a more useful quantitative estimate than grating acuity for patients with cortical visual loss.530

Role of Visual Attention

Despite the billions of neurons that constitute the CNS, the visual environment is of such complexity and richness that the brain must actively choose which aspects it will process. This selective processing is termed visual attention. The primary role of impaired visual attention in contributing to CVI, PVL, and DVM (discussed below) is now increasingly recognized.110,584 Clinical and electrophysiologic tests of visual function may fall short in predicting visual potential or functional vision when injury to higher cortical centers produces selective deficit in visual attention.

The lateral geniculate nucleus, thalamic reticular nucleus, superior colliculus, and pulvinar are among the widely distributed networks of brain areas that subserve visual attention and operate across various processing areas. The lateral geniculate nucleus is the first stage at which visual input is modulated by bottom-up visual attention.264 Its modulation may be under direct control of the thalamic reticular nucleus, which operates as a local integrator of visual information.

Intermediate cortical areas V4 and TEO (cytoarchitectonic area located in the inferotemporal and occipital cortex, ventral to area V4) act as filter sites to reduce the amount of unwanted visual information. The posterior parietal cortex contributes significantly to top-down attentional visual function.110,412,537 More specifically, higher-order areas in the lateral intraparietal area and frontal eye fields integrate information from the visual system and provide a top-down attentional control via feedback connections. The pulvinar may act as an additional integrator receiving information from both the visual system and the higher-order areas via the superior colliculus.309

The overall view that emerges is that neural mechanisms of selective attention operate at multiple stages in the visual system, and that visual attention is subserved by a bottom-up stimulus driven process and a top-down feedback attentional network.264,310,419 The extent to which cortical visual loss can be purely attentional in children with cystic periventricular leukomalacia (particularly those with normal VEPs) or DVM remains to be determined.139

Subcortical Visual Loss (Periventricular

Leukomalacia)

As noted earlier, the umbrella term cortical visual injury comprises two conditions; one having a term injury that predominantly involves the striate and peristriate cortex and the other having preterm injury that predominantly involves the subcortical white matter, including the optic radiations. The lumping together of term cortical and preterm subcortical visual injury

creates terminologic confusion and obscures the fact that these two complex mechanisms of injury produce distinct constellations of neuro-ophthalmologic signs.76 Prematurity is a common cause of neurologic morbidity and visual impairment in c hildren.32,174,210,265,271,341,599About 40% of cases of cerebral palsy occur in children of very low birth weight.449 An increasing number of premature children with PVL are surviving to manifest central visual impairment.36,99,265,281 Neuroimaging abnormalities in these children are frequently confined to subcortical white matter (optic radiations and corticospinal tracts) as opposed to the cortical gray matter injury that predominates in

term anoxia.32,35,36,144,174,265,280,281,341,349,599

Preterm injury to the developing brain that primarily injures subcortical white matter produces PVL.76 PVL is ­usually seen in ventilator-dependent premature infants who survive longer than a few days.32 It arises between the 27th and 34th week of gestation when the premature infant’s cortex and underlying white matter receive their blood supply from ventriculopetal branches of the blood vessels on the surface of the hemispheres.32 While birth injury is an important pathogenetic factor, it is now believed that most PVL originates before birth. The occurrence of white matter injury is likely related to many different factors, including intrauterine infection, premature rupture of membranes, maternal chorioamnionitis, and hypotension with impaired autoregulation.434,591,593,597,599,630 In a study by Olsén et al449 of premature children with birth weights lower than 1,750 g, the incidence of PVL was 32%. PVL was observed in all children with cerebral palsy, in 25% with minor neurological dysfunction, and in 25% of healthy preterm children. PVL is an important cause of cerebral palsy (mainly spastic diplegia), intellectual

impairment, and visual impairment.41,42,46,48,82,83,89,280,349,448,449,587

Some children with PVL are neurologically normal and function within the normal range at detailed neuropsychological and cognitive testing.23,494,618 However, even premature infants with normal neurologic outcomes have a high incidence of neurocognitive impairment.61,488,489 In addition to mild cognitive impairment, these children have a high prevalence of low-severity dysfunctions, including learning disabilities, borderline intellectual functioning, attention deficit/hyperactivity disorders, and specific neuropsychological deficits; behavioral problems reportedly occur in 50% to 70%.224,423,558 Abnormal outcome is associated with increasing severity of white-matter injury, as well as ventriculomegaly and intraventricular hemorrhage (IVH).410

Neuroimaging Abnormalities and their Implications

PVL is usually first identified on ultrasonographic examination in the newborn nursery, leading to MR investigation. MR imaging in PVL shows a reduction in the amount of periventricular white matter, a compensatory ventricular dilation, an irregular outline of the lateral ventricle, and an

abnormally high signal intensity of the periventricular white matter on T2-weighted images (Fig. 1.17).29,35–37,76 Lesser degrees of injury to the occipital cortex may be seen in severe cases.144,349 Periventricular gliosis may be present when the gestational age is greater than 28 weeks. Premature infants with profound asphyxia show more severe injury, as manifested by signal abnormalities, encephalomalacia, or shrinkage of the thalami, basal ganglia, brain stem, and cerebellum (Fig. 1.17).37,76,366,521 Some patients with PVL show loss of volume within the corpus callosum, and some patients seem to develop new visual processing strategies that allow them to function normally.514,618 This plasticity may reflect remodeling of existing gray-white matter regions, refinement and selection of dendritic connections, rerouting of white matter tracts to circumvent obstructions, and development of alternative cortical processing strategies.618

Directed MR imaging studies in infants with white matter injury also show disturbances in cerebral growth, with a reduced volume of both gray and white matter.275 An autopsy study of PVL patients showed gray matter lesions in a third or more of cases, with neuronal loss in the thalamus, globus pallidus, and cerebellar dentate nucleus, and gliosis in the deep gray nuclei (thalamus and basal ganglia) and basis pontis.463 The authors suggested the term “perinatal panencephalopathy” to more accurately describe the scope of the neuropathology. Therefore, the focal subcortical white matter injury that we diagnose as PVL or subcortical visual loss should probably be viewed as a marker for more global neu-

rological injury rather than the isolated causative lesion for visual system dysfunction in these patients. A recent study using diffusion tractography imaging performed at termequivalent age41 found development of the white matter in the optic radiations to be the best correlate with visual development in preterm infants.

Recent use of diffusion-weighted MR imaging has challenged our concept of the spastic diplegia that so often accompanies PVL. This condition has long been attributed to the location of the anterior periventricular white matter injury. Because the lower extremity axons course medially to the upper extremity axons, they are more affected by periventricular injury, and motor function is more affected in the lower extremities (spastic diplegia).34 However, diffusion tensor MR imaging has recently implicated interruption of sensory feedback from the posterior thalamic radiation, which connects the thalamus and the parieto-occipital lobe, and is mostly related to sensory dysfunction, in the pathogenesis of spastic diplegia.49,255 Thalamic injury may also play a direct role in the abnormal development of visual function in infants with PVL.477

Neuro-Ophthalmologic Findings

Clinically, PVL can produce decreased visual acuity, inferior visual field constriction, visual cognitive impairment, ocular motility disturbances, optic nerve hypoplasia,

Fig. 1.17  Periventricular leukomalacia. (a) In a mild case, axial FLAIR MR image shows focal high signal in the periatrial white matter compatible with gliosis. (b) Severe PVL in which the axial T1-weighted image

demonstrates thinning of the periventricular white matter with encephalomalacia of the striate cortex. In this case, there is decreased volume and increased signal within the thalami bilaterally. With permission from Brodsky et al76

Fig. 1.18  Tonic downgaze as a sign of periventricular leukomalacia. With permission from Brodsky et al76

pseudoglaucomatous cupping, spastic diplegia (Fig. 1.18).76,280 PVL is associated with tonic downgaze in infancy (Fig. 1.19), esotropia more often than exotropia, latent or manifest latent nystagmus, and optic nerve hypoplasia.76 The etiology of tonic downgaze may relate to the coexistent IVH and its associated hydrocephalus, or to thalamic hemorrhage (which produces tonic downgaze, esotropia, and pupillary constriction in adults).76,171,555 IVH is attributed to venous stasis rather than to the hypoxic-ischemic injury that characterizes PVL although the two mechanisms sometimes overlap in premature infants.598 However, associated pupillary miosis is not seen in children with IVH.276 In one study,76 IVH did not increase the prevalence of tonic downgaze in children with periventricular leukomalacia. Phillips et al462 noted a high prevalence of esotropia in patients with grade 3 and 4 IVH, whereas lower grade hemorrhage did not predict esotropia, suggesting that the degree of parenchymal damage and the ocular morbidity may be related.

Children with PVL often have esotropia with associated latent nystagmus, dissociated vertical divergence, and superior oblique muscle overaction with binocular intorsion (producing an A pattern). The age of onset of esotropia is variable, ranging from the first few months of life to many years later. This esotropia can usually be distinguished from infantile esotropia on the basis of concurrent signs such as ROP, optic nerve hypoplasia or atrophy, and neuroimaging findings.468 More severely affected patients are said to exhibit exotropia rather than esotropia,76,280 and others display a

dyskinetic strabismus, in which an exotropia­ changes to an esotropia on a moment-to-moment basis. Strabismus surgery for the esotropia in PVL is prone to overcorrection. Normal surgical doses should therefore be reduced. Unlike in infantile esotropia, some children with esotropia and PVL spontaneously convert to an exotropia.280,286 Given these complexities, and the minimal potential for fusion in children with PVL, the current trends for early strabismus surgery in children with infantile esotropia should not be loosely applied to premature children with PVL.

Latent nystagmus also appears to be particularly common in PVL. Jacobson et al286 found nystagmus in 16 of 19 children with PVL, with latent nystagmus in 12 of these patients. It is unclear whether the latent nystagmus of PVL is simply a physiological epiphenomenon of infantile strabismus, a result of afferent injury to the optic radiations, or whether the bilateral white matter lesions of periventricular leukomalacia can anatomically disrupt efferent corticotectal pathways to the nucleus of the optic tract (the neural generator of latent nystagmus).79 Patients with dyskinetic cerebral palsy may display “dyskinetic” eye movements (difficulty with voluntary saccades, pursuit, and fixation, producing tiredness, illness, anxiety, stress, discomfort, and straining that adversely affect visual performance.297 Premature infants with moderate-to-severe white matter injury have greater disruption in fixation and conjugate gaze that improves with time.196 Reduced accommodation is also common and often overlooked in children with cerebral palsy.392,398 Reduced accommodation can impair learning and requires dynamic retinoscopy to diagnose.392,508

Finally, PVL is a common cause of optic nerve hypoplasia77 and pseudoglaucomatous optic atrophy.284 Children may show increased retinal vascular tortuosity,243 suggesting that abnormal fetal development may influence endothelial cell function. Some patients with PVL show garden-variety optic nerve hypoplasia, suggesting that intrauterine retrograde transsynaptic degeneration has diminished the optic nerve size. However, the small optic nerves in children with PVL are not associated with pituitary deficiency. In 1996, Jacobson et al284 recognized that PVL produced a unique optic nerve configuration characterized by an abnormally large optic cup and a thin neuroretinal rim contained in a normal-sized optic disc defect (Fig. 1.19). They attributed this morphologic characteristic to bilateral injury to the optic radiation, with retrograde transsynaptic degeneration of retinogeniculate axons after the scleral canals had established normal diameter. Because injury to oligodendrocytes may also affect synaptogenesis at the level of the geniculate bodies, we now consider these optic disc changes to be more properly designated as a form of congenital optic atrophy. In some cases, pseudoglaucomatous cupping is accompanied by pallor of the neuroretinal rim (Fig. 1.19). This pseudoglaucomatous cupping of PVL is more properly designated as a form of optic atrophy.