NIOM ALERT: COMMENTARY

Simultaneous Direct Cortical Motor Evoked Potential Monitoring and Subcortical Mapping for Motor Pathway Preservation During Brain Tumor Surgery: Is it Useful? Patrick Landazuri and Matthew Eccher

Abstract of Reviewed Article The warning-sign hierarchy between quantitative subcortical motor mapping and continuous motor evoked potential monitoring during resection of supratentorial brain tumors: clinical article. Seidel K, Beck J, Steiglitz L, Schucht P, Raabe A. J Neurosurg 2013; 118:287-296. Objective: Mapping and monitoring are believed to provide an early warning sign to determine when to stop tumor removal to avoid mechanical damage to the corticospinal tract (CST). The objective of this study was to systematically compare subcortical monopolar stimulation thresholds (1–20 mA) with direct cortical stimulation (DCS)–motor evoked potential (MEP) monitoring signal abnormalities and to correlate both with new postoperative motor deficits. The authors sought to define a mapping threshold and DCS-MEP monitoring signal changes indicating a minimal safe distance from the CST. Methods: A consecutive cohort of 100 patients underwent tumor surgery adjacent to the CST while simultaneous subcortical motor mapping and DCSMEP monitoring were used. Evaluation was performed regarding the lowest subcortical mapping threshold (monopolar stimulation, train of 5 stimuli, interstimulus interval 4.0 milliseconds, pulse duration 500 microseconds) and signal changes in DCS-MEPs (same parameters, 4 contact strip electrode). Motor function was assessed 1 day after the surgery, at discharge, and at 3 months postoperatively. Results: The lowest individual motor thresholds (MTs) were as follows (MT in mA, number of patients): .20 mA, n ¼ 12; 11 to 20 mA, n ¼ 13; 6 to 10 mA, n ¼ 20; 4 to 5 mA, n ¼ 30; and 1 to 3 mA, n ¼ 25. Direct cortical stimulation showed stable signals in 70 patients, unspecific changes in 18, irreversible alterations in 8, and irreversible loss in 4 patients. At 3 months, 5 patients had a postoperative new or worsened motor deficit (lowest mapping MT 20 mA, 13 mA, 6 mA, 3 mA, and 1 mA). In all 5 patients, DCS-MEP monitoring alterations were documented (2 sudden irreversible threshold increases and 3 sudden irreversible MEP losses). Of these 5 patients, 2 had vascular ischemic lesions (MT 20 mA, 13 mA) and 3 had mechanical CST damage (MT: 1 mA, 3 mA, and 6 mA; in the latter 2 cases, the resection continued after mapping and severe DCS-MEP alterations occurred thereafter). In 80% of patients with a mapping MT of 1 to 3 mA and in 75% of patients with a mapping MT of 1 mA, DCS-MEPs were stable or showed unspecific reversible changes, and none had a permanent motor worsening at 3 months. In contrast, 25% of patients with irreversible DCS-MEP changes and 75% of patients with irreversible DCS-MEP loss had permanent motor deficits.

J Clin Neurophysiol 2013;30: 623–625 From the The Neurological Institute, Department of Neurology, University Hospitals Case Medical Center, Cleveland, Ohio, U.S.A. Address correspondence and reprint requests to Matthew Eccher, MD, MS, 11100 Euclid Avenue, LKS 6058, Cleveland, OH 44106, U.S.A.; e-mail: matthew_ [email protected]. Copyright  2013 by the American Clinical Neurophysiology Society

ISSN: 0736-0258/13/3006-0623

Conclusions: Mapping should primarily guide tumor resection adjacent to the CST. Direct cortical stimulation-motor evoked potential is a useful predictor of deficits, but its value as a warning sign is limited because signal alterations were reversible in only approximately 60% of the present cases and irreversibility is a post hoc definition. The true safe mapping MT is lower than previously thought. The authors postulate a mapping MT of 1 mA or less where irreversible DCS-MEP changes and motor deficits regularly occur. Therefore, they recommend stopping tumor resection at an MT of 2 mA at the latest. The limited spatial and temporal coverage of contemporary mapping may increase error and may contribute to false, higher MTs.

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he transcranial motor evoked potential (MEP) technique is a widely used component of the NIOM toolkit. Direct cortical stimulation of similar parameters (at lower current intensities) is less frequently used despite having been described first (Taniguchi et al., 1993). Intermittent stimulation for monitoring purposes was first reported in 1996 (Cedzich et al., 1996), with subsequent articles (Kombos et al., 2001, 2003; Sala and Lanteri, 2003) expressing enthusiasm for the use of direct cortical MEP (DCS-MEP) to prevent motor deficit in hemispheric respective surgery. Unfortunately, these articles present patient data in an insufficiently rigorous fashion to inform decision rules for use of the technique. More recently, a potentially complementary technique, obtaining subcortical MEP (scMEP) by stimulation of the resection margin wall, has been evaluated for its ability to assess proximity to the corticospinal tract (CST). Provided cathodal pulses are delivered in a monophasic, “monopolar” fashion (anode distant, e.g., at Fpz), estimates have converged on 1.0 to 1.5 mA/mm from the CST. Kamada et al., (2009) reported the use of a monopolar probe for scMEP and found that smaller stimulation thresholds correlated with closer proximity to the CST by comparing preoperative MR tractography with intraoperative stimulation. Prabhu et al., (2011) confirmed these findings and went 1 step further by comparing scMEP with intraoperative (versus only preoperative) MR tractography, thus accounting for brain shift during surgery. Nossek et al., (2011) also confirmed the findings of Kamada et al., but used intraoperative 3dimensional ultrasonography instead of MRI. By coupling DCS-MEP and scMEP together, a neurophysiologist could conceivably provide a greater degree of proactive guidance to the surgeon to affect a maximization of resection volume. Said more plainly, scMEP can be used to accurately assess the proximity to the CST, whereas concurrent DCS-MEP is used to detect changes to the CST functional integrity, thereby maximizing resection while preserving neurologic function. Seidel et al. provide the first attempt at evaluating the efficacy of just that approach. They report 100 consecutive patients undergoing resection of a pericentral subcortical supratentorial lesion: primary

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Journal of Clinical Neurophysiology  Volume 30, Number 6, December 2013

tumor in 76, metastasis in 17, and cavernoma in 7. Forty-four patients had preoperative motor deficitsd1 MRCS grade 2, 10 grades 3 to 4, and another 33 very subtle weakness “M41.” Patients underwent total intravenous anesthesia with propofol and remifentanil without neuromuscular blockade. EMG needle electrodes were placed in facial muscles and the proximal and distal muscles of both the upper and lower limbs (exactly which muscles not specified). For DCS-MEP monitoring, a 1 · 4 electrode strip was placed over central sulcus using the phase reversal median nerve SSEP technique. Consistent with the originally described technique (Taniguchi et al., 1993), the contact with the highest N20 response, immediately anterior to the phase reversal, was chosen for the delivery of cortical MEP stimulation. Trains of 0.5 msec anodal pulses were used (cathode location unstated), 5 to a train at 250 Hz, repeated every 2 seconds (0.5 Hz). The authors state they then “slightly adjusted” the strip position until MEP response was seen in “all contralateral target muscles. with a threshold below 10 mA.” Stimulation was then continued at 0.5 Hz during subcortical resection. The surgeon was alerted for significant DCS-MEP change, defined as either complete loss of responses or for a change greater than 4 mA in the stimulation threshold necessary for the elicitation of motor responses. The article does not describe how the 4 mA cutoff was established. If there were changes in the DCS-MEP threshold, neuroprotective measures were instituted. These measures included ruling out technical confounders, suspension of tissue excision, removal of retractor, increasing cerebral perfusion pressure to normal, local application of nimodipine, and normalizing anesthesia. For scMEP, cathodal monopolar pulses (anode at Fpz) were delivered with a 1.6-mm probe electrode, using identical train parameters. Timing was at the surgeon’s discretion, but when thresholds were below 10 mA, “motor mapping was repeated every 2 mm of tumor resection with high temporal and spatial frequency.” Resection was halted either (1) when a threshold of 3 mA was reached or (2) when a threshold of 5 mA was reached with normal DCS-MEP if, “the surgeon judged from the intraoperative setting that he would not be able to remove the tumor completely,” with judgment aided by intraoperative ultrasound (K. Seidel, personal communication, February 6, 2013). The authors present the performance of the 2 physiologic tests both including and excluding patients with deficits because of vascular injury (VI, by which is meant ischemia), which is detectable by neither DCS-MEP nor scMEP. This is reasonable, as DCS-MEP can only provide prognostic information after an event has occurred. Subcortical MEP describes an effect local to the stimulating electrode at a single point in time. Exonerating these cases is problematic, as VI may be an intrinsic risk inherent to aggressive approach. Although this approach may be appropriate given the goal of gross total resection, intraoperative VI remains a potentially profound source of morbidity for these procedures. Therefore, it is important that the surgical team is aware of what etiologies these 2 monitoring techniques are able to effectively safeguard against. Despite these concerns, we still agree that it stands to reason that VI cases should be excluded from an efficacy analysis of either technique because both the techniques are incapable of preventing this sort of injury. Consistent with previous publications, Seidel et al. reported that only patients who had significant DCS-MEP change experienced postoperative neurologic deficit at 3 months (Kombos et al., 2001, 2003). In their study population, the significant DCS-MEP cohort represented 12 patients. Of those 12 patients, 5 had persistent neurologic deficit at 3 months. Two of these patients had deficits from VI; their subcortical MTs were 13 and 20 mA, respectively. The remaining 3 patients all had injury that was attributed to direct 624

CST surgical trauma. Two patients had sudden, significant DCSMEP change with last recorded scMEP values of 6 mA and 3 mA, respectively. The third patient, who had a cavernoma, had a scMEP value of 1 mA, but resection continued, “As it was a cavernoma, we believed that we could removed it completely, despite having reached a mapping MT of 1 mA.” Regarding scMEP, the authors emphasize 2 observations. First, only 2 of the 58 patients had DCS-MEP significant change at a scMEP .4 mA, whereas 8 of the 20 patients had DCS-MEP loss at a scMEP of 1 to 4 mA (significant at P , 0.05), again excluding the 2 patients with significant DCS-MEP change secondary to VI. The other scMEP observation was that 2 of the 25 patients with scMEP thresholds of 1 to 3 mA had decreased neurologic function at 3 months, 1 of the 20 patients with scMEP thresholds of 6 to 10 mA had decreased neurologic function at 3 months, and 2 of the 55 patients had scMEP thresholds of .10 mA at decreased neurologic function at 3 months (these 2 patients both had VI). From these findings, the authors arrived at 3 main conclusions. First, unchanged or reversible DCS-MEP findings gave a 100% negative predictive value for postoperative deficit at 3 months. Therefore, if DCS-MEP is preserved throughout the case, motor function is predicted with 100% confidence to be preserved at 3 months. However, irreversible DCS-MEP change is a suboptimal indicator intraoperatively, as it is a post hoc test, a point the authors also acknowledge. When there is an irreversible change, the damage is done. Second, scMEP has a “safe” corridor in which the neurophysiologist and the surgeon can be confident they are sufficiently distant from the CST to not cause iatrogenic damage. This corridor was determined by examining the difference between the scMEP thresholds measured at the time of significant and nonsignificant DCS-MEP changes. As direct surgical damage occurred at a statistically significant lower rate when scMEP is .4 mA, the authors asserted resection could safely proceed at those higher scMEP levels with reasonable certainty that the risk of iatrogenic injury was low. Last, the authors asserted that since the incidence of decreased neurologic deficit at 3 months was relatively low for scMEP thresholds of 1 to 3 mA (2 of the 25 patients), the safe scMEP threshold for resection could be pushed as low as 2 mA. Although Seidel et al. presented sensitivity and specificity values for DCS-MEP and scMEP independently, it seems that their combined use provides more clinically useful data. Therefore, assessing the sensitivity/specificity figures for a combined rule would be appropriate. With a dual criteria of DCS change .4 mA or DCS loss combined with sMEP #3 mA, we find a sensitivity of 66.67% and a specificity of 96.84%. This corresponds with a positive predictive value of 40% and a negative predicative value of 98.92%. Increasing the scMEP criteria to $6 mA yields an increase in the sensitivity to 100% with a specificity of 93.68%. The corresponding positive and negative predicative values are 33.33% and 100%, respectively. These statistical values were found when excluding the two VI cases. In addition, by constructing a receiver operator curve (ROC), an area under the curve (AUC) of 0.79 was found, consistent with good test performance (K. Seidel, personal communication, February 10, 2013; Lowry, 2013). The statistical values for DCSMEP and scMEP as a combined warning criteria provide solid grounding that allow the neurophysiologist to be confident and more proactive in assessing the patient’s neurologic status. Similarly, it is vital to realize that the sensitivity and specificity of scMEP, and to a lesser extent DCS-MEP, is largely dependent on the expertise of the surgeon administering these techniques. Subcortical MEP requires slow, meticulous periods of stimulation to ensure appropriate spatial and temporal mapping of Copyright  2013 by the American Clinical Neurophysiology Society

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the resection cavity. If scMEP is not accurately performed adequately for either of these conditions, the sensitivity and specificity will decrease accordingly. (This is, incidentally, a very interesting situation, as sensitivity and specificity are supposed to be intrinsic characteristics of a clinical test, but this must remain beyond our scope for this review.) This was noted and acknowledged by the authors, who used patient 7 as a case example of a patient who had persistent neurologic injury despite a relatively high scMEP threshold of 6 mA. Therefore, even when this technique is applied appropriately, there is intrinsic risk when a more aggressive resective approach is pursued. In conclusion, we agree the combined technique is an exciting new tool for neurophysiologists and surgeons to use for the prevention of neurologic injury while maximizing resection. Given the very high sensitivity, specificity, and negative predicative value of the combined statistical data for a DCS-MEP change .4 mA or DCS loss combined with scMEP #6 mA, we advocate for repeat scMEP with dense spatial coverage every millimeter after a 6 mA threshold is established while DCS-MEP recordings remain stable. We strongly agree with Seidel et al. that neuroprotective measures should be instituted with any DCS-MEP loss change .4 mA, as the data suggest that DCS-MEP is largely useful to predict prognosis of patients regarding neurologic injury. However, the primary use of scMEP is not as a warning sign. Instead, its use lies only in extending resection volume because unfortunately, scMEP does not assess neurologic function or CST integrity: only CST proximity. Ultimately, the guiding considerations are oncologic, not physiologic. If aggressive resection is deemed of essential importance for gross total resection, then some risks of permanent motor deficit should be accepted, with scMEP used as another tool to guide the surgeon toward a maximal resection.

Copyright  2013 by the American Clinical Neurophysiology Society

Motor Pathway Preservation

ACKNOWLEDGMENT Dr. Landazuri reports no disclosures. Dr. Eccher reports no disclosures. REFERENCES Cedzich C, Taniguchi M, Schäfer S, Schramm J. Somatosensory evoked potential phase reversal and direct motor cortex stimulation during surgery in and around the central region. Neurosurgery 1996;38:962–970. Kamada K, Todo T, Ota T, et al. The motor-evoked potential threshold evaluated by tractography and electrical stimulation. J Neurosurg 2009;11:785– 795. Kombos T, Suess O, Ciklatekerlio O, Brock M. Monitoring of intraoperative motor evoked potentials to increase the safety of surgery in and around the motor cortex. J Neurosurg 2001;95:608–614. Kombos T, Kopetsch O, Suess O, Brock M. Does preoperative paresis influence intraoperative monitoring of the motor cortex? J Clin Neurophys 2003;20:129–134. Lowry R. Simple ROC curve analysis [Vassar Stats website]. 2001-2013. Available at: http://www.vassarstats.net/roc1.html#down. Accessed May 6, 2013. Nossek E, Korn A, Shahar T, et al. Intraoperative mapping and monitoring of the corticospinal tracts with neurophysiological assessment and 3-dimensional ultrasonography-based navigation. J Neurosurg 2011;114:738– 746. Prabhu SS, Gasco J, Tummala S, et al. Intraoperative magnetic resonance imagingguided tractography with integrated monopolar subcortical functional mapping for resection of brain tumors. J Neurosurg 2011;114:719–726. Sala F, Lanteri P. Brain surgery in motor areas: the invaluable assistance of intraoperative neurophysiological monitoring. J Neurosurg Sci 2003;47:79– 88. Seidel K, Beck J, Stieglitz L, et al. The warning-sign hierarchy between quantitative subcortical motor mapping and continuous motor evoked potential monitoring during resection of supratentorial brain tumors. J Neurosurg 2013;118:284–296. Taniguchi M, Cedzich C, Schramm J. Modification of cortical stimulation for motor evoked potentials under general anesthesia: technical description. Neurosurgery 1993;32:219–226.

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Simultaneous direct cortical motor evoked potential monitoring and subcortical mapping for motor pathway preservation during brain tumor surgery: is it useful?

The warning-sign hierarchy between quantitative subcortical motor mapping and continuous motor evoked potential monitoring during resection of suprate...
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