Ocular Immunology & Inflammation, 19(3), 167170, 2011 Copyright 2011 Informa Healthcare USA, Inc.

. ISSN: 0927-3948 print/ 1744-5078 online DOI: 10.3109/09273948.2011.560411

Original Article

Optic Nerve Involvement with Panuveitis in Sweet Syndrome

Ann-Marie Lobo, MD1, Rebecca Stacy, MD, PhD1, Dean Cestari, MD1, John H. Stone, MD2, Frederick A. Jakobiec, MD1, and Lucia Sobrin, MD, MPH1
1

Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA, and 2 Department of Rheumatology, Massachusetts General Hospital, Boston, Massachusetts, USA Abstract

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Purpose: To report a case of a patient with optic nerve involvement in neuro-Sweet syndrome and review the literature on this systemic disease. Methods: Interventional case report and review of the literature. Results: A 49-year-old man developed an acute exacerbation of bilateral panuveitis and optic disc edema together with symptoms of a papular rash on his forearms, fevers, malaise, and arthalgias. Laboratory findings revealed an aseptic meningitis and neutrophilic leukocytosis. Biopsy of the skin rash demonstrated an intense neutrophilic infiltrate in the dermis consistent with the diagnosis of neuro-Sweet syndrome. The patient continued to require corticosteroids for inflammation control in spite of immunomodulatory therapies, including tumor necrosis factor-alpha inhibitor infliximab. Conclusions: Sweet syndrome can present with optic nerve involvement. Screening for underlying etiologies, including autoimmune disease, malignancy, and offending drugs, is important for targeted therapy. Keywords infliximab, neuro-Sweet, optic nerve, sweet syndrome

Case Report
A 49-year-old Caucasian man with no significant medical history presented to the emergency room in April 2007 complaining of pain and redness in his left eye. On examination, visual acuity was 20/20 in the right eye and 20/25 in the left. There was a left afferent pupillary defect. There was no dyschromatopsia. Visual field testing was normal on the right and showed an enlarged blind spot on the left. Slit-lamp and funduscopic examinations demonstrated panuveitis with optic disc edema in the left eye (Figure 1A). Serologies for underlying systemic diseases were unremarkable except for a mildly elevated lysozyme of 21 (reference range, 917g/mL). Brain magnetic resonance imaging (MRI) demonstrated nonspecific T2 hyperintensities in the subcortical white matter. Computerized tomographic scanning of the lungs was normal. Oral prednisone was initiated with improvement in symptoms and ocular inflammation; however, on

attempted tapering of steroids, inflammation recurred. Steroid-sparing immunomodulatory therapy with mycophenolate mofetil was started in August 2007. The patient had intermittent flares of inflammation in the left eye over several months and was noted to have persistent bilateral optic disc edema (Figure 1B). Cyclosporine was added as an additional immunomodulatory therapy in 2008 to control the flares of inflammation. The inflammation was controlled on this regimen and visual acuity improved to 20/16 in both eyes. A repeat MRI of the brain/orbits with gadolinium in February 2009 demonstrated increased T2 hyperintense signal in the right optic nerve; visual acuity was 20/20 in the right eye (Figure 1C). Due to the persistent optic disc edema despite inflammation control, a lumbar puncture was performed in July 2009. Opening pressure was 22 cmH2O; total protein was elevated at 110, but the cell count was zero. Ten days after the lumbar puncture, the patient began complaining of arthralgias, fevers, malaise,

Received 03 November 2010; accepted 31 January 2011 Correspondence Ann-Marie Lobo, MD, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA. E-mail: AnnMarie_Lobo@meei.harvard.edu

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A B C

Figure 1. (A) Fundus photograph of the left eye demonstrating optic nerve edema and vitritis. (B) Fundus photograph of the right eye demonstrating optic nerve edema. (C) MRI of the orbit with gadolinium demonstrating mildly increased T2 signal intensity in right optic nerve on STIR images.

chills, and a nodular rash on his forearms. On hospital admission, he was febrile with a temperature of 102.3F. Pertinent laboratory tests included a white blood cell count of 17.1 (normal range 4.511103 cells/mm3) with 85% neutrophils, a sedimentation rate of 86mm/h, a C-reactive protein of 255mg/L (normal range < 8mg/L), cerebrospinal fluid (CSF) total protein 72, and CSF cell count of 4 with CSF lymphocytes 56% and CSF neutrophils 16%. Pertinent negative laboratory tests included tests for syphilis, anti-neutrophil cytoplasmic antibody, anti-nuclear antibody, angiotensin converting enzyme, cryoglobulins, blood cultures, and tuberculin purified protein derivative skin test. One day after hospital admission, the patient reported decreased vision in his left eye. On examination, visual acuity was 20/25 in the right eye and 20/60 in the left. There was no afferent pupillary defect. Slit-lamp and funduscopic examinations demonstrated significant bilateral panuveitis, greater in the left than the right with bilateral papillitis. The rash continued to spread bilaterally to his forearms and hands and was described as blanching dark red papules on an erythematous base (Figure 2A). A skin biopsy demonstrated florid neutrophilic inflammation and edema within the papillary dermis with an intact overlying epidermis (Figure 2B). No evidence of vasculitis was discovered (Figure 2C). Systemic methlyprednisolone was initiated with gratifying improvement in the rash, arthralgias, and eye symptoms. The diagnosis of Sweet syndrome was made. A workup for an underlying malignancy was negative. There was no history or evidence of oral or genital ulcerations. The patient was discharged on 80mg of oral prednisone. On follow-up examination, he was noted to have a rising creatinine level, which was felt to be secondary to prophylaxis with trimethoprimsulfamethoxazole. This medication had been started at the time of treatment with high-dose steroids and was subsequently discontinued. A renal biopsy demonstrated interstitial nephritis and his creatinine gradually improved on no further treatment. He was transitioned to therapy with infliximab infusions and the oral steroids were tapered. His visual acuity

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improved to 20/20 OU; however, the patient continued to have flares of ocular inflammation over the course of several months, requiring a left sub-Tenons kenalog injection for persistent cystoid macular edema secondary to panuveitis in March 2010. The patient also required oral prednisone to control ocular inflammation in spite of infliximab therapy at 5mg/kg/infusion every 4 weeks and this medication was discontinued after 7 months. His visual acuity has stabilized at 20/20 OU and he has been able to taper to low-dose corticosteroids (<10mg/day).

Discussion
Sweet syndrome (SS) or acute febrile neutrophilic dermatosis is an inflammatory disease characterized by erythematous plaques and papules on the limbs and face in the setting of fever and leukocytosis.1 Skin biopsy demonstrates a neutrophilic infiltrate in the dermis without evidence of vasculitis.1 Neuro-Sweet disease has been used to describe cases of SS involving the central nervous system, specifically cases with meningitis or encephalitis.2-4 We present a case of neuroSweet syndrome with optic nerve involvement. Ocular involvement in SS has been well documented in up to one-third of affected patients.5, 6 Conjunctivitis and episcleritis are the most frequently reported eye findings; however, there have been reports of iritis, limbal nodules, peripheral ulcerative keratitis, and scleritis in patients with SS.5, 7 Posterior segment involvement is uncommon and there have been only two reports of retinal vasculitis and occlusive vasculitis in SS.8, 9 Our patient had both panuveitis as well as optic disc edema in both eyes. MRI findings were suggestive of right optic nerve enhancement prior to the onset of the skin rash. The patient also had symptoms of malaise and fever with CSF findings suggestive of aseptic meningitis coincident with the development of the papular skin rash. The combination of the clinical presentation of decreased vision, the examination findings of bilateral optic disc edema, the optic nerve enhancement on MRI,
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Optic Nerve and Panuveitis in Sweet Syndrome 169

A B C

Figure 2. (A) Clinical picture of erythematous papules on hands and forearms. (B) Histopathology of skin demonstrating a dense neutrophilic infiltrate (N) in the dermis with an intact overlying epithelium. The reticular dermis is edematous (E). Several giant cells are seen to the left of the field (arrow). (C) Histopathology of the dermis of the skin lesion. Vessels are evident (arrows) without vasculitis.

and the CSF findings supports the diagnosis of neuroSweet syndrome. Hisanaga etal. described neuro-Sweet disease based on neurologic findings (encephalitis or meningitis, usually accompanied by fever), dermatologic lesions (painful, dull red erythematous plaques on the face, neck, upper limbs, or trunk with predominant neutrophilic infiltration of the dermis), absence of vasculitis or typical uveitis (which is seen in Behets disease), and HLA association (B54 or Cw1 positive, B51 negative in Japanese patients).3 There have also been documented associations between HLA-B54 typing and SS, which is in contrast with Behet disease patients, who are more likely to be HLA-B51 positive.10 Neuro-Sweet disease, like SS, is notable for significant response of disease activity to corticosteroids. Unlike Behet disease, neuroSweet is associated with a more benign clinical course lacking severe neurologic deficits.2, 4 There are many features of SS and Behet disease that overlap. One study speculated on the presence of a common etiology shared by the two diseases, including a potential infectious trigger of an immune hypersensitivity reaction in genetically predisposed patients.3 Our patient lacked clinical criteria for the diagnosis of Behet disease, including oral or genital ulcers, and HLA testing was not performed.10 SS can be subcategorized based on clinical setting: (1) classical SS, occurring in patients with history of autoimmune diseases, such as inflammatory bowel disease, systemic lupus erythematosus, sarcoidosis, and Behet disease, or in pregnant women; (2) malignancy-associated SS, seen most often with hematologic malignancies at both disease onset and recurrence; and (3) drug-induced SS, encountered with a number of antibiotics and other medications, including nitrofurantoin, tetracyclines, and trimethoprimsulfamethoxazole, antiepileptics, and retinoids.5, 6, 1012 Granulocyte-colony stimulating factor treatments in hematologic diseases have also been reported to cause neutrophil accumulation with dose-dependent effects contributing to the development of SS.13 The present report describes a patient with an idiopathic panuveitis that preceded the development of the skin rash and other classic findings of SS.
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In many reported cases of ocular involvement in SS, the ocular findings occur simultaneously or shortly after the development of the skin rash.5, 8, 9, 14 In our patient, there was an acute exacerbation of ocular inflammation and disc edema at the time of the skin rash and fever. One study on neuro-Sweet syndrome suggests that neurologic involvement may precede the development of the dermal lesions; in many patients, recurrences of benign encephalitis were asymptomatic, not associated with skin lesions, and only detected based on abnormal signal intensities on MRI of the brain, which disappeared after treatment with corticosteroids.3 Our patient fits the category of classic SS with the potential of an underlying autoimmune disease as manifested as idiopathic panuveitis. However, the reports of neuroSweet patients with neurologic involvement prior to the skin rash also raise the possibility that the patients initial panuveitis with disc edema was secondary to neuro-Sweet syndrome prior to onset of the skin lesions. In this regard, the uvea is topographically and embryologically continuous with the leptomeninges. We have yet to identify in our patient any underlying factor, such as drugs or malignancy, associated with the development of SS. Perhaps prior immunosuppressive therapy prevented the earlier development of the other features of SS. The current patient responded well to corticosteroids as do all patients with SS.6 Steroid-sparing therapy with infliximab was instituted given the similarities of the patients disease components including panuveitis to that of patients with Behet disease.15 Steroid-sparing therapies are important in cases with frequent recurrences of inflammation, which occurred in our patient. One study described recurrences of inflammation in up to 1525% of SS patients.6 Infliximab has been used successfully in patients with SS to treat and prevent recurrent skin lesions.16, 17 In our patient, infliximab was not effective in preventing recurrent panuveitis and cystoid macular edema. There has been one report of a patient who developed ocular relapse of SS while on infliximab therapy that was only responsive to corticosteroids.18 Although our patients inflammation remained refractory to steroid-sparing medications, his rapid response

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170 A-M Lobo etal. to corticosteroids and his retention of excellent visual acuity were consistent with the benign course and sequelae of SS. Neuro-Sweet syndrome can present with optic nerve involvement, which may precede the emergence of the characteristic dermal papules. In any case of SS, screening for potential malignancy and identifying the drugs that the patient is taking is of utmost importance. The results of this quest should lead to the introduction of appropriate therapy for any underlying systemic disease or withdrawal of the offending drug.
(Sweet syndrome): new cases and review of the literature. Surv Ophthalmol. May-Jun 2008;53(3):219226. [6] von den Driesch P. Sweets syndrome (acute febrile neutrophilic dermatosis). J Am Acad Dermatol. Oct 1994;31(4):535 556; quiz 557560. [7] Medenblik-Frysch S, von den Driesch P, Jonas JB, Meythaler FH. Ocular complications in Sweets syndrome. Am J Ophthalmol. Aug 15 1992;114(2):230231. [8] Song WK, Bang D, Choi YJ, Lee SC, Oh SH. Sudden visual loss due to occlusive venous vasculitis associated with Sweet syndrome. Arch Dermatol. Feb 2009;145(2):216 218. [9] Sato M, Kawamura T, Hase S, Katsumata S, Oshika T. A case of bilateral retinal vasculitis associated with Sweet syndrome. Retina. Sep 2005;25(6):800802. [10] Karadogan SK, Baskan EB, Alkan G, Saricaoglu H, Tunali S. Generalized Sweet syndrome lesions associated with Behcet disease: a true association or simply co-morbidity? Am J Clin Dermatol. 2009;10(5):331335. [11] Hiari N, Borland C. A 47-year-old man with neuro-Sweet syndrome in association with Crohns disease: a case report. J Med Case Reports. 2009;3:8997. [12] Fett DL, Gibson LE, Su WP. Sweets syndrome: systemic signs and symptoms and associated disorders. Mayo Clin Proc. Mar 1995;70(3):234240. [13] White JM, Mufti GJ, Salisbury JR, du Vivier AW. Cutaneous manifestations of granulocyte colony-stimulating factor. Clin Exp Dermatol. Mar 2006;31(2):206207. [14] Nicolaides A, Packles MR, Schutzer PJ, Weinberg JM. Iritis associated with Sweets syndrome. Clin Exp Dermatol. Jun 2000;25(4):352353. [15] Niccoli L, Nannini C, Benucci M, et al. Long-term efficacy of infliximab in refractory posterior uveitis of Behcets disease: a 24-month follow-up study. Rheumatology (Oxford). Jul 2007;46(7):11611164. [16] Malheiros AP, Teixeira MG, Takahashi MD, de Almeida MG, Kiss DR, Cecconello I. Sweet syndrome associated with ulcerative colitis. Inflamm Bowel Dis. Dec 2007;13(12):1583 1584. [17] Foster EN, Nguyen KK, Sheikh RA, Prindiville TP. Crohns disease associated with Sweets syndrome and Sjogrens syndrome treated with infliximab. Clin Dev Immunol. Jun 2005;12(2):145149. [18] Michel G, Lhermitte B, Cribier B, Speeg-Schatz C, Bourcier T. Sweet syndrome presenting as resistant conjunctivitis. Cornea. Dec 2008;27(10):11891190.

ACKNOWLEDGMENT
Supported by a Research to Prevent Blindness Career Development Award (L.S.), NIH EY16335-02 (L.S.), and a Harvard Catalyst Program for Faculty Development and Diversity Faculty Fellowship Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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References
[1] Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol. Aug-Sep 1964;76:349356. [2] Hisanaga K, Hosokawa M, Sato N, Mochizuki H, Itoyama Y, Iwasaki Y. Neuro-sweet disease: benign recurrent encephalitis with neutrophilic dermatosis. Arch Neurol. Aug 1999;56(8):10101013. [3] Hisanaga K, Iwasaki Y, Itoyama Y. Neuro-Sweet disease: clinical manifestations and criteria for diagnosis. Neurology. May 24 2005;64(10):17561761. [4] Nobeyama Y, Kamide R. Sweets syndrome with neurologic manifestation: case report and literature review. Int J Dermatol. Jun 2003;42(6):438443. [5] Gottlieb CC, Mishra A, Belliveau D, Green P, Heathcote JG. Ocular involvement in acute febrile neutrophilic dermatosis

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