Of all neoplastic lesions and across all medical specialties, Eosinophilic meningitis triggered by implanted Gliadel wafers: case report

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1 CASE REPORT J Neurosurg 126: , 2017 Eosinophilic meningitis triggered by implanted Gliadel wafers: case report Kiyotaka Saito, MD, 1 Kouji Yamasaki, MD, 1 Kiyotaka Yokogami, MD, PhD, 1 Asya Ivanova, MD, 1 Go Takeishi, MD, 1 Yuichiro Sato, MD, PhD, 2 and Hideo Takeshima, MD, PhD 1 1 Department of Neurosurgery, Division of Clinical Neuroscience, and 2 Department of Diagnostic Pathology, Miyazaki University Hospital, Faculty of Medicine, University of Miyazaki, Japan Although carmustine (Gliadel) wafers improve local tumor control and extend the overall survival in patients with malignant glioma, adverse effects have been documented. The authors report the first case of eosinophilic meningitis triggered by the placement of Gliadel wafers. A 61-year-old man with a history of alimentary allergy and glioblastoma in the right frontal lobe underwent resection followed by the implantation of Gliadel wafers. Three weeks later he suffered the sudden onset of headache, vomiting, and progressive consciousness disturbance. Computed tomography revealed enlargement of the ventricular system and subdural space on the side of the tumor. His CSF leukocyte count increased up to 3990 cells/mm 3 ; 95% of the cells were eosinophilic granulocytes (EGs), suggesting eosinophilic meningitis. Laboratory examination showed the patient to have various elevated allergy indicators. The administration of corticosteroids failed to improve his condition. Despite the insertion of a lumbar drain his symptoms failed to improve. He underwent a second surgical intervention to remove the Gliadel wafers. Histologically, EGs had assembled around the wafers. Eosinophilic infiltrate was present in the brain parenchyma around small vessels. After ventriculoperitoneal shunting his course was favorable. A drug lymphocyte stimulation test against the Gliadel wafers failed to demonstrate a positive reaction; polifeprosan, the wafer matrix without 1,3-bis(2-chloroethyl)-1-nitrosourea, yielded a positive reaction. These findings strongly suggest that although extremely rare, polifeprosan (the wafer matrix) can elicit an allergic reaction. When eosinophilic meningitis is suspected after the implantation of Gliadel wafers, their immediate removal should be considered. KEY WORDS eosinophilic meningitis; Gliadel wafer; high-grade glioma; oncology; infection Of all neoplastic lesions and across all medical specialties, high-grade gliomas, including glioblastoma, are some of the most difficult tumors to treat. The combination of maximal resection followed by radiation therapy and adjuvant chemotherapy (temozolomide) is the standard treatment leading to the best clinical course. However, the prognosis remains unfavorable and most patients succumb to the disease. Carmustine wafers (known by their trade name Gliadel) were approved by the US FDA and the European Medicines Agency for the local chemotherapy of malignant gliomas. 7 In Japan, Gliadel wafers were approved in 2012 as an adjuvant treatment for high-grade gliomas. The Gliadel wafer is an implant for intracranial use; it contains 7.7 mg of carmustine (1,3-bis[2-chloroethyl]-l-nitrosourea, BCNU) and the biodegradable copolymer polifeprosan 20, 7 which consists of polycarboxyphenoxypropane and sebacic acid in a 20:80 ratio. 4 Gliadel wafers, placed along the wall of the tumor resection cavity, release carmustine continuously with diffusion into the parenchyma. Peak release occurs in the first 2 weeks and controlled release continues for approximately 3 weeks. 2,7,14 Local chemotherapy with Gliadel wafers is well tolerated and offers a survival benefit to patients with malignant glioma. 2,5,11,12,18 However, adverse effects have been reported. Postoperative wound healing abnormalities including wound effusion and CSF leakage account for about 3% of adverse effects. 6,11 The incidence of cerebral edema was reported to be about 25%. 11,18 Intracranial infection and -hypertension, and cyst formation in the resection cavity, have also ABBREVIATIONS BCNU = 1,3-bis(2-chloroethyl)-1-nitrosourea; DLST = drug lymphocyte stimulation test; EG = eosinophilic granulocyte; IgE = immunoglobulin E; WBC = white blood cell. SUBMITTED November 27, ACCEPTED April 6, INCLUDE WHEN CITING Published online June 10, 2016; DOI: / JNS AANS, 2017 J Neurosurg Volume 126 June

2 K. Saito et al. been documented. In this report we present a patient with eosinophilic meningitis that developed after the implantation of Gliadel wafers. To the best of our knowledge, this is the first report of this rare complication. Case Report Patient History This 61-year-old man with a history of alimentary allergy to beef presented with consciousness disturbance and left hemiparesis. MRI demonstrated an intraaxial mass in the right frontal lobe with marked perifocal edema and midline shift. The lesion had a heterogeneous component and manifested ring-like enhancement after the administration of contrast medium (Fig. 1A and B). Preoperatively, high-grade glioma, most likely glioblastoma, was strongly suspected and he underwent resection. Because intraoperative histopathological study demonstrated the proliferation of astrocytic cells with high cellularity, suggesting high-grade glioma, 8 carmustine wafers (Gliadel) were placed. Before their placement, the resection cavity was completely separated from the ventricular system using oxicellulose and fibrin glue. Postoperative histopathological examination revealed the lesion to be glioblastoma. His clinical condition improved and MRI confirmed the gross-total removal of the contrast-enhanced lesion (Fig. 1C and D). In accordance with the Stupp protocol we delivered adjuvant chemotherapy with temozolomide and concomitant radiotherapy. Examination and Workup On postoperative Day 21, 2 days after the start of adjuvant therapy, the patient experienced new symptoms including headache, vomiting, and progressive consciousness disturbance. No fever or neck rigidity was present and no other clinical signs of meningeal irritation were noted. A brain CT scan obtained on Day 7 showed no ventricular enlargement (Fig. 2A). A blood test performed on postoperative Day 25 revealed no evident cause of his consciousness disturbance except for a slight elevation of the eosinophil count. The white blood cell (WBC) count was 7500/μl (reference range /μl) with eosinophils accounting for 7.7% (reference range 0.7% 7.0%), and C- reactive protein was 0.09 mg/dl (reference range < 0.14 mg/dl). His baseline kidney and liver function were normal. Considering the side effects of temozolomide, corticosteroids (dexamethasone 6.6 mg daily) were administered; they did not improve his symptoms. CT studies showed progressive ventricular enlargement and expansion of the right frontal subdural space (Fig. 2B and C). We considered the ventricular enlargement and symptoms to reflect secondary hydrocephalus. On postoperative Day 41 we performed emergency spinal drainage. CSF findings were suggestive of eosinophilic meningitis: the lumbar fluid was cloudy, protein was 224 mg/dl (reference range mg/dl), the WBC count was 3990 cells/ mm 3 (reference range 0 5/mm 3 ), glucose was 20 mg/dl (50% 66% serum, serum glucose 93 mg/dl), and 95% of the cells were eosinophilic granulocytes (EGs). The workup for eosinophilic meningitis by multiple-dot enzyme-linked immunosorbent assay ruled out parasitic FIG. 1. Axial Gd-enhanced preoperative (A and B) and postoperative (C and D) MR images. A and B: T1-weighted (A) and T2-weighted (B) images obtained at the time of admission to our institution. Note the mass in the right frontal lobe with heterogeneous Gd enhancement and strong perifocal edema around the tumor. C and D: T1-weighted (C) and T2- weighted (D) images confirming gross-total tumor resection and showing placement of the Gliadel wafers (arrows). infection. The serum b-d glucan level gave no evidence of fungal infection. The CSF culture was negative for bacteria and fungi. Cytologically there was no dissemination of the glioblastoma to the CSF. In blood tests immunoglobulin E (IgE) was IU/ml (reference range IU/ml); the eosinophil count continued to increase until insertion of the lumbar drain on Day 41 (Fig. 3). We diagnosed his eosinophilic meningitis to be attributable to an allergic reaction. An allergy component-specific IgE test showed that the patient was allergic to latex, cedar pollen, Japanese cypress, and kiwi fruit. A drug lymphocyte stimulation test (DLST) was negative for Gliadel wafers and temozolomide but positive for polifeprosan (procured from Eisai Co. Ltd.), the biodegradable copolymer used to control the release of carmustine from Gliadel wafers. Although the insertion of a lumbar drain markedly reduced the EG count, his condition did not improve significantly. Reoperation On postoperative Day 55 we performed a right frontal craniotomy for debridement and the removal of all 8 Gliadel wafers and the surrounding brain parenchyma. A catheter was introduced into the left ventricular horn for ventricular drainage. During the reoperation, the tumor resection cavity was noted to communicate with the right anterior horn of the lateral ventricle via a small fissure in 1784 J Neurosurg Volume 126 June 2017

3 Eosinophilic meningitis triggered by implanted Gliadel wafers FIG. 2. Axial CT images obtained 7 (A), 25 (B), and 53 days (C) after tumor resection. Gliadel wafers (arrows) are noted as high density. Note the progressive ventricular enlargement and expansion of the right frontal subdural space. the oxycellulose. No wafer material had dislocated or migrated into the anterior horn. Postoperative Course Histological examination of the Gliadel wafers and brain tissue showed the accumulation of EGs around the wafers from the side of the resection cavity. In addition, eosinophilic infiltrates were observed in brain tissue around small vessels (Fig. 4). After the removal of the Gliadel wafers the EG count in the CSF returned to the normal range (Fig. 3). His hydrocephalus failed to improve. On Day 98 after the first surgery, a right occipital ventriculoperitoneal shunt was placed, which resolved the condition. After adjuvant therapy the patient was deemed stable and admitted to a related hospital for rehabilitation. Discussion Glioblastoma is the most aggressive and challenging cancer to treat. Despite the implementation of the current standard treatment (known as the Stupp protocol ), the prognosis of patients with glioblastoma remains poor. Various additional molecular targeted therapies have been developed. Drugs available in Japan for the treatment of glioblastoma are limited to certain chemotherapeutic agents such as temozolomide and nimustine. Due to its efficacy, the use of Gliadel has increased in Japan. 1,6 The implantation of Gliadel is not recommended when intraoperative opening of the ventricular system is expected, because the wafers may dislocate and migrate into the ventricular system, leading to obstructive hydrocephalus. However, Bock et al. 3 reported that sealing the ventricular system with fibrinogen-coated collagen fleece effectively separates the resection cavity and prevents Gliadel wafers from dislocating and contaminating the ventricular system. Taking that into consideration, we chose to use Gliadel wafers as adjuvant therapy in this case despite the opening of the ventricular system. Due to the absence of meningeal irritation and general signs of inflammation, the diagnosis of eosinophilic meningitis was difficult in our patient. Follow-up CT studies showed only an expansion of the lateral ventricles and enlargement of the subdural space ipsilateral to the tumor resection cavity; these are considered to be nonspecific imaging findings. Study of the CSF obtained by lumbar drainage resulted in a diagnosis of eosinophilic meningitis. FIG. 3. Graph of eosinophil counts obtained in the course of hospitalization by blood and CSF tests. The blood eosinophil count increased markedly after postoperative Day 25 and started to decrease after the implantation of a lumbar drain on Day 41. After the Gliadel wafers were removed on postoperative Day 55 the CSF eosinophil count normalized. SP = spinal; TMZ = temozolomide; VP = ventriculoperitoneal; VT = ventricular. J Neurosurg Volume 126 June

4 K. Saito et al. FIG. 4. Photomicrographs showing pathological findings of the Gliadel wafers and brain tissue. A and B: EG aggregates are on the side of the resection cavity (arrow). They demarcate the Gliadel wafer. A significant number of eosinophilic and other inflammatory cells populate the area between necrotic and brain tissue (arrowhead). H&E. Original magnification 25 (A) and 200 (B). C and D: EGs are amassed around small blood vessels in the brain tissue (D); note the presence of sporadic tumor cells. H&E. Original magnification 100 (C) and 200 (D). The presence of more than 10 eosinophils per microliter in the CSF or CSF eosinophilia of at least 10% is defined as eosinophilic meningitis,15 a rare clinical condition. Its most common etiology is invasion of the CNS by parasites, especially Angiostrongylus cantonensis, Baylisascaris procyonis, and Gnathostoma spinigerum.15 Other eliciting factors are fungal infection, syphilis, and tuberculosis. Noninfectious etiologies have also been reported. For example, some patients with lymphoma developed eosinophilic meningitis after ventriculoperitoneal shunting and after the intraventricular administration of antibiotics or iophendylate dye. Different from eosinophilic meningitis attributable to infection, the noninfectious form does not tend to elicit the classic clinical signs of meningeal irritation such as nuchal rigidity.8,10,16,17 In our patient, besides the lack of signs of meningeal irritation, elevated allergy indicators led to a suspicion of an allergic reaction to the implanted Gliadel wafers. While our initial DLST results against Gliadel wafers per se failed to show a positive reaction, when we performed the test against the polifeprosan wafer matrix without BCNU the test was positive. We posit that our patient s allergic reaction to polifeprosan was veiled by the cell-killing effect of BCNU released by the wafers. Polifeprosan contains sebacic acid,4 which has been reported to be capable of inducing an allergic reaction. It is an organic compound that is a derivative of castor oil obtained by pressing the seeds of the castor oil plant Ricinus communis. Cases of allergic contact dermatitis attributable to exposure to sebacic acid compounds have been reported J Neurosurg Volume 126 June 2017 Our patient manifested late-onset elevation of the blood eosinophil count; it was recognized 25 days after the implantation of the Gliadel wafers at the first operation. We believe that this reflects the lasting duration and the released concentration of BCNU from the Gliadel wafers. Fung et al.9 reported that in the monkey brain, concentrations of carmustine (BCNU) were present in an area up to about 5 cm from the drug implant site for as long as 30 days. The time lag in the manifestation of elevated blood eosinophil levels may be attributable to the prolonged cytotoxicity of BCNU released by the Gliadel wafers and the accumulation of eosinophils might be inhibited early on. Taken together, our observations suggest that anticancer or immunosuppressant drugs may return false-negative DLST results due to cell destruction or the inhibition of immune-, and thus allergic reactions. Our patient responded to the removal of all 8 Gliadel wafers and subsequent ventriculoperitoneal shunting. Suspecting adverse effects of temozolomide, as an initial treatment we administered corticosteroids to alleviate his symptoms. However, because this did not markedly improve his level of consciousness, headache, and vomiting, we next performed CSF drainage via a lumbar drain. Although the EG count in his CSF and blood was markedly reduced (Fig. 3), it failed to return to the normal range. We posit that the EG count decreased before removal of the wafers on postoperative Day 55 because the antigen concentration in the CSF was markedly reduced after insertion of the lumbar drain on Day 41 (Fig. 3). However, as the tumor resection cavity communicated with the lat-

5 Eosinophilic meningitis triggered by implanted Gliadel wafers eral ventricle, the antigen was not removed completely. Based on his allergic diathesis and neurological status we decided to remove all Gliadel wafers and some of the surrounding brain tissue. Histological examination after the second operation revealed eosinophilic aggregates around the Gliadel wafers and the surrounding brain tissue, especially in the perivascular area. Although corticosteroids tend to improve eosinophilic meningitis, their administration had no significant beneficial effects. Only removal of the wafers and placement of a ventriculoperitoneal shunt resulted in his recovery. To the best our knowledge, this is the first report of a patient with eosinophilic meningitis elicited by the implantation of Gliadel wafers. Because of its rarity, eosinophilic meningitis attributable to Gliadel wafers is difficult to predict, thus it is very important to be aware of their potential adverse effects. Before their placement, special attention must be paid in patients with an allergic diathesis. If there is a strong suspicion of eosinophilic meningitis after the placement of Gliadel wafers we recommend their immediate removal and CSF drainage. References 1. Aoki T, Nishikawa R, Sugiyama K, Nonoguchi N, Kawabata N, Mishima K, et al: A multicenter phase I/II study of the BCNU implant (Gliadel wafer) for Japanese patients with malignant gliomas. Neurol Med Chir 54: , Attenello FJ, Mukherjee D, Datoo G, McGirt MJ, Bohan E, Weingart JD, et al: Use of Gliadel (BCNU) wafer in the surgical treatment of malignant glioma: a 10-year institutional experience. Ann Surg Oncol 15: , Bock HC, Cohnen J, Keric N, Kantelhardt SR, Giese A: Occlusion of surgical opening of the ventricular system with fibrinogen-coated collagen fleece: a case collection study. Acta Neurochir (Wien) 153: , Brem H, Mahaley MS Jr, Vick NA, Black KL, Schold SC Jr, Burger PC, et al: Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 74: , Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, et al: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345: , Chowdhary SA, Ryken T, Newton HB: Survival outcomes and safety of carmustine wafers in the treatment of highgrade gliomas: a meta-analysis. J Neurooncol 122: , Dörner L, Ulmer S, Rohr A, Mehdorn HM, Nabavi A: Space-occupying cyst development in the resection cavity of malignant gliomas following Gliadel implantation incidence, therapeutic strategies, and outcome. J Clin Neurosci 18: , Fulkerson DH, Boaz JC: Cerebrospinal fluid eosinophilia in children with ventricular shunts. J Neurosurg Pediatr 1: , Fung LK, Ewend MG, Sills A, Sipos EP, Thompson R, Watts M, et al: Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res 58: , Gavin PJ, Kazacos KR, Shulman ST: Baylisascariasis. Clin Microbiol Rev 18: , Giese A, Bock HC, Kantelhardt SR, Rohde V: Risk management in the treatment of malignant gliomas with BCNU wafer implants. Cent Eur Neurosurg 71: , Hart MG, Grant R, Garside R, Rogers G, Somerville M, Stein K: Chemotherapy wafers for high grade glioma. Cochrane Database Syst Rev 16:CD007294, Kimura M, Kawada A: Contact dermatitis due to diethyl sebacate. Contact Dermat 40:48 49, Kleinberg L: Polifeprosan 20, 3.85% carmustine slow-release wafer in malignant glioma: evidence for role in era of standard adjuvant temozolomide. Core Evid 7: , Lo Re V III, Gluckman SJ: Eosinophilic meningitis. Am J Med 114: , Ramirez-Avila L, Slome S, Schuster FL, Gavali S, Schantz PM, Sejvar J, et al: Eosinophilic meningitis due to Angiostrongylus and Gnathostoma species. Clin Infect Dis 48: , Tsai HC, Liu YC, Kunin CM, Lee SS, Chen YS, Lin HH, et al: Eosinophilic meningitis caused by Angiostrongylus cantonensis: report of 17 cases. Am J Med 111: , Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, et al: A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 5:79 88, 2003 Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author Contributions Conception and design: Saito, Takeshima. Acquisition of data: Yamasaki, Yokogami, Takeishi, Sato, Takeshima. Reviewed submitted version of manuscript: Saito, Ivanova, Takeshima. Approved the final version of the manuscript on behalf of all authors: Saito. Correspondence Kiyotaka Saito, Department of Neurosurgery, Division of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki , Japan. kiyotaka_saitou@med.miyazaki-u.ac.jp. J Neurosurg Volume 126 June