Ординатура / Офтальмология / Английские материалы / Practical Manual of Intraocular Inflammation_Dick, Okada, Forrester_2008

Figure 6 Composite fundus color photographs of retinitis. (A, B) Retinitis secondary to CMV retinitis in an immunocompromised bone marrow transplant patient. (C) Other areas of partially healed perivascular retinitis (arrow). Similarly, herpetic retinopathy may present with an outer retinal necrosis. (D) Varicella zoster–associated progressive outer retinal necrosis.

However, progressive choroidal lesions may present a diagnostic dilemma and should alert to the possibility of neither an infectious nor an autoinflammatory cause (Fig. 8).

Clinical Signs of Structural Changes Associated with PSII

The current consensus is that inflammation generates structural changes that are not specific for definition or characterization of the anatomical location of uveitis (intermediate, posterior, or panuveitis). Structural changes that should be assessed include

Figure 8 Composite fundus color photographs of patient with intraocular B-cell lymphoma. The composite photographs show both discrete and confluent choroidal lesions increasing over six weeks. Subsequent vitreous and lesional cytology confirmed the diagnosis of intraocular B-cell lymphoma.

DETERMINING INFECTIOUS VS. NONINFECTIOUS PSII

This issue when a patient presents to you, is whether his or her intraocular inflammation is infective or not. Obviously, this determines the best-directed treatment. While clearly, there is a large spectrum of infectious agents that may cause PSII, the likelihood of any one specific agent varies globally and is dependent on endemic status of organism and the immune constitution of the patient. All this becomes increasingly apparent with accurate history and systems inquiry. Clearly, as we will see in chapter 3, there are clinical features that direct our management toward investigations to establish which infection is responsible for intraocular inflammation while contemporaneously treating infection with a “broad spectrum” antiviral or antibacterial approach (Fig. 9). So overall, the paradigm to follow is to use clinical signs to determine whether the inflammation is infective or noninfective so that appropriate therapy can be instituted initially to provide the best chance to preserve vision. Changing treatments or reinvestigating is paramount once investigations and results flood in, but should not preclude starting treatment if the vision is threatened acutely.

Figure 9 Generic algorithm for treatment of PSII. As you will discern in chapter 3, there are some features that make the diagnosis of infectious PSII very likely. The clinical features will therefore help in treating and investigating that patient appropriately. For the others, there may be no signs or history inquiry to highlight infection and therefore, the clinical decision for treatment should be based on sight-threatening features. Obviously, the treatments for infectious causes are microbe specific, and can be instituted generically as for presumed herpetic retinopathy or toxoplasmosis until investigations guide otherwise or further hone and tailor therapy accordingly. For treatment algorithm of sight-threatening noninfectious PSII, see fig. 10. Abbreviation: PSII, posterior segment intraocular inflammation.

DETERMINING SIGHT-THREATENING DISEASE

In terms of noninfectious PSII, one of the most important clinical decisions to make is whether or not there is presence of sight-threatening disease. Although we recognize that untreated PSII will lead to visual loss and, in the majority, will require immunosuppression of some form or the other [i.e., local versus systemic therapy (chaps. 4 and 5)] in the majority of cases, the decision as to whether there is a likelihood of acute visual loss or visual loss in the short term is paramount and will determine the extent of immunosuppressive therapy given initially, i.e., treating sight-threatening disease.

An accurate systemic workup as well as ocular signs will assist in determining sight-threatening disease. The issue becomes straightforward when the patient presents with visual loss either due to intense vitritis or chorioretinitis affecting the macular or retinal vasculitis. We also recognize that certain disorders have a higher prevalence of visual loss and a poorer long-term prognosis without treatment, which include Behc¸et’s disease, Vogt-Koyanagi-Harada, central retinal vasculitis, and the more insidious birdshot chorioretinopathy and serpiginous choroiditis. Diagnosis of such cases is overviewed in chapter 3, engaging the international guidelines for diagnostic purposes.

Here we have developed a simple schema to assist in the treatment of patients with noninfectious PSII (Fig. 10). Treatment is often instituted at the same time with investigating patients for underlying systemic associations (see below), but is based on determining (i) whether PSII is noninfective and (ii) ocular signs of sight-threatening nature. These signs include

To determine sight-threatening nature of PSII, ancillary imaging including fluorescein and indocyanine angiography, optical coherence tomography (OCT), and neuroimaging is frequently employed and directed following initial clinical assessment of patient (see below).

ASSESSING COEXISTING SYSTEMIC DISEASE IN PSII

Whether or not to have a blanket approach/screen in investigating patients is open to question. Given constraints on health care funding, most centers employ an iterative tailored approach in investigating underlying coexisting systemic

Figure 10 Generic algorithm for a suggested scheme for patients with noninfectious PSII. aCorticosteroid therapy—either oral (1–1.5 mg/kg/day) or intravenous (1 g/day for 3 days). Regimes vary depending on centers. bAdditional immunosuppressives are varied and will be covered in chapter 5. Commonly used immunosuppressives include methotrexate, cyclosporine A, azathioprine, and more recently, tacrolimus and cellcept (mycophenolate mofetil). cWith disease control, there should be drug-maintained remission for a minimum of six to nine months prior to further tapering of therapy. dIf disease is difficult to control, then reconsider diagnosis of either underlying lymphoproliferative disease or infection (chronic herpetic retinopathy or ocular tuberculosis for example). eSome cases of PSII require “triple” immunosuppression by the addition of another agent (e.g., corticosteroids, cellcept, and tacrolimus). More recently, “biologic” therapy (anti-TNF and alpha-interferon therapy) has been instituted at this stage or even earlier in severe cases such as Behc¸et’s disease with associated occlusive retinal vasculitis (chap. 5). Abbreviation: PSII, posterior segment intraocular inflammation. Source: Adapted from Ref. 4.

disease. There are some important points to make. First, the investigations of choice vary globally, depending on the prevalence of causes of uveitis in the area of investigation—particularly with relation to infectious PSII; second, the investigations should be tailored only after full ocular and systemic assessment of the patient, which will assist in directing your investigations.

General Investigations

These tests form background to baseline assessment prior to immunosuppressive therapy as well as assessing underlying systemic disease when looking for indicators of systemic immune activation with raised acute-phase responses and abnormal liver function tests or presence of systemic vasculitis (rare), raised blood pressure, proteinuria or microscopic hematuria, glycosuria, raised creatinine, and reduced eGFR.

Tailored Investigations

l Serum angiotensin converting enzyme (ACE)

lImmune profile—antinuclear antibodies (dsDNA), anticardiolipin, lupus anticoagulant, ANCA including ELISA for anti-myeloperoxidase and anti Proteinase 3 (PR3) (polyarteritis nodosa and Wegener’s granulomatosis, respectively)

lInfectious—HIV, VDRL (venereal disease research laboratory) or Fluorescent Treponemal antibody (FTA) for syphilis, mantoux or TB

interferon-g (IFNg) Elispot, ELISA for Borrelia or Bartonella

l Ocular fluid sampling for polymerase chain reaction (PCR) for herpesviruses, Toxoplasma, IL-10 levels (lymphoma) or immunophenotyping and cytology

l Genetic studies [e.g., HLA (human leukocyte antigen)-B51 status and Behc¸et’s disease, HLA-B27 and seronegative arthropathies]

l Lumbar puncture studies

Tailored investigations are also governed by the institution and vary globally, so different regions/countries employ different tests to screen, and therefore, the following is only a guide.

Tuberculosis Though screening for TB varies globally, in general, a mantoux test (intradermal tuberculin) is employed if a patient is not already on immunosuppression, otherwise, results are inaccurate because of immunosuppression-mediated anergy. 48 to 72 hours after injection, a measurement of 6 to 15 mm suggests previous exposure (including environmental mycobacterium) or prior Bacillus Calmette-Gue´rin (BCG) vaccination and that greater than 15 mm is indicative of active mycobacterium tuberculosis exposure. The interpretation depends, however, on the risk, so in patients from endemic areas or high-risk occupational groups, a reading of greater than 6 mm may indicate infection. Also, HIV and immunosuppression or recent viral infections can produce a false-negative result. The more recent IFNg Elispot may be beneficial as it is more sensitive and not as influenced by prior BCG vaccination or concurrent immunosuppression.

Syphilis Syphilis detection tests vary between laboratories. In the majority, the tests used may include VDRL, TPHA (Treponema pallidum hemagglutination assay), RPR (rapid plasma reagin test), and FTA-ABS (flourescent treponemal antibody absorption).

HIV Screening and diagnosis are tightly governed by most countries’ department of health guidelines and should be referred to.

Lumbar puncture Following neuroimaging (see below), particularly in suspected cases of CNS-related uveitis conditions, lumbar puncture is indicated. This will help determine extent of involvement and assist in diagnosis of multiple sclerosis, Vogt-Koyanagi-Harada, neurosarcoid or oculocerebral lymphoma. Of note, the opening cerebral spinal fluid (CSF) pressure (contributing to idiopathic intracranial hypertension) as well as measurement of protein, cells (pleocytosis/ lymphocytosis), and presence of oligoclonal bands should be noted (Table 6).

Ocular fluid sampling Both aqueous (aspiration) and vitreous sampling (including formal vitrectomy) are important tools to determine diagnosis. When diagnosis is indicative of herpes infection, PCR analysis of either aqueous or vitreous may confirm the diagnosis and tailor more specific antiviral therapy. Similarly, in cases of suspected intraocular lymphoma, initial aqueous sampling to demonstrate raised IL-10 levels may serve as a useful screen (5). More formal vitreous sampling is required to confirm diagnosis for immunophenotyping, cytology, and PCR molecular analysis.

aPleocytosis refers to an increase in cell numbers, which is largely lymphocytosis in noninfectious PSII. bOligoclonal bands are bands of immunoglobulin (IgG), which are found in both CSF and serum. Paired sample is required to observe if its presence in cerebrospinal fluid (CSF), is specific and not just secondary to bloodbrain barrier breakdown. Normally, two to five bands are considered significant. Interpretation of CSF oligoclonal bands in isolation is meaningless.

þþ indicates high prevalence of oligoclonal bands or pleocytosis.

Tailored Imaging

lNeuroangiography or systemic angiography in cases of suspected systemic vasculitis

Most ancillary systemic investigations are performed in consort with guidance from intern.

Sarcoidosis The presence of raised ACE alone is not a sensitive predictor of sarcoidosis without either chest X-ray changes (e.g., bihilar lymphadenopathy) or confirmation by high-resolution spiral CT. Tissue diagnosis confirms diagnosis of sarcoidosis, and may be acquired via bronchoscopy or mediastinoscopic approach for lymph node biopsy if no other systemic features (e.g., peripheral lymphadenopathy or skin or conjunctival nodules) are more easily accessible for biopsy. Gallium scans are expensive but if positive with accompanying raised serum ACE, then are 98% specific for diagnosis.

Systemic vasculitis Remember this is a rare cause of PSII and retinal vasculitis. However, if clinical findings point toward the diagnosis (e.g., raised blood pressure, chest X-ray changes, proteinuria, and hematuria), further investigations are

warranted. Backed by serological evidence (e.g., ANCA-positive), these warrant referral to appropriate intern for possible mesenteric angiography, neuroimaging, and renal or lung biopsy to ascertain diagnosis. Patients with vasculitis and no evidence of associated systemic inflammatory disease have increased morbidity for premature vascular disease (cerebral and cardiac). Therefore, ancillary investigations may also include factor V leiden, homocysteine, proteins C and S, and antithrombin 3 if predominant venous occlusive disease is present.

UTILIZING OCULAR IMAGING IN THE MANAGEMENT OF NONINFECTIOUS PSII

Frequently, despite accurate clinical assessment, the extent and severity of ocular inflammation and the degree of structural damage are gauged by an advantage of easy access and imaging of the retinal vasculature and tissue. These ancillary investigations are important to clearly define sight-threatening disease when there is doubt and also as a baseline to monitor therapeutic response and efficacy.

Angiography

Commonly employed are fluorescein angiography (FA) and indocyanine green angiography (ICGA). This enables the clinician to view with both FA and ICGA both the retinal and choroidal circulation, respectively. Fluorescein leaks readily from damaged (inflamed) retinal vessels and, conversely, will not flow through occluded vasculature. As a result, we are able to pick up with relative sensitivity

Conversely, indocyanine green (ICG), which has a high-affinity binding to lipoproteins and is of larger molecular weight compared to FA, does not leak readily from vasculature. In the choroid, ICG will leak slowly from the fenestrated vessels, and with time, more ICG becomes sequestered into the choroidal stroma. The other advantage facilitating imaging of the choroid is that ICG fluoresces in the infrared (830 nm) range, allowing visualization through the retinal pigment epithelium. Therefore, with ICGA one can illustrate