chronic lymphocytic inflammation with pontine perivascular - brain
TRANSCRIPT
BRAINA JOURNAL OF NEUROLOGY
Chronic lymphocytic inflammation withpontine perivascular enhancementresponsive to steroids (CLIPPERS)Sean J. Pittock,1,2 Jan Debruyne,3 Karl N. Krecke,4 Caterina Giannini,2 Jelle van den Ameele,3
Veerle De Herdt,3 Andrew McKeon,1,2 Robert D. Fealey,1 Brian G. Weinshenker,1
Allen J. Aksamit,1 Bruce R. Krueger,1 Elizabeth A. Shuster5 and B. Mark Keegan1
1 Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
2 Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
3 Department of Neurology, Ghent University Hospital, Ghent, B.9000, Belgium
4 Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
5 Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA
Correspondence to: Dr B. Mark Keegan,
Department of Neurology,
Mayo Clinic College of Medicine,
200 First St. SW Rochester,
MN 55905, USA
E-mail: [email protected]
The classification and pathological mechanisms of many central nervous system inflammatory diseases remain uncertain. In this
article we report eight patients with a clinically and radiologically distinct pontine-predominant encephalomyelitis we have
named ‘chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids’ (CLIPPERS). The pa-
tients were assessed clinically, radiologically and pathologically at Mayo Clinic, USA and Ghent University Hospital, Belgium
from 1999 to 2009. Median follow-up duration from clinical onset was 22 months (range 7–144 months). Patients underwent
extensive laboratory (serum and cerebrospinal fluid), radiological and pathological testing (conjunctival, transbronchial and brain
biopsies) to search for causes of an inflammatory central nervous system disorder. All eight patients (five female, three male)
presented with episodic diplopia or facial paresthesias with subsequent brainstem and occasionally myelopathic symptoms and
had a favourable initial response to high dose glucocorticosteroids. All patients had symmetric curvilinear gadolinium enhance-
ment peppering the pons and extending variably into the medulla, brachium pontis, cerebellum, midbrain and occasionally
spinal cord. Radiological improvement accompanied clinical response to glucocorticosteroids. Patients routinely worsened fol-
lowing glucocorticosteroid taper and required chronic glucocorticosteroid or other immunosuppressive therapy. Neuropathology
of biopsy material from four patients demonstrated white matter perivascular, predominantly T lymphocytic, infiltrate without
granulomas, infection, lymphoma or vasculitis. Chronic lymphocytic inflammation with pontine perivascular enhancement re-
sponsive to steroids is a definable, chronic inflammatory central nervous system disorder amenable to immunosuppressive
treatment. The T cell predominant inflammatory pathology in affected central nervous system lesions and the clinical and
radiological response to immunosuppressive therapies is consistent with an immune-mediated process.
Keywords: brain stem; neuroinflammation; encephalitis
Abbreviations: CLIPPERS = chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids
doi:10.1093/brain/awq164 Brain 2010: 133; 2626–2634 | 2626
Received February 15, 2010. Revised March 17, 2010. Accepted May 14, 2010. Advance Access publication July 17, 2010
� The Author (2010). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
Dow
nloaded from https://academ
ic.oup.com/brain/article/133/9/2626/352369 by guest on 13 February 2022
IntroductionThe immunopathogeneses of most inflammatory CNS disorders,
including those with and without accompanying demyelination,
remain poorly understood (Kalman, 2008). Advances in clinical,
radiological, serological and pathological evaluation have facili-
tated disease classification and differentiation of distinctive disease
entities (Kalman, 2008). Examples include: (i) revised diagnostic
criteria for multiple sclerosis (Polman et al., 2005; based on clinical
and radiological data and supportive paraclinical investigations
importantly with ‘no better explanation’); (ii) novel autoantibody
markers of autoimmune optic neuritis and myelitis [aquaporin-
4-immunoglobulin G (IgG) (Lennon et al., 2005; Wingerchuk
et al., 2007); collapsin response mediator protein (CRMP-5-IgG)
(Cross et al., 2003; Keegan et al., 2008)] and encephalitis [voltage
gated potassium channel (Tan et al., 2008) Ma (Dalmau et al.,
2004) and NMDA receptor antibodies (Dalmau et al., 2008)] and
(iii) immunopathological characterization of neuromyelitis optica
[i.e. loss of aquaporin-4 immunoreactivity, vasculocentric distribu-
tion of immunoglobulin deposition and complement activation
(Roemer et al., 2007)]. We report clinical, radiological and patho-
logical features of a treatable, brainstem-predominant, clinical and
radiological entity, which we term chronic lymphocytic inflamma-
tion with pontine perivascular enhancement responsive to steroids
(CLIPPERS).
Patients and methodsThe study was approved by Mayo Clinic Institutional Review Board.
The 8 patients were assessed clinically, radiologically and pathologically
at Mayo Clinic (n = 6) (Rochester, MN and Jacksonville, FL) and
at Ghent University Hospital (n = 2) (Ghent, Belgium) from 1999 to
2009. Patients underwent extensive laboratory (serum and cerebro-
spinal fluid), radiological and pathological testing (conjunctival,
transbronchial and brain biopsies) to search for causes of an inflam-
matory brainstem-predominant CNS disorder.
Autoimmune serological evaluationFive of six Mayo Clinic patients had serum (n = 4) or CSF (n = 2) avail-
able for neural autoantibody testing including: cation channel antibo-
dies [voltage-gated calcium channels (P/Q-type and N-type),
voltage-gated potassium channels and nicotinic acetylcholine receptors
(muscle-type and ganglionic-type)]; skeletal muscle striational antibo-
dies; anti-neuronal nuclear autoantibodies types 1, 2 and 3; Purkinje-
cell cytoplasmic autoantibodies types 1, 2 and Tr; anti-glial/neuronal
nuclear antibody type 1; collapsin response-mediator protein-5 IgG;
amphiphysin IgG and glutamic acid decarboxylase and thyroid auto-
antibodies. Testing for potential novel or unclassified neural-specific
autoantibodies was also performed blinded in a routine clinical labora-
tory setting using a composite 4 mm frozen section of mouse cerebel-
lum and brainstem, gut and kidney (standardized to detect
paraneoplastic autoimmunity) (Pittock et al., 2006). To minimize inter-
ference by non-neural-specific antibodies, sera were preabsorbed (at
1 : 240 dilution) with bovine liver powder. Fluorescein-conjugated goat
anti-human IgG (Southern Biotechnology; Birmingham, AL) detected
bound IgG.
ImagingBrain MRI was performed in 1.5 T MRI scanners, and images from
T1 (pre and post administration of gadolinium), T2, fluid attenuation
inversion recovery and proton density sequences were acquired.
A median of five MRIs (range 3–12) per patient were available for re-
view, spanning a median interval of six months (range 1–104 months)
and including pre and post therapy images. Vascular neuroimaging
was available for review in four patients, specifically magnetic reson-
ance angiography (n = 2) and conventional cerebral angiography
(n = 2). Spinal cord MRI exams with gadolinium were available for
five patients. All patients underwent chest CT imaging to address
the possibility of sarcoidosis, and three patients also had CT examin-
ation of abdomen and pelvis.
Pathological methodsThree patients underwent brain biopsy at Mayo Clinic (Patients 1,
2 and 5) and one at Ghent University Hospital (Patient 6). Tissue
slides were made from formalin fixed paraffin embedded brain speci-
mens and stained with haematoxylin and eosin, luxol fast blue coun-
terstained with periodic acid-Schiff and silver impregnations (modified
Bielschowsky). Immunohistochemical stains obtained included: glial fi-
brillary acid protein for astrocytes (clone GA5, 1/1,000; BioGenex),
CD68 (clone KP-1, 1/200 dilution; Dako) for microglia/macrophages,
CD3, CD1a, CD20, CD117 and placental alkaline phosphatase.
Results
Clinical characteristics
Symptoms
The clinical characteristics of the eight patients (median age at
onset 45.5 years; range 16–86 years; five females and three
males) are shown in the Table 1. All patients had subacute gait
ataxia and diplopia. Seven patients also developed dysarthria (pri-
marily ataxic but with some spastic features). An altered sensation
or tingling of the face or scalp was reported by five of eight pa-
tients. Other symptoms included non-specific dizziness, nausea,
dysgeusia, pseudobulbar affect (pathological crying or laughter),
tinnitus, tremor, nystagmus, paraparesis, sensory loss and spasti-
city. None had significant systemic symptoms nor weight loss,
fever, meningism, lymphadenopathy, polydipsia/polyuria or other
symptoms of hypothalamic dysfunction, uveitis or oral and/or
genital ulcers.
Neuroimaging
Brain MRI in all eight patients revealed a characteristic pattern of
punctate and curvilinear enhancement peppering the pons (Fig. 1)
and extending variably into the medulla, brachium pontis and
mid-brain. A subtler radiating pattern of similar enhancing lesions
extended into the basal ganglia and inferior cerebellar white
matter in three patients, corpus callosum in one patient and
spinal cord in three patients (Fig. 2). Lesions were typically less
numerous and smaller as distance from the pons increased. The
largest single punctate lesion was 9 mm in greatest dimension, but
most lesions measured between 1 and 3 mm. One patient pre-
sented with asymmetric enhancement in the left pons and right
CLIPPERS Brain 2010: 133; 2626–2634 | 2627
Dow
nloaded from https://academ
ic.oup.com/brain/article/133/9/2626/352369 by guest on 13 February 2022
Tab
le1
Cli
nic
alfe
ature
sof
eight
pat
ients
wit
hC
LIPPER
S
Pat
ient
Sex
Age
atonse
t(y
ears
)
Dura
tion
of
foll
ow
-up
from
onse
t(m
onth
s)
Sym
pto
ms
atonse
tSy
mpto
ms
duri
ng
illn
ess
evolu
tion
Loca
tion
of
per
ivas
cula
rco
ntr
ast
enhan
cem
ent
on
MR
I
CSF
abnorm
alit
ies
Tim
efr
om
onse
tto
bra
inbio
psy
(month
s)
Tim
efr
om
onse
tto
glu
coco
rtic
ost
eroid
ther
apy
(month
s)
Init
ial
dose
,ro
ute
and
resp
onse
toglu
coco
rtic
ost
eroid
s
Mai
nte
nan
cetr
eatm
ent
and
foll
ow
-up
1F
78
20
Ata
xia,
dip
lopia
Ata
xic
dys
arth
ria,
dip
lopia
,al
tere
dfa
cial
sensa
tion,
action
trem
or,
pse
udobulb
araf
fect
(pat
holo
gic
alcr
ying),
pal
atal
myo
clonus
Sym
met
ric
inm
edulla
,pons
(bra
chiu
mpontis)
,m
idbra
inan
dbas
algan
glia
10
white
blo
od
cells
,pro
tein"
,N
SE"
912
Pre
dnis
one
80
mg
dai
ly:
radio
logic
alim
pro
ve-
men
tw
ithout
mar
ked
clin
ical
impro
vem
ent
Ora
lpre
dnis
one,
reso
lution
of
gad
olin
ium
enhan
cing
lesi
ons
but
per
sist
ent
impai
rmen
t
2M
37
144
Epis
odic
faci
altinglin
gA
taxi
a,sp
astic
atax
icdys
arth
ria,
dip
lopia
,pse
udobulb
araf
fect
(pat
holo
gic
alla
ughte
r),
nau
sea,
diz
zines
s,neu
rogen
icbla
dder
Sym
met
ric
inm
edulla
,pons,
infe
rior
and
super
ior
cere
bel
lar
ped
uncl
es.
Upper
cerv
ical
spin
alco
rdin
volv
emen
t
Pro
tein"
,O
CB"
36
41
gIV
MP
dai
lyfo
r5
day
s:dra
mat
icim
pro
vem
ent
Initia
llyuse
dpuls
eIV
MP
and
pre
dnis
one
taper
for
firs
tfe
wye
ars
then
com
bin
edora
lpre
dnis
-one
and
met
hotr
exat
e.Pat
ient
now
stab
leon
met
hotr
exat
em
onoth
erap
y3
M47
7Ep
isodic
horizo
nta
ldip
lopia
Ata
xia,
atax
icdys
arth
ria,
dip
lopia
,al
tere
dsc
alp
and
limb
sensa
tion,
dys
phag
ia,
spel
ls(las
ting
seco
nds)
of
spee
char
rest
and
leg
stiffe
nin
g
Sym
met
ric
par
amid
line
mid
bra
in,
pons,
cere
bel
lar
ped
uncl
es
Pro
tein"
Bio
psy
not
done
51
gIV
MP
dai
lyfo
r5
day
s:m
oder
ate
impro
vem
ent
Ora
lpre
dnis
one
4F
86
25
Horizo
nta
ldip
lopia
Ata
xia,
atax
icdys
arth
ria,
dip
lopia
,al
tere
dfa
cial
sensa
tion,
diz
zines
s,in
term
itte
nt
lighth
eaded
nes
s
Sym
met
ric
mid
bra
in(lef
tce
rebra
lped
uncl
e),
pons
and
exte
ndin
gm
inim
ally
into
the
mid
dle
cere
bel
lar
ped
uncl
es
OC
B"
,N
SE"
Bio
psy
not
done
71
gIV
MP
dai
lyfo
r5
day
s:dra
mat
icim
pro
vem
ent
1g
IVM
Pev
ery
10-1
4day
s:die
d16
month
sla
ter
from
pulm
onar
yem
bolu
s
5M
70
22
Horizo
nta
ldip
lopia
Ata
xia,
atax
icdys
arth
ria,
alte
red
faci
alan
dlim
bse
nsa
tion,
nau
sea,
fatigue,
tinnitus,
tongue
wea
knes
s
Sym
met
ric
dors
alm
edulla
,pons
and
mid
bra
in
Pro
tein"
20
21
1g
IVM
Pdai
lyfo
r5
day
s:m
oder
ate
impro
vem
ent
Ora
lpre
dnis
one
60
mg
for
thre
em
onth
sta
per
ing
by
10
mg
ever
ytw
ow
eeks
6F
41
14
Dip
lopia
Ata
xia,
atax
icdys
arth
ria,
diz
zines
s.C
ereb
ella
rped
uncl
esright
gre
ater
than
left
,pons
Initia
l"O
CB
then
OC
Bnorm
aliz
edon
repea
tC
SF
13
1IV
MP;
reso
lution
within
2w
eeks
Initia
ted
mitoxa
ntr
one
inad
ditio
nto
glu
coco
rtic
ost
eroid
s.
7F
16
43
Dip
lopia
Ata
xia,
par
apar
esis
,dip
lopia
,ve
rtic
alupbea
tnys
tagm
us
Sym
met
ric
pons,
cere
bel
lum
,m
idbra
in.
Cer
vica
lan
dth
ora
cic
spin
alco
rdin
volv
emen
t
Norm
alBio
psy
not
done
11
gIV
MP
dai
lyfo
r5
day
sw
ith
ora
lpre
dnis
one
taper
for
2w
eeks
;co
mple
tere
solu
tion
of
bra
inst
emsy
mpto
ms
Wors
ened
follo
win
gglu
coco
rtic
ost
eroid
taper
.A
zath
ioprine
added
late
rto
glu
coco
rtic
ost
eroid
sdid
not
contr
olre
curr
ence
8F
44
7H
orizo
nta
ldip
lopia
Ata
xia,
dys
arth
ria,
dys
geu
sia,
par
apar
esis
,hyp
erac
usi
s
Sym
met
ric
pons,
cere
bel
lum
,m
idbra
in.
Cer
vica
lan
dth
ora
cic
spin
alco
rdin
volv
emen
t
Pro
tein"
Bio
psy
not
done
31
gIV
MP
dai
lyfo
r5
day
sw
ith
ora
lpre
dnis
one
taper
for
2w
eeks
;dra
mat
icim
pro
vem
ent
Wors
ened
follo
win
gpre
dnis
one
taper
s.R
einitia
ted
pre
dnis
one.
NSE
=neu
ron
spec
ific
enola
se;
OC
B-C
SF=
uniq
ue
olig
ocl
onal
ban
ds;
IVM
P=
intr
aven
ous
met
hyl
pre
dnis
olo
ne;
M=
mal
e;F
=fe
mal
e;"
=el
evat
ed.
2628 | Brain 2010: 133; 2626–2634 S. J. Pittock et al.
Dow
nloaded from https://academ
ic.oup.com/brain/article/133/9/2626/352369 by guest on 13 February 2022
mesencephalon that progressed over 6 months to become more
extensive and symmetric (Fig. 3). Cervical and thoracic spinal cord
MRI performed with and without contrast was normal in two
patients, and in three patients showed foci of punctate gadolinium
enhancement within the spinal cord (Fig. 2). There were no other
remote supratentorial parenchymal white or grey matter enhan-
cing lesions, no hypothalamic-pituitary involvement and no bony,
meningeal or pial lesions. There was patchy non-specific increased
T2 signal in the corresponding regions of gadolinium enhance-
ment. None of the lesions had significant mass effect.
Intracranial magnetic resonance angiography performed in two
patients and conventional angiography of neck and intracranial
vessels in two other patients were normal without angiographic
evidence of vasculitis.
Differential diagnosesDiagnoses considered included: neurosarcoidosis, CNS lymphoma,
lymphomatoid granulomatosis, CNS vasculitis, Bickerstaff brain-
stem encephalitis, paraneoplastic disease, chronic perivascular
infectious process (tuberculosis, neurosyphilis, Whipple’s disease,
parasitic infection), glioma, CNS demyelinating disease, CNS
Behcet’s and histiocytosis including Langerhans cell histiocytosis
and Erdheim-Chester disease.
Laboratory investigationsExtensive systemic work-up included: complete blood count; renal
and liver function (all values normal in eight patients tested); sedi-
mentation rate (normal in four tested); angiotensin converting
enzyme (one of seven patients tested had an elevated value of
74 U/l; normal range 7–46 U/l); anti-nuclear antibody [one of six
tested was seropositive (4.8 U; normal51 U; double stranded DNA
antibody was negative)]; antibodies against extractable nuclear
antigens [negative in three tested; Sjogren syndrome B (SSB) min-
imally elevated in one (value 1.1 U; normal 51.0 U who was
anti-nuclear antibody negative)]; and viral, fungal and syphilis serol-
ogies (negative in eight tested). Radiological investigations negative
in all patients were: CT chest (all eight patients), CT abdomen and
pelvis (three patients), whole body PET (two patients), testicular
ultrasound (two patients) and mammogram (two patients).
No neural specific IgGs were identified in the five patients
(sera n = 4, CSF n = 2) tested. Serum antibodies against the
aquaporin-4 water channel (neuromyelitis optica immunoglobulin
G; NMO-IgG) were assessed and negative in 4 Mayo Clinic
patients and one patient whose CSF was tested. One Belgian
patient’s serum (Patient 7) tested was NMO-IgG negative.
Pathological investigations other than brain biopsy included:
conjunctival biopsy in three patients and transbronchial lung
biopsy in 1, all of which yielded normal tissue.
Electrophysiological assessments done and normal were visual
evoked response (n = 2), brainstem auditory evoked response
(n = 2) and somatosensory evoked potentials (n = 1).
Cerebrospinal fluid analysesCSF abnormalities were found in four of eight patients
tested: mildly elevated protein in four (47–65 mg dl-1; normal
reference range 15–45 mg dl-1) and pleocytosis in 1 (10 white
blood cells ul�1, 98% lymphocytes). Elevated unique CSF oligoclo-
nal bands were found in three of six tested, including one patient
whose electrophoretic pattern reverted to normal. CSF cytology
Figure 1 Characteristic pontine-predominant MRI characteristics of CLIPPERS syndrome. MRI brain with gadolinium showing foci of
pontine enhancement with a curvilinear pattern highly suggestive of a perivascular distribution in all eight patients.
CLIPPERS Brain 2010: 133; 2626–2634 | 2629
Dow
nloaded from https://academ
ic.oup.com/brain/article/133/9/2626/352369 by guest on 13 February 2022
with flow cytometry was negative for malignant cells in all eight
patients. Fungal cultures (7) and Tropheryma whippelii polymer-
ase chain reaction (2) were also negative.
NeuropathologySites chosen for brain biopsies in four of eight patients were the
pons in one and cerebellum in three. The biopsy findings were
similar in each case and revealed a marked lymphocytic infiltrate
in the white matter with perivascular predominance, but also a
more diffuse parenchymal inflammatory infiltrate (Fig. 4). The
lymphocytic infiltrate was composed predominantly of CD3 react-
ive T lymphocytes and some CD20 positive B lymphocytes. CD68
positive histiocytes and activated microglia were present in mod-
erate number. Myelin was intact. Special stains for fungi
and mycobacteria (Grocott methenamine silver and auramine
rhodamine) were negative. Characteristic findings of sarcoidosis,
histiocytosis, lymphoma, lymphomatoid granulomatosis, multiple
sclerosis or other diseases were not found.
TreatmentAll patients were treated initially with glucocorticosteroids [intra-
venous methylprednisolone (1 g daily for 5 days) in seven and oral
prednisone (80 mg daily) in one]. The median time from symptom
onset to glucocorticosteroid treatment initiation was 6.75 months
(range 1–21 months). All seven patients treated with intravenous
methylprednisolone showed improvements in gait, diplopia, head
and limb sensation and dysarthria between Days 2 and 4 of
treatment. Patient 1 treated with 80 mg oral prednisone did not
experience clinical improvement. The number and size of perivas-
cular enhancing lesions was reduced on post-treatment MRI
exams in all patients (Fig. 5). Lesion distribution continued to be
concentrated in the pons. Long-term therapeutic response varied,
ranging from excellent (Patient 2) to incomplete with ongoing
inflammatory disease despite immunosuppressive medications
(Patient 6).
All treated patients required maintenance immunosuppression to
sustain clinical improvements (Table 1). In 6 cases in which with-
drawal or reduction of glucocorticosteroids was attempted, clinical
relapse ensued.
Illustrative case history—Patient 2Two years prior to evaluation at Mayo Clinic, the patient noticed
episodic facial tingling but was well otherwise. Six months prior,
he developed painless, horizontal, binocular diplopia and subse-
quently gait ataxia, worsening over 2 months. Brain MRI
showed brainstem gadolinium enhancing abnormalities centred
within the pons. Serological investigations were normal and CSF
demonstrated elevated unique oligoclonal bands. He was treated
for five consecutive days with 1000 mg intravenous methylpredni-
solone and his symptoms improved. Further investigations were
unrevealing. He remained in clinical remission without ongoing
treatment for 1 year, after which he experienced worsening gait
ataxia, dysarthria and recurrent horizontal diplopia. Repeat brain
MRI demonstrated enlarging areas of gadolinium enhancing le-
sions within the brainstem (Fig. 5A). A pontine biopsy was per-
formed while on no therapy (Fig. 4D–F). He was retreated with
five consecutive days of 1000 mg intravenous methylprednisolone
and he again had marked symptomatic improvement. He then had
three more similar episodes of symptomatic worsening within the
following 8 months that all reliably improved with intravenous
corticosteroids, only to relapse following their discontinuation.
Chronic therapy with oral prednisone 60 mg every other day
was therefore initiated and he experienced steady improvement
Figure 2 Representative MRI findings outside of primary
brainstem abnormalities. Similar foci of gadolinium
enhancement seen in upper thoracic cord (A), upper cervical
cord (B), mid-lower thoracic cord (C) and basal ganglia (D).
2630 | Brain 2010: 133; 2626–2634 S. J. Pittock et al.
Dow
nloaded from https://academ
ic.oup.com/brain/article/133/9/2626/352369 by guest on 13 February 2022
in diplopia, dysarthria, gait ataxia and dysphagia. Brain MRI
showed significant improvement in the gadolinium enhancing le-
sions (Fig. 5B).
Oral hydroxychloroquine (400 mg daily) was introduced and
prednisone was weaned over months because of glucocorticoster-
oid side effects. Six months later, brain MRI showed radiological
progression of the inflammatory lesions (Fig. 5C) although clinic-
ally he remained stable. Following reinitiation of oral prednisone
(60 mg every other day), a follow-up brain MRI scan showed
improvement, the hydroxychloroquine was discontinued and oral
methotrexate (7.5 mg once weekly) was started and gradually
increased to 20 mg weekly.
After 1.5 years of clinical and radiological stability on metho-
trexate and prednisone, alternate day treatment with oral prednis-
one was reduced by 5 mg each month and at last follow-up he
remained on oral methotrexate (10 mg weekly) monotherapy
without radiological recurrence (Fig. 5D). He has developed
neither symptoms or radiological evidence of other CNS diseases
such as multiple sclerosis nor a systemic disease despite follow-up
of 12 years.
DiscussionWe suggest that the constellation of clinical, radiological and
pathological findings reported in these eight patients represents
a definable, treatable inflammatory CNS, brainstem-predominant
syndrome (CLIPPERS). Clinical and radiological findings point to a
pontine-centric disorder with variable involvement of adjacent
structures. All patients experienced cranial sensory abnormalities,
diplopia, ataxia and dysarthria, and had a signature MRI punctate
pattern of patchy gadolinium enhancement ‘peppering’ the pons,
brainstem, cerebellum and spinal cord. Neuropathology in four of
eight patients revealed a prominent perivascular lymphocytic infil-
trate. Immunosuppressive therapy was successful in improving
clinical symptoms and radiological disease; however, early gluco-
corticosteroid taper was accompanied by recurrence of both symp-
toms and radiological progression, and therefore prolonged
therapy appears to be necessary for the majority of cases.
Other disorders likely to present with these findings were care-
fully excluded. Neurosarcoidosis (Spencer et al., 2005; Brown
et al., 2008), CNS lymphoma (Batchelor and Loeffler, 2006) and
CNS vasculitis (Salvarani et al., 2007; Miller et al., 2009) were the
three alternative diagnoses most strongly favoured in the initial
evaluation. Although not characteristic, each of these entities
could show a similar pattern of perivascular or infiltrative gadolin-
ium enhancement on MRI. Pathological review of lung, conjunc-
tival or brain biopsy tissues failed to reveal non-necrotizing
granulomas with giant cells typical of sarcoidosis. CSF cytology,
systemic imaging, haematologic investigations and neuropathology
revealed no evidence of lymphoma. Vasculitis was not found on
conventional or magnetic resonance angiography, and pathology
showed no partial or transmural destructive vascular inflammation
involving leptomeningeal or parenchymal vessels (Miller et al.,
2009) in biopsy specimens.
Figure 3 Progression of lesions over 6 months in Patient 3. MRI brain (T1 weighted post gadolinium) at presentation shows asymmetric
enhancement in the left pons and right mesencephalon (A, top panels), which progressed over 6 months (B, bottom panels) to
become more extensive and symmetric.
CLIPPERS Brain 2010: 133; 2626–2634 | 2631
Dow
nloaded from https://academ
ic.oup.com/brain/article/133/9/2626/352369 by guest on 13 February 2022
Figure 4 Neuropathology from Patients 1, 2, and 5. Marked perivascular and parenchymal lymphocytic infiltrates in the white matter
(haematoxylin and eosin stain), for Patients 1 (A�100, B�200), 2 (D�40, E� 200), and 5 (G�100). The lymphocytic infiltrate
was composed predominantly of CD3 positive (T) lymphocytes in all cases (Patient 1, C� 400; Patient 2, F� 400; Patient 5, H� 200);
similar pathology was demonstrated in Patient 6 (results not shown).
2632 | Brain 2010: 133; 2626–2634 S. J. Pittock et al.
Dow
nloaded from https://academ
ic.oup.com/brain/article/133/9/2626/352369 by guest on 13 February 2022
Other diagnoses considered but excluded were: histiocytosis X
(Prayer et al., 2004; Langerhans cells were absent and neuroima-
ging was inconsistent), paraneoplastic disease (Ellison et al., 2008;
systemic workup for malignancy, paraneoplastic autoantibody
markers were negative and neuropathology lacked characteristic
microglial nodules and neuronophagia), demyelinating disease
(Lucchinetti et al., 2008; no evidence of demyelination on path-
ology, nor were there typical MRI findings). The clinical course,
negative microbiology workup, improvement with immunosup-
pressants and absence of well-formed microglial nodules, necrotiz-
ing granulomata or stainable microorganisms argue strongly
against infectious processes.
Bickerstaff brainstem encephalitis deserves particular attention,
as it is also a brainstem-predominant inflammatory disease. This
diagnosis was excluded in these patients by the observed neuro-
pathology and radiological features and lack of peripheral nerve
involvement (Odaka et al., 2003; Ito et al., 2008). Diagnostic
features of Bickerstaff brainstem encephalitis include drowsiness
or coma, progressive external ophthalmoplegia, ataxia and corti-
cospinal tract signs; the vast majority of cases occur following
viral illness and have a monophasic course and a good prognosis.
MRI abnormalities occur in a minority (10–31%) of patients with
Bickerstaff brainstem encephalitis and, when present, typically
appear as a homogenous, non-gadolinium enhancing lesion
easily differentiated from the pepper-like gadolinium enhancement
seen as a hallmark MRI feature in our patients (Chataway et al.,
2001; Mondejar et al., 2002). Furthermore, peripheral polyneur-
opathy and serum anti-ganglioside GQ1b IgG antibodies are
present in the majority of patients with Bickerstaff brainstem
encephalitis, and thus it is now considered to be in the spectrum
of Miller Fisher Guillain Barre syndrome with coexistent CNS
involvement.
Although only eight subjects were identified, we suspect that
this disorder may be under-recognized, considering the relatively
short duration over which these patients were identified in three
academic centres. Despite a characteristic clinical and radiological
syndrome, other, as yet undefined, aetiologies could present in a
similar fashion and perhaps were not excluded in the four patients
lacking pathological examination. Those without pathological
confirmation seemed to have similar imaging, outcome and
radiological response to therapy as those in whom this was
accomplished. Although the median duration of follow-up was
short (median 20 months), it was reassuring that those patients
with the longest follow-up experienced neither dissemination of
the disease in the CNS nor any underlying systemic illness nor
evidence of idiopathic inflammatory demyelinating disease such
as multiple sclerosis despite follow-up as long as 12 years.
Despite the eloquence of the primarily involved CNS region
(brainstem, cerebellar peduncles), pathological examination was
accomplished in four cases and showed identical pathology that
corresponded to the neuroimaging abnormalities noted in all the
patients. It remains possible, given the sample size limitations
Figure 5 Marked reduction in extent of gadolinium enhancement following immunotherapy in Patient 2. Axial T1 MRI brain with
gadolinium. (A) At time of relapse, off of all immunosuppressive therapy and prior to brain biopsy. (B) Near complete resolution of
gadolinium enhancing lesions following chronic oral prednisone. (C) Recurrent gadolinium enhancing lesions following discontinuation
of prednisone. (D) Improvement and stability for over 1.5 years on methotrexate monotherapy.
CLIPPERS Brain 2010: 133; 2626–2634 | 2633
Dow
nloaded from https://academ
ic.oup.com/brain/article/133/9/2626/352369 by guest on 13 February 2022
required to prevent neurological injury, other pathology may have
been missed. However, the biopsies were of substantial quality
and size for pathological interpretation and there were no cases
where the biopsy suggested an alternative pathology, even around
the margins of the submitted sample. Extensive evaluations were
done in all patients and no alternative diagnoses were found.
The clinical course and neuroimaging features were similar
between those with and those without tissue pathology, although
an alternative pathological process could not be excluded as
causing this identical syndrome in patients where pathology was
not documented.
The pathogenesis of CLIPPERS is unknown. The presence
of a perivascular and parenchymal inflammatory cell infiltrate
in affected CNS tissue combined with the clinical response to
immunosuppressive therapies suggests an autoimmune or other
inflammatory mediated pathogenesis. If organ-specific auto-
immunity is its basis, then the location of the inflammatory infil-
trate suggests that the target autoantigen is likely to be located
in perivascular regions. A limited form of multiple sclerosis is
excluded given the lack of development of more typical attacks
and MRI lesions and the neuropathological findings.
We recommend full evaluation with both non-invasive and min-
imally invasive procedures to attempt to make a clear diagnosis if
similar cases are encountered. The patients who underwent biop-
sies did not experience adverse effects of the neurosurgical pro-
cedure. Given the location of the prominent abnormalities within
the brainstem, however, caution needs to be taken prior to con-
sideration of this in similar cases. Biopsy should be considered in
patients when alternative diagnoses remain likely and experienced
neurosurgical colleagues recommend that it may be performed
safely. Conversely, if alternative diagnoses are rigorously excluded,
the clinical and radiological features may be sufficiently distinctive
that CLIPPERS could be diagnosed and treated without
pathological examination.
Conflict of interestDr. Keegan is compensated as a Section Editor for Neurology� and
as Chief Editor for eMedicine. The authors report no other conflict
of interests.
ReferencesBatchelor T, Loeffler J. Primary CNS lymphoma. J Clin Oncol 2006; 24:
1281–8.
Brown E, Gray F. Bacterial infections. In: Love S, Louis DN, editors.Greenfield’s Neuropathology 8th edn. London: Edward Arnold
Publishers Ltd; 2008. p. 1391–445.
Chataway S, Larner A, Kapoor R. Anti-GQ1b antibody status, magnetic
resonance imaging, and the nosology of Bickerstaff’s brainstemencephalitis. Eur J Neurol 2001; 8: 355–7.
Cross S, Salomao D, Parisi J, Kryzer T, Bradley E, Mines J, et al.
Paraneoplastic autoimmune optic neuritis with retinitis defined by
CRMP-5-IgG. Ann Neurol 2003; 54: 38–50.
Dalmau J, Gleichman A, Hughes E, Rossi J, Peng X, Lai M, et al. Anti-
NMDA-receptor encephalitis: case series and analysis of the effects of
antibodies. Lancet Neurol 2008; 7: 1091–8.
Dalmau J, Graus F, Villarego A, Posner J, Blumenthal D, Thiessen B, et al.
Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004; 127:
1831–44.
Ellison DW, Perry A, Rosenblum M, Asa S, Reid R, Louis DN. Tumours:
non-neuroepithelial tumours and secondary effects. Greenfield’s
Neuropathology 8th edn. London: Edward Arnold Publishers Ltd;
2008. p. 2002–2146.
Ito M, Kuwabara S, Odaka M, Misawa S, Koga M, Hirata K, et al.
Bickerstaff’s brainstem encephalitis and Fisher syndrome form a
continuous spectrum. J Neurol 2008; 255: 674–82.
Kalman B. Disorders of the central and peripheral nervous systems
related to known or assumed system-immune abnormalities. In:
Kalman B, editor. Neuroimmunology in clinical practice. Oxford,
UK: Blackwell Publishing, Ltd, 2008. p. 179–259.
Keegan BM, Pittock S, Lennon V. Autoimmune myelopathy associated
with collapsin response-mediator protein-5 immunoglobulin G.
Ann Neurol 2008; 63: 531–4.
Lennon V, Kryzer T, Pittock S, Verkman A, Hinson S. IgG marker of
optic-spinal multiple sclerosis binds to the aquaporin-4 water channel.
J Exp Med 2005; 202: 473–7.
Lucchinetti C, Gavrilova R, Metz I, Parisi J, Scheithauer B, Weigand S,
et al. Clinical and radiographic spectrum of pathologically confirmed
tumefactive multiple sclerosis. Brain 2008; 131: 1759–75.
Miller D, Salvarani C, Hunder G, Brown R, Parisi J, Chirstianson T, et al.
Biopsy findings in primary angiitis of the central nervous system.
Am J Surg Pathol 2009; 33: 35–43.
Mondejar R, Santos J, Villalba E. MRI findings in a remitting-relapsing
case of Bickerstaff encelphalitis. Neuroradiology 2002; 44: 411–4.
Odaka M, Yuki N, Yamada M, Koga M, Takemi T, Hirata K, et al.
Bickerstaff’s brainstem encephalitis: clinical features of 62 cases and
a subgroup associated with Guillain-Barre syndrome. Brain 2003; 126:
2279–90.
Pittock S, Yoshikawa H, Ahlskog J, Tisch S, Benarroch E, Kryzer T, et al.
Glutamic acid decarboxylase autoimmunity with brainstem, extrapyr-
amidal, and spinal cord dysfunction. Mayo Clin Proc 2006; 81:
1207–14.
Polman C, Reingold S, Edan G, Filippi M, Hartung H, Kappos L, et al.
Diagnostic criteria for multiple sclerosis: 2005 revisions to the
"McDonald Criteria". Ann Neurol 2005; 58: 840–6.
Prayer D, Grois N, Prosch H, Gadner H, Barkovich A. MR imaging pre-
sentation of intracranial disease associated with Langerhans cell histio-
cytosis. AJNR Am J Neuroradiol 2004; 25: 880–91.
Roemer S, Parisi J, Lennon V, Benarroch E, Lassmann H, Bruck W, et al.
Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes
neuromyelitis optica from multiple sclerosis. Brain 2007; 130:
1194–205.
Salvarani C, Brown R, Calamia K, Christianson T, Weigand S, Miller D,
et al. Primary central nervous system vasculitis: analysis of 101 patients.
Ann Neurol 2007; 62: 442–51.
Spencer T, Campellone J, Maldonado I, Huang N, Usmani Q,
Reginato A. Clinical and magnetic resonance imaging manifestations
of neurosarcoidosis. Semin Arthritis Rheum 2005; 34: 649–61.
Tan K, Lennon V, Klein C, Boeve B, Pittock S. Clinical spectrum of
voltage-gated potassium channel autoimmunity. Neurology 2008;
70: 1883–90.
Wingerchuk D, Lennon V, Lucchinetti C, Pittock S, Weinshenker B.
The spectrum of neuromyelitis optica. Lancet Neurol 2007; 6:
805–815.
2634 | Brain 2010: 133; 2626–2634 S. J. Pittock et al.
Dow
nloaded from https://academ
ic.oup.com/brain/article/133/9/2626/352369 by guest on 13 February 2022