NEUROLOGICAL RARITY
CLIPPERS: Chronic Lymphocytic
1
Department of Neurology,
Fondation Ophtalmologique
Adolphe de Rothschild, Paris,
France
2
Department of Radiology,
Fondation Ophtalmologique
Adolphe de Rothschild, Paris,
France
Correspondence to
Dr D Biotti, Department
of Neurology, Fondation
Ophtalmologique Adolphe de
Rothschild, 25 Rue Manin,
75019 Paris, France;
dbiotti@hotmail.com
Inflammation with Pontine
Perivascular Enhancement
Responsive to Steroids
Damien Biotti,1 Romain Deschamps,1 Eimad Shotar,1 Elisabeth Maillart,1
Mickaël Obadia,1 Ivan Mari,1 Julien Savatovsky,2 Olivier Gout1
A 56-year-old previously healthy
man developed progressive cerebellar
ataxia and binocular horizontal diplo-
pia, worsening over several weeks.
An MR scan of brain showed multi-
ple punctate hyperintensities in T2
weighted images, confined to the pons,
medulla oblongata and cerebellum,
with curvilinear gadolinium enhance-
ment in T1 weighted images. The clini-
cal and radiological features suggested
the CLIPPERS syndrome (Chronic
Lymphocytic Inflammation with
Pontine Perivascular Enhancement
Responsive to Steroids). The symp-
toms and MR findings improved dra-
matically with high dose parenteral
corticosteroids.
Introduction
CLIPPERS syndrome (Chronic
Lymphocytic Inflammation with
Pontine Perivascular Enhancement
Responsive to Steroids) is a recently
described CNS inflammatory disor-
der.1 Since 2010, several new possi-
ble cases have been published.2–5 We
report a further patient with features
consistent with this syndrome.
Case report
A previously healthy 56-year-old man
was admitted with a several week
history of progressive ataxia and
binocular horizontal diplopia. On
initial neurological examination, he
showed dysarthria, left sixth nerve
palsy, a right-sided extensor plantar
response, right-sided sensory loss and
Practical Neurology 2011;11:349–351. doi:10.1136/practneurol-2011-000043
cerebellar limb and gait ataxia; oph-
thalmoscopy was normal. MR scan
of the brain (T2 weighted images)
showed multiple punctate hyperin-
tensities in the pons, medulla oblon-
gata and cerebellum (figure 1A), with
curvilinear gadolinium enhancement
in T1 weighted images (figure 1B, C).
Diffusion weighted MR images gave
no additional information. MR scans
of the spine confirmed that only the
upper cervical cord was affected.
The MR brain scan also showed
two distinct cerebral arteriovenous
malformations, fed by the left mid-
dle cerebral artery and confirmed
by cerebral angiography. There was
no clinical or laboratory evidence of
vasculitis. CSF showed elevated pro-
tein at 0.89 g/l (0.15–0.45), a nor-
mal white cell count at 2/µl (normal
≤5), no malignant cells and normal
glucose. The following CSF inves-
tigations were normal or negative:
interferon α level, bacterial cultures
and PCR for Listeria monocytogenes,
Tropheryma whipplei, human polyo-
mavirus (BK), Epstein–Barr virus
(EBV), herpes simplex virus (HSV),
cytalomegalovirus (CMV), human
herpes virus-6 (HHV6), HHV8, JC
(John Cunningham) virus, parvovirus
B19 and varicella zoster virus (VZV).
There was no evidence of intrathecal
immunoglobulin synthesis. An exhaus-
tive biological blood screening for
infections was negative, including for
HSV, VZV, EBV, CMV, HHV6 and 8,
349
 NEUROLOGICAL RARITY
Figure 1 MR scan of brain before (A–C) and after (D–F) corticosteroids. Typical hyperintensities are confined to the pons,
cerebellum and medulla oblongata. (A) Axial T2 weighted images; (B) gadolinium enhancement in axial images; (C) gadolinium
enhancement in sagittal T1 weighted images.
enterovirus, parvovirus B19, JC, BK, HIV, hepa-
titis C virus, hepatitis B virus, L monocytogenes,
T whipplei, syphilis serology and Lyme serology.
Autoimmune screening was also negative, includ-
ing serum tests for antinuclear antibodies, anti-
extractable nuclear antigen, anti-double stranded
DNA antibodies, antineutrophil cytoplasmic anti-
body, antithyroglobulin, antithyroperoxidase,
antiganglioside antibodies (including anti-GQ1b)
and serum angiotensin converting enzyme.
Serum tests for neoplastic disorders were also
negative, including onconeural antibodies and
tumour markers. Accessory salivary gland biopsy
and whole body fluorodeoxyglucose-positron
emission tomography were normal.
Because of the progressively worsening cerebel-
lar ataxia, he was given high parenteral corticos-
teroids (1 g daily for 5 days), followed by oral
prednisolone (1 mg/kg body weight). There was
a dramatic clinical improvement within 1 week,
followed by improvement of the MR imaging
(figure 1D,F). We diagnosed CLIPPERS syndrome
and started azathioprine as a corticosteroid spar-
ing agent. At the 7 month follow-up, there was
no relapse and only mild persisting ataxia.
350 Practical Neurology 2011;11:349–351. doi:10.1136/practneurol-2011-000043
Discussion
This patient’s clinical, radiological and treatment
response features strongly suggest CLIPPERS
syndrome, as recently described by Pittock et al1
in eight patients. Our patient shared several clini-
cal, imaging and treatment response characteris-
tics with the previously described patients.
■ Firstly, the clinical symptoms related directly to
brainstem involvement, particularly the subacute
gait ataxia and diplopia (seen in all of Pittock et al’s
patients), and the cerebellar dysarthria (seen in
seven of the eight patients).
■ Secondly, the MRI findings were of multiple, small,
patchy T2 weighted hyperintensities, mainly in the
pons but also sometimes in the midbrain, medulla
oblongata and/or cerebellum. There was also
curvilinear gadolinium enhancement. Less specific
MRI presentations were recently proposed in a
possible new case of CLIPPERS but this unique
finding should be considered with caution.2 6
■ Thirdly, previous authors have highlighted symptom
improvement within a few days of parenteral
corticosteroids, and a very high risk of relapse
during their reduction (in six of eight patients for
Pittock et al1 and in two of Kastrup et al’s three
patients5). These observations justified starting
immunosuppressive therapy early in our patient,

even though the natural history of CLIPPERS
syndrome is not yet known.
■ Finally, we needed to exclude various inflammatory,
infectious and paraneoplastic disorders, as well as
excluding vasculitis on cerebral angiography.
Our patient fulfilled all of these ‘criteria’, mak-
ing the diagnosis highly probable and justifying
the avoidance of brain biopsy. Such a non-invasive
approach in ‘typical cases’ was already suggested
by Pittock et al,1 who treated 50% of patients with-
out biopsy. When a brain biopsy is performed,
histological examination shows a predominantly
perivascular lymphocytic infiltrate (CD3 reactive
T lymphocytes and CD20 B lymphocytes) with
no evidence of demyelination.
Interestingly, our patient had two large arte-
riovenous malformations, which is an unex-
pected association, reported for the first time.
However, these lesions were not associated
with vasculitis, were away from the inflamma-
tory lesions and did not explain the patient’s
symptoms. The finding may well have been
incidental. Another point is our patient’s lack
of CSF oligoclonal bands. Among Pittock et al’s
patients, three of the six tested had oligoclonal
bands.1 One of them reverted to normal and this
also happened in List et al’s patient,3 6 suggest-
ing a dynamic immune mediated mechanism.
We need more data to understand the diagnos-
tic and prognostic value of a negative, persist-
ing or reverting profile of oligoclonal bands in
CLIPPERS syndrome.
Another intriguing and unexplained feature is
why the perivascular inflammation involves the
pontine and peripontine areas. This could suggest
NEUROLOGICAL RARITY
a particular local immunological target; more
specific immunological and histological studies
should focus on this. Kastrup et al5 noted elevated
IgE levels in two of their patients, suggesting
that the inflammatory process in CLIPPERS syn-
drome could be triggered by an allergic process.
CLIPPERS syndrome is a new entity affecting
the CNS, whose characteristics still await better
definition.
Acknowledgements We thank Mark Wardle, Cardiff, UK,
for reviewing this article.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not
commissioned; externally peer reviewed.
References
1. Pittock SJ, Debruyne J, Krecke KN, et al. Chronic
lymphocytic inflammation with pontine perivascular
enhancement responsive to steroids (CLIPPERS). Brain
2010;133:2626–34.
2. Duprez TP, Sindic CJ. Contrast-enhanced magnetic resonance
imaging and perfusion-weighted imaging for monitoring
features in severe CLIPPERS. Brain 2011;134(Pt 8):e184.
3. List J, Lesemann A, Wiener E, et al. A new case of chronic
lymphocytic inflammation with pontine perivascular
enhancement responsive to steroids. Brain 2011;134(Pt 8):e185.
4. Taieb G, Wacongne A, Renard D, et al. A new case of
chronic lymphocytic inflammation with pontine perivascular
enhancement responsive to steroids with initial normal
magnetic resonance imaging. Brain 2011;134(Pt 8):e182.
5. Kastrup O, van de Nes J, Gasser T, et al. Three cases of
CLIPPERS: a serial clinical, laboratory and MRI follow-up
study. J Neurol 2011 (in press).
6. Keegan BM, Krecke KN, Pittock SJ. Reply to Duprez et al.
and List et al. regarding chronic lymphocytic inflammation
with pontine perivascular enhancement responsive to steroids.
Brain 2011;134(Pt 8):e186.
Practical Neurology 2011;11:349–351. doi:10.1136/practneurol-2011-000043 351