Ocular Manifestations of Hemophagocytic Lymphohistiocytosis Syndrome
Hemophagocytic lymphohistiocytosis (HLH) or hemophagocytic syndrome (HS) is a rare, life-threatening multisystem 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.
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.
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).  
Criteria for diagnosis
- Cytopenia involving at least 2 cell types.
- Hypertriglyceridemia or hypofibrinogenemia.
- 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 %.
- 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.
- Conjunctival chemosis: in 5 patients.
- Conjunctivitis: in 34 patients.
- Subconjunctival hemorrhage: in 11 patients. 
- Keratitis: in 16 patients.
- Steroid-induced glaucoma: in 5 patients. 
- Radiation cataract: in one patient. 
- Retinal hemorrhages: it is the most common ocular finding.
- 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 patientswere 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 patientshad 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. 
- 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. 
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%)|
|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. 
- Regarding the prognosis in the patients associated with ophthalmic affection, 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.
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