Title Preemptive medicine for cerebral aneurysms Author(s)

18 Pages·2017·1.13 MB·English

TITLE:
Preemptive medicine for cerebral
aneurysms
AUTHOR(S):
AOKI, Tomohiro; NOZAKI, Kazuhiko
CITATION:
AOKI, Tomohiro ...[et al]. Preemptive medicine for cerebral aneurysms.
Neurologia Medico-Chirurgica 2016, 56(9): 552-568
ISSUE DATE:
2016-09
URL:
http://hdl.handle.net/2433/226828
RIGHT:
This article is applied Creative Commons Attribution Non-Commercial-
NoDerivs License (CC BY-NC-ND) by the publisher.
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Special Topic doi: 10.2176/nmc.st.2016-0063
Neurol Med Chir (Tokyo) 56, 552–568, 2016 online April 6, 2016
Preemptive Medicine for Cerebral Aneurysms
Tomohiro Aoki1 and kazuhiko NozAki2
1Innovation Center for Immunoregulation Technologies and Drugs,
Kyoto University Graduate School of Medicine, Sakyo, Kyoto;
2Department of Neurosurgery, Shiga University of Medical Science, Otsu, Shiga
Abstract
Most of cerebral aneurysms (CAs) are incidentally discovered without any neurological symptoms
and the risk of rupture of CAs is relatively higher in Japanese population. The goal of treatments for
patients with CAs is complete exclusion of the aneurysmal rupture risk for their lives. Since two cur-
rently available major treatments, microsurgical clipping and endovascular coiling, have inherent
incompleteness to achieve cure of CAs with some considerable treatment risks, and there is no effec-
tive surgical or medical intervention to inhibit the formation of CAs in patients with ruptured and
unruptured CAs, new treatment strategies with lower risk and higher efficacy should be developed to
prevent the formation, growth, and rupture of CAs. Preemptive medicine for CAs should be designed
to prevent or delay the onset of symptoms from CAs found in an asymptomatic state or inhibit the de
novo formation of CAs, but we have no definite methods to distinguish rupture-prone aneurysms from
rupture-resistant ones. Recent advancements in the research of CAs have provided us with some clues,
and one of the new treatment strategies for CAs will be developed based on the findings that several
inflammatory pathways may be involved in the formation, growth, and rupture of CAs. Preemptive
medicine for CAs will be established with specific biomarkers and imaging modalities which can sen-
sor the development of CAs.
key words: cerebral aneurysm, prevention, pathogenesis, preemptive medicine
Introduction number of surgically treated patients has been
increasing. intriguingly, the risk of rupture of CAs
Cerebral aneurysms (CAs) is a common disease in is relatively higher in Japanese and Finnish popula-
general public with prevalence between 1% and tion than other peoples,2) making the treatment of
5%,1) and subarachnoid hemorrhage (SAH) mostly CAs important especially in our country.
caused by rupture of CAs is still a serious disease Preemptive medicine is a new idea of inter-
and a relevant health problem in the middle- and ventional therapy to prevent or delay the onset
old-aged populations. Although clinical outcomes of diseases with predictive and precise diagnosis
in patients with ruptured CAs have improved in and adequate treatments on people who are in an
recent advances of microsurgical and endovascular asymptomatic state in which clinical symptoms or
techniques and intensive care and management, severe tissue damages have not occurred or who are
nearly half of cases suffer from severe morbidity free from diseases (Fig. 1). Therefore, the treatment
and mortality. Most of the CAs are incidentally to achieve preemptive medicine should be based
discovered without any neurological symptoms on pathogenesis and triggering/promoting mecha-
through imaging studies such as magnetic resonance nisms of diseases considering disease-related risks,
imaging (MRi) and indication of surgical interven- and its goal is to maintain health and to prevent
tion to unruptured CAs are still a matter of debate onset or progression of the disease by focusing on
considering several factors including each patient’s not only individual but also community health. To
background, nature of the lesion, and risk of surgical date, there is no non-surgical treatment available
intervention. in Japan, because of widespread brain for cerebral aneurysmal growth and rupture except
dock, many unruptured CAs are detected and the control of systemic blood pressure and cessation
of smoking, and therefore microsurgical clipping
Received February 24, 2016; Accepted March 4, 2016 and endovascular coiling are performed to prevent
552 Neurol Med Chir (Tokyo) 56, September, 2016
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Preemptive Medicine for CAs 553
according to the risk of rupture and growth. The
size of unruptured CAs is a strong risk of rupture,4)
and effective interventions to reduce rupture risk
by controlling growth and rupture of unruptured
CAs are to be developed.
There are modifiable and non-modifiable risk factors
for CAs.1,5,6) These factors can affect the formation,
growth (morphological changes), and rupture of
CAs. in modifiable risk factors, smoking appears
to increase the risk in the formation of CA, and
also is an independent and important risk factor
for SAH. Although the effectiveness of antihyper-
tensive medication in prevention is not proven yet,
Fig. 1 Idea of preemptive medicine adequate control of systemic blood pressure seems to
exert against aneurysmal rupture because untreated
hypertension is seen frequently in patients with
first and repeated rupture and resultant SAH. Avail- ruptured aneurysms. Excessive alcohol use may
able and apparently effective preventive therapy also be a risk factor for aneurysm development and
for CAs is surgical intervention for unruptured rupture. other possible factors for growth include
lesions to reduce the risk of first rupture and for female sex, younger age, aneurysm location, multi-
ruptured lesions to reduce the risk of re-rupture, plicity of aneurysms, specific genetic background;
and preemptive medicine for CAs has not been family history of SAH, specific disorders such as
put in practice and its development depends polycystic kidney disease, type iV Ehlers-Danlos
on future advancements in cerebral aneurysmal syndrome, Marfan syndrome, coarctation of the
research. Thereby, considering the relatively small aorta, pseudoxanthoma elasticum, hereditary hemor-
number of rupture events among unruptured cases, rhagic telangiectasia, and neurofibromatosis type
the intrinsic risk of complication in any surgical 1. other risk factors for SAH include age (greater
intervention, the loss of social productivity due to than 70 years old), female sex, race (particularly
SAH after rupture of CAs, and high prevalence of Japanese and Finnish), size/location/ shape of the
CAs in adult population, a new treatment options CA, previous history of SAH, family history of SAH,
with lower risk and higher efficacy should be and familial aneurysms (at least one first-degree
developed to prevent the formation, growth, and family member with CA). The risk estimation and
rupture of CAs. stratification of unruptured CAs considering each
The objective of this article is to overview the patient’s risk factors is useful to individualize CA
current standards in the management of CAs and managements. Prospective studies to assess the
to discuss the possible interventions in the future effectiveness of intervention by dealing with risk
including preemptive medicine considering current factors are needed either on general population or
progress in basic and clinical research. high-risk population basis to evaluate the burden
of modifiable risk factor.
Risk Factors
Risk factors for aneurysm development, growth,
Annual incidence of SAH is 5–20 per 100,000 and rupture: recommendations
people, and the number is higher in Japan and 1. Given that smoking appears to increase the risk
Finland as compared with other countries. The of unruptured intracranial aneurysm (UiA) formation,
estimated prevalence of unruptured CAs in a patients with UiA should be counseled regarding
healthy population with a mean age of 50 years the importance of smoking cessation (Class i; Level
old is calculated to be 3.2% with higher prevalence of Evidence B).
in women and an increased prevalence with age,1) 2. Given that hypertension may play a role in
and almost 30% of all unruptured CAs in people growth and rupture of intracranial aneurysms (iAs),
of working age seem to rupture during a lifelong patients with UiA should monitor blood pressure
follow-up.3) Because all detected unruptured CAs and undergo treatment for hypertension (Class i;
do not necessarily rupture during their lives and Level of Evidence B).
SAH may occur from aneurysms which are not 3. Aneurysmal growth may increase the risk of
detected, unruptured CAs should be stratified rupture, and intermittent imaging studies to follow
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554 T. Aoki et al.
those UiAs managed conservatively should be with CA.8) New diagnostic modalities for preemptive
considered (Class i; Level of Evidence B). medicine should be aimed to identify “dangerous”
(Guidelines for the Management of Patients with CAs with new imaging techniques or specific
Unruptured intracranial Aneurysms : A Guideline for biomarkers.
Healthcare Professionals From the American Heart
Association/American Stroke Association, 2015). I. Diagnosing/imaging: recommendations
1. DSA can be useful compared with non-invasive
Diagnosis imaging for identification and evaluation of CAs if
surgical or endovascular treatment is being consid-
imaging studies for CAs have developed and refined ered (Class iia; Level of Evidence B).
with advancements in magnetic resonance angiog- 2. DSA is reasonable as the most sensitive imaging
raphy (MRA), three-dimensional (3D) computed for follow-up of treated aneurysms (Class iia; Level
tomography angiography (CTA), and digital subtrac- of Evidence C).
tion angiography (DSA). Each modality has been 3. CTA and MRA are useful for the detection and
adapted in different purposes such as initial follow-up of UiA (Class i; Level of Evidence B).
screening imaging, pre-interventional surgical view, 4. it is reasonable to perform MRA as an alterna-
and follow-up imaging. MRA is usually used for tive for follow-up for treated aneurysms, with DSA
screening in patients with no or minimal symptoms, used as necessary when deciding on therapy (Class
and 3D-CTA is used to assess pre-interventional iia; Level of Evidence C).
precise assessment of surgical anatomy of the 5. Coiled aneurysms, especially those with wider
aneurysm and surrounding vessels. DSA, a rather neck or dome diameters or those that have residual
invasive examination, is also performed as pre- and filling, should have follow-up evaluation (Class i;
post-interventional assessment of the treatment to Level of Evidence B). The timing and duration of
obtain not only arterial but also venous informa- follow-up is uncertain, and additional investigation
tion, but further improvement of CTA and MRA is necessary.
technology may reduce the necessity of DSA in 6. The importance of surveillance imaging after
the management of CAs. Although MRi seems to endovascular treatment of UiAs lacking high-risk
be a good tool in the follow-up of endovascular- features for recurrence remains unclear, but surveil-
treated aneurysms, it is not suitable for clipped lance imaging is probably indicated (Class iia; Level
aneurysms. in the future, specific anatomical or of Evidence C).
biological features of the aneurysm should be evalu-
ated to properly estimate the risk of each aneurysm II. Screening: recommendations
and select appropriate management. Subarachnoid 1. Patients with ≥ 2 family members with iA or
blood is detected in computed tomography (CT) SAH should be offered aneurysmal screening by
in the early phase after SAH, but the sensitivity CTA or MRA. Risk factors that predict a particularly
decreases with time after the onset of SAH. Fluid- high risk of aneurysm occurrence in such families
attenuated inversion recovery (FLAiR) magnetic include history of hypertension, smoking, and female
resonance (MR) seems to be comparable with CT sex (Class i; Level of Evidence B).
in the acute phase of SAH and superior to CT in 2. Patients with a history of autosomal dominant
a few weeks following SAH. polycystic kidney disease, particularly those with
Morphological risk factors for growth or rupture a family history of iA, should be offered screening
of CAs are size/location/shape of the CA.1–6) However, by CTA or MRA (Class i; Level of Evidence B), and
there is no specific diagnostic tool to assess the it is reasonable to offer CTA or MRA to patients
nature of being prone to rupture. Recently, vascular with coarctation of the aorta and patients with
wall imaging has been developed in high magnetic microcephalic osteodysplastic primordial dwarfism
field MR using high resolution sequences. identifica- (Class iia; Level of Evidence B).
tion of the rupture site in patients with multiple (Guidelines for the Management of Patients with
CAs has been demonstrated using T -weighted black Unruptured intracranial Aneurysms : A Guideline for
1
blood vessel wall sequence (turbo spin echo acqui- Healthcare Professionals From the American Heart
sition) before and after intravenous administration Association/American Stroke Association, 2015).
of contrast agent, gadolinium.7) Nagahata et al. also
reported that rupture site could be detected in high Treatment Modalities
specificity and sensitivity using the 3D turbo spin
echo sequence with motion-sensitized driven equi- Microsurgical clipping introduced by Walter Dany
librium imaging after gadolinium injection in patients in 1937 excludes aneurysmal sac from the parent
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Preemptive Medicine for CAs 555
artery and blocks blood flow into the lesion. The international Study of Unruptured intracranial
improvements of microsurgical instruments and Aneurysms (iSUiAs) reported that overall morbidity
intraoperative imaging studies such as indocyanine and mortality (defined as death and modified Rankin
green (iCG) angiography and endoscopic inspection Scale 3–5 or impaired cognitive status) at 1 year
further reinforce its efficacy. First introduced in was 12.6% (if no prior history of SAH) and 10.1%
1991, endovascular coiling has been an alternative (if prior history of SAH) in 1,917 patients who
to microsurgical clipping, and its use for ruptured received microsurgical clipping and 9.8% (if no
and unruptured CAs has been increasing over the prior history of SAH) and 7.1% (if prior history of
years along with the improvements and wide avail- SAH) in 451 patients who received endovascular
ability of endovascular techniques and devices. The coiling.14) Complete obliteration was accomplished
superiority of each treatment modality should be in 55% of patients, incomplete obliteration in 24%,
assessed depending on several aspects including and no obliteration in 3% in endovascular group,
overall morbidity and mortality, completeness and but the degree of aneurysmal obliteration was not
durability of aneurysmal occlusion, necessity of determined in microsurgical group.
retreatment, post-treatment management, rehemor- Based on the clinical trials above, microsurgical
rhage (intra- and post-procedural aneurysm rupture), clipping and endovascular coiling have inherent
and both treatments should be tested if they have incompleteness to achieve cure of CAs with some
a long-term treatment effect. considerable treatment risks. it is true that larger
The international Subarachnoid Aneurysm Trial the aneurysm, higher the chance of rupture and the
(iSAT) and Cerebral Aneurysm Rerupture After higher the risk of treatments. Thereby, procedural
Treatment (CARAT) studies reported rerupture risk and rupture risks and long-term benefit should be
once after the treatment of ruptured CAs.9–13) The precisely assessed in the decision for or against
iSAT study showed that the risk of rebleeding at intervention in each case, taking into account
1 year was low in both groups (2 per 1,276 patient each patient’s background, intrinsic factors of each
years and 0 per 1,081 patient years for endovascular lesion, and burden of the intervention. Ruptured
and microsurgical treatment, respectively), and CAs causing SAH should be treated as early as
that the rate of occlusion was higher in clipped logistically and technically possible to reduce the
aneurysms (82%) as compared to coiled ones risk of rebleeding, and any treatment should be
(66%), and that endovascular coiling resulted in done at least within 72 h after onset. Generally,
a significantly decreased rate of death or depend- microsurgical clipping is in favor of patients with
ency as compared to clipping (23.7% vs. 30.6%).9) younger age, presence of space-occupying intrac-
Rebleeding rates were low but more frequent in the erebral hematoma, relatively superficially located
coiled group and the rate of epilepsy was higher aneurysms, wide-neck aneurysms, and aneurysms
in microsurgical patients.9,10) Nine-year follow- with arterial branches exiting directly out of the
up data revealed 24 rehemorrhages, 13 from the aneurysmal sac. Endovascular coiling is in favor
treated aneurysms (10 treated by coiling and 3 by of patients with age above 70 years old, no space-
clipping).11) Eighteen-year follow-up data showed occupying intracerebral hematoma, deep-located
that at 10 years, 83% of coiled patients and aneurysms, and small neck aneurysms. From iSAT
79% of clipped patients were still alive, 82% of data, if the aneurysm appears to be equally effec-
coiled patients and 78% of clipped patients were tively treated by either coiling or clipping, coiling is
independent, and although the risk of rebleeding the preferred treatment, but the decision should be
was higher in the coiled group, the probability of based on several confounding factors in each case
disability-free survival was significantly greater as including patient’s age, SAH grade, comorbidity,
compared to the clipped group.12) presence of intracerebral hematoma, aneurysm size,
Long-term data from the CARAT study showed shape, and location.
that there were 19 reruptures during 4 years of
follow-up in 1,001 treated patients (3.4% risk of Recommendations
rerupture for coiling and 1.3% for clipping), and 1. Several factors should be considered in the
concluded that the degree of aneurysmal occlusion selection of the optimal management of an UiA,
after initial treatment in both microsurgical clipping including the size, location, and other morphological
and endovascular coiling is a strong predictor of characteristics of the aneurysm; documented growth
the risk of rebleeding; 1.1% risk of rehemorrhage in on serial imaging; the age of the patient; a history
complete occlusion as compared with a 2.9% risk of prior aneurysmal SAH; family history of CA; the
for small residual neck, a 5.9% risk for residual presence of multiple aneurysms; or the presence
neck, and a 17.6% risk for partial occlusion.13) of concurrent pathology such as an arteriovenous
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556 T. Aoki et al.
malformation or other cerebrovascular or inherited vascular wall or modify hemodynamic stress to
pathology that may predispose to a higher risk of the site of lesion. Endosaccular coiling induces
hemorrhage (Class i; Level of Evidence C). flow stasis-mediated luminal thrombosis of CAs for
2. Patients with unruptured CAs who are consid- possible promotion of endothelialization of aneu-
ered for treatment should be fully informed about rysmal orifice and serves as scaffold for recruitment
the risks and benefits of both endovascular and of cells that synthesize extracellular matrix and
microsurgical treatment as alternatives to secure induce fibrosis. Recent developments in several
the UiAs and prevent bleeding (Class i; Level of kinds of coil materials and new stents such as flow
Evidence B). diverters have changed endovascular treatments for
3. The results of UiA treatment are inferior at CAs, but optimal modification or reconstruction of
low-volume centers, and hence treatment is recom- normal vascular wall has never been obtained by
mended to be performed at higher-volume centers endovascular techniques. Any available surgical
(Class i; Level of Evidence B). intervention itself cannot modify or reduce the
4. Data from prospective and retrospective studies risk of CA formation in the same location or other
from multiple national and international investigations locations of cerebral arterial trees in patients with
indicate that microsurgical clip ligation may confer unruptured or ruptured CAs.
more durable protection against aneurysm regrowth, Surgical intervention effectively reduces further
but coil embolization may be superior to surgical rupture, rerupture, or growth of treated CAs, but
clipping with respect to procedural morbidity and both endovascular and microsurgical interventions
mortality, length of stay, and hospital costs. So it had a risk of rupture or rerupture in treated patients
may be reasonable to choose endovascular therapy (Table 1). The occurrence of SAH in treated patients
over surgical clipping in the treatment of select UiAs, with CAs is attributable to incomplete obliteration
particularly in cases for which surgical morbidity is in treated aneurysms or formation of de novo aneu-
high, such as at the basilar apex and in the elderly rysms.9–25) it should be noted that both unruptured
(Class iib; Level of Evidence B). and ruptured CAs carry a risk of rupture in a long
5. The treatment risk of patients with UiAs is term follow-up even after apparently effective and
related to advancing age, medical comorbidities, complete treatments, and patients with CAs have
and aneurysm location and size, so in older patients an inherent risk of de novo aneurysms which may
(> 65 years of age) and those with associated medical rupture during their lives. Endovascular coiling
comorbidities with small asymptomatic UiAs and low may not reduce the risk of growth and rupture of
hemorrhage risk by location, size, morphology, family thrombosed aneurysms, particularly giant lesions,
history, and other relevant factors, observation is a and it has been also reported that endovascular
reasonable alternative (Class iia; Level of Evidence B). deployment of flow diverters has a considerable
(Guidelines for the Management of Patients with risk of rupture.26) There is no effective surgical or
Unruptured intracranial Aneurysms : A Guideline for medical intervention to inhibit the de novo formation
Healthcare Professionals From the American Heart of CAs in patients with ruptured and unruptured
Association/American Stroke Association, 2015). CAs. Smoking cessation might reduce the formation
of CAs, and antihypertensive medication or changes
Prevention in life style may reduce the risk of rupture, but the
effects have not been proven. Recently, possible
The goal of treatments for patients with CAs is medical intervention has been investigated in CA
complete exclusion of the aneurysmal rupture risk animal models to evaluate the effect of several drugs
for their lives. Available surgical interventions for on the formation and rupture of CAs.
unruptured and ruptured CAs include microsur-
gical clipping or trapping, endovascular coiling Preemptive Intervention
or stenting, and obliterate CAs in morphological
aspects. However, they do not seem to have reason- Preemptive medicine for CAs should be designed
able preventive effects on the recurrence of the to prevent or delay the onset of symptoms from
lesion at the same or remote sites. Microsurgical CAs found in an asymptomatic state or to inhibit
neck clipping mechanically closes the orifice of the de novo formation of CAs (Fig. 1). in order to
aneurysmal sac and interfaces endothelial cell layers establish the preemptive medicine in the treatment
which promote reconstruction and modification of of CAs, new principles of treatments based on the
histological endothelium. it seems to reconstruct pathogenesis of CAs should be developed and, at
normal vascular layers, but surgical clipping itself the same time, specific biomarkers and adequate
cannot promote the normalization of pathological imaging modalities are mandatory. Although most
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Preemptive Medicine for CAs 557
Table 1 Recurrence of subarachnoid hemorrhage/cerebral aneurysms after surgical intervention
Mean follow-up Risk of recurrence
Author (year) Study design Endovascular surgery
period (microsurgery)
Tsutsumi et al. 220 ruptured cases 9.9 y (3–17 y) Recurrent SAH 2.7%
(1998) (6/220) (de novo 2)
retrospective (2.2% at 10 y, 9.0% at 20 y)
Tsutsumi et al. 115 unruptured cases 8.8 y (median) SAH 4/115 (regrowth 2,
(1999) de novo 2)
retrospective (1.4% in 10 y, 12.4%
in 20 y)
Tsutsumi et al. 140 clipped aneurysms, 9.0 y (3–21 y) Recurrent aneurysm 2.9%
(2001) 112 cases (4/140)
including ruptured (3/125 complete clipping,
and unruptured 1/14 incomplete clipping)
retrospective De novo 8.0% (9/112
cases) (0.89%/y)
Sluzewski et al. 393 consecutive Late rebleeding 1.27%
(2005) ruptured cases (5/393)
retrospective (0.32%/y)
CARAT (2006) 1010 ruptured cases Rerupture after 1 y; 0/711 Rerupture after 1 y; 1/299
prospective cohort (0.11%/y)
Aikawa et al. 227 ruptured cases 4.2 y Late rebleeding 2.6%
(2007) retrospective (6/227)
Johnston et al. 1,001 ruptured cases 4.0 y Rerupture 1.3% Reruptured 3.4%
(2008)
ambidirectional cohort (median time to
rerupture 3 d)
Molyneux et al. 1,582 ruptured cases 9 y (6–14 y) 7/769 (de novo 3) 17/813 (de novo 3)
(2009)
prospective cohort 3/769 occurred in 4–7 y 10/813 occurred in 2–5 y
from treated aneurysms from treated aneurysms
Schaafsma et al. 283 coiled cases 6.3 y (1.0–12.2 y) 17/748 (4 from treated 3/283 (1 confirmed, 2
(2009) (> 90% occlusion) aneurysms, de novo 13) possible SAH)
748 clipped cases 7.6 y (0.04–19.5 y)
all ruptured, retrospective
Gonda et al. 2,509 unruptured 7 y (median; incidence of non-traumatic
(2014) cases 4–12 y) intracranial hemorrhage
observational analysis 5.9% (92/1,565) 4.8% (45/944)
of a database
Molyneux et al. 1,644 ruptured cases 10.0–18.5 y Recurrent SAH after 1 y; 33
(2015) cases (17 from treated
aneurysms, 16 from another
source)
prospective cohort 0.64% 2.16%
SAH: subarachnoid hemorrhage
of CAs which are incidentally detected show rather inherent high risk of rupture.6,27) These aneurysms
stable clinical courses and reveal less inflammatory may rupture even if they are small in size in the
or degenerative changes in their walls, and their early phase of development or enlarge in a short
risk of rupture is relatively low, some of the unrup- time because of wall thinning by advancement of
tured CAs follow the rather unstable course with degenerative changes. it is of clinical relevance to
significant changes in size and shape seemingly with estimate accurately the rupture risk of individual
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558 T. Aoki et al.
CA, but we have no definite methods to distinguish
rupture-prone aneurysms from rupture-resistant ones.
I. Pathogenesis
Molecular mechanisms of the occurrence, develop-
ment, or rupture of CAs have been experimentally
investigated. The formation of CAs initiates in response
to excessive hemodynamic stress to intracranial arterial
wall of vascular bifurcation. The successive common
pathway involves endothelial dysfunction/injury, infil-
tration of inflammatory cells, phenotypic modulation
and degeneration of smooth muscles, remodeling of
extracellular matrix, and subsequent cell death and
vessel wall degeneration. in this process, hemodynamic
stress, inflammatory reaction by activated macrophages,
and vascular smooth muscle cell death are presumably
crucial for the formation of CAs.28,29) The pathological Fig. 2 Inflammatory process in the development of cerebral
findings in CAs are characterized by protrusion of aneurysms. COX-2: cyclooxygenase-2, EP2: prostaglandin
vascular wall at bifurcations with disruption of elastic E2 receptor 2, MCP-1: monocyte chemotactic protein-1,
NF-kB: nuclear factor-kappa B, PGE2; prostaglandin E2,
laminae, thinning of smooth muscle cell layer, and
TNF-α: tumor necrosis factor-α
vascular remodeling, most often degenerative remod-
eling, coupled with massive inflammatory infiltrates is
considered to be an essential part in the pathogenesis producing enzyme, cyclooxygenase (CoX), is induced
of CAs. The infiltration of T cells, neutrophils, and and NF-κB signaling is activated in these cells. Pros-
macrophages in particular, is a hallmark of CAs, and taglandin E produced by CoX-2 then acts on pros-
2
the role of nuclear factor-kappa B (NF-kB)-mediated taglandin E2 receptor 2 (EP2), one of the prostaglandin
monocyte chemotactic protein-1 (MCP-1) expression E receptor subtype, to evoke inflammation including
seems therefore pivotal in recruiting macrophages NF-κB activation. intriguingly, because NF-κB tran-
into the wall of CAs, triggering and exacerbating the scriptionally induces CoX-2 expression as a master
inflammatory reaction and thus contributing to aneu- transcription factor, amplification loop consisting of
rysm formation and progression. Histopathological CoX-2-prostaglandin E-EP2-NF-κB forms to maintain/
2
studies show that the ruptured CAs manifest significant exacerbate inflammation once triggered by hemody-
endothelial damage, structural change of the wall, namic stress loaded, resulting in long-lasting chronic
and massive inflammatory cell invasion compared inflammation. Same amplification loop is formed in
with unruptured CAs.30) The wall of ruptured CAs macrophages, which are recruited by NF-κB-mediated
is found to be fragile, possibly because infiltration MCP-1 induction in endothelial cells and macrophages
of inflammatory cells, mainly macrophages, into the themselves and becomes a major type of inflamma-
aneurysmal wall resulting in loss of smooth muscle tory cells in CAs, contributing to further exacerbation
cells and excessive degeneration of matrix proteins. of inflammation in lesions. Here, because TNF-α can
Symptomatic unruptured CAs resemble ruptured activate NF-κB, TNF-α presumably functions with
aneurysms in their pathology and show significant prostaglandin signaling to further enhance inflam-
endothelial cell damage, structural changes of the matory responses leading to CA progression.
wall, and inflammatory cell infiltration.
From recent experimental studies using animal II. Biomarkers
models, several pro-inflammatory cascades seem to Several studies reported possible biomarkers for
be activated during aneurysmal progression including formation, growth, and rupture of CAs, but there has
NF-κB, tumor necrosis factor-α (TNF-α), prostaglandin, not been proven available markers to monitor the
myeloperoxidase, and reactive oxygen species. Thereby, pathological condition of CAs yet. Hussain et al.
CA is one of the chronic inflammatory diseases like performed literature review for biomarkers of CAs
atherosclerosis, cancer, or insulin intolerance. in and found that CAs were associated with an increase
these pathways, contribution of prostaglandin pathway in levels of immunologic markers such as complement
and NF-κB signaling to CA formation and progression C3 and C9, immunoglobulins igG and igM, M1/M2
is well studied and supported by several studies macrophages, monocytes, B and T lymphocytes, cell
(Fig. 2). in brief, hemodynamic stress activates adhesion molecules, and other cerebral proteins related
endothelial cells at the bifurcation and prostaglandin to brain and vascular damage such as neurofilament
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Preemptive Medicine for CAs 559
heavy chain SM135 and S-100, in both the formation arteries is challenging because of many aspects
and progression to rupture of CAs.31) However, it is including anatomic variability, tortuosity, small
not clarified whether each biomarkers has clinical wall thickness, relatively large motion artifact, and
importance in the management of CAs. Recently insufficient contrast from surrounding brain paren-
Chalouhi et al. demonstrated the increase of some chyma and CSF. Black blood MRi with additional
cytokines, such as regulated on activation, normal CSF suppression at higher tesla MR with several
T cell expressed and secreted (RANTES), iL-8 and modified sequences has been applied to vascular
iL17, in plasma from CA lesion compared with one diseases including atherosclerosis, dissection,
from femoral artery.32) Currently, it is technically and vasculitis. Gounis et al. reported the use of
impossible to detect changes of these cytokines in myeloperoxidase-specific MR signal enhancement
plasma from peripheral vessels because the change for imaging inflammation in a rabbit model of
is of course too tiny, but technical advancement may carotid artery aneurysm.36) Ultrasmall superpara-
overcome the limitation. Xu et al. applied lectin- magnetic particles of iron oxide (USPio) uptake
affinity enrichment of glycoproteins coupled with into inflammatory cells has been investigated in
quantitative isobaric Tag for Relative and Absolute major arterial wall such as aortic aneurysms and
Quantitation (iTRAQ) labeling proteomic techniques cervical carotid plaques. Early accumulation of
and identified cerebrospinal fluid (CSF) proteins either USPio within hours is not necessarily associated
distinctively changed in ruptured or unruptured CAs with inflammatory cells, but USPio uptake revealed
or commonly changed in ruptured and unruptured on T *-weighted MR images seems to be useful
2
CAs, and found that both CSF and plasma Axl (a in human CAs to monitor the condition of each
tyrosine kinase membrane receptor) levels are signif- lesion.37,38) Because USPio-mediated contrast in
icantly elevated in patients with ruptured CAs, and aneurysmal wall detected by MR images could be
concluded that Axl might serve as a promising partly ameliorated in patients with aspirin uptake,39)
biomarker to predict the rupture of CAs.33) Since Axl a clinical study is ongoing to prove the useful-
has oncogenic potential and interacts with other ness of USPio-mediated MR contrast imaging for
membrane receptors and the involvement of Axl in rupture risk assessment of human CAs. Molecular
the process of CA development is not clarified, the imaging of cerebral arterial wall may exert as a
role of Axl as a biomarker of CAs is to be elucidated. useful detector of CA progression and biological
Li et al. carried out microarray assays in a screening marker of its growth and rupture. Further study
cohort of 40 patients with CAs (20 unruptured and 20 is warranted to visualize molecular and cellular
ruptured) and 20 healthy volunteers to clarify whether events in cerebral vessels with thin wall.
circulating micro ribonucleic acids (microRNAs) image-based computational fluid dynamics (CFD)
could be used as biomarkers for CAs, and found that have been applied to intraluminal flow analysis in
miR-16 and miR-25 were independent factors for CA CAs and may be a promising role in the evalua-
occurrence.34) Jin et al. investigated warning effect of tion of CAs as a tool to stratify rupture risk and to
serum miRNAs for rupture of CAs through microarray perform pre- and post-interventional simulation to
hybridization, and showed that several differently obtain optimal results.40) Previous reports indicated
expressing serum microRNAs are detected in different that both high and low wall shear stress sometimes
levels between normal people and aneurysm patients, accompanied with turbulent flow to the wall of
as well as among different groups of aneurysms such CAs have been related to growth and rupture and
as daughter aneurysms group, aneurysm without the results may be influenced by preset parameter
daughter aneurysms group, ruptured aneurysms group, definitions, hypothesized calculations, and the time
and angiography negative group.35) at which flow data are obtained. Although wall shear
Although it is not plausible that serum or CSF stress and related analyses among several parameters
molecules act as a sensitive monitor for small intrac- seem to be a predictor of growth and rupture of
ranial lesions such as CAs, future investigations are CAs, the interpretation of CFD should be carefully
necessary to confirm the clinical relevance of each performed before determining its clinical utility.
candidate as a new diagnostic/prognostic biomarker Since most of CFD studies have been simulated
of CAs. in steady, non-pulsatile flow with phase contrast
magnetic resonance-derived volumetric inflow rate,
III. Imaging the findings by CFD should be proven in clinical
imaging of molecules or cells may provide situations to validate the risk of unruptured CAs,
us with important information regarding active and hemodynamic-biologic mechanisms should
remodeling, progression, and even risk of rupture be clarified before establishing reliable models to
of CAs. However, molecular imaging of cerebral predict growth and rupture risk of CAs by CFD.
Neurol Med Chir (Tokyo) 56, September, 2016
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560 T. Aoki et al.
IV. Cell therapy factor-1α (SDF-1α)-coated coils together with EPCs
in order to achieve complete cure of CAs, recon- transplantation in mechanically-produced common
struction of vascular wall with normal endotheliali- carotid artery aneurysms and showed that SDF-1α-
zation is necessary. The aim of endovascular coiling coated coils plus EPCs transplantation produced a
and stenting is to form intraluminal thrombus and well-organized fibrous tissue bridging the orifice of
sequestration of aneurysmal sac from circulation. aneurysms and concluded that combination of these
Since metal materials themselves may not recruit treatments is a safe and effective treatment for rat
effective cell populations which repair and recon- aneurysms.50) kuwabara et al. studied the effect of
struct normal vasculature, cell-mediated remodeling intravenous infusion of xenogeneic MSCs on rupture
process is necessary to achieve permanent occlu- rate of elastase-hypertension induced iAs in mice, and
sion of the aneurysm and reconstitution of the showed statistically significant decrease in aneurysmal
luminal surface of the arterial segment harboring rupture rate in the MSC-treatment group as compared
the aneurysm. Several cell therapy modalities with with the control group.51) Marbacher et al. showed the
endothelial progenitor cells (EPCs), mesenchymal aggravation of degeneration of aneurysmal wall by
stem cells (MSCs), vascular smooth muscle cells removing VSMCs from the aneurysmal tissue and the
(VSMCs), and fibroblasts have been shown to be reduction of angiographic recurrence by implanting
effective and feasible in animal studies (Table 2).41–53) VSMCs inside occluded aneurysms in decellularized
it is well known that circulating EPCs, as committed aneurysms and better histologic outcomes in both
linage specific stem cells to endothelial cells, play decellularized and non-decellularized aneurysms.52)
an important role in maintaining vascular integrity Dai et al. applied fibroblasts for aneurysm treatment
by replacing injured and dysfunctional endothelial using platinum coils in a rabbit elastase aneurysm
cells. Li et al. examined the potential of endothelial model, and showed that the treatment group showed
colony-forming cells (ECFCs) transfusion on vascular significant histologic improvement over the control
degeneration after CA induction in a rat model and group at 2 weeks but the difference did not persist
found that ECFCs transfusion confers protection at later time points.53)
against degeneration of aneurysmal wall by inhib- Although aneurysm cell therapy studies seem
iting inflammatory cascades and SMCs apoptosis.49) to be promising, the precise mechanisms of cell
Gao et al. tested the efficacy of stromal cell-derived therapy should be clarified and the study should be
Table 2 Reported cell therapy for cerebral aneurysms (Modification of Table 1 in Ref 41)
Author (year) Creation of aneurysm Site of aneurysm Animal Cell type Delivery
Raymond (1999) Venous side-wall pouch Common carotid artery Dog VSMC Fibrin glue
infrarenal abdominal
Marbacher et al. (2014) Arterial side-wall pouch Rat VSMC Fibrin glue
aorta
kawakami (2005) Venous pouch on artery Common carotid artery Rabbit Fibroblast Coil
Dai et al. (2007) End sac + local elastase Common carotid artery Rabbit Fibroblast Coil
Marx (2001) End sac + local elastase Common carotid artery Rabbit Fibroblast Coil
Aronson (2012) End sac + local elastase Common carotid artery Rabbit EPC Fibrin glue
Systemic
Li (2013) End sac + local elastase Common carotid artery Rabbit EPC
intravenous
infrarenal abdominal Via abdominal
zhang (2014) Arterial side-wall pouch Rat EPC
aorta aorta
Rouchaud (2013) End sac + local elastase Common carotid artery Rabbit MSC intraluminal
Hypertension + CSF Systemic
kuwabara et al. (2014) Cerebral artery Mouse MSC
elastase intravenous
Gao et al. (2014) End sac Common carotid artery Rat EPC intraluminal
CSF: cerebrospinal fluid, EPC: endothelial progenitor cell, MSC: mesenchymal stem cell, VSMC: vascular smooth muscle
cell
Neurol Med Chir (Tokyo) 56, September, 2016