Albert & Jakobiec's Principles & Practice of Ophthalmology, 3rd Edition

CHAPTER 140 - Neuroretinitis

Valerie Purvin

Key Features

  

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Acute, painless, unilateral visual loss of variable severity

  

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Usually affects healthy young individuals

  

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Acutely: disk edema often with peripapillary serous detachment

  

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Ten days later: macular hard exudates in star pattern

  

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Due to cat scratch disease in two-thirds of cases

  

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One-quarter of cases are idiopathic despite thorough evaluation

  

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Generally good prognosis regardless of treatment

  

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Consider antibiotics for suspected bacterial infection

  

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Steroids may be considered as well

HISTORIC PERSPECTIVE

In 1916 Theodor Leber described a condition characterized by acute unilateral visual loss with disk edema and macular exudates arranged in a star pattern.[1] Believing the condition to be a primary retinal disorder, he used the term 'stellate maculopathy'. This concept was challenged by Gass in 1977, who noted that disk edema precedes the formation of exudates in this condition.[2] He further demonstrated by fluorescein angiography that the site of the leakage is in fact not the macula but the optic disk and suggested the term neuroretinitis (NR). In some patients a specific infectious agent has been implicated; cases in which no infectious etiology is identified are designated as Leber's idiopathic stellate NR. The series by Dreyer et al[3] and by Maitland and Miller[4] in 1984 furnished a description of the typical clinical features of this disorder. Since that time a number of papers have reported additional cases of NR due to a wide range of infections (this is discussed in the following).

 

 

PATHOPHYSIOLOGY

Inflammation of disk capillaries causes leakage of protein and lipid that spreads into the peripapillary subretinal space and outer plexiform layer. Resorption of the serous component leaves lipid exudates that are subsequently ingested by macrophages. Due to the loose, radial configuration of the outer plexiform layer, a star pattern is formed[5] (Fig. 140.1). This location of fluid accumulation has more recently been confirmed with ocular coherence tomography (OCT).[6] It is not entirely clear whether the disk inflammation in this disorder represents direct infection or a secondary autoimmune response.

Click to view full size figure  

 

FIGURE 140.1  Ophthalmoscopic appearance of idiopathic NR in a 36-year-old woman. Fundus photograph of the patient's left eye taken 1 month after onset of visual loss shows mild residual disk edema with pallor and a robust macular star. Serologic testing for specfic inflammatory diseases was unrevealing.

 

 

 

 

ETIOLOGIES

Cases of NR have been reported in association with a variety of infectious agents (see Table 140.1).[7-23] The single most common of these is cat scratch disease (CSD) which accounted for two-thirds of cases in one large series.[24] Despite thorough evaluation, approximately one quarter of cases remain idiopathic.[24] Occasional cases are due to noninfectious forms of uveitis such as sarcoidosis, inflammatory bowel disease, and periarteritis nodosa. NR has also been described as a part of other retinal inflammatory disorders including idiopathic retinal vasculitis and aneurysms (IRVAN syndrome) and diffuse unilateral subacute neuroretinitis (DUSN) which is caused by a nematode.[25] Other noninflammatory conditions may also cause disk edema with a macular star figure[26] and it is important for the clinician to be alert to these (see Table 140.2). Notably, increased intracranial pressure (papilledema), hypertensive retinopathy, ischemic optic neuropathy and diabetic papillopathy may all cause a similar funduscopic appearance. The term NR should be reserved for those cases in which the underlying mechanism is inflammatory.


TABLE 140.1   -- Etiologies

Bartonella species (mostly B. henselae)

Spirochete: syphilis (2° or 3°), Lyme disease (stage II), leptospirosis

Viral or postviral: mumps, chicken pox, herpes simples, herpes zoster, HIV, hepatitis B, Coxsackie B, influenza A, Epstein-Barr, cytomegalovirus

Tuberculosis

Toxoplasmosis

Nematode: Toxocara canis, DUSN

Histoplasmosis capsulatum

Rocky Mountain spotted fever

Salmonella

Postvaccination: Rabies

Noninfectious uveitis: sarcoidosis, inflammatory bowel disease, periarteritis nodosa

Uncertain mechanism: Parry-Romberg syndrome (progressive facial hemiatrophy), IRVAN syndrome, tubulointerstitial nephritis and uveitis (TINU syndrome)

 


TABLE 140.2   -- Differential Diagnosis for Disk Edema with Macular Star

Hypertensive retinopathy

Papilledema (? intracranial pressure)

Anterior ischemic optic neuropathy

Diabetic papillopathy

Branch retinal vein occlusion/papillophlebitis

Optic disk tumor: melanocytoma, juxtapapillary angioma

 

 

 

CLINICAL CHARACTERISTICS

NR usually affects children and young adults (average age 22-30 years) but the age range is broad.[3,4] Males and females are affected equally. Approximately 50% of affected individuals experience an antecedent flu-like illness, usually affecting the upper respiratory tract.[3,4] In patients with cat scratch NR these prodromal symptoms usually include sore throat, headache, myalgias, and lymphadenopathy. Visual loss typically takes the form of painless unilateral blurring of central vision which progresses over several days. Visual loss is usually painless although occasional patients experience a mild retrobulbar ache. While mild disk edema is occasionally seen in the fellow eye, symptomatic bilateral NR is quite unusual and should always suggest the alternative possibility of hypertensive retinopathy or raised intracranial pressure.

VISUAL FUNCTION

Visual acuity is usually between 20/50 and 20/200 with a 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, is a cecocentral or central scotoma, consistent with the presence of edema in the papillomacular bundle.[3] Other patterns including arcuate defects and altitudinal loss are occasionally seen. A relative afferent pupillary defect (RAPD) is often present although not with the same constancy or magnitude as in demyelinating optic neuritis. This difference reflects a different mechanism of visual loss in these two conditions: visual loss is due in large part to maculopathy in NR versus optic nerve dysfunction in optic neuritis (ON).

 

 

FUNDUSCOPIC FINDINGS

Posterior vitreous cells are usually present; anterior chamber cell and flare are occasionally seen as well. The funduscopic appearance depends in large part on when the patient is examined. Isolated optic disk edema is the earliest finding (Fig. 140.2). Disk swelling is usually diffuse but can be segmental, a finding that may be better appreciated with fluorescein angiography. The degree of disk edema is variable; when severe it may be accompanied by peripapillary nerve fiber layer hemorrhages. In most cases, disk edema is associated with an exudative peripapillary serous retinal detachment. It takes 9-12 days for the characteristic macular hard exudates to appear and at this stage the disk edema is usually diminishing (Fig. 140.3). The star is initially sharply defined and spoke-like; over time the exudates develop a more globby appearance and eventually, after a number of months, disappear completely, often leaving residual subfoveal RPE defects in the macula. Disk edema resolves over 8-12 weeks in most cases.[3] The disk may eventually return to normal or may show pallor and/or gliotic changes.

Click to view full size figure  

 

FIGURE 140.2  Ophthalmoscopic appearance of NR due to CSD. The patient was a 22-year-old man who developed decreased vision in the left eye 2 weeks after onset of fever, headache, and muscle aches. Acutely the disk is swollen with nerve fiber layer hemorrhage and peripapillary serous detachment.

 

 

Click to view full size figure  

 

FIGURE 140.3  Same patient as in Figure 140.1 but 4 weeks later. There has been much resolution of disk edema with the new appearance of hard exudates tracking to the macula in a star pattern. Serologic testing confirmed recent B. henselae infection.

 

 

In addition to these characteristic changes involving the disk and macula, small, discrete yellow-white chorioretinal spots are sometimes identified.[27] These spots are at the level of the deep retina or choriocapillaris and may be seen in both symptomatic and asymptomatic eyes. These CR lesions are especially characteristic of patients with NR due to CSD but have also been found in patients with other causes of NR and in those with the idiopathic variety. Their occurrence serves as evidence of a hematogenously spread infectious agent rather than an autoimmune process. These spots resolve slowly, becoming small chorioretinal scars.

 

 

ANCILLARY TESTING

Fluorescein angiography in patients with acute NR demonstrates abnormal capillary permeability, particularly from the capillaries deep within the optic disk. Such leakage may persist even after the disk has returned to its normal appearance. While there may be slight staining of peripapillary vessels, the macular vasculature is entirely normal. Disk staining is often segmental and is found in the contralateral (asymptomatic) eye in 10-15% of cases. Chorioretinal white spots, when present, show late hyperfluorescence. OCT has shown accumulation of fluid in the outer plexiform layer with or without serous detachment of the sensory retina.[6]

 

 

PROGNOSIS

Most patients with NR enjoy excellent recovery of vision without intervention. In the series of Dreyer et al, for example, visual acuity at last follow-up examination (median 14 months) was 20/20 or better in 66% of cases, 20/25 to 20/40 in 31% and remained at 20/300 in one eye.[3] A repeat event either in the previously affected or the fellow eye is unusual.

There appears to be a subset of patients, however, with a somewhat different clinical picture in whom the prognosis is more guarded. Two of the patients in the series of Dreyer et al had disk-related field defects and a large relative afferent defect and in both of these cases the visual outcome was poor.[3] Of the 12 patients with NR described by Maitland and Miller, only three failed to experience excellent recovery and in two of these cases there was evidence of a previous similar event in the fellow eye.[4] Purvin and Chioran reported a series of seven such patients who experienced 2-7 attacks of NR at intervals of 1-10 years (average interval 2.7 years).[28] Following repeated episodes, visual loss is cumulative and can be quite substantial. This variant of NR may be suspected following an initial episode by virtue of a large relative afferent pupillary defect, disk-related field loss and poor visual recovery. Such patients should be considered to be at relatively high risk for a future similar event and should be counseled accordingly. In some cases, prophylactic treatment to prevent a repeat attack may be considered (this is discussed in the following).

 

 

RELATIONSHIP TO MULTIPLE SCLEROSIS

One particular aspect of prognosis bears specific comment, namely the possible relationship of NR to multiple sclerosis (MS). It has been well established that patients who experience an attack of ON are at increased risk for the future development of MS. Insofar as NR can be considered a form of papillitis, one might assume that patients with this condition would be at similarly high risk. A large survey of affected patients, however, found no such increased risk.[29] This difference in prognosis is presumably related to differences in pathophysiology in these two conditions. In demyelinating ON the target tissue of the inflammatory response is the myelin sheath, whereas in NR the target is the optic disk vasculature. However, a retrospective review of 35 patients with NR seen in a single university-based practice identified three patients who had already been diagnosed with MS.[30] All three of these patients were on ?-interferon and the authors suggested that perhaps this treatment influenced the permeability of disk vessels thus affecting the funduscopic appearance. Despite this one report, the management of patients with NR should be clearly distinguished from those with ON.

 

 

DIFFERENTIAL DIAGNOSIS

The approach to diagnosis depends in part on when the patient is seen in the course of the illness. When seen acutely, i.e., before formation of a macular star, the main alternative diagnosis is ON. Both NR and ON typically present as acute monocular visual loss in a previously healthy young person and optic disk edema is seen in both conditions. Several features are helpful in making this distinction. The presence of eye pain in most patients with ON is extremely helpful since this is a very uncommon symptom in NR. The absence of a RAPD in the presence of monocular visual loss speaks strongly against ON as the cause. Similarly, a disproportion between the visual loss and the RAPD (large drop in visual acuity with only a small RAPD) speaks in favor of NR. The presence of peripapillary serous detachment is characteristic of NR but unexpected in ON. Disk hemorrhages are sometimes present in NR but extremely unusual in ON. Finally, the results of orbital MRI scanning in ON are abnormal in 90% of cases, whereas in NR such scans are typically normal.

When seen after appearance of the macular star the differential diagnosis is different. The first step is to decide if the patient actually has NR or has, instead, another cause of macular hard exudates. The presence of more extensive retinopathy should suggest an alternative diagnosis such as CRVO or BRVO (retinal hemorrhages predominate) or severe hypertension (hemorrhages and exudates usually present). When these changes are bilateral, particular attention should be directed to the possibility of hypertensive retinopathy. In increased intracranial pressure (papilledema) the findings are also typically bilateral but the changes are usually confined to the disk and macula. In the case of papilledema and in anterior ischemic optic neuropathy the macular star is usually partial, seen just on the nasal side of the macula in contrast with its appearance 360° around the macula in most cases of NR. Finally, prolonged duration of disk edema and macular exudates should suggest a noninflammatory disorder, specifically CRVO, papillophlebitis, or an optic disk tumor.

 

 

EVALUATION

HISTORY AND PHYSICAL

A thorough history is important and should include the following features: travel (particularly to areas in which Lyme disease is prevalent), animal exposure, sexual contact, ingestion of unpasteurized or uncooked foods. The patient should be questioned about systemic symptoms including fever, lymphadenopathy, myalgias, skin rash or other skin lesions, sore throat, and headache. Complete physical and ocular examinations are also essential.

 

 

LABORATORY TESTING

The list of diseases that have on occasion caused NR is extensive. Laboratory testing should be tailored to the individual patient based on information obtained from the history and physical examinations. In most cases, serologic testing should include cat scratch titers (Bartonella species), a fluorescent treponemal antibody absorption (FTA-ABS) test, and a PPD. In endemic areas and in patients with a history of tick exposure and/or characteristic symptoms of Lyme disease, titers for these antibodies should also be obtained. Other testing should be obtained as indicated by specific findings from the history and physical examination.

 

 

TREATMENT

Treatment generally depends on the results of testing for specific infectious agents. The most common causative organism, Bartonella henselae, is sensitive to a variety of antibiotics and most authors recommend treatment accordingly. There are no controlled studies, however, comparing the results of treatment with the natural history of the disease or comparing the efficacy of different antibiotic regimen. A retrospective study found the following oral medications to be of benefit: rifampin (effective in 87% of patients), ciprofloxacin (84%), and trimethaprim-sulfamethoxazole (58%).[31] In another smaller series, patients with NR due to CSD did well with a combination of doxycycline 100 mg and rifampin 300 mg twice daily with minimal side-effects.[9] Golnik and associates reported a similar favorable outcome in four patients with CSD-NR treated with ciprofloxacin 500 mg twice daily.[11] Treatment is usually initiated while results of serologic testing are pending and continued for anywhere from 10 days to 6 weeks if results confirm CSD infection. The use of doxycycline and ciprofloxacin should be avoided in children, however. Some patients are also treated with steroids although there is no evidence that this addition improves the visual outcome. Unlike treatment considerations for demyelinating ON, there is no reason to favor intravenous over oral administration in this setting.

Patients with idiopathic NR usually enjoy good visual recovery regardless of treatment. Some are treated with corticosteroids although the possible benefit of such treatment is unknown. In cases with particularly severe visual loss (either idiopathic or due to a specific organism) treatment with corticosteroids is often advised. In patients with recurrent idiopathic NR, the addition of long-term immunosuppression has been shown to decrease the number of recurrences.[32]

Summary: Cat Scratch NR

  

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Most common identifiable cause of NR

  

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Usually due to B. henselae

  

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Most often affects children

  

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80% of CSD infections are self-limited

  

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Mild local infection is followed by tender regional lymphadenopathy then fever, malaise, and headache

  

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Other ocular manifestations include conjunctivitis, anterior uveitis, focal retinal vasculitis or choroiditis, branch retinal artery occlusion, and peripapillary angiomatous lesions

 

Tip File

  

1.   

Other conditions besides NR can cause disk edema with macular hard exudates. Before initiating an extensive evaluation for specific etiologies, rule out other mechanisms

  

2.   

Be especially cautious in cases of bilateral NR. In most cases this clinical picture is due to hypertensive retinopathy or occasionally increased intracranial pressure

  

3.   

NR is most common in young people. In older individuals consider the alternative possibility of anterior ischemic optic neuropathy

  

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In cases with acute unilateral visual loss, suspect NR rather than ON in cases with little or no RAPD

 

 

REFERENCES

1. Leber T: Die pseudonephritischen Netzhauterkrankungen, die Retinitis stellata: Die Purtschersche Netzhautaffektion nach schwerer Schadelverletzung.   In: Graefe AC, Saemische T, ed. Graefe-Saemisch Handbuch der Augerheilkunde,  2nd edn. Leipzig, Germany: Englemann; 1916:1319.

2. Gass JDM: Diseases of the optic nerve that may simulate macular disease.  Trans Am Acad Ophthalmol Otolaryngol  1977; 83:766-769.

3. Dreyer RF, Hopen G, Gass JDM, Smith JL: Leber's idiopathic stellate neuroretinitis.  Arch Ophthalmol  1984; 102:1140-1145.

4. Maitland CG, Miller NR: Neuroretinitis.  Arch Ophthalmol  1984; 102:1146-1150.

5. Wolter JR, Philips RL, Butler GR: The star-figure of the macular area.  Arch Ophthalmol  1958; 60:49-59.

6. Stewart JW, Brazis PW, Barrett KM, et al: Optical coherence tomography in a case of bilateral neuroretinitis.  J Neuroophthalmol  2005; 25:131-133.

7. Bar S, Segal M, Shapira R, Savir H: Neuroretinitis associated with cat-scratch disease.  Am J Ophthalmol  1990; 110:703-705.

8. Chrousos GA, Drack AV, Young M, et al: Neuroretinitis in cat scratch disease.  J Clin Neuroophthalmol  1990; 10:92-94.

9. Reed JB, Scales DK, Wong MT, et al: |ce:italic|Bartonella henselae|/ce:italic| neuroretinitis in cat scratch disease: diagnosis, management and sequelae.  Ophthalmology  1998; 105:459-466.

10. Fish RH, Hoskins JC, Kline LB: Toxoplasmosis neuroretinitis.  Ophthalmology  1993; 100:1177-1182.

11. Golnik KC, Marotto ME, Fanous MM, et al: Ophthalmic manifestations of Rochalimaea species.  Am J Ophthalmol  1994; 118:145-151.

12. Ulrich GG, Waecker Jr NJ, Meister SJ, et al: Cat scratch disease associated with neuroretinitis in a 6-year-old girl.  Ophthalmology  1992; 99:246-249.

13. Weiss AH, Beck RW: Neuroretinitis in childhood.  J Pediatr Ophthalmol Strabismus  1989; 26:198-203.

14. Ormerod LD, Skolnick KA, Menosky MM, et al: Retinal and choroidal manifestations of cat scratch disease.  Ophthalmology  1998; 105:1024-1031.

15. Solley WA, Martin DF, Newman NJ, et al: Cat scratch disease: posterior segment manifestations.  Ophthalmology  1999; 106:1546-1553.

16. Johnson BL, Wisotzkey HM: Neuroretinitis associated with herpes simplex encephalitis in an adult.  Am J Ophthalmol  1977; 83:481-489.

17. Selbst RG, Selhorst JB, Harbison JW, et al: Parainfectious optic neuritis: report and review following varicella.  Arch Neurol  1983; 40:347-350.

18. Folk JC, Weingeist TA, Corbett JJ, et al: Syphilitic neuroretinitis.  Am J Ophthalmol  1983; 95:480-486.

19. Lesser RL, Kornmehl EW, Pachner AR, et al: Neuro-ophthalmologic manifestations of Lyme disease.  Ophthalmology  1990; 97:699-706.

20. Mansour AM: Cytomegalovirus optic neuritis.  Curr Opinion Ophthalmol  1997; 8:55-58.

21. Fusco R, Magli A, Guacci P: Stellate maculopathy due to |ce:italic|Salmonella typhi|/ce:italic|. A case report.  Ophthalmologica  1986; 192:154-158.

22. Beck RW, Sergott RC, Barr CC, Annesley WH: Optic disc edema in the presumed ocular histoplasmosis syndrome.  Ophthalmology  1984; 91:183-185.

23. Saxena R, Sethi HS, Rai HK, Menon V: Bilateral neuro-retinitis following chick embryo cell anti-rabies vaccination: a case report.  BMC Ophthalmol  2005; 5:20.

24. Suhler EB, Lauer AK, Rosenbaum JT: Prevalence of serologic evidence of cat scratch disease in patients with neuroretinitis.  Ophthalmology  2000; 107:871-876.

25. Bird AC, Smith JL, Curtin VT: Nematode optic neuritis.  Am J Ophthalmol  1970; 69:72-77.

26. Shoari M, Katz B: Recurrent neuroretinitis in an adolescent with ulcerative colitis.  J Neuroophthalmol  2005; 25:286-288.

27. Carroll DM, Franklin RM: Leber's idiopathic stellate retinopathy.  Am J Ophthalmol  1982; 93:96-101.

28. Purvin VA, Chioran G: Recurrent neuroretinitis.  Arch Opthalmol  1994; 112:365-371.

29. Parmley VC, Schiffman JS, Maitland CG, et al: Does neuroretinitis rule out multiple sclerosis.  Arch Neurol  1987; 44:1045-1048.

30. Williams KE, Johnson LN: Neuroretinitis in patients with multiple sclerosis.  Ophthalmology  2004; 111:335-341.

31. Margileth A: Antibiotic therapy for cat-scratch disease: clinical study of therapeutic outcome in 268 patients and a review of the literature.  Pediatr Infect Dis J  1992; 11:474-478.

32. Purvin V, Ranson N, Kawasaki A: Idiopathic recurrent neuroretinitis: effects of long-term immunosuppression.  Arch Ophthalmol  2003; 121:65-67.