Older male with

headaches and confusion

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

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

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

• 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

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

• Repeat Imaging

• Where?• What?

• 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

CNS VASCULITIS

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

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

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

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

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

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

Differential Diagnosis of vascular constriction and ectasia/beading

VasospasmInfectionEmboliAthereosclerosisHypercoaguable state

Biopsy

• Gold standard• Sampling of leptomeninges and

underlying cortex• One case series found 25% false negative • Positive – still need to stain for organisms

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

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