Middle-Aged Male with Confusion and Headaches: A Case of CNS Vasculitis

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 amaas 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% • SedRate 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/wogadolinium • 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, polyarteritisnodosa, Wegener’s, Churg-Strauss, cryoglobulinemicvasculitis • 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, leptomeningealenchancement, 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