It is recommended that EEG evaluation be included in the ancillary diagnostic testing of patients who present with cryptogenic acute blindness, even in the absence of obvious clinical symptoms of epilepsy. Infants with infantile spasms or constant seizures may seem blind because the seizure activity precludes visual attentiveness. The EEG in infants with infantile spasms shows hypsarrhythmia; affected infants sometimes show hundreds of small seizures daily. If visual pathway abnormalities are excluded with neuroimaging studies, the visual function may be expected to improve, sometimes dramatically, once the seizures are controlled.

Postictal blindness in infants was described as early as 1884 by Nettleship.436 Kosnik et al328 found an occipital focus in about 50% of children with seizures. They explained the predilection of occipital involvement in children with seizures by the presence of unstable electrical activity due to a putative relative immaturity of the occipital cortex in children. This high incidence of occipital lobe seizure activity in children explains why postictal blindness is more common in children. The precise pathophysiologic basis of postictal blindness is unknown, but a mechanism similar to Todd’s paralysis has been suggested (Fig. 1.13). Todd’s paralysis denotes the postictal occurrence of focal neurologic deficits,

which are mostly motor, but sensory deficits may also be associated. The mechanism of Todd’s paralysis itself also remains speculative, with Jasper301 suggesting, and Miller409 supporting as the best available explanation, the occurrence of “neuronal exhaustion” due to hypoxia or high metabolic demands postictally. This notion is supported by the observation of one patient with postictal blindness who demonstrated marked hyperperfusion in both occipital regions on an ictal (single photon emission computed tomography) SPECT, carried out at the onset of the seizure.42

Occasionally, the seizure activity itself may be associated with drug toxicity. For example, a young patient with a blood cyclosporine level almost six times the therapeutic value suffered transient cortical blindness associated with continuous focal occipital EEG discharge.492 Cortical blindness and seizures have also been reported following cisplatin treatment.250,586

Visual disturbances are recognized as common side effects of anticonvulsant therapy.474 Side effects of common antiseizure medications usually include sedation, with a decreased level of alertness that may adversely affect visual performance during the examination. Other visual disturbances associated with anticonvulsant therapy include vertical or horizontal diplopia and oscillopsia, as well as pursuit and gaze-holding disorders, nystagmus, convergence spasm, and gaze palsy.354 These symptoms may be ascribed to ophthalmoplegia, vertical nystagmus, or abnormalities of the vestibulo-ocular reflex.474

Despite the best efforts to uncover the cause of cortical damage in patients with CVI, some cases elude classification into any of the etiologies previously detailed (Figs. 1.14 and 1.15).

Fig. 1.13  MR imaging in 21-month-old girl with cerebral palsy and seizure disorder secondary to perinatal asphyxia who developed status epilepticus. The MR imaging obtained after control of status shows edema of nearly entire cerebral hemisphere, especially posteriorly, presumably as result of status epilepticus and sustained metabolic demands placed on left hemisphere as a result

Associated Neurologic and Systemic Disorders

Cortical visual loss is often accompanied by cerebral palsy, seizures, and microcephaly. Because cerebral palsy is so prevalent in children with CVI, a short discussion of its clinical spectrum is in order. Cerebral palsy represents a heterogenous group of disorders caused by nonprogressive disturbances of the developing brain, leading to dysfunction of movement and postural development.18,45,198,496 Other impairments (vision, sensation, cognition, communication, perception, behavioral, seizure disorder) often accompany the motor dysfunction.18,188 The motor disturbances associated with cerebral palsy can range from mild to severe and may dramatically impair a child’s functional abilities. Children with cerebral palsy frequently have mixed motor disorders (e.g., spasticity, athetosis, ataxia, weakness), and each likely impairs their functional movement in a different way. Despite the coexisting motor disorders, children with

Fig. 1.14  T2-weighted MRI of 1-year-old girl with congenital profound CVI and developmental delay reveals marked atrophy of occipital regions of uncertain etiology

cerebral palsy often fall into one of two classifications: “spastic” or “extrapyramidal.” Although children with cerebral palsy and strabismus tend toward esotropia more than exotropia, both occur commonly. Gaze apraxia may cause them to use horizontal or vertical head thrusts to facilitate gaze shifts.188 Saccades, smooth pursuits, and fixation are also impaired.188 Some may have the coexistent ocular motor nerve dysfunction.151

Hypertonia and athetosis are primary neurologic findings of extrapyramidal cerebral palsy, presumably as a result of abnormalities in basal ganglia-cortical circuits. Hypertonia can be divided into spasticity, dystonia, and rigidity. Spasticity is defined as increasing resistance to increasing speed of stretch relative to the direction of joint movement or a rapid rise in resistance above a speed or joint position threshold.513 Studies of spasticity in the lower extremities have not correlated well with aspects of gait function.1 Children with “spastic” cerebral palsy characteristically present with a combination of spasticity, weakness, and loss of manual dexterity due to abnormalities in descending motor pathways and motor cortex. In spasticity, resistance to passive stretch is dependent on speed. When the examiner moves the patient’s arms passively and slowly, there is initially no resistance in spasticity, but with increased velocity of movement, resistance increases.

Fig. 1.15  Axial CT scan from infant with cerebral palsy, CVI, seizures, and deafness, demonstrating early gestational injury with diffuse tissue resorption of posterior hemispheres. Etiology was unknown

Dystonia is defined as sustained or intermittent muscle contractions­ causing twisting and slow repetitive movements or abnormal postures.513 It can manifest as overflow of activity to muscles that are normally silent during a voluntary movement (e.g., other muscles in that limb or other limbs) or involuntary activation of muscles at rest.384 Children with dystonia cannot voluntarily relax their muscles completely. Rigidity is secondary to cocontraction of agonist and antagonist. With effort, children with rigidity can assume a posture with normal baseline muscle activity.46

Cocontraction can also occur in dystonia, so this is not the distinction between rigidity and dystonia. Cocontraction does not characterize spasticity. The vast majority of children with cerebral palsy display mixed hypertonia with some degree of spasticity and dystonia.513 Newer quantitative testing measures can distinguish between these different motor disorders.213 Hemiplegic cerebral palsy is now one of the most common types, with a prevalence of approximately 3 per 4,000 live births.251 This condition may often be due to vascular events. Athetosis produces slow, writhing movements of the extremities secondary to extrapyramidal lesions.

Once considered a monolith, cerebral palsy comprises a group of disorders with different etiologies, which constitutes a useful socio-medical framework for certain children with motor disabilities and special needs.329 Cerebral palsy results from an acquired lesion in most cases. Cerebral malformations are rare, and most cases show clear lesional

patterns of different timing. Thus, the common assumption that obstetric caregivers can prevent cerebral palsy by actions taken during labor and delivery is based largely on erroneous assumptions.377 Well-designed studies have shown that lack of oxygen causes only a small proportion of cases. Furthermore, cerebral palsy associated with birth injuries has never been shown to be preventable.432

Known risk factors for cerebral palsy include chorioamnionitis, death of a cotwin in utero, arterial ischemic stroke in the fetus or newborn, an umbilical cord wrapped tightly around the neck of the fetus, and premature birth.331 Other possible antenatal risk factors under investigation include viral infection, fetal thrombophilias, and polymorphisms of genes regulating inflammation, coagulation, and endothelial activation.193,433 In 10 developed countries, including the United States, the incidence of cerebral palsy has remained steady, at about 1 in 500 births, despite a fivefold increase in cesarean deliveries over recent decades, driven in part by the use of fetal monitoring. Thus, while some causes of cerebral palsy are known, most are unknown, not foreseeable before birth, and not currently preventable. Patients with cerebral palsy may vary in topography (diplegia, hemiplegia, quadriplegia), physiology (spasticity, dyskinesia, dystonia, and ataxia), and neurologic comorbidities involving vision, hearing, and epilepsy.

In the Bax study,44 white matter abnormalities were present in 43% overall and in 71% of children with diplegia, 34% of children with hemiplegia, and 35% of children with quadriplegia. Other important neuroimaging findings included basal ganglia abnormalities in 13%, malformation in 9.1%, cortical and/or subcortical abnormalities in 9.4%, and focal infarcts in 7%. Of children with basal ganglia and thalamic injury, 76% had dystonia. Of children with hemiplegic cerebral palsy, 27% had focal infarcts. Cerebellar vermian atrophy has also been described in a significant proportion of patients who have neonatal hypoxic-ischemic encephalopathy.515

Periventricular leukomalacia is now considered the most common cause of cerebral palsy.46,422 However, about 8% of children with spastic diplegia have normal MR imaging results, and 25% of children with periventricular leukomalacia on MRI do not have any neurological disorder.449 Ocular abnormalities are a common problem in children with cerebral palsy.338 In one prospective study,338 neuro-ophthalmo- logical abnormalities were found in 28.2% of children with cerebral palsy. More than half (61.9%) of those with neuroophthalmological abnormalities were completely blind. Optic atrophy and strabismus were each seen in 50%, and cortical visual loss was found in 47.7%. Spastic quadriplegia was associated with an increased risk of neuro-ophthalmo- logical abnormalities. Although Jan et al297 have suggested that some children with cerebral palsy behave as blind because of a “dyskinetic” eye movement disorder, causing

impaired motor control of saccades, pursuit, or fixation, Roulet-Perez and Deonna490 questioned whether these movements­ may be secondary to a central visual disorder rather than to a distinct ocular motor abnormality. Whether they are consequent to decreased vision or to superimposed motor disturbances, these children have been found to have a variety of ocular motor disturbances.188,512 Difficulties with accommodation have also been reported.392

Characteristics of Visual Function

The degree of CVI in a given child can range from a defect that is barely detectable to complete blindness. The visual acuity may be spared in unilateral cortical lesions or bilateral lesions, with sparing of cortical regions subserving the macula. In patients with profound visual impairment, appropriate methods of visual function assessment must be employed. Generally, it is very difficult to distinguish whether an infant is unable to see or simply unable to interpret visual input (visual agnosia). Snellen acuity measurements and similar methods have little to no utility in visual assessment of children with severe CVI. It is more relevant to obtain a measure of overall visual function than to simply attempt measuringt of visual acuity. Can the child recognize various objects in the environment, navigate effectively, and interact visually with other people? Obtaining a visual history from the parents and spending some time playing with these children provides valuable information about the children’s overall visual function.296

Because the visual impairment in these infants may span a number of neurological functions, it is conceptually useful to separately consider the four As of visual loss: acuity, assimilation, attention, and apraxia.

Children with CVI typically see better in a familiar environment. They often use touch to identify objects of interest.296 They prefer to view objects at close range (independent of refractive errors) and appear to have a crowding phenomenon wherein individual objects are seen better against a plain background than against a patterned background or amongst a group of objects. The preference of close viewing may be to produce linear magnification (by shortening the focal length) or to reduce crowding by viewing the object singly at close range. They frequently look away from objects of interest, as if trying to use their peripheral vision.

Patients with CVI display on-again, off-again vision with wide fluctuations. Their visual function may be noted to vary widely from day to day and even from hour to hour.296 This variability may correspond to changes in lighting conditions, attentiveness, tiredness, medications, illness, seizures, or environmental changes (e.g., noise, colors) but may also

­parallel the variable performance in other neurologic spheres that is characteristic of brain-damaged children. In some instances, variability of visual test results may arise from the presence of a “Swiss-cheese” visual field in which an object may or may not be seen, depending on whether it falls within a region of intact field. The extreme variability of visual function found in some patients with CVI may sometimes lead to the impression that the child is “faking.” To be differentiated from true CVI is the visual disregard and intermittent visual inattention often seen in patients with developmental delay and other neurological disorders with intact posterior visual pathways. The phenomenon of decreased visual attention to novel stimuli in infants who later prove to be mentally retarded or autistic should also be borne in mind.153

Children may show a tendency to gaze at room lights, especially fluorescent lights or other bright objects, including the sun (light gazing).295 The precise explanation for this phenomenon is unknown, but it has been considered by some investigators to be a bad sign, indicating severe visual system injury. Paradoxically, instead of light gazing, some degree of photophobia may be present in about one-third of children,293 but this is usually much less than the severe photophobia so characteristic of retinal conditions, such as congenital achromatopsia. The cause of this photophobia is unknown, but damage to retinal, thalamic, or cortical structures may be responsible. It is possible that, in some cases, it may be of a retinal origin, arising from a hypoxiadamaged retina.

Visual acuity of some children with cortical visual loss is better under low-luminance conditions than under normal luminance conditions.206 Nickel and Hoyt440 have shown that hypoxic insults can cause transient but notable ERG changes in children. The photophobia may be a result of associated damage to the thalamus, a phenomenon called “thalamic dazzle.”101 Most cases of photophobia are thought to arise from damage to the striate cortex itself.293 This may be analogous to the photophobia observed in Macaque monkeys when the occipital lobes are amputated.119

The visual performance of some patients is better for moving objects than static objects. This holds true for striate cortex and ventral stream pathology but is often not the case in children who have dorsal stream dysfunction, which may be associated with akinetopsia or at least dyskinetopsia (see below). Some affected children see better when traveling in a car, while the opposite is true in others.296 Some ambulatory children with CVI show better visual function in terms of navigating successfully and avoiding obstacles than in performing near-vision tasks. Jan et al296,300 postulated that the most plausible explanation for this discrepancy is the presence of an extrageniculostriate (collicular) visual system, calling this “travel vision.” However, the role of any

accessory system in humans remains controversial (see “blindsight” below).

Patients are often able to identify the color of objects better than the form and shape of objects. This discrepancy has been attributed to several factors: (1) Color perception requires fewer neurons than form perception.604 (2) Color perception, unlike form perception, is bilaterally represented in the cerebral hemispheres (but with dominance in one hemisphere), so it is more resilient to injuries that may affect form perception. (3) Color perception is diffusely represented in the striate cortex and the lingual and fusiform gyri.

(4) Color perception may be preserved within the extrageniculostriate visual system.542

Some children with CVI turn their head a certain way or look away to either side, usually with a slight downward gaze, when reaching out for an object.296 They display preference for peripheral vision over central vision, viewing objects eccentrically. This may result from bilateral central scotomas associated with sparing of the temporal crescent, which is represented by the most anterior portion of the striate cortex. Alternatively, it could be a manifestation of the complex gaze apraxia that so often accompanies cerebral palsy.188

Accurate evaluation of the visual fields is notoriously difficult in children with CVI. Clinical clues may be obtained by moving colorful toys in their visual fields while observing the child’s reaction. Even children with severe visual impairment often show asymmetric involvement, with preferential relative sparing of either the right or the left visual fields.296 Visual evoked potential recordings with separate hemispheric electrodes may help assess the presence of relative hemianopic defects in some children. When quantitative visual fields can be performed, many children with CVI show severely constricted peripheral visual fields.588

Neuro-Ophthalmologic Findings

The neuro-ophthalmologic signs of CVI are summarized in Table 1.1. In a retrospective review of 50 patients,76 Brodsky et al. found the four common neuro-ophthalmologic signs to

Table1.2  Neuro-ophthalmologic findings in cortical visual impairment versus subcortical injury (periventricular leukomalacia)

Fig. 1.16  Congenital horizontal gaze deviation with ipsiversive head turn as a sign of CVI. With permission from Brodsky et al76

be horizontal conjugate gaze deviation, a constant exotropia, absence of nystagmus, and normal optic discs or a mild degree of optic atrophy. The finding of horizontal conjugate gaze deviation (Table 1.2) in infancy is a useful diagnostic sign of CVI. In this condition, both eyes are tonically deviated to one side (Fig. 1.16), and the head is tonically deviated in the ipsiversive direction, so that the child appears to be trying to look behind the head. This oculocephalic dyskinesia reflects a multiplicity of mechanisms by which asymmetric injury to cortical eye movement command centers can modulate horizontal conjugate gaze. These include unilateral epileptic excitation, saccadic or pursuit imbalance between the two hemispheres, optokinetic asymmetries, congenital homonymous hemianopia, unilateral injury to visual attention centers.76 CVI is a recognized cause of congenital exotropia.76 As isolated congenital exotropia is rare, it is important to consider the diagnosis of cortical visual loss in children with congenital exotropia and to look closely for signs of visual and neurologic impairment.1

A regular rhythmical conjugate nystagmus is rare in CVI, but occasional patients display roving eye movements while others display a fine, erratic intermittent nystagmus that is superimposed upon a horizontal conjugate gaze deviation,76 or occasional, unsustained beats of nystagmus. Bilateral occipital lobectomy in monkeys results in latent, but not manifest, nystagmus.623 Fielder and Evans165 have speculated that an intact geniculostriate pathway is a prerequisite for the development of congenital nystagmus. This is corroborated by the observation of Jan et al290 of the disappearance of nystagmus in a patient with anterior visual pathway dysfunction after the onset of cerebral disease. It is also supported by the observation that horizontal nystagmus, due to various

disorders of the eye or anterior visual pathway, appears to develop at an age when the geniculostriate system is emerging functionally (around 2–3 months of age). Fielder and Evans165 argued that patients with CVI who, by definition, do not have a normally functioning geniculostriate pathway, would not be expected to develop nystagmus. However, the frequent finding of either latent nystagmus or, less commonly, congenital nystagmus in premature children with periventricular leukomalacia would seem to belie this explanation. Tusa et al570 have suggested that “sensory” nystagmus results from interference with gaze-holding mechanisms, probably via visual deafferentation of the flocculus by the inferior olivary nucleus.

Patients with CVI and a few beats of nystagmus are likely to have coexisting anterior visual pathway dysfunction or to have developed the visual loss before the first year of life. Patients with “mixed mechanism” visual loss with both anterior as well as posterior visual pathway dysfunction are not uncommon. The degree and characteristics of nystagmus in these visually impaired children may theoretically be used as a rough assessment of the severity of the anterior visual pathway dysfunction. In light of evidence suggesting that the geniculostriate pathway is a prerequisite for the development of nystagmus,165 one can infer that a patient with mixed mechanism visual loss may not show significant nystagmus even in the presence of severe anterior visual pathway damage if significant posterior pathway damage coexists. Conversely, finding sustained nystagmus in patients with anterior and posterior pathway disease indicates that the posterior component is not severe.

The optic discs are commonly said to be normal in patients with CVI, but involvement of the retina, optic nerves, or chiasm is not unusual, arising from the same disease process that caused the cerebral damage. Some children with poor vision that may be readily attributable to other developmental ophthalmologic abnormalities may harbor at least a component of CVI as well. In children with cortical visual loss, Brodsky et al76 found normal discs in 56%, optic atrophy in 24%, optic nerve hypoplasia without atrophy in 8%, and combined hypoplasia with atrophy in 12%. Thus, optic atrophy is seen much more commonly than optic nerve hypoplasia in CVI. The presence of optic atrophy in patients with CVI due to hypoxia-ischemia should not be surprising;209 it may be argued that the reportedly low prevalence of concurrent optic atrophy may itself be surprising. Six out of 30 children with hypoxic CVI described by Lambert et al341 showed mild optic atrophy. In a series of infants with significant hypoxic encephalopathy, Good et al209 found that less than 15% had optic atrophy.

The fact that many children with severe ischemic cortical damage do not show optic atrophy signifies that the anterior visual pathways are more resistant to the effects of hypoxia

than the posterior visual pathways. However, it may be argued that concurrent anterior visual pathway involvement is underreported, in part due to mistakenly considering such defects to be the sole cause of the visual impairment.491 For example, about 20% of children with optic nerve hypoplasia also show hemispheric abnormalities77,78 that may involve the posterior visual pathway. Quantitative studies showing that patients with CVI have smaller optic nerve heads with increased excavation and temporal pallor may have included patients with periventricular leukomalacia.491

Coexisting CVI should be suspected when the degree of visual deficit is not fully explained by the ocular defects.613 Associated optic atrophy may be due to concomitant anterior pathway insult or to retrograde transsynaptic degeneration of the retinogeniculate pathway.498 Patients with “mixed mechanism” visual loss with both anterior and posterior visual pathway dysfunction are not uncommon. This “mixed” category has been largely underemphasized in the literature but represents a diagnostic challenge in terms of determining the weighted contribution to the visual impairment of each insult.

Retrograde transsynaptic degeneration of the retinogeniculate pathway is known to occur in nonhuman primates following cerebral lesions even in adult life.127 In contrast, retrograde transsynaptic degeneration in humans is said to occur only if the cortical lesion occurred in utero.113,259,340 However, the presence of even severe postnatal cortical insults or malformations does not appear to be sufficient for the occurrence of transsynaptic degeneration. For instance, the literature contains well-described cases of severe occipital lesions, even tomographic absence of the occipital cortex550 with normal fundus and optic disc appearance. In general, descriptions of normal optic discs in children with CVI may be explained by one of the following: (1) Cortical damage may involve the visual association areas without significant damage to the geniculostriate pathway.19 (2) Subtle mild optic nerve pallor may be overlooked in infants and young children. (3) The nature, location, timing, or extent of the cerebral lesion is not sufficient to cause transsynaptic degeneration. (4) Other heretofore undetermined factors that are necessary for the development of transsynaptic degeneration may be lacking.

Generally, optic disc pallor found in association with cortical damage may be due to the same process that caused the cortical damage, subsequent hydrocephalus, transsynaptic degeneration, a direct disruption of synaptogenesis at the geniculate level (especially in PVL), or an entirely unrelated process. A primary insult to the retinogeniculate pathway with optic atrophy may be theoretically distinguishable from transsynaptic degeneration by the following means: (1) Documentation of healthy optic disc appearance shortly after the cortical insult, with subsequent corresponding optic atrophy (typically, years afterward) not explicable by other interceding disorders would argue for transsynaptic degeneration.

(2) Because significant primary anterior visual pathway disease in early life may be accompanied or followed by nystagmus, one may be tempted to use this sign to distinguish between primary versus transsynaptic optic atrophy. However, it has been argued that an intact visual cortex is necessary for the development of such nystagmus,165 so that children with combined anterior and posterior pathway insults may not show nystagmus. Hence, we lose the opportunity to use nystagmus as a relatively reliable sign of profound anterior pathway disease in early life. (3) Scrutiny of optic discs in patients with unilateral or asymmetric postgeniculate pathway disease for signs of corresponding band atrophy would provide strong evidence of transsynaptic degeneration, assuming that the original damage did not involve the geniculate nucleus or optic tract on the same side.

(4) Patients with pure cortical blindness usually show normal pupillary reactions. However, it appears that the pupillomotor fibers, which do not synapse at the lateral geniculate nucleus but at the pretectal area, may also be susceptible to transsynaptic degeneration.572 On the basis of this evidence, the pupillary examination may not be sufficient in distinguishing anterior visual pathway disease from CVI in all instances.

Transsynaptic degeneration has been proposed to occur in humans after lesions during adult life in a variety of other locations in the nervous system. For instance, reduction in the number of lower motor units and electromyographic denervation activity have been found following upper motor neuron lesions caused by injury to the spinal cord or by cerebral hemorrhage; transsynaptic dysfunction has been presumed responsible.55,81,325,393 Crossed cerebellar atrophy has been demonstrated on neuroimaging following cerebral hemorrhage or infarction; transsynaptic degeneration of the corticopontocerebellar tract and the cerebellorubrothalamic tract has been proposed as an explanation.233

Oculopalatal myoclonus is thought to result from hypertrophy of the inferior olive because of transsynaptic degeneration.350 Nerve fiber layer atrophy may also occur in conditions affecting outer retinal elements, presumably due to transsynaptic degeneration.193,285,438 Iris heterochromia has been demonstrated in patients with acquired Horner’s syndrome; transsynaptic degeneration of postganglionic sympathetic fibers has been suggested as an explanation.108 Transsynaptic degeneration of postganglionic parasympathetic fibers has been suggested as an explanation for cholinergic super-sensitivity of the iris sphincter noted after preganglionic oculomotor nerve lesions.279 Transsynaptic degeneration of the visual pathways may also be antegrade. For example, the cells of the lateral geniculate nucleus showed transsynaptic degeneration following injury to the optic nerve in adult patients.507,538

Transsynaptic degeneration was postulated to affect the retinal ganglion cells of humans after postnatal cerebral