Biomedical subjects
Alfredo A Sadun
Publications and source records attributed to Alfredo A Sadun.
Scotomas of age-related macular degeneration detected and characterized by means of a novel three-dimensional computer-automated visual field test.
PURPOSE: We used the recently devised three-dimensional computer-based threshold Amsler grid test to acquire and identify typical patterns of visual field defects (scotomas) caused by age-related macular degeneration (AMD). METHODS: Patients with AMD traced on a computer touch screen the borders of those areas on an Amsler grid that were missing from their field of vision. Scotomas were repeatedly outlined and recorded at different grid contrast levels. The resulting three-dimensional "hole" in the central 25 degrees of the visual field was further characterized by its slope, location, shape, and depth. The results were compared with fundus photographs and fluorescein angiograms. RESULTS: Twenty-five patients and 41 eyes were examined. The three-dimensional depictions consistently demonstrated central scotomas with "scallop"-shaped borders and steplike patterns, with either steep slopes or a combination of steep and shallow slopes. The steep slopes corresponded to nonexudative AMD, while the shallow slopes indicated exudative AMD. CONCLUSION: The three-dimensional computer-automated threshold Amsler grid test may demonstrate characteristic scotoma patterns in patients with AMD that conform to the respective fluorescein angiograms. The test shows promise as an effective tool in accurately evaluating, characterizing, and monitoring scotomas in patients with AMD. It may have the potential as a screening tool for the early diagnosis of AMD.
Hertel curve: orbital volume increment and proptosis in a cadaver model.
PURPOSE: This study examined the relation between effective orbital volume increment and proptosis induced by an inflatable orbital implant in a human cadaver orbit. METHODS: A 25-ml inflatable latex balloon was inserted between the periorbita and orbital floor in 15 human cadavers. Hertel measurements were taken for each milliliter over a total 7-ml volume increment. Five trials per orbit for 15 cadavers resulted in 525 data points. RESULTS: Average exophthalmos per milliliter of volume increment was plotted over 7 ml, using 1-ml volume increments. The resultant curve, which was termed a Hertel curve, was linear over 7 ml (R > 99%) and had a slope of 0.62 mm per milliliter of volume increment. CONCLUSIONS: An inflatable orbital implant is an effective tool for introducing a specified amount of volume in the cadaver orbit. The predictable relation between proptosis and volume increment (Hertel curve) may be a useful tool for surgeons in planning the size of an implant required to surgically correct enophthalmos.
Chromatic and luminance contrast sensitivities in asymptomatic carriers from a large Brazilian pedigree of 11778 Leber hereditary optic neuropathy.
PURPOSE: To determine whether asymptomatic 11778 LHON carriers demonstrated impairments in (1) chromatic red/green (R/G) and blue/yellow (B/Y) contrast sensitivity functions (CSF) and in (2) luminance contrast sensitivity functions in the spatial CSF (SCSF) and temporal CSF (TCSF) domains. METHODS: Twenty-five carriers (8 male, 17 female; 34.1 +/- 15.1 years of age) of homoplasmic 11778 LHON from the same well-described family and 30 age-matched controls (17 male, 13 female; 29.2 +/- 7.1 years of age) were tested in one eye, randomly selected. Of the 25 eyes tested, 18 had normal fundus, 5 had swelling and microangiopathy, and 2 had temporal pallor. The R/G and B/Y CSFs were obtained after equiluminance correction with bichromatic horizontal sinusoidal gratings at 0.3, 0.7, and 2 cycles per degree (cpd); the SCSFs were obtained with achromatic gratings at 0.3, 2, 6, and 12 cpd; and the TCSFs were obtained at 2, 10, 20, and 33 Hz with sinusoidal modulation of a 2.7 degrees field with a superimposed spatial Gabor function. RESULTS: Differences between carriers and controls were statistically significant for all spatial frequencies of chromatic and luminance SCSFs, but not for the TCSFs. R/G equiluminance settings of carriers differed from those of controls (P < 0.001), requiring higher luminance in the green; B/Y equiluminance settings were not statistically different in carriers and controls. Fundus findings did not correlate with CS results. CONCLUSIONS: Luminance and chromatic spatial CS losses that affected all tested spatial frequencies, are reported in LHON asymptomatic carriers with the mtDNA 11778 mutation. No losses were found in the temporal CSF. An intriguing finding is that the blue system is substantially spared in this LHON family. These represent subclinical visual impairments in otherwise asymptomatic LHON carriers.
Optical coherence tomography can measure axonal loss in patients with ethambutol-induced optic neuropathy.
PURPOSE: To map and identify the pattern, in vivo, of axonal degeneration in ethambutol-induced optic neuropathy using optical coherence tomography (OCT). Ethambutol is an antimycobacterial agent often used to treat tuberculosis. A serious complication of ethambutol is an optic neuropathy that impairs visual acuity, contrast sensitivity, and color vision. However, early on, when the toxic optic neuropathy is mild and partly reversible, the funduscopic findings are often subtle and easy to miss. METHODS: Three subjects with a history of ethambutol (EMB)-induced optic neuropathy of short-, intermediate-, and long-term visual deficits were administered a full neuro-ophthalmologic examination including visual acuity, color vision, contrast sensitivity, and fundus examination. In addition, OCT (OCT 3000, Humphrey-Zeiss, Dublin, CA) was performed on both eyes of each subject using the retinal nerve fiber layer (RNFL) analysis protocol. OCT interpolates data from 100 points around the optic nerve to effectively map out the RNFL. RESULTS: The results were compared to the calculated average RNFL of normal eyes accumulated from four prior studies using OCT, n=661. In all subjects with history of EMB-induced optic neuropathy, there was a mean loss of 72% nerve fiber layer thickness in the temporal quadrant (patient A, with eventual recovery of visual acuity and fields, 58% loss; patient B, with intermediate visual deficits, 68% loss; patient C, with chronic visual deficits, 90% loss), with an average mean optic nerve thickness of 26+/-16 microm. There was a combined mean loss of 46% of fibers from the superior, inferior, and nasal quadrants in the (six) eyes of all three subjects (mean average thickness of 55+/-29 microm). In both sets (four) of eyes of the subjects with persistent visual deficits (patients B and C), there was an average loss of 79% of nerve fiber thickness in the temporal quadrant. CONCLUSIONS: The OCT results in these patients with EMB-induced optic neuropathy show considerable loss especially of the temporal fibers. This is consistent with prior histopathological studies that show predominant loss of parvo-cellular axons (or small-caliber axons) within the papillo-macular bundle in toxic or hereditary optic neuropathies. OCT can be a valuable tool in the quantitative analysis of optic neuropathies. Additionally, in terms of management of EMB-induced optic neuropathy, it is important to properly manage ethambutol dosing in patients with renal impairment and to achieve proper transition to a maintenance dose once an appropriate loading dose has been reached.
Ophthalmologic findings in a large pedigree of 11778/Haplogroup J Leber hereditary optic neuropathy.
PURPOSE: To report the ophthalmologic characteristics of a newly identified seven-generation pedigree of 11778/Haplogroup J Leber hereditary optic neuropathy consisting of 328 living individuals, 111 of whom are maternally related. DESIGN: Observational population cohort study. METHODS: This prospective study of a large Brazilian Leber hereditary optic neuropathy pedigree was carried out as a field investigation in Brazil. We describe the ophthalmologic findings of 192 eyes from 96 maternally related individuals of this pedigree. Spouses were used as control subjects. We conducted comprehensive neuro-ophthalmologic examinations with psychophysical tests, Humphrey visual fields, and fundus photographs. We also correlated the ophthalmologic findings with the previously published epidemiologic assessment of risk factors. RESULTS: We examined 76 carriers and 20 affected individuals. The affected individuals showed severe disease with a mean visual acuity of 2.04 logarithm of the minimal angle of resolution and without evidence of recovery. All the affected individuals showed diffuse optic atrophy with a cup-to-disk ratio greater than 0.5 in 55% of cases. Moreover, among Affected individuals, smokers had a poorer visual acuity (P =.002). Among carriers there were several subclinical abnormalities, including microangiopathy, swelling of nerve fibers, and visual field abnormalities that did not correlate with tobacco or alcohol consumption. CONCLUSIONS: Our results demonstrate a significant influence of environmental risk factors, particularly smoking, for developing Leber hereditary optic neuropathy and for the severity of its clinical expression. However, smoking did not correlate with the subclinical abnormalities detected in carriers. Moreover, subclinical abnormalities were equally distributed between gender.
Mitochondrial dysfunction as a cause of optic neuropathies.
Mitochondria are increasingly recognized as central players in the life and death of cells and especially of neurons. The energy-dependence of retinal ganglion cells (RGC) and their axons, which form the optic nerve, is singularly skewed. In fact, while mitochondria are very abundant in the initial, unmyelinated part of the axons anterior to the lamina cribrosa, their number suddenly decreases as the myelin sheath begins more posteriorly. The vascular system also presents different blood-brain barrier properties anterior and posterior to the lamina, possibly reflecting the different metabolic needs of the optic nerve head (unmyelinated) and of the retrobulbar optic nerve (myelinated). Mitochondrial biogenesis occurs within the cellular somata of RGC in the retina. It needs the coordinated interaction of nuclear and mitochondrial genomes. Mitochondria are then transported down the axons and distributed where they are needed. These locations are along the unmyelinated portion of the nerve, under the nodes of Ranvier in the retrobulbar nerve, and at the synaptic terminals. Efficient transportation of mitochondria depends on multiple factors, including their own energy production, the integrity of the cytoskeleton and its protein components (tubulin, etc.), and adequate myelination of the axons. Any dysfunction of these systems may be of pathological relevance for optic neuropathies with primary or secondary involvement of mitochondria. Leber's hereditary optic neuropathy (LHON) is the paradigm of mitochondrial optic neuropathies where a primary role for mitochondrial dysfunction is certified by maternal inheritance and association with specific mutations in the mitochondrial DNA (mtDNA). Clinical phenocopies of this pathology are represented by the wide array of optic neuropathies associated with vitamin depletion, toxic exposures, alcohol and tobacco abuse, and use of certain drugs. Moreover, the recent identification of mutations in the nuclear gene OPA1 as the causative factor in dominant optic atrophy (DOA, Kjer's type) brought the unexpected finding that this gene encodes for a mitochondrial protein, suggesting that DOA and LHON may be linked by similar pathogenesis. Polymorphisms in this very same gene may be associated with normal tension glaucoma (NTG), which might be considered a genetically determined optic neuropathy that again shows similarities with both LHON and DOA. Exciting new developments come from first examples of mitochondrial optic neuropathies in animal models that are genetically determined or are the result of ingenious engineering of mitochondrial gene expression, or from biochemical manipulations of the respiratory complexes. Even more exciting is the first successful attempt to correct the LHON-related complex I dysfunction by the allotopic nuclear expression of the recoded mitochondrial gene. There is hope that the genetic complexities, biochemical dysfunctions, and integrated anatomical-physiological cellular relationships will soon be precisely delineated and that promising therapeutic and prophylactic strategies will be proposed.
Visual electrophysiologic findings in patients from an extensive Brazilian family with Leber's hereditary optic neuropathy.
Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease, associated with mitochondrial DNA (mtDNA) point mutations and characterized by bilateral, usually sequential, rapid loss of central vision. The purpose of this study was to investigate electrophysiologically a small cohort of members from an extensive Brazilian family affected by LHON. Pattern-reversal visual evoked potentials (PVEP), and full-field electroretinograms (ERG) were performed on the four index members, all carrying the 11778 homoplasmic mtDNA mutation. They were a 14-year-old recently affected male, his unaffected mother, and her two affected brothers. The three affected members all had bilateral profound visual loss with visual acuities that ranged from 20/250 to CF, cecocentral defects, and severe dyschromatopsia (by FM-100). The unaffected (carrier) female had normal visual acuities, visual fields and color discrimination. Severely prolonged P100 latencies and decreased N75-P100 peak amplitudes were found in pattern-reversal VEPs for three affected members. Normal PVEP responses were found in the carrier female. Rod and cone ERG responses were normal in two affected members, but both the carrier mother and her affected son showed reduced peak-to-peak amplitude for single-flash cone response and 30 Hz flicker, with normal b-wave implicit times. Thus, optic nerve function, evaluated by PVEP, was severely reduced in LHON affected members and normal in the carrier female. However, reduced ERG cone responses suggest that LHON can also affect retinal elements, even in the absence of fundus and other clinical changes that constitute the full and classical expression of LHON.
Eye movement abnormalities in a case of X-linked dystonia-Parkinsonism (lubag).
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Devastating complications from alcohol cauterization of recurrent Rathke cleft cyst. Case report.
Rathke cleft cysts are commonly found on autopsy but are seldom symptomatic. Conventional treatment of these lesions consists of transsphenoidal drainage with partial excision of the cyst, and recurrence is rare. Alternatively, the instillation of absolute alcohol into the cyst has been described in several reports, with no complications. The authors report on a woman with Rathke cleft cyst that recurred three times after the initial treatment; the lesion was treated with alcohol cauterization on the final recurrence with devastating complications. This 51-year-old woman presented in 1992 with headaches and visual disturbances. Admission magnetic resonance imaging revealed a sellar/suprasellar lesion that was treated with conventional surgery and was subsequently confirmed to be a Rathke cleft cyst. The patient again presented with recurrence of the cyst at 22, 26, and 31 months after the initial presentation. On the final recurrence the cyst was treated with alcohol cauterization. Postoperatively, the patient awoke blind and suffered a seizure from leakage of the alcohol. The patient remains completely blind in both eyes and is also anosmic and has left lid ptosis and exotropia, which signify damage to the first through third cranial nerves. Rathke cleft cysts have been known to recur after primary surgery; however, this is the first report of a single cyst recurring three times despite conventional surgical treatment. Additionally, this is the first report in which devastating complications from alcohol cauterization of the cyst have been described. The authors therefore advocate caution when attempting alcohol cauterization and advise that meticulous care be taken to ensure the patency of the cyst.
Mitochondrial function and dysfunction within the optic nerve.
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Ophthalmic education: where have we come from, and where are we going?
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Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy.
PURPOSE: To conduct systematic epidemiologic, neuro-ophthalmologic, psychophysical, and mitochondrial DNA (mtDNA) genetic examinations on a newly identified pedigree with Leber hereditary optic neuropathy (LHON). DESIGN: Observational population cohort study. METHODS: A prospective investigation of an entire Brazilian LHON family. SETTING: A field investigation by an international team conducted in a remote part of Brazil. STUDY POPULATION: We evaluated 265 (both eyes) of the 328 living family members of this LHON pedigree. Only members of this pedigree were studied. Those entering the pedigree as spouses were used as controls. OBSERVATION PROCEDURES: We conducted epidemiologic interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmologic examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for mitochondrial genetic analysis. RESULTS: We reconstructed a seven-generation maternal lineage descended from a common ancestor dating to the 1870s. All maternally related family members were invariably homoplasmic 11778 with a haplogroup J mtDNA, 33 being affected, of which 22 are still living. With each subsequent generation, there was a progressive decrease of penetrance, and only males were affected in the last two generations. A significant exposure (greater than 95% confidence intervals) to a variety of environmental risk factors characterized the affected individuals, with smoking as the most common (P <.01). Both affected and carriers (95% confidence intervals) presented with a significantly lower incidence of hypertension and high cholesterol compared with the control group (P <.05). CONCLUSIONS: Almost 95% of a 328-living-member pedigree with LHON 11778/J haplogroup was comprehensively studied. Our initial results indicate the strong influence of environmental risk factors. The remarkably reduced incidence of cardiovascular risk in the maternal lineage is discussed. Further genetic analysis may reveal a role for the nuclear genome.
Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida, May 5-10, 2002.
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Death associated with an indwelling orbital catheter.
We report a case of a 38-year-old woman who underwent revision of an orbital implant. A flexible indwelling orbital catheter was placed for postoperative anesthesia. Marcaine, administered to the patient through the 5.25-inch catheter while the patient was at home, led to respiratory arrest. After unsuccessful resuscitation, the patient died. At autopsy, it was noted that the catheter passed through the superior orbital fissure, with evidence of injection of marcaine in the subarachnoid space. This patient had signs and symptoms of Stickler syndrome. This leads us to believe that deficiencies in collagen II led to a weakness of the connective tissue surrounding the superior orbital fissure, leading to facilitated passage of the catheter into the subarachnoid space. This may be the first report of this type of outcome when using indwelling catheters for ophthalmic surgery. We recommend that placement of orbital indwelling catheters be performed in a controlled hospital setting.