Journal of Neuro-Ophthalmology, June 2005, Volume 25, Issue 2

Recurrent Optic Neuritis as the Presenting Manifestation of Primary Hypereosinophilic Syndrome

Two patients sustained multiple attacks of optic neuritis with persistent visual loss. An elevated eosinophil count was initially considered an incidental finding. Years later, the diagnosis of primary hypereosinophilic syndrome (HES) was confirmed by skin and bone marrow in one patient and by lung biopsy in the other. Treatment with hydroxyurea in one patient and with continuous low-dose prednisone in the other stopped the optic neuritis attacks, 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 diagnosis and treatment of primary HES can lead to visual morbidity.

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 neuritis with persistent visual loss. An elevated eosinophil count was initially considered an incidental finding. Years later, the diagnosis of primary hypereosinophilic syndrome ( HES) was confirmed by skin and bone marrow in one patient and by lung biopsy in the other. Treatment with hydroxyurea in one patient and with continuous low- dose prednisone in the other stopped the optic neuritis attacks, 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 diagnosis and treatment of primary HES can lead to visual morbidity. ( J Neuro- Ophthalmol 2005; 25: 116- 121) The primary hypereosinophilic syndrome ( primary HES) is a hematologic abnormality with a persistent total eosinophil count of greater than 1.5 X 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 State University of New York at Buffalo School of Medicine and Biomedical Sciences, The Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, New York. Address correspondence to Norah S. Lincoff, MD, Associate Clinical Professor of Neurology and Ophthalmology, The Jacobs' Neurological Institute, Buffalo General Hospital, 100 High Street, Buffalo, NY 14203; E- mail: Lincoff@ acsu. buffalo. edu 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. CASE REPORTS Case 1 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. 1 A). Ophthalmoscopy showed bilateral attenuation of the nerve fiber layer and optic disc pallor ( Fig. IB). 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 Tl- 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 116 J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 Recurrent Optic Neuritis J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 TABLE 1. Previously reported ophthalmic hypereosinophilic syndrome Source Chusid, 19754 Farcet, 1982s Fauci, 19826 Binaghi, 19827 Chaine, 1982s Spry, 19839 Moore, 198510 Catalano, 198811 Guidetti, 199112 % of Patients with ophthalmic manifestations 1/ 14 1/ 1 9/ 50 1/ 1 1/ 12 8/ 12 1/ 15 1/ 52 1/ 52 1/ 52 1/ 1 1/ 3 manifestations associated with primary Ophthalmic manifestations Diplopia Retinal arteritis Retinal occlusive disease Episcleritis Retinal occlusive disease Transient diplopia ( right sixth) Retinal vascular disease ( arterial occlusive disease, choroidal infarction, microaneurysms, and capillary dropout) " Visual impairment" Retinal embolus; homonymous hemianopia Transient monocular visual loss " Optic atrophy" ( no history given) Adie pupil Optic neuritis weakness. A repeat MRI showed new areas of hyper-intensity 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). FIG. 1. Case 1. A. Humphrey visual fields in November 1994 show double arcuate scotoma . B. Oph­thalmoscopy shows bilateral optic disc pallor. 117 J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 Lincoff and Schlesinger 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. 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 hypersomno-lence 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 Despite treatment with intravenous methylpred-nisolone 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). FIG. 3. Case 1. Goldmann visual fields in May 1996 reveal a left central scotoma consistent with left optic neuritis. 118 © 2005 Lippincott Williams & Wilkins Recurrent Optic Neuritis J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 hydroxyurea ( 500 mg three times daily) for 5 years and has not been treated with prednisone for 3 years. Case 2 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 methylpredniso-lone. 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. FIG. 5. Case 1. Bone marrow biopsy in May 1996 demon­strates excessive eosinophilia. 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. DISCUSSION 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). 119 J Neuro- Ophthalmol, Vol. 25, No. 2, 2005 Lincoff and Schlesinger FIG. 6. Case 1. Humphrey visual fields in July 1996 show mild improvement relative to November 1994. 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 2( 3 ( 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 \ \ f-n B FIG. 7. Case 2. A. Humphrey visual fields show a right cecocentral sco­toma. B. 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