Results and current trends of multimodality treatment for infectious intracranial aneurysms.

The authors retrospectively reviewed their cases of infectious intracranial aneurysms and discuss results and trends of current treatment modalities including medical, neurosurgical, and endovascular. Twenty patients (10 males and 10 females; mean age 46 years) with 23 infectious aneurysms were treated by various treatment modalities during a 15-year period. Fifteen cases (75.0%) were caused by infective endocarditis. Eleven aneurysms (47.8%) were ruptured. Two aneurysms (8.7%) presented a mass effect and 7 (30.4%) were unruptured and asymptomatic. The average aneurysm size was 6.5 ± 4.8 mm (range 1-22 mm). The aneurysms were located in proximal cerebral circulation in 7 (30.4%) and distal in 16 (69.6%). Six (26.1%) aneurysms were treated surgically (5: trapping, 1: neck clipping), 10 (43.5%) endovascularly (7: trapping, 2: proximal occlusion, 1: saccular coiling), and the remaining 7 (30.4%) medically. Endovascular treatment was gradually increased with time. Medical and surgical treatments were continuously performed during the study period. Surgery was preferred for the patient with intraparenchymal hematoma or treated by bypass surgery. Three periprocedural minor complications occurred in endovascular treatment. There was one postoperative infarction with permanent deficit developed from surgical treatment. During the follow-up period (mean 28.8 months), none of the aneurysms presented a recurrence or rebleeding. Thirteen patients (65.0%) had favorable clinical outcomes (modified Rankin Scale: 0-2), although four (20.0%) had poor outcomes (modified Rankin Score: 5-6). A multimodal approach for the management of infectious aneurysms achieved satisfactory results. Endovascular intervention is a feasible and efficacious treatment option and surgical intervention is still an indispensable procedure.

Introduction

Infectious intracranial aneurysms are rare but potentially ruinous type of aneurysm. “Infectious aneurysm” (IA) maybe a better term than mycotic aneurysm because bacteria, fungi, and other microbes may elicit intracranial aneurysms.[1)] They often develop as a result of septic emboli from infective endocarditis (IE) and are mostly distributed in the distal cerebral arteries. In addition, they also develop as a result of the contiguous spread of sinusitis or meningitis and are located at the proximal cerebral arteries.[1–4)]

They were conventionally treated by medical treatment with antibiotics and/or direct surgery.[1,5–8)] Currently, endovascular intervention is becoming more popular and is adopted as an alternative treatment option instead of craniotomy.[9–14)] Although endovascular intervention might be recommended for the patients especially with poor conditions like cardiovascular instability,[6,9,13,14)] therapeutic management of infectious intracranial aneurysms is still controversial.

In this article, the authors retrospectively reviewed their cases of infectious intracranial aneurysm and discuss trends and results of the current treatment modalities including medical treatment, neurosurgical operation, and endovascular intervention.

Materials and Methods

Twenty patients (10 males and 10 females; mean age 46.0 ± 20.4 years, range 18–81) with 23 infectious intracranial aneurysms were treated by various treatment modalities between April 1999 and November 2013 at Nagoya University and 7 hospitals in Chubu district in Japan. The clinical features, procedural results, and clinical outcomes were retrospectively investigated according to the treatment modality (medical alone, medical and neurosurgical, or medical and endovascular treatment).

Results

Procedural and clinical results are summarized in Tables 1 and 2. Table 1 demonstrates the summary of 20 patients with infectious intracranial aneurysms. Table 2 represents the summary of 23 IAs according to treatment modality. Five patients were initially presented with subarachnoid hemorrhage (25.0%) and intraparenchymal hemorrhage (25.0%) each, 3 (15.0%) with cerebral infarction, and 2 (10.0%) with mass effect (1 was unknown). In 5 cases, however, aneurysms were discovered by screening magnetic resonance imaging (MRI) or computed tomography (CT) imaging for IE. They were neurologically asymptomatic. In addition, two aneurysms were discovered concomitant with a ruptured aneurysm. In 3 cases with initially infarction, one became to rupture and the other showed aneurysm enlargement. Out of 23 aneurysms, 11 aneurysms (47.8%) were ruptured, two aneurysms (8.7%) presented a mass effect, and 7 (30.4%) were unruptured and asymptomatic.

Table 1

Summary of 20 patients with infectious intracranial aneurysms

Case No.	Age	Sex	Presentation	Multiple	Location, size (mm)	Shape	Primary disease	Pathogen	Treatment	Recurrence/Rebleeding	Clinical outcome (mRS)	Follow up (month)
													1	46	F	ICH	No	Distal MCA, 4	Fusiform	IE	α-streptococcus	Surgery	No	1	165
2	21	M	ICH	Yes	Distal ACA, 1	Fusiform	IE	Streptococcus uberis	Endovascular	No	1	2
			Infarction		Distal MCA, 1.5	Fusiform			Endovascular	No
3	81	F	SAH	Yes	ICA supralinoid, 7	Saccular	Sinusitis	NA	Surgery	No	6	6
			Imaging		ICA cavernous (unruptured), 8	saccular			Medical	No
4	63	F	SAH	No	Distal MCA, 5	Fusiform	IE	Streptococcus sanguis	Surgery	No	0	110
5	28	F	Imaging	No	Distal MCA, 2	Saccular	IE	Staphylococcus aureus	Medical	No	0	2
6	51	F	Imaging	No	Distal MCA, 2	Saccular	IE	α-streptococcus	Medical	No	0	91
7	56	M	ICH	No	Distal MCA, 5	Saccular	IE	Streptococcus mitis	Endovascular	No	6	5
8	27	F	Mass effect	No	ICA cavernous, 15	Fusiform	Sepsis	Enterococcus	Endovascular	No	1	4
9	73	M	SAH	No	Distal MCA, 6	Fusiform	IE	NA	Surgery	No	3	62
10	69	M	ICH	No	Distal PCA, 2	Fusiform	IE	Enterococcus	Medical	No	4	3
11	18	M	Infarction→Enlargement	No	MCA (M1–2), 22	Fusiform	IE	NA	Surgery	No	2	42
12	19	F	NA	No	Distal PCA, 7	Saccular	IE	NA	Surgery	No	0	12
13	68	M	SAH	No	Distal SCA, 7.5	Fusiform	IE	Streptococcus mitis	Endovascular	No	0	32
14	47	M	Imaging	No	PCA (P1–2), 9	Fusiform	IE	Staphylococcus aureus	Medical	No	1	2
15	22	F	Imaging	No	Distal MCA, 7	Saccular	IE	Staphylococcus aureus	Medical	No	0	7
16	35	M	Imaging	No	Distal MCA, 7	Saccular	IE	NA	Endovascular	No	0	6
17	51	F	Mass effect	No	ICA cavernous, 5.5	Saccular	Meningitis	Streptococcus	Endovascular	No	0	13
18	23	M	ICH	Yes	Distal MCA, 8	Saccular	Sepsis	Staphylococcus aureus	Endovascular	No	5	3
			Imaging		Distal MCA (unruptured), 1	Fusiform			Medical
19	64	F	SAH	No	Distal MCA, 5	Fusiform	IE	Streptococcus	Endovascular	No	3	4
20	57	M	Infarction→SAH	No	PCA (P1–2), 11	Fusiform	Sinusitis	Aspergillus	Endovascular	No	5	4

ACA: anterior cerebral artery, F: female, ICA internal carotid artery, ICH: intracerebral hemorrhage, IE: infective endocarditis, M: male, MCA: middle cerebral artery, mRS: modified Rankin Score, NA: not achieved, PCA: posterior cerebral artery, SAH: subarachnoid hemorrhage, SCA: superior cerebellar artery.

Table 2

Summary of 23 infectious intracranial aneurysms according to treatment modality

Location	Case no. (Table 1)	Presentation (mm)	Size	Shape	Primary disease	Pathogen	Procedure	Complication	Recurrence or (re) bleeding	Year of treatment
Medical treatment
ICA cavernous	3	Imaging	8	Saccular	Sinusitis	NA		NA	None	2004
Distal MCA	5	Imaging	2	Saccular	IE	Staphylococcus aureus		NA	None	2004
Distal MCA	6	Imaging	2	Saccular	IE	α-streptococcus		NA	None	2005
Distal PCA	10	ICH	2	Fusiform	IE	Enterococcus		NA	None	2009
PCA (P1-2)	14	Imaging	9	Fusiform	IE	Staphylococcus aureus		NA	None	2011
Distal MCA	15	Imaging	7	Saccular	IE	Staphylococcus aureus		NA	None	2012
Distal MCA	18	Imaging	1	Fusiform	Sepsis	Staphylococcus aureus		NA	None	2013
Surgical treatment
Distal MCA	1	ICH	4	Fusiform	IE	α-streptococcus	Trapping	None	None	1999
ICA supraclinoid	3	SAH	7	Saccular	Sinusitis	NA	Clipping	Ischemia (permanent deficit)	None	2004
Distal MCA	4	SAH	5	Fusiform	IE	Streptococcus sanguis	Trapping	None	None	2004
Distal MCA	9	SAH	6	Fusiform	IE	NA	Trapping	None	None	2008
MCA (M1-2)	11	Infarction→Enlargement	22	Fusiform	IE	NA	Trapping with bypass	None	None	2010
Distal PCA	12	NA	7	Saccular	IE	NA	Trapping	None	None	2011
Endovascular treatment
Distal ACA	2	ICH	1	Fusiform	IE	Streptococcus uberis	Trapping with glue	None	None	2001
Distal MCA	2	Infarction	1.5	Fusiform	IE	Streptococcus uberis	Trapping with glue/coil	None	None	2001
Distal MCA	7	ICH	5	Saccular	IE	Streptococcus mitis	Trapping with glue	Ischemia (transient deficit)	None	2005
ICA cavernous	8	Mass effect	15	Fusiform	Sepsis	Enterococcus	Trapping with coil	None	None	2007
Distal SCA	13	SAH	7.5	Fusiform	IE	Streptococcus mitis	Proximal occlusion with glue	None	None	2011
Distal MCA	16	Imaging	7	Saccular	IE	NA	Trapping with coil/glue	None	None	2012
ICA cavernous	17	Mass effect	5.5	Saccular	Meningitis	Streptococcus	Saccular coiling	None	None	2012
Distal MCA	18	ICH	8	Saccular	Sepsis	Staphylococcus aureus	Proximal occlusion with glue	Perforation (asymptomatic)	None	2013
Distal MCA	19	SAH	5	Fusiform	IE	Streptococcus	Trapping with glue	None	None	2013
PCA (P1-2)	20	Infarction→SAH	11	Fusiform	Sinusitis	Aspergillus	Trapping with coil	Bleeding (asymptomatic)	None	2013

ACA: anterior cerebral artery, ICA: internal carotid artery, ICH: intracerebral hemorrhage, IE: infective endocarditis, MCA: middle cerebral artery, NA: not achieved, PCA: posterior cerebral artery, SAH: subarachnoid hemorrhage, SCA: superior cerebellar artery.

The aneurysm site was internal carotid artery (ICA) in 4 cases (17.4%) and proximal middle cerebral artery (MCA) in 1 (4.3%), proximal posterior cerebral artery (PCA) in 2 (8.7%), distal anterior cerebral artery (ACA) in 1 (4.3%), distal MCA in 12 (52.2%), distal PCA in 2 (8.7%), and distal superior cerebellar artery in 1 (4.3%).

The average aneurysm size was 6.5 ± 4.8 mm (range 1–22 mm). Thirteen aneurysms were fusiform in shape and 10 had a saccular shape.

Fifteen cases (75%) were caused by IE, 2 (10%) by sinusitis, 2 (10%) by sepsis from other organ, and 1 (5%) by meningitis. The causative pathogen was Staphylococcus aureus in 4 cases (20.0%), Streptococci in 8 (40.0%), Enterococci in 2 (10.0%) and Aspergillus in 1 (5.0%). The causes were unknown or unspecified in 5 cases (25.0%).

Sixteen aneurysms (69.6%) were treated surgically or endovascularly in addition to medical therapy. Six aneurysms were treated surgically, and 10 endovascularly. Surgical treatment was continuously performed during the study period, although endovascular treatment was gradually increased with time (Table 2, Fig. 1). Usually, aneurysms which were refractory to medical treatment (including the enlargement of aneurysm size) and the aneurysms with hematoma tended to be treated by either intervention. However, indication for intervention depended on the interventionists at each institute. Two aneurysms initially presented with infarction and, thereafter, enlargement and bleeding of the aneurysm required surgical and endovascularly intervention, respectively. These cases were included in a surgically/endovascularly treated case. In surgical operation, 5 aneurysms were treated by trapping of parent artery and 1 by neck clipping. One of them was associated with large intraparenchymal hematoma (Case 1). One case of MCA (M1–M2) fusiform aneurysm was treated by surgical trapping and bypass surgery (Case 11). In endovascular intervention, 7 aneurysms were treated by internal trapping of a parent artery, 2 by proximal occlusion of a parent vessel, and 1 by saccular coiling. Regarding the embolization material for endovascular therapy, N-butyl-2-cyanoacrylate (NBCA) was used in 5 cases, detachable coil in 3, and combination of NBCA and coil in 2. Among them, the authors already reported a case with two infectious MCA aneurysms treated by NBCA as a case report elsewhere.[15)]

Fig. 1.

Biennial number of infectious intracranial aneurysm treated by each modality. A: medical treatment alone, B: surgical treatment, C: endovascular treatment. *: one patient with two infectious aneurysms treated endovascularly.

One procedural complication occurred in endovascular treatment. A microguidewire perforated the small vessel during the access to a distal MCA aneurysm (Case 18). Fortunately, it was asymptomatic and did not accompany neurological impairment. Endovascularly, one patient with distal MCA aneurysm had transient ischemic symptoms after parent artery occlusion (Case 7). There was no intra-procedural complication in surgical treatment. But one patient with ICA aneurysm treated by neck-clipping had experienced cerebral infarction postoperatively (Case 3). Neurological deficit remained in this case.

During the follow-up period (mean 28.8 months), none of the aneurysms treated with direct or endovascular surgery presented an angiographical recurrence or rebleeding. Additionally, aneurysms treated with medical treatment alone also did not present recurrence or rebleeding. Thirteen patients (65.0%) had favorable clinical outcomes (modified Rankin Scale: 0–2) although four (20.0%) had poor outcomes (modified Rankin Score: 5–6) in total.

Discussion

Management of infectious intracranial aneurysm is still controversial. It is well known that these aneurysms could spontaneously resolve, decrease in size, or thrombose under medical treatment with antibiotics.[1)] Unless large, symptomatic or enlarging, unruptured aneurysms can be managed with antibiotics and followed-up by serial neuroimaging. If the aneurysm is ruptured, symptomatic, or enlarging, neurosurgical/endovascular intervention should be considered.[1,4,6,7,13,16)]

Medical treatment

Advance of neuroimaging has provided more opportunity to discover unruptured IAs. In this series, 6 of 7 unruptured aneurysms treated by medical treatment alone were discovered by imaging. Unruptured IA may be treated medically. In our series, most unruptured aneurysms (6 of 8) were managed by medical treatment.

Medical management consists of antibiotics and serial imaging.[17,18)] In this series, 7 aneurysms (6 unruptured, 1 ruptured) were treated by medical therapy alone. All of them disappeared and there was no aneurysm recurrence or rebleeding afterward. Although the indication for intervention depended on the interventionists, selection of the aneurysms for medical treatment was properly conducted.

Surgical intervention

Infectious aneurysms sometimes locate at the proximal cerebral arteries as a result of the contiguous spread of sinusitis or meningitis.[19,20)] The microsurgical approach to the aneurysm at proximal intracranial vessels includes neck clipping or reconstruction, proximal parent artery occlusion, and parent artery trapping with/without resection.[4,6)] Aneurysm clipping with preserving parent artery is thought to be the most suitable option. However, the aneurysm is often unclipped in shape and has fragile features, so reconstructive clipping is technically challenging. The authors had applied neck clipping for one case of ICA supraclinoid aneurysm due to sinusitis. Unfortunately, the patient had been suffering from ischemic complication. If the patients cannot tolerate parent artery occlusion, an extracranial to intracranial bypass is required to cover the distal blood flow.[21–23)] In such situation, surgical operation is indispensable. In our series, one case of MCA fusiform aneurysm was treated by surgical trapping and bypass surgery.

For the treatment of a distally located IA, when a tiny aneurysm hides under brain tissue, surgical intervention often involves the difficulty of detection despite an image-guiding navigation system.[1,14)] However, if an aneurysm is located on the brain surface, it is more easily managed by direct surgery than endovascular procedure. Nevertheless, when the aneurysm is associated with large intraparenchymal hematomas, it should be treated by neurosurgical intervention. The hematoma helps localize the aneurysm and, after evacuation, creates a wide space for the operation.[6)] The authors experienced one case of IA concomitant with a large intraparenchymal hematoma, which was treated by emergency surgical evacuation.

Endovascular intervention

Currently, endovascular intervention is becoming more popular and is adopted as an alternative treatment option. Endovascular intervention might be recommended for the patients, especially, with cardiovascular instability. Patients with IE often suffered from heart failure and need acute heart valve replacement with perioperative anticoagulation.[1,4)] Furthermore, the patients with IA are occasionally in an immunocompromised state.[5)] Endovascular intervention is a minimally invasive procedure and contains less fear of postoperative wound bleeding induced by anticoagulation and wound infection. In addition, it is potentially performed under local anesthesia, which decreases the risk of general anesthesia for the patients with cardiovascular instability and enables functional testing of the patient before parent artery occlusion in cooperative patients.

In many cases of distal IAs, the size of the parent artery is small and advancing the microcatheter to the lesion poses some difficulty.[13,14)] Additionally, arterial wall is thought to be fragile due to the previous infection.[1)] The authors experienced one case of microguidewire perforation at the small vessel during the access to distal IA. Therefore, several aneurysms had been treated from a proximally located microcatheter (proximal parent artery occlusion or embolization with NBCA).

Parent artery occlusion can be safely performed to the vessel supplying non-eloquent area and distally located with good collateral flow. If the vessel was supplying eloquent territory, balloon occlusion test or provocation test would be helpful to evaluate the tolerance in a cooperative patient.[6,13,14)] However, in fact, a considerable number of patients can tolerate parent artery occlusion. That is often explained by the pathophysiology of IA formation. At first, initial septic embolization occurs at a distal vessel. Ischemic presentation is owing to this setting. Subsequently, after vessel necrosis and resultant occlusion, blood flow might recanalize and formation of the IA might be induced. If this initial embolic event is tolerated, parent artery occlusion by endovascular embolization is likely to be tolerated as well.[9)]

In endovascular intervention, it must be considered that introduction of foreign materials into an infected area might exacerbate the local infection or induce abscess formation. However, there have been no cases deteriorating or new infectious complications as a result of endovascular treatment in the literature (there is no report of an infected detachable coil or cast of liquid embolization material in the treatment for IAs).[6,7,13)] Similarly, the authors did not observe such complications in all 10 endovascularly treated cases. The application of antibiotics before and after endovascular intervention may prevent these infectious complications.[8)] Besides, it is suggested that septic emboli occur in the acute phase and IAs develop in a subacute stage. Thus, patients are often aseptic at the time of rupture.

Recently, several papers of stent-assisted coiling,[11)] flow-diverting stenting,[24)] Onyx embolization[12)] for IAs have been reported.[13)] But the safety and efficacy of those treatments are not yet sufficiently established.

Clinical management algorithm

Based on our experience and previous literatures, the authors propose the management algorithm for multimodality management of infectious intracranial aneurysms (Fig. 2). The major determinants to manage IA are whether the aneurysm had ruptured or not, hematoma with mass effect, aneurysm location, need for revascularization, and underlying comorbidities. All patients with IA should treated by antibiotic therapy according to the antibiogram. Patients with unruptured one could be managed with medical therapy alone. Some of them may resolve with medical treatment only. Unruptured IA managed with medical therapy should be followed-up with serial imaging. If IA enlarges, fails to resolve, or rupture during medical therapy, they should be treated by neurosurgical or endovascular intervention. Endovascular intervention is a minimally invasive procedure and preferred for patients in an immunocompromised state or cardiovascular instability. Intracranial IAs are mostly caused by IE and patients with IA usually pose that unfavorable condition. So that, endovascular intervention is probably be the first considerable treatment option for ruptured IA. Patients with ruptured IA with hematoma and mass effect should be treated by surgical intervention. Surgical intervention is considered if the parent vessel supplies eloquent areas and revascularization (including bypass technique) is required to spare the distal arteries. In addition, if endovascular intervention is not technically feasible, surgical intervention should be considered.

Fig. 2.

Clinical management algorithm for multimodality treatment of infectious intracranial aneurysm.

Trends of multimodality treatment

In our experience, the number of endovascular treatment was increased in these past 15 years. Especially, in the present years, endovascular intervention has become the first treatment option. The clinical and procedural result of endovascular treatment is quite satisfactory. The number of medical treatment was constant or increased a little. This might be due to more opportunity to discover unruptured IA by neuroimaging. Initially, the surgical approach was limited treatment option for ruptured IA. Although endovascular intervention has alternated the surgical intervention, surgery was continuously performed hitherto. Surgical procedure is required when the aneurysm is associated with massive intraparenchymal hematomas, and when an extracranial to intracranial bypass or vessel reconstruction is applied to compensate the distal blood flow. The authors reckon that surgical intervention is still an essential treatment option.

Conclusion

Our series demonstrated that the multimodal approach for the management of infectious intracranial aneurysms achieved satisfactory results, with approximately two-thirds of patients showing favorable clinical outcomes. Medical, surgical, or endovascular treatment were properly selected for the management of infectious intracranial aneurysms. Endovascular intervention is a feasible and efficacious option as an alternative treatment and surgical intervention is still an indispensable procedure.