Normal Implicit Times Research Articles

Diagnostic Testing and Disease Monitoring in Birdshot Chorioretinopathy

Birdshot chorioretinopathy (BSCR) is a rare form of posterior uveitis in which hypopigmented choroidal lesions are scattered throughout the posterior pole. In order to avoid the poor natural history of BSCR, many practitioners would argue that it is critical to diagnose and carefully monitor the often subtle activity of this disease; BSCR can progress insidiously in a white and painless eye, and treatment algorithms based on visual acuity, vitreous inflammation, and retinal vascular leakage of fluorescein alone have been ineffective. This article reviews the various modalities that can be used to diagnose and monitor BSCR, including the clinical and ophthalmoscopic features, diagnostic criteria, electroretinography (ERG- full field, multifocal, and pattern), fluorescein angiography (FA), indocyanine green (ICG) angiography, optical coherence tomography (OCT), fundus autofluorescence (AF), visual fields, HLA A29 testing, and other laboratory testing. HLA-A29 testing can be useful in diagnostically borderline cases, but a positive test is not as useful as one might think in cases where the clinical suspicion for BSCR is low. Out of all the testing modalities, the ERG has been studied most extensively in its relationship to successful treatment. The key parameter is the 30 Hz flicker implicit time, which is abnormal in 70% of patients at baseline. A normal implicit time is correlated with the chance that a patient can be successfully tapered from systemic immunomodulatory therapy without recurrence. Alternatively, some practitioners use ICG angiography or visual field testing for adjunctive monitoring. OCT is used most commonly to follow macular edema. While there is no consensus on how to best monitor disease activity, our institution uses serial ERGs as an adjunct to the normal exam.

Gradient of deficit in cone responses in the incomplete form of congenital stationary night blindness revealed by multifocal electroretinography

Multifocal electroretinograms were recorded in one case of incomplete form of congenital stationary night blindness. First order kernel revealed reduced cone macular P1 responses with normal implicit time (22.7 nV, 33.3 ms; normal 43.3 +/- 8.2 nV, 32.7 +/- 0.6 ms) whereas more peripheral responses exhibited low responses of extremely delayed implicit time (5.1 nV, 47.5 ms; normal 7.4 +/- 2.1 nV, 32.3 +/- 0.8 ms). Responses from the first slice of the second kernel were present in the macular area but absent from the more peripheral areas. In comparison, mfERGs in the complete form of CSNB showed normal amplitude but slightly delayed responses at all eccentricities and normal second kernel responses. Results are discussed in terms of the dichotomy in synaptic transmission between macular and peripheral cones.

The albino chick as a model for studying ocular developmental anomalies, including refractive errors, associated with albinism

Albinism is associated with a variety of ocular anomalies including refractive errors. The purpose of this study was to investigate the ocular development of an albino chick line. The ocular development of both albino and normally pigmented chicks was monitored using retinoscopy to measure refractive errors and high frequency A-scan ultrasonography to measure axial ocular dimensions. Functional tests included an optokinetic nystagmus paradigm to assess visual acuity, and flash ERGs to assess retinal function. The underlying genetic abnormality was characterized using a gene microarray, PCR and a tyrosinase assay. The ultrastructure of the retinal pigment epithelium (RPE) was examined using transmission electron microscopy. PCR confirmed that the genetic abnormality in this line is a deletion in exon 1 of the tyrosinase gene. Tyrosinase gene expression in isolated RPE cells was minimally detectable, and there was minimal enzyme activity in albino feather bulbs. The albino chicks had pink eyes and their eyes transilluminated, reflecting the lack of melanin in all ocular tissues. All three main components, anterior chamber, crystalline lens and vitreous chamber, showed axial expansion over time in both normal and albino animals, but the anterior chambers of albino chicks were consistently shallower than those of normal chicks, while in contrast, their vitreous chambers were longer. Albino chicks remained relatively myopic, with higher astigmatism than the normally pigmented chicks, even though both groups underwent developmental emmetropization. Albino chicks had reduced visual acuity yet the ERG a- and b-wave components had larger amplitudes and shorter than normal implicit times. Developmental emmetropization occurs in the albino chick but is impaired, likely because of functional abnormalities in the RPE and/or retina as well as optical factors. In very young chicks the underlying genetic mutation may also contribute to refractive error and eye shape abnormalities.

Progressive cone dystrophy with deutan genotype and phenotype

To study the electroretinographic signals originating in the long-wavelength-sensitive (L) and middle-wavelength-sensitive (M) cone pathways by means of large-field and multifocal cone type-specific electroretinograms (ERGs) in a patient with progressive cone dystrophy. A 65-year-old male patient with colour vision disturbances (age at onset 10 years), loss of visual acuity (14 years), and central visual field defects (40 years) was investigated. Large-field flicker-ERG responses to stimuli that exclusively modulated the L-cones or the M-cones, or the two simultaneously (both in-phase and in counter-phase), were measured. Short-wavelength-sensitive (S) cones were not modulated. Multifocal ERGs (mfERGs) were also recorded, with a pattern-reversing display that modulated only the L- or the M-cones at equal cone contrasts and average quantal catches. Genetic analysis of L- and M-pigment genes was performed on genomic DNA isolated from peripheral venous blood. The patient showed a normal rod-driven ERG but reduced cone-driven electroretinographic amplitudes with normal implicit times in the International Society for Clinical Electrophysiology of Vision (ISCEV) standard ERG. The large-field flicker-ERG responses to pure L-cone modulation were significantly above noise level but were substantially reduced in comparison with both normal trichromatic subjects and (otherwise normal) deuteranopes. The L-cone driven electroretinographic implicit times and phases were within normal limits. The M-cone driven electroretinographic responses were not detectable. A model fit of all the L- and M-cone driven flicker-ERG data revealed that the responses were exclusively driven by the L-cones. Consistently, the cone type-specific mfERGs showed severely reduced but detectable responses to L-cone-isolating stimuli. The M-cone driven multifocal-ERG responses were undistinguishable from noise. The L- and M-pigment gene array consisted of only a single L-pigment gene. The complete coding sequence of this gene was determined and showed no abnormality. This patient exhibits a coincidence of progressive cone dystrophy and deuteranopia. The molecular genetic data of the L/M-pigment gene array is consistent with the deutan phenotype. It cannot be excluded that the rearrangement of the X-chromosome pigment gene array is responsible for the cone dystrophy in this patient. It is, however, suggested that the dichromacy and the cone dystrophy have different and independent genetic origins.

Localized retinal electrophysiological and fundus autofluorescence imaging abnormalities in maternal inherited diabetes and deafness.

To investigate retinal function in patients with maternally inherited diabetes and deafness (MIDD) and to correlate the findings with fundus autofluorescence (FAF) imaging. FAF was imaged in five patients (age range, 49-60 years) confirmed to have the mitochondrial DNA nucleotide A3243G point mutation. Retinal function was measured by full-field (Ganzfeld) electroretinography (ERG) and pattern ERG, incorporating the International Society for Clinical Electrophysiology of Vision (ISCEV) standards. Multifocal ERG (mfERG) was also performed. For analysis of the mfERG data, five regional ring groups of equal eccentricity were formed. For each ring, the peak amplitude (defined as the difference between P1 and N1) and the implicit time of P1 were determined and compared with normative values. Visual acuity in the patients was between 20/20 and 20/40 (Early Treatment Diabetic Retinopathy Study [ETDRS] chart). Irregular increased FAF signals were observed adjacent to and between areas of atrophy of the retinal pigment epithelium (RPE). Ganzfeld ERGs were within normal limits in three patients. Pattern ERG was abnormal in five eyes of three patients. mfERG peak amplitude abnormalities were particularly present in rings 2 and 3 and were consistent with the distribution of FAF abnormalities. In all but one eye, no implicit times changes were present. Significant mfERG abnormalities with normal Ganzfeld ERG are consistent with nonuniform damage to the central retina in MIDD, in keeping with the FAF findings. Reduced peak amplitudes with normal implicit times in the mfERG suggest localized loss of function and may indicate damage to the cone photoreceptor outer segments or cone photoreceptor loss in MIDD.

Mitochondrial maculopathy: geographic atrophy of the macula in the MELAS associated A to G 3243 mitochondrial DNA point mutation

PURPOSE: To report ocular findings in the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) in a family with the A to G 3243 mitochondrial (mt) DNA point mutation.METHODS: Case reports. Ocular findings are described from four family members with the MELAS associated A to G 3243 mt DNA point mutation.RESULTS: Findings included ophthalmoplegia, neurosensory deafness, reduction of photopic and scotopic electroretinogram b-wave amplitudes, and myopathy, as well as macular retinal pigment epithelial atrophy. No family members had nyctalopia, attenuation of retinal blood vessels, or retinal bone spicule pigmentation.CONCLUSION: The finding of slowly progressive macular retinal pigment epithelial atrophy expands the reported phenotypic diversity of patients with A3243G mt DNA mutations. MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a maternally inherited disorder associated with abnormal mitochondria, manifesting in tissues highly dependent on oxidative metabolism. Ocular changes in MELAS syndrome have included reversible scotomata, ophthalmoplegia, pigmentary retinopathy, marked attenuation of the scotopic electroretinogram, myopia, and nuclear cataract.1,2We highlight some of these ocular manifestations in a family with MELAS syndrome and describe a distinct maculopathy. A 48-year-old woman was referred for evaluation of an asymptomatic maculopathy. Her medical history included mild sensorineural hearing loss; her family history included a mother with congestive heart failure, diabetes mellitus, ophthalmoplegia, and parafoveal atrophy as well as a deceased brother who had an unknown ocular disease, deafness, diabetes, and heart failure. Ocular examination disclosed best-corrected visual acuities of RE: 20/25 and LE: 20/30, normal results from Ishihara color plate testing, significant limitation of gaze in all fields (as much as 70% of expected), and several patches of macular retinal pigment epithelial atrophy bilaterally, which were noted to have become slightly larger compared with fundus photographs taken 8 years earlier. These regions of atrophy correlated with scotomata on Amsler grid and visual field testing (Figures 1 and 2). Her electroretinogram disclosed reduction of photopic and scotopic b-wave amplitudes with normal implicit times. Screening for mitochondrial disorders was suggested but refused by the patient.Several months later, the patient’s sister was diagnosed with MELAS syndrome after presenting with stroke; she was found to have bilateral neurosensory deafness, bicuspid aortic valve, and diabetes mellitus, and a muscle biopsy was positive for ragged red muscle fibers. She was noted to have ophthalmoplegia but did not have ophthalmic complaints. No family members had nyctalopia, waxy pallor of the optic nerve, or attenuation of the retinal vessels. The four tested members of the family, including the sister with MELAS syndrome as well as the original patient and her daughter and son, were found to have the A to G 3243 mt DNA mutation heteroplasmic with wild-type mt DNA.This report amplifies and corroborates some of the ophthalmic features of MELAS syndrome by describing geographic atrophy of the macula in families with the syndrome. The symptoms associated with MELAS syndrome typically appear in childhood and often cause death by the fourth decade.3 Two mt DNA mutations have been associated with this syndrome and are both located in the tRNAleu (UUR) gene. In 80% of cases, the mutation is an A to G transition at mt-3243, and in 10% of cases, the mutation is an A to G transition at mt-3271.4 Many maternal relatives of patients with MELAS syndrome exhibit a scarcity of symptoms secondary to the presence of “heteroplasmy,” a mixture of mutant and wild-type intracellular mitochondria. The mutant phenotype is expressed only when an intracellular threshold of mt DNA has been reached. Mitochondrial mutation is uncommon in the general population; however, patients with the mutation were recently shown to have a wider range of phenotypic diversity than previously reported.5 Nutritional supplementation should be considered, although no large, well-designed trial has studied its efficacy.1 Atrophic macular pigment epithelial atrophy associated with motility disorders and deafness should precipitate an evaluation for mitochondrial disorders.

Helicoidal peripapillary chorioretinal degeneration: electrophysiology and psychophysics in 17 patients

AIMSTo characterise retinal function using electrophysiological and psychophysical tests in 17 patients with helicoidal peripapillary chorioretinal degeneration.METHODSThe electroretinogram (ERG) was recorded using gold foil corneal electrodes. The electro-oculogram (EOG) was...

G106R rhodopsin mutation is also present in Spanish ADRP patients.

A large family affected with autosomal dominant retinitis pigmentosa (ADRP) with a sectorial phenotype showed a previously described (G to A) mutation in the rhodopsin gene resulting in the substitution of a glycine residue by an arginine in codon 106 of rhodopsin. This mutation shows some unusual characteristics, such as initial pathology of the inferior retina, superior visual field with normal disc and retinal vessels, and ERG findings that show a modest reduction in both cone and rod amplitudes with normal implicit times. The Gly 106 Arg mutation has been previously reported in American and British patients. Its presence in a Spanish ADRP family confirms that it and its homogeneous associated phenotype are geographically widespread.

Macular Dystrophy Associated with Mutations at Codon 172 in the Human Retinal Degeneration Slow Gene

Recently, mutations in the retinal degeneration slow (rds) gene which codes for peripherin-rds have been implicated as a cause of autosomal dominant retinitis pigmentosa. Because this gene is expressed in both rods and cones, mutations in the rds gene might be expected to cause degeneration affecting either the scotopic or photopic systems. Mutations at codon 172 of the rds gene have been identified in three families with autosomal dominantly inherited, progressive macular dystrophy. Affected individuals underwent ophthalmic examination, scotopic perimetry, dark adaptometry, measurement of color-contrast sensitivity, and electroretinography to characterize the photoreceptor dysfunction. In all but one affected member, symptoms of progressive central visual loss developed in the third or fourth decade of life accompanied by central scotoma and well-demarcated atrophy of the retinal pigment epithelium and choriocapillaris of the macula. In general, cone and rod thresholds were elevated, and color-contrast sensitivity was absent in the central visual field. Peripherally, the scotopic sensitivities were normal, as was the recovery from bleach. Cone electroretinograms were diminished in amplitude, and delayed in all affected adults except one. Rod electroretinograms were normal or near normal in amplitude, and had normal implicit times. Affected asymptomatic children had macular changes, abnormal color-contrast sensitivity, and reduced pattern and cone electroretinograms. These results indicate that mutations in the rds gene can be expressed as a macular dystrophy, with evidence of primary cone dysfunction and preservation of peripheral rod function.

Autosomal Dominant Retinitis Pigmentosa

Four types of autosomal dominant retinitis pigmentosa (RP) were discernible in 84 patients by clinical, electrophysiologic, and psychophysical criteria. Type 1 patients showed diffuse fundus pigmentary changes and nondetectable electroretinographic (ERG) cone and rod functions. Both type 2 and type 3 patients showed fundus pigmentary changes more apparent within the inferior retina. Type 2 patients showed marked loss in rod ERG function, with prolonged cone implicit times, whereas type 3 patients showed substantial rod function and normal cone implicit times. Type 4 patients had a funduscopically and functionally "delimited" disease, with substantial cone and rod ERG amplitudes and normal implicit times. The classification of dominantly inherited RP is important for studies of natural history in disease progression, for patient counseling, and for various laboratory investigations of patients with RP in which patient homogeneity should be maximized.

Progressive External Ophthalmoplegia and Benign Retinal Pigmentation

A 17-year-old boy had progressive external ophthalmoplegia, normal visual acuity, and a pigmentary retinopathy. Neurologic evaluation showed an abnormal electroencephalogram with diffuse slow (theta) waves. Myasthenia gravis was excluded. Fluorescein angiography showed a normal vascular pattern with diffuse hyper- and hypopigmentation. Results of retinal testing, including color vision, visual fields, electroretinography, and dark adaptometry, were within normal limits except for a slightly subnormal electroretinogram with normal implicit times. Progressive external ophthalmoplegia may be associated with either progressive or non-progressive pigmentary retinopathies, and adequate evaluation of retinal function in these cases must be obtained.