Panuveitis is also called diffuse uveitis. It refers to a condition in which inflammation affects the entire uvea without being localized to the anterior, intermediate, or posterior parts.
According to the classification of the Standardization of Uveitis Nomenclature (SUN) Working Group, uveitis is anatomically divided into the following four types6).
Uveitis is further classified by etiology into endogenous (non-infectious) and exogenous (infectious), and by nature into granulomatous and non-granulomatous. Panuveitis can span across these classifications.
The incidence and prevalence of uveitis vary by region and study, and it is one of the important causes of visual impairment in adults. Panuveitis is one of the leading causes of blindness and visual impairment.
QHow is panuveitis different from other types of uveitis?
A
Anterior uveitis mainly involves inflammation localized to the iris and ciliary body, intermediate uveitis to the vitreous, and posterior uveitis to the choroid and retina. Panuveitis is the most extensive type, with inflammation affecting all these areas, and the underlying cause is often systemic.
Panuveitis presents a variety of findings from the anterior to the posterior segment.
Anterior Segment Findings
Keratic precipitates: Deposits of inflammatory cells on the corneal endothelium. They appear mutton-fat in granulomatous uveitis and fine dust-like in non-granulomatous uveitis.
Anterior chamber cells and flare: Protein leakage and inflammatory cell infiltration due to breakdown of the blood-aqueous barrier. Graded from 1+ to 4+.
Hypopyon: White purulent exudate consisting of inflammatory cells sedimented in the inferior anterior chamber.
Iris nodules: Koeppe nodules (at the pupillary margin) and Busacca nodules (on the iris surface) are observed in granulomatous inflammation.
Posterior synechiae: Adhesion between the iris and the anterior lens capsule. Can cause pupillary block.
Posterior segment findings
Vitreous opacity: diffuse opacity. In sarcoidosis, snowball and string of pearls opacities are characteristic.
Retinal vasculitis: vascular dilation, tortuosity, and sheathing. In sarcoidosis, segmental periphlebitis is observed.
Optic dischyperemia and swelling: commonly observed in many types of uveitis.
In uveitis associated with sarcoidosis, panuveitis is the most common type even in pediatric studies, and interestingly, it has been reported that anterior segment inflammation is non-granulomatous in most panuveitis cases7).
QWhat are the possible complications?
A
Frequent complications include secondary glaucoma, complicated cataract, and cystoid macular edema. The causes of secondary glaucoma are diverse, including trabecular meshwork clogging/inflammation, angle nodules, peripheral anterior synechiae, and steroid response.
Panuveitis can be caused by various factors. It is broadly classified into infectious, non-infectious (autoimmune/inflammatory), neoplastic, and traumatic types.
Sarcoidosis: A systemic disease characterized by non-caseating granulomas. It is the most common cause of uveitis in Japan. The International Workshop on Ocular Sarcoidosis (IWOS) has proposed seven signs: mutton-fat keratic precipitates, iris nodules, vitreous snowball opacities, multiple peripheral chorioretinal lesions, segmental periphlebitis, and optic nerve head nodules 7). Involvement of the anaerobic bacterium Propionibacterium acnes has also been suggested.
Behçet’s disease: Characterized by oral aphthous ulcers, genital ulcers, and recurrent panuveitis. Retinal vasculitis (occlusive) is the main cause of visual impairment, and non-granulomatous hypopyon may be observed. An association with HLA-B51 is well established.
Vogt-Koyanagi-Harada (VKH) disease: A T-cell-mediated autoimmune disease directed against melanocyte-containing tissues. It presents with bilateral panuveitis, along with meningeal irritation, hearing loss, and skin vitiligo. There is an association with HLA-DR4. Early stages show serous retinal detachment and choroidal folds, while late stages exhibit a sunset glow fundus.
Sympathetic ophthalmia: Bilateral granulomatous panuveitis that develops after penetrating trauma or multiple vitreoretinal surgeries. It is caused by immune sensitization to melanin-associated proteins within uveal tissue.
Inflammatory bowel disease (IBD): Panuveitis rarely occurs in association with Crohn’s disease or ulcerative colitis5). In Crohn’s disease, it is hypothesized that autoantibodies against intestinal antigens cross-react with ocular tissues5).
Syphilis: Caused by Treponema pallidum infection, it presents with a wide variety of ocular findings, earning it the nickname “the great imitator.” During the systemic dissemination stage, bilateral posterior uveitis or panuveitis is most common8). In one study, granulomatous iridocyclitis accounted for 46%, non-granulomatous iridocyclitis for 25%, and panuveitis for 13% of cases8).
Tuberculosis: Intraocular inflammation occurs due to direct infection by Mycobacterium tuberculosis or an immune-mediated hypersensitivity reaction to tuberculous antigens. Findings include mutton-fat keratic precipitates, vitritis, choroidal nodules, and retinal vasculitis.
Toxoplasmosis: The most common cause of infectious retinitis in immunocompetent individuals. It often results from reactivation of congenital infection, with a peak incidence between 10 and 35 years of age.
Intraocular malignant lymphoma, retinoblastoma, and leukemia can mimic panuveitis. In intraocular malignant lymphoma, a veil-like vitreous opacity described as “aurora-like” is characteristic. If response to steroids is poor, this must always be included in the differential diagnosis. An IL-10/IL-6 ratio greater than 1 in the vitreous fluid aids in diagnosis.
Cases of bilateral exudative retinal detachment and panuveitis associated with multiple myeloma have been reported, with retinal vascular damage due to hyperviscosity syndrome (HVS) and direct infiltration of neoplastic plasma cells proposed as etiologies1).
Panuveitis following COVID-19 mRNA vaccination (BNT162b2) has also been reported. A 68-year-old woman who received a booster vaccination two days after cataract surgery developed acute panuveitis on the third postoperative day, presenting with findings similar to acute postoperative endophthalmitis4). Cultures were negative, and given the temporal association with vaccination, rapid visual recovery (from hand motion to 20/80 within 48 hours), and complete recovery to 20/20 after 19 days, vaccine-related immune inflammation was suspected as the cause4).
QCan Crohn's disease cause uveitis?
A
Ocular inflammatory disease occurs in 0.3–13% of IBD patients5). Anterior uveitis is most common, but panuveitis can also occur rarely. Young age, female sex, colonic involvement, and family history are considered risk factors for ocular complications5).
The diagnosis of panuveitis is based on a careful medical history and systematic ophthalmic examination, combined with systemic evaluation to identify the underlying cause. Particularly in recurrent or bilateral cases, identifying the cause is essential.
Slit-lamp examination: Assess anterior chamber inflammation (cells, flare), characteristics of keratic precipitates (fine vs. mutton-fat), iris nodules, and posterior synechiae. Gonioscopy is used to check for angle nodules or tent-shaped peripheral anterior synechiae.
Fundus examination: Evaluate the degree of vitreous opacity (1+ to 4+), retinal vasculitis, exudates, hemorrhages, and choroidal lesions.
Fluorescein angiography (FA): Effective for detecting increased retinal vascular permeability, neovascularization, and cystoid macular edema. In Behçet’s disease, fern-like fluorescein leakage may be observed even during non-attack periods.
Indocyanine green angiography (IA): In VKH disease, blurring of medium-to-large choroidal vessels and hypofluorescent spots due to choroidal circulatory disturbance are observed.
OCT examination: Useful for detecting cystoid macular edema and serous retinal detachment, as well as evaluating treatment response. Enhanced depth imaging (EDI-OCT) allows assessment of choroidal thickening 9).
Intraocular fluid testing: Detection of viral DNA by PCR of aqueous humor (for herpes iridocyclitis, acute retinal necrosis, cytomegalovirus retinitis) and diagnosis by Q value (ratio of intraocular/serum antibody titers) in toxoplasmosis.
Ultrasound (B-scan): Useful for assessing retinal detachment when vitreous opacity is severe and the fundus cannot be visualized.
Before initiating immunosuppressive therapy, confirm complete blood count, liver and kidney function, QuantiFERON test, chest X-ray, hepatitis B/C serology, and HIV test.
QHow common is uveitis of unknown cause?
A
Approximately 40% of cases are considered unclassifiable with conventional diagnostic techniques. In recent years, advances in multiplex PCR for pathogen DNA and intraocular fluid cytokine testing have led to an increasing number of confirmed diagnoses.
Treatment of panuveitis consists of two main pillars: specific treatment according to the underlying disease and nonspecific treatment to control inflammation.
Used to relieve spasm of the iris sphincter and ciliary muscle, reduce pain, and prevent or break posterior synechiae. Atropine 1% eye drops are a representative agent.
This is the central drug for controlling inflammation and is used according to the route of administration as follows.
Eye drops: Prednisolone 1% or difluprednate 0.05%. Used to control anterior segment inflammation.
Periocular injection: Sub-Tenon injection. Expected to have a local effect on posterior segment inflammation.
Systemic administration: Oral prednisolone (starting at 1 mg/kg/day and tapering). Indicated for bilateral or severe cases. Systemic administration is the standard for acute phases of Vogt-Koyanagi-Harada disease and sarcoidosis.
Syphilis: Penicillin is the first choice. In case of penicillin allergy, tetracycline or erythromycin is used.
Tuberculosis: Standard antituberculosis therapy (isoniazid, rifampicin, ethambutol, pyrazinamide).
Toxoplasmosis: Combination of clindamycin, sulfadiazine, pyrimethamine, co-trimoxazole, atovaquone, azithromycin, etc.
Crohn’s disease-related: Steroid eye drops are basic. For poor responders, sub-Tenon injection or azathioprine may be considered. When associated with active Crohn’s disease, infliximab and adalimumab are effective for both gastrointestinal and ocular symptoms5).
The uvea is a vascular-rich layer covering the inner side of the sclera and consists of the iris, ciliary body, and choroid. The iris is responsible for metabolism of the anterior segment via aqueous humor, the ciliary body secretes aqueous humor, and the choroid supplies nutrients to the outer retina. Although these three structures are topographically separate, they are anatomically continuous, so inflammation in one area can easily spread to other regions.
Mechanisms of non-infectious (autoimmune) panuveitis
In VKH disease, T-cell autoimmunity against melanin proteins is considered the pathogenic mechanism. Infections such as Epstein-Barr virus and cytomegalovirus have been suggested as possible triggers, but the detailed mechanism by which autoimmunity is suddenly induced remains unknown.
In Behçet’s disease, occlusive retinal vasculitis due to non-granulomatous inflammation predominantly involving neutrophils is characteristic, and fluorescein angiography reveals increased capillary permeability as fern-like leakage even during non-attack periods.
In sarcoidosis, non-caseating granulomas of unknown cause are formed. A diverse population of immune cells, including epithelioid cells, macrophages, and lymphocytes, is involved in the pathology, and an excessive immune response to genetic predisposition and environmental antigens (such as Mycobacterium tuberculosis, Cutibacterium acnes, and inorganic substances like silica) is suspected 7).
In endogenous infection, pathogens such as syphilis and tuberculosis reach the eye hematogenously. In tuberculous uveitis, intraocular inflammation occurs not only from direct infection by Mycobacterium tuberculosis but also from an indirect immune-mediated hypersensitivity reaction to tuberculous antigens at distant sites.
Eosinophilic Inflammation and Intraocular Inflammation
Bing et al. (2020) showed that in an animal model of experimental autoimmune uveitis (EAU), uveitis with eosinophilic intraocular infiltration develops even in the absence of both IFN-γ and IL-17A 10). It has been suggested that GM-CSF may drive eosinophilic inflammation as a major effector cytokine.
In panuveitis associated with multiple myeloma, multiple mechanisms are presumed 1).
Direct tumor cell infiltration: Plasma cells directly infiltrate intraocular tissues.
Hyperviscosity syndrome (HVS): Overproduction of immunoglobulins increases serum viscosity, leading to retinal vascular damage.
Immunoglobulin maculopathy (IM): Immunoglobulins accumulate in the neurosensory retina and subretinal space, causing fluid retention due to osmotic gradients1).
QCan uveitis occur after vaccination?
A
Uveitis after various vaccinations, including after COVID-19 mRNA vaccination, has been reported4). A systematic review from 1984 to 2015 identified 289 cases of vaccine-associated uveitis. It is hypothesized that inflammatory cytokines such as IL-6 and TNF-α increase after vaccination, potentially triggering intraocular inflammation4).
Cases of panuveitis associated with idiopathic hypereosinophilic syndrome (HES) have been reported 3). Although ocular findings improve with steroids, eosinophil counts may rise again upon tapering, and mepolizumab (300 mg every 4 weeks), an anti-IL-5 monoclonal antibody, was effective for hematologic control 3). The mepolizumab group had a lower HES relapse rate compared to the placebo group (28% vs 53%), and it has been reported as a safe and effective treatment alternative 3).
Kim et al. (2022) reported a case of panuveitis and choroidal mass associated with systemic Rosai-Dorfman disease (RDD) treated with peginterferon alfa-2b (1.5 μg/kg/week) for 14 months, achieving stabilization of systemic and ocular lesions 2). This may represent a new treatment option for multi-organ RDD that is difficult to control with steroids.
Management of multiple myeloma-related ocular lesions
Nguyen et al. (2024) administered oral steroids and plasma exchange therapy for bilateral exudative retinal detachment and panuveitis associated with multiple myeloma, and observed a decrease in IgA levels (4879→1562 g/L) along with improvement of subretinal and intraretinal fluid on OCT1). After 8 months, complete resolution was noted in the right eye, while residual subretinal fluid remained in the left eye. Understanding the complex pathology involving HVS-related retinopathy, immunoglobulin proteinopathy maculopathy, and inflammation is important for future treatment strategies 1).
Development of noninvasive in vivo observation techniques is underway, utilizing autofluorescence to obtain qualitative information on cells and proteins in the anterior chamber, and applying laser flare cell meters. If inflammatory cell characteristics and protein components infiltrating the eye can be identified noninvasively, the diagnosis and treatment efficacy evaluation of uveitis may greatly advance.
Nguyen NV, Konstantinou EK, Sherif N, et al. Bilateral exudative retinal detachments and panuveitis in a patient with multiple myeloma. Ocul Immunol Inflamm. 2024;32(7):1448-1453.
Kim L, Bavinger JC, Shantha JG, et al. Long-term management of panuveitis and choroidal mass associated with Rosai Dorfman Disease with pegylated interferon. Ocul Immunol Inflamm. 2022;30(5):1078-1082.
Burggraaf-Sánchez de las Matas R, Garijo-Bufort M, Juan-Ribelles B, et al. Panuveitis associated with idiopathic hypereosinophilic syndrome. J VitreoRetinal Diseases. 2025;1-6.
Kung TP, Zhang C, Sieminski SF. Acute panuveitis after COVID-19 mRNA booster vaccination following cataract surgery. Am J Ophthalmol Case Reports. 2022;28:101726.
Senthamizh T, Senthamizhselvan K, Sahoo NK, et al. Panuveitis in a patient with active Crohn’s disease. BMJ Case Rep. 2021;14:e239058.
Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140(3):509-516. PMID: 16196117. doi:10.1016/j.ajo.2005.03.057.
Jones NP. Sarcoid uveitis in children. Ocul Immunol Inflamm. (Sarcoid Uveitis in Children review).
Gonzalez-Lopez JJ, Llorenç V, Adán A, et al. Demystifying ocular syphilis: a major review. Ocul Immunol Inflamm.
Bing SJ, Silver PB, Jittayasothorn Y, Mattapallil MJ, Chan CC, Horai R, Caspi RR. Autoimmunity to neuroretina in the concurrent absence of IFN-gamma and IL-17A is mediated by a GM-CSF-driven eosinophilic inflammation. J Autoimmun. 2020;114:102507. PMID: 32593472. PMCID: PMC7572578. doi:10.1016/j.jaut.2020.102507.
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