Reintroduction of treatment with lamotrigine in combination with valproate after an initial allergic skin reaction

INTRODUCTION: Lamotrigine (LTG) is effective for a variety of seizure types especially against absence seizures in cotherapy with valproate (VPA). Skin rash is the most frequent side effect leading to LTG discontinuation. OBSERVATIONS: We report two patients with refractory absence epilepsy and a previous history of allergic reaction to LTG in which LTG was rechallenged. LTG was effective in both cases without incident. DISCUSSION: High initial dose and rapid dose escalation is associated with increased rash rate. LTG is contraindicated in patients who have demonstrated hypersensitivity to the drug. However, because the initial dose and the dose titration play a crucial role, LTG was reintroduced with a very low initial dose and very slow titration schedule without recurrence of skin rash. CONCLUSION: Patients who have experienced a previous mild skin allergy may be reconsidered for a rechallenge with LTG if the expected therapeutic response to the drug is high. Patients must be warned about the risks.     

Lamotrigine Hypersensitivity in Childhood Epilepsy

Summary: Purpose: To evaluate the effect of lamotrigine (LTG) on several humoral and cellular immune functions in children with epilepsy and the change in immunological status in patients with LTG-induced rash.
Methods: Sixteen children with epilepsy of unknown origin or secondary to various etiologies undergoing treatment with LTG participated in the humoral and cellular immunological study. Of these, 2 patients developed a rash during LTG treatment and are described in detail.
Results: No modifications of humoral or cellular immunity (measured at 1 and 3 months) were noted in 14 of the 16 patients during this treatment. In the 2 children who manifested rash, basal immune function was normal. In both, immediately after the skin rash appeared, there was a high increase in the percentage of activated T-helper lymphocytes (CDCDR) and activated T-suppressor lymphocytes (CDS-DR), a slight increase in percentage of B lymphocytes (CD19), and a greater increase in serum concentration of IgE. In 1 of the 2 patients, reevaluation of immunity 20 days after the rash appeared and after LTG suspension showed normal percentages of CDCDR, CDS-DR, and CD19, whereas the serum concentration of IgE had decreased.
Conclusions: The observed immunological results indicate that LTG-induced rash may be considered an immune-mediated hypersensitivity reaction.     

Adding Lamotrigine to Valproate: Incidence of Rash and Other Adverse Effects

PURPOSE: Valproate (VPA) triples the half-life of lamotrigine (LTG), and combined use may be difficult. The adverse effect (AE) profile of this combination needs clarification. METHODS: We prospectively recorded our experience in adding LTG to VPA-containing regimens in 108 patients. Data collected included medications, seizure types and syndromes, and AEs. Patients were followed up to 27 months, until a stable dose was reached, or until LTG was discontinued. Patient management was not altered by this study. There were 60 patients with partial-onset seizures, 30 with generalized onset, and 12 with the Lennox-Gastaut syndrome. In 37, LTG was added to VPA monotherapy, and in 71, to VPA and other drugs. The median starting dose of LTG in our adult patients was 20.8 mg/day. RESULTS: LTG was added successfully in 86 (80%) patients. It was discontinued in 22 (20%): seven because of rash, seven for other AEs, and nine for other reasons. Rash occurred in 14 (13%) but caused discontinuation of LTG in only seven. We found a rash rate of 14.2% and a discontinuation rate because of rash of 8.7% among 310 patients in whom LTG was added to drug regimens not including VPA. Other AEs included fatigue (12%), gastrointestinal (GI) symptoms (9%), dizziness, headache, and insomnia (3% each). Serious AEs were hallucinations (two patients), hepatic enzyme elevations (two patients), irritability (one patient), and low white blood cell count (one patient). Whether LTG was added to VPA monotherapy or polytherapy made no difference in overall AE rate. CONCLUSIONS: LTG can be added to VPA with an acceptable incidence of side effects. LTG-induced rashes are no more common with VPA than with other drugs when LTG is added at very low initial dosages. Rashes are potentially serious and should be evaluated promptly.     

Lamotrigine Monotherapy in Newly Diagnosed Untreated Epilepsy: A Double-Blind Comparison with Phenytoin

PURPOSE: Lamotrigine is an effective add-on therapy against a range of epileptic seizure types. Comparative studies with carbamazepine (CBZ) as monotherapy in newly diagnosed epilepsy suggest similar efficacy. In this study, lamotrigine (LTG) and phenytoin (PHT) are compared. METHODS: In a double-blind parallel-groups study, 181 patients with newly diagnosed untreated partial seizures or secondarily or primary generalised tonic-clonic seizures were randomised to two treatment groups. One group (n = 86) received LTG titrated over 6 weeks from a starting dose of 100 mg/day. The other (n = 95) received PHT titrated from 200 mg/day. Treatment continued for < or =48 weeks. RESULTS: The percentages of patients remaining on each treatment and seizure free during the last 24 and 40 weeks of the study, and times to first seizure after the first 6 weeks of treatment (dose-titration period), did not differ significantly between the treatment groups. These were measures of efficacy. Time to discontinuation, a composite index of efficacy and safety, likewise did not distinguish between treatments. Adverse events led to discontinuation of 13 (15%) patients from LTG and 18 (19%) from PHT. The adverse-event profile for LTG was dominated by skin rash [discontinuation of 10 (11.6%) patients compared with five (5.3%) from PHT] rather than central nervous system side effects: asthenia, somnolence, and ataxia were each significantly more frequent in the PHT group. The high rate of rash with LTG was probably due to the high starting dose and may be avoidable. A quality-of-life instrument, the SEALS inventory, favoured LTG. Patients taking PHT showed the biochemical changes expected of an enzyme-inducing drug, whereas those taking LTG did not. CONCLUSIONS: LTG and PHT monotherapy were similarly effective against these seizure types in patients with newly diagnosed epilepsy. LTG was better tolerated, more frequently causing rash, but with a lower incidence of central nervous system side effects.     

Lamotrigine High-Dose Tolerability and Safety in Patients with Epilepsy: A Double-Blind, Placebo-Controlled, Eleven-Week Study

Summary: Purpose: This study was undertaken to evaluate the dose tolerability and safety of a chronic ascending twice-daily (b.i.d.) dosage regimen of 700 mg/day larnotrigine (LTG) and to include determination of the LTG pharmacokinetic profile at doses 500 mg/day in patients receiving concomitant enzyme-inducing antiepileptic drugs (AEDs). Methods: Twelve adult male epileptic patients treated with enzyme-inducing AEDs received 700 mg/day (b.i.d.) oral LTG (n = 8) or placebo (controls, n = 4). For 3 weeks, as outpatients they had their LTG dosage increased from 100 to 400 mg/day. Then, in a clinical research study unit, patients received regimens of 500, 600, and 700 mg/day for 1 week each. Controls received matching placebo in the same sequence. At study end, dosages were tapered in 2 weeks. Follow-up evaluations were made 7 days later. Results: Five LTG patients tolerated 700 mg/day for 1 week. LTG was reduced to 600 mg/day in a patient with mild diplopia and to 500 mg/day in a patient with mild oscillopsia and diplopia. One patient discontinued 300-mg/day therapy with a moderately intense diffuse papular skin rash, attributed to LTG. Headache, drowsiness, faintness, and diplopia, the common adverse events (AEs), were mild to moderate in intensity and occurred in 50–75% of patients in both groups (except for diplopia, occurring only with LTG). Concomitant AED plasma concentrations were not markedly changed by LTG. LTG pharmacokinetics were linear over the range of 500–700 mg/day. Conclusions: LTG doses 700 mg/day can be tolerated in patients receiving concomitant enzyme-inducing AEDs.     

Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy

PURPOSE: This randomised, double-blind study compared the newer antiepileptic drugs (AEDs) gabapentin (GBP) and lamotrigine (LTG) as monotherapy in newly diagnosed epilepsy. METHODS: Patients with partial seizures with and/or without secondary generalization or primary generalized tonic-clonic seizures were randomized to either GBP or LTG. During 2- and 6-week titration periods, respectively, GBP dosage reached 1,800 mg/day, and LTG, 150 mg/day. In the subsequent 24-week maintenance phase, the dose could be adjusted based on seizure control or adverse events between 1,200 and 3,600 mg/day for GBP and 100 and 300 mg/day for LTG. The primary end point was time to exit, a composite of efficacy and tolerability. Evaluable patients were used for the primary efficacy analysis, whereas tolerability was examined on an intent-to-treat basis. RESULTS: A total of 309 patients was randomized, and 291 (148 GBP, 143 LTG) were included in the evaluable population. Nineteen patients in each group had an exit event. The median time to exit was 69 days for GBP and 48 days for LTG. The hazard ratio was estimated as 1.043 (90% confidence intervals, 0.602-1.809). Overall, 106 (71.6% of the evaluable population) GBP-treated and 96 (67.1%) LTG-treated patients completed the study. Of those, 80 (75.5%) patients taking GBP and 73 (76.0%) taking LTG remained seizure free during the final 12 weeks of treatment. Only 14 (8.9%) GBP-treated patients and 15 (9.9%) LTG-treated patients withdrew because of study drug-related adverse events. CONCLUSIONS: GBP and LTG monotherapy were similarly effective and well tolerated in patients with newly diagnosed epilepsy.     

Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group.

In a multicentre, double-blind trial 150 elderly patients (mean age 77 years) with newly diagnosed epilepsy were randomised in a 2:1 ratio to treatment with lamotrigine (LTG) or carbamazepine (CBZ). Following a short titration period, the dosage was individualised for each patient while maintaining the blind over the next 24 weeks. The main difference between the groups was the rate of drop-out due to adverse events (LTG 18% versus CBZ 42%). This was in part a consequence of the lower rash rate with LTG (LTG 3%, CBZ 19%; 95% CI 7-25%). LTG-treated patients also complained less frequently of somnolence (LTG 12%, CBZ 29%; 95% CI 4-30%). Although there was no difference between the drugs in time to first seizure, a greater percentage of LTG-treated patients remained seizure-free during the last 16 weeks of treatment (LTG 39%, CBZ 21%; P = 0.027). Overall, more patients continued on treatment with LTG than CBZ (LTG 71%, CBZ 42%; P < 0.001) for the duration of the study. The hazard ratio for withdrawal was 2.4 (95% CI 1.4-4.0) indicating that a patient treated with CBZ was more than twice as likely to come off medication than one taking LTG. In conclusion, LTG can be regarded as an acceptable choice as initial treatment for elderly patients with newly diagnosed epilepsy.     

拉莫三嗪治疗成人部分性发作癫癎的临床疗效与安全性研究

目的评价拉莫三嗪治疗成人部分性发作癫癎的临床疗效与安全性。方法收集成人部分性发作癫癎患者89（76）例,分别给予拉莫三嗪单药、替换或添加治疗,进行开放性自身对照研究,随访24周发作情况,登记监测不良反应。结果 89例中76例完成终点试验,总有效率为82.8%,平均起效剂量为（99.7±18.6）mg/d,平均起效时间为（17.8±5.4）d,保留率为85.39%。不良反应发生率为15.8%,皮疹发生率为2.2%。结论拉莫三嗪是一种安全、有效的抗癫癎药物。     

Lamotrigine as first-line drug in childhood absence epilepsy: a clinical and neurophysiological study

To investigate to which extent lamotrigine (LTG) may be effective and tolerated as a monotherapy for the treatment of newly diagnosed childhood absence seizures and, secondly, to evaluate the efficacy of this drug on the circadian interictal generalized epileptiform discharges, 20 consecutive newly diagnosed patients (five males, 15 females), aged 3-10 years (mean 6.9 years), affected by childhood absence epilepsy, were administered LTG as first-line drug at the initial dose of 0.5 mg/kg/day for 2 weeks, followed by 1.0 mg/kg/day for an additional 2 weeks. Thereafter, doses have been increased in 1-mg/kg/day increments up to 9-12 mg/kg/day in accordance with the clinical response. Each patient underwent an ambulatory (24 h) EEG monitoring before starting LTG therapy (time 0) and during the maintenance period at the end of LTG titration (time 1). After a mean follow-up period of 10.8 months (range 3-28 months), a 100% seizure control was obtained in 11 children (55.5%), a more than 75% seizure decrease was present in four (20%), and a >50% seizure decrease in five (25%), with a mean LTG dose of 6.2 mg/kg/day (range 1.2-11) in the controlled group. Adverse events were present in three patients (15%); they were generally mild and transient. Our series confirms that LTG monotherapy may control typical childhood absence seizures in about half the children as well as it may decrease interictal generalized spike and wave discharges both in seizure-free and uncontrolled patients. The slow titration phase of the drug due to the risk of the skin rash may eventually reduce compliance.     

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.     

Tolerability and pharmacokinetics of oral loading with lamotrigine in epilepsy monitoring units

PURPOSE: To investigate the tolerability and pharmacokinetics of oral loading with lamotrigine (LTG) among epilepsy patients after temporary drug discontinuation in an epilepsy monitoring unit. METHODS: We conducted a pilot study among epilepsy patients (18 years or older) receiving maintenance doses of LTG. LTG was discontinued on admission and restarted at the end of epilepsy monitoring. LTG was given as a single oral dose calculated based on the population expected volume of distribution (Vd, 1.0 L/kg) and target blood level on admission. Baseline and serial blood levels of LTG were determined hourly for 10 to 12 h after the loading dose. Outcome measures: (a) frequency of patients with side effects; (b) time to maximum concentration (Tmax), maximum concentration (Cmax), actual volume of distribution, and half-life. RESULTS: Twenty-four patients received a single oral load of LTG (mean, 6.5 +/- 2.7 mg/kg). Overall, LTG loading was well tolerated with no serious adverse events or skin rash observed. Two patients had transient and mild nausea 1 to 2 h after the oral load. The mean estimated pharmacokinetic parameters are as follows: Tmax, 3.1 +/- 2.1 h; Cmax, 8.2 +/- 6.5 mg/L; Vd, 1.1 +/- 1.0 L/kg; clearance, 0.08 +/- 0.08 mg/L/h; half-life, 22 +/- 30 h. All patients reached their target blood levels. CONCLUSIONS: Epilepsy patients temporarily discontinued from LTG can be restarted with a single oral loading dose. This was well tolerated, and therapeutic levels can be achieved within 1 to 3 h.     

Lamotrigine in Treatment of 120 Children with Epilepsy

Summary: One hundred twenty children aged 10 months to 16 years 9 months were included in three studies with lamotrigine (LTG): a single-blind study (n = 60), a pharmacokinetic study (n = 23), and a compassionate group (n = 37). At 3 months, 11 patients had become seizure-free and 34 had >50% decrease in seizure frequency. The best results involved absence epilepsy, Lennox-Gastaut syndrome (LGS), and other symptomatic generalized epilepsy. Forty-two patients were followed > 1 year, 22 for a mean of 2.2 years, and there was no significant increase in seizure frequency as compared with 3-month follow-up. Fourteen patients became seizure-free for >6 months; all except 1 had generalized epilepsy. For 12 patients, treatment could be reduced to monotherapy, but for those with valproate (VPA) comedication LTG dosage had to be increased; 25% of patients with VPA monotherapy exhibited skin rash, appearing 3–18 days after starting LTG. For 4 patients, LTG could be reintroduced after VPA was withdrawn. Ten patients had ataxia and/or drowsiness and 2 had vomiting. For all other patients, tolerance was excellent.     

Cortical excitability in patients after loading doses of lamotrigine: a study with magnetic brain stimulation

PURPOSE: Transcranial magnetic stimulation (TMS) of the brain allows the pharmacologic effects of anti-convulsant drugs (AEDs) on the excitability of motor corticospinal pathways to be evaluated in patients with epilepsy and normal subjects. However, no study has yet documented the changes in motor excitability in patients treated with lamotrigine (LTG). We aimed to study the effects of loading doses of LTG on TMS recordings in patients with epilepsy at the beginning of their treatment. METHODS: We investigated single-pulse TMS in six patients with complex partial seizures. The TMS recordings were performed in five sessions before and during 5 weeks of treatment. Motor threshold, motor-evoked potential (MEP) amplitude, cortical silent period, and peripheral conduction velocity were used as parameters of evaluation. LTG was started with a dosage of 25 mg/day until a daily maintenance dosage of 200 mg/day was reached. RESULTS: The motor threshold activation of thenar muscles was significantly increased by LTG after 2 weeks of treatment and was increased in a parallel way to the loading dose of the drug at week 3 and 5 of treatment. The MEP size recorded from the thenar muscles did not show significant changes at high- or low-intensity stimulation. The cortical silent period remained unchanged at low- and high-intensity stimulation. The absolute latency of MEPs after cortical and cervical stimulation was unchanged, as was the central motor conduction time. CONCLUSIONS: Our study documents that loading doses of LTG, administered as monotherapy, progressively increases patients' motor thresholds over short periods.     

Expanding Antiepileptic Drug Options: Clinical Efficacy of New Therapeutic Agents

Summary: Results of double-blind, placebo-controlled, add-on trials of topiramate (TPM), lamotrigine (LTG), and vigabatrin (VGB) in refractory partial epilepsy were reviewed. In three European multicenter studies of TPM, the clinical efficacy of 400–, 600–, and 800-mg/day target dosages was demonstrated. In a similarly designed United States trial, LTG was significantly superior to placebo at a 500-mg/day dosage but not at a 300-mg/day dosage. A meta-analysis of a number of smaller trials of VGB suggests that a ≥50% reduction in seizures is observed in approximately 45% of patients with refractory partial epilepsy. All of these newer antiepileptic drugs have shown efficacy in well-controlled trials and should contribute significantly to our ability to manage partial epilepsy.     

Lamotrigine and Seizure Aggravation in Severe Myoclonic Epilepsy

Summary: Purpose: In severe myoclonic epilepsy of infancy (SME), multiple drug-resistant focal and generalized seizure types occur. Lamotrigine (LTG), found effective in many generalized and partial seizures, has been little used in severe childhood epilepsy syndromes with multiple seizure types. We studied the effects of LTG in SME.
Methods: Twenty-one patients with SME, aged 2–18 years, were treated with LTG, 20 in add-on and one in monotherapy. LTG was started at 0.2–2.5 mg/kg/day and increased to 2.5–12.5 mg/kg/day. For each seizure type, excluding atypical absences, >50% variations compared with the 2 months preceding LTG were considered indicators of response, also taking into account the degree of disability each seizure type produced.
Results: LTG induced worsening in 17 (80%) patients, no change in three, and improvement in one. There was >50% increase in convulsive seizures in eight (40%) of 20 patients. Myoclonic seizures worsened in six (33%) of 18 patients. Of five patients improving in at least one seizure type, four had concomitant worsening of more invalidating seizures. Clear-cut worsening appeared within 3 months in most patients but was insidious in some. LTG was suspended in 19 patients after 15 days-5 years (mean, 14 months) with consequent improvement in 18.
Conclusions: The pronounced seizure deterioration during LTG treatment was not attributable to the natural course of the disease and could be a direct effect of therapeutic LTG doses. LTG treatment seems inappropriate in SME.     

Lamotrigine Therapy in Juvenile Neuronal Ceroid Lipofuscinosis

PURPOSE: To evaluate the effects of lamotrigine (LTG) therapy on epileptic seizures and general well-being in patients with juvenile neuronal ceroid lipofuscinosis (JNCL). METHODS: LTG was initiated in 28 patients with JNCL. The mean age of the patients at the initiation of LTG was 13.7 years (range, 6.7-28.2 years). LTG was started at a dosage of 0.1-0.5 mg/kg/day and increased every 2 weeks until a maintenance dose of 1.25-15 mg/kg/day was reached. On the basis of the indication for LTG therapy, the patients could be divided into four groups. In the first group, LTG was initiated on an add-on basis; in the second group, LTG was started as the first antiepileptic drug (AED) because of seizures, and in the third group, despite no preceding seizures, because of epileptiform activity in the whole-night polysomnography; in the fourth group, LTG replaced valproate (VPA), which was discontinued because of adverse side effects. The efficacy was assessed after 1 year on LTG. The mean follow-up time was 2.8 years (range, 1.3-5.8). RESULTS: LTG had a favorable effect in 23 of 28 patients. A decrease in frequency of seizures of > or =50% was observed in 10 and a decrease in severity of seizures in nine of the 22 patients who had preceding seizures. Increases in well-being were found in 18 of 28. During the follow-up, LTG was continued as monotherapy in 13 of 19 patients. CONCLUSIONS: In light of our experiences, LTG seems to be a valuable drug in JNCL.     

Effectiveness of First Antiepileptic Drug

PURPOSE: To investigate the interaction among efficacy, tolerability, and overall effectiveness of the first antiepileptic drug (AED) in patients with newly diagnosed epilepsy. METHODS: The 470 patients were diagnosed, treated and followed up from January 1984 at a single center. Outcome was classified as seizure freedom for at least the last year or failure of initial treatment because of inadequate seizure control, adverse events, or for other reasons. RESULTS: Overall, 47% of patients became seizure-free with the first prescribed AED. A higher proportion (p = 0.025) of patients with symptomatic or cryptogenic epilepsy changed treatment because of intolerable side effects (17%), and a lower proportion (p = 0.007) became seizure-free (43.5%) compared with those with idiopathic epilepsy (8.5% and 58%, respectively). Most patients (83%) received carbamazepine (CBZ; n = 212), sodium valproate (VPA; n = 101), or lamotrigine (LTG; n = 78). The majority of seizure-free patients required only a moderate daily AED dose (93.1% with < or =800 mg CBZ, 91.3% with < or =1,500 mg VPA, 93.8% with < or =300 mg LTG), with commonest dose ranges being 400-600 mg for CBZ, 600-1,000 mg for VPA, and 125-200 mg for LTG. Most withdrawals due to poor tolerability also occurred at or below these dose levels (CBZ: 98%; VPA: 100%; LTG: 75%). Patients taking CBZ (27%) had a higher incidence of adverse events necessitating a change of treatment than did those treated with VPA (13%) or LTG (10%), resulting in fewer becoming seizure-free (CBZ vs. VPA, p = 0.02; CBZ vs. LTG, p = 0.002). CONCLUSIONS: Nearly 50% of newly diagnosed patients became seizure-free on the first-ever AED, with >90% doing so at moderate or even modest dosing. Tolerability was as important as efficacy in determining overall effectiveness.     

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.     

Pharmacological outcomes in newly diagnosed epilepsy

The response to antiepileptic drugs (AEDs) has been examined in 780 adult and adolescent patients with newly diagnosed epilepsy presenting with a range of seizure types and epilepsy syndromes over a 20-year period. Carbamazepine (CBZ, n=312), sodium valproate (VPA, n=315), and lamotrigine (LTG, n=249) were the most common AEDs prescribed as monotherapy. More patients with localization-related epilepsies became seizure free with LTG (63%) than with CBZ (45%, P=0.006) or VPA (42%, P=0.006). For idiopathic generalized epilepsies a greater proportion of patients achieved control with VPA (68%) than with CBZ (31%) or LTG (45%). In particular, more patients with juvenile myoclonic epilepsy responded to VPA (75%) compared with LTG (39%, P=0.014). Seizure freedom was achieved with modest or moderate daily doses (median CBZ 400mg, VPA 1000 mg, (LTG) 150 mg) of all three AEDs in the majority of patients achieving remission. Time to first seizure did not differ among these three drugs when given as first treatment. Adverse effects leading to withdrawal were more frequent with CBZ (16%) than with VPA (7%, P=0.03) or LTG (7%, P=0.018). In patients failing initial monotherapy, response to a combination of two AEDs (27%) was not different from that with alternative monotherapy (32%). The majority of patients with newly diagnosed epilepsy responding to treatment did so rapidly and completely with moderate doses of AEDs, with no differences in time to first seizure.