Allergy identification for neurosurgical patients: updates for management

Allergic reactions in neurosurgical procedures are uncommon, but they are detrimental to a patient’s prognosis and recovery. By synthesizing data collected from other surgical fields, possible triggers and alternatives have been identified. Current treatment guidelines involve stabilizing the patient in emergency situations, symptom management, and identification of causative allergens. Preoperative allergy screening is uncommon due to the low prevalence of perioperative hypersensitivity reactions. However, preoperative questionnaire screening can identify when preoperative allergy screening, premedication, or use of a material alternative is necessary. Greater emphasis on material alternatives, increased preoperative screening, and more data can improve the prognosis of neurosurgical patients at risk of perioperative allergic complications.


Introduction
An allergy is an abnormal immune response from exposure to a generally harmless environmental substance, which primes the immune system to respond when the antigen presents again. These immunologic reactions are mediated through IgE or non-IgE mediated mechanisms [1]. An IgE-mediated reaction follows the classical mechanism where an allergen-derived antigen interacts with IgE bound to the Fc0εRI receptor on mast cells or basophils. Allergen-specific IgE and T helper 2 cells recognize antigens, which then causes anaphylaxis, allergic rhinitis, asthma, and food allergy flare-ups. Meanwhile, allergic This is an open access article under the CC-BY license. (https://creativecommons.org/licenses/by/4.0/) contact dermatitis is more linked to cellular, non-IgE mediated mechanisms [2]. Overall, IgE-mediated anaphylaxis is more severe than that of non-IgE-mediated.
Allergic reactions may occur anytime foreign substances are introduced in medical treatment; thus, any neurosurgical procedures exposing patients to extrinsic triggers can potentially cause allergic reactions. Complications caused by allergies in neurosurgical procedures are similar to those in cardiac modulation and neural stimulation surgeries. The incidence of hypersensitivity reactions occuring perioperatively is approximately 1:10,000 [3]. Though allergic reactions occurring perioperatively in neurosurgical patients are uncommon, largely misunderstood, and often unexpected, recognition of these rare cases may assist providers in early detection of surgical complications [4]. Possible allergens include contrasts, antibiotics, metals in hardware or metal implants, and dural substitutes. Allergic reactions in neurosurgical patients can be classified into two categories: perioperative anaphylaxis or postoperative anaphylaxis. Perioperative anaphylaxis typically manifests with cardiopulmonary changes including hypotension, bronchospasm, and tachycardia.
When an allergic reaction is suspected, infectious etiology should be ruled out first, then supported by patch testing by a dermatologist or allergist. Dermatologists can test for a specialty series of metals, polyurethanes, and other relevant allergens involved in neurosurgery [5]. However, skin patch testing can be unreliable after a month [6], but laboratory tests and provocation tests can corroborate the diagnosis.

Preventative management of allergic response
Preventive management of allergic response can take different paths depending on the presence or lack thereof in the relevant history of a previous allergic response. In patients with a previous history of allergic response, guidelines suggest that pre-operative allergic evaluation could establish the likelihood of perioperative anaphylaxis [7]. Perioperative anaphylaxis may develop as a result of exposure to an allergen into a life-threatening immediate hypersensitivity reaction that may be mediated by IgE [8]. This pre-operative allergic evaluation serves as a screening tool for perioperative anaphylaxis.
A preoperative questionnaire looks to identify any relevant pre-existing conditions [9]. Along with the preoperative questionnaire, a history of unexplained perioperative anaphylaxis is taken into consideration as a risk factor for future anaphylaxis, and an allergy workup is recommended [10]. When a history of unexplained anaphylaxis is positive, a secondary prevention test is recommended by guidelines. These secondary tests entail skin testing with future perioperative agents as allergens [11]. Included in these perioperative agents, iodinated and gadolinium-based contrast media have been observed to cause IgEmediated allergic reactions. The radiocontrast media are available to test for hypersensitivity in intradermal skin testing, however, it was found to be ineffective in prevention unless a history of drug hypersensitivity reaction was noted [12]. Even though not commonly used, drug provocation tests (DPT) are the gold standard for drug allergy investigation in the event of a positive history of unexplained anaphylaxis [13]. DPT is most importantly used when attempting to discover the potential of an anesthetic used in a future surgery causing an allergic reaction and its pharmacological effects [13]. The collaboration of an immunologist/allergist and an anesthesiologist is recommended to properly investigate drugs tested in DPTs that are planned to be used during the perioperative setting [14]. DPTs use a fraction of one tenth of the drug's therapeutic dose to investigate for allergy if the drug is characterized to be a potent agent. Some examples of potent drugs that are commonly tested for reactions are anesthetic drugs, opioids, and vasopressors [14]. All other drugs desired to test for allergy that are not potent agents are tested up to their full therapeutic dose. Examples of non-potent agents frequently tested in DPTs include antibiotics, local anesthetics, NSAIDs, and antiemetics [14].

Benefits of early-identification
Neurosurgical patients should be screened for a history of contact allergies before the procedure. Managing postoperative allergic reactions will involve a multidisciplinary team with neurosurgeons, dermatologists, allergists, and manufacturers [5]. Allergies to contrast agents can be preemptively determined with skin tests and cellular in vitro tests, such as basophil activation tests, lymphocyte transformation test, and ELISpot assays [15]. These cellular in vitro tests are not conclusive as they have a specificity of over 90%, but sensitivity lower than 50% [16]. IgE diagnostic tests are also commercially available for beta-lactams, latex, and anesthetics, but their sensitivity is less than 60% [6]. These test findings, patient history data, drugs to be avoided, and recommended alternative drugs are compiled into an allergy passport and kept in the patient's chart. The recommended alternatives and allergies can be used in the future to avoid cross-reactivity to other drugs or food stuff.
Skin testing in longitudinal studies has proven to prevent most future cases of perioperative anaphylaxis, with rare instances attributed to gaps in past medical history and undetected mast cell disorders [17]. Though the passport cannot completely prevent all future reactions, it can prevent a course from being as severe as the original reaction in 90% of recurring cases [6].
Generally, allergic reactions occurring perioperatively in neurosurgical procedures are rare. In addition, skin prick tests and blood tests might cause potential harm to the patient, and they are uncomfortable and expensive. Therefore, allergy screening before surgical procedures is not a standard protocol. Though the rates of having allergies to individual triggers are also rare, having an allergy passport can prevent complications in pharmacological or surgical therapy due to hypersensitivity in the future. Moreover, it can individualize the necessary pre-medication to prevent perioperative hypersensitivity reactions.

Pre-medication for prevention against perioperative anaphylaxis
Premedication in the form of antihistamines, corticosteroids, and acetaminophen serves as pretreatment for perioperative drug hypersensitivity reaction [7]. However, the evidence does not support the use of pre-medication such as corticosteroids or antihistamines with the goal of avoiding perioperative anaphylaxis [18]. Guidelines have established that the involvement of antihistamines is recommended as a premedication unless histamine release due to hypersensitivity reaction is suspected [19] (Figure 1). Therefore, the introduction of antihistamines preoperative medication is considered impractical to mitigating IgE-mediated hypersensitivity reactions associated with perioperative anaphylaxis [20]. Moreover, a single dose of corticosteroids preventing perioperative hypersensitivity reactions was reported unsuccessful [21]. Proper avoidance of known allergens and common unexplained allergens previously reported continues to be the most efficacious method to preventing perioperative hypersensitivity and anaphylaxis [8].
The current use of low-osmolar nonionic iodinated contrast media (ICM) is responsible for less basophil and mast cell degranulation compared to abandoned high osmolar ionic ICMs [22]. This mechanism of histamine degranulation-caused adverse effects is shown to be mitigated by the use of antihistamines and corticosteroids [23]. By exerting an antiinflammatory action against mast cells and basophils, corticosteroids, H1/H2 antihistamines, and ephedrine have proven a more significant reduction in patients experiencing a low hypersensitivity reaction compared to moderate to severe hypersensitivity reaction [24,25].
Current guidelines support allergy evaluation and identifying safer alternative contrast media in patients with a previous history of hypersensitivity reactions to ICMs contrary to the routine use of antihistamines and/or corticosteroids ( Figure 1) [26]. Guidelines weigh the slight benefit of administering antihistamines and/or corticosteroids to the side effects of these associated with delay in radiological diagnosis and prolonged hospitalization. Studies have shown that changing the class of ICMs that resulted in a prior hypersensitivity reaction is more effective than premedication in patients at high risk of allergic reaction [27], Similarly, gadolinium-based contrast media follow a similar approach to ICMs when a hypersensitivity reaction is observed. Nevertheless, this contrast media is considered to have a lower incidence of hypersensitivity compared to ICMs as gadolinium is reported to be a non-histamine-releaser in vitro [28].
The development of a reliable pre-screening tool for preoperatively diagnosing penicillin and/or cephalosporin allergy has not been supported by evidence to be beneficial in avoiding hypersensitivity reactions [7]. A study sought to examine the effectiveness of an allergy screening in patients of low-risk penicillin allergy by de-labeling allergy histories from patients before surgery. Savic et al. reported that the vast majority of the de-labeled group received the correct perioperative antibiotic based on the allergy screening tool which confirmed the reassurance of the process [29]. Despite the success of appropriate perioperative antibiotic administration by de-labeling patients with an unverified low-risk penicillin allergy, a significant number of data supports that there is a low risk for a hypersensitivity reaction in this group of patients when administered cefazolin [30].

Management of surgically-induced allergic reactions
Management of surgically induced allergic reactions can be either perioperative or postoperative. Perioperative anaphylaxis is typically more severe and fatal than postoperative anaphylaxis. This heightened severity can be attributed to the IV drug administration, open wounds, and sensitivity to physiologic perturbations during anesthetized neurosurgery. Postoperative management largely involves alleviating symptoms of allergic reaction.

Detecting allergic reactions
Blood should be collected during or shortly after the reaction for evaluation. Blood evaluation should follow the management of the hypersensitivity reaction. If the reaction is allergy-related, it may show elevation of tryptase released only by mast cells and basophils. Tryptase is elevated in 68% of IgE-mediated reactions and 4% of non-IgE-mediated reactions [31] within the first two hours of clinical symptoms. If tryptase levels increase at least 2 ng/ml over 20% of the baseline within 24 hours of the reaction, an allergic reaction is suspected. Since tryptase elevation occurs only in some allergic reactions, it is an unreliable indicator. However, histamine, histamine metabolites, and prostaglandins are considered even less reliable indicators of anaphylaxis ( Figure 2).
Clinical diagnosis of allergic reaction is based on the presence of characteristic signs and measurement of blood biomarkers, but there is no foolproof way to determine if an allergic reaction has occurred. Timing can be used to determine which triggers and mechanisms were responsible for the perioperative allergic response. Anaphylaxis during the first half hour of anesthesia are likely caused by antibiotics, neuromuscular-blocking agents, or hypnotic induction agents. Hypotension and tachycardia are likely present, but may also be attributed to effects of sedation or pharmacological side effects [3]. Moreover, an early response indicates an IgE-mediated response. Anaphylaxis presenting after the first half hour of anesthesia are more likely caused by latex, dyes, contrast agents, dural substitutes, and metal components of neuromodulation devices.
If a clear trigger cannot be determined based on time, skin prick tests are conducted 4 weeks to 6 months post-reaction to identify the trigger. Skin reactions often present as local dermatitis, erythema, and pruritus, which can be mistaken for a surgical site infection ( Figure 3) [5]. Skin reactions can also be missed during procedures when concealed by surgical drapes [3]. If low-dose skin prick tests are insufficient in producing a response, intradermal tests may be administered, especially in the case of a severe allergic reaction. In the case of negative skin and laboratory test results, provocation tests should be used as they are the gold standard of diagnostic allergy testing [3].

Perioperative management of anaphylaxis
Initial assessment of hypersensitivity, similar to any other emergency situation, involves securing the ABCs: airway, breathing, and circulation [32]. Then, stabilizing conditions requires prompt hemodynamic resuscitation with epinephrine, IV fluids, and antihistamines [33]. Most successful treatments exhibited early use of epinephrine and beta agonists [31].
If such measures return the patient to a stable condition, the next step would be to decide whether or not to proceed with the surgery, depending on the cardiopulmonary stability, severity of reaction, and urgency of the neurosurgical procedure. Severity of anaphylactic reactions are rated from grades 1-4 where: 1 or 2 are limited to non-life-threatening cutaneous and vital sign changes, 3 is severe hypotension or bronchospasm, and 4 is cardiac arrest or failure to ventilate. Surgeries are often abandoned with allergic reactions of grade 3 or higher [34]. Following a procedure with a possible anaphylactic reaction, the patient should be referred to an allergy specialist for an allergy evaluation to identify the allergen and prevent future attacks.

Post-operative management of allergic reaction
Post-operative management focuses on treating and alleviating symptoms of allergic reaction. Despite the various potential allergenic triggers in neurosurgical procedures, the symptoms and treatment guidelines of these allergic reactions are the same. Moreover, treatment guidelines are similar to treating any allergic reaction. Antihistamines are administered to reduce overall severity of the reaction by suppressing the immunologic reaction and restoring homeostasis. Generally, mild reactions such as itching and hives are considered self-limiting and do not require treatments. However, if the redness, itching, dryness, and scaling persists, topical corticosteroids, such as dexamethasone, can be used to reduce inflammation. Beta-2 agonists are used along with oxygen to treat bronchospasms. A course of oral antibiotics may also be administered to avoid bacterial infections while the immune defenses are suppressed [35]. Along with alleviating symptoms, another aim is to minimize exposure to the triggering allergen through the removal of neuromodulation devices or dural implants.

Potential triggers Anesthetics & neuromuscular blocking agents
Neuromuscular blocking agents (NMBA) are used as general anesthetics, and are one of the most common triggers of perioperative drug reactions. In fact, muscle relaxants cause 59% of perioperative anaphylactic reactions [36]. For instance, succinylcholine, which may cause nonimmunologic histamine release, has also led to IgE-mediated mechanisms in some patients, based on RAST studies. The first discovered anestheticrelated allergic reaction and one of the most common is caused by thiopental, a short-acting barbiturate. However, structural and material alternatives have been identified to replace succinylcholine and thiopental [37]. Cross-reactivity between NMBA and antibiotics, other anesthetics, opioids, NSAIDs, and benzodiazepines can also be a contributing factor to the hypersensitivity. While allergic reactions to NMBA are already rare, they can also lead to false-positive skin prick test results because of their histamine-releasing properties [38]. Meanwhile, provocation tests are not recommended because of their pharmacological activity profile. Symptoms are typically cardiac-related, with reports of hypotension, tachycardia, myocardial ischemia, and paradoxical bradycardia [39].

Latex
Latex is the second leading cause of perioperative anaphylaxis, accounting for approximately one-fifth of all cases, which are even more common in countries without latex alternatives [40]. Adverse reactions to latex are becoming increasingly prevalent, due to increased exposure and contact to latex products in clinical practice [41]. Most hypersensitivity reactions to latex occur within ten minutes of exposure when allergenic latex proteins directly contact skin and mucous membranes [42]. The fast reaction is characteristic of IgE-mediated reactions that form antibodies against latex in gloves, drains, and catheters touching highly vascularized, mucosal tissue. Signs of latex hypersensitivity include contact dermatitis, tachycardia, urticaria, angioedema, and dyspnea [42]. People with the myelomeningocele spina bifida are especially at risk of developing reactions to latex. Though the exact cause of sensitization to latex in spina bifida populations is unknown, the most common theory suggests that it relates to the high exposure to latex products through repeat surgical procedures, catheterization, and latex implants in early developmental stages [43]. Meanwhile, people with spinal cord injury or chronic neurologic defects from the injury exhibit low risks of latex sensitization [44].

Antibiotic allergies and hypersensitivity
Although perioperative anaphylaxis from penicillin is rare, penicillin allergy is the most common reported drug allergy [45]. With approximately 10% of the U.S. population being allergic to penicillin-based antibiotics, physicians must consider its associations with lower cure rates, longer hospital stays, increased recurrence, increased risks for adverse effects from second-line antibiotics, and increased mortality [46,47].
More importantly, penicillin allergies have been correlated with a higher incidence of surgical site infections [48]. A U.S. retrospective study found 30 out of 717 cases of perioperative anaphylaxis were caused by antibiotics [49]. Moreover, studies at Mayo Clinic and Massachusetts General Hospital identified cases of perioperative anaphylaxis with antibiotics, specifically cefazolin, as the most common cause of the event [49,50]. Hepner et al. claimed that the incidence of anaphylaxis due to penicillin choice of antibiotic is one to five per 10,000 patients. More significantly, one to two per 100,000 patients that were treated with penicillin-based antibiotics suffered fatal anaphylaxis [51].

Gadolinium and iodine in MRI
Gadolinium and iodine are common substances in contrast agents for MRI scanning before and during neurosurgical procedures [54]. These two substances generally have the Gadolinium-based contrast agents (GBCAs) rarely cause immediate drug hypersensitivity reactions (0.001% to 0.01%) [55], but the probability of anaphylaxis increases at high IV concentrations during MRIs but seldom results in fatality (40 deaths out of 51 millions GBCA doses) [56]. When contrast agents do cause reactions, it is presumed that they cause nonspecific histamine release [57]. Immediate reactions occurring most of the time involve erythema and urticaria with or without angioedema.
Mechanisms of immediate reactions are affected by (1) direct membrane effects influenced by ICM osmolality; (2) complement system activation; and (3) formation of bradykinin [58]. Neither hypersensitivity reactions of gadolinium nor iodine are IgE-mediated. Gadolinium hypersensitivity can also cause chronic symptoms secondary to exposure, which can be mistaken for "gadolinium deposition disease" [59]. Severe cases of iodine sensitivity may result in acute kidney injury known as contrast-induced nephropathy. Nonimmediate reactions often result in maculopapular rashes [58]. The recurrence of these hypersensitivity reactions is around 30% [28], and patients are often switched to another contrast agent after signs of an allergic reaction. Knowing the possibility of developing hypersensitivity reactions to GBCA, some recommend skin tests and basophil activation tests prior to brain MRIs to enhance the safety of contrast agent use [15].

Fluorodeoxyglucose (FDG) in PET
FDG is a simple sugar radioactive agent that, when injected into the bloodstream, emits gamma ray energy in PET scans. There are only two documented cases of allergic reactions caused by FDG [60,61]. Adverse reactions by FDG are presumed to be caused by radiation exposure instead of pharmacologic effects. Both cases reported pruritic, erythematous papules on the skin, but only one of the cases observed severe hypotension. Nevertheless, both cases cited that the diagnosis of anaphylaxis caused by FDG is solely based on observation. Tryptase and histamine levels were not obtained to conclude anaphylaxis, nor were skin tests conducted after the reaction to check for FDG hypersensitivity.

SonoVue in CEUS
SonoVue, or microbubbles, are phospholipid shells filled with sulfur hexafluoride gas that enable visualization of tiny vessels in capillary beds [62]. Severe adverse reactions, such as anaphylactic shock and fatality, caused by SonoVue are estimated between 0.0086% and 0.9% [63]. Though hypersensitivity to SonoVue is rare, the few and mild reactions it causes commonly involve skin erythema, tachycardia, and palpitations [62]. Sonovue is often used as an imaging contrast alternative for those with iodinated contrast allergy.

Dural grafts and lyoplants
Dural grafts are safe and common implants used to help develop watertight closures when the native dura cannot be approximated. Bovine dural substitutes in cranial and spinal duraplasty are from the skin, pericardium, or tendon of fetal bovine. The acellular and avascular grafts for a collagen matrix, allowing the growth of host cells [64]. The lyoplant is a dural substitute derived from the bovine pericardium [65]. However, as with any implanted material, dural grafts can generate symptomatic immune reactions [4]. Signs of postsurgical allergic reactions include leukocytosis, slowed recovery, and possible pseudomeningoceles. A rare reaction from bovine graft duraplasty is aseptic allergic eosinophilic meningitis, which exhibits elevated eosinophil and IgE levels. Signs of eosinophilic meningitis range from redness, scaling, and swelling of skin to headaches, nausea, and vomiting [35]. Treatment of eosinophilic meningitis involves reducing inflammation and preventing future infection with corticosteroids, antibiotics, and/or graft explantation [66].

Metals in neuromodulation devices
While it is presumed that hypersensitivity to neuromodulation devices is rare, the true incidence and prevalence is unknown [5]. Implantable neuromodulators are tools that execute neurostimulating therapies, consisting of 3 parts: the implantable pulse generator (IPG), leads, and electrode contacts on the leads [5]. The IPG is often surrounded by a metal casing of pure titanium, and is responsible for conducting voltage and current of circuit. Metal casings also include trace amounts of iron, nickel, tin, antimony, molybdenum, and manganese [29016950]. Leads are usually silver, stainless steel, or nickel to allow for stability and corrosion-resistance in these insulated cables transmitting electrical signals [5].
The most common allergen identified in neuromodulation devices is polyurethane [6]. Reactions to nickel in implanted neuromodulation devices is the most frequent cause of allergic reactions to metals in neurosurgery [5]. Nickel allergies are observed in up to 20% of the patch tested populations [67]. Metal hypersensitivity to Co, Cd, and Zn are a significant complication of implant failure, and lead to further operations for implant removal, as shown in a prospective cohort study following patients with receiving a titanium cranioplasty. Alternative materials, such as polyetheretherketone (PEEK) is indicated in case of metal hypersensitivity [68]. Of all metals present in neuromodulation devices, only titanium comes in direct contact with human tissue and can cause Type IV hypersensitivity reactions -delayed responses that are most commonly encountered causes of allergic contact dermatitis [69]. The most common presentation of hypersensitivity was skin changes -drainage, pain, swelling, impaired wound healing -over the IPG site [6]. Meanwhile, Type I reactions are immediate type urticarial responses common in nickel reactions [5].

Alternative materials Alternatives for titanium implant allergy: PEEK
Titanium's high resistance to corrosion and biocompatibility as an implant makes it the first material of choice for intraosseous use [70]. Its common use as an intraosseous implant has also unveiled the knowledge that titanium can be considered an allergen. Metals, such as titanium, may form bonds with native proteins resulting in haptenic antigens and/or the triggering of degranulation of mastocytes and basophils. The presence of the antigens and triggering of degranulation makes an organism one step closer to developing type I or type IV hypersensitivity [71]. The common allergic reactions observed in literature can range from skin allergic reactions such as urticaria, eczema, or edema, to impaired healing of the fracture site with associated pain, necrosis, or proliferative hyperplastic tissue [72].
Even though guidelines do not specify the administration of a diagnostic test for titanium allergy for patients, it is advised to administer a form of a diagnostic test to those at higher risk of developing hypersensitivity due to a previous history of metal allergic reactions. To those at higher risk of presenting a titanium allergy, it is recommended to perform a metal allergy assessment and allergy testing to avoid a failure of the implant due to a hypersensitivity reaction prior to the placement of a permanent implant [73]. In the case that the failure of implant placement is observed due to an allergic reaction, a reason for this failure must be explored [74]. Any of the signs of allergic reaction discussed above such as urticaria, eczema, edema, or impaired healing [75] are sufficient to acknowledge a possible allergic reaction and allergy testing must be then performed.
Studies are ambiguous over what diagnostic test to confirm a titanium implant allergy, however, we will discuss common diagnostic tools used such as assays and blood tests, as well as future prospects in allergy identification. An allergy blood test can be used to confirm a delayed hypersensitivity reaction with the presence of IgE [76]. The memory lymphocyte immuno-stimulation assay test is a validated test that is able to detect hypersensitivity to titanium and other metals [77]. Future prospects in the diagnosis of titanium allergy include blood tests that can detect allergic reactions based on the measurement of IL-17 and IL-22. IL-17 and IL-22 are released from a T-cell line Th-17 [78] and have been associated with inflammatory diseases and pro-inflammatory effects, respectively [79,80]. Due to their association with inflammatory effects, it would be interesting to develop a blood test that can predict hypersensitivity to titanium metal based on the presence of IL-17 and/or IL-22.
The increasing incidence of titanium hypersensitivity has forced the development of alternative metal substitutes to titanium for implant use. PEEK is a partially crystalline polyaromatic linear thermoplastic that possesses superior mechanical properties and comparable bone-forming capabilities to rough titanium [81]. PEEK has been introduced into neurosurgery with the potential as an alternative to titanium in cranioplasty. Studies have shown that PEEK is a tough, rigid, and biocompatible material, and its mechanical properties provide better protection when used in a cranioplasty [82]. Its modulus of elasticity has been reported to be near the human cortical bone and its strength, stiffness, durability, and inertness contribute to the advantages of using this material in cranioplasty [83].
Looking at three comparative studies [84][85][86] we found differences in success rate, complication rate, cost, cosmetic patient satisfaction, and brain function improvement ( Figure 1). However, we found no differences and/or reported data in days of recovery stay and operation room time (Figure 1). Zhang et al. is the only study we found reporting a change in brain function and cosmetic patient satisfaction [86]. Overall, PEEK seems to be the best choice of material for cranioplasty over titanium. This is explained by its higher success rate, cosmetic patient satisfaction, brain function improvement, and lower complication rate. Nevertheless, it is important to mention that the cost of PEEK for cranioplasty was found to be higher than a titanium implant [87]. Therefore, if a patient presents with a prior history of metal allergies, after confirming titanium allergy through allergy testing, you may use PEEK as an alternative implant material.

Alternatives for dural substitutes
Hypersensitivity reactions associated with dural repair are exceedingly uncommon [4], but preoperative history-taking and allergy screening can identify which dural substitute would be most appropriate for the individual. While there are many options to prevent allergic reactions from bovine-based Lyoplant material [88] xenografts, autografts, and allografts each present their own unique challenges [89]. Patients with bovine allergies may consider autologous fat grafts, allografts from cadavers, or xenografts made from synthetic materials [90]. Synthetic materials are intended to be fine-tuned, more easily manipulated dural substitutes, but possible hypersensitivity to these synthetic xenografts can still impair healing [91]. New absorbable synthetic polymer dural substitutes, such as Cerafix and Chitosan [92], are still being improved to maximize safety and sealing abilities in dural repair [93]. Autologous fat grafts are more biologically compatible, available, and affordable, but also leads to enlarged incisions with higher risks, pain, and discomfort [94].
Though this method is least likely to cause hypersensitivity, it relies on the size and location of the defect and condition of the patient [95]. It was expected that allografts from cadavers would also lessen the likelihood of allergies [96], but hypersensitivity is rare but possible [93]. Furthermore, it can transmit viral infections [97] or Creutzfeldt-Jakob disease [98]. Of all options, synthetic materials are most commonly used to minimize risks of allergic reactions to dural substitutes.

Alternatives for penicillin antibiotic allergy: cefazolin
In the perioperative period, the cross-reactivity between penicillin and cephalosporin should be taken into account when given to a patient with an allergy to penicillin [45]. Cefazolin is a first-line cephalosporin preoperative antibiotic commonly used in surgical procedures as it has been demonstrated to be superior to second-line antibiotics [99,100]. However, cefazolin is known to be one of the most common causes of anaphylaxis in the United States [101]. A retrospective study reported that patients with a verified penicillin allergy did not show a difference in hypersensitivity reactions regardless of the use of penicillin or cephalosporin as a preoperative antibiotic [102]. Interestingly, patients identified to have a cephalosporin allergy were found to have a higher risk of coexisting allergies to both penicillin and cephalosporins [103]. Findings reassure that the use of cephalosporins for patients with unverified penicillin allergy is safe, but confirm that a higher risk of perioperative anaphylaxis exists in patients with verified penicillin allergy when using cephalosporins [104]. These studies summarize that even though cefazolin is one of the most common causes of anaphylaxis, it is not clinically supported to avoid its appropriate use as a perioperative antibiotic in patients that have an unverified and/or low risk for penicillin allergy [98]. Guidelines for patients with a verified and/or high risk of penicillin allergy follow consultations with an allergist prior to administration of either penicillin or cefazolin.

Alternatives for local anesthetics: diphenhydramine hydrochloride
If allergies to "-caine" local anesthetics such as lidocaine or mepivacaine were noted in a medical history, an alternative local anesthetic like diphenhydramine hydrochloride (DPH) is considered to prevent the possibility of a type four hypersensitivity reaction during the procedure [105]. DPH is a first-generation, sedating, oral antihistamine that used as a topical anesthetic can present favorable anesthetic and antipruritic effects. DPH injections have worked as effective local anesthetic due to its chemical structure [105]. A 1% solution of DPH is the recommended dosage when injected for adequate anesthetic usage. Similar to lidocaine, the duration of this drug (15 minutes to 1 hour) and low cost makes it a perfect candidate for dermatological procedures in patients of present allergy history to "-caine" local anesthetics [106].

Conclusion
Although allergic reactions in neurosurgical procedures are rare, they can cause short-term and long-term health effects, impede the recovery process, and even at times be fatal. Materials in neurosurgical procedures overlap with materials widely used in the medical field; thus, potential triggers have been identified through an array of studies exhibiting perioperative hypersensitivity reactions in other surgical specialties. During neurosurgical procedures, patients may be exposed to triggers such as NMBAs, latex, antibiotics, dural substitutes, and metal hardware in implants.
Currently, management of reactions involve (1) securing airway, breathing, and circulation in emergency resuscitation; (2) administering fluids and epinephrine; (3) blood collection for allergy testing; (4) and managing symptoms with corticosteroids, antibiotics, and antihistamines. Allergy screening, such as the skin prick test and provocation tests, can cause potential harm and be inconvenient or expensive to the patient. Considering the low rates of perioperative hypersensitivity reactions resulting in anaphylaxis, preventative allergy screening is not a standard preoperative protocol, unless the patient has a history of relevant allergies. Therefore, a preoperative questionnaire screening for potential allergens that the patient may be exposed to during the procedure can determine if screening tests are necessary. If the screening tests indicate the patient is at high risk of developing a perioperative hypersensitivity reaction, premedication in the form of corticosteroids or antihistamines may be recommended. Screening tests also recognize when an alternative material should be used to diminish the risk of perioperative anaphylaxis and surgical complications leading to fatality. Alternatives discussed in this review include PEEK as a titanium substitute and cefazolin for penicillin.
Based on this review, an increased use of alternatives, development of new alternatives, and preoperative allergy screening is expected to avoid future cases of perioperative anaphylaxis. Possible future research directions could involve studying the prevalence of perioperative allergic complications, specifically in the neurosurgery field. As more allergic complications are observed in neurosurgical patients, a more robust treatment guideline can be established in neurosurgery.  Schematic shows future prevention guidelines with expanded populations undergoing allergy surveillance (history-taking and screening) will increase administration of premedication and subsequently decrease the likelihood of perioperative anaphylaxis, when compared to current prevention guidelines.