Epidemiology and pathogenesis

The only known reservoir for syphilis is in the human, and historically, infection had been limited to populations with poor hygiene, limited access to healthcare, and low socioeconomic status. Worldwide, syphilis cases have increased in the past 10 years, up 33.5% between 2000 and 2004 in the USA and 41.5% between 1999 and 2001 in the UK.^3,5 The most current surveillance in the USA indicates that the number of reported cases is rising each year, up 39% since 2006 in the USA. Specifically, the rates are rising sharply among young black men between the ages of 15 and 24, with 58.2 cases per 100 000 compared to 19.3 in 2005.³

The local and systemic response to T. pallidum is complex, and is initiated as the bacteria enter the body through intact mucosa. Local invasion of the tissues ensues, and dissemination occurs via blood and the lymphatic system. On the microscopic level, lymphocytic infiltration is seen, either diffuse or focal, surrounding the blood vessels of affected organs. In the eye, this can be found in the iris, ciliary body, and choroid, along with chronic granulomatous inflammation, including epithelioid histiocytes and multinucleated giant cells. Mononuclear cells, sensitized T lymphocytes, macrophages, and plasma cells can also be seen. This inflammation and the resulting adaptive immune response cause the tissue destruction characteristic of syphilis as the bacteria do not produce an intrinsic toxin.

Local antibodies are also produced against the lipid, protein, and lipoprotein components of T. pallidum. The majority of bacteria are eradicated by opsonization and engulfed by macrophages. Those organisms that are resistant to phagocytosis may persist locally at the site of inoculation. Dissemination can occur despite the development of the humoral and cellular response, and without treatment, the bacteria can persist in the human host for decades, resulting in continued transmission and end-organ damage.⁸

Ocular manifestations

Uveitis is the most common ocular finding, occurring in 2.5–5% of patients with tertiary disease.⁶ Findings can include keratic precipitates and iritis in the anterior segment of the eye. The iritis and iridocyclitis may manifest as either granulomatous or nongranulomatous inflammation. Dilated iris capillaries may also be noted (roseola), and these dilated and tortuous vessels may be a result of obliterative endarteritis. Chorioretinitis is also common and can present in a variety of ways. Vitritis, vasculitis, papillitis, periphlebitis, exudative retinal detachment, uveal effusion, central retinal vein occlusion, subretinal neovascular membrane formation, retinal necrosis, and neuroretinitis have all been described.^9–13 Yellow or gray placoid lesions can often be seen in the macula or juxtapapillary locations. This condition is also termed acute syphilitic posterior placoid chorioretinitis.^7,14 The lesions often have atrophic centers and are flat, with no evidence of fluid or hemorrhage. Fluorescein angiography reveals early hypofluorescence and late stain of the lesion with distinctive “leopard spot” hypofluorescence (Fig. 84.1). In patients with HIV, posterior uveitis is more common. A dense vitritis can also be the only presenting sign of syphilitic uveitis in HIV-positive patients.^9,15,16 Recently, a more defined presentation of diffuse, creamy retinitis with overlying punctuate retinal precipitates has been described in HIV-positive patients diagnosed with syphilitic uveitis.^17–19

Fig. 84.1 Late fluorescein angiographic image of the left eye in a patient with ocular syphilis with focal hypofluorescence, leakage of the optic disc, and staining of the retinal veins.

(Reproduced with permission from Chao JR, Khurana RN, Fawzi AA, et al. Syphilis: reemergence of an old enemy. Ophthalmology 2006;113:2074–9.)

Other ocular findings include interstitial keratitis of the cornea; chancre and nonspecific papillary reaction of the conjunctiva; episcleral and scleral inflammation, most commonly associated with conjunctival involvement; and inflammation of the optic nerve presenting as optic neuritis. Cataract can also be seen, both in congenital as well as acquired disease. Glaucoma in syphilis is often due to uveitis, though it may occur in either congenital or acquired infection. Lastly, the classic pupillary finding in syphilis is the Argyll Robertson pupil, which is seen in late syphilis or early neurosyphilis, manifesting with anisocoria and light-near dissociation upon clinical testing.

Findings in neurosyphilis are variable and dependent on the stage of disease. These may include stroke-like symptoms due to vasculitis and vascular compromise in early neurosyphilis, which may affect the cranial nerve nuclei as well as the centers for saccadic and smooth pursuit. Focal intracranial gummas may cause visual field deficits and superior orbital fissure syndrome, depending on the location of origination. Horner syndrome and internuclear ophthalmoplegia may also be observed in these patients. Late neurosyphilis may result in general paresis and tabes dorsalis.

Diagnosis

A high level of clinical suspicion is required for the appropriate diagnosis of syphilitic uveitis, due to its variable clinical presentation. In HIV-infected individuals, the presentation of syphilitic uveitis may be atypical; thus a strong clinical suspicion is especially important in evaluating those patients. Appropriate laboratory studies can aid in confirming the diagnosis and rule out other disease entities. Visualization of the organism in lesion exudates or tissue via dark-field microscopy with immunofluorescent staining is considered the gold standard and the quickest and most direct approach for establishing the diagnosis; however, the availability of such facilities limits its utility in clinical practice.²⁰ In addition, these tests are highly specific, but not very sensitive for widespread detection of infection.

Serologic testing with nontreponemal and treponemal tests is most commonly used in ophthalmic clinical practice. Nontreponemal tests detect the antibody to cardiolipin cholesterol antigen, and most clinicians are familiar with the Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests. These tests are best suited for general screening in a population with a low prevalence of syphilis, as well as for monitoring treatment efficacy as the titers decrease with appropriate therapy.

Treponemal tests, such as the fluorescent treponemal antibody absorption tests (FTA-ABS) and the microhemagglutinin assay for T. pallidum (MHA-TP), are more specific than the nontreponemal tests and may be just as sensitive. However, they are more expensive and a proportionate increase in false positives can occur if they are applied to a low-risk population. Thus, they may be used initially in patients who have a high probability of infection. Generally, once these tests are positive, the patient remains positive for life.

The use of a singular type of serologic test is insufficient for diagnosis, as each has its limitations, specifically the false-positive test results in patients without syphilis. False-positive test results may be associated with certain infections (e.g., Lyme disease, leptospirosis, malaria) and medical conditions (e.g., autoimmune disorders, intravenous drug use, pregnancy). A good rule of thumb in the evaluation of the patient with suspected syphilitic infection is to obtain a nontreponemal test and, if the initial study is reactive, confirm the diagnosis with a treponemal test. For those individuals with a positive treponemal screening test, a standard nontreponemal test with titer should be ordered to guide therapeutic decisions. If the nontreponemal test is negative, a different treponemal study should be ordered to confirm the results of the initial test. If the second treponemal test is positive, treatment should be initiated; alternatively, those patients with a history of prior therapy should be followed by observation unless a review of their sexual history indicates a likelihood of re-exposure.^21,22

Newer testing, which may not always be available to the clinician, includes polymerase chain reaction (PCR) assays and rapid specific treponemal tests. PCR assays, if available, should be conducted on frozen specimens (shipped according to the laboratory specifications), but cannot discern between live or dead organisms. The rapid tests, which may use as little as 10–50 µL of sample, are considered to be equivalent to the older specific treponemal antibody tests, and have similar limitations in terms of distinguishing active versus inactive infection.^23,24

For HIV-infected individuals, these serologic tests are often accurate and reliable for diagnosis as well as following the response to therapy. Atypical results (i.e., unusually high/low/fluctuating titers) without corresponding clinical findings suggestive of early syphilis should prompt the clinician to investigate further and consider other tests to confirm the diagnosis.²¹ False-negative tests may occur due to insufficient production of antibody to the bacterial proteins, or an overall lack of immunoreactivity.

Consideration of further testing is warranted in all patients with neurosyphilis, as no single test can be used to diagnose this presentation in all instances. Cerebrospinal fluid (CSF) analysis, along with VDRL and FTA-ABS tests, may need to be considered in confirming the diagnosis of neurosyphilis.⁴ CSF FTA-ABS is often too sensitive and thus the role of this test is still controversial. CSF VDRL does have the advantage over CSF FTA-ABS in cases requiring differentiation of current active infection from past infection. Leukocytosis and elevated protein concentrations can be seen in the CSF and these findings are often present for more than 1 year in those individuals with neurologic symptoms. This is consistent with neurosyphilis and warrants treatment even if test results are negative.

In summary, the reagin tests (VDRL, RPR) are used in screening for early syphilis infection. The treponemal tests (FTA-ABS, MHA-TP) can be used to confirm the diagnosis and guide management. The nontreponemal tests with titer (VDRL, RPR) can be used to follow therapeutic adequacy. Lastly, further investigation should be considered in patients with HIV, or in cases of neurosyphilis.

Differential diagnoses

The clinical findings and possible differential diagnoses for syphilitic uveitis are listed in Table 84.1. The most critical diagnosis to make may be acute syphilitic posterior chorioretinitis, and one must rule out acute posterior multifocal placoid pigment epitheliopathy and atypical serpiginous choroidopathy. In these instances, the use of intravitreal steroid or systemic immunosuppressive therapy for treatment of these conditions may unmask an underlying infection.¹⁴ It is important to emphasize that a high degree of clinical suspicion is vital in order to make the diagnosis, and that serologic confirmation is required.

Table 84.1 Differential diagnosis of ocular syphilis with laboratory workup

IgM/IgG, immunoglobulin M/G; ELISA, enzyme-linked immunoabsorbent assay; PCR, polymerase chain reaction; HLA, human leukocyte antigen; CSF, cerebrospinal fluid; PPD, purified protein derivative.

Treatment

The clinician who diagnoses syphilitic infection in a patient has two responsibilities: to report the case to the state Department of Health;²⁵ and to determine if he or she is comfortable in managing and following the therapeutic regimen for the patient. A survey of infectious disease practitioners conducted in 2008 found variation in the management of syphilis among the experts, particularly in cases where patients were coinfected with HIV.²⁰ It is the recommendation of the authors that the ophthalmologist treat the patient in consultation with an infectious disease specialist.

Penicillin G is the preferred treatment for all stages of syphilis (Table 84.2). The dose, route of administration, and duration of therapy are determined by the stage and clinical findings. Sexual partners of the infected individual also need to be evaluated and treated.²¹ For patients with a penicillin allergy, alternative antibiotics may be used; however, as the other medications are not as effective as penicillin, skin testing and desensitization are recommended, especially in those patients who are coinfected with HIV. As for patients diagnosed with congenital syphilis, treatment with aqueous penicillin G or procaine penicillin G via intravenous administration is recommended. Other antibiotics such as ceftriaxone and ampicillin have been used, but there is no optimal therapy for congenital syphilis noted at this time.

Table 84.2 Recommended treatment of syphilis

Notes: (1) Human immunodeficiency virus-positive patients should be treated with penicillin at all stages of infection, and those allergic to penicillin should be desensitized and then treated with the full regimen. (2) All patients with tertiary syphilis should have a cerebrospinal fluid analysis and be evaluated for neurosyphilis.

(Adapted from Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR 2010;59:26–40.)

Syphilitic uveitis or other ocular manifestations associated with neurosyphilis should be treated according to the recommendations for neurosyphilis.⁴ A CSF examination is recommended for all patients with syphilitic eye disease to guide therapy. The recommended regimen is aqueous crystalline penicillin G delivered intravenously, as no alternative has been proven scientifically effective. In those patients who have failed primary therapy and show evidence of tertiary syphilis, asymptomatic neurosyphilis may be present and may warrant evaluation of the CSF.²¹ With regard to neurosyphilis in the HIV-positive patient, treatment with intravenous penicillin utilizing the neurosyphilis recommendations results in rapid resolution of findings.¹⁹ It is important to note that therapy must be of a duration and dose sufficient to cure neurosyphilis, regardless of CSF findings.²⁶

Success with therapy may be evaluated by improvement in clinical findings and seroconversion or low titers upon nontreponemal testing. The published criteria for treatment of early syphilis describe four- to eightfold decreases in nontreponemal titers that should occur by 3–6 months, respectively. It is important to realize that these criteria cannot be used in monitoring treatment efficacy in HIV-positive patients. In these individuals, serologic testing may be inaccurate, and this often justifies the aggressive treatment regimen in this population.

Once the infection has been appropriately treated, adjunctive therapy with corticosteroids may be applied for any residual ocular inflammation related to syphilis. Topical corticosteroids are beneficial for anterior uveitis and interstitial keratitis, whereas systemic corticosteroid therapy may be required in order to resolve symptoms of residual scleritis, posterior uveitis, or optic neuritis. Corticosteroid regimens should always be administered concurrently with antibiotic therapy.

Course and outcome

Outcomes of syphilitic uveitis and systemic disease are dependent on early diagnosis and appropriate antibiotic therapy. These cases often result in full visual recovery and improvement in other systemic findings. Untreated cases of syphilitic uveitis often lead to worsening of intraocular inflammation, development of glaucoma secondary to chronic uveitis, and retinal necrosis. Chronic vitritis and optic atrophy may also occur. Treatment in HIV-positive individuals should be initiated early and aggressively, utilizing the regimen recommended for neurosyphilis.

Epidemiology and pathogenesis

In the USA, the endemic areas are clustered around three regions: (1) the northeast, down as far south to Virginia, with hyperendemic regions in Connecticut and New York; (2) the Midwest, in the states of Michigan, Wisconsin, and Minnesota; and (3) the west, primarily in northern California. Certain areas of Europe and Asia are also affected, particularly in regions with a temperate climate. It is unclear why there is a preponderance of cases localized to the northeastern USA.³⁰

The pathogenesis of the disease is similar to that induced by the spirochete T. pallidum, and follows in three distinct stages. The first stage, or early infection, is believed to be due to spirochetemia. After an incubation period of 3–32 days, the spirochete multiplies and induces proinflammatory responses in both the innate and adaptive immune systems. This is clinically observed as the characteristic skin rash, erythema migrans, at the site of the tick bite.³³ Within days to weeks, B. burgdorferi can be recovered from many areas of the body. All affected tissues show some infiltration of lymphocytes and plasma cells, along with vascular damage (e.g., mild vasculitis or hypervascular occlusion).

The immunological response of the host to parasitic invasion is the likely etiology for the manifestations of stage 2 and 3 disease.³⁴ The specific immunoglobulin M (IgM) response provides for polyclonal B-cell activation and increased levels of circulating immune complexes, while the specific IgG response develops over weeks in response to spirochetal polypeptides and nonprotein antigens.³⁰ Spirochetal killing is primarily due to bactericidal B-cell responses and utilizes the complement pathway. For the majority of cases, the innate and adaptive response is capable of controlling widespread dissemination of the disease without antibiotic therapy; however, without appropriate therapy, B. burgdorferi can survive for several years in particular loci, such as joints, skin, and nervous system.²⁹

Ocular manifestations

Ocular findings in Lyme disease are less prominent compared to the significant systemic manifestations and can appear at any stage of disease. Conjunctivitis is the most common finding, present in 11% of patients with early-stage Lyme disease.³⁵ Ophthalmologists are generally not consulted as the nonspecific findings of conjunctival and periorbital inflammation are mild in nature and self-limiting. Neuro-ophthalmic complications are associated with the neurologic involvement in stage 2 disease and commonly manifest as ocular motility problems due to cranial nerve palsies, optic neuritis, papilledema, and pseudotumor cerebri in the setting of meningoencephalitis.^31,36,37 Stromal keratitis, episcleritis, and symblepharon formation have been reported in stage 3 disease.³⁸

Intraocular inflammation often presents as chorioretinitis and vitreous inflammation, though there have been a variety of clinical presentations associated with Lyme disease.^35,39,40 Vitreous involvement may be nonspecific, with or without associated retinal pathology, such as retinal vasculitis.⁴⁰ Clinically, the presence of disc edema in the setting of posterior-segment inflammation may be related to chronic posterior-segment inflammation rather than the neurologic involvement from borreliosis (Fig. 84.2). Appropriate neuro-ophthalmic testing should be undertaken to evaluate the potential of other central nervous system complications.

Fig. 84.2 Fluorescein angiogram depicting disc edema and mild vitritis in a 44-year-old Caucasian male with positive serology for Lyme borreliosis. There is a nonspecific window defect temporal to the fovea.

(Courtesy of Thomas J. Federici, MD.)

Diagnosis

The clinical diagnosis of Lyme disease is dependent on the following: appearance of the pathognomonic skin rash (erythema migrans) in a patient with a history of tick bite and/or residence in an endemic region; or the appearance of the skin lesion in addition to involvement of two organ systems in those patients without a history of a tick bite or residence in a nonendemic region. The diagnostic criteria for Lyme disease as recommended by the Centers for Disease Control and Prevention (CDC) are listed in Table 84.3.^41,42

Table 84.3 Criteria for diagnosis of Lyme disease

(Adapted from Case definitions for public health surveillance. MMWR Morb Mortal Wkly Rep 1997;46(RR-10):1–55 and Recommendations for public health surveillance. MMWR Morb Mortal Wkly Rep 1995;44:590–1.)

Culture of B. burgdorferi from peripheral blood, areas of skin rash, and CSF provides for definitive diagnosis.^43,44 However, positive cultures are often difficult to obtain as they mainly occur early on in the disease process. In these cases, sensitivity is highest in tissue culture, with the positive rates of culture dropping significantly for plasma and CSF.³⁰ For ocular disease, serological testing is often more helpful in diagnosis as these manifestations can occur several years after initial inoculation. These results, along with a clinical history suggestive of infection, provide the basis for diagnosis of Lyme disease.

The CDC recommends a two-step approach in which serologic samples are tested: first, an enzyme-linked immunosorbent assay (ELISA) is performed to detect the presence of IgG and IgM specific for B. burgdorferi. Equivocal results are then tested by Western blotting. According to CDC criteria, the IgM Western blot is considered positive if two of the following three bands are present: the 23, 39, and 41 kDa, though the combination of the 23 and 41 kDa bands may still be considered a false-positive result. The IgG Western blot may be considered to be positive if five of the following 10 bands are present: 18, 23, 28, 30, 39, 41, 45, 58, 66, and 93 kDa.⁴¹ The results still need to be interpreted with care, as a portion of the normal population has IgG reactivity to the 41-kDa flagellar antigen of the spirochete and thus the presence of the band alone cannot be utilized in serologic diagnosis.³⁰

As a final note of caution, these tests, though commonly used, can be insensitive during the first few weeks of infection, prior to the development of host antibody response. Actively infected individuals will have a positive IgG response. For those patients with active disease lasting more than 4–8 weeks, an elevated IgM response is likely to be a false positive, and thus an IgM response should not be used to support the diagnosis of an infection after that time period.³⁰ In instances where the disease course is much more aggressive and severe than initially anticipated, coinfection with Babesia microti or Ehrlichia phagocytophilia (causing human babesiosis and granulocytic anaplasmosis, respectively) should be considered.^45–47

Differential diagnoses

Given the various ocular manifestations of Lyme disease, the clinician needs to rule out both infectious and noninfectious etiologies with similar clinical presentations. In terms of other infectious etiologies, findings on the clinical examination as well as appropriate serologic/diagnostic tests should be undertaken to rule out syphilis, tuberculosis, viral meningitis/encephalitis, viral keratitis, infectious arthritis and mononucleosis, and mumps. Examination should also incorporate the following noninfectious etiologies in the differential diagnosis: sarcoidosis, collagen vascular diseases, vasculitis, Vogt–Koyanagi–Harada syndrome, and multiple sclerosis.

Treatment

Therapy for Lyme borreliosis consists of antibiotic treatment for the systemic infection, though preventive measures (i.e., protective clothing, repellents, and acaricides), landscape modifications, and tick checks are often the best defense against infection as they reduce exposure. Vaccination was once offered to individuals between the ages of 15 and 70 years who may travel to or live in endemic regions;⁴⁸ however, the vaccine is no longer available, as the manufacturer has discontinued production, citing low demand. Currently, a single dose of doxycycline (200 mg) can be prescribed for individuals as a preventive measure within 72 hours of a documented tick bite.⁴⁹

With regard to management of ocular findings, the most effective treatment strategy is still unclear.³⁵ Systemic therapy should be initiated in consultation with an infectious disease specialist (Table 84.4). Diplopia secondary to cranial nerve palsies should be addressed according to the severity of patient symptoms. Adjunct corticosteroids have been beneficial in treating the specific ocular manifestations: topical applications for anterior-segment manifestations (e.g., keratitis and episcleritis), and intravitreous injections for macular edema.^38,50–52 Systemic corticosteroids have been utilized in more severe cases of ocular inflammation, such as vision-threatening uveitis, scleritis, or optic neuritis; however, the use may be controversial, as a higher incidence of relapses has been observed.³¹ Inadequate treatment in the early stages may lead to relapses and development of late-stage manifestations.³¹ Treatment of concomitant infections should also be addressed if the clinical findings persist despite prolonged antibiotic therapy.

Table 84.4 Treatment of Lyme disease

Notes: (1) Avoid doxycycline in pregnant women. (2) Chronic Lyme disease symptoms seen in late disease may require long-term antibiotic therapy (2 or more months of oral antibiotics, or 1 or more months of IV antibiotics).

(Adapted from Steere AC. Lyme disease. N Engl J Med 2001;345:115–25.)

Disease course and outcome

The majority of patients respond well to systemic antibiotic therapy; however, posterior uveitis, stromal keratitis, and neurotrophic keratitis can be slow to respond to treatment. Untreated disease can have a relapsing course for several years, though the number of patients with chronic symptoms, most notably arthritis, decreases 10–20% each year, with few individuals having symptoms beyond 5 years.³⁰

Epidemiology and pathogenesis

The genus Leptospira consists of two strains: L. interrogans, which causes the infectious disease in humans, and L. biflexia, which is a saprophytic strain. The natural reservoir for Leptospira is wild animals, particularly rodents, but dogs and other domestic livestock may also be affected. The spirochete colonizes the renal tubules of the animal host, and survives excretion in the urine. It also survives as a free-living organism in contaminated soil or water. Individuals at high risk for infection include abattoir workers, farmers, veterinarians, miners, and sewer workers who contract the disease via direct contact with diseased animals. Indirect contact is more common after exposure to wet soil or water through occupational exposure or recreational exposures (e.g., water sports in either fresh or sea water, ecotourism in endemic regions) as the spirochete has the ability to enter the human body through intact mucosa or abraded epidermis. The appearance of this rural tropical disease in urban centers of developing regions is often secondary to a lack of sanitation in areas of rapid expansion and growth. Sporadic outbreaks have also been reported in developed countries.^57,58

Hematogenous dissemination allows the organisms to invade the central nervous system as well as the aqueous humor of the eye; transendothelial migration occurs via systemic vasculitis, resulting in a broad spectrum of presentations, including pulmonary hemorrhage, damage to the renal tubule structures, and hepatic cell destruction.⁵⁹ It is unclear which mechanism allows for Leptospira to cause infection: innate bacterial virulence factors, direct tissue damage secondary to hemolytic toxins, or innate host immune responses.

In the eye, the mechanisms surrounding leptospiral uveitis remain unclear. Invasion of the vitreous by neutrophils, macrophages, lymphocytes, and plasma cells can be seen within 10 days of infection in a rabbit model.⁶⁰ Antibodies to Leptospira in the aqueous coincided with the intraocular appearance of plasma cells. Extensive veterinary studies on equine recurrent uveitis (ERU) suggest that it is an organ-specific, autoimmune disorder, and that leptospiral uveitis in horses is a separate and distinct subset of ERU.⁶¹ Molecular studies on human eyes are not currently available.

Ocular manifestations

In the acute phase of infection, the incidence of ocular signs ranges from 2 to 90% of cases, suggesting that the majority of findings may be nonspecific and diagnosed only when there is a high index of suspicion. Conjunctival hyperemia, chemosis, and subconjunctival hemorrhage are most commonly seen in these cases. Changes in the retinal vasculature and the presence of retinal hemorrhages have been reported, along with disc hyperemia and retinal vasculitis.⁵⁷

After the initial septicemic phase, a period of relative quiescence precedes the development of ocular symptoms. These can range from a localized anterior uveitis to diffuse panuveitis. Findings are generally nongranulomatous, though granulomatous reactions may be seen in rare cases. Anterior-segment findings can include hypopyon in 12% of cases, and a fibrinous reaction may be present. Cataract can also be present, and, in rare cases, spontaneous absorption of the lens opacity has been reported. The symptoms of photophobia, blurred vision, and pain are generally self-limited.⁶²

In the posterior segment, vitritis is common, and the presentation of vitreous strands, or veil opacities that attach to the optic disc, can often be seen. There may be other vitreous precipitates in the posterior vitreous, and snowbanking may be seen. Nonocclusive vasculitis, periphlebitis, choroiditis, and papillitis have also been described.⁵⁷

Diagnosis

Clinical diagnosis of systemic leptospirosis is difficult given the nonspecific symptoms and variable presentations reported in the literature. The diagnostic dilemma extends to the ocular manifestations, where the differential diagnosis for leptospiral uveitis includes such entities as human leukocyte antigen (HLA)-B27-associated uveitis, Behçet disease, and sarcoidosis (Table 84.5). The clinician cannot rely on the examination alone; rather, a high index of suspicion in an endemic region, or in individuals who may have exposure due to socioeconomic or recreational factors, needs to be taken into account. The ophthalmologist faced with a potential diagnosis of leptospirosis will also need to look toward laboratory testing to confirm the clinical suspicion.

Table 84.5 Differential diagnosis of leptospirosis

HLA, human leukocyte antigen.

The gold standard for laboratory testing is the microscopic agglutination test (MAT), which is comprised of the agglutination of live leptospires by titrated amounts of patient serum.^53,56 Generally, 12–16 of the known serovars of any given geographic region are used in the test with the endpoint read using dark-field microscopy. A fourfold change in the titer or seroconversion is considered positive, with a compatible clinical presentation. Of note, false negatives can occur if the infection is due to a serovar not present in the testing panel, and false positives can also occur if there are any residual antibodies to a prior exposure in an endemic area. In chronic cases, a titer of 1 : 100 is considered a positive test. The main difficulty in obtaining MAT testing lies in that large numbers of leptospiral cultures need to be maintained; thus, only large reference laboratories are able to conduct this laboratory test. Other diagnostic procedures, including a Leptospira dipstick test, ELISA, and microscopic slide agglutination tests, may be more widely available. Newer laboratory techniques, including PCR for the detection of leptospiral DNA, are currently in development.⁶³

Treatment

Antibiotic therapy for systemic disease is extremely effective. Supportive care, when required, should be initiated for those individuals suffering from multiorgan involvement. Intravenous penicillin G has been effective for severe systemic infection, but for less severe presentations, doxycycline given 100 mg twice daily for 1 week was shown to be effective in eradicating leptospires from all target organs within 3 days.⁶⁴ Azithromycin has been studied for the treatment of leptospirosis in those individuals unable to take or tolerate doxycycline; further clinical trials are warranted to determine whether this could be considered a reasonable alternative.⁶⁵

Treatment for leptospiral uveitis includes local administration of corticosteroids, as they are the mainstay for therapy for ocular inflammation. Dose and route of delivery are dependent on the location, laterality, and severity of the symptoms. It is unclear if systemic antibiotic therapy during the early phase of infection provides any protective role in the prevention of immunologic sequelae such as uveitis, though a recent study suggests that those treated in the septicemic phase developed only mild disease.⁶⁶

Disease course and outcome

Visual recovery and potential are generally good, with one large series reporting that more than 50% of patients regained 20/20 vision.⁶² Most patients have mild disease (anicteric) and recover within 1–2 weeks. For systemic disease, mortality varies from less than 1% to more than 20%, and is dependent on the severity of disease and involvement of multiple organ systems.⁵³