Fig. 3.1
(a) Maculopapular skin rash in a patient with Mediterranean spotted fever. (b) Dark spot, also called “tache noire,” in a patient with Mediterranean spotted fever
3.4.2 Ocular Disease
Ocular involvement is common in patients with rickettsiosis, but because it is usually asymptomatic and self-limited, it may be easily overlooked [3, 10]. Affected patients, however, may present with ocular complaints, including vision blurring, scotomata, floaters, or redness. Retinitis, retinal vasculitis, and optic nerve involvement are the most common ocular findings, but an array of other ocular manifestations also may occur.
3.4.2.1 Adnexal and Anterior Segment Manifestations
Conjunctiva may be a portal of entry for R. rickettsii, as well as R. conorii infection, by a spurt of ticks blood. This may result in unilateral conjunctivitis that can accompany a Parinaud’s oculoglandular syndrome (Fig. 3.2) [11, 12]. Bilateral conjunctivitis also has been described in patients with MSF, as well as RMSF [13]. Subconjunctival hemorrhages, conjunctival petechiae, keratitis, nongranulomatous anterior uveitis, and iris nodule have also been reported in association with rickettsial disease [11, 14, 15].
Fig. 3.2
Parinaud’s oculoglandular syndrome in a patient with Mediterranean spotted fever. Slit-lamp photograph of the left eye shows unilateral conjunctivitis with purulent discharge. There was an associated ipsilateral swollen preauricular lymph node
3.4.2.2 Retinochoroidal Involvement
Retinochoroidal involvement is common, affecting, for instance, more than 80 % of patients with acute MSF [3]. However, it is often asymptomatic. Posterior segment manifestations typically include retinitis, retinal vascular changes, and optic disc involvement, with mild or no vitritis.
Retinitis
Retinitis, primarily involving the inner retinal layers, is the most common clinical finding, occurring in approximately one third of patients with acute MSF [3, 16–20]. It presents as white retinal lesions, variable in size and number, involving the posterior pole or the peripheral retina, typically adjacent to retinal vessels (Figs. 3.3a and 3.4a). Small lesions in the posterior fundus may strikingly resemble cotton-wool spots. Fluorescein angiography shows early hypofluorescence and late staining of large retinal lesions and isofluorescence or moderate hypofluorescence of small retinal lesions [3]. Optical coherence tomography (OCT) exhibits increased internal reflectivity of retinal lesions, with posterior shadowing. It also usually shows macular edema and serous retinal detachment in association with large white retinal lesions (Fig. 3.4b and c) [6].
Fig. 3.3
A 43-year-old woman with a history of recent febrile illness complained of blurred vision in the right eye. Visual acuity was 20/20. (a) Fundus photograph of the right eye shows a juxtavascular white retinal lesion superotemporally, close to the optic disc. Note the presence of associated retinal vascular sheathing and optic disc hyperemia. Fluorescein angiography shows early hypofluorescence (b) and late staining (c) of the white retinal lesion, retinal vascular leakage, and mild optic disc hyperfluorescence. Serology was positive for R. conorii. The patient received doxycycline (100 mg twice a day) for 10 days. (d) Fundus photograph of the same eye, taken 2 months after initial presentation shows an almost complete resolution of the white retinal lesion without obvious chorioretinal scarring. Note the residual periarterial sheathing
Fig. 3.4
A 37-year-old woman with Mediterranean spotted fever presented with vision loss in the left eye. Visual acuity was 20/200. (a) Fundus photograph of the left eye shows juxtapapillary white retinal lesions temporally and superiorly with associated small retinal hemorrhage. (b, c) OCT shows increased internal reflectivity with posterior shadowing corresponding to the temporal retinal lesion and associated cystoid macular edema and serous retinal detachment
There are reports of multiple small white retinal lesions in other rickettsioses including RMSF, Queensland tick typhus, and murine typhus [21–26]. Multiple retinal lesions similar to those seen in multiple white dot syndrome have also been reported [14, 27].
The pathogenesis of rickettsial retinal involvement remains speculative. Retinitis could develop as a consequence of multiplication of rickettsial microorganisms within retina. Alternatively, immune response to bacteremia might induce immune complexes and inflammatory cells to form white infiltrates through deposition in retinal vessels [3].
Rickettsial retinitis has a self-limited evolution in most patients with progressive resolution of white retinal lesions, within several weeks. There is usually no visible residual chorioretinal scarring [3].
Retinal Vascular Involvement
The marked tropism of rickettsial organisms for retinal vasculature is evidenced by the frequent occurrence of retinal vascular involvement. This may include focal or diffuse retinal vascular sheathing; arterial plaques similar to toxoplasmic Kyrieleis arteritis; superficial, deep, or white-centered retinal hemorrhages; and retinal vascular leakage on fluorescein angiography, mostly in the vicinity of white retinal lesions (Fig. 3.3). Vascular occlusive events may occur, usually in the form of asymptomatic or symptomatic branch retinal arteriolar occlusion that is usually intimately related to a white retinal inflammatory lesion. Central retinal artery occlusion and retinal vein occlusions have been less commonly reported [3, 10, 28–32].
3.4.2.3 Neuro-ophthalmic Manifestations
Optic nerve involvement is common, reflecting the tropism of rickettsial organisms for optic disc vasculature besides retinal vasculature. It may include optic disc edema, optic disc hyperfluorescence, optic neuritis, neuroretinitis, and ischemic optic neuropathy. Third and sixth cranial nerve palsies have also been reported in this setting [3, 10, 16–18, 33, 35–39].
3.5 Diagnosis
Diagnosis of rickettsial infection is usually suspected on the basis of clinical features (ocular and systemic) and epidemiological data. Serology is the most widely used method to confirm the diagnosis. Serum may be tested by immunofluorescence (IF) for rickettsial antigens, which is the gold standard for laboratory diagnosis. IF is considered positive when there is either initial high antibody titer or a fourfold rise of the titer in the convalescent serum. Case confirmation with IF might take 2–3 weeks. Other serological tests include Weil-Felix test, latex agglutination, indirect hemagglutination, immunoperoxidase assay, and ELISA. Cell culture systems and molecular methods for isolating rickettsial agents from human samples including quantitative PCR (qPCR) are less available techniques and performed only in selected cases [1, 17, 40].
In a patient suspected as having rickettsial systemic disease, a systematic fundus examination, revealing frequently abnormal, fairly typical findings, can help to establish the diagnosis while serologic testing is pending [3].
3.6 Differential Diagnosis
The differential diagnosis of rickettsiosis includes numerous systemic infectious and noninfectious diseases manifesting with acute febrile illness, such as typhoid fever, measles, rubella, enteroviral infection, meningococcemia, disseminated gonococcal infection, secondary syphilis, leptospirosis, cat scratch disease, infectious mononucleosis, arbovirus infection, Kawasaki disease, Behçet’s disease and other systemic vasculitic disorders, idiopathic thrombocytopenic purpura, and drug reaction.
Specific epidemiological data, history, systemic symptoms and signs, and ocular findings can help differentiate rickettsial ocular disease from other infectious or noninfectious causes of retinitis, retinal vasculitis, or optic neuropathy. The differential diagnosis includes toxoplasmosis, cat scratch disease, syphilis, herpetic disease, chikungunya, Behçet’s disease, and sarcoidosis. Small retinal infiltrates in the posterior fundus should be differentiated from cotton-wool spots that may be associated with a wide variety of ocular or systemic conditions [16–18].
3.7 Management
Early empirical antibiotic treatment should be given for any suspected rickettsiosis. Doxycycline (100 mg every 12 hours for 7–10 days) is the drug of choice for the treatment of rickettsial disease. Antibiotic treatment for systemic disease may be terminated 48 hours after the patient is afebrile. Other tetracyclines, chloramphenicol, and fluoroquinolones are also effective. Macrolides, including clarithromycin, azithromycin, and particularly josamycin can be used as alternative therapy in children and pregnant women [1, 41].
Additional therapeutic agents may be required for ocular disease: topical antibiotics for conjunctivitis or keratitis; topical corticosteroids and mydriatics for anterior uveitis; systemic corticosteroids for severe ophthalmic involvement, including extensive retinitis threatening the macula or optic disc, serous retinal detachment, macular edema, retinal vascular occlusion, severe vitritis, and optic neuropathy; and anticoagulant agents for retinal vascular occlusions. The role of antibiotic therapy, as well as that of oral steroids, on the course of posterior segment involvement, remain unknown. The effect of anticoagulants on the course of retinal occlusive complications is also unclear [3, 16–18].
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