Long-Term Follow-Up of Cerebral Aneurysms after Endovascular Therapy–Prediction and Outcome of Retreatment

Definition of Angiographic Results

After GDC embolization, multiple angiographic projections were obtained to assess the result according to the classification as proposed by Roy et al.²⁴ Embolization was considered to be complete (c/o) if there was no contrast filling of the dome, body, or neck of the aneurysm. A neck remnant (n/r) was defined as residual filling of the neck or part of the neck of an aneurysm; a residual aneurysm (r/a) was indicated by contrast agent in the body or dome, or both, of an aneurysm. A recurrence was defined as any increase in aneurysmal filling at follow-up. A decreased filling in terms of a progressive thrombosis was categorized as a stable result. Aneurysmal size was calculated on the basis of a calibration method with an affixed coin of known dimensions.

Follow-Up Strategy and Selection Criteria for Retreatment

Follow-up cerebral angiograms were scheduled at 6 and 12 months after embolization. In stable cases, we requested MRA every 12 months to evaluate aneurysmal reopening. If follow-up angiograms demonstrated evidence of minor aneurysmal recanalization in terms of minimal coil compaction at the aneurysmal neck (Fig 1), another 6-month follow-up was recommended.

Additional treatment (endovascular coil embolization or direct surgical clipping) was suggested if the recurrence was categorized as morphologically significant (Fig 1). Recurrences were categorized to be significant if 1 or more of the following morphologic modifications were given: coil loosening with increasing patency between loops, resulting in progressive contrast filling within the aneurysmal sac; coil compaction with unchanged aneurysmal boundaries, but exposition of an aneurysmal part not covered by coils; and aneurysmal regrowth in increasing boundaries compared with initial aneurysmal size. The major criterion for the decision for retreatment was the exposure of the aneurysmal sac uncovered by coils that resulted in a recurrence of more than 2 mm to provide an appropriate cavity for an additional placement of coils (Fig 1). On the basis of multiple projection images (DSA), the most senior-level neuroradiologist available in the angiography laboratory (U.G., H.Z., J.F.) made the decision whether an aneurysm had to be treated again.

Demographic and Clinical Data

The male-to-female ratio was 1:2.8 (group A), 1:3.3 (group B), and 1:1.5 (group C). The median age of the patients was 50 years (range, 12–80 years) in group A, 51 years (range, 22–76 years) in group B, and 51 years (range, 18–77 years) in group C. Patients with subarachnoid hemorrhage (SAH) were categorized according to the scale of Hunt and Hess (HH). Table 1 displays the clinical presentation before initial treatment. To classify patient outcome, we used the Glasgow Outcome Scale (GOS) with the following categories: 1) dead, 2) vegetative state, 3) severe disability, 4) moderate disability but able to live independently, and 5) good recovery, able to return to work.

Data Analysis

We performed statistical analysis with SPSS version 13 (SPSS, Chicago, Ill). We calculated risk for anatomic localizations, aneurysmal anatomy, clinical presentation (HH), and initial treatment result. We performed univariate binary logistic regression analysis to identify predictors of aneurysmal retreatment. Parameters with a P value of <0.1 in the univariate analysis were entered into a multivariate logistic regression analysis. The odds ratio (OR) with 95% confidence intervals (95% CI) was calculated for these groups. The positive predictive value (PPV) and negative predictive value (NPV) were calculated if the risk was significantly increased. Significance level was predefined as P < .05.

Regression Analysis

In the univariate regression analysis, the category of “unfavorable anatomy” (aneurysmal size >10 mm and/or neck width >4 mm), and the initial treatment result were found to be significantly associated with retreatment (Table 2). Aneurysmal size and aneurysmal neck width were associated with each other (Pearson χ² 123.35, P < .001). For the multivariate logistic regression analysis, all aneurysms with a neck width >4 mm and/or aneurysmal size >10 mm were combined in “unfavorable anatomy,” and the remaining aneurysms were defined as “favorable anatomy.” “Unfavorable anatomy” was significantly associated with retreatment (Table 2).

Furthermore, the multivariate logistic regression analysis confirmed the initial treatment result (complete occlusion vs neck remnant and residual aneurysm) to be a significant predictor. After categorization into subgroups, only “residual aneurysm” was a significant predictor, whereas “neck remnant” was not (Table 2).

Reasons for Retreatment

Asymptomatic aneurysmal recanalization owing to coil compaction without rupture accounted for most of the first retreatment sessions (22/33, 66.7%). Other reasons for first retreatment included SAH (4/33, 12.1%), asymptomatic aneurysmal regrowth (5/33, 15.2%), and migration of coils in thrombus material within the aneurysmal sac (1/33, 3.0%).

In 1 patient who was treated initially with the stent remodeling technique, no contrast filling of the aneurysm was observed after deployment of the stent; therefore, coiling was set aside. Because the first control angiogram of this patient showed aneurysmal filling with contrast media, occlusion with a single coil was again achieved (1/33, 3.0%).

A total of 4 patients underwent retreatment twice (1 after surgical clipping as first retreatment technique), and 3 had a retreatment session 3 times (all endovascular). Within this group of patients, the reason for second and third retreatment included aneurysmal regrowth with coil loosening (n = 6), coil compacting (n = 2), adjacent enlarging aneurysm (n = 1), and recurrence of hemorrhage as a result of aneurysmal regrowth (n = 1).

Outcome after Retreatment and Rebleeding

Good outcome (GOS 5) after first retreatment (including surgical clipping in 3/33, 9.1%) was achieved in 87.8% (29/33) of patients. In 6.1% (2 /33) of patients, outcome was unchanged compared with the preoperative status. In 6.1% (2/33), outcome was rated GOS 1 after rebleeding. Early rebleeding occurred in 0.6% (2/323) of patients (initial clinical presentation in both patients was HH V) within 24 hours after incomplete coil embolization. Both patients underwent repeat treatment immediately after rebleeding. One patient died, and one patient showed a good recovery score (GOS 5).

Late rebleeding occurred in another 0.9% (3/323) of patients. One patient (initial clinical presentation HH II) missed the 6-month control angiogram and presented 11 months after initial complete aneurysmal occlusion with an HH grade V hemorrhage. Retreatment was performed, but the patient died of multiple cerebral infarcts resulting from cerebral vasospasm. The second patient (initial clinical presentation HH IV) presented 56 months after a first retreatment (GOS 5) with an HH grade III hemorrhage. In this patient, a control angiogram was also missed since the first retreatment. After the second retreatment, a third session 4 years later was necessary. Outcome for this patient was GOS 4. The third patient presented with rebleeding (HH 1) on the evening after the regular control angiogram. This patient was treated surgically; a second treatment session (endovascular) 5 months later was necessary, with a final GOS of 5. All other patients with multiple retreatment sessions showed no clinical changes compared with their particular preoperative status.

Dependent on initial HH grade, the rate of retreatment ranged from 1 of 18 (5.6%) patients with an HH of IV to 5 of 26 (19.2%) patients with an HH of V. Clinical presentation was not identified as a predictor for retreatment by univariate analysis (P > .1) and therefore was not entered into the multivariate analysis (Table 2).

Location and Morphologic Features of Aneurysms

The rate of patients who underwent repeat treatment was significantly associated with the size of the aneurysm. The mean size in group A was 7.9 mm (range, 2–29 mm); in group B, 8.6 mm (range, 2–23 mm); and in group C, 13.2 (range, 3–44 mm).

Retreatment in small aneurysms with small necks was performed in 6 of 214 (2.8%) of patients. In all other aneurysmal configurations (small aneurysms with wide neck and large aneurysms), the rate of retreatment ranged from 19.7% to 28.6%. When summarizing all these types of aneurysms as a “risk group” (128/342, 37.4%), the OR for retreatment was considerably increased to 3.11 (95% CI: 1.43–6.75; P = .004). The PPV was 0.21 (95% CI: 0.14–0.29). The NPV was 0.97 (95% CI: 0.94–0.99). The sensitivity was 0.81 (95% CI: 0.65–0.93). The specificity was 0.67 (95% CI: 0.62–0.73).

Retreatment was performed in 6 of 75 (8.0%) aneurysms of the internal carotid artery (ICA), in 7 of 83 (8.4%) aneurysms of the anterior (communicating) cerebral artery (ACA/AcomA), in 3 of 27 (11.1%) aneurysms of the middle cerebral artery (MCA), in 3 of 42 (7.1%) aneurysms of the posterior (communicating) cerebral artery (PCA/PcomA), and in 14 of 94 (14.9%) aneurysms of the basilar artery (BA). No retreatment was performed in the 23 aneurysms of the vertebral artery (VA).

Morphologic Features at Initial Session of Embolization

In line with others, we found basilar tip aneurysms to have the highest relative propensity for a recurrence (Table 1). The rate of retreatment dependent on location ranged from 0 of 23 in the VA aneurysms to 14 of 94 (14.9%) in the basilar tip aneurysms. Aneurysm location was not identified as a predictor for retreatment by univariate analysis (P > .1) and therefore was not entered into the multivariate analysis (Table 2).

Angiographic Results before and after Retreatment

In accordance with the classification of Roy et al,²⁴ the immediate angiographic results in group A were considered to be complete obliteration (c/o) in 73.0% (n = 197), neck remnants (n/r) in 18.1% (n = 49), and residual aneurysm (r/a) in 8.9% (n = 24) of cases. In group B, the angiographic results were c/o in 64.1% (n = 25), n/r in 25.6% (n = 10), and r/a in 10.3% (n = 4) of cases. In group C, angiographic results were c/o in 48.5% (n = 16), n/r in 24.2% (n = 8), and r/a in 27.3% (n = 9) of cases (Table 1).

Surgical clipping as a first retreatment was performed in 9.0% (n = 3) of patients. Angiographic results after first endovascular repeat treatment were c/o in 45.5% (n = 15) and n/r in 45.5% (n = 15). Seven patients underwent a second retreatment session (preceding results were c/o in 4 patients, n/r in 2 patients; and aneurysm regrowth after surgical clipping in 1 patient); c/o was achieved in 3, n/r in 2, and r/a in 2 patients. Three patients underwent a third retreatment session (preceding results: c/o in 1 patient, n/r in 1, and r/a in 1 patient) in which complete occlusion of the aneurysms was achieved.

The rate of retreatment dependent on the initial treatment result was 16 of 238 (6.7%) in aneurysms with initial complete occlusion, 8 of 67 (11.9%) in aneurysms with neck remnants, and 9 of 37 (24.3%) in aneurysms with a residual aneurysm as a result of the initial treatment.

When residual aneurysms was defined as a “risk group,” the OR for retreatment was significantly increased to 3.96 (95% CI: 1.48–10.65; P = .006). The PPV was 0.24 (95% CI: 0.12–0.41). The NPV was 0.92 (95% CI: 0.88–0.95). The sensitivity was 0.27 (95% CI: 0.13–0.45). The specificity was 0.91 (95% CI: 0.87–0.94).

How Often Is An Aneurysmal Recurrence Observed and How Often Is It Treated?

The observed rate of recanalization (21.1%) and rate of retreatment (9.6%) in our study population compares well with those published in the literature, in which recanalization rates ranged from 10% to 33.6%, and retreatment rates were from 4.7% to 12.3% (Table 3). Murayama et al⁶ reported recanalization rates of 26.1% in aneurysms treated during their first 5 years experience with endovascular treatment. The rate decreased to 17.2% in those aneurysms treated in their later 6 years of experience. These findings are in concordance with our experiences. Although 61.7% (387/627) of aneurysms at our institution were treated after December 1999, the major portion of the aneurysms that needed retreatment (66.6%, 22/33) was treated before this date. Similar experiences were reported by Raymond et al.¹⁴

Which Aneurysms Underwent Repeat Treatment?

The best single predictor for patients who needed retreatment was aneurysmal anatomy (Table 2). Our results imply that it can be expected that a small aneurysm with a narrow neck will need no retreatment in about 97% of cases. From a practical standpoint, these aneurysms are definitely treated with conventional coil techniques. In turn, to show the benefit of bioactive coils for the clinically relevant end point “rate of retreatment” in these patients (who represent almost two thirds of our group), a very large study would be needed.

The risk of retreatment in the remaining patients with a neck width of >4 mm or an aneurysm size of >10 mm is probably increased about threefold. In contrast, Raymond et al¹⁴ found recurrences not significantly increased when the neck size was >4 mm. One possible explanation is that recurrences in small aneurysms actually do occur rarely but are treated in an even smaller portion (Table 1). This observation might be explained, in part, by the fact that small aneurysms have usually small recurrences, which do not exceed our predefined threshold of ≥2 mm for a reintervention. However, this finding is still meaningful from a clinical standpoint because these small recurrences are probably less likely to bleed but, as previously suggested,²⁵ are more dangerous to treat. However, the risk of bleeding in these small recurrences cannot be ruled out completely.²⁶

Location of the aneurysm was no significant predictor of recurrent treatment. In line with previous observations, we found variations in the rate of recurrent treatments,^{14, 16} which did not reach significance levels.

It is not surprising that the initial treatment result was a significant predictor for the rate of retreatment. If the initial aneurysmal treatment was achieved only with a residual aneurysm, a further growth of the remnant with need for retreatment was about 4 times as often in completely occluded aneurysms or in aneurysms with neck remnants. This finding is in line with previous observations in which a residual aneurysm was a significant predictor for recurrence (OR 3.60, 95% CI: 1.60–8.09).¹⁴ However, aneurysms with neck remnants had no significantly increased risk. These data suggest that complete treatment does not necessarily need to be enforced.

We found no association between the initial clinical presentations (HH grade) and the rate of retreatment. It is noteworthy also that the patients with incidentally treated aneurysms (HH 0, Table 1), in whom interventions can be planned and prepared in advance, did not necessarily have lower rates of recurrence and retreatment. In contrast, Raymond et al¹⁴ found significantly lower rates of recurrence in incidental aneurysms. Differences in patient selection might explain these results.

Is Retreatment Beneficial and Stable?

The major problem with the prediction of recurrent treatment was the fact that we do not know whether the retreatment was indicated in the treated patients because objective or generally accepted criteria do not exist for a retreatment of reopened cerebral aneurysms after endovascular GDC treatment. The ideal end point would be aneurysm (re-)rupture because the intention of angiographic follow-up and additional treatment must imply the reduction of the risk of hemorrhage or recurrent hemorrhage. However, the prediction of retreatment is at least a step closer to that end point.

The natural history of aneurysmal neck remnants after endovascular coil embolization is often benign,²⁷ but bleeding from incompletely coiled aneurysms is a well-documented threat.²⁸ Byrne et al²⁸ reported that rebleeding occurred in 3 of 38 (7.9%) recurrent aneurysms and in 1 of 221 (0.4%) aneurysms that appeared stable on angiograms. Slob et al²⁹ observed no rebleeding in patients with complete or near-complete occlusion after additional coiling, but 2 episodes of rebleeding occurred during the added time of observation of 66 person-years (3.0%) in patients with incompletely occluded aneurysms. Therefore, aneurysms that are incompletely treated, which are more unstable, may be considered for retreatment in particular, as was done in our series.

The overall rate of rebleeding in our patient group was 0.6% p.a., which compares well with the data from the literature (Table 3). In consideration of these low rates of rebleeding, an aggressive retreatment strategy does not necessarily seem to be indicated. Even if rebleeding from completely occluded aneurysms on angiograms has been reported,⁵ a further impetus for control angiograms is the detection of treatable aneurysmal recurrences, which are thought to be a risk factor for SAH, perhaps more often with noninvasive techniques such as MRA.^{30, 31}

A single retreatment of an aneurysm recurrence was performed in 7.6%, and multiple retreatments in 2.0% of our study population. These data suggest that single retreatment is stable in most of the patients. In line with our data, Henkes et al¹⁶ reported a first retreatment in 12.7% and 2 or more retreatment sessions in 5.3% in their patients, which suggests that most patients undergo repeat treatment only once.

Is Retreatment Safe?

Complication rates during retreatment are reported to be lower if compared with initial treatment (Table 3). Despite a single aneurysmal rupture during treatment, we observed no resulting morbidity and mortality from the retreatment procedures. The delay between presenting SAH and retreatment is usually long enough to lower the risk of an intraprocedural rupture, which is higher in recently ruptured aneurysms.^32–34 From our experience, the complication rate for patients who undergo repeat treatment can be expected to be at least comparable or lower than the complication rate in the patients with incidental aneurysms. However, Park et al³⁵ found morbidity for retreatment of aneurysms as high as 10%.

Limitations of the Study

Our reported rebleeding rate was well within the range reported in the literature (Table 3). Because of the considerable number of patients lost to follow-up (135/596, 22.7%), the significance of our results in regard to the incidence of rebleeding has to be referred to as limited. Also, the total number of patients included in this study (323) was a small sample. Therefore, we do not claim our results to be considered definite.