Monitoring of optic nerve function in Neurofibromatosis 2 children with optic nerve sheath meningiomas using multifocal visual evoked potentials.

Monitoring optic nerve sheath meningiomas (ONSM) in Neurofibromatosis type 2 (NF2) patients remains difficult. Other ocular manifestations of NF2 may obscure ophthalmic assessment of optic nerve function in these patients. Serial magnetic resonance imaging (MRI) used to assess the optic nerve is not without limitations, being expensive and often requiring general anaesthetic in children, with associated risks. This study was undertaken to describe the use of multifocal visual evoked potentials (multifocal VEP, mfVEP) in the regular monitoring of NF2 patients with ONSM. This study involved three NF2 patients with ONSM who undertook mfVEP testing at an academic ophthalmic centre. Same day mfVEP and routine ophthalmic testing were undertaken. Topographical function of the optic nerve was assessed, utilising tools such as asymmetry deviation and accumap severity index. Results were assessed alongside MRI and visual acuity (VA). From the three patients, five eyes had ONSMs, of which two caused unilateral blindness. The remaining three affected eyes had initial VAs 6/6, 6/24, and 6/18. Over follow up, ranging from 5 to 12 years, all tumours progressed, and VA declined for all patients. Multifocal VEP detected optic nerve functional loss corresponding with visual decline. This case series suggests mfVEP is effective in the objective topographic monitoring of optic nerve function in NF2 patients with ONSM. Due also to its safety in a paediatric population, the test may be considered in the routine monitoring of these patients, to be used to assist regular ophthalmic review and MRI scans.

Refractive change in thyroid eye disease (a neglected clinical sign).

BACKGROUND/AIMS: The literature on refractive change in thyroid eye disease (TED) is limited. This study documents the refractive change in patients with TED undergoing orbital decompression. The authors propose possible mechanisms for their acquired refractive error. METHODS: This is a retrospective observational case study of five patients with progressive TED. Their detailed eye examinations including refractive state preoperatively and postoperatively are presented. RESULTS: An acquired hypermetropic shift with active TED before orbital decompression of up to 3.75 D spherical equivalent refraction (SER) is reported in one patient. Post-orbital decompression, an induced myopic shift of between 1.00-2.50 D SER for all patients is observed, noted to range from 1 day following surgery to up to 9 months, dependent on the availability of data. Axial length increased in two cases corresponding to postoperative myopic shift. Magnetic resonance imaging findings of one patient demonstrate flattening of the posterior pole as a cause of the acquired preoperative hypermetropia. CONCLUSIONS: TED has a significant effect on the refractive state of patients. The proposed mechanism of acquired hypermetropia relates to increased volume of orbital contents with flattening of the posterior globe. This is reversed with successful orbital decompression. Documentation of refractive error in all cases of progressive TED is recommended. Progressive acquired hypermetropia may be suggestive of TED activity.

Modulation of MHC class II expression in the absence of lymphocytic infiltrates in Alzheimer's retinae.

This study describes the expression of MHC class II antigens in retinal flat mounts from normal donors and patients with Alzheimer's disease (AD). We confirm previous observations of MHC class II immunoreactivity on microglia in normal retinae, while observing insignificant levels of reactivity on endothelial cells (EC). A significantly increased level of MHC class II expression was detected in AD retinae. This increased immunoreactivity was found to occur in the absence of lymphocytic infiltrates, suggesting that the pathogenesis of AD in the retina may be distinct from that reported to occur in some regions of the brain. MHC class II expression, measured using computerized optical densitometry, appeared to be increased principally as a result of induced MHC class II immunoreactivity on EC. Ramified microglia and perivascular macrophages, although hypertrophied, appeared to show unchanged levels of MHC class II expression. These findings are consistent with earlier suggestions that both aberrant MHC class II expression and suppressor activity of resident macrophages may restrict immune responses.

Early differentiation of ganglion, amacrine, bipolar, and Muller cells in the developing fovea of human retina.

We examined the differentiation and maturation of neurons and glia of the inner nuclear layer (INL) and ganglion cell layer (GCL) in the retina of a human fetus of 15 weeks gestation. Serial, ultrathin sections were cut from a resin-embedded specimen from the posterior pole of the retina. The region of the putative fovea was defined by the absence of rod photoreceptors from the outer nuclear layer; only sections through the putative fovea were studied. Cell somata were classified on the basis of morphological criteria and, through the analysis of serial sections, morphological characteristics of the cell processes were established. In the inner plexiform layer (IPL), the types of synapses were analysed. The majority of cells in the INL and GCL were differentiated and could be identified. Ganglion cell somata were observed in the GCL and INL. Of 186 somata analysed in the INL, 66 were Muller cells, 21 amacrine cells, and 2 ganglion cells; a further 7 cells were classified as either amacrine or ganglion. Bipolar cells were thought to comprise the majority of the remaining 90 somata, but these could not be positively identified, as it was not possible to trace bipolar cell axons to their cell bodies deep in the INL. A detailed description of the morphological characteristics of the identified cells and their processes, and of the axonal processes of bipolar cells, is provided. Puncta adherentia and other simple intercellular junctions were commonly seen in the IPL and involved all cell types. Amacrine cell synapses and immature, monad bipolar cell synapses were common within the IPL. Dyad bipolar synapses were uncommon at this stage of development. A possible sequence of synaptogenesis in the IPL is discussed.

Development of the human retina: patterns of cell distribution and redistribution in the ganglion cell layer.

Neurogenesis in the ventricular layer and the development of cell topography in the ganglion cell layer have been studied in whole-mounts of human fetal retinae. At the end of the embryonic period mitotic figures were seen over the entire outer surface of the retina. By about 14 weeks gestation mitosis had ceased in central retina and differentiation of photoreceptor nuclei was evident within a well-defined area which constituted about 2% of total retina area. This area was approximately centered on the site of the putative fovea, identified by the exclusive development of cone nuclei at that location. The area of retina in which mitosis had ceased increased as gestation progressed. By mid-gestation mitosis in the ventricular layer occupied about 77% of the outer surface of the retina and by about 30 weeks gestation mitosis in the ventricular layer had ceased. Cell density distributions in the ganglion cell layer were nonuniform at all stages studied (14-40 weeks). Densities were highest at about 17 weeks gestation, and by mid-gestation the adult pattern of cell topography was present with maps showing elevated cell densities in posterior retina and along the horizontal meridian. Cell densities generally declined throughout the remainder of the gestation period, except in the posterior retina, where densities in the perifoveal ganglion cell layer remained high during the second half of gestation. There is a rapid decline in cell density in the foveal ganglion cell layer toward the end of gestation, and it is suggested that the persistence of high densities in the perifoveal region may be related to migration of cells away from the developing fovea. The total population of cells in the ganglion cell layer was highest (2.2-2.5 million cells) between about weeks 18 and 30 of gestation. After this the cell population declined rapidly to 1.5-1.7 million cells. It is suggested that naturally occurring neuronal death is largely responsible for this decline.

Human fetal optic nerve: overproduction and elimination of retinal axons during development.

We have estimated the number of axons in the optic nerves of human fetuses ranging in gestational age from approximately 10 to 33 weeks. At 10-12 weeks of gestation there were an estimated 1.9 million axons in the optic nerve. A peak count of 3.7 million axons was obtained from a specimen of 16-17 weeks gestation. The estimated number of axons then declined, stabilizing at an estimated 1.1 million axons by about week 29 of gestation. This figure is in close agreement with an estimate of 1.1-1.3 million optic axons in the human adult optic nerve. The results indicate that at least 70% of optic axons generated during development of the primary visual pathway are lost during fetal life. Part of this loss probably occurs as a result of the refinement of the terminal distribution of ganglion cell projections within their target nuclei. The significance of the relatively prolonged period of axonal loss is discussed.

Development of microglial topography in human retina.

The development of microglial topography in wholemounts of human retina has been examined in the age range 10-25 weeks gestation (WG) using histochemistry and immunohistochemistry for CD45 and major histocompatibility complex class II antigens. Microglia were present in three planes corresponding to the developing nerve fibre layer/ganglion cell layer, the inner plexiform layer and the outer plexiform layer. Distribution patterns of cells through the retinal thickness and across the retinal surface area varied with gestational age. Microglia were elongated in superficial retina, large and ramified in the middle plane, and small, rounded and less ramified in deep retina. Intensely labeled, rounded profiles seen at the pars caeca of the ciliary processes, the retinal margin and at the optic disc may represent precursors of some retinal microglia. At 10 WG, the highest densities of microglia were present in middle and deep retina in the far periphery and at the retinal margin, with few superficial microglia evident centrally at the optic disc. At 14 WG, high densities of microglia were apparent superficially at the optic disc; microglia of middle and deep retina were distributed at more central locations although continuing to concentrate in the retinal periphery. Microglia appear to migrate into the developing human retina from two mains sources, the retinal margin and the optic disc, most likely originating from the blood vessels of the ciliary body and iris, and the retinal vasculature, respectively. The data suggest that the development of microglial topography occurs in two phases, an early phase occurring prior to vascularization, and a late phase associated with the development of the retinal vasculature.

Vincristine- and cisplatin-induced apoptosis in human retinoblastoma. Potentiation by sodium butyrate.

Chemotherapy alone has largely been unsuccessful in controlling retinoblastoma growth, and has traditionally been limited in use as an alternative to irradiation for the treatment of retinoblastoma. Recently, clinical studies combining chemotherapy with local therapies, including radiotherapy, laser therapy or cryotherapy and in some cases, cyclosporine A, have been effective in treating retinoblastoma. Differentiating agents may also be combined with chemotherapy to enhance the action of cytotoxic drugs on tumor cell growth, although this approach has not been fully investigated in retinoblastoma. In this study, we evaluated the cytotoxic response of human retinoblastoma cell lines (Y79 and WERI-Rb1) to two chemotherapy agents commonly used in treating retinoblastoma, vincristine (VCR) and cisplatin (CDDP). Retinoblastoma cells have been shown to be sensitive to the differentiating agent sodium butyrate, and cell lines were also treated with a combination of VCR or CDDP with sodium butyrate, and the effects on retinoblastoma viability assessed. Both VCR and CDDP induced dose-dependent death of Y79 and WERI-Rb1 cells, accompanied by nuclear and cytoplasmic condensation and DNA laddering, features characteristic of apoptosis. Inhibitors of macromolecular synthesis, cycloheximide and actinomycin-D, significantly reduced VCR- and CDDP-induced apoptosis, although putative endonuclease inhibitors zinc sulphate and aurintricarboxylic acid had no apparent effect. Treatment with 0.5 mM or 1 mM sodium butyrate combined with VCR or CDDP significantly increased induction of apoptosis by these agents. This augmentation of chemotherapy-induced apoptosis may have implications for retinoblastoma therapy.

A thin I-125 seed eye plaque to treat intraocular tumors using an acrylic insert to precisely position the sources.

A thin re-usable stainless steel ophthalmic applicator is described. The radioactive Iodine-125 sources are inserted in an acrylic button which fits neatly into a stainless steel shell 1 mm thick. The applicator can be assembled with the radioactive sources precisely positioned without the use of adhesives or mechanical devices such as clamps or screws in a matter of a few minutes, (under sterile conditions if necessary). The applicator can be dismantled in seconds after which it is ready for cleaning and re-sterilization. The overall thickness of the plaque is 2.6 mm, but this has the potential to be reduced to 2.1 mm. Suture holes are provided on a flange subtending 120 degrees around the circumference of the shell and are exactly matched on a stainless steel template.

Ganglion cell topography in human fetal retinae.

Whole-mounted human fetal retinae of gestational ages 14-40 weeks have been studied. These preparations clearly show the distribution of retinal ganglion cells or their precursors across the retina, and the pattern of the retinal vessels and vessel primordia. The ganglion cell layer is present at 14 weeks of gestation and distribution of cells in this layer (ganglion cell precursors) is at first uniform. Ganglion cell density gradients that foreshadow those seen in the adult retina become evident by about 20 weeks gestation. Both mature ganglion cells and precursor cells are present in retinae at about 24 weeks and precursor cells are still seen in the peripheral parts of the retina at about 30 weeks of gestation. The development of mature ganglion cells would appear to coincide with the establishment of retinal circulation, and proceeds in centrifugal sequence from central retinal.

Multifocal topographic visual evoked potential: improving objective detection of local visual field defects.

PURPOSE: To investigate the relationships between the pattern stimulation of different parts of the visual field (up to 25 degrees of eccentricity), the electrode position, and the cortical response to improve objective detection of local visual field defects. METHODS: The human visual evoked potential (VEP) was assessed using multifocal pseudorandomly alternated pattern stimuli that were cortically scaled in size. Monopolar and bipolar electrode positions were used. The visual field was investigated up to 26 degrees of eccentricity. Twelve normal subjects and seven subjects with visual field defects of different nature were studied. RESULTS: Although the monopolar response is heavily biased toward the lower hemifield, bipolar leads overlying the active occipital cortex (straddling the inion) demonstrate good signals from all areas of the visual field tested. The amplitude is almost equal for the averaged upper and lower hemifields, but the polarity is opposite, causing partial cancellation of the full-field VEP. The degree of cancellation depends mainly on latency differences between the vertical hemifields. The bipolar VEP corresponded well with Humphrey visual field defects, and it showed a loss of signal in the scotoma area. CONCLUSIONS: The multifocal VEP demonstrates good correspondence with the topography of the visual field. Recording with occipital bipolar electrode placement is superior to standard monopolar recording. To avoid a full-field cancellation effect, a separate evaluation of upper and lower hemifields should be used for the best assessment of retinocortical pathways. This technique represents a significant step toward the possible application of the multifocal VEP to objective detection of local defects in the visual field.

Objective perimetry in glaucoma: recent advances with multifocal stimuli.

The introduction of multifocal stimulus recording has enhanced our ability to examine the human visual field with electrophysiologic techniques. We have adapted the multifocal pattern visual evoked potential (PVEP) to detect visual field loss. In glaucoma patients we sought to determine the extent to which the PVEP amplitudes correlate with perimetric thresholds. Multifocal pseudorandomly alternated pattern stimuli, which were cortically scaled in size, were presented with use of the VERIS-Scientific system. Bipolar occipital straddle electrode positions were used. The visual field up to 25 degrees of eccentricity was investigated. Forty-three glaucoma patients with reproducible visual field defects were tested. The bipolar PVEP corresponded well with Humphrey visual field defects, showing loss of signal in the scotoma area. For Humphrey quadrant threshold totals and PVEP quadrant amplitudes, the correlation coefficient was strong (r = 0.49, P < 0.0001). The multifocal PVEP demonstrates good correspondence with the topography of the visual field. This technique represents the first practical application of the multifocal PVEP to objective detection of visual field defects in glaucoma.

Ophthalmological examination of the infant. Developmental aspects.

In recent years, the ophthalmic examination of infants has been of increasing interest to both clinicians and vision researchers. Clinicians have documented a greater risk of retinopathy, strabismus and amblyopia in premature infants, especially those of low birthweight. In addition to the external and retinal examination of the infant eye, a number of clinical tests can help the ophthalmologist to detect visual dysfunction through the evaluation of pupillary responses and ocular motility. Recently, the development of objective techniques (optokinetic nystagmus, forced choice preferential looking, and visually evoked potentials) have not only aided in the detection of ophthalmic disorders in infants; they have contributed to useful definitions of "normal" vision at various ages and to the understanding of factors that influence the pre- and post-gestational development of visual function.

Monocular axial myopia associated with neonatal eyelid closure in human infants.

We studied eight infants who developed unilateral axial myopia associated with neonatal eyelid closure. Clinical findings and ultrasonographic biometric measurements suggested that axial elongation of the eye may occur as a result of neonatal eyelid closure, a finding similar to that for experimental myopia produced in neonatal animals after eyelid fusion. Early treatment of eyelid occlusion in the neonate may prevent axial myopia and subsequent anisometropic amblyopia.

Trauma to the lacrimal system in children.

We repaired damage to the lacrimal drainage system in a series of 393 children who had lacrimal obstruction caused by congenital obstruction or facial injuries. Delayed surgery for traumatic obstruction of the nasolacrimal duct in children, including infants, was successful in all cases.

Induction of apoptosis by sodium butyrate in the human Y-79 retinoblastoma cell line.

The mode of cell death induced in the Y-79 human retinoblastoma cell line by sodium butyrate (SB), a short-chain fatty acid with potent inhibitory effects on the growth of many transformed cell lines, was investigated by fluorescence and transmission electron microscopy, agarose gel electrophoresis, and metabolic studies. While SB (< 1 mM) resulted in marked morphological differentiation, higher concentrations (1-4 mM) induced predominantly apoptotic involution in Y-79 in a concentration-dependent fashion after a latent period of 24 h. Dying cells displayed the characteristic morphology of apoptosis accompanied by DNA laddering with agarose gel electrophoresis. Extensive cell necrosis was apparent with 0.5 M SB. Induction of apoptosis and DNA laddering by SB was reduced by putative inhibitors of RNA and protein synthesis, but not putative endonuclease inhibitors. These results are important for understanding the mode of action of sodium butyrate as a potential cancer chemotherapeutic agent.

Visual failure in allergic aspergillus sinusitis: case report.

We present a case of rapid progressive unilateral visual loss in a 69-year-old woman who presented with facial pain, ipsilateral proptosis and restriction of eye movements, and nasal symptoms suggestive of sinusitis. A diagnosis of allergic aspergillus sinusitis was made on the basis of local histopathology and systemic features. Over a three-week period vision deteriorated to bare perception of light but showed a dramatic improvement to a level of 6/9 central vision on systemic steroid therapy. The mechanism of visual failure in the context of allergic aspergillus sinusitis and the therapeutic implications are discussed.

Maternal anticonvulsants and optic nerve hypoplasia.

Seven patients with optic nerve hypoplasia, born of epileptic mothers, are presented. All the mothers took anticonvulsants during pregnancy. The possibility that maternal anticonvulsant therapy may play a role in the genesis of optic nerve hypoplasia is discussed in the light of what is known about the teratogenicity of these agents.

Optic neuropathy in ketogenic diet.

A symmetrical, bilateral optic neuropathy is reported in 2 patients being treated with ketogenic diets for seizure control. Laboratory tests suggested a thiamine deficiency, and both patients recovered normal visual function after several weeks of treatment with thiamine. The risk of optic nerve dysfunction occurring during the treatment with a ketogenic diet can be minimised if routine vitamin B supplements are given and periodic evaluation of optic nerve function undertaken.

Surgical treatment of chronic papilloedema in children.

A surgical technique for optic nerve decompression in children is described and contrasted with other techniques described in the literature. The operation was effective in relieving long-standing disc oedema in two cases in which the swelling was due to raised intracranial pressure. Photographic evidence is presented. The indications for surgery and how its effect is exerted are discussed.