Intraoperative stimulation techniques = for functional pathway preservation and glioma resection; Neurosurgical = FOCUS

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February 2010 = Volume 28, Number = 2

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Intraoperative stimulation techniques = for=20 functional pathway preservation and glioma = resection

Nader Sanai, M.D., and = Mitchel S. Berger, = M.D.

Brain = Tumor=20 Research Center, Department of Neurological Surgery,=20 University of California, San Francisco,=20 California

Abbreviations used in this = paper:=20 CS =3D cortical stimulation; DT =3D diffusion tensor; = fMR =3D=20 functional MR; HGG =3D high-grade glioma; LGG =3D = low-grade=20 glioma.

Address correspondence = to: Nader=20 Sanai, M.D., Department of Neurological Surgery, = University of=20 California, San Francisco, 505 Parnassus Avenue, M779, = Box=20 0112, San Francisco, California 94143. email: Nader.Sanai@bnaneuro.net.

DOI: 10.3171/2009.12.FOCUS09266

Figures = and Tables=20

Abstract	IntroductionEvolution of Cortical = Map...Variability in Cortical = L...Preservation of = Functiona...The Role of Functional = Im...Current Intraoperative = La...Assessing the Value of=20 Gl...ConclusionsDisclosureReferences

Although a primary tenet of=20 neurosurgical oncology is that survival can improve = with=20 greater tumor resection, this principle must be = tempered by=20 the potential for functional loss following a radical = removal.=20 Preoperative planning with functional and = physiological=20 imaging paradigms, combined with intraoperative = strategies=20 such as cortical and subcortical stimulation mapping, = can=20 effectively reduce the risks associated with operating = in=20 eloquent territory. In addition to identifying = critical motor=20 pathways, these techniques can be adapted to identify = language=20 function reliably. The authors review the technical = nuances of=20 intraoperative mapping for low- and high-grade = gliomas,=20 demonstrating their efficacy in optimizing resection = even in=20 patients with negative mapping data. Collectively, = these=20 surgical strategies represent the cornerstone for = operating on=20 gliomas in and around functional = pathways.

KEYWORDS:language mapping; = motor tract;=20 cortical stimulation; extent of resection.

Introduction	AbstractIntroduction = <<Evolution of Cortical = Map...Variability in Cortical = L...Preservation of = Functiona...The Role of Functional = Im...Current Intraoperative = La...Assessing the Value of=20 Gl...ConclusionsDisclosureReferences

Central nervous = system tumors=20 are a major cause of morbidity and death, with ~ = 18,000 new=20 cases of primary intracranial tumors diagnosed each = year in=20 the US. This represents ~ 2% of all tumors found in = adults in=20 this country. More than half of these are HGGs. These = lesions=20 are extremely aggressive and the vast majority of = patients=20 invariably have tumor recurrence, with the median = survival=20 time ranging from 1 to 3 years after initial = diagnosis.=20 Despite facing a better prognosis when compared with=20 higher-grade glial tumors, 50=E2=80=9375% of patients = harboring LGGs=20 eventually die of their disease. Median survival times = have=20 been reported to range between 5 and 10 years, and = estimates=20 of 10-year survival rates range from 5 to 50%.

Although a primary tenet of neurosurgical oncology = is that=20 survival can improve with greater tumor resection, = this=20 principle must be tempered by the potential for = functional=20 loss following a radical removal. Current = neurosurgical=20 innovations aim to improve our anatomical, = physiological, and=20 functional understanding of the surgical region of = interest to=20 prevent potential neurological morbidity during = resection.=20 Emerging imaging technologies, as well as = state-of-the-art=20 intraoperative techniques, can facilitate a greater = extent of=20 resection while minimizing the associated morbidity = profile.=20 Specifically, the value of mapping motor and language = pathways=20 is well established for the safe resection of = intrinsic=20 tumors.

Interestingly, controversy persists regarding = prognostic=20 factors and treatment options for both low- and = high-grade=20 hemispheric gliomas. Among the various tumor- and=20 treatment-related parameters=E2=80=94including tumor = volume,=20 neurological status, timing of surgical intervention, = and the=20 use of adjuvant therapy=E2=80=94patient age and tumor = histological=20 characteristics have been identified as primary = predictors of=20 patient prognosis. However, location of the tumor in = an=20 eloquent area (Fig. 1) = has=20 recently emerged as another critical factor affecting = outcome,=20 particularly as it relates to tumor extent of=20 resection.¹⁰=20 Importantly, despite significant advances in operative = technique and preoperative planning, the effect of = glioma=20 extent of resection in prolonging tumor-free = progression=20 and/or survival remains unclear. Although the value of = glioma=20 resection in obtaining tissue diagnosis and = decompressing mass=20 effect are unquestionable, a lack of Class I evidence = prevents=20 similar certainty in assessing the influence of extent = of=20 resection. Even though LGGs and HGGs are distinct in = their=20 biological features, clinical behaviors, and outcomes, = understanding the effect of surgery remains equally = important=20 for both. This is also true for lesions in areas of = eloquence,=20 where the proximity of critical pathways, often = related to=20 language and motor function, can present a significant = challenge to standard operative strategies.

View = larger=20 version (103K)

Fig. 1. = Illustration=20 of eloquent cortical and subcortical sites = in the=20 supratentorial compartment. (Reprinted by=20 permission. Originally published in Chang = et al.:=20 Preoperative prognostic classification = system for=20 hemispheric low-grade gliomas in adults. = J=20 Neurosurg 109:817=E2=80=93824, = 2008.)

Evolution of Cortical Mapping=20 Strategies	AbstractIntroductionEvolution of Cortical Map...=20 <<Assessing the Value of=20 Gl...ConclusionsDisclosureReferences

Direct CS has been used in neurosurgery since 1930, = first=20 by Foerster,²⁶ and then=20 later by Penfield and colleagues.^{72=E2=80=9374}=20 In recent years, the technique of intraoperative CS = has been=20 adopted for the identification and preservation of = language=20 function and motor pathways. Stimulation depolarizes a = very=20 focal area of cortex, which in turn evokes certain = responses.=20 Although the mechanism of stimulation effects on = language are=20 poorly understood, the principle is based on the=20 depolarization of local neurons and also of passing = pathways,=20 inducing local excitation or inhibition, as well as = possible=20 diffusion to more distant areas by way of orthodromic = or=20 antidromic propagation.⁸⁵ Studies=20 in which optical imaging of bipolar CS was used in = monkey and=20 human cortex have shown precise local changes, within = 2=E2=80=933 mm,=20 after the activation of cortical tissue.^30,31 With the=20 advent of the bipolar probe, avoidance of local = diffusion and=20 more precise mapping have been enabled with an = accuracy=20 estimated to be ~ 5 mm.³⁰

Language mapping techniques were = historically=20 developed in the context of epilepsy surgery, in which = large=20 craniotomies exposed the brain well beyond the region = of=20 surgical interest to localize multiple cortical = regions=20 containing stimulation-induced language and motor = function=20 (that is, =E2=80=9Cpositive=E2=80=9D sites) prior to = resection. Until=20 recently, it has been thought that such positive site = controls=20 must be established during language mapping before any = other=20 cortical area could be safely resected. Using this = tactic,=20 awake craniotomies traditionally identify positive = language=20 sites in 95=E2=80=93100% of the operative exposures. = Brain tumor=20 surgery, however, is now evolving toward a different = standard=20 of language mapping, in which smaller, tailored = craniotomies=20 often expose no positive sites, and tumor resection is = therefore directed by the localization of cortical = regions=20 that when tested contained no stimulation-induced = language or=20 motor function (that is, =E2=80=9Cnegative=E2=80=9D = sites). This =E2=80=9Cnegative=20 mapping=E2=80=9D strategy represents a paradigm shift = in language=20 mapping technique by eliminating the neurosurgeon's = reliance=20 on the positive site control in the operative = exposure,=20 thereby allowing for minimal cortical exposure = overlying the=20 tumor, less extensive intraoperative mapping, and a = more=20 time-efficient neurosurgical procedure.

Variability in Cortical = Language=20 Localization	AbstractIntroductionEvolution of Cortical = Map...Variability in Cortical L...=20 <<Assessing the Value of=20 Gl...ConclusionsDisclosureReferences

Prediction of cortical language sites = based on=20 classic anatomical criteria is inadequate in light of = the=20 significant individual variability of cortical=20 organization,^35,64,66,70 the=20 distortion of cerebral topography from tumor mass = effect, and=20 the possibility of functional reorganization through=20 plasticity mechanisms.^71,95,121 A=20 consistent finding of language stimulation studies has = been=20 the identification of significant individual = variability among=20 patients.⁶⁴ Speech=20 arrest is variably located and can go well beyond the = classic=20 anatomical boundaries of the Broca area for motor = speech. It=20 typically involves an area contiguous with the = face-motor=20 cortex, and yet in some cases is seen several = centimeters from=20 the sylvian fissure. This variability has also been = suggested=20 by studies designed to predict the location of speech = arrest=20 preoperatively, based on the type of frontal opercular = anatomy⁸³ or by=20 using functional neuroimaging.^{15,43,94,105,111=E2=80=93113}=20 Similarly, for temporal lobe language sites, one study = of=20 temporal lobe resections assisted by subdural grids=20 demonstrated that the distance from the temporal pole = to the=20 area of language function varied from 3 to 9 = cm.¹⁴=20 Functional imaging studies have also corroborated such = variability.²⁵=20 Furthermore, because functional tissue can be located = within=20 the tumor nidus,¹⁰² the=20 standard surgical principle of debulking tumor from = within to=20 avoid neurological deficits is not always safe. = Consequently,=20 the use of intraoperative cortical and subcortical = stimulation=20 to detect functional regions and pathways accurately = is=20 essential for safely removing dominant-hemisphere = gliomas to=20 the greatest extent possible.

Preservation of Functional = Pathways by=20 Using Intraoperative Stimulation = Mapping	AbstractIntroductionEvolution of Cortical = Map...Variability in Cortical = L...Preservation of Functiona...=20 <<Assessing the Value of=20 Gl...ConclusionsDisclosureReferences

Intraoperative CS has yielded critical = data=20 regarding essential language sites, which seem to be = organized=20 in discrete mosaics that occupy a much smaller area of = cortex=20 than described by traditional language maps.^65,67,69=20 Interestingly, the majority of these language sites = are=20 surrounded by cortex that, when stimulated, produce no = language errors.⁶⁸ In the=20 temporal lobe, identification of speech areas within = the=20 superior and middle temporal gyri has been documented = within 3=20 cm of the temporal lobe tip.⁶⁴ In this=20 region, the distance of the resection margin from the = nearest=20 language site is the most important variable in = predicting the=20 improvement of preoperative language deficits. = Accordingly, if=20 the distance to the resection margin from the nearest = language=20 site is > 1 cm, significantly fewer permanent = language=20 deficits occur.²⁹ Strict=20 adherence to this principle when operating in any = region of=20 the dominant hemisphere can substantially reduce the = risk of=20 inadvertently resecting functional tissue.

The Role of Functional Imaging = for=20 Eloquent Tissue Localization	AbstractIntroductionEvolution of Cortical = Map...Variability in Cortical = L...Preservation of = Functiona...The Role of Functional Im...=20 <<Assessing the Value of=20 Gl...ConclusionsDisclosureReferences

Because the need to preserve cortical language = function=20 must be balanced with the goal of maximal tumor = resection,=20 intraoperative language mapping is advocated by some = as the=20 rule, rather than the exception.¹⁰⁸ The=20 greatest risk of tumor recurrence is located within 2 = cm of=20 the contrast-enhancing rim on imaging studies,^37,117=20 supporting the concept that the resection should = ideally go=20 beyond the gross tumor margin apparent on preoperative = imaging. However, because of the infiltrating nature = of=20 gliomas, it is more than likely that a portion of the = mass=20 will occupy, or be continuous with, functional tissue. = Again,=20 this emphasizes the need for CS mapping to avoid = injuring=20 these critical areas, particularly language pathways. = Although=20 it was classically thought that patients who were=20 neurologically intact or minimally affected = preoperatively had=20 their functional pathways either displaced or = obliterated by=20 infiltrative tumors, we now know that normally = functioning=20 language, motor, or sensory tissue can blend with=20 tumor.¹⁰²=20 Therefore, it is not only patients with tumors located = within=20 the frontal operculum who benefit from intraoperative = language=20 mapping, but also those with lesions in proximity to = this=20 region, because there is significant variability in = this=20 region's anatomical and functional = organization.^23,83

Functional imaging has advanced = considerably in=20 both technology and availability, raising the question = of=20 whether it may supplant intraoperative CS mapping. = Devices=20 such as fMR imaging, PET, and magnetoencephalography = units may=20 aid in the preoperative planning of the resection = strategy,=20 but these techniques remain too imprecise for complex=20 functions such as language mapping: their sensitivity = (PET,=20 75%; fMR imaging, 81%) and specificity (PET, 81%; fMR = imaging,=20 53%) are suboptimal.^25,34 These=20 modalities highlight language-associated areas of=20 indeterminate significance,⁷ = and they=20 do not offer real-time information intraoperatively. = To this=20 end, MR neuronavigational techniques not only = facilitate=20 greater resection, but embedding of DT = imaging=E2=80=93based=20 tractography can prevent inadvertent resection of = adjacent=20 subcortical pathways.^107,120 In a=20 recent study of 238 patients with glioma who were = randomized=20 to DT imaging=E2=80=93based imaging versus traditional = MR=20 neuronavigation with DT imaging, postoperative motor=20 deterioration occurred in 32.8% of control cases, = whereas it=20 occurred in only 15.3% of the study cases. Although = the use of=20 DT imaging=E2=80=93based tractography has not been = shown to impact=20 patient survival directly, the literature highlights = the=20 utility of this technology in maximizing tumor = resection while=20 minimizing morbidity. Nevertheless, for the = identification of=20 functional language pathways and guidance of safe = tumor=20 removal, these diagnostic imaging tools are still only = supplements, not substitutes, for direct = intraoperative=20 stimulation mapping.

Current Intraoperative = Language and=20 Motor Mapping Techniques	AbstractIntroductionEvolution of Cortical = Map...Variability in Cortical = L...Preservation of = Functiona...The Role of Functional = Im...Current Intraoperative La...=20 <<ConclusionsDisclosureReferences

In general, a limited craniotomy should expose the = tumor=20 and up to 2 cm of surrounding brain. Using bipolar = electrodes,=20 cortical mapping is started at a low stimulus (1.5 mA) = and=20 increased to a maximum of 6 mA, if necessary. A=20 constant-current generator delivers biphasic square = wave=20 pulses (each phase, 1.25 msec) in 4-second trains at = 60 Hz=20 across 1-mm bipolar electrodes separated by 5 mm. = Stimulation=20 sites (~ 10=E2=80=9320 per patient) can be marked with = sterile=20 numbered tickets. Throughout motor and language = mapping,=20 continuous electrocorticography should be used to = monitor=20 afterdischarge potentials, and therefore eliminate the = chance=20 that speech or naming errors are caused by subclinical = seizure=20 activity.

Awake CS and Impact of Language = Mapping=20

Speech arrest is based on blocking number counting = without=20 simultaneous motor response in the mouth or pharynx.=20 Dysarthria can be distinguished from speech arrest by = the=20 absence of perceived or visible involuntary muscle = contraction=20 affecting speech. For naming or reading sites, CS is = applied=20 for 3 seconds at sequential cortical sites during a = slide=20 presentation of line drawings or words, respectively. = All=20 tested language sites should be repeatedly stimulated = at least=20 3 times. A positive essential site can be defined as = an=20 inability to name objects or read words in 66% or more = of the=20 testing per site. In all cases, a 1-cm margin of = tissue should=20 be measured and preserved around each positive = language site=20 to protect functional tissue from the = resection.⁴⁹ The=20 extent of resection is directed by targeting=20 contrast-enhancing regions for high-grade lesions and=20 T2-hyperintense areas for low-grade lesions. Some = groups=20 advocate the use of language mapping along subcortical = white=20 matter pathways as well.^19,21

Despite the considerable evidence supporting the = use of=20 intraoperative CS mapping of language function, the = efficacy=20 of this technique in preserving functional outcome = following=20 aggressive glioma resection remains poorly understood. = Nevertheless, it is important to define the long-term=20 neurological effects after using this technique for = large,=20 dominant-hemisphere gliomas to advocate its use=20 accurately.⁸⁸

Our experience with 250 consecutive = patients=20 with dominant-hemisphere glioma (WHO Grades = II=E2=80=93IV) suggests=20 that functional language outcome following awake = mapping can=20 be favorable, even in the case of an aggressive=20 resection.⁸⁹ Overall,=20 159 of these 250 patients (63.6%) had intact speech=20 preoperatively. At 1 week postoperatively, 194 (77.6%) = remained at their baseline language function, whereas = 21=20 (8.4%) worsened and 35 (14.0%) had new speech = deficits.=20 However, by 6 months, 52 (92.8%) of 56 patients with = new or=20 worsened language deficits returned to baseline or = better, and=20 the remaining 4 (7.1%) were left with a permanent = deficit.=20 Interestingly, among these patients, any additional = language=20 deficit incurred as a result of the surgery had either = improved by 3 months or not all (Fig. 1). = Thus,=20 using language mapping, only 1.6% (4 of 243 survivors) = of all=20 glioma patients develop a permanent postoperative = language=20 deficit. One explanation for this favorable = postoperative=20 language profile may be our strict adherence to the=20 =E2=80=9Cone-centimeter rule,=E2=80=9D first described = by Haglund et=20 al.,²⁹ which=20 demonstrated that, for temporal lobe tumors, a = resection=20 margin of 1 cm or more from a language site = significantly=20 reduces postoperative language deficits.

Cortical and Subcortical Motor = Mapping=20 Techniques=20

For patients with gliomas that are = located=20 within or adjacent to the rolandic cortex, and thus = the=20 descending motor tracts, stimulation mapping of = cortical and=20 subcortical motor pathways enables the surgeon to = identify=20 these descending motor pathways during tumor removal = and to=20 achieve an acceptable rate of permanent morbidity in = these=20 high-risk functional areas.^8,20,47 In a=20 recent study, new immediate postoperative motor = deficits were=20 documented in 59.3% of patients in whom a subcortical = motor=20 tract was identified intraoperatively and in 10.9% of = those in=20 whom subcortical tracts were not observed. However, = permanent=20 deficits were observed in 6.5% and 3.5%, = respectively.⁸ = In another=20 study of subcortical motor pathways in 294 patients = who=20 underwent surgery for hemispheric gliomas, 14 patients = (4.8%)=20 had a persistent motor deficit after 3 months. = Interestingly,=20 patients whose subcortical pathways were identified=20 intraoperatively were more prone to develop an = additional=20 transient or permanent motor deficit (27.5 vs = 13.1%).⁴⁷ In=20 another study with an 87% gross- or subtotal resection = rate,=20 the overall neurological morbidity was 5% after using = cortical=20 motor mapping.²⁰ Thus,=20 collectively the recent literature suggests that=20 intraoperative cortical and subcortical motor mapping = can=20 safely identify corridors for resection, as well as = define the=20 limits of tumor resection.

Tailored Craniotomies and the Value = of Negative=20 Mapping=20

In contrast to the classic mapping principles = practiced in=20 epilepsy surgery, where 95=E2=80=93100% of operative = fields contain a=20 positive language site, a paradigm shift is emerging = in brain=20 tumor language mapping, where positive language sites = are not=20 always found prior to resection (Fig. 2). = In our=20 practice, because of our use of tailored cortical = exposures,=20 < 58% of patients have essential language sites = localized=20 within the operative field. Our experience suggests = that it is=20 safe to use a minimal exposure of the tumor and resect = based=20 on a negative language map, rather than rely on a wide = craniotomy to find positive language sites well beyond = the=20 lesion. However, language mapping techniques such as = this are=20 generally more successful and safer at high-volume=20 neurosurgical centers.

View = larger=20 version (142K)

Fig. 2. = Negative=20 language map indicating the percentage of = negative=20 stimulations per square centimeter of the = dominant=20 cerebral hemisphere. (Reprinted by = permission.=20 Adapted with permission from Fig. 2=20 in Sanai et al.: Functional outcome after = language=20 mapping for glioma resection. N Engl J = Med=20 358:18=E2=80=9327, 2008. Copyright = =C2=A9 2008,=20 Massachusetts Medical Society. All rights=20 reserved.)

Negative language mapping, however, = does not=20 necessarily guarantee the absence of eloquent sites = (Fig. 2).=20 Despite negative brain mapping, permanent = postoperative=20 neurological deficits have been reported.¹⁰⁸ In our=20 experience with 250 consecutive patients with=20 dominant-hemisphere glioma, all 4 of our patients with = permanent postoperative neurological deficits had no = positive=20 sites detected prior to their resections. Other cases = of=20 unexpected postoperative deficits have also been = attributed to=20 progressive tumor infiltration into functional = areas.³=20 Furthermore, both intraoperative stimulation and = functional=20 imaging techniques have provided evidence for = redistribution=20 of functional neural networks in cases of = stroke,^11,95,118=20 congenital malformations,^54,56 brain=20 injury,²⁷ and=20 tumor progression.^24,95,121 Not=20 surprisingly, it has been hypothesized that brain = infiltration=20 by gliomas leads to reshaping or local reorganization = of=20 functional networks as well as = neosynaptogenesis.^18,109 This=20 would explain the frequent lack of clinical deficit = despite=20 glioma growth into eloquent brain areas,^17,24,95 as well=20 as the transient nature of many postoperative = deficits. In the=20 case of language function located in the dominant = insula, the=20 brain's capacity for compensation of functional loss = has also=20 been associated with recruitment of the left superior = temporal=20 gyrus and left putamen.¹⁷

Assessing the Value of Glioma = Extent=20 of Resection	AbstractIntroductionEvolution of Cortical = Map...Variability in Cortical = L...Preservation of = Functiona...The Role of Functional = Im...Current Intraoperative = La...Assessing the Value of Gl...=20 <<ConclusionsDisclosureReferences

Microsurgical resection remains a critical = therapeutic=20 modality for all gliomas.^4,28,45,122=20 However, there remains no general consensus in the = literature=20 regarding the efficacy of extent of resection in = improving=20 patient outcome.^{32,36,60,78,81,87,92} With the=20 exception of WHO Grade I tumors, gliomas are difficult = to cure=20 with surgery alone, and the majority of patients will=20 experience some form of tumor recurrence. Patients = with=20 glioblastomas have median survival rates of = 12.2=E2=80=9318.2=20 months,³³ whereas=20 those with anaplastic astrocytomas can expect to = survive 41=20 months, on average.⁴⁶=20 Low-grade gliomas carry a better prognosis, although = the vast=20 majority of patients eventually die of their disease = and=20 5-year survival percentages range from 42 to 92% in = the=20 literature.^{51,52,59,76,84,96,97,123}

For all gliomas, the identification of universally=20 applicable prognostic factors and treatment options = remains a=20 great challenge. Among the many tumor- and = treatment-related=20 parameters, only patient age and tumor histological=20 characteristics have been identified as reliable = predictors of=20 patient prognosis, although tumor location in an = eloquent area=20 and a patient's functional status can also be = statistically=20 significant. Surprisingly, despite significant = advances in=20 brain tumor imaging and intraoperative technology = during the=20 last 15 years, the effect of glioma resection in = extending=20 tumor-free progression and patient survival remains=20 unknown.

Although LGGs and HGGs are distinct in their = biology,=20 clinical behavior, and outcome, understanding the = efficacy of=20 surgery remains equally important for each. With this = in mind,=20 an examination of the modern neurosurgical literature = (1990 to=20 present) reveals clues as to the role of extent of = resection=20 in outcome for glioma patients (Fig. = 3).

View = larger=20 version (48K)

Fig. 3. = Chart showing=20 absolute number of LGG studies in the=20 neurosurgical literature from 1990 to 2009 = that=20 statistically examined the effect of = extent of=20 resection on patient = survival.

Extent of Resection Studies for = LGG=20

In the last 2 decades, mounting = evidence in the=20 literature suggests that a more extensive resection of = an LGG=20 is associated with a more favorable life expectancy = (Fig. 3).=20 In addition to providing longer overall survival, more = aggressive resections for LGG can also influence the = risk of=20 malignant transformation, raising the possibility that = a=20 surgical intervention can alter the natural history of = the=20 disease.⁸⁷ These=20 associations are evident not only within the = population with=20 general hemispheric LGGs,^9,103 but=20 also for those with specific LGGs limited to specific = eloquent=20 subregions, such as insular LGGs.^90,100 An=20 overall review of the modern neurosurgical literature = reveals=20 23 studies^{2,12,40,42,44,52,55,57,59,61,63,75,76,84,86,90,93,96,98,103,115,119,123} since=20 1990 that have applied statistical analysis to examine = the=20 efficacy of extent of resection in improving survival = and=20 delaying tumor progression among patients with LGG. = Six of=20 these studies included volumetric analysis of extent = of=20 resection.^{12,44,90,98,103,115} Of the=20 nonvolumetric studies, 14 demonstrated evidence = supporting=20 extent of resection as a statistically significant = predictor=20 of either 5-year survival or 5-year progression-free = survival.=20 These studies were published between 1990 and 2009, = and most=20 commonly used a combination of multivariate and = univariate=20 analyses to determine statistical significance. = Interestingly,=20 of the 3 nonvolumetric studies that did not support = extent of=20 resection as a predictor of patient outcome, none of = these=20 reports evaluated progression-free survival, but = instead=20 focused solely on 5-year survival.

Extent of Resection Studies for = HGG=20

Twenty-nine studies^{1,5,6,13,16,22,38,39,41,45,46,48=E2=80=9350,53,58,62,77,79,80,82,91,99,101,104,106,110,114,116} since=20 1990 have applied statistical analysis to examine the = efficacy=20 of extent of resection in improving survival and = delaying=20 tumor progression among patients with HGG. Four of = these=20 studies included volumetric analysis of extent of=20 resection.^45,46,49,79 Of the=20 nonvolumetric studies, 16 demonstrated evidence = supporting=20 extent of resection as a statistically significant = predictor=20 of either time to tumor progression or overall = survival.=20 Although some of these reports showed extent of = resection to=20 have a significant effect on both tumor progression = and=20 overall survival, every study showed a survival = benefit. Ten=20 studies, however, demonstrated no significant benefit = based on=20 extent of resection. Notably, the distribution of = adjuvant=20 chemotherapy and radiation treatment was comparable = among all=20 extent of resection studies for HGG. Echoing the = nonvolumetric=20 study results, half of all HGG volumetric studies = showed a=20 significant survival advantage with greater extent of=20 resection.

Conclusions	AbstractIntroductionEvolution of Cortical = Map...Variability in Cortical = L...Preservation of = Functiona...The Role of Functional = Im...Current Intraoperative = La...Assessing the Value of=20 Gl...DisclosureReferences

Intraoperative stimulation for = cortical and=20 subcortical mapping is a reliable, robust method to = maximize=20 resection and minimize morbidity, even when removing = gliomas=20 within or near adjacent functional pathways. Unlike = motor=20 function, speech and language are variably distributed = and=20 widely represented, thus emphasizing the utility of = language=20 mapping in this particular patient population. Gliomas = located=20 in eloquent territories can displace predicted fiber = pathways=20 in unpredictable conformations. The combination of = advanced=20 imaging paradigms, such as neuronavigational DT = imaging=E2=80=93based=20 tractography, with intraoperative mapping techniques = can best=20 assure preservation of critical function. Using this = approach,=20 and in conjunction with standardized neuroanesthesia = and=20 neuromonitoring, the postoperative motor and language=20 resolution profiles following glioma resection may be=20 predictable. Specifically, in our experience, any = additional=20 language deficit incurred as a result of the surgery = will=20 improve by 3 months or not all. Our experience also = emphasizes=20 the value of negative language mapping in a patient = with a=20 tailored cortical exposure. Although the value of = extent of=20 resection remains less clear, the available literature = for=20 both low-grade and high-grade hemispheric gliomas = demonstrates=20 mounting evidence that a more extensive resection is=20 associated with a more favorable life expectancy for = patients=20 with both LGG and HGG. This objective should be = cautiously=20 pursued for all gliomas, even those in an eloquent=20 location.

Disclosure	AbstractIntroductionEvolution of Cortical = Map...Variability in Cortical = L...Preservation of = Functiona...The Role of Functional = Im...Current Intraoperative = La...Assessing the Value of=20 Gl...ConclusionsDisclosure <<

The authors report no conflict of interest = concerning the=20 materials or methods used in this study or the = findings=20 specified in this paper.

Author contributions to the study and = manuscript=20 preparation include the following. Conception and = design: N=20 Sanai, MS Berger. Drafting the article: N Sanai, MS=20 Berger.

References	AbstractIntroductionEvolution of Cortical = Map...Variability in Cortical = L...Preservation of = Functiona...The Role of Functional = Im...Current Intraoperative = La...Assessing the Value of=20 Gl...ConclusionsDisclosureReferences = <<

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