24 Infectious Chorioretinal Inflammatory Conditions
24.1 Introduction
Bacterial, viral, protozoan, and helminthic infections of the posterior segment have characteristic ophthalmoscopic features that help clinicians deduce the type of infection and apply appropriate treatment. Some organisms possess such distinctive patterns of growth that a diagnosis can be made by fundus examination alone. The best example of this is cytomegalovirus (CMV) retinitis. Pattern recognition is relatively easy in the posterior segment of the eye because of the flat architecture, transparency of the retina, and multiplicity of tissues that may be affected differentially before full-thickness infection of all ocular coats occurs. 1
Visual diagnosis of posterior segment infections (Table 24-1) is assisted by an understanding of the fundamental characteristics of each infection: route of infection and preferential tissue of infection, host factors in susceptibility, characteristics of specific infections, and response to medication. In ocular inflammatory disease of infectious causes, compared with most other types of uveitis, diagnosis is the critical step leading to specific therapies that may be curative. Sampling of serum or intraocular fluids to determine the presence of host antibodies and non-host DNA, culture of intraocular fluids or tissue, histopathologic analysis, identification of infection in another body site, and response to therapy may all be used to confirm the suspected diagnosis.
24.2 Pathogenesis and Natural History
24.2.1 Route of Infection
Nonsurgical, nontraumatic infections of the posterior segment of the eye are typically blood borne. In acutely ill, septic patients, an endogenous endophthalmitis is considered with presentation of a red, painful, opacified eye. Bacterial culture of blood, urine, sputum, cerebrospinal fluid, or other suspected infected sites may help confirm the diagnosis when cultures of the ocular fluids are not obtainable or negative. The older publications on bacterial endogenous endophthalmitis mainly concern acutely ill patients, many of whom were likely treated only with intravenous antibiotics, which can be successful therapy due to the breakdown of the blood–retinal barrier. 11 , 12 Okada et al summarized the sites cultured and the bacterial organisms isolated in a case series from 1994. 13
Gram-positive organisms continue to account for the majority of bacterial endogenous endophthalmitis, 14 but the underlying source of infection has shifted, with fewer cases attributable to meningitis and more cases attributable to the expanded use of indwelling medical devices. Klebsiella is an emerging source of endogenous endophthalmitis in Asia and in the Western Hemisphere, often associated with liver abscess. 15 Fungal infection remains the most important cause of endogenous endophthalmitis. Earlier use of antifungal agents is decreasing the incidence of fungal endophthalmitis in medical settings. 16 Nine percent of patients in a multicenter study had signs of fungal choroiditis when examined within 72 hours of positive candidal blood cultures in 1994 17 compared to less than 1% in 2011. 15
There appear to be two mechanisms by which blood-borne infection of the eye occurs. The first is through direct infection of the retina via the retinal blood vessels. CMV infection of the endothelium of a large retinal vessel with subsequent spread to surrounding tissues is the classic example of this type of entry (Fig. 24-1). Retinal hemorrhages and cotton-wool spots are also common in septicemia and may be a forme fruste of endophthalmitis. 18 In general, endogenous bacterial endophthalmitis infects surrounding retina and vitreous so rapidly that the exact site of intravascular infection and penetration into the retina is usually not identified except at the time of vitrectomy. However, low-pathogenicity organisms can cause discrete, focal lesions of bacterial retinitis before producing a diffuse and destructive infection. Listeria monocytogenes and Staphylococcus aureus are the classic examples of this type of infection (Fig. 24-2). One characteristic of retinal vascular entry is that the retinal pigment epithelium (RPE) is relatively spared. Unusual organisms such as Corynebacterium species or Rhodococcus equi may also produce this type of focal infection. 19 , 20
The second type of entry into the eye is via the choroidal circulation. Enhanced depth ocular coherence tomography can detect choroidal masses in fungal endophthalmitis. 10 Yeasts are the predominant species producing endogenous endophthalmitis, affecting 39 patients compared to 14 patients infected with molds in a 22-year retrospective study. 21 Risk factors for mold infection were iatrogenic immunosuppression and organ transplantation. Mold-infected eyes were more likely to have hypopyon, shorter duration before presentation, and worse visual acuity.
Special Considerations
Endogenous endophthalmitis presents with a spectrum of severity. Culture of extraocular sites and intravenous treatment, vitreous tap and injection, or therapeutic vitrectomy with intravitreal antibiotics may all be appropriate in certain settings. The Endophthalmitis Vitrectomy Study (EVS) findings cannot be extrapolated directly to endogenous endophthalmitis.
Routes of entry other than the blood are less common. Acute necrotizing herpetic retinitis (acute retinal necrosis [ARN]) appears to begin as a neural infection. This assumption is based on the latency of varicella-zoster and herpes simplex virus (HSV) within nerve ganglia and on animal models that document transmission of herpetic infection from one eye to the other via the anterior visual and pupillary pathways. 22 The confluent, peripheral, circumferential infection with centripetal spread represents death of the neurons in the retina at their termini and a dying back of neurons to the center. The fact that a strict neural pattern is not preserved is presumed to relate to lysis of infected cells with infection of adjacent elements (Fig. 24-3).
The course of infection varies widely among infectious agents, from the potentially years-long course of diffuse unilateral subacute neuroretinitis (DUSN) to the acute endophthalmitis. Presentation depends on factors such as the replication speed of the organisms: never for the nematodal agents of DUSN, hours for viruses and fungi, and minutes for bacteria. Toxins, such as the lytic enzymes produced by streptococci and bacillus species, also modify the course of disease.
Understanding the pattern of disease assists clinicians in forming a provisional diagnosis and initiating treatment. It may be difficult to culture for all classes of organisms with small amounts of intraocular fluid. Spirochetes and toxoplasmosis 23 can be cultured only in living cells, and organisms sequestered in the retina may require chorioretinal biopsy rather than vitreous fluid sampling to be identified. Pattern recognition is powerful, but when characteristic patterns have been obliterated by dissemination within the eye and opacification of the media, ancillary diagnostic studies are essential. Analysis of aqueous humor is now routine for the diagnosis of viral retinitis and extensive toxoplasmosis. 24 , 25 Syphilis can be diagnosed by either aqueous humor polymerase chain reaction (PCR) 26 or by antibody determinations. The following text box displays an algorithm for the diagnosis and initial treatment of posterior segment disease.
Pearls for the Initial Management of Infectious Posterior Uveitis
Chorioretinitis
Treat classic recurrent toxoplasma chorioretinitis according to current guidelines with optional serology for toxoplasma
Treat neuroretinitis according to current guidelines for Bartonella infection and obtain serology
For other chorioretinitis, obtain specimens for diagnostic testing
Blood for quantitative RPR, FTA-ABS, human immunodeficiency virus (HIV), CMV, toxoplasmosis
Aqueous humor for PCR studies as indicated
CMV, HSV 1, HSV 2, varicella, toxoplasma
• Day 1: Start empiric therapy for viral infection
Intravitreal antiviral injection in affected eye(s)
Oral acyclovir or valacyclovir
Day 3 to 4: Check RPR and FTA results
If RPR positive, HIV negative
Aqueous procaine pen G IM 2.4 million u/d for 10 days with probenecid 500 mg four times a day or intravenous therapy
Suspend antiviral treatment
Lumbar puncture
If RPR or FTA-ABS positive and HIV positive
Admit for intravenous aqueous penicillin
Suspend antiviral treatment
Lumbar puncture
If RPR and FTA-ABS negative
Continue antiviral treatment and reinject
Consider sending aqueous humor for syphilis antibody
Day 5 to 10: Assess response to empiric therapy
Adjust therapy according to PCR results
Consider diagnostic vitrectomy if diagnosis is uncertain—this may include aspiration or biopsy of retinal and subretinal lesions
Panuveitis with Suspected Infection: For diffuse inflammation without prominent focal lesions or no view
Day 1
RPR, FTA-ABS
Detailed review of systems and medical history
Culture of other infected sites, blood, and urine
Consider chest X-ray and echocardiography
Consider diagnostic vitrectomy for cytology and culture
Delay therapy until after diagnostic specimens obtained if possible
Pearls
Plan carefully for the specimens to be taken during a diagnostic vitrectomy. Undiluted specimens are used for cytology and immunohistochemistry, culture, PCR, and antibody studies. Diluted specimens are ideal for flow cytometry and can be concentrated for bacterial and fungal culture or injected into aerobic and anaerobic blood culture bottles.
24.2.2 Host Factors
Intraocular infection may occur because a large number of organisms are circulating in the blood, or they may be circulating for a long time or intermittently, as in intravenous drug abusers, thereby increasing the chances of inoculation of the eye. Individuals most likely to experience overwhelming infection are, in general, those least able to mount defenses. If endogenous infection is suspected, a complete medical history of the past several months must be taken into consideration to see if instrumentation of intravascular structures has occurred, if intravascular medical devices have been implanted, or if intravenous drugs have been abused. Risk factors for HIV infection should be queried. In the case of fungal endophthalmitis, the active systemic infection may be remote and the eye may be the only site of residual infection.
The asymptomatic, uninstrumented patient is a diagnostic challenge. Dental work or colonic polyps may lead to brief seeding of the bloodstream and endogenous infection (Fig. 24-4). Bronchiectasis or sinusitis may create prolonged reservoirs of infection. Usually, the number of organisms that enter the bloodstream from these sources is so small that the immune system rapidly clears the offenders. Subacute bacterial endocarditis with intermittent seeding of the bloodstream may also be difficult to diagnose. Transesophageal echography is useful to detect small vegetations on heart valves.
HIV infection has produced several interesting exceptions to the standard rules regarding infectious disorders. Syphilis in patients with acquired immunodeficiency syndrome (AIDS) may be difficult to treat even with high-dose penicillin. 27 Recurrences are common and not always accompanied by a positive quantitative RPR. 28 Prolonged impairment of the cellular immune system with depletion of CD4- and CD8-bearing lymphocytes appears to lead to susceptibility to viruses of the herpes class, especially CMV, 29 which can grow in a multitude of cell types and organs. Some individuals may have an unusual predisposition to a specific opportunistic infection that is based not on any global index of immunosuppression but on quite specific defects in the immunologic repertoire that, at present, cannot be measured. Functional assays of CMV-specific CD4-and CD8-positive T lymphocytes do not predict which HIV patients are likely to develop CMV retinitis during follow-up. 30 Improvement in CMV-specific T-cell responses is associated with treatment with highly active antiretroviral therapy (HAART) and immune recovery as well as resistance to recurrence of CMV retinitis. 31 Empirically, sustained elevation of CD4+ T lymphocytes greater than 100 cells per microliter for 6 months supports discontinuation of CMV-specific antiviral therapy. 32
24.3 Specific Infections
24.3.1 Viral Retinitis
Cytomegalovirus Retinitis
Cytomegalovirus (CMV) retinitis is generally a slow-growing infection that produces an expanding lesion with a granular border and a central, atrophic zone (Fig. 24-5). The virus propagates every 18 hours and spreads from cell to cell within the retina and probably within the RPE. Infection originates in endothelial cells. 33 In the HAART era, progression of the active border by greater than or equal to 0.5 disc diameter occurred at a rate of 1.4/100 person-years of follow-up in patients with treated disease and immune recovery versus 28/100 person-years in newly diagnosed and untreated patients.
First described as a complication of organ transplantation, CMV retinitis occurred in only 1% of solid organ recipients from 1995 to 2005, presumably due to improved immunosuppression regimens and CMV surveillance programs with prophylactic treatment of recipients of organs from CMV-positive donors. 34 The incidence of CMV retinitis has also fallen in HIV-positive individuals in the HAART era and, in 2012, was reported to be 0.36/100 person-years in the Longitudinal Study of the Ocular Complications of AIDS. 35
Any part of the retina can be infected, although most patients have relatively posterior disease at the time their disease is diagnosed. 36 Posterior disease may have the so-called fulminant appearance with secondary exudative retinal detachments (Fig. 24-6). The degree of hemorrhage within lesions is variable; hemorrhage is more common with untreated posterior lesions, whereas a granular, nonhemorrhagic retinitis is more common in peripheral disease. In the HAART era, overall mortality of patients with CMV retinitis remains high at 9.8 deaths/100 person-years on a U.S. prospective multicenter study of 503 patients. 37 The rate of retinitis progression in that study was 7/100 person-years and rate of retinal detachment was 2.3/100 person-years. 37 Poor long-term visual outcomes after retinal detachment repair with silicone oil are of increasing importance in the HAART era 38 because patients will likely live longer after surgery. Silicone oil removal should be attempted in patients with stable repairs.
Treatment of CMV retinitis is generally with oral valganciclovir rather than intravenous ganciclovir or foscarnet. Intravenous ganciclovir and foscarnet are equivalent in time to remission 39 and intravenous ganciclovir and valganciclovir are also equivalent. The ganciclovir implant is superior to either, 40 but was taken off the market in 2013. Weekly intravitreal therapy with ganciclovir (2 mg per dose) provides excellent intraocular drug levels. 41 Intravitreal therapy is acceptable for induction, maintenance, or salvage therapy. Table 24-2 summarizes common dosing regimens for these agents. All three drugs require dosage adjustment for renal function; foscarnet is nephrotoxic. Shorter treatment courses of specific anti-CMV therapy are typical in the era of HAART. 32
With improvement in the immune status of most HIV-positive patients, CMV retinitis is no longer a common retinal infection, although CMV is a common virus with increasing prevalence with aging. 42 Although better prophylaxis after organ transplantation has reduced the frequency of retinitis, CMV retinitis remains a clinical problem for patients with other types of iatrogenic immunosuppression and the elderly, who may have lost their specific immunity to CMV. Because CMV is a virus that propagates initially in the vascular endothelium, it may increase the risk of occlusions of the retinal circulation, especially if there is concomitant cardiovascular disease. 43 , 44 Such infections can be difficult to diagnose, in part because suspicion for CMV retinitis is low in the non–HIV-infected population and in part because the retinitis itself can be indolent and difficult to recognize. Diagnosis by PCR followed by oral valganciclovir for 3 months may be adequate treatment 45 ; intravitreal injections of antivirals are also helpful in treatment. Interestingly, there are case reports of CMV retinitis occurring de novo after intravitreal injection of triamcinolone. 46
Necrotizing Herpetic Retinitis
This disorder was named acute retinal necrosis before infections with varicella-zoster 47 or HSV types 1 and 2 48 , 49 were proven to be the cause. There is recognition that vertical transmission of HSV type 2 may play a role in many cases of HSV type 2 ARN in young persons. 50 The original description is that of a young, healthy person with a bilateral, confluent, rapidly progressive, necrotizing retinitis starting in the periphery and spreading centripetally. Intense vitritis, granulomatous iritis, and episcleritis are common associated features. Generally, the patient has consulted an ophthalmologist and received treatment for iritis or episcleritis for 7 to 10 days before the posterior segment lesions are recognized and treated. The retinal whitening in the far periphery may be difficult to see in the early stages or may not exist in the early stages. After the retinitis is established, optic neuritis and retinal arteriolitis with vascular occlusion may occur (Fig. 24-7). Decreases in velocity in the central retinal artery suggest a reduction in retinal blood flow. 51 Retinal ischemia contributes to vision loss. It is not clear whether aspirin or pentoxifylline treatment can alter the visual outcome by reducing vascular occlusions or improving retinal blood flow.
Combination therapy with both systemic and intravitreal foscarnet has been reported to be more effective than systemic therapy alone in decreasing the risk of retinal detachment and severe vision loss. 52
Infection may be bilateral in up to two-thirds of affected individuals. If infection of the second eye occurs, it is usually within 6 weeks, although markedly delayed cases have been described. 53 One of the principal benefits of systemic antiviral treatment may be to reduce the final rate of infection of the second eye from roughly 65% to about 17%, based on one retrospective series. 53 Infections of the second eye are generally less severe than those of the first, perhaps because of prompt recognition and treatment. A 3-month course of 400 to 800 mg of oral acyclovir three to five times daily or valacyclovir 500 to 1,000 mg one to three times daily may provide important prophylaxis during the period of greatest risk for fellow eye involvement. 54
There is a high risk for retinal detachment 8 to 12 weeks after onset of ARN. Whether retinal detachment occurs or not seems to be a principal determinant of visual outcome. 55 Inflammation, preretinal membrane formation, and hypotony can compromise surgical results. Prophylactic treatment with laser photocoagulation to demarcate the borders of the retinitis may reduce the rate of retinal detachment (Fig. 24-8). 56
In patients with AIDS, necrotizing herpetic retinitis is commonly associated with prior herpes zoster dermatitis, including ipsilateral herpes zoster ophthalmicus, 57 and a high incidence of bilaterality with rapid progression to retinal detachment and blindness. 58 The infection is often not controlled by intravenous acyclovir in the usual doses of 10 mg/kg three times daily for 7 to 10 days. Improved results with ganciclovir or ganciclovir and foscarnet as intravenous combined therapy have been reported. 57 Intravitreal injection of antiviral agents, either ganciclovir 2 mg three times per week for 2 to 3 weeks and then weekly as needed or foscarnet 2.4 mg on the same schedule is likely more effective than systemic treatment alone. The known involvement of the central nervous system during active necrotizing herpetic retinitis 49 and a report of progressive, extensive involvement of visual pathways in the brain 59 in an AIDS patient underscore the need for concomitant systemic treatment. The ideal duration of treatment is uncertain; once the virus resumes a latent state, it may be easier to maintain in remission than CMV or require less intensive medication to treat. However, recurrences have been reported as medication is reduced. 60 Intravenous or oral ganciclovir may provide adequate maintenance therapy and also provide prophylaxis against CMV disease.
In cases in which the diagnosis is unclear, amplification of DNA by the PCR 24 or comparative serology in aqueous humor and serum for varicella immunoglobulin G (IgG) antibody and HSV IgG antibody may be useful. 61 A disproportionately high titer of intraocular antibody supports a specific etiologic diagnosis. In patients with AIDS who have no inflammatory reaction, antibody titers are less likely to be positive; PCR is less likely to be positive more than 1 week after onset. 24
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