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Biomedical subjects

Gerald A Fishman

Publications and source records attributed to Gerald A Fishman.

At least 19 recordsLinked to original sources
PubMed2007

Continued use of dorzolamide for the treatment of cystoid macular oedema in patients with retinitis pigmentosa.

AIM: To determine the value of a topical carbonic anhydrase inhibitor for extended treatment of cystoid macular oedema (CME) in patients with retinitis pigmentosa (RP). METHOD: Eight patients with RP and foveal cystic-appearing lesions observed on fundus examination and by optical coherence tomography (OCT) testing were treated with a topical form of carbonic anhydrase inhibitor. RESULTS: Foveal cystic-like spaces were documented by OCT testing in all eight patients before treatment. All patients had a significant reduction in their foveal thickness (FT) and foveal zone thickness (FZT) in at least one eye after using 2% dorzolamide three times a day for 1 or 2 months. Six patients had an improvement in both eyes. After an additional 6-13 months of the same treatment regimen, out of six patients who had a sustained reduction in FT and FZT in at least one eye, four had this reduction in both eyes. While they were still taking Trusopt, a recurrence (rebound) of CME in both eyes was observed in two patients, whereas one patient had a sustained improvement in one eye and rebound of CME in the other eye. Out of 8 patients, 3 showed an improvement in their visual acuity by > or =7 letters, in at least one eye, on Snellen acuity charts, which was determined as clinically significant. CONCLUSION: Results from this study suggest that patients with RP could potentially sustain a beneficial effect from continued treatment with a topical form of carbonic anhydrase inhibitor.

Carbonic Anhydrase Inhibitors↗
PubMed2006

Multifocal ERG findings in carriers of X-linked retinoschisis.

PURPOSE: To determine whether retinal dysfunction in obligate carriers of X-linked retinoschisis (XLRS) could be observed in local electroretinographic responses obtained with the multifocal electroretinogram (mfERG). METHODS: Nine obligate carriers of XLRS (mean age, 46.2 years) were examined for the study. Examination of each carrier included an ocular examination and mfERG testing. For the mfERG, we used a 103-scaled hexagonal stimulus array that subtended a retinal area of approximately 40 degrees in diameter. The amplitudes and implicit times in each location for the mfERG were compared with the corresponding values determined for a group of 34 normally-sighted, age-similar control subjects. RESULTS: Mapping of 103 local electroretinographic response amplitudes and implicit times within a central 40 degrees area with the mfERG showed regions of reduced mfERG amplitudes and delayed implicit times in two of nine carriers. CONCLUSIONS: The mfERG demonstrated areas of retinal dysfunction in two carriers of XLRS. When present, retinal dysfunction was evident in the presence of a normal-appearing fundus. Multifocal ERG testing can be useful for identifying some carriers of XLRS.

Adult↗
PubMed2006

Comparison of visual acuity loss in patients with different stages of Stargardt's disease.

PURPOSE: To investigate a previously reported observation that the presence of diffuse, as compared with localized, fundus flecks is an indicator of a more severe course for visual acuity (VA) loss beyond 20/200 in patients with Stargardt's disease. DESIGN: Retrospective clinic-based cross-sectional study. PARTICIPANTS: Four hundred five patients with Stargardt's disease. METHODS: Visual acuity in 405 patients with Stargardt's disease was analyzed at their initial and most recent visits. The stage of Stargardt's disease and appearance of the macula were recorded. The diagnosis and stage of Stargardt's disease were based on the extent and appearance of fundus flecks. MAIN OUTCOME MEASURES: Best-corrected VA, stage of Stargardt's disease, and appearance of the macula at the initial and most recent visits were used in the cross-sectional analysis. RESULTS: At their initial visit, 199 patients were identified as having stage 1 Stargardt's disease, of whom 97.5% maintained 20/200 or better VA in at least one eye. One hundred eighty-five were identified as having stage 2 or stage 2-3 Stargardt's disease combined, of whom 83.2% maintained 20/200 VA or better. Patients with stage 1 were more likely to maintain 20/200 or better VA in at least one eye when compared with patients with stage 2/stage 2-3 Stargardt's disease (chi2(1) = 21.25, P<0.001). Ninety-nine percent of stage 1 patients and 94.1% of stage 2/stage 2-3 patients maintained 20/400 or better VA in at least one eye (chi2(1) = 5.72, P = 0.017). CONCLUSIONS: Patients with stage 1 Stargardt's disease exhibiting fundus flecks limited to the posterior pole are more likely to maintain a level of VA at 20/200 or better when compared with patients with stage 2/stage 2-3 disease who have diffuse fundus flecks. Nevertheless, over 80% of the patients with stage 2/stage 2-3 Stargardt's disease still maintained VA of 20/200 or better. Only 5.9% of patients with stage 2/stage 2-3 had VA levels worse than 20/400. In our cohort of patients with Stargardt's disease and diffuse fundus flecks, the majority of patients did not lose VA to a greater extent than those with localized flecks.

Adolescent↗
PubMed2006

Topical dorzolamide for the treatment of cystoid macular edema in patients with retinitis pigmentosa.

PURPOSE: To determine if topical dorzolamide, as observed with the use of systemic acetazolamide and methazolamide, would be effective in treating cystoid macular edema (CME) in patients with retinitis pigmentosa (RP). DESIGN: Prospective, nonrandomized clinical trial. METHODS: setting: Institutional. patients: Fifteen patients with CME and RP. intervention: A baseline visual acuity and optical coherence tomography (OCT) measurements were obtained in all patients. Each one of them was then treated with topical dorzolamide, three times a day, for at least four weeks in both eyes. main outcome measures: Significant decrease in "foveal thickness" (more than 16%) and "foveal zone thickness" (more than 11%), as measured by OCT. RESULTS: Thirteen (87%) of 15 patients showed a significant decrease in retinal thickness in at least one eye after use of topical dorzolamide for at least four weeks. Five patients (33%) demonstrated improvement in both eyes. All patients, except one, who responded showed the effect within four weeks, but were monitored for a period of two to nine months (average 4.5 months). Four patients (31%) who showed an initial improvement in macular edema showed worsening with continued treatment. CONCLUSIONS: The present study documents the potential efficacy of topical dorzolamide for treating CME in patients with RP. We observed that some patients may show a "rebound phenomenon" with continued use of the medication; hence, there is a need for careful follow-up in patients being treated.

Administration, Topical↗
PubMed2006

Activation phase of cone phototransduction and the flicker electroretinogram in retinitis pigmentosa.

This study examined the relationship between the activation phase of cone phototransduction and the flicker electroretinogram (ERG) in 15 patients with retinitis pigmentosa (RP) and 12 age-equivalent, visually normal control subjects. Values of Rmp3 (maximum amplitude of P3, the massed cone photoreceptor response) and S (sensitivity of cone phototransduction) were derived from a delayed Gaussian model applied to the leading edge of the ERG a-wave. Fundamental amplitude and phase of the flicker ERG were derived from responses to sinusoidal flicker presented at temporal frequencies ranging from 7.8 to 100 Hz. Patients with RP who had a reduced value of Rmp3 alone had an overall reduction in flicker ERG amplitude with a normal response phase across temporal frequency. Patients with RP who had a reduced value of S, whether or not Rmp3 was reduced, had the greatest amplitude reduction at temporal frequencies above 40 Hz and phase lags across a range of temporal frequencies. At high temporal frequencies, the amplitude reduction of the flicker ERG was predicted by the product of Rmp3 and S for all of the subjects except the three patients with RP who had the lowest fundamental amplitudes. The results indicate that there is a systematic relationship between the derived parameters of the activation phase of cone phototransduction and the characteristics of the flicker ERG in patients with RP, although the phase changes in the flicker ERG were generally greater than predicted by the derived parameters alone.

Adult↗
PubMed2006

Novel de novo mutation in a patient with Best macular dystrophy.

OBJECTIVE: To report a novel de novo vitelliform macular dystrophy (VMD2) mutation in a patient with Best macular dystrophy. METHODS: Best-corrected visual acuity, dilated fundus examination, and electro-oculography were performed in a patient with Best macular dystrophy and his parents. Both the patient and his parents also had blood samples drawn, and their DNA was analyzed by direct genomic sequencing. RESULTS: A heterozygous VMD2 gene missense mutation in exon 2 (Thr6Ala [ACA>GCA]) was identified in the proband. This mutation was not present in his clinically unaffected parents. CONCLUSIONS: A novel de novo mutation in the VMD2 gene was found in a patient whose phenotype and electro-oculographic findings were characteristic of Best macular dystrophy, whereas both parents were phenotypically and genetically unaffected. The findings in this family document that a de novo mutation needs to be considered when an isolated family member is found to have a Best disease phenotype.

Bestrophins↗
PubMed2006

Use of dorzolamide for patients with X-linked retinoschisis.

PURPOSE: To determine the value of a topical carbonic anhydrase inhibitor for the treatment of foveal lesions in patients with X-linked retinoschisis (XLRS). METHODS: Eight patients with XLRS and foveal cystic-appearing spaces by fundus examination and by optical coherence tomography (OCT) were treated with a topical form of carbonic anhydrase inhibitor. Changes in "foveal thickness" and "foveal zone thickness" were measured by OCT, and changes of best-corrected visual acuity were measured by Early Treatment Diabetic Retinopathy Study (ETDRS) charts. RESULTS: Seven of eight patients treated with 2% dorzolamide had a noticeable reduction in foveal thickness as well as cystic-appearing spaces by OCT. This reduction was found in both eyes in four of these patients and in one eye in one patient after 1 month of treatment. After an additional 1 month to 2 months of the same treatment regimen, two additional patients also had a noticeable reduction in foveal thickness as well as cystic-appearing spaces. Of these seven patients who had an improvement shown by OCT with treatment, five also had improvement of their visual acuity by >or=7 letters in at least one eye on ETDRS charts. CONCLUSION: The present study shows the efficacy of topical dorzolamide for treating foveal cystic-appearing lesions in patients with XLRS.

Administration, Topical↗
PubMed2006

CRB1 heterozygotes with regional retinal dysfunction: implications for genetic testing of leber congenital amaurosis.

PURPOSE: To test human CRB1 heterozygotes for possible clinical or functional retinal changes and to evaluate whether a patient with Leber congenital amaurosis (LCA) with CRB1 mutations not consistent with previously described CRB1 phenotypes carried a modifier allele in another LCA gene. METHODS: Seven unrelated heterozygous carriers of CRB1 mutations underwent phenotyping by full eye examinations (indirect ophthalmoscopy and slit lamp biomicroscopy) and functional testing (standard full-field electroretinography [ERG] and multifocal ERG). For genotyping of the LCA patients and their parents, denaturing high-performance liquid chromatography (dHPLC) analyses were performed, followed by sequence analysis of CRB1, followed by sequence analysis of the AIPL1 and CRX genes to identify a putative modifier effect in a patient with an atypical CRB1 phenotype. RESULTS: Reduced full-field ERG b-wave amplitudes were observed with scotopic -2 dB flash (140 microV; P < 0.05), normal full-field cone ERGs, and significant regional retinal dysfunction on mfERG in five of seven carriers of CRB1 mutations. A known AIPL1 mutation (p. R302L) was identified as a potential modifier allele in a patient with LCA carrying two CRB1 mutations and with a prominent maculopathy. CONCLUSIONS: In human heterozygotes of CRB1 mutations (parents of offspring with LCA), distinctive regional retinal dysfunctions were found by multifocal ERG measurements that were consistent with the focal histologic abnormalities reported for the two CRB1 knockout mice models. This phenotypic finding may identify CRB1 carriers and point to the causal gene defect in affected LCA offspring, significantly facilitating the molecular diagnostic process. Evidence suggests a modifier allele in AIPL1 in a patient with LCA with prominent atrophic macular lesions and homozygous defects in CRB1.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6.

We report three unrelated patients with mutations in the GRM6 gene that normally encodes the glutamate receptor mGluR6. This neurotransmitter receptor has been shown previously to be present only in the synapses of the ON bipolar cell dendrites, and it mediates synaptic transmission from rod and cone photoreceptors to this type of second-order neuron. Despite the synaptic defect, best visual acuities were normal or only moderately reduced (20/15 to 20/40). The patients were night blind from an early age, and when maximally dark-adapted, they could perceive lights only with an intensity equal to or slightly dimmer than that normally detected by the cone system (i.e., 2-3 log units above normal). Electroretinograms (ERGs) in response to single brief flashes of light had clearly detectable a-waves, which are derived from photoreceptors, and greatly reduced b-waves, which are derived from the second-order inner retinal neurons. ERGs in response to sawtooth flickering light indicated a markedly reduced ON response and a nearly normal OFF response. There was no subjective delay in the perception of suddenly appearing white vs. black objects on a gray background. These patients exemplify a previously unrecognized, autosomal recessive form of congenital night blindness associated with a negative ERG waveform.

Adolescent↗
PubMed2005

A substitution of G to C in the cone cGMP-phosphodiesterase gamma subunit gene found in a distinctive form of cone dystrophy.

OBJECTIVE: To identify genes responsible for cone dystrophies and determine the functional consequences of their underlying mutations. DESIGN: Case-control study. PARTICIPANTS: Two hundred forty unrelated patients diagnosed with cone dystrophy, cone-rod dystrophy, macular dystrophy, macular degeneration, or Stargardt disease, 95 control individuals, and 2 unrelated families with a distinctive type of cone dystrophy. METHODS: The DNAs of the 240 probands were screened for sequence variants in the PDE6H gene (that encodes the inhibitory gamma-subunit of cone cyclic guanosine monophosphate [cGMP]-phosphodiesterase [PDE]) by single-strand conformation polymorphism electrophoresis. The effect of a nucleotide substitution in the DNA of a patient on gene expression efficiency was analyzed by in vitro transcription/translation. MAIN OUTCOME MEASURES: Cone-specific gene variants, fundus, visual field and electroretinogram (ERG) findings, and protein synthesis efficiency. RESULTS: We found a heterozygous G to C substitution in the 5' untranslated region (UTR) of the PDE6H gene in the DNA of a patient with a distinctive form of cone dystrophy, her sibling, and their father. This rare form of disease is very different in manifestation from other cone dystrophies and has been described as "cone dystrophy with nyctalopia and supernormal rod responses," "cone dystrophy with supernormal scotopic ERGs" and "supernormal and delayed rod ERG syndrome." Among the 240 patients that we studied, only 1 proband had the G to C variant. Furthermore, none of the 95 controls used in this study had this nucleotide change. We also determined that the PDE6H variant was not present in another family affected with this particular type of cone dystrophy. Because the 5' UTR of mRNAs plays a critical role in the regulation of protein synthesis, we determined the effect of the G to C change in this process. By use of in vitro transcription/translation experiments, we demonstrated that this substitution could lead to an increase in PDE6H gene expression. CONCLUSIONS: Our results indicate that mutations in the PDE6H gene are not common, because only 1 of 240 patients with cone dystrophy showed a single nucleotide substitution in the 5' UTR of PDE6H mRNA that could be associated with the disease. If the effect of the G to C substitution we observed in vitro also occurs in vivo, it will lead to PDE6H overexpression in the photoreceptors. Excess of PDEgamma may affect normal cone cGMP-PDE function by inhibiting the catalytic PDEalpha,beta activity and lead to pathogenic elevation of cGMP and eventual degeneration of cone photoreceptors.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2005

Clinical phenotypes in carriers of Leber congenital amaurosis mutations.

OBJECTIVE: To determine the clinical phenotypes in carriers with probable disease-causing sequence variations in 1 of 6 genes established to cause Leber congenital amaurosis (LCA). DESIGN: Observational prospective comparative study. PARTICIPANTS: Thirty carriers with various probable disease-causing sequence variations in 1 of 6 genes known to cause LCA. METHODS: After the establishment of various disease-causing sequence variations in 37 (33.6%) of 110 patients with LCA, we examined a number of carriers who were either parents or offspring and who were willing to participate in our study. Evaluations included assessment of visual acuity, slit-lamp biomicroscopy, dilated fundus examination, and full-field electroretinogram (ERG) measurements. MAIN OUTCOME MEASURES: Dilated fundus examination and full-field ERGs. RESULTS: Of the 30 carriers with probable disease-causing sequence variations for LCA, 5 (16.7%) carriers had an AIPL1 variation, 4 (13.3%) CRB1, 0 (0%) CRX, 5 (16.7%) GUCY2D, 9 (30%) RPE65, and 7 (23.3%) carriers had a RPGRIP1 variation. Twenty-nine (96.7%) carriers had 20/20 or better visual acuity in their better seeing eye with correction. Drusenlike deposits were more selectively observed in carriers with mutations in the AIPL1, CRB1, RPE65, and RPGRIP1 genes, whereas mild peripheral chorioretinal atrophy was only observed in AIPL1 and RPE65 carriers. A reduced dark-adapted isolated rod ERG response and/or maximal combined cone and rod response was recorded in carriers with mutations in the AIPL1, GUCY2D, and RPGRIP1 genes. A reduced light-adapted ERG response to a single-flash and/or 32-Hz flicker was recorded in carriers with mutations in the AIPL1, CRB1, GUCY2D, and RPGRIP1 genes. Overall, our cohort of LCA carriers did not describe significant subjective visual difficulties, including nyctalopia and/or photosensitivity. CONCLUSIONS: The variation of phenotypic expression in carriers among 5 LCA genotypes indicates that there is considerable phenotypic overlap. However, phenotypic trends were noted in carriers' fundus findings and ERG responses for each genetic subtype. Observations of phenotypic associations with specific disease-causing sequence variations in carriers have potential practical value for molecular screening strategies of patients with LCA.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Correlation of optical coherence tomography findings with visual acuity and macular lesions in patients with X-linked retinoschisis.

PURPOSE: To evaluate and correlate findings obtained by optical coherence tomography (OCT) imaging with visual acuity (VA) and macular lesions in patients with X-linked retinoschisis (XLRS). DESIGN: Prospective comparative case series. PARTICIPANTS: Thirty-one patients with confirmed XLRS. METHODS: Best-corrected VA was determined using Early Treatment Diabetic Retinopathy Study charts, and a dilated funduscopic examination was performed on all patients. For all patients, the macula in each eye was OCT imaged. A correlation between VA, macular presentation, and OCT images was determined. MAIN OUTCOME MEASURES: Analysis of findings on OCT images, including foveal thickness and the area of macular cystic-appearing lesions, and their correlation with VA. RESULTS: Twenty-five patients with funduscopically evident cystic-appearing macular lesions demonstrated cysticlike spaces on OCT images. No statistically significant correlation was observed between the macular area of the cysticlike spaces, foveal thickness, and VA. Three patients with no funduscopic or OCT evidence of foveal cysts demonstrated thinning of the fovea on OCT images and more extensive reduction of their VA. Retinal papillomacular bundle nerve fiber layer thickness on OCT images showed no significant difference between control and patient groups. CONCLUSIONS: In XLRS patients with cystic-appearing macular lesions, there was a lack of correlation between VA, foveal thickness, and cystic area. The anatomical appearance of smaller perifoveal cysts on OCT imaging was most consistent with their location being primarily within the inner nuclear layer of the retina. In older patients, macular cysts were no longer apparent clinically or by OCT imaging, and foveal thickness was reduced. The findings on OCT images are consistent with the hypothesis of a primary Muller cell defect in patients with XLRS.

Adolescent↗
PubMed2005

Characteristics of contrast processing deficits in X-linked retinoschisis.

Contrast sensitivity and contrast discrimination were evaluated in six males with X-linked retinoschisis (XLRS), a form of early-onset macular degeneration, using testing paradigms designed to favor either the magnocellular (MC) or parvocellular (PC) pathway. Compared to a group of age-similar control observers, the patients with XLRS showed a pronounced loss of contrast sensitivity at high spatial frequencies, consistent with their reduced visual acuities. At low spatial frequencies, the patients' deficits were greater under conditions favoring the MC pathway, for both contrast sensitivity and contrast discrimination. The pattern of contrast sensitivity loss shown by the patients with XLRS could be simulated in control observers by testing at a parafoveal locus, although by optical coherence tomography, none of the patients with XLRS had eccentric fixation. The pattern of findings indicates that the foveas of patients with XLRS functionally resemble the normal parafoveal retina.

Adult↗
PubMed2005

Abnormal distribution of red/green cone opsins in a patient with an autosomal dominant cone dystrophy.

PURPOSE: To define the distribution of the red/green and blue opsins in cones from donor eyes from an affected member of a clinically well-characterized family with an autosomal dominant form of cone dystrophy. METHODS: Tissue was fixed and processed for immunohistochemistry. Cryosections were studied by indirect immunofluorescence, using well-characterized antibodies to cone cytoplasm, rhodopsin, and cone opsins. The cone-associated matrix was also labeled with the lectin PNA. The affected donor eyes were compared to a postmortem matched normal eye. RESULTS: Electroretinogram (ERG) testing three years prior to the affected member's death showed normal rod function, while the cone b-wave amplitude was reduced 40% below the lower limit of normal. Fundus exam showed only isolated drusen within the macula. Either a normal-appearing or only nonspecific macular findings were noted in the other affected family members who were examined. Immunofluorescence studies showed that blue cone opsin was restricted to the outer segments of blue cones in the affected retina. Red/green opsins were distributed along the entire plasma membrane of these cone types, from the tip of the outer segment to the synaptic base. Cone-associated matrix displayed a heterogeneous distribution. These patterns were observed both in the macula and in the periphery of the affected retina. Cone pedicles appeared larger than normal. In contrast, rhodopsin staining appeared normal. CONCLUSIONS: The immunocytochemical data obtained suggest that the clinical manifestation of this dystrophy is associated with an abnormal distribution of cone red/green opsins. Additionally, changes in the cone pedicles could have contributed to the abnormal cone ERG in this patient.

Aged↗
PubMed2005

Short-term inter-visit variability of erg amplitudes in normal subjects and patients with retinitis pigmentosa.

PURPOSE: To evaluate the short-term test/retest variability in visually normal subjects and patients with retinitis pigmentosa (RP), and to assess the effect of stimulus intensity and baseline amplitude on electroretinogram (ERG) variability. METHODS: Eighteen patients with RP and nine visually normal subjects had a series of three unilateral ERGs, with an inter-visit interval of no less than 2 days and no more than 2 weeks. Responses to dark-adapted and both light-adapted single flash and 32 Hz flicker stimuli were recorded from a dilated eye over a range of stimulus intensities. B-wave amplitudes were compared to baseline amplitudes recorded at initial visit, and the resulting inter-visit percent difference was compared between stimulus intensities. Inter-visit variability was determined by one-way repeated measures analysis of variance using a 95% confidence interval to calculate threshold criteria for significant change. Analysis of variance followed by Bonferroni test for pairwise comparison was used to test for differences in inter-visit variability between two RP patient subgroups (higher versus lower baseline amplitudes) and visually normal subjects. The effect of stimulus intensity on amplitude reproducibility was also assessed. RESULTS: Threshold for significant increase or decrease in inter-visit ERG amplitudes at a 95% confidence level for patients with RP and visually normal subjects was often at or above 25% and not infrequently at or above 40% for certain stimuli and test conditions. While no statistical difference in inter-visit variability was demonstrated between visually normal subjects and patients with RP who were arbitrarily categorized as having relatively higher baseline amplitudes, there was a difference between each of these two groups and a smaller group of patients with RP categorized as having lower baseline amplitudes. Although the authors could not demonstrate that percent inter-visit differences varied with stimulus intensity in either controls or patients with RP, the 32 Hz flicker stimulus generally produced less amplitude variability than either dark- or light-adapted single flash stimuli in patients with RP. CONCLUSIONS: When using ERG amplitude for monitoring either the natural history of functional loss in retinal disease or as an outcome measure during a therapeutic trial, it becomes vital to define inter-visit variability of ERG amplitudes. These findings suggest that a percentage of patients with RP with appreciably lower baseline ERG amplitudes may manifest greater inter-visit ERG amplitude variability than patients with RP with higher baseline amplitudes or controls. Stimulus intensity had no clinically significant effect on inter-visit amplitude variability.

Adult↗