OCULAR INVOLVEMENT IN HEMOPHAGOCYTIC SYNDROME: A NOVEL FUNDUSCOPIC MANIFESTATION AND REVIEW OF THE LITERATURE

Abstract

Purpose:

Hemophagocytic syndrome (HS) is a rare disease with a spectrum of ocular findings. The authors report a unique funduscopic presentation of HS in a neonate and a discussion of diagnosis, typical features, management, and outcome.

Methods:

Single case report with retrospective analysis of the published literature of patients with HS and ocular findings from 1950 to present using the key terms hemophagocytic, lymphohistiocytosis, ocular, and ophthalmic. Literature search from 1950 to the present was performed through PubMed/MEDLINE and the Cochrane database. Requirement for inclusion was that the article or abstract was written in English.

Results:

A 4-week-old neonate with HS demonstrated bilateral discrete white dots within the retina, which resolved incompletely over the course of the next months but showed increased pigmentation.

Conclusion:

With so few documented ophthalmic cases of HS in existence, the ocular findings at this point can be seen as diverse and variable. However as more cases are reported, hopefully this will allow for increased recognition of the ophthalmic manifestations and sequelae and in turn lead to improved treatment of this disease.

Hemophagocytic syndrome (HS) (hemophagocytic lymphohistiocytosis) is a heterogeneous group of disorders characterized by fever, hepatosplenomegaly, and lymphadenopathy. It is a multisystemic disease that can cause varying degrees of end organ failure most commonly involving the liver, central nervous system, and bone marrow. Hemophagocytic syndrome can be divided into subgroups by etiology which include rheumatologic diseases, viral infections, and genetics.¹ There are only 12 published cases of ophthalmic findings related to HS.^1–10 Cases have been associated with serous pigment epithelial detachments, retinal hemorrhages, perivenous infiltrates, retinal detachment, uveitis, and macular and disk edema. Our patient was a neonate with HS presenting with bilateral white dots throughout the retina, a unique presentation not previously described in the literature.

Case Report

A previously healthy 1-month-old full-term female neonate was brought to her local emergency department for lethargy while breast feeding. An abdominal mass was detected on physical examination. Preliminary laboratory workup revealed abnormal liver function tests and bilirubin, anemia, and thrombocytopenia. On initial ocular examination, multiple white spots were noted on the retina. There was no maternal history of sexually transmitted diseases and extensive serological studies including TORCH (Toxoplasmosis, Other, Rubella, Cytomegalovirus, and Herpes simplex virus) titers were negative.

Given the extensive differential diagnosis, the patient was transferred to the Children’s Hospital of New York (CHONY). Repeat ocular examination revealed no afferent pupillary defect, intact extraocular movements, and normal anterior segment by pen light examination. Dilated funduscopic examination revealed multiple bilateral small white dots throughout the macula and beyond the arcades. The dots seem to be located in the deep retina, retinal pigment epithelium, or choroid because the retinal vessels are not obscured. No gross vitritis was noted. Some dots seemed active, whereas others appeared atrophic. Both were associated with pigmentary change within or at their borders. The optic nerves had well-defined borders with no pallor or hyperemia (Retcam pictures in Figure 1). Computed tomography of the thorax, abdomen, and head revealed lymphadenopathy in the axilla, mesentery, and retroperitoneum, hepatosplenomegaly, and intracranial hemorrhage without mass effect. A bone marrow biopsy demonstrated histiocytosis with phagocytosis and increased soluble interleukin 2 receptor. Further testing revealed that the mother had low natural killer cell activity and the father had no natural killer cell activity, although family history was not notable for any sudden or early deaths. A treatment regimen of cyclosporine A, dexamethasone, and etoposide was initiated and empiric coverage with antibiotics.

Fig. 1.

Retcam photographs of the right eye (A) and left eye (B) at initial presentation. Multiple bilateral small white dots throughout the macula and beyond the arcades.

At 2 months follow-up, incomplete resolution but slightly increased pigmentation of the retinal lesions was noted (Figure 2). The patient ultimately died elsewhere after stem cell transplantation. Retcam pictures (not shown) taken there 3 months later were similar to the ones last obtained at CHONY.

Fig. 2.

Retcam photographs of the right and left eye at two-month follow-up. Increased pigmentation of retinal lesions with incomplete resolution.

Discussion

Hemophagocytic syndrome is caused by Th1 proinflammatory cytokine dysfunction. There is hyperproduction of the cytokines that make up the Th1 profile including Interferon-g, tumor necrosis factor-a, Interleukin (IL)-6, IL-10, IL-12, sIL-2 R (CD25), which results in T-lymphocyte and macrophage activation.²

Diagnosis is made by adherence to international criteria which incorporates all the following major criterion 1) fever, 2) splenomegaly, 3) cytopenia involving at least 2 cell lines, 4) hypertriglyceridemia or hypofibrinogenemia, and 5) hemophagocytosis demonstrated in the bone marrow, liver, or lymph node. Additional criteria include 1) a markedly elevated serum ferritin, 2) low or absent natural killer cell activity, and 3) elevated serum soluble IL-2 receptor.¹ Treatment often involves a combination of immunotherapeutic medications including dexamethasone, etoposide, antithymocyte globulin, and intrathecal methotrexate if there is central nervous system involvement.¹ In cases of severe or refractory disease, allogeneic bone marrow transplantation is the most successful treatment.⁵

Our patient presented with typical systemic features of HS but novel ophthalmic ocular features, consisting of bilateral multiple white dots about the posterior pole which regressed, pigmented, and stabilized over the course of several months. As histopathological examination of the eye could not be performed, one can only hypothesize based on previous investigations that the discrete white dots represent infiltration of histiocytes within the retina and/or choroid. The progressive pigmentary change associated with the lesions suggests involvement of the pigment epithelium. Six previously published cases have documented postmortem microscopic examination of the eye showing lymphohistiocytic infiltration of a variety of ocular structures including trabecular meshwork, iris, ciliary body, retina, choroid, and optic nerve.^3–6 Kawamura et al⁷ also described a case of ocular HS with perivenous white patches of the retina and similarly suggested histiocytic infiltration as the origin of the retinal patches.

Other ophthalmic manifestations and age, clinical features, and patient outcome have been published, which we have outlined in Tables 1 and 2. The 12 cases of HS can be divided into 2 categories, 8 patients with primary familial HS which includes familial hemophagocytic lymphohistiocytosis and four patients with secondary or acquired HS. All documented cases of acquired HS with ophthalmic manifestations have been viral-induced, otherwise known as virus-associated HS. Further etiological divisions are still under investigation.¹

Table 1.

Familial Hemophagocytic Lymphohistiocytosis

Age/Gender	Clinical Features*	Ocular Findings	Outcome
16 mo/M6	Fever, rash, vomiting, ICH, HSM	Periorbital edema, bilateral papilledema, vitreous haze with fluffy white opacities	Death
5 mo/F3	Fever, rash, vomiting, meningismus, seizures, HSM, ICH	Bilateral papilledema and perivenous infiltrates	Death
7 yr/M4	Meningismus, fever, pneumonia	Bilateral choroidal effusions with secondary retinal detachments	Death
5 yr/M4	Fever, vomiting, diarrhea, seizures, HSM	Papilledema	Death
19 mo/F5	Fever, HSM, seizures	Dilated pupils and bilateral papilledema	Death
9 wk/F5	Fever, HSM, shock	Histiocytic infiltration of iris, trabecular meshwork, ciliary body, choroid, and optic nerve on autopsy	Death
(5) 10 yr/M†,7	Fever and HSM	Unilateral upper lid edema, bilateral papilledema, retinal hemorrhages, and perivenous white patches	Resolution with inactive appearing retinal scars
6 yr/F1	“Pink eye”	Unilateral panuveitis, retinal detachment, perivascular exudates, and hemorrhages of the retina	Unknown
4 wk/F	HSM and ICH	Bilateral white dots throughout the posterior pole	Unknown

^*On presentation.

^†ophthalmic presentation at age 10.

HSM, hepatosplenomegaly; ICH, intracranial hemorrhage.

Table 2.

Viral-Associated Hemophagocytic Lymphohistiocytosis

Age/Gender	Clinical Features*	Ocular Findings	Outcome
14 yr/M9	Fever, fatigue, chills, and dry cough	Blurry vision, scattered perimacular flame-shaped hemorrhages with and without white centers, and mildly tortuous vasculature	Resolution of all hemorrhages at 1.5-month follow-up
55 yr/M10	Fever	Dot-like hemorrhages with multiple white patches around the optic disk and 2–3 disk diameter perivascular white lesions	Normal looking retina, hypofluorescence in early phase, and choroidal vascular filling defect on ICG
31 yr/F2	Fever, weight loss, HSM, and ascites	Multiple bilateral serous pigment epithelial detachments with macular edema	Death
51 yr/M8	Blurry vision	Multiple serous pigment epithelial detachments with macular edema and scattered hemorrhages	Death

^*On presentation.

HSM, hepatosplenomegaly; ICG, indocyanine green.

Patients with familial hemophagocytic lymphohistiocytosis ranged between the ages of 4 weeks and 5 years old. Previous studies have shown that 90% of patients are symptomatic by 2 years of age.⁷ Virus-associated HS did not show predilection for any age group.^2,8–10 The primary ocular chief complaint for patients with virus-associated HS was blurry vision. No cases of virus-associated HS have had documented histopathological examination of the eyes, although intravenous fluorescein angiography was performed in two of the reported cases. Lee and Mieler demonstrated fundus findings with multiple pigment epithelial detachments comparable with the ocular findings in Vogt–Koyanagi–Harada disease, and Suzuki et al noted retinal white dots which corresponded to a pattern of early blocking and late hyperfluorescence analogous to multifocal placoid pigment epitheliopathy.^2,10 None had documented disk involvement.

Owing to the age of presentation, the patients with familial hemophagocytic lymphohistiocytosis were most often subjected to ophthalmic examination because of their systemic symptoms. Common findings included CNS involvement, optic nerve swelling, and those with pathology showed diffuse infiltration of ocular structures.

Untreated HS has a very high mortality, but as diagnostic measures and treatment protocols have evolved, there have been cases that have shown improvement and resolution of ophthalmic pathology.^1,7,10 Prompt recognition and initiation of immunomodulatory therapy could lead to improved ophthalmic manifestations as noted in our patient.