Recurrence pattern predicts aneurysm rupture after coil embolization.

INTRODUCTION: Hemorrhage from a recurrent aneurysm is a major concern after coiling for intracranial aneurysms. We aimed to identify aneurysm recurrence patterns associated with hemorrhage.
MATERIAL AND METHODS: We investigated radiological data of patients who underwent coiling for intracranial aneurysms in 2008-2016 and were followed-up for at least 6 months. Aneurysm recurrence patterns were classified as: type Ⅰ, enlargement of aneurysm neck; type Ⅱ, recurrent cavity within the coil mass; type Ⅲ, recurrent cavity along the aneurysm wall; and type Ⅳ, formation of a daughter sac. We evaluated the incidence of various recurrence patterns with or without hemorrhage.
RESULTS: Of the 173 aneurysms included in the study (mean follow-up period, 32 months; range, 6-99 months), 22 (13%) recurred and required re-treatment. The recurrence patterns included type Ⅰ, Ⅱ, Ⅲ, and Ⅳ in 7 (4%), 4 (2%), 9 (5%), and 2 (1%) cases, respectively. Most of the type Ⅰ, Ⅱ, and Ⅲ recurrences occurred within 1 year, and type Ⅳ occurred at 7 years after coiling. Three aneurysms exhibited hemorrhage, one with type Ⅲ and two with type Ⅳ pattern. The two aneurysms with type Ⅳ recurrence initially occurred as type Ⅰ; however, the recurrent neck enlarged gradually, resulting in new sac formation.
CONCLUSIONS: We recommend prompt re-treatment for aneurysms recurring with type Ⅲ or Ⅳ patterns, as such patterns were associated with hemorrhage. Furthermore, we need a special care to type Ⅰ recurrence with enlargement of recurrent neck because this specific pattern may develop to type Ⅳ.

Introduction

Endovascular embolization with detachable coils is widely performed and currently considered a safe, minimally invasive, and reliable technique to obliterate intracranial aneurysms [1-3]. However, aneurysm recurrence is more frequent after coil embolization than after surgical clipping [4, 5]. Several risk factors for recanalization after coil embolization have been proposed, including a ruptured aneurysm, large size, wide neck, posterior circulation location, and low volume embolization ratio (VER) [6-10]. Some studies using computational fluid dynamics analysis reported that hemodynamic forces may be related to the recanalization of coiled aneurysms [11, 12].

Hemorrhage from a recurrent aneurysm is associated with high mortality and morbidity [13-15]. To reduce the risks of hemorrhage after recurrence, angiographic follow-up and prompt re-treatment are necessary. The choice of re-treatment strategy depends on the aneurysm recurrence pattern. However, it remains unknown which recurrence pattern carries a higher risk of hemorrhage and would likely need re-treatment. The goal of the present study was to classify recurrent aneurysms by recurrence patterns and to assess the relationship of recurrence pattern with the need for re-treatment and the incidence of hemorrhage.

Materials and methods

This study was reviewed and approved by the Independent Ethics Committee of Kanazawa University School of Medicine (No. 1781). Informed consent was obtained in writing from all patients or their next of kin.

Patients and aneurysm data

We retrospectively investigated the clinical and radiological data on 231 aneurysms in 209 consecutive patients who underwent endovascular coiling for intracranial saccular aneurysms over a period of approximately 9 years (between January 2008 and June 2016). Only patients followed-up for more than 6 months after coiling were included. Fifty-eight aneurysms were excluded. The follow-up period of 55 aneurysms was shorter than 6 months, including 43 aneurysms followed up at another hospital and 12 aneurysms in patients who died within 6 months of endovascular coiling. One aneurysm that underwent a second coiling procedure at 3 months after the first procedure and two aneurysms with re-hemorrhage at 3 and 21 days after coiling were also excluded.

The final study population included 154 patients with 173 aneurysms. General patient information and aneurysm characteristics are summarized in Table 1. Posterior communicating artery (PcomA) and paraclinoid internal carotid artery aneurysms were the most frequent (19.7%), followed by anterior communicating artery (AcomA) aneurysms (15.0%).

Table 1

Characteristics of patients and aneurysms treated with endovascular coiling.

Characteristic		Value (%)
Patients		154
Aneurysms		173
Age, years		58±11
Female sex		111 (72)
Ruptured		64 (37)
Location
ICA	Cavernous	1 (0.6)
	OphA	7 (4.0)
	PcomA	34 (19.7)
	Tip	4 (2.3)
	Paraclinoid	34 (19.7)
	Other	14 (8.1)
ACA	Proximal	3 (1.7)
	AcomA	26 (15.0)
	Distal	2 (1.2)
MCA	Proximal	2 (1.2)
	Bifurcation	10 (5.8)
	Distal	3 (1.7)
PCA	P1 segment	1 (0.6)
	Distal	1 (0.6)
BA	Tip	12 (6.9)
	Trunk	4 (2.3)
	SCA	5 (2.9)
VA	PICA	7 (4.0)
	Other	3 (1.7)

ACA, anterior cerebral artery; AcomA, anterior communicating artery; BA, basilar artery; ICA, internal carotid artery; MCA, middle cerebral artery; OphA, ophthalmic artery; PCA, posterior cerebral artery; PcomA, posterior communicating artery; PICA, posterior inferior cerebellar artery; SCA, superior cerebellar artery; VA, vertebral artery

Endovascular procedure

Aneurysm coiling was performed with the patient under general anesthesia. Before coiling, a bolus of 3,000–5,000 IU of heparin was administered intravenously, followed by bolus infusion of 1,000 IU per hour. Anticoagulation aimed to maintain the activated clotting time at twice the normal value during catheterization and coil placement. Coiling was performed with various types of standard platinum coils. Stent or balloon assistance was indicated in case of wide-necked aneurysms. The initial angiographic results of coiling were graded according to the Modified Raymond-Roy Classification (MRRC) [16]: class I, complete obliteration; class Ⅱ, residual neck; class Ⅲa, residual aneurysm with contrast within the coil interstices; class Ⅲb, residual aneurysm with contrast along the aneurysm wall. VER was determined as the ratio of the coil volume to the aneurysm volume.

Imaging follow-up and additional treatment

The patients were regularly followed up with MRI every 6 months for one year after treatment, and every year thereafter. In case of incompletely-treated aneurysms, follow-up MRI was taken more often. Digital subtraction angiography (DSA) was performed when recurrence was suspected on MRI. Major recurrence was defined as aneurysm recurrence needing re-treatment. Additional treatment was considered if: (1) contrast filling was noted in a cavity occupying > 20% of the volume of the original aneurysm in case of adequately-treated aneurysms or (2) contrast filling was further increased in case of incompletely-treated aneurysms or (3) hemorrhage was noted from the recurrent aneurysm. Minor recurrence was defined as aneurysm recurrence not needing re-treatment.

“Aneurysm growth” was defined as an enlargement of the aneurysm diameter on MRI or DSA. When coil mass became loose on skull anteroposterior view and lateral view, we called “coil compaction”.

Definition of recurrent patterns

We proposed the following classification of aneurysm recurrence patterns: type Ⅰ, enlargement of the aneurysmal neck due to coil compaction or neck growth (Fig 1A and 1E); type Ⅱ, recurrent cavity within the coil mass (Fig 1B and 1F); type Ⅲ, recurrent cavity along the aneurysm wall (Fig 1C and 1G); and type Ⅳ, formation of a daughter sac (Fig 1D and 1H). We stratified re-treated aneurysms according to recurrence pattern and subsequently identified the recurrence patterns associated with hemorrhage and the need for re-treatment.

Fig 1

Classification of aneurysm recurrence patterns.

(A and E) Type Ⅰ, enlargement of aneurysm neck. (B and F) Type Ⅱ, recurrent cavity within the coil mass. (C and G) Type Ⅲ, recurrent cavity along the aneurysm wall. (D and H) Type Ⅳ, formation of a daughter sac. Black arrow indicates a daughter sac.

Statistical analysis

Univariate analysis was performed for intergroup comparisons, as appropriate. The data are reported as means ± standard deviation for continuous variables and the number of observations (frequency, %) for categorical variables. The statistical significance was analyzed using the Fisher’s exact test for categorical, nominal variables, or the Mann-Whitney U test for continuous, numerical variables. Multivariate logistic regression analysis included all variables that were found to be significant on univariate analysis at a P-value of < 0.05. Results of logistic regression were reported as odds ratio (OR) with P-value < 0.05 for a 95% confidence interval (CI), which was considered statistically significant. Univariate and multivariate analyses were performed using SPSS (IBM SPSS Statistics 23, Chicago, IL, USA).

Kruskal-Wallis one-way non-parametric ANOVA was performed for each parameter (maximum diameter, neck width, and volume embolization ratio) for each of the five groups (no re-treatment, recurrence type I, type II, type III, and type IV). Post-hoc pairwise group comparisons were performed using Dunnett’s multiple-testing correction. Each re-treatment group (recurrence type I, II, III, and IV) was compared with the control group of no re-treatment group. Statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). A value of α = 0.05 was selected as the significance threshold.

Results

Factors associated with re-treatment after coil embolization

Of the 173 aneurysms included in this study, 22 had major recurrence required re-treatment (12.7%). Factors associated with re-treatment after coil embolization are summarized in Table 2. In the re-treatment group, the proportion of patients with ruptured aneurysms was significantly higher (P<0.001), maximum size and neck width were significantly larger (P = 0.003, 0.002), the proportion of BA and MRRC class IIIb were significantly higher (P = 0.032, 0.025), VER was significantly lower (P<0.001) than in the no re-treatment group. No significant difference was found in terms of using balloon or stent. In multivariate analysis, rupture status (OR 18.20, 95% CI 4.00–82.60, P<0.001) and maximum diameter (OR 1.25, 95% CI 1.00–1.56, P = 0.049) were statistically significant.

Table 2

Factors associated with re-treatment after coil embolization.

		Univariate analysis			Multivariate analysis
		No re-treatment n = 151	Re-treatment n = 22	P	OR	95% CI	P
Age		58.1±10.9	60.4±11.8	0.283
Female (%)		109 (72.2)	13 (59.1)	0.218
Rupture (%)		46 (30.5)	18 (81.8)	<0.001	18.20	4.00–82.60	<0.001
Location
ICA (%)		86 (57.0)	8 (36.3)	0.107
ACA (%)		25 (16.6)	6 (27.3)	0.237
MCA (%)		13 (8.6)	2 (9.1)	1.000
PCA (%)		2 (1.3)	0	1.000
BA (%)		15 (9.9)	6 (27.3)	0.032	1.40	0.26–7.53	0.694
VA (%)		10 (6.6)	0	0.365
Size
maximum, mm		7.8±3.2	10.2±4.2	0.003	1.25	1.00–1.56	0.049
neck width, mm		4.0±1.9	5.6±2.3	0.002	0.95	0.65–1.40	0.802
Coiling procedure
balloon-assisted (%)		36 (23.8)	4 (18.1)	0.787
stent-assisted (%)		15 (9.9)	2 (9.1)	1.000
Result
MRRC Class I (%)		46 (30.5)	3 (13.6)	0.131
MRRC Class II (%)		70 (46.4)	8 (36.4)	0.493
MRRC Class IIIa (%)		29 (19.2)	7 (31.8)	0.172
MRRC Class IIIb (%)		6 (3.9)	4 (18.2)	0.025	5.37	0.60–48.20	0.133
VER, %		24.2±5.3	19.8±5.3	<0.001	0.96	0.86–1.07	0.432

MRRC, Modified Raymond-Roy Classification; VER, volume embolization ratio

Recurrence patterns associated with re-treatment

Of the 173 coiled aneurysms in this study, 151 had no re-treatment, and 22 had major recurrence requiring re-treatment (12.7%), showing the following recurrence patterns; type Ⅰ, 7 aneurysms (4.0%); type Ⅱ, 4 aneurysms (2.3%); type Ⅲ, 9 aneurysms (5.2%); and type Ⅳ, 2 aneurysms (1.2%). The aneurysm characteristics and results of coiling are summarized in Table 3.

Table 3

Characteristics of recurrence patterns.

	No re-treatment n = 151 (87.3%)	Recurrence pattern				P
		Type I n = 7 (4.0%)	Type II n = 4 (2.3%)	Type III n = 9 (5.2%)	Type IV n = 2 (1.2%)
Initially ruptured (%)	46 (31)	6 (86)	3 (75)	7 (78)	2 (100)
Size
maximum diameter, mm	7.8±3.2	9.4±6.5	10.7±1.2	11.1±3.0*	7.3±1.6	0.0045
neck width, mm	4.0±1.9	3.8±2.0	7.6±1.2*	6.5±1.7*	3.4±1.6	0.0002
Coiling procedure
balloon assisted (%)	36 (23.8)	2 (29)	1 (25)	1 (11)	0
stent-assisted (%)	15 (9.9)	0	1 (25)	1 (11)	0
Results
MRRC class I (%)	46 (31)	2 (29)	0	1 (11)	0
MRRC class II (%)	70 (46)	2 (29)	3 (75)	2 (22)	1 (50)
MRRC class IIIa (%)	29 (19)	3 (43)	1 (25)	2 (22)	1 (50)
MRRC class IIIb (%)	6 (4)	0	0	4 (44)	0
VER, %	24.2±5.3	22.6±4.7	18.8±1.4*	17.2±6.2*	23.5±2.1	0.0053
Major recurrence
within 6 months (%)		4 (57)	2 (50)	8 (89)	0
from 6 to 12 months (%)		3 (43)	1 (25)	1 (11)	0
from 12 to 18 months (%)		0	1 (25)	0	0
Aneurysm growth (%)		1 (14)	0	0	1 (50)
Coil compaction (%)		4 (57)	0	1 (11)	0
Aneurysm growth + Coil compaction (%)		2 (29)	4 (100)	8 (89)	1 (50)
Recurrent hemorrhage (%)		0	0	1 (11)	2 (100)

Kruskal-Wallis tests

*Variable significantly compared to no re-treatment group

MRRC, Modified Raymond-Roy Classification; VER, volume embolization ratio

In the Type I, four of 7 patients of Type I had major recurrence 6 months after coiling. Three of 7 patients of Type I had minor recurrence 6 months after coiling, and developed major recurrence 12 month after coiling. The proportion of coil compaction is higher than other recurrence patterns. In the Type II, the neck width was significantly larger (P = 0.007), and VER was significantly lower (P = 0.038) than in the no re-treatment group. Two of 4 patients of Type II had major recurrence 6 months after coiling. Another 2 patients of Type II had major recurrence 12 and 18 months after coiling, respectively. Aneurysm growth and coil compaction were noted in all of Type II recurrence aneurysms. In the Type III, the maximum diameter and neck width were significantly larger (P = 0.005, 0.001) than in the no re-treatment group. The proportion of patients with MRRC class IIIb was higher than any other group. VER was significantly lower (P = 0.028) than in the no re-treatment group. Eight of 9 patients of Type III had major recurrence within 6 months after coiling. Aneurysm growth and coil compaction were noted in 8 patients. No type Ⅳ recurrence occurred within 18 months. The time from coiling to recurrence of the two type Ⅳ aneurysms was 83 and 94 months.

Recurrence patterns associated with hemorrhage

Hemorrhage from recurrent aneurysms occurred in three patients, corresponding to an overall incidence of 1.7% (3/173). Relevant clinical and imaging data of the three patients with re-hemorrhage are summarized in Table 4.

Table 4

Clinical and imaging data of the three patients with hemorrhage from recurrent aneurysm.

Case	Age	Sex	Location	Size, mm	H&K grade	WFNS grade	VER	MRRC class	Time from coiling to hemorrhage	Recurrence pattern	Re-treatment
1	59	F	BA tip	12.0	3	2	10.4	Ⅲb	6 months	Type Ⅲ	Coiling
2	63	F	ICA-PcomA	8.4	1	1	24.9	Ⅱ	83 months	Type Ⅳ	Coiling
3	59	F	BA tip	6.1	2	1	21.5	Ⅲa	94 months	Type Ⅳ	Coiling

BA, basilar artery; F, female; H&K, Hunt-Kosnik; ICA, internal carotid artery; MRRC, Modified Raymond-Roy Classification; PcomA, posterior communicating artery; VER, volume embolization ratio; WFNS, World Federation of Neurological Surgeon

The basilar tip aneurysm in case #1 (Fig 2A) was embolized, resulting in incomplete occlusion with a VER of 10.4% (Fig 2B). No change was observed on MRA 1 month after coiling, but recurrence with type III was observed on MRA 4 months after coiling. Re-hemorrhage occurred 2 months after final MRA (Fig 2C), and the patient underwent re-coiling.

Fig 2

Recurrent hemorrhage after coil embolization of an intracranial aneurysm in a 59-year-old woman (case #1).

(A and B) Basilar tip aneurysm embolized using coils. Initial embolization was angiographically graded as MRRC class Ⅲb, with a VER of 10.4%. (C) Re-hemorrhage occurred at 6 months after coiling, with angiography indicating type Ⅲ recurrence (i.e., recurrent cavity along the aneurysm wall).

In cases #2 and #3, re-hemorrhage occurred extremely late after coiling, with type Ⅳ recurrence in both patients. The PcomA aneurysm in case #2 (Fig 3A) was embolized with coils. Angiography indicated that initial embolization resulted in an occlusion of MRRC class Ⅱ with a VER of 24.9% (Fig 3B). Follow-up annual MRA showed that the remnant neck had gradually increased in size until 6th year (Fig 3C and 3D), eventually giving rise to a new sac at 7th year after coiling. Although re-treatment was scheduled, re-hemorrhage occurred 2 months after the final MRA (Fig 3E). The basilar tip aneurysm in case #3 recurred at 6 years after first coiling (Fig 4A). A second coiling procedure was performed, resulting in occlusion of MRRC class Ⅲa with a VER of 21.5% (Fig 4B). This aneurysm recurred with neck enlargement (Fig 4C and 4D), eventually, a new sac was formed at 7th year after treatment. Although re-treatment was scheduled, re-hemorrhage occurred 2 months after the final MRA (Fig 4E).

Fig 3

Recurrent hemorrhage after coil embolization of an intracranial aneurysm in a 64-year-old woman (case #2).

(A and B) Posterior communicating artery aneurysm embolized using coils. Initial embolization was angiographically graded as MRRC class Ⅱ, with a VER of 24.9%. (C) MRA at 2 years after coiling indicated a remnant neck. (D) MRA at 5 years after coiling indicated enlargement of the recurrent neck. (E) Re-hemorrhage at 7 years after coiling, with angiography indicating the formation of a daughter sac.

Fig 4

Recurrent hemorrhage after coil embolization of an intracranial aneurysm in a 59-year-old woman (case #3).

(A and B) Basilar tip aneurysm recurring at 6 years after first coiling, treated via a second coiling procedure. Embolization via second coiling was evaluated angiographically as MRRC class Ⅲa, with a VER of 21.5%. (C) Digital subtraction angiography at 5 years after second coiling indicating a recurrent neck. (D) MRA at 6 years after second coiling, indicating enlargement of the recurrent neck. (E) Hemorrhage at 7 years after coiling, with angiography indicating the formation of a daughter sac.

Discussion

In the present study, we evaluated risk factors associated with re-treatment after coil embolization. Moreover, we proposed a new classification of recurrence patterns and detected recurrence patterns associated with re-treatment and hemorrhage.

In the International Subarachnoid Aneurysm Trial (ISAT) [3], late re-treatments (later than 3 months after the coiling) were performed in 9.0% (94/1,045) of patients after aneurysm recurrence or rebleeding. The mean interval to retreatment was 20.7 months (range, 3 to 80 months). Younger age, larger lumen size, and incomplete occlusion were risk factors for late re-treatment after coiling. In this study, re-treatments were performed in 12.7% (22/173). Ruptured aneurysms, larger size, wider neck, BA location, MRRC class IIIb, and lower VER correlated with re-treatment. In particular, rupture status and maximum diameter were risk factors for re-treatment after coiling.

The Modified Raymond-Roy Classification [16] used for the angiographic results after coil embolization is useful to predict recurrence or progressive occlusion, but it is difficult to express with or without recurrence. Therefore, in this study, we proposed a novel classification limited to recurrence aneurysm after coil embolization. We divided recurrence aneurysms into 4 types of recurrence patterns, and detected recurrence patterns associated with re-treatment and hemorrhage. Larger size and wider neck ruptured aneurysms with low VER tended to recur with Type II or III. In the Type III recurrence group, the proportion of MRRC class IIIb aneurysms was higher than other recurrence types. Almost of all Type III recurrence occurred within 6 months. Recurrent hemorrhage was associated with Type III and IV recurrence.

Hemorrhage from a recurrent aneurysm is typically classified as early or late hemorrhage, with early hemorrhage defined as re-bleeding within 30 days after coiling associated with worsening of the patient’s condition. In our study, we excluded two patients with early re-hemorrhage. Thrombosis is formed in true aneurysms or pseudoaneurysms after rupture, and subsequent thrombus resolution after coiling can lead to reopening of the aneurysm lumen, resulting in early re-hemorrhage [13]. These recurrence mechanisms underlying early re-hemorrhage are completely different from those associated with late hemorrhage.

Late hemorrhage from a recurrent aneurysm is defined as the occurrence of re-bleeding later than 1 month after coiling [17, 18]. In our study, the incidence of the late re-bleeding was 1.7% (3/173), with type Ⅲ and Ⅳ recurrence patterns. The patient described as case #1 had re-hemorrhage with type Ⅲ recurrence at 6 months after coiling. The cause of re-hemorrhage appeared to be a low VER. Sluzewski et al. [19] described five cases of late re-hemorrhage of ruptured aneurysms treated with coils. Risk factors for late re-hemorrhage include large aneurysm size and incomplete aneurysm occlusion after initial embolization or on follow-up. Angiograms after re-hemorrhage were available in three of the described cases, which had occurred at 12, 30, and 40 months after initial coiling. In all three cases, the recurrence pattern was of type Ⅲ. Two case reports of delayed rupture of a previously coiled unruptured aneurysm indicated that aneurysms in the middle cerebral artery bifurcation and AcomA ruptured at 18 and 23 months, respectively, after initial coiling [20, 21]. Both these aneurysms showed recanalization with a type Ⅲ pattern.

The aneurysms in cases #2 and #3 recurred with type Ⅳ patterns extremely late phase after coiling. In both cases, the aneurysm was originally of type Ⅰ but progressed to type Ⅳ, which is in agreement with observations from longitudinal follow-up. Liu et al. [22] reported delayed rupture of a previously coiled unruptured AcomA aneurysm. This aneurysm recurred with a type Ⅰ pattern at 8 months after coiling, and a new sac was formed from the recurrent neck (type Ⅳ pattern) at 38 months after coiling. Recurrent hemorrhage from the new sac occurred one day after final angiography. We need a special care to type Ⅰ recurrence with enlargement of recurrent neck because this specific pattern may develop to type Ⅳ.

Conclusions

We recommend immediate re-treatment in patients with recurrent aneurysms of type Ⅲ or Ⅳ because these recurrence patterns were associated with hemorrhage. While no hemorrhage was noted for aneurysms with type Ⅰ recurrence, new sac is sometimes formed from the recurrent neck after a long time follow-up, resulting in hemorrhage. Therefore, it may be advisable to follow carefully for type Ⅰ recurrence.

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31 Dec 2020

PONE-D-20-27179

Recurrence pattern predicts aneurysm rupture after coil embolization

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Reviewer #1: This is an interesting paper about the recurrence pattern prediction of aneurysm rupture after coil embolization. However, aneurysm rupture occurred only in three cases. Therefore, the significance of these findings is very low.

Reviewer #2: Authors should specify the initial treatment of the recurrent aneurysms (simple coling/ballon or stent assisted coiling etc.) in order to evaluate whether does a relation exist with the recurrence. It would be of some interest tie the recurrence type with the initial technique used to coil the aneurysm.

Reviewer #3: The authors present a single institution retrospective review of coiled cerebral aneurysms with a focus on recurrences, and they propose a grading system to characterize recurrence patterns. While this topic is interesting, I believe that they authors should revise their analysis of this population to make a more meaningful conclusion.

1) Please state very clearly how recurrence was defined in incompletely-treated aneurysms.

2) It is nice that you focus on the three cases that hemorrhaged as this is ultimately the event that we would like to avoid in coiled aneurysm patients. Please report as much as possible regarding the results of interval scans in these patients so that we can better understand the natural history of aneurysm recurrence.

3) Along similar lines, reporting the results of interval scans for all of the recurrent aneurysms would be valuable. The occurrence and rate of aneurysm growth and/or coil compaction may be just as important a finding as the pattern of recurrence.

4) Although risk factors for aneurysm recurrence after coiling have been previously described, this manuscript would be much stronger if you performed a multivariate analysis of risk factors associated with recurrence (both overall and for each recurrence pattern) and hemorrhage.

5) Please discuss whether you think there is a continuum between your recurrence patterns.

6) The CFD data is interesting but adds little to this study since it was only used for two examples. If possible, this manuscript would be significantly stronger with a more complete CFD analysis of recurrent aneurysms.

7) Please include percentages of patients in each recurrence group (rather than just absolute numbers) in the Abstract, Results, and Tables

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Reviewer #3: No

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

22 Feb 2021

February 14, 2021

Stephan Meckel, MD, PhD

Academic Editor

PLOS ONE

Dear Editor:

I would like to re-submit an original article for publication in PLOS ONE, titled “Recurrence pattern predicts aneurysm rupture after coil embolization.” The manuscript number is PONE-D-20-27179.

The manuscript has been carefully rechecked and appropriate changes have been made in accordance with the reviewers’ suggestions. The responses to their comments have been prepared and attached herewith.

We thank you and the reviewers for your thoughtful suggestions and insights, which have enriched the manuscript and produced a more balanced and better account of the research. We hope that the revised manuscript is now suitable for publication in your journal.

I look forward to your reply.

Sincerely,

Kouichi Misaki

Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University

13-1 Takara-machi, Kanazawa

Ishikawa 920-8641, Japan

Phone: +81-76-265-2384

Fax: +81-76-234-4262

Email: misaki@med.kanazawa-u.ac.jp

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

21 Jun 2021

PONE-D-20-27179R1

Recurrence pattern predicts aneurysm rupture after coil embolization

PLOS ONE

Dear Dr. Misaki,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Please address all my comments below!

==============================

Please submit your revised manuscript by Aug 05 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see:  http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at  https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Stephan Meckel, MD, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments (if provided):

Special comments from Editor:

- please leave the CFD analysis out completely as it has no relevance with only addressing 5 cases!

- No statistical correction for multiple testing of your dataset has been performed - please contact dedicated statistician to solve this problem - your dataset was tested with many statistical tests for many different questions!

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I have no objections. The authors have adequately addressed all comments raised in a previous round of review.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

2 Aug 2021

We thank for your thoughtful suggestions and insights, which have enriched the manuscript and produced a more balanced and better account of the research. We hope that the revised manuscript is now suitable for publication in your journal.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

23 Aug 2021

PONE-D-20-27179R2

Recurrence pattern predicts aneurysm rupture after coil embolization

PLOS ONE

Dear Dr. Misaki,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please find my additional comments below at the bottom of this letter.

Please submit your revised manuscript by Oct 07 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see:  http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at  https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Stephan Meckel, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

1. Thank you for the added statistics with regards to multiple testing correction - any changes to the results?

2. As stated previously, CFD should be left out from the paper: I still see in in the methods section as well as results & discussion - please correct!

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

6 Oct 2021

Comment 1: “Thank you for the added statistics with regards to multiple testing correction – any changes to the results?”

Response: Thank you for taking the time to read our manuscript and reply. In the previous results, the maximum diameter and neck width (Type II and III) were significantly larger, and VER (Type II and III) were significantly lower than in the no re-treatment group. In the multiple testing correction, there was no statistically significant difference in the maximum diameter in the Type II.

Comment 2: “CFD should be left out from the paper.”

Response: According to your suggestion, we have left out the CFD analysis from Abstract, Methods, Results, and Discussion. Instead of CFD analysis, we have added some words (page 2; line 35-36, page2; line 38-40, page 23; line 347-348, page 23; line 353-355).

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

16 Dec 2021

Recurrence pattern predicts aneurysm rupture after coil embolization

PONE-D-20-27179R3

Dear Dr. Misaki,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Stephan Meckel, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

1 Sep 2022

PONE-D-20-27179R3

Recurrence pattern predicts aneurysm rupture after coil embolization

Dear Dr. Misaki:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Prof. Dr. Stephan Meckel

Academic Editor

PLOS ONE