grating acuity to classify children as legally blind for social service purposes as doing so may overestimate their visual function and unjustifiably deny financial benefits to qualified children. While conventional visual evoked potential (VEP) testing has not proved to be a reliable method of quantitative visual evaluation in patients with cerebral palsy, mental retardation, or severe neurological disease,19,61,176,182,395,396,557 modified techniques using sweep and step VEP may provide more accurate information.200,375,376

In children with poor vision and nystagmus due to anterior visual pathway disorders, Jan et al298 proposed the performance of the “unequal nystagmus test” to determine which eye, if either, has better vision. The test is performed by noting the degree of nystagmus while the child views an attractive toy at a distance with both eyes open and then with alternate eyes covered. The nystagmus is similar in patients with similar acuity in both eyes. When the acuities are different, wider and slower excursions of nystagmus are noted in the worse eye, and faster and smaller-amplitude nystagmus is noted in the better eye. Other batteries of tests with the stated purpose of evaluating vision in children with severe visual deficits have been recently described.132

Much valuable clinical information about visual impairment in children has been gleaned from the collaborative efforts of various subspecialists working as multidisciplinary diagnostic teams. The collaborative efforts of pediatric ophthalmologists, pediatric neurologists, electrophysiologists, behavioral psychologists, and developmental specialists, among others, will be needed to further enhance our understanding of the various disorders discussed within.

Besides rendering accurate diagnoses and treating the remediable causes of blindness, the clinician should be acquainted with the mental, psychological, neuroendocrinologic, developmental, and educational needs of visually impaired children. Knowledge of the various available programs that may act as resources for affected children and their families is essential, especially because, unfortunately, definitive treatment of many of the underlying conditions remains elusive.

This chapter addresses causes of blindness that are neurological in origin or that have features that warrant including them in the differential diagnoses of neurologic causes of blindness. Emphasis will be placed on CVI and related disorders. Causes of blindness due to congenital ocular disorders associated with obvious structural ocular abnormalities (e.g., albinism, congenital cataracts, chorioretinal colobomas, ROP) are discussed elsewhere.

Hereditary Retinal Disorders

Causes of blindness in infancy due to opacities of the optical media or to refractive errors are usually discovered during a

thorough ophthalmologic evaluation. Optic nerve hypoplasia may be potentially overlooked if the examiner mistakes the border of the outside ring in the classic double-ring sign with the border of the disc.342 Generally, hereditary diseases of the retina should be suspected in children who present with a bilateral decrease in vision, light sensitivity, color deficiency, visual impairment confined to either daytime or nighttime, and a tendency to bump into objects and to hold objects very close to the face. A family history of similarly affected members may be elicited, and a history of consanguinity is highly suggestive, because many of these disorders are recessively inherited.

Many patients with congenital retinal dystrophies have characteristic features that are highly suggestive, if not virtually diagnostic, of a specific underlying disorder. For instance, profound photophobia and high-frequency nystagmus in a blind child with otherwise normal-appearing eyes suggest rod monochromatism, whereas blindness and nystagmus in the presence of diffuse pigmentary retinal changes suggest LCA. Unfortunately, not all patients can be pigeonholed into these classic presentations; some require further investigation, for instance, the blind infant with an ostensibly normal fundus appearance who has LCA. Many congenital retinal dystrophies are distinguishable on the electrophysiological level but remain otherwise poorly defined as simply cone dystrophies, cone–rod dystrophies or rod–cone dystrophies, although diagnosis at the molecular level is rapidly becoming available.

Leber Congenital Amaurosis

LCA is a congenital retinal dystrophy involving both rods and cones.244 It is usually autosomally recessive, but occasionally autosomal dominant.565 It is characterized by the onset of blindness at birth, a variable fundus picture, and an absent or extremely attenuated ERG. Photophobia is seldom present and is never of the degree found in congenital achromatopsia. Patients show roving eye movements, poorly reactive or unreactive pupils, and a positive oculodigital sign of Franceschetti (pushing on the eyes or rubbing them with a finger or fist) to create phosphenes. The fundus picture may appear normal at birth or shortly thereafter. However, a variety of pigmentary changes may develop over months or years (Fig. 1.3). These include salt-and-pepper pigmentation, yellowish flecks, a mosaic pattern, periarteriolar distribution of yellow lesions, a retinitis pigmentosa–like fundus, macular colobomas that may gradually enlarge, and pseudopapilledema.549 The abnormal retinal appearance may be progressive, leading to a variable picture of chorioretinal degenerative changes, vascular narrowing, and optic disc pallor. The vascular narrowing is probably present at birth but is easily overlooked.

Patients have a higher-than-normal risk of developing keratoconus and cataracts later in life.

The pattern VEP is absent, as is the flash VEP in most cases. This disorder is now known to comprise a number of genetically heterogeneous conditions.241,549 The visual acuity ranges from 20/200 (rare) to no light perception.346,347 Parents can be reassured that the visual impairment is usually nonprogressive, despite the visible progression of the fundus findings.241 Exceptional cases showing further visual deterioration with time belong either to the subgroup of LCA with macular colobomas or to harbor cataracts or keratoconus.241 Conversely, some patients with Leber amaurosis may show some visual improvement in the first several years of life, enough to have visually guided behavior and measurable grating acuity. A similar phenomenon occurs in some patients with albinism and some children with optic nerve hypoplasia. It is attributed to a secondary delay in maturation of the posterior visual pathways.166,168

As many as half of the patients with LCA examined before 1 year of age may show a normal retinal appearance,241 although careful examination using direct ophthalmoscopy shows marked arteriolar narrowing. Because nystagmus may not be present during the first few months of life, the normal retinal appearance in many infants with LCA may pose a diagnostic dilemma, raising the specter of CVI or DVM, among other conditions. The ERG is the definitive test in establishing the diagnosis of LCA. The range of refractive errors associated with LCA is wide, ranging from high hyperopia to high myopia, with high hyperopia being far more common. Some studies have suggested that associated high hyperopia differentiates a distinct subset of the disorder, uncomplicatedbyneurologicorsystemicdisease.180a Subsequent studies disproved this distinction, showing that high hyperopia (which is associated with the CRB1 mutation)3 cannot be

used to differentiate complicated cases from uncomplicated ones.565 One to three percent have nephronophthiasis, osteoporosis, ataxia, cardiomyopathy, or cerebellar disease. The purported association with mental retardation is mainly attributable to the inadvertent inclusion of children with peroxisomal disorders. Although some mutations (RPGRIPI and CRB1) are expressed in the brain, there are no reported LCA patients with these genotypes who have brain abnormalities.565 A careful consideration of neurologic, systemic, and biochemical disorders should be offered to patients with LCA, regardless of refractive error.346

The optic discs appear normal early but may later develop pallor (Fig. 1.3). Sullivan et al549 retrospectively reviewed the optic disc findings in 77 patients with LCA. Sixty-nine percent showed normal discs, 23% showed varying degrees of optic atrophy, 3% showed pseudopapilledema, and 1% showed gray discs. They concluded that the optic discs are frequently normal, even in older patients with LCA, and suggested that the finding of significant optic atrophy in an infant suspected of having LCA should suggest one of the systemic, metabolic disorders associated with infantile retinal dystrophies (e.g., peroxisomal disorders). In our experience, careful examination using direct ophthalmoscopy shows a striking diffuse arteriolar narrowing in otherwise normal optic discs.

A number of systemic disorders manifesting a congenital retinal dystrophy in association with other neurologic or systemic disorders have been previously grouped with LCA. These include medullary cystic kidney disease or nephronophtisis (Senior–Löken syndrome), cone-shaped epiphyses of the hand and cerebellar ataxia (Saldino–Mainzer syndrome), vermis hypoplasia, ocular motor disturbances and neonatal respiratory problems (Joubert syndrome), psychomotor retardation, mental retardation, autistic behavior, ­hydrocephalus, deafness, epilepsy, or cardiomyopathy.

The admixture of neurologic or systemic disease in patients who have been diagnosed with LCA is well-recognized.565 Patients with systemic diseases that do not manifest early in infancy continue to be misdiagnosed as having LCA because vision loss occurs early and dominates the clinical phenotype early in the course of the disease. One of the common and challenging diagnostic situations involves the blind infant with a provisional diagnosis of LCA who shows behavioral and developmental abnormalities that are interpreted by some as being caused by the visual impairment and by others by the associated neurological abnormalities. The association of an LCA ocular phenotype with autism or other neurodevelopmental diseases has been well documented by a number of authors.12,56,88,155,441,518 Autistic behavior consequent to early interactive visual experiences can be prevented through specific strategies of intervention.155

The ever-increasing identification of distinct disorders once grouped with LCA and the heterogeneity of the findings associated with LCA reflect the fact that LCA is not a single nosologic entity but rather a group of genetically heterogeneous disorders, many of which have now been characterized.9 Furthermore, many children with peroxisomal disorders and blindness get classified as having LCA until their underlying metabolic disturbance becomes evident.226 It should be noted that the various disorders of congenital retinal dystrophy described earlier do not have identical clinical presentations. For instance, most children with neurometabolic disorders who are misdiagnosed as having LCA early in life show better visual acuity than the typical child with LCA. Thus, the finding of an extinguished ERG in a young child with good vision should arouse clinical suspicion of an underlying neurometabolic syndrome.

A number of oculocerebral disorders associated with peroxisomal dysfunction and a high blood level of very longchain fatty acids177,465 may simulate LCA. The peroxisome is a single-membrane subcellular organelle that mediates the catabolism of very long-chain fatty acids, phytanic acid, and pipecolic acid, as well as the biosynthesis of some types of membrane lipids.539 Cerebro-hepato-renal syndrome (Zellweger syndrome), neonatal adrenoleukodystrophy, and infantile Refsum disease are associated with peroxisomal dysfunction and progressive deterioration of rod and cone function.625 All three conditions show rapidly progressive neurological deterioration, but the initial manifestation before this deterioration occurs may resemble LCA both clinically and electrophysiologically. In fact, it is felt that some patients described in the older literature (before the advent of advanced metabolic testing) with LCA and neurological disease might have had one of these disorders. In an infant with poor vision and nystagmus, the findings of seizures, failure to thrive, developmental delay, neurosensory deafness, neurological deterioration, or dysmyelination of the brain on MRI should suggest a peroxisomal disorder and

prompt a metabolic workup. Therefore, infants or young children suspected of harboring LCA, especially if other neurodevelopmental abnormalities exist, should not only have a thorough ophthalmologic examination but should also be seen by a pediatrician or pediatric neurologist experienced in metabolic disorders.112

A minority of patients with LCA may show associated neuroimaging abnormalities, such as ventriculomegaly, dysmyelination, or cerebellar vermis hypoplasia.540 The finding of vermis hypoplasia should suggest a diagnosis of Joubert syndrome (discussed below). Recently, CPE290 mutations, which were first identified in Joubert syndrome, were discovered in patients with seemingly pure LCA (without structural or functional brain and without renal disease).118 A dosage model has been proposed that is similar to the dosage model that attempts to explain that retinitis pigmentosa, cone-rod dystrophy, and Stargardt macular dystrophy are all caused by ABCA4 mutations.118 According to this model, when the CEP290 protein is completely abolished, Joubert syndrome ensues, while if there is remaining CEP290 protein, albeit low and abnormal, neurological and renal disease is prevented, and only photoreceptor death occurs, causing isolated LCA.

Does early-onset blindness due to ocular disorders such as Leber amaurosis affect myelination and maturation of the posterior visual pathway? The optic radiations normally appear hyperintense on T2-weighted images and hypointense on T1-weighted images.320 Although the issue remains controversial,102,541 quantitative MR imaging has shown that early-onset blindness produces reduced white matter volumes in the optic tract, optic radiations, and significant gray matter losses in the visual cortex.451 In one child with bilateral anophthalmia, MR imaging showed complete agenesis of the anterior and posterior optic pathways.10

LCA should be differentiated from nonocular causes of blindness like cortical blindness or DVM. Infants with LCA may be thought to have CVI in the first few weeks of life, before the nystagmus appears. Conditions that are commonly mistaken for LCA include CSNB, achromatopsia, infantileonset retinitis pigmentosa, peroxisomal disorders, Joubert syndrome, and neuronal ceroid lipofuscinosis.346

ERG is particularly helpful in distinguishing between the various disorders in infants with poor vision, nystagmus, and a seemingly normal ocular examination.252 The three most common such disorders are LCA, CSNB, and congenital achromatopsia. LCA is characterized by extinguished or markedly attenuated ERG. Achromatopsia shows markedly attenuated or nonremarkable cone-mediated ERG; the rodmediated ERG is usually spared. CSNB shows a normal a wave but an attenuated b wave on rod-mediated ERG; the cone-mediated ERG may also be abnormal. It is important to realize that ERG is not a prognostic test. It simply indicates which retinal components are affected and to what extent,

but the test needs to be repeated if one is to determine whether or not a disorder is progressive (and at what rate) in a given individual.

Eleven different genes are responsible for 70% of cases of LCA.544 They involve six functional categories: phototransduction, cell polarity, intracellular transport, protein chaperoning, transcription regulation, and cell cycle progression.544 The identification of distinctive clinical characteristics in patients lumped together under the syndrome of LCA is becoming increasingly important diagnostically as well as therapeutically.565 For example, some patients with the CRX genotype show spontaneous marked improvement in vision in the first decade of life.324 Other mutations may give rise to gene-specific pharmacologic intervention, retinal transplantation, stem-cell based approaches, and gene therapy.13,56,118,323 The best known example of therapy for retinal diseases in general, and for LCA in particular, involves the Briard dog model, in which the defective RPE65 gene was replaced by a normal copy via transfer by an adeno-associated viral vector. Gene therapy in humans with this mutation has recently been shown to produce visual improvement and has so far been found to be safe and effective.28,379,396a Subsequent analysis of treated eyes by ERG revealed a substantial restoration of both rod and cone function confirmed by behavioral tests.6,431 Genetic testing also yields valuable prognostic information by identifying autosomal dominant (CRX) mutations or cases resulting from uniparental isodisomy.

Joubert Syndrome

Joubert syndrome was first described in 1969.302 It is characterized by a variable combination of the following features: episodic neonatal tachypnea and apnea, rhythmic protrusion of the tongue, ataxia, hypotonia, and variable degree of psychomotor retardation.343 The episodic tachypnea presents in the neonatal period and alternates with periods of apnea, resembles the panting of a dog, and usually resolves or improves. Notable associated eye findings may include congenital retinal dystrophy, nystagmus, abnormal supranuclear eye movements, colobomas, or congenital ocular fibrosis and other forms of strabismus. A congenital retinal dystrophy is seen in approximately 50% of patients with Joubert syndrome.277,319 This retinal dystrophy was at first labeled a variant of LCA. It was subsequently considered different from LCA in that the visual loss is usually not as profound (20/60– 20/200, compared with counting fingers or worse), and the VEPs are relatively spared (mild to moderate reduction in amplitudes, compared with absent or highly attenuated signals). Both conditions show flat or highly attenuated ERGs. Ocular motor disorders described in Joubert syndrome include slow, hypometric saccades, ocular motor apraxia, periodic

alternating gaze deviation, pendular torsional nystagmus, see-saw nystagmus, skew deviation, and defective smooth pursuit as well as optokinetic and vestibular responses.343

Dysgenesis or hypoplasia of the cerebellar vermis is a typical and a highly characteristic morphological feature of Joubert syndrome and Related Disorders (JSRD)316 (Fig. 1.4). MR imaging shows a “molar tooth” sign in the axial plane, which consists of an abnormally deep cleft in the isthmus of the brainstem, thickened and reoriented superior cerebellar peduncles, and vermian hypoplasia.332 The pathological findings include vermian hypoplasia or dysplasia, elongation of the caudal midbrain tegmentum, and marked dysplasia of the caudal medulla. These findings reflect a lack of decussation of the superior cerebellar peduncles, central pontine tegmental tracts, and corticospinal tracts.456 Genetically, Joubert syndrome is a heterogenous group of disorders with mapping to more than one chromosome site (9q34, 11p12-q13, 2q13, and 6q23). Two genes have been linked to Joubert syndrome. Mutations of AHI1 or Jouberin on chromosome on chromosome 6p23 usually presents with the classic form of Joubert syndrome.128,159 Patients with mutations of CEP290 on chromosome 12q usually present with additional ocular and kidney involvement.580 Classic Joubert syndrome has also been mapped to chromosome 9q34.3,497 while Joubert syndrome with additional eye and kidney involvement has been mapped to chromosome 11p12-q13.3.580

Complete agenesis of the cerebellar vermis may also occur, which is usually distinguishable from the vermian agenesis that occurs with the Dandy–Walker variant by the associated findings. For instance, hydrocephalus and cystic dilatation of the fourth ventricle do not occur with Joubert syndrome. However, 10% of patients with a Dandy–Walker cyst have the molar tooth sign and are clinically similar to classic Joubert syndrome patients. Such patients are referred to as Dandy–Walker Plus.383 Additional sporadic structural defects reported in association with the Joubert syndrome include other cerebellar midline defects, a dilated fourth ventricle, short neck, occipital meningoencephalocele, microcephaly, unsegmented midbrain tectum, absence of the corpus callosum and brainstem, multicystic kidneys, congenital ocular fibrosis, and bilateral retinal colobomas. The condition may be sporadic, but familial cases are inherited in an autosomal recessive pattern.

The Joubert syndrome has some overlapping features with the Arima syndrome (cerebro-oculohepato-renal syndrome), COACH syndrome, and Senior-Löken syndrome.516 The Arima syndrome exhibits pigmentary degeneration suggestive of LCA, severe psychomotor retardation, hypotonia, characteristic facies, polycystic kidneys, and absent cerebellar vermis. Joubert and Arima syndromes may be distinguished by such clinical features as neonatal tachypnea, which is one of the cardinal features of Joubert syndrome. The ocular motor features of this condition are discussed in Chap. 7.