**4.2 Anesthesia and surgical techniques**

350 Advances in the Biology, Imaging and Therapies for Glioblastoma

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

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

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

risk of intraoperative seizures.

months.

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 remifentanil is administered.

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

Multimodal Approach to the Surgical Removal of Gliomas in Eloquent Brain Regions 353

Undoubtedly, CSES has gained a prominent role in neurosurgery above all because a large number of studies worldwide have shown a clear advantage in terms of usefulness, safety, and neurological and oncological outcomes (Berger 1994; Duffau et al. 2005; Duffau 2006; Kim et al. 2009; Sanai & Berger 2009; De Benedictis et al. 2010; Spena et al. 2010). The spatial accuracy and the ability to perform functional resection (that is, a resection in which limits are represented by spared functions) have met the approval of many neurosurgeons, who now use CSES routinely. However, there are some technical and methodological drawbacks of CSES that have yet to be addressed. First, the application of an electric current on the brain can have effects that are more complex than anticipated. For example, the excitation of the stimulated cortex can diffuse to near or far cortex by short or long-range white matter tracts. Consequently, the observed effect of the stimulation may not be related (or not only) to that portion of a gyrus. In this case the tumor resection might be prematurely arrested. At the same time, at which point is the surgeon sure that a functional area is essential and cannot be substituted by other epicenters? The concept of plasticity can explain recovery after various brain injuries, but the stimulation of a functional site intraoperatively cannot give information about the brain's potential to substitute that site. Another highly debated issue in CSES is the technique of negative stimulation, which means pursuing resection where no positive site is detected. Although results of such strategy have been encouraging (Sanai & Berger 2008; Kim et al. 2009), the question arises concerning the possibility of missing a positive site because of a false negative result during the intraoperative tests. This is especially true for cognitive functions, given that an awake patient has a limited time span for testing before fatigue arrives (normally no more than 90 minutes in our experience). Further, intraoperative cognitive tests (language, calculation, writing, visuo-spatial abilities) are limited to very simple tasks that cannot account for more complex functions. From this point of view, fMR allows a more comprehensive analysis of brain function because all the epicenters involved during a specific task are visualized and a real-time mapping is generated. If this represents a limitation of the spatial accuracy of fMR for surgical planning, at the same time it offers a means to non-invasively study a patient pre- and postoperatively, which is undoubtedly a unique opportunity to gain precious insights into

functional organization and post-lesional adaptation at the individual level.

brain regions.

results.

Direct mapping methods such as CSES are, at the moment, the safest procedures to achieve the most extensive resections with controllable risks. Preoperative brain mapping is useful when planning awake surgery to estimate the relationship between the tumor and functional brain regions. However, these techniques cannot directly lead the surgeon during resection. Intraoperative brain mapping is necessary to safely guide maximal resection and to guarantee a satisfying neurological outcome. It is unlikely that the study of functional connectivity and the longitudinal modification of brain maps will leave behind the integration of repeated fMR. This multimodal approach is more aggressive, leads to better outcomes, and should be used routinely for resection of lesions in eloquent

It is probably no longer necessary to compare different methods of brain mapping because of their intrinsically different functioning; rather, we propose that now it would be most desirable to share preoperative (fMR, DTI, and neuropsychology) and postoperative protocols in order to accumulate a major cohort of patients in multicenter studies. At the same time, results of intraoperative stimulations should be well documented and standardized to create a common comprehensive database of intraoperative brain mapping

to confirm reproducibility of the response. Once the proper current intensity is set, the entire surface of the tumor is thoroughly examined in order to exclude the presence of functional sites. When tumors are located in language areas, a neuropsychologist administers tests on a laptop screen (a series of slides with black and white pictures preceded by the words "this is a….") and describes the type of language disturbance observed (speech arrest, anarthria, anomia, or reading errors). These same tests are administered the day before surgery in order to detect baseline errors or hesitations that could be misinterpreted during intraoperative stimulation. Intraoperatively, the patient is unaware of the timing of stimulation, and the current is delivered just before presentation of the slide. After disruption of a language area, the patient rests for a while, then spontaneous speech and slide reading are tested, and stimulation starts again. Every time a positive response is encountered, a numbered tag is left in place and the function associated to the stimulation of that point is recorded. If the tumor is separated from a functional gyrus by a sulcus, maximal attention is paid in order to respect the arachnoid plane and the vasculature of the sulcus. If the tumor invades functional gyri or subcortical functional tracts, the resection must to be very careful since no anatomical limit is present between the infiltrated parenchyma and the normal functioning cortex. In these situations as well as for subcortical tumors, we test language or motor function throughout the resection even when no stimulation is applied, stopping whenever anomalies appear. Many authors have for a long time postulated a need to maintain a safe distance of at least 1 cm from a functional site (Haglund et al. 1994; Carrabba et al. 2007; Sanai & Berger 2008). More recently, this concept has been evolving because accumulated experiences have clearly demonstrated that continuous cortical and subcortical stimulations can enable the surgeon to identify and preserve eloquent cortex and the white matter bundles. Abandoning the idea of leaving a "safe margin" in favor of reaching functional boundaries yields an increase of the extent of resection, and thus, it is believed, has an increased impact on the natural history of the tumor. This more aggressive strategy is related to a higher percentage of transient postoperative neurological deficits, but it has also led to very satisfying long-term neurological outcomes (Gil-Robles & Duffau 2010).

In order to collect the largest amount of information about the unique functional organization of each individual patient, it is very important to record all the possible data from pre-, intra- and postoperative observations, including intraoperative photographs or films and, in cases of language area tumors, recordings of patients' voices. It also is important to register parameters such as current intensity, reproducibility of stimuli, and seizure occurrence, as well as the degree of pain control (at minimum a visual analog scale should be checked) and other anesthesiology concerns, such as nausea, vomiting, and need for respiratory support or for switching to general anesthesia.
