Preferential accumulation of the active S-(+) isomer in murine retina highlights novel mechanisms of vigabatrin-associated retinal toxicity.

((S)-(+)/(R)-(-)) vigabatrin (SabrilR; γ-vinyl GABA), an antiepileptic irreversibly inactivating GABA-transaminase, was administered to male C57Bl6 J mice via continuous infusion (0, 40, 80 mg/kg/d) for 12 days. Our study design pooled retina, eye (minus retina), whole brain and plasma from n = 24 animals for each dose to provide n = 8 triplicates per treatment group. Hypothesizing that (S)-(+) VGB (active isomer) would preferentially accumulate in retina, we determined VGB isomers, comprehensive amino acids, and pharmacokinetic parameters. In brain, eye and plasma, the ((S)-(+)/(R)-(-)) ratio varied from 0.73 to 1.29 and 13.3 in retina, accompanied by a partition coefficient (tissue/plasma, ((S)-(+);(R)-(-))) of 5.8;0.34, 0.63;0.49, and 0.51;0.34 in retina, eye and brain, respectively. Racemic VGB (nmol/g; plasma, nmol/mL, range of means for dose) content was: retina, 25-36; eye (minus retina), 4.8-8.0; brain, 3.1-6.8 and plasma, 8.7-14.9. GABA tissue content (nmol/g) was 1246-3335, 18-64 and 2615-3200 as a function of VGB dose for retina, eye (minus retina) and brain, respectively. The retinal glial cell toxin 2-aminoadipic acid also increased with VGB dose (76-96 nmol/g). Partitioning of active (S)-(+) VGB to retina suggests the involvement of a stereospecific transporter, the identification of which could reveal new therapeutic paradigms that might mitigate VGB's well-known retinal toxicity and expand its clinical utility.

Fulminant vigabatrin toxicity during combination therapy with adrenocorticotropic hormone for infantile spasms: Three cases and review of the literature.

Vigabatrin (VGB), adrenocorticotropic hormone (ACTH), and prednisone are first-line treatments for infantile spasms (IS). A recent study reported benefits from the use of combination VGB and hormonal therapy over hormonal treatment alone in IS. We describe three patients with IS who developed acute encephalopathy with extrapyramidal symptoms, vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM), and death in one patient shortly after initiation of therapy with VGB and ACTH. A literature review supports increased risk of fulminant, symptomatic VABAM in patients receiving VGB in association with hormonal therapy, raising concerns regarding its safety in IS.

mTOR Inhibition Mitigates Molecular and Biochemical Alterations of Vigabatrin-Induced Visual Field Toxicity in Mice.

BACKGROUND: Gamma-vinyl-γ-aminobutyric acid (GABA) (vigabatrin) is an antiepileptic drug and irreversible GABA transaminase inhibitor associated with visual field impairment, which limits its clinical utility. We sought to relate altered visual evoked potentials associated with vigabatrin intake to transcriptional changes in the mechanistic target of rapamycin (mTOR) pathway and GABA receptors to expose further mechanisms of vigabatrin-induced visual field loss. METHODS: Vigabatrin was administered to mice via an osmotic pump for two weeks to increase GABA levels. Visual evoked potentials were examined, eye samples were collected, and gene expression was measured by quantitative reverse transcription-polymerase chain reaction. Similarly, human retinal pigment epithelial cells (ARPE19) were exposed to vigabatrin and treated with mTOR inhibitors for mTOR pathway analysis and to assess alterations in organelle accumulation by microscopy. RESULTS: Dysregulated expression of transcripts in the mTOR pathway, GABAA/B receptors, metabotropic glutamate (Glu) receptors 1/6, and GABA/glutamate transporters in the eye were found in association with visual evoked potential changes during vigabatrin administration. Rrag genes were upregulated in both mouse eye and ARPE19 cells. Immunoblot of whole eye revealed greater than three fold upregulation of a 200 kDa band when immunoblotted for ras-related guanosine triphosphate binding D. Microscopy of ARPE19 cells revealed selective reversal of vigabatrin-induced organelle accumulation by autophagy-inducing drugs, notably Torin 2. Changes in the mTOR pathway gene expression, including Rrag genes, were corrected by Torin 2 in ARPE19 cells. CONCLUSIONS: Our studies, indicating GABA-associated augmentation of RRAG and mTOR signaling, support further preclinical evaluation of mTOR inhibitors as a therapeutic strategy to potentially mitigate vigabatrin-induced ocular toxicity.

Optical coherence tomography to monitor vigabatrin toxicity in children.

PURPOSE: The antiepileptic drug vigabatrin is known to cause permanent loss of vision. Both visual field testing and electroretinogram are used to detect retinal damage. Adult data on optical coherence tomography (OCT) shows that retinal nerve fiber layer (RNFL) thinning may be an early indicator of vigabatrin-induced retinal toxicity. The purpose of this study was to investigate whether OCT can detect early vigabatrin-induced retinal toxicity in children. METHODS: Pediatric patients (≤18 years of age) requiring vigabatrin for seizure control who were followed at our institution were invited to participate. Patients were examined according to manufacturer guidelines, with most examinations taking place under general anesthesia. RNFL thickness was measured by OCT (Stratus Model 3000, Zeiss) and compared to total cumulative dose of vigabatrin. In most cases, indirect ophthalmoscopy, fundus photography, and electroretinography were also performed. RESULTS: OCT and complete dosing data was available for 19 patients. Patients with tuberous sclerosis (TS, n = 12) received higher cumulative doses (mean, 1463 g) than non-TS patients (mean, 351 g, P = 0.044). RNFL thinning was detected in the nasal (P < 0.01), superior (P < 0.01), and inferior (P < 0.05) quadrants in patients with TS, particularly once cumulative dose exceeded 1500 g. CONCLUSIONS: In our study population of patients with TS, higher cumulative doses of vigabatrin were associated with RNFL thinning in the nasal, superior, and inferior quadrants. These findings were pronounced once cumulative dose exceeded 1500 g. This pattern of RNFL thinning is similar to what has been shown in adult patients taking vigabatrin.

Genotoxic and mutagenic effects of vigabatrin, a γ-aminobutyric acid transaminase inhibitor, in Wistar rats submitted to rotarod task.

Vigabatrin (VGB) is an antiepileptic drug thatincreases brain γ-aminobutyric acid (GABA) levels through irreversible inhibition of GABA transaminase. The aim of this study was to evaluate neurotoxicological effects of VGB measuring motor activity and genotoxic and mutagenic effects after a single and repeated administration. Male Wistar rats received saline, VGB 50, 100, or 250 mg/kg by gavage for acute and subchronic (14 days) treatments and evaluated in the rotarod task. Genotoxicity was evaluated using the alkaline version of the comet assay in samples of blood, liver, hippocampus, and brain cortex after both treatments. Mutagenicity was evaluated using the micronucleus test in bone marrow of the same animals that received subchronic treatment. The groups treated with VGB showed similar performance in rotarod compared with the saline group. Regarding the acute treatment, it was observed that only higher VGB doses induced DNA damage in blood and hippocampus. After the subchronic treatment, VGB did not show genotoxic or mutagenic effects. In brief, VGB did not impair motor activities in rats after acute and subchronic treatments. It showed a repairable genotoxic potential in the central nervous system since genotoxicity was observed in the acute treatment group.

Glutamatergic synapse protein composition of wild-type mice is sensitive to in utero MTHFR genotype and the timing of neonatal vigabatrin exposure.

The enzyme methylenetetrahydrofolate-reductase (MTHFR) is part of the homocysteine and folate metabolic pathways. In utero, Mthfr-deficient environment has been reported as a risk factor for neurodevelopmental disorders such as autism and neural tube defects. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between Mthfr deficiency and neonatal exposure to the GABA-potentiating drug vigabatrin (GVG) in mice alters anxiety, memory, and social behavior in a gender-dependent manner. In addition, a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the cerebral cortex was shown. Here we show that in utero MTHFR deficiency is sufficient to alter the levels of glutamate receptor subunits GluR1, GluR2, and NR2B in the cerebral cortex and hippocampus of adult offspring with a WT genotype. In addition, FMRP1, CAMKII α and γ, and NLG1 levels in WT offspring were vulnerable to the in utero genotype. These effects depend on brain region and the cellular compartment tested. The effect of in utero MTHFR deficiency varies with the age of neonatal GVG exposure to modify GluR1, NR2A, reelin, CAMKII α, and NLG1 levels. These changes in molecular composition of the glutamatergic synapse were associated with increased anxiety-like behavior. Complex, multifactorial disorders of the nervous system show significant association with several genetic and environmental factors. Our data exemplify the contribution of an in utero MTHFR-deficient environment and early exposure to an antiepileptic drug to the basal composition of the glutamatergic synapses. The robust effect is expected to alter synapse function and plasticity and the cortico-hippocampal circuitry.

Detection of Mild and Reversible Neurohistopathological Changes in the Brain of Juvenile (Preweaned) Beagle Dogs Treated with Vigabatrin for up to 91 Days.

Neurohistopathological changes in the brain were assessed in juvenile beagle dogs given vigabatrin at 30 or 100 mg/kg/day by oral gavage from postnatal day 22 (PND22) until 16 weeks of age (PND112), when brain myelination is considered to reach the adult stage in dogs. Separate subgroups were treated from PND22 to PND35 or PND36 to PND49 to assess early effects. In addition to extensive brain histopathology, there were assessments of toxicokinetics, clinical condition, body weight, organ weights, and macroscopic pathology. In animals treated for 14 days from PND22, minimal or slight vacuolation was seen in the neuropil of the septal nuclei, hippocampus, hypothalamus, thalamus, cerebellum, and globus pallidus at 100 mg/kg/day and minimal vacuolation in the thalamus, globus pallidus, and cerebellum at 30 mg/kg/day. In animals given 100 mg/kg/day for 91 days from PND22, minimal or slight vacuolation was observed only in the hippocampus, hypothalamus, and thalamus. No vigabatrin-related brain vacuolation was observed in animals given 30 or 100 mg/kg/day for 14 days from PND36. Clear evidence of recovery was observed after 14-day and 6-week off-dose periods that followed treatment from PND22 to PND35 or PND22 to PND112, respectively.

The effects of taurine on vigabatrin, high light intensity and mydriasis induced retinal toxicity in the pigmented rat.

The overall purpose of this study was to establish a model that may be used for examining the effect of Vigabatrin-induced retinal toxicity in pigmented rats, and subsequently examine the possible effects of taurine on the retinal toxicity. In the first part of the study, pigmented Long Evans rats were subjected to combinations of induced mydriasis, low/high light intensities (40/2000 lx) and oral administration of near-MTD (Maximum Tolerated Dose) doses (200 mg/kg/day) of Vigabatrin for up to 6 weeks. The combination of mydriasis and high light intensity applied to Long Evans rats resulted in retinal damage that was increased by the administration of Vigabatrin. In the second part of the study Long Evans rats were subjected to combinations of induced mydriasis and high/low light intensity (40/2000 lx) while being orally administered low (30 mg/kg/day) or high (200 mg/kg/day) doses of Vigabatrin for up to 6 weeks. In addition, selected groups of animals were administered taurine via the drinking water (20 mg/ml), resulting in systemic taurine concentrations of approximately threefold the endogenous concentration. The combined results of the studies demonstrate that retinal damage can be induced in pigmented animals when combining mydriasis and high light intensity. Retinal damage was functionally evaluated by electroretinography (ERG), then confirmed by histopathology. While depending on mydriasis and high light intensity, administration of Vigabatrin increased the retinal toxicity and resulted in the formation of rosette-like structures in the retina in a dose-related manner. Administration of taurine did not alleviate the Vigabatrin-induced retinal toxicity, as demonstrated either functionally by ERG or morphologically, although systemic concentrations of 3-fold the endogenous levels were reached, and it was thus not possible to demonstrate a protective effect of taurine in these pigmented animals.

Vigabatrin-induced retinal toxicity is partially mediated by signaling in rod and cone photoreceptors.

Vigabatrin (VGB) is a commonly prescribed antiepileptic drug designed to inhibit GABA-transaminase, effectively halting seizures. Unfortunately, VGB treatment is also associated with the highest frequencies of peripheral visual field constriction of any of the antiepileptic drugs and the mechanisms that lead to these visual field defects are uncertain. Recent studies have demonstrated light exposure exacerbates vigabatrin-induced retinal toxicity. We further assessed this relationship by examining the effects of vigabatrin treatment on the retinal structures of mice with genetically altered photoreception. In keeping with previous studies, we detected increased toxicity in mice exposed to continuous light. To study whether cone or rod photoreceptor function was involved in the pathway to toxicity, we tested mice with mutations in the cone-specific Gnat2 or rod-specific Pde6g genes, and found the mutations significantly reduced VGB toxicity. Our results confirm light is a significant enhancer of vigabatrin toxicity and that a portion of this is mediated, directly or indirectly, by phototransduction signaling in rod and cone photoreceptors.

Effects of vigabatrin on the skeletal system of young rats.

Long-term administration of antiepileptic drugs may be connected with the risk of impairment of bone remodeling. Contrary to the reported unfavorable effect of classic antiepileptic drugs on bone metabolism, little is known about the effect of the next generation antiepileptics on bone remodeling. The aim of the present study was to investigate the effect of vigabatrin, as a representative of new antiepileptics, on the skeletal system of young rats, in comparison with conventional drugs--phenytoin and valproic acid. The experiments were carried out on 4-week-old male Wistar rats, divided into the control rats, and rats receiving vigabatrin (250 mg/kg p.o. daily), phenytoin (20 mg/kg p.o. daily) or valproic acid (250 mg/kg p.o. daily). The drugs were administered for 28 days. Histomorphometric parameters of the tibia and femur, mechanical properties of the femur, and bone length, diameter, mass, content of mineral substances and calcium were examined. After administration of phenytoin or valproic acid, the investigated bone parameters did not significantly differ from those observed in the control rats. Administration of vigabatrin caused profound impairment of bone accrual with impairment of bone histomorphometric parameters, along with the significant decrease in the body mass gain.

Oral toxicity of vigabatrin in immature rats: characterization of intramyelinic edema.

OBJECTIVES: Two toxicologic studies of vigabatrin were conducted with immature Sprague Dawley rats to characterize intramyelinic edema (IME) formation and assess potential impact on behavioral measures. Study 1 was a dosage-ranging characterization of overall toxicity of vigabatrin in young, developing rats. Study 2 evaluated vacuolar brain lesions found in Study 1. METHODS: During Study 1, immature Sprague Dawley rats were orally administered deionized water (vehicle control), or vigabatrin at 5, 15, or 50mg/kg/day for ≤ 9 weeks, beginning at postnatal day 4 (PND 4) and followed by a recovery period. Toxicologic observations were collected, including adverse clinical signs, body weight gains, food consumption, ophthalmoloscopy, electroretinograms, sexual maturation, motor activity, memory, and learning behaviors. At sacrifice, CNS tissues were examined by light microscopy for evidence of IME. In Study 2, immature Sprague Dawley rats were again orally administered vigabatrin (50mg/kg/day for ≤ 9 weeks, beginning at PND 4). At sacrifice, CNS tissues were examined by both light and transmission electron microscopy for evidence of IME. RESULTS: At 5-50mg/kg/day, dosage-related reduced food consumption, decreased body weight, and delayed sexual maturation were found. Persisting through recovery, effects were more pronounced in males. Increased degrees of vacuolation were observed on PND 67 only after a dosage of 50mg/kg/day, and were attenuated during recovery. Vacuolar-change morphology was characteristic of IME, with no evidence of cellular or neuritic degeneration. Ultrastructural analyses revealed brain vacuoles initiated as splits of myelin sheaths along intra-period lines. These splits expanded, evolving into large membrane-rich vacuoles, and were more prominent at later stages of myelin development. Hypomyelination and gliopathy were noted from PNDs 4-15, and were likely related to vigabatrin exposure during active myelination. A lesser degree of hypomyelination was observed from PNDs 4-46 and 4-65. Vacuolation was markedly attenuated in post-recovery-period rats. CONCLUSIONS: The present studies indicated toxicities in young rats at vigabatrin dosages lower than those reported for toxicities in older rats. Dosages <50mg/kg/day did not affect CNS, behavior, and reproductive development. However, at the greatest dosage, some retardation of physical growth, delay in sexual maturation, reduction in physical strength, and induction of CNS stimulation (handling-induced spasms) occurred. The key pathologic finding was vacuolar brain lesions in the white and gray matter, which generally reversed upon drug discontinuation. Vacuoles were confined to myelin sheaths, consistent with observations in adult rats. Vigabatrin delayed but did not eliminate myelination despite continued dosing, an effect greatest during active myelination.

Dose-related changes in retinal function and PKC-alpha expression in rabbits on vigabatrin medication. Effect of vigabatrin in the rabbit eye.

BACKGROUND: To investigate, in a rabbit model, the effect of two different doses of vigabatrin (VGB) on retinal function and morphology. METHODS: Twenty-nine rabbits of mixed strain were divided into two groups, receiving either high-dose (n = 15) or low-dose (n = 14) oral VGB treatment (cumulative dose 29.8 +/- 2.9 g and 14.2 +/- 0.6 g respectively). Ten rabbits receiving water served as control animals. The rabbits underwent three baseline ff-ERG measurements before initiation of VGB medication and two ff-ERG registrations during treatment, after 8 and 12-14 weeks respectively. At the end of the study, the expression of protein kinase C-alpha (PKC-alpha), gamma amino butyric acid (GABA) A receptors, vimentin, glial fibrillary acidic protein (GFAP) and peanut agglutinin (PNA) was examined in retinal sections from all rabbits. RESULTS: In animals of the high-dose group, the ff-ERG measurements revealed a significant decrease of isolated rod b-wave amplitudes, combined rod-cone b-wave amplitudes and amplitudes of oscillatory potentials (OPs); OP1, OP2 and OP3. In the low-dose group, the b-wave amplitudes of combined rod-cone responses as well as OP2 and OP3 were significantly reduced. PKC-alpha labeling demonstrated a dose-related translocation of the enzyme in rod bipolar cells, also revealing a significant decline of the number of PKC-alpha labeled rod bipolar cells in treated animals. Vimentin labeling showed a dose-related deviant labeling pattern of Müller cells, with strikingly low labeling intensity in the outer parts of the cells; in the outer limiting membrane (OLM) as well as the outer nuclear layer (ONL). Labeling with antibodies against GABA A receptors and GFAP, as well as PNA staining, revealed no differences between treated animals and controls. CONCLUSIONS: In this study, VGB medication was associated, in a dose-related manner, with a decrease of ff-ERG amplitudes as well as with altered protein expression in rod bipolar cells and Müller cells, suggesting alterations of inner retinal function. The dose-related morphological and electrophysiological changes indicate a retinal pathology that may explain the constricted visual fields seen in some patients treated with VGB.

Visual fields at school-age in children treated with vigabatrin in infancy.

PURPOSE: The use of vigabatrin (VGB) as an antiepileptic drug (AED) has been limited by evidence showing that it causes vigabatrin-attributed visual field loss (VAVFL) in at least 20-40% of patients exposed at school age or later. VGB is an effective drug for infantile spasms, but there are no reports on later visual field testing after such treatment. Our aim was to investigate the risk of VAVFL in school-age children who had received VGB in infancy. METHODS: Visual fields of 16 children treated with VGB for infantile spasms were examined by Goldmann kinetic perimetry at age 6-12 years. Normal fields were defined as the temporal meridian extending to more than 70 degrees , and mild VAVFL between 50 and 70 degrees . Abnormal findings were always confirmed by repeating the test. Exposure data were collected from hospital charts. RESULTS: Vigabatrin was started at a mean age of 7.6 (range, 3.2-20.3) months. The mean duration of therapy was 21.0 (9.3-29.8) months and cumulative dose 655 g (209-1,109 g). Eight children were never treated with other AEDs, five received only adrenocorticotropic hormone (ACTH) in addition to VGB, and three children had been treated with other AEDs. Fifteen children had normal visual fields. Mild VAVFL was observed in one child (6%) who had been treated with VGB for 19 months and who received a cumulative dose of 572 g. CONCLUSIONS: The risk of VAVFL may be lower in children who are treated with VGB in infancy compared to patients who receive VGB at a later age.

Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy.

PURPOSE: Vigabatrin used to treat infantile spasms (IS) has been associated with transient magnetic resonance imaging (MRI) abnormalities. We carried out a retrospective review to better characterize the frequency of those abnormalities in IS and in children and adults treated with vigabatrin for refractory complex partial seizures (CPS). METHODS: Medical records and 332 cranial MRIs from 205 infants (aged 16 years) with CPS were re-reviewed. Prespecified MRI abnormalities were defined as any hyperintensity on T(2)-weighted or fluid-attenuated inversion-recovery (FLAIR) sequences with or without diffusion restriction not readily explained by a radiographically well-characterized pathology. MRIs were read by two neuroradiologists blinded to treatment group. The incidence and prevalence of MRI abnormalities associated with vigabatrin were estimated. RESULTS: Among infants with IS, the prevalence of prespecified MRI abnormalities was significantly higher among vigabatrin-treated versus vigabatrin-naive subjects (22% vs. 4%; p < 0.001). Of nine subjects in the prevalence population with at least one subsequent determinate MRI, resolution of MRI abnormalities occurred in six (66.7%)-vigabatrin was discontinued in four. Among adults and children treated with vigabatrin for CPS, there was no statistically significant difference in the incidence or prevalence of prespecified MRI abnormalities between vigabatrin-exposed and vigabatrin-naive subjects. DISCUSSION: Vigabatrin is associated with transient, asymptomatic MRI abnormalities in infants treated for IS. The majority of these MRI abnormalities resolved, even in subjects who remained on vigabatrin therapy.

[Epilepsy and Sabril]. / L'epilepsie et le Sabril.

This article presents a litterature overview of the ophthalmologic secondary effects due to Sabril. First, a review of the visual field loss that can be related to Sabril treatment is presented; the epidemiological and physiopathological aspects of this visual field loss are considered based on experimental and clinical data. The link that can be established between electrophysiology and physiopathology following these data is further examined. Finally, two ophthalmologic follow-up algorithms are proposed for patients treated by Sabril, one for adults and the other for children.

Fetal exposure to GABA-acting antiepileptic drugs generates hippocampal and cortical dysplasias.

PURPOSE: The management of epilepsy during pregnancy entails a number of concerns. While seizures may affect adversely maternal and fetal outcome, antiepileptic drugs (AEDs) may increase the incidence of congenital abnormalities and possibly affect postnatal cognitive development in the offspring. Experimental animal studies can aid in assessing teratogenic features associated with individual AEDs and/or with seizures, and to identify the mechanisms involved. The purpose of this study was to investigate the consequences of prenatal exposure to (a) different AEDs and (b) maternal seizures on brain maturational processes in rats. METHODS: Pregnant rats received from embryonic days 14 to 19 intraperitoneal injections of carbamazepine (20 mg/kg/day), vigabatrin (200 mgkg/day), and valproate (100 mg/kg/day) at doses not widely different from those used clinically. Pups exposed to AEDs in utero were analyzed postnatally. Animals born to "kindled" pregnant animals that had experienced one generalized convulsive seizure per day during the same gestational period were analyzed in parallel. RESULTS: Prenatal exposure to vigabatrin and valproate, which act on GABA signaling, induced hippocampal and cortical dysplasias, which were likely to result from a neuronal migration defect and neuronal death. By contrast, offspring of rats exposed to carbamazepine (which at the dose used produced low plasma concentrations) or to generalized convulsive seizures showed no clear-cut evidence of dysplasias. CONCLUSIONS: We suggest that AEDs that increase the extracellular concentration of GABA might induce severe neuronal migration disorders. Drugs acting through other molecular targets would also perturb cortical maturation. The potential clinical relevance of these results should be a subject of future research.

[Electrophysiological monitoring of epileptic patients treated with Vigabatrin]. / Surveillance électrophysiologique des patients épileptiques traités par Vigabatrin.

Vigabatrin is a GABA mimetic antiepileptic agent that has been used for 10 years in cases of epilepsy that resist other treatments. Since 1997, concentric visual field defects have been reported. Before any visual symptom complaint, they quickly become irreversible and highly disabling. To prevent this visual impairment, the monitoring protocol must be defined with reliable and well-supported tests, so that patients treated with Vigabatrin can be regularly monitored. Our purpose was to know if EOG impairments were frequent, if their severity was proportional to visual impairment, and if the Arden ratio could be a predictive criterion of Vigabatrin toxicity. Seventy-two patients treated with Vigabatrin for 2-10 years were examined, and EOG results were compared with a normal population EOG and then the patient's visual field. The monitoring protocol proposed includes EOG, which seems to be the most sensitive and specific diagnostic tool for screening Vigabatrin-treated patients.

Maternal exposure to the antiepileptic drug vigabatrin affects postnatal development in the rat.

The objective was to investigate, in the rat, the effects of maternal exposure to vigabatrin (VGB) on the postnatal motor-cognitive behaviour of the offspring. We used an experimental evaluator-blind, placebo-controlled study in the rat. Ten pregnant rats were divided into five groups and treated with different doses of VGB (250, 500, 750, 1000 mg/kg/day) or placebo from gestation day (GD) 6 to GD10. After delivery, 56 pups (40 pups prenatally exposed to VGB and 16 pups exposed to placebo) were evaluated for motor-cognitive behaviour throughout postpartum day 40. At the end of testing sessions the animals were sacrificed and brain tissues processed for biochemical analysis of GABA levels. Body weight of pups and young rats whose mothers were treated with a dose of 750 mg/kg/day were significantly lower both at birth and during the whole postnatal life with respect to the control groups. Young rats of this group exhibited impaired performance in both the open-field and water maze tasks. Brain GABA contents were dramatically increased in this group of rats. No other significant nutritional, biochemical or behavioural changes were observed after treatments with doses of VGB lower than 750 mg/kg/day. The exposure to a dose of 1000 mg/kg caused abortion. Maternal exposure to VGB at relatively high doses (750 mg/kg/day) is likely to cause some important changes of the nutritional status during the pre- and postnatal life. Thus, the biochemical and cognitive abnormalities observed in this study could be related to some disturbances of brain development induced by malnutrition and/or to a disturbance of neuronal programming of the gabaergic system.