Original Article
Transcranial Electric Stimulation for Intraoperative Motor Evoked Potential Monitoring: Dependence of Required Stimulation Current on Interstimulus Interval Value Boban Joksimovic1
Aleksandar Damjanovic2
Aleksandra Damjanovic2
1 Clinic for Neurosurgery, Clinical Centre of Serbia, Belgrade, Serbia 2 Clinic for Psychiatry, Clinical Centre of Serbia, Belgrade, Serbia
Lukas Rasulic1
Address for correspondence Lukas Rasulic, MD, PhD, Clinic for Neurosurgery, Clinical Centre of Serbia, Visegradska 26, 11000 Belgrade, Serbia (e-mail: [email protected]).
J Neurol Surg A 2015;76:190–198.
Abstract
Keywords
► intraoperative motor evoked potentials ► stimulation parameters ► transcranial electric stimulation
Study Objective To evaluate the relationship between stimulus intensity by constant current transcranial electric stimulation and interstimulus interval (ISI) for eliciting muscle motor evoked potentials (MEPs) in three different hand muscles and the tibialis anterior muscles. Patients/Material and Methods We tested intraoperatively different monophasic constant current pulses and ISIs in 22 patients with clinically normal motor function. Motor thresholds of contralateral muscle MEPs were determined at 0.5 milliseconds (ms) pulse duration and ISIs of 1, 2, 3, 4, 5, and 10 ms using a train of 2, 3, and 5 monophasic constant current pulses of 62 to 104 mA before craniotomy and after closure of the dura mater. Results The lowest stimulation threshold to elicit MEPs in the examined muscles was achieved with a train of 5 pulses (ISI: 3 ms) before craniotomy, which was statistically significant compared with 2 pulses (ISI: 3 ms) as well as 3 pulses (ISIs: 3 and 10 ms). An ISI of 3 ms gave the lowest motor thresholds with statistical significance compared with the ISIs of 4 ms (2 pulses) and of 1 ms (3 pulses). All current intensity (mA) and ISI (ms) relationship graphs had a trend of the exponential function as y ¼ a þ bx þ cρx, where y is intensity (mA) and x is ISI (ms). The minimum of the function was determined for each patient and each muscle. The difference was statistically significant between 3 and 5 pulses before craniotomy and between 3 and 5 pulses and 2 and 5 pulses after closure of the dura mater. Conclusion In adult neurosurgical patients with a normal motor status, a train of 5 pulses and an ISI of 3 ms provide the lowest motor thresholds. We provided evidence of the dependence of required stimulation current on ISI.
Introduction In 1993 Taniguchi et al introduced the methodology for intraoperative use of muscle motor evoked potentials (MEPs) elicited by a train of transcranially applied electric
received March 12, 2014 accepted after revision September 15, 2014 published online January 16, 2015
stimuli.1 At present, there is no standard within the neurophysiologic monitoring community for either montage of the stimulating electrodes used for transcranial electric stimulation (TES) or the stimulation parameters. Therefore, stimulation parameters published by different authors are rarely
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1396438. ISSN 2193-6315.
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190
comparable. There are official guidelines that discuss pulse duration, number of pulses, and interstimulus interval (ISI) in MEP monitoring.2,3 Train pulse number and ISI in milliseconds (ms) or frequency in Hz (ISI ¼ 1000/frequency) are not standardized. Adding pulses reduces the MEP threshold and increases the amplitude, duration, and polyphasia. Calancie et al used 3 or 4 pulses, which seems to be a reasonable starting point for facial MEPs.4–6 Five pulses are another reasonable starting point, although fewer may be sufficient for some patients and more may be needed for others. Some practitioners apply 6 to 8 pulses for long-duration polyphasic MEPs.7 Previous studies have shown that a 4-ms ISI allows full D-wave recovery, minimizes muscle MEP threshold, and may be a good general starting point.8–10 A 1- to 2-ms ISI may be a reasonable starting point when monitoring only facial and/or hand MEPs, which can also separate a stimulus artifact from short latency facial MEPs.6,11 Van Hal et al found large intra- and interindividual differences between the mean optimum interstimulus interval (OISI) of the tibialis anterior (TA) and abductor pollicis brevis (APB) muscles (range: 1.78–2.73 ms).3 The ISI was varied between 0.5 and 4.0 ms, where OISI was defined as the ISI with the highest muscle MEP amplitude for each muscle group. In this study we used the pulse duration and stimulating electrode montage recommended by Szelényi et al10(pulse duration: 0.5 ms; ISI: 4 ms; the stimulating electrode montage C1/C2 or C2/C1 for both the APB and TA muscles and C3/Cz or C4/Cz and Cz/Cz þ 6 cm for the APB muscle, according to the 10–10 system12). Our study was designed to evaluate the TES parameters for eliciting muscle MEPs at threshold intensity by applying constant current transcranial electric stimulation in 2, 3, and 5 monophasic constant current pulses and with ISIs of 1, 2, 3, 4, 5, and 10 ms. Establishing the optimal stimulation model for eliciting MEPs with the lowest stimulation intensity possible may help reduce movement of the patient and might reduce current shunting.
Patients/Material and Methods Patients This study was conducted at the University Hospital of JWG University, Frankfurt/Main, Germany. Participating patients underwent a variety of neurosurgical procedures for brain tumors (meningioma, craniopharyngioma, astrocytoma, hemangioma, glioblastoma multiforme, metastasis), vascular neurosurgical procedures, and spine surgery where intraoperative neurophysiologic monitoring with muscle MEPs is a routine procedure. We tested intraoperatively different monophasic constant current pulse durations and ISI in 22 patients and 27 muscles (median age: 47 20.28 years; 8 women, 14 men). All patients had an unaffected preoperative motor status at the clinical examination, no evidence of seizures, and no implanted devices (e.g., cardiac pacemaker, cochlear implant). Neither
Joksimovic et al.
changes of MEPs nor postoperative paresis was detected in the 22 patients; thus we cannot discuss predictive values for postoperative paresis depending on the different stimulation setups. There were no adverse events caused by the stimulation setup such as a seizure. In the brain tumor cases, the location of the lesion did not involve the corticospinal tract or motor cortex (e.g., the tumors were located in the cerebellum, occipital lobe, prefrontal cortex, and at the skull base). Patients with intrinsic spinal cord or brainstem tumors were also not included in the study. Informed consent was obtained prior to surgery. Upon induction of anesthesia, all stimulating and recording electrodes were attached to the patient. A bite block (rolled gauze) was placed in the mouth to prevent bite injuries due to contraction of masticatory muscles.
Anesthesia Management Intravenous (IV) propofol (200 μg/kg), fentanyl (250 μg), and midazolam (2 mg) were used for anesthesia induction, and propofol (6–12 mg/kg/h) and fentanyl (0.5 μg/kg/h) for maintenance. A short-acting muscle relaxant (cisatracurium, 20 mg IV), was administered for intubation only. The train-of-four technique (percutaneous stimulation of the right median nerve [40 mA, 0.2 ms pulse duration]) and recording of the compound muscle action potentials from the right abductor pollicis brevis muscle was used to monitor muscle relaxation.
Neurophysiologic Methods The ISIS IOM system (Inomed Co., Emmendingen, Germany) equipped with a constant current stimulator (maximum stimulator output: 220 mA) was used for TES and for recording muscle MEPs.
Transcranial Electric Stimulation Corkscrew electrodes for TES (CS electrodes, Inomed Co., Emmendingen, Germany) were placed subcutaneously at C3, C1, Cz, C2, C4, and Cz þ 6 cm according to the international 10–10 electroencephalogram system.12 Later in this text, the first electrode (mentioned in the pair) served as the anode and the second as the cathode (e.g., C1/C2 ¼ C1 anode/ C2 cathode).
Recording of Muscle MEPs Muscle MEPs were recorded by pairs of needle electrodes inserted in the APB, the biceps brachii (BB), the extensor digitorum communis (EDC), and the TA muscles bilaterally with a 2- to 3-cm distance between electrodes. The cutoff value for the impedance of the intramuscular needle electrodes was 2 kΩ. They were recorded on a 100-ms epoch length, a bandpass filter of 1.5 to 853 Hz, and amplified 10,000 times. The motor threshold was defined as the stimulation current that elicited muscle MEPs of a minimum of 30 µV amplitude from the target muscle within three consecutive trials at a 1-Hz train repetition rate. Journal of Neurological Surgery—Part A
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Intraoperative Motor Evoked Potential Monitoring
Intraoperative Motor Evoked Potential Monitoring
Joksimovic et al.
Table 1 Function minimum for all examined muscles elicited at optimal montage with 5, 3, and 2 pulses before craniotomy and after closure of dura mater n
Mean
SD
Med
Min
5 before
27
60.52
27.76
67.00
27.00
125.00
5 after
27
64.81
31.03
55.00
29.00
123.00
3 before
27
70.74
30.21
71.00
30.00
145.00
Max
3 after
27
71.70
35.24
56.00
31.00
137.00
2 before
19
82.05
40.67
77.00
35.00
160.00
2 after
18
86.44
46.72
72.50
34.00
170.00
Function minimum, mA, with number of pulses p value Before
After
3 vs 5
0.005
2 vs 5
0.061
2 vs 3
0.740
3 vs 5
< 0.001
2 vs 5
0.014
2 vs 3
0.098
Abbreviation: SD, standard deviation. The p values were calculated with the Wilcoxon signed rank test.
Motor Thresholds Evaluated at ISIs of 1, 2, 3, 4, 5, and 10 ms TES was performed with multiple trains consisting of 2, 3, and 5 stimuli each. Within each train the individual pulse duration was always 0.5 ms, but the ISI was varied to determine the train configuration requiring the lowest motor thresholds in eliciting muscle MEPs. Maximum stimulation current was 220 mA. These study parameters were selected in accordance with available literature. For all patients, the trains consisting of 2, 3, and 5 stimuli at six different ISIs (1, 2, 3, 4, 5, and 10 ms) were tested. Each train of stimuli was tested at ISIs of 1, 2, 3, 4, 5, and 10 ms. The stimulating electrodes were positioned at C4/Cz and C2/C1 for right hemispheric stimulation and at C3/Cz and C1/C2 for left hemispheric stimulation. Motor thresholds for the left BB (two patients), EDC (three patients), and APB muscles (five patients) were obtained with C4/Cz and C2/C1, for the right BB (one patient), EDC (four patients), and APB muscles (nine patients) with C3/Cz and C1/C2. For both TA muscles (three patients), motor thresholds were obtained with Cz/Cz þ 6 cm montage. The testing was performed before craniotomy and during the opening phase of the surgery and after closure of the dura mater to provide comparable conditions with spinal surgeries (►Table 1).
Analysis and Statistics The analysis of individual number of pulses in the train and ISI was performed by the Friedman test. If the difference was statistically significant (p < 0.05), p values for each pair were calculated with the Wilcoxon signed rank test (►Tables 2 and 3). We recorded 250 mA for measurements without Journal of Neurological Surgery—Part A
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MEP with applied stimulation current of 220 mA. Graphs INTENSITY ¼ F (ISI) were plotted in the OriginPro program.
Results Motor Thresholds Evaluated at ISIs of 1, 2, 3, 4, 5, and 10 ms Number of Stimuli in the Train The lowest stimulation threshold to elicit muscle MEPs in the examined muscles is achieved with a train of 5 pulses (ISI: 3 ms) before craniotomy with statistical significance compared with 2 pulses (ISI: 3 ms) as well as 3 pulses (ISI: 3 and 10 ms) (►Table 4).
Interstimulus Interval An ISI of 3 ms gave the lowest motor thresholds, with statistical significance compared with an ISI of 4, 5, and 10 ms. There was no statistical significant difference between an ISI of 2 and 3 ms with 5 pulses within the train.
Relation between the Current Intensity and ISI for 2, 3, and 5 Pulses Shown in the Graphics (►Figs. 1, 2, and 3) All graphs INTENSITY ¼ F (ISI), that is, y ¼ f(x), have a trend of exponential function y ¼ a þ bx þ cρx, where y is intensity (mA) and x is ISI (ms). The function has a linear part a þ bx and an exponential part cρx (exponential function for base ρ: ρx ¼ exlnρ). Coefficients a, b, c, and ρ are different in formulas of fitted curves with restriction 0 < ρ< 1. This means that different muscles have the same trend of response regardless of stimulus intensity and ISI. The minimum of the function was determined for each patient and each muscle. The
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192
5
3
2
5
3
2
5
3
2
5
3
2
5
3
2
5
3
2
Pulses
2
1
0.003
5
< 0.001
3
< 0.001
Abbreviation: ISS, interstimulus interval.
10
5
4
3
2
1
ISI
< 0.001
< 0.001
3
0.02
< 0.001
< 0.001
5
0.875
0.003
2
3
< 0.001
0.812
0.297
0.003
3
0.004
< 0.001
0.149
5
0.002
0.011
0.006
2
4
< 0.001
0.009
0.115
0.02
3
0.001
< 0.001
0.018
0.614
< 0.001
5
< 0.001
0.001
0.256
2
5
< 0.001
0.098
0.005
0.005
0.02
0.086
3
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< 0.001
2
2
Table 2 The p values before craniotomy
0.003
< .001
< 0.001
< 0.001
0.001
0.006
5
0.001
< 0.001
< 0.001
200 mA) are applied (or have to be increased during surgery). Previous comparison of muscle MEPs elicited cortically with TES with those elicited by stimulation at a brainstem level demonstrated that the latter were simpler in form and 1.8 ms shorter in latency.14 Therefore, the change of the muscle MEP configuration combined with a decrease in latency is further evidence of brainstem stimulation. Our results provide reference values for motor thresholds of EDC muscles for the first time. All motor thresholds for APB and TA are within standard deviation of reference values provided by Szelényi et al.10 The motor threshold values presented here can be used as a guide in patients with a normal motor status. Journal of Neurological Surgery—Part A
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Fig. 2 Relation between the current intensity and interstimulus interval (ISI) for 3 pulses.
Commercially available stimulators with a cutoff intensity of 220 mA are recommended because the threshold values from lower extremity muscles reach 100 mA. This limitation may impair monitoring in a group of patients where the thresholds, especially for lower extremity muscles, may be higher particularly due to neurologic impairment (e.g., cervical myelopathy, spinal cord tumors, brain tumors located parasagittal at the central region). Standardized anesthetic protocol was performed during TES. Individual blood drug levels and individual skull thickness and tissue impedance have an unpredictable effect on the motor threshold levels to TES, which was previously recognized.15–17 One of the most important results of this study is the evidence of the required stimulation current dependence on the value of ISI and the determination of the minimum current value. Very similar functional dependencies and the presence of a minimum in such dependencies were detected in all experimental observations without exception. These experimental dependencies can be adequately described by the following function: y ¼ a þ bx þ cρx. Given
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References 1 Taniguchi M, Cedzich C, Schramm J. Modification of cortical
2
3
4
5
Fig. 3 Relation between the current intensity and interstimulus interval (ISI) for 5 pulses.
the properties of the summands in this formula, that is, linear and exponential functions, this simple mathematical model guarantees the existence of exactly one minimum, which is what was observed in the experiments. In this model, we also have a monotonic decrease of functional dependence to the left of the previously mentioned minimum, and a monotonic increase to the right of this minimum. It is also important to note that the function is convex. All these properties of the introduced mathematical model are in good compliance with experimental results, which allows us to conclude that the proposed mathematical model adequately describes the dependency of the required electrical stimulation parameters on the value of ISI.
Conclusion This study is the first to demonstrate the dependence of required stimulation current on ISI value in TES for intraoperative MEP monitoring. This dependence has a welldefined minimum for all observations. A mathematical model was introduced and its adequacy to the experiments was
6
7
8
9
10
11
12
stimulation for motor evoked potentials under general anesthesia: technical description. Neurosurgery 1993;32(2):219–226 Macdonald DB, Skinner S, Shils J, Yingling C; American Society of Neurophysiological Monitoring. Intraoperative motor evoked potential monitoring: a position statement by the American Society of Neurophysiological Monitoring. Clin Neurophysiol 2013; 124(12):2291–2316 van Hal C, Hoebink E, Polak HE, Racz I, de Kleuver M, Journee HL. Optimum interpulse interval for transcranial electrical train stimulation to elicit motor evoked potentials of maximal amplitude in both upper and lower extremity target muscles. Clin Neurophysiol 2013;124(10):2054–2059 Calancie B, Harris W, Broton JG, Alexeeva N, Green BA. “Thresholdlevel” multipulse transcranial electrical stimulation of motor cortex for intraoperative monitoring of spinal motor tracts: description of method and comparison to somatosensory evoked potential monitoring. J Neurosurg 1998;88(3):457–470 Calancie B, Harris W, Brindle GF, Green BA, Landy HJ. Thresholdlevel repetitive transcranial electrical stimulation for intraoperative monitoring of central motor conduction. J Neurosurg 2001;95(2, Suppl):161–168 Dong CC, Macdonald DB, Akagami R, et al. Intraoperative facial motor evoked potential monitoring with transcranial electrical stimulation during skull base surgery. Clin Neurophysiol 2005; 116(3):588–596 Quiñones-Hinojosa A, Lyon R, Zada G, et al. Changes in transcranial motor evoked potentials during intramedullary spinal cord tumor resection correlate with postoperative motor function. Neurosurgery 2005;56(5):982–993; discussion 982–993 Deletis V, Isgum V, Amassian VE. Neurophysiological mechanisms underlying motor evoked potentials in anesthetized humans. Part 1. Recovery time of corticospinal tract direct waves elicited by pairs of transcranial electrical stimuli. Clin Neurophysiol 2001a;112(3):438–444 Deletis V, Rodi Z, Amassian VE. Neurophysiological mechanisms underlying motor evoked potentials in anesthetized humans. Part 2. Relationship between epidurally and muscle recorded MEPs in man. Clin Neurophysiol 2001b;112(3):445–452 Szelényi A, Kothbauer KF, Deletis V. Transcranial electric stimulation for intraoperative motor evoked potential monitoring: stimulation parameters and electrode montages. Clin Neurophysiol 2007;118(7):1586–1595 Scheufler KM, Reinacher PC, Blumrich W, Zentner J, Priebe HJ. The modifying effects of stimulation pattern and propofol plasma concentration on motor-evoked potentials. Anesth Analg 2005; 100(2):440–447 Nuwer MR, Comi G, Emerson R, et al; International Federation of Clinical Neurophysiology. IFCN standards for digital recording of clinical EEG. Electroencephalogr Clin Neurophysiol 1998;106(3): 259–261
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proven. The lowest stimulation threshold to elicit muscle MEPs in the BB, EDC, APB, and TA muscles, by using a current intensity of 70 to 92 mA, is achieved with a train of 5 pulses. Furthermore, we demonstrated that an ISI of 3 ms gave the lowest motor thresholds (62 29 mA). The most focal stimulating electrode montage for the EDC muscles serves C3/Cz for the right side and C2/C1 cm for the left side. Results of this study can be used as a reasonable starting point. The setup procedure for each individual patient undergoing TES-MEP is the next step in determining the optimal parameter settings when using supramaximal intensity of TES.
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13 Brocke J, Irlbacher K, Hauptmann B, Voss M, Brandt SA. Trans-
cranial magnetic and electrical stimulation compared: does TES activate intracortical neuronal circuits? Clin Neurophysiol 2005; 116(12):2748–2756 14 Rothwell J, Burke D, Hicks R, Stephen J, Woodforth I, Crawford M. Transcranial electrical stimulation of the motor cortex in man: further evidence for the site of activation. J Physiol 1994;481(Pt 1): 243–250 15 Hicks R, Burke D, Stephen J, Woodforth I, Crawford M. Corticospinal volleys evoked by electrical stimulation of human motor
cortex after withdrawal of volatile anaesthetics. J Physiol 1992; 456:393–404 16 Kalkman CJ, Drummond JC, Ribberink AA, Patel PM, Sano T, Bickford RG. Effects of propofol, etomidate, midazolam, and fentanyl on motor evoked responses to transcranial electrical or magnetic stimulation in humans. Anesthesiology 1992;76(4):502–509 17 Ubags LH, Kalkman CJ, Been HD. Influence of isoflurane on myogenic motor evoked potentials to single and multiple transcranial stimuli during nitrous oxide/opioid anesthesia. Neurosurgery 1998;43(1):90–94; discussion 94–95
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Transcranial Electric Stimulation for Intraoperative Motor Evoked Potential Monitoring: Dependence of Required Stimulation Current on Interstimulus Interval Value Boban Joksimovic1
Aleksandar Damjanovic2
Aleksandra Damjanovic2
1 Clinic for Neurosurgery, Clinical Centre of Serbia, Belgrade, Serbia 2 Clinic for Psychiatry, Clinical Centre of Serbia, Belgrade, Serbia
Lukas Rasulic1
Address for correspondence Lukas Rasulic, MD, PhD, Clinic for Neurosurgery, Clinical Centre of Serbia, Visegradska 26, 11000 Belgrade, Serbia (e-mail: [email protected]).
J Neurol Surg A 2015;76:190–198.
Abstract
Keywords
► intraoperative motor evoked potentials ► stimulation parameters ► transcranial electric stimulation
Study Objective To evaluate the relationship between stimulus intensity by constant current transcranial electric stimulation and interstimulus interval (ISI) for eliciting muscle motor evoked potentials (MEPs) in three different hand muscles and the tibialis anterior muscles. Patients/Material and Methods We tested intraoperatively different monophasic constant current pulses and ISIs in 22 patients with clinically normal motor function. Motor thresholds of contralateral muscle MEPs were determined at 0.5 milliseconds (ms) pulse duration and ISIs of 1, 2, 3, 4, 5, and 10 ms using a train of 2, 3, and 5 monophasic constant current pulses of 62 to 104 mA before craniotomy and after closure of the dura mater. Results The lowest stimulation threshold to elicit MEPs in the examined muscles was achieved with a train of 5 pulses (ISI: 3 ms) before craniotomy, which was statistically significant compared with 2 pulses (ISI: 3 ms) as well as 3 pulses (ISIs: 3 and 10 ms). An ISI of 3 ms gave the lowest motor thresholds with statistical significance compared with the ISIs of 4 ms (2 pulses) and of 1 ms (3 pulses). All current intensity (mA) and ISI (ms) relationship graphs had a trend of the exponential function as y ¼ a þ bx þ cρx, where y is intensity (mA) and x is ISI (ms). The minimum of the function was determined for each patient and each muscle. The difference was statistically significant between 3 and 5 pulses before craniotomy and between 3 and 5 pulses and 2 and 5 pulses after closure of the dura mater. Conclusion In adult neurosurgical patients with a normal motor status, a train of 5 pulses and an ISI of 3 ms provide the lowest motor thresholds. We provided evidence of the dependence of required stimulation current on ISI.
Introduction In 1993 Taniguchi et al introduced the methodology for intraoperative use of muscle motor evoked potentials (MEPs) elicited by a train of transcranially applied electric
received March 12, 2014 accepted after revision September 15, 2014 published online January 16, 2015
stimuli.1 At present, there is no standard within the neurophysiologic monitoring community for either montage of the stimulating electrodes used for transcranial electric stimulation (TES) or the stimulation parameters. Therefore, stimulation parameters published by different authors are rarely
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1396438. ISSN 2193-6315.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
190
comparable. There are official guidelines that discuss pulse duration, number of pulses, and interstimulus interval (ISI) in MEP monitoring.2,3 Train pulse number and ISI in milliseconds (ms) or frequency in Hz (ISI ¼ 1000/frequency) are not standardized. Adding pulses reduces the MEP threshold and increases the amplitude, duration, and polyphasia. Calancie et al used 3 or 4 pulses, which seems to be a reasonable starting point for facial MEPs.4–6 Five pulses are another reasonable starting point, although fewer may be sufficient for some patients and more may be needed for others. Some practitioners apply 6 to 8 pulses for long-duration polyphasic MEPs.7 Previous studies have shown that a 4-ms ISI allows full D-wave recovery, minimizes muscle MEP threshold, and may be a good general starting point.8–10 A 1- to 2-ms ISI may be a reasonable starting point when monitoring only facial and/or hand MEPs, which can also separate a stimulus artifact from short latency facial MEPs.6,11 Van Hal et al found large intra- and interindividual differences between the mean optimum interstimulus interval (OISI) of the tibialis anterior (TA) and abductor pollicis brevis (APB) muscles (range: 1.78–2.73 ms).3 The ISI was varied between 0.5 and 4.0 ms, where OISI was defined as the ISI with the highest muscle MEP amplitude for each muscle group. In this study we used the pulse duration and stimulating electrode montage recommended by Szelényi et al10(pulse duration: 0.5 ms; ISI: 4 ms; the stimulating electrode montage C1/C2 or C2/C1 for both the APB and TA muscles and C3/Cz or C4/Cz and Cz/Cz þ 6 cm for the APB muscle, according to the 10–10 system12). Our study was designed to evaluate the TES parameters for eliciting muscle MEPs at threshold intensity by applying constant current transcranial electric stimulation in 2, 3, and 5 monophasic constant current pulses and with ISIs of 1, 2, 3, 4, 5, and 10 ms. Establishing the optimal stimulation model for eliciting MEPs with the lowest stimulation intensity possible may help reduce movement of the patient and might reduce current shunting.
Patients/Material and Methods Patients This study was conducted at the University Hospital of JWG University, Frankfurt/Main, Germany. Participating patients underwent a variety of neurosurgical procedures for brain tumors (meningioma, craniopharyngioma, astrocytoma, hemangioma, glioblastoma multiforme, metastasis), vascular neurosurgical procedures, and spine surgery where intraoperative neurophysiologic monitoring with muscle MEPs is a routine procedure. We tested intraoperatively different monophasic constant current pulse durations and ISI in 22 patients and 27 muscles (median age: 47 20.28 years; 8 women, 14 men). All patients had an unaffected preoperative motor status at the clinical examination, no evidence of seizures, and no implanted devices (e.g., cardiac pacemaker, cochlear implant). Neither
Joksimovic et al.
changes of MEPs nor postoperative paresis was detected in the 22 patients; thus we cannot discuss predictive values for postoperative paresis depending on the different stimulation setups. There were no adverse events caused by the stimulation setup such as a seizure. In the brain tumor cases, the location of the lesion did not involve the corticospinal tract or motor cortex (e.g., the tumors were located in the cerebellum, occipital lobe, prefrontal cortex, and at the skull base). Patients with intrinsic spinal cord or brainstem tumors were also not included in the study. Informed consent was obtained prior to surgery. Upon induction of anesthesia, all stimulating and recording electrodes were attached to the patient. A bite block (rolled gauze) was placed in the mouth to prevent bite injuries due to contraction of masticatory muscles.
Anesthesia Management Intravenous (IV) propofol (200 μg/kg), fentanyl (250 μg), and midazolam (2 mg) were used for anesthesia induction, and propofol (6–12 mg/kg/h) and fentanyl (0.5 μg/kg/h) for maintenance. A short-acting muscle relaxant (cisatracurium, 20 mg IV), was administered for intubation only. The train-of-four technique (percutaneous stimulation of the right median nerve [40 mA, 0.2 ms pulse duration]) and recording of the compound muscle action potentials from the right abductor pollicis brevis muscle was used to monitor muscle relaxation.
Neurophysiologic Methods The ISIS IOM system (Inomed Co., Emmendingen, Germany) equipped with a constant current stimulator (maximum stimulator output: 220 mA) was used for TES and for recording muscle MEPs.
Transcranial Electric Stimulation Corkscrew electrodes for TES (CS electrodes, Inomed Co., Emmendingen, Germany) were placed subcutaneously at C3, C1, Cz, C2, C4, and Cz þ 6 cm according to the international 10–10 electroencephalogram system.12 Later in this text, the first electrode (mentioned in the pair) served as the anode and the second as the cathode (e.g., C1/C2 ¼ C1 anode/ C2 cathode).
Recording of Muscle MEPs Muscle MEPs were recorded by pairs of needle electrodes inserted in the APB, the biceps brachii (BB), the extensor digitorum communis (EDC), and the TA muscles bilaterally with a 2- to 3-cm distance between electrodes. The cutoff value for the impedance of the intramuscular needle electrodes was 2 kΩ. They were recorded on a 100-ms epoch length, a bandpass filter of 1.5 to 853 Hz, and amplified 10,000 times. The motor threshold was defined as the stimulation current that elicited muscle MEPs of a minimum of 30 µV amplitude from the target muscle within three consecutive trials at a 1-Hz train repetition rate. Journal of Neurological Surgery—Part A
Vol. 76
No. A3/2015
191
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Intraoperative Motor Evoked Potential Monitoring
Intraoperative Motor Evoked Potential Monitoring
Joksimovic et al.
Table 1 Function minimum for all examined muscles elicited at optimal montage with 5, 3, and 2 pulses before craniotomy and after closure of dura mater n
Mean
SD
Med
Min
5 before
27
60.52
27.76
67.00
27.00
125.00
5 after
27
64.81
31.03
55.00
29.00
123.00
3 before
27
70.74
30.21
71.00
30.00
145.00
Max
3 after
27
71.70
35.24
56.00
31.00
137.00
2 before
19
82.05
40.67
77.00
35.00
160.00
2 after
18
86.44
46.72
72.50
34.00
170.00
Function minimum, mA, with number of pulses p value Before
After
3 vs 5
0.005
2 vs 5
0.061
2 vs 3
0.740
3 vs 5
< 0.001
2 vs 5
0.014
2 vs 3
0.098
Abbreviation: SD, standard deviation. The p values were calculated with the Wilcoxon signed rank test.
Motor Thresholds Evaluated at ISIs of 1, 2, 3, 4, 5, and 10 ms TES was performed with multiple trains consisting of 2, 3, and 5 stimuli each. Within each train the individual pulse duration was always 0.5 ms, but the ISI was varied to determine the train configuration requiring the lowest motor thresholds in eliciting muscle MEPs. Maximum stimulation current was 220 mA. These study parameters were selected in accordance with available literature. For all patients, the trains consisting of 2, 3, and 5 stimuli at six different ISIs (1, 2, 3, 4, 5, and 10 ms) were tested. Each train of stimuli was tested at ISIs of 1, 2, 3, 4, 5, and 10 ms. The stimulating electrodes were positioned at C4/Cz and C2/C1 for right hemispheric stimulation and at C3/Cz and C1/C2 for left hemispheric stimulation. Motor thresholds for the left BB (two patients), EDC (three patients), and APB muscles (five patients) were obtained with C4/Cz and C2/C1, for the right BB (one patient), EDC (four patients), and APB muscles (nine patients) with C3/Cz and C1/C2. For both TA muscles (three patients), motor thresholds were obtained with Cz/Cz þ 6 cm montage. The testing was performed before craniotomy and during the opening phase of the surgery and after closure of the dura mater to provide comparable conditions with spinal surgeries (►Table 1).
Analysis and Statistics The analysis of individual number of pulses in the train and ISI was performed by the Friedman test. If the difference was statistically significant (p < 0.05), p values for each pair were calculated with the Wilcoxon signed rank test (►Tables 2 and 3). We recorded 250 mA for measurements without Journal of Neurological Surgery—Part A
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MEP with applied stimulation current of 220 mA. Graphs INTENSITY ¼ F (ISI) were plotted in the OriginPro program.
Results Motor Thresholds Evaluated at ISIs of 1, 2, 3, 4, 5, and 10 ms Number of Stimuli in the Train The lowest stimulation threshold to elicit muscle MEPs in the examined muscles is achieved with a train of 5 pulses (ISI: 3 ms) before craniotomy with statistical significance compared with 2 pulses (ISI: 3 ms) as well as 3 pulses (ISI: 3 and 10 ms) (►Table 4).
Interstimulus Interval An ISI of 3 ms gave the lowest motor thresholds, with statistical significance compared with an ISI of 4, 5, and 10 ms. There was no statistical significant difference between an ISI of 2 and 3 ms with 5 pulses within the train.
Relation between the Current Intensity and ISI for 2, 3, and 5 Pulses Shown in the Graphics (►Figs. 1, 2, and 3) All graphs INTENSITY ¼ F (ISI), that is, y ¼ f(x), have a trend of exponential function y ¼ a þ bx þ cρx, where y is intensity (mA) and x is ISI (ms). The function has a linear part a þ bx and an exponential part cρx (exponential function for base ρ: ρx ¼ exlnρ). Coefficients a, b, c, and ρ are different in formulas of fitted curves with restriction 0 < ρ< 1. This means that different muscles have the same trend of response regardless of stimulus intensity and ISI. The minimum of the function was determined for each patient and each muscle. The
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192
5
3
2
5
3
2
5
3
2
5
3
2
5
3
2
5
3
2
Pulses
2
1
0.003
5
< 0.001
3
< 0.001
Abbreviation: ISS, interstimulus interval.
10
5
4
3
2
1
ISI
< 0.001
< 0.001
3
0.02
< 0.001
< 0.001
5
0.875
0.003
2
3
< 0.001
0.812
0.297
0.003
3
0.004
< 0.001
0.149
5
0.002
0.011
0.006
2
4
< 0.001
0.009
0.115
0.02
3
0.001
< 0.001
0.018
0.614
< 0.001
5
< 0.001
0.001
0.256
2
5
< 0.001
0.098
0.005
0.005
0.02
0.086
3
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< 0.001
2
2
Table 2 The p values before craniotomy
0.003
< .001
< 0.001
< 0.001
0.001
0.006
5
0.001
< 0.001
< 0.001
200 mA) are applied (or have to be increased during surgery). Previous comparison of muscle MEPs elicited cortically with TES with those elicited by stimulation at a brainstem level demonstrated that the latter were simpler in form and 1.8 ms shorter in latency.14 Therefore, the change of the muscle MEP configuration combined with a decrease in latency is further evidence of brainstem stimulation. Our results provide reference values for motor thresholds of EDC muscles for the first time. All motor thresholds for APB and TA are within standard deviation of reference values provided by Szelényi et al.10 The motor threshold values presented here can be used as a guide in patients with a normal motor status. Journal of Neurological Surgery—Part A
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Fig. 2 Relation between the current intensity and interstimulus interval (ISI) for 3 pulses.
Commercially available stimulators with a cutoff intensity of 220 mA are recommended because the threshold values from lower extremity muscles reach 100 mA. This limitation may impair monitoring in a group of patients where the thresholds, especially for lower extremity muscles, may be higher particularly due to neurologic impairment (e.g., cervical myelopathy, spinal cord tumors, brain tumors located parasagittal at the central region). Standardized anesthetic protocol was performed during TES. Individual blood drug levels and individual skull thickness and tissue impedance have an unpredictable effect on the motor threshold levels to TES, which was previously recognized.15–17 One of the most important results of this study is the evidence of the required stimulation current dependence on the value of ISI and the determination of the minimum current value. Very similar functional dependencies and the presence of a minimum in such dependencies were detected in all experimental observations without exception. These experimental dependencies can be adequately described by the following function: y ¼ a þ bx þ cρx. Given
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References 1 Taniguchi M, Cedzich C, Schramm J. Modification of cortical
2
3
4
5
Fig. 3 Relation between the current intensity and interstimulus interval (ISI) for 5 pulses.
the properties of the summands in this formula, that is, linear and exponential functions, this simple mathematical model guarantees the existence of exactly one minimum, which is what was observed in the experiments. In this model, we also have a monotonic decrease of functional dependence to the left of the previously mentioned minimum, and a monotonic increase to the right of this minimum. It is also important to note that the function is convex. All these properties of the introduced mathematical model are in good compliance with experimental results, which allows us to conclude that the proposed mathematical model adequately describes the dependency of the required electrical stimulation parameters on the value of ISI.
Conclusion This study is the first to demonstrate the dependence of required stimulation current on ISI value in TES for intraoperative MEP monitoring. This dependence has a welldefined minimum for all observations. A mathematical model was introduced and its adequacy to the experiments was
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stimulation for motor evoked potentials under general anesthesia: technical description. Neurosurgery 1993;32(2):219–226 Macdonald DB, Skinner S, Shils J, Yingling C; American Society of Neurophysiological Monitoring. Intraoperative motor evoked potential monitoring: a position statement by the American Society of Neurophysiological Monitoring. Clin Neurophysiol 2013; 124(12):2291–2316 van Hal C, Hoebink E, Polak HE, Racz I, de Kleuver M, Journee HL. Optimum interpulse interval for transcranial electrical train stimulation to elicit motor evoked potentials of maximal amplitude in both upper and lower extremity target muscles. Clin Neurophysiol 2013;124(10):2054–2059 Calancie B, Harris W, Broton JG, Alexeeva N, Green BA. “Thresholdlevel” multipulse transcranial electrical stimulation of motor cortex for intraoperative monitoring of spinal motor tracts: description of method and comparison to somatosensory evoked potential monitoring. J Neurosurg 1998;88(3):457–470 Calancie B, Harris W, Brindle GF, Green BA, Landy HJ. Thresholdlevel repetitive transcranial electrical stimulation for intraoperative monitoring of central motor conduction. J Neurosurg 2001;95(2, Suppl):161–168 Dong CC, Macdonald DB, Akagami R, et al. Intraoperative facial motor evoked potential monitoring with transcranial electrical stimulation during skull base surgery. Clin Neurophysiol 2005; 116(3):588–596 Quiñones-Hinojosa A, Lyon R, Zada G, et al. Changes in transcranial motor evoked potentials during intramedullary spinal cord tumor resection correlate with postoperative motor function. Neurosurgery 2005;56(5):982–993; discussion 982–993 Deletis V, Isgum V, Amassian VE. Neurophysiological mechanisms underlying motor evoked potentials in anesthetized humans. Part 1. Recovery time of corticospinal tract direct waves elicited by pairs of transcranial electrical stimuli. Clin Neurophysiol 2001a;112(3):438–444 Deletis V, Rodi Z, Amassian VE. Neurophysiological mechanisms underlying motor evoked potentials in anesthetized humans. Part 2. Relationship between epidurally and muscle recorded MEPs in man. Clin Neurophysiol 2001b;112(3):445–452 Szelényi A, Kothbauer KF, Deletis V. Transcranial electric stimulation for intraoperative motor evoked potential monitoring: stimulation parameters and electrode montages. Clin Neurophysiol 2007;118(7):1586–1595 Scheufler KM, Reinacher PC, Blumrich W, Zentner J, Priebe HJ. The modifying effects of stimulation pattern and propofol plasma concentration on motor-evoked potentials. Anesth Analg 2005; 100(2):440–447 Nuwer MR, Comi G, Emerson R, et al; International Federation of Clinical Neurophysiology. IFCN standards for digital recording of clinical EEG. Electroencephalogr Clin Neurophysiol 1998;106(3): 259–261
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proven. The lowest stimulation threshold to elicit muscle MEPs in the BB, EDC, APB, and TA muscles, by using a current intensity of 70 to 92 mA, is achieved with a train of 5 pulses. Furthermore, we demonstrated that an ISI of 3 ms gave the lowest motor thresholds (62 29 mA). The most focal stimulating electrode montage for the EDC muscles serves C3/Cz for the right side and C2/C1 cm for the left side. Results of this study can be used as a reasonable starting point. The setup procedure for each individual patient undergoing TES-MEP is the next step in determining the optimal parameter settings when using supramaximal intensity of TES.
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cranial magnetic and electrical stimulation compared: does TES activate intracortical neuronal circuits? Clin Neurophysiol 2005; 116(12):2748–2756 14 Rothwell J, Burke D, Hicks R, Stephen J, Woodforth I, Crawford M. Transcranial electrical stimulation of the motor cortex in man: further evidence for the site of activation. J Physiol 1994;481(Pt 1): 243–250 15 Hicks R, Burke D, Stephen J, Woodforth I, Crawford M. Corticospinal volleys evoked by electrical stimulation of human motor
cortex after withdrawal of volatile anaesthetics. J Physiol 1992; 456:393–404 16 Kalkman CJ, Drummond JC, Ribberink AA, Patel PM, Sano T, Bickford RG. Effects of propofol, etomidate, midazolam, and fentanyl on motor evoked responses to transcranial electrical or magnetic stimulation in humans. Anesthesiology 1992;76(4):502–509 17 Ubags LH, Kalkman CJ, Been HD. Influence of isoflurane on myogenic motor evoked potentials to single and multiple transcranial stimuli during nitrous oxide/opioid anesthesia. Neurosurgery 1998;43(1):90–94; discussion 94–95
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