Rubella is an infectious disease caused by a single-stranded RNA virus (family Togaviridae, genus Rubivirus). It causes inflammatory changes in the eye in both congenital and postnatal infections, and its clinical presentation varies greatly depending on the timing of infection and the pattern of immune response.
Ocular diseases caused by rubella virus are classified into the following three types based on pathogenesis and clinical features.
Acquired rubella-associated uveitis: When adults contract rubella, mild iridocyclitis may occur from the peak to the convalescent phase, and scattered small white spots at the level of the retinal pigment epithelium appear in the posterior pole of the fundus. These disappear spontaneously without scarring after 2 to 3 weeks. Subsequently, stellate or granular opacities may be observed in the macula.
Ocular complications of congenital rubella syndrome (CRS): Rubella infection during early pregnancy (especially the first trimester) directly damages the fetal ocular tissues. Cataracts and rubella retinopathy (salt-and-pepper retinopathy) are the major ocular complications, forming the main complications along with heart disease and hearing loss.
Fuchs heterochromic iridocyclitis (rubella-associated type): This is a chronic unilateral uveitis characterized by the triad of iris heterochromia, iridocyclitis, and cataract. The detection of rubella virus genome in the aqueous humor of patients suggests an association with rubella virus. The specific pathogenesis remains unknown.
In a domestic survey (3,055 cases) of the Uveitis Clinical Practice Guidelines (2019), Fuchs heterochromic iridocyclitis accounted for 0.7% (21 cases)1). Regarding acquired rubella uveitis, reports of ocular symptoms increased after rubella outbreaks predominantly in adult males in 2012 and 2018–2019. The widespread use of the MMR vaccine has drastically reduced new cases of congenital rubella syndrome, and most ophthalmic CRS cases are now limited to past infected generations.
Rubella virus genome has been detected in the aqueous humor of patients with Fuchs heterochromic iridocyclitis, and rubella virus antibody titers (Goldmann-Witmer coefficient) in the aqueous humor are elevated, suggesting some association between the two 2, 3). The pathogenesis is unknown, but a hypothesis has been proposed that persistent intraocular infection is established after rubella infection in early childhood. Not all cases of Fuchs heterochromic iridocyclitis are rubella-related; some cases are negative for aqueous humor PCR.
Clinical findings differ greatly among the three disease types. The characteristics of each are summarized below.
Acquired rubella uveitis
Mild iridocyclitis: Mild flare and cells in the anterior chamber.
Small white spots at the posterior pole of the fundus: Scattered white spots at the level of the retinal pigment epithelium. They disappear spontaneously after 2 to 3 weeks without leaving scars.
Macular opacity: May later present as stellate or granular opacities.
Congenital rubella syndrome (rubella retinopathy)
Salt-and-pepper retinopathy: Presents with a salt-and-pepper appearance characterized by diffuse, fine depigmented spots and pigmented spots mixed together from the posterior pole to the equator.
Stationary lesion: Typically, the retinopathy is stationary without treatment and has little effect on visual function.
ERG abnormalities: Visual function is often preserved, but ERG may show abnormalities.
Complications: May be accompanied by cataract, glaucoma, and microphthalmos.
Fuchs Heterochromic Cyclitis
Fine keratic precipitates (KP): White, fine, stellate KP are diffusely distributed over the entire corneal endothelium.
Diffuse iris atrophy: Check without mydriasis compared to the fellow eye. Note that atrophy becomes less visible after dilation.
No posterior synechiae: The absence of posterior synechiae is an important diagnostic finding.
Koeppe/Busacca nodules: Iris nodules may be observed.
Cataract: Often accompanied by posterior subcapsular cataract, with rapid progression.
In acquired rubella uveitis, symptoms such as blurred vision, mild conjunctival injection, and anterior chamber inflammation may occur during rubella infection. In congenital rubella syndrome, decreased vision due to cataract may appear from infancy. Fuchs heterochromic iridocyclitis often progresses asymptomatically and is frequently discovered due to decreased vision from cataract or floaters (from vitreous opacities).
In Japanese individuals, iris heterochromia (difference in iris color between eyes) is less noticeable due to brown irises. The key to diagnosis is to observe, without mydriasis, diffuse iris atrophy, blurring of iris crypts, and indistinctness of the iris collarette compared to the fellow eye. Since atrophy becomes less apparent after mydriasis, it is important to always perform observation without mydriasis first.
Acquired: Rubella virus enters the eye via the bloodstream during systemic infection, causing intraocular dissemination. The main ocular inflammation is thought to be immune-mediated.
Congenital (CRS): Maternal infection in early pregnancy (especially before 8 weeks) leads to direct damage to fetal eye tissues through the placenta. Rubella virus has high affinity for lens epithelium and retinal pigment epithelium, causing cataracts and retinopathy.
Fuchs heterochromic iridocyclitis: A leading hypothesis is that persistent infection in the anterior chamber after rubella infection in early childhood leads to chronic low-grade inflammation. CD8+ T cell-mediated immune inflammation is thought to induce iris atrophy and neovascularization.
| Disease type | Key tests | Diagnostic points |
|---|---|---|
| Acquired rubella uveitis | Serum rubella IgM antibody, aqueous humor rubella PCR and Q value | History of rubella infection or exposure, timing of onset (peak to convalescent phase) |
| Congenital rubella syndrome (CRS) | Confirm maternal history, infant rubella IgM antibody titer | Salt-and-pepper fundus, cataract, congenital heart disease/hearing loss |
| Fuchs heterochromic iridocyclitis | Clinical ocular findings (iris atrophy, no posterior synechiae, stellate KP), anterior chamber rubella PCR (research) | No specific test. Diagnosis based on ocular findings |
Diagnosis requires investigation of maternal history of rubella infection or rubella vaccination, elevation of rubella antibody titers, and measurement of rubella IgM antibody titers in the infant. Characteristic retinopathy (salt-and-pepper appearance) has high diagnostic value.
There is no specific test for Fuchs heterochromic iridocyclitis; diagnosis is based on ocular findings. The combination of the following findings provides the basis for diagnosis.
Rubella virus PCR in aqueous humor and Goldmann-Witmer coefficient (Q value) are used in research to confirm the association between Fuchs and rubella 2, 3).
| Disease | Key differentiating features |
|---|---|
| HSV/VZV iridocyclitis | Sectoral iris atrophy, decreased corneal sensation, dendritic keratitis |
| Posner-Schlossman syndrome | Paroxysmal high intraocular pressure (40–70 mmHg), recurrent |
| CMV anterior uveitis | Coin-shaped KP, linear KP, CMV-PCR positive |
| Sarcoidosis | Bilateral, mutton-fat KP, systemic findings (skin, lungs, lymph nodes) |
The two can be differentiated by three points: onset timing, clinical presentation, and laboratory findings. Acquired rubella uveitis occurs as iridocyclitis during adult rubella infection (peak to recovery phase) and serum IgM antibody is positive. Congenital rubella syndrome presents with cataracts, salt-and-pepper retinopathy, hearing loss, and heart disease from infancy, and diagnosis is based on maternal history of infection in early pregnancy and the infant’s IgM antibody titer.
In many cases, the condition resolves spontaneously within 2–3 weeks, so observation is the main approach. If iridocyclitis is prominent, the following symptomatic treatments are used.
Rubella retinopathy itself is nonprogressive and often does not require specific ophthalmic treatment. However, the following management is important.
Even with steroid administration for anterior chamber inflammation, complete resolution is difficult, and long-term use increases the risk of complications such as glaucoma. Therefore, it is important to minimize steroid eye drops. Since posterior synechiae do not occur, mydriatic agents are usually unnecessary.
Postnatal rubella infection is almost entirely preventable with the MMR vaccine, and congenital rubella syndrome (CRS) can also be largely prevented by protecting the mother from rubella infection 5). A decreasing trend in the incidence of Fuchs heterochromic iridocyclitis has been reported in areas with widespread vaccination, suggesting that the preventive effect of the rubella vaccine may extend to Fuchs-associated types 7). However, the pathogenesis of Fuchs heterochromic iridocyclitis is not fully understood, and factors other than rubella may also be involved.
When adults are infected with rubella virus, dissemination into the eye occurs during the period of viremia. The main inflammation in the eye is thought to be immune-mediated rather than direct viral infection, and immune responses primarily involving T cells and NK cells cause iridocyclitis and retinal pigment epithelial lesions. The inflammation is self-limiting and resolves within 2–3 weeks as viremia subsides.
If a mother is infected with rubella virus in early pregnancy (especially before 8 weeks of gestation), infection is transmitted to the fetus via the placenta. Rubella virus has a strong affinity for lens epithelial cells and retinal pigment epithelial cells, directly damaging fetal ocular tissues.
Detection of rubella virus genome (RNA) in the aqueous humor of patients 2) and evidence of intraocular rubella virus-specific antibody production (elevated Goldmann-Witmer coefficient) 3) suggest the possibility of persistent rubella virus infection within the eye. The most widely accepted hypothesis is that after rubella infection in early childhood, a low-grade persistent infection is established in the anterior chamber, and subsequent breakdown of intraocular immune tolerance leads to chronic inflammation primarily mediated by CD8+ T cells, inducing iris atrophy, neovascularization, and keratic precipitates. However, many aspects of the specific pathogenesis remain unclear.
de Groot-Mijnes et al. (2006) detected rubella virus RNA by PCR in the aqueous humor of patients with Fuchs heterochromic iridocyclitis and confirmed intraocular rubella antibody production in 75% (48 of 64 cases) of a European cohort 2). This report is considered a pioneering large-scale study demonstrating the association between rubella virus and Fuchs.
Quentin & Reiber (2004) reported elevated Goldmann-Witmer coefficient (Q value) in the aqueous humor of patients with Fuchs heterochromic iridocyclitis, indicating the presence of a rubella virus-specific immune response within the eye 3).
Ruokonen et al. (2010) examined intraocular antibody production against multiple microorganisms in patients with Fuchs heterochromic iridocyclitis and found that intraocular antibody production against rubella virus was the most frequent 4).
Suzuki et al. (2010) performed anterior chamber fluid PCR on Japanese patients with Fuchs heterochromic iridocyclitis, confirmed the detection of rubella virus RNA, and suggested that rubella virus may be the cause of this disease in Japan as well 7).
With the widespread use of the MMR vaccine, the incidence of congenital rubella syndrome (CRS) has nearly disappeared in countries that have introduced the vaccine. Birnbaum et al. (2007) examined the relationship between the rubella vaccination program in the United States and the prevalence of Fuchs heterochromic iridocyclitis, reporting a decreasing trend in the proportion of patients among the vaccinated generation 5). Long-term epidemiological follow-up is expected to clarify the impact of vaccination policy on the incidence of Fuchs.
Winchester et al. (2013) confirmed persistent rubella virus infection in the eyes of patients with Fuchs heterochromic iridocyclitis associated with congenital rubella syndrome 6). This report provides important evidence of a direct link between CRS and rubella-related uveitis.
Advances in multiplex PCR technology using aqueous humor have enabled accurate differentiation among rubella virus, CMV, and HSV. Particularly in Asian populations, there are many reports of CMV-positive Fuchs-like anterior uveitis, and PCR-based classification of disease type (selection of antiviral drugs) may lead to improved treatment outcomes. Antiviral therapy such as ganciclovir eye drops for rubella-associated Fuchs heterochromic cyclitis has also been attempted, but its efficacy is not yet established.
In a Slovenian cohort study by Stunf et al. (2012), high concordance of intraocular rubella antibody production was confirmed in patients with Fuchs heterochromic cyclitis 8). These data strongly support the possibility that rubella virus is the main cause of Fuchs heterochromic cyclitis in Europe, and provide a basis for research examining differences in association by region and ethnicity.
