RESUMEN
OBJECTIVE: Dravet syndrome (DS) is a rare cause of severe and pharmacoresistant epileptic encephalopathy. Stiripentol (STP) has a significant therapeutic benefit in the pediatric DS population. However, STP effects on adult patients have not been well studied. In our adult STP-naive DS patient population, STP initiation was associated with encephalopathy, despite decreases in valproate and clobazam dosage. Here we explored the cause and treatment of encephalopathic manifestations associated with STP in adults. METHODS: Twenty-eight patients with a confirmed clinical and genetic diagnosis of DS who attended the Adult Epilepsy Genetics Clinic were identified retrospectively. Patients who declined or discontinued STP after fewer than 3 months of use, patients who were deceased before starting STP or seizure-free when the genetic diagnosis was confirmed, and those who started STP before leaving the pediatric system (<18 years) were excluded. Levels of ammonia, carnitine, and other anti-epileptic drugs (AEDs) were observed for patients receiving STP. Patients with high ammonia levels who received carnitine supplementation were reevaluated. They were also offered an increased dosage of stiripentol if treatment with carnitine improved the encephalopathy. RESULTS: We observed hyperammonemic encephalopathy in 77% of patients treated with STP. In seven of nine patients, we observed a rate of improvement in ammonia levels of 35% (95% confidence interval [CI] 21%-49%) at a mean carnitine dose of 991 ± 286 mg/d (range 660-1320 mg/d). Five patients whose ammonia levels normalized were also offered an increase in STP dose and they were able to tolerate higher doses with improvement in side effects. Despite such adjustments, the mean maximum stiripentol dose reached was 14.89 ± 8.72 mg/kg/d, which is lower than what is typically recommended in children (50 mg/kg/d). SIGNIFICANCE: We report hyperammonemia in adult STP-naive patients who were on valproate and clobazam, despite dose reduction of the latter drugs. We also report that treatment with carnitine improved hyperammonemia, allowing the continuation of STP.
Asunto(s)
Amoníaco , Anticonvulsivantes/efectos adversos , Carnitina/administración & dosificación , Dioxolanos/efectos adversos , Epilepsias Mioclónicas/tratamiento farmacológico , Hiperamonemia/inducido químicamente , Adulto , Amoníaco/sangre , Anticonvulsivantes/administración & dosificación , Estudios de Cohortes , Dioxolanos/administración & dosificación , Epilepsias Mioclónicas/sangre , Femenino , Humanos , Hiperamonemia/sangre , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: The use of therapeutic drug monitoring (TDM) for antiseizure medications (ASMs) may contribute to treatment optimization in individual patients. This study included patients with Dravet syndrome as they often require close monitoring because of polypharmacy with various ASMs. The aim was to use long-term TDM to investigate pharmacokinetic variability of ASMs in these patients. METHODS: Retrospective data from patients with Dravet syndrome were collected from the TDM database at the Section for Clinical Pharmacology, National Center for Epilepsy in Norway (2008-2018). Concentration/(dose/kg)ratios (C/D ratios) were calculated for the ASMs and the concentration (C/C ratio) for N-desmethylclobazam. In patients with at least 3 measurements, the CV for C/D ratios for intrapatient and interpatient variability was calculated. RESULTS: Fifty-three patients (30 male patients/23 female patients) between 2 and 50 years of age (mean, 16 years) were included. Pharmacokinetic variability of the total number of measurements of valproate (n = 417), clobazam and N-desmethylclobazam (n = 328), and levetiracetam (n = 238) was determined. Interpatient variability was more pronounced than intrapatient variability (coefficient of variations: valproate, 65% vs. 24%; levetiracetam, 71% vs. 27%; and clobazam/N-desmethylclobazam, 47%/77% vs. 35%/55%) (P < 0.01). Comedication with stiripentol (n = 16) increased the C/D ratio of valproate by 63% and of clobazam by 133% and the C/C ratio of N-desmethylclobazam/clobazam by 104% (P < 0.05). Younger age also contributed to pharmacokinetic variability. CONCLUSIONS: Long-term TDM revealed extensive variability in serum concentrations over time; the variability was lowest for levetiracetam, moderate for valproate, and highest for clobazam. Pharmacokinetic variability and interactions can thus be identified and adjusted to facilitate decision making to achieve the optimal treatment outcome.
Asunto(s)
Clobazam/sangre , Clobazam/farmacocinética , Epilepsias Mioclónicas/sangre , Levetiracetam/sangre , Levetiracetam/farmacocinética , Ácido Valproico/sangre , Ácido Valproico/farmacocinética , Adolescente , Adulto , Anticonvulsivantes/sangre , Anticonvulsivantes/farmacocinética , Benzodiazepinas/sangre , Benzodiazepinas/farmacocinética , Niño , Preescolar , Clobazam/uso terapéutico , Dioxolanos/sangre , Dioxolanos/farmacocinética , Monitoreo de Drogas/métodos , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsia/sangre , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Levetiracetam/uso terapéutico , Masculino , Persona de Mediana Edad , Noruega , Estudios Retrospectivos , Ácido Valproico/uso terapéutico , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the potential impact of concomitant clobazam (CLB) use on the efficacy of cannabidiol (CBD) treatment in patients with Dravet syndrome and Lennox-Gastaut syndrome using meta-analytical techniques. METHODS: We searched for randomized, placebo-controlled, single- or double-blinded trials. The proportion of patients who achieved ≥50% reduction from baseline in seizure frequency during the treatment period was assessed according to CLB status. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated. RESULTS: Four trials were included and enrolled 714 participants, 429 for the add-on CBD group and 285 for the add-on placebo group. Among CBD-treated patients, 240 (55.9%) were taking concomitant CLB (CLB-On) and 189 (44.1%) were not taking concomitant CLB (CLB-Off); in placebo-treated patients, 158 (55.4%) were CLB-On and 127 (44.6%) CLB-Off. The percentages of patients who had at least 50% reduction in seizure frequency during the treatment period were 29.1% in the CBD arm and 15.7% in the placebo group among CLB-Off patients (RR = 1.80, 95% CI = 1.12-2.90, P = .015). Among CBL-On patients, the ≥50% reduction in seizure frequency was found in 52.9% and 27.8% in the CBD and placebo groups, respectively (RR = 1.85, 95% CI = 1.40-2.44, P < .001). SIGNIFICANCE: CBD was associated with a higher rate of seizure response in comparison to placebo when added to the existing antiepileptic regimen both in patients taking and in those not taking concomitant CLB. The lack of randomization for CLB status and the limited sample size need to be considered in the interpretation of the findings.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Cannabidiol/administración & dosificación , Clobazam/administración & dosificación , Convulsiones/tratamiento farmacológico , Anticonvulsivantes/sangre , Cannabidiol/sangre , Clobazam/sangre , Quimioterapia Combinada , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/tratamiento farmacológico , Humanos , Síndrome de Lennox-Gastaut/sangre , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Convulsiones/sangre , Resultado del TratamientoRESUMEN
Four pivotal randomized placebo-controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting, in particular, in a 3.4- to 5-fold increase in plasma concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions in determining the reduction in seizure frequency in CBD-treated patients, and the question of whether CBD per se has clinically evident antiseizure effects. We appraised available evidence on the clinical consequences of the CBD-CLB interaction, focusing on subgroup analyses of seizure outcomes in patients on and off CLB comedication in the pivotal CBD trials, as provided by the European Medicines Agency Public Assessment Report. Evaluation of the results of individual trials clearly showed that improvement in seizure control over placebo was greater when CBD was added on to CLB than when it was added on to other medications. However, seizure control was also improved in patients off CLB, and despite the small sample size the difference vs placebo was statistically significant for the 10 mg/kg/d dose in one of the two LGS trials. Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB emerges from meta-analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication. Although these results need to be interpreted taking into account methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects, and a greater burden of adverse effects, are observed when CBD is combined with CLB.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Cannabidiol/administración & dosificación , Clobazam/administración & dosificación , Medicina Basada en la Evidencia/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Convulsiones/tratamiento farmacológico , Anticonvulsivantes/sangre , Cannabidiol/sangre , Clobazam/sangre , Interacciones Farmacológicas/fisiología , Quimioterapia Combinada , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/tratamiento farmacológico , Humanos , Síndrome de Lennox-Gastaut/sangre , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Convulsiones/sangreRESUMEN
BACKGROUND: Ambroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD. METHODS: ABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed. RESULTS: Enhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2-8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events. CONCLUSIONS: Long-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD.
Asunto(s)
Ambroxol/administración & dosificación , Terapia de Reemplazo Enzimático , Epilepsias Mioclónicas/tratamiento farmacológico , Enfermedad de Gaucher/tratamiento farmacológico , Adolescente , Biomarcadores/sangre , Niño , Relación Dosis-Respuesta a Droga , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/patología , Femenino , Enfermedad de Gaucher/sangre , Enfermedad de Gaucher/patología , Glucosilceramidasa/sangre , Humanos , MasculinoRESUMEN
We herein report the case of a 3-year-old girl with severe myoclonic epilepsy of infancy known as Dravet syndrome (DS) on a ketogenic diet (KD) whose glucose concentrations were controlled by using a flash glucose monitoring system. Two-hundred ninety-three events of moderate hypoglycemia with a minimum of 45 mg/dL, not related to day or night, were recorded during the observational period. Hypoglycemia rate declined from 24.5% of all measurements to 11.8% over time; one hypoglycemia-associated seizure and one seizure due to ketone concentrations below the therapeutic range were observed. In summary, this case report broadens our understanding of hypoglycemia risk in patients with DS on a KD. Especially in childhood, the painless and easy detection of low glucose concentrations might lead to improved cognitive performance, and the reduction of hypoglycemia-induced seizures.
Asunto(s)
Glucemia/análisis , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/dietoterapia , Hipoglucemia/sangre , Cetonas/sangre , Preescolar , Dieta Cetogénica , Femenino , Humanos , Monitoreo FisiológicoRESUMEN
We sequenced the mitochondrial genome from a 40-year-old woman with myoclonus epilepsy, retinitis pigmentosa, leukoencephalopathy and cerebral calcifications. Histological and biochemical features of mitochondrial respiratory chain dysfunction were present. Direct sequencing showed a novel heteroplasmic mutation at nucleotide 5513 in the MT-TW gene that encodes tRNATrp. Restriction Fragment Length Polymorphism analysis confirmed that about 80% of muscle mtDNA harboured the mutation while it was present in minor percentages in mtDNA from other tissues. The mutation is predicted to disrupt a highly conserved base pair within the aminoacyl acceptor stem of the tRNA. This is the 17° mutation in MT-TW gene and expands the known causes of late-onset mitochondrial diseases.
Asunto(s)
Epilepsias Mioclónicas/genética , Predisposición Genética a la Enfermedad , Leucoencefalopatías/genética , Mutación/genética , ARN de Transferencia de Triptófano/genética , Retinitis Pigmentosa/genética , Calcificación Vascular/genética , Adulto , Secuencia de Bases , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/diagnóstico por imagen , Femenino , Humanos , Leucoencefalopatías/sangre , Leucoencefalopatías/diagnóstico por imagen , Retinitis Pigmentosa/sangre , Retinitis Pigmentosa/diagnóstico por imagen , Análisis de Secuencia de ADN , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome. METHODS: Patients aged 4-10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and suicidality. RESULTS: Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose-proportional (AUC0-t). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed. CONCLUSIONS: Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. CBD resulted in more AEs than placebo but was generally well-tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well-tolerated.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Cannabidiol/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacocinética , Benzodiazepinas/farmacocinética , Benzodiazepinas/uso terapéutico , Cannabidiol/efectos adversos , Cannabidiol/farmacocinética , Niño , Preescolar , Clobazam/farmacocinética , Clobazam/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Epilepsias Mioclónicas/sangre , Estudios de Seguimiento , Humanos , Resultado del TratamientoRESUMEN
OBJECTIVE: Stiripentol (STP), valproate (VPA) and topiramate (TPM) are reported to have efficacy for Dravet syndrome. In this study, we sought to elucidate the mechanisms underlying the increased serum VPA concentrations following STP adjunctive therapy in patients with Dravet syndrome. METHODS: Twenty-eight patients with Dravet syndrome (age range, 1-35 years) undergoing combination therapy with VPA and STP were included in this study. We evaluated VPA and clobazam (CLB) serum concentrations before and after add-on STP. We also investigated potential factors impacting VPA metabolism during add-on STP therapy, including add-on TPM and CYP2C9 and CYP2C19 gene polymorphisms. The effect of STP on the metabolism of concomitantly administered CLB was also investigated. RESULTS: Add-on STP was significantly associated with the serum concentration-to-dose (CD) ratio of VPA. Two patients, who were concomitantly treated with TPM, developed severe anorexia and thrombocytopenia because of marked increases in serum VPA concentrations. Further analysis revealed that the rate of increase in the VPA CD ratio was positively correlated with TPM dose. In patients not receiving TPM, STP enhanced the rate of increase in the VPA CD ratio to a significantly greater extent in CYP2C19 extensive metabolizers than in CYP2C19 poor metabolizers. Add-on STP was also associated with significant increases in CLB and N-desmethyl-CLB serum concentrations. CONCLUSION: Our findings suggest that serum VPA concentrations should be carefully monitored during STP adjunctive therapy, particularly in patients receiving concomitant TPM therapy.
Asunto(s)
Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Dioxolanos/uso terapéutico , Fructosa/análogos & derivados , Ácido Valproico/sangre , Ácido Valproico/uso terapéutico , Adolescente , Adulto , Anticonvulsivantes/efectos adversos , Benzodiazepinas/sangre , Benzodiazepinas/uso terapéutico , Niño , Preescolar , Clobazam , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/genética , Femenino , Fructosa/uso terapéutico , Humanos , Lactante , Masculino , Polimorfismo Genético , Estudios Retrospectivos , Topiramato , Ácido Valproico/efectos adversosRESUMEN
Mitochondrial diseases have a special predilection to involve the brain in view of its high metabolic demand and the tendency for the formation of excitatory neurotransmitters when there is deficiency of intracellular ATP. These diseases have a great phenotypic variation and need a high degree of suspicion. However, some specific syndromes are well defined, both genotypically and phenotypically. Some of the drugs are potentially fatal mitochondrial poisons and an insight into that may be lifesaving as well as prevent serious morbidities.We report a typical case of myoclonic epilepsy with ragged red fibers (MERRF) with classical phenotype and genotype. There was rapid multiaxial deterioration with the introduction of sodium valproate which partly reversed on introducing mitochondrial cocktail and withdrawal of the offending drug.Sodium valproate, phenobarbitone, chloramphenicol and many anti-viral agents are mitochondrial poisons that increase the morbidity and mortality in patients with mitochondrial disease. More harm to the patient can be avoided with insight into this information.
Asunto(s)
Epilepsias Mioclónicas/patología , Síndrome MERRF/diagnóstico , Mitocondrias/patología , Enfermedades Mitocondriales/terapia , Adolescente , Quimioterapia Combinada , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/complicaciones , Femenino , Humanos , Enfermedades Mitocondriales/patologíaRESUMEN
AIM: The aim of this study was to describe the pharmacokinetics of clobazam and its active metabolite N-desmethylclobazam (N-CLB) in children with Dravet syndrome receiving the stiripentol/valproic acid/clobazam combination therapy of reference and to determine the concentrations of clobazam and N-CLB obtained in this population for the usual 0.2 mg/kg twice-daily dose. METHODS: Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using NONMEM(®) software). Four blood samples were drawn per patient. Area under the plasma concentration-time curve (AUC) and trough concentration (C trough) values for clobazam and N-CLB were simulated for 12,000 theoretical children weighing between 10 and 60 kg. RESULTS: The pharmacokinetics of clobazam were described by a one-compartment model with first-order absorption, and elimination, formation and elimination of N-CLB were also first-order processes. The apparent total clearance (CL/F) and distribution volume (V CLB/F) of clobazam and the elimination rate constant of N-CLB (Kem) were related to body weight by allometric equations. Mean population estimates (% inter-individual variability) were 1.23 L/h (29%) for CL/F, 39.1 L (18%) for V CLB/F and 0.0706 h(-1) (26%) for Kem. The AUC values for clobazam and N-CLB were found to increase by 100% when bodyweight increased from 10 to 60 kg, and the simulated C trough values were higher than the currently accepted target values (0.03-0.3 mg/L for clobazam and 0.3-3 mg/L for N-CLB). CONCLUSION: This is the first simultaneous pharmacokinetic model for clobazam and N-CLB in epileptic children. Indicative values for the routine therapeutic drug monitoring of clobazam in children with Dravet syndrome treated by stiripentol are provided. The possible consequences of the weight-related changes on clobazam and N-CLB exposures should be further evaluated.
Asunto(s)
Anticonvulsivantes/farmacocinética , Benzodiazepinas/farmacocinética , Dioxolanos/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/metabolismo , Ácido Valproico/uso terapéutico , Anticonvulsivantes/administración & dosificación , Benzodiazepinas/administración & dosificación , Benzodiazepinas/efectos adversos , Benzodiazepinas/sangre , Peso Corporal/efectos de los fármacos , Niño , Preescolar , Clobazam , Interacciones Farmacológicas , Quimioterapia Combinada , Epilepsias Mioclónicas/sangre , Femenino , Humanos , Masculino , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Dravet syndrome presents with generalized and unilateral clonic or clonic-tonic seizures that occur during the first year of life, followed by severe epilepsy. Prolonged seizures are often provoked by fever and usually followed by recovery of the previous condition. We describe the case of a 13-month-old girl with Dravet syndrome who experienced severe neurological sequelae as a result of human herpesvirus 6-associated encephalopathy. Biphasic clinical course was observed, with fever and prolonged seizures at onset and late seizures refractory against antiepileptic agents. Serum concentrations of proinflammatory cytokines and matrix metalloproteinase-9, which have been associated with development of acute encephalopathy, were not markedly increased in this patient, suggesting that these molecules were not the main causes of neuronal damage in this patient. Instead, seizure susceptibility due to SCN1A mutation may have contributed to acute encephalopathy in our patient.
Asunto(s)
Epilepsias Mioclónicas/complicaciones , Infecciones por Roseolovirus/complicaciones , Adolescente , Encéfalo/patología , Encéfalo/virología , Citocinas/sangre , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/patología , Femenino , Herpesvirus Humano 6/patogenicidad , Humanos , Imagen por Resonancia Magnética , Metaloproteinasa 9 de la Matriz/sangre , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Infecciones por Roseolovirus/sangre , Infecciones por Roseolovirus/patologíaRESUMEN
Psychoemotional status and blood serotonin level were investigated in 69 patients with different forms of idiopathic epilepsy during the seizures and interictal period. Twenty-two patients with juvenile myoclonic epilepsy, 22 patients with absence forms and 22 patients with generalized convulsive seizures, aged 10-47 years, were included in the study. We found the significant decrease in blood serotonin levels during the interictal period, with the lower levels seen after generalized convulsive and myoclonic seizures. After the treatment with antidepressant fluvoxamine as add-on treatment, 16 patients revealed improved psychoemotional well-being and quality of life as well as a decreased number of generalized convulsive seizures along with the increasing of blood serotonin level.
Asunto(s)
Antidepresivos de Segunda Generación/uso terapéutico , Emociones/efectos de los fármacos , Epilepsia Generalizada/sangre , Epilepsia Generalizada/tratamiento farmacológico , Fluvoxamina/uso terapéutico , Serotonina/sangre , Transmisión Sináptica , Adolescente , Adulto , Anticonvulsivantes/uso terapéutico , Niño , Quimioterapia Combinada , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/psicología , Epilepsia Tipo Ausencia/sangre , Epilepsia Tipo Ausencia/tratamiento farmacológico , Epilepsia Tipo Ausencia/psicología , Epilepsia Generalizada/psicología , Epilepsia Tónico-Clónica/sangre , Epilepsia Tónico-Clónica/tratamiento farmacológico , Epilepsia Tónico-Clónica/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Several unrelated disorders can lead to 5-methyltetrahydrofolate (5MTHF) depletion in the cerobrospinal fluid (CSF), including primary genetic disorders in folate-related pathways or those causing defective transport across the blood-CSF barrier. We report a case of cerebral folate transport deficiency due to a novel homozygous mutation in the FOLR1 gene, in an effort to clarify phenotype-genotype correlation in this newly identified neurometabolic disorder. A previously healthy infant developed an ataxic syndrome in the second year of life, followed by choreic movements and progressive myoclonic epilepsy. At the age of 26 months, we analyzed CSF 5MTHF by HPLC with fluorescence detection and conducted magnetic resonance (MR) imaging and spectroscopy studies. Finally, we performed mutational screening in the coding region of the FOLR1 gene. MR showed a diffuse abnormal signal of the cerebral white matter, cerebellar atrophy and a reduced peak of choline in spectroscopy. A profound deficiency of CSF 5MTHF (2 nmol/L; NV 48-127) with reduced CSF/plasma folate ratio (0.4; NV 1.5-3.5) was highly suggestive of defective brain folate-specific transport across the blood-CSF/brain barrier. Mutation screening of FOLR1 revealed a new homozygous missense mutation (p.Cys105Arg) that is predicted to abolish a disulfide bond, probably necessary for the correct folding of the protein. Both parents were heterozygous carriers of the same variant. Mutation screening in the FOLR1 gene is advisable in children with profound 5MTHF deficiency and decreased CSF/serum folate ratio. Progressive ataxia and myoclonic epilepsy, together with impaired brain myelination, are clinical hallmarks of the disease.
Asunto(s)
Ataxia/genética , Epilepsias Mioclónicas/genética , Receptor 1 de Folato/genética , Mutación Missense , Ataxia/sangre , Ataxia/líquido cefalorraquídeo , Ataxia/complicaciones , Niño , Consanguinidad , Progresión de la Enfermedad , Electromiografía , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/líquido cefalorraquídeo , Epilepsias Mioclónicas/complicaciones , Ácido Fólico/sangre , Ácido Fólico/líquido cefalorraquídeo , Homocigoto , Humanos , Masculino , Mutación Missense/fisiología , LinajeRESUMEN
Myoclonic epilepsy associated with ragged-red fibers is one of the mitochondrial encephalomyopathies. Pathogenic mitochondrial DNA mutations have been identified in the mitochondrial transfer RNA (tRNA)(Lys) at positions 8344 and 8356. Characteristics of myoclonic epilepsy associated with ragged-red fibers include myoclonic epilepsy, generalized epilepsy, hearing loss, exercise intolerance, lactic acidosis, and ragged-red fibers. The elevated lactate level is one of the most important symptoms needed to make a diagnosis of mitochondrial encephalomyopathy. In the present case, however, myoclonic epilepsy was associated with ragged-red fibers but without increased lactate levels. Therefore, myoclonic epilepsy associated with ragged-red fibers should be suspected in a patient who has myoclonic epilepsy that is difficult to control with antiepileptic medications and who has other symptoms of mitochondrial disease, such as mental retardation, even if the patient's lactate level is normal.
Asunto(s)
Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/diagnóstico , Ácido Láctico/sangre , Encefalomiopatías Mitocondriales/sangre , Encefalomiopatías Mitocondriales/diagnóstico , Adolescente , Anticonvulsivantes/uso terapéutico , Análisis Mutacional de ADN , ADN Mitocondrial , Diagnóstico Diferencial , Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/tratamiento farmacológico , Humanos , Masculino , Encefalomiopatías Mitocondriales/complicaciones , Músculo Esquelético/patología , Mutación , Linaje , ARN de Transferencia de Lisina/genéticaRESUMEN
PURPOSE: To study the impact of pregnancy on the serum concentration/dose ratio (C/D-ratio) of topiramate (TPM). METHODS: Twelve women with epilepsy using TPM during pregnancy, and 15 pregnancies were studied. The main target variable was the C/D-ratio at baseline and during pregnancy. Additional variables were changes in TPM dose, concomitant use of other antiepileptic drugs, seizure frequency, and pregnancy outcome. Clinical and pharmacological data were obtained from the women's medical records. RESULTS: The average C/D-ratios in the second and third trimester were 30% (p = 0.002, n = 11) and 34% (p = 0.001, n = 8) lower than the baseline values, respectively. The interindividual variability was pronounced. Increased seizure frequency was common in pregnant women using TPM, but a correlation to the decline in TPM C/D-ratio could not be established from our data. DISCUSSION: Dose-corrected serum concentrations of TPM appear to decline gradually throughout pregnancy. The underlying mechanisms are not known. Increased glomerular filtration may play a major role. During pregnancy, therapeutic drug monitoring of TPM may be useful.
Asunto(s)
Anticonvulsivantes/farmacocinética , Epilepsia/sangre , Fructosa/análogos & derivados , Complicaciones del Embarazo/sangre , Anomalías Inducidas por Medicamentos/etiología , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Parciales/sangre , Epilepsias Parciales/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Epilepsia Tipo Ausencia/sangre , Epilepsia Tipo Ausencia/tratamiento farmacológico , Epilepsia Tónico-Clónica/sangre , Epilepsia Tónico-Clónica/tratamiento farmacológico , Femenino , Fructosa/efectos adversos , Fructosa/farmacocinética , Fructosa/uso terapéutico , Humanos , Recién Nacido , Tasa de Depuración Metabólica/fisiología , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Resultado del Embarazo , Primer Trimestre del Embarazo , Segundo Trimestre del Embarazo , Tercer Trimestre del Embarazo , Topiramato , Resultado del TratamientoAsunto(s)
Antibacterianos/efectos adversos , Epilepsias Mioclónicas/complicaciones , Convulsiones/inducido químicamente , Tienamicinas/efectos adversos , Adolescente , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/tratamiento farmacológico , Femenino , Humanos , Meropenem , Tienamicinas/farmacología , Tienamicinas/uso terapéuticoRESUMEN
Coenzyme Q10 (Q10) is available as an over-the-counter dietary supplement in the United States. While its use could be considered a form of alternative therapy, the medical profession has embraced the use of Q10 in specific disease states, including a series of neurologic and muscular diseases. Clinical laboratory monitoring is available for measurement of total Q10 in plasma and tissue and for measurement of redox status, ie, the ratio of reduced and oxidized forms of Q10. Many published studies have been anecdotal, in part owing to the rarity of some diseases involved. Unfortunately, many studies do not report Q10 levels, and, thus, the relationship of clinical response to Q10 concentration in plasma frequently is not discernible. Consistent laboratory monitoring of patients treated with this compound would help ease interpretation of the results of the treatment, especially because so many formulations of Q10 exist in the marketplace, each with its own bioavailability characteristics. Q10 has an enviable safety profile and, thus, is ideal to study as an adjunct to more conventional therapy. Defining patient subpopulations and characteristics that predict benefit from exogenous Q10 and defining therapeutic ranges for those particular applications are major challenges in this field.
Asunto(s)
Enfermedades Musculares/sangre , Enfermedades del Sistema Nervioso/sangre , Ubiquinona/análogos & derivados , Ubiquinona/sangre , Coenzimas , Epilepsias Mioclónicas/sangre , Ataxia de Friedreich/sangre , Humanos , Enfermedad de Huntington/sangre , Síndrome de Kearns-Sayre/sangre , Encefalomiopatías Mitocondriales/sangre , Enfermedad de Parkinson/sangre , Ubiquinona/deficienciaRESUMEN
Progressive myoclonic epilepsies (EPM) are difficult to treat and refractory to most antiepileptic drugs. Besides epilepsy, EPMs also involve continuous neurological deterioration. Oxidative stress is thought to be an important factor in this process. We therefore analyzed a series of antioxidant enzymes in the blood of patients and compared with healthy age matched controls. In addition patients were given high doses of N-acetylcysteine (NAC), a glutathione percursor to determine if symptoms of EPM would improve. Five patients, four with EPM 1 (Unverricht-Lundborg disease) and one patient with EPM2 (Lafora body disease) were treated with 6 g/day of NAC. Before treatment, plasma samples were analyzed for glutathione peroxidase activity, catalase activity, extracellular superoxide dismutase (SOD) and CuZn-SOD and compared with the controls. Erythrocyte CuZn-SOD was significantly lower in the EPM patients compared to controls. NAC improved markedly and stabilized the neurological symptoms in patients with EPM 1 but had a doubtful effect in the patient with EPM 2.
Asunto(s)
Epilepsias Mioclónicas/enzimología , Glutatión Peroxidasa/metabolismo , Superóxido Dismutasa/metabolismo , Acetilcisteína/uso terapéutico , Adulto , Epilepsias Mioclónicas/sangre , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/fisiopatología , Eritrocitos/enzimología , Femenino , Humanos , Enfermedad de Lafora/sangre , Enfermedad de Lafora/tratamiento farmacológico , Enfermedad de Lafora/enzimología , Enfermedad de Lafora/fisiopatología , Masculino , Valores de Referencia , Síndrome de Unverricht-Lundborg/tratamiento farmacológico , Síndrome de Unverricht-Lundborg/metabolismo , Síndrome de Unverricht-Lundborg/fisiopatologíaRESUMEN
Normeperidine, a major metabolite of meperidine, is half as potent as meperidine as an analgesic but two to three times more potent as a convulsant. Renal failure significantly increases the plasma half-life of normeperidine. The intensity of the central nervous system excitation is highly correlated with the plasma concentration of normeperidine. Moreover, normeperidine toxicity is not reversed by naloxone, which may exacerbate it. We report a patient with end-stage renal disease undergoing maintenance continuous cycler peritoneal dialysis who had been receiving meperidine for pain control. The patient subsequently developed myoclonic contractions and a grand mal seizure. The patient was successfully treated with hemodialysis (using an F8 dialyzer) for presumed normeperidine-induced seizure. During hemodialysis, normeperidine average blood clearance was 73 mL/min, average plasma clearance was 50 mL/min, and average percentage of plasma extraction was 24%. There also was a 26% reduction in plasma concentration of normeperidine over 3 hours of hemodialysis. In conclusion, our findings suggest that hemodialysis may be used effectively for treating patients with suspected normeperidine-induced neurotoxicity.