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ORIGINAL ARTICLE
The Uveo-Meningeal Syndromes
Paul W. Brazis, MD,* Michael Stewart, MD,* and Andrew G. Lee, MD†
Background: The uveo-meningeal syndromes are a group of
disorders that share involvement of the uvea, retina, and meninges.
Review Summary: We review the clinical manifestations of uveitis
and describe the infectious, inflammatory, and neoplastic conditions
associated with the uveo-meningeal syndrome.
Conclusions: Inflammatory or autoimmune diseases are probably
the most common clinically recognized causes of true uveo-meningeal syndromes. These entities often cause inflammation of various
tissues in the body, including ocular structures and the meninges (eg,
Wegener granulomatosis, sarcoidosis, Behçet disease, Vogt-Koyanagi-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
specific organism responsible for a meningeal syndrome. One
should consider the diagnosis of primary ocular-CNS lymphoma in
patients 40 years of age or older with bilateral uveitis, especially
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
vitritis and may have signs of cerebrospinal fluid inflammation.
Key Words: uveitis, vitritis, choroiditis, retinitis, uveo-meningeal
syndrome, meningitis
(The Neurologist 2004;10: 171–184)
T
he uveo-meningeal syndromes are a heterogeneous group
of disorders that share involvement of the uvea, retina,
and meninges. Etiologies of this syndrome include infectious,
inflammatory, and neoplastic disorders (Table 1) with the
From the *Department of Ophthalmology, Mayo Clinic—Jacksonville, Jacksonville, Florida; and the †Departments of Ophthalmology, Neurology,
and Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City,
Iowa.
This work was supported in part by an unrestricted grant from Research to
Prevent Blindness, Inc., New York, NY.
Reprints: Paul Brazis, MD, Department of Ophthalmology, Mayo Clinic—
Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail:
[email protected].
Copyright © 2004 by Lippincott Williams & Wilkins
ISSN: 1074-7931/04/1004-0171
DOI: 10.1097/01.nrl.0000131145.26326.ff
The Neurologist • Volume 10, Number 4, July 2004
main clinical features being a meningitis or meningoencephalitis associated with uveitis. The meningeal involvement is
often chronic and may cause cranial neuropathies, polyradiculopathies, and hydrocephalus. In this review we define
and describe the clinical manifestations of different types of
uveitis and discuss the individual entities most often associated with the uveo-meningeal syndrome. We review the
distinctive signs in specific causes for uveo-meningeal disease and discuss our evaluation of these patients.
The uveo-meningeal syndromes are a
heterogeneous group of disorders that share
involvement of the uvea, retina, and meninges.
UVEITIS
The uveal tract consists of the iris anteriorly, the ciliary
body (the pars plicata anteriorly and the pars plana posteriorly) in the middle, and the choroid posteriorly (Fig. 1).
Inflammation of any of these structures is called uveitis. The
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,
multifocal, or diffuse choroiditis, retinochoroiditis, or neurouveitis with optic nerve inflammation), and panuveitis.1,2
Anterior uveitis may be subdivided into acute or
chronic and granulomatous or nongranulomatous forms. Patients with acute anterior uveitis present with eye pain,
redness, tearing, photophobia, and decreased vision in the
affected eye. There is a perilimbal flush caused by dilation of
the circumcorneal conjunctival vessels and often clumps of
inflammatory cells called keratic precipitates on the posterior
cornea (Fig. 2). The characteristic finding is inflammatory
cells and protein in the aqueous humor (cell and flare). With
severe inflammation there may be a layering of inflammatory
cells in the inferior anterior chamber (hypopyon). Chronic
anterior uveitis often develops in a more gradual fashion with
patients experiencing decreased vision. Affected eyes are
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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
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 mediated 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
vitreous inflammatory cells may cause vitreous “snowballs.”
Mounds of inflammatory white exudates may accumulate
because of gravity on the inferior pars plana (“snow banks”).
The release of vasoactive agents lead to macular edema
which may cause decreased or distorted vision.
Patients with posterior segment inflammation (choroiditis and retinitis) present with reduced vision, distorted vision,
and floaters of acute or insidious onset. Pain, redness, tearing,
and photophobia are often absent. Inflammation of the retinal
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FIGURE 1. This cross-section drawing of the eye shows the
uveal tract (highlighted in brown) with its 4 anatomic components: iris, ciliary body (pars plicata), pars plana, and choroid.
FIGURE 2. Peri-limbal flush, seen here as fine red lines on the
sclera just outside the iris, indicates dilated capillaries and small
arterioles resulting from iritis. The multifocal accumulation of
protein and inflammatory cells on the corneal endothelial
surface forms keratic precipitates (KPs).
arterioles and venules causes sheathing, focal vascular narrowing and irregularity. Exudates may cluster along vessels
appearing as “candle wax drippings” (tache d’bougie). With
© 2004 Lippincott Williams & Wilkins
The Neurologist • Volume 10, Number 4, July 2004
choroidal and retinal inflammation, cells are often noted in
the vitreous (vitritis). The macula and optic nerve may also
become swollen or ischemic. Retinitis is characterized by
areas of retinal whitening and thickening, while choroiditis is
characterized by deeper yellow or cream-colored lesions
beneath the retinal pigment epithelium. Vascular leakage
from choroidal inflammation may cause exudative retinal
detachment. The association of retinitis or choroiditis with a
swollen optic disc is referred to as neuroretinitis.
The evaluation of uveitis thus requires thorough ophthalmologic examination including assessment of visual acuity and color vision, external examination (for conjunctival or
episcleral injection), slit-lamp biomicroscopy (cell and flare,
keratic precipitates, iris atrophy, iris nodules, syneciae, cataract, etc.), measurement of intraocular pressures, and dilated
fundus examination.2,3 Fluorescein angiography is often useful to confirm retinal vasculitis, macular edema, and areas of
retinitis, choroiditis, ischemia, or retinal detachment.
It is important to identify the predominant
location of the uveitis (anterior, intermediate,
posterior) because the differential diagnosis
differs according to location.
ETIOLOGIES
The causes of uveitis include traumatic, infectious,
inflammatory, or neoplastic etiologies. It is important to
identify the predominant location of the uveitis (anterior,
intermediate, posterior) because the differential diagnosis
differs according to location. The most common causes of
nontraumatic anterior uveitis are idiopathic (38 to 56% of
cases), the seronegative spondyloarthropathies (21 to 23%),
juvenile rheumatoid arthritis (9 to 11%), and herpetic keratouveitis. Most of intermediate uveitis cases are idiopathic
(pars planitis). Toxoplasmosis is the most common cause of
posterior uveitis and the most common causes of panuveitis
are idiopathic (22 to 45%) and sarcoidosis (14 to 28%).4,5
INFECTIOUS ETIOLOGIES OF THE UVEOMENINGEAL SYNDROME
Almost any infectious agent may cause a meningoencephalitis and many agents may cause uveitis. The association of an
infectious uveitis with an acute or chronic meningitis or meningoencephalitis is unusual. However, occasionally the eye examination may suggest an infectious etiology or even a specific
organism responsible for a meningeal syndrome. Infectious
agents commonly associated with different types of uveitis are
© 2004 Lippincott Williams & Wilkins
Uveo-Meningeal Syndromes
outlined in Table 2. Only infectious agents known to cause a
meningeal syndrome possibly associated with uveitis will be
discussed.
BACTERIAL INFECTIONS
The major bacterial etiologies for uveo-meningeal syndrome include cat scratch disease, Whipple disease, syphilis,
tuberculosis, and Lyme disease.
Cat scratch disease is usually manifested by a regional
lymphadenopathy following the scratch or bite of a kitten or
adult cat and is a result of infection by Bartonella henselae.
A common ophthalmologic manifestation of cat scratch disease is optic disc edema (Fig. 3) with a macular star
(ODEMS).6 This neuroretinitis may be associated with anterior uveitis. Cat scratch disease may cause a focal, multifocal,
or diffuse retinitis or choroiditis (Fig. 4).7–9 In a study of 24
patients (35 eyes) with choroidal, retinal, or optic disc manifestations 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
scratch disease develop signs of meningeal irritation and
TABLE 2. Types of Uveitis Associated with Specific
Infectious Agents
Anterior uveitis
Bacteria (endogenous), mycobacteria, and spirochetes—Listeria
Monocytogenes, Neisseria meningitidis, Haemophilus
Influenzae, Yersenia, Klebsiella, leprosy, tuberculosis,
mycoplama pneumoniae, Whipple disease, syphilis
Viral—Herpes zoster, herpes simplex, cytomegalovirus, HIV,
hepatitis B
Fungi—Candida albicans, coccidiomycosis
Protozoa—Toxoplasmosis
Rickettsiae—Rocky Mountain spotted fever
Intermediate uveitis and vitritis
Bacteria, mycobacteria, and spirochetes—cat scratch disease,
Whipple disease, tuberculosis, Lyme disease
Viral—Cytomeglovirus, EB virus
Protozoa—Toxoplasmosis
Posterior uveitis
Bacteria, mycobacteria, and spirochetes—Neisseria
meningitidis, Leptospira, Brucella, Nocardia asteroides,
Whipple disease, cat scratch disease, tuberculosis, Lyme
disease, syphilis
Viral—Cytomegalovirus, herpes simplex, herpes zoster,
Rubella, (German measles), Rubeola, HIV
Fungi—Candida, Histoplama capsulatum, Cryptococcus
neoformans, Aspergillus, Coccidiodes immitis, Blastomyces
dermatidis
Parasite—Toxoplasmosis, Toxocara canis, Cysticercus
cellulosae, Onchocerca volvulus
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Brazis et al
FIGURE 3. Optic disc swelling in cat scratch neuroretinitis.
FIGURE 4. Focal choroiditis in cat scratch disease.
fever beginning 1 to 6 weeks after the onset of lymphadenopathy or about 3 to 8 weeks after initial animal contact.
Other neurologic manifestations include encephalitis, radiculitis, myelitis, or a combination of these findings.10 The
diagnosis is confirmed by serologic testing for Bartonella
henselae and antibiotic therapy with azithromycin, ciprofloxacin or doxicycline may be useful. Most cases improve
over time though some patients experience permanent visual
loss.
Whipple disease is characterized by arthralgia, abdominal pain, and weight loss. The causative organism is Troph-
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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 drowsiness, confusion, amnesia, behavioral abnormalities, intellectual 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. Appropriate 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 Mycobacterium 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 consequence 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
changes. Within several weeks, a well-defined meningitic
phase develops with headache, meningismus, vomiting, confusion, and multiple cranial neuropathies.23 The diagnosis
may require positive skin testing (eg, purified protein derivative), chest radiography, or cerebrospinal fluid (CSF) analysis. PCR for TB may be positive in the CSF or tissue.
Choroidal biopsy may establish the presence of acid-fast
bacilli. Appropriate long-term multidrug anti-TB therapy
with isoniazid, rifampin, ethambutol, and pyrazinamide is
generally required for TB meningitis.
Syphilis, the great mimicker, may present with anterior or posterior uveitis. The disease is caused by Treponema pallidum. The most common ocular presentation is a
nonspecific iritis or iridocyclitis.24 The anterior uveitis
© 2004 Lippincott Williams & Wilkins
The Neurologist • Volume 10, Number 4, July 2004
may be granulomatous or nongranulomatous, unilateral, or
bilateral. Multiple forms of posterior uveitis have been
described, including retinal vasculitis, necrosis, and optic
disc swelling. Diffuse or multifocal chorioretinitis is the
most common type of chorioretinal inflammation in patients with acquired syphilis.25 This chorioretinitis is usually bilateral and associated with vitritis. Other types of
chorioretinitis include disseminated choroiditis, areolar
choroiditis (characterized by individual foci of choroiditis
with subsequent lesions developing further and further
peripherally), localized central chorioretinitis, and isolated
retinitis.26 Most ocular manifestations occur with secondary syphilis. Meningitis frequently complicates secondary
syphilis27 with spirochetes sometimes seen on dark field
examination of the CSF. General paresis, tabes dorsalis,
and meningovascular neurosyphilis occur in the tertiary
stage of this disease. The diagnosis is made by serologic
and CSF testing for Treponemal (eg, Fluorescent Treponemal antibody or Microhemagglutination for Treponema
pallidum) and non-Treponemal testing (eg, rapid plasma
reagin or Venereal Disease Research Laboratory). The
diagnosis of neurosyphilis in cases of uveo-meningeal
syndromes is important because the treatment of tertiary
and neurosyphilis requires high-dose intravenous penicillin therapy (4 million units every 4 hours) and therapy is
generally longer duration than primary or secondary syphilis regimens (eg, 2 weeks).
Lyme disease is a spirochetal infection that results
from tick-borne transmission of Borrelia burgdorferi. The
disease progresses through 3 stages.28 The first stage (early
localized disease) usually includes a rash (erythema chronicum 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, arthralgias, 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, meningoradiculitis, 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.
© 2004 Lippincott Williams & Wilkins
Uveo-Meningeal Syndromes
FUNGAL INFECTIONS
Various fungi may cause chronic granulomatous or
nongranulomatous uveitis or other intraocular infections. The
fungi may reach the eye via penetrating trauma (exogenous)
or through hematogenous spread of infection (endogenous).
Immunocompromised hosts (eg, cancer patients, transplant
recipients on immunosuppresive medications, intravenous
drug abusers, patients with chronic indwelling catheters,
AIDS patients, etc.) are especially susceptible to systemic
fungal infections. Fungal organisms that may cause uveitis in
the setting of menigoencephalitis include Candida albicans,
Coccidiodes immitis, Cryptococcus neoformans, Histoplasmosis capsulatum, Blastomyces dermatitidis, and Aspergillus.
Candida albicans may cause an endogenous endophthalmitis presenting with ocular pain, decreased vision, and
floaters.35,36 The typical lesion of Candida endophthalmitis is
a fluffy, white chorioretinal lesion with overlying vitreous
haze. The infection often extends into the vitreous, causing
cotton ball-like opacities so characteristic in appearance as to
be almost pathognomonic of Candida infection.37 Progressive
retinochoroiditis with satellite lesions may occur. Other manifestations include anterior uveitis with hypopyon, scleritis,
keratitis (Fig. 5), papillitis, or even panophthalmitis. CNS
candidiasis usually develops in the setting of disseminated
candidiasis and manifests as meningitis, sometimes associated with cerebral granulomas.
Coccidiodes immitis infection is endemic in certain
areas of the southwestern United States as well as Central and
South America. It may cause iridocyclitis, iris granuloma,
choroiditis, chorioretinitis, or diffuse endophthalmitis.38,39
Pulmonary infection is the most common manifestation of
FIGURE 5. Fungal corneal abscess.
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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. Progressive 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 asymptomatic when diagnosed. These lesions may be associated
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
both.40,42 Overlying vitritis may also be present.
Histoplasmosis capsulatum is responsible for 3 different forms of ocular involvement: Histoplasma endophthalmitis with diffuse uveal and retinal infection from disseminated
histoplasmosis; solitary histoplasmic chorioretinal granuloma; and the presumed ocular histoplasmosis syndrome
(POHS).43 The presumed ocular histoplasmosis syndrome is
endemic in the Ohio and Mississippi River Valleys of the
Eastern United States and consists of peripapillary chorioretinal atrophy and scarring, peripheral punched-out chorioretinal scars, choroidal neovascularization with hemorrhage into
the macula, and absence of anterior segment or vitreous
inflammation. Solitary histoplasmic granuloma is extremely
rare and consists of a variable ill-defined white choroidal
lesion. Neither the POHS nor solitary histoplasmic granuloma is associated with meningeal involvement. Histoplasmic
endophthalmitis usually occurs in immunosuppressed individuals, especially in patients with AIDS, as part of a disseminated histoplasmosis infection. Affected patients complain of decreased vision, floaters and eye pain. Ophthalmic
manifestations include conjunctival injection, anterior uveitis,
vitritis, and multiple white retinochoroidal foci of infection
(Fig. 6).43,44 Although meningitis with disseminated histoplasmosis is usually mild and subclinical, some patients
may develop severe meningitis, focal or diffuse encephalitis,
or myelitis.45 Disseminated histoplasma infection is frequently fatal.
Blastomyces dermatitidis causes a systemic disease
called blastomycosis that occurs primarily in the southeastern
and south central United States. The portal of entry for
blastomycosis is the lung; ocular and CNS involvement is
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FIGURE 6. Focal retinochoroiditis in AIDS patient with acquired, disseminated histoplasmosis.
caused by dissemination from a primary pulmonary infection.
Unlike most fungi, Blastomyces dermatitidis is capable of
producing disease in immune competent patients. Virtually
every structure of the eye can be affected though the organism has a predilection for the uveal tract. Ocular findings
include anterior uveitis with hypopyon, iridocyclitis, posterior uveitis, multifocal choroidal and peripapillary scarring,
and panuveitis.46,47 CNS blastomycosis may cause pyogranulomas or meningitis.48,49
Immunocompromised patients may develop invasive
Aspergillus infections with organisms spreading to the CNS
either directly from a paranasal sinus or hematogenously
from distant sites of infection. Intraocular infection by aspergillus is uncommon with the majority of cases resulting in
endogenous endophthalmitis with chorioretinitis.50,51 Orbital
infections, manifesting as eye pain, proptosis, optic neuropathy, and ophthalmoparesis, are far more common than intraocular infections. Acute or chronic aspergillus meningitis
is rare but may result from spread of infection from the
paranasal sinuses, middle or inner ear, or orbit.52
The diagnosis of a specific fungal etiology generally
requires identification of fungal elements in a tissue specimen, fungal stain or positive culture. Appropriate antifungal
therapy should be directed at the causative agent in fungal
uveo-meningeal disease.
PARASITIC AND PROTOZOAL INFECTIONS
These are uncommon causes for uveo-meningeal disease in the United States. Ocular toxoplasmosis, caused by
Toxoplasma gondii, is the most common cause of posterior
segment inflammation. Most cases of toxoplasmosis retinochoroiditis are because of reactivation of prior infection.
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Acquired toxoplasmosis is unusual in immunocompetent individuals and more commonly occurs as an acute disseminated infection in immunocompromised persons, especially
patients immunosuppressed after organ transplantation. Acquired toxoplasmosis causes an acute choroiditis, retinitis, or
chorioretinitis that is usually unilateral, as opposed to the
bilateral disease that occurs in patients with congenital toxoplasmosis.53 The intense, white inflammatory focus is generally adjacent to a prior chorioretinal scar and is associated
with a severe vitritis (“headlight in the fog”) (Fig. 7). A
neuroretinitis can also occur.54 Necrotizing retinitis may be
seen especially in immunodeficient patients. Disseminated
toxoplasmosis with CNS involvement is a common cause of
neurologic disease in patients with AIDS. Clinical manifestations include encephalitis, meningoencephalitis, meningitis,
or expanding mass lesions. Appropriate antitoxoplasmosis
therapy with daraprim, sulfasalazine, clindamycin, or trimethaprim/sulfamethoxazole is usually administered and is
especially important in immunocompromised patients.
Gnathostomiasis is a helminth infection resulting from
Gnathostoma spinigerum. This organism may rarely cause
anterior, posterior, or pan-uveitis and may also cause meningitis or encephalitis.55 Other less common parasitic and
protozoan causes of uveo-meningeal syndrome should be
considered in patients from endemic areas.
VIRAL INFECTIONS
Many viruses may cause uveitis; Herpes simplex and
varicella-zoster virus may often cause blepharitis, conjunctivitis, scleritis, keratitis, iridocyclitis, vitritis, and retinitis. The
FIGURE 7. Focal recurrent toxoplasma retinochoroiditis with
overlying vitritis (“headlight in the fog” appearance).
© 2004 Lippincott Williams & Wilkins
Uveo-Meningeal Syndromes
iridocyclitis caused by these organisms can vary from a mild
anterior chamber inflammatory reaction to severe exudative
infection with hypopyon. Various viruses are known to infect
the retina or choroid resulting in posterior uveitis. Common
viral agents causing posterior uveitis include cytomegalovirus
(CMV), herpes simplex, and varicella-zoster; rare viral agents
causing posterior uveitis include herpes B virus, Epstein-Barr
virus, coxsackie virus, and rubella. Rift Valley fever, because
of infection via Phlebovirus species endemic in Africa, may
also cause retinitis, retinal vasculitis, and, occasionally, severe encephalitis.56
CMV retinitis is the most common ocular infection in
patients with AIDS though its incidence has dramatically
decreased with the development of highly active antiretroviral therapy (HAART). Patients who develop CMV retinitis
typically complain of blurred vision in one or both eyes,
although when the disease occurs in the periphery, it may be
asymptomatic. The infection often starts with white granular
foci of infection in a perivascular distribution with or without
associated vitritis (Figs. 8, 9). The lesions typically grow and
spread over weeks to months eventually resulting in fullthickness necrosis of the retina often with associated hemorrhage.56 CMV-induced meningoencephalitis is not uncommon in immunodeficient patients with other CNS
manifestations of CMV infection including encephalitis, ventriculo-encephalitis, and CNS vasculitis.56
Herpes simplex virus may cause retinitis and chorioretinitis. Acute retinal necrosis syndrome is a diffuse uveitis
characterized by a peripheral necrotizing retinitis and retinal
vasculitis associated in many cases with anterior chamber
inflammation, vitritis, papillitis, or a combination of these
FIGURE 8. Peripapillary CMV retinitis with mild hemorrhages
in AIDS patient.
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FIGURE 9. The CMV retinitis appears as a granular, nearconfluent retinal infiltration with varying amounts of hemorrhage at its leading edge.
FIGURE 11. Dendritic ulcer in patient with Herpes simplex
keratitis.
manifestations (Fig. 10). This syndrome may be a result of
herpes simplex infection and may occur in isolation, or it may
occur after, or concurrent with, primary herpes simplex infection, including herpes simplex keratitis (Fig. 11) and
encephalitis. Herpes simplex virus is one of the most common causes of viral encephalitis in the United States and
many other countries, particularly in children, and intraocular
inflammation affecting the retina, choroid, optic nerve, or a
combination of these occasionally occurs concurrently with
this encephalitis.56
Varicella-zoster infection often may cause corneal,
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.
FIGURE 10. Acute retinal necrosis (ARN) in patient with coexisting Herpes simplex encephalitis. Photo reveals diffuse, necrotic retinal whitening with moderate intraretinal hemorrhage.
178
Inflammatory or autoimmune diseases are
probably the most common clinically
recognized causes of true uveo-meningeal
syndromes.
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Uveo-Meningeal Syndromes
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.
INFLAMMATORY ETIOLOGIES OF THE
UVEO-MENINGEAL SYNDROME
Inflammatory or autoimmune diseases are probably the
most common clinically recognized causes of true uveomeningeal syndromes. These entities often cause granulomatous inflammation of various tissues in the body, including
ocular structures and the meninges. Most of these inflammatory disorders are associated with systemic signs and symptoms. A complete review of systems should, therefore, be
performed in all patients with a uveo-meningeal syndrome.
The review should include assessment of the skin (eg, rash),
mucous membranes (eg, oral ulcers), joints (eg, arthritis),
heart (eg, pericarditis), lungs (eg, hilar adenopathy, interstitial
disease), sinuses (eg, sinusitis), kidneys (eg, glomerulonephritis), gastrointestinal system (eg, diarrhea), and genitourinary (eg, genital ulcers) systems.
Wegener granulomatosis is characterized by necrotizing granulomatous lesions of the respiratory tract, glomerulonephritis, and systemic vasculitis. In some patients, ocular,
meningeal, or cerebral inflammation may be the earliest
manifestation of Wegener and, indeed, may occur with no
evidence of pulmonary, sinus, or renal involvement (“limited
Wegener granulomatosis”).57 Ocular structures are affected
in 30 to 60% of patients with both generalized and limited
Wegener.58 The main categories of ocular involvement include orbital granuloma, scleritis with or without peripheral
keratitis (Fig. 13) or iritis, and vascular complications from
vasculitis. Retinal involvement includes asymptomatic cotton-wool spots or severe diffuse retinal vasculitis with widespread retinal vascular occlusions and perivascular venous
sheathing, vitreous hemorrhages, and glaucoma. Anterior or
© 2004 Lippincott Williams & Wilkins
retrobulbar optic neuropathy may occur. Neurologic manifestations occur in 20 to 50% of patients and may include diffuse
or focal meningeal involvement.59,60
Sarcoidosis is a systemic disease of unknown etiology
characterized pathologically by the presence of noncaseating
granulomas. Almost any tissue can be affected, but the lungs
and thoracic lymph nodes are major sites of involvement.
Ocular involvement may be the initial manifestation of sarcoidosis in approximately 20% of patients61 and approximately 25 to 80% of patients with sarcoidosis develop ocular
manifestations at some time during the course of the disease.62 Anterior uveitis is the most common ocular manifestation of this disease. It is usually bilateral and granulomatous
and is characterized by the formation of grayish-white “mutton-fat” keratic precipitates on the endothelial surface of the
cornea. Occasional patients with sarcoidosis present with
acute unilateral nongranulomatous or granulomatous anterior
uveitis or iridocyclitis with sudden eye pain, redness, photophobia, and decreased vision. Patients with chronic anterior
uveitis develop granulomatous nodules on the iris (Koeppe
nodules and Busacca nodules). Although sarcoid uveitis is
usually confined to the anterior chamber, some patients develop an isolated vitritis or even a panuveitis. Intermediate
uveitis often presents with discrete gray-white spherical bodies that may occur in chains like a “string of pearls” or
“snowballs” in the inferior vitreous. Retinal periphlebitis may
occur with segments of retinal blood vessels showing an
irregular waxy yellow coating described as “candle wax
drippings.” Other posterior segment manifestations include
multifocal or serpiginous chorioretinitis, choroidal nodules,
retinal vein occlusions, retinal and vitreous hemorrhages, and
optic nerve head granulomas (Fig. 14).63 The diagnosis can
be suggested by chest imaging (eg, chest radiography, chest
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Brazis et al
FIGURE 14. Retinal vasculitis and optic nerve granuloma in
patient with active sarcoidosis.
computed tomography, Gallium scan) and laboratory testing
(eg, serum or CSF angiotensin converting enzyme). Generally, however, a tissue diagnosis (eg, conjunctiva, bronchial,
lymph node) is preferred.
Neurosarcoidosis occurs in 5 to 10% of patients.64 In
some cases the neurologic manifestations are the presenting
features of the disease and in some of these, there is no overt
evidence of sarcoidosis elsewhere in the body. Patients develop multifocal or diffuse leptomeningeal granulomas that
may cause nonspecific meningeal symptoms (eg, headache,
stiff neck), mentation changes, hydrocephalus, cranial neuropathies, hypothalamic dysfunction, and pituitary abnormalities.63,64 Sarcoid meningitis may be acute but is more often
chronic. Single or multiple parenchymal granulomas may
also develop. The treatment of sarcoidosis is usually corticosteroids but additional immunosuppressive therapy with
methotrexate, azathioprine, or cyclosporine may be required
in unresponsive cases. The prognosis is variable but generally
good.
Behçet disease is a chronic relapsing syndrome characterized by the clinical triad of oral ulcerations (essentially
the sine qua non for diagnosis), genital ulcerations, and
uveitis. Most cases are reported from Eastern Mediterranean
countries and Japan. Although anterior uveitis (eg, acute
bilateral nongranulomatous iridocyclitis) with hypopyon may
occur, posterior uveitis develops in most patients.58,65 Although ocular inflammation is seldom the initial manifestation of the disease, bilateral uveitis ultimately develops in
approximately 70% of patients. Retinal vasculitis, usually
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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 neuroBehçet becomes important because of its prognostic value as
it indicates severe and possibly fatal disease.67 The treatment
is generally immunosuppression therapy with systemic corticosteroids, chlorambucil, cyclophosphamide, azathioprine,
and cyclosporine.
Vogt-Koyanagi-Harada (VKH) syndrome consists of
2 clinical entities: an anterior granulomatous iridocyclitis
associated with poliosis, vitiligo, alopecia, and dysacusis
(summarized by J. Lawton Smith’s pneumonic, “Too bad if
you got PUVAD”) described by Vogt and Koyanagi and a
posterior granulomatous choroiditis with multifocal serous
retinal detachment, meningeal findings, and cerebrospinal
fluid pleocytosis described by Harada. The 2 clinical entities
combine to make a clinical syndrome characterized by panuveitis, neurologic impairment, and skin changes.68,69 The
disease usually affects darkly pigmented Asian, American
Indian, Hispanic, or Afro-American adults; it is only rarely
seen in Caucasians. The syndrome can be divided into 4
clinical phases. The first phase or prodromal phase consists of
a flu-like illness associated with meningeal involvement manifesting as meningismus, headaches, mental status changes,
cerebrospinal fluid pleocytosis, tinnitus, and dysacusis.69,70
An autoimmune attack against melanin containing cells in the
cochlea and meninges causes these symptoms.71 The second
or uveitic phase is associated with acute granulomatous
iridocyclitis, vitritis, optic disc edema, and multiple serous
retinal detachments. The anterior iritis is usually bilateral
with mutton-fat keratic precipitates, aqueous cell and flare,
peripheral anterior synechiae, depigmentation of the perilimbus (Sugiura sign), iris nodules, cataracts, and glaucoma.68,69
Anterior and posterior uveitis may occur independently or
simultaneously. Posterior segment findings include vitritis,
disc swelling, and retinal hemorrhages and exudates. Recurrent bilateral serous retinal detachments, most commonly
inferiorly and multiple, are essentially pathognomonic for the
disease. The third or convalescent phase of the disease is
associated with subsidence of the uveitis but with the onset of
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The Neurologist • Volume 10, Number 4, July 2004
skin manifestations and diffuse depigmentation of the choroid. Choroidal pigment decreases resulting in a mottled
“sunset glow” depigmented fundus and multiple peripheral
yellowish-white lesions (Dalen-Fuchs nodules) occur in the
inferior peripheral retina. Cutaneous manifestations include
alopecia, vitiligo, and poliosis (whitening) of the eyebrows,
eyelashes, and hair of the head. The fourth phase of the
disease consists of continuous recurrent inflammatory attacks
characterized primarily by anterior uveitis. The major ophthalmic complications of the disease occur most often in this
recurrent phase. Corticosteroid therapy is generally the first
line of treatment but poorly responsive cases require azathioprine, cyclophosphamide and cyclosporine.
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a disease of unknown etiology typically
affecting young adults 20 to 30 years of age without gender or
racial predilection. It often begins with a prodromal phase of
nonspecific upper respiratory complaints followed by sudden
loss of central vision. Fundus examination shows multiple
round, discrete, pale yellow-white lesions in the posterior pole at
the level of the retinal pigment epithelium.72 Both eyes are
usually affected and spontaneous recovery usually occurs within
3 weeks though mottling of the retinal pigment epithelium may
be permanent. Older patients, however, may have a less favorable prognosis. Patients with APMPPE occasionally have other
ocular findings including iridocyclitis, corneal thinning, retinal
vasculitis with serous retinal detachment, and optic neuritis.58
Some patients with APMPPE have neurologic manifestations
including headache, meningoencephalitis, cerebrospinal fluid
pleocytosis, tinnitus, hearing loss, and cerebral vasculitis with
stroke.58,73–75 Fortunately, cerebral vasculitis occurs rarely, but
immunosuppressive treatment should be considered if this leads
to strokes.76
NEOPLASTIC AND PARANEOPLASTIC
ETIOLOGIES OF THE UVEO-MENINGEAL
SYNDROME
Lymphoma may affect both ocular structures and the
meninges. Categories of intraocular lymphoma include: 1)
Primary non-Hodgkin malignant lymphoma of the CNS with
ocular involvement primarily of the vitreous or retina; 2)
Secondary or metastatic intraocular involvement in systemic
non-Hodgkin lymphomas, in which the uveal tract is most
frequently affected; 3) Lymphoid hyperplasia (or lymphoid
tumor) of uvea; 4) Angiotropic lymphoma (formerly neoplastic angioendotheliomatosis); and 5) Hodgkin disease and
mycosis fungoides.
Primary Ocular-CNS non-Hodgkin Lymphoma may
present with neurologic or ocular findings.77–79 Twelve to
15% of primary CNS lymphoma patients present with associated ocular signs or symptoms while a further 10 to 20% of
primary CNS lymphoma patients eventually develop ocular
findings. On the other hand, 80 to 90% of primary ocular
© 2004 Lippincott Williams & Wilkins
Uveo-Meningeal Syndromes
lymphoma patients concurrently or subsequently develop
CNS or systemic involvement while only 10 to 20% stay
ocular. Ocular lymphoma (usually a large B-cell lymphoma)
appears to arise primarily in the vitreous and subretinal
pigment epithelial space and only secondarily extends into
the retina, choroid, and optic nerve. Patients with primary
CNS large-cell lymphoma may present only with visual
signs. Although any part of the visual system may be involved, the most common ocular presentation is uveitis. Both
eyes are usually affected although the disease may begin
monocularly. Patients typically complain of mild decreased
vision or “floaters” in one or both eyes associated with mild
to moderate unilateral or bilateral uveitis unassociated with
eye pain or redness. Vitritis is always present but there may
be cells in the anterior chamber as well. Some patients either
concurrently or subsequently develop multifocal yellow-orange or white infiltrates beneath the retina or retinal pigment
epithelium. Other patients develop exudative retinal detachments produced by subretinal pigment epithelium collections
of tumor cells, retinal vasculitis, retinal artery occlusions,
retinal or vitreous hemorrhages, or retinal necrosis.
One should consider the diagnosis of primary ocularCNS lymphoma in patients 40 years or older with bilateral
vitritis that fails to respond to treatment. Also consider this
diagnosis if vitritis accompanies neurologic symptoms. Primary CNS lymphoma usually manifests as focal or multifocal
parenchymal lesions but may be limited to the meninges.80
Other forms of lymphoma may cause an uveo-meningeal syndrome.77 Systemic non-Hodgkin lymphoma with
secondary (metastatic) ocular involvement may present as
anterior uveitis with hypopyon or hyphema but more commonly with diffuse choroidal infiltration (Fig. 15) or a choroidal mass. Systemic visceral or lymph node involvement
precedes ocular involvement in approximately 57% of patients though bilateral uveal lesions may occasionally be the
first manifestation of lymphoma. Angiotrophic large cell
lymphoma or intravascular lymphomatosis may also
present with decreased visual acuity, cortical blindness, small
white retinal or choroidal infiltrates, retinal pigment epithelial
changes, retinal artery occlusions, retinal hemorrhages, retinal vascular sheathing, vitritis, or iridocyclitis.
Metastatic carcinoma to the eye is generally regarded
as the most common intraocular malignant tumor. Because of
the distribution of ocular blood flow, most intraocular metastases involve the choroid and present with yellowish-white,
round or oval lesions. Exceptionally metastatic carcinoma to
the eye may present with infiltration of the retina or even
dispersed vitreous cells.81,82 Lung and breast carcinomas are
the most common sources of metastatic tumors. A uveomeningeal syndrome may be produced by concomitant ocular
metastasis and carcinomatous meningitis.
A paraneoplastic visual disorder with combined optic
neuritis (Fig. 16) and retinitis has been described, usually in
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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.
patients with small-cell lung cancer or, less often, thymoma
or other malignancies. These cases are defined serologically
by the presence of a paraneoplastic IgG autoantibody CRMP5-IgG.83,84 Neurologic findings include chorea, cranial neuropathy, loss of olfaction and taste, peripheral neuropathy,
autonomic neuropathy, cerebellar ataxia, myelopathy, dementia, 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
retinitis documented in 5. Vitreous cells were noted in 9 cases
and diagnostic vitrectomy revealed reactive lymphocytosis in
4 of 4 patients.
APPROACH TO THE PATIENT WITH THE
UVEO-MENINGEAL SYNDROME
Our diagnostic approach to the uveo-meningeal syndromes is summarized as follows:
1. All patients should undergo extensive and complete ocular
and medical histories and examinations to identify any
systemic findings that might suggest a specific diagnosis.
2. The immune status should be determined. Immunocompromised individuals should be evaluated more aggressively for infectious etiologies (eg, Candida, Cryptococcus, Cytomegalovirus).
3. The eye should be scrutinized for distinctive signs of a
specific etiology. Table 3 lists the distinctive signs in
182
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
disease (eg, sarcoidosis, tuberculosis, syphilis). Most patients with a uveo-meningeal process should at least undergo a magnetic resonance imaging (MRI) with gadolinium and a lumbar puncture. Patients from Lyme endemic
areas or with a history of erythema chronica migrans
should be considered for Lyme serology. More specific
TABLE 3. Distinctive Presentations in Uveo-Meningeal
Disease
Optic disc edema with a macular
star figure
Focal chorioretinitis with massive
vitritis (“headlight in the fog”)
Acute retinal necrosis in peripheral
retina
Diarrhea and intermediate uveitis
Hemorrhagic, perivascular necrotic
retinitis
Multifocal serous retinal
detachments
Hypopyon uveitis, genital or oral
ulcers
Acute, multifocal, placoid, pigment
epitheliopathy
Bilateral chronic uveitis in an
elderly patient
Cat scratch disease
Toxoplasmosis
Herpetic disease
Whipple disease
Cytomegalovirus
Vogt-Koyanagi-Harada
Behçet disease
AMPPE
Ocular lymphoma
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The Neurologist • Volume 10, Number 4, July 2004
studies should be directed by the history and examination
and we discourage a “shot-gun” approach to laboratory
testing.
5. Special studies (eg, acid-fast-staining, polymerase chain
reaction testing, cytology) may be necessary in cases
where routine laboratory and radiographic tests are unremarkable. In some cases, the diagnosis requires vitreous or
meningeal biopsy. The least invasive site for tissue diagnosis should be biopsied in patients with multisystem
involvement.
6. Treatment should be directed at the causative agent and
appropriate consultation should be obtained for inflammatory (eg, rheumatology), infectious (eg, infectious disease), neoplastic (eg, oncology) etiologies. Patients with
uveo-meningeal processes typically require a multidisciplined approach to establish the diagnosis and formulate
an effective treatment plan. It is incumbent upon the
primary physician to involve appropriate consultants and
direct the work-up of these complex patients. Utilizing a
thoughtful, methodical approach, a correct diagnosis can
be established in the majority of these cases.
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