Neurosarcoidosis, Pachymeningitis, Behcet’s...
Transcript of Neurosarcoidosis, Pachymeningitis, Behcet’s...
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Neurosarcoidosis,Pachymeningitis, Behcet’s Disease
Jeffrey M. Gelfand, MD, MAS, FAANAssistant Professor of Clinical Neurology
UCSF Department of NeurologyMS and Neuroinflammation Center
AAN 2018 – Los AngelesNeuro-Rheumatology Course
Disclosures
Dr. Gelfand reports research support from Genentech and MedDay (both to UCSF).
Dr. Gelfand serves a steering committee member for a clinical trial sponsored by Genentech.
Dr. Gelfand has received personal compensation for medical legal consulting from government and commercial entities for medical legal consulting.
Dr. Gelfand receives grant support for training clinical fellows from the National MS Society.
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Objectives
1)Neurosarcoidosis Update
2)Pachymeningitis Update
3)Behcet’s Disease Update
Sarcoidosis
Autoinflammatory, multisystem disorder,characterized by non-necrotizing granulomatous
inflammation histopathologically
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80X
7X 3-5X0
20
40
60
80Complex genetic disorder
Genetics of Sarcoidosis
Sverrild, et. al. Thorax 2008; Rybicki, et. al. Am J Epidemiol 2001; Rybicki, et. al. AJRCCM 2001
Sarcoidosis- 35-71/100,000 prevalence African-Americans- 3X more common age-adjusted incidence in African Americans than Whites
Neurosarcoidosis- 1/100,000 Southwest England/Wales - Disease of working age adults
Rivera, American Journal of Respiratory and Critical Care Medicine, 2016
Sarcoidosis Immunology• Understanding is based almost entirely on pulmonary and blood samples
from patients with pulmonary/systemic sarcoidosis – no good animal model of sarcoidosis, yet – need for modern studies of sarcoidosis neuroinflammation
• CD4 T cells isolated from people with sarcoidosis are partially oligoclonaland presumed to be antigen specific.
• Emerging role of Th17.1 (vs classical TH1)
Ramstein and Koth, et. al., AJRCCM 2015
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The granuloma – Hallmark of Sarcoidosis
Leptomeninges, H&E, Neurosarcoidosis
H&E
H&E CD68 (Macrophage)
Multinucleated Giant Cell
Hilar Lymph Node, Higher PowerHilar Lymph Node
AFB GMS
H&E
H&E
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Blindness
Corticosteroids + Azathioprine
Hypopituitarism
First available
archived MRI,
age 40
2.4 years later 2.7 years 3.3 years 4.1 years 8 years 9.25 years 9.67 years 9.75 years 9.9 years
Infliximab 5 mg/kg load
then Q8 weeks
Cognitive Impairment
Infliximab 7 mg/kg
Q6 weeks
Cognitive Problems Resolved
Brain Biopsy
CSF Exam
7 WBC
Glucose 52
Protein 112
IgG Index 0.9
4 OCBs
CSF ACE <3
CSF Exam
9 WBC
Glucose 50
Protein 81
CSF ACE<3
10.8 years
First available
archived MRI,
age 40
2.4 years later 2.7 years 3.3 years 4.1 years 8 years 9.25 years 9.67 years 9.75 years 9.9 years 10.8 years
Progression of CNS Sarcoidosis for over a decade…Viewed through the lens of granuloma maintenance
Gelfand, Bradshaw, et. al. Neurology 2017
Volkman et. al., Science 2010
Interfering with granuloma maintenance as a therapeutic strategy?
- Is continuous blood-brain barrier crossing of macrophages/T cells/?other necessary for granuloma maintenance in the CNS?
- Granulomas are thought to be dynamic structures. Are there more targeted therapeutic approaches we should be considering when treating sarcoidosis and CNS sarcoidosis specifically?
- Role of “resident macrophages” (i.e. microglia) vs monocytes/macrophages derived from the periphery?
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Infection and Sarcoidosis? Pathogenesis? Shared pathways?
• Many postulated agents, none confirmed
• Antigenic responses to mycobacterial proteins
• Active pulmonary sarcoidosis and active TB gene expression similar
• Concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) can improve chronic skin/lung sarcoidosis -antimicrobial vs anti-inflammatory effects?
Koth, L, et. al. AJRCCM, 2011
Metagenomic deep sequencing (MDS) of CSF Negative in Biopsy-confirmed Neurosarcoidosis
• MDS of CSF in a prospective cohort of subjects with diagnostically challenging subacute or chronic leptomeningitis with or without encephalitis
• MDS of CSF identified a causative pathogen in some (i.e. Taenia solium, (neurocysticercosis), Cryptococcus neoformans, HIV-1, others)
• No organisms identified in clinically presumed non-infectious cases including CNS sarcoidosis (N=8)
Wilson*, Donovan*, Gelfand*, Derisi, et. al. JAMA Neurology, 2018
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Defining Neurosarcoidosis: Challenges
Definite – CNS Biopsy confirmation of non-caseatinggranulomatous inflammation in a patient with a typical clinical syndrome
Probable – CSF or MRI evidence of inflammation plus evidence of systemic sarcoid by biopsy, Kveim testing or 2 out of 3 of the following: gallium scan, chest imaging, elevated ACE (??)
Possible – Typical Clinical Syndrome
Zajicek, et. al., QJM, 1999
Gelfand and Stern, Neurosarcoidosis, Scientific American Neurology 2015and consistent with Judson, et. al., Sarcoidosis Vasc Diffuse Lung Dis 2014
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Sarcoidosis vs “Sarcoid-like” reactions
• Classically a “multisystem” disease
• However, “sarcoidosis-like” reactions can occur in the context of inflammatory reactions to cancer; can also be organ specific (gut, skin, ??? CNS)
• ~20-30% of pathology proven neurosarcoidosiscases are “isolated” to the CNS – is this the same disease or should we carve these out conceptually as “non-infectious sarcoid-like reaction of the CNS”?
Lancet, 2002
Small Fiber Neuropathy in Sarcoidosis
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CNS Sarcoidosis (UCSF Experience)Total CNS Sarcoidosis (Biopsy-proven) N=53Definite/Highly Probable (CNS Biopsy) N=26
Probable (extra-CNS Biopsy) N=27
Age at neurological syndrome onset 43 years (IQR 36 to 50), range 21-68 years
Female 53%
BlackWhite Non-HispanicWhite HispanicOther
36%48%11%5%
Family history of sarcoidosis 8%
Known sarcoidosis at time of neurological presentation
10%
(90% did NOT have known sarcoidosis at first neurological presentation!)
Evidence of pulmonary sarcoidosis at time of neurological presentation
58%(and almost 30% are isolated CNS)
Whole Body PET provided diagnostic insight beyond conventional CT
5/12 (39%)
Gelfand, et al. In preparation
Challenge of Biomarkers - CNS Sarcoidosis
Biopsy Proven CNS Sarcoidosis N=53
Serum ACE Elevated (>67)N=35 14%
CSF ACE elevatedN=22 14%
CSF Pleocytosis (>5 WBC)N=44 80%
CSF Protein elevation (>50)N=44 73%
CSF Glucose Abnormally LowN=41 27%
IgG index elevatedN=44 36%
Gelfand, et al. In preparation
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CNS Sarcoidosis – Pearls
1) Infiltrates within favored CNS sites
2) Tends to spread locally
3) Often involves adjacent meninges
4) Causes a clinical syndrome that reflects the underlying affected neuroanatomy
Evaluation of suspected neurosarcoidosis
• A chest CT with contrast is probably the most helpful test to survey for pulmonary involvement when there is a high pretest probability/index of suspicion
• When the Chest CT is negative, a whole-body FDG-PET can be valuable to identify sites of metabolically active disease, including “hot” lymph nodes that can be normal in size (and thereby appear normal on CT)
• Survey the entire neuroaxis, as there can be distant, subclinical sites of disease involvement
• Tissue diagnosis is favored
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Real-world example of CNS Sarcoidosis evaluation…
7 months prior (after MVA)
T2 T1 Post-Gadolinium (sequential cuts) T1 PostT2
6 months later
Whole body FDG-PET in sarcoidosis
Transbronchial biopsy: Non-caseating granulomas consistent
with sarcoidosis
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CNS Sarcoidosis - Clinical Pearls
- The affected neuroanatomy determines the clinical syndrome
- Abnormal contrast enhancement -- most typically nodular/lobulated +/- perivenular, & often involving overlying meninges (pia), is a sign of active neurosarcoidosis
Syndrome: Optic Neuropathy
FLAIR
T1 Post-Contrast
T1 Post-
Contrast
CNS Biopsy: Noncaseating Granulomatous Inflammation
T1 Post-
Contrast
FLAIR
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Sagittal T1 Post-GadCoronal T1 Post-Gad
Syndrome: Hypopituitarism, headaches
T1 Post-Gad over time shows extension into
periventricular meningeal spaces
Annals of Neurology, 2016
-- Subpial enhancement 62% NS vs 12% NMO
-- Ring Enhancement 0% NS vs 35% NMO
-- Spinal cord PET 50% NS vs 0% NMO (small sample for both)
-- Low CSF glucose 11% NS vs 0% NMO
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Sarcoidosis Myelitis
7 months prior (after MVA)
T2 T1 Post-Gadolinium (sequential cuts) T1 PostT2
6 months later
Neuromyelitis Optica(+AQP4 IgG,
astrocytic target)
For Comparison
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Syndrome: optic neuropathy, myelopathy, cognitive impairment
T2 T1 Post-Gad
T1 Post-Gad
T2 Sagittal
T2 Axial
T1 Post-Gad
T1 Post-Gad
Syndrome: Myelopathy
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Nodular enhancing appearance on MRI –Syndrome: Meningitis then Progressive Myelopathy
T2 Sagittal
T2 Axial
T1 Post-Gad
T1 Post-Gad
T1 Post-Gad
T1 Post-Gad
Nodular enhancing appearance on MRI (same patient as last slide)
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CNS Sarcoidosis – Observations - 2
- “Relapses” tend to occur in anatomical sites of previous disease activity
- Resolution of abnormal MRI enhancement is usually a good indicator of remission (whereas T2/FLAIR lesions can persist)
- CSF can be an important marker of disease activity even when the MRI is negative
Blindness
Corticosteroids + Azathioprine
Hypopituitarism
First available
archived MRI,
age 40
2.4 years later 2.7 years 3.3 years 4.1 years 8 years 9.25 years 9.67 years 9.75 years 9.9 years
Infliximab 5 mg/kg load
then Q8 weeks
Cognitive Impairment
Infliximab 7 mg/kg
Q6 weeks
Cognitive Problems Resolved
Brain Biopsy
CSF Exam
7 WBC
Glucose 52
Protein 112
IgG Index 0.9
4 OCBs
CSF ACE <3
CSF Exam
9 WBC
Glucose 50
Protein 81
CSF ACE<3
10.8 years
First available
archived MRI,
age 40
2.4 years later 2.7 years 3.3 years 4.1 years 8 years 9.25 years 9.67 years 9.75 years 9.9 years 10.8 years
Progression of CNS Sarcoidosis for over a decade…Viewed through the lens of granuloma maintenance
Gelfand, Bradshaw, et. al. Neurology 2017
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A 6 Year View of Biopsy-Proven CNS Sarcoidosis…The disease spreads by regional propagation, waxing and waning over years
Baseline 40 months4 months 22 months 2 years 27 months 28 months 30 months 3 years
42 months 4 years 53 months 56 months 59 months 65 months 66 months 69 months 70 months
CNS biopsy
Corticosteroids, taper then increase, then taper… Methotrexate trial
Stopped
Steroids
Stopped
methotrexatePred
60 mg
Taper Pred
10 mgPulse steroids + azathioprine
Infliximab
Baseline + 1 month
Baseline
+ 3 months
+ 6 months+ 3 months + 7 months
+ 7 months + 11 months + 14 months
IV Contrast
not given
for this study
+ 6 months
+ 11 months + 14 months+ 1 month
Biopsy-Proven CNS Sarcoidosis over the course of a year
Optic Nerve Sheath BiopsyCSF:67 WBC
Glucose 44 (serum 99)
Protein 89
IV then PO corticosteroids Steroid Taper Steroids + MTX Infliximab
Bilateral vision loss, weight loss
fatigue, hyponatremiaBack to Normal
Vision worsens,
Hyponatremia againSubstantial but incomplete visual recovery
(severe constricted fields)
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Treatment - CNS Sarcoidosis
- Treat organ system involvement, not “sarcoidosis”
- Not all manifestations of sarcoidosis need to be treated, but prominent CNS sarcoidosis usually does
- Aggressive immunosuppression is often needed to achieve and maintain true remission
- A multidisciplinary team is invaluable when there is multiorgan system involvement
Immunosuppression Protocol for Treatment of CNS Sarcoidosis
1) Glucocorticoids (start high and cautious tapers)
1) Weekly oral methotrexate (up to 20 mg/week) with folic acid; azathioprine; mycophenolatemofetil may also be considered
1) Infliximab 5 mg/kg IV Q4-8 weeks(Should we start this earlier in higher-risk patients?)
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Bitouin, et. al. Neurology 2017
Joubert, et. al. JAMA Neurology 2017
-- More relapses (neuro and/or other organs) with mycophenolate compared to methotrexate and other immunosuppressants
-- Raises questions about the optimal role of MMF as a top-line treatment for neurosarcoidosis
Gelfand, Bradshaw, et. al. Neurology 2017
Probable CNS SarcoidosisDefinite CNS Sarcoidosis
39 (59.1%)27 (40.0%)
Isolated CNS sarcoidosis 13 (19.7%)
Age Mean 47.5 years, range 24 to 71
Infliximab Exposure Median 1.5 years
MRI RESPONSEWorsenedNo changePartial ImprovementComplete Remission
N=562 (3%)8 (12.1%)17 (25.8%)29 (43.9%)
CLINICAL RESPONSEWorsenedStableImprovement with some residual disabilityComplete Recovery
N=652 (3%)12 (18.2%)32 (48.5%)19 (28.8%)
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Complete remission of CNS sarcoidosis after 6 years of refractory disease causing myelopathy, blindness & cognitive dysfunction
T2 T1 Post-Gad T1 Post-GadT2
T1 Post-Gad
T1 Post-Gad
*After treatment
with infliximab
- 2 patients discontinued infliximab with >1 year of radiological remission the disease recurred in the same neuroanatomical distribution within 3-4 months
- Another patient with thoracic myelitis, meningitis and subclinical pulmonary sarcoidosis exhibited sustained remission except recurrent chronic meningitis with discontinuation
Recurrence after Infliximab discontinuation
FLAIR FLAIR T1 Post Contrast T1 Post Contrast
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Neurosarcoidosis: Take Home Points
• Seed within the CNS at favored neuroanatomic sites and persist for months/years
• Nodular/lobulated enhancement on MRI is a sign of active disease; often involves nearby meninges (pia/subpia)
• CSF can be helpful to detect intrathecal inflammation, even when the MRI is negative or hard to interpret
• Relapses tend to occur at sites of previous activity
• FDG-PET can be helpful diagnostically, especially when the Chest CT is negative
• Aggressive therapy to induce remission may be best for severe disease, beware of relapse when discontinuing
• Caution attributing new neurological symptoms to neurosarcoidosis even in people with known sarcoidosis without a careful evaluation
Objectives
1)Neurosarcoidosis
2)Pachymeningitis
3)Behcet’s Disease
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Pachymeningitis
• Inflammation of the pachymeninges (dura) – vs. leptomeningitis (pia-arachnoid)
• Can sometimes be challenging to secure a final diagnosis because:
– The CSF examination samples the subarachnoid space (i.e. it does not directly sample the pachymeninges)
– Ddx includes infection, autoimmunity and malignancy with imperfect non-invasive diagnostics
– Dural biopsy may be needed to be definitive
Dural Thickening Concerning for Pachymeningitis
MalignancyMeningiomaMetastasis
Hematologic
VascularVenous thrombosis
Dural AVFHematoma
Infection
TB/AFBFungal
Bacterial
Autoimmune
Idiopathic hypertrophicIgG4 related disease
GPA / ANCA associatedSarcoidosis
RA associatedOther rheum associations?
CSF
Intracranial Hypotension
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Headache, RA, on TNF-alpha inhibitor
Syndrome of Intracranial HypotensionDiffuse dural enhancement + history
Psoriatic Arthritis, Breast Ca, immunosuppression
T1 Post T1 Post FLAIR
Hypertrophic Pachymeningitis (biopsy), “Idiopathic”Improvement over time with Steroids, Cyclophosphamide, Rituximab
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Serum IgG4 elevated to 141 mg/dL(reference range 4–86 mg/dL)
H&E CD20 cells
CD138 plasma cells IgG4+ plasma cells
Schubert, Gelfand, et. al. Neurology Neuroimmunology 2016
IgG4-Related Hypertrophic Pachymeningitis
- IgG4 related disease – increasingly recognized as a unifying pathology for many seemingly unrelated organ specific syndromes
- Remarkably, a subset (8-29% in published series) of patients formerly said to have “idiopathic” hypertrophic pachymeningitis have IgG4-disease
- Glucorticoids are the mainstay of treatment; data for methotrexate and increasingly Rituximab
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ANCA-associated Pachymeningitis
-- Pachymeningitis can be seen in association with Granulomatosis with Polyangiitis (GPA), formerly known as Wegener’s. The dural pathology is typically granulomatous (rather than frankly vasculitic).
-- GPA can also manifest in the CNS with parenchymal lesions (probably vasculitic) or stroke.
-- Many reports of pachymeningitis in association with either MPO or PR3 antibodies.
-- Suggest that in some patients this should be considered an organ system limited form of vasculitis, i.e. CNS-limited MPO+ GPA, much like the concept renal-limited vasculitis
Objectives
1)Neurosarcoidosis
2)Pachymeningitis
3)Behcet’s Disease
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Behcet’s Disease
• Recurrent oral ulcers (*usually painful)
(Plus 2 of the following for research criteria):
- Recurrent genital ulcers (*usually painful)
- Uveitis (*often bilateral, panuveitis)
- Skin lesions (E Nodosum, pseudofolliculitis, papulopustular, acneiform)
- Positive pathergy test (skin prick with 20g needle, papule/pusture 48 hours later)
International Behcet’s Disease Study Group
CNS Behcet’s
“Parenchymal” (i.e. brain inflammation/vasculitis)- Brainstem, brain, spinal cord
“Non-parenchymal”- Venous sinus thrombosis (intracranial hypertension)- Intracranial aneurysm- Extracranial aneurysm/Dissection- Meningitis (rare but reported)- Optic neuropathy (rare)- Mass lesion (rare)- Psychiatric symptoms (reported associations)
Al-Araji and Kidd, Lancet Neurology, 2009
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Maggi, et. al. Annals of Neurology, 2018
-- MRI study of 52 RRMS and 31 inflammatory CNS vasculopathypatients evaluating the “central vein sign” using 3D T2* (a gradient echo sequence) and post-gad FLAIR.
-- Frequency of perivenular lesions in MS 88% (median) vs 14% in inflammatory vasculopathy – in the non-MS group perivenularlesions with central vein signs was seen most frequently in Behcet’s(34%), then PACNS (14%), compare to SLE (0%)
Maggi, et. al. Annals of Neurology, 2018
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Uygunoglu, et. al. Annals of Neurology 2017
- “A central lesion with hypointense core and hyperintense rim with or without contrast enhancement” -- the “Bagel Sign” – was seen in nearly all of these 11 BD patients with myelopathy
- Note that this is describing the T2 pattern (not post-con)
Neuro-Behcet’s Disease - Pearls• Pathology of many BD implicated lesions is usually vasculitis
(and can affect large, medium and small vessels); however the CNS may just be inflammatory without frank vasculitis
• Diagnosis of BD and CNS-BD is truly syndromic – there is no one test or biomarker
• There is a differential diagnosis for each of the syndromic features, so detailed phenotyping and caution is advisable
• Important to cast a broad differential diagnosis when evaluating neurological symptoms in a patient with BD and not just reflexively assume neuro-Behcets; at the same time knowledge of BD manifestations can guide diagnostics (i.e. headache in known BD, whether to consider venous imaging, CSF exam, etc)
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Image from Dr. Jeffrey Gelfand
Neurosarcoidosis,Pachymeningitis, Behcet’s Disease
Jeffrey M. Gelfand, MD, MAS, FAANAssistant Professor of Clinical Neurology
UCSF Department of NeurologyMS and Neuroinflammation Center
AAN 2018 – Los AngelesNeuro-Rheumatology Course
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Rationale for TNF-alpha inhibition in Sarcoidosis
- In mouse models, TNF-alpha is expressed when granulomas develop (BCG liver infection). When given early, TNF-alpha inhibitors prevent granuloma formation.When given later, TNF-alpha inhibitors lead to rapid dissolution of established granulomas.
- Epithelioid and giant cells in human sarcoidosis granulomas avidly express TNF-alpha
- In a patient with pulmonary sarcoidosis who was treated with infliximab (TNF-alpha inhibitor) and whose lung was subsequently removed 11 days later for lung transplant, there was near complete absence of CD68+ macrophages in what was left of previously active granulomas in the explanted lung, with residual fibrinoid necrosis
Bachwich, et. al. Am J Pathology, 1986Baughman, RP. J Lab Clin Med, 1990Myatt, N., et. al. J Clin Pathol. 1994
Milman, et. al. Clin Res Journal, 2007
Kindler V, et. al. Cell. 1989