Rheumatol Int (2008) 28:1261–1264 DOI 10.1007/s00296-008-0599-3 C A S E RE P O RT Encephalic large arteries narrowness and peripheral neuropathy in a patient with adult-onset Still’s disease Hong Zhao · Yun Yuan · Yue Li · Chong-Wen Si · Geng-Shan Tian · Gui-Qiang Wang · Xue-Dong Yang Received: 9 January 2008 / Accepted: 29 April 2008 / Published online: 21 May 2008 © Springer-Verlag 2008 Abstract Adult-onset Still’s disease (AOSD) is a rare, systemic inXammatory disorder, characterized by spiking high fever, fever-associated evanescent rash, arthritis, myalgia, serositis and hepatosplenomegaly. White blood cell count, neutrophilic cell count, and serum ferritin level are markedly elevated in the active stage of the disease. Neurological complications of AOSD commonly were cranial nerve palsies, seizures, aseptic meningoencephalitis, peripheral neuropathy and Miller–Fisher syndrome. We report a previously healthy 60-year-old Chinese man who fulWlled the criteria for AOSD and had a combination of focal and peripheral neurological symptoms. Magnetic resonance angiography (MRA) and transcranial Doppler ultrasonography (TCD) showed narrowness of cerebral blood vessel. Peripheral neuropathy was conWrmed by electromyography and sural nerve biopsy. His generalized neuropathy and other symptoms were rapidly improved by receiving glucocorticoid therapy. We do a literature review about neurological manifestations observed in AOSD patients. H. Zhao (&) · C.-W. Si · G.-S. Tian · G.-Q. Wang Department of Infectious Diseases, Peking University First Hospital, 8, Xishiku Street, West District, 100034 Beijing, People’s Republic of China e-mail: minmin2001@gmail.com Y. Yuan Department of Neurology, Peking University First Hospital, 100034 Beijing, China Y. Li Beijing Di Tan Hospital, Beijing, China X.-D. Yang Department of Radiology, Peking University First Hospital, 100034 Beijing, China Keywords Adult-onset Still’s disease · Narrowness · Neurological manifestation Introduction Adult-onset Still’s disease (AOSD) is a rare, systemic inXammatory disorder characterized by spiking high fever, fever-associated evanescent rash, arthritis, myalgia, serositis and hepatosplenomegaly. White blood cell count, neutrophilic cell count, and serum ferritin level are markedly elevated in the active stage of the disease. Markers of autoimmune disorders [such as rheumatoid factor (RF), antinuclear antibody (ANA), and antineutrophilic cytoplasmic antibodies (ANCA)] are usually negative. Due to lack of speciWc tests, the diagnosis of AOSD is mainly based on clinical manifestations, as well as exclusion of other febrile polyarthritis [1, 2]. Neurological manifestations such as cranial nerve paresis, seizures, brainstem hemorrhage, peripheral neuropathy, meningoencephalitis, and pyramidal tract signs in AOSD have been described. We present a case with rapid progression of neurological manifestations with involvement of both the center and peripheral nerve system simultaneously. Transcranial Doppler ultrasonography (TCD) and magnetic resonance angiography (MRA) suggested a large cerebral blood artery lesion. Electromyography (EMG) and sural nerve biopsy showed axonal peripheral neuropathy. Case report A 60-year-old male farmer was admitted to the hospital in October 2006. His major complaints included fever (38– 39°C) for 5 months, polyarthritis, and exacerbation for 123 1262 1 week accompanied with weakness of left side limb, anarthria, and sensor weakness. He had a spiking fever for 5 months. The fever occurred from late afternoon to early morning. The joint pain, especially in the left shoulder, was associated with fever spikes. The joints looked physically normal but the function was limited due to the pain associated with movement. He was diagnosed with typhoid at the beginning of the illness based upon a positive Widal’s reaction (H 1:320, O 1:160). He was treated with antibiotics (levoXoxacin and cephalosporins) for 10 days with no improvement of symptoms. His temperature could reach normal when dexamethasone (5 mg) was applied. After stopping dexamethasone, the joint pain worsened with persistent, spiking high fever. He failed to respond to various antibiotics. One week before admission, high fever persisted all day with weakness of the limbs, especially the left side. Three days later, he was found to have bradylalia. His body temperature was 39.1°C, blood pressure 130/ 70 mmHg, pulse 98 beats per minute. There was no rash, oropharynx redness and enlargement, jaundice, lymph nodes enlargement, and goiter. Chest examination revealed a normal proWle. The spleen was palpable for 3 cm from the left costal edge with no tenderness. There were no signs of joints’ redness and arthrocele. Neurological examination showed that the left naso-labial groove became shallow, muscle strength of the left limbs was 3/5 and the right limbs was 4/5. Hypotonus was found in all extremities. The pain, tactile, and vibration sensory decreased in the left side. The deep tendon reXexes were absent. There were no pathological reXexes and stiV-neck. Laboratory tests revealed the following: the white blood cell count was 11.9–19.4 £ 109/L (neutrophil 85.7–93%), hemoglobin was 131 g/L, and platelet count was 312– 449 £ 109/L. Erythrocyte sedimentation rate (ESR) was 63–140 mm/h. C-reactive protein (CRP) was 268 mg/dL (normal <8 mg/dL). Alanine aminotransferase (ALT) was 48 IU/L, and aspartate aminotransferase (AST) was 46 IU/ L. Serum ferritin was higher than 1,500 ng/mL (normal 20– 362 ng/ml). Negative/normal tests included: blood culture 3£, Widal reaction, viral hepatitis (A, B, C, E), anti-cytomegalovirus-IgM, anti-EBV-IgM, Brucella agglutinin reaction, PPD, antinuclear antibodies, anti-double-stranded DNA antibodies, anti-streptolysis O titer, complement levels, rheumatoid factor, immunoglobin (A, M, G) level, ANCA, anti-proteinase-3 (anti-PR3), anti-myeloperoxidase (anti-MPO), anti-glomerular basement membrane (anti-GBM). The bone marrow revealed marked granulocytic hyperplasia and the culture was negative. The cerebrospinal Xuid (CSF) was normal. Type B ultrasound found calculi in his liver and right kidney. A heart ultrasound found no pericardiac eVusion and valve excrescence. The chest X-ray showed litter pleural eVusion. TCD revealed the narrowness of the initial part of the left internal carotid, 123 Rheumatol Int (2008) 28:1261–1264 the left subclavian artery, the right middle cerebral artery, and the right internal carotid, and the increased blood Xow rate of fundus artery. Head MRI showed many long-T2 signs in the radiating coronal of right hemisphere. Head MRA showed that the diameters of the horizontal part of bilateral middle cerebral artery were less uniform, particularly in the right side (Fig. 1). Electromyography showed that the sensory conduction velocity of right ulnar nerve, left median nerve, and left tibial nerve was decreased. The biopsy of the sural nerve showed signiWcant neuraxon lesion, accompanied with mild demyelination (Fig. 2). LevoXoxacin and penicillin G were given for 3 days after admission with no eVect. On the third day after administration, his tongue leaned to the left when extended, accompanied with anarthria; his muscular strength of the left limbs was 0/5 and the proximal of right limbs was 4/5, with distal as 3/5. Tendon reXexes disappeared. Sensory examination cannot be cooperated. He was diagnosed as AOSD and was treated with intravenous methylprednisolone 40 mg/day. His temperature declined to normal after 3 days. He could speak Xuently on the fourth day. His muscular strength gradually recovered and on the eighth day, the muscular strength of the left limbs was 4/5 while it was 5/5 in the right limbs. Arthralgia had disappeared. CRP was 39.1 mg/dL, ESR was 95 mm/h, serum ferritin was higher than 1,500 ng/mL. He was discharged and arranged for a clinical visit with a prescription of hydroprednisone 50 mg/ day. Hydroprednisone was tapered to 20 mg/day, 4 months later. He had no symptoms and signs. WBC count, ESR, Fig. 1 MRA of the patient showed that the diameters of the horizontal part of bilateral middle cerebral artery were less uniform, particularly in the right side Rheumatol Int (2008) 28:1261–1264 1263 Fig. 2 Sural nerve biopsy showed axonal degeneration (a, c), thinly myelinated axons (b), and a cluster of myelinization (d). Toluidine blue, original magniWcation £400 and CRP were normal. Serum ferritin was not tested. He stopped the drug by himself due to Wnancial reasons. Two weeks after his discontinuation, his body temperature rose to 38°C with reappeared arthalgia. There were no neurological manifestations before he started hydroprednisone at 60 mg/day again. He did no blood test this time. The temperature and arthalgia disappeared within 2 days. Discussion The patient showed clinical manifestations of high spiking fever, arthralgias, neutrophilic leucocytosis, splenomegaly, hepatic dysfunction, marked high serum ferrtin and negative ANA, RF, and ANCA. The diagnosis at discharge was AOSD, based upon the criteria proposed by Yamaguchi [3] and Fautrel [4]. In addition, satisfactory response to glucocorticoid therapy strongly supports the diagnosis. The prevalence of neurological manifestations in AOSD is approximately 7–12%. Peripheral neuropathy in patients with AOSD was not uncommon in previous case reports. There were other neural manifestations, such as cranial nerve palsies, seizures, aseptic meningoencephalitis, Miller–Fisher syndrome, and disseminated thrombotic microangiopathy in previous reports [5–11]. Neurological manifestations, which were an obvious trait in our patient, emerged 5 months after disease onset and worsened gradually. The cause of the hemiplegy in our patient was possibly the dissymmetrical narrowness in the encephalic large vessel that had been found by MRA and TCD. His peripheral neuropathy resulted from a nerve neuraxon lesion that was shown in the sural nerve biopsy and electrophysiology. All these neurological abnormities and other manifestations of AOSD were improved rapidly after receiving glucocorticoid treatment. The exact cause of the encephalic arteries narrowness in this patient remains unknown. The MRI showed no signs of encephaloma, hematoma, and atherosclerosis. It was hard to consider arteries constriction as the reason of narrowness because it was rapidly improved by glucocorticoid treatment. Aseptic inXammation was another possible cause for this patient’s encephalic arteries narrowness. It is easy to understand that dissymmetry symptoms rapidly improved by glucocorticoid treatment for its suppressing inXammatory eVect. There was no tangible evidence of large vessel vasculitis because we could not do brain biopsy. Our patient’s renal function, routine urine test, eosinophil granulocyte count, and serum IgE were all normal. Purpura was not found. ANCA, anti-PR3 and anti-MPO were negative. That meant that we had no direct evidence of small vessels vasculitis in this patient. ANCA-negative small-vessel vasculitis had been previously reported in AOSD patients. Tadej et al. [12] reported a 12-year-old girl with systemic juvenile idiopathic arthritis who developed nasal septum perforation 6.5 years after diagnosis. Skin biopsy revealed small-vessel neutrophilic vasculitis with ANCA being negative. The author considered that her nasal septum perforation was caused by vasculitis. The girl responded very well to a high dose of glucocorticoids. Yu et al. [13] studied skin and muscle 123 1264 biopsy of 41 AOSD patients with negative ANCA, antiMPO, and anti-PR3. Non-necrotizing vasculitis was observed in all 41 patients. Cellular immunity induced by T lymphocytes inWltration might be an important factor for pathogenesis of AOSD, as T lymphocytes inWltration, rather than immune deposits, is often observed in small vessel walls. In summary, we described a combination of focal central and peripheral neurological symptoms in a patient that fulWlls the criteria for AOSD. The good eYcacy of glucocorticoids and synchronous improvement in other symptoms deduced that his generalized neuropathy was one of the aspects of AOSD. Vascular involvement may be the cause of generalized neuropathy in this patient. Future research must be done in the mechanism of AOSD. Acknowledgments The authors are grateful to two anonymous reviewers for their critical reading of the manuscript and suggestions. References 1. Efthimiou P, Paik PK, Bielory L (2006) Diagnosis and management of adult onset Still’s disease. Ann Rheum Dis 65:564–572 2. Crispin JC, Martinez-Banos D, Alcocer-Varela J (2005) Adult-onset Still disease as the cause of fever of unknown origin. Medicine (Baltimore) 84:331–337 3. 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