Our understanding of neuroretinitis (NR) has continued to evolve since its first description by Theodor Leber in 1916 (1). Leber reported a patient with acute unilateral visual loss with disc edema and macular exudates arranged in a star pattern and used the term “stellate maculopathy.” This localization was challenged by Gass in 1977 (2), who noted that disc edema precedes the formation of exudates in this condition. Using fluorescein angiography (FA), he demonstrated that the site of the leakage is, in fact, not the macula but the optic disc and suggested the term “neuroretinitis.” In recent years, the concept that NR is caused by an increased permeability of optic disc vasculature with secondary leakage into the surrounding retina has been confirmed and further delineated using retinal and optic nerve imaging (3-5).
The series by Dreyer et al (6) and by Maitland and Miller (7) furnished a description of the typical clinical features of this disorder. Since that time, a number of articles have reported additional cases of NR due to a wide range of infections (see below). Nomenclature has varied including stellate retinopathy (1), NR (2), Leber idiopathic stellate NR (8), and optic disc edema with a macular star (ODEMS) (9). Brazis and Lee have suggested using the term ODEMS for idiopathic cases and the term NR preceded by the infectious agent for those in which a specific etiology is identified. For this review, we use the term “neuroretinitis” coupled with a designation of idiopathic or a specific etiology when determined.
The primary process in NR involves inflammation of optic disc vasculature causing exudation of fluid into the peripapillary retina. An elegant study by Kitamei et al (5) using FA and indocyanine green angiography coupled with optical coherence tomography (OCT) in a patient with idiopathic NR demonstrated massive leakage of dye from a single arteriole on the disc surface, rather than widespread leakage from optic disc capillaries. Lipid-rich fluid flowed directly into the outer nuclear-plexiform space but only the aqueous phase then passed through the external limiting membrane to accumulate beneath the neurosensory retina. Due to the loose, radial configuration of the outer plexiform layer, the lipid-rich exudates form a star pattern (10).
The mechanism of disc vasculitis in NR is unclear. The presence of a flu-like prodrome in many cases has been taken as evidence of a viral etiology, either due to direct invasion of the nerve or a virally induced autoimmune response (7). The former mechanism was supported by the autopsy findings in 1 case of NR associated with herpes simplex encephalitis in which intranuclear viral inclusion particles were identified in the optic nerve and retina (11). Alternatively, NR may be due to an actual focal infectious process induced by an agent with a predilection for vasculature, notably cat scratch disease (CSD). A variety of posterior segment manifestations of CSD have been described and a common feature in these cases is vascular leakage due to retinal vasculitis (12). Evidence for a blood-borne agent as the cause of NR includes the presence of chorioretinal white spots, occasional bilateral involvement, and the segmental nature of the disc staining in symptomatic and asymptomatic eyes consistent with access to the optic nerve via the ciliary or central arterial system (6). In cases of NR with recurrent attacks, local invasion via hematogenous spread is highly unlikely, and in these cases, an autoimmune vasculitis seems more likely, although reactivation of a localized infectious organism, as seen in toxoplasmosis, remains a possibility.
Not all cases of ODEMS are due to NR, and it is important for the clinician to be alert to these other disorders that might be mistaken for NR (Table 1). In cases of hypertensive retinopathy and in most cases of papilledema (increased intracranial pressure [ICP]), fundus abnormalities are bilateral, whereas most cases of NR are unilateral. Another helpful feature is the presence of cotton wool spots scattered throughout the posterior pole in hypertensive retinopathy. These should be distinguished from the deep chorioretinal white spots that are sometimes seen in NR (17). Macular exudates are occasionally seen with papilledema and the presence of symptoms and other signs of increased ICP should lead to the correct diagnosis. Brain neuroimaging and lumbar puncture may be needed for confirmation. Rarely, a macular star is observed in nonarteritic anterior ischemic optic neuropathy (NAION), causing potential confusion with NR. The exudation in such cases is typically less robust, and the star often incomplete. The presence of vitreous cells would be consistent with NR rather than with NAION. In such cases, distinction between NAION and NR is made on the basis of other clinical findings, such as age and vascular risk factors. Patients with diabetic papillopathy may also exhibit a macular star, and some of these cases are bilateral.
Cases of NR have been reported in association with a wide variety of infectious agents (Table 2). The single most common of these is CSD, which accounted for two thirds of cases in one series (33). Because the prevalence of CSD varies widely with climate and geography (84), this percentage may vary in different locations. The introduction of an indirect fluorescent antibody test for Bartonella henselae, the causative organism of CSD, has facilitated the accurate diagnosis of this disease (85). In retrospect, some cases previously designated as idiopathic NR may in fact have been due to CSD. For idiopathic cases, a viral etiology has been assumed, but this has never been proven.
NR has also been described as a part of other retinal inflammatory disorders, including idiopathic retinal vasculitis, aneurysms and NR (IRVAN) syndrome (82,83) and diffuse unilateral subacute neuroretinitis (DUSN), the latter caused by a nematode (75). Occasional cases of NR are due to noninfectious forms of uveitis, such as sarcoidosis (78) and periarteritis nodosa (81). In addition, there have been 3 reported cases of NR associated with inflammatory bowel disease (33,79,80). One of our patients with recurrent NR was diagnosed with ulcerative colitis 9 years after the second attack of NR (86). Because of the long interval between the 2 conditions, it is difficult to be certain of a causal relationship.
Relationship to Multiple Sclerosis
Individuals with demyelinating optic neuritis (retrobulbar or papillitis) are at an increased risk for the future development of multiple sclerosis (MS). Since NR is a form of papillitis, one might assume that patients with this condition would be similarly at a high risk. A large survey of patients with NR, however, found no such increased risk (87). This difference in prognosis is presumably related to differences in pathophysiology of these 2 conditions. In demyelinating optic neuritis, the target tissue of the inflammatory response is the myelin sheath, whereas in NR, the target is the optic disc vasculature. However, a retrospective review of 35 patients with NR seen in a single university-based practice identified 3 patients who had already been diagnosed with MS (88). All 3 patients were on β-interferon, and the authors suggested that perhaps, this treatment influenced the permeability of disc vessels, thus affecting the funduscopic appearance. One of our patients developed relapsing remitting MS 11 years after a bout of NR secondary to CSD. We believe that these 2 conditions are coincidental. Despite these unusual cases, the management of patients with NR should be clearly distinguished from that of patients with optic neuritis. Specifically, the diagnosis of NR is not considered a risk factor for the future development of MS.
PROPOSED CLASSIFICATION OF NEURORETINITIS
NR can be classified on the basis of etiology (idiopathic vs specific infectious agent), although this classification is not always clear-cut. The large series reported by Dreyer et al (6) was designated as idiopathic. However, the authors acknowledged that 3 of their cases were strongly suspected to have CSD. In the series of Maitland and Miller (7), one patient had a preceding varicella infection. With further advances in serologic testing, more cases may be moved out of the idiopathic category and into that of a specific cause.
Idiopathic cases can be further subdivided into those with a single episode of NR and those with recurrent attacks. Some case reports, case series, and reviews have not clearly distinguished among these different forms of NR, and it is unclear if the clinical features vary among these subsets. This distinction is of interest for several reasons. First, since the basis for idiopathic NR is unknown, it would be helpful to know if the clinical features more closely resemble CSD-NR due to an infectious agent, or if the disorder is more similar to recurrent idiopathic NR, which is thought to be due to an autoimmune process. Second, it would be helpful to know how aggressively to pursue a workup for a specific etiologic agent in an individual patient. Finally, management decisions may differ in these subgroups.
To better characterize these features, we reviewed the literature and our own experience with the 3 most common forms of NR: idiopathic NR, cat scratch NR, and recurrent idiopathic NR. We identified publications using the Ovid search engine from 1950 to June 2010 using the subject heading neuroretinitis and limiting the search to articles in English and involving humans. Additional cases were collected from articles on CSD.
The clinical features of idiopathic NR have been described in several case series and single case reports (6,7,9,17,21,33,89,90) and summarized in a number of reviews (8,9,91). NR usually affects young adults (average age, 28 years), but the age range is broad (8-55 years). In published cases, more than half experienced a preceding flu-like illness, usually affecting the upper respiratory tract. Visual loss is usually painless, although occasional patients experience a mild retrobulbar discomfort.
Most cases are unilateral, but bilateral cases have been described. Some of these are characterized by bilateral visual loss, whereas in others, asymptomatic disc edema is observed in the fellow eye. Visual acuity is usually between 20/50 and 20/200 but can range from 20/20 to light perception. The most common pattern of visual field loss, found in 24 of 29 eyes in the series of Dreyer et al (6), is a cecocentral or central scotoma, consistent with the presence of edema in the papillomacular bundle. A relative afferent pupil defect (RAPD) is often present, although not with the same frequency or magnitude as in demyelinating optic neuritis. This difference reflects the different mechanism of visual loss in these 2 conditions: visual loss is due largely to maculopathy in NR and entirely to optic nerve dysfunction in optic neuritis.
Posterior vitreous cells are usually present; anterior chamber cell and flare are occasionally seen as well. The funduscopic appearance depends in large part on the timing of the examination (Fig. 1). The earliest finding is an isolated optic disc edema, which may be diffuse or segmental. Peripapillary nerve fiber layer hemorrhages are sometimes present. In most cases, optic disc edema is associated with an exudative peripapillary serous retinal detachment. It typically takes 9 to 12 days for the characteristic macular exudates to appear, and at this stage, disc edema is usually diminishing. The star figure is initially sharply defined and spoke-like; over time, the exudates become less well defined and eventually, after a number of months, disappear completely, often leaving residual subfoveal retinal pigment epithelial defects (Fig. 2). In most cases, optic disc edema resolves over 8 to 12 weeks. The disc may eventually regain a normal appearance or demonstrate pallor and/or gliotic changes.
Many patients with idiopathic NR have been managed conservatively, others treated with steroids. Most experience excellent recovery of vision with or without intervention, with a final acuity of 20/40 or better in 90% of reported cases. There appears to be a subset of patients, however, with a somewhat different clinical picture, in whom the visual prognosis is more guarded. Of the 12 patients with NR described by Maitland and Miller (7), 3 failed to experience excellent recovery. Two of the patients in the series of Dreyer et al (6) had disc-related field defects and a large RAPD, and in both of these cases, the visual outcome was poor. The authors suggested that these patients had a virus-induced occlusive vasculitis involving prelaminar arterioles, which led to disc infarction.
One recent report documented the results of treatment with intravitreal steroids plus bevacizumab in a patient with idiopathic NR (92). In this single case report, the diagnosis was made 10 days after onset of visual loss, treatment was given 3 days later, and at 1-week follow-up, visual acuity had returned to normal and macular edema resolved. One month later, optic disc edema had resolved as well. The significance of this report is difficult to evaluate, in part because the natural history of NR is usually favorable and also because 2 different forms of treatment were given. Furthermore, in cases of NR with poor visual outcome, the limiting factor for visual recovery appears to be residual optic nerve damage rather than maculopathy. Since the intravitreal treatment in this report did not hasten resolution of disc edema, it is not clear that it would improve the outcome in such cases.
Cat Scratch Neuroretinitis
The most common form of infectious NR is due to CSD. A number of single case reports and small case series have described the clinical features of NR secondary to CSD. We reviewed a total of 65 reported cases, 4 of which were bilateral (69 eyes) (see Table, Supplemental Digital Content 1, https://links.lww.com/WNO/A14). From the data available, the average age at onset was 24.5 years (median: 21 years) with a range of 4 to 64 years. There was a female to male predominance of 1.8:1, and both eyes were affected equally. Systemic symptoms were reported in 47 (73%) of 64 cases and eye pain in 4 (7.7%) of 52 cases.
Initial Snellen acuity was 20/40 or better in 14.5% of eyes, between 20/50 and 20/200 in 33.3%, and worse than 20/200 in 52.2%. Final acuity was available for 58 eyes and was much improved in almost all cases: 93% had vision of 20/40 or better and none was worse than 20/200. The average number of lines gained was 7.7. The pattern of visual field loss was available for 27 eyes and usually consisted of a central defect (88%). A RAPD was present in 25 eyes (67.5%) and was variable in magnitude. There were 7 eyes with count fingers vision in which a RAPD was absent. This would suggest that much or all of the visual loss in these cases of NR secondary to CSD was due to serous detachment of the macula rather than optic nerve dysfunction. In these 7 eyes, visual acuity returned to 20/40 or better. In addition to optic disc edema and macular star formation, focal areas of chorioretinitis may be seen with CSD-NR (Fig. 3). In rare cases, visual recovery has been limited by macular hole formation (93,94)
A retrospective study found that antibiotic treatment shortened the course of the systemic disease in moderate to severe CSD (95). In this study, the following oral medications were most effective: rifampin (87% of cases), ciprofloxacin (84%), and trimethoprim-sulfamethoxazole (58%). In our literature review of NR due to CSD, 14 patients received no treatment, 37 patients received antibiotics only, 10 received steroids plus antibiotics, and 3 were given steroids alone. In small case series, patients have been reported to do well with a combination of doxycycline and rifampin (28) and ciprofloxacin (24). Because of the high degree of spontaneous visual recovery in NR due to CSD, no conclusions can be made from these data regarding the possible efficacy of treatment for this condition. It should be noted that ciprofloxacin is not recommended for use in children or during pregnancy. Azithromycin is a good alternative treatment for CSD and can be used in both children and adults.
Recurrent Idiopathic Neuroretinitis
The majority of reported cases of recurrent NR are idiopathic. With the exception of toxoplasmosis, most infectious agents do not cause recurrent attacks. Two of the patients in the series of idiopathic cases reported by Maitland and Miller (7) had evidence of a previous attack in the fellow eye, and an additional case was reported by Vaphiades et al (46). A patient with recurrent NR and inflammatory bowel disease has been described (80). The designation of recurrent idiopathic NR as an identifiable syndrome was based on a case series of 7 patients (96). An additional 6 cases were subsequently added in an article (97) focusing on the results of immunosuppressive therapy for this syndrome.
We further expanded this series in a recent review of 41 patients including clinical features and results of treatment (86). Median age at onset was 28 years with a range of 10 to 54 years. Average follow-up was 67 months. Overall, 147 episodes were documented in 75 eyes with an average of 3.6 attacks per patient and an average interval between attacks of 3 years (range, 1 month to 16 years). Most were not preceded by systemic symptoms, and eye pain was uncommon. Patterns of visual field loss consisted primarily of a central scotoma plus nerve fiber bundle defects, and loss was cumulative with repeated episodes. Some eyes sustained extensive field loss, despite preservation of visual acuity. In this series, only 36% of eyes were left with 20/40 or better acuity and retained more than two thirds of their visual field. The fundus features in recurrent NR were similar to other cases of NR but with repeated episodes, exudates may not form a macular star (Fig. 4).
We performed an additional analysis of a subgroup of these patients, looking only at features of the acute event in a previously unaffected eye. We analyzed data from 23 eyes of 21 patients and found several differences when compared to our CSD and idiopathic cases. Visual acuity was similar at onset in all 3 groups, but the pattern and magnitude of visual field loss were different in recurrent cases. Whereas visual field loss was confined to the central field in the majority of CSD and idiopathic cases, this pattern was uncommon in recurrent NR. Rather, one half of the recurrent cases demonstrated a combination of central and nerve fiber bundle defects. This difference in visual field involvement may be due to the fact that in idiopathic and CSD cases, visual loss in large part reflects macular dysfunction, whereas in recurrent idiopathic cases, visual loss is due to optic disc vasculitis leading to optic neuropathy. In addition, the severity of field loss was significantly greater in recurrent cases, and recovery of both acuity and field was less substantial. This lesser degree of recovery also manifest as a smaller percentage of patients who showed improvement in the magnitude of the RAPD at follow-up (11% vs 59% and 50% of CSD and idiopathic cases, respectively). The fundus features at onset were similar in all 3 groups, except for the presence of chorioretinal white spots (Fig. 3), which were more common in CSD patients and rare in idiopathic NR. The presence of such white spots has been taken as evidence of a hematogenously spread organism in cases of CSD-NR, and likewise their absence in idiopathic cases favors a different mechanism. In cases of recurrent NR, hard exudates often become less prominent and more localized during subsequent attacks (Fig. 4).
Of 147 episodes of recurrent NR (86), most patients were treated acutely with corticosteroids, given orally or intravenously, but without significant improvement. In addition, 21 patients received long-term immunosuppressive treatment, and in 13 of these cases, adequate long-term information was available to judge efficacy. There were 40 episodes of NR during 67.4 patient-years prior to initiation of immunosuppression vs 11 episodes in 67.1 patient-years after starting treatment. This represents a reduction in the attack rate of 0.43 per year, amounting to a 72% decrease in the attack frequency. Treatment in our cases of recurrent idiopathic NR consisted of low-dose alternate day prednisone and/or azathioprine.
Retinal Imaging Techniques
OCT is a sensitive method for detecting serous retinal detachment, particularly in the early stages of NR before the appearance of a macular star. In occasional cases of optic disc edema secondary to CSD, peripapillary serous detachment occurs but a macular star never develops (98,99). In such cases, OCT may help establish the diagnosis. FA is not usually necessary for diagnosis but may furnish additional information. FA typically demonstrates diffuse disc edema and peripapillary dye staining during the midvenous and late phases of the angiogram. This staining may be segmental and is occasionally present in the fellow eye even when visual loss is unilateral. Fundus autofluorescence may also be helpful for demonstrating macular exudates (100).
Magnetic Resonance Imaging
Initial interest in the MRI findings in NR focused on the detection of periventricular white matter changes as seen in MS. The consistent absence of these changes and the failure to develop clinical MS on long-term follow-up (87) have put this issue to rest. Dedicated MRI of the orbit with fat suppression and intravenous contrast has emerged as the more sensitive sequence for the evaluation of optic neuropathies, but there are relatively few reports using this technique in patients with NR. Schmalfuss et al (101) evaluated the MRI findings in 82 patients with various optic neuropathies, including 9 with CSD. Of these 9 cases, 5 had macular exudates, and in 4 of these, MRI showed enhancement of the optic disc extending up to 4 mm posteriorly along the optic nerve. The authors suggested that this “short segment enhancement” is highly specific for CSD-NR. Two additional cases with similar findings have been reported (46,102). However, other authors have found other neuroimaging results in patients with NR. Wals et al (103) reported a patient with idiopathic NR in whom MRI showed enhancement confined to the optic nerve sheath. A combination of optic nerve and sheath enhancement was seen on CT in 1 case of idiopathic NR (104) and on MRI in 1 patient with recurrent idiopathic NR (46).
We reviewed the orbital MRI scans in 36 of our cases, looking particularly for features that might differentiate subtypes of NR. In the CSD-NR group, 2 of 4 scans were abnormal, both showing enhancement confined to the optic disc. In patients with idiopathic NR, 2 of 6 scans were abnormal, one showing disc enhancement and the other enhancement of the disc with slight posterior extension, similar to what has been described in CSD-NR (101). In patients with recurrent NR, 3 showed enhancement confined to the disc (Fig. 5) and 1 showed retrobulbar optic nerve enhancement; scans in the remaining 22 were normal. Based on these findings, it seems likely that the MRI findings described by Schmalfuss et al (101) are indeed characteristic of NR but not specific for NR due to CSD. Additional MRI studies in NR are needed to clarify this issue.
Incidence of Recurrent Neuroretinitis
It is possible that recurrent NR is more common than would appear from the literature. Because the characteristic macular star is not present at the time of visual loss, the diagnosis may be missed if a careful repeat fundus examination is not performed at least 2 weeks after onset. In the absence of a macular star, such cases might be termed “recurrent optic neuritis” or “papillitis” rather than NR. Increased recognition of the syndrome of recurrent NR may lead to the diagnosis of more cases and greater accuracy of its frequency.
From informal communication with colleagues, we have the impression that recurrent NR is more common in the Midwestern United States and rare in other parts of the country. One way to examine this issue would be a survey of the membership of the North American Neuro-Ophthalmology Society (NANOS). Collection of this information could be helpful in determining incidence as well as possible geographic clustering of cases. Another approach to the question of geographic distribution would be the examination of the database from a large tertiary referral base, such as Mayo Clinic, which draws from a large geographic area and tends to see a large number of such complex and rare disorders.
Advances in Serologic Testing
If recurrent NR cases have a particular geographic distribution, this might be a clue as to etiology. For example, the Midwest has a higher incidence of presumed ocular histoplasmosis syndrome (POHS), and we have considered this as a potential cause of recurrent NR. Our patients do not have a high frequency of fundus changes typical of POHS, but since serologic testing for this condition is not available, it remains a possibility. If recurrent NR is in fact an autoimmune disorder, progress in testing for other autoantibodies may reveal a marker for the disease, as we have seen for neuromyelitis optica.
Continued technical advances in retinal imaging, particularly the ability to correlate different imaging modalities, should further our understanding of these disorders. The work of Kitamei et al (5) is an example of the value of such correlation. These authors documented an isolated leakage from a single vessel in a case of idiopathic NR, in contrast to previous reports, which have described a more diffuse leakiness of disc capillaries. This focal leakage was more easily appreciated with indocyanine green than with FA, and it is not clear whether these findings are typical of NR or represent an unusual occurrence. Perhaps, the pathophysiology is different in the various subgroups of NR. Further application of these techniques should further our understanding of the pathophysiology in NR.
As the typical clinical findings in NR are better characterized, atypical “outlier” cases will be easier to identify. For example, pain is an uncommon feature in all 3 forms, described by about one fourth of all our patients with a similar frequency in all 3 groups (unpublished data). When present, pain is mild. The presence of severe pain, especially with eye movement, should suggest an alternative diagnosis. In our series of patients initially diagnosed as NR, 3 cases were subsequently reclassified as having idiopathic posterior scleritis based on characteristic findings on ultrasonography. Each of these patients had recurrent attacks with severe pain that was steroid responsive. Extensive enhancement of the retrobulbar optic nerve (beyond 4 mm behind the globe) is suggestive of idiopathic NR, particularly the recurrent variety and, to our knowledge, has not been described in CSD-NR.
The optic disc edema in NR is self-limited. In cases with protracted disc edema, alternative diagnoses should be considered, such as disc tumor or chronic inflammatory disorders including sarcoidosis, diffuse subacute nematode syndrome (DUSN), or IRVAN.
Bilateral simultaneous NR is uncommon and should suggest the more likely possibility of malignant hypertension or increased ICP. When NR does present with bilateral involvement, it may also be due to a specific infectious etiology. For example, bilaterality occurred in only 2 of 27 patients in series of Dreyer et al (6) and in 2 of 12 in that of Maitland and Miller (7). In contrast, bilateral NR has been reported in patients with Bartonella infection (31,45), Lyme disease (63), mumps (65), secondary syphilis (59), toxoplasmosis (57), rabies vaccine (77), chikungunya fever (72,73), and dengue (74).
Management guidelines are given in Table 3. In obtaining a history in patients with NR, the clinician should focus on possible risk factors for specific infectious agents, such as animal exposure (especially cats), travel to endemic areas (Lyme disease or tuberculosis), exposure to waste material (leptospirosis), and sexual contact (syphilis). Patients should be questioned about systemic symptoms, such as fever, headache, lymphadenopathy, and skin rash. Laboratory testing should be tailored to the individual, based on information from the history and examination. In most cases, serologic testing should include cat scratch titers (Bartonella species), fluorescent treponemal antibody absorption test (FTA-ABS), and a tuberculosis skin test (PPD). In endemic areas and in patients with a history of tick exposure and/or characteristic symptoms, hematologic studies for Lyme disease should be obtained. Additional testing may include angiotensin-converting enzyme measurements and chest radiograph.
Cases that are strongly suspicious for CSD but with negative serologies should be retested 6 weeks later to look for rising IgG titers. A rise in convalescent IgG titers may be diagnostic, even in the absence of elevated IgM antibodies. In addition to a history of cat exposure, features that would be considered “suspicious” for CSD include young age (younger than 16 years), preceding systemic symptoms, and poor visual acuity but with small or no RAPD. In contrast, features that suggest a low likelihood of CSD and a high risk of recurrence are no systemic symptoms, visual field defect outside the central field, preserved acuity with a large RAPD, poor recovery, and evidence of a previous episode in either eye. In cases with the latter features, steroid treatment should be considered. Simultaneous bilateral involvement is suggestive of an underlying infectious etiology, although not specifically CSD. In most cases seen acutely, treatment with a broad-spectrum antibiotic is reasonable while serologic tests are pending, especially in cases with findings suggestive of an infectious cause. In patients with recurrence, long-term immunosuppressive treatment should be considered.
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