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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