Metal allergy and neurovascular stenting: A systematic review

Abstract

Background

Intracranial stents and flow diverters contain significant amounts of metals, notably nickel, which can cause allergic reactions in a considerable portion of the population. These allergic responses may lead to complications like in-stent stenosis (ISS) and TIA/Stroke in patients receiving stents or flow diverters for intracranial aneurysms.

Methods

We conducted a systematic review of studies from inception until July 2023, which reported outcomes of patients with metal allergy undergoing neurovascular stenting. The skin patch test was used to group patients into those with positive, negative, or absent patch test results but with a known history of metal allergy.

Results

Our review included seven studies with a total of 39 patients. Among them, 87% had a history of metal allergy before treatment. Most aneurysms (89%) were in the anterior circulation and the rest (11%) were in the posterior circulation. Skin patch tests were performed in 59% of patients, with 24% showing positive results and 33% negative. Incidental ISS was observed in 18% of patients, and the rate of TIA/Stroke was reported in 21%. The pooled rates of ISS and TIA/Stroke were higher in the first group (43% and 38%) compared to the second (18% and 9%) and third groups (15% and 15%), but these differences were not statistically significant.

Conclusions

The current neurosurgical literature does not provide a conclusive association between metal allergy and increased complications among patients undergoing neurovascular stenting. Further studies are necessary to gain a more comprehensive understanding of this topic.

Introduction

The utilization of stents in the treatment of intracranial aneurysms has witnessed a significant surge in the past decade, particularly with the advent of flow diverter stents.^1–4 These stents are constructed using metal alloys, including nickel-based components like cobalt chromium and nitinol. While rare, there have been isolated instances of adverse events, such as allergic reactions and reversible cranial parenchymal changes observed on MRI following coil embolization of cerebral aneurysms.^5,6

Metal allergy, notably nickel allergy, is relatively common, with a prevalence as high as 17% in women and 3% in men in the general population. ⁷ Consequently, some researchers have suggested that post-procedural events may be linked to the release of nickel ions into the bloodstream. Nickel ions have been shown to modulate the expression of intercellular adhesion molecule 1 on endothelial cells’ surface, which, in turn, recruits inflammatory cells.^8,9 Nevertheless, Vanent et al. conducted an analysis of nickel ion release from various brands of neurovascular stents and found contradictory evidence, concluding that the amount of nickel released is insufficient to induce hypersensitivity reactions. ¹⁰

In the cardiology literature, metal allergy raises concerns about delayed hypersensitivity and subsequent in-stent stenosis (ISS), a significant cause of stroke.^11,12 Moreover, individual immune system responses can vary greatly, with some individuals exhibiting extreme reactions to minute amounts of metals. As a result, comprehensive clinical investigation into this phenomenon holds significant importance. Thus, we conducted a systematic review of clinical studies focusing on the association between metal allergy and procedural complications following neurovascular stenting procedures.

Methods

Search strategy

Following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, we conducted a thorough search of the medical literature. The search strategy employed a combination of relevant keywords and standardized index terms, such as “Nickel,” “Cobalt,” “Stainless steel,” “Nitinol,” “Metal,” “Allergy,” “Atopic hypertensives,” “Cerebral aneurysm,” and “Stent” or “Flow diversion” or “Flow diverter.” The search was performed on 20 July 2023, in the PubMed (Medline) database. Articles were included in our study if they met specific criteria, namely being published in English, reporting data for a consecutive series of patients who received stenting or a flow diverter for intracranial aneurysms with a history of cutaneous metal allergy, and providing an identifiable report of primary outcomes. On the other hand, we excluded reviews, guidelines, technical notes, comments, conference abstracts, animal studies, and editorials.

Study selection process

The study selection process involved screening titles, abstracts, and full-text articles using EndNote (Clarivate Analytics, Philadelphia, PA). Two authors conducted these screenings, and any conflicts that arose were resolved by a senior author.

Data extraction and outcome measures

We extracted relevant data from each article, including baseline patient and aneurysm characteristics, the diagnosis and type of metal allergy, and technical information about the stenting procedure. To assess outcomes, we categorized patients into three groups based on the performance of the skin patch test: the first group comprised patients with a positive skin patch test, the second group included patients with a negative skin patch test, and the third group consisted of patients without a patch test but with a confirmed history of metal allergy. Our primary outcomes of interest were in-stent thrombosis/stenosis (ISS) and the risk of post-procedural TIA (transient ischemic attack)/Stroke. ISS was defined as luminal narrowing with >50% diameter stenosis of a stented vascular segment or within 5 mm of stent edge. Additionally, we examined secondary outcomes, such as other complications and mortality rates.

Statistical analysis

Continuous variables were summarized using means and standard deviations (mean ± SD), while categorical variables were presented as frequencies and proportions. The Chi-squared test was employed for analyzing categorical variables. The data analyses were performed using the JAMOVI open-source R-based statistical software version 2.3.21 (R Project for Statistical Computing).

Results

Study selection & baseline characteristics

After conducting an initial review of 12 results from a PubMed library search, we included seven relevant studies (Figure 1: PRISMA flow diagram) comprising a total of 39 patients (Table 1).^13–19 All the studies selected were either case reports or series that focused on patients experiencing adverse events following cerebral aneurysm treatment.

Figure 1.

PRISMA flow diagram of included studies. PRISMA: preferred reporting items for systematic reviews and meta-analyses.

Table 1.

Summary of included studies.

Study, first author	Year	Patient number	Device	ISS	TIA/Stroke
Marcos-Gonzalez et al. 12	2017	1	PED	N/A	1
Kocer et al. 13	2017	6	1 PED 2 FRED 3 SILK	4	0
Park et al. 14	2017	2	1 Enterprise stent 1 Enterprise stent and platinum detachable coils	0	2
Tonetti et al. 15	2018	2	PED	0	0
Wallace et al. 10	2019	20	PED	3	3
Fujii et al. 11	2022	1	PED	1	1
Baranoski et al. 16	2023	7	2 self-expanding Nitinol stents, 7 Flow Divertrers	0	0

Abbreviations: FD, Flow diverters; PED, Pipeline embolization device; ISS: in-stent stenosis.

Detailed demographics regarding gender were reported in four out of seven studies included. Among the patients included, 25 out of 26 (92.5%) were women, and 24 out of 27 (88%) were aged 40 years or older (Table 2). Notably, 34 out of 39 (87%) patients had a known history of metal allergy, Furthermore, 23 out of 39 patients (68%) were diagnosed or suspected to have a metal allergy before the procedure, while the remaining 16 (41%) were diagnosed or suspected after the procedure or the occurrence of an adverse event. Among 17 patients, the type of metal used was reported, with nickel being used in 13 (76%), nitinol in 3 (18%), and cobalt in 1 (6%). A skin patch test for diagnosis was performed in only 19 out of 39 (49%) patients, of which 8 (24%) tested positive and 11 (33%) tested negative. There was no significant difference in the median follow-up periods between these two groups (12 [IQR: 10] vs. 10 [IQR: 13], p = 0.44).

Table 2.

Baseline characteristics of 39 patients with metal allergy and stenting.

Baseline characteristics	N (%)	Denominator
Age (years)	_	_
Younger than 40	3 (9)	33
Between 40–69	28 (85)	33
Older than 70	5 (15)	33
Gender
Female	25 (92.5)	26
Male	1 (7.5)	26
Comorbidities
Hypertension	11 (55)	20
Hyperlipidemia	3 (15)	20
Diabetes mellitus	1 (5)	20
Smoking	8 (40)	20
Known history of metal allergy	34 (87)	39
Total aneurysm count	50
Aneurysm size (mm), median	5	36
Range	2–32
Reported locations of aneurysms that were treated in the study
ICA	26 (79)	33
MCA	3 (9)	33
VBS*	4 (12)	33
Treatment device
Intracranial stents
Enterprise stent	2 (5)	39
Intracranial flow diverters	37 (90)	39
PED	25 (64)	39
FRED	2 (5)	39
SILK	3 (7)	39
Flow Diverter (Other)	7(18)	39
Presentation of metal allergy
Neurologic	4 (10)	39
Asymptomatic	35 (90)	39
Skin patch test
Positive	8 (21)	39
Negative	11 (28)	39
Not done	20 (51)	39
Metal type
Nickel	13 (81)	16
Cobalt	1 (6)	16
Nitinol	3 (19)	16
Allergic reaction (outcome)
Partially resolved	4 (44)	9
Completely resolved	5 (56)	9
Pretreatment antiplatelet therapy	30 (94)	32
Angiographic follow-up, median (range), month	12 (1–64)	39
In-stent stenosis (ISS)	7 (18)	38
TIA/Stroke	8 (21)	39
Death	0 (0)	39

Abbreviations: VBS*, vertebrobasilar system. Includes all the patients whose target lesion was in posterior circulation.

In the cumulative cohort, a total of 35 unruptured aneurysms were reported among 32 patients, with a median size of 5 mm (range: 2–32 mm). Among the 33 aneurysms with location reported, 29 (88%) were located in the anterior circulation and 4 (12%) in the posterior circulation. There were no significant differences in the location of the aneurysms (Table 3). The flow diverter stents used included Pipeline Embolization Device (PED; Medtronic, Minneapolis, Minnesota, USA, contains 27% of Nickel by weight and 30–35% metal coverage) in 25 out of 32 (78%) patients, SILK® (Balt Extrusion, Montmorency, France, consisting of Nickel-titanium alloy Nitinol with 35–55% coverage) in three patients (9.3%), and FRED® (MicroVention, Tustin, CA, USA, consisting 55% of Nitinol) in two (6%). Enterprise stent (Codman Neurovascular, Raynham, MA, USA, 50.8% Nickel, metal coverage not available) was used in two (6%) patients. ²⁰ Information about the type of flow diverter or intracranial stent used was not reported for seven patients. Thirty out of 32 (94%) patients received antiplatelet therapy prior to treatment. No data regarding antiplatelet regimen was reported for the remaining two patients.

Table 3.

Baseline characteristics and outcomes by skin patch test results.

Variable, (%)	Skin patch test result
	Positive (n = 8)	Negative (n = 11)	Not done (n = 20)	p-value
Location				0.66 a
ICA	4/5 (80)	7/8 (88)	15/20 (79)
MCA	0/5 (0)	0/8 (0)	3/20 (9)
VBS	1/5 (20)	1/8 (12)	2/20 (12)
Metal type				N/A
Nickel	7/8 (87)	1/1	5/9 (55)
Cobalt	1/8 (13)	N/A	N/A
Nitinol	0/8 (0)	N/A	3/9 (45)
Treatment device				0.02 a
PED	5/8 (62)	8/11 (73)	12/13 (92)
FRED	2/8 (25)	0/11 (0)	0/13 (0)
SILK	0/8 (0)	3/11 (27)	0/13 (0)
Enterprise stent	1/8 (13)	0/11 (0)	1/13 (8)
In-stent stenosis (ISS)	3/7 (43)	2/11 (18)	3/20 (15)	0.31 a
TIA/stroke	3/8 (38)	1/11 (9)	3/20 (15)	0.26 a

^aFisher's exact test.

Positive Skin Patch test result: These include patients who had history of allergy as well as those whose allergy was detected after immune reaction. Statitistically significant values are marked in bold (Significance was determined by p < 0.05)

Outcomes

Following the endovascular procedure, 35 out of 39 (90%) patients presented with asymptomatic immune reactions, while four (10%) experienced neurological manifestations, such as abducens nerve palsy, right facial palsy, dysphagia, and left-sided sensory disturbance. Two patients with a known history of nickel allergy exhibited symptoms of local erythema and pruritis consistent with contact dermatitis 24 h after direct attachment of PED stents to their arms. However, their reaction resolved spontaneously after the removal of the PED, and neither of them experienced any further reaction after the PED embolization procedures. ¹⁸ All studies reported the clinical course of immune reactions, with complete resolution in five out of nine (56%) patients and partial resolution in the rest (44%), as described in the management details below.

In-stent stenosis

During post-procedural follow-up imaging, ISS was incidentally detected in eight out of 38 (18%) patients over a median angiographic follow-up period of 12 months (range 1–64). Remarkably, all eight patients with ISS were asymptomatic. While five (71%) patients did not require any treatment, two (29%) received mechanical thrombectomy to maintain stent patency. For instance, one patient with a 15 mm right paraclinoid ICA aneurysm treated with PED underwent thrombectomy via stent-retriever to maintain stent patency and was subsequently discharged on oral steroids and antihistamines. No ISS progression was observed on the 14-month DSA imaging. Another patient underwent PED embolization for a 32 mm MCA bifurcation aneurysm but experienced infarcts in the MCA territory immediately after the procedure. However, it remains unclear whether the allergy was directly related to the complication. The patient received aspiration thrombectomy to manage in-stent thrombosis, and the stent remained patent during the 14-month follow-up.

Neurological complications

TIA/Stroke was reported among seven out of 39 (21%) patients, of which all but six (86%) were symptomatic. Among the six symptomatic patients, wo showed spontaneous resolution without any intervention, two resolved with high-dose steroids, and one required a combination of high-dose steroids and second-generation antihistamines to alleviate symptoms. The sixth symptomatic patient experienced left hemiparesis due to in-PED thrombosis, which was treated with aspiration thrombectomy without any residual complications. None of the studies reported any permanent disability or mortality.

There were no significant differences in baseline characteristics among the outcome groups classified based on the performance of the skin patch test. The pooled rates of ISS and TIA/Stroke were slightly higher in the positive skin patch test group (43% and 38%, respectively) compared to the second (18% and 9%) and third groups (15% and 15%). However, these differences were not statistically significant (Table 3).

Discussion

This systematic review comprehensively summarizes the current evidence regarding the impact of metal allergy on neurovascular stenting outcomes. Over the past decades, intracranial stents have primarily been used for revascularization of atherosclerotic vessels outside the brain. However, their utilization has significantly expanded with the introduction of stent-assisted coil techniques and flow diverters. Nickel is a common component in intracranial stents and flow diverters, comprising percentages between 27% to 55% of the stent's weight. ²¹ Despite this, limited data exists on hypersensitivity reactions to nickel-containing intracranial stents and their association with post-procedural serious complications, such as stroke and ISS. Within our review of 39 patients with a positive history of metal allergy, the rates of ISS and TIA/Stroke were 18% and 21%, respectively. Additionally, four (12%) patients experienced critical neurological complications requiring immediate intervention. Among patients with a positive history of metal allergy, the rates of ISS and TIA/Stroke were higher in those with a positive skin patch test compared to patients with a negative test and those who did not undergo the test, but the difference did not reach statistical significance.

ISS is a common issue associated with the placement of flow diverter stents. Peg et al., in a systematic review of 5043 patients undergoing neurovascular stenting, reported a rate of ISS of 14.8% including 28% of them experiencing subsequent neurological symptoms and concluded metal allergy seems to add additional risk for ISS upon a comparison of the ISS rate (26%) within the cumulative cohort of this to the general population (14.8%). ²² The current hypothesis suggests that the release of nickel ions from the stent into the bloodstream induces an inflammatory response, subsequently leading to neointimal hyperplasia and fibrocellular intimal proliferation. ²³ The SSYLVIA trial (Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries), a large-scale prospective, nonrandomized, international trial assessing the safety and feasibility of NEUROLINK stent system for revascularization of vertebral or intracranial artery stenosis, indicated in a linear regression model that diabetes as one of the factors that increased likelihood of restenosis at 6-month follow-up, as described by other studies. ²⁴ In a systematic review of 1223 patients with metal allergy confirmed via skin patch test and received coronary stenting, Gong et al. found that allergic reactions to metal materials of the stents were associated with increased risk of ISS (odds ratio (OR): 2.65, 95% confidence interval (CI); 1.82–3.82).^11,12 They also found that, among patients with metal allergy, patients of Asian origins were associated with a higher risk of ISS (OR: 3.71, 95% CI; 1.91–7.21) compared to the European patients (OR: 2.25, 95% CI; 1.43–3.53). In the neurology literature, the evidence available on this phenomenon is extremely scarce. Adam et al. ¹³ reported a rate of ISS of 13% including two patients with asymptomatic and one symptomatic ISS resulting in a major stroke. The author also found that, among the two patients with asymptomatic ISS, Hemoglobin A1C was 13% in one patient with a major ISS (65% occluded), suggesting diabetes could be an additional risk factor of ISS in patients with metal allergy and neurovascular stenting. However, the evidence of this study is insufficient to investigate this question.

Although the incidence of ISS reduced with the advent of drug-eluting stents, sporadic cases still occur, indicating that ISS is a multifactorial process. ²⁵ The reduction in restenosis has been attributed to sirolimus and paclitaxel therapy which have shown great promise in blocking smooth muscle proliferation and lessening neointimal proliferation. ²⁵ To our knowledge, Köster et al. were one of the first to analyze the association between metal contact allergy and occurrence of coronary ISS. ²⁶ They found a higher frequency of ISS in patients with delayed-type hypersensitivity to metals, particularly to nickel as compared to those without sensitivity to metals, and concluded that contact nickel allergies trigger restenosis to a clinically relevant degree. ²⁶ Although we could not locate any analogous literature in the field of neurosurgery, our review appears to corroborate the author's conclusions. We observed higher rates of ISS among patients with a positive skin patch test; however, this difference did not reach statistical significance. The limited sample size of this study may be a contributing factor to the lack of statistical significance. Furthermore, in the cardiology literature, several cohort studies declined any association of metal allergy with an increased likelihood of ISS, suggesting that pre-operative allergy testing may not routinely be necessary.^27,28

With limited neurosurgery literature on this topic and the several limitations that this study faced, such as a lack of comparative studies in the neurovascular literature and incomplete reporting of demographic characteristics and past medical history by included studies, our findings are inconclusive on the idea that metal allergy may contribute to ISS risk in patients undergoing neurovascular stenting. The evidence on the association between metal allergy and ISS and stroke in patients receiving intracranial stents appears weak and conflicting. Factors influencing outcomes in patients with metal allergy, such as the number of nickel ions released from stents, antiplatelet status before and after treatment, premorbid medication status, and individual variations in immune system responses, are not well-studied and need further investigation.^17,29–31 Patients with suspected or known metal allergy should undergo a pre-operative allergy history assessment and, if necessary, a skin patch test along with other metal constituents in the planned device. For exceptional cases requiring nickel-containing stents, nickel desensitization might be considered. Further multi-center longitudinal studies are warranted to better understand the pathophysiology of this entity and develop appropriate treatment protocols.

Limitations

This systematic review mainly comprises case reports, which introduces a high potential for publication and selection biases. Metal allergy remains profoundly underrecognized in real-life practice, and routine evaluation is lacking. Consequently, the reported rates of ISS and TIA/Stroke in patients with neurovascular stenting and metal allergy may be either higher or lower due to the limited strength of the current evidence stemming from the scarcity of available studies.

While the cardiology literature provides valuable insights into metal allergy, it is essential to acknowledge that cardiovascular devices possess varying technical and chemical characteristics when compared to intracranial stents. Moreover, the studies published in the neurovascular literature lack crucial details regarding patients’ use of antihistamines or immunosuppressive medications before the procedure, or their adherence to antiplatelet therapy. Additionally, upon critical examination of published studies, investigators appear hesitant to conclusively attribute events to allergic reactions.

Conclusions

Our systematic review involving 39 patients with metal allergy undergoing neurovascular stenting procedures provided valuable insights into the association between metal allergy and complications like ISS and TIA/Stroke. However, the neurovascular literature still appears to be divided on this topic. The rates of ISS and TIA/Stroke were found to be relatively high among these patients. Those with confirmed metal allergy through a positive skin patch test demonstrated higher incidences of ISS and stroke, although the difference was not statistically significant, likely due to the small sample size. However, there is extensive literature on the use of coronary stents in patients with metal allergies that suggests pre-operative allergy testing may not routinely be necessary, supporting the evidence against the impact of metal allergy on outcomes of neurovascular stenting. In conclusion, the relationship between metal allergy and intracranial stent outcomes remains a contentious issue. Further investigation through large-scale longitudinal case-control and prospective studies is warranted to gain a more comprehensive understanding of this phenomenon