One More Issue, if You Please

The diagnosis and management of uveitis can be complicated. The condition can be anterior or posterior, granulomatous or nongranulomatous, unilateral or bilateral, acute or chronic, sudden or insidious. It may be accompanied by fibrin, keratic precipitates, hypopyon, iris nodules, or elevated IOP. Uveitis etiologies can be extensive. To name a few, it may be caused by autoimmune disease, a herpetic etiology, a parasite, a fungus, a connective tissue disorder, vasculitis, sexually transmitted disease, or a tick bite.^1,2 It also may not be a patient’s only eye problem.

The old saying goes, “Better the devil you know than the devil you don’t.” A tweak of this adage sums up the case presented here: Better the disease you know than the disease you don’t.

CASE PRESENTATION AND INITIAL MANAGEMENT

A 79-year-old man, familiar to the glaucoma clinic, presented to the triage clinic. He stated that he had developed a red, watery right eye with blurred vision, light sensitivity, and dull pain 10 days earlier. His ocular history was significant for severe bilateral dry eye disease and an epiretinal membrane in the right eye. The patient also had primary open-angle glaucoma that was severe and threatening fixation in the right eye and moderate in the left eye.

Upon presentation, his BCVA was counting fingers OD and 20/40 OS. According to his chart, the patient’s BCVA 2 months earlier had been 20/60 OD and 20/40 OS. An examination of the cornea of the right eye found 2+ diffuse punctate epithelial erosions, moderate edema with Descemet folds, and 3+ cell. The pupil of the right eye was dilated and minimally responsive to light; this had not been documented in the chart or noticed by the patient, so the onset was unknown. The view of the optic nerves was hazy; the cup-to-disc ratios were 0.90 OD and 0.40 OS.

Anterior, unilateral, nongranulomatous uveitis was diagnosed. Given the corneal involvement and mydriatic pupil, the suspected underlying etiology was herpes simplex virus (HSV). Therapy with acyclovir 400 mg five times per day for 10 days and hourly prednisolone 1% was initiated. Laboratory tests were not ordered because this was the first occurrence of uveitis, the patient reported no systemic symptoms, and the inflammation was unilateral and nongranulomatous.

FOLLOW-UP VISITS

A Few Days Later

The patient reported a significant improvement in all his symptoms, aside from the blurry vision. The appearance of the cornea and anterior chamber of the right eye had improved, but the pupil remained dilated. His BCVA was still counting fingers OD and 20/40 OS.

A secondary differential diagnosis for the patient’s vision loss was discussed. One possibility was that an IOP spike had snuffed out the vision in his already fragile right optic nerve. Another possibility was that the uveitis had caused significant macular edema. OCT imaging, however, demonstrated a fairly stable optic nerve, and stable epiretinal membrane.

The patient was referred to our department’s neuro-ophthalmologist for a second opinion.

Less Than 1 Week Later ...

The patient was seen in the triage clinic for follow-up of his uveitis. A few hours later, he was seen by the neuro-ophthalmologist. During the first visit of the day, the patient’s BCVA was still counting fingers OD and 20/40 OS. In the middle of his appointment with the neuro-ophthalmologist, the patient’s UCVA decreased to 20/400 OS (Figure 1). The clinical examination was otherwise unchanged.

The patient was immediately sent for a laboratory workup that included a complete blood count with auto differential; basic metabolic, comprehensive metabolic, and rheumatoid factor panels; an erythrocyte sedimentation rate (ESR); C-Reactive protein (CRP) and antinuclear antibody tests with interpretation; an HLA-B27 test; a syphilis total immunoglobulin G/immunoglobulin M (IgG/IgM) immunoassay; tests for Toxoplasma gondii antibody and angiotensin converting enzyme; a Bartonella antibody test; and a Lyme disease antibody panel.

The patient’s ESR was 90.0 mm/hr, his CRP was 1.55 mg/dL, and he tested positive for Lyme IgM. His lab testing was otherwise unremarkable.

The preliminarily diagnosis by the neuro-ophthalmologist was giant cell arteritis (GCA). The patient began therapy with an oral corticosteroid (prednisone 70 mg/day). A temporal artery biopsy was performed 5 days later, and it indicated treated temporal arteritis.

As for the possible Lyme disease, although the patient’s Lyme IgM was positive, his IgG was negative and he had no known exposure to Lyme disease or tick bites. Moreover, he had not traveled outside of Columbia, Missouri, in the past several months, which made the likelihood of Lyme disease low. He stated that he had not experienced a rash, myalgia, facial droop, recent heart issues, fever, chills, or weakness. Nor did he have an elevated white blood count. The test result for Lyme IgM was assumed to have been a false positive. The patient was nevertheless referred to the organization’s retina specialist, who has a background in internal medicine. At the visit with the retina specialist, it was deemed that the patient had developed panuveitis and the Lyme IgM, which had previously been assumed to be false-positive, was confirmed with a western blot. Although these findings pointed to an underlying etiology of Lyme disease, the patient was still encouraged to continue treatment with oral prednisone for the GCA, but twice daily dosing of 100 mg doxycycline was now also prescribed. The patient was also scheduled for a computed tomography scan 1 week later if no improvement was observed.

Three weeks later, the patient’s BCVA improved to 20/150 OD and 20/40 OS (Figure 2).

DISCUSSION

Which diagnosis was correct—herpes simplex keratouveitis, GCA, Lyme disease, or a combination of the three? The answer may never be known, but a discussion of the specific signs, testing, and treatments of each differential diagnosis follows.

Herpes Simplex Virus

Although testing such as a polymerase chain reaction (PCR) permits direct evaluation of the anterior chamber and therefore can offer a definitive diagnosis of HSV, it is not always practical, possible, or necessary.^2,3 A clinical evaluation with some key findings typically allows the proper diagnosis to be made without the use of PCR.

Optometrists are familiar with the typical presentation of uveitis, but it is important for them to be aware of anterior segment signs that can point to an underlying diagnosis of HSV. If a patient has nontraumatic iritis, HSV is a top differential diagnosis because nearly 10% of nontraumatic iritis cases are caused by HSV.⁴ Key characteristics of HSV include unilateral presentation, older age, and an acute IOP spike. Iris atrophy and pupillary dilation have been reported in as many as 70% of cases.^3,5

The patient in this case did not have elevated IOP, but his ongoing treatment with ocular hypotensive medications might have prohibited this. He did, however, have unilateral presentation, corneal edema, and pupillary damage, which puts an underlying etiology of HSV very high on the differential list. Oral antivirals are usually a low-risk medication for patients and are frequently prescribed when an underlying etiology of HSV is suspected. Appropriate options include acyclovir 400 mg five times per day, valacyclovir 500 mg three times per day, and famciclovir 250 mg three times per day for 7 days.

Giant Cell Arteritis

GCA is a well-known cause of sudden vision loss. If GCA is left untreated, vision loss in the fellow eye occurs in up to 50% of patients within weeks.⁶ Uveitis stemming from GCA or vice versa has been documented in only a handful of cases.^7,8 A patient older than 50 years of age who experiences sudden vision loss, although likely unrelated to the uveitis, should be fully evaluated for GCA.⁹ A thorough workup includes a detailed review of symptoms. In particular, the provider should inquire about sudden weight loss, neck pain, scalp tenderness, headache, and jaw claudication.^6,9 The following laboratory tests should be ordered: ESR, CRP, and a complete blood count with special attention to the platelets. An ESR higher than the patient’s age divided by two raises concern for GCA in men; an ESR higher than the patient’s age plus 10 divided by two raises concern for GCA in women. A CRP test result that is higher than 2.45 mg/dl, and platelets higher than 400,000 per mL are also suggestive of GCA.¹¹ ESR and CRP can be more than 97% specific for GCA if these values are met.¹¹ A temporal artery biopsy can be performed for confirmation.⁶

If the suspicion of GCA is high or confirmed, therapy with systemic corticosteroids (1 mg/kg/d), which is typically between 40 mg and 60 mg per day, should be initiated. Higher amounts or a 3-day induction dose of intravenous methylprednisolone has been suggested for individuals with ocular involvement.^6,10 The funduscopic examination typically shows a swollen or pale optic nerve, but an evaluation of the remaining rim may be limited in a patient with advanced glaucoma, such as in this case.

Lyme Disease

Uveitis from Lyme disease is poorly understood. Part of the complexity is that the uveitis may be anterior, posterior, or intermediate.¹² It often presents with posterior involvement, including retinal vasculitis. If it does not, a diagnosis can be elusive.¹² Complicating matters is that patients may have ocular comorbidities, such as cranial nerve palsies and optic atrophy, significant systemic associations, a rash, and arthritis.

When Lyme disease is suspected, the Centers for Disease Control and Prevention recommends a two-step verification test. First, the patient undergoes testing (IgG and IgM) for the Borrelia burgdorferi antibody. B burgdorferi is the Lyme disease spirochete.¹³ A positive IgM result indicates recent exposure, whereas a positive IgG result indicates a previous infection. If antibody testing is positive, a confirmatory test such as a western blot is performed. If Lyme disease is confirmed, treatment with oral doxycycline 100 mg twice daily for 14 to 21 days (for adults) should be initiated.¹³

THE TAKE-HOME MESSAGE

With strong clinical indications, lab work, and/or biopsies confirming each differential diagnosis and with the patient showing improvement with treatments for HSV, GCA, and Lyme disease, it remains unclear which diagnosis was correct. This makes eye care a bit frustrating, but also an art form. The real lessons of the case are to continue searching for answers when things do not add up, not to be afraid to combine subspecialties when necessary, and to remember that patients are not limited to a single problem.