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 Erythema nodosum • ~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 • 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 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 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 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, 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 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 • 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