or if the child is symptomatic. Nutrient supplementation should provide adequate trace elements for children treated with the KD. The KD requires close monitoring of the overall nutritional status.     

Effects of surgical stress on brain prostaglandin E2 production and on the pituitary-adrenal axis: attenuation by preemptive analgesia and by central amygdala lesion

Surgical stress is the combined result of tissue injury, anesthesia, and postoperative pain. It is characterized by elevated levels of adrenocorticotropin (ACTH), corticosterone (CS), and elevated levels of prostaglandin E2 (PGE2) in the periphery and in the spinal cord. The present study examined the effects of perioperative pain management in rats undergoing laparotomy on serum levels of ACTH, CS, and on the production of PGE2 in several brain regions, including the amygdala. The amygdala is known to modulate the pituitary-adrenal axis response to stress. We, therefore, also examined the effects of bilateral lesions in the central amygdala (CeA) on laparotomy-induced activation of the pituitary-adrenal axis in rats. In the first experiment, rats either underwent laparotomy or were not operated upon. Half the rats received preemptive analgesia extended postoperatively, the other received saline. ACTH, CS serum levels, and ex vivo brain production of PGE2 were determined. In the second experiment, rats underwent bilateral lesions of the CeA. Ten days later, rats underwent laparotomy, and ACTH and CS serum levels were determined. Laparotomy significantly increased amygdala PGE2 production, and CS and ACTH serum levels. This elevation was markedly attenuated by perioperative analgesia. Bilateral CeA lesions also attenuated the pituitary-adrenal response to surgical stress. The present findings suggest that the amygdala plays a regulatory role in mediating the neuroendocrine response to surgical stress. Effective perioperative analgesia attenuated the surgery-induced activation of pituitary-adrenal axis and PGE2 elevation. The diminished elevation of PGE2 may suggest a mechanism by which pain relief mitigates pituitary-adrenal axis activation.     

肾移植患者围术期麻醉管理：40例资料回顾

背景：从肾移植患者围术期血生化检测结果可以看到,一些酸碱指标及生化指标的变化可能与血液稀释有关。 目的：通过监测肾移植患者围术期血流动力学的变化以及电解质、血生化的改变,麻醉药物使用情况,探讨肾移植患者理想的麻醉管理方法。 方法：分析40例肾移植患者麻醉前、肾动脉血流开放前、血流开放后10 min、手术结束时(T4)各时点平均动脉压、中心静脉压、心率、电解质、血糖和血气参数的变化。 结果与结论：与肾移植患者麻醉前比较,血流开放后10 min平均动脉压、中心静脉压、pH、HCO3-、BE显著降低(P < 0.01),K+和葡萄糖明显增加(P < 0.01)。与肾动脉血流开放前比较,血流开放后10 min平均动脉压、葡萄糖、pH、HCO3-、BE明显降低而心率明显增高(P < 0.05)。说明充分的移植前准备,合理的麻醉药物选择,以及围术期的循环、呼吸及水电解质酸碱平衡的维持是肾移植术全身麻醉成功的关键。     

Ketogenic diet for treatment of infantile spasms

This study sought to evaluate the efficacy, tolerability, and safety of a ketogenic diet (KD) in the treatment of infantile spasms (IS), incorporating a revised protocol based on our previous experience with KD. We undertook a retrospective analysis of 43 children who suffered from catastrophic IS and tried KD from June 1995 to May 2004 in two Korean epilepsy centers. Outcome measures included seizure frequency, electroencephalograms (EEGs), adverse reactions, and neurological development. Overall, the diet achieved the seizure-free state in 53.5% (23/43) of patients and a greater than 90% reduction of seizure frequency in 62.8% (27/43) of patients. The seizure outcomes were highly concordant with improvements in EEG findings and development. In addition, KD could be maintained more safely and more comfortably because of our revised protocol that included an initial non-fasting diet, a short-term trial of 8 months, a more protein-rich diet with a lipid to non-lipid ratio of 3:1, and liquid ketogenic milk. Most complications were transient and KD was well tolerated in most cases. KD can be an effective alternative therapy for catastrophic IS, and additional benefits may be derived from constant revision of the diet in the future.     

Diet-Induced Ketosis Does Not Cause Cerebral Acidosis

Ketosis is beneficial for seizure control, possibly through induction of cerebral acidosis. However, cerebral intracellular pH has not previously been measured in ketotic humans and the animal data are sparse. We describe a high-fat diet, avidly consumed by rats, that induced consistent and moderate ketosis. Adult male rats were fed either the high-fat ketogenic diet, a high-carbohydrate diet with the same protein content as the ketogenic diet, or regular laboratory chow. Five to 6 weeks later, the rats were anesthetized, paralyzed, and injected with neutral red; their brains were frozen in situ. Intracellular pH of the cerebral cortex and cerebral glucose, lactate, ATP, phosphocreatine, and y-aminobutyric acid (GABA) levels were measured. Rats fed the ketogenic diet had > 10–fold increase in their plasma ketones, but we noted no significant differences in cerebral pH or in cerebral metabolites and GABA levels among the three groups. Therefore, the antiepileptic effect of the ketogenic diet probably is not mediated by cerebral acidosis or changes in total cerebral GABA levels.     

生酮饮食对MPTP 小鼠帕金森病模型黑质TH、Bcl-2和caspase-3基因表达的影响

目的 研究生酮饮食对PD小鼠黑质多巴胺能神经元的抗凋亡作用. 方法 1-甲基-4-苯基-1、2、3、6-四氢吡啶(MPTP)腹腔注射方法 制备PD模型小鼠.实验分为正常饮食模型组(正常饮食喂养后造模)、实验组(生酮饮食喂养后造模)、正常饮食组(不造模,正常饮食喂养)和生酮饮食组(不造模,生酮饮食喂养).初次MPTP给药前及末次给药后的次日进行滚轴实验并采集血清样本检测血清酮体和血糖浓度.荧光定量PCR技术检测黑质酪氨酸羟化酶(TH)、Bcl-2及caspase-3基因水平的表达情况. 结果 经过生酮饮食喂养后的小鼠经MPTP给药后,死亡率较正常饮食模型组降低;滚轴实验中实验组在转盘上停留时间较正常饮食模型组延长,差异均有统计学意义(P＜0.05).实验组和生酮饮食组的血清酮体浓度较其他2组明显升高,差异有统计学意义(P＜0.05).荧光定量PCR检测发现,与正常饮食模型组相比,实验组黑质中TH基因的表达明显升高,抗凋亡作用的Bcl-2基因也明显升高,促凋亡作用的caspase-3基因的表达明显减少,差异均有统计学意义(P＜0.05). 结论 生酮饮食逆转了MPTP给药后的黑质中Bcl-2基因表达的下调和caspase-3基因表达的上调,进而抑制了多巴胺能神经元的凋亡,起到了保护黑质多巴胺能神经元的作用.     

The effect of sodium bicarbonate on CBF and intracellular pH in man: Stable Xe-CT and 31P-MRS

The effects of sodium bicarbonate on cerebral blood flow (CBF) and intracellular pH were studied in five normal volunteers. CBF and intracellular pH were measured by stable xenon computed tomography and phosphorus-31 magnetic resonance spectroscopy (³¹P-MRS) respectively. Each patient received 7% sodium bicarbonate (3.5 ml/kg body weight) infused intravenously for 15 minutes. Before and after this injection, CBF, intracellular pH and physiological parameters were measured. CBF and PaCO₂ were significantly increased. On the other hand, hematocrit and intracellular pH were decreased. These result suggests that three factors are thought to contribute to increase CBF during administration of sodium bicarbonate in humans: 1) arterial dilatation in response to carbon dioxide 2) an decrease of hematocrit 3) intracellular acidosis.     

Topiramate and metabolic acidosis in infants and toddlers

PURPOSE: Topiramate (TPM) inhibits carbonic anhydrase, with metabolic acidosis as a possible side effect, although this has been reported in only two adult cases. We investigated the acid-base metabolism in infants and toddlers treated with TPM. METHODS: Nine infants and toddlers aged 5 months to 2.3 years (median, 6 months) were treated with TPM at maximal doses of 8.2-26 mg/kg/day (median, 11 mg/kg/day). The maximal TPM dose was achieved after 8-35 days (median, 17 days). TPM was given in addition to other antiepileptic drugs (AEDs) in five cases and as a sole AED in four patients with refractory epilepsy resistant to multiple AEDs. The diagnoses were infantile spasms (n = 5), epilepsia partialis continua (n = 1), infantile epileptic encephalopathy (n = 1), and Lennox-Gastaut syndrome (n = 2). RESULTS: The blood gases were normal before treatment with TPM in all nine children. Metabolic acidosis developed in eight children after 8-26 days (median, 14 days) of TPM treatment with a minimum of serum bicarbonate between 15 to 18 mM (median, 17 mM), a minimal base excess between -6.2 and -11.2 mM (median, -7.9 mM), and pH between 7.22 and 7.40 (median, 7.35). Four of nine children showed clinical signs of hyperventilation and received oral sodium bicarbonate (1-2 mmol/kg), while TPM was still effective. CONCLUSIONS: Because metabolic acidosis developed in eight of the nine infants and toddlers taking TPM, we would suggest that the acid-base metabolism be monitored in young children who receive TPM.     

Anesthesiological and intensive care considerations in children undergoing extensive cerebral excision procedure for congenital epileptogenic lesions

Introduction Epilepsy is a relatively common condition in childhood with a generally favorable prognosis of the affected population. Nevertheless, a significant minority of the treated children do not respond to the medical treatment so that surgical treatment is necessary. While minor surgical procedures have a negligible incidence of mortality, major ones may carry a significant risk of perioperative complications. The leading cause of mortality is represented by hemorrhagic derangements after high intraoperative and postoperative blood loss, mostly in very young patients. Therefore, restoration of euvolemia, detection and correction of related bleeding disorders represent the major concern for pediatric neuroanesthesiologists and intensivists throughout the perioperative period. The present report is focused on the anesthesia and intensive care management of the surgical epileptic patient.Conclusion Authors recommend that these high-risk procedures should be performed in highly experienced centers where pediatric neurosurgery is performed daily.     

The relationship of ketosis and growth to the efficacy of the ketogenic diet in infantile spasms

The ketogenic diet (KD) is a treatment of infantile spasms (IS). Here, we examine the efficacy of KD in medically refractory IS, examine its impact on growth in infants, and explore its mechanism of action. At 1-3 months after the initiation of the KD, 46% of twenty-six patients had a greater than 90% reduction in IS. No significant relationships between reduction in IS and serum β-hydroxybutyrate, or glucose levels were identified. Also, the KD had not significantly altered patient's growth parameters. Thus, in corroborating with prior studies, we demonstrate the KD is a well-tolerated and efficacious treatment of IS.