Current Neuropharmacology, 2011, 9, 437-448 437
Central Nervous System Vasculitis: Still More Questions than Answers
Marco A. Alba, Georgina Espígol-Frigolé, Sergio Prieto-González, Itziar Tavera-Bahillo,
Ana García-Martínez, Montserrat Butjosa, José Hernández-Rodríguez and Maria C. Cid*
Vasculitis Research Unit, Department of Systemic Autoimmune Diseases, Hospital Clinic, University of Barcelona,
Institut d´Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Villarroel 170, 08036 Barcelona, Spain
Abstract: The central nervous system (CNS) may be involved by a variety of inflammatory diseases of blood vessels.
These include primary angiitis of the central nervous system (PACNS), a rare disorder specifically targeting the CNS
vasculature, and the systemic vasculitides which may affect the CNS among other organs and systems. Both situations
are severe and convey a guarded prognosis. PACNS usually presents with headache and cognitive impairment. Focal
symptoms are infrequent at disease onset but are common in more advanced stages. The diagnosis of PACNS is difficult
because, although magnetic resonance imaging is almost invariably abnormal, findings are non specific. Angiography has
limited sensitivity and specificity. Brain and leptomeningeal biopsy may provide a definitive diagnosis when disclosing
blood vessel inflammation and are also useful to exclude other conditions presenting with similar findings. However,
since lesions are segmental, a normal biopsy does not completely exclude PACNS. Secondary CNS involvement by
systemic vasculitis occurs in less than one fifth of patients but may be devastating. A prompt recognition and aggressive
treatment is crucial to avoid permanent damage and dysfunction. Glucocorticoids and cyclophosphamide are recom-
mended for patients with PACNS and for patients with secondary CNS involvement by small-medium-sized systemic
vasculitis. CNS involvement in large-vessel vasculitis is usually managed with high-dose glucocorticoids (giant-cell
arteritis) or glucocorticoids and immunosuppressive agents (Takayasu’s disease). However, in large vessel vasculitis,
where CNS symptoms are usually due to involvement of extracranial arteries (Takayasu’s disease) or proximal portions of
intracranial arteries (giant-cell arteritis), revascularization procedures may also have an important role.
Keywords: Vasculitis, Central nervous system.
1. INTRODUCTION it appears to be more frequent in males in their fourth and
fifth decades of life [2, 9]. PACNS may represent 1.2% of
The central nervous system (CNS) vasculature may be
vasculitis involving the CNS [3].
targeted by an heterogeneous group of inflammatory dis-
eases. In its isolated, primary form, angiitis of the CNS 2.2. Pathogenesis
(PACNS) is a rare form of vasculitis of unknown etiology
The pathogenesis of PACNS is unknown. Similar to
primarily affecting small and medium sized vessels supply-
other chronic inflammatory or autoimmune diseases, PACNS
ing the brain parenchyma, spinal cord and leptomeninges [1-
3]. PACNS results in signs and symptoms of CNS dysfunc- is thought to be triggered by infection. Cytomegalovirus,
Ebstein-Barr virus, varicella-zoster virus, human immuno-
tion with no clinically apparent participation of other organs.
deficiency virus, mycoplasma and chlamydia have been con-
The CNS may also be targeted, among other territories, by
sidered given the ability of these agents to produce vasculitic
systemic vasculitides [4, 5]. This review will focus on diag-
lesions [10-15]. However, in the majority of patients with
nostic and therapeutic aspects of PACNS and secondary
PACNS a potential relationship with these or other infectious
CNS involvement by systemic vasculitides in adulthood.
Primary and secondary CNS vasculitis in childhood have agents cannot be demonstrated.
been addressed in excellent recent reviews [6-8]. The granulomatous nature of the vascular inflammatory
lesions in most cases suggests a Th1-mediated response [3,
2. PRIMARY CNS VASCULITIS
16]. Th1-related cytokines may promote vascular inflamma-
2.1. Epidemiology tion in PACNS as suggested by several experimental models.
Intracerebral injections of interferon-gamma have been
Because of the rarity of PACNS and the absence of de-
shown to trigger inflammatory lesions and vasculitis in rats.
finitive diagnostic tests, epidemiologic studies are virtually [17]. Tumor necrosis factor (TNF) and interleukin-6 pro-
inexistent. An annual incidence of 2.4 per million people has
inflammatory functions may also contribute to vascular in-
been recently estimated in North America [9]. PACNS has
flammation in PACNS [18, 19]. TNF/TNF receptor p75
been reported in children [6-8] and in the elderly. However,
transgenic mice develop multifocal CNS ischemic injury
secondary to vasculitis [18]. Elevated CSF IL-6 has been
*Address correspondence to this author at the Systemic Autoimmune found in 3 patients with different types of vasculitis (polyar-
Diseases Department Hospital Clínic Villarroel 170 08036-Barcelona Spain; teritis nodosa, temporal arteritis and Behcet's disease) in-
Tel: +34 93 2275774; Fax: +34 93 2271707; E-mail: volving the CNS [19]. Current knowledge of the pathophysi-
1570-159X/11 $58.00+.00 ©2011 Bentham Science Publishers
, 438 Current Neuropharmacology, 2011, Vol. 9, No. 3 Alba et al.
ology of PACNS is very limited delaying progress in the major phenotypes: 1) Acute or more commonly subacute
diagnosis and management of affected patients. encephalopathy, presenting as a confusional syndrome with
progression to stupor and coma; 2) Disease presentation re-
2.3. Pathology
sembling atypical multiple sclerosis with a variety of focal
PACNS typically involves small-medium sized arteries symptoms such as optic neuropathy, brain stem episodes,
and veins, especially those located in leptomeninges and seizures, headaches, encephalopathic episodes or hemi-
subcortical areas. The characteristic histopathologic findings spheric stroke-like events and 3) Intracranial mass lesions,
consist of inflammatory infiltration of vessel walls by T with headache, drowsiness, focal signs and elevated intracra-
lymphocytes and activated macrophages which undergo nial pressure [24, 25].
granulomatous differentiation with giant-cell formation [3,
It has also been suggested that predominant involvement
16]. Inflammatory cells infiltrate the adventitia and subse-
of small versus medium-sized vessel may influence disease
quently progress through the artery wall causing fragmenta- presentation. Small-vessel PACNS manifests as a subacute
tion of the internal elastic lamina. Intimal proliferation and
or acute encephalopathy with persistent headaches, cognitive
fibrosis leading to vascular occlusion is frequently observed
impairment, confusion, and seizures. MRI usually discloses
[3, 16] (Fig. 1). This granulomatous pattern is the most
marked meningeal contrast enhancement whereas angiogra-
commonly seen and led to the previously used term granu-
phy may not reveal changes because the affected vessels are
lomatous angiitis of the CNS [3, 16, 20]. However, granulo-
small, beyond the detection threshold [26, 27]. This form of
matous features may not be always observed and some PACNS may respond to glucocorticoid monotherapy but
specimens disclose the so-called atypical CNS angiitis pat-
25% of patients relapse. In contrast, when medium-size ves-
terns consisting in predominantly lymphocytic infiltrates
sels are involved, in addition to headaches and general CNS
(lymphocytic pattern), necrotizing vasculitis with fibrinoid
dysfunction, focal neurologic deficits and stroke are more
necrosis (necrotizing pattern) or mixed patterns [20]. In some
common and angiography is more likely to reveal vascular
cases, B lymphocytes and plasma cells can also be observed
abnormalities [9, 26, 27]. Four clinical features are associ-
[21]. Vascular amyloid deposits may be found in a subset ated with an increased mortality in patients with PACNS:
of patients [20].
focal neurological deficit, cognitive impairment, cerebral
Although most patients with PACNS present primarily infarction and involvement of larger vessels [9].
with CNS dysfunction, necropsy studies may disclose
General symptoms and findings suggesting some extent
clinically asymptomatic vasculitis in additional locations
of systemic involvement may occur. Fever, weight loss,
including lungs, kidneys and gastrointestinal tract [3, 5, 16].
livedo reticularis, rash, peripheral neuropathy, arthritis and
Distinction from systemic vasculitis with prominent CNS night sweats may be recorded in 20% of patients [2, 9].
involvement may be sometimes difficult to establish.
2. 5. Diagnosis
2.4. Clinical Manifestations
The diagnosis of PACNS is a challenge because of the
Depending on the areas of the brain involved, PACNS
lack of highly sensitive and specific diagnostic tests. Clini-
may convey a wide variety of clinical findings. Moreover,
cal, analytical, neuroimaging, and histopathologic data are
disease severity and rapidity of progression may be highly
important, both in supporting the diagnostic suspicion and in
variable among patients, increasing heterogeneity in clinical excluding other conditions which may present with similar
presentation.
features.
In the largest series reported including 101 patients [9],
2.5.1. Laboratory Test Abnormalities
the median age at diagnosis was 47 years (range 17-84
years). The majority of patients presented with subacute Routine laboratory tests are frequently within the normal
manifestations of diffuse CNS dysfunction. Acute presenta- range [2, 9, 28]. In some patients features of systemic
tion was highly unusual. The most common initial symptoms inflammatory response including anemia, leukocytosis and
were headache (63%) and cognitive impairment (50%). moderately increased acute phase reactants (ESR, C-reactive
Headaches were initially of low intensity and progressively protein and platelet counts) can be observed [2, 9]. Labora-
worsened. Cognitive impairment was also insidious. Focal tory tests are useful to rule out other diseases which may
symptoms usually appeared later in the course of the disease present with similar symptoms such as infection, systemic
and included hemiparesis (44%), stroke (40%), aphasia vasculitis, malignancy, drug abuse and hypercoagulability
(28%), transient ischemic attack (28%), ataxia (19%), sei- states [5, 28, 29].
zures (16%), dysarthria (15%) and blurred vision or de-
Cerebrospinal fluid (CSF) is abnormal in 80-90% of pa-
creased visual acuity (11%). Infrequent manifestations, oc-
tients [9]. Increased protein concentration is the most com-
curring in less than 10% of patients, included intracranial
mon finding. In a series of 101 patients, mean CSF protein
hemorrhage, amnesic syndrome, spinal cord manifestations
concentration was 7 gr/L (range 1.5-10.3 gr/L) [9]. Pressure
such as paraparesis o quadriparesis, parkinsonism, vertigo,
is increased in 50% of patients and elevated lymphocyte
dizziness or cranial nerve palsy. Most patients had multiple
manifestations. Other published series report similar findings counts may be observed in 50-80%. CSF oligoclonal immu-
noglobulins may be found in up to 50% of individuals with
[22, 23].
PACNS [5, 23]. CSF pleocytosis is modest, rarely exceeding
In order to facilitate clinical recognition and early diag- 250 cells/μL. Higher leukocyte counts and the presence of
nosis, clinical manifestations have been grouped in three neutrophils are uncommon and, when present, should alert
Central Nervous System Vasculitis: Still More Questions than Answers
Marco A. Alba, Georgina Espígol-Frigolé, Sergio Prieto-González, Itziar Tavera-Bahillo,
Ana García-Martínez, Montserrat Butjosa, José Hernández-Rodríguez and Maria C. Cid*
Vasculitis Research Unit, Department of Systemic Autoimmune Diseases, Hospital Clinic, University of Barcelona,
Institut d´Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Villarroel 170, 08036 Barcelona, Spain
Abstract: The central nervous system (CNS) may be involved by a variety of inflammatory diseases of blood vessels.
These include primary angiitis of the central nervous system (PACNS), a rare disorder specifically targeting the CNS
vasculature, and the systemic vasculitides which may affect the CNS among other organs and systems. Both situations
are severe and convey a guarded prognosis. PACNS usually presents with headache and cognitive impairment. Focal
symptoms are infrequent at disease onset but are common in more advanced stages. The diagnosis of PACNS is difficult
because, although magnetic resonance imaging is almost invariably abnormal, findings are non specific. Angiography has
limited sensitivity and specificity. Brain and leptomeningeal biopsy may provide a definitive diagnosis when disclosing
blood vessel inflammation and are also useful to exclude other conditions presenting with similar findings. However,
since lesions are segmental, a normal biopsy does not completely exclude PACNS. Secondary CNS involvement by
systemic vasculitis occurs in less than one fifth of patients but may be devastating. A prompt recognition and aggressive
treatment is crucial to avoid permanent damage and dysfunction. Glucocorticoids and cyclophosphamide are recom-
mended for patients with PACNS and for patients with secondary CNS involvement by small-medium-sized systemic
vasculitis. CNS involvement in large-vessel vasculitis is usually managed with high-dose glucocorticoids (giant-cell
arteritis) or glucocorticoids and immunosuppressive agents (Takayasu’s disease). However, in large vessel vasculitis,
where CNS symptoms are usually due to involvement of extracranial arteries (Takayasu’s disease) or proximal portions of
intracranial arteries (giant-cell arteritis), revascularization procedures may also have an important role.
Keywords: Vasculitis, Central nervous system.
1. INTRODUCTION it appears to be more frequent in males in their fourth and
fifth decades of life [2, 9]. PACNS may represent 1.2% of
The central nervous system (CNS) vasculature may be
vasculitis involving the CNS [3].
targeted by an heterogeneous group of inflammatory dis-
eases. In its isolated, primary form, angiitis of the CNS 2.2. Pathogenesis
(PACNS) is a rare form of vasculitis of unknown etiology
The pathogenesis of PACNS is unknown. Similar to
primarily affecting small and medium sized vessels supply-
other chronic inflammatory or autoimmune diseases, PACNS
ing the brain parenchyma, spinal cord and leptomeninges [1-
3]. PACNS results in signs and symptoms of CNS dysfunc- is thought to be triggered by infection. Cytomegalovirus,
Ebstein-Barr virus, varicella-zoster virus, human immuno-
tion with no clinically apparent participation of other organs.
deficiency virus, mycoplasma and chlamydia have been con-
The CNS may also be targeted, among other territories, by
sidered given the ability of these agents to produce vasculitic
systemic vasculitides [4, 5]. This review will focus on diag-
lesions [10-15]. However, in the majority of patients with
nostic and therapeutic aspects of PACNS and secondary
PACNS a potential relationship with these or other infectious
CNS involvement by systemic vasculitides in adulthood.
Primary and secondary CNS vasculitis in childhood have agents cannot be demonstrated.
been addressed in excellent recent reviews [6-8]. The granulomatous nature of the vascular inflammatory
lesions in most cases suggests a Th1-mediated response [3,
2. PRIMARY CNS VASCULITIS
16]. Th1-related cytokines may promote vascular inflamma-
2.1. Epidemiology tion in PACNS as suggested by several experimental models.
Intracerebral injections of interferon-gamma have been
Because of the rarity of PACNS and the absence of de-
shown to trigger inflammatory lesions and vasculitis in rats.
finitive diagnostic tests, epidemiologic studies are virtually [17]. Tumor necrosis factor (TNF) and interleukin-6 pro-
inexistent. An annual incidence of 2.4 per million people has
inflammatory functions may also contribute to vascular in-
been recently estimated in North America [9]. PACNS has
flammation in PACNS [18, 19]. TNF/TNF receptor p75
been reported in children [6-8] and in the elderly. However,
transgenic mice develop multifocal CNS ischemic injury
secondary to vasculitis [18]. Elevated CSF IL-6 has been
*Address correspondence to this author at the Systemic Autoimmune found in 3 patients with different types of vasculitis (polyar-
Diseases Department Hospital Clínic Villarroel 170 08036-Barcelona Spain; teritis nodosa, temporal arteritis and Behcet's disease) in-
Tel: +34 93 2275774; Fax: +34 93 2271707; E-mail: volving the CNS [19]. Current knowledge of the pathophysi-
1570-159X/11 $58.00+.00 ©2011 Bentham Science Publishers
, 438 Current Neuropharmacology, 2011, Vol. 9, No. 3 Alba et al.
ology of PACNS is very limited delaying progress in the major phenotypes: 1) Acute or more commonly subacute
diagnosis and management of affected patients. encephalopathy, presenting as a confusional syndrome with
progression to stupor and coma; 2) Disease presentation re-
2.3. Pathology
sembling atypical multiple sclerosis with a variety of focal
PACNS typically involves small-medium sized arteries symptoms such as optic neuropathy, brain stem episodes,
and veins, especially those located in leptomeninges and seizures, headaches, encephalopathic episodes or hemi-
subcortical areas. The characteristic histopathologic findings spheric stroke-like events and 3) Intracranial mass lesions,
consist of inflammatory infiltration of vessel walls by T with headache, drowsiness, focal signs and elevated intracra-
lymphocytes and activated macrophages which undergo nial pressure [24, 25].
granulomatous differentiation with giant-cell formation [3,
It has also been suggested that predominant involvement
16]. Inflammatory cells infiltrate the adventitia and subse-
of small versus medium-sized vessel may influence disease
quently progress through the artery wall causing fragmenta- presentation. Small-vessel PACNS manifests as a subacute
tion of the internal elastic lamina. Intimal proliferation and
or acute encephalopathy with persistent headaches, cognitive
fibrosis leading to vascular occlusion is frequently observed
impairment, confusion, and seizures. MRI usually discloses
[3, 16] (Fig. 1). This granulomatous pattern is the most
marked meningeal contrast enhancement whereas angiogra-
commonly seen and led to the previously used term granu-
phy may not reveal changes because the affected vessels are
lomatous angiitis of the CNS [3, 16, 20]. However, granulo-
small, beyond the detection threshold [26, 27]. This form of
matous features may not be always observed and some PACNS may respond to glucocorticoid monotherapy but
specimens disclose the so-called atypical CNS angiitis pat-
25% of patients relapse. In contrast, when medium-size ves-
terns consisting in predominantly lymphocytic infiltrates
sels are involved, in addition to headaches and general CNS
(lymphocytic pattern), necrotizing vasculitis with fibrinoid
dysfunction, focal neurologic deficits and stroke are more
necrosis (necrotizing pattern) or mixed patterns [20]. In some
common and angiography is more likely to reveal vascular
cases, B lymphocytes and plasma cells can also be observed
abnormalities [9, 26, 27]. Four clinical features are associ-
[21]. Vascular amyloid deposits may be found in a subset ated with an increased mortality in patients with PACNS:
of patients [20].
focal neurological deficit, cognitive impairment, cerebral
Although most patients with PACNS present primarily infarction and involvement of larger vessels [9].
with CNS dysfunction, necropsy studies may disclose
General symptoms and findings suggesting some extent
clinically asymptomatic vasculitis in additional locations
of systemic involvement may occur. Fever, weight loss,
including lungs, kidneys and gastrointestinal tract [3, 5, 16].
livedo reticularis, rash, peripheral neuropathy, arthritis and
Distinction from systemic vasculitis with prominent CNS night sweats may be recorded in 20% of patients [2, 9].
involvement may be sometimes difficult to establish.
2. 5. Diagnosis
2.4. Clinical Manifestations
The diagnosis of PACNS is a challenge because of the
Depending on the areas of the brain involved, PACNS
lack of highly sensitive and specific diagnostic tests. Clini-
may convey a wide variety of clinical findings. Moreover,
cal, analytical, neuroimaging, and histopathologic data are
disease severity and rapidity of progression may be highly
important, both in supporting the diagnostic suspicion and in
variable among patients, increasing heterogeneity in clinical excluding other conditions which may present with similar
presentation.
features.
In the largest series reported including 101 patients [9],
2.5.1. Laboratory Test Abnormalities
the median age at diagnosis was 47 years (range 17-84
years). The majority of patients presented with subacute Routine laboratory tests are frequently within the normal
manifestations of diffuse CNS dysfunction. Acute presenta- range [2, 9, 28]. In some patients features of systemic
tion was highly unusual. The most common initial symptoms inflammatory response including anemia, leukocytosis and
were headache (63%) and cognitive impairment (50%). moderately increased acute phase reactants (ESR, C-reactive
Headaches were initially of low intensity and progressively protein and platelet counts) can be observed [2, 9]. Labora-
worsened. Cognitive impairment was also insidious. Focal tory tests are useful to rule out other diseases which may
symptoms usually appeared later in the course of the disease present with similar symptoms such as infection, systemic
and included hemiparesis (44%), stroke (40%), aphasia vasculitis, malignancy, drug abuse and hypercoagulability
(28%), transient ischemic attack (28%), ataxia (19%), sei- states [5, 28, 29].
zures (16%), dysarthria (15%) and blurred vision or de-
Cerebrospinal fluid (CSF) is abnormal in 80-90% of pa-
creased visual acuity (11%). Infrequent manifestations, oc-
tients [9]. Increased protein concentration is the most com-
curring in less than 10% of patients, included intracranial
mon finding. In a series of 101 patients, mean CSF protein
hemorrhage, amnesic syndrome, spinal cord manifestations
concentration was 7 gr/L (range 1.5-10.3 gr/L) [9]. Pressure
such as paraparesis o quadriparesis, parkinsonism, vertigo,
is increased in 50% of patients and elevated lymphocyte
dizziness or cranial nerve palsy. Most patients had multiple
manifestations. Other published series report similar findings counts may be observed in 50-80%. CSF oligoclonal immu-
noglobulins may be found in up to 50% of individuals with
[22, 23].
PACNS [5, 23]. CSF pleocytosis is modest, rarely exceeding
In order to facilitate clinical recognition and early diag- 250 cells/μL. Higher leukocyte counts and the presence of
nosis, clinical manifestations have been grouped in three neutrophils are uncommon and, when present, should alert
