Neurosarcoidosis

David B Clifford, MD Washington University in St Louis Conflicts/Support

• Funding: NIH: NIAID, NINDS, NIMH, NIA, Alzheimer’s Association • Consulting: Amgen, Biogen, BMS, Genentech, Genzyme, GSK, Jannsen, Millennium, Novartis, Pfizer, Roche • Research support: Bavarian Nordic, Biogen, BMS, Gilead, GSK, Lilly, Pfizer, Roche • Speaking Support: Sun Case History, March 2007

• 23 yo, Caucasian, single mother • 3 yr hx of refractory , one wk , n/v, radiating pain into left arm • LP: glu <20, protein 92, 86 cells (lyms) • Extensive wu for infections, vasculitis, autoimmune dx, carcinomatosis negative • Sarcoid eval: ACE normal in CSF and blood, Chest CT, endobronchial bx, bone scan, muscle and nerve , lymph node bx all negative • Brain Bx via craniotomy: granulomatous inflammation found and no organisms detected

Course

• Steroid responsive but mood swings and weight increasing to almost 400 lb, unable to have relief <100 mg/d prednisone • Other rx: methotrexate, mycophenylate, , alemtuzumab, , rituximab, radiation • developed requiring VP shunt • Efforts to taper therapy resulted in recurrent temporal lobe dx resulted in amnestic syndrome 2010 – Attempt to taper meds Course

• Steroid responsive but mood swings and weight increasing to almost 400 lb, unable to have relief <100 mg/d prednisone • Other rx: methotrexate, mycophenylate, infliximab, alemtuzumab, cyclophosphamide, rituximab, radiation • Hydrocephalus developed requiring VP shunt • Recurrent temporal lobe dx resulted in amnestic syndrome • Died in nursing care with sepsis four years later Who are the experts?

• Few neurologists/neuroscientists have made this condition a career focus • Prevalence such that most neurologists see a few cases, but seldom enough to become “expert” with this condition • Ideally suited to multicenter investigation if progress is to be made 1975 definition

• “Sarcoidosis is a multisystem graulomatous disorder of unknown etiology, most commonly affecting young adults and presenting most frequently with bilateral hilar adenopathy, pulmonary infiltration, skin or eye lesions.” • “Diagnosis most securely established when clinical and radiographic evidence are supported by histologic evidence of widespread non-caseating epithelioid in more than one organ” Prevalence and Incidence

• Sarcoid – Prevalence ~40 / 100,000 – Incidence ~35 / 100K in African Americans, ~10 / 100K in Caucasians • Neurosarcoid – Prevalence ~ 2 – 6 / 100,000 – Isolated NS 0.2 / 100K • Compare to – Prevalence in Minnesota ~175 / 100,000 • Typical academic medical center referred ~5-10 cases / year • At autopsy frequency of sarcoid like lesions much greater than clinically apparent

Proposed Causes of Sarcoidosis Sarcoid Pathogenesis Pathophysiology

• Noncaseating – Epithelioid cells – Giant cells – Central CD4+ cells – Peripheral CD8+ cells – B • Production of IL-2, interferon-γ, TNFα • Fibrosis • Increased familial risk x5 with parent/sibling • GWAS – variant of annexin A11 gene as risk • Likely polygenic/complex associations Pathology of Granulomas in Infectious – necrotizing/tight Hypersensitivity – non-necrotizing/loose

Foreign body reaction (talc) Sarcoidosis – non-necrotizing, tight Systemic Sarcoid

• Preferred sites – Lung – Ocular – Skin • Muscle • Other: , kidney Lofgren’s Syndrome Hilar Adenopathy

Erythema nodosum

Judson, 2008. Sarcoid - Skin

• ~25 % sarcoid cases with skin lesions • Erythema nodosum

• Plaques Lupus Pernio • Maculopapular eruptions • Subcutaneous nodules

Photos from Wikipedia Diagnostic Tests for Sarcoid

• None sensitive or specific • Serum angiotensin converting enzyme (ACE) assay • – injection of sarcoid granuloma, bx 4 wks later – rarely if ever done now • Screen for systemic sarcoid: CXR, chest/abd CT, PFT with diffusing capacity, eye exam (slit lamp), endoscopic eval of nose/sinuses, gallium scan, FDG PET scan, thigh muscle MRI, biopsy (skin, conjunctival, pulmonary, muscle)

Angiotensin Converting Enzyme Assay

• Catalyzes Angiotensin I to Angiotensin II • Results in vasoconstriction and elevated BP • ACE inhibitors key mechanism for BP meds • Part of Renin Angiotensin System (RAS) • ACE secreted in and kidneys by cells in inner layer of blood Dipeptidyl Carboxypeptidase vessels • Blood and CSF ACE neither specific nor sensitive Diagnosis Neurosarcoidosis • Diagnosis of exclusion • Presence of system sarcoid is suggestive • Many have no systemic sarcoid • Even pathology is not firmly diagnostic Clinical Presentation of Neurosarcoidosis

Zajicek et al: a case series of 68 NS patients Challenges Intrinsic to NS

• Multiple forms/presentation

Scott et al MRI Lesions in Neurosarcoid Cranial Neuropathies

• Facial palsy common • Olfaction often involved (evaluate sinuses as well) • Optic nerves • CN VIII – hearing or vestibular • Trigeminal (numbness or paresthesia)

Meningitis and Hydrocephalus

• Common manifestation of NS • Differential of chronic essential to consider • Symptoms: cranial neuropathies, , constitutional sx, cognitive complaints • Elevated ICP (+/- hydrocephalus) • MRI may or may not show meningeal enhancement Dx

• Common and serious presentation • Weakness, bladder sx common • Biopsy more difficult to justify • Aggressive therapy commonly recommended

Intramedullary (and roots) /Muscle

• Mononeuritis • Mononeuritis multiplex • Generalized sensory • Generalized motor • Generalized sensorimotor • Demyelinating or axonal • Small or large fiber Focal invasion and replacement of non-necrotic muscle fiber by • Can mimic GBS granuloma cells

WUSTL Neuromuscle Website PNS/Muscle Sarcoid Evaluation

• NCV/ EMG MRI-short inversion • Muscle/nerve biopsy time inversion recovery

FDG PET CT-PET MRI Muscle Bx from B www.thelancet.com/journals/lancet/article/PIIS014067361260837 CSF in Neurosarcoidosis CNS Parenchymal Disease

• Brain and/or spinal cord may be involved • MRI sensitive to NS lesions • Symptoms depend on location – Hypothalmus: thirst, insipidus, SIADH, endocrine disorders (), sleep disturbance, altered appetite, even central fever – Variable lesions in gray or – may occur – Strokes (may be embolic with cardicac sarcoid)

Isolated Neurosarcoidosis

• ~5-10% of CNS sarcoid is isolated with several years of follow-up • Systemic sarcoid rarely follows NS (cf MS) • Prognosis may be worse with CNS disease only • Extra-axial disease seems to have better prognosis than intraparenchymal disease

Neuropathologic Differential of NS

• Wegener granulomatosis – more necrotizing, more vasculitis, associated with sinus dx, ANCA positive • Idiopathic intracranial pachymeningitis – more fibrotic and less granulomatous • Tolosa-Hunt syndrome – granulomatous inflammation limited to cavernous sinus and adjacent tissues.(may be localized NS) • Other infectious causes (mycoses, TB, acanthamoeba) Value of Biopsy in Sarcoidosis

Looking for non-necrotic (non-caseating) granulomas Diagnostic Certainty

Clinical Diagnostic Infection/ Pathology Therapeutic Picture eval malignancy response ruled out Possible NS   Probable NS     (systemic) Definite NS     (nervous  (response system) x 1 yr)

Zajicek, Q J Med 1999 Therapy: Sarcoid vs Neurosarcoidosis

• Sarcoid often relatively easy to treat, may not require treatment at all – Corticosteroids, sometimes MTX • Neurosarcoidosis – variable but parenchymal disease and sometimes meningeal disease can be refractory – Early aggressive treatment increasingly recommended by experts Scott et al, Aggressive Rx for NS: Long term Followup of 48 treated patients Therapy

• Make as secure a diagnosis as possible FIRST – Symptomatic biopsy proven NS should be treated immediately – Symptomatic conditions consistent with NS where system sarcoid documented should be treated after exclusion of infection (rx can contribute to dx) – Asymptomatic lesion rx must be individualized recognizing real risk of therapy and uncertain risk of progressive neurological disease • Pick parameter to follow for response • Goal is sustained remission of symptoms / signs

Basis for Choice of Therapy

• Extrapolated from systemic sarcoid • Expert opinion • Uncontrolled case series • No randomized controlled trials in this disease • No FDA approved therapy Therapy - Steroids

• Response to corticosteroids typical and brisk • Generally clinically serious lesions should be treated with steroids first • Serious disease often treated with 1 gm methylprednisolone IV x 3-5 days • Prednisone 1 mg/kg or more to start with slow taper over ~6-12 months • Chronic therapy for > 6 mo often needed Steroids Therapy

• Long term therapy often required for CNS or spinal parenchymal disease – Varies on presentation with cranial neuropathies often requiring briefer interventions • Permanent injury can accrue with break through disease as dose tapered • Side effects of corticosteroids common

Corticosteroid Side Effects

• Weight gain • Fat redistribution • Cataracts • Diabetic exacerbation • Mood/behavioral • Skin thinning • Muscle loss • Edema • , fractures • Infection risks Treatment Approach for Spinal Neurosarcoid

Varron et al, 2008 Therapy – Immune Modulatory

• Steroid sparing strategies varied – Infliximab – Mycophenylate – Methotrexate – Choroquine/ – Cyclophosphamide – Cyclosporine – Azathioprine – – Combinations (eg Infliximab/Mycophenylate) Infliximab • CNS dx failing Cytoxan • 4/4 showed infliximab response • Given with MTX • Prompt response (2-4 infusions(earlier than anticipated for MTX) • Allowed stop or decrease in steroids • Well tolerated rx

T1, T2 gad

Corticosteroid and azathioprine refractory Infliximab in Rx Resistant Pt Prior treatment high dose steroids, azathioprine, methotrexate, hydroxychloquine, cyclosporine with 2 yr hx

FLAIR

T1, gad

Pettersen et al, 2002

Thalidomide - Phocomelia Thalidomide is TNFa Antagonist Mycophenylate

• Kouba et al (BritJDerm 2003; 148:147) report 5 cases of NS • Mycophenolate mofetil (MMF) used up to 3000 mg/d with hydroxychloroquine • Refractory to CS and multiple agents • Improvement of 70-100% in 3 months after CS, azathioprine, MTX failure, topoisomeraseb Lower EE, Broderick JP, Brott TG, Baughman RP. Diagnosis and management of neurological sarcoidosis. Arch Intern Med 1997;157:1 Methotrexate

• Lower, et al suggest corticosteroids and methotrexate for therapy of more than mild neurosarcoidosis • 61% stabalized or improved with MTX • Cyclophosphamide used for MTX failures giving 85% response rate • Early aggressive therapy for dangerous parencyhmal dx (spinal cord, brain) advocated

Lower EE, Weiss KL. Neurosarcoidosis. Clinics in Chest Medicine 2008;29:475-492. Lower EE, Broderick JP, Brott TG, Baughman RP. Arch Intern Med 1997;157:1864-1868.

MTX Use

• Folic acid analogue with potential to spare steroid use • Weekly dosing titrated for efficacy ~15 mg/wk with maximal dose of 30 mg/wk • Monitor CBC, LFT • Supplement with folic acid a mg daily • Well tolerated, oral therapy • Relatively inexpensive

Cyclophosphamide

• Many case reports suggest highly active therapy • Can be given orally titrating WBC or in IV pulses • Acute toxicity suggests it is second line drug at this time Moravan and Segal Infliximab and MMF

• Bx proven sarcoid with CNS involvement who were steroid failue • 7/7 had symptomatic improvement • Many had headache and neuropathic pain relief by 4 th infusion • TNFa drugs often used with anti-metabolites to prolong efficacy (autoantibodies not as common) Therapy - Surgical

• Biopsy – Important for diagnosis – May provide opportunity to develop better biomarkers – Optimize understanding of pathogenesis • Treatment of hydrocephalus – Shunting – Third ventriculostomy Radiation Challenges Intrinsic to NS

• Multiple forms/presentation • No reliable biomarkers identified • Angiotensin converting enzyme (ACE) is as close to useless • Imaging and CSF may have opportunities for biomarkers not well explored • ?Tissue analysis might help unravel pleomorphic aspects of this condition Could NeuroNEXT Support Progress?

• Enroll defined cohort of newly diagnosed neurosarcoid patients – Collect CSF, tissue samples (whenever possible), DNA for genetic analysis – Maintain specimen access for collaborative scientific study going forward • Randomize to two alternative therapy approaches and follow systematically – Consider adaptive design to evolve study interventions over time Could NeuroNEXT Support Progress?

• Enroll defined cohort of newly diagnosed neurosarcoid patients – Collect CSF, tissue samples (whenever possible), DNA for genetic analysis – Maintain specimen access for collaborative scientific study going forward • Randomize to two alternative therapy approaches and follow systematically – Consider adaptive design to evolve study interventions over time Goal/Trajectory

• Define modest and attainable starting point for an initial study/proof of principle • Work to elaborate into a program project that would coordinate translational studies allowing more effective basic studies • Use basic studies to elaborate on more effective intervention strategies Numbers

• Prevalence • Broad NeuroNEXT participation should be possible, perhaps with 20 sites • Sites should enroll 2-4 new patients annually • Accrual of a cohort of 100 should be possible in two years, allowing two years followup supported by a 5 yr initial grant Basic Research on Tissues Require Linked Grants • Tissue resource could be distributed early, but eventually might be centralized • Genetic studies should be anticipated, but may take some time to accumulated set of informative samples • Collection of imaging data will required coordinated collection of images Is there a future for this?

• Comparative study - ?pick 2 – Corticosteroids only – CS followed by Methotrexate – CS followed by Mycophenylate – Infliximab • Biomarkers – CSF – Imaging – TNFa activity or other inflammatory (MCP1) – Exam driven (difficult!) – ?other ideas Thanks

• Washington U • Robert Schmidt • John Atkinson • Mayo Clinic • Allen Aksamit • U Maryland • Barney Stern

Suggestions

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