1. Older male with headaches and confusion

2. History Middle-aged, right handed Caucasian male no home medications, no PMH Three week history of low grade fever and frontal headache Diagnosed by PCP as sinus infection and given antibiotics With no improvement admitted to OSH – LP: 73 WBC (73% L), 11 RBC, 44 protein. Viral testing and cultures were negative. Discharged home one day later ama as he felt better Readmitted 5 days later for somnolence and confusion. CT head: two new low density lesions. MRI: multiple acute infarcts in various distributions Remote hx of pilonidal cyst removal, smokes 1ppd, no sick contacts

3. Further work up at KU Infectious – West Nile CSF IgM/IgG, Cryptococcal antigen, Influenza, Monospot, Enterovirus PCR, Hepatitis screen, HIV, VZV, HSV 1/2, Syphilis antibody, bacterial, fungal, viral cultures, T spot Autoimmune – Rheumatoid factor, C3/C4, ACE, C- ANCA, P-ANCA, anti-double strand, myeloperoxidase, Serine protease, anti SSA, SSB, ANA screen Hypercoagable – Factor V Leiden in one allele (heterozygous) – Cardiolipin, protein C & S, antithrombin III, factor 2 mutation LdL 89, A1C 5.6% Sed Rate 15, CRP 0.05 Two LPs with WBC 21-29, protein 41-49 Paraneoplastic panel negative No oligoclonal bands, CSF ACE <4, CSF IgG was normal CSF flow cytometry was negative x2

4. Imaging Radiology – IR Arteriogram Smooth vessels, no evidence of vasculitis – MRI Brain w/wo gadolinium Patchy areas of subacute ischemia – PET scan Normal – Transesophageal echocardiogram unremarkable – CT chest RLL pulmonary artery clot

5. Factor V Leiden heterozygous positive 5-10 fold increase in venous thrombosis Ophthalmology found right eye papilledema but no known cause Discharged home after five days on coumadin, strokes thought likely to be due to FVL, smoking, athereosclerosis

6. Re-admission Re-admitted 2 weeks later with new onset imbalance and left arm and leg weakness Found to have new acute infarcts Mental status detoriated and transient episodes of hemiplegia upon awakening Episodes of unresponsiveness, rigid, hypertension, tachycardia and fever. Transferred to ICU and intubated Started on AEDs and VEEG monitoring. No epileptiform discharges. Thought to have autonomic storming Eventually had tracheostomy and percutaneous enteral feeding tube placed

7. Repeat Imaging

8. Where? What?

9. Brain biopsy “Although the changes are not specific or diagnostic of a particular disorder, and while the current biopsy does not contain an infarct, the vascular changes observed would be compatible with a vascular-ischemic disorder, such as vasculitis, a leading clinicoradiological impression. A neoplastic process is not recognized." Pt started on high dose IV steroids, cytoxan Propanolol for storming Mental status plateaued Discharged to L-TACH 6 weeks after admission

10. CNS VASCULITIS

11. CNS Vasculitis aka Primary Angiitis of the CNS (PACNS) Inflammation of small and medium sized arteries only in CNS causing CNS dysfunction – Unexplained neurologic or psychiatric deficit – Classic angiographic or histopathologic features – No evidence of systemic vasculitis Difficult to diagnose and study – Rarity – about 500 cases reported since 1959 – Nonspecific and various presentations – No useful animal models

12. Pathology Pathologic findings include Langerhans or foreign body giant cells, necrotizing vasculitis or lymphocytic vasculitis Inflammation causes vessels to become narrowed, occluded and thrombosed More likely to affect blood vessels in cerebral cortex and leptomeninges more than subcortical regions Cause is unknown – Infection Mycoplasma gallisepticum, VZV, WNV, HIV have been proposed

13. Clinical Manifestations Suspected when in patients with recurrent strokes with no identifiable cause or other CNS dysfunction with no cause Male 2:1 predominance Mean age is 42 but can occur at any age Series of 116 patients presented with – 83% had decreased cognition, 56% headache, 30% seizure, 14% stroke, 12% cerebral hemorrhage Strokes/TIAs occur in 30-50% of patients

14. Differential Reversible cerebral vasoconstriction syndrome (Call-Fleming) Systemic vasculitis involving the brain – Behcet’s, polyarteritis nodosa, Wegener’s, Churg-Strauss, cryoglobulinemic vasculitis Connective tissue diseases – SLE, NAIM, rheumatoid vasculitis, antiphospholipid syndrome Infections – Varicella zoster, HIV, hepatitis C, CMV, Atherosclerotic disease – – Premature intracranial, Chronic hypertension Demyelinating- MS, ADEM, PML Embolic disease – cardiogenic Malignancy – Intravascular lymphoma Miscellanous – PRES, sarcoidosis, Susac, CADASIL, MELAS, moyamoya

15. Testing ESR and CRP- usually normal Complete infectious and rheumatologic work up Drugs of abuse screen- cocaine CSF- abnormal in 80-90% of patients but no specific abnormalities – Elevated protein and wbc – important to rule out other diseases

16. Imaging MRI – used frequently in work up to assess for stroke, leptomeningeal enchancement, follow progress of lesions Angiography: ectasia and stenosis “beading” usually in small arteries with involvement of several sites. – Also has multiple occlusions with sharp cutoffs and circumferential or eccentric vessel irregularities – Two series of patients found sensitivity of 60%. Cannot use negative exam to rule out Vessels usually beyond resolution of exam

17. Differential Diagnosis of vascular constriction and ectasia/beading Vasospasm Infection Emboli Athereosclerosis Hypercoaguable state

18. Biopsy Gold standard Sampling of leptomeninges and underlying cortex One case series found 25% false negative Positive – still need to stain for organisms

20. Treatment Initial- with infection excluded – Glucocorticoids- no trials on route, dose or length of treatment Biopsy confirmed – Glucocorticoids – Cyclophosphamide- 600-750mg/m2 qmonth for three to sixth months – Once in remission for 3-6 months switch to alternative agents MMF, Azathioprine and MTX – Serial MRIs

21. Conclusion PACNS is a difficult disease to identify and treat Should be entertained in patients who have new onset neurologic deficits and multifocal strokes with no other apparent cause Diagnosis is arrived at by exclusion of other causes and a combination of clinical history, CSF findings, radiologic and pathologic findings