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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..