Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

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12.1 Introduction

Ocular structures as well as the brain can be affected by many infectious diseases. The blood– brain barrier controls the passage of molecules or potential sources of infection from the blood into the brain. In the presence of meningitis the blood–brain barrier is disrupted and allows molecules or infectious agents to penetrate the eyes. Inflammatory processes such as septicemia or viremia trigger the liberation of large amounts of inflammatory molecules within the bloodstream. The upregulation of the inflammatory cascade produces a rupture of the blood–brain or blood– ocular barrier so that infectious agents can then penetrate into the eyes or the brain.

Neuroophthalmic examination can reveal the presence of cranial nerve palsies, pupillary reflex anomalies, retinal lesions or optic disc swelling. Cerebrospinal fluid analysis will reveal the presence of concomitant brain infection.

Classic infectious agents simultaneously affecting the brain and ocular structures belong to 12 two main groups: those causing zoonotic diseases (i.e., transmitted by animals) and those caused by

sexually transmitted diseases.

Most of these diseases will be revealed only by a careful ocular or neurological examination. A close collaboration is necessary between ophthalmologists and neurologists. Specific retinal manifestations of infectious disease are helpful for guiding further clinical and laboratory investigations.

12.2 Ocular Zoonosis

Zoonosis means a wide group of infectious disea­ ses that can be transmitted by animals to humans. The incidence of disease in humans is particularly high in areas where animals are infected endemically. A better understanding of the mode of transmission of the disease is an important step in the development of prevention programs.

geographic regions and population groups on the basis of numerous factors. According to the Third National Health and Nutrition Examination Survey, the overall age-adjusted seroprevalence was 22.8% (95% confidence interval, CI, 21.1–23.9) [24]. In France about 67.3% of pregnant women have been previously infected. Most primary infections are asymptomatic and the infection then enters a latent phase. Bradyzoites are present, forming cysts in nervous and muscle tissues. Ocular infection is estimated to occur in about 2% of individuals infected with T. gondii. However, the incidence of ocular involvement (retinochoroidal scars) may be much higher: about 17.7% of the population of South Brazil presents with retinal lesions.

The infection occurs when raw or partly cooked meat is eaten: pork, lamb and venison are the main sources of infection. Contamination can also occur after contact with contaminated instruments (knives, cutting boards or food that have been in contact with raw meat). Hand-to- mouth contact is also a source of infection when a cat’s litter box is cleaned. Ingestion of unpasteurized cow’s or goat’s milk is also a source of contamination. More recently, the ingestion of contaminated water was also mentioned as a potential source of infection [24].

Flu-like symptoms occur during acute infection. Swollen lymph nodes are present and muscle aches and pain can last for more than a month. During the acute phase of the disease a dissemination of trophozoites occurs. The disease remains asymptomatic for years in most cases. Bradyzoites are present and form cysts in nervous and muscle tissues. In about 2% of individuals, eye structures are colonized and reactivation of the disease can occur later in life. The natural history of toxoplasmosis depends on the immune response of the host; three conditions have to be considered: congenital toxoplasmosis, reactivation of ocular toxoplasmosis and toxoplasmosis in patients with acquired immunodeficiency syndrome (AIDS).

Toxoplasmosis has a worldwide distribution and is related to Toxoplasma gondii infection. The prevalence of T. gondii infection varies between

When primary infection of the mother occurs during pregnancy, the devastating consequences of congenital toxoplasmosis can be seen. About 0.5%

of pregnant women throughout the world are affected by primary toxoplasmosis infection. The risk of transmission of the disease to the fetus varies from 30% to 60%. During the first trimester of pregnancy transmission occurs in about 10% of cases, 30% in the second trimester and 60% in the third trimester. During the early stage of pregnancy, toxoplasmosis is responsible for spontaneous abortion [19]. Later, congenital infection leads to the development of a cataract or chorioretinitis. Macular scars appeared in 54% of treated patients; 23% were bilateral [38]. In the absence of therapy, historical cases have shown that 82% of congenitally infected individuals will develop ocular lesions by adolescence. The diagnosis of congenital infection is accepted when an infection is confirmed at an age of less than 2.5 months at the time of referral.

Systemic manifestations include anemia, petechiae associated with thrombocytopenia, pneumonitis, diarrhea and jaundice (associated with hepatoor splenomegaly).

Neurologic manifestations are severe and correspond to hemiparesis, seizure, microcephaly, hydrocephalus, intracranial calcification and encephalomalacia. Psychomotor or mental retardation is frequent [12].

Summary for Clinicians

■Severe manifestations of congenital toxoplasmosis are seen when the transmission of the disease occurs at the beginning of pregnancy: microcephaly, hydrocephalus, intracranial calcifications or cataract.

■When the primary infection occurs in the late stage of pregnancy, chorioretinitis can be observed.

12.2.1.2Reactivation

of Toxoplasmosis

in Immunocompetent Patients

Ocular toxoplasmosis is the most frequent cause of posterior uveitis. The aspect of retinitis does not differ between congenital and acquired toxo-

12.2  Ocular Zoonosis 207

plasmosis. Patients complain of photophobia, blurred vision and decreased visual acuity. Lesions are located mainly in the posterior pole (75% of cases) whereas only 25% are located in the periphery [17]. Slit-lamp examination reveals the presence of granulomatous anterior chamber inflammation with Mutton fat precipitates (Fig. 12.1). During the active phase of the disease, fundus examination reveals the presence of a yellowish focus of inflammation; this lesion corresponds to a focal chorioretinitis (Fig. 12.2). Usually, spontaneous resolution of the disease is seen in about 4–12 weeks.

In the presence of posterior uveitis a relapse of disease is observed in 29% of cases during the first year and in 57% of cases within 2 years. Intraocular cysts are not destroyed by anti-toxo- plasmic medication. Most current medications are only active against tachyzoites but not against tissular cysts. Recurrence of the disease occurs near old chorioretinal scars (satellite lesion). In immunosuppressed patients, the disease has a more severe evolution.

Complications of ocular toxoplasmosis include: macular scar, vascular occlusion, exudative retinal detachment, macular star, subretinal neovascularization, epiretinal membrane formation, and macular edema. Retinal detachment has been correlated to the severity of ocular inflammation.

The diagnosis of the disease is mainly clinical. Serological tests are used to confirm previous systemic infection with T. gondii. IgG antibodies usually appear 1–2 weeks after the onset of infection by T. gondii. Titers peak within 1–2 months and remain positive for the rest of that person’s life. IgM antibodies appear earlier and decrease faster than IgG antibodies. IgM antibodies disappear 6 months to 18 weeks after primary infection.

Current therapy of ocular toxoplasmosis consists of anti-protozoan therapy of sulfadiazine (3–4 g) and pyrimethamine (50 mg) combined with oral prednisone therapy (1 mg/kg) [21]. Other therapeutic options include atovaquone and spiramycin. Azithromycin was recently proposed as an alternative therapy [47, 63]. The aim of the therapy is to block the multiplication of the parasite during the period of active chorioretinitis. The introduction of therapy during the acute phase does not protect individuals from a

recurrence of the disease. When the recurrence occurs repetitively near the macula, prophylactic therapy with trimethoprim/sulfamethoxazole has a beneficial effect in the prevention of recurrences when administered intermittently on a long-term basis [51].

Neuroophthalmologic manifestations consist mainly of the presence of arcuate visual field defects that correspond to nerve fiber loss due to juxtapapillary retinochoroiditis [36]. Anterior optic neuritis (papillitis) can be observed when the lesion occurs within the optic disc. The lesion

is associated with an afferent pupillary defect. Neuroretinitis can also be observed.

Summary for Clinicians

■Toxoplasmosis is a common cause of retinochoroiditis.

■The disease can result from a primary infection or from a reactivation of dormant intraretinal cysts of Toxoplasmosis.

■Juxtapapillary toxoplasmosis can be responsible for the development of arcuate scotoma.

12.2.1.3Ophthalmic Toxoplasmosis in AIDS Patients

Ocular toxoplasmosis appears rarely in AIDS patients, but ocular lesions are more extensive than in immunocompetent patients. No spontaneous resolution of chorioretinitis has been reported to occur in AIDS patients. Small hemorrhages can be observed within the lesions. Rare cases of iris infection have also been reported.

Neuroophthalmologic manifestations correspond to lesions affecting the visual and ocular motor pathways in the presence of encephalitis or meningoencephalitis [44].

12.2.1.4Neurologic Manifestation of Toxoplasmosis

in AIDS Patients

Prophylaxis of cerebral toxoplasmosis is a major concern in the treatment of AIDS patients. The clinical and pathological incidence of cerebral toxoplasmosis in AIDS patients before the era of highly active antiretroviral therapy (HAART) were, respectively, 11.3% and 40%. Central nervous system (CNS) toxoplasmosis develops during the advanced stage of AIDS. Among patients with positive toxoplasma serology one in three will develop cerebral toxoplasmosis when the CD4 count is below 100×106/l. Symptoms of cerebral toxoplasmosis include headache, confusion, fever, lethargy and correspond to the presence of encephalitis or meningoencephalitis. The intro-

12.2  Ocular Zoonosis 209

duction of systemic prophylaxis of toxoplasmosis with trimethoprim/sulfamethoxazole or dapsone and pyrimethamine may decrease the incidence of cerebral toxoplasmosis. The diagnosis of cerebral toxoplasmosis remains difficult in AIDS patients, as false-negative laboratory results can result from a depressed antibody response.

Disseminated infections have been rarely observed in immunosuppressed or immunodeficient patients with pneumonitis, myocarditis, pericarditis and lymphadenitis [56].

12.2.1.5Radiologic Manifestation of Toxoplasmosis in AIDS

Neuroimaging reveals the presence of multiple intraparenchymal lesions that can be localized in the cerebral hemispheres, thalamus, brainstem or cerebellum. Lesions appear hypodense on a computed tomography (CT) scan in the absence of contrast material and are enhanced after injection of contrast material. Hyperdense lesions can be observed in unenhanced CT scans in the presence of hemorrhages. Magnetic resonance (MR) images are helpful in the detection of cerebral lesions that appear hypodense in unenhanced T1weighted images, and cerebral edema surrounding the lesions is seen in T2-weighted images.

Neuroradiologic imaging is not specific and the presence of CNS lymphoma, bacterial or fungal abscess must be ruled out. In AIDS, the probability of a solitary mass being CNS toxoplasmosis is 35%, whereas it is 62% in the presence of multiple lesions [7]. Lumbar puncture is performed to exclude the diagnosis of cryptococcosis.

Summary for Clinicians

■Cerebral toxoplasmosis is the commonest manifestation of toxoplasmosis in AIDS patients.

■Primary prophylaxis in patients with positive serology with a CD4+ cell count of less than 200×106/l is therefore recommended: co-trimoxazole or dapsone with pyrimethamine.

12.2.2 Toxocariasis

12.2.2.1 Introduction

Toxocara canis is a parasite responsible for visceral larva migrans or ocular toxocariasis. Dogs are the definitive host of Toxocara canis, with more than 80% of puppies being infected. Humans are infected when ingesting infective-stage eggs of the parasite. Young children are frequently infected when they play in contaminated sand areas. In young children, visceral larva migrans is a common manifestation of the disease, which is characterized by hepatomegaly, pulmonary signs and marked eosinophilia [48]. However, most infected individuals are asymptomatic. Parasitic infection is associated with hypereosinophilia. About 4.5%–31% of children test positive for Toxocara canis [15,46]. Among the 106 patients who tested positive for Toxocara canis, none had ocular infection [15].

12.2.2.3 Neurologic Manifestations

Hematogenous dissemination of the larvae to the brain or spinal cord has been observed. In the early stage of the disease, vascular occlusion of the vessels is seen, which can be followed by vessel rupture and intracranial hemorrhages. When the parasite subsequently dies a secondary granuloma develops. The lesions consist of lymphocytes, eosinophils, plasma cells, fibroblasts and epithelioid cells.

Summary for Clinicians

■Toxocara canis is a rare cause of ocular or cerebral infection.

■The diagnosis of retinoblastoma must be ruled out in the presence of leucocoria.

12 12.2.2.2 Ocular Manifestations

When the parasites migrate towards the eyes, the term ocular toxocariasis is used (less than 1% of uveitis). In young children ocular toxocariasis is a cause of leucocoria which can mimic the presence of a retinoblastoma. According to Zane F. Pollard, titers of 1:8 or greater should be considered as positive for ocular toxocariasis [43]. 17 out of 20 patients [43] . Concomitant visceral larva migrans is rare, as only 5/245 cases of ocular toxocariasis simultaneously had visceral larva migrans [5].

Ocular lesions are usually unilateral, and may present as posterior chorioretinitis, peripheral chorioretinitis, papillitis, neuroretinitis, endophthalmitis, motile chorioretinal nematode or diffuse unilateral subacute neuroretinitis (DUSN) [50]. Keratitis, conjunctivitis and lens involvement have also been described [50].

When the patient is asymptomatic and an ocular lesion is found, no therapy is necessary. The administration of albendazole, an anti-para- sitic drug, can be associated with severe ocular inflammation. In the presence of a severe ocular inflammation, an anti-parasitic drug must be used in association with systemic steroid therapy and/or vitrectomy.

12.2.3Diseases Transmitted by Ticks

12.2.3.1 Introduction

Two main diseases can be transmitted by tick bites: tick-borne encephalitis, which is caused by a flavivirus [13], and Lyme disease caused by the bacteria Borrelia burgdorferi. Both are transmitted by Ixodes ricinus ticks. Lyme disease is much more frequent than tick-borne encephalitis. In Switzerland about 1 tick out of 1000 is infected by the flavivirus while about 20% of ticks are infected with B. burgdorferi.

12.2.3.2 Tick-Borne Encephalitis

The following diseases are produced by a flavivirus: dengue fever, yellow fever, Japanese encephalitis and tick-borne encephalitis. Tickborne encephalitis is produced by an arbovirus, the flavivirus of the family Flaviviridae and of the genus Flavivirus. Tick-borne encephalitis is an important cause of morbidity and mortality in endemic areas. The disease is endemic in Central and Eastern Europe, Russia and Far East. The disease was first described by Schneider in 1931. The main hosts and reservoirs are small rodents; the

vectors are Ixodes ricinus and Ixodes persulcatus. Two routes of infection are classically admitted: the virus may enter the body through a tick bite or after ingestion of infected unpasteurized milk. The virus initially multiplies at the site of inoculation. Later it spreads through the reticuloendothelial cells of the lymph nodes and eventually it will produce a viremia through the thoracic duct.

Clinical manifestations of tick-borne encephalitis occur after a short incubation period of 7–14 days (range 2–28 days). A biphasic rise of fever occurs. The first period of fever is followed by an asymptomatic period of 2–10 days. The second rise of fever is associated with signs of meningitis or meningoencephalitis. During the acute stage of the disease

Flavivirus can be responsible for granulomatous inflammation of the eyes but ocular manifestations are much less frequent than encephalitis [13, 54].

12.2.3.3 Lyme Disease

12.2.3.3.1 Introduction

Lyme disease is a bacterial infection resulting from tick bite. About 60,000 cases are reported each year in Europe [41], where the disease has a more aggressive neurologic presentation than in USA. In USA, endemic areas for Lyme disease are in the Northeast (from Maine to Maryland), in the Midwest (Wisconsin and Minnesota) and in the West (North California and Oregon). In Europe the disease is mainly present in the middle of Europe and Scandinavia. American neuroborreliosis is caused predominantly by B. burgdorferi sensu stricto, whereas European disease is caused by B. garinii or B. afzelii (B. burgdorferi senso lato). Genetic differences between these subspecies appear considerable. Infection is transmitted by nymphs and adult ticks (Ixodes ricinus). Maturation from larval to nymphal and later adult stages requires the ticks to consume a blood meal. Risk of tick transmission remains low; fewer than 3.2% of patients bitten by ticks in endemic areas develop Lyme disease. The risk increases when ticks feed for 72 h or longer [49].

Borrelia burgdorferi belongs to the spirochetes, and, like syphilis, the disease has three stages. Early infection consists of localized erythema

12.2  Ocular Zoonosis 211

migrans (stage 1), followed within days or weeks by disseminated infection affecting the nervous system, heart, or joints (stage 2) and, weeks or months later, by the late or persistent stage of infection (stage 3).

1.Stage 1: localized erythema migrans occurs at the site of tick bite. Acute infection is associated with flu-like symptoms such as malaise, fatigue or headaches. In patients infected by B. afzelii a particular skin manifestation called acrodermatitis atrophicans may occur during chronic stage of the disease.

2.Stage 2: corresponds to the dissemination of the infection. It occurs in about 15% of untreated patients in USA [53]. Cardiac manifestations can be seen in 5% of untreated patients. Common manifestations correspond to a fluctuating degree of atrioventricular block, acute myopericarditis or mild left ventricular dysfunction.

3.Stage 3: up to 5% of untreated patients in USA will progress to the third stage of the disease which corresponds mostly to immunologic manifestations of the disease.

12.2.3.3.2Ophthalmologic and Neuroophthalmologic Manifestations

Ocular manifestations can be seen at any stage of the disease. Conjunctivitis appears during Stage 1 in about 10% of patients. The other manifestations are cranial nerve palsies, cortical blindness, optic disc edema, optic neuritis, neuroretinitis and retinitis. Endophthalmitis occurs mostly during Stages 2 and 3. Facial nerve paresis accounts for 80%–90% of all cranial nerve dysfunction of Lyme disease. Borreliosis must always be ruled out in the presence of a facial palsy in children (Fig. 12.3a). In most cases, resolution occurs after therapy (Fig. 12.3b). Abducens nerve paresis is another manifestation of disseminated Lyme disease [30]. Lyme uveitis is a granulomatous uveitis associated with keratic precipitates and posterior synechiae. Intermediate uveitis is a common manifestation in Lyme disease (Fig. 12.4) [61]. A mild to severe vitritis is present, and snowballs or snowbanks can be seen at the pars plana. Stromal keratitis with superficial and deep corneal infiltrates can also be observed in Stage 3 of the disease [33].