The primary hypereosinophilic syndrome (primary HES) is a hematologic abnormality with a persistent total eosinophil count of greater than 1.5 × 9/L for more than 6 months, evidence of organ system involvement, and no known cause for the eosinophilia (1). In contrast to primary HES, secondary HES is caused by hypersensitivity reactions, allergic diseases, parasitic infection, collagen vascular diseases, or neoplastic disorders (2).
In primary HES, central nervous system complications are common, caused by an eosinophilic-derived neurotoxin and direct infiltration with eosinophilic cells (2). Cranial and peripheral neuropathies have also been reported (3). The kidneys, lungs, heart, and skin are frequently involved.
Ophthalmologic manifestations are reported in 18% of cases, including reduced vision, diplopia, amaurosis fugax, hemianopic field loss, retinal hemorrhages, retinal and choroidal vascular occlusive disease, Adie pupil, ocular hypertension, and keratitis (Table 1) (4-13). Optic neuritis has not been reported.
We present two cases of recurrent retrobulbar optic neuritis as a part of HES that was unrecognized for many years. Once the diagnosis was made and the patient placed on treatment, no further attacks of optic neuritis occurred over several years' follow-up.
A 58-year-old woman reported 16 episodes of acute visual loss in one eye or the other over the previous 9 years. Each attack had caused persistent reduction in vision despite treatment with variable doses of prednisone. She also had systemic hypertension, episodes of transient diplopia, hypersomnolence, imbalance, and a rash on her right leg. Eosinophils had measured 13% and 16% (normal 0%-6%) of total white blood cells on two occasions, a finding dismissed as incidental.
Neuro-ophthalmologic examination in November 1994, after 9 years of recurrent attacks of optic neuritis, revealed best-corrected visual acuities of 20/20-3 OD, 20/30 OS. Pupils were briskly reactive to light without afferent pupillary defect. Humphrey visual field testing revealed double arcuate scotoma (Fig. 1A). Ophthalmoscopy showed bilateral attenuation of the nerve fiber layer and optic disc pallor (Fig. 1B). There was an excoriated macular rash over the right anterior tibial surface of her leg.
Previous brain magnetic resonance imaging (MRI) had been normal, but a recent MRI revealed an area of T2-weighted hyperintensity extending from the left internal capsule to the diencephalon and dorsolateral midbrain with intense enhancement on T1-weighted images (Fig. 2A). Treatment with intravenous methylprednisolone 1 g/d for 4 days, followed by a 3-day course of oral prednisone, caused most of her systemic and visual symptoms to improve over 2 weeks, but the symptoms recurred by the third week. At that time, she also reported confusion and left-sided facial weakness. A repeat MRI showed new areas of hyperintensity and enhancement in the right internal capsule extending into the midbrain and pons (Fig. 2B); the previously noted left-sided abnormalities were resolving. After re-treatment with intravenous methylprednisolone, her symptoms resolved again within 1 month and MRI showed substantial resolution of signal abnormalities (Fig. 2C).
Despite treatment with intravenous methylprednisolone and different tapering doses of oral prednisone (5-15 mg/day), the patient experienced four further attacks of optic neuritis over the next 2 years, together with recurrent pruritic rashes mainly involving her lower legs.
In May 1996, acute loss of vision OS developed. Visual acuities were 20/20 OD, 20/30 OS. Goldmann visual field testing revealed a dense central scotoma OS (Fig. 3) and MRI showed enhancement of the left optic nerve (Fig. 2D).
A lumbar puncture revealed eight white blood cells with 50% granulocytes and 50% lymphocytes, a protein of 53 (normal 15-45), and no oligoclonal bands.
Normal studies included a standard chemistry profile, sedimentation rate, ANA, dsDNA, ssDNA, ACE, SPEP, Lyme titer, RPR, and thyroid function profile. The eosinophil percent was 10.6% with a total count of 792/mm3 (upper limit of normal = 450/mm3). Treatment with corticosteroids reduced the eosinophils to less than 5% within 1 month. Skin biopsy demonstrated fibrosis and a perivascular inflammatory reaction consisting of numerous eosinophils, lymphocytes, and histiocytes (Fig. 4). Bone marrow biopsy demonstrated moderate eosinophilia in both the aspirate and biopsy (15% eosinophils) with two lymphoid aggregates (Fig. 5). The diagnosis of primary HES was established.
After institution of hydroxyurea (500 mg twice daily), she noted a marked improvement in hypersomnolence and in the skin rash. Visual acuity improved to 20/20 OD, 20/25 OS, with slight improvement in visual fields (Fig. 6). She has remained stable on treatment with hydroxyurea (500 mg three times daily) for 5 years and has not been treated with prednisone for 3 years.
A 46-year-old woman had had three attacks of retrobulbar optic neuritis over 11 years. Vision had improved or stabilized within 1 month of each attack after treatment with prednisone or intravenous methylprednisolone. She had reported transient sensory numbness in her hands and feet lasting several minutes, episodic severe fatigue that resolved with rest, and episodic imbalance lasting for seconds. She had persistent visual loss OD and numbness of the right hand.
Brain MRI had disclosed high T2-weighted signal in the peri-ventricular white matter bilaterally. Lumbar puncture had shown no abnormalities of IgG synthesis, but had shown two oligoclonal bands in the gamma region (none in the serum). She carried the diagnosis of atypical multiple sclerosis for 15 years.
Previous blood counts had shown eosinophilia between 24.4% and 59% and an eosinophil count as high as 1700/mm3, which had been dismissed as incidental. In 1998, she had symptoms of upper airway disease that consisted of cough, reactive airway disease, and pleuritic chest pain. Her 02 saturation was 92% to 95%. A chest computed tomography demonstrated a pleural effusion, hilar adenopathy, and bilateral infiltrates. Bronchoscopic lung biopsy revealed an eosinophilic infiltrate consistent with pulmonary interstitial eosinophilia. A diagnosis of primary HES was made and she was placed on prednisone 10 mg every other day.
Neuro-ophthalmologic examination 2 years later revealed best-corrected visual acuities of 20/40 OD, 20/20 OS, a right afferent pupil defect, and a cecocentral scotoma OD by Humphrey visual field testing (Fig. 7A). Disc pallor was present in both eyes (Fig. 7B). Neurologic examination revealed diminished pinprick sense over the fourth and fifth digits of her right hand and mild hyperreflexia of the right arm. In the succeeding 4 years, she has had no recurrent neurologic or ophthalmologic symptoms.
Our two cases of primary HES are unusual in that recurrent optic neuritis, not previously reported in this condition, was a presenting manifestation.
Primary HES is an idiopathic leukoproliferative disorder marked by an eosinophilia of greater than 3% (14,15). Untreated cases are characterized by the presence of more than 1500 eosinophils/mm3 for more than 6 months or an eosinophilia more than 20% of the peripheral total white cell count together with organ damage attributed to the eosinophilia. There is no direct relationship, however, between the eosinophil count and the severity of the clinical complications. The number of degranulated eosinophils may be more important than the total number of eosinophils (16,17). Confirmatory tests of primary HES include skin or bone marrow biopsy, which show increased numbers of mature eosinophils suggesting increased generations of eosinophils. More common in men than women (9:1), primary HES tends to occur between the ages of 20 and 50 (2,19). Although it may manifest acute cardiac or neurologic complications, it tends to be insidious in onset. Pruritic rashes, daytime hypersomnolence, tiredness, cough, shortness of breath, fever, myalgias, and angioedema are common early symptoms. The major cause of mortality is heart disease (3).
Neurologic complications occur in up to 65% of primary HES patients, who may present with encephalopathy, sensory polyneuropathy, cranial neuropathy, or stroke (10). Eosinophils, found in the involved tissues, are thought to cause damage by local degranulation of toxic eosinophilic proteins such as eosinophilic cationic protein and eosinophil major basic protein (18). Some reports have suggested that axonal damage is caused by increased endoneurial pressure from leakage of damaged capillary endothelium, whereas others blame eosinophilic cationic proteins (19). Similar pathologic changes, including infiltration of the myocardium with eosinophils, are seen in the muscles of patients with eosinophilic myositis, whose biopsy samples show necrosis, thrombosis, and fibrosis.
Neurotoxicity caused by eosinophils was first described in 1933 by Gordon and called the Gordon Phenomenon (20). Injected intrathecally into test animals, eosinophil-derived neurotoxin produced loss of Purkinje cells and spongiform vacuolation in the white matter of the cerebellum, brain stem, and spinal cord (21,22).
Fluctuating corticosteroid-responsive white matter MRI lesions are commonly seen in patients with neurologic complications of primary HES. They are attributed to a regionally active inflammatory process with destruction of the blood-brain barrier provoked by eosinophilic-derived neurotoxin (21). Unlike demyelinating plaques or the lesions seen in central nervous system vasculitis, the MRI lesions largely resolve within weeks of initiating corticosteroid treatment, as in our case 1 (Fig. 4).
Treatment with corticosteroids usually induces only temporary remission in HES. In patients unresponsive to corticosteroids, or who are corticosteroid-intolerant, hydroxyurea, a DNA inhibitor, has been used effectively. It works by lowering the peripheral blood eosinophil count (18). Other chemotherapeutic agents that suppress peripheral eosinophilia, including azathioprine, cyclophosphamide, vincristine, cyclosporine, and interferon alpha 2β (23), agents are usually reserved for refractory cases (2).
There is a previous case report of a patient with optic neuritis and primary HES, but the optic neuritis was considered incidental (12). In another report of a series of primary HES patients, “optic atrophy” was noted in one patient but was not further described (10).
Early recognition of HES, with institution of appropriate treatment, can decrease the visual morbidity from recurrent optic neuritis. Hydroxyurea is a useful corticosteroid-sparing agent in this condition.
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