Immunocompromised patients: Because of the progressive nature of the disease in this patient population, most clinicians elect to treat all cases of ocular toxoplasmosis in immunosuppressed patients, including peripheral lesions without immediate threat to vision [73]. The following issues should be considered when treating immunosuppressed patients. Pyrimethamine is often avoided because of the preexisting bone marrow suppression. Corticosteroids are often avoided to prevent further suppression of the patient’s immune system. A high incidence of sulphonamide allergies is present in AIDS patients, and caution should be used when prescribing and monitoring treatment.

16.3  Viral Diseases

Viruses are the most common causes of retinitis in newborns and children. Congenital abnormalities have long been recognized as manifestations of prenatal viral infection. Ocular manifestations of prenatal and acquired viral disease in children have received increasing attention with the epidemic of AIDS, increased use of chemotherapy used for treatment of malignancies, and widespread use of immunosuppression after organ transplantation. Congenital and acquired Cytomegalovirus infection is the most common cause of viral retinitis in children. Other important causes of viral retinitis in children include herpes simplex, herpes zoster, and rubella. Rare but important causes of pediatric viral retinitis include measles, mumps, influenza, Epstein barr virus, Herpes b virus, HTLV, choriomeningitic virus, and Rift Valley fever virus.

16.3.1  Cytomegalovirus Retinitis

Cytomegalovirus (CMV) is a ubiquitous member of the herpes group of viruses. It is highly species specific in many animals including humans. Like other herpes viruses, primary infection is followed by persistent infection that may or may not be followed by active disease. In most cases, infection is subclinical [83]; however, in immunosuppressed, immmunodeficient and congenitally infected newborns, serious lifethreatening disease can occur [84].

CMV is a double stranded DNA virus and is member of herpes – virdae and subfamily beta herpes virinae.

The virus causes cell enlargement with intranuclear inclusions that simulate those associated with HSV and Varicella Zoster. CMV infection occurs in the T lymphocytes and is associated with asymptomatic infection in healthy adults [85, 86]. Virus is excreted in the urine and saliva, and infection is probably life long.

Worldwide, congenital CMV infection is the most common intrauterine viral infection occurring in 0.5– 2.5 % of all newborns [87]. Around 30,000–40,000 infants are born with CMV infection in the USA each year [88]. An average 1% of infant population is infected in utero, and a further 8–60% become infected during the first 6 month of life. By the age of 13 years, the virus infects as many as 80% of children [89], with the risk of infection being affected by socioeconomic class and other factors.

Transmission of the disease is not fully understood but can occur by direct or indirect contact. Sources of transmission include oropharyngeal secretion, urine, cervical and vaginal excretions, breast milk, tears, feces, semen, blood, and organ transplantation and blood [90].

Pregnant women may acquire the disease by sexual or nonsexual routes, and the majority of acutely infected women remain asymptomatic [87, 91]. Infection during second pregnancies is more common than during first pregnancies, presumably because the mother acquires a primary infection from her first child, often thought related to daycare exposure [91]. Congenital CMV can develop by transplancental infection due to primary acquired or recurrent maternal infection. Fetal infection from reactivated maternal CMV has fewer serious implications for the fetus [92]. Contact with infected genital secretion at the time of delivery or ingestion of breast milk causes perinatal infection, but infection at this time is not associated with ocular or systemic serious disease.

16.3.1.1  Congenital CMV Infection

Serious clinical disease is more common in the offsprings of women with primary infection than in mothers who develop recurrent infection or reinfection during pregnancy. Up to 50–90% of mothers have serum antibodies to CMV either at conception or at the first prenatal visit. These antibodies appear to be protective to the fetus [93, 94]. Among infants of mothers acquiring their first CMV infection during pregnancy, 50% will acquire

a congenital CMV infection, though only 5–15% will exhibit clinical manifestations at birth [87].

CMV in a congenitally infected newborn primarily affects the reticuloendothelial system and the CNS. Clinical findings in symptomatic infants include microcephaly, thrombocytopenic purpura with a petechiae rash, hepatomegaly, jaundice, anemia, and pneumonitis [95, 96]. Splenomegaly and hepatomegaly are the most >>common findings and may persist for an average of 10–21 months [97]. Clinical manifestations may be absent in the first 24 h of life [98] but are typically present at the time of birth in severe cases. Mild to severe mental retardation is not uncommon [97]. Other manifestations include deafness, seizures, microcephaly, and intracranial calcifications. Some asymptomatic patients will also eventually develop CNS abnormalities, including developmental delay [99, 100]. In order for the infant to be classified as having congenital CMV infection, the virus must be detected in the tissues, saliva, or urine within the first 3 weeks of life [92]. Virus may be shed for months, or even years after birth.

The infection may become latent for any period and may be reactivated at a later date. Some of the sequel of congenital infection, especially progressive or late onset hearing loss, may be due to chronic or reactivated CMV infection in infants or older children [101, 102]. Hearing loss eventually develops in up to 17% of patients with asymptomatic congenital CMV as well [103].

16.3.1.2  Ocular Manifestations

Coats et al. (2000) [103], systematically evaluated the ophthalmic findings in children with congenital CMV infection in a prospective study comparing symptomatic CMV patients with asymptomatic CMV patients and with controls. Symptomatic patients were those with one or more clinical manifestation at birth after exclusion of other causes. Asymptomatic patients had no obvious clinical sign of the disease but had positive urine culture for CMV, and the control group was CMV culture negative.

Fundus abnormalities were common in the symptomatic group and infrequent in asymptomatic and control patients. Out of 42 symptomatic patients, 7% had optic atrophy, 7% had unilateral macular scars, and 14% had peripheral retinal scars, half of which were bilateral. Only one patient had active choroiditis at the time of ophthalmic evaluation. No retinal hemorrhage

was present in this patient suggesting that active CMV retinitis can occur without hemorrhage in congenitally infected patients. None of the asymptomatic patients had optic atrophy, bilateral macular scars, or peripheral retinal scars. In another large series of CMV patients, 10% of symptomatic patients were noted to have chorioretinal lesions (Fig. 16.5) [104]. Reports of reactivation of CMV retinitis [104] and late onset or progressive loss of hearing due to CMV [101, 102] emphasize the potential for CMV chorioretinitis to reactivate or have late onset. In our experience of following more than 100 patients with congenital CMV infection on a longterm basis, we have not seen recurrent or new ocular disease, however. Congenital CMV retinitis should be differentiated from other TORCH syndromes, namely toxoplasmosis, rubella, herpes simplex, syphilis, and varicella zoster. Clinical features, combined with serological tests and cultures from the mother and the neonate, help to make this distinction.

Visual impairment is reported to be more severe in symptomatic patients [103, 105]. Cortical visual impairment and optic atrophy were the most common causes of bilateral severe visual loss in symptomatic patients [103]. The cause of optic atrophy and cortical visual impairment was not known but may be the result of infection early in the first trimester with direct infection of the CNS, optic nerve or both by the virus.

Other ocular manifestations include strabismus, which appears to be common in symptomatic patients. In one study 30% of symptomatic patients had strabismus [103]. Other isolated reports of ophthalmic manifestations include anophthalmia, Peter’s anomaly [106] and incomplete cyclopia [107].

Fig. 16.5  Active congenital CMV retinitis

16.3.1.3  Acquired CMV Infection

In healthy immunocompetent children and adults, CMV is usually asymptomatic. However, some patients will develop a syndrome indistinguishable from infectious mononucleosis with fever, lymphadenopathy, and hepatosplenomegaly. This infectious mononucleosis-like syndrome, however, is the most common clinical presentation in immunocompromised. Immunocompromised states that may be associated with acquired CMV infection include AIDS, lymphoma, leukemia, and other malignancies. Chemotherapy used to treat malignancies and to suppress renal or other organ transplant rejection is also associated with acquired CMV infection. CMV is the most common viral pathogen in patients with AIDS [108] and can affect a variety of organ systems.

Although the association of CMV with AIDS has overshadowed its association with other causes of immunosuppression, CMV infection is a severe complication of immunosuppression after organ transplantation [109]. A 13% incidence in systemic CMV infection by pathological and clinical diagnosis was found in children following cardiac transplantation [110]. In another study, 15% of children with cardiac transplantation had lesions consistent with past or new CMV retinitis [109].

16.3.1.4  Ocular Disease

Most of the data describing clinical appearance of CMV retinitis are available from AIDS patients infected with CMV. Few large long-term prospective studies have been published to document the incidence and course of CMV retinitis in the pediatric age group, but the available data shows that the incidence of CMV retinitis in children with AIDs is much lower than the incidence in adult patients with AIDS. In one study, only 1 patient out of 33 HIV positive children followed for 2 years developed retinitis [111]. In another study, 2 patients out of 40 HIV positive children had CMV retinitis [112]. Du et al. (1999) [121]confirmed the low incidence of CMV retinitis in children with AIDS with only 4 patients (3.4%) out of 116 patients followed for approximately 44 months having retinitis. In adults, CMV retinitis in AIDS patients is more likely to occur when the CD4 count drops below 50. In children however, it has been suggested that a CD4 count below 20 and a CD4/ALC ratio below 2% are needed [113].

Because children often do not report vision loss, CMV retinitis may be advanced at the time of diagnosis (Fig. 16.6). Frequent follow-up of at-risk children, particularly with very low CD4 and/or CD4/ALC ratio, is prudent [113].

Diagnosis of CMV retinitis is usually based on clinical manifestations. Retinal infection can be unilateral or bilateral; however, in unilateral cases, it is not uncommon to see progression of the disease to involve the second eye through hematogenous spread [114]. Spontaneous regression is uncommon. Untreated patients can present with a fulminant or indolent course. Fulminant retinitis with confluent areas of retinal whitening and edema that usually follow the course of retinal blood vessels has been most common (Fig. 16.7). Extensive hemorrhages and inflammatory vascular sheathing are typically present (Fig. 16.8). Cotton-wool spots may be seen and may initially be confused with AIDS retinopathy until more obvious signs of CMV retinitis develop. The second type is the

Fig. 16.6  CMV retinitis, note the extensive retinal edema and necrosis

Fig. 16.7  Advanced CMV retinitis. (Photo courtesy of Peter Buch, University at Buffalo, Ross Eye Institute, Buffalo, NY, USA)

Fig. 16.8  CMV retinitis with vascular sheathing. (Photo courtesy of Peter Buch, University at Buffalo, Ross Eye Institute)

indolent/granular type with faint opacification, rare hemorrhages, minimal or no vascular sheathing, and lesions that do not usually follow the course of retinal vessels. The lesions in both clinical presentations have irregular borders, which are dry and granular and which help to differentiate CMV retinitis from other common cause of retinitis such as toxoplasmosis.

In immunosuppressed patients, CMV retinitis should be differentiated from other forms of retinitis. Patients with AIDS and CMV retinitis rarely have anterior chamber reaction, and the vitreous is usually clear. Other forms of retinitis are more commonly associated with considerable reaction in the aqueous and the vitreous. Simultaneous infection with multiple organisms has been reported in AIDS patients and includes herpes simplex virus, candida, and T. gondii [115, 116]. Concurrent CMV infection with other infections should be suspected when the picture is not typical of CMV retinitis and when there is a lack of response to anti-CMV treatment.

Minimal vitreous reaction and anterior chamber reaction are typical features of CMV retinitis. Small satellite lesions sometimes may be encompassed with the lesion. Regression typically occurs only with treatment. The healing stage is characterized by the disappearance of satellite lesions, waning of the venous sheathing, cessation of the sharp advancing border, and a more grayish appearance of the lesion [117]. The resultant appearance varies from mottled depigmentation to hypopigmented lesions. Reactivation, which may occur with persistence of the immunocompromised state, often presents as new lesions appearing at the edge of previously atrophic retina. The disease does

not recur in areas previously damaged by the infection. CMV retinitis can result in either serous or rhegmatogenous detachment. Rhegmatogenous detachment is more common [118, 119].

CMV can occasionally lead to an appearance of acute retinal necrosis with peripheral retinitis and vasculitis with considerable reaction in the vitreous and the anterior chamber, thus CMV is now considered in the viral etiologies of this syndrome [120].

A new intraocular inflammatory syndrome has evolved secondary to mediated increase in the CD4 T lymphocyte count in the absence of active CMV retinitis [121, 122]. The syndrome is called immune recovery vitritis, also known as immune recovery uveitis. This syndrome is characterized by a predominantly posterior segment inflammatory response with clinical manifestations including vitritis, papillitis, cystoid macular edema, and epiretinal membrane formation, resulting in floaters and decreased vision in the affected eye [121]. Partial recovery of the immune function as a result of HAART is thought to cause this syndrome.

Periphlebitis is an important manifestation of AIDS-related CMV retinitis [123] resembling classic CMV retinitis but with extensive sheathing of the retinal vessels even at sites that are remote from the original retinal lesion. This frosted branch angitis-like picture, not uncommon in adults with AIDS, is uncommon in children. Reports of frosted branch angitis in children suggest their unresponsiveness to anti-CMV therapy. Still a trial of anti-CMV treatment may be warranted in those children. Corticosteroids have also been demonstrated to be helpful. [124].

Optic nerve involvement has been reported with CMV infection in AIDS patients. Involvement may occur in the form of optic neuritis [119, 125], optic disc edema and atrophy. Optic nerve hypoplasia has been reported in prenatally infected infants [126, 127]. Optic nerve neovascularization has been reported [128]. Nonretinal manifestations of CMV infection include iridocyclitis, punctate keratitis [129], and corneal endothelial changes [130].

16.3.1.5  Pathology

Evidence of CMV infection can be found in every organ of the body in individuals with severe disseminated disease. In CMV retinitis, the lesions are characterized by full thickness necrosis. The infected cells