Q J Med 2005; 98:643–654
Advance Access publication 22 July 2005
Primary angiitis of the central nervous system:
K. MACLAREN, J. GILLESPIE1, S. SHRESTHA, D. NEARY2and F.W. BALLARDIE
Departments of General Medicine,1Radiology, and2Neurology, Manchester Royal Infirmary,
Received 21 December 2004 and in revised form 9 April 2005
Background: Primary angiitis of the central nervous
system (PACNS), a serious disease, has not featured
prominently in the spectrum of multi-organ disease
seen in vasculitis clinics.
Aim: To evaluate the presentation, natural history
and features of PACNS variants and compare to
those of systemic vasculitides.
Design: Retrospective analysis.
Methods: Patients (n¼105) presented during 1988–
2003 to a tertiary regional vasculitis clinic receiving
unselected disease types. Data were collected
from a clinical database, patient and laboratory
Results: The frequency of PACNS presentation rose
over the study period, compared with most of the
other vasculitides. When PACNS was divided into
small- and middle-sized vessel disease (SVD/MVD),
their clinical courses differed substantially. SVD
PACNS was responsive to immunosuppressive
drugs, but relapsed during prolonged periods in
all patients on maintenance immunosuppressives,
or after withdrawal of treatment, causing recurrent,
severe and irreversible CNS injury. MVD PACNS
had isolated episodes at presentation, with a paucity
of relapses during prolonged follow-up.
Discussion: Similarities between SVD PACNS and
microscopic polyarteritis suggest the former may
represent a limited form of the latter. MVD PACNS
has a distinctly more benign relapse pattern than
its multisystem counterpart polyarteritis nodosa.
Acute-phase serology was useful in designating
inflammatory processes at presentation of patients
presenting with encephalopathy caused by SVD
only, but were unhelpful in defining relapses in
this form of PACNS, the definition of which in
all cases rested on clinical assessment and MR
scanning. Direct cerebral angiography was not diag-
nostic in any case of SVD PACNS; positive brain
biopsy is diagnostically unequivocal, but the total
clinical syndrome with imaging may establish a
diagnosis with highest probability. In MVD PACNS,
angiography with MR scan proved diagnostic.
We suggest an algorithm for a rational, minimally
invasive approach to investigation. In PACNS, SVD
and MVD are important variants, and decisions
about therapy should incorporate these distinctions.
Address correspondence to Dr F.W. Ballardie, Manchester Royal Infirmary, Oxford Road, Manchester M13
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by guest on December 30, 2015
Primary angiitis of the central nervous system
(PACNS) is a serious disease, potentially causing
3–5% of cerebrovascular accidents in patients aged
550 years,1but the syndrome has not featured
prominently in the spectrum of unselected, multi-
organ disease seen in vasculitis clinics.2Between
1959 and 1986, only 46 cases of PACNS had been
described in the literature, most of these diag-
nosed at post-mortem.3In 1991, Crane and Kerr
illustrated 11 cases from the preceding decade,4
and more recently a six-patient series had mag-
netic resonance (MR) and angiographic findings
Clinical experience suggests more
patients suffering PACNS are now being recognized,
but there are no data to evaluate whether this
represents a true increase in incidence, or if it
reflects insight and acumen in previously undiag-
PACNS was not commonly recognized when
the American College of Rheumatology (ACR)6and
Chapel Hill Consensus Conference (CHCC)7criteria
for the classification of primary systemic vasculitides
were drawn up. Calabrese and Mallek suggested
definitive criteria for the diagnosis of isolated
angiitis of the central nervous system:3,8(i) an
acquired neurological deficit that remained unex-
plained after complete evaluation; (ii) a diagnostic
cerebral angiogram that included diffuse areas
of symmetric narrowing of vessels with areas of
dilation and/or beaded vessel appearance, displace-
ment of vessels or vessel occluded; (iii) no evidence
of systemic vasculitis or any other condition that
could mimic the angiogram findings.
This definition of PACNS excludes CNS disease
where other vasculitic syndromes are partially
or wholly identifiable and which encompass earlier
descriptions that conferred heterogeneity in CNS
disease by vessel size, or histologically, by presence
or absence of granuloma.6,7Diffuse cerebritis in
small-vessel PACNS often manifests as subacute or
acute encephalopathy, with persistent unexplained
headache, altered higher mental function, confu-
sion, and deteriorating conscious level, progressing
to grand mal convulsions resistant to therapy,
whereas middle-sized-vessel PACNS is more likely
to present as a cerebrovascular accident in one or
more defined or limited areas in patients without
risk factors for arteriosclerotic disease. Central
nervous system vasculitis is protean in its presen-
tation, but enters the differential diagnosis of a
patient when the pattern of disease is atypical, or
when there are ischaemic infarcts, (occasionally
haemorrhage8) temporally related, in separate and
distinct vessel territories. Unifocal or absent MR
findings do not exclude occult or more extensive
CNS, multiple-vessel territory vasculitis9which may
be definable only on direct angiography of the
CNS, in certain cases.
No therapeutic regimen for PACNS has been the
subject of a controlled trial to assess comparative
efficacies of drugs10(corticosteroids, alone or in
combination with cytotoxics) vs. risks of treatment,
nor is this a likely prospect. A priori, the use of
corticosteroids (with or without cytotoxic agents)
to suppress disease activity in other organs, notably
kidney and lung,11and to sustain remission in the
morecommon systemic vasculitides
similar vessel types outside of the central nervous
nodosa, Wegener’s granulomatosis) with similar
vessel types within the CNS, seems a prudent initial
approach to treatment. Recent descriptions of CNS
vasculitis support the use of cytotoxics in addition
to corticosteroids, but fall short of precisely how
regimens should be managed in the longer term.12
Knowledge of the natural history of PACNS in
long-term follow-up is critical in deciding optimal
treatment regimens for patients. We therefore
analysed data for patients presenting
15-year period to a tertiary regional vasculitis
clinic, to identify patterns, organ injuries, natural
history and features of PACNS compared to the
The records of all patients attending the regional
vasculitis clinic at Manchester Royal Infirmary
between 1988 and 2003 were reviewed; 105 were
included in the study. The final diagnoses identified
were: polyarteritis nodosa (PAN); cutaneous vascu-
litis (variant, limited polyarteritis nodosa, or leuco-
cytoclastic vasculitis) (CV); PACNS; Churg-Strauss
syndrome (CSS); Wegener’s granulomatosis (WG);
microscopic polyarteritis (MPA); adult Henoch
Scho ¨nlein purpura (HSP); and SLE vasculitis.
For inclusion in these groups, the patients had
to meet the criteria set out by the ACR for PAN,
CSS, WG, and SLE vasculitis; for HSP, an additional
requirement of demonstration of typical glomerular
mesangial deposition of immunoglobulin A was
imposed. CHCC criteria were used for MPA and
leukocytoclastic cutaneous vasculitis. For PACNS,
Calabrese and Mallek’s criteria were primary,
using brain biopsy only when clinical and radio-
graphic evidence was equivocal. The information
abstracted is summarized in Table 1.
Data were entered into an Excel spreadsheet and
analysed using the Stats Direct package. Analyses
644 K. MacLaren et al.
by guest on December 30, 2015
index of clinical suspicion has become an essential
in establishing the diagnosis. Imbesi9described a
case where the MR scan was negative despite
angiography showing evidence of foci of irregular
narrowing within the cerebral vasculature. This
inconsistency was thought to be due to timing,
the MR scan not being positive during the process
of ischaemic change. They concluded that this
showed the necessity to perform angiography in
all cases with high clinical suspicion. Our findings
show that normal areas of the CNS on MR scan can
coexist temporally with abnormalities on angio-
graphy in MVD PACNS, presumably because
ischaemia has not yet become critical. This empha-
sizes the need for angiography in all cases where
there is a high index of suspicion of middle-size
multiple-vessel territory disease is an uneqivocal
diagnostic criterion, as is characteristic single vessel
abnormality in patients who do not have evidence
of atheromatous disease, both of higher diagnostic
sensitivity than MR scan alone. Our findings suggest
an optimal risk–benefit diagnostic algorithm for
patients when SVD or MVD PACNS is suspected
All patients with MVD PACNS were relapse-
free during 6 years follow-up, and all had discon-
tinued low-dose prednisolone and azathioprine
by 24 months from presentation. Its potential
systemic equivalent PAN, both in our experience
Figure 11. Algorithm for management of suspected small-vessel, or middle-sized vessel PACNS, suggested from analysis
of this series.
Primary CNS angiitis 653
by guest on December 30, 2015
(data not shown), and that of others,26(both
systemic and the cutaneous-limited variant), is an
indolent, frequently relapsing vasculitis, with a
propensity to cause progressive organ injuries over
long periods: MVD PACNS is more benign after
initial presentation than either PAN or PACNS SVD.
The natural histories of SVD and MVD PACNS
are strikingly distinct, as are their clinical, serologi-
cal acute-phase, and radiographic characteristics.
Our findings suggest that PACNS is not a unifying
diagnosis, and that these distinctions should be
two variants of PACNS. Although acute-phase
parameters are useful in designating inflammatory
processes at presentation in SVD PACNS, they
are unhelpful in defining relapses in this form of
PACNS, the diagnosis of which rested in all cases
on clinical acumen and MR scans. Delineation of
the two forms of PACNS has important implications
in optimizing risks and benefits of immunosuppres-
sive regimens. In SVD PACNS, treatment should be
at least as intensive, and potentially more prolonged
than for the equivalent antineutrophil antibody-
positive small-vessel systemic vasculitis, whereas
in MVD PACNS, our data suggest that immuno-
suppressives can safely be discontinued after 2 years
or less. SVD and MVD PACNS may be best
considered separate, frequently encountered, enti-
ties in the context of secondary and tertiary referral
practice in systemic vasculitis.
treatment for the
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