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 headaches, one wk diplopia, 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 biopsy, 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, infliximab, alemtuzumab, cyclophosphamide, rituximab, radiation

• Hydrocephalus 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

Sarcoidosis 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 granulomas 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 multiple sclerosis – 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 granuloma

– Epithelioid cells – Giant cells – Central CD4+ cells – Peripheral CD8+ cells – B lymphocytes

• 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 Lung Infectious – necrotizing/tight Hypersensitivity – non-necrotizing/loose

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

Systemic Sarcoid

• Preferred sites – Lung – Ocular – Skin

• Muscle • Other: heart,

kidney

Lofgren’s Syndrome Hilar Adenopathy

Erythema nodosum

Judson, 2008.

Sarcoid - Skin

• ~25 % sarcoid cases with skin lesions

• Erythema nodosum • Plaques • Maculopapular

eruptions • Subcutaneous

nodules

Photos from Wikipedia

Erythema nodosum

Lupus Pernio

Diagnostic Tests for Sarcoid

• None sensitive or specific • Serum angiotensin converting enzyme (ACE)

assay • Kveim test – 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 lungs and kidneys by cells in inner layer of blood vessels

• Blood and CSF ACE neither specific nor sensitive

Dipeptidyl Carboxypeptidase

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

meningitis essential to consider

• Symptoms: cranial neuropathies, headache, constitutional sx, cognitive complaints

• Elevated ICP (+/- hydrocephalus)

• MRI may or may not show meningeal enhancement

Spinal Cord Dx

• Common and serious presentation

• Weakness, bladder sx common

• Biopsy more difficult to justify

• Aggressive therapy commonly recommended

Intramedullary (and roots)

Peripheral Neuropathy/Muscle

• Mononeuritis • Mononeuritis multiplex • Generalized sensory • Generalized motor • Generalized

sensorimotor • Demyelinating or axonal • Small or large fiber • Can mimic GBS

WUSTL Neuromuscle Website

Focal invasion and replacement of non-necrotic muscle fiber by granuloma cells

PNS/Muscle Sarcoid Evaluation

• NCV/ EMG • Muscle/nerve biopsy

www.thelancet.com/journals/lancet/article/PIIS014067361260837 FDG PET CT-PET MRI Muscle Bx from B

MRI-short inversion time inversion recovery

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, diabetes insipidus, SIADH, endocrine disorders (thyroid), sleep disturbance, altered appetite, even central fever

– Variable lesions in gray or white matter – Seizures 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 Picture

Diagnostic eval

Infection/ malignancy ruled out

Pathology Therapeutic response

Possible NS

Probable NS (systemic)

Definite NS (nervous system)

(response 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 • Osteoporosis, fractures • Infection risks

Treatment Approach for

Spinal Neurosarcoid

Varron et al, 2008

Therapy – Immune Modulatory

• Steroid sparing strategies varied – Infliximab – Mycophenylate – Methotrexate – Choroquine/hydroxychloroquine – Cyclophosphamide – Cyclosporine – Azathioprine – Thalidomide – 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

T2 T1, gad

Corticosteroid and azathioprine refractory

Infliximab in Rx Resistant Pt

FLAIR

T1, gad

Prior treatment high dose steroids, azathioprine, methotrexate, hydroxychloquine, cyclosporine with 2 yr hx

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

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.

Lower EE, Broderick JP, Brott TG, Baughman RP. Diagnosis and management of neurological sarcoidosis. Arch Intern Med 1997;157:1

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

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)

Moravan and Segal

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

• cliffordd@wustl.edu