Final results from 18 years of the International Lamotrigine Pregnancy Registry.

OBJECTIVE: To monitor for a signal for major teratogenicity following in utero lamotrigine exposure. METHODS: Health care providers reported lamotrigine exposure during pregnancy, and subsequent outcomes, on a voluntary basis. Prospective reporting early in pregnancy was encouraged. Major congenital malformations (MCMs) were classified according to the Centers for Disease Control and Prevention (CDC) criteria and were reviewed by a pediatrician on the Registry's Scientific Advisory Committee. The proportion of infants with MCMs was calculated by trimester and therapy type and descriptively compared to population-based reference estimates. RESULTS: Over an 18-year period, 35 infants with MCMs were observed among 1,558 first-trimester monotherapy exposures: 2.2%(95% confidence interval [CI] 1.6%-3.1%). This was similar to estimates from general population-based cohorts. The observed proportion of infants with MCMs among 150 lamotrigine/valproate polytherapy exposures was 10.7% (95% CI 6.4%-17.0%) and was 2.8% (95% CI 1.5%-5.0%) among 430 infants exposed to lamotrigine polytherapy without valproate. No consistent pattern of malformation type, or malformation frequency by dose, was observed. DISCUSSION: The Registry did not detect an appreciable increase in MCM frequency following first-trimester lamotrigine monotherapy exposure. With over 1,500 first-trimester monotherapy exposures, the Registry was powered to detect major teratogenicity. The proportion of infants with MCMs following lamotrigine/valproate polytherapy exposure was high, but similar to that previously reported with valproate monotherapy. The Registry failed to observe an increased MCM frequency with increasing lamotrigine dose. Monitoring of specific malformations among lamotrigine-exposed pregnancies will continue through case-control surveillance in the European Congenital Anomalies and Twins Registers network.

Lamotrigine extended-release as adjunctive therapy for partial seizures.

OBJECTIVE: To evaluate the efficacy and tolerability of once-daily adjunctive lamotrigine extended-release (XR) for partial seizures in epilepsy. METHODS: Patients more than 12 years old diagnosed with epilepsy with partial seizures and taking one to two baseline antiepileptic drugs were randomized to adjunctive once-daily lamotrigine XR or placebo in a double-blind, parallel-group trial. The study comprised a baseline phase, a 7-week double-blind escalation phase, and a 12-week double-blind maintenance phase during which doses of study medication and concomitant antiepileptic drugs were maintained. RESULTS: Of the 243 randomized patients, 239 (118 lamotrigine XR, 121 placebo) entered the escalation phase and received study medication. Lamotrigine XR was more effective than placebo with respect to median percent reduction from baseline in weekly partial seizure frequency (primary endpoint-entire 19-week treatment phase: 46.6% vs 24.5%, p = 0.0001 [corrected] via Wilcoxon test; escalation phase: 29.8% vs 15.6%, p = 0.027; maintenance phase: 58.4% vs 26.8%, p [corrected] < 0.0001). The percentage of patients with >or=50% reduction in partial seizure frequency (44.0% vs 20.8%, p = 0.0002) [corrected] and time to >or=50% reduction in partial seizure frequency (p = 0.0001) [corrected] also favored lamotrigine XR over placebo. A similar pattern of results was observed for secondarily generalized seizures. The most common adverse events were headache (lamotrigine XR 16%, placebo 18%) [corrected] and dizziness (lamotrigine XR 19%, [corrected] placebo 5%). Differences between lamotrigine XR and placebo on health outcomes measures were not significant. CONCLUSIONS: Once-daily adjunctive lamotrigine extended-release compared with placebo effectively reduced partial seizure frequency and was well tolerated in this double-blind study. Results support the clinical utility of this new once-daily formulation.

Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures.

OBJECTIVE: To evaluate the efficacy and tolerability of adjunctive lamotrigine in primary generalized tonic-clonic (PGTC) seizures in a randomized, double-blind, placebo-controlled trial. METHODS: Patients with a diagnosis of epilepsy with PGTC seizures who were receiving one or two antiepileptic drugs at study entry were eligible. Patients with partial seizures were excluded on the basis of seizure history and screening EEGs. The study comprised a baseline phase, an escalation phase during which study medication was titrated to a target dose, and a 12-week maintenance phase during which doses of lamotrigine/placebo and concomitant antiepileptic drugs were maintained. RESULTS: Of the 121 randomized patients ages 2 to 55 years, 117 (58 lamotrigine, 59 placebo) entered the escalation phase and received study medication. During the escalation and maintenance phases combined, median percent reduction in PGTC seizure frequency was 66.5% with lamotrigine compared with 34.2% with placebo (p = 0.006). The corresponding numbers for lamotrigine and placebo were 60.6% and 32.8% (p = 0.038) during the escalation phase and 81.9% and 43.0% (p = 0.006) during the maintenance phase. During the maintenance phase, 72% of lamotrigine-treated patients compared with 49% of placebo-treated patients experienced a > or = 50% reduction in frequency of PGTC seizures (p = 0.014). A similar pattern of results was observed for all generalized seizures. The most common drug-related adverse events were dizziness (5% lamotrigine, 2% placebo), somnolence (5% lamotrigine, 2% placebo), and nausea (5% lamotrigine, 3% placebo). CONCLUSIONS: Adjunctive lamotrigine is effective in the treatment of primary generalized tonic-clonic seizures and has a favorable tolerability profile.

The tolerability of lamotrigine in children.

Lamotrigine is a novel anticonvulsant, which has proven to be effective both as add-on and monotherapy. 13 studies have demonstrated efficacy in 1096 children with a variety of seizure types. Tolerability information in these studies was collected in a standard fashion, where investigators reported all adverse events regardless of the perceived relationship to the test therapies. Generally, lamotrigine treatment in these clinical trials was generally given at higher initial doses and faster dose escalations than are currently recommended. Most adverse events associated with lamotrigine were mild to moderate in severity and did not result in discontinuation of treatment. Results from placebo-controlled, add-on trials showed that 85% of lamotrigine recipients experienced an adverse event compared with 83% of placebo recipients. Lamotrigine was associated with an increased risk of adverse events in the nervous system (dizziness, tremor, ataxia, and diplopia), gastrointestinal tract (nausea), and urinary tract (infection). The incidence of most adverse events was lower among lamotrigine recipients in monotherapy trials than in add-on trials, suggesting that concurrent anticonvulsant treatment or drug interactions can be confounding risk factors above that of lamotrigine treatment alone. Skin rash associated with hospitalisation and the discontinuation of study drug was reported more frequently by lamotrigine recipients than by placebo recipients and more frequently by children than by adults. The simultaneous use of valproic acid (sodium valproate) was associated with an increased incidence of rash. Lamotrigine, an effective broad spectrum anticonvulsant, is well tolerated in children. The qualitative features of adverse events that occur with lamotrigine treatment are similar for children and adults. The incidence of rash may be reduced with proper initial dosing and dose escalation.

Rash in adult and pediatric patients treated with lamotrigine.

Data from clinical trials with lamotrigine indicate that the risk of serious rash in pediatric patients is higher than in adults. The incidence of rash associated with hospitalization among adults treated with lamotrigine is 0.3% and among pediatric patients 1.0%. The incidence of cases reported as possible Stevens-Johnson syndrome is 0.1% for adult patients and 0.5% for pediatric patients. These rates reflect lamotrigine dosing and concomitant AEDs used in these trials, both of which are risk factors for rash. Since many of the trials were conducted prior to the establishment of the current dosing recommendations, the incidence of serious rash in clinical trials does not necessarily reflect the incidence to be expected with use of current dosing recommendations. The higher incidence of serious rash in pediatric patients may at least partially be accounted for by the differential effects of the risk factors of dosing and concomitant use of valproic acid in these patients.

Heart period variability during vagal nerve stimulation.

Vagal nerve stimulation is an emerging therapy for epilepsy, yet little is known regarding the effects of this stimulation on heart period variability. We selected 10 patients (two female, eight male) who were receiving high-frequency, high-intensity left vagal nerve stimulation for intractable epilepsy. Electrocardiogram data were recorded for a 7 min baseline, 2.5 min of stimulation and a 7 min post-stimulation period. We found no significant changes in average heart period, instantaneous changes of successive R-to-R intervals greater than 50 ms or fractal dimension. We also found no significant changes in the total power in the 0.0-0.04 Hz, 0.04-0.12 Hz and 0.2-0.4 Hz bands with stimulation of the left vagus nerve. This study suggests that left vagal nerve stimulation has little acute effect on the cardiac rhythm or heart period variability.

Adult experience with lamotrigine.

Lamotrigine is a phenyltriazine derivative with anticonvulsant properties that initially was tested in adults with partial seizures. Pharmacokinetics in adults includes a volume of distribution of 1.0 to 1.3 L/kg. Plasma protein binding is 55% and none of the metabolites are active as anticonvulsants. The placebo-controlled studies evaluated the responder rate as the percent of patients with 50% or greater seizure reduction when compared to baseline assessment. The responder rate for 300 mg per day was 20% and 36% for 500 mg per day dosages. Adverse events were infrequent but the occurrence of rash appeared to correlate with rapid ascension dosing and comedication with valproic acid. Slow titration is required when initiating treatment with lamotrigine. Accumulating experience in adults suggests that lamotrigine has a broad spectrum of effect; data from further controlled trials should suggest other clinically important forms of epilepsy that respond to lamotrigine.

Seizures in lung transplant recipients.

PURPOSE: We wished to assess organ transplant recipients, who incur a significant risk for seizures. METHOD: We reviewed 85 lung transplants performed in 81 patients at the University of North Carolina hospitals between 1991 and 1994. All patients were reviewed for age, reason for transplant, detailed description of seizures, neurological examination, medications, and laboratory results, including cyclosporine level, EEG, and brain imaging. RESULTS: Eighteen of 81 (22%) patients experienced seizures. Patients aged < 25 years had the greatest risk of seizures and 15 of the 18 patients had cystic fibrosis. Sixteen of the 18 (89%) patients, by history, had partial-onset seizures. Eleven of the 18 (61%) patients had seizures < or = 10 days after initiation of intravenous methylprednisolone for allograft rejection. Two patients had seizures associated with sustained hypertension: 1 of these patients was simultaneously being treated for rejection. Four patients had strokes (1 before transplant) and seizures. Two patients were receiving imipenem. Magnetic resonance imaging (MRI) of the brain demonstrated areas of increased T2 signal in 8 of 9 patients. CONCLUSIONS: Our findings demonstrate multiple etiologies for seizures in our transplant recipients. However, we believe that patients, especially those aged < 25 years, being treated with intravenous methylprednisolone for rejection may be at increased risk of seizures. We hypothesize that the focal loss of blood-brain barrier (BBB) may play a significant role in the development of partial seizures in lung transplant recipients.

Improvement of epileptic seizure control with treatment of obstructive sleep apnoea.

Sleep deprivation increases the risk of recurrent seizures in epileptic patients. We identified 10 patients with recurrent seizures and sleep disruption related to obstructive sleep apnoea. Two patients were treated with positional therapy and the remaining eight patients were treated with continuous positive airway pressure. Three of the patients became seizure free and a fourth patient had a greater than 95% reduction in seizure frequency following only the initiation of therapy for the sleep apnoea. Three of these four patients responding to therapy, had a state-dependent seizure pattern. Two of the four responders did not exhibit the typical body habitus for obstructive sleep apnoea. Three additional patients improved in seizure frequency with change in anticonvulsant medication and treatment of the obstructive sleep apnoea. The remaining three patients had less than 50% reduction in seizure frequency with treatment of the obstructive sleep apnoea. These results indicate sleep disruption caused by sleep apnoea may increase the seizure frequency in some epileptic patients. Regardless of body habitus, epilepsy patients should be questioned carefully for a history of sleep disturbance and state dependence to their seizures. Treatment of sleep disorders in this population may lower the frequency of recurrent seizures.

Heart period variability in sleep.

Analysis of heart period variability is a dynamic noninvasive technique to quantify the autonomic control over the heart period. We recorded electroencephalographic, electro-oculographic, electromyographic and electrocardiographic data from 10 normal subjects during sleep using an ambulatory polysomnographic monitor. R-R intervals were determined for 10 min segments of electrocardiographic data from wakefulness, stage 2 sleep, slow wave sleep and REM sleep. Average heart period, instantaneous changes greater than 50 msec and fractal dimension were calculated and the time domain and phase plots were depicted. The R-R interval time domain plots were subsequently analyzed using the discrete Fourier transform. We found sleep stage specific, time domain and frequency domain changes in heart period variability, particularly using spectral analysis of heart period. Increased power in the 0.2-0.4 Hz band was associated with stage 2 sleep when compared to awake and slow wave sleep states. Power in the 0.0-0.04 and 0.04-0.12 Hz bands was increased in association with REM sleep when compared to non-REM sleep, and slow wave sleep had diminished power in all frequency bands. Our results support other investigations demonstrating stage 2 sleep is associated with increased parasympathetic influences and REM sleep is associated with increased sympathetic and neurohumoral influences. We feel that spectral analysis of heart period variability is an effective noninvasive method to quantify changes in the autonomic influences over the heart during sleep.

Lamotrigine.

Lamotrigine (LTG) is a novel antiepileptic drug (AED) with a spectrum of activity in animal models of epilepsy similar to that of phenytoin and carbamazepine. In some models it appears to have a broader spectrum and better tolerability than these agents, however. One mechanism of action of LTG is the marked inhibition of release of the excitatory neurotransmitters glutamate and aspartate under conditions of sustained repetitive firing. LTG appears to do this by blocking voltage-sensitive sodium channels and has no direct effect on N-methyl-D-aspartate (NMDA) receptors. In clinical trials as add-on therapy in medically refractory partial seizure patients, LTG has consistently produced a 50% reduction in seizure frequency in 25-34% of subjects. LTG is well tolerated, even in the add-on situation. In part, this appears to be related to positive behavioral effects. Desirable pharmacologic properties of LTG include low protein binding (55%), an absence of enzyme induction, and linear pharmacokinetics. The most significant adverse effect is rash, leading to a withdrawal rate of 2% of patient exposures in clinical trials.

Venous irritation related to intravenous administration of phenytoin versus fosphenytoin.

STUDY OBJECTIVE: To compare the frequency, severity, and time course of venous irritation after administration of a single intravenous dose of phenytoin with an equimolar dose of fosphenytoin, a water-soluble phenytoin prodrug. DESIGN: Randomized, double-blind, two-period, crossover study. SETTING: University hospital clinical research unit. PATIENTS: Twelve healthy volunteers within 15% of ideal body weight and with no clinically significant abnormalities on physical examination, medical history, or laboratory assessment. INTERVENTIONS: Volunteers randomly received a 30-minute infusion of phenytoin sodium 250 mg (250 mg/5 ml) or an equimolar dose of fosphenytoin 375 mg (375 mg/5 ml). Subjects returned for the crossover treatment 14-21 days later. MEASUREMENTS AND MAIN RESULTS: Subjects assessed venous irritation (pain, burning, itching), and investigators evaluated phlebitis (erythema, swelling, tenderness), induration, exudation, and cording. Phenytoin was associated with a significantly higher degree of pain at the infusion site in all subjects and a significant degree of phlebitis in eight subjects (p < 0.05); cording occurred in six subjects. The time course of phenytoin-induced phlebitis was bimodal. Erythema and tenderness were prominent at the end of the infusion and again at 24 hours. Cording was first noted between 24 hours and 1 week after infusion. In contrast, fosphenytoin was associated with mild pain in two subjects, one incident of phlebitis, and no erythema or cording. CONCLUSIONS: Fosphenytoin administration resulted in significantly less venous irritation and phlebitis compared with an equimolar dose of phenytoin. The clinical use of this water-soluble phenytoin prodrug should minimize the frequency and severity of infusion-site reactions and should allow convenient, rapid, intravenous administration of drug, undiluted or admixed with intravenous solutions.

Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. U.S. Lamotrigine Protocol 0.5 Clinical Trial Group.

We evaluated the efficacy and safety of lamotrigine (300 and 500 mg/day) as add-on therapy in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of 216 patients with refractory partial seizures. During 6 months of treatment, median seizure frequency decreased by 8% with placebo, 20% with 300 mg lamotrigine, and 36% with 500 mg lamotrigine. Seizure frequency decreased by > or = 50% in one-third of the 500-mg group and one-fifth of the 300-mg group. Reductions in seizure frequency and seizure days were statistically significant, compared with placebo, for the 500-mg group but not the 300-mg group. Most adverse events were minor and resolved over time. Nine percent of patients on lamotrigine withdrew because of adverse experiences. Lamotrigine plasma concentrations appeared to be a linear function of dose, and the drug did not affect plasma concentrations of concomitant antiepileptic drugs. Lamotrigine was safe, effective, and well tolerated as add-on therapy for refractory partial seizures.

Vitamin B12 deficiency and nervous system disease in HIV infection.

BACKGROUND: Vitamin B12 deficiency may result in a number of neurological and neuropsychiatric disorders. Patients with human immunodeficiency virus type 1 (HIV-1) infection may have a high rate of vitamin B12 deficiency and nervous system disease. Vitamin B12 deficiency may contribute to neurological disease in HIV-1-infected individuals. OBJECTIVE: To evaluate the possible contribution of vitamin B12 deficiency to neurological disease in HIV-1-infected individuals. MAIN OUTCOME MEASURES: Comparison of serum vitamin B12 levels with neurological, neuropsychological, and mood state abnormalities in 153 HIV-1-positive subjects and 57 high-risk seronegative controls. A subgroup of 67 subjects underwent additional extensive clinical neurophysiological, cerebrospinal fluid, and magnetic resonance imaging evaluations. RESULTS: No statistically significant relationships were noted between vitamin B12 levels and abnormalities on any of the measures examined. CONCLUSIONS: This study does not indicate an important role for vitamin B12 deficiency in the neurological disease of HIV-1 infection.

Felbamate: a double-blind controlled trial in patients undergoing presurgical evaluation of partial seizures.

We studied the efficacy and safety of felbamate, an investigational antiepileptic drug, in a unique, double-blind, placebo-controlled trial. Sixty-four patients with refractory partial-onset seizures who completed a routine evaluation for epilepsy surgery met seizure frequency entry criteria. Each patient received felbamate or placebo in addition to the anticonvulsant regimen present at the conclusion of the presurgical evaluation. The treatment phase consisted of an 8-day inpatient period and a 21-day outpatient period. The efficacy variable was time to fourth seizure. The difference in time to fourth seizure was statistically significant (p = 0.028) in favor of felbamate. Eighty-eight percent of the patients in the placebo group had a fourth seizure during the treatment phase compared with 46% of the patients in the felbamate group (p = 0.001). Adverse experiences with felbamate were generally mild or moderate in severity. This trial demonstrated the ability of felbamate to quickly and safely reduce the occurrence of frequent partial-onset seizures and maintain effective seizure control following reductions in the dosages of standard antiepileptic drugs.

Cerebrospinal fluid analysis in human immunodeficiency virus infection.

Cerebrospinal fluid (CSF) analytes were evaluated in 59 human immunodeficiency virus (HIV+) individuals to assess neurological involvement. Glucose, total protein, cell counts, p24 antigen, CSF: serum albumin/IgG ratios, and oligoclonal bands were measured. Eighty percent of samples showed abnormalities in one or more analyte. In some patients samples, these abnormalities could mimic those of secondary opportunistic infection when none was present. The presence of oligoclonal banding in CSF (31 percent) and disturbances in CSF: serum albumin/IgG ratio (30 percent) were related to decreases in serum CD4+ lymphocytes. Disturbances in CSF: Serum albumin/IgG ratio were also related to severity of non-neurological HIV disease staging. Cerebrospinal fluid oligoclonal bands were distinct from that found in serum in the same subjects. Since immune complexes between immunoglobulins and enzymes are observed in these same patients, these oligoclonal bands may result in artifactually elevated enzyme results secondary to decreased clearance leading to erroneous clinical decisions. There was no significant relationship between any abnormalities and the presence of neurologic disease as established by a wide variety of other studies. It is important to recognize the limits of CSF interpretation in this patient group.

Event-related potentials in human immunodeficiency virus infection. A prospective study.

P3 event-related evoked potentials (ERP) were recorded from 47 human immunodeficiency virus (HIV)-positive subjects examined twice and 29 HIV-positive subjects examined three times at 6-month intervals. The P3 latency significantly increased over time for asymptomatic subjects and subjects with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. N2 latency was prolonged relative to control values in both HIV-positive groups but did not increase with time. The P3 latency correlated with neuropsychologic measures of motor control and speed of mental processing. Confounding factors (active or previous substance abuse, developmental disabilities, and history of closed head injury or epilepsy) did not significantly affect ERP latencies. Endogenous ERP components are frequently abnormal in HIV-positive subjects and the P3 latency progressively increases over time. Continued follow-up is required to determine the clinical utility of ERP studies in the HIV-positive population.

Peripheral neuropathy in a cohort of human immunodeficiency virus-infected patients. Incidence and relationship to other nervous system dysfunction.

A cohort of 94 patients infected with human immunodeficiency virus was evaluated clinically and electrophysiologically for the presence of peripheral neuropathy, and the results were compared with evaluations of central nervous system function. Thirty-two (34%) had some degree of peripheral neuropathy; 18 (19%) (six [12%] of the 49 asymptomatic patients, five [45%] of the 11 patients with acquired immunodeficiency syndrome [AIDS], and seven [21%] of the 34 patients with AIDS-related complex) had neuropathy on clinical examination; and 21 (23%) (eight [16%] asymptomatic, four [36%] AIDS, and nine [26%] AIDS-related complex) had neuropathy on electrophysiologic evaluation. There was a significant correlation between the presence of neuropathy and evidence of central nervous system dysfunction.

Evaluation of the pharmacokinetic interaction between diazepam and ACC-9653 (a phenytoin prodrug) in healthy male volunteers.

The protein binding and pharmacokinetics of diazepam, ACC-9653 (a phenytoin prodrug), and phenytoin were evaluated in nine healthy male volunteers following administration of diazepam and ACC-9653, alone or concomitantly, in a randomized crossover design. No significant differences were observed in the fraction unbound or pharmacokinetic parameters of ACC-9653, phenytoin, or diazepam when ACC-9653 was administered alone compared to concomitant administration with diazepam. The phenytoin fraction unbound increased significantly with increased concentrations of ACC-9653, indicating displacement of phenytoin from its binding sites by ACC-9653. ACC-9653 also demonstrated concentration dependent binding. The lack of a significant pharmacokinetic drug interaction between ACC-9653 and diazepam suggests that these drugs may be safely administered together, although this conclusion should be confirmed in the intended patient population.