Neuroretinitis, a great mimicker

Neuroretinitis is a less-known clinical entity, which can be funduscopically confused with papillitis or papilledema and with hypertensive, renal and infiltrative retinopathies as well as with retinal vein occlusion or anterior ischemic optic neuropathy. Report: Two young patients presented with sudden onset of blurring of vision. Ophthalmic evaluation revealed a characteristic picture of neuroretinitis. Detailed study of the cases failed to indicate any specific etiology, thereby suggesting the diagnosis of idiopathic neuroretinitis. Although funduscopy showed marked inflammatory changes in the retina and optic nerve head, the recovery following medical treatment was remarkable. Comment: Familiarity with the fundus picture and awareness of the specific causes of neuroretinitis among neurologists and physicians may enable a prompt clinical diagnosis, avoidance of expensive brain imaging studies and early referral for appropriate and effective therapy. A brief review of the literature is presented suggesting a need for further studies to establish specific environmentally determined etiological factors such as infections and the effectiveness of the current modalities of treatment.


Introduction
Neuroretinitis is a type of optic neuropathy characterized by an acute unilateral visual loss in the setting of optic disc swelling accompanied by hard exudates characteristically arranged in a star shape around the fovea. [1] In fact, it is classiÞ ed as one form of optic neuritis, the other forms being the more common retrobulbar neuritis and papillitis. Funduscopically, neuroretinitis is oft en confused with hypertensive, renal and inÞ ltrative retinopathies as well as with papillitis, papilledema, anterior ischemic optic neuropathy and retinal vein occlusion. It is an entity that physicians, pediatricians and neurologists are poorly exposed to, since the diagnosis and management are almost exclusively performed by the ophthalmologist. Pathogenesis and etiology of neuroretinitis are distinctly different from other funduscopically resembling conditions encountered by neurologists very oft en during their training and clinical practice; further, these have obviously diff erent principles of management and prognosis. Prognosis for visual recovery is reported to be excellent, although not uniform. [2] Our objective is to present two typical cases of neuroretinitis and highlight the need for neurologists to distinguish it from optic neuritis or retinal disorders that it closely mimics. optic nerve sheath with a mild elevation of 1 mm of the optic nerve head. The other eye was unremarkable. The remaining cranial nerves and the results of neurological examination were normal. There were no meningeal signs. There was no lymphadenopathy, rashes and the result of the remaining physical examination was also normal. ELISA for cysticercosis, tuberculosis, Lyme disease, leptospirosis, brucellosis, toxoplasmosis and toxocariasis and Weil-Felix test showed negative result. Serum HIV, HBsAg, VDRL, Herpes, CMV and Rubella serology, Paul Bunnel test and cold agglutinins showed negative result. The serology for Bartonella henselae, which is responsible for cat-scratch disease (CSD), could not be performed. Antinuclear and antiphospholipid antibodies revealed negative result. The Þ ndings of computed tomography, MRI and MR venogram of the brain were normal. Following a diagnosis of idiopathic neuroretinitis, the patient was administered oral prednisolone for three weeks. The vision improved to 6/12 aft er a period of two weeks. Six months later, the deep exudates remained but otherwise the fundus became normal with the return of visual acuity to 6/9. No neurological symptoms supervened at any time. The patient remained asymptomatic during a follow-up period of the next two years.

Case 2
A 26-year-old female presented with a progressive decrease in vision in the right eye for three weeks. There was no history of trauma or contact with cats or other pets. There was no fever or other symptoms at the onset of this problem. On examination, the bestcorrected visual acuity was 6/12 in the right eye and 6/6 in the left eye. The optic disc was hyperemic with blurred margins. The veins were dilated and tortuous. At the initial presentation, a slit-lamp examination with a 90-D lens conÞ rmed the presence of a mild macular edema. The retinal periphery was normal [ Figure 2]. Patient developed stellate maculopathy three weeks later. Color vision was severely impaired in the right eye. VEP showed a lower amplitude on the right side with a latency of 107 ms but ERG was normal. Fluorescein angiography showed diff use leakage from the disc but not from the macula or retina. Central Þ elds of this patient revealed a centrocaecal scotoma in the right eye and normal left eye Þ elds. A systemic examination of the patient was normal. Ultrasonography of the right eye showed an elevation of 2 mm of the optic nerve head. The other eye was unremarkable in all aspects. Radiological examination of the skull and paranasal sinuses was normal. MRI of the brain and MR venogram were within normal limits. The results of all blood tests, including serological tests for syphilis, Lyme disease, toxoplasmosis and toxocariasis and the remaining serology, similar to that in case 1 was negative. A general physical examination of the patient was also normal. Idiopathic stellate neuroretinitis was diagnosed. No speciÞ c treatment was administered in the light of relatively minimal impairment of the visual acuity. Six weeks aft er the onset, the optic nerve swelling had decreased but the macular star-shaped figure persisted. The vision had returned to normal, and she continued to be asymptomatic over a follow-up period of one year.

Discussion
Neuroretinitis presents with sudden visual loss, swelling of the optic disc, peripapillary and macular exudates that may occur in a star-shaped patt ern and cells in the vitreous. [1] It aff ects persons of all ages, more oft en in the third and fourth decades of life, with no gender predilection. [2,3] Visual acuity at the time of initial examination ranges from 6/6 to light perception (PL). The most common Þ eld defect is caecocentral scotoma,  but central scotomas, arcuate defects and even altitudinal defects may also be present. A relative aff erent pupillary defect is present in most patients, unless the condition is bilateral. VEP is useful in the sett ing of suspected multiple sclerosis in which there is a prolongation of latency of the P100 wave and a decrease in amplitude. The amplitude of VEP may be abnormal in neuroretinitis too. ERG is usually normal since it assesses the functional integrity of the retinal layers and hence grossly normal in a disorder involving ganglion cells and optic nerve, such as neuroretinitis. An early defect in color vision is common as one would expect in a disease aff ecting ganglion cells and the macula.
The degree of the optic disc swelling ranges from mild to severe, which depends, in part, on the timing of the Þ rst examination. In severe cases, splinter hemorrhages may be present. A macular star-shaped Þ gure composed of lipid (hard exudates) may not be present when the patient is examined immediately aft er the onset of visual symptoms, but tends to become more prominent as the optic disc swelling resolves. [4] The posterior inß ammatory signs consisting of vitreous cells and venous sheathing as well as mild anterior uveitis may occur as noted in one of the cases encountered by us.
Diagnostically, the fundus picture may be confused with a few other entities. Papillitis, papilledema, central retinal vein occlusion and anterior ischemic optic neuropathy are the close mimickers funduscopically. [5] Diff erentiation, however, is not diffi cult by performing detailed ophthalmic, nervous system and general examination. Table 1 illustrates the differentiating features between these conditions. The etiopathology of neuroretinitis is obscure. Neuroretinitis is thought to be an infectious or immunemediated process that may be precipitated by a number of diff erent agents. [2] Commonly associated with an antecedent viral syndrome, in up to 50% of the cases, viruses are seldom cultured from vitreous and aqueous humor and CSF of such patients, and the serological evidence of a concomitant viral infection is usually lacking. Proposed causative viral agents include herpes simplex, hepatitis B, mumps and the herpes viruses associated with the acute retinal necrosis syndrome. Other common infections that cause neuroretinitis are CSD, spirochetosis especially syphilis, Lyme disease and leptospirosis. Presumed etiologies for neuroretinitis also include toxoplasmosis, toxocariasis and histoplasmosis.
The pathogenesis of neuroretinitis is associated with the direct involvement of the optic nerve Þ bres by the infectious process or the inß ammation leading to edema and ß uid exudation from the inß amed cellular area of the peripapillary retina. Since macular exudates result more likely from the primary optic nerve disease, rather than from the inß ammation of the retina, the idiopathic variety is also called as 'idiopathic optic disc edema with a macular star' rather than 'neuroretinitis'. [6] When optic disc swelling and macular star are associated with focal or multifocal inß ammatory lesions in the retina (retinitis), especially if an infectious cause is documented, the term 'neuroretinitis' is indeed unquestionable. The macular exudates may not develop until two weeks aft er the onset; hence, the need to reexamine patients with acute papillitis with a normal macula within two weeks for the development of a macular star.

Variants of neuroretinitis
In the absence of a proven etiology to the disease, the condition is diagnosed as Leber's idiopathic stellate retinopathy. [7] It is a diagnosis of exclusion made aft er ruling out other known causes of neuroretinitis. It occurs most oft en in healthy young subjects presenting with acute unilateral visual loss. Although treatments with systemic steroids have been att empted, there is no deÞ nite evidence that such treatment alters either the speed of recovery or the ultimate outcome. [8] The prognosis is usually good, with a spontaneous resolution within 6-12 weeks, although the macular star-shaped structure may persist beyond this period. Diff use unilateral subacute neuroretinitis (DUSN) is a related condition thought to be caused by one or more types of helminths, [9] probably by a motile worm. In approximately 25% of the cases, a worm is visualized during the eye examination. Laser treatment for killing the worm is the only reliable way to cease the progression of this disease. [10] The most characteristic feature of idiopathic retinal vasculitis and aneurysms associated with neuroretinitis (IRVAN) syndrome [11] is the presence of macroaneurysms in the retinal and optic nerve head arterioles. Typically noted in young, healthy, female subjects, this bilateral condition is not associated with any systemic abnormalities and its etiology remains unknown . . Another association is with the CSD [12] observed in young, otherwise healthy individuals with fever, malaise, lymphadenopathy and a history of exposure to or puncture wounds by cats, with neuroretinitis as a characteristic clinical feature, caused by the organism Bartonella henselae. Some evidence even indicate that Leber's neuroretinitis is nothing but a manifestation of CSD, but the extent of association remains to be determined. AIDS-associated CSD neuroretinitis may additionally have conjunctival and retinal bacillary angiomatosis. Although a self-limiting disorder, systemic corticosteroids with or without systemic antibiotics have been reported to be eff ective in this condition. [13] Azithromycin, ciproß oxacin, rifampicin, parenteral gentamicin, or trimethoprim-sulfamethoxazole have been found to be effective in immunocompromised patients. A bilateral neuroretinitis with severe anterior uveitis can occur in syphilis and other spirochaetal infections, such as borreliosis and leptospirosis, where meningeal and cerebral involvement may coexist.
There is now a consensus that multiple sclerosis is one condition that is not associated with neuroretinitis, [2] although anterior and retrobulbar neuritis are intimately linked to multiple sclerosis. There is no increased risk of development of multiple sclerosis, in neuroretinitis patients. Thus, when an acute optic neuropathy is diagnosed as neuroretinitis rather than anterior optic neuritis, it substantially alters the neurological prognosis, despite some anecdotal reports of patients with 'multiple sclerosis who developed 'neuroretinitis'. [14] The presence of a macular star-shaped structure militates strongly against subsequent development of multiple sclerosis. [5] Visual and associated neurological symptoms of neuroretinitis att est the fact that this is a disease of both the retina and contiguous neuronal elements.
In the two cases discussed above, there was no conÞ rmed etiology despite extensive evaluation; hence, a diagnosis of Leber's idiopathic stellate neuroretinitis would be appropriate. The disease is self-limiting but patients are oft en treated empirically with steroids in the acute phase. In this idiopathic variety, a general prognosis for visual recovery is good, as was the case with our patients; however, there are a few reports of severe residual visual loss a well. In the secondary forms wherein there is an identiÞ ed or strongly associated infectious agent, specific therapy against the organisms along with steroids appears justiÞ able from anecdotal reports. One form of speciÞ c secondary neuroretinitis produced by herpes virus infection can result in blindness from severe necrotizing neuroretinitis. No reliable data is available on any acute phase prognostic markers for the eventual visual outcome. Patients with recurrent att acks may not experience good recovery of optic nerve function.

Conclusions
Neuroretinitis should be distinguished from several funduscopically confusing conditions. The time course, presence or absence of pain, pattern of visual loss (particularly visual field defects) and funduscopic appearance help to diff erentiate it from the common forms of optic neuropathies [15] such as papilledema, ischemic optic neuropathy, optic neuritis, compressive lesions, toxic/nutritional deÞ ciencies, and hereditary forms; though, neuroretinitis can mimic any of these entities and pose a diagnostic challenge even to a wellexperienced clinician. However, the extent of diagnostic investigations in neuroretinitis should be based on the presence or absence of associated constitutional symptoms and corroborative evidences. In the idiopathic variety, the patient is most likely to recover vision within weeks to months. Most of the current information regarding this entity has been drawn from observations from small series and anecdotal reports. Although a few well-known etiological factors have been identiÞ ed, they are by themselves not common conditions (e.g., CSD) and many of the reported cases do not have uniform data. The role of steroids as a treatment remains unclear in both the primary and secondary types. Hence, a prospective multicentric registry systematically taking into account the etiological factors and outcome of the standardized treatment may provide a bett er insight into the etiopathology, diagnosis and management of neuroretinitis.