The Uveo-Meningeal Syndromes

Home , Intermediate uveitis, Orbital lymphoma, Uveitis

ORIGINAL ARTICLE

Paul W. Brazis, MD,* Michael Stewart, MD,* and Andrew G. Lee, MD†

main clinical features being a meningitis or meningoenceph- Background: The uveo-meningeal syndromes are a group of disorders that share involvement of the uvea, retina, and meninges. alitis associated with uveitis. The meningeal involvement is Review Summary: We review the clinical manifestations of uveitis often chronic and may cause cranial neuropathies, polyra- and describe the infectious, inflammatory, and neoplastic conditions diculopathies, and hydrocephalus. In this review we define associated with the uveo-meningeal syndrome. and describe the clinical manifestations of different types of Conclusions: Inflammatory or autoimmune diseases are probably uveitis and discuss the individual entities most often associ- the most common clinically recognized causes of true uveo-menin- ated with the uveo-meningeal syndrome. We review the geal syndromes. These entities often cause inflammation of various distinctive signs in specific causes for uveo-meningeal dis- tissues in the body, including ocular structures and the meninges (eg, ease and discuss our evaluation of these patients. Wegener granulomatosis, sarcoidosis, Behçet disease, Vogt-Koy- anagi-Harada syndrome, and acute posterior multifocal placoid pigment epitheliopathy). The association of an infectious uveitis with an acute or chronic meningoencephalitis is unusual but occasionally the eye examination may suggest an infectious etiology or even a The uveo-meningeal syndromes are a specific organism responsible for a meningeal syndrome. One should consider the diagnosis of primary ocular-CNS lymphoma in heterogeneous group of disorders that share patients 40 years of age or older with bilateral uveitis, especially involvement of the uvea, retina, and meninges. with prominent vitritis, that fails to respond to treatment or who has associated neurologic findings. A paraneoplastic disorder has been described in patients who have combined optic neuritis and retinitis defined serologically by the presence of a paraneoplastic IgG autoantibody CRMP-5-IgG. These patients may have an inflammatory UVEITIS vitritis and may have signs of cerebrospinal fluid inflammation. The uveal tract consists of the iris anteriorly, the ciliary Key Words: uveitis, vitritis, choroiditis, retinitis, uveo-meningeal body (the pars plicata anteriorly and the pars plana posteri- syndrome, meningitis orly) in the middle, and the choroid posteriorly (Fig. 1). Inflammation of any of these structures is called uveitis. The (The Neurologist 2004;10: 171–184) anatomic division of the uveal tract serves as the basis for classifying uveitis into anterior uveitis (iritis, anterior cyclitis, iridocyclitis), intermediate uveitis, or posterior uveitis (focal, he uveo-meningeal syndromes are a heterogeneous group multifocal, or diffuse choroiditis, retinochoroiditis, or neur- Tof disorders that share involvement of the uvea, retina, ouveitis with optic nerve inflammation), and panuveitis.1,2 and meninges. Etiologies of this syndrome include infectious, Anterior uveitis may be subdivided into acute or inflammatory, and neoplastic disorders (Table 1) with the chronic and granulomatous or nongranulomatous forms. Pa- tients with acute anterior uveitis present with eye pain, From the *Department of Ophthalmology, Mayo Clinic—Jacksonville, Jack- redness, tearing, photophobia, and decreased vision in the sonville, Florida; and the †Departments of Ophthalmology, Neurology, affected eye. There is a perilimbal flush caused by dilation of and Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, the circumcorneal conjunctival vessels and often clumps of Iowa. inflammatory cells called keratic precipitates on the posterior This work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY. cornea (Fig. 2). The characteristic finding is inflammatory Reprints: Paul Brazis, MD, Department of Ophthalmology, Mayo Clinic— cells and protein in the aqueous humor (cell and flare). With Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail: severe inflammation there may be a layering of inflammatory [email protected]. cells in the inferior anterior chamber (hypopyon). Chronic Copyright © 2004 by Lippincott Williams & Wilkins ISSN: 1074-7931/04/1004-0171 anterior uveitis often develops in a more gradual fashion with DOI: 10.1097/01.nrl.0000131145.26326.ff patients experiencing decreased vision. Affected eyes are

The Neurologist • Volume 10, Number 4, July 2004 171 Brazis et al The Neurologist • Volume 10, Number 4, July 2004

TABLE 1. Etiologies of the Uveo-Meningeal Syndrome

Infectious Bacterial Cat-scratch disease Whipple disease Mycobacterial—tuberculosis Syphilis Lyme disease Fungal Toxoplasmosis Viral Gnathostomiasis Inflammatory Wegener granulomatosis Sarcoidosis Behçet disease VKH syndrome APMPPE Neoplastic Lymphoma Metastatic disease Paraneoplastic syndrome of combined optic neuritis and retinitis defined serologically by CRMP-5-IgG FIGURE 1. This cross-section drawing of the eye shows the uveal tract (highlighted in brown) with its 4 anatomic compo- nents: iris, ciliary body (pars plicata), pars plana, and choroid. often not gray (ie, they are “quiet”) but may have pigmented keratic precipitates, aqueous cells and flare, and areas where the iris has become adherent to the anterior lens capsule (posterior synechiae). Iris nodules may occur on the pupillary margin (Koeppe nodules) or away from the pupillary margin (Busacca nodules). When large keratic precipitates (“mutton fat” precipitates) are present with nodules on the iris, the inflammation is said to be granulomatous. If these iris nodules or mutton fat keratic precipitates are absent, the uveitis is called nongranulomatous. Posterior subcapsular cataracts often occur with chronic anterior uveitis. Inflammatory medi- ated scarring between the iris and peripheral cornea (anterior synechiae) may lead to chronic glaucoma. Inflammation of the ciliary body (cyclitis and pars planitis) presents with the gradual onset of blurred vision or floaters in a quiet eye. The anterior chamber may have a few cells but there are diffuse cells in the vitreous. Clumps of FIGURE 2. Peri-limbal flush, seen here as fine red lines on the vitreous inflammatory cells may cause vitreous “snowballs.” sclera just outside the iris, indicates dilated capillaries and small Mounds of inflammatory white exudates may accumulate arterioles resulting from iritis. The multifocal accumulation of because of gravity on the inferior pars plana (“snow banks”). protein and inflammatory cells on the corneal endothelial The release of vasoactive agents lead to macular edema surface forms keratic precipitates (KPs). which may cause decreased or distorted vision. Patients with posterior segment inflammation (choroiditis and retinitis) present with reduced vision, distorted vision, arterioles and venules causes sheathing, focal vascular nar- and floaters of acute or insidious onset. Pain, redness, tearing, rowing and irregularity. Exudates may cluster along vessels and photophobia are often absent. Inflammation of the retinal appearing as “candle wax drippings” (tache d’bougie). With

choroidal and retinal inflammation, cells are often noted in outlined in Table 2. Only infectious agents known to cause a the vitreous (vitritis). The macula and optic nerve may also meningeal syndrome possibly associated with uveitis will be become swollen or ischemic. Retinitis is characterized by discussed. areas of retinal whitening and thickening, while choroiditis is characterized by deeper yellow or cream-colored lesions BACTERIAL INFECTIONS beneath the retinal pigment epithelium. Vascular leakage The major bacterial etiologies for uveo-meningeal syn- from choroidal inflammation may cause exudative retinal drome include cat scratch disease, Whipple disease, syphilis, detachment. The association of retinitis or choroiditis with a tuberculosis, and Lyme disease. swollen optic disc is referred to as neuroretinitis. Cat scratch disease is usually manifested by a regional The evaluation of uveitis thus requires thorough oph- lymphadenopathy following the scratch or bite of a kitten or thalmologic examination including assessment of visual acu- adult cat and is a result of infection by Bartonella henselae. ity and color vision, external examination (for conjunctival or A common ophthalmologic manifestation of cat scratch dis- episcleral injection), slit-lamp biomicroscopy (cell and flare, ease is optic disc edema (Fig. 3) with a macular star keratic precipitates, iris atrophy, iris nodules, syneciae, cata- (ODEMS).6 This neuroretinitis may be associated with ante- ract, etc.), measurement of intraocular pressures, and dilated rior uveitis. Cat scratch disease may cause a focal, multifocal, fundus examination.2,3 Fluorescein angiography is often use- or diffuse retinitis or choroiditis (Fig. 4).7–9 In a study of 24 ful to confirm retinal vasculitis, macular edema, and areas of patients (35 eyes) with choroidal, retinal, or optic disc man- retinitis, choroiditis, ischemia, or retinal detachment. ifestations of cat scratch disease, discrete white retinal or choroidal lesions were the most common posterior segment finding (46% of eyes, 63% of patients) followed by macular star (43% of eyes, 63% of patients).9 Some patients with cat It is important to identify the predominant scratch disease develop signs of meningeal irritation and location of the uveitis (anterior, intermediate, posterior) because the differential diagnosis TABLE 2. Types of Uveitis Associated with Specific differs according to location. Infectious Agents Anterior uveitis Bacteria (endogenous), mycobacteria, and spirochetes—Listeria Monocytogenes, Neisseria meningitidis, Haemophilus ETIOLOGIES Influenzae, Yersenia, Klebsiella, leprosy, tuberculosis, The causes of uveitis include traumatic, infectious, mycoplama pneumoniae, Whipple disease, syphilis inflammatory, or neoplastic etiologies. It is important to Viral—Herpes zoster, herpes simplex, cytomegalovirus, HIV, identify the predominant location of the uveitis (anterior, hepatitis B intermediate, posterior) because the differential diagnosis Fungi—Candida albicans, coccidiomycosis differs according to location. The most common causes of Protozoa—Toxoplasmosis nontraumatic anterior uveitis are idiopathic (38 to 56% of Rickettsiae—Rocky Mountain spotted fever cases), the seronegative spondyloarthropathies (21 to 23%), Intermediate uveitis and vitritis juvenile rheumatoid arthritis (9 to 11%), and herpetic kera- Bacteria, mycobacteria, and spirochetes—cat scratch disease, Whipple disease, tuberculosis, Lyme disease touveitis. Most of intermediate uveitis cases are idiopathic Viral—Cytomeglovirus, EB virus (pars planitis). Toxoplasmosis is the most common cause of Protozoa—Toxoplasmosis posterior uveitis and the most common causes of panuveitis Posterior uveitis are idiopathic (22 to 45%) and sarcoidosis (14 to 28%).4,5 Bacteria, mycobacteria, and spirochetes—Neisseria meningitidis, Leptospira, Brucella, Nocardia asteroides, INFECTIOUS ETIOLOGIES OF THE UVEO- Whipple disease, cat scratch disease, tuberculosis, Lyme MENINGEAL SYNDROME disease, syphilis Almost any infectious agent may cause a meningoenceph- Viral—Cytomegalovirus, herpes simplex, herpes zoster, alitis and many agents may cause uveitis. The association of an Rubella, (German measles), Rubeola, HIV infectious uveitis with an acute or chronic meningitis or menin- Fungi—Candida, Histoplama capsulatum, Cryptococcus goencephalitis is unusual. However, occasionally the eye exam- neoformans, Aspergillus, Coccidiodes immitis, Blastomyces dermatidis ination may suggest an infectious etiology or even a specific Parasite—Toxoplasmosis, Toxocara canis, Cysticercus organism responsible for a meningeal syndrome. Infectious cellulosae, Onchocerca volvulus agents commonly associated with different types of uveitis are

eryma whippelii. Ocular manifestations include chronic anterior uveitis, vitreous opacities (described as “clumps of mulberries”), diffuse chorioretinal inflammation, and varying degrees of retinitis and vitritis.11–16 Although diarrhea and other gastrointestinal signs and symptoms are common, they may be absent in central nervous system Whipple disease. Neurologic manifestations are usually because of parenchymal rather than meningeal involvement and include drowsi- ness, confusion, amnesia, behavioral abnormalities, intellec- tual deterioration, ataxia, vertical gaze impairment, and supranuclear ophthalmoplegia. A distinct and presumed pathognomonic condition called oculomasticatory myorhythmia may occur in Whipple disease. It is characterized by constant, 0.5 Hz rhythmic convergence of the eyes associated with synchronous contractions of the eyelids, mouth, face, and neck.17–19 The diagnosis of Whipple disease can be made by small bowel biopsy. Polymerase chain reaction (PCR) testing of tissue or cerebrospinal fluid might be diagnostic. Appro- FIGURE 3. Optic disc swelling in cat scratch neuroretinitis. priate and often long-term antibiotic therapy with penicillin, tetracycline, or trimethaprim/sulfamethoxazole may be required in central nervous system (CNS) Whipple disease. The prognosis is variable but recurrent disease is common in patients with neurologic involvement. Tuberculosis (TB) is a multisystem infectious disorder with protean manifestations. The causative organism is My- cobacterium tuberculosis. TB may cause a chronic granulomatous iridocyclitis that is usually bilateral.20,21 The disease may less often present with high-grade, nongranulomatous anterior chamber inflammation. The most common posterior ocular presentation is a bilateral multifocal choroiditis, with or without overlying retinal necrosis and vitritis.20 Retinal periphlebitis may be seen. Choroidal tuberculosis may present as tubercles or tuberculomas (large solitary masses).22 Intraocular inflammation may be acute, relapsing, or chronic and persistent. Tuberculous meningitis arises as a conse- quence of bacteremia that occurs after primary infection or may also occur after late reactivation of TB elsewhere in the body. It often starts with a prodrome characterized by malaise, low-grade fever, headache and mentation, or personality FIGURE 4. Focal choroiditis in cat scratch disease. changes. Within several weeks, a well-defined meningitic phase develops with headache, meningismus, vomiting, confusion, and multiple cranial neuropathies.23 The diagnosis fever beginning 1 to 6 weeks after the onset of lymphade- may require positive skin testing (eg, purified protein deriv- nopathy or about 3 to 8 weeks after initial animal contact. ative), chest radiography, or cerebrospinal fluid (CSF) anal- Other neurologic manifestations include encephalitis, radic- ysis. PCR for TB may be positive in the CSF or tissue. ulitis, myelitis, or a combination of these findings.10 The Choroidal biopsy may establish the presence of acid-fast diagnosis is confirmed by serologic testing for Bartonella bacilli. Appropriate long-term multidrug anti-TB therapy henselae and antibiotic therapy with azithromycin, cipro- with isoniazid, rifampin, ethambutol, and pyrazinamide is floxacin or doxicycline may be useful. Most cases improve generally required for TB meningitis. over time though some patients experience permanent visual Syphilis, the great mimicker, may present with an- loss. terior or posterior uveitis. The disease is caused by Trepo- Whipple disease is characterized by arthralgia, abdom- nema pallidum. The most common ocular presentation is a inal pain, and weight loss. The causative organism is Troph- nonspecific iritis or iridocyclitis.24 The anterior uveitis

may be granulomatous or nongranulomatous, unilateral, or FUNGAL INFECTIONS bilateral. Multiple forms of posterior uveitis have been Various fungi may cause chronic granulomatous or described, including retinal vasculitis, necrosis, and optic nongranulomatous uveitis or other intraocular infections. The disc swelling. Diffuse or multifocal chorioretinitis is the fungi may reach the eye via penetrating trauma (exogenous) most common type of chorioretinal inflammation in pa- or through hematogenous spread of infection (endogenous). tients with acquired syphilis.25 This chorioretinitis is usu- Immunocompromised hosts (eg, cancer patients, transplant ally bilateral and associated with vitritis. Other types of recipients on immunosuppresive medications, intravenous chorioretinitis include disseminated choroiditis, areolar drug abusers, patients with chronic indwelling catheters, choroiditis (characterized by individual foci of choroiditis AIDS patients, etc.) are especially susceptible to systemic with subsequent lesions developing further and further fungal infections. Fungal organisms that may cause uveitis in peripherally), localized central chorioretinitis, and isolated the setting of menigoencephalitis include Candida albicans, retinitis.26 Most ocular manifestations occur with second- Coccidiodes immitis, Cryptococcus neoformans, Histoplas- ary syphilis. Meningitis frequently complicates secondary mosis capsulatum, Blastomyces dermatitidis, and Aspergillus. Candida albicans may cause an endogenous endoph- syphilis27 with spirochetes sometimes seen on dark field thalmitis presenting with ocular pain, decreased vision, and examination of the CSF. General paresis, tabes dorsalis, floaters.35,36 The typical lesion of Candida endophthalmitis is and meningovascular neurosyphilis occur in the tertiary a fluffy, white chorioretinal lesion with overlying vitreous stage of this disease. The diagnosis is made by serologic haze. The infection often extends into the vitreous, causing and CSF testing for Treponemal (eg, Fluorescent Trepo- cotton ball-like opacities so characteristic in appearance as to nemal antibody or Microhemagglutination for Treponema be almost pathognomonic of Candida infection.37 Progressive pallidum) and non-Treponemal testing (eg, rapid plasma retinochoroiditis with satellite lesions may occur. Other man- reagin or Venereal Disease Research Laboratory). The ifestations include anterior uveitis with hypopyon, scleritis, diagnosis of neurosyphilis in cases of uveo-meningeal keratitis (Fig. 5), papillitis, or even panophthalmitis. CNS syndromes is important because the treatment of tertiary candidiasis usually develops in the setting of disseminated and neurosyphilis requires high-dose intravenous penicil- candidiasis and manifests as meningitis, sometimes associ- lin therapy (4 million units every 4 hours) and therapy is ated with cerebral granulomas. generally longer duration than primary or secondary syph- Coccidiodes immitis infection is endemic in certain ilis regimens (eg, 2 weeks). areas of the southwestern United States as well as Central and Lyme disease is a spirochetal infection that results South America. It may cause iridocyclitis, iris granuloma, from tick-borne transmission of Borrelia burgdorferi. The choroiditis, chorioretinitis, or diffuse endophthalmitis.38,39 disease progresses through 3 stages.28 The first stage (early Pulmonary infection is the most common manifestation of localized disease) usually includes a rash (erythema chroni- cum migrans) characterized by an expanding erythematous margin, often with a central area of clearing, at the site of the tick bite. Associated symptoms include fever, malaise, ar- thralgias, and a flu-like illness. Conjunctivitis is the most common ocular manifestation of early Lyme disease and occurs in approximately 10% of cases. The secondary and tertiary stages of the disease (early disseminated and chronic disseminated stages) are characterized by neurologic impairment, cardiac disease, and arthritis. Neurologic manifestations include cranial nerve palsies (especially facial nerve impairment), meningitis, encephalitis, myelitis, meningora- diculitis, peripheral neuropathies and, rarely, pseudotumor cerebri.29 Uveitis is a relatively rare manifestation of Lyme disease, but may occur in the later stages. Unilateral or bilateral anterior uveitis, intermediate uveitis, vitritis, and choroiditis have been described, with other ocular manifestations including keratitis, episcleritis, optic neuritis, neuroretinitis, and motility problems.30–34 The diagnosis is made by serologic testing and appropriate antibiotic therapy may be curative. FIGURE 5. Fungal corneal abscess.

symptomatic infection, but subacute or chronic meningitis, usually without abscess or granuloma formation, may develop. Cryptococcal retinochoroiditis occurs in immunosuppressed patients (especially those with AIDS, lymphoma, sarcoidosis, or diabetes mellitus) and may be associated with meningitis or meningoencephalitis.40 Cryptococcus is the most common cause of clinically recognized fungal meningitis or meningoencephalitis in adults or children. The onset of this meningitis is often insidious but acute meningitis may also occur. Patients may complain of headache, somnolence, irritability, and clumsiness that may be present for weeks or months before the patient seeks medical attention. Progres- sive visual loss because of papilledema and fungal optic nerve sheath invasion may occur.41 Most cases of intraocular Cryptococcus infection manifest as posterior segment infection with initial small white spheres in the superficial retina or vitreoretinal interface. These initial lesions are often asymp- FIGURE 6. Focal retinochoroiditis in AIDS patient with ac- tomatic when diagnosed. These lesions may be associated quired, disseminated histoplasmosis. with adjacent retinal hemorrhage and most patients eventually develop more extensive whitish lesions that may or may not be associated with hemorrhages in the retina, choroid, or caused by dissemination from a primary pulmonary infection. both.40,42 Overlying vitritis may also be present. Unlike most fungi, Blastomyces dermatitidis is capable of Histoplasmosis capsulatum is responsible for 3 differ- producing disease in immune competent patients. Virtually ent forms of ocular involvement: Histoplasma endophthalmi- every structure of the eye can be affected though the organ- tis with diffuse uveal and retinal infection from disseminated ism has a predilection for the uveal tract. Ocular findings histoplasmosis; solitary histoplasmic chorioretinal granulo- include anterior uveitis with hypopyon, iridocyclitis, poste- ma; and the presumed ocular histoplasmosis syndrome rior uveitis, multifocal choroidal and peripapillary scarring, (POHS).43 The presumed ocular histoplasmosis syndrome is and panuveitis.46,47 CNS blastomycosis may cause pyogranu- endemic in the Ohio and Mississippi River Valleys of the lomas or meningitis.48,49 Eastern United States and consists of peripapillary chorioreti- Immunocompromised patients may develop invasive nal atrophy and scarring, peripheral punched-out chorioreti- Aspergillus infections with organisms spreading to the CNS nal scars, choroidal neovascularization with hemorrhage into either directly from a paranasal sinus or hematogenously the macula, and absence of anterior segment or vitreous from distant sites of infection. Intraocular infection by as- inflammation. Solitary histoplasmic granuloma is extremely pergillus is uncommon with the majority of cases resulting in rare and consists of a variable ill-defined white choroidal endogenous endophthalmitis with chorioretinitis.50,51 Orbital lesion. Neither the POHS nor solitary histoplasmic granu- infections, manifesting as eye pain, proptosis, optic neurop- loma is associated with meningeal involvement. Histoplasmic athy, and ophthalmoparesis, are far more common than in- endophthalmitis usually occurs in immunosuppressed indi- traocular infections. Acute or chronic aspergillus meningitis viduals, especially in patients with AIDS, as part of a dis- is rare but may result from spread of infection from the seminated histoplasmosis infection. Affected patients com- paranasal sinuses, middle or inner ear, or orbit.52 plain of decreased vision, floaters and eye pain. Ophthalmic The diagnosis of a specific fungal etiology generally manifestations include conjunctival injection, anterior uveitis, requires identification of fungal elements in a tissue speci- vitritis, and multiple white retinochoroidal foci of infection men, fungal stain or positive culture. Appropriate antifungal (Fig. 6).43,44 Although meningitis with disseminated his- therapy should be directed at the causative agent in fungal toplasmosis is usually mild and subclinical, some patients uveo-meningeal disease. may develop severe meningitis, focal or diffuse encephalitis, or myelitis.45 Disseminated histoplasma infection is fre- PARASITIC AND PROTOZOAL INFECTIONS quently fatal. These are uncommon causes for uveo-meningeal dis- Blastomyces dermatitidis causes a systemic disease ease in the United States. Ocular toxoplasmosis, caused by called blastomycosis that occurs primarily in the southeastern Toxoplasma gondii, is the most common cause of posterior and south central United States. The portal of entry for segment inflammation. Most cases of toxoplasmosis retino- blastomycosis is the lung; ocular and CNS involvement is choroiditis are because of reactivation of prior infection.

Acquired toxoplasmosis is unusual in immunocompetent in- iridocyclitis caused by these organisms can vary from a mild dividuals and more commonly occurs as an acute dissemi- anterior chamber inflammatory reaction to severe exudative nated infection in immunocompromised persons, especially infection with hypopyon. Various viruses are known to infect patients immunosuppressed after organ transplantation. Ac- the retina or choroid resulting in posterior uveitis. Common quired toxoplasmosis causes an acute choroiditis, retinitis, or viral agents causing posterior uveitis include cytomegalovirus chorioretinitis that is usually unilateral, as opposed to the (CMV), herpes simplex, and varicella-zoster; rare viral agents bilateral disease that occurs in patients with congenital tox- causing posterior uveitis include herpes B virus, Epstein-Barr oplasmosis.53 The intense, white inflammatory focus is gen- virus, coxsackie virus, and rubella. Rift Valley fever, because erally adjacent to a prior chorioretinal scar and is associated of infection via Phlebovirus species endemic in Africa, may with a severe vitritis (“headlight in the fog”) (Fig. 7). A also cause retinitis, retinal vasculitis, and, occasionally, se- neuroretinitis can also occur.54 Necrotizing retinitis may be vere encephalitis.56 seen especially in immunodeficient patients. Disseminated CMV retinitis is the most common ocular infection in toxoplasmosis with CNS involvement is a common cause of patients with AIDS though its incidence has dramatically neurologic disease in patients with AIDS. Clinical manifes- decreased with the development of highly active antiretrovi- tations include encephalitis, meningoencephalitis, meningitis, ral therapy (HAART). Patients who develop CMV retinitis or expanding mass lesions. Appropriate antitoxoplasmosis typically complain of blurred vision in one or both eyes, therapy with daraprim, sulfasalazine, clindamycin, or tri- although when the disease occurs in the periphery, it may be methaprim/sulfamethoxazole is usually administered and is asymptomatic. The infection often starts with white granular especially important in immunocompromised patients. foci of infection in a perivascular distribution with or without Gnathostomiasis is a helminth infection resulting from associated vitritis (Figs. 8, 9). The lesions typically grow and Gnathostoma spinigerum. This organism may rarely cause spread over weeks to months eventually resulting in full- anterior, posterior, or pan-uveitis and may also cause menin- thickness necrosis of the retina often with associated hemor- gitis or encephalitis.55 Other less common parasitic and rhage.56 CMV-induced meningoencephalitis is not uncom- protozoan causes of uveo-meningeal syndrome should be mon in immunodeficient patients with other CNS considered in patients from endemic areas. manifestations of CMV infection including encephalitis, ven- triculo-encephalitis, and CNS vasculitis.56 VIRAL INFECTIONS Herpes simplex virus may cause retinitis and chori- Many viruses may cause uveitis; Herpes simplex and oretinitis. Acute retinal necrosis syndrome is a diffuse uveitis varicella-zoster virus may often cause blepharitis, conjuncti- characterized by a peripheral necrotizing retinitis and retinal vitis, scleritis, keratitis, iridocyclitis, vitritis, and retinitis. The vasculitis associated in many cases with anterior chamber inflammation, vitritis, papillitis, or a combination of these

FIGURE 7. Focal recurrent toxoplasma retinochoroiditis with FIGURE 8. Peripapillary CMV retinitis with mild hemorrhages overlying vitritis (“headlight in the fog” appearance). in AIDS patient.

FIGURE 9. The CMV retinitis appears as a granular, near- FIGURE 11. Dendritic ulcer in patient with Herpes simplex confluent retinal infiltration with varying amounts of hemor- keratitis. rhage at its leading edge. manifestations (Fig. 10). This syndrome may be a result of many other countries, particularly in children, and intraocular herpes simplex infection and may occur in isolation, or it may inﬂammation affecting the retina, choroid, optic nerve, or a occur after, or concurrent with, primary herpes simplex in- combination of these occasionally occurs concurrently with fection, including herpes simplex keratitis (Fig. 11) and this encephalitis.56 encephalitis. Herpes simplex virus is one of the most com- Varicella-zoster infection often may cause corneal, mon causes of viral encephalitis in the United States and scleral, and conjunctival infection often with anterior uveitis. Progressive outer retinal necrosis (PORN) may occur with zoster infection, especially in AIDS patients, and is very difﬁcult to treat. It consists of infection of the outer layers of the retina unassociated with vitritis and with little or no clinical evidence of retinal vasculitis (Fig. 12).56 The syndrome of acute retinal necrosis, particularly in older individuals, is often because of varicella-zoster infection. Aseptic meningitis, encephalitis, and myelitis are relatively rare in patient with varicella-zoster infection.56 Appropriate antiviral therapy should be directed against the causative agent in viral uveo-meningeal disease. Many patients with viral retinitis can be effectively treated with intraocular drug therapy.

Inflammatory or autoimmune diseases are probably the most common clinically

FIGURE 10. Acute retinal necrosis (ARN) in patient with coex- recognized causes of true uveo-meningeal isting Herpes simplex encephalitis. Photo reveals diffuse, ne- syndromes. crotic retinal whitening with moderate intraretinal hemorrhage.

FIGURE 13. Noninfectious, peripheral corneal ulceration in patient with Wegener granulomatosis. FIGURE 12. PORN in AIDS patient with Herpes zoster infection. Photo shows numerous foci of outer retinal whitening. retrobulbar optic neuropathy may occur. Neurologic manifestations occur in 20 to 50% of patients and may include diffuse INFLAMMATORY ETIOLOGIES OF THE or focal meningeal involvement.59,60 UVEO-MENINGEAL SYNDROME Sarcoidosis is a systemic disease of unknown etiology Inflammatory or autoimmune diseases are probably the characterized pathologically by the presence of noncaseating most common clinically recognized causes of true uveo- granulomas. Almost any tissue can be affected, but the lungs meningeal syndromes. These entities often cause granuloma- and thoracic lymph nodes are major sites of involvement. tous inflammation of various tissues in the body, including Ocular involvement may be the initial manifestation of sar- ocular structures and the meninges. Most of these inflamma- coidosis in approximately 20% of patients61 and approxi- tory disorders are associated with systemic signs and symp- mately 25 to 80% of patients with sarcoidosis develop ocular toms. A complete review of systems should, therefore, be manifestations at some time during the course of the dis- performed in all patients with a uveo-meningeal syndrome. ease.62 Anterior uveitis is the most common ocular manifes- The review should include assessment of the skin (eg, rash), tation of this disease. It is usually bilateral and granulomatous mucous membranes (eg, oral ulcers), joints (eg, arthritis), and is characterized by the formation of grayish-white “mut- heart (eg, pericarditis), lungs (eg, hilar adenopathy, interstitial ton-fat” keratic precipitates on the endothelial surface of the disease), sinuses (eg, sinusitis), kidneys (eg, glomerulone- cornea. Occasional patients with sarcoidosis present with phritis), gastrointestinal system (eg, diarrhea), and genitouri- acute unilateral nongranulomatous or granulomatous anterior nary (eg, genital ulcers) systems. uveitis or iridocyclitis with sudden eye pain, redness, photo- Wegener granulomatosis is characterized by necrotiz- phobia, and decreased vision. Patients with chronic anterior ing granulomatous lesions of the respiratory tract, glomeru- uveitis develop granulomatous nodules on the iris (Koeppe lonephritis, and systemic vasculitis. In some patients, ocular, nodules and Busacca nodules). Although sarcoid uveitis is meningeal, or cerebral inflammation may be the earliest usually confined to the anterior chamber, some patients de- manifestation of Wegener and, indeed, may occur with no velop an isolated vitritis or even a panuveitis. Intermediate evidence of pulmonary, sinus, or renal involvement (“limited uveitis often presents with discrete gray-white spherical bod- Wegener granulomatosis”).57 Ocular structures are affected ies that may occur in chains like a “string of pearls” or in 30 to 60% of patients with both generalized and limited “snowballs” in the inferior vitreous. Retinal periphlebitis may Wegener.58 The main categories of ocular involvement in- occur with segments of retinal blood vessels showing an clude orbital granuloma, scleritis with or without peripheral irregular waxy yellow coating described as “candle wax keratitis (Fig. 13) or iritis, and vascular complications from drippings.” Other posterior segment manifestations include vasculitis. Retinal involvement includes asymptomatic cot- multifocal or serpiginous chorioretinitis, choroidal nodules, ton-wool spots or severe diffuse retinal vasculitis with wide- retinal vein occlusions, retinal and vitreous hemorrhages, and spread retinal vascular occlusions and perivascular venous optic nerve head granulomas (Fig. 14).63 The diagnosis can sheathing, vitreous hemorrhages, and glaucoma. Anterior or be suggested by chest imaging (eg, chest radiography, chest

bilateral and affecting both arteries and veins, occurs frequently and may be the initial manifestation of Behçet disease. Retinal vasculitis may result in vascular occlusion, hemorrhagic retinal necrosis, neovascular glaucoma, and blindness.58 Other ocular manifestations include conjunctivitis, keratitis, vitritis, and scleritis. Neurologic manifestations of Behçet disease may be a result of meningitis, meningoencephalitis, or focal parenchymal involvement. Meningitis or meningoencephalitis occurs in 4 to 29% of patients with Behçet disease but rarely as the initial manifestation. However, approximately 5% of patients develop neurologic involvement weeks or months before other clinical features of the disease (“neuro-Behçet disease”).66 Focal or multifocal neurologic deficits occur with the brainstem being the most frequent site of focal involvement. The diagnosis is made clinically. Identifying neuro- Behçet becomes important because of its prognostic value as it indicates severe and possibly fatal disease.67 The treatment is generally immunosuppression therapy with systemic cor- ticosteroids, chlorambucil, cyclophosphamide, azathioprine, FIGURE 14. Retinal vasculitis and optic nerve granuloma in and cyclosporine. patient with active sarcoidosis. Vogt-Koyanagi-Harada (VKH) syndrome consists of 2 clinical entities: an anterior granulomatous iridocyclitis associated with poliosis, vitiligo, alopecia, and dysacusis computed tomography, Gallium scan) and laboratory testing (summarized by J. Lawton Smith’s pneumonic, “Too bad if (eg, serum or CSF angiotensin converting enzyme). Gener- you got PUVAD”) described by Vogt and Koyanagi and a ally, however, a tissue diagnosis (eg, conjunctiva, bronchial, posterior granulomatous choroiditis with multifocal serous lymph node) is preferred. retinal detachment, meningeal findings, and cerebrospinal Neurosarcoidosis occurs in 5 to 10% of patients.64 In fluid pleocytosis described by Harada. The 2 clinical entities some cases the neurologic manifestations are the presenting combine to make a clinical syndrome characterized by panu- features of the disease and in some of these, there is no overt veitis, neurologic impairment, and skin changes.68,69 The evidence of sarcoidosis elsewhere in the body. Patients de- disease usually affects darkly pigmented Asian, American velop multifocal or diffuse leptomeningeal granulomas that Indian, Hispanic, or Afro-American adults; it is only rarely may cause nonspecific meningeal symptoms (eg, headache, seen in Caucasians. The syndrome can be divided into 4 stiff neck), mentation changes, hydrocephalus, cranial neu- clinical phases. The first phase or prodromal phase consists of ropathies, hypothalamic dysfunction, and pituitary abnormal- a flu-like illness associated with meningeal involvement man- ities.63,64 Sarcoid meningitis may be acute but is more often ifesting as meningismus, headaches, mental status changes, chronic. Single or multiple parenchymal granulomas may cerebrospinal fluid pleocytosis, tinnitus, and dysacusis.69,70 also develop. The treatment of sarcoidosis is usually cortico- An autoimmune attack against melanin containing cells in the steroids but additional immunosuppressive therapy with cochlea and meninges causes these symptoms.71 The second methotrexate, azathioprine, or cyclosporine may be required or uveitic phase is associated with acute granulomatous in unresponsive cases. The prognosis is variable but generally iridocyclitis, vitritis, optic disc edema, and multiple serous good. retinal detachments. The anterior iritis is usually bilateral Behçet disease is a chronic relapsing syndrome char- with mutton-fat keratic precipitates, aqueous cell and flare, acterized by the clinical triad of oral ulcerations (essentially peripheral anterior synechiae, depigmentation of the perilim- the sine qua non for diagnosis), genital ulcerations, and bus (Sugiura sign), iris nodules, cataracts, and glaucoma.68,69 uveitis. Most cases are reported from Eastern Mediterranean Anterior and posterior uveitis may occur independently or countries and Japan. Although anterior uveitis (eg, acute simultaneously. Posterior segment findings include vitritis, bilateral nongranulomatous iridocyclitis) with hypopyon may disc swelling, and retinal hemorrhages and exudates. Recur- occur, posterior uveitis develops in most patients.58,65 Al- rent bilateral serous retinal detachments, most commonly though ocular inflammation is seldom the initial manifesta- inferiorly and multiple, are essentially pathognomonic for the tion of the disease, bilateral uveitis ultimately develops in disease. The third or convalescent phase of the disease is approximately 70% of patients. Retinal vasculitis, usually associated with subsidence of the uveitis but with the onset of

skin manifestations and diffuse depigmentation of the cho- lymphoma patients concurrently or subsequently develop roid. Choroidal pigment decreases resulting in a mottled CNS or systemic involvement while only 10 to 20% stay “sunset glow” depigmented fundus and multiple peripheral ocular. Ocular lymphoma (usually a large B-cell lymphoma) yellowish-white lesions (Dalen-Fuchs nodules) occur in the appears to arise primarily in the vitreous and subretinal inferior peripheral retina. Cutaneous manifestations include pigment epithelial space and only secondarily extends into alopecia, vitiligo, and poliosis (whitening) of the eyebrows, the retina, choroid, and optic nerve. Patients with primary eyelashes, and hair of the head. The fourth phase of the CNS large-cell lymphoma may present only with visual disease consists of continuous recurrent inflammatory attacks signs. Although any part of the visual system may be in- characterized primarily by anterior uveitis. The major oph- volved, the most common ocular presentation is uveitis. Both thalmic complications of the disease occur most often in this eyes are usually affected although the disease may begin recurrent phase. Corticosteroid therapy is generally the first monocularly. Patients typically complain of mild decreased line of treatment but poorly responsive cases require azathio- vision or “floaters” in one or both eyes associated with mild prine, cyclophosphamide and cyclosporine. to moderate unilateral or bilateral uveitis unassociated with Acute posterior multifocal placoid pigment epitheli- eye pain or redness. Vitritis is always present but there may opathy (APMPPE) is a disease of unknown etiology typically be cells in the anterior chamber as well. Some patients either affecting young adults 20 to 30 years of age without gender or concurrently or subsequently develop multifocal yellow-or- racial predilection. It often begins with a prodromal phase of ange or white infiltrates beneath the retina or retinal pigment nonspecific upper respiratory complaints followed by sudden epithelium. Other patients develop exudative retinal detach- loss of central vision. Fundus examination shows multiple ments produced by subretinal pigment epithelium collections round, discrete, pale yellow-white lesions in the posterior pole at of tumor cells, retinal vasculitis, retinal artery occlusions, the level of the retinal pigment epithelium.72 Both eyes are retinal or vitreous hemorrhages, or retinal necrosis. usually affected and spontaneous recovery usually occurs within One should consider the diagnosis of primary ocular- 3 weeks though mottling of the retinal pigment epithelium may CNS lymphoma in patients 40 years or older with bilateral be permanent. Older patients, however, may have a less favor- vitritis that fails to respond to treatment. Also consider this able prognosis. Patients with APMPPE occasionally have other diagnosis if vitritis accompanies neurologic symptoms. Pri- ocular findings including iridocyclitis, corneal thinning, retinal mary CNS lymphoma usually manifests as focal or multifocal vasculitis with serous retinal detachment, and optic neuritis.58 parenchymal lesions but may be limited to the meninges.80 Some patients with APMPPE have neurologic manifestations Other forms of lymphoma may cause an uveo-menin- including headache, meningoencephalitis, cerebrospinal fluid geal syndrome.77 Systemic non-Hodgkin lymphoma with pleocytosis, tinnitus, hearing loss, and cerebral vasculitis with secondary (metastatic) ocular involvement may present as stroke.58,73–75 Fortunately, cerebral vasculitis occurs rarely, but anterior uveitis with hypopyon or hyphema but more com- immunosuppressive treatment should be considered if this leads monly with diffuse choroidal infiltration (Fig. 15) or a cho- to strokes.76 roidal mass. Systemic visceral or lymph node involvement precedes ocular involvement in approximately 57% of pa- NEOPLASTIC AND PARANEOPLASTIC tients though bilateral uveal lesions may occasionally be the ETIOLOGIES OF THE UVEO-MENINGEAL first manifestation of lymphoma. Angiotrophic large cell SYNDROME lymphoma or intravascular lymphomatosis may also Lymphoma may affect both ocular structures and the present with decreased visual acuity, cortical blindness, small meninges. Categories of intraocular lymphoma include: 1) white retinal or choroidal infiltrates, retinal pigment epithelial Primary non-Hodgkin malignant lymphoma of the CNS with changes, retinal artery occlusions, retinal hemorrhages, reti- ocular involvement primarily of the vitreous or retina; 2) nal vascular sheathing, vitritis, or iridocyclitis. Secondary or metastatic intraocular involvement in systemic Metastatic carcinoma to the eye is generally regarded non-Hodgkin lymphomas, in which the uveal tract is most as the most common intraocular malignant tumor. Because of frequently affected; 3) Lymphoid hyperplasia (or lymphoid the distribution of ocular blood flow, most intraocular metas- tumor) of uvea; 4) Angiotropic lymphoma (formerly neoplas- tases involve the choroid and present with yellowish-white, tic angioendotheliomatosis); and 5) Hodgkin disease and round or oval lesions. Exceptionally metastatic carcinoma to mycosis fungoides. the eye may present with infiltration of the retina or even Primary Ocular-CNS non-Hodgkin Lymphoma may dispersed vitreous cells.81,82 Lung and breast carcinomas are present with neurologic or ocular findings.77–79 Twelve to the most common sources of metastatic tumors. A uveo- 15% of primary CNS lymphoma patients present with asso- meningeal syndrome may be produced by concomitant ocular ciated ocular signs or symptoms while a further 10 to 20% of metastasis and carcinomatous meningitis. primary CNS lymphoma patients eventually develop ocular A paraneoplastic visual disorder with combined optic findings. On the other hand, 80 to 90% of primary ocular neuritis (Fig. 16) and retinitis has been described, usually in

FIGURE 16. Optic nerve swelling with mild vitritis in patient with CRMP-5-IgG paraneoplastic syndrome because of lung carcinoma.

FIGURE 15. Diffuse creamy choroidal infiltrates in patient with systemic lymphoma. selected uveo-meningeal processes. 4. Patients without a specific etiology identified by careful history and examination should undergo screening tests for treatable or common etiologies for uveo-meningeal patients with small-cell lung cancer or, less often, thymoma disease (eg, sarcoidosis, tuberculosis, syphilis). Most pa- or other malignancies. These cases are defined serologically tients with a uveo-meningeal process should at least un- by the presence of a paraneoplastic IgG autoantibody CRMP- dergo a magnetic resonance imaging (MRI) with gadolin- 83,84 5-IgG. Neurologic findings include chorea, cranial neu- ium and a lumbar puncture. Patients from Lyme endemic ropathy, loss of olfaction and taste, peripheral neuropathy, areas or with a history of erythema chronica migrans autonomic neuropathy, cerebellar ataxia, myelopathy, de- should be considered for Lyme serology. More specific mentia, and neuromuscular junction disorders.83,84 Spinal fluid studies often show inflammatory changes. Cross has described a subset of 172 patients with neurologic disorders and CRMP-5-IgG.84 Fifteen patients had optic neuritis with TABLE 3. Distinctive Presentations in Uveo-Meningeal retinitis documented in 5. Vitreous cells were noted in 9 cases Disease and diagnostic vitrectomy revealed reactive lymphocytosis in Optic disc edema with a macular Cat scratch disease 4 of 4 patients. star figure Focal chorioretinitis with massive Toxoplasmosis APPROACH TO THE PATIENT WITH THE vitritis (“headlight in the fog”) UVEO-MENINGEAL SYNDROME Acute retinal necrosis in peripheral Herpetic disease Our diagnostic approach to the uveo-meningeal syn- retina dromes is summarized as follows: Diarrhea and intermediate uveitis Whipple disease Hemorrhagic, perivascular necrotic Cytomegalovirus 1. All patients should undergo extensive and complete ocular retinitis and medical histories and examinations to identify any Multifocal serous retinal Vogt-Koyanagi-Harada systemic findings that might suggest a specific diagnosis. detachments 2. The immune status should be determined. Immunocom- Hypopyon uveitis, genital or oral Behçet disease promised individuals should be evaluated more aggres- ulcers sively for infectious etiologies (eg, Candida, Cryptococ- Acute, multifocal, placoid, pigment AMPPE epitheliopathy cus, Cytomegalovirus). Bilateral chronic uveitis in an Ocular lymphoma 3. The eye should be scrutinized for distinctive signs of a elderly patient specific etiology. Table 3 lists the distinctive signs in

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