---
title: "CLIPPERS"
docid: "ba394f3b-bbff-4128-90b5-3e1c07564c5f"
authors:
- key: "5cff4116-3654-4b3a-bb75-5ebe0b8c9850"
value: "Anne G. Osborn, MD, FACR"
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name: "CLIPPERS"
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documentVersionId: "259b8c88-93cc-45d6-93d8-75d279e9ead2"
imageCount: 12
lastUpdated: "08/05/20"
pageDescription: "CLIPPERS"
pageKeywords: "Brain, Diagnosis, Pathology-Based Diagnoses, Infectious, Inflammatory, and Demyelinating Disease, Inflammatory and Demyelinating Disease, CLIPPERS"
pageTitle: "CLIPPERS | STATdx"
enhancedTitle: "CLIPPERS"
type: "DX"
references: true
breadcrumbs:
- "Brain"
- "Diagnosis"
- "Pathology-Based Diagnoses"
- "Infectious, Inflammatory, and Demyelinating Disease"
- "Inflammatory and Demyelinating Disease"
- "CLIPPERS"
---
# KEY FACTS
- ## Terminology
- **C**hronic **l**ymphocytic **i**nflammation with**p**ontine **p**erivascular **e**nhancement **r**esponsive to **s**teroids (CLIPPERS)
- ## Imaging
- Location predominantly pons/cerebellum **but****may extend
- Laterally into cerebellar peduncles or hemispheres
- Rostrally into midbrain
- Caudally into medulla, spinal cord
- ≈ 60% have CNS lesions **outside**pontocerebellar region
- Basal ganglia, hemispheric white matter, cortex
- MR
- Punctate/curvilinear enhancing foci "peppering" pons
- May exhibit subtle radiating pattern
- No ring or patchy enhancement
- Patchy/"speckled" punctate hyperintensities on T2/FLAIR
- Does not significantly exceed areas of T1 C+ enhancement
- Caution: May begin as isolated, enhancing mass in pons/cerebellar peduncle before exhibiting typical pattern of multifocal punctate pontine lesions
- ## Top Differential Diagnoses
- Angiocentric (intravascular) lymphoma
- Neurosarcoidosis
- Demyelinating disease (multiple sclerosis, MOG spectrum)
- Vasculitis (primary, secondary, Behçet)
- Lymphomatoid granulomatosis
- Histiocytosis (e.g., hemophagocytic lymphohistiocytosis)
- ## Pathology
- Perivascular predominance lymphohistiocytic infiltrates + diffuse adjacent parenchymal inflammatory infiltrate
- May be type of macrophage activation syndrome (secondary hemophagocytic lymphohistiocytosis)
- ## Clinical Issues
- Mean age at onset 50 years (range: 13-86 years)
- Subacute pontocerebeller dysfunction
- Often relapsing-remitting course (without treatment)
- Keep in mind: CLIPPERS is diagnosis of exclusion!
# TERMINOLOGY
- ## Abbreviations
- **C**hronic **l**ymphocytic **i**nflammation with**p**ontine **p**erivascular **e**nhancement responsive to **s**teroids (CLIPPERS)
- ## Definitions
- Recently described inflammatory CNS disorder
- Distinct form of nonneoplastic encephalitis with predominant T-cell pathology
- Predominantly involves brainstem, adjacent rhombencephalic structures
- Striking clinical, imaging response to glucocorticosteroids
# IMAGING
- ## General Features
- ### Best diagnostic clue
- Enhancing punctate/curvilinear lesions "peppering" pons
- ### Location
- Predominantly pons/cerebellum **but**may extend
- Caudally into medulla, spinal cord
- Rostrally into midbrain
- ≈ 60% have CNS lesions **outside** pontocerebellar region
- Basal ganglia, hemispheric white matter, cortex
- Meningeal inflammation
- Caution: May begin as isolated, enhancing mass in pons/cerebellar peduncle before exhibiting typical pattern of multifocal punctate pontine lesions
- ### Size
- Usually (but not always) ≤ 3mm
- ### Morphology
- Typically small, punctate or curvilinear
- ## CT Findings
- Usually normal
- ## MR Findings
- ### T1WI
- Usually normal
- Pontocerebellar/cerebellar, cord, cerebral atrophy may be late changes
- ### T2WI
- ± faint, patchy or "speckled" punctate hyperintensities on T2/FLAIR
- Minimal or no mass effect, vasogenic edema
- Homogeneous hyperintensity; does not significantly exceed T1 C+ enhancement
- ### T2* GRE
- Usually negative
- ### DWI
- Usually absent
- ### T1WI C+
- Punctate &/or curvilinear enhancing foci ("peppering" pons)
- No ring or patchy enhancement
- ↓ to absence of enhancement following steroids
- ## Angiographic Findings
- DSA normal without evidence for vasculitis
- ## Imaging Recommendations
- ### Best imaging tool
- MR ± contrast (include coronal T1C+), DWI, T2*
# DIFFERENTIAL DIAGNOSIS
- ## Lymphoma, Angiocentric (Intravascular)
- Stroke-like symptoms, dementia
- Hemorrhage, foci of restricted diffusion common
- [Neurosarcoidosis](/document/neurosarcoid/fef69139-0019-4be3-9bdc-e26bc3644251)
- Dura, leptomeningeal lesions common
- Pituitary-hypothalamus often affected
- [Vasculitis](/document/miscellaneous-vasculitis/5a4d4cbd-67e3-4722-8a44-8d411cbb98f0)
- Primary angiitis of CNS (PACNS), systemic vasculitides
- Neuro-Behçet
- [Demyelinating Disease](/document/multiple-sclerosis/7892b2a2-f52a-4d7f-9858-a326f2b7ab04)
- Multiple sclerosis (MS), MOG antibody-associated disease
- Seropositive autoimmune encephalitides
- ## Lymphomatoid Granulomatosis
- Brain often more diffusely involved
- [CNS Histiocytosis](/document/langerhans-cell-histiocytosis-skul-/6515bdbb-ce3d-47ef-9930-2dbb1949f807)
- Hemophagocytic lymphohistiocytosis (HLH) resembles CLIPPERS on brain biopsy
# PATHOLOGY
- ## General Features
- ### Etiology
- May be type of macrophage activation syndrome (secondary HLH)
- ## Microscopic Features
- Perivascular predominance lymphohistiocytic infiltrates + diffuse adjacent parenchymal inflammatory infiltrate
- Marked CD3-positive T lymphocytes, variable macrophage components
- Variable tissue destruction, astrogliosis, myelin loss
# CLINICAL ISSUES
- ## Presentation
- ### Most common signs/symptoms
- Subacute pontocerebeller dysfunction
- ± other CNS symptoms (e.g., cognitive dysfunction, myelopathy)
- ## Demographics
- ### Age
- Mean age at onset 50 years (range: 13-86 years)
- ### Sex
- M:F = 3:1
- ## Natural History & Prognosis
- Generally subacute presentation
- Often relapsing-remitting course (without treatment)
- Relapse rare when daily glucocorticoids ≥ 30 mg
- Diagnosis of exclusion
- Requires careful exclusion of alternative diagnoses
- ## Treatment
- Corticosteroids (marked clinical, imaging response key to diagnosis)
- Corticosteroid responsiveness also common but not universal in non-CLIPPERS diagnoses
- Relapse off treatment common
- Hydroxychloroquine has been reported to induce, maintain remission of symptoms
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## References
# Selected References
1. [Li Z et al: CLIPPERS, a syndrome of lymphohistiocytic disorders. Mult Scler Relat Disord. 42:102063, 2020](http://www.ncbi.nlm.nih.gov/pubmed/?term=32234602%5Bpmid%5D)
1. [Turnquist C et al: CLIPPERS: a case report with radiology, three serial biopsies and a literature review. Clin Neuropathol. 39(1):19-24, 2020](http://www.ncbi.nlm.nih.gov/pubmed/?term=31661071%5Bpmid%5D)
1. [Taieb G et al: CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS. J Neurol Neurosurg Psychiatry. 90(9):1027-38, 2019](http://www.ncbi.nlm.nih.gov/pubmed/?term=31072955%5Bpmid%5D)
1. [Berzero G et al: CLIPPERS mimickers: relapsing brainstem encephalitis associated with anti-MOG antibodies. Eur J Neurol. 25(2):e16-7, 2018](http://www.ncbi.nlm.nih.gov/pubmed/?term=29356261%5Bpmid%5D)
1. [Tian D et al: Case 259: Primary central nervous system lymphomatoid granulomatosis mimicking chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Radiology. 289(2):572-7, 2018](http://www.ncbi.nlm.nih.gov/pubmed/?term=30332362%5Bpmid%5D)
1. [Tobin WO et al: Diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain. 140(9):2415-25, 2017](http://www.ncbi.nlm.nih.gov/pubmed/?term=29050399%5Bpmid%5D)
1. [Taieb G et al: Punctate and curvilinear gadolinium enhancing lesions in the brain: a practical approach. Neuroradiology. 58(3):221-35, 2016](http://www.ncbi.nlm.nih.gov/pubmed/?term=26700824%5Bpmid%5D)
1. [Gul M et al: Atypical presentation of CLIPPERS syndrome: a new entity in the differential diagnosis of central nervous system rheumatologic diseases. J Clin Rheumatol. 21(3):144-8, 2015](http://www.ncbi.nlm.nih.gov/pubmed/?term=25807094%5Bpmid%5D)
1. [Dudesek A et al: CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. Review of an increasingly recognized entity within the spectrum of inflammatory central nervous system disorders. Clin Exp Immunol. 175(3):385-96, 2014](http://www.ncbi.nlm.nih.gov/pubmed/?term=24028073%5Bpmid%5D)
1. [Pittock SJ et al: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain. 133(9):2626-34, 2010](http://www.ncbi.nlm.nih.gov/pubmed/?term=20639547%5Bpmid%5D)
## Images
### Selected Images
and medulla 
.](images/app.statdx.com_image_thumbnail_3b810ab1-5bad-4ec7-936d-bc3cf0683b4d_annotated_true_size_900_quality_90_665175a0_20251018T122457Z.jpg)
*Sagittal FLAIR MR in a 56-year-old woman with weight loss and a 3-week history of diplopia and disequilibrium shows confluent and punctate hyperintensities in the pons and medulla .*
*Sagittal FLAIR MR in a 56-year-old woman with weight loss and a 3-week history of diplopia and disequilibrium shows confluent and punctate hyperintensities in the pons and medulla .*
*Sagittal FLAIR MR in a 56-year-old woman with weight loss and a 3-week history of diplopia and disequilibrium shows confluent and punctate hyperintensities in the pons and medulla .*
*Axial T1 C+ MR in the same patient shows multiple punctate and curvilinear enhancing foci "peppering" the pons . Additional lesions are present in both cerebellar peduncles, vermis, and the left cerebellar hemisphere.*
*Axial T1 C+ MR in the same patient shows multiple punctate and curvilinear enhancing foci "peppering" the pons . Additional lesions are present in both cerebellar peduncles, vermis, and the left cerebellar hemisphere.*
lesions involving the upper pons.](images/app.statdx.com_image_thumbnail_bbe0d150-9cfd-4e4c-b8ca-2d1adceadb6b_annotated_true_size_900_quality_90_8ea0b444_20251018T122457Z.jpg)
*More cephalad T1 C+ MR scan in the same patient shows the punctate and curvilinear lesions involving the upper pons.*
*More cephalad T1 C+ MR scan in the same patient shows the punctate and curvilinear lesions involving the upper pons.*
*Coronal T1 C+ FS MR in the same patient shows the lesions "peppering" the pons. Note cephalad extension into the cerebral peduncles and inferior extension into the medulla and upper cervical cord . DSA (not shown) was negative. The lesions resolved with corticosteroids, so this is a presumed case of CLIPPERS.*
*Coronal T1 C+ FS MR in the same patient shows the lesions "peppering" the pons. Note cephalad extension into the cerebral peduncles and inferior extension into the medulla and upper cervical cord . DSA (not shown) was negative. The lesions resolved with corticosteroids, so this is a presumed case of CLIPPERS.*
### Additional Images
*Sagittal FLAIR in a 52-year-old man with diplopia, dysarthria, and facial numbness shows confluent hyperintensity in the pons .*
*Sagittal FLAIR in a 52-year-old man with diplopia, dysarthria, and facial numbness shows confluent hyperintensity in the pons .*
*Axial T1 C+ MR shows scattered, faint, punctate enhancing foci as well as larger confluent, nodular , and partial ring-enhancing lesions in the pons.*
*Axial T1 C+ MR shows scattered, faint, punctate enhancing foci as well as larger confluent, nodular , and partial ring-enhancing lesions in the pons.*
*Coronal T1 C+ MR in the same patient shows large, confluent, patchy enhancing lesions in the pons. Differential diagnosis included lymphoma, lymphomatoid granulomatosis, vasculitis, and CLIPPERS. The patient improved on steroids.*
*Coronal T1 C+ MR in the same patient shows large, confluent, patchy enhancing lesions in the pons. Differential diagnosis included lymphoma, lymphomatoid granulomatosis, vasculitis, and CLIPPERS. The patient improved on steroids.*
*Sagittal FLAIR in the same patient obtained a year later when symptoms relapsed off steroids shows multiple punctate hyperintensities "peppering" the pons and medulla . Note extension into upper spinal cord .*
*Sagittal FLAIR in the same patient obtained a year later when symptoms relapsed off steroids shows multiple punctate hyperintensities "peppering" the pons and medulla . Note extension into upper spinal cord .*
*Axial T1 C + FS MR in the same patient shows small, punctate foci of enhancement "peppering" the pons, cerebellar peduncles.*
*Axial T1 C + FS MR in the same patient shows small, punctate foci of enhancement "peppering" the pons, cerebellar peduncles.*
*More inferior T1 C+ FS MR in the same patient shows additional small enhancing foci in the medulla .*
*More cephalad T1 C+ FS MR in the same patient shows additional lesions in the midbrain and medial temporal lobe .*
*More cephalad T1 C+ FS MR in the same patient shows a solitary enhancing lesion in the subcortical white matter of the "hand knob." One of the cerebellar lesions was biopsied and disclosed CD4+ T-cell perivascular infiltrates, consistent with CLIPPERS. In rare cases, CLIPPERS initially manifests as a more mass-like confluent pontine lesion before the typical peppering pattern emerges.*