Brain Stimulation xxx (2014) 1e5

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Original Research

Safe Use of Repetitive Transcranial Magnetic Stimulation in Patients With Implanted Vagus Nerve Stimulators Noah S. Philip a, b, c, *, S. Louisa Carpenter a, Linda L. Carpenter b, c a b c

Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, RI, USA Laboratory for Clinical and Translational Neuroscience, Butler Hospital, USA Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 December 2013 Received in revised form 31 March 2014 Accepted 2 April 2014 Available online xxx

Vagus nerve stimulation (VNS) and repetitive transcranial stimulation (rTMS) devices are FDA cleared for therapeutic use in treatment resistant depression. Since VNS systems have ferromagnetic components and large-scale safety testing has not been done, the implanted VNS device is considered a contraindication for rTMS therapy. This contraindication should not be considered absolute, as VNS components typically lie outside the electromagnetic field generated by an rTMS treatment coil. We solicited information from clinicians at several academic medical centers through an informal survey about their use of rTMS for depressed patients with implanted VNS systems, and reviewed relevant safety issues with one rTMS device manufacturer. rTMS clinical practices may use special consent procedures and take additional precautions to enhance safety in these situations. Specific recommendations are provided for minimizing risks (heating or movement of VNS components and unintended change in VNS stimulation parameters) when delivering rTMS to patients with implanted VNS systems. Ó 2014 Elsevier Inc. All rights reserved.

Keywords: Repetitive transcranial magnetic stimulation Vagus nerve stimulation Treatment-resistant depression Safety

Introduction Electroconvulsive Therapy (ECT) and Vagus Nerve Stimulation (VNS) are device-based treatments approved for episodes of major depression that do not remit with pharmacotherapy (commonly referred to as treatment resistant depression [TRD]). Cyberonics’ surgically implanted device for stimulation of the left cervical vagus nerve was approved by the U.S. FDA in 2006, after open-label data showed superior 1-year outcomes in a TRD sample with adjunct VNS therapy, compared to a similar cohort receiving naturalistic treatment [1]. Owing to specific inclusion criteria used in the pivotal clinical trials and the surgical nature of the treatment, VNS patients tend to have a relatively high degree of treatment resistance and illness chronicity compared to other samples. While many VNS patients report partial or substantial reduction in

Financial disclosures: In the last two years, both Dr. Noah Philip and Dr. Linda Carpenter have received support for research from Neuronetics Inc., NeoSync Inc., and Cervel Neurotech Inc., through clinical trial contracts with Butler Hospital. Additionally, Dr. Linda Carpenter reports a consulting relationship with Magstim Inc. Ms. S. Louisa Carpenter has no conflicts to disclose. * Corresponding author. 830 Chalkstone Avenue, Providence, RI 02908, USA. E-mail address: [email protected] (N.S. Philip). 1935-861X/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2014.04.001

depressive symptoms, the majority still does not show 50% improvement after one year [1]. These VNS “non-responders” often face relatively few remaining treatment options, as most have already failed multiple antidepressant medication trials (and perhaps ECT) prior to electing surgical implantation of the VNS device. The use of repetitive transcranial magnetic stimulation (rTMS) to alleviate symptoms of depression is a rapidly growing area of psychiatric clinical practice and research. Two devices are currently U.S. FDA cleared to deliver rTMS therapy for TRD. The first such device, Neuronetics’ NeuroStarÒ, became commercially available in 2008 following pivotal trials demonstrating efficacy and safety for stimulation of the left prefrontal cortex with a fixed set of parameters and use of a simple fixed-distance measurement to determine coil placement on the patient’s head [2,3]. Recent data on naturalistic outcomes since the NeuroStar device has been incorporated into real-life clinical practices confirms efficacy and safety of rTMS delivery with this device [4]. A second device (Brainsway “Deep” TMS System) was FDA cleared for the treatment of depression in early 2013 [5]. Commercial launch of this system in the US remains in relatively early stages at present. The introduction and availability of rTMS devices for clinical (i.e., nonresearch) use in the US offers new hope for

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many VNS nonresponders e a group likely to be eager to try a promising new method of noninvasive brain stimulation using electromagnetic field pulses to gain relief from severe and disabling depressive symptoms. Published literature to date suggests that concurrent use of VNS and rTMS should be safe. Schrader et al. [6] investigated induction of current in VNS lead wires placed in conductive gel phantom tissue by single TMS pulses delivered by a Magstim TMS coil. They applied maximal intensity TMS 5 mm from the VNS wire, and induced only a 200 nA, 1.0 ms current. For reference, the peak induced current they measured was below the 0.25e3.5 mA current range programmed for delivery to the vagus nerve during standard VNS therapy. Furthermore, both during and after direct application of TMS pulses over the VNS pulse generator, the VNS system continued to function normally. In an experiment designed to evaluate whether VNS stimulation changed cortical excitability in 5 patients with refractory epilepsy, Di Lazzaro et al. [7] applied single and paired TMS pulses to the motor cortex in patients with implanted VNS systems at baseline and after a month of chronic VNS therapy. They did not report any adverse outcomes or safety considerations related to concurrent TMS and VNS device operation in that study. A TMS consensus safety guidelines document published by Rossi et al. [8] summarized nearly 30 ex vivo or small human sample studies that used TMS in patients with implanted stimulation or recording electrodes. Based on the limited available evidence, the consensus group concluded that TMS is safe in individuals with VNS systems “.as long as the TMS coil is not activated near the components located in the neck or chest,” but they did not provide specific guidance regarding what comprises a safe distance between the two device components. Moreover, they recommended that TMS should only be done in VNS patients “if there are scientifically or medically compelling reasons” to do so, since “unintended neural stimulation” could results from “potentially significant voltages and currents” induced between electrode leads and an internal pulse generator (IPG) if a TMS coil were discharged close to the implanted wires that connected them. Based upon these theoretical safety considerations, patients with intracranial (head and neck) metal objects (including implanted VNS systems) or cardiac pacemakers were systematically excluded from participation in the rTMS registration clinical trials. Therefore, rTMS safety data for this patient population has never been collected. Accordingly, device labeling for the rTMS devices includes warning language based on the theoretical risk of discharging the rTMS coil in close proximity to ferromagnetic metal components. In recognition of the lack of device compatibility data, the FDA issued a Class II Special Controls Guidance Document: Repetitive Transcranial Magnetic Stimulation (rTMS) Systems (26 July 2011) that requires all commercial rTMS devices approved for therapeutic use to carry the following statement as part of their device labeling: “Implanted Stimulator Devices in or near the Head: rTMS devices are contraindicated for use in patients who have active or inactive implants (including device leads), including deep brain stimulators, cochlear implants, and vagus nerve stimulators. Contraindicated use could result in serious injury or death” [9]. Reflecting this requirement, the “Depression Patient’s Manual” distributed with the NeuroStar device describes a general contraindication for use “in patients who have magnetic-sensitive metals implanted in their head or are non-removable and near (within 12 inches) the NeuroStar treatment coil” and cautions further that the device should “not be used in patients who have an implanted device that may not properly function in the presence of the NeuroStar TMS System, even if the device is located outside this (12 inch) distance” [10]. To our knowledge, there are no published reports describing use of rTMS to treat depression in patients with an implanted VNS

device. Nevertheless, the practice is carried out in some academic and nonacademic clinical practice centers. We therefore sought to review and clarify the safety issues surrounding this practice, informed by survey data from academic clinical practices offering treatment with both VNS and rTMS modalities. Methods To generate descriptive data, we reached out via email to clinicians at 20 academic centers that were known to have conducted clinical research with VNS and/or rTMS treatment modalities. There was no incentive or compensation for sites participating in the survey, and no specific patient data were requested or provided. The survey included questions about how referrals of VNS nonresponders to their TMS clinic were received or processed, and how many VNS patients the center had treated thus far. Other items in the survey included an inquiry about the rTMS informed consent process for VNS patients, and also whether the site had ever encountered any adverse events or VNS-specific safety problems when treating with rTMS. We solicited descriptions from each practice about how they managed concurrent delivery of stimulation with both VNS and rTMS, and we asked them to estimate the overall response rate observed for VNS patients treated with rTMS. Results We were able to confirm receipt of the email survey by 17 (85%) academic medical centers. Data from these 17 centers were pooled with experience from our own clinic. Survey respondents consistently identified the potential safety issues for this group as 1) heating or movement of implanted VNS lead wires and coils due to proximal electromagnetic fields from rTMS coil on ferromagnetic components and 2) potential change in the VNS stimulation parameters (settings previously programmed into the internal pulse generator), from induced electrical current in the lead wires. Six sites confirmed they had past experience with delivery of rTMS to one or more VNS patients, six had never declined to treat VNS patients but had no experience to date, and one site had declined to treat a VNS patient due to concern of interaction between the TMS magnet and VNS device. Of the six sites with experience using rTMS in VNS patients, three exclusively used the NeuroStar device, one used both Magstim and NeuroStar devices, and two sites utilized either a Magstim or Magventure device. Pooled experience described by the six experienced sites represented rTMS treatment of 20 VNS patients. None of the sites had experienced any unique adverse events during treatment of VNS patients with rTMS therapy. All of the sites continue to receive referrals for rTMS therapy delivery to patients who remain depressed after a trial of VNS and have implanted VNS device components. Some of the sites we surveyed employ a distinct consent process prior to treating VNS patients than they use for other rTMS patients. Some consent forms incorporate additional language highlighting the unique risks for VNS patients. At least one site had developed a separate consent form especially for patients with implanted metal. All sites indicated their routine procedures involve documentation in the medical record about steps taken to educate VNS patient about risks during rTMS therapy (see Supplemental information for a consent form example). Regarding VNS management during the 4e6 week course of rTMS therapy, most practices indicated they routinely discontinue VNS therapy, i.e., set stimulation intensity to 0 mA prior to starting rTMS and leave it off for the duration of the course of TMS. One group described a practice of turning the VNS stimulator off prior to, and on again immediately following, each individual rTMS session, based on the possibility that the two treatments might act

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synergistically. One site permitted the VNS to remain on during some TMS sessions. Pooled data from the survey indicated that 6 of the 20 (30%) VNS patients treated met their clinic’s standard criteria for positive categorical “response” to rTMS therapy. We contacted Neuronetics to solicit additional information about safety of NeuroStar treatments in patients with implanted VNS systems. The company indicated that, “the compatibility of implanted VNS devices with the NeuroStar TMS magnetic field has not been tested or verified by either VNS’ or NeuroStar TMS’s device manufacturer. Therefore, the NeuroStar labeling includes a warning statement that NeuroStar TMS is contraindicated for use in patients with implanted VNS devices or lead wires. The NeuroStar labeling also requires that the treatment coil is kept at least 30 cm (11.8 inches) from the VNS stimulator (Fig. 1). In practice, the NeuroStar TMS magnetic field diminishes rapidly with distance from the face of the coil, i.e., the magnetic field’s peak occurs at the surface of the scalp and decreases to less than 10% at a distance of about 7 cm (2.75 inches) from the scalp (along the central axis of the treatment coil). Therefore, 30 cm provides a wide margin to prevent device interactions. Regarding VNS lead wires, typically, the closest proximity of the TMS coil is about 15 cm (approximately 6 inches), so again, a wide margin for device interaction is obtained (Fig. 2). Potential interaction could be reduced further indirectly due to the circuitous anatomical pathways by which the induced currents would reach the lead wire. In terms of adverse effects of TMS on VNS pulse generator signals, these devices are designed to reject spurious signals from various electromagnetic sources (e.g. metal detectors) however data regarding detection of signals from TMS devices has not been rigorously tested” (Neuronetics, personal communication). Conclusions While the use of rTMS in VNS patients should certainly be undertaken with caution, there is theoretical support and ex vivo experimental data suggesting that rTMS þ VNS can be safely used in this population, since the distance from implanted VNS lead wires or VNS pulse generators to the rTMS coil typically precludes significant interaction of peaking magnetic energy fields with metal. Our qualitative safety data describing uneventful courses of treatment in 20 depressed VNS patients also confirms that rTMS can

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safely be delivered in clinical practice and underscores the notion that there is no “absolute contraindication” to rTMS therapy based on the presence of a VNS system, assuming device components are implanted in the conventional location in the patient’s neck and chest wall. Particularly for the more severely depressed VNS patients who remain disabled after exhausting multiple standard treatment options, the risk-benefit ratio for undertaking a course of rTMS therapy may compare favorably with alternatives like deep brain stimulation and ECT. Prospective studies with this special population are needed to better determine the likelihood of positive efficacy outcomes following rTMS therapy, but the 30% response rate reported by survey respondents indicates that at least some VNS nonresponders (or those who previously benefitted from VNS but relapsed despite ongoing VNS therapy) will benefit from a trial of rTMS. The safety considerations identified and reviewed in this manuscript and by our survey respondents are based on experience with standard Magstim or Magventure figure-of-eight coils and with the NeuroStar iron-core coil. The spatial distribution of the energy field emanating from the Brainsway H1-coil or from other coils of various shapes and sizes may be significantly broader or penetrate more deeply [11], requiring additional caution for safe use in VNS patients. Until systematic safety data are available for concurrent VNS þ rTMS, practices such as use of special informed consent procedures and thorough medical record documentation remain important from a medicolegal standpoint. Implementing special practices may also serve to raise the patient’s and clinic staff members’ awareness of risks and enhance vigilance while monitoring for adverse events associated with VNS þ rTMS patient care. Guidance from relevant professional societies may be helpful to shape informed consent procedures for situations such as this in the future. Additional conservative steps might include measurement of the distance between coil placement on the scalp and the most cephalad aspect of the VNS coils in the neck (estimated by visual inspection of scar or palpation of the patient’s neck), though no specific distance guarantees safety. A distance of 15 cm (6 inches) or more from the point directly underneath the coil on the patient’s scalp to the location of VNS metal components in the patient’s neck likely results in exposure of the VNS device system to very weak electromagnetic fields that are unlikely to impact its integrity or

Figure 1. Peak magnetic field magnitude falloff along the central axis of a 70 mm figure-8 coil with the stimulator set to a drive level corresponding to an average resting motor threshold (i.e., 1.0 SMT). A: Neuronetics’ product labeling safety margin for metal and implanted devices. Data modeled using “Magnet” software by Infolytica, Montréal, Québec.

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Figure 2. Peak magnetic field magnitude falloff along the central axis of a 70 mm figure-8 coil at a stimulation level setting of 1.0 SMT. Y-axis indicates peak magnetic flux density in Tesla. X-axis indicates distance from coil, in centimeters. A: Closest proximity of the coil to a VNS lead wire, at approximately 15 cm; B: Neuronetics’ product labeling safety margin for metal and implanted devices. Data modeled using “Magnet” software by Infolytica, Montréal, Québec.

function. Alerting the VNS patient to monitor him- or herself closely and to report any new sensations felt in the left chest, neck/ throat, face/ear, or in voice quality may be useful to ensure that no inadvertent change in VNS parameter settings has occurred. Turning the VNS stimulator off prior to each or all rTMS treatments in a given series is perhaps the safest approach for protecting the patient and equipment. It is not known whether resuming VNS therapy after a successful course of rTMS will aid in maintenance of clinical benefits or otherwise amplify antidepressant effects, but adopting a systematic practice of turning VNS back on for interrogation and device diagnostics immediately following completion of a series of rTMS treatments ensures the clinician will have an opportunity for assessment of the VNS device function and for collection of data regarding the safety of concurrent VNS þ rTMS treatment with each individual case. We also suggest that good clinical practice might incorporate notification of device manufacturers when delivering VNS þ rTMS treatment. This would ensure accurate reporting of such use in post-market safety monitoring. Our data on experience with VNS þ rTMS are limited by several factors. First, due to the nonsystematic collection of data through surveys emailed to clinicians at selected academic medical centers, the results reflect primarily qualitative data and the impressions of responding clinicians, rather than comprehensive or quantitative metrics. However, considering the low prevalence of VNS patients in the general population, a larger scale study of rTMS in VNS patients may not be feasible to investigate the important safety and efficacy questions we have addressed. A descriptive database like the one we have started, or a formal registry to which any clinician could add data, could provide valuable information to inform clinical practice. Second, as in all surveys, the omission of data from those who do not participate may have introduced bias. Although there was an 85% survey response rate, it is possible that the other three medical centers chose not to reply owing to adverse efficacy or safety experiences with VNS þ rTMS therapy, or due to medicolegal concerns. In summary, a review of the theoretical risks and informal sampling of current clinical practice in several academic institutions suggests that most VNS patients are able to safely receive

rTMS therapy when caution is applied and heightened attention is given to consent procedures. Acknowledgments We wish to thank Mark Riehl and Mark Demitrack, M.D., at Neuronetics for their assistance. We thank the individuals who responded to surveys, including the five clinics in addition to our own that described patient experience with TMS þ VNS (Medical University of South Carolina Brain Stimulation Service; Sheppard Pratt Health System; Berenson-Allen Center for Noninvasive Brain Stimulation, Beth-Israel Deaconess Hospital; University of Pennsylvania Department of Psychiatry Behavioral Health/UMNDJ-SOM Department of Psychiatry; UCLA TMS Treatment Service at UCLA’s Semel Institute for Neuroscience and Human Behavior). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.brs.2014.04.001. References [1] George MS, Rush AJ, Marangell LB, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry 2005 Sep 1;58(5):364e73. [2] O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry 2007 Dec 1;62(11):1208e16. [3] George MS, Wassermann EM, Williams WA, et al. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport 1995 Oct 2;6(14):1853e6. [4] Carpenter LL, Janicak PG, Aaronson ST, et al. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety 2012 Jul;29(7):587e96. [5] Zangen A, Roth Y, Voller B, Hallett M. Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-coil. Clin Neurophysiol 2005 Apr;116(4):775e9.

N.S. Philip et al. / Brain Stimulation xxx (2014) 1e5 [6] Schrader LM, Stern JM, Fields TA, Nuwer MR, Wilson CL. A lack of effect from transcranial magnetic stimulation (TMS) on the vagus nerve stimulator (VNS). Clin Neurophysiol 2005;116:2501e4. [7] Di Lazzaro V, Oliviero A, Pilato F, et al. Effects of vagus nerve stimulation on cortical excitability in epileptic patients. Neurology 2004 Jun 22;62(12):2310e2. [8] Rossi S, Hallet M, Rossini PM, Pascual-Leone A, Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 2009;120:2008e39.

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[9] U.S. Food and Drug Administration, Center for Devices and Radiological Health. Guidance for Industry and Food and Drug Administration Staff: Class II Special Controls Guidance Document: Repetitive Transcranial Magnetic Stimulation (rTMS) Systems. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuid ance/GuidanceDocuments/ucm265269.htm; Accessed 01.12.13. [10] NeuroStar TMS therapy system user manual, revision F. Malvern, PA: Neuronetics; 2010. [11] Deng ZD, Lisanby SH, Peterchev AV. Electric field depth-focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs. Brain Stimul 2013 Jan;6(1):1e13.