Ocular Manifestations of Whipple Disease

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Article initiated by:
Cameron Reinisch
All contributors:
Gabriela Lee Aguirre MD, Hunter Drenth, Cameron Reinisch
Assigned editor:
Review:
Assigned status Update Pending
.


Disease Entity

Whipple's disease (WD) is a rare, chronic, multisystemic infectious disease caused by Tropheryma whipplei (TW), a gram-positive filamentous actinobacterium. Systemic disease is characterized by low-grade fevers, lymphadenopathy, abdominal pain, diarrhea, weight-loss, and a non-deforming episodic polyarthritis. Ocular involvement is uncommon, reported in approximately 2.7–11% of patients with confirmed systemic TW infection.[1] Ocular symptoms are often coupled with systemic manifestations, but isolated ocular involvement has been well-documented and should not preclude the diagnosis of WD. Untreated, it is progressive and potentially fatal.[2]  Even with appropriate antibiotic therapy, relapse occurs in up to 33% of patients, frequently involving the CNS. [1] The mean time from symptom onset to diagnosis is approximately 6.4 years.[3]  In 70–80% of patients with ocular WD, systemic findings are also present.[4][5]  Mean time from onset of ocular symptoms to diagnosis is approximately 11 months (range 2–28 months).[6]

Epidemiology

Approximately 1,000 cases have been reported since the initial description with an incidence less than 1 per million per year. [7]The disease predominantly affects middle-aged Caucasian males (male-to-female ratio approximately 8:1) with a mean age of onset in the fifties.[8]  Recent epidemiological data suggest an increasing mean age at diagnosis and a higher proportion of female patients.[9]

T. whipplei is ubiquitous in the environment, and it is identified in sewage effluent and human waste.[10][11]

Among patients diagnosed with WD, 29% were found to have diabetes.[11]

CNS involvement is found in up to 50% of cases at the time of autopsy; clinical CNS involvement ranges from 6–63%, with most estimates 10–43%.[12] Ocular involvement is seen in approximately 6% of systemic WD patients (Mayo Clinic series: 4/217 = 1.8%).[6]

Ocular manifestations

Symptoms
Floaters (most common patient complaint)
Blurry vision, often bilateral
Loss of visual acuity
Photophobia
Conjunctival injection/hyperemia
Irritation/Pain (some cases are painless)
Chemosis

Anterior Segment

Anterior segment involvement with WD is less common than posterior segment involvement. [13]  Classic uveitic findings reveal anterior chamber cell and flare, granulomatous keratic precipitates, and posterior synechiae. Ocular surface manifestations include keratitis, corneal opacities, and keratoconjunctivitis; the latter is characterized by a fibrovascular pannus that is typically bilateral and may occur with or without pigmented limbal nodules. [2] [14] Intraocular crystalline-like deposits can be seen in up to 13% of cases with intraocular WD. The location of these deposits includes the corneal endothelium, iris, IOL/capsular bag, and even the preretinal or subretinal space. [7] Scleral nodules are a very rare finding on the ocular surface.[15]

Posterior Segment

The primary intraocular manifestation of WD is chronic, typically bilateral, granulomatous panuveitis.[6] [13] Over 80% of patients with posterior involvement of WD will have vitritis. Retinal vasculitis is an additional finding that is present bilaterally in 50% of patients. [2]Additional posterior findings include periphlebitis and small peripheral chorioretinal lesions. [4] Macular edema, optic nerve head edema, and optic atrophy may also be seen. Fluorescein angiography and ocular coherence tomography may be helpful ancillary tests to elucidate the above findings.

Adnexal and orbital manifestations

Adnexal and orbital manifestations in WD are exceedingly rare and primarily described in isolated case reports. These manifestations may occur in the setting of active infection, disease relapse, or immune reconstitution inflammatory syndrome (IRIS). [16][17][18][19]

Symptoms
Diplopia
Pain (periorbital)
Limitation of ocular movements
Mechanical ptosis (eyelid abscess)
Reduced visual acuity

External examination may reveal exophthalmos, periorbital edema, and conjunctival chemosis/injection. Ocular motility testing may demonstrate extraocular movement deficits from orbital myositis. [16][17] In severe cases, optic nerve dysfunction (reduced visual acuity, diminished color testing, visual field defects, and a relative afferent pupillary defect) may be a consequence of optic nerve compression. [19]

Neuro-ophthalmic manifestations

Neuro-ophthalmic manifestations are seen in 24% of patients with WD and reflect central nervous system involvement.[20]

Oculomasticatory myorhythmia is present in approximately 24% of all CNS-WD cases and is pathognomonic for the disease. This consists of pendular or smooth vergent nystagmus associated with tongue and mandibular myoclonus.[4]  While OMM may be pathognomonic, a vertical supranuclear gaze palsy is the most common manifestation of CNS-WD, occurring in 59% of cases.[12]

Differential diagnosis

Whipple’s disease is known and characterized as a “great mimic” thanks to its ability to present multi-systemically with features that overlap with numerous inflammatory, infectious, and neoplastic conditions.[6] Since ocular manifestations can be the sentinel/primary signs of the disease, clinicians must maintain a high index of suspicion, particularly in cases involving unexplained uveitis or orbital inflammation that proves refractory to first-line treatment.[6]

●      Exogenous or endogenous indolent endophthalmitis (bacterial, fungal)

●      Infectious panuveitis (herpetic, toxoplasmosis, syphilis, tuberculosis, mycobacterium avium-intracellulare infection, Lyme, bartonella)

●      Primary Vitreoretinal Lymphoma

●      Sarcoidosis

●      Histoplasmosis

●      Multifocal choroiditis and panuveitis

●      Amyloidosis

●      Behçet's disease

●      Granulomatosis with polyangiitis

[2]

In older patients and those presenting with intractable vitritis, amyloidosis, and neoplastic masquerades such as vitreoretinal lymphoma should be considered. Early diagnostic pars plana vitrectomy with PCR and genomic sequencing is often necessary. [4]

If ocular surface involvement with crystalline keratopathy, other causes of corneal crystals, including infectious keratitis (both bacterial and fungal), Schnyder’s crystalline dystrophy, and systemic plasma cell dyscrasias synch as Multiple Myeloma, or Waldenstrom’s macroglobulinemia should also be considered. [2]

Neuro-ophthalmic WD may be the only ocular manifestation alongside systemic pathology, and it is important to collaborate with a neurologist to consider broaden the differential diagnosis, including:

●      Progressive supranuclear palsy (PSP): most important differential; key differences include younger age in WD (mean 48 vs. 69 years), more rapid progression, complete horizontal gaze palsy is less common in PSP, myoclonus is rare in PSP.[21]

●      Multiple system atrophy[22]

●      Anti-Ma2 paraneoplastic encephalitis[21]

●      Niemann-Pick C (vertical SGP)[21]

●      Spinocerebellar ataxia type 1 (vertical SGP)[21]

●      Gaucher disease (horizontal SGP)[21]

Diagnosis

WD should be on the differential for a patient with a uveitis of unknown etiology. A standard serologic uveitis workup (FTA, RPR, ACE, lysozyme, HLA-B27, QuantiFeron gold, etc.) is negative in WD.

Molecular diagnosis: PCR testing is the most applicable method for identifying TW. Non-ophthalmic forms include blood PCR, which is positive in approximately 59% of reported cases; gut PCR, which is positive in approximately 63% of bowel biopsies; and CSF PCR, which is positive in approximately 59.1%. First-line screening tests for WD include stool and saliva PCR, and when combined, the positive predictive value reaches 95.2%.[23] [21]  For ocular WD, aqueous humor and vitreous PCR are key diagnostic tests with vitreous preferred. When available, metagenomic next-generation sequencing of aqueous humor is effective even when the vitreous biopsy is non-diagnostic.[24][9][2]

Imaging: A brain MRI should be obtained if there is concern for CNS involvement. It is abnormal in 85% of CNS-WD, with most often multiple T2 hyperintensities in mediobasal and deep periventricular areas and contrast enhancement in ~27%. A normal MRI does not exclude CNS-WD, and unfortunately, imaging findings are nonspecific.[21] If there is orbital involvement, including the lacrimal gland and extraocular muscles, orbital MRI is preferred and would find enlargement of these structures. Bone involvement has not been reported.[25]  If there are scleral nodules, ultrasound biomicroscopy demonstrates a homogeneous hypo-reflective subconjunctival lesion forming scleral nodules and scleral thinning. [15]

Management

Antimicrobial Therapy

Therapeutic management requires an antimicrobial regimen that targets the eye and CNS as sanctuary sites to prevent neurological relapse. Agents with high blood-brain and blood-ocular barrier penetration are required. [6][13]

●      Induction Phase: Intravenous Ceftriaxone (2g daily) or a combination of Penicillin G and Streptomycin for a duration of two to four weeks. [4][6]

●      Maintenance Phase: Trimethoprim-Sulfamethoxazole (160/800 mg twice daily) for a duration of 1-2 years. [4]

●      Alternatives: For patients with penicillin allergies, consider the use of meropenem or desensitization for the induction phase. Doxycycline combined with Hydroxychloroquine or Rifampin can be utilized in cases of sulfonamide intolerance or treatment resistance but have lower CNS penetration. [13]

Topical Antibiotics: Avoid as primary therapy. Minimal clinical improvement has been observed with topical agents, as they fail to penetrate the corneal epithelium or address the systemic load of T. whipplei.. [26]

Relapse: In conjunction with GI and Infectious Disease colleagues, patients need close surveillance during and after treatment, often with body fluid analyses (repeat endoscopy/biopsy, stool/saliva/CSF PCR) to ensure appropriate treatment response and confirm no relapse.[4]

  • Relapse occurs in 33% of cases and requires re-induction or a transition to alternative microbial cases. [4][6]

Corticosteroids

The use of corticosteroids in WD is controversial, and while managing secondary inflammatory symptoms, they carry a significant risk of masking active infection and exacerbating clinical course. [6][13] Treatment is indicated in cases with suspected IRIS-related disease, which has been documented to lead to rapid improvement in proptosis pain, motility, and restriction. [20] Notably, rapid improvement with steroids may suggest IRIS rather than active infection.

Surgical Management

Pars plana vitrectomy (PPV): Indicated with dense, recalcitrant vitreous debris or diagnostic uncertainty, especially when systemic work-up is non-revealing. [4][6]

●      Therapeutic: Clearance of vitreous opacities to improve visual quality and reduce the antigenic load. [6]

●      Diagnostic: PPV provides necessary intraocular specimens for cytopathology that characterizes PAS-positive foamy macrophages and PCR-based molecular confirmation of Tropheryma whipplei. [4][6]

Scleral Nodules: Primary surgical excision is indicated in isolated cases and may serve an important diagnostic source. Serves as the definitive treatment for symptomatic relief, while also local resolution of the lesion. [6]

Orbital decompression: Indicated for compressive optic neuropathy with accompanying exophthalmos or restricted EOM. Outcomes in reported cases document significant visual recovery and improvement in proptosis. [19]

Clinical Contraindication

  • Isolated Immunosuppression (topical/systemic corticosteroids or immunomodulators): Without concurrent antibiotic coverage, these agents mask active infection and accelerate disease progression. [13][27]

Prognosis

WD is a frequently underdiagnosed disease that carries a significant risk of morbidity and mortality if left untreated, owing to its serious GI and CNS complications.​​With appropriate antibiotic therapy, the prognosis is generally favorable, and early diagnosis/treatment can result in complete resolution without lasting visual consequences. According to Schoenberger, CNS involvement (⅓ of patients) equates to a worse prognosis, with 25% of patients with CNS involvement having fatal outcomes.[26]

References

  1. ↑ 1.0 1.1 Fenollar F., Puéchal X., and Raoult D., Whipple′s disease, The New England Journal of Medicine. (2007) 356, no. 1, 55–66, 2-s2.0-33846003174.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Rasool N. Ophthalmic manifestations of Whipple's disease. Curr Opin Ophthalmol. 2024 Jan 1;35(1):83-88. doi: 10.1097/ICU.0000000000000989. Epub 2023 Oct 13. PMID: 37830937.
  3. ↑ Lagier, Jean-Christophe MD; Lepidi, Hubert MD, PhD; Raoult, Didier MD, PhD; Fenollar, Florence MD, PhD. Systemic Tropheryma whipplei: Clinical Presentation of 142 Patients With Infections Diagnosed or Confirmed in a Reference Center. Medicine 89(5):p 337-345, September 2010. | DOI: 10.1097/MD.0b013e3181f204a8
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 Chan RY, Yannuzzi LA, Foster CS. Ocular Whipple’s disease: earlier definitive diagnosis. Ophthalmology. 2001;108 (12):2225–2231. doi:10.1016/S0161-6420(01)00818-1.
  5. ↑ Touitou V, Fenollar F, Cassoux N, et al. Ocular Whipple’s disease: therapeutic strategy and long-term follow-up. Ophthalmology. 2012;119(7):1465–1469. doi:10.1016/j.ophtha.2012.01.024.
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 Salman AR, Salomao DR, Dalvin LA, Olsen TW, Smith WM. Ocular Whipple Disease: Cases Diagnosed Over Four Decades. Ocul Immunol Inflamm. 2024 Oct;32(8):1863-1868. doi: 10.1080/09273948.2023.2271995. Epub 2023 Nov 2. PMID: 37917881.
  7. ↑ 7.0 7.1 Schneider T, Moos V, Loddenkemper C, Marth T, Fenollar F, Raoult D. Whipple’s disease: new aspects of pathogenesis and treatment. Lancet Infect Dis. 2008;8(3):179–90.
  8. ↑ Dutly F, Altwegg M. 2001. Whipple's Disease and “Tropheryma whippelii”. Clin Microbiol Rev 14:.https://doi.org/10.1128/cmr.14.3.561-583.2001
  9. ↑ 9.0 9.1 Abu Al Ghanam, O., Mudhar, H. S., Spiteri-Cornish, K., Wagner, B., & Brand, C. (2025). Chronic Bilateral Uveitis as the Presenting Manifestation of Ocular Whipple’s Disease Confirmed by Vitreous PCR. Ocular Immunology and Inflammation, 33(10), 2577–2580. https://doi.org/10.1080/09273948.2025.2588212
  10. ↑ Maiwald M, Schuhmacher F, Ditton HJ, von Herbay A. Environmental occurrence of the Whipple's disease bacterium (Tropheryma whippelii). Appl Environ Microbiol 1999; 64:760–762.
  11. ↑ 11.0 11.1 Elchert JA, et al. Epidemiology of Whipple’s Disease in the USA between 2012 and 2017: a Population-Based National Study. Dig Dis Sci vol. 2019;64(5):1305–11. 10.1007/s10620-018-5393-9.
  12. ↑ 12.0 12.1 Bally JF, Méneret A, Roze E, Anderson M, Grabli D, Lang AE. Systematic review of movement disorders and oculomotor abnormalities in Whipple's disease. Mov Disord. 2018 Nov;33(11):1700-1711. doi: 10.1002/mds.27419. Epub 2018 Oct 19. PMID: 30338868.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 Lequain H, Abramowicz S, Seiller J, et al. Immune recovery uveitis in Whipple’s disease: an unusual ocular presentation. J Ophthalmic Inflamm Infect. 2024;14(1):10
  14. ↑ Madu AA, Mayers M. Ocular manifestation of systemic infections. Curr Opin Ophthalmol. 1995;6(6):88-91.
  15. ↑ 15.0 15.1 Alsarhani WK, Alkhalifah MI, Alkatan HM, Alsolami AL, Maktabi AMY, Alsuhaibani AH. Whipple's disease scleral nodules: a novel presentation in 2 consecutive patients. BMC Ophthalmol. 2020 Oct 16;20(1):413. doi: 10.1186/s12886-020-01695-4. PMID: 33066757; PMCID: PMC7566054.
  16. ↑ 16.0 16.1 Parkash, V., Mudhar, H.S., Wagner, B.E. et al. (6 more authors) (2016) Bilateral Ocular Myositis Associated with Whipple's Disease. Ocular Oncology and Pathology, 3. pp. 17-21. ISSN: 2296-4681
  17. ↑ 17.0 17.1 Feurle, G. E., & Moos, V. (2022). Orbital Manifestation of Immune Reconstitution Inflammatory Syndrome in Whipple's Disease. Deutsches Arzteblatt international, 119(43), 734. https://doi.org/10.3238/arztebl.m2022.0205
  18. ↑ Dearment, M. C., Woodward, T. A., Menke, D. M., Brazis, P. W., Bancroft, L. W., & Persellin, S. T. (2003). Whipple's disease with destructive arthritis, abdominal lymphadenopathy, and central nervous system involvement. The Journal of rheumatology, 30(6), 1347–1350.
  19. ↑ 19.0 19.1 19.2 Lieger, O., Otto, S., Clemetson, I. A., Arnold, M., & Iizuka, T. (2007). Orbital manifestation of whipple's disease: an atypical case. Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery, 35(8), 393–396. https://doi.org/10.1016/j.jcms.2007.03.005
  20. ↑ 20.0 20.1 Marth, T., Moos, V., Müller, C., Biagi, F., & Schneider, T. (2016). Tropheryma whipplei infection and Whipple's disease. The Lancet. Infectious diseases, 16(3), e13–e22. https://doi.org/10.1016/S1473-3099(15)00537-X
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 Maslias E, Anker R, Euskirchen P, Diserens K, Bally JF. Movement Disorders and Oculomotor Abnormalities in Whipple's Disease: An Updated Systematic Review. Tremor Other Hyperkinet Mov (N Y). 2025 Nov 11;15:57. doi: 10.5334/tohm.1075. PMID: 41245003; PMCID: PMC12617415.
  22. ↑ Shaikh AG, Ghasia FF. Novel Eye Movement Disorders in Whipple's Disease-Staircase Horizontal Saccades, Gaze-Evoked Nystagmus, and Esotropia. Front Neurol. 2017 Jul 11;8:321. doi: 10.3389/fneur.2017.00321. PMID: 28744253; PMCID: PMC5504231.
  23. ↑ Fenollar F, Laouira S, Lepidi H, Rolain JM, Raoult D. Value of Tropheryma whipplei quantitative polymerase chain reaction assay for the diagnosis of Whipple disease: usefulness of saliva and stool specimens for first-line screening. Clin Infect Dis. 2008 Sep 1;47(5):659-67. doi: 10.1086/590559. PMID: 18662136.
  24. ↑ Waked R, Moore JK, Winward B, Ham S, Hoyt HW, Azis L. Tropheryma whipplei infection presenting as indolent endophthalmitis. IDCases. 2025 Feb 4;39:e02178. doi: 10.1016/j.idcr.2025.e02178. PMID: 39995818; PMCID: PMC11847721.
  25. ↑ Asiri, A.Y., Alzaben, K.A., AlOtaibi, Y.A. et al. Eyelid abscess as an initial manifestation of whipple’s disease: a case report and comprehensive literature review. BMC Ophthalmol 25, 111 (2025). https://doi.org/10.1186/s12886-025-03902-6
  26. ↑ 26.0 26.1 Schoenberger, Scott D., Thinda, Sumeer, Kim, Stephen J., Tropheryma whipplei Crystalline Keratopathy: Report of a Case and Updated Review of the Literature, Case Reports in Ophthalmological Medicine, 2012, 707898, 7 pages, 2012. https://doi.org/10.1155/2012/707898
  27. ↑ Razonable RR, Pulido JS, Deziel PJ, Dev S, Salomão DR, Walker RC. Chorioretinitis and vitreitis due to Tropheryma whipplei after transplantation: case report and review. Transpl Infect Dis. 2008;10(6):413-418.
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