Original Article
Intracranial Aneurysms in Autosomal Dominant Polycystic Kidney Disease
N Engl J Med 1992; 327:916-920September 24, 1992
- Abstract
- Abstract
Background and Methods.
Intracranial aneurysms are a feature of autosomal dominant polycystic kidney disease, but their prevalence is uncertain. We studied 92 subjects with autosomal dominant polycystic kidney disease who had no symptoms or signs of any neurologic disorder. To determine the prevalence of intracranial aneurysms, we performed high-resolution computed tomography (CT) in 60 subjects, four-vessel cerebral angiography in 21, and both procedures in 11.
Results.
Four of the 88 subjects in whom the radiologic studies were successfully completed had intracranial aneurysms (4 percent; 95 percent confidence interval, 0.1 to 9 percent), as compared with the prevalence of 1 percent reported for an angiographic study of the general population. Three of the four subjects had multiple aneurysms. Seven subjects for whom the results of CT studies were suspicious underwent cerebral angiography: two had aneurysms, and five had normal vascular structures that accounted for the suspicious results of tomography. Four subjects who had normal CT imaging studies also had normal angiographic examinations. Eight of the 32 subjects who underwent angiography (25 percent) had transient complications, as compared with 22 of 220 control subjects (10 percent) who did not have polycystic kidney disease (P<0.05). We could not identify any risk factor in these subjects that was related to the occurrence of aneurysm.
Conclusions.
Asymptomatic intracranial aneurysms appear to be more frequent in people with polycystic kidney disease than in the general population, although our 95 percent confidence interval includes the possibility of no difference. Because cerebral angiography is associated with increased morbidity in people with polycystic kidney disease, we recommend high-resolution CT as a screening test. (N Engl J Med 1992;327: 916–20.)
Article Activity
- Article
AUTOSOMAL dominant polycystic kidney disease can involve multiple organs, including the heart and gastrointestinal tract, as well as the kidneys.1 , 2 Affected persons may also have intracranial aneurysms,3 4 5 6 a fact that provides additional evidence of the systemic nature of this disorder. The exact frequency of intracranial aneurysm in people with polycystic kidney disease is uncertain, however; the reported prevalence rates vary from 0 to 41 percent.3 4 5 6 7 8 9 10
Studying all patients with autosomal dominant polycystic kidney disease by angiography to detect intracranial aneurysms appears to be inappropriate, according to decision analysis.11 Therefore, identifying clinical features that predict a high risk of intracranial aneurysms in people with this disease and developing less expensive and less risky diagnostic techniques are necessary steps toward an acceptable method of diagnosis. To determine the prevalence of intracranial aneurysms and identify risk factors for their development, we performed a prospective study of 92 subjects with polycystic kidney disease who had no symptoms or signs of neurologic disorder.
Methods
Subjects with Autosomal Dominant Polycystic Kidney Disease
We studied 92 adults with autosomal dominant polycystic kidney disease from 67 families between June 1985 and August 1990. The study subjects were part of a group of 378 subjects participating in our study of the natural history of polycystic kidney disease. Eighty-two of the 378 subjects were excluded from this study, for the following reasons: age less than 17 years (22 subjects), age over 65 years (21 subjects), serum creatinine concentration above 3.0 mg per deciliter (265 μmol per liter) (33 subjects), previously diagnosed intracranial aneurysm (5 subjects), and death shortly after the initial visit (1 subject). Among the remaining 296 subjects, 92 (31 percent) agreed to participate. None of the subjects studied were pregnant or breast-feeding, and none had had a previous reaction to the injection of any iodinated contrast agent. This study was approved by the Human Subjects Committee of the University of Colorado Health Sciences Center. Written informed consent was obtained before each procedure.
The diagnosis of autosomal dominant polycystic kidney disease was based on the detection by ultrasonography of a total of five or more cysts in both kidneys and usually on a family history of polycystic kidney disease unassociated with hepatic fibrosis. Five subjects (5 percent) had no family history of cystic renal disease but were considered to have the autosomal dominant type of polycystic kidney disease on the basis of typical ultrasonographic findings and the absence of liver dysfunction and hypokalemia. Subjects were considered to be hypertensive if their blood pressures measured in the sitting position were higher than 150/90 mm Hg on three separate occasions or if they were receiving antihypertensive therapy at the time of the study. Other factors assessed for possible association with the development of intracranial aneurysms included age, sex, and the extrarenal manifestations of hepatic cysts and mitral-valve prolapse. All the subjects underwent hepatic ultrasonography,12 and 41 subjects had echocardiography.13
The determination of a family history of ruptured intracranial aneurysm required documentation of an aneurysm in another family member at autopsy, by radiologic imaging techniques, or on the basis of a history of an acute neurologic event compatible with the rupture of an intracranial aneurysm as evaluated by a neurologist.
The subjects were asked to undergo direct four-vessel cerebral angiography (i.e., angiography of the entire brain). If they declined, high-resolution computed tomography (CT) was offered. Subjects whose initial CT studies raised the possibility that an intracranial aneurysm was present were then asked to undergo angiography.
Control Patients
We also studied the cerebral angiograms of 30 sex-matched patients without autosomal dominant polycystic kidney disease who underwent angiography during the same period for clinical reasons other than aneurysmal rupture. The purpose was to determine the frequency of infundibular dilatations in a contemporaneous population without polycystic kidney disease. A second control group consisted of 220 consecutive hospitalized patients without polycystic kidney disease who underwent direct four-vessel cerebral angiography for clinical reasons during the first two years of the study. Information on adverse effects was sought specifically by interviewing each patient and reviewing the hospital record.
Radiologic Procedures
Selective angiography with iothalamate meglumine (Conray 282, Mallinckrodt, St. Louis) was performed through the right femoral artery, with injections into the left and right internal carotid and vertebral arteries. Images were obtained on cut film or by digital subtraction recording.
CT of the brain (Picker 1200 SX; Picker, Highland Heights, Ohio) was performed with a total of approximately 100 ml of diatrizoate meglumine (Angiovist 282, Berlex, St. Paul, Minn.) given intravenously. A 10-ml test injection of contrast material was given to reduce nausea or vomiting during the filming sequence and ensure that contrast material entered the vein without extravasation. Then a 30-ml bolus injection was given at a rate of 1 ml per second, followed by an infusion of 30 ml at a rate of 0.2 ml per second. During the slow infusion, axial scanning with 2-mm contiguous sections was performed from the inferior aspect of the third ventricle down to the cavernous sinuses. The subject was then placed in the prone position, and during an additional 30-ml infusion at a rate of 0.2 ml per second, 2-mm contiguous coronal sections (adjusted to minimize artifacts caused by dental work) were obtained through the region of the circle of Willis. The pixel size for each image was 0.31 mm2. The subjects were asked to report any symptoms during the procedure and for 48 hours afterward.
All the images were interpreted by two neuroradiologists working together who were unaware of the diagnosis of polycystic kidney disease when they were assessing the frequency of infundibular dilatation. Angiographic results were categorized as positive, negative, or incomplete (when the study could not be completed because of adverse reactions or technical difficulties). An angiogram that showed an abnormal vascular dilatation was considered positive for an intracranial aneurysm. Saccular aneurysms were defined as eccentric pouching of the vessel wall. An infundibular dilatation was defined as any bulbous or funnel-shaped concentric dilatation larger than the diameter of the distal vessel at the origin of the posterior communicating or anterior choroidal arteries.
The results of CT were defined as suspicious, negative, or incomplete (when the study could not be completed because of adverse reactions or technical difficulties). A suspicious CT image was defined as a region of apparent dilatation that could not be explained by the normal course of an artery or an arterial branch.
Statistical Analysis
Chi-square analysis was used to determine whether sex, hypertension, mitral-valve prolapse, hepatic cysts, and a family history of ruptured intracranial aneurysm were significant risk factors for the development of intracranial aneurysm. Chi-square analysis was also used to compare the frequencies of intracranial aneurysms, infundibular dilatations, and complications in the group with autosomal dominant polycystic kidney disease and the two groups of control patients. Rank-sum analysis was used to compare the ages of the subjects who had intracranial aneurysms with those who did not have such aneurysms. Confidence intervals for proportions were calculated by the formula
in which p represents the number of subjects positive for the finding, q the number negative, and n the total number studied.Results
The mean age of the 92 subjects with autosomal dominant polycystic kidney disease was 36 years (range, 17 to 62). Fifty-six were women, and 36 were men. Twenty-one subjects underwent only angiography, and 71 subjects underwent CT. Two studies of each type were incomplete because of technical failure or adverse reactions, as described subsequently. Eleven of the 69 subjects successfully studied by CT subsequently underwent angiography. Overall, therefore, 32 subjects had angiography (11 of whom also had CT), and 60 had only CT.
The results are shown in Figure 1Figure 1
Results of Cranial Imaging of 92 Subjects with Autosomal Dominant Polycystic Kidney Disease.. Two of the 19 subjects studied only with angiography had intracranial aneurysms. In 11 of the 69 subjects who successfully underwent CT (16 percent), the results were suspicious for aneurysms. Seven of these 11 subjects underwent angiography, and 2 had aneurysms. The remaining five subjects had vascular structures that matched the suspicious areas seen by CT. In one subject, the CT images revealed three branches in the region of the anterior communicating artery so close together that an aneurysm could not be ruled out. On subsequent angiographic imaging, the three branches in this region continued to overlap. The presence of a tiny aneurysm could not be excluded with certainty, but we considered the images negative. Two subjects had branching vessels at sites of suspicion on the CT images (both near a proximal branch of the middle cerebral artery). One subject had a suspicious CT image in the distal part of one middle cerebral artery, which proved to be a vein. This subject also had a trigeminal artery. In one subject the bifurcation of the basilar artery was indistinguishable from an aneurysm on CT images, but angiography revealed four distal branches arising from the enlargement, in a manner consistent with a normal variant. Four subjects for whom CT images were suspicious declined angiography. In addition, four subjects with normal CT studies had normal angiographic studies.Therefore, 4 of the 88 subjects for whom one or both imaging studies were successfully completed had intracranial aneurysms (4 percent; 95 percent confidence interval, 0.1 to 9 percent). The number, nature, size, and location of the aneurysms are shown in Table 1Table 1
Intracranial Aneurysms in Four Subjects with Autosomal Dominant Polycystic Kidney Disease.. All the aneurysms were saccular. The CT and angiographic images of Subject 1 are shown in Figure 2Figure 2
High-Resolution Coronal CT Images (Panels A and B) and an Angiogram (Panel C) Showing an Oblique View of the Right Internal Carotid Artery in a Subject with Two Saccular Aneurysms.. All four subjects with intracranial aneurysms also had infundibular dilatations. Fifty percent of the subjects with polycystic kidney disease who underwent angiography had such dilatations, as did 67 percent of the 30 control subjects.The mean age of the four subjects with intracranial aneurysms was 42 years. Three were men, and one was a woman. Two of the 4 were among the 29 subjects (7 percent) with a family history of ruptured intracranial aneurysm, and the other 2 were among the 59 subjects (3 percent) without such a history. There was no relation between the presence of aneurysms and any of the following variables: family history of a ruptured intracranial aneurysm, age, sex, hypertension, mitral-valve prolapse, and hepatic cysts. The 92 subjects studied were younger than the 204 subjects who declined to be studied and were likely to have a family history of ruptured aneurysm (Table 2Table 2
Characteristics of Subjects with Polycystic Kidney Disease Who Were Studied and Those Who Declined to Be Studied.).Complications of the Imaging Studies
No subject had an increase of more than 0.4 mg per deciliter (35 μmol per liter) in the serum creatinine concentration after the administration of contrast material for either angiography or CT. Eight of the 32 subjects who underwent angiography (25 percent) had transient complications (i.e., for less than 48 hours), as compared with 22 of the 220 subjects (10 percent) without polycystic kidney disease studied at this institution who were specifically reviewed for the occurrence of complications (P<0.05). Two related subjects had transient complete closure of an internal carotid artery due to spasm. Both were asymptomatic during the study; they had severe nausea, vomiting, and headaches, but no focal neurologic deficits, after the procedure. Neither had a history of migraine, and their symptoms resolved completely within 48 hours with no treatment. Two other subjects had severe transient headaches that began within the hour after the procedure. Three subjects had scotomata during the procedure, one of whom also had numbness of the right hand; these symptoms disappeared completely within 24 hours. One subject had a dissection of the left vertebral artery during angiography that was asymptomatic.
Three of the 71 subjects who underwent CT (4 percent) had transient side effects: hives, acute laryngeal edema, and local infiltration of contrast material. These side effects all responded to treatment and resolved completely.
Discussion
In this study of relatively young subjects with autosomal dominant polycystic kidney disease who had no neurologic problems, the frequency of unruptured aneurysm was 4 percent, significantly higher than the 1 percent (P<0.04) found by Atkinson et al. in an angiographic study of a general population.14 Torres et al. found no aneurysms in 96 subjects with polycystic kidney disease but no neurologic symptoms, although 11 percent were thought to have an aneurysm on the basis of CT images,15 similar to the 16 percent in our study. These investigators obtained images at 3-mm intervals and only in the axial plane. By contrast, in three angiographic studies of Japanese subjects with polycystic kidney disease, the frequencies of unruptured aneurysms were higher: 41 percent of 17 subjects with no neurologic symptoms in one study,9 37 percent of 19 patients with neurologic symptoms in the second study,16 and 60 percent of 5 subjects with no neurologic symptoms in the third.17
Five of the 264 adults in our program who were not studied had previous aneurysmal rupture. Four of these five had multiple aneurysms, and the fifth had a solitary aneurysm of the vertebral artery. If 50 percent of intracranial aneurysms rupture,18 one could predict that another five subjects in this unstudied population would have unruptured aneurysms, yielding a predicted frequency of 4 percent (10 of 264), not different from the 4 percent found in this study.
The aneurysms were in locations similar to those in which aneurysms are found in the general population.14 Three of the four subjects had multiple aneurysms, as did four of the five subjects with previously ruptured aneurysms. Multiple aneurysms occur in 18 to 37 percent of unselected patients19 , 20 and in even higher percentages among patients with a familial occurrence of aneurysms.21 This may reflect a genetic defect of the vasculature.22 One subject had a persistent trigeminal artery, a persistent anomalous vessel from the fetal carotid—basilar circulation that is rare in the general population.23 This anomaly is associated with the formation of intracranial aneurysms,23 and both have been described in a patient with polycystic kidney disease.24 The four subjects with aneurysms also had infundibular dilatations, a finding associated with an increased occurrence of aneurysm.25 , 26
Direct angiography is the most sensitive and specific test for intracranial aneurysms. However, CT may be a valuable screening test. Schmid et al. reported that the sensitivity of high-resolution CT for detecting intracranial aneurysms was 97 percent.27 In our study, all suspicious structures seen on CT images proved to be vascular structures on angiography. It is important to point out that no aneurysms other than those predicted by CT were found, but only 4 of the 58 subjects with negative CT scans underwent angiography.
Twenty-five percent of the subjects who underwent angiography had complications, a significantly higher complication rate than that found in patients without polycystic kidney disease studied at our institution. Two related subjects had severe occlusive carotid vasospasm. Subjects with polycystic kidney disease have a high frequency of headaches not related to hypertension2 and may have abnormal neurovascular systems that render them more prone to complications of angiography. Therefore, arteriography should be undertaken with even more caution than usual.
In conclusion, subjects with autosomal dominant polycystic kidney disease may have intracranial aneurysms more often than the general population. Our results could be underestimates, because the study population was young and the frequency of aneurysmal rupture and possibly of aneurysms increases with age.28 Second, these subjects may have more complications of angiography than the general population. For this reason, we think that high-resolution CT is the most appropriate initial test in these patients.
This study does not clarify the important issue of the need for subjects with polycystic kidney disease to be screened by CT for intracranial aneurysm. At present we recommend that those with a family history of intracranial aneurysm should undergo such screening arbitrarily every 5 to 10 years.
Supported by a grant (DK34039) from the National Institute of Diabetes and Digestive and Kidney Diseases and a grant (MO-RR00051) from the General Clinical Research Center of the National Institutes of Health.
Source Information
From the Departments of Medicine (A.B.C., A.M.J., P.A.G., W.D.K.), Radiology (D.R., J.C.S.), and Neurology (R.H., M.P.E.), University of Colorado School of Medicine; University Hospital (A.B.C., D.R., J.C.S., W.D.K.); Denver General Hospital (A.B.C., R.H., M.P.E., P.A.G.); and the Department of Veterans Affairs Medical Center (W.D.K.); all in Denver. Address reprint requests to Dr. Kaehny at P.Q.D. Research, U.C.H.S.C. C-283, 4200 E. 9th Ave., Denver, CO 80262.
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