Cerebral vasculitis

Vasculitis

Inflammation and necrosis of blood vessel wall

Classification

Classification
LARGE-VESSEL VASCULITIS
Aorta and
large
branches to
extremities,
head, and
neck

Giant-cell
(temporal)
arteritis

Granulomatous inflammation; frequently involves the temporal artery.

Usually occurs in patients older than age 50 and is associated with
polymyalgia rheumatica.

Takayasu
arteritis

Granulomatous inflammation usually occurring in patients younger than

age 50

MEDIUM-VESSEL VASCULITIS
Main visceral
arteries and
their
branches

Polyarteritis
nodosa

Necrotizing inflammation typically involving renal arteries but sparing

pulmonary vessels

Kawasaki
disease

Arteritis with mucocutaneous lymph node syndrome; usually occurs in

children. Coronary arteries can be involved with aneurysm formation and/or
thrombosis.

SMALL-VESSEL VASCULITIS
Arterioles,
venules,
capillaries,
and
occasionally
small
arteries

Wegener
granulomatosis

Granulomatous inflammation involving the respiratory tract

(Rhinolaryngologic, without asthma) and necrotizing vasculitis affecting
small vessels, including glomerular vessels. Associated with PR3(c)ANCAs.

Churg-Strauss
syndrome

Eosinophil-rich granulomatous inflammation involving the respiratory tract

and necrotizing vasculitis affecting small vessels. Associated with asthma
and blood eosinophilia. Associated with MPO-(p)ANCAs.

Microscopic
polyangiitis

Necrotizing small-vessel vasculitis with few or no immune deposits;

necrotizing arteritis of small and medium-sized arteries can occur.
Necrotizing glomerulonephritis and pulmonary capillaritis are common.
without granulomas or asthma. Associated with MPO-(p)ANCAs.

Classification 2

PACNS

Pathophysiology
Vasculitis
Infection
of vascular
walls
(Infectiou
s
vasculitis
)

Immunemediated
inflammation
(Noninfectiou
s vasculitis)
Immune
Complex
Associate
d
Vasculitis
PAN, Drugs,
HBV & HCV +
cryoglobuline
mya

Antineutroph
il
Cytoplasmic
Antibodies
Wegener,
ChurgStrauss,
Microscopi
c
polyangiiti
s

AntiEndothelia
l Cell
Antibodies
Kawasa
ki

Pathogenic T
lymphocyte
responses
and
granuloma
formation
Giant cell
arteritis,
Takayasu's
arteritis
PACNS

Drug
induced

Collagen
vascular
diseases
Systemic
lupus
erythematos
us
Rheumatoid
arthritis
Scleroderma
Sjgren
syndrome

Paraneoplas
tic

Isolated
vasculitis of
the central
nervous
system

Drug induced vasculitis

carbamazepine,
phenytoine,
thiouracil,
allopurinole,
minocycline,
penicillamine,
MTX
isotretinoine

Pathophysiology - Immune Complex

Associated Vasculitis
1. Formation of circulating immune complexes:
antigen (exogenous or endogenous) combines
with antibody within the circulation
Polyarteritis nodosa Antigen Involved:
Hepatitis B virus antigens

2. Deposition of antigen-antibody complexes in

tissues
3. Inflammatory reaction at the sites of
immune complex deposition complement
activation (classical pathway: binding of C1
to IgG1 or IgG3 or IgM; activation is
expressed by the decrease in serum levels
of C3) recruitment of leukocytes by
complement products and Fc receptors
release of enzymes and other toxic
molecules

Pathophysiology - Antineutrophil
Cytoplasmic Antibodies
Antineutrophil cytoplasmic antibodies
cytoplasmic (c-ANCA) target antigen: proteinase-3 (PR3)
Wegeners granulomatosis

perinuclear (p-ANCA) target antigen: myeloperoxidase (MPO)

microscopic polyangiitis, Churg-Strauss

ANCA formation:
1. Neutrophils stimulated by TNF- or IL-1
2. MPO or PR3 translocate to the cell membrane
3. Neutrophil surface expression or release of PR3 and MPO incites
ANCA formation; alternatively, drugs or cross-reactive microbial
antigens induce ANCAs
4. Interaction between surface MPO/PR3 and extracellular ANCA
5. Neutrophils activation endothelial damage

CNS incolvement in systemic

vasculitis
Large vessel
Giant cell arteritis temporal arteritis
Takayasu stroke secondary to aorta disease
in young patient

Medium vessel
Cerebral involvement may occur in PAN, but is
very unusual in Kawasaki syndrome

Small vessel
With ow without ANCA
PACNS

CNS vasculitis
Fibrinoid necrosis of the arterial wall, formation of
giant cells, or non-necrotizing vasculopathy in
vessel walls

Stenosis/occlusion or rupture of an artery,

In the
capillary,
or venule
In the central
Meningeal
nervous
system

peripheral
nervous
system

granulomatou
s involvement

Other organs

that occur with variable timing Variable

clinical course
Fulminant ( infectious v.)

Indolent ( non-infectious v.)

Different neurologic
presentation:
peripheral neuropathy
(polyneuropathy,
mononeuropa- thy, or
mononeuropathy multiplex),
cranial neuropathy,
muscle disease,
visual loss,
encephalopathy,
seizures,
headache,
behavioral or personality
changes, dementia,
venous thrombosis,
ischemic or hemorrhagic
stroke
+/- involvement of skin,
kidney,
Fluctuations
in clinical
lungs,
sinuses,
signs
cardiovascular
system, or
joints
Angiogenesis (compensatory
response to secondary tissue
ischemia)

CNS vasculitis
Major symptoms:
Stroke
Headache
Encephalopathy
Other:
Seizure
Cranial nerve palsies
myelopathies

CNS vasculitis Laboratory

findings
raised erythrocyte sedimentation rate
(ESR) and increased values of C-reactive
protein (CRP).
Anemia, thrombocytosis, elevated liver
enzymes
Low complement in vasculitides
associated with immune complexes

In PACNS, serum findings usually are normal

CNS vasculitis CSF

examination

Mild lympho(mono)cytosis,
increased protein,
elevated inflammatory markers,
normal glucose

CNS vasculitis serologic tests

Antinuclear antibodies (ANA)
Antibody to double-stranded DNA (antidsDNA)
Extractible nuclear antigens (ENA)
Rheumatoid factor
Anticardiolipin antibodies
Neutrophil cytoplasmic antibodies (c-ANCA, pANCA)

Hepatitis B surface antigen (HBsAg)

Cryoglobulins

CNS vasculitis - MRI

multiple small intraparenchymal (gray or white
matter) lesions consistent with ischemic stroke
Small hemorrhages or larger areas of hemorrhage
Some patients may have enhancement of the
meninges or small penetrating arteries
Angio-MR:
segmental areas of stenosis or occlusion in
multiple intracranial vessels (sausage-like)
Usually negative (involvement of medium caliber
arteries) arteriography is usually required

CNS vasculitis - Imaging

18-fluorodeoxyglucose positron emission
tomography (PET) is very sensitive in revealing
inflamed vessels allow the visualization of
vessel wall inflammation when the lumen is still
unaffected on angiography.
Color doppler: usefull in extracranial vasculitis
for the study of inflammation, stenosis,
occlusion and aneurysms
Angiography: segmental narrowing or dilation
and occlusions that affect multiple cerebral
vessels

CNS vasculitis - EEG

Diffuse or focal slow activity

CNS vasculitis - biopsy

Vasculitis restricted to the brain
brain and meningeal biopsy
Multisystem vasculitides Biopsy of
skin, muscle, peripheral nerve, or
temporal artery

CNS vasculitis - therapy

In general, a combination of steroids
(Methylprednisolone, 1 g/day for 3-5 days
prednisone 1 mg/kg for 4-6 weeks, then taper)
and cyclophosphamide (CYC; oral: 150mg/day;
iv: 1000 mg/month) is recommended for
induction treatment.
An alternative option is the use of the antiCD20 antibody rituximab.
Methotrexate, azathioprine (100mg/day) and
mycophenolate mofetil are recommended as
alternatives to CYC once remission is achieved.

Cyclophosphamide
Complications:
Life threatening infections,
leukopenia
ovarian insufficiency
hemorrhagic toxic cystitis
risk of bladder cancer and risk of a
myelodysplastic syndrome with a
cumulative CYC dose of >30g/year

Cyclophosphamide
Oral protocol:
1.5 to 2 mg/kg per day.
Pulse protocol:
15mg/kg infusions every month about
15g/year are given
Supportive therapies:
antiemetics,
bladder protection with NaCl infusions and
uromitexane perfusor
ovarian protection

Azathioprine
Used for maintainance therapy (6-12 months)
1-2 mg/kg (100 mg/day)
The usual starting dose for azathioprine is 50 mg/day; obtain a complete
blood count (CBC) after two weeks of therapy to assure that the counts are
stable
Then increase the daily dose by 50 mg each week to 1.5 mg/kg/day
Obtain CBCs, a platelet count, and liver function tests monthly initially,
and once a stable dose is achieved, perform testing every three
months.
Up to 6 months before terapeutic effects
Adverse effectsSystemic flu-like reactions associated with fever and
gastrointestinal complaints develop in up to 12 percent of patients treated
with azathioprine. Other side effects include bone marrow suppression,
pancreatitis, and liver toxicity. Long-term side effects may include increased
risk of malignancy.

Methotrexate
Once-a-week administration either orally or parenterally
Greater difficulty to cross BBE
The usual starting dose for methotrexate is 15 mg/week. If there is an
inadequate response after two to three months, this can be increased
slowly by 2.5 mg increments to 25 mg/week
Add 5 mg of folinic acid once weekly, 8 to 12 hours after MTX
administration .
Adverse effectsMethotrexate toxicity, including stomatitis,
gastrointestinal symptoms, and leukopenia, can be seen with low-dose
therapy. Attention to hepatotoxicity (avoid in liver disease and in those who
drink alcohol) and pulmonary toxicity

Rituximab
1 gram each 14 days

Giant cells arteritis

F:M = 5:3, 65 years or more
Neurological symptoms: persisting headache, jaw
claudication, visual symptoms or rarely stroke
Systemic symptoms: fever, malaise and weight loss,
polymyalgia rheumatica
Laboratory: raised ESR and increased values of CRP
Clinical: tenderness or decreased pulsatility of the
temporal arteries
Colour duplex sonography: dark halo around temporal
artery
Temporal artery biopsy: mononucleated cell infiltrates
of all mural layers and occurrence of giant cells

Giant cells arteritis

Pathophysiology: CD4+ T cell immune
response
against antigen located in the
internal elastic layer of the vessel
wall
arteries of the anterior intracerebral
circulation are infrequently affected
because these lack an internal elastic
layer

Activation of macrophages IL1, IL

Giant cells arteritis

Therapy:
Prednisone 1 mg/kg daily
started immediately in suspected TA
Corticosteroid treatment must not be delayed by temporal artery biopsy The biopsy
is positive even after a few days of steroid treatment.
Prosecution: as soon as the acute phase reactants have returned to normal, tapering
of the steroids may begin
Tapering should be performed cautiously by no more than 2.5mg every 2weeks; when
a daily dose of 15mg is reached, dose reduction should not exceed 1 mg per month
Whenever symptoms or acute phase proteins recur during tapering, the last effective
dose plus 10 mg should be adminis- tered
The majority of patients require corticosteroid treatment for a time period of more than
2 years.

In the case of a vascular emergency in TA (blindness, stroke), start therapy

with 1000mg of prednisone daily for 5 days, followed by oral treatment at a
dose of 1 mg per kg body weight
Other: due to the TNF role, infliximab and etanercept (anti-TNF) have been
evaluated in patients with TA, but showed a slight but nonsignificant effect

Takayasu
Modified American College of Rheumatology criteria for the
diagnosis of Takayasus arteritis (at least three of six):
1.
2.
3.
4.

Age at disease onset <50 years

Claudication of extremities
Decreased brachial artery pulse
Blood pressure [systolic] difference > 10mmHg between
arms
5. Bruit over subclavian arteries or abdominal aorta
6. Arteriographic narrowing or occlusion of the aorta, its
primary branches or large arteries (not due to
arteriosclerosis, fibromuscular dysplasia or similar causes)

Takayasu
Anti-endothelial antibodies (AEA) have been
reported but are not an obligatory finding.
Digital subtraction angiography is the gold standard
for diagnosis
Vascular inflammation can be detected by:
delayed contrast-enhanced MRI sequences
18F-FDG-PET uptake

Therapy:
As other CNS vasculitis
treat the associated renovascular hypertension with
angiotensin II receptor antagonists
ASA + statins

PAN
PAN may be associated with hepatitis virus (HV) infection
peripheral nerve involvement in particular is more prevalent in
HV-associated PAN
Brain involvement has
been reported in up to
20% of patients
Ischemic stroke,
hemorrhages and a
progressive
encephalopathy with or
without seizures
Myalgias and a
polyneuropathy of the
multiplex type are very
frequent neurological
fea- tures A combined
biopsy of muscle and

PAN
Therapy
negative hepatitis serology:
prednisone and CYC
in emergency situations, plasmapheresis

HV associated PAN:
prednisone + virustatics
HBV: lamivudine
HCV: interferone-alpha and ribavirine

Wegener
Neurological involvement:
in 22-33.6% of patients cerebrovascular neurological
symptoms, polyneuropathies, myelopathies
necrotizing granulomas of the nose and the paranasal
sinuses compression of neighborhood structures with
cranial nerve lesions, diabetes insipidus or exophthalmus
Non-septic meningitis with hydrocephalus
cANCA/PR3 are
present in 70%
of patients
with limited
WG and in
>90% of
systemic WG
cases

Wegener
Therapy:
Prednisone + cyclophosphamide (pulse
CYC)
Alternative induction treatment:
MTX 20-25mg per week
Rituximab
AZA

After remission Trimethoprime

Sulfamethoxazol 320+1600 may be
sufficient

Churg-Strauss
pANCA/MPO are present in 40% of patients
CNS involvement:
in 68% of patients
cerebral infarctions, intracerebral hemorrhages
and subarachnoid hemorrhages

PNS involvement:
multineuropathy in ANCA-positive patients
Symmetrical polyneuropathies in ANCAnegative patients

Churg-Strauss
1.
2.
3.
4.
5.

Five factor score:

proteinuria > 1 g/day,
creatinine > 1.58 mg/dl,
gastrointestinal involvement,
cardiomyopathy,
neurological involvement

Absence of these
factors:
Prednisone alone

2 or more of these
factors:
Prednisone +
CYC

Behets disease
Vasculitis affecting predominantly the venous
system
Diagnostic criteria:
recurrent oral ulcerations must be present in
combination with at least two of the following:
recurrent genital ulceration,
eye lesions (uveitis, cells in the vitreous on slit lamp
examination or retinal vasculitis),
skin lesions (erythema nodosum)
a positive pathergy test result

Increased antibodies against phosphatidylserine

and ribosomal phosphoproteins

NeuroBehet
CNS involvement occurs in about 30% of patients
after an average of 5 years
80% motor tract signs, stroke and headache.
Frequently, the brainstem is predominantly involved
20% sinus thrombosis with pseudotumour

Therapy:
Methylprednisolone 1 g ev for 3-5 days daily
prednisone 1 mg/kg, tapered in 2-3 months
Add an immunosuppressive drug: CYC, MTX, interferonalpha, or AZA
Add oral anticoagulation in case of sinus thrombosis

Primary angiitis of the central

nervous system (PACNS)
Consider when:
multifocal or diffuse CNS disorder

remitting or progressive course

headache, strokes, seizures, myelopathy, and encephalopathy

symptoms develop gradually over weeks, with a fluctuating or stepwise
progressive course

CSF: pleocytosis (in 50%) and a protein elevation (common)

MRI findings: ischemic and hemorrhagic lesions of different ages,
leukencephalopathies, tumor-like lesions, or gadolinium enhancement of
the meninges
angiography with a vasculitic pattern (segmental narrowing or dilation and
occlusions that affect multiple cerebral vessels). The sensitivity of
angiography is rather poor, because PACNS often involves blood vessels
below the resolution of conventional angiography
leptomeningeal and parenchymatous biopsy proving vasculitis
organ manifestations other than the CNS are an exclusion criterion for the
diagnosis

But is rare! 700 cases published worldwide

PACNS

PACNS
Common symptoms:
Cognitive decline (80%)
Headache (60%)
Focal motor deficits (50%)
Seizure (30%)
The 3 essential diagnostic criteria for PACNS are:
1. demonstration of CNS angiitis,
2. exclusion of other conditions, and
3. restriction to the CNS.

3 separate types of angiitis have been distinguished:

.granulomatous,
.lymphocytic,
.necrotizing

PACNS
A brain and leptomeningeal biopsy demonstrating angiitis
remains the gold standard for the diagnosis of PACNS

Avoid false negative biopsy sufficiently large (1 1 1 cm)

open wedge biopsy that contain leptomeninges, cortex, and
subcortical white matter targeted from radiographically
involved areas

PACNS
Therapy:
Initial: Prednisone + CYC (3-6
months)
Exclude a systemic infection before CYC!
spirochetal (neurosyphilis, borreliosis),
rickettsial (typhus, Rocky Mountain spotted
fever)
viral (varicella-zoster-, cyto- megalo-, human
immunodeficiency virus)
bacterial endocarditis

Mantainance: AZA

PACNS

anti-TNF:
infliximab and
etanercept

PACNS - Differential
diagnosis
Infections
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)
an autosomal dominant disorder that leads to strokes and a progressive vascular encephalopa- thy in young adults.

Moyamoya
progressive bilateral narrowing of the terminal internal carotid artery and the proximal segments of the middle and
anterior cerebral arteries stroke and headache

Reversible cerebral vasoconstriction syndrome (RCVS)

segmental narrowing of cerebral arteries associated with a variety of clinical conditions including abrupt severe
(thunderclap) headaches, eclampsia, hypertensive en- cephalopathy, migraine, and use of vasoactive drugs.
RCVS comprise a group of disorders characterized by reversible cerebral vasoconstriction, acute onset of thunderclap
headaches with or without neurologic deficit, and normal findingson CSF analysis.
It can be associated with postpartum state, sympathomimetic agents, and use of selective serotonin reuptake inhibitors.
The cerebral vascular studies demonstrate typical areas of beading in multiple vessel beds that are usually reversible in
follow-up studies. The suggested pathophysiology of RCVS is that of vasospasm, since the pathologic findings do not
indicate any vasculitic pattern.
Treatmen: Prednisone + Verapamil

CAA
Intravascular lymphomas
Molecular testing for T and B clonality should be performed to exclude this entity

Sarcoidosis
In the absence of systemic sarcoidosis, differentiation from PACNS may be difficult. In sarcoidosis, granulomata are
present in the leptomeninges and in the parenchyma where they are largely perivascular

MELAS

Vasculitis in collagen vascular

diseases
An immune-complex-related cerebral
vasculitis is possible in:
systemic lupus erythematosus (SLE)
strokes are often caused by a secondary
antiphospholipid syndrome

rheumatoid arthritis
Sjoegrens syndrome