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Recovery from Multiple Cranial Nerve Palsy of Wegener's Granulomatosis with Infliximab To the Editor: Wegener's granulomatosis (WG)-related intracranial involvement is classified into 3 forms: contiguous invasion of granuloma from extracranial sites, remote intracranial granuloma, and central nervous system vasculitis1,2. We describe a case of WG in which the extension of granuloma from extracranial sites of the skull base resulted in refractory multiple cranial nerve palsy that was dramatically resolved by infliximab therapy. A 42-year-old man had developed bilateral hearing loss and facial nerve palsy since November 2004. Pulmonary nodules were observed and partial resection of the left upper lobe was performed, with a pathological finding of necrotizing vasculitis with granulomatous formation. Otitis media, facial nerve palsy, hearing loss, and swallowing disturbance become apparent, and he was referred to our hospital in June 2005. On admission, neurological examinations revealed peripheral cranial palsies of bilateral trigeminal, facial, vagal, and hypoglossal nerves. Other cranial nerves, pyramidal tract, and extrapyramidal tract were not involved. In audiometry, the right hearing level was scaled out and the left was 111.3 dB. The C-reactive protein (CRP) level had increased to 7.95 mg/dl, but proteinase 3 antineutrophil cytoplasmic autoantibodies [PR3-ANCA (PR3-ANCA kit; Euro–Diagnostica AB, Malmö, Sweden)] were negative. T1-weighted magnetic resonance imaging (MRI) of the brain with gadolinium-diethylenetriamine (Gd-DPTA) infusion showed a remarkably enhanced lesion from the skull base. According to the international classification criteria3, he was diagnosed as having WG complicated with intracranial granuloma formation, extending from the skull base. He was treated with oral prednisolone (PSL; 60 mg/day) and cyclophosphamide (CYC; 100 mg/day) for 2 months. CRP improved slightly from 7.95 mg/dl to 4.87 mg/dl; however, neither cranial nerve palsy nor abnormal MRI lesion changed with treatment (Figure 1A). Moreover, manic-depressive psychosis, probably due to corticosteroid therapy, had appeared, leading to reduction of PSL dosage from 60 to 30 mg/day at 2 months. Considering the therapeutic time course, this patient appeared to have WG that was difficult to cure by standard therapy. A protocol for therapy with infliximab was approved by the Institutional Review Board of Nagasaki University, and scheduled according to the same sequential regime used in rheumatoid arthritis in Japan (3 mg/kg), with continuation of CYC and PSL.
After the second infusion at 6 weeks, CRP diminished to 0.08 mg/dl and the Birmingham Vasculitis Activity Score (BVAS)4 fell from 22 to 4. Swallowing disturbance as well as trigeminal and facial nerve palsy gradually improved. In nerve conduction velocity studies, the amplitude of the facial nerves also improved: improvement was found in the right orbicularis oculi muscle (from 0 to 200 µV), left orbicularis oculi muscle (from 500 to 920 µV), left nasalis muscle (from 270 to 1610 µV), and left orbicularis oris muscle (from 104 to 540 µV) at 14 weeks after the third infusion. The right auditory disorder did not resolve, but the left hearing level improved from 111.3 dB to 45.0 dB. Pulmonary nodules also disappeared. MRI detection of the enhancement area at proximate infliximab infusion (Figure 1A) was significantly reduced compared with 14 weeks (Figure 1B) and 80 weeks (Figure 1C). Remission (BVAS 0) was achieved at 14 weeks. Infliximab infusion was continued every 8 weeks up to 78 weeks (11 infusions), when PSL was tapered from 30 to 5 mg/day. CYC dosage reached 10 g, then was switched to azathioprine. BVAS remained 0 at 78 weeks, and then infliximab was discontinued. Remission still remained at 102 weeks. This is a case of ANCA-negative, biopsy-proven WG with severe intracranial granulomatous involvement with multiple cranial nerve palsies. Reinhold-Keller, et al reported that ANCA-negative WG shows more serious CNS involvement than PR3-ANCA-positive WG5, which is consistent with our case. Efficacy of TNF blockage agents in WG is reviewed in several reports6. On the basis of high rates of adverse events, etanercept use is not recommended for WG; however, Mukhtyar and Luqmani have described an excellent effect of infliximab, demonstrating that 43 of 53 patients (81%) given infliximab experienced remission. In addition, 37 of these 53 patients (69%) had been classified as refractory cases with standard treatment6. Infliximab, in most cases, is administered with concurrent treatment6. Since the therapeutic duration of CYC and PSL is short, 2 months in this case, a delayed efficacy of CYC and PSL could become apparent after infliximab. However, high BVAS, abnormal MRI lesion, and high serum CRP concentration were still present, before infliximab, regardless of the administration of 100 mg/day CYC and PSL (at least 30 mg/day) for 2 months, and these indicators rapidly improved in 6 weeks after infliximab. We suggest these therapeutic outcomes indicate the efficacy of infliximab. Our case is the first infliximab-induced recovery of intracranial involvement of WG. We hope this experience encourages the consideration of infliximab treatment for refractory and life-threatening WG. KEITA FUJIKAWA, MD; ATSUSHI KAWAKAMI, MD; KATSUMI EGUCHI, MD, Unit of Translational Medicine, Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Address reprint requests to Dr. Fujikawa. 2. Nishino H, Rubino F, DeRemee R, et al. Neurological involvement in Wegener's granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol 1993;33:4-9. [MEDLINE] 3. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum 1990;33:1101-7. [MEDLINE] 4. Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM 1994;87:671-8. [MEDLINE] 5. Reinhold-Keller E, de Groot K, Holl-Ulrich K, et al. Severe CNS manifestations as the clinical hallmark in generalized Wegener's granulomatosis consistently negative for antineutrophil cytoplasmic antibodies (ANCA). A report of 3 cases and a review of the literature. Clin Exp Rheumatol 2001;19:541-9. [MEDLINE] 6. Mukhtyar C, Luqmani R. Current state of tumor necrosis factor a blockade in Wegener's granulomatosis. Ann Rheum Dis 2005;64:31-6. [MEDLINE]
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