Eosinophilic orbital disease

Etiology

The differential diagnosis for eosinophilic disorders with orbital involvement includes:

• Eosinophilic granulomatosis with polyangiitis (EGPA)
• Kimura’s Disease (KD)
• Angiolymphoid hyperplasia with eosinophilia (ALHE)
• Eosinophilic angiocentric fibrosis (EAF)
• Hypereosinophilic syndrome (HES)
• Eosinophilic asthma
• Parasitic infection

Epidemiology

EGPA

• Prevalence 2-22 per million
• Annual incidence 0.3-3.7 per million
• Occurs primarily during adulthood in bimodal distribution, with peak at 30-40 years-old, and is rare in children (Akella, Ophthalmic Plast Reconstr Surg 2019)
• No gender predominance or ethnic predisposition

Kimura’s disease

• Occurs most frequently in young East Asian men in the 2nd to 4th decades of life
• Orbital involvement may occur in older patients (Buggage, Surv Ophthalmol 1999)

ALHE

• Commonly seen in middle-aged Caucasian individuals, often in the 3rd and 4th decades
• Female predominance

EAF

• Unknown prevalence and epidemiology

HES

• Unknown prevalence
• Most often affects people ages 20-50

Eosinophilic asthma

• Unknown prevalence
• Approximately 10% of all asthma is categorized as severe adult-onset eosinophilic asthma
• Most commonly diagnosed in adults 35-50 years old, although it can be seen in older adults and children (Walford, J Asthma Allergy 2014)

Parasitic infection

• More prevalent in geographic areas where environmental factors and poor sanitary conditions favor transmission from animal hosts
• Toxocariasis is the most prevalent human helminthic infection in industrialized countries (Padhi, Surv Ophthalmol 2017)

Clinical features

EGPA

• Systemic vasculitis of small-to-medium sized blood vessels
• Typically presents in three phases: (Akella, Ophthalmic Plast Reconstr Surg 2019)
  1. Prodromal asthmatic and allergic phase: second and third decades of life, asthmatic and allergic symptoms, such as nasal congestion, shortness of breath, and cough
  2. Eosinophilic phase: peripheral eosinophilia and eosinophilic infiltration of multiple organs, typically lungs and gastrointestinal tract, manifesting with asthma and/or gastroenteritis
  3. Vasculitic phase: life-threatening vasculitis, occurs 8-10 years after asthmatic phase
• Ocular involvement can be divided into 2 groups (Takanashi, Ophthalmology 2001)
  1. Orbital inflammatory-type
  • Conjunctival nodules, myositis, diffuse orbital inflammation, dacryoadenitis, cranial nerve palsy
  2. Ischemic vasculitis-type
     • Retinal artery and vein occlusions, ischemic optic neuropathy, retinal vasculitis

Kimura’s Disease

• Nontender subcutaneous inflammatory nodules of the head and neck (Kanazawa, Graefe’s Arch Clin Exp Ophthalmol 1999)
• Orbital signs include palpable mass, proptosis, motility restriction, and eyelid edema
• Often have regional lymphadenopathy, salivary gland involvement, nephropathy, systemic eosinophilia (Buggage, Surv Ophthalmol 1999)
• Disease duration up to 25 years
• Believed to be autoimmune-related

ALHE

• Similar to Kimura’s Disease with nontender subcutaneous nodules in the head and neck
• Orbital signs include proptosis and eyelid edema
• Disease duration generally shorter than Kimura’s Disease (1-4 years) (Azari, JAMA Ophthalmol 2014)
• Believed to be a reactive or neoplastic proliferation of vascular endothelium

EAF

• Unclear whether it is a neoplasm or a fibroinflammatory lesion mimicking a neoplasm
• Some believe it to be on the spectrum of IgG4-related disease and/or related to granuloma faciale (Roberts, Histopathology 1985)
• Typically affects the sinonasal and respiratory tracts and rarely involves the orbit (Deshpande, Am J Surg Pathol 2011)

HES

• A myeloproliferative disorder characterized by eosinophilia
• Diagnosis of exclusion after ruling out other causes of eosinophilia
• May be asymptomatic or with severe symptoms consistent with end-organ damage due to eosinophilic infiltration of skin, heart, lungs, and central nervous system (Curtis, Clin Rev Allergy Immunol 2016)
• Can present as orbital inflammation with proptosis and dacryoadenitis (Das Indian J Ophthalmol 2018, Zenone Presse Med 2005) or retinal vascular changes due to hypercoagulability

Eosinophilic asthma

• A subtype of asthma, which is severe, adult-onset, and resistant to corticosteroids
• Asthmatic and allergic symptoms such as nasal congestion, shortness of breath, cough
• May involve dacryoadenitis

Parasitic infection

• Various presentations including cyst or solid nodule in the orbit, extraocular muscles, eyelid, or conjunctiva, as well as uveitis, retinitis, and optic neuritis (Padhi, Surv Ophthalmol 2017)
• Inflammatory signs if cyst ruptures
• Systemic manifestations including gastrointestinal, hepatobiliary, pulmonary, cardiovascular, and central nervous system (Padhi, Surv Ophthalmol 2017)

Testing

Laboratory testing

• EGPA
  • Peripheral eosinophilia
  • Positive ANCA in 30-40% of cases, most commonly myeloperoxidase-ANCA (P-ANCA) and proteinase 3 (Radice Autoimmun Rev 2013)
• Kimura’s Disease
  • Peripheral eosinophilia
  • Elevated serum IgE
  • May have elevated serum IgG4 levels (Kamisawa Lancet 2015)
• ALHE
  • Peripheral eosinophilia much less common than Kimura’s Disease
• EAF
  • Peripheral eosinophilia (Deshpande, Am J Surg Pathol 2011)
• HES
  • Peripheral eosinophilia
  • Need to rule out other etiologies
• Parasitic infection (Padhi, Surv Ophthalmol 2017)
  • Peripheral eosinophilia
  • Elevated serum IgE
  • Stool sample for ova/parasites
  • Serological tests such as complement fixation, ELISA, and indirect hemagglutination
  • Cerebrospinal fluid tests
• Eosinophilic asthma (Walford, J Asthma Allergy 2014)
  • Sputum eosinophils >1-3%
  • Peripheral eosinophilia
  • Elevated serum IgE
  • Fractional exhaled nitric oxide level
  • Serum periostin levels

Imaging

• EGPA
  • CT or MRI demonstrates an orbital mass or infiltration (57%), enhancement or enlargement of rectus muscles (29%), lacrimal gland enlargement (36%), and/or optic nerve sheath enhancement (14%) (Akella, Ophthalmic Plast Reconstr Surg 2019)
• Kimura’s Disease
  • CT or MRI demonstrates an orbital mass, enlargement extraocular muscles
• Parasitic infection
  • Ultrasonography is helpful in detecting scolex in cysticercosis (Padhi, Surv Ophthalmol 2017)
  • CT or MRI demonstrates a cystic orbital lesion

Histopathology

• EGPA
  • Necrotizing vasculitis
  • Extravascular eosinophil rich granulomatous inflammation
• Kimura’s Disease
  • 3 components (Buggage, Surv Ophthalmol 1999)
    • Cellular (eosinophilic infiltrate and follicular hyperplasia)
    • Fibrocollagenous
    • Vascular
  • Lymphoid hyperplasia within germinal centers
  • Eosinophilic microabscesses (McKelvie, Pathology 2012)
• ALHE
  • Proliferation of arterioles, venules, and capillaries (compared to mainly capillaries in Kimura’s Disease) (Azari, JAMA Ophthalmol 2014)
  • Endothelial cell atypia
  • Paucity of follicles and fibrosis
  • Endothelial cells with epithelioid or histiocytoid changes (Buggage, Surv Ophthalmol 1999)
  • Eosinophilia
• EAF
  • Concentric layers of fibrosis surrounding small-caliber arterioles (Benlemlih, Ann Pathol 2012)
  • Eosinophilic infiltrate
• HES
  • Eosinophilic tissue infiltration
• Eosinophilic asthma
  • Eosinophilic cellular infiltrate
• Parasitic infection
  • Parasite at the center of a lesion with eosinophilic or necrotizing granuloma

Diagnostic criteria

EGPA: Per the American College of Rheumatology, diagnosis requires the presence at least 4 of 6 conditions (Masi, Arthritis Rheum 1990)

• Asthma
• Eosinophilia of greater than 10%
• Neuropathy
• Migratory or transient pulmonary opacities
• Abnormalities of the paranasal sinuses
• Extravascular eosinophils on biopsy

HES: As defined by Chusid et al. there are 3 criteria (Chusid, Medicine (Baltimore) 1975)

• Eosinophil count >1500 cells/microliter persisting longer than 6 months
• Single or multiple organ system dysfunction attributable to cytotoxic injury by eosinophils
• No identifiable etiology to explain the eosinophilia

Figure 1. Case 1. (A) Clinical photograph demonstrating mild, bilateral lacrimal gland enlargement. (B) Biopsy of the left lacrimal gland reveals infiltration of eosinophils, lymphocytes, and plasma cells without granuloma, necrosis, or vasculitis (Hematoxylin and eosin x400). (C) Biopsy of the right lacrimal gland demonstrates dense lymphoid infiltrate with follicular hyperplasia and fibrosis without eosinophils (Hematoxylin and eosin x400).

Figure 2. Case 2. (A) Clinical photograph showing left upper eyelid edema, ptosis, chemosis, and injection. (B) Axial T1 post-contrast with fat suppression MR image demonstrating enlargement of the left lacrimal gland. Biopsy of the left lacrimal gland reveals the presence of marked eosinophils in the glandular tissue (C) and stroma (D) without granuloma or vasculitis (Hematoxylin and eosin x400).

• Granulomatosis with polyangiitis (Wegener’s granulomatosis)
• Microscopic polyangiitis
• Lymphoma
• Sarcoidosis
• Tuberculosis
• Idiopathic orbital inflammation

Treatment options

EGPA

• Systemic corticosteroids (high-dose prednisone 1 mg/kg/day until remission attained with gradual taper) – if acute multiorgan disease, higher dose 1 g IV methylprednisolone 1g/day for 3 days followed by above therapy) (Akella, Ophthalmic Plast Reconstr Surg 2019)
• Immunosuppressants (cyclophosphamide is first line, others include azathioprine, methotrexate, leflunomide)

Kimura’s Disease

• Primarily surgical excision (Kanazawa, Graefe’s Arch Clin Exp Ophthalmol 1999)
• Other treatments: radiation, oral and/or intralesional steroids (though with recurrence after cessation of treatment), chemotherapeutic agents (Buggage, Surv Ophthalmol 1999)

ALHE

• Primarily surgical excision or debulking (Cunniffe, Int Ophthalmol 2014)
• Other treatments: radiation, oral and/or intralesional steroids, chemotherapeutic agents, and laser (Buggage, Surv Ophthalmol 1999)
• Observation after biopsy is reasonable, as most lesions regress spontaneously

EAF

• Surgical excision of lesions
• Immunosuppressive therapy (systemic corticosteroids, steroid-sparing agents) may be less effective with recurrence of the lesion (Deshpande, Am J Surg Pathol 2011)

HES

• Systemic corticosteroids (high-dose prednisone 1 mg/kg/day)
• Other treatments: hydroxyurea, cyclosporin, interferon-alpha
• Biologics: imatinib mesylate, mepolizumab (anti-IL5 antibody), stem cell transplantation (Curtis, Clin Rev Allergy Immunol 2016)

Parasitic infection (Padhi, Surv Ophthalmol 2017)

• Treatment depends on the parasite
• Surgical excision of the nodule, removal of worm
• Anti-helminthic therapy (albendazole, mebendazole, praziquantel, ivermectin, etc.) – agent depends on the pathogen
• Systemic or periocular corticosteroids
• Laser ablation of worm

Eosinophilic asthma

• Systemic corticosteroids (high-dose prednisone 1 mg/kg/day)
• T-helper type 2 (Th2) targeted treatments, such as mepolizumab (IL-5 inhibitor) (Drick BMC Pulm Med 2018, Corren, Discov Med 2012)
• IL-4 and IL-13 inhibitors are undergoing studies (Walford, J Asthma Allergy 2014)
• Omalizumab (anti-IgE monoclonal antibody) (Walford, J Asthma Allergy 2014)

• Systemic corticosteroid complications – avoid long-term use of high-dose systemic corticosteroids
• Surgical complications
• Immunosuppressant complications
• Anti-helminthic therapy can cause cyst rupture – rule out cysts in brain before starting cysticidal medications and monitor neurologic status

EGPA

• Cardiovascular compromise, renal failure, and neurologic decline
• Untreated patients have a 50% risk of death within 3 months of vasculitis onset, whereas treated EGPA patient has a 70-90% survival at 5 years (Takanashi, Ophthalmology 2001)
• Heart disease most common cause of death (50%) (Akella, Ophthalmic Plast Reconstr Surg 2019)

Kimura’s Disease

• Lesions gradually enlarge and increase over time or spontaneously regress (Buggage, Surv Ophthalmol 1999)
• Recurrence can occur with incomplete excision

AHLE

• Recurrence can occur with incomplete excision (Azari, JAMA Ophthalmol 2014)

EAF

• Lesions are benign but progressive and tend to recur with many patients undergoing multiple surgeries for alleviation of symptoms

HES

• Eosinophilic infiltration can cause end-organ damage of the heart, lungs, and central nervous system (Curtis, Clin Rev Allergy Immunol 2016)

Parasitic infection

• End-organ damage from worm (neurologic, cardiac, ocular)

EGPA

• First described in 1951 by Churg and Strauss (Churg and Strauss, Am J Pathol 1951)
• Previously known as Churg-Strauss syndrome or allergic granulomatosis and angiitis
• In 1956 Cury et al. became the first to describe ophthalmic involvement (Cury, AMA Arch Ophthalmol 1956)

Kimura’s Disease

• First reported in 1937 by Kimm and Szeto as eosinophilic hyperplastic lymphogranuloma
• Kimura et al. in 1948 described similar cases (Kimura, Trans Soc Pathol Jpn 1948)

ALHE

• Described by Wells and Whimster in England in 1969, hey suggested similarity to Kimura’s Disease (Wells, Br J Dermatol 1969)
• Rosai et al. were the first to suggest Kimura’s Disease and ALHE were different entities due to the lack of cellular atypia in Kimura’s Disease (Rosai, Am J Dermatopathol 1982) (Rosai, Hum Pathol 1979)

EAF

• First described by Roberts and McCann in 1985 (Roberts, Histopathology 1985)

HES

• First described by Hardy and Anderson in 1968 (Hardy, Ann Intern Med 1968)

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