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Dementia and Panuveitis: A Case of Whipple Disease

This rare but potentially fatal disease should be considered in unexplained uveitis in the setting of malabsorption or neurologic deficits.

By: REBEKAH H. GENSURE, MD, PHD, CHRISTINA J. FLAXEL, MD
New Retinal Physician October 1, 2022 Vol Retinal Physician 19, Issue October 2022 Page(s): 10-12, 14

This is a case report of a 49-year-old man presenting with hypopyon uveitis and hyphema in the right eye, no view to the posterior pole, 2 weeks of worsening redness, and limited exam in the setting of pre-existing early onset dementia. The patient was initially referred to the retina service due to concern for endophthalmitis.

Review of systems was unable to be conducted due to advanced dementia. Presenting visual acuity was hand motion in the right eye and 20/80 in the left eye with normal intraocular pressures in both eyes. Examination of the right eye demonstrated significant injection, corneal endothelial heme, 3+ anterior chamber mixed cells with mild fibrin, posterior synechiae, neovascularization of the iris, and a nuclear sclerotic cataract with no view posteriorly as demonstrated on external slit lamp photograph (Figure 1A). Examination of the left eye demonstrated a white and quiet sclera with quiet anterior chamber, normal iris without synechiae or neovascularization, and clear lens (Figure 1B).

FIGURE 1: External slit lamp photographs of the 49-year-old patient’s eyes. The right eye (A) demonstrates conjunctival injection with 360° posterior synechiae, neovascularization of the iris, and hyphema; the left eye (B) shows quiet anterior chamber and no hyphema or synechiae. IMAGES COURTESY BETH SNODGRASS
FIGURE 1: External slit lamp photographs of the 49-year-old patient’s eyes. The right eye (A) demonstrates conjunctival injection with 360° posterior synechiae, neovascularization of the iris, and hyphema; the left eye (B) shows quiet anterior chamber and no hyphema or synechiae. IMAGES COURTESY BETH SNODGRASS

Posterior exam of the left eye was extremely challenging due to vitritis, but widefield fundus imaging demonstrated prominent vitreous cells and debris, a cupped optic disc, and a normal-appearing macula with multiple discrete areas of retinal whitening concerning for infiltration (Figure 2). Optical coherence tomography (OCT) image of the left eye demonstrated subtle perivascular changes and some temporal transmission defects but otherwise no obvious macular lesions (Figure 3). Fluorescein angiography of the left eye revealed early vascular staining without obvious vascular leakage and blocked fluorescence in the areas of the chorioretinal infiltrative lesions (Figure 4). On initial B-scan ultrasonography of the right eye, there was a closed funnel 360° tractional retinal detachment with very thin retina (Figure 5). B-scan of the left eye demonstrated a posterior vitreous detachment elevated out to the mid-vitreous with moderate-to-dense vitreous opacities and a highly reflective appearance of the hyaloid face, suggestive of layered opacities (Figure 6). The left optic nerve had a cupped appearance on B-scan ultra-sonography.

FIGURE 2: Optos widefield fundus image of the left eye demonstrating vitreous haze and snowballs with optic disc cupping, complete posterior vitreous detachment with Weiss ring, and discrete areas of retinal whitening concerning for retinal infiltrative lesions (arrow). IMAGE COURTESY BETH SNODGRASS
FIGURE 2: Optos widefield fundus image of the left eye demonstrating vitreous haze and snowballs with optic disc cupping, complete posterior vitreous detachment with Weiss ring, and discrete areas of retinal whitening concerning for retinal infiltrative lesions (arrow). IMAGE COURTESY BETH SNODGRASS
FIGURE 3: Macular OCT of the left eye demonstrating perivascular lesions, mild epiretinal membrane, and a few discrete areas of shadowing/transmission defects. IMAGE COURTESY BETH SNODGRASS
FIGURE 3: Macular OCT of the left eye demonstrating perivascular lesions, mild epiretinal membrane, and a few discrete areas of shadowing/transmission defects. IMAGE COURTESY BETH SNODGRASS
FIGURE 4: Fluorescein angiography of the left eye showing early optic disc leakage (A) and vascular staining (B) without obvious vascular leakage with blocked fluorescence in the areas of the chorioretinal infiltrative lesions in late frames (C and D). IMAGES COURTESY BETH SNODGRASS
FIGURE 4: Fluorescein angiography of the left eye showing early optic disc leakage (A) and vascular staining (B) without obvious vascular leakage with blocked fluorescence in the areas of the chorioretinal infiltrative lesions in late frames (C and D). IMAGES COURTESY BETH SNODGRASS
FIGURE 5: B-scan ultrasonography of the right eye demonstrates closed funnel retinal detachment with thin retina and preretinal proliferative membranes. IMAGE COURTESY MICHELLE DUBOIS AND PHILLIP TURNER
FIGURE 5: B-scan ultrasonography of the right eye demonstrates closed funnel retinal detachment with thin retina and preretinal proliferative membranes. IMAGE COURTESY MICHELLE DUBOIS AND PHILLIP TURNER
FIGURE 6: B-scan ultrasonography of the left eye demonstrates posterior vitreous detachment, lifted to the mid-vitreous, with moderate vitreous opacities and attached retina within field of view. The hyaloid face is highly reflective, which is echographically suggestive of layered opacities. IMAGE COURTESY MICHELLE DUBOIS AND PHILLIP TURNER
FIGURE 6: B-scan ultrasonography of the left eye demonstrates posterior vitreous detachment, lifted to the mid-vitreous, with moderate vitreous opacities and attached retina within field of view. The hyaloid face is highly reflective, which is echographically suggestive of layered opacities. IMAGE COURTESY MICHELLE DUBOIS AND PHILLIP TURNER

Serum laboratory studies identified elevated C-reactive protein and erythrocyte sedimentation rate with initial systemic infectious workup unremarkable (positive VZV IgG consistent with immunity vs prior infection; negative results for FTA and serum RPR as well as Quantiferon gold, CMV IgM and IgG, toxoplasma IgM and IgG, HIV 1 and 2, and no growth on blood cultures). COVID-19 polymerase chain reaction (PCR) was also negative, and additional uveitic laboratory workup for sarcoidosis and inflammatory etiology was unremarkable.

Tap and injection was the preferred initial treatment. However, due to the difficulty with cooperation, this was not possible to perform in clinic. Initial treatment was initiated with topical steroid and cycloplegia (atropine twice daily and prednisolone four times a day) while awaiting scheduling for exam under anesthesia (EUA). On inpatient day 2, EUA was performed with vitreous biopsy and intravitreal injection of vancomycin, amikacin, and voriconazole. Vitreous microbial PCR results were negative for herpes zoster, varicella zoster, cytomegalovirus, Toxoplasma gondii, Mycobacterium tuberculosis, and Borrelia burgdorferi. Lumbar puncture was performed by the inpatient team, and cerebral spinal fluid laboratory studies demonstrated nonspecific findings of low glucose and high protein with negative HSV 1 and 2, VZV, VDRL, bacterial, and fungal cultures. Electron microscopy and PCR studies confirmed presence of Tropheryma whipplei, which was consistent with a diagnosis of Whipple disease with ophthalmic involvement.

Retinal detachment repair surgery was not recommended for the right eye funnel retinal detachment given evidence suggesting chronicity with extensive atrophy. Systemic steroids were avoided initially due to the concern for infection (which was ultimately confirmed from the vitreous biopsy). Topical steroid and cycloplegic were slowly tapered.

Given the rarity of Whipple disease with ocular findings, the infectious disease (ID) service was consulted for further assistance in care of this complex patient. Infectious disease service recommended systemic antimicrobials including oral trimethoprim-sulfamethoxazole (TMP-SMX) and rifampin for a full year. The patient returned to his adult care home in stable condition upon hospital discharge after completing a 14-day course of intravenous ceftriaxone with plans for 12 months total of TMP-SMX and rifampin according to the ID service recommendations.

At follow-up month 1, vision exam remained stable in both eyes with slight improvement in left eye vitritis and right eye hyphema despite persistent neovascularization of the iris (NVI). At month 2, vision improved to 20/70 in the left eye (although visual acuity measurement remained difficult due to dementia) with improvement in exam as seen in widefield imaging (Figure 7A). At the latest follow-up at month 6, vision was 20/100 in the left eye with marked improvement in vitreous haze and snowballs as well as reduction in size of infiltrative lesions (Figure 7B). Unfortunately, because the diagnosis was identified long after the onset of severe dementia, the patient’s neurologic status remained unchanged.

FIGURE 7: Widefield fundus images of the left eye at month 2 (A) and month 6 (B) after initiation of antibiotic therapy demonstrate significant improvement in vitreous haze and snowballs and reduction in size of infiltrative lesion along superior arcade. IMAGES COURTESY BETH SNODGRASS
FIGURE 7: Widefield fundus images of the left eye at month 2 (A) and month 6 (B) after initiation of antibiotic therapy demonstrate significant improvement in vitreous haze and snowballs and reduction in size of infiltrative lesion along superior arcade. IMAGES COURTESY BETH SNODGRASS

DISCUSSION

Whipple disease, first described in 1907 by the pathologist George Hoyt Whipple, is a rare cause of uveitis that affects multiple organ systems.1 Although its initial description did not include bacteria as a cause, observational studies of response to antibiotics and confirmation from electron microscopy studies in the 1960s led to the understanding that the disease is associated with systemic effects from a bacterial infection. Ultimately, with advances in techniques for bacterial culture and identification, the gram-positive bacillus Tropheryma whipplei was isolated and identified as the causative agent.1 The bacteria’s only naturally occurring environment is in the human intestine. The name derives from the Greek words trophe for nourishment and eryma for barrier, which combine to describe the organism’s main effect—malabsorption.

The disease itself is rare, with true prevalence difficult to measure but estimated around 3 per 1 million people according to one Italian study2 and estimated annual incidence of approximately 1 to 6 new cases per 10 million people per year worldwide.3 The low incidence and prevalence persist despite high reported rates of bacterial inhabitation of the human gut by T. whipplei. The typical age of presentation is in the fifth decade, with male predominance reported.4 Transmission presumably occurs via fecal-oral route sometime during childhood, and in the setting of a fully intact immune system, asymptomatic colonization is the usual result. However, lack of a protective immune response in the setting of T. whipplei colonization can lead to creation of an anti-inflammatory milieu, which further encourages spread of the bacteria, resulting in systemic disease.

Owing to the slow replication and requirement for a living host eukaryotic cell, culture of the organism is complex and requires special axenic medium. Electron microscopy with periodic acid-Schiff (PAS) staining or immunostaining can be used to visualize the intracellular rod-shaped organisms within gut macrophages. Polymerase chain reaction tests are the most commonly used tool for modern diagnosis of Whipple disease, but usually from duodenal biopsy; in this case, a less-invasive approach with vitreous biopsy allowed for confirmation of the diagnosis.

Clinical presentation classically includes a systemic triad of findings with arthralgias, diarrhea, and weight loss. Because the main etiology is an immune-mediated malabsorption, patients often present with other malabsorption symptoms including abdominal pain, hypoalbuminemia, and anemia. Patients may also present with lymphadenopathy. Arthralgias may precede other symptoms by months or years, and the diagnosis should be considered in patients presenting with these classic findings.5,6 Central nervous system (CNS) findings have also been reported without any gastrointestinal findings (as in the case of our patient); neurologic manifestations may include seizures, dementia, ataxia, headaches, somnolence, and even meningitis.7,8 Endocarditis, pericarditis, and other cardiac abnormalities may also coexist.

Eye findings are considered part of the late presentation and appear to be quite rare. In one of the largest case series, reported by Dobbins in 1987 with 676 patients, ocular symptoms were identified in only 19 patients (2.7%).9 Ophthalmologic findings in Whipple disease tend to be nonspecific and may include chemosis, epiphora, crystalline keratopathy, corneal ulcers, glaucoma, papilledema, optic atrophy, and retinal hemorrhages.5,10 If considering Whipple disease based on systemic findings in cases where significant vitritis is present, vitreous PCR studies may be valuable as an alternative to the gold standard duodenal biopsy PCR.5 Interestingly, association with HLA-B27 antigen positivity in patients with Whipple disease has been previously reported in a small case series.4

Trimethoprim-sulfamethoxazole with rifampin is recommended as an effective therapy for both classic Whipple disease and late forms of the disease. Although symptoms may improve rapidly with initial treatment, a long treatment course is typically necessary (usually 12 months total according to current recommendations11 based on a small randomized controlled trial by Feurle et al).12 Prognosis is not well known due to the low incidence; deaths have been attributed to failure to initiate adequate antibiotic treatment, cardiac effects, delay in diagnosis, and complications due to disease relapse. Recurrence rates are higher for patients with late manifestations of Whipple disease, specifically those with eye, heart, and central nervous system involvement. Supplementation of antibiotic treatment with interferon gamma has been suggested as a possible means to enhance treatment efficacy.13

CONCLUSION

Although Whipple disease is incredibly rare, it can be lethal if the diagnosis is missed and thus warrants consideration in cases of unexplained uveitis with malabsorption symptoms or CNS disturbance. NRP

DR. GENSURE, a vitreoretinal surgeon, recently completed a fellowship with the Casey Eye Institute at the Oregon Health and Science University (OHSU) in Portland, Oregon. She currently practices at the Eye Institute of Utah, Salt Lake City. She reports no relevant disclosures. Reach Dr. Gensure at RHGensure@gmail.com.

DR. FLAXEL is a professor of ophthalmology at the OHSU Casey Eye Institute in Portland. She reports no relevant disclosures.

REFERENCES

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