A prospective study of treatments for adult-onset divergence insufficiency-type esotropia.

PURPOSE: To describe 10-week and 12-month outcomes following treatment for divergence insufficiency-type esotropia in adults. METHODS: In this prospective observational study, 110 adults with divergence insufficiency-type esotropia, with a distance esodeviation measuring 2Δ to 30Δ and at least 25% larger at distance than near, and binocular diplopia present at least "sometimes" at distance, were enrolled at 28 sites when initiating new treatment. Surgery, prism, or divergence exercises/therapy were chosen at the investigator's discretion. Diplopia was assessed at enrollment and at 10-week and 12-month outcome examinations using a standardized diplopia questionnaire (DQ). Success was defined as DQ responses of "rarely" or "never" when looking straight ahead in the distance, with no alternative treatment initiated. RESULTS: Of the 110 participants, 32 (29%) were prescribed base-out prism; none had received prior treatment for esotropia. Success criteria were met by 22 of 30 at 10 weeks (73%; 95% CI, 54%-88%) and by 16 of 26 at 12 months (62%; 95% CI, 41%-80%). For the 76 (68%) who underwent strabismus surgery (82% of whom had been previously treated with prism), success criteria were met by 69 of 74 at 10 weeks (93%; 95% CI, 85%-98%) and by 57 of 72 at 12 months (79%; 95% CI, 68%-88%). CONCLUSIONS: In this study cohort, both base-out prism as initial therapy and strabismus surgery (usually following prism) were successful in treating diplopia for most adults with divergence insufficiency-type esotropia when assessed during the first year of follow-up.

Resolution of hypertropia with correction of intermittent exotropia.

PURPOSE: We describe the spontaneous resolution of hypertropia in a subset of patients with preoperative exotropia and hypertropia, who underwent surgery for intermittent exotropia alone. DESIGN: This was a retrospective case series. METHODS: The charts were reviewed of 17 patients who underwent surgical correction for an intermittent exotropia, who additionally were noted on preoperative exam to have greater than 5 prism dioptres of vertical deviation in primary position. Patients were excluded if they had prior strabismus surgery, dissociated vertical deviation, and paretic or restrictive deviations. RESULTS: All patients were documented to have complete resolution of any vertical deviation in any field of gaze. This effect was noted to persist. CONCLUSIONS: We propose that the measured distance hypertropia, which is coincident with intermittent exotropia, even with the appearance of superior oblique dysfunction or inferior oblique overaction, is not created by a true vertical or cyclovertical muscle imbalance. Further, that the reduction of the hypertropia at near fixation predicts its resolution with horizontal muscle surgery. Therefore, vertical surgery should not be performed to address the coincident vertical deviation in these patients.

2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure.

Temporal lobe epilepsy is a common form of drug-resistant epilepsy that sometimes responds to dietary manipulation such as the 'ketogenic diet'. Here we have investigated the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in the rat kindling model of temporal lobe epilepsy. We show that 2DG potently reduces the progression of kindling and blocks seizure-induced increases in the expression of brain-derived neurotrophic factor and its receptor, TrkB. This reduced expression is mediated by the transcription factor NRSF, which recruits the NADH-binding co-repressor CtBP to generate a repressive chromatin environment around the BDNF promoter. Our results show that 2DG has anticonvulsant and antiepileptic properties, suggesting that anti-glycolytic compounds may represent a new class of drugs for treating epilepsy. The metabolic regulation of neuronal genes by CtBP will open avenues of therapy for neurological disorders and cancer.

Localized domains of G9a-mediated histone methylation are required for silencing of neuronal genes.

Negative regulation of transcription is an important strategy in establishing and maintaining cell-specific gene expression patterns. Many neuronal genes are subject to active transcriptional repression outside the nervous system to establish neuronal specificity. NRSF/REST has been demonstrated to regulate at least 30 genes and contribute to their neuronal targeting by repressing transcription outside the nervous system. Further, human genome database searches reveal that over 800 genes contain an NRSE. Here we report that NRSF recruits the histone methylase G9a to silence NRSF target genes in nonneuronal cells. We show that G9a generates a highly localized domain of dimethylated histone H3-K9 around NRSEs, but H3-K27 remains unmethylated. The NRSEs are also associated with HP1. Finally, we demonstrate that dominant-negative G9a abrogates silencing of chromosomal neuronal genes. These findings implicate a role for histone methylation in targeting neuronal gene expression to the nervous system.