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doi: 10.2169/internalmedicine.8533-16
Intern Med Advance Publication
http://internmed.jp
【CASE REPORT 】
Chronic Lymphocytic Inflammation with Pontine
Perivascular Enhancement Responsive to Steroids
(CLIPPERS) with Limbic Encephalitis
Yasuyuki Ohta, Emi Nomura, Keiichiro Tsunoda, Toru Yamashita, Yoshiaki Takahashi,
Kota Sato, Mami Takemoto, Nozomi Hishikawa and Koji Abe
Abstract:
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIP-
PERS) is an inflammatory central nervous system disorder that mainly involves in the brainstem, basal gan-
glia and cerebellum. We herein report the case of a patient with CLIPPERS, which was diagnosed based on
the clinical and radiological features. After initially responded to steroid treatment, the patient developed lim-
bic encephalitis. The patient presented with memory disturbance, a delirious state and emotional inconti-
nence. A cerebrospinal fluid study revealed interleukin-6 elevation and enhanced bilateral hippocampal le-
sions were observed on MRI. The patient was successfully treated with methylprednisolone pulse therapy.
This is the first case of CLIPPERS with limbic encephalitis involving the bilateral hippocampus.
Key words: CLIPPERS, hippocampus, IL-6, limbic encephalitis, meningoencephalitis, MRI
(Intern Med Advance Publication)
(DOI: 10.2169/internalmedicine.8533-16)
Introduction
Chronic lymphocytic inflammation with pontine perivas-
cular enhancement responsive to steroids (CLIPPERS) is an
inflammatory central nervous system (CNS) disorder that
mainly involves in the brainstem, basal ganglia, cerebellum
and spinal cord, with T lymphocyte infiltration (1, 2). The
clinical characteristics of CLIPPERS emerge from CNS le-
sions, and usually include oculomotor abnormalities, facial
palsy, dysarthria, paraparesis and ataxia (1-4). Limbic en-
cephalitis with hippocampal lesions has not previously been
reported in CLIPPERS. We herein report the first case of
CLIPPERS with bilateral limbic encephalitis in a patient
who presented with memory disturbance and a delirious
state. The patient’s condition was successfully treated with
methylprednisolone pulse therapy.
Case Report
A 37-year-old woman was admitted to our hospital with
progressive numbness and muscle weakness on the left side
of her face, and left upper and lower extremities, which had
persisted for 9 days, and vertigo, which had persisted for 6
days. A neurological examination revealed vertical and lat-
eral gaze limitation, nystagmus in the bilateral eyes, dysar-
thria and dysphagia. She showed hyperreflexia in all ex-
tremities, and left Hoffmann, Babinski and Chaddock re-
flexes were all positive. She showed marked truncal and
mild limb ataxia. Hypoesthesia was observed in the left up-
per and lower extremities and left trunk. Her mini-mental
state examination (MMSE) score (30/30), Hasegawa demen-
tia score-revised (HDS-R; 30/30), frontal assessment battery
(FAB) score (18/18) and Montreal cognitive assessment
(MoCA) score (27/30) showed normal cognitive and frontal
cerebral functions (Table). Her geriatric depression scale
(GDS) score (6/15) suggested a depressive state, but the
apathy scale (AS; 16/42) and Abe’s Behavioral and Psycho-
logical Symptoms of Dementia (ABS) score (0/44) (5) were
normal.
Magnetic resonance imaging (MRI) revealed high inten-
sity spots in the midbrain, pons, bilateral middle cerebellar
Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan
Received: November 10, 2016; Accepted: February 15, 2017; Advance Publication by J-STAGE: August 21, 2017
Correspondence to Dr. Koji Abe, yasuyuki@okayama-u.ac.jp
Intern Med Advance Publication DOI: 10.2169/internalmedicine.8533-16
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Figure
1. Brain magnetic resonance image (MRI) on the first admission. Fluid-attenuated inver-
sion recovery (FLAIR) MRI showed hyperintense lesions in the midbrain (a, arrowhead), pons, bilat-
eral middle cerebellar peduncles, thalamus (b, arrowheads) and basal ganglia (c, arrows). Numerous
punctuate and curvilinear enhanced lesions were also observed in the same lesions on T1-weighted
imaging (WI) (d-f, arrowheads).
Table
1. Cognitive Functions and CSF Parameters.
1st admisson 2nd admission
(Normal range) Before treatment After treatment
Cognitive
function
MMSE 30 23 29
HDS-R 30 22 28
FAB 18 14 18
MoCA 27 21 26
Affective
function
GDS 6 9 6
AS 16 16 14
ABS 0 0 0
Serum SIL2R (122 - 496 U/mL) 245 249 ne
AQP4 (0 - 5 U/mL) <1.3 1.6 ne
CSF Cell (0 - 5 /μL) 11 12 4
Pro (10 - 40 mg/dL) 54 70 63
MBP(0 - 102 pg/mL) 67.4 144 ne
IL-6 (0 - 4 pg/mL) 119 96.8 3.3
OCB + + ne
ne: not examined
MMSE: mini-mental state examination, HDS-R: Hasegawa dementia score-revised, FAB: frontal assessment
battery, MoCA: Montreal cognitive assessment, GDS: geriatric depression scale, AS: apathy scale, ABS: Abe’s
behavioral and psychological symptoms of dementia, SIL2R: soluble IL-2 receptor, AQP-4: anti-aquaporin 4,
Pro: protein, MBP: myelin basic protein, IL-6: interleukin-6, OCB: oligoclonal bands
peduncles, thalamus and basal ganglia on T2-weighted and
fluid-attenuated inversion recovery (FLAIR ) images
(Fig. 1a-c, Supplementary material Fig. 1a, b, arrowheads,
arrows) with numerous punctuate and curvilinear enhance-
ments (Fig. 1d-f, arrowheads). Magnetic resonance angiogra-
phy revealed normal findings. Spine MRI revealed no cervi-
cal, thoracic or lumbar cord lesions. All laboratory and cere-
brospinal fluid (CSF) analyses to detect infection, malig-
nancy, sarcoidosis, collagen disease and neuromyelitis optica
were negative or normal-as were tests for antibodies
Intern Med Advance Publication DOI: 10.2169/internalmedicine.8533-16
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Figure
2. Representative brain fluorodeoxyglucose-position emission tomography (
18FDG-PET;
a-c) and methionine PET (11C-Met-PET; d-f) images, suggesting the absence of malignant lesions.
for parasites, antigens for fungi, a polymerase chain reac-
tion (PCR) for tuberculosis, tumor markers and soluble
interleukin (IL)-2 receptor (SIL2R), autoantibodies with
anti-ganglioside and anti-glutamate receptor antibodies,
angiotensin-converting enzyme (ACE), and anti-aquaporin 4
(AQP-4) antibodies. The patient’s human leukocyte antigen
type was A11, A33, B67 and B44. A CSF analysis revealed
that the patient’s level of myelin basic protein (MBP) was
normal (67.4 pg/mL), while her IL-6 level was markedly
elevated (119.0 pg/mL) (Table). The CSF cytology was class
II. The patient was positive for oligoclonal bands (OCB).
Whole body computed tomography, fluorodeoxyglucose-
position emission tomography (PET) and methionine PET
suggested no inflammatory or malignant lesions in the
whole body, including the brain (Fig. 2). The suspected di-
agnosis was CLIPPERS. All of her symptoms showed a
marked improvement following two courses of methylpred-
nisolone pulse therapy (1 g daily for 3 days). She was dis-
charged without additional oral prednisolone at 10 days after
the steroid treatment.
However, 3 weeks after discharge, she began to show pro-
gressive symptoms with headache, nausea, double vision,
numbness of the left face and memory disturbance, and was
thus admitted again at 30 days after the initial discharge. On
the second admission, left extra oculomotor muscle distur-
bance, muscle weakness and sensory disturbance of the left
face and left upper and lower extremities were observed.
Her deep tendon reflexes still displayed hyperreflexia in all
extremities without pathological reflexes. She developed
marked truncal ataxia again. Her MMSE and HDS-R scores
decreased to 23/30 and 22/30, and she showed immediate
and recent memory disturbance (Table). Her FAB and
MoCA scores also decreased to 14/18 and 21/30, respec-
tively. Her GDS score worsened to 9/15; however, her AS
score and ABS were the same as at the first admission (16/
42 and 0/44, respectively). She also showed delirium and
emotional incontinence.
MRI at the second admission revealed high intensity spots
in the midbrain, pons and bilateral middle cerebellar pedun-
cles and thalamus, as well as in bilateral hippocampus and
parahippocampal gyrus on a T2-weighted and FLAIR im-
ages (Fig. 3a, arrowheads, arrows) with enhancement in the
bilateral hippocampus and parahippocampal gyrus on T1-
weighted imaging (Fig. 3b, c, arrows). Magnetic resonance
spectroscopy (MRS) of the dorsal hippocampus showed bi-
lateral increases of choline (Cho) peaks (Fig. 4, arrowheads)
with normal levels of N-acetyl acetate (NAA) peaks (Fig. 4,
arrows), suggesting demyelination or necrosis, but not a tu-
mor. All of the laboratory and CSF measurements for malig-
nancy and sarcoidosis including tumor markers with SIL2R,
ACE or anti-glutamate receptor antibodies were again either
negative or normal. At the second admission, the patient’s
CSF cytology was class II and had not changed. A CSF
analysis, revealed MBP and IL-6 elevation (144.0 pg/mL
and 96.8 pg/mL, respectively), the patient was still positive
for OCB (Table).
The patient’s immediate and recent memory disturbance
and psychiatric symptoms were attributable to limbic en-
Intern Med Advance Publication DOI: 10.2169/internalmedicine.8533-16
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Figure
3. Brain magnetic resonance image (MRI) on the second admission, when the patient pre-
sented with memory disturbance and a delirious state. Fluid-attenuated inversion recovery (FLAIR)
MRI showed new hyperintense lesions in the bilateral hippocampus (a, arrowheads) and parahippo-
campal gyrus (a, arrows) with enhancement on T1-WI (b, c, arrows). After treatment with three
courses of methylprednisolone pulse therapy, the bilateral hippocampal and parahippocampal gyrus
lesions showed marked improvements (d) with the disappearance of enhancement (e, f).
cephalitis affecting the bilateral hippocampus, which was
closely associated with CLIPPERS. After treatment with
three courses of methylprednisolone pulse therapy, followed
by oral prednisolone (60 mg per day), all of the patient’s
symptoms subsided, including the memory disturbance and
psychiatric symptoms, and her cognitive function improved
to the normal range (Table). The patient’s pleocytosis, CSF
level of IL-6, and the multiple lesions with enhancement on
brain MRI, also greatly improved (Table, Fig. 3d-f). The
oral prednisolone dosage was tapered without recurrence.
Discussion
CLIPPERS is primarily diagnosed based on the clinical
and radiological features (1, 4). Clinically, CLIPPERS is
characterized by subacute symptomatology related to the
brainstem, cranial nerve or cerebellar involvement. In pa-
tients with CLIPPERS, MRI shows characteristic lesion pat-
terns including numerous punctate or nodular enhancing
‘peppering’ lesions in the pons, with or without lesions in
the brachium pontis or cerebellum. On our patient’s first ad-
mission, CLIPPERS was suspected based on the clinical and
Intern Med Advance Publication DOI: 10.2169/internalmedicine.8533-16
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Figure
4. Representative magnetic resonance spectroscopy (MRS) images of the dorsal hippocam-
pus. MRS showed bilateral increases of choline (Cho) peaks (a, b, arrowheads) with normal N-acetyl
acetate (NAA) peaks (a, b, arrows), suggesting demyelination or necrosis, but not tumors.
neurological findings (Fig. 1). Serum, CSF and FDG and
Met-PET (Fig. 2) studies excluded other neurological dis-
eases. OCB is often observed in CLIPPERS (1). Although
the patient was not examined for antibodies to myelin-
oligodendrocyte glycoprotein (MOG), a CLIPPERS patient
with longitudinally extensive transverse myelitis was re-
ported to have antibodies to MOG, suggesting that CLIP-
PERS is a syndrome rather than a distinct disease (6). The
clinical symptoms and multiple enhanced lesions observed
on MRI in the present case improved after methylpredniso-
lone pulse therapy, which was compatible with a diagnosis
of CLIPPERS (1, 4). The CSF IL-6 level is elevated in a
number of CNS disorders (7), but has never been reported
in CLIPPERS. Our patient showed marked CSF IL-6 eleva-
tion, which improved after methylprednisolone pulse ther-
apy, suggesting that the CSF IL-6 level could become a new
biomarker of disease activity in CLIPPERS.
Cognitive dysfunction, including dysexecutive syndrome
and amnestic deficits, are found in some patients with CLIP-
PERS (3, 4). However, limbic encephalitis combined with
hippocampal and parahippocampal gyrus lesions has never
been reported in CLIPPERS (8). On the patient’s second ad-
mission, she presented with immediate and recent memory
disturbance and psychiatric symptoms, which were accom-
panied by enhanced intensity of the bilateral hippocampus
and parahippocampal gyrus on MRI. These findings im-
proved following methylprednisolone pulse therapy (Fig. 3).
On MRI, the lesions of the midbrain, pons, thalamus, bilat-
eral hippocampus and parahippocampal gyrus were con-
nected, suggesting that the brainstem lesions might progress
to thalamus, hippocampus and parahippocampal gyrus.
Based on the serum, CSF and MRS findings, we considered
that the limbic encephalitis in this patient was associated
with CLIPPERS (Fig. 4). The results of these analyses did
not support the diagnosis of other neurological disorders.
Our case suggests that limbic encephalitis with CLIPPERS
responds well to high-dose steroid therapy.
The authors state that they have no Conflict of Interest (COI).
Financial Support
This work was partly supported by Grant-in-Aid for Scientific
Research (B) 2529320216, (C) 24591263 and Challenging Re-
search 24659651, and by Grants-Aid from the Research Commit-
tees (Nakashima K, Mizusawa H, Aoki M, Tsuji S, and Sakurai
T) from the Ministry of Health, Labour and Welfare of Japan.
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