Chorioretinitis

Inflammation associated with chorioretinitis is usually caused by congenital viral, bacterial, or protozoal infections in neonates. Congenital toxoplasma and cytomegalovirus (CMV) infection are the most common etiologies in this age group. Fungal infections are commonly identified, and emergent pathogens such as West Nile virus and lymphocytic choriomeningitis virus (LCMV) have been described.[1, 2] In rare instances, chorioretinitis is part of a systemic noninfectious process.

Chorioretinitis associated with congenital viral infections like CMV tends to be stable or improve in infancy, whereas chorioretinitis associated with asymptomatic congenital toxoplasmosis (CTP) progresses for years after birth and is more likely to be clinically significant at an older age.

Although CMV is the most common congenital infection in the developed world, affecting approximately 1% of all infants born in the United States, only 10% of all infants born in the United States with congenital CMV infection have symptomatic disease at birth, including chorioretinitis.[3]

Congenital disseminated infections such as CMV and toxoplasmosis may also manifest with extraocular findings such as intrauterine growth retardation, microcephaly, microphthalmia, cataract, uveitis, hearing defect, osteomyelitis, hepatosplenomegaly, lymphadenopathy, dermal erythropoiesis, carditis, and congenital heart disease.

Beyond the neonatal period, chorioretinitis can be diagnosed in diverse clinical conditions and can reflect newly acquired diseases or reactivation. CTP is the most common cause of infectious chorioretinitis in immunocompetent children.[4] Chorioretinitis can also result from a dissemination of parasitic infections like Toxocara or Baylisascaris (the raccoon roundworm) in immunocompetent patients.[5] In severely immunodeficient patients, including those with acquired immunodeficiency syndrome (AIDS), chorioretinitis may be associated with Epstein-Barr virus (EBV), CMV, varicella-zoster virus, various fungi (eg, Candida, Aspergillus, Fusarium, dimorphic fungi), and Toxoplasma.[6] See the image below.

In addition, with increasing air travel and globalization, several emerging infectious diseases have been recognized as causing ocular disease, including retinitis, chorioretinitis, retinal vasculitis, and optic nerve involvement. These include rickettsiosis, Rift Valley fever, dengue fever, and Chikungunya virus.[7]

Chorioretinitis affects the uveal tract, which consists of the iris, ciliary body, and choroid. Inflammatory conditions are generally classified according to the predominant compartment of involvement (eg, anterior and posterior uveitis). Inflammation of the posterior uveal tract of the eye is generally termed choroiditis; because the retina is invariably involved, the terms chorioretinitis or retinochoroiditis are generally used.[8]

The extent of ocular involvement depends on the organism. Bilateral focal or extensive exudative chorioretinitis or panuveitis may be seen in patients with Toxoplasma gondii infection. A single large choroidal lesion with extensive inflammation or endophthalmitis is usually observed in patients with Toxocara canis, whereas interstitial keratitis or iritis is most common in patients with Treponema pallidum. Strabismus and optic atrophy may accompany chorioretinitis caused by CMV. The central retinal lesions of CMV cannot be clinically distinguished from those of toxoplasmosis. However, unlike congenital toxoplasma infection, the retinitis caused by CMV does not progress.[8, 9]

Vessel trauma caused by other organisms, such as Toxocara or Baylisascaris larvae, may be associated with severe inflammatory responses.

Congenital infection

In immunocompetent children, chorioretinitis is usually associated with congenital infection; acquired infection is a less likely cause. T gondii and CMV are the leading causes of congenital infections associated with chorioretinitis.

Viral etiologies include vertical or perinatal infections, including HSV, rubella, varicella, Epstein-Barr virus (EBV), lymphocytic choriomeningitis virus (LCMV) and, possibly, flavivirus. With the recent increase in the incidence of congenital infection after being at a nadir since 1991, syphilis should be considered in an infant born with chorioretinitis whose mother has untreated or inadequately treated syphilis, particularly if she also has human immunodeficiency virus infection (HIV).[10, 11]  Distinguishing these infections from perinatal transmission of other viral illnesses, including HSV, hepatitis B, and HIV is important. The risk of intrauterine infection is highest in infants of women with primary infection and is much less with recurrent infections.

Acquired chorioretinitis may occur in immunocompetent children. Some children who ingest embryonated T canis or Baylisascaris procyonis eggs may develop visceral larva migrans or ocular larva migrans. Another acquired infection that may lead to chorioretinitis is B henselae.[12]  More than 90% of patients with catscratch disease have a history of recent contact with a cat, often a kitten, and 50-87% of these patients have been scratched.

Immunocompromised children

Chorioretinitis may be associated with systemic infection due to a vast array of pathogens. Any of the infections discussed above may be seen; however, the presentation in an immunocompromised individual may be atypical. Other infections may include congenital or acquired Lyme disease, Yersinia enterocolitica, and Mycobacterium tuberculosis (MTB).[13, 14]

Invasive fungal infections may result from Candida, Cryptococcus species, and histoplasmosis.[15]  A species of blackfly (Simulium species) can transmit onchocerciasis (in tropical Africa, Yemen, Saudi Arabia, and parts of Latin America).[16]

Noninfectious disease

Systemic noninfectious disease, such as sarcoidosis, collagen vascular disease, chronic granulomatous disease (CGD), Behcet disease, and juvenile rheumatoid arthritis may cause chorioretinitis.[17]

Other possible noninfectious processes include chronic infantile, neurological, cutaneous, and articular syndrome (CINCA) syndrome, also known as neonatal onset multisystemic inflammatory disease.[18]

United States data

Chorioretinitis due to CTP occurs much less frequently in the United States than in Europe. Rates of seroprevalence vary and depend on the population studied. An estimated 400-4,000 cases of CTP occur in the United States each year.[19] Rates of seroprevalence are much higher in certain European countries (eg, France, Denmark, Germany) where active surveillance systems are in place to detect symptomatic and asymptomatic cases.[20, 21] The risk of retinochoroiditis rises from 10% in infancy to approximately one third by age 12 years in children whose infection was identified by screening. By school age, 20% of infected children with CTP have one or more retinochoroidal lesion.[22] More than 90% of children have normal vision in their best eye; severe bilateral impairment is rare.

One of the most commonly acquired childhood eyesight impairments in the United States is due to T canis, probably because of the high prevalence of young pet dogs. The incidence is higher in people living in the south-central and southeastern parts of the country. Annually, more than 700 people infected with Toxocara experience permanent partial loss of vision.[23]

Age-related demographics

Chorioretinitis due to congenital infections or occasionally other causes is usually evident at birth; progression and prognosis depends on the etiology. Acquired chorioretinitis occurs at any age, depending on the underlying illness.

Except when caused by congenital toxoplasmosis (CTP), prognosis for individuals with chorioretinitis depends on the originating process but tends to be self-limited. Chorioretinitis due to CTP is progressive, and the outcome is not usually predictable. Late-onset retinal lesions can occur many years after birth, but the overall ocular prognosis of congenital toxoplasmosis is satisfactory when the infection is identified early and treatment is instituted appropriately.[24]

In patients with symptomatic congenital CMV infection, chorioretinitis was found to be a risk factor associated with the development of cortical visual impairment.[25] Thus, the researchers recommend yearly ophthalmologic examinations for such patients.

Morbidity/mortality

If left untreated or if the condition does not respond to treatment, severe chorioretinitis can result in partial or total loss of vision in the affected eye. Morbidity is due to concurrent damage to major organ systems, especially damage to the brain (eg, developmental delays, seizures). Mortality due to chorioretinitis depends on the nature and progression of the underlying illness.

Complications

A delay in the initiation of specific therapies for treatable etiologies of the patient with chorioretinitis results in further loss of vision especially in immunocompromised infants and children.

Aim educational efforts at reducing the incidence of primary toxoplasmosis in pregnant women. Screen pregnant women for the presence of toxoplasmosis immunoglobin (Ig)G and educate these individuals to avoid consuming undercooked meat and handling a cat litter box.

In the summer and fall seasons, public health measures can be used to reduce the risk of mosquito-borne viral encephalitis or tick-borne Lyme disease. During peak season for mosquitos and ticks, educate pregnant women to avoid insect bites (eg, cover up, apply insecticide to clothing items) and carry out limited larvicidal spraying to control mosquito infestation.

In most individuals with chorioretinitis (CR), the history may or may not aid in establishing causal agents. For example, in patients with chorioretinitis associated with congenital infections, eliciting the maternal history of primary viral or flulike illnesses during pregnancy is usually not easy. Dietary habits (preference of raw meat) and pet care (cleaning cat litter box) may imply toxoplasmosis or contact with kittens (catscratch disease). Lack of immunizations in a pregnant woman may also provide some clues to the diagnosis (eg, rubella). On the other hand, a pregnant woman with symptomatic West Nile viral meningoencephalitis may be readily diagnosed using historical, epidemiologic, and laboratory data.

Many maternal primary infections due to cytomegalovirus (CMV), rubella, herpes simplex virus (HSV), and syphilis occur insidiously and may not be clinically apparent. A retrospective study reported that the clinical manifestations of syphilitic chorioretinitis include impaired vision, shadow blocking, or photopsia of one or both eyes.[26]

A recent history that includes strabismus, vision loss, and CNS involvement in a toddler exposed to raccoon waste or who has a newly acquired puppy suggests zoonotic roundworm larval infestation (Baylisascaris or Toxocara). These children have an increased risk of developing visceral larva migrans and ocular larva migrans.

Parinaud oculoglandular syndrome (fever, follicular conjunctivitis, ipsilateral preauricular lymphadenitis), neuroretinitis, and focal retinochoroiditis in children or young adults exposed to kittens may suggest infection due to Bartonella henselae (catscratch disease), especially if they were scratched.

If the inflammation is unilateral, the child may squint, favor the "good eye," or report blurred vision or an inability to see objects. Older children with chorioretinitis may present with photophobia and clumsiness with poor walking balance. The "red eye" phenomenon in snapshots of a child with chorioretinitis may reveal incongruency.

Include an ophthalmologic examination as part of a detailed physical examination. A pediatric ophthalmologist should perform a thorough examination of all visible components of the eye in an infant in whom any congenital infection is suspected. This examination is electively performed and is documented with photographs of the abnormalities in the lens, uvea, and retina and an age-appropriate assessment of vision, visual acuity, and fields. Ophthalmologic examination is also an integral part of monitoring treatment efficacy and disease progress.

Ophthalmologic examination can reveal exudative "cotton balls" (ie, focal atrophic and pigmented scars of the retina). Vitreous inflammations can manifest as transient floating opacities. However, these findings are common in all patients with chorioretinitis regardless of the etiology. Other abnormal ophthalmologic findings may include cataract and uveitis.

Other abnormal physical findings should be documented; these include intrauterine growth retardation, microcephaly, microphthalmia, hearing defect, osteomyelitis, hepatosplenomegaly, lymphadenopathy, dermal erythropoiesis, carditis, and congenital heart disease.

Involvement of the central nervous system (CNS) may include abnormal muscle tone, changes in reflexes, or both. A complete neurological examination is warranted.

If amnionitis is suspected at delivery, thorough examination and culture of amniotic fluid and placenta may elicit the pathogen.

Routine laboratory screening in chorioretinitis (CR) includes the following:

• Complete blood cell (CBC) count and platelet count: Depression of all 3 lines (ie, erythrocytes, white cells, platelets) implies an infection that causes bone marrow suppression, which may be seen with congenital infections. Platelet count can be low in patients with some viral infections or intravascular coagulation.

• Liver function tests: Measure alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, bilirubin (total, direct, and indirect), albumin, and total protein levels. Also obtain activated partial thromboplastin time and prothrombin time. All or some of these measurements can be abnormal in most congenital infections.

• Renal function tests: Assess creatinine and blood urea nitrogen (BUN) levels. Urinalysis can be helpful in the detection of hematuria or casts.

Herpes simplex virus (HSV) types I and II, Epstein-Barr virus (EBV), varicella, and human immunodeficiency virus (HIV) are elicited by cultures or polymerase chain reaction (PCR) of blood, cerebrospinal fluid (CSF), or tissues. Immunoglobulin titers (immunoglobulin [Ig]G) from CNS fluid, serum, and other body fluids (particularly in a newborn) are of uncertain value, except for screening purpose in HIV vertical infection, toxoplasmosis, and West Nile virus infection. Positive values in a newborn may represent passive transfer of maternal antibody.

Congenital rubella can infect infants of nonimmune individuals and is diagnosed by interpreting results of viral culture and IgM and IgG titers in both infants and mothers.

Cytomegalovirus (CMV) is shed in the urine of infants who are congenitally infected, and diagnosis is indicated by positive urine culture results in infants younger than 3 weeks. In immunodeficient hosts, a CMV antigenemia test using a peripheral blood sample is helpful in establishing recurrence or infection. The CMV antigenemia uses immunofluorescent assay on buffy coat polymorphonuclear cells to detect CMV-infected cells. CMV-PCR is also being increasingly used, although at the present time its interpretation in congenital infection remains unclear.

Toxoplasma species are detected by specific IgA, IgM, IgG, Sabin-Feldman dye test, and PCR. Document Toxoplasma status of pregnant women and individuals who are immunocompromised.

Lyme disease is detected by using PCR assay of CSF and serum. The presence of specific IgM and IgG on Western blot result of serum may be significant for diagnosis and staging of infection.

Yersinia species are detected by special stool culture and acute and convalescent IgG titers.

Syphilis is detected by using serology tests (eg, nontreponemal rapid plasma reagent, Venereal Disease Research Laboratory test in CSF) and specific treponemal tests (eg, fluorescein treponemal antibody absorption, microhemagglutination-Treponema pallidum).

Mantoux skin test, acid-fast stain, and cultures of bronchial washings or biopsy samples of tissues detect M tuberculosis (MTB). MTB-PCR is available in many reference laboratories to detect the presence of MTB from biopsy and tissue samples, blood, and CSF. The QuantiFERON tuberculosis (TB) test, which measures lymphocyte interferon response to TB antigen, may aid in the diagnosis of TB.

Toxocariasis serology can be tested by using an enzyme-linked immunoabsorbent assay (ELISA) and confirmed by using a specific Western blot (available from the Centers for Disease Control and Prevention [CDC]).

Several serology tests for catscratch disease have been developed, including indirect immunofluorescent antibody (IFA) testing, which shows good correlation with strict clinical criteria. Demonstration of rising IgG titer provides the best evidence of infection.

Baylisascaris tests can be performed using serum and CSF. ELISA and Western blot are available from the Department of Veterinary Pathobiology at Purdue University.

Nitroblue tetrazolium test (or flow cytometry with dihydrorhodamine) is used to detect chronic granulomatous disease (CGD). In a healthy host, 95% or more of neutrophils produce superoxide radicals. In a host with a typical X-linked CGD, fewer than 5% of neutrophils have such ability.

Vertical HIV infection is suggested by hypergammaglobulinemia and a depressed CD4+ T-cell count. An HIV DNA PCR of the newborn can be used to confirm diagnosis of HIV infection in the presence of maternal antibodies. Testing with DNA PCR should be done when the infant is aged 2 weeks, 1 month, and 4 months in all infants at risk for vertical HIV infection.

Some experts also recommend obtaining an HIV DNA polymerase chain reaction test at birth. For children aged 18 months and older, an HIV antibody test should be used.

A pediatric ocular imaging system (RetCam3) may be used in newborns, infants, and uncooperative children.

Perform sonography, CT scanning, and/or MRI of the CNS or specific organs in patients in whom congenital infections are suspected or in an immunocompromised host.

Perform chest radiography, CT scanning, or both in patients in whom TB or sarcoidosis is suspected. CT scanning is helpful in identifying sites on which to perform biopsy for diagnostic purposes.

Perform CT scanning of the abdomen for hepatic or splenic dissemination of disease.

Perform radiography or bone scanning of the skeleton in patients in whom syphilis is suspected.

Perform echocardiography in patients with congenital rubella infection.

Perform a skin biopsy for rare cases of dermal hematopoiesis (blueberry muffin infant syndrome) in patients in whom congenital CMV or congenital toxoplasmosis (CTP) is suspected.

Chorioretinitis is usually diagnosed using ophthalmologic examination and not using histologic findings of the retina. However, evidence of lymphocytic infiltrations and exudates characteristic of vasculitis is found in many sites.

Granulomatous changes can be evident in biopsy samples of lymph nodes, liver, or spleen in histoplasmosis, sarcoidosis, and tuberculosis. Fungal elements are rarely found in biopsy or postmortem samples.

Medical care in chorioretinitis (CR) focuses on the establishment of specific therapies for treatable etiologies and on the stabilization of the patient with chorioretinitis to prevent further loss of vision, especially in immunocompromised infants and children.

Care for individuals with chorioretinitis is complex and requires thorough consideration of short-term and long-term care and goals to maintain quality of life.

Available treatment options for specific causes of chorioretinitis are as follows:

• Antivirals: Four drugs have been licensed for the systemic treatment of cytomegalovirus (CMV) infection. These include ganciclovir, valganciclovir (oral prodrug of ganciclovir), foscarnet, and cidofovir. Fomivirsen is licensed for intravitreal administration to treat CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). Newer drugs such as maribavir, which has the potential to be useful in ganciclovir-resistant strains of CMV, are under clinical investigation.[9, 27]

• For children with human immunodeficiency virus (HIV) infection, the drug of choice for initial treatment for CMV retinitis is intravenous ganciclovir. Oral valganciclovir is an option primarily for older children who are able to receive the adult dose and tablet formulation of valganciclovir. An alternative to treat CMV disease or for use in ganciclovir-resistant CMV infections in children with HIV is foscarnet. Combination therapy with ganciclovir and foscarnet delays progression of retinitis in certain patients failing monotherapy and can be used as initial therapy among children with sight-threatening disease. Intravenous ganciclovir and foscarnet may also be considered in initial therapy of CMV CNS disease. However, combination therapy is associated with substantial rates of adverse effects.

• Several agents are used to treat toxoplasmosis. Treatment with antiparasitic drugs is effective for active infections but not for the encysted form. The classic treatment includes triple drug therapy with pyrimethamine (0.5-1 mg/kg/d), sulfadiazine (120-150 mg/kg/d), and prednisone. Concurrent folinic acid helps to minimize bone marrow toxicity produced by the pyrimethamine. High-performance liquid chromatography with ultraviolet and mass spectrometric detection has been developed for monitoring the plasma levels of pyrimethamine and sulfadiazine during treatment using a small amount of plasma (25 mcL). This may be helpful in determining the relationship between plasma concentrations and treatment efficacy.[28]

• Alternative antibiotic treatments include atovaquone (40 mg/kg/d has been used in adults, no dosage for children), azithromycin (5 mg/kg/d) and trimethoprim-sulfamethoxazole (40 mg/kg/d sulfamethoxazole, 8 mg/kg/d trimethoprim). Adjunctive clindamycin (20 mg/kg/d) is used for coverage against the encysted form. Treatment duration for congenital infection is typically 1 year.

• Prevention of fetal infection after maternal Toxoplasma seroconversion during pregnancy is attempted with spiramycin administration. A 60% decrease has been reported in the congenital infection rate in patients who received this treatment; however, it does not ameliorate the fate of infants who are infected.

• Catscratch disease is usually a self-limited disease in immunocompetent patients. B henselae is sensitive to many antibiotics in vitro, but only aminoglycosides have bactericidal activity. In immunocompetent patients, doxycycline at 200 mg/d is usually administered because of its property to cross the blood-brain and blood-ocular barrier. Caution should be used if administered to children because it may cause dental changes. Ciprofloxacin (1.5 g/d), gentamicin (3-5 mg/kg/d), erythromycin (20-50 mg divided into 3 doses; adults, 2 g/d), trimethoprim-sulfamethoxazole (40 mg/kg/d sulfamethoxazole, 8 mg/kg/d trimethoprim) are good alternatives and, like doxycycline, are usually given for 14-28 days. Immunodeficient patients need a more prolonged course of treatment, usually as long as 4 months. Steroids are also indicated for ocular disease.[29, 30]

• Treatment of chorioretinitis due to fungal infections can be difficult and prolonged. Intravitreous amphotericin B (5-10 mcg) has been used to treat serious fungal chorioretinitis.

  • Candida species infection: Fluconazole (6-12 mg/kg/d) and amphotericin B (0.75-1 mg/kg/d) has been recommended as preferred antifungals for treatment of Candida endophthalmitis. New-generation triazoles (eg, voriconazole, posaconazole, ravuconazole) are changing the conventional approach to fluconazole-resistant Candida strains, as well as the approach to fungal endophthalmitis. Caspofungin is the first echinocandin approved to treat fungal endophthalmitis. Concomitant systemic caspofungin and voriconazole therapy has successfully treated endophthalmitis due to Candida albicans.[31, 32, 33, 34] Experimental intraocular voriconazole (≤ 25 mcg/mL) has been used for azole-resistant Candida infection with some success.

  • Ocular histoplasmosis: Treatment is limited to photocoagulation of neovascular membranes, particularly when the macula is threatened. Antifungal therapy has no role in treatment of this disease because no actively replicating organisms are present. Amphotericin B is used to treat systemic disease (0.75-1 mg/kg/d).[35]

  • Cryptococcus species infection: Amphotericin B (0.75-1 mg/kg/d) is used.

• Antituberculosis drugs are administered in patients with M tuberculosis (MTB) and include isoniazid (10-30 mg/kg/d), rifampicin (10-20 mg/kg/d), pyrazinamide (30 mg/kg/d), and ethambutol (15 mg/kg/d). Other drugs, such as aminoglycosides and quinolones, may be used for treatment of drug-resistant organisms. Duration of therapy depends on the extent of the disease and on the immune status of the host.

• Anthelmintics, including diethylcarbamazine (6 mg/kg/d), albendazole (400 mg PO bid), and mebendazole (100-200 mg PO bid), are usually administered with corticosteroids in patients with toxocariasis or baylisascariasis.

• Etiologic treatments may not alter the clinical course of chorioretinitis because the pathologic changes may be due to an inflammatory and/or immunologic response instead of infection.

• Treatment of other infectious etiologies, such as syphilis, yersiniosis, neuroborreliosis, depends on extent of disease but is likely to be successful in most patients.

Eye symptoms can be treated as follows:

• Steroids may have a role in the acute management of many vasculitides, collagen vascular diseases, or sarcoidosis; in some infectious processes (eg, MTB); or in some cases infections caused by Toxoplasma species.

• Laser treatment of retinal lesions is used in certain conditions with good results.

Vitrectomy is usually not needed and is reserved for severe cases that are resistant to conservative medical treatment.

Ocular cytology used to detect the presence of eosinophils, ocular antibody, and immunoglobulin E (IgE) levels should always be performed to differentiate toxocaral ocular larva migrans from malignant retinoblastoma to prevent unnecessary enucleations.

Involvement of the following specialists is helpful in performing a diagnostic workup, determining the length of treatment, and planning the total management of a child with chorioretinitis:

• Ophthalmologist - For determination of eye damage, treatment, and long-term follow-up care

• Infectious disease specialist - For diagnostic workup, selection of therapeutic agents and options, investigation of potential drug toxicities, and determination of treatment length in consultation with the ophthalmologist

Other specialists include the following:

• Neurologist - For seizure control and long-term follow-up care of neurologic deficits

• Allergy and immunology/rheumatology specialist - To treat other associated conditions (ie, juvenile rheumatoid arthritis)

• Audiologist - For assessment and corrective measures to detect and treat deafness (if possible)

• Physical therapist - For maximization of functions and range of motions of muscles and joints and for referral to an orthopedist for surgical intervention if needed

Occasionally, genetic testing is required to investigate possible dysmorphic syndromes.

Over the last few years the list of therapeutic options available has grown. This section includes information on specific treatment options available.

Class Summary

Treatment of congenital viral infections with chorioretinitis, such as HSV (CNS, mucocutaneous, sepsis), CMV, or varicella-zoster virus, has resulted in lower mortality rates. Older children may benefit from intravitreal administration, which requires consultation with an ophthalmologist.

Foscarnet (Foscavir)

Analog of pyrophosphate. Inhibits DNA polymerase of CMV and reverse transcriptase of HIV. Virostatic with renal excretion. As effective as ganciclovir. Median time to relapse is 53 d.

In the foscarnet and ganciclovir CMV retinitis trial, 234 newly diagnosed patients were randomized. Same efficacy was reported for controlling retinitis and preserving vision. Survival with foscarnet was 12.6 mo versus 8.5 for ganciclovir group; mortality risk was 1.79x. Controlling for antiretroviral use, still better survival with foscarnet. Foscarnet has anti-HIV activity but has more dose-limiting toxicity.

Valganciclovir (Valcyte)

L-valyl ester prodrug of ganciclovir used to treat CMV retinitis in patients with AIDS. Ganciclovir is synthetic analogue of 2'-deoxyguanosine, which inhibits replication of human CMV in vitro and in vivo. Inhibits viral activity by inhibiting viral DNA synthesis. Has the advantage of once daily or bid PO administration. Achieves levels comparable to those obtained with IV ganciclovir.

Acyclovir (Zovirax, Avirax)

Indicated for neonatal HSV and varicella-zoster infections. Treatment is most efficacious when started earlier in disease course. More effective in younger children than in adults.

Ganciclovir (Cytovene)

Indicated for CMV retinitis. Synthetic guanine derivative active against CMV. An acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Levels of ganciclovir-triphosphate are as much as 100-fold more than in CMV-infected cells than in uninfected cells, possibly due to preferential phosphorylation of ganciclovir in virus-infected cells. For patients who experience progression of CMV retinitis while receiving a maintenance treatment with either dosage form of ganciclovir, the reinduction regimen should be administered.

Cidofovir (Vistide)

Used for CMV retinitis. Nucleotide analog that selectively inhibits viral DNA production in CMV and other herpes viruses.

Class Summary

Pyrimethamine and sulfadiazine are synergistic against Toxoplasma species. Spiramycin is used to treat pregnant women. Clindamycin has occasionally been administered to patients with AIDS and CNS toxoplasmosis. It is also used in patients who are unable to tolerate pyrimethamine and sulfadiazine due to side effects. Other treatments with atovaquone and newer macrolide antibiotics are being investigated.

Pyrimethamine (Daraprim)

Folic acid antagonist that selectively inhibits plasmodial dihydrofolate reductase. Highly selective against plasmodia and T gondii. Length of treatment is not well documented. Some infants with active chorioretinitis have been treated for more than 6 mo. Most often combined with sulfadiazine or clindamycin.

Sulfadiazine (Microsulfon)

Used synergistically with pyrimethamine. Length of treatment is not well documented. Some infants with active chorioretinitis have been treated for more than 6 mo. Administer with pyrimethamine.

Spiramycin

Used in European countries to lower risk of vertical transmission of toxoplasmosis in primoinfections of pregnant women by 60% but does not ameliorate fate of infants who are infected. Not commercially available in the US (obtain from FDA). Take on an empty stomach.

Clindamycin (Cleocin)

Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. As an alternative to sulfonamides, clindamycin may be beneficial when used with pyrimethamine in acute treatment of CNS toxoplasmosis in patients with AIDS.

Dapsone (Avlosulfon)

Bactericidal and bacteriostatic against mycobacteria; mechanism of action is similar to that of sulfonamides where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth.

Class Summary

Amphotericin B and its various lipid forms are the principal drugs for parenteral use. For synergy, 5 flucytosine (5FC) could be administered with amphotericin B. Azoles (chiefly fluconazole, itraconazole, and voriconazole) are agents of choice for long-term oral therapy. Both voriconazole and caspofungin are being increasingly used in patients with susceptible fungal infections as well as those resistant to conventional antifungal agents

Amphotericin B (Amphocin, Fungizone)

Produced from a strain of Streptomyces nodosus. Antifungal activity of amphotericin B results from its ability to insert itself into fungal cytoplasmic membrane at sites containing ergosterol or other sterols. Aggregates of amphotericin B accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium). At low concentrations, the main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity; however, at higher concentrations, pores of 40-105 nm in cytoplasmic membrane are produced, leading to large losses of ions and other molecules. A second effect of amphotericin B is its ability to cause auto-oxidation of the cytoplasmic membrane and release of lethal free radicals. Main fungicidal activity of amphotericin B may reside in ability to cause auto-oxidation of cell membranes.

Particularly active against Candida, Cryptococcus, and Aspergillus species.

Fungal endophthalmitis has been treated with intraocular injection of amphotericin B. An infectious diseases specialist should be consulted regarding the appropriate protocol and dosage. Several studies have shown poor intravitreal penetration when administered systemically.

Special attention is required when making the dilutions and injecting in gas-filled eyes because it has a narrow therapeutic range and can cause retinal toxicity. Subconjunctival injections of amphotericin B have no role in fungal ocular infections.

Flucytosine (Ancobon)

Although the exact mode of action is unknown, flucytosine is believed to act directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and is believed to act indirectly by intracellular metabolism, in which it is converted to 5-fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against Candida and Cryptococcus species; generally used in combination with amphotericin B.

Use in combination with another agent because acquired resistance develops frequently when flucytosine is administered alone.

Well absorbed PO but should be administered IV to critically ill patients.

Fluconazole (Diflucan)

Synthetic PO antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. Available as tablets for PO administration, as a powder for PO susp, and as a sterile solution for IV use. Has fewer adverse effects and better tissue distribution than older systemic imidazoles.

Effective against Candida, Cryptococcus, and Aspergillus species. Bioavailability following PO administration is comparable with parenteral administration. Good CSF and intravitreal penetration is achieved after systemic administration.

Itraconazole (Sporanox)

Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Voriconazole (VFEND)

Used for primary treatment of invasive aspergillosis and treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. Has also proven to be effective for the treatment of disseminated Candida infections as well as other fungal infections (eg, cryptococcus, Blastomyces).

Caspofungin (Cancidas)

Used to treat refractory invasive aspergillosis. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall. Also approved for the treatment of candidemia and general invasive candidiasis in adult patients. Emerging role in treating fungal endophthalmitis with or without voriconazole.

Class Summary

Parasite biochemical pathways are different from those of the human host; thus, the toxicity is directed to the parasite, egg, or larvae. The mechanism of action varies within the drug class. Antiparasitic actions may include the following:

- Inhibition of microtubules, which causes irreversible block of glucose uptake

- Tubulin polymerization inhibition

- Depolarizing neuromuscular blockade

- Cholinesterase inhibition

- Increased cell membrane permeability, resulting in intracellular calcium loss

- Vacuolization of the schistosome tegument

- Increased cell membrane permeability to chloride ions via chloride channels alteration

Albendazole (Albenza)

A benzimidazole carbamate drug that inhibits tubulin polymerization, resulting in degeneration of cytoplasmic microtubules. Decreases ATP production in worms, causing energy depletion, immobilization, and, finally, death. Converted in the liver to its primary metabolite, albendazole sulfoxide. Less than 1% of the primary metabolite is excreted in the urine. Plasma level is noted to significantly rise (as much as 5-fold) when ingested after high-fat meal. Experience with patients < 6 y is limited.

To avoid inflammatory response in CNS, patients must also be started on anticonvulsants and high-dose glucocorticoids.

Diethylcarbamazine (Hetrazan)

A piperazine derivative, diethylcarbamazine has effects on the 5-lipoxygenase pathway, targets the cyclooxygenase pathway and COX-1, and enhances the phagocytosis of the parasite.

Mebendazole (Vermox)

Exerts inhibitory effect on tubulin polymerization resulting in loss of cytoplasmic microtubules in the parasite.

Children with congenital infections and chorioretinitis (CR) face many possible handicaps, including partial or total loss of vision, deafness, seizure disorders, and mental retardation. Short-term care for individuals with chorioretinitis includes diagnostic and management planning. Management planning requires participation of several specialists included but not limited to the ophthalmologist, infectious disease specialist, neurologist, physiotherapist, and child development specialist.

Long-term care should alleviate debilitating conditions and improve functions for patients with chorioretinitis. An involved primary care physician should work closely with the specialists, the school system, and social workers.