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Stereotactic radiosurgery for cerebral cavernous malformations: a systematic review
and meta-analysis
Authors
Michiel H.F. Poorthuis MD,1 Leon A. Rinkel BSc,2 Simon Lammy MRCS (Ed),3 Rustam Al-
Shahi Salman MA PhD FRCP(Edin).4
Affiliations
1. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University
Medical Center Utrecht, Utrecht, The Netherlands.
2. University of Groningen, University Medical Centre Groningen, Groningen, The
Netherlands.
3. Department of Neurosurgery, Institute of Neurological Sciences, Queen Elizabeth
University Hospital, Glasgow, UK.
4. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
Corresponding Author
Professor Rustam Al-Shahi Salman, Centre for Clinical Brain Sciences, University of
Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
Email addresses co-authors:
MP: [email protected], LR: [email protected], SL: [email protected]
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Keywords
Cerebral cavernous malformations, epilepsy, intracranial hemorrhage, stereotactic
radiosurgery, Gamma Knife.
Word count
Abstract – 259 words
Manuscript – 2345 words
Number of references: 49
Number of tables: 5
Figures 1
Funding
This study was not industry-sponsored.
MP: Reports no disclosures
LR: Reports no disclosures
SL: Reports no disclosures
RA-SS: Reports no disclosures
Statistical analysis:
All statistical analysis were performed by MP, University Medical Centre Utrecht, and LR,
University Medical Centre Groningen.
Supplementary data:
Appendix 1: Checklists for reporting standards
Appendix 2: Search strategies
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Appendix 3: Overview of overlapping studies
Appendix 4: Excluded studies, with the reasons for their exclusion
Appendix 5: Characteristics of each included study
Appendix 6: Summary of methodological characteristics of the included studies
Appendix 7: Risk of bias summary
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ABSTRACT
Background and objective The efficacy of stereotactic radiosurgery (SRS) for the treatment
of cerebral cavernous malformations (CCMs) is uncertain, so we set out to quantify clinical
outcomes after SRS for CCM and compare them to microsurgical excision or conservative
management.
Methods We searched PubMed and Ovid EMBASE from inception until June 1, 2018 for
peer-reviewed publications describing clinical outcomes after SRS for ≥10 people with CCM
in cohorts with or without a comparison group treated with neurosurgical excision or
conservative management. Two reviewers independently extracted data from the included
studies to quantify cohort characteristics and the incidence of the primary outcome (death
attributable to CCM and/or its treatment) and secondary outcomes (non-fatal symptomatic
intracerebral hemorrhage [ICH] and non-hemorrhagic persistent focal neurological deficit
[FND]). We assessed whether comparative studies showed a “dramatic” effect (meaning the
conventionally calculated probability of two differently managed patient groups from the
same population was <0.01 with a rate ratio greater than 10).
Results We included 30 cohort studies involving a total of 1,576 patients undergoing SRS for
CCM. Four non-randomized studies compared SRS to other treatment strategies, but did not
demonstrate dramatic associations. During a median follow-up of 48 (IQR 35-62) months
after SRS, the annual incidences (95%CI) of outcomes were: death 0.18% (0.10-0.31), ICH
2.40% (2.05-2.80), FND 0.71% (0.53-0.96), and the composite of death, ICH or FND 3.63%
(3.17-4.16). Outcomes did not differ by CCM location or type of SRS.
Conclusions After SRS for CCM, the annual incidences of death, ICH and FND are low and
seem comparable to outcomes without SRS. A randomized trial of SRS for CCM is needed.
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Registration This systematic review was registered (PROSPERO CRD42016025463 ) .
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INTRODUCTION
Cerebral cavernous malformations (CCMs) are intracranial vascular malformations that are
found in 0.15% to 0.44% of the population.1, 2 CCM may present with intracerebral
hemorrhage (ICH), non-hemorrhagic focal neurological deficits (FND),3 or epileptic seizures.
All of these complications may recur and might be prevented by CCM treatment.
In clinical practice, patients with CCM are managed conservatively or treated with
neurosurgical excision or stereotactic radiosurgery (SRS), but the role of the latter remains
controversial. However, randomized trials have not been performed and observational studies
at low risk of bias have not shown dramatic associations between treatment and better
outcome.4 Therefore, the most effective treatment modality for CCM is unknown and this
therapeutic dilemma has been identified as the top priority for further research by a priority
setting partnership.5
A systematic review assessed the outcomes of SRS for brainstem CCM, but it had
limitations.6 The review included five retrospective case series, but did not assess their risk of
bias.7 The authors performed a meta-analysis comparing the risk of ICH before and after SRS,
but such un-controlled before-and-after study designs are unreliable,8 and the reduction in
ICH risk after SRS may simply reflect the known reduction in the risk of CCM re-bleeding
over time.9 The review was restricted to studies of brainstem CCM published before
September 2013 and included only 178 patients, but many other studies report outcomes after
SRS.
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Consequently, a recent North American guideline deemed that there was only class II-III level
B-C evidence to support a recommendation that SRS might be considered for solitary CCM
with previous symptomatic ICH located in the CCM lies in eloquent areas that carry an
unacceptably high risk for neurosurgical excision (class IIb, level B), and a recommendation
against SRS for asymptomatic CCM, familial CCM, and CCM that are surgically accessible
(class III, level C).10
Therefore, we set out to perform an updated systematic review of all studies of SRS for CCM
in all locations and assess studies’ risk of bias in order to quantify all important clinical
outcomes after SRS for CCM with precision and compare these outcomes to microsurgical
excision or conservative management in studies with comparison groups.
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MATERIALS AND METHODS
Registration and reporting standards
We conducted this systematic review according to a protocol that we registered (PROSPERO
CRD42016025463 ) , and report the results consistent with the Preferred Reporting Items for
Systematic Reviews and Meta-analyses (PRISMA) (appendix 1).11, 12
Search strategy
We used comprehensive electronic strategies (appendix 2) to search PubMed Medline, Ovid
EMBASE and The Cochrane Library from inception to June 1, 2018 for articles meeting our
eligibility criteria to update our previous systematic review and meta-analysis of all
treatments for CCM.13 We performed backward citation searching using the bibliographies of
included studies and searched for randomized trials in ClinicalTrials.gov.
Eligibility criteria
We included randomized trials or observational cohort studies (with or without a comparison
group), published in any language in peer-reviewed journals, reporting ten or more patients of
any age diagnosed with CCM by MRI or histopathology, who were treated with SRS,
reporting clinical outcomes of interest (at least death, but also ICH and FND) during a
quantified period of follow-up of at least 30 days.
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Study selection
Three reviewers (MHFP, LR, and SL) independently used Covidence to screen all titles and
abstracts for eligibility, and assess the full text of potentially eligible studies for final
inclusion. In case of disagreement, MHFP, LR, SL and RA-SS resolved discrepancies in
consensus meetings. If multiple studies of the same cohort were published, we prioritized
inclusion of the study reporting a comparison group, but otherwise we included the study with
the largest sample size (appendix 3).
Data extraction
Two authors (MHFP and LR) independently extracted the characteristics of each cohort
according to the treatment received (SRS [Gamma Knife, linear accelerator, CyberKnife],
neurosurgical excision, or conservative management).
Study characteristics
We extracted aspects of study design such as institution, country, years in which treatment
took place, setting study, number of study centers, study design, design of data-collection,
design of follow-up, consecutiveness, and use of selection criteria.
Risk of bias
We used Cochrane criteria7 to assess the following domains: 1) random sequence generation;
2) allocation concealment; 3) blinding of participants and personnel; 4) blinding of outcome
assessment; 5) incomplete outcome data; 6) selective outcome reporting; and 7) other bias.
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Each potential source of bias was independently graded as high, low, or unclear risk of bias
by two reviewers (MHFP and LR).
Patient and CCM characteristics
We recorded the total number of patients, total number of CCMs, presenting symptoms, age,
number of children, number of female patients, number of patients with family history, and
number of patients with a genetic mutation. We recorded CCM location, number of patients
with multiple CCMs, size, and number of CCMs associated with developmental venous
anomaly. We recorded the number of patients that had undergone neurosurgical excision or
SRS at baseline.
CCM treatment
We recorded the type of stereotactic radiosurgery, maximum and margin dose, and number of
patients undergoing repeat radiosurgery.
Outcomes
The primary outcome was death attributed to CCM and/or its treatment. The secondary
outcomes were: non-fatal symptomatic ICH; non-fatal and non-hemorrhagic persistent FND;
a composite of death attributed to CCM and/or its treatment or non-fatal ICH or non-fatal and
non-hemorrhagic persistent FND; epileptic seizures; adverse radiation effects; and functional
outcome. We collected the numbers of primary and secondary outcomes (using authors’
descriptions of ICH, because most studies began before standards for reporting of CCM ICH
were published,3 but we contacted authors for clarification if it was unclear whether ICHs
were symptomatic or accompanied by radiographic evidence of new hemorrhage). We aimed
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to collect these outcomes in three timeframes: 1) 30 days after intervention; 2) between 30
days and 1 year after intervention; 3) more than 1 year after intervention. If data were
provided in such a way that it was not possible to separate the outcomes according to these
timeframes, we collected all outcomes during the entire duration of follow-up.
Statistical analyses
We quantified the distribution of cohort-level characteristics with descriptive analyses. For
each comparative observational study, we determined whether it found a “dramatic”
association, defined as the conventionally calculated probability of the two differently
managed patient groups from the same population being <0.01 with a rate ratio >10.14 We
quantified the occurrence of outcomes after SRS either during the total person-years of
follow-up described, or by multiplying the median (or mean if median was not provided)
follow-up duration by the total number of treated patients. We calculated annual incidence
rates and their 95% CI with Poisson distributions using the Poisson command in STATA 15.
We intended to perform the following subgroup analyses: 1) outcomes in cohorts that
included 80% or more patients with brainstem CCM, 2) outcomes in cohorts that described
Gamma Knife SRS, and 3) by mode of CCM presentation. Our analyses are based on the
published aggregate results of individual studies, so individual-level data cannot be made
publicly available. All extracted data from the individual studies and the code used for
performing the meta-analyses can be made available upon reasonable request to the
corresponding author.
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Ethical approval
Approval from an institutional or regional review board was not required as all data used in
this study was extracted from publications.
Data availability
The analysis for this study is based on published results from individual studies. Therefore,
individual-level data cannot be made publicly available. All extracted data from the individual
studies and the code used for performing the meta-analyses can be made available upon
reasonable request to the corresponding author.
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RESULTS
After screening 361 references and excluding ineligible studies and smaller overlapping
reports of included studies (appendices 3 and 4), we included 30 studies of SRS treatment for
CCMs (figure 1 and appendix 4):15-44 three studies compared SRS to neurosurgery, one study
compared SRS to neurosurgery and conservative management,17, 19, 21, 35 and one study
compared two cohorts receiving different types of SRS,24 leaving 25 cohort studies of SRS
alone.15, 16, 18, 20, 22, 23, 25-34, 36-44
Study characteristics
In the 31 cohorts receiving SRS in 30 studies, including a total of 1,576 patients, the median
cohort-level attributes were: sample size 34 patients, duration of follow-up 48 months, age at
treatment 40 years, 48% female, 91% presented with ICH due to CCM, 65% CCM were
infratentorial and 35% were supratentorial (Table 1 and appendix 5). Twenty-nine (97%)
studies were from single centres15-21, 23-44 and one (3%) was multicenter (appendix 6).22 Fifteen
(50%) studies were from Asia,16, 19, 21-26, 28, 32, 34, 35, 38, 41, 43 nine (30%) from Europe,15, 17, 18, 20, 27, 29, 31,
39, 42 four (13%) from North America,30, 33, 36, 37 and two (7%) from South America.40, 44
In general, included studies were at medium to high risk of bias (appendices 6 and 7). None of
the studies was randomized, none concealed treatment allocation, and none used blinding of
allocation or outcome assessment, so they were at high risk of performance bias (appendix 7).
In the five studies (17%) with a comparison group, three studies were at high risk of selection
bias because there were significant differences between groups, but it was unclear if there
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were differences in the other two. Three (10%) cohorts identified patients prospectively,15, 30, 33
eight (27%) studies identified consecutive patients,15, 18-20, 26, 39, 41, 44 and four (13%) followed
patients prospectively. Twenty-seven (90%) studies appeared to be at low risk of attrition bias
and two (7%) confirmed full reporting of pre-specified outcomes. All studies were at low risk
of performance and detection bias for the primary outcome, since the outcome death is not
influenced by lack of blinding of participants and personnel.
Outcome after SRS compared other treatment strategies
One non-randomized study compared radiosurgery to neurosurgery and conservative
management21, three compared radiosurgery to neurosurgery,17, 19, 35 and one compared
Gamma Knife and linear accelerator SRS.24 These studies showed no dramatic associations
with primary and secondary outcomes and none was at low risk of bias (table 2).
Outcome after SRS
In 31 separate cohorts reporting the outcome after SRS in 30 studies for a total of 1,576
patients, 1,386 (88%) were treated with Gamma Knife SRS, 159 (10%) were treated with
linear accelerator SRS, and 31 (2%) were treated with CyberKnife SRS. The median margin
dose was 15 Gy and the median maximum dose was 25 Gy. We were unable to quantify
outcomes in our prespecified timeframes, so we calculated the incidence of outcomes per 100
person-years of follow-up over the durations of follow-up described in included studies. We
were unable to reliably quantify the frequency of adverse radiation effects, epileptic seizures,
and functional outcome in these studies because of variation between studies in the methods
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and completeness of reporting these outcomes. We were unable to quantify outcomes
according to mode of CCM presentation, because studies did not stratify their reporting of
outcomes by mode of presentation (which was mostly ICH, table 1).
The annual incidence of the primary outcome of death attributable to CCM or SRS was 0.18%
(95% CI 0.10-0.31) (table 3). The annual incidence of the secondary outcomes were:
symptomatic ICH 2.40% (95% CI 2.05-2.80), non-hemorrhagic persistent FND 0.71% (95%
CI 0.53-0.96), and in the 26 cohorts reporting on all components of the composite outcome,
the annual incidence was 3.63% (95% CI 3.17-4.16).
In nine studies that included 80% or more patients with brainstem CCM, 303 patients (298
[98%] of whom had a brainstem CCM) were treated with a median margin dose of 13 Gy and
median maximum dose 26 Gy. Their annual risks of death, ICH, and FND were not different
from the primary and secondary outcomes of the main analysis (table 4).
In twenty studies, 1,386 patients were treated with Gamma Knife SRS with a median margin
dose of 14 Gy and median maximum dose 30 Gy. Their annual risks of death, ICH, and FND
were not different from the primary and secondary outcomes of the main analysis (table 5).
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DISCUSSION
In this systematic review of SRS for CCM, we did not find any randomized trials, but
included 30 observational studies involving a total of 1,576 patients (median sample size 34,
age 40 years, 91% presented with ICH, 65% infratentorial CCM, and follow-up 48 months).
These studies were at medium to high risk of bias because of the lack of randomization,
allocation concealment, and blinding, although the risk of attrition bias was generally low.
Five (17%) non-randomized studies compared SRS to another treatment strategy, but none of
these studies was both at low risk of bias as well as finding dramatic associations with
outcome. Nonetheless, our pooled estimates of the outcomes after SRS reflect clinical practice
around the world, in which the annual incidences were: death attributable to CCM or SRS
0.18% (95% CI 0.10-0.31), symptomatic ICH 2.40% (95% CI 2.05-2.80), non-hemorrhagic
persistent FND 0.71% (95% CI 0.53-0.96), and the composite of all these outcomes was
3.63% (95% CI 3.17-4.16). We found no differences in studies focused on brainstem CCM or
using Gamma Knife SRS. We were unable to consistently extract and summarize data on
adverse radiation effects, epileptic seizures, or functional outcome.
The strengths of this review were its prespecified protocol, comprehensive literature searches,
absence of language restrictions, standardized assessment of risk of bias, the precision of the
pooled estimates of outcomes after SRS compared to a previous systematic review,6 and
exploration of two sub-groups. However, this review has some limitations. The included
studies were non-randomized, mostly lacked comparison groups, and were at moderate to
high risk of bias. We obtained aggregate data, and not individual patient data, so we could
only explore whether presentation with ICH and type of SRS were associated with differences
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in outcome, but we could not determine time trends in outcome over time. One new cohort of
45 patients and an update of an included cohort were published after the date of our literature
search and were not included,45-47 but are unlikely to have changed our conclusions.
Our pooled estimates of the risks of SRS for CCM over approximately four years after
treatment can be applied to clinical practice, especially for patients with CCM that have
caused ICH. The risks after SRS appear similar to the untreated clinical course of CCM, by
indirect comparison with the overall 5-year risk of ICH found in a patient-level meta-analysis
(15.8%, 95% CI 13.7-17.9).9 However, it is not possible to be confident in the beneficial
effects of SRS for CCM because of the shortage of comparative studies at low risk of bias,
leaving reassurance only from indirect comparisons with untreated clinical course or
neurosurgery.13, 48
Our findings have several implications for future research. Comparative, ideally randomized,
studies at low risk of bias with blinded assessment and standardized definitions of outcome3
are needed to be certain about the overall risks and benefits of SRS for CCM. The outcomes
observed in the cohort studies in this systematic review can inform sample size calculations in
future randomized trials (https://www.nihr.ac.uk/funding-and-support/funding-opportunities/
18186-active-management-vs-conservative-management-for-symptomatic-brain-cavernoma/
9700).
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ACKNOWLEDGEMENTS
We thank Bruce Pollock, Roman Liščák, Yang-Hsin Shih, Remedios López-Serrano, Sharon
Jay, and Yoshihisa Kida for providing further information about some of the cohorts included
in this systematic review. We are very grateful to Gabor Nagy, Jozsef Dobai, László Bognar,
Dániel Bereczki, Michael Poon, Murat Akyol, Ebru Mumcu, Shoichiro Sato, Kazutaka
Sonoda, Joan Marti Fabregas and Elena Lebedeva for helping with the translation and data
extraction from publications in Hungarian, Chinese, Turkish, Japanese, Spanish and Russian.
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Appendix. Author contributions
Name Location Role Contribution
Michiel Poorthuis
University Medical Centre Utrecht, The Netherlands
First author
Design and conceptualized study; Screened titles and abstracts of initial search and its update. Assessed full-text articles and reference lists of included studies; Extracted data from included studies; analyzed the data; drafted the manuscript for intellectual content
Leon Rinkel
University Medical Centre, Groningen, The Netherlands
Author
Screened titles and abstract of search update. Assessed full-text articles and reference lists of included studies; Extracted data from included studies; analyzed the data; drafted the manuscript for intellectual content
Simon Lammy
Queen Elizabeth University Hospital, Glasgow, UK
Author
Design and conceptualized study; Registered this study on PROSPERO. Performed initial literature search and removed duplicates; screened title and abstracts of initial search and assessed full-text articles; revised the manuscript for intellectual content
Rustam Al-Shahi Salman
Centre for Clinical Brain Sciences, University of Edinburgh, UK
Corresponding author
Design and conceptualized study; Interpreted the data; revised the manuscript for intellectual content; study supervision
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Table 1. Summary of the characteristics of all studies of SRS
Characteristics Median (inter-quartile range)
Cohorts reporting
characteristic
Patients reported
Number of patients treated 34 (16-82) 31 1576Duration of follow-up, months 48 (35-62) 30 1563Mid-year of treatment 2001 (1997-2014) 30 1565Age, years 40 (37.6-41.7) 28 1521Female sex, % 48 (45-57) 27 1504Multiple CCMs, % 7 (0-15) 23 1075Children, % 0 (0-0) 15 337Size, mm 15.5 (14.9-18) 4 342Size, cm3 1.37 (0.6-1.86) 20 807Previously treated with SRS 0 (0-2.4) 20 797Previously treated with surgery 0 (0-10.3) 19 705Re-treated after SRS with SRS 0 (0-1.0) 17 679Treated after SRS with surgery 0 (0-4.4) 16 576CCM associated with DVA, % 7 (0-23) 8 283CCM location Total supratentorial, % 35 (4-73) 28 1430 Lobar, % 18 (0-60) 28 1430 Basal ganglia and thalamus, % 13 (0.1-23) 28 1430 Total infratentorial, % 65 (27-96) 28 1430 Brainstem, % 61 (18-96) 28 1430 Cerebellum, % 0 (0-7.1) 28 1430Clinical presentation without symptoms, %
0 (0-0) 27 1409
Clinical presentation with ICH, % 91 (53-100) 26 1321Clinical presentation with seizures, %
4.8 (0-22) 26 1301
Marginal SRS dose (Gy) 15 (13-16) 30 1463Maximum SRS dose (Gy) 25 (22-30) 20 1218
CCM = cerebral cavernous malformation, SRS = stereotactic radiosurgery, DVA = developmental venous anomaly, ICH = intracerebral hemorrhage, Gy = Gray
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Table 2. Overview of outcomes in comparative cohorts
First author, year of
publication
Outcome Comparison of
treatment modalities
Number of
patients treated
(index / reference
group)
Number of patients
with outcome
(index / reference
group)
Statistical analyses comparing the
outcomes after treatment
1. Frischer et al, 201417 Death GKS vs. NS 38 / 29 0 / 0 Not performed
2. Hsu et al, 200719 Death GKS vs. NS 14 / 15 0 / 0 Not performed
ICH GKS vs. NS 14 / 15 0 / 0 Not performed
FND GKS vs. NS 14 / 15 0 / 0 Not performed
3. Kayali et al, 200421 Death GKS vs. NS vs. CM 13 / 3 / 21 0 / 1 / 0 Not performed
ICH GKS vs. NS vs. CM 13 / 3 / 21 0 / 0 / 0 Not performed
FND GKS vs. NS vs. CM 13 / 3 / 21 0 / 0 / 0 Not performed
4. Kim et al, 200224 Death GKS vs. LINAC 11 / 11 0 / 0 Not performed
ICH GKS vs. LINAC 11 / 11 1 / 0 Not performed
FND GKS vs. LINAC 11 / 11 0 / 2 No significant difference in
occurrence of FND
5. Shih and Pan, 200535 Death GKS vs. NS 30 / 16 0 / 0 Not performed
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ICH GKS vs. NS 30 / 16 1 / 0 Not performed
FND GKS vs. NS 30 / 16 NA / 0 Not performed
Abbreviations: ICH = symptomatic intracerebral hemorrhage. FND = Non-hemorrhagic persistent focal neurological deficit. GKS = Gamma
Knife Surgery. LINAC = Linear accelerator.
NS = Neurosurgery. CM = Conservative Management. NA= not available.
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Table 3. Incidence of outcomes after SRS
Cohorts (%)
Patients Total number of outcome events / total person-years
Median per cohort (inter-quartile range)
Outcome event annual incidence (95% CI) per 100 person-years
Follow-up, PY 30* 1563 - 124 (53-344) -Primary outcomeDeaths attributable to CCM or its treatment
30 1563 13 / 7305 0 (0-0) 0.18 (0.10-0.31)
Secondary outcomesICH 28 1403 160 / 6670 3 (1-4) 2.40 (2.05-2.80)FND 27 1383 44 / 6191 2 (0-3) 0.71 (0.53-0.96)Composite outcome of death, ICH or FND
26 1261 209 / 5754 5 (2-6) 3.63 (3.17-4.16)
CCM = cerebral cavernous malformation, CI = confidence interval, FND = non-fatal non-hemorrhagic persistent focal neurological deficit, ICH = non-fatal symptomatic intracranial hemorrhage with persistent focal neurological deficit.* One study describing SRS, neurosurgical intervention, and conservative management provided the total number of patient-years for all patients combined. Total number of patient-years could not be estimated for the different management options separately.
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Table 4. Incidence of outcomes after SRS in cohorts with ≥80% brainstem CCMs
Cohorts (%)
Patients Total number of outcome events / total person-years
Median per cohort (inter-quartile range)
Outcome event annual incidence (95% CI) per 100 person-years
Follow-up, PY 9 303 - 123 (70-146) -Primary outcomeDeaths attributable to CCM or its treatment
9 303 2 / 1163 0 (0-0) 0.17 (0.04-0.69)
Secondary outcomesICH 9 303 30 / 1163 3 (2-4) 2.58 (1.80-3.69)FND 9 303 8 / 1163 0 (0-1) 0.69 (0.34-1.38)Composite outcome of death, ICH or FND
9 303 40 / 1163 5 (2-6) 3.44 (2.52-4.69)
CCM = cerebral cavernous malformation, CI = confidence interval, FND = non-fatal non-
hemorrhagic persistent focal neurological deficit, ICH = non-fatal symptomatic intracranial
hemorrhage with persistent focal neurological deficit.
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Table 5. Incidence of outcomes after Gamma Knife SRS
Cohorts (%)
Patients Total number of outcome events / total person-years
Median per cohort (inter-quartile range)
Outcome event annual incidence (95% CI) per 100 person-years
Follow-up, PY 20 1386 - 156 (88-421) -Primary outcomeDeaths attributable to CCM or its treatment
20 1386 11 / 6504 0 (0-1) 0.17 (0.09-0.31)
Secondary outcomesICH 18 1226 139 / 5870 3 (1-6) 2.37 (2.01 -2.80)FND 17 1206 31 / 5390 1 (0-3) 0.58 (0.40-0.82)Composite outcome of death, ICH or FND
16 1084 173 / 4953 5 (2-9) 3.49 (3.01-4.05)
CCM = cerebral cavernous malformation, CI = confidence interval, FND = non-fatal non-
hemorrhagic persistent focal neurological deficit, ICH = non-fatal symptomatic intracranial
hemorrhage with persistent focal neurological deficit.
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