The Ameliorative Effect of Empagliflozin in Vigabatrin-Induced Cerebellar/Neurobehavioral Deficits: Targeting mTOR/AMPK/SIRT-1 Signaling Pathways.

Introduction. Vigabatrin (VGB) is an antiepileptic drug that acts to irreversibly inhibit the γ-aminobutyric acid (GABA) transaminase enzyme, elevating GABA levels. Broad studies have established that long-term treatment and/or high doses of VGB lead to variable visual defects. However, little attention has been paid to its other side effects, especially those demonstrating cerebellar involvement. Sodium glucose-linked co-transporter 2 (SGLT2) inhibitors are antidiabetic agents with protective effects far greater than expected based on their anti-hyperglycemic effect. Method. Our study herein was designed to investigate the possible ameliorative effect of empagliflozin, the SGLT2 inhibitors, in VGB-induced cerebellar toxicity. A total of 40 male Wistar rats were allocated equally into 4 groups: Group I: control group; Group II: VGB group; Group III empagliflozin treated VGB group; and Group IV: empagliflozin treated group. All groups were subjected to the detection of cerebellar messenger RNA gene expression of silent mating type information regulation 2 homolog 1 (SIRT1) and Nucleoporin p62 (P62). Mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK), and beclin1 levels were assessed by the ELISA technique while malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected spectrophotometrically. Immuno-histochemical studies, focusing on glial fibrillary acidic protein (GFAP) and S100 were performed, and the optical color density and the mean area percentage of GFAP positive astrocytes and the number of S 100 positive cells were also counted. Results. Following empagliflozin treatment, we documented significant upregulation of both SIRT1 and P62 mRNA gene expression. Additionally, AMPK, Beclin1 levels, and SOD activity were significantly improved, while both mTOR and MDA levels were significantly reduced. Conclusions. We concluded for the first time that empagliflozin efficiently ameliorated the VGB-induced disrupted mTOR/AMPK/SIRT-1 signaling axis with subsequent improvement of the autophagy machinery and mitigation of the oxidative and inflammatory cellular environment, paving the way for an innovative therapeutic potential in managing VGB-induced neurotoxicity.

Vigabatrin - new data on indications and safety in paediatric epilepsy.

INTRODUCTION: Vigabatrin (VGB), a second-generation antiepileptic drug, is effective for the treatment of infantile spasms and focal seizures, primarily in tuberous sclerosis complex (TSC) patients. However, reports of adverse events of VGB, including VGB-associated visual field loss and brain abnormalities in neuroimaging, have raised concerns about the broader use of VGB and thus significantly limited its application. AIM OF THE STUDY: The goal of this review was to summarise the recent therapeutic guidelines, the use of VGB in focal seizures and new VGB applications as a disease-modifying treatment in TSC patients. Moreover, we discuss the current opinions on potential VGB-associated toxicity and the safety of VGB.

Vigabatrin-associated Reversible MRI Abnormalities in an Infant with Tuberous Sclerosis.

Vigabatrin therapy is commonly used in infants diagnosed with tuberous sclerosis complex, particularly in the setting of epilepsy. Utilization of vigabatrin can result in bilateral and symmetric abnormal sequence changes within the deep brain matter and brainstem on magnetic resonance imaging. These abnormalities occur predominantly in infancy, are reversible, and can be asymptomatic or result in symptomatic clinical manifestations. We present a case with classic neuroimaging findings. Familiarity with these findings can prevent unnecessary follow up tests or studies and the cost of continuing or discontinuing vigabatrin therapy should be weighed heavily against the potential manifestation of extrapyramidal symptoms.

Efectos Adversos del Tratamiento con Vigabatrina en Síndrome de West: reporte de 2 casos / Adverse Effects of Vigabatrin Use for West Syndrome treatment: a report of 2 Clinical Cases

El síndrome de West (SW) es un síndrome epiléptico de la infancia temprana. Dentro de los fármacos de primera línea utilizados para su tratamiento se encuentran la hormona adrenocorticotropa (ACTH) y Vigabatrina. Estudios sugieren igual efectividad en el uso a largo plazo de ambos para controlar el SW. En Chile, el uso de Vigabatrina ha aumentado dada su mayor disponibilidad, facilidad de uso y menor costo. Se describen 2 casos clínicos presentando complicaciones agudas infrecuentes secundarias a su uso. Ambos pacientes con antecedentes de SW y trisomía 21. Primer caso: Lactante de 11 meses que inicia tratamiento con 100 mg/kg/día de Vigabatrina a los 7 meses, aumentando a 150 mg/kg/día por mala respuesta. Evolucionó con un síndrome extrapiramidal, con alteraciones radiológicas características. Segundo caso: Lactante de 7 meses, que tras iniciar tratamiento con vigabatrina (100 mg/kg/día) desarrolla rash facial sugerente de hipersensibilidad a fármacos antiepilépticos (FAEs), sin compromiso mucoso ni alteraciones sistémicas. Ambas regresan a su basal luego de suspensión o disminución de dosis del medicamento. Destaca la importancia de la monitorización de efectos adversos en el uso de FAEs y atender la aparición de reacciones poco conocidas. Las alteraciones imagenológicas por Vigabatrina son conocidas, no así el síndrome extrapiramidal asociado (primer caso). Por otra parte, las reacciones cutáneas están ampliamente descritas para múltiples FAEs, pero no para Vigabatrina (segundo caso). Dado el uso frecuente de Vigabatrina para tratar SW y otras epilepsias, es fundamental conocer y manejar reacciones adversas poco conocidas como las aquí presentadas. Palabras claves: Síndrome de West, Síndrome de Down, espasmos infantiles, vigabatrina, reacciones adversas, toxicidad, alergia, rash.

West Syndrome is an epileptic syndrome which typically presents in early childhood. In regard to treatment, the first line includes adrenocorticotropic hormone (ACTH) and Vigabatrin. Studies suggest similar response in the long term to both treatments. In Chile, Vigabatrin is being used more frequently as it is more available, of easier administration and lower cost. We present in the following report 2 clinical cases that presented acute infrequent complications secondary to its use in patients with both Down and West Syndrome. First case: 11-month-old infant who was initially treated with 100mg/kg/day of Vigabatrin at 7 months of age and increased to 150mg/kg/day due to lack of response. She evolved with an extrapyramidal syndrome with radiological manifestations. The second case: 7-month old toddler who initiated treatment with 100mg/kg/day of Vigabatrin and developed a facial rash, suggestive of hypersensitivity to antiepileptic drugs, with no mucosal or systemic involvement. Both patients returned to their previous condition shortly after Vigabatrin was decreased or discontinued. We emphasize the importance of the early monitorization of adverse effects in the use of antiepileptic drugs and awareness of less common reactions. Radiological findings associated with the use of Vigabatrin are well known, but not the clinical evolution with symptomatic extrapyramidal symptoms, as in the first case. Allergic reactions to the use of antiepileptic drugs have also been reported to several drugs, but not to Vigabatrin (second case). As Vigabatrin is being used more frequently to treat WS and other epilepsies it is important to know and manage uncommon adverse reactions as the ones presented in this report. Keywords: West Syndrome, Down Syndrome, infantile spasms, vigabatrin, adverse reactions, toxicity, allergy, rash

Efficacy of vigabatrin therapy for tuberous sclerosis with infantile spasms.

Objective: To evaluate the effects and tolerability of vigabatrin (VGB) in children with tuberous sclerosis (TS) with infantile spasms or tonic seizures. Methods: We examined the impact of VGB on a series of 17 children with TS visiting Tohoku University Hospital in Japan during April 2010 and May 2015. To minimize potential adverse effects, VGB was given to the patients for limited 6 months with titration from 30 mg/kg/day as an initial dose. Results: Main seizure types were classified into spasms (n=10) or tonic seizures (n=7). Seizure reduction was positively associated with seizure type of infantile spasms, lower maximum dosage, younger age on VGB administration, and earlier VGB treatment after the diagnosis. Seizure type of infantile spasm was an independent favorable predictor and also associated with long-term seizure reduction. Major adverse events included psychiatric symptoms (n=7) and electroretinogram (ERG) abnormalities (n=2). All symptoms were recovered by reducing the dosage of VGB. Conclusion: VGB is effective and well tolerated as first-line treatment for TS children with infantile spasms. Our "low dosage and limited period" protocol is efficient for improving seizure control as well as minimizing the potential risks of VGB.

Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study.

AIM: The aim of this study was to examine whether vigabatrin treatment had caused visual field defects (VFDs) in children of school age who had received the drug in infancy. METHOD: In total, 35 children (14 males, 21 females; median age 11y, SD 3.4y, range 8-23y) were examined by static Humphrey perimetry, Goldmann kinetic perimetry, or Octopus perimetry. The aetiologies of infantile spasms identified were tuberous sclerosis (n=10), other symptomatic causes (n=3), or cryptogenic (n=22). RESULTS: Typical vigabatrin-attributed VFDs were found in 11 out of 32 (34%) children: in one out of 11 children (9%) who received vigabatrin for <1 year (group 1), in three out of 10 children (30%) who received vigabatrin for 12 to 24 months (group 2), and in seven out of 11 children (63%) who received vigabatrin treatment for longer than 2 years (group 3). VFDs were mild in five and severe in six children. Patients with tuberous sclerosis were at higher risk of VFDs (six out of 10 children). The mean cumulative doses of vigabatrin were 140.5, 758.8, and 2712g in group 1, 2, and 3, respectively. INTERPRETATION: VFDs were found in 34% of the cohort of children in this study. The rate of VFD increased from 9% to 63% as duration of treatment increased. The results of this study showed that the risk-benefit ratio should always be considered when using vigabatrin.

[Ocular toxicity of drugs]. / Toxicité oculaire des médicaments.

Numerous systemic medications have a potential ocular toxicity leading to permanent visual loss. Physiopathologic mechanisms associated with these toxic effects are yet unclear and, besides discontinuation of the drug, when possible, there is no current validated treatment once visual loss is present. Prevention lies on an awareness of potential risks of both the patient and the practitioner, a constant evaluation of the risk/benefice ratio of any treatment and, for some drugs, regular visual evaluations according to now more standardized protocols. In that respect, a tight link between the ophthalmologist and the referring practitioner is critical. Among oculotoxic drugs, anti-malarial treatment represents the most commonly prescribed. A better recognition of clinical characteristics of ocular toxicity along with progress in functional and structural evaluation of the visual system has modified follow-up protocols to obtain the earliest detection but a better knowledge in toxic mechanisms is still necessary.

Vigabatrin for infantile spasms.

Infantile spasms describe a pediatric epilepsy syndrome characterized by frequent clusters of brief symmetric muscle contractions; the condition is often associated with developmental delay. When infantile spasms are accompanied by hypsarrhythmia on electroencephalogram, the condition is labeled West syndrome. The mainstay of treatment for infantile spasms is adrenocorticotropic hormone; however, vigabatrin, a vinyl derivative of γ-aminobutyric acid, has been used for the treatment of infantile spasms in Europe since 1989. In 2009, vigabatrin was approved by the United States Food and Drug Adminstration (FDA) for use as monotherapy in the treatment of infantile spasms in patients aged 1 month-2 years when the benefits of treatment outweigh the risks. Results from numerous trials examining the role of vigabatrin in infantile spasms have been published; many of these trials were small, open-label, or noncontrolled. Although clinical trials have provided some insight into the utility of vigabatrin for the treatment of infantile spasms, these studies have notable limitations. In addition, vigabatrin is associated with a black-box warning that describes the potential for permanent bilateral concentric visual field defects. Currently, vigabatrin is available through a manufacturer-sponsored program in accordance with its FDA-approved Risk Evaluation and Mitigation Strategy. Although several guidelines recommend vigabatrin as a first-line therapy for infantile spasms, specifically infantile spasms related to tuberous sclerosis, it is still unclear whether vigabatrin should supersede hormone therapy as first-line therapy. Further research comparing the two therapies is needed.

Visual fields in neuro-ophthalmology.

Visual field assessment is important in the evaluation of lesions involving the visual pathways and should be performed at baseline and periodically in the follow-up. Standard automated perimetry has been shown to be adequate in neuro-ophthalmic practise and is now the technique of choice for a majority of practitioners. Goldman kinetic visual fields are useful for patients with severe visual and neurologic deficits and patients with peripheral visual field defects. Visual fields are useful in monitoring progression or recurrence of disease and guide treatment for conditions such as idiopathic intracranial hypertension (IIH), optic neuropathy from multiple sclerosis, pituitary adenomas, and other sellar lesions. They are used as screening tools for toxic optic neuropathy from medications such as ethambutol and vigabatrin. Visual field defects can adversely affect activities of daily living such as personal hygiene, reading, and driving and should be taken into consideration when planning rehabilitation strategies. Visual field testing must be performed in all patients with lesions of the visual pathway.

Vigabatrina aumenta atividade da superóxido dismutase no corpo estriado de ratos após crises convulsivas induzidas pela pilocarpina / Vigabratine increases superoxide dismutase activity in striatum of rat after pilocarpine-induced seizures

CONTEXTO: Tem sido sugerido que durante as crises convulsivas induzidas pela pilocarpina pode ser observado aumento no estresse oxidativo cerebral. Estudos sugerem que compostos com atividade antioxidante podem fornecer certo grau de proteção contra a neurotoxicidade induzida pelas crises convulsivas. OBJETIVOS: O presente estudo investigou as ações farmacológicas da vigabatrina nas alterações comportamentais e na atividade enzimática da superóxido dismutase (SOD) no corpo estriado de ratos adultos. MÉTODOS: Ratos Wistar adultos (2 meses de idade) foram usados nos experimentos e divididos em quatro grupos. O primeiro foi tratado com solução salina 0,9 por cento (grupo controle). O segundo grupo foi tratado com pilocarpina (400 mg/kg, i.p., grupo P400). O terceiro grupo foi tratado com vigabatrina (500 mg/kg, i.p., grupo VGB) e o quarto grupo foi tratado com vigabatrina (500 mg/kg, i.p.) e 30 minutos depois com pilocarpina (400 mg/kg, i.p., grupo VGB + P400). Os animais que apresentaram crises convulsivas, estado de mal epiléptico e não morreram durante o período de 24 horas de observação foram sacrificados para dissecação do corpo estriado para realização da determinação da atividade da SOD. RESULTADOS: Os estudos comportamentais revelaram que, após administração de pilocarpina, todos os animais apresentaram sinais colinérgicos periféricos, movimentos estereotipados e tremores. No mesmo grupo, foram observados, em 75 por cento dos animais, crises convulsivas e o estado de mal epiléptico. Por sua vez, o pré-tratamento com vigabatrina produziu redução significativa de 50 por cento nas crises convulsivas. Com relação aos estudos neuroquímicos, não foram observadas alterações na atividade da SOD no corpo estriado do grupo P400, em comparação aos valores do grupo controle. No entanto, no grupo VGB + P400 foi visto aumento significativo na atividade da SOD de 34 por cento e 35 por cento, quando comparado aos grupos controle e P400, respectivamente. ...

BACKGROUND: Pilocarpine-induced seizures have been suggested to be mediated by increases in oxidative stress. Current studies have suggested that antioxidant compounds may afford some level of neuroprotection against the neurotoxicity of seizures. OBJECTIVES: This study investigated the pharmacological actions of vigabatrin on behavioral changes and superoxide dismutase (SOD) activity in striatum of adult rats. METHODS: Adult rats (2 months old) were used in the experiments and divided into four groups. The first was treated with 0.9 percent saline (control group). The second group was treated with pilocarpine (400 mg/kg, i.p., P400 group). The third group received vigabatrin alone (500 mg/kg, i.p., VGB group) and the fourth group was treated with vigabatrin (500 mg/kg, i.p.) and 30 minutes later received pilocarpine (400 mg/kg, i.p., VGB + P400 group). The animals which had seizures and status epilepticus (SE) and did not die within 24 hours of observation were sacrificed to perform the neurochemical studies. RESULTS: Behavioral studies showed that the administration of pilocarpine produces peripheral cholinergic signs, tremors and stereotyped movements in all animals. An amount of 75 percent of those rats developed to seizures and SE. In turn, the pre-treatment with vigabatrin produced a 50 percent reduction in the rate of seizures and SE. Regarding the neurochemical studies, there were no changes in the striatal SOD activity in P400 group as compared to the control group. However, in the VGB + P400 group it was verified significant increases in SOD activity of 34 percent and 35 percent as compared to control and P400 group, respectively. DISCUSSION: Our results indicate that behavioral changes occur during seizures, but SOD activity remained unaltered during the acute phase of the convulsive crisis. Our findings suggest that the anticonvulsant effect of vigabatrin may be the result of modulation of this enzyme, in an attempt to protect ...

In utero exposure to vigabatrin: no indication of visual field loss.

The purpose of the study was to determine whether in utero exposure to vigabatrin caused visual field loss. Three mothers with four children who had been exposed to vigabatrin in utero and who were subsequently formula fed were identified. All seven individuals underwent perimetry and imaging of the retinal nerve fiber layer (RNFL). All individuals yielded reliable outcomes to perimetry and RNFL images of acceptable quality. Two of the three mothers exhibited vigabatrin-attributed visual field loss and an abnormally attenuated RNFL. The third exhibited an upper left quadrantanopia, consistent with previous temporal lobe surgery, and a normal RNFL. All four children yielded normal visual fields and RNFL thicknesses. The presence of the normal findings for the children is reassuring and, if representative, suggests a lack of vigabatrin visual toxicity and therefore obviates the need for ophthalmological examination of those exposed to vigabatrin prenatally.

Vigabatrin in the treatment of childhood epilepsy: a retrospective chart review of efficacy and safety profile.

PURPOSE: To review the efficacy, cognitive outcome and safety profile in children treated with vigabatrin (VGB) for infantile spasms (IS) and partial epilepsies related to tuberous sclerosis complex (TSC) and other etiologies. METHODS: Retrospective review of children followed in the Pediatric Epilepsy Program of Massachusetts General Hospital for Children between May 2001 and March 2006 who were treated with VGB. RESULTS: Eighty-four children were treated with VGB, 68 of them were treated for IS, and 59 were treated for partial seizures (PS). Etiology (TSC or other) was the only predictive factor for IS control with VGB (p < 0.0003). IS control was achieved in 73% of children with TSC and 27% of children with other etiologies (combined 56%). Partial onset seizures were controlled in 34% of all children, (17% seizure free,17%reduction in seizure frequency >50%) and no predictive factor was found. Shorter time from seizure onset to VGB treatment (p < 0.027) and longer total time on VGB (p < 0.045) was associated with better IQ-developmental quotient (DQ) outcome in children treated for IS, but not with IS control. Adverse events were seen in 13%. Electroretinogram and/or behavioral visual field (VF) testing was done in 52%. VGB was discontinued in one case due to abnormal electroretinogram (ERG) findings. CONCLUSION: We confirm the efficacy of VGB in the treatment of IS and PS in an American population. VGB may improve cognitive outcome in the absence of complete IS control, but this finding is of uncertain clinical significance. VGB was well tolerated, and ophthalmologic side effects were uncommon.

Vigabatrina no tratamento da síndrome de West: avaliação clínica e eletrencefalográfica em 13 pacientes / Treatment of West syndrome with vigabatrin: clinical and electroencephalographic evaluation of 13 patients

Avaliamos a eficácia da vigabatrina (VGB) como monoterapia inicial para síndrome de West (SW), os seus efeitos colaterais e a evolução a curto prazo do eletrencefalograma (EEG), num estudo prospectivo, aberto e não controlado. A amostra foi de 13 lactentes atendidos entre outubro/2001 a setembro/2002 no ambulatório do IMIP ou em clínica privada. A dose média utilizada da VGB foi 118 mg/kg/dia. Houve supressão dos espasmos em 4 crianças (31 por cento), controle parcial em 3 (23 por cento), ausência de resposta em 5 (38 por cento) e piora em 1 (8 por cento). Dos 2 pacientes portadores de esclerose tuberosa, um ficou livre dos espasmos e o outro teve controle parcial. Efeitos colaterais ocorreram em 8 crianças (62 por cento) e consistiram de irritabilidade, insônia, sonolência e agitação, sendo todos toleráveis. Ocorreu desaparecimento da hipsarritmia no segundo EEG em 6 crianças (46 por cento), tendo 4 destas ficado livre dos espasmos. Nossos dados sugerem que a VGB é eficaz e bem tolerada como monoterapia inicial para a SW.

We evaluated the efficacy of vigabatrin (VGB) as a first drug to be used as monotherapy for West syndrome (WS), its side effects and correlations with the electroencephalogram (EEG). The sample consisted of 13 infants examined between October 2001 and September 2002 at IMIP ambulatory patientsÆ office or private clinic. Administration of vigabatrin was around 118 mg/kg/day. Suppression of spasms was obtained in 4 children (31 percent), partial control in 3 (23 percent), 5 of them did not present therapeutic response (38 percent) and just one (8 percent) got worse. On the two patients with tuberous sclerosis, one was seizure-free and in another there was partial control. Side effects happened in 8 children (62 percent) and consisted of irritability, insomnia, somnolence and agitation, and all of them have been well tolerated. The second EEG showed disappearance of hipsarrhythmia in 6 patients (46 percent). Four of these were seizure-free. We conclude that VGB is effective and well tolerated as initial monotherapy for WS.

Autistic regression associated with seizure onset in an infant with tuberous sclerosis.

We report here on a male diagnosed with tuberous sclerosis at 6 months of age. The child was treated with vigabatrin at age 6 months after an abnormal electroencephalogram but before onset of seizures. Vigabatrin was discontinued at age 13 months to avoid possible visual field defects. At 21 months, the child developed partial seizures with secondary generalization and infantile spasms. Standardized developmental assessments were performed at 12, 18, 24, 30, and 36 months of age. Cognitive and social development were normal until age 21 months and the onset of seizures. When assessed at 24 months, the child met criteria for autism and learning disability. This case indicates that the onset of epilepsy during an early stage in brain development can be associated with autistic regression and persistent developmental disorder. The case suggests the need to consider if possible visual field defects with vigabatrin outweigh the potentially deleterious effects of uncontrolled seizures.

Ocular complications of neurological therapy.

Treatments used for several neurological conditions may adversely affect the eye. Vigabatrin-related retinal toxicity leads to a visual field defect. Optic neuropathy may result from ethambutol and isoniazid, and from radiation therapy. Posterior subcapsular cataract is associated with systemic corticosteroids. Transient refractive error changes may follow treatment with acetazolamide or topiramate, and corneal deposits and keratitis with amandatine. Intraocular pressure can be elevated in susceptible individuals by anticholinergic drugs, including oxybutynin, tolterodine, benzhexol, propantheline, atropine and amitriptyline, and also by systemic corticosteroids and by topiramate. Nystagmus, diplopia and extraocular muscle palsies can occur with antiepileptic drugs, particularly phenytoin and carbamazepine. Ocular neuromyotonia can follow parasellar radiation. Congenital ocular malformations can result from in utero exposure to maternally prescribed sodium valproate, phenytoin and carbamazepine. Neurologists must be aware of potential ocular toxicity of these drugs, and appropriately monitor for potential adverse events.

Avaliação da eficácia e tolerabilidade da vigabatrina na síndrome de West / Efficacy and tolerability of vigabatrin in West syndrome

A síndrome de West (SW) é uma epilepsia grave específica da infância, que se caracteriza pela tríade: espasmos em salvas, deterioração ou atraso neuropsicomotor e hipsarritmia ao eletrencefalograma. OBJETIVO: Avaliar a eficácia e segurança da vigabatrina (VGB) no tratamento da SW. MÉTODO: Foram sujeitos do estudo todos os pacientes com diagnóstico estabelecido de SW, que freqüentam ou freqüentaram o Ambulatório de Epilepsia Infantil do Hospital das Clínicas da UNICAMP, usam ou usaram VGB na tentativa de controlar as crises. Avaliamos sexo, idade, etiologia (sintomática ou criptogênica), doença(s) associada(s), idade do início dos espasmos, freqüência das crises antes e após o uso de VGB, achados de neuroimagem, EEG antes e depois do uso de VGB, medicações associadas, tempo para controle das crises, eletroretinograma, queixa visual após uso de VGB, efeitos adversos e história familial de epilepsia. RESULTADOS: Foram avaliados 23 pacientes, sendo 16 do sexo masculino. A idade variou entre 1ano e 3 meses a 11 anos e 5meses (média = 5anos e 3meses). Dezesseis (69,5 por cento) pacientes apresentaram controle completo das crises, 5 (22 por cento) tiveram controle parcial e em 2 (8,5 por cento) pacientes os espasmos não foram controlados. Apenas uma paciente teve retinopatia gabaérgica. Seis pacientes (26 por cento) apresentaram eventos adversos - sonolência, agressividade ou retinopatia. Os pacientes com o início da SW após 6 meses de idade apresentaram melhor resposta à VGB (p<0,05). Não houve diferença na resposta ao tratamento quanto ao tempo de introdução da VGB ou à etiologia (p>0,05). Após o tratamento com VGB, nenhum EEG apresentou hipsarritmia e 50 por cento normalizaram. CONCLUSÃO: Apesar do risco de retinopatia gabaérgica, os resultados acima mostram que o uso da VGB no controle dos espasmos infantis se justifica em pacientes com SW.

Vigabatrin-induced modification of Ki-67 expression in gingival epithelium: immunohistochemical study of a short series.

OBJECTIVE: To study the expression and role in vigabatrin (VGB)-induced gingival enlargement of Ki-67 antigen and p27KIP1, p21WAF1, and p53, proteins that activate or inhibit cell-cycle progression. MATERIALS AND METHODS: Six patients treated with VGB for partial epileptic seizures refractory to classic anticonvulsant treatment were studied. Gingival biopsies were taken from four of these patients for immunohistochemical studies; 10 control biopsies from individuals with healthy gingiva and 10 from patients with periodontal disease were also evaluated. RESULTS: Four of the six patients presented some degree of gingival enlargement (mild or moderate). Nuclear expression of Ki-67 was elevated (mean of 894 positive cells/mm2 in VGB-induced gingival enlargement vs. 391 cells/mm2 in controls with healthy gingiva and 425 cells/mm2 in controls with periodontal disease) (p < 0.01, analysis of variance: anova), and nuclear expression of cyclin-dependent kinase (cdk) inhibitors p27KIP1 and p21WAF1 was reduced. The patients with gingival enlargement presented inflammatory infiltrate in lamina propria, mainly composed of T lymphocytes (CD3+) and plasma cells (CD38+), which was even more intense than in the biopsies of patients with periodontal disease. CONCLUSION: The overexpression of antigen Ki-67 and slight underexpression of cdk-inhibitors p27KIP1 and p21WAF1 suggest that VGB induced an increase in cell proliferation and contributed, together with concomitant periodontal disease, to the gingival enlargement.