Ophthalmic Aspects of Lyme Disease Overview of Lyme Disease

Lyme disease is the most common arthropod-related disease in the United States, Europe, and portions of Japan. The disease is transmitted by the bite of an Ixodes tick infected with Borrelia burgdorferi. Ehrlichiosis and babesiosis are also transmitted by the Ixodes tick. Lyme disease is a multisystem spirochetal disorder that can mimic many other diseases. As in syphilis, another spirochetal illness, Lyme disease occurs in 3 stages. Ocular manifestations of Lyme disease may involve any portion of the eye and vary depending on the stage of the disease (see General and Ocular Manifestations, below). With early detection and treatment, the prognosis is favorable.^{[1, 2, 3, 4]}

For more information, see Lyme Disease and Pediatric Lyme Disease.

For patient education information, see the Bites and Stings Center and Arthritis Center, as well as Ticks.

The pathogenesis of Lyme disease is not well understood, but the symptoms are believed to be due to direct infection and a delayed hypersensitivity mechanism. A controversial aspect of the disease is the form of the disease known as late or chronic Lyme disease. Some patients may develop chronic or relapsing inflammation (including uveitis). It is unknown if these patients truly have Lyme disease and if they represent treatment failures, a persistence of organism, an infection with another tick-borne pathogen, or an autoimmune phenomenon.

Of the cases of Lyme disease, 75% occur during the summer months. Clusters of Lyme disease occur in 3 geographic areas of the United States: the Northeast, especially in southern Connecticut, Westchester County, and Long Island in the state of New York; the Midwest, in Minnesota and Wisconsin; and the Northwest, in Washington, Oregon, and northern California.

Lyme disease has been reported in Europe and South America.

With Lyme disease, there is a bimodal distribution of age groups with 2 peaks, one in children aged 5-14 years and one in adults aged 30-59 years.^[5]

Stages of Lyme disease

The clinical manifestations of untreated Lyme disease occur in the following 3 stages^[6] :

• Stage 1 is the localized bull's-eye skin rash of erythema chronicum migrans; this pathognomonic skin rash begins 3-30 days after the tick bite, but as many as 18% of patients can present without the skin rash
• Stage 2 follows weeks to months later; these patients may develop neurologic (15%), cardiac (5%), or arthritic (60%) manifestations; neurologic signs can include cranial neuropathy (especially Bell palsy), meningitis, headache, or neuritis
• In stage 3, the most common manifestation is chronic Lyme arthritis; chronic neurologic syndromes include neuropsychiatric disease and peripheral neuropathy

Ocular manifestations of stage 1 disease

In stage 1 Lyme disease, the ocular manifestations are conjunctivitis and photophobia. These symptoms are mild and transient, and ophthalmologists usually are not consulted.

Ocular manifestations of stage 2 disease

During stage 2 Lyme disease, significant ophthalmic complications first appear. The most common are various neuro-ophthalmologic signs. Typically, the patient may first present with cranial nerve VII palsy (Bell palsy). Some patients may present with the triad of Lyme neuroborreliosis consisting of cranial nerve palsy, meningitis, and radiculopathy.^{[7, 8, 9, 10]}

Blurred vision also can be noted during stage 2, secondary to papilledema, optic atrophy, optic or retrobulbar neuritis, or pseudotumor cerebri. Optic nerve disease may be unilateral or bilateral and solitary or associated with other neurologic or neuro-ophthalmologic manifestations. Some evidence exists that children are more predisposed to optic nerve disease than adults.^[5]

Ocular manifestations of late stage 2 and stage 3 disease

In late stage 2 or stage 3 Lyme disease, most of the severe ocular manifestations of the disease are seen. These include episcleritis, symblepharon, keratitis, iritis, posterior or intermediate uveitis, pars planitis, vitreitis, chorioretinitis, exudative retinal detachment, retinal pigment epithelial detachment, cystoid macular edema, branch artery occlusion, retinal vasculitis, orbital myositis, and cranial nerve palsies. Of this group, keratitis, vitreitis, and pars planitis are the most common.

The keratitis usually is a bilateral, patchy, nummular stromal keratitis. Posterior segment inflammatory disease generally presents as a bilateral pars planitis associated with granulomatous iritis and vitreitis. Many of these patients also have granulomatous keratic precipitates and posterior synechiae.^[11]

Diagnostic considerations

Because Lyme disease is a disease with varied and complex (and confusing) manifestations, it can be difficult to diagnose. There often are problems with the initial diagnosis, and there can be delays in diagnosis. In addition, there can be a tendency to overdiagnose the disease, especially in patients with a lifestyle that puts them in a high-risk category.

The best way to avoid these problems is to follow the Centers for Disease Control and Prevention (CDC) guidelines regarding diagnosis and to obtain the assistance of an infectious disease expert when one has any questions. Also, be careful as to how the laboratory tests are interpreted, and be sure that they are obtained from a reputable laboratory with experience in testing for Lyme disease.

Differentials

The differential diagnosis of Lyme disease includes the following:

• Bell Palsy
• Conjunctivitis, Viral
• Diplopia
• Episcleritis
• Herpes Simplex
• Herpes Zoster
• Horner Syndrome
• Oculomotor Nerve Palsy
• Optic Neuritis
• Papilledema
• Rocky Mountain Spotted Fever
• Sarcoidosis
• Scleritis
• Trochlear Nerve Palsy
• Uveitis

Other problems to be considered include the following:

• Macular edema
• Orbital myositis
• Orbital pseudotumor
• Choroidal neovascular membrane
• Paralytic strabismus

Because many patients with suspected Lyme disease do not recall the tick bite or skin rash, laboratory tests are important in establishing the diagnosis. However, much confusion can occur in the interpretation of the tests used for Lyme disease.^[12]

The organism and its DNA can be detected in cerebrospinal fluid (CSF), urine, and sera but only early in the disease. Polymerase chain reaction (PCR) is superior to culture, but it is not standardized and not widely available.

IFA and ELISA

The 2 most frequently used tests are the immunofluorescent assay (IFA) and the enzyme-linked immunosorbent assay (ELISA). The principal limitation of these serologic tests has been the high frequency of both false-negative results and false-positive results. False-negative results occur during the acute phase of Lyme disease before patients have developed a sufficient antibody response to give a positive serologic test. False-positive results are due to serologic cross-reactivity between Lyme disease, syphilis, Rocky Mountain spotted fever, and other disorders.

To improve diagnostic ability, some laboratories use the immunoblot (Western blot) test. This test is more specific, sensitive, and reliable than the ELISA.

Two-step protocol

The National Conference on Lyme Disease recommends a 2-step protocol for disease testing. The first step is to use either Lyme IFA or Lyme ELISA.^[13] A Venereal Disease Research Laboratory (VDRL) test and a fluorescent treponemal antibody-absorption (FTA-ABS) test should be completed at the same time. Any positive or equivocal test mandates that immunoglobulin G (IgG) and immunoglobulin M (IgM) immunoblots be performed.

Other tests

In patients with orbital disease possibly associated with Lyme disease, MRI and contrast-enhanced CT scans may be helpful.

Difficulties can arise in choosing the appropriate antibiotic treatment regimen, especially in children or potentially pregnant women. Again, an infectious disease consult is helpful in these situations. Finally, if one decides to become actively involved in the management of these patients, stay abreast of the literature, especially in the rapidly changing areas of diagnosis and treatment.^[14]

Stage 1 treatment

All patients with stage 1 Lyme disease should be treated with any one of the following oral antibiotics for 2-3 weeks: tetracycline, 500 mg 4 times a day; doxycycline, 100 mg 2 times a day; phenoxymethyl penicillin, 500 mg 4 times a day; or amoxicillin, 500 mg 3-4 times a day.

Children, pregnant women, patients who cannot tolerate tetracycline, and patients who are allergic to penicillin may be given erythromycin, 500 mg 4 times a day.

Later-stage treatment

Patients in the later stages of Lyme disease can be treated with oral antibiotics, but these patients usually need 30 days of therapy. Patients with severe disease (eg, meningitis, neuroborreliosis, carditis) require parenteral therapy with beta-lactam antibiotics, such as 14-21 days of one of the following: intravenous penicillin G, 3-4 million units every 4 hours; intravenous ceftriaxone, 2 g/d in divided doses; parenteral penicillin and ceftriaxone in combination; or roxithromycin and cotrimoxazole in combination.

Combination therapy may be worthwhile in patients who do not respond to monotherapy. Physicians should observe patients closely for possible Jarisch-Herxheimer reactions after the institution of therapy; this allergic/inflammatory response may manifest in the skin, mucous membranes, viscera, or nervous system.

Other treatments

Stage 1 conjunctivitis and photophobia require no therapy. Stage 2 Bell palsy is self-limited but requires supportive therapy to prevent the complications of exposure keratitis. Keratitis and episcleritis benefit from topical corticosteroids, usually a short course of prednisolone acetate 1% or fluorometholone 0.1%.

A treatment regimen for severe neuro-ophthalmic disease (involving the optic nerve) or posterior segment disease (eg, pars planitis, vitreitis) has not been established. Oral corticosteroids without concomitant antibiotics should not be used. The best approach for these patients might be a therapeutic antibiotic trial, in which patients can receive 2-3 weeks of intravenous penicillin or ceftriaxone. If patients respond to treatment, the trial is successful, ocular Lyme disease is diagnosed, and no further therapy is needed. Recurrences of Lyme uveitis, once adequate intravenous therapy has been given, can be treated with judicious corticosteroids.

Deterrence and prevention

Preventive measures for Lyme disease rely on personal protection. People in endemic areas should wear long pants and light-colored clothing and use insect repellents whenever venturing into the wooded areas preferred by the Ixodes tick. They should inspect clothing before removal and use appropriate landscape measures around homes. However, for patients who live in endemic areas of Lyme disease and who will be outdoors, the vaccine may be advisable.

In December 1998, the Food and Drug Administration (FDA) approved the use of the vaccine LYMERix (Smith-Kline-Beecham) to prevent Lyme disease. However, because of poor demand for the product, the sale of the vaccine was discontinued in the United States (2002).^[15]

The vaccine is considered a supplement and not a replacement for standard precautions against Lyme disease. The best way to prevent Lyme disease is for individuals to take preventive measures against tick bites. The vaccine is a recombinant outer-surface protein A (rOspA) of B burgdorferi, the bacteria that causes Lyme disease. It induces antibodies that prevent the bacteria from causing illness in vaccinated individuals.

However, use of the vaccine presents certain difficulties. The vaccine is approved only for people aged 15-70 years. It is not approved for children, elderly individuals, pregnant woman, or people with chronic joint or neurologic Lyme disease. In addition, for maximum protection, at least 3 dosages are required over 1 year: the first dose at 0 time, the next dose at 1 month, and the last dose at 12 months. Finally, the vaccine is not expected to give immunity. Patients require periodic boosters. Current evidence indicates that, even in the best-case scenario, the vaccine has an efficacy of about 80%. Therefore, it is only indicated for patients at high risk.

Other problems with the use of the vaccine are that it does not protect against other diseases carried by the deer tick, such as ehrlichiosis and babesiosis. The vaccine costs approximately $100 per individual per year, and some insurance companies may not cover the vaccine. The duration of protection is unknown, and the long-term safety of the vaccine has not been determined. Finally, patients should be warned that they probably will develop some local adverse affects, including swelling, pain, and inflammation in the area of the vaccine.