Wireless Dorsal Root Ganglion Stimulation for Treatment of Chronic Pain: A Review and Update on Recent Advances with Minimally Invasive Stimwave Wireless Technology

Wireless Dorsal Root Ganglion Stimulation for Treatment of Chronic Pain: A Review and Update on Recent Advances with Minimally Invasive Stimwave Wireless Technology

Stimwave Technologies Incorporated, Pompano Beach, Florida

Corresponding author: Dr. Laura Tyler Perryman, Stimwave Technologies, Inc. 1310 Park Central Blvd South, Pompano Beach, Florida 33064, USA. Tel: 800-965-5134; Email: laura@stimwave.com

“There is plenty of room at the bottom” Richard Feynman, 1959, a lecture on nanotechnology, American Physical Society meeting at Caltech.

Abstract

Background: Neuromodulation for relief of chronic back has been accepted as a treatment of choice because of its cost effec- tiveness while the technology has evolved to recruit new targets for stimulation and minimally invasive techniques. Dorsal root ganglion (DRG) is one such new target and wireless stimulation is an advancement in neuromodulation.

Objective: Review of Dorsal root ganglion stimulation (DRGS) as an alternative neuromodulation technique to conventional spinal cord stimulation (SCS). DRGS by a novel, minimally invasive wireless technology in the management of chronic back pain and leg pain following failed back surgery.

Material and Methods: Animal experiments have demonstrated DRG as sensory gateway with unique properties of electrical conduction. Its location in the neural foramina and lack of cerebrospinal fluid dynamics promise a stable delivery of stimula- tion. Refined implant designs have improved access to the DRG and prospective multicenter studies have demonstrated utility of DRGS in providing a long lasting relief in chronic pain syndromes. A recent pilot study using our minimally invasive device activated by a wireless system (Stimwave Technologies) reported its safety and feasibility.

Results: DRGS provided more than 50% relief in multicenter studies by conventional apparatus with risks of CSF leak (8%) and wound infection (10%). Motor stimulation in 11% and loss of stimulation in 4% were observed. Wireless DRGS in our pilot study was safe and took an average time of 10 minutes to complete the procedure. Overall pain reduction was close to 60%. From the implantation to the explant (45 days) no adverse events were noted. Results from our other ongoing studies are awaited.

Conclusion: Chronic pain is challenging at all frequencies of stimulation and with the currently available targets and technolo- gies. DRGS by a novel miniature stimulation system with wireless operational capabilities is a feasible approach to minimize the adverse events and to improve the acceptability of the available neuromodulation methods.

Keywords: Neuromodulation; Wireless Stimulation; Dorsal Root Ganglion; Chronic Pain; Spinal Cord Stimulation

Introduction

Therapeutic application of electrical stimulation of dorsal col- umns of spinal cord, known as spinal cord stimulation (SCS) has been in use since Shealy et al described in 1967 for relief of pain in terminally ill patient [1]. SCS has its basis in gate control therapy, and acts by attenuation of pain transmission by activating the afferent A fibers [2]. It also recruits multi- ple fiber tracts supplying several dermatomes and structures probably not responsible for the pain generation. The dorsal column stimulation also has limitations pertaining to the re- gional anatomy within the spinal cord, where the stimulation is applied, like the size/shape of the bony spinal canal, the spi- nal cord, the relative positions, the cerebrospinal fluid volume at the given vertebral level. These variables can certainly influ- ence the stimulation parameters and the energy consumption required for achieving optimum pain relief [3].

Conventional SCS applied at the low frequency range to the dorsal columns was extensively studied in its cost effectiveness and has been a standard of care in chronic pain management [4,5] but not devoid of complications, failures and adverse events [6,7]. The goal remains to be a very specific stimulation of a specific anatomical part of the body or even a dermatome. Targeting intraspinal alternatives like dorsal root ganglion, has been promising in its results compared to the conventional dorsal column SCS [8,9].

Dorsal Root Ganglion (DRG) Characteristics

DRG, a cluster of nerve cell bodies, originates from the neural crest cell in embryo and not from the neural tube; thus con- sidered as gray matter of the spinal cord in the periphery. The ganglia are located in the intervertebral foramina below the pedicle on both sides in the epidural space laterally. DRG axons are sensory afferents relaying pressure, temperature, chemical and nociceptive stimulation to the spinal cord. Action poten- tials initiated in these pseudo-uniploar nerve cells from a dis- tal process can propagate proximally to synapse in the posteri- or horn by-passing the cell body. Following injury, DRG become more and in chronic pain models they have ectopic discharges even at half the normal threshold, making it an ideal target for neuromodulation [10-14].

DRG received attention as a sensory relay station suitable for therapeutic interventions in the form of injections, radiofre- quency lesions and surgical excision [15-28].

While injections provided temporary relief, ablative proce- dures and surgical excisions produced sensory loss and motor paralysis and sometimes led to deafferentation pain [24].

Electrical stimulation on the other hand being reversible, non-ablative and adjustable, appeared to be a more suitable method to therapeutically modulate the DRG and strategies

have been developed with modest beginnings [8,29,30].

The anatomical location and electrical conduction properties of DRG upon stimulation, are expected to provide benefits in particular, reaching the painful areas like feet independent of posture changes at lower energy demands and possibly the lead migration rates would be lower compared to convention- al SCS [31,32]. These advantages are possible following DRGS because of the close proximity of the electrode to the target of stimulation.

Anatomical variations affecting DRGS

SCS has failures and limitations, sometimes not so much due to the technology but because of the spine architecture and dimensions along with the volume/thickness of cerebrospinal fluid (CSF) column. These measurements affect the placement of electrodes and stimulation parameters required to achieve optimum pain relief. Similarly, degenerative changes of spine also affect the intervertebral foramina, pedicles and the spi- nal canal in general changing the relationship with DRG. Ad- ditionally size of the ganglion also varies with the spinal level as reported by Hasegawa et al and by Hamanishi et al. Using MR images, ganglion size was measured and the authors [33] observed that at lower levels of spine, ganglion size was larger (mean width, length and height is 5.7 3 7.1 3 7.3 mm3 for L3

DRG, 6.2 3 8.4 3 8.2 mm3 for L4 DRG, 5.9 3 9.4 3 8.3 mm3 for

L5 DRG). Additionally, 2-8% of the ganglia were not located in the neural foramen of lumbar spine.

In patients with low back pain or sciatica, lumbosacral DRG was categorized as extra or intraforminal or intraspinal by lo- cation. DRG was found outside the neural foramen in 100% of L2, 48% of the L3 level and 27% of the L4. Only 12% of the L5 level DRG were extraforaminal (34). Asymmetry of the gangli- on was also observed in some cases.

DRGS and technology: Earlier workers attempted placement of the conventional lead at the neural foramen, but with very little activation of the DRG itself, while there was stimulation of the dorsal columns and the nerve root instead [30]. Further studies established the lower threshold required for the ac- tion potential in the damaged nerve fibers (responsible for the neuropathic pain) and the propagation of the electrical activity to the dorsal horn [13,35]; necessitating selective neuromod- ulation that reduced the electrical activity propagating to the dorsal horn resulting in pain relief [36].

Conventional SCS apparatus met with difficulties from the de- sign of electrodes and their maneuverability around the neu- ral foramina thus limiting the safety and efficacy of DRGS. The bulky design of the leads with rigid wiring were not very con- genial to operate in the narrow space available for DRG due to risks of compression of the ganglion and stimulation of neigh- boring neural elements as well [29,30,37].

Advancements in the electrode design yielded a specific DRGS lead that is much smaller with more flexibility and proportion- ately compact contacts along with a technique that approaches the superior dorsal aspect of DRG from contralateral inter-lam- inar route using a cursed introducer sheath and stylet.

Clinical Experience with DRGS

A DRGS pilot study concluded in 2012 on 10 patients reported 70% reduction in pain following stimulation, most important- ly in specific locations like back and foot without any adverse events [32]. Next prospective multicenter trial across Europe and Australia in 32 patients with pain resulting from a vari- ety of pathologies (from 51 recruits) demonstrated pain relief of more than 50%, maintained during a 6 month follow up. Adverse events included infection in 10%, CSF leak in 8.6%, and inflammation in 8.6% and inadequate pain relief in 5.7%. There was temporary motor stimulation in 11.4% as well as uncomfortable or failed stimulation in 4.1% [38].

These patients over 1 year follow up period had overall pain reduction by 56.3% with significant reductions in back pain, leg pain and foot pain [31]. A total of 7 patients had explanta- tion of device performed during this follow up.

Wireless DRG Stimulation (Stimwave) system

A minimally invasive percutaneous electrode placement sys- tem with an implantable miniaturized passive lead was intro- duced and studied for its safety and feasibility in 2016. This system is devoid of any other components of neuromodulation than an electrode that communicates with an external power generator via an in-built receiver (Figures 1,2).

Figure 1. Neuro-stimulator electrode, MRI compatible, for both 1.5 and 3 Tesla.

Figure 2. Neurostimulator receiver.

The power generator is external (outside the patient’s body) in a wearable antenna assembly (WAA) and provides the en- ergy and stimulation parameters, as desired by the physician (Figure 3). The distance between the implant and the WAA is short and the energy emitted remains very low to cause any harm because the proprietary wavelength and stimulation are designed to reduce the risk related to wireless energy emis- sion [39,40].

Figure 3. Freedom SCS external device.

In this pilot study, every patient received one stimulator each, placed between L1 and L5 in the neural foramina, for 45 days. The placement of the electrode was percutaneous, under fluo- roscopic guidance (Figure 4,5).

Figure 4. X-ray lumbar spine AP view showing the placement of DRG stimulator.

After proper placement of the lead, DRG was stimulated with parameter settings of 500 ms pulse width and 100Hz frequen- cy. The implantation duration was minimal (mean time of 10 minutes) and even with minimal migration in a few patients, pain relief was not affected [41]. In these11 patients the wire-

less DRGS system was reported to be safe, feasible and promis- ing. The emphasis was not only the minimally invasive nature compared to the bulky implantable conventional SCS appara- tus that requires multiple incisions, but also the power con- sumption required for effective stimulation. Earlier studies with SCS have demonstrated that rechargeable IPG offer sig- nificant savings of 100,000 USD to 300,000 USD per patient life time [42]. While the reduced surgery duration and minimal nature of procedure would not only cut costs of procedure but also offer better cosmetic result in the absence of implantable battery along with the additional wirings; saving the energy consumption as required stimulation parameters kept at low power setting, will be offering a cost effective therapy. How- ever, elucidation of these factors would require further larger multicenter trials and analysis of multiple variables.

Figure 5. The DRG stimulator lead seen in X ray lumbar spine Lateral view.

At present, the wireless DRG stimulation system is being stud- ied for pain relief in chronic intractable conditions like FBSS at various institutions and results have been very promising [43].

 

Discussion

One in five patients receiving conventional SCS fail to respond and relief of leg pain as well as axial pain remain unsatisfactory [44,45]. DRG with its unique functional properties stands out as a neuromodulation target in providing pain relief for these patients. Refined for DRG location, designs of the stimulator systems offer better treatment options and DRGS in recent studies have shown encouraging results [31,32,38].

Also, the postural changes encountered during stimulation along with uncomfortable paresthesias from traditional SCS have been answered by DRGS. The present system however, suffers from the drawbacks of the bulky traditional SCS appa- ratus and the implantable nature of all its components. Sig- nificant equipment related adverse events have been reported [4-7].

A recent pilot study on DRGS using a miniature wireless stimu- lation system has demonstrated the safety, ease and feasibility in 11 patients with back pain [41]. High frequency stimulation (10KHz, pulse width of 30 microseconds, 1.5-2.5 mA inten- sity) delivered by wireless device in a recently reported case of failed back surgery syndrome provided significant relief from chronic pain [46]. In another small group of patients also (study in progress) the wireless DRGS demonstrated encour- aging results. Further studies are, however, required in larger patient population to establish the long term benefits of the wireless device in its efficacy, cost containment, health care impact, cosmetic result and sustenance.

DRGS requires lower stimulation setting compared to a con- ventional SCS system targeting a different anatomical entity while wireless stimulation system reported here might keep the energy levels and power consumption reasonably lower [31,32,38]. Both these variables have to be considered in fu- ture studies because of the economic impact they might pro- vide.

Conventional stimulation produces measurable pain inhibition which may not translate in to clinical relief [46]. Additionally, SCS at low thresholds elicits pain relief less than a supra-per- ception level SCS in cases with chronic neuropathic pain [47].

These are some of the important parameters to be evaluated thoroughly and a minimally invasive system not only has clini- cal but experimental utility also. It is a worthwhile observation that at any given intensity complete reversal of mechanical hy- persensitivity could not be achieved and no-responders to all combinations of frequencies and intensities were observed in animal studies. In clinical practice too, there was never com- plete relief from pain, only satisfactory reduction is considered as treatment success [48,49]. Studies in humans have taken more than 50% relief as a positive therapeutic effect. Thus, there is very significant room for improvement in pain man- agement. Minimally invasive techniques and wireless stimula- tion methods are such improvements in this direction. Several possible new indications for DRG neuromodulation include ischemic pain, chronic regional pain syndrome and restless leg syndrome.

References
  1. Shealy CN, Mortimer JT, Reswick JB. Electrical inhibition of pain by stimulation of the dorsal columns: preliminary clinical report. Anesth Analg. 1967,46(4): 489–491.
  2. Melzack R, Wall PD. Pain mechanisms: A new theory. Science. 1965, 150: 971–979.
  3. Van Kleef M, Mekhail N, van Zundert J. Evidence-based guidelines for interventional pain medicine according to clini- cal diagnoses. Pain Pract. 2009, 9:247–251.
  4. Kumar K, Hunter G, Demeria D. Spinal cord stimulation in treatment of chronic benign pain: challenges in treatment planning and present status, a 22-year experience. Neurosur- gery. 2006, 58:481–496.
  5. North RB, Kidd DH, Zahurak M, James CS, Long DM. Spinal cord stimulation for chronic, intractable pain: experience over two decades. Neurosurgery. 1993, 32:384–394.
  6. Turner JA, Loeser JD, Deyo RA, Sanders SB. Spinal cord stim- ulation for patients with failed back surgery syndrome or com- plex regional pain syndrome: a systematic review of effective- ness and complications. Pain. 2004, 108:137–147.
  7. Mekhail NA, Mathews M, Nageeb F, Guirguis M, Mekhail MN, Cheng J. Retrospective review of 707 cases of spinal cord stimulation: indications and complications. Pain Pract. 2011, 11:148–153.
  8. Pope JE, Deer TR, Kramer J. A systematic review: Current and future directions of dorsal root ganglion therapeutics to treat chronic pain. Pain Med. 2013,14:1477-1496.
  9. Chang Chien GC, Mekhail N. Alternate intraspinal targets for spinal cord stimulation: A systematic review. Neuromodula- tion: Technology at the neural interface 2017. Epub ahead of print.
  10. Devor M. Ectopic discharge in A-beta afferents as a source of neuropathic pain. Exp Brain Res. 2009,196(1):115–128.
  11. Wu G, Ringkamp M, Hartke TV, Murinson BB, Campbell JN, Griffin JW et al. Early onset of spontaneous activity in unin- jured C-fiber nociceptors after injury to neighboring nerve fi- bers. J Neurosci. 2001,21(8):RC140.
  12. Lirk P, Poroli M, Rigaud M, Fuchs A, Fillip P, Huang CY et al. Modulators of calcium influx regulate membrane excitability in rat dorsal root ganglion neurons. Anesth Analg. 2008,107(2): 673–685.
  13. Kovalsky Y, Amir R, Devor M. Simulation in sensory neu- rons reveals a key role for delayed Na+ current in subthreshold oscillations and ectopic discharge: implications for neuropath- ic pain. J Neurophysiol. 2009,102(3):1430–1442.
  14. Rush AM, Cummins TR, Waxman SG. Multiple sodium chan- nels and their roles in electrogenesis within dorsal root gangli- on neurons. J Physiol. 2007, 579(Pt.1):1–14.
  15. Koopmeiners AS, Mueller S, Kramer J, Hogan QH. Effect of electrical field stimulation on dorsal root ganglion neuronal function. Neuromodulation. 2013,16(4):304–311.
  16. Nagda JV, Davis CW, Bajwa ZH, Simopoulos TT. Retrospec- tive review of the efficacy and safety of repeated pulsed and continuous radiofrequency lesioning of the dorsal root gangli- on/segmental nerve for lumbar radicular pain. Pain Physician. 2011,14(4):371–376.
  17. van Kleef M, Barendse GA, Dingemans WA, Wingen C, Lous- berg R, de Lange S et al. Effects of producing a radiofrequency lesion adjacent to the dorsal root ganglion in patient with tho- racic segmental pain. Clin J Pain. 1995,11(4): 325–332.
  18. Van Zundert J, Lamé IE, de Louw A, Jansen J, Kessels F, Pati- jn J et al. Percutaneous pulsed radiofrequency treatmentof the cervical dorsal root ganglion in the treatment of chronic cervi- cal pain syndromes: a clinical audit. Neuromodulation. 2003, 6(1):6–14.
  19. Van Wijk RM, Geurts JW, Wynne HJ. Long-lasting analgesic effect of radiofrequency treatment of the lumbosacral dorsal root ganglion. J Neurosurg. 2001,94:227–231.
  20. Teixeira A, Grandinson M, Sluijter ME. Pulsed radiofrequen- cy for radicular pain due to herniated intervertebral disc: an initial report. Pain Pract. 2005,5(2): 111–115.
  21. Tsou HK, Chao SC, Wang CJ, Chen HT, Shen CC, Lee HT et al. Percutaneous pulsed radiofrequency applied to the L2 dorsal root ganglion for treatment of chronic low-back pain: 3-year experience. J Neurosurg Spine. 2010,12(2):190–196.
  22. Acar F, Miller J, Golshani KJ, Israel ZH, McCartney S, Burchiel KJ. Pain relief after cervical ganglionectomy (C2 and C3) for treatment of medically intractable occipital neuralgia. Stereo- tact Funct Neurosurg. 2008,86(2): 106–112.
  23. Taub A, Robinson F, Taub E. Dorsal root ganglionectomy for intractable monoradicular sciatica. A series of 61 patients. Ste- reotact Funct Neurosurg. 1995,65(1-4): 106–110.
  24. Weigel R, Capelle HH, Schmetz M, Krauss JK. Selective tho- racic ganglionectomy for the treatment of segmental neuro- pathic pain. Eur J Pain. 2012,16(10): 1398–1402.
  25. Wilkinson HA, Chan AS. Sensory ganglionectomy: theory, technical aspects, and clinical experience. J Neurosurg. 2001, 95(1): 61–66.
  26. Vad VB, Bhat AL, Lutz GE, Cammisa F. Transforaminal epi- dural steroid injections in lumbosacral radiculopathy: a pro- spective randomized study. Spine (Phila Pa 1976). 2002, 27(1): 11–16.
  27. Ghahreman A, Ferch R, Bogduk N. The efficacy of transfo- raminal injection of steroids for the treatment of lumbar radic- ular pain. Pain Med. 2010, 11(8): 1149–1168.
  28. Chang Chien GC, Knezevic NN, McCormick Z, Chu SK, Tres- cot AM, Candido KD. Transforaminal versus interlaminar ap- proaches to epidural steroid injections: a systematic review of comparative studies for lumbosacral radicular pain. Pain Phy- sician. 2014,17(4):E509–E524.
  29. Wright RE, Collition JW. Neurostimulation of the L2 dorsal root ganglion for intractable disc pain: Description of a novel technique. Presented at 3rd Conference of International Func- tional Electrical Stimulation Society: September 17–20, 1998; Lucence, Switzerland. 1998.
  30. Lynch PJ, McJunkin T, Eross E, Gooch S, Maloney J. Case re- port: Successful epiradicular peripheral nerve stimulation of the C2 dorsal root ganglion for postherpetic neuralgia. Neuro- modulation. 2011,14(1):58–61.
  31. Liem L, Russo M, Huygen FJ, Van Buyten JP, Smet I, Verrills P et al. One-year outcomes of spinal cord stimulation of the dor- sal root ganglion in the treatment of chronic neuropathic pain. Neuromodulation. 2015,18(1): 41–48.
  32. Deer TR, Grigsby E, Weiner RL, Wilcosky B, Kramer JM. A prospective study of dorsal root ganglion stimulation for the relief of chronic pain. Neuromodulation. 2013, 16(1): 67–71.
  33. Hasegawa T, Mikawa Y, Watanabe R, An HS. Morphometric analysis of the lumbosacral nerve roots and dorsal root ganglia by magnetic resonance imaging. Spine (Phila Pa 1976). 1996, 21(9):1005–1009.
  34. Hamanishi C, Tanaka S. Dorsal root ganglia in the lumbosa- cral region observed from the axial views of MRI. Spine (Phila Pa 1976). 1993,18(13):1753–1756.
  35. Krames ES. The role of the dorsal root ganglion in the de- velopment of neuropathic pain. Pain Med. 2014,15(10): 1669– 1685.
  36. Gemes G, Koopmeiners A, Rigaud M, Lirk P, Sapunar D, Ban- garu ML et al. Failure of action potential propagation in senso- ry neurons: mechanisms and loss of afferent filtering in C-typeunits after painful injury. J Physiol. 2013,591(4): 1111–1131.
  37. Slavin KV, Wess C. Trigeminal branch stimulation for in- tractable neuropathic pain: Technical note. Neuromodulation. 2005,8(1): 7–13.
  38. Liam L, Russo M, Huyten FJPM, Van Buyten JP, Smet I, Ver- rills P et al. A multicenter, prospective trial to assess the safety and performance of the spinal modulation dorsal root ganglion neurostimulator system in the treatment of chronic pain. Neu- romodulation. 2013,16(5): 471-482.
  39. Yearwood TL, Perryman LT. Peripheral Neurostimula- tion with a Microsize Wireless Stimulator. Prog Neurol Surg. 2015,29:168-191.
  40. Tyler Perryman L, Larson P, Glaser J. Tissue depth study for a fully implantable, remotely powered and programmable wireless neural stimulator. Int J Nano Stud Technol. S2: 001, 1-6.
  41. Weiner RL, Yeung A, Garcia CM, Perryman LT, Speck B. Treatment of FBSS low back pain with a novel percutaneous DRG wireless stimulator: pilot and feasibility study. Pain Medi- cine. 2016,17(10): 1911-1916.
  42. Hornberger J, Kumar K, Verhulst E, Clark MA, HernandezJ. Rechargeable spinal cord stimulation versus non-recharge- able system for patients with failed back surgery syndrome: A cost-consequences analysis. Clin J Pain. 2008, 24(3): 244–252.
  43. Billet B, Wynendaele R, Vanquathem NE. Wireless neuro- modulation by a minimally invasive technique for chronic re- fractory pain. Report of preliminary observations. Medical Re- search Archives 2017,5 (8).
  44. Kemler MA,De Vet HC, Barendse GA, Van Den Wildenberg FA, Van Kleef M. Effect of spinal cord stimulation for chronic complex regional pain syndrome type I:five-year final fol- low-up of patients in a randomized controlled trial. J Neuro- surg. 2008,108(2): 292–298.
  45. Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J et al. Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain. 2007,132(1-2): 179–188.
  46. Bart B, Wynendaele R, Vanquathem NE. Wireless neuro- modulation for chronic back pain: Delivery of high frequency dorsal root ganglion stimulation by a minimally invasive tech- nique. Case reports in Medicine. 2017
  47. Wolter T, Kiemen A, Porzelius C, Kaube H. Effects of subper- ception threshold spinal cord stimulation in neuropathic pain:A randomized controlled double-blind crossover study. Eur J Pain. 2012, 16(5):648–655.
  48. Meyerson BA, Linderoth B. Mode of action of spinal cord stimulation in neuropathic pain. J Pain Symptom Manage. 2006, 31(4 suppl):S6–12.
  49. Carter ML. Spinal cord stimulation in chronic pain: A re- view of the evidence. Anaesth Intensive Care. 2004, 32:11–21.

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