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Home , Lyme disease, Syphilis

Fads and Epidemics in Infectious Disease: , Lyme and Bartonella Laura J. Balcer, M.D. Philadelphia, PA Objectives preantibiotic era estimated that syphilis would infect as At the conclusion of this program, participants will be able many as 10% of Americans during their lifetimes.1 to With the development of (particularly 1. Identify the neuro-ophthalmologic and ocular manifes- ) and the institution of measures to tations of syphilis, , and Bartonella control the spread of disease, incidence rates of primary henselae . and secondary infection reduced dramatically, reaching a 2. Apply current techniques for the diagnosis and treat- nadir in 2000 when only 5979 cases were reported in the ment of syphilis, Lyme disease, and Bartonella U.S.1 Since that time, overall incidence rates have again henselae infection with neurologic or ocular involve- increased, with marked variation with respect to geo- ment. graphic, racial, and other demographic factors. Epidemio- 3. Discuss important aspects of the epidemiology and logic studies have also suggested that syphilis increases pathogenesis of syphilis, Lyme disease, and Bartonella susceptibility to human immunodeficiency (HIV) henselae infection. infection, and increases the likelihood that patients with both syphilis and HIV will transmit HIV infection.1 To CME Questions control increases in the incidence of primary and second- 1. Which of the following neuro-ophthalmologic manifes- ary syphilis, the U.S. Centers for Disease Control and tations may occur in patients with syphilis, Lyme Prevention (CDC) have launched a National Plan to disease, or Bartonella henselae infection (i.e., which Eliminate Syphilis, with the goal of reducing the annual are common to all three disorders)? number of cases to 1,000 (incidence rate of 0.4/100,000/ a. year) by 2005.2 b. Optic nerve dysfunction c. II. Review of Clinical and Neuro-Ophthalmologic d. Both b and c Features Both the congenital and acquired forms of syphilis may be 2. Adult patients with Lyme disease and ocular or neuro- divided into disease stages. includes an logic involvement should receive which of the following early stage that develops before age 2 and resembles the treatments (assuming no allergies to )? secondary stage of acquired syphilis, and a late stage that a. 2 g IV once/day for 14-28 days corresponds to tertiary syphilis in acquired cases.2 b. Ceftriaxone 1 g IV once/day for 14-28 days Children with early congenital syphilis develop mucocuta- c. 100 mg orally twice daily for 14-21 neous , , and osteochondritis within days several weeks after birth.2 The most common ocular d. Ceftriaxone 2g IV once/day for 3 months manifestations of this stage include uveitis, , and retinal (salt-and-pepper retinal pigmentary 3. Which of the following are indications for performing a mottling (Table 1).2 Untreated early congenital syphilis in patients with syphilis? progresses to the late stage, characterized by bony and a. Neurologic or ocular are dental abnormalities. develops in present children with late congenital syphilis, most commonly b. Patient is HIV positive between the ages of 5 and 20 years (Table 1).2 c. RPR titer is 1:32 or higher Acquired syphilis includes four stages: primary, second- d. All of the above ary, latent (including early and late phases), and tertiary syphilis. Patients with primary syphilis develop a Syphilis () at the site of with I. Definition and Epidemiology pallidum; this manifestation occurs within 2-6 weeks 1, 2 Syphilis is an infectious disease caused by the spirochete, following exposure. The chancre is generally painless .1, 2 In a manner similar to Lyme and may go unnoticed, although regional disease (see below), acquired syphilis infection is charac- may also accompany this stage of infection. terized by a series of overlapping stages, including In untreated patients, secondary syphilis develops primary, secondary, latent, and tertiary disease.1 Infants approximately 4-10 weeks after the appearance of the 1 may also acquire congenital syphilis through maternal- chancre. A diffuse develops in >90% of patients, 1 fetal . Syphilis is transmitted through contact and is a presenting manifestation in 70%. The rash of with infectious lesions or body fluids. Studies from the secondary syphilis, while initially macular in , may 97 become maculopapular or papulosquamous if left un- treponemal tests in up to 1% of patients.1 The treated, affecting the hands and soles of the feet in RPR and VDRL, while useful for screening purposes, addition to other areas.1 Secondary syphilis represents may be negative in patients with . While it dissemination of infection, and is associated with ophthal- was once taught that treponemal test results remained mologic, neurologic, renal, gastrointestinal, and hepatic positive throughout the lifetimes of patients following disease, as well as constitutional symptoms.1, 2 While the primary infection, a recent study of 857 patients demon- most common ocular manifestation of secondary syphilis strated persistently positive MHA-TP and FTA-ABS is uveitis, this stage also overlaps with early neurosyphilis results in only 87% and 76% of patients, respectively, (a consequence of primary or secondary stages), charac- after a first episode of primary syphilis.1 terized by , cranial neuropathies, optic neuropa- As recommended by CDC criteria, a lumbar puncture thies (optic and perineuritis) and meningovascular should be performed in patients with syphilis and any one disease (Table 1).3 Signs and symptoms of secondary of the following features: 1) neurologic or ocular symp- syphilis generally resolve even without treatment, although toms or signs; 2) late latent syphilis or syphilis of unknown recurrences are common (25%).1 The early latent and duration in a patient with HIV; 3) active tertiary syphilis late latent stages of syphilis have been defined by the (i.e., iritis, , ); or 4) treatment failure for CDC as infection during the first year non-neurologic/ocular syphilis.1 Some authors suggest that following initial infection (early latent) or during the period a lumbar puncture should be performed in any patient thereafter (late latent).1 with HIV and syphilis, since these patients, and those with At least 30% of patients with untreated syphilis RPR titers of 1:32 or higher, are at greater risk for central develop late manifestations (tertiary syphilis) between 1 nervous system (CNS) involvement.1 and 50 years following infection.1 Uveitis is again the The interpretation of (CSF) results most common ocular finding, occurring in 2.5-5% of in patients with syphilis is complicated by the fact that patients who progress to this stage.2 Manifestations of many patients with syphilis also have HIV infection, late neurosyphilis may include meningitis, occlusive which may itself cause a pleocytosis or elevated protein menigovasculitis, cortical atrophy with dementia (general levels.1 CSF VDRL establishes the diagnosis of neuro- ), degeneration of the posterior columns (tabes syphilis if the result is positive, but such testing is only 30- dorsalis), and optic atrophy.2, 3 Cardiovascular disease is 70% sensitive.1 CSF FTA-ABS testing, however, is highly also a frequent manifestation of tertiary syphilis. Table 1 sensitive, and a negative result suggests strongly against highlights the most common ocular and neuro-ophthalmo- neurosyphilis.1 Treatment for neurosyphilis (see below) logic manifestations of syphilis, including all stages of should be considered in all patients with syphilis and with disease.1-6 CSF pleocytosis (>5 white blood cells/mm3) or elevated CSF protein level (>45 mg/dL). III. Diagnosis of Syphilis Since Treponema pallidum cannot be cultured, and IV. Treatment and Prevention darkfield examination and direct fluorescent Treatment recommendations for all stages of syphilis, stains from mucocutaneous lesions are insensitive, non- including patients with ocular and neurologic disease, have treponemal serologic tests (rapid plasma regain [RPR] been published by the CDC,1, 2 and are outlined in Table 2. and venereal disease research laboratory [VDRL]) and Parenteral penicillin G is the preferred treatment for all confirmatory treponemal specific tests (T. pallidum stages of syphilis.2 The recommended dose, duration, particle agglutination [TPPA], microhemagluttin assay for preparation, and route of administration (i.e., intravenous Treponema pallidum [MHA-TP], and fluorescent [IV] vs. intramuscular [IM] vs. oral [for doxycycline]) for treponemal [FTA-ABS]) are the laboratory treatment depend upon the stage of disease, the presence tests of choice for patients with suspected syphilis.1 The of neurologic/ocular involvement, and other factors. sensitivity of non-treponemal tests ranges from 78-86% in All patients with syphilis should receive clinical follow- primary syphilis, is approximately 100% at the secondary up with serologic testing at 6 and 12 months following stage, and decreases to 95% in latent disease. False- treatment (testing at 3, 9, and 24 months for HIV+ positive non-treponemal serologic tests (RPR titers <1:8 in patients).1 Persistence of signs or symptoms, failure of 90% of cases) may occur in the setting of autoimmune non-treponemal test titers to decline 4-fold (2 dilutions) disease, , and HIV infection, as well as other within 6 months, or sustained 4-fold increase in titers entities.1 In the non-HIV-infected patient, the FTA-ABS following treatment all constitute criteria for treatment or MHA-TP should almost always be positive in the failure.1 Lumbar puncture should be repeated at 3-6 setting of neuro-ophthalmologic signs and symptoms months to verify normalization of CSF in patients with suggestive of syphilis.3 HIV infection, however, may neurosyphilis. All patients with syphilis should receive cause false-negative results for both treponemal and non- testing for HIV and other sexually transmitted diseases. While a is not yet available, recently identified T. 98 pallidum immunogens may prove useful for vaccine (44%), (42%), and chills (39%), development.1 and lymphadenopathy (23%).7, 9 Stage 2 of early Lyme disease (early disseminated Lyme Disease disease) represents dissemination of the infection to I. Definition and Epidemiology various systems, and is characterized by neurologic Lyme disease is a multisystem disorder caused by infec- (particularly meningitis, cranial neuropathies, tion with the spirochete. The infection was first radiculoneuropathies), rheumatologic, and cardiac mani- described in the United States by Steere et al.7-9 in 1977, festations. Ocular signs also occur during stage 2 of early when he reported an epidemic form of among 51 Lyme disease. Late Lyme disease, or stage 3, may occur residents of three contiguous communities in , months to years following infection. Clinical manifesta- including Old Lyme. Transmission of Lyme disease by an tions of stage 3 include chronic arthritis, acrodermatitis arthropod was suggested by both early epidemio- chronica atrophicans, keratitis, and .7-9 logic studies and by the observation that the illness was This classification of disease stages has been incorpo- preceded by a skin lesion, rated into descriptions of the major neuro-ophthalmologic migrans (EM).7-9 Two important species of , and ophthalmic manifestations of Lyme disease, as (formerly Ixodes dammini) in the outlined in Table 3.7-13 eastern U.S. and in the western U.S. were subsequently implicated in disease transmission III. Diagnosis of Lyme Disease from their hosts (white-footed mice and white-tailed deer) While a definitive diagnosis of Lyme disease may be to humans.7 made by the culture of B. burgdorferi from specimens in Approximately 15,000 cases of Lyme disease are Barbour-Stoenner-Kelly medium (100% specificity), this reported in the U.S. each year, occurring primarily in the method has limited sensitivity (10% under ideal condi- Northeast (from Maine to Maryland), Midwest (Wiscon- tions) and is therefore not practical.7, 8 Polymerase chain sin and ), and West (northern California and reaction (PCR) testing is superior to culture for detecting Oregon).7 Lyme disease is likewise prevalent in Europe B. burgdorferi DNA in joint fluid and CSF, but is most and Scandinavia, and is also found in Russia, China, and helpful in cases of early disease and has been shown to Japan.7, 8 The causative agent for Lyme disease includes be positive in only a few patients with chronic three pathogenic species of spirochete; these include B. .7-9 burgdorferi in the U.S. and B. afzelii and B. garinii in The diagnosis of Lyme disease in the U.S. most often Europe and Asia. Differences in the clinical profiles of relies upon recognition of characteristic clinical findings, Lyme disease in North America vs. Europe and Asia have history of exposure in an area, observation of the been outlined in detail;7, 8 this review will focus on North EM rash (if present), and a positive antibody response to American Lyme disease (caused by B. burgdorferi). B. burgdorferi by enzyme-linked immunosorbent assay (ELISA) and .7 These criteria should be II. Review of Clinical and Neuro-Ophthalmic applied and interpreted according to guidelines published Features by the Centers for Disease Control and Prevention, which The clinical manifestations of Lyme disease have been has established a case definition for national surveil- divided into three chronological stages, analogous to those lance.7, 8 However, since B. burgdorferi may cause in syphilis.7-9 However, not all patients with Lyme disease asymptomatic infection, particularly in endemic areas, pass though each stage, and the signs and symptoms caution must be used in attributing clinical manifestations attributable to each stage are varied. It is more useful, to Lyme disease in all seropositive patients. therefore, to refer to the clinical features of Lyme disease While serologic testing is positive in only 20-30% of in terms of early and late manifestations.9 patients during the first several weeks of infection Early Lyme disease includes stage 1 (early localized (predominantly IgM response), the yield increases to 70- disease), characterized by the appearance of erythema 80% by 2-4 weeks, when most patients have IgG antibod- migrans (EM). EM is a slowly expanding erythematous ies for B. burgdorferi, even following treat- rash that occurs at the site of a tick bite, usually within 8- ment.7 Patients with initially negative Lyme serologies 9 days (range 2-28 days).7-9 Although EM is considered should therefore be retested later in their course. While the only pathognomonic criterion for the diagnosis of Western blot analysis is used to confirm the results of a Lyme disease (see Diagnosis), its presence may be noted positive ELISA or to clarify ambiguous results, this by only 60-80% of patients.7 The EM rash is usually itself technique is neither informative nor recommended in the asymptomatic, but is frequently accompanied by flu-like setting of a negative, reliable ELISA.9 Since patients with symptoms, including (54%), (44%), syphilis may have false-positive Lyme ELISA results, some authors have recommended that the Venereal 99 Disease Research Laboratory (VDRL) test and of improve more slowly, but no role microhemagglutination-Treponema (MHATP) test, or the has been demonstrated for treatment with IV antibiotics fluorescent treponemal antibody absorption (FTA-ABS) beyond a 4-week period.7, 9 test be obtained in patients with suspected Lyme disease.9 The issue of whether patients with I. scapularis tick The Ixodes scapularis tick vector is also responsible bites should be treated with prophylactic antibiotics was for the transmission of human granulocytic recently addressed by Nadelman et al.18 in a randomized, (HGE), a gram-negative bacterial infection that may placebo-controlled trial. In this study, EM developed at the mimic Lyme disease with respect to systemic symptoms site of the tick bite in 0.4% of patients treated with a (fever, , headache, myalgias, and rash).14-15 single 200 mg dose of doxycycline (given within 72 hours Patients with HGE also develop , elevated of the tick bite), while 3.2% of the placebo group devel- hepatic transaminases, and elevated erythrocyte sedimen- oped EM (p>0.04, Fisher’s exact test). Since the trans- tation rates. Therefore, although laboratory diagnostic mission of B. burgdorferi increases with the length of methods for HGE are not as well standardized as they are time that the tick is attached (maximum at 48 hours), for Lyme disease, it is recommended that patients with prompt removal is likely important in the prevention of suspected Lyme disease also receive indirect immunofluo- infection.9 Other measures for the prevention of Lyme rescence assay testing for HGE in areas in which HGE is disease include avoidance of tick-infested areas, use of endemic (Connecticut, New York, , Wiscon- protective clothing and repellents (DEET: N, N-diethyl-m- sin, Minnesota).14-15 toluamide), inspection for , and landscape modifica- In patients with meningitis or other acute neurologic tion in residential areas.7, 19 manifestations of Lyme disease, intrathecal antibody Two , consisting of recombinant B. burgdorferi production (IgM, IgG, or IgA) may be demonstrated by outer-surface protein A (Osp A) in adjuvant, have been antibody-capture-enzyme immunoassay.7 While this test is developed for Lyme disease.8, 20, 21 The Advisory Commit- less often positive in patients with chronic neurologic tee on Practice of the CDC advises that manifestations, it may be helpful in determining whether a for Lyme disease should be considered for positive serum titer reflects previous infection or is related patients aged 15-70 years who live in or visit high-risk to present neurologic signs.9 The presence of a lympho- areas and have frequent exposure to I. scapularis monocytic pleocytosis in the CSF is also consistent with ticks.8, 20, 21 Patients who have been treated for EM are active neurologic involvement.8 also candidates for vaccination.

IV. Treatment and Prevention Bartonella Henselae Infection Evidence-based recommendations for the treatment of I. Definition and Epidemiology Lyme disease, including recommendations for the duration The first clinical descriptions of ocular bartonellosis were of therapy in early disease, have been outlined in several provided by Henri Parinaud in 1889, when he reported recent reports (Table 4).7, 8, 16-18 For patients (older than 8 three patients with chronic fever, regional lymphadenopa- years of age) with early Lyme disease (stage 1) or thy, and follicular conjunctivitis.20 During the early 1900’s, disseminated infection (stage 2) without evidence of this was associated with cat exposure in some neurologic or ocular involvement, oral doxycycline is patients, and was subsequently known as Parinaud recommended.7, 8 In pregnant women, children, or patients oculoglandular syndrome.22 While the association of this who are allergic to doxycycline, is a second- syndrome with cat scratch disease has been confirmed by choice alternative. Although the recommended duration of numerous reports during the past 50 years, serologic oral therapy is 14 to 21 days, Wormser et al.16 recently evidence of Bartonella infection in association with demonstrated that 10 days of oral doxycycline in patients neuroretinitis, now the most well recognized ocular with early Lyme disease yielded similar outcomes to those manifestation, was not documented until 1994.22-23 treated for 20 days. While IV ceftriaxone is effective in Bartonella are small, fastidious, gram- early and disseminated Lyme disease, its efficacy did not negative rods.22 While a number of novel Bartonella exceed oral doxycycline alone in studies of patients species have been identified during the past decade, without neurologic involvement.7, 16 Bartonella henselae, the causative agent in cat scratch With the possible exception of isolated unilateral disease, is most often associated with ocular manifesta- peripheral VIIth nerve palsy without CSF abnormalities, tions.22 Reviews published in the year 2000 estimated that patients with neurologic or ocular manifestations should, in Bartonella henselae infection affects approximately most cases, receive a 2-4-week course of IV ceftriaxone 22,000 patients annually in the U.S.22 Cats are the (or alternative IV agents – Table 4).7, 8 Acute neurologic primary mammalian reservoir for B. henselae; seroposi- symptoms usually resolve within weeks, and relapse is tivity in cats is apparently most prevalent in areas with rare following a 4-week course of treatment. Symptoms large populations of , and in warm areas with higher 100 amounts of rainfall (Hawaii, coastal California, Pacific Answers to CME Questions Northwest).22 Cat bites and scratches are the primary 1. d mode of transmission of infection to humans. 2. a 3. d II. Review of Clinical and Neuro-Ophthalmologic Features Since the eye is the most commonly affected non- References lymphatic organ in patients with cat scratch disease,20 recognition of characteristic ocular findings, and subse- Syphilis: 1. Golden MR, Marra CM, Holmes KK: Update on syphilis: Resurgence quent serologic testing, are important factors in establish- of an old problem, JAMA 290:1510, 2003. ing the diagnosis of B. henselae infection. Patients often 2. Aldave AJ, King JA, Cunningham ET: Ocular syphilis, Curr Opin report a flu-like illness and regional lymphadenopathy Ophthalmol 12:433, 2001. 3. Liu GT, Volpe NJ, Galetta SL (eds.): Neuro-Ophthalmology: prior to the development of neuro-ophthalmologic mani- Diagnosis and Management. Philadelphia: W.B. Saunders Company, festations.22-23 Systemic symptoms also include headache, 2001. 4. Kuo IC, Kapusta MA, Rao NA: Vitritis as the primary manifestation , anorexia, nausea, and vomiting. Pustules, of ocular syphilis in patients with HIV infection, Am J Ophthalmol maculopapular , and may also 125:306, 1998. occur. Ocular involvement occurs in 5-10% of cases, and 5. Browning DJ: Posterior segment manifestations of active ocular 22 syphilis, their response to a neurosyphilis regimen of penicillin 1-2% may develop . Table 5 outlines the therapy, and the influence of human immunodeficiency virus status ocular and neuro-ophthalmologic manifestations of B. on response, Ophthalmology 107:2015, 2000. henselae infection.22-26 6. Danesh-Meyer H, Kubis KC, Sergott RC, et al.: Not so slowly progressive visual loss, Surv Ophthalmol 44:247, 1999.

III. Diagnosis of Bartonella henselae Infection Lyme Disesase: The diagnosis of B. henselae infection has significantly 7. Steere AC: Lyme disease, N Engl J Med 345:115, 2001. advanced by the development of an indirect immunofluo- 8. Hengge UR, Tannapfel A, Tyring SK, et al.: Lyme borreliosis, Lancet Infect Dis 3:489, 2003. rescence test for the detection of serum anti-B. henselae 9. Balcer LJ, Winterkorn JMS, Galetta SL: Neuro-ophthalmic antibodies.22 This serologic test, developed by the CDC, manifestations of Lyme disease, J Neuro-ophthalmol 17:108, 1997. has sensitivities and specificities that are >90% for 10. Mikkilä HO, Seppälä IJT, Wiljanen MK, et al.: The expanding 22 clinical spectrum of ocular Lyme borreliosis, Ophthalmology immunocompetent patients (<70% for HIV+ patients). 107:581, 2000. Isolation of Bartonella from blood or specimens is 11. Karma A, Seppälä I, Mikkilä H, et al.: Diagnosis and clinical possible but difficult, and growth of bacteria may require characteristics of ocular Lyme borreliosis, Am J Ophthalmol 119:127, 1995. up to 4 weeks. 12. Krist D, Wenkel H: Posterior scleritis associated with (Lyme disease) infection, Ophthalmology 109:143, 2002. IV. Treatment and Prevention 13. Rothermel H, Hedges III TR, Steere AC: Optic neuropathy in B. henselae infection is generally self-limited, and children with Lyme disease, Pediatrics 108:477, 2001. immunocompetent patients tend to do well even without 14. Frohman L, Lama P. Annual update of systemic disease – 1999; 22 Emerging and re-emerging . J Neuro-Ophthalmol antibiotic therapy. As such, uniform treatment recom- 19;263:1999. mendations have not been established.22 Nonetheless, 15. Weinberg GA. Laboratory diagnosis of ehrlichiosis and babeosis. some authors have reported that doxycycline (100 mg Pediatr Infect Dis J 20:435:2001. 16 Wormser GP, Ramanathan R, Nowakowski J, et al.: Duration of orally twice daily) and rifampin (300 mg orally twice antibiotic therapy for early Lyme disease, Ann Intern Med 138:697, daily) shorten the course of infection when compared 2003. 3, 23 17. Steere AC: Duration of antibiotic therapy for Lyme disease with historical controls. Treatment with these medica- [editorial], Ann Intern Med 138:761, 2003. tions is therefore considered in immunocompetent patients 18. Nadelman RB, Nowakowski J, Fish D, et al.: Prophylaxis with with severe ocular or neurologic involvement, and is single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite, N Engl J Med 345:79, 2001. recommended in patients with HIV infection. 19. Hayes EB, Piesman J: How can we prevent Lyme disease? N Engl J Immunocompromised patients should minimize their Med 348:2424, 2003. exposure to cat scratches and fleas, since B. henselae 20. Steere AC, Sikand VK, Meurice F, et al.: Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface infections in this group may be severe and even fatal. A with adjuvant, N Engl J Med 339:209, 1998. Children who are less than 8-12 years of age should not 21. Hayes EB, Dennis DT: Immunization against Lyme disease [letter], be treated with doxycycline (due to risk of tooth discol- N Engl J Med 339:1637, 1998. oration), and should be managed in consultation with a 22 Bartonella henselae Infection: pediatric infectious disease specialist. 22. Cunningham ET, Koehler JE: Ocular Bartonellosis, Am J Ophthalmol 130:340, 2000. 23. Reed JB, Scales DK, Wong MT, et al.: Bartonella henselae neuroretinitis in cat scratch disease: Diagnosis, management, and sequelae, Ophthalmology 105:459, 1998. 101 24. Suhler EB, Lauer AK, Rosenbaum JT: of serologic evidence of cat scratch disease in patients with neuroretinitis, Ophthalmology 107:871, 2000. 25. Ormerod LD, Skolnick KA, Menosky MM, et al.: Retinal and choroidal manifestations of cat-scratch disease, Ophthalmology 105:1024, 1998. 26. Kawasaki A, Wilson DL: Mass lesions in the posterior segment associated with Bartonella henselae, Br J Ophthalmol 248, 2002.

102 Table 1: Neuro-Ophthalmologic and Ocular Manifestations of Syphilis

Description/Signs/Symptoms Disease References/ Stages Reviews

Keratitis • Interstitial keratitis most commonly associated Congenital Aldave et al.2 with congenital syphilis in pre-antibiotic era Tertiary • Stromal keratitis occurs in both congenital and tertiary syphilis

Uveitis • Most common ocular manifestation of both Secondary Aldave et al.2 secondary and tertiary syphilis Tertiary Kuo et al.4 • Includes granulomatous and non-granulomatous iridocyclitis, vitritis, chorioretinitis, panuveitis, posterior uveitis, and keratouveitis • May cause increased IOP, secondary glaucoma

Retinitis/Retinal • Includes retinal vasculitis and , focal Secondary Aldave et al.2 Vasculitis retinitis, periphlebitis, exudative retinal Tertiary Browning5 detachment • Occurs in setting of syphilitic uveitis • Appearance may resemble other causes of retinitis

Optic Nerve • Manifests as retrobulbar , papillitis, Secondary Liu et al.3 Dysfunction perineuritis, and neuroretinitis Tertiary Danesh-Meyer et al.6 • Severity of visual loss is variable • Optic atrophy and progressive visual loss may occur in tertiary syphilis

Pupillary • Pupils are small, irregular, exhibit light-near Tertiary Liu et al.3 Abnormalities dissociation (Argyll-Robertson) • Damage to interneurons connecting pretectal with Edinger-Westphal nuclei

Meningitis/Cranial • Most common clinical manifestations of early Secondary Golden et al.1 Neuropathies/ neurosyphilis Tertiary Meningovascular • Occur within weeks to a few years after infection Disease

General Paresis • Rapidly-progressive dementia with psychotic Tertiary Golden et al.1 features • Common feature of late neurosyphilis

Tabes Dorsalis • Spinal cord disorder with sensory , bowel Tertiary Golden et al.1 and bladder dysfunction • Common feature of late neurosyphilis

103 Table 2: Treatment Recommendations for Syphilis *

Clinical Manifestation/ Drug Dosage Disease Stage

Primary Syphilis, Benzathine penicillin G 2.4 million units IM, single dose Secondary Syphilis, Early Latent Syphilis Alternative: Doxycycline 100 mg orally twice daily for 14 days

Late Latent Syphilis, Benzathine penicillin G 2.4 million units IM weekly for 3 weeks Syphilis of Unknown Duration, Tertiary Syphilis Alternative: Doxycycline 100 mg orally twice daily for 28 days

Neurosyphilis, Aqueous crystalline 18-24 million units per day, administered as 3-4 Syphilitic , penicillin G million units IV every 4 hours (or continuous Syphilitic Auditory Disease infusion) for 14 days

Procaine penicillin+ 2.4 million units IM daily + probenecid 500 mg orally 4 times daily for 10-14 days

Congenital Syphilis Aqueous crystalline 100,000 – 150,000 units/kg/day, administered penicillin G as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life, and every 8 hours thereafter for a total of 10 days

* Table adapted from Golden MR, Marra CM, Holmes KK: Update on syphilis: Resurgence of an old problem, JAMA 290:1510, 2003, with permission. Recommendations are based on guidelines from the Centers for Disease Control and Prevention (CDC).1 All dosages should be verified based on other sources prior to treatment.

+Patients with neurosyphilis who have non-life-threatening allergies to penicillin should ideally be desensitized.

104 Table 3: Neuro-Ophthalmologic and Ocular Manifestations of Lyme Disease

Description/Signs/Symptoms Disease References/ Stages Reviews

Follicular • Occurs in 10-11% of patients with EM Early Balcer et al.9 Conjunctivitis • , periorbital edema, , localized – Mikkilä et al.10 subconjunctival hemorrhages Stage 1 Karma et al.11 • Usually mild and self-limited

Keratitis • Rare, yet perhaps best documented ocular Late – Stage 3 Balcer et al.9 sequela of untreated Lyme disease Mikkilä et al.10 • Bilateral scattered hazy infiltrates in deep Karma et al.11 and superficial stroma w/o involvement of Descemet’s membrane • Generally mild; corneal neovascularization uncommon and visual axis usually spared • Responds to treatment w/ alone

Uveitis • Includes iridocyclitis, iritis, pars planitis, Early Balcer et al.9 vitritis, panophthalmitis disseminated – Mikkilä et al.10 • Cases of neuroretinitis, choroiditis, and retinal Stage 2 Karma et al.11 vasculitis have also been reported Krist et al.12

Orbital • Few cases reported Late – Stage 3 Balcer et al.9 • Orbital pain, proptosis, Late – Stage 3 • Resolved with corticosteroids and antibiotics • Possible invasion of muscle by B. burgdorferi, subsequent immune reaction

Pupillary • Few cases reported Early Balcer et al.9 Abnormalities • Best documented for Horner’s syndrome disseminated – Mikkilä et al.10 Stage 2 Karma et al.11

Optic Nerve • commonly associated with Early Balcer et al.9 Dysfunction meningitis, increased intracranial pressure disseminated – Mikkilä et al.10 • Optic atrophy as sequela of papilledema Stage 2 Karma et al.11 • No definitive evidence to associate Lyme Rothermel et al.13 disease with optic neuritis or AION

Meningitis/Cranial • Meningitis occurs in 15% of patients 4 weeks Early Balcer et al.9 Neuropathies after initial infection; papilledema may occur disseminated – Mikkilä et al.10 • CSF: mildly elevated protein, lymphocytic or Stage 2 Karma et al.11 plasma cell pleocytosis (100 cells/mm3) • III, IV, VI, VII individually or in combination (VII most common)

105 Table 4: Treatment Recommendations for Lyme Disease *

Clinical Manifestation/ Drug Dosage Disease Stage

Early Infection (Local or Disseminated)

Adult Dosages Doxycycline 100 mg orally twice daily for 14-21 days Amoxicillin 500 mg orally 3 times daily for 14-21 days

If allergic to above: axetil 500 mg orally twice daily for 14-21 days 250 mg orally 4 times daily for 14-21 days

Pediatric Dosages Amoxicillin 250 mg orally 3 times daily, or 50 mg/kg/day in 3 divided doses for 14-21 days If allergic to penicillin: 125 mg orally twice daily, or 30 mg/kg/day in 2 divided doses for 14-21 days Erythromycin 250 mg orally 3 times daily, or 30 mg/kg/day in 3 divided doses for 14-21 days

Neurologic or Ocular Disease

Adult Dosages Ceftriaxone 2 g IV once/day for 14-28 days 2 g IV every 8 hours for 14-28 days Penicillin G sodium 3.3 million units every 4 hours (20 million units/day) for 14-28 days

If allergic to above: Doxycycline 100 mg orally 3 times daily for 30 days

Pediatric Dosages Ceftriaxone 75-100 mg/kg/day (maximum 2 g) IV once/ day for 14-28 days Cefotaxime 150 mg/kg/day in 3-4 divided doses IV (maximum 6 g) for 14-28 days Penicillin G sodium 200,000 – 400,000 units/kg/day in 6 divided doses IV for 14-28 days

* Table adapted from Steere AC: Lyme disease, N Engl J Med 345:115, 2001, with permission. Recommendations are based on guidelines from the Infectious Diseases Society of America.7, 8 All dosages should be verified based on other sources prior to treatment.

106 Table 5: Neuro-Ophthalmologic Manifestations of Bartonella Infection

Description/Signs/Symptoms References/Reviews

Parinaud • Most common ocular of cat scratch disease (5%) Cunningham et al.20 Oculoglandular • Follicular conjunctivitis, fever, regional lymphadenopathy Syndrome • Unilateral eye redness, foreign body sensation, epiphora, lid swelling, serous discharge • Granulomatous conjunctival lesions on palpebral or bulbar surface

Neuroretinitis • Most common posterior segment manifestation of Liu et al.3 B. henselae (2%) Cunningham et al.20 • Optic neuropathy with disc edema, partial or complete Reed et al.21 macular star Suhler et al.22 • Usually unilateral but bilateral cases reported • Frequently referred to as Leber’s stellate neuroretinitis • Cat scratch disease may be most common cause • Moderate VA loss (20/40 – 20/200), optic nerve dysfunction • Visual prognosis generally good, although some may develop disc pallor, dyschromatopsia, abnormal contrast sensitivity

Focal • May accompany disc swelling in neuroretinitis and, when present, Cunningham et al.20 Retinochoroiditis provides strong support for diagnosis of B. henselae infection Omerod et al.23 • Also occurs in absence of disc edema or macular exudates Kawasaki et al.24 • May cause serous retinal detachment

Retinal Vaso- • Potential complication of focal retinochoroiditis Cunningham et al.20 Occlusive Disease • Includes branch retinal artery and vein occlusions Omerod et al.23

Uveitis • Vitreous cells present in 90% of patients with neuroretinitis Liu et al.3 • Anterior/posterior segment inflammation may occur in absence Cunningham et al.20 of neuroretinitis or retinochoroiditis Omerod et al.23

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