Clinical Neurology and Neurosurgery 173 (2018) 101–104 Contents lists available at ScienceDirect Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro Case Report Clinical diagnostic utility of contrast-enhanced three-dimensional ﬂuidattenuated inversion recovery for selection of brain biopsy sites in neurosarcoidosis: A case report T ⁎ Tatsuya Uenoa, , Rie Desakia, Tomoya Kona, Rie Hagaa, Jin-ichi Nunomuraa, Kensuke Murakamib, Masahiko Tomiyamaa a b Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan Department of Neurosurgery, Aomori Prefectural Central Hospital, Aomori, Japan A R T I C LE I N FO A B S T R A C T Keywords: Neurosarcoidosis Fluid-attenuated inversion recovery Three-dimensional image Contrast media Biopsy Neurosarcoidosis is diﬃcult to diagnose, because deﬁnite diagnosis requires detailed histology of the central nervous system. Three-dimensional contrast-enhanced ﬂuid-attenuated inversion recovery (CE-FLAIR) is more useful for detecting leptomeningeal lesions compared with 3D CE-T1 weighted imaging. However, the clinical diagnostic utility of 3D CE-FLAIR for neurosarcoidosis is unclear. We describe a case of a 46-year-old Japanese woman who was admitted to our department due to chronic headache with fever and diplopia. Using 3D CEFLAIR, we performed brain biopsy from right cerebellar lesion. The histological examination revealed typical non-caseating granulomas, indicating neurosarcoidosis. Our ﬁndings suggest that 3D CE-FLAIR may detect leptomeningeal lesions that are candidates for biopsy in chronic meningitis undetermined etiology. 1. Introduction 2. Case report Neurosarcoidosis is a rare neuroinﬂammatory granulomatous disease with various sequelae , and nervous system involvement occurs in about 5%–15% of patients with sarcoidosis . The diﬀerential diagnoses for neurosarcoidosis include tuberculosis, mycosis, lymphoma, leptomeningeal metastases, and vasculitis . Diagnosis is diﬃcult, and requires detailed central nervous system histology. Fluid-attenuated inversion recovery (FLAIR) imaging uses an inversion recovery pulse with an inversion time that nulls signal from the cerebrospinal ﬂuid (CSF). During blood-brain barrier breakdown, intravenous injection of gadolinium chelates leads to increased signal inside the CSF on FLAIR images . Leptomeningeal lesions caused by infective leptomeningitis and leptomeningeal carcinomatosis can be better detected on contrast-enhanced (CE) FLAIR than on CE T1weighted imaging . Therefore, CE-FLAIR is useful for assessing neoplasm- and infection-induced meningitis. However, the clinical diagnostic utility of CE-FLAIR for autoimmune leptomeningitis is unknown. We herein report a rare case of chronic leptomeningitis due to deﬁnite neurosarcoidosis, revealed via a brain biopsy conducted according to CE-FLAIR ﬁndings. The patient provided written informed consent for publication of this report. A 46-year-old Japanese woman was admitted because of chronic headache with fever and diplopia. Four months previously, she had developed occipital headache and appetite loss. Three months previously, she had developed intermittent fever (≥ 38 °C), diﬃculty walking, nausea, and diplopia. Her primary care physician prescribed loxoprofen for the headache and fever. Her medical history and family history were unremarkable. On admission, her vital signs and physical examination were normal. Neurological examination revealed bilateral optic disc redness, decreased deep tendon reﬂex of the right biceps, and impairment of tandem standing/walking, but no neck stiﬀness. The Bielschowsky head-tilt test was positive only for tilting toward the left, indicating left trochlear nerve palsy. Visual acuity was 20/16 bilaterally. Bilateral plantar responses were ﬂexor. All other ﬁndings were normal. The patient’s laboratory results are shown in Table 1 (negative for general inﬂammatory response, electrolyte abnormalities, autoantibodies, tumor marker elevation, and infection). Serum angiotensinconverting enzyme (ACE) and lysozyme concentrations were normal, whereas CSF analysis revealed pleocytosis, elevated ACE, elevated adenosine deaminase (ADA), and elevated β2-microglobulin. Oligoclonal bands were positive (two bands). Whole-body computed tomography showed mild mediastinal lymphadenopathy without pulmonary ⁎ Corresponding author at: Department of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori 030-8551, Japan. E-mail address: email@example.com (T. Ueno). https://doi.org/10.1016/j.clineuro.2018.08.006 Received 5 December 2017; Received in revised form 21 July 2018; Accepted 1 August 2018 Available online 04 August 2018 0303-8467/ © 2018 Elsevier B.V. All rights reserved. Clinical Neurology and Neurosurgery 173 (2018) 101–104 T. Ueno et al. Table 1 Laboratory data on admission. Hematology Serology WBC (/μL) RBC (×104/μL) Hb (g/dL) Platelet (×104/μL) ESR (mm/h) 3800 412 12.9 26.4 10 Biochemistry TP (g/dL) Alb (g/dL) T-Bil (mg/dL) AST (IU/L) ALT (IU/L) ALP (IU/L) γ-GTP (IU/L) LDH (IU/L) BUN (md/dl) Cr (md/dl) Calcium (md/dl) Glucose (md/dl) β2-MCG (md/dl) 7.3 4.5 1.11 18 24 140 33 183 11.8 0.49 9.7 124 1.2 ACE (IU/mL) Lysozyme (IU/mL) IgG (md/dl) IgG 4 (md/dl) sIL-2R (U/mL) CRP (md/dl) ANA anti-SS-A Ab anti-SS-B Ab anti-ds-DNA Ab anti-Sm Ab anti-RNP Ab MPO-ANCA PR3-ANCA Urinalysis Calcium (mg/day) CSF 15.5 7.2 1000 59.5 485 0.1 Negative Negative Negative Negative Negative Negative Negative Negative 277 Infection Pressure (mmH2O) Cell (cells/μL) Mononuclear (%) Glucose (md/dl) Protein (md/dl) ACE (IU/mL) ADA (U/L) IgG index β2-MCG (md/dl) OB Cytology 180 167 100 27 191 1.7 15.2 0.73 11.5 Positive Negative Tumor Marker CEA (ng/mL) AFP (ng/mL) CA19-9 (U/mL) SCC (U/mL) NSE (ng/mL) CYFRA (ng/mL) SLX (U/mL) Pro-GRP (pg/mL) 2.3 1.6 3.7 0.4 14.2 0.5 25.9 22.3 Bacterial culture in CSF RPR TPHA HIV Ab HSV DNA PCR in CSF EBV DNA PCR in CSF VZV DNA PCR in CSF β-D-glucan Aspergillus IgG Ab Aspergillus antigen Candida antigen Fungal culture in CSF Cryptococcal antigen in CSF Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Mycobacterium tuberculosis IGRA CSF PCR CSF culture Negative Negative Negative Laboratory data on admission. WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, TP: total protein, Alb: albumin, T-Bil: total bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, Cr: creatinine, ACE: angiotensin-converting enzyme, sIL-2R: soluble interleukin-2 receptor, CRP: C-reactive protein, Ig: immunoglobulin, ANA: antinuclear antibody, Ab: antibody, MPO-ANCA: myeloperoxidase-antineutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3-antineutrophil cytoplasmic antibody, ADA: adenosine deaminase, β2-MCG: beta2-microglobulin, OB: oligoclonal band, CEA: carcinoembryonic antigen, AFP: alpha-fetoprotein, CA19-9: carbohydrate antigen 19-9, SCC: squamous cell carcinoma antigen, NSE: neuron-speciﬁc enolase, CYFRA: cytokeratin 19 fragment, SLX: sialyl Lewis Xi antigen, Pro-GRP: pro-gastrinreleasing peptide, RPR: rapid plasma regain, TPHA: Treponema pallidum hemagglutination assay, HIV: human immunodeﬁciency virus, HSV: herpes simplex virus, EBV: Epstein-Barr virus, VZV: varicella zoster virus, IGRA: interferon-gamma release assay. Fig. 1. Brain magnetic resonance imaging. Unlike three-dimensional (3D) contrast-enhanced (CE)-Cube T1-weighted imaging (A–C), 3D CE-Cube FLAIR imaging (D–F) revealed possible bilateral cerebellar leptomeningeal lesions. Arrowheads indicate the biopsied leptomeningeal lesion. dimensional CE-FLAIR (Fig. 1D–F) more clearly visualized the cerebellar meninges lesions than did 3D CE-T1-weighted imaging (Fig. 1A–C). Furthermore, diﬀusion-weighted imaging revealed a hyperintense white matter lesion in the right hemisphere. The MRI abnormalities. Gallium-67 scintigraphy revealed no abnormities. Brain magnetic resonance imaging (MRI) 1 day after admission revealed gadolinium-enhancing meningeal lesions, primarily on the posterior cranial fossa, thereby indicating basal meningitis (Fig. 1A–F). Three102 Clinical Neurology and Neurosurgery 173 (2018) 101–104 T. Ueno et al. leptomeningeal lesions . Although most studies use 2D CE-FLAIR, Fukuoka et al.  showed that 3D CE-FLAIR better detected leptomeningeal lesions than did 3D CE-T1-weighted imaging. Three-dimensional FLAIR allows thinner-section images to be obtained in any plane, and minimizes the partial-volume eﬀect between small lesions and surrounding tissues. Additionally, 3D FLAIR suppresses CSF ﬂow artifacts. An in vitro ﬂow study revealed that 3D CE-FLAIR signal intensity in blood vessels is reduced by the high ﬂow velocity in the dural sinuses and cortical veins . Blood-brain barrier breakdown due to leptomeningeal disease results in leptomeningeal vessel leakage into the CSF. Therefore, 3D CE-FLAIR is more eﬃcacious than CE-T1-weighted imaging for detecting leptomeningeal lesions . Our ﬁndings indicate that 3D CE-FLAIR, but not 3D CE-T1-weighted imaging, can be used to detect cerebellar leptomeningeal lesions that are candidates for biopsy. Our patient had no clinical features of sarcoidosis in serum laboratory studies, but had elevated ACE, ADA, and β2-microglobulin in the CSF, consistent with neurosarcoidosis, Mycobacterium tuberculosis, and leptomeningeal metastasis. However, these laboratory studies could not reveal the cause of the chronic meningitis. Although our patient had mild mediastinal lymphadenopathy, mediastinal lymph node biopsy is rarely nonspeciﬁc. Furthermore, although non-caseating granulomas were shown by minor salivary gland biopsy in neurosarcoidosis with leptomeningeal inﬁltration , our patient had a severe headache, diplopia, meningitis-induced appetite loss, cerebral infarction, and no evidence of salivary gland involvement. Therefore, we performed a brain biopsy, but not a mediastinal lymph node biopsy, because a quick diagnosis was required. Deﬁnite and probable diagnoses of neurosarcoidosis were made in 25% and 59% of previous studies, respectively . Thus, a deﬁnite diagnosis is less frequent, probably because central nervous system histology is required and patients are often reluctant to undergo biopsy because of the risk of neurological sequelae and other complications. Our patient developed basal meningitis, making brain biopsy diﬃcult. Although 3D CE-T1weighted imaging did not reveal a cerebellar leptomeningeal lesion that was a good candidate for biopsy, we successfully detected a candidate using 3D CE-FLAIR, allowing brain biopsy from the right cerebellar surface. We thus deﬁnitively diagnosed neurosarcoidosis. In patients with chronic meningitis without diﬀuse leptomeningeal lesions, 3D CEFLAIR may be useful for detecting leptomeningeal lesions that carry a low risk for brain biopsy, even in chronic inﬂammatory disease. This could enable early diagnosis and treatment. According to a systematic review of neurosarcoidosis studies, ﬁrst line therapy consisting of corticosteroids was started in 434 of 539 patients (81%); subsequently, 24% of these patients were switched from ﬁrst line to second or third line therapy . The therapeutic strategy for neurosarcoidosis recommends steroid monotherapy for the ﬁrst 6–8 weeks . Therefore, we initially selected prednisolone monotherapy because additional immunosuppressive treatments are not necessarily required. However, the patient’s symptoms worsened with tapering of the prednisolone, and additional immunosuppressive treatment was required, as reported previously [1,2]. Fig. 2. Hematoxylin and eosin staining. Microscopic examination shows noncaseating granuloma consistent with sarcoidosis in the cerebellar leptomeninges. (A and B), Bar = 100 μm. protocol is detailed in the Supplementary Material. Gadolinium-enhanced spinal MRI showed diﬀuse spinal cord meningeal lesions. Based on the 3D CE-FLAIR ﬁndings, we performed an open brain biopsy of the right cerebellar lesion on day 16 post-admission. Histological examination revealed typical non-caseating granulomas (Fig. 2), with Grocott’s staining and acid-fast staining both being negative. The patient was ﬁnally diagnosed with neurosarcoidosis-induced basal meningitis. On day 20, we started steroid pulse therapy (methylprednisolone 1000 mg/day) for 3 days, followed by oral steroid therapy (prednisolone 50 mg/day). The patient’s headache, fever, and diplopia subsequently improved. On day 41, CSF analysis showed an improved leukocyte count, and improved protein, ACE, ADA, and β2-microglobulin levels. The gadolinium-enhancing lesion was moderately ameliorated, and the patient was discharged on day 72. After discharge, azathioprine (50 mg/day) was added because weakness and numbness developed in both lower extremities 1 month after reducing prednisolone to 30 mg/day. However, the azathioprine was discontinued because of nausea, and was exchanged for methotrexate (8 mg/week). Finally, the patient’s symptoms stabilized. 4. Conclusion Three-dimensional CE-FLAIR may be useful for both assessment of chronic meningitis and brain biopsy site selection. Conﬂicts of interest 3. Discussion None Ethical approval This case suggests that 3D CE-FLAIR may be useful for both assessing chronic meningitis and selecting brain biopsy sites. Three-dimensional CE-FLAIR may facilitate the detection of leptomeningeal lesions due to chronic inﬂammatory disease, including neurosarcoidosis. CE-FLAIR is more useful than CE-T1-weighted imaging for detecting All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/ or national research committee and with the 1964 Helsinki declaration 103 Clinical Neurology and Neurosurgery 173 (2018) 101–104 T. Ueno et al. and its later amendments or comparable ethical standards.  Acknowledgements  The authors would like to thank Dr. Tsugumi Sato and Dr. Hidekachi Kurotaki for performing the histological evaluation, and the staﬀ at the Department of Radiology, Aomori Prefectural Central Hospital.  Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.clineuro.2018.08.006.  References  D. Fritz, D. van de Beek, M.C. Brouwer, Clinical features, treatment and outcome in 104 neurosarcoidosis: systematic review and meta-analysis, BMC Neurol. 16 (1) (2016) 220. E. Hoitsma, C.G. Faber, M. Drent, O.P. Sharma, Neurosarcoidosis: a clinical dilemma, Lancet Neurol. 3 (7) (2004) 397–407. A. Bozzao, R. Floris, F. Fasoli, L.M. Fantozzi, C. Colonnese, G. Simonetti, Cerebrospinal ﬂuid changes after intravenous injection of gadolinium chelate: assessment by FLAIR MR imaging, Eur. Radiol. 13 (3) (2003) 592–597. H. 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