Ординатура / Офтальмология / Английские материалы / Electrodiagnosis of Retinal Disease_Miyake_2005

Patients with cone dystrophy belong clinically and genetically to a heterogeneous group of patients with inherited retinal dystrophies. They are characterized by widespread degeneration of the cone photoreceptors, leading to impaired central vision, loss of color vision, and photophobia [1, 2]. The disease process is progressive. At the advanced stage, most patients with cone dystrophy also have abnormal scotopic vision (cone–rod dystrophy) [2, 3]. Because impairment of the cones is widespread, the full-field photopic ERG is always severely depressed, which is key to diagnosing cone dystrophy (Fig. 2.94). Localized macular problems, as with some types of macular dystrophy, do not lead to a significant reduction of the photopic ERGs (see Section 1.2.2).

The fundus in patients with cone dystrophy may be within normal limits or may have subtle changes in the early stage [1, 2, 4]. These changes may progress to bull’s-eye maculopathy and diffuse atrophy of the RPE in the far-advanced stage (Fig. 2.95) [2]. It should be noted that the appearance of the fundus and fluorescein angiograms may be essentially normal even when full-field photopic ERGs are

absent [1, 3, 4]. In such cases, patients may be misdiagnosed as having optic nerve disease, central nerve system disease, amblyopia, or occult macular dystrophy [5] (see Section 2.19) unless the full-field ERGs are carefully evaluated. We have reported that the findings from vitreous fluorophotometry are normal in most patients with cone dystrophy, indicating that the barrier function of the RPE is well preserved until the advanced stage [6]. This is in marked contrast to patients with retinitis pigmentosa (rod–cone dystrophy), in whom vitreous fluorophotometry may reveal significant abnormalities even during the early stage.

Long-term follow-up of the full-field ERGs in two patients with autosomal dominant (A) and recessive (B) cone dystrophy is shown in Fig. 2.96 [2]. In 1981 the rod ERG was normal, but the cone and 30-Hz flicker ERGs were extremely reduced (B). Thereafter, the rod ERG gradually decreased (cone–rod dystrophy), and in 1998 it was essentially absent. The fundus in 1998 showed diffuse RPE degeneration with attenuation of the retinal vessels—similar to findings in patients with retinitis pigmentosa (rod–cone dystrophy).

To date, mutations in the peripherin/RDS [7], CRX 8 [7], GUCY2D [9], and GUCA1A [10] genes have been reported to cause autosomal dominant cone dystrophy. Patients with cone dystrophy caused by GUCAIA mutations have relatively well preserved rod function until the late stage [10]. ABCR gene mutations have been reported to cause autosomal recessive cone dystrophy [11], and RPGR gene mutations cause X- linked recessive cone dystrophy [12].

GUCY2D is the gene coding for retinal guanylate cyclase-1 (PETGC-1), which consists of a membrane guanylate cyclase with PETGC-2. PETGC-1 is an important enzyme in the phototransduction cascade and catalyzes the conversion of guanosine triphosphate (GTP) to cyclic 3¢,5¢-guanosine monophosphate (cGMP) [9].

Two Japanese families with RC38C and R838H mutations [13] are shown in Fig. 2.97.All of the affected members have high myopia and poor visual acuity (0.1–0.6) with central or paracentral scotoma and severe color vision defects. The full-field rod ERGs are relatively well preserved with nearly undetectable cone and 30-Hz flicker ERGs (Fig. 2.98). The fundus has myopic changes, including chorioretinal atrophy around the optic disk, but minimal ophthalmoscopic abnormalities in the macula. Fluorescein angiography showed mild hyperfluorescent pigmentary changes or small, round hyperfluorescent areas in the macula (Fig. 2.99).

Fig. 2.97. Pedigrees of two families with autosomal dominant cone dystrophy, showing the affected (solid symbols) and unaffected (open symbols) members. Family and patient numbers correspond to those in Figs. 2.98 and 2.99Arrows point to probands. Individuals whose DNA was tested are indicated by an ¥. Squares, males; circles, females; slash through symbol, deceased. (From Ito et al. [13])

Fig. 2.98. Full-field ERGs recorded from a normal subject and three patients in the two families shown in Figs. 2.96 and 2.97.The family and case numbers in parentheses correspond to those shown in Fig. 2.96. (From Ito et al. [13])

The concept of regional cone dystrophy has been suggested by some clinicians [14], and these eyes were thought to have central or peripheral cone dystrophy. With central or peripheral cone dystrophy, the central or peripheral cone system is predominantly impaired and the rod system is completely preserved, even in the area where the cone system is impaired.

“Occult macular dystrophy” [5] is an example of a central cone dystrophy and is described later. We have reported that some patients with occult macular dystrophy show the pathophysiological properties of a central cone dystrophy, where only the macular cones are affected with preservation of the macular rods. These findings were detected by rod–cone sensitivity profiles in the macula area (see Section 2.19).

We have reported three patients from two pedigrees whose peripheral cone system was more affected than the central cone system and whose rod system was relatively normal [2, 15]. The fundi of these patients with peripheral cone dystrophy are essentially normal except

for mild temporal pallor of the optic disk in some of the patients (Fig. 2.100). The corrected visual acuity in the three patients ranged from 1.2 to 0.2, and the color vision was abnormal in two of the three. The full-field cone ERGs were significantly reduced, but the rod responses were normal, as in patients with typical cone dystrophy (Fig. 2.101).

However, the focal macular cone ERG were well preserved (Fig. 2.102), and the results of multifocal ERGs support the findings made by full-field and focal macular ERGs (Fig. 2.103). One of the patients (case 3) was examined 4 years after the initial examination using focal macular ERG because he had reported progressively increased blurring of his paracentral vision in the left eye. The responses clearly had become smaller during the 4 years (Fig. 2.101), suggesting that his retinopathy was progressive, even though his visual acuity was unchanged. Psychophysical rod–cone perimetry demonstrated that only the peripheral cone system was impaired, and the peripheral rod sensitivity was completely normal (Fig. 2.103).

We reported a 20-year-old Japanese woman who had an acute onset of unilateral cone dysfunction associated with bull’s-eye maculopathy [16]. She complained of blurred central vision and abnormal color sensitivity of 3 days’ duration in her right eye. Her family history was negative, and her medical history revealed no previous or current systemic illnesses.

At her initial visit,visual acuity was 0.03 (OD) and 1.5 (OS) with a central scotoma in the right eye. The fundus and fluorescein angiograms were normal at that time, but 3 months later bull’s-eye maculopathy appeared in the right eye; her left fundus remained normal (Fig. 2.105).

The full-field ERGs recorded from this patient are shown in Fig. 2.106.As shown in Fig. 2.106A, her rod responses and mixed rod–cone (bright white) responses were normal, and little

difference was observed between the right and left eyes. However, the cone-mediated responses (cone and 30-Hz flicker) were severely reduced only in the right eye. The on and off components of the photopic ERGs (Fig. 2.106B) elicited by long-duration stimuli were undetectable in the right eye.

Kinetic visual field showed a relative central scotoma within 10° of fixation in the right eye, whereas the left eye was normal (Fig. 107A). The cone and rod perimetry (two-color perimetry) showed normal sensitivity in both rod and cone in the right eye, but only the cone sensitivity was severely depressed in the left eye (Fig. 107B).

The pathogenesis of this disorder with severe impairment of the cone photoreceptors is unknown. However, a group of inherited