Functional observations in vitamin A deficiency: diagnosis and time course of recovery.

AIMS: To describe the effects of vitamin A deficiency (VAD) on retinal function and the subsequent recovery following treatment in three patients with systemic conditions (two with Crohn disease; one secondary to IgE syndrome). METHODS: Electrophysiological testing (including pattern electroretinogram, PERG; electroretinogram, ERG; visual-evoked potential) established the diagnosis of VAD. Repeat testing was carried out in two patients to monitor the time course of recovery following intramuscular vitamin A injection. The third patient had repeat recordings following 13 months of oral supplementation. RESULTS: All three patients initially displayed a characteristic absence of rod function associated with VAD. In addition, delayed and reduced amplitude cone ERGs, loss of short wavelength cone (S-cone) function and subnormal macular function were observed in two patients. Restoration of rod and generalised cone function was rapid in the two patients who received intramuscular injection, with normalisation of some electrophysiological responses after only 3 days. Normal S-cone amplitudes and cone latencies were reached within 12 days of vitamin A injection. Macular function returned to within normal limits by 12 days postinjection in one patient, but remained mildly subnormal in the second patient. Full recovery was present after 13 months oral supplementation in the third patient. CONCLUSIONS: Novel observations regarding dark-adapted cone function, S-cone function, and PERG are presented. The differences between the effects of VAD on rod and cone function, and their rate of recovery, may reflect differences in the visual cycle between the two photoreceptor classes. The importance of rapidly and accurately diagnosing VAD, a treatable condition, is noted.

Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy.

Isotretinoin (13-cis retinoic acid) is frequently prescribed for severe acne [Peck, G. L., Olsen, T. G., Yoder, F. W., Strauss, J. S., Downing, D. T., Pandya, M., Butkus, D. & Arnaud-Battandier, J. (1979) N. Engl. J. Med. 300, 329-333] but can impair night vision [Fraunfelder, F. T., LaBraico, J. M. & Meyer, S. M. (1985) Am. J. Ophthalmol. 100, 534-537] shortly after the beginning of therapy [Shulman, S. R. (1989) Am. J. Public Health 79, 1565-1568]. As rod photoreceptors are responsible for night vision, we administered isotretinoin to rats to learn whether night blindness resulted from rod cell death or from rod functional impairment. High-dose isotretinoin was given daily for 2 months and produced systemic toxicity, but this caused no histological loss of rod photoreceptors, and rod-driven electroretinogram amplitudes were normal after prolonged dark adaptation. Additional studies showed, however, that even a single dose of isotretinoin slowed the recovery of rod signaling after exposure to an intense bleaching light, and that rhodopsin regeneration was markedly slowed. When only a single dose was given, rod function recovered to normal within several days. Rods and cones both showed slow recovery from bleach after isotretinoin in rats and in mice. HPLC analysis of ocular retinoids after isotretinoin and an intense bleach showed decreased levels of rhodopsin chromophore, 11-cis retinal, and the accumulation of the biosynthetic intermediates, 11-cis and all-trans retinyl esters. Isotretinoin was also found to protect rat photoreceptors from light-induced damage, suggesting that strategies of altering retinoid cycling may have therapeutic implications for some forms of retinal and macular degeneration.

Photopic and scotopic light detection in patients with seasonal affective disorder and control subjects.

BACKGROUND: Retinal sensitivity may play a role in the pathogenesis of seasonal affective disorder (SAD) and response to light therapy. METHODS: Using a dark adaptation procedure, SAD patients and normal control subjects were tested in the winter and summer, with patients retested after light treatment. The eyes were preadapted to bright light followed by 30 min in darkness, during which subjects detected a dim signal titrated around the detection threshold. Photopic (cone-mediated) and scotopic (rod-mediated) components of the data were identified by nonlinear exponential curve fits to successive threshold estimates. RESULTS: Patients (n = 24) showed significantly lower cone and rod thresholds in the summer than winter, while control subjects (n = 12) showed a similar trend. Relative to the control subjects, however, patients were supersensitive in winter (lower cone final threshold, faster rod recovery). Clinical responders to morning light showed a small summer-like increase in cone sensitivity, whereas nonresponders became subsensitive. In comparison to darker-eyed patients, blue-eyed patients showed a larger summertime increase in cone sensitivity and a similar trend after response to morning light. CONCLUSIONS: Heightened retinal sensitivity with increased light exposure, and supersensitivity of patients relative to control subjects in winter, may play roles in the pathogenesis of winter depression and the action of therapeutic light.

Rod plateaux during dark adaptation in Sorsby's fundus dystrophy and vitamin A deficiency.

PURPOSE: To investigate the transitory plateaux observed during dark adaptation after partial bleaches in Sorsby's fundus dystrophy (SFD) and in systemic vitamin A deficiency (VAD). METHODS: Psychophysical dark adaptation functions were measured after bleaching exposures isomerizing from 2% to 99% of the rhodopsin. Narrow-band stimuli of 1.7 degrees diameter and 200 msec duration were presented at an eccentricity of 30 degrees. RESULTS: After a full bleach, the patients showed typical dark adaptation abnormalities reported for these diseases. The cone recovery was slowed, and the time to the rod-cone break was delayed; the final phase of rod recovery was also slowed but led to a normal final rod threshold. After partial bleaches, short wavelength stimuli produced a biphasic recovery function, with an initial rapid component and plateau, followed by a subsequent break-off and eventual return to prebleach thresholds. Action spectra obtained during the plateaux were consistent with thresholds for shorter wavelength stimuli mediated by rods and thresholds for longer wavelength stimuli mediated by cones. In the patient with VAD, vitamin A supplementation led to accelerated recovery and disappearance of the transitory rod plateaux. CONCLUSIONS: The biphasic dark adaptation functions resulting from fractional bleaches in SFD and VAD appear superficially similar to the classic biphasic adaptation functions obtained with full bleaches. However, thresholds during the plateaux are lower than the cone threshold, and action spectra indicate rod mediation. These transitory rod plateaux may increase our understanding of the normal visual cycle and its perturbation in retinal disease.

Red blood cell fatty acid levels in patients with autosomal dominant retinitis pigmentosa.

Fatty acid profiles were determined in red blood cell (RBC), plasma lipids and lipid fractions from 50 patients with autosomal dominant retinitis pigmentosa (ADRP) and 20 normal-sighted controls. In plasma of affected patients, significant increases in omega 6 long-chain derivatives compared to controls resulted in elevated fatty acid unsaturation whereas, in RBCs, significant decreases in the levels of omega 6 and omega 3 long-chain polyunsaturates and a reduced unsaturation index were demonstrated (P < 0.01). The disproportionate levels of long-chain fatty acids in plasma vs. RBCs were consistent with abnormal function of acyl group transfer from plasma lipids to target tissues such as RBCs or, possibly, retina. Metabolic lipid anomalies were evaluated in two sub-groups of patients with ADRP; ten with the highest and ten with the lowest RBC lipid levels of the omega 3 fatty acid, docosahexaenoic acid (DHA). Fatty acid product/precursor relationships in the sub-groups revealed reduced chain elongation and omega 3 fatty acid desaturation associated with reduced ratios of rod-to-cone electroretinographic amplitudes. Based on these results, we suggest that the heterogenic ADRP population includes a sub-group of patients characterized by abnormal fatty acid metabolism that may effect membrane structure and visual function.