Not All That Flickers Is Snow.

ABSTRACT: A woman presented with bilateral visual disturbances that had been diagnosed as visual snow. Dilated ophthalmic examination and multimodal imaging were strongly suggestive of birdshot chorioretinopathy, meriting initiation of systemic immunomodulatory therapy. Visual snow requires a thorough ophthalmologic exam to exclude other ocular diseases.

ABSENCE OF MACULAR DEGENERATION IN A PATIENT WITH ACERULOPLASMINEMIA.

PURPOSE: To describe the clinical, histological, electrophysiologic, and multimodal imaging findings in a 76-year-old patient with aceruloplasminemia with low genetic risk of age-related macular degeneration (AMD). METHODS: Clinical examination as well as multimodal imaging including fundus photography, optical coherence tomography, fluorescence lifetime imaging ophthalmoscopy imaging, and full-field and multifocal electroretinography were performed on one patient with aceruloplasminemia. The ceruloplasmin gene was sequenced to confirm a known mutation. Single nucleotide polymorphism genotyping of known AMD risk alleles was performed to characterize the AMD risk profile of the patient. Prussian blue staining in postmortem retinal sections was used to confirm iron accumulation. RESULTS: A homozygous mutation in the ceruloplasmin gene was detected at position c.395-1 G>A. The clinical assessment and imaging of the patient did not show any findings of AMD. Fundus examination revealed yellow flecks in the midperiphery with notable absence of macular drusen or geographic atrophy. Genotyping for AMD risk alleles revealed a low AMD risk profile. Histopathologic analysis confirms iron accumulation in retinal pigment epithelial cells. CONCLUSION: In contrast to a previous report, these findings suggest that neither aceruloplasminemia nor iron accumulation was sufficient to cause AMD in this patient.

The electrooculogram.

The electrooculogram (EOG) measures the cornea-positive standing potential relative to the back of the eye. By attaching skin electrodes outside the eye near the lateral and medial canthus, the potential can be measured by having the patient move the eyes horizontally a set distance. The voltage becomes smaller in the dark, reaching its lowest potential after 8-12min, the so-called dark trough. When the lights are turned on, the potential rises, reaching a peak by about 10min. When the size of the light peak is compared to the dark trough, the normal ratio should be near 2:1. A light peak:dark trough ratio of less than 1.7 is considered abnormal. The origin of electrooculographic potentials is the pigment epithelium of the retina interacting with the midretina. The light rise of the potential requires both a normal pigment epithelium and normal midretinal function. The most common use of the electrooculogram is to confirm Best disease. Best disease is identified by the appearance of an egg-yellow fundus and can be confirmed by recording both an electroretinogram (ERG) and electrooculogram (EOG). The ERG will be normal and the EOG will be abnormal. The EOG is also used for tracking eye movement.

Electroretinograms.

The electroretinogram (ERG) is an electrical response of the retina to photic stimulation. A flash of light or bright appearance of a pattern elicits a biphasic negative/positive waveform. The a-wave originating in the receptor level of rods and cones is the initial large negative wave. The b-wave originating in the midretina is the following large positive component. Protocols include full-field and multifocal ERGs. Full-field ERGs are recorded if one is most interested in the global health of the retina, such as in retinitis pigmentosa. A limitation of the full-field ERG is that the recording is a massed potential from the whole retina. Multifocal ERGs can map small scotomas in the central 40+ degrees of visual field. Abbreviated methods are used with infants and in the operating room as part of an exam under anesthesia. The effects of toxic medications can be detected and quantified using ERGs. The ERG is useful to assess cases of retinal foreign bodies and trauma to estimate the extent of retinal dysfunction. Foreign bodies affect retinal function depending on the extent of trauma to the retina and the location and composition of the object. Systemic metabolic disorders usually reduce ERG b-wave amplitudes, particularly the scotopic dim flash ERGs.

Visually evoked potentials.

The term visually evoked potential (VEP) refers to electrical potentials recorded from scalp overlying visual cortex that have been extracted from the electroencephalogram by signal averaging. Usually the recording electrode is placed on the midline of the occipital scalp at the back of the head. VEPs are used to quantify the functional integrity of the optic nerves, pathways to the visual cortex of the brain, and occipital cortex. Any abnormality that affects the visual pathways or visual cortex in the brain can affect the VEP. Examples include slowing neuronal transmission, such as produced by myelin plaques common in multiple sclerosis, or gliomas on optic nerves in neurofibromatosis slowing the speed of the VEP wave peaks. Compression of the optic pathways, such as from hydrocephalus or from a pituitary tumor, affects the VEP. There are several methods of recording VEPs. In patients over about 3 years of age VEPs are usually recorded using a video monitor presenting patterned stimuli. In sedated patients and infants, flashes of light from a strobe flash or an array of LEDs are used to stimulate the eye. Multifocal VEPs expand the visual field topographic mapping to beyond 40 degrees of the central visual field.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.

ATF6 Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement.

PURPOSE: Photoreceptor degeneration (PRD) is a genetically heterogeneous retinal disorder. Although a number of genes involved in PRD have been identified, their genetic basis remains unknown in a significant number of patients. In this study, we aimed to identify novel disease-causing genes of PRD. METHODS: Comprehensive ocular examinations were performed in a 2-year-old patient diagnosed with early onset PRD. Retinal capture sequencing was performed to screen causative mutations in known retinal disease-causing loci. Whole-exome sequencing (WES) and a series of variant-filtering strategies were applied for identifying novel disease-causing genes. Retina ATF6 expression was confirmed by immunohistochemistry. RT-PCR was performed to identify ATF6 mRNA in the patient. RESULTS: The patient showed typical PRD features, with macular involvement and ellipsoid zone irregularities. Results of retinal capture sequencing were negative. WES data led to identification of biallelic loss-of-function mutations in the ATF6 gene. The first variant generates a premature stop codon (NCBI accession no. NM_007348: c.1126C>T, p.R376*) and the second variant affects a splicing donor site (NM_007348: c.1533+1G>C). Sanger sequencing confirmed the 2 alleles are from 1 parent each. Both of the variants are extremely rare in the population. The splicing variant causes either intron inclusion or exon skipping in the patient, thus severely disrupting ATF6 functional domains. ATF6 is expressed in three neuronal cell layers of mouse retina. CONCLUSIONS: Our results support ATF6 as a novel disease-causing gene for PRD and suggest that disrupted protein quality control mechanisms may be a novel pathological mechanism underlying human retinal degeneration.

Ophthalmologic features of Vici syndrome.

PURPOSE: To report and compile the ophthalmological features critical to diagnosis of Vici syndrome, a rare congenital disorder characterized principally by agenesis of the corpus callosum, cataracts, cardiomyopathy, immune defects, and hypopigmentation. METHODS: A child with Vici syndrome (OMIM 242840) is reported with emphasis on the ophthalmologic evaluation. Ophthalmologic assessments including fundus examination, visual evoked potentials (VEPs), and ocular coherence tomography are presented. These findings are compared with those identified in other published cases of children with Vici syndrome. RESULTS: Ophthalmologic findings included bilateral nuclear and anterior polar cataracts, bilateral optic nerve atrophy, and mild fundus hypopigmentation. Evoked potentials recorded across the mid-occipital scalp demonstrated misrouting of optic pathways typical of albinism. Optical coherence tomography exhibited a poorly defined fovea demonstrating a lesser degree of foveal depression also consistent with ocular albinism. Review of reported children with Vici syndrome identifies bilateral cataracts, nystagmus, fundus hypopigmentation, visual impairment, and optic nerve hypoplasia as common ophthalmologic features. CONCLUSIONS: Ophthalmologic findings are critical to the diagnosis of Vici syndrome. Most common are bilateral cataracts and relative fundus hypopigmentation. VEPs can identify misrouting of optic pathways typical of ocular albinism, thereby establishing the diagnosis in challenging cases.

An inherited disorder with splenomegaly, cytopenias, and vision loss.

We describe a novel inherited disorder consisting of idiopathic massive splenomegaly, cytopenias, anhidrosis, chronic optic nerve edema, and vision loss. This disorder involves three affected patients in a single non-consanguineous Caucasian family, a mother and two daughters, who are half-sisters. All three patients have had splenectomies; histopathology revealed congestion of the red pulp, but otherwise no abnormalities. Electron microscopic studies of splenic tissue showed no evidence for a storage disorder or other ultrastructural abnormality. Two of the three patients had bone marrow examinations that were non-diagnostic. All three patients developed progressive vision loss such that the two oldest patients are now blind, possibly due to a cone-rod dystrophy. Characteristics of vision loss in this family include early chronic optic nerve edema, and progressive vision loss, particularly central and color vision. Despite numerous medical and ophthalmic evaluations, no diagnosis has been discovered.

Multifocal electroretinograms.

A limitation of traditional full-field electroretinograms (ERG) for the diagnosis of retinopathy is lack of sensitivity. Generally, ERG results are normal unless more than approximately 20% of the retina is affected. In practical terms, a patient might be legally blind as a result of macular degeneration or other scotomas and still appear normal, according to traditional full field ERG. An important development in ERGs is the multifocal ERG (mfERG). Erich Sutter adapted the mathematical sequences called binary m-sequences enabling the isolation from a single electrical signal an electroretinogram representing less than each square millimeter of retina in response to a visual stimulus. Results that are generated by mfERG appear similar to those generated by flash ERG. In contrast to flash ERG, which best generates data appropriate for whole-eye disorders. The basic mfERG result is based on the calculated mathematical average of an approximation of the positive deflection component of traditional ERG response, known as the b-wave. Multifocal ERG programs measure electrical activity from more than a hundred retinal areas per eye, in a few minutes. The enhanced spatial resolution enables scotomas and retinal dysfunction to be mapped and quantified. In the protocol below, we describe the recording of mfERGs using a bipolar speculum contact lens. Components of mfERG systems vary between manufacturers. For the presentation of visible stimulus, some suitable CRT monitors are available but most systems have adopted the use of flat-panel liquid crystal displays (LCD). The visual stimuli depicted here, were produced by a LCD microdisplay subtending 35-40 degrees horizontally and 30-35 degrees vertically of visual field, and calibrated to produce multifocal flash intensities of 2.7 cd s m(-2). Amplification was 50K. Lower and upper bandpass limits were 10 and 300 Hz. The software packages used were VERIS versions 5 and 6.

A novel method for screening the multifocal electroretonogram in patients using hydroxychloroquine.

PURPOSE: To evaluate retinal function in patients on hydroxychloroquine using multifocal electroretinography. METHODS: A retrospective chart review was performed for 23 patients (46 eyes) on hydroxychloroquine therapy and referred for multifocal electroretinogram (mfERG) testing. Duration of treatment, daily hydroxychloroquine dose, visual acuity, fundus examination, color vision testing, Amsler grid testing, visual field examination, and fluorescein angiography results were obtained when available. Multifocal electroretinogram response amplitudes were calculated for the central and paracentral regions and compared with previously published normal values. The central and paracentral regions of the mfERG color difference plot, which assigns colors to localized areas of the mfERG based on deviation from normal, were assessed using a novel Color Difference Plot Scoring System which relies on the color pattern observed within each region. RESULTS: Ninety-two regions were assessed for response amplitudes, 31 of which showed a depressed response amplitude. Of the 17 eyes which had at least one region with a depressed response amplitude, clinical examination findings were relatively benign. Color difference plot scoring showed strong agreement with response amplitude, with a Color Difference Plot Scoring System score of 2 or 3 showing 93.55% sensitivity and 60% specificity for a depressed response amplitude. Interrater reliability of the scoring system as measured by Kendall's W coefficient of concordance was 0.6484 (P < 0.00001). CONCLUSION: The mfERG appears to be able to detect decreased retinal function in hydroxychloroquine patients with normal clinical examinations, and may be useful in identifying patients that require close monitoring for the development of clinically relevant toxicity. The Color Difference Plot Scoring System may be used as a tool to aid in the interpretation of results of the mfERG in the clinic setting.

Autosomal dominant cone dystrophy caused by a novel mutation in the GCAP1 gene (GUCA1A).

PURPOSE: To describe the clinical features and genetic analysis of a family with an autosomal dominant cone dystrophy (adCD). METHODS: Selected members of a family with an autosomal dominant cone dystrophy underwent ophthalmic evaluation. Blood samples were obtained, genomic DNA was isolated, and genomic fragments were amplified by PCR. Linkage to locus D6S1017 was established. DHPLC mutational analysis and direct sequencing were used to identify a mutation in GUCA1A, the gene encoding the guanylate cyclase activating protein 1 (GCAP1). RESULTS: Of 24 individuals who are at risk of the disease in a five generation family, 11 members were affected. Clinical presentations included photophobia, color vision defects, central acuity loss, and legal blindness with advanced age. The disease phenotype was observed in the second and third decades of life and segregated in an autosomal dominant fashion. An electroretinogram performed on one proband revealed profoundly subnormal and prolonged photopic and flicker responses, but preserved scotopic ERGs, consistent with a cone dystrophy. Mutational analysis and direct sequencing revealed a C451T transition in GUCA1A, corresponding to a novel L151F mutation in GCAP1. Like the E155G mutation, this mutation occurs in the EF4 hand domain, a region of GCAP1 critical in conferring calcium sensitivity to the protein. The leucine at this position is highly conserved among vertebrate guanylate cyclase activating proteins. CONCLUSIONS: A novel L151F missense mutation in the EF4 high affinity Ca2+ binding site of GCAP1 is linked to adCD in a large pedigree. The cone dystrophy in this family shares clinical and electrophysiologic characteristics with other previously described adCD caused by mutations in GUCA1A.

Persistent severe visual and electroretinographic abnormalities after intravenous Cisplatin therapy.

A 55-year-old man inadvertently received four times the intended dose of intravenous cisplatin as part of a chemotherapeutic salvage regimen for non-Hodgkin lymphoma. Immediately after treatment, he developed bilateral irreversible visual loss. Visual acuity was 20/300 in OU and visual fields showed central scotomas bilaterally. Although the fundus examination findings were normal, an electroretinogram showed markedly reduced a-wave amplitudes and absent b-waves. At autopsy 8 months later, photoreceptors appeared normal. Splitting of the outer plexiform layer was present, consistent with loss of the ERG b-wave. This is the first reported case of persistent visual loss from intravenous cisplatin toxicity and the first case to describe ocular histopathologic findings.