Reversible bilateral internuclear ophthalmoplegia associated with FK506.

A 50 year old man developed tonic-clonic seizures while receiving cyclosporin A after orthotopic cardiac transplant. The seizures resolved after cessation of cyclosporin A. Thirteen months later, he developed diplopia from bilateral internuclear ophthalmoplegia while receiving intravenous FK506. A temporal association was found between his symptoms and the serum FK506 concentrations. Withdrawal of the intravenous FK506 led to prompt resolution of the bilateral internuclear ophthalmoplegia.

Quantification of optic nerve axon loss associated with a relative afferent pupillary defect in the monkey.

OBJECTIVE: To quantify the amount of optic nerve axonal loss associated with the presence of a mild relative afferent pupillary defect (RAPD) in an experimental monkey model. METHODS: The right macula of 5 rhesus monkeys (Macaca mulatta) was treated with concentrically enlarging diode laser burns until an RAPD was detected using a transilluminator light and measured with neutral density filters. Intervals between treatments were 3 to 7 days over a period of 2 months. Pupillary responses to light stimulation were recorded with a monocular infrared television pupillometer. Two months after detection of an RAPD, 5 treated and 4 control monkeys underwent euthanasia and enucleation. Histopathologic analysis and quantification of optic nerve axon counts using an image analysis system were performed. RESULTS: No RAPD was observed despite an estimated ganglion cell loss of up to 26%. A 0.6 log unit RAPD was present in 5 monkeys when the laser scar incorporated the entire macula within the temporal vascular arcades. One eye had progressive vitreomacular traction with worsening of the RAPD to 1.8 log units without further laser treatment. Histopathologic evaluation disclosed complete loss of the normal retinal architecture within the macula. The average fiber loss for the 4 treated eyes with 0.6 log unit RAPDs compared with fellow eyes was 53.3% (95% confidence interval [CI], 45.0%-61.6%). The average difference in axon counts between untreated pairs of optic nerves was 12.8% (95% CI, 10.0%-15.6%). Optic nerve axon loss between pairs of experimental and control eyes was statistically significant (P<.001). CONCLUSION: In rhesus monkeys, an RAPD develops after an approximate unilateral loss between 25% and 50% of retinal ganglion cells. CLINICAL RELEVANCE: Owing to redundancy in the anterior visual pathways, unilateral retinal ganglion cell loss may occur prior to the observation of an RAPD. The presence of an RAPD measuring 0.6 log units implies that significant retinal ganglion cell injury has occurred.

Choroidal infarction, anterior ischemic optic neuropathy, and central retinal artery occlusion from polyarteritis nodosa.

PURPOSE: Ocular ischemia from polyarteritis nodosa (PAN) is rare. The authors present a case of multifocal ocular infarction from PAN. METHODS AND RESULTS: A 70-year-old woman developed hand and foot numbness followed by intermittent blurred vision and binocular horizontal diplopia. Two weeks later, she suddenly lost vision in the right eye from a central retinal artery occlusion and then developed a left anterior ischemic optic neuropathy and bilateral triangular choroidal abnormalities consistent with infarction. Her erythrocyte sedimentation rate and C-reactive protein were elevated. Although giant cell arteritis was suspected, a multiple mononeuropathy was demonstrated by electromyogram and nerve conduction velocity studies. Biopsy specimens from her sural nerve and biceps muscle showed a necrotizing vasculitis with fibrinoid necrosis, consistent with PAN. CONCLUSIONS: Polyarteritis nodosa can produce ischemia of a variety of ocular structures, including the retina, choroid, and optic nerve. In our patient, all three structures were affected. To our knowledge, this is the first reported case of the triangular sign of Amalric in PAN.

Rhino-orbital mucormycosis in a patient with acquired immunodeficiency syndrome (AIDS) and neutropenia.

PURPOSE: To present a case of rhino-orbital mucormycosis in a patient with AIDS and neutropenia managed without exenteration. METHODS: Case report. RESULTS: A 60-year-old African-American man with AIDS developed neutropenia that was probably secondary to antiretroviral therapy. He developed right rhino-orbital mucormycosis and was treated with right partial ethmoidectomy with debridement and liposomal amphotericin B. The infection was cured without need for orbital exenteration, although visual acuity in his right eye ultimately was no light perception. CONCLUSION: Rhino-orbital mucormycosis is uncommon in patients with AIDS. When rhino-orbital mucormycosis occurs, patients require a careful search for an underlying metabolic derangement such as neutropenia. Treatment should be aggressive, but these patients may not require orbital exenteration.

Hereditary optic neuropathies.

Hereditary optic neuropathies comprise a group of disorders of the optic nerve that may be inherited in an autosomal recessive, autosomal dominant, X-linked, or maternal familial pattern. These disorders should be included in differential diagnosis of both congenital and acquired vision loss. They often present with a painless, slowly progressive, bilateral decreased vision. As in the case of LHON, a hereditary optic neuropathy may have an acute presentation. Clinical examination is characterized by bilateral decreased visual acuity, central scotomas on visual field testing, decreased color vision, and optic atrophy. Though a combination of family history, clinical presentation, age of onset, and associated findings may distinguish disorders, diagnosis may be facilitated by genetic testing.

Sickle cell disease presenting with extensive peri-macular arteriolar occlusions in a nine-year-old boy.

PURPOSE: To report a dramatic occlusive event of the macula surrounding the foveal avascular zone, causing severe and permanent loss of vision in a child with sickle cell disease. METHODS: Case report. A nine-year-old boy with SS hemoglobinopathy and oculocutaneous albinism developed acute unilateral loss of vision. RESULTS: Ophthalmoscopy revealed a pale, milky white, thickened retinal lesion centered on the fovea in the right eye as well as foveal hypoplasia in the left eye. The presence of macular malformation associated with oculocutaneous albinism precluded formation of a cherry-red spot. Fluorescein angiography of the right eye demonstrated extensive occlusions of the arterioles surrounding the foveal avascular zone. The presence of occlusions surrounding the fovea from multiple directions suggested the possibility of central retinal artery occlusion with migration of microemboli downstream. CONCLUSION: The patient, the youngest case reported, developed an irreversible macular infarction that was not improved by an exchange erythrocyte transfusion. He was placed on a long-term monthly transfusion protocol to protect his unaffected eye.

Clinical and genetic analysis of a family with X-linked congenital nystagmus (NYS1).

PURPOSE: To describe a family with X-linked congenital nystagmus and identify the genetic interval within which the gene is located. METHODS AND DESIGN: Clinical examination with genotyping of 30 individuals from a multi-generational Caucasian family with congenital nystagmus inherited in an X-linked pattern using markers from Xq26-q27, followed by linkage analysis and sequencing of a candidate gene, solute carrier family 25, member 14 (SLC25A14), in four affected individuals from four families linked to this region. RESULTS: The pattern of inheritance in the family was consistent with X-linkage with incomplete penetrance among carrier females. No affected males had affected sons. Based on the extended pedigree, the estimated penetrance among obligate female carriers (daughters of affected males) was 29% (6 of 21). Visual acuity among 15 affected individuals ranged from 20/20 to 20/70 (median 20/30). Clinical examinations, including electroretinography in two individuals, were otherwise normal except for the presence of nystagmus. Significant LOD scores (theta = 0) were found with markers DXS8057, DXS8044, DXS1047, DXS1062, DXS8072, and DXS8078, placing the gene within a approximately 5 cM interval flanked by DXS9909 and DXS1211 on the long arm of the X chromosome. Sequencing the candidate gene SLC25A14 in four affected individuals from four families linked to this region failed to reveal any mutations. CONCLUSIONS: NYS1 appears to be a common gene for familial congenital idiopathic nystagmus. Linkage analysis of this family further reduces the interval in which NYS1 is located.

A case-control study of tobacco and alcohol consumption in Leber hereditary optic neuropathy.

PURPOSE: To determine if tobacco or alcohol consumption is associated with vision loss among sibships harboring pathogenic mitochondrial mutations associated with Leber hereditary optic neuropathy. METHODS: Retrospective case-control study with questionnaires obtained from both affected and unaffected siblings from 80 sibships with Leber hereditary optic neuropathy. Sibships harbored molecularly confirmed mitochondrial DNA mutations at nucleotide positions 11778 (63), 14484 (10), and 3460 (7). Exposure in affected individuals was calculated based on reported consumption before vision loss. RESULTS: For male probands (67 sibships), the recurrence risk within a sibship was 10.3% (eight of 78) for males and 3.1% (three of 98) for females. For female probands (13 sibships), the recurrence risk within a sibship was 17.6% (three of 17) for males and 0% (zero of 22) for females. Greater risk of vision loss was associated with male sex (odds ratio [OR] = 6.63; 95% confidence interval [CI] = 2.96 to 14.84; P =.00001) and harboring a 3460 or 14484 in comparison with the 11778 mutation (OR = 2.071; 95% CI = 1.19 to 3.58; P =.0095). No significant association of maximal intensity of smoking or cumulative smoking, whether light or heavy, with vision loss was observed. Light (OR = 0. 31; 95% CI = 0.17 to 0.56; P =.0001) and heavy alcohol consumers (OR = 0.25; 95% CI = 0.11 to 0.58; P =.0011) were less likely to be affected than individuals who did not consume alcohol after adjusting for age, sex, and mutation. In a categorical analysis of sibships with the 3460 or 14484 mutation, no relationship of vision loss with tobacco or alcohol consumption was observed. CONCLUSION: Unlike previous studies, the present study calculated exposure based on self-reported consumption of tobacco or alcohol before vision loss. No significant deleterious association between tobacco or alcohol consumption and vision loss among individuals harboring Leber hereditary optic neuropathy mutations was observed. Tobacco and alcohol do not appear to promote vision loss in Leber hereditary optic neuropathy.

Stages of improvement in visual fields after pituitary tumor resection.

PURPOSE: To use static threshold perimetry to examine the stages of improvement and the potential for late improvement of visual fields after surgical resection of pituitary adenomas causing visual loss from compression of the anterior visual pathways. METHODS: Retrospective review of charts of patients with pituitary tumors and abnormal static threshold perimetry before or soon after treatment who had subsequent visual fields. Quantification of the visual field mean deviation overall, superotemporally, and inferotemporally was performed and compared between visits. Postoperative visits were considered in five time periods: visit 1 (surgery to 1 week), visit 2 (1 month to 4 months), visit 3 (6 months to 1 year), visit 4 (2 years), and visit 5 (3 or more years). RESULTS: Sixty-two patients were included (33 men and 29 women; mean age 54 years [SD +/- 15 years; range, 22 to 83 years]). At visit 1, the relative improvement of the overall mean deviation for the right eye was 30.8% (P =.01) and for the left eye was 13.7% (P =.3067). At visit 2, the relative improvement of the overall mean deviation for the right eye was 30. 4% (P =.0142) and for the left eye was 32.6% (P =.0092). At visits 1 and 2, the inferotemporal quadrants were the quadrants with greatest improvement (visit 1, right eye, 37.8% [P =.0082]; visit 2, left eye, 30.8% [P =.0074]). At visits 3, 4, and 5, an overall trend toward mild improvement was observed with statistical significance only for the inferotemporal quadrant of the left eye from visit 2 to visit 3, which improved 19.7% (P =.0270). CONCLUSION: The pattern of recovery of visual function after decompression of the anterior visual pathways suggests at least three phases of improvement. The early fast phase (surgery to 1 week) of improvement may lead to normalization of visual fields in some individuals. The early slow phase (1 month to 4 months) is the period of most notable improvement. A late phase (6 months to 3 years) of mild improvement does not appear significant overall but may be marked in some individuals. Each of these phases may have one or more mechanisms underlying the observed improvement.

Isolated Horner's syndrome and syringomyelia.

Although syringomyelia has been associated with Horner's syndrome, it is typically associated with other neurological findings such as upper limb weakness or numbness. A patient is described who had an isolated Horner's syndrome as the only manifestation of syringomyelia. A 76 year old woman was discovered to have right upper lid ptosis and right pupillary miosis. Neurological examination was unremarkable, and pharmacological testing was consistent with localisation of the lesion to a first or second order sympathetic neuron. Neuroimaging disclosed a Chiari I malformation with a syrinx extending to the C2 to C4 level. An isolated Horner's syndrome may be the presenting manifestation of syringomyelia.

Coffee and doughnut maculopathy: a cause of acute central ring scotomas.

AIMS: To report the clinical features of five patients with non-progressive central ring scotomas of acute onset associated with excellent retained visual acuity. METHODS: Complete neuro-ophthalmological examinations were performed. Visual fields were performed by tangent screen, Goldmann, or Humphrey perimetry. In some cases further testing was carried out including fundus photography, fluorescein angiography, ERG, VEP, and neuroimaging. RESULTS: The patients were three women and two men whose ages ranged from 25 to 57 years. Four patients were heavy caffeine consumers while the fifth patient experienced an episode of hypotension. Vision loss was acute in all cases. The onset of vision loss was bilateral/simultaneous in three cases, bilateral/sequential in one case, and unilateral in one case. All affected eyes retained visual acuities of 20/25 or better. Colour vision was subnormal in three of four cases. Visual field defects were characterised by a central ring scotoma having an outer diameter less than 10 degrees. Fundus examination demonstrated temporal optic nerve pallor in three patients (five of 10 affected eyes) and reddish, petaloid macular lesions in one patient. Good visual acuity was maintained for the duration of follow up in all five patients. CONCLUSION: Central ring scotomas with excellent retained visual acuity may present as an acute, bilateral syndrome in patients who are heavy caffeine consumers. The configuration of visual field loss and its location, combined with the presence of temporal pallor in five eyes, suggest that the defect localises to the inner layers of the macula. While these cases could be considered an expansion of the clinical spectrum of acute macular neuroretinopathy, some may represent a distinct entity.

Histopathologic studies of ischemic optic neuropathy.

PURPOSE: To define the histopathologic features of eyes in which a pathologic diagnosis of ischemic optic neuropathy had been made in the years 1951 through 1998. METHODS: The following data were documented: age of patient, race, sex, source of tissue, cause of death, clinical history, interval from loss of vision to death, enucleation, exenteration, and biopsy. The histopathologic criteria for diagnosis of ischemic optic neuropathy were the presence of localized ischemic edema, cavernous degeneration, or an area of atrophy located superior or inferior in the optic nerve. Cases with history of abrupt loss of vision were combined with reports from the literature to construct a time table of histopathologic features and associated conditions. RESULTS: Ischemic optic neuropathy was present in 193 eyes. There were 88 females and 65 males. The average age was 71.6 years. Ischemic edema without (early) and with (later) gitter macrophages was present in 26 (13.5%). Cavernous degeneration was present in 69 nerves (36%). Mucopolysaccharide (MPS) was present in 37 cavernous lesions 1 month or longer after loss of vision. Cavernous lesions were seen in 3 eyes in which peripapillary retinal nerve fiber layer hemorrhage had been observed prior to death. Atrophic lesions, the most common pattern, were observed in 133 optic nerves (66.8%). More than 1 ischemic lesion was seen in 38 optic nerves (19.7%). Bilateral ischemic lesions were seen in 50 (35.2%) of 142 paired eyes. CONCLUSIONS: Ischemic optic nerve lesions are initially acellular and later show macrophage infiltration. Cavernous lesions with MPS are present 4 weeks or longer after vision loss. The location of MPS posteriorly and along the internal margin suggests that MPS is produced at the edges of lesions. Progressive vision loss in ischemic optic neuropathy may be secondary to compression of intact nerve from ischemic edema and cavernous swelling, or a second ischemic lesion.

Neuro-ophthalmology of the phacomatoses.

The phacomatoses are a group of disorders that feature multiple hamartomas of the central and peripheral nervous system, eye, skin, and viscera. Most of these disorders have a well-defined Mendelian pattern of inheritance because of a mutation in a single gene which has been identified. In other instances, no clear patterns of inheritance or genetic susceptibility have been recognized. The combination of ocular and central nervous system manifestations in patients with phacomatoses makes neuro-ophthalmologic evaluation particularly important in diagnosis and management. This review provides an overview of the phacomatoses with emphasis on recent reports of significance to neuro-ophthalmology.

The phacomatoses.

The phacomatoses are disorders characterized by multiple hamartomas of the central and peripheral nervous system, eye, skin, and viscera. Many of these diseases have well-defined Mendelian patterns of inheritance because of a mutation of a single gene. In other instances, no clear patterns of inheritance or genetic susceptibility have been identified. In some cases, patients are at increased risk of malignancy. The combination of ocular and CNS manifestations seen in patients with the phacomatoses makes neuro-ophthalmologic evaluation particularly important in the diagnosis and management of these patients.

Genetic heterogeneity of dominant optic atrophy, Kjer type: Identification of a second locus on chromosome 18q12.2-12.3.

OBJECTIVE: To evaluate a family with autosomal dominant optic atrophy, which has been previously linked to the Kidd blood group. DESIGN: Clinical evaluation with the assessment of visual acuity, color vision, and optic nerve appearance to determine affection status. Linkage analysis using polymorphic DNA markers. RESULTS: Visual acuities ranged from 20/20 to 6/200. Although linkage was excluded for chromosome 3q28-29, markers from chromosome 18 in the vicinity of the Kidd locus were linked to the disorder (D18S34 [maximal lod score (lodmax) of 5.38 at recombination fraction (theta) of 0.14], D18S548 [lod(max)=7.26, theta=0.09], D18S861 [lod(max)= 5.32, theta = 0.07], and D18S479 [lod(max) = 3.28, 0 = 0.12:]). Multipoint linkage analysis demonstrated lod scores of greater than 3 in an approximately 3-centimorgan region flanked by D18S34 and D18S479, using 98% penetrance and a phenocopy rate of 1/50. CONCLUSIONS: Dominant optic atrophy is genetically heterogeneous, with loci assigned to chromosomes 3q28-29 and 18q12.2-12.3. Dominant optic atrophy linked to 18q shows intrafamilial variation similar to that previously reported in families linked to 3q, with visual acuities ranging from normal to legal blindness. The overall distribution of visual acuities appears more favorable with the 18q phenotype. Both phenotypes appear to have a similar rate of visual decline.

Congenital motor nystagmus linked to Xq26-q27.

Congenital motor nystagmus (CMN) is a hereditary disorder characterized by bilateral ocular oscillations that begin in the first 6 mo of life. It must be distinguished from those genetic disorders-such as ocular albinism (OA), congenital stationary night blindness (CSNB), and blue-cone monochromatism (BCM)-in which nystagmus accompanies a clinically apparent defect in the visual sensory system. Although CMN is presumed to arise from a neurological abnormality of fixation, it is not known whether the molecular defect is located in the eye or in the brain. It may be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern. Three families with CMN inherited in an X-linked, irregularly dominant pattern were investigated with linkage and candidate gene analysis. The penetrance among obligate female carriers was 54%. Evaluation of markers in the region of the genes for X-linked OA, CSNB, and BCM revealed no evidence of linkage, supporting the hypothesis that CMN represents a distinct entity. The gene was mapped to chromosome Xq26-q27 with the following markers: GATA172D05 (LOD score 3.164; recombination fraction [theta] = 0.156), DXS1047 (LOD score 10.296; theta = 0), DXS1192 (LOD score 8.174; theta = 0.027), DXS1232 (LOD score 6.015; theta = 0.036), DXS984 (LOD score 6.695; theta = 0), and GATA31E08 (LOD score 4.940; theta = 0.083). Assessment of haplotypes and multipoint linkage analysis, which gave a maximum LOD score of 10.790 with the 1-LOD-unit support interval spanning approximately 7 cM, place the gene in a region between GATA172D05 and DXS1192. Evaluation of candidate genes CDR1 and SOX3 did not reveal mutations in affected male subjects.