ANCA-Negative Wegener's Granulomatosis with Multiple Lower Cranial Nerve Palsies
A 54-yr-old female was referred for neurologic consultation due to progressive dysarthria, dysphagia and left facial palsy for past 5 month in January 2011. She had no underlying medical illness such as diabetes mellitus, and had underwent first functional endoscopic sinus surgery (FESS) for bilateral maxillary sinusitis 4 yr ago. She had remained tolerable after the surgery for about 3. 5 yr then the symptoms of headache, hearing difficulty, dysarthria and dysphagia slowly emerged and progressed for about 6 months. Under the diagnosis of recurrent sinusitis involving frontal, ethmoid, sphenoid and maxillary sinuses, second FESS and broad-spectrum antibiotics were treated. Although these surgical and medical treatments were adequately performed, her symptoms worsened as aggravated hearing problem, severe bulbar symptoms and newly developed left facial palsy. The first brain MRI with using contrast enhancement was performed, only to reveal still existing bilateral otomastoiditis and extensive sinusitis (). Cerebrospinal fluid (CSF) had no cell counts and normal protein level. The empiric steroid therapy (methysol 2 mg/kg/day) without definite diagnosis has somewhat stabilized these series of aggravating symptoms. At then, she was referred to our clinic for more detailed evaluation.\nIn January 2011 when she was admitted in our clinic, all the vital signs including body temperature were stable. Accompanied by severe bulbar symptoms of dysarthria and dysphagia, she complained of constitutional symptoms such as general weakness, poor oral intake and weight loss of up to 12 kilograms during past 6 months. Neurologic examination revealed various lower cranial nerve palsies of both sides, which were overall more prominent on left side than right side. Demonstrated clinical manifestations and positive neurologic findings are; facial diplegia, progressive hearing difficulty resulting in near-deafness, bilateral tinnitus and hyperacusis, right deviation of uvula, bilateral decreased gag reflexes, flaccid dysarthria with breathy voice and hypernasality, dysphagia especially in liquid food, left vocal cord palsy, left sternocleidomastoid muscle weakness, impaired tongue protrusion and giggling, and fasciculation with slight atrophy on the left side tongue. In contrast to these various lower cranial nerve involvements, there was no afferent pupillary defect, and no limitation in extraocular eye movements. Otolaryngology report was given as extensive sinusitis involving bilateral frontal, sphenoid, and maxillary sinuses with nasal cartilage erosion and bilateral chronic otitis media.\nLaboratory studies revealed increased C-reactive protein (CRP) of 29.90 mg/dL (normal range 0-0.3 mg/dL), increased erythrocyte sedimentation rate (ESR) of 67 mm/hr, mild anemia (hemoglobin 10.8 g/dL), but no eosinophila and mild leukocytosis (12,800/µL). Renal function (BUN 15 mg/dL, creatinine 0.6 mg/dL, glomerular filtration rate 111 mL/min) and microscopic urine analysis were normal. Serology test for anti-Ro/SSA, anti-La/SSB, antinuclear, anticardioplin antibody, and ANCA were negative. Neither immunofluorescence method nor direct enzyme-linked immunosorbent assay method for proteinase 3 and myeloperoxidase antigens could detect ANCA. FANA screening and VDRL were also negative, and angiotensin converting enzyme was within normal as 28 U/L (normal range 18-55 U/L). Rheumatoid factor was minimally elevated up to 20.4 IU/mL (normal range 10-18 IU/mL). Serum folate, vitamin B1 and vitamin B12 were measured as normal level. Tumor markers including AFP, CEA, CA19-9, and CA125 were normal.\nChest CT revealed no hilar enlargement or parenchymal lung lesion. Neck CT showed high density lesions in the nasopharynx with enhancement, penetrating the skull base and extensive sinusitis expanding into orbit and retromaxillary fat-pad (). Whole body positron emission tomography (PET) showed hypermetabolic lesion in bilateral tonsil area with multiple lymph nodes in level II/III of neck and also in bilateral frontal, ethmoid, sphenoid, and maxillary sinuses ().\nIn the facial nerve conduction study, the compound muscle action potential (CMAP) amplitude of left facial nerve was decreased to 60% that of right side. Blink reflex test showed delayed ipsilateral R1 and R2, but normal contralateral R2 responses on both supraorbital nerve stimulations. These electrophysilogical findings were indicative of bilateral facial neuropathies, more severe in the left side.\nEndoscopic biopsy was performed twice due to failure to obtain pathologic confirmation at first biopsy. The first biopsy specimen was obtained from nasopharyeal wall layer through a punch biopsy under local anesthesia, but the second endoscopic biopsy was performed far deeper layer of retropharyngeal area under general anesthesia. Tissues obtained from the second biopsy showed granulomatous inflammation and vasculitis involving small sized blood vessels with ischemic necrosis and destruction of cartilage (). Period acid-Schiff, Gomori methenamine silver and acid-fast bacilli stains showed no histological evidence of fungal organism or mycobacterium. Immunostains for CD3 and CD56 had no abnormal infiltration of natural killer T cells. Ebstein-Barr virus-encoded RNA in situ hybridization resulted in negative findings.\nAll the clinical manifestations, laboratory and imaging studies indicated ANCA negative WG involving otolaryngeal space, upper respiratory tract and multiple lower cranial nerves. She was transferred to rhematology department and began therapy with steroid (methysol 1 mg/kg/day) and cyclophosphamide (2 mg/kg/day). Within the ten days of these treatments, the patient stated that her sufferings of headache and constitutional symptoms were prominently diminished. The hearing difficulty, which compelled her to wear a hearing aid, improved dramatically leaving no more need of the device. After three months of combination therapy of tapering steroid (prednisolone 0.6 mg/kg/day) and steady cyclophosphamide (2 mg/kg/day), the patient restored to almost her normal bulbar function and removed nasogastric tube for oral intake. Further repeated ANCA study was negative. Brain MRI was re-evaluated with a time interval of five months from the first MRI study, and showed persistent sinusitis of both frontal, ethmoid, sphenoid, and maxillary sinuses, in despite of marked improvement of clinical symptoms. Moreover, focal thickening with enhancement of the meninges around the area of tentorium cerebelli, inferior aspect of frontotemporal lobe adjacent to sinuses and nasopharynx were newly observed (). Clinical significance of these imaging findings was somewhat debatable because previous neurologic defects such as dysarthria, dysphagia, and hearing impairment had improved remarkably. However, re-evaluated CRP was still high as 5.75 mg/dL, which implied for further immunotherapy. Ultimately, potent immunotherapy consisting of high dose steroid (methysol 2 mg/kg/day) and cyclophosphamide (3 mg/kg/day) was performed. Three weeks later, the follow up CRP fall to 0.39 mg/dl and ESR normalized as 3 mm/hr. Taking only cyclophosphamide (0.25 mg/kg/day) after tapering steroid, she is still in a remission state for more than a year.