Development and characterization of a rodent model of methanol-induced retinal and optic nerve toxicity.

Methanol is an important public health and environmental concern because of the selective actions of its neurotoxic metabolite, formic acid, on the retina, optic nerve and central nervous system. Humans and non-human primates are uniquely sensitive to methanol-induced neurotoxicity as a consequence of the limited capacity of primate species to oxidize and thus detoxify formic acid. The toxic syndrome in primates is characterized by formic acidemia, metabolic acidosis and blindness or serious visual impairment. Nonprimate species are normally resistant to the accumulation of formate and associated metabolic and visual toxicity. We have characterized retinal and optic nerve toxicity in a nonprimate model of methanol toxicity using rats in which folate-dependent formate oxidation has been selectively inhibited, allowing formate to accumulate to toxic concentrations following methanol administration. Methanol-intoxicated rats developed formic acidemia, metabolic acidosis and visual toxicity analogous to the human methanol poisoning syndrome. Visual dysfunction was manifested as reductions in the electroretinogram and the flash-evoked cortical potential which occurred coincident with blood formate accumulation. Histological studies revealed mitochondrial disruption and vacuolation in the retinal pigment epithelium, photoreceptor inner segments and optic nerve. The temporal relationship between methanol administration and the onset and development of ocular toxicity, as well as, the degree of metabolic acidosis and extent of formic acidemia in this rodent model are remarkably similar to that documented in human methanol intoxication. Moreover, the functional and morphologic findings in methanol-intoxicated rats are consistent with the hypothesis that formate acts as a mitochondrial toxin in the retina and optic nerve. The establishment and characterization of this nonprimate animal model of methanol intoxication will facilitate research into the mechanistic aspects of methanol toxicity and the development and testing of treatments for human methanol poisoning.

Formate-induced alterations in retinal function in methanol-intoxicated rats.

Formic acid is the toxic metabolite in methanol poisoning. Permanent visual damage in methanol-intoxicated humans and non-human primates has been associated with prolonged exposures (> 24 hr) to blood formate concentrations in excess of 7 mM; however, little information is available on the toxicity associated with chronic low-level or repeated exposure to methanol. The present studies compared the effects on retinal function and structure of rapidly increasing formate concentrations typical of acute methanol intoxication with low-level plateau formate concentrations more likely to be generated by subacute or chronic methanol exposure. Rats that accumulated formate concentrations of 8-15 mM developed metabolic acidosis, retinal dysfunction, and retinal histopathologic changes. Retinal dysfunction was measured as reductions in the a- and b-waves of the electroretinogram that occurred coincident with blood formate accumulation. Histopathologic studies revealed vacuolation in the retinal pigment epithelium and photoreceptor inner segments. Rats exposed to formate concentrations ranging from 4 to 6 mM for 48 hr showed evidence of retinal dysfunction in the absence of metabolic acidosis and retinal histopathology. These data indicate that formic acid generated from methanol oxidation acts as a direct retinal toxin. Formate-induced retinal dysfunction in methanol-intoxicated rats can be produced by steadily increasing concentrations of formate and importantly can also be produced by prolonged exposure to lower concentrations of formate. Our findings substantiate evidence based on clinical case reports and a small number of epidemiological studies and support the hypothesis that the visual system toxicity produced by acute, subacute, or chronic methanol poisoning share a common mechanism.

Echographic pseudoextension of uveal melanomas.

BACKGROUND: Standardized echography is routinely utilized to assess uveal melanomas. Echographic pseudoextension is defined as normal structures mimicking intrascleral or extrascleral extension of tumor on echography. METHODS: The records of 151 consecutive uveal melanoma patients evaluated with standardized echography over a 6-year period (1986-1991) were reviewed to identify those in which pseudoextension or true extension was diagnosed. RESULTS: Fourteen (9%) cases of pseudoextension were noted, with causes including juxtapapillary tumor location (seven cases), extraocular muscle insertion (five cases), vortex ampullae (one case), and post-brachytherapy changes (one case). Clinical, echographic, and/or histopathologic follow-up confirmed absence of true extension. Six (4%) cases of true extrascleral extension were identified and confirmed histopathologically. CONCLUSION: Differentiating extraocular tumor extension from pseudoextension is critical, and use of standardized A-scan and contact B-scan echography is integral in this assessment.

Echographic monitoring of response of extraocular muscles to irradiation in Graves' ophthalmopathy.

PURPOSE: Confirmation of the efficacy of orbital irradiation in Graves' ophthalmopathy is needed due to the unpredictable natural history of the disease, the variation in individual clinical presentations, the contribution of other simultaneous treatments, and the lack of controlled studies using objective criteria to classify and assess response over time. Orbital echography before and at select intervals following orbital irradiation is proposed as an objective parameter of tissue response to orbital irradiation over time. METHODS AND MATERIALS: From January, 1983 to September, 1993, 55 patients with progressive Graves' ophthalmopathy underwent 20 Gy retrobulbar irradiation. On retrospective review, standardized orbital echography was performed randomly prior to irradiation in 37 of the 55 patients to assess the acoustic characteristics of the extraocular muscles and to quantitate their individual and summed diameters. Twenty-one patients had at least one follow-up echographic evaluation at random intervals of 0 to 27.5 months following completion of irradiation. Twelve patients received steroids before or during irradiation, which were tapered in proximity to completion of radiation. Follow-up ranged from 2 to 65 months with the majority followed at least 6 months (18 patients). RESULTS: Of the 21 patients with serial studies, 18 showed an interval decrease in individual and summed muscle size over time and return of symmetry. Interval improvement was documented as early as the 1 month follow-up study, with continued improvement seen during the 3-9-month studies, with stability typically achieved within 12 months. One patient had further changes between the 21 and 27.5 month follow-up studies. Exacerbation of disease was, however, echographically demonstrated in three patients at 6.5, 8.5, and 13 months. Follow-up studies in two of these patients again revealed improvement, one following tapered steroids. The third patient required orbital decompression. CONCLUSION: Objective parameters of response are needed to document both the immediate and long-term outcome of orbital irradiation on the course of Graves' ophthalmopathy and confirm its efficacy. Serial echography is proposed as a new technique for providing parameters to judge response.

Pseudophakia for traumatic cataracts in children.

PURPOSE: The purpose of this prospective study is to evaluate the postoperative visual acuity, refractive error, intraocular pressure, and status of the posterior capsule in children with traumatic cataracts who undergo extracapsular cataract extraction and insertion of a posterior chamber lens. METHODS: Extracapsular cataract extraction and primary endocapsular fixation of a posterior chamber lens implant were performed in eight children (age range, 4-17 years) with unilateral traumatic cataracts. RESULTS: There were no intraoperative complications, and seven of eight eyes achieved 20/40 or greater spectacle visual acuity during an average follow-up interval of 10 months (range, 5-20 months). The average postoperative spherical equivalent refractive error was +0.33 diopter (D) (range, -2.25 to +2.12 D); the average postoperative anisometropia was approximately 1 D (range, 0-2.25 D). In one patient, a coagulase-negative staphylococcal endophthalmitis developed 10 days after surgery. In three eyes that had opacified posterior capsules, YAG laser capsulotomy was performed. CONCLUSIONS: These preliminary results suggest that intraocular lens (IOL) implantation may be a safe and effective method of optical correction for children with traumatic cataracts.

Electro-oculography in autosomal dominant vitreoretinochoroidopathy.

Thirteen members of a family presumed to be harboring the gene for autosomal dominant vitreoretinochoroidopathy were examined. In four affected members, electro-oculography demonstrated marked reduction of the Arden ratio (range, 1.1 to 1.5; normal, > or = 1.8), despite electroretinographic evidence of mildly affected rod function and normal cone function. These findings suggested that a diffuse disturbance of the photoreceptor-pigment epithelium complex may have been present prior to wide-spread loss of photoreceptor function in the affected members of this family. As in previously described families, the pattern of inheritance appeared consistent with autosomal dominance.

Affected females in X-linked congenital stationary night blindness.

Most heterozygous (carrier) females in families with X-linked congenital stationary night blindness are asymptomatic. Several anecdotal cases of manifesting females in X-linked congenital stationary night blindness have been reported, but few clinical details are available. The authors report clinical, electroretinographic, and dark adaptation studies of four affected females from a five-generation family with X-linked congenital stationary night blindness. Each of the manifesting females was the daughter of a different, asymptomatic, carrier mother. None of the 14 daughters of the 9 affected males showed signs or symptoms of congenital stationary night blindness. Uneven X-chromosomal lyonization is the most likely reason for these females manifesting this X-linked disorder.

Methanol poisoning. A rodent model with structural and functional evidence for retinal involvement.

Methanol ingestion can lead to visual impairment, central nervous system dysfunction, or death. The extent of ocular involvement has been difficult to determine because the toxicity is restricted to humans and nonhuman primates due to species differences in methanol metabolism. A rodent model of methanol toxicity recently developed by us was used to evaluate retinal dysfunction in methanol poisoning. Formic acidemia and visual toxic reactions developed in methanol-intoxicated rats. Electroretinographic analysis indicated a significant early deficit in b-wave amplitude followed by a temporally delayed, lesser reduction in a-wave amplitude. Histologic evaluation of the eyes 60 hours after methanol administration revealed generalized retinal edema and vacuolation in the photoreceptors and retinal pigment epithelium. Ultrastructural examination showed swelling and disruption of the mitochondria in photoreceptor inner segments, optic nerve, and the retinal pigment epithelium. These studies document direct retinal involvement in this nonprimate model of methanol toxicity.

Color Doppler flow imaging of the normal and abnormal orbit.

Twenty-six normal orbits (16 subjects) and seven patients with suspected orbital disease were studied with color Doppler flow imaging CDFI). Arterial structures consistently identified included the ophthalmic artery, central retinal artery, and posterior ciliary branches. The terminal lacrimal branch was seen in the majority of orbits (n = 19). Venous structures consistently seen included the central retinal vein and venae vorticosae; the superior ophthalmic vein was identified in the majority of normal orbits (n = 22). Response of the superior ophthalmic vein to the Valsalva maneuver was assessed in six of the normal subjects (12 orbits). Retrograde flow was typically seen during the maneuver and accentuated antegrade flow after cessation of the maneuver. Pathologic entities correctly diagnosed with CDFI included a dural arteriovenous malformation (AVM) with spontaneous carotid-cavernous fistula, an orbital AVM, and superior ophthalmic vein thrombosis. Vascular lesions were excluded in two patients with orbital masses. Bilaterally enlarged superior ophthalmic veins were identified in a patient with unilateral symptoms suggestive of a varix; CDFI results were confirmed with computed tomography, but orbital venograms were interpreted as normal. These findings suggest that CDFI may be helpful in the evaluation of suspected vascular orbital disease.