Refractory Complex Partial Seizures Research Articles

A concise review on analytical profile of Vigabatrin

Vigabatrin (VGB) is a drug of Anticonvulsant class. It works by decreasing abnormal electrical activity in the brain. It inhibits the GABA-degrading enzyme i.e. GABA transaminase, it increases the GABA concentrations in the brain. Vigabatrin is used for the treatment of refractory complex partial seizures in adults and also used for children 2 years of age and older and infantile spasms in children. Vigabatrin was approved for anticonvulsant medication by USFDA on August 21, 2009. Therefore, in the present review article, we have enlisted different analytical method such as Ultraviolet (UV) visible spectroscopy, High-performance liquid chromatography (HPLC), Ultra-performance liquid chromatography (UPLC) and Gas Chromatography for both qualitative and quantitative analysis of VGB in pharmaceutical and biological. In the future, this review article will assist researchers regarding the development of a new analytical method for VGB.

Rapid determination of plasma vigabatrin by LC-ESI-MS/MS supporting therapeutic drug monitoring in children with infantile spasms.

Vigabatrin is one of the second-generation anti-seizure medications (ASMs) designated orphan drugs by the FDA for monotherapy for pediatric patients with infantile spasms from 1 month to 2 years of age. Vigabatrin is also indicated as the adjunctive therapy for adults and pediatric patients 10 years of age and older with refractory complex partial seizures. Ideally, the vigabatrin treatment entails achieving complete seizure freedom without significant adverse effects, and the therapeutic drug monitoring (TDM) will make a significant contribution to this aim, which provides a pragmatic approach to such epilepsy care in that the dose tailoring can be undertaken for uncontrollable seizures and in cases of clinical toxicity guided by the drug concentrations. Thus, reliable assays are mandatory for TDM to be valuable, and blood, plasma, or serum are the matrixes of choice. In this study, a simple, rapid, and sensitive LC-ESI-MS/MS method for the measurement of plasma vigabatrin was developed and validated. The sample clean-up was performed by an easy-to-use method, i.e., protein precipitation using acetonitrile (ACN). Chromatographic separation of vigabatrin and vigabatrin-13C,d2 (internal standard) was achieved on the Waters symmetry C18 column (4.6 mm × 50 mm, 3.5 μm) with isocratic elution at a flow rate of 0.35 mL min-1. The target analyte was completely separated by elution with a highly aqueous mobile phase for 5 min, without any endogenous interference. The method showed good linearity over the 0.010-50.0 μg mL-1 concentration range with a correlation coefficient r2 = 0.9982. The intra-batch and inter-batch precision and accuracy, recovery, and stability of the method were all within the acceptable parameters. Moreover, the method was successfully used in pediatric patients treated with vigabatrin and also provided valuable information for clinicians by monitoring plasma vigabatrin levels in our hospital.

Therapeutic effect of the mesenchymal stem cells on vigabatrin-induced retinopathy in adult male albino rat.

Vigabatrin (VGB) is an effective antiepileptic drug used mainly to treat infantile spasms and refractory complex partial seizures. However, using VGB was restricted as it was known to cause retinal toxicity that appears as a severe peripheral visual field defect. Accordingly, this study was conducted to examine the histopathological and biochemical effects of VGB on the retina in adult male albino rats and assess the possible therapeutic role of mesenchymal stem cells (MSCs) against this potential toxicity. The rats were divided into three groups (control group, VGB group, and VGB/MSCs group), one week after 65 days of VGB treatment ±MSCs. The right eyeballs were prepared for histological and immunohistochemical examination, whereas the left eyeballs were prepared for real-time polymerase chain reaction analysis. Our results demonstrated that MSCs ameliorated retinal pathological changes and downregulated the expression of glial fibrillary acidic protein, vascular endothelial growth factor, and synaptophysin after VGB administration suggesting MSCs function and vascular modulating effect. Moreover, MSCs regulate retinal tissue gene expression of BAX, Bcl-2, BDNF, NGF, synapsin, interleukin (IL)-6, IL-1β, and occludin suggesting MSCs antiapoptotic and immunomodulating effect. In conclusion, MSCs administration could be a suitable therapeutic line to ameliorate VGB-induced retinopathy.

OV329, a novel highly potent γ-aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala-kindled rats.

An attractive target to interfere with epileptic brain hyperexcitability is the enhancement of γ-aminobutyric acidergic (GABAergic) inhibition by inactivation of the GABA-metabolizing enzyme GABA aminotransferase (GABA-AT). GABA-AT inactivators were designed to control seizures by raising brain GABA levels. OV329, a novel drug candidate for the treatment of epilepsy and addiction, has been shown in vitro to be substantially more potent as a GABA-AT inactivator than vigabatrin, an antiseizure drug approved as an add-on therapy for adult patients with refractory complex partial seizures and monotherapy for pediatric patients with infantile spasms. Thus, we hypothesized that OV329 should produce pronounced anticonvulsant effects in two different rat seizure models. We therefore examined the effects of OV329 (5, 20, and 40mg/kg ip) on the seizure threshold of female Wistar Unilever rats, using the timed intravenous pentylenetetrazole (ivPTZ) seizure threshold model as a seizure test particularly sensitive to GABA-potentiating manipulations, and amygdala-kindled rats as a model of difficult-to-treat temporal lobe epilepsy. GABA-AT inactivation by OV329 clearly increased the threshold of both ivPTZ-induced and amygdala-kindled seizures. OV329 further showed a 30-fold greater anticonvulsant potency on ivPTZ-induced myoclonic jerks and clonic seizures compared to vigabatrin investigated previously. Notably, all rats were responsive to OV329 in both seizure models. These results reveal an anticonvulsant profile of OV329 that appears to be superior in both potency and efficacy to vigabatrin and highlight OV329 as a highly promising candidate for the treatment of seizures and pharmacoresistant epilepsies.

Effectiveness of Reaction Time Training & Physical Exercises on Rt & Quality of Life of Epileptics- A Case Series

Quality of Life of Epileptics- A Case SeriesVaijanti JainJr O.T (KEMH) BothAbstractAim: To study Effectiveness of Reaction time training & physical exercises on RT & quality of life ofEpileptics- a case series.Objectives: Finding the effect of RT training & physical exercises on Reaction time (RT) & quality of life(QOL) in Complex partial seizures (CPS)Methodology: 4 subjects (OPD patients,OT dept KEMH) age 20-40 yrs, of Refractory CPS with or withoutsecondary generalization with atleast three years of period of onset were included in a 4 week study. TheOutcome was measured on RT machine, WHO BREF QOL questionnaire, Mini Mental status examination(MMSE) & neurological evaluation. Pre & post intervention changes were assessed with RT machine &WHO BREF QOL questionnaire. The Occupational therapy intervention consisted of 30-45 mins of trainingon 1) RT simulated machine & activities & 2)physical activities twice a week with home programme.Results: The (paired) t value of post intervention RT is 4.0691 (significant at p=0.05). The (paired) t values ofdifferences in individual domain scores for physical domain =23.0638 (significant at p=0.001),psychological=5.6949 (significant at p=0.02) & social =3.4762 ((significant at p=0.05). The study suggests a definiteavenue for OT intervention in patients with epilepsy.Conclusion: RT & QOL can be improved using RT training & Physical exercises. However a study has tobe done on larger sample size with a longer follow up to confirm the efficacy of the study

Vigabatrin: Lessons Learned From the United States Experience.

Vigabatrin was introduced as an antiseizure medication in the United Kingdom in 1989 and was extensively used until 1997 when concerns arose regarding peripheral visual field loss. When the drug was approved in the United States in 2009, it carried a black box warning for the risk of permanent visual loss, and the pharmaceutical company was mandated to create a drug registry to assess for visual deficits. The vigabatrin drug registry has documented a relatively large percentage (37%) of preexisting, baseline visual deficits and a paucity (2%) of potential new visual findings. The vigabatrin vision study, a prospective, longitudinal, single-arm, open-label study, confirmed that adult patients with refractory complex partial seizures had a large number of visual deficits at baseline. An unexpected finding during the first year of therapy with vigabatrin was an increase in retinal thickness on optical coherence tomography. The experience from vigabatrin in the United States emphasizes the importance of baseline eye findings when considering the potential of drug toxicity involving the visual pathways.

Vigabatrin Lacks Proarrhythmic Potential: Results from a Thorough QT/QTc Study in Healthy Volunteers

PurposeA thorough QT study was performed to assess the proarrhythmic potential of vigabatrin, an antiepileptic drug approved in the United States for the treatment of infantile spasms and refractory complex partial seizures. MethodsIn this Phase I, randomized, double-blind, placebo- and active-controlled (moxifloxacin), 4-sequence, crossover study conducted at a single center, healthy participants received 1 of 4 randomly assigned treatments: 3.0g vigabatrin solution (therapeutic dose) and 1 moxifloxacin placebo tablet; 6.0g vigabatrin solution (supratherapeutic dose) and 1 moxifloxacin placebo tablet; 400 mg moxifloxacin and vigabatrin placebo solution; moxifloxacin placebo tablet and vigabatrin placebo solution. FindingsMean changes from baseline in placebo-corrected QTcF, QTcB, and QTcI with vigabatrin 3.0 g and 6.0 g indicated no signal for any QTc effect relative to baseline. All 1-sided upper 95% confidence intervals for the differences between each vigabatrin dose and placebo were <10 ms at all time points. QTcF was unaffected by increasing plasma vigabatrin concentrations; no arrhythmias were observed in any treatment group. Low rates of first-degree atrioventricular block, sinus tachycardia, and sinus bradycardia occurred in all treatment groups. Most adverse events were mild. ImplicationsThe findings from this thorough QT study are consistent with existing clinical data and confirm a lack of proarrhythmic potential of vigabatrin.

Retinal structure and function in vigabatrin‐treated adult patients with refractory complex partial seizures

Evaluate visual-field and retinal-structure changes following adjunctive vigabatrin treatment in vigabatrin-naive adults with refractory complex partial seizures (rCPS). Prospective, longitudinal, single-arm, open-label study (NCT01278173). Eligible patients (≥2 seizures/month who failed ≥3 therapies) who could reliably perform perimetry (Humphrey automated static) and retinal-structure assessment (spectral-domain optical coherence tomography) prior to vigabatrin exposure. Following vigabatrin initiation, testing occurred within 1 month (reference) and 3, 6, 9, and 12 months. End points included mean change from reference in mean deviation (dB) and average retinal nerve fiber layer (RNFL) thickness, visual-acuity changes from baseline, and number of patients who met predefined vision-parameter changes at two (confirmed) or three (persistent) consecutive visits. Sixty-five of 91 screened patients received ≥1 vigabatrin dose (all-patients-treated set [APTS]); 55 had valid reference and ≥1 post-reference assessments (full-analysis set [FAS]). Thirty-six APTS patients with valid pre-/post-reference values completed all planned visits (per-protocol set [PPS]). Thirty-eight (59%) APTS patients completed the study; 27 (42%) withdrew (none for visual-field changes); 32% and 15% had abnormally thin RNFL and abnormal visual acuity at baseline, respectively; 20% had abnormal central 30 degree visual fields in the reference period. No significant mean near visual-field changes were observed (PPS); mean change in average RNFL thickness increased significantly (1-year data: Left-eye: 6.37 μm, confidence interval (CI) 4.66-8.09; right-eye: 7.24 μm CI 5.47-9.01; PPS). No confirmed three-line decreases in visual acuity (FAS) were observed; five patients had predefined confirmed/persistent visual-field changes (FAS). All vision-related adverse events were nonserious; the most common was vision blurred (9%). Prior to vigabatrin initiation, rCPS patients may already exhibit vision deficits. Up to 1 year of adjunctive vigabatrin treatment did not significantly change population near visual fields. Five patients met predefined visual-field-change criteria. RNFL thickening of unknown clinical significance was observed. Limitations include single-arm, open-label design; patients' inability to perform ophthalmic/visual-field examinations; and limited vigabatrin-exposure duration.

Which children receive vigabatrin? Characteristics of pediatric patients enrolled in the mandatory FDA registry.

Vigabatrin (Sabril®) is an antiepileptic drug (AED) currently indicated in the US as a monotherapy for patients 1month to 2years of age with infantile spasms (IS) and as adjunctive therapy for patients ≥10years of age with refractory complex partial seizures (rCPS) whose seizures have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss. The approval required an FDA mandated registry. This article describes 5years of demographic and treatment exposure data from US pediatric patients (<17years). Participation is mandatory for all US Sabril® prescribers and patients. A benefit-risk assessment must be documented for patient progression to maintenance therapy. This includes demographic diagnosis and reports of ophthalmologic assessments (where available). Patient data were grouped by age as proxies for indication (IS: <3years, rCPS: ≥3 to <17years). As of August 26, 2014, 5546/6823 enrolled patients were pediatric/total; 4472 (81%) were vigabatrin-naïve. Seventy-one percent of patients were <3years of age; 29% were ≥3 to <17years of age. Etiologies of IS were identified as cryptogenic (21%), symptomatic tuberous sclerosis (17%), and symptomatic other (42%). The majority of patients with IS (56%) attempted no prior treatments; 16% received adrenocorticotropic hormone prior to vigabatrin. A third of patients with IS were receiving 1 concomitant treatment with vigabatrin. For patients with rCPS, 39% attempted 1-3 prior treatments; 27% were receiving 2 concomitant treatments at enrollment. A total of 1852 (41%) patients did not undergo baseline ophthalmological assessment; 25% of patients with IS and 42% of patients with rCPS were exempted for neurologic disabilities. Kaplan-Meier estimates predict that 71% and 65% of vigabatrin-naïve patients with IS and rCPS, respectively, would remain in the registry at 6months. Most pediatric vigabatrin patients have IS as an underlying diagnosis, especially those <3years of age. A proportion of those with rCPS remain on long-term vigabatrin despite the risk of adverse events.

Sabril Vision Study: Retinal Structure and Function in Adult Patients with Refractory Complex Partial Seizures (rCPS) Treated with Vigabatrin (S14.004)

Sabril Vision Study: Retinal Structure and Function in Adult Patients with Refractory Complex Partial Seizures (rCPS) Treated with Vigabatrin (S14.004)

Sabril® registry 5-year results: Characteristics of adult patients treated with vigabatrin.

Vigabatrin (Sabril®), approved in the US in 2009, is currently indicated as adjunctive therapy for refractory complex partial seizures (rCPS) in patients ≥ 10 years old who have responded inadequately to several alternative treatments and as monotherapy for infantile spasms (IS) in patients 1 month to 2 years of age. Because of reports of vision loss following vigabatrin exposure, FDA approval required a risk evaluation mitigation strategy (REMS) program. Vigabatrin is only available in the US through Support, Help, And Resources for Epilepsy (SHARE), which includes a mandated registry. This article describes 5 years of demographic and treatment exposure data from adult patients (≥ 17 years old) in the US treated with vigabatrin and monitored in the ongoing Sabril® registry. Registry participation is mandatory for all US Sabril® prescribers and patients. A benefit-risk assessment must be documented by the physician for a patient to progress to maintenance therapy, defined as 1 month of vigabatrin treatment for patients with IS and 3 months for patients with rCPS. Ophthalmologic assessments must be documented during and after completion of therapy. As of August 26, 2014, a total of 6823 patients were enrolled in the registry, of which 1200 were adults at enrollment. Of these patients, 1031 (86%) were naïve to vigabatrin. The majority of adult patients (n=783, 65%) had previously been prescribed ≥ 4 AEDs, and 719 (60%) were receiving ≥ 3 concomitant AEDs at vigabatrin initiation. Prescribers submitted an initial ophthalmological assessment form for 863 patients; an ophthalmologic exam was not completed for 300 (35%) patients and thus, were considered exempted from vision testing. Of these patients, 128 (43%) were exempted for neurologic disabilities. Clinicians discontinued treatment in 8 patients because of visual field deficits (VFD) (5 patients naïve to vigabatrin and 3 patients previously exposed). Based on Kaplan-Meier survival estimates, it is estimated that approximately 71%, 55%, and 40% of adult patients naïve to vigabatrin would remain in the registry at 3, 6, and 12 months, respectively. These demographic data suggest that a proportion of adult patients remain on vigabatrin long-term despite the risks of adverse events and significant underlying AED resistance and neurologic disease.

Interictal dysphoric disorder in patients with localization-related epilepsy: Diagnostic relationships with DSM-IV psychiatric disorders and the impact of psychosocial burden.

Some patients with epilepsy develop intermittent and pleomorphic affective-somatoform symptoms, termed interictal dysphoric disorder (IDD). Other psychiatric disorders have been extensively investigated in patients with epilepsy, but there are few clinical studies investigating the comorbidity patterns of IDD and common psychiatric disorders (PDs). In particular, the impact of IDD on the psychosocial burden of patients remains unclear. The participants were 128 adult Japanese outpatients with localization-related epilepsy (LRE). In order to determine the comorbidity patterns for IDD and PDs, we conducted a comprehensive diagnostic investigation for IDD and DSM-IV psychiatric disorders. Based on these analyses, participants were divided into groups according to the comorbidity patterns for IDD and PDs in order to compare both suicide risk and quality of life (QOL). The findings indicated that 19.5% of participants had IDD, and 55.5% had PDs. Younger age at epilepsy onset and refractory complex partial seizures were associated with IDD, but the duration and type of epilepsy were not. Patients with IDD were more likely to have comorbid PDs as follows: mood disorders (odds ratio, OR: 8.30; 95% confidence interval, CI: 3.15-21.83), anxiety disorders (OR: 8.81; 95% CI: 3.30-23.49), and psychotic disorders (OR: 7.72; 95% CI: 2.83-21.06). Group comparisons demonstrated that there were no patients with IDD but without PD. Furthermore, patients with IDD and with PDs had a significantly higher suicide risk and lower QOL compared to the other groups, even after adjusting for the influences of confounding factors. Interictal dysphoric disorder adds extreme psychosocial burden and is associated with multiple PDs in patients with LRE. The present study suggests that IDD has a specific prognostic significance. However, whether IDD is nosologically independent from conditions diagnosed using standardized psychiatric diagnostic systems such as DSM-IV must be further assessed by future research.

Vigabatrin pediatric dosing information for refractory complex partial seizures: results from a population dose-response analysis.

We predicted vigabatrin dosages for adjunctive therapy for pediatric patients with refractory complex partial seizures (rCPS) that would produce efficacy comparable to that observed for approved adult dosages. A dose-response model related seizure-count data to vigabatrin dosage to identify dosages for pediatric rCPS patients. Seizure-count data were obtained from three pediatric and two adult rCPS clinical trials. Dosages were predicted for oral solution and tablet formulations. Predicted oral solution dosages to achieve efficacy comparable to that of a 1g/day adult dosage were 350 and 450mg/day for patients with body weight ranges 10-15 and >15-20kg, respectively. Predicted oral solution dosages for efficacy comparable to a 3g/day adult dosage were 1,050 and 1,300mg/day for weight ranges 10-15 and >15-20kg, respectively. Predicted tablet dosage for efficacy comparable to a 1g/day adult dosage was 500mg/day for weight ranges 25-60kg. Predicted tablet dosage for efficacy comparable to a 3g/day adult dosage was 2,000mg for weight ranges 25-60kg. Vigabatrin dosages were identified for pediatric rCPS patients with body weights ≥10kg.

Population dose-response analysis of daily seizure count following vigabatrin therapy in adult and pediatric patients with refractory complex partial seizures.

Vigabatrin is an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T) and is used as an adjunctive therapy for adult patients with refractory complex partial seizures (rCPS). The purpose of this investigation was to describe the relationship between vigabatrin dosage and daily seizure rate for adults and children with rCPS and identify relevant covariates that might impact seizure frequency. This population dose-response analysis used seizure-count data from three pediatric and two adult randomized controlled studies of rCPS patients. A negative binomial distribution model adequately described daily seizure data. Mean seizure rate decreased with time after first dose and was described using an asymptotic model. Vigabatrin drug effects were best characterized by a quadratic model using normalized dosage as the exposure metric. Normalized dosage was an estimated parameter that allowed for individualized changes in vigabatrin exposure based on body weight. Baseline seizure rate increased with decreasing age, but age had no impact on vigabatrin drug effects after dosage was normalized for body weight differences. Posterior predictive checks indicated the final model was capable of simulating data consistent with observed daily seizure counts. Total normalized vigabatrin dosages of 1, 3, and 6 g/day were predicted to reduce seizure rates 23.2%, 45.6%, and 48.5%, respectively.

Population pharmacokinetics analysis of vigabatrin in adults and children with epilepsy and children with infantile spasms.

Vigabatrin is an inhibitor of γ-aminobutyric acid transaminase. The purpose of these analyses was to develop a population pharmacokinetics model to characterize the vigabatrin concentration-time profile for adults and children with refractory complex partial seizures (rCPS) and for children with infantile spasms (IS); to identify covariates that affect its disposition, and to enable predictions of systemic vigabatrin exposure for patients 1-12months of age. Vigabatrin pharmacokinetic data from six randomized controlled clinical trials and one open-label study were analyzed using nonlinear mixed-effects modeling. Data collected from 349 adults with rCPS and 119 pediatric patients with rCPS or IS were used in the analyses. A two-compartment model with first-order elimination and transit-compartment absorption consisting of five transit compartments adequately described the vigabatrin concentration-time data for these adult and pediatric patient populations. An exponential error model was used to estimate inter-individual variability for the transit-rate constant (k tr) (24.2%), elimination rate constant (k) (14.7%) and apparent central volume of distribution (V c/F) (18%). For the study of children with IS, inter-occasion variability was estimated for k tr (58.1%) and relative bioavailability (F) (26.9%). Covariate analysis indicated that age, creatinine clearance (CLCR), and body weight were important predictors of vigabatrin pharmacokinetic parameters. Vigabatrin apparent clearance increased with increasing CLCR, consistent with renal excretion (primary pathway of vigabatrin elimination). Rate of vigabatrin absorption was dependent on age. The rate was slower in younger patients, which resulted in a smaller predicted maximum concentration and longer predicted time to maximum concentrations. Vigabatrin V c/F, apparent inter-compartmental clearance between the central and peripheral compartment, and apparent peripheral volume of distribution were increased with greater patient body weights. Sex did not contribute significantly to vigabatrin pharmacokinetic variability. The model adequately described vigabatrin pharmacokinetic and enabled predictions of systemic exposures in pediatric patients 1-12months of age.

Utility of ocular coherence tomography in monitoring vigabatrin retinal toxicity

Vigabatrin, FDA-approved in 2009 to treat refractory complex partial seizures in adults and infantile spasms, may cause permanent peripheral visual field (VF) loss. VF testing is the most sensitive way to detect vigabatrin toxicity but is often not feasible in children. Fundus examination alone does not detect early changes, and electroretinogram (ERG) is difficult to perform in young children and displays wide variations among normal subjects in this age group. Ocular coherence tomography (OCT) objectively measures retinal nerve fiber layer thickness (rNFLT) and may aid in detecting early vigabatrin toxicity in children.

Retinal Structure and Function in Adults with Refractory Complex Partial Seizures (rCPS) Treated with Vigabatrin: Initial Results of the Sabril Vision Study (P6.286)

Retinal Structure and Function in Adults with Refractory Complex Partial Seizures (rCPS) Treated with Vigabatrin: Initial Results of the Sabril Vision Study (P6.286)

Modelling the Risk of Visual Field Loss Arising from Long-Term Exposure to the Antiepileptic Drug Vigabatrin: A Cross-Sectional Approach

The antiepileptic drug vigabatrin has been used widely since 1989, but has only been approved for use in the US since 2009. The risk:benefit of vigabatrin is generally predicated upon an assumed frequency of associated visual field loss (VAVFL) of approximately 31%. This estimate is based upon relatively short-term usage (up to 4-5years) and it is essential to determine whether the frequency of VAVFL increases with longer-term usage. The aim of this study was to model, from cross-sectional evidence, over greater ranges of treatment duration and cumulative dose than previously evaluated, the risk (frequency) of VAVFL with increasing exposure to vigabatrin. This was a retrospective cohort study undertaken in a regional hospital epilepsy clinic. The cohort comprised 147 consecutive patients treated with vigabatrin for refractory complex partial (focal) seizures, who had all undergone ophthalmological examination and who had undertaken perimetry, reliably, according to a standard and robust protocol. The visual field plots were evaluated masked to treatment duration and dose. The risk (frequency) of VAVFL with increasing exposure to vigabatrin was modelled, from the cross-sectional evidence, by standard and plateau logistic regression. The cohort comprised 80 females and 67 males (mean age 40.3years, standard deviation 13.7). The median duration of vigabatrin exposure was 7.9years (interquartile range 3.6-11.0, range 0.2-16.1years); 46 patients (31%) had received vigabatrin for over 10years. Eighty-seven patients (59%) exhibited VAVFL; the proportion with VAVFL was higher in males (66%) than females (54%). The plateau model for duration and for cumulative dose exhibited a better fit than the standard model (both p<0.001). The modelled frequency of VAVFL increased with increasing exposure up to approximately 6years duration and 5kg cumulative dose, and plateaued at approximately 76% (95% CI 67-85) and 79% (95% CI 70-87), respectively. Severity of VAVFL, classified in terms of the visual field index Mean Deviation, was not significantly associated with either duration or cumulative dose of therapy. Clinicians and patients, in enabling informed choice, should be alert to the possible substantial increased risk:benefit for VAVFL with increasing long-term exposure to vigabatrin and the ensuing increased cost:benefit resulting from the necessary additional visual assessments.

Long-term radiosurgery effects in the treatment of temporal lobe epilepsy

Epilepsy surgery is an effective treatment for medically resistant temporal lobe epilepsy (TLE). To minimize complication rates and potentially improve neuropsychology outcomes, stereotactic radiosurgery (SRS) has been explored as an alternative. Two pilot trials have demonstrated the effectiveness of SRS for the treatment of medically resistant TLE, with seizure-free outcomes for approximately 65% of patients at last follow-up. Despite encouraging results, no conclusive long-term outcomes are available for SRS. This article discusses a single patient who presented with recurrent seizures, worsening headaches, and persistent abnormal MRI findings 7 years and 8 months after SRS. This 29-year-old woman with a history of medically refractory complex partial seizures since childhood was referred for evaluation. Medical management had failed in this patient. The workup was compatible with left mesial temporal lobe onset, with MRI findings suggestive of mesial temporal sclerosis. In 2003, at the age of 23 years, she underwent Gamma Knife surgery (GKS) targeting the left temporal mesial area with a dose of 24 Gy at the 50% marginal isodose line. After GKS, the patient's seizures decreased in frequency over several months, but auras were persistent. Nine months after treatment, she developed worsening headaches. A follow-up MRI study demonstrated a thick, irregular, enhancing lesion in the medial part of the temporal lobe. She was placed on corticosteroids, with resolution of her headaches. Her seizures and headaches recurred in March 2010. An MRI study showed a 2.2-cm, ill-defined, enhancing cystic lesion in the left mesial temporal lobe with T2 and FLAIR hyperintensity, which was presumably radiation induced. At that time, the patient opted for left temporal lobe resection to control her seizures. Histological examination showed moderately severe, remote, longstanding sclerosis at the level of the hippocampus. A vascular lesion was identified, and it was most consistent with radiation-induced capillary hemangioma. The entorhinal region was severely damaged, with hemorrhage, necrosis, neuronal loss, astrogliosis, and hemosiderin deposition. There was evidence of radiation vasculopathy. Radiation-induced lesions after SRS for the treatment of epilepsy are not well documented. Although GKS is a promising technique for the treatment of medically resistant TLE, the ideal candidate is not yet well defined. The selection of the appropriate technical parameters to obtain a desirable functional effect without histological damage to the surrounding neural tissue remains a challenge. This case illustrates the need for long-term follow-up when radiosurgery is used for epilepsy.

Phase IV Vision Study Evaluates Retinal Structure and Function in Adult Patients with Refractory Complex Partial Seizures Treated with Vigabatrin (P07.255)

Objective: To evaluate change in retina structure and function in vigabatrin-naive patients, we initiated a prospective, 1-year open-label trial in patients requiring vigabatrin treatment. Background An important safety issue for vigabatrin is risk of bilateral concentric constriction of visual fields. Design/Methods: ∼80 patients with rCPS for ≥1 year (with ≥2 seizures/month averaged over prior 3 months) will be enrolled at ∼25 US sites. Patients must have failed ≥3 prior therapies for lack of efficacy and must be receiving concomitant AEDs. Vigabatrin-naive patients ≥18 years of age will have visual static perimetry and optical coherence tomography (OCT) assessments at baseline, and 3, 6, 9, and 12 months following vigabatrin initiation. Key endpoints include change from reference value in field width (static perimetry), and change from reference value in retinal nerve fiber layer thickness (OCT and macular thickness OCT). After commencing vigabatrin, patients are assessed every 3 months through automated static perimetry (both standard 30-2 and horizontal meridian full field), OCT, and ancillary exploratory visual endpoints such as visual acuity, color vision, and visual fields by Tangent Corner Test. If deficits are discovered, investigators conduct benefit/risk assessments with patients. Results: By October 2011, 8 sites had been initiated. Screening was initiated for 8 patients. Five were screen failures, and three patients were enrolled. Of these three, two are ongoing study participants, and one was an early termination (seizures returned to baseline rate and patient was discontinued following benefit/risk assessment). One patient had abnormal baseline OCT results (before vigabatrin therapy), emphasizing that patients may have pre-existing afferent visual system conditions. Conclusions: This study is designed to provide a better definition of onset and progression of peripheral visual field defects, to assess the risk of developing vision loss during first year of exposure, and to evaluate OCT for monitoring retinal changes. Supported by: Lundbeck Inc. Disclosure: Dr. Sergott has received personal compensation for activities with Pfizer, Serono, Lundbeck, and Centocor as a speaker and consultant. Dr. Sergott has received personal compensation in an editorial capacity for Current Opinion in Neuro-Opthamology. Dr. Faught has received personal compensation for activities with Pfizer Inc, UCB Pharma, Ortho-McNeil Pharmaceutical, Inc., Valeant Pharmaceuticals, Ovation Pharmaceuticals, Inc., GlaxoSmithKline, Inc., Abbott Laboratories, Inc., and Novartis as a consultant or speaker. Dr. Faught has received research support from Eisai Inc., Marinus, Ortho-McNeil Pharmaceutical, Inc., and Schwarz Biosciences. Dr. Torri has received personal compensation for activities with Lundbeck Research USA as an employee. Dr. Wesche has received personal compensation for activities with Lundbeck Research USA, Inc as an employee.