Awake Surgery for Brain Tumors

Abstract

Surgery is one of the most important steps in most of brain tumors management. In this regard, the extent of resection has been considered as an important prognostic factor. However, the resection may be limited by the presence of functional brain tissue around or in the tumor. Preventing functional damage during brain surgery is essential to keep a good postoperative performance status and for facing the successive steps in brain tumor management (i.e., radio- and/or chemotherapy). This chapter will describe all the procedures around an awake surgery for a brain tumor: from presurgical preparation to postoperative treatments and follow-up. It will not focus only on surgical approaches, but also on the specific aspect of the disciplines that are involved in this procedure.

1. Introduction

Principles of brain tumor surgery consist of the achievement of maximal resection by preserving the function. In this regard, different tools have been developed in the last decades, which help neurosurgeons to achieve that goal. Presurgical functional and anatomical studies, neuronavigation, fluorescence-guided surgery, and intraoperative neurophysiological monitoring (IONM) have become a standard in neuro-oncological surgery.

IONM has not only demonstrated being useful in preserving the function, but also its use is associated with an increase in the extent of resection and an improvement in the quality of life. IONM includes different techniques, and among them, direct cortical and subcortical stimulations in an awake patient are considered as the gold standard for the identification and preservation of functional areas. The information provided by direct cortical and subcortical stimulation in an awake patient cannot be completely substituted by any presurgical imaging or functional study. Therefore, bearing in mind that different complex functions should be preserved to maintain or improve, not only the neurological status, but also the quality of life in each patient, awake surgery for brain tumors is a widespread technique.

This chapter performs a narrative review about awake surgery in brain tumors, addressing the whole procedure (from patient selection to postsurgical rehabilitation) and adding the author’s point of view derived from their own experience.

2. Indications of an awake surgery in brain tumor patients

Awake craniotomy is indicated in any patient with a supratentorial intra-axial lesion adjacent or in eloquent areas, that is, regions with functional importance for the patient, among which, we highlight the motor and language areas. However, there are other functions, relevant and frequently underestimated in patients who are undergoing surgical treatment, such as working memory, attention, mentalizing, semantics [1]. In fact, monitoring during the surgical procedure must be adapted not only to the lesion location, but also to preserve all relevant functions that ensure a good quality of life.

The lesions that are usually operated by awake craniotomy are mainly low- and high-grade gliomas, since in these cases an attempt is made to achieve the maximum tumor resection with the least possible neurological damage (overall survival is related to the extent of tumor resection). However, it is also used in patients with refractory epilepsy, deep brain stimulation, and vascular injury surgery, especially arteriovenous malformations [2].

Regarding glial lesions, there is controversy in the indication of awake surgery in tumor recurrences, but there are several studies that confirm that glioma recurrence surgery does not provide neuropsychological sequelae, since no significant differences are detected in the pre- and post-surgical neuropsychological status of the patient in his/her first- and second-surgery [1].

Until a few years ago, patients with right hemisphere lesions were usually operated under general anesthesia, except if it was necessary to monitor sensorimotor function and motor evoked potentials or somatosensory evoked potentials were not available. However, to maintain the quality of life of brain tumor patients, it is also necessary to preserve other functions (visuospatial function, executive functions such as memory, attention, judgment). For this reason, nowadays the benefit of an awake craniotomy is considered for all patients with a supratentorial glial lesion, regardless of their location (dominant or non-dominant hemisphere).

Therefore, the awake surgery aims to maximize the extent of resection (EOR) but mainly preserve (but not restricted to) the following functions:

Sensorimotor function. It is considered when the lesion is located within or adjacent to the perirrollandic cortex, the supplementary motor area, or the corticospinal tract. Direct electrostimulation (DES) has elucidated the complexity and breadth of motor function. The corticospinal tracts present a somatotopic organization, like the supplementary motor network, responsible for stopping or accelerating movement when stimulated in awake patients [3]. Furthermore, there is evidence of bilateral motor responses caused by unilateral subcortical stimulation, which indicates the existence of a wide and complex bilateral cortico-subcortical network that connects premotor areas, basal ganglia, and spinal cord to control bimanual coordination, language, movement, and cognition [4].

Likewise, the use of DES has demonstrated motor interference when stimulating sensitive tracts, probably related to transient inhibition of fibers, indicating the existence of a wide fronto-thalamic-parietal network involved in sensorimotor control [3].

Visual area. Direct stimulation of optical radiation can cause a temporary visual field deficit (homonymous hemianopia) if the stimulation is of the fibers that connect with the calcarine fissure, or visual hallucinations if the stimulation is of the fibers that connect with the association visual cortex, involved in visual processing [3].

Language. Since the introduction of direct intraoperative cortical and subcortical stimulation, Broca-Wernicke’s model (“localizationist model”) has been re-evaluated, providing a new model based on the existence of multiple interconnected direct and indirect cortico-subcortical networks involved in phonological, articulatory, syntactic, and semantic processes [5]. Theoretically, there is a dual-flow language model: a ventral pathway (semantics) and a dorsal pathway (phonological and articulatory processes). The dorsal pathway is projected toward the parietal and inferior frontal lobe, involving the superior longitudinal fasciculus (DES) and the arcuate fasciculus (AF) as white matter pathways [6]. During the picture-naming task, the DES of the inferior parietal lobe and inferior frontal gyrus is associated with the appearance of phonological paraphasias, while cortical stimulation of the ventral premotor cortex, supramarginal gyrus, and posterior portion of the superior temporal gyrus generates articulatory mistakes. Likewise, AF stimulation causes conduction aphasia and SLF has been implicated in working phonological memory, essential for learning new words and syntactic processing. In the ventral or semantic pathway, one has to consider the role of the inferior fronto-occipital fascicle (IFOF) and an indirect circuit composed of the inferior longitudinal fascicle (ILF), temporal pole, and the uncinate fasciculus (UF). IFOF stimulation during the picture-naming task leads to semantic paraphasias [7] and can also produce verbal perseveration, suggesting a role in semantic control [8]. The indirect circuit (ILF and UF) participates in verbal semantic processing and the posterior portion of the ILF is important for visual recognition and reading [9].

Others. Depending on the patient’s profile, the cortico-subcortical mapping can be adapted to preserve specific functions that may be associated with the self-perceived quality of life. For example, multi-language mapping and the ability to voluntarily switch languages, mathematical calculation in teachers, music processing and interpretation in musicians, visuospatial perception in dancers, or bimanual coordination in pianists.

2.1 Contraindications

The only absolute contraindication for awake craniotomy is the patient’s denial of it. Relative contraindications include the following: neurological causes (severe dysphasia, drowsiness, confusional state, or cognitive disorders that limit patient collaboration); claustrophobia; psychiatric instability; tumor characteristics (large size producing midline displacement >2 cm or highly vascularized lesions); difficulties to control the airway (uncontrollable cough, morbid obesity, obstructive apnea); and medical conditions that associate with high surgical risk and contraindicate any type of neurosurgical intervention. Age is not considered a contraindication for awake craniotomy (ages recorded in the last 10 years range from 9 to 90 years) [1].

2.2 Advantages and disadvantages

The main objective of glioma surgery is to improve overall survival and quality of life by maximizing tumor resection and it is known that awake surgery, with direct cortical and subcortical electrostimulation, allows locating and protecting the relevant functions for each patient. Thus, greater and safer resection can be achieved, by reducing postoperative sequelae and improving the prognosis.

Awake surgery has been demonstrated to reduce morbidity and mortality, with better control of postsurgical seizures and a higher postsurgical Karnofsky performance status (KPS). All of this leads to a shorter hospital stay and lower healthcare costs.

The main disadvantage that may be associated with awake surgery is the emotional stress for the patient (10–40% of patients experienced anxiety perioperatively) and up to 30% reported pain during the procedure [10].

3. Presurgical preparation for an awake surgery

3.1 Neuropsychological evaluation

Awake surgery for brain tumors aims to extend the life of the patient, preserve their capabilities, functionality, and quality of life through real-time intra-surgical monitoring of sensorimotor, visuospatial, language, executive, and behavioral functions [11]. For this reason, pre- and intrasurgical work requires careful preparation in which different professionals are involved: neurosurgeon, anesthesiologist, neuropsychologist. Regarding the work of neuropsychology, the importance of its role in awake brain surgeries has been already highlighted in international protocols [12].

The presurgical neuropsychological evaluation allows to know the psychological, cognitive, and functional state of the person. A presurgical neuropsychological evaluation should include the following aspects:

Personal aspects: Decision-making capacity, previous experiences (especially with cancer), disposition of social and family resources, coping strategies, personality type, substance abuse, patient expectations in relation to surgery, and their disease or stress level.

Emotional aspects: It will especially affect the presence of anxiety. Anxiety may be related to the patient’s own characteristics but also to the uncertainty associated with the disease and/or the procedure, fear, or the lack of perception of control. This is a factor that can affect attention/concentration capacity and leads to emission mistakes and generates difficulties in establishing the baseline and surgical intervention. Depressive symptoms should also be evaluated. These symptoms may be related to the tumor pathology itself, the difficult adaptation process, or other characteristics or circumstances of the patient. In any case, the preparation of a depressed patient will always require a higher level of attention from the staff.

As Boele et al. highlighted, a wide range of brain tumor patients present psychotic symptoms or hallucinations that should also be explored before surgery as well as a decrease in the level of arousal, irritability, or agitation [13].

Cognitive factors: The evaluation of these aspects will allow the establishment of a baseline and increase the chances of success during the intervention. Some cognitive functions have been described as basic for the correct participation of a patient in awake surgery [14]. A complete neuropsychological evaluation allows to examine normal or impaired performance and determine the strengths and weaknesses that a patient has, as well as the implications that their cognitive deficits have so that they can reintegrate, in the best way, in the activities of their daily life or at the same time. In any case, a minimum evaluation protocol should include the analysis of the following: attentional processes, language in all its aspects, amnestic processes, executive functions, and perceptual abilities. A fluent language to express oneself and be able to communicate cognitive and physical alterations and discomfort during surgery; verbal comprehension for cooperation and following instructions; memory to guarantee the storage of information and instructions to follow during the surgery; care for the performance of intraoperative activities and visual skills in case of picture-naming tasks is needed.

Most studies show that language is the cognitive domain that has been most evaluated in awake surgery. However, in recent years various tests have already been used to map other cognitive functions, such as visuospatial functions, calculation, emotions, facial recognition, or executive functions. This fact, together with the great diversity of psychological variables that must be evaluated, makes it necessary to have a neuropsychology professional within the multidisciplinary team involved in the management of awake brain surgery candidate patient. In our team, the neuropsychologist is the expert who not only supports the patient in this surgical situation but is also the professional who must determine if the affectation observed during the mapping is due to electrostimulation or if it is caused by other causes, such as problems to concentrate or psychological factors.

3.2 Task selection and adaptation

The selection of tasks for intraoperative monitoring is done during the presurgical phase considering the location of the lesion, the age, and the educational-cultural level of the patient and cognitive abilities. To minimize the risk of false positives, only those items in which the patient performs flawlessly will be selected.

Using language domain as an example of function monitored during an awake surgery, the most common tasks used are naming objects, counting, naming verbs, naming famous people, reading sequences, naming colors, naming days of the week or months of the year, or repetition. These tasks can be associated with other motor control tasks such as the movement of an arm or tapping tasks or previous tasks such as promoting spontaneous language through a conversation about the patient’s life (with information that has been obtained in the presurgical evaluation), or if the patient is comfortable or feels pain or cold, etc.

Regarding language monitoring, one must bear in mind:

Language without semantic content: Automatic speech tasks require motor planning and articulatory processing. To evaluate this type of language, the patient is encouraged to recall the numbers from 1 to 20 or to say the months of the year. This type of tasks uses overlearned sequences of words. Repetition of phonemes quickly (e.g., Fa-Ma-Ba) or word/nonword repetition can also be used.

Lexico-semantic processes: The most frequently used task is the presentation of drawings or pictures of objects for naming. In several studies, an introductory phrase has been added (this is a …). Following Ojemann and Mateer, adding the introductory phrase allows us to distinguish between an anomic error and a speech arrest, but a failure could be the result of an orthographic mistake or an inability to read. Another frequently used task is action-naming [15]. A drawing, image, or video of a person performing an action are presented to the patient and the patient must name the action in the infinitive. The famous face naming requires the same processes as object naming, adding facial recognition and access to biographical information. Auditory object naming is used too. In this case, the patient hears a description of the object and its use, and then it must be named.

The pyramids and palms test is frequently used in intrasurgical monitoring. The patient must choose between two stimuli that are associated with an image presented at the top of the screen. This test allows to know the capacity of access to the semantic information of the pictures and the words and associate this information.

Grammatical processes: Naming actions (already described previously) have been used frequently. Other tasks are reading sentences slowly or complete sentences, in which one word is missing (to allows assess different grammatical), sentence repetition, writing sentences.

3.3 Evaluation of presurgical imaging studies

When the decision to perform an awake surgery must be taken, one can use the information provided by a set of tools that allow us to decide the degree of eloquence for a specific function. The location of the lesion or the clinical information is not enough to evaluate the relationship between the lesion and its functional boundaries.

However, in this point, it is essential to define more precisely what we understand as an “eloquent area.” This concept has significantly evolved in the last decades, from considering eloquent areas only those involved in motor control and language, to considering other regions involved in sensorial and cognitive processing. The evolution of this concept is also associated with the better understanding of brain function that has currently been achieved. The “localizationist” vision has again been abandoned and substituted by an hodotopic view, where connectivity between one brain regions to another becomes relevant to the development of a function [16]. Furthermore, the hodotopic model includes a dynamic representation of functional systems (i.e., that change with time), fitting better with the current knowledge in brain plasticity. Therefore, an “eloquent area” can be considered as the gray matter and white matter pathways that are essential for the development of a specific function that, in the personal context of each patient, must be preserved. Each “eloquent area” can change its location with time, thanks to brain plasticity mechanisms that are activated in disease situations.

The identification of eloquent areas before a surgical procedure for a brain tumor may help in different ways:

1. To identify the anatomical relationship between the tumor and eloquent areas.

2. To decide which tasks are the most appropriate to activate eloquent areas involved in a specific function.

3. To establish an anatomic and functional map of gray matter regions and white matter pathways that is useful for the planification of the surgery.

4. To evidence the existence of functional migration to nonexpected location secondary to the plasticity mechanisms.

One of the tools that have demonstrated to be useful in achieving these aims is magnetic resonance imaging (MRI) [17]. The use of this technique is widely extended, and it constitutes an essential part of the diagnostic protocol of a brain lesion. Apart from the images acquired for diagnosis, additional sequences and procedures can be performed to obtain functional information. More specifically, the use of functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) allows us to identify cortical regions and white matter tracts, respectively, that are involved in specific functions [18].

Functional MRI is based on the detection of changes in magnetization secondary to the levels of oxyhemoglobin, which increases in brain regions whose neurons increase their activity to be able to perform a specific task. fMRI has been demonstrated to be useful in the identification of the somato-motor regions using simple motor tasks with high sensitivity and specificity. However, the reported values of sensitivity and specificity for the identification of language processing areas are much lower. This difference is more pronounced during the evaluation of the sensitive component of this complex task. Furthermore, there is also a lack of evidence about the use of fMRI to map the regions involved in other cognitive tasks in patients with a brain tumor, although a significant amount of literature has described the relationship between the activities in specific regions with a specific function, but they are all in the research environment. In this regard, the development of new language tasks or paradigms to be used in fMRI studies might improve the reliability of the information provided by this technique. In the same way, cognitive tasks adapted to fMRI should be tested in brain tumor patients, to identify their usefulness in presurgical brain mapping.

Regarding the selection of fMRI tasks for presurgical mapping, one must bear in mind that there is a significant restriction of movement inside the scanner; thus, the selected task must not be associated with the excessive movement. Furthermore, we consider that the fMRI task should be as similar as possible to the task that is going to be performed during the surgical procedure.

The combination of fMRI with DTI would give us much information that may be useful to predict the cortical regions that will be positive during stimulation as well as the white matter tracts that are associated with the tumor. All this information will help us to decide which tasks will be used during the procedure; to decide the location and the size of the craniotomy; to predict the entry point to perform the corticectomy; and to give a precise information to the patient and relatives about the risks and prognosis.

3.4 Training and preparation of the patient

Once an awake craniotomy is considered for a patient, a multidisciplinary team should discuss about the feasibility of performing this procedure in this patient. The multidisciplinary team includes, necessarily, anesthesiologists, neuropsychologists/speech therapists, and neurosurgeons. Additionally, this team could also include radiologists and clinical psychologists. These professionals would finally decide if the patient is a good candidate for an awake surgery and they will plan the training of the patients for the procedure.

Keeping awake during the whole or part of a surgical procedure that involves the brain is an additional stress not only for the patient but also for the surgical team. This stress would be associated with the beliefs or expectations that may have the patient in terms of pain, immobility, or the experiencing of intraoperative complex situations. Regarding the surgical team, the lack of familiarity with the procedure may hinder the anticipation of possible complications that may appear during the surgery.

Bearing all this in mind, to achieve a successful procedure, it is essential that both the patient and the surgical team have to be instructed and trained before the surgery.

Regarding the surgical team, the ideal would be to designate a specific team for this kind of surgery. A group of anesthesiologists, surgeons, and nurses, after adequate training, should accumulate experience in such procedures, avoiding global changes in the members of the team, but allowing the occasional participation of new members to acquire experience.

On the other hand, regarding the training of the patient, we consider that he/she must know and understand the purpose of each step of the procedure. The patient must understand why an awake surgery is planned and what are its aims. After that, the patient must be explained in detail how the procedure will be taken place, from the arrival to the surgical area, to the admission in the postsurgical area. Apart from all the explanations, it is adequate to perform a specific training that should include the tasks that have been selected for the surgery, the positioning, and the layout of the operating room. In this sense, it is advisable that this training is performed in simulation conditions, mimicking the conditions that the patient will find during the surgery.

In our center, the training of the selected tasks is performed by the same neuropsychologist who has evaluated the patient and who is going to be during the surgery. This reinforces the link between the patient and the professional and contributes in reducing the anxiety and stress related to the procedure. Furthermore, the neuropsychologist can use the training sessions to adapt the tasks to the situation and features of the patient. This may lead to a more efficient procedure, thus lesser surgical times. The simulation of the procedure (positioning and operating room distribution) is performed in a room with a stretcher and with furniture that mimics those, we found in an operating room. The patient is explained about the positioning and is indicated about the interlocutors during the surgery. This may help to know the people with whom the patient must communicate with. The number of training sessions is adjusted by the functional and cognitive status of each patient. We usually recommend at least two training sessions for tasks and two for simulating the procedure.

3.5 Surgery planning

The plan of the surgery should consider different aspects:

1. The aim of the surgery (resection vs. biopsy).

   Most of the awake surgeries are performed to maximize the extent of tumor resection, but, in some cases, an awake surgery may be indicated for a biopsy. This is the case of lesions located in or near eloquent regions and/or the patient may not be in good condition for a long surgery. In those cases, less time will be required for the surgery and probably only direct cortical stimulation will be performed.

2. The clinical status of the patient (including cognitive evaluation).

   As it was previously explained, a complete cognitive evaluation is mandatory in any patient considered for awake surgery. This evaluation added to the clinical assessment will draw a precise picture of the clinical situation of the patient, determining the functional and cognitive state of the patient. In our experience, patients, who present any neurological or cognitive deficit, usually present shorter periods of adequate attention and collaboration in performing the selected tasks, independently of precise anesthetic management. In other words, patients with functional or cognitive dysfunction usually show fatigue symptoms before the patients without the neurological impairment. This must be considered in the planification of the procedure, trying to shorten the presurgical period (vascular accesses, material preparation, patient positioning, surgical field preparation), and the surgical approach (cutaneous phase and craniotomy). Bearing this in mind, the first DCS will be performed in a brief period and, if the surgery course is adequately developed, the subcortical stimulation may also start sooner. This can limit the negative effect of fatigue in the development of awake surgery.

3. Structural and functional findings of presurgical studies.

   DTI for tractography and fMRI studies have both a significant role in surgical planning. DTI studies are useful to identify the white matter pathways around or in the tumor, while the fMRI allows identifying cortical regions that are functionally involved in specific tasks. Both imaging techniques may help us to decide the size and location of the craniotomy, as well as the place of the corticectomy. They also allow us to predict the result of the direct cortical and subcortical stimulation.

Regarding these considerations, an awake procedure should fulfill the following premises:

• The procedure must be safe.

• The patient must not feel pain or discomfort.

• The patient must not feel anxiety or fear.

• The procedure must be efficient regarding time.

4. Anesthetic considerations in awake surgery

The role of the anesthesiologist during awake brain surgery is to ensure that the patient can actively and comfortably participate in tasks during DCS in a comfortable way. As we previously indicated, the first thing when considering awake surgery is to make a correct patient selection through a prior clinical and neuropsychological evaluation. It is essential to assess the airway and inquire about sleep apnea, cognitive impairment, psychiatric disorders, and to know the neurological deficits that the patient presents before the surgery.

4.1 Anesthetic modalities for performing awake brain tumor surgery

There are three anesthetic modalities that may be considered for an awake surgery: asleep-awake-asleep, conscious sedation, and completely awake.

4.1.1 Asleep-awake-asleep

It consists of general anesthesia in the initial phase, waking up the patient during stimulation/mapping and subsequently, reintroducing general anesthesia for closure. During the general anesthesia phase, the ideal is to achieve airway control with a laryngeal mask (it offers advantages over the placement of a tracheal tube as it is easier to place, avoids head extension, and associates less risk of coughing with vomiting).

Generally, this anesthetic modality is achieved with the use of propofol and remifentanil, since they are short-acting drugs and allow sedation with rapid awakening (5–20 min). The great advantage of propofol is its rapid recovery and a titratable sedative effect, which helps to avoid excessive and unnecessary sedation, but also reduces intracranial pressure and has anti-seizure and anti-emetic properties [19]. In the case of propofol, the infusion should be stopped 15 minutes before the onset of cortical stimulation in adults, 20 minutes before in children [2], and should be restarted for dura closure. It is usually given in combination with a low dose of remifentanil.

The advantages of this modality are better airway control and adequate deep sedation with greater comfort for the patient in the initial phases. In fact, this is the modality that best adjusts to prolonged procedures (>5 h). However, the drawbacks include the complexity involved in repositioning the device in the airway for closure and that general anesthesia increases the risk of hypoventilation, nausea, and agitation during brain mapping [2, 20].

4.1.2 Conscious sedation

It consists of the administration of sedation during the first stage of the awake craniotomy without airway control (patient breathes spontaneously) [20]. A combination of propofol and remifentanil has been the standard for sedation, but it has been associated with a higher risk of respiratory depression. Dexmedetomidine, a selective alpha2 agonist with sedative, anxiolytic, analgesic, and opioid-sparing properties, has recently been shown to provide easily reversible sedation without associated ventilation depression risk [21]. Likewise, compared with the propofol-remifentanil combination, it reduces the incidence of vomiting and coughing, increasing patient comfort during surgery, and facilitating surgical resection by reducing cerebral blood flow [2]. The advantages and disadvantages of this anesthetic modality are registered in Table 1.

	Asleep-awake-asleep	Conscious sedation	Awake
Advantages	Good airway control	No adverse effects of sedation	Less adverse effects tan AAA
	Greater comfort for the patient	Better communication with the patient	Greater comfort in adjusting the patient’s position
	Preferable for prolonged procedures (> 5 h)	Less postoperative pain
Disadvantages	Complexity for device repositioning in the airway.	Not recommended for long-term procedures	Not recommended for long-term procedures
	Increased risk of vomiting, agitation, hypoventilation	Worse airway control	Worse airway control
		Requires more collaboration from the patient	Requires more collaboration from the patient

Table 1.

Advantages and disadvantages of each anesthetic modality for awake brain surgery.

4.1.3 Awake

This modality is the least commonly used. It consists of using local anesthesia and avoiding sedation in any of the stages of surgery with the idea of avoiding the inconveniences of general anesthesia/sedation. It raises the option of avoiding pain, through the infiltration of the scalp and selective blocking of the trigeminal sensory branches [2]. In addition to reducing postoperative pain, it has the great advantage of being able to optimize patient position and improve considerably communication with the patient by avoiding sedative medication [20, 22]. In these cases, some protocols propose the use of hypnosis to produce a dissociative state [23, 24]. The advantages and disadvantages of this anesthetic modality are registered in Table 1.

4.2 Anesthetic monitoring during the procedure. Complications

Premedication is not standardized. Corticosteroids are often used to reduce the mass effect of the tumor lesion and nausea. The risk of seizures is higher than standard surgery due to DCS; thus, anticonvulsant therapy is also usually administered prophylactically, although there is not enough literature evidence to support this indication.

In addition to premedication, it is essential to carry out rigorous anesthetic monitoring during the procedure. This monitoring should include electrocardiogram, invasive blood pressure measurement, pulse oximetry, respiratory rate, capnography, temperature, urinary catheterization, and BIS encephalographic recording.

Although it is usually a safe procedure in experienced professionals, some intraoperative complications related to the anesthetic procedure may occur: seizures (3–30%), high blood pressure (17–24%), desaturation/hypoventilation (7–16%), nausea and vomiting (0–9%), and brain swelling (7–14%) [25]. However, the conversion to a general anesthesia procedure only occurs in less than 2% of surgeries and there is no relationship between failure rate and the type of anesthetic modality [26].

5. Development of awake brain tumor surgery

5.1 Surgical field preparation

Awake surgery involves several specialists (neurophysiologists, neuropsychologists, surgeons, anesthesiologists, nurses) that must stay together in the operating room; thus, an adequate distribution of the space is essential. First, the position of the patient must ensure not only its comfort but also access to the surgical field; an access to the airway and vascular catheters; and the possibility to perform the corresponding tasks during the procedure. As in any operation, care must be taken to avoid nerve, vascular, ischemic, and musculo-ligamentous injuries related to compression or traction.

Regarding positioning, the most common position for temporal, insular, and low frontoparietal lesions is the patient lying supine with slight lateralization toward the contralateral side of the lesion with cephalic support (Mayfield®, Integra), with the contralateral arm extended and the ipsilateral resting on the body. If the lesion is in the frontal or parietal lobes, it is also possible to use a semi-sitting supine position.

After confirming that the patient is comfortable, the surgical field is prepared. The first step is to remove the hair that interferes with the opening and closure of the skin incision, preferably with an electric razor, followed by washing with antiseptic shampoo. Then, the skin is cleaned with antiseptic (povidone Iodine or chlorhexidine) for three times. Subsequently, the drapes are placed to isolate the surgical field, preferably using a sterile and transparent paper that is placed toward the basal side; in this way, we allow the surgeon to have visual access to the content that is being shown to the patient in any moment.

5.2 Local anesthesia and regional block

Regardless of the anesthetic modality, local anesthesia must also be used. Bupivacaine, mepivacaine, levo-bupivacine, and lidocaine are the local anesthetics most frequently used in skull surgery. Lidocaine is very useful for dura mater infiltration, but it increases the risk of seizures. The use of an anesthetic with a vasoconstrictor reduces the risk of bleeding, ensures a prolonged duration, and reduces the risk of toxicity (once infiltrated, it is necessary to wait 15 minutes to rule out acute toxicity). The total amount of local anesthetic use during the procedure will be determined by the patient’s weight, comorbidities, and the concentration of the anesthetic.

Bearing in mind the locations for local anesthesia, the infiltration of the head support anchor points and infiltration of the skin incision is recommended. If we want to achieve a selective blockade (more effective for pain control during the procedure), the following locations should be also infiltrated:

• Supraorbital and supratrochlear nerves (branch of the frontal nerve).

• Zygomatic-temporal nerve (terminal branch of the zygomatic nerve).

• Temporal auricle and great occipital nerve (posterior branch of C2).

• Occipital minor (anterior branches of C2–C3).

In long-term procedures, the appearance of pain in the temporal area and its relationship with the manipulation of the dura mater are common. In these cases, additional infiltration of the zygomatic-temporal branch is recommended.

5.3 Brain mapping

Direct cortical and subcortical stimulation is used to identify the cortical regions and tracts involved in the functions we are interested in. This stimulation produces depolarization of a specific region, leading to a neuronal excitation by current diffusion, both anti- and orthodromic. The stimulation can be performed using bipolar or monopolar probes. Bipolar stimulation is performed using a pair of 2-mm-tip stimulators with 5 mm of separation between tips. This is considered a more precise method for stimulation than monopolar (2–3 mm single-tip stimulator). However, when a more precise sensorimotor mapping is going to be performed, monopolar stimulation is preferred, because the use of bipolar probes may result in ambiguous spatial distribution.

The stimulation is initiated from 1.5 to 2 mA and progressively increases 0.5 mA to achieve 6 mA of stimulation current when no response is observed. The generator supplies a constant current with biphasic quadratic waves of 1.25 ms in 4-second trains at 60 Hz. Subcortical stimulation must be done each 2 mm of resected tumor near eloquent areas.

Regions considered with positive stimulation are those where a disruption during the performance of the task is observed during the stimulation. Those regions will be identified by using a kind of marker. The positive region covered approximately 1 cm² around the position of the tip of the stimulator.

Apart from the direct stimulation, in most of the centers that awake surgeries with direct stimulation are performed, electrocorticography is usually performed for the detection of after-discharge potentials, which are a subclinical indicator of epileptic activity.

During brain mapping, we do not usually use mannitol or hypertonic saline to avoid brain shift and changes in the elastance of the brain that may influence the results of mapping or make the dissection of the lesion more difficult. Furthermore, if subarachnoid dissections must be done, we perform it once the lesion is functionally disconnected from subcortical pathways because the excessive release of cephalo-spinal fluid may also influence the results of mapping.

5.4 Concomitant use of other tools to maximize the degree of resection

Brain mapping during an awake procedure can also be combined with other techniques or tools that are useful in brain tumor resection. Image-guided surgery, using neuronavigation or real-time imaging systems (intraoperative MRI or ultrasound), is perfectly compatible with awake surgery. On the other hand, the use of fluorescent compounds (5 aminolevulinic acid, fluorescein, or indocyanine green), which allows to identify the areas of tumor invasion or regions where the blood-brain barrier is disrupted, can also be used during awake surgeries. In any case, the limitations of the resection will always be defined by the functional boundaries established by the direct cortical and subcortical stimulation during task performance.

5.5 Continuous evaluation of patient’s feedback

It is essential to maintain continuous communication with the patient during the surgery. The key to succeeding in an awake surgery lies in adequate preparation of the patient; adequate control of sedation levels; the correct use of analgesia; and ensuring a comfortable position for the patient. Therefore, continuous monitoring of all these aspects contributes to achieve good results in awake surgery for brain tumor.

6. Postsurgical follow-up after an awake surgery

6.1 Cognitive follow-up

Apart from the regular clinical-radiological assessment after the surgery, a neuropsychological evaluation is particularly important in patients who have been operated awake.

Cognitive deficits are one of the most frequent symptoms in patients with brain tumors, mainly in attention, memory, language, and executive functions. These deficits may not only be present before surgery but can also appear after it because of the tumor itself or due to the surgical procedure. Cognitive dysfunction negatively impacts the quality of life of patients and their reincorporation into their daily functioning. Therefore, it is necessary to plan an intervention adapted to the circumstances of each patient.

Neuropsychological rehabilitation combines the application of cognitive intervention strategies and compensatory systems. These targeted strategies reduce emotional problems and promote socio-labor integration. According to scientific evidence, effective intervention methods are those that combine metacognitive and emotional regulation strategies and generalization of their effects on daily life [27, 28]. These interventions combine psychoeducational programs (providing information on cognitive functioning and their consequences in daily life, from both the patients and their families) with direct or compensatory training of the affected functions and environmental strategies (focused on restructuring the patient’s environment to meet the new demands of daily activity).

6.2 Optimization of postsurgical rehabilitation in the context of adjuvant treatments

After any brain surgery, even when it has not been associated with any complication, a recovery period for normal brain function is needed. Sometimes, the improvement in the neurological function appears immediately after the surgery because the de-lesion was producing a mass effect or dysfunction in the surrounding regions. However, it is relatively common that, after surgery, brain tumor patients (mainly those whose lesion is in or near eloquent regions, as those who present an indication for an awake procedure) show a worsening in some neurological functions, even when the mapping technique and the surgery have been adequately performed. In fact, a worsening in language function has been reported in 14–50% of patients, but 78–100% of patients have recovered a normal function at 1 month. Furthermore, postsurgical transitory cognitive dysfunction in 55% of patients treated with an awake procedure has been reported. This worsening is associated with the increase of edema related to surgical handling, as well as the presence of blood resting in the tumor cavity. In our experience, this worsening is normally higher in patients with high- than low-grade gliomas.

In any case, after the surgery, a recovery period must be considered in all patients, which may include the indication of simple tasks to facilitate the spontaneous recovery process or an organized rehabilitation program. This therapy would try to accelerate and/or modify brain plasticity mechanisms to make them more efficient. However, the recovery period after brain surgery may be truncated or limit their effectiveness due to the use of other oncological adjuvant treatments. More specifically, the early use of radiotherapy in low- and high-grade gliomas or brain metastasis may slow the normal process of recovery down by damaging and limiting the development of brain plasticity mechanisms. From a tumoral biology point of view, the best moment for applying radiotherapy is in the first 4–6 weeks after the surgery. Plasticity mechanisms can develop until 8–12 weeks after surgery; thus, radiotherapy may constitute a limitation in the recovery capacity of neuro-oncological patients. This aspect may be considered in future studies because if the surgical aim is to achieve the maximal extent of resection but preserving the function, adjuvant treatments should not undermine what surgery has achieved. In this regard, we consider that radiotherapy should be delayed as much as possible, without limiting its effectiveness related to tumor biology. On the other hand, the rehabilitation program should start as soon as possible after the surgery, in an intensive and integrative manner. This will allow us to take advantage of the “plasticity window” after the surgery. In any case, it would be useful to identify serological or imaging neural plasticity biomarkers for a better follow-up, to decide the best moment to start the rest of the oncological treatments.

7. Conclusions

Awake surgery for a brain tumor is a safe procedure that should be considered in all patients with a brain tumor whose neurological function may be compromised during the surgical procedure, especially in those cases in which the function that must be preserved cannot be monitored under general anesthesia. The implication of a multidisciplinary team, a presurgical training period, and a standardized surgical protocol are essentials for the success of the procedure. Finally, adequate recovery periods, attending to brain plasticity mechanisms, must be considered in each patient by appropriately scheduling the rest of adjuvant treatments.