Navigated Transcranial Magnetic Stimulation
Navigated transcranial magnetic stimulation is considered investigational for all purposes, including but not limited to the preoperative evaluation of patients being considered for brain surgery, when localization of eloquent areas of the brain (e.g., controlling verbal or motor function) is an important consideration in surgical planning.
Navigated transcranial magnetic stimulation (nTMS) is a noninvasive imaging method for the evaluation of eloquent brain areas (e.g., controlling motor or language function). nTMS is being evaluated as an alternative to other noninvasive cortical mapping techniques for presurgical identification of eloquent areas.
Surgical management of brain tumors involves resecting the brain tumor and preserving essential brain function. “Mapping” of brain functions, such as body movement and language, is considered to be most accurately achieved with DCS, an intraoperative procedure that increases operating time and requires a wide surgical opening. Even if not completely accurate compared with DCS, preoperative techniques that map brain functions may aid in planning the extent of resection and the operative approach. Although DCS is still usually performed to confirm the brain locations associated with specific functions, preoperative mapping techniques may provide useful information that improves patient outcomes.
The most commonly used tool for the noninvasive localization of brain functions is functional magnetic resonance imaging (fMRI). fMRI identifies regions of the brain where there are changes in localized cortical blood oxygenation, which correlates with neuronal activity associated with a specific motor or speech task being performed as the image is obtained. The accuracy and precision of fMRI is dependent on the patient’s ability to perform the isolated motor task, such as moving the single assigned muscle without moving others. This may be difficult in patients in whom brain tumors have caused partial or complete paresis. The reliability of fMRI in mapping language areas has been questioned. Guissani et al (2010) reviewed several studies comparing fMRI and DCS of language areas and found large variability in sensitivity and specificity of fMRI. (1) The discussion also pointed out a major conceptual point in how fMRI and DCS “map” language areas: fMRI identifies regional oxygenation changes, which show that a particular region of the brain is involved in the capacity of interest, whereas DCS locates specific areas in which the activity of interest is disrupted. Regions of the brain involved in a certain activity may not necessarily be required for that activity and could theoretically be safely resected.
Magnetoencephalography (MEG) also is used to map brain activity. In this procedure, electromagnetic recorders are attached to the scalp. In contrast to electroencephalography, MEG records magnetic fields generated by electric currents in the brain, rather than the electric currents themselves. Magnetic fields tend to be less distorted by the skull and scalp than electric currents, yielding improved spatial resolution. MEG is conducted in a magnetically-shielded room to screen out environmental electric or magnetic noise that could interfere with the MEG recording. See MPRM policy 6.01.21 for additional information about magnetoencephalography and magnetic source imaging.
nTMS is a noninvasive imaging method for the evaluation of eloquent brain areas. Transcranial magnetic pulses are delivered to the patient as a navigation system calculates the strength, location, and direction of the stimulating magnetic field. The locations of these pulses are registered to a magnetic resonance imaging (MRI) image of the patient’s brain. Surface electromyography (EMG) electrodes are attached to various limb muscles of the patient. Moving the magnetic stimulation source to various parts of the brain causes EMG electrodes to respond, indicating the part of the cortex involved in particular muscle movements. For evaluation of language areas, magnetic stimulation areas that disrupt specific speech tasks are thought to identify parts of the brain involved in speech function. nTMS can be considered a noninvasive alternative to DCS, in which electrodes are directly applied to the surface of the cortex during craniotomy. nTMS is being evaluated as an alternative to other noninvasive cortical mapping techniques, such as fMRI and MEG, for presurgical identification of cortical areas involved in motor and language functions.
The Nexstim® (Helsinki, Finland) eXimia Navigated Brain Stimulation (NBS) System received FDA 510(k) marketing clearance in 2009 for non-invasive mapping of the primary motor cortex of the brain to its cortical gyrus for preprocedural planning.
Similarly, the Nexstim NBS System 4 and NBS System 4 with NexSpeech® received FDA 510(k) clearance in May 2012 for noninvasive mapping of the primary motor cortex and for localization of cortical areas that do not contain speech function, for the purposes of preprocedural planning.
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Test Performance in Healthy Volunteers
In some studies, navigated transcranial magnetic stimulation (nTMS) has been repeated in patients over a relatively short time interval to evaluate whether the test is reliable, that is, produces a similar result. In these studies, it is assumed that nothing in the patient has changed, and any difference in result is due to variations in the testing procedure and any natural variability in the patient.
In a 2013 study by Forster et al., 12 healthy participants underwent nTMS in 2 different sessions, separated by an average of 10 days. (2) Five muscle groups in the upper and lower extremity in each patient were stimulated, and hotspots (points of optimal cortical stimulation) and center of gravity (amplitude-weighted center of the muscle area sensitive to stimulation) for each patient were identified. Mean distance between these points between sessions for each muscle were calculated. The intraclass coefficient in the x axis (mediolateral) and the y axis (anteroposterior) for each muscle was calculated. Overall, across all muscles, mean difference (SD) in hotspot location between sessions was 0.79 (0.47) cm. Mean difference in center of gravity location was 0.57 (0.32) cm. Intraclass coefficients in the anteroposterior axis ranged from 0.54 to 0.89, consistent with moderate to excellent reliability. In the mediolateral axis, intraclass coefficients ranged from 0.11 to 0.89, with several of the coefficients less than 0.49, which is generally regarded as poor reliability.
A 2013 study by Weiss et al. also evaluated the reliability of nTMS and functional MRI (fMRI) in 10 healthy patients. (3) Muscles in the hand, foot, and face were evaluated. in a large proportion of patients, nTMS to evaluate the face and tongue was not feasible due to technical constraints and other artifacts. In contrast, fMRI produced interpretable findings for all muscle groups in all sessions. Mean difference (SD) in hotspot location, as identified by nTMS between sessions, was 10.8 (1.9) mm. Mean difference in maximum activation, as identified by fMRI between sessions, was 6.2 (1) mm, thus showing that fMRI was more reliable than nTMS in locating a specific point associated with a particular muscle. In another type of analysis in which spatial extent of a particular muscle’s activity was mapped by either nTMS or fMRI, neither technique yielded reliable results. Extent of spatial overlap between sessions was very low for both techniques (<32% for each), and intraclass correlation coefficients were also both less than 50%, indicating poor reliability.
Schmidt et al. (2014) in Germany designed a study to examine confounding factors that affect nTMS performance.4 In a 3-part design, investigators differentiated variance due to physiological factors (e.g., tissue conductivity, brain rhythms, cognitive state, peripheral sensory input, preinnervation, brain dysfunction) from physical variation of the nTMS device (i.e., coil location, orientation, and tilt, stimulation strength). Twenty healthy volunteers participated in 2 experiments to compare targeted stimulation (optimal stimulus location, orientation, and tilt parameters) with nontarget-controlled stimulation. Four healthy volunteers participated in a third experiment of maximal physiological confounding variance (e.g., patients were instructed to maximally contract the target muscle). Spatial resolution of nTMS (defined as variation in the area of cortical stimulation that leads to maximum muscle contraction) was found to be approximately 5 mm so that “even small physical fluctuations can confound the statistical comparison of corticospinal excitability measurements.”4 The authors recommended step-wise regression to partition physical from physiological variance in nTMS results and to produce more interpretable data.
Studies in Patients with Brain Lesions
Most studies of nTMS are small case series of patients with brain tumors,5-7 cavernous angiomas,8 arteriovenous malformations,9 or other brain lesions; these are not ideal studies to ascertain diagnostic characteristics. Because of the use of nTMS and/or other methods to identify motor or language centers in the cortex to determine surgical approach, the reference standard of direct cortical stimulation (DCS) may be biased; that is, The DCS procedure may be limited or altered because of the tumor resection or other surgical factors. It is not possible to verify all nTMS sites identified, because the surgical field is limited. Because of this necessarily limited verification, it is difficult to ascertain diagnostic characteristics of nTMS.
nTMS is being studied as a technique to augment preoperative detection of motor corticospinal tracts (CSTs), which are currently identified using diffusion tensor imaging (DTI), an MRI technique. (10,11) Conti et al. (2014) compared the size and location of (cortical) motor maps determined by the cortical end of CSTs, identified using DTI only and nTMS-DTI, to nTMS maps. (10) Twenty patients who underwent brain surgery at a single center in Italy were prospectively enrolled. All brain lesions (70% brain tumors [glioma, astrocytoma, glioblastoma multiforme], 20% cavernous angioma, 10% metastasis) were located within 10 mm of the motor cortex. nTMS-DTI was performed the day before surgery, and standard DTI was obtained after surgery using preoperative imaging data. Direct subcortical stimulation (functional tractography) was applied to confirm tract location. Overlap between nTMS cortical maps and cortical end-regions of CSTs was greater with nTMS-DTI compared with standard DTI (90% vs 58%). Direct subcortical stimulation confirmed CST location in all patients. A potential limitation of the study is lack of DCS to confirm nTMS-determined motor maps. Larger comparative studies with clinical outcomes are needed to assess the clinical relevance of these results.
Comparison With Direct Cortical Stimulation
Picht et al. (2011) evaluated 17 patients with brain tumors using both nTMS and DCS. (12) Both techniques were used to elicit “hotspots,” the point at which either nTMS or DCS produced the largest electromyographic response in the target muscles. Target muscles were selected based on the needs of each particular patient in regard to tumor location and clinical findings. Intraoperative DCS locations were chosen independently of nTMS, and the surgeon was unaware of the nTMS hotspots. For 37 muscles in 17 patients, both nTMS and DCS data were available. Mean (SE) distance between nTMS and DCS hotspots was 7.83 (1.18) mm for the abductor pollicis brevis muscle (95% confidence interval: 5.31 to 10.36) and 7.07 (0.88) mm for the tibialis anterior muscle. When DCS was performed during surgery, there was large variation in the number of stimulation points, and the distance between nTMS and DCS was much less when a larger number of points were stimulated.
Forster et al. (2011) performed a similar study in 11 patients. (13) fMRI also was performed in this study. The distance between corresponding nTMS and DCS hotspots was 10.49 (5.67) mm. The distance between the centroid of fMRI activation and DCS hotspots was 15.03 (7.59) mm. However, it was unclear whether hotspots elicited by either device could be elicited by the other. In at least 2 excluded patients, hotspots were elicited by DCS but not by nTMS.
A 2012 study by Tarapore et al. evaluated distance between nTMS and DCS hotspots. (14) Among 24 patients who underwent nTMS, 18 of whom underwent DCS, 8 motor sites in 5 patients were corresponding. Median distance between nTMS and DCS hotspots was 2.13 (0.29) mm. In the craniotomy field in which DCS mapping was performed, DCS did not elicit any new motor sites that nTMS failed to identify. The study also evaluated magnetoencephalography (MEG); the median distance between MEG motor sites and DCS was 12.1 (8.2) mm.
Mangravati et al. (2012) evaluated the distance between nTMS and DCS hotspots in 7 patients. (5) It is unclear how many hotspots were compared and how many potential comparisons were unavailable due to failure of either device to find a particular hotspot. It appeared that the mean distance between hotspots was based on locations of hotspots for 3 different muscles. The overall mean difference between nTMS and DCS was 8.47 mm, which was less than the mean difference between the fMRI centroid of activation and DCS hotspots (12.9 [5.7] mm).
Krieg et al. (2012) compared nTMS with DCS in 14 patients. (15) However, the navigation device employed appeared to differ from the FDA-approved device. Additionally, the comparison of nTMS to DCS used a different methodology. Both nTMS and DCS were used to map out the whole volume of the motor cortex, and a mean difference between the borders of the mapped motor cortex was calculated. Mean distance between the two methods was 4.4 (3.4) mm.
These studies assessing the distance between nTMS and DCS hotspots appear to show that stimulation sites in which responses can be elicited from both techniques tend to be mapped within 1 cm of each other. This distance tends to be less than the distance between fMRI centers of activation and DCS hotspots. It is difficult to assess the clinical significance of these data, in terms of the utility of the information for presurgical planning.
nTMS for Language Mapping
A 2013 study by Picht et al. evaluated the accuracy of nTMS for identifying language areas. (16) Twenty patients underwent evaluation of language areas over the whole left hemisphere, which was divided into 37 regions. DCS was necessarily performed only in areas accessible in the craniotomy site. data for both methods were available in 160 regions in the 20 patients. Using DCS as the reference standard, there were 46 true positives, 83 false positives, 26 true negatives, and 5 false negatives. Considering the analysis as 160 independent data points for each brain region, nTMS had a sensitivity of 90%, specificity of 24%, positive predictive value (PPV) of 36%, and negative predictive value (NPV) of 84%. An analysis of regions considered to be in the classic Broca’s area (involved in speech production) showed a sensitivity of 100%, specificity of 13%, PPV of 57%, and NPV of 100%.
A 2013 study by Tarapore et al. also evaluated nTMS for identifying language areas (n=12). (17) MEG was also evaluated. A total of 183 regions were evaluated with both nTMS and DCS. In these 183 regions, using DCS as the reference standard, there were 9 true positives, 4 false positives, 169 true negatives, and 1 false negative. This translates to a sensitivity of 90%, specificity of 98%, PPV of 69%, and NPV of 99%.
A research group in Germany published 2 studies of nTMS for mapping cortical language sites, one in healthy volunteers (18) and one in patients with brain tumors. (19) In a case series of 10 healthy volunteers, nTMS test-retest reliability varied across error type (e.g., neologism, semantic error) and cortical region (i.e., anterior or posterior), but overall, both intra- and interobserver reliability were low (range of concordance correlation coefficients: intraobserver, –0.222-0.505; interobserver, –0.135-0.588). (18) In a case report of 3 patients with language-eloquent brain tumors who underwent nTMS and DCS for both initial surgery and repeat surgery for recurrence, nTMS performance characteristics varied by definition of a positive nTMS finding (i.e., a language error made in response to stimulation). (19) For positivity defined by error rates (percentage of stimulations that produced errors) ranging from 5% to 25%, sensitivity was 90% to 10%, specificity was 28% to 89%, PPV was 21% to 17%, and NPV was 93% to 82%. Plasticity of language areas in both healthy volunteers and in patients with brain lesions was identified as a source of variation in nTMS studies across time. As noted in one review, the language network appears to spread over both hemispheres, increasing the complexity of presurgical language mapping.20
The 2013 study by Picht et al. that showed a large proportion of false positives raises concerns about the utility of nTMS for identifying language areas. Even if nTMS were used to rule out areas in which language areas are unlikely, sensitivity of 90% may result in some language areas not appropriately identified.
Studies of Clinical Utility
Formal comparison studies are being conducted evaluating effects on health outcomes of nTMS versus other strategies without nTMS in patients being considered for surgical resection of brain tumors. Such studies would be difficult to design and may be impractical or unethical (discussed further next). Given that results of diagnostic workups of brain tumor patients may determine which patients undergo surgery, the counseling given to patients, and the type of surgery performed, it would be difficult to compare outcomes of groups of patients with qualitatively different outcomes. For example, it is difficult to compare the health outcome of a patient who ends up not being operated on, who conceivably has a shorter overall lifespan but a short period of very high quality of life, with a patient who undergoes operation and has some moderate post-operative disability, but a much longer lifespan.
The Nexstim website (21) lists 2 single-center studies from Germany that compared clinical outcomes in patients with motor-eloquent brain tumors who underwent surgical resection with or without preoperative nTMS. (11, 22) Both studies used historical controls. Frey et al (2014) enrolled 250 consecutive patients who underwent nTMS preoperative mapping and identified 115 similar historical controls. (11) Fifty-one percent of the nTMS group and 48% of controls had WHO grade II to IV gliomas; remaining patients had brain metastases from other primary cancers or other lesions. Intraoperative motor cortical stimulation to confirm nTMS findings was performed in 66% of the nTMS group. British Medical Research Council and Karnofsky scales were used to assess muscle strength and performance status, respectively. Outcomes were assessed at postoperative day 7 and then at 3-month intervals. At 3 months follow-up, 6.1% of the nTMS group and 8.5% of controls had new postoperative motor deficits (chi-square test, p=NS); changes in performance status postoperatively also were similar between groups. Other outcomes were reported for patients with glioma only (n=128 nTMS patients, n=55 controls). Based on postoperative MRI, gross total resection was achieved in 59% of nTMS patients and in 42% of controls (chi-square test, p<0.05). At mean follow-up of 22 months (range, 6-62) in the nTMS group and 25 months (range, 9-57) in controls, mean PFS was similar between groups (mean PFS, 15.5 months [range, 3-51] nTMS vs 12.4 months [range, 3-38] controls; statistical test for survival outcomes not specified, p=NS). In the subgroup of patients with low-grade (grade II) glioma (n=38 nTMS patients, n=18 controls), mean PFS was longer in the nTMS group (mean PFS, 22.4 months [range, 11-50] nTMS vs 15.4 months [range, 6-42] controls; p<0.05), and new postoperative motor deficits were similar (7.5% vs 9.5%, respectively; chi-square test, p=NS). Overall survival did not differ statistically between treatment groups. Interpretation of these findings is limited by: the single-center setting (because nTMS is an operator-dependent technology, applicability may be limited), use of historical controls (surgeon technique and practice likely improved over time), selective outcome reporting (survival outcomes in glioma patients only), and uncertain validity of statistical analyses (primary outcome not identified, no correction for multiple testing, statistical tests not identified). In an accompanying editorial, Jensen outlined the following additional issues complicating interpretation of the study results (23):
In the second study from Germany, Krieg et al. (2014) enrolled 100 consecutive patients who underwent nTMS preoperative mapping and identified 100 historical controls who were matched for tumor location, preoperative paresis, and histology. (22) Most patients had glioblastoma (37%), brain metastasis (24%), or astrocytoma (29%). Data analysis was performed blinded to group assignment. The primary efficacy outcome was not specified. Median follow-up was 7.1 months (range, 0.2–27.2) in the nTMS group and 6.2 months (range, 0.1–79.4) in controls. Incidence of residual tumor by postoperative MRI was less in the nTMS group compared with controls (22% vs. 42%; odds ratio [OR]=0.38 [95% CI: 0.21 to 0.71]). Incidence of new surgery-related transient or permanent paresis did not differ between groups. However, “when also including neurological improvement [undefined] in the analysis,” more patients in the nTMS group improved (12% nTMS vs 1% controls), and similar proportions of patients worsened (13% nTMS vs 18% controls) or remained unchanged (75% nTMS vs. 81% controls; Mann-Whitney-Wilcoxon test, p=0.006). Limitations of this study include the single-center setting, use of historical control, uncertain outcome assessments (“neurological improvement” not defined), and uncertain validity of statistical analyses (primary outcome not identified, no correction for multiple testing).
In his editorial, Jensen challenged the assertion that randomized trials of nTMS would be unethical, suggesting instead that equipoise exists about the best among several noninvasive mapping techniques (fMRI, magnetoencephalography, nTMS). (23) Krieg et al concurred, stating that “a randomized trial on the comparison with the gold standard of intraoperative mapping seems mandatory to gain level I evidence for this modality.” (22)
A (2012) study by Picht et al. attempted to determine the clinical utility of nTMS by assessing whether a change in management occurred as a result of knowledge of nTMS findings. (24) In this study, surgeons first made a surgical plan based on all known information without nTMS findings. After being informed of nTMS findings, the surgical plan was reformulated if necessary. Among 73 patients with brain tumors in or near the motor cortex, nTMS was judged to have changed the surgical indication in 2.7%, changed the planned extent of resection in 8.2%, modified the approach in 16.4%, added awareness of high-risk areas in 27.4%, added knowledge that was not used in 23.3%, and only confirmed the expected anatomy in 21.9%. The first 3 categories in which it was judged that surgery was altered because of nTMS findings were summed to determine “objective benefit,” which was 27.4%.
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov, found 1 ongoing RCT of nTMS, the NICHE trial (NCT02089464), sponsored by Nexstim (Helsinki, Finland). NICHE compares active with sham nTMS for the treatment of post-stroke motor impairment. Expected enrollment is 200 patients, and estimated completion date is July 2016.
Clinical Input Received From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
In response to requests, input was received from 1 physician specialty society (2 reviewers) and 2 academic medical centers while this policy was under review in 2013. Most reviewers considered nTMS to be investigational.
Summary of Evidence
Overall, the literature on navigated transcranial magnetic stimulation (nTMS) is at a preliminary stage for demonstrating effectiveness. Relatively small studies have demonstrated the distance between nTMS hotspots and direct cortical stimulation (DCS) hotspots for the same muscle. Although the average distance in most studies is 1 cm or less, this does not take into account the degree of error in this average distance, or whether there are missed hotspots. It is difficult to fully verify nTMS hotspots because only exposed cortical areas can be verified with DCS. Limited studies of nTMS to evaluate language areas show a high false positive rate (low specificity) and sensitivity that may be insufficient for clinical use. Two studies with methodologic limitations showed similar postoperative motor deficits and improved incidence of complete resection in patients with brain tumors who underwent preoperative evaluation with nTMS compared with historical controls; progression-free survival was improved with nTMS in one subgroup. Another study attempted to demonstrate how clinical decision making has been changed as a result of nTMS results. These studies do not provide strong evidence of the efficacy of nTMS. Based on the limited evidence available and results of clinical vetting, nTMS is considered investigational for all indications.
Practice Guidelines and Position Statements
No guidelines or statements were identified.
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force has not addressed navigated transcranial magnetic stimulation for any indication.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
Motor function mapping using noninvasive navigated transcranial magnetic stimulation (nTMS) for therapeutic treatment planning, upper and lower extremity
C71.0 - C71.9
Malignant neoplasm of the brain code range
Measurement, physiological devices, stimulator – codes for central nervous and peripheral nervous systems
New Policy. Policy created with literature search through August 2013; considered investigational.
Update Related Policies. Remove 6.01.47 as it was archived.
Update Related Policies. Add 6.01.21.
Annual Review. Policy updated with literature review through November 20, 2014; references 4, 6-11, and 18-23 added; policy title changed (acronym deleted); policy statement unchanged.
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