Bilateral Abducens Nerve Palsy Due to Idiopathic Intracranial Hypertension As an Initial Manifestation of Systemic Lupus Erythematosus

□ CASE REPORT □

Bilateral Abducens Nerve Palsy due to Idiopathic Intracranial Hypertension as an Initial Manifestation of Systemic Lupus Erythematosus

Eri Katsuyama 1, Ken-ei Sada 1, Noriko Tatebe 1, Haruki Watanabe 1, Takayuki Katsuyama 1, Mariko Narazaki 1, Koichi Sugiyama 1, Katsue S. Watanabe 1, Hiroshi Wakabayashi 1, Tomoko Kawabata 1, Jun Wada 1 and Hirofumi Makino 2

Abstract

Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure and presents as an intractable headache, vomiting, and ophthalmologic manifestations. We herein report the case of a young girl who presented with bilateral abducens nerve palsy due to IIH as the onset of systemic lupus erythematosus (SLE). The patient was successfully treated with corticosteroid therapy. Our case lacked the typical symptoms of IIH, such as headache or nausea; therefore, it is necessary to carefully determine the cause of bilateral abducens nerve palsies. The development of IIH in SLE patients is a rare occurrence, but this manifestation should not be overlooked.

Key words: idiopathic intracranial hypertension, systemic lupus erythematosus, abducens nerve palsy, diagnosis, treatment

(Intern Med 55: 991-994, 2016) (DOI: 10.2169/internalmedicine.55.5990)

high fever that had lasted for a few days in March 2010. Introduction She had been treated for asthma and allergic rhinitis, and she had not suffered from any asthma attacks for several Idiopathic intracranial hypertension (IIH) is characterized years. At the first visit, the patient was tentatively diagnosed by symptoms of elevated intracranial pressure, elevated cere- with a viral infection, and her fever subsided with palliative brospinal fluid (CSF) pressure, normal CSF content, and care. normal neuroimaging studies (1). Although IIH generally However, the subsequent laboratory data revealed leuko- emerges in overweight women of childbearing age (2), it is penia, proteinuria, microscopic hematuria, positive antinu- known that IIH is also induced by medication, infection, or clear antibodies (ANA) and an increased serum level of anti- medical disorders such as endocrinological disease, vitamin double-stranded DNA (dsDNA) antibodies. Ten days after deficiency, and autoimmune diseases (3). We herein present this admission, the patient became aware of diplopia and a case of IIH as the onset of systemic lupus erythematosus was referred to our hospital for a further examination for (SLE) with bilateral abducens nerve palsy without headache ophthalmological abnormalities. She was not receiving any or nausea. medications, such as corticosteroids or antibiotics, or any supplements, including vitamin A, which are known to be Case Report risk factors for IIH. She did not complain of either headache or nausea. Upon changing hospitals, an examination of her A 14-year-old girl was admitted to a local hospital with a vital signs demonstrated no abnormalities except for slight

１Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan and ２Okayama University Hospital, Japan Received for publication June 16, 2015; Accepted for publication July 22, 2015 Correspondence to Dr. Ken-ei Sada, [email protected]

991 Intern Med 55: 991-994, 2016 DOI: 10.2169/internalmedicine.55.5990

Figure. Fundus images a) at onset and b) after treatment. Brain magnetic resonance imaging based on c) MR angiography and d) fluid-attenuated inversion recovery (FLAIR). diastolic hypertension (125/92 mmHg). Her height was normal activity of the optic nerves. The laboratory findings 155.7 cm, her body weight was 54.3 kg and her body mass showed pancytopenia with a high titer of anti-dsDNA anti- index was 22.4 kg/m2, indicating that she was not obese. bodies and hypocomplementemia. The anti-cardiolipin anti- She had a malar rash and palmar erythema, and her palpe- bodies were slightly positive, whereas lupus anticoagulant bral conjunctiva was anemic. She was alert with no signs of and anti-β2GPI antibodies were negative (Table). The meningeal irritation. On neurological examination, the ab- prothrombin time (11.6 sec) and activated partial throm- duction of both eyes was insufficient (left; 3/5, right 4/5) boplastin time (27.5 sec) were normal. The D-dimer level and became exacerbated while she was looking to the left was slightly elevated (2.5>0.9 μg/mL); however, there were side. Her pupils were symmetrical and reactive to light. She no signs of thrombotic or hemorrhagic activity. A urinalysis had no other cranial neuropathy, no motor or sensory neuron revealed proteinuria and hematuria with active cellular casts. disorders, and no pathological reflexes. The viral specific antibody profile revealed no evidence of Ophthalmological examinations demonstrated papilledema active viral infection (Table). during both distal and proximal sight, indicative of bilateral Brain magnetic resonance imaging (MRI), MR angiogra- incomplete abducens nerve palsy with papilledema (Fig- phy and plain computed tomography (CT) showed no find- ure a). There were no accommodation disturbances, and her ings of ischemia, thrombosis or vasculitis (Figure c, d), visual field and visual activity (vision without correction: while a CSF analysis revealed an extremely high opening right: 0.3, left: 0.4; vision with correction: right: 1.5, left: pressure (320 mmH2O) with normal CSF indices (Table). 1.2) were normal. A critical flicker frequency test revealed There was no evidence of malignancy (cytology class 2) or

992 Intern Med 55: 991-994, 2016 DOI: 10.2169/internalmedicine.55.5990

Table. Laboratory Data on Admission. The pancytopenia recovered the day after the first treatment Value unit Normal range with methylprednisolone pulse therapy (WBC: 2,160 to Blood test 8,990/μL, Hb: 7.4 to 10.9 g/dL, platelets: 5.6 to 14.8×103/ White blood cell 2,160 /PL 3,500-8,500 μL). The bilateral abducens palsies and papilledema rapidly Hemoglobin 7.4 g/dL 11.5-15.0 improved over the course of a week (Figure b). The visual Lymphocyte 1,015 /PL Platelet 5.6*104 /PL 15-35*104 activity was well maintained (vision without correction: C-reactive protein 0.03 mg/dL 0.0-0.3 right: 0.4, left: 0.3; vision with correction: right: 1.5, left: Complement 3 38.2 mg/dL 65-135 1.5) and the papilledema disappeared. The anti-dsDNA anti- Complement 4 6.2 mg/dL 13.0-35.0 CH50 10.0 U/dL 30-50 body titer, complement level, and proteinuria also gradually Antinuclear antibody 78.2 index 0.0-19.0 improved. The level of D-dimer promptly normalized (2.5 to Anti-dsDNA antibody 252.3 IU/mL 0.0-12.0 0.6 μg/mL), and there was no thrombotic tendency without Anti-cardiolipin antibody 18.6 U/mL 0.0-9.9 anticoagulant therapy. Although the concomitant use of Anti-E2GPI antibodies <=1.2 U/mL <3.5 Lupus anticoagulant 1.1 - 0.0-1.3 azathioprine for maintenance was discontinued due to the Anti-GM1 IgG 0.025 COI <0.4 development of leukopenia in January 2011, remission was antibody subsequently maintained with prednisolone at a dose of 3 Anti-GQ1b IgG 0.041 COI <0.4 antibody mg/day for five years. Viral antibodies Cytomegalovirus 0 count 0 Discussion -pp65 antigen (C0C11) EBV-VCA-IgG 7.5 index <0.5 EBV-VCA-IgM 0.0 index <0.5 IIH is defined by the modified Dandy criteria as follows: EBV-EBNA 2.8 index <0.5 [1] symptoms and signs of increased intracranial pressure; measles IgG 3.45 TV <0.5 [2] no localized neurologic signs, except for unilateral or bi- VZV IgG 44.0 index 0-2 Parvovirus IgM 0.32 index 0.00-0.79 lateral 6th nerve palsies; [3] increased CSF opening pressure Rubella IgG 113 IU/mL <10 >200 mmH2O, but normal CSF composition; [4] no evi- Rubella IgM 0.13 TV <0.8 dence of hydrocephalus, mass, structural, or vascular lesions Mumps IgG 0.84 TV <0.35 on imaging; and [5] no other cause of increased intracranial E-D glucan <6.0 pg/mL 0.0-11.0 Urine test pressure (ICP) identified (1). Proteinuria 2+ - Negative IIH is a rare disease in Japan compared to other countries. Hematuria 3+ - Negative Yabe et al. reported that IIH occurred in only 0.03 per Urine protein 1.71 g/day - Creatinine clearance 142.5 L/day 82.3-111.6 100,000 people (two of 5,780,000 patients) in Hokkaido, Granular cell cast 3 /Whole field Negative compared with 0.9-1.1 per 100,000 people in the United Fatty cast 1 /Whole field Negative States (5). According to previous reports, the characteristics CSF findings of IIH patients with SLE demonstrate several differences L-Total Protein 15 mg/dL 10-40 L-Albumin 8.91 mg/dL - from other IIH patients. First, SLE patients have a higher L-Glucose 54 mg/dL 40-75 prevalence of IIH than the general population. Hershko et al. Cellular count 2/PL-reported that IIH occurred in 10 of 651 hospitalized SLE patients (prevalence, 1.5%) compared to 19 per 100,000 reported in the general population (6). Second, obesity is a infection. These findings indicated that the patient had IIH risk factor for IIH in the general population (7); however, that caused bilateral incomplete abducens nerve palsy with Kim et al. reported that all eight SLE patients with IIH in papilledema. The levels of interleukin (IL)-6 were also in- their study had a normal body mass index (BMI <30 kg/ creased (at 6.4 pg/mL) as was the ribosome P IgG antibody m2) (8). titer (at 3.0 U; normal <1.0 U) in the CSF. A diagnosis of Corticosteroids and immunosuppressive agents were effec- definitive SLE was promptly made according to the Ameri- tive for the IIH in the present case. Most of the IIH in SLE can College of Rheumatology (ACR) SLE classification cri- cases can be treated using high-dose corticosteroids followed teria on hospital day 1 (4). The slight increases in the levels by immunosuppressants (6), which differs from IIH cases in of IL-6 and ribosome P IgG antibodies in the CSF were general, which are treated using acetazolamide or mannitol thought to be due to neuropsychiatric SLE. Lupus nephritis and weight loss. The pathophysiology of IIH may include was also subsequently diagnosed and histologically classi- the impairment of CSF absorption and venous outflow, fied as International Society of Nephrology/Renal Pathology rather than an increase in CSF production (9). The patho- Society (ISN/RPS) class III (A/C). genesis of IIH in SLE patients is still unclear; however, Intravenous methylprednisolone pulse therapy (500 mg/ some case reports showed that IIH develops in active SLE day) was immediately administered for three days, followed patients, and other previous reports suggested a possible re- by oral treatment with 60 mg of prednisolone daily. lationship between anti-phospholipid antibodies (aPL) or Monthly intravenous cyclophosphamide pulse (IVCY) at a antiphospholipid syndrome (APS) and IIH (6, 10). There- dose of 500 mg was concomitantly administered six times. fore, thrombosis and hypercoagulability may cause impaired

993 Intern Med 55: 991-994, 2016 DOI: 10.2169/internalmedicine.55.5990

CSF absorption and lead to IIH in patients with SLE. Some Nordisk, Pfizer, Takeda, and Tanabe Mitsubishi. Jun Wada: Em- authors have proposed that it is better to perform MR ployment, Astellas and Boehringer Ingelheim; Honoraria, Novar- venography in atypical cases (11). In our case, we per- tis, Boehringer Ingelheim and Novo Nordisk. formed imaging studies using MRI, magnetic resonance angiography (MRA), and plain CT, in addition to common co- References agulation testing. However, evaluations for venous thrombosis and specific coagulation testing, such as the platelet ag- 1. Thurtell MJ, Wall M. Idiopathic intracranial hypertension (pseudo- gregation activity, were not performed. Although we cannot tumor cerebri): recognition, treatment, and ongoing management. fully exclude the possibility that venous thrombosis or hy- Curr Treat Options Neurol 15: 1-12, 2013. 2. Corbett J. Idiopathic intracranial hypertension. 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Incidence to SLE; however, the anemia in our case was mild, was un- of idiopathic intracranial hypertension in Hokkaido, the northern- likely to be the cause of the IIH, and recovered quickly. most island of Japan. J Neurol 247: 474-475, 2000. Headache and vomiting are present in almost all IIH 6. Hershko AY, Berkun Y, Mevorach D, Rubinow A, Naparstek Y. In- creased intracranial pressure related to systemic lupus erythemato- cases; however, the present case did not exhibit these symp- sus: a 26-year experience. Semin Arthritis Rheum 38: 110-115, toms. There have been reports in Japan of IIH that was inci- 2008. dentally diagnosed during a medical checkup or ophthalmol- 7. Hoffmann J, Goadsby PJ. Update on intracranial hypertension and ogy consultation without any clinical symptoms (12-14). Al- hypotension. Curr Opin Neurol 26: 240-247, 2013. though it is not clear what mechanisms are involved in the 8. Kim JM, Kwok SK, Ju JH, Kim HY, Park SH. 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Idiopathic intracranial hypertension also be caused by infection, vasculitis, thrombosis, or other in a pediatric population: a retrospective analysis of the initial im- central nervous system events. Therefore, the present case aging evaluation. J Child Neurol 23: 1308-1311, 2008. had to be carefully distinguished from cranial nerve palsy in 12. Nikaido J, Yasukura T, Hiramoto Y, et al. Diagnostic difficulties in a case of papilledema without manifest symptoms. Rinsho Ganka the differential diagnosis. (Japanese Journal of Clinical Ophthalmology) 59: 1883-1888, In conclusion, we experienced a case of SLE with bilat- 2005 (in Japanese, Abstract in English). eral abducens nerve palsies due to IIH. The presence of IIH 13. Tomita H, Kanagami S, Matsubara M. A case of idiopathic intrac- in SLE patients is rare, but this potential occurrence should ranial hypertension with papilledema as the sole manifestation. not be overlooked. Rinsho Ganka (Japanese Journal of Clinical Ophthalmology) 60: 357-361, 2006 (in Japanese, Abstract in English). 14. Sakushima K, Tsuji S, Niino M, Yabe I, Sasaki H. Idiopathic in- Author’s disclosure of potential Conflicts of Interest (COI). tracranial hypertension without headache detected during a routine Hirofumi Makino: Employment, AbbVie, Astellas and Teijin; health check. Rinsho Shinkeigaku (Clinical Neurology) 48: 430- Honoraria, Astellas, Boehringer Ingelheim, Chugai, Daiichi 432, 2008 (in Japanese, Abstract in English). 15. Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, No- De Simone R, Marano E, Bilo L, et al. Idiopathic intracranial hypertension without headache. Cephalalgia 26: 1020-1021, 2006. vartis, Pfizer, Takeda, and Tanabe Mitsubishi; Research funding, 16. Aylward SC, Aronowitz C, Reem R, Rogers D, Roach ES. Intrac- Astellas, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Su- ranial hypertension without headache in children. J Child Neurol mitomo, Kyowa Hakko Kirin, Mochida, MSD, Novartis, Novo 30: 703-706, 2015.

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