What is the Etiology of the Uveitis?

The Work-up of the Uveitis Patient

Ramana S. Moorthy, MD FACS

 Classification

• Non-Infectious Uveitis
– “Auto-immune”

– Underlying systemic immunologic abnormalities

and idiopathic cases account for majority of cases
 Classification
• Infectious Uveitis
– Viral
• Herpes group viridae
• HSV1 and2; VZV, CMV, ?EBV

– Bacterial
• Syphilis
• Tuberculosis
• Lyme disease
• Bartonellosis
• Rickettsial diseases
• **Endophthalmitis
 Classification
• Infectious Uveitis
– Fungal
• Candida
• Aspergillus
• Histoplasmosis
• Coccidioidomycosis, Blastomycosis

– Protozoal
• Toxoplasmosis

– Helminthic
• Toxocariasis
• DUSN
• Onchocerciasis, cysticercosis
 Classification

• Masquerade Syndromes
– Neoplastic

– Non-Neoplastic
 Classification
• Anatomic
– Anterior uveitis
– Intermediate uveitis
– Posterior uveitis
– Panuveitis
• Time Course
– Acute
– Chronic
– Recurrent
Anterior Uveitis
 POLL: What is the most common
anatomic type of uveitis encountered in
clinical practice?
1. Intermediate Uveitis

2. Anterior Uveitis

3. Posterior Uveitis

4. Panuveitis
 What is the Etiology?
Key Points
• The key to determining the cause of the uveitis :
– Obtain an accurate and thorough history and perform a thorough
ophthalmic and physical exam.
• Laboratory testing or tissue biopsy may then confirm and narrow
the spectrum of etiology
– Labs are not a substitute for a thorough history and physical
examination
– However, if infection is suspected, cultures and PCR are diagnostic
and crucial for proper management
– And if neoplasia is suspected, tissue biopsy is essential
 What is the Etiology?
Comprehensive history
• Past medical history
– Medication history – particularly for drug induced uveitis
– History of autoimmune disorders
– Prior ocular surgery

• Complete review of systems

• Family history
• Social history: smoking, travel, occupation, drug use

10
 What is the Etiology?
• Key Considerations
– Review of Systems
– Systemic illness
• Fevers, chills, weight loss
• Other organ systems – Mucocutaneous, lungs, GI tract, GU tract, Lymphatic, Veterenary, Travel
• Poor Nutrition – malnourished, hyperalimentation
• Immunocompromised –
– cancer (leukemia/lymphoma),
– Iatrogenic – chemotherapy, indwelling catheters
– Acquired – HIV

– Local Factors
• Recent surgery
• Trauma
 What is the Etiology?
Examination

• Best corrected visual acuity

• Pupillary function

• Motility, confrontation fields

12
 What is the Etiology?
Examination
• Slit lamp exam

– Conjunctival nodules/granulomas

– Cornea

• Epithelium-dendrites

• Stroma- Infiltrates or cells

• Endothelium

– KPs:

» Size: small, non-granulomatous; large, granulomatous

» Color: white, pigmented

» Distribution: Arlt’s13triangle, diffuse

 What is the Etiology?
Examination
• Slit Lamp Exam
– Anterior Chamber
• Depth – Shallow- ?angle closure
• Cells - ?hypopyon, hyphema, pigment cells
• Flare - ?fibrinous
• Structural changes (peripheral anterior synechiae, rubeosis)

– Iris:
• Color, contour, ? heterochromia, atrophy
• Posterior or anterior synechiae
• Nodules (Koeppe, Busacca)

– Lens: ?cataract

14
 What is the Etiology?
Examination

• IOP

– Applanation tonometry

• Evaluate angle by gonioscopy in patients with elevated IOP,

hypotony

15
 What is the Etiology?
Examination - Fundus
• Macula:

– CME?

– Atrophy?

• Vessels

• Retina

• Choroid

• Optic nerve

• Examine retinal periphery

16
 What is the Etiology?
• Key Considerations
– Laterality
• Unilateral cases – consider HSV, VZV, CMV, Toxocariasis, toxoplasmosis
– IOP elevation (herpetic disease and toxoplasmosis)
– Sectoral iris atrophy – VZV or HSV
– Corneal scarring/edema – HSV and VZV
– Characterisitic clinical features

• Not always helpful

– Many non-infectious entities present unilaterally
» HLAB27+ anterior uveitis
» scleritis
 What is the Etiology?
• Non-Ocular Clinical Clues
– Cutaneous
• Vesicular and/or dermatomal rash
– HSV/VZV

• Palmar or plantar exanthematous rash

– Secondary syphilis

• Erythema chronicum migrans

– Lyme borreliosis

Photographs (1 and 2) courtesy of Debra A. Goldstein, MD

 What is the Etiology?
• Other Cutaneous Signs
– Psoriasis
 What is the Etiology?
• Sarcoidosis
– Glandular Inflammation
• Dacryoadenitis

• Parotitis : Heerfordt’s Syndrome

 What is the Etiology?

– Hypopyon – sterile, infectious, neoplastic

– Infectious
• Toxoplasmosis – unilateral, focal choroditis
• VZV/HSV anterior uveitis – corneal scars, iris atrophy, IOP increased, diffuse KPs
• Late onset endophthalmitis – Pseudophakia, history, capsular opacities
• Aspergillus endophthalmitis– necrotic granuloma in posterior pole and “hyaloidal
hypopyon”)
• CMV retinitis – one of four patterns – “pizza pie”, granular, brushfire, frosted branch
angiitis
• Toxocariasis – peripheral granuloma, focal macular granuloma, diffuse endophthalmitis
 What is the Etiology?

• Still not sure?

• Combine the Historical findings with Pattern Recognition

– Hypopyon – sterile, infectious, neoplastic
– Infectious
• Toxoplasmosis – unilateral, focal choroditis
• VZV/HSV anterior uveitis – corneal scars, iris atrophy, IOP increased, diffuse KPs
• Late onset endophthalmitis – Pseudophakia, history, capsular opacities
• Aspergillus endophthalmitis– necrotic granuloma in posterior pole and “hyaloidal hypopyon”)
• CMV retinitis – one of four patterns – “pizza pie”, granular, brushfire, frosted branch angiitis
• Toxocariasis – peripheral granuloma, focal macular granuloma, diffuse endophthalmitis
 Hypopyon

Rifabutin Endophthalmitis

Pseudohypopyon Behçet disease

 Vitritis

Photograph Copyright to American Academy of Ophthalmology – Focal Points

Toxoplasma Retinochoroiditis

Note: Bartonella focal choroiditis in children can look identical

Tuberculous Uveitis

Photograph courtesy of Debra A. Goldstein, MD 26

 Tuberculosis:
Multifocal Tuberculous Serpiginoid Choroditis
Ocular Bartonellosis

Photograph courtesy of Debra A. Goldstein, MD 28

Cytomegalovirus Retinitis
Necrotizing Herpetic Retinitis

30
(© 2006 Ramana S Moorthy MD. Used by permission.)
What is the Etiology?

Behçet Disease
What is the Etiology?

Vogt-Koyanagi-Harada Syndrome – Acute and Chronic Phases

What is the Etiology?

HLAB27 Associated fibrinous hypopyon uveitis with psoriasis

What is the Etiology?

Photograph courtesy of Debra A. Goldstein, MD.

POLL: Every uveitis patient who has a work –up
should be tested for which conditions?

1. Rheumatoid arthritis and Systemic Lupus

2. HSV, VZV, CMV infection

3. Toxoplasmosis

4. Sarcoidosis, syphilis, and tuberculosis

 What is the Etiology?:
Testing
EVERY UVEITIS PATIENT THAT HAS A WORK-UP SHOULD BE TESTED FOR
SARCOIDOSIS, SYPHILIS, AND TUBERCULOSIS

• Specific tests for syphilis (e.g., FTA-ABS, MHA-tp)

• Sarcoid: CXR, ACE, consider CT chest

• TB: PPD, CXR, interferon gamma release assay (QUANTIferon Gold)

• Other tests based on clinical features (tailored approach)

– e.g., HLA-B27 for acute anterior uveitis

– e.g., ANA for chronic iritis in child

36
Syphilis
 Figure 4 In vitro assays of cell function

Ermann, J. et al. (2015) Immune cell profiling to guide therapeutic decisions in rheumatic diseases
Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2015.71
 Pulmonary Sarcoidosis

http://www.intechopen.com/books/sarcoidosis/clinical-manifestations-of-sarcoidosis
 PCR

Diagnostic Testing in Uveitis : Van Gelder, R. Focal Points . Module 4. 2013. AAO
 What is the Etiology?
• Diagnostic Testing – Combine with clinical appearance
– ALWAYS RULE OUT: Tuberculosis, Syphilis, and Sarcoidosis
– Serology in Infectious causes
• Syphilis – Treponemal specific tests - most useful
• Toxoplasma – Anti-Toxoplasma Ab.
– IgG (recurrent); IgM (acquired)

• Quantiferon TB (T-Spot TB)

• Lyme Serology – confirmed by Western Blot
• Toxocariasis – Anti-Toxocara IgG antibody
• Anti-HSV/VZV/CMV antibody titers only helpful if negative for ruling out a
diagnosis
 What is the Etiology?
• Diagnostic Testing – Combine with clinical appearance
– Serology in non-infectious causes
• HLAB27 – helpful in acute fibrinous and hypopyon iridocyclitis
• ACE and Lysozyme – only marginally helpful
• Urinary Beta-2 microglobulin - TINU
• No serologic tests for Sympathetic Ophthalmia, VKH, Behçet
disease
• RF , ANA, ant- Ds DNA, pANCA, cANCA - Scleritis
• ANA and RF – JIA associated uveitis / uveitis in children
Confirming Etiology is Infectious:
– Diagnostic Testing
• Cultures and Gram stains
– Vitreous and Aqueous
– Useful for bacteria and fungi not for viridae
• PCR can be done to identify the following:
– HSV I&II, VZV, CMV, EBV
– Toxoplasma gondii
– Mycobacterium tuberculosis (65 kDA sAg )
– Borrelia burgdorferi (41 kda flagellin gene )
– Propionibacterium (Pa1, rPa2, rPa3 antigens)
– Fungi (28S rRNA gene)
– Tropheryma whipelli (16S rRNA gene)
– Intraocular lymphoma (IgH gene)
– Yield varies with site based on clinical presentation
» Aqueous vs. Vitreous
– Pan-fungal, Pan-Bacterial primers avaialable
43
 POLL: Corticosteroids should
never be used alone in the
treatment of infectious uveitis.

1. True

2. False
 POLL; Corticosteroids have no
role in the treatment of infectious
uveitis.

1. True

2. False
Treating Etiology if Infectious:
• Therapy
– Specific Antibiotic - essential
• Anti-viral, anti-bacterial, anti-protozoal, etc.

– Later addition of corticosteroids - essential

• Soon after antibiotic therapy initiated
– Host immune response and inflammation is more damaging than
infectious agent

• Never use corticosteroids alone for suspected infectious uveitis

– Particularly avoid intravitreal, periocular – cannot be removed
 Confirming Etiology is Masquerade:

• Neoplastic Masquerade
– Based on history & exam findings
– Tissue Biopsy is Essential
• Histopathologic Confirmation
• PPV for Intraocular Primary CNS Lymphoma
• Communication with Pathologist - ESSENTIAL

• Non-Neoplastic Masquerade
– Suspect based on history and exam findings
• IOFB, Pigment dispersion syndrome, chronic RD
 POLL: The patient has poor vision, severe anterior chamber
inflammation, small pupil with very limited view of the fundus,
and the labs are pending, you should:

1. Start intraocular corticosteroids

2. Start periocular corticosteroids

3. Start systemic corticosteroids

4. Start Topical corticosteroids

 What is the Etiology?
• Still not sure?
– Do not make it irretrievably worse
• Avoid regional or intraocular corticosteroids
• Choose the most serious infectious or neoplastic condition and treat
– Systemic and/or intraocular anti-microbials
• Frequent topical corticosteroids with cycloplegics
• Oral corticosteroids – if observed closely
• E.g. Hypopyon in an otherwise healthy young male

– Lack of response or worsening to corticosteroids suggests infectious or

masquerade etiology
• Need for diagnostic and therapeutic intervention
– Histopathologic confirmation
 Case 1
– 27 year old white male with floaters in both eyes and shortness of
breath.
– PMHx- Weight loss of 30lbs over 6 months
– Meds – None
– SocHx- Lives in trailer with several cats
– Exam : Va 20/50 both eyes
• Cornea : Granulomatous KPs
• AC- 3+ cells and 2+flare
• Vitreous ; 3+ cells
• Fundus: CME OU and
Case 1
Case 1
Case 1
 Case 1
• Laboratory work up – Negative FTA-ABS,
Quantiferon-TB and PPD, ACE- high normal;
Lysozyme –normal;anti- Bartonella quintana
and henselae IgG and IgM titers- negative
• Radiologic Chest CT- Positive – adenopathy
• Dyspnea – Pulmonary hypertension
Contrasted chest CT demonstrating significantly enlarged
paratracheal lymph nodes (arrows). Multiple other enlarged
mediastinal and retrocrural lymph nodes were present as well.
Contrasted chest CT demonstrating a massively dilated main
pulmonary artery (4.7 cm, thick arrow) and a significantly
enlarged subcarinal lymph node (thin arrow). Multiple other
enlarged mediastinal and retrocrural lymph nodes were
present as well.
Noncontrasted abdomen CT demonstrating a significantly
enlarged liver (20 cm in
craniocaudal length).
Noncontrasted abdomen CT demonstrating a significantly
enlarged left peri-aortic lymph node measuring 3 cm x 2.2 cm
(thin arrow). In addition, multiple other enlarged retroperitoneal
lymph nodes were present.
 Case 1 :

• Physical Exam:
– Lymphadenopathy – Biopsy : granulomatous
inflammation→ Sarcoid; No TB found
– Systemic steroids started : Inflammation
improved then worsened with taper
– Then fevers developed.
 Case 1:

• What Next?
– Infectious ? Non-Infectious? Neoplastic?

• “Tissue is the issue”

• Biopsy What ?
 Case 1:

• Biopsy – Vitreous – Preretinal white material

– Mixed lymphocytes and large macrophages
containing PAS positive material

– PCR – Qualitative + for Tropheryma whipplei

Case 1 : Duodenal Biopsy
 Case 1

• Diagnosis: Whipple’s Disease

• Management: 6 months of therapy with

Rifampin and Bactrim

• Inflammation free of all meds for 5 years.

 Case 2

• 79 year old man with unilateral severe granulomatous anterior

uveitis and vitritis with hazy view of posterior pole and 20/40 vision
LE is treated with intraocular corticosteroids and sent for
evaluation for rapid worsening 2 weeks later
• Va – 20/25 RE; LP LE; Ta-15 RE; 12 LE;
• RE: Pseudophakos
• LE: Pseudophakos; anterior chamber 2+ cells and 1+flare; 4+ vitritis
Case 2
Case 2
Case 2
Case 2
Case 2
Case 2
Case 2
Case 2
 Case 2

• What 2 possibilities are at the top of the list of

causes?
– Necrotizing herpetic retinitis

– Toxoplasmosis
 Case 2

• Treatment?
– Diagnostic pars plana vitrectomy

– PCR for toxoplasmosis; VZV, HSV1 and 2; CMV

– Intravitreal clindamycin 300mcg and ganciclovir

2mg
 Case 2
• Outcome:
– Quantitative PCR positive for Toxoplasma gondii
• Treated with
– Intravitreal clindamycin 300 mcg/0.1 cc– multiple weekly injections
– Systemic Pyrimethamine 25mg BID and Sulfadaizine 500mg QID for 8
weeks and then maintenance Bactrim DS once daily

– 20/100 with CME in left eye

– 20/25 right eye
Case 2
 Case 2

• Lessons Learned
– Never give intravitreal or periocular
corticosteroids without antibiotic coverage if
infection is even remotely suspected

– TISSUE is always the ISSUE for infectious uveitis

 Case 3
• 69 year old white female with painless subacute vision
loss over 1 week in both eyes
• Symptoms : Metamorphopsia and a few floaters; no
photopsias
• PMHx: Hypertension
• POHx : Noncontributory
• ROS: Dyspnea; pleuritic pain; weight loss; arthralgias
 Case 3
• Ophthalmologic Exam
– Va -20/60 OU
– Ta- 14 OD; 12 OS
– Conjunctiva – no injection
– Anterior Chamber : 0.5 cells in each eye; no synechiae
– Vitreous – 1+ cells
– Retina : Subtle disc hyperemia and serous retinal detachment
of posterior pole in each eye; no peripheral choroidal lesions
seen; no vasculitis
Case 3 – Right Eye FA
Case 3 – Left Eye FA
 Case 3
• What Next?
– ROS – No hearing loss, vitiligo, poliosis, headache
or meningismus
– Serology
• PPD skin test, FTA, ACE, Lysozyme
• Chest X-ray – Dyspnea
• ?ANA
 Case 3
• Laboratory Work-up
– FTA-Abs – Negative; PPD – Negative; ACE and
Lysozyme – normal; ANA > 1:4000+; +dsDNA
– Chest X-ray – Bilateral pleural effusions
– Pleural Fluid – High positive ANA titer >1:4000
– Urinalysis – no WBC casts; Mild Proteinuria
– Serum :BUN and Creatinine - normal
 Case 5
• Diagnosis : SLE – lupus choroidopathy
– Diagnostic criteria - >4/11 met
• Therapy :
– Systemic corticosteroids and Imuran
– Ocular findings resolved in 3 months
– Disease free for 10 years
– Durable remission off all meds except low dose plaquenil
for last 5 years
Case 4
 Case 4

• OPHTHALMOLOGIC EXAMINATION

• Visual acuity LE:(CF) at one foot; RE 20/20. The right eye

was unaffected.

• Biomicroscopy:
– RE- normal;

– LE- Fine inferior KPs, 1+ cells in AC; no synechiae ; 1+ vitreous

cells

• Retina – RE-normal; LE:

Case 4
Case 4
Case 4
Case 4
Case 4
Case 4
Case 4
 Case 4
• What is the differential diagnosis?
– Iatrogenically Immune compromised ?
– Subretinal abscess
• Fungal - Aspergillus, tuberculosis, Bacterial

– Primary CNS Lymphoma

• Lab Testing : Serology : IgG and IgM antibodies against
Toxoplasma gondii, Toxocara spp, Histoplasma capsulatum,
Aspergillus spp, Candida spp, and Coccidioides immitus
were negative. PPD negative; FTA - negative
 Case 4

• Plan?
– Empiric anti-fungal therapy- IV amphotericin

– Hold Cyclophosphamide therapy, continue oral

prednisone

– 10 days later -→
Case 4
Case 4
Case 4
 Case 4
• Plan Now?
• PPV – vitreous and subretinal biopsy; laser; GFX; intravitreal
ampho B, vancomycin, amikacin, clindamycin
• Biopsy results :
– Histopathologic evaluation – macrophages, lymphocytes, neutrophils
in vitreous and subretinal space
– Gram /Giemsa stains were negative
– PCR negative for toxoplasmosis, HSV1, HSV2, and VZV
– Fungal and bacterial cultures of subretinal material – no growth
Case 4 – 2 months later
Case 4
 Case 4
• Not Infectious!
• Abscess resolved
– total of 27 grams of cyclophosphamide
– Low dose oral prednisone
– Switched to azathioprine for 5 years
– Now on Methotrexate with disease remission for 8
years
GPA with retinal vasculitis and choroiditis
GPA with retinal vasculitis and choroiditis
GPA with retinal vasculitis and choroiditis
GPA with retinal vasculitis and choroiditis
 Case 5
• 64 year old cachectic white female presents with
floaters and blurred vision for 1 month in the right eye.
• PMHx – Squamous cell carcinoma of the lung T1N2M0
treated with radiation and chemorx- considered
controlled; “immunocompromised”
• POHX- Noncontributory
• ROS – smoker 70 pk years; cat at home
 Case 5

• Va- 20/60 RE; 20/20 LE

• Ta-15 RE, 16 LE
• Anterior segment - 0.5 cells in right eye; otherwise
normal
• Vitreous – clumped white vitreous cells RE, Normal LE
• Retina – RE- ; LE normal
Case 5
Case 5
Case 5
Case 5
Case 5
 Case 5
• Differential Diagnosis
– Toxoplasmosis
– Viral retinitis
– Paraneoplastic syndrome – not likely with NSCLC
– Sarcoidosis
• Lab Work up –
– Toxoplasmosis titers IgG and IgM– negative
– FTA- Neg; Quantiferon – Neg; ACE and lysozyme – normal
 Case 5
• Therapy
– Suspicion that this is infectious is high
– Empirically start Oral valacyclovir
• Psychosis after 2 days
• Discontinue medication

– No Progression :
• Patient refused therapy

– After 6 weeks – no change

Case 5
 Case 5
• What Next ?
• Plan PPV and vitreous biopsy
– Intravitreal GCV 2mg, vancomycin, amikacin;
amphotericin; clindamycin
– PCR for toxoplasmosis, HSV1, HSV2, VZV - neg
– Bacterial and fungal cultures - neg
– Cytopathology and Permanent section →
 Case 5

• PPV: Specimens obtained

– Undiluted vitreous sample

– Preretinal membrane

– Vitrectomy cassette
 Case 5
• Gram stain: negative

• CMV PCR: negative

• VZV PCR: negative

• HSV 1 PCR: negative

• HSV 2 PCR: negative

• Aerobic and anaerobic culture: negative

• Fungal culture: negative

 Case 5

Retinal Müller cell

Papanicolaou stain (Low power)

Case 5

Papanicolaou stain (High power)

Case 5

Keratinizing cells,
pleomorphic nuclei,
nuclear irregularity,
hyperchromasia,
increased cellularity
Papanicolaou stain (Low power)
 Case 5
Keratinizing cells,
increased mitoses,
severely dysplastic
squamous cells

Hematoxylin and Eosin stain (Low power)

 Case 5
Features consistent
with squamous cell
carcinoma, although
invasion not noted in
scant tissue specimen

Hematoxylin and Eosin stain (High power)

 Case 5

Positive nuclear staining in

abnormal cells - consistent
with squamous origin

p63 immunoperoxidase stain

 Case 5

POM #3 - Note gliotic area near disc appears less, was removed at vitrectomy, so
no disc involvement and only prepapillary vitreous involvement.
 Case 5

• Patient refused all therapy.

• She presented one year later :

 Case 5

• Not Infectious!

• But Diagnosis Achieved with no harm done

from therapy to patient
 What is the Etiology?
• Steps to Correct Diagnosis
1. Obtain accurate History and Review of Systems
2. Use Non-Ocular Clues
3. Use Pattern Recognition
4. Obtain Laboratory Serology (especially if Infectious)
5. Choose therapies that will improve but not harm
a. Avoid intravitreal and periocular corticosteroid injections if infection suspected
b. Treat the worst possible diagnosis

6. Obtain ocular tissue when

a. Suspicions remain high
b. No response to therapy
c. Fellow eye becomes involved