Neuroretinitis is a focal inflammation of the optic nerve and peripapillary retina or macula of either infectious or idiopathic etiology.
Neuroretinitis ICD9 363.05
Neuroretinitis is an inflammation of the neural retina and optic nerve. It was originally described by Leber in 1916 as a "stellate maculopathy," but this definition was challenged by Don Gass in 1917, citing that disc edema precedes macular exudates. Subsequently, Gass confirmed optic disc leakage by fluorescein angiography and suggested the term "neuroretinitis." More recent retinal and optic nerve imaging has supported Gass' description.
Risk factors for neuroretinitis relate to susceptibility to each particular causative agent. Patients immunocompromised from chronic disease, HIV/AIDS, medications, health care workers, recent immigrants or those with recent travel to endemic areas are all high-risk populations.
Direct invasion or autoimmune activation against the optic nerve may cause optic nerve vascular inflammation with secondary inflammation and edema in the nerve fiber layer of the retina.
Neuroretinitis is characterized by an inflammation of the optic disc vasculature with exudation of fluid into the peripapillary retina. The lipid-rich component of the exudate is further able to penetrate into the outer plexiform layer, creating what is clinically seen as a macular star pattern. Only the aqueous phase is then able to pass through the external limiting membrane to accumulate beneath the neurosensory retina (Figure 2, large arrow). The exact origin of the inflammation of the optic disc vasculature is unclear. A flu-like prodrome in some patients supports a viral etiology: either a virally-induced autoimmune response or direct invasion of the nerve. One case report has cited autopsy findings of herpes simplex virus in the optic nerve substance.
Figure 2. Macular OCT showing thickening in different layers of retina. Small arrow shows location of Henle's layer, where exudates are deposited (see Figure 6). These exudates are seen clinically as the macular star pattern. The large arrow shows subretinal fluid causing local neurosensory retinal detachment.
Neuroretinitides may be broadly classified as infectious or idiopathic.
Most infectious cases are due to cat-scratch disease, caused by Bartonella species. In a review article by Purvin et al., review of literature shows an average age of onset is 24.5 years with a range from 4 to 64 years and a female:male incidence of 1.8:1. Seventy-three percent of these patients manifest systemic symptoms, while only 7.7% manifest eye pain.
Initial visual acuity is 20/200 or worse in 52.2% of patients, while final visual acuity is 20/40 or better in 93%. Eighty-eight percent have a central visual field defect, and 67.5% manifest a relative afferent pupillary defect (RAPD). One study reported seven eyes with count finger visual acuity and no RAPD, suggesting that visual impairment in neuroretinitis is due to macular pathology rather than optic nerve dysfunction. Vision in these seven patients returned to 20/40.
Cases in which a clear infectious or inflammatory etiology is not found are categorized as idiopathic. Average age of onset in these cases is 28 years with a range from 8 to 55 years of age. In published cases, more than 50% have a preceding flu-like illness, usually an upper respiratory infection (URI). Visual loss is usually painless.
Most cases of visual loss are unilateral and vision is usually between 20/50 and 20/200, though vision has been shown to range from 20/20 to light perception only (LPO). The most common visual field loss pattern is a central or cecocentral scotoma from edema of the papillomacular bundle. Though an RAPD may be present, it is not as prominent as in demyelinating disease.
Examination usually manifests posterior chamber cells and occasionally anterior chamber cell and flare. Early in the course of the disease, the fundus shows isolated optic disc edema with exudative peripapillary serous retinal detachment. After 9-12 days, macular edema is present and disc edema is diminished. Over time, exudates become less well-defined, then disappear, and, finally, only RPE defects remain. At 8-12 weeks, the disc edema has resolved, leaving a normal or pallorous nerve.
Most patients with idiopathic neuroretinitis recover excellent visual acuity with or without intervention: 20/40 or better in 90% of reported cases. One small subset in a case series fared poorly with large disc-related defects and APD; the authors attributed these findings to a vaso-occlusive mechanism of prelaminar arterioles with subsequent disc infarction.
Treatment choice and efficacy is unclear. One report documents use of intravitreal steroids and bevacizumab. Patients in this report were diagnosed with idiopathic neuroretinitis ten days after vision initially decreased and received treatment three days after. Vision had returned to baseline and macula appeared normal at one week, and the disc appeared normal at one month. Since two treatments were administered, and since the natural course of the disease is recovery anyway, assessing efficacy of treatment is difficult.
Some cases of idiopathic neuroretinitis are recurrent. In these cases, visual loss tends to be more related to optic disc disease with central and nerve fiber layer-related visual defects. Recurrence tends to result in an optic neuropathy with less visual and field recovery. Hard exudates are less prominent in subsequent attacks.
Treatment for recurrent idiopathic neuroretinitis is debatable. One recommendation is low-dose alternate day azathioprine and/or prednisone.
Avoidance of exposure to causative agents, infected individuals, and high-risk areas and practices limit susceptibility to causative bacterial and viral agents.
Complete history and ophthalmologic physical exam should be performed. Additional testing, such as full systemic physical exam or ancillary testing should be guided by clinical suspicion.
Time of onset, laterality, and duration of symptoms should be elicited on examination. A history of similar episodes may be noteworthy. Social history, particularly for history of recent travel, contact with sick individuals or animals, and sexual activity should be documented. Review of systems to assess pulmonary status, skin changes, cardiovascular issues, unintentional weight changes, and constitutional symptoms should be sought. If brainstem signs are evident, patient should be asked about nausea, vomiting, hearing difficulty, tinnitus, dysphagia, dysphonia, and syncope. Depending on acuity of visual loss and quality of vision change, questions should be asked to rule out giant cell arteritis. Patients may also be asymptomatic.
Complete slit lamp examination and examination of retina should be performed. Color vision and Amsler grid may assist in diagnosing optic nerve or localizing macular pathology, respectively. Fluorescein angiography may be performed to assess for disc leakage or vascular pathology within the macula.
External exam for evidence of skin lesions should be performed. Lids and lashes should be examined for herpetic lesions. Anterior segment should be evaluated for keratic precipitates, anterior chamber reaction, iris nodules, posterior synechiae, or anterior vitritis. Optic disc should be evaluated for pallor, and vasculature for sheathing or perivascular hemorrhage. Macula may manifest hard exudates in a star pattern with associated retinal thickening or subretinal fluid.
Patients may exhibit painless decrease in central vision, decreased color vision, or, occasionally, may be asymptomatic.
Direct or indirect fundus examination of the posterior pole may reveal an inflamed optic disc and/or a macular star pattern. As the macular star may take 1-2 weeks to manifest, only optic disc inflammation may be evident in an early presentation. Macular star generally becomes apparent a few weeks (Left) after onset of visual symptoms and resolves thereafter over several weeks. In a recurrent episode, a macular star may or may not be evident and even if present may not exhibit classic star pattern (Middle, Right). Hard exudates in a somewhat radial pattern relative to the fovea may be the only obvious finding. Chronically disc pallor may be present.
Figure 4. (Left) Classic macular star pattern. (Middle, Right) Irregular pattern of exudates in recurrence of neuroretinitis.
Fluorescein angiography may reveal disc edema and leakage and blockage of fluorescence in areas of hard exudates. Occasionally, staining may be found in the seemingly uninvolved contralateral eye.
Figure 5. Time lapse images of fluorescein angiography showing progressive leakage of single vessel from an inflamed disc in neuroretinitis.
Optical coherence tomography reveals retinal thickening, possible subretinal fluid (large arrow), and fluid or exudates (arrowheads) within the outer plexiform layer (Henle's layer). OCT may also be useful in detecting a serous retinal detachment before a macular star forms. It may also be useful the minority of cases in which a star never forms. Autofluorescence may assist in detecting macular exudates.
Figure 6. Large arrow shows neurosensory retinal detachment from fluid that has diffused through all retinal layers. Arrowheads draw attention to orange flecks representing exudates in Henle's layer, seen clinically as a macular star.
Laboratory testing should be guided by clinical suspicion and tailored to history and physical examination. By frequency, cat-scratch titers should be obtained. FTA-ABS, PPD (Picture), Lyme serology, ACE, and chest x-ray may serve as adequate baseline tests.
Figure 7. Positive PPD in patient with neuroretinitis from tuberculosis.
Though optic nerve enhancement may be seen on MRI, the literature suggests that MRI findings for neuroretinitis are characteristic but not sufficiently specific to merit routine imaging.
Differential diagnosis for macular star includes hypertensive retinopathy, papilledema, anterior ischemic optic neuropathy, diabetic papillopathy, posterior vitreous traction, disc and juxtapapillary tumors, and toxic etiologies, including bis-chloroethyl,nitrosourea and procarbazine. Many of the disease processes in the differential, however, tend to be bilateral in nature, unlike neuroretinitis. As such, clinical suspicion should guide additional testing and diagnosis.
The treatment of neuroretinitis is directed at the underlying etiology. Suspicion for infectious etiology, particularly tuberculosis, may merit consultation with an infectious disease specialist. If causative agent is found to be cat-scratch disease, various treatment methods are found in the literature, including no treatment, antibiotics only, antibiotics and steroids, and steroids only. As a high degree of spontaneous visual recovery exists in cat-scratch disease neuroretinitis, definite conclusions cannot be made regarding antibiotic efficacy.
If an infectious etiology is suspected, appropriate work-up with broad spectrum antibiotic treatment while results are pending is appropriate. Recommended antibiotics are ciprofloxacin or azithromycin for adults and azithromycin or sulfamethoxazole-trimethoprim for children. For the idiopathic variety, high-dose oral corticosteroids have been administered. Antibiotics may be considered to cover cat-scratch disease while serologies are pending.
Medical follow up
If an infectious etiology is suspected but serologies are negative, retesting at six weeks for rising IgG titers is appropriate.
Complications stem from side effects from pharmacologic therapy or chronic visual loss from recurrence. Anti-tuberculous treatments are well-known for ocular complications, including retrobulbar neuritis with ethambutol and significant anterior uveitis and hypopyon with rifabutin therapy.
Optic disc edema is generally self-limited. Otherwise, another etiology such as disc tumor or sarcoid should be considered. Most patients with idiopathic neuroretinitis achieve excellent visual recovery with or without intervention. In infectious neuroretinitis, one report cites 93% of patients achieving 20/40 final visual acuity or better, and no patients with less than 20/200 vision.
Ghauri R, Lee A. Optic Disk Edema With a Macular Star. Survey of Ophthalmology. 43(3): 270-274, 1998.
Purvin V, Sundaram S, Kawasaki A. Neuroretinitis: Review of the Literature and New Observations. J Neuro-Ophthalmology. 31: 58-68, 2011.