Fundus Autofluorescence in Retinitis Pigmentosa



Fundus Autofluorescence in Retinitis Pigmentosa


Anthony G. Robson

Isabelle Audo

Phil Hykin

Andrew R. Webster



Retinitis pigmentosa (RP) is a heterogeneous group of disorders characterized by progressive retinal dysfunction affecting mainly rods with secondary cone involvement. Patients with RP classically present with impaired night vision and progressive visual field constriction with ultimate loss of central vision. Typically, as photoreceptors die, intraretinal pigment migration (“bone-spicules”) is observed along the midperipheral retina. Retinal blood vessel attenuation and disc pallor are seen in advanced stages. Fundus examination can be normal, especially early in the course of the disease. Full-field electroretinogram (ERG) demonstrates rod-cone dysfunction and may be essential in establishing the diagnosis and severity of the condition.

Autosomal dominant (AD), recessive (AR), and X-linked forms of inheritance can be observed in families affected with RP, with rare cases of mitochondrial and digenic forms. In general, AD RP has a better prognosis for retention of central vision than recessive or X-linked disease, although there is wide mutation-specific variability. In addition, RP can be isolated or be part of a syndrome. More than 180 genes implicated in retinal dystrophies have been mapped and more 120 genes have been cloned, highlighting the complexity of the disease (for a recent summary, see the Retinal Information Network, www.sph.uth.tmc.edu/Retnet/). However, more than half of all cases are due to unidentified genetic defects. Thus, precise phenotyping is critical to better understand the disorder, identify candidate genes, and to develop novel therapies.


MOLECULAR BASIS AND PATHOLOGY

The majority of cases of RP are nonsyndromic (isolated); about 25% occur as part of a syndrome, the most common being Usher syndrome (RP and neurosensory hearing loss), which represents 14% of all RP cases (1). Other syndromic forms include Bardet-Biedl syndrome (RP, polydactyly, obesity, renal abnormality, and mental retardation), Refsum disease, and other disorders associated with renal, metabolic, skeletal, or neurological disease (2,3). The prevalence of isolated RP varies according to the inheritance pattern; recent estimates suggest that AD RP forms account for approximately 30%, AR RP for 20%, and X-linked for 15% of cases (4). A further 5% have been classified as early-onset forms of RP (Leber congenital amaurosis). The other 30% represent sporadic cases, which are most likely to be AR, but X-linked or de novo dominant forms might also be included in this group (4). To add to the complexity, different genes have been implicated in similar patterns of inheritance. Since the identification of the RHODOPSIN (RHO) gene as the first gene implicated in AD RP (5), more than 180 genes have been linked to the physiopathology of retinal dystrophies. The products of these genes are implicated in very diverse cellular functions, including the phototransduction cascade, retinoid cycle, photoreceptor structures,
transcription factors, outer segment renewal, splicing factors, and intracellular trafficking (3). For most of these genes, expression is restricted to the photoreceptors, especially rods, and/or the retinal pigment epithelium (RPE), but others, such as splicing factors, are more ubiquitously expressed. The mechanism by which a ubiquitously expressed gene is responsible for a restricted photoreceptor disease is not well understood, but it may relate to the uniquely high metabolic demand of the photoreceptors.

In addition, in AD RP, nonpenetrance has been described associated with certain genotypes (e.g., PRPF31 mutations [6]), which may complicate genetic counseling. Some genes are implicated in different phenotypes; for instance, RHO is the gene most commonly implicated in AD RP (20%-30% of AD RP [7]), but it can also be involved (less commonly) in AR RP and AD congenital stationary night blindness (8,9). Similarly, NR2E3, which is responsible for Enhanced S Cone syndrome (10), a recessive disorder, can be found in 1%-3% of cases of AD RP (11,12).

Because of the genetic heterogeneity of RP, the precise molecular mechanisms leading to photoreceptor cell death are still not fully understood. It is thought that photoreceptors degenerate through a common final pathway by apoptosis (13,14), which may involve calpains (15,16). Causes of apoptosis include ionic imbalance, protein aggregates, or default in photoreceptor structure (3). Explanations have also been given to the secondary cone cell death in the case of mutation in genes expressed only in rods, and evidence suggests that cones rely on rods to survive (17,18).


FINDINGS ON FUNDUS EXAMINATION

Fundus examination can be normal (RP sine pigmento), especially in the early stages of the disease. In the course of RP, RPE changes will appear in the midperiphery with pigment migration into the inner retinal layers as photoreceptors die. Blood vessel attenuation and pallor of the optic disc are hallmarks of advanced stages and are thought to result from the decreased metabolic demand with photoreceptor degeneration. The posterior pole is usually preserved until late in the course of the disorder. However, in about 63% of all cases of RP, foveal lesions are present, including atrophic changes (43%) and cystic changes (20%), mainly oedematous, that can be documented with fluorescein angiography (FA) or optical coherence tomography (OCT) (19, 20, 21) (see below). These macular changes will cause early loss of central vision. Premature posterior subcapsular cataract may also occur, resulting in impaired visual acuity.


ELECTRODIAGNOSTIC FINDINGS

ERG is essential for establishing the diagnosis of RP when there are no or only subtle abnormalities on fundus examination. In RP, the dark-adapted bright flash ERG a-wave, which predominantly reflects rod photoreceptor hyperpolarization, is abnormal with milder photopic ERG abnormalities, indicating milder cone-system involvement. The degree of macular cone system involvement varies among patients and may be assessed by pattern ERG (PERG) (22) and multifocal ERG (mfERG) (23). The PERG P50 component is a response to an alternating checkerboard stimulus that depends on the integrity of macular cones and has been used extensively as an objective index of macular function (24,25). Multifocal ERG is typically performed using a stimulus array comprised of 61 or 103 hexagonal stimulus elements centered at the fovea and usually extending over the central 55-60 degrees. The mfERG responses
are mathematically derived using a cross-correlation algorithm and allow assessment of localized cone-system function at multiple retinal locations across the posterior pole (26). Both PERG (27, 28, 29, 30, 31) and mfERG (32, 33, 34, 35) recordings have been used to objectively assess macular function in RP. The extent of macular involvement is not always related to the severity of generalized or peripheral dysfunction, and serial testing with either technique may prove to be of prognostic value for predicting functional sparing of the macula or the rate of disease progression.


IMAGING TECHNIQUES


Fluorescein Angiography

Historically, fluorescein angiography (FA) has played a major role in assessing morphological abnormalities in RP, but it has been replaced by noninvasive techniques such as fundus autofluorescence (AF) and OCT. FA classically shows a variable mottled increased fluorescence in affected areas due to window defects (transmission defects though atrophic changes in the RPE). Pigment clumping/bone spicules block fluorescence transmission from blood in the retinal vessels or from the choroid. Narrowing of blood vessels with no filling delay is also a classical sign. Vascular leakage is not unusual in the course of the disease; cystoid macular oedema (CMO) may also occur and can be documented by FA (36).


Indocyanine-Green Angiography

Because of the physical properties of its dye, indocyanin green (ICG) angiography is mainly used to assess the choroidal vasculature and its involvement in retinal disease. This imaging technique has little value in the management of primarily photoreceptor diseases and is currently not performed for the diagnosis or management of patients with RP.


Optical Coherence Tomography

OCT is increasingly being used in the evaluation of patients with RP. This noninvasive and noncontact imaging technique is at least as sensitive as FA in the detection of CMO, and is valuable for the accurate diagnosis and management of patients with nonleaking CMO (37, 38, 39). OCT can also document atrophic changes. Ultra-high-resolution OCT allows a more precise assessment of changes in the neurosensory retina (40) and may be used in combination with scanning laser ophthalmoscopy (SLO; for review see Podoleanu and Rosen [41]). These new and complementary techniques will allow a better evaluation of macular photoreceptor changes during the course of RP and will be especially useful for monitoring future treatments.


Fundus Autofluorescence

Fundus AF imaging can reveal otherwise invisible manifestations of disrupted RPE metabolism, and the technique has an increasingly important role in the assessment and management of RP. Early detection of macular involvement may have prognostic implications for retention of central vision, and attempts to establish functional correlates of abnormal AF have outlined its value in monitoring disease progression.


Early reports documented a close spatial correspondence between absent AF and outer retinal atrophy in RP (42). Almost all adult patients with RP have a decreased AF signal in the midperiphery (43). More recently, OCT has demonstrated a spatial correspondence between the lateral extension of the outer retinal high-reflectance band and preserved macular AF (44), suggesting preservation of outer retinal structure within this area. At the central macula, abnormal patterns of increased fundus AF may be present (43, 44, 45) and are usually associated with impaired visual acuity. In patients with CMO, round or oval areas of increased AF can be detected at the fovea. In chronic CMO, RPE atrophy may ensue and a reduced AF signal may be observed.

An abnormal parafoveal ring of increased AF, not visible on slit-lamp biomicroscopy (Fig. 11A.1), is commonly observed and has been reported in AD, AR, sporadic cases (28,30,31,44,46), and X-linked RP (47). The ring has been described in patients as young as 2 years old (48), but is not always present in affected children. A cross-sectional analysis of dominant pedigrees suggested that the ring can be a relatively late manifestation of RP, manifesting only in adolescence or adulthood (28). Few surveys have quantified the incidence of this abnormality, but estimates range from about 50% in a heterogeneous group of RP patients (31) to 95% in a cohort with Usher syndrome type 2 (45). Fundus AF is usually preserved in areas internal and external to this ring of abnormal AF, but in adults there is often a patchy or reduced AF signal in more eccentric regions that usually encroach upon the vascular arcades (Fig. 11A.1D). The diameter of the ring has been reported to vary between approximately 3-20 degrees and usually exhibits a high degree of interocular symmetry.

Parafoveal rings of increased AF are not specific to RP. Similar annular AF abnormalities have been documented in other retinal dystrophies, including Leber congenital
amaurosis (see also Chapter 11D) (49), cone-rod dystrophy (Fig. 11A.2B,D) (50, 51, 52, 53, 54) and “cone dystrophy with supernormal rod ERG” (see also Chapter 11B) (55,56), Best disease (see also Chapter 11F) (57), X-linked retinoschisis (see also Chapter 11C) (58), and other forms of maculopathy (59,60). The incidence of parafoveal rings of increased AF in non-RP cases was recently reviewed (30). In cone-rod dystrophy, the annular areas of increased AF may be indistinguishable from those seen in RP (Fig. 11A.2A,B) (see also Chapter 11B), and full-field ERG may be essential in the differential diagnosis. However, once the cone-rod dystrophy progresses, atrophic macular RPE changes usually ensue, demonstrating a reduced AF signal within the ring (Fig. 11A.2D). An important caveat is that dense macular pigment may resemble early atrophic changes at the fovea, and two-wavelength AF (61) utilizing wavelengths that are differently absorbed by luteal pigment may help to identify subtle abnormalities. Unlike in RP, the ring of increased AF in cone-rod dystrophy evolves differently as the maculopathy worsens (see later).

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Aug 29, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Fundus Autofluorescence in Retinitis Pigmentosa
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