Congenital Rubella Syndrome
Congenital rubella syndrome (CRS) is the most common cause of vaccine-preventable birth defects. The most common manifestation of congenital rubella syndrome is ocular disease, presenting most commonly as pigmentary retinopathy, cataracts, microphthalmia, and/or glaucoma.
CRS is caused by maternal infection with the rubella virus, a togavirus. Humans are the only known host of the rubella virus, which is transmitted via respiratory droplets to unvaccinated hosts or via direct transmission. The virus can then be spread vertically from mother to fetus and cause CRS. In an individual infected with the rubella virus, the virus may be shed in nasal, throat, urine, blood, and cerebrospinal fluid specimens on average up to 10 days after the rash begins, except in those specifically with CRS who are contagious and shed the virus for significantly longer, up to years in some reports.
Cases of congenital rubella syndrome have been decreasing as rubella-containing vaccines are promoted and the elimination of rubella is achieved in many countries. Over 100,000 cases of rubella were estimated worldwide each year prior to the introduction of the rubella vaccine in 1964. High rates of vaccination in developed countries led to the elimination of rubella in the United States in 2004 with fewer than 10 cases reported annually since. Globally, there were 49,136 rubella cases reported in 2019 which decreased to 10,194 in 2020 thanks to recent vaccination efforts. Nearly 70% of infants worldwide received vaccination against rubella in 2020, and 93 countries have verified elimination of rubella. As of 2020, globally reported CRS cases increased to 603 from 302 in 2012 due to increased surveillance for CRS, specifically in the populous countries of Bangladesh, India, Indonesia, and Pakistan. CRS is prevalent in several African, Southeast Asian, and Eastern Mediterranean countries which have been slower to introduce rubella vaccination and have increased surveillance for CRS. It is estimated that 25% of the 50,000 children born blind from congenital cataract in India each year are a result of CRS but lack of readily available serologic testing makes it difficult to have accurate numbers of CRS cases worldwide. In the worldwide rubella epidemic between 1963 and 1965, 30% of infants from infected mothers developed congenital disease with ocular manifestations being most frequent. Current estimates suggest that congenital defects occur in nearly 85% of neonates when infected in the first trimester.
Infection of the rubella virus during pregnancy, specifically the first trimester, increases the risk of the constellation of birth defects that constitute congenital rubella syndrome. Lack of vaccination with rubella-containing vaccines in pregnant women increases risk as a single dose of the rubella-containing vaccine often confers lifelong protection.
CRS is multifactorial and the pathophysiology is not entirely elucidated. Manifestations are predominantly caused by non-inflammatory necrosis of chorionic epithelium, inhibition of actin assembly restricting mitosis of precursor cells, and upregulation of cytokines.
While ocular manifestations are the most common findings in CRS, the cardiovascular and central nervous systems are also commonly impacted. Congenital heart defects include patent ductus arteriosus, peripheral pulmonary artery stenosis, ventricular septal defects, and atrial septal defects. Studies have reported congenital heart disease in over half of individuals with CRS, and high association of ocular manifestations with cardiovascular malformations. Sensorineural hearing loss is also common, resulting in deafness. Other neurologic manifestations include microcephaly, cerebral calcifications, meningoencephalitis, and mental retardation. A “blueberry muffin” rash is sometimes seen due to dermal erythropoiesis as well as late onset of insulin-dependent diabetes and thyroid disease.
Chorioretinitis is one of the most common ocular manifestations found in up to half of CRS patients. It may be unilateral or bilateral and is classically described as a “salt-and-pepper retinopathy.” These changes are usually not visually significant and have variable distributions and severity. The disseminated dusty or mottled pigmentation which is most prevalent in the macula increases over several years, and very rarely leads to subretinal neovascularization. This retinopathy has been said to sometimes appear like retinitis pigmentosa as the pigment deposits vary from fine, sprinkled, and granular shapes to resembling the bone-spicule RP pattern. Pigmentary changes are most common at the posterior pole and occur due to atrophy and pigment alterations of the RPE. Most cases of retinopathy are stagnant and very rarely progress to subfoveal choroidal neovascularization causing sudden visual loss.
Congenital rubella syndrome is associated with congenital nuclear cataracts characterized by their ‘pearly white’ appearance. This occurs due to the rubella virus slowing the proliferation and mitosis of epithelial cells in the lens. As a result, lens fibers degenerate and become opaque, forming the cataract. This only occurs when the mother contracts the rubella virus in the first trimester. The cataracts may be bilateral or unilateral due to one eye developing faster than the other. Cataracts are more likely to be bilateral, with rates as high as 89% of the subjects with cataracts having bilateral cataracts in one study. Cases of spontaneous resorption of a cataract have been described. Cataracts are reported in 16-85% of cases in a variety of studies, so the exact prevalence is difficult to determine, though some studies suggest cataracts are a more common ocular manifestation than retinopathy.
Microphthalmos commonly occurs in CRS when a newborn’s eyes measure less than 16.6 mm in diameter. This too may be unilateral or bilateral and is often mild in nature. It is estimated in about 10-20% of children with CRS. The cause is also believed to be due to the delayed growth of the eye due to the virus interfering with mitosis. These eyes have higher rates of nystagmus, cataracts, and retinopathy which lead to poorer visual outcomes. Due to the small nature of the eyes, hyperopia is much more common than myopia.
Congenital glaucoma with concurrent cloudy corneas and buphthalmos is another common complication of CRS. This occurs due to failure of absorption of the mesoderm in the angle or failure of the canal of Schlemm to differentiate. This finding is usually isolated in children with CRS, and thus is rarely associated with cataracts or microphthalmos. Secondary glaucoma, however, may also occur as a consequence of cataracts or microphthalmos in the second decade of life. This presentation confers a very poor visual prognosis and is thought to be a result of persistent viral damage to the eye and trabeculodysgenesis. Glaucoma is reported in 2 to 25% of cases in the literature.
Strabismus is a common finding of CRS as a result of amblyopia secondary to other ocular manifestations. Some studies have estimated strabismus to be prevalent in around 25% of cases, and patients are 4 times more likely to have strabismus than individuals without CRS. Esotropia is more common, but exotropia may also occur. Latent, fine-amplitude, and jerk nystagmus are also reported in individuals with CRS.
Both rubella infection and congenital rubella syndrome have been associated with playing a role in Fuchs’ uveitis syndrome (FUS), an intraocular syndrome diagnosed clinically. FUS is characterized clinically by iris heterochromia, low-grade anterior uveitis, and cataract, and is also associated with other infections including herpes simplex, toxoplasmosis, and toxocariasis. The pathogenesis of FUS has been suggested to be associated with autoantibodies against the cornea. Patients with FUS and CRS have been found to produce an intraocular antibody against rubella virus, though it is unknown if patients with CRS are more prone to FUS than those with a non-congenital rubella infection. It is theorized that the persistence of viral infection in CRS increases risk for FUS, though the exact mechanism and prevalence of FUS in CRS is unknown and statistically cannot be confirmed. As FUS is not present at birth, it is proposed that it may represent a delayed manifestation of CRS in patients with heterochromia documented since birth due to rubella infection in later stages of pregnancy rather than the first trimester.
Rarely, reports of iris atrophy have occurred in individuals with CRS due to poor development of the dilator muscles. This may result in difficulty with pupil dilation in patients with CRS.
A full eye exam should be performed in any patient with suspected or confirmed congenital rubella as rates of ocular manifestations vary widely.
Laboratory diagnosis of rubella in early pregnancy is confirmed with IgG and IgM titers when rubella-like illness occurs. Viral genome can then be analyzed on amniotic fluid, fetal blood, or chorionic villus biopsies for prenatal fetal diagnosis. ELISA analysis for IgG antibodies of neonatal serum is done to diagnose CRS postnatally. This can then be confirmed by detection of the rubella virus via PCR.
a. Infectious: i. Congenital cytomegalovirus ii. Congenital Herpes Simplex virus 6 iii. Congenital Varicella iv. Toxoplasmosis v. Syphilis vi. Enteroviruses vii. Parvovirus B19 b. Genetic: i. Retinitis pigmentosa ii. X-linked ocular albinism
There is no curative medical therapy for congenital rubella syndrome, only supportive therapy. Pregnant women who are confirmed positive may be offered termination of pregnancy when there is high risk of infection. Children with congenital rubella are considered contagious until they are at least one year old, unless two cultures come back negative one month apart. Isolation and proper hand hygiene should be used to reduce transmission from urine of the neonates.
Ocular manifestations of CRS should be treated surgically when visually significant and/or causing amblyopia. Patients with cataracts should undergo cataract surgery early in life as nuclear cataracts often progress to total cataracts postnatally. Rubella virus does persist in the lens, so surgeons who are rubella non-responders (<5%) should be cognizant of the risk of contracting rubella and should make an informed decision if there is any possibility of pregnancy. A single dose of a rubella-containing vaccine confers lifelong protection to 97% of people, so it is important for ophthalmologists to be up to date on vaccines when treating these patients. Interference by the virus in the development of the iris can cause poor pupil dilation and a more difficult cataract surgery. Additionally, high rates of microphthalmos in patients with CRS may impact decision making during cataract surgery, and most of these patients are traditionally left aphakic leaving them prone to develop secondary glaucoma. Management of glaucoma and strabismus may also require surgical interventions. In one study, 43% of patients with CRS who underwent cataract extraction developed secondary glaucoma, with 56% of those patients going on to require a trabeculectomy.
Many cases of CRS result in miscarriage and stillbirth, though patients that make it to birth often have significant birth defects with ocular manifestations being common. During the rubella epidemic from 1963 to 1965, it was estimated that more than 13,000 fetal or early infant deaths occurred due to the severity of fetal injury from the virus. The mechanism of fetal damage by the virus is not completely understood, but gestational outcomes are heavily dependent on timing of maternal infection during gestation with worst outcomes early in gestation during organogenesis.
At the time of birth, most manifestations of CRS are present, and ocular manifestations are often the first indicator of CRS in patients when maternal rubella infection was not diagnosed. Patients with pigmentary retinopathy typically develop to have vision 20/60 or better without other complications. This retinopathy rarely progresses to neovascularization, and peripheral vision and electrophysiologic tests are typically normal, so most often no treatment is required other than regular retinal examination. Cataracts are managed with early surgery to confer a good visual prognosis.
Beyond the congenital manifestations at birth, there are very few delayed manifestations of CRS into adolescence and adulthood. Of note, patients with CRS are more likely to develop secondary glaucoma after surgical removal of cataractous lenses or spontaneous resorption. Unlike the primary glaucoma from CRS, secondary glaucoma can be much more difficult to manage and confers a worse visual prognosis as discussed earlier. Keratitic precipitates, keratoconus, and corneal hydrops are other rare manifestations that have been reported as late-onset ocular defects of CRS.
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