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

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

     NEUROLOGICAL DILEMMAS

     How to manage
     the patient with
     a family history
     of aneurysmal
     subarachnoid
     haemorrhage
     P. M. White
     Consultant Neuroradiologist
     Department of Clinical Neurosciences, University
     of Edinburgh, Western General Hospital,
     Crewe Road, Edinburgh, EH4 2XU, UK; E-mail:
     pmw@skull.dcn.ed.ac.uk
     Practical Neurology, 2004, 4, 88–103
     © 2004 Blackwell Publishing Ltd
How to manage the patient with a family history of aneurysmal subarachnoid haemorrhage
APRIL 2004          89

INTRODUCTION                                          WHAT IS THE FREQUENCY OF INTRA-
‘The truth is rarely pure and never simple’. So       CRANIAL ANEURYSMS IN THE GENERAL
said Oscar Wilde, and this is certainly the case      POPULATION?
for individuals with an unruptured intracranial       What is anyone’s risk of harbouring an aneu-
aneurysm or a family history of aneurysmal            rysm, after all incidental aneurysms are com-
subarachnoid haemorrhage (SAH). Before you            monly found at autopsy? Rinkel et al. identified
can counsel these people, it is first necessary for   autopsy studies where the prevalence of unrup-
the clinician to have a grasp of this complex         tured aneurysms ranged from 0.4% to 3.6% for
area because once you have told the patient           retro and prospective studies, respectively, and
something it cannot be untold. You might sub-         in retro and prospective angiography studies
sequently expand on the information imparted,         from 3.7% to 6%, respectively (Rinkel et al.
but you cannot remove it – correct or incorrect       1998). More recent studies are more in line with
– from the patient’s mind (Fuller 2001). In this      the higher figures from the prospective studies     ‘The truth is rarely
article I will summarize the relevant knowledge,      (Kojima et al. 1998; Ronkainen et al. 1998). In a
and offer some advice, on management in this          higher-risk group of patients, because they had        pure and never
rather fraught area of medicine.                      already ruptured an aneurysm, 20–25% had at
                                                      least one unruptured aneurysm on angiography                          simple’
                                                      (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
   There are several stages of assessment and            aneurysms and/or SAH (Hughes et al. 1996;
management to consider:                                  Ruggieri et al. 1994);
• What is an individual’s risk of harbouring an       • type IV Ehlers–Danlos syndrome (Schievink
   aneurysm?                                             et al. 1990);
• How best to detect an aneurysm without              • possibly pseudoxanthoma elasticum (Muny-
   exposing the patient to unnecessary stress or         er & Margulis 1981), although this has been
   risk?                                                 refuted (van den Berg et al. 1999);
• If an asymptomatic aneurysm is found, what          • hereditary haemorrhagic telangiectsaia
   is the risk of rupture?                               (Roman et al. 1978);
• What treatment, if any, should be offered and       • neurofibromatosis type I (Mulvihill et al.
   what are the risks involved?                          1990; Morooka & Waga 1991);
Most importantly, the risk at each stage must be      • alpha1-antitrypsin deficiency (Schievink et
weighed against the risk of not doing anything.          al. 1996).
The pros and cons of screening for aneurysms             Marfan’s syndrome was thought to be associ-
will also be briefly considered to place some of      ated with aneurysms but a detailed study of 135
this information in context.                          patients (mean age 21 years) found no evidence
                                                                                                            © 2004 Blackwell Publishing Ltd
How to manage the patient with a family history of aneurysmal subarachnoid haemorrhage
90    PRACTICAL NEUROLOGY

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

                                              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 first- 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

                                             of a relationship (van den Berg et al. 1996),           (Table 2). The relative risk for SAH in relatives
                                             although the patients may not have been old             compared with the background population was
                                             enough for the aneurysms to have developed.             2.9–6.6 for first-degree relatives and 1.6–2.1 for
                                                In addition, aneurysmal SAH may affect sev-          second degree. Whilst these relative risks appear
                                             eral members of a family without any specific           large, it is important to remember the small
                                             genetic ‘disease’. Familial SAH has been defined        absolute number of relatives affected: only 156/
                Approximately                inconsistently, so here I mean a family in which        21054 (0.74%) first-degree relatives were them-
                                             two or more close blood relatives (first or second      selves affected by SAH. In our Scottish study (in
             one in 20 of the                degree) have a history of aneurysmal SAH with-          press) the risk of SAH among family members
                                             out any other known heritable disease (first-           over the decade after the index case had their
            population aged                  degree relatives = parents, siblings, children;         SAH was 1.2% for first-degree and 0.5% for
                                             second degree = grandparents, grandchildren,            second-degree relatives (some 12 and 5 times,
             over 30 harbour                 aunts and uncles, nieces and nephews; third             respectively, the background population SAH
                                             degree = cousins, great grandparents, great             risk) (Wardlaw et al., in press).
                an unruptured                grandchildren)                                              Familial intracranial aneurysms may have
                                                It has been suggested that many cases of             distinguishing biological features, including:
                         aneurysm            ‘familial intracranial aneurysms’ might simply          rupture at a younger age (most frequently in the
                                             represent accidental aggregation (ter Berg et al.       fifth decade compared to the sixth decade for
                                             1992); on the basis of chance alone, each SAH           sporadic SAH) (Bromberg et al. 1995); worse
                                             patient has a 5.6% possibility of having a first- to    clinical outcome; and an increased prevalence
                                             third-degree relative also affected by SAH (ter         of middle cerebral artery aneurysms (Kojima
                                             Berg et al. 1992), and the proportion of SAH            et al. 1998; Bromberg et al. 1995). There may
                                             patients with third-degree relatives who had            be a younger age of rupture in subsequent
                                             had an SAH is the same as the proportion with           generations, implying ‘anticipation’ (Interna-
                                             SAH in the control population (De Braekeleer            tional Subarachnoid Aneurysm Trial 2002) but
                                             et al. 1996).                                           familial aneurysms may also have a predilection
                                                Since 1987, 10 studies have examined the             towards rupture in the same decade in individu-
                                             prevalence of unruptured aneurysms and/or               als of the same family, particularly in siblings
                                             SAH amongst relatives of patients with SAH              (Leblanc 1997).
     © 2004 Blackwell Publishing Ltd
Table 2 Summary of population based studies of familial subarachnoid haemorrhage*

                                                           NUMBER                                 NUMBER OF RELATIVES SURVEYED   NUMBER OF RELATIVES WITH SAH   % 1°
                                                           OF INDEX                                                                                             WITH
                                   STUDY                   SUBJECTS        LOCATION               1°       2°        3°          1°        2°           3°      SAH     COMMENT
                                   Norrgard 1987           485             Umea, Sweden           1352     /         /           22        /            /       4.7     sibs only surveyed –
                                                                           (sibs only)                                                                                  average six per index case

                                   Wang 1995               149/171†        Washington, USA        N/S      N/S       N/S         18        16           /               11.4 OR for SAH in 1°
                                                                                                                                                                        relative = 1.8, 2° = 2.4

                                   Schievink 1995          76/81†          Rochester, USA         608      N/S       N/S         11        5            /       1.8     RR of SAH in 1° relative = 4.1
                                                                                                                                                                        2° = 1.6

                                   Bromberg 1995           163             Utrecht, Netherlands   1290     3588      N/S         10 + 7‡   4 + 12‡      /       1%      RR of SAH in 1° relative = 6.6
                                                                                                                                                                        definite, and 2.7 possible SAH

                                   de Braekeleer 1996      533 (+ 1599     Quebec, Canada         N/S      N/S       N/S         48        51           77      /       RR of SAH in 1° relative = 4.7,
                                                           controls)                                                                                                    2° = 2.1, 3° = 1.1 compared to
                                                                                                                                                                        general pop

                                   Ronkainen§ 1997         91              Kuopio, Finland         716 relatives in total →      76            37 relatives     10.6¶   Risk of unruptured aneurysm in 1°
                                                                           (1°, 2° and 3°)               (2° and 3°)                           in total →               or 2°4x greater than general pop.

                                   Raaymakers 1999         160             Utrecht, Netherlands   626      /         /           4         /            /       0.6     3.7% of 1° had an unruptured
                                                                                                                                                                        aneurysm

                                   Gaist 2000              6175            Denmark (1977–95)      14781    /         /           19        /            /       0.1     RR 2.9, 4.5 for 77% cases admitted

                                   Davie Cooper Study      453             Scotland               3023     5668                  87        65                   2.9     RR 2.3–2.4. Ten year prospective
                                                                                                                                                                        risk 1.2% in 1°, 0.5% in 2°

                                   Okamoto 2003            200             Japan                  N/S      /         /           29        /            /       N/S     OR for SAH in 1° relative = 4.0

                                  *Wardlaw in press.
                                  †
                                   number surveyed/total sample available.
                                  ‡
                                    definite + possible SAH.
                                  §
                                    relatives with SAH or aneurysm.
                                  ¶
                                    % of all relatives not just first degree.
                                  OR, odds ratio; RR, relative risk; N/S = not stated
                                  / = no data.
                                                                                                                                                                                                             APRIL 2004

© 2004 Blackwell Publishing Ltd
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92    PRACTICAL NEUROLOGY

                                       WHICH RELATIVES ARE MOST                             risk was 0.07% (Cloft et al. 1999). Non-invasive
                                       FREQUENTLY AFFECTED BY SAH?                          tests, such as magnetic resonance angiography
                                       In families with more than one person with           (MRA), dynamic spiral CT Angiography (CTA)
                                       SAH, the most frequent relationship is index         and transcranial Doppler sonography (TCDS)
                                       patient to sibling, followed by index patient to     (Fig. 2) are attractive for detecting asympto-
                                       parent (Wardlaw & White 2000). However, a            matic intracranial aneurysms but they have to
                                       parent was affected in only 29% so in less than      be extremely accurate to replace IADSA. So how
                                       one-third of affected families was there a clear     accurate are they?
                                       warning of the potential for SAH from a previ-          Analysis of accuracy per patient rather than
                                       ous generation. Interestingly, one study found       per aneurysm is of more clinical relevance to
                                       a much stronger familial link to maternal SAH        ‘screening’ an individual for aneurysms. Most
                                       than to paternal or sibling SAH (Okamoto et al.      studies reported apparently excellent results but
                                       2003) and in another study, the slightly more        were in patients with a recent SAH so the aneu-
                                       commonly affected first-degree relatives were        rysm prevalence was high (Table 4) (White et al.
                                       also parents (38%) rather than siblings (33%)        2000). As a result the sensitivities, specificities
                                       (Wardlaw, in press). Only our Scottish study has     and predictive values must be interpreted with
                                       prospectively investigated the interaction be-       caution, particularly if one is extrapolating to
                                       tween the type of relationship and involvement       using the non-invasive test in a low aneurysm
                                       of more than one family member (with SAH)            prevalence population where far more positive
                                       on the risk of SAH to the other family members       test results will be false positives. Crucially, the
                                       (Table 3). Here, there was a hierarchy of ascend-    results for non-invasive imaging methods are
                                       ing risk from a second-degree relative and no        significantly poorer for aneurysms < 5 mm in
                                       other family members affected (0.3% cumula-          size, which constitute as many as one-third of
                                       tive lifetime SAH risk) to the highest risk in a     aneurysms in asymptomatic patients (Kojima
                                       member of a family with at least two first-degree    et al. 1998) (Fig. 3). Sensitivities are in the order
                                       relatives affected (7% cumulative lifetime SAH       of 35%, 57% and 35% for aneurysms < 5 mm
                                       risk) (Wardlaw in press).                            diameter for MRA, CTA and TCDS, respectively
                                                                                            (White et al. 2001; White et al. 2001) ICA an-
                                       HOW BEST TO DETECT AN ANEURYSM?                      eurysms are even harder to detect (White et al.
                                       The gold standard is an intra-arterial digital       2000, 2001). Ultrasound has the advantage of
                                       subtraction angiogram (IADSA) with selective         the lowest capital cost, and portability, and with
                                       cerebral arterial injections and multiple projec-    contrast agents and 3-D imaging the accuracy
                                       tions, particularly using the 3D DSA technique       may improve towards the level of CTA/MRA
                                       (Fig. 1). However, IADSA is invasive, costly, and    (Wardlaw & White 2000). Unfortunately, about
                                       not without risk of a permanent neurological         10% of patients will not have an adequate bone
                                       complication. In patients with SAH, suspected        window and the technique is operator depend-
                                       aneurysm or arteriovenous malformation, this         ent.

                                        Table 3 Relationship between the family history of an index subarachnoid haemorrhage (SAH) case and the
                                       risk of SAH to other family members
                                                                                         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 first-degree relative                             7                          0.8%
                                        No first but at least two second-degree relatives     1                          1%
                                        One first and at least one second-degree relative    2                           2%
                                        At least two first-degree relatives                  4                           7%

                                       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.
     © 2004 Blackwell Publishing Ltd
APRIL 2004          93

                       *

                                                      

(a)                                                       (b)

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*.

(a)                                             (b)                                                 (c)

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.

                                                                                                                       © 2004 Blackwell Publishing Ltd
94    PRACTICAL NEUROLOGY

                                          More recently there have been further studies        more reliably, than less experienced observers
                                       of non-invasive imaging tests vs. IADSA (White          (Okahara et al. 2002; White et al. 2003).
                                       et al. 2001a; White et al. 2001b; Okahara et al.
                                       2002; Chung et al. 1999; Jager et al. 2000; Me-         IF AN ASYMPTOMATIC ANEURYSM IS
                                       tens et al. 2000; Suzuki et al. 2003; Pedersen et al.   FOUND WHAT IS ITS RISK OF RUPTURE?
                                       2001) and a CTA meta-analysis was published in          The best available data on rupture risk are sum-
                                       2002 (Chappell et al. 2003). These later studies        marised in Table 5. A systematic review by Rin-
                                       have in general been of better quality although         kel et al. found an overall annual rupture rate of
                                       there was still a marked preponderance of               1.9% (Rinkel et al. 1998). Aneurysms were twice
                                       patients with SAH rather than asymptomatic              as likely to rupture in women than in men and
                                       unruptured aneurysms. The sensitivities and             the risk of rupture increased with age. Symp-
                                       specificities were similar to those in the earlier      tomatic aneurysms were significantly more
                                       systematic review. Two small studies suggest            likely to rupture than incidental or additional
                                       that dynamic contrast MRA (rapid MRA dur-               (asymptomatic) aneurysms (6.5% vs. 0.8% vs.
                                       ing an intravenous injection of gadolinium)             1.4%, respectively). Posterior circulation and
                                       may be more accurate than time of flight MRA            large (> 10 mm) aneurysms were significantly
                                       (Metens et al. 2000; Suzuki et al. 2003), but they      more likely to rupture. In a logistic regression
                                       do suffer from the methodological problems of           model, the only factor significantly related to
                                       the early time-of-flight MRA studies and might          aneurysm rupture was the size of the aneurysm
                                       be over-optimistic. Two studies, which looked at        – 7 mm or larger aneurysms had a relative risk
                                       the effect of observer experience on aneurysm           of rupture of 2.24 compared with smaller aneu-
                                       detection found, not surprisingly, that experts         rysms (Juvela et al. 1993). Virtually all patients
                                       detected substantially more aneurysms, and              in this study had had a previous SAH. In the

             (a)                                          (b)

                                                          (d)

             (c)

                                                         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).

     © 2004 Blackwell Publishing Ltd
APRIL 2004         95

Table 4 Sensitivity and specificity of non-invasive tests for intracranial aneurysms (White
et al. 2000)

             MRA (PP)*         CTA (PP)†   TCDS (PP)‡     MRA (PA)§     CTA (PA)¶ TCDS (PA)**
 Sensitivity 87                92          –              87            90        82
 Specificity 92                 94          –              95            86        95

*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, identification of a patient as having or not having an aneurysm; PA, identification of an
individual aneurysm correctly; MRA, magnetic resonance angiography; CTA, computerized
tomography angiography; TCDS, transcranial Doppler sonography.

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

                                                                      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

*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 figure for the subgroups of posterior circulation aneurysms > 7 mm and for anterior
circulation aneurysms > 12 mm.
                                                                                                                             © 2004 Blackwell Publishing Ltd
96    PRACTICAL NEUROLOGY

                                       same study, repeat angiography during follow-         those with prior SAH, the rupture risk was 0.3%
                                       up showed, in patients with later SAH, that the       pa for aneurysms < 7 mm with no significant
                                       size of the aneurysms had increased from the          difference from the no SAH group for larger
                                       start of follow-up, whereas in those without          aneurysms (International Study of Unruptured
                                       later SAH the size did not change, and new an-        Intracranial Aneurysms & Investigators 2003).
                                       eurysms formed during the study in 19%, giving        49/51 ruptures occurred within five years of
                                       an approximate rate of formation of 2.2% per          diagnosis and only 2/41 ruptures in the no
                                       year (Juvela et al. 1993).                            prior SAH group were of aneurysms < 7 mm
                                          Rinkel et al. (pers. comm.) identified a total     (both were posterior circulation aneurysms),
                                       of 1145 years of patient follow-up in individu-       compared with 7/10 in those with prior SAH.
                                       als with asymptomatic aneurysms and no prior          It is worth noting that aneurysms < 2 mm were
                                       SAH (the group we are really looking at in this       arbitrarily excluded from ISUIA, though these
                                       article). 93% of the aneurysms were 10 mm or          can rupture.
                                       less in size. There were nine ruptures – and all
                                       but one occurred in aneurysms 10 mm or larger.        WHAT TREATMENT, IF ANY, SHOULD BE
                                       Thus, the annual rupture rate for asymptomatic        OFFERED AND WHAT ARE THE RISKS
                                       aneurysms 10 mm or less was about 0.1%.               INVOLVED?
                                          The International Study of Unruptured              Whether any treatment for an asymptomatic
                                       Intracranial Aneurysms (ISUIA) is the largest         aneurysm should be offered or not depends
                                       ever study to follow up unruptured aneurysms          critically on the balance between the long-term
                                       (International Study of Unruptured Intracra-          rupture risk (i.e. untreated natural history risk)
                                       nial Aneurysms & Investigators 2003). Some            vs. the immediate treatment risk. Both of these
                                       patients had asymptomatic aneurysms with no           risks in turn depend on the age, gender and life-
                                       prior SAH, and others had previously sustained        style factors of the individual patient.
                                       SAH from another aneurysm. In the retrospec-
                                       tive arm, there was a tiny rupture risk of 0.05%      Treatment risks
                                       per annum for small aneurysms (< 10 mm                Aneurysms are treated by surgical clipping or
                                       diameter) in patients who had not had an SAH          by interventional neuroradiology – coiling.
                                       previously, and of 0.5% per annum for large           A systematic review of surgical treatment for
                                       aneurysms and all aneurysms in patients who           unruptured aneurysms identified 61 studies
                                       had previously sustained an SAH (International        between 1966 and 1996, but only eight were
                                       Study of Unruptured Intracranial Aneurysms            prospective and unfortunately, in virtually all,
                                       & Investigators 1998). This 0.05% risk is in          the neurosurgeon performing the operation
                                       fact quite similar to the re-calculation of the       was also the observer of outcome (Raaymakers
                                       rupture risk of 0.1% for aneurysms < 10 mm            et al. 1998). Permanent morbidity occurred in
                                       from Rinkel′s systematic review (Rinkel et al.        10.9% of patients and the case fatality was 2.6%.
                                       1998). In the patients that had not previously        The lowest morbidity and mortality was found
                                       had an SAH, only 1/12 aneurysmal ruptures             with small anterior circulation aneurysms (case
                                       occurred of an aneurysm < 10 mm in diameter           fatality 0.8%, morbidity 1.9%), and the high-
                                       (of concern to us in this article), compared with     est with large posterior fossa aneurysms (case
                                       17/20 patients in those who had previously had        fatality 9.6%, morbidity 38%). The lack of in-
                                       an SAH (International Study of Unruptured In-         dependent outcome assessment and the effect
                                       tracranial Aneurysms & Investigators 1998).           of publication bias must have underestimated
                                          The more robust prospective data in ISUIA,         the surgical risk. The prospective arm of ISUIA
                                       albeit based on rather small numbers, suggest a       (Fig. 4) found the surgery-related case fatality
                                       negligible rupture risk for anterior circulation      at 1 years was 2.7% in patients with no prior
                                       aneurysms < 7 mm in those without prior SAH           SAH and 0.6% in patients who had previously
                                       (none ruptured), 0.5% pa for anterior circula-        suffered SAH. Morbidity was the same at 10%
                                       tion aneurysms 7–12 mm, but substantially             (International Study of Unruptured Intracra-
                                       higher risk for larger anterior circulation aneu-     nial Aneurysms & Investigators 2003). Age was
                                       rysms (3–8% pa). The relative risk of rupture for     the only independent predictor of outcome:
                                       posterior circulation (including posterior com-       surgery-related morbidity and mortality at
                                       municating) aneurysms was 3–3.2 compared              one year was about five times higher in those
                                       with anterior circulation aneurysms of the            > 64 years of age compared with patients <
                                       same size. Of no direct concern to this article, in   45 years of age (International Study of Unrup-
     © 2004 Blackwell Publishing Ltd
APRIL 2004          97

                35                                                         tured Intracranial Aneurysms & Investigators
   Clipping
   Coiling      30
                                                                           1998).
                                                                              The effectiveness and risks of aneurysm
                25                                                         coiling in unruptured aneurysms are less cer-
                                                                           tain because the technique is newer and still
  Combined 20
death/disability                                                           developing. Guigliemi detachable coils (GDC)
     rate        15
                                                                           were introduced in 1991 and revolutionised the
                10
                                                                           endovascular treatment of intracranial aneu-
                                                                           rysms (Guglielmi et al. 1991) (Fig. 5). System-
                 5
                                                                           atic reviews of aneurysm coiling have identified
                 0                                                         48 studies (all observational, mostly retrospec-
                      ≤ 12 mm         > 12 mm   ≤ 12 mm          > 12 mm
                                                                           tive) including 1383 patients – but these were
                         Anterior circulation      Posterior circulation
                                                                           predominantly of ruptured aneurysms (Brilstra
Figure 4 Treatment risks for unruptured aneurysms (adapted from the        et al. 1999). Permanent complications (death/
ISUIA data)                                                                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-
      There is a negligible risk of rupture of                             national Subarachnoid Aneurysm Trial 2002).
                                                                           This demonstrated a relative risk reduction in
      anterior circulation aneurysms < 7mm                                 death/dependency for coiling over clipping of
                                                                           23% at one year – an absolute risk reduction of
       in those without prior subarachnoid                                 7%. Most ISAT patients had anterior circula-
                                                                           tion aneurysms < 10 mm so the trial was not
                            haemorrhage                                    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-
                                                                           ficult 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%).

                                                                                                                      © 2004 Blackwell Publishing Ltd
98    PRACTICAL NEUROLOGY

                                                                              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
      (a)                                                                  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).
      (b)                                                                  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 figure 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
                                       Figure 5 Basilar tip aneurysm       additional unruptured aneurysms will often be
                                       with false sac (*) before (a) and   indicated but life expectancy, comorbidity and
                                       after coiling (b) with complete     treatment risks must be assessed carefully on an
                                       occlusion achieved. Image           individual basis. But other factors such as pa-
                                       (c) demonstrates a three-           tient anxiety and implications for employment
                                       dimensional GDC coil of the        may all have an important impact on the final
      (c)                              type commonly used as an initial    treatment decision.
                                       coil in such procedures.

     © 2004 Blackwell Publishing Ltd
APRIL 2004          99

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 ANEURYSMS                              It is difficult to know for certain
Unfortunately, we cannot tell when aneurysms
are going to rupture or form de novo. It is diffi-   who to screen, when to screen
cult to know for certain who to screen, when to
screen and how often, which aneurysms to treat       and how often to screen
(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         half of those with an asymptomatic murmur
up-to-date information on aneurysm rupture           became anxious after detection of the murmur
rates, diagnostic test accuracy and treatment        despite the normal echocardiogram (McDon-
morbidity rates have all concluded that routine      ald et al. 1996). The presence of an unruptured
screening is not warranted. The MARS study           asymptomatic aneurysm is considered to be in-
used MRA to screen 626 asymptomatic first-           cidental by the UK Driver and Vehicle Licensing
degree relatives of 193 SAH patients and found       Authority for ordinary driving licences but for
31 aneurysms in 23 relatives (4%). IADSA             heavy goods vehicle and public service vehicle li-
confirmed the presence of all 31 aneurysms, but      cences, the licence depends on a specialist assess-
was not performed in the other 603 relatives, so     ment of the risks on an individual patient basis.
the number of aneurysms missed is unknown            This might have considerable employment and
(MARS study Group 1999). The MARS in-                financial implications for some patients. Fur-
vestigators found surgery-related morbidity          thermore, one needs to consider the effect of
occurred in 11/18 operated relatives, and no         finding a small aneurysm where knowledge of it
ruptures occurred in the non-operated relatives      will generate considerable anxiety but where the
with aneurysms but over what period was not          simple balance of natural history vs. treatment
stated. Overall surgery increased life expectancy    risk does not favour treatment. Such a scenario
by 2.5 years per operation but at the expense        could again have significant employment and
of 19 years of decreased function per person         insurance implications. Will the patient be able
treated. The study investigators calculated          to cope with this situation? It may be in their best
that 298 relatives would need to be screened         interests not to find out.
to prevent one fatal SAH (MARS study Group              So the message here is that, in general, screen-
1999). This would not be cost effective at about     ing of relatives of SAH patients is inappropriate
12 million euros per life (MARS study Group          and not cost effective. So only screen for an
1999; Johnston 2000). Similar conclusions were       asymptomatic aneurysm if the pre-test prob-
reached in two other recent studies (Baba et al.     ability of an aneurysm in an individual is very
2000; Yoshimoto & Wakai 1999).                       high and if their age and any comorbidity would
   The stress of being screened is difficult to      not militate against treatment. It is also vital to
quantify but is not insignificant. McDonald et al.   explain to the patient before screening that, if an
assessed reassurance after a normal echocar-         aneurysm is detected, treatment would only be
diogram in patients with a cardiac murmur.           appropriate for about one half of the aneurysms
All those presenting with symptoms remained          found. This proportion will be even lower for
anxious despite the normal test result, and over     patients over the age of 50.
                                                                                                            © 2004 Blackwell Publishing Ltd
100    PRACTICAL NEUROLOGY

                                        SO WHAT SHOULD I SAY TO THE PATIENT                   it. Again it is common sense and good medical
                                        PRESENTING TO MY CLINIC WITH A                        practice not to investigate ‘just for reassurance’
                                        FAMILY HISTORY OF ANEURYSMAL SAH                      without discussing first what an aneurysm
                                        WHO IS WORRIED ABOUT HIS OR HER                       means and what treatment, if indicated (and
                                        OWN RISK?                                             it might not be), involves. If a patient wants to
                                        The first thing is to document their family his-      consider investigation and treatment once in the
                                        tory and the presence or absence of other life-       full possession of these facts then it is appropri-
                                        style risk factors.                                   ate to refer for imaging. Explain briefly what the
                                                                                              test involves and that they will be reviewed with
                                        If the family history is weak                         the result. It is worth emphasising that there is
                                        For example, if one first or second degree, or        no urgency about investigation or subsequent
                                        even two second-degree relatives, are affected        treatment. If there are any compounding risk
                                        the individual should be reassured strongly that      factors, such as smoking, emphasise the impor-
                                        further investigation is not indicated because        tance of modifying behaviour.
                                        there is a very low risk of SAH (lifetime risk of
                                        no more than 2–3% vs. background population           How to screen?
                                        risk of about 0.6%). If they are not reassured,       As most aneurysms < 5 mm in asymptomatic
                                        although most are, further explanation about          patients without SAH would not merit treat-
                                        what is involved such as the uncertainty of           ment, it is reasonable to screen first with CTA or
                                        non-invasive tests, the risk of treatment and         MRA – provided a unit has the appropriate ex-
                                        possible implications on employment, driving,         perience. Which test to do will depend on local
                                        insurance, etc. if an aneurysm is detected, will      availability and patient factors that make one or
                                        lead many people to conclude that it is not in        other the better option for that individual. How-
                                        their interests to pursue further investigation.      ever, patients must be warned of the limitations
                                        Investigation without a clear discussion of these     of a one-off CTA or MRA scan – a negative result
                                        facts is not in the best interests of patients, and   does not mean they don’t have an aneurysm, just
                                        will cause considerable anxiety.                      that they probably don’t have one large enough
                                           This advice assumes that you have the benefit      to require treatment now. Also an aneurysm
                                        of a consultation without the patient having          could develop in the future. Whether to repeat
                                        too many adverse preconceptions of their risk.        screening examinations and if so how and when
                                        If there are adverse preconceptions, then I’m         is completely unknown.
                                        afraid it is just going to be very difficult. For
                                        example, if a doctor has explained the concept        WHAT TO SAY ABOUT TREATMENT?
                                        of aneurysms that are discovered incidentally to      It is reasonable to stick to generalities at this
                                        a patient in terms of a time-bomb ticking away        stage. An explanation of the two treatment
                                        in their head and then refers them on to the re-      options available and an outline of their risks
                                        gional neuroscience centre! Once a patient has        is enough. Explain that the most appropriate
                                        heard an ill-judged phrase such as ‘time-bomb’        treatment option will depend on the site and
                                        and then had time to worry throughout the             size of any aneurysm found and possibly the
                                        referral process, no amount of facts and figures      patient’s age. Reiterate that for many asympto-
                                        will reassure them. They will almost always de-       matic aneurysms treatment is not needed. Local
                                        mand treatment come what may.                         expertise and availability of treatment may also
                                                                                              come into play but it is not necessary to discuss
                                        If the family history is strong                       that yet. Finally, this is a complex and difficult
                                        If, for example, two or more first-degree rela-       enough field for doctors, let alone the patients.
                                        tives are affected, or there is autosomal domi-       We try and provide some basic information the
                                        nant polycysctic kidney disease with a family         patients can take away and read, and frequently
                                        history of aneurysmal SAH, individuals are at         bring them back for a second clinic visit to go
                                        a substantially greater risk of both harbouring       over the facts again before embarking on any in-
                                        an aneurysm and sustaining an SAH compared            vestigation. If an aneurysm is identified at a site
                                        with the background population. They may              and of a size to warrant treatment, the patient
                                        merit screening for aneurysms provided they           should be referred to a specialist multidiscipli-
                                        would contemplate treatment if that proves to         nary neurovascular clinic, but if that is unavail-
                                        be appropriate and their life expectancy justifies    able to a vascular neurosurgeon.

      © 2004 Blackwell Publishing Ltd
APRIL 2004          101

                                 The role of coiling as opposed to clipping
                                in the treatment of unruptured aneurysms
                                                      is promising

PRACTICE POINTS                                                     overall risk. A substantial number of asymptomatic an-
• Symptomatic aneurysms are those causing SAH follow-               eurysms fall into this category.
  ing rupture, or exerting symptoms by a space occupying        •   Treatment risks rise with age and also depend on the
  effect (most commonly oculomotor nerve palsy pro-                 site and size of the aneurysm. The greatest risks are with
  duced by a posterior communicating artery aneurysm).              larger aneurysms, posterior circulation aneurysms and
• Asymptomatic aneurysms are additional aneurysms                   in older people (> 50 years). In all these groups coiling
  found in patients with a symptomatic aneurysm, which              is safer than clipping – the substantially lower risk of
  are not responsible for the clinical presentation, or an-         treatment favours coiling despite the uncertainty over
  eurysms found in patients investigated because they               durability.
  are at risk (of harbouring an aneurysm).                      •   Treatment risks of coiling and clipping for asympto-
• Incidental aneurysms are those found unexpectedly in              matic small, anterior circulation aneurysms in patients
  patients undergoing investigation for some other sus-             < 50 years are similar, so the unproven long-term dura-
  pected problem.                                                   bility of coiling is a particular issue in this group.
• About one in 20 of the general population aged over the       •   In patients with no prior history of SAH, risk benefit anal-
  age of 30 harbours an unruptured asymptomatic aneu-               ysis favours treatment in people < 50 years old except for
  rysm.                                                             those with anterior circulation aneurysms < 7 mm in size
• Individuals most at risk of aneurysmal SAH are those              (but these account for nearly 50% of the total).
  with a family history of at least two first-degree relatives   •   For people > 50 years, treatment is only clearly favoured
  with an SAH, or patients with an underlying genetic               for aneurysms > 12 mm, and other factors such as life
  condition – most commonly autosomal dominant poly-                expectancy and coexistent conditions need to be taken
  cystic kidney disease.                                            into account.
• The risk seems highest if at least one of the affected        •   Routine screening for unruptured intracranial aneu-
  relatives is a sibling or mother. Lifestyle factors such          rysms in individuals with a family history of SAH is not
  as smoking, heavy alcohol consumption and hyperc-                 warranted.
  holesterolaemia may further increase the risk. A single       •   Asymptomatic individuals with only one family member
  relative (especially if second-degree) affected by SAH            affected by SAH do not have a sufficiently increased risk
  suggests a very small absolute risk of SAH to an indi-            to outweigh the risks of screening (and treatment).
  vidual without SAH.                                           •   Those patients with the greatest risk of having an unrup-
• CT angiography and MR angiography, performed and                  tured aneurysm, and of it then rupturing, are those aged
  reported by experts, can reliably detect aneurysms                over 30 years from families with two or more first degree
  larger than 5 mm. These techniques are unreliable at              relatives affected by SAH. They are perhaps at further
  detecting smaller aneurysms. A negative study may                 increased risk if they have additional risk factors such
  therefore offer false reassurance. This problem should            as smoking and hypercholesterolaemia. Such individu-
  be discussed with anyone referred for imaging to look             als and autosomal dominant polycystic kidney disease
  for an asymptomatic aneurysm.                                     patients with a family history of SAH should be assessed
• Rupture risk depends predominantly on the site and size           on an individual basis – taking all the relevant risk factors
  of an aneurysm and whether or not the patient has suf-            into account – for screening for intracranial aneurysms.
  fered a previous SAH. If not, small aneurysms (< 7 mm),       •   The role of coiling as opposed to clipping in the treat-
  particularly if anterior circulation, have an extremely           ment of unruptured aneurysms is promising, particu-
  low rupture risk. Other factors such as age and lifestyle         larly in patients > 50 years, and for posterior circulation
  factors also then need to be considered to determine              aneurysms.

                                                                                                         © 2004 Blackwell Publishing Ltd
102    PRACTICAL NEUROLOGY

                                                                                                      Fuller G (2001) What should I tell a patient after an iso-
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