PIII and Derived PII Analysis in a Patient with Retinal Dysfunction with Supernormal Scotopic ERG

Purpose: To present electroretinographic (ERG) findings in a patient with retinal dysfunction with supernormal scotopic ERG, and to analyze rod and cone PIII components and rod inner nuclear layer (derived PII) responses. Patient: A Japanese 11-year-old girl complained of poor visual acuity. There was no parental consanguinity in her family. The corrected visual acuity was 0.7 in both eyes. No abnormal finding was observed in both fundi. Methods: The patient underwent full-field ERGs. Rod and cone a-waves were analyzed using photoreceptor models. The derived PII responses were analyzed using a technique described by Hood and Birch. Results: In the photopic ERG, responses to single flash and 30-Hz flicker were attenuated. In the scotopic ERG, b-wave was supernormal in amplitude in response to intense flashes, but smaller than normal and markedly delayed over a lower range of flash intensities. By the PIII analysis, phototransductions (values of S) of both rod and cone were remarkably decreased. The derived PII responses for this patient were larger than the responses for normal subjects, and the onset of the PII responses in this patient are significantly delayed compared to those in normal subjects. Conclusions: The ophthalmological findings in this patient are consistent with previous publications of this disease. Although it has been reported that the sites of disease action were beyond the outer segment (values of S were within the normal range), our results suggest that photoreceptors could be involved in sites of disease action in at least some patients with this disease.     

Clinical electroretinography in diabetic retinopathy: a review

The electroretinogram (ERG) is a noninvasive, objective technique to evaluate retinal function that has become increasingly important in the study of diabetic retinopathy.We summarize the principles and rationale of the ERG, present findings from recent clinical studies that have used the full-field ERG, multifocal ERG, and pattern ERG to evaluate neural dysfunction in patients with diabetes, and weigh the strengths and limitations of the technique as it applies to clinical studies and management of patients with diabetic retinopathy. Taken together, ERG studies have provided convincing evidence for dysfunction of the neural retina in patients with diabetes, including those who have no clinically-apparent retinal vascular abnormalities. Recent full-field ERG findings have pointed to the intriguing possibility that photoreceptor function is abnormal in early-stage disease. Pattern ERG data, in conjunction with recently developed photopic negative response analyses, indicate inner retina dysfunction. In addition, multifocal ERG studies have shown spatially localized neural abnormalities that can predict the location of future microaneurysms. Given the insights provided by the ERG, it is likely to play a growing role in understanding the natural history of neural dysfunction in diabetes, as well as providing an attractive outcome measure for future clinical trials that target neural preservation in diabetic retinopathy.     

Full-field ERG in patients with Batten/Spielmeyer-Vogt disease caused by mutations in the CLN3 gene

Purpose: To investigate, using full-field ERG, the retinal function in patients with Batten/Spielmeyer-Vogt disease caused by mutations in the CLN3 gene. Methods: Batten disease status of five patients was confirmed by the presence of vacuolated lymphocytes in peripheral blood and the identification of mutations in the Batten disease gene ( CLN3 ). Visual acuity, fundus appearance, and full-field ERG were examined in all patients (age 4-19 years). The examination was repeated in one patient after 16 months. Results: Three unrelated patients were homozygous for the most common mutation in CLN3, the 1.02 kb deletion; two patients (sisters) were heterozygous for the 1.02 kb deletion and an as yet unidentified mutation in the CLN3 gene. Full-field ERG recordings in all five patients demonstrated no rod responses and only small remaining cone responses, which could be detected with 30 Hz-flicker stimulation. Re-examination of a six-year-old girl after 16 months revealed a fast progression of the retinal degeneration. Conclusion: Full-field ERG recordings in Batten disease patients, both homozygous and heterozygous for the 1.02 kb deletion in the CLN3 gene, confirm retinal degeneration to be severe, widespread, and with a rapid progression early in the disease course. The onset of visual failure may be delayed when compared to the classic disease course, particularly in patients who are not homozygous for the most common CLN3 mutation, a 1.02 kb deletion. In that case, the disease progression in terms of other symptoms may also be further delayed.     

Retinal dysfunction in combined methylmalonic aciduria and homocystinuria (Cblc) disease: a spectrum of disorders

BACKGROUND: Cobalamin C methylmalonic aciduria with homocystinuria (cblC disease) is a rare hereditary inborn error of cobalamin metabolism, characterised by neurological, haematological and ophthalmological abnormalities. PATIENTS AND METHODS: Three consecutive patients with Cblc disease were examined. Investigations included slit lamp and fundus examination and full-field ERG. RESULTS: A maculopathy associated with both photopic and scotopic abnormal ERG was present in two cases and a salt and pepper retinopathy with abnormal photopic ERG was detected in the third patient. CONCLUSIONS: Despite early treatment and regular metabolic controls, all our patients exhibited both retinal and ERG abnormalities. There was no correlation between funduscopic appearance and the type of photoreceptor dysfunction. A literature review disclosed a retinopathy in 29 / 70 cases with cblC disease, with an abnormal ERG in 8 of the 12 tested cases, most with retinopathy. Retinal dysfunction in cblC disease may be more frequent than previously thought, and can involve cones only or both rods and cones. We recommend a formal ocular examination with full-field ERG in patients with Cblc disease.     

Unilateral electronegative ERG of non-vascular aetiology

BACKGROUND: Full field and pattern electroretinograms (ERG, PERG) are performed to assess generalised retinal function and macular function, respectively. An (electro) negative full field ERG usually describes an ISCEV standard maximal response in which the b-wave is smaller than a normal or minimally reduced a-wave and indicates dysfunction that is post-phototransduction. The most common cause of a unilateral negative ERG is central retinal artery occlusion (CRAO) or birdshot chorioretinopathy (BCR). This study examines the clinical and electrophysiological features of patients with unilateral negative ERG who do not have CRAO or BCR. METHODS: 12 patients were ascertained with a unilateral negative ERG in whom a vascular aetiology and BCR were excluded. Most presented with symptoms of central retinal dysfunction. In 11 of the 12 patients additional long duration photopic stimuli were used to test cone system ON and OFF responses. RESULTS: All 12 patients had unilateral electronegative bright flash full field ERGs indicating total or relative preservation of rod photoreceptor function, but dysfunction post-phototransduction. Seven of these patients had non-specific inflammatory changes in the eye with the negative ERG. Six patients, including five with inflammatory signs, had involvement of the cone ON response with complete preservation of cone OFF responses. A further three patients showed evidence of cone ON response abnormality with less severe OFF response involvement. CONCLUSION: The ERGs in this heterogeneous group of patients predominantly showed post-phototransduction involvement of the ON pathways. Sparing of the cone OFF response was often observed. The majority of patients had signs of previous inflammation and it is speculated that these highly unusual unilateral changes may be mediated via an autoimmune mechanism.     

L- and M-cone driven large-field and multifocal electroretinograms in sector retinitis pigmentosa

The purpose was to study long- (L-) and middle-wavelength-sensitive (M-) cone-driven ERGs and multifocal ERGs (mfERGs) in sector retinitis pigmentosa (sector RP). Two eyes of two patients with sector RP were measured. ERG responses were measured to stimuli which modulated exclusively the L- or the M-cones or the two simultaneously (both in-phase and in counter-phase) with predefined cone contrast leaving the S-cones unmodulated. For comparison, mfERGs were recorded with the visual evoked response imaging system, using a resolution of 61 hexagonal elements within a 30-degree visual field. The two sector RP patients exhibited a general reduction of the L-/M-cone driven ERG sensitivity. Patient 1 exhibited a slight delay of the M-cone driven ERG. In patient 2, L-cone driven ERG was moderately delayed. In both patients, the phases of the L- and the M-cone driven ERGs were positively correlated with cone contrast. The data of the L/M-cone driven ERGs, the mfERGs and the standard photopic ERGs matched each other qualitatively. We conclude that the sector RP patients were clearly different from normal for both the L- and M-cone driven large-field and the multifocal ERGs. Previously, we investigated L- and M-cone driven ERGs in patients with generalized RP and found several features that differ from the sector RP patients. Our data are in agreement with our previous proposition that amplitudes and phases of the L- and M-cone driven ERGs can be differently affected by retinal disorders.     

Prognostic significance of aqueous humour lactic dehydrogenase activity.

The lactic dehydrogenase (LDH) activity of the aqueous humour has been estimated in both eyes of 7 patients having uniocular retinoblastoma. In 1 patient the aqueous humour LDH activity in the healthy eye was above normal, but there was no clinical evidence of malignancy. Tumour tissue was detected in this eye 9 months later, and the aqueous humour showed a rise in LDH activity. A high LDH activity persisted even after irradiation, though no tumour tissue was visible ophthalmoscopically. It is suggested that the estimation of the LDH activity in the aqueous humour of the healthy eye in cases of uniocular retinoblastoma might be of value in the early detection of a bilateral retinoblastoma.     

Juvenile X-linked retinoschisis with normal scotopic b-wave in the electroretinogram at an early stage of the disease

PURPOSE: To report four cases of genetically verified juvenile X-linked retinoschisis (XLRS) with normal scotopic b-waves in full-field ERG, including one patient with a novel mutation (W50X) in the RS1 gene. METHODS: Four XLRS patients from different families were examined with regard to visual acuity, kinetic perimetry, fundus photography, full-field ERG, and OCT. Two of these patients were also examined with multifocal-ERG (mfERG). Mutations in the RS1 gene were identified by sequence analysis. RESULTS: The full-field ERG presented normal b-wave amplitudes on scotopic white-light stimulation. OCT and mfERG presented macular schisis and macular dysfunction. Genetic analysis revealed a deletion of exon 1 and the promotor region in one patient and mutations giving rise to the amino acid substitutions R209C and W96R in two others. The fourth patient carried a novel mutation in exon 3 of the RS1 gene (nt 149 G-->A), causing the introduction of a stop codon after amino acid 49 in the RS protein. CONCLUSION: Four young males with XLRS did not present with reduction in the scotopic b-wave amplitude on full-field ERG, which is otherwise often considered to be characteristic of the disease. Full-field ERG and molecular genetic analysis of the RS1 gene still remain the most important diagnostic tools for this retinal disorder, although the OCT can be a valuable complement in order to make the diagnosis at an early stage.     

Retinal dysfunction in a presymptomatic patient with Huntington’s disease

Purpose

Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances. Studies have shown retinal abnormalities in patients and mouse models with HD; however, to our knowledge, no prior research papers evaluated retinal structure and function in a presymptomatic patient with HD. The aim of this report is to present a case of retinal dysfunction in a presymptomatic patient with HD.

Methods

We investigated retinal structure and function in a 25-year-old male who tested positive for the gene that causes HD, but did not have any symptoms normally associated with HD. Vision and ocular testing included a comprehensive dilated ophthalmic examination, 24-2 full-threshold Humphrey visual field, spectral-domain optical coherence tomography (SD-OCT), fundus photography, full-field electroretinogram (ERG), and multifocal electroretinogram (mfERG).

Results

Visual electrophysiology testing showed rod and cone functional anomalies in both eyes. Full-field ERG amplitudes were subnormal in both eyes for the dark-adapted (DA) 0.01 ERG, DA 3 ERG, DA 3 oscillatory potentials (OPs), DA 10 ERG, light-adapted (LA) 3 ERG, and LA 30 Hz flicker, but peak times for the six standard ERG responses were not significantly different from normals. mfERGs revealed functional anomalies of the central retina with attenuated P1 amplitudes for five of the six concentric rings in the right eye and all six rings in the left eye. mfERG P1 peak times were normal at all eccentricities. Dilated fundus examination, SD-OCT, and fundus photography were unremarkable in both eyes. The visual field was normal in the right eye, but there was a mild paracentral field defect in the left eye.

Conclusions

Our results illustrate that the ERG and mfERG detected early retinal dysfunction in a presymptomatic patient with HD consistent with electroretinogram findings in animal models of HD. However, our report was limited to one patient and additional studies are needed to verify whether the ERG and/or mfERG can uncover neural dysfunction before motor, behavioral, and cognitive abnormalities are discernible in patients with HD.

     

Molekulargenetische Ergebnisse bei Patienten mit kongenitalen Zapfenfunktionsstörungen

PURPOSE: This study compares clinical and molecular genetic findings in patients with congenital cone dysfunction. METHODS: In this study 28 patients underwent a basic ophthalmologic examination. Except for a 1-year-old boy, color vision, perimetry, and full-field ERG (ISCEV standard) were evaluated in all patients. Blood samples were taken for molecular genetic analysis of the CNGA3, CNGB3, or GNAT2 genes. RESULTS: Two patient groups could be distinguished: patients without and with residual cone function in the ERG. In 14 of 17 patients without cone function, mutations in one of the three genes were detected, and except for one patient mutations in both alleles could be determined. In these patients, visual acuity was reduced to 20/400 and color discrimination was absent. In 2 of 11 patients with residual cone function, mutations in one allele of the CNGB3 gene were detected. It is of interest that 6 of 16 patients with mutations perceived their disease as progressive; in three of them we could determine a progression. Only in 4 of 16 patients was the ocular fundus normal. The other patients with mutations presented with central pigment irregularities, attenuated vessels, or pale optic disk. CONCLUSION: In patients with congenital cone dysfunction without cone function in the ERG, an analysis of the CNGA3, CNGB3, or GNAT2 gene is advisable. In contrast, patients with residual cone function did not show clear association with mutations in one of the three genes. In patients with mutations, retinal alterations and nystagmus are frequent. In contrast to the designation of these disorders as stationary, in some patients with mutations in the CNGA3 and CNGB3 gene slow progression was observed.