Fig. 11.1
Fundus photograph of the right eye of a patient with cat-scratch disease shows optic disk edema with telangiectasis, a complete macular star, and retinal and preretinal hemorrhages
Neuroretinitis usually has a self-limited course. Most patients recover excellent visual acuity over a period of several weeks to months [7]. The macular star usually resolves in approximately 8–12 weeks, but it may be present for up to 1 year. A few patients may be left with mild pallor of the optic disk [8]. Retinal pigment epithelial changes also may develop after resolution of a prominent macular star. Cat-scratch disease may occasionally present with a large inflammatory mass or exudate of the optic nerve head [9].
One or more white areas of inner retinitis or chorioretinitis, typically juxtavascular in location, may accompany neuroretinitis [7, 10] or occur in the absence of obvious optic disk involvement [7, 11, 12]. These retinal lesions were found to be more common than neuroretinitis by some authors [11]. They may be associated with an angiomatous-like proliferation of retinal capillaries, which is more clearly characterized by fluorescein angiography [13, 14]. The inner white retinal lesions in the posterior fundus may simulate cotton-wool ischemic spots, but their distribution in the fundus is not necessarily associated with the distribution of a first-order arteriole as is the case with cotton-wool spots. Branch retinal arteriolar occlusion [10, 11, 15] or branch retinal venous occlusion [8, 15] may be associated with an area of focal retinitis. A case of central retinal artery and vein occlusion has been reported [16].
Less common chorioretinal manifestations of CSD include large inflammatory retinal mass in the posterior pole [9], subretinal mass associated with an abnormal vascular network [16], intermediate uveitis with retinal vasculitis [17], unilateral panuveitis with clinical and fluorescein angiographic features simulating Vogt-Koyanagi-Harada disease [18], isolated serous macular detachment [19], serous macular detachment simulating central serous chorioretinopathy [20], macular hole [21], and vitreous hemorrhage [22].
11.2.4 Laboratory Investigations
The earliest test for the diagnosis is a positive skin test in response to CSD antigen. This test is likely to remain positive for life. Another possibility for the diagnosis is the detection of histopathological changes in a lymph node or conjunctival biopsy (the Warthin-Starry silver impregnation stain). The blood culture isolation of B. henselae is difficult, expensive, and requires 12–45 days. Thanks to the development of serological tests, the diagnosis of CSD is now much easier [23]. An indirect fluorescent antibody (IFA) test was developed to detect the humoral response to the organism. The sensitivity and specificity of this assay appear to be 90 % or better for immunocompetent patients [24]. Enzyme-linked immunoassays (EIA) and Western blot procedures were later developed, and EIA was shown to have IgG sensitivity of 86–95 % and specificity of 96 % compared with IFA [25]. A single positive indirect fluorescent antibody or enzyme immunoassay titer for IgG or IgM is sufficient to confirm the diagnosis of CSD. Positive IgM test is related to acute disease, but production of IgM is ephemeral. IgG titers less than 1:64 suggest the patient does not have Bartonella infection. Titers between 1:64 and 1:256 characterize possible infection, and the test should be repeated in 10–14 days. Titers greater than 1:256 suggest active or recent infection [1].
More recently, a polymerase chain reaction-based assay for the detection of B. henselae 16S ribosomal RNA gene in a very small sample of serum or other body fluids has been employed for diagnosis purposes [26].
11.2.5 Differential Diagnosis
Differential diagnosis of neuroretinitis includes several infectious and inflammatory diseases, including syphilis, Lyme disease, tuberculosis, sarcoidosis, diffuse unilateral subacute neuroretinitis (DUSN), toxoplasmosis, toxocariasis, leptospirosis, salmonella, chickenpox, herpes simplex, ehrlichiosis, rickettsioses, and recurrent idiopathic neuroretinitis [2]. Other causes of optic disk edema and macular star include systemic hypertension, diabetes mellitus, increased intracranial pressure, branch retinal vein occlusion, and anterior ischemic optic neuropathy.
11.2.6 Treatment
Till now, there are no guidelines for the treatment of CSD or its ocular complications. For most immunocompetent patients the disease has a self-limited course. Many physicians do not treat mild to moderate systemic CSD. They treat severe ocular or systemic complications of B. henselae infection in immunocompetent patients and all immunocompromised patients. They often use doxycycline, erythromycin, ciprofloxacin, azithromycin, trimethoprim-sulfamethoxazole, rifampin, or intramuscular gentamicin [23, 27].
A typical regimen for immunocompetent patients older than age 8 consists of doxycycline, 100 mg orally twice daily for 2–4 weeks. In case of severe infection, doxycycline may be given intravenously or used in combination with rifampin, 300 mg orally twice daily. Among immunocompromised individuals, treatment duration is extended to 4 months. Children with CSD may be treated with azithromycin. Paradoxical response to treatment has been reported in ocular bartonellosis [28]. The role of oral corticosteroids in the management of ocular CSD is unknown.
To prevent CSD, it is recommended to wash and disinfect any wounds immediately after a cat scratch or bite, and avoid contact with stray felines. Immunocompromised patients should be especially careful to avoid scratches and to control flea infestation. Long-term use of doxycycline or a macrolide antibiotic such as erythromycin may be useful for preventing recurrences in HIV-positive patients [2].
11.3 Lyme Disease
Lyme disease or Lyme borreliosis is an emerging tick-borne infection caused by a group of related spirochetes [29].
11.3.1 Epidemiology
Lyme disease is a worldwide-distributed infection. In North America, the only species of Lyme Borrelia known to cause human disease is Borrelia burgdorferi. In Europe, at least five species of Lyme Borrelia (B. afzelii, B. garinii, B. burgdorferi, B. spielmanii, and B. bavariensis) can cause the disease [29].
Lyme disease affects men slightly more often than women and has a bimodal age distribution, with peaks in children aged 5–14 years and in adults aged 30–59 years. Most cases occur between May and September.
11.3.2 Life Cycle and Pathogenesis
Animal reservoirs include deer, horses, cows, rodents, birds, cats, and dogs. The spirochete is transmitted to humans through the bite of infected ticks. The main vector of Lyme Borrelia in Europe is Ixodes ricinus, whereas Ixodes persulcatus is the main vector in Asia. Ixodes scapularis is the main vector in northeastern and upper midwestern USA, and Ixodes pacificus is the vector in western USA [29]. The pathogenesis of ocular involvement remains controversial, but the symptoms are believed to be due to direct ocular infection and a delayed hypersensitivity mechanism.
11.3.3 Clinical Features
11.3.3.1 Systemic Features
The clinical manifestations of Lyme disease have been divided into three stages: early, disseminated, and persistent or late stages [29, 30]. Early stage is characterized by erythema migrans that occurs 7–10 days following the bite, fever, and lymphadenopathy. Disseminated stage occurs few days to several months after the bite and may manifest with erythema chronica migrans, lymphocytoma, arthritis, and cardiac and neurologic manifestations. In late stage, patients may develop arthritis of major joints, progressive encephalomyelitis, and skin disorders.
11.3.3.2 Ocular Features
Ocular inflammation is uncommon and occurs mainly in the second and late stages of the disease. It may manifest as anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis [30–40]. Intermediate uveitis with associated granulomatous anterior chamber reaction and papillitis is the most common clinical presentation (Fig. 11.2). Retinal vasculitis may result in macular edema, vascular occlusion, and cotton-wool spots [41, 42]. A distinct clinical entity of peripheral multifocal choroiditis has been described in patients with Lyme disease. It is characterized by multiple, small, round, punched-out lesions associated with vitritis similar to those seen with sarcoidosis [31, 43]. Choroidal involvement may lead to retinal pigment epithelial clumping resembling the inflammatory changes seen with syphilis or rubella.
Fig. 11.2
Intermediate uveitis in a patient with Lyme disease with vitritis, retinal vasculitis, optic disk hyperfluorescence, and macular edema
Optic nerve involvement includes papillitis, optic neuritis, neuroretinitis, and papilledema associated with meningitis [44–46]. Neuro-ophthalmic manifestations include multiple cranial nerve involvement (II, III, IV, V, VI, and, most commonly, VII) unilaterally or bilaterally, either sequentially or simultaneously [30]. Horner syndrome, tonic pupil, and mydriasis have also been reported [30].
11.3.4 Laboratory Investigations
The diagnosis of Lyme disease is based on epidemiological data, medical history, clinical ocular and systemic presentation, and serology. However, false-positive serological tests may lead to incorrect diagnosis in the presence of conditions such as infectious mononucleosis, rheumatoid disease, autoimmune diseases, and other spirochetal infections. A testing approach using ELISA for IgM and IgG, followed by Western blot testing, is recommended [49].
PCR-based assays have been successfully used to amplify both genomic and plasmid B. burgdorferi DNA from a variety of tissues including ocular fluids, with the highest yields being obtained from the skin [32].
11.3.5 Differential Diagnosis
The differential diagnosis of uveitis associated with Lyme disease includes syphilis, tuberculosis, rubella, cat-scratch disease, sarcoidosis, leptospirosis, rickettsioses, and Whipple’s disease [30].
11.3.6 Treatment
Treatment of Lyme disease is based on combination of antibiotics and corticosteroids. The most commonly used antibiotics are amoxicillin, doxycycline, cefotaxime, and cefuroxime. Intraocular inflammation associated with Lyme disease may be treated with oral doxycycline 200 mg/day or intravenous ceftriaxone at the dose of 2 g IV qd in adults for at least 3 weeks [37]. New ketolide antibiotics such as telithromycin and cethromycin are very effective against Borrelia organisms with high plasma and tissue concentrations following oral administration and hold promise as alternative treatments for Lyme disease [50].
Anterior segment inflammation may be treated with topical corticosteroids and mydriatics.
One case of macular edema associated with Lyme disease treated with intravitreal triamcinolone has been reported [42].
A Jarisch-Herxheimer reaction with transient worsening of ocular symptoms after treatment has been reported in Lyme disease [31, 32].
Prevention strategies for Lyme disease include avoiding tick-infested habitats, use of tick repellents, wearing protective outer garments, prompt removal of attached ticks, and reducing tick populations.
Doxycycline chemoprophylaxis can reduce the chance of developing Lyme borreliosis after removal of an I. scapularis or an I. persulcatus tick. One 200 mg dose of doxycycline within 72 h of tick removal should be considered for individuals in highly endemic areas [29].
A trial on new vaccine against Lyme disease showed promising results [51].
11.4 Whipple’s Disease
Whipple’s disease is a rare, chronic, multisystem disease, caused by the gram-positive bacillus, Tropheryma whipplei. It was first described by George Hoyt Whipple in 1907 [52].
11.4.1 Epidemiology
Whipple’s disease is most common in middle-aged white men. The sex ratio is three males to one female, mostly of Caucasian origin. Mean age at diagnosis is 48–54 years for male patients and a few years older for female patients [53].
11.4.2 Clinical Features
Systemic involvement in Whipple’s disease includes migratory arthritis and gastrointestinal symptoms, including diarrhea, steatorrhea, and malabsorption [53]. Intestinal loss of protein results in pitting edema and weight loss. Cardiomyopathy and valvular disease can also occur. Central nervous system involvement occurs in 10 % of cases and may result in seizures, dementia, and coma [54].
Ocular involvement is rare in patients with Whipple’s disease and may occur alone or with gastrointestinal, neurologic, or other systemic manifestations. It occurs in less than 5 % of cases, usually late in the course of the disease [55]. However, in up to one third of the patients, ocular involvement may be the only clinical manifestation of disease before performing systemic investigations [56, 57].
A broad spectrum of ocular manifestations in Whipple’s disease has been reported including uveitis, retinitis, choroiditis, retinal vasculitis, retinal hemorrhages, and cystoid macular edema [55–65]. Patients can present with bilateral panuveitis and retinal vasculitis. Both granulomatous or nongranulomatous anterior uveitis and moderate to severe vitritis may be present. Diffuse chorioretinal inflammation and diffuse retinal vasculitis may occur. Retinal vascular occlusions, retinal hemorrhages, and vitreous hemorrhage may result from the vasculitis. Optic disk edema (Fig. 11.3) and, later, optic atrophy may occur. Other neuro-ophthalmic manifestations can include cranial nerve palsies, nystagmus, ophthalmoplegia, ptosis, and convergence paresis associated with oculomasticatory myokymia. Some patients develop progressive supranuclear palsy-like condition.
Fig. 11.3
Optic disk edema in a patient with Whipple’s disease
11.4.3 Laboratory Investigations
Diagnosis of ocular Whipple’s disease is challenging, especially in the absence of gastrointestinal involvement. Cytologic diagnosis, based on the observation of periodic acid-Schiff (PAS)-positive macrophages in biopsy of the duodenal mucosa, is still used routinely. It remains highly sensitive but is nonspecific. Electron microscopy can demonstrate the presence of degenerated bacillary microorganisms in the vitreous or gastrointestinal tract.
PCR analysis of peripheral blood and vitreous or cerebrospinal fluid may show T. whipplei DNA and confirm the diagnosis [64]. Culturing of T. whipplei is difficult, but possible [65].
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