Neuro-inflammation

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Research paper

CLIPPERS and its mimics: evaluation of new criteria

for the diagnosis of CLIPPERS
Guillaume Taieb,‍ ‍ 1 Patricia Mulero,2 Dimitri Psimaras,3 Bob W van Oosten,4
Jörg D. Seebach,5 Romain Marignier,6 Fernando Pico,7,8 Valérie Rigau,9 Yuji Ueno,10
Claire Duflos,11 Vera Fominykh,12 Vincent Guiraud,13 Christine Lebrun-Frénay,14
Jean-Philippe Camdessanché,6,15 Philippe Kerschen,16 Guido Ahle,17 Nieves Téllez,18
Alex Rovira,2 Khe Hoang-Xuan,3 Jean Pelletier,19 Pierre Labauge,1 in cooperation with
the French CLIPPERS group

►► Additional material is Abstract mean age at onset is 50 years (range 13–86 years),
published online only. To view Objective  To evaluate the accuracy of the recently with male predominance (male to female ratio
please visit the journal online
(http://d​ x.​doi.o​ rg/​10.​1136/​ proposed diagnostic criteria for chronic lymphocytic 3:1). As mentioned in its acronym, CLIPPERS is
jnnp-​2018-​318957). inflammation with pontine perivascular enhancement defined by steroid-responsive symptomatic hind-
responsive to steroids (CLIPPERS). brain punctate and curvilinear enhancing lesions.
For numbered affiliations see Methods  We enrolled 42 patients with hindbrain These pontine and cerebellar enhancing lesions
end of article. could spread rostrally up to the juxtacortical areas,
punctate and/or linear enhancements (<3 mm in
diameter) and tested the CLIPPERS criteria. and caudally up to the conus. White and deep
Correspondence to
Dr Guillaume Taieb, Department Results After a median follow-up of 50 months (IQR grey matter are both involved, while the cortex
of Neurology, CHU Montpellier, 25–82), 13 out of 42 patients were CLIPPERS-mimics: is spared. Relapses usually occur in the absence
Hôpital Guy de Chauliac, systemic and central nervous system lymphomas of long-term steroid therapy, which explains its
Montpellier 34295, France; ​ (n=7), primary central nervous system angiitis (n=4) chronic course. Enhancing lesions seen on MRI are
taiebguillaume@g​ mail.​com related to perivascular lymphohistiocytic infiltrates
and autoimmune gliopathies (n=2). The sensitivity and
Received 7 June 2018 specificity of the CLIPPERS criteria were 93% and 69%, with no evidence of necrotising vasculitis, granu-
Revised 20 February 2019 respectively. Nodular enhancement (≥ ‍ 3‍  mm in diameter), loma, remote demyelinating lesion or lymphoma.
Accepted 10 April 2019 considered as a red flag in CLIPPERS criteria, was present Pittock and colleagues1 suggested that brain biopsy
in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 is not mandatory in the presence of other typical
patients with CLIPPERS, explaining the lack of sensitivity. CLIPPERS features and in the absence of differen-
Four out of 13 CLIPPERS-mimics who initially met the tial diagnosis on non-invasive investigations. Since
CLIPPERS criteria displayed red flags at the second its first description, well-characterised diseases such
attack with a median time of 5.5 months (min 3, max as multiple sclerosis and myelin oligodendrocyte
18), explaining the lack of specificity. One of these four glycoprotein (MOG) antibody-associated diseases
patients had antimyelin oligodendrocyte glycoprotein may mimic clinical and radiological CLIPPERS
antibodies, and the three remaining patients relapsed features.5 6 Furthermore, cases of primary angiitis
despite a daily dose of prednisone/prednisolone ≥ ‍ of the CNS (PACNS), primary CNS lymphoma
‍30 mg and a biopsy targeting atypical enhancing lesions (PCNSL) and CNS lymphomatoid granulomatosis
revealed a lymphoma. (CNS-LYG) initially presenting with all CLIPPERS
Conclusions  Our study highlights that (1) nodular features, including histological characteristics, have
enhancement should be considered more as an unusual been reported.7–9
finding than a red flag excluding the diagnosis of In 2017, Tobin and colleagues10 proposed a
CLIPPERS; (2) red flags may occur up to 18 months new set of criteria for the diagnosis of CLIPPERS.
after disease onset; (3) as opposed to CLIPPERS-mimics, However, these new criteria have not yet been eval-
no relapse occurs when the daily dose of prednisone/ uated, especially over a long period of follow-up.
prednisolone is ≥‍ ‍30 mg; and (4) brain biopsy should
target an atypical enhancing lesion when non-invasive Methods
investigations remain inconclusive. Patients and brain imaging
© Author(s) (or their We conducted an international retrospective study
employer(s)) 2019. No to evaluate the 2017 CLIPPERS criteria. Since
commercial re-use. See rights 2011, University Hospitals of Montpellier gathered
and permissions. Published
by BMJ. Introduction data of patients presenting with hindbrain punctate
CLIPPERS (the acronym for chronic lymphocytic and/or curvilinear gadolinium enhancements and
To cite: Taieb G, Mulero P, inflammation with pontine perivascular enhance- collected clinical, radiological and histological data.
Psimaras D, et al. J Neurol
ment responsive to steroids) is a chronic central Forty-two out of 62 patients presenting with hind-
Neurosurg Psychiatry Epub
ahead of print: [please nervous system (CNS) inflammatory disorder of brain perivascular gadolinium enhancements sugges-
include Day Month Year]. unknown origin.1 Since its first description in tive of CLIPPERS were enrolled (France (n=30),
doi:10.1136/jnnp-2018- 2010 by Pittock and colleagues,1 about 60 cases the Netherlands (n=5), Spain (n=4), Switzerland
318957 have been reported throughout the world.2–4 The (n=1), Luxembourg (n=1) and Russia (n=1)). The
Taieb G, et al. J Neurol Neurosurg Psychiatry 2019;0:1–12. doi:10.1136/jnnp-2018-318957 1
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serum was performed according to the method described by
Box 1  Investigations in patients referred for a suspicion Cobo-Calvo and colleagues,21 and detection of antiglial fibrillar
of CLIPPERS acidic protein (GFAP) alpha antibodies in the serum and cere-
brospinal fluid (CSF) was performed using cell-based assays
►► Routine blood tests (including C reactive protein level, serum
according to the method previously described by Fang and
protein electrophoresis), serum lactate deshydrogenase level colleagues.22 When stereotactic brain biopsy was performed,
and IgE level. histological sections were stained with H&E, Bielschowsky stain,
►► Serological tests for infections (HIV, hepatitis B virus, hepatitis
Perls’ iron stain, and the following antigens: CD20, CD3, CD4,
C virus, Epstein-Barr virus, Lyme and syphilis). CD8, granzyme B, CD68, CD 38, CD 138, CD1a, beta-amy-
►► Serological tests for connective tissue diseases (antinuclear
loid, neurofilament and glial fibrillar acid protein. A myelin stain
antibodies, (anti-double stranded DNA), extractable nuclear (Klüver-Barrera) and a proliferation marker (Ki-67) were also
antigens, rheumatoid factor, complement C3 and C4, used. In situ hybridisation studies were performed for Epstein-
lupus anticoagulant, anticardiolipin and antiphospholipid Barr virus early RNA-1.
antibodies), systemic vasculitis (antineutrophil cytoplasm The diagnosis of lymphoma was made according to the WHO
antibodies and cryoglobulinaemia), sarcoidosis (ACE), classification, and the diagnosis of PACNS was made according
demyelinating disorders (aquaporin-4 antibody and MOG- to the Calabrese and Mallek criteria (ie, presence of an acquired
IgG), antineuronal and antiganglioside antibodies (in 42/42 and otherwise unexplained neurological deficit, with the pres-
patients). ence of either classic angiographic or histopathological features
►► CSF analysis (in 42/42 patients) including flow cytometry
of angiitis within the CNS and no evidence of systemic vasculitis
and B cell and T cell receptor rearrangements in case of or any condition that could elicit the angiographic or patholog-
lymphocytic pleocytosis (in 11/42 patients). ical features).23 24
►► Bone marrow biopsy and aspiration (in 11/42 patients).
►► Whole body CT or PET scan (in 42/42 patients).
►► GFAP-alpha antibody in serum and CSF (2/42 patients, cases Initial and final diagnoses
1 and 7). At each attack during follow-up, patients were assigned in three
►► Electromyogram and nerve conduction studies (1/42 patients, categories according to the 2017 CLIPPERS criteria specified
case 1). in box 2: non-CLIPPERS (ie, patients did not meet the clinical,
radiological and/or histological criteria), probable CLIPPERS (ie,
CLIPPERS, chronic lymphocytic inflammation with pontine perivascular patients met the clinical and radiological criteria) and definite
enhancement responsive to steroids; CSF, cerebrospinal fluid; GFAP, glial CLIPPERS (ie, patients met the clinical, radiological and histo-
fibrillar acidic protein; MOG, myelin oligodendrocyte glycoprotein; PET,
logical criteria). The initial diagnosis was the diagnosis at first
positron emission tomography.
attack, and the final diagnosis was the diagnosis at the end of
follow-up.
20 remaining patients were excluded due to lack of data. Among
the 42 enrolled patients, including 33 male and 9 female, all had Data analysis
brainstem signs and/or symptoms. Seventeen out of 42 patients Sensitivity and specificity of the initial diagnosis (test proce-
have already been reported elsewhere, but none of them have been dure) were calculated, relatively to the final diagnosis (refer-
used to elaborate the 2017 CLIPPERS criteria.4 11–18 The median ence procedure). For this calculation, we pooled probable and
age of onset was 48.5 (IQR 41.25–56.75). All the patients of our definite CLIPPERS in the CLIPPERS category, because they are
study were assessed clinically and examined with a 1.5-Tesla or eligible to the same follow-up with no evidence of an alterna-
a 3-Tesla MRI. Brain MRIs were obtained using the following tive diagnosis on our ancillary investigations. The lack of histo-
sequences: precontrast and postcontrast T1-weighted images logical confirmation in probable CLIPPERS is due to the risk
(WI), T2WI, fluid-attenuated inversion recovery, T2*-weighted of the cerebral biopsy and no other consideration. Thus, we
gradient-echo images (T2*WI), diffusion-weighted imaging, had two groups of patients at each assessment: CLIPPERS and
apparent coefficient diffusion map (ADC), and magnetic reso- non-CLIPPERS.
nance angiography (MRA). Spinal MRIs were obtained using the We also identified red flags, by gathering all features of
following sequences: precontrast and postcontrast T1WI and patients, at all attacks. Each clinical, radiological and histological
T2WI. According to the radiological definitions, punctate gado- feature that did not match the CLIPPERS criteria was defined
linium enhancement (Gd+) is a dot-like enhancement with a as atypical. Atypical features only present in patients who were
diameter less than 3 mm, nodular Gd+ is a round homogeneous non-CLIPPERS at the final diagnosis were referred as red flag.
enhancement with a diameter ranging from 3 mm to 9 mm, and For this analysis, we named the non-CLIPPERS at the final diag-
large Gd+ has a diameter greater than 9 mm.11 19 Patchy (ie, nosis ‘CLIPPERS-mimics’.
cloudy) Gd+ is an ill-delimited enhancement. Brain, hindbrain The qualitative data are presented as number and the quanti-
and/or spinal cord ‘on fire’ is defined by linear Gd+ along the tative data are presented as median (IQR).
deep medullary veins, spreading from the ependymal surface to
the subpial areas without interruption.20 A brain CT scan was Results
systematically performed in the presence of T2* hypointensities Diagnostic values of the initial diagnosis
on brain MRI, and digital subtraction angiography (DSA) was Among the 42 patients, 11, 20 and 11 were, respectively, classi-
made when vascular involvement was present on MRI (ie, brain fied as non-CLIPPERS, probable CLIPPERS and definite CLIP-
infarction, haematoma and arterial narrowing on MRA). PERS at first attack (test procedure; figure 1, tables 1 and 2).
Patients (n=42) were followed during a median of 50 months
Assessment of alternative diagnoses (IQR 25–82). The median number of attacks per patient was 3
Investigations performed to exclude alternative diagnoses are (IQR 2–4). At the second attack, 2 out of 20 patients with prob-
specified in box 1. Detection of anti-MOG antibodies in the able CLIPPERS and 2 out of 11 patients with definite CLIPPERS
2 Taieb G, et al. J Neurol Neurosurg Psychiatry 2019;0:1–12. doi:10.1136/jnnp-2018-318957
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Patients moving from the probable or definite CLIPPERS
Box 2 Diagnostic criteria for CLIPPERS10
category at the initial diagnosis to the non-CLIPPERS
category at the final diagnosis
►► Clinical.
Concerning the two patients who fulfilled the 2017 criteria for
Subacute pontocerebellar dysfunction, with or without
probable CLIPPERS at the initial diagnosis (patients 10 and
other CNS symptoms such as cognitive dysfunction and
11), the final diagnoses were grade III CNS-LYG and MOG
myelopathy.
antibody-associated disease. Atypical clinical and MRI features
CNS symptoms responsive to corticosteroid therapy.
occurred at the second attack 4 and 7 months after disease onset,
Absence of peripheral nervous system disease.
respectively (table 1, figure 3). In the latter patient, anti-MOG
Lack of alternative better explanation for clinical
antibodies were only performed at the second attack, in the pres-
presentation.
ence of atypical findings.
►► MRI.
About the two patients who fulfilled the 2017 criteria for defi-
Homogeneous, gadolinium enhancing nodules without ring
nite CLIPPERS at the initial diagnosis (patients 12 and 13), the
enhancement or mass effect predominating in the pons and
final diagnoses were PCNSL. Atypical clinical and MRI features
cerebellum, measuring <3 mm in diameter.
occurred at the second attack 3 and 18 months after disease
Marked improvement in abnormal gadolinium enhancement
onset, respectively (table 1, figure 3).
with corticosteroid treatment.
Homogeneous T2 signal abnormality where the degree
of T2 does not significantly exceed the size of the area of Patients moving from the non-CLIPPERS category at the initial
postgadolinium enhancement. diagnosis to the probable or definite CLIPPERS category
Spinal cord lesions with similar T2 and gadolinium enhancing Two patients had spinal cord enhancing lesion extending from
lesions as above. the C1 to C2 level at their first attack (patients 20 and 33; table 2,
►► Neuropathology. figure 4). They were assigned to the non-CLIPPERS category
Dense lymphocytic inflammation with perivascular because the size of the spinal cord enhancing lesion exceeded
predominance and parenchymal diffuse infiltration; both 3 mm (Box 2). A nodular spinal cord enhancing lesion in both
white matter and grey matter could be involved. patients disappeared under steroid therapy and did not relapse
T cells predominating infiltration (CD4 > CD8) with variable during the follow-up (ie, 71 months with 2 further attacks in
macrophage components. patient 20 and 229 months with 3 further attacks in patient 33).
Absence of myelin loss or focal secondary myelin loss. At their second attack, patients 20 and 33 met the 2017 criteria
Lack of alternative better explanation for pathological for probable and definite CLIPPERS, respectively. At the end of
presentation. follow-up, clinical course, radiological features and investiga-
►► Definite CLIPPERS: patients fulfilling all clinical, radiological tions, and brain biopsy in patient 33 remained compatible with
and neuropathological criteria. the diagnosis of CLIPPERS in both patients.
►► Probable CLIPPERS: patients fulfilling all clinical and
radiological criteria without available neuropathology. Identification of red flags
CLIPPERS, chronic lymphocytic inflammation with pontine perivascular Clinical criteria in patients with CLIPPERS and CLIPPERS-mimic
enhancement responsive to steroids; CNS, central nervous system. All patients with CLIPPERS (n=29) met the clinical criteria
defined by steroid-responsive brainstem signs and symptoms,
without peripheral neuropathy, and no evidence of differen-
tial diagnosis. Conversely, 9 out of 13 patients with CLIP-
had atypical clinical and/or radiological features and were reas- PERS-mimic did not meet the clinical criteria, at their first (n=5)
signed to the non-CLIPPERS category. Conversely, atypical or at their second (n=4) attack. Aphasia was present in one
radiological findings disappeared in 2 out of 11 non-CLIPPERS patient with PACNS, clinical unresponsiveness to a high dose of
patients (n=13), leading to reclassification of each of them to steroids was seen in two patients with CNS-LYG and one patient
probable (n=19) and definite (n=10) CLIPPERS, respectively. with PCNSL, and axonal polyneuropathy was diagnosed in the
No other category changes were observed after the second attack patient presenting with an autoimmune GFAP astrocytopathy. As
(reference procedure; figure 1). The median time to reach the defined above, all clinical atypical features could be considered
definitive category was 11 months (min 3, max 18). Considering as clinical red flags. Investigations providing alternative diag-
that 6 out of 42 patients were misclassified at their first attack, nosis to CLIPPERS were anti-MOG and anti-GFAP antibodies
the sensitivity and specificity of the proposed 2017 criteria (n=2), DSA showing arterial stenosis (n=2) or multiple sulcal
were 93% and 69%, respectively. Figure 2 provides the MRI microaneurysms (n=1), and positron emission tomography
section of the hindbrain at the first evaluation in patients with (PET) scan-guided lymph node biopsy revealing Hodgkin’s
atypical MRI features during their disease course (ie, 13 CLIP- lymphoma (n=1) (tables 1 and 3).
PERS-mimics and 2 patients without alternative diagnosis to
CLIPPERS). MRI criteria in patients with CLIPPERS and CLIPPERS-mimic
Typical punctate enhancing lesion (as defined in the CLIPPERS
Description of alternative diagnoses at the final diagnosis criteria) is characterised by (1) its size (ie, <3 mm), (2) its shape
The 13 non-CLIPPERS patients, coined CLIPPERS-mimics, (ie, homogeneous and not ring-shaped), (3) its location (ie,
all had an alternative diagnosis: CNS lymphomas (n=6; 4 pontocerebellar and spinal cord), (4) its lack of mass effect, (5)
CNS-LYG, 2 PCNSL), systemic Hodgkin’s lymphoma (n=1), its response to steroids and (6) the presence of small foci of T2
PACNS (n=4), and glial-autoimmune diseases with seropos- hyperintensity in the corresponding area (Box 2). All patients
itivity for MOG (n=1) and GFAP-alpha (n=1) autoantibodies with CLIPPERS except two (n=27) met the MRI criteria. These
(table 1). Conversely, none of the patients with probable and two patients had cervical spinal cord nodular Gd+ (ie, ranging
definite CLIPPERS (n=29) had an alternative diagnosis (table 2). from 3 mm to 9 mm), but not during their relapses. Conversely,
Taieb G, et al. J Neurol Neurosurg Psychiatry 2019;0:1–12. doi:10.1136/jnnp-2018-318957 3
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Figure 1  Classification of patients according to the CLIPPERS criteria during the follow-up period. CLIPPERS, chronic lymphocytic inflammation with
pontine perivascular enhancement responsive to steroids.

all patients with CLIPPERS-mimic except one (n=12) did not and CNS small vessel angiitis (PACNS with normal DSA (n=1)),
meet the MRI criteria, at their first (n=8) or at their second respectively (table 3, online supplementary file).
(n=4) attack. Furthermore, once present, atypical MRI features The following are additional discriminating features between
relapsed in the case of new attacks. CLIPPERS and its mimics (table 3): CLIPPERS had a chronic
Atypical MRI features in CLIPPERS-mimics included (1) course with relapses in the absence of long-term steroid therapy
unusual size with large Gd+ and (2) non-homogeneous Gd+ or immunosuppressive drugs. When glucocorticoid therapy
with ring-shaped Gd+ and patchy Gd+. There were also (3) (ie, prednisone/prednisolone) was ≥ ‍ ‍30 mg/day, while relapses
unusual locations as subpial and cranial nerve Gd+, cortical occurred in 5 out of 13 patients with CLIPPERS-mimic, none
Gd+, subarachnoid round Gd+ related to microaneurysm, and of our patients with CLIPPERS relapsed. These five patients
diffuse linear Gd+ along the perivenular spaces, involving either had PACNS (n=1) and CNS lymphomas (CNS-LYG (n=2) and
the whole CNS (ie, ‘CNS on fire’), or limited to the brain and/ PCNSL (n=2)).
or hindbrain (‘brain on fire’ and ‘hindbrain on fire’); (4) mass Besides postcontrast T1WI and T2WI abnormalities, diffu-
effect; (5) lack of steroid responsiveness; and (6) large T2 hyper- sion restriction on ADC map, arterial stenosis on MRA and
intensities. Thus, all atypical MRI features except nodular Gd+ T2*WI hypointensities were only present in patients with
could be considered as MRI red flags (tables 1 and 3, figure 3). CLIPPERS-mimic. Arterial stenosis (confirmed on DSA) and
diffusion restriction were seen in PACNS (n=2), and T2*WI
Neuropathological criteria in patients with CLIPPERS and CLIPPERS- hypointensities were present in PACNS (n=3) but also in the
mimic patient with anti-MOG-related disease (n=1) and in the patient
All patients with CLIPPERS who had brain biopsy (n=11) presenting with Hodgkin’s lymphoma relapse (n=1). T2*WI
met the neuropathological criteria defined by perivascular and hypointensities were related to gadolinium enhancing lesions in
parenchymal lymphohistiocytic infiltrates, with predominance anti-MOG-related disease, Hodgkin’s lymphoma, and one out
of CD4 cells, in the absence of remote demyelination and no of three PACNS. In the other two patients with PACNS, T2*WI
evidence of alternative diagnosis. Conversely, all brain biopsies hypointensities matched with microcalcifications on CT scan
of patients with CLIPPERS-mimic which concerned MRI red and sulcal microaneurysms on DSA, respectively (figure 3).
flags did not meet the neuropathological criteria and revealed CLIPPERS criteria discriminated CLIPPERS from its mimics
an alternative diagnosis (n=7). In three of them, the first brain only at the second attack in 4 out of 13 patients with CLIP-
biopsy of typical punctate Gd+ showed characteristic histolog- PERS-mimic. In these patients, red flags occurred at the
ical findings, while the second brain biopsy of MRI red flags second attack with a median time of 5.5 months (min 3, max
revealed a lymphoma. Anti-CD20 staining associated with hybri- 18). Additional discriminating features described above were
disation for Epstein-Barr virus and Perls’ iron stain were useful also only present during the second attack: relapse occurred
to reveal CNS lymphomas (PCNSL (n=2), CNS-LYG (n=4)), despite glucocorticoid therapy ≥ ‍ 3
‍ 0 mg/day in three of them,
4 Taieb G, et al. J Neurol Neurosurg Psychiatry 2019;0:1–12. doi:10.1136/jnnp-2018-318957
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Table 1  Clinical characteristics, radiological findings, treatment and outcome concerning patients with CLIPPERS-mimic
Attacks CLIPPERS categories
(n); Atypical clinical and radiological mRS at Treatment failed Free of relapse along follow-up/time to
Age at onset/sex/ follow-up PCGd+ findings during attack (attack the last to prevent with or without reach definitive category
Case/Reference significant background (months) localisation number) visit relapse treatment (months)/final diagnosis
1 42/male/no 2 attacks; Brain, Axonal polyneuropathy, brain, 2 No Yes, 6 cycles of CYC, Non-CLIPPERS/NA/
33 months hindbrain, hindbrain and spinal cord ‘on fire’, then CT 4 mg/day + autoimmune GFAP
spinal cord no predominance in the pons, T2 AZT 150 mg/day astrocytopathy
hyperintensities wider than Gd+ (1, 2)
212 46/male/no 6 attacks; Brain, Brain ‘on fire’ involving predominantly 0 MTX Yes since 192 Non-CLIPPERS/NA/CNS-LYG
228 hindbrain, the corpus callosum (1–6), T2 months after AHSCT III† on BB
months spinal cord hyperintensities wider than Gd+ (6)
316 56/male/no 4 attacks; Brain, Margin of the pons + fifth nerve Gd+ 6 IVMP, NA Non-CLIPPERS/NA/CNS-LYG
15 months hindbrain (1, 2, 3); relapse while on 60 mg/day CT >60 mg/day, III† on second BB targeting
of CT with pontine ring-like Gd+ and RB, MTX the pons
necrotic centre (4)
4 38/male/MAS-related to 1 attack; Brain, Cerebellar hemisphere and frontal 1 No Yes without Non-CLIPPERS/NA/CNS-LYG
EBV at 37 9 months hindbrain patchy Gd+ (1) treatment since 4 I† on BB
months
5 75/female/no 2 attacks; Brain, Brain infarctions and multiple arterial 3 CT 14 mg/day Yes with CT 20 Non-CLIPPERS/NA/PACNS
16 months hindbrain stenosis (1, 2) mg/day on DSA
617 50/male/no 2 attacks; Brain, Cortical nodular Gd+ (1); relapse while 1 CT 60 mg/day, CYC Yes since 56 months Non-CLIPPERS/NA/PACNS on
61 months hindbrain, on 60 mg/day of CT with large pontine after RB, currently BB, DSA was normal
spinal cord Gd+ and T2* hypointense lesions CT 8 mg/day + AZT
matching with nodular and PCGd+ (2) 100 mg/day
7 60/female/no 5 attacks; Brain, Brain ‘on fire’ + cerebellar patchy Gd+ 4 No NA Non-CLIPPERS/NA/PACNS
40 months hindbrain + T2* hypointense lesions related to on DSA
calcifications matching with PCGd+
and arterial stenosis + brain infarction
with aphasia (1–5)
818 37/female/no 4 attacks; Brain, Sulci Gd+ and T2* hypointense lesions 2 AZT 150 mg/day Yes with MTX 15 Non-CLIPPERS/NA/PACNS
73 months hindbrain related to microaneurysms (1) mg/week on DSA
9 25/male/HL (IV*) at 21 5 attacks; Hindbrain, HL relapses + T2* hypointense lesions 0 AHSCT, several Yes with CT 10 Non-CLIPPERS/NA/HL relapse
120 spinal cord matching with PCGd+ (1, 2, 3, 4, 5) lines of mg/day II* on nodal biopsy
months chemotherapy
10 49/male/no 2 attacks; Brain, Relapse while on 80 mg/day of CT 6 CT 80 mg/day NA Probable CLIPPERS, then non-
4 months hindbrain with large pontine Gd+ and worsening CLIPPERS/4 months/CNS-LYG
despite IVMP (2) III† on BB
1122 44/male/no 2 attacks; Hindbrain T2 hyperintensities wider than Gd+, 1 AZT 100 mg/day Yes with CT 10 mg/ Probable CLIPPERS, then
46 months large pontine Gd+ around the fourth day + non-CLIPPERS/7 months/MOG-
ventricle, T2* hypointensities matching AZT 150 mg/day related disease
with PCGd+ (2)
1219 33/male/no 2 attacks; Hindbrain, Relapse while on 30 mg/day of CT with 6 IVMP, NA Definite CLIPPERS, then non-
9 months spinal cord pontine ring-like Gd+ and necrotic CT 60 mg/day, CLIPPERS/3 months/PCNSL on
centre, and worsening despite IVMP (2) PLEX, second BB
CYC
134 20 58/male/no 3 attacks; Brain, Relapse while 40 mg/day of CT, 6 CT 40 mg/day, NA Definite CLIPPERS, then non-
37 months hindbrain persistence of Gd+ under CT (2); large AZT 150 mg/day CLIPPERS/18 months/PCNSL on
pontine and corpus callosum Gd+ (3) second BB
*According to Ann Arbor staging system for lymphoma.
†LYG grading (I–III) according to the WHO classification.
AHSCT, autologous haematopoietic stem cell transplant; AZT, azathioprine; BB, brain biopsy;CLIPPERS, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; CNS, central
nervous system; CNS-LYG, CNS lymphomatoid granulomatosis; CT, corticosteroids; CYC, cyclophosphamide; DSA, digital subtraction angiography; EBV, Epstein-Barr virus;GFAP, glial fibrillar acidic protein; Gd+,
gadolinium enhancement; HL, Hodgkin's lymphoma; IVMP, intravenous methylprednisolone; MAS, macrophage activation syndrome;MOG, myelin oligodendrocyte glycoprotein; mRS, modified Rankin Scale; MTX,
methotrexate; NA, not applicable;PACNS, primary angiitis of the CNS; PCGd+, punctate and curvilinear gadolinium enhancement;PCNSL, primary CNS lymphoma; PLEX, plasma exchange; RB, rituximab.

and the presence of T2*WI hypointensities in the patient with assessed at the first attack, the sensitivity and specificity of this
Hodgkin’s lymphoma. The number of red flags in patients with new set of criteria were 93% and 69%, respectively. All atypical
CLIPPERS-mimic increased with the time of follow-up. At the clinical, MRI and neuropathological features were exclusively
end of follow-up, all patients with CLIPPERS-mimic but one associated with CLIPPERS-mimics and could be considered as
(n=12) had two or more red flags for CLIPPERS. Demographic red flags, except enhancing lesion ≥ ‍ 3
‍ mm in diameter. In our
data (ie, gender and age of onset) and CSF findings (ie, blood cell study, Gd+ ≥ 3
‍ ‍ mm is present in CLIPPERS-mimics (n=4) but
counts, protein levels and presence of oligoclonal bands) did not also in CLIPPERS (n=2), explaining why the sensitivity does
distinguish CLIPPERS from its mimics. not reach 100%. Tobin and colleagues10 described these MRI
findings in 7 out of 12 non-CLIPPERS and in 3 out of 23 CLIP-
Discussion PERS. Interestingly, by contrast to our patients with CLIPPERS,
We describe the most important cohort of patients presenting Gd+ ≥ ‍ ‍3 mm were larger (ie, >9 mm) and systematically associ-
with symptomatic hindbrain perivascular enhancements. At the ated with one or more additional red flags in our patients with
end of follow-up, about one-third of patients had an alternative CLIPPERS-mimic. Thus, to increase the sensitivity, nodular Gd+
diagnosis to CLIPPERS, including lymphomas, either systemic (ie, 3–9 mm) should be considered as an atypical MRI feature
or restricted to the CNS, autoimmune gliopathies, and PACNS more than an MRI red flag. In addition, while pons, cerebellum
(ie, CLIPPERS-mimics). Furthermore, the present study has and spinal cord are described as usual areas of punctate Gd+ in
evaluated the recently published CLIPPERS criteria at different CLIPPERS, white matter and deep grey matter in the supraten-
times and provides some clues to improve their accuracy.10 When torial compartment are omitted and should be added into the
Taieb G, et al. J Neurol Neurosurg Psychiatry 2019;0:1–12. doi:10.1136/jnnp-2018-318957 5
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Table 2  Clinical characteristics, radiological findings, treatment and outcome concerning patients with probable and definite CLIPPERS
CLIPPERS categories along
Attacks (n); mRS at Free of relapse follow-up/time to reach
Age at onset/sex/ follow-up PCGd+ Atypical findings during the last Treatment failed to with or without definitive category (months)/
Case/Reference significant background (months) localisation attack (attack number) visit prevent relapse treatment alternative diagnosis
14 32/male/no 1 attack; Brain, None 0 No Yes, without Probable CLIPPERS/NA/no
10 months hindbrain, treatment
spinal cord
15 63/male/no 1 attack; Hindbrain None 1 No Yes, without Probable CLIPPERS/NA/no
61 months treatment
16 60/male/no 1 attack; Hindbrain, None 0 No Yes, without Probable CLIPPERS/NA/no
77 months spinal cord treatment
17 38/female/NHL (I*) at 32 1 attack; Brain, None 0 No Yes, without Probable CLIPPERS/NA/no
2 months hindbrain, treatment
spinal cord
18 50/male/no 1 attack; Hindbrain, None 0 No MTX 7.5 mg/week Definite CLIPPERS/NA/no
17 months spinal cord
194 39/male/no 8 attacks; Brain, hindbrain No 1 CT 10 mg/day + CYC Yes, Probable CLIPPERS/NA/no
83 months CT 20 mg/day
204 32/male/no 3 attacks; Brain, Yes, confluent Gd+ 1 CT 10 mg/day MTX Yes, Non-CLIPPERS/probable
71 months hindbrain, extended from C1 to C2 7.5 mg/week MTX 15 mg/week CLIPPERS/15 months/no
spinal cord level (1), not seen at the
second attack
214 21 48/male/SAS 3 attacks; Hindbrain, No, lacunar midbrain 1 CT 7.5 mg/day Yes, Probable CLIPPERS/NA/no
67 months spinal cord infarction in relapse-free MTX 12.5 mg/week
period at 52 years old
224 62/male/no 3 attacks; Brain, hindbrain No 3 CT 7.5 mg/day Yes, Probable CLIPPERS/NA/no
27 months MTX 12.5 mg/week
234 53/female/no 5 attacks; Brain, hindbrain No 3 CT 7.5 mg/day + AZT Yes, since 20 Probable CLIPPERS/NA/no
108 months 150 mg/day months after 10
cycles of CYC
24 64/male/fibrosarcoma 2 attacks; Brain, No, MAS of unknown 1 No Yes, Probable CLIPPERS/NA/no
resection at 59 43 months hindbrain, origin during relapse-free CT 20 mg/day
spinal cord period (69 months after the
second attack)
25 46/male/postinfectious 3 attacks, Brain, No, APTM negative for 2 CT 17 mg/day, MTX Yes, CT 30 mg/day Probable CLIPPERS/NA/no
APTM at 45 23 months hindbrain, AQP4/MOG-Ab before 15 mg/week, + ongoing CYC
spinal cord disease onset MMF 2 g/day (fourth cycle)
26 49/male/no 2 attacks, Hindbrain, No 0 No Yes without Probable CLIPPERS/NA/no
34 months spinal cord treatment
27 66/male/cured prostate 2 attacks; Brain, No 1 No Yes, MTX 15 mg/ Probable CLIPPERS/NA/no
adenocarcinoma at 61 33 months hindbrain, week + CT 20
spinal cord mg/day
28 41/male/MGUS IgGK 2 attacks; Brain, No 1 No Yes, after weaning Probable CLIPPERS/NA/no
24 months hindbrain from CT, without
treatment since 3
months
29 57/male/no 4 attacks; Brain, No 2 Attack (n°4) 8 months Yes, after 10 cycles Probable CLIPPERS/NA/no
137 months hindbrain, after 4 cycles of CYC of CYC, no therapy
spinal cord since 47 months
30 45/male/SAS 4 attacks; Brain, No 3 Attacks (n°3, n°4) 5 Yes, after 9 cycles Probable CLIPPERS/NA/no
143 months hindbrain, months after 5 cycles of CYC, no therapy
spinal cord of CYC and 38 months since 59 months
after 10 cycles of CYC,
respectively
31 50/male/no 2 attacks; Hindbrain No 2 No Yes, no treatment Probable CLIPPERS/NA/no
54 months since 29 months
324 52/male/no 4 attacks; Hindbrain No 4 Attacks (n°3, n°4) Yes, CT 8 mg/week Definite CLIPPERS/NA/no
74 months during CYC and CT 7 + MTX 15 mg/
mg/day + MTX 15 mg/ week
week, respectively
334 46/male/no 4 attacks; Brain, Yes, confluent Gd+ 4  No Yes, no relapse Non-CLIPPERS/definite
229 months hindbrain, extended from C1 to C2 since 47 months CLIPPERS/18 months/no, including
spinal cord level (1), not seen during after 6 cycles of on BB
relapses CYC
344 13/male/no 12 attacks; Brain, No, pneumopathy with 6 No Yes, no relapse Definite CLIPPERS/NA/no
420 months hindbrain, fatal outcome 12 months during 12 months
spinal cord after RB after 1 course of RB
354 48/female/no 2 attacks; Hindbrain No 1 CT 10 mg/day Yes, CT 20 mg/ Definite CLIPPERS/NA/no
30 months day + MTX 15 mg/
week
364 46/female/no 3 attacks; Hindbrain No 3 No Yes, every 2 months Definite CLIPPERS/NA/no
63 months 1 cycle of CYC
alternating with 3 g
of IVMP

Continued

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Table 2  Continued
CLIPPERS categories along
Attacks (n); mRS at Free of relapse follow-up/time to reach
Age at onset/sex/ follow-up PCGd+ Atypical findings during the last Treatment failed to with or without definitive category (months)/
Case/Reference significant background (months) localisation attack (attack number) visit prevent relapse treatment alternative diagnosis
37 50/male/no 3 attacks; Brain, hindbrain No 2 AZT 100 mg/day Yes, AZT 150 mg/ Definite CLIPPERS/NA/no
96 months preceding by 9 cycles day
of CYC
38 72/male/no 4 attacks; Brain, No, initially misinterpreted 2 Chemotherapy by Yes, CT 25 mg/day Definite CLIPPERS/NA/no
22 months hindbrain, as PCNSL at the first MTX + temozolomide
spinal cord reading of the brain biopsy
39 33/male/no 2 attacks; Hindbrain, No 1 No Yes, AZT 150 mg/ Definite CLIPPERS/NA/no
111 months spinal cord day
40 55/male/no 5 attacks; Brain, No 3 Natalizumab, initial Yes, CT 10 mg/day Definite CLIPPERS/NA/no
60 months hindbrain, diagnosis was MS on alternating days
spinal cord
41 69/female/HIV under 2 attacks; Hindbrain No 1 No Yes without therapy Definite CLIPPERS/NA/no
HAART 36 months
42 43/female/no 4 attacks; Brain, No 4 Attack (n°4) 117 Yes, CT 20 mg/day Definite CLIPPERS/NA/no
129 months hindbrain, months after 6 cycles
spinal cord of CYC
*According to Ann Arbor staging system for lymphoma.
APTM, acute partial transverse myelitis; AQP4-Ab, aquaporin-4 antibody; AZT, azathioprine; BB, brain biopsy; CLIPPERS, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids;
CNS, central nervous system; CT, corticosteroids; CYC, cyclophosphamide; Gd+, gadolinium enhancement; HAART, highly active antiretroviral therapy; IVMP, intravenous methylprednisolone; MAS, macrophage
activation syndrome; MGUS, monoclonal gammopathy of undetermined significance; MMF, mycophenolate mofetil; MOG, myelin oligodendrocyte glycoprotein; mRS, modified Rankin Scale; MS, multiple sclerosis; MTX,
methotrexate; NA, not applicable; NHL, non-Hodgkin's lymphoma; PCGd+, punctate and curvilinear gadolinium enhancement; PCNSL, primary CNS lymphoma; RB, rituximab; SAS, sleep apnoea syndrome.

MRI criteria. Indeed, supratentorial punctate Gd+ is frequently Regarding the specificity, our results highlight that some MRI
reported in CLIPPERS and was observed in more than half of red flags and additional discriminating radiological features
our patients with CLIPPERS (table 2). may suggest a specific diagnosis. Ring-shaped Gd+ with mass

Figure 2  MRI section of the hindbrain at the first evaluation in patients presenting with atypical MRI features during their disease course, including 13
patients with CLIPPERS-mimics (cases 1–13) and 2 patients with CLIPPERS (cases 20 and 33). The final diagnosis for each patient is indicated between
brackets. CLIPPERS, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; CNS, central nervous system; CNS-LYG,
CNS lymphomatoid granulomatosis; GFAP, glial fibrillar acidic protein; HL, Hodgkin’s lymphoma; MOG, myelin oligodendrocyte glycoprotein-related disease;
PACNS, primary angiitis of the CNS; PCNSL, primary CNS lymphoma.
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Figure 3  Atypical radiological findings in CLIPPERS-mimics axial contrast T1WI showing large pontine round (A) or trident-shaped (B) Gd+, Gd+ lining
the pial surface of the pons with trigeminal nerve involvement (C), ring-like Gd+ with necrotic centre (D), cerebellar patchy Gd+ (E), and perivenular spaces
Gd+ with ‘hindbrain on fire’ (F). Contrast T1WI showed ‘brain on fire’ with perivenular spaces Gd+ on axial (G) and sagittal (H) sections. Axial contrast
T1WI showed cortical nodular (3–9 mm) Gd+ (I) matching with hypointense lesion on T2*WI (J), and sulcal Gd+ (arrowhead, K) matching with hypointense
lesion on T2*WI (arrowhead, L) related to microaneurysm on DSA (arrowhead, M). In two other patients, pontine hypointensities on T2*WI (N) matched with
microcalcifications on cranial CT scan (O), and DSA showed stenosis involving the first segment of the left anterior cerebral artery supplying both the anterior
cerebral artery territories (arrowhead, P), and bilateral frontal infarctions were seen on DWI (Q). The final diagnosis for each patient is indicated between
brackets. CLIPPERS, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; CNS, central nervous system; CNS-LYG,
CNS lymphomatoid granulomatosis; DSA, digital subtraction angiography; DWI, diffusion-weighted imaging; Gd+, gadolinium enhancement; GFAP, glial
fibrillar acidic protein; PACNS, primary angiitis of the CNS; T1WI, T1-weighted image; T2*WI, T2*-weighted gradient-echo image.

effect, pial and cranial nerve Gd+, and steroid-resistant Gd+ an autoimmune GFAP astrocytopathy.26 27 Concerning addi-
imply lymphoma (PCNSL or CNS-LYG). Sulcal and cortical tional discriminating radiological features, diffusion restriction
Gd+ are observed in PACNS, and diffuse linear Gd+ (‘CNS on on ADC map, arterial stenosis on MRA (confirmed by DSA) and
fire’) suggests autoimmune GFAP astrocytopathy, as described T2*WI hypointensities were only seen in CLIPPERS-mimics
in the literature.22 25 Before the knowledge of anti-GFAP anti- and suggest PACNS. To our knowledge, only one reported
bodies, some patients presenting with these similar characteristic case with clinical and radiological features of CLIPPERS (prob-
diffuse perivenular enhancements were considered as CLIP- able CLIPPERS according to the CLIPPERS criteria) had foci
PERS. Although speculative, these patients might actually have of T2*WI hypointensities matching with previous punctate
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Figure 4  Spinal cord MRI in CLIPPERS and its mimics. In two patients with CLIPPERS, sagittal postcontrast T1WI showed confluent enhancing lesions in
the cervical spinal cord that extended from C1 to C2 level (A, C), matching with T2WI hyperintensities with bright spotty lesions (B, D). In another patient
with CLIPPERS, punctate enhancing lesions were seen in the medulla oblongata and in the cervical spinal cord on sagittal postcontrast T1WI (E), together
with punctate T2WI hyperintensities in the corresponding areas (F). Sagittal postcontrast T1WI of the spinal cord revealed Gd+ along the ependymal canal
(ie, ‘spinal cord on fire’, G) matching with cervical and thoracic longitudinal extensive transverse myelitis on sagittal T2WI (H) in a patient with autoimmune
GFAP astrocytopathy. The final diagnosis for each patient is indicated between brackets. CLIPPERS, chronic lymphocytic inflammation with pontine
perivascular enhancement responsive to steroids; Gd+, gadolinium enhancement; GFAP, glial fibrillar acidic protein; T1WI, T1-weighted image; T2WI, T2-
weighted image.

enhancements.28 Thus, ADC map and MRA may be useful to the absence of a specific biomarker for CLIPPERS, a time crite-
detect CLIPPERS-mimics; however, it is probably too early to rion challenging the diagnosis of CLIPPERS at each new attack
consider T2*WI hypointensity as an MRI red flag. may help to increase the specificity of the CLIPPERS criteria.
Considering alternative diagnoses of CLIPPERS, in the pres- In keeping with our results, we propose a practical approach in
ence of red flags, non-invasive investigations should include the presence of symptomatic hindbrain punctate Gd+ (figure 5).
ADC map, T2*WI, MRA, DSA in case of arterial stenosis on The question of whether CLIPPERS is a disease or a syndrome
MRA, CSF analysis, whole body CT or PET scan, and anti-MOG remains unsolved. We believe that three hypotheses are conceiv-
and anti-GFAP antibodies. When non-invasive investigations able. First, CLIPPERS is a syndrome including prestage or unusual
are inconclusive, neuropathological examination should be presentation of well-determined diseases such as autoimmune
performed and target MRI red flags. Anti-CD20 staining asso- gliopathies, small vessels PACNS, systemic and restricted CNS
ciated with hybridisation for Epstein-Barr virus and Perls’ iron lymphomas, and probably other diseases. Second, CLIPPERS is
stain should be used to search for CNS lymphoma (Epstein-Barr a prelymphoma state, which may transform into a high-grade
virus-mediated or not) and PACNS, respectively. lymphoma with a similar or close pathophysiological process
CLIPPERS has a relapsing remitting course in the absence of described in lymphomatoid granulomatosis.29 Third, CLIPPERS
long-term steroid therapy or immunosuppressive drugs.1–4 10 could correspond to an unknown inflammatory disease. In this
Our results show that a daily dose of 30 mg of glucocorticoids issue, we cannot exclude that a subset of CLIPPERS could be trig-
or above prevents further relapses in patients with CLIPPERS gered by lymphomas. Interestingly, Tobin and coworkers10 did
but not in patients with CLIPPERS-mimic. Thus, the presence not exclude the diagnosis of CLIPPERS in a patient developing
of relapse despite a glucocorticoid therapy ≥‍ 3
‍ 0 mg/day might be a PCNSL and in patients with ongoing systemic lymphomas.10
considered as a clinical red flag for the diagnosis of CLIPPERS. However, considering that red flags arise relatively early in the
Finally, our study demonstrates that red flags could only occur course of the disease (at the first or the second attack), but also
at the second attack in CLIPPERS-mimics, with a median time that treatment guidelines exist for lymphomas in contrast to
of 5.5 months (min 3, max 18). The delay of red flag emergence CLIPPERS, we have chosen to keep lymphomas in the CLIP-
explains the lack of specificity of the CLIPPERS criteria. Our PERS-mimic category.30–32 We assume that our choice may partly
results underscore the necessity for re-evaluating the CLIPPERS explain the decrease in the specificity of the 2017 CLIPPERS
criteria at each new attack, especially in the first 18 months. In criteria. Recently, Blaabjerg and colleagues33 showed activation
Taieb G, et al. J Neurol Neurosurg Psychiatry 2019;0:1–12. doi:10.1136/jnnp-2018-318957 9
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Table 3  Discriminative findings between CLIPPERS and its mimics during attacks
CLIPPERS
CLIPPERS-mimics (n=13) (n=29)
Clinical red flags
Cortical signs. 1 PACNS. 0
Polyneuropathy. 1 GFAP. 0
Clinical steroid resistance. 3 (2 CNS-LYG, 1 PCNSL). 0
MRI red flags

4 (1 MOG-opathy, 1 PACNS, 1 CNS-LYG, 1 PCNSL). 0

2 (1 CNS-LYG, 1 PCNSL). 0
i. Size: large Gd+. 2 (1 PACNS, 1 CNS-LYG). 0
ii. Shape: ring-shaped Gd+.
–– Patchy Gd+.
iii. Location. 1 CNS-LYG. 0
–– Pial and cranial nerve Gd+. 1PACNS. 0
–– Cortical Gd+. 1 PACNS. 0
–– Sulcal Gd+ related to microaneurysms. 1 GFAP. 0
–– Diffuse linear Gd+ in the CNS (’CNS on fire’). 2 (1 PACNS, 1 CNS-LYG). 0
–– Hindbrain or brain linear Gd+ (‘hindbrain or brain on fire’). 0
iv. Mass effect. 3 (2 CNS-LYG, 1 PCNSL). 0
v. Steroid-resistant Gd+. 3 (2 CNS-LYG, 1 PCNSL). 0
vi. Large T2WI hyperintensities. 6 (1 MOG-opathy, 1 GFAP, 2 PACNS, 2 CNS-LYG).
Additional discriminating features
Relapse when daily dose of glucocorticoids 30 mg. 5 (1 PACNS, 2 CNS-LYG, 2 PCNSL). 0
Hypointense lesions on T2*WI. 5 (1 MOG-opathy, 3 PACNS, 1 Hodgkin’s lymphoma). 0
Vascular stenosis on MRA (confirmed on DSA). 2 PACNS. 0
Diffusion restriction on ADC map. 2 PACNS. 0
Biopsy of PCGd+ with histological CLIPPERS features. 3 (1 CNS-LYG, 2 PCNSL). 12
Biopsy of MRI red flags with alternative diagnosis. 7 (1 PACNS, 4 CNS-LYG, 2 PCNSL). 0
Red flags only at the second attack. 4 (MOG-opathy, 1 CNS-LYG, 2 PCNSL) 0
Red flags only after the second attack. 0 0
Number of red flags 2 at the end of follow-up. 12 (all except Hodgkin’s lymphoma). 0
ADC, apparent coefficient diffusion map; CLIPPERS, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; CNS, central nervous
system; CNS-LYG, CNS lymphomatoid granulomatosis; DSA, digital subtraction angiography; GFAP, glial fibrillar acidic protein; Gd+, gadolinium enhancement; MOG, myelin
oligodendrocyte glycoprotein; MRA, magnetic resonance angiography; PACNS, primary angiitis of the CNS; PCGd+, punctate and curvilinear gadolinium enhancement; PCNSL,
primary CNS lymphoma; T2WI, T2-weighted image; T2*WI, T2*-weighted gradient-echo image.

of complement in the pathophysiological process of CLIPPERS. should be added. These considerations may help to increase both
In addition, high levels of vascular cell adhesion protein-1 in sensitivity and specificity of the current CLIPPERS criteria.
CSF were present in their five patients with CLIPPERS in
contrast to patients with multiple sclerosis. These results should Author affiliations
1
be confirmed and tested in other CLIPPERS-mimics. Indeed, our Department of Neurology, University Hospital of Montpellier, Montpellier, France
2
Centre d’Esclerosi Mútiple de Catalunya, Hospital Universitari Vall d’Hebron,
results may be biased by several mechanisms. First, as our study Barcelona, Spain
is retrospective, all cases of brainstem punctate Gd+ may not 3
Department of Neurology, AP-HP Pitié-Salpêtrière, Service de Neurologie Mazarin,
have been referred to us. Nevertheless, we think that the missing Paris, France
4
cases were patients with a more obvious alternative diagnosis, Department of Neurology, VU University Medical Center, Amsterdam, Netherlands
5
and that our study population comprises probably the most Department of Immunology and Allergology, University Hospital of Genève, Geneva,
Switzerland
difficult cases. Thus, the sensitivity and specificity in our study 6
Centre de Recherche en Neurosciences de Lyon, INSERM U1028 and CNRS
would be reduced by this selection bias. Second, as differential UMR5292, Equipe FLUID, Lyon, France
diagnoses must be excluded before making a diagnosis of CLIP- 7
Department of Neurology, Centre Hospitalier de Versailles, Versailles, France
8
PERS, the diagnostic values of the proposed criteria will depend University of Versailles Saint Quentin en Yvelines et Paris Saclay, Versailles, France
9
Department of Neuropathology, University Hospital of Montpellier, Montpellier,
on the accuracy of the tests used to assess alternative diagnoses.
France
However, in our study population, final alternative diagnoses 10
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
were confirmed by many ways, which reduces the probability 11
Clinical Research and Epidemiology Unit, DIM, University Hospital of Montpellier,
of this particular bias. Third, although we did not observe the Montpellier, France
12
apparition of differential diagnoses after 18 months, we cannot Department of Neurology, University Hospital of Moscow, Moscow, Russia
13
Department of Neurology, University Hospital of Saint-Etienne, Saint-Etienne,
exclude that some alternative diagnoses would appear later. France
Pending specific biomarkers for CLIPPERS, the current criteria 14
Department of Neurology, Hospital of Nice, Nice, France
are necessary. However, as nodular enhancements could be seen 15
Department of Neurology, University Hospital of Sainte Anne, Paris, France
16
in CLIPPERS and its mimics, this MRI finding should be consid- Department of Neurology, University Hospital of Luxembourg, Luxembourg,
ered more as an unusual radiological feature than a radiological Luxembourg
17
Department of Neurology, Hospital of Colmar, Colmar, France
red flag. Finally, as clinical, MRI and neuropathological red flags 18
Department of Neurology, Hospital Clinico de Valladolid, Valladolid, Spain
could be initially absent in CLIPPERS-mimics, a time criterion 19
APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de
challenging the diagnosis of CLIPPERS along the disease course Neurologie, Marseille, France

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Figure 5  Practical approach of symptomatic hindbrain punctate gadolinium enhancements. CLIPPERS, chronic lymphocytic inflammation with pontine
perivascular enhancement responsive to steroids; CNS, central nervous system; CNS-LYG, CNS lymphomatoid granulomatosis; DSA, digital subtraction
angiography; Gd+, gadolinium enhancement; MRA, magnetic resonance angiography; PCNSL, primary CNS lymphoma; T2WI, T2-weighted image.

Acknowledgements  Benjamin Taieb helped design the figures, and Michael Drake Data availability statement  All data relevant to the study are included in the
helped edit the manuscript. article or uploaded as supplementary information.
Collaborators  Elsa Kaphan, Bertrand Audoin, MD (Department of Neurology,
APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, References
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Contributors  GT and PL had full access to all of the data in the study and take 9 Wang X, Huang D, Huang X, et al. Chronic lymphocytic inflammation with pontine
responsibility for the integrity of the data and the accuracy of the data analysis. perivascular enhancement responsive to steroids (CLIPPERS): a lymphocytic
Study concept and design: GT and PL. Acquisition, analysis or interpretation of reactive response of the central nervous system? A case report. J Neuroimmunol
data: all authors. Drafting the manuscript: GT, BWvO, FP, VG, CL, J-PC, GA, JP and 2017;305:68–71.
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Ethics approval  The Ethics Committee of Montpellier University Hospital Research
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approved the study, and individual consent was obtained from all patients.
Provenance and peer review  Not commissioned; externally peer reviewed.

Taieb G, et al. J Neurol Neurosurg Psychiatry 2019;0:1–12. doi:10.1136/jnnp-2018-318957 11

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12 Taieb G, et al. J Neurol Neurosurg Psychiatry 2019;0:1–12. doi:10.1136/jnnp-2018-318957