Ocular Manifestations of Hemophagocytic Lymphohistiocytosis Syndrome

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Article initiated by:

Abdelrahman M. Elhusseiny, MD, MSc, Ahmed Sallam, MD PhD FRCOphth, Joseph Toma, MD, MSc, PhD, S. Nazem Ibrahim, MD, MSc

All contributors:

Abdelrahman M. Elhusseiny, MD, MSc, Ahmed Sallam, MD PhD FRCOphth, Joseph Toma, MD, MSc, PhD, S. Nazem Ibrahim, MD, MSc, S. Grace Prakalapakorn, MD, MPH, Abdelrahman M. Elhusseiny, MD, MSc, Caroline DeBenedictis, MD

Assigned editor:

Caroline DeBenedictis, MD

Review:

Assigned status Up to Date

 by Caroline DeBenedictis, MD on August 2, 2024.

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Contributing Editors:	add

Disease entity

Hemophagocytic lymphohistiocytosis (HLH) or hemophagocytic syndrome (HS) is a rare, life-threatening multi-system disorder of immune regulation that can result in end-organ damage most commonly involving the liver, central nervous system, and bone marrow and eventually death. The diagnosis of HLH is often challenging due to the diverse clinical manifestations and the presence of several diagnostic mimics. Several ocular manifestations have been reported in association with HLH.

Types

HLH is classified as familial which is caused by inherited genetic mutations and acquired that arises because of external triggers like viral infection (most common trigger), malignancy, rheumatologic disease, stem cell transplantation, drug hypersensitivity, or other causes.

Epidemiology of Hemophagocytic lymphohistiocytosis disease

• The mean age at the time of HLH diagnosis is 1.8 years for familial HLH, while in acquired cases it is 50 years.
• The incidence of HLH ranges from 1 to 225 per 300,000 live births.
• Regarding adult population, there are fewer studies documenting the incidence and sex distribution.

Epidemiology of Hemophagocytic lymphohistiocytosis cases associated with ophthalmic manifestations

• The mean age at time of presentation was 30.21 (14.42) years.
• 94 patients (62%) were males and 58 patients (38 %) were females.

Pathophysiology

HLH is caused by Th1 proinflammatory cytokine dysfunction. There is hyperproduction of the cytokines that make up the Th1 profile including Interferon-γ, tumor necrosis factor-α, Interleukin (IL)-6, IL-10, IL-12, sIL-2 R (CD25), which results in T-lymphocyte and macrophage activation (Figure 1).

Figure 1. Hemophagocytic lymphohistiocytosis (HLH) is a disease process that is not the result of a single condition or stimulus but is instead caused by a constellation of genetic predispositions, changes in immune status, and triggers all of which result in sustained CD8⁺ T-cell activation. The cells most classically involved in this activation are macrophages and antigen-presenting cells each contributing to an inflammatory milieu. Some of the values most classically used to detect these changes are (1) ferritin, (2) sCD163, and (3) sIL-2R (all demarked by * in the figure). The cellular activation can be caused by direct alterations to the immune system through genetic deficiencies, primary immune deficiency, or impaired host response to Epstein-Barr virus (EBV) infection all of which contribute to the uncontrolled activation of CD8⁺ T-cell and the runaway amplification of cytokine signaling seen in HLH. As a whole, HLH could be worsened by either an overactive immune system or underactive immune system; however, triggering events are often emphasized in the literature. Such triggers include intracellular pathogens, innate immune activation caused by toll-like receptor stimulation, drugs, immunotherapy, or hematologic malignancy

Criteria for diagnosis

The international major criteria for diagnosis include the following:

1. Fever.
2. Splenomegaly.
3. Cytopenia involving at least 2 cell types.
4. Hypertriglyceridemia or hypofibrinogenemia.
5. Hemophagocytosis demonstrated in the bone marrow, liver, or lymph node.

Risk factors for ophthalmic involvement:

A recent retrospective analysis conducted by Wang et al. screened HLH cases in a single center in China from 2013 to 2021. Out of 1525 HLH patients, 341 had ocular examinations, and 133 (133/341, 39.00%) had ocular abnormalities. The following risk factors were found to be significant to predict ocular affection:

• Old age.
• Autoimmune disorders.
• Decreasing red blood cell count.

• Decreasing platelet count.
• Increasing fibrinogen level.

Ophthalmic manifestations of Hemophagocytic lymphohistiocytosis

• After reviewing the literature from 1968 till May 2023, a total of 152 patients of HLH were reported to have ophthalmic  involvement .
• 14 patients were familial and 138 were acquired. Eptein-Barr Virus (EBV) Infection was the most common underlying cause.
• In the largest study by Wang et al. 2023 , posterior segment involvement was reported in 50 % (retinal hemorrhage was the most common sign), ocular surface infection in 38 %, uveitis in 8 %, adnexal abnormalities and strabismus in 6 %, and anterior segment complications in 4.5 %.

External examination:

• Lid edema: in 2 patients.
• Strabismus and ocular motility limitation: in 3 patients.
• Dacryoadenitis: in 2 patients.
• Dacryocystitis: in one patient.
• Orbital cellulitis: in 2 patients.
• Orbital pseudotumor: in 2 patients.

Ocular surface:

• Conjunctival chemosis: in 5 patients.
• Conjunctivitis: in 34 patients.
• Subconjunctival hemorrhage: in 11 patients.
• Keratitis: in 16 patients.

Anterior segment:

• Steroid-induced glaucoma: in 5 patients.

• Radiation cataract: in one patient.

Uveitis:

• Panuveitis: in 2 patients.
• Anterior uveitis: in 11 patients

Posterior segment:

• Retinal hemorrhages: it is the most common ocular finding.
  • Flame-shaped or pinpoint hemorrhages with or without white centers were reported in 55 patients.
  • Intraretinal, preretinal and subretinal hemorrhages were also reported.  

• Purtscher-like retinopathy: inner retinal whitening associated with cotton-wool spots were noticed in 1 patient. Optical coherence tomography (OCT) findings in the same patient were consistent with paracentral acute middle maculopathy (PAMM) lesion.

• Retinal white lesions: 4 patients were reported to have white flat or sometimes fluffy lesions not associated with vitritis at the posterior pole around 2 disc diameter in size.

• Serous retinal detachment: 10 patients had serous retinal detachment whether reported clinically or after OCT.

• Acute macular neuroretinopathy (AMN): outer plexiform layer hyperreflecitivity consistent with AMN was reported in 2 patients.

• Cytomegalovirus retinitis: one patient was diagnosed with cytomegalovirus (CMV) retinitis.

• Perivenous exudation and infiltrates: were reported in 3 patients.

• Choroidal hypoperfusion: was found in one patient after OCT angiography, and in another patienton Indocyanine Green Angiography (ICGA).

• Macular edema: OCT macula was done and revealed macular edema in 2 patients and ellipsoid zone disruption in one patient.

• Afferent pupillary defect: 2 patients had afferent pupillary defects.

• Optic disc swelling: was detected in 15 patients.

Tissue pathology:

Histopathological assessment and immunohistochemistry were done in 4 patients after autopsy showing histocytic infiltration of mainly trabecular meshwork and choroid and to a lesser extent infiltration of retina, optic nerve, ciliary body and iris.

Table illustrating the reported ophthalmic manifestations associated with HLH (Total 152 patients):

Location	Opthalmic findings	Number of patients (%)
External examination	Lid edema	2 (1 %)
	Strabismus and ocular motility limitation	3 (2 %)
	Dacryoadenitis	2 (1 %)
	Dacryocystitis	1 (0.6 %)
	Orbital cellulitis	2 (1 %)
	Orbital pseudotumor	2 (1 %)
Ocular surface	Conjunctival chemosis	5 (3%)
	Subconjunctival hemorrhage	11 (7%)
	Conjuctivitis	34 (22%)
	Keratitis	16 (10%)
Anterior segment	Steroid-induced glaucoma	5 (3%)
	Radiation cataract	1 (0.6 %)
Uveitis	Anterior uveitis	11 (7%)
	Panuveitis	2 (1 %)
Posterior segment	Retinal hemorrhages	55 (36 %)
	Retinal white lesions	4 (3%)
	Serous retinal detachment	10 (7%)
	Purtscher-like retinopathy	1 (0.6 %)
	Perivenous exudation and infiltrates	3 (2 %)
	Acute macular neuroretinopathy	2 (1 %)
	Cytomegalovirus retinitis	1 (0.6 %)
	Choroidal hypoperfusion	2 (1 %)
	Macular edema	2 (1 %)
	Optic disc swelling	15 (10%)
	Afferent pupillary defect	2 (1 %)

Prognosis of Hemophagocytic lymphohistiocytosis disease

• Familial HLH has a poor prognosis without treatment and has a median survival of 1 to 2 months. In adults the outcome is variable with the worst prognosis for malignancy-associated HLH.
• Prognosis in patients associated with ophthalmic manifestations, 12 patients (6 in each category ) died within a few months shortly after presentation. Resolution of the condition followed by discharge was reported in only 3 acquired and 1 familial patients. However, there are no sufficient data in literature regarding the prognosis of the remaining patients.