Fig. 1.5  Bilateral occipital encephalomalacia. Axial T1-weighted MR image shows bilateral occipital injury with loss of the posterior periventricular white matter and ventricular dilatation. With permission from Brodsky et al76

congenital or early-acquired cortical visual loss in children may be quite different from the acquired variety in adult life. The immature, extremely adaptable infantile brain may react differently to injury than the adult brain. As the entity of CVI in infants and children is explored further in this chapter, the reader should keep in mind that some qualifying remarks are necessary for each of the classic features included in the above definition. First, the visual loss need not be severe; CVI represents a spectrum of disability. Second, although most children with cortical visual loss have obvious neurologic deficits,281,318 the diagnosis of CVI should be suspected in all children with unexplained bilaterally decreased vision, even when there are no overt neurological problems.372 In this setting, a history of prematurity is highly suggestive of periventricular leukomalacia (discussed below). Third, the pupillary reaction to light may not be completely normal. This finding may be due to coexisting disorders of the anterior visual pathway, the sympathetic and parasympathetic pathways, transsynaptic degeneration of the pupillomotor fibers if the cortical lesion is prenatal, or direct geniculate injury in some cases.572

On the basis of clinical evidence derived from patients with congenital homonymous hemianopia due to congenital occipital lesions, 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 Fourth, affected patients may display intermittent, unsustained bursts of nystagmus. Characteristic wandering eye movements seen in severe CVI should not be mistaken for nystagmus. Finally, the eye examination may reveal coexistent optic atrophy due to associated anterior pathway disease or transsynaptic degeneration of the retinogeniculate pathway.

Causes of Cortical Visual Loss

A wide range of etiologies for CVI have been documented.76,262,264,318 These include trauma (accidental and nonaccidental),217,229neurodegenerativedisorders,hypoglycemia,425 hemodialysis,415 infectious disorders,63 encephalitis/meningitis,4,5,146,439,531,562 hydrocephalus,17,96,371 and seizures.328 The major causes of cortical visual loss are discussed below.

Perinatal Hypoxia-Ischemia

The most common cause of CVI in children has long been considered to be hypoxic brain insult (asphyxia).262,264–266 In full-term infants who sustain hypoxic-ischemic injury, neurons that are primarily in the deep gray nuclei and perirolandic cortex are most likely to be injured.160,597,598,601 Hypoxia and the accompanying hypercarbia causes a loss of vascular autoregulation in the brain, resulting in a pressure-passive blood flow.116 The resulting pattern of injury has been described to be within the “watershed zones” of the cerebral cortex (the areas between the anterior and middle cerebral artery circulation and the middle and posterior cerebral artery

circulation).160,262,264–266

In full-term infants, the watershed zones lie in the regions between the anterior and middle cerebral arteries and between the middle and posterior cerebral arteries. The resulting watershed area is termed the parasagittal region. Ischemic lesions most commonly involve either the frontal region or the parieto-occipital region at the posterior parasagittal area (so that the visual cortex is particularly susceptible to injury). Many watershed zones between two arteries exist in the brain, but the only triple watershed areas are the parietooccipital areas and the area of the body of the caudate nucleus. It is in these watershed zones that tissues are most vulnerable to hypoxia and hypotension. It should be noted that damage to the radiations carries a worse prognosis than damage to the cortical areas.341 Ischemic brain damage may occur perinatally or any time after birth, as it may occur following respiratory or cardiac arrest.

However, the longstanding view that neonatal brain injury is uniform and due primarily to acquired insults such as birth asphyxia has also undergone some revision.27 Most neonatal brain injury is now viewed as metabolic, whether from transient ischemia-reperfusion events or from defects in inherited metabolic pathways expressed soon after birth.160 In addition to hypoxia, it is known that oxidative stress, excitotoxicity, inflammation, and apoptosis play important roles.160 The cellular and molecular mechanisms involved in the pathogenesis of cortical visual loss are becoming clear. Oxidative stress and excitotoxicity, through downstream intracellular signaling, produce both inflammation and repair. Cell death begins immediately and continues over days to weeks. The cell-death phenotype changes from an early necrotic morphology to a pathology resembling apoptosis.160

Postnatal Hypoxia-Ischemia

Perinatal strokes, defined as occurring between 28 weeks of gestation and 7 days of age, have an estimated incidence of up to 1 in 4,000 live births.374 They are often arterial in origin and ischemic in nature160 although at least 30% are due to sinovenous thrombosis.123 Prepartum factors such as preeclampsia and intrauterine growth restriction have been implicated.617 Most strokes occur at or near the time of birth, resulting in hemiplegic cerebral palsy. Coagulation abnormalities (decreased levels of protein C, protein S, and antithrombin III and elevated plasma levels of Lp[a] lipoprotein and homocysteine), as well as certain genetic mutations and polymorphisms (including factor V Leiden G 1691A, factor II G20210A, and methylenetetrahydrofolate reductase C677T) have been identified as risk factors,222,402 especially in neonates with stroke due to cerebral venous thrombosis.160,616 Newborns with stroke usually have more than one risk factor, and perinatal complications such as hypoxic-ischemic events are frequently present.160,242,616

Postnatal hemodynamic changes associated with generalized hypotension, cerebral angiography, cardiac surgery, cardiac arrest, and air embolism may result in CVI by diminishing the blood supply to the posterior visual pathway. Hypertensive crisis may result in occlusion of the posterior cerebral arteries, causing a similar problem. Transtentorial herniation may cause compression of the posterior cerebral arteries. Infarcts may also result from vascular malformations or from congenital central nervous system (CNS) tumors directly compressing cranial vessels. The most common cause of embolic phenomena in the neonatal brain is congenital cyanotic heart disease. Thrombotic disorders may result from polycythemia, trauma, meningitis, and obliterative arteritis associated with neurofibromatosis and sickle cell disease. Anoxia may have been the etiology of cortical blindness in a patient with acute intermittent porphyria.339

Cerebral Malformations

A variety of cerebral malformations may be associated with CVI or congenital homonymous hemianopia. These include occipital or parietal encephaloceles, Chiari malformations, Dandy–Walker complex, hydranencephaly, porencephalic cysts (from either vascular compromise, infective processes, or hemorrhagic dissection),546 or neuronal migrational abnormalities.32

During the seventh week of gestation, a neural layer known as the germinal matrix is formed through proliferation of neurons in the subependymal layer of the walls of the lateral ventricle. In the eighth gestational week, these neurons begin to migrate centrifugally from the germinal matrix to form the cerebral cortex. The route of neuronal migration is guided by radial glial fibers extending from the germinal matrix to the cortex. Events that interfere with this migration (e.g., infections, ischemia, metabolic derangements) can cause a migrational abnormality. A migrational anomaly shows normal neurons in an abnormal location, somewhere between the walls of the lateral ventricles and the cortex. The clinical manifestations of migrational abnormalities depend on the severity, nature (diffuse versus focal), and location of the abnormalities. Differences in the timing and severity of the migrational arrest result in different categories of abnormalities. The most severe of the migrational anomalies is lissencephaly, which includes agyria (absence of gyra on the surface of the brain) or pachygyria (a few broad, flat gyri), or both (Fig. 1.6). In polymicrogyria, the neurons reach the cortex but distribute abnormally,

Fig. 1.6  Proton density axial MR imaging scan from child with cortical blindness and Walker–Warburg syndrome demonstrating lissencephaly (agyria) and hydrocephalus

Fig. 1.7  Axial MR imaging showing large, bilateral porencephalic cysts in 6-year-old boy with cerebral palsy and cortical blindness

forming multiple small gyri. Neuronal heterotopias are focal collections of neurons in abnormal locations. Schizencephaly denotes gray matter–lined clefts extending from the lateral ventricles to the surface of the brain.33 Unilateral megalencephaly consists of a hamartomatous overgrowth of all or part of one cerebral hemisphere, with migrational anomalies (pachygyria, polymicrogyria, and neuronal heterotopia) and gliosis of the affected hemisphere.

Strictly speaking, porencephaly refers to a focal cavity devoid of surrounding glial reaction resulting from the localized brain destruction that occurs during the first 20 weeks of gestation (Figs. 1.7–1.9). It differs from schizencephaly, a migrational anomaly resulting from destruction of a portion of the germinal matrix and consisting of a gray matter–lined cavity. Porencephaly also differs from encephalomalacia, which occurs later in pregnancy or anytime thereafter. These forms of cerebral dysgenesis are detailed in Chap. 11.

Head Trauma

Nonaccidental trauma (shaken baby syndrome) has been identified as a common cause of CVI in infancy. The diagnosis is established by the characteristic retinal hemorrhages and associated CNS abnormalities (subdural or epidural

Fig. 1.8  MRI scan of 7-year-old boy with spastic diplegia, mental retardation, betaketothiolase deficiency, and severe CVI. Note posterior, porencephalic-like dilatation of occipital horns of lateral ventricles. Only thin margin of overlying cortex remains

hematoma), the appropriate social picture, and the fastidious exclusion of other mechanisms of intracranial injury. In this setting, the retinal hemorrhages resolve but the child remains blind or severely visually impaired. The spectrum of traumatic head injury may range from mild concussion to a severe contusion, laceration, or diffuse axonal damage. The injury may also cause or be followed by epidural, subdural, subarachnoid, intracerebral, or optic nerve sheath hemorrhage.619 Permanent visual loss in shaken baby syndrome is usually caused by CVI.391 Diffusion-weighted MR imaging is the study of choice to identify the posterior cerebral ischemia that causes permanent visual loss, and the subdural hematomas that characterize this condition.60 In some children, however, the resulting visual morbidity may be attributable to retinal detachment, retinal folds, macular hole, or epiretinal membrane, alone or in combination with CNS injury.149,450

It is useful to separate cases occurring after minor or trivial trauma, which have a benign course, from those occurring after severe head trauma that often lead to permanent neurological and visual sequelae. Patients in the latter category usually show external or radiological signs of trauma (e.g.,

Fig. 1.9  (a) Axial and (b) coronal MR imaging of 3-year-old girl with left homonymous hemianopia and questionable history of viral infection at about 8 weeks gestation. Note large, right cerebral poren-

cephalic cyst, compensatory hemihypertrophy of left cerebral hemisphere and macrogyria with limited sulcal formation

skull fracture, frank cerebral injury, intracranial hemorrhages, hemotympanum). For example, a 13-year-old boy was hit with a baseball bat on his occiput, and he lost consciousness for 4 min. On recovering consciousness, he was noted to be agitated, disoriented, and blind. Neuroimaging displayed comminuted skull fractures and contusions of both occipital lobes and the right parietal lobe. Various neurological complications, including papilledema, developed. Vision recovered in 10 days, but visual field defects persisted. Follow-up CT showed atrophy of the previously injured lobes.313 In patients with severe trauma, neuroimaging of the brain may demonstrate cerebral edema, massive brain swelling, hemorrhage, or resulting hydrocephalus. The visual loss may be permanent, or it may resolve partially or totally over several weeks. Children with nonreactive pupils and those who are ventilator-dependent carry a worse prognosis.318

Older children with transient CVI after minor or apparently trivial trauma may have total or partial blindness, homonymous hemianopia, palinopsia, a patchy visual loss, or a “whiteout” of the visual fields, or they may describe fine flickering of vision resembling a snow storm.147,236 Affected children usually have an otherwise normal examination, but they may occasionally show soft tissue swelling and tenderness corresponding to the area of cranial trauma. Neuroimaging studies are typically nonrevealing. In all reported cases, blindness occurred within several hours of head injury and lasted less than 24 h. Patients characteristically do not experience loss of consciousness. They

typically show visual recovery, which may occur from minutes to days after injury (on average, a few hours).217,236

Such patients may have electroencephalographic (EEG) findings that initially show either generalized or posterior, bioccipital slowing that subsequently normalizes. The younger child may not report visual loss and may not recognize blindness but may display any combination of the following signs and symptoms: agitation, restlessness, uncooperativeness, confusion, irritability, disorientation, headaches, vomiting, drowsiness, and unsteady gait. To avoid underdiagnosis, it has therefore been recommended that traumatic CVI should be suspected in trauma patients who exhibit such findings.621 Whether the associated agitation and restlessness are a psychological reaction to the blindness or a result of traumatic brain dysfunction is uncertain.

The nature of traumatic cerebral dysfunction may include a concussive cerebral injury, localized edema, ischemia, or epilepsy. Damage to the posterior visual pathway may occur via a coup or contracoup mechanism. Patients with transient blindness after minor trauma often have a family history of migraine, implicating a possible vascular role (a migraine equivalent), possibly local cerebral vasospasm.147 The visual snow storms described in some patients are also described with migraine, and many of the abovementioned associated symptoms and signs are common in migraines. The patient who loses vision after voluntarily striking a soccer ball with his head236 shows close clinical