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Biomedical subjects

A A Sadun

Publications and source records attributed to A A Sadun.

At least 19 recordsLinked to original sources
PubMed2007

Linezolid-induced optic neuropathy: a mitochondrial disorder?

We report a case of bilateral mitochondrial optic neuropathies secondary to long-term linezolid treatment, show the nature of recovery, review the findings in the literature and propose a potential mitochondrial mechanism for linezolid-induced mitochondrial optic neuropathy. This is an observational case report and literature review with presentation of the clinical course of linezolid mitochondrial optic neuropathies through clinical and psychophysical documentation. Main outcome measures included: visual acuity, funduscopical examinations and peripapillary retinal nerve fibre layer (PRNFL) optical coherence tomography (OCT). A 6-year-old boy presented with bilateral optic neuropathies secondary to 1 year of linezolid treatment for osteomyelitis of the mandible. On presentation, visual acuities were 20/400 in both eyes, with considerable optic disc oedema, hyperaemia and PRNFL swelling confirmed by OCT. 2 weeks after the discontinuation of linezolid, visual acuities returned to 20/25 in both eyes, with reduction in the optic disc oedema, hyperaemia and PRNFL swelling. 3 months after the discontinuation of linezolid treatment, visual acuities were stable at 20/20 in both eyes, with a marked decrease in PRNFL swelling confirmed by OCT, and the development of mild temporal optic disc pallor in both eyes. Doctors should be aware of impairments of vision among patients on long-term linezolid treatment and promptly discontinue treatment to prevent irreversible vision loss. The development and resolution of bilateral optic neuropathies with considerable PRNFL swelling in this patient provide insight into the more general rubric of mitochondrial optic neuropathies.

Acetamides↗
PubMed2006

Colour vision defects in asymptomatic carriers of the Leber's hereditary optic neuropathy (LHON) mtDNA 11778 mutation from a large Brazilian LHON pedigree: a case-control study.

AIMS: To determine if asymptomatic carriers from a previously identified large pedigree of the Leber's hereditary optic neuropathy (LHON) 11778 mtDNA mutation have colour vision deficits. METHODS: As part of a comprehensive analysis of over 200 members of a large Brazilian LHON pedigree spanning seven generations, colour vision tests were obtained from 91 members. Colour vision was tested one eye at a time using the Farnsworth-Munsell 100 (FM-100) hue colour vision test. The test was administered under uniform conditions, taking into account: ambient light levels, daylight colour temperature of 6700 kelvin, and neutral uniform background. Tests were scored using the FM-100 MS-Excel computer scoring program. Defects were determined and categorised as tritan, deutan, or protan. Categorisation of each dyschromatopsia was based on review of demonstrated axis computer generated plots and age adjusted error scores which coincided with Verriest 95% confidence intervals. Only the axis with the greatest magnitude error score was used to classify the defect. 55 of the 91 test subjects were LHON mtDNA 11778 J haplotype mutation carriers, proved by mtDNA analysis. The remaining 36 subjects were age matched non-blood relatives (off pedigree), who served as controls. RESULTS: 27 of 55 carriers (49.10%) were shown to have colour vision defects in one or both eyes. 13 of the 27 (48%) abnormal tests in the carrier group were tritan defects and the remaining 14 (52%) were deutan defects. Nine of the 27 (33%) abnormals in the carrier group were identified as having bilateral defects. Six of these were deutan, and the remaining three were tritan dyschromatopsias. Only six of the 36 (16.66%) age matched controls were found to have any type of dyschromatopsia. Five (83.3%) of these were deutan defects. The remaining one was a tritan defect. The difference between the two groups using a chi(2) test with one degree of freedom was statistically significant with a p value less that 0.001. CONCLUSIONS: Until now, LHON has always been characterised by a sudden, devastating vision loss. Asymptomatic carriers, those without vision loss, were considered unaffected by the disease. It now appears that asymptomatic carriers of the LHON mutation are affected by colour vision defects and may manifest other subtle, yet chronic, changes.

Brazil↗
PubMed2005

Threshold Amsler grid as a screening tool for asymptomatic patients on hydroxychloroquine therapy.

BACKGROUND/AIMS: Patients taking hydroxychloroquine (HCQ) are at risk of developing classic bull's eye maculopathy. Currently, the standard Amsler grid (AG) is one of the most useful methods to identify such lesions. However, AG is a suprathreshold target and may not detect relative central scotomas. The aim of this study was to determine if the threshold Amsler grid (TAG) test, which varies light transmission through two cross polarising filters, allows increased detection of scotomas caused by HCQ toxicity. METHODS: 56 rheumatological patients taking HCQ and 12 similar patients not taking HCQ were tested by AG, red Amsler grid (RAG), and TAG. RESULTS: No scotomas were observed in patients never treated with HCQ. Among patients who had been treated with HCQ, AG revealed scotomas in two of 56 (3.64%) patients; in contrast, six (10.7%) and 37 (66.1%) scotomas were identified by RAG and TAG testing respectively. Additionally, the average area of each scotoma detected by all three methods expanded from 34.5 square degrees of central field loss on AG testing to 71 square degrees on RAG and 117 on TAG. CONCLUSION: By decreasing the perceived luminance of the suprathreshold AG, TAG testing provides a novel alternative to detect shallow scotomas and areas of depressed retinal activity secondary to HCQ toxicity.

Adult↗
PubMed2005

Correlation between retinal nerve fibre layer thickness and optic nerve head size: an optical coherence tomography study.

AIM: To investigate the correlation between retinal nerve fibre layer (RNFL) thickness and optic nerve head (ONH) size in normal white subjects by means of optical coherence tomography (OCT). METHODS: 54 eyes of 54 healthy subjects aged between 15 and 54 underwent peripapillary RNFL thickness measurement by a series of three circular scans with a 3.4 mm diameter (Stratus OCT, RNFL Thickness 3.4 acquisition protocol). ONH analysis was performed by means of six radial scans centred on the optic disc (Stratus OCT, Fast Optic Disc acquisition protocol). The mean RNFL values were correlated with the data obtained by ONH analysis. RESULTS: The superior, nasal, and inferior quadrant RNFL thickness showed a significant correlation with the optic disc area (R = 0.3822, p = 0.0043), (R = 0.3024, p = 0.026), (R = 0.4048, p = 0.0024) and the horizontal disc diameter (R = 0.2971, p = 0.0291), (R = 0.2752, p = 0.044), (R = 0.3970, p = 0.003). The superior and inferior quadrant RNFL thickness was also positively correlated with the vertical disc diameter (R = 0.3774, p = 0.0049), (R = 0.2793, p = 0.0408). A significant correlation was observed between the 360 degrees average RNFL thickness and the optic disc area and the vertical and horizontal disc diameters of the ONH (R = 0.4985, p = 0.0001), (R = 0.4454, p = 0.0007), (R = 0.4301, p = 0.0012). CONCLUSIONS: RNFL thickness measurements obtained by Stratus OCT increased significantly with an increase in optic disc size. It is not clear if eyes with large ONHs show a thicker RNFL as a result of an increased amount of nerve fibres or to the shorter distance between the circular scan and the optic disc edge.

Adolescent↗
PubMed2005

Human extraocular muscles in mitochondrial diseases: comparing chronic progressive external ophthalmoplegia with Leber's hereditary optic neuropathy.

AIMS: To compare the ultrastructural aspects of human extraocular muscles in two types of mitochondrial disease: chronic progressive external ophthalmoplegia (CPEO) and Leber's hereditary optic neuropathy (LHON). METHODS: Muscle samples of the medial rectus obtained from surgery in a sporadic case of CPEO associated with deleted mitochondrial DNA, and post mortem in a case of 3460/ND1 LHON were processed for electron microscopy (EM). The medial rectus from an autoptic time to fixation matched control was used to exclude postmortem artefacts. RESULTS: The CPEO specimen revealed focal areas of disruption and abnormalities of mitochondria in some muscle fibres, creating a "mosaic-like" pattern. In the LHON specimen a diffuse increase in both number and size of mitochondria (mean diameter 0.85 mum v 0.65 mum of control, p<0.0001) with swollen appearance and disorganised cristae filled all spaces of sarcoplasmic reticulum. In some areas the excessive number of mitochondria slightly distorted myofibrils. CONCLUSION: EM investigation of extraocular muscles in CPEO and LHON reveals marked differences. A "mosaic-like" pattern caused by a selective damage of muscle fibres was evident in CPEO, whereas a diffuse increase in mitochondria with preservation of myofibrils characterised the LHON case. These ultrastructural changes may relate to the different expression of the two diseases, resulting in ophthalmoplegia in CPEO and normal eye movements in LHON.

Aged↗
PubMed2004

Characteristics of optic nerve damage induced by chronic intraocular hypertension in rat.

PURPOSE: To set up the Sharma's chronic intraocular hypertension model and investigate the intraocular pressure (IOP) as well as the optic nerve damage of this model in rat. METHODS: The operations of the chronic intraocular hypertension model were performed as described by Sharma in 60 Male Lewis albino rats. IOP was measured using the Tono-Pen XL immediately after surgery and then at 5 day, 2 week or 4 week intervals. Cresyl violet staining of whole-mounted retinas was used to label retinal ganglion cells (RGCs), then RGCs were counted. Paraphenylenediamine (PPD) staining was performed in the semi-thin cross sections of optic nerve of rat, in order to know whether the axons of optic nerve were degenerated or not. RESULTS: There were 47 rats with higher IOP after the episcleral veins cauterized in 60 rats. The ratio of elevated IOP was 78.3%. The IOPs were stable in 4 weeks. After cresyl violet staining, the RGCs loss was 11.0% and 11.3% was found in the central and peripheral retina respectively after 2 weeks of increased IOP. After 4 weeks of increased IOP, the loss of RGCs was 17% for the central retina and 24.6% for the peripheral retina. In the retinas without higher IOP, there was no loss of RGCs. PPD staining showed that optic nerve of rat with about 5.3% damage of axons located at the superior temporal region. Region of affected optic nerve 1 mm posterior to the globe by light microscope showed evidence of damaged axons with axonal swelling and myelin debris. CONCLUSION: Sharma's chronic intraocular hypertension model is a reproducible and effective glaucoma model, which mimics human glaucoma with chronically elevation IOP and induced RGCs loss and damage of optic nerve.

Animals↗
PubMed2002

Morphometry of axons in optic nerves of Siamese's twins.

PURPOSE: To observe the development of optic nerve, we examined four optic nerves from Siameses Twins by absolute counts of axons. METHODS: Mean axon diameter, mean axon density, totally axonal population and optic nerve area were noted for each optic nerve. The mean axon diameter and the mean axon density were compared between paraxial (inner sectors) and cortical(outer sectors) areas of the nerves. RESULTS: More myelinated axons were seen in the inner sectors as compared to the outer sectors (average 11 axons/1000 microm2 in inner sectors and 34 axons/1000 microm2 in outer sectors (P = 0.036). The myelinated fibers were also smaller (63 microns) in the outer sectors as compared to the inner sectors (72 microns) (P = 0.001). The average cross sectors area for the four 40 week stage optical nerves of Siamese Twins was 3.32 x 103 as compared to 1 million axons for 32-week-old normals. CONCLUSION: Our finding of fewer axonal number and small myelinated fibers in the Siamese Twins suggests hypoplasia. Myelination was more abnormal in the paraxial optic nerve than that in the peripheral sectors, suggesting anomalous development of optic nerve peripherally and delayed developnent centrally. Axonal density is higher in inner sectors than that in outer sectors, suggesting delayed development of the outer nerve sector.

Anthropometry↗
PubMed2001

Retinal nerve fiber layer evaluation in human immunodeficiency virus-positive patients.

PURPOSE: To determine the effect of human immunodeficiency virus (HIV) infection on topographic measures of the optic disk and the retinal nerve fiber layer. METHODS: A cross-sectional study at the Acquired Immunodeficiency Syndrome (AIDS) Ocular Research Unit at the University of California, San Diego. Retinal nerve fiber layer thickness at the optic nerve head was evaluated using the Heidelberg Retinal Tomograph, a confocal scanning laser tomograph in 38 HIV-positive and 24 age-matched HIV-negative subjects. RESULTS: HIV-positive patients without CMV retinitis showed significant differences from HIV-negative normal controls in a number of measures of the retinal nerve fiber layer. This indicated a loss of retinal ganglion cells in HIV-positive patients without retinitis. HIV-positive patients with CMV retinitis were worse in most measurements than both HIV-negative controls and HIV-positive patients without CMV. CONCLUSIONS: Significant thinning of the retinal nerve fiber layer occurs in HIV-positive patients without infectious retinopathy, and there are further changes in the optic disk associated with CMV retinitis. Confocal scanning laser tomography may be of use in the diagnosis of early HIV-associated visual function loss.

AIDS-Related Opportunistic Infections↗
PubMed2001

Neuron specific enolase in retinal detachment.

PURPOSE: Neuron Specific Enolase (NSE) is released following central nervous system (CNS) distress. As retina is part of the CNS, NSE levels were measured in the subretinal fluid (SRF), aqueous, and serum of patients with primary rhegmatogenous retinal detachment (RD). METHODS: Radioimmunoassay was used to determine NSE levels in the SRF, aqueous, and serum of 13 patients (28-92 years old, mean = 71 years) with RD. As controls, NSE was measured in the aqueous of 6 patients undergoing cataract surgery and in serum of 18 patients without ophthalmological or neurological diseases. RESULTS: SRF levels of NSE ranged from 50-200 microg/l (mean +/- s.d. = 150 +/- 57). NSE levels in aqueous from patients with RD were 2-140 microg/l (mean +/- s.d. = 39 +/- 42), significantly higher than in controls (0-6 microg/l; mean +/- s.d. = 1.58 +/- 2.24; p = 0.04). Serum NSE levels in RD patients ranged from 6.5-80 microg/l (mean +/- s.d. = 26 +/- 21) and was significantly higher than in controls (5.3 +/- 1.66 microg/l; p = 0.005). CONCLUSIONS: Retinal neuron injury in retinal detachment (RD) releases sufficient Neuron Specific Enolase (NSE) to be detected in subretinal fluid, aqueous, and even in serum. Thus, NSE could index disease severity in RD and provide a means by which to assess the response to neuroprotection in RD.

Adult↗
PubMed2001

Histopathology and ultrastructural examination of optic nerve sheath biopsies after optic nerve sheath decompression with and without mitomycin.

PURPOSE: We chose to compare histologically and ultrastructurally changes in the optic nerve sheath after optic nerve sheath decompression, initially after a second surgery and after treatment with mitomycin-C. The mechanism by which optic nerve sheath decompression alleviates papilledema can be further understood in consideration of the results. METHODS: Tissue was obtained by biopsy from 3 first-time surgical and 4 reoperative cases with and without mitomycin-C in patients with idiopathic intracranial hypertension. The sheaths were fixed in a mixture of 2% paraformaldehyde and 2% glutaraldehyde, osmicated and dehydrated in a series of ethanol, and finally embedded in epon. Tissue blocks were sectioned at 1 microm and stained with both PPD and toluidine blue. Thin sections were examined by transmission electron microscopy. RESULTS: Normal meningeal tissue obtained at the time at optic nerve sheath decompression consisted mainly of collagen, closely packed and roughly parallel to the axis of the optic nerve. Collagen deposition seen in scar tissue after secondary optic nerve sheath decompression was extremely disorganized and irregular, with the individual fibers laid down seemingly at random. There was little sense of layering or of parallel arrays. Mitomycin-C appeared to influence collagen deposition in such a way that the collagen was more regularly packed and more closely resembled unoperated tissue. CONCLUSIONS: The regular well-organized collagen packing seen in normal sheath tissue is disrupted and replaced by less organized but compact scar tissue after optic nerve sheath decompression. With mitomycin use, more regular collagen packing closely approximating that found in unoperated sheath occurs. This configuration of fibers lends support for the filtration mechanism of optic nerve sheath decompression in treating papilledema.

Antibiotics, Antineoplastic↗
PubMed2000

Ethambutol-induced vacuolar changes and neuronal loss in rat retinal cell culture: mediation by endogenous zinc.

Ethambutol is an efficacious antituberculosis agent. However, its use has been limited by the occurrence of ocular toxicity. To investigate characteristics and possible mechanisms of ethambutol ocular toxicity, we used primary rat retinal cultures as a model. Primary rat retinal cultures were obtained from newborn Sprague-Dawley rats and used for experiments after maturation (DIV > or = 10). Cytopathologic changes were examined under light and electron microscopes. Thy-1 (a membrane glycoprotein expressed by retinal ganglion neurons)-containing neurons and gamma-aminobutyric acid (GABA)-ergic neurons were identified immunocytochemically. Exposure of retinal cultures for 24-48 h to ethambutol induced cytoplasmic vacuolar changes and neuronal loss. Vacuolar changes were partially reversible with the termination of ethambutol exposure. Of neurons, Thy-1(+) ganglion neurons were more vulnerable than GABA(+) neurons. Glutamate antagonists, an antioxidant (trolox), or cycloheximide, did not attenuate either vacuolar changes or neuronal loss. A cell-permeant zinc chelator N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) markedly attenuated vacuolar degeneration and neuronal loss, while the addition of zinc augmented both. In rat retinal cultures, ethambutol induces reversible vacuolar degeneration as well as irreversible neuronal loss, more preferentially of Thy-1(+) ganglion neurons. Contrary to the current theories, ethambutol-induced retinal cytotoxicity in the present study is mediated not by excitotoxicity or zinc deficiency but by a mechanism requiring intracellular zinc. In addition, features of the ethambutol-induced cell death were not consistent with those of apoptosis.

Animals↗
PubMed2000

Correlation between static automated and scanning laser entoptic perimetry in normal subjects and glaucoma patients.

OBJECTIVE: To compare the effectiveness of scanning laser entoptic perimetry with static automated perimetry as a noninvasive instrument for screening for glaucomatous damage in visually asymptomatic subjects within the central 60 degrees (diameter) of vision. DESIGN: A masked cross-sectional study comparing entoptic perimetry to achromatic threshold perimetry. PARTICIPANTS: Twenty-three subjects and controls from the Sharp Rees-Stealy Hospital and the Shiley Eye Center at the University of California, San Diego. TESTING: Virtual reality-based entoptic perimetry was compared with achromatic threshold perimetry. MAIN OUTCOME MEASURES: For each testing session, we compared the presence of a disturbance in the entoptic perimetry stimulus with the presence of defects in visual function as measured by Humphrey automated visual field perimetry. RESULTS: Scanning laser entoptic perimetry reasonably estimates the overall visual field loss for moderate-to-severe scotomas as measured by the pattern deviation in standard visual field perimetry. Scanning laser entoptic perimetry has a sensitivity from 27% to 90% and a specificity from 50% to 100% for screening moderate-to-severe visual field defects caused by glaucoma within the central 60 degrees diameter of vision. CONCLUSIONS: Scanning laser entoptic perimetry may be an effective and inexpensive screening test in hospitals and community clinics for diagnosing visual field loss caused by glaucoma.

Cross-Sectional Studies↗
PubMed2000

Leber's hereditary optic neuropathy differentially affects smaller axons in the optic nerve.

PURPOSE: Leber's hereditary optic neuropathy (LHON), though known to be due to 1 of 3 pathogenic mtDNA point mutations (nucleotide positions 11,778, 3460, and 14,484), usually manifests itself acutely in young adulthood with a stereotypical presentation of dyschromatopsia, loss of central vision, and loss of the papillomacular bundle nerve fiber layer. Histopathologic investigations have demonstrated devastating losses of axons with relative sparing of the most peripherally placed fibers in the optic nerves. This study was designed to morphometrically investigate the nerve fiber spectrum from ultrastructural studies of optic nerves obtained from 2 patients with LHON. METHODS: Two cases of LHON were molecularly characterized and the optic nerves from these cases studied by light microscopy and electron microscopy. Montages were made of electron micrographs cut orthogonal to fibers obtained from the periphery of each optic nerve, and these were then used for the measurement of each axon (short and long axis) and its myelin sheath. From this, a spectrum of nerve fiber layer was generated, yielding axon caliber profiles that could be compared between optic nerves. RESULTS: The total depletion of optic nerve fiber population in the 2 cases of LHON varied from 95% to 99%. Those fibers that were spared were limited to the peripheral optic nerve. The nerve fiber layer spectra of these remaining fibers showed a marked diminution of the first peak of axons of less than 1 micron in diameter, with relative emphasis of a second peak of axons of about 2 microns in diameter. In comparison to normal controls, this reflected a preferential loss of the smallest axons corresponding to the P-cell population. CONCLUSIONS: The clinical features of dyschromatopsia and central scotoma (with preservation of pupils) in LHON suggests the selective loss of the P-cell population known to subserve these (and not pupil) functions. This also correlates well with the fundus findings of early losses of the papillomacular bundle. The present study extends these findings to demonstrate a relative preservation of the M-cells in the optic nerve as reflected by the nerve fiber spectral profile. This selective loss of smaller fibers and their corresponding smaller retinal ganglion cells may, in addition to explaining the clinical features in LHON, provide valuable insights as to the exact pathophysiologic mechanisms by which mitochondrial impairment may induce apoptosis in vulnerable neurons.

Adult↗
PubMed2000

Plasma levels of orally and subcutaneously administered pentoxifylline in rabbits.

In addition to its ability to improve microcirculation, pentoxifylline also has anti-tumor necrosis factor-alpha (TNF) actions which have prompted investigations into its potential efficacy in disease states involving elevated TNF levels. One such disease entity is AIDS where aberrant TNF seems to mediate axonal degeneration within thecentral nervous system. To this end, we have previously established a rabbit model of TNF-mediated axonal degeneration, and demonstrated that pentoxifylline attenuates this effect. Unfortunately, there has been to date only one limited report on the pharmacokinetics of pentoxifylline in rabbits. Therefore, the present report evaluates plasma levels of pentoxifylline and two of its primary metabolites through high-performance liquid chromatography after both the oral and subcutaneous administration of pentoxifylline. Our results indicate that in rabbits there is a very rapid absorption and metabolism of pentoxifylline after either oral or subcutaneous administration. In comparison with the mouse, the rabbit seems to absorb and metabolize pentoxifylline slower. In contrast to man, the rabbit had lower metabolite plasma levels than the parent drug itself.

Administration, Oral↗