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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 [1], and nervous system involvement occurs
in about 5%–15% of patients with sarcoidosis [2]. The differential diagnoses for neurosarcoidosis include tuberculosis, mycosis, lymphoma,
leptomeningeal metastases, and vasculitis [2]. 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 [3]. Leptomeningeal lesions caused by
infective leptomeningitis and leptomeningeal carcinomatosis can be
better detected on contrast-enhanced (CE) FLAIR than on CE T1weighted imaging [4]. 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: tatsuya_ueno@med.pref.aomori.jp (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 [4]. Although most studies use 2D CE-FLAIR,
Fukuoka et al. [4] 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 [4]. 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 [4]. 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 [5], 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 [1]. 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 [1]. The therapeutic strategy for
neurosarcoidosis recommends steroid monotherapy for the first 6–8
weeks [2]. 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.
[2]
Acknowledgements
[3]
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.
[4]
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.
[5]
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