NEUROLOGICAL DILEMMAS How to manage the patient with …aneurysm or a family history of aneurysmal subarachnoid haemorrhage (SAH). Before you can counsel these people, it is ﬁ rst

PRACTICAL NEUROLOGY88

© 2004 Blackwell Publishing Ltd

How to manage the patient with a family history of aneurysmal subarachnoid haemorrhage

NEUROLOGICAL DILEMMAS

P. M. WhiteConsultant NeuroradiologistDepartment of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK; E-mail: [email protected] Neurology, 2004, 4, 88–103

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INTRODUCTION‘The truth is rarely pure and never simple’. So said Oscar Wilde, and this is certainly the case for individuals with an unruptured intracranial aneurysm or a family history of aneurysmal subarachnoid haemorrhage (SAH). Before you can counsel these people, it is fi rst necessary for the clinician to have a grasp of this complex area because once you have told the patient something it cannot be untold. You might sub-sequently expand on the information imparted, but you cannot remove it – correct or incorrect – from the patient’s mind (Fuller 2001). In this article I will summarize the relevant knowledge, and offer some advice, on management in this rather fraught area of medicine.

‘The truth is rarely

pure and never

simple’

There are several stages of assessment and management to consider:• What is an individual’s risk of harbouring an

aneurysm?• How best to detect an aneurysm without

exposing the patient to unnecessary stress or risk?

• If an asymptomatic aneurysm is found, what is the risk of rupture?

• What treatment, if any, should be offered and what are the risks involved?

Most importantly, the risk at each stage must be weighed against the risk of not doing anything. The pros and cons of screening for aneurysms will also be briefl y considered to place some of this information in context.

WHAT IS THE FREQUENCY OF INTRA-CRANIAL ANEURYSMS IN THE GENERAL POPULATION?What is anyone’s risk of harbouring an aneu-rysm, after all incidental aneurysms are com-monly found at autopsy? Rinkel et al. identifi ed autopsy studies where the prevalence of unrup-tured aneurysms ranged from 0.4% to 3.6% for retro and prospective studies, respectively, and in retro and prospective angiography studies from 3.7% to 6%, respectively (Rinkel et al. 1998). More recent studies are more in line with the higher fi gures from the prospective studies (Kojima et al. 1998; Ronkainen et al. 1998). In a higher-risk group of patients, because they had already ruptured an aneurysm, 20–25% had at least one unruptured aneurysm on angiography (Lozano & Leblanc 1987). So approximately one in 20 of the population aged over 30 harbour an unruptured aneurysm. However, it is important to remember that, with an aneurysmal SAH in-cidence of about 8 per 100 000 per annum (Wardlaw & White 2000), clearly only a very small proportion of these aneurysms actually rupture (about 0.1–0.2% pa).

ARE SPECIFIC GROUPS AT PARTICU-LARLY HIGH RISK OF INTRACRANIAL ANEURYSMS?The risk factors for SAH and for having an unruptured intracranial aneurysm are very similar (Table 1). In addition, several genetic conditions are associated with intracranial aneurysms, although these represent less than 10% of all cases:• 10–15% of patients with adult polycystic

kidney disease (ADPKD) (Rinkel et al. 1998), particularly if there is a family history of aneurysms and/or SAH (Hughes et al. 1996; Ruggieri et al. 1994);

• type IV Ehlers–Danlos syndrome (Schievink et al. 1990);

• possibly pseudoxanthoma elasticum (Muny-er & Margulis 1981), although this has been refuted (van den Berg et al. 1999);

• hereditary haemorrhagic telangiectsaia (Roman et al. 1978);

• neurofi bromatosis type I (Mulvihill et al. 1990; Morooka & Waga 1991);

• alpha1-antitrypsin defi ciency (Schievink et al. 1996).Marfan’s syndrome was thought to be associ-

ated with aneurysms but a detailed study of 135 patients (mean age 21 years) found no evidence



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of a relationship (van den Berg et al. 1996), although the patients may not have been old enough for the aneurysms to have developed.

In addition, aneurysmal SAH may affect sev-eral members of a family without any specifi c genetic ‘disease’. Familial SAH has been defi ned inconsistently, so here I mean a family in which two or more close blood relatives (fi rst or second degree) have a history of aneurysmal SAH with-out any other known heritable disease (fi rst-degree relatives = parents, siblings, children; second degree = grandparents, grandchildren, aunts and uncles, nieces and nephews; third degree = cousins, great grandparents, great grandchildren)

It has been suggested that many cases of ‘familial intracranial aneurysms’ might simply represent accidental aggregation (ter Berg et al. 1992); on the basis of chance alone, each SAH patient has a 5.6% possibility of having a fi rst- to third-degree relative also affected by SAH (ter Berg et al. 1992), and the proportion of SAH patients with third-degree relatives who had had an SAH is the same as the proportion with SAH in the control population (De Braekeleer et al. 1996).

Since 1987, 10 studies have examined the prevalence of unruptured aneurysms and/or SAH amongst relatives of patients with SAH

(Table 2). The relative risk for SAH in relatives compared with the background population was 2.9–6.6 for fi rst-degree relatives and 1.6–2.1 for second degree. Whilst these relative risks appear large, it is important to remember the small absolute number of relatives affected: only 156/21054 (0.74%) fi rst-degree relatives were them-selves affected by SAH. In our Scottish study (in press) the risk of SAH among family members over the decade after the index case had their SAH was 1.2% for fi rst-degree and 0.5% for second-degree relatives (some 12 and 5 times, respectively, the background population SAH risk) (Wardlaw et al., in press).

Familial intracranial aneurysms may have distinguishing biological features, including: rupture at a younger age (most frequently in the fi fth decade compared to the sixth decade for sporadic SAH) (Bromberg et al. 1995); worse clinical outcome; and an increased prevalence of middle cerebral artery aneurysms (Kojima et al. 1998; Bromberg et al. 1995). There may be a younger age of rupture in subsequent generations, implying ‘anticipation’ (Interna-tional Subarachnoid Aneurysm Trial 2002) but familial aneurysms may also have a predilection towards rupture in the same decade in individu-als of the same family, particularly in siblings (Leblanc 1997).

Approximately

one in 20 of the

population aged

over 30 harbour

an unruptured

aneurysm

RISK OF PREVALENCE OF RELATIVE

RISK FACTOR ANEURYSM SAH ANEURYSMS RISK REFERENCE

Female gender + + 1.6 Linn et al. 1996

Current smoking + + 1.9 Teunissen et al. 1996

Hypertension – + 2.8 Teunissen et al. 1996

Alcohol (heavy consumption) – + 4.7 Teunissen et al. 1996

Oral contraceptive pill ? + 1.5 (low dose) Johnston et al. 1998

1.9 (high dose)

Heavy physical exertion – + 2.7 (odds ratio) Anderson et al. 1993

Atherosclerosis ? + 2.3 Rinkel et al. 1998

Ischaemic heart disease in woman + + (4.3) Uehara et al. 1998

Cholesterol > 6.3 mmol/L ? + 10.2 (odds ratio) Adamson et al. 1994

Autosomal dominant polycystic + + 10–15% 4.4 Rinkel et al. 1998

kidney disease

Familial (2 or more fi rst- or second- + + 9.8% 4.0 Rinkel et al. 1998

degree relatives)

First-degree relatives in families + + 4.5% 1.8 see Table 2

with one affected member

Table 1 Risk factors for intracranial aneurysms, and for subarachnoid haemorrhage



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WHICH RELATIVES ARE MOST FREQUENTLY AFFECTED BY SAH?In families with more than one person with SAH, the most frequent relationship is index patient to sibling, followed by index patient to parent (Wardlaw & White 2000). However, a parent was affected in only 29% so in less than one-third of affected families was there a clear warning of the potential for SAH from a previ-ous generation. Interestingly, one study found a much stronger familial link to maternal SAH than to paternal or sibling SAH (Okamoto et al. 2003) and in another study, the slightly more commonly affected fi rst-degree relatives were also parents (38%) rather than siblings (33%) (Wardlaw, in press). Only our Scottish study has prospectively investigated the interaction be-tween the type of relationship and involvement of more than one family member (with SAH) on the risk of SAH to the other family members (Table 3). Here, there was a hierarchy of ascend-ing risk from a second-degree relative and no other family members affected (0.3% cumula-tive lifetime SAH risk) to the highest risk in a member of a family with at least two fi rst-degree relatives affected (7% cumulative lifetime SAH risk) (Wardlaw in press).

HOW BEST TO DETECT AN ANEURYSM?The gold standard is an intra-arterial digital subtraction angiogram (IADSA) with selective cerebral arterial injections and multiple projec-tions, particularly using the 3D DSA technique (Fig. 1). However, IADSA is invasive, costly, and not without risk of a permanent neurological complication. In patients with SAH, suspected aneurysm or arteriovenous malformation, this

NUMBER OF SAH CUMULATIVE SAH RISK

FAMILY HISTORY OF SAH EVENTS OCCURRING (BIRTH TO 70 YEARS)

One second-degree relative with SAH 6 0.3%

One fi rst-degree relative 7 0.8%

No fi rst but at least two second-degree relatives 1 1%

One fi rst and at least one second-degree relative 2 2%

At least two fi rst-degree relatives 4 7%

Table 3 Relationship between the family history of an index subarachnoid haemorrhage (SAH) case and the

risk of SAH to other family members

Analysis based on 3213 relatives of 148 index cases.

Risk prior to 30 years of age is extremely low.

For comparison, the background population risk of SAH is ~0.06% per decade.

risk was 0.07% (Cloft et al. 1999). Non-invasive tests, such as magnetic resonance angiography (MRA), dynamic spiral CT Angiography (CTA) and transcranial Doppler sonography (TCDS) (Fig. 2) are attractive for detecting asympto-matic intracranial aneurysms but they have to be extremely accurate to replace IADSA. So how accurate are they?

Analysis of accuracy per patient rather than per aneurysm is of more clinical relevance to ‘screening’ an individual for aneurysms. Most studies reported apparently excellent results but were in patients with a recent SAH so the aneu-rysm prevalence was high (Table 4) (White et al. 2000). As a result the sensitivities, specifi cities and predictive values must be interpreted with caution, particularly if one is extrapolating to using the non-invasive test in a low aneurysm prevalence population where far more positive test results will be false positives. Crucially, the results for non-invasive imaging methods are signifi cantly poorer for aneurysms < 5 mm in size, which constitute as many as one-third of aneurysms in asymptomatic patients (Kojima et al. 1998) (Fig. 3). Sensitivities are in the order of 35%, 57% and 35% for aneurysms < 5 mm diameter for MRA, CTA and TCDS, respectively (White et al. 2001; White et al. 2001) ICA an-eurysms are even harder to detect (White et al. 2000, 2001). Ultrasound has the advantage of the lowest capital cost, and portability, and with contrast agents and 3-D imaging the accuracy may improve towards the level of CTA/MRA (Wardlaw & White 2000). Unfortunately, about 10% of patients will not have an adequate bone window and the technique is operator depend-ent.



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Figure 1 (a) Imaging of a large anterior communicating artery aneurysm (arrow) with standard 2D intra-

arterial digital subtraction angiography (IADSA). By comparison, the 3D IADSA image (b) demonstrates

the detailed anatomy of the aneurysm, particularly the neck, far more clearly. Note additional right middle

carotid artery aneurysm*.

Figure 2 (a) Right terminal carotid bifurcation aneurysm (arrow) demonstrated on 2D intra-arterial digital subtraction angiography (b) MRA

– Maximum Intensity Projection (MIP) and (c) CTA MIP images. This was a ruptured aneurysm and the associated haematoma results in marked T1

breakthrough effect on the MRA MIP image – highlighting the location of the aneurysm. This effect (or the blood distribution on CT) is one reason

why diagnostic accuracy studies on SAH patients cannot be readily extrapolated into the screening context.

�

*

(a) (b)

(a) (b) (c)



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More recently there have been further studies of non-invasive imaging tests vs. IADSA (White et al. 2001a; White et al. 2001b; Okahara et al. 2002; Chung et al. 1999; Jager et al. 2000; Me-tens et al. 2000; Suzuki et al. 2003; Pedersen et al. 2001) and a CTA meta-analysis was published in 2002 (Chappell et al. 2003). These later studies have in general been of better quality although there was still a marked preponderance of patients with SAH rather than asymptomatic unruptured aneurysms. The sensitivities and specifi cities were similar to those in the earlier systematic review. Two small studies suggest that dynamic contrast MRA (rapid MRA dur-ing an intravenous injection of gadolinium) may be more accurate than time of fl ight MRA (Metens et al. 2000; Suzuki et al. 2003), but they do suffer from the methodological problems of the early time-of-fl ight MRA studies and might be over-optimistic. Two studies, which looked at the effect of observer experience on aneurysm detection found, not surprisingly, that experts detected substantially more aneurysms, and

Figure 3 (a) Left terminal carotid bifurcation aneurysm (arrow) on 2D intra-arterial digital

subtraction angiography. (b) Although the terminal carotid is irregular in appearance, the

very small aneurysm cannot be readily appreciated on the MRA MIP image and even the

base image (c) does not clearly demonstrate the aneurysm – illustrating the problems

of detecting very small aneurysms with non-invasive imaging methods. However, the

aneurysm was detected on transcranial Doppler sonography – arrowed ‘An’ (d).

(a) (b)

(c)

(d)

more reliably, than less experienced observers (Okahara et al. 2002; White et al. 2003).

IF AN ASYMPTOMATIC ANEURYSM IS FOUND WHAT IS ITS RISK OF RUPTURE?The best available data on rupture risk are sum-marised in Table 5. A systematic review by Rin-kel et al. found an overall annual rupture rate of 1.9% (Rinkel et al. 1998). Aneurysms were twice as likely to rupture in women than in men and the risk of rupture increased with age. Symp-tomatic aneurysms were signifi cantly more likely to rupture than incidental or additional (asymptomatic) aneurysms (6.5% vs. 0.8% vs. 1.4%, respectively). Posterior circulation and large (> 10 mm) aneurysms were signifi cantly more likely to rupture. In a logistic regression model, the only factor signifi cantly related to aneurysm rupture was the size of the aneurysm – 7 mm or larger aneurysms had a relative risk of rupture of 2.24 compared with smaller aneu-rysms (Juvela et al. 1993). Virtually all patients in this study had had a previous SAH. In the



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MRA (PP)* CTA (PP)† TCDS (PP)‡ MRA (PA)§ CTA (PA)¶ TCDS (PA)**

Sensitivity 87 92 – 87 90 82

Specifi city 92 94 – 95 86 95

Table 4 Sensitivity and specifi city of non-invasive tests for intracranial aneurysms (White

et al. 2000)

*926 subjects in 20 studies; †677 subjects in 16 studies; ‡No studies reported data

per patient; §1596 aneurysms in 926 subjects; ¶1582 aneurysms in 677 subjects; **97

aneurysms in 162 subjects.

PP, identifi cation of a patient as having or not having an aneurysm; PA, identifi cation of an

individual aneurysm correctly; MRA, magnetic resonance angiography; CTA, computerized

tomography angiography; TCDS, transcranial Doppler sonography.

INTERNATIONAL STUDY OF INTERNATIONAL STUDY OF UNRUPTURED

UNRUPTUREDINTRACRANIAL ANEURYSMS INTRACRANIAL ANEURYSMS

RINKEL ET AL. 1998* & INVESTIGATORS 1998 (RETROSPECTIVE) & INVESTIGATORS 2003 (PROSPECTIVE)

No. of subjects 95 1449 1692 (unoperated cohort)

No. of aneurysms – 193 686

Duration of follow-up 3907

(patient years) (mean of mean follow-ups 5.5, 12023 7587

range 2.1–13.7 years) (mean 8.3 years) (mean 4.5 years)

Number ruptured 75 32 51

Overall rupture rate (% pa) 1.9 0.27 0.67

Rupture rate

< 10 mm 0.7 0.05 < 7 mm all sites no prior SAH ~0.07

> 10 mm 4.0 0.5 < 7 mm all sites prior SAH ~0.41

> 7 mm all sites all patients ~0.1†

Cumulative aneurysm 10% per decade 0.5–5% per decade 0.7–1.5% per decade†

rupture rate

(from Juvela et al. 1993)

Incidental aneurysm 6.5 data not extractable data not extractable

rupture rate

Asymptomatic aneurysm 0.8 but 7/8 ruptures in data not extractable < 7 mm ~0.07

rupture rate aneurysms > 10 mm > 7 mm ~2.1

Asymptomatic aneurysm 1.4 data not extractable ~0.36 all sizes

rupture rate

Posterior circulation aneurysm 4.4 data not extractable 0.5 (< 7 mm) – 10% (> 24 mm)

rupture rate

Age

20–39 0 data not extractable data not extractable

40–59 3.5

60–79 5.7

Table 5 Summary of data on annual risk of rupture of unruptured aneurysms

*Additional data to that published in the systematic review were kindly supplied by Dr Gabriel Rinkel to allow calcuation of duration of follow up.

The paper by Juvela et al. 1993 contributed 28% of the patients to the systematic review but almost half the patient-years of follow up.†No difference in rates between groups for larger aneurysms.

The rupture rate is much higher than the combined overall fi gure for the subgroups of posterior circulation aneurysms > 7 mm and for anterior

circulation aneurysms > 12 mm.



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same study, repeat angiography during follow-up showed, in patients with later SAH, that the size of the aneurysms had increased from the start of follow-up, whereas in those without later SAH the size did not change, and new an-eurysms formed during the study in 19%, giving an approximate rate of formation of 2.2% per year (Juvela et al. 1993).

Rinkel et al. (pers. comm.) identifi ed a total of 1145 years of patient follow-up in individu-als with asymptomatic aneurysms and no prior SAH (the group we are really looking at in this article). 93% of the aneurysms were 10 mm or less in size. There were nine ruptures – and all but one occurred in aneurysms 10 mm or larger. Thus, the annual rupture rate for asymptomatic aneurysms 10 mm or less was about 0.1%.

The International Study of Unruptured Intracranial Aneurysms (ISUIA) is the largest ever study to follow up unruptured aneurysms (International Study of Unruptured Intracra-nial Aneurysms & Investigators 2003). Some patients had asymptomatic aneurysms with no prior SAH, and others had previously sustained SAH from another aneurysm. In the retrospec-tive arm, there was a tiny rupture risk of 0.05% per annum for small aneurysms (< 10 mm diameter) in patients who had not had an SAH previously, and of 0.5% per annum for large aneurysms and all aneurysms in patients who had previously sustained an SAH (International Study of Unruptured Intracranial Aneurysms & Investigators 1998). This 0.05% risk is in fact quite similar to the re-calculation of the rupture risk of 0.1% for aneurysms < 10 mm from Rinkel′s systematic review (Rinkel et al. 1998). In the patients that had not previously had an SAH, only 1/12 aneurysmal ruptures occurred of an aneurysm < 10 mm in diameter (of concern to us in this article), compared with 17/20 patients in those who had previously had an SAH (International Study of Unruptured In-tracranial Aneurysms & Investigators 1998).

The more robust prospective data in ISUIA, albeit based on rather small numbers, suggest a negligible rupture risk for anterior circulation aneurysms < 7 mm in those without prior SAH (none ruptured), 0.5% pa for anterior circula-tion aneurysms 7–12 mm, but substantially higher risk for larger anterior circulation aneu-rysms (3–8% pa). The relative risk of rupture for posterior circulation (including posterior com-municating) aneurysms was 3–3.2 compared with anterior circulation aneurysms of the same size. Of no direct concern to this article, in

those with prior SAH, the rupture risk was 0.3% pa for aneurysms < 7 mm with no signifi cant difference from the no SAH group for larger aneurysms (International Study of Unruptured Intracranial Aneurysms & Investigators 2003). 49/51 ruptures occurred within fi ve years of diagnosis and only 2/41 ruptures in the no prior SAH group were of aneurysms < 7 mm (both were posterior circulation aneurysms), compared with 7/10 in those with prior SAH. It is worth noting that aneurysms < 2 mm were arbitrarily excluded from ISUIA, though these can rupture.

WHAT TREATMENT, IF ANY, SHOULD BE OFFERED AND WHAT ARE THE RISKS INVOLVED?Whether any treatment for an asymptomatic aneurysm should be offered or not depends critically on the balance between the long-term rupture risk (i.e. untreated natural history risk) vs. the immediate treatment risk. Both of these risks in turn depend on the age, gender and life-style factors of the individual patient.

Treatment risksAneurysms are treated by surgical clipping or by interventional neuroradiology – coiling. A systematic review of surgical treatment for unruptured aneurysms identifi ed 61 studies between 1966 and 1996, but only eight were prospective and unfortunately, in virtually all, the neurosurgeon performing the operation was also the observer of outcome (Raaymakers et al. 1998). Permanent morbidity occurred in 10.9% of patients and the case fatality was 2.6%. The lowest morbidity and mortality was found with small anterior circulation aneurysms (case fatality 0.8%, morbidity 1.9%), and the high-est with large posterior fossa aneurysms (case fatality 9.6%, morbidity 38%). The lack of in-dependent outcome assessment and the effect of publication bias must have underestimated the surgical risk. The prospective arm of ISUIA (Fig. 4) found the surgery-related case fatality at 1 years was 2.7% in patients with no prior SAH and 0.6% in patients who had previously suffered SAH. Morbidity was the same at 10% (International Study of Unruptured Intracra-nial Aneurysms & Investigators 2003). Age was the only independent predictor of outcome: surgery-related morbidity and mortality at one year was about fi ve times higher in those > 64 years of age compared with patients < 45 years of age (International Study of Unrup-



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tured Intracranial Aneurysms & Investigators 1998).

The effectiveness and risks of aneurysm coiling in unruptured aneurysms are less cer-tain because the technique is newer and still developing. Guigliemi detachable coils (GDC) were introduced in 1991 and revolutionised the endovascular treatment of intracranial aneu-rysms (Guglielmi et al. 1991) (Fig. 5). System-atic reviews of aneurysm coiling have identifi ed 48 studies (all observational, mostly retrospec-tive) including 1383 patients – but these were predominantly of ruptured aneurysms (Brilstra et al. 1999). Permanent complications (death/disability) occurred in 3.7%. However, only 54% of aneurysms were completely occluded after one procedure, although 88% were sub-stantially (> 90%) coiled (Brilstra et al. 1999). The re-bleeding rate from partially treated an-eurysms is higher, and partial occlusion is well recognised to be more common with coiling than clipping. The technology of coils and coil-ing assist devices is improving all the time, so the partial occlusion rate is likely to decline.

There is only one large randomised trial that has compared coiling with clipping – the International Subarachnoid Aneurysm Trial (ISAT) – but only in ruptured aneurysms (Inter-national Subarachnoid Aneurysm Trial 2002). This demonstrated a relative risk reduction in death/dependency for coiling over clipping of 23% at one year – an absolute risk reduction of 7%. Most ISAT patients had anterior circula-tion aneurysms < 10 mm so the trial was not completely representative of the generality of aneurysms. However, anterior circulation an-eurysms < 12 mm accounted for about 65% of the unoperated subjects and 67% of the surgi-cally treated individuals in ISUIA (International Study of Unruptured Intracranial Aneurysms & Investigators 2003). The prospective ISUIA data on treatment outcomes are interesting although directly comparing clipping and coiling is dif-fi cult because patient characteristics differ be-tween the cohorts. There were proportionately far more elderly patients, posterior circulation and large aneurysms (all predisposing to poorer outcome) in the endovascular cohort. Never-theless, for those with no prior SAH the com-bined morbidity and mortality at 1 year was 12.6% for clipping and 9.8% for coiling – a 22% relative risk reduction. For prior SAH patients at one year the relative risk reduction was 30% (7.1% vs. 10.1%).

There is a negligible risk of rupture of

anterior circulation aneurysms < 7mm

in those without prior subarachnoid

haemorrhage

Figure 4 Treatment risks for unruptured aneurysms (adapted from the

ISUIA data)

0

5

10

15

20

25

30

35

Combined

death/disability

rate

≤ 12 mm > 12 mm ≤ 12 mm > 12 mm Anterior circulation Posterior circulation

ClippingCoiling



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In unruptured aneurysms the long-term du-rability after treatment is of particular concern. Although the durability of surgical clipping is widely accepted, the literature on re-bleeding from a previously clipped aneurysm is actu-ally quite scanty and nearly all the information on re-bleeding rates after coiling or clipping relates to previously ruptured aneurysms which are probably more likely to re-bleed after treatment than an unruptured aneurysm. In a purely surgical series, 17 patients presented with ruptured or symptomatic recurrences post clipping – 0.1% per annum (Lin & Fox 1989). A centre, which treated 466 patients with coiling between 1992 and 2002, found major aneurysm recurrences in 21% of treated aneurysms. Three patients re-bled from a coiled aneurysm dur-ing a mean follow-up of 31 months – a risk of approximately 0.25% (Raymond et al. 2003). ISAT will eventually provide 5 and then 10-year follow-up, which will help resolve the issue of endovascular treatment durability.

How to assess if treatment should be offered?The ‘effective natural history risk’ is the indi-vidual’s life expectancy multiplied by the annual rupture risk of their aneurysm. For treatment to be worthwhile at all, the natural history risk should substantially exceed the treatment risk – after all the treatment risk is at once, whereas the untreated risk accumulates over time. As an example, a giant posterior circulation aneurysm has an annual rupture rate of 10% but a treatment risk of 40% (International Study of Unruptured Intracranial Aneurysms & Investigators 2003). If a patient has a life expectancy of 20 years, the chance of rupture far exceeds the 40% treatment risk. On the other hand if the patient is a 71 years old male with, for example, a 4-year life expect-ancy, the effective natural history risk minus the 40% treatment risk is about zero. In practice, a sensible fi gure in order to at least consider treat-ing an asymptomatic unruptured aneurysm in an individual is for the effective natural history risk to exceed the treatment risk by at least 5–10 years. In patients with prior SAH, treatment of additional unruptured aneurysms will often be indicated but life expectancy, comorbidity and treatment risks must be assessed carefully on an individual basis. But other factors such as pa-tient anxiety and implications for employment may all have an important impact on the fi nal treatment decision.

*

Figure 5 Basilar tip aneurysm

with false sac (*) before (a) and

after coiling (b) with complete

occlusion achieved. Image

(c) demonstrates a three-

dimensional GDC coil of the

type commonly used as an initial

coil in such procedures.

(a)

(b)

(c)



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Are there other worthwhile interven-tions?Stopping smoking, careful control of blood pressure, avoidance of risk factors for athero-sclerosis (careful diet, regular exercise, etc.), while unproven, may help reduce both the risk of formation of aneurysms and their risk of rup-ture, as well as improving general health.

SCREENING FOR ANEURYSMSUnfortunately, we cannot tell when aneurysms are going to rupture or form de novo. It is diffi -cult to know for certain who to screen, when to screen and how often, which aneurysms to treat (or sometimes how best to treat) and which to leave alone.

Several groups have applied detailed models to the screening decision-analysis process for aneurysms (MARS study Group 1999; Leblanc et al. 1994; Obuchowski et al. 1995; ter Berg et al. 1988; King et al. 1995; Kallmes et al. 1998; Crawley et al. 1999; Baba et al. 2000; Yoshimoto & Wakai 1999). The most recent studies using up-to-date information on aneurysm rupture rates, diagnostic test accuracy and treatment morbidity rates have all concluded that routine screening is not warranted. The MARS study used MRA to screen 626 asymptomatic fi rst-degree relatives of 193 SAH patients and found 31 aneurysms in 23 relatives (4%). IADSA confi rmed the presence of all 31 aneurysms, but was not performed in the other 603 relatives, so the number of aneurysms missed is unknown (MARS study Group 1999). The MARS in-vestigators found surgery-related morbidity occurred in 11/18 operated relatives, and no ruptures occurred in the non-operated relatives with aneurysms but over what period was not stated. Overall surgery increased life expectancy by 2.5 years per operation but at the expense of 19 years of decreased function per person treated. The study investigators calculated that 298 relatives would need to be screened to prevent one fatal SAH (MARS study Group 1999). This would not be cost effective at about 12 million euros per life (MARS study Group 1999; Johnston 2000). Similar conclusions were reached in two other recent studies (Baba et al. 2000; Yoshimoto & Wakai 1999).

The stress of being screened is diffi cult to quantify but is not insignifi cant. McDonald et al. assessed reassurance after a normal echocar-diogram in patients with a cardiac murmur. All those presenting with symptoms remained anxious despite the normal test result, and over

It is diffi cult to know for certain

who to screen, when to screen

and how often to screen

half of those with an asymptomatic murmur became anxious after detection of the murmur despite the normal echocardiogram (McDon-ald et al. 1996). The presence of an unruptured asymptomatic aneurysm is considered to be in-cidental by the UK Driver and Vehicle Licensing Authority for ordinary driving licences but for heavy goods vehicle and public service vehicle li-cences, the licence depends on a specialist assess-ment of the risks on an individual patient basis. This might have considerable employment and fi nancial implications for some patients. Fur-thermore, one needs to consider the effect of fi nding a small aneurysm where knowledge of it will generate considerable anxiety but where the simple balance of natural history vs. treatment risk does not favour treatment. Such a scenario could again have signifi cant employment and insurance implications. Will the patient be able to cope with this situation? It may be in their best interests not to fi nd out.

So the message here is that, in general, screen-ing of relatives of SAH patients is inappropriate and not cost effective. So only screen for an asymptomatic aneurysm if the pre-test prob-ability of an aneurysm in an individual is very high and if their age and any comorbidity would not militate against treatment. It is also vital to explain to the patient before screening that, if an aneurysm is detected, treatment would only be appropriate for about one half of the aneurysms found. This proportion will be even lower for patients over the age of 50.



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SO WHAT SHOULD I SAY TO THE PATIENT PRESENTING TO MY CLINIC WITH A FAMILY HISTORY OF ANEURYSMAL SAH WHO IS WORRIED ABOUT HIS OR HER OWN RISK?The fi rst thing is to document their family his-tory and the presence or absence of other life-style risk factors.

If the family history is weakFor example, if one fi rst or second degree, or even two second-degree relatives, are affected the individual should be reassured strongly that further investigation is not indicated because there is a very low risk of SAH (lifetime risk of no more than 2–3% vs. background population risk of about 0.6%). If they are not reassured, although most are, further explanation about what is involved such as the uncertainty of non-invasive tests, the risk of treatment and possible implications on employment, driving, insurance, etc. if an aneurysm is detected, will lead many people to conclude that it is not in their interests to pursue further investigation. Investigation without a clear discussion of these facts is not in the best interests of patients, and will cause considerable anxiety.

This advice assumes that you have the benefi t of a consultation without the patient having too many adverse preconceptions of their risk. If there are adverse preconceptions, then I’m afraid it is just going to be very diffi cult. For example, if a doctor has explained the concept of aneurysms that are discovered incidentally to a patient in terms of a time-bomb ticking away in their head and then refers them on to the re-gional neuroscience centre! Once a patient has heard an ill-judged phrase such as ‘time-bomb’ and then had time to worry throughout the referral process, no amount of facts and fi gures will reassure them. They will almost always de-mand treatment come what may.

If the family history is strongIf, for example, two or more fi rst-degree rela-tives are affected, or there is autosomal domi-nant polycysctic kidney disease with a family history of aneurysmal SAH, individuals are at a substantially greater risk of both harbouring an aneurysm and sustaining an SAH compared with the background population. They may merit screening for aneurysms provided they would contemplate treatment if that proves to be appropriate and their life expectancy justifi es

it. Again it is common sense and good medical practice not to investigate ‘just for reassurance’ without discussing fi rst what an aneurysm means and what treatment, if indicated (and it might not be), involves. If a patient wants to consider investigation and treatment once in the full possession of these facts then it is appropri-ate to refer for imaging. Explain briefl y what the test involves and that they will be reviewed with the result. It is worth emphasising that there is no urgency about investigation or subsequent treatment. If there are any compounding risk factors, such as smoking, emphasise the impor-tance of modifying behaviour.

How to screen?As most aneurysms < 5 mm in asymptomatic patients without SAH would not merit treat-ment, it is reasonable to screen fi rst with CTA or MRA – provided a unit has the appropriate ex-perience. Which test to do will depend on local availability and patient factors that make one or other the better option for that individual. How-ever, patients must be warned of the limitations of a one-off CTA or MRA scan – a negative result does not mean they don’t have an aneurysm, just that they probably don’t have one large enough to require treatment now. Also an aneurysm could develop in the future. Whether to repeat screening examinations and if so how and when is completely unknown.

WHAT TO SAY ABOUT TREATMENT?It is reasonable to stick to generalities at this stage. An explanation of the two treatment options available and an outline of their risks is enough. Explain that the most appropriate treatment option will depend on the site and size of any aneurysm found and possibly the patient’s age. Reiterate that for many asympto-matic aneurysms treatment is not needed. Local expertise and availability of treatment may also come into play but it is not necessary to discuss that yet. Finally, this is a complex and diffi cult enough fi eld for doctors, let alone the patients. We try and provide some basic information the patients can take away and read, and frequently bring them back for a second clinic visit to go over the facts again before embarking on any in-vestigation. If an aneurysm is identifi ed at a site and of a size to warrant treatment, the patient should be referred to a specialist multidiscipli-nary neurovascular clinic, but if that is unavail-able to a vascular neurosurgeon.



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The role of coiling as opposed to clipping

in the treatment of unruptured aneurysms

is promising

PRACTICE POINTS• Symptomatic aneurysms are those causing SAH follow-

ing rupture, or exerting symptoms by a space occupying effect (most commonly oculomotor nerve palsy pro-duced by a posterior communicating artery aneurysm).

• Asymptomatic aneurysms are additional aneurysms found in patients with a symptomatic aneurysm, which are not responsible for the clinical presentation, or an-eurysms found in patients investigated because they are at risk (of harbouring an aneurysm).

• Incidental aneurysms are those found unexpectedly in patients undergoing investigation for some other sus-pected problem.

• About one in 20 of the general population aged over the age of 30 harbours an unruptured asymptomatic aneu-rysm.

• Individuals most at risk of aneurysmal SAH are those with a family history of at least two fi rst-degree relatives with an SAH, or patients with an underlying genetic condition – most commonly autosomal dominant poly-cystic kidney disease.

• The risk seems highest if at least one of the affected relatives is a sibling or mother. Lifestyle factors such as smoking, heavy alcohol consumption and hyperc-holesterolaemia may further increase the risk. A single relative (especially if second-degree) affected by SAH suggests a very small absolute risk of SAH to an indi-vidual without SAH.

• CT angiography and MR angiography, performed and reported by experts, can reliably detect aneurysms larger than 5 mm. These techniques are unreliable at detecting smaller aneurysms. A negative study may therefore offer false reassurance. This problem should be discussed with anyone referred for imaging to look for an asymptomatic aneurysm.

• Rupture risk depends predominantly on the site and size of an aneurysm and whether or not the patient has suf-fered a previous SAH. If not, small aneurysms (< 7 mm), particularly if anterior circulation, have an extremely low rupture risk. Other factors such as age and lifestyle factors also then need to be considered to determine

overall risk. A substantial number of asymptomatic an-eurysms fall into this category.

• Treatment risks rise with age and also depend on the site and size of the aneurysm. The greatest risks are with larger aneurysms, posterior circulation aneurysms and in older people (> 50 years). In all these groups coiling is safer than clipping – the substantially lower risk of treatment favours coiling despite the uncertainty over durability.

• Treatment risks of coiling and clipping for asympto-matic small, anterior circulation aneurysms in patients < 50 years are similar, so the unproven long-term dura-bility of coiling is a particular issue in this group.

• In patients with no prior history of SAH, risk benefi t anal-ysis favours treatment in people < 50 years old except for those with anterior circulation aneurysms < 7 mm in size (but these account for nearly 50% of the total).

• For people > 50 years, treatment is only clearly favoured for aneurysms > 12 mm, and other factors such as life expectancy and coexistent conditions need to be taken into account.

• Routine screening for unruptured intracranial aneu-rysms in individuals with a family history of SAH is not warranted.

• Asymptomatic individuals with only one family member affected by SAH do not have a suffi ciently increased risk to outweigh the risks of screening (and treatment).

• Those patients with the greatest risk of having an unrup-tured aneurysm, and of it then rupturing, are those aged over 30 years from families with two or more fi rst degree relatives affected by SAH. They are perhaps at further increased risk if they have additional risk factors such as smoking and hypercholesterolaemia. Such individu-als and autosomal dominant polycystic kidney disease patients with a family history of SAH should be assessed on an individual basis – taking all the relevant risk factors into account – for screening for intracranial aneurysms.

• The role of coiling as opposed to clipping in the treat-ment of unruptured aneurysms is promising, particu-larly in patients > 50 years, and for posterior circulation aneurysms.



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ACKNOWLEDGEMENTSThis paper was reviewed by Jan van Gijn, Utrecht, the Netherlands.

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Documents

NEUROLOGICAL DILEMMAS How to manage the patient with …aneurysm or a family history of aneurysmal subarachnoid haemorrhage (SAH). Before you can counsel these people, it is ﬁ rst