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Unruptured Cerebral Aneurysms
Aman B. Patel, MDVice-Chair, Department of Neurosurgery
Director, Cerebrovascular & Endovascular Robert & Jean Ojemann ProfessorMassachusetts General Hospital
Harvard Medical School
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Disclosures
I have the following relevant financial relationship with a commercial interest to disclose:
Microvention – consultant, proctor
Medtronic – consultant, proctor
Penumbra – consultant
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3.
1. Name 3 prospective natural history studies of unruptured aneurysms and discuss their strengths and weaknesses.
2. What aneurysm location is frequently cited as most common in series of ruptured aneurysms, but not unruptured aneurysms?
3. What risk factors are associated with aneurysmal rupture?
Summary of Questions You Should be Able to Answer
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There are NO randomized clinical trial data that define the optimum management of an unruptured intracranial aneurysm.
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5.
1. ISUIA – International Study of Unruptured Intracranial Aneurysms (North America & Europe)1. ISUIA Investigators. Unruptured intracranial aneurysms – risk of rupture and risks of surgical intervention. NEJM 1998;339:1725-
33.
2. Wiebers DO et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003;362:103-10.
2. UCAS – Unruptured Cerebral Aneurysm Study (Japan)1. Morita A et al. The natural course of unruptured cerebral aneurysms in a Japanese cohort. NEJM 2012;366:2474-82.
3. SUAVe Study – Small Unruptured Intracranial Aneurysm Verification Study (Japan)
1. Sonobe M et al. Small unruptured intracranial aneurysm verification study: SUAVe study, Japan. Stroke 2010;41:1969-77.
Natural history studies of unruptured intracranial aneurysms
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NATURAL HISTORYISUIA (2003)
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7.
• Eligibility and Exclusion Criteria
– Eligible patients were prospectively enrolled between 1991-8.
– Patients were eligible for enrollment if they had at least one unrupturedaneurysm.
– Patients were excluded if they had any of: (1) fusiform, traumatic, or mycotic aneurysms; (2) aneurysms < 3-mm; or (3) were bedridden or unable to communicate at the time of diagnosis.
• Patients were assigned to one of two cohorts – operated or unoperated – based on whether surgical or endovascular treatment of at least one unruptured intracranial aneurysm was planned on clinical grounds at the time the patient was first seen at the ISUIA center.
• All patients underwent catheter cerebral angiography.
ISUIA (2003)
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8.
Patients’ Baseline Characteristics (n=1692 untreated patients)
• Age (years, mean [SD]) 55.2±13.1
• Women (%) 91.6%
• Total # of unruptured aneurysms 2686
• Size of aneurysm (mm), (# of patients [%])
– 2-7 1049 (62.0%)
– 7-12 390 (23.0%)
– 13-24 198 (11.7%)
– ≥ 25 55 (3.2%)
ISUIA (2003)
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9.
Patients’ Baseline Characteristics (n=1692 untreated patients)
• Aneurysm location Untreated (UT) Total %UT
(# of patients, [%])– Cavernous carotid 210 (12.4%) 337 (8.3%) 62.3%
– ICA 387 (22.9%) 1213 (29.9%) 31.9%
– AComA or ACA 175 (10.3%) 500 (12.3%) 35.0%
– MCA 475 (28.1%) 1179 (29.1%) 40.3%
– PComA 246 (14.5%) 345 (8.5%) 71.3%
– VB system 87 (5.1%) 199 (4.9%) 43.7%
– Tip of basilar artery 112 (6.6%) 284 (7.0%) 39.4%
– TOTAL 1692 4057
ISUIA (2003)
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10.
Natural History• 1692 patients with 2686 aneurysms had conservative management
• Mean follow-up (4.1 years, SD 2), 6544 patient-years of follow-up
• 51 patients (3%) in the unoperated cohort had a confirmed aneurysmal rupture; in 49 of these, the rupture occurred within 5 years of diagnosis
ISUIA (2003)5-year Cumulative Rupture Rates
<7-mm < 7-mm 7-12 mm 13-24-mm ≥ 25-mm
Group 1 Group 2
Cavernous(n-210)
0 0 0 3.0% 6.4%
AC/MC/IC(n=1037)
0 1.5% 2.6% 14.5% 40%
Post-Pcom(n=445)
2.5% 3.4% 14.5% 18.4% 50%
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11.
• The 5-year mortality rate, calculated with the Kaplan-Meier method, was 12.7% (11.7-13.7).
• In the 51 patients who had unruptured aneurysms at baseline, but with subsequent hemorrhage, 33 (65%) died.
• Of the 193 patients who died during the follow-up period, these are the reasons for death.
– Intracranial hemorrhage 52
– Cancer 44
– Myocardial infarction 14
– Respiratory disease 16
– Cerebral infarction 5
– Congestive heart failure 7
ISUIA (2003)Mortality Rate in Untreated Group
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NATURAL HISTORY
UCAS (2012)
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13.
• Large, prospective cohort study with recruitment of patients between January 2001 through April 2004.
• Patients were eligible if they were 20 years of age or older and had an aneurysm that was 3-mm or greater.
• Patients were excluded if they …– Had a previous episode of ICH (unknown or untreated cause)
– Presented with a modified Rankin score of more than 2
– Harbored dissecting or fusiform aneurysms
– Demonstrated a single cavernous aneurysm
• The treatment strategy was chosen by the patient or was determined on the basis of the physician recommendation.
• A diagnosis of aneurysm was based on images obtained through MRA, CTA, and catheter angiography. 3D image sets were commonly available to size the aneurysm.
UCAS (2012)
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14.
Patients’ Baseline Characteristics (n=3647 untreated aneurysms)
• Age (years, mean [SD]) 65.0±10.4
• Women (%) 68%
• Size of aneurysm (mm), (# of aneurysms [%])
– 3-4 2000 (54.8%)
– 5-6 861 (23.6%)
– 7-9 462 (12.7%)
– 10-24 310 (8.5%)
– ≥ 25 14 (0.4%)
UCAS (2012)
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15.
Patients’ Baseline Characteristics (n=3647 untreated aneurysms)
• Aneurysm location Untreated (UT) Total %UT
(# of aneurysms, [%])– MCA 1210 (33.2%) 2425 (36.2%) 49.9%
– AComA 530 (14.5%) 1037 (15.5%) 51.1%
– ICA 696 (19.1%) 1245 (18.6%) 55.9%
– ICA-PComA 602 (16.5%) 1037 (15.5%) 58.1%
– Basilar tip / SCA 327 (9.0%) 445 (6.6%) 73.5%
– VA/PICA/VBJ 80 (2.2%) 123 (1.8%) 65.0%
– TOTAL 3647 6697
UCAS (2012)
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16.
• Our analysis showed that 111 aneurysms ruptured during 11,660 aneurysm-years of follow-up.
• The annual risk of rupture was 0.95% (95% CI, 0.79-1.15).
• The multivariate Cox proportional-hazards model that
– the size of the lesion,
– the specific location, and
– the presence or absence of a daughter sac
• were significant independent factors affecting the risk of rupture, with a clear stratification of risk according to these factors.
UCAS (2012)
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17.UCAS (2012)
Aneurysm morphology
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18.
Comparing ISUIA (2003) and UCAS (2012)
ISUIA UCAS
enrollment period 1991-8 2001-4
age 55.2+13.1 years 65.0±10.4 years
% female 91.6% 68%
total UR aneurysms 2,686 3,647
size 85% (≤12-mm) 91.1% (≤9-mm)
f/u (patient-years) 6,544 11,600
locations w/ risk PComA, post circ PComA, AComA
other factors assoc. size, previous SAH size, daughter sac,
with risk female sex
Comparing ISUIA and UCAS
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19.
Comparing ISUIA (2003) and UCAS (2012)
Understanding Bias From Non-Random Selection
Comparing ISUIA and UCAS
0
10
20
30
40
50
60
70
80
ICA MCA AComA PComA
ISUIA
UCAS
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NATURAL HISTORY
SUAVe Study (2010)
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21.
• The SUAVe study is a multicenter, prospective clinical study conducted at 12 Japanese centers. Enrollment was between September 2000 and January 2004. Only aneurysms less than 5 mm in diameter were included in the study population.
• In total, 448 aneurysms (374 cases) were analyzed.
• 7 cases (1.9% of all patients) experienced ruptures during follow-up (1306.2 person-years, 1153 aneurysm-years). 6 cases were female and 4 had multiple aneurysms.– Average annual rupture incidence (single) … 0.34%/yr
– Average annual rupture incidence (multiple) … 0.95%/yr
– Average annual rupture incidence (overall) … 0.54%/yr
• Also interesting, although the sizes of aneurysms were unchanged during follow-up, 4 of the 7 rupture cases showed aneurysmal enlargement at the time of rupture.
SUAVe (2010)
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22.SUAVe (2010)
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23.
Predictive Factors for Aneurysm Enlargement
• During follow-up, 30 aneurysms (25 cases) enlarged (6.7% of cases / aneurysms).
• The significant independent risk factors for aneurysm enlargement were …
Characteristics HR 95%CI P
• Women 2.95 1.04-8.35 0.042
• Size ≥ 4.0-mm 3.34 1.53-7.31 0.0025
• Multiplicity 1.72 1.24-3.75 0.036
• Current smoking 3.59 1.19-10.86 0.027
SUAVe (2010)
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24.
Interesting Observations From SUAVe Study
• The SUAVe study did not find a history of SAH to be associated with aneurysmal rupture, although aneurysm multiplicity was revealed to be significantly associated with rupture.
• During follow-up in the SUAVe study, 10 patients with high-risk aneurysms, due to morphological change, were operated on. This may likely have caused bias toward underestimation of the aneurysm rupture rate.
• The SUAVe study showed the overall % of AComA aneurysms < 5-mm in size to be 13.4%. It is noteworthy that the percentage of unruptured aneurysms in the current study is much lower than the usual 30% reported for ruptured AComA aneurysms.
SUAVe (2010)
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RISK FACTORS FOR ANEURYSMAL RUPTURE
What risk factors are associated with aneurysmal rupture?
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26.
ISUIA (2003)• Aneurysm location
– PComA
– Posterior circulation
• Aneurysm size
• History of prior SAH
Risk Factors for Aneurysmal Rupture
UCAS (2012)• Aneurysm location
– PComA
– AComA
• Aneurysm size
• Aneurysm daughter sac
• Female sex
SUAVe (2009)• Aneurysm size
• Age < 50 years-old
• Hypertension
• Multiple aneurysms
Feigin (2005)• Smoking
• Hypertension
• Excessive EtOH intake
• Non-white ethnicity
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27. Risk Factors for Aneurysmal RupturePHASES Score
• The PHASES investigators performed a systematic review and pooled analysis of individual patient data from 8,382 participants in 6 prospective cohort studies with SAH as the outcome.
• Rupture occurred in 230 patients during 29,166 person-years of follow-up.
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28. Risk Factors for Aneurysmal RupturePHASES Score
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29.MCA – Wide neck
PHASES = 61 – HTN3 – Size2 – MCA
1.7% 5 year
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30.MCA Aneurysms
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31.ACOM Aneurysm
PHASES = 81 – HTN3 – Size4 – MCA
3.2% 5 year
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32.ACOM Aneurysm
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Imaging Guidelines for Small, Unruptured Aneurysms
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34.
Illustrative Case …
3.2-mm
AComA Aneurysm
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35.
Illustrative Case …
AComA Aneurysm
3.2-mm
How are we going to manage this aneurysm?
Treat Upfront Followup Imaging
• Interval ?• Modality ?• Duration ?
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36.
Stroke 2015;46:2368-2400.
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37.
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38.
• To summarize evidenceabout the growth andrupture risk of UIAs ≤ 7-mmand
• To explore differences ingrowth and rupture risks ofvery small (≤ 3-mm) andsmall (≤ 5-mm) aneurysms.
• Annualized growth rate< 3%
• Annualized rupture rate
• Very small (≤ 3)0%
• Small (≤ 5)0.5%
• Less than 7-mm< 1%
Ann Intern Med 2017;167:26-33.
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39.
Neurology
The ELAPSS score consistsof 6 easily retrievablepredictors and can helpphysicians in decisionmaking on the need for andtiming of follow-up imagingin patients with unrupturedintracranial aneurysms.
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40.
JAMA Neurol 2018;75(1):27-34.
We performed a comparativeeffectiveness analysis from a societalperspective to assess the following 5strategies in managing tiny aneurysmsmeasuring 3-mm or less:
• Annual surveillance using MRA• Biennial surveillance using MRA• Surveillance using MRA every5 years• Coiling and MRA follow-up• No treatment or preventive follow-up
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41.
JAMA Neurol 2018;75(1):27-34.
1-Way Sensitivity Analysis Varying Annual Growth Rate of Tiny Aneurysms
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42.
JAMA Neurol 2018;75(1):27-34.
1-Way Sensitivity Analysis Varying Rupture Risk of Growing Aneurysms
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43.
JAMA Neurol 2018;75(1):27-34.
1-Way Sensitivity Analysis Varying Rupture Risk of Non-Growing Aneurysms
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44.
JAMA Neurol 2018;75(1):27-34.
A 2-way sensitivity analysis was performed, varying both the risk of rupture ofgrowing aneurysms (0%-40%) and the proportion of growing aneurysms (0%-40%) among all tiny aneurysms.
The result shows that when either the proportion or risk of rupture of growinganeurysms is lower than 4%, no follow-up is the optimal strategy regardless ofthe value of the other variable.
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45.
JAMA Neurol 2018;75(1):27-34.
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46.Summary
AH
A/A
SA G
uid
elin
es (
20
15
) Newer evidence is accumulating that tiny, low-risk aneurysms may not have to be followed at all.
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47.Future Directions
47
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Visualization of Aneurysmal Flow using Computational Simulation
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49.
Anticipation of aneurysm rupture
Rupture during obs Stable
New therapy based on CFD
Anticipation of aneurysm growth
Treatment Planning
Aim of CFD Analysis
Is it useful for clinical practice?
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Case Example of growing UIA: 40 yo Physician
High pressure area may be important factor of aneurysm growth
Courtesy of Y. Muryama
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51.
Streamline
WSS Pressure
60 y/o Male
UnrupturedRt MCA
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52.60 y/o Male
UnrupturedLt MCA
Streamline
PressureWSS
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• CFD evaluation can provide additional information to anticipate aneurysm growth and rupture.
• Inflammatory and other biomarkers may provide information regarding high risk aneurysms
• Basic researchers and physicians should work together for optimal research.
