Intracranial aneurysms and dolichoectasia in autosomal dominant polycystic kidney disease

Stefan Graf1, Alexander Schischma2, Knut E. Eberhardt3, Roland Istel4, Birgit Stiasny1 and Bernd D. Schulze1,

1 Department of Nephrology, University of Erlangen-Nürnberg, 2 Department of Medicine, Division of Nephrology, University of Frankfurt, Frankfurt, 3 Division of Neuroradiology, Department of Neurosurgery, University of Erlangen-Nürnberg and 4 Department of Radiology, Klinikum Nürnberg Süd, Nürnberg, Germany



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Intracranial saccular aneurysms (ICA) are a known extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). In order to facilitate the definition of subgroups who are at risk for ICA and to determine the prevalence of ICA in these subgroups we studied ADPKD patients with a positive family history for a cerebral event, including cerebral stroke (group I) and intracranial bleeding or known ICA (group II).

Methods. Within an enrolment period of 21 months, 43 ADPKD patients from our outpatient clinic and hospital were examined with cerebral magnetic resonance angiography (MRA).

Results. ICA were detected in six patients (14%). Three out of 32 patients (9.4%) in group I and three out of 11 patients (27.3%) in group II had an ICA. A dolichoectasia of intracerebral vessels was found in two out of 43 patients (4.7%).

Conclusions. Using MRA a high prevalence of ICA was shown only in patients with a family history of cerebral bleeding or ICA. A family history for cerebral stroke does not imply an elevated risk for ICA. However, dolichoectasia, rare in the normal population, was detected in two patients. We recommend screening for ICA in patients with a positive family history for cerebral bleeding or ICA. Because of potential complications, examiners should direct their attention to dolichoectasia in ADPKD patients.

Keywords: ADPKD; aortic aneurysm; dolichoectasia; intracranial aneurysm; polycystic kidney disease



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases affecting approximately 1 in 1000 individuals [1]. ADPKD is a systemic disorder with various extrarenal manifestations including an increased prevalence of intracranial aneurysms (ICA). The prevalence reported in the literature varies from 0 to 41% [2]; however, recent data suggest an overall prevalence of 5–10% in ADPKD patients [3,4].

With regard to the high mortality and morbidity from aneurysm rupture, screening of ADPKD patients for ICA must be considered. A decision analysis by Levey et al. [5] in 1983 demonstrated that ADPKD patients would not significantly benefit from routine arteriographic screening, considering the potential risks of conventional angiography. Recently, the development of magnetic resonance angiography (MRA) offers a non-invasive method to visualize ICA with a sensitivity of 86–95% and a specifity of up to 100% [6]. A re-examination of Levey's conclusion from Butler et al. [7] in 1996 showed that a screening strategy with MRA would increase the life expectancy of young patients with ADPKD.

Nevertheless, identifying clinical features that predict a high risk of intracranial vessel malformations is useful to define new screening strategies for these patients. Earlier studies showed a higher prevalence of ICA in families with a positive history of intracranial bleeding or ICA. However, in clinical practice, exact medical information about earlier cerebral events in family members was often not available. Therefore, we decided to extend our inclusion criteria to all ADPKD patients with a positive family history for a cerebral event, including those cases with missing information on the exact cause of the cerebral event.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Within an enrolment period of 21 months, patients from the outpatient clinic and from the department of nephrology were screened. ADPKD was diagnosed according to common ultrasonographic criteria and a positive family history for polycystic kidney disease.

Inclusion criteria for the study were: a positive family history for cerebral stroke in ADPKD patients. Cerebral stroke was defined as acute focal neurological deficiency due to cerebral ischaemia or intracranial bleeding in first- and second-degree relatives with known ADPKD.

Fifty-eight patients fulfilled the inclusion criteria. Fifteen patients were not included due to the following reasons: missing consent (n=7), contraindication for MRA (n=2), incomplete tests (n=4), and unknown address (n=2).

Forty-three ADPKD patients (22 women, 21 men) from 35 families with a mean age of 45.7 years (16–73 years) were included in the study.

In 31 of 43 cases the index persons were first-degree relatives, in 10 of 43 cases second-degree relatives.

Out of 43 patients who fulfilled inclusion criteria, 11 patients had a family history for a known cerebral bleeding or known ICA (group II). The remaining 32 patients had a positive family history for cerebral stroke (ischaemia or unknown cause) as inclusion criterion (group I).

In all patients the following clinical data were registered.

(i) Blood pressure (BP) in the sitting position. Arterial hypertension was defined as a BP of more than 140/90 mmHg at three different occasions or known elevated BP with anti-hypertensive treatment.
(ii) Duration of hypertension according to the patient's history and medical records and the number of anti-hypertensive drugs.
(iii) Serum creatinine level at the time of MRA. The Cockroft and Gault formula was used to estimate glomerular filtration rate. In patients with end-stage renal failure (ESRF) the duration and mode of renal replacement therapy were registered.

No data could be obtained on the genotype of the included patients.

ICA were defined as excentric pouching of the vessel wall. Dolichoectasia was defined as elongation and dilatation of a segment of a cerebral artery.

MRA
Cerebral vessels were examined with a 0.5 T imaging system (Gyroscan T5-II, Release 3, Philips Medical Systems, The Netherlands). MRA was performed using three-dimension phase-contrast imaging sequences (velocity 50 cm/s, 60 slices, 1 mm thick, orientation transverse TE 6.9 ms, {alpha}=20) and a two-dimensional inflow image sequence (velocity 50 cm/s, 50 slices, 4 mm thick, GAP -2 mm, orientation transverse TE 6.9 ms, {alpha}=60). With both post-processing maximum intensity projection images were generated. Additionally, a standard magnetic resonance imaging of the head with a T2-weighted TSE coronal sequence was performed (TE 80 ms, TR 2468 ms, 23 slices, 6 mm thick).

If an ICA was detected, conventional cerebral angiography was recommended and further action discussed with the neurosurgeon. In three patients with an ICA smaller than 10 mm, conventional cerebral angiography was not performed due to missing consent or medical reasons (allergy to contrast medium or advanced renal failure). These patients are checked at regular intervals for growth of the aneurysms by MRA.

Statistical analysis
Statistical evaluation was performed using two-sample t-test, Mann–Whitney U-test, {chi}2 analysis, and Fisher's exact test, respectively. Only two-tailed P values are reported.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
ICA or dolichoectasia were detected in eight (four women, four men) of 43 patients (18.6%). Six patients (four women, two men) showed saccular ICA (14%), two patients (both men) had a dolichoectasia (4.6%).

The size and location of ICA and dolichoectasia are shown in Table 1Go.


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Table 1.  Location and size of ICA and dolichoectasia

 
Most of the saccular aneurysms arose from the middle cerebral artery (n=5), followed by the internal carotid artery (n=3), and vertebrobasilar artery (n=2). One dolichoectasia was located at the vertebrobasilar artery, the other at the middle cerebral artery.

Multiple ICA were found in two of six patients. One patient had two aneurysms and one patient had three aneurysms. Neither the number nor size of the ICA was associated with the age of the patients.

A comparison of the inclusion groups I and II showed no significant differences in gender, hypertension, duration of hypertension, or renal function (Table 2Go).


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Table 2.  Patient characteristics and inclusion groups

 
Table 3Go shows the prevalence of ICA and dolichoectasia among the inclusion groups I and II. Saccular aneurysms were found in three (9.4%) of 32 patients in group I and in three (27.3%) of 11 patients in group II. Dolichoectasia was found in one of 32 patients in group I and in one of 11 patients in group II (Table 3Go).


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Table 3.  ICA/dolichoectasia and inclusion groups

 
Comparing the patients with ICA (n=6), dolichoectasia (n=2), and patients without intracranial vessel malformations (n=35) no significant differences in the presence and duration of hypertension and renal function could be shown. The mean age of the four women and two men with ICA was 45.7±12.9 years, the mean age of two men with dolichoectasia was 51.5±20.5 years, and the mean age of patients without ICA or dolichoectasia was 45.4±12.9 years. This difference was statistically not significant.

However, it is remarkable that the patients with dolichoectasia were male, hypertensive, and suffered from ESRF. Age and duration of hypertension tended to be higher and longer, respectively. Because of low patient numbers, these differences were not statistically significant. Two female patients with ICA died of subarachnoid haemorrhage, one of them did not give consent to surgical intervention, the other patient died before the aneurysm could be clipped. In both patients multiple aneurysms were present. One 57-year-old patient had two ICA (basilar artery and middle cerebral artery) and one 39-year-old patient had three ICA (middle cerebral arteries left and right). Both patients had no previously demonstrated aneurysm. Aneurysm rupture occurred 14 weeks after initial diagnosis in one patient who was in preparation for clipping of the aneurysm. The other patient, who had not given consent to surgical intervention died 3 months after initial diagnosis. Both ruptured aneurysms were greater than 10 mm in size. The patient with an ICA of the basilar artery (greater than 10 mm) and middle cerebral artery was symptomatic with a headache before rupture. Another patient with ICA underwent surgical clipping successfully. Out of two patients with dolichoectasia, one patient with a dolichoectasia of the basilar artery died of brainstem infarction. All patients, except the one patient with a headache before rupture, were asymptomatic.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
ICA are a known manifestation of ADPKD. With regard to the high mortality and morbidity from aneurysmal rupture (40% mortality after 30 days), routine screening of ADPKD patients must be considered. With MRA a non-invasive screening method is available. Previous studies have shown that MRA is a useful method to screen appropriate patients with ADPKD for ICA [4,8]. For screening purposes the method offers a sufficient sensitivity of 86–95% and a specifity of up to 100% [6].

A prevalence of ICA in ADPKD patients from 0 to 41% has been reported in earlier studies [2]. More recent data, however, suggest an overall prevalence in ADPKD patients of 5–10% [3,4,8]. Previous studies have also shown a higher prevalence of 22 [4] to 25.8% [8] in ADPKD patients with a positive family history for intracerebral bleedings or ICA.

In this study we tried to define a subgroup of ADPKD patients with an increased risk for ICA through a simple criterion like a cerebral stroke in the family history. We found an overall prevalence of 14% for saccular ICA in ADPKD patients with a positive family history for a cerebral event. This prevalence is higher than the overall prevalence of 5–10% for ADPKD patients reported in the literature [3,4,8]. However, in patients with a positive family history for cerebral bleeding or known ICA (group I) we found a prevalence of 27.3% for ICA, in contrast to a prevalence of 9.4% for patients with a positive family history for a cerebral stroke (group II). Thus, our study confirms the higher prevalence of ICA in ADPKD patients with a positive family history for cerebral bleeding or ICA. We could not show an increased prevalence of ICA for patients with a positive family history for a cerebral stroke compared with the data reported in the literature for ADPKD patients [4,8]. Screening strategies for ICA in ADPKD patients are still controversial. Theoretical models suggest that screening for asymptomatic ICA is not efficacious in populations with genetic syndroms like ADPKD [9]. However, these models have not been evaluated in clinical studies. A decision analysis in 1996 has shown the benefit of screening with MRA for a 20-year-old ADPKD patient, based on a prevalence for ICA of 15% for all ADPKD patients [7]. To date, there has been no analysis for patients with a positive family history for ICA or cerebral bleeding with a higher prevalence, as shown in our study and in studies from the literature. Pirson and Chauveau [10] suggested screening with MRA for 18- to 35-year-old ADPKD patients with a family history of ICA and recommended MRA re-screening every 5 years in ICA-negative patients. However, as long as a decision analysis for patients with a family history of ICA or cerebral bleeding is missing and further data on the natural history of ICA in ADPKD patients are not available, we would recommend screening for this patient subgroup irrespective of age, based on a relatively high prevalence of 27.3%.

Two female patients with ICA and multiple aneurysms died of aneurysm rupture after initial diagnosis. One patient with ICA of the basilar artery and middle cerebral artery suffered from headache before rupture, the other patient with ICA of the middle cerebral artery was asymptomatic. Unfortunately, in the latter patient the aneurysm rupture occurred before the planned aneurysm clipping could take place. Both patients had a positive family history for ICA or intracerebral bleeding. Therefore, particularly in symptomatic patients with a positive family history for ICA or intracerebral bleeding a high index of suspicion for ICA is recommended. Early screening might prevent those fatal intracerebral bleedings.

The results of a cooperative study in 1998 showed an exceedingly low likelihood of aneurysm rupture of less than 0.05% per year in sporadic ICA smaller than 10 mm in diameter without previous subarachnoid haemorrhage. For aneurysms 10 mm or more in diameter, the rupture rate approached 1% per year [11]. However, in familiar ICA the annual risk of aneurysm rupture was shown to be higher [12] and several studies in patients with familiar ICA and ADPKD-associated ICA showed that aneurysm rupture occurs at an earlier age [13,14] and with smaller diameters [14]. In our study, two (more than 10 mm in diameter) out of 10 ICA ruptured, exceeding the reported annual risk for sporadic aneurysms by far. It is likely, that the course of sporadic ICA including the risk of rupture is different to the course of ADPKD-associated ICA. Therefore, surgical repair or endovascular treatment of aneurysms even smaller than 10 mm in diameter should be considered in ADPKD patients.

Dolichoectasia was found in two out of 43 ADPKD patients. The prevalence of the malformation in the normal population is very low. An autopsy study conducted in 1967 showed a prevalence of less than 0.2% [15]. Yu et al. [16] reviewed 10000 angiograms and found a prevalence of 0.06%. In ADPKD patients, dolichoectasia was so far rarely described. The prevalence was 1.2–2.2% [4,8], but patient numbers were very low. A recent study by Schievink et al. [17] demonstrated with a sufficient number of patients (n=307) a prevalence of 2.3% in ADPKD compared with 0% in patients without ADPKD.

Dolichoectatic vessel malformations are of clinical importance as potential complications may arise. In our study, one patient with megadolichobasilar artery had a brainstem infarction and died of this complication. Brainstem infarction occurs in up to 30% of patients with dolichoectatic malformations of the vertebrobasilar circulation [18]. Other ischaemic signs include transient ischaemic attacks and vertebrobasilar insufficiency, including arterial dissection [19]. Signs of compression include facial spasm and impairment of the lower cranial nerves. These potential complications show clearly the importance of an early diagnosis of dolichoectasia in ADPKD patients. Prophylactic treatment, e.g. aspirin, depends upon the clinical course and complications of the individual patient.

In conclusion, a prevalence of 27.3% for ICA among ADPKD patients with a positive family history for cerebral bleeding or ICA, justifies a screening with MRA, until new decision analysis, based on further data, clarify the recommendations for this patient subgroup. A positive family history for cerebral stroke does not indicate an increased risk for ICA. However, we detected two patients with dolichoectasia in our study population. Because of potential complications, examiners should direct their attention to these vessel malformations in ADPKD patients.



   Notes
 
Correspondence and offprint requests to: Prof. Dr med. Bernd D. Schulze, Medizinische Klinik 4, Universität Erlangen-Nürnberg, Breslauer Straße 201, D-90471 Nürnberg, Germany. Email: berndd.schulze{at}t\|[hyphen]\|online.de Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 13. 1.01
Accepted in revised form: 12.12.01





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