Unilateral peripapillary myelinated nerve fibers with myopia and/or amblyopia.

This report describes 12 patients with unilateral peripapillary myelinated nerve fibers associated with myopia and/or amblyopia. Seven patients had myopia with a mean of -13.00 diopters of anisometropia and abnormal maculae varying from a decreased reflex to pigment dispersion. These patients had final visual acuities of 20/200 or less following conventional amblyopia therapy. In contrast, five patients had myopia with a mean of -3.75 diopters of anisometropia and normal maculae. These patients had final visual acuities of 20/30 or greater with identical therapy. There was a statistically significant difference between the mean diopters of anisometropia of these two groups. However, the range of diopters of anisometropia overlapped, and the critical feature that determined which patients could achieve good vision was the macular appearance. This condition is distinct from simple unilateral myopia with amblyopia and from myelinated nerve fibers without myopia or amblyopia.

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.

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.

Development of the subretinal space in the preterm human eye: ultrastructural and immunocytochemical studies.

To investigate the development of the subretinal space in the human infant, eyes were obtained from 12 live-born, anomaly-free, preterm infants from 20 to 32 weeks gestation and from one 3-month postterm infant. The retinas were studied by light microscopy, electron microscopy, and immunocytochemistry. The immunocytochemical studies utilized rabbit antiserum against purified bovine interstitial retinol binding protein (IRBP). A subretinal space containing IRBP was present in the central retina at 20 weeks and extended further into the periphery (expressed as a percentage of the distance from the optic disc to the ora serrata in the temporal hemisphere) as the retina developed. At 28 weeks, IRBP was absent only from the most peripheral 25% of the retina and reached the temporal ora serrata at 32 weeks. At 3 months postterm, IRBP immunofluorescence outlined fully developed photoreceptors, which were present from the optic disc to the ora serrata. The appearance of IRBP in the subretinal space correlated with the development of the first photoreceptor outer segment discs.

Retinal and central nervous system abnormalities: syndromes which resemble retrolental fibroplasia.

Recently, the mechanism of the development of severe retrolental fibroplasia has been shown to occur by gap junction formation between adjacent mesenchymal spindle cells in the nerve fiber layer. Multiple syndromes with oculo-cerebral malformations give rise to retinal dysplasia (disturbances of neuroectodermal migration and/or differentiation) or retinal vascular abnormalities (disturbances of mesenchymal differentiation) which resemble clinically retrolental fibroplasia. Case 1 is an example of retinal dysplasia (disturbed neuroectodermal migration and/or differentiation) with normal retinal vascularization simulating superficially an active peripheral retinal detachment of retrolental fibroplasia in the preterm infant. Case 2 is an example of normal retinal differentiation with abnormal retinal vascularization (disturbed mesenchymal differentiation) simulating identically cicatricial dragging of the retinal vessels temporally of retrolental fibroplasia in the preterm infant. Thus, cases of central nervous system malformation should prompt an early ophthalmologic examination to document retinal abnormalities in term infants which occur without the administration of oxygen congenitally, from true retrolental fibroplasia in preterm infants which occurs following changes in oxygen tension approximately 8 weeks postnatally.

Suppression of severe retinopathy of prematurity with vitamin E supplementation. Ultrastructural mechanism of clinical efficacy.

Three clinical trials enrolling 418 infants (less than or equal to 1500 g birth weight) and an ultrastructural data base of 71 pairs of whole eye donations have elucidated the efficacy of vitamin E in suppressing the development of severe retrolental fibroplasia (ROP). Only continuous vitamin E supplementation to adult physiologic levels from the first hours of life suppresses the development of severe ROP. Supplementation does not increase the incidence of necrotizing enterocolitis, sepsis, intraventricular hemorrhage, or mortality. Only multivariate analysis, which considers all risk factors simultaneously, is appropriate when appraising the efficacy of supplementation since all the clinical risk factors uniquely impinge on the oxygen dynamics of the developing retina. Mesenchymal spindle cells are the cellular mediators of the induction of ROP by oxygen in which increased oxygen tension triggers extensive gap junction formation between adjacent spindle cells. This cellular event, which occurs as early as four days of life, halts the normal vasoformative process and triggers neovascularization, which becomes clinically evident some 8 to 12 weeks later.

Intraventricular hemorrhage and vitamin E in the very low-birth-weight infant: evidence for efficacy of early intramuscular vitamin E administration.

To determine whether early intramuscular vitamin E supplementation influences the incidence of intraventricular hemorrhage (IVH) in infants with birth weight less than or equal to 1,500 g, data were analyzed from 134 infants enrolled on a protocol to evaluate the efficacy of intramuscular plus oral vitamin E v oral supplementation alone in the treatment of retrolental fibroplasia. All 134 infants received, via nasogastric tube, 100 mg/kg/d of vitamin E daily (dl-alpha-tocopheryl acetate in MCT [medium-chain triglyceride] oil; 150 mosM) for at least 8 weeks with the first dose administered within the first eight hours of life. Sixty-four patients received, in addition, intramuscular vitamin E on days 1, 2, 4, and 6 of life and 70 patients received placebo injections in a randomized double-blind fashion. In the first week, vitamin E plasma levels were significantly higher in the 64 patients given intramuscular vitamin E. In spite of this difference no change in the incidence of sepsis or necrotizing enterocolitis was observed. Both the incidence and severity of intraventricular hemorrhage were reduced significantly in the patients given intramuscular vitamin E as compared to the patients given placebo (P = .013 and P = .04, respectively). The data suggest that vitamin E, a natural antioxidant, may play an important role in protecting the CNS microcirculation from the effects of hypoxic/ischemic injury.

Amiodarone treatment of critical arrhythmias in children and young adults.

The majority of sudden cardiac deaths in children occur in patients with prior arrhythmias and an abnormal heart. Amiodarone was given to 39 young patients (35 with an abnormal heart) with arrhythmias unresponsive to conventional treatment. Their age ranged from 6 weeks to 30 years with nine patients younger than 2 years of age. Atrial flutter was present in 16 patients, ventricular tachycardia in 14 patients and supraventricular tachycardia in 9 patients. The most common diagnosis (14 patients) was postoperative repair of congenital heart disease. The dose ranged from 2.5 to 21.6 mg/kg per day (mean 8.2). Elimination of arrhythmia (on 24 hour electrocardiography) occurred in 15 of 16 patients with atrial flutter, 11 of 14 with ventricular tachycardia and 5 of 9 with supraventricular tachycardia. Symptomatic side effects were: rash (three patients), headache (two patients), nausea (one patient) and peripheral neuropathy (one patient); seven patients had asymptomatic corneal microdeposits which normalized in all after the drug was discontinued. No side effects occurred in patients younger than 10 years of age. The following changed with treatment (p less than 0.05): heart rate decreased (three patients with atrial flutter and sick sinus syndrome required pacemaker implantation for bradycardia) and QTc increased; thyroxine (T4) and serum reverse triiodothyronine (T3) increased. During follow-up study (range 6 months to 3 years), 21 of the 39 patients continued to take amiodarone with complete control of arrhythmias, 9 were no longer taking the drug and 9 died (7 nonsudden and 2 sudden deaths). Amiodarone is an extremely effective treatment for infants and children with tachyarrhythmias resistant to conventional treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin E protects against retinopathy of prematurity through action on spindle cells.

In the premature infant, exposure of the incompletely vascularized retina to increased oxygen tension can result in the development of a blinding disease, retinopathy of prematurity (ROP). Despite the judicious curtailment of oxygen, the incidence of ROP is on the increase due to the technological advances that have improved the survival of the very young preterm infant. Six clinical trials have documented the efficacy of vitamin E supplementation in suppressing the development of severe ROP, but the mechanism of this protection has remained unknown. This report proposes that spindle cells, mesenchymal precursors of the inner retinal capillaries, are the primary inducers of the neovascularization associated with ROP. Exposure of spindle cells to elevated oxygen tension increases their gap junction area. This early morphologic event immediately halts the normal vasoformative process and eventually triggers the neovascularization that is observed clinically 8-12 weeks later. Vitamin E supplementation above the deficient plasma levels of these infants suppresses gap junction formation and clinically reduces the severity without altering the total incidence of ROP.

Atypical vitelliform macular dystrophy in a 5-generation family.

Five generations of a family with autosomal dominant atypical vitelliform macular dystrophy (A-VMD) were studied. This dystrophy is similar to autosomal dominant Best's vitelliform dystrophy (B-VMD) but clinically more closely resembles sporadic pseudovitelliform macular degeneration (P-VMD). Of the family members who were 14 years or older 43 (24 females and 19 males) of the 101 at risk (43%) were affected. Vision varied from 20/20 to 20/200. Field defects and tritan colour defects were invariably present only when vision was less than or equal to 20/200, but these defects were sometimes present when vision was good. The electrooculographic studies (LP/DT ratios) in this family were found to be normal or reduced and did not correlate with visual acuity. Minimal retinal findings consisted of macular or extramacular punctate yellow lesions or both in the retinal pigment epithelium, which were hypofluorescent by angiography, and retinal pigment epithelial defects in the temporal nerve fibre bundle, which were hyperfluorescent by angiography. Fluorescein angiographic changes were invariably present when retinal lesions were noted, and this was the most reliable test in identifying genotypically affected family members with minimal phenotypic expression.

Retrolental fibroplasia and vitamin E in the preterm infant--comparison of oral versus intramuscular:oral administration.

To evaluate the efficacy of four early intramuscular injections of vitamin E given in addition to continuous minimal oral vitamin E supplementation, 168 very low-birth-weight infants (less than or equal to 1,500 g) have enrolled in a randomized, double-masked, clinical study. All infants received vitamin E orally, 100 mg/kg/d. In addition, on days 1, 2, 4, and 6, seventy-nine infants received vitamin E intramuscularly, 15, 10, 10, and 10 mg/kg, respectively. On the same days, 89 control infants received placebo intramuscular injections. Multivariate analysis of the 135 infants who survived greater than or equal to 10 weeks showed no significant difference in the development of severe retrolental fibroplasia between these two supplementation schedules (P = .86). Plasma vitamin E levels never exceeded a mean of 3.3 mg/100 mL, and no toxicity was observed. Ultrastructural analyses of seven pairs of whole eye donations from infants receiving IM vitamin E demonstrated identical kinetics of gap junction formation between adjacent spindle cells as compared with 13 pairs of whole eye donations from control infants (P greater than .3). Therefore, oral vitamin E supplementation affords retinal protection against the development of severe retrolental fibroplasia when initiated on the first day of life and maintained continuously until retinal vascularization is complete.

Retrolental fibroplasia: further clinical evidence and ultrastructural support for efficacy of vitamin E in the preterm infant.

To further evaluate the efficacy of oral vitamin E in preventing the development of severe retrolental fibroplasia (RLF) in very low-birth-weight infants, 100 infants treated with 100 mg/kg/d of vitamin E (dl-alpha-tocopheryl acetate) were compared with 75 infants treated with 5 mg/kg/d of vitamin E (dl-alpha-tocopherol) in the same nursery during the previous year. All 175 infants weighed less than or equal to 1,500 g at birth and required supplemental oxygen. A total of 120 infants (69 treatment; 51 control) survived greater than or equal to 10 weeks. Multivariate analysis of the control population identified five risk factors (P less than or equal to .10): gestational age, level and duration of oxygen administration, intraventricular hemorrhage, sepsis, and birth weight. When multivariate analysis was applied to both control and treatment groups, the severity of RLF was found to be significantly reduced in infants given the treatment dose of vitamin E (P = .003). Ultrastructural analyses of 58 pairs of whole-eye donations from high-risk infants surviving less than 10 weeks suggest that the initial morphologic event is gap junction increases between the plasma membranes of adjacent spindle cells of the van-guard retina. Such extensively gap junction-linked spindle cells are apparently removed from the vasoformative process as early as 4 days of life, forming a barrier to further normal vascular development and triggering retinal and vitreal neovascularizations approximately 8 weeks later. These events are maximally suppressed by elevated plasma vitamin E levels in infants greater than or equal to 27 weeks gestational age.

Vitamin E and retrolental fibroplasia: ultrastructural mechanism of clinical efficacy.

Administration of control, oral or combined intramuscular and oral vitamin E to 418 high risk, preterm infants (1500 g or less birth weight; 32 weeks or less gestational age; 305 surviving more than 10 weeks) led to raised peak plasma levels of the vitamin of between 0.6 and 3.3 mg% in three consecutive clinical trials. This early, non-toxic, prophylactic supplementation suppressed the development of severe retrolental fibroplasia when the antioxidant was given continuously from the first day of life until retinal quiescence. Studies of 63 pairs of eyes by transmission electron microscopy revealed that spindle cells (the embryonic precursors of inner retinal capillaries) were the primary target of the vitamin E-induced suppression of severe retrolental fibroplasia. Extensive increases in the gap junctions between adjacent spindle cells in unsupplemented infants, or in supplemented infants of 27 weeks gestational age or less, triggered both neovascularization from the most nascent capillaries at the rearguard-vanguard retinal interface, and dilatation and tortuosity in the rearguard (posterior) retinal vessels. Continuous vitamin E supplementation permanently preserved the embryonic state of the spindle cells in infants of 28 weeks gestational age or more, and transiently retarded gap junction increases in infants of 27 weeks gestational age or less.

Linkage of atypical vitelliform macular dystrophy (VMD-1) to the soluble glutamate pyruvate transaminase (GPT1) locus.

One hundred twenty-eight blood samples were drawn from members of a single family with atypical vitelliform macular dystrophy (VMD-1) characterized by variable expressivity in affected members of at least 5 generations. Because of the late onset of detectable retinal lesions in most family members, phenotype data from only 93 individuals who were at least 14 years of age were analyzed for linkage. Phenotype data from the remaining 35 members of the family who were under age 14 were excluded from the analysis. Maximum-likelihood analysis for linkage between VMD-1 and 13 biochemical and serological markers in the family demonstrated linkage between VMD-1 and the soluble glutamate pyruvate transaminase (GPT1) locus, which has been tentatively assigned to the short arm of chromosome 16. A maximum lod score of Z = 4.34 (odds favoring linkage of approximately 22,000 to 1) was obtained at a recombination fraction of theta = .05.

Linkage studies in carriers of Lowe oculo-cerebro-renal syndrome.

A black family with two male infants affected with the X-linked Lowe syndrome was studied. All three females in the pedigree were found to be carriers on the basis of lenticular opacities. Each female had one son. Of these, two were affected and one was unaffected. The Xg blood-group locus and the G6PD locus were determined in these six individuals. Two of the carrier females were heterozygous for G6PD isoenzymes A- and B. Skewing of the A-:B ratio in isolated erythrocytes, lymphocytes, granulocytes, platelets, and cultured skin fibroblasts from these females may be the result of either selection against cells expressing the Lowe gene product or random X-chromosome inactivation. At least one instance of recombination was found between the G6PD and the Lowe syndrome loci. At least two instances of recombination between Xg blood-group and Lowe syndrome loci.