Transcript Slide 1

Vasculitis and Central Nervous System
Ghaffarpour. M
Iranian Center of Neurological Research
Tehran University of Medical Sciences
Tehran – Iran
29 April 2012
Definition
• Vasculitis is a clinicopathologic process that results when
autoimmune mechanisms are directed against blood vessel’s
wall.
• It may be primary or sole manifestation of the disease or may
be secondary to other conditions such as drugs, infection,
serum sickness, malignancy and connective tissue diseases.
• May be confined to a single organ such as skin, or may simultaneously involves several organ systems, thus broad &
heterogeneous syndromes may develop, depending on type,
size and location of involved vessels.
Classification
There is no universally agreed classification for vasculitis,
because of heterogeneity and overlapping.
For the purpose of our speak, we mention to classifications of:
1) Scott
2) Harrison
Scott’s Classification of vasculitis syndromes (1988)
I- Systemic nectrotizing vasculitis
• PAN and microscopic polyangiitis
• Allergic angiitis and granulomatosis (Churg – Strauss)
• Polyangiitis overlap syndrome
II- Wegener’s granulomatosis
III-Temporal arteritis (common form of giant cell infiltration: Extracranial)
IV-Takayasu’s arteritis (rare form of giant cell infiltration: Aortic)
V- Henoch-schonlein purpura (anaphylactoid purpura)
IV – Predominantly cutaneous vasculitis (Hypersensitivity)
A- Exogenic stimuli
- Serum sickness and serum sickness – like reactions
- Infections
- Drugs
B – Endogenous stimuli
- Neoplasms (particularly lymphoid malignancies)
- Connective tissue diseases
- Congenital deficiency of complement system
- Other underlying diseases (SLE, RA, Cryoglobulinemia,
Sjogren’s syndrome, SBE, EB and HIV infections, Chronic active
hepatitis, Biliary cirrhosis, 1-antitrypsin deficiency, Intestinal bypass
surgery, Relapsing polychondritis)
VII – Other vasculitis syndromes
- Buerger’s disease (thromboangiitis obliterance)
- Behcet’s disease
- Kawasaki disease
- Isolated CNS vasculitis
- Miscellaneous vasculitis
Harrison’s classification of the major vasculitis syndromes
Primary
Wegener’s granulomatosis
Churg – Strauss syndrome
Polyarteritis nodosa (PAN)
Microscopic polyangiitis *
Giant cell arteritis
Takayasu’s arteritis
Henoch – Schonlein purpura
Idiopathic cutaneous vasculitis
Essential mixed cryoglobulinemia
Bechcet’s syndrome
Isolated vasulitis of CNS
Cogan’s syndrome
Kawasaki disease
Secondary
Serum sickness vacuities
Drugs
Amphetamine
Allopurinol
Antibiotics
Cocaine, crack, heroin
Ephedrine & other
sympathomimetics
Vasculitis associated with
other primary disease:
Infections
Malignancy
Connective tissue
diseases
* : On the basis of the smaller size of the affected vessels and presence of P-ANAC,
Lhote et al have differentiated this entity.
Pathophysiolog and pathogenesis
Generally, most of the vasculitis syndromes are assumed to be
mediated, at least in part, by immune-pathogenic mechanisms.
However, evidence supporting this hypothesis is for the most
part indirect and may reflect epiphenomena as opposed to true
causality.
Potential mechanisms of vessel damage are:
 Pathogenic immune – complex formation and / or
deposition.
Vacuities is generally considered within the broader category
of immune-complex disease that include serum sickness and
certain connective tissue diseases, of which SLE in the
prototype. Others include:
• Henoch – Schonlein purpura
• Serum sickness and cotaneous vasculitis syndromes
• Hepatitis C – associated mixed cryoglobulinemia
• Hepatitis B – associated polyarteritis nodosa
 Production of Antineutrophilic cytoplasmic abs (ANCA).
ANCA are antibodies against certain proteins in the cytoplasmic
granules of neutrophils and monocytes, that are found in a high
percentage of patients with systemic vasculitis syndromes,
particularly:
Wegener’s granulomatosis
Microscopic polyangiitis
Necrotizing and crescentic glumerulonephritis
Churg- strauss (in 50%)
• There are two major categories of ANCA :
1) Perinuclear (P-ANCA)
Has several targets. However only antibodies to
myeloperoxidase
have been convincingly associated with vasculitis.
P-ANCA occurs in variable percentage of:
- Polyarteritis nodosa
- Churg - Strauss
- Crescentic glumerulonephritis
- Goodpasture’syndrome
- Microscopic polyangiitis
- Wegener’s granulomatosis
- It was also been associated with nonvasculitic entities
such
as rhaumatic and non-rheumatic diseases including:
IBD
Certain drugs
Infections such as endocarditis and bacterial
airway
infections in patients with cystic fibrosis
2) Cytoplasmic (C-ANCA)
Found in more than 90% of patients with typical active
wegener’s granulomatosis and active glomerulonephritis.
C-ANCA may also be found in intravascular lymphoma
(Adams, P:732).
C-ANCA is specific for Wegener’s granulomatosis and churgstrauss and helps to differentiate it from polyarteritis (which display
P-ANCA) and from carcinoma, chordoma, sarcoidosis and zoster
(Adams, P:1138).
There is no conclusive evidence that ANCA are directly
involved in the pathogenesis of vasculitis syndromes
because :
Patients may have vasculitis in the absence of ANCA.
The absolute ANCA titers dose not correlate well with
disease activity and remission of vasculitis,
particularly in patients with wegener’s granulomatosis.
High titers of C-ANCA may continue for years.
 Pathogenic T – lymphocyte responses and granuloma
formation
Mechanisms other than immune – complex – mediated
mechanisms as well as ANCA , may be involved in damage
to
vessels.
• The most prominent mechanism of this type are delayed
hypersensitivity and cell-mediated immune injury as
reflected in the histological feature of granulomatous
vasculitis.
• Vascular endothelial cells can express HLA class II
following activation of cytokines such as IFN-y, that
allows these cells to participate in immunologic
reactions such as interaction with CD + T cells.
• Other factor is secretion of IL-1 from endothelial
cells,
which may activate endothelial leukocyte and vascular
cell adhesion molecules (ELAM1 and VCAM1) that
enhance the adhesion of leukocytes to endothelial cell
in the blood vessel wall.
• Related disorders to this mechanism include:
Giant cell arteritis
Takayasu’s disease
Wegener’s granulomotosis
Churg – Strauss syndrome
Approach to the patient with vasculitis
• The diagnosis of vasculitis is often considered in any patients with
an unexplained systemic illness. However , there are certain
clinical abnormalities that when present alone or in combination,
should suggest a diagnosis of vasculitis. These include:
- palpable purpura
- Pulmonary infiltrates and Microscopic hematuria
- Mononeuritis multiplex
- Chronic inflammatory sinusitis
- Unexplained ischemic events
- Unexplained cerebral or spinal lesions.
- Glumerulonephritis with evidence of multi-system disease.
• A number of nonvasculitic diseases may also produce some or
all of these abnormalities, thus the first step in the workup of
patient with suspected vasculitis is to exclude the conditions
that can mimic vasculitis such as:
A - Infections
Bacterial endocarditis
Disseminated gonococcal infection
Pulmonary histoplasmosis
Coccidioidiomycosis
Syphilis and Lyme disease
Rocky Mountain spotted fever
Whipple’s disease
B – Coagulopathies / thrombotic microangiopathies
Antiphospholipid ab syndrome
Thrombotic thrombocytopenic purpura
C- Neoplasms
Artial myxoma,carcinomatosis, Hodgkin & nonHodgkin
lymphoma, Lung cancer.
D- Drug toxicity
Amphetamines, Arsenic, Cocaine, crack, Heroin
Ergot
alkaloids and Methysergide.
E- Others:
Sarcoidosis, Atheroembolic disease, Goodpasture,
Amyloidosis, Migraine,Cryofibrinogenemia.
Once diseases that mimic vasculitis have been excluded, the
workup should follow a series of progressive steps, that
establish the diagnosis of vasulitis and determine, where
possible, the category of the syndromes according to the
following algorithm, demonstrated below.
•
Angiogram of organs with suspected involvement should be
performed when syndromes such as the following are
suspected.
1) PAN
2) Takayasu’s disease
3) CNS vasculitis
However angiograms should not be performed routinely
when patients present with localized cutaneous vasculitis
with no clinical indication of visceral involvement.
The definitive diagnosis of vasculitis is made upon biopsy
of involved tissue. The yield of blind biopsies of organs
with no subjective or objective evidence of involvement is
very low and should be avoided.
The constellation of clinical, laboratory, biopsy and
radiographic findings usually allows proper categorization
to a specific syndrome, and therapy (where appropriate).
Treatment should be initiated according to the treatment
guidelines.
Treatment guidelines
• If an offending antigen that precipitates the vasulitis is recognized, it
should be removed where possible.
• If the vasulitis is associated with underlying disease, the latter should
be treated.
• If the syndrome does not resolve following removal of the offending
antigen or treatment of an underlying disease, treatment should be
initiated according to the category of the vasculits syndrome.
• Treatment options will be considered under the individual syndromes
and general principles of therapy.
General principles of therapy
 Glucocorticoids and / or immunosuppressives should be used
immediately in diseases where irreversible organ system
dysfunction and high mortality and morbidity have been
clearly established.
 In patients with Wegener’s granulomatosis and PAN
combination therapy with glucocorticoid and
cyclophosphamide is initiated, in others prednisone is the first
step of treatment.
 Methotrexate may be useful In refractory Takayasu’s
disease. Methotrexate is an acceptable alternative in
patients
who do not tolerate cyclophosphamide or who do not wish
it because of side effects such as infertility or sterility.
 PE and cyclophosphamide are beneficial in rapidly
progressive cases of Henoch – Schonlein.
 Cyclophosphamide (2mg/kg for one or more) is a choice
drug.
Cystistis occurs in 30% and bladder cancer in at least
6%. The latter may occur several years after dicontinaction
of cyclophosphamide.
Leukocyte count should be maintained > 3000 / µL, which
maintains the neutrophil count at approximately 1500 / µL.
Nutropenia may become more pronounced as glucocorticoid
is tapered.
 Aggressive therapy should be avoided for cases that revely
result in irreversible organ system disfunction and that
usually do not respond to such therapy.
For example, Idiopathic cutaneous vasculitis usually
resolves with symptomatic treatment and prolonged steroid
therapy uncommonly result in clinical benefit.
Nervous system involvement may be an early or presenting
feature
of systemic vasculitis and in some cases the sole manifestation
of an
autoimmunity.
In general CNS vasulitis may be:
1) Primary (vasculitis limited to CNS)
2) Secondary (to systemic vasculitis) which is much more
common
than primary or isolated CNS vasculitis.
A brief review of secondary CNS vasculitis
• Cerebral vasculitis is uncommon in:
- Essential cryoglobulinemia
- Microscopic polyangiitis
- RA (mostly JRA) and diffuse sclerosis
- Henoch – Schonlein purpura (usually in children aged 4-7 years)
SLE
Nervous system involvement and psychological problems had been
reported in 25-75% and 59% respectively.
SLE is frequently complicated by stroke. The most common cause of
stroke is embolism from cardiac mural thrombosis. A prothrombotic
state is other mechanism. CNS vasculitis is found in 12.5% of cases.
PAN
Affects men twice as often as women and neurological abnormalities
occur in 50% of cases (PNS>CNS).
Churg-strauss
The frequency of cerebral vasculitis in patients with Churg
Strauss is similar to PNA, but is more prevalent in females &
is characterized bye asthma, peripheral and tissue eosinophilia,
extravascular gramuloma and vasculitis of multiple organ
system.
Patient often exhibit fever, malaise, anorexia and weight loss.
Pulmonary findings clearly dominated the clinical picture.
Mononeuritis multiplex is the second most common
manifestation that occurs in 72%.
Allergic rhinitis or sinusitis (61%) skin lesions (51%) and are
other
manifestations.
The renal disease is less common and generally less severe than
those
with Wegener’s granulomatosis and microscopic polyangitis.
Eosinophilia (>1000 cells/ µL) occurs in >80% evidence of
inflammation
(increased ESR, α2-globulins) can be found in 81%.
Approximately 48% shows circulating ANCA. That is usually
antimyelo-peroxidase.
MI is the must common cause of death.
Glucocorticoids alone appear to be effective in many patients. In
steroid failure or in the with fulminant multisystem involvement
combination of steroid and cyclophosphamide is used.
Wegener’s granulomatosis
Is an uncommon (3/100000) disease, that can be seen at any age but
affects usually adults and is rare before adolescence (M /F ratio is : 1 / 1:1)
Pulmonary involvement occurs in 85%- 90%.
CNS involvement is reported in 11-44% and occurs in the late of the
course of the disease and usually takes two common clinical forms:
1) Polyneuropathy and more frequently mononeuropathy
multiplex.
2) Multicranial neuropathy as a result of direct extension of
the nasal and sinus granulomas, often with severe paranasal pain
and usual discharge. There may be septal perforation leading to
saddle nose. Serious otitis media may occur.
Arterial thrombosis, ICH and SAH may also be seen.
Cerebral vasculitis and/or granuloma are rare presentations.
Diagnosis is made by biopsy (necrotizing granulomatous vasculitis).
Positive C-ANCA has high specificity, but false positive titers
have
been reported in certain infections and neoplastic diseases.
Treatment: combination of glucosteroid and cyclophosphamide.
Giant cell arteitis
occurs almost exclusively in individuals > 50 years and is
more common in women.
The superficial temporal, vertebral, ophthalmic and
posterior ciliary arteries are more often affected than the
ECA or ICA, and intracranial arteries almost never (HU
Rehman 2000).
Michel (1992) reported that CNS involvement occurs in
4% of cases as TIA or stroke, with predilection to
posterior circulation.
Multi-infarct dementia, myelopathy, seizures, tremor and
encephalopathy are less common.
Takayasu’s disease
Incidence: 1.2 to 2.6 / million.
is similar in many ways to giant cell arteritis except for its
propensity to involve the proximal rather than the distal
brunches of the aorta.
The affected arteries no longer pulsate (Pulse less disease). Most of
patients have been young Asian women (usually before age 30:
Merritt) However in non-Asian individuals pulse less disease is
usually due to atherosclerosis.
The disease may be asymptomatic. Symptomatic cases show
both generalized (identical to T-arteritis) and vascular
manifestations.
HTN occurs in 32 to 93% and contributes to renal, cardiac and
cerebral injury.
Neurologic manifestations arise from HTN (renal artery occlusion)
or vertebral artery involvement. CHF may be prominent.
Headaches are frequent, visual blurring specially during
activity, dizziness, hemiparesia, hemisenory loss are usual
neurological manifestations.
Some authors have emphasized the frequency of posture
induced symptoms as well as infrequent strokes, despite of
multiple TIAs.
Some have reported syncope and visual disturbances as the
main neurological manifestations.
Diagnosis depends on 3 from 6 criteria:
- Age under 40
- Claudication of arms or logs
- Diminished brachial artery pulse
- Blood pressure differences in arms
- Subclavian bruit
- Diagnosis is confirmed by arteriography, that shows
irregular
walls, stenosis, post stenotic dilatation, aneurism ,
occlusion
and evidence of increased collaterals.
Behcet’s vasculitis
Neurological signs and symptoms are reported in up to 49%
(Harrison: 6-10%) of patients, 5% of which occur at presentation.
Headache, pyramidal, cerebellar signs and dysarthria are the
most
common presentations.
Neurological insult appears mainly in parenchymal form (80% of
cases).
it is often associated with brainstem involvement thus has a
serious
prognosis.
Dural sinus thrombi occur in 20% of patients.
Diagnostic criteria include:
Recurrent oral ulceration plus two of the following:
- recurrent genital ulceration
- Eye lesions
- Skin lesions
- Positive pathergy test.
Sjogren’s syndrome
The disease affects predominantly middle-aged women
(F/M:9/1)
although it may occur in all ages including children.
It can be seen alone (primary :0.5 -1%).
30% of other autoimmune disease such as RA, SLE,
Sclerodermia
and mixed connective tissue disease suffer from secondary
sjogren’s syndrome.
Is defined by clinical triad of 1) Xerophthalmia
2) Xerostomia
3) and non-deforming arthritis
A small but significant number may develop malignant
lymphoma
and 1/3 of patients present with systemic manifestations.
It is characterized by lymphocytic infiltration of the exocrine glands
and B lymphocyte hypersensitivity, as illustrated by circulating
antibodies.
Enlargement of the parotid or other major salivary glands occurs in
two third of patients with primary sjogren’s syndrome but is
uncommon in patients with the secondary type.
Sera of patients often contain a number of autoantibodies, rhematoid
factors and RO/SS-A, LA/SS-B.
Diagnostic tests include sialometry, sialography and scintigraphy. The
labial minor salivary gland biopsy permits histopathoologic
confirmation of the focal lymphocytic infiltrates. The latter is needed
when the diagnosis is uncertain.
Extraglandular (systemic) manifestations are seen in 1/3 of the
Patients with primary syndrome.
Presentation
Percent
Arthritis/ arthralgia
60
Raynaud phenomenon
37
Lymphadenopalthy
14
Lung, Kidney, Liver involvement
14,9,6
respectively
Vasculitis
11
Lymphoma
6
splenomegaly
3
Peripheral neuropathy
2
Myositis
1
Cutaneous vasculitis may present as a picture of non-thrombocytopenic
purpura or utricaria.
Arthritis of small joints occurs in more than 80% (generally symmetrical).
PNS complications occur in 10-32% of patients and includes Sensory
neuropathy: (60%), sensorimotor neuropathy: (17%),polyradiculopathy:
(11%) and less commonly mononeuropathy.
Among CNS complications (which are <PNS) mild cognitive
dysfunction and aseptic meningitis (may be recurrent) are common.
Hemiparesia, aphasia, hemianopia, focal seizures, INO, nystagmus, and
ataxia have all been reported.
Spinal involvement may take one of the following forms:
1) Acute transverse myelitis
2) Intraspinal hemorrhage
3) Progressive myelopathy
Sensorineural hearing loss was found in 50% of cases and
correlates
with the presence of APL antibodies.
CSF shows increased protein and IgG ,and positive OCB.
Cogan’s syndrome
Is non-syphilitic interstitial keratitis together with vestibuloauditory symptoms. Complications include aortic insufficency and
mesenteric sichemia. It occurs predominently in young adults with
sudden onset of keratitis, nausea, vomiting, tinnitus, progressing to
complete hearing loss. The vestibular symptoms gradually subsides.
It may be associated with a systemic vasculitis, particularly with
involvement of the aortic valve.
Glucocorticoids are the mainstay of treatment.