Combined use of intraoperative MRI and awake tailored microsurgical resection to respect functional neural networks: preliminary experience

DOI: https://doi.org/https://doi.org/10.57187/smw.2023.40072

Introduction

Primary central nervous system (CNS) tumours are heterogeneous and derived from cells within the CNS. They can be benign or malignant, while the most malignant tumours are gliomas with a 5-year overall survival (OS) not greater than 35% [1]. The resection extent is associated with OS [2–4], with a larger resection reducing tumour recurrence and further malignant transformation of low-grade gliomas [5, 6]. The introduction of fluorescence-guided microsurgical resection further improved the extent of resection [7, 8]. Initially, intraoperative MRI was considered to lead to a 20% increase in resection extent [9, 10], particularly for low-grade gliomas, but more recent series indicate that this benefit is much higher [11, 12].

CNS pathologies located within eloquent areas pose a specific challenge, particularly to their gross-total microsurgical resection. The primary goal remains neurological function preservation while maximising the extent of resection to optimise long-term neurooncological outcomes and neurological function. In such instances, intraoperative electrical stimulation helps to define cortical areas underlying eloquent function [13−15].

Conscious or awake craniotomy has a long neurosurgical track record and was initially recommended for patients at risk of language function and intractable epilepsy [16]. The current goal of awake craniotomy is to preserve motor, language and cognitive neurological functions for patients with any type of pathology anatomically located near or within eloquent areas of the brain [17]. Consequently, there is a need for the combined use of intraoperative MRI and awake microsurgical resection for both primary brain tumours and epilepsy of various origins to achieve a tailored microsurgical resection to respect functional neural networks [18].

In most of the available literature with regards to the combined management using awake intraoperative MRI and awake microsurgical resection for primary brain tumours, there is heterogeneity in terms of complete initial tumour resection, further resection, no further resection, or complete resection post-surgery [17, 19−25]. Complete initial resection was reported between 10 to 58.3%, while further resection after intraoperative MRI was 36.7% and the final rate of complete resection was between 40.5% and 70% [17, 19−25]. There is also heterogeneity in terms of final results, as some authors describe this as resection to an eloquent margin, subtotal, gross total, near-total or complete resection [17, 19−25], which may confuse the interpretation of the published data.

Our hospital has benefited from the first intraoperative MRI installation in France in 2014, so we sought to review our experience as a referral centre for the operative techniques of combined awake craniotomy and intraoperative MRI. Herein, we present a detailed overview of our data using standardised scales and complete patient information to provide a broader view of combined management awake microsurgical resection and intraoperative MRI in patients with gliomas as well as other pathologies. Moreover, we illustrate some of the indications also covering various eloquent anatomical areas and describe our asleep-awake-asleep technique.

Methods

Study design

The study was a retrospective, non-randomised, case series. The case report form for each patient was retrospectively analysed. All patients provided informed consent and this historical case series review was approved by the Lille University Hospital Ethical Committee. Initially, we published a series of 56 cases with lesions adjacent to eloquent areas managed by intraoperative MRI [26] but herein, we focus on those benefiting from the combined management of awake microsurgical resection and intraoperative MRI. The CNIL number was 791.

Inclusion and exclusion criteria

The inclusion criteria were patients aged more than 18 years, able to provide written informed consent, with either a primary brain tumour or epileptic focus anatomically located within a motor and/or language area (table 1; the illustrative cases are shown in figures 1 and 2). Exclusion criteria were patients aged less than 18 years at the time of surgery, unable to provide written informed consent, minimal residual motor function, pronounced aphasia, a score under 23 on the Mini Mental Status examination, and those with an apathic/disorganised comportment, large vascular lesions or potential airway difficulties [27].

Figure 1 Illustrative cases benefiting from the combined use of awake surgery and intraoperative MRI. Case 1: Preoperative evolutive primary brain tumor (insular astrocytoma IDH 1 mutated) WHO II, in contact on its medium pole with the inferior fronto-occipital fasciculus (IFOF). Case 2: Recurrent (multioperated and irritiated) brain metastasis, localized in the central area, in contact with the corticospinal tract (in red, interrupted by the tumor).

Figure 2 Illustrative cases benefiting from the combined use of awake surgery and intraoperative MRI. Case 3: Cortical dysplasia, with structural T1 preoperative MRI (left), functional task-based fMRI showing that the lesion is in contact with premotor and motor areas of the hand (center) and diffusion tensor imaging showing the motor tract (in blue, left). Case 4: cavernous malformation, located at the junction between the inferior parietal and the posterior temporal lobe (Wernicke area).

Patient population

Eighteen patients were treated with this approach at Lille University Hospital, France, from November 2016 until the end of May 2020 (see table 1 for patient details) and all procedures were performed by the senior neurosurgeon (NR). The mean patient age was 38.4 years (median 37.1, range 20.8−66.9) and the male-to-female ratio was 7:11. The mean overall follow-up period was 15.8 months (median 12, range 3−36) and the preoperative symptoms included partial seizure in 11 patients (61.1%), generalized seizure in 4 patients (22.2%), a motor deficit in 1 patient (5.6%), headaches in 1 patient (5.6%) and incidental in 1 patient (5.6%). In terms of preoperative neurological deficits, one patient had a right superior upper limb deficit. The exact anatomical location was insular with various extensions, frontal, temporal or fronto-temporal in 8 patients (44.4%), parietal in 3 patients (16.7%), fronto-opercular in 4 patients (22.2%), Rolandic in two patients (11.1%), and the supplementary motor area (SMA) in 1 patient (5.6%).

Pre- and postoperative clinical assessment

Clinical assessment was performed by a board-certified neurosurgeon preoperatively and at 3, 6, and 12 months postoperatively using the Karnofsky performance score (KPS). The neuropsychological exam was performed by a specialized neuropsychologist (co-author OS) for patients' task-based functional MRI (fMRI) to check for their dominant hemisphere. Complementary diffusion tensor imaging by fibre tracking (DTI) was performed to evaluate the position of major fascicles including, but not limited to, the corticospinal tract, arcuate fasciculus, inferior fronto-occipital fasciculus (IFOF), and arcuate fasciculus (AF) [28]. Postoperative MRI was usually performed within the first 48 hours after surgery and at 3 and 6 months.

The awake surgery technique

The most common procedure performed in our institution is the combination of general anaesthesia and an awake technique, referred to as “asleep awake asleep” (AAA). During this approach, the patient is placed under general anaesthesia before and after brain mapping and/or finalised resection. Usually, there is an initial phase of general anaesthesia, followed by intraoperative awakening and then back to general anaesthesia.

All patients in this case series underwent craniotomy under general anaesthesia. The opening of the dura was performed in the awake condition after local anaesthesia with Lidocaine (without noradrenaline). The intraoperative MRI was generally performed in the awake condition with patients remaining awake during the second resection if required. They were placed back to sleep if no further resection was performed for their comfort, except for in three cases who expressed the desire to remain awake.

The electrical stimulation mapping was performed using a bipolar electrical stimulator probe (5 mm between tips) connected to a pulse generator (Ojemann Cortical Stimulator, Integra LifeSciences), which was placed outside the 5-gauss field to further prevent electrical interference. Typically, stimulation was performed over the entire exposed cortical surface using biphasic square wave pulses (0.5 msec per pulse, 50 Hz, 2-second duration) starting at 2.5 mA. The identification of eloquent areas during cortical stimulation was as follows: somatosensory cortex – paresthesia appeared, receptive language cortex (Wernicke area) - speech arrest and anomia, motor language cortex (Broca area) – speech arrest during number counting. Cortex points that did not elicit an effect on stimulation were deemed non-eloquent. Identification sterile tags were not routinely placed over the brain area, only in selected cases as presented in the literature.

Intraoperative evaluation of microsurgical resection

For primary brain tumours, tumour removal was performed by dissecting circumferentially around the tumour border, as determined by the registered preoperative MR images displayed on the neuronavigation system. Microsurgical resection was guided by the surgeon’s intraoperative observation and assessment of tumour margins. An intraoperative MRI was performed as described below.

Intraoperative MRI: general considerations and specific sequences

A new intraoperative MRI was performed when the neuronavigation became insufficiently accurate and/or to assess the presence of a residual tumour.

Before translating the patient into the MRI, a checklist was completed to ensure the absence of metallic material in the surgical site that could interfere with the magnetic field.

Before performing the intraoperative MRI evaluation to assess the extent of resection, the dura mater and skin were approximated. A sterile field was placed over the operative field and the head was held using a Mayfield MR/X-Ray Skull clamp with Excite 3.0T Adaptor (Integra Lifescience, New Jersey, USA). All patients benefitted from an intraoperative 1.5 Tesla MRI (General Electric®, Boston, MA) and the imaging sequences for neuronavigation were 3D T1 after gadolinium injection with 1-mm slice thickness. Additional sequences, such as 3D FLAIR (especially for low-grade gliomas), diffusion (B1000 and ADC), and T2 with gradient echo, were also performed if required. An intraoperative tractography was performed when the gliomas were close to functional areas (e.g., corticospinal tract). The neuronavigation data update procedure was performed using the automatic coregistration provided by Brainlab® Munich, Germany, with the quality and accuracy of the coregistration double-checked by an imaging engineer and the board-certified neurosurgeon [28]. The MRI was discussed with the neuroradiologist to evaluate the extent of resection.

The surgical microscope (OPMI Pentero^® Zeiss, Germany) was connected to the imaging network and could be used for neuronavigation.

Volumetric assessment of primary brain tumours

Two independent neurosurgeons measured all volumetric primary brain tumour volumes using the Intellispace Portal (Philips®, Amsterdam, Netherlands) module BTumour tracking software.The lesions without contrast enhancement or slightly enhanced after gadolinium infusion were contoured using the T2/FLAIR hypersignal MR sequences and highly contrast-taking tumours were segmented using the T1 hypersignal after gadolinium infusion sequences. After segmentation, volumes were calculated in cubic centimetres (cc). For a discrepancy > 10% between the two observers, both segmentations were compared to achieve a consensus volume. The extent of resection was reported in both cc and percentages.

Histological analysis of primary brain tumours

For each patient, the definitive histologic subtype was reviewed by a senior neuropathologist based on the 2016 WHO classification.

The diagnosis in the present series (n= 13, primary brain tumours, table 1) included astrocytoma WHO grade II in 5 patients (27.8%), oligoastrocytoma WHO grade II in 1 patient (5.6%), oligodendroglioma WHO grade II in 2 patients (11.1%), pleomorphic xantoastrocytoma WHO grade II in 1 patient (5.6%), anaplastic astrocytoma WHO grade III in 2 patients (11.1%), glioblastoma WHO grade IV and brain metastasis in 1 patient (5.6%) each, respectively.

Short review of the literature

A short review of the literature is presented in table 2 and further detailed in the results section [11, 17, 20−25, 29−31].

Intractable epilepsy: a multidisciplinary assessment using SEEG

For patients with intractable epilepsy or unknown or doubtful origin, SEEG was used before any microsurgical resection is performed, even in the case of an identified structural lesion on preoperative MRI. This is the standard approach together with the specialised team in our hospital.

The histological diagnosis for cases with intractable epilepsy (n= 5) in the present series was cortical dysplasia in 3 (16.7%), gliosis and cavernoma in 1 (5.6%) each, respectively.

Results

The mean operative time and duration of intraoperative MRI, lesion remnant, pre- and postoperative deficits are presented in table 3, showing a mean duration of microsurgery of 4.1 hours (median 4.2, range 2.6−6.4) and intraoperative MRI of 28.8 minutes (median 25, range 13−55; figure 3). The tumour remnants were most commonly located posterior (5/9) or anterior (2/9) insular and in proximity with the motor strip (1/9) or language areas (e.g. Broca, 1/9).

Figure 3 Intraoperative MRI duration (minutes).

Microsurgery for primary brain tumours: further resection after the first intraoperative MRI and potential adjuvant therapies

The mean preoperative tumour volume of the primary brain tumours was 34.7 cc (median 10.7, range 0.534−130.25; standard deviation 41.2 cc).

Overall, 61% (11/18) of cases underwent further resection, with no further resection in seven patients because there were no remnants (3/7), cortical stimulation approaching eloquent areas (3/7) and non-lesional epilepsy (1/7).  

The mean postoperative volume was 3.8 cc (median 0.5, range 0−17.4; standard deviation 5.6 cc; figure 4, upper level, absolute values, in cc; lower level, in percentages, according to the reference preoperative volume of 100%). A Mann-Whitney test was performed to compare the mean perioperative tumour volumes (in cc) resected at the time of intraoperative MRI and the final resected tumour volumes showing that they were not statistically significant (p= 0.6, figure 4, upper part). However, the total tumour volumes resected at the time of intraoperative MRI (as by 100% tumour volumes preoperatively) compared to the final results were statistically significant (p= 0.01, figure 4, lower part).

Figure 4 The impact of intraoperative MRI on the microsurgical resection in terms of volumes (as cc, upper side; as percentages, lower side).

After multidisciplinary discussion, 8 (8/13, 61.5%) cases benefitted from a standard protocol of combined radiotherapy (50.4 Gy) and six cycles of Temozolomide, 1 patient (1/13, 7.7%) was involved in the EORTC 1709 (the Stupp protocol plus Marizomib) and two (2/13, 15.4%) cases were subsequently followed-up.

At the last follow-up, 12 (12/13, 92.3%) patients had volumetric tumour stability or a decreased volume. One (7.7%) patient with oligoastrocytoma WHO II required further surgery at 21.6 months after the first resection due to volumetric progression and drug-resistant epilepsy, with LPFS achieved (see figure 5).

Figure 5 Illustrative case of an oligodendroglioma WHO II, 1p19q co-deleted.

A short review of the literature on this topic is provided in table 2, presenting the initial complete resection rates, as well as those at the end of the surgery. The mean initial resection rate at the time of the first intraoperative MRI was 36.4% (median 36.3, range 10−58.3) and at the end of surgery was 56.4% (median 60, range 40.5−77).

Microsurgery for epilepsy: further resection after the first intraoperative MRI and clinical outcome

One case with cortical dysplasia type IIb underwent further surgery after the initial procedure. The patients with cortical dysplasia had, among the epilepsy cases, the longest follow-up in the present series and all experienced a major decrease in seizure frequency and duration (see table 3 for the Engel classes).

The patient with non-lesional epilepsy (number 17) experienced no crisis to date (3-month follow-up, previously several crises per week) and the patient with cavernoma had no seizures after 3 months of follow-up.

Neurological complications

Transient neurological complications were encountered in 3/18 (16.7%) cases, each one with transient hemiparesis, ataxia and dysgraphia, and right-hand hypoesthesia.

Definitive neurological complications occurred in 2/18 (11.1%) patients, each with neuropathic pain and partial motor seizures and right-hand hypoesthesia, respectively.

Neuropsychological exam and Karnofsky performance status

A neuropsychological exam was performed in 5 cases with no statistically significant difference between the pre-and postoperative assessment (table 4). Also, there was no statistically significant difference between the pre-and postoperative Karnofsky performance status (table 4).

Discussion

The present study evaluated our preliminary results of the combined technique of awake microsurgical resection and intraoperative MRI for primary brain tumours (including gliomas and brain metastasis) and epilepsy surgery (including cortical dysplasia, non-lesional epilepsy, and cavernoma). The combined intraoperative MRI and awake microsurgical resection is a challenging approach and the patient needs to be cooperative and motivated to participate in all language and/or motor tasks. The role of the anesthesiologist is crucial, both preoperatively (determining if the patient is a suitable candidate, medically and emotionally) and intraoperatively, while maintaining anT appropriate level of anaesthesia and analgesia. There is also much real-time information for the surgeon to process, so this approach requires a skilled and cohesive operative team and a compliant patient.

The anaesthetic technique in an awake brain surgical procedure varies from light or deep sedation [32] to general anaesthesia with an endotracheal tube [33] or laryngeal mask [34]. The anaesthetic goals are mainly to maintain an awake and cooperative patient during cortical mapping while ensuring the safety of the airway, and providing adequate cerebral perfusion and brain relaxation [35]. Inherent challenges are desaturation or hypercapnia during surgery and it is possible that this awake-asleep-awake (AAA) paradigm would potentially interfere with intra-operative testing of the respective eloquent areas due to anaesthesia remnants. Therefore, to avoid such interference, we use a laryngeal mask and Remifentanil, a short-acting synthetic opioid analgesic. The advantage of such a drug is that the context-sensitive half-life remains at 4 minutes after, for example, 4 hours of administration [36] and it is also associated with fewer seizures compared with other opioids. In general, factors that might potentially modulate the effects of anaesthetic agents include but are not limited to, patient age, physical and medical conditions, and pharmacogenetics. Also, dural local anaesthetics are used once the patient is awake. To date, no randomised trials comparing our approach with the awake tumour resection under local anaesthetic [37] have been performed but it is acknowledged that awake tumour resection can be completed using only local anaesthesia [38]. Nevertheless, in our experience, using sedative drugs can be particularly helpful for craniotomy and closure. Due to a lack of comparative studies, there is no evidence showing the superiority of one technique over the other [39].

Of note, the craniotomy is performed when the patient is asleep and the dura mater is not opened during this first step. Once the patient is awake, completely stable and calm, the dura mater is infiltrated to further proceed to its opening, thereby avoiding increased intraoperative intracranial pressure in the transition from asleep to awake with its potential inherent consequences.

The entry cortical point is always selected using the neuronavigation system and if this point is formally contraindicated after cortical stimulation, we proceed to further changes. Indeed, the response of the cortical stimulation provides multiple possibilities for cortical routes and the cranial flap is designed to provide enough room. Naropein-immersed cottonwoods are not used on the dura for local anaesthesia [40], rather the dura is indirectly infiltrated [41]. Importantly, the brain is not pain sensitive, while the basal dura and larger vessel manipulation could potentially engender pain [42].

Cortical stimulation can generate seizures, with an incidence of 5−20% [43]. In our centre, these episodes can be managed by cold Ringer’s lactate solution irrigation of the cortex and patience without the need for intravenous antiepileptic medication [44].

The interruption time due to the intraoperative MRI is usually small, around 30 minutes (15 minutes couch in, 15 minutes couch out).

With regards to the use of such an approach for primary brain tumours and particularly for gliomas, the literature review [11, 17, 20−25, 29−31] shows a clear benefit, increasing the mean extent of resection by approximately 20% for primary brain tumours. Tuominen et al. [24] showed that this approach reduces the risk of postoperative impairment following resection of tumours located in or near speech and motor areas, whilst Mehdorn et al. [23] suggested that there was a slight preponderance in redo surgeries for tumour remnants in the first (11.2%, before the use of intraoperative MRI) compared to the second period (7.4%, after the use of intraoperative MRI). Moreover, interestingly, patients with low-grade gliomas in the second series (using intraoperative MRI) did not experience recurrences as frequently as those in the first series.

The aim of epilepsy surgery is either complete excision or disconnection of the epileptic network while conserving the structure and function of the eloquent cortex [45]; we consider that presurgical correct diagnosis is mandatory for this. Modern epileptologists can use multimodal diagnostic tools, including semiology analysis, electrophysiological recordings, functional testing and complex neuroimaging techniques [45], complementary modalities that define the location and boundaries of the epileptic zone. In challenging cases, stereo-electroencephalography (SEEG) by depth electrodes is considered [46]. The existence of a lesion does not automatically relate to an epileptogenic network solely driven by that specific lesion. Moreover, a lesion can recruit and further drive other epileptogenic zones in the brain, making diagnosis even more challenging [47, 48]. In our experience, SEEG is used when necessary to establish a preoperative project, which proposes an area of microsurgical resection including the electrodes for which intraoperative MRI can refine the pre-planned resection area and evaluate the extent of resection. Together with subcortical mapping and other aiding tools, the surgeon can determine whether further resection is required. The awake component remains crucial for function preservation, thus complete resection becomes strictly related to an SEEG preoperative project.

The infection rate in these particular procedures involving intraoperative MRI and additional staff is approximately 1.2%, which is similar to our overall cohort in classical brain surgeries.

The present study has several inherent limitations. First, the retrospective nature of this study with all the inherent bias. Second, there may be small variations in the volumetric analysis depending on the slice thickness etc. A third limitation is the inclusion of multiple pathologies such as gliomas, brain metastasis, cavernomas, cortical dysplasia etc. However, they all share the same goal, which is for infiltrative brain tumours, the gross-total resection and for others, microsurgical resection while respecting functional neural networks present at their boundaries.

Conclusion

Intraoperative MRI and awake microsurgical resection is a feasible approach with extensive planning and multidisciplinary collaboration. These two methods can be considered complementary and synergic rather than competitive, aimed at improving patient oncological outcomes and quality of life. This case series shows a statistical significance when comparing the percentage initially resected at the time of intraoperative MRI and the final extent of resection for primary brain tumours and although the series is small, these results might translate to a clear neurooncological benefit if extended to a large population of patients.

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