David B. Granet

Lanosterol reverses protein aggregation in cataracts

The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

Randomized clinical trial of treatments for symptomatic convergence insufficiency in children

OBJECTIVE To compare home-based pencil push-ups (HBPP), home-based computer vergence/accommodative therapy and pencil push-ups (HBCVAT+), office-based vergence/accommodative therapy with home reinforcement (OBVAT), and office-based placebo therapy with home reinforcement (OBPT) as treatments for symptomatic convergence insufficiency. METHODS In a randomized clinical trial, 221 children aged 9 to 17 years with symptomatic convergence insufficiency were assigned to 1 of 4 treatments. MAIN OUTCOME MEASURES Convergence Insufficiency Symptom Survey score after 12 weeks of treatment. Secondary outcomes were near point of convergence and positive fusional vergence at near. RESULTS After 12 weeks of treatment, the OBVAT groups mean Convergence Insufficiency Symptom Survey score (15.1) was statistically significantly lower than those of 21.3, 24.7, and 21.9 in the HBCVAT+, HBPP, and OBPT groups, respectively (P < .001). The OBVAT group also demonstrated a significantly improved near point of convergence and positive fusional vergence at near compared with the other groups (P <or= .005 for all comparisons). A successful or improved outcome was found in 73%, 43%, 33%, and 35% of patients in the OBVAT, HBPP, HBCVAT+, and OBPT groups, respectively. CONCLUSIONS Twelve weeks of OBVAT results in a significantly greater improvement in symptoms and clinical measures of near point of convergence and positive fusional vergence and a greater percentage of patients reaching the predetermined criteria of success compared with HBPP, HBCVAT+, and OBPT. Application to Clinical Practice Office-based vergence accommodative therapy is an effective treatment for children with symptomatic convergence insufficiency. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00338611.

The Relationship between Convergence Insufficiency and ADHD

Background: Children being evaluated for attention deficit hyperactivity disorder (ADHD) often have an eye exam as part of their evaluation. The symptoms of convergence insufficiency (CI) can make it difficult for a student to concentrate on extended reading and overlap with those of ADHD. Methods: A retrospective review of 266 patients with CI presenting to an academic pediatric ophthalmology practice was performed. All patients included were diagnosed with CI by one author (DBG) and evaluated for the diagnosis of ADHD. A computerized review was also performed looking at the converse incidence of CI in patients carrying the diagnosis of ADHD. Results: We reviewed 266 charts of patients with CI. Twenty-six patients (9.8%) were diagnosed with ADHD at some time in their clinical course. Of the patients with ADHD and CI, 20 (76.9%) were on medication for ADHD at the time of diagnosis for CI while 6 (23.1%) were either not on medication or the medication was discontinued several months before the diagnosis of CI. The review of computer records showed a 15.9% incidence of CI in the ADHD population. Conclusion: We report an apparent three-fold greater incidence of ADHD among patients with CI when compared with the incidence of ADHD in the general US population (1.8–3.3%) (12). We also note a seeming three-fold greater incidence of CI in the ADHD population. This may simply represent an association and not be a causative relationship. Until further studies are performed, however, patients diagnosed with ADHD should be evaluated to identify the small subset that may have CI – a condition that responds well to treatment at home.

Validity of the convergence insufficiency symptom survey: a confirmatory study.

Purpose. The objectives of the present study were to evaluate whether investigator bias influenced the Convergence Insufficiency Symptom Survey (CISS) scores of children with normal binocular vision (NBV) in our original validation study, reevaluate the usefulness of the cutoff score of 16, and reexamine the validity of the CISS. Methods. Six clinical sites participating in the Convergence Insufficiency Treatment Trial (CITT) enrolled 46 children 9 to <18 years with NBV. Examiners masked to the child’s binocular vision status administered the CISS. The mean CISS score was compared with that from the children with NBV in the original, unmasked CISS study and also to that of the 221 symptomatic convergence insufficiency (CI) children enrolled in the CITT. Results. The mean (±standard deviation) CISS score for 46 subjects with NBV was 10.4 (±8.1). This was comparable with our prior unmasked NBV study (mean = 8.1 (±6.2); p = 0.11) but was significantly different from that of the CITT CI group (mean = 29.8 ± 9.0; p < 0.001). Eighty-three percent of these NBV subjects scored <16 on the CISS, which is not statistically different from the 87.5% found in the original unmasked study (p = 0.49). Conclusions. Examiner bias did not affect the CISS scores for subjects with NBV in our prior study. The CISS continues to be a valid instrument for quantifying symptoms in 9 to <18-year-old children. These results also confirm the validity of a cut-point of ≥16 in distinguishing children with symptomatic CI from those with NBV.

Graded orbital decompression based on severity of proptosis

OBJECTIVE To study the results of orbital decompression based on the severity of preoperative proptosis. DESIGN A retrospective noncomparative interventional case series. PARTICIPANTS Thirty-nine orbits in 23 patients with thyroid-related orbitopathy at a university-based referral center. INTERVENTION Graded orbital decompression was performed in all patients based on the severity of preoperative exophthalmometry. MAIN OUTCOME MEASURES Exophthalmometry, visual acuity, margin-to-reflex distance, prism cover testing, and intraocular pressure. RESULTS Mean proptosis reduction in all orbits was 6.4 +/- 2.7 mm (P < 0.01). In group 1 (preoperative exophthalmometry <22 mm), proptosis decreased with a mean of 4.8 +/- 1.3 mm (P < 0.01); mean proptosis reduction was 6.0 +/- 2.3 mm (P < 0.01) and 8.9 +/- 3.4 mm (P < 0.01) in group 2 (exophthalmometry between 22-25 mm) and group 3 (exophthalmometry >25 mm), respectively. In four of five eyes with compressive optic neuropathy there was an improvement of best-corrected visual acuity of 2 lines or more. Margin-to-reflex distance of the upper and lower lids and intraocular pressure were reduced in all groups. New-onset diplopia developed in two patients (8.7%); 13 of 15 patients (86.7%) who had diplopia preoperatively had persistent diplopia postoperatively. Two patients (13.3%) had relief of diplopia postoperatively. CONCLUSIONS Graded orbital decompression based on the severity of preoperative exophthalmometry is useful to determine the type and amount of orbital surgery to be performed.

Prosthetic motility in pegged versus unpegged integrated porous orbital implants.

Purpose To objectively measure and compare prosthetic motility in pegged versus unpegged orbital implants and to determine subjective patient assessment of motility after the pegging procedure. Methods A prospective case series of 10 patients with integrated porous orbital implants, who had secondary motility peg placement procedure, were studied. Infrared oculography was used to quantitatively assess pegged and unpegged prosthetic eye motility in horizontal and vertical excursions. Results For horizontal excursions, prosthetic motility in unpegged implants retained an average of 49.6% of measured motility of the contralateral normal eye, which increased to 86.5% with peg placement (P <0.05). For vertical excursions, prosthetic motility in unpegged implants retained an average of 51.3% of measured motility of the contralateral normal eye, which increased to 54.3% with peg placement (P >0.3). Nine of 10 patients judged their motility as “significantly improved,” and 1 patient gave a rating of “some improvement” after peg placement. Four of 10 patients had granulomas around the peg sites. Conclusions Objective assessment of prosthetic motility shows a significant increase in horizontal gaze after motility peg placement.

Lens regeneration using endogenous stem cells with gain of visual function

The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells.

Improvement in Academic Behaviors After Successful Treatment of Convergence Insufficiency

Purpose. To determine whether treatment of symptomatic convergence insufficiency (CI) has an effect on Academic Behavior Survey (ABS) scores. Methods. The ABS is a six-item survey developed by the Convergence Insufficiency Treatment Trial Group that quantifies the frequency of adverse school behaviors and parental concern about school performance on an ordinal scale from 0 (never) to 4 (always) with total scores ranging from 0 to 24. The ABS was administered at baseline and after 12 weeks of treatment to the parents of 218 children aged 9 to 17 years with symptomatic CI, who were enrolled in the Convergence Insufficiency Treatment Trial and randomized into (1) home-based pencil push-ups; (2) home-based computer vergence/accommodative therapy and pencil push-ups; (3) office-based vergence/accommodative therapy with home reinforcement; and (4) office-based placebo therapy with home reinforcement. Participants were classified as successful (n = 42), improved (n = 60), or non-responder (n = 116) at the completion of 12 weeks of treatment using a composite measure of the symptom score, nearpoint of convergence, and positive fusional vergence. Analysis of covariance methods were used to compare the mean change in ABS between response to treatment groups while controlling for the ABS score at baseline. Results. The mean ABS score for the entire group at baseline was 12.85 (SD = 6.3). The mean ABS score decreased (improved) in those categorized as successful, improved, and non-responder by 4.0, 2.9, and 1.3 points, respectively. The improvement in the ABS score was significantly related to treatment outcome (p < 0.0001), with the ABS score being significantly lower (better) for children who were successful or improved after treatment as compared to children who were non-responders (p = 0.002 and 0.043, respectively). Conclusions. A successful or improved outcome after CI treatment was associated with a reduction in the frequency of adverse academic behaviors and parental concern associated with reading and school work as reported by parents.

Clinical efficacy of olopatadine vs epinastine ophthalmic solution in the conjunctival allergen challenge model

SUMMARY Background: Olopatadine hydrochloride 0.1% ophthalmic solution (Patanol*) and epinastine hydrochloride 0.05% ophthalmic solution (Elestat†) are two topical antiallergic agents. Olopatadine is indicated for the treatment of the signs and symptoms of allergic conjunctivitis that include itching, redness, tearing, lid swelling, and chemosis. Epinastine is indicated for the prevention of itching associated with allergic conjunctivitis. Objective: This study compared the clinical efficacy of olopatadine and epinastine in the prevention of itching and conjunctival redness in the conjunctival allergen challenge (CAC) model. Research design and methods: This was a prospective, randomized, double-masked, contralaterally-controlled, single center allergen challenge study. Ninety-six subjects with a history of allergic conjunctivitis were screened, and the 66 who responded to conjunctival allergen challenge at visits 1 and 2 were randomized into 1 of 3 treatment groups at visit 3 to receive one drop of study medication in each eye: (1) olopatadine in one eye and epinastine in the fellow eye, (2) olopatadine in one eye and placebo in the fellow eye, and (3) epinastine in one eye and placebo in the fellow eye. Five minutes after study drop instillation, subjects were bilaterally challenged with the allergen concentration that had elicited a positive conjunctival allergic response at Visits 1 and 2. Subjective itching assessments were given at 3 min, 5 min, and 7 min post challenge. Objective redness and chemosis assessments were made at 10 min, 15 min, and 20 min post challenge. Paired sample two-tailed t-tests were performed on the mean scores at each time point to assess statistical significance in the differences between treatments. Main outcome measures; results: Fifty-three subjects were randomized into the olopatadine/epinastine treatment group, the primary analysis group. Olopatadine treated eyes exhibited significantly lower mean itching and conjunctival redness scores than the contralateral epinastine treated eyes, –0.19 ( p = 0.003) and –0.52 ( p < 0.001), respectively. Olopatadine treated eyes also exhibited significantly less chemosis –0.24 ( p < 0.001), ciliary redness –0.55 ( p < 0.001), and episcleral redness –0.58 ( p < 0.001) than epinastine treated eyes. Conclusion: Olopatadine is significantly more effective than epinastine in controlling itching, redness and chemosis associated with allergic conjunctivitis in the CAC model. * Patanol is a registered tradename of Alcon Laboratories Inc, Forth Worth, TX, USA

Comparison of the efficacy of combined fluticasone propionate and olopatadine versus combined fluticasone propionate and fexofenadine for the treatment of allergic rhinoconjunctivitis induced by conjunctival allergen challenge.

BACKGROUND One approach to treating allergic rhinoconjunctivitis is the concomitant use of an intranasal spray such as fluticasone propionate to alleviate nasal symptoms and a topical or systemic agent to relieve ocular symptoms. It has not yet been determined whether a topical or systemic agent is more effective for the latter purpose. OBJECTIVE This study compared the efficacy of combined use of fluticasone and olopatadine with combined use of fluticasone and fexofenadine in the treatment of the signs and symptoms of allergic rhinoconjunctivitis. METHODS This 2-site, randomized, double-masked, placebo-controlled, parallel-group study employed the conjunctival allergen challenge (CAC) model, a standardized method of inducing ocular and nasal signs and symptoms of allergic rhinoconjunctivitis. At visit 1, subjects underwent CAC to determine the dose of allergen required to elicit a positive reaction. The allergen dose was confirmed at visit 2, and, according to a randomization schedule, subjects were dispensed fluticasone, olopatadine, and placebo pill; fluticasone, fexofenadine, and tear substitute; or placebo nasal spray, placebo pill, and tear substitute. CAC took place at visit 3, after patients had used the assigned medications for 2 weeks. Study medication was instilled 2 hours before CAC, after which allergic signs and symptoms were graded on standardized scales. The primary efficacy variables were ocular itching, ocular redness, and overall nasal symptoms. RESULTS Eighty subjects completed the study: 30 received fluticasone and olopatadine, 30 fluticasone and fexofenadine, and 20 placebo. Women constituted 63.8% of the study population and men 36.3%; 91.3% were white, 3.8% black, 2.5% Hispanic, 1.3% Asian, and 1.3% other. Concomitant use of fluticasone and olopatadine produced significantly greater improvements in ocular itching at 3 and 7 minutes after CAC compared with fluticasone and fexofenadine (P < 0.05). There were no significant differences in redness scores between groups; however, concomitant use of fluticasone and olopatadine produced significantly greater improvements in redness at 2 time points in each of the 3 vessel beds (ciliary, conjunctival, and episcleral) compared with placebo, and fluticasone and fexofenadine produced significantly greater improvement in redness at 1 time point in I vessel bed compared with placebo (both comparisons, P < 0.05). The 2 treatments had similar effects on total nasal symptom efficacy scores. CONCLUSIONS In this study, concomitant use of the topical agents fluticasone and olopatadine was more effective than concomitant use of fluticasone plus fexofenadine for overall treatment of the signs and symptoms of induced allergic rhinoconjunctivitis.