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Vasculitis in the central nervous system.

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ARTHRITIS & RHEUMATISM
Vol. 40, No. 7, July 1997, pp 1189-1201
0 1997, American College of Rheumatology
Arthritis & Rheumatism
~~
Official Journal of the American College of Rheumatology
REVIEW
VASCULITIS IN THE CENTRAL NERVOUS SYSTEM
LEONARD H. CALABRESE, GEORGE F. DUNA, and J. T. LIE
Among the many manifestations of systemic vasculitis, central nervous system (CNS) involvement remains one of the areas least understood. Factors inhibiting our understanding include 1) lack of specific signs
and symptoms; 2) lack of specific noninvasive tests; 3 )
limited pathologic material for pathophysiologic investigation; 4) lack of appropriate animal models; and 5 )
absence of controlled therapeutic trials. Despite these
formidable limitations, the spectre of CNS vasculitis
persists as a common clinical diagnostic and therapeutic
challenge.
Vasculitis affecting the CNS can be conveniently
viewed as eitherprimary, when the CNS is the sole or
dominant target organ, or secondary, when it is the end
result of some systemic process (e.g., infection, drug
toxicity, or systemic disease) (Table 1). Unfortunately,
the literature on CNS angiitis is limited and problematic
to analyze since much of our current understanding
comes from small case series and individual case reports.
Not only is the number of cases from which to draw
relatively small, many are incompletely or poorly pathologically documented. In others, histologic evidence of
vasculitis is absent, with the presumptive vasculitic etiology based on neurodiagnostic investigations (i.e., angiography, magnetic resonance imaging [MRI], etc.). This
review will attempt to summarize recent advances in the
field of CNS vascular inflammatory disease, emphasizing
data derived primarily from clinical series, but also from
Leonard H. Calabrese, DO, George F. Duna, MD: Cleveland
Clinic Foundation, Cleveland, Ohio; J. T. Lie, MD: University of
California, Davis Medical Center, Sacramento, California. Dr. Duna is
currently with Baylor College of Medicine, Houston, Texas.
Address reprint requests to Leonard H. Calabrese, DO, Vice
Chairman, Department of Rheumatic and Immunologic Diseases,
Cleveland Clinic Foundation, Cleveland, OH 44195.
Submitted for publication September 10, 1996; accepted in
revised form February 19, 1997.
informative case reports, and finally, from our own
experience. Areas in which clinical consensus has been
achieved will be stressed, and in areas where no such
consensus exists, controversies will be highlighted.
Primary angiitis of the central nervous system
(PACNS) overview
Vasculitis predominantly affecting the CNS has
been given many labels. The term granulomatous angiitis
of the central nervous system (GANS) was applied because of the characteristic pathology from early reported
cases. However, more recent analysis of larger numbers
of reported cases has documented nongranulomatous
pathology in a sizable percentage (l),thus limiting the
usefulness of this term. The label isolated angiitis of the
central nervous system (IACNS) has been advocated by
some (2), while others ( 3 ) argue that the term is
inappropriate in view of occasional cases demonstrating
limited pathologic involvement outside the CNS. We
(1,3) and others favor the term primary angiitis of the
central nervous system, or PACNS, because it reflects
the anatomic site of the predominant clinical pathology
and is not limited by histologic features.
A full understanding of PACNS must be viewed
in historical context. From the early modern clinical
descriptions of the disease in 1959 through 1986, only 46
cases were identified in the literature (4). The disease
was considered genuinely rare and highly fatal, with
most patients diagnosed at postmortem examination. In
the 1970s and 1980s, with the increasing availability of
cerebral angiography, the disease became more frequently reported. As a result, and in contrast to the early
experience, more recently reported cases have been
frequently defined by angiography alone, and in the
absence of premortem biopsy or postmortem histologic
1189
CALABRESE ET AL
1190
Table 1. Vasculitis of the central nervous system (CNS)
I Primary angiitis of the CNS
Pathologically defined
(b) Mass presentation
(a) Spinal cord variant
Angiographically defined
I1 Causes of secondary CNS vasculitis
Infection (viral, bacterial, fungal, rickettsial, mycoplasmal,
protozoal)
Systemic vasculitis
Connective tissue disease
Sarcoidosis
Drug associated (sympathomimetics, drugs of abuse)
Malignancy-related states
Others
111 Vasculitis mimics
Atherosclerosis
Moyamoya disease
Emboli (including cardiac myxoma)
Hypercoagulable states (including anticardiolipin antibody
syndrome)
Intravascular neoplasms (angioendotheliomatosis)
Thrombotic thrombocytopenic purpura
Reversible vasoconstriction of any cause
Dissections of cerebral arteries
Radiation vasculopathy
Angiocentric lymphoproliferative diseases
Others
evidence of vasculitis. This reliance on cerebral angiography as a “gold standard” for diagnosis is illustrated by
the 1986 proposal for diagnostic criteria, which relied
equally on histopathology or, alternatively, cerebral angiography in the appropriate clinical setting (4).
Since 1986, there have been significant advances
in our understanding of PACNS. As a result of a growing
body of data that will be discussed later, consensus
points regarding this disorder include the following. 1)
The early literature on PACNS represents a clear mixture of pathologically and nonpathologically documented cases. This has obscured the fact that PACNS is
far more heterogeneous than was previously recognized.
2) Cerebral angiography, while a powerful tool for
detecting abnormalities of the cerebral circulation, is
neither sensitive for detecting inflammatory vascular
disease nor specific for differentiating it from noninflammatory vascular pathology. 3) The previous view of
PACNS as an inexorably fatal disorder may have been
too severe, and in the absence of controlled clinical
trials, mandates for aggressive therapy in all cases should
be reconsidered.
mented in the English-language medical literature
and/or the clinical archives of the Cleveland Clinic
Foundation (5). This number represents a mixture of
histologically confirmed and unconfirmed cases. Several
recent reviews of this subject have collectively viewed
cases that were documented histologically (i.e., by antemortem biopsy or postmortem examination) and those
documented by angiography alone (4,6). We believe this
is misleading and suggest that, for a more accurate
clinical description of the disorder, it is essential that
cases be analyzed separately, based on the presence or
absence of histologic evidence of an arteritic process. A
collective analysis would be appropriate only if cases
documented pathologically or angiographically represented an equivalent means of diagnostic ascertainment
and therefore clinical equivalence.
Based on subgroup analysis of the literature,
according to the presence or absence of histologic
evidence of vasculitis, we and others (7-11) have con-
Table 2. Clinical and laboratory features of PACNS, based on
method of diagnosis*
Pathologically Not pathologically
documented
documented
P
PACNS pathologically defined
Sex, no. (%)
Males
Females
Age, mean 2 SD
Headache, no. (%)
Yes
No
Stroke, no. (%)
Yes
No
Seizure, no. (%)
Yes
No
Cerebral hemorrhage,
no. (%)
Yes
No
Diffuse neurologic
dysfunction, no. (%)
Yes
No
Decreased cognition,
no. (%)
Yes
No
Days from symptom
onset to diagnosis,
mean t SD
Abnormal CSFitotal
tested (%)
Through the end of 1995, over 168 cases of
PACNS fulfilling the 1986 proposed criteria were docu-
* An abnormal cerebrospinal fluid (CSF) sample had >5 cells/mm3
and/or protein >55 mg%. PACNS = primary angiitis of the central
nervous system.
78 (69.0)
38 (31.0)
46 ? 17
17 (30.8)
38 (69.1)
33 t 14
63 (55.8)
50 (44.3)
43 (78.2)
12 (21.8)
13 (13.5)
83 (86.5)
15 (32.6)
31 (67.4)
29 (30.2)
67 (69.8)
11(23.9)
35 (76.1)
13 (11.5)
100 (88.5)
5 (9.1)
50 (90.9)
77 (68.1)
36 (31.9)
26 (47.3)
29 (52.7)
64 (83.1)
13 (16.9)
170 ? 261
20 (76.9)
6 (23.1)
46 I 7 3
11/82 (11.8)
26/27 (49.1)
<0.001
<0.001
<0.008
<0.009
<0.001
(0.005
CNS VASCULITIS
1191
Figure 1. A, Brain biopsy findings of granulomatous vasculitis in primary angiitis of the central nervous system side-by-side with a
polyarteritis-type necrotizing vasculitis (large open arrow) and 2 normal arterioles (small arrows). B, Close-up view of the boxed area
in showing foreign-body (short arrow) and Langhans' (long arrows) giant cells in the granulomatous vasculitis. (Hematoxylin and
eosin stained, magnification X 64 and X 400, respectively.)
cluded that cases are not equivalent. These studies have
suggested that among the angiographically documented
cases is a clinically distinctive subset that has a more
benign clinical course and outcome. A problem in all
such studies is that patients diagnosed by angiography
alone who survive rarely undergo confirmatory biopsies,
which leaves the diagnosis of CNS vasculitis less than
secure. While angiography can clearly detect vasculopathy, its power to discriminate between inflammatory and
noninflammatory vascular disease and other forms of
vascular pathology is poor (12). The perfect study in
which every patient undergoes a biopsy, an angiogram,
and a postmortem examination will probably never be
done, and thus, much of our understanding of this
enigmatic disorder has, and will, come from inferential,
and at times circular, reasoning.
The clinical features of pathologically documented cases of PACNS are outlined in Table 2. The
disease is male predominant and has been reported over
a wide range of age groups. Ultimately, the majority of
patients (85%) develop a variety of focal neurologic
deficits, but this occurs mostly in the presence of some
element of diffuse neurologic dysfunction, such as decreased mentation or altered level of consciousness.
Simple stroke as well as pure dementia are distinctively
uncommon presentations, but both have occasionally
been reported (2,13). Headaches, which may vary in
quality, ranging from mild to severe and from chronic to
hyperacute, are among the most commonly encountered
symptoms. The pattern of headaches is quite variable,
and they may spontaneously remit for long periods.
Virtually any neurologic deficit can be encountered,
reflecting the wide distribution of CNS ischemia. Clinical findings of transient ischemic attacks, strokes, paraparesis, quadriparesis, cranial neuropathies, seizures,
and ataxia have been occasionally described (1,2,6).
CALABRESE ET AL
1192
Figure 2. A, Brain biopsy findings of Iymphocytic vasculitis in primary angiitis of the central nervous system, with thrombosis. B,
Close-up view of the boxed area in A, showing the lymphocytic infiltrate in the vessel wall. (Hematoxylin and eosin stained,
magnification X 64 and X 400, respectively.)
Interestingly, 15% of cases have spinal cord involvement
(5); these will be addressed separately.
In patients with pathologically documented
PACNS, the mean duration of symptoms before diagnosis is -5 months, with many patients having much longer
documented prodromal periods. Acute onset is less
common. It should be noted that the vast majority of case
reports from which these data were accrued have come
from tertiary centers, and thus, our current view of PACNS
no doubt reflects a significant degree of referral bias.
served in the same biopsy specimen and even in close
adjacent areas, given an adequate sized sample. The
varieties may include any or all of the following: the
classic granulomatous angiitis side-by-side with a polyarteritis nodosa-type necrotizing vasculitis, with normal
arteries and veins nearby. Both foreign-body and Langhans’ giant cells may be present in granulomatous angiitis (Figure l),or there may be only necrotizing lymphocytic vasculitis (Figure 2).
Clinical subsets of pathologically documented PACNS
Pathology
PACNS is primarily a leptomeningeal and cortical vasculitic disease involving the small and mediumsized leptomeningeal cortical arteries and, less frequently, the veins and venules (14). An assortment of
histologically different patterns of angiitis may be ob-
Since the manifestations of PACNS are highly
variable, unusual presentations are expected to occur.
Whereas PACNS may not be routinely considered in the
differential diagnosis of mass lesion presentation, spinal
cord problems, or CNS hemorrhage, such presentations
occur commonly enough to deserve special attention (5).
CNS VASCULITIS
Primary granulomatous angiitis of the central
nervous system. Among cases of histopathologically
documented angiitis, the most distinct nosologic entity is
that previously referred to as granulomatous angiitis of
the central nervous system. Unfortunately, the literature
shows that this term has been applied loosely for all
patients with proven or suspected angiitis confined to
the CNS, regardless of the pathology or method of
diagnosis (i.e., angiography versus biopsy). This term
should be reserved for patients with pathologically documented angiitis with granulomatous features, affecting
the small and medium-sized arteries and, rarely, veins of
the brain and/or meninges. Clinically, this subset is
generally associated wih a long clinical prodrome of 6
months or longer and a clinical course that is progressive.
The clinical consideration of primary GANS often arises in the differential diagnosis of a patient with
an unexplained chronic meningitis. The diagnosis of this
entity is best accomplished by biopsy of the leptomeninges and underlying cerebral cortex (see “Biopsy of the
CNS” below), since angiography is normal in -40% (9).
Rarely, primary GANS, complete with characteristic
pathology and clinical course, may arise in a patient with
recent herpes zoster infection or in the setting of
lymphoma (3,9).
Mass lesion presentations of PACNS. Mass lesion presentations account for 15% of reported PACNS
cases (25 of 168) (5). While focal CNS symptoms
predominate (84%), headaches are expectedly common
(64%) and other diffuse CNS symptoms (cognitive
changes, alterations in level of consciousness) are frequent (56%). Angiographic examination reveals abnormal findings in the majority of cases (83%), primarily
reflecting the presence of a mass lesion. Angiographic
findings suggestive of vasculitis (areas of stenosis and/or
ectasia in cerebral vessels) are rare (17%). Mass lesions
are generally defined by computed tomography (CT) or
MRI, but their appearance is not specific, and enhancement has been variably observed (1,12,22-24).
The diagnosis of PACNS is therefore usually
established when a brain biopsy, performed to evaluate
for neoplastic diseases, unexpectedly reveals CNS vasculitis. Granulomatous vasculitis of the CNS accounts
for the majority of such cases (87%). Reported treatment modalities and outcomes were generally similar to
those in the overall PACNS group. Whether excisional
biopsy of focal lesions would consistently result in a
benign course in the absence of immunosuppressive
therapy remains to be determined (15).
Spinal cord involvement in PACNS. Spinal cord
involvement was documented in 14% of reported cases
1193
of PACNS (24 of 168) (5). Myelopathy resulting in
progressive paraparesis was the most common clinical
manifestation of spinal cord vasculitis. CT had limited
sensitivity in detecting spinal cord lesions (abnormal in 4
of 13; sensitivity 31%). MRI, which was only rarely
performed, commonly revealed increased signal intensity within the spinal cord (abnormal in 4 of 4; sensitivity
100%). Examination of cerebrospinal fluid yielded abnormal findings in the majority of cases (84%), revealing
elevated protein levels and/or pleocytosis, often to the
highest levels seen in this condition. While the majority
of cases were pathologically documented at autopsy
(58%), premortem biopsies confirmed the diagnosis in
the other patients (42%). Granulomatous vasculitis of
the CNS accounted for the majority of cases (77%).
Vasculitis of the spinal cord has been reported in
association with Hodgkin’s as well as non-Hodgkin’s
lymphoma (16-20).
CNS hemorrhage in PACNS. CNS hemorrhage
was documented in 11% of reported PACNS cases in
our registry (18 of 168) (5). Intracerebral hemorrhage
was the most common, followed by subarachnoid and
spinal subdural hemorrhage. In several cases, CNS hemorrhage was related to aneurysmal rupture of cerebral,
leptomeningeal, or spinal arteries. Pathologic documentation of CNS vasculitis was available in 72% of cases
(postmortem in 50% and premortem in 22%). The
diagnosis was established angiographically in the remainder of patients (28%), undoubtedly representing a
mix of CNS angiopathy (e.g., postpartum state, exposure
to sympathomimetic drugs or drugs of abuse) and true
CNS vasculitis. Lymphoproliferative disorders (i.e., leukemia and lymphoma) were present in a significant
proportion of cases with pathologically documented
CNS vasculitis presenting with hemorrhage (30%).
Diagnostic modalities
Evaluation of suspected cases of PACNS is hindered by the lack of reliable noninvasive studies or
laboratory tests of sufficient predictive value to exclude
or secure such a diagnosis. Traditionally, the diagnosis
has depended on either biopsy evidence of vasculitis or
angiographic evidence of vascular disease compatible
with vasculitis. Such “gold standards” are, however,
subject to numerous limitations and interpretation
biases.
Laboratory blood tests. General laboratory parameters are not of sufficient sensitivity or specificity to
include or exclude consideration of PACNS in differential diagnoses. Hemoglobin levels, white blood cell
1194
counts, and erythrocyte sedimentation rates are normal
in 83%, 58%, and 35% of cases, respectively (4). The
diagnosis of PACNS should not therefore be abandoned
when the findings of general laboratory tests and acutephase reactants are found to be normal. In the absence
of clinical features suggestive of connective tissue diseases or systemic vasculitides, testing for a variety of
autoantibodies (e.g., antinuclear antibody or antineutrophi1 cytoplasmic antibody) is of extremely limited value.
The choice to obtain serologic tests for infectious diseases (e.g., human immunodeficiency virus [HIV], hepatitis C, syphilis) should be guided by clues obtained
during history and physical examination.
Cerebrospinal fluid analysis. Cerebrospinal fluid
(CSF) analysis is an essential part of the diagnostic
process for PACNS. The CSF findings are abnormal in
80-90% of pathologically documented cases of PACNS.
However, when the diagnosis is based on angiography
alone, the reported sensitivity of an abnormal CSF is
only 50-53% (4,21,22). CSF findings usually reflect
aseptic meningitis, with a modest pleocytosis and elevated protein levels (mean protein 177 mg%, median
100 mg%; mean number of cells 77/mm3, median 55
cells/mm3). Increased IgG synthesis and the presence of
oligoclonal bands are occasionally detected, but lack
sensitivity as well as specificity, and are generally not
useful. Most importantly, CSF analysis should include
appropriate stains, cultures, and serologic tests to search
for CNS infection. In a group of patients referred to us
for evaluation of possible PACNS, the positive predictive value of an abnormal CSF was only 37%, undoubtedly reflecting poor specificity (40%) (12).
Computed tomography and magnetic resonance
imaging. Noninvasive imaging studies are integral to the
diagnostic approach to most neurologic syndromes. In
the evaluation of PACNS, CT is generally less sensitive
than MRI (65% versus 90%, respectively) (5). As seen
with CSF examination, the sensitivity of MRI is greater
among histologically confirmed cases compared with
those diagnosed by angiography alone (95-100% versus
75-80%, respectively) (21,22). Unfortunately, both CT
and MRI results lack specificity (36%) (12). The most
common findings are multiple bilateral, supratentorial
infarcts distributed in the cortex, deep white matter,
and/or leptomeninges (7,14,23,24). With the use of
contrast agents, enhancement of parenchymal and/or
leptomeningeal lesions may be seen, but this finding is
not specific (5). Of note, the combination of normal
MRI and CSF test results has a strong negative predictive value and will exclude consideration of CNS vascu-
CALABRESE ET AL
litis in most clinical situations, thus obviating the need
for further invasive tests (1,12,22).
Angiography. Over the last 2 decades, there has
been an increased reliance on conventional cerebral
angiography in the diagnosis of suspected inflammatory
vascular disease of the CNS. When PACNS is diagnosed
on the basis of angiography alone, the test sensitivity is,
by definition, 100%. Among pathologically documented
cases however, cerebral angiography may be normal in
up to 40% of cases (sensitivity of 60%) (10,13). Even
when cerebral angiograms are abnormal, “classic” findings of arteritis (i.e., alternating areas of stenosis and
ectasia in multiple vascular distributions) occur in <40%
of cases (1). Furthermore, multiple microaneurysms,
which are so characteristic of vasculitis on abdominal or
renal angiograms for example, are distinctly rare in the
CNS (7).
Interpretation of cerebral angiography is further
limited by poor specificity (26%) (12). Angiographic
findings compatible with vasculitis are commonly encountered in nonvasculitic conditions such as vasospasm,
CNS infection, and even atherosclerosis (12,23,24). In
particular, cerebral vasospasm may be seen with a
variety of disorders (e.g., drug exposure, postpartum
state, hypertension) and is angiographically indistinguishable from the findings considered characteristic of
vasculitis (25,26). From the clinicians perspective, there
is a demonstrative risk of angiographic studies being
“over read” when reported as “consistent with” or
“diagnostic of” cerebral vasculitis. The cerebral angiogram, like all clinical tests, can only be fully interpreted
in the context of the details of the case at hand.
Serial angiographic studies may occasionally
demonstrate progression, stabilization, or improvement
of angiographic changes in concordance with the clinical
course (27). In view of the discussed limitations however,
the value of serial angiography has not been firmly
established and is unlikely to be uniform.
Other imaging techniques. Other imaging techniques are now commonly applied to the study of the
cerebral circulation and include magnetic resonance
angiography (MRA), positron emission tomography,
and single-photon-emission computed tomography.
Such techniques have not been formally evaluated in
CNS vasculitis. In view of its lower spatial resolution,
MRA should not be viewed as being equivalent to
conventional angiographic techniques for the detection
of CNS vasculitis. Functional imaging of the brain with
SPECT or PET has recently added to our understanding
of neurologic and psychiatric disorders. A diffuse pattern of perfusion abnormalities coupled with multiple
CNS VASCULITIS
small focal perfusion defects have been described in
neuropsychiatric lupus, cocaine use, HIV-associated dementia, and other conditions (28).
While functional brain imaging may be used to
evaluate for CNS vasculitis, the results should be interpreted with caution for the following reasons. 1) Defects
in cerebral blood flow do not always correlate with or
predict neurologic symptoms (28-30). 2) Perfusion defects do not distinguish vasculitis from other forms of
vasculopathy (e.g., vasospasm, atherosclerosis, thromboembolic disease). 3) Abnormalities may not differentiate
primary CNS processes (e.g., CNS vasculitis) from neurologic manifestations of extracranial disease (e.g. malignant hypertension, and uremia).
Biopsy of the CNS. Histologic confirmation remains the clinical standard for diagnosis of all forms of
vasculitis, including PACNS. Biopsy of the CNS is
particularly important in evaluating for a variety of
mimicking conditions, such as lymphoproliferative diseases, certain infections, sarcoidosis, and others. This
subject has recently been reviewed (31). Brain biopsy is
limited by poor sensitivity (12). Premortem biopsies
yield false-negative results in about 25% of autopsydocumented cases (10). Sampling the leptomeninges as
well as the underlying cortex will likely increase the
diagnostic yield, since vasculitis may be present in only 1
of the 2 sites (10,31). Biopsy of a radiographically
abnormal area, particularly in the presence of abnormal
enhancement, similarly improves the sensitivity of the
procedure (3 1,32). (This is of particular importance
when the syndrome of primary GANS is suspected.)
In the absence of focal lesions, the temporal tip
of the nondominant hemisphere is the preferred biopsy
site (1,31). Sampling the basilar meninges is important
when attempting to exclude certain indolent infections
or sarcoidosis (1,31). Deep or stereotactic biopsy samples are probably not indicated unless approaching a
mass lesion (2,3,33). Regardless of technique, tissue
samples should be stained and cultured for microorganisms, with efforts made to preserve frozen tissue for
subsequent investigations. Although false-positive biopsy results are rarely reported, areas of vascular inflammation may be encountered in lymphoproliferative disease and CNS infections (12). Since the specificity of a
biopsy is not loo%, even a positive biopsy result should
be interpreted in light of the entire clinical picture.
PACNS angiographically defined
Among the 168 cases of PACNS, 44 were documented only by cerebral angiography, without patho-
1195
logic confirmations (5,13). The clinical features of these
patients are shown in Table 2. In contrast to the patients
who have pathologically documented vasculitis, these
patients are more likely to be female and to have a
clinical picture dominated by headache, and are less
likely to have diffuse neurologic dysfunction or clinical
involvement of the spinal cord. Patients who are defined
solely by angiography are also more likely to present
acutely, unlike patients who are recommended for biopsy, who more often have a long prodromal period.
Diagnostically, such patients are less likely to have
significant abnormalities on CSF examination. Prognostically, they are more likely to have a benign outcome (11).
Several groups, including our own (8,9,11), favor
the term angiopathy when referring to patients diagnosed on the basis of angiography alone, since it reflects
the uncertainty of the underlying vascular pathology.
More importantly, however, the recognition of the differences in the clinical picture and natural history of
patients documented to have PACNS on the basis of
angiography alone (versus those histologically documented) has added considerable insight into our understanding of the disorder and has raised significant questions regarding the underlying pathophysiology of the
vascular disease in this group.
One possible explanation for these differences is
that most cases defined solely on angiographic grounds
merely represent a more benign spectrum of PACNS,
and conceivably, may have a similar though unproven
underlying histopathology to the pathologically documented cases. Indeed, -40% of histopathologically documented cases have similar angiographic abnormalities,
and there is no doubt that among cases reported on the
basis of angiography alone, some cases of true vasculitis
are included (10).
Another possibility is that the angiographically
documented cases are enriched with another generally
more benign disease that may reflect an alternative form
of underlying vascular pathology. Evidence supporting
this theory includes numerous isolated cases of putative
PACNS, diagnosed exclusively on the basis of angiography, with seemingly benign outcomes that are reported with labels such as isolated benign cerebral
vasculitis, isolated benign cerebral arteriopathy, and
reversible cerebral segmental vasoconstriction (34-37).
In 1993, we proposed the term benign angiopathy of the
central newous system (BACNS) in an effort to further
define this subgroup (11). Among patients presenting
with high-probability angiographic findings for CNS
vasculitis, a relatively benign subset could be identified
based on clinical features. Such patients were more
1196
likely to be female, to have an acute focal neurologic
event, normal or near-normal CSF, and to experience a
clinical course that was more often monophasic and
benign than did patients with histologically confirmed
cases. A similar clinical and angiographic picture has
been reported in patients exposed to sympathomimetic
drugs (38,39), with pheochromocytoma (40), in the
setting of complex headaches such as migraine or exertional headaches (25,41), and in the angiopathy described in the postpartum period (42-44). The striking
similarity among these latter conditions suggests that
reversible vasoconstriction may cause the same angiographic picture as does true arteritis. Unfortunately, in
the absence of definitive pathophysiologic investigations, the underlying pathology of patients with this
presentation remains unknown. Several groups, including our own, have suggested that such patients may not
require equally aggressive therapy with corticosteroids
and cytotoxic drugs, though no controlled therapeutic
trials have been reported (4S,46).
From a practical perspective, this syndrome
should be suspected in any individual, particularly a
young woman, presenting with the abrupt onset of a
headache with or without focal neurologic signs, a
normal or near-normal CSF, and a high-probability
angiogram consistent with “vasculitis.” In that setting it
is important to search for associated conditions or
precipitants such as 1) a drug history, including use of
over-the-counter agents such as ephedrine or phenylpropanolamine (even in recommended doses) or herb remedies such as the ephedrine-containing ephedra or ma
huang, 2) a history of complicated headaches, 3) pheochromocytoma, and 4) postpartum state. In our experience there is also often a history of the heavy use of
nicotine, caffeine (a known pharmacologic potentiator
of phenylpropanolamine), or the use of oral contraceptives or estrogen replacement therapy. The role of these
possible cofactors is unknown at present.
Pathophysiology
The etiology and pathogenesis of PACNS, defined by either histopathology or angiography, are unknown. Among the factors that limit our understanding
of the disorder are the scant amounts of pathologic
material available for potentially revealing studies, such
as culture, immunohistochemistry, and in situ identification of potentially invading organisms. Despite these
limitations, data from numerous sources suggest that 2
associated comorbidity factors may be critically involved
in the etiopathogenesis, namely, an association with
CALABRESE ET AL
systemic viral illnesses and an association with diseases
which alter host defenses. Among the 168 cases analyzed
by Duna et a1 ( 5 ) , 29 were associated with an illness
characterized by an immunosuppressive state, including
corticostcroid therapy, lympho- or myeloproliferative
disorders, and HIV infection, as well as a variety of
miscellaneous conditions including post-allograft transplantation and others. In addition, a variety of pathogens have been documented in association with CNS
arteritis, including varicella-zoster virus (VZV), HIV,
and cytomegalovirus (1,47,48).
It is possible that, in the setting of altered integrated host defense mechanisms, a virus or other pathogen may lead directly or indirectly to diffuse cerebral
arteritis. In support of this hypothesis is the well-defined
clinical syndrome of post-herpes zoster ophthalmicus
contralateral hemiplegia (6). In this syndrome, several
weeks to months following VZV infection of the trigeminal nerve, the patient suffers an ischemic event secondary to vasculitis of the middle cerebral artery, several of
its branches, and occasionally, the internal carotid artery. The mechanism appears to be a retrograde spread
of VZV to the intracranial vascular structures via the
gasserian ganglion (48). Viral particles have been identified in the cytoplasm and nuclei of smooth muscle cells
within the walls of affected vessels (48,50). Usually, the
disease remains anatomically localized and monophasic
in its course (48). Occasionally, in the setting of altered
host defenses, the vasculitis may become generalized,
demonstrating both clinical and histologic findings indistinguishable from the original descriptions of GANS
(3,s1-53). HIV infection has similarly been described in
such settings (54).
It may be argued that patients with defects in
immunity may all harbor infectious agents contributing
directly or indirectly to the vascular inflammatory process, and thus, should receive nosologic distinction.
However, attempts to identify pathogens (including
VZV and HIV) in pathologic materials have generally
been unsuccessful. Specific evidence against such a
mechanism has been the failure to find viral-like structures in the vast majority of cases, even when specific
searches for them have utilized immunohistochemistry
(9). Two patients with primary GANS had Mycoplasmalike structures within giant cells in the inflammatory
infiltrate, but cultures for Mycoplasma were negative (6).
Despite these negative reports, such cases (i.e., PACNS
and immunosuppresive states or disorders) should all be
viewed as potentially infected until more systematic
investigations are performed. The use of more sensitive
techniques such as polymerase chain reaction to pin-
CNS VASCULITIS
point latent viral or other infections within the CNS, a
procedure which has been successfully applied in the
identification of herpes simplex infection in cases of
recurrent Bell’s palsy (55), has yet to be systematically
reported in studies of PACNS.
The etiology of cases identified by angiography
alone is similarly unknown and investigation even further hampered by a total lack of access to underlying
histopathology. As previously noted, the strong similarity of many of these cases to reversible angiopathic states
reported in the setting of complicated headache, hypertension, and the puerperium strongly suggests alterations in vascular tone. The regulation of cerebral
vascular tone is highly complex and the factors contributing to vasospasm are poorly understood, but may
include perturbations of a variety of mediators including
endothelins (56), nitric oxide (56), cytokines (57), and
others (58).
Treatment and outcome
There are no controlled trials of therapy in
PACNS diagnosed by either antemortem biopsy or
angiography. As previously discussed, early experience
with the disease led to the conclusions that it was
relentlessly progressive and nearly uniformly fatal.
These conclusions were highly influenced by historical
bias that failed to account for the fact that the majority
of cases described before the mid-1970s were identified
at autopsy. A small, uncontrolled, but successfully
treated, series by Cupps et a1 (59) suggested that aggressive combination therapy with corticosteroids and cyclophosphamide was beneficial. A recent analysis of
PACNS cases has suggested a far more favorable prognosis for PACNS, regardless of the method of diagnosis
(mortality 4.4% for biopsy proven; 3.6% for angiographically defined) despite the use of corticosteroids
alone in 30.4% of biopsy-proven cases and 49.1% of
angiographically defined cases (21). In our opinion,
aggressive therapy (a cytotoxic agent and high-dose
corticosteroids) should be reserved for patients who
experience a progressive neurologic illness and when at
least an attempt has been made to define the condition
by histology. This is nearly always the case in patients
with confirmed primary GANS. The optimal duration of
therapy is unknown, but usually, it is continued for 6-12
months after clinical remission is achieved (1,2).
For patients with acute focal presentations associated with normal findings on CSF examination, whose
diagnosis is inferred on the basis of angiography alone, a
diagnosis of BACNS is appropriate. In such instances,
1197
we (1) and others (45,46) believe that there is rarely an
indication for initial therapy with aggressive combination immunosuppressive agents. The use of a relatively
brief (3-6-week) course of high-dose corticosteroids in
conjunction with a calcium channel blocker has, in our
experience, been frequently successful. Since it is assumed that reversible vasoconstriction plays some role in
these patients, it is important that they avoid other
thrombogenic or vasoconstrictive stimuli, such as oral
contraceptives, nicotine, and sympathomimetic drugs
such as ephedrine (found in some natural herbal remedies) and phenylpropanolamine (found in more than 80
over-the-counter products) (60).
Unfortunately, the above-outlined diagnosis and
treatment are frequently complicated by inconclusive
diagnostic studies (i.e., equivocal angiograms or nondiagnostic biopsies) or failure to respond to the suggested
therapies. Given the lack of specific diagnostic features
of PACNS and the statistical likelihood of dealing with
an alternative disorder, the accuracy of the underlying
diagnosis should be revisited frequently.
Secondary CNS vasculitis
When cerebral vasculitis arises as a result of an
exogenous influence such as a drug, toxin, infection, or
systemic disease, it is classified as secondary. Such a
designation may be clinically important when removal of
the specific inciting agent or control of the associated
systemic disease may result in amelioration of the CNS
vasculitis. The relationship between many of these secondary associations is often unclear, without good evidence of direct cause and effect. Despite this limitation,
a diligent search for secondary factors is essential in the
approach to the patient with suspected CNS vasculitis.
Infections
Many organisms including viruses, bacteria,
fungi, rickettsiae, and protozoa are associated with
systemic and CNS vasculitis. These cases have recently
been reviewed (47,61). In many instances, the organism
may be angioinvasive, but in others, the vascular inflammatory reaction may result from alterations in host
defenses with secondary damage to host tissues (62).
Table 3 lists pathogens that have been described in
association with either focal or diffuse cerebral vasculitis. In the evaluation of all suspected cases of CNS
vasculitis, it is important to routinely search for infection
through detailed microbiologic analysis of CSF and
biopsy tissues. Current epidemiologic trends have given
CALABRESE ET AL
1198
Table 3. Infectious etiologies of CNS arteritis*
Lymphoproliferative diseases
Viruses (HIV-1, cytomegalovirus, varicella-zoster virus, others)
Syphilis
Borrelia buqdorferi
Bartonella
Mycobactenurn tuberculosis
Fungi (Aspergillus, Coccidioides, others)
Bacteria (multiple)
Rickettsiae (Rocky Mountain spotted fever, typhus, others)
CNS vasculitis has been reported in association
with Hodgkin’s lymphoma, non-Hodgkin’s lymphoma,
and angioimmunolymphoproliferative lesions (AIL)
(1,7). The lymphoproliferative disease itself may be
detected outside or within the CNS. Although the
clinical presentation is generally similar to that of
PACNS, reported clinicoradiographic presentations
have included mass lesions, spinal cord involvement, and
CNS hemorrhage ( 5 ) . The pathology of the CNS lesions
may be indistinguishable from that of PACNS with
widespread granulomatous angiitis (1).It may be particularly challenging to differentiate lymphocytic angiitis
from AIL (1,12). When appropriate, detailed immunohistochemistry and T cell receptor and/or B cell immunoglobulin genetic analysis may help to clarify the
diagnosis. Therapy is generally directed at the underlying lymphoproliferative disease and may consist of combination chemotherapy and/or radiotherapy. Favorable
neurologic responses have been reported (69-71). As
noted in the “Pathophysiology” section, it is tempting to
speculate that these cases may ultimately be demonstrated to harbor occult infections, such as ubiquitous
viruses (i.e., VZV, others) or retroviruses, but until
systematic investigations clearly demonstrate the presence of such microbes, it seems useful to view them
separately.
* CNS = central nervous system; HIV-1
virus type 1.
=
human immunodeficiency
certain pathogens increased importance; these include
syphilis, HIV, and VZV. Suspicion of other pathogens
should be influenced by clinical and epidemiologic features on a case-by-case basis.
Drugs
The relationship between drug exposure and
CNS vasculitis is highly complex and has recently been
reviewed (63). A variety of drugs, particularly those with
sympathomimetic properties, have been associated with
cerebrovascular complications, including cerebral infarcts, intracerebral bleeding, and subarachnoid hemorrhage. Implicated drugs include oral and intravenous
amphetamines, cocaine, heroin, ephedrine, and phenylpropanolamine (64,65). Of note, most reported cases of
“drug-induced CNS vasculitis” have been defined by
cerebral angiography alone, in the absence of pathologic
confirmation. Since drug-induced cerebral vasospasm,
malignant hypertension, subarachnoid hemorrhage, and
cerebral emboli can all mimic the angiographic appearance of CNS vasculitis, such cases may have represented
CNS angiopathy rather than a true angiitis (12,26,43).
Ascertaining the relationship between a particular drug
exposure and “CNS vasculitis” is further complicated by
the presence of numerous confounding factors, such as
exposure to multiple substances (or impurities) and/or
coexisting infections (63). In the absence of histologic
confirmation of vasculitis, prolonged immunosuppressive therapy may not be necessary and can be deleterious. Consideration should be given to the use of calcium
channel blockers (1).
On the other hand, histologically documented
cases of drug-associated CNS vasculitis do exist. Pathologists have described findings ranging from perivascular
cuffing of small cerebral vessels to frank vasculitis, with
or without necrosis in these cases (63-68).
Systemic vasculitides
The neurologic presentations and manifestations
of systemic vasculitides have recently been reviewed
(6,72). Vasculitis of the CNS may occur with any of the
systemic vasculitides, but is most commonly reported in
polyarteritis nodosa, Behget’s syndrome, Wegener’s
granulomatosis, and Churg-Strauss syndrome (7). The
prevalence of CNS angiitis is difficult to estimate since
the diagnosis is most often presumed on clinical grounds
(i.e., in the absence of angiographic or pathologic evidence of arteritis), when focal and/or diffuse neurologic
deficits develop in the setting of systemic disease. It
would be prudent, in such situations, to consider alternative explanations for CNS dysfunction, such as infections, drug toxicities, and the effects of extracranial
end-organ damage (e.g., renal failure or pulmonary
insufficiency) (7).
Connective tissue diseases
CNS involvement is not uncommon in connective
tissue disorders, including systemic lupus erythematosus
CNS VASCULITIS
(SLE) and Sjogren’s syndrome. In SLE, brain pathology
most often reveals a vasculopathy, with small vessel
thickening, hyalinization, intramural platelet deposition,
and thrombus formation (73). Frank vasculitis is uncommon (<7%) but has been documented in patients with
acute, dramatic, and often fatal CNS presentations
(74-76). The pathology and pathogenesis of vascular
injury in SLE have recently been reviewed (77). When
SLE patients present with neurologic events, it is important to consider mechanisms other than CNS vasculitis,
such as antiphospholipid antibody-related thrombosis,
cardiac emboli, and thrombotic thrombocytopenic purpura (78). In Sjogren’s syndrome, CNS manifestations
may be caused by a mononuclear inflammatory vasculopathy involving the small vessels of the cortex and
meninges (79). Angiographic abnormalities consistent
with vasculitis are uncommonly seen (20%), and only a
few patients have been studied histologically. The prevalence, pathogenesis, and treatment of CNS vasculitis in
Sjogren’s syndrome remain largely unresolved issues.
Diagnostic terminology
In an effort to clarify future work in the area of
CNS arteritis, it would be desirable to have a more
standardized nomenclature including diagnostic terms
and criteria. A set of working criteria were proposed in
1988 by Calabrese and Mallek, which relied equally on
angiography or biopsy of the CNS to establish a diagnosis of PACNS (4). Given our current appreciation of the
heterogeneity of disease fulfilling these criteria, some
further refinement of this definition is needed. Utilizing
the framework for nomenclature utilized in a recent
international consensus conference on vasculitis (80), we
propose the following.
Nomenclature. As a broad classification of CNS
vasculitis, the disease should be viewed as either
secondary-when related to a recognized precipitin such
as a drug, infection, or systemic disease known to involve
the CNS--or primary (PACNS)-when unassociated
with any such factor. Among patients with PACNS, the
only subset currently deserving of nosologic distinction is
primary GANS. Benign angiopathy of the CNS (BACNS)
is a term which should be reserved for angiographically
defined disease with specific clinical features.
Definition of disease. Primary GANS is a disease
characterized by granulomatous vasculitis involving
small and medium-sized vessels, primarily arteries, that
is confined primarily to the CNS, with a chronic and
progressive course if left untreated. BACNS refers to
disease defined by an angiographic picture compatible
1199
with vasculitis in the setting of the abrupt onset of
headache or focal neurologic deficit, with normal or
near-normal CSF. Since the underlying pathology and
pathophysiology are unknown in this syndrome, the
presence of any precipitating factor or condition known
to produce a similar clinical and angiographic picture
(i.e., sympathomimetic drug use, complicated headaches, pheochromocytoma, postpartum state, etc.)
should be noted. Patients without the clinical, radiographic, and/or pathologic features of primary GANS or
BACNS, but with a suspected vasculitic process confined
to the CNS (e.g., vasculitis within a mass lesion, vasculitis with leukocytoclastic features, low-probability
angiographic abnormalities, etc.), should be described in
descriptive terms, based on the time course, neurologic
deficits, pathologic description, and/or angiographic
findings.
Finally, there appears to be insufficient data to
justify recommendation of classification or diagnostic
criteria for these syndromes. Establishment of such
would best be accomplished by a multicenter cooperative effort. Hopefully, these proposed diagnostic terms
and definitions may serve as a logical starting point for
such a process.
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