Primary CNS Vasculitis - diagnostic and therapeutic challenges

Primary CNS Vasculitis –Diagnostic and Therapeutic

Challenges

Case presentation

38 yo Caucasian M - ED with severe frontal headache. 10 days prior- hit his head getting into his car and he was urged by his wife to come and be evaluated. Head CT-negative.

Headaches initially improved, then returned. 2nd ED admission: Ongoing headache for 6 days: constant, located in frontal region, throbbing, worse with forward motion of the head and sitting up. Denied photophobia, fevers, neck stiffness, dizziness. Ameliorated by dilaudid. Poor sleep. Nausea/vomiting episodes. Weakness+. Change in vision in his left eye.

Wife reported:

Speech is difficult “talks like tongue is swollen”

Severe weakness

Gait unbalanced

Confused for several days

Initial wok-up was started at OSH then he was transferred to UCMC Neurology service

Physical exam

General Lying in bed with eyes closed, somewhat drowsy and confused

HEENT: Left eye lower half of eye injected/conjutivitis

Cardiac +pulm exam: CTAB, RRR, normal S1 and S2, no murmurs

GI: soft, non-tender, non-distended

Neurologic exam

Oriented to person, NOT oriented to place or time- not even state or City. Thought he was at Children's hospital, then said Columbus for state. Able to follow most simple commands but confused and frustrated with complex commands. Minimal dysarthria.

CN: II PERRLA; visual fields intact to finger count except L inferior temporal distribution ; III,. IV, VI: Very difficult to obtain extraocular motor test. Pt could NOT understand this test.; V: Facial sensation was intact to light touch ; VII: L facial droop ; Vii-XII normal

Motor: strenght 5/5 Throuout; Normal Tone.; Reflexes LE+3; Positive Babinski bilateraly

Light touch- diminished on left ; Could not discriminate sharp from dull bilaterallyVibration intact bilaterally

Coordination: Patient had very difficult time understanding this test.

Gait: Narrow based ;Patient did NOT understand how to do heel-to-toe despitedemonstration and multiple explainations

Labs

CBC, Renal panel, Liver panel, PT/INR –normal

ESR 42, CRP 19.5 elevated

Protein electrophoresis –normal

Urine electrophoresis- normal

Vit B12 normal

TSH normal

IGG, IGA normal, IGM slightly elevated 358

Negative Tox screen (Lead, Arsenic, Bleach)

TEST Result

Lyme AB NEGATIVE

Lyme WB NEGATIVE

Mycoplasma Pneumo IgM NEGATIVE; IGG POSITIVE

CMV, blood IGM NEGATIVE; IGG POSITIVE

CMV, CSF NEGATIVE

Enterovirus NEGATIVE

HSV 1, 2;HHV6 PCR NEGATIVE

VZV PCR, IG M CSF NEGATIVE

VZV EIA IgG POSITIVE; IGM -1.29 high

West Nile, CSF IGG positive, IGM negative

HIV 1&2 NEGATIVE

Hepatitis B Ab –reactive, no viral load, no HBs Ag detected

Hepatitis C NEGATIVE

Crypto Ag, CSF NEGATIVE

Histoplasma, CSF NEGATIVE

RPR blood, VSRL -CSF NEGATIVE

Cystocercosis IgG NEGATIVE

AFB smear NEGATIVE

Quantiferon TB NEGATIVE

Blood Cultures NEGATIVE

CSF cultures NEGATIVE

Infectious work-up

CSF analysis

LP ED 4 days after

Color colorless colorless

Clarity clear clear

TNC 2 10

RBC 2 0

Monocytes 15%

Ly 85% 88-91%

Macrophage 10

Glucose 74 68

Protein 148 142

ACE normalCSF/serum index 34 (High)IgG index, CSF -0.6IgG /albumin CSF ratio 0.11IgG, CSF 15.5 (H)Oligoclonal bands -0VDRL, CSF negativeIndia Ink- negativeAcid fast culture negativeCSF-cytology no malignant cellsFlow genetics –no abnormal

immunophenotype/malignancy

Autoimmune work-up

Cryoglobulin- not detectedKappa, Lambda -normal

Imaging studies

MRI – at admission

MRI brain -multiple small subcentimeter scattered areas of abnormal T2 signal throughout the white matter.

Cerebral angiogram- normal, no evidence of vasculitis

MRI at transfer- 4 days after

Fulminant intracranial process markedly progressive since admission MR

Predominant pattern of diffuse abnormal leptomeningeal enhancement along both cerebral and cerebellar hemispheres with diffuse abnormality of the cortex and multiple foci of white matter abnormality

Additional studies

MRI cervical and thoracic spine –normal

PET scan- negative for sarcoidosis

TTE-normal; TEE- EF 60-65%, no LA thrombus, small mobile mass distal to right coronary cusp in the proximal ascending aorta(papillary fibroelastoma) No shunt.

Carotid doppler -normal

EEG: Variability of amplitudes which do not appear to have eliptiform or spike type features. Mild slowing as well.

Brain Biopsy

R frontal dura –extensive fibrosis, no evidence of vasculopathy, amyloid, vasculitis, inflammation or granuloma, or malignancy

R frontal cortex and white matter–early acute ischemic changes (eosinophilic “red”neurons); microscopic focus of acute infarction

CD3 immunostain for T Ly negative

No viral inclusions; No evidence of malignancy

Primary CNS Vasculitis –Diagnostic and Therapeutic

Challenges

History

Mid-1950s when Cravioto and Feigin described several cases of non-infectious granulomatous angiitis associated with the nervous system

Cravioto H, Feigin I. Noninfectious granulomatous angiitis with a predilection for the nervous system. Neurology 1959; 9: 599–609.

Equivalents

Granulomatous angiitis of the CNS

Non-infectious or idiopathic granulomatous angiitis of the CNS

Giant-cell arteritis of the CNS

Isolated angiitis of the CNS

Primary angiitis of the CNS

Benign angiopathy of the CNS

Epidemiology

Mayo Clinic series – incidence in Olmsted County, MI, USA, was estimated to be 2·4 cases per 1 000 000 person-years ;

no gender predilection

Median age at diagnosis is about 50 years (50% of patients were between 37 and 59 years of age at diagnosis)

Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 2007; 62: 442–51.

Primary vs secondary CNS vasculitis

Primary (PCNSV)– primary involvement of blood vessels in the brain or spinal cord; PCNSV may affect small- and medium-sized cerebral blood vessels over diffuse areas of the CNS.

Secondary - the term used if the inflammatory process affecting the CNS is a part of a systemic process, such as an infectious or inflammatory disorder.

Clinical manifestations

Acute onset or more frequently insidious and slowly progressive.

75% cases are diagnosis within 6 months of the symptoms

Clinical

1.Headache, the most common

symptom, (generalized / localized,

slowly worsening, spontaneously

remitting for periods, and varies in

severity)

2.Cognitive impairment - insidious in

onset

3.Focal neurological manifestations

!!! Constitutional symptoms (fever

and weight loss) are uncommon.

Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol2007; 62: 442–51.

† P , 0.05 versus 1983–2003 cohort.‡ Defined as the presence of at least 1 of the following: fatigue, anorexia, weightloss, arthralgia.

PCNSV work up

Serology

CSF

NeuroimagingCerebral

angiography

Brain Biopsy

Markers of inflammation

ESR, CRP usually normal

If elevated, raise the suspicion of systemic process (inflammatory or infectious)

Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 2007; 62: 442–51.

Serology

Test Result

ANARFRo/SSA, La/SSB, Sm, and RNP antigensDsDNAANCASerum C3 and C4Serum cryoglobulinsSerum and urine protein electrophoresis Quantitative IG levels (IgG, IgM, IgA)

Normal

Lumbar puncture

CSF analysis important

to exclude infectious or malignant process

rule out reversible cerebral vasoconstriction syndrome (RCVS)(CSF normal/ SAH)

CSF is abnormal in 80-90% of patients with pathologically documented disease.

Hajj-Ali RA, Singhal AB, Calabrese LH; Reversible cerebral vasoconstrictive syndrome; Arthritis Rheum. 2008;58

No specific abnormalities of the CSF

Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 2007; 62: 442–51.

NEUROIMAGING

MRI/MRA

MRI/MRA in PCNSV

MRI is THE MAIN neuroradiographically modality of work up

Sensitive (up to 90-100%) but not specific;

Normal MRI is rare but possible; make the diagnosis unlikely

MRI findings in histologically proven PCNSV

Normal

Progressive confluent white matter lesions

Cortical and subcortical T2 lesions

Multiple diffusion positive lession

Large intraparenchimal hematoma

Multiple microhemorrhages

Multiple small enhancing lessions

Large single and multiple enhancing mass lesions

Enhancing small vessel mall

Leptomeningeal enhancement

IschemiaFluid attenuation inversion recovery (FLAIR)-weighted MRI shows a large abnormality within the right cerebral hemisphere consistent with ischaemia

MRI shows diffuse, asymmetric, nodular, and linear leptomeningeal enhancement, with dura only slightly affected.

Leptomeningeal enhancement

Salvarani C, Brown R, Hunder G. Adult primary central nervous system vasculitis Lancet 2012; 380: 767–77

Periventricular and juxtacortical lesions

26-year-old female with PCNSV-MRI/ FLAIR shows hyperintense lesions at periventricular

and juxtacortical areas, which represents encephalomalacia and gliosis

Olga Vera –Lastra et al. Primary and secondary CNS vasculitis Clin Rheumatol (2015) 34:729–738

White matter lesions, micro and macro-hemorrhages

Salvarani C, Brown R, Hunder G. Adult primary central nervous system vasculitis Lancet 2012; 380: 767–77

Tumor –like lesion

Kumar RS et al. Primary angiitis of central nervous system: Tumor-like lesion. PMID:20228492 ; Molloy ES, Singhal AB, Calabrese LH. Tumour-like mass lesion: An under-recognized presentation of primary angiitis of the central nervous system. Ann Rheum Dis 2008;67:1732-5

MCA distribution infarct, lacunar infarcts

Martin G. Pomper et al. AJNR Am J Neuroradiol

1999;20:75-85

©1999 by American Society of Neuroradiology

R subcortical

white matter

(posterior MCA

distribution)

Lacunar

infarcts in the

globus pallidi

Infarcts left

subcortical white

matter (PCA

distribution) and

posterior left

hippocampus

Post-gadolinium enhancement?

Vessel wall thickening and intramural enhancement of large arteries are specific to PCNSV, may extend into the adjacent leptomeningeal tissue (Fat-suppressed T1-weighted images are especially sensitive)

High-resolution 3-Tesla contrast-enhanced MRI might be able to differentiate enhancement patterns of intracranial atherosclerotic plaques (eccentric) vs inflammation (concentric)

Hammad TA, Hajj-Ali RA. Primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome. CurrAtheroscler Rep. 2013;15(8):346)

Vessel wall enhancement –HR MRI with contrast(a)PCNS vasculitis- shows vessel wall enhancement and thickening (arrow) while RCVS

patient (b) shows minimal wall enhancement (arrow).

Hammad TA, Hajj-Ali RA. Primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome. CurrAtheroscler Rep. 2013;15(8):346)

MR Angiography (MRA)

Less invasive than is cerebral angiography

Less sensitive in detection of lesions associated with posterior circulation and distal vessels.

MRA can overestimate the severity of stenoses at points of vessel branching or vascular occlusions.

CT

CT is less sensitive than is MRI, apart from cerebral haemorrhage.

Cerebral Angiography

Remains the gold standard

“Classic” findings of ectasia and stenosis referred to as "beading," usually in the small and medium size arteries with involvement of several sites of the cerebral circulation

Salvarani C, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 2007; 62: 442–51. 16 Duna GF, Calabrese LH. Limitations of invasive modalities in the diagnosis of PACNS. J Rheumatol 1995; 22: 662–67.

Harris KG et al. Diagnosing intracranial vasculitis: the roles of MR and angiography. AJNR Am J Neuroradiol 1994; 15: 317–30.

Bilateral lesions, large and small vessel involvement

Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 2007; 62: 442–51. 16

Angiogram in PCNSV

Smooth- wall narrowing & dilatation of cerebral arteries or arterial occlusions affecting many cerebral

vessels both large arteries (internal carotid and intracranial vertebral arteries, basilar artery, and their

primary branches) and smaller arteries; BILLATERAL in the absence of proximal vessel

atherosclerosis; alternating areas. Microaneurysms are rarely seen.

Salvarani C, Brown R, Hunder G. Adult primary central nervous system vasculitis Lancet 2012; 380: 767–77

Pitfalls

One abnormality in several arteries or several abnormalities in one artery is less consistent with primary CNS vasculitis.

Angiography might be normal (pathologically documented cases, suggesting that vascular abnormalities can occur in arteries smaller than the resolution of angiography)

Diagnosis should not be based on positive angiography alone, its results should always be interpreted in conjunction with clinical, laboratory, and MRI findings.

Salvarani C et al. Angiography-negative primary central nervous system vasculitis: a syndrome involving small cerebral vessels. Medicine (Baltimore) 2008; 87: 264–71.

Angiogram sensitivity low (40-90%) and low specificity 30%

6/14 patients (43%) of angiograms

undertaken at diagnosis in patients

with histologically proven primary CNS

vasculitis were diagnostic for vasculitis

Salvarani C et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 2007; 62:

442–51. 16

Correlation between MR and Cerebral angiogram

MR and Cerebral angiogram

Only 65% of MR lesions were evident on angiograms;

44% of the lesions revealed on angiograms were detected by MR.

The modest correlation between MR imaging and angiography suggests that the two techniques provide different information about PCNSV and both types of studies are needed for a complete assessment

Martin G. Pomper et al. AJNR Am J Neuroradiol 1999;20:75-85

Brain and leptomeningeal biopsy

the gold standard for the diagnosis

Optimal sample = dura, leptomeninges, cortex, and whitematter.

Biopsy of a radiologically abnormal area

In the absence of a focal lesion within the brain parenchyma, thetemporal tip of the nondominant hemisphere is the preferredbiopsy site

Moore PM. Diagnosis and management of isolated angiitis of the central nervous system. Neurology 1989; 39: 167–73.Parisi JE, Moore PM. The role of biopsy in vasculitis of the central nervous system. Semin Neurol 1994; 4: 341–48.; Miller DV, Salvarani C et al. Biopsy findings in primary angiitis of the central nervous system. Am J Surg Pathol 2009; 33: 35–43.; Alrawi A, Trobe JD, Blaivas M, Musch DC. Brain biopsy in primary angiitis of the central nervous system. Neurology 1999; 53: 858–60.

Biopsy

Skilled surgeons - 1% risk of neurological sequelae

Histopathology = transmural vascular inflammation of leptomeningeal or parenchymal vessels

Vasculitis affects arteries in a segmental way

Therefore a negative biopsy does not exclude diagnosis.

A positive biopsy sample verifies the presence of vasculitis, and excludes mimickers

Is biopsy the answer?

Sensitivities of 53% -63% (false negatives as high as 25%)

78% of targeted biopsies were diagnostic, whereas none of the untargeted biopsies showed vasculitis.

Inclusion of leptomeninges might increase the diagnostic yield

Stereotactic guidance can be used for deeper lesions

Duna GF, Calabrese LH. Limitations of invasive modalities in the diagnosis of primary angiitis of the central nervous system. J Rheumatol1995; 22: 662–67.Miller DV, Salvarani C et al. Biopsy findings in primary angiitis of the central nervous system. Am J Surg Pathol 2009; 33: 35–43.

Histology patterns

Granulomatous vasculitisis the most common (58%), showing vasculocentric mononuclear inflammation

and well formed granulomas with multinucleated cells (figure 1A).

Salvarani C, Brown R, Hunder G. Adult primary central nervous system vasculitis ancet 2012; 380: 767–77

Granulomatous vasculitisAmyloid deposition is seen in almost 50% of biopsy specimens with this pattern

(figure 1B), but is rarely noted in specimens with non- granulomatous primary CNS

vasculitis.

Salvarani C, Brown R, Hunder G. Adult primary central nervous system vasculitis ancet 2012; 380: 767–77

Lymphocytic vasculitisThe second most common pattern (28%). Lymphocytic inflammation predominates,

with occasional presence of plasma cells and vessel destruction (figure 1C).

Typically reported in children with angiography-negative PCNSV

Salvarani C, Brown R, Hunder G. Adult primary central nervous system vasculitis Lancet 2012; 380: 767–77

Necrotising vasculitisThe least common pattern (14%); is characterized by transmural fibrinoid necrosis

similar to that seen in PAN (figure 1D). This process is associated with intracranial

haemorrhage

Salvarani C, Brown R, Hunder G. Adult primary central nervous system vasculitis Lancet 2012; 380: 767–77

Special Clinical Subsets

11–12% of patients with ICH/SAH; less likely to

have altered cognition, a persistent neurological deficit,HP-Necrotising

vasculitis

Salvarani C,, et al. Primary CNS vasculitis with spinal cord involvement. Neurology 2008; 70: 2394–400Salvarani C et al. Primary central nervous system vasculitis with prominent leptomeningeal enhancement: a subset with a benign outcome. Arthritis Rheum 2008; 58: 595–603.Salvarani C, et al. Rapidly progressive primary central nervous system vasculitis. Rheumatology (Oxford) 2001; 50: 349–58.Salvarani C et al. Primary central nervous system vasculitis presenting with intracranial hemorrhage. Arthritis Rheum 2011; 63: 3598–606.Salvarani C et al.. Primary central nervous system vasculitis: comparison of patients with and without cerebral amyloid angiopathy. Rheumatology (Oxford) 2008;47: 1671–77

Cognitive dysfunction (high CSF protein, Angiography-negative, biopsy-positive; leptomeningeal or parenchymal enhancing on MRI); favorably response to treatment, good

¼ with Biopsy-positive cerebral amyloid

angiopathy(granulomatous+ vascular

deposits of amyloid β);Cognitive dysfunction and enhancing meningeal lesions on MRI; Monophasic disease

course ;Good response TX

5%-Spinal cord (thoracic)

4% of patients tumor with solitary -like mass lesion; Excision of the lesion has been curative; Aggressive IS favorable

Rapidly progressive primary CNS vasculitis -

fatal outcome; Angio: bilateral large cerebral infarctions are seen on; HP -= granulomatous or

necrotising; Poor response TX

Differential Diagnosis

Secondary causes of CNS vasculitis

Salvarani C, Brown R, Hunder G. Adult primary central nervous system vasculitis Lancet 2012; 380: 767–77

PCNSV vsReversible Cerebral Vasoconstriction syndrome

Hajj-Ali R, Calabresse et al. Primary CNS vasculitis Lancet Neurol 2011; 10:561-72

Diagnostic criteria

Calabrese and Mallek Criteria

1. History or clinical findings of an acquired neurologicaldeficit of unknown origin after a thorough initial basicassessment;

2. Cerebral angiogram with classic features of vasculitis,or a CNS biopsy sample showing vasculitis;

3. No evidence of systemic vasculitis or any other disorderto which the angiographic or pathological featurescould be secondary.

Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore) 1988; 67: 20–39.

Birnbaum and Hellmann

DEFINITE

Patients with biopsy-proven cerebral vasculitis

PROBABLE

Patients without histological verification but

with a high-probability angiogram

an abnormal MRI and cerebrospinal fluid (CSF) analysis consistent with primary CNS vasculitis.

Birnbaum J, Hellmann DB. Primary angiitis of the central nervous system. Arch Neurol 2009; 66: 704–09.

Symptoms

subacute / chronic headache, cognitive decline,focal neurologic deficits etc

MRI abnormal

Angio abnormal

CSF abnormal

Biopsy positive

Treatment PCNSV

Biopsy negative

Consider treating

MRI normal

Angio abnormal

CSF normal

RCVS or secondary CNSV

Treatment

No randomized clinical trials

Has been derived from therapeutic strategies used in other vasculitides/ case reports/ from cohort studies.

Induction: High Dose Prednisone - 1 mg/kg alone/ in combination with

Oral Cyclophosphamide 2 mg/kg (most common) (150mg/day)

IV Cyclophosphamide 1000mg/ month

Treatment is initiated for 3–6 months until remission

Maintenance therapy

Long term: 12–18 months is adequate in most patients

Azathioprine (1–2 mg/kg daily)

Mycophenolate mofetil (1–2 g daily)

Methotrexate (20–25 mg/week)

Methotrexate has generally been avoided due to potential poor penetrance to the CNS.

Salvarani et al. Adult Primary Central Nervous System Vasculitis Treatment and Course Analysis of One Hundred Sixty-Three PatientsARTHRITIS & RHEUMATOLOGY Vol. 67, No. 6, June 2015, pp 1637–1645

Mayo Clinic Experience

Salvarani et al. Adult Primary Central Nervous System Vasculitis Treatment and Course Analysis of One Hundred Sixty-Three PatientsARTHRITIS & RHEUMATOLOGY Vol. 67, No. 6, June 2015, pp 1637–1645

High-dose prednisone alone (60 mg/day median initial dose) and Prednisone plus cyclophosphamide (median dose 150 mg/day or IV 0·75 g/m2/ month for 6 months).

French Experience52 patients (30 males; median age at diagnosis 43.5 years ) PCNSV was diagnosed

between 1996 and 2012. CS (1mg/kg/day, preceded by IV methylprednisolone 1-

5days); Twenty-eight patients (54%) took aspirin.

Tx Dose Total Pts

Biopsyproven

CCA-proven

Induction Prednisone alone 1mg/kg/day 7 (14%) 2 5

CYP+Prednisone IV 0.6-0.7 mg/m2; very 2–4 weeks for the first 3 pulses, then monthly, for a total of

3–12 pulses)

44 (85%)

17 27

CYP (po) 1

Rituximab IV +prednisone

375 mg/m2 weekly, for a total of 4 infusions

1

Maintenance Azathioprine Methotrexate

Mycophenolatemofetil.

2mg/kg/day 24 (50%)

11

de Boysson H, Zuber M, Naggara O, et al. Revised primary angiitis of the central nervous system: description of the first 52 adults enrolled in the French COVAC’ cohort. Arthritis Rheum. 2014.

MMF as alternative ?

+ 16 patients treated with MMF

+ 8 MMF + GCs (3 patients started MMF simultaneously to GCs, the other 5

within 3 months from the starting of GCs)

+ 3 patients received MMF + GCs for a recurrence

+ 5 patients - maintenance therapy after induction with CYP+GCs

+ MMF treated-had a less severe disability score at last follow-up (p

= 0.023)

+ No statistically significant differences were observed regarding

relapses

Resistant to Steroids and Immunosuppression?

Tumour necrosis factor α (TNFα) inhibitors

Infliximab (5 mg/kg) seemed to rapidly and effectively improve the neurological status and MRI abnormalities (one patient)

Etanercept (50 mg/week) stopped relapse and led to the discontinuation of prednisone (one patient)

Prophylactic treatment for osteoporosis and prophylaxis against Pneumocystis jirovecii infection

Salvarani C, Brown RD Jr, Calamia KT, et al. Efficacy of tumor necrosis factor alpha blockade in primary central nervous system vasculitisresistant to immunosuppressive treatment. Arthritis Rheum 2008; 59: 291–96. 104 Sen ES, Leone V, Abinun M, et al. Treatment of primary angiitis of the central nervous system in childhood with mycophenolate mofetil. Rheumatology (Oxford) 2010; 49: 806–11.

Prognosisand

Response to treatment

Clinical factors influencing treatment

Salvarani et al. Adult Primary Central Nervous System VasculitisTreatment and Course Analysis of One Hundred Sixty-Three Patients ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 6, June 2015, pp 1637–1645

Factor OR 95% CI P value Outcome

Large vessel involvement

6.14 1.71-22 0.005 Poor response to TX

Cerebral infarction

3.32 1.23-8.96 0.018 Poor response to TX

Prominent gadolinium-

enhanced cerebral lesions or

meninges

2.28 1.04-5 0.04 Longer duration of TX

Prednisone alone Tx

2.90 1.4 -6 0.006 More relapses

0 No symptoms at all

1 No significant disability despite symptoms;

2 Slight disability; unable to carry out all previous activities

3 Moderate disability; requiring some help, but able to walk

4 Moderately severe disability; unable to walk /attend to own bodily needs without assistance

5 Severe disability; bedridden, incontinent and requiring constant nursing care and attention

6 Dead

Rankin Modified Score

Mayo Experience

Patients with low disability at diagnosis continued to have low disability at last follow-up

Patients with severe disability at diagnosis had less disability at follow-up.

The need for early diagnosis, since prompt treatment frequently leads to a favorable outcome.

Salvarani et al. Adult Primary Central Nervous System Vasculitis Treatment and Course Analysis of One Hundred Sixty-Three PatientsARTHRITIS & RHEUMATOLOGY Vol. 67, No. 6, June 2015, pp 1637–1645

French Experience

de Boysson H, Zuber M, Naggara O, et al. Revised primary angiitis of the central nervous system: description of the first 52 adults enrolled in the French COVAC’ cohort. Arthritis Rheum. 2014.

Univariate and multivariate Cox proportional hazards models .† Data were available for 129 patients.

Salvarani et al. Adult Primary Central Nervous System Vasculitis Treatment and Course Analysis of One Hundred Sixty-Three PatientsARTHRITIS & RHEUMATOLOGY Vol. 67, No. 6, June 2015, pp 1637–1645

Increased Mortality -15% (Mayo) vs 6% (French)

Relapse

Relapse was defined as a recurrence or worsening of symptoms of PCNSV or progression of existing or evidence of new lesions on subsequent MRI while the patient was receiving no medication or a stable dosage of medication.

Mayo - Relapses occurred in 44/159 (28%) (28 had 1 relapse, 10 had 2 relapses, and 6 had >3 relapses)

French -13/53 (27%) relapse

Relapse free survival curvesA. Relapse rates in the 2 groups

(biopsy-proven vs conventional

cerebral angiography (CCA)–

diagnosed PCNSV) were comparable

(P 0.57) –same in Mayo experience

B. The relapse rate was significantly

higher in those with meningeal

gadolinium enhancements

(P 0.001)

Boysson H. et al. Primary Angiitis of the Central Nervous SystemDescription of the First Fifty-Two Adults Enrolled in the French Cohort of Patients With Primary Vasculitis of the Central Nervous SystemARTHRITIS & RHEUMATOLOGY Vol. 66, No. 5, May 2014, pp 1315–1326

Relapse free survival curves

C, Survival curves for patients with

and those without seizures. The

relapse rate was significantly

higher in patients with seizures

(P 0.04).

Boysson H. et al. Primary Angiitis of the Central Nervous SystemDescription of the First Fifty-Two Adults Enrolled in the French Cohort of Patients With Primary Vasculitis of the Central Nervous SystemARTHRITIS & RHEUMATOLOGY Vol. 66, No. 5, May 2014, pp 1315–1326

Survival in PCNSV vs Secondary CNSV

Salvarani C et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 2007; 62: 442–51. 16

M0nitoring disease

Careful neurological examinations, are useful to monitor diseasecourse

Serial MRI/ MRA (4–6 weeks after the beginning of treatment, thenevery 3–4 months during the first year of treatment, or when a newneurological deficit arises)

In patients with stable imaging but worsening clinical symptoms,repeat spinal fluid examination and repeat angiography

Back to our patient…….

Treatment initiated and MRI repeated

Methylprednisolone 1g IV x 7 days; with symptomatic relief

MRI after 4 days of steroids Significant improvement in previously described diffuse leptomeningeal enhancement (persistent mild leptomeningeal enhancement overlying the bilateral cerebellar hemispheres) Extensive patchy white matter signal abnormality, overall similar; though a single lesion in the splenium of the corpus callosum has mildly increased.

However…..

Patient developed hallucinations and it was stopped for two days with return in his headaches; Started on Seroquel

Another MRI after stopping steroids: Significant interval worsening of the diffuse nodular leptomeningealenhancement as well as the focal enhancement of many of the intra-parenchymal lesions

Continuation….

Methylprednisolone 1g was resumed x 7days, then started 60 mg Prednisone every day

Before discharge receive first dose of IV Cytoxan 1g/ monthly

Physical exam at discharge: able to talk in full sentences. Following commands. AoX3 ; CN II-XII normal; speech still difficult, some comprehension difficulties; Motor, sensory normal; Hyperreflexis; Babinski – equivocal; discharged to Inpatient rehab

3 infusions so far

MRI -3 months after treatment with steroids and Cytoxan

Stable to slightly less conspicuous appearance of multiple intraparenchymal signal abnormality within the periventricular white matter, bilateral cerebellar hemispheres, and corpus callosum. The area of signal abnormality within the right internal capsule is slightly increased compared to prior, suggesting some aspect of ongoing process.

Significant decrease in leptomeningeal and parenchymal enhancement.

THANK YOU!

Pathophysiology

Causes remain unknown.

Triggers? Infectious agents ?varicella zoster virus. Inoculation of turkeys IV with Mycoplasma gallisepticum induced cerebral vasculitis similar to primary CNS vasculiti (diagnosed at autopsy, EM showed structures resembling mycoplasma organisms within giant cells in the wall of affected cerebral arteries)

Immunohistochemical staining of a biopsy sample showed predominant infiltration by CD45R0+ T cells in and around small cerebral vessels (?memory T cells in the pathogenesis of vasculitis, suggesting that primary CNS vasculitis can result from an antigen-specific immune response occurring in the wall of cerebral arteries.

effector molecules, matrix metalloproteinases (MMPs), particularly MMP-9, seem to be pivotal in animal models of vasculitis.

Finally, the link between primary CNS vasculitis and cerebral amyloid angiopathy is noteworthy

The inflammatory reaction to the presence of amyloid β varies from little or no inflammation, to perivascular infiltrates, and to granulomatous vasculitis. The inflammatory response to vascular amyloid reported in a transgenic mouse model of cerebral amyloid angiopathy accords with a role for amyloid deposition as a trigger of vascular inflammation.

Over-representation of the APOE ε4/ε4 genotype in patients with inflammation related to cerebral amyloid angiopathy, raising the possibility that the ε4 isoform of apolipoprotein E might play a part in the progression of inflammation to cerebral amyloid angiopathy..