Blindsight

Only when the neck musculature and head control are sufficiently mature, do the characteristic head thrusts emerge to strongly suggest the diagnosis. Unless associated with Joubert syndrome, children with congenital ocular motor apraxia would be expected to have normal VEPs and ERGs.

Blindsight

There has been considerable controversy regarding the existence of an extrageniculostriate visual system that subserves a cruder form of visual discrimination (blindsight) in man.83,385,460,626,628 The precise function of such a system is debatable, but it is thought to be integrated with the geniculostriate system and to mediate the unconscious awareness of motion in the peripheral field, spatial localization, and visuospatial orientation.300 Neuro-anatomically, it is estimated that 20–30% of the optic nerve fibers in humans terminate in structures other than the lateral geniculate body.89 In primates, some such fibers go to the pretectal area and others to the superior colliculus which, in turn, project to the secondary, parastriate visual cortex (areas 18 and 19) and other areas of the brain via the pulvinar.71 The function of the pretectal fibers is to mediate pupillary reaction to light, while collicular-pulvinar-parastriate fibers are presumed to subserve a subcortical form of vision that bypasses the geniculostriate pathway (blindsight).

The term blindsight refers to unconscious residual visual ability detected within a visual field defect corresponding to a lesion of the striate cortex. In humans, data supporting the existence of blindsight has been largely derived from studies demonstrating the ability of some patients with cortical blindness or hemianopia to detect and localize stimuli that they do not report seeing within a perimetrically blind hemifield, as well as the ability to determine the orientation, motion, or color of such stimuli.472 For example, when an image is flashed in the blind hemifield, affected patients are able to point to the location of the image or to guess correctly when it appeared. Despite insistence on seeing nothing, the typical patient scores better than what would be expected from chance alone. The results of such studies are open to question on the basis that some residual cortical function may still remain in the area subserving the blind fields due to incomplete destruction of the striate cortex30,71,83,157 or that they may represent an artifact of poor fixation or light scattering.83 In humans, neurologic injury to the striate cortex usually involves some degree of injury to the overlying visual association cortex.606 Even in experimental studies after bilateral occipital lobectomy in primates, residual visual function may stem from subtotal resection of the anterior striate cortex.119 The phenomenon of blindsight is unconscious. Conscious awareness of residual visual function in a patient with cortical blindness renders the possibility of an

underlying blindsight mechanism, which is subcortically mediated, quite unlikely.

Since the early reports of blindsight, a wide range of residual functions without an acknowledged awareness have been called “Type I” blindsight.605 These include target detection and localization by saccadic eye movements or manual pointing, movement direction detection, relative velocity discrimination, and stimulus orientation detection. Other subjects show “Type II” blindsight characterized by residual visual abilities with awareness such as consciously detecting a fast-moving stimulus and its direction607 or semantic priming from words presented in a blind field.380

One notion of blindsight revolves around the idea that the extrageniculostriate system may act as a backup visual system if the geniculostriate system is defective.70 Adults with acquired complete destruction of both areas 17 are usually totally blind,71,89 “despite a preserved tectal system.”109 Whether a similar generalization applies to prenatal or neonatal lesions in humans is unknown. The age at the time of insult is important because many animal studies have suggested that the immature brain has a greater potential for recovery than the adult brain.606 Evidence derived from experiments with cats indicates that visual cortex damage in neonatal kittens, but not in adult cats, is followed by the significant compensatory rewiring of the nervous system that reduces the otherwise expected visual handicap. A similar adaptability of the human embryonic CNS may underlie some cases that defy ready explanation on the basis of electrophysiologic and neuroimaging evidence.

Summers and MacDonald550 described a 14-month-old infant who showed intact central vision despite the absent patterned VEPs and tomographic absence of the occipital cortex. The cerebral lesion might have resulted from a prenatal developmental defect. The authors speculated that the intact central vision may be explained on the basis of a heterotopic occipital cortex, a subcortical collicular system, or rewiring of the brain after the prenatal lesion.

Adults who have sustained damage to the occipital lobes commonly have a degree of perception of movement that is either conscious or subconscious. Soldiers who sustained occipital injury during World War I were found by Riddoch (1917) to be aware of movement in the “blind” visual field. This statokinetic dissociation is known as the Riddoch ­phenomenon. Adults who are blind because of cerebral damage may manifest a relatively subconscious awareness of moving targets, lights, and colors in the blind area. When asked to guess the position of a moving target, they do so more frequently than is probable by chance alone.605 In ­monkeys, orientation to visual stimuli and visually guided movement takes place despite bilateral occipital lobectomy.270 The brain structures that subserve blindsight may include residual striate cortex, light scatter from the seeing hemifield, extrastriate cortex, and the superior colliculus and pulvinar.68,98,458,537,543,606

Blindsight has only recently been studied in children. Boyle et al65 found evidence of blindsight in 19 of 541 children with profound visual impairment and four with hemianopia. They noted that helping the parents and caregivers to both recognize and make use of their child’s blindsight can facilitate bonding. When feeding children with profound cerebral visual impairment, for example, the child does not open his or her mouth when the spoon approaches the mouth from straight ahead. However, bringing the spoon in an arc moving through the peripheral visual field can result in the child’s mouth opening to receive the food. Adults with blindsight who see movement only may report improved conscious awareness of movement when rocking back and forth.137 In children who choose to rock to and fro when they want to see something, it may be counterproductive to discourage such behavior.192 While some success has been obtained in training adults to gain a conscious awareness of their blindsight,627 there is greater potential for improvement when the damage to the primary visual cortex is sustained early in life.458

Unlike in humans, primates show the preservation of visuospatial orientation and recognition of moving targets after bilateral destruction of both areas.270 The interspecies difference may be theoretically explained from a phylogenetic viewpoint; that is, the greater the development of the newer cortical visual structures, the less the contribution of the older tectal and collicular structures to visual function. In lower vertebrates, the superior colliculus is the major visual processing center. In humans, unconscious perceptual processes are subserved by the activity of subcortical visual pathways, including the superior colliculus and other pathways bypassing the primary visual cortex.353,594 In one patient, functional MRI demonstrated activation of the amygdala in response to a conditioned visual stimulus that correlated with activity levels in the superior colliculus and pulvinar, suggesting that a route that bypasses VI may remain intact for activation by emotional events.421,606 A study of diffusion tensor tractography in hemispherectomized patients demonstrated strong ipsilateral and contralateral projections from the superior colliculus to primary visual areas, visual association areas, precentral areas/frontal eye fields and the internalcapsuleoftheremaininghemisphereinhemispherectomized patients with type I or “attention blindsight.”353 These results support an essential role for the superior colliculus in blindsight.

In both humans and primates with V1 ablation, medial temporal cortex (MT) responsiveness is reduced but not eliminated and motion perception persists. Although it has long been believed that visual information could reach the extrastriate cortex without traversing V1 by going from retina to superior colliculus to pulvinar to MT, the region of the pulvinar receiving input from the superior colliculus may possess only a few neurons that project to MT.527 In infant

cats with cortical visual injury, one particular anatomical pathway that runs directly from the dorsal lateral geniculate nucleus to the posteromedial lateral suprasylvian cortex has been implicated in the superior visual recovery. This nor- mally-transient pathway is retained and expanded after visual cortical injury in infancy but not in adulthood.219,220,535,564

Although Sorenson and Rodman534 could find no direct pathway from the dorsal lateral geniculate nucleus to MT or medial superior temporal cortex (MST) using retrograde tracers, Sincich et al527 found a direct projection in the macaque monkey, from the lateral geniculate nucleus to the motion-selective middle temporal area (MT or V5), a cortical area not previously considered primary. The constituent neurons sent virtually no collateral axons to the primary visual cortex (V1) and equaled about 10% of the V1 population innervating MT. The authors proposed that this pathway could explain the persistence of motion sensitivity in subjects following injury to V1 and suggested that residual perception after damage in a primary area may arise from sparse thalamic input to secondary cortical areas.

In their book Sight Unseen, Milner and Goodale413 document how selective ventral stream injury can produce a syndrome of blindsight. Balint syndrome is caused by bilateral superior (dorsal stream) parieto-occipital lesions in the watershed areas resulting from anoxia, hypotension, or infarction.240 The features of Balint syndrome that may occur together or separately592 include the following: (1) despite the normal range of ocular movements, the patients seem unable to fixate an object voluntarily, and, if fixated, gaze tends to involuntarily drift away (“psychic paralysis of gaze”); (2) inability to guide arm and hand movements by using visual feedback, with inaccurate reaching and grasping (“optic ataxia”); and (3) inability to attend to more than one visual stimulus in the whole visual field at a time (“piecemeal vision”) and, often, unawareness of extramacular stimuli (bilateral visual neglect). The visual acuity is intact, and visual agnosia is absent (i.e., the patient recognizes what he sees), because the parietal and temporal association areas are intact. Balint syndrome has recently been described in children.133,194 However, the diagnosis is usually missed, possibly due to difficulties in testing. While Balint syndrome represents the extreme variant of dorsal stream dysfunction, mild variants are much more common.

In summary, most investigators now acknowledge the existence of an extrageniculostriate system that persists and expands following early injury to the visual cortex.83 This pathway probably involves projections from the superior colliculus as well as direct projections form the dorsal lateral geniculate nucleus to extrastriate area MT. These pathways may normally function to subconsciously mediate body orientation during traveling.83 The selective neuroanatomic pathways subserving blindsight are still being elucidated, and this controversial phenomenon has led to some intriguing

questions about the nature of consciousness and the potential role of the extrageniculostriate system in visual performance. These pathways may also play a role in modulating the normal visual processing that occurs in the absence of conscious awareness.606 The observation that visual attention still has a determining impact on unconscious processing demonstrates that visual attention cannot be loosely equated with visual consciousness.428a

The Effect of Total Blindness on Circadian Regulation

In the current cost-conscious climate of medical practice, the contribution of expensive and complicated surgical procedures to the overall quality of life comes under increasing scrutiny. A case in point would be the patient with stage 5 ROP who undergoes extensive vitreoretinal surgery only to achieve “anatomical success,” sometimes with no better than light perception vision. A question then arises whether the low functional vision attained with surgery contributes sufficiently to the patient’s overall quality of life to justify the total cost. While questions like this are difficult to answer, there is an increasing evidence to suggest that restoring any visual input may have significant impact on the overall wellbeing of the child in a manner unrelated to the meager improvement in visual function.506 This evidence derives from studies demonstrating the importance of light input in the entrainment of circadian timing systems.322 From the clinical standpoint, these adverse effects of blindness may manifest as sleep disturbances or depression following the visual loss, among other disorders.373

Light input to the eye controls a panorama of life’s major functions, such as fertility, seasonal gestation, sleep/wake rhythms, adrenal behavior, hibernation, and mood itself.373 Systemically, the circadian pacemaker (or biological clock) regulates the timing of a host of physiologic parameters across the biological day.420,582,602 Free-running circadian rhythms can cause problems with sleep/wake cycles, mood, growth, reproductive functioning and other endocrine systems, cell division, and aging.387 Circadian rhythms may even impact maturation, developmental milestones, and longevity. Even though a blind person has no light perception, he or she may indeed have a functioning retinohypothalamic tract pathway because the level of light needed to stimulate the system and synchronize the suprachiasmatic nucleus may be very low. Thus, minimal vision (and perhaps the intact eye in patients with no light perception) should be preserved in individuals with eye disease in order to avoid disturbances in circadian rhythm and clinical symptoms related to gonadal dysfunction, sexual maturation, infertility, mood disturbances, and the daily sleep/wake cycle.373

Research on circadian timing systems in mammals have shown that three components of such a system exist: (1) a visual pathway connected to the circadian pacemaker, (2) a pacemaker (which in mammals, including possibly, humans, is the suprachiasmatic nucleus of the hypothalamus), and (3) efferent pathways coupling the pacemaker to effector systems that display circadian function.417 Disruption in any of these components would result in circadian dysfunction. Total elimination of environmental light input may result in loss of circadian entrainment with subsequent free-running circadian rhythms. The endogenous, free-running, sleep-wake rhythms of humans is about 25 h, a shift of 1 h from the normal, entrained rhythm.104,503 This shift results in sleep disturbances, wherein affected patients are periodically awake at night and sleep during the day. Therefore, the pacemaker needs to be synchronized or entrained to the external 24-hour day.

Light through the eyes has been shown to be the primary synchronizer.103,503,611 The anatomical locus for the biological clock is the hypothalamic suprachiasmatic nuclei,84 and its molecular “clockwork” within individual neurons that form the basis for pacemaker rhythmicity.57,136,476 Photic information conveyed from the retina via the retinohypothalamic tract to the suprachiasmatic nuclei provides the daily phase shifts necessary to maintain entrainment).322 Timing,317 intensity,62,624 and wavelength68,368 have all been shown to be important factors in the resetting effects of light. The importance of retinohypothalamic connections in circadian rhythm regulation has been amply demonstrated in experimental animals. Bilateral transection of the optic nerves in rats resulted in loss of synchronized endogenous circadian rhythm, while bilateral transection of the optic tracts had no such effect.

Retinohypothalamic fibers project directly from the optic nerves to the suprachiasmatic nucleus of the hypothalamus, the circadian pacemaker (Fig. 1.23). These findings are also applicable to humans. In mammals, retinohypothalamic projections to the pineal gland provide the primary stimulus that serves to regulate melatonin secretion. Plasma melatonin levels rise at night and plummet during the day. Melatonin free running may explain why many blind patients have chronic insomnia. Blind patients without chronic insomnia maintain normal melatonin levels, while those with insomnia are found to have lost their ability to regulate these levels. Melatonin is available in a synthetic form for oral use. Recent studies have shown promising results for the possibility of treating certain sleep disorders by entraining the circadian pacemaker with external administration of melatonin.289,499,501 Of all the parameters with endogenous circadian variation, the rhythm of melatonin secretion has proved to be the most reliable marker of circadian phase.362 Melatonin is secreted by the pineal gland, and levels are high during the night and low during the day.360 This pattern of secretion is the same in both nocturnal (night-active) and diurnal (day-active) species, and so ­melatonin secretion can be thought of as a marker for the

Fig. 1.23  Graphic overview of visual pathways influenced by melanopsin. CG ciliary ganglion; SCN suprachiasmatic nucleus; PVN periventricular nucleus; LGN lateral geniculate nucleus, IGL intergeniculate leaflet;

Table 1.3  Characteristics of photoreceptors and melanopsin-containing retinal ganglion cells

Adapted, with permission, from Kawasaki et al312

biological­ night. Melatonin levels are suppressed by light but are relatively unperturbed by other types of stimuli.361

The recent discovery of melanopsin, a novel vertebrate opsin in ganglion cells of the retina, provided a missing explanation of why eyes are necessary for circadian photoentrainment but the photoreceptors are not (Table 1.3).312 In rodents, only 1–3% of all retinal ganglion cells contain melanopsin.237 These melanopsin-containing ganglion cells are scattered throughout the retina, with somewhat higher density superiorly.230,237 This novel vertebrate opsin is directly photosensitive, redistributing pigmented organelles when illuminated.57

Melanopsin-containing ganglion cells in the retina do not project to the lateral geniculate nucleus but to the suprachiasmatic nucleus to maintain the nonvisual functions of photoentrainment of the circadian system.461 They also project directly to pupillary centers to modulate the pupillary light reflex. These neurons depolarize either from transsynaptic activation initiated by phototransduction in the rods and

OPN olivary pretectal nucleus; EW Edinger-Westphal nucleus; SCG superior cervical ganglion; IML intermediolateral nucleus of the spinal cord. With permission from Berson et al57

cones, by intrinsic activation via melanopsin-mediated phototransduction, or both.311 Melanopsin is a novel opsin-based photopigment that renders these cells intrinsically photosensitive. Melanopsin-containing retinal ganglion cells are intrinsically photosensitive, with peak sensitivity in the short wavelength (around 480 nm), so they are particularly sensitive to blue light,57,237 which, when used during pupillary examination, can isolate the contribution of the ganglion cells to the pupillary light reflex in various retinal degenerations.311 In patients who are blind from retinitis pigmentosa, use of a blue light may therefore elicit some detectable pupillary response.311

Although melanopsin-deficient mice entrain normally to bright light-dark cycles, under constant darkness their oscillator is less sensitive to discrete pulses of light, thus establishing an important role for melanopsin in circadian photoentrainment.57,237,453,493 These novel retinal ganglion cell photoreceptors are far less sensitive and far more sluggish than rods and cones, with latencies as long as one minute.57 Selective sparing of these cells may help to explain the puzzling phenomenon of disabling photophobia responses that accompany the congenital retinal dystrophies. Because melanopsin-containing cells are inhibited by blue cones and stimulated by red and green cones, it may also explain the paradoxical pupillary phenomenon. In retinal dystrophies causing loss of red and green cones, turning off the room lights may remove blue-cone inhibition from melanopsin-containing photoreceptors, allowing them to constrict the pupils.311

Photoentrainment of circadian rhythms can occur in the absence of classical photoreceptors (rods and cones)179,180 but not in animals without eyes.453 Selective genetic ablation of melanopsin abolishes the intrinsic light response (the ability of individual ganglion cells to respond to light), it has surprisingly little effect on circadian photoentrainment.453,493 Thus, under normal circumstances, classical photoreceptors