Horizons

also help to synchronize the circadian clock57 and help to drive the suprachiasmatic nuclei,8 and light continues to affect circadian phase (albeit less effectively) when the direct photosensitivity of intrinsically-photosensitive retinal ganglion cells is eliminated by knockout of melanopsin.57 This and other nonvisual responses are lost only when the melanopsin deficiency is coupled with mutations that disable classical rod and cone photoreceptors, suggesting that melanopsincontaining retinal ganglion cells also receive rod and cone driven synaptic inputs.239 Suprachiasmatic nuclei-projecting retinal ganglion cells can respond to light both via an intrinsic melanopsin-based signaling cascade and a synaptic pathway driven by classical rod and/or cone photoreceptors. Recently, a medium-wavelength opsin has also been found to contribute.129,453 It is unclear how the retinal ganglion cells integrate these temporally distinct inputs to generate the signals that mediate circadian photoentrainment and other nonvisual responses to light.

Blind people have a high incidence of sleep complaints, with some suffering intractable sleep disorders, suggesting that circadian disruption may be at fault.406,407,453,505 Patients with congenital blindness have been shown to have abnormalities of other circadian rhythm regulation.430,453,603 In these patients, excessive daytime napping may be a sign of circadian dysfunction.370,603 In addition, many totally blind people have free-running temperature, cortisol, melatonin, and sleep-activity rhythms. In addition to sleep propensity and alertness, circadian variation can be seen in clinical phenomena such as fasting glucose level and myocardial infarction.427,500,503,568 However, some blind human patients continue to suppress melatonin production when exposed to light.105,505 In patients with congenital retinal or optic nerve blindness, sleep disturbances may be secondary to an absent melanopsin function, while in others with CNS disease, it may be secondary to associated hypothalamic injury. Sleep disturbances in visually impaired infants are often responsive to melatonin,299 although there are concerns that this hormonal medication may interfere with normal progression of puberty.589

Although most individuals lacking light perception have free-running circadian rhythms, some maintain circadian entrainment,369 albeit sometimes with an abnormal phase.502 It remains unclear what zeitgebers (time cues) mediate entrainment among blind persons who are without light perception and yet are able to maintain synchronization to the 24-hour day. Furthermore, light has been shown capable of constricting pupils, suppressing plasma melatonin levels, and resetting circadian phase in some individuals lacking subjective light perception. The quantity of light needed may fall below the level of conscious visual perception (which is estimated to have as a threshold the loss of 95–97% of photoreceptors).505

In summary, the intrinsic melanopsin photoreceptive system within the ganglion cells that mediates the circadian

resetting effects of light is distinct from the rods and cones that mediate vision.150 Total elimination of light input into the hypothalamus may, accordingly, have far-reaching consequences on various circadian systems with potentially significant negative impact on the patient’s health and wellbeing. Sadun et al505 prophetically state that “In the future, ophthalmologists­ may consider the potential impact on the neuroendocrine system when assessing the relative risks and benefits of therapy. Salvaging light perception vision may be of greater significance than previously thought.”

Horizons

Our understanding of the major retinal and CNS disorders that produce blindness in infancy continues to be refined by new diagnostic techniques. Although neuroimaging is relatively insensitive to identifying dysfunction of the visual cortex and higher cortical areas, newer diagnostic modalities using high-strength magnets, diffusion tractography, diffu- sion-weighted imaging, and functional imaging change our understanding of many neurological disorders that affect the visual system.221 Although the role of the clinician has traditionally been limited to providing information, counseling, and support, a number of new and promising therapies are on the horizon.

Gene therapy has achieved early success in patients with LCA. Pharmacological treatments, growth factors, and neuroprotective factors are all being used to tip the scales toward neuronal survival in children with perinatal brain injury.160 Stem cells, nanoparticles, and agents to promote neural plasticity should also find application in the near future. Refinement of preventive measures and early treatment of underlying causes to prevent neuronal damage in premature infants will hopefully reduce the incidence of periventricular leukomalacia.160 Rescuing sick axons to prevent their death is assumes an important role in areas of research concerned with brain injury. Research to prevent transsynaptic degeneration after brain damage also holds promise,517 although it is not clear whether such prevention would have a clinically desirable outcome. Older therapeutic interventions such as placement of a shunt for hydrocephalus or antibiotic treatment for meningitis are of obvious importance to limit the extent of neuronal damage.

Visual stimulation is a therapeutic modality that is, generally speaking, not popular with ophthalmologists. However, some authorities who work regularly with visually impaired children believe that certain techniques of visual stimulation may result in visual improvement but acknowledge that this reflects their clinical experience rather than results of scientific research. Visual stimulation rests on the premise that vision is a learned skill, and like physical therapy, good