Biomedical subjects

David A Leske

Publications and source records attributed to David A Leske.

At least 19 recordsLinked to original sources

PubMed2006

A symptom survey and quality of life questionnaire for nasolacrimal duct obstruction in children.

PURPOSE: To develop and validate a new parental questionnaire addressing symptoms and health-related quality of life (HRQL) in childhood nasolacrimal duct obstruction (NLDO). DESIGN: Cross-sectional study. PARTICIPANTS: Children ages 6 to younger than 48 months with and without clinical signs of NLDO. METHODS: A new questionnaire was developed using semistructured interviews with parents of children with NLDO and through discussions with expert clinicians. Questionnaires were completed by parents of children with and without NLDO. Cronbach's alpha was calculated as a measure of internal-consistency reliability. Factor analysis was used to evaluate a priori subscales: symptoms and HRQL. Discriminant construct validity was assessed by comparing questionnaire scores between children with and without NLDO and between affected and unaffected eyes of children with unilateral NLDO. Instrument responsiveness was determined by comparing presurgical and postsurgical intervention scores in a subset of NLDO patients who underwent surgical treatment. MAIN OUTCOME MEASURE: The NLDO questionnaire score. RESULTS: Eighty-seven children were enrolled, 56 with and 31 without NLDO. All but 2 questions on the questionnaire showed a good distribution of responses, a high correlation with the rest of the questionnaire, and excellent discrimination between patients with and without NLDO. Cronbach's alpha values were good for the overall questionnaire (0.95), and for 2 predetermined subscales: symptoms (0.95) and HRQL (0.85). On a 0 to 4 scale, NLDO patients had worse scores compared with non-NLDO patients for both symptoms (mean difference, 2.1; 95% confidence interval [CI], 1.9-2.3) and HRQL (mean difference, 1.2; 95% CI, 0.9-1.5) subscales. The NLDO patients had worse scores before intervention compared with after intervention for both the symptoms (mean difference, 2.2; 95% CI, 1.6-2.9) and HRQL (mean difference, 1.4; 95% CI, 0.8-2.1) subscales. Finally, NLDO patients had worse symptom scores for affected eyes compared with unaffected eyes (mean difference, 2.3; 95% CI, 1.9-2.6). CONCLUSIONS: This novel NLDO questionnaire is useful in quantifying parental perception of symptoms and HRQL in childhood NLDO. The questionnaire may have a role in future clinical studies of NLDO.

Child, Preschool↗

PubMed2006

Real depth vs randot stereotests.

PURPOSE: To compare the performance of real depth and Randot stereotests in strabismic and nonstrabismic patients. DESIGN: Observational case series. METHODS: Stereoacuity was tested in 182 patients with a variety of strabismic conditions, using the Frisby-Davis 2 (FD2) distance stereotest, the near Frisby (nF) (both real depth tests), the Preschool Randot (nR), and Distance Randot (dR) tests (both based on Polaroid vectographs). RESULTS: Patients appreciated finer disparities with the nF test than the nR test at near and with the FD2 test than the dR test at distance. CONCLUSIONS: The type of stereotest influences measurable thresholds, and the results from different tests are not interchangeable. The choice of test should depend on the question being asked; nF and FD2 would be appropriate for determining presence or absence of stereopsis and best measurable stereopsis. The more rigorous Randot tests would be appropriate for determining subtle changes.

Adolescent↗

PubMed2006

The relationship of retinal VEGF and retinal IGF-1 mRNA with neovascularization in an acidosis-induced model of retinopathy of prematurity.

PURPOSE: Acidosis-induced retinopathy (AIR) in the neonatal rat provides an alternative model for retinopathy of prematurity (ROP). We studied the relationship of vascular endothelial growth factor (VEGF) retinal mRNA and insulin-like growth factor-1 (IGF-1) retinal mRNA expression with the emergence of neovascularization (NV) in AIR. METHODS: Two hundred seventy-five newborn Sprague-Dawley rats were raised in 11 expanded litters of 25. Using our established AIR model, acidosis was induced by twice-daily gavage with NH4Cl from day 2 to day 8 of life (n=175). Rats were sacrificed at days 5, 8, and 10. Nongavaged rats were used as age-matched controls (n=100). Retinae from left eyes were dissected, flatmounts were ADPase-stained, and the presence and severity of NV was scored in a masked manner. Individual right retinae were processed for analysis of retinal VEGF and IGF-1 mRNA using quantitative real-time reverse-transcriptase PCR (qRT-PCR). RESULTS: Retinal VEGF mRNA was increased 1.4-fold at day 10 in AIR, when compared with age-matched controls (p=0.03). This correlated with maximal NV at day 10 in AIR. Retinal IGF-1 mRNA was decreased to 82% of its normal expression on day 8 (p=0.006), prior to maximal NV, before returning to normal expression at day 10, when compared with nonacidotic controls. CONCLUSIONS: In AIR, preretinal neovascularization is associated with decreased retinal IGF-1 mRNA prior to maximal NV and increased retinal VEGF mRNA at the time of maximal NV. These growth factor changes in AIR are similar to those seen with hypercarbic oxygen-induced retinopathy. The retinal IGF-1 pathway may provide an alternative target for therapeutic intervention in abnormal retinal angiogenesis.

Acidosis↗

PubMed2005

Anti-thyroid methimazole in an acidosis-induced retinopathy rat model of retinopathy of prematurity.

PURPOSE: Methimazole (MMI), an anti-thyroid drug known to reduce serum levels of L-thyroxine (T4) and insulin-like growth factor-1 (IGF-1), has been previously reported to increase the incidence of neovascularization (NV) in an oxygen-induced retinopathy (OIR) model of retinopathy of prematurity (ROP) in rats. We investigated the effect of MMI on the incidence and severity of NV in a non-oxygen-induced model of ROP, acidosis-induced retinopathy (AIR). METHODS: Newborn Sprague Dawley rats were raised in expanded litters of 25 in room air for four or ten days under one of the two following conditions: (1) Our established model of AIR (acidosis via NH4Cl gavage (10 mmol/kg) twice daily from days 2 to 7, followed by two days of recovery) or (2) MMI (given as a 0.1% solution to nursing mothers) in the above AIR model. Left eyes were fixed, and retinas were dissected and ADPase-stained. Flat mounted retinas were graded in a masked manner for presence and severity of NV, and retinal vascular areas were quantified. Serum IGF-1 and T4 concentrations were measured by radioimmunoassay on days 4 and 10. Arterial blood pH measurements were performed on day 4. RESULTS: The incidence and severity of NV were similar between AIR and MMI-AIR rats (incidence: 24% and 33%). Serum IGF-1 concentrations in 10 day MMI-AIR rats were significantly lower than untreated non-acidotic controls (medians: 158 ng/ml and 207 ng/ml; p=0.03). Serum IGF-1 concentrations were similar between 10 day AIR rats and untreated non-acidotic controls (medians: 189 ng/ml and 207 ng/ml; p>0.9). CONCLUSIONS: MMI does not increase the incidence or severity of NV in an AIR neonatal rat model of ROP. Although serum IGF-1 has been considered permissive for NV in immature retinas, supranormal concentrations of serum IGF-1 may not be necessary for abnormal retinal angiogenesis. Further studies are warranted on the roles of serum IGF-1 and L-thyroxine in the pathogenesis of ROP.

Acidosis↗

PubMed2005

New methods for quantifying diplopia.

PURPOSE: To develop new methods for quantifying diplopia and test their validity, test-retest reliability, and responsiveness to treatment. DESIGN: Prospective case series. PARTICIPANTS: Adult patients with diplopia in 2 tertiary referral practices. Diagnosis included cranial nerve palsies, thyroid eye disease, supranuclear palsies, and ocular myasthenia gravis. METHODS: The new diplopia questionnaire and cervical range of motion (CROM) diplopia examination were tested in a 15-patient validity study against the standard diplopia field performed on the Goldmann perimeter (each scored 0 [no diplopia] to 100 [constant diplopia in all fields]). The test-retest reliability of the CROM diplopia examination was determined in 27 patients. The responsiveness to treatment of the diplopia questionnaire and the CROM examination was tested in 15 patients who underwent strabismus surgery or received systemic prednisone for ocular myasthenia gravis. MAIN OUTCOME MEASURES: Validity was evaluated by the intraclass correlation coefficient (ICC) compared with the standard Goldmann diplopia field. Test-rest reliability was evaluated by the ICC. Responsiveness to treatment was evaluated by comparing pretreatment and posttreatment scores. RESULTS: There was excellent agreement between the diplopia questionnaire score and Goldmann diplopia field score (ICC, 0.90) and between the CROM diplopia examination score and Goldmann diplopia field score (ICC, 0.88). Intertester reliability of the CROM diplopia examination score was excellent (ICC, 0.87; 95% confidence interval, 0.74-0.94). Postintervention scores were significantly lower than baseline (P = 0.0003 for CROM and P = 0.0001 for the questionnaire), with a median postintervention improvement of 48 for the CROM diplopia score (quartiles 12-68) and 36 for the diplopia questionnaire (quartiles 20-52). CONCLUSIONS: Our new diplopia questionnaire and new CROM diplopia examination are valid, reliable, and responsive measures of diplopia severity. The tests are easy to administer and require less expensive and less cumbersome equipment than previously available.

Adult↗

PubMed2005

Differences between rat strains in models of retinopathy of prematurity.

PURPOSE: Genetic factors appear to modulate the incidence and severity of retinopathy of prematurity (ROP). Different rat strains may be analogous to genetic differences across human ethnic groups. We investigated the incidence and severity of neovascularization (NV) in Brown Norway (BN) and Sprague Dawley (SD) rats in oxygen-induced retinopathy (OIR) and acidosis-induced retinopathy (AIR) models for ROP. We also studied whether there was a difference in retinal vascular endothelial growth factor (VEGF) mRNA levels in OIR animals. METHODS: Newborn SD and BN rats (110 in both groups) were raised in standardized litters of ten (four OIR, twelve AIR, six non-gavaged room air controls). Beginning on day 1 of life, OIR litters were exposed to seven cycles of hyperoxia (80% O2, 20.5 h) and hypoxia (10% O2, 0.5 h) with a gradual return to 80% O2 over 3 h. This was followed by room air recovery for five days. OIR and OIR control rats were sacrificed on day 13 of life. AIR rats were gavaged twice daily with NH4Cl (10 mmol/kg) from day 2 to day 7 of life, or 15 mmol/kg twice daily on day 2 and then 10 mmol/kg twice daily from day 3 to day 7. AIR and AIR control rats were sacrificed on day 10 or day 13. Retinas from left eyes were dissected, ADPase stained and flatmounted. Presence and severity of NV (clock hours, 0 to 12) was scored by a masked observer. Right retinas from OIR and room air controls were processed for VEGF mRNA analysis. RESULTS: In OIR rats, the incidence of NV was higher in BN than SD rats (100% compared to 5%, p<0.0001). NV was more severe in BN rats (1 to 10 clock hours, median 7 clock hours compared to 0 to 1 clock hours, p=0.0001). In contrast, the incidence of NV in AIR rats was similar in BN and SD rats (4% compared to 0%, p=1.0) in the 10 mmol/kg study, and 18% compared to 0%, (p= 0.15) in the 15 mmol/kg study. Increased levels of retinal VEGF mRNA were found in BN OIR animals when compared to BN room air controls (1.4 fold increase) whereas retinal VEGF mRNA levels were similar between SD OIR and SD room air control animals. CONCLUSIONS: BN rats differ from SD rats in incidence and severity of NV in OIR. The findings in AIR were limited by the low incidence of NV and intolerance to higher multiple doses of NH4Cl. In OIR, the higher severity of NV was associated with higher retinal VEGF mRNA in BN OIR rats. Studies are warranted to investigate the genetic differences between Brown Norway and Sprague Dawley rats in models of ROP. These genetic studies may yield further clues into the pathogenesis of clinical ROP.

Acid-Base Equilibrium↗

PubMed2005

The effect of L-thyroxine supplementation on retinal vascular development in neonatal rats.

PURPOSE: Thyroxine (T4) plays a role in neuroretinal maturation, but little is known regarding its role in retinal vascularization. The neonatal rat retina is incompletely vascularized at birth, providing a model for the human premature infant retina and for retinopathy of prematurity (ROP). We hypothesized that T4 supplementation would accelerate vascular development of normal neonatal rat retina. METHODS: Two hundred twenty Sprague-Dawley rats were raised in litters of 10 in room air and received either 0.05 microg/g, 0.5 microg/g, or 1.0 microg/g of intraperitoneal T4 or saline control beginning on day 1 of life for 3 days, 7 days, or 3 days followed by 4 days recovery. Rats were sacrificed on either day 4 or day 8 of life. Left eyes were fixed, retinae dissected and ADPase-stained. Flat mounted retinae were digitized and total retinal areas and retinal vascular density were evaluated in a masked manner. Serum T4, thyroid stimulating hormone (TSH), and insulin-like growth factor-1 (IGF-1) were measured at each time point. RESULTS: Retinal vascular density was reduced in animals receiving daily 1 microg/g T4 compared with saline controls after 3 days of T4 (16.8 +/- 1.4 vessels/mm vs. 18.3 +/- 1.3 vessels/mm, p = 0.04) and 7 days of T4 (14.4 +/- 1.3 vessels/mm vs. 16.8 +/- 1.1 vessels/mm, p < 0.0006). However, retinal vascular density returned to normal after 3 days of treatment and 4 days of recovery. Vascularized retinal area was reduced in animals receiving 1 microg/g T4 for 3 days followed by 4 days recovery compared with saline controls (85 +/- 6% vs. 92 +/- 3%, p = 0.002). At lower doses of T4 (0.05 microg/g and 0.5 microg/g for 3 or 7 days) and at 1 microg/g T4 for 7 days, there was no effect on vascularized retinal area. Serum T4 levels were increased, with corresponding TSH suppression, after T4 treatment for 3 or 7 days. Serum IGF-1 levels were unaffected by T4 supplementation. CONCLUSIONS: Systemic T4 supplementation at 1 microg/g per day was detrimental to retinal vascular development in neonatal animals. If these effects are paralleled in human neonates, T4 supplementation might increase, rather than decrease, the risk of developing ROP. Further work on the role of T4 in the pathogenesis of ROP is warranted.

Animals↗

PubMed2004

Effect of bicarbonate on retinal vasculature and acidosis-induced retinopathy in the neonatal rat.

BACKGROUND: Systemic acidosis induces preretinal neovascularization (NV) analogous to retinopathy of prematurity (ROP) in the neonatal rat. Sodium bicarbonate is used in human neonates to treat acidosis. The effects of alkali administration on the developing retinal vasculature and on acidosis-induced retinopathy (AIR) are unknown. We investigated the effect of sodium bicarbonate gavage on the retinal vasculature of normal and acidotic neonatal rats to determine (1) whether bicarbonate treatment is associated with preretinal NV and (2) whether AIR can be prevented with systemic bicarbonate treatment. METHODS: The extent of acidosis and alkalosis were initially determined from carotid arterial blood samples. In the bicarbonate-alone study, newborn rats were randomized into litters of 25 and received bicarbonate doses of 15 mmol/kg twice daily and 20 mmol/kg once daily from days 2 to 7. Control animals received saline gavage. In the AIR treatment study, acidosis was induced in neonatal rats by intraperitoneal injection of acetazolamide 200 mg/kg from days 2 to 7. Acetazolamide-treated rats received either additional bicarbonate gavage or no additional treatment. Eyes were enucleated on day 13, and the retinal vasculature was assessed for NV using ADPase staining techniques and light microscopy. RESULTS: Systemic alkalosis (peak pH 7.55+/-0.02; mean +/- SD) was confirmed with bicarbonate gavage, and partial reversal of acidosis was confirmed when acetazolamide-treated rats received bicarbonate. Surviving rats receiving bicarbonate 15 mmol/kg twice daily (28% survival) and 20 mmol/kg bicarbonate once daily (45% survival) had an incidence of preretinal NV of 9% and 8%, respectively. No NV was seen in saline-control rats. In the acetazolamide-treated rats, the incidence of preretinal NV in surviving rats was numerically lower in bicarbonate-treated rats than acetazolamide-only controls (8% versus 24%, p=0.065) but with only 19% survival in the bicarbonate-treated rats. CONCLUSIONS: In the neonatal rat, alkalosis induced by bicarbonate gavage is associated with a low incidence of mild, preretinal NV similar to ROP. Although treating acidotic rats with bicarbonate may reduce the incidence of preretinal NV, treatment was associated with an unacceptable mortality rate.

Acetazolamide↗

PubMed2004

Long-term retinal transgene expression with FIV versus adenoviral vectors.

PURPOSE: Gene therapy for chronic retinal diseases will require long-term expression of therapeutic transgenes. Lentiviral and adenoviral (Ad) vectors are gene delivery systems with markedly different properties. Lentiviral vectors require integration into the host genome, which facilitates long-term expression, while Ad vectors remain episomal. We compared time course, location, and extent of transgene expression from replication-deficient feline immunodeficiency virus (FIV) vectors and Ad vectors in neonatal rat retina. METHODS: A dose-response study was conducted to determine the optimal subretinal dose for comparison of FIV and Ad vectors with an internal cassette expressing beta-galactosidase under transcriptional control of the CMV immediate-early gene promoter/enhancer. Forty-two five-day old Sprague-Dawley rats received subretinal injections of 2 microl containing 2x10(3) transducing units (TU, n=14), 2x10(4) TU (n=14) or 2x10(5) TU (n=14) of FIV vector (right eye) and Ad vector (left eye). Expression was evaluated 48 h after transduction. In the subsequent long-term expression study, 60 five-day old rats received a subretinal injection of 2x10(5) TU FIV vector (right eye) and Ad vector (left eye). Ten pairs of eyes were analyzed at 1 week, 1 month, 3 months, 6 months, 12 months, and the remainder at 16 months. Eye cups were evaluated in a masked manner for extent of beta-galactosidase expression (graded 0-5) by whole mount microscopy and by cross sectional histology. RESULTS: In the dose-response study, 2x10(5) TU resulted in consistent, widespread retinal transduction with both vectors and was selected as the dose for the subsequent study. In the long-term expression study, FIV vector resulted in a higher grade of expression than Ad at multiple single time points and produced higher overall expression when data from all eyes across the entire 16 month study were analyzed (p=0.01). Retinal expression was present at 16 months with both vectors. beta-galactosidase expression was limited to the retinal pigment epithelium (RPE) until the first month, but later was also found to a lesser extent in neurosensory retina with each vector. In contrast to FIV, most Ad injected eyes showed signs of focal accumulation of macrophage-like cells with disrupted retinal architecture. CONCLUSIONS: Both FIV and Ad vectors result in long-term transgene expression in RPE after subretinal injection. FIV vectors show more promise than Ad as delivery systems for retinal diseases since they transduce greater areas of RPE, result in less cellular infiltrate, and cause less disruption of retinal architecture. The persistent expression at 16 months of follow-up suggests that these lentiviral vectors are useful for gene therapy of chronic retinal diseases.

Adenoviridae↗

PubMed2004

The role of VEGF and IGF-1 in a hypercarbic oxygen-induced retinopathy rat model of ROP.

PURPOSE: We have previously described a severe form of oxygen-induced retinopathy (OIR) in the neonatal rat, analogous to human retinopathy of prematurity (ROP), where carbon dioxide is added to the inspired environment (hypercarbic OIR). We studied the time course of emergence and resolution of neovascularization (NV) in normocarbic OIR and hypercarbic OIR and the associated changes in VEGF and IGF-1 mRNA levels in hypercarbic OIR. METHODS: 550 newborn Sprague-Dawley rats were raised in 22 expanded litters of 25. Beginning at day 1 of life, rats were exposed to 7 daily cycles of hyperoxia (80% O2, 20.5 h) and hypoxia (10% O2, 0.5 h) with a gradual return to 80% O2 over 3 h. Inspired CO2 was maintained at 0.2% for 200 rats (normocarbic OIR) and 10% for 100 rats (hypercarbic OIR). Rats were sacrificed after a subsequent 5 day room air recovery period. An additional 250 rats raised in room air served as age matched controls. Retinae from left eyes were dissected and flatmounts were ADPase-stained. The presence and severity of NV was scored in a masked manner. Right eyes in hypercarbic OIR litters and room air controls were processed for analysis of VEGF and IGF-1 mRNA. RESULTS: In normocarbic OIR, NV started to emerge before room air recovery began at day 8. It was maximal at day 10 and resolved by day 20. In hypercarbic OIR, a similar pattern was seen, with emergence prior to day 8, peak at day 13 and resolution by day 20. In hypercarbic OIR, retinal VEGF mRNA was decreased at day 8 and increased at day 10 compared to room air controls, correlating with maximal NV. Retinal IGF-1 mRNA was not increased at any time in hypercarbic OIR compared to room air controls. CONCLUSIONS: Neovascularization resulting from normocarbic OIR or hypercarbic OIR occurs before room air recovery. Retinal VEGF mRNA was downregulated and subsequently upregulated prior to maximal NV in hypercarbic OIR. Neovascularization in the hypercarbic OIR model does not appear to be associated with increased retinal IGF-1 mRNA.

Animals↗

PubMed2004

Comparison of the amblyopia treatment study HOTV and electronic-early treatment of diabetic retinopathy study visual acuity protocols in children aged 5 to 12 years.

PURPOSE: To compare two established visual acuity protocols: the Amblyopia Treatment Study HOTV (ATS HOTV) visual acuity protocol and the Electronic-Early Treatment of Diabetic Retinopathy Study (E-ETDRS) protocol, in children aged 5 to 12 years. DESIGN: Prospective cohort study. METHODS: Crowded HOTV optotypes and crowded ETDRS optotypes were presented to 236 consecutive children aged 5 to 12 years using an electronic visual acuity tester (Palm handheld, personal computer, and monitor). Twenty-three percent of the children were classified as amblyopic, 35% as having uncorrected refractive error, 36% as normal, and 6% as other. Visual acuity test results were converted to logarithm of minimal angle of resolution (logMAR) units for analysis. RESULTS: In developmentally normal children (n = 230), testability was 100% for HOTV in 5- to 12-year-olds and 100% for E-ETDRS in 7- to 12-year-olds. The E-ETDRS testing could be completed in 52% of 5-year-olds and in 87% of 6-year-olds. Visual acuity performance was better when measured by HOTV compared with E-ETDRS (median difference 0.06 logMAR [three letters on a chart with five letters/line], P =.0001), and the difference was found in normal eyes, eyes with refractive error, and amblyopic eyes. CONCLUSIONS: The ATS HOTV protocol yields slightly better visual acuity performance compared with E-ETDRS in 5- to 12-year-olds, but on average by less than a logMAR level. This systematic difference is important when a physician changes testing modality as a child matures and should be considered when interpreting the results of recent and ongoing clinical trials in amblyopia.

Amblyopia↗

PubMed2004

Maximum angle of horizontal strabismus consistent with true stereopsis.

BACKGROUND: We prospectively evaluated the performance of three stereoacuity tests in patients with a wide range of strabismus angles to determine the maximum angle of horizontal strabismus consistent with true stereopsis as well as the extent of false-positive results. METHODS: Subjects age > or = 5 years old (n = 186) with constant horizontal strabismus were prospectively studied. Stereoacuity was measured using the Titmus Fly, Animals, and Circles tests; the original Preschool Randot test; and the Frisby test. We defined a false-positive result as any positive response to a stereoacuity test when a patient had > 20 prism diopters (PD) of deviation. Based on the results from our previous study of monocularly patched adults, we then defined a true-positive result as Titmus circles five to nine, at least 400" on the original Preschool Randot test, or a pass on the Frisby test. Data were then analyzed to determine a maximum deviation consistent with true stereopsis. RESULTS: False-positive results occurred with Titmus Fly (6%), Titmus Animals (10%), Titmus Circles (35%), and the 800 seconds of arc (") level of the original Preschool Randot test (10%). No false-positive results were seen with the Frisby test. Applying the criteria for a true-positive result, we found that no patient with > 10 PD of deviation had true stereopsis. The two patients with 10 PD and 6 PD deviations could not subsequently pass the Frisby test and were therefore deemed not to have true stereopsis. We concluded that the threshold for true stereopsis may be as low as 4 PD of horizontal deviation. CONCLUSION: In summary, the Titmus Fly, Titmus Animals, and Titmus Circles (the first four circles) tests possess monocular clues that limit their usefulness for clinical testing. The Frisby test is particularly useful for rapid assessment of whether stereopsis is present or absent. The new Preschool Randot test is valuable for quantifying stereopsis in both children and adults. True stereopsis may be rare when a patient has a horizontal deviation > 4 PD.

Adolescent↗

PubMed2004

Incidence, associations, and evaluation of sixth nerve palsy using a population-based method.

PURPOSE: To determine the incidence of sixth nerve palsy in a population-based study, with particular emphasis on associated coexisting medical conditions and to use these data to develop a management algorithm. DESIGN: Retrospective, population-based case series. PARTICIPANTS: All residents of Olmsted County, Minnesota, USA, diagnosed with sixth nerve palsy between January 1, 1978 and December 31, 1992. METHODS: All cases were identified by using the Rochester Epidemiology Project medical records linkage system, which captures all patient-physician encounters in Olmsted County. The entire medical record of each patient was reviewed to confirm the diagnosis, document county residency, and to determine associated medical conditions. We used stringent predetermined criteria to define diabetes mellitus and hypertension as associations. Incidence rates were adjusted to the age and gender distribution of the 1990 white population in the United States. MAIN OUTCOME MEASURES: Etiology or systemic associations of the palsy. RESULTS: We identified 137 new cases of sixth nerve palsy over the 15-year period. The age- and gender-adjusted annual incidence of sixth nerve palsy was 11.3/100 000 (95% confidence interval, 9.3-13.2/100 000). Causes and associations were: undetermined (26%), hypertension alone (19%), coexistent hypertension and diabetes (12%), trauma (12%), multiple sclerosis (7%), neoplasm (5%), diabetes alone (4%), cerebrovascular accident (4%), postneurosurgery (3%), aneurysm (2%), and other (8%). When sixth nerve palsy was the presenting sign in cases of neoplasm (n = 1) and aneurysm (n = 3), history and examination revealed the presence of other neurologic symptoms or signs. CONCLUSIONS: We provide population-based data on the incidence of sixth nerve palsy with a notably lower incidence of neoplasm and higher incidence of diabetes and hypertension than previous institution-based series. We suggest that patients with nontraumatic neurologically isolated sixth nerve palsy may undergo a focused medical evaluation followed by close observation, whereas non-neurologically isolated cases warrant a full neurologic evaluation, including prompt neuroimaging.

Abducens Nerve Diseases↗

PubMed2004

The anti-thyroid drug methimazole induces neovascularization in the neonatal rat analogous to ROP.

PURPOSE: To determine the effect of methimazole (MMI), an anti-thyroid drug known to reduce serum l-thyroxine (T4), and insulin-like growth factor (IGF)-1 concentrations, on retinal vascular development in neonatal rats. METHODS: Sprague-Dawley rats (n=175) were raised in expanded litters of 25 in room air and were exposed to MMI from birth (given as a 0.1% solution to nursing mothers for either 4 or 10 days). Experiments ended on day 4 (n=25) or 10 (n=50) of life. A third group was exposed to MMI for the initial 4 days of life and then allowed to recover for the next 6 days (n=50). Fifty control rats were analyzed on day 4 (n=25) or 10 (n=25) of life. Left eyes were fixed, and retinas were dissected and stained with adenosine diphosphatase (ADPase). Retinas were graded for presence and severity of neovascularization (NV) in a masked manner, and retinal vascular areas were quantified. In a subsequent study, serum IGF-1 and T4 levels were measured by radioimmunoassay in an additional 200 rats exposed to treatments identical to those described. RESULTS: Retinal NV occurred in 31% of rats exposed to 10 days of MMI and 4% (P=0.02) of rats exposed to 4 days of MMI, followed by 6 days of recovery. None of the rats exposed to 4 days of MMI alone and none of the control animals was graded positive for NV. Retinal vascular areas were significantly reduced in rats exposed to 4 days of MMI compared with 4-day control animals (36% +/- 6% vs. 50% +/- 6%, P=0.0001). Serum IGF-1 levels were markedly reduced in 4-day MMI rats compared with age-matched control animals (42 ng/mL vs. 133 ng/mL, P=0.0001) and in 10-day MMI rats compared with 10-day control animals (133 ng/mL vs. 206.5 ng/mL, P=0.005). Serum T4 levels were similarly suppressed in the MMI-exposed litters compared with control animals at day 10 (P=0.008). In contrast, rats exposed to 4 days of MMI followed by 6 days of recovery had normal serum IGF-1 and T4 levels by day 10. CONCLUSIONS: The anti-thyroid drug, MMI, induces NV in neonatal rats. This may be mediated by the initial suppression of serum IGF-1. Nevertheless, the lower incidence of NV when serum IGF-1 levels are initially suppressed followed by complete recovery, is contrary to a purely permissive role for serum IGF-1, as reported previously. The relationship between the temporal course of serum IGF-1 and NV in immature retinas needs further investigation.

Animals↗

PubMed2003

Comparison of wild-type and class I integrase mutant-FIV vectors in retina demonstrates sustained expression of integrated transgenes in retinal pigment epithelium.

BACKGROUND: In neonatal and adult rodent retina, substantial lentiviral vector expression has been detected primarily in retinal pigment epithelium (RPE), except in very young animals (2-5 days post-natal). In non-retinal tissues, studies of lentiviral vectors have utilized various controls. Among the most stringent are class I integrase mutants, which selectively block the integration reaction while leaving all other gag/pol-encoded functions intact. For HIV-1 vectors injected into brain, these have been used to simultaneously control for pseudotransduction and verify that long-term expression requires integration. Such experiments compare particles that differ only in a single amino acid within a single enzyme that forms a very small molar fraction of the virion. Class I integrase mutants have not been described for feline immunodeficiency virus (FIV) integrase, or tested in the eye for any lentiviral vector. METHODS: We compared subretinally and intravitreally injected FIV vectors and followed animals for up to 7 months, a duration that exceeds prior studies. We also compared the wild-type (WT) vector with one incorporating a single class I amino acid mutation in FIV integrase (D66V). A mock vector (packaging construct absent) was an alternative control. All vectors were vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped and were injected on day 7 of life. One group of animals received either subretinal or intravitreal injections of WT vector in the right eyes. Control left eyes were injected with mock vector. These animals were sacrificed at 2 or 7 days post-injection. A second group received subretinal injections of either WT vector or equivalent D66V vector (reverse transcriptase-normalized to WT), and were analyzed after 2, 3 and 7 months. All eyes were scored for marker gene (beta-galactosidase) expression by an observer blinded to vector assignments. RESULTS: Subretinal FIV vector injections were much more effective than intravitreal injections. The RPE was the principal retinal layer transduced by the WT vector, and at least 50% of the area of the retina expressed the marker gene at 3 and 7 months. Occasional cells in inner retinal layers also expressed beta-galactosidase at these time points. The sustained retinal expression produced by subretinally injected vector was blocked by the D66V mutation. CONCLUSIONS: These results show that class I integrase mutant FIV vectors are useful control vectors, and that VSV-G-pseudotyped FIV vectors produce extensive retinal expression for at least 215 days, the longest duration yet reported for lentiviral vectors in retina. Transgene expression is mostly restricted to RPE after post-natal day 7 in rats, suggesting that FIV vectors could be used to target RPE for gene therapy.

Age Factors↗

PubMed2003

Telemedicine approach to screening for severe retinopathy of prematurity: a pilot study.

PURPOSE: To evaluate the use of remote reading of digital retinal photographs in the diagnosis of severe (referral-warranted) retinopathy of prematurity (ROP) during longitudinal screening for ROP. STUDY DESIGN: Prospective, longitudinal cohort study. SUBJECTS: Forty-four consecutive premature infants at risk for ROP. METHODS: All infants were examined longitudinally, over a series of examinations, by indirect ophthalmoscopy (gold standard) and digital photography using the RetCam-120 Digital Retinal Camera (Massie Research Laboratories Inc., Dublin, CA) equipped with an ROP lens. Images were stored and read remotely by a masked reader. Referral-warranted ROP was defined as ROP in zone 1, the presence of plus disease or the presence of any stage 3 ROP. We determined whether and when referral-warranted ROP was diagnosed for each eye, of each infant, on each examination, during the course of each of the infant's screening. RESULTS: Severe (referral-warranted) ROP was diagnosed in 23 eyes by indirect ophthalmoscopy during their series of examinations. Digital photography had a sensitivity of 100% and a specificity of 96% in detecting referral-warranted ROP. The positive predictive value of digital photography was 92%, and the negative predictive value was 100%. In 87% of eyes, referral-warranted ROP was diagnosed by digital photography before or at the same time as indirect ophthalmoscopy. CONCLUSIONS: Longitudinal remote reading of digital photographs using the RetCam-120 system has excellent specificity and sensitivity in detecting referral-warranted ROP. This pilot study has shown that remote reading of digital photographs has promise for telemedicine strategies in ROP screening.

Cohort Studies↗

PubMed2003

Birth prevalence of visually significant infantile cataract in a defined U.S. population.

PURPOSE: To determine the birth prevalence of visually significant infantile cataract, using population-based comprehensive medical record retrieval, in a defined US population. DESIGN: Retrospective, population-based, medical record retrieval. METHODS: We reviewed records of all pediatric patients (0-17 years) coded as cataract during a 20-year period (1978 to 1997) using the resources of the Rochester Epidemiology Project. "Infantile cataract" was defined as a cataract diagnosed within the first year of life. "Possible infantile cataract" was defined as a cataract, diagnosed after the first year in a child born in Olmsted County, where there was no evidence of an acquired traumatic, acquired systemic, or acquired ocular etiology. Visually insignificant cataracts were excluded. RESULTS: Ten incident cases of visually significant infantile cataract were identified during the 20-year study period, yielding a birth prevalence of 3.0 per 10,000 live births (95% CI: 1.5-5.6 per 10,000). Five additional cases of visually significant "possible infantile cataract" were identified, diagnosed between the ages of 2 and 8 years. Inclusion of these "possible infantile cataracts" would result in an estimate of overall birth prevalence for visually significant infantile cataract of 4.5 per 10,000 live births (95% CI: 2.5-7.5 per 10,000). CONCLUSIONS: Using population-based medical record retrieval methods, we estimate the birth prevalence of visually significant infantile cataract to be 3.0 to 4.5 per 10,000. Infantile cataracts are an important cause of visual impairment in children and these data are useful in planning clinical trials and allocating health care resources.

Cataract↗

PubMed2002

Long-term outcomes after surgical management of chronic sixth nerve palsy.

BACKGROUND: In a multicenter prospective data collection study of chronic sixth cranial nerve palsy, we previously reported that the initial successful outcome rate was 39% after a single surgical intervention and 25% after surgery combined with botulinum toxin (Botox), using strict success criteria. We now report the longer term outcome of these patients. METHODS: A previously described cohort of 31 patients in 18 centers who underwent strabismus surgery for a sixth nerve palsy of greater that 6 months duration was studied prospectively. Twenty-three had strabismus surgery alone and 8 surgery with Botox. Fourteen (45%) were complete palsies and 17 (55%) were incomplete. Seven (23%) were bilateral and 24 (77%) were unilateral. Outcome was classified at time of last follow-up, which was 5 weeks to 24 months postoperatively. Success was defined as no diplopia in primary position at distance fixation. Partial success was defined as no more than 10 PD esotropia despite diplopia. RESULTS: Overall, 16 (52%) of the patients were classified as successes, 7 (23%) as partial successes, and 8 (25%) as failures. Three (43%) of the partial successes were using prism. Eight (35%) of the patients classified as successes or partial successes required 2 surgical procedures. Of all patients (10, 32%) who had a second surgery, only 2 (20%) remained failures. CONCLUSIONS: Despite our reported poor initial surgical success rate in chronic sixth nerve palsy, additional strabismus surgery, longer follow-up, and the use of prism or face turn for small residual deviations yields an overall surgical success rate of 75%. More than 1 surgical procedure and prism are often necessary in the management of chronic sixth nerve palsy.

Abducens Nerve Diseases↗