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(Stroke. 1995;26:961-963.)
© 1995 American Heart Association, Inc.

Articles

Outcome in Familial Subarachnoid Hemorrhage

J.E.C. Bromberg, MD; G.J.E. Rinkel, MD; A. Algra, MD; M. Limburg, MD J. van Gijn, MD, FRCPE

From the University Department of Neurology, Utrecht (J.E.C.B., G.J.E.R., A.A., J. van G.), and the University Department of Neurology, Academic Medical Centre, Amsterdam (M.L.), Netherlands.

Correspondence to Jacoline E.C. Bromberg, MD, University Department of Neurology, PO Box 85500, 3508 GA Utrecht, Netherlands.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose The outcome of subarachnoid hemorrhage in patients with familial occurrence of subarachnoid hemorrhage (familial SAH) is an important but neglected factor in balancing the risks of screening for asymptomatic aneurysms and repairing these in unaffected members of such families.

Methods We studied the outcome of familial SAH in a prospective, hospital-based series of patients with at least one first-degree relative with SAH and compared it with the outcome in a prospectively collected hospital series of patients selected for the absence of SAH in first- and second-degree relatives. Outcome was graded in three categories: independence, dependence, or death. Poor outcome was defined as death or dependence.

Results Of 29 patients with familial SAH, 52% had a poor outcome, whereas only 37% of 125 patients with sporadic SAH had a poor outcome. The crude relative risk for poor outcome in familial SAH was 1.4 (95% confidence interval [CI], 0.9 to 2.1; P=.14); the odds ratio adjusted for age and sex was 2.5 (95% CI, 1.0 to 6.0; P=.04). This risk is probably an underestimation due to our strict patient selection criteria.

Conclusions Patients with familial SAH have a greater risk of poor outcome than patients with sporadic SAH. This adds to the factors in favor of screening unaffected first-degree relatives of patients with familial SAH.

Key Words: aneurysm • hereditary diseases • outcome • subarachnoid hemorrhage

	Introduction

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Some families are affected by clustering of subarachnoid hemorrhage (SAH).^{1 2 3 4 5} For members of such families, the risks of screening for and repair of asymptomatic aneurysms must be weighed against the risk of SAH. An important but neglected factor in this balance of risks is the outcome in SAH with familial occurrence. The prognosis of SAH in families with clustering of SAH (familial SAH) has always been presumed to be identical to that of nonfamilial instances of SAH (sporadic SAH). If the outcome of familial SAH differs from that of sporadic SAH, however, the decision of whether or not to screen might change substantially.

To assess the outcome of patients with familial SAH, we studied a series of patients with SAH who had at least one first-degree relative with SAH. We compared the outcomes in this series of familial SAH with those in a large, prospectively collected series of patients selected for the absence of SAH in first- and second-degree relatives.

	Subjects and Methods

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From September 1991 to October 1992, we prospectively collected a series of patients with aneurysmal SAH admitted to the Academic Medical Centre, Amsterdam, and the university hospitals of Rotterdam and Utrecht, Netherlands. Patients with perimesencephalic, nonaneurysmal SAH were excluded, since this is a distinct clinical entity with an invariably good outcome.^{6 7} Informed consent was obtained from the patient or next of kin and was refused in 37 of 200 consecutive patients. In 20 of these 37 patients, the index patient had died. A pedigree was drawn up for each family. All first-degree relatives (parents, children, and siblings) and all second-degree relatives (grandparents, grandchildren, aunts, uncles, nephews, and nieces) were interviewed by telephone and questioned about a history of SAH; any illness with sudden, severe headache; or any other form of stroke. For deceased relatives the history was obtained from the next of kin. Medical charts were retrieved whenever possible. Patients with one or more first-degree relatives with SAH were designated as having familial SAH. Patients who had no relatives with a history of SAH served as the reference group (sporadic SAH). Patients with only second-degree relatives who had suffered SAH or with relatives in whom the diagnosis was suspected but could not be proved were excluded from both series. Patients admitted to Utrecht University Hospital with SAH in the year following the study were all asked about close relatives with SAH; patients with familial SAH thus found and patients who were referred to our outpatient clinic because of familial SAH were also included. Relatives were excluded from the outcome analysis if they died before reaching a hospital or if they had their SAH before 1975, since our control series is hospital based and recent.

All histories and medical documents were classified independently and without information about relatives by two observers (J.E.C.B. and G.J.E.R.) according to criteria decided on in advance. When medical documents described clinical features suggestive of SAH in combination with blood in the basal cisterns on a CT scan, or xanthochromic CSF, or an aneurysm proved by angiography or autopsy, the relative was classified as having had SAH. Similarly, sudden, severe headache in combination with a normal neurological examination and hemorrhagic CSF followed by sudden deterioration consistent with rebleeding was also designated as SAH. Other descriptions of episodes suggestive of SAH were not included as SAH. The neurological condition on admission was graded according to the World Federation of Neurological Surgeons (WFNS) scale.⁸ Outcome at discharge from the hospital was graded according to the modified Glasgow Outcome Scale in three categories: independence, dependence, or death.⁹ In the outcome analysis we defined poor outcome as death or dependence. In the comparison of outcome for patients with familial and sporadic SAH, we used relative risks with matching 95% confidence intervals (CIs). Since baseline characteristics differed for the two groups, we used logistic regression analysis to calculate the odds ratio after adjustment for age and sex. We did not adjust for the condition at admission, since this variable was unknown in 8 of the 29 familial cases.

	Results

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We identified 14 families with at least two first-degree relatives with SAH. Nine of these families were detected during the prospective study period of 1 year. In these 14 families, we identified 35 members who had suffered SAH. Six of these relatives were excluded from the outcome analysis: 5 (4 of whom with poor outcome) because they had their SAH before 1975, and 1 because he died before reaching a hospital. The remaining 29 subjects with familial SAH were included in the outcome analysis. One hundred twenty-five patients fulfilled the criteria for sporadic SAH and constituted the control group. Baseline characteristics and outcomes of patients and relatives with familial SAH and patients with sporadic SAH are shown in the Table. There were fewer women in the familial group (55%) than in the nonfamilial group (62%), but this difference in sex ratio was not statistically significant (95% CI, -13% to +27%). The mean age at which SAH occurred was lower (8.7 years; 95% CI, 3 to 14) in familial patients. The clinical condition on admission was similar in the two groups: 38% of familial patients and 42% of nonfamilial patients were in poor condition (WFNS grade 4 or 5). Treatment did not differ significantly between familial and sporadic cases: in 62% of familial and 76% of sporadic cases the aneurysm was clipped (95% CI of difference, -33% to +5%). We found two families with autosomal dominant polycystic kidney disease. In one family only the index patient had suffered SAH; in the other a relative had had a possible SAH. No connective tissue disorders were reported in any of the families.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics and Outcome of Patients and Relatives With SAH

Of the 29 familial cases, 52% had a poor outcome, whereas of the 125 patients with sporadic SAH, 37% had a poor outcome. The relative risk for poor outcome in a patient with familial SAH was 1.4 (95% CI, 0.9 to 2.1; P=.14); the odds ratio was 1.8 (95% CI, 0.8 to 4.2; P=.14). After adjustment for age and sex, the odds ratio was 2.5 (95% CI, 1.0 to 6.0; P=.04). Mortality alone in the patients with familial SAH was 38%, which is again higher than the 26% mortality in the series of sporadic SAH, with a relative risk of 1.5 (95% CI, 0.9 to 2.6).

	Discussion

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Our results suggest that patients with familial SAH have a poor outcome 1.5 times as often as patients with sporadic SAH (52% vs 37%). The difference in the proportion of patients with a poor outcome between familial and sporadic SAH is almost statistically significant, with 95% confidence limits of the relative risk only just containing the value 1, despite the small number of patients with familial SAH and despite several causes of bias toward a better outcome in familial cases.

Our reference group is a prospective, hospital-based series of patients with sporadic SAH in whom extensive study revealed no first- or second-degree relatives with SAH or suspected SAH. Our series of familial SAH, in which the index patients were prospectively collected and hospital based, also includes relatives whose SAH had occurred previously but after 1975. Baseline characteristics of the two series were comparable: there was no difference in sex ratios or clinical condition at admission, but the mean age at which SAH occurred was significantly lower in familial patients. Although this lower mean age in familial patients would lead one to expect a better outcome in familial than in sporadic SAH, we found a worse outcome in familial SAH. In fact, after adjustment for age and sex the odds ratio for poor outcome in familial patients increased from 1.8 to 2.5 (95% CI, 1.0 to 6.0; P=.04).

Several other factors may have caused an underestimation of the proportion of patients with poor outcome in familial SAH. First, because the prognosis of SAH may have improved in the last decades,¹⁰ we excluded from our series of familial SAH 5 relatives who had their SAH before 1975. Four of these 5 had a poor outcome. Second, we excluded relatives with SAH who died before reaching a hospital, since our control series is hospital based. Third, our selection criteria exclude relatives with stroke in a poor clinical condition who died before ancillary investigations could be performed. Since at least some of these relatives had suffered an SAH, this is another source of bias toward a favorable outcome. All these factors influence the results in such a way that the difference in proportions of poor outcomes between familial and sporadic SAH is probably underestimated in our study.

We cannot explain the less favorable outcome in patients with familial SAH with certainty. It has been postulated that a hereditary defect in the arterial wall (for example, a connective tissue disorder) could be responsible for the development of intracranial aneurysms.^{4 11 12 13} One could hypothesize that this defect is more severe in familial cases, thus causing a more fragile vessel wall with larger aneurysms, which may entail a worse prognosis.¹⁴ However, since we included patients regardless of their clinical condition and therefore do not have complete data on the sizes of the aneurysms of our patients, we cannot test this explanation, and the similarity of the clinical condition at admission between familial and sporadic cases even challenges it. Although it is attractive to assume a structural factor in familial cases, collagen deficiency or other structural abnormalities of connective tissue have thus far not been demonstrated in familial cases of SAH.¹⁵

With the development of MR angiography, noninvasive screening for intracranial aneurysms now seems in the offing. The morbidity and mortality of elective surgery of unruptured aneurysms has become less than 3% in experienced hands,¹⁶ even for aneurysms of the posterior circulation.¹⁷ A recent decision analysis has indicated that catheter angiography to screen for familial intracranial aneurysms is justified in individuals between the ages of 40 and 60 years.¹⁸ The mortality and morbidity rates in this analysis were taken from older series,¹⁹ but happen to be similar to the rates we found in our series of familial SAH. The advice to screen for familial intracranial aneurysms between the ages of 40 and 60 years therefore still holds true. If, however, MR angiography is available, perhaps subjects at risk for familial SAH should be screened even in the age range of 20 to 70 years.²⁰ This screening should be repeated at regular intervals, since new aneurysms can develop at any age.^{20 21 22}

	Acknowledgments

 
This study was partially supported by the Dutch Heart Foundation (grant 90.321). We are indebted to E.F.M. Wijdicks, MD, for his stimulating guidance and Mrs P. Greebe for her inexhaustible search for information about relatives. We would like to thank D. Hasan, MD, for his assistance in collecting patients for our study and C.A.F. Tulleken, MD, and S. Boomstra, MD, for referring their patients to us.

Received December 9, 1994; revision received March 13, 1995; accepted March 14, 1995.

	References

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