Neurosurg Rev (2008) 31:447–450 DOI 10.1007/s10143-008-0149-1 CASE REPORT Possible involvement of interferon β in post-operative vasculitis restricted to the tumour bed: a case report Tatsuya Abe & Kenji Sugita & Masaki Morishige & Kouhei Ohnishi & Keisuke Ishii & Tohru Kamida & Takamitsu Hikawa & Minoru Fujiki & Hidenori Kobayashi & Kenji Kashima & Shigeo Yokoyama Received: 2 August 2007 / Revised: 2 January 2008 / Accepted: 4 May 2008 / Published online: 11 July 2008 # Springer-Verlag 2008 Abstract Cerebral vasculitis is a very rare complication after brain tumour surgery. We herein report a case and discuss the origins of this complication. A 52-year-old female was admitted because of motor aphasia due to a left frontal lobe brain tumour. The magnetic resonance imaging (MRI) study revealed a non-enhanced tumour. A partial resection of the tumour and the placement of an Ommaya’s reservoir were performed. The pathological diagnosis was an oligoastrocytoma. The patient recovered well without any neurological deficits. Post-operative radiotherapy and the intravenous injection of interferon β were performed. During these treatments, the patient showed a continued high fever. An MRI scan revealed multiple enhanced lesions in the residual tumour, thus raising suspicions about a post-operative infection. We therefore performed a tumour biopsy and the removal of the exogenous materials. The histopathological diagnosis was vasculitis in the residual tumour. The patient’s consciousness and neurological symptoms recovered quickly with the steroid treatment. Following the radiotherapy (50 Gy total), complete remission of the tumour was rapidly obtained and no recurrence was observed. Cerebral vasculitis confined to the tumour bed is an unusual complication; however, this special condition was of critical importance for a successful tumour regression in this patient. T. Abe (*) : K. Sugita : M. Morishige : K. Ohnishi : K. Ishii : T. Kamida : T. Hikawa : M. Fujiki : H. Kobayashi Department of Neurosurgery, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan e-mail: abet@med.oita-u.ac.jp K. Kashima : S. Yokoyama Department of Pathology, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan Keywords Brain tumour . Oligoastrocytoma . Vasculitis . Interferon β . Irradiation Introduction Primary vasculitis of the central nervous system (CNS) is a serious type of inflammatory angiitis that solely affects the CNS vessels in the absence of an overt systemic inflammatory process. Cerebral vasculitis is a very rare complication after a craniotomy. In this report, we describe the patient with a brain tumour presenting as a left frontal glioma. The post-operative vasculitis occurred in the tumour bulk during the radio-immunotherapy with interferon (INF) β. We herein present the case and discuss the origins of this complication. Case report A 52-year-old female was admitted to our hospital because of motor aphasia. On admission, she demonstrated both a motor aphasia and a right facial paralysis. A computed tomography scan revealed a left frontal tumour. A magnetic resonance imaging (MRI) study also showed a huge tumour in the left frontal lobe and basal ganglia. A T1-weighted image exhibited the low signal intensity of the tumour, and a T2-weighted image showed a high intensity. The borders between the tumour and the brain were not clear, and several cysts within the tumour, peritumoural edema and a midline shift were observed (Fig. 1a). A contrast-enhanced axial T1-weighted image showed a poorly enhanced tumour. A left frontal osteoplastic craniotomy under a general aenesthesia, a partial removal of the tumour, and the 448 Fig. 1 a A pre-operative Gd-enhanced T1-weighted MRI scan shows a tumour in the left frontal lobe. A mass effect and a midline shift are observed. The tumour is not enhanced. b A post-operative T2weighted MRI scan demonstrates the residual tumour. c A Gdenhanced T1-weighted imaging study shows the enhanced lesions in the residual tumour during a high fever. d At 2 months after the radiotherapy, the tumour shows complete remission placement of Ommaya’s reservoir were performed. Histologically, oligodendroglial and astroglial components were diffusely intermingled. A diffuse admixture of both a glial fibrillary acidic protein-positive astrocytoma and Olig2positive oligodendrocytes was observed. A fluorescent in situ hybridization study [11] showed somatic deletions on the short arm of chromosome 1 (loss of heterozygosity of 1p). The pathological diagnosis was an oligoastrocytoma (Fig. 2a) and the MIB-1 index was 3%. Post-operatively, the patient was treated with steroids to reduce the brain oedema for several post-operative days. She recovered well without any neurological deficits. Two weeks after the operation, the patient suffered from a herpes zoster virus infection of the left trigeminal nerve (V1) area. In addition to the viral dermatitis, propinibacterium acunes was detected by the bacterial culture, and, therefore, she was treated with acyclovir and antibiotics. Since the chemotherapy with the procarbazine, lomustine and vincristine regimens may affect immune suppression and possibly re-activate the infection, she selected a post-operative course of radiotherapy (2 Gy/ day, total of 50 Gy) and immunotherapy using INF-β (3× 106 U/day; Daiichi-Sankyo, Tokyo, Japan). When the patient received 18 Gy of radiotherapy, she received a third intravenous injection with INF-β. Thereafter, she showed a Neurosurg Rev (2008) 31:447–450 high fever (39–41°C). We investigated the cerebrospinal fluid (CSF) from the Ommaya’s reservoir to rule out an infection, but it was negative (13/3) at this point. We administrated the antibiotics and acyclovir again. However, these treatments were not effective. The intermittent high fever continued, and her decline in consciousness and motor aphasia became progressively more severe. Although the Creactive protein levels slightly increased, they normalized soon thereafter. The peripheral white blood cell (WBC) count was normal, but the cerebrospinal fluid examinations on the seventh day after the fever onset showed 123 WBCs of which 98% were lymphocytes, an abnormally high level of protein (5,164 mg/dl) and a low glucose level (26 mg/dl). A culture of the CSF and the serological examinations were all negative. Multiple enhanced lesions in the residual tumour, aggravated brain edema and a midline shift were detected by an MRI scan on the seventh day (Fig. 1c). We stopped the INF-β treatment and suspected the presence of a post-operative infection. We, therefore, performed a tumour biopsy and the removal of exogenous materials, such as the Ommaya’s reservoir, dura substitude (MVP®) and titanium burr hole clamp (craniofix®). A microscopic examination revealed a perivascular infiltration of both lymphocytes and histiocytes (Fig. 2b). However, no apparent neutrophil invasion was observed. A polymerase chain reaction (PCR) for the herpes simplex virus and the herpes (varicella) zoster virus was also negative in the excised brain tumour tissue. Two pathologists finally diagnosed the patient with postoperative cerebral vasculitis restricted to the field of the remnant tumour. We, therefore, administered prednisone (50 mg/day). Her consciousness thereafter gradually improved and she was able to speak again. She continued to take 2.5 mg prednisone daily by mouth. During the resumed radiotherapy, the tumour showed a shrinking. A total radiotherapy of 50 Gy was performed and more than a Fig. 2 a A photomicrograph of the tumour stained by haematoxylin and eosin shows an oligoastrocytoma. b The tumour biopsy tissue obtained at the second operation shows vasculitis (magnification, ×200) Neurosurg Rev (2008) 31:447–450 90% reduction of the tumour was observed. The follow-up MRI, which was performed 2 months after the radiotherapy, showed the complete remission of the tumour (Fig. 1d). The patient has been followed up for more than 2 years, and no signs of recurrence have been observed. Discussion Cerebral angiitis is an inflammation of the small arteries in the brain. Cerebral angiitis is a type of vasculitis in which an aberrant immune response results in the inflammation and destruction of the small arteries [7]. Frequently, a CNS vasculitis occurs in the context of a systemic vasculitis, systemic disease, an infection or a post-radiation vasculopathy. This disease is known as one symptom of an autoimmune disease [12]. We, therefore, examined the autoantibodies. However, the laboratory investigations demonstrated normal findings. The post-operative vasculitis in this case might have been triggered by either infections, including both viral and bacterial irradiation, a xenobiotic reaction to an exogenous material, or by the interferon β. The patient had suffered from herpes zoster and a septic dermatitis 2 weeks before the onset. A herpes zoster infection has been reported to cause angiitis of the central nervous system [9]. We suspected the presence of a post-operative infection due to the herpes virus. However, the PCR test for herpes infection was negative. Another possible mechanism of this complication is radiation-induced cerebral vasculitis [5]. However, such radiation vasculitis usually occurs at least several years after treatment with a low incidence of occurrence. Even though a xenobiotic reaction against Ommaya’s reservoir is also a possible cause of vasculitis, no evidence of an allergic reaction was observed in the tumour samples. The combined treatment with both anti-cancer agents and INF-β has been used in daily medical practice for the treatment of a malignant glioma in Japan [1]. The INF-β has a potent immune-modulating effect, although its mechanisms of action are still not completely understood. In addition to the common clinical side effects of INF-β, such as the flu-like symptoms, some infrequent rare but possible side effects are described, which include various immune reactions, e.g. a capillary leak syndrome and a thrombotic thrombocytopenic purpura [6]. Moreover, there is evidence of a worsening of an autoimmune disease under the INF treatment and, in particular, of vasculitis, as may be seen with lupus erythematosus [3, 4]. Bosche et al. [2] presented the case of a female patient with multiple sclerosis. After the introduction of the INF-β treatment, she showed a further progression of her neurological symptoms and finally suffered an ischaemic cerebral infarction due to a cerebral vasculitis. Watts [13] 449 also reported and reviewed the worsening of vasculitis and other autoimmune disease under the INF treatment. In particular, the induction of changes in the vascular endothelium by INF is discussed as a possible mechanism [3, 4, 10]. In this case, the patient received a third round of an intravenous injection with INF-β and thereafter showed a continued high fever. Many factors may be involved in an outbreak of cerebral vasculitis. However, it is highly possible that the INF-β triggered a hypersensitive response, thus resulting in vasculitis. The mechanism of vasculitis, which is restricted to the field of the remnant tumour, remains unclear. Pathological conditions, such as tumours, are known to damage the blood-brain barrier (BBB) and lead to an increase in the permeability of the BBB. The BBB differs from the peripheral microvascular endothelium due to the presence of tight junctions between the neighbouring endothelial cells. It is reported that a deficient BBB often forms in the presence of a brain tumour and that an endothelial cell dysfunction leads to the progression of the vascular disorders. Furthermore, INF-β enhances the major histocompatibility complex 1 molecule expression, with a local release of inflammatory cytokines and chemokines. These immune reactions might have induced the further progression of the vasculitis [13]. In this case, the increase in vascular permeability and the subsequent inflammatory responses by the vasculitis might contribute to the production of pathogenic cofactor responsible for the rapid tumour reduction. A biopsy of the brain tissue is reported to be the most definitive test, since it reveals any inflammation and the immune system activity which affects the small arteries of the brain. Lanthier et al. [7] recommended a brain biopsy of a radiologically affected area before initiating immune suppression in the patient with a suspected angiitis to rule out the presence of an intracranial infection or neoplasm. In this case, the patient showed a continued high fever, causing suspicion of either an intracranial infection or a tumour progression. Without performing such a biopsy, we could not make an accurate diagnosis. Untreated cerebral vasculitis inevitably progresses to death, often within a year of onset. The administration of a high dose corticosteroids is the mainstay treatment for this disease. Cyclophosphamide is also given as an immunosuppressive therapy. MacLaren et al. [8] divided cerebral vasculitis into both small- and middle-sized vessel disease. The small-sized vessel vasculitis was responsive to the immunosuppressive therapy, but it tended to relapse during the prolonged periods on the maintenance therapy or after the withdrawal of the treatment. In our case, the high dose prednisone treatment (50 mg/day), as the initial induction therapy, promoted the healing of the progressive vessel inflammation, while the low dose prednisone (2.5 mg/day) has also effectively prevented any relapses for more than 2 years. 450 Cerebral vasculitis is very rare complication after brain tumour surgery. However, the consideration of cerebral vasculitis should be included in the differential diagnosis in those cases presenting with an unusual progression of a tumour, because a timely diagnosis and an aggressive treatment are of critical importance for the successful recovery of such patients. Acknowledgements We thank Dr. Keisuke Ueki and Yoshifumi Okada (Dokkyo University School of Medicine) for the valuable discussions. References 1. 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Groothuis DR, Mikhael MA (1986) Focal cerebral vasculitis associated with circulating immune complexes and brain irradiation. Ann Neurol 19:590–592 6. Iyoda K, Kato M, Nakagawa T, Kakiuchi Y, Sugiyasu Y, Fujii E, Fujimoto K, Michida T, Kaneko A, Hayashi N, Yamamoto K, Kurosawa K, Ikeda M, Masuzawa M (1998) Thrombotic thrombocytopenic purpura developed suddenly during interferon treatment for chronic hepatitis C. J Gastroenterol 33:588–592 7. Lanthier S, Lortie A, Michaud J, Laxer R, Jay V, deVeber G (2001) Isolated angiitis of the CNS in children. Neurology 56:837–842 8. MacLaren K, Gillespie J, Shrestha S, Neary D, Ballardie FW (2005) Primary angiitis of the central nervous system: emerging variants. QJM 98:643–654 Neurosurg Rev (2008) 31:447–450 9. Picard O, Brunereau L, Pelosse B, Kerob D, Cabane J, Imbert JC (1997) Cerebral infarction associated with vasculitis due to varicella zoster virus in patients infected with the human immunodeficiency virus. Biomed Pharmacother 51:449–454 10. Schmidt S, Hertfelder HJ, von Spiegel T, Hering R, Harzheim M, Lassmann H, Deckert-Schluter M, Schlegel U (1999) Lethal capillary leak syndrome after a single administration of interferon beta-1b. Neurology 53:220–222 11. Ueki K (2005) Oligodendroglioma: impact of molecular biology on its definition, diagnosis and management. Neuropathology 25:247–253 12. Volcy M, Toro ME, Uribe CS, Toro G (2004) Primary angiitis of the central nervous system: report of five biopsy-confirmed cases from Colombia. J Neurol Sci 227:85–89 13. Watts RA (2000) Musculoskeletal and systemic reactions to biological therapeutic agents. Curr Opin Rheumatol 12:49–52 Comments Tomokatsu Hori, Tokyo, Japan This is an interesting report of rare case of possible involvement of interferon β in post-operative vasculitis. Particular in this case, Ommaya reservoir has been implanted at the time of tumour removal. This makes it a little difficult to interpret this vasculitis as involved by interferon β. In usual Japanese neurosurgical service, implantation of Ommaya reservoir is not routinely performed except for cases of malignant lymphoma. Anyway, this unusual complication is very rare, and the authors examined this patient thoroughly and it is worth to be reported. Nicholas C. Bambakidis, Phoenix, USA This is an interesting case report describing the development of vasculitis following the resection of a low grade glioma. It is unclear what the etiology of the vasculitis might be, although the authors propose that the etiology is the use of the interferon administered intravenously. Additionally, the authors note that they routinely follow resection with the placement of an Ommaya reservoir for analysis of cerebrospinal fluid and to prevent dissemination of tumour. At our institution, we do not routinely perform these procedures. This report describes an interesting case which must be considered when similar findings are observed in the future.