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Zhuang et al. J Med Case Reports
https://doi.org/10.1186/s13256-021-02814-5

Open Access

CASE REPORT

Chronic lymphocytic inflammation
with pontine perivascular enhancement
responsive to steroids, a mimicker
of malignancy: a case report and review
of the literature
Eric Zhuang1*, Lisa Shane2, Nima Ramezan2, Ameera F. Ismail2 and Nilesh L. Vora2,3

Abstract
Background: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids is
a clinically and radiographically distinct inflammatory syndrome affecting multiple structures of the brain, including
the cerebellum, brainstem, and spinal cord. The clinical presentation can be variable, including ataxia, nystagmus,
dysarthria, dysphagia, and other subacute brainstem, cranial nerve, or cerebellar symptoms. These symptoms can be
subacute to chronic, episodic, and progressive, making the diagnosis challenging. The hallmark radiographic magnetic resonance imaging findings are gadolinium-enhancing punctate lesions predominantly “peppering” the pons in
a perivascular pattern.
Case presentation: Here, we describe a case and literature review of a 74-year-old Caucasian male who presented
with subacute symptoms of ataxia, diplopia, and generalized fatigue. Physical examination was notable for horizontal
nystagmus and wide-based gait. Magnetic resonance imaging revealed angiocentric enhancement predominantly in
the brainstem and cerebellum, with involvement of the basal ganglia, thalami, and supratentorial white matter. Meanwhile, a screening computed tomography scan demonstrated a right upper lobe mass with biopsy proving primary
lung cancer. Biopsy of one of the brain lesions showed perivascular infiltrate primarily composed of CD3+ T cells, scattered CD20+ B cells, and no signs of malignancy. The patient was started on high-dose glucocorticoids followed by a
maintenance regimen with rapid improvement clinically and radiographically. Given extensive work-up was negative,
these clinical and radiographic findings were consistent with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids.
Conclusions: This case illustrates the difficulty of diagnosing chronic lymphocytic inflammation with pontine
perivascular enhancement responsive to steroids, given its variable presentation, lack of specific laboratory findings,
and poorly understood pathogenesis. We demonstrate a case that responded well to oral corticosteroid burst followed by a taper to the lowest corticosteroid dose clinically possible. Failure to recognize this syndrome could result
in permanent central nervous system morbidity. Therefore, earlier recognition is crucial for this treatable condition.

*Correspondence: Ezhuan2@gmail.com
1
Department of Medicine, University of California Irvine, 101 The City
Drive South, Orange, CA 92688, USA
Full list of author information is available at the end of the article
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Page 2 of 7

Keywords: CLIPPERS, Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to
steroids, Lymphohistiocytic inflammation, Lung cancer, Glucocorticoids, Immunosuppression

Background
Chronic lymphocytic inflammation with pontine
perivascular enhancement responsive to steroids
(CLIPPERS) is a clinically and radiologically distinct
pontine-predominant encephalomyelitis with marked
glucocorticoid responsiveness. This was first described
in 2010 by Pittock et al. after eight patients presented
with similar clinical and magnetic resonance imaging (MRI) findings: subacute diplopia, ataxia, facial
paresthesia, and punctate and curvilinear gadoliniumenhancing lesions “peppering the pons.” Nystagmus,
dysarthria, dysphagia, and other subacute brainstem,
cranial nerve, or cerebellar symptoms occurred. Biopsy
of lesions typically demonstrate perivascular lymphohistiocytic infiltrate without granulomas, infection,
lymphoma, or vasculitis [1]. Clinical and radiological
response follows the administration of glucocorticoid
or other immunosuppressive therapy [2, 3]. Characteristics of CLIPPERS are summarized in Table 1. The
overall course of the disease appears to be favorable;
however, most patients routinely worsen following
glucocorticoid taper and require chronic glucocorticoid therapy or other immunosuppressive therapy [4].
In patients not on chronic steroid therapy or other

immunosuppressive agents, the disease has a relapsing–remitting course, with an approximate mean
annual relapse rate (ARR) of 0.5 (range, 0.25–2.8) [2].
Clinical and radiological improvement is nearly systematically observed following readministration of high
doses of steroids. Since often no progressive morbidity
occurs following immunosuppressive treatment, the
clinical and radiological sequelae that persist may be
due to previously unrecognized or untreated relapses.
This suggests that maintaining this disease in remission
may prevent the accumulation of disability. Multiple
reports observed no further relapses when chronic corticosteroid therapy was maintained above 20 mg/day [4,
5]. We present a case of CLIPPERS in which the diagnosis was complicated, given the patient’s lung cancer,
and we underline the successful diagnosis, treatment,
and disease course.

Case presentation
A 74-year-old Caucasian male presented to his primary
care physician with a 3-month history of ataxia, diplopia, and generalized fatigue. He had a medical history
of hypertension, coronary artery disease, and peripheral vascular disease. On examination, the patient had a

Table 1 Core features and proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement
responsive to steroids (adapted from Tobin et al. [7])
Clinical
Subacute pontocerebellar dysfunction with or without other CNS symptoms such as cognitive dysfunction and myelopathy
CNS symptoms responsive to corticosteroid therapy
Absence of peripheral nervous system disease
Lack of alternative explanation for clinical presentation
Radiological
MRI with homogeneous, gadolinium-enhancing nodules without ring enhancement or mass effect predominating in the pons or cerebellum measuring < 3 mm
Marked improvement in gadolinium enhancement after corticosteroid treatment
Homogeneous T2 signal abnormality where degree of T2 does not significantly exceed the size or area of post gadolinium enhancement
Spinal lesions with similar T2 and gadolinium-enhancing lesions as above
Pathological
Lymphocytic inflammation with perivascular predominance and parenchymal diffuse infiltration
T cells predominating infiltration with variable macrophage components
Absence of myelin loss or focal secondary myelin loss
Lack of alternative explanation for pathological presentation
Definite CLIPPERS: patient fulfilling all clinical, radiological, and pathological criteria
Probable CLIPPERS: patient fulfilling all clinical and radiological criteria without available pathology
Differential diagnoses, including CNS lymphoma, lymphomatoid granulomatosis, glioma, primary CNS vasculitis, paraneoplastic syndrome, neurosarcoidosis, demyelinating disease, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO) neuro-Behcet’s disease, Sjögren’s
syndrome, tuberculosis, Whipple’s disease, and histiocytosis, should be excluded

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wide-based gait with postural instability, and horizontal
nystagmus. He had normal reflexes, no focal motor deficits, no focal muscle atrophy, no focal sensory deficits,
and no localized deafness or tinnitus. MRI of the brain
with contrast was performed, which revealed numerous
1–2 mm intraaxial fluid-attenuated inversion recovery
(FLAIR) hyperintense lesions scattered predominantly
throughout the central brain, with several periventricular and subcortical lesions concerning for possible central
nervous system (CNS) lymphoma, metastatic cancer, or
an atypical granulomatous, inflammatory, or infectious
etiology. The patient was subsequently admitted for further work-up.
Lumbar puncture showed mildly elevated protein
at 64 mg/dL but was otherwise unremarkable. ´There
were no oligoclonal bands or malignant cells. Laboratory work including antinuclear antibody (ANA),
anti-double stranded deoxyribonucleic acid (DNA)
(anti-dsDNA) antibody, anti-single-stranded DNA
(anti-ssDNA) antibody, antimitochondrial antibody,
and serum angiotensin-converting enzyme (ACE) were
unremarkable. The patient also tested negative for Coccidioides, toxoplasmosis, Cryptococcus, Q fever, Rickettsia typhi, Borrelia burgdorferi, syphilis, Mycobacterium
tuberculosis, cytomegalovirus (CMV), Epstein–Barr virus
(EBV), and human immunodeficiency virus (HIV). The
patient underwent computed tomography (CT) imaging for malignancy work-up, which revealed a spiculated
right upper lobe lung mass compatible with lung cancer.
CT-guided biopsy of the lung mass revealed primary
lung squamous carcinoma. The patient underwent
staging positron emission tomography (PET)/CT that
showed intense fluorine-18 deoxyglucose (FDG) accumulation at the site of the patient’s known lung cancer but
no pathological thoracic or mediastinal lymph nodes or
any other sites suggestive of distant metastatic disease.
There was relatively symmetrical FDG accumulation
into the cerebral cortices, subcortical gray matter, and
cerebellar hemispheres. An MRI brain stealth protocol
with contrast was performed and demonstrated angiocentric enhancement predominantly in the brainstem
and cerebellum, with involvement of the basal ganglia,
thalami, and supratentorial white matter (Fig. 1). This
raised suspicion for CLIPPERS; however, the differential
diagnosis also included neurosarcoidosis, lymphomatoid
granulomatosis, angiocentric lymphoma, vasculitis, cerebral amyloid disease, and leptomeningeal carcinomatosis, though less likely given the lack of leptomeningeal
enhancement.
Neurosurgery was consulted, and a brain biopsy was
planned. A cerebellar biopsy was performed, given it was
the area with the highest density of enhancement. The
specimen showed perivascular infiltrates of lymphocytes

Page 3 of 7

Fig. 1 a, b Coronal magnetic resonance imaging T1 postcontrast
images demonstrating angiocentric enhancement predominantly in
the brainstem and cerebellum with involvement of the basal ganglia,
thalami, and supratentorial white matter

(Fig. 2). No malignant cells or neutrophils were seen.
Immunohistochemical staining revealed mostly CD3+
T cells with scattered CD20+ B cells (Fig. 3). Given the
clinical, radiological, and pathological findings were
consistent with CLIPPERS,the patient was started on an
empiric trial of steroid therapy: prednisone 40 mg oral
daily.

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Fig. 3 a CD20 highlighting lesser numbers of B lymphocytes. b CD3
highlighting predominance of T lymphocytes

Fig. 2 Sections of cerebellum. a Lymphohistiocytic infiltrate. b
Higher power shows small “mature” lymphocytes and admixed
histiocytes. No well-formed granuloma or immature cell population. c
Inflammatory cells surrounding a small vessel

On follow-up a month later, the patient reported that
he had felt “back to himself.” He reported the ataxia,
diplopia, and generalized fatigue were significantly

improved, though not yet completely resolved. This was
confirmed on physical examination. After 2 months
on steroid therapy, MRI of the brain showed dramatic
improvement radiologically, with the enhancing lesions
throughout the brain seen on prior studies resolved. Clinically the patient reported he was “doing amazingly well,”
his ataxia had resolved, and he was no longer requiring
a cane or walker to ambulate. Therefore, the patient had
done well on steroids. It was determined that the patient
should be tapered off steroids; the patient tapered off
steroids over 1 month, for a total of 3 months on steroid
therapy.
As the brain biopsy was negative for malignant cells,
and the PET/CT demonstrated no overt signs of any
other metastatic disease, the patient’s lung cancer was
clinically stage IA. He subsequently underwent robotic
right upper lobectomy with hilar and mediastinal lymph
node dissection. Surgical findings demonstrated T1bN0
disease, consistent with pathological stage IA2 lung

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cancer. No adjuvant therapy was indicated, and surveillance CT scans as of 1 year have demonstrated no
recurrence.
Four months after stopping steroid therapy, the patient
began to have a return of ataxia, and during this episode
he also developed intermittent expressive aphasia that
would spontaneously resolve after several hours. MRI
of the brain with contrast was performed and demonstrated reappearance of the multiple lesions in the brain.
This was concerning for relapsed CLIPPERS. The patient
was treated with intravenous dexamethasone 4 mg every
6 hours over 1 day, followed by a maintenance regimen
of prednisone 20 mg once daily. On 2-month follow-up,
the patient had no further events or symptoms and MRI
of the brain showed improvement of the lesions in the
brain.

Discussion and conclusion
We encountered a patient whose clinical and radiological findings were concerning for metastatic lung cancer;
however, the patient was found to have CLIPPERS. This
case highlights two important issues. The first is the challenging nature of diagnosing CLIPPERS. The second is
the treatment regimen.
To date, validated diagnostic criteria for CLIPPERS
are not available, and thorough work-up is mandatory
to exclude alternative conditions (Table 1) including
vascular, inflammatory, infectious, neoplastic, and paraneoplastic conditions that can overlap with CLIPPERS
syndrome. Several papers have proposed criteria to make
the diagnosis [2, 4, 6, 7]. Simon et al. highlighted clinical, radiological, corticosteroid response, and histopathological features as diagnostic criteria. Taieb et al. have
characterized CLIPPERS as subacute episodic brainstem
signs and symptoms, punctate and curvilinear enhancing lesions mainly involving the pons, prompt clinical
and radiological steroid sensitivity, and in the absence
of alternative diagnosis. Tobin et al. have published criteria modified from Simon et al., where they propose
“definite CLIPPERS,” defined as a patient who fulfills
all clinical, radiological and neuropathological criteria,
and “probable CLIPPERS,” defined as a patient who fulfills all clinical and radiological criteria without available
neuropathology.
This patient presented with subacute symptoms of
ataxia, diplopia, and generalized fatigue. The neurological examination was important in differentiating central
and peripheral nervous system disease in this patient. He
demonstrated a wide-based gait with postural instability and horizontal nystagmus with a lack of deafness or
tinnitus, suggestive of a central etiology [8]. Given the
patient’s lung cancer was discovered around the same
time as the brain lesions, it was important to exclude

Page 5 of 7

metastatic malignancy, which would require a different
therapeutic approach. With no specific biomarker for
CLIPPERS, we felt brain biopsy was necessary prior to
initial treatment to exclude another disease entity that
would require alternative treatment. Given our patient
demonstrated clinical signs of ataxia and diplopia, radiological signs of punctate enhancing lesions involving the
pons, pathological perivascular lymphocytic inflammation, absent signs of peripheral nervous system disease,
and prompt clinical and radiological steroid responsiveness, this case is likely a case of “definite CLIPPERS” as
defined by Tobin et al.
It is possible that CLIPPERS could be a marker, a paraneoplastic marker of malignancy. CLIPPERS has been
reported in cases of lymphoma, before the emergence of
lymphoma, preceding colon cancer, and after lymphoma
remission [9–16]. Taieb et al. suggests that, in the setting
of lymphoma, the presence of CLIPPERS features could
relate to (1) paraneoplastic vasculitis involving small
vessels, (2) lymphoma cell infiltration, and (3) sentinel
lesions. Sentinel lesions, considered as host immunity
fighting against cancer, have been described as responsive to steroids preceding primary CNS lymphoma. However, primary CNS lymphoma, unlike CLIPPERS, is often
associated with rapid disease progression and death,
after an initial but transient improvement with steroids
[17]. Whether CLIPPERS is truly an independent disease entity or a manifestation of another systemic disease
remains uncertain.
In the absence of randomized placebo-controlled trials, formal recommendations of the optimal treatment
modality for CLIPPERS are yet to be determined. This is
likely due to the relatively few patients with CLIPPERS
reported so far. A number of papers have proposed the
initial treatment should begin with high-dose steroids,
such as a course of intravenous high-dose methylprednisolone daily for 5 days [1, 2, 4, 5, 18–20]. This is followed
by an oral maintenance corticosteroid regimen that is
slowly tapered to an equivalent of prednisone 20 mg/
day. Of important note, tapering the steroid regimen
to below 10–20 mg/day frequently leads to inevitable
relapse [5]. The patient illustrated in this case underwent initial treatment with prednisone 40 mg followed
by a slow taper to cessation over 3 months with significant clinical and radiological improvement. Time from
symptom onset to corticosteroid initiation was approximately 76 days. As predicted, after withdrawal of steroid
therapy, the patient relapsed. During this relapse, the
patient was administered dexamethasone 16 mg intravenously over 1 day with rapid improvement, followed by a
maintenance regimen of prednisone 20 mg/day. The successful treatment of the disease during the acute phase
with prednisone 40 mg oral daily and later exacerbation

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with dexamethasone 4 mg every 6 hours over 1 day, followed by a prednisone oral taper, suggests that high-dose
steroids over 5 days may not be necessary and a shorter
initial course of high-dose steroids may be adequate in
some cases. After a short course of high-dose steroid
therapy, the patient remained stable on maintenance
steroid therapy of prednisone 20 mg once per day, and so
chronic long-term immunosuppressive therapy appears
to be warranted to keep CLIPPERS in remission. Based
on other clinical observations, steroid-sparing treatment
has also been proposed using methotrexate, cyclophosphamide, hydroxychloroquine, or azathioprine [2].
Overall, CLIPPERS represents a distinct clinical, radiological, and pathological process that can be diagnosed
after exclusion of other differential diagnoses. However, the pathogenesis of CLIPPERS is still unknown,
and it remains unclear whether it represents a separate
and independent disease entity or a syndrome with heterogeneous etiologies. For now, the primary treatment is
with high-dose corticosteroids. Physicians must be aware
of this condition and differential diagnoses, given it has
been shown that early diagnosis and corticosteroid-based
treatment can prevent irreversible morbidity. Our observations are consistent with previous reports that treatment with corticosteroids leads to prompt clinical and
radiological improvement, and the cessation of therapy
leads to relapse. Further studies to determine the pathophysiology, potential biomarkers, and reliable diagnostic
criteria, as well as the optimal form and duration of treatment, are necessary.
Abbreviation
CLIPPERS: Chronic lymphocytic inflammation with pontine perivascular
enhancement responsive to steroids.
Acknowledgements
Not applicable.
We declare that this manuscript is original, has not been published before
is not currently being considered for publication elsewhere.
Authors’ contributions
EZ, LS, NR, AFI, and NLV were major contributors in writing the manuscript. LS
performed the histological examination of the brain biopsy and created the
pathology slide images for the manuscript. AFI performed the radiographic
examination of the brain and obtained the radiographic images for the manuscript. All authors read and approved the final manuscript.
Funding
This manuscript was not funded.
Availability of data and materials
Not applicable.

Declarations
Ethics approval and consent to participate
Not applicable.

Page 6 of 7

Consent for publication
Written informed consent was obtained from the patient for publication of
this case report and any accompanying images. A copy of the written consent
is available for review by the Editor-in-Chief of this journal.
Competing interests
We know of no conflicts of interest associated with this publication.
Author details
Department of Medicine, University of California Irvine, 101 The City Drive
South, Orange, CA 92688, USA. 2 Long Beach Memorial Medical Center, Long
Beach, CA, USA. 3 Todd Cancer Institute, Long Beach, CA, USA.

1

Received: 13 January 2021 Accepted: 22 March 2021

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