Efficacy and tolerability of rufinamide in the treatment of epilepsy (experience of the Svt. Luka’s Institute of Child Neurology and Epilepsy)

Background. Despite significant advances in epileptology, approximately one-third of epilepsy patients suffer from drug-resistant seizures. Numerous approaches are currently available to treat epilepsy; however, there are still many patients with treatment-resistant epilepsy, in whom surgical treatment is impossible and alternative methods (vagus nerve stimulation and ketogenic diet) are ineffective. Therefore, searching for novel effective antiepileptic drugs (AEDs) is crucial for these patients.Objective: analysis of own data on the efficacy and tolerability of rufinamide in patients with severe forms of epilepsy and seizures typical of Lennox–Gastaut syndrome (LGS).Materials and methods. The study included 31 patients aged between 4 and 26 years (mean age 7.5 years) that received rufinamide (inovelon). The study cohort comprised 21 males and 10 females. Fifteen patients were diagnosed with LGS, whereas 16 patients were diagnosed with structural focal epilepsy with a phenocopy of LGS. Five patients had an evolution of West syndrome to LGS. The majority of patients (n = 22) experienced predominantly axial tonic seizures and epileptic spasms that were considered as indications for introduction of rufinamide. All patients underwent electroencephalography, video-electroencephalography monitoring during wakefulness and sleep, magnetic resonance imaging (MRI) (including high-resolution MRI with special epilepsy protocols when indicated), genetic examination (tandem mass spectrometry, hereditary epilepsy gene panel test and chromosomal microarray analysis) when indicated, and laboratory tests to assess tolerability of antiepileptic drugs.Results. Good therapeutic effect (more than 50 % reduction in seizure frequency) was achieved in 14 (45.2 %) patients. A less than 50 % reduction in seizure frequency occurred in 5 (16.1 %) patients; in 2 of them seizures became shorter and milder without a significant reduction in their frequency. Rufinamide was ineffective in 9 (29 %) patients. Three (9.7 %) patients experienced aggravation (increased seizure frequency) after the introduction of rufinamide. Thus, treatment with rufinamide was effective in 19 (61.3 %) patients. Rufinamide was well tolerated by most of the patients. Side effects were observed in 6 (19 %) participants. Side effects (forced normalization) caused withdrawal of rufinamide in 1 (3.2 %) patient. Currently, 10 (32 %) patients continue to take rufinamide. Sixteen patients received rufinamide for <6 months, 17 patients – for >6 months, 5 patients – for >12 months, and 1 patient – for >2 years.Conclusion. Our findings are consistent with the results obtained by foreign authors in routine clinical practice. In our study, rufinamide was used only in patients with drug-resistant epilepsy that earlier received many of currently available AEDs (both in monotherapy and in combination with other drugs). All study participants were earlier treated with at least three different AEDs that were ineffective. Seven patients received more than 8 AEDs in various combinations. This initial drug resistance should be taken into account when analyzing the data, which can not be extrapolated to patients with unknown drug resistance. We assume that the early introduction of rufinamide (prior to the detection of drug resistance) might have yielded better results.

Download Full-text

DDRE-27. METABOLIC SWITCHING AS A MECHANISM OF DRUG RESISTANCE AGAINST NAMPT INHIBITION IN GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noab196.311 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi80-vi80

Author(s):

Pratibha Sharma ◽

Vinay Puduvalli

Keyword(s):

Drug Resistance ◽

Energy Metabolism ◽

Cross Reactivity ◽

Alternative Methods ◽

Cross Resistance ◽

Significant Heterogeneity ◽

Drug Resistant ◽

High Accumulation ◽

Metabolic Switch ◽

Nicotinamide Phosphoribosyltransferase

Abstract BACKGROUND Gliomas exhibit significant heterogeneity in treatment response and characteristically deploy resistance mechanisms that render conventional therapies ineffective. Recently, novel agents have been developed that target regulators of differential energy pathways specifically utilized by gliomas. We previously reported on the targeting of Nicotinamide Phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway and its essential role in glioma cell energy metabolism. Here, we determined the mechanisms by which glioma cells bypass blockade of energy metabolism and develop resistance to NAMPT inhibitors. METHODS Using isogenic parental and drug-resistant patient-derived glioma stem-like cells (GSCs), we examined adaptive changes after NAMPT inhibition in glycolysis, mitochondrial function (oxidative state, basal respiration rate, spare respiratory capacity, maximum respiration capacity and proton leak) and metabolite levels using Agilent Seahorse assay and targeted metabolomics. Cross reactivity across various NAMPT inhibitors was measured using Cell Titer Glo assay. RESULTS GSCs exposed for an extended period to sub-lethal doses of FK866, a potent NAMPT inhibitor, acquired drug resistance to the agent which were also cross-resistant to other NAMPT inhibitors. Drug-resistant GSCs showed a decrease in extracellular acidification rate and oxygen consumption rate compared to isogenic parental lines. Further, metabolomic analysis showed a high accumulation of glutamate, creatine and histidine metabolites in these cells. These results indicate a shift in metabolism of drug-resistant GSCs from carbon metabolism to nitrogen metabolism. CONCLUSIONS GSCs resistant to the NAMPT inhibitor, FK866 showed cross resistance to other NAMPT inhibitors indicating specificity of this effect. The resistance mechanism involves a shift of preferential energy generation from glycolysis to amino acid metabolism which allows the cells to use alternative methods to generate NAD. Additional results from ongoing studies to delineate the mechanisms of metabolic switch in the drug resistance lines will be presented that will help develop strategies to combat resistance to NAMPT inhibitors.

Download Full-text

Stereoelectroencephalography-Guided Radiofrequency Thermocoagulation (SEEG-Guided RF-TC) in Patients with Drug-Resistant Focal Epilepsy

Translational Neuroscience and Clinics ◽

10.18679/cn11-6030_r.2017.006 ◽

2017 ◽

Vol 3 (1) ◽

pp. 40-47

Author(s):

Chengwei Xu ◽

Wenjing Zhou

Keyword(s):

Radio Frequency ◽

Surgical Resection ◽

Seizure Frequency ◽

Palliative Treatment ◽

Focal Epilepsy ◽

Epileptogenic Zone ◽

Drug Resistant ◽

Functional Area ◽

Presurgical Evaluation ◽

Epileptic Patients

For some patients with drug-resistant focal epilepsy, we usually select conventional surgical resection, which has brought better outcomes. However, others are not eligible for a conventional open surgical resection of the epileptogenic zone because of the proximity of a functional area or the implication of a larger epileptogenic network. Initially, stereoelectroencephalography (SEEG) exploration was a method of electroencephalography recording that was used in the presurgical evaluation of epileptic patients with complex epilepsy. Later, intracerebral electrodes used for SEEG were applied to produce radio frequency thermocoagulation (RF-TC) in epileptic patients. SEEG-guided RF-TC has produced some promising results, especially in the last dacade. Now, it has become popular as a palliative treatment to reduce seizure frequency in patients with drug-resistant focal epilepsy. This article presents a review of SEEG-guided RF-TC.

Download Full-text

High-frequency oscillations in scalp EEG mirror seizure frequency in pediatric focal epilepsy

Scientific Reports ◽

10.1038/s41598-019-52700-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Ece Boran ◽

Johannes Sarnthein ◽

Niklaus Krayenbühl ◽

Georgia Ramantani ◽

Tommaso Fedele

Keyword(s):

Seizure Frequency ◽

Epilepsy Surgery ◽

High Frequency ◽

Focal Epilepsy ◽

Low Noise ◽

Drug Resistant ◽

Scalp Eeg ◽

High Frequency Oscillations ◽

Custom Made ◽

Active Epilepsy

Abstract High-frequency oscillations (HFO) are promising EEG biomarkers of epileptogenicity. While the evidence supporting their significance derives mainly from invasive recordings, recent studies have extended these observations to HFO recorded in the widely accessible scalp EEG. Here, we investigated whether scalp HFO in drug-resistant focal epilepsy correspond to epilepsy severity and how they are affected by surgical therapy. In eleven children with drug-resistant focal epilepsy that underwent epilepsy surgery, we prospectively recorded pre- and postsurgical scalp EEG with a custom-made low-noise amplifier (LNA). In four of these children, we also recorded intraoperative electrocorticography (ECoG). To detect clinically relevant HFO, we applied a previously validated automated detector. Scalp HFO rates showed a significant positive correlation with seizure frequency (R2 = 0.80, p < 0.001). Overall, scalp HFO rates were higher in patients with active epilepsy (19 recordings, p = 0.0066, PPV = 86%, NPV = 80%, accuracy = 84% CI [62% 94%]) and decreased following successful epilepsy surgery. The location of the highest HFO rates in scalp EEG matched the location of the highest HFO rates in ECoG. This study is the first step towards using non-invasively recorded scalp HFO to monitor disease severity in patients affected by epilepsy.

Download Full-text

The peculiarities of focal epilepsy in pregnant women

Kazan medical journal ◽

10.17750/kmj2017-729 ◽

2017 ◽

Vol 98 (5) ◽

pp. 729-732 ◽

Cited By ~ 1

Author(s):

Sh Y Melikova

Keyword(s):

Status Epilepticus ◽

Sleep Deprivation ◽

Pregnant Women ◽

Antiepileptic Drug ◽

Antiepileptic Drugs ◽

Seizure Frequency ◽

Focal Epilepsy ◽

Average Duration ◽

Convulsive Status Epilepticus

Aim. To investigate the peculiarities of focal epilepsy in pregnant women. Methods. 70 pregnant women with symptomatic focal epilepsy during the period from 2013 to 2017 were studied. Results. The average age at the onset of epilepsy was 18.2±0.6 years. The average duration of epilepsy by the time of pregnancy was 6.6±0.7 years. 15 (21.4±4.9%) women remained seizure-free during pregnancy. Seizures during pregnancy were observed in 55 (78.6±4.9%) women: seizure frequency increased in 22 (31.4±5.5%) cases, decreased in 17 (24.3±5.1%), remained unchanged in 8 (11.4±3.8%), in 8 (11.4±3.8%) women the onset of epilepsy occurred during pregnancy. 72.7% of women who were seizure-free for 1 year prior to pregnancy remained seizure-free during pregnancy. In 21 (40.4%) of 52 women with epilepsy diagnosed prior to pregnancy and treated with antiepileptic drugs, the increase of seizure frequency was observed, which can be explained by non-compliance with the regimen and therapy and sleep deprivation in 15 (71.4%) of them. Generalized convulsive status epilepticus during pregnancy was observed in 1 (1.4±1.4%) woman after a sudden withdrawal of the antiepileptic drug. Conclusion. The risk of seizures during pregnancy is lower in women who were seziure-free for 1 year prior to pregnancy; non-compliance with the regimen and therapy and sleep deprivation may lead to worsening of epilepsy during pregnancy.

Download Full-text

Supplementation of Water Extract of Purple Sweet Potato (Ipomoeo Batatas L) in Improving the EEG Image, Decreasing the Seizure Frequency and Reducing the Frequency of Drugs Resistant of Focal Epilepsy in Children

Biomedical & Pharmacology Journal ◽

10.13005/bpj/1622 ◽

2019 ◽

Vol 12 (1) ◽

pp. 141-147

Author(s):

I. Gusti Ngurah Made Suwarba ◽

Soetjiningsih Soetjiningsih ◽

I. Made Bakta ◽

I. Made Jawi ◽

I. Dewa Made Sukrama ◽

...

Keyword(s):

Serum Level ◽

Sweet Potato ◽

Seizure Frequency ◽

Focal Epilepsy ◽

Water Extract ◽

Anticonvulsant Effect ◽

Drug Resistant ◽

Dependent Variables ◽

Potato Extract ◽

Purple Sweet Potato

The water extract of purple sweet potato contains of anthocyanin, a sub-class of flavonoid that has powerful antioxidant, antiinflammatory, and anticonvulsant effect. The aim of this study was to determine the effectiveness of supplementation of water extract of purple sweet potato towards recovery (remission) of drug resistant focal epilepsy (DRFE) in children with standard conventional antiepileptic medicine. It was found that the supplementation of purple sweet potato extract had a pure effect in improving all of the dependent variables, including decreased of the serum level of 8-OHdG by 1.611 pg/mL (p<0.001); decreased the serum level of IL-6 by 3.320 pg/mL (p<0.001); increased the total SOD serum level by 0.208 IU/mL (p=0.003); improved the EEG image (p=0.004); and decreased the seizure frequency at the end of the sixth week by 3.972 times (p<0.001), compared to the control. There is a significant effect on the use of supplementation of purple sweet potato extract in decreasing the serum level of 8-OHdG, decreasing the serum level of IL-6, increasing the total SOD serum level, improving the EEG image, decreasing the seizure frequency at the end of the sixth week, which at the end reducing the frequency of drugs resistant of focal epilepsy in children.

Download Full-text

Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy

Neurology ◽

10.1212/wnl.0000000000005755 ◽

2018 ◽

Vol 91 (2) ◽

pp. 74-81 ◽

Cited By ~ 33

Author(s):

Andres M. Kanner ◽

Eric Ashman ◽

David Gloss ◽

Cynthia Harden ◽

Blaise Bourgeois ◽

...

Keyword(s):

Antiepileptic Drugs ◽

Seizure Frequency ◽

Focal Epilepsy ◽

Juvenile Myoclonic Epilepsy ◽

Absence Epilepsy ◽

Review Literature ◽

Third Generation ◽

High Quality ◽

New Antiepileptic Drugs ◽

New Onset

ObjectiveTo update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy with second- and third-generation antiepileptic drugs (AEDs).MethodsThe 2004 AAN criteria were used to systematically review literature (January 2003–November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength.ResultsSeveral second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic-clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy.RecommendationsLamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years of age with new-onset focal epilepsy. Unless there are compelling adverse effect–related concerns, ethosuximide or valproic acid should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval.

Download Full-text

Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy

Epilepsy Currents ◽

10.5698/1535-7597.18.4.260 ◽

2018 ◽

Vol 18 (4) ◽

pp. 260-268 ◽

Cited By ~ 22

Author(s):

Andres M. Kanner ◽

Eric Ashman ◽

David Gloss ◽

Cynthia Harden ◽

Blaise Bourgeois ◽

...

Keyword(s):

Antiepileptic Drugs ◽

Seizure Frequency ◽

Focal Epilepsy ◽

Juvenile Myoclonic Epilepsy ◽

Absence Epilepsy ◽

Review Literature ◽

Third Generation ◽

High Quality ◽

New Antiepileptic Drugs ◽

New Onset

Objective: To update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy (GE) with second- and third-generation antiepileptic drugs (AEDs). Methods: The 2004 AAN criteria was used to systematically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Results: Several second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic–clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy. Recommendations: Lamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years with new-onset focal epilepsy. Unless there are compelling adverse-effect–related concerns, ethosuximide (ETS) or valproic acid (VPA) should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (Level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent FDA strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval.

Download Full-text

Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy

Epilepsy Currents ◽

10.5698/1535-7597.18.4.269 ◽

2018 ◽

Vol 18 (4) ◽

pp. 269-278 ◽

Cited By ~ 5

Author(s):

Andres M. Kanner ◽

Eric Ashman ◽

David Gloss ◽

Cynthia Harden ◽

Blaise Bourgeois ◽

...

Keyword(s):

Antiepileptic Drugs ◽

Seizure Frequency ◽

Extended Release ◽

Focal Epilepsy ◽

Immediate Release ◽

Juvenile Myoclonic Epilepsy ◽

Review Literature ◽

Treatment Resistant ◽

New Antiepileptic Drugs ◽

Frequency Level

Objective: To update the 2004 American Academy of Neurology (AAN) guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs). Methods: 2004 criteria were used to systematically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Results: Forty-two articles were included. Recommendations: The following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment; rufinamide for Lennox–Gastuat syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic–clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal epilepsy (TRCFE) (1 month to 16 years), TR GTC seizures, and TR juvenile myoclonic epilepsy; clobazam for LGS (add-on therapy); zonisamide for TRCFE (6–17 years); oxcarbazepine for TRCFE (1 month to 4 years). The text presents Level C recommendations. AED selection depends on seizure/syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. This evidence-based assessment informs AED prescription guidelines for TR epilepsy and indicates seizure types and syndromes needing more evidence. A recent FDA strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years of age and perampanel as monotherapy received FDA approval.

Download Full-text

Cenobamate: A New Adjunctive Agent for Drug-Resistant Focal Onset Epilepsy

Annals of Pharmacotherapy ◽

10.1177/1060028020941113 ◽

2020 ◽

pp. 106002802094111 ◽

Cited By ~ 2

Author(s):

Christopher T. Buckley ◽

Olivia R. Waters ◽

George DeMaagd

Keyword(s):

Clinical Trials ◽

Seizure Frequency ◽

Focal Epilepsy ◽

Data Extraction ◽

Seizure Freedom ◽

Drug Resistant ◽

Phase 2 ◽

Median Percentage ◽

Phase 2 Trial ◽

Pubmed Database

Objective: To review the pharmacology, efficacy, and safety of oral cenobamate in the treatment of uncontrolled focal epilepsy. Data Sources: The PubMed database and ClinicalTrials.gov were searched using the following terms: cenobamate, Xcopri, and YKP3089. Study Selection and Data Extraction: Articles published in English between January 2000 and April 2020 related to pharmacology, safety, and clinical trials were assessed. Data Synthesis: In a phase 2 trial, cenobamate reduced the median percentage change in seizure frequency from baseline by 56% compared with 22% for placebo ( P < 0.0001). In another phase 2 trial of multiple cenobamate doses, cenobamate reduced seizure frequency by 36% ( P = 0.0071) in the 100-mg group and 55% ( P < 0.0001) in both the 200- and 400-mg groups, compared to 24% with placebo. Adverse effects of cenobamate appear to be similar to those of other antiseizure medications and primarily affect the neurological system. Relevance to Patient Care and Clinical Practice: In patients taking antiseizure medications who continue to have focal seizures, cenobamate has efficacy at multiple doses and is generally well tolerated. Cenobamate may be distinguished from other antiseizure medications by high rates of seizure freedom not seen in previous placebo-controlled trials, which has the potential to significantly improve quality of life. However, despite this efficacy, Drug Reaction with Eosinophilia and Systemic Symptoms may remain a significant concern with cenobamate. Conclusion: As seen in clinical trials, cenobamate as an adjunctive, once-daily treatment represents an efficacious and generally well-tolerated therapy for patients with drug-resistant focal epilepsy.

Download Full-text

DRUG-RESISTANT EPILEPSY IN CASE OF CRANIOCEREBRAL DISPROPORTION. A PILOT STUDY

Manual Therapy ◽

10.54504/1684-6753-2021-83-3-19-23 ◽

2021 ◽

Vol 83 (3) ◽

pp. 19-23

Author(s):

Oleg Biketov

Keyword(s):

Drug Resistance ◽

Drug Therapy ◽

Pilot Study ◽

Antiepileptic Drugs ◽

Pathological Process ◽

Research Trends ◽

Drug Resistant ◽

The Past ◽

Craniocerebral Disproportion ◽

Drug Resistant Epilepsy

The problem of ineff ective drug therapy of epilepsy continues to be relevant during many decades and determines many key research trends in clinical and fundamental epileptology. Despite the emergence of a large number of various antiepileptic drugs the eff ectiveness of drug therapy for epilepsy has remained almost unchanged over the past decades. In this article drug-resistance in epilepsy is considered as a consequence of a concomitant pathological process in the form of craniocerebral disproportion.

Download Full-text