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Spinal cord stimulation for peripheral vascular diseases

Dr Georgios Matis

Neurosurgeon, University Hospital of Cologne

Dr Georgios Matis is a neuroscientist from Greece, where he finished his residency. After spending six months at Weill Cornell Medical College in New York as a research fellow, he moved to Switzerland where he got a scholarship at the University Hospital of Zurich and spent 12 months in the department of neuro-radiology. He was later introduced to neuromodulation by Dr Kuluzakis in Thessaloniki and moved to Germany to learn how to perform these surgeries. He is now the head of the pain and spasticity section in the department of stereotactic and functional neurosurgery at the University Hospital of Cologne, focusing on patients with chronic pain and spasticity.

What is a peripheral vascular disease and how can it be treated with neuromodulation?

For people who have never heard of the term neuromodulation,  you could visit the official site of the international neuromodulation society neuromodulation.com where you can find many definitions of diseases and therapies. To put it simply, neuromodulation is the electrical (electrical impulses) or chemical (drugs) modification of the nervous system, which leads to a different response of the nervous system to a stimulus or a pathological condition. In this context of neuromodulation, we have many many therapies. I’m particularly interested in the intrathecal therapies, the pump therapy and the spinal cord stimulation.

In the spinal cord stimulation, we are trying to implant one or two leads near the spinal cord, apply electrical impulses and modificate the function of the nervous system. There are many indications for this therapy. This includes patients with failed back surgery syndrome or persistent spinal pain syndrome, patients that have already been operated on the spine and still have pain, complex original pain syndrome, vascular disease, angina pectoris or polyneuropathies and many other indications.

Peripheral vascular disease is a huge problem. Worldwide there are approximately 200 million people with peripheral vascular disease, 7 million in the United States and with the prevalence of as high as 30% in older populations. It’s a huge number of patients that could be treated with spinal cord stimulation.

Peripheral vascular disease or peripheral arterial disease is simply the narrowing of the arteries. All or most of the patients have atherosclerosis, i.e. they have lipids in their vessels. Risk factors are considered smoking, hypertension, diabetes and dyslipidemia. It’s a common condition and many of our patients are really under-treated.

What are the different stimulation protocols and can we combine two different neuromodulation techniques?

Jonathan: Now with new stimulation protocols, like burst stimulation, we can properly conduct blinded randomised controlled trials (RCTs). Is that your contention?

Georgios: The scope of writing the article is to draw the colleagues’ attention to spinal cord stimulation for this disease and underline that all the results are based on this tonic stimulation. Now we have new stimulation paradigms/waveforms, like sub-perception with tingling,  burst-like and other sub-perception waveforms. It would be very interesting to examine what will happen if we apply these waveforms or a combination of them at the same time in the same patient. For example, apply tonic stimulation and burst at the same time or apply these waveforms sequentially. e.g. tonic stimulation for one hour and sub-perception stimulation for the next hours. This way we can do double-blinded studies because the patient does not feel any tingling with sub-perception waveforms and we can be sure that the person is telling the truth, which is also a problem in studies. We can also conduct controlled RCTs and examine those patients in whom pain is relieved even if you don’t activate the system. In peripheral vascular disease patients, it’s a little different because you can also see, for example, the colour of the skin when the therapy is working. It would be also fascinating to see how we can combine spinal cord stimulation with other neuromodulation options, such as spinal cord stimulation and dorsal root ganglion stimulation or spinal cord stimulation and peripheral nerve stimulation.

Jonathan: Would that be a double dose of neuromodulation, or is there some non-linear interaction?

Georgios: We are targeting different neural structures. If you stimulate the peripheral nerves, you stimulate the third-order neuron. When using spinal cord stimulation, you’re stimulating the second-order neuron. Maybe if both are simultaneously stimulated, the effect would be much better.

Jonathan: Or maybe you cancel out the effect of the stimulus.

Georgios: Or it could be much worse, this is also an option!

How challenging is device programming in spinal cord stimulation?

Jonathan: In neuromodulation, there is this combinatorial explosion of possibilities, however, a drug is a static asset. It does what it is licensed for and when given to the patient you can vary a couple of parameters like the dose or the time that is taken, but it’s a relatively low dimensional parameter space. Whereas with neuromodulation we immediately get into these very high-dimensional combinatorial explosions. So what does programming look like with this kind of patient? Is there a kind of feedback loop of adjusting parameters and is it as complex or is it simpler?

Georgios: It’s not simpler! Programming is a science, but also an art. It takes many years of experience to be able to program these things. It now becomes more difficult because we have many more options and much more complicated software. However, we have patients who are not satisfied with this option.

Getting to the definition of neuromodulation, we can use leads or drugs intrathecally to influence all neural targets. So we can theoretically treat all diseases involving the nervous system. There is no limit for these indications, this is why I love neuromodulation, it’s an evolving field and every six months at the latest we have something new not only in the spinal cord stimulation but also in all other options. We have vagus nerve stimulation for example which is a very good therapy and currently used only for depression and epilepsy, however, it could be used in the future for autoimmune diseases as well and many other indications.

What we really need is something that we can measure objectively. Pain cannot be measured and this is a massive problem. If you have a person with diabetes you can measure the glucose level in the blood, however, if you have someone with pain you trust the patient, i.e. if the patient says “I have pain” then they have pain. It would be a very good idea to find a biomarker which could help us determine if the patient has pain and how intense this pain is.

The first step in this closed-loop technology that we have had for 4 or 5 years is also fascinating because when we implant the lead, we can not only stimulate the spinal cord but at the same time we can measure the reaction of the spinal cord to the stimulation and turn up the stimulation according to this response. This is one more therapeutic option and I’m sure all companies that are active in this spinal cord stimulation field are going to use it in the future

Is closed-loop stimulation currently used in patients and what are the risks?

Jonathan: Are these evoked potentials used clinically, to program or identify signatures within them that show whether or not you’re likely to get a therapeutic effect?

Georgios: This is not science fiction, it is used every day in practice as we have the technology. There is one specific company that provides this technology at this point. We have already implanted 10 patients in my hospital, and we can see that the results are excellent. Why do we need closed-loop stimulation? Because if we don’t have it, we may be giving much less or even more electrical impulses to the spinal cord, which are not needed. Hence, you have overstimulation or hypostimulation. Neither is good for the patient. In spinal cord stimulation, the closed-loop stimulation stays almost 90% of the time within a small therapeutic window, meaning that the patient gets the electrical impulses that they need and not more than that.

This is a simple explanation of the technology, but we should also mention the disadvantages of this option. And even though it is a fascinating therapy, it is a surgical procedure meaning that major complications could happen in a minority of the patients where they may have infections or bleeding. If the surgeon is inexperienced, they can injure a nerve, and in the long run, a dislocation/movement of the leads in the spinal canal can occur. It’s not a zero-risk therapy; there’s no zero-risk surgery, but the danger is negligible, especially in experienced hands, i.e., surgeons with significant volumes of operations.

What are the limiting factors for scaling the field of neuromodulation?

Jonathan: A lot of people say that the real scalability of neuromodulation lies in non-invasive neuromodulation. Only once we achieve non-invasive approaches to treating these conditions will neuromodulation’s full potential be realized. Then people could essentially receive a device in the post and maybe use it at home with no more complexity than taking an aspirin. However, we’re away from being able to stimulate and record with the same level of fidelity as you can with indwelling devices.

Georgios: You are right. If I were a patient, I would surely choose a non-invasive approach. However, at this point and for the next ten years at least, the implantable systems are the most reliable option as the clinical results are much better

Jonathan: What do you see as the main limiting step in this area? Is it related to clinical research? Is it technological? If someone was going to university and would like to work in this area with a significant impact, should they become an engineer, a clinician, or both?

Georgios: This is also a combination! I think the results would be much better if all of us were interested in doing at least two things in parallel. Maybe it’s not enough to be only a physician or a biomedical engineer, perhaps if you are both of them is much better. Regarding clinical research, if we don’t get enough patients we cannot have big randomized controlled trials with thousands of patients, which is a prerequisite for many insurance companies. And if we don’t conduct these studies then the insurance companies will not pay for the therapy and we cannot help the patients. It’s a difficult situation but it’s also a mentality problem because there are many indications for these therapies and nevertheless there are colleagues, for example, neurologists, who are not referring patients although the data, the publications and the randomized control trials are there.

So I think the first problem that we have to face is how to convince our colleagues that this is a viable option and the insurance companies that it is a cost-effective option because if the system stays for at least three years in the human body then we save money as a society. Unfortunately, neuromodulation is still an exotic thing.

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