A small foveal avascular zone may be an historic mark of prematurity.

OBJECTIVE: To compare in children the area and diameter of the foveal avascular zone (FAZ) of former preterm infants, when no significant retinopathy of prematurity (ROP) developed, to the area and diameter of the FAZ of former term infants. DESIGN: Retrospective observational case series and literature review. PARTICIPANTS: Forty-nine children (39 former preterm infants and 10 former term infants) between the ages of 1 and 17 years had fluorescein angiograms. All of these children had been appropriate weight for gestational age at birth and had no genetic disorders. Neither eye of any of these children had any macular ectopia or vessel traction, had been treated for active ROP, had developed active ROP >stage 3 mild, or had any refractive error > +/- five diopters. Every child had a visual acuity of 20/40 or better in both eyes. METHODS: The area and greatest diameter of the FAZ were measured using digital image analysis of masked fundus fluorescein angiograms. Variables of gender, race, multiple birth, gestational age, birth weight, ROP stage, age, and refraction at the time of fluorescein angiography, and final visual acuity were recorded. RESULTS: Increasing FAZ area and greatest diameter correlated significantly with increasing gestational age and birth weight: FAZ area (microm2) versus gestational age (weeks) (R/F/P = 0.88/166.70/<0.0001); FAZ greatest diameter (microm) versus gestational age (weeks) (R/F/P = 0.87/151.10/<0.0001); FAZ area (micro/m2) versus birth weight (g) (R/F/P = 0.88/167.06/<0.0001); and FAZ greatest diameter (microm) versus birth weight (g) (R/F/P = 0.87/148.74/ <0.0001). A small or absent FAZ was found in all former preterm infants who had been < or = 30 weeks gestational age or had weighed < or = 1100 g at birth. A normal FAZ was present in all children who had been > or = 36 weeks gestational age or had weighed > or = 2650 g at birth. None of the other parameters studied correlated with FAZ area or greatest diameter. CONCLUSION: This study provides evidence that the FAZ in developing humans is initially densely vascularized with a fine meshwork of inner retinal vessels during vasculogenesis. This vascular meshwork undergoes regression by apoptosis in all infants > or = 36 weeks gestational age at birth to form a normal FAZ, but apoptosis almost never occurs in preterm infants < or = 30 weeks gestational age at birth. Although there is no effect on final visual acuity, a small or absent FAZ may be an historic mark of prematurity.

Long-term form identification vision after early, closed, lensectomy-vitrectomy for stage 5 retinopathy of prematurity.

PURPOSE: Form identification vision after early, closed, lensectomy-vitrectomy for retinopathy of prematurity (ROP) stage 5 open funnel retinal detachment is reported from a database that included 45 eyes of 27 infants. The focus of this report is the verbal responses at a mean age of 7.0 years for nine nonamblyopic (preferred) eyes of nine preterm infants with minimal developmental delay (good central nervous system function). METHODS: All 45 eyes underwent initial cryotherapy for threshold ROP to the avascular retina to decrease the angiogenic stimulus (mean postconceptual age = 34.8 weeks) and subsequently underwent multiple cryotherapy sessions to the avascular retina and shunt with scleral buckling to decrease retinal traction (mean postconceptual age = 38.0 weeks). When tractional retinal detachment occurred with an open funnel, each eye underwent an early, closed, lensectomy-vitrectomy (mean postconceptual age = 45.7 weeks). The 34 eyes with a successful anatomic result were fitted with contact lenses as soon as possible after surgery. RESULTS: The nine nonamblyopic eyes of nine preterm infants with minimal developmental delay had the following visual acuities using Allen figures or Snellen test types: one eye 20/80, one eye 20/200, two eyes 20/400, three eyes 20/800, and two eyes 20/ 1600. CONCLUSION: These nine eyes support the thesis that form identification vision can be obtained by early vitrectomy for ROP stage 5 open funnel retinal detachments.

Peripheral retinopathy in offspring of carriers of Norrie disease gene mutations. Possible transplacental effect of abnormal Norrin.

BACKGROUND: The Norrie disease (ND) gene (Xp11.3) (McKusick 310600) consists of one untranslated exon and two exons partially translated as the Norrie disease protein (Norrin). Norrin has sequence homology and computer-predicted tertiary structure of a growth factor containing a cystine knot motif, which affects endothelial cell migration and proliferation. Norrie disease (congenital retinal detachment), X-linked primary retinal dysplasia (congenital retinal fold), and X-linked exudative vitreoretinopathy (congenital macular ectopia) are allelic disorders. METHODS: Blood was drawn for genetic studies from members of two families to test for ND gene mutations. Sixteen unaffected family members were examined ophthalmologically. If any retinal abnormality were identified, fundus photography and fluorescein angiography was performed. RESULTS: Family A had ND (R109stp), and family B had X-linked exudative vitreoretinopathy (R121L). The retinas of 11 offspring of carrier females were examined: three of seven carrier females, three of three otherwise healthy females, and one of one otherwise healthy male had peripheral inner retinal vascular abnormalities. The retinas of five offspring of affected males were examined: none of three carrier females and none of two otherwise healthy males had this peripheral retinal finding. CONCLUSIONS: Peripheral inner retinal vascular abnormalities similar to regressed retinopathy of prematurity were identified in seven offspring of carriers of ND gene mutations in two families. These ophthalmologic findings, especially in four genetically healthy offspring, strongly support the hypothesis that abnormal Norrin may have an adverse transplacental (environmental) effect on normal inner retinal vasculogenesis.

Postnatal retinal vascularization in former preterm infants with retinopathy of prematurity.

PURPOSE: To study the postnatally vascularized retina in former preterm infants in whom retinopathy of prematurity (ROP) stages 2 to 4a developed and spontaneously regressed. METHODS: Matched fundus photographs and fluorescein angiograms of the temporal peripheral retinas of 133 eyes (72 patients) were obtained after 2 years of age (mean, 7.7 years; range, 2-16.2 years) and were quantified by two masked observers with respect to the following parameters: (1) macular ectopia (in disc diameters); (2) vessel traction (in 30 degrees sectors); (3) radial length of postnatally vascularized retina (in disc diameters); and (4) capillary scaffolding of postnatally vascularized retina (as a density). These cicatricial outcomes were then compared with their active worst ROP stage. RESULTS: Of the 133 retinal montages, the following active worst ROP stages had been documented: 30 with stage 2, 42 with stage 3 mild, 32 with stage 3 moderate, 20 with stage 3 severe, and 9 with stage 4a. As active worst ROP stage increased, macular ectopia and vessel traction increased, and radial length and capillary scaffolding of postnatal retinal vascularization decreased. Retinal holes were documented frequently in eyes with high myopia. CONCLUSIONS: The peripheral retina in former preterm infants warrants close scrutiny for possible late rhegmatogenous retinal detachments. Prolonged retinal traction (by remnant shunt and extraretinal fibrovascular proliferation) between stable, posterior, prenatally vascularized retina, and unstable, postnatally vascularized retina may lead to the development of retinal holes characteristically located in the fragile, anterior, undifferentiated, nonvascularized retina.

Free radicals and ocular disease.

Ames, Shigenaga, and Hagen recently published a thorough review of the relationship between oxidants, antioxidants, and degenerative diseases of ageing. They point out that only 9% of Americans daily consume the two fruits and three vegetables recommended by the National Cancer Institute and the National Research Council/National Academy of Science. In addition to antioxidants, these foodstuffs contain many essential micronutrients. To date, specific recommendations for antioxidant supplementation have not been made by any governmental agency or professional association. A number of clinical, basic, and epidemiological studies have implicated free radical induced lipid peroxidation in various ocular disorders. It would seem prudent that those persons at greatest risk for these disorders take some precautions, which could include sunglasses that filter ultraviolet light; hats that shield the eyes from direct sunlight; and the ingestion of fruits, vegetables, and antioxidants.

The pattern visual-evoked potential in former preterm infants with retinopathy of prematurity.

PURPOSE: Flash and pattern visual-evoked potentials (VEPs) were recorded in 89 former preterm infants (< or = 1500 g birth weight), in whom retinopathy of prematurity (ROP) developed that spontaneously regressed without macular detachment (stages 2-4a). METHODS: Linear and stepwise regression analyses were performed to determine the correlations between transient pattern-reversal P1 VEP latency (n = 154 eyes) at a mean of 7.2 years (median, 6.9 years) postnatal age using a check size nominally equivalent to 20/100 (30 minutes) and the following nine parameters: three immaturity parameters (gestational age at birth, birth weight, and ROP zone at 1 month postnatal age); one postnatal insults parameter (worst ROP stage); two structural outcome parameters (macular ectopia and vessel traction); one functional outcome parameter (visual acuity); and two methodological parameters (postnatal age at VEP testing and VEP amplitude). RESULTS: Linear regression analyses, with P1 VEP latency as a dependent variable, identified the worst ROP stage (r = +0.42; P < 0.0001), macular ectopia (r = +0.42; P < 0.0001), visual acuity (r = -0.40; P < 0.0001), and vessel traction (r = +0.35; P < 0.0001) as significant correlates. Stepwise regression analysis demonstrated that worst ROP stage and macular ectopia accounted for 18% and 4% of the cumulative variance, respectively. CONCLUSIONS: P1 VEP latency correlates with postnatal insults, structural outcome, and functional outcome parameters in former preterms in whom ROP developed that spontaneously regressed without macular detachment. A permanent arrest in the development of the macula and/or prolonged traction on the incompletely developed macula may alter VEPs.

Criteria to detect minimal expressivity within families with autosomal dominant aniridia.

Autosomal dominant aniridia with complete penetrance without Wilms' tumor in five generations with 27 affected family members has been reassigned from chromosome 2p25 to chromosome 11p13. Clinically, aniridia was obvious in affected individuals with variable expressivity when they had rudimentary iris stumps, typical or atypical iris colobomata, or round, eccentric pupils. However, iris and retinal fluorescein angiography was required to detect abnormal vascular remodeling that resulted in incomplete iris collarettes and decreased retinal foveal avascular zones in 27 family members at risk with round, central pupils. These angiograms distinguished five affected and 22 unaffected individuals, and were the critical criteria required to detect minimal expressivity of aniridia in family members with round, central pupils.

Visual acuity correlates with severity of retinopathy of prematurity in untreated infants weighing 750 g or less at birth.

Visual acuity was assessed in 72 patients who weighed 750 g or less at birth, had intact visual pathways as confirmed with computed tomography or magnetic resonance imaging, and had at least one eye evaluated for cicatricial sequelae after active, untreated retinopathy of prematurity without macular detachment (stage 4a or better). Visual acuities were obtained for 137 untreated, sighted eyes. Severity parameters for retinopathy of prematurity (stage of retinopathy of prematurity, refraction [in spherical equivalents], macular ectopia [in disc diameters], and vessel traction [in 30 degrees sectors]) was were significant predictors of visual acuity (P less than .0001) based on results of linear regression and stepwise regression analyses; however, parameters of retinal immaturity (birth weight, gestational age, and zone of retinopathy of prematurity) were not significant predictors of visual acuity. Visual acuity of the study eyes was good (median, 20/30; geometric mean, 20/33.58), with no statistical differences between eyes evaluated on last examination with linear Allen figures and those evaluated with linear Snellen test types.

The pathogenesis of retinopathy of prematurity as it relates to surgical treatment.

Our current surgical treatment for threshold retinopathy of prematurity (ROP) is based upon three concepts which emerged from morphologic and biochemical study of 250 pairs of whole eye donations obtained over a ten year period. 1) Spindle cells normally migrate and canalize to form inner retinal vessels, but when stressed, spindle cells secrete angiogenic factors. The clinical implication is that transretinal cryotherapy to the avascular retina is efficacious because it obliterates spindle cells. The number and timing of cryosessions are determined by the migration and kinetics of spindle cells. 2) Myofibroblasts originate from the shunt, are the major cellular component of extraretinal fibrovascular proliferation (EFP), and contract to produce retinal distortion and detachment. The clinical implication is that a second transretinal cryotherapy session should obliterate the shunt and the EFP, and should eliminate the source of retinal traction. 3) Anterior ocular growth occurs exponentially during the period when ROP develops and is treated. The clinical implication is that a prophylactic scleral buckle supports the fixed surface area of the developing retina while the choroid and sclera enlarge anteriorly. Retinal distortion produces misaligned photoreceptors, and retinal detachment results in rapid retinal death.

The rationale for cryotherapy with a prophylactic scleral buckle for Zone I threshold retinopathy of prematurity.

Our current surgical protocol for Zone I threshold retinopathy of prematurity (ROP) has evolved over 15 years and is rationalized by increasing knowledge of two pathologic processes of ROP: 1) angiogenic stimulation of spindle cells (clinically invisible) near the vitreal surface of the avascular retina; and 2) tractional forces of myofibroblasts [clinically visible as extraretinal fibrovascular proliferation (EFP)] in the vitreous overlying the vascular retina. These two pathologic processes occur concomitantly with normal anterior ocular growth with a constant optic disc-macular distance. Our current surgical protocol for Zone I threshold ROP, involves complex surgeries to achieve success defined as a macula which always remains anatomically attached, but which may be distorted or ectopic. This protocol requires cryotherapy in at least two sessions. The first is to the avascular retina to destroy spindle cells. The second is to the EFP to destroy myofibroblasts and to the shunt to eliminate the site of origin of myofibroblasts. The protocol also requires the concomitant placement of a prophylactic scleral buckle to allow formation of a new complete ora serrata while remnant myofibroblasts contract and while anterior ocular growth continues.

Morphologic changes of K-Sol preserved human corneas.

Supplementation of tissue culture medium with chondroitin sulfate has been shown to enhance donor corneal preservation. We assessed the efficacy of one of these chondroitin-supplemented media (K-Sol) in comparison with McCarey-Kaufman (MK) medium in maintaining corneal cellular morphology. Thirty-six human corneas, obtained within 8.6 h after death, were placed into K-Sol medium for up to 20 days preservation, and five paired control corneas were placed into MK medium for up to 6 days preservation. Specular photomicrographs were obtained every second to third day for a predetermined storage interval, then studied morphologically in a masked protocol by light microscopy, transmission electron microscopy, and scanning electron microscopy. Endothelial cell loss by specular microscopy averaged 5.8% after 1 week (6 to 8 days) and 7.4% after 13 days in K-Sol medium. Epithelial changes were erratic throughout the 20 day K-Sol preservation period. However, substantial keratocyte changes occurred after 10 days, and endothelial morphology uniformly deteriorated after 17 days. The morphologic data suggest that human corneas may be able to be preserved in K-Sol medium at 4 degrees C for up to 10 days but should be cautiously used thereafter.

Abnormal axonemes in X-linked retinitis pigmentosa.

Sperm of patients with X-linked retinitis pigmentosa (RP) was studied to assess the state of the axoneme in this genetic subtype. Semen samples were collected from eight patients with X-linked RP and compared with a database of 31 controls. Semen was also collected from two patients with other retinal degenerations (choroideremia and fundus flavimaculatus) and patients with simplex RP. All controls and patients were studied under a masked protocol. There was a significant increase in the percentage of abnormal sperm tails at both the light and electron microscopic levels in patients with X-linked RP only. Thus, X-linked RP is associated with an alteration in sperm axoneme structure. Sperm cell analysis may serve as a useful model system for additional investigations into the pathogenesis of this disease.

Abnormal sperm and photoreceptor axonemes in Usher's syndrome.

Axonemes are organelles that are composed of microtubule doublets and singlets with a complex assembly of associated proteins. This study was designed to investigate the possibility that an abnormal axoneme is involved in the pathogenesis of Usher's syndrome. A masked structural and functional analysis of sperm was performed on samples from ten patients with Usher's syndrome and 33 controls, including duplicate samples from six patients and three controls. In the functional analyses, there was a significant decrease in patient sperm motility and velocity. Structurally, there was a significant increase in tail abnormalities at both the light and electron microscopic levels. Ejaculate volume and sperm concentration were normal in the patient population. The presence of abnormal axonemes was also confirmed in remnant photoreceptors of a whole eye donation from a patient with Usher's syndrome. The data suggest that defective connecting cilia axonemes may be involved in the irreversible, progressive loss of photoreceptors in Usher's syndrome.

An interpretation of retinopathy of prematurity in terms of spindle cells: relationship to vitamin E prophylaxis and cryotherapy.

Spindle cells in the hyperoxygenated, avascular, vanguard retina are proposed to be the peripheral inducers of the neovascularization associated with retinopathy of prematurity (ROP). The induction of ROP is conceptualized in terms of three basic events. First, activation of spindle cells results initially in the increase in gap junctions between adjacent spindle cells, secondarily in the increase in cytoplasmic volume of rough endoplasmic reticulum, and ultimately in the synthesis and secretion of angiogenic factors Second, maturation of spindle cells is associated with a decrease in gap junctions, a diminished cytoplasmic volume of rough endoplasmic reticulum, and a cessation of synthesis and secretion of angiogenic factors. Third, myofibroblasts invade the vitreous concomitantly with spindle cell maturation and provide the tractional force that can produce retinal separation. The extent of interstitial retinol binding protein within the subretinal space explains the gestational-age-dependent efficacy of vitamin E in suppressing the development of severe ROP. The kinetics of both spindle cell activation/maturation and myofibroblast invasion predict the efficacy of appropriately timed and placed transretinal cryotherapy.

Abnormal axonemes in sperm of fertile men.

Sperm of 20 men aged 20-44 years was analyzed for motility and tail deformities in a Makler chamber and for axoneme abnormalities by transmission electron microscopy. In the quantitative analyses, 12.5 +/- 5.5% deformed tails at the light microscopic level and 24.4 +/- 7.7% abnormal axonemes in the principal piece. This high incidence of abnormalities in the sperm of fertile men indicated that micrographs of abnormal axonemes alone could not be used to imply the pathogenesis of infertility or sperm immotility without statistical comparison with a control group. Axoneme abnormalities were subdivided into three types. There was an asymmetry of abnormal axoneme types along the length of the sperm tail. Based on this asymmetry and on images of longitudinally sectioned sperm, the different types of abnormal axonemes most likely represented a single process of doublet microtubule detachment and foldback. Correlation of electron and light microscopy suggested that axoneme foldback progressed to focal tail defects and subsequent collapse. The presence of these abnormalities in fertile donors indicated that they were part of a normal process of axoneme instability in human sperm.

Syndromes with lissencephaly. II: Walker-Warburg and cerebro-oculo-muscular syndromes and a new syndrome with type II lissencephaly.

Lissencephaly (smooth brain) is an abnormality of brain development characterized by incomplete neuronal migration and a smooth cerebral surface. At least two distinct pathological types occur, each associated with several recognized syndromes. In this paper, we report on the clinical and pathologic manifestations of four additional patients and classify and delineate three separate disorders with type II lissencephaly. We also report on a previously undescribed abnormality in one of the four patients--dilated rough endoplasmic reticulum cisternae containing an unknown osmiophilic secretory product, probably a glycoprotein.

Phagocytosis and killing of Brucella by human polymorphonuclear leukocytes.

Although cellular immunity involving activated macrophages is important in resistance to Brucella, serum factors and polymorphonuclear leukocytes (PMNLs) play some role in the initial response to infection. The interaction between human PMNLs and virulent and attenuated strains of Brucella abortus and Brucella melitensis was studied by in vitro techniques. Virulent and attenuated strains of both species were rapidly phagocytosed after opsonization with normal human serum (NHS); nonopsonized bacteria were not phagocytosed. In contrast, NHS devoid of detectable antibodies was bactericidal for strains of B. abortus but not of B. melitensis. In addition, intracellular killing of ingested bacteria was shown for virulent B. abortus but not for B. melitensis. Ultrastructural studies revealed morphological alterations in about one-half of phagocytosed B. abortus and B. melitensis after incubation for 10 min; thereafter, nearly 100% of B. abortus showed some degree of degeneration, whereas B. melitensis remained intact during 120 min of observation.