Clinical course of untreated cerebral cavernous malformations:  A meta-analysis of individual patient data

the Cerebral Cavernous Malformations Individual Patient Data Meta-analysis Collaborators; Margaret A Horne; Kelly D.  Flemming; I-Chang  Su; Christian Stapf; Jin Pyeong  Jeon; Da  Li; Susanne S. Maxwell; Philip White; Teresa J.  Christianson; Ronit Agid; Won-Sang  Cho; Chang Wan  Oh; Zhen  Wu; Jun-Ting  Zhang; Jeong Eun  Kim; Karel   ter Brugge; Robert  Willinsky; Robert D.  Brown; Gordon D Murray; Rustam Al-Shahi Salman

doi:10.1016/S1474-4422(15)00303-8

Clinical course of untreated cerebral cavernous malformations: A meta-analysis of individual patient data

the Cerebral Cavernous Malformations Individual Patient Data Meta-analysis Collaborators, Margaret A Horne, Kelly D. Flemming , I-Chang Su , Christian Stapf, Jin Pyeong Jeon , Da Li, Susanne S. Maxwell, Philip White, Teresa J. Christianson, Ronit Agid, Won-Sang Cho , Chang Wan Oh , Zhen Wu, Jun-Ting Zhang , Jeong Eun Kim , Karel ter Brugge , Robert Willinsky, Robert D. Brown , Gordon D MurrayRustam Al-Shahi Salman

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Background: Cerebral cavernous malformations (CCMs) can cause symptomatic intracranial haemorrhage (ICH), but the estimated risks are imprecise and predictors remain uncertain. We aimed to obtain precise estimates and predictors of the risk of ICH during untreated follow-up in an individual patient data meta-analysis.

Methods: We invited investigators of published cohorts of people aged at least 16 years, identified by a systematic review of Ovid MEDLINE and Embase from inception to April 30, 2015, to provide individual patient data on clinical course from CCM diagnosis until first CCM treatment or last available follow-up. We used survival analysis to estimate the 5-year risk of symptomatic ICH due to CCMs (primary outcome), multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in a meta-analysis.

Findings: Among 1620 people in seven cohorts from six studies, 204 experienced ICH during 5197 person-years of follow-up (Kaplan-Meier estimated 5-year risk 15·8%, 95% CI 13·7–17·9). The primary outcome of ICH within 5 years of CCM diagnosis was associated with clinical presentation with ICH or new focal neurological deficit (FND) without brain imaging evidence of recent haemorrhage versus other modes of presentation (hazard ratio 5·6, 95% CI 3·2–9·7) and with brainstem CCM location versus other locations (4·4, 2·3–8·6), but age, sex, and CCM multiplicity did not add independent prognostic information. The 5-year estimated risk of ICH during untreated follow-up was 3·8% (95% CI 2·1–5·5) for 718 people with non-brainstem CCM presenting without ICH or FND, 8·0% (0·1–15·9) for 80 people with brainstem CCM presenting without ICH or FND, 18·4% (13·3–23·5) for 327 people with non-brainstem CCM presenting with ICH or FND, and 30·8% (26·3–35·2) for 495 people with brainstem CCM presenting with ICH or FND.

Interpretation: Mode of clinical presentation and CCM location are independently associated with ICH within 5 years of CCM diagnosis. These findings can inform decisions about CCM treatment.

Funding: UK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.

Original language	English
Pages (from-to)	166–173
Number of pages	8
Journal	Lancet Neurology
Volume	15
Issue number	2
Early online date	1 Dec 2015
DOIs	https://doi.org/10.1016/S1474-4422(15)00303-8
Publication status	Published - 1 Feb 2016

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Cerebral Amyloid Angiopathy and intracerebral Haemorrage
Salman, R.
MRC
1/08/11 → 31/01/17
Project: Research
MRC HUB NETWORK WORK
Murray, G.
MRC
1/01/09 → 31/08/15
Project: Research
MRC clinician scientist fellowship: prognosis and management of intracranial vascular malformations in adults
Salman, R.
MRC
1/11/05 → 28/02/11
Project: Research

Invited speaker
Rustam Al-Shahi Salman (Speaker)
10 May 2016 → 12 May 2016
Activity: Academic talk or presentation types › Invited talk

Rustam Salman
- Rustam.Al-Shahied.acuk
- Deanery of Clinical Sciences - Personal Chair of Clinical Neurology
- Centre for Clinical Brain Sciences
- Anne Rowling Regenerative Neurology Clinic
- Edinburgh Neuroscience
- Edinburgh Imaging
- Cerebrovascular Research Group
- Edinburgh Clinical Trials Unit
Person: Academic: Research Active

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the Cerebral Cavernous Malformations Individual Patient Data Meta-analysis Collaborators, Horne, M. A., Flemming , K. D., Su , I.-C., Stapf, C., Jeon , J. P., Li, D., Maxwell, S. S., White, P., Christianson, T. J., Agid, R., Cho , W.-S., Oh , C. W., Wu, Z., Zhang , J.-T., Kim , J. E., ter Brugge , K., Willinsky, R., Brown , R. D., ... Salman, R. A.-S. (2016). Clinical course of untreated cerebral cavernous malformations: A meta-analysis of individual patient data. Lancet Neurology, 15(2), 166–173. https://doi.org/10.1016/S1474-4422(15)00303-8

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title = "Clinical course of untreated cerebral cavernous malformations: A meta-analysis of individual patient data",

abstract = "Background: Cerebral cavernous malformations (CCMs) can cause symptomatic intracranial haemorrhage (ICH), but the estimated risks are imprecise and predictors remain uncertain. We aimed to obtain precise estimates and predictors of the risk of ICH during untreated follow-up in an individual patient data meta-analysis.Methods: We invited investigators of published cohorts of people aged at least 16 years, identified by a systematic review of Ovid MEDLINE and Embase from inception to April 30, 2015, to provide individual patient data on clinical course from CCM diagnosis until first CCM treatment or last available follow-up. We used survival analysis to estimate the 5-year risk of symptomatic ICH due to CCMs (primary outcome), multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in a meta-analysis.Findings: Among 1620 people in seven cohorts from six studies, 204 experienced ICH during 5197 person-years of follow-up (Kaplan-Meier estimated 5-year risk 15·8%, 95% CI 13·7–17·9). The primary outcome of ICH within 5 years of CCM diagnosis was associated with clinical presentation with ICH or new focal neurological deficit (FND) without brain imaging evidence of recent haemorrhage versus other modes of presentation (hazard ratio 5·6, 95% CI 3·2–9·7) and with brainstem CCM location versus other locations (4·4, 2·3–8·6), but age, sex, and CCM multiplicity did not add independent prognostic information. The 5-year estimated risk of ICH during untreated follow-up was 3·8% (95% CI 2·1–5·5) for 718 people with non-brainstem CCM presenting without ICH or FND, 8·0% (0·1–15·9) for 80 people with brainstem CCM presenting without ICH or FND, 18·4% (13·3–23·5) for 327 people with non-brainstem CCM presenting with ICH or FND, and 30·8% (26·3–35·2) for 495 people with brainstem CCM presenting with ICH or FND.Interpretation: Mode of clinical presentation and CCM location are independently associated with ICH within 5 years of CCM diagnosis. These findings can inform decisions about CCM treatment.Funding: UK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.",

author = "{the Cerebral Cavernous Malformations Individual Patient Data Meta-analysis Collaborators} and Horne, {Margaret A} and Flemming, {Kelly D.} and I-Chang Su and Christian Stapf and Jeon, {Jin Pyeong} and Da Li and Maxwell, {Susanne S.} and Philip White and Christianson, {Teresa J.} and Ronit Agid and Won-Sang Cho and Oh, {Chang Wan} and Zhen Wu and Jun-Ting Zhang and Kim, {Jeong Eun} and {ter Brugge}, Karel and Robert Willinsky and Brown, {Robert D.} and Murray, {Gordon D} and Salman, {Rustam Al-Shahi}",

year = "2016",

month = feb,

day = "1",

doi = "10.1016/S1474-4422(15)00303-8",

language = "English",

volume = "15",

pages = "166–173",

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the Cerebral Cavernous Malformations Individual Patient Data Meta-analysis Collaborators, Horne, MA, Flemming , KD, Su , I-C, Stapf, C, Jeon , JP, Li, D, Maxwell, SS, White, P, Christianson, TJ, Agid, R, Cho , W-S, Oh , CW, Wu, Z, Zhang , J-T, Kim , JE, ter Brugge , K, Willinsky, R, Brown , RD, Murray, GD & Salman, RA-S 2016, 'Clinical course of untreated cerebral cavernous malformations: A meta-analysis of individual patient data', Lancet Neurology, vol. 15, no. 2, pp. 166–173. https://doi.org/10.1016/S1474-4422(15)00303-8

Clinical course of untreated cerebral cavernous malformations: A meta-analysis of individual patient data. / the Cerebral Cavernous Malformations Individual Patient Data Meta-analysis Collaborators; Horne, Margaret A; Flemming , Kelly D. et al.
In: Lancet Neurology, Vol. 15, No. 2, 01.02.2016, p. 166–173.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Clinical course of untreated cerebral cavernous malformations

T2 - A meta-analysis of individual patient data

AU - the Cerebral Cavernous Malformations Individual Patient Data Meta-analysis Collaborators

AU - Horne, Margaret A

AU - Flemming , Kelly D.

AU - Su , I-Chang

AU - Stapf, Christian

AU - Jeon , Jin Pyeong

AU - Li, Da

AU - Maxwell, Susanne S.

AU - White, Philip

AU - Christianson, Teresa J.

AU - Agid, Ronit

AU - Cho , Won-Sang

AU - Oh , Chang Wan

AU - Wu, Zhen

AU - Zhang , Jun-Ting

AU - Kim , Jeong Eun

AU - ter Brugge , Karel

AU - Willinsky, Robert

AU - Brown , Robert D.

AU - Murray, Gordon D

AU - Salman, Rustam Al-Shahi

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Background: Cerebral cavernous malformations (CCMs) can cause symptomatic intracranial haemorrhage (ICH), but the estimated risks are imprecise and predictors remain uncertain. We aimed to obtain precise estimates and predictors of the risk of ICH during untreated follow-up in an individual patient data meta-analysis.Methods: We invited investigators of published cohorts of people aged at least 16 years, identified by a systematic review of Ovid MEDLINE and Embase from inception to April 30, 2015, to provide individual patient data on clinical course from CCM diagnosis until first CCM treatment or last available follow-up. We used survival analysis to estimate the 5-year risk of symptomatic ICH due to CCMs (primary outcome), multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in a meta-analysis.Findings: Among 1620 people in seven cohorts from six studies, 204 experienced ICH during 5197 person-years of follow-up (Kaplan-Meier estimated 5-year risk 15·8%, 95% CI 13·7–17·9). The primary outcome of ICH within 5 years of CCM diagnosis was associated with clinical presentation with ICH or new focal neurological deficit (FND) without brain imaging evidence of recent haemorrhage versus other modes of presentation (hazard ratio 5·6, 95% CI 3·2–9·7) and with brainstem CCM location versus other locations (4·4, 2·3–8·6), but age, sex, and CCM multiplicity did not add independent prognostic information. The 5-year estimated risk of ICH during untreated follow-up was 3·8% (95% CI 2·1–5·5) for 718 people with non-brainstem CCM presenting without ICH or FND, 8·0% (0·1–15·9) for 80 people with brainstem CCM presenting without ICH or FND, 18·4% (13·3–23·5) for 327 people with non-brainstem CCM presenting with ICH or FND, and 30·8% (26·3–35·2) for 495 people with brainstem CCM presenting with ICH or FND.Interpretation: Mode of clinical presentation and CCM location are independently associated with ICH within 5 years of CCM diagnosis. These findings can inform decisions about CCM treatment.Funding: UK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.

AB - Background: Cerebral cavernous malformations (CCMs) can cause symptomatic intracranial haemorrhage (ICH), but the estimated risks are imprecise and predictors remain uncertain. We aimed to obtain precise estimates and predictors of the risk of ICH during untreated follow-up in an individual patient data meta-analysis.Methods: We invited investigators of published cohorts of people aged at least 16 years, identified by a systematic review of Ovid MEDLINE and Embase from inception to April 30, 2015, to provide individual patient data on clinical course from CCM diagnosis until first CCM treatment or last available follow-up. We used survival analysis to estimate the 5-year risk of symptomatic ICH due to CCMs (primary outcome), multivariable Cox regression to identify baseline predictors of outcome, and random-effects models to pool estimates in a meta-analysis.Findings: Among 1620 people in seven cohorts from six studies, 204 experienced ICH during 5197 person-years of follow-up (Kaplan-Meier estimated 5-year risk 15·8%, 95% CI 13·7–17·9). The primary outcome of ICH within 5 years of CCM diagnosis was associated with clinical presentation with ICH or new focal neurological deficit (FND) without brain imaging evidence of recent haemorrhage versus other modes of presentation (hazard ratio 5·6, 95% CI 3·2–9·7) and with brainstem CCM location versus other locations (4·4, 2·3–8·6), but age, sex, and CCM multiplicity did not add independent prognostic information. The 5-year estimated risk of ICH during untreated follow-up was 3·8% (95% CI 2·1–5·5) for 718 people with non-brainstem CCM presenting without ICH or FND, 8·0% (0·1–15·9) for 80 people with brainstem CCM presenting without ICH or FND, 18·4% (13·3–23·5) for 327 people with non-brainstem CCM presenting with ICH or FND, and 30·8% (26·3–35·2) for 495 people with brainstem CCM presenting with ICH or FND.Interpretation: Mode of clinical presentation and CCM location are independently associated with ICH within 5 years of CCM diagnosis. These findings can inform decisions about CCM treatment.Funding: UK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.

U2 - 10.1016/S1474-4422(15)00303-8

DO - 10.1016/S1474-4422(15)00303-8

M3 - Article

SN - 1474-4422

VL - 15

SP - 166

EP - 173

JO - Lancet Neurology

JF - Lancet Neurology

IS - 2

ER -

Clinical course of untreated cerebral cavernous malformations: A meta-analysis of individual patient data

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Projects

Cerebral Amyloid Angiopathy and intracerebral Haemorrage

MRC HUB NETWORK WORK

MRC clinician scientist fellowship: prognosis and management of intracranial vascular malformations in adults

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Invited speaker

Profiles

Rustam Salman

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