doi:10.1093/brain/awv205
BRAIN 2015: 138; 1–4
| e397
LETTER TO THE EDITOR
Chronic lymphocytic inflammation with pontine perivascular enhancement
responsive to steroids with lesions distributed predominantly in spinal cord
Bo Song, Yuan Gao, Hui Fang, Panxing Li, Yusheng Li and Yuming Xu
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
Correspondence to: Yuming Xu,
Department of Neurology,
The First Affiliated Hospital of Zhengzhou University,
No.1 Jianshe E Rd,
Erqi District,
Zhengzhou, 450052,
Henan,
China
E-mail: [email protected]
Sir,
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) syndrome is a newly described immune-mediated, treatable and
inflammatory CNS disease first reported by Pittock et al.
(2010). The authors concluded that the characterized features of CLIPPERS are punctate and curvilinear pattern
‘peppering’ lesions within the pons on post-contrast T1weighted images, together with an initial responsiveness to
steroids therapy. Three of eight clinic patients in the original
article were described foci of punctate gadolinium enhancement lesions extending down to spinal cord. To the best of
our knowledge, the enhancing lesions distributed in pontine
and peripontine regions, and some cases may additionally
extend to the spinal cord, thalamus, basal ganglia, capsula
interna and the cerebral white matter (Pittock et al., 2010).
However, cases with lesions predominantly distributed in
spinal cord have not been reported, now we present a
patient with lesions distributed mainly in the spinal cord
and with lesions extending up to the medulla oblongata.
A previously healthy 53-year-old man noticed general
weakness and abnormal fatigue for 2 weeks before admission. He then developed numbness of bilateral lower limbs,
walking difficulties and incontinence for urine. There was
no evidence of diplopia, gait ataxia or dysarthria. The
past medical history and family history were negative.
Neurological examination on admission revealed muscle
strength score of bilateral lower limbs was 2 of 5
(Medical Research Council scale), tendon reflexes were
decreased in the knees and ankles, hypoaesthesia of bilateral
lower limbs, bilateral pathological reflexes were positive.
The rest of the neurological examinations were normal.
Laboratory investigations revealed complete blood
count was normal except monocyte percentage 26.9%
(N: 3–10%), monocyte 1.67 109/l (normal range: 0.1–
0.6 109/l). Renal and liver function tests were normal.
Serum vitamin B12, folic acid was normal. Thyroid hormone levels, anti-thyroid peroxidase antibody were
normal, thyroid ultrasonography was normal. Serum IgG
and/or IgM of HIV, hepatitis B virus, varicella zoster virus,
cytalomegalovirus, Epstein-Barr virus, herpes simplex virus,
and syphilis were all negative. Cultures of bone marrow of
mycoplasma, chlamydia, rickettsia, Brinell coli, and legionella bacteria were all negative. Erythrocyte sedimentation
rate and C-reactive protein were normal. Serum immunological study, anti-aquaporin 4 antibody, angiotensin-converting
enzyme,
rheumatoid
factor,
perinuclear
antineutrophil cytoplasmic antibody, cytoplasmic antineutrophil cytoplasmic antibody, double-stranded DNA antibodies,
anti-Sm
antibody,
antinuclear
antibody,
extractable nuclear antigens anti-SS-A and anti-SS-B antibodies, anti-RNP antibodies were all negative. Serum and
CSF tumour markers were all negative. Onconeural antibodies (anti-Hu, anti-Yo, anti-Ma, anti-amphiphysin) were
Advance Access publication July 14, 2015
ß The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
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| BRAIN 2015: 138; 1–4
Letter to the Editor
Table 1 CSF examination was performed 1 week before and 2 and 12 weeks after the initial treatment with steroids
Lumber
puncture
results
Opening
pressure
(mmH2O)
Cells
count (ml)
Portent
level (mg/dl)
IgGcsf
(mg/l)
ALBcsf
(mg/l)
IgG index
IgG synthesis
rate
Oligoclonal
bands
1 week before
2 weeks after
12 weeks after
Reference
220
160
150
80–180
160
98
8
0–5
114.2
64.7
23.9
15–45
166.0
123.0
24.6
7.51–15.6
722.1
534.3
144.9
136–246
1.51
1.15
0.87
0.3–0.7
56.57
27.81
5.68
3.3–6
Positive
Negative
Negative
Negative
ALBcsf = albumin of CSF.
Figure 1 Brain and spinal cord MRI performed before the initial treatment with steroids. Upper cervical (A, B and F), thoracic and
lumbar (C) spinal cord and brain (D and E) MRI performed 1 week before the initial treatment with steroids showed multiple, punctate
hyperintense lesions disseminated in the medulla oblongata, cervical, thoracic, and lumbar spinal cord. MRI demonstrated patchy pattern
hyperintense lesions in the upper cervical spinal cord [sagittal T2-weighted images (A)]. Multiple punctate and ‘peppering’ hyperintense lesions
were showed in the spinal cord [sagittal (B), sagittal (C) and coronal (F) post-contrast T1-weighted image], less numerous and smaller lesions
were observed in the lumber spinal cord and conus (C). Brain (D and E) MRI revealed multiple punctate hyperintense lesions in the medulla
oblongata and upper cervical spinal cord [coronal (D) and sagittal (E) post-contrast T1-weighted images]. Hr = head right; Fl = feet left; Fa = feet
anterior; Fr = feet right; Ha = head anterior.
negative. CT scans of the abdomen, chest and brain were
normal.
CSF examination was performed 3 weeks after symptom
onset and the examination revealed pleocytosis (160
nucleated cells/ml, 85% lymphocytes) and 114.2 mg/dl
total protein, IgGcsf was 166.0 mg/l, IgG index was 1.51,
oligoclonal bands were positive (Table 1). Manual CSF
cytology did not reveal any malignant cells. MRI scans of
Letter to the Editor
BRAIN 2015: 138; 1–4
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Figure 2 Spinal cord MRI performed 2 weeks after the initial treatment with steroids. Upper cervical (A, B, C), thoracic and lumber
(D) spinal cord MRI performed 2 weeks after the treatment with intravenous methylprednisolone. Patchy hyperintense lesions showed dramatic
improvement in upper cervical spinal cord [sagittal (A) T2-weighted images]. Punctate and ‘peppering’ heperintense lesions were resolved
completely in cervical (B and C), thoracic and lumber (D) spinal cord [sagittal (B and D) and coronal (C) post-contrast T1-weighted images].
Hr = head right; Ha = head anterior.
brain were normal. Interestingly, MRI scans of the cervical
spinal cord showed multiple patchy hyperintense lesions in
T2-weighted images (Fig. 1A), with spots and curvilinear
contrast enhancement lesions predominantly in the spinal
cord, extending up to the medulla oblongata and down to
the conus in T1-weighted images (Fig. 1B–F). Less numerous
and smaller lesions were observed in the lumber spinal cord
and conus (Fig. 1C). Surprisingly, no lesions were found in
the pons, cerebellar and midbrain. However, the ‘peppering’
lesions on post-contrast T1-weighted MRI in the spinal cord,
matched the characteristics of CLIPPERS. And the diagnosis
of CLIPPERS could not be ruled out in this patient.
The authors appropriately concluded that full evaluation
using non-invasive and minimally invasive procedures should
be made before considering brain or spinal biopsy, and
before an initiate treatment without pathological examination, sufficient evaluation of clinical and radiological conditions should be made (List et al., 2011). Therefore, our
patient was given a trial of low-dose methylprednisolone
120 mg intravenously for 5 days, then 80 mg per day intravenously for 2 weeks, followed by oral prednisolone at an
initial dose of 40 mg daily, maintenance immunosuppressive
therapy by oral prednisolone 10 mg per day was continued.
Within 2 weeks after the initial treatment with steroids
the symptoms improved dramatically and MRI showed
complete remission of the lesions in the medulla oblongata
and spinal cord (Fig. 2). Spinal cord biopsy was not performed. CSF examinations were performed 2 and 12 weeks
after the initial treatment with steroids, CSF analysis results
showed decrease of the opening pressure, cytology, protein
levels, IgG index and negative of the oligoclonal band
(Table 1). No relapse of symptoms was observed in our
patient for 6 months follow-up.
The diagnosis of CLIPPERS needs to carefully rule out
other similar diseases. Acute disseminated encephalomyelitis deserved particular attention, for the initial symptom
and CSF analysis, while this diagnosis was excluded by
the dramatic clinical and radiological response to steroids,
and without history of vaccination and infection of virus.
The patient had no symptoms of blurred vision and pain in
the eyes, anti-aquaporin-4 antibody were negative in serum
and CSF, the multiple punctate enhancement lesions within
the spinal cord and sensitive reaction to corticosteroids do
not support the diagnosis of neuromyelitis optica (NMO)
and NMO spectrum disorders. Additionally, the detailed
clinical, radiological, serological and CSF investigations
performed in this patient, together with the clinicoradiological response to steroid therapies were highly suggestive of an immune-mediated CNS inflammatory disorder. Other similar disorders including primary CNS
vasculitis, multiple sclerosis, paraneoplastic diseases,
neuro-behçet, neurosarcoidosis, and primary CNS lymphoma were carefully ruled out.
In this case, the key points were that no lesions of the
pons were observed and features of a related syndrome
were lacking, the ‘peppering’ lesions on post-contrast T1weighted magnetic resonance images were observed
predominantly in the spinal cord and sensitive reaction to
steroids, additionally, other similar diseases were carefully
ruled out, all these features matched the diagnosis of
CLIPPERS.
As the authors predicted, CLIPPERS may be under recognized and some features are not described in reported cases
(Taieb et al., 2011). In summary, CLIPPERS is a newly
defined disease, and clinicians may be unaware of the
clinic, radiological, treatment and natural course of the
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| BRAIN 2015: 138; 1–4
disease. Any new data would be helpful to improve the
understanding of the natural course of CLIPPERS.
References
List J, Lesemann A, Wiener E, Walter G, Hopmann D, Schreiber S,
et al. A new case of chronic lymphocytic inflammation with pontine
perivascular enhancement responsive to steroids. Brain 2011; 134,
e185; author reply e186.
Letter to the Editor
Pittock SJ, Debruyne J, Krecke KN, Giannini C, van den Ameele J, De
Herdt V, et al. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain
2010; 133: 2626–34.
Taieb G, Wacongne A, Renard D, Figarella-Branger D, Castelnovo G,
Labauge P. A new case of chronic lymphocytic inflammation with
pontine perivascular enhancement responsive to steroids with initial
normal magnetic resonance imaging. Brain 2011; 134: e182; author
reply e183.