347 lines
24 KiB
Markdown
347 lines
24 KiB
Markdown
---
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title: "CLIPPERS"
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docid: "ba394f3b-bbff-4128-90b5-3e1c07564c5f"
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authors:
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- key: "5cff4116-3654-4b3a-bb75-5ebe0b8c9850"
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value: "Anne G. Osborn, MD, FACR"
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breadcrumbs:
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-
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name: "Brain"
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slug: "brain"
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treeNodeId: "6d8829f1-14d7-45af-8675-255189aa526a"
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-
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name: "Diagnosis"
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slug: "diagnosis"
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treeNodeId: "51c00394-446e-4a38-94af-d3b1d14d34e8"
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-
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name: "Pathology-Based Diagnoses"
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slug: "pathology-based-diagnoses"
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treeNodeId: "d9d3a8ed-f21b-4831-8c77-591a3500ef77"
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-
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name: "Infectious, Inflammatory, and Demyelinating Disease"
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slug: "infectious-inflammatory-and-demyel-"
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treeNodeId: "7210f860-fe5f-4a2d-81cc-4fe06c769607"
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-
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name: "Inflammatory and Demyelinating Disease"
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slug: "inflammatory-and-demyelinating-dis-"
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treeNodeId: "62ab4dc3-dbf6-45a9-8532-f0e962aa62dc"
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-
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name: "CLIPPERS"
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slug: "clippers"
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treeNodeId: null
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category: "Brain"
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documentVersionId: "259b8c88-93cc-45d6-93d8-75d279e9ead2"
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imageCount: 12
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lastUpdated: "08/05/20"
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pageDescription: "CLIPPERS"
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pageKeywords: "Brain, Diagnosis, Pathology-Based Diagnoses, Infectious, Inflammatory, and Demyelinating Disease, Inflammatory and Demyelinating Disease, CLIPPERS"
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pageTitle: "CLIPPERS | STATdx"
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enhancedTitle: "CLIPPERS"
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type: "DX"
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references: true
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breadcrumbs:
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- "Brain"
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- "Diagnosis"
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- "Pathology-Based Diagnoses"
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- "Infectious, Inflammatory, and Demyelinating Disease"
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- "Inflammatory and Demyelinating Disease"
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- "CLIPPERS"
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---
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# KEY FACTS
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- ## Terminology
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- **C**hronic **l**ymphocytic **i**nflammation with**p**ontine **p**erivascular **e**nhancement **r**esponsive to **s**teroids (CLIPPERS)
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- ## Imaging
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- Location predominantly pons/cerebellum **but****may extend
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- Laterally into cerebellar peduncles or hemispheres
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- Rostrally into midbrain
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- Caudally into medulla, spinal cord
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- ≈ 60% have CNS lesions **outside**pontocerebellar region
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- Basal ganglia, hemispheric white matter, cortex
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- MR
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- Punctate/curvilinear enhancing foci "peppering" pons
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- May exhibit subtle radiating pattern
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- No ring or patchy enhancement
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- Patchy/"speckled" punctate hyperintensities on T2/FLAIR
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- Does not significantly exceed areas of T1 C+ enhancement
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- Caution: May begin as isolated, enhancing mass in pons/cerebellar peduncle before exhibiting typical pattern of multifocal punctate pontine lesions
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- ## Top Differential Diagnoses
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- Angiocentric (intravascular) lymphoma
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- Neurosarcoidosis
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- Demyelinating disease (multiple sclerosis, MOG spectrum)
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- Vasculitis (primary, secondary, Behçet)
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- Lymphomatoid granulomatosis
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- Histiocytosis (e.g., hemophagocytic lymphohistiocytosis)
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- ## Pathology
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- Perivascular predominance lymphohistiocytic infiltrates + diffuse adjacent parenchymal inflammatory infiltrate
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- May be type of macrophage activation syndrome (secondary hemophagocytic lymphohistiocytosis)
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- ## Clinical Issues
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- Mean age at onset 50 years (range: 13-86 years)
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- Subacute pontocerebeller dysfunction
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- Often relapsing-remitting course (without treatment)
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- Keep in mind: CLIPPERS is diagnosis of exclusion!
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# TERMINOLOGY
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- ## Abbreviations
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- **C**hronic **l**ymphocytic **i**nflammation with**p**ontine **p**erivascular **e**nhancement responsive to **s**teroids (CLIPPERS)
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- ## Definitions
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- Recently described inflammatory CNS disorder
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- Distinct form of nonneoplastic encephalitis with predominant T-cell pathology
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- Predominantly involves brainstem, adjacent rhombencephalic structures
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- Striking clinical, imaging response to glucocorticosteroids
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# IMAGING
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- ## General Features
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- ### Best diagnostic clue
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- Enhancing punctate/curvilinear lesions "peppering" pons
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- ### Location
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- Predominantly pons/cerebellum **but**may extend
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- Caudally into medulla, spinal cord
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- Rostrally into midbrain
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- ≈ 60% have CNS lesions **outside** pontocerebellar region
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- Basal ganglia, hemispheric white matter, cortex
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- Meningeal inflammation
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- Caution: May begin as isolated, enhancing mass in pons/cerebellar peduncle before exhibiting typical pattern of multifocal punctate pontine lesions
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- ### Size
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- Usually (but not always) ≤ 3mm
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- ### Morphology
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- Typically small, punctate or curvilinear
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- ## CT Findings
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- Usually normal
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- ## MR Findings
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- ### T1WI
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- Usually normal
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- Pontocerebellar/cerebellar, cord, cerebral atrophy may be late changes
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- ### T2WI
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- ± faint, patchy or "speckled" punctate hyperintensities on T2/FLAIR
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- Minimal or no mass effect, vasogenic edema
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- Homogeneous hyperintensity; does not significantly exceed T1 C+ enhancement
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- ### T2* GRE
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- Usually negative
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- ### DWI
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- Usually absent
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- ### T1WI C+
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- Punctate &/or curvilinear enhancing foci ("peppering" pons)
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- No ring or patchy enhancement
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- ↓ to absence of enhancement following steroids
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- ## Angiographic Findings
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- DSA normal without evidence for vasculitis
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- ## Imaging Recommendations
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- ### Best imaging tool
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- MR ± contrast (include coronal T1C+), DWI, T2*
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# DIFFERENTIAL DIAGNOSIS
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- ## Lymphoma, Angiocentric (Intravascular)
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- Stroke-like symptoms, dementia
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- Hemorrhage, foci of restricted diffusion common
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- [Neurosarcoidosis](/document/neurosarcoid/fef69139-0019-4be3-9bdc-e26bc3644251)
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- Dura, leptomeningeal lesions common
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- Pituitary-hypothalamus often affected
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- [Vasculitis](/document/miscellaneous-vasculitis/5a4d4cbd-67e3-4722-8a44-8d411cbb98f0)
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- Primary angiitis of CNS (PACNS), systemic vasculitides
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- Neuro-Behçet
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- [Demyelinating Disease](/document/multiple-sclerosis/7892b2a2-f52a-4d7f-9858-a326f2b7ab04)
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- Multiple sclerosis (MS), MOG antibody-associated disease
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- Seropositive autoimmune encephalitides
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- ## Lymphomatoid Granulomatosis
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- Brain often more diffusely involved
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- [CNS Histiocytosis](/document/langerhans-cell-histiocytosis-skul-/6515bdbb-ce3d-47ef-9930-2dbb1949f807)
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- Hemophagocytic lymphohistiocytosis (HLH) resembles CLIPPERS on brain biopsy
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# PATHOLOGY
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- ## General Features
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- ### Etiology
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- May be type of macrophage activation syndrome (secondary HLH)
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- ## Microscopic Features
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- Perivascular predominance lymphohistiocytic infiltrates + diffuse adjacent parenchymal inflammatory infiltrate
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- Marked CD3-positive T lymphocytes, variable macrophage components
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- Variable tissue destruction, astrogliosis, myelin loss
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# CLINICAL ISSUES
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- ## Presentation
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- ### Most common signs/symptoms
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- Subacute pontocerebeller dysfunction
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- ± other CNS symptoms (e.g., cognitive dysfunction, myelopathy)
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- ## Demographics
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- ### Age
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- Mean age at onset 50 years (range: 13-86 years)
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- ### Sex
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- M:F = 3:1
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- ## Natural History & Prognosis
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- Generally subacute presentation
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- Often relapsing-remitting course (without treatment)
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- Relapse rare when daily glucocorticoids ≥ 30 mg
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- Diagnosis of exclusion
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- Requires careful exclusion of alternative diagnoses
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- ## Treatment
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- Corticosteroids (marked clinical, imaging response key to diagnosis)
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- Corticosteroid responsiveness also common but not universal in non-CLIPPERS diagnoses
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- Relapse off treatment common
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- Hydroxychloroquine has been reported to induce, maintain remission of symptoms
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0e17b374-1564-4020-a6e2-552480332e98
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## References
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# Selected References
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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## Images
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### Selected Images
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*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 <img src='img/arrows/WO.png'/> and medulla <img src='img/arrows/WS.png'/>.*
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*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 <img src='img/arrows/WO.png'/> and medulla <img src='img/arrows/WS.png'/>.*
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*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 <img src='img/arrows/WO.png'/> and medulla <img src='img/arrows/WS.png'/>.*
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*Axial T1 C+ MR in the same patient shows multiple punctate and curvilinear enhancing foci "peppering" the pons <img src='img/arrows/WS.png'/>. Additional lesions are present in both cerebellar peduncles, vermis, and the left cerebellar hemisphere.*
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*Axial T1 C+ MR in the same patient shows multiple punctate and curvilinear enhancing foci "peppering" the pons <img src='img/arrows/WS.png'/>. Additional lesions are present in both cerebellar peduncles, vermis, and the left cerebellar hemisphere.*
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*More cephalad T1 C+ MR scan in the same patient shows the punctate <img src='img/arrows/WS.png'/> and curvilinear <img src='img/arrows/WC.png'/> lesions involving the upper pons.*
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*More cephalad T1 C+ MR scan in the same patient shows the punctate <img src='img/arrows/WS.png'/> and curvilinear <img src='img/arrows/WC.png'/> lesions involving the upper pons.*
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*Coronal T1 C+ FS MR in the same patient shows the lesions "peppering" the pons. Note cephalad extension into the cerebral peduncles <img src='img/arrows/WO.png'/> and inferior extension into the medulla <img src='img/arrows/WC.png'/> and upper cervical cord <img src='img/arrows/WS.png'/>. DSA (not shown) was negative. The lesions resolved with corticosteroids, so this is a presumed case of CLIPPERS.*
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*Coronal T1 C+ FS MR in the same patient shows the lesions "peppering" the pons. Note cephalad extension into the cerebral peduncles <img src='img/arrows/WO.png'/> and inferior extension into the medulla <img src='img/arrows/WC.png'/> and upper cervical cord <img src='img/arrows/WS.png'/>. DSA (not shown) was negative. The lesions resolved with corticosteroids, so this is a presumed case of CLIPPERS.*
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### Additional Images
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*Sagittal FLAIR in a 52-year-old man with diplopia, dysarthria, and facial numbness shows confluent hyperintensity in the pons <img src='img/arrows/WS.png'/>.*
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*Sagittal FLAIR in a 52-year-old man with diplopia, dysarthria, and facial numbness shows confluent hyperintensity in the pons <img src='img/arrows/WS.png'/>.*
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*Axial T1 C+ MR shows scattered, faint, punctate enhancing foci <img src='img/arrows/WS.png'/> as well as larger confluent, nodular <img src='img/arrows/WO.png'/>, and partial ring-enhancing <img src='img/arrows/WC.png'/> lesions in the pons.*
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*Axial T1 C+ MR shows scattered, faint, punctate enhancing foci <img src='img/arrows/WS.png'/> as well as larger confluent, nodular <img src='img/arrows/WO.png'/>, and partial ring-enhancing <img src='img/arrows/WC.png'/> lesions in the pons.*
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*Coronal T1 C+ MR in the same patient shows large, confluent, patchy enhancing lesions <img src='img/arrows/WS.png'/> in the pons. Differential diagnosis included lymphoma, lymphomatoid granulomatosis, vasculitis, and CLIPPERS. The patient improved on steroids.*
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*Coronal T1 C+ MR in the same patient shows large, confluent, patchy enhancing lesions <img src='img/arrows/WS.png'/> in the pons. Differential diagnosis included lymphoma, lymphomatoid granulomatosis, vasculitis, and CLIPPERS. The patient improved on steroids.*
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*Sagittal FLAIR in the same patient obtained a year later when symptoms relapsed off steroids shows multiple punctate hyperintensities "peppering" the pons <img src='img/arrows/WS.png'/> and medulla <img src='img/arrows/WC.png'/>. Note extension into upper spinal cord <img src='img/arrows/WO.png'/>.*
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*Sagittal FLAIR in the same patient obtained a year later when symptoms relapsed off steroids shows multiple punctate hyperintensities "peppering" the pons <img src='img/arrows/WS.png'/> and medulla <img src='img/arrows/WC.png'/>. Note extension into upper spinal cord <img src='img/arrows/WO.png'/>.*
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*Axial T1 C + FS MR in the same patient shows small, punctate foci of enhancement <img src='img/arrows/WS.png'/> "peppering" the pons, cerebellar peduncles.*
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*Axial T1 C + FS MR in the same patient shows small, punctate foci of enhancement <img src='img/arrows/WS.png'/> "peppering" the pons, cerebellar peduncles.*
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*More inferior T1 C+ FS MR in the same patient shows additional small enhancing foci in the medulla <img src='img/arrows/WS.png'/>.*
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*More cephalad T1 C+ FS MR in the same patient shows additional lesions in the midbrain <img src='img/arrows/WS.png'/> and medial temporal lobe <img src='img/arrows/WC.png'/>.*
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*More cephalad T1 C+ FS MR in the same patient shows a solitary enhancing lesion <img src='img/arrows/WS.png'/> 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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