Roth spots may be ocular sign of hemophagocytic lymphohistiocytosis

The Neuro-Connection: Clinicians should be aware of unusual but characteristic signs, symptoms, findings

While Roth spots have been classically described in bacterial endocarditis, they may occur in a number of systemic conditions, including lymphoproliferative disorders.

Hemophagocytic lymphohistiocytosis is a rare disease with a range of ocular findings, and a study has revealed a case which also included the formation of Roth spots in the eyes. The patient was a 33-year-old African-American male with a history of human immunodeficiency virus (HIV) and hypertension who presented with fever, splenomegaly, and bilateral vision loss.

Multiple Roth spots were found bilaterally by ophthalmoscopy. The patient was found to have hypertriglyceridemia, elevated serum ferritin, pancytopenia, and elevated soluble interleukin 2 receptor levels.

A bone marrow biopsy confirmed hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis is rare and can be a life-threatening, multisystem, inflammatory syndrome caused by overactive macrophages and lymphocytes.

Though ocular involvement in hemophagocytic lymphohistiocytosis is known, to our knowledge, this is the first case of Roth spots as the presenting ocular sign of hemophagocytic lymphohistiocytosis in the English-language ophthalmic literature. Clinicians should be aware of the unusual but characteristic signs, symptoms, and findings. 

Case presentation

The patient had a history of HIV and hypertension on active antiretroviral therapy (HAART), admitted for fever and refractive pancytopenia, reported acute, painless, bilateral central vision loss.

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Physical examination revealed the patient was a poorly nourished cachectic male. He also has concurrent intermittent epistaxis, melena, and severe generalized fatigue. Medications include emtricitabine, tenofovir, darunavir, cobicistat, folic acid, metaprolol, and ondensetron. Social history was significant for smoking and marijuana use. His family history was noncontributory. Neuro-ophthalmic examination showed best-corrected visual acuity of 20/400 in his right eye (OD) and 20/70 in his left eye (OS).

Pupils were regular and reactive and were 4 mm in dark and 3 mm in bright light without anisocoria or relative afferent pupillary defect. The extraocular motility was normal, and confrontation visual field testing showed a central scotoma OD that was normal OS. External and anterior segment was normal. Intraocular pressure measured 12 mm Hg in both eyes (OU). Ophthalmoscopy revealed multifocal large blot hemorrhages with pale centers consistent with Roth spots OU.

There was a large hemorrhage over the macula OD consistent with 20/400 vision (Figure 1). Optical coherence tomography (OCT) of the macula demonstrated a large subinternal limiting membrane hemorrhage, dome elevation OD, and a small subinternal limiting membrane hemorrhage OS (Figure 2).

Hematologic evaluation showed serum white blood cell count: 0.25k/ ul (4.5–11 k/ul); red blood cell count: 2.13 m/ul (4.4–6 m/ul); platelet count: 10 k/ul (150–400 k/ul),
hemoglobin: 6.3 gm/dl (14–18 gm/ dl), hematocrit: 19%, CD4%: 13% (37–47%), reticulocyte count: 3.2% (0.5–2.1%), triglyceride: 731 mg/ dl (Reference <150 mg/dl) serum ferritin: 85,951 ng/ml (range 30–400ng/ml).

Serum soluble interleukin (IL) 2R was markedly elevated at 17412 unit/ml (Reference: 45–1105), CD163 was high at 8744 ng/ mL (Reference: 387–1785).

Hemophagocytic histiocytes were present on bone marrow biopsy consistent with the diagnosis of HLH. An MRI of the brain and spine showed chronic anemia changes with diffuse abnormal bone marrow signal. CSF analysis was normal. Serum PCR was positive for cytomegalovirus (CMV) and Epstein-Barr virus (EBV).

A CT scan of the abdomen showed hepatomegaly, worsening splenomegaly with infarctions confirmed by USG. The patient was treated with platelet and RBC transfusions, HAART for HIV, etoposide, dexamethasone, and intravenous immunoglobulin (IVIG). Despite treatment, the patient’s condition deteriorated due to acute respiratory failure, and vancomycin-resistant Enterococcus sepsis, and he died from organ failure.

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Discussion

Our patient meets the diagnostic criteria for HLH including fever, splenomegaly, hypertriglyceridemia, elevated serum ferritin, cytopenia, elevated soluble IL2-R level (12,114) and a diagnostic bone marrow biopsy demonstrating hemophagocytic histiocytes. Nonspecific retinal hemorrhages have been described in HLH and two of these cases were virus-associated HLH. 1, 2, 3

Yao et al. reported multifocal retinal hemorrhages interspersed with numerous detachments of the pigment epithelium and macular edema.Hemorrhage involving the nerve fiber layer was found in a patient with CMV-associated HLH by Liao and Thompson.2 Roth spots are white-centered retinal hemorrhages that appear in a variety of disease processes and most commonly occur within the periphery of the retina.4

Roth spots in HLH have been reported previously and could be secondary to the pancytopenia or infections that occur during the course of the disease. Argyraki et al. reported a single case of Roth spots in an HLH patient with endocarditis.5 Although Roth spots were classically described in bacterial endocarditis, they may occur in a number of systemic conditions including lymphoproliferative disorders.

Our patient’s Roth spots could have been secondary to underlying anemia and thrombocytopenia as a consequence of HLH status complicated with underlying HIV, which is again independently found to be associated with Roth spots. Clinicians should be aware of the ocular manifestations of HLH and should consider the diagnosis in any patient fulfilling the diagnostic criteria.

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Disclosures:

Andrew G. Lee, MD
P: 713/441-8843
E: aglee@houstonmethodist.org
Dr. Lee, editor of The Neuro-Connection column, is affiliated with the Blanton Eye Institute, Houston Methodist Hospital. He did not indicate proprietary interest.

References:

1. Kawamura H, Hatsukawa Y, Furukawa A, Inoue M, Kawa K. Ophthalmic findings in a case of hemophagocytic syndrome. American Journal of Ophthalmology. 1997;124:261-263.

2. Liao PM, Thompson JT. Ophthalmic manifestations of virus-associated hemophagocytic syndrome. Archives of Ophthalmology. 1991;109:777-777.

3. Yao H, Liu Y, Ding W, Xu Y, Cheng Y. Ocular Findings in a Patient with Virus-Associated Hemophagocytic Syndrome. Ocular Immunology and Inflammation. 2012;20:233-234.

4. Ruddy SM, Tivakaran VS. Roth Spots. [Updated 2018 Oct 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482446/

5. Argyraki CK, Gabeta S, Zachou K, Boulbou M, Polyzos A, Dalekos GN. Favourable outcome of life-threatening infectious-related haemophagocytic syndrome after combination treatment with corticosteroids and intravenous immunoglobulin infusions. European Journal of Internal Medicine. 2011;22:e155-e157.