The spirochetes pathogenic to humans include members of the genera Treponema, Borrelia, and Leptospira. The principal diseases associated with each genus are syphilis, Lyme borreliosis, and leptospirosis, respectively (Table 1). All are highly invasive organisms that readily disseminate from the initial site of infection, spread hematogenously, invade multiple organs, and produce chronic infections with prominent immunopathologic reactions.

TABLE 1. Spirochetes Pathogenic to Humans

None of these bacteria can be easily or rapidly cultured. Diagnosis is typically clinical and is based on a combination of history, physical manifestations, microscopic detection, serologic confirmation, or polymerase chain reaction (PCR) detection of organisms. Eye disease is associated with chronic spirochetal infection, with various inflammatory and degenerative manifestations.

Fig. 1 Annual reported rates (per 100,000) of primary and secondary syphilis in males and females in the United States and male-to-female rate ratios, 1981–2002. Figure provided by the Centers for Disease Control and Prevention.3

PATHOPHYSIOLOGY OF VENEREAL SYPHILIS

Transmission of Treponema pallidum subspecies pallidum results from direct contact with early syphilitic lesions; entry is thought to occur through microscopic fissures in the epidermis or mucous membranes. T. pallidum proliferates at the initial site of infection, resulting in well-circumscribed, indurated, painless lesions called chancres that often become ulcerated or encrusted. This primary stage of syphilis occurs within 10 to 90 days postinfection and typically will resolve within a few weeks. The organism disseminates during this period, and the patient enters into a period of latent infection, in which there are no signs of infection other than serologic reactivity.

Secondary syphilis occurs in nearly one third of untreated cases, appearing within 6 weeks to 6 months postinfection. Manifestations consist of multiple macular or papular skin lesions, often accompanied by mucous membrane lesions, patchy hair loss, “nickel-and-dime” lesions on the palms of the hands and soles of the feet, fever, malaise, and lymphadenopathy. Primary and secondary skin and mucosal lesions contain large numbers of T. pallidum and are highly infectious. Syphilitic patients are considered to be infectious during the first year of infection.

A period of latent, asymptomatic infection occurs in all untreated individuals and may last the lifetime of the patient. Approximately two-thirds of syphilis patients in the United States are diagnosed by serologic reactivity during the early (<1 year postinfection) or late (≥1 year) latent stages.

Tertiary (also called late) manifestations of syphilis typically occur after years to decades in approximately one third of untreated patients and consist of gummatous, cardiovascular, and neurosyphilis forms. Gummas are granuloma-like accumulations of mononuclear cells that can occur in any organ, causing damage through the displacement of normal tissue. Cardiovascular syphilis may present as aortic aneurysm or cardiac valve abnormalities. Neurosyphilis can actually occur at either early or late stages of syphilis and may result in meningovascular inflammation, spinal cord demyelination and deterioration of dorsal root ganglia (tabes dorsalis), or frank infection of the brain (paresis).

Congenital syphilis occurs following transmission of T. pallidum across the placenta during the second or third trimester of pregnancy. The range of manifestations includes stillbirth, fulminant, multiorgan infection at birth, and asymptomatic infection at birth followed by the constellation of symptoms that constitute late congenital syphilis.

OCULAR MANIFESTATIONS

Interstitial keratitis and uveitis in congenital syphilis patients were first reported by Jonathan Hutchinson in 1858.³² Since that time, ophthalmic manifestations have been recognized as common complications of both sexually transmitted (acquired) and congenital syphilis. Any region of the eye can be affected, and presentations include interstitial keratitis, granulomatous and non-granulomatous iridocyclitis, panuveitis, retinitis, retinal vasculitis, and optic atrophy.^6,86 Uveitis in nearly all forms may occur at either the secondary or late stages, months to years after the initial infection. In the preantibiotic era, the majority of interstitial keratitis cases were caused by untreated late congenital syphilis, occurring at 5 to 20 years of age. Acquired syphilis also caused uveitis in up to 5% of patients.

With the wide availability of penicillin in the mid 1940s, the incidence of syphilis and its impact on ocular disease decreased dramatically in countries where health care and antibiotic therapy were readily available. Any reduction in incidence may apply only to countries and regions with health care access; occurrence of all forms of syphilis (including congenital disease) in some areas of sub-Saharan Africa and Asia often reflect preantibiotic era rates. Recent studies in the United States indicate that syphilis is still a cause of corneal scarring with ghost vessels but is rarely associated with active keratitis.⁸⁶ In a referral center in New York City,¹¹ 8% of uveitis patients had reactive treponemal antibody tests, but other potential causes could be ruled out in only 4% of patients.

Ulcerative early lesions of syphilis are thought to increase the transmission rate of human immunodeficiency virus (HIV). Conversely, HIV infection may affect the manifestations of syphilis,^31,50 including ocular lesions. For example, dense vitreitis was identified in three patients infected with HIV.³⁷ In addition, coinfection with HIV, particularly in the late symptomatic phase, may result in deficient antibody responses and lack of reactivity in nontreponemal and treponemal serologic tests for syphilis. For these reasons, it is recommended that patients suspected of having syphilis also be tested for HIV antibody reactivity. Another consideration is that corticosteroid treatment may alter the ocular manifestations of syphilis or serologic reactivity.

LABORATORY DIAGNOSIS

No ocular manifestations are pathognomonic for syphilis, so diagnosis is largely dependent on a combination of history, general clinical signs, detection of T. pallidum (when early lesions are present), and serologic analysis.⁵¹ A general scheme for the diagnosis of syphilis is depicted in Figure 2.

T. pallidum in patient specimens can be detected by darkfield microscopy, immunofluorescent staining, polymerase chain reaction (PCR), or animal inoculation. Characteristic primary or secondary lesions combined with the demonstration of T. pallidum in lesion exudates or biopsy samples by darkfield microscopy or immunostaining techniques is considered to be a definitive diagnosis.⁵¹ However, detection of T. pallidum by these means is not always available. In addition, spirochetes are present in exceedingly low numbers past the primary and secondary stages and are then difficult to detect by any method.

Immunofluorescent identification usually involves direct fluorescent antibody (DFA-TP) staining of lesion exudates or tissue using fluorescein-labeled anti-T. pallidum polyclonal or monoclonal antibodies.^38,51 Immunohistochemical techniques have also been developed.²⁹ T. pallidum has been detected in aqueous humor using darkfield microscopy or immunofluorescence of concentrated samples,^68,87 but the numbers are exceedingly small and artifacts can yield false-positive interpretations.

PCR has been used to detect T. pallidum DNA in blood, tissue, and cerebrospinal fluid^56,74 but is not routinely available. Inoculation of a rabbit was used to isolate the type strain T. pallidum subspecies pallidum Nichols from a patient's cerebrospinal fluid in 1906, and animal inoculation is still the only procedure available for the isolation of T. pallidum strains. It is conceivable that these sensitive methods could be used to detect or isolate T. pallidum from ocular fluids or biopsies.

Diagnosis of syphilis is highly dependent on serologic tests, including the so-called nontreponemal and treponemal antibody assays.^8,16,51 Nontreponemal tests detect reaginic antibodies that react with cardiolipin combined with lecithin; these antibodies arise for unknown reasons during treponemal infections. The Rapid Plasma Reagin (RPR) circle card test is the most commonly used nontreponemal assay, although the Venereal Disease Research Laboratory (VDRL) test is the only assay available for testing the reactivity of cerebrospinal fluid. Treponemal assays detect anti-T. pallidum antibodies using whole T. pallidum, sonicates, or recombinant antigens. The T. pallidum particle agglutination assay (TP-PA) replaced the microhemagglutination T. pallidum (MHA-TP) test and is widely used today, but the fluorescent treponemal antibody-absorbed (FTA-ABS) test and enzyme immunoassays are also available. The nontreponemal tests are of value because they can be quantitated by titration, and typically the reciprocal titer decreases after treatment. The treponemal tests have the advantage of being specific for treponemal antigens, but reactivity is usually retained after treatment. Both types of tests may yield false-positive reactions in autoimmune disease, which should be kept in mind when attempting to distinguish autoimmune from syphilitic disease.

TREATMENT

Treatment should be consistent with the stage of disease, HIV status, and other factors.² A single dose of benzathine penicillin (2.4 million units intramuscularly [IM]) is currently recommended for primary, secondary, and early latent syphilis, whereas three equivalent dosages at weekly intervals are recommended for late latent, latent of unknown duration, or tertiary syphilis.² Aqueous crystalline penicillin G is recommended for neurosyphilis (3–4 million units intravenous [IV] every 4 hours for 10–14 days) and for congenital syphilis in infants (100,000–150,000 units/kg per day for 10 days). Re-covery of viable T. pallidum from CSF has been reported in neurosyphilis patients treated with benzathine penicillin, consistent with its poor penetration of blood–brain barrier; recurrence of manifestations in HIV-positive individuals also occurred.⁴⁴ For this reason, treatment of patients with ocular syphilis with a regimen of aqueous penicillin G consistent with current neurosyphilis treatment guidelines should be considered.

ANIMAL MODELS

The earliest report of an animal model of ocular syphilis occurred before the discovery of T. pallidum. In 1881, Haensell³⁰ described the occurrence of keratitis and iritis after inoculation of a syphilitic lesion exudate into the anterior chamber of a rabbit eye. In 1906, 1 year after T. pallidum was first identified by Schaudinn and Hoffman,⁶⁵ Bertarelli¹⁴ also demonstrated the occurrence of corneal lesions in rabbits after T. pallidum inoculation. As part of their extensive characterization of experimental syphilis in the rabbit, Brown and Pearce¹⁷ described the eye manifestations observed after infection. In the 1960s, Wells and Smith⁸⁴ and Elsas et al.²⁶ were able to demonstrate ocular manifestations after inoculation of owl monkeys or squirrel monkeys with T. pallidum via the cornea, vitreous, cisterna magna, carotid artery, skin, and intravenous routes. The pathologic findings varied but included pupillary inequality, non-granulomatous iridocyclitis, retinal hemorrhage, multiple lens opacities, and flare. In addition, T. pallidum could be found in the aqueous humor using either darkfield microscopy or immunofluorescent staining up to 1 year after inoculation. Although five of the six monkeys studied developed serologic reactivity in the VDRL, FTA-ABS, and T. pallidum immobilization (TPI) tests, the reactivity was often weak (e.g., VDRL titers never exceeded 1:4). It is unclear whether this low reactivity was caused by poor antibody responses in these animals or by the inadequacy of the serologic tests for serum samples obtained from monkey species.

Concerns have long existed that corneal transplants could serve as a potential source of T. pallidum infection. Corneas from donors with reactive RPR tests were excluded from the transplant pool, resulting in a substantial reduction in the number of corneas available for transplant. In an extensive study by Dr. Elliot Randolph published in 1949,⁵⁹ the presence of infectious organisms in corneas from rabbits infected with T. pallidum for 3 or more months was analyzed to provide information on the potential for transmission by corneal transplantation. None of the recipient rabbits was infected after injection of corneal extracts from 40 infected ``donor'' rabbits. In more recent studies,⁴⁵ rabbits were infected by intratesticular inoculation, and 10 days later the corneas were removed, minced, and extracted. When injected into naïve rabbits, these extracts produced lesions if not washed with saline before extraction, indicating the presence of T. pallidum. However, with saline rinsing, no lesions were obtained, consistent with the presence of viable treponemes in blood or ocular fluids but not in the corneal tissue itself. In addition, incubation of T. pallidum in OptiSol® cornea storage medium was found to render the organisms noninfectious within 24 hours. These data were used in combination with other information to remove RPR reactivity as a criterion for the exclusion of corneas for transplantation.

PATHOPHYSIOLOGY OF NONVENEREAL TREPONEMATOSES

Nonvenereal treponematoses are typically transmitted by non-sexual contact with active lesions during childhood or adolescence. The degree of systemic manifestations of endemic syphilis tends to be somewhat less than that of venereal syphilis; yaws and pinta each exhibit progressively more localized skin lesions and less systemic involvement.^7,63 Congenital disease occurs rarely in endemic syphilis and is not thought to occur in yaws and pinta.

OCULAR MANIFESTATIONS

Relatively few studies address the occurrence of ocular lesions in endemic syphilis, yaws, and pinta. Tabbara et al.⁷⁶ examined late endemic syphilis patients in nomadic Bedouins in Saudi Arabia in the 1980s and found uveitis, chorioretinal scars, and optic atrophy. An extensive study of yaws patients in Venezuela^69,70 found a high percentage of cases of abnormal pupils (32%), abnormal fundi (26%), or optic atrophy (20%). Evidence of chorioretinitis and abnormal pupils was also observed in some pinta patients.⁶⁹

Spirochetes were identified by darkfield microscopy or immunofluorescence in the aqueous humour of some yaws patients and in one pinta patient, but positive results were also obtained in 10% of presumed-normal controls. Many of these presumed-positive results were described as ``nonfluorescent spiral forms,'' meaning that they did not bind anti-T. pallidum antibodies; interestingly, photomicrographs provided for several cases (especially cases 175 and 178) bear a strong resemblance to Leptospira, which also has a high incidence in this region.⁶⁹ Taken together, the data available indicate that ocular manifestations can occur in patients with endemic (nonvenereal) treponematoses but that care must be taken to distinguish these diseases from other infections (or co-infections).

The predominant arthropod vectors of the disease are hard-bodied Ixodes ticks, including Ixodes scapularis in North America and Ixodes ricinus in Europe and Asia. Lyme Borrelia are maintained through an infectious cycle between small mammals (or birds) and the Ixodes ticks; large mammals, most notably deer, are required for feeding and ovulation of the adult ticks. Humans can be infected by nymphal or adult ticks, and human-to-human transmission does not occur. Although small numbers of cases occur in almost every state of the United States, most reported cases are concentrated in the northeastern and mid-Atlantic states, with another focus in Wisconsin and Minnesota.

PATHOPHYSIOLOGY OF LYME BORRELIOSIS

The clinical course has been subdivided into three stages, with the understanding that these stages commonly overlap.⁷¹ Stage 1 is the initial, localized infection and typically consists of erythema migrans, a well-demarcated expanding erythematous rash with central pallor that develops at the site of the tick bite. Regional lymphadenopathy and flu-like constitutional symptoms, including fever and chills, myalgias, arthralgias, malaise, and nausea are also often present. Stage 2 represents disseminated infection, occurring weeks to months after the initial presentation. Migrating monoarthritis of the knee and other large joints, neuroborreliosis (including cranial neuropathy, aseptic meningitis, headache, encephalitis, or peripheral neuritis), cardiac atrioventricular block, and ophthalmic manifestations can occur during this stage.

The third or chronic stage of Lyme borreliosis is characterized by oligoarthritis, chronic neurologic manifestations, and a hypopigmented skin lesion called acroderma chronicum atrophicans (ACA). Arthritis is the most common stage 3 symptom of B. burgdorferi infection and, hence, is seen commonly in North America. In contrast, neurologic symptoms predominate the chronic stage of B. garinii infection, and B. afzelii gives rise to ACA; thus, these manifestations are found more commonly in Europe and Asia.⁸³

Other tick-transmitted diseases, including babesiosis, human monocytic ehrlichiosis, and human granulocytic ehrlichiosis (caused by Anaplasma phagocytophilum), occur in areas endemic for Lyme borreliosis and may cause co-infections.

OCULAR MANIFESTATIONS

As in syphilis, Lyme borreliosis can affect any segment of the eye.^10,13,48,92 Mild follicular conjunctivitis, subconjunctival hemorrhages, photophobia, and periorbital edema may coincide with erythema migrans during the early stage of the disease. The occurrence of conjunctivitis is reported to be 10% during this stage, but this value may be underestimated. During stage 2, diplopia may result from cranial neuropathy, although involvement of cranial nerve VII (with resulting Bell's palsy) is much more common than paresis of cranial nerve VI, III, or IV. Blurred vision also occurs at this stage and may be associated with papilledema, optic atrophy, optic or retrobulbar neuritis, or pseudotumor cerebri. These may coincide with aseptic meningitis and associated symptoms, which are present in approximately 15% of untreated Lyme borreliosis patients 4 weeks after the appearance of erythema migrans.

The most severe manifestations typically occur months to years after the initial infection and may include pars planitis, iritis, vitreitis, keratitis, and a wide variety of forms of posterior uveitis.^10,92 Although the first reported case of ocular Lyme borreliosis resulted in unilateral blindness,⁷² eye involvement typically is mild to moderate, responsive to therapy, and not associated with loss of visual acuity.

LABORATORY DIAGNOSIS

The diagnosis of Lyme disease remains primarily clinical. The recognition of the erythema migrans lesion and other associated symptoms, a history of tick bite or potential exposure, and residence in (or travel to) an endemic area are the most important diagnostic clues. Verification is usually performed by detection of antibodies against Borrelia antigens, although culture, immunologic staining of tissue specimens, or PCR can also be used.¹⁸

The currently recommended method for serodiagnosis is a two-tiered approach.^1,88 Either serum or CSF can be examined. An enzyme immunoassay using a whole-cell lysate of Lyme disease Borrelia or recombinant antigens is used as a screening test. If a positive result is obtained, the enzyme-linked immunosorbent assay (ELISA) is followed by Western blot analysis; both whole-cell extracts and mixtures of recombinant proteins have been used as the antigens in immunoblots. Serologic tests are nonreactive during the erythema migrans stage in approximately one half of the patients, but seroconversion may occur after therapy. Sensitivity approaches 100% at later stages. Specificity of whole–cell-based immunoassays is limited by the occurrence of cross-reactive antibodies, particularly in patients with autoimmune disease or syphilis; therefore, serologic testing is recommended only when there is a strong suspicion (>20%) of Lyme borreliosis. Recently, a rapid "first-tie" test using chimeric recombinant proteins with epitopes from multiple B. burgdorferi antigens has been developed.²⁸ In addition, immunoassays using recombinant protein constructs³⁹ or the C6 synthetic peptide⁴² of the Borrelia antigenic variation protein VlsE have been shown to be highly sensitive and specific.^9,67

Direct detection of Borrelia by culture or PCR is another means of confirmation but is not recommended for general diagnostic use because of low sensitivity.¹⁸ In one study, culture of skin punch biopsy samples from the advancing edge of erythema migrans lesions in Barbour-Steiner-Kelly (BSK) medium yielded positive results in 60% of cases.⁸⁹ Blood cultures are positive in one fourth of early Lyme disease cases; this sensitivity was only achieved by using serum as opposed to whole blood and by using high sample volumes.⁹¹ Spirochetes with characteristics of Lyme disease Borrelia were cultured from tissue removed during sector iridectomy and prepupillary membranectomy in a case of recurrent Lyme uveitis after treatment with systemic doxycycline; however, organisms were detected only after 16 subcultures.⁵⁷

PCR has also been examined as a possible means of laboratory confirmation of Lyme borreliosis.^18,22,23,66 Skin and synovial fluid yield the highest rates of PCR positivity (68% and 73%, respectively), whereas CSF and plasma have lower rates (18% and 29%).²² Mikkilä et al.⁴⁷ reported positive PCR results in 7 of 20 cases of ocular Lyme borreliosis. Spirochetes resembling B. burgdorferi were detected histologically in vitreous debris by Dieterle silver staining of a surgical specimen in a case of panophthalmitis.⁷² However, microscopic detection of Lyme Borrelia in tissue specimens is difficult because of low numbers and possible artifacts; interpretation is aided by the use of immunofluorescence or immunohistochemical techniques. Overall, culture, PCR, and microscopic detection are currently research techniques and are not generally available for routine confirmation of Lyme borreliosis.

TREATMENT

The preferred treatment of uncomplicated stage 1 disease, arthritis, or cranial nerve palsies consists of oral regimens of either amoxicillin or doxycycline, with cefuroxime as an alternative.^83,90 Ocular symptoms associated with stage 1 disease (e.g., conjunctivitis and photophobia) resolve with oral therapy. The recommended therapy for central nervous system Lyme borreliosis is parenteral treatment with ceftriaxone (preferred), cefotaxime, or penicillin G for 14 to 28 days.^83,90 Although standardized regimens for ophthalmic disease have not been developed, eye involvement should be provided treatment consistent with that of CNS disease to optimize ocular penetration.^{10,13,34,75,92}

The benefit of systemic corticosteroid treatment as an adjunct therapy is unclear, but such treatment without antibiotic therapy is contraindicated. A Jarisch-Herxheimer reaction (hypotension, chills, fever, arthralgia, and myalgia) occurs following treatment in approximately 14% of patients with Lyme borreliosis and may result in a worsening of optic manifestations. This effect can be counteracted by treatment with nonsteroidal antiinflammatory agents or corticosteroids.⁷³

ANIMAL MODELS

Infection of the eyes and conjunctivitis has been reported to occur consistently in Syrian hamsters inoculated with B. burgdorferi.^24,33 Conjunctivitis has also been noted in experimentally infected hamsters and rhesus monkeys.⁵⁵ However, animal models of ocular Lyme borreliosis have not been studied in detail.

Eye involvement is common in tick-borne relapsing fever and can result in a rapid and severe loss of visual acuity and permanent vision deficits.¹⁹ Most ocular disease reported is caused by infection with B. duttonii, B. hispanica, and B. turicatae. Manifestations include iridocyclitis, choroiditis, and optic neuritis. In one study in East Africa, the incidence of optic neuritis or uveitis was 11%. Ocular manifestations of louse-borne relapsing fever have not been reported. Treatment with β-lactam antibiotics or tetracycline derivatives is highly effective but may result in a Jarisch-Herxheimer reaction.

A number of animal models of tick-borne relapsing fever are available, the most widely used of which is mouse infection.¹⁹ Changes in the variable small protein (Vsp) antigenic variation proteins of B. turicatae have been shown to affect pathogenesis in mice, in some cases resulting in a neurotropic clonotype that causes measurable neurologic deficits.²⁰

Leptospira commonly infect a variety of both wild and domestic animals, including rodents, bats, mongooses, possums, dogs, horses, and cattle.¹⁵ Animals become chronically infected, and Leptospira colonize the renal tubules and are shed in large numbers in the urine. Infection of humans occurs as the result of exposure of broken skin, mucous membranes, or conjunctiva to urine or tissue of infected animals, or to water contaminated by urine.

Leptospirosis is generally related to occupational or recreational exposure or residence in rural or underdeveloped urban areas. Outbreaks frequently are associated with flooding, in which effluent from soil contaminates untreated water supplies.^61,64 Urban epidemics occur in areas of poor sanitation as the result of rat infestation or contamination of water supplies.^37,78,80 An outbreak of leptospirosis among 98 of 834 triathlon athletes after an event in Springfield, Illinois underlines the global distribution of pathogenic Leptospira.⁴⁹ Insufficient reporting or epidemiologic analysis is available to estimate the incidence of leptospiral infection, but it may be the most common spirochetal pathogen in humans as well as domestic and wild animals.

PATHOPHYSIOLOGY OF LEPTOSPIROSIS

The infection in humans and animals follows a similar course. The organism multiplies rapidly and disseminates by the hematogenous route, resulting in spirochetemia and invasion of virtually every tissue. During this acute phase, manifestations include headache, fever, malaise, myalgia, and conjunctival chemosis (sometimes accompanied by subconjunctival hemorrhage).⁶⁰ In 10% to 15% of untreated cases, a severe spirochetemia accompanied by endothelial damage and hemorrhage results in Weil's disease, which has a fatality rate ranging from 10% to 50% in different reports.

The acute phase is followed by a period of asymptomatic infection lasting 2 to 20 months. The immune phase then develops. Immunologic reactions lead to damage to the liver, kidneys, eyes, and other organs. Damage to endothelial cells and resulting vasculitis, hemorrhage, ischemia, and tissue necrosis appear to be the major pathogenic mechanisms. The expression of LPS, which is not found in Treponema or Borrelia, is likely to be involved in endothelial damage, fever, malaise, and hypotension. Jaundice, anuria, altered sensorium, and rhabdomyolysis are indicators of poor prognosis.⁶⁰

OCULAR MANIFESTATIONS

Conjunctival suffusion and hemorrhage are frequent manifestations in patients hospitalized for leptospirosis, with rates ranging from 28.5% to 99% in different studies.¹⁵ During the late stages of leptospirosis, uveitis is a common occurrence that can potentially lead to blindness. Panuveitis is characterized by rapid onset, severe manifestations, and relapses. Nongranulomatous uveitis occurs more frequently than the granulomatous form, and hypopyon and moderate to severe vitreitis (with membranous opacities) are also common presentations. Intermittent perivasculitis can be distinguished from Behçet disease by the relative infrequency of vascular occlusion. Anterior forms of leptospiral uveitis tend to be less severe and gradual in onset. Cataracts and glaucoma are also associated with leptospirosis.

LABORATORY DIAGNOSIS

The diagnosis of early leptospirosis is complicated by its varied and indistinct symptomology that could be mistaken as influenza, hepatitis, and many other infections.^36,40,41 The latent and late forms may be even more challenging because of the lack of recognition of early disease, prolonged asymptomatic periods (e.g., 2 months to 2 years), and varied forms of late presentation. Careful assessment of potential exposure to contaminated water or soil, close contact with animals, and travel to high-incidence areas is needed. Exclusion of other potential causes and consistency of the ocular and systemic manifestations with leptospiral infection are of course also important.

Culture of Leptospira is possible and leads to a definitive diagnosis; however, it requires the specialized EMJH medium, which contains long-chain fatty acids required for growth. In addition, culture can only be performed from blood or other samples during the fulminant early stage of infection, and outgrowth may require several weeks. Immunohistochemical methods for detecting Leptospira in tissue specimens have been developed.⁸⁵

The microscopic agglutination test (MAT) is considered the gold standard of serologic analysis but is a technically cumbersome procedure. A panel of Leptospira serovars (typically 12 to 16) that occur commonly in the geographic region are cultured, washed, and frozen. The cells are combined with increasing dilutions of the patient's serum along with appropriate controls and examined microscopically to determine the endpoint where more than 50% of the organisms are agglutinated. A four-fold increase in titer during the acute phase or a titer >1:100 in chronic disease with one or more of the serovars tested is considered to be diagnostic. False-negative results can be obtained if the infecting serovar is missing from the test panel, and false-positive results may occur because of persistent antibodies from previous leptospiral infections. Because of the complexity of the MAT, a number of new immunoassay techniques, including ELISA, macroagglutination assays, and a rapid leptospira dipstick test (Lepto-DST) are in use or undergoing evaluation.⁴⁰

PCR is of particular value in ocular disease. In one study in south India,²¹ 80% of aqueous humor samples from patients with four or more signs suggestive of leptospiral uveitis (e.g., panuveitis, anterior chamber cells, flare, and vasculitis) were positive for leptospiral DNA. Only 5% of patients with uveitis or cataracts inconsistent with leptospirosis were PCR-positive. Very similar results were obtained for the detection of leptospiral uveitis in horses by PCR,²⁷ in which leptospiral DNA was detected in 70% of leptospirosis cases and only 6% of control cases. Less than one third of PCR-positive cases were culture-positive.

TREATMENT

No standardized treatment guidelines have been developed for leptospirosis, and few controlled studies exist that clarify the value of antimicrobial therapy. While all experts would agree that severe leptospirosis should be treated, some controversy exists regarding the treatment of early leptospirosis. Levett⁴¹ indicated that patients with early leptospirosis and only mild fever and flu-like symptoms need only supportive therapy, in that the course of disease is usually self-limiting. Conversely, other authors would argue that availability of an effective, inexpensive, antimicrobial regimen for early mild leptospirosis would prevent the potential occurrence of Weil disease or other severe sequelae in a significant number of patients.⁷⁹ A practical, and important, side of this issue is that the availability of medical care may be extremely limited in many of the indigent populations in which leptospirosis is common.

In a recent randomized, open-label, nonplacebo study, Panaphut et al.⁵² determined that ceftriaxone and aqueous penicillin reduced the duration of fever in severe leptospirosis cases to 3 days; however, the mortality rate was still 50% in both treatment groups. In another study, Kobayashi³⁶ found that β-lactam antibiotics are bactericidal in vitro against actively growing L. interrogans but are considerably less effective against organisms in the stationary phase. This result may explain why penicillin generally has a limited or varied effect on the course of late or severe disease.^25,35,36,82

Streptomycin is particularly effective in treating Leptospira infections,³⁶ presumably because of its bactericidal effect on organisms in both logarithmic growth and stationary phases. Doxycycline therapy (100 mg twice per day for 7 days) of icteric leptospirosis reduced the disease severity and the period of illness by 2 days.⁴⁶ Studies in hamsters indicate that doxycycline is capable of clearing experimental L. interrogans serovar icterohaemorrhagiae infection, whereas penicillin was only partially effective and ofloxacin was noneffective.⁷⁷ Such analyses may be useful in optimizing therapies for clinical trials in humans.

ANIMAL MODELS

Leptospirosis is a zoonotic infection in which humans are accidental hosts. Leptospira species can infect a wide variety of small and large mammals, ranging from mice, rats, and bats to neotropical opossums, dogs, horses, and cattle.¹⁵ It thus represents a substantial problem in both livestock and pet veterinary practices. Different Leptospira species and serovars preferentially infect certain mammalian hosts, contributing to the variation in distribution and epidemiology of Leptospira variants in geographic regions. These strains in turn have different patterns of pathogenesis in humans. Studies in horses^{27,43,53,54,81} and hamsters¹² have been particularly helpful in understanding the pathobiology of ocular and kidney infections, respectively.

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