Variants in the WDR45 Gene Within the OPA-2 Locus Associate With Isolated X-Linked Optic Atrophy.

Purpose: To describe clinical and molecular findings of two families with X-linked optic atrophy and present two new pathogenic variants in the WDR45 gene. Methods: Case series and molecular analysis of two families of Jewish Ashkenazi descent with early onset bilateral optic atrophy. Whole-exome sequencing (WES) and bioinformatic analysis were performed, followed by Sanger sequencing and segregation analysis. Results: In both families, male siblings (three in family 1, two in family 2) had early-onset isolated bilateral optic atrophy. The sibling's healthy mother (and in the second family also one healthy sister) had a mild presentation, suggesting a carrier state and an X-linked inheritance pattern. All participants were otherwise healthy, apart from mild learning disabilities and autism spectrum disorder in two siblings of the second family. Variants in known optic atrophy genes were excluded. Analysis revealed a point variant in the WDR45 gene-a missense variant in the first family, NM_001029896.2:c.107C>A; NP_001025067.1:p.Pro36His (variant ID: 1704205), and a splice site variant in the second family, NM_001029896.2:c.236-1G>T; NP_009006.2:p.Val80Leu (variant ID: 1704204), located on Xp11.23 (OPA2 locus). Both variants are novel and predicted as pathogenic. In both families, the variant was seen with full segregation with the disease, occurring in all affected male participants and in one allele of the carrier females, as well as none of the healthy participants. Conclusions: Among two families with isolated X-linked optic atrophy, molecular analysis revealed novel variants in the WDR45 gene in full segregation with the disease. This gene resides within the OPA2 locus, previously described to associate with X-linked optic atrophy. Taken together, these findings suggest that certain pathogenic variants in the WDR45 gene are associated with isolated X-linked optic atrophy.

Ocular Behçet Disease-Clinical Manifestations, Treatments and Outcomes According to Age at Disease Onset.

Behçet disease (BD) is a multisystemic disease that commonly involves the eyes. Although it affects patients in all age groups, data on ocular disease by age of onset are limited. This retrospective, multicenter study aimed to compare epidemiology, systemic and ocular manifestations, treatments and outcomes between three age groups: juvenile (<18 years), adult (18-39 years) and late (≥40 years) disease onset. The study included 175 ocular BD patients (303 eyes) from Israel and Palestine: juvenile-onset (n = 25, 14.3%), adult-onset (n = 120, 68.6%) and late-onset (n = 30, 17.1%). Most patients in all groups were male. Systemic manifestations were similar in all groups. Systemic co-morbidities were more common in late-onset patients. Bilateral panuveitis was the most common ocular manifestation in all patients. Non-occlusive retinal vasculitis, peripheral vessel occlusions, cataract and elevated intraocular pressure were found more commonly among juvenile-onset eyes. Anterior uveitis and macular ischemia were most common among late-onset eyes, while branch retinal vein occlusion was most common in adult and late-onset eyes. All patients were treated with corticosteroids. Methotrexate, immunomodulatory combinations and biologic treatments were more commonly used for juvenile-onset patients. All groups had a similar visual outcome. Our study showed that patients with ocular BD have varied ocular manifestations and require different treatments according to age of disease onset, but visual outcome is similar.

Retinal vascular occlusions in ocular Behçet disease - a comparative analysis.

PURPOSE: The literature on retinal vascular occlusions in Behçet disease (BD) patients is limited. The aim of this study is to thoroughly investigate retinal vascular occlusions among ocular BD patients. METHODS: Retrospective, multicentre case-control study. Three-hundred and three eyes of 175 patients with ocular BD, from 13 hospitals in Israel and Palestine, were included. Patients were assigned into two groups according to the presence of retinal vascular occlusion. Epidemiology, systemic and ocular manifestations, treatments and outcomes were compared between the groups and risk factors for retinal vascular occlusions were identified. RESULTS: One hundred twenty-five patients (71.4%) were male. The mean age at presentation was 28.2 ± 0.86 years. Retinal vascular occlusions were found in 80 eyes of 54 (30.9%) patients, including branch retinal vein occlusion (51.3%), peripheral vessels occlusions (32.5%), central retinal vein occlusion (13.8%) and arterial occlusions (7.5%). Systemic manifestations were similar among both groups. Anterior uveitis was more common in non-occlusive eyes (p < 0.01). Non-occlusive retinal vasculitis (p = 0.03) and ocular complications were more common in occlusive eyes (p < 0.01). Treatments including mycophenolate mofetil, Infliximab or a combination therapy of anti-metabolite and calcineurin inhibitor were more commonly used by occlusive patients (p < 0.05). Occlusive patients underwent more cataract surgeries (p = 0.03). The occlusive group had worse mean best-corrected visual acuity (BCVA) throughout follow-up (p < 0.01). Risk factors for retinal vascular occlusions included male sex and Jewish ethnicity (p < 0.05). CONCLUSION: Retinal vascular occlusions were found in a third of ocular BD patients. Occlusive eyes had a worse prognosis. Risk factors for vascular occlusions were identified.

The effect of thermo-mechanical device (Tixel) treatment on evaporative dry eye disease - A pilot prospective clinical trial.

PURPOSE: To examine the effects of treatment with a thermomechanical skin device to the eyelid area on the clinical signs and symptoms of patients who suffer from dry eye disease (DED) secondary to meibomian gland dysfunction (MGD). METHODS: Forty patients aged 45 years or older with DED due to MGD were recruited. Both eyes (n = 80) of each patient received three treatments with the Tixel device (Novoxel®, Israel), with each treatment separated by a 2-week period. Treatment was applied across the upper and lower eyelids, with the same intensity, tip protrusion distance, and contact duration. Two additional follow-up visits were performed at 2-week intervals after treatment cessation. DED status was evaluated during each visit via SPEED II questionnaire, tear break-up time (TBUT), corneal staining score (CSS), MGD score, and frequency of lubricant use. Visual acuity (VA) was recorded during first and last visits. RESULTS: Mean age was 64.3 ± 12.4 years and 72.5 % (n = 29) were female. 45 % (n = 18) had a history of blepharitis, 12.5 % (n = 5) had chalazia, and 17.5 % (n = 7) suffered from allergic conjunctivitis. Mean follow-up time was 2.1 ± 0.6 months. Comparing the first and last visits, all parameters showed significant improvement after Tixel treatment: mean SPEED II scores (16.5 ± 5.9 to 11.8 ± 6.7, p < 0.001), CSS (2.0 ± 1.3 to 0.5 ± 0.9, p < 0.001), TBUT (2.7 ± 0.8 s to 6.5 ± 2.2 s, p < 0.001), MGD score (2.7 ± 0.5 to 1.2 ± 0.4, p < 0.001), and rate of lubricant use (3.4 ± 2.4 per day to 1.9 ± 2.0, p < 0.001). VA also improved (0.10 ± 0.11 logMAR to 0.08 ± 0.10 logMAR, p < 0.05). No major side effects were observed. CONCLUSIONS: In this pilot study Tixel treatment induced significant improvement of signs and symptoms among patients with DED due to MGD. Benefits persisted for at least one month. Further randomized controlled double-blinded studies are needed.

Cat-scratch disease: ocular manifestations and treatment outcome.

PURPOSE: To characterize cat-scratch disease (CSD) ocular manifestations and visual outcome and evaluate the effect of systemic antibiotics and corticosteroids on final visual acuity (VA). METHODS: Multicentre retrospective cohort study. Medical records of 86 patients with ocular disease (107 eyes) of 3222 patients identified in a national CSD surveillance study were reviewed. RESULTS: Mean age was 35.1 ± 14.2 years. Median follow-up was 20 weeks (range 1-806 weeks). Of 94/107 (88%) eyes with swollen disc, 60 (64%) had neuroretinitis at presentation, 14 (15%) developed neuroretinitis during follow-up, and 20 (21%) were diagnosed with inflammatory disc oedema. Optic nerve head lesion, uveitis, optic neuropathy and retinal vessel occlusion were found in 43 (40%), 38 (36%), 34 (33%) and 8 (7%) eyes, respectively. Good VA (better than 20/40), moderate vision loss (20/40-20/200) and severe vision loss (worse than 20/200) were found in 26/79 (33%), 35/79 (44%) and 18/79 (23%) eyes at baseline and in 63/79 (80%), 11/79 (14%) and 5/79 (6%) eyes at final follow-up, respectively (p < 0.001). Significant VA improvement (defined as improvement of ≥3 Snellen lines at final follow-up compared to baseline) occurred in 12/24 (50%) eyes treated with antibiotics compared with 14/16 (88%) eyes treated with antibiotics and corticosteroids (p = 0.02). Multivariate logistic regression was suggestive of the same association (odds ratio 7.0; 95% CI 1.3-37.7; p = 0.024). CONCLUSION: Optic nerve head lesion is a common and unique manifestation of ocular CSD. Most patients improved and had final good VA. Combined antibiotics and corticosteroid treatment was associated with a better visual outcome.

Characterization and comparison of the 10-2 SITA-standard and fast algorithms.

PURPOSE: To compare the 10-2 SITA-standard and SITA-fast visual field programs in patients with glaucoma. METHODS: We enrolled 26 patients with open angle glaucoma with involvement of at least one paracentral location on 24-2 SITA-standard field test. Each subject performed 10-2 SITA-standard and SITA-fast tests. Within 2 months this sequence of tests was repeated. RESULTS: SITA-fast was 30% shorter than SITA-standard (5.5 ± 1.1 vs 7.9 ± 1.1 minutes, P < 0.001). Mean MD was statistically significantly higher for SITA-standard compared with SITA-fast at first visit (Δ = 0.3 dB, P = 0.017) but not second visit. Inter-visit difference in MD or in number of depressed points was not significant for both programs. Bland-Altman analysis showed that clinically significant variations can exist in individual instances between the 2 programs and between repeat tests with the same program. CONCLUSIONS: The 10-2 SITA-fast algorithm is significantly shorter than SITA-standard. The two programs have similar long-term variability. Average same-visit between-program and same-program between-visit sensitivity results were similar for the study population, but clinically significant variability was observed for some individual test pairs. Group inter- and intra-program test results may be comparable, but in the management of the individual patient field change should be verified by repeat testing.

Compositional differences among commercially available botulinum toxin type A.

PURPOSE OF REVIEW: Since the advent of botulinum neurotoxin (BoNT) in the facial cosmetic field, it has become the leading nonsurgical cosmetic procedure in the USA, and several different formulations are currently in use. The aim of this study is to review the major 'players' in order to help the physician understand the clinically relevant dissimilarities between the products and by that promote treatment efficacy and patient satisfaction. RECENT FINDINGS: The different available formulations can be classified into two groups by the existence of absence of complexing proteins. Most of the influence that was previously attributed to these proteins has been found to be less relevant clinically, the immune response being the only remaining issue with supporting evidence in the literature. SUMMARY: Botulinum toxin type A is widely utilized in the cosmetic field, and it seems that all available and approved formulations are both well tolerated and effective in treating facial rhytids. The treating physician must be familiar with the differences between all the products, especially the fact that they are not interchangeable in respect to their recommended dosage.

Treatment of dry eye syndrome with orally administered CF101: data from a phase 2 clinical trial.

OBJECTIVE: To explore the safety and efficacy of CF101, an A(3) adenosine receptor agonist, in patients with moderate to severe dry eye syndrome. DESIGN: Phase 2, multicenter, randomized, double-masked, placebo-controlled, parallel-group study. PARTICIPANTS: Sixty-eight patients completed the study, 35 patients in the placebo group and 33 patients in the CF101 group. INTERVENTION: Patients were treated orally with either 1 mg CF101 pills or matching vehicle-filled placebo pills, given twice daily for 12 weeks, followed by a 2-week posttreatment observation. MAIN OUTCOME MEASURES: An improvement of more than 25% over baseline at week 12 in one of the following parameters: (1) tear break-up time (BUT); (2) superficial punctate keratitis assessed by fluorescein staining results; and (3) Schirmer tear test 1 results. Clinical laboratory safety tests, ophthalmic examinations, intraocular pressure (IOP) measurements, electrocardiographic evaluations, vital sign measurements, and monitoring of adverse events. RESULTS: A statistically significant increase in the proportion of patients who achieved more than 25% improvement in the corneal staining and in the clearance of corneal staining was noted between the CF101-treated group and the placebo group. Treatment with CF101 resulted in a statistically significant improvement in the mean change from baseline at week 12 of the corneal staining, BUT, and tear meniscus (TM) height in the CF101-treated group. CF101 was well tolerated and exhibited an excellent safety profile with no serious adverse events. A statistically significant decrease from baseline was observed in the IOP of the CF101-treated group in comparison with the placebo group. CONCLUSIONS: CF101, given orally, induced a statistically significant improvement in the corneal staining and an improvement in the BUT and TM in patients with moderate to severe dry eye syndrome. The drug was very well tolerated. These data and the anti-inflammatory characteristic of CF101 support further study of the drug as a potential treatment for the signs and symptoms of dry eye syndrome. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

A retrospective study of the eligibility for tonsillectomy.

BACKGROUND: The criteria for tonsillectomy for recurrent tonsillitis were established by prospective studies in the pediatric population and are applied to adults as well. No studies have been conducted to assess whether these guidelines are followed. OBJECTIVES: To examine the eligibility for tonsillectomy of tonsillectomized patients who were referred because of recurrent acute tonsillitis. METHODS: A retrospective case series in an ambulatory military otolaryngology clinic was conducted, and the medical records of 44 tonsillectomized patients who suffered from throat infections during the year before surgery were analyzed. The number of tonsillar infections that met the referral criteria was counted. RESULTS: The average number of throat infections that met the referral criteria was 1.89 per year. The average number of visits to the clinic due to upper respiratory tract infection was 12.92 (range 2-36) per year. The average number of visits for any cause was 45.13 (range 6-64) per year. One patient with eight documented throat infections met the criterion of more than six infections in the last year. CONCLUSION: Although the referral criteria were not strictly met, we speculate that surgery was probably beneficial. This study shows that the indications for tonsillectomy referral are not strictly followed, and that new criteria for referral of adults for tonsillectomy need to be established.

Wireless capsule endoscopy in Israeli Defense Force: two years of experience.

OBJECTIVES: Evaluate outcome and diagnostic yield of capsule endoscopy (CE) in soldiers with suspected small bowel disease, in comparison to traditional diagnostic procedures. METHODS: 27 consecutive soldiers who underwent CE between June 2002 and February 2004 were enrolled. Results of CE were compared to standard techniques. RESULTS: CE was normal in 16 patients (59.3%). Findings could not explain any signs or symptoms were observed in 11.1%. Definite diagnosis of Crohn's disease was obtained in 11.1%. Patients (62.5%) with a triad of symptoms (abdominal pain, changed bowel habits, and gastrointestinal bleeding) versus 15.8% without that triad, had either diagnostic or suspicious CE (p = 0.015). Diagnostic yield of CE was higher in gastrointestinal bleeding (25%) in comparison to suspected Crohn's disease (15.8%). Three out of 6 patients (50%) with suggestive findings of Crohn's disease in the preliminary workup were diagnosed as definite Crohn's by capsule endoscopy. CE allowed the physician to conclude workup in 71% patients. CONCLUSION: CE should be used when obscure gastrointestinal bleeding or Crohn's disease is suspected without a conclusive diagnosis. Furthermore, when a triad of symptoms exists CE should be considered as first line examination.

Screening and treating amblyopia: are we making a difference?

PURPOSE: To determine the rate of amblyopia in native Jewish Israelis compared with those who immigrated from the former Soviet Union (U.S.S.R.) after they were 10 years of age. METHODS: Health records of all 16-year-old subjects examined in the Israel Defense Forces Recruitment Center between 1998 and 2003 were analyzed. The number of subjects with best corrected visual acuity (BCVA) of 6/12 or less in at least one eye among native Israelis and among those who immigrated to Israel from the U.S.S.R. after they were 10 years of age was determined. Subjects who had any ocular disease except cataract, corneal opacity, strabismus, or ptosis were excluded. RESULTS: Of 305,712 subjects examined between 1998 and 2003, 292,255 were enrolled in the study. Of those, 260,186 (89%) were born in Israel and 32,069 (11%) were born in the U.S.S.R. and immigrated to Israel after they were 10 years of age. There were 2565 (0.98%) native Israelis and 483 (1.5%) immigrants who had BCVA of 6/12 or less in at least one eye (chi(2) test, P < 0.00001). The rate of amblyopia among subjects who had refractive errors was 14.6% among immigrants, as opposed to 8.0% among native Israelis (P < 0.0001), whereas amblyopia rates among those with strabismus, cataract, or ptosis were similar in native Israelis and immigrants (34.4%, 38.6%, 12.8% as opposed to 34%, 37.5%, 15.4%, respectively, P = 0.5-0.61). CONCLUSIONS: The difference in the rate of refractive amblyopia as opposed to strabismic and deprivation amblyopia may be due to the difference in vision screening methods between both countries.