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.

Constructing benchmark databases and protocols for medical image analysis: diabetic retinopathy.

We address the performance evaluation practices for developing medical image analysis methods, in particular, how to establish and share databases of medical images with verified ground truth and solid evaluation protocols. Such databases support the development of better algorithms, execution of profound method comparisons, and, consequently, technology transfer from research laboratories to clinical practice. For this purpose, we propose a framework consisting of reusable methods and tools for the laborious task of constructing a benchmark database. We provide a software tool for medical image annotation helping to collect class label, spatial span, and expert's confidence on lesions and a method to appropriately combine the manual segmentations from multiple experts. The tool and all necessary functionality for method evaluation are provided as public software packages. As a case study, we utilized the framework and tools to establish the DiaRetDB1 V2.1 database for benchmarking diabetic retinopathy detection algorithms. The database contains a set of retinal images, ground truth based on information from multiple experts, and a baseline algorithm for the detection of retinopathy lesions.

Adiponectin receptor 1 gene (ADIPOR1) variant is associated with advanced age-related macular degeneration in Finnish population.

Adiponectin is an adipocyte-expressed protein that regulates the glucose, lipid, and energy metabolism via adiponectin receptors 1 and 2. Obesity is a known risk factor for age-related macular degeneration (AMD). We, therefore, examined associations of single nucleotide polymorphisms in Adiponectin (ADIPOQ) and Adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) genes with the prevalence of advanced AMD in Finnish population. Thirty-seven markers for ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in a sample collection of 91 men and 177 women having exudative AMD and 18 men and 26 women having severe atrophic AMD. Patients were diagnosed by fundus photographs and fluorescein angiography. The control group (no signs of AMD in fundus photographs) consisted of 55 men and 111 women. Inclusion criteria age was over 65 years old without diabetes diagnosis. Out of the tested SNPs, rs10753929 located in intron of ADIPOR1 gene was significantly associated (p=0.0471) with AMD status when using a permutation procedure that controlled for the number of tested genotypes and genetic models. Odds ratio (OR) for the association was 1.699 (95% CI 1.192-2.423). The SNP consists of C/T alleles and the risk allele T had a minor allele frequency (MAF) of 20.4%. Distribution of proportion of cases/controls between alleles revealed an additive genetic model. Our findings reveal that rs10753929 ADIPOR1 variant is a novel candidate for AMD genetic risk factor in Finnish population.

Is reduced ornithine-δ-aminotransferase activity the cause of vigabatrin-associated visual field defects?

BACKGROUND: A gabaergic antiepileptic drug, vigabatrin (VGB), is known to induce bilateral concentric visual field defects (VFD) in 30-40% of treated patients. Although the clinical and electrophysiological features of VFDs are well documented, the mechanism of retinal toxicity is still unclear. PURPOSE: To determine if low basal ornithine-δ-aminotranspherase (OAT) activity is implicated in the etiology of VGB retinotoxicity, resulting in a phenotype of a mild form of gyrate atrophy. METHODS: Assays of OAT activity in lymphocytes and GABA-transaminase activity in platelets were performed, and plasma levels of GABA, ornithine, lysine, glutamic acid and glutamine were measured, and visual fields were examined. A total of 47 subjects, aged 14-78 years, were examined. Twenty-one epileptic patients were off VGB more than 1 year; 11 patients with VGB-induced VFD and 10 with normal visual fields. Ten epileptic patients were on current VGB therapy more than 1 year; four patients with VGB-induced VFD and six with normal visual fields. The results were compared with those of 10 epilepsy patients taking tiagabine and six patients who suffered from gyrate atrophy (GA) or were obligate carriers of the disease. RESULTS: In patients who had stopped VGB and who had VFDs, OAT activity was significantly reduced as compared with those who had normal visual fields (77.4pmol P5C/min/mgPro vs. 181.9pmol P5C/min/mgPro, p=0.002). In patients with ongoing VGB therapy, no difference was found between the patients with and without VFDs (149.4pmol P5C/min/mgPro vs. 159.1pmol P5C/min/mgPro). CONCLUSIONS: : The results suggest that VGB retinotoxicity might be associated with elevated retinal ornithine mediated by low basal OAT activity.

Mechanisms of protein aggregation in the retinal pigment epithelial cells.

The pathogenesis of age-related macular degeneration (AMD) essentially involves chronic oxidative stress, increased accumulation of lipofuscin in retinal pigment epithelial (RPE) cells and extracellular drusen formation, as well as the presence of chronic inflammation. The capacity to prevent the accumulation of cellular cytotoxic protein aggregates is decreased in senescent cells which may evoke lipofuscin accumulation into lysosomes in postmitotic RPE cells. This presence of lipofuscin decreases lysosomal enzyme activity and impairs autophagic clearance of damaged proteins which should be removed from cells. Proteasomes are another crucial proteolytic machine which degrade especially cellular proteins damaged by oxidative stress. This review examines the cross-talk between lysosomes, autophagy and proteasomes in RPE cell protein aggregation, their role as a possible therapeutic target and their involvement in the pathogenesis of AMD.

Color vision and contrast sensitivity in epilepsy patients treated with initial tiagabine monotherapy.

The purpose of the study was to determine whether the use of a GABAergic antiepileptic drug (AED), tiagabine, affects color vision and contrast sensitivity. Twenty newly diagnosed patients with partial epilepsy (aged 19-72 years), receiving tiagabine as their initial monotherapy for 5-41 months were examined. Color vision was examined with the Standard Pseudoisochromatic Plates 2 (SPP2), with the Farnsworth-Munsell 100 Hue Test (FM100) and with the Color Vision Meter 712 (CVM) anomaloscope. Contrast sensitivity was measured with the Pelli-Robson letter chart. Three patients excluded from the color vision evaluation for congenital red-green color vision defects. Seven out of 17 patients (41%) had acquired color vision deficit examined with the FM100. The CVM anomaloscope revealed minor defects in two patients. Contrast sensitivity function was within normal ranges. The present study suggests that AED therapy with tiagabine, like with other established and newer AEDs may interfere with color perception.

Ophthalmologic and neurologic findings in two children exposed to vigabatrin in utero.

Vigabatrin (VGB) is an important treatment option for infantile spasms. Vigabatrin-induced visual field defects are at present the most important safety issue in the use of the drug. The knowledge concerning VGB-associated visual dysfunction in pediatric patients, particularly in those who have been exposed to VGB in utero is limited. We explored ophthalmic and neurologic findings in two children who have been exposed prenatally to VGB.

Visual function in epilepsy patients treated with initial valproate monotherapy.

PURPOSE: To investigate whether initial valproate (VPA) monotherapy for the treatment of epilepsy causes visual field defects and visual dysfunction. METHODS: In a cross-sectional study, visual fields were examined with the kinetic Goldmann and automated Humphrey perimeters, contrast sensitivity function with the Pelli-Robson letter chart and colour vision with the Standard Pseudoisochromatic Plates Part 2 (SPP 2) and Farnsworth-Munsell 100 Hue test (FM 100) in eighteen epilepsy patients (aged 18--50 years, 30.2.+/-10 years, mean+/-S.D.) treated with initial valproate monotherapy for 2--20 years (8.4+/-5.1 years). RESULTS: None had vigabatrin-type, concentric visual field defect with the kinetic Goldmann or automated Humphrey perimetries. In the Humphrey perimetry, the mean deviation for the group was within normal limits varying from -2.53 to 0.59 dB (-0.74+/-0.80 dB) in the right eye and from -2.66 to 0.67 dB (-0.78+/-0.82 dB) in the left eye. In the FM 100 test, acquired colour vision deficiency was found in two out of 18 patients (11%, 95% CI: 0--25%). However, the mean total error score was lower in the patient group than in the control group. All patients had normal contrast sensitivity function. CONCLUSIONS: The use of VPA in the treatment of epilepsy is not associated with visual field defects similar to vigabatrin, but may induce abnormalities in colour vision.