Comment

Intracranial aneurysms: individualising the risk of rupture
The decision of what to do with asymptomatic
unruptured intracranial aneurysms is a fairly newproblem. Although these aneurysms have been known
to exist for centuries through autopsies and for several
decades through catheter angiography, their true
prevalence did not begin to emerge until the use of
non-invasive angiograms became widespread in therecent past. Now we know that nearly 3% of the general
population has an unruptured intracranial aneurysm.1
Comparatively, subarachnoid haemorrhages fromaneurysmal rupture are relatively uncommon. This
discrepancy indicates that many intracranial aneurysms
are not destined to rupture. Yet, the consequences ofrupture can be devastating.2 Treatment of the aneurysm
by craniotomy and clipping or by endovascular coilingcan eﬀectively eliminate the risk of subarachnoid
haemorrhages, but treatment of all unruptured
intracranial aneurysms is neither prudent, because of
the risk of iatrogenic complications, nor parsimonious,
because of the high ﬁnancial cost.3 Thus, when advisinga patient with an asymptomatic unruptured intracranial
aneurysm we face a diﬃcult problem. An adequate
solution can only be based on individualisation of therupture risk.
In The Lancet Neurology, Jacoba Greving andcolleagues4 present their analysis of individual patient
data pooled from six prospective cohort studies on thenatural history of unruptured intracranial aneurysms(three from Japan, one from the Netherlands, one fromFinland, and one from the USA, Canada, and various
European countries). The large sample size of the
combined population allowed the researchers to reﬁnethe estimation of rupture risk at 1 and 5 years, deﬁne thestrongest predictors of rupture among those evaluatedin the original studies, and develop a score (namedPHASES) to gauge the individual risk of rupture using
readily available information. The information provided
is solid and has practical value. I plan to use it whenadvising my patients, although keeping in mind certaincaveats.
The PHASES score is calculated from the region oforigin of the patient (attributing a higher risk to Finnishand Japanese patients than to all others, althoughspeciﬁc information is not available for most worldregions), presence of hypertension, patient’s age(dichotomised at 70 years), maximum diameter of theaneurysm (by far the strongest predictor of rupture),
previous history of subarachnoid haemorrhage fromanother aneurysm, and the site of the aneurysm (witha higher risk assigned to aneurysms arising from theanterior cerebral arteries, posterior communicatingarteries, or the posterior circulation vessels). Notableabsences include smoking (at entry and on follow-up),5
hypertension control, family history of subarachnoid
haemorrhage, multiplicity of unruptured intracranial
aneurysms, other anatomical and haemodynamic
factors of the aneurysm (inﬂow angle, concentrated
inﬂow jets, complex ﬂow patterns, non-sphericalshape, dome-to-neck ratio),6 and, most importantly,
evidence of aneurysm growth over time.7 Yet, these
additional factors also deserve careful consideration.
Smoking cessation and control of hypertension might
reduce rupture risk.8 Follow-up imaging to exclude
aneurysm growth is necessary because growth isstrongly associated with increased risk of subarachnoid
haemorrhage,7 although the optimum frequency andduration of radiological follow up is not well deﬁned.
The Article also incorporates charts oﬀering speciﬁc
5-year risk prediction for diﬀerent populations. Readers
should note that the chart that would apply to North
America and European countries other than Finlandis based on information from the large ISUIA cohort(1691 patients with a median follow-up of 9 years)9

Published Online
November 27, 2013
http://dx.doi.org/10.1016/
S1474-4422(13)70272-2
See Online/Articles
http://dx.doi.org/10.1016/
S1474-4422(13)70263-1

Diagnosis of unruptured
intracranial aneurysm

Individual estimate ofrupture risk (PHASES score)
LowHigh

Smoking cessation
Control of hypertension

Smoking cessation
Control of hypertension

Clinical and radiologicalfollow-up

Aneurysm treatment

Treat aneurysm if symptoms
or evidence of growth

Figure: Proposed algorithm for the management of unruptured intracranial
aneurysms

www.thelancet.com/neurology Published online November 27, 2013 http://dx.doi.org/10.1016/S1474-4422(13)70272-2

1

Commentand the much smaller Dutch cohort of the study byWermer and colleagues (93 patients with a medianfollow-up of 2·2 years).10 The risk predictions on thischart are therefore mainly derived from the ISUIA
cohort, which highlights the limitations of pooling datafrom heterogeneous cohorts of very diﬀerent sizes.
Nonetheless, the information on this chart is presented
in a visually appealing and user-friendly format andrepresents a reﬁnement of individual risk stratiﬁcation.
The greatest caveat in the interpretation of these risk
estimates is that they are based on cohorts of patientsfor whom treatment of the aneurysm was left at thediscretion of the patient’s physician. Patients thought to
be at high risk of rupture might have been treated at ﬁrst
recognition of the aneurysm (thus not being enteredinto the observational cohort) or after developing
symptomatic or asymptomatic aneurysm growth
without rupture (thus being censored from the cohort inwhich they had been enrolled). This selection bias aﬀects
the reliability of the risk predictions presented in thisanalysis. If aneurysms deemed at greatest risk of rupture
had not been treated, the observed rates of rupture
would probably have been higher. Consequently, therupture rates presented in this pooled analysis might
be an underestimation of the actual risks. Yet, this bias
should not aﬀect the value of the predictive factors for
rupture identiﬁed in the proposed model.
As correctly pointed out by the investigators, apure natural history study on the risk of rupture of
intracranial aneurysms is impossible because treatment
is favoured over observation in a substantial proportionof cases. Whether treatment is truly a better option for
all patients with unruptured intracranial aneurysm is2a question that could only be answered by a rigorous
randomised clinical trial. As the matter stands, we haveto rely on our clinical judgment and the best available
information about risk of rupture to oﬀer individualised
advice to our patients (ﬁgure). Such information
is provided by Greving and colleagues’ study4 andpragmatically summarised in the PHASES score.
Alejandro A Rabinstein
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
rabinstein.alejandro@mayo.edu
I declare that I have no conﬂicts of interest.
12345678910Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured
intracranial aneurysms, with emphasis on sex, age, comorbidity, country,
and time period: a systematic review and meta-analysis. Lancet Neurol
2011; 10: 626–36.
Rabinstein AA, Lanzino G, Wijdicks EF. Multidisciplinary management andemerging therapeutic strategies in aneurysmal subarachnoid
haemorrhage. Lancet Neurol 2010; 9: 504–19.
Brinjikji W, Kallmes DF, Lanzino G, Cloft HJ. Hospitalization costs forendovascular and surgical treatment of unruptured cerebral aneurysms in
the United States are substantially higher than medicare payments.
AJNR Am J Neuroradiol 2012; 33: 49–51.
Greving JP, Wermer MJH, Brown RD Jr, et al. Development of the PHASES
score for prediction of risk of rupture of intracranial aneurysms: a pooled
analysis of six prospective cohort studies. Lancet Neurol 2013; published
online Nov 27. http://dx.doi.org/10.1016/S1474-4422(13)70263-1.
Vlak MH, Rinkel GJ, Greebe P, Algra A. Risk of rupture of an intracranialaneurysm based on patient characteristics: a case-control study. Stroke2013; 44: 1256–59.
Cebral JR, Mut F, Weir J, Putman CM. Association of hemodynamic
characteristics and cerebral aneurysm rupture. AJNR Am J Neuroradiol 2011;32: 264–70.
Burns JD, Huston J 3rd, Layton KF, et al. Intracranial aneurysm enlargement
on serial magnetic resonance angiography: frequency and risk factors.
Stroke 2009; 40: 406–11.
Lindekleiv H, Sandvei MS, Romundstad PR, et al. Joint eﬀect of modiﬁable
risk factors on the risk of aneurysmal subarachnoid hemorrhage: a cohort
study. Stroke 2012; 43: 1885–89.
International Study of Unruptured Intracranial Aneurysms Investigators.
Unruptured intracranial aneurysms: natural history, clinical outcome, andrisks of surgical and endovascular treatment. Lancet 2003; 362: 103–10.
Wermer MJ, van der Schaaf IC, Velthuis BK, Majoie CB, Albrecht KW,Rinkel GJ. Yield of short-term follow-up CT/MR angiography for small
aneurysms detected at screening. Stroke 2006; 37: 414–18.

www.thelancet.com/neurology Published online November 27, 2013 http://dx.doi.org/10.1016/S1474-4422(13)70272-2