Evaluation of the ARMD1 locus on 1q25-31 in patients with age-related maculopathy: genetic variation in laminin genes and in exon 104 of HEMICENTIN-1.

The age-related maculopathy (ARM) genetics program at Columbia University utilizes comprehensive genetic analysis of candidate genes in large case-control studies to determine genotypes associated with the ARM complex trait. Genes encoding laminins, a class of extracellular matrix proteins, represent attractive candidates for two reasons. First, the presence of laminins in the basal lamina of the retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris suggests a possible role in the pathophysiology of ARM. Second, three laminin genes, LAMC1, LAMC2, and LAMB3, are located in the 1q25-31 region, within the previously mapped ARMD1 locus. The entire open reading frame of the three laminin genes was screened for variants by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing in at least 92, and up to 368 ARM patients and matched unaffected controls. Sixty-nine sequence variants were detected in the 69 exons of the LAMC1, LAMC2, and LAMB3 genes. Screening of exon 104 of the recently proposed ARMD1 gene, HEMICENTIN-1, residing in the 1q25-31 locus, did not detect the suggested causal variant, Q5345R, in 632 study subjects. Overall, we did not find statistically significant differences in the frequency of variants between ARM-affected individuals and age-matched controls. Four rare, non-synonymous, variants were detected in single cases of ARM patients. Our data on relatively limited numbers of study subjects do not suggest a significant role for genetic variation in the three laminin genes and in exon 104 of HEMICENTIN-1 in predisposing individuals to ARM. However, as in many instances in similar studies, involvement of rare amino acid-changing variants in a fraction of ARM cannot be ruled out.

Change on the horizontal and vertical meridians of the cornea after cataract surgery.

PURPOSE: To compare the course and magnitude of change on the horizontal and vertical meridians of the cornea after 5 different incisions for cataract: extracapsular cataract extraction (ECCE), 6 mm superior scleral tunnel (6Sup), 3 mm superior scleral tunnel (3Sup), 3 mm temporal scleral tunnel (3Temp), and 3 mm temporal corneal incision (3Cor). METHODS: Retrospective chart review of 665 cases of preoperative regular astigmatism. The preoperative keratometry (K) reading was subtracted from the postoperative K reading to determine mean net change on each meridian at 1 day, 1 week, 2 weeks, 1 month, 1.5 months, 2 months, 4 months, 6 months and 12 months and at 6 month intervals thereafter. After the superior incisions, the temporal changes on each meridian are well described by an analytic model with an initial and final plateau. The changes after the temporal incisions are described by a linear equation. RESULTS: After each superior incision, the steepness and length of the transition from the initial to final plateau for each meridian depend on incision length. Considering the uncertainty of measuring K, the corneal meridians stabilized 4.5 months after ECCE, 1.2 months after 6Sup, and 0.3 months after 3Sup. No significant change was detected on the horizontal and vertical meridians after 3Temp and 3Cor. CONCLUSION: The magnitude and the duration of changes on the horizontal and vertical meridians of the cornea after cataract surgery depend on both incision length and location. Small temporal incisions induce less change than superior incisions.

An action spectrum for UV-B radiation and the rat lens.

PURPOSE: To determine an action spectrum for UV-B radiation and the rat lens and to show the effect of the atmosphere and the cornea on the action spectrum. METHODS: One eye of young female rats was exposed to 5-nm bandwidths of UV-B radiation (290, 295, 300, 305, 310, and 315 nm). Light scattering of exposed and nonexposed lenses was measured 1 week after irradiation. A quadratic polynomial was fit to the dose-response curve for each wave band. The dose at each wave band that produced a level of light scattering greater than 95% of the nonexposed lenses was defined as the maximum acceptable dose (MAD). Transmittance of the rat cornea was measured with a fiberoptic spectrophotometer. The times to be exposed to the MAD in Stockholm (59.3 degrees N) and La Palma (28 degrees N) were compared. RESULTS: Significant light scattering was detected after UV-B at 295, 300, 305, 310, and 315 nm. The lens was most sensitive to UV-B at 300 nm. Correcting for corneal transmittance showed that the rat lens is at least as sensitive to UV radiation at 295 nm as at 300 nm. The times to be exposed to the MAD at each wave band were greater in Stockholm than in La Palma, and in both locations the theoretical time to be exposed to the MAD was least at 305 nm. CONCLUSIONS: After correcting for corneal transmittance, the biological sensitivity of the rat lens to UV-B is at least as great at 295 nm as at 300 nm. After correcting for transmittance by the atmosphere, UV-B at 305 nm is the most likely wave band to injure the rat lens in both Stockholm and La Palma.

Age-related changes in the absorption characteristics of the primate lens.

PURPOSE: To quantitate aging of the primate lens by changes in the absorption characteristics that are related to the yellowing of lens protein. METHODS: The lenses of lower primates and humans were sectioned anterior to posterior every 0.25 mm, and the UV-visible spectrum of each section was measured to determine the cumulative spectra along the visual axis. The ratio of the absorbance at 320 nm (formed with aging) to the absorbance at 365 nm (present in the young lens) was correlated with the age of the lens. RESULTS: In the young primate UV-B is transmitted to the retina, and UV-A is transmitted to the nucleus of the lens. By puberty, changes in the absorption characteristics of the lens that are associated with the yellowing of lens protein prevented most of the UV-B from reaching the retina and by the eighth decade, the transmittances at 320 and 365 nm to the nucleus of the lens were approximately 40% and 79%, respectively. A linear relationship between the ratio of absorbance at 320 to 365 nm and age was found for both lower primates and humans to the age of 80 years. This is surprising, because the maximum life span of the lower primate is approximately 35 years, whereas humans may live 100 years. CONCLUSIONS: These data suggest that the observed spectral changes associated with the yellowing of the lens are the result of a chronological process, such as chemical or photochemical modifications, not biological aging.

Transmission spectra of light to the mammalian retina.

A simple method has been developed to determine the optical properties of the anterior segment of the intact eye. This consists of a probe that is inserted into the posterior sclera and detects light passing through the anterior segment. The probe is connected to a charge-coupled device spectrophotometer via a fiber optic bundle. It was determined that the young rat anterior segment transmits light down to 300 nm, whereas calf and rabbit eyes transmit no UVB and only part of the UVA to the posterior segment. The absorbing species in these animals is most likely NAD(P)H, which has an absorption maximum at approximately 345 nm and is associated with zeta-crystallin. A young primate anterior segment transmits almost no UV with a steep increase in transmission at CA 400 nm. Because some experiments employed a light tube that is used to illuminate the retina during vitrectomies, this method can be used to determine the transmission spectra of the anterior segment of humans in vivo.

The optical properties of the anterior segment of the eye: implications for cortical cataract.

Epidemiological studies have correlated cortical cataract with exposure to light and have suggested that this is due primarily to relatively short wavelengths of ultraviolet radiation (UV-B). In addition, some cellular and animal models also implicate UV-B. In order to evaluate the likely role of different wavelengths of light in the etiology of cortical cataracts, the optical characteristics of several animal models were ascertained and compared to the primate. This study shows that the mouse model absorbs UV-B almost exclusively whereas other animal models such as the rabbit and the guinea pig also contain chromophores that absorb UV-A. The absorptive characteristics of the human lens varies drastically with age. The young lens absorbs primarily UV-A, whereas with age, there are increases in absorptions at 320 nm and out to wavelengths as long as 550 nm. By sectioning human lenses it was found that these changes in absorption properties increased toward the central and the nuclear regions. These absorptive characteristics were then compared to the amount of light reaching the surface of the lens. It was found that UV-B is a minor component of total energy reaching the surface of the human lens and old human lens proteins absorb 2 orders of magnitude more UV-A and visible light than UV-B. It is concluded that it is premature to exclude UV-A or even visible light in the etiology of human cortical cataracts.

Fine-needle aspiration diagnosis of enterogenous cyst of the orbit: a case report.

Enterogenous cyst is a benign lesion derived from misplaced endodermal epithelium. We report the aspiration cytology findings of an orbital cyst from a 32-year-old woman. The smears contain benign-appearing cuboidal glandular cells with focal mucinous features. Carcinoembryonic antigen level in the cyst fluid was markedly elevated. These findings are consistent with recurrence of the enterogenous cyst initially diagnosed 7 years earlier.

Astigmatism and visual recovery after 'large incision' extracapsular cataract surgery and 'small' incisions for phakoemulsification.

PURPOSE: This study compares the change over time of the astigmatism caused by "large" incision extracapsular cataract extraction (ECCE) and three smaller incisions for phakoemulsification. Based on this data, a mathematical model that predicts the course of astigmatism after a superior incision of length 3 to 12 mm has been developed. The relationship of axial length and preoperative astigmatism to induced post-operative astigmatism, the recovery of visual acuity, and the rate of YAG laser capsulotomy after each procedure also are documented. METHODS: Induced astigmatic change was calculated using a simple method of vector analysis. The change in induced astigmatism was calculated for 8 years after ECCE (n = 144), for 3 years after 6 mm superior incisions (6SUP) (n = 93), for 2 years after 3 mm superior incisions (3SUP) (n = 120), and for 18 months after 3 mm temporal incisions (3Temp) (n = 65). Plotted semi-logarithmically, the astigmatic change in each group may be represented mathematically. RESULTS: Two weeks after ECCE the mean induced cylinder was +3.47 D, which decayed to about -1.25 D after 6 months. Induced cylinder increased gradually to about -1.6 D after 8 years, although this further change was not significantly different than that at 6 months after surgery. For the phako groups, the net induced cylinder on the first post-operative day was: +1.23 D (6SUP), +0.49 D (3Sup), and -0.19 D (3Temp). After 6Sup the wound was astigmatically stable after approximately 3 months, and 3 years after surgery net induced cylinder was -0.66 D. After 3Sup the wound was astigmatically stable after about 6 weeks, and after 18 months net induced cylinder was -0.35 D. No significant change in astigmatism was detected at any time after 3Temp. Maximum visual acuity was reached after a mean of approximately 6 weeks after ECCE, 2 weeks after 6Sup, and between 1 day and 1 week after 3Sup and 3Temp. The rate of YAG laser capsulotomy was higher after ECCE than after any of the phakoemulsification procedures. No relationship of axial length or preoperative astigmatism to astigmatic change was detected. CONCLUSIONS: Incision size and location affect post-operative astigmatism. Induced astigmatism decreases with wound size, and only the 3 mm temporal incision is astigmatically neutral. The time for visual recovery increases with wound size. There appears to be less need for laser capsulotomy after phakoemulsification with capsulorrhexis than after ECCE. Axial length does not affect induced astigmatism after any of the 4 incisions, and preoperative astigmatism does not affect astigmatic change after ECCE and 6Sup.

Iris hooks for phacoemulsification of the subluxated lens.

Phacoemulsification of the lens in eyes with zonular loss risks dislocation of the lens into the vitreous cavity. We describe the use of iris hooks after capsulorhexis to support the lens during surgery. With iris hooks, the lens can be stabilized, helping prevent additional loss of zonules and permitting retention of the capsule to support an intraocular lens.

Experimental model of light focusing of the peripheral cornea.

PURPOSE: Epidemiologic studies have shown that the onset of cortical cataract occurs primarily in the inferonasal human lens and that the incidence of cortical cataract is correlated with ultraviolet light. Ray tracing analysis has suggested that the peripheral cornea concentrates light on the opposite peripheral lens and that the nose and orbit block peripheral light, except temporally, resulting in a relative concentration of light on the inferonasal lens. Studies were performed to test these theories. METHODS: A model cornea and anterior chamber, set on a disc of light-sensitive paper, was placed in the orbit of a human skull coated with wax to simulate soft tissue. The "eye" was exposed to summer sunlight at various times of day, with and without sunglasses. Discs from the different experimental groups were scanned, and the digitized images were analyzed densitometrically using image analysis software. RESULTS: With the head upright, the inferonasal section of the disc exhibited the most intense exposure under all lighting conditions. Sunglasses decreased the intensity of overall light exposure but did not eliminate the inferonasal bias. Only blocking the temple eliminated this effect. CONCLUSIONS: This model supports the idea that the peripheral cornea focuses light on the inferonasal portion of the human lens. These results may explain the correlation between light and the location of cortical cataract.

The concentration of light in the human lens.

PURPOSE: This thesis explores the idea that light energy, especially ultraviolet light, contributes to the unequal distribution of cataract around the world and to the development of cortical opacities. METHODS: In the first section, the thesis reviews historical concepts of the function of the lens and the nature of cataract, epidemiologic data on the global distribution of cataract, and clinical observations of the predominant location of cortical opacification. Second, computer ray tracings and geometric optics demonstrate the passage of light of varying angle of incidence within the lens. Third, two models of the human eye are used to study the refraction of light by the cornea and lens and illustrate the concentration of energy at the equatorial plane of the lens. RESULTS: Cataract prevalence increases with proximity to the earth's equator, and cortical cataract is most common in the inferior and inferonasal lens. Theoretical studies and the eye models both demonstrate that the concentration of light within the lens increases with angle of incidence, and the eye models suggest that the inferior and inferonasal lens receives significantly more energy than other sections of the lens. CONCLUSION: The prevalence of cataract and exposure to ultraviolet energy both increase with decreasing latitude. The most common location of cortical cataract in the inferonasal lens is consistent with the greater dose of light energy received by this portion of the lens. These studies suggest that the global distribution of cataract and the development of cortical cataract are at least in part dependent on the dose of ultraviolet light received by the lens.

Rehabilitation of a child with partial unilateral cryptophthalmos and multiple congenital anomalies.

PURPOSE: This paper describes the surgical rehabilitation of a child with craniofacial anomalies, unilateral syndactyly, and partial unilateral cryptophthalmos associated with inferior colobomata of the iris and optic nerve and agenesis of the inferior rectus and inferior oblique muscles. The clinical presentation of cryptophthalmos is described. METHODS: The medical literature since the original description of cryptophthalmos in 1872 was reviewed to define patterns of inheritance and the incidence of associated anomalies. RESULTS: Including this patient, 149 case reports of cryptophthalmos were identified. In two families transmission from parent to child suggests dominant inheritance. None of the five dominant cases had any other anomalies, and all had bilateral complete cryptophthalmos. The incidence of cryptophthalmos in the remaining families is consistent with autosomal recessive inheritance. This group includes patients with bilateral, unilateral, and partial cryptophthalmos. Other anomalies are common, including those of the ear and nose, limbs, genitourinary system, and mouth and palate. Mortality in the perinatal period is associated with renal agenesis, laryngeal atresia, and pulmonary hypoplasia. CONCLUSIONS: Cryptophthalmos is a rare congenital anomaly with two patterns of inheritance.

Enterogenous cyst of the orbital apex and superior orbital fissure.

BACKGROUND: Enterogenous cysts of the central nervous system are rare congenital tumors with a single layer of mucin-secreting epithelial cells resembling gastrointestinal epithelium. The tumor is located most commonly at lower cervical and cervicothoracic spinal levels; only 22 intracranial cases have been reported. To the authors knowledge, this entity has not been described in the orbit. METHODS: A 23-year-old woman with painful loss of vision and ophthalmoplegia in the left eye was treated with oral and intravenous corticosteroids for presumed orbital inflammation. After a cystic lesion in the left orbital apex was demonstrated on computed tomographic scan and magnetic resonance imaging, various diagnoses, including optic nerve tumor, granulomatous inflammation, lymphoma, vascular anomaly, and pseudotumor, were considered until transcranial biopsy established the correct diagnosis. The tumor subsequently recurred twice. RESULTS: More than 3 years after the last recurrence, the patient has no pain but had unilateral optic atrophy, significant visual field loss, limited motility, and an anesthetic cornea in the left eye. CONCLUSION: The diagnosis of enterogenous cyst is difficult without adequate biopsy because the radiologic and clinical presentation of this rare tumor may be confused with other lesions. Previous attempts to explain intracranially placed enterogenous cysts offer no explanation for an orbital occurrence nor do they adequately describe a mechanism for an intracranial location in general. An embryologically based explanation that takes into account the occurrence of this entity from the caudal to rostral extent of the neuraxis is described. This theory suggests that the orbit is the most rostral possible location for an enterogenous cyst.

Extracapsular cataract extraction and posterior-lip sclerectomy with viscoelastic.

A review of 15 cases suggests that posterior-lip sclerectomy can be performed safely with extracapsular cataract extraction (ECCE) and posterior chamber lens implantation. The anterior chamber was filled with viscoelastic at the end of each procedure; no case required reoperation for shallow chamber or hypotony. The mean intraocular pressure after 1 year was 12.1 mm Hg. The astigmatism induced by the triple procedure did not differ significantly from that caused by ECCE alone during the initial 2 postoperative years. A new mathematical model that describes the change over time of postoperative astigmatism associated with these procedures is described.

Prenatal cocaine exposure and the development of the human eye.

PURPOSE: The use of cocaine during pregnancy has been associated with congenital abnormalities of the developing eye. The authors report a prospective, controlled study of 40 cocaine-exposed and 40 nonexposed (control) preterm and full-term infants. METHODS: Detailed maternal and obstetric histories were obtained by chart review and interview. Infants with a positive urine toxicology screen for cocaine at birth or whose mothers tested positive for cocaine were recruited into the exposed group. Nonexposed infants were recruited at random from newborns admitted to the authors' nurseries. Mothers of these infants received routine prenatal care in the authors' clinics, and nonexposure was documented by maternal history and/or negative urine toxicologies that were available in 30% of these mother-infant pairs. General physical and ocular examinations, including measurement of axial length and intraocular pressure, were performed on all infants. RESULTS: Forty infants were recruited in each group, with gestational ages ranging from 25 to 42 weeks. Twenty-nine of the exposed infants and 26 of the control infants were full-term (gestational age, 37 weeks or older). A total of 160 eyes were examined. No differences were seen in the incidence of congenital anomalies, subconjunctival hemorrhages, retinal hemorrhages, or optic nerve abnormalities between the two groups. No differences in mean axial length (16.9 +/- 0.6 mm [exposed group] versus 17.1 +/- 0.7 mm [control group]) or intraocular pressure (15.4 +/- 3.8 mmHg [exposed group] versus 15.0 +/- 3.0 mmHg [control group]) were seen between full-term infants in both groups. Axial length correlated strongly with gestational age, birth weight, head circumference, and body length over the range of gestational ages evaluated in both groups. No effect of cocaine exposure on these correlations was demonstrated. The range of axial length was 12.1 to 18.0 mm in the exposed group and 12.4 to 18.6 mm in the control group. CONCLUSION: In this study group, no significant effect of prenatal cocaine exposure was seen on the infant eye. In both exposed and nonexposed groups, axial length measurements agreed closely with known statistical norms and correlated closely with other parameters of fetal growth.

Mesenchymal chondrosarcoma of the orbit. Report of three new cases and review of the literature.

BACKGROUND: Extraskeletal mesenchymal chondrosarcoma is a rare tumor characterized by undifferentiated mesenchymal cells with islands of mature hyaline cartilage. Considering all sites, long-term survival is approximately 30%. Only seven cases of orbital mesenchymal chondrosarcoma have been reported. METHODS: The records of three cases of orbital mesenchymal chondrosarcoma treated at the Columbia-Presbyterian Medical Center, and the seven previously reported cases of this tumor were reviewed to determine clinical characteristics and appropriate therapy. RESULTS: Nine of the 10 patients were female; age of onset ranged from 10 to 35 years. Of eight patients with at least 2 years of observation, five survived 5 or more years after resection, or after resection plus adjuvant therapy. Two patients died of metastatic disease 2 and 5 years, respectively, after the initial treatment, and one died of pneumonia 6 months after surgery. Review of the histology of the three cases treated at Columbia-Presbyterian Medical Center did not identify distinct histologic types that might guide therapy. Presenting symptoms were typical of symptoms of an orbital mass: proptosis, pain, diplopia, change in visual acuity, ptosis, and tearing. CONCLUSION: The small number of reported cases of mesenchymal chondrosarcoma of the orbit prevents definitive conclusions, but it appears that resection is adequate therapy in some cases. Extraskeletal mesenchymal chondrosarcoma of the orbit may have a better prognosis than tumors in other sites.

Radiation retinopathy: electron microscopy of retina and optic nerve.

A 4 1/2 year old female was treated for embryonal rhabdomyosarcoma of the left orbit in 1975 with radiation (59.5 Gy in 5 weeks), followed by chemotherapy. An electroretinogram (ERG) in March, 1988 revealed cone responses 3% of normal and no rod responses in the left eye, and normal responses in the right eye. The eye was enucleated in April 1988. In the fovea no choroidocapillaris was seen at the intact Bruch's membrane, and the pigment epithelium was preserved only in small patches. No photoreceptor cells were seen in the areas devoid of pigment epithelial cells. The parafoveal and peripheral (30 degrees eccentricity) retina was better preserved. The thickness of the layer of rods and cones and of Henle's fiber layer was reduced. Very few outer segments were present. Macrophages had invaded the retinal tissue in moderate numbers. The retinal vessels were ensheathed by several layers of collagen fibrils. The spatial densities of pigment epithelial, cone, rod, and bipolar cells had been reduced. The optic nerve contained a total number of 1,022,000 nerve fibers.

Evidence of genotoxic damage in human cataractous lenses.

Lens epithelial fragments (tags) recovered from individuals during routine cataract extraction have been assessed for cellular changes reflective of genotoxic damage. A high percentage of tags exhibited a population of micronucleated and polyploid cells. The presence and number of micronuclei (MN) in the epithelia of cataract patients appears to be independent of age and sex. However, a large number of MN in the epithelial cells of some individuals strongly suggests a history of compromised genomic integrity. While the study was not designed to define the role of DNA damage in the development of cataracts or to monitor human populations at risk of exposure to exogenous mutagens/cataractogens, the potential of the methodology to address each is demonstrated.