Levetiracetam vs. phenytoin as 2nd-line treatment for status epilepticus: A systematic review and meta-analysis.

OBJECTIVE: The objective of the study was to perform a systematic review and meta-analysis to evaluate the efficacy and safety of levetiracetam (LEV) or phenytoin (PHT) as second-line treatment for status epilepticus (SE). METHODS: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Latin American and Caribbean Health Sciences Literature (LILACS), Scopus, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Google Scholar were assessed for prospective randomized trials comparing LEV with PHT as second-line treatment of SE published from inception until December 18th, 2019. The primary outcome was seizure cessation. Data were analyzed using a random-effects model. Quality analysis was performed using version 2 of the Cochrane risk-of-bias tool (RoB 2). The study protocol was registered on PROSPERO (CRD42020136417). RESULTS: Nine studies with a total of 1732 patients were included. Overall, seizure cessation occurred in 657 of 887 (74%) of patients in the LEV group and 600 of 845 (71%) in the PHT group. Treatment success did not differ significantly between groups, and the relative risk (RR) was 1.05 (95% confidence interval (CI): 0.98-1.12; I2 = 53%). Six of the studies were at low risk of bias, one study had some risk, and two studies had high risk. CONCLUSIONS: The use of LEV or PHT as second-line agents after benzodiazepine (BZD) for the treatment of SE was not associated with a difference in seizure cessation. Because there are minimal differences in efficacy at this time, clinicians should consider alternative factors when deciding on an antiepileptic drug (AED).

Neuroprotective and anti-inflammatory activity of DAT inhibitor R-phenylpiracetam in experimental models of inflammation in male mice.

R-phenylpiracetam (R-PhP, (4R)-2-(4-phenyl-2-oxopyrrolidin-1-yl)acetamide) is an optical isomer of phenotropil, a clinically-used nootropic drug that improves physical condition and cognition. Recently, R-PhP was shown to bind to the dopamine transporter (DAT). Since growing evidence suggests that dysfunction of the dopaminergic system is associated with persistent neuroinflammation, the aim of this study was to determine whether R-PhP, an inhibitor of DAT, has neuroprotective and anti-inflammatory effects in male mice. The pharmacokinetic profiles of R-PhP in mouse plasma and its bioavailability in brain tissue were assessed. To study possible molecular mechanisms involved in the anti-inflammatory activity of R-PhP, target profiling was performed using radioligand binding and enzymatic activity assays. To clarify the neuroprotective and anti-inflammatory effects of R-PhP, we used a lipopolysaccharide (LPS)-induced endotoxaemia model characterized by reduced body temperature and overexpression of inflammatory genes in the brain. In addition, the antinociceptive and anti-inflammatory effects of R-PhP were tested using carrageenan-induced paw oedema and formalin-induced paw-licking tests. R-PhP (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (ip) and peroral (po) injections. The maximal concentration of R-PhP in the brain tissues was 28 µg/g and 18 µg/g tissue after ip and po administration, respectively. In radioligand binding assays, DAT was the only significant molecular target found for R-PhP. A single ip injection of R-PhP significantly attenuated the LPS-induced body temperature reduction and the overexpression of inflammatory genes, such as tumour necrosis factor-α (TNF-α), interleukin 1 beta (IL-1ß) and inducible nitric oxide synthase (iNOS). Seven-day po pretreatment with R-PhP dose-dependently reduced paw oedema and the antinociceptive response, as shown by the carrageenan-induced paw oedema test. In addition, R-PhP decreased the nociceptive response during the inflammatory phase in the formalin-induced paw-licking test. Our study showed that R-PhP possesses neuroprotective and anti-inflammatory effects, demonstrating the potential of DAT inhibitors as effective therapeutics.

Etiology of neonatal seizures and maintenance therapy use: a 10-year retrospective study at Toulouse Children's hospital.

BACKGROUND: No guidelines exist concerning the maintenance antiepileptic drug to use after neonatal seizures. Practices vary from one hospital to another. The aim of this study was to investigate etiologies and to report on the use of maintenance antiepileptic therapy in our population of full-term neonates presenting neonatal seizures. METHODS: From January 2004 to October 2014, we retrospectively collected data from all full-term neonates with neonatal seizures admitted to the Children's Hospital of Toulouse, France. RESULTS: Two hundred and forty-three neonates were included (59% males, 48% electroencephalographic confirmation). The frequencies of etiologies of neonatal seizures were: hypoxic-ischemic encephalopathy (HIE) (n = 91; 37%), ischemic infarction (n = 36; 15%), intracranial hemorrhage (n = 29; 12%), intracranial infection (n = 19; 8%), metabolic or electrolyte disorders (n = 9; 3%), inborn errors of metabolism (n = 5; 2%), congenital malformations of the central nervous system (n = 11; 5%), epileptic syndromes (n = 27; 12%) and unknown (n = 16; 7%). A maintenance therapy was prescribed in 180 (72%) newborns: valproic acid (n = 123), carbamazepine (n = 28), levetiracetam (n = 17), vigabatrin (n = 2), and phenobarbital (n = 4). In our cohort, the choice of antiepileptic drug depended mainly on etiology. The average duration of treatment was six months. CONCLUSIONS: In our cohort, valproic acid was the most frequently prescribed maintenance antiepileptic therapy. However, the arrival on the market of new antiepileptic drugs and a better understanding of the physiopathology of genetic encephalopathies is changing our practice. TRIAL REGISTRATION: Retrospectively registered. Patient data were reported to the "Commission Nationale Informatique et Libertés" under the number 2106953 .

Potent and selective pharmacodynamic synergy between the metabotropic glutamate receptor subtype 2-positive allosteric modulator JNJ-46356479 and levetiracetam in the mouse 6-Hz (44-mA) model.

OBJECTIVE: We previously demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate subtype 2 (mGlu2 ) receptors have potential synergistic interactions with the antiseizure drug levetiracetam (LEV). The present study utilizes isobolographic analysis to evaluate the combined administration of JNJ-46356479, a selective and potent mGlu2 PAM, with LEV as well as sodium valproate (VPA) and lamotrigine (LTG). METHODS: The anticonvulsant efficacy of JNJ-46356479 was evaluated in the 6-Hz model of psychomotor seizures in mice. JNJ-46356479 was administered in combination with LEV using 3 fixed dose-ratio treatment groups in the mouse 6-Hz (44-mA) seizure test. The combination of JNJ-46356479 with LEV was also evaluated in the mouse corneal kindling model. The potential interactions of JNJ-46356479 with the antiseizure drugs VPA and LTG were also evaluated using fixed dose-ratio combinations. Plasma levels were obtained for analysis of potential pharmacokinetic interactions for each combination studied in the mouse 6-Hz model. RESULTS: JNJ-46356479 was active in the 6-Hz model at both 32-mA and 44-mA stimulus intensities (median effective dose = 2.8 and 10.2 mg/kg, respectively). Using 1:1, 1:3, and 3:1 fixed dose-ratio combinations (LEV:JNJ-46356479), coadministration was significantly more potent than predicted for additive effects, and plasma levels suggest this synergism was not due to pharmacokinetic interactions. Studies in kindled mice further demonstrate the positive pharmacodynamic interaction of LEV with JNJ-46356479. Using 1:1 dose-ratio combinations of JNJ-46356479 with either VPA or LTG, there were no significant differences observed for coadministration. SIGNIFICANCE: These studies demonstrate a synergistic interaction of JNJ-46356479 with LEV, whereas no such effect occurred for JNJ-46356479 with either VPA or LTG. The synergy seems therefore to be specific to LEV, and the combination LEV/mGlu2 PAM has the potential to result in a rational polypharmacy approach to treat patients with refractory epilepsy, once it has been confirmed in clinical studies.

Why we prefer levetiracetam over phenytoin for treatment of status epilepticus.

Over last fifty years, intravenous (iv) phenytoin (PHT) loading dose has been the treatment of choice for patients with benzodiazepine-resistant convulsive status epilepticus and several guidelines recommended this treatment regimen with simultaneous iv diazepam. Clinical studies have never shown a better efficacy of PHT over other antiepileptic drugs. In addition, iv PHT loading dose is a complex and time-consuming procedure which may expose patients to several risks, such as local cutaneous reactions (purple glove syndrome), severe hypotension and cardiac arrhythmias up to ventricular fibrillation and death, and increased risk of severe allergic reactions. A further disadvantage of PHT is that it is a strong enzymatic inducer and it may make ineffective several drugs that need to be used simultaneously with antiepileptic treatment. In patients with a benzodiazepine-resistant status epilepticus, we suggest iv administration of levetiracetam as soon as possible. If levetiracetam would be ineffective, a further antiepileptic drug among those currently available for iv use (valproate, lacosamide, or phenytoin) can be added before starting third line treatment.

Pharmacokinetics of rectal levetiracetam as add-on treatment in dogs affected by cluster seizures or status epilepticus.

BACKGROUND: Levetiracetam can be used for seizure control alone or in combination with other antiepileptic medications. A previous study achieved the minimum targeted serum drug concentration after rectal administration of levetiracetam in healthy dogs. The purpose of the present study was to determine the pharmacokinetics of rectal LEV in dogs presented for cluster seizures or status epilepticus and potentially in treatment with other anti-epileptic drugs. Furthermore, preliminary information on response to this treatment as add-on to the standard treatment protocol is reported. RESULTS: Eight client-owned dogs were enrolled. Plasma levetiracetam concentrations (measured at 0, 30, 60, 90, 120, 180, 240, 360, 720, and 1440 min after drug administration) reached the minimum target concentration (5 µg/ml) at 30 min in all but one patient. At T1 (30 min) the mean concentration was 28.2 ± 15.5 µg/ml. Plasma concentrations remained above the targeted minimum concentration in all patients until 240 min and in 7/8 until 360 min. Six out of eight patients experienced no seizures in the 24-h period after hospitalization and were classified as "responders". CONCLUSIONS: Minimum plasma levetiracetam concentration can be reached after rectal administration of 40 mg/kg in dogs affected by cluster seizures and status epilepticus and concurrently receiving other antiepileptic drugs. These preliminary results may encourage the evaluation of rectal levetiracetam as an additional treatment option for cluster seizures and status epilepticus in a larger number of dogs.

Population pharmacokinetic model of levetiracetam in Korean neonates with seizures
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OBJECTIVE: This study was conducted to develop a population pharmacokinetic (PK) model of levetiracetam in Korean neonates with seizures. MATERIALS AND METHODS: Data were obtained from a retrospective study of 18 neonates with seizures admitted to the Neonatal Intensive Care Unit (NICU) of Severance Children's Hospital for the period of from 2013 to 2015. Sampling and dosing times were recorded by clinical research coordinators on case report forms. Demographic factors and laboratory results were tested as potential covariates for PK parameters. Model development was performed within a mixed-effect modeling framework using NONMEM. RESULTS: With a one-compartment model with first-order elimination chosen as a basic PK model based on theory-based allometric relationships, postmenstrual age and serum creatinine were found to have significant influences on clearance (CL). Typical parameter estimates of the final PK model obtained, evaluated at covariate medians, were 1.08 L/kg for volume of distribution (V) and 0.073 L/h/kg (= 1.23 mL/min/kg) for CL, illustrating that V in Korean neonates is a little larger than in Western population while CL is similar. CONCLUSION: A population PK model of levetiracetam for Korean neonates with seizures was developed in this study. The result of this study can be used as a basis to develop an optimal dosage regimen in Korean neonates with seizures.
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Population pharmacokinetics of levetiracetam in neonates with seizures.

WHAT IS KNOWN AND OBJECTIVE: This study developed a population pharmacokinetic (PK) model of levetiracetam (LEV) for treating neonatal seizures (NS) and determined the influence of clinically relevant covariates to explain the interindividual variability and residual error. METHODS: Twenty newborns admitted to the Neonatal Intensive Care Unit at the Hospital Central "Dr. Ignacio Morones Prieto" were included. LEV doses were administered by intermittent infusion. Blood samples were drawn 3 times post-infusion. Levetiracetam was quantified by a chromatographic technique. NONMEM software was used to determine the population PK model of LEV in neonates and the influence of clinical covariates on drug disposition. RESULTS AND DISCUSSION: The LEV PK in neonates is described by a one-compartment open model with first-order elimination. The influence of creatinine clearance (CRCL) and body weight (BW) on clearance (CL[L/h] = 0.47*CRCL), as well as the volume of the distribution (Vd[L] = 0.65*BW) of LEV, were confirmed, considering interindividual variabilities of 36% and 22%, respectively, and a residual error of 13%. WHAT IS NEW AND CONCLUSION: Based on the PK of LEV in neonates and the influence of the final PK model, a priori dosing guidelines are proposed considering CRCL, BW and LEV plasma concentrations between 6 and 20 mg/L for NS treatment.

Disposition of levetiracetam in healthy adult horses.

Nine horses received 20 mg/kg of intravenous (LEVIV ); 30 mg/kg of intragastric, crushed immediate release (LEVCIR ); and 30 mg/kg of intragastric, crushed extended release (LEVCER ) levetiracetam, in a three-way randomized crossover design. Crushed tablets were dissolved in water and administered by nasogastric tube. Serum samples were collected over 48 hr, and levetiracetam concentrations were determined by immunoassay. Mean ± SD peak concentrations for LEVCIR and LEVCER were 50.72 ± 10.60 and 53.58 ± 15.94 µg/ml, respectively. The y-intercept for IV administration was 64.54 ± 24.99 µg/ml. The terminal half-life was 6.38 ± 1.97, 7.07 ± 1.93 and 6.22 ± 1.35 hr for LEVCIR , LEVCER, and LEVIV , respectively. Volume of distribution at steady-state was 630 ± 73.4 ml/kg. Total body clearance after IV administration was 74.40 ± 19.20 ml kg-1  hr-1 . Bioavailability was 96 ± 10, and 98 ± 13% for LEVCIR and LEVCER , respectively. A single dose of Levetiracetam (LEV) was well tolerated. Based on this study, a recommended dosing regimen of intravenous or oral LEV of 32 mg/kg every 12 hr is likely to achieve and maintain plasma concentrations within the therapeutic range suggested for humans, with optimal kinetics throughout the dosing interval in healthy adult horses. Repeated dosing and pharmacodynamic studies are warranted.

Effects of parenteral papaverine and piracetam administration on cochlea following acoustic trauma.

INTRODUCTION: Noise exposure, the main cause of hearing loss in countries with lot of industries, may result both in temporary or permanent hearing loss. The goal of this study was to investigate the effects of parenteral papaverine and piracetam administration following an acoustic trauma on hearing function with histopathologic correlation. MATERIALS AND METHODS: Eighteen Wistar albino rats exposed to noise for 8 h in a free environment were included. We divided the study population into three groups, and performed daily intraperitoneal injections of papaverine, piracetam, and saline, respectively, throughout the study. We investigated the histopathologic effects of cellular apoptosis on inner hair cells (IHCs) and outer hair cells (OHCs) and compared the distortion product otoacoustic emissions (DPOAEs) thresholds among the groups. RESULTS AND DISCUSSION: On the 3rd and 7th days, DPOAE thresholds at 8 kHz were significantly higher both in papaverine and piracetam groups compared with the control group (P = 0.004 for 3rd day, P = 0.016 and P = 0.028 for 7th day, respectively). On the 14th day, piracetam group had significantly higher mean thresholds at 8 kHz (P = 0.029); however, papaverine group had similar mean thresholds compared to the control group (P = 0.200). On the 3rd and 7th days following acoustic trauma, both IHC and OHC loss were significantly lower in both papaverine and piracetam groups. On the 7th day, the mean amount of apoptotic IHCs and OHCs identified using Caspase-3 method were significantly lower in both groups, but the mean amount identified using terminal deoxynucleotidyl transferase dUTP nick end labeling method were similar in both groups compared to the control group. CONCLUSION: We demonstrated the effects of papaverine and piracetam on the recovery of cochlear damage due to acoustic trauma on experimental animals using histopathologic and electrophysiologic examinations.

Resting-state fMRI revealed different brain activities responding to valproic acid and levetiracetam in benign epilepsy with central-temporal spikes.

OBJECTIVES: Our aim was to investigate regional difference in brain activities in response to antiepileptic drug (AED) medications in benign epilepsy with central-temporal spikes (BECTS) using resting-state functional magnetic resonance imaging (fMRI). METHODS: Fifty-seven patients with BECTS underwent resting-state fMRI scans after receiving either valproic acid (VPA) (n = 15), levetiracetam (LEV) (n = 21), or no medication (n = 21). fMRI regional homogeneity (ReHo) parameter among the three groups of patients were compared and were correlated with total doses of AED in the two medicated groups. RESULTS: Compared with patients on no-medication, patients receiving either VPA or LEV showed decreased ReHo in the central-temporal region, frontal cortex, and thalamus. In particular, the VPA group showed greater ReHo decrease in the thalamus and milder in cortices and caudate heads compared with the LEV group. In addition, the VPA group demonstrated a negative correlation between ReHo values in the central-temporal region and medication dose. CONCLUSION: Both VPA and LEV inhibit resting-state neural activity in the central-temporal region, which is the main epileptogenic focus of BECTS. VPA reduced brain activity in the cortical epileptogenic regions and thalamus evenly, whereas LEV reduced brain activity predominantly in the cortices. Interestingly, VPA showed a cumulative effect on inhibiting brain activity in the epileptogenic regions in BECTS. KEY POINTS: • Regional differences in brain activity in response to different AEDs in BECTS. • AEDs inhibit resting-state neural activity in epileptogenic and subcortical regions in BECTS. • Valproic acid effect on the cortical epileptogenic regions and thalamus evenly. • Levetiracetam effect seen predominantly in cortices. • Valproic acid has a cumulative effect on inhibiting brain activity in epileptogenic regions.

Comparison of Levetiracetam Dosing Regimens in End-Stage Renal Disease Patients Undergoing Intermittent Hemodialysis.

BACKGROUND: Levetiracetam (LEV) is primarily renally eliminated. In end-stage renal disease (ESRD) patients on hemodialysis (HD), pharmacokinetic studies recommend daily dosing with 50% supplemental doses after 4-hour HD sessions. However, poor medication adherence after HD could result in fluctuating plasma drug levels. OBJECTIVE: To compare two LEV dosing regimens, daily versus twice-daily (BID), in ESRD patients undergoing HD. METHODS: Consecutive ESRD patients (April 2013 to May 2014) receiving maintenance inpatient HD and prescribed LEV prior to admission to our academic tertiary hospital were prospectively analyzed. Demographics, initial lab values, adverse reactions, seizures, and LEV regimens were recorded. LEV levels were obtained pre-HD and post-HD along with levels after receiving post-HD doses. Recovery of plasma levels after HD was assessed by comparison of levels predialysis versus postdialysis and post-HD doses. RESULTS: We identified 22 patients who met inclusion criteria; 14 BID and 8 daily dosing. Mean predialysis, postdialysis, and post-HD dose plasma levels were higher in patients receiving LEV BID compared with daily (43.1 ± 6.3, 19.4 ± 5.2, 34.9 ± 4.3 vs 21.1 ± 3.9, 6.9 ± 1.5, 11.9 ± 1.7 µg/mL; P < 0.05). BID post-HD levels were 41.9 ± 4.6% of predialysis levels versus 36.9 ± 7.3% with daily dosing ( P = 0.275). Post-HD dose levels were 81.4±4.3% of predialysis on LEV BID versus 65.7 ± 8.8% on LEV daily ( P = 0.045). No seizures were reported during hospital admission in either group. CONCLUSIONS: Compared to LEV daily, BID dosing achieved significantly higher levels and a better recovery to predialysis levels. Although limited by small numbers, a similar relationship between postdialysis levels was not detected.

Lacosamide and sodium channel-blocking antiepileptic drug cross-titration against levetiracetam background therapy.

OBJECTIVE: To assess prospectively the effectiveness of lacosamide (LCM) added to levetiracetam (LEV) after down-titration of a concomitant sodium channel blocker (SCB) among patients with focal epilepsy not adequately controlled on LEV and SCB. METHODS: In this open-label trial, LCM was initiated at 100 mg/day and up-titrated to 200-600 mg/day over 9 weeks; SCB down-titration started when LCM dose reached 200 mg/day. Patients remained on stable LCM/LEV doses for 12 weeks' maintenance (21-week treatment period). The primary outcome was retention rate on LCM. RESULTS: Due to recruitment challenges, fewer than the planned 300 patients participated in the trial, resulting in the trial being underpowered. Overall, 120 patients (mean age 39.7 years) started and 93 completed the trial. The most frequently used SCBs were lamotrigine (39.2%), carbamazepine (30.8%) and oxcarbazepine (27.5%). Eighty-four patients adhered to protocol and discontinued their SCB after cross-titration, but there was insufficient evidence for 36 patients. Retention rate was 73.3% (88/120) for all patients and 83.3% (70/84) for those with evidence of SCB discontinuation. Seizure freedom for patients completing maintenance was 14.0% (13/93). Discontinuation due to adverse events (6.7%) and lack of efficacy (3.3%) occurred primarily during cross-titration. Most frequently reported adverse events during treatment were dizziness (23.3%), headache (15.0%) and fatigue (8.3%). CONCLUSIONS: In patients with uncontrolled seizures on LEV/SCB, the LCM/LEV combination appeared to be effective and well tolerated. A cross-titration schedule-flexible LCM up-titration, concomitant SCB down-titration and stable background LEV-could present a feasible and practical approach to initiating LCM while minimizing pharmacodynamic interactions with a SCB.

The efficacy of different kinds of intravenously applied antiepileptic drugs in the treatment of status epilepticus. How can it be determined?

We explored the influence of four different efficacy criteria on the results of observational studies concerning the treatment of status epilepticus (SE) and its subtypes. We compared and contrasted the results of four different efficacy criteria for the effectiveness of phenytoin, valproate, levetiracetam, and lacosamide. Criterion 1=the last antiepileptic drug (AED) administered before SE termination. Criterion 2=the last drug introduced into the antiepileptic therapy within 72h before the cessation of SE and without changes in dosage or number of the co-medication. Criterion 3=the last drug introduced into the antiepileptic therapy or increased in dose within 24h before termination of the SE without changes in the co-medication. Criterion 4=the last drug introduced into the antiepileptic therapy within 72h before the cessation of SE even allowing changes in the co-medication. We used two-tailed χ2-tests with the Yates adjustment for small samples to evaluate statistical differences between efficacy rates of different AEDs in the entire group and in subgroups of SE according to the second level of subdivisions in axis 1 and according to axis 2 of the new ILAE classification. A total of 145 treatment episodes in 124 patients (47 male, 77 female) were evaluated. There were 23 significant differences in efficacy according to the different criteria. Only criteria 1 and 3 led to significant results in our analysis. When incorporating theoretical considerations and the results of this study, criterion 3 seems to be the most appropriate measure for the evaluation of efficacy of an AED in the treatment of SE, because it seems to be more reasonable than criterion 1.

Quality of life, mood and seizure control in patients with brain tumor related epilepsy treated with lacosamide as add-on therapy: A prospective explorative study with a historical control group.

OBJECTIVE: Brain tumor-related epilepsy (BTRE) is often drug resistant and patients can be forced to take polytherapy that can adversely affect their quality of life (QoL). Lacosamide (LCM) is a new antiepileptic drug (AED) used as adjunctive therapy in patients with partial seizures with or without secondary generalization, with a favorable pharmacokinetic profile that seems to be effective and well tolerated. Therefore it represents a possible therapeutic choice for patients with BTRE. We propose a prospective study with a historical control group to evaluate the effect of LCM as add-on therapy on seizure control and quality of life in patients with BTRE. This study has been designed to test the superiority of Lacosamide over Levetiracetam as an add-on. We compared a prospective cohort of 25 patients treated with Lacosamide with a historical control group (n=19) treated with Levetiracetam as an add-on. METHODS: We recruited 25 adult patients (M 18, F 7; mean age 41.9) affected by BTRE with uncontrolled partial-onset seizures treated with AED polytherapy. We added LCM as an add-on. Patients were evaluated at baseline, after 3months and at 6months. This population has been compared with a historical control group of 19 BTRE adult patients (M 13, F 6; median age 48.0, range: 28-70) with uncontrolled partial-onset seizures treated with LEV as add-on. The patients underwent QoL, mood and adverse events tests (Adverse Event Profile-AEP) and evaluation of seizure frequency. RESULTS: Twelve patients had high grade gliomas, and thirteen had low grade gliomas. During follow-up, thirteen patients underwent chemotherapy, three radiotherapy and five patients had disease progression. Nine patients had simple partial seizures, eight had complex partial seizures, and eight had secondary generalized seizures. Fifteen patients were in monotherapy and ten in polytherapy with AEDs. LCM was added up to reach the maximum dosage of 400mg/die (mean final dose 300mg/die). Four patients dropped out due to poor compliance and 1 for inefficacy. In the historical control group treated with LEV (mean final dose 2000mg/die) 12 patients had high-grade gliomas, and 7 had low grade gliomas. Thirteen patients were in monotherapy and 6 in polytherapy with AEDs. In the 22 patients evaluable of 25 patients treated with LCM, we observed at final follow-up 7 patients seizure free, 12 with a significant reduction of seizures≥50%, 2 stable and 1 patient with number of seizures increased. Mean seizure frequency at baseline compared with baseline period: the mean number of seizures significantly decreased from baseline (9.4) to final follow-up (1.2) (P=0.005). The Responder Rate was 86.4%. Comparing responder rate of 22 evaluable patients with LCM with responder rate of 19 patients with LEV we didn't observe significant differences (p=0.31). In our patients treated with LCM we didn't observe significant difference at 3 and 6months in QoL tests results; we observe a significant reduction in the mean score of Karnofsky Performance Status (KPS) and Barthel Index (BI) between baseline and 6months of follow-up (KPS p=0.003; BI p=0.007). No clinical side effects were observed. CONCLUSION: Comparing the LCM with the historical group treated with LEV in add-on, we observed that LCM seems to have a higher clinical efficacy than LEV. In our patients, we did not observe any significant changes in QoL tests, indicating stability in all quality of life domains explored, despite the objective worsening in their functional status. Although this is a small series with a relatively short follow-up, our data indicates that LCM in add-on in patients with BTRE appears to be as effective as LEV in add-on, without impact on mood and quality of life.

Haemodialysis significantly reduces serum levetiracetam levels inducing epileptic seizures: Case report.

WHAT IS KNOWN AND OBJECTIVE: Levetiracetam is used in the treatment of some forms of epilepsy. In renal impairment and patients on chronic haemodialysis, dose adjustment is required. We report a case. CASE DESCRIPTION: This case report describes a woman on levetiracetam treatment who presented with generalized tonic-clonic seizures during a haemodialysis session. We report on treatment adjustment and on the impact of dialysis on levetiracetam levels. WHAT IS NEW AND CONCLUSION: Haemodialysis reduces serum levetiracetam concentration and can lead to subtherapeutic levels. Close monitoring is necessary when dialysis is used on patients receiving anticonvulsant drugs that are extensively eliminated by the procedure.

Review and update of the Hong Kong Epilepsy Guideline on status epilepticus.

Convulsive status epilepticus is the most extreme form of seizure. It is a medical and neurological emergency that requires prompt and appropriate treatment. Treatment of convulsive status epilepticus is usually divided into stages/steps. The International League Against Epilepsy has released a new definition of status epilepticus that may help to unify the definition in future studies. Over the last few years new information has become available regarding its management. The Rapid Anticonvulsant Medication Prior to Arrival Trial demonstrated non-inferiority of intramuscular midazolam in early status epilepticus compared with intravenous lorazepam. Valproate and levetiracetam have also emerged as possible alternatives to phenytoin in established status epilepticus. The potential role of lacosamide in this stage of status epilepticus remains to be defined. The ongoing Established Status Epilepticus Treatment Trial may help to determine the most effective treatment for benzodiazepine-resistant status epilepticus. Management of refractory status epilepticus and super-refractory status epilepticus remains mostly non-evidence-based. Increasing recognition of a possible autoimmune aetiology has led to the use of immune-modulation in super-refractory status epilepticus. Ketamine is also increasingly used in this challenging condition. There are also reports of potential use of a ketogenic diet and magnesium.

The influence of thermal treatment and type of insoluble poly(meth)acrylates on dissolution behavior of very soluble drug from hypromellose matrix tablets evaluated by multivariate data analysis.

Hypromellose matrices exhibit extended burst effect immediately after contact with aqueous medium, especially when a water-soluble drug is incorporated. The objective of this study was to reduce burst effect and maintain complete dissolution of a very soluble levetiracetam over 12 h period from hypromellose K4M matrices to obtain zero-order kinetics. Desired changes were achieved by applying water dispersions of insoluble Eudragits® (NE, NM, RL, RS) as a granulation liquid to the drug/microcrystalline cellulose mixture during high-shear granulation (non-thermal treated set) and consequently by thermally treating granules or final tablets (TT), respectively. Applying Eudragit® water dispersions to the drug/microcrystalline cellulose mixture was recognized as an effective method of significantly reducing the burst release (25.4-33.7%) of levetiracetam in comparison with a reference sample without Eudragit®. Multivariate data analysis showed that the addition of Eudragit® reduced burst effect, increased fitting with zero-order kinetics, and supported matrix erosion as the supplementary mechanism to predominant diffusion. Moreover, resulting PCA sub-model revealed the addition of Eudragit® RL and thermal treatment of tablets to be the most suitable method of all. For a 12 h dissolution profile, characterized by low burst effect and drug release close to 100% at the 12th hour, sample RL_TT was the most suitable.

Similarity of symptoms between transient epileptic amnesia and Lewy body disease.

Epilepsy with the main symptom of amnesia is known as transient epileptic amnesia (TEA). Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia. The concept that Lewy body disease includes Parkinson's disease with dementia and dementia with Lewy bodies was proposed in the 2005 revision of the Clinical Diagnostic Criteria. Here, we describe a woman with cognitive impairment, olfactory dysfunction, and reduced 123 I-meta-iodobenzylguanidine uptake on myocardial scintigraphy. The patient and her family and friends were unaware of parkinsonism, visual hallucinations, or epilepsy for a long period. After syncope occurred twice within a short interval, electroencephalography revealed sharp waves from the bilateral frontal to parietal lobes, indicating a diagnosis of TEA. The present case prompted us to compare the symptoms of TEA with the clinical diagnostic criteria for dementia with Lewy bodies, revealing their similarities. We also discuss whether Lewy body disease may cause TEA rather than having an incidental association with it.