Management of Cerebral Aneurysms in Autosomal Dominant Polycystic Kidney Disease

Transcription

1 DISEASE OF THE MONTH EBERHARD RITZ, FEATURE EDITOR J Am Soc Nephrol 13: , 2002 Management of Cerebral Aneurysms in Autosomal Dominant Polycystic Kidney Disease YVES PIRSON,* DOMINIQUE CHAUVEAU, and VICENTE TORRES *Université Catholique de Louvain, Cliniques Universitaires St-Luc, Department of Nephrology, Brussels, Belgium; Hôpital Necker, Service de Néphrologie, Paris, France, Mayo Clinic, Rochester, New York. The association of intracranial aneurysm (ICA) and autosomal dominant polycystic kidney disease (ADPKD) has been known for many years. Its prevalence has only been estimated reliably over the past decade, thanks to the development of noninvasive detection techniques, mainly magnetic resonance (MR) angiography. A prevalence of 8% of asymptomatic ICA has been derived from three prospective series totaling 266 patients (1 4), i.e., a rate four to five times above that found in the general population (5). Although this association has been attributed in the past to the occurrence of hypertension in many affected patients, several lines of evidence strongly suggest a causal role of the mutated ADPKD gene. PKD1, the gene responsible for 85% of ADPKD cases, encodes polycystin 1, an 11-pass membrane protein with a large extracellular region mediating cell-cell and cell-matrix interactions (6). PKD2, which accounts for the vast majority of the remaining cases, encodes polycystin 2, a 6-pass membrane protein with homology to voltage-activated calcium channels (7). Polycystin 2 is believed to interact with polycystin 1 to transduce signals from extracellular ligands (8). Recent experimental evidence has suggested that both PKD1 and PKD2 play a role in the structural integrity of blood vessels. Mouse embryos homozygous for a targeted mutation in the mouse homolog of PKD1 exhibit vascular leaks and rupture of blood vessels, leading to death in utero (9). Focal hemorrhages have also been noticed in mouse embryos homozygous for a PKD2 null allele (10). In humans, both polycystin 1 and polycystin 2 are strongly expressed in vascular smooth-muscle cells of normal adult elastic arteries, whereas a staining of variable intensity is observed in the walls of ICA specimens from patients with as well as without ADPKD (11,12). Polycystins could thus be instrumental in the functional interaction between arterial smooth-muscle cells and adjacent elastic tissue or endothelial cells; a mutation in their genes could disrupt this interaction and weaken the vessel wall (13). Specific types of mutation might predispose to the development of ICA, as Correspondence to Yves Pirson, Université Catholique de Louvain, Cliniques Universitaires St-Luc, 10 Avenue Hippocrate, Brussels, Belgium. Phone: ; Fax: ; PIRSON@NEFR.UCL.AC.BE / Journal of the American Society of Nephrology Copyright 2001 by the American Society of Nephrology suggested by some clustering of ICA in families that carry both PKD1 (14) and PKD2 (15), as well as by the identification of the same PKD1 mutation in two different pedigrees with ICA affecting one and three members, respectively (16). However, both the absence of ICA in other relatives with ADPKD within such families as well as the wide intrafamilial variability in the occurrence and/or severity of this (and other) manifestation(s) of ADPKD indicate that other factors also play a role in the formation and rupture of ICA. Somatic mutations in the normal PKD allele ( the second hit ) and/or modifying genes could be such factors. Among the latter, the gene(s) responsible for non-adpkd familial ICA, as yet not identified, might be involved (ICA is said to be familial when two or more firstdegree relatives are affected) (17,18). The contributory role of acquired factors should also be considered: in the general population, cigarette smoking and arterial hypertension have indeed been recognized as the most significant risk factors for both the development and the rupture of sporadic as well as familial ICA (19,20). The natural history of ICA in ADPKD remains largely unknown. We fortunately know that all ICA do not rupture. When they do, this event entails a 35% to 55% risk of combined case fatality and morbidity (14,21). We review this complication, focusing on clinical presentation, diagnostic work-up, and current management. We then discuss the pros and cons of screening patients with ADPKD for asymptomatic ICA. Because data for an ADPKD population are quite often unavailable, we frequently refer to information on sporadic and familial ICA obtained in the general population, acknowledging the limitations of such extrapolations. Aneurysm Rupture The incidence of ICA rupture in patients with ADPKD has been estimated to be 1/2000 person-years in Rochester (21), i.e., a rate five times higher than in the general population (19). This 5/1 ratio roughly parallels that of the prevalence of ICA, which suggests that the risk of rupture of ICA among patients with ADPKD is quite similar to that observed in the general population. Demographics The profile of the patient with ADPKD admitted for ICA rupture has been delineated on the basis of three studies that

2 270 Journal of the American Society of Nephrology J Am Soc Nephrol 13: , 2002 included 191 patients (14,17,21,22). Age at the time of ICA rupture averages 41 yr. This is close to that observed in other familial forms of ICA but a decade lower than that reported in the sporadic form (17). In our series, 10% of the patients are 21 yr old (14). Occasionally, ICA rupture is the presenting manifestation of ADPKD. As expected from the mean age at rupture, 54% of the patients still have a normal renal function at that time, and 26% had a BP within the normal range before rupture (22). The prevalence of clinical manifestations related to ADPKD is not different in patients with and without ICA rupture. The only feature clearly associated with ICA rupture in ADPKD is a family history of ICA, which we found five times more often in patients with than in a control group without ICA rupture (22). The influence of smoking and arterial hypertension has yet to be properly assessed in ADPKD. Clinical Presentation Because cerebral arteries are contained within arachnoidal cisterns, ICA rupture results in subarachnoid hemorrhage (SAH). Blood tracks into cerebrospinal fluid and may extend into brain (cerebral hematoma) and ventricles (ventricular hemorrhage). Early recognition of SAH is crucial, because any delay adversely affects patient outcome. Common diagnostic pitfalls have been thoroughly reviewed elsewhere (19,23). The cardinal feature of SAH is a sudden intense headache, often described as a blow or an explosion inside the head, the worst ever experienced by the patient (19,23,24). Headache is more often diffuse than local. It subsequently radiates into the occipital or cervical region. Some patients with proven SAH have only minor bleeding, which causes less severe and less diffuse headaches, often misinterpreted as migraine. Doctors should be alerted by the unusual character of headaches. Between 20% and 50% of patients admitted for SAH have a history of acute and transient headache in the days or weeks before the index episode of bleeding. This warning headache is most likely due to a first, limited leak from the ICA. It is frequently overlooked both by the patient and the doctor (19,23). Unusual headaches in a patient with ADPKD should also evoke other causes, especially those that are treatable (Table 1). It should be first remembered that the majority of acute neurologic events affecting patients with ADPKD do not result from ICA rupture but from primary hypertensive intracranial hemorrhage or ischemic stroke (25). In addition, headaches may be related to other, rarer manifestations of ADPKD or posttransplant immunosuppression. Spontaneous dissection of vertebral/basilar and internal carotid artery has been reported in some patients with ADPKD (26,27). Two patients with ADPKD and postural headaches characteristic of intracranial hypotension were found to have leaking spinal meningeal diverticula (28). Four patients with ADPKD presenting with headaches and/or hemiparesis suffered from a subdural hematoma (29). In a context of posttransplant immunosuppression, occurrence of headaches should also raise the suspicion of opportunistic infection or tumor. Other symptoms or signs of SAH include nausea and vomiting, photophobia, focal neurologic deficit, seizures, lethargy, and transient loss of consciousness. Physical examination may show neck stiffness, focal neurologic signs, and retinal hemorrhages. SAH-associated high BP or cardiac arrhythmias may lead to the incorrect diagnosis of hypertensive emergency or primary cardiopathy, respectively (23). Diagnostic Studies The first diagnostic step to assess the possibility of SAH should be noncontrast cerebral computed tomography (CT) with very thin cuts (Figure 1). Hemorrhage appears as areas of increased density, the degree of which depends on the hemoglobin concentration (23). The bleeding pattern may indicate Table 1. Treatable causes of unusual headaches in patients with autosomal dominant polycystic kidney disease Sudden/acute onset subarachnoid hemorrhage ischemic or hemorrhagic stroke hypertensive emergency cervicocephalic artery dissection meningitis or encephalitis a Subacute onset leaking spinal meningeal diverticula subdural hematoma brain lymphoma a a After kidney transplantation. Figure 1. Diagnostic investigation of the patient with clinical suspicion of subarachnoid hemorrhage. CT, computed tomography.

3 J Am Soc Nephrol 13: , 2002 Cerebral Aneurysms in ADPKD 271 the site of the ICA. Coexisting intracerebral hematoma or ventricular hemorrhage may be seen. The total amount of subarachnoid blood is thought to predict the risk of subsequent cerebral ischemia. Blood is rapidly cleared from the subarachnoid space; the sensitivity of CT in detecting hemorrhage decreases, thus, over time, from 92% on the day of rupture to 86% 1 d, 76% 2 d, and 58% 5 d later (23). If SAH is strongly suspected on clinical grounds but not confirmed by CT, a lumbar puncture should be performed. In the presence of a bloody cerebrospinal fluid, it is critical to distinguish a traumatic lumbar tap from a true hemorrhage. Xanthochromia (yellow discoloration due to the metabolizing of hemoglobin to oxyhemoglobin and bilirubin) of the supernatant after centrifugation of the cerebrospinal fluid is diagnostic of SAH (19). It takes about 12 h to appear and is best appreciated by spectrophotometry (23). If both CT scan and cerebrospinal fluid are normal, the diagnosis of SAH is very unlikely. Once established, SAH should be further investigated under the direction of a neurologist/neurosurgeon team. Conventional angiography is usually performed as soon as possible in order to localize the ruptured ICA, delineate its size and neck, assess the degree of vasospasm, and detect other unruptured ICA. Just as in the general population, 90% of the ruptured ICA detected in patients with ADPKD are located in the anterior circulation, the middle cerebral artery being the most common site (14,21). The size distribution of 27 ruptured ICA in patients with ADPKD was as follows: 5 mm, 19%; 5 to 9 mm, 33%; 10 to 24 mm, 26%; and 25 mm, 22% (21). Multiple ICA were found in 24% to 31% of patients with ADPKD with ICA rupture, compared with 16% in the general population (21,22); four-vessel angiography is therefore warranted. CT angiography is increasingly used in the evaluation of SAH. It is easily performed immediately after noncontrast CT. In rare instances, it reveals the ruptured ICA even when noncontrast CT is inconclusive (22). Its sensitivity for localizing ruptured ICA reached 90% in a series of 100 patients with non-adpkd with SAH (30). In patients with ADPKD with renal insufficiency, its indication must be weighed against the risk of further impairing renal function, especially when it is followed by conventional angiography. Future studies should indicate whether CT angiography is able to replace conventional angiography in the preoperative evaluation of ruptured ICA. This would be welcome in the ADPKD population, in whom an increased risk of complications from conventional cerebral angiography has been reported (1). Treatment The patient with ADPKD with SAH should be managed in a neurosurgical unit. For patients with chronic renal failure or who are on renal replacement therapy, the neurosurgeon and the nephrologist should closely cooperate to prescribe medical therapy and take decisions about ICA treatment. Treatment currently recommended for patients with non-adpkd with SAH roughly applies to the patient with ADPKD (19,31). Its key points may be summarized as follows. Headaches can be treated with paracetamol, dextropropoxyphene, or codeine, but aspirin should be avoided (31). Besides nursing, treatment is aimed at preventing both cerebral ischemia and rebleeding. In up to 25% of patients, ICA rupture is complicated by cerebral ischemia, mainly between days 5 and 14 after bleeding (31). Its mechanism, not yet completely elucidated, involves vasospasm of large arteries adjacent to the bleeding area. Clinical features include deterioration of consciousness, development of focal neurologic deficits, and even cerebral infarction if blood flow is severely impaired. The calcium antagonist nimodipine (60 mg every 4 h), known to reduce the frequency of cerebral infarction, is given prophylactically by most neurosurgeons. The patient should be kept normotensive and normovolemic, because arterial narrowing is exacerbated by both hypotension and dehydration. In this regard, particular attention should be paid to the patient with ADPKD who is on maintenance dialysis. Without intervention, the cumulative risk of rebleeding is 5% within 24 h, 20% within 2 wk, and 50% within 6 mo after the initial hemorrhage, case fatality after rebleeding reaching 50%. The current trend is therefore to intervene as soon as possible. Early occlusion of ICA also permits further volume expansion, which is sometimes required to treat cerebral ischemia. The classical intervention is surgical clipping of the ICA neck. Endovascular treatment has been recently developed as an alternative to surgery. The currently favored technique is the placement of a detachable platinum coil into the ICA dome, inducing thrombosis by electrothermocoagulation. In a review on this technique applied in 509 ruptured ICA, Brilstra at al. (32) found procedure-related mortality and morbidity rates as low as 1.1% and 2.4%, respectively. Complete occlusion of the ICA was, however, obtained in only 52% of the cases. The first prospective randomized trial comparing this technique with surgical clipping in 109 patients with ICA rupture judged suitable for both treatments disclosed a technique-related mortality rate of 2% in the endovascular group versus 4% in the surgical group. The obliteration rate of the ICA and clinical outcome at 3 mo were not significantly different between treatment groups (33). The long-term results of endovascular treatment are awaited, especially for ICA that were not totally occluded: minor ICA neck remnants are indeed known to dilate and form a new ICA with a risk of rebleeding. In the meantime, an increasing number of patients are given endovascular treatment as the initial attempt at ICA obliteration. Another potential advantage of this technique is that patients with multiple ICA may be treated in a single session, even during the acute phase of SAH (34), although this attitude is disputed. Outcome As in the general population, ICA rupture in patients with ADPKD entails a combined mortality-morbidity rate of 35% to 55% (14,19). As expected, mortality is correlated with both age and severity of hemorrhage, assessed by various grading systems (22). In the long term, survivors are threatened by recurrent rupture arising from the remnant neck of a previously treated ICA

4 272 Journal of the American Society of Nephrology J Am Soc Nephrol 13: , 2002 or from another ICA, either left untreated or developed de novo after the first ICA rupture (35). During an 8-yr follow-up of 52 patients with ADPKD who had had a successful ICA clipping, rupture of another ICA occurred with a 1.4% annual incidence. Among the 48 patients in whom a four-vessel angiography was available at the time of first rupture, the annual incidence of rupture of another ICA averaged 4% in patients with multiple ICA and 1.2% in those without detectable intact ICA at clipping (4). A similar incidence of rupture of a second ICA was found among patients with non-adpkd with multiple ICA at the time of the first ICA clipping (36). Several steps may prevent a second rupture. First, any intact ICA detected at the time of first rupture should be treated together with (or shortly after the treatment of) the ruptured ICA, whenever feasible. Second, the result of treatment should be assessed with an angiography 3 to 6 mo later. Third, patients should be screened for a further ICA by either MR angiography (if the clip is not ferromagnetic!) or spiral CT, so as to allow prophylactic treatment. The optimal interval for screening is not defined. On the basis of our study, we suggest a2to3yr interval. Symptomatic Unruptured Aneurysm In the general population, ICA may cause symptoms other than SAH. Focal signs such as cranial nerve palsy (particularly oculomotor) or seizures may herald compression by a large ICA. Transient ischemic attacks may result either from an embolus from an ICA or from direct compression of adjacent vessels. Such manifestations are rarely observed in ADPKD. Should they be recognized, prompt diagnostic evaluation is required and surgical/endovascular treatment considered, with relative urgency for acutely symptomatic ICA, just as recommended in the general population (37). In a recent cost-utility analysis, Johnston et al. (38) compared no treatment, surgical clipping, and endovascular embolization as three options for symptomatic unruptured ICA in a hypothetical cohort of non-adpkd 50-yr-old women (see below). Both clipping and embolization resulted in a net gain of quality-adjusted life years for symptomatic ICA of any size (Table 2). Asymptomatic Aneurysm The decision to screen patients with ADPKD for asymptomatic ICA depends on a comparison between the morbidity and mortality of untreated ICA and the risks of the screening procedure followed, if indicated, by a therapeutic intervention. Decision analysis requires therefore several sets of data: the prevalence of ICA in various ADPKD patient categories, the natural history of ICA, the yield and risks of the screening procedure and, finally, the yield and risks of therapeutic intervention. We will first review the evidence for each of these items and eventually analyze the conclusions drawn from decision analysis. Prevalence of ICA in ADPKD In two prospective studies of patients with ADPKD screened by cerebral MR angiography, no association was found between the presence of ICA and age, gender, presence of hypertension, and reduced renal function (2,3). The only characteristic clearly associated with the presence of ICA is a family history of ICA or SAH: in three large prospective studies, an ICA was detected in 15.6% of 77 patients with a positive family history versus only 5.9% of 186 patients without such history (1 4). Of note, the degree of kinship was not provided in all families. We may conclude that the prevalence of asymptomatic ICA in patients with ADPKD is 6% in the absence of a familial history of ICA or SAH and 16% in patients with such history. Natural History of ICA Most available information is derived from the general population. The International Study of Unruptured Intracranial Aneurysms (ISUIA) recently published phase 1 retrospective data assessing rupture rates among patients without (group 1) and with (group 2) a history of previous SAH (39). This study identified size, location in the posterior circulation, and previous history of SAH from another ICA as predictors of rupture. Table 2. Effects of endovascular coiling or surgical clipping of unruptured intracranial aneurysms on quality-adjusted life years, as compared with no treatment in a hypothetical cohort of 50-yr-old women without autosomal dominant polycystic kidney disease a 10 mm 10 mm No Past SAH b Past SAH No Past SAH Past SAH Asymptomatic coiling 0.6 ( 0.8, 0.2) 0.5 ( 0.1, 1.4) 1.7 (0.6, 3.2) 1.7 (0.1, 4.5) clipping 1.6 ( 2.1, 1.1) 0.5 ( 1.1, 0.5) 0.8 ( 0.3, 2.5) 0.8 ( 0.8, 4.0) Symptomatic coiling 2.5 (2.2, 2.7) 3.0 (2.6, 3.5) 3.6 (2.8, 4.5) 3.6 (2.7, 5.2) clipping 1.4 (1.0, 1.8) 2.0 (1.5, 2.7) 2.7 (2.0, 2.8) 2.7 (1.7, 4.9) a Data from reference 38. Means (95% confidence limits). b SAH, subarachnoid hemorrhage.

5 J Am Soc Nephrol 13: , 2002 Cerebral Aneurysms in ADPKD 273 In group 1 patients, the likelihood of rupture of ICA 10 mm in diameter was as low as 0.05% per year. In group 2, ICA of similar size were 11 times more likely to rupture (0.5% per year). The likelihood of rupture of ICA 10 mm in diameter was 1% per year in both groups but reached 6% in the first year for giant ICA ( 25 mm in diameter). The relative risk of rupture was higher for ICA in the posterior communicating artery, basilar tip, and vertebrobasilar or posterior cerebral distribution. Although the retrospective character of the ISUIA study has raised controversy about patient selection, it still represents the most comprehensive effort to date to document of the natural history of unruptured ICA (37). Whether the very low risk of rupture of small ICA in the general population found in the ISUIA can be extrapolated to patients with ADPKD remains to be proved. A limited 7-yr follow-up study of small ( 6 mm) unruptured ICA discovered by presymptomatic screening in patients with ADPKD disclosed no significant growth or rupture (40). However, it should be remembered that, in a retrospective survey, the size of ruptured ICA in patients with ADPKD was found to be 10 mm in 52% of patients (21). We may conclude that the likelihood of rupture rises with a history of previous SAH and the size and location of the ICA. Screening Procedure When current MR and helical CT angiography techniques are used, a skilled neuroradiologist can detect virtually all ICA measuring 5 mm in diameter and even some ICA as small as 2 mm in diameter (Figure 2). MR angiography is the most convenient test and carries essentially no risk, because it does not require intravascular administration of contrast material. In a study published in 1994, the sensitivity of MR angiography to detect ICA was 100%, 88%, 68%, 60%, and 56% for ICA measuring 5, 4, 3, and 2 mm in diameter, without false-positive results (41). Because of the improvements in MR technology since that time, it is likely that the vast majority of ICA measuring 3 mmin diameter are currently detected. Intra-arterial angiography, which is still necessary before any intervention, carries a 5% risk of complications, including a 0.5% risk of permanent neurologic deficit in the general population (37). This risk could be higher in patients with ADPKD (1). We may Figure 2. Magnetic-resonance angiography in a woman with autosomal dominant polycystic kidney disease (ADPKD) and a history of intracranial aneurysm rupture in two of nine ADPKD-affected relatives. Two aneurysms were detected: one at the bifurcation of the right middle cerebral artery (arrow) and the other at the tip of the basilar artery (double arrow). At subsequent conventional angiography, their sizes were 6 and 5 mm, respectively. Taking family history into consideration, prophylactic treatment was performed: the aneurysm of the middle cerebral artery was treated by surgical clipping and the other by endovascular embolization, both successfully.

6 274 Journal of the American Society of Nephrology J Am Soc Nephrol 13: , 2002 conclude that MR angiography is currently the first-choice screening test for ICA. Treatment Outcome Only studies conducted in the general population are available. Although most of them deal with surgical clipping, an increasing number are now reported with endovascular treatment. Surgical Clipping. In a meta-analysis of 61 studies encompassing 2460 patients, Raaymakers et al. (42) found that clipping of an unruptured ICA was associated with a mortality of 2.6% and a morbidity of 10.9%, which led half of the patients to dependency in daily life. This morbidity rate is probably underestimated in the absence of systematic assessment of neuropsychological function. Duration of follow-up was not specified in most studies. The ISUIA study was the first to systematically assess cognitive status before and after surgery and provided 1-yr follow-up. In 798 patients without previous history of SAH, mortality and disability rates were 2.3% and 15.3% at 1 mo and 3.8% and 12% at 1 yr, respectively, after surgery (39). Endovascular Treatment. Coil embolization has become increasingly popular to treat unruptured ICA. A meta-analysis of 90 cases reported no death related to the procedure and a 6.7% rate of permanent complications. Of note, total obliteration of the ICA was obtained in only 45% of the cases (32). Comparisons between Clipping and Coiling. In a retrospective study conducted at 60 university hospitals, Johnston et al. (43) compared complications of surgical clipping and coil embolization performed as the primary treatment modality in 2357 and 255 cases, respectively. Surgery was associated with an increased (although not statistically significant) mortality rate (2.3% versus 0.4%) and a significantly higher rate of additional adverse outcomes defined as transfer to a nursing home or to a rehabilitation hospital at discharge (16.2% versus 10.2%). A more recent comparison of two groups of patients considered candidates for either procedure revealed mortality rates of 1% and 2% and a significant worsening in neurologic function in 25% and 8% of the patients treated by surgical clipping or endovascular coiling, respectively (44). The lower early morbidity rate of embolization should, however, be weighed against the uncertainty of its long-term efficacy: of concern is the high rate ( 40%) of incomplete obliteration of the ICA associated with this procedure (31,45). With both treatment modalities, outcome is strongly influenced by patient characteristics such as age and comorbid conditions (e.g., chronic renal failure), ICA characteristics (large size and posterior location are associated with poorer outcome), and medical team experience (37,39,42). We may conclude that treatment of an unruptured ICA is associated with a mortality rate of 1% to 2% and a complication rate of 8% to 25%. Endovascular treatment seems to be associated with fewer complications than clipping, but the long-term efficacy of this method is, as yet, unproved. Screening Policy: Decision Analysis The risks of screening asymptomatic ICA followed by treatment should be weighed against the risks of SAH (natural history). Several investigators have addressed this issue with a Markov decision model that compares the expected outcomes of screening versus no screening. The strategy of choice is the one that provides a gain in life expectancy, or, even better, the best quality-adjusted survival, i.e., the gain in years of good functional health. Sporadic ICA. A recent cost-utility analysis that used rupture rates found in the ISUIA study (39) compared three treatment options in a hypothetical cohort of 50-yr-old women: no treatment, surgical clipping, and endovascular coil embolization (38). The mortality and permanent complication rates of surgical clipping were derived from the most recent metanalyses and the results of endovascular coiling from a large study in the University Health Systems Consortium (43). Endovascular coil embolization of an ICA was assumed to provide a 90% protection against SAH. Eight clinical scenarios were defined on the basis of ICA size, symptoms, and a previous history SAH from a different ICA (Table 2). Both procedures resulted in a net loss of quality-adjusted life years for asymptomatic ICA 10 mm in diameter in patients with no history of SAH due to a different ICA. On the other hand, both treatments added quality-adjusted life years and were cost-effective for ICA 10 mm in diameter. The MARS investigators have screened 626 asymptomatic first-degree relatives of 160 patients with sporadic SAH. An ICA was found in 25 subjects (4%), 18 of whom underwent clipping. In the latter, ICA diameter ranged from 5 to 11 mm in 5 patients or was 5 mm in 11 others; the last two patients had both small- and medium-size ICA. Surgery resulted in a decrease of neurologic function in 11. Even under the assumption of an annual risk of rupture markedly higher than that in the ISUIA study (0.46%, 0.95%, and 6.8% for ICA 5,5to 12, and 12 mm, respectively), it was found that surgery increased estimated life expectancy by only 2.5 yr for these 18 subjects (or by 0.9 mo per person screened), and that at the expense of 19 yr of decreased function per person. The authors concluded that implementation of a screening program for the first-degree relatives of patients with sporadic SAH was not warranted (46). ADPKD-Associated ICA. Decision models have been applied to an ADPKD population. In 1983, Levey et al. (47) assessed the issue of screening patients with ADPKD with cerebral angiography. On the basis of their assumptions (a prevalence rate of ICA 30%, a surgical complication rate of 1%, and an annual risk of rupture of 2%), the benefit of cerebral arteriography and surgery exceeded 1 yr of life only for patients 25 yr of age. In 1996, Butler et al. (48) reexamined this issue after the introduction of MR imaging as a screening method. They concluded that a MR screening strategy followed by surgery of the detected ICA increased life expectancy without neurologic disability by 1 yr in a 20-yr-old patient with ADPKD. In that decision analysis, however, the authors used an age-independent prevalence of ICA in ADPKD of 15%, an annual rate of rupture of 1.6%, and mortality and

7 J Am Soc Nephrol 13: , 2002 Cerebral Aneurysms in ADPKD 275 morbidity rates from surgical clipping of 1% and 4.1%, none of which are supported by recent data, with a resulting bias toward the screening strategy. Most of the ICA detected in patients with ADPKD are 5 mm in diameter (2). If the risk of rupture of these ICA is similar to that from the ISUIA for ICA of the same size in the general population, it is extremely unlikely that the screening of all asymptomatic patients with ADPKD followed by prophylactic intervention would be cost effective. Because patients with ADPKD with a family history of ICA have a higher prevalence of ICA and may be at increased risk for rupture, we currently recommend periodic screening (every 3 to 5 yr) only for patients with this history and a reasonable estimated life expectancy, recognizing that the natural history of incidental ICA in this subgroup of patients has yet to be defined with accuracy (4). Periodic screening is clearly advisable in patients with a previously ruptured ICA, because they have a high rate of recurrence of ICA and subsequent bleeding (see above). In practice, the decision of screening should also take into consideration patients knowledge and feeling about the respective risks of ICA rupture and prophylactic treatment. Some patients with a distressful family history of ICA rupture will require screening for either reassurance or treatment. Others will choose not to be screened because they prefer to avoid the immediate risk of treatment, even at the cost of a later risk of bleeding. Our current approach in the ADPKD population may be summarized as follows. Patients without family history of ICA are not screened, except the rare individuals who firmly request it. In patients with a positive family history (documented ruptured ICA or stroke before age 50 yr), we explain the risks of harboring an unruptured ICA, as well as the benefits and risks of screening: in case of negative screening, reassurance but also the risk of missing a tiny ICA and therefore the need for further periodic screening; and in case of positive screening, periodic surveillance of a small ICA or arteriography followed by appropriate treatment of ICA 10 mm in diameter. ICA in the posterior circulation, particularly those with a ratio of maximal ICA diameter to neck diameter 2, are best treated by endovascular coiling. Reassurance, reevaluation at yearly intervals, smoking cessation, and strict control of hypertension and hyperlipidemia are recommended for ICA 5 mm in diameter. Some physicians argue and current data support that asymptomatic unruptured ICA 5 to 9 mm in diameter should also be managed medically. However, considering that 50% of ruptured ICA in ADPKD are 10 mm in diameter (see above), the treatment of ICA 5 mm in diameter is increasingly considered (Figure 2), especially in young individuals who have an ICA treatable by coil embolization (22). There is significant disagreement among neurovascular surgeons, neurologists, and neuroradiologists in this matter. A prospective randomized study will probably be necessary to settle this controversy (49). Acknowledgments We thank Michel Jadoul and Charles van Ypersele for helpful advice and Karin Voss and Lucie Ronck for secretarial assistance. References 1. Chapman AB, Rubinstein D, Hughes R, Stears JC, Earnest MP, Johnson AM, Gabow PA, Kaehny WD: Intracranial aneurysms in autosomal dominant polycystic disease. N Engl J Med 327: , Huston J III, Torres VE, Sulivan PP, Offord KP, Wiebers DO: Value of magnetic resonance angiography for the detection of intracranial aneurysms in autosomal dominant polycystic kidney disease. 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Ann Neurol 48: 5 6, 2000 This article can be accessed in its entirety on the Internet at along with related UpToDate topics