Imran Karim Janmohamed
Foundation Year 1 Doctor, East Surrey Hospital, Redhill, Surrey
Introduction
Neonatal ophthalmic pathologies should be identified as early as possible in order to address problems before they progress and become irreversible. In the UK, this is made achievable by the standard Newborn Infant Physical Examination. This comprises an assessment looking for external structural abnormalities in the eye which may inform a number of genetic syndromes, identifying the red reflex, direct ophthalmoscopy and other tests. I have written an overview of the newborn eye examination in a separate article, which can be found here. This article aims to provide an overview of the manifestations of congenital eye infections and their management.
Toxoplasmosis
Epidemiology
In Europe, the World Health Organization (WHO) estimates a prevalence of 0.5 to 1.6 per 1,000 live births (1).
Aetiology
Congenital toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii that enters the body via contaminated food or water with oocytes, infected meats, or direct contact with feline faeces carrying oocytes. Primary infection is often associated with waterborne outbreaks.
Clinical Manifestation
Primary infection during pregnancy often presents asymptomatically in the mother but can be transferred to the foetus. The classical triad is characterised by hydrocephalus, intracranial calcification and chorioretinitis. Typically, the most severe sequelae result from infection in the first trimester, resulting in foetal death, intellectual disability and blindness.
Infections acquired in the third trimester may present asymptomatically at birth, but up to 85% progress months to years later to develop retinitis, central nervous system problems (e.g. seizures or learning disabilities) or delayed growth (2). Thus, a neurological examination and ophthalmic examination of the retina should be performed in newborns suspected of congenital infection.
Management
The evidence surrounding the efficacy of preventing foetal infection by treating the pregnant mother is conflicting (3). A multicentre observational study reported that treatment during pregnancy reduces sequelae in infants but had no effect on maternal-foetal transmission (4). However, other studies show treatment to reduce transmission to the foetus from 44% without treatment to 29% with treatment (5,6). Newborns should be treated for 1 year with pyrimethamine and sulfadiazine plus calcium folinate (7).
Rubella
Epidemiology
As part of the European Vaccine Action Plan 2015-2020, the WHO European Region passed a resolution aiming for the elimination of measles, rubella, and Congenital Rubella Syndrome (CRS). The ‘Progress Toward Rubella Elimination’ report summarises that rubella incidence has declined from 234.9 cases per 1 million population in 2005 to 0.7 cases per 1 million population by 2019 (8).
Aetiology
Rubella is caused by the rubella virus, a togavirus. Humans are the only natural host and transmission is mostly through contact with nasopharyngeal secretions.
Clinical manifestation
Ocular abnormalities include cataract, microphthalmia, glaucoma, and retinopathy. Studies show cataracts and microphthalmia are the commonest ocular pathologies that present (9,10). These are often associated with systemic disease; a study analysing 125 CRS patients over 32 years reported ocular disease and sensorineural hearing loss (SNHL), and ocular and cardiac disease, were frequently associated, but not significantly correlated (10). Glaucoma has been seen to significantly correlate with microphthalmia (9,10).
Management
Treatment for rubella is largely supportive, and the best management is prevention. Reports estimate the rubella vaccine is approximately 97% effective in preventing rubella after a single dose (11). Intramuscular immunoglobulin may be offered to some susceptible and exposed pregnant women; however the evidence is insufficient for its efficacy in preventing transmission to the foetus (12).
Herpes Simplex Virus
Epidemiology
The global prevalence of neonatal HSV is estimated at around 10 per 100,000 live births (13).
Aetiology
Bacterial causes tend to predominate in ophthalmia neonatorum, but viral causes like HSV are underestimated and potentially blinding – although common in adults, they are rare in neonates. Both HSV-1 and HSV-2 are causes of eye infections, but HSV-1 is more common in neonates (14). Transmission is more likely via vaginal delivery.
Clinical Manifestation
Predominant features include blepharoconjunctivitis and keratitis (15). Differentiation from ophthalmia neonatorum can be made due to the presence of conjunctival hyperaemia, eyelid swelling and the relatively early presentation.
Management
Referral to ophthalmology should be made promptly. Diagnosis is made by polymerase chain reaction (PCR) of conjunctival swabs; cerebrospinal fluid analysis may be considered if there are also features of central nervous system (CNS) involvement. Immediate empirical treatment should be commenced with intravenous (IV) acyclovir and supportive therapy. Treatment should last for 14 days if HSV is limited to skin or mucous membranes, and 21 days for disseminated or CNS disease (16,17). Suppressive therapy with oral acyclovir is often required to reduce the risk of recurrence. Appropriate follow-up should be made with ophthalmology on discharge.
Cytomegalovirus
Epidemiology
Cytomegalovirus (CMV) is the commonest congenital viral infection in the developed world, with a prevalence of nearly 0.6% (18).
Aetiology
CMV is a ubiquitous herpesvirus that most people will have been exposed to by adult life. Transmission modes include person-to-person (e.g. kissing and sexual intercourse), vertical transmission (mother-to-child transmission [MTCT]), blood transfusion, organ transplantation and haematopoietic stem cell transplantation.
Clinical manifestation
CMV is possible to diagnose in the antenatal period and should be suspected if there is symptomatic or asymptomatic maternal seroconversion during pregnancy, or if abnormalities have been detected on antenatal ultrasound (19). Approximately 90% of infants will be asymptomatic at birth. In 15-20%, presenting features may include microcephaly, hepatosplenomegaly, petechiae or purpura, or SNHL. Chorioretinitis is seen in a large proportion of symptomatic infants; other common ophthalmic signs include optic atrophy, cortical visual impairment and strabismus (20,21). Therefore, all infants presenting with symptomatic CMV should undergo thorough ophthalmologic screening and assessment.
Management
There is no strong evidence to recommend treating asymptomatic to mild CMV. Moderate-to-severe disease is treated with oral valganciclovir from the first month of life for 6 months (22). IV ganciclovir is rarely used, and neutropenia is a frequent side effect (23).
Human Immunodeficiency Virus
Epidemiology
70-80% of Human Immunodeficiency Virus (HIV) patients have required treatment for eye disease. Given the efficacy of HIV antiretroviral therapy (ART), this has been reducing. The risk of MTCT of HIV is estimated to now be lower than 1% if the correct treatment regime is followed (24).
Aetiology
HIV is caused by the retroviruses HIV-1 and HIV-2. It is a blood-borne virus transmitted via sexual intercourse, sharing needles for intravenous drugs, vertical transmission, or occupational exposure, e.g. blood transfusion and organ transplant.
Clinical manifestation
CD4+ T-cell levels may be used to predict certain opportunistic conditions associated with HIV. A CD4+ T-cell count < 100/mL is associated with CMV retinitis, progressive outer retinal necrosis and retinal or conjunctival microvasculopathy (25). However, the ocular manifestations of HIV/AIDS in the paediatric population are considerably fewer compared to those in adults, including CMV retinitis (26). This is perhaps due to an altered immune response or lower prevalence of CMV seropositivity in children (25).
Management
ART forms the mainstay of treatment of HIV. Although ART reduces the risk of most opportunistic infections, treatment is required to treat specific opportunistic conditions. ART may require modification to minimise the risk of drug interactions, whilst ensuring virological suppression (27).
Varicella Zoster Virus
Epidemiology
Congenital Varicella Syndrome (CVS) arises in around 2% of babies born following maternal infection in the first or second trimester (28). The risk is highest between 13-20 weeks’ gestation (29).
Aetiology
Varicella is caused by primary infection with the Varicella Zoster Virus (VZV). Following initial presentation, VZV establishes long-term latency in the dorsal root ganglia and cranial nerves. In up to one third of cases, it reactivates later in life as shingles (herpes zoster) (30).
Clinical manifestation
Features of CVS include cutaneous scarring, limb hypoplasia, microcephaly, and learning disabilities. Ophthalmic defects include microphthalmia, cataracts, and chorioretinitis (31).
Management
In contexts where the mother is infected with VZV, neonatal varicella should be prevented by isolating baby from the mother until her lesions have crusted and dried. If the mother develops a rash 5 prior to 2 days following birth, there is an increased risk of neonatal varicella, and the newborn should be immediately treated with Varicella Zoster Immunoglobulin and IV acyclovir (32).
Conclusion
Ophthalmic manifestations of congenital eye infections can sometimes be cardinal features of neonatal illness and must be considered among the constellation of systemic features. Management varies according to the nature of illness and should be guided by ophthalmology referral and follow-up within the multidisciplinary team.
References
1. Torgerson PR, Mastroiacovo P. The global burden of congenital toxoplasmosis: a systematic review. Bull World Health Organ. 2013;91(7):501-508. doi:10.2471/BLT.12.111732
2. Wilson CB, Remington JS, Stagno S, Reynolds DW. Development of adverse sequelae in children born with subclinical congenital Toxoplasma infection. Pediatrics. 1980. doi:10.1542/peds.66.5.767
3. Wallon M, Liou C, Garner P, Peyron F. Congenital toxoplasmosis: systematic review of evidence of efficacy of treatment in pregnancy. BMJ. 1999;318(7197):1511-1514. doi:10.1136/BMJ.318.7197.1511
4. Foulon W, Villena I, Stray-Pedersen B, et al. Treatment of toxoplasmosis during pregnancy: a multicenter study of impact on fetal transmission and children’s sequelae at age 1 year. Am J Obstet Gynecol. 1999;180(2 Pt 1):410-415. doi:10.1016/S0002-9378(99)70224-3
5. Dunn D, Wallon M, Peyron F, Petersen E, Peckham C, Gilbert R. Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counselling. Lancet (London, England). 1999;353(9167):1829-1833. doi:10.1016/S0140-6736(98)08220-8
6. Desmonts G, Couvreur J. Congenital toxoplasmosis. A prospective study of 378 pregnancies. N Engl J Med. 1974;290(20):1110-1116. doi:10.1056/NEJM197405162902003
7. McLeod R, Boyer K, Karrison T, et al. Outcome of treatment for congenital toxoplasmosis, 1981-2004: the National Collaborative Chicago-Based, Congenital Toxoplasmosis Study. Clin Infect Dis. 2006;42(10):1383-1394. doi:10.1086/501360
8. O’Connor P, Yankovic D, Zimmerman L, Mamou M Ben, Reef S. Progress Toward Rubella Elimination — World Health Organization European Region, 2005–2019. MMWR Morb Mortal Wkly Rep. 2021;70(23):833-839. doi:10.15585/MMWR.MM7023A1
9. O’Neill JF. The ocular manifestations of congenital infection: a study of the early effect and long-term outcome of maternally transmitted rubella and toxoplasmosis. Trans Am Ophthalmol Soc. 1998;96:813. /pmc/articles/PMC1298415/?report=abstract. Accessed March 18, 2022.
10. Givens KT, Lee DA, Jones T, Ilstrup DM. Congenital rubella syndrome: ophthalmic manifestations and associated systemic disorders. Br J Ophthalmol. 1993;77(6):358-363. doi:10.1136/BJO.77.6.358
11. McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: Summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Reports. 2013.
12. Young MK, Cripps AW, Nimmo GR, van Driel ML. Post-exposure passive immunisation for preventing rubella and congenital rubella syndrome. Cochrane database Syst Rev. 2015;2015(9). doi:10.1002/14651858.CD010586.PUB2
13. Pinninti SG, Kimberlin DW. Neonatal herpes simplex virus infections. Pediatr Clin North Am. 2013;60(2):351-365. doi:10.1016/J.PCL.2012.12.005
14. Matos RJC, Pires JMS, Cortesão D. Management of Neonatal Herpes Simplex Infection: A Rare Case of Blepharoconjunctivitis and Concurrent Epithelial and Stromal Keratitis. Ocul Immunol Inflamm. 2018;26(4):625-627. doi:10.1080/09273948.2016.1242017
15. Malik ANJ, Hildebrand GD, Sekhri R, Russell-Eggitt IM. Bilateral macular scars following intrauterine herpes simplex virus type 2 infection. J AAPOS Off Publ Am Assoc Pediatr Ophthalmol Strabismus. 2008;12(3):305-306. doi:10.1016/J.JAAPOS.2008.01.002
16. Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001;108(2):230-238. doi:10.1542/PEDS.108.2.230
17. Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol. 2007;31(1):19-25. doi:10.1053/J.SEMPERI.2007.01.003
18. Swanson EC, Schleiss MR. Congenital Cytomegalovirus Infection: New Prospects for Prevention and Therapy: for Pediatric Clinics of North America: Advances in Evaluation, Diagnosis and Treatment of Pediatric Infectious Disease. Pediatr Clin North Am. 2013;60(2):335-349. doi:10.1016/J.PCL.2012.12.008
19. Revello MG, Gerna G. Pathogenesis and prenatal diagnosis of human cytomegalovirus infection. J Clin Virol. 2004;29(2):71-83. doi:10.1016/J.JCV.2003.09.012
20. Coats DK, Demmler GJ, Paysse EA, Du LT, Libby C. Ophthalmologic findings in children with congenital cytomegalovirus infection. J AAPOS Off Publ Am Assoc Pediatr Ophthalmol Strabismus. 2000;4(2):110-116. doi:10.1067/MPA.2000.103870
21. Ghekiere S, Allegaert K, Cossey V, Van Ranst M, Cassiman C, Casteels I. Ophthalmological findings in congenital cytomegalovirus infection: when to screen, when to treat? J Pediatr Ophthalmol Strabismus. 2012;49(5):274-282. doi:10.3928/01913913-20120710-03
22. Rawlinson WD, Boppana SB, Fowler KB, et al. Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Lancet Infect Dis. 2017;17(6):e177-e188. doi:10.1016/S1473-3099(17)30143-3
23. Kimberlin DW, Lin CY, Sánchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003;143(1):16-25. doi:10.1016/S0022-3476(03)00192-6
24. Townsend CL, Byrne L, Cortina-Borja M, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000-2011. AIDS. 2014;28(7):1049-1057. doi:10.1097/QAD.0000000000000212
25. Rosignoli L, Azeez LS, Sohn J-H. Ocular Manifestations of HIV Infection: Overview, Adnexal Manifestations, Anterior Segment Manifestations. https://emedicine.medscape.com/article/1216172-overview#a1. Accessed March 18, 2022.
26. Dennehy PJ, Warman R, Flynn JT, Scott GB, Mastrucci MT. Ocular Manifestations in Pediatric Patients With Acquired Immunodeficiency Syndrome. Arch Ophthalmol. 1989;107(7):978-982. doi:10.1001/ARCHOPHT.1989.01070020040025
27. Panel on Opportunistic Infections in Adults T. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV How to Cite the Adult and Adolescent Opportunistic Infection Guidelines: Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf Accessed March 18, 2022.
28. Pastuszak AL, Levy M, Schick B, et al. Outcome after maternal varicella infection in the first 20 weeks of pregnancy. N Engl J Med. 1994;330(13):901-905. doi:10.1056/NEJM199403313301305
29. Enders G, Bolley I, Miller E, Cradock-Watson J, Ridehalgh M. Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. Lancet (London, England). 1994;343(8912):1548-1551. doi:10.1016/S0140-6736(94)92943-2
30. Gnann JW, Whitley RJ. Clinical practice. Herpes zoster. N Engl J Med. 2002;347(5):340-346. doi:10.1056/NEJMCP013211
31. Lissauer T, Carroll W. Illustrated Textbook of Paediatrics Fifth Edition.; 1981.
32. Blumental S, Lepage P. Management of varicella in neonates and infants. BMJ Paediatr Open. 2019;3(1):e000433. doi:10.1136/BMJPO-2019-000433