Long sleep duration and frequent day-time naps of the infants can be protective for vigabatrin-induced visual field defects.

Sir,

Vigabatrin (VGB) is used for the adjunctive treatment of refractory partial epilepsy and for initial monotherapy of infantile spasm because of its action that inhibits GABA transaminase leading to increased levels of inhibitory neurotransmitter GABA in presynaptic nerve terminals.[1] One of the important concerns that limit its use is irreversible visual field defects. Incidence of visual field defects is reported in up to 40% of adult patients but is lower in pediatric patients at 19–22%.[2-4] Also, a recent study stated that the risk of visual field defects may be lower in children who are treated with VGB in infancy compared with patients who receive VGB at a later age.[5]

Retinal toxicity of VGB was first described in albino rats.[6] VGB can accumulate in retina and concentrations can reach as much as five-fold higher than in the brain.[7] It was shown that the most obvious retinal change was disorganization of the peripheral retinal photoreceptor layer.[8] It was suggested that VGB mediates phototoxicity, as it was found that retinal explants exposed to light of strong intensity showed photoreceptor degeneration in the presence of VGB. Solely, high GABA concentrations did not cause acute retinotoxicity, even in the presence of strong light. It was suggested that brief VGB exposure damages the outer retina by sensitizing photoreceptors to light-induced damage and this phototoxic damage also involves reactive oxygen species.[9]

Melatonin is a hormone synthesized by the pineal gland and retinal photoreceptors under a cyclic rhythm with peak levels occurring during night period.[10] Melatonin synthesized by photoreceptors is thought to act as a paracrine neurohormone with local effects in the retina.[11] Melatonin is involved in photoreceptor outer segment disc where they perform shedding, phagocytosis, and delays photoreceptor degeneration.[12] It is an efficient direct scavenger of the highly toxic hydroxyl radical and also reduces oxidative damage by activating enzymes of anti-oxidative defense system including superoxide dismutase, catalase, and glutathione peroxidase.[1314] Paradoxically, inappropriate (i.e., daytime) exposure of retinal cells to melatonin may be detrimental to photoreceptor cell survival, as supported by reports that melatonin increases the degree of light-induced photoreceptor cell death. Chronic melatonin exposure of the retina at inappropriate times of day and lighting conditions may increase the risk of susceptibility of photoreceptors to damage by environmental illumination.[1516] The highest melatonin levels are found in children younger than 4 years old with longer sleep durations and frequent day-time naps.[17] Zhdanova et al. compared two doses of melatonin in 12 volunteers to evaluate its effect on sleep and reported that administration of 0.3 mg melatonin elevated serum melatonin to levels within the normal nocturnal range. This dose neither caused any side effects on mood and performance nor altered sleep architecture significantly in subjects with normal sleep.[18]

Hypothesis: Despite the fact that immature and developing nervous system of children has much more plasticity, is more prone to toxic insults and longer treatment durations and higher total doses needed, VGB retinotoxicity is less common than adults. The hypothesis we propose here is that the possible explanation of this is high melatonin levels, longer sleep durations, and frequent day-time naps of infants. This physiological status protects retinal cells of infants from oxidative stress and exposure to intense light, which concurrently protects from the VGB-induced visual field defects. We also think that low oral doses of melatonin given to adult patients several hours before habitual bedtime may prevent VGB-related visual field defects.