Editorial
Cephalalgia
Diagnostic challenges in RCVS, PACNS,
and other cerebral arteriopathies
Aneesh B Singhal
In the field of vascular neurology, few conditions pose
greater diagnostic and therapeutic challenges than the
intracranial cerebral arteriopathies (Table 1). They are
a common cause of secondary headaches (vascular
headaches), and perhaps the most common cause of
stroke, accounting for 20–35% of strokes in young
adults (1–2) and over 50% in children (3). In older
adults, intracranial atherosclerosis alone accounts for
10–50% of stroke (4), and lipohyalinotic small-vessel
disease another 15%. Intracranial arteriopathies can
be classified according to etiology or the affected age
group. From the diagnostic standpoint it is convenient
to classify them according to the size of the affected
artery as medium-vessel or small-vessel; the former
induce abnormalities visible on transfemoral angiogra-
phy, whereas the latter affect distal small vessels that
are beyond the current resolution of angiography.
Some arteriopathies, such as the reversible cerebral
vasoconstriction syndromes (RCVS) and primary angii-
tis of the central nervous system (PACNS), can affect
both the medium and the small vessels.
The diagnosis of small-vessel cerebral arteriopathies
requires a high level of clinical suspicion, astute inter-
pretation of imaging findings, and a detailed examina-
tion of the skin, eye, or other organ systems. They are
often disclosed by the presence of recurrent small-vessel
infarcts in patients with chronic headaches, skin lesions,
known systemic infections, or MRI findings of scat-
tered small-vessel infarcts or micro-hemorrhages with
or without white matter lesions. Several small-vessel
arteriopathies (e.g. CADASIL (5); see Table 1) have
established diagnostic criteria or can be confirmed
with specialized tests, such as skin or brain biopsy, or
genetic, immunological, or microbiological tests. Some
small-vessel arteriopathies can be comfortably diag-
nosed with clinical-imaging correlation, for example
lipohyalinotic small-vessel disease in patients with
chronic hypertension, a lacunar stroke syndrome,
and a corresponding small cerebral infarction in the
distribution of a ‘penetrator’ artery. Others such as
PACNS continue to pose diagnostic challenges because
31(10) 1067–1070
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definitive diagnostic tests such as brain biopsy are often
false-negative, and tests such as cerebrospinal fluid
examination and angiography have low specificity (6).
Medium-vessel cerebral arteriopathies are typically
disclosed when CT- or MR- angiography, performed
during the routine evaluation of stroke or headache,
reveal arterial irregularities. Alternately, they are sug-
gested by clinical clues such as recurrent thunderclap
headaches; stroke in the setting of recent headache,
infection, stereotyped transient ischemic attacks,
recent pregnancy, or illicit drug use; or imaging findings
of unilateral deep border zone infarcts (7). Once arterial
irregularity is documented, it becomes imperative to
determine the etiology in order to initiate appropriate
therapy. Unfortunately, in the absence of validated
diagnostic criteria or confirmatory tests for most
medium-sized arteriopathies, the approach remains
variable and uncertain. Older adults are usually
assumed to have intracranial atherosclerosis if they
have vascular risk factors or calcified proximal cerebral
arteries. In children, the diagnosis is particularly chal-
lenging given the need for serial angiography or
advanced imaging (e.g. 3-Tesla MRI) to diagnose con-
ditions such as transient cerebral arteriopathy and
intracranial dissection that are more common in child-
hood. Young adults with intracranial arterial irregular-
ities typically undergo a battery of expensive diagnostic
tests, most of which have relatively low sensitivity and
specificity, often culminating in a brain biopsy or
empirical treatment for cerebral ‘vasculitis’, which is
not without risks.
Linn et al. (8) report a study of nine patients with
headache, variable clinical deficits, and a medium-
vessel cerebral arteriopathy, who developed clinical
Harvard Medical School, USA.
Corresponding author:
Aneesh B Singhal, ACC-729-C, Department of Neurology, Massachusetts
General Hospital, Boston, MA 02114, USA
Email: asinghal@partners.org
1068 Cephalalgia 31(10)

Table 1. Cerebral arteriopathies

1. Intracranial atherosclerosis
2. Small-vessel diseases from chronic hypertension, diabetes (lipohyalinosis and leukoaraiosis)
3. Inflammatory/immunological vasculitis (e.g. giant cell arteritis, Takayasu arteritis, primary angiitis of the CNS, polyarteritis nodosa,
scleroderma, systemic lupus erythematosus, Behçet’s’s disease, Churg–Strauss syndrome, Kohlmeier–Degos disease, Eale’s ret-
inopathy, Spatz–Lindenberg disease, vasculitic cerebral amyloid angiopathy)
4. Infectious arteritis (e.g. tuberculosis, syphilis, cysticercosis, herpes zoster, HIV, bacterial meningitis)
5. Reversible cerebral vasoconstriction syndromes (Call–Fleming syndrome, benign angiopathy of the CNS, postpartum angiopathy,
and cerebral vasoconstriction associated with vasoactive drug use, recurrent thunderclap headaches, etc)
6. Posterior reversible encephalopathy syndrome
7. Moyamoya disease
8. Intracranial cerebral artery dissection
9. Transient cerebral arteriopathy of childhood
10. Genetic, inherited and developmental anomalies (e.g. Fabry’s disease, fibromuscular dysplasia, dolichoectasia, cerebral autosomal-
dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal-recessive arteriosclerosis
with subcortical infarcts and leukoencephalopathy (CARASIL), sickle cell disease, COL4A1 mutation, hereditary endotheliopathy
with retinopathy, nephropathy, and stroke (HERNS), Osler–Weber–Rendu syndrome, Ehlers–Danlos syndrome type IV, Marfan
syndrome, neurofibromatosis type 1, retinal vasculopathy with cerebral leukodystrophy (RVCL), pseudoxanthoma elasticum, acute
posterior multifocal placoid pigment epitheliopathy (APMPPE), osteogenesis imperfecta)

worsening within days of presentation. RCVS was sus-
pected, but conditions such as PACNS and Moyamoya
disease could not be excluded. On the basis of the idea
that nimodipine may reverse RCVS-associated vaso-
constriction and thereby prevent clinical decline, all
patients received intra-arterial nimodipine treatment.
Patients eventually diagnosed with RCVS showed
prompt reversal of vasoconstriction with intra-arterial
nimodipine, unlike those eventually diagnosed as
PACNS, Moyamoya, and intracranial atherosclerosis.
The authors (8) propose that in suspected RCVS
patients with clinical worsening, the vasodilator
response to intra-arterial nimodipine could be used a
diagnostic test to confirm RCVS and exclude mimics.
Given the historic difficulties in diagnosing medium-
sized cerebral arteriopathies and the potential impact
of accurate diagnosis on subsequent management, these
results are relevant. However, over 95% of RCVS
patients have benign clinical outcome despite initial
clinical or angiographic progression (9–12). It is impor-
tant to consider instances in which an interventional
diagnostic procedure may be warranted, the diagnostic
accuracy, efficacy, and safety of such procedures, and
the appropriate steps in diagnosing RCVS and other
medium-vessel arteriopathies.
Linn et al. (8) suspected RCVS on the basis of head-
ache and angiographic abnormalities. Only five of nine
patients were ultimately diagnosed with RCVS, show-
ing how difficult it can be to diagnose arteriopathies in
the acute setting. Historically, it has been challenging to
distinguish RCVS from mimics such as PACNS
because of overlapping features such as headache and
angiographic irregularities (13–14). Recent studies
characterizing RCVS (9–12) and PACNS (15–16)
suggest that diagnostic accuracy in the acute setting
can be enhanced by considering specific characteristics
of the presenting headache, the clinical setting, and
brain and vascular imaging findings. Patients with
RCVS invariably have a dramatic presentation with
recurrent and severe thunderclap headaches; brain
imaging can be normal or shows ‘watershed’ territory
infarcts, convexity subarachnoid hemorrhages, lobar
hemorrhages, and reversible brain edema; and cerebral
angiography shows smoothly tapered segmental arterial
narrowing (sausage-on-a-string appearance) of the
circle of Willis arteries and their branches. Further,
RCVS frequently occurs in specific clinical settings
(e.g. the post-partum state), and cerebrospinal fluid
examination results are invariably normal. Patients
with PACNS typically have insidious-onset subacute
headaches and encephalopathy; 97% have abnormal
brain imaging findings, including scattered small-vessel
infarcts, white matter changes and leptomeningeal
enhancement; and less than a third develop proximal-
vessel angiographic abnormalities. Other arteriopathies
such as Moyamoya disease and intracranial atheroscle-
rosis are not associated with recurrent thunderclap
headaches, and they often have characteristic imaging
features, for example the cigar-like narrowing of the
intracranial internal carotid artery with a ‘puff of
smoke’ appearance of the lenticulostriate collateral
pathways (Moyamoya disease), or calcifications and
irregular focal stenosis of 1–2 proximal arteries (intra-
cranial atherosclerosis).
Given the above, it is likely that most patients with
RCVS can easily be diagnosed acutely, without the
need for follow-up angiography to document reversibil-
ity. The problem of distinguishing RCVS from mimics
Editorial
will therefore only apply to a minority with atypical
features. In such patients, an interventional diagnostic
procedure can only be justified if urgent diagnosis is
imperative for management, for example if RCVS still
needs to be excluded before proceeding to brain biopsy
or immunosuppressive therapy for PACNS. Linn et al.
(8)’s results suggest a diagnostic role for intra-arterial
nimodipine infusion. However, the retrospective nature
and small sample size of this study, the reliance on
follow-up angiography alone for final diagnosis in all
but one patient, and the potential for irreversible vaso-
constriction due to secondary inflammation in some
RCVS patients (17) suggest the need for further studies
to determine the diagnostic accuracy of this procedure.
Many authors including Linn et al. (8) have pro-
posed a therapeutic role for intra-arterial approaches
such as the application of nimodipine or other cal-
cium-channel blockers, milrinone, or balloon angio-
plasty, in patients with probable RCVS (18–22). The
efficacy of such procedures may be overestimated
because most RCVS patients do well despite initial
angiographic or clinical progression. The vasodilator
response to calcium-channel blockers can be transient
and followed by ‘rebound’ vasoconstriction, and open-
ing the artery incurs the risk of reperfusion injury, brain
edema, and hemorrhage (18). Hence at present it seems
reasonable to withhold intervention if the only markers
for progression are isolated recurrent headaches, minor
worsening of the neurological examination, or angio-
graphic progression without clinical change. Simple
observation with pain control is usually adequate in
most patients, and oral calcium-channel blockers may
reduce the frequency and intensity of headaches. Only
in RCVS patients judged to have ‘significant’ clinical
worsening despite conservative management, as in the
study under discussion (8), should interventional strat-
egies be considered. Of course, waiting too long may
render any intervention ineffective, and therefore much
depends on clinical experience and judgment.
The study by Linn et al. (8) emphasizes the need to
develop non-invasive tools to diagnose cerebral arter-
iopathies in the acute setting. Advanced MRI tech-
niques may provide clues to diagnosis; for example,
high-resolution 3-Tesla MRI may be useful to distin-
guish inflammatory from atherosclerotic or other cere-
bral arteriopathies (23), and contrast-enhanced MRI
findings of vessel wall thickening and enhancement
may suggest vasculitis (24). Cerebral vasoreactivity
tests may prove useful for diagnosing RCVS (12).
A prospective multicenter collaborative study pooling
clinical, laboratory, radiographic, and pathological
data of patients with acute cerebral arteriopathies is
needed to validate existing preliminary diagnostic crite-
ria (13), develop diagnostic and prognostic biomarkers,
and lay the foundation for treatment trials (25).
1069
The fact that Linn et al. (8) accumulated nine patients
with arteriopathy-associated clinical worsening within
2.5 years, and that recent publications reported rela-
tively large numbers of arteriopathy cases at single cen-
ters (9–12,15–16), suggest that prospective studies and
clinical trials are feasible.
Funding
This work was supported by NIH-NINDS (award R01 NS
051412).
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