**4.1 Introduction and indications**

Direct electrical stimulation of the brain surface is a technique that has regained greater interest worldwide in the past decade than it has had since its introduction by Foerster, Penfield and Rasmussen in 1930 (Foerster 1931, Penfield & Boldrey 1937, Penfield & Erickson 1941, Penfield & Rasmussen 1950). More recently Berger introduced the technique of subcortical stimulation to spare functional white matter bundles that are very often infiltrated by gliomas (Berger 1994). Indeed, refinement of technical equipment and, mostly, the

Multimodal Approach to the Surgical Removal of Gliomas in Eloquent Brain Regions 349

Fig. 5. 63 y.o. woman, transient speech disturbance. A) Preoperative contrast enhanced MR showing an inhomogeneous mass in the white matter of the left fronto-parietal passage. B) Intraoperative picture after cortical mapping (1, 2 speech arrest; 7 anartria; 6 motor area of the mouth; 8, 9 anartria). *Red arrow*: sylvian fissure; *red arrow-head*: central sulcus. The white tags show an area of negative mapping that was chosen to reach the subcortical tumor. Postoperative MR (C with gadolinium and D without) showing complete removal of the

In some cases, CSES can also guide in the detection of the safest route for removing purely subcortical tumors. In these circumstances, the surgeon will choose a non-responsive cortical area to perform cortectomy and then will follow a subcortical corridor by alternating stimulation and dissection until the tumor is exposed. Then resection continues, together with the stimulation and monitoring of neurological function of the patient even during

From a practical point of view, indication for an awake surgery and CSES is primarily based on the localization of the tumor on an anatomical MR followed by confirmation of the activation pattern on fMR. Typical regions that should be considered for intraoperative mapping are the central regions (sensory-motor areas) on both the dominant and nondominant hemispheres. Preoperative neurological evaluation is fundamental to detect any sensory, coordination or muscles strength disturbance. For non-dominant hemisphere tumors in the occipito-temporo-parietal junction we also perform a global neuropsychological evaluation of the visuo-spatial abilities (Rey's tangled figures test, copying, spontaneous drawing, clock drawing test, apraxia tasks, line cancellation test, line bisection test, Diller's letter cancellation test, line completion test). It has been established that awake surgery is mandatory since the patient will experience subjective dysaesthesias and will interact with the surgeon, for motor areas there is still debate. In many centers

tumor. The patient did not present speech disturbance.

stages of non-stimulation (see fig. 5).

availability of ultra-short acting anesthetics and new analgesics, have given a strong impetus to the revival of awake surgery and CSES. The goal of CSES is to detect the areas of the brain that are necessary to a given function. The stimulation of neurons provokes either a positive effect (i.e. movement on contralateral muscles or dysaesthesias) or a suppressive effect (speech arrest, anomia, anarthria). In both cases the aim is to define the effect of the resection of that part of brain in order to avoid deficits. The main use of CSES is for intrinsic brain tumors because cortical and mostly subcortical boundaries are very often impossible to define. Moreover, it has been demonstrated that gliomas are frequently located in eloquent areas, thus they are sometimes treated with only a biopsy or a very limited resection. The availability of the direct control of functional topography during surgical tumor resection not only gives the opportunity to avoid permanent neurological impairment, it can also facilitate a larger extirpation. During resection of a tumor, the surgeon does not have to follow anatomical limits, but will follow functional boundaries (Fig. 4). CSES makes it possible to continuously check the integrity of a circuitry at both the cortical and the subcortical level. The ability to maximize resection while preserving a satisfying functional outcome is of particular interest in brain gliomas for two reasons: first, gliomas mostly affect young adults in full social and working activity, so functional outcome is of the utmost relevance. Second, many different studies (Berger 1994; Keles et al. 2001; Sanai & Berger 2009; Stendel 2009) have by now demonstrated that total or subtotal resection has a clear impact on survival and, for LGG (low grade glioma), on malignant transformation, and that the extent of resection is strongly affected by eloquence of the tumor location (Chang et al. 2008).

Fig. 4. Female, 38 years old suffering from seizures. (A) Preoperative FLAIR MR showing a left large premotor low grade glioma invading also the supplementary motor area. B) Intraoperative picture: the blue line surrounds the tumor cortical margins. 1, 2, 3, 7, 8: motor area of the face; 10: anartria with face contraction; 4, 5, 6: motor area of the hand. 11: speech arrest). No functional site (neither motor nor language) was detected on the surface of the tumor. C) At subcortical level, resection was stopped when descending motor pathway were stimulated (D and C). D) Postoperative MR showing a residue of tumor on the posterior part of the cavity infiltrating descending motor pathways.

availability of ultra-short acting anesthetics and new analgesics, have given a strong impetus to the revival of awake surgery and CSES. The goal of CSES is to detect the areas of the brain that are necessary to a given function. The stimulation of neurons provokes either a positive effect (i.e. movement on contralateral muscles or dysaesthesias) or a suppressive effect (speech arrest, anomia, anarthria). In both cases the aim is to define the effect of the resection of that part of brain in order to avoid deficits. The main use of CSES is for intrinsic brain tumors because cortical and mostly subcortical boundaries are very often impossible to define. Moreover, it has been demonstrated that gliomas are frequently located in eloquent areas, thus they are sometimes treated with only a biopsy or a very limited resection. The availability of the direct control of functional topography during surgical tumor resection not only gives the opportunity to avoid permanent neurological impairment, it can also facilitate a larger extirpation. During resection of a tumor, the surgeon does not have to follow anatomical limits, but will follow functional boundaries (Fig. 4). CSES makes it possible to continuously check the integrity of a circuitry at both the cortical and the subcortical level. The ability to maximize resection while preserving a satisfying functional outcome is of particular interest in brain gliomas for two reasons: first, gliomas mostly affect young adults in full social and working activity, so functional outcome is of the utmost relevance. Second, many different studies (Berger 1994; Keles et al. 2001; Sanai & Berger 2009; Stendel 2009) have by now demonstrated that total or subtotal resection has a clear impact on survival and, for LGG (low grade glioma), on malignant transformation, and that the extent of resection is strongly

Fig. 4. Female, 38 years old suffering from seizures. (A) Preoperative FLAIR MR showing a left large premotor low grade glioma invading also the supplementary motor area. B) Intraoperative picture: the blue line surrounds the tumor cortical margins. 1, 2, 3, 7, 8: motor area of the face; 10: anartria with face contraction; 4, 5, 6: motor area of the hand. 11: speech arrest). No functional site (neither motor nor language) was detected on the surface of the tumor. C) At subcortical level, resection was stopped when descending motor pathway were stimulated (D and C). D) Postoperative MR showing a residue of tumor on the

posterior part of the cavity infiltrating descending motor pathways.

affected by eloquence of the tumor location (Chang et al. 2008).

Fig. 5. 63 y.o. woman, transient speech disturbance. A) Preoperative contrast enhanced MR showing an inhomogeneous mass in the white matter of the left fronto-parietal passage. B) Intraoperative picture after cortical mapping (1, 2 speech arrest; 7 anartria; 6 motor area of the mouth; 8, 9 anartria). *Red arrow*: sylvian fissure; *red arrow-head*: central sulcus. The white tags show an area of negative mapping that was chosen to reach the subcortical tumor. Postoperative MR (C with gadolinium and D without) showing complete removal of the tumor. The patient did not present speech disturbance.

In some cases, CSES can also guide in the detection of the safest route for removing purely subcortical tumors. In these circumstances, the surgeon will choose a non-responsive cortical area to perform cortectomy and then will follow a subcortical corridor by alternating stimulation and dissection until the tumor is exposed. Then resection continues, together with the stimulation and monitoring of neurological function of the patient even during stages of non-stimulation (see fig. 5).

From a practical point of view, indication for an awake surgery and CSES is primarily based on the localization of the tumor on an anatomical MR followed by confirmation of the activation pattern on fMR. Typical regions that should be considered for intraoperative mapping are the central regions (sensory-motor areas) on both the dominant and nondominant hemispheres. Preoperative neurological evaluation is fundamental to detect any sensory, coordination or muscles strength disturbance. For non-dominant hemisphere tumors in the occipito-temporo-parietal junction we also perform a global neuropsychological evaluation of the visuo-spatial abilities (Rey's tangled figures test, copying, spontaneous drawing, clock drawing test, apraxia tasks, line cancellation test, line bisection test, Diller's letter cancellation test, line completion test). It has been established that awake surgery is mandatory since the patient will experience subjective dysaesthesias and will interact with the surgeon, for motor areas there is still debate. In many centers

Multimodal Approach to the Surgical Removal of Gliomas in Eloquent Brain Regions 351

general and anaesthesiological factors that can contraindicate awake surgery are summarized. The idea of undergoing an awake surgery is a source of anxiety for psychologically intact patients. It is essential that a thorough and clear relationship between medical staff and the patient is established and that the patient is correctly informed about every event that he or she is going to experience. Different authors have demonstrated that good preoperative communication is even more effective in alleviating anxiety than

Severe cardio-pulmonary dysfunction (>ASA 3)

The goal of anesthesia is to obtain an easily reversible sedation while maintaining spontaneous respiration. We do not use tracheal masks or other intubation devices. Two large bore venous accesses are sufficient and intra-arterial pressure monitoring is required. Positioning on the operating table is very important and the patient must feel comfortable in order to avoid pain or the need to continuously move. We usually prefer lateral decubitus with the contralateral arm and leg free from drapes so that reaction during stimulation can be easily detected. In men, a urethral catheter is avoided and a condom-like urine reservoir ("Texas catheter") is applied instead. Scalp anesthesia is achieved through nerve block by infiltration of levobupivacaine (0.75%) and mepivacaine (1%). During craniotomy, we sedate spontaneously breathing patients with intravenous remifentanil (0.01 to 0.08 mg/Kg/min) and propofol (0.3 to 1 mg/Kg/h), continuously throughout the procedure. Lidocaine filled cotton paddies are used to locally anesthetize the dura. Before opening the dura, drugs are arrested and the patient is completely awakened. At this time a rapid check of responsiveness and collaboration as well as control of comfort and pain is very important. In case of pain and depending on the site of pain, local anesthetics or intravenous low dose

The craniotomy is targeted to expose the area of the tumor and the motor and/or sensory strips upon which current intensity will be determined by establishing the minimum current required to generate a movement or a dysaesthesia. If the tumor is not visible at the cortical surface, it is important to delineate the superficial projection of its boundaries by using a neuronavigation system or an ultrasound. A bipolar fork, measuring 6 mm in distance between the electrodes (Nimbus, Newmedic, Labege, France), is used to deliver a nondeleterious, biphasic square-wave current in 4-second trains at 60 Hz. We start stimulation at 1 mA and increase by increments of 0.30 mA until the initiation of contralateral face or upper limb movements and paresthesias. Normally no more than 4 mA are necessary to have a positive response. In our experience, factors necessitating higher current intensity are large or deep-seated tumors and the presence of edema. Every positive site is restimulated

Factors predicting difficult intubation

Prior difficult intubation

Generalized anxiety disease

Table 1. General and anesthesiology factors contraindicating awake surgery.

Claustrophobia

Severe obesity Sleep apnea

**4.2 Anesthesia and surgical techniques** 

remifentanil is administered.

preoperative sedative drugs (Egbert 1963; Aglio 2001).

worldwide, neurosurgeons prefer not to operate on awake patients for tumors in motor areas. They argue that the motor responses such as the contraction of muscles do not require a conscious patient. For motor stimulation in an anesthetized patient either the motor evoked potentials (MEPs) method (Kombos et al. 2001; Fujiki et al. 2006; Yoshikawa et al. 2006) or CSES can be chosen. For the former it must be noted that only the action potentials of selected muscles can be controlled, which may hamper both the detection and the avoidance of motor deficits in non-monitored muscles. Furthermore, no information is obtained on the function of cortex adjacent to the central region, and intraoperative evoked potentials presently cannot be used to perform mapping of language or other higher functions. Concerning CSES and the sleeping patient, higher currents are normally required for stimulation, leading to a higher number of intraoperative seizures that can reduce the reliability of mapping. In our experience (Spena et al. 2010) mapping of the motor cortex in an awake patient guarantees more precise cortical and subcortical mapping with a very low risk of intraoperative seizures.

When the tumor is located in the so-called "language areas" (dominant perisylvian, posterior part of F1 and F2, premotor cortex, inferior parietal, posterior temporal, and insular lobes) the first step is to document the hemispheric dominance. A neuropsychological assessment (handedness tests by Edinburgh inventory) and the fMR are sufficient to establish dominance (Stippich et al. 2007). In addition, a detailed and extensive language assessment (Aachen Aphasia Test; WAISS) is necessary to highlight possible subclinical language deficit and to prepare the patients for the intraoperative tests (reading, pictures naming, famous faces naming, counting). At our institution patients with severe motor deficit or language impairments that do not improve after one week of steroid therapy are not considered for awake surgery. This is particularly true for high grade gliomas (HGG) in eloquent areas that more often present with some kind of clinical symptom. These cases merit special consideration because of their natural history and very low survival. In these patients we prefer not to attempt extirpation in cases of low performance status (<70 KPS or >3 Rankin score) unresponsive to steroid drugs; however, we may decide to perform a biopsy. Operating on delicate brain regions often produces a transient deterioration in postoperative status related mostly to manipulation and inflammation, and the presence of rapidly evolving tumors can further impede recovery. Therefore, we can anticipate that a more careful selection of patients with high-grade gliomas located in very delicate regions is the best way to prevent unsatisfying results.

Neurological and neuropsychological tests have a prominent role when treating eloquent area tumor because of different reasons. In general, accumulating information about preoperative neurological and neuropsychological status of the patient gives a great opportunity not only to better document the clinical course and improvements, but also to study the biological behavior of the tumor. In fact, the relapse of a tumor or the passage to a higher grade of malignancies is sometimes predicted by even subtle changes in neuropsychological performance. Moreover, it's fundamental to correlate intraoperative findings with postoperative tests in order to create robust outcome measurements and to document that the resection of a "negative" site has no actual negative effect. That's why tests must be repeated in the early postoperative period (7-10 days) and at least after 3 and 6 months.

Once the surgeon has established the indication for awake surgery, it is very important to consider the patient's general status as well as the psychological profile. In Table 1, some general and anaesthesiological factors that can contraindicate awake surgery are summarized. The idea of undergoing an awake surgery is a source of anxiety for psychologically intact patients. It is essential that a thorough and clear relationship between medical staff and the patient is established and that the patient is correctly informed about every event that he or she is going to experience. Different authors have demonstrated that good preoperative communication is even more effective in alleviating anxiety than preoperative sedative drugs (Egbert 1963; Aglio 2001).


Table 1. General and anesthesiology factors contraindicating awake surgery.
