Normal electro-oculography in a young Omani male with genetically confirmed best disease complicated by choroidal neovascularization.

Best vitelliform macular dystrophy (VMD) is an autosomal dominant macular dystrophy caused by heterozygous mutations in the bestrophin1 gene. Patients with this condition typically have an abnormal electrooculogram. We report a case of a 16-year-old male who presented with gradual progressive vision loss in the right eye. Ophthalmic assessment included funduscopy, optical coherence tomography (OCT), fluorescein angiography, electro-oculography, electroretinography, and genetic testing. Visual acuity was 20/500 and 20/20 in the right and left eyes, respectively. Ophthalmoscopy revealed round yellow lesions in both foveae similar to what is typically seen in Best disease. A subretinal hemorrhage surrounding the right foveal lesion was also noted. OCT demonstrated an elevated neurosensory retina with a subretinal lesion in the right macula. Fluorescein angiography of the right eye confirmed the presence of choroidal neovascularization. Genetic analysis of VMD2/BEST1 sequences confirmed the diagnosis of Best disease. However, contrary to what was expected, the patient's electro-oculography was normal. The findings of this case support a small number of previous reports demonstrating cases of Best disease with normal electro-oculography. While an abnormal electro-oculography along with the typical features of Best disease confirms the diagnosis, a normal result may not exclude the diagnosis. Genetic testing is probably the most important test for establishing the diagnosis of Best disease.

Introduction

Best disease, also known as vitelliform macular dystrophy (VMD) (OMIM #153700) is an autosomal-dominant macular dystrophy and is known to be caused by heterozygous mutations in the bestrophin1 gene (BEST1) on chromosome 11q13.[1] Best disease is characterized by a highly variable inter- and intra-familial expressivity, but near complete penetrance of abnormalities.

Classically, Best disease manifests as bilateral, slightly elevated, yellow macular vitelliform lesions due to the accumulation of lipofuscin in the retinal pigment epithelial (RPE), cells and material in the subretinal space and loss of photoreceptors.[2] It has been classified into various stages based on ophthalmoscopic appearance. Patients with Best disease may present with reduced visual acuity in childhood. However, they maintain a relatively good visual acuity throughout the disease but may experience a dramatic reduction in vision with the development of choroidal neovascularization (CNV). Electrooculography (EOG) typically reveals a lower than normal ratio of light peak to dark trough (Arden ratio). This abnormal EOG is considered an important diagnostic feature of Best disease, not only in affected individuals but also in clinically unaffected carriers[3] and is helpful in confirming the diagnosis when there is a clinical suspicion of the condition.

We report a case of genetically confirmed Best disease with normal EOG in a young male patient complicated by CNV and treated by intravitreal ranibizumab injections.

Case Report

A 16-year-old healthy boy was referred to the retina service with a progressive reduction in vision in his right eye of 6 months. There was no history of ocular trauma, or symptoms or signs suggestive of previous ocular inflammation. He had no symptoms in the left eye and was systemically well. His family history was unremarkable [Figure 1].

Figure 1

Family pedigree of the patient

Ophthalmic examination revealed best-corrected visual acuity (BCVA) of 0.04 (20/500) in the right eye (OD) and 1.0 (20/20) in the left eye (OS). Intraocular pressures were 16 and 18 mmHg in the right and left eyes, respectively. Anterior segment examination was unremarkable in both eyes (OU). Dilated fundus examination revealed bilateral, yellow macular lesions. The right eye lesion was elevated and surrounded by a relatively fresh subretinal hemorrhage and fluid consistent with minimally active CNV [Figure 2a] and relatively flat in the left eye [Figure 2b]. Fluorescein angiography showed a central hyperfluorescent area surrounded by well-circumscribed hypofluorescence caused by the subretinal hemorrhage, which is consistent with minimally active CNV OD [Figure 2c]. Fundus Fluorescein angiography (FFA) of the left eye was essentially normal [Figure 2d].

Figure 2

Fundus photograph of a yellow lesion in the macula with subretinal hemorrhage (a). A similar but smaller lesion with no hemorrhage was found in the left macula (b). FFA of the right fundus (c) showed a central hyperfluorescent area (leakage) surrounded by well-circumscribed hypofluorescence (blockage), consistent with choroidal neovascularization. FFA of the left fundus was unremarkable (d)

Optical coherence tomography revealed a subretinal, hyperreflective lesion causing elevation of the neurosensory retina in the macular area [Figure 3a]. A small, subretinal, hyperreflective area was seen in the left eye, without retinal elevation [Figure 3b].

Figure 3

Optical coherence tomography of the right macula (a) showing elevated neurosensory retina with an underlying hyper-reflective lesion and sub retinal fluid. A smaller hyper-reflective subfoveal lesion was revealed on left eye optical coherence tomography (b)

Electroretinogram, both full field (FFERG) and pattern (PERG), as well as electrooculogram (EOG) were performed using the LKC (UTAS 3000, USA) machine and following the ISCEV standard protocols. The FFERG showed a reduction in both rod and mixed scotopic responses. Moreover, there was a reduction in P50 and N90 amplitude in the right eye PERG [Figure 4]. The EOG was normal in both eyes with Arden ratio of 3.06 in the right eye and of 3.66 in the left eye (normal Arden ratio: >1.8–2.0) [Figure 5].

Figure 4

Pattern electroretinogram showing marked reduction in P50 (arrow head) and N95 (arrow) waves amplitude in the right eye and normal waves in the left eye. This indicates a severe macular dysfunction in the right eye

Figure 5

Electro-oculogram from both eyes showing normal peak/trough (Arden) ratio in both eyes. Right eye 3.08; Left eye 3.66 (normal >1.8–2)

Molecular diagnostic workup was performed and confirmed the diagnosis of Best disease. VMD2/BEST1 sequences analysis confirmed that the patient is heterozygous for a reported mutation in the VMD2/BEST1 gene (p.Q96R:C.287A>G). The parents were also screened. The mother's fundus examination revealed RPE changes over the macula, whereas the father's fundus examination was unremarkable. They were genetically tested for Best disease, and patient's mother was found to be heterozygous for the BEST1 gene (c.287A>G), and father was found to be negative. After a thorough discussion with the patient and his father about the condition, its natural history and the treatment options for CNV, a series of intravitreal ranibizumab (Lucentis™, Genentech, Inc., San Francisco, CA, USA) injections were planned. Unfortunately, as the patient presented late for the first injection, he had already developed subfoveal fibrosis surrounded by subretinal hemorrhage and fluid. After two intravitreal ranibizumab injections (0.05 ml/0.5 mg) 4 weeks apart, subjective improvement in vision and resolution of subretinal hemorrhage with a slight reduction in the subretinal fluid were noted. Visual improvement was minimal, which is likely attributable to the presence of subfoveal fibrosis. Further injections were not given at this stage, as further improvement was not expected. In the last follow-up visit, 3 years after the 2nd injection, his BCVA had been stable at 0.05 (20/400) OD and 1.0 (20/20) OS. He had subfoveal fibrosis OD, without clinically active CNV. The left eye macular lesion remained the same.

Discussion

The diagnosis of Best disease is considered when a child or a young adult presents with bilateral visual impairment, and fundus examination reveals typical features of the condition. However, at times the funduscopic appearance may be atypical, or a patient may be seen in the presymptomatic stage as part of the screening.

In such instances, EOG, which shows a reduced light peak to dark trough ratio, is very helpful in making the diagnosis. The Arden ratio may be abnormal as early as the initial stage when the macula has a normal appearance.

Rarely patients with clinical findings of Best disease and a mutation in BEST1 may have a normal EOG,[345678] as seen in our patient. In some patients, the normal EOG becomes abnormal over time,[7] but in some remains normal throughout the disease. Previous reports of normal EOG in Best disease have been in children and in older patients, with mild-to-severe phenotype, and a variety of mutations [Table 1]. Thus, normal EOG in Best disease does not appear to be related to the age of the patient, stage of the disease, or a particular genotype.

Table 1

Summary of previous reports of patients with Best disease with normal electrooculography

Author	Number of patients	Age in years	Clinical features	Mutation in BEST1 gene
Birndof and Dawson, 1973	1	48	Vitelliform lesion OU	Not available
Kramer et al., 2000	2 members of one family	15	Vitelliruptive lesion OU	Ala243Val
		51	Previtelliform lesion OU
Pollack et al., 2005	4 members of one family	63	Macular atrophy OU	Ala234Val
		37	Vitelliruptive OU
		33	Vitelliform OU
		30	Vitelliform OU
Wabbels et al., 2006*	2 members of one family	7	Pseudohypopyon OD, previtelliform OS	Gln58Leu
		11	Previtelliform OU
Testa et al., 2008	3 members of one family	34	Vitelliruptive OU	Phe305Leu
		10	Previtelliform OD; Vitelliform OS
		5	Pseudo-hypopyon OU
Low et al., 2011	4 members of 2 families (3 members of family 1, 1 member of family 2)	48	Vitelliform lesion and subretinal	Phe305Ser
		44	thickening OD (abnormal EOG)	Phe305Ser
		42	Vitelliform lesion OU (near normal EOG)
		53	Vitelliform lesion OU (abnormal EOG)
			Vitelliform lesion OU (near normal EOG)

*EOG became abnormal 5 years after presentation in both patients. EOG: Electrooculography, OU: Both eyes, OD: Right eye, OS: Left eye, BEST1: Bestrophin1

Heterozygous mutations in the BEST1 gene have been identified as the cause for Best disease. Mutations in BEST1 disrupt bestrophin function. Bestrophin is a protein located on the basolateral membrane of the RPE cell that mediates chloride and calcium transport across the plasma membrane. Disruptions in the RPE pump lead to accumulation of pathological material or fluid in the subretinal space.[9] Moreover, the defective light peak in EOG has been shown to correlate with the defective conductance of chloride as a result of the abnormal bestrophin protein.[10] Genetic testing is particularly helpful in confirming a clinical diagnosis of Best disease in patients with atypical phenotypic presentations. Once the disease-causing mutation is identified, identification of carriers is possible. The information also helps in identifying family members at risk for developing the disease.

CNV is a rare complication of Best's disease. After confirming the diagnosis, treatment should be started without delay otherwise fibrosis and scaring will eventually form, limiting the visual outcome. Treatment options include photodynamic therapy, series of intravitreal anti-vascular endothelial growth factor (VEGF) injections or a combination of both.

Ranibizumab (Lucentis™, Genentech, Inc., San Francisco, CA, USA) is a recombinant, humanized, monoclonal antibody antigen-binding fragment (Fab) that neutralizes all biologically active forms of VEGF and is effectively being used in the treatment of neovascular age-related macular degeneration and its use has been widely expanded to include other causes of CNV including Best's disease, diabetic macular edema, macular edema secondary to vascular occlusions and others.[11]

Querques et al. reported a 13-year-old boy diagnosed with left eye CNV associated with Best's disease managed with intravitreal ranibizumab. His vision had improved from 20/126 to 20/40 without subsequent recurrences during 6 months’ follow-up period.[11]

Bevacizumab (Avastin) in Best's disease has been described in the literature. Leu et al. reported a 13-year-old boy with CNV secondary to confirmed Best's disease treated successfully with a single intravitreal injection of bevacizumab without recurrences during 6 months after the treatment. His vision had improved from 20/40 to 20/20.[12]

In conclusion, a normal EOG does not exclude the possibility of Best disease. In such patients, genetic testing is essential to confirm the clinical diagnosis of the disease. Genetic testing and examination of family members are recommended. Patients who continue to have compromised vision despite appropriate treatment will need low vision rehabilitation. Treating Best disease complicated by CNV with intravitreal anti-VEGF remains the best options and may lead to improvement in vision, provided the treatment is delivered as early as CNV is recognized.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.