ABSTRACT
OBJECTIVE: In pregnancy, it is important to balance the risks of uncontrolled epileptic seizures to the mother and fetus against the potential teratogenic effects of antiseizure medications. Data are limited on pregnancy outcomes among patients taking lacosamide (LCM), particularly when taken as monotherapy. The objective of this analysis was to evaluate the pregnancy outcomes of LCM-exposed pregnancies. METHODS: This analysis included all reports in the UCB Pharma pharmacovigilance database of exposure to LCM during pregnancy from spontaneous sources (routine clinical settings) or solicited reports from interventional clinical studies and noninterventional postmarketing studies. Prospective and retrospective reports were analyzed separately. RESULTS: At the data cutoff (August 31, 2021), there were 202 prospective pregnancy cases with maternal exposure to LCM and known outcomes. Among these cases, 44 (21.8%) patients received LCM monotherapy and 158 (78.2%) received LCM polytherapy. Most patients received LCM during the first trimester (LCM monotherapy: 39 [88.6%]; LCM polytherapy: 143 [90.5%]). From the prospective pregnancy cases with maternal LCM exposure, there were 204 reported outcomes (two twin pregnancies occurred in the polytherapy group). The proportion of live births was 84.1% (37/44) in patients who received LCM as monotherapy, and 76.3% (122/160) for LCM polytherapy. The overall proportion of abortions (for any reason) was 15.9% (7/44) with LCM monotherapy, and 22.5% (36/160) with LCM polytherapy. Congenital malformations were reported in 2.3% (1/44) of known pregnancy outcomes with maternal exposure to LCM monotherapy, and 6.9% (11/160) with polytherapy. SIGNIFICANCE: Our preliminary data do not raise major concerns on the use of LCM during pregnancy. Most pregnancies with LCM exposure resulted in healthy live births, and no new safety issues were identified. These findings should be interpreted with caution, as additional data are needed to fully evaluate the safety profile of LCM in pregnancy.
Subject(s)
Anticonvulsants , Epilepsy , Lacosamide , Pregnancy Complications , Pregnancy Outcome , Humans , Pregnancy , Female , Lacosamide/adverse effects , Lacosamide/therapeutic use , Anticonvulsants/adverse effects , Anticonvulsants/therapeutic use , Adult , Pregnancy Complications/drug therapy , Pregnancy Complications/epidemiology , Pregnancy Outcome/epidemiology , Epilepsy/drug therapy , Prospective Studies , Retrospective Studies , Pharmacovigilance , Abnormalities, Drug-Induced/epidemiology , Abnormalities, Drug-Induced/etiology , Young Adult , Infant, NewbornABSTRACT
OBJECTIVE: To examine serologic markers of vascular risk under treatment with commonly used antiepileptic drugs (AEDs) in the elderly in a randomized setting, and to determine whether the reduced exposure to hydroxymethylglutaryl-CoA reductase inhibitors ("statins") caused by carbamazepine reduces the effectiveness of the drugs as lipid-lowering agents. METHODS: Standard lipid fractions, lipoprotein(a), and C-reactive protein (CRP) were examined in a subset of those participating in the STEP-ONE trial, in which elderly patients with new epilepsy were randomized to treatment with carbamazepine, lamotrigine, or levetiracetam. Separate comparisons were made by individual AED, among those treated with statins, and, for CRP, among those treated with anti-inflammatory drugs. RESULTS: One hundred ninety-four patients had the aforementioned serologic measurements. In patients not taking statins, those treated with carbamazepine had higher total cholesterol than those treated with levetiracetam (+16.6 mg/dL, P = 0.053), with values from patients on lamotrigine intermediate, whereas cholesterol fractions were subject to drug-gender interactions which did not show a consistent pattern. Lipoprotein(a) was significantly lower in lamotrigine patients than in the carbamazepine and levetiracetam groups. After accounting for the effects of steroids, CRP was higher in carbamazepine patients than in other patients. Patients taking a statin had lower lipid levels than those not taking a statin regardless of AED, but the differences between statin-treated and non-statin-treated patients were much larger (50%-100% or more) in the lamotrigine and levetiracetam groups than in the carbamazepine group (P = 0.035 for interaction effect of statin use and AED on total cholesterol). SIGNIFICANCE: Here, we demonstrate that carbamazepine significantly interferes with the ability of statins to lower total cholesterol, thus making it a poor choice for hyperlipidemic patients or those with cardiovascular disease. Native AED effects on lipids were inconsistent and subject to drug-gender interaction, in contrast with other studies; further investigation is necessary to determine if these latter findings are genuine or spurious.
Subject(s)
Anticonvulsants/therapeutic use , C-Reactive Protein/metabolism , Epilepsy/drug therapy , Epilepsy/metabolism , Lipid Metabolism/drug effects , Lipoproteins/metabolism , Aged , Aged, 80 and over , Carbamazepine/therapeutic use , Cholesterol, LDL/metabolism , Double-Blind Method , Drug Interactions , Female , Humans , Lamotrigine/therapeutic use , Levetiracetam/therapeutic use , Male , Triglycerides/metabolismABSTRACT
BACKGROUND: Few clinical trials have evaluated the efficacy and tolerability of antiepileptic drugs (AEDs) as initial monotherapy for elderly patients. METHODS: This post-hoc subgroup analysis of data from an unblinded, randomized, 52-week superiority study (KOMET) compared the effectiveness of levetiracetam (LEV) with extended-release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients aged ≥ 60 years with newly diagnosed epilepsy. The physician chose VPA or CBZ as preferred standard treatment; patients were randomized to standard AEDs or LEV. The primary endpoint was time to treatment withdrawal. Results are exploratory, since KOMET was not powered for a subgroup analysis by age. RESULTS: Patients (n = 308) were randomized to LEV (n = 48) or VPA-ER (n = 53) in the VPE-ER stratum or to LEV (n = 104) or CBZ-CR (n = 103) in the CBZ-CR stratum. Mean age was 69.6 years, range 60.2-89.9 years (intention-to-treat population n = 307). Time to treatment withdrawal hazard ratio [HR] (95 % confidence interval [CI]) for LEV vs. standard AEDs was 0.44 (0.28-0.67); LEV vs. VPA-ER: 0.46 (0.16-1.33); LEV vs. CBZ-CR: 0.45 (0.28-0.72). Twelve-month withdrawal rates were: LEV vs. standard AEDs, 20.4 vs. 38.7 %; LEV vs. VPA-ER, 10.4 vs. 23.1 %; LEV vs. CBZ-CR, 25.0 vs. 46.6 %. Time to first seizure was similar between LEV and standard AEDs (HR: 0.92, 95 % CI: 0.63-1.35), LEV and VPA-ER (0.77, 0.38-1.56), and LEV and CBZ-CR (1.02, 0.64-1.63). Adverse events were reported by 76.2, 67.3, and 82.5 % of patients for LEV, VPA-ER, and CBZ-CR, respectively. Discontinuation rates due to AEs were 11.3, 10.2, and 35.0 % for LEV, VPA-ER, and CBZ-CR, respectively. CONCLUSIONS: Time to treatment withdrawal was longer with LEV compared with standard AEDs. This finding was driven primarly by the result in the CBZ-CR stratum, which in turn was likely due to the more favorable tolerability profile of LEV. Results of this post-hoc analysis suggest that LEV may be a suitable option for initial monotherapy for patients aged ≥ 60 years with newly diagnosed epilepsy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00175903 ; September 9, 2005.
Subject(s)
Carbamazepine/therapeutic use , Epilepsy/drug therapy , Piracetam/analogs & derivatives , Valproic Acid/therapeutic use , Aged , Aged, 80 and over , Anticonvulsants/therapeutic use , Female , Humans , Levetiracetam , Male , Middle Aged , Piracetam/therapeutic use , Seizures/drug therapyABSTRACT
OBJECTIVE: To compare the effectiveness of controlled-released carbamazepine (CR-CBZ) to levetiracetam (LEV) and to lamotrigine (LTG) in elderly patients with newly diagnosed focal epilepsy. METHODS: Randomized, double-blind, parallel-group trial conducted between January 2007 and August 2011, in 47 ambulatory or hospital sites in Germany, Austria, or Switzerland. Eligible participants were aged ≥ 60, had new-onset epilepsy, had no acute illness as the cause of their seizures, and had no contraindication to the drugs in the trial. Patients were randomized 1:1:1 to CR-CBZ, LTG, or LEV. Doses were up-titrated for 6 weeks and could be maintained or adjusted depending on seizure relapse or tolerability over an additional period of 52 weeks. Primary outcome was the retention to treatment at week 58; secondary measures related to seizure and adverse event frequency. RESULTS: Of 361 randomized patients, 359 were included (CR-CBZ n = 121, LTG n = 117, LEV n = 122) in the modified intent-to-treat population (mean age [range] 71.4 [60-95] years). At week 58, the retention rate for LEV was significantly higher than for CR-CBZ (61.5% vs. 45.8%, p = 0.02), and similar to LTG (55.6%). Seizure freedom rates at weeks 30 and 58 were not different across the groups. Twice as many patients receiving CR-CBZ discontinued due to adverse events or death compared to those in the LEV group (32.2% vs. 17.2%; odds ratio 2.28, 95% confidence interval [CI] 1.25-4.19, p = 0.007), whereas discontinuation was intermediate for LTG (26.3%). Median daily doses of completers (n = 195) were CR-CBZ 380.0 mg/day (333.0-384.0), LTG 95 mg/day (94.0-97.0), and LEV 950 mg/day (940.0-985.0). SIGNIFICANCE: In the initial monotherapy of focal epilepsy in the elderly, 1-year retention to LEV was higher compared to CR-CBZ due to better tolerability. Retention of LTG was intermediate and close to LEV, but did not differ significantly from either comparators. NCT00438451, www.clinicaltrials.gov.
Subject(s)
Anticonvulsants/therapeutic use , Epilepsies, Partial/drug therapy , Aged , Dose-Response Relationship, Drug , Double-Blind Method , Europe , Female , Humans , Kaplan-Meier Estimate , Logistic Models , Longitudinal Studies , Male , Middle Aged , Retrospective Studies , Time Factors , Treatment OutcomeABSTRACT
PURPOSE: Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand in clinical development for the treatment of epilepsy. This phase III study (N01252; NCT00490035) evaluated the efficacy and safety/tolerability of BRV (20, 50, and 100 mg/day) compared with placebo (PBO) in patients aged 16-70 years with uncontrolled focal seizures with/without secondary generalization, despite treatment with one to two concomitant antiepileptic drugs at a stable and optimal dosage. METHODS: This was a double-blind, randomized, placebo-controlled trial conducted across Europe and India. Eligible patients had two or more focal seizures/month for 3 months prior to screening and eight or more focal seizures during the 8-week prospective baseline. Concomitant use of levetiracetam was limited to 20% of randomized patients. Patients were randomized (1:1:1:1) to BRV 20, 50, 100 mg/day or PBO with no up-titration for 12 weeks, followed by down-titration or entry into a long-term follow-up study. The primary efficacy end point was percent reduction over PBO in baseline-adjusted focal seizure frequency/week over the 12-week treatment period. Comparison of BRV with PBO was sequential to control for multiplicity (50, 100, 20 mg/day), and thus required BRV to demonstrate superiority over PBO at 50 mg/day to meet the primary efficacy end point. Secondary efficacy variables were median percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate, and seizure freedom (all seizure types). Safety assessments included treatment-emergent adverse events (TEAEs). KEY FINDINGS: Of 399 randomized patients, 398 were included in the intent-to-treat (ITT) and safety populations. Overall, 367 (92.2%) of 398 patients completed the study (BRV: 93.9%, 88.9%, and 94.0% for 20, 50, and 100 mg/day, respectively; PBO: 92.0%) and 345 (86.7%) of 398 patients continued into long-term follow-up studies (BRV: 87.9%, 82.8%, and 88.0% for 20, 50, and 100 mg/day, respectively; PBO: 88.0%). The study did not meet its primary efficacy end point based on the predefined sequential testing strategy. Indeed, percent reduction over PBO in baseline-adjusted focal seizure frequency/week (primary efficacy analysis) was 6.8% (p = 0.239), 6.5% (p = 0.261), and 11.7% (p = 0.037) for BRV 20, 50, and 100 mg/day, respectively. Median percent reduction from baseline in focal seizure frequency/week was 30.0% (p = 0.019), 26.8% (p = 0.092), and 32.5% (p = 0.004) for BRV 20, 50, and 100 mg/day, respectively, compared with 17.0% for PBO. Responder rates (≥50%) were 27.3% (p = 0.339), 27.3% (p = 0.372), and 36.0% (p = 0.023) for BRV 20, 50, and 100 mg/day, respectively, compared with 20.0% for PBO. Complete seizure freedom was reported by 2/99, 0/99, and 4/100 patients on BRV 20, 50, and 100 mg/day, respectively, compared with 0/100 on PBO. The incidence of TEAEs was higher for BRV 20 (56/99, 56.6%), 50 (62/99, 62.6%), and 100 mg/day (63/100, 63.0%) than PBO (53/100, 53.0%); most TEAEs were mild or moderate in severity. The most frequently reported TEAEs in the BRV groups were headache, somnolence, dizziness, and fatigue. SIGNIFICANCE: In this study of adjunctive BRV (20-100 mg/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50 mg/day dose was not statistically significant. However, BRV 100 mg/day reduced baseline-adjusted focal seizure frequency/week by 11.7% over PBO, achieving statistical significance (p = 0.037). Secondary efficacy analyses (percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate) provided supportive evidence for the efficacy of BRV 100 mg/day. BRV 20-100 mg/day was well tolerated without up-titration, with a high completion rate.
Subject(s)
Anticonvulsants/therapeutic use , Epilepsies, Partial/drug therapy , Pyrrolidinones/therapeutic use , Adolescent , Adult , Aged , Anticonvulsants/administration & dosage , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Pyrrolidinones/administration & dosage , Treatment Outcome , Young AdultABSTRACT
To investigate whether epileptiform activity in the immature brain is modulated by dopamine, we examined the effects of dopaminergic agonists and antagonists in an intact in vitro preparation of the isolated corticohippocampal formation of immature (postnatal days 3 and 4) C57/Bl6 mice using field potential recordings from CA3. Epileptiform discharges were induced by a reduction of the extracellular Mg(2+) concentration to 0.2 mM. These experiments revealed that low concentrations of dopamine (<0.3 µM) attenuated epileptiform activity, whereas >3 µM dopamine enhanced epileptiform activity. The D1-agonist SKF38393 (10 µM) had a strong proconvulsive effect, and the D2-like agonist quinpirole (10 µM) mediated a weak anticonvulsive effect. The proconvulsive effect of 10 µM dopamine was completely abolished by the D1-like receptor antagonist SCH39166 (2 µM) or the D2-like antagonist sulpiride (10 µM), whereas the D2 antagonist L-741626 (50 nM) and the D3 antagonist SB-277011-A (0.1 µM) were without effect. The anticonvulsive effect of 0.1 µM dopamine could be suppressed by D1-like, D2, or D3 receptor antagonists. A proconvulsive effect of 10 µM dopamine was also observed when AMPA, NMDA, or GABA(A) receptors were blocked. In summary, these results suggest that 1) dopamine influences epileptiform activity already at early developmental stages; 2) dopamine can bidirectionally influence the excitability; 3) D1-like receptors mediate the proconvulsive effect of high dopamine concentrations, although the pharmacology of the anticonvulsive effect is less clear; and 4) dopamine-induced alterations in GABAergic and glutamatergic systems may contribute to this effect.
Subject(s)
Dopamine/physiology , Epilepsy/physiopathology , Hippocampus/physiopathology , Magnesium Deficiency/physiopathology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Animals, Newborn , Benzazepines/pharmacology , Data Interpretation, Statistical , Dopamine/pharmacology , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Indoles/pharmacology , Mice , Mice, Inbred C57BL , Nitriles/pharmacology , Piperidines/pharmacology , Quinpirole/pharmacology , Receptors, Dopamine D2/agonists , Synapses/drug effects , Tetrahydroisoquinolines/pharmacologyABSTRACT
INTRODUCTION: Sepsis-associated delirium (SAD) increases morbidity in septic patients and, therefore, factors contributing to SAD should be further characterized. One possible mechanism might be the impairment of cerebrovascular autoregulation (AR) by sepsis, leading to cerebral hypo- or hyperperfusion in these haemodynamically unstable patients. Therefore, the present study investigates the relationship between the incidence of SAD and the status of AR during sepsis. METHODS: Cerebral blood flow velocity was measured using transcranial Doppler sonography and was correlated with the invasive arterial blood pressure curve to calculate the index of AR Mx (Mx>0.3 indicates impaired AR). Mx was measured daily during the first 4 days of sepsis. Diagnosis of a SAD was performed using the confusion assessment method for ICU (CAM-ICU) and, furthermore the predominant brain electrical activity in electroencephalogram (EEG) both at day 4 after reduction of sedation to RASS >-2. RESULTS: 30 critically ill adult patients with severe sepsis or septic shock (APACHE II 32 ± 6) were included. AR was impaired at day 1 in 60%, day 2 in 59%, day 3 in 41% and day 4 in 46% of patients; SAD detected by CAM-ICU was present in 76 % of patients. Impaired AR at day 1 was associated with the incidence of SAD at day 4 (p = 0.035). CONCLUSIONS: AR is impaired in the great majority of patients with severe sepsis during the first two days. Impaired AR is associated with SAD, suggesting that dysfunction of AR is one of the trigger mechanisms contributing to the development of SAD. TRIAL REGISTRATION: clinicalTrials.gov ID NCT01029080.
Subject(s)
Cerebrovascular Circulation/physiology , Homeostasis/physiology , Sepsis-Associated Encephalopathy/diagnostic imaging , Sepsis-Associated Encephalopathy/physiopathology , Sepsis/diagnostic imaging , Sepsis/physiopathology , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Ultrasonography, Doppler, Transcranial/methodsABSTRACT
OBJECTIVE: To characterize efficacy, safety/tolerability, and pharmacokinetics of padsevonil (PSL) administered concomitantly with ≤3 antiseizure medications (ASMs) for observable focal seizures in adults with drug-resistant epilepsy in two multicenter, randomized, double-blind, placebo-controlled, parallel-group trials. METHODS: The phase 2b dose-finding trial (EP0091/NCT03373383) randomized patients 1:1:1:1:1 to PSL 50/100/200/400 mg or placebo twice daily (b.i.d.). The phase 3 efficacy trial (EP0092/NCT03739840) randomized patients 1:1:1:1 to PSL 100/200/400 mg or placebo b.i.d. Patients with observable (focal aware with motor symptoms, focal impaired awareness, focal to bilateral tonic-clonic) focal seizures for ≥3 years, experiencing them ≥4 times per 28 days including during the 4-week baseline period despite treatment with ≥4 lifetime ASMs including current ASMs, were enrolled. RESULTS: In EP0091 and EP0092, 410 and 231 patients, respectively, were randomized and received at least one dose of trial medication. In patients in EP0091 on PSL 50/100/200/400 mg b.i.d. (n = 80/82/81/81, respectively) versus placebo (n = 81), outcomes included percentage reductions over placebo in observable focal seizure frequency during the 12-week maintenance period: 17.2%, 19.1% (p = 0.128), 19.2% (p = 0.128), 12.4% (p = 0.248); 75% responder rates (p-values for odds ratios): 13.8%, 12.2% (p = 0.192), 11.1% (p = 0.192), 16.0% (p = 0.124) versus 6.2%; 50% responder rates: 33.8% (p = 0.045), 31.7% (p = 0.079), 25.9% (p = 0.338), 32.1% (p = 0.087), versus 21.0%; TEAEs were reported by 82.7% (67/81), 78.3% (65/83), 74.4% (61/82), 90.1% (73/81) versus 78.3% (65/83). In patients in EP0092 on PSL 100/200/400 mg b.i.d. (n = 60/56/56, respectively) versus placebo (n = 54), outcomes included percentage reductions over placebo: -5.6% (p = 0.687), 6.5% (p = 0.687), 6.3% (p = 0.687); 75% responder rates: 15.3% (p = 0.989), 12.5% (p = 0.989), 14.3% (p = 0.989) versus 13.0%; 50% responder rates: 35.6% (p = 0.425), 33.9% (p = 0.625), and 42.9% (p = 0.125) versus 27.8%; TEAEs were reported by 80.0% (48/60), 78.9% (45/57), 83.1% (49/59) versus 67.3% (37/55). SIGNIFICANCE: In both trials, the primary outcomes did not reach statistical significance in any PSL dose group compared with placebo. PSL was generally well tolerated, and no new safety signals were identified.
Subject(s)
Drug Resistant Epilepsy , Epilepsies, Partial , Adult , Humans , Epilepsies, Partial/drug therapy , Epilepsies, Partial/chemically induced , Anticonvulsants , Treatment Outcome , Drug Therapy, Combination , Drug Resistant Epilepsy/drug therapy , Seizures/drug therapyABSTRACT
PURPOSE: To quantify extrastriatal and striatal D2/D3 receptor binding in patients with juvenile myoclonic epilepsy (JME) using the high-affinity dopamine D2/D3 receptor positron emission tomography (PET) ligand (18) F-Fallypride ([(18) F]FP). METHODS: Twelve patients with JME and 21 age-matched control subjects were studied. Dynamic images (180 min) were acquired after injection of [(18) F]FP. Patients had been seizure-free of all seizure types for at least 10 days before scanning. Parametric images of binding potential (BP) were created using the simplified reference tissue model. The images were stereotactically normalized using a ligand-specific template. We performed a voxel-based analysis with statistical parametric mapping (SPM2). Region of interest (ROI) analysis was done comparing the BP of the thalamus, caudate nucleus, anterior (ventral) and posterior (dorsal) putamen, ventral striatum, and temporal lobe. RESULTS: Compared to controls, patients with JME showed a significant decrease in [(18) F]FP BP (SPM analysis corr. p < 0.001 at cluster level) restricted to the bilateral posterior putamen. There was no significant alteration of [(18) F]FP binding in other brains regions. ROI analysis revealed a significant (p < 0.05) decrease of [(18) F]FP BP in the left (mean -14.8%) and right (mean -16.9%) posterior putamen, but not in the anterior putamen, caudate, ventral striatum, thalamus, or temporal lobe. DISCUSSION: Patients with JME showed a reduction in D2/3 receptor binding restricted to the bilateral posterior putamen, suggesting a specific alteration of the dopaminergic system. Whether these changes can be regarded as merely functional or whether they relate to the pathophysiology of juvenile myoclonic epilepsy still remains unclear.
Subject(s)
Brain/metabolism , Dopamine/metabolism , Myoclonic Epilepsy, Juvenile/metabolism , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Adolescent , Adult , Basal Ganglia/diagnostic imaging , Basal Ganglia/metabolism , Benzamides/metabolism , Brain/diagnostic imaging , Corpus Striatum/diagnostic imaging , Corpus Striatum/metabolism , Fluorine Radioisotopes/metabolism , Functional Laterality , Humans , Male , Myoclonic Epilepsy, Juvenile/diagnosis , Myoclonic Epilepsy, Juvenile/diagnostic imaging , Positron-Emission Tomography/statistics & numerical data , Putamen/diagnostic imaging , Putamen/metabolism , Pyrrolidines/metabolism , Temporal Lobe/diagnostic imaging , Temporal Lobe/metabolism , Tissue DistributionABSTRACT
PURPOSE: Alterations in dopamine neurotransmission in animal models of epilepsies have been frequently demonstrated using invasive neuroscience or ex vivo techniques. We aimed to test whether corresponding alterations could be detected by noninvasive in vivo brain imaging with positron emission tomography (PET) in the chronic phase of the rat pilocarpine model of temporal lobe epilepsy. METHODS: Six pilocarpine-treated Wistar rats exhibiting spontaneous recurrent seizures and nine control rats were studied with PET using [(18)F]-fallypride, a high-affinity dopamine D(2/3) receptor ligand. Parametric images of [(18)F]-fallypride specific binding were calculated using a reference tissue method, and the two groups were contrasted by whole-brain voxel-based analysis implemented in statistical parametric mapping (SPM5). RESULTS: Dopamine D(2/3) receptor availability was 27% lower in the bilateral anterior caudate-putamen of pilocarpine-treated rats as compared to controls (p < 0.05), but binding was unaffected in other striatal or extrastriatal regions. CONCLUSIONS: The finding of substantially reduced availability of dopamine D(2/3) receptors in the anterior caudate-putamen of rats during the chronic phase of the pilocarpine model is in agreement with results of invasive (microinjection, microdialysis) animal studies that have revealed increased dopamine tonus and a D(2/3) receptor-mediated anticonvulsant action of dopamine in the anterior segment of the rat striatum. The present PET approach could be prospectively applied for monitoring dopamine receptor changes longitudinally, that is, at different phases of the epileptogenic process, and opens perspectives for testing dopaminergic agents as potential antiepileptogenic drugs.
Subject(s)
Corpus Striatum/diagnostic imaging , Epilepsy, Temporal Lobe/diagnostic imaging , Receptors, Dopamine/metabolism , Animals , Autoradiography/statistics & numerical data , Benzamides/metabolism , Brain/diagnostic imaging , Brain/metabolism , Brain Mapping , Corpus Striatum/metabolism , Disease Models, Animal , Dopamine/metabolism , Epilepsy, Temporal Lobe/chemically induced , Epilepsy, Temporal Lobe/metabolism , Humans , Male , Pilocarpine , Positron-Emission Tomography/methods , Positron-Emission Tomography/statistics & numerical data , Pyrrolidines/metabolism , Rats , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolismABSTRACT
Postictal motor deficits may occur in patients following partial and generalized tonic-clonic seizures. Frequency is unclear, epidemiology being hampered by heterogeneous populations and variable methods of detection. Postictal paresis may affect any body part, may be bilateral, and may occur more frequently in seizures involving the sensorimotor cortex. Duration varies depending on the precise mode of testing from a few minutes to 36 hours. Sensory deficits following seizures have been rarely reported but may be missed if not specifically tested for. The lateralizing value of postical paresis is high (>90%), pointing to a seizure origin in the opposite frontal lobe. Postictal paresis often is lesion associated and should encourage MRI, particularly in new-onset epilepsy. Etiology is unclear, neuronal exhaustion and hyperinhibition being the main pathophysiological theories discussed. As disability from seizures may be increased, postictal paresis should more systematically be asked and tested for and should also be included when evaluating the success of anticonvulsive treatment.
Subject(s)
Brain/physiopathology , Paralysis/etiology , Seizures/complications , Humans , Paralysis/physiopathology , Seizures/physiopathologyABSTRACT
Therapeutic options for patients with treatment-resistant epilepsy represent an important unmet need. Addressing this unmet need was the main factor driving the drug discovery program that led to the synthesis of padsevonil, a first-in-class antiepileptic drug candidate that interacts with two therapeutic targets: synaptic vesicle protein 2 and GABAA receptors. Two PET imaging studies were conducted in healthy volunteers to identify optimal padsevonil target occupancy corresponding to levels associated with effective antiseizure activity in rodent models. Optimal padsevonil occupancy associated with non-clinical efficacy was translatable to humans for both molecular targets: high (>90%), sustained synaptic vesicle protein 2A occupancy and 10-15% transient GABAA receptor occupancy. Rational dose selection enabled clinical evaluation of padsevonil in a Phase IIa proof-of-concept trial (NCT02495844), with a single-dose arm (400 mg bid). Adults with highly treatment-resistant epilepsy, who were experiencing ≥4 focal seizures/week, and had failed to respond to ≥4 antiepileptic drugs, were randomized to receive placebo or padsevonil as add-on to their stable regimen. After a 3-week inpatient double-blind period, all patients received padsevonil during an 8-week outpatient open-label period. The primary endpoint was ≥75% reduction in seizure frequency. Of 55 patients randomized, 50 completed the trial (placebo n = 26; padsevonil n = 24). Their median age was 36 years (range 18-60), and they had been living with epilepsy for an average of 25 years. They were experiencing a median of 10 seizures/week and 75% had failed ≥8 antiepileptic drugs. At the end of the inpatient period, 30.8% of patients on padsevonil and 11.1% on placebo were ≥75% responders (odds ratio 4.14; P = 0.067). Reduction in median weekly seizure frequency was 53.7% and 12.5% with padsevonil and placebo, respectively (unadjusted P = 0.026). At the end of the outpatient period, 31.4% were ≥75% responders and reduction in median seizure frequency was 55.2% (all patients). During the inpatient period, 63.0% of patients on placebo and 85.7% on padsevonil reported treatment-emergent adverse events. Overall, 50 (90.9%) patients who received padsevonil reported treatment-emergent adverse events, most frequently somnolence (45.5%), dizziness (43.6%) and headache (25.5%); only one patient discontinued due to a treatment-emergent adverse event. Padsevonil was associated with a favourable safety profile and displayed clinically meaningful efficacy in patients with treatment-resistant epilepsy. The novel translational approach and the innovative proof-of-concept trial design maximized signal detection in a small patient population in a short duration, expediting antiepileptic drug development for the population with the greatest unmet need in epilepsy.
ABSTRACT
Acute deafferentation of a limb results in bilateral cortical reorganization, but the behavioral consequences of this phenomenon are unknown. Here we found rapid improvements in tactile spatial acuity and changes in cortical processing for the left hand during cutaneous anesthesia of the right hand. The site-specific improvement in tactile spatial acuity may represent a behavioral compensatory gain.
Subject(s)
Evoked Potentials, Somatosensory/physiology , Sensory Thresholds/physiology , Touch/physiology , Action Potentials/physiology , Adolescent , Adult , Afferent Pathways/physiology , Anesthesia, Local/methods , Female , Foot/innervation , Foot/physiology , Hand/innervation , Hand/physiology , Humans , Male , Middle Aged , Nerve BlockABSTRACT
The level of excitability within the motor cortex can be described as a balance between excitation and inhibition, but it is unknown how well both processes correlate. To address this question, the authors measured motor cortical excitability and inhibition in healthy human subjects, comparing the recruitment of motor evoked potentials (MEPs) and the duration of the cortical silent period (CSP) after transcranial magnetic stimulation (TMS). Single-pulse "focal" TMS was applied at intensities varying between 90% and 200% of motor thresholds to the right motor cortex of 15 healthy volunteers. The peak-to peak size of MEP responses and the duration of the CSP were measured in small hand muscles. Stimulus-response (S-R) curves were constructed by plotting the MEP size and CSP duration against stimulus intensities. The absolute duration of CSP and the size MEPs correlated significantly and to a similar extent with stimulus intensity (r = 0.60 and 0.53, respectively). The slope of the MEP-S-R was steeper compared with CSP-S-R, particularly at low stimulation intensities. CSP duration saturated earlier and CSP-S-Rs were shifted upwards at a given stimulus intensity compared with MEP-S-Rs. The findings suggest that recruitment of inhibition and excitation within the sensorimotor cortex correlate. However, inhibitory effects are recruited at lower intensities and saturate earlier than excitation.
Subject(s)
Evoked Potentials, Motor/physiology , Motor Cortex/physiology , Neural Inhibition/physiology , Recruitment, Neurophysiological/physiology , Adult , Female , Humans , Male , Middle Aged , Transcranial Magnetic StimulationABSTRACT
BACKGROUND: Further options for monotherapy are needed to treat newly diagnosed epilepsy in adults. We assessed the efficacy, safety, and tolerability of lacosamide as a first-line monotherapy option for these patients. METHODS: In this phase 3, randomised, double-blind, non-inferiority trial, patients from 185 epilepsy or general neurology centres in Europe, North America, and the Asia Pacific region, aged 16 years or older and with newly diagnosed epilepsy were randomly assigned in a 1:1 ratio, via a computer-generated code, to receive lacosamide monotherapy or controlled-release carbamazepine (carbamazepine-CR) twice daily. Patients, investigators, and trial personnel were masked to treatment allocation. From starting doses of 100 mg/day lacosamide or 200 mg/day carbamazepine-CR, uptitration to the first target level of 200 mg/day and 400 mg/day, respectively, took place over 2 weeks. After a 1-week stabilisation period, patients entered a 6-month assessment period. If a seizure occurred, the dose was titrated to the next target level (400 or 600 mg/day for lacosamide and 800 or 1200 mg/day for carbamazepine-CR) over 2 weeks with a 1-week stabilisation period, and the 6-month assessment period began again. Patients who completed 6 months of treatment and remained seizure-free entered a 6-month maintenance period on the same dose. The primary efficacy outcome was the proportion of patients remaining free from seizures for 6 consecutive months after stabilisation at the last assessed dose. The predefined non-inferiority criteria were -12% absolute and -20% relative difference between treatment groups. This trial is registered with ClinicalTrials.gov, number NCT01243177. FINDINGS: The trial was done between April 27, 2011, and Aug 7, 2015. 888 patients were randomly assigned treatment. 444 patients taking lacosamide and 442 taking carbamazepine-CR were included in the full analysis set (took at least one dose of study treatment), and 408 and 397, respectively, were included in the per-protocol set. In the full analysis set, 327 (74%) patients in the lacosamide group and 308 (70%) in the carbamazepine-CR group completed 6 months of treatment without seizures. The proportion of patients in the full analysis set predicted by the Kaplan-Meier method to be seizure-free at 6 months was 90% taking lacosamide and 91% taking carbamazepine-CR (absolute treatment-difference: -1·3%, 95% CI -5·5 to 2·8 relative treatment difference: -6·0%). Kaplan-Meier estimates results were similar in the per-protocol set (92% and 93%; -1·3%, -5·3 to 2·7; -5·7%). Treatment-emergent adverse events were reported in 328 (74%) patients receiving lacosamide and 332 (75%) receiving carbamazepine-CR. 32 (7%) patients taking lacosamide and 43 (10%) taking carbamazepine-CR had serious treatment-emergent adverse events, and 47 (11%) and 69 (16%), respectively, had treatment-emergent adverse events that led to withdrawal. INTERPRETATION: Treatment with lacosamide met the predefined non-inferiority criteria when compared with carbamazepine-CR. Therefore, it might be useful as first-line monotherapy for adults with newly diagnosed epilepsy. FUNDING: UCB Pharma.
Subject(s)
Acetamides/therapeutic use , Anticonvulsants/therapeutic use , Carbamazepine/administration & dosage , Epilepsy/drug therapy , Treatment Outcome , Adolescent , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Drug Delivery Systems , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Lacosamide , Male , Middle Aged , Young AdultABSTRACT
Objective: To assess the safety profile of lacosamide monotherapy in elderly (≥65 years) subjects with diabetic neuropathic pain (DNP). Methods: Of 1,863 DNP subjects in double-blind, randomized, placebo-controlled trials of lacosamide monotherapy (NCT00861445, NCT00235469, NCT00238524, NCT00135109, NCT00350103), 502 were elderly. Safety data from elderly subjects were compared with that of younger subjects (<65 years) within these DNP trials. It should be noted that lacosamide is approved for the treatment of focal (partial-onset) seizures; it is not approved/recommended for the treatment of DNP. Results: Overall, cardiovascular diseases were prevalent in the DNP population, as was the use of cardiac, blood pressure, diabetes, and cholesterol-lowering medications among both young and elderly subjects. The most frequently reported adverse events (AEs) for lacosamide monotherapy (200, 400, and 600 mg/day combined) in elderly versus younger subjects were dizziness (16.2% vs. 13.2%), nausea (10.0% vs. 9.4%), and headache (8.0% vs. 8.7%). Incidences of cardiac disorder AEs were higher in elderly versus younger subjects receiving placebo (6.2% vs. 3.9%), lacosamide 200 (4.8% vs. 3.3%), lacosamide 400 (7.0% vs. 4.1%), and lacosamide 600 mg/day (7.7% vs. 4.0%). Discontinuation rates because of any AE in the elderly versus younger subjects were similar for placebo (8.8% vs. 7.0%) and lacosamide 200 mg/day (9.6% vs. 11.9%) and higher for lacosamide 400 (25.1% vs. 10.8%) and lacosamide 600 mg/day (52.7% vs. 28.3%). Significance: Lacosamide monotherapy was well tolerated in elderly subjects with DNP, with an overall AE profile consistent with that reported in epilepsy trials.
ABSTRACT
The generation, propagation and pharmacological properties of low-Mg2+ -induced epileptiform activity were examined in the intact corticohippocampal formation (CHF) of the newborn (P0-4) mouse in vitro. Multi-site field potential recordings in dentate gyrus (DG), CA3, CA1, entorhinal cortex (EC) and temporal cortex (TC) revealed in 0.2 mM Mg2+ -containing ACSF a stable pattern of spontaneous epileptiform activity consisting of recurrent ictal-like events (ILEs) and interictal events (IEs). Although this activity could be consistently observed as early as P0, ILEs were smaller in amplitude, less frequent and showed a slower onset in P0-2 as compared to P3-4 animals. In all age groups, epileptiform events were largest in CA3 and smallest in EC and TC. A specific pacemaker region could not be identified since ILEs appeared simultaneously at all recording sites. Reducing the extracellular Mg2+ concentration to 0.1 mM or nominally zero caused an increase in ILE frequency. Pharmacological studies in the P3-4 age group with 0.2 mM Mg2+ revealed a complete blockade of the ILEs by an NMDA receptor antagonist and a pronounced suppression of epileptiform activity by an AMPA/kainate antagonist. Application of a GABA-A receptor antagonist induced repetitive bursts of interictal discharges, which persisted for at least 1.5 h after washout of the antagonist. Our data demonstrate that the intact CHF in vitro preparation of the newborn mouse offers a most valuable model to study epileptiform activity in the immature limbic system.
Subject(s)
Action Potentials/physiology , Cerebral Cortex/metabolism , Epilepsy/metabolism , Hippocampus/metabolism , Magnesium Deficiency/metabolism , Magnesium/metabolism , Age Factors , Animals , Animals, Newborn , Cerebral Cortex/growth & development , Disease Models, Animal , Electrophysiology , Hippocampus/growth & development , Limbic System/growth & development , Limbic System/metabolism , Mice , Mice, Inbred C57BL , Neural Pathways/metabolism , Organ Culture Techniques , Statistics, NonparametricABSTRACT
The use of antiepileptic drugs (AED), their primary indication, comorbid conditions, and concomitant medications were collected from 565 nursing homes (NH) residents of six NH located around the city of Mainz, Germany representing 5.05% of all NH residents in the area. Data were collected from the electronic pharmacy files and by reviewing all available medical records. Average age was 82.2 +/- 2.4 years, 85.5% were women. Of 565 NH residents 28 (4.96%) received AED therapy, of which in 17 (63%) AED were prescribed for a seizure-related diagnosis. In 76.5% seizure types were unspecified and a distinction in focal and generalized epilepsy was made in only 23.5% of patients. Three patients never had epileptic seizures and in four residents the reason for AED use was unclear. AEDs most frequently prescribed were carbamazepine (37.1%), valproic acid (25.9%), and phenytoin (14.8%). Five patients received benzodiazepines (18.5%), newer generation AED were used in only four (14.8%) cases. Residents on average took n = 5.6 +/- 3.3 other drugs. Opportunities exist for health care professionals to improve the medical management of nursing facility residents receiving AEDs.
Subject(s)
Anticonvulsants/therapeutic use , Drug Utilization Review , Epilepsy/drug therapy , Homes for the Aged/statistics & numerical data , Nursing Homes/statistics & numerical data , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Germany , Humans , Male , PharmacoepidemiologyABSTRACT
PURPOSE: To assess the latency of interictal epileptiform discharges (IED) and seizures in long-term EEG recordings of patients with epilepsy. METHOD: IED latency was measured in 210 consecutive patients (mean (SD) age 38.6 ± 13.9 years) with active epilepsy and the relationship to clinical variables was analyzed retrospectively. Median duration of EEG recording was 101.5h (95% confidence interval [CI] 92 to 117 h). RESULTS: IEDs were absent in 45 (21.4%) and present in 165 (78.6%) patients who had a longer duration (p < 0.001) and early onset (p < 0.01) of epilepsy and more often had IEDs in prior standard EEGs (p < 0.01), a structural etiology (OR 2.4, CI: 2.1-2.7), or temporal lobe epilepsy (OR 9.6, CI: 9.0-10.2). IED latency did not correlate with other clinical variables. Median latency to the emergence of the first IED was 9.3h (CI: 7.5-11.4) occurring in 7.3%, 9.7%, 74.6%, 87.9%, and 96.4% within 20 min, 30 min, 24h, 48 h, and 72 h, respectively. Seizure frequency was higher in patients with (n = 165) than without IEDs (n = 45) (72.1% vs. 46.6%, p < 0.01) and seizure latency (median 21.6h, CI: 16.8-27.3) was influenced by the presence of IEDs, whereas the presence of seizures did not influence the latency and frequency of IEDs. CONCLUSION: If present, in the majority of epilepsy patients IEDs occurred during the first 72 h of long-term video-EEG recording. Repeated video-EEG or video recordings of habitual seizures are needed to minimize false negative studies.
Subject(s)
Brain/physiopathology , Electroencephalography , Epilepsy/physiopathology , Adult , Anticonvulsants/therapeutic use , Brain/drug effects , Electroencephalography/methods , Epilepsy/drug therapy , Female , Humans , Male , Retrospective Studies , Seizures/drug therapy , Seizures/physiopathology , Time Factors , Video Recording/methodsABSTRACT
OBJECTIVE: Dopamine is an endogenous neuromodulator in cortical circuits and the basal ganglia. In animal models of temporal lobe epilepsy (TLE), seizure threshold is modulated to some extent by dopamine, with D1-receptors having a pro- and D2-receptors an anticonvulsant effect. We aimed to extend our previously reported results on decreased D2/D3 receptor binding in the lateral epileptogenic temporal lobe and to correlate them with demographic and seizure variables to gain a more comprehensive understanding of the underlying involvement of the dopaminergic system in the epileptogenesis of TLE. METHODS: To quantify D2/D3 receptor binding, we studied 21 patients with TLE and hippocampal sclerosis (13 left- and eight right-sided) and 18 controls using PET with the high-affinity dopamine D2/D3-receptor ligand 18F-Fallypride to image striatal and extrastriatal binding. TLE was defined by interictal and ictal video-EEG, MRI and 18F-Fluorodeoxyglucose PET. Voxel-based statistical and regions-of-interest analyses were performed. RESULTS: 18F-Fallypride binding potential was significantly reduced in the affected temporal lobe and bilateral putamen. A positive correlation between age at onset of epilepsy and [18F]FP BPnd (binding potential non-displaceable) in temporal regions on the epileptogenic side was found, as well as a negative correlation between epilepsy duration and [18F]FP BPnd in the temporal pole on the epileptogenic side and a positive correlation between the estimated number of lifetime GTCS and [18F]FP BPnd in the hippocampus on the epileptogenic side. SIGNIFICANCE: The areas of reduced D2/D3 receptor availability correspond to "the irritative zone" surrounding the epileptogenic area. Moreover, reduced D2/D3 receptor availability was detectable in the basal ganglia, which are suspected to be involved in a control circuit for epileptic seizures. The correlational analysis additionally suggests that increased epilepsy duration leads to increasing impairment of the dopaminergic system.