Neurosarcoidosis, Pachymeningitis, Behcet s Disease. Disclosures

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1 Neurosarcoidosis, Pachymeningitis, Behcet s Disease Jeffrey M. Gelfand, MD, MAS, FAAN Assistant Professor of Clinical Neurology UCSF Department of Neurology MS and Neuroinflammation Center AAN 2018 Los Angeles Neuro-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. 1

2 Objectives 1)Neurosarcoidosis Update 2)Pachymeningitis Update 3)Behcet s Disease Update Sarcoidosis Autoinflammatory, multisystem disorder, characterized by non-necrotizing granulomatous inflammation histopathologically 2

3 Genetics of Sarcoidosis X Complex genetic disorder 7X 3-5X Sverrild, et. al. Thorax 2008; Rybicki, et. al. Am J Epidemiol 2001; Rybicki, et. al. AJRCCM 2001 Rivera, American Journal of Respiratory and Critical Care Medicine, 2016 Sarcoidosis /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 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 oligoclonal and presumed to be antigen specific. Emerging role of Th17.1 (vs classical TH1) Ramstein and Koth, et. al., AJRCCM

4 The granuloma Hallmark of Sarcoidosis H&E Multinucleated Giant Cell Leptomeninges, H&E, Neurosarcoidosis H&E CD68 (Macrophage) H&E H&E Hilar Lymph Node AFB Hilar Lymph Node, Higher Power GMS 4

5 Progression of CNS Sarcoidosis for over a decade Viewed through the lens of granuloma maintenance Brain Biopsy First available archived MRI, age 40 Corticosteroids Blindness 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 + Azathioprine Hypopituitarism Infliximab 5 mg/kg load then Q8 weeks Cognitive Impairment Infliximab 7 mg/kg Q6 weeks 10.8 years Cognitive Problems Resolved First available archived MRI, age 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 CSF Exam 9 WBC Glucose 50 Protein 81 CSF ACE<3 CSF Exam 7 WBC Glucose 52 Protein 112 IgG Index OCBs CSF ACE <3 Gelfand, Bradshaw, et. al. Neurology 2017 Interfering with granuloma maintenance as a therapeutic strategy? Volkman et. al., Science 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? 5

6 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 noninfectious cases including CNS sarcoidosis (N=8) Wilson*, Donovan*, Gelfand*, Derisi, et. al. JAMA Neurology,

7 Defining Neurosarcoidosis: Challenges Definite CNS Biopsy confirmation of non-caseating granulomatous 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 2015 and consistent with Judson, et. al., Sarcoidosis Vasc Diffuse Lung Dis

8 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 neurosarcoidosis cases 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? Small Fiber Neuropathy in Sarcoidosis Lancet,

9 CNS Sarcoidosis (UCSF Experience) Age at neurological syndrome onset Total CNS Sarcoidosis (Biopsy-proven) N=53 Definite/Highly Probable (CNS Biopsy) N=26 Probable (extra-cns Biopsy) N=27 43 years (IQR 36 to 50), range years Female 53% Black White Non-Hispanic White Hispanic Other 36% 48% 11% 5% Family history of sarcoidosis 8% Known sarcoidosis at time of neurological presentation Evidence of pulmonary sarcoidosis at time of neurological presentation Whole Body PET provided diagnostic insight beyond conventional CT 10% (90% did NOT have known sarcoidosis at first neurological presentation!) 58% (and almost 30% are isolated CNS) 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 elevated N=22 14% CSF Pleocytosis (>5 WBC) N=44 80% CSF Protein elevation (>50) N=44 73% CSF Glucose Abnormally Low N=41 27% IgG index elevated N=44 36% Gelfand, et al. In preparation 9

10 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 10

11 Real-world example of CNS Sarcoidosis evaluation 7 months prior (after MVA) T2 T1 Post-Gadolinium (sequential cuts) T2 T1 Post 6 months later Whole body FDG-PET in sarcoidosis Transbronchial biopsy: Non-caseating granulomas consistent with sarcoidosis 11

12 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: FLAIR Noncaseating Granulomatous Inflammation T1 Post-Contrast 12

13 Syndrome: Hypopituitarism, headaches Sagittal T1 Post-Gad Coronal T1 Post-Gad T1 Post-Gad over time shows extension into periventricular meningeal spaces Annals of Neurology, 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 13

14 Sarcoidosis Myelitis 7 months prior (after MVA) T2 T1 Post-Gadolinium (sequential cuts) T2 T1 Post 6 months later For Comparison Neuromyelitis Optica (+AQP4 IgG, astrocytic target) 14

15 Syndrome: optic neuropathy, myelopathy, cognitive impairment T1 Post-Gad T2 T1 Post-Gad Syndrome: Myelopathy T2 Axial T1 Post-Gad T2 Sagittal T1 Post-Gad 15

16 Nodular enhancing appearance on MRI Syndrome: Meningitis then Progressive Myelopathy T2 Axial T1 Post-Gad T2 Sagittal T1 Post-Gad Nodular enhancing appearance on MRI (same patient as last slide) T1 Post-Gad T1 Post-Gad 16

17 CNS Sarcoidosis Observations 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 Progression of CNS Sarcoidosis for over a decade Viewed through the lens of granuloma maintenance Brain Biopsy First available archived MRI, age 40 Corticosteroids Blindness 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 + Azathioprine Hypopituitarism Infliximab 5 mg/kg load then Q8 weeks Cognitive Impairment Infliximab 7 mg/kg Q6 weeks 10.8 years Cognitive Problems Resolved First available archived MRI, age 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 CSF Exam 9 WBC Glucose 50 Protein 81 CSF ACE<3 CSF Exam 7 WBC Glucose 52 Protein 112 IgG Index OCBs CSF ACE <3 Gelfand, Bradshaw, et. al. Neurology

18 A 6 Year View of Biopsy-Proven CNS Sarcoidosis The disease spreads by regional propagation, waxing and waning over years CNS biopsy Baseline 4 months 22 months 2 years 27 months 28 months 30 months 3 years 40 months Corticosteroids, taper then increase, then taper Methotrexate trial 42 months 4 years 53 months 56 months 59 months 65 months 66 months 69 months 70 months Stopped methotrexate Stopped Steroids Pred 60 mg Taper Pred 10 mg Pulse steroids + azathioprine Infliximab Biopsy-Proven CNS Sarcoidosis over the course of a year IV then PO corticosteroids Steroid Taper Steroids + MTX Infliximab IV Contrast not given for this study Baseline + 1 month + 3 months + 6 months + 7 months + 11 months + 14 months Bilateral vision loss, weight loss fatigue, hyponatremia Back to Normal Vision worsens, Hyponatremia again Substantial but incomplete visual recovery (severe constricted fields) Baseline + 1 month + 3 months + 6 months + 7 months + 11 months + 14 months CSF: Optic Nerve Sheath Biopsy 67 WBC Glucose 44 (serum 99) Protein 89 18

19 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; mycophenolate mofetil may also be considered 1) Infliximab 5 mg/kg IV Q4-8 weeks (Should we start this earlier in higher-risk patients?) 19

20 Bitouin, et. al. Neurology 2017 Joubert, et. al. JAMA Neurology 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 Sarcoidosis Definite 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 MRI RESPONSE Worsened No change Partial Improvement Complete Remission CLINICAL RESPONSE Worsened Stable Improvement with some residual disability Complete Recovery Median 1.5 years N=56 2 (3%) 8 (12.1%) 17 (25.8%) 29 (43.9%) N=65 2 (3%) 12 (18.2%) 32 (48.5%) 19 (28.8%) 20

21 Complete remission of CNS sarcoidosis after 6 years of refractory disease causing myelopathy, blindness & cognitive dysfunction T1 Post-Gad T1 Post-Gad T2 T2 T1 Post-Gad T1 Post-Gad *After treatment with infliximab Recurrence after Infliximab discontinuation - 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 FLAIR FLAIR T1 Post Contrast T1 Post Contrast 21

22 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 22

23 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 CSF Intracranial Hypotension Vascular Venous thrombosis Dural AVF Hematoma Malignancy Meningioma Metastasis Hematologic Autoimmune Infection TB/AFB Fungal Bacterial Idiopathic hypertrophic IgG4 related disease GPA / ANCA associated Sarcoidosis RA associated Other rheum associations? 23

24 Headache, RA, on TNF-alpha inhibitor Syndrome of Intracranial Hypotension Diffuse dural enhancement + history Psoriatic Arthritis, Breast Ca, immunosuppression T1 Post T1 Post FLAIR Hypertrophic Pachymeningitis (biopsy), Idiopathic Improvement over time with Steroids, Cyclophosphamide, Rituximab 24

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26 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 26

27 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 27

28 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,

29 Maggi, et. al. Annals of Neurology, MRI study of 52 RRMS and 31 inflammatory CNS vasculopathy patients 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 perivenular lesions 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,

30 Uygunoglu, et. al. Annals of Neurology 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) 30

31 Image from Dr. Jeffrey Gelfand Neurosarcoidosis, Pachymeningitis, Behcet s Disease Jeffrey M. Gelfand, MD, MAS, FAAN Assistant Professor of Clinical Neurology UCSF Department of Neurology MS and Neuroinflammation Center AAN 2018 Los Angeles Neuro-Rheumatology Course 31

32 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. Kindler V, et. al. Cell Epithelioid and giant cells in human sarcoidosis granulomas avidly express TNF-alpha Bachwich, et. al. Am J Pathology, 1986 Baughman, RP. J Lab Clin Med, 1990 Myatt, N., et. al. J Clin Pathol 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 Milman, et. al. Clin Res Journal,