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title, docid, authors, breadcrumbs, category, documentVersionId, imageCount, lastUpdated, pageDescription, pageKeywords, pageTitle, enhancedTitle, type, references, breadcrumbs
title docid authors breadcrumbs category documentVersionId imageCount lastUpdated pageDescription pageKeywords pageTitle enhancedTitle type references breadcrumbs
CLIPPERS ba394f3b-bbff-4128-90b5-3e1c07564c5f
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5cff4116-3654-4b3a-bb75-5ebe0b8c9850 Anne G. Osborn, MD, FACR
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Brain brain 6d8829f1-14d7-45af-8675-255189aa526a
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Diagnosis diagnosis 51c00394-446e-4a38-94af-d3b1d14d34e8
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Pathology-Based Diagnoses pathology-based-diagnoses d9d3a8ed-f21b-4831-8c77-591a3500ef77
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Infectious, Inflammatory, and Demyelinating Disease infectious-inflammatory-and-demyel- 7210f860-fe5f-4a2d-81cc-4fe06c769607
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Inflammatory and Demyelinating Disease inflammatory-and-demyelinating-dis- 62ab4dc3-dbf6-45a9-8532-f0e962aa62dc
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CLIPPERS clippers null
Brain 259b8c88-93cc-45d6-93d8-75d279e9ead2 12 08/05/20 CLIPPERS Brain, Diagnosis, Pathology-Based Diagnoses, Infectious, Inflammatory, and Demyelinating Disease, Inflammatory and Demyelinating Disease, CLIPPERS CLIPPERS | STATdx CLIPPERS DX true
Brain
Diagnosis
Pathology-Based Diagnoses
Infectious, Inflammatory, and Demyelinating Disease
Inflammatory and Demyelinating Disease
CLIPPERS

title: "CLIPPERS" docid: "ba394f3b-bbff-4128-90b5-3e1c07564c5f" authors:

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  • name: "CLIPPERS" slug: "clippers" treeNodeId: null category: "Brain" 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

    • Chronic lymphocytic inflammation withpontine perivascular enhancement responsive to steroids (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 outsidepontocerebellar 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

    • Chronic lymphocytic inflammation withpontine perivascular enhancement responsive to steroids (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

    • Dura, leptomeningeal lesions common
    • Pituitary-hypothalamus often affected

  • Vasculitis

    • Primary angiitis of CNS (PACNS), systemic vasculitides
    • Neuro-Behçet

  • Demyelinating Disease

    • Multiple sclerosis (MS), MOG antibody-associated disease
    • Seropositive autoimmune encephalitides

  • Lymphomatoid Granulomatosis

    • Brain often more diffusely involved

  • CNS Histiocytosis

    • 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

0e17b374-1564-4020-a6e2-552480332e98

References

Selected References

  1. Li Z et al: CLIPPERS, a syndrome of lymphohistiocytic disorders. Mult Scler Relat Disord. 42:102063, 2020
  2. Turnquist C et al: CLIPPERS: a case report with radiology, three serial biopsies and a literature review. Clin Neuropathol. 39(1):19-24, 2020
  3. 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
  4. Berzero G et al: CLIPPERS mimickers: relapsing brainstem encephalitis associated with anti-MOG antibodies. Eur J Neurol. 25(2):e16-7, 2018
  5. 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
  6. Tobin WO et al: Diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain. 140(9):2415-25, 2017
  7. Taieb G et al: Punctate and curvilinear gadolinium enhancing lesions in the brain: a practical approach. Neuroradiology. 58(3):221-35, 2016
  8. 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
  9. 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
  10. Pittock SJ et al: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain. 133(9):2626-34, 2010

Images

Selected Images

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 . 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.

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.

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.

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.

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 .

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.

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.

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 .

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.

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 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 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. 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.

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