Part 4 • Infectious Uveitic Conditions

Chapter 10 Spirochetal Diseases

diagnosis of yaws and pinta is based on clinical findings in the setting of positive syphilis serologic findings.

Prognosis

Yaws may undergo spontaneous clinical and serologic resolution at any stage of the disease without therapy; however, antibiotic treatment improves the cure rate. Untreated patients may experience periarticular ulcers causing crippling contractures and osteomyelitis. Patients with untreated pinta experience depigmented patches of the skin, which may lead to social ostracization, the major consequence of pinta.

Treatment

Penicillin is the preferred drug to treat yaws and pinta. The treatment recommendations are outlined in the section on endemic syphilis.

Borrelia infection

Lyme disease

Etiology and Epidemiology

In the spring and summer of 1975, a group of children living in Lyme, Connecticut, presented with an inflammatory arthropathy similar to that in juvenile rheumatoid arthritis.43 A characteristic rash was associated with the illness, as were neurologic and cardiac abnormalities. In 1977 Steere and others43 labeled this illness Lyme disease. Epidemiologic studies implicated ticks as the vector for the disease, but the etiologic agent remained elusive.

Similar rashes called erythema migrans or erythema chronicum migrans had been associated with tick bites and systemic disease in Europe, and spirochete-like structures had been found in skin specimens from several patients.44 In the United States, evidence was accumulating that patients with Lyme disease who were treated with penicillin fared better than untreated patients. A tick-borne organism was suspected as the causative agent, and in 1982, Burgdorfer and coworkers45 found spirochetes in Ixodes dammini ticks while looking for the cause of Rocky Mountain Spotted Fever in their Montana laboratory. Spirochetes were later isolated from patients with Lyme disease in the United States, as well as from patients in Europe with erythema migrans and Bannwarth’s syndrome (a chronic lymphocytic meningitis associated with erythema chronicum migrans).46 The previously unrecognized spirochete was isolated by Burgdorfer and Barbour47 and was named Borrelia burgdorferi.

Along with Leptospira and Treponema, Borrelia belongs to the eubacterial phylum of spirochetes.48 These organisms are usually more loosely coiled than other spirochetes, but if coiled, they have a corkscrew appearance and look exactly like T. pallidum. Borrelia species are easy to isolate from infected ticks but difficult to isolate from infected patients. B. burgdorferi is transmitted by certain Ixodes ticks. In the United States, the preferred host for the larval and nymphal forms of the tick is the white-footed mouse,49 whereas the preferred host for the adult form of the tick is the whitetailed deer.50 The ticks have now been found on at least 30 species of animal and 49 species of bird.51 Lyme disease also occurs in domestic animals, including cats, dogs, and horses. Ixodes ticks are ‘multitalented’ and transmit babesiosis and tularemia in addition to Lyme disease.

From 1980 to 1988, 13 795 cases of Lyme disease were reported in the United States.52 During 1992–2006 a total of 248 074 cases of Lyme disease were reported in the 50 states, the District of Columbia, and US territories.53 The annual count increased 101% from 9908 cases in 1992 to 19 931 cases in 2006. Most of the cases were reported from 10 states (Connecticut, Delaware, Massachusetts, Maryland, Minnesota, New Jersey, New York, Pennsylvania, Rhode Island, and Wisconsin).53 Lyme disease is thought to be the most common vector-borne infection in the US, and it has been reported throughout the world, especially North America, Europe, and Asia. The rapid spread of the disease has been attributed to an increase in forested areas that house the tick-infested deer and to the migration of susceptible residents into these areas. For example, during a 7-year period 35% of 190 residents living adjacent to a nature preserve in Ipswich, Massachusetts, acquired Lyme disease.54 The number of cases continues to grow as awareness of the disease by both physicians and patients increases.

Clinical Manifestations

Lyme disease is usually described as occurring in stages (Box 10-3). Early infection is divided into stage 1 (local) and stage 2 (disseminated). Late infection is categorized as stage 3 (persistent). After infection, the spirochete spreads locally in the skin in 60–80% of patients and causes the characteristic rash, erythema migrans,51,55 which is an oval or anular erythematous lesion with expanding borders that usually fades within 3–4 weeks in untreated patients but may recur later in the disease (Fig. 10-5). Patients recall being bitten by a tick about half of the time. Specific antibody to B. burgdorferi is often lacking at this stage of the disease, during which patients may have minor flu-like constitutional symptoms and regional lymphadenopathy. The most common ocular finding in early Lyme disease is conjunctivitis.55

Stage 2 disease occurs within days to weeks after infection, during which time the spirochete can spread to many organs via the blood, causing a multitude of signs and symptoms. These systemic manifestations are mainly characterized by cardiac and neurologic involvement, although patients may experience secondary anular skin lesions. Neurologically, patients have severe headache and mild stiffness of the neck. The CSF is normal early on in the disease but later reveals a lymphocytic pleocytosis with a cell count in the range of 100/mm3, elevated protein concentration, and normal glucose concentration.56 Peripheral neuropathies, intermittent arthralgia, and musculoskeletal pain are common, and unilateral and bilateral Bell’s palsy is the most common cranial neuropathy.57

Box 10-3  Lyme disease – key features

•Caused by the spirochete Borrelia burgdorferi

•Transmitted in the Ixodes dammini tick

•Disease is divided into stages. Early infection is divided into stage 1 (local) and stage 2 (disseminated). Late infection is categorized as stage 3 (persistent)

•After infection the spirochete spreads locally in the skin in 60–80% of patients, causing the characteristic erythema migrans rash

•Conjunctivitis is the most common ocular finding in early Lyme disease

Figure 10-5.  Characteristic lesions of erythema migrans associated with Lyme disease.

Figure 10-6.  Retinal vasculitis in a patient with ocular Lyme disease. Sheathing of peripheral retinal vessels and mild vitritis are seen in this patient on this fluorescein angiogram. The patient also had a scleritis.

The ocular findings resolved after treatment with intravenous ceftriaxone.

From 4% to 8% of patients have cardiac involvement with fluctuating atrioventricular block.58 Fewer patients have been reported with acute myopericarditis. About 6 months after infection patients can acquire oligoarticular arthritis with a white blood cell count in joint fluid of 500–110 000/mm3. Other manifestations of stage 2 Lyme disease include hepatitis, nonproductive cough, microscopic hematuria or proteinuria, and orchitis.51 The ocular findings most commonly reported in stage 2 disease are conjunctivitis and uveitis.

Stage 3 infection is characterized by prolonged episodes of arthritis. Chronic neurologic manifestations include ataxia, chronic encephalomyelitis, spastic paraparesis, and dementia. Patients often have chronic fatigue, and erythema migrans can occur late in the disease. Bilateral keratitis is described as a characteristic finding in late infection.57–61

Transplacental transmission of B. burgdorferi has been reported in two infants whose mothers had Lyme disease in the first trimester of pregnancy,62–64 although a study of 463 infants from endemic or nonendemic areas showed no association between congenital malformations and the presence of detectable antibody to B. burgdorferi in cord blood.65

Ocular Manifestations

In initial reports, the only consistently reported ocular finding in Lyme disease was transient conjunctivitis, occurring in 11% of persons with stage 1 disease.55 Other ocular findings reported in the early stages of disease include epi­ scleritis, iridocyclitis with posterior synechiae, and retinal vasculitis (Fig. 10-6).66,67 Steere and associates68 reported on a case of a 45-year-old woman who, 4 weeks after the onset of erythema migrans, experienced unilateral iritis followed by panophthalmitis; spirochetes were found in specimens of vitreous debris obtained at surgery.

In March 1987, Bertuch and associates59 reported on three patients with ocular findings of Lyme disease. The first patient presented with bilateral Bell’s palsy and lateoccurring optic neuritis. The other two patients experienced patchy intrastromal infiltrates of the cornea from Bowman’s layer to Descemet’s membrane. These corneal infiltrates caused reduced vision but no pain, and occurred late in the course of disease. Dramatic resolution of the keratitis occurred after treatment with topical corticosteroids, suggesting an immune mechanism rather than a direct infection

Figure 10-7.  Multiple intrastromal lesions of Lyme keratitis. (Courtesy of Ernest Kornmehl, M.D., From Albert & Jacobiec, Principles and Practices of Opthalmology, Copyright Elsevier.)

with the spirochete. Baum and associates60 reported three patients who acquired bilateral keratitis long after Lyme disease was diagnosed and treated, and also noted the effectiveness of topical corticosteroid therapy. Since then, several other papers have documented keratitis late in the course of Lyme disease (Fig. 10-7).61,66,67,69–72

Less common ocular findings associated with Lyme disease have also been reported in single case reports. Bialasiewicz and associates73 described a patient with meningeal symptoms and diffuse choroiditis, cystoid macular edema, and exudative retinal detachments initially misdiagnosed as Vogt–Koyanagi–Harada disease. Immunofluorescence results for Lyme disease were positive, and the patient improved markedly after treatment with doxycycline. Koch and associates74 reported retinal pigment epithelial detachments in a man with neuroborreliosis. Scholes and Teske75 tested 19 patients with intermediate uveitis for Lyme disease, and seven of 19 patients had positive antibody titers, suggesting a possible association between Lyme disease and pars planitis. Copeland and associates76 reported on two patients with intermediate uveitis that was only partially responsive to steroids who were later diagnosed with Lyme disease after positive Lyme titers were obtained. The uveitis

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in both patients cleared rapidly with systemic antibiotic treatment. In a report by Winward and colleagues,77 patients with intermediate uveitis associated with Lyme disease demonstrated more significant anterior segment inflammation. Subsequent studies confirmed the presence of significant posterior segment inflammation, especially vitritis and retinal vasculitis, in some cases of Lyme disease.71,72,78,79

Neuro-ophthalmic findings in Lyme disease are common.44,80 Involvement of the CNS by Lyme disease causes cranial nerve palsies. Unilateral and bilateral Bell’s palsies are the most common cranial nerve palsies and often result in exposure keratitis. Diplopia due to sixth, fourth, and third cranial nerve palsies can occur. Wu and associates81 described a 7-year-old child who had bilateral disc edema in association with Lyme disease. A similar patient was described by Jacobson and Frens82 and was diagnosed with a pseudotumor cerebri syndrome associated with Lyme disease. Optic disc edema may be the sole presenting sign of Lyme disease.83 Other reported neuro-ophthalmic manifestations of Lyme disease include optic neuritis (Fig. 10-8), cortical blindness, and orbital myositis.84,85–87 The association of some of these ocular findings with Lyme disease stems from one or two case reports in which the diagnosis of Lyme disease was based predominantly on positive serologic findings. Because serologic results for Lyme disease may be falsely positive, some of the cases may have been wrongly diagnosed.88 A list of the ophthalmic manifestations associated with Lyme disease is presented in Table 10-6.

Diagnosis

Techniques for the diagnosis of Lyme disease are not ideal. A patient with a history of a tick bite who later experiences erythema migrans most surely has Lyme disease; however, a tick bite is recalled in only about 50% of cases, and a pathognomonic rash may be overlooked or may not occur in a significant number of patients. Erythema migrans is the only clinical sign of clear diagnostic value; however, earlobe lymphocytoma, meningoradiculoneuritis (Garin–Bujadoux– Bannwarth syndrome), and acrodermatitis chronica atrophi-

Table 10-6  Ocular manifestations of lyme disease

EARLY INFECTION

Conjunctivitis

Episcleritis

Posterior scleritis

Iridocyclitis

Retinal vasculitis

Optic disc edema

Panophthalmitis

Choroiditis

Pars planitis

Exudative retinal detachment

Retinal pigment epithelial detachment

Exposure keratitis

Diplopia

Cortical blindness

Orbital myositis

LATE INFECTION

Keratitis

Episcleritis

cans may be of some diagnostic value.89 Because of the difficulty of culturing B. burgdorferi from patients, laboratory diagnosis is made by serologic findings. Most patients have elevated antibody titers to B. burgdorferi several weeks after infection. Both immunofluorescent assays and enzymelinked immunosorbent assays (ELISAs) are used in the diagnosis of Lyme disease, although the ELISA is more sensitive in all stages of the disease. Unfortunately, serologic testing has not been standardized, and interlaboratory variability is significant, although improving.90–92 The sensitivity of the ELISA for Lyme disease in several laboratories approaches 90% after the first few weeks of infection. Many laboratories confirm positive ELISA results with Western blot assays. Nevertheless, the clinician must be aware of false-negative and false-positive results. False-negative results occur during the first few weeks of infection, when antibody titers may be low and may be missed by serologic tests of lower sensitivi-