Contribution of Convexal Subarachnoid Hemorrhage
to Disease Progression in Cerebral Amyloid Angiopathy
Markus Beitzke, MD; Christian Enzinger, MD; Gerit Wünsch, DSc; Martin Asslaber, MD;
Thomas Gattringer, MD; Franz Fazekas, MD
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Background and Purpose—Cerebral amyloid angiopathy–related cortical superficial siderosis (cSS) seems to indicate an
increased risk of subsequent intracerebral hemorrhage (ICH). We wanted to identify the mechanisms and sequence of
hemorrhagic events which are responsible for this association.
Methods—During a 9-year-period, we identified patients with spontaneous convexal subarachnoid hemorrhage (cSAH) and
performed a careful longitudinal analysis of clinical and neuroimaging data. A close imaging–histopathologic correlation
was performed in one patient.
Results—Of 38 cSAH patients (mean age, 77±11 years), 29 (76%) had imaging features of cerebral amyloid angiopathy
on baseline magnetic resonance imaging. Twenty-six (68%) had cSS. Sixteen subjects underwent postcontrast magnetic
resonance imaging. Extravasation of gadolinium at the site of the acute cSAH was seen on all postcontrast scans. After a
mean of 24±22 (range 1–78) months of follow-up, 15 (39%) had experienced recurrent cSAHs and 14 (37%) had suffered
lobar ICHs. Of 22 new ICHs, 17 occurred at sites of previous cSAHs or cSS. Repeated neuroimaging showed expansion
of cSAH into the brain parenchyma and evolution of a lobar ICH in 4 patients. Propagation of cSS was observed in 21
(55%) patients, with 14 of those having experienced recurrent cSAHs. In the autopsy case, leakage of meningeal vessels
affected by cerebral amyloid angiopathy was noted.
Conclusions—In cerebral amyloid angiopathy, leakage of meningeal vessels seems to be a major cause for recurrent
intrasulcal bleedings, which lead to the propagation of cSS and indicate sites with increased vulnerability for future
ICH. Intracerebral bleedings may also develop directly from or in extension of a cSAH. (Stroke. 2015;46:1533-1540.
DOI: 10.1161/STROKEAHA.115.008778.)
Key Words: cerebral amyloid angiopathy ◼ intracerebral hemorrhage ◼ subarachnoid hemorrhage
I
ntracerebral hemorrhage (ICH) is the most devastating form
of stroke and a major public health problem.1 Despite all preventive efforts, the incidence of ICH among elderly people rises
dramatically.2 An increasing rate of bleeding-prone cerebral
small vessel disorders in the aging population might account
for this phenomenon. Among those, cerebral amyloid angiopathy (CAA)—an up to now untreatable disorder characterized
by deposition of amyloid in cerebral vessels—seems to be most
relevant. CAA was previously considered to be a curiosity,
but—as people grow older—is emerging as a rather common
cerebral small vessel disorders and major cause of spontaneous
ICH.3 The risk of ICH in CAA patients has been related to various factors, such as the extent of associated leukoaraiosis,4 the
number of lobar microbleeds5 (MB), or the number of previous clinical episodes of hemorrhage.6 Cortical superficial siderosis (cSS) has recently been suggested as another indicator
of increased risk for future ICH in this population.7,8 cSS is
characterized by the deposition of blood breakdown products
in the superficial layers of the cerebral cortex and meninges
and seems to be a frequent and characteristic imaging feature
of bleeding-prone CAA.9 In a longitudinal observation of 51
patients with cSS, ≈50% experienced intracranial bleedings
during a period of 35 months.7 A European multicenter study
of 118 CAA patients confirmed that the presence of cSS on
magnetic resonance imaging (MRI) significantly increases the
risk of future symptomatic lobar ICH and suggested cSS as
a useful and independent prognostic marker of intracerebral
bleeding risk in CAA.8 The mechanisms for this close association, however, are not entirely clear.
Nontraumatic convexal subarachnoid hemorrhage (cSAH)
has also been associated with CAA,10–12 and it has been speculated that recurrent intrasulcal bleedings potentially cause
cSS.11 This is supported by experimental data, which showed
that cSS originates from recurrent bleeding into the subarachnoid space13 because blood products from subarachnoid hemorrhage (SAH) penetrate the pia mater and are deposited in
Received January 15, 2015; final revision received March 11, 2015; accepted April 1, 2015.
From the Department of Neurology, Medical University of Graz, Graz, Austria (M.B., C.E., T.G., F.F.); Division of Neuroradiology, Department of
Radiology, Medical University of Graz, Graz, Austria (C.E.); Department of Pathology, Medical University of Graz, Graz, Austria (M.A.); and Department
for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria (G.W.).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
115.008778/-/DC1.
Correspondence to Markus Beitzke, MD, Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, A-8036 Graz, Austria. E-mail
[email protected]
© 2015 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.115.008778
1533
1534 Stroke June 2015
superficial cortical layers. Furthermore, isolated CAA-related
cSAH also seems to indicate poor outcome.12 However,
clinical observations of cSAH or associated lobar ICH are
scarce.10,14
Based on the assumption that CAA-associated cSAH, cSS,
and lobar ICH are intimately related, we therefore wanted
to explore the mechanisms and sequence of events in this
association by performing a careful longitudinal analysis of
clinical and imaging data of a series of consecutive patients
with spontaneous isolated cSAH. This was supported by the
possibility of a close imaging–histopathologic correlation in
one patient.
Subjects and Methods
Selection of Patients
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We retrospectively searched the computed tomography (CT) reports
at an academic primary and tertiary care hospital for all patients
identified with an SAH from October 2004 to March 2014. From all
patients with SAH, we extracted subjects with nontraumatic, nonaneurysmal SAH for a review of the CT scans (Figure 1). According
to own previous work, we defined cSAH by evidence for acute blood
in ≥1 adjacent cortical sulci at the convexity of the brain. Patients
with concomitant evidence of blood in the basal cisterns, interhemispheric or Sylvian fissures, with intracerebral bleedings that might
have ruptured into the subarachnoid space, or with damage to the
brain parenchyma adjacent to the cSAH were excluded.12 We also
excluded patients with cSAH related to recanalization procedures or
subjects who had not undergone MRI at baseline. When our search
method identified multiple cSAHs in a single patient, the first cSAH
was considered the baseline event. The study was approved by the
hospital institutional review board and ethics committee.
Data Collection
We used the medical and nursing documentation and communication
network of Styria (MEDOCS) to collect clinical and neuroimaging
data for a careful longitudinal analysis. MEDOCS is a hospital information system implemented in all 21 public hospitals in the district
of Styria15 with 1 210 971 registered inhabitants in the year 2013 and
450 000 people living in the direct catchment area of the University
Hospital of Graz. MEDOCS provides access to all laboratory, clinical,
and neuroimaging data acquired in the 21 public hospitals. We collected all available information on clinical symptomatology that prompted
the admission of the cSAH patients to hospitals or the initiation of
neuroimaging and extracted from the system all CT and MRI scans
of the brain for a subsequent systematic review. Moreover, we invited
all identified patients for a clinical and MRI follow-up examination.
Neuroimaging Data
MRI of the brain was performed at 1.5 T and included axial fluid–
attenuated inversion recovery, diffusion-weighted imaging, and
gradient echo T2*-weighted sequences (slice thickness 5 mm) for
detection of past bleedings.16,17
A single expert (C. Enzinger), who was blinded to clinical data,
evaluated the baseline MRI scans in a standardized manner, assessed
the exact location and extent of the cSAH, and recorded the presence
of old intraparenchymal hemorrhages (lesion with presumed hemosiderin deposition of >5 mm in diameter), MBs (areas of T2* signal loss
≤5 mm),16,17 and cSS which was defined by linear signal loss along the
cerebral cortex on gradient echo T2*-weighted sequences.9 The presence and number of focal diffusion-weighted imaging abnormalities,
old infarcts/lacunes, and other morphological abnormalities were also
recorded. White matter hyperintensities were rated as absent (score 0),
punctate (score 1), early confluent (score 2), or confluent (score 3).17,18
Images were also assessed for the presence of focal or diffuse brain
swelling and evidence for contrast enhancement. Possible or probable
CAA was defined according to the modified Boston criteria.9
Figure 1. Flow diagram of patient selection,
their neuroimaging findings, and disease
course. CAA indicates cerebral amyloid
angiopathy; cSAH, convexal subarachnoid hemorrhage; and ICH, intracerebral
hemorrhage.
Beitzke et al Course of cSAH 1535
For longitudinal analysis, we retrieved all brain imaging data from
MEDOCS and reviewed them for recurrent acute cSAH, new ICH, or
ischemic infarction. The blinded expert also performed a side-by-side
comparison of the baseline and subsequent scans regarding the overlap
in location of initial abnormalities and subsequent bleeding events.
Repeat MR scans were assessed for evidence of propagation of cSS,
which was defined by the occurrence of new areas with signal loss at
the surface of the cerebral cortex on the T2*-weighted sequence.
Clinical Data
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We reviewed medical records for clinical symptoms at presentation, presence of cerebrovascular risk factors, and demographics.
Hypertension, diabetes mellitus, and dyslipidemia were coded as previously described.12
The clinical information collected regarding neurological symptomatology was reviewed by an experienced stroke neurologist (M.
Beitzke). An acute stroke syndrome was diagnosed if a patient had
typical symptoms that lasted longer than 24 hours. Transient neurological attacks (TNA) were defined as attacks of sudden neurological symptoms that completely resolved within 24 hours. TNAs were
further dichotomized into (1) TNA with transient focal symptoms,
including motor symptoms like weakness or limb shaking, sensory
symptoms, or aphasia and (2) TNA with transient nonfocal symptoms, including sudden onset of confusion, dizziness, or unwell feelings.19 Clinical follow-up was performed in 2 phases (2004–2010 and
2010–2014). The stroke neurologist screened all eligible participants
in person and interviewed the patient or next of kin or their guardians for occurrence of focal or nonfocal TNA by asking for transient
neurological symptoms and carefully registered symptoms and attack
characteristics. Additional clinical information was obtained by contacting family physicians directly or by telephone.
and neuroimaging work-up, including baseline MRI, and
follow-up data were available in 38 cSAH patients (Figure 1).
Demographic, clinical, and MRI characteristics of the patients at
baseline cSAH are detailed in Table. Baseline clinical and imaging data of 18 of these patients have been reported previously.12
Neuroimaging Characteristics at Baseline
Figure 2 shows representative neuroimaging findings from a
68-year-old man.
Of the 38 cSAH patients, 29 (76%) had imaging features of
CAA on the baseline MRI (Figure 1). Ten (26%) had possible
and 19 (50%) had probable CAA. Imaging features of CAA
consisted of past parenchymal bleedings in 18 (47%) and cSS
in 26 (68%) patients. Seven of the 18 patients with old parenchymal bleedings had old ICHs and 16 had cerebral MBs. In
the latter, a total of 486 MBs was found with 431 (89%) of
the MBs located cortico-subcortically. A single patient (under
chronic hemodialysis) had 360 MBs. Of the 26 patients with
cSS, 10 (38%) had cSS in the absence of any evidence of past
intracerebral bleedings (MBs or old ICH).
Table. cSAH Patients’ Characteristics
Characteristic
Values
Demographics
Age, years (range)
Women
70±11 (37–82)
21 (55%)
Medical history
Pathology
Postmortem analyses were performed on one patient within 5 days
from CT scanning that had shown an acute cSAH in one hemisphere
and a lobar ICH without rupture into the subarachnoid space in the
other. At autopsy, the brain was coronally dissected, guided by the
CT images, to target the intrasulcal bleeding and the adjacent cerebral
cortex. Tissue from that area was immediately fixed in 10% neutral
buffered formalin and embedded in paraffin.
10-μm-thick sections of formal-fixed paraffin-embedded brain
tissue were deparaffinized and treated with heat-induced epitope retrieval at 98°C for 40 minutes in water bath, cooled down to room
temperature for 20 minutes, and treated with the blocking solution
S2023 from DAKO. The primary Amyloid P antibody (polyclonal
rabbit antihuman P-Component, Cat. No. A0302; DAKO, Vienna,
Austria) was stained in a dilution of 1:300 for 30 minutes at room
temperature. The antibody reactions were detected with DAKO
K5001 Detection System using AEC Substrate as chromogen. H&E
staining was done on deparaffinized tissue with a progressive Meyer’s
hematoxylin and counterstaining with Eosin Y.
Statistical Analysis
Relevant demographic, clinical, and radiological data were tabulated.
Quantitative data are expressed as mean±SD. The Mann–Whitney U
test was used to compare age between patient groups. The Fisher exact test and Pearson Chi-Square test were used to compare the clinical
and imaging characteristics between patients with and without a new
ICH or a recurrent cSAH. The level of significance was set at P<0.05.
Incidence rates were calculated based on person-years of observation.20 The Statistical Package for the Social Sciences (version 20.0;
SPSS Inc., Chicago, IL) was used for data analysis.
Results
We identified 1178 patients diagnosed with SAH. Two-hundredforty-nine (21%) had nontraumatic, nonaneurysmal SAH and
45 (3.8%) fulfilled the criteria of cSAH. Comprehensive clinical
Hypertension
19 (49%)
Diabetes mellitus
5 (13%)
Dyslipidemia
8 (21%)
Coronary artery disease
4 (10%)
Atrial fibrillation
8 (21%)
Previous symptomatic ICH
4 (10%)
Hemodialysis
1 (2.6%)
Magnetic resonance characteristics
Cortical superficial siderosis
Focal cSS (≤3 sulci)
Disseminated cSS (>3 sulci)
Acute lobar ICH
Acute ischemic lesions
26 (68%)
8 (21%)
18 (47%)
7 (18%)
11 (28%)
Territorial infarcts
3 (8%)
Small cortico-subcortical DWI lesions
8 (21%)
Old ICH
7 (18%)
Old infarcts/lacunes
5 (13%)
White matter hyperintensities
Scores 0 or 1
12 (32%)
Scores 2 or 3
26 (68%)
Presence of microbleeds
16 (42%)
Cortico-subcortical
14 (37%)
Basal ganglia
5 (13%)
Brain stem
5 (13%)
Baseline demographic, clinical and magnetic resonance imaging
characteristics of the 38 cSAH patients. cSAH indicates convexal subarachnoid
hemorrhage; cSS, cortical superficial siderosis; DWI, diffusion-weighted
imaging; and ICH, intracerebral hemorrhage.
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Figure 2. Representative images from a 68-year-old convexal subarachnoid hemorrhage (cSAH) patient presenting with recurrent sensory
transient neurological attacks (TNA): A, Linear hyperdensity within the right precentral sulcus on unenhanced brain computed tomography
(CT; left-handed image) and hyperintensity on fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI; right-handed
image) consistent with acute cSAH. Swelling (arrows) and CT hypodensity of the adjacent brain parenchyma indicating localized edema.
B, Intrasulcal signal loss on gradient echo T2*-weighted MRI (left-handed image) at the site of the acute cSAH (compact arrow) and along
the superficial layers of the cerebral cortex (open arrow) consistent with cortical superficial siderosis (cSS). Linear intrasulcal enhancement at the site of the acute cSAH (arrow) on axial postcontrast T1-weighted MRI (right-handed image), indicating vascular leakage of
multiple small meningeal vessels. C, Sagittal postcontrast T1-weighted MRI (left-handed image) shows that linear enhancement (arrow)
is also present in adjacent cortical sulci of the frontal lobe where acute bleeding was not evidenced, suggestive of more widespread
vascular damage. Note that there is no intrasulcal signal hyperintensity on corresponding precontrast sagittal T1-weighted MRI (image
on the bottom). FLAIR MRI (right-handed image) as a result of persistent TNAs 2 months after the acute cSAH shows intrasulcal signal
hyperintensity (arrows): D, At that point, the corresponding T2*-weighted sequences reveal signal loss (compact arrows), consistent with
repeated intrasulcal bleeding (left-handed image). Note also the propagation of superficial siderosis (open arrow) when compared with
T2*-weighted MRI at baseline (image above B). In addition, axial postcontrast T1-weighted MRI at reevaluation (right-handed image)
reveals intrasulcal enhancement in the sulcus centralis superior at the site of a recurrent cSAH which was not present at baseline (image
above B), indicating disease progression.
Post-contrast MRI was available in 16 patients and showed
linear extravasation of gadolinium at the location of the cSAH
in all of them. Eight (50%) of these patients had more widespread leptomeningeal enhancement, which was not restricted
to the site of the cSAH but occurred also in adjacent cerebral
sulci (Figure 2).
Nineteen cSAHs were located in the right hemisphere, 14
in the left hemisphere, and 5 were bilateral. Convexal SAH
involved 1 sulcus (n=19), 2 to 3 sulci (n=11), or >3 sulci
(n=8). Focal swelling of the cortex in the immediate vicinity
of the intrasulcal bleedings was noted in 34 patients (89%) on
CT and confirmed on MRI in all of those. Five (13%) cSAH
patients had concurrent acute lobar ICH, which was located
in the contralateral hemisphere (n=4) or in the ipsilateral
hemisphere but remote from the cSAH (n=1), and 2 patients
had developed a lobar ICH at the site of the cSAH when the
baseline MRI was performed. Three (8%) patients had territorial ischemic infarcts and 8 (21%) had concurrent small
cortico-subcortical lesions on diffusion-weighted imaging,
which were also remote from the cSAH.
Longitudinal Analysis of Neuroimaging Data
The 38 subjects were followed over a mean period of 24±22
(range 1–78) months (75.5 person-years) during which they
underwent a total of 123 CT and 49 MRI scans of the brain.
New intracranial bleedings, that is, a new ICH or recurrent
cSAH occurred in 19 (50%) of 38 patients. Sixteen (84%)
of them had imaging features of CAA on the baseline MRI,
and all 16 patients had cSS (Table I in the online-only Data
Supplement). Twenty-five patients underwent repeated T2*
MRI for the assessment of cSS propagation.
New ICH
During the observational period, 14 (37%) patients experienced 22 symptomatic intracerebral bleedings. The incidence
rate for a new ICH was 19×100 years−1. Imaging features of
Beitzke et al Course of cSAH 1537
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CAA on baseline MRI had been present in 11 (78%) of those
14 new ICH (ICH+) patients. All subsequent intracerebral
bleedings were lobar, that is, occurred in a cortico-subcortical
location. Seventeen new ICHs were located at sites of previous cSAHs or cSS. In 8 subjects, new ICHs occurred at the
site of a previous cSAH (Figure I in the online-only Data
Supplement). In 4 patients, serial neuroimaging documented
expansion of a primary cSAH into the adjacent brain parenchyma as the cause of intracerebral bleeding (Figure 3). Ten
patients had preexistent cSS at the sites of new lobar ICHs.
Two patients suffered large fatal ICHs at sites where cSAH,
cSS, and MBs had been documented on repeated previous
scans. Five new ICHs had no relation to previous cSAH, cSS,
or MBs.
There were no clinical factors that predicted subsequent
intracerebral bleedings, except arterial hypertension (new
ICH+ versus new ICH−; 10 of 14 versus 9 of 24, P=0.044).
Neuroimaging findings of more advanced cerebral small vessel disorders were associated with new ICH (Table II in the
online-only Data Supplement). There was no significant difference of age between new ICH+ and new ICH− patients.
cSAH was a clinically silent (incidental) imaging finding in 13 subjects. Of those, 3 had territorial ischemic
infarcts and 10 had acute lobar ICH. Recurrent transient
neurological symptoms occurred in 14 (66%) of the 21
patients in whom propagation of cSS was documented on
repeated MRI. Seven patients had propagation of cSS in the
absence of clinical symptoms. Focal TNAs were associated
with both new ICH and recurrent cSAH (new ICH+ versus
new ICH−; 12 of 14 versus 8 of 24, P=0.002 and recurrent
cSAH+ versus recurrent cSAH−; 11 of 15 versus 9 of 23,
P=0.039).
Six patients presented with thunderclap headache, suggestive of a reversible cerebral vasoconstriction syndrome at
the first occurrence of cSAH, and none of them experienced
a recurrent cerebrovascular event during the observational
period.
Recurrent cSAH
Neuroimaging provided evidence of 34 recurrent acute cSAHs
in 15 (39%) of the 38 patients. The incidence rate for recurrent acute cSAH thus was 20×100 years−1. Imaging features of
CAA on the baseline MRI had been present in 14 (93%) of the
15 patients who suffered a recurrent cSAH. Eight (53%) had
several recurrent intrasulcal bleedings. New cSAHs occurred
together with large lobar ICHs in 6 patients. Neuroimaging features of advanced cerebral small vessel disorders were associated with recurrent cSAHs (Table III in the online-only Data
Supplement). There was no association of cerebrovascular risk
factors and recurrent cSAH and no significant difference of age
between recurrent cSAH+ and recurrent cSAH− patients.
Propagation of cSS
Propagation of cSS was noted in 21 of 25 (84%) patients who
underwent repeated T2* MRI (incidence rate for cSS propagation: 28×100 years−1). Six patients had propagation of cSS
at sites of baseline intrasulcal contrast enhancement where
acute bleeding was not seen on baseline MRI. Fourteen (66%)
of 21 patients with cSS propagation had recurrent cSAHs on
repeated imaging. Propagation of cSS was associated with
both recurrent cSAH and new ICH (recurrent cSAH+ versus
recurrent cSAH−, 14 of 14 versus 7 of 11, P=0.014 and new
ICH+ versus new ICH−, 13 of 13 versus 8 of 12, P=0.023).
Subsequent Ischemic Strokes
Three patients suffered territorial infarcts and 7 patients had
small cortico-subcortical diffusion-weighted imaging lesions
(incidence rate for ischemic events: 13×100 years−1).
Clinical Symptoms
The most frequent clinical presentation of cSAH were TNAs
(26 [68%] of the 38 patients; Table I in the online-only Data
Supplement). Repeated stereotyped transient symptoms were
recorded in 18 (47%) patients. TNA with transient focal
symptoms occurred in 20 and TNA with transient nonfocal
symptoms in 6 patients.
Figure 3. Expansion of cSAH. Serial images from a 67-year-old
male. A, Initial unenhanced CT shows a subarachnoid bleeding in the right central sulcus. B, Unenhanced CT only 15 hours
later because of neurological deterioration shows expansion
of the hematoma from the subarachnoid space to the adjacent
brain parenchyma (left-handed image). Magnetic resonance
imaging (MRI) at gradient T2* sequences on day 7 illustrates
the extended ICH (right-handed image). C, 12 months later,
gradient T2* MRI reveals distinct cSS (open arrow), whereas the
residual parenchymal defect (compact arrow) is relatively small
(left-handed image). A small number of cerebral microbleeds
(compact arrows) in cortico-subcortical location and cSS (open
arrows) suggestive of CAA are also evidenced (right-handed
image). CAA indicates cerebral amyloid angiopathy; cSAH, convexal subarachnoid hemorrhage; cSS, cortical superficial siderosis; and ICH, intracerebral hemorrhage.
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Figure 4. Pathological substrates of imaging findings. A, Unenhanced brain computed tomography (CT) of a 71-year-old patient with acute
cSAH in the right central sulcus (arrow) shows focal swelling, signal hypointensity of the adjacent parenchyma, and a large concomitant
lobar ICH in the contralateral hemisphere. Inspection of the coronally dissected brain reveals focal swelling of the cerebral cortex in close
vicinity to the central sulcus (open arrows). Note also the singular small subcortical parenchymal bleed (compact arrow). B, H&E stains
(original magnification 200×) revealed irregular hyalinosis of small arteries in the arachnoidea and corresponding edema (area between
arrows) indicative of distinct vessel-leakage. C, Immunostaining (original magnification 50×) confirms amyloid deposition in meningeal and
small cortical vessels. D, Pronounced leakage of a cortical artery with extravasation of erythrocytes (original magnification 100×).
Pathological Evaluation
Histopathologic analyses were performed on postmortem
brain samples in a 71-year-old woman who had been admitted with a large lobar ICH in the left hemisphere and an acute
concurrent cSAH in the right central sulcus. On day 4, she
had developed several episodes of limb shaking of the left
arm. On day 5, she finally died of treatment-resistant cardiac
arrhythmia.
Macropathological inspection of the coronally dissected
brain revealed focal edematous swelling of the cerebral cortex
in close vicinity to the right central sulcus (Figure 4).
Histopathologic evaluation of this region by H&E stains
showed irregular hyalinosis of blood vessels in the arachnoidea. Perivasal and diffuse edema, indicative of distinct
vessel-leakage, was pronounced adjacent to the arachnoidea.
Extravasation of erythrocytes illustrative of vessel leakage
was also noted in the cerebral cortex adjacent to the cSAH.
Immunostaining revealed deposition of amyloid in the wall
of several small leptomeningeal vessels but only in a small
amount of cortical vessels (Figure 4).
Discussion
This clinical study confirms the findings of previous work
on hemorrhagic events in CAA and extends them in several
directions. This encompasses (1) frequent recurrence of CAArelated cSAH, which was associated with a substantial risk for
future symptomatic ICH, (2) widespread leakage of meningeal vessels in association with intrasulcal bleedings, which
appeared to add to the propagation of cSS, and (3) direct
development of lobar ICH from or in extension of cSAH.
Experimental data indicate that repeated bleeding into the
subarachnoid space causes cSS.13 However, clinical observations of recurrent cSAH as the cause of cSS propagation are
scarce.11 We observed repeated cSAH in 39% of our patients,
and 66% of those with cSS propagation had repeatedly experienced a cSAH. At MRI follow-up, cSS often extended to
sites without actual intrasulcal bleeding, but where leakage
of contrast material had been present at baseline imaging. We
cannot determine whether this indicates that already minimal
seepage of erythrocytes suffices to cause cSS or whether small
intrasulcal bleedings had developed later at these sites. It is
quite obvious from our observations, however, that (recurrent) cSAHs may easily escape detection because they may
be clinically silent or cause only subtle symptoms which are
noncharacteristic for intracranial bleedings, including focal
or nonfocal TNA. The observation that TNAs associated with
cSS often occur repeatedly over limited time periods is in
line with these considerations.21 Furthermore, CT scanning
will also miss the detection of smaller cSAHs because they
become isodense after a few days.
Cortical SS has been reported to indicate an increased risk
for future symptomatic ICH.7,8 We also found that cSS on the
baseline MRI was present in 84% of patients with acute cSAH
who suffered subsequent bleedings. On the other hand, subsequent hemorrhage was infrequent when baseline MRI showed
no preexisting cSS. The sequence of events and mechanisms
underlying the association between cSS and future ICH, however, are not yet fully clear8,22 and several scenarios seem possible. cSS and ICH may occur as independent phenomena
from increased fragility of cerebral small vessels. ICH itself
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may cause meningeal hemosiderosis by ruptures into the subarachnoid space. We here suggest a further possibility, that
is, the development of ICH directly from or in extension of
initially subarachnoid or cortical bleeding. In our series, we
captured 4 patients with hematomas that expanded from an
acute intrasulcal bleeding into the parenchyma. We assume
that such evolution may have escaped previous investigations
because it will only become apparent with rapid imaging of
patients in the early phase of the disease, that is, before the
hematoma has developed. In this context, the variable and
often nonspecific clinical presentations of cSAH pose a particular problem. Our observation is also supported by some
autopsy data, which suggest that bleedings in patients with
sporadic type of CAA often occur first in the cerebral sulci
and only subsequently expand into the brain parenchyma.23
Hematoma expansion from cSAH into the brain parenchyma
may thus be an under-recognized mechanism of lobar ICH
development in CAA.
We found linear contrast enhancement at the site of intrasulcal bleeding and observed that subsequent hematoma expansion developed primarily along the involved cerebral sulci.
This could suggest contrast enhancement in the subarachnoid
space to indicate a local clustering of multiple small diseased
meningeal vessels. Such fragile vessels in the subarachnoid
space would also seem susceptible to secondary shearing
injury and rupture as the hematoma expands in a local cascade. Such process based on secondary shearing of blood
vessels surrounding an ICH has been demonstrated in a neuropathological study,24 and also clustering of diseased vessels
in CAA has been suggested previously.25 Presence of a generally increased vulnerability of the cerebral microvasculature is
also supported by the rather frequent co-occurrence of remote
small cortico-subcortical ischemic lesions. However, we certainly cannot exclude that some ICH in our series have arisen
independent of all these mechanisms.
The conclusions from our neuroimaging observations are
supported and extended by the histopathologic findings in a
71-year-old woman. We found moderate to severe CAA in
several leptomeningeal vessels and evidence of distinctive
meningeal vessel leakage at the site of acute cSAH. Signs of
vascular leakage were also seen in the swollen cerebral cortex adjacent to the acute cSAH, albeit immunostaining did
not identify a large amount of CAA-diseased cortical vessels.
We can thus only speculate on the pathomechanisms causing
the focal cortical swelling in the immediate vicinity of acute
cSAHs observed in the vast majority of our patients. These
include vessel dysfunction related directly to the presence of
β-Amyloid in cortical vessels,26,27 vessel dysfunction caused
by CAA-related inflammation,28 or vascular leakage caused
by clusters of cortical spreading depression.29
There are several limitations to our study which come
from single center observation, retrospective subject identification, nonstandard follow-up, and the limited sample size.
The results should therefore be viewed with some caution
and certainly cannot be transferred to patients with CAA in
general. Focussing on leptomeningeal bleeding may indeed
identify a subset of subjects within the broad spectrum of
imaging manifestations of CAA. We also lacked statistical power to identify predictors of CAA-related ICH in a
multifactorial manner. Larger multicentre prospective studies
will thus be needed to confirm our results and clarify the role
of CAA-related cSAH in predicting future ICH among other
types of associated morphological damage. Despite these
limitations, our study provides first evidence that in CAA,
leakage of locally clustered, diseased, or at least affected
meningeal blood vessels in the subarachnoid space causes
intrasulcal hemorrhage. Several such bleedings promote the
propagation of CAA-related cSS. Moreover, our results raise
awareness of cSAH as a sign of active and probably more
widespread meningeal disease in CAA that is prone to major
lobar hemorrhage, which may develop directly from or in
extension of cSAH.
Disclosures
None.
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Contribution of Convexal Subarachnoid Hemorrhage to Disease Progression in Cerebral
Amyloid Angiopathy
Markus Beitzke, Christian Enzinger, Gerit Wünsch, Martin Asslaber, Thomas Gattringer and
Franz Fazekas
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
Stroke. 2015;46:1533-1540; originally published online May 7, 2015;
doi: 10.1161/STROKEAHA.115.008778
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http://stroke.ahajournals.org/content/suppl/2016/04/04/STROKEAHA.115.008778.DC2
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1
SUPPLEMENTARY MATERIAL
2
Supplemental Table I. Clinical symptoms and magnetic resonance imaging characteristics in each of the 38 cSAH patients at baseline and
at reevaluation
Patient
Nr./
age/
sex
Baseline
Course of disease
Magnetic resonance imaging
Clinical symptoms
Old ICH (n) /
MB (n)
cSS
Acute
ICH/Stroke
MB (2)
focal
1/65/m
Repeated fTNA
2/37/m
Stroke syndrome,
thunderclap headache
Moderate headache
0
0
Small diffusion
lesion
stroke
0
focal
0
fTNA, thunderclap
headache
Repeated fTNA
0
0
0
MB (10)
disseminated
0
0
0
0
0
0
Small diffusion
lesion
3/80/m
4/37/f
5/82/f
6/54/m
7/78/f
nfTNA
Repeated fTNA, moderate
headache
8/68/f
fTNA
Old ICH (2) and
MB (26)
disseminated
0
9/77/f
10/63/f
11/78/f
12/77/m
Stroke syndrome
fTNA, moderate headache
Thunderclap headache
Repeated fTNA
MB (1)
0
0
Old ICH (3) and
MB (1)
0
0
0
disseminated
stroke
ICH
0
0
13/80/m
Repeated fTNA
disseminated
0
14/65/m
Generalized seizure
Old ICH (4) and
MB (23)
Old ICH (1) and
MB (4)
disseminated
0
15/76/f
16/82/m
17/69/m
Generalized seizure
Generalized seizure
Stroke syndrome,
repeated fTNA
MB (13)
0
Old ICH (1) and
MB (1)
0
disseminated
disseminated
0
0
ICH
Clinical symptoms and imaging
Repeated fTNA revealing acute cSAH at 4 months, small cortical stroke at 33 months with cSS
propagation on MRI, cardiac death at 43 months
Clinically uneventful, no recurrent cerebrovascular events on repeated MRI during 78 months
nfTNA revealing recurrent cSAH during the early course of disease, stroke syndrome revealing a
major ischemic stroke at 1 month, sudden death at 36 months
Clinically uneventful, no recurrent cerebrovascular events on repeated MRI during 58 months
Stroke syndrome revealing a large occipital ICH with concurrent acute cSAH and cSS
propagation at 57 months
Stroke syndrome revealing an ischemic stroke at 51 months
Recurrent cSAH during early course of disease, transient focal symptoms revealing small
ischemic cortico-subcortical infarcts and cSS propagation at 27 months, stroke syndrome
revealing a large (fatal) right frontal ICH and remote concurrent cSAH at 55 months
Stroke syndrome revealing a right frontal ICH at 66 months, cSS propagation, confusion and
headache revealing recurrent cSAH and subsequent ICH at 73 months, recurrent cSAH followed
by a large (fatal) ICH at 74 months.
Stroke syndrome revealing a major (fatal) ischemic stroke at 4 months
Clinically uneventful during 43 months, cSS propagation on MRI at 4 months
Uneventful at 4 months, refused further reevaluation
Transient focal symptoms revealing small ischemic cortico-subcortical infarcts at 3 weeks,
fTNA and headache revealing multiple recurrent cSAHs at 2 months, right frontal ICH at 41
months, propagation of cSS
Slowly progressive neurological and cognitive decline but no recurrent bleeding events on
repeated imaging during 48 months
Repeated seizure at 2 and fTNA at 4 months revealing recurrent cSAHs on imaging, stroke
syndrome revealing a right frontal ICH with concurrent left cSAH at 27 months, cSS propagation
on MRI
Stroke syndrome revealing a major right frontal ICH at 23 months, cSS propagation
No recurrent cerebrovascular events, cardiac death at 28 months
Stroke syndrome revealing Ischemic stroke at 2 months, major left frontal ICH with concurrent
right cSAH at 4 months, cSS propagation, large (fatal) left fronto-pariental ICH at 7 months
3
Supplemental Table I (continued). Clinical symptoms and magnetic resonance imaging characteristics in each of the 38 cSAH patients at
baseline and at reevaluation
Patient
Nr./
age/
sex
Clinical symptoms
18/78/m
Baseline
Course of disease
Magnetic resonance imaging
Old ICH (n) /
MB (n)
cSS
Acute
ICH/Stroke
Repeated fTNA
MB (22)
disseminated
19/64/m
Stroke syndrome
MB (9)
focal
Small diffusion
lesion
ICH
20/73/m
Repeated fTNA
MB (2)
disseminated
0
21/79/m
Repeated fTNA
0
disseminated
22/78/f
23/55/f
MB (360)
0
focal
0
24/70/m
25/82/f
26/79/m
27/64/f
28/66/f
29/77/f
30/60/f
31/76/f
Generalized seizure
nfTNA, thunderclap
headache
Stroke syndrome
Repeated fTNA
Stroke syndrome
Thunderclap headache
Thunderclap headache
Repeated fTNA
Moderate headache
Repeated fTNA
Old ICH (1)
0
0
0
0
MB (9)
0
MB (2)
focal
focal
focal
0
0
disseminated
focal
disseminated
Small diffusion
lesion
0
Small diffusion
lesion
ICH
0
stroke
0
0
ICH
0
0
32/82/f
33/77/f
34/81/m
nfTNA
Stroke syndrome
Repeated fTNA
MB (1)
0
0
disseminated
disseminated
disseminated
35/72/f
36/65/f
37/68/m
Moderate headache
Repeated fTNA
Repeated fTNA
Old ICH (6)
0
0
disseminated
disseminated
disseminated
38/78/f
fTNA
0
0
0
ICH
Small diffusion
lesion
0
ICH
Small diffusion
lesion
Small diffusion
lesion
Clinical symptoms and imaging
Recurrent fTNA at 2 months, Stroke syndrome revealing major left frontal ICH with multiple
concurrent cSAHs at the convexity of the right hemisphere at 36 months, cSS propagation
Stroke syndrome revealing a major lobar ICH at 28 and at 30 months, Stroke syndrome revealing
small ischemic cortico-subcortical infarcts at 29months , cSS propagation. nfTNA revealing
recurrent cSAH at 34 months
Stroke syndrome revealing a large (fatal) right frontal ICH with concurrent left cSAH at 20
months, cSS propagation
Stroke syndrome revealing a large right frontal ICH at 28 months, recurrent right frontal ICH
at 30 months, cSS propagation
Stroke syndrome revealing a major ischemic stroke at 5 months, cSS propagation on MRI
Uneventful at 9 months
nfTNA revealing recurrent cSAH at 9 months, cSS propagation
Uneventful at 11 months
Sudden death at 13 months
Uneventful at 5 months
Uneventful at 13 months
Stroke syndrome revealing ICH in the early course of disease, uneventful at 4 months
Uneventful at 7 months, cSS propagation
fTNA revealing recurrent cSAH at 7 months, stroke syndrome revealing a major lobar ICH at 8
months, recurrent cSAH with two subsequent ICHs at 9 months, cSS propagation
nfTNA revealing recurrent cSAH at 4 months, cSS propagation
Uneventful at 5 months
Uneventful at 5 months
Uneventful at 3 months
Uneventful at 3 months, cSS propagation
Repeated fTNA revealing recurrent cSAH at 3 months, cSS propagation
Stroke syndrome revealing a right frontal ICH at 1 month, cSS propagation
Supplemental Table I. cSAH indicates convexal subarachnoid hemorrhage; ICH, intracerebral hemorrhage; MB, cerebral microbleeds; cSS, cortical
superficial siderosis; fTNA, focal transient neurological attack; nfTNA, non-focal transient neurological attack.
4
Supplemental Figure I: Course of cSAH
5
Figure Legend. Supplemental Figure I.
Course of cSAH. Serial images from a 68-year old patient with repeated hemorrhagic events
following an acute convexal subarachnoid hemorrhage (cSAH) in the right central sulcus.
(A) T2*-weighted MRI (left-handed image) at baseline cSAH (not shown) reveals multiple
cortical bleedings and widespread right hemispheric cortical superficial siderosis (cSS). Sixtysix months later T2* MRI (right-handed image) due to sudden onset of confusion and leftsided hemiparesis shows a right frontal intracerebral hemorrhage (compact arrow) and
pronounced propagation of cSS (open arrows) not related to parenchymal hemorrhage.
Clinical symptoms in the interval were not noted by this patient. (B) 73 months from baseline
cSAH unenhanced brain CT due to confusion shows a recurrent small acute cSAH (arrow) in
the left sulcus temporalis inferior (left-handed image). Only 24 hours later brain CT shows an
intracerebral hemorrhage at the site of the new cSAH (arrow). At that point CCT also reveals
several small bleedings in cortical sulci (arrows) of both hemispheres (right-handed images).
(C) Routine MRI performed 14 days later (left-handed image) depicts linear high signal
intensity on the FLAIR sequence in the right sulcus intraparietalis (arrow) with signal loss on
corresponding gradient echo T2*-weighted MRI (not shown) consistent with another small
acute cSAH, which had been clinically silent. Only a few days later the patient was admitted
to the local neurology department. Brain CT at that point (right-handed image) reveals a space
occupying finally fatal intracerebral hemorrhage.
6
Supplemental Table II: Association of baseline magnetic resonance imaging
characteristics and new ICH in patients with cSAH
All cSAH
cSAH patients
cSAH without
patients
with new ICH
new ICH
n=38 (%)
n=14 (%)
n=24 (%)
Cortical superficial siderosis
26 (68)
11 (78)
15 (62)
P=0.3
Focal cSS (≤3 sulci)
8 (21)
1 (7)
7 (29)
P=0.1
Disseminated cSS (> 3Sulci)
18 (47)
10 (71)
8 (33)
P=0.023
Acute lobar ICH
7 (18)
3 (21)
4 (17)
P=0.71
Acute DWI abnormalities
11 (28)
4 (28)
7 (29)
P=0.97
Old ICH
7 (18)
4 (28)
3 (12)
P=0.22
Old infarcts/lacunes
5 (13)
2 (14)
3 (12)
P=1
White Matter Hyperintensities score 2-3
26 (68)
14 (100)
12 (50)
P=0.001
Presence of Microbleeds
16 (42)
11 (78)
5 (21)
P=0.001
Neuroimaging characteristic
P value
Supplemental Table II. ICH indicates, intracerebral hemorrhage; cSAH, convexal
subarachnoid hemorrhage; cSS, cortical superficial siderosis; DWI, diffusion weighted
imaging.
7
Supplemental Table III: Association of baseline magnetic resonance imaging
characteristics and repeated cSAH
All cSAH
Patients with
Patients without
patients
recurrent cSAH
recurrent cSAH
n=38 (%)
n=15 (%)
n=23 (%)
Cortical superficial siderosis
26 (68)
14 (93)
12 (52)
P=0.008
Focal cSS (≤3 sulci)
8 (21)
4 (27)
4 (17)
P=0.49
Disseminated cSS (> 3Sulci)
18 (47)
10 (67)
8 (35)
P=0.054
Acute lobar ICH
7 (18)
3 (20)
4 (17)
P=0.84
Acute DWI abnormalities
11 (28)
3 (20)
8 (35)
P=0.33
Old ICH
7 (18)
5 (33)
2 (9)
P=0.055
Old infarcts/lacunes
5 (13)
2 (13)
3 (13)
P=1
White Matter Hyperintensities score 2-3
26 (68)
14 (93)
12 (52)
P=0.008
Presence of Microbleeds
16 (42)
11 (73)
5 (22)
P=0.002
Neuroimaging characteristic
P value
Supplemental Table III. cSAH indicates convexal subarachnoid hemorrhage; cSS, cortical
superficial siderosis; ICH, intracerebral hemorrhage; DWI, diffusion weighted imaging.
24
Stroke 日本語版 Vol. 10, No. 3
Abstract
脳アミロイド血管症の増悪における円蓋部くも膜下出血の関与
Contribution of Convexal Subarachnoid Hemorrhage to Disease Progression in Cerebral
Amyloid Angiopathy
Markus Beitzke, MD1; Christian Enzinger, MD1,2; Gerit Wünsch, DSc3, et al.
1
Department of Neurology; 2Division of Neuroradiology, Department of Radiology; and 3Department for Medical Informatics, Statistics and
Documentation, Medical University of Graz, Graz, Austria.
背景および目的：脳アミロイド血管症に関連した皮質表在
性鉄沈着（ cSS ）は，その後の脳内出血（ ICH ）のリスク増
加を示唆すると考えられている。本研究では，この関連性
の原因となる出血性イベントのメカニズムと順序の特定を
目的とした。
方 法：9 年 間 に わ た っ て 非 外 傷 性 円 蓋 部 く も 膜 下 出 血
（ cSAH ）患者を特定し，臨床データおよび脳神経画像検査
データの詳細な縦断的解析を行った。1 例の患者で画像検
査と病理組織学的所見の相関を綿密に調べた。
結果： cSAH 患者 38 例（ 平均年齢 77 ± 11 歳 ）のうち 29
例（ 76% ）に，調査開始時の磁気共鳴断層撮影（ MRI ）で脳
アミロイド血管症の画像的特徴があることが明らかになっ
た。cSS は 26 例（ 68% ）に認められた。16 例に造影 MRI
を施行した。全ての造影画像において，急性 cSAH 部に
ガドリニウム漏出がみられた。平均 24 ± 22 カ月（ 範囲：
1 ∼ 78 カ月 ）の追跡調査後，15 例（ 39% ）が cSAH を再発
し，14 例（ 37% ）が脳葉性 ICH を発症した。新規に発症し
た 22 件の ICH 中 17 件が，以前の cSAH もしくは cSS の
部位に生じた。繰り返し脳神経画像検査を行ったところ，
4 例で cSAH が脳実質内へ拡大し，
脳葉性 ICH が発症した。
21 例（ 55% ）で cSS の拡大がみられたが，そのうち 14 例
で cSAH が再発していた。剖検例では，脳アミロイド血
管症による髄膜の血管の漏出が明らかになった。
結論： 脳アミロイド血管症では，脳溝内出血再発の主な
原因は髄膜血管の漏出であると考えられ，これによって
cSS が進行し，この部位において、その後の ICH に対す
る脆弱性が増加することが示唆される。ICH はまた，直接
cSAH から，もしくは cSAH が拡大することで生じる可能
性がある。
Stroke 2015; 46: 1533-1540. DOI: 10.1161/STROKEAHA.115.008778.
画像に対応する病理学的所見。A：71 歳の急性 cSAH 患者の単純 CT 画像。右側中心溝の急性 cSAH（ 矢印 ）では，病巣部の腫脹，
隣接する脳実質の低信号がみられ，対側の大脳半球では同時に生じた大きな脳葉性 ICH を認める。脳の冠状断面では，近傍から中心
溝まで大脳皮質の病巣部の腫脹が認められる（ 白抜きの矢印 ）。皮質下の実質領域における小さな出血点にも注目（ 黒枠の矢印 ）。B：
図 4 H&E 染色（ 原寸の 200 倍 ）により，くも膜下の小血管に不規則な硝子変性と対応する浮腫（ 矢頭に挟まれた部位 ）を認め，顕著な血
管の漏出があることを示している。C：免疫染色（原寸の 50 倍）により，髄膜の血管と皮質の小血管にアミロイド沈着が確認された。
D：赤血球の溢出を伴う皮質動脈の顕著な漏出（原寸の100 倍）
。
iris
main.indd 24
28-Sep-15 11:42:59