Primary CNS Vasculitis - diagnostic and therapeutic challenges

Primary CNSVasculitis –
Diagnostic andTherapeutic
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 5/5Throuout; NormalTone.; Reflexes LE+3; Positive Babinski bilateraly
 Light touch- diminished on left ; Could not discriminate sharp from dull bilaterally
Vibration intact bilaterally
 Coordination: Patient had very difficult time understanding this test.
 Gait: Narrow based ;Patient did NOT understand how to do heel-to-toe despite
demonstration 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
 NegativeTox screen (Lead, Arsenic, Bleach)

TEST Result
LymeAB NEGATIVE
LymeWB 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 HBsAg detected
Hepatitis C NEGATIVE
Crypto Ag, CSF NEGATIVE
Histoplasma, CSF NEGATIVE
RPR blood,VSRL -CSF NEGATIVE
Cystocercosis IgG NEGATIVE
AFB smear NEGATIVE
QuantiferonTB 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 normal
CSF/serum index 34 (High)
IgG index, CSF -0.6
IgG /albumin CSF ratio 0.11
IgG, CSF 15.5 (H)
Oligoclonal bands -0
VDRL,CSF negative
India Ink- negative
Acid fast culture negative
CSF-cytology no malignant cells
Flow genetics –no abnormal
immunophenotype/malignancy

Autoimmune work-up
Cryoglobulin- not detected
Kappa, Lambda -normal

MRI – at admission
 MRI brain -multiple small subcentimeter scattered areas of
abnormalT2 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 forT Ly negative
 No viral inclusions; No evidence of malignancy

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 RDJr, 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 Neurol
2007; 62: 442–51.

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

PCNSV work up
Serology
CSF
Neuroimaging
Cerebral
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
ANA
RF
Ro/SSA, La/SSB, Sm, and RNP antigens
DsDNA
ANCA
Serum C3 and C4
Serum cryoglobulins
Serum 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.

MRI/MRA in PCNSV
 MRI isTHE 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 subcorticalT2 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

Ischemia
Fluid 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
OlgaVera –Lastra et al. Primary and secondaryCNS vasculitis Clin Rheumatol (2015) 34:729–738

White matter lesions, micro and macro-hemorrhages

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)
HammadTA, Hajj-Ali RA. Primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome. Curr
Atheroscler 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).
HammadTA, Hajj-Ali RA. Primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome. Curr
Atheroscler 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.

CerebralAngiography
 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 RDJr, 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.

Pitfalls
 One abnormality in several arteries or several abnormalities in one artery is
less consistent with primaryCNS 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 white
matter.
 Biopsy of a radiologically abnormal area
 In the absence of a focal lesion within the brain parenchyma, the
temporal tip of the nondominant hemisphere is the preferred
biopsy 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,TrobeJD, 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 Rheumatol
1995; 22: 662–67.
Miller DV, Salvarani C et al. Biopsy findings in primary angiitis of the central nervous system. AmJ Surg Pathol 2009; 33: 35–43.

Granulomatous vasculitis
is 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 vasculitis
Amyloid 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 vasculitis
The 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

Necrotising vasculitis
The 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

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: 2394–400
Salvarani 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 responseTX
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
responseTX

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

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

Calabrese and Mallek Criteria
1. History or clinical findings of an acquired neurological
deficit of unknown origin after a thorough initial basic
assessment;
2. Cerebral angiogram with classic features of vasculitis,
or a CNS biopsy sample showing vasculitis;
3. No evidence of systemic vasculitis or any other disorder
to which the angiographic or pathological features
could 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 PrimaryCentral Nervous System VasculitisTreatment and Course Analysis of One Hundred Sixty-Three
PatientsARTHRITIS & RHEUMATOLOGYVol. 67, No. 6, June 2015, pp 1637–1645

Mayo Clinic Experience
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 Experience
52 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
Biopsy
proven
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
Mycophenolate
mofetil.
2mg/kg/day 24
(50%)
1
1
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.

+ 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 vasculitis
resistant to immunosuppressive treatment. Arthritis Rheum 2008; 59: 291–96.
104 Sen ES, LeoneV, Abinun M, et al.Treatment of primary angiitis of the central nervous system in childhood with mycophenolate mofetil.
Rheumatology (Oxford) 2010; 49: 806–11.

Prognosis
and
Response to treatment

Clinical factors influencing treatment
Salvarani et al. Adult Primary Central Nervous SystemVasculitisTreatment and Course Analysis of One Hundred Sixty-Three Patients
ARTHRITIS & RHEUMATOLOGYVol. 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 toTX
Cerebral
infarction
3.32 1.23-8.96 0.018 Poor response toTX
Prominent
gadolinium-
enhanced
cerebral lesions or
meninges
2.28 1.04-5 0.04 Longer duration ofTX
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.

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.
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
curves
A. 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 System
Description of the First Fifty-TwoAdults Enrolled in the French
Cohort of PatientsWith PrimaryVasculitis of theCentral 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 System
Description of the First Fifty-TwoAdults Enrolled in the French
Cohort of PatientsWith PrimaryVasculitis of theCentral 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 disease
course
 Serial MRI/ MRA (4–6 weeks after the beginning of treatment, then
every 3–4 months during the first year of treatment, or when a new
neurological deficit arises)
 In patients with stable imaging but worsening clinical symptoms,
repeat spinal fluid examination and repeat angiography

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 leptomeningeal
enhancement 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.

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..

Primary CNS Vasculitis - diagnostic and therapeutic challenges

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