Nov 20, 2024
For certain diagnoses and patients who meetclinical criteria, neuromodulation can provide profound,long-lasting relief that significantly improves quality oflife.
Inthis episode, Aaron Berkowitz, MD, PhD, FAAN speaks with PrasadShirvalkar, MD, PhD, author of the article “Neuromodulation forNeuropathic Pain Syndromes,” in the Continuum® October2024 Pain Management in Neurology issue.
Dr.Berkowitz is a Continuum® Audio interviewer and aprofessor of neurology at the University of California SanFrancisco in the Department of Neurology and a neurohospitalist,general neurologist, and clinician educator at the San Francisco VAMedical Center at the San Francisco General Hospital in SanFrancisco, California.
Dr.Shirvalkar is an associate professor in the Departments ofAnesthesia and Perioperative Care, Neurological Surgery, andNeurology at Weill Institute for Neurosciences at the University ofCalifornia, San Francisco in San Francisco, California.
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Readthe article:Neuromodulation for Neuropathic PainSyndromes
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Host:@AaronLBerkowitz
Guest:@PrasadShirvalka
Full episode transcript availablehere
DrJones: This is DrLyell Jones, Editor in Chief of Continuum, the premiertopic-based neurology clinical review and CME journal from theAmerican Academy of Neurology. Thank you for joining us onContinuum Audio, which features conversations withContinuum's guest editors and authors, who are the leadingexperts in their fields. Subscribers to the ContinuumJournal can read the full article or listen to verbatim recordingsof the article and have access to exclusive interviews not featuredon the podcast. Please visit the link in the episode notes for moreinformation on the article, subscribing to the journal, and how toget CME.
DrBerkowitz: This is DrAaron Berkowitz, and today I'm interviewing Dr Prasad Shirvalkarabout his article on neuromodulation for painful neuropathicdiseases, which appears in the October 2024 Continuumissue on pain management in neurology. Welcome to the podcast, andif you wouldn't mind, please introducing yourself to ourlisteners.
DrShirvalkar: Thanks,Aaron. Yes, of course. So, my name is Prasad Shirvalkar. I'm anassociate professor in anesthesiology, neurology and neurologicalsurgery at UCSF. I am one of those rare neurologists that'sactually a pain physician.
DrBerkowitz: Fantastic.And we're excited to have you here and talk to you more about beinga neurologist in in the field of pain. So, you wrote a fascinatingarticle here about current and emerging neuromodulation devices andtechniques being used to treat chronic pain. And in our interviewtoday, I'm hoping to learn and for our listeners to learn aboutthese devices and techniques and how to determine which patientsmay benefit from them. But before we get into some of the clinicalaspects here, can you first just give our listeners an overview ofthe basic principles of how neuromodulation of various regions ofthe nervous system is thought to reduce pain?
DrShirvalkar: Yeah, I wouldlove to try. But I will promise you that I will not succeed becauseI think to a large extent, we don't understand how neuromodulationworks to treat pain, to describe or to define neuromodulation.Neuromodulation is often described as using electrical stimuli or achemical stimuli to alter nervous system activity to reallyinfluence local activity, but also kind of distant network activitythat might be producing pain. On one level, we don't fullyunderstand how pain arises, specifically how chronic pain arises inthe nervous system. It's a huge focus of study from the NIH HealInitiative and many labs around the world. But acute pain, which iskind of when you stub your toe or you burn your finger, is thoughtto be quite different from the changes over time and the kind ofplasticity that produces emotional, cognitive and sensorydimensions. Really what I think is its own disease, chronic pain,of which there are multiple syndromes when we use neuromodulation,either peripheral nerve stimulation or electrical spinal cordstimulation. One common or predominant theory actually comes from apaper in science from 1967 and people still use it, foundationaltheory and it's called the gate control theory. Two authors,Melzack and Wall, postulated that at the spinal level, there are,there's a local inhibitory circuit or, you know, there's a localcircuit where if you provide input to either peripheral nerves oreither spinal cord ascending fibers that to kind of summarize it,there's only so much bandwidth, you know, that nerves can carry.And so that if you literally pass through artificial signalselectrically, that you will help gate out or block naturalpathological but natural pain signals that might be arising fromthe periphery or spinal cord. So, you know, one idea is that youare kind of interfering with activity that's arising for chemicalneuromodulation. The most common is something known as intrathecaldrug infusion drug delivery ITTD for that we quite literally put acatheter in the spinal fluid, you know, at the level of the dorsalhorn neurons that we think are responsible for perpetuating orcreating the pain.
Where's thepain generator? And you really, you can infuse local anesthetic,you can infuse opioids. And what's nice is you avoid a lot ofsystemic side effects and toxicity because it goes right to thespinal cord, you know, by infusing in the fluid. So there's acouple of modalities, but I will say just, like maybe all of ourliving experience, pain is in the brain. And so, we don't reallyunderstand, I would say, what neuromodulation is doing to thehigher spinal or brain levels.
DrBerkowitz: Fascinatingtopic. And yeah, very interesting to hear both what our currentunderstanding is that some of our current understanding is based ondata that's 60 years old and that we're actually probably learningabout pain by using these modulation techniques, even though wedon't really understand how they might be working. So interestingfeedback loop there as well as in as in the as in this land. So,your article very nicely organizes the neuromodulation techniquesfrom peripheral to central. So, encourage our listeners to checkout your article. And first before we get into some of the clinicalapplications, just to give the listeners the lay of the land, canyou sort of lay out the devices and techniques available fortreating pain at each level of the neuroaxis? We'll get into someof the indications in patient selection in a moment, but just sortof to lay out the landscape. What's available that you and yourcolleagues can use or implant at different levels when we'rethinking of referring patients too?
DrShirvalkar: Absolutely.So, starting from the least invasive or you know, over the counterpatients can purchase themselves a TENS machine. Many folkslistening to this have probably tried a TENS machine in the past.And the idea is that you put a couple of pads, at least two. So youhave like a dipole or you have a positive and a negative lead andyou basically inject some current. So, the pads are attached to abattery and you can put these pads over muscle. If you have areaswhere myofascial pain or sore muscles, you can put them, frankly,over nerves as well and stimulate nerves that are deeper. Most TENSmachines kind of use electrical pulses that occur at differentrates. You change the rates, you can change the amplitude andpatient can kind of have control for what works best. Then gettingslightly more invasive, we can often stimulate electricallyperipheral nerves. To do this we implant through a needle, a smallwire that consists of anywhere from one electrical contact to fouror even eight electrical contact. What I think is particularlycool, like TENS, which is transcutaneous electrical nervestimulation that goes through the skin. Peripheral nervestimulation aims to stimulate nerves, but you don't have to beright up against the nerve. So, yeah. We typically do this under anultrasound and you can visualize a nerve like the sciatic nerve,peroneal nerve, or you know, even if someone has an ulnar or aneuropathy, you know, that's the compression. There's a roleobviously for surgery and release, but if they have predominantlypain, it's not related to a mechanical problem per se, you couldprevent a wire from a peripheral nerve stimulator as far as onecentimeter from a nerve and it'll actually stimulate that thatmodulated and then, you know, kind of progressing even more deeply.The spinal cord stimulation, SCS, it's probably the most ubiquitousor popular form of neuromodulation for pain. People use it for allkinds of diseases. But what it roughly involves is a trial period,which is a placement of either two cylindrical wires, not directlyover the spinal cord, but actually in the epidural space, right?So, it's kind of like when you get an epidural injection or doinglabor and delivery, when women get epidural catheters, placingspinal cord stimulator leads in that same potential space outsidethe dura, and you're stimulating through the dura to actuallytarget the ascending dorsal column fibers. And so, you do a trialperiod or a test drive where the patients get these wires put in.They're coming out of the skin, they're connected to a battery, andthey walk around at home for about a week, take careful notes,check in with them, and they keep a diary or a log about how muchit helps. Separately. I will say it's hard to distinguish this, theplacebo effect often, but you know, sometimes we want to use theplacebo effect in clinical practice, but it is a concern, you know,with such invasive things. But you know, if the trial works well,right, you basically can either keep the leads where they are andplace a battery internally. And it's for neurologists. You'refamiliar with deep brain stimulation. These devices are verysimilar to DVS devices, but they're specifically made for spinalcord stimulation. And there's now like seven companies that offermanufacturers that offer it, each with their own proprietaryalgorithm or workflow. But going yet more invasive, there isintrathecal drug delivery, which I mentioned, which involvesplacement of the spinal catheter and infusion of drug into spinalfluid. You could do a trial for that as well.
Keep apatient in the hospital for a few days. You've all probably hadexperience with lumbar drains. It's something real similar. It justgoes the other way. You know, you're infusing drugs, and it couldalso target peripheral nerves or nerve roots with catheters, andthat's often done.
And last butnot least, there's brain stimulation. Right now, it's allexperimental except for some forms of TMS or transcranial magneticstimulation, which is FDA approved for migraine with aura. Thereare tens machine type devices, cutaneous like stimulators where youcan wear on your head like a crown or with stickers for varioussorts of migraines. I don't really talk about them too much in inthe article, but if there's a fast field out there for adjunctivetherapy as well,
DrBerkowitz: Fantastic.That's a phenomenal overview. Just so we have the lay on the landof these devices. So, from peripheral essentially have peripheralnerve stimulators, spinal cord stimulators, intrathecal drugdelivery devices and then techniques we use in other areas ofneurology emerging for pain DBS deep brain stimulation and TMStranscranial magnetic stimulation. OK let's get into some clinicalapplications now. Let's start with spinal cord stimulators, which -correct me if I'm wrong - seem to be probably the most commonlyseen in practice. Which patients can benefit from spinal cordstimulators? When should we think about referring a patient to youand your colleagues for consideration of implantation of one ofthese spinal cord stimulator devices?
DrShirvalkar: So, you know,it's a great question. I would say it's interesting how to definewhich patients or diagnosis might be appropriate. Technically,spinal cord stimulators are approved for the treatment of mostrecently diabetic peripheral neuropathy. And so, I think that's areally great category if you have patients who have been failed bymore conservative treatments, physical therapy, etcetera, but morecommonly even going back, neuropathic low back pain and neuropathicleg pain. And so, you think about it and it's like, how do youdefine neuropathic pain. Neuropathic pain is kind of broadlydefined as any pain that's caused by injury or some kind of lesionin the somatosensory nervous system. We now broaden that to be morethan just somatosensory nervous system, but still, what if youcan't find a lesion, but the pain still feels or seems neuropathic.Clinically, if something is neuropathic, we often use certainqualitative descriptors to describe that type of pain burning,stabbing, electric light, shooting radiates. There's oftenhyperpathia, like it lingers and spreads in space and time asopposed to, you know, arthritis, throbbing dull pain or as opposedto muscle pain might be myofascial pain, but sometimes it's hard totell. So, there aren't great decision tools, I would say to helpdecide. One of the most common syndromes that we use spinal cordstimulation for is what used to be called failed back surgerysyndrome. We never like to, we now try to shy away from explicitlysaying something is someone has failed in their clinical treatment.So, the euphemism is now, you know, post-laminectomy syndrome. Butin any case, if someone has had back surgery and they still have anervy or neuropathic type pain, either shooting down their legs andoften there's no evidence on MRI or even EMG that that something iswrong, they might be a good candidate, especially if they'rerelying on long term medications that have side effects or thingslike full agonist opioids, you know that that might have sideeffects or contraindication. So, I would say one, it's not a firstline treatment. It's usually after you've gone through physicaltherapy for sure. So, you've gone through tried some medications.Basically, if chronic pain is still impacting your life and yourfunction in a meaningful way that's restricting the things you wantto do, then it it's totally appropriate, I think, to think aboutspinal cord stimulation. And importantly, I will add a hugepredictor of final court stimulation success is psychologicalcomposition, you know, making sure the person doesn't have anyuntreated psychological illness and, and actually making sure theirexpectations going in are realistic. You're not going to cureanyone's pain. You may and that's, you know, a win, but it's veryunlikely. And so, give folks the expectation that we hope to reduceyour pain by 50% or we want you to list personally, I likefunctional goals where you say what is your pain preventing youfrom doing? We want to see if you can do X,Y, and Z during thetrial period. Pharmacostimulation right now. Yeah. Biggestindication low back leg pain, Diabetic peripheral neuropathy. Thereis also an indication for CRPS, complex regional pain syndrome, alesser, I'd say less common but also very debilitating paincondition. For better or worse. Tertiary quaternary care centers.You often will see spinal cord stem used off label for neuropathictype pain syndromes that are not explicitly better. That may be forexample, like a nerve injury that's peripheral, you know, it's notresponding. A lot of this off label use is highly variable and, youknow, on the whole at a population level not very successful. Andso, I think there's been a lot of mixed evidence. So, it'ssomething to be aware about.
DrBerkowitz: That's a veryhelpful framework. So, thinking about referring patients to whohave most commonly probably the patients with chronic low back painhave undergone surgery, have undergone physical therapy, are onmedications, have undergone treatment for any potentialpsychological psychiatric comorbidities, and yet remain disabled bythis pain and have a reasonable expectation and goals that youthink would make them a good candidate for the procedure. Are thosesimilar principles to peripheral nerve stimulation I wasn'tfamiliar with that technique, I'm reading your article, so are theprinciples similar and if so, which particular conditions wouldpotentially benefit from referral for a trial peripheral nervestimulation as opposed to spinal cord stimulation?
DrShirvalkar: Yeah, theprinciples are similar overall. The peripheral nerve stimulation,you know, neuropathic pain with all the characteristics you listed.Interestingly enough, just like spinal cord stim, most insurancesrequire a psychological evaluation for peripheral nerve stim aswell. And we want to make sure again that their expectations arereside, they have good social support and they understand the kindof risks of an invasive device. But also, for peripheral nervestem, specifically, if someone has a traumatic injury of anindividual peripheral nerve, often we will consider it seeing kindof super scapular stimulation. Often with folks who've had shoulderinjuries or even sciatic nerve stimulation. I have done a fewperoneal nerve stimulations as well as occipital nerve stimulationfrom migraine, so oxygen nerve stimulation has been studied a lot.So, it's still somewhat controversial, but in the right patient itcan actually be really helpful.
DrBerkowitz: Very helpful.So, these are patients who have neuropathic pain, but limited toone peripheral nerve distribution as opposed to the more widespreadback associated pains, spine associated pains.
DrShirvalkar: Yeah, Yeah,that's right. And maybe there's one exception actually to this,which is brachial plexopathy. So, you know, folks who've hadsomething like a brachial plexus avulsion or some kind of traumaticinjury to their plexus, there is I think good Class 2 evidence thatperipheral nerve stem can work. It falls under the indication. Noone is as far as to my knowledge, No one's done an explicit trial,you know PNS randomized controlled trial. Yeah, that's, you know,another area one area where PNS or peripheral nerve stems emergingis actually, believe it or not in myofascial low back pain toactually provide muscle stimulation. There are some, there's acompany or two out there that seeks to alter the physiology of themultifidus muscle, one of your spinal stabilizer muscles to reallysee if that can help low back pain. And they've had someinteresting results.
DrBerkowitz: Veryinteresting. You mentioned TENS units earlier, transcutaneouselectrical nerve stimulation as something a patient could get overthe counter. When would you encourage a patient to try TENS andwhen would you consider TENS inadequate and really be thinkingabout a peripheral nerve stimulator?
DrShirvalkar: Yeah, youknow TENS we think of as really appropriate for myofascial pain.Folks who have muscular pain, have clear trigger points or taughtmuscle bands can often get relief from TENS If you turn a TENSmachine up too high, you'll actually see muscle infection. So,there's an optimal level where you actually can turn it up toinduce, like, a gentle vibration.
And so folkswill feel paresthesia and vibrations, and that's kind of the sweetspot. However, I would say if folks have pain that's limited ortemporary in time or after a particular activity, TENS can bereally helpful. The unfortunate reality is TENS often has verytime-limited benefits - just while you're wearing it, you know? So,it's often not enduring. And so that's one of thelimitations.
DrBerkowitz: That'shelpful to understand. We've talked about the present landscape inyour article, also talk a little bit about the future and youalluded to this earlier. Tell us a little bit about some off labelemerging techniques that we may see in future use. Who, which typesof patients, which conditions might we be referring to you and yourcolleagues for deep brain stimulation or transcranial magneticstimulation or motor cortex stimulation? What's coming down thepipeline here?
DrShirvalkar: That's agreat question. You know, one of my favorite topics is deep brainstimulation. I run the laboratory that studies intracranial signalstrying to understand how pain is processed in the brain. But,believe it or not, chronic pain is probably the oldest indicationfor which DBS has been studied. the first paper came out in 1960, Ibelieve, in France. And you know, the, the original pivotal trialsoccurred even before the Parkinson's trial and so fell out of favorbecause in my opinion, I think it was just too hard or toodifficult or a problem or too heterogeneous. You know, many things,but there are many central pain syndromes, you know, poststrokepains, there's often pains associated with Parkinson's disease,epilepsy, or other brain disorders for which we just don't havegood circuit understanding or good targets.
So, I thinkwhat's coming down the pipeline is a better personalized targetidentification, understanding where can we stimulate to actuallyalleviate pain. The other big trend I think in neuromodulation isusing closed loop stimulation which means in contrast totraditional electrical stimulation which is on all the time, youknow it's 24/7, set it and forget it. Actually, having stimulationrespond or adapt to ongoing physiological signals. So that'ssomething that we're seeing in spinal cord stem, but also trying todevelop in deep brain stimulation and noninvasive stimulation. TMSis interestingly approved for neuropathic pain in Europe, but notapproved by the FDA in the US. And so I think we may see thatcoming out of pipeline broader indication. And finally, MR guidedfocused ultrasound is, is a kind of a brand new technique now. Youknow, focused ultrasound lesions are being used for essentialtremor without even making an incision in the skull or drilling inskull. But there are ways to modulate the brain without lesioning.And, you know, I think a lot of research will be emerging on thatin the next five years for, for pain and many other neuronaldisorders.
DrBerkowitz: That'sfascinating. I didn't know that history that DBS was first studiedfor pain and now we think of it mostly for Parkinson's and othermovement disorders. And now the cycle is coming back around to lookat it for pain again. What are some of the targets that are beingstudied that are thought to have benefit or are being shown by yourwork and that of others to have benefit as far as DBS targets for,for chronic pain?
DrShirvalkar: You know,that's a great question. And so, the hard part is finding onetarget that works for all patients. So, it may actually requirepersonalization and actually understanding what brain circuitphenotypes do you have with regards to your chronic pain and thenbased on that, what target might we use? But I will say the oldertargets. Classical targets were periaqueductal gray, which is kindof the opioid center in your brain. You know, it's thought to justrelease large amounts of endogenous opioids when you stimulatethere and then the ventral pusher thalamus, right. So, the sensoryascending system may be through gait control theory interferes withpain, but newer targets the answer singlet there's some interest inin stimulating there again, it doesn't work for everybody. We foundsome interesting findings with the medial thalamus as well asaspects of the caudate and other basal ganglion nuclei that wehopefully will be publishing soon in a data sciencepaper.
DrBerkowitz: Fantastic.That's exciting to hear and encourage all of our listeners to checkout your article. That goes into a lot more depth than we had timeto do in this short interview, both about the science and about theclinical indications, pros and cons, risks and benefits of some ofthese techniques. So again, today I've been interviewing Dr PrasadShirvalkar, whose article on neuromodulation for painfulneuropathic diseases appears in the most recent issue ofContinuum on pain management in neurology. Be sure tocheck out Continuum Audio episodes from this and otherissues. And thank you again to our listeners for joiningtoday.
DrShirvalkar: Thank you forhaving me. It was an honor.
DrMonteith: This is DrTeshamae Monteith, associate editor of Continuum Audio. Ifyou've enjoyed this episode, you'll love the journal, which is fullof in depth and clinically relevant information important forneurology practitioners. Use this link in the episode notes tolearn more and subscribe. AAN members, you can get CME forlistening to this interview by completing the evaluation atcontinpub.com/AudioCME. Thank you for listening toContinuum Audio.
