Epilepsy and antiepileptic drug therapy in juvenile neuronal ceroid lipofuscinosis

PURPOSE: To survey the characteristics of epilepsy in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) and determine the antiepileptic drug (AED) treatment most suitable for these patients. METHODS: The study included 60 patients with JNCL; their mean age was 16.5 years (range 5-33). The age at onset of epilepsy, type of seizures, effect of the first AED on seizures, and the current seizure frequency and AED therapy were studied. The side effects of the AEDs were also clarified. RESULTS: Fifty of the 60 patients had epilepsy. Patients' first epileptic seizure occurred at a mean age of 10.0 years (range 5-16), the most common type being generalized seizures. As the first AED tried, valproate (VPA) and lamotrigine (LTG) appeared equally effective, with 80% of the patients responding to these AEDs. During the study year, the median seizure frequency was four seizures a year (range 0-120), and 72% of the patients had good or satisfactory seizure control (0-6 seizures a year). In the different AED therapy groups, the proportion of patients with good or satisfactory seizure control ranged from 25% to 100%. LTG in monotherapy or in combination with clonazepam (CZP) was superior to other AEDs or combinations, but VPA also seemed effective. Adverse effects leading to the discontinuation of an AED were observed in 25% of the patients, most frequently in patients receiving phenobarbital (PB). No patient receiving LTG had to discontinue the drug due to adverse effects. CONCLUSION: Epilepsy in JNCL can usually be successfully treated with the current AEDs. In Finnish patients with JNCL, treatment is based on LTG, or, secondarily, VPA. In combination therapy, CZP seems a valuable add-on AED.     

Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy

Seizures in patients with medically refractory epilepsy remain a substantial clinical challenge, not least because of the dearth of evidence-based guidelines as to which antiepileptic drug (AED) regimens are the most effective, and what doses of these drugs to employ. We sought to determine whether there were regions in the dosage range of commonly used AEDs that were associated with superior efficacy in patients with refractory epilepsy. We retrospectively analyzed treatment records from 164 institutionalized, developmentally disabled patients with refractory epilepsy, averaging 17 years of followup per patient. We determined the change in seizure frequency in within-patient comparisons during treatment with the most commonly used combinations of 12 AEDs, and then analyzed the response to treatment by quartile of the dose range for monotherapy with carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), or phenytoin (PHT), and the combination LTG/VPA. We found that of the 26 most frequently used AED regimens, only LTG/VPA yielded superior efficacy, similar to an earlier study. For the monotherapies, patients who were treated in the lowest quartile of the dose range had significantly better long-term reduction in seizure frequency compared to those treated in the 2nd and 3rd quartiles of the dose range. Patients with paired exposures to CBZ in both the lowest quartile and a higher quartile of dose range experienced an increase in seizure frequency at higher doses, while patients treated with LTG/VPA showed improved response with escalation of LTG dosage. We conclude that in this population of patients with refractory epilepsy, LTG/VPA was the most effective AED combination. The best response to AEDs used in monotherapy was observed at low dosage. This suggests that routine exposure to maximally tolerated AED doses may not be necessary to identify those patients with drug-resistant seizures who will have a beneficial response to therapy. Rather, responders to a given AED regimen may be identified with exposure to low AED doses, with careful evaluation of the response to subsequent titration to identify non-responders or those with exacerbation of seizure frequency at higher doses.     

Changes of seizures activity during rapid withdrawal of lamotrigine

Quantitatively evaluating the rapid withdrawal effects of lamotrigine (LTG) and carbamazepine (CBZ) on seizure activity during pre-surgical evaluation in patients with pharmacoresistant complex partial epilepsy. The duration and frequency of seizure activities and electrographic seizure onset of 41 patients totally withdrawing from CBZ monotherapy (n = 20), LTG monotherapy (n = 10) and CBZ + LTG combined therapy (n = 11) were intensively studied by therapeutic intensive seizure analysis (TISA) method. Study phases ran from the baseline phase to the antiepileptic drug (AED) withdrawal phase until the AED free phase, 3 days for each phase. Seizure duration and frequency obviously increased during the withdrawal process in each group (P < 0.05). The duration of secondarily generalized clonic signs markedly increased with the tapering of each drug; tonic signs, however, only in the AED free phase (P < 0.05). The frequency of secondary tonic and clonic signs only increased in the CBZ and CBZ + LTG group. Intergroup comparisons of all variables were insignificant (P > 0.05). There was no change of ictal EEG localization during all withdrawal protocols. All patients experienced more severe seizures during the withdrawal processes. An earlier aggravation of the clonic signs than the tonic signs was observed in each group. Difference between the withdrawal effects of LTG and CBZ monotherapy and LTG + CBZ polytherapy was mainly in the frequency change of ictal signs. The withdrawal process did not influence the ictal EEG localization. This study justified the withdrawal in pre-surgical localization, rationalized precautions for possible accompanying risks, and also aroused attentions in clinical anticonvulsant trials and substitutions involving withdrawal process.     

Successful use of fenfluramine as an add-on treatment for Dravet syndrome

Purpose: Despite the development of new antiepileptic drugs, Dravet syndrome frequently remains therapy resistant and is a catastrophic epilepsy syndrome. Fenfluramine is an amphetamine‐like drug that has been used in the past as a part of antiobesity treatments. Because of the possible cardiac adverse effects (valve thickening, pulmonary hypertension) associated with use of fenfluramine, it was withdrawn from the market in 2001. In Belgium, a Royal Decree permitted examination of the potential anticonvulsive effects of fenfluramine in a clinical trial consisting of a small group of patients diagnosed with Dravet syndrome. Methods: Herein, we report 12 patients, 7 female and 5 male, with a genetically proven (11 of 12) diagnosis of Dravet syndrome who received fenfluramine as add‐on therapy. Key Findings: Their ages at their last evaluation ranged from 3–35 years. The mean dosage of fenfluramine was 0.34 (0.12–0.90) mg/kg/day. Exposure duration to fenfluramine ranged from 1–19 years. Seven of the patients who were still receiving the fenfluramine treatment at the time of the last visit had been seizure‐free for at least 1 year. In total, patients had been seizure‐free for a mean of 6 (1–19) years. In seven patients, the fenfluramine treatment was interrupted once during the follow‐up; seizures reappeared in three of the seizure‐free patients. Subsequent reintroduction of fenfluramine controlled the seizures in these three patients again. Only two patients exhibited a mild thickening of one or two cardiac valves without clinical significance. Significance: Compared with a recent long‐term follow‐up series in which a maximum of 16% of patients with Dravet syndrome were seizure‐free, our result of 70% of patients with Dravet syndrome remaining seizure‐free is noteworthy. Given the limitations of this observational study, a larger prospective study should be undertaken to confirm these promising results.     

Dravet syndrome and deep brain stimulation: Seizure control after 10 years of treatment

Dravet syndrome is a genetically determined severe epilepsy associated with cognitive decline and ataxia. The many types of seizures seen in these patients are typically pharmacoresistant. Here we describe two adults with Dravet syndrome who were treated with thalamic deep brain stimulation (DBS) and followed for 10 years. One patient with partial onset seizures received DBS at age 19 and showed a marked improvement in seizure control after DBS insertion and stimulation. The other patient with generalized onset seizures received DBS at age 34 and did not show any immediate benefit. No side effects or changes in cognition were observed in either of the patients. This is the first report of (short‐ and) long‐term results in Dravet patients treated with thalamic DBS. We speculate that the results of DBS for epilepsy in patients with Dravet syndrome may be related to age at initiation of DBS treatment and seizure type.     

Prevalence and Characteristics of Vaccination Triggered Seizures in Dravet Syndrome in Hong Kong: A Retrospective Study

BackgroundDravet syndrome is a rare epileptic encephalopathy characterized by treatment-resistant polymorphic seizures. Seizure onset usually occurs during the first year of life, and seizures are often associated with heat-related triggering factors (e.g., fever, photosensitivity, or hot bath). It has been reported that children with Dravet syndrome often present with recurrent febrile seizures and vaccination-related seizures.MethodsWe analyzed the occurrence of vaccination-related seizures (defined as the development of a seizure within 48 hours post vaccination) in 54 patients with Dravet syndrome. Patients were divided into two groups according to whether seizures occurred within 48 hours of vaccination (i.e., vaccination-proximate group) or not (vaccination-distant group).ResultsThere was no significant difference in the vaccination-proximate group and vaccination-distant group for the presence of SCN1A mutation. In our Dravet syndrome cohort, the vaccination-proximate group consisted of 17 (31.5%) patients with Dravet syndrome. Thus vaccination-related seizures are a common triggering factor in Dravet syndrome, reported in up to one third of our patients.ConclusionVaccination-related seizures may act as the triggering factor for the onset of seizures in children with Dravet syndrome, especially before the definitive diagnosis of Dravet syndrome can be made within the first year of life. We suggest further study of guidelines and protocols for the prevention and management of vaccination-related seizures in children with recurrent febrile seizures pending a definitive diagnosis of Dravet syndrome in the first 12 months of life.     

Dravet syndrome: Characteristics,comorbidities, and caregiver concerns

The Dravet Syndrome Foundation (DSF) conducted the largest in-depth survey of parents and caregivers of patients with Dravet syndrome (DS) to date, in order to (1) identify top concerns among caregivers, (2) establish an approximate frequency of characteristics and comorbidities of DS beyond seizures, and (3) provide direction for clinicians and researchers looking to study the effects of DS on the patient and family unit. Two hundred fifty-six responses were received representing a patient age range of 9 months to 32 years with a median age group of 7–10 years (IQR = 8). In an open response, caregivers ranked speech/communication, impacts on siblings, and cognitive impairment as their top concerns after seizure control, and nearly two-thirds of caregivers reported having suffered from depression. Some characteristics of DS such as gait issues increased with patient age, while others, including photosensitivity, hypotonia, and ataxia, were present from a young age. Comorbidities such as sleep disturbances and cardiac abnormalities were more frequently reported than in previous studies and some (including bradycardia) were correlated with SCN1A mutation status. This survey supports the concept of Dravet syndrome as a disease of the central nervous system with far-reaching effects and highlights the importance of the patient voice in determining appropriate research objectives. While seizure frequency is a relatively well-understood objective, seizures represent only a portion of parent and caregiver concerns. Studying the characteristics of DS described herein may identify additional outcomes significant for research.     

Predictors for long-term seizure outcome in juvenile myoclonic epilepsy: 25-63 years of follow-up

Purpose: The long‐term seizure outcome of juvenile myoclonic epilepsy (JME) is still controversial; the value of factors that are potentially predictive for seizure outcome remains unclear. The aim of this study was both to investigate the long‐term seizure outcome in patients with JME after a follow‐up of at least 25 years and to identify factors that are predictive for the seizure outcome. Methods: Data from 31 patients (19 women) with JME were studied. All of them had a follow‐up of at least 25 years (mean 39.1 years) and were reevaluated with a review of their medical records and direct telephone or face‐to‐face interview. Key Findings: Of 31 patients 21 (67.7%) became seizure‐free; in six of them (28.6%) antiepileptic drug (AED) treatment was discontinued due to seizure freedom. The occurrence of generalized tonic–clonic seizures (GTCS) preceded by bilateral myoclonic seizures (BMS) (p = 0.03), a long duration of epilepsy with unsuccessful treatment (p = 0.022), and AED polytherapy (p = 0.023) were identified as significant predictors for a poor long‐term seizure outcome, whereas complete remission of GTCS under AED significantly increased the chance for complete seizure freedom (p = 0.012). The occurrence of photoparoxysmal responses significantly increases the risk of seizure recurrence after AED discontinuation (p = 0.05). Significance: This study shows conclusively that JME is a heterogeneous epilepsy syndrome. Life‐long AED treatment is not necessarily required to maintain seizure freedom. Several long‐term outcome predictors that can potentially increase the ability of clinicians and their confidence to recommend different treatment options to patients with JME were identified.     

Lamotrigine therapy of epilepsy in tuberous sclerosis

PURPOSE: Lamotrigine (LTG), a newer antiepileptic drug (AED), has activity against both partial-onset and generalized seizures. Its reported benefits for behavior, and its effectiveness in Lennox-Gastaut syndrome and other forms of refractory epilepsy, make it a logical choice for treatment of epilepsy in tuberous sclerosis complex (TSC). We present our experience with LTG therapy of epilepsy in 57 patients with TSC. METHODS: Patients fulfilled the diagnostic criteria for clinically definite TSC. LTG was initiated and increased until improvement in seizure frequency was noted, intolerable side effects occurred, or maximal doses were reached. Seizure frequency and behavioral changes were recorded during LTG therapy and compared with those prior to the introduction of LTG. RESULTS: Twenty-four (42%) were seizure free, and 21 (37%) had a >50% reduction in seizure frequency. Eighteen (32%) had subjectively improved behavior and/or alertness with daily activities. Thirty-eight (67%) had no change in this regard, whereas one (2%) became worse. Responders were more likely to not have a history of infantile spasms, and to have experienced only partial seizures (p < 0.05). Otherwise no phenotypic correlations with response were apparent. CONCLUSIONS: Among patients with TSC and epilepsy, LTG was effective and well tolerated, including as initial monotherapy. Improved alertness and behavior were apparent in many patients. The incidence of side effects is similar to that reported for other pediatric populations with symptomatic partial epilepsy. The usefulness of LTG in TSC may relate to an underlying defect of glutamatergic neurotransmission in partial epilepsy.     

Dravet syndrome - considerable delay in making the diagnosis

Objectives – To assess delay in diagnosis and clinical characteristics of Dravet syndrome based on the Dravet register at The National Centre for Epilepsy in Norway. Material and methods – Medical records of patients diagnosed with Dravet syndrome since 2007 were analysed. Results – Twenty‐two patients were identified. In 15, genetic screening disclosed mutations/deletions in the SCN1A gene. Average time from seizure onset to diagnosis was 7.4 years. Mean age at seizure onset was 6.7 months, nine had hemiconvulsions and 13 had generalized tonic‐clonic seizures. The seizures were precipitated by fever in 17, by external heating in three. During second year of life, multiple seizure types and cognitive and motoric stagnation occurred. No patients became seizure‐free with antiepileptic drugs. The effect of vagal nerve stimulation was disappointing. Conclusions – By making an early diagnosis, an extensive presurgical evaluation may be avoided, and the patient and their parents may be offered genetic guidance.     

Prospective study on the withdrawal and reinstitution of antiepileptic drugs among seizure-free patients in west China

This study explored the relapse rates and risk factors for seizure recurrence after discontinuing antiepileptic drug (AED) therapy among seizure-free patients in west China, and explored whether to reinstitute AED immediately after a single seizure after AED withdrawal. Patients with epilepsy who were seizure-free for at least 2 years and decided to gradually stop AED therapy were followed up every 3 months for seizure relapse. Patients who experienced their first seizure after drug withdrawal were divided into two groups according to their willingness to reinstitute AED therapy, and were followed up until their second seizure. In the mean 29.35 months of follow-up, 37 patients (37/162, 22.8%) suffered at least one seizure after withdrawal. The cumulative probability of seizure recurrence was 16% at 12 months and 20.2% at 24 months. AED response time >1 year and multiple types of seizure were identified as risk factors for seizure recurrence. Eight patients (8/32, 25%) suffered a second seizure within 1 year after the first whether or not they reinstituted AED immediately. There were no significant demographic or clinical differences between patients who reinstituted AED therapy and those who did not. The epilepsy recurrence rate after AED withdrawal is relatively low, with a relatively slow tapering process. Patients with long AED response times and/or multiple types of seizures have a higher risk of seizure recurrence. The first seizure after drug withdrawal is not an indication for immediate AED reinstitution, but may be recommended after a second seizure.     

Lamotrigine XR Conversion to Monotherapy: First Study Using a Historical Control Group

The efficacy and safety of lamotrigine extended-release tablets (LTG XR) as monotherapy for partial seizures were evaluated using the conversion-to-monotherapy design, and historical data as the control. This methodology was recently approved by the United States Food and Drug Administration, and this study is the first historical control design in epilepsy to complete enrollment. Patients ≥13 years old with uncontrolled partial epilepsy receiving monotherapy with valproate or a noninducing antiepileptic drug were converted to once-daily LTG XR (250 mg or 300 mg) as monotherapy and were followed up for 12 additional weeks. Efficacy was measured by the proportion of patients meeting predefined escape criteria for seizure worsening compared with aggregated pseudoplacebo control data from 8 previously conducted conversion-to-monotherapy trials. Nonoverlap of the 95% confidence limit for LTG XR and the 95% prediction interval of the historical control denotes efficacy. Of 226 randomized patients, 174 (93 in 300 mg/day group and 81 in 250 mg/day group) started withdrawal of the background AED and were evaluated for escape. In the historical control analysis population, the lower 95% prediction interval of the historical control (65.3%) was not overlapped by the upper 95% confidence limit of either LTG XR (300 mg/day; 37.2%) or LTG XR (250 mg/day; 43.4%). Adverse events were reported in 53% and 61% of patients receiving LTG XR (300 mg/day and 250 mg/day, respectively). LTG XR (250 mg or 300 mg once daily) is effective for conversion-to-monotherapy treatment of partial seizures in patients ≥13 years old.     

2005 AES Annual Course: Evidence Used to Treat Women with Epilepsy

Summary:  Although most female-specific considerations for treatment of epilepsy cannot be answered by Class I evidence, significant progress in our knowledge base has occurred in the past few years. Open-label studies of progesterone supplementation showed promising results; an ongoing randomized trial may provide definitive evidence for therapeutic use of progesterone in women. A randomized trial of hormone replacement therapy demonstrated a dose-related increase in seizure frequency in postmenopausal women with epilepsy. The use of different AED regimens during pregnancy cannot be explored with randomized, controlled trials; we must rely on the best available evidence from ongoing observational studies. The consistent findings of large prospective pregnancy registries reveal a consistent pattern of amplified risk for major congenital malformations in pregnancies exposed to valproate. These registries have also highlighted the concern for the effect of shifting hormones on AED concentrations. An increased frequency of seizures during pregnancy has been noted with lamotrigine (LTG) and oxcarabazepine, both of which undergo glucuronidation. Other studies have demonstrated an increased clearance of LTG during pregnancy and with exogenous estrogen use. It may be prudent to closely monitor serum concentrations of these AEDs with hormonal changes. An increased risk for neurodevelopmental consequences has been demonstrated for the fetus exposed to AED polytherapy, valproic acid, or frequent maternal convulsive seizures. Preliminary information about breastfeeding with LTG and levetiracetam is available. These newly released findings provide the tools to begin to practice evidence-based medicine when treating our female patients during their reproductive and postmenopausal years.     

Lamotrigine Therapy for Partial Seizures: A Multicenter, Placebo-Controlled, Double-Blind, Cross-Over Trial

Summary: The efficacy and safety of lamotrigine (LTG), a new antiepileptic drug (AED), were evaluated in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 98 patients with refractory partial seizures. Each treatment period lasted 14 weeks. Most patients were titrated to a LTG maintenance dose of 400 mglday. Seizure frequency with LTG decreased by ≥50%, as compared with placebo, in one fifth of patients. Overall median seizure frequency decreased by 25% with LTG as compared with placebo (p < 0.001). With LTG, the number of seizure days decreased by 18% as compared with placebo (p < 0.01), and investigator global evaluation of overall patient clinical status favored LTG by 2: 1 (p = 0.013). Plasma LTG concentrations appeared to be linearly related to dosage. LTG had no clinically important effects on the plasma concentrations of concomitant AEds. Adverse experiences were generally minor and most frequently were CNS-related (e.g., ataxia, dizziness, diplopia, headache). Most were transient and resolved without discontinuing treatment. Five patients withdrew as a result of adverse experiences while receiving LTG, including 3 patients with rash. One placebo patient was also withdrawn because of rash. The addition of twice-daily LTG to an existing AED regimen was safe, effective, and well tolerated in these medically refractory partial seizure patients.     

Lamotrigine in add-on therapy: assessment of efficacy in drug resistant epilepsy

The authors presented the results of treatment with lamotrigine (LTG, Lamictal) in 13 patients with drug resistant epilepsy (add-on therapy). There were 8f, 5m. aged 16-60 years, mean age 28.8 years. Generalized seizures occurred in 8 patients (62%). In this group there was 1 patient (aged 16 years) with the Lennox-Gastaut syndrome and 1 patient (aged 20 years) with valproate resistant juvenile myoclonic epilepsy. Complex partial seizures and complex partial with secondary generalization occurred in 5 patients (38%). Before LTG addition mean seizure frequency was from 3/month to several times/day. The mean duration of epilepsy was 16.6 years. The 8 patients were treated with CBZ and VPA, one with PHT and VPA, one CBZ and VGB. Monotherapy with VPA was introduced in 3 patients. After 6 months of treatment with LTG the efficacy was evaluated. 12 patients took LTG with VPA, 1 LTG with CBZ. Complete reduction of seizures was achieved in 3 cases (23%), at least 50% reduction in 3 patients (23%), reduction below 50% in 4 patients (31%). In 3 cases (23%) the results of treatment were negative (increase or no change in seizure frequency). Beneficial psychotropic effect was observed in 9 patients (69%). Adverse effects occurred in 2 patients (15%). Headache, vertigo, sleepness were observed in one case. Rash occurred in 1 patient (treated with LTG and VPA). After 6 months 3 patients were excluded from the study because of negative effects of treatment. LTG is helpful and well tolerated in drug-resistant epilepsy.     

Outcomes of Add-on Treatment with Lamotrigine in Partial Epilepsy

Summary: The need for new antiepileptic drugs (AEDs) and more sensitive methods of assessing their efficacy is well recognized. This study was designed to evaluate the efficacy and safety of lamotrigine (LTG), a potential new AED and to develop and test new outcome measures. A health-related quality of life (HRQL) model was developed which contains previously validated measures of anxiety, depression, happiness, overall mood, self-esteem, and mastery and a specifically designed seizure severity scale with patient- and caregiver-based components. This HRQL model was used in a randomized, placebo-controlled, double-blind, cross-over study of LTG in 81 patients with refractory partial seizures. Seizure frequency was the primary measure and seizure severity and the HRQL were secondary measures of efficacy. The reduction in seizure frequency with LTG, relative to placebo, was 29.7% [95% confidence interval (CI) 17.8%, 39.9%] for total seizure count, 33.4% (95% CI 14.8%, 47.9%) for complex partial seizures (CPS) and 20.3% (95% CI 0.3%, 36.2%) for secondarily generalized tonic-clonic seizures (GTCS). However, although 41 patients elected to continue with LTG, only 11 experienced at least 50% reduction in total seizures, indicating that other factors influenced their decision. The score with LTG, relative to placebo, was significantly lower for the ictal (p = 0.017) and caregivers (p = 0.035) subscales of the seizure severity scale and significantly higher for happiness (p = 0.003) and mastery (p = 0.003). Simple correlation and multiple-regression analyses indicate that the effects on seizure frequency, seizure severity, and psychological variables appear to be independent of each other. This study indicates that LTG is effective in reducing seizure frequency and has additional favorable effects on seizure severity, mood, and perceived internal control. Some of the scales used indicate the potential of secondary measures of efficacy to enhance the sensitivity of trials of new AEDs.     

Conversion from immediate-release to extended-release lamotrigine improves seizure control

BackgroundImmediate release lamotrigine (LTG-IR) dosing can be limited by peak toxicity. It is thought that peak levels are responsible for some adverse effects such as dizziness, blurred vision, double vision and unsteadiness. At the same time, trough levels may be associated with reduced seizure threshold. The use of extended release lamotrigine (LTG-XR) to replace LTG-IR will be associated with less fluctuation in drug levels-lower peak levels may reduce adverse effects and higher trough levels may improve seizure control. This hypothesis was tested by analyzing seizure control and adverse effects before and after conversion from LTG-IR to LTG-XR in patients who underwent such conversion in 2009–2011.MethodsWe searched our patient database to identify patients converted from LTG-IR to LTG-XR for persistent seizures or adverse effects from August 2009 until December 31, 2011. We included only patients who took LTG-IR and LTG-XR for at least 6 months each. We excluded patients with nonepileptic seizures, progressive cause of epilepsy, or not keeping a seizure record. We collected the following parameters: age at conversion, LTG-IR dose and dosing schedule, duration on that dose, LTG-XR dose and dosing schedule, LTG serum level before and after conversion, duration of LTG-XR treatment, seizure frequency before and after conversion, and change in adverse experience profile. We also recorded baseline AEDs and any AED change during the course of the analysis.ResultsFifty five patients (26 female) satisfied the inclusion/exclusion criteria. Their mean age was 45 years (range 23 to 86). Ten were on LTG-IR monotherapy, 24 took LTG-IR plus one other AED, most commonly levetiracetam, and the remaining 21 took LTG-IR plus at least 2 other AEDs. The mean LTG-IR dose was 544 mg/day (range 150–1100 mg/day). The mean LTG-IR serum level was 11.6 (available in 53 patients-range 4.6–21 mcg/ml). Twenty six patients were converted to the same dose and one patient took a mixture of LTG-XR and LTG-IR at the same total daily dose, while 21 had their dose slightly increased and 7 had their dose slightly decreased due to adverse effects. The mean serum level after conversion was 11.8 (available in 49 patients-range 2.6–21.2 mcg/ml). As a result of the conversion, 26 patients (47%) experienced >50% reduction in seizure frequency. There was a 46% median reduction in seizure frequency overall. Seven patients reported improvement in adverse effects.ConclusionA conversion from LTG-IR to LTG-XR can help improve seizure control in some individuals with drug-resistant epilepsy, in addition to improving tolerability. While it is indicated in individuals experiencing peak adverse effects, it should also be considered in patients who have received incomplete seizure control from LTG-IR.     

Lamotrigine add-on therapy for childhood-onset refractory epilepsy: comparison of the efficacy between 3 months and 6 months after initiation

We investigated the effect of lamotrigine (LTG) add-on therapy in 50 patients with childhood-onset refractory epilepsy (25 males and 25 females): 15 with localization-related epilepsy, 33 with generalized epilepsy, and 2 with undetermined epilepsy. Twenty-four patients had experienced a period of West syndrome during their clinical course. Age at the start of LTG therapy ranged from 2 years 6 months to 41 years 2 months: <16 years in 43 and > or = 16 years in 7. Seizure frequency was > or = 1 per day in 36 patients (72%) and > or = 1 per week in 14 (28%). We increased the LTG dosage every two weeks in accordance with usage recommendations. We evaluated efficacy at two points: 3 and 6 months after the start of LTG. At the 6-month point, seizure freedom was achieved in 2 patients (4%), > or = 50% seizure reduction in 14 (28%), 25 to 50% seizure reduction in 20 (40%), no effect in 6 (12%), and aggravation in 4 (8%). Only 4 patients (8%) stopped LTG therapy within 6 months due to LTG-related mild skin rash in 2 and suspicion of seizure aggravation in the other 2. In terms of seizure types, seizure freedom or > or = 50% seizure reduction was achieved in 29% for epileptic spasms, 32% for tonic seizures, and 29% for partial seizures. A comparison between the 3- and 6-month points revealed that the efficacy level was increased or maintained in 77% of the patients and decreased in 23%. In most cases, the highest level of efficacy appeared within 3 months with doses that were smaller than maintenance doses. Observed CNS-related adverse effects included somnolence in 16 patients, irritability in 14, and sleep disturbance in 11. Positive psychotropic effects in daily activities were seen in 28 patients (56%). These effects appeared regardless of the change in seizure frequency with doses that were smaller than maintenance doses.     

Gabapentin and lamotrigine in Indian patients of partial epilepsy refractory to carbamazepine

52 patients (25 males and 27 females) suffering from refrectory partial seizures, of not more than two years duration and on carbamazepine monotherapy were enrolled in this study. Patients were randomly put on gabapentin (19 males and 8 females) or lamotrigine (6 males and 19 females) as add on therapy. The efficacy of the drugs was assessed by the seizure frequency, pattern of seizures and seizure free interval. The safety was evaluated from the biochemical investigations and the adverse effects observed or reported by the patients during the course of the study. The average frequency of basal partial seizures was 6.26+3.86 and 5.04+2.47 which decreased significantly (p<. 001) after 12 weeks of add on therapy to 1.75+2.16. and 1.68+2.94 in the GBP and LTG group respectively. However, there was no significant difference between the two drugs after 12 weeks of add on therapy. The PCB (primary change in basal seizure frequency) values decreased to -72+34.92 and -76.22+29.68 in the GBP and LTG group respectively. The difference in these two groups was not significant. The responder rate was 77.7% and 92% respectively in GBP and LTG group respectively. GBP was found to be more effective in partial seizures with secondarily generalization while LTG was effective in all subtypes of partial seizures. The abnormal scalp EEG was recorded in 33.3% (9 of 27 patients) in GBP group and 40 %( 10 of 25 patients) in LTG group and it did not revert to normal in 33.3% and 40% of patients in either of groups (GBP/LTG). Minor side effects which were self limiting were noticed in 80% in groups I and 74% were groups II.     

The Efficacy of Lamotrigine in Children and Adolescents with Refractory Generalized Epilepsy: A Randomized, Double-Blind, Crossover Study

Summary: Purpose: We report a double-blind, placebo-controlled crossover study of lamotrigine (LTG) as add-on treatment in therapy-resistant, generalized epilepsy in children and adolescents (n = 30).
Methods: Twenty patients had Lennox-Gastaut syndrome. Each patient acted as his or her own control. LTG and placebo were randomly added to existing antiepileptic medication (AEDs). The LTG dosage was individualized in an open phase preceding the placebo/treatment phase. Patients who responded to LTG in the open phase went on to the double-blind phase. "Responders" were defined as patients with a >50% seizure reduction or less severe seizures or both, or improved behavior or improved motor skills or both. "Nonresponders" were defined as children who showed no positive effects of LTG with plasma levels of 10 μg/ml or children who had adverse events during the open phase.
Results: There was a clear statistically significant reduction of seizure frequency in LTG compared with placebo treatment. None of the children studied showed abnormal biochemical or hematologic findings, or changes in plasma levels of concomitantly administered AEDs.
Conclusions: LTG is a well-tolerated and effective treatment in children with intractable generalized epilepsies, including those with Lennox-Gastaut syndrome. The study design allowed a double-blind placebo-controlled assessment of LTG although the participating children used 19 different AED combinations at entry.