Idiopathic Neuroretinitis – Mini Review
*Corresponding author: Samet Gulkas, Department of Ophthalmology, Sanliurfa Training and Research Hospital, Yenice St, Yenice Rd, No:1, postal code: 63200, Sanliurfa / Turkey. Tel: +90 (531 943 8931); Email: email@example.com
Neuroretinitis (NR) is an inflammatory disease characterized by optic disc edema and formation of macular exudates called as macular star.  The first description of NR was by Thedor Leber in 1916. He used the term‘stellate maculopathy’ in his case report.  Later, Gass  revealed that the formation of exudates followed by disc edema. He showed that the primer site of leakage is, in fact, on the optic disc, not on the macula, and suggested the term ‘Neuroretinitis’. Recent studies demonstrated that disturbed optic disc vasculature and an inflammatory process are responsible for pathogenesis of NR. [4, 5] NR has an inflammatory process that is preceded with optic disc swelling, and resulted in serous retinal detachment with hard exudates on the level of outer plexiform layer, and finally macular star formation. [5-8] However, it is very important to consider that other several retinopathies may masquerade NR in their clinical findings, particularly in differential diagnosis of optic disc edema with a macular star. (Table-1)
NR is generally classified within different subtypes based on underlying etiology are either infectious or noninfectious (inflammatory or idiopathic). Various cases of NR underlying infectious etiology have been reported in the literature.[9-15] Most common infectious etiology in NR is cat scratch disease (CSD), which is responsible for about two-third of cases. [16, 17] In the noninfectious subgroup, several cases of NR associated with the various inflammatory diseases, such as sarcoidosis, inflammatory bowel disease and periarteritis nodosa were also reported. [18-20] However, the definitive etiology in nearly one-half of NR cases still remains unclear, thereby idiopathic. It has been suspected that the underlying etiology for idiopathic NR may be related to a virus, yet lack of a certain proof.
We here focus on the idiopathic subgroup of NR with emphasis on the proposed classification, presumed underlying pathophysiology, differential clues in the clinical course as a useful guide for an appropriate approach in the treatment of the disease and, finally we will have a brief discussion about possible treatment options for idiopathic NR.
Proposed Classification of Idiopathic Neuroretinitis
Idiopathic NR can be further classified into those with a single episode and those with recurrent attacks. [22-24] reported that most of the idiopathic cases have single episode, whereas recurrent cases rarely occurs. Although the clinical features can be various and unclear to distinguish the subtypes, this distinction is considerable issue to appropriate approach in the treatment decision. The diagnosis of idiopathic NR should be considered in case of eliminating infectious or noninfectious reasons.  suggested that it could be very useful to know if certain clinical features are more similar to presentation of a CSD –NR or a recurrent idiopathic NR which is thought to be with underlying autoimmune process. Indeed, several studies have revealed that recurrent idiopathic NR might indicate a worse visual prognosis with poorer visual recovery. [22, 24, 25]
Briefly, it could be essential to predict whether the disease would progress to recurrent form prior to treatment decision. We will discuss about these distinctive clinical features in the final section.
Common Clinical Features of Idiopathic Neuroretinitis
Idiopathic NR generally affects young adults with a range between 8-55 years old. According to case reports, more than half of the cases preceded with a flu-like illness.[26, 27] Visual loss is frequently painless, but may be occasionally with a mild degree ocular discomfort. Most of cases have unilateral involvement in idiopathic NR. Visual acuity at presentation can vary from 20/20 to light perception, but usually with a range from 20/50 to 20/200.[1, 23, 28] The patients most commonly have a cecocentral or central scotoma consistent with edema in the papillomacular bundle. Although not as frequent as the demyelinating optic neuritis, some patients may have a relative afferent pupil defect (RAPD).[23-26] Differently, in idiopathic NR, the cases generally have a low grade RAPD.  suggested that this difference indicates these two situations optic neuritis and NR have different mechanism of visual loss, in the former is due to optic nerve dysfunction, but in the latter is mostly due to maculopathy. In slit lamb examination, posterior vitreous cells may be seen, but anterior chamber cells are rarely seen. Fundoscopic examination may reveal various findings depending on the timing of examination. An isolated segmental or diffuse optic disc edema is usually the earliest finding of NR. [1, 23, 28] Occasionally, hemorrhages on the peripapillary nerve fiber layer may be occured. Macular exudates typically appear after 9 to 12 days, subsequently disc edema starts to diminish. After characteristic star formation, it takes to a few months to diseappear, and a residual retinal pigment epithalial defect may often remain in subfoveal region.[1, 21, 29] Since idiopathic NR is a diagnosis of exclusion, a detailed history and subsequently a compherensive laboratory work-up is very essential to eliminate a possible underlying infection. Thus, specific questions on taking history, such as animal exposure, travel to endemic regions and sexual contact should be considered.
Idiopathic Neuroretinitis with Single Episode
Idiopathic NR with single episode is usually self-limiting that can be managed conservatively. The most of patients have a good visual prognosis with a final acuity ranging from 20/40 to 20/20. Nevertheless, in a number of case series, it has been reported that some patients cannot have an excellent visual prognosis as well as subsets of patients.[1, 28] Up to now, there has not still been a consensus for a standart treatment for idiopathic NR with single episode. On the other hand, a few cases were documented related to different treatment approach in idiopathic NR with single episode. reported that a case with idiopathic NR was treated with combined intravitreal bevacizumab and triamcinolone injection at 3 days of the presentation. As a result, macular edema diseappeared with 20/20 of vision one week later, subsequently optic disc edema resolved one month later. The author proposed the additive effect of combined treatment in resolving macular edema and papillitis to obtain a quick effect in the treatment. Similarly. documented a case report of idiopathic NR treated with intravitreal dexamethasone implant. After exclusion of all suspected infectious etiology by labarotory and imaging work-up, the patient received the implant at 1 week of the presentation. The vision improved from 20/50 to 20/20 at 1 week of the treatment, subsequently, optic disc edema and subretinal fluid completely recovered one month later. The patient was stable without any recurrence during 12 months after treatment.
Recurrent Idiopathic Neuroretinitis
In 1994, Purvin was  first identified recurrent idiopathic NR with the basis of a report of case series of 7 patients. The definition is occurance of two or more episodes of idiopathic NR in one eye. This subgroup of NR is commonly seen in young adults (28 of average age) without a gender predilection unlike optic neuritis. The underlying pathology for recurrent idiopathic NR has still not been defined. However, due to favorable response to long-term immunosuppression therapy in some of the patients, it is presumed that an autoimmune vasculitis may be the reason as underlying pathology.  In a compherensive review of 41 patients of recurrent idiopathic NR,  reported that 147 episodes occurred in 75 eyes with an average of 3.6 attacks per cases. Additionally, the mean interval between the episodes was 3 years with a range from 1 month to 16 years. Most of the patients were not associated with a systemic symptom, and ocular pain was very rare. The fundus appearance in recurrent idiopathic NR resembles to other forms of NR, yet macular exudates may not form a star figure with repeated attacks.  Recurrent idiopathic NR has usually a poor visual prognosis unlike in those with single episode. Each episode tends to be unilateral, but involvement of the fellow eye is also occured with repetating attacks. It was reported in the same case series that both eyes were finally involved in 83% of the patients. More than half of the patients had a vision with lower than 6/12. Similar to other subgroups, visual field (VF) defect is commonly as a pattern of cecocentral or arcuate defect, whereas VF loss gradually deterioriates with the cumulative effect of recurrences. This review revealed that nearly 60% of the eyes had permenant VF loss almost two-thirds of their VF.
Because of the poor visual prognostic feature of the recurrent idiopathic NR, it is suggested that the treatment should be focus to prevent recurrent attacks on in this subgroup. [22-24, 29] Quick control of acute inflammation and prevention of recurrences should be the main purposes of the treatment.  documented that systemic steroid in pulse form of methylprednisolone or oral prednisone improves disc edema quickly, however, it has no effect on vision. Although it has no effect on final vision, we suppose that intravitreal dexamethasone injection which is free of a systemic steroid (oral or intravenous form) side effects may be reasonable to obtain a quick response for disc edema and subretinal fluid. More importantly, in terms of prevention recurrences, Sundaram et al. demonstrated that Azathioprine, as an immunosuppresive agent, reduced recurrence rate amount of 72% (with a mean of attack rate from 0.58 to 0.16 per year). According to results, it can be considered that immunosuppresive therapy can provide a better prognosis on the recurrent subgroup of NR.
Distinctive Features in Clinical Course and Imaging for Idiopathic NR
As mentioned above, it could be essential to predict whether the disease would progress to recurrent idiopathic NR prior to treatment decision. Firstly, eliminating of masquerading diseases in differential diagnosis of NR is crucial to achieve a successful treatment. In clinical findings, pain is very rare for all subgroups of NR (infectious, inflammatory or idiopathic). The presence of severe pain, in particular associated with eye movement should lead the clinician to another possible alternative diagnosis. Similarly, involvement of both eyes at the same presentation should also suggest possibility of a NR masquerading disease.  Nevertheless, a number of cases were also reported that bilateral involvement in NR might occur with an underlying infectious etiology, such as Bartonella infection, toxoplasmosis, Lyme disease or mumps. [12, 13, 32-34] Purvin et al was also suggested that in the presence of protracted disc edema, clinician should be suspicious for an alternative diagnosis, such as sarcoidosis, idiopathic retinal vasculitis, aneurysms and NR (IRVAN) or a disc tumor. The author also underlines that the distinctive features, such as a VF defect outside of the central field, no systemic findings, a large amount of RAPD incompatible with a preserved vision, poor recovery and presence of any evidence in the fellow eye. These findings may be indicative for high risk of recurrent idiopathic NR.
In fact, NR is mainly a clinical diagnosis with characteristic findings in physical examination, yet imaging methods can be occasionally used as an ancillary test in the diagnosis of NR.  reported the magnetic resonance imaging (MRI) finding of an idiopathic NR patient, and MRI showed isolated enhancement in the optic nerve sheath, while in several case reports it was observed that both optic nerve and sheath enhancement on CT in one case of the idiopathic NR, and also on MRI in one case of recurrent idiopathic NR. [36, 37] Orbital MRI scans of 36 of NR cases were evaluated in a study.In idiopathic NR group, 2 of 6 scans showed abnormal appearance, one of the scans was with isolated disc enhancement, and another one showed enhancement the optic disc with posterior extention. In recurrent subgroup, 3 of scan demonstrated isolated disc enhancement, and one case showed retrobulber optic nerve enhancement.  Overall, these results indicate that MRI findings can be characteristic in NR, but can vary between the subgroups.Optical coherence tomography (OCT) has been used to demonstrate subretinal fluid and optic disc edema, and also in evaluating the treatment response in patients with NR. More importantly, OCT enables to show subclinical evidence of subretinal fluid compared with slit-lamb examination. [7, 8] In a recent article by Zatreanu et al.  defined two very early findings of NR in spectral domain OCT. The author noted the presence of ‘Epipapillary infiltrates’ as a very early finding prior to formation of macular star that is presumed to be accumulations of inflammatory cells in the vitreous near to optic disc border. In particular, these epipapillary infiltrates are not seen in masquerading pathologies, such as anterior ischemic optic neuropathy or papiledema. Another characteristic finding was the spesific pattern of retinal folds, which is characteristically with inner retinal folds expanding outwardly as concentric rings into the macula. It is thought that these distinctive retinal folds unlike other patterns in other causes of disc edema occur due to mechanical effects of retinal edema.
In this review, we propose that it is very important to correctly evaluate an idiopathic NR patient. First, physician should address the questions of is it a masquerader or NR?, infectious or idiopathic?, and is there a high risk of recurrence for the patient or not?. To address all these questions requires a compherensive taking history, clinical examination, laboratory work-up and imaging. The treatment option of idiopathic NR varies depending on a single episode or recurrence. (Table-2)
In particular, immunosuppresive treatment should be considered in recurrent subgroup. In addition, in cases with single episode, patients’ preferences should also be taken into account for a quick visual response in treatment. However, we suggest that further studies, which take distinctive features of NR within the subgroups into account, will need to be undertaken.
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