Predicting the pathogenicity of RPE65 mutations.

To assist in distinguishing disease-causing mutations from nonpathogenic polymorphisms, we developed an objective algorithm to calculate an "estimate of pathogenic probability" (EPP) based on the prevalence of a specific variation, its segregation within families, and its predicted effects on protein structure. Eleven missense variations in the RPE65 gene were evaluated in patients with Leber congenital amaurosis (LCA) using the EPP algorithm. The accuracy of the EPP algorithm was evaluated using a cell-culture assay of RPE65-isomerase activity The variations were engineered into plasmids containing a human RPE65 cDNA and the retinoid isomerase activity of each variant was determined in cultured cells. The EPP algorithm predicted eight substitution mutations to be disease-causing variants. The isomerase catalytic activities of these RPE65 variants were all less than 6% of wild-type. In contrast, the EPP algorithm predicted the other three substitutions to be non-disease-causing, with isomerase activities of 68%, 127%, and 110% of wild-type, respectively. We observed complete concordance between the predicted pathogenicities of missense variations in the RPE65 gene and retinoid isomerase activities measured in a functional assay. These results suggest that the EPP algorithm may be useful to evaluate the pathogenicity of missense variations in other disease genes where functional assays are not available.

Ophthalmic presentation of giant cell arteritis in African-Americans.

PurposeTo determine the differences in the presentation of ophthalmic giant cell arteritis between African-Americans and Caucasians.MethodsThis was a multicenter retrospective case series comparing African-American patients with ophthalmic GCA to a previously published Caucasian cohort. Neuro-ophthalmic centers across the United States were contacted to provide data on African-American patients with biopsy-proven ophthalmic giant cell arteritis. The differences between African-American and Caucasian patients with respect to multiple variables, including age, sex, systemic and ophthalmic signs and symptoms, ocular ischemic lesions, and laboratory results were studied.ResultsThe Caucasian cohort was slightly older (mean=76.1 years) than the African-American cohort (mean=72.6 years, P=0.03), and there was no difference in sex distribution between the two cohorts. Headache, neck pain, and anemia were more frequent, while jaw claudication was less frequent in African-Americans (P<0.01, <0.001, 0.02, and 0.03 respectively). Acute vision loss was the most common presentation of giant cell arteritis in both groups, though it was less common in African-Americans (78 vs 98% of Caucasians, P<0.001). Eye pain was more common in African-Americans (28 vs 8% of Caucasians, P<0.01).ConclusionsThe presenting features of ophthalmic giant cell arteritis in African-Americans and Caucasians are not markedly different, although a few significant differences exist, including higher rates of headache, neck pain, anemia, and eye pain, and lower rates of jaw claudication and acute vision loss in African-Americans. Persons presenting with suspicious signs and symptoms should undergo evaluation for giant cell arteritis regardless of race.

Automated Quantitation of Spinal CSF Volume and Measurement of Craniospinal CSF Redistribution following Lumbar Withdrawal in Idiopathic Intracranial Hypertension.

BACKGROUND AND PURPOSE: Automated methods for quantitation of tissue and CSF volumes by MR imaging are available for the cranial but not the spinal compartment. We developed an iterative method for delineation of the spinal CSF spaces for automated measurements of CSF and cord volumes and applied it to study craniospinal CSF redistribution following lumbar withdrawal in patients with idiopathic intracranial hypertension. MATERIALS AND METHODS: MR imaging data were obtained from 2 healthy subjects and 8 patients with idiopathic intracranial hypertension who were scanned before, immediately after, and 2 weeks after diagnostic lumbar puncture. Imaging included T1-weighted and T2-weighted sequences of the brain and T2-weighted scans of the spine. Repeat scans in 4 subjects were used to assess measurement reproducibility. Whole CNS CSF volumes measured prior to and following lumbar puncture were compared with the withdrawn amounts of CSF. RESULTS: CSF and cord volume measurements were highly reproducible with mean variabilities of -0.7% ± 1.4% and -0.7% ± 1.0%, respectively. Mean spinal CSF volume was 77.5 ± 8.4 mL. The imaging-based pre- to post-CSF volume differences were consistently smaller and strongly correlated with the amounts removed (R = 0.86, P = .006), primarily from the lumbosacral region. These differences are explained by net CSF formation of 0.41 ± 0.18 mL/min between withdrawal and imaging. CONCLUSIONS: Automated measurements of the craniospinal CSF redistribution following lumbar withdrawal in idiopathic intracranial hypertension reveal that the drop in intracranial pressure following lumbar puncture is primarily related to the increase in spinal compliance and not cranial compliance due to the reduced spinal CSF volume and the nearly unchanged cranial CSF volume.

Visual loss from idiopathic intracranial pachymeningitis.

We report three patients with chronic headaches and optic neuropathy due to widespread meningeal thickening shown on enhanced MRI; all had biopsy-proven intracranial pachymeningitis (fibrosclerosis of the meninges). Two patients had bilateral optic neuropathy, elevated CSF protein, and polyclonal serum hypergammaglobulinemia. They developed temporal lobe cortical necrosis or sagittal sinus thrombosis, presumably due to compromised dural venous drainage from extensive meningeal fibrosis. The other patient had multiple cranial nerve palsies and unilateral optic neuropathy with normal CSF. Corticosteroid therapy improved visual function in all three patients, although all had persisting visual deficits. Gadolinium-enhanced MRI was essential in identifying meningeal inflammation and locating suitable biopsy sites.

Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 1. Chloro-substituted 1,2,3,4-tetrahydroisoquinolines.

In a search for inhibitors of epinephrine biosynthesis as potential therapeutic agents, a series of 13 ring-chlorinated 1,2,3,4-tetrahydroisoquinolines was prepared. These compounds were tested initially for their ability to inhibit rabbit adrenal phenylethanolamine N-methyltransferase (PNMT) in vitro. Enzyme-inhibitor dissociation constants, determined for the six most potent members of the series, indicated the following order of decreasing potency: 7,8-Cl2 greater than 6,7,8-Cl3 greater than 7-Cl approximately 5,6,7,8-Cl4 greater than 5,7,8-Cl3. These compounds were subsequently examined for PNMT-inhibiting activity in intact rats and mice. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (13, SK&F 64139) was the most potent member of the series both in vitro and in vivo and is currently undergoing clinical investigation.

An analysis of allelic variation in the ABCA4 gene.

PURPOSE: To assess the allelic variation of the ATP-binding transporter protein (ABCA4). METHODS: A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to systematically screen this gene for sequence variations in 374 unrelated probands with a clinical diagnosis of Stargardt disease, 182 patients with age-related macular degeneration (AMD), and 96 normal subjects. RESULTS: There was no significant difference in the proportion of any single variant or class of variant between the control and AMD groups. In contrast, truncating variants, amino acid substitutions, synonymous codon changes, and intronic variants were significantly enriched in patients with Stargardt disease when compared with their presence in subjects without Stargardt disease (Kruskal-Wallis P < 0.0001 for each variant group). Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants. CONCLUSIONS: Of the 97 amino acid substitutions, 11 occurred at a frequency that made them unlikely to be high-penetrance recessive disease-causing variants (HPRDCV). After accounting for variants in cis, one or more changes that were compatible with HPRDCV were found on 35% of all Stargardt-associated alleles overall. The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1).

Atypical retinochoroidal coloboma in patients with dysplastic optic discs and transsphenoidal encephalocele.

OBJECTIVE: To evaluate the clinical significance of V- or tongue-shaped infrapapillary retinochoroidal depigmentation in association with dysplastic optic discs. METHODS: Clinical data from all patients with V- or tongue-shaped infrapapillary retinochoroidal depigmentation and dysplastic optic discs were evaluated retrospectively. RESULTS: Five patients with this atypical colobomatous anomaly had transsphenoidal encephalocele. A sixth patient had an ectopic midline pharyngeal mass with no skull-base defect. CONCLUSION: In patients with optic disc dysplasias, the finding of this V- or tongue-shaped retinochoroidal pigmentary anomaly should prompt neuroimaging to look for transsphenoidal encephalocele.

Prevalence of foveal lesions in type 1 and type 2 Usher's syndrome.

PURPOSE: To evaluate possible differences in the prevalence of clinically detectable foveal lesions between patients with type 1 and type 2 Usher's syndrome. METHODS: Records of 48 patients with type 1 and 98 patients with type 2 Usher's syndrome were retrospectively evaluated for the presence of a foveal lesion. The age, gender, and racial distribution of patients were similar in the two subtypes. Two investigators reviewed fundus photographs from all patients and, when available, fluorescein angiograms. RESULTS: In the 48 patients with type 1 Usher's syndrome, 30 (62%) showed a clinically apparent atrophic- or cystic-appearing foveal lesion, whereas in the 98 patients with type 2 Usher's syndrome, 33 (34%) had either an atrophic- or a cystic-appearing foveal lesion. Logistic regression analysis showed that the probability of exhibiting a foveal lesion in both type 1 and type 2 Usher's syndrome increases with age and that patients with type 1 Usher's syndrome are more likely to have a foveal lesion than are patients with type 2 Usher's syndrome. CONCLUSIONS: Patients with type 1 Usher's syndrome show a greater probability of having either an atrophic- or cystic-appearing foveal lesion than do patients with type 2 Usher's syndrome. This higher prevalence of foveal lesions is consistent with a previous observation that the severity of visual acuity impairment with age is greater for patients with type 1 than type 2 Usher's syndrome. These data are useful in counseling such patients as to their prognosis for central visual function.

Comparison of pupil responses to luminance and colour in severe optic neuritis.

OBJECTIVE: The pupil response to light flux increments is abnormal in severe optic neuritis, but little is known about the effects of this condition on the pupil colour response. The aim of this study was to examine how optic neuritis affects pupil responses to light flux and colour modulation and the extent to which such pupil responses mirror the loss and recovery of vision. METHODS: A new pupil examination technique that makes use of sinusoidal modulation of either luminance contrast or chromatic saturation was employed. This technique enables the automatic extraction of both pupil response amplitude and latency and achieves a high signal to noise ratio with fewer averages. RESULTS: The study reveals a greater loss of pupil response amplitude and significantly longer latencies to chromatic modulation (i.e. approximately 80 ms). Stimulation of the unaffected eye in the optic neuritis group results in smaller response amplitudes when compared to the normal group for both light flux and colour modulation. CONCLUSIONS: Pupil response components can be affected differently in optic neuritis. These findings suggest that the pupil colour response, in particular, may provide a useful, objective estimator to judge the extent of damage and recovery in diseases of the optic nerve.

Early-onset autosomal dominant retinitis pigmentosa with severe hyperopia.

We studied a four-generation family with early-onset autosomal dominant retinitis pigmentosa, severe hyperopia, and axial eye lengths of less than 20 mm. The affected members had decreased vision, night blindness, typical peripheral retinal pigmentary changes, and electroretinographic abnormalities characteristic of retinitis pigmentosa. This pedigree suggests there is another variant of retinitis pigmentosa associated with hyperopia besides Leber's congenital amaurosis and preserved para-arteriole retinal pigment epithelium.

Bilateral posterior ischemic optic neuropathy after spinal surgery.

PURPOSE: To report the association between bilateral posterior ischemic optic neuropathy and spinal surgery. METHOD: Case report. RESULTS: After prone-position spinal surgery of 8 hours' duration, a 68-year-old woman was completely blind in both eyes. Moderate periorbital edema and temporal conjunctival chemosis were present bilaterally. Ophthalmic examination disclosed normal-appearing optic nerve heads, except for bilateral nasal fullness related to bilateral optic nerve drusen, and no retinal edema. Immediate cerebral arteriography, magnetic resonance imaging, and electroretinography were normal. Visual-evoked response was not detectable, and 7 weeks later, severe bilateral optic nerve head pallor developed. CONCLUSIONS: Severe selective hypoperfusion of the retrobulbar optic nerves may occur after spinal surgery. Pressure to the periorbital region may be a contributing factor.

Prevalence of palpebral fissure asymmetry in white persons.

PURPOSE: Because palpebral fissure asymmetry in horizontal gaze is reportedly common in otherwise normal persons, we determined the prevalence of physiologic palpebral fissure asymmetry for primary and horizontal gazes. METHODS: We measured the palpebral fissure height of both eyes of 88 healthy white subjects. Measurements were obtained with high-resolution videography, with the eyes in primary position, in 45-degree right gaze, and in 45-degree left gaze. RESULTS: Of the 88 subjects, 36 (41%) were male and 52 (59%) were female. The ages ranged from 12 to 50 years, with a mean of 32.5 +/- 9.0 years. When a criterion of equal to or greater than 1 mm was used, the prevalence of physiologic palpebral fissure asymmetry was 5.7% (five of 88) in primary gaze, 18.2% (16 of 88) in right gaze, and 14.8% (13 of 88) in left gaze. The largest observed palpebral fissure asymmetry was 2.1 mm. After correcting for any existing fissure asymmetry in primary gaze, two-tailed trivariate analysis of variance showed that the fissure of the adducting eye tended to be wider. The mean increase in the palpebral fissure of the adducting eye was 0.12 mm for right gaze (P = .052) and 0.13 mm for left gaze (P = .034). Additionally, a chi 2 test indicated that the occurrence of wider adducting eye in both right and left gazes was highly significant (P = .0023). CONCLUSIONS: In this sample of white subjects, palpebral fissure height asymmetry increased in horizontal gaze to the right and to the left, which is in part because of a tendency of the adducting eye to widen slightly. In contrast to previous reports, the prevalence of palpebral fissure asymmetry was low, and the abducting eye did not widen significantly.

The prevalence of simple anisocoria.

We photographed the pupils of 128 normal subjects in dim light, morning and afternoon, for five consecutive days. Fifty-two of the subjects (41%) had an anisocoria of 0.4 mm or more at one time or another during these five days, but only four (3%) had unequal pupils of 0.4 mm or more in all ten photography sessions. At any given examination, a fairly constant 19% (24 of 128) of the subjects showed this amount of anisocoria. These numbers shifted dramatically when anisocoria was defined as a pupillary inequality of greater than, or less than, 0.4 mm. The prevalence of anisocoria did not vary with the time of day, from day to day, or from week to week, nor was it influenced by the sex, age, or iris color of the subject.

Optic tract compression from dolichoectatic basilar artery.

PURPOSE: To report a case of optic tract compression caused by a dolichoectatic basilar artery. DESIGN: Observational case report. METHODS: A 74-year-old man with progressive loss of vision over 13 years and no other neurologic signs or symptoms was found to have bilateral optic nerve head pallor and a left homonymous hemianopia. RESULTS: Magnetic resonance imaging and angiography revealed a severe dolichoectatic basilar artery compressing the right optic tract. CONCLUSION: Basilar artery dolichoectasia may rarely cause compression of the optic tract and progressive visual loss.

Kestenbaum's number as an indicator of pupillomotor input asymmetry.

We compared the direct light response of both eyes in 90 patients who had anterior visual pathway disease using two different testing methods. We measured Kestenbaum's number in millimeters of pupillary diameter. Kestenbaum's number (K) is the difference in the pupil size attained in each eye under direct illumination while the other eye is occluded. We then measured the relative afferent pupillary defect (RAPD) in log units using neutral density filters. The two tests gave similar results (K = 0.88 x RAPD). Kestenbaum's number is the less precise measure, but it can be quickly and cheaply estimated even in dark brown eyes. The filter test requires a set of filters and at least one well-innervated iris sphincter. Kestenbaum's number can be measured without filters, but the iris sphincter and dilator muscles in both eyes must be normally innervated.

Ocular manifestations of Seckel syndrome.

PURPOSE: To report ophthalmic findings in three siblings with Seckel syndrome. METHODS: Observational case report. Three siblings with Seckel syndrome were examined. RESULTS: Severe bilateral pigmentary retinopathy with severe myopia and astigmatism was found in all three patients. Electroretinography was performed on the eldest sibling and showed no detectable rod or cone responses. CONCLUSION: Severe, early onset, bilateral retinal degeneration with severe myopia and astigmatism may be associated with Seckel syndrome.

Racial differences in the prevalence of atrophic-appearing macular lesions between black and white patients with retinitis pigmentosa.

We compared the prevalence of atrophic-appearing macular lesions between black and white patients with isolated or various genetic types of retinitis pigmentosa to determine if an appreciable difference existed between these two groups. The study included 720 patients of whom 138 (19.2%) were black patients from 115 families and 582 (80.8%) were white patients from 478 families. A logistic regression analysis combining isolated and all genetic types but randomly selecting one patient per family showed a statistically significant difference in the prevalence of atrophic-appearing macular lesions between black and white patients for the right eye (P = .0012) and left eye (P = .002). When considering either all patients or one patient per family, the estimated odds ratios were approximately 2.0 for blacks relative to whites. Our findings indicate that black patients with retinitis pigmentosa are approximately twice as likely as white patients to develop an atrophic-appearing macular lesion. This observation has implications for the prognosis of central visual function in such patients.

Retinitis pigmentosa associated with a dominant mutation in codon 46 of the peripherin/RDS gene (arginine-46-stop).

PURPOSE: We identified genetic mutations and characterized their associated phenotypes in patients with retinitis pigmentosa. METHODS: Patients with retinitis pigmentosa were prospectively examined and screened for genetic mutations. RESULTS: A 46-year-old man with retinitis pigmentosa was found to have a heterozygous mutation in the peripherin/RDS gene (arginine-46-stop). He had late onset of symptoms and demarcated peripheral retinal atrophy. All five first-degree relatives including his parents had no detectable mutations or retinitis pigmentosa. Genotypic data were consistent with reported family structure. CONCLUSIONS: This study shows that new dominant mutations are a rare cause of isolated, or simplex, cases of retinitis pigmentosa. Identification of these mutations is helpful for genetic counseling.

Idiopathic intracranial hypertension in children and adolescents.

PURPOSE: To investigate sex distribution, frequency of obesity, and other associated conditions among children and adolescents with idiopathic intracranial hypertension. METHODS: We conducted a retrospective chart review of patients aged 18 years or younger diagnosed with idiopathic intracranial hypertension between 1988 and 1995 at two medical centers. Meta-analyses were performed using our data pooled with published information. RESULTS: Of 374 patients, 175 (46.8%) were male and 199 (53.2%) were female. Obesity was noted in 50 (29.6%) of the 169 patients for whom relevant data are available, and other associated conditions were noted in 185 (53.2%) of the 348 patients. CONCLUSIONS: Idiopathic intracranial hypertension among children and adolescents affects boys and girls equally; concurrent obesity occurs less frequently than in adults; and other associated conditions or secondary causes are common.

Visual prognosis in macular retinoblastomas.

Since 1979, we have treated 11 patients who had macular retinoblastomas. Two patients eventually recovered 20/20 visual acuity despite the presence of subretinal fluid in the fovea at the time of diagnosis. The diagnosis was made at 11 and 14 months of age, and follow-up periods were ten and seven years, respectively. One case was sporadic and the other was hereditary. Both patients were treated with external radiation; one patient was also treated with chemotherapy. The lesions regressed markedly after treatment. These cases demonstrate that visual prognosis in macular retinoblastomas is not uniformly poor even when a foveal detachment is present. Visual acuity may be good in some cases, which supports the merits of medical treatment rather than enucleation in selected patients.