of affected parents places the disease in the recessively inherited category. Involvement of only male siblings should alert the clinician to a possible X-linked inheritance pattern. Simplex cases of retinitis pigmentosa are cases with no family history, and generally represent recessive forms or new mutations in the genome. The recessive varieties, including autosomal and X-linked recessive, tend to be more severe with earlier onset. Evolutionary basis for the preponderance of the dominant forms may relate to the relatively innocuous nature of these mutations during the reproductive years.

A detailed examination of vision, pupils, motility and retina is a crucial aspect of patient evaluation. Most patients with congenital blindness, in addition to poor fixation, will suffer from considerable nystagmus and poor pupillary reactivity, as seen among patients with LCA. Cycloplegic refraction can help determine the presence of associated pathologic levels of ametropia. While reduction in central acuity can be easily documented in the older pediatric age group, visual field compromise can only be inferred from peripheral inattention and relatively crude confrontational testing in younger patients. Again, pupillary reaction can be of considerable help in assessing the level and symmetry of the visual compromise, especially in cases of asymmetric disease. Fundus examination of the retinal periphery generally shows varying levels of pigment atrophy, from subtle stippling in early retinitis pigmentosa and Usher syndrome to large semiconfluent areas of scalloped atrophy seen in gyrate atrophy and myopia.

Electrophysiologic studies can provide important additional information to narrow the diagnosis of hereditary retinopathies. Generally, infants and young children require sedation for the study and older children must be cooperative enough to tolerate contact lens electrode placement on the cornea. In the pediatric age group, often only gross changes or deficits can be reliably recorded by these techniques, and results should mainly supplement findings from careful clinical history and exam. Subtle gradations and variations in electroretinography are generally not clinically meaningful. Electrooculography is somewhat more reliable in this age group and largely used in cases of pigment epithelial dystrophies and central macular findings, which are discussed in a separate chapter.

Molecular diagnostic testing may be helpful in some cases. Classically, only a handful of conditions are amenable to such testing. However, the numbers are increasing as larger number of disease loci and

mutations are identified. Already several laboratories across the country offer limited diagnostic testing for specific conditions as a part of the National Eye Institute-foundedEYEGENEconsortium. Additionally commercial sources such as Asper Biotech and Kimball Genetics provide some genotype analysis services by screening for specific genetic mutations or risk factor loci. High false negative rates due to the large gaps in the library of known loci and mutations have limited the widespread use and application of this emerging technology. Further growth of molecular information will likely remedy this shortcoming of molecular testing in years to come.

Finally, it is important to recognize that an unrushed, staged approach with repeated examinations over the course of several visits may be more advantageous than a rapid, intensive push to come to a final diagnosis. Observation of the clinical course gives valuable data regarding the stationary or progressive nature of the disease and helps predict the visual function in these children much better than an intensive, one-time evaluation. As children get older, many of the artifacts resulting from lack of cooperation are resolved and the need for sedation or anesthesia diminishes. In general, immediacy of precise diagnosis is not a major issue from a therapeutic standpoint in these disorders yet. The relative benefits, risks, stress and discomfort must be judiciously weighed before exposing patients and their families to time-consuming and potentially inconclusive studies.

12.4  Inherited Disorders of Retinal

Structure and Function

12.4.1  Retinitis Pigmentosa

12.4.1.1  Overview with Clinical Significance

Retinitis pigmentosa is caused by abnormalities in photoreceptor function and integrity, and is one of the most common forms of inherited retinal degeneration. All forms of the disease can present in the pediatric population in the first or second decade of life, either in isolated form or in association with a systemic syndrome. The disease poses a significant challenge for clinicians, pediatric patients and their families. The more severe

forms, particularly X-linked and recessively inherited variants, will present with earlier onset and tend to have poorer prognosis. Associated systemic conditions, such as deafness in Usher Syndrome, may compound the visual disability caused by retinitis pigmentosa.

Ophthalmologists play a crucial role in managing these patients by identifying the disease as accurately as possible, determining the extent of disability, providing a visual prognosis, and instituting treatment when available. While physicians cannot currently offer therapies to arrest the disease, vitamin A supplementation, low vision aids and reassurance regarding the relatively slow pace of disease progression can be helpful to patients. Substantial visual adaptation can occur over the course of several years that may pass before reaching end-stage vision loss. In addition, these patients are tremendous resources for investigating the basis of retinal pathogenesis and normal retinal function. They may frequently be provided with a cautiously optimistic outlook towards visual prognosis, given the rapid developments in the areas of diagnostic and therapeutic interventions.

12.4.1.2  Genetics

As mentioned previously, genetics is a major criterion in the classification of retinitis pigmentosa and allied retinopathies. Although the disease can occur in simplex form with no family history, classically it is thought of as having autosomal dominant, autosomal recessive or X-linked recessive patterns. Determination of the inheritance pattern can be challenging, especially given that disease manifestations may range from subtle subclinical disease to full-blown disease within the same family. Examination of other family members may therefore be necessary to detect subclinical disease, or disease that has yet to manifest. More recently, the determination of the inheritance pattern has become even more complicated as the notion of monogenic inheritance has been challenged by molecular findings that suggest genetic modifiers and digenic forms of retinitis pigmentosa [17]. In this recently discovered mode of genetic transmission, autosomal recessive carriers of two distinct gene mutations may produce offspring with one copy of each recessive gene. The resultant phenotype may exhibit a new and unique manifestation of disease. This digenic inheritance pattern was first discovered for retinitis pigmentosa, and only begins to elucidate the vast variability seen in this disease.

Mutations in a variety of genes involved in photoreceptor function and metabolism have been associated with various forms of retinitis pigmentosa [3]. Mutations in the rhodopsin gene on chromosome 3 were the first to be reported [1] and the repertoire of these mutations has since grown to include over 100 mutations involving various residues of the molecule. Rhodopsin gene mutations account for approximately 10% of all retinitis pigmentosa cases, and are 25 times more likely to be transmitted in a dominant than recessive pattern. The P23H allele on the rhodopsin gene is the most common mutation associated with autosomal dominant retinitis pigmentosa in the United States. However, despite the relative prevalence of this mutation, rhodopsin remains only one of over 30 known genes associated with retinitis pigmentosa. More than half of causative genes for this disorder are as yet unidentified [18].

This molecular heterogeneity is reflected in the variability in phenotype and disease course among different families. Additional variations in genetic background, modifiers, and environmental factors complicate disease expression and lead to further divergence of disease phenotype. Disease expression may vary from asymptomatic, minimal retinal findings to severe vision loss even within the same family. The common thread among all these mutations is that they ultimately lead to loss of photoreceptor integrity, galvanizing the degeneration of the rest of the retina.

12.4.1.3  Pathophysiology

The exact sequence of pathologic events leading to the degeneration of predominantly rod photoreceptors, followed by cones and ultimately the entire retina, is essentially unknown. Examination of postmortem eyes from patients with advanced retinitis pigmentosa has revealed prominent loss of the photoreceptors with atrophy of pigment epithelium, together with deposition of pigment along the retinal vessels [19]. The earlier intervening steps between the mutation of photoreceptor proteins and loss of retinal integrity are the subjects of intensive investigation [20].

Studies of in vitro and animal models suggest that gene mutations most likely disrupt the normal protein processing pathways that are responsible for daily renewal of photoreceptor outer segments. Mutations in the RDS gene on chromosome 6, for example, lead to abnormally long outer segments which are not normally shed and processed by retinal pigment epithelium [8].

Additionally, the photoreceptors with the mutant proteins may not process light-activated intermediates efficiently, hence leading to increased susceptibility to light-induced cumulative damage [21]. Programmed cell death appears to follow as the final common pathway in retinal degenerative disorders with loss of photoreceptors. Secondary effects on cones and neuronal connections ultimately lead to generalized retinal degeneration.

12.4.1.4  Prevalence

Prevalence is variable among different populations. Estimates range from 1:5,000 in the United States’ Maine population [22] to 1:2,000 among Native Americans [23] to roughly 1:4,000 among African Americans. The average estimated prevalence is approximately 1:4,000. The role of environmental vs. genetic factors in determining prevalence of clinical disease remains unresolved.

12.4.1.5  Patient History and Evaluation

A detailed patient history, especially the family history, can be immensely helpful in arriving at an accurate diagnosis. History of prenatal TORCH infections such as rubella and syphilis, which may be confused with retinitis pigmentosa due to mottling of the retinal pigment epithelium, is usually lacking. A generalized review of systems will point to no other systemic involvement in nonsyndromic forms. Affected children as early as preschool years can present with difficulty in navigating in dim light or finding dropped objects. School vision testing frequently does not uncover these disorders, as color and central vision can remain normal in early stages of disease.

In nonsyndromic forms of juvenile-onset disease, abnormalities in ophthalmic exam are predominantly confined to the posterior segment. Normal visual acuities are generally the rule in this condition, even with early onset variants, unless complicated by cystoid macular edema or cataracts. Pupils will symmetrically react, albeit sometimes at a sluggish pace. Nystagmus and absence of pupil reactivity is not expected and if present, should alert the clinician to an alternate diagnosis of LCA. External and anterior segment exams are generally undisturbed in nonsyndromic forms of retinitis pigmentosa. Slit lamp examination reveals none or few abnormal findings, although in later years some pigment dusting and posterior subcapsular cataracts can be noted.

In both isolated and syndromic forms, the usual triad of peripheral bone spicules, vascular attenuation, and optic disc pallor (Fig. 12.1) may be partially or completely missing in early forms of the disease. Retinal pigment atrophy will typically spare the macula. Careful examination may also show some degree of disc pallor or vascular attenuation in a number of patients who have not yet developed pigmentary changes in their retinas. In the sine pigmento form, the abnormal pigment is nearly completely absent even in the later stages of the disease.

Visual field loss is an important characteristic finding of retinitis pigmentosa. The typical pattern includes progressive, midperipheral absolute scotomas, which coalesce into a ring pattern that correlates in location and shape to the extent of fundus pathology. In the absence of field defects, the diagnosis of congenital stationary night blindness (CSNB) should be entertained, especially if there is minimal posterior segment involvement. The posterior segment can have variable appearances even in typical disease, ranging from diffuse to no visible involvement. Extraocular involvement in syndromic forms can range from the isolated loss of auditory or middle ear function seen with Usher syndrome, to widespread systemic pathologies seen with the mucopolysaccharidoses.

12.4.1.6  Diagnostic Testing

In addition to a family history and fundus exam, electrophysiologic testing is crucial for establishing the diagnosis of RP in most cases [24, 25]. Sedation may be required for dark adaptation in the pediatric population in order to obtain an ERG of adequate quality [26]. A rod-cone dystrophic pattern with substantial reduction and delay in the dark adapted a-wave is an expected hallmark feature common to the electroretinograms of all patients. This is seen even with the earliest forms of the disease and is attributable to attrition in the rod photoreceptor population. Generally, the amplitudes are reduced to levels substantially below 100 mv and frequently to less that 10 mv with no distinct alteration in the b-wave to a-wave ratio. Implicit time, the time from stimulus onset to peak of response, is generally prolonged as in other forms of degenerative disorders. The 30 Hz flicker study demonstrates that cone amplitudes are affected to a lesser extent, although there is substantial decrement in the magnitude of the response that is consistent with collateral loss of cones (see

Chap. 3, Figs. 3.7 and 3.8 for representative electroretinograms). One should also note that reduction of amplitude against a tested normal population can sometimes be a nonspecific result of a variety of retinal conditions.

Formal visual field testing or perimetry can also be of considerable importance in establishing the diagnosis of retinitis pigmentosa. Loss of photoreceptors will produce deep and absolute scotomas that are readily apparent on kinetic perimetry. Visual field loss is an important indication of the degenerative nature of this disorder and distinguishes retinitis pigmentosa from other forms of stationary retinal dysfunction.

Additional laboratory diagnostic testing and intravenous fluorescein angiography (IVFA) is of limited value in confirming the diagnosis and uncovering associated conditions. Generally, IVFA is not greatly hyperfluorescent, showing several window defects that correspond to the numerous foci of pigment epithelial atrophy. Central leakage may be present in cases with associated cystoid macular edema. In many cases,

however, the IVFA fails to reveal leakage despite the presence of cystoid changes in the macula. In these patients, optical coherence tomography can be of value in confirming the presence of cystoid macular edema and in objectively following its resolution with treatment. Additionally high resolution spectral domain OCT can point to widespread thinning and loss of outer retinal cells in subtle disease with minimal bone spicules. Laboratory testing, including syphilis serology, phytanic acid levels and other metabolic parameters, can help rule out other potential etiologies underlying the clinical picture.

Retinitis pigmentosa can be confused with a number of other retinal dystrophies and clinical entities that cause a pigmentary retinopathy. Diffuse and macular dystrophies such as cone rod dystrophy, LCA, Stargardt disease and choroideremia, can mimic the fundus appearance of retinitis pigmentosa in the early stages. These may be distinguished by ERG and visual field evaluation. Syphilis, rubella and measles in the perinatal periods can also produce clinical pictures