HPI
A 7-year-old male was brought in by his mother after recurrent symptoms of left eye pain, tearing, redness, and photophobia for the past 2 weeks. He was initially seen 2 weeks ago by another eye care provider for an urgent visit and was found to have 1+ fine keratic precipitates, 4+ anterior chamber cell, and a 0.5mm hypopyon in his left eye; his right eye exam was unremarkable. He was treated with topical prednisolone acetate 1% (every 1 hour), which improved his symptoms up until 3 days ago when inflammation progressed to involve his right eye. He then presented to the ED and was found to have persistent 0.5+ anterior chamber cell in his left eye and new 4+ anterior chamber cell and a 1mm hypopyon in his right eye. He was discharged with topical prednisolone acetate 1% (every 2 hours OD and 4 times daily OS), topical cyclopentolate 1% (twice daily OU), and scheduled for urgent follow-up to the uveitis clinic.

Past Ocular History
No prior concerns

Ocular Medications
Topical prednisone acetate 1% every 2 hours OD and 4 times daily OS
Topical cyclopentolate 1% twice daily OU

Past Medical History
Seizures
Staring spells
Speech and language delay
Dental caries

Surgical History
Comprehensive Dental Rehabilitation

Past Family Ocular History
None

Social History
Lives at home with mom and stepdad
Attends elementary school

Medications
Divalproex 750 mg daily

Allergies
No known drug allergies

ROS
Worsening vision OU
Eye pain, redness, tearing, and photophobia OU
A complete uveitis-oriented review of systems questionnaire was positive for oral canker sores, not noted by prior providers

Ocular Exam

Visual Acuity (cc)
OD:20/80
OS:20/300

IOP (iCare tonometry)
OD: 7 mmHg
OS: 16 mmHg

Pupils
OD: 8mm in dark; 6mm in light; round; reactive to light, no APD
OS: 8mm in dark; 6mm in light; round; reactive to light, no APD

Extraocular Movements
OD: Full
OS: Full

Confrontational Visual Fields (Toys)
OD: Full
OS:Full

Slit Lamp:

	RIGHT EYE	LEFT EYE
External	+1 injection	1+ injection
Lids and Lashes	Normal	Normal
Conjunctiva/Sclera	White and quiet	White and quiet
Cornea	Diffuse dusting	Clear, no keratic precipitates
Anterior Chamber	Deep, 4+ cell, 0.5mm hypopyon	Deep, occasional cell
Iris	Posterior synechiae at 0300, 0500-0700, 0900, 1100	Few posterior synechiae scattered at 0300, 0600, 0900
Lens	Clear	Clear
Anterior Vitreous	2-3+ AV cell, 2+ haze	2-3+ AV cell

Dilated Fundus Examination:

	RIGHT EYE	LEFT EYE
Disc	Mild disc blurring	Mild disc blurring
C/D Ratio	0.1	0.1
Macula	Appears largely flat	Appears largely flat
Vessels	No vasculitis noted	No vasculitis noted
Periphery	No inflammatory lesions to brief views	No inflammatory lesions to brief views

Other Imaging Acquired:
Optos

 

Limited wide field Optos imaging shows shadowing from posterior synechiae limiting pupillary dilation OU and 2+ vitreous haze OD. This imaging session was noted by the photographer to be limited due to poor fixation.

Optical Coherence Tomography (OCT)

The right eye shows central intra-retinal fluid without subretinal fluid and largely preserved EZ/IZ (ellipsoid zone and interdigitation zone) photoreceptor bands. The left eye shows significant macular atrophy with 2 visible areas of inner>outer retinal thinning (marked by arrows) as well as generalized loss of the central EZ/IZ bands in the outer retina.

Additional Lab Results

CBC: Unremarkable
CMP: Unremarkable
Lab Test +/– (Associated Disease):
HLA-B51+ (diagnosis spoiler), RPR– (syphilis), TPPA– (syphilis), QTB– (tuberculosis), ANA– (broad autoimmune marker), RF– (rheumatoid arthritis), HLA-B27– (psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease, reactive arthritis), ACE– (sarcoidosis), Lysozyme– (sarcoidosis), CCP– (rheumatoid arthritis), ANCA– (vasculitis marker), Urine β2-microglobulin– (tubulointerstitial nephritis and uveitis)

Diagnosis

This is a 7-year-old male with history of seizures and recurrent oral canker sores who presents with photosensitivity OU, anterior/intermediate uveitis OD with CME, and panuveitis OS with notable features (hypopyon, areas of full thickness retinal thinning suggestive of prior occlusive retinal vasculitis). Uveitis workup was notable for a positive HLA-B51 test. This constellation of findings is most concerning for Behçet’s Disease (BD), a rare multisystem autoimmune vasculitis.¹

Differential Diagnosis

Juvenile Idiopathic Arthritis (JIA)
While JIA can present with uveitis in up to 20% of cases, inflammation is usually limited to the anterior segment, unlike this case with extensive posterior segment involvement discovered on OCT.2 Furthermore, JIA uveitis is commonly associated with joint pain, joint swelling, and positive lab findings for ANA rather than HLA-B51.

Tubulointerstitial Nephritis and Uveitis (TINU)
Although bilateral panuveitis in a young patient is also a common presentation for patients with TINU, evidence of kidney disease such as flank pain, nephritis, or a positive urine β2-microglobulin would also be expected for this diagnosis.

HLA-B27 Spectrum Disease
HLA-B27 includes a complex overlap of disease entities including psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease, and reactive arthritis. It can present with similar symptoms of anterior uveitis and hypopyon; however, it does not commonly include posterior segment involvement and HLA-B27 serology would be positive. Of note, the hypopyon of Behçet’s Disease has been described uniquely as a “shifting hypopyon” that moves with head position because of a lack of fibrin in the anterior chamber when compared with the fibrinous reaction and static hypopyon seen in HLA-B27.3

Systemic Lupus Erythematous (SLE)
SLE also can present with ocular inflammation and mucosal ulcers like in our patient, but the large majority of these patients are ANA positive. Furthermore, a history of recurrent skin lesions, joint pain, fatigue, and fevers are expected symptoms in these patients.

Sarcoidosis
Sarcoidosis can also present with autoimmune panuveitis. Remember, sarcoidosis should be in every differential for uveitis as it is one of the “Great Masqueraders” due to its variability in presentation. Sarcoid uveitis, however, would likely present with granulomatous features (mutton-fat keratic precipitates, Koeppe/Busacca/Berlin iris nodules, granulomas in the vitreous/retina/choroid, or tache de bougie perivascular inflammation), while Behçet’s uveitis is classically nongranulomatous. Furthermore, it often presents with other system involvements such as the skin, bone, lung, or cardiac disease. Sarcoid biomarkers, such as ACE and lysozyme, may be positive. In the present case, CNS sarcoidosis should also be considered given the patient’s history of seizures.

Infection
Infectious diseases such as tuberculosis, syphilis, Lyme disease, toxoplasmosis, cytomegalovirus, herpes virus, or HIV can induce ocular inflammation. However, given this patient’s negative lab markers for infectious pathologies and other absent symptoms such as fevers, recent illness, or sick contacts, infection is less likely.

Allergic Conjunctivitis
While this patient’s presentation of bilateral eye pain, tearing, and redness can sometimes result from allergies, the initial slit lamp exam with evidence of intraocular inflammation rules out this more benign differential.

Definition
Behçet’s Disease is a rare systemic vasculitis characterized by oral aphthous ulcers, genital ulcers, skin lesions, arthritis, gastrointestinal issues, and ocular inflammation.¹ This autoinflammatory disorder was first reported in 1937 by Dr. Hulusi Behçet, a dermatologist from Istanbul who was treating three patients with recurrent genital ulcers, mouth ulcers, and iritis.¹ Since its discovery, BD has been increasingly documented across the world with a dominant prevalence in East Asia, the Middle East, and the Mediterranean.² Present in up to 70% of BD cases, ocular Behçet’s most commonly presents as a bilateral nongranulomatous panuveitis.³ Among all features of BD, eye involvement is widely regarded as the most concerning finding because it is strongly associated with permanent vision loss.³

Examination
Early symptoms of BD are often nonspecific and may include eye redness, pain, photophobia, or reduced visual acuity; however, prompt diagnosis of ocular involvement is paramount to diminish the risks of blindness.³ Slit lamp findings can include anterior chamber cells, anterior vitreous cells, ephemeral pearl-like retinal lesions, posterior synechiae, and mobile hypopyons—a special hypopyon that shifts with head position and is unique to BD.^3,4 It is also important to note that in our patient, posterior synechiae was not observed until the patient’s eyes were dilated. This phenomenon sometimes occurs because lens adhesions may be hidden until they are exposed following dilation and contraction of the iris (and is a reminder that all patients with uveitis must be dilated for a complete exam).⁵ Compared to other uveitic processes, less common findings in BD include isolated anterior uveitis, (mutton-fat) keratic precipitates, band keratopathy, cataracts, and scleritis.⁴ Alongside a thorough physical examination, obtaining a detailed history for symptoms such as recurrent oral ulcers, genital ulcers, arthritis, gastrointestinal problems, or skin lesions can help narrow this diagnosis.¹

Diagnostics
Given the ambiguous presentation of BD, a workup with various diagnostic techniques including OCT, fluorescein angiography, and lab testing is essential.⁴ OCTs are extremely valuable for their ability to provide detailed cross-sectional imaging of the retina.^4,6 Posterior segment abnormalities, like CME and retinal thinning in our patient, are the most critical signs for potential vision loss and require early detection.^6,7 Fluorescein angiography can also provide insights into the extent of retinal vasculitis and occlusions, which are both indicative of significant blood vessel damage.⁴ In regard to lab testing, HLA-B51 is the most important genetic factor for BD and can significantly increase both the odds of disease development and severity.^8,9 Additionally, infectious and rheumatological work up is also important to rule out other differential diagnoses. Lastly, a less common, but highly specific, clinical test for Behçet's disease is the pathergy test.¹⁰ In this exam, a sterile needle prick or saline injection is administered to the skin, and a positive result is indicated by the formation of a small pustule at the injection site after 24 hours.¹⁰

Treatment
Medication therapies for ocular Behçet’s includes topical corticosteroids (prednisolone acetate or difluprednate), antimetabolites (azathioprine, methotrexate, or mycophenolate are common), and TNFα inhibitors (adalimumab, infliximab). Calcineurin inhibitors (cyclosporine, tacrolimus) may be used in severe cases, but their use is becoming less common in practice due to their side effect profiles.¹¹ Topical corticosteroids serve as effective agents during acute anterior inflammation. However, due to side effects from chronic steroid use (cataract and IOP elevation), patients are often transitioned to long-term immunomodulatory therapies for disease maintenance.¹¹ As mentioned earlier, CME in the good eye without occlusion is an extremely concerning finding because it is indicative of potential permanent vision loss in this patient’s monocular eye. In addition to vigilant OCT monitoring of the macula, emerging studies have shown that TNFα inhibitors are especially effective in the treatment of Behçet’s-associated CME.⁴ Theories for this phenomenon are attributed to TNFα’s prominent activity in eyes with BD compared to other uveitic diseases such as Vogt-Koyanagi-Harada or HLA-B27 syndromes.¹²

1. Which of the following findings, even when prominent, may be undetectable or hidden despite a thorough non-dilated slit-lamp exam?
a. Hypopyon
b. Conjunctivitis
c. Posterior synechiae
d. Cataracts

2. Which of the following signs is most concerning for irreversible vision loss in a patient with Behçet’s uveitis?
a. Oral ulcers
b. Photophobia
c. Mobile hypopyon
d. Cystoid macular edema

3. Which of the following lab findings is associated with Behçet’s Disease?
a. HLA-B51
b. HLA-B27
c. Antinuclear antibody
d. Rheumatoid factor

4. After identifying CME on OCT in a patient with Behçet’s Disease, you start patient on methotrexate but do not notice any regression or improvement of CME. What medication would serve as the most effective additional treatment to target CME?
a. Cyclosporine
b. Azathioprine
c. Anti-VEGF injections
d. Adalimumab

1. Which of the following findings, even when prominent, may be undetectable or hidden despite a thorough non-dilated slit-lamp exam?

C. Posterior synechiae
In the present case, the initial exam of pupils described them as round with no identification of posterior synechiae. However, following dilation, the slit lamp exam demonstrated obvious and extensive posterior synechiae in both eyes. This phenomenon occurred because posterior synechiae can be exposed when the iris contracts following dilation, which can expose adhesion points to the lens that were otherwise imperceptible.⁵

2. Which of the following signs is most concerning for irreversible vision loss in a patient with Behçet’s uveitis?

D. Cystoid Macular Edema
Cystoid macular edema, which can effectively be imaged on OCT, is strongly associated with severe vision loss and is one of the most concerning findings in patients with Behçet’s Disease.⁴ Other signs of posterior segment disease also serve as ominous signs for potential vision loss and include retinal vasculitis, branch retinal vessel occlusions, or optic nerve atrophy.⁶

3. Which of the following lab findings is associated with Behçet’s Disease?

A. HLA-B51
HLA-B51 serves as the most important genetic marker for Behçet’s Disease. It has been found to be prevalent in up to 75% in certain populations with Behçet’s Disease, compared to a 15-20% prevalence in nonaffected individuals.⁸ Furthermore, it has been reported that BD patients with HLA-B51 undergo more intense disease courses.^8,9

4. After identifying CME on OCT in a patient with Behçet’s Disease, you start patient on methotrexate but do not notice any regression or improvement of CME. What medication would serve as the most effective additional treatment to target CME?

D. Adalimumab
TNFα blockers such as adalimumab and infliximab are extremely effective in the treatment of Behçet’s-associated cystoid macular edema.¹¹ TNFα has been shown to be an important molecule in the pathophysiology of ocular Behçet’s, especially in eyes with posterior uveitis.¹² In some investigations, they have demonstrated that TNFα levels were very abundant in the aqueous humor of BD patients, more so than other inflammatory diseases such as Vogt-Koyanagi-Harada or HLA-B27 diseases.¹²

References
1. Adil A, Goyal A, Quint JM. Behcet Disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; February 22, 2023.
2. Davatchi F. Behcet's disease: global perspective. Indian J Rheumatol. 2007;2(2):65-71.
3. Zając, Hanna, and Anna Turno-Kręcicka. “Ocular Manifestations of Behçet's Disease: An Update on Diagnostic Challenges and Disease Management.” Journal of clinical medicine. vol. 10,21 5174. 5 Nov. 2021
4. Tugal-Tutkun, Ilknur et al. “Review for Diagnostics of the Year: Multimodal Imaging in Behçet Uveitis.” Ocular immunology and inflammation vol. 25,1 (2017): 7-19.
5. Belliveau, Michel J, and Brian W Arthur. “Dilating pupils.” CMAJ : Canadian Medical Association journal; journal de l'Association medicale canadienne vol. 183,12 (2011): 1400.
6. Ozdal, P C et al. “Posterior segment involvement in ocular Behçet's disease.” European journal of ophthalmology. vol. 12,5 (2002): 424-31. doi:10.1177/112067210201200514
7. Basic and clinical science course (BCSC), Section 9: Intraocular Inflammation and Uveitis, San Francisco: American Academy of Ophthalmology; 2014
8. Takeno, Mitsuhiro. “The association of Behçet's syndrome with HLA-B51 as understood in 2021.” Current opinion in rheumatology. vol. 34,1 (2022): 4-9.
9. de Menthon, Mathilde et al. “HLA-B51/B5 and the risk of Behçet's disease: a systematic review and meta-analysis of case-control genetic association studies.” Arthritis and rheumatism. vol. 61,10 (2009): 1287-96.
10. Davatchi F, Chams-Davatchi C, Ghodsi Z, Shahram F, Nadji A, Shams H, Akhlaghi M, Larimi R, Sadeghi-Abdolahi B. Diagnostic value of pathergy test in Behcet's disease according to the change of incidence over the time. Clin Rheumatol. 2011 Sep;30(9):1151-5.
11. Barroso-García, Nuria et al. “Anti-TNF vs tocilizumab in refractory uveitic cystoid macular edema due to Behcet's disease. Multicenter study of 49 patients.” Seminars in arthritis and rheumatism. vol. 58 (2023): 152153.
12. El-Asrar, Ahmed M Abu et al. “Cytokine profiles in aqueous humor of patients with different clinical entities of endogenous uveitis.” Clinical immunology (Orlando, Fla.) vol. 139,2 (2011): 177-84.