Vasculitides in Surgical Neuropathology Practice

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Brain lesions with angiocentric pattern Disease Entity Primary CNS Lymphoma vs. treated lymphoma Therapy Whole brain RT & High dose methotrexate Vasculitis Immunosuppressive Infections Antibiotics

Angiocentric CNS lesions Establish whether true vasculitis is present (i.e. vs. perivascular inflammation) Rule out vascular/perivascular neoplasm lymphoma Establish whether vasculitis is intracranial vs. extracranial Determine whether vasculitis is primary in the CNS or secondary systemic Is the process granulomatous, lymphocytic, or necrotizing?

Vasculitis affecting the Nervous System Primary CNS vasculitis ( Primary angiitis of the CNS ) Systemic vasculitis involving CNS Large arteries Giant cell arteritis Takayasu arteritis Medium sized arteries Polyarteritis nodosa Kawasaki syndrome Small vessels Granulomatosis with polyangiitis (Wegener s disease) Churg-Strauss syndrome Secondary vasculitis affecting the CNS INFECTIONS: Bacterial, viral, fungal, other SLE; Sjogren s disease Drug or Malignancy-related

Primary CNS vasculitis: Synonyms: Primary angiitis of the central nervous system Granulomatous angiitis Incidence: Location: 2.4 cases per million Multifocal involvement of small and medium-sized vessels limited to the brain and spinal cord Age range: Peak incidence between 40 60 years (rare in children) Slight female predominance A clinicopathologic diagnosis

Primary CNS vasculitis: Diagnostic Criteria Clinical: Acquired neurologic deficit that remains unexplained after thorough evaluation Must exclude Reversible vasoconstriction syndrome (RCVS) Imaging: Alternating stenosis and dilatation of vessels (angiography) Variable ischemic-like lesions on MRI (non-specific) Criteria for Exclusion: No systemic vasculitis No infection No neoplastic condition

Primary CNS vasculitis: Imaging Parenchymal & leptomeningeal enhancement Increased signal intensity on T2 and FLAIR Infarctions in about 50% of cases Alternating stenosis and dilatation of vessels

Challenges of biopsy for PCNSV: Sampling error due to lesion focality 37% non-diagnostic despite positive angiogram 26% positive biopsy despite negative angiogram Small risk of hemorrhage or other complication Biopsy should include: leptomeninges, cortex, white matter Some involved arteries too small for angiographic detection Increased probability of success if lesion targeted for biopsy Must see vascular wall destruction with relatively little infiltration of surrounding CNS tissue

Primary CNS Vasculitis Histological Patterns: Granulomatous Most common Type seen in Ab-related cerebral amyloid angiopathy Lymphocytic Most common type seen in children Necrotizing Least common Frequently associated with hemorrhage

Giant cell arteritis (temporal arteritis) Most common primary vasculitis affecting the nervous system Incidence: 15-25 / 100,000 Female/male: 2:1 Peak incidence: 75-85 y/o Disorder of cell-mediated immunity with CD4+T lymphocytes playing a key pathogenic role in the activation of monocytes/macrophages and the formation of multinucleated giant cells.

Giant cell arteritis Normal sed. rates in up to 17% of cases Sensitivity of C-reactive protein: 97% Sensitivity of ESR and CRP: 99% About 30-40% of patients with GCA will also have polymyalgia rheumatica Responsive to therapy: Glucocorticoids, Tocilizumab

Giant cell arteritis Panarteritis grossly nodular thickenings Gold standard for diagnosis: Temporal artery biopsy Medium and large extracranial branches of the aorta Internal and external carotids Subclavian and axillary arteries Superficial temporal Ophthalmic, posterior ciliary Vertebral

Temporal artery Giant cell arteritis

Giant cell arteritis: Granulomatous inflammation with multinucleated giant cells centered on internal elastic lamina

Giant cell arteritis: Length of temporal artery biopsy: Size matters! Length of TA Biopsy-positive GCA 5 mm (or less) 20% 6-20 mm 71-77% > 20 mm 89% Breuer GS, Nesher R, Nesher G: Effect of biopsy length on the rate of positive temporal artery biopsies. Clin Exp Rheumatol 2009, 27(Suppl 52):S10 S13.

Polyarteritis nodosa Typically affects medium to small-sized arteries CNS involved in 20-40% of cases PNS involved in > 50% of cases Mononeuropathy multiplex Due to focal, segmental inflammation with an infiltrate of polymorphonuclear neutrophils and fibrinoid necrosis 30% of patients in the U.S. are positive for serum hepatitis B antigen

Polyarteritis nodosa

Primary CNS vasculitis Differential Diagnosis If granulomatous: Rule out Ab-related cerebral amyloid angiopathy (ABRA) If lymphocytic: Rule out encephalitis Rule out lymphoma If necrotizing: Rule out systemic vasculitis - polyarteritis nodosa Rule out INFECTION

Vasculitis (lymphocytic) Intramural lymphocytes Less parenchymal lymphocytes usually perivascular Microglial activation Perivascular No microglial nodules Neuronophagia none/rare Edema perivascular Leptomeningeal involvement: Yes Encephalitiss Encephalitis Perivascular lymphocytes Diffuse parenchymal lymphocytes Microglial activation Diffuse Microglial nodules Neuronophagia Edema diffuse Leptomeningeal involvement: Yes

Secondary CNS vasculitis associated with infection Granulomatous Fungal, tuberculous, other infections Lymphocytic Viral, others Necrotizing Bacterial Toxoplasmosis Amoebic (Acanthamoeba)

Angioinvasive CNS fungal infection Young patient with severe combined immunodeficiency disorder Multifocal hemorrhagic infarcts

CNS fungal infection

CNS tuberculous infection Granulomatous inflammation localized to basal subarachnoid space and vessels Persistent infection results in endarteritis obliterans

CNS Syphyllis Meningovascular neurosyphilis Hubner s arteritis Also may result in endarteritis obliterans

Viral encephalitis Perivascular lymphoid cuffing and microglial nodules are non-specific histological features Varicella-zoster virus and HIV may produce vasculitis Syphilis, Lyme disease, Rickettsial diseases may also cause vasculitis

Necrotizing vasculitis: infectious Granulomatous Amoebic Encephalitis: Acanthamoeba species

Cerebral Toxoplasmosis: Cyst with bradyzoites

CNS Vasculitis: Take Home Points Establish whether true vasculitis is present (i.e. vs. perivascular inflammation) Rule out vascular/perivascular neoplasm lymphoma Establish whether vasculitis is intracranial vs. extracranial Determine whether vasculitis is primary (PCNSV) or secondary (PAN) Is the process granulomatous, lymphocytic, or necrotizing?

CNS Vasculitis: Take Home Points If granulomatous, rule out infections and ABRA If lymphocytic: Consider altered lymphoid cell content under prior glucocorticoid therapy Often etiology cannot be established without epidemiological, clinical, serological correlation Even after extensive work-up, most cases of vasculitis (especially lymphocytic) remain without clear etiology If necrotizing: Assess whether patient is immunocompromised (HIV) Inquire about recreational or therapeutic drugs that might be causative.

THANK YOU With special thanks to: B.K. Kleinschmidt DeMasters, MD Caterina Giannini, MD Murat Gokden, MD Christopher Dunham, MD