Possible Delayed Foreign Body Reactions against Titanium Clips and Coating Materials after Unruptured Cerebral Aneurysm Surgery

Abstract

Delayed foreign body reactions to either or both clipping and coating materials have been reported in several small series; however, studies in the titanium clip era are scarce. This study aims to survey the contemporary status of such reactions to titanium clips and coating materials. Among patients who received a total of 2327 unruptured cerebral aneurysmal surgeries, 12 developed delayed intraparenchymal reactions during outpatient magnetic resonance imaging (MRI) follow-up. A retrospective investigation was conducted. The patients' average age was 58.6 (45-73) years, and 11 were women. The aneurysms were located in the middle cerebral artery (n = 7), internal carotid artery (n = 4), or anterior communicating artery (AComA, n = 1). In 10 patients, additional coating with tiny cotton fragments was applied to the residual neck after clipping with titanium clips; however, only the clipping with titanium clips was performed in the remaining two. The median time from surgery to diagnosis was 4.5 (0.3-60) months. Seven (58.3%) patients were asymptomatic, and three developed neurological deficits. MRI findings were characterized by a solid- or rim-enhancing lobulated mass adjacent to the clip with surrounding parenchymal edema. In 11 patients, the lesions reduced in size or disappeared; however, in one patient, an AComA aneurysm was exacerbated, necessitating its removal along with optic nerve decompression. In conclusion, cotton material is a strongly suspected cause of delayed foreign body reactions, and although extremely rare, titanium clips alone may also induce such a reaction. The prognosis is relatively good with steroid therapy; however, caution is required when the aneurysm is close to the optic nerve, as in AComA aneurysms.

Introduction

Despite recent advances in endovascular procedures, open surgical clipping remains a widely accepted treatment for unruptured intracranial aneurysms according to the location, size, and shape of the aneurysm.^1,2) In addition, reinforcement of the residual or unclippable aneurysmal wall with coating materials is still an occasionally utilized procedure during open surgery.^3-5)

Although rare, delayed foreign body reactions against clipping and coating materials have been reported in several case reports and small series. Of these materials, cotton, muslin, and gauze used for aneurysmal coating or wrapping have been relatively well described.^3,4,6-16) In addition, allergic reactions to nickel-containing clips were identified in four case reports^17-20) as the concept of nickel allergy became widely known.²¹⁾ Stainless-steel clips were mostly replaced by titanium clips because titanium alloys were considered more biocompatible.^21-23)

However, studies on possible foreign body reactions after aneurysmal surgery in the titanium clip era are scarce. Therefore, in the present study, we surveyed the contemporary status of delayed foreign body reactions to titanium clips and coating materials.

Materials and Methods

This retrospective observational study was approved by the Institutional Review Board of Hokkaido University Hospital, Sapporo, Japan (No. 017-0074). We surveyed a prospectively maintained surgical database at Hokkaido University Hospital and its affiliated hospitals, Teine Keijinkai Hospital and Asahikawa Red Cross Hospital. We identified 2589 patients who underwent unruptured aneurysmal clipping surgery between April 2008 and March 2021. We excluded patients in whom clips other than titanium clips were used intraoperatively (n = 11) or patients who could not receive outpatient follow-up at least once after discharge (n = 251). In total, 2327 patients (89.9%, 1561 women and 766 men) underwent outpatient follow-up after unruptured aneurysmal clipping surgery using titanium clips, and the mean follow-up period was 58.8 (range: 1-168) months. Our unified magnetic resonance imaging (MRI) protocol was as follows: 1) MRI was conducted at least once each before and within seven days after surgery; 2) during the outpatient follow-up, MRI was performed two to four times in the first year postoperatively and once a year after the second year.

Delayed foreign body reaction was defined as newly developed hyperintense lesions adjacent to the clipping site on follow-up T2-weighted images (T2WI) or fluid-attenuated inversion recovery (FLAIR) images that had not been detected on MRI within seven days postoperatively. All lesions were differentiated from infectious or neoplastic diseases through the careful observation of their clinical course, laboratory tests, and radiological findings by board-certified neurosurgeons, neurologists, and radiologists. We identified 12 patients who were diagnosed with delayed foreign body reactions and were the subjects of this study. Informed consent was obtained from all patients included in this study.

We retrospectively examined the medical history, location and size of the aneurysm, surgical procedure, materials used in surgery (both surgical clip and coating material), pattern of onset, radiological features of the developed lesion, timing of the diagnosis from surgery, and the subsequent clinical course.

Results

The patients' information is summarized in Table 1. The mean age of the patients at the time of surgery was 58.0 (range: 43-73 years), and 11 were women. One patient (Patient 2) had a history of allergy to iodine contrast agents; however, the remaining 11 patients had no history of allergy. Two patients (Patients 6 and 7) underwent the patch test and drug-induced lymphocyte stimulation test; however, all tests yielded negative results. The mean timing of diagnosis (detection of an MRI abnormality) was 12.0 months (range: 0.3-60) postoperatively. Of these, seven (58.3%) patients were asymptomatic at the time of diagnosis, and four developed headaches. Furthermore, neurological deficits were observed in three patients (Patients 5, 11, and 12).

Table 1.

Clinical characteristics of patients with delayed foreign body reactions

Patient No.	Age	Sex	History of allergy	Aneurysm		Surgical procedure	Diagnosis from op.	Symptoms
				Location	Size (mm)
1	71	F	None	Rt MCA	5	Clipping & Coating	24 mo.	None
2	43	F	Iodine	Rt ICA (C3)	5	Clipping	16 d.	Headache
3	61	F	None	Rt ICA (C2)	5	Clipping & Coating	60 mo.	None
4	55	F	None	Rt MCA	8	Clipping & Coating	2 mo.	None
5	55	F	None	AComA	5	Clipping & Coating	26 mo.	Visual disturbance
6	60	F	None	Lt MCA	5	Clipping & Coating	9 d.	None
7	58	F	None	Rt MCA	5.7	Clipping & Coating	3 mo.	Headache
8	47	F	None	Rt MCA	3	Clipping	10 mo.	None
9	73	F	None	Rt IC-PComA	6	Clipping & Coating	4 mo.	None
10	60	F	None	Rt MCA	4	Clipping & Coating	6 mo.	None
11	68	M	None	Lt IC-AChoA	8	Clipping & Coating	5 mo.	Headache, mild hemiparesis, memory disturbance
12	45	F	None	Rt MCA	5	Clipping & Coating	3 mo.	Headache, sensory disturbance

Abbreviation op.: operation, F: female, Rt: right, MCA: middle cerebral artery, mo.: month, ICA: internal carotid artery, d.: day, AComA: anterior communicating artery, Lt: left, PComA: posterior communicating artery, AChoA: anterior choroidal artery

In 10 patients, single aneurysms were clipped. In the remaining two patients, two aneurysms each were clipped in one surgical session. Of these, the locations of the aneurysms that induced delayed foreign body reactions were the middle cerebral artery (MCA, n = 7), internal carotid artery (ICA, n = 4), and anterior communicating artery (AComA, n = 1). The mean aneurysm size was 5.4 mm (range: 3-8 mm). All aneurysms were clipped using titanium clips (YASARGIL Aneurysm Clip System titanium clip, B. Braun Aesculap Japan, Tokyo, Japan), and the number of clips applied varied from one to five. In 10 of 12 patients, the remnant aneurysmal neck was coated with small (approximately 0.5 × 2.0 mm square) cotton fragments (BEMSHEETS, Kawamoto Corporation, Osaka, Japan) with fibrin glue. The materials used in surgery are summarized in Table 2.

Table 2.

Materials used in surgery

Patient No.	Aneurysm	Materials
		Clipping	Coating
1	Rt MCA	Titanium clip (FT722T)	Cotton & Fibrin glue
2	Rt ICA (C3)	Titanium clip (FT752T)	None
3	Rt ICA (C2)	Titanium clip (FT720T, FT692T)	Cotton & Fibrin glue
4	Rt MCA	Titanium clip (FT722T, FT692T, FT692T, FT694T, FT694T)	Cotton & Fibrin glue
5	AComA	Titanium clip (FT722T, FT692T, FT694T)	Cotton & Fibrin glue
	Rt MCA	Titanium clip (FT680T)	None
6	Lt MCA	Titanium clip (FT692T, FT680T)	Cotton & Fibrin glue
7	Rt MCA	Titanium clip (FT692T, FT802T)	Cotton & Fibrin glue
	Rt IC-PComA	Titanium clip (FT682T, FT692T)	Cotton & Fibrin glue
8	Rt MCA	Titanium clip (FT690T, FT694T)	None
9	Rt IC-PComA	Titanium clip (FT692T)	Cotton & Fibrin glue
10	Rt MCA	Titanium clip (FT692T, FT902T)	Cotton & Fibrin glue
11	Lt IC-AChoA	Titanium clip (FT722T, FT722T)	Cotton & Fibrin glue
12	Rt MCA	Titanium clip (FT682T, FT722T, FT802T)	Cotton & Fibrin glue

Regarding the MRI findings, white matter hyperintense edema was observed in all patients at the site adjacent to the clip artifact (Fig. 1). Gadolinium-enhanced T1-weighted imaging (Gd-T1WI) was conducted in nine patients, and solid- or rim-enhancing lobulated mass lesions were found inside the edematous lesion. In two patients (Patients 6 and 9), the internal portion of the rim-enhancing mass was hyperintense on diffusion-weighted imaging (DWI), mimicking an abscess.

Fig. 1.

Magnetic resonance images at the time of diagnosis for Patients 2-4 (A-E) and 6-12 (F-T). Fluid-attenuated inversion recovery images (FLAIR, A, E, I, M, P, R, and T), T2-weighted images (T2WI, B, F, and K), gadolinium-enhanced T1-weighted images (Gd-T1WI, C, G, J, L, N, Q, and S), and diffusion-weighted images (DWI, D, H, and O) are shown.

The clinical courses after the diagnosis are summarized in Table 3. After diagnosis, nine patients were treated with steroids, in six of whom the dose of steroids was gradually decreased and finally ceased. The MRI abnormality completely disappeared in eight patients and decreased in size in three, regardless of whether steroid therapy was administered. Typically, the lesion size fluctuated (i.e., repeated increases and decreases in size) during remission (Fig. 2A-H). Along with the improvement in MRI abnormalities, most clinical symptoms improved; however, in one patient (Patient 11), a mild neurological deficit (memory disturbance) remained. In one patient (Patient 5), in whom the AComA aneurysm was clipped and coated, the MRI abnormality expanded with progressive visual disturbance despite steroid therapy. Therefore, a second surgery was performed, including partial lesion resection and optic nerve decompression. Histopathological examination, which was conducted only in this patient, revealed chronic granulation with inflammatory cell infiltration, suggesting a foreign body granuloma (see also the next section).

Table 3.

Treatments and clinical course

Patient No.	Treatment	Follow-up
		Period (mo.)	Radiological	Symptom
1	None	112	Lesion disappeared	Stable
2	Steroid (1 mo.)	18	Lesion disappeared	Headache improved
3	Steroid (7 mo.)	79	Lesion disappeared	Stable
4	None	92	Lesion disappeared	Stable
5	Steroid (continued) / 2nd op.	42	Lesion enlarged despite steroid therapy/ Lesion reduced after 2nd op.	Progressing visual disturbance despite steroid therapy/ Symptom stabilized but remained after 2nd op.
6	Steroid (9 mo.)	63	Lesion disappeared	Stable
7	Steroid (21 mo.)	66	Lesion disappeared	Improved headache
8	Steroid (continued)	141	Lesion disappeared	Stable
9	Steroid (4 mo.)	131	Lesion reduced	Stable
10	Steroid (49 mo.)	75	Lesion reduced	Stable
11	Steroid (continued)	103	Lesion reduced but perilesional brain atrophy remained	Headache and hemiparesis improved, memory disturbance alleviated but remained
12	None	18	Lesion disappeared	Headache and sensory disturbance improved

Fig. 2.

Patient 1 (Upper). FLAIR (A-D) and Gd-T1WI (E-F) at the time of diagnosis (A and E), 1 (B and F), 2 (C and G), and 3 years after the diagnosis (D and H) showing gradual remission of the lesion despite repeated increases and decreases in size.

Patient 5 (Lower). T2WI and Gd-T1WI at the time of diagnosis (I and J), and T2WI after steroid pulse therapy (K) and before the second surgery (L). Hematoxylin-Eosin staining of the specimen (M). T2WI and Gd-T1WI one-year after the second surgery (N and O).

Case presentation (Patient 5)

A 57-year-old woman with no medical history underwent clipping surgery for unruptured AComA and right MCA aneurysms. Through a right pterional approach, the AComA aneurysm was clipped using four titanium clips, and the partially residual neck was coated with cotton fragments and fibrin glue. The MCA aneurysm was also clipped without any coating. The surgery was completed without complications. A follow-up T2WI 26 months postoperatively revealed hyperintense lesions in the bilateral frontal lobes adjacent to the clips (Fig. 2I). Ring-like conglomerated enhanced lesions were also observed around the clips on Gd-T1WI (Fig. 2J). After the introduction of steroid therapy (prednisolone 5 mg/day), the lesion had decreased in size over six months; however, after the reduction of steroids, she presented with visual field constriction. After methylprednisolone pulse therapy (1 g/day) for three days, her symptoms and MRI abnormalities immediately recovered (Fig. 2K). However, during a six-month period of tapering steroids, the MRI change was exacerbated once again. Despite the gradual increase in the dose of steroids, the lesion continued to increase in size (Fig. 2L), and she again presented with visual field constriction. A second surgery was performed, including partial lesion resection and opening of the optic canal with extradural anterior clinoidectomy. Histopathological examination of the lesion showed granulation with inflammatory cell infiltration. Pathogenic microorganisms or neoplastic cells were not detected (Fig. 2M). Postoperatively, steroid pulse therapy was repeated, and her visual symptoms partially recovered (Fig. 2N and O). Subsequently, the patient has continued steroid therapy.

Discussion

In this study, we investigated delayed foreign body reactions against titanium clips and additional coating materials after clipping surgery for unruptured cerebral aneurysms, which were identified in approximately 0.51% (12 out of 2327) of patients. Cotton fragments were used as an additional coating in 10 of 12 patients, and cotton was the most suspected cause of this MRI change. Notably, these reactions were also observed in two patients in whom only clipping with titanium clips was performed. This suggests that the titanium clip can independently induce a foreign body reaction after surgery. In most (11 out of 12) of the patients, these lesions were reduced in size or disappeared with the use of steroid therapy. However, in a patient with an AComA aneurysm, the lesion caused aggressive visual field constriction, requiring additional surgical treatment.

Foreign body reactions or cell-based allergies to the cotton gauze have been well described in the literature, and these were also referred to as “muslinoma,” “gauzoma,” or “adhesive arachnoiditis.”^3,4,6-16) In this study, fibrin glue, which could potentially contribute to these reactions, was also used in conjunction with cotton as a coating material. In fact, there have been two reports suggesting allergic reactions to the intracranial use of fibrin glue.^24,25) Yasuda et al. reported interesting experimental results, wherein, when a cellulose cotton sheet and fibrin glue were used to coat the common carotid artery of rabbits, the cotton was not absorbed after 12 weeks, inducing connective tissue proliferation, inflammatory cell infiltration, and intimal thickening.⁵⁾ These observations indicated that cotton gauze was prone to induce allergic reactions to the adjacent tissue. The present study's results strongly support these reports. In our facilities, starting in 2013, we began using polyglycolic acid (PGA) felt with fibrin glue instead of cotton as coating materials, gradually replacing them over time. Notably, none of the patients in whom PGA felt and fibrin glue were used in clipping surgery exhibited delayed reactions. Based on the results of this study, the use of cotton gauze should be avoided unless there is a valid reason, such as an unexpected aneurysmal wall injury.

An interesting finding of this study was that such allergic reactions might have been induced by clips containing only titanium alloy. To our knowledge, this is the first report of possible foreign body reactions to titanium materials in the cranium. Only four case reports on foreign body reactions in the form of Type IV allergic reactions or allergic vasculitis to clips made of cobalt alloy (YASARGIL Phynox Aneurysm Clip) have been published.^17-20) Along with previous reports on delayed reactions against endovascular materials such as stents, the nickel component was strongly suspected as the cause of such reactions.^21,26,27) Because the titanium metal surface is passivated with chemically stable titanium, titanium alloys have been generally considered highly biocompatible and less likely to induce allergic reactions.²⁸⁾ However, according to the literature in other disciplines, suspected titanium allergies have been documented in knee or hip arthroplasties,²⁹⁾ osteosynthesis,³⁰⁾ and dental implants.³¹⁾ Recently, Gan et al. reported a case of foreign body granuloma caused by titanium clips after breast-conserving surgery.²²⁾ Hosoki et al. reported the results of patch testing with 28 types of metal allergens, including four titanium allergens. The resultant prevalence of allergic reactions to titanium allergens was lower compared with other metal allergens; however, 6.3% of the patients exhibited positive reactions to the titanium allergens.²⁸⁾ Therefore, titanium alloys can induce allergic reactions in certain patients and play an important role in implant failure. Since the titanium clip (Ti-6A-l4V) is comprised of 90% titanium, 6% aluminum, and 4% vanadium, the latter two might also be sources of allergens. One possible countermeasure to prevent such intracranial allergic reactions is preoperative patch testing using a titanium clip. However, the sensitivity and specificity of such testing for intracranial pathologies are not clear. Long-term observation using appropriate imaging modalities should be recommended even after surgery.

In this study, most (11 out of 12) of the patients were women, and a similar trend was observed in previous literature.^15,16,21) Although the pathophysiological mechanism behind the difference in sex was not fully elucidated, there is an evident clinical difference between female and male patients with other allergic diseases, such as food allergies, atopic dermatitis, and allergic asthma.^32,33) Genes, sex hormones (e.g., estrogen), environmental factors, and immunological factors were thought to contribute to these sex disparities.³⁴⁾

Regarding the MRI features, a solid- or rim-enhancing lobulated mass on contrast-enhanced T1WI and surrounding edema on T2WI or FLAIR were the typical findings, and these changes were all observed at the site closely abutting to the clip artifacts. In some patients, hyperintensity was observed on DWI in the ring-like enhancement masses, suggesting adhesive arachnoiditis or an abscess. These findings are consistent with previous reports on allergic reactions.^{3,4,10,14,16)}

Our long-term postoperative outpatient MRI follow-up indicated that a certain number of asymptomatic patients had delayed MRI abnormalities. Fortunately, this study revealed that the prognosis of asymptomatic patients was good regardless of whether steroid therapy was administered. However, caution should be taken in patients with AComA aneurysms because this lesion is located close to the optic chiasma, and surgical materials may inevitably be directly attached to the optic nerve. According to previous reports, allergic materials can induce optochiasmatic arachnoiditis, leading to aggressive, severe visual dysfunction.^{3,4,6-9,11-13,15,16)}

Limitations

As this was a retrospective study, our results should be interpreted with caution. As a certain number of asymptomatic patients were likely overlooked, a prospective study is needed to more accurately elucidate the prevalence of such allergic reactions. Additionally, this study excluded patients with ruptured aneurysms due to the potential influence of various factors, such as primary brain damage, brain swelling, and vasospasm, on the imaging findings. Therefore, further research would be required to determine whether delayed reactions can occur after surgery for ruptured aneurysms.

Conclusion

Cotton coating material was a strongly suspected cause of allergic reactions in the present study. Notably, titanium clips alone may be able to induce such a reaction, although the frequency was quite low. The prognosis of the delayed reaction was relatively good with steroid therapy; however, in cases in which the aneurysm was close to the optic nerve, special caution should be exercised.

Abbreviations

MRI = magnetic resonance imaging; T2WI = T2-weighted image; FLAIR = fluid-attenuated inversion recovery; DWI = diffusion-weighted imaging; MCA = middle cerebral artery; ICA = internal carotid artery; AComA = anterior communicating artery; Gd-T1WI = Gadolinium-enhanced T1-weighted image; PGA = polyglycolic acid

Sources of Funding

None

Conflicts of Interest Disclosure

The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.