Recurrent Optic Neuritis As the Presenting Manifestation of Primary Hypereosinophilic Syndrome: a Report of Two Cases

ORIGINAL CONTRIBUTION

Recurrent Optic Neuritis as the Presenting Manifestation of Primary Hypereosinophilic Syndrome: A Report of Two Cases

Norah S. Lincoff, MD and David Schlesinger, MD

Abstract: Two patients sustained multiple attacks of optic and choroidal vascular occlusive disease, Adie pupil, ocular neuritis with persistent visual loss. An elevated eosinophil hypertension, and keratitis (Table 1) (4-13). Optic neuritis count was initially considered an incidental finding. Years has not been reported. later, the diagnosis of primary hypereosinophilic syndrome We present two cases of recurrent retrobulbar optic (HES) was confirmed by skin and bone marrow in one neuritis as a part of HES that was unrecognized for many patient and by lung biopsy in the other. Treatment with years. Once the diagnosis was made and the patient placed hydroxyurea in one patient and with continuous low-dose on treatment, no further attacks of optic neuritis occurred prednisone in the other stopped the optic neuritis attacks, over several years' follow-up. resolved systemic manifestations, and stabilized neurologic manifestations. These cases emphasize that primary HES may be a cause of recurrent optic neuritis, and that delay in CASE REPORTS diagnosis and treatment of primary HES can lead to visual morbidity. Case 1 A 58-year-old woman reported 16 episodes of acute (J Neuro-Ophthalmol 2005;25: 116-121) visual loss in one eye or the other over the previous 9 years. Each attack had caused persistent reduction in vision de he primary hypereosinophilic syndrome (primary HES) spite treatment with variable doses of prednisone. She also Tis a hematologic abnormality with a persistent total had systemic hypertension, episodes of transient diplopia, eosinophil count of greater than 1.5 X 9/L for more than hypersomnolence, imbalance, and a rash on her right leg. 6 months, evidence of organ system involvement, and no Eosinophils had measured 13% and 16% (normal 0%-6%) known cause for the eosinophilia (1). In contrast to primary of total white blood cells on two occasions, a finding dis HES, secondary HES is caused by hypersensitivity reac missed as incidental. tions, allergic diseases, parasitic infection, collagen vascu Neuro-ophthalmologic examination in November lar diseases, or neoplastic disorders (2). 1994, after 9 years of recurrent attacks of optic neuritis, re In primary HES, central nervous system complica vealed best-corrected visual acuities of 20/20-3 OD, 20/30 tions are common, caused by an eosinophilic-derived OS. Pupils were briskly reactive to light without afferent neurotoxin and direct infiltration with eosinophilic cells (2). pupillary defect. Humphrey visual field testing revealed Cranial and peripheral neuropathies have also been reported double arcuate scotoma (Fig. 1 A). Ophthalmoscopy showed (3). The kidneys, lungs, heart, and skin are frequently bilateral attenuation of the nerve fiber layer and optic disc involved. pallor (Fig. IB). There was an excoriated macular rash over Ophthalmologic manifestations are reported in 18% the right anterior tibial surface of her leg. of cases, including reduced vision, diplopia, amaurosis Previous brain magnetic resonance imaging (MRI) fugax, hemianopic field loss, retinal hemorrhages, retinal 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 State University of New York at Buffalo School of Medicine and intense enhancement on Tl-weighted images (Fig. 2A). Biomedical Sciences, The Jacobs Neurological Institute, Buffalo General Treatment with intravenous methylprednisolone 1 g/d for Hospital, Buffalo, New York. 4 days, followed by a 3-day course of oral prednisone, caused Address correspondence to Norah S. Lincoff, MD, Associate Clinical most of her systemic and visual symptoms to improve over Professor of Neurology and Ophthalmology, The Jacobs' Neurological Institute, Buffalo General Hospital, 100 High Street, Buffalo, NY 14203; 2 weeks, but the symptoms recurred by the third week. At E-mail: [email protected] that time, she also reported confusion and left-sided facial

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TABLE 1. Previously reported ophthalmic manifestations associated with primary hypereosinophilic syndrome % of Patients with ophthalmic Source manifestations Ophthalmic manifestations

Chusid, 19754 1/14 Diplopia s Farcet, 1982 1/1 Retinal arteritis Fauci, 19826 9/50 Retinal occlusive disease Episcleritis 7 Binaghi, 1982 1/1 Retinal occlusive disease Chaine, 1982s 1/12 Transient diplopia (right sixth) 8/12 Retinal vascular disease (arterial occlusive disease, choroidal infarction, microaneurysms, and capillary dropout) Spry, 19839 1/15 "Visual impairment" Moore, 198510 1/52 Retinal embolus; homonymous hemianopia 1/52 Transient monocular visual loss 1/52 "Optic atrophy" (no history given) 11 Catalano, 1988 1/1 Adie pupil Guidetti, 199112 1/3 Optic neuritis weakness. A repeat MRI showed new areas of hyper- After re-treatment with intravenous methylprednisolone, intensity and enhancement in the right internal capsule her symptoms resolved again within 1 month and MRI extending into the midbrain and pons (Fig. 2B); the showed substantial resolution of signal abnormalities previously noted left-sided abnormalities were resolving. (Fig. 2C).

FIG. 1. Case 1. A. Humphrey visual fields in November 1994 show double arcuate scotoma . B. Oph thalmoscopy shows bilateral optic disc pallor.

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FIG. 2. Case 1. Serial magnetic resonance imaging (MRI) scans. A. November 1994. T2-weighted images (top) show high signal involving the left internal capsule and ventral midbrain; these areas enhance on T1-weighted images (bottom). B. December 1994. T2-weighted images (top) show high signal involving the right greater than internal capsule and right ventral midbrain; the right-sided lesions enhance on T1-weighted images (bottom). C. January 1995. T2-weighted images show partial resolution of signal abnormalities noted 7 weeks earlier. D. May 1996. T1 -weighted image shows enhancement of the left optic nerve during an attack of acute optic neuritis OS.

Despite treatment with intravenous methylpred- A lumbar puncture revealed eight white blood cells nisolone and different tapering doses of oral prednisone with 50% granulocytes and 50% lymphocytes, a protein of (5-15 mg/day), the patient experienced four further attacks 53 (normal 15-45), and no oligoclonal bands. of optic neuritis over the next 2 years, together with recur Normal studies included a standard chemistry profile, rent pruritic rashes mainly involving her lower legs. sedimentation rate, ANA, dsDNA, ssDNA, ACE, SPEP, In May 1996, acute loss of vision OS developed. Visual Lyme titer, RPR, and thyroid function profile. The eosin acuities were 20/20 OD, 20/30 OS. Goldmann visual field ophil percent was 10.6% with a total count of 792/mm3 testing revealed a dense central scotoma OS (Fig. 3) and (upper limit of normal — 450/mm3). Treatment with cor MRI showed enhancement of the left optic nerve (Fig. 2D). ticosteroids reduced the eosinophils to less than 5% within 1 month. Skin biopsy demonstrated fibrosis and a peri vascular 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 lym phoid 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 FIG. 3. Case 1. Goldmann visual fields in May 1996 reveal OD, 20/25 OS, with slight improvement in visual fields a left central scotoma consistent with left optic neuritis. (Fig. 6). She has remained stable on treatment with

FIG. 5. Case 1. Bone marrow biopsy in May 1996 demon strates excessive eosinophilia.

Neuro-ophthalmologic examination 2 years later re vealed 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 hydroxyurea (500 mg three times daily) for 5 years and has revealed diminished pinprick sense over the fourth and fifth not been treated with prednisone for 3 years. digits of her right hand and mild hyperreflexia of the right arm. In the succeeding 4 years, she has had no recurrent Case 2 neurologic or ophthalmologic symptoms. A 46-year-old woman had had three attacks of retrobulbar optic neuritis over 11 years. Vision had im proved or stabilized within 1 month of each attack after DISCUSSION treatment with prednisone or intravenous methylpredniso- Our two cases of primary HES are unusual in that lone. She had reported transient sensory numbness in her recurrent optic neuritis, not previously reported in this hands and feet lasting several minutes, episodic severe condition, was a presenting manifestation. fatigue that resolved with rest, and episodic imbalance Primary HES is an idiopathic leukoproliferative lasting for seconds. She had persistent visual loss OD and disorder marked by an eosinophilia of greater than 3% numbness of the right hand. (14,15). Untreated cases are characterized by the presence Brain MRI had disclosed high T2-weighted signal in of more than 1500 eosinophils/mm3 for more than 6 months the peri-ventricular white matter bilaterally. Lumbar punc or an eosinophilia more than 20% of the peripheral total ture had shown no abnormalities of IgG synthesis, but had white cell count together with organ damage attributed to shown two oligoclonal bands in the gamma region (none in the eosinophilia. There is no direct relationship, however, the serum). She carried the diagnosis of atypical multiple between the eosinophil count and the severity of the clinical sclerosis for 15 years. complications. The number of degranulated eosinophils Previous blood counts had shown eosinophilia may be more important than the total number of eosinophils between 24.4% and 59% and an eosinophil count as high (16,17). Confirmatory tests of primary HES include skin as 1700/mm3, which had been dismissed as incidental. In or bone marrow biopsy, which show increased numbers of 1998, she had symptoms of upper airway disease that mature eosinophils suggesting increased generations of eo consisted of cough, reactive airway disease, and pleuritic sinophils. More common in men than women (9:1), pri chest pain. Her 02 saturation was 92% to 95%. A chest mary HES tends to occur between the ages of 20 and 50 computed tomography demonstrated a pleural effusion, (2,19). Although it may manifest acute cardiac or neuro hilar adenopathy, and bilateral infiltrates. Bronchoscopic logic complications, it tends to be insidious in onset. Pruritic lung biopsy revealed an eosinophilic infiltrate consistent rashes, daytime hypersomnolence, tiredness, cough, short with pulmonary interstitial eosinophilia. A diagnosis of ness of breath, fever, myalgias, and angioedema are com primary HES was made and she was placed on prednisone mon early symptoms. The major cause of mortality is heart 10 mg every other day. disease (3).

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Neurotoxicity caused by eosinophils was first de scribed in 1933 by Gordon and called the Gordon Phenom enon (20). Injected intrathecally into test animals, eosinophil- derived neurotoxin produced loss of Purkinje cells and spongiform vacuolation in the white matter of the cer ebellum, 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 FIG. 6. Case 1. Humphrey visual fields in July 1996 show mild improvement relative to November 1994. the blood-brain barrier provoked by eosinophilic-derived neurotoxin (21). Unlike demyelinating plaques or the le sions seen in central nervous system vasculitis, the MRI Neurologic complications occur in up to 65% of lesions largely resolve within weeks of initiating cortico primary HES patients, who may present with encephalop steroid treatment, as in our case 1 (Fig. 4). athy, sensory polyneuropathy, cranial neuropathy, or stroke Treatment with corticosteroids usually induces only (10). Eosinophils, found in the involved tissues, are thought temporary remission in HES. In patients unresponsive to to cause damage by local degranulation of toxic eosino corticosteroids, or who are corticosteroid-intolerant, hy philic proteins such as eosinophilic cationic protein and droxyurea, a DNA inhibitor, has been used effectively. It eosinophil major basic protein (18). Some reports have works by lowering the peripheral blood eosinophil count suggested that axonal damage is caused by increased (18). Other chemotherapeutic agents that suppress periph endoneurial pressure from leakage of damaged capillary en eral eosinophilia, including azathioprine, cyclophosphamide, dothelium, whereas others blame eosinophilic cationic pro vincristine, cyclosporine, and interferon alpha 2(3 (23), teins (19). Similar pathologic changes, including infiltration agents are usually reserved for refractory cases (2). of the myocardium with eosinophils, are seen in the mus There is a previous case report of a patient with optic cles of patients with eosinophilic myositis, whose biopsy neuritis and primary HES, but the optic neuritis was con samples show necrosis, thrombosis, and fibrosis. sidered incidental (12). In another report of a series of

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FIG. 7. Case 2. A. Humphrey visual fields show a right cecocentral sco toma. B. Ophthalmoscopy shows bilateral optic disc pallor.

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