Persistent Bilateral Optic Disc Swelling in Non-Syndromic Retinitis Pigmentosa: A Case Report

Introduction

Retinitis pigmentosa (RP) is a genetically heterogeneous retinopathy and is one of the most prevalent hereditary retinal dystrophies. RP is characterized by atrophy of the retinal pigment epithelium (RPE) and retinal photoreceptors, which eventually results in severe visual loss [1,2]. Clinically, it is characterized by night blindness and constricted visual fields, which are associated with the classical appearance of RPE mottling and bone spicules, in addition to retinal vascular narrowing [3]. In RP, the optic nerve head typically exhibits a pale, waxy appearance, and demonstrates pseudo-swelling due to drusen in the optic nerve, which is strongly associated with RP [4,5]. However, true optic disc edema is rarely reported in cases of RP, and a clear explanation for this phenomenon is lacking [6–9].

Here, we describe the case of an 8-year-old boy who was diagnosed with non-syndromic RP that was associated with persistent bilateral swollen optic nerves, with no improvement since presentation.

Case Report

An 8-year-old boy with an unremarkable medical and surgical history was referred to our institute after having blurred vision in both eyes, especially at nighttime. He underwent a computed tomography scan (CT scan) of the head at the primary treating facility because of bilateral optic nerve head edema, which reportedly showed an unremarkable skull base and no calcification at the optic nerve head, indicating the absence of drusen. The patient denied a history of headache, tinnitus, transient visual obscuration, or diplopia. His body mass index was 19.6 kg/m2, and he had not previously received any medications, including vitamin A. His perinatal history was uneventful, with no complications during pregnancy or after delivery. His diet and nutritional habits were regular. On examination, his best-corrected visual acuity was 20/200 in both eyes, and intraocular pressure was 13 mmHg in the right eye and 11 mmHg in the left eye. Anterior segment examination was unremarkable. Pupil assessment revealed equal but sluggish reactivity, with no anisocoria. Full ocular motility was observed in both eyes, with mild exophoria noted upon ocular alignment.

Fundoscopic assessment revealed dispersed RPE mottling with a dull foveal reflex and moderate attenuation of the retinal vasculature in both eyes. The optic nerve head showed significant swelling and hyperemia with peripapillary opacification, in addition to a tilted appearance in both eyes and the absence of spontaneous venous pulsation (Figure 1). Fundus autofluorescence (FAF) indicated abnormal patterns of widespread hypoautofluorescent areas scattered throughout the periphery as well as oval-shaped macular hyperautofluorescence in both eyes. Fluorescein angiography (FFA) revealed a peripheral symmetrical abnormal fluorescence pattern and bilateral early disc hyperautofluorescence that increased in the late phase and extended beyond the optic margin. This was more noticeable in the left eye. Ocular ultrasonography revealed bilateral swelling and elevation of the optic nerve head, with the absence of drusen. Optical coherence tomography revealed increased bilateral thickness of the retinal nerve fiber layer. This was also more pronounced in the left eye (Figure 2).

In Goldman visual field testing, symmetrical blind spot enlargement and a constricted field were evident in both eyes (Figure 3). Full-field electroretinography (ff-ERG) showed reduced photopic responses with greater reduction in scotopic responses (Figure 4). Pattern visual evoked potentials were unremarkable bilaterally with normal amplitude and implicit time. Although the initial head CT scan was normal, further neuroimaging with contrast-enhanced magnetic resonance imaging (MRI) was performed to ensure a more comprehensive evaluation. This confirmed bilateral swelling of the optic nerve heads, with no optic nerve enhancement or any radiographic signs of intracranial hypertension, with patent venous sinuses on magnetic resonance venography (MRV) and absence of vascular fistula on magnetic resonance angiography (MRA) (Figure 5). Extensive laboratory work-up was ordered, including glycosylated hemoglobin, toxic screening, nutritional panel (including levels of vitamin B12, folate, thiamine, copper, vitamin A, and pyridoxine), and infectious and inflammatory investigations, which all had normal results. Whole-genome sequencing revealed a homozygous pathogenic c.1256G>A p.(Arg419GIn) variant in the Tubby-like protein 1 gene (TULP-1), which is involved in retinal photoreceptor integrity. To investigate the swollen optic nerves, a lumbar puncture was performed, showing normal opening pressure (18 cm water) and cerebrospinal fluid analysis. The parents were counseled regarding a short trial of oral prednisolone but they preferred only observation given the possible adverse effects of the steroids. The patient was followed up regularly, with the last visit recorded 2 years after presentation, and his examination remained remarkable for stable but persistent swelling of the optic nerve heads with no change in visual function compared to baseline. Given the clinical stability and the absence of new neurological symptoms, repeated neuroimaging was not considered necessary during follow-up (Figures 6, 7).

Discussion

The purpose of this report is to highlight and explain the pathophysiology of the unusual phenotype of true optic nerve head edema associated with RP. RP is characterized by rod–cone degeneration, where early rod degeneration is followed by cone degeneration as the disease progresses [1,3]. While RP characteristically presents with bone spicules, attenuated retinal vessels, and a waxy, pale optic disc [3], less common findings include macular edema, epiretinal membrane, macular holes, optic disc drusen (causing pseudo-swelling), and posterior subcapsular cataract [6,8]. In addition to the typical optic nerve pallor and the less common optic nerve head drusen, the optic nerve can be affected by true disc swelling in RP. However, unilateral or bilateral true optic disc swelling in RP, with an unremarkable workup, has rarely been reported [6–9].

Further investigation is required when patients present with true unilateral or bilateral optic disc swelling, including when this occurs in a setting of RP. The etiology of bilateral optic disc edema includes papilledema, due to increased intracranial pressure; diabetic or hypertensive papillopathy, papillitis, and pseudo-swelling-mimicking disc edema [6]. Although pseudoedema of the optic disc is more prevalent in RP than true edema, the multimodal imaging pattern favors the latter. The absence of calcification on the head CT scan and ultrasound B scan, the lack of optic disc hyperautofluorescence, and the considerable late leakage on FFA were all strongly indicative of true optic disc edema. Intracranial hypertension should always be considered in RP, as it is an associated condition. The relationship between these 2 pathologies includes obesity in syndromic RP and intake of vitamin A, which is a traditional treatment for RP, but which is associated with increased intracranial pressure. A previous study on idiopathic intracranial hypertension and RP found conflicting results regarding the relationships of intracranial pressure with obesity and vitamin A. The study concluded that high vitamin A levels and obesity were found in only 13% of the population with high intracranial pressure, but these patients had surprisingly low vitamin D and B12 levels, which could worsen optic nerve function [10,11]. After the exclusion of obesity and vitamin A intake as the principal risk factors, no other theory has been suggested for the association between RP and increased intracranial pressure. Although our patient had normal opening pressure on lumbar puncture, in addition to normal hormonal levels, high intracranial pressure should always be investigated in patients with RP if they present with true bilateral optic disc swelling.

The pathophysiology of optic head swelling in cases of RP with an unremarkable workup is unclear. A literature review revealed the occurrence of disc edema in syndromic RP, including in Usher and Bardet–Biedl syndromes [6,7]. However, our patient had non-syndromic RP caused by a genetic mutation in TULP1. This suggests that disc edema and optic neuropathy cannot be explained by the direct effect of genetic mutations, given the variety of reported genotypes. Mutations involving TULP1 are linked to retinal degeneration, including RP. The gene encodes a protein that is essential for the transport of rhodopsin, a light-sensitive receptor protein, from the inner segment to the outer segment of photoreceptors. A mutation in this gene leads to photoreceptor damage and consequently to the development of disc pallor, which differs from our patient’s presentation of a hyperemic and swollen optic disc [10]. Given the prior reports of RP in the setting of TULP1 genetic mutations, which typically describe optic disc pallor rather than disc swelling, it is plausible that the disc edema observed in our patient was an inflammation-dependent phenomenon rather than a direct effect of the specific genetic mutation itself [9–11].

RP is associated with photoreceptor degeneration, which in turn can upregulate inflammatory markers [12,13]. Analysis of vitreous specimens from patients with RP confirmed the presence of abnormally high levels of inflammatory cytokines [13]. In patients with RP, disc edema may be caused by inflammation secondary to photoreceptor and RPE degeneration [6]. Inflammation can lead to vascular changes, and altered vascular permeability may explain the retinal findings associated with RP, including early posterior vitreous detachment, cystoid macular edema, and epiretinal membrane formation [6,14]. Disc edema may be explained by the same pathophysiology, in which increased disc vessel permeability is an inflammatory response that eventually leads to disc edema [6].

This theory of inflammation is confirmed to some extent by the partial resolution of the disc swelling after steroid treatment [8,9]. Previous studies have documented the effects of steroid therapy on disc and macular edema, with either full or partial resolution, indicating that inflammatory cytokines had been downregulated by the treatment [8,9]. Our patient did not receive steroid therapy, which may explain the persistence of the disc swelling. Although the persistence of swelling of the optic disc is very unusual, it is consistent with the proposed mechanism in the setting of RP. RP is characterized by continuous photoreceptor damage and shedding, leading to subtle, ongoing inflammation that can manifest as dilated blood vessels overlying the optic nerve head, with secondary persistent optic disc swelling. Nonetheless, previous reports have also mentioned the partial persistence of disc swelling or the absence of a response to steroid intake, which cannot be clearly explained at present [6].

Conclusions

Unilateral or bilateral disc edema is uncommon in patients with RP. Any patient with this presentation needs a thorough workup, regardless of the retinal pathology. The theory of inflammatory optic disc edema appears to be the most logical etiology of RP with a negative workup. Based on the inflammatory theory, a trial of systemic steroid therapy may improve disc swelling and should be considered in such cases. However, our patient was asymptomatic, despite disc swelling, and steroid treatment was declined by the caregivers. This may explain the persistence of the swelling even after 2 years of observation.