 We're going to speak today about current management of diaphragm paralysis. My name is Dr. Matthew Kaufman. The other speakers will be Dr. Thomas Bauer, who's the chairman of surgery at Jersey Shore University Medical Center, the chief of thoracic surgery at Jersey Shore University Medical Center and the associate professor of surgery at HMH School of Medicine and Dr. David Brown, who's the outpatient medical director and director of the electrodiagnostic laboratory at JFK Johnson Rehabilitation Institute, part of the HMH system in Edison, New Jersey. And I'm a plastic and reconstructive surgeon and the co-director for the Center for Treatment of Paralysis and Reconstructive Nerve Surgery at Jersey Shore. I also have an appointment at UCLA Medical Center. Before we begin, just a few housekeeping items. In order to receive your CME credits, please make sure you either entered your full name when you logged on or you can also send it through chat, your full name. And we will use this to process your CMEs. We do need to acknowledge the fact that we will be recording this talk today. And there will be a link sent out to access it at a later time. We will be taking questions, but please reserve them to the end. You can enter them in the chat prompt and we will address them at the end of the talk. And please kindly mute your audio during the talk to help everyone to hear better. And we'll begin. We have no financial disclosure and as I mentioned, the lecture will be recorded. We know that the phrenic nerve is uniquely suited as the nerve that supplies innervation to the diaphragm on both the right and left sides. It's originating from the cervical root C3, 4, and 5. It also has some sensory components to the pleuropericardium and abdominal components. In the neck area, the phrenic nerve runs in a rather tight space along the anterior scaling muscle and under the pre-rotable fascia. It then courses under the subclavian vein and runs in the mediastinum and chest down to the diaphragm. The C4 and the C5 are the dominant root innervation to the phrenic nerve. We'll talk about poorly understood compression and radiculopathy that can be a source of pathology. We see a lot of pathology also from intrathoracic injuries either in the mediastinum from things like thymectomy or from cardiac procedures such as cardiac ablations or cardiac surgery. In the neck, we see compression injuries from things that we call wear and tear as well as more understandable injuries such as iatrogenic or traumatic causes. In the neck, you can see a tight area of anatomy where the phrenic nerve runs between the scaling muscle, the pre-rotable fascia, and some of the crossing vessels off of the thyrocervical trunk. The diaphragm is the primary respiratory muscle, it separates the abdominal and thoracic cavities and when we breathe in with an inspiratory effort, it contracts and flattens, pushes down the abdominal contents and allows the lung to have greater domain. Upon the expiration, the opposite happens and the diaphragm moves back into its static position. We see lots of different etiologies in terms of the peripheral etiologies, iatrogenic probably being the most common from surgery in the neck or chest as mentioned, anesthetic blocks and even chiropractic manipulation. We see acute or chronic trauma from blunt or penetrating injuries and some of these are more long-term wear and tear type injuries and for example individuals that do heavy lifting or work with their arms over their head. We also see this sort of classic viral neuritis, Parsons Turner type syndromes and other viral causes. We also take care of patients with central nervous system disorders that result in diaphragm dysfunction from primarily spinal cord injury, cord compression, other types of cervical spinal cord injuries and even stroke. There are also systemic diseases that we see and obviously these may or may not be amenable to surgery but things of the central nervous system from MS or stroke, spinal cord injuries related to trauma or other systemic diseases and then peripheral nerve systemic disorders that can cause unilateral bilateral phrenic nerve weakness. We also occasionally see muscular disorders from systemic disease such as muscular dystrophy and myostinia gravis. The typical iatrogenic injuries are scaling blocks from shoulder surgery, chiropractic manipulation of the neck, cardiac surgery procedures and even cardiac ablation and where we'll talk about our approaches and treatment and protocols for these types of injuries. There's also a phenomenon that we talk about in the world of peripheral nerve surgery called double crush which was described in 1973 and it's very applicable to more simple things like carpal tunnel but basically if a nerve is impaired at one location it makes it more susceptible to entrapments in other areas along the same neural pathway. So for example if a patient has a cervical spine degeneration or disc herniation it takes less injury to the nerve itself so in the example of the phrenic nerve less direct injury to the phrenic nerve before there would be diaphragm dysfunction. Our presurgical evaluation is comprehensive. We treat symptomatic patients. We all know that there are cases where diaphragm dysfunction can be well tolerated but we're treating patients that have symptoms primarily exertional dyspnea, positional dyspnea or thoughtnea, easy fatigue ability, recurrent pneumonia is something we see often and even more common is sleep disorder breathing. Sleep disorder breathing involves chest fluoroscopy or sniff testing, pulmonary function testing. We do in-office maximal inspiratory pressure or MIP testing, electro diagnostics and imaging as needed of both the neck chest and spinal cord. The symptoms we see sleep disorder breathing very common. Many patients are on mask ventilation systems or need to be and their sleep studies are in accordance with a version of sleep disorder breathing from the diaphragm paralysis. They may not have had pre-existing sleep apnea, positional dyspnea patients often say they have difficulty tying their shoes and obviously exertion. The long-term consequences are exercise intolerance, sleep disturbances that require some type of intervention, weight gain, reduced quality of life susceptibility to infections or other pulmonary disorders, profession and even sexual dysfunction. I'm going to turn it over to Dr. Brown now who will talk about our electro diagnostic evaluations that go into patient work up. Yes, good morning. Unfortunately, I lost my video feed but Matt if you can just advance the slides for me. I think we can do this. Sure. So the overview is I'm going to talk a little bit about neuroanatomy, neurophysiology and classification of nerve injury as it applies to the electrodiagnostic techniques and talk a little bit about ultrasound of the diaphragm. Next slide please. And I think we're on the diagnostic slide confirmed with as Dr. Kauffman was saying fluoroscopy, chest radiography, sometimes chest CT scan, pulmonary function test but the phrenic nerve conduction studies and diaphragm EMGs are actually functional studies of the neuromuscular pathway and we find them to be very valuable in helping to evaluate the function of the neuromuscular system and also the viability for that system for repair. According to the diaphragm is useful to help with evaluating diaphragm function. The next slide please. Phrenic nerve is a large myelinated nerve thematic and fast and it's capable of being studied with standard EMG-NCV studies. Next slide. The large myelinated nerve consists of the cell body which is the axon which extends peripherally and then the satellite cells which are multilayered proteolypid myelin axis the insulator. And next slide please. This is a screen shot of the peripheral nerve shows the axon with the myelin sheath, the underneurium and then bundles of axon surrounded by the perineum and then the epineurium which surrounds the entire nerve provides strength to the nerve against crush and stretch injuries. Significantly if the epineurium is in place in the event of axon damage the axon has the potential to grow back spontaneously in the periphery and that's at a rate of about a millimeter a day or about an inch a month. Next slide please. So the neuroanatomy of the motor unit consists of the basic functional element of the neuromuscular system and that consists of the anterior horn cell or the motor nucleus, the motor axon, the neuromuscular junction and all the muscle fibers that it innervates. Next slide please. So the neuroanatomy here of the motor unit, this is a screen shot through the cervical spine area but it applies to the diaphragm and the thoracic nerve as well. So this system can have disruptions in any segment. Number one would be the motor nucleus or the anterior horn cell and think of things such as ALS and motor neuron disease or polio. So the nerve itself can be traumatized but it's also susceptible to various entities, such as drugs, alcohol, guavaclavinamia, toxins, heritable disorders, endocrinopathy such as diabetes, thyroid disease, also in uremia, autoimmune processes, infections including idiopathic neuritis and also perineoplastic syndrome. And down at the neuromuscular junction as Dr. Kauffman was saying myosinia gravis can interfere with neuromuscular transmission to the muscle fibers, myosinic syndrome and I've seen a number of infants with botulism poisoning which causes paralysis at this level. And then finally at the muscle level there are congenital and acquired myopathies which can cause dysfunction in the system. Next slide please. So the nerve's electrical activity is key to functional analysis. You can stimulate the nerve artificially, measure the velocity and also measure the amplitude or magnitude of response. Next slide please. And the muscle can be evaluated then for its electrical characteristics with a needle electrode to look at recruitment, membrane stability and also the health of the muscle through motor unit analysis. Next slide please. So in the classification of nerve injuries there's myelin damage. This can lead to conduction block or slowing. Classic case isn't Guillain-Barre or acute inflammatory peripheral polyneuropathy. Remyelination is possible with complete or incomplete return to normal transmission. Next slide please. Neural injuries can be caused by focal cross stretch, fan section, peripheral neuropathy. And if the axon is severed completely then there's a disruption of axon plasmic flow and then the nerve dies, the axon dies. Next slide please. At that point then there's malaria and degeneration from point of injury distally. And in motor nerves this will be complete in about seven days. The nerve digests itself basically. Sensory nerves a little longer. Next slide please. So the value of the electrodiagnostics then is we can quantify the degree of phrenic nerve dysfunction by measuring conduction delay, axonal loss and the quality of motor activity within the diaphragm muscle itself. Next slide please. And so we can stimulate the phrenic nerve in the neck, usually posterior to the sternoplyton mastoid muscle. We generate enough charge with a stimulator that a threshold is reached and then the nerve propagates its own discharge through salt-tutorial conduction from notavronv-a to notavronv-a down to the diaphragm and we'll get a muscle contraction. Next slide please. And so this is just showing the normal setup for this particular study, stimulating up in the neck, picking up over the anterior chest wall leads. Technical difficulties arise with high BMI and the stimulator charge may be quite high in order to get complete discharge of the nerve. Pick up over the anterior chest wall can be a problem also in patients with high BMI due to the fact that the surface electrode can be quite a distance from the discharging diaphragm, making the amplitude quite variable. Next slide please. And this is a screenshot of patients normal side. The discharge occurs and then nine milliseconds later there is the initiation of the phrenic nerve and diaphragm action potential. And this will vary in time depending upon the health of the myelin but also the height of the individual. Usually this comes in at about 8 to 11 millisecond. The amplitude here is .200 millivolts and this is quite normal and this can vary quite widely we've seen in our series of patients from say .125 millivolts up to .550 millivolts. Next slide please. And this is a side that's the affected side and you'll notice that the latency, the time of discharge is almost double and that the amplitude of response is about 30 percent compared to the normal side. So obviously there's axonal damage going on, loss of fast axons and some demyelination as well. Next slide please. So we use the ultrasound now to help with accurate needle placement when we're going to assess the diaphragm but it also allows us to have direct view of the diaphragm to assess its appearance and its motion. Next slide please. And so here the transducer is placed anterior axillary line over the eighth rib. Next slide please. And here you see two screenshots and this is looking the AA letters designate the diaphragm and on the normal side we've seen that thickness of the diaphragm usually be between 0.19 and 0.23 millimeters and this is taken, this measure is taken at the end of expiration when the diaphragm is relaxed. On the affected side the diaphragm tends to atrophy fairly quickly and it'll usually be around 0.9 to 0.1 centimeters, about half the normal thickness compared to the healthy side. Next diagram please. So what this represents is a monopolar needle placement into the diaphragm and this is done over the eighth rib anterior axillary line through the skin, through the fat, through the intercostal muscles and then down to the diaphragm. And next slide please. And this shows a screen representation of the motor units in this particular patient's diaphragm and what we're seeing here is very discreet motor unit activity. So there's through maybe three motor units firing in this patient's diaphragm, the normal would fill the screen. So putting all of this data together we have a patient with a incomplete phrenic neuropathy showing axonal characteristics. Next slide. The protocol that we use here in the office includes of course taking the history, auscultating the lungs, doing a strength, a reflex, sensory examination and then doing motor and sensory, the bilateral median and all of their nerves. We're looking for a generalized peripheral neuropathy to put in context with the focal neuropathy of the diaphragm nerves. And then we also do EMG of the selected C5 to Q1 muscles and the cervical paraspinal is looking for a concomitant regioplexopathy, cervical radiculopathy. And final slide. This is the protocol we've been using for the last 360 or so patients and we feel that this gives us very strong data points in order to clarify the type and quality of the phrenic neuropathy. Dr. Kaufman back to you. Thanks Dave. So moving on to treatment options. We know that there are non-surgical options for diaphragm paralysis, medication which is rather unaffected, ineffective rather. And pulmonary rehab and diaphragm PT, which is an important part of either our preoperative assessment and certainly in the post-surgical rehabilitation phase and we'll talk a little bit about that later. As mentioned previously, a CPAP and BiPAP are found to be very helpful and of great utility for the sleep disorder of breathing that can be concomitant with the diaphragmatic paralysis as mentioned even in patients that don't have preexisting sleep apnea. As far as the surgical treatment, we're going to cover each of these diaphragm placation, phrenic nerve reconstruction and diaphragm pacemakers. Our center and including the speakers today are part of a multidisciplinary program and we see and evaluate thousands of patients over the last 10 or 11 years and have treated over 500. So a great experience and an ability to use each of these treatments in an effective and algorithmic way which we'll cover. We've also published this algorithm. I'm not going to go into too much detail and we'll speak about it again at the end but basically use all these different modalities including some of the non-surgical modalities to best treat these patients by optimal care and based upon extensive workup including the electrodiagnostics which are so valuable to provide what we believe and what we've published as well to be the best and overall optimal care of these patients. So I'm now going to turn it over to Dr. Bauer who will speak about diaphragm placation. Thank you, Dr. Kauffman. Next slide, please. And as I'm getting started, Dr. Kauffman pointed this out and I just want to underscore that I think what makes the program successful that we have is the fact that it's multidisciplinary and so we're frequently on the phone reviewing films, scenarios or having patients fly in and see both of us and then go up and see Dr. Brown. So it's putting everybody's expertise together that enables us to be successful. As Dr. Kauffman pointed out early, the phrenic nerve, it amazes me that it's not injured more frequently. This is a patient with a thymic tumor that is very close to the phrenic nerve. The internal mammary artery which is harvested for a lot of cardiac operations is again runs right underneath the phrenic nerve high up where it's mobilized. And then ablation procedures, just below where I have the SVC outlined are the pulmonary vein. And when they're doing cardiac ablation, they're right beside the phrenic nerve. And if there's full thickness burn, that ends up injuring the nerve as well. Next slide, please. So the majority of our patients are almost all are evaluated in a multidisciplinary fashion and we reserve that sort of thoracoscopy for those patients that are deemed not to be a candidate. And as Dr. Kauffman goes through his algorithm, it will be obvious which those patients are. Traditionally, it was done as an open technique, a normal, large posterior lateral thoracotomy. And that is still the treatment of choice in most centers. But with our experience doing minimally invasive surgery and doing an extensive amount of it, doing this as a VATS approach actually provides superior view and technical ability over a thoracotomy and enables us to do it with three small incisions. Takes about 45 minutes to do the procedure. We've done it robotically as well as the standard VATS. The benefit of the VATS, in my opinion, is I'm just doing two 10-millimeter incisions and one 5-millimeter incision with the robot. I'm typically making a few more incisions, which adds to a little bit more discomfort but provides no benefit. So they're all done without the robot at this point. Patients are typically able to go home the day after surgery for those patients that are flying from various parts of the country. They usually fly in the day before surgery. We'll spend two days in the hospital. We'll spend an additional day or two in the area, be seen again in the office and then be able to fly home in less than a week. Next slide, please. So Dr. Kaufman's already reviewed this. But the benefit of application is it's restoring the diaphragm to a lower level. This is especially problematic when patients like that flat. And the majority of the patients we're doing placations on tend to be the older population, tend to be more symptomatic and tend toward being slightly overweight. And the comorbidities worsen their, make their symptoms more significant. And the added weight on in the abdomen when they lay flat pushes the diaphragm further up. So the primary focus of the application is to lower the diaphragm to as normal a location as possible on full inspiration and then allow the accessory muscles to be able to increase the volume and improve air flow. And it minimizes the upward excursion of the diaphragm when they're lying flat or bending over and our patients have a significant improvement in their symptomatic relief as a result of this operation. Next slide, please. These are just examples on the right. You see an elevated diaphragm over the liver and the slide on your screen left is a post-op. So by tailoring how we do the flication, we're able to reconstruct the costofrenic angle and lower the diaphragm. It should be mentioned that doing the right side it's harder because you're having to push the liver down. And when they're obese, if you have any loss of domain in the abdomen, that's typically what is limiting our ability to lower the diaphragm. Next slide. And so the way that this is done is with an instrument called an endose ditch, but basically it's pictured it shuttles the needle back and forth. And so we go typically medial to lateral and medial flication. There are usually two or three sutures that are then tied and as you get to the middle, you're able to placate more, but the placation sutures are bringing it in two different directions. It's bringing the rows of sutures together, which shortens the diaphragm from medial to lateral. And by running them in a typical anterior posterior fashion, it shortens it in that direction as well. And then as you get more laterally, you're taking less sutures and bringing less tissue together to affect a more normal curvature of the diaphragm. Next slide, please. So the benefits, it provides an immediate improvement in their inter thoracic volume. And so our patients tend to be older and more symptomatic that need an immediate improvement. It's done in a minimally invasive approach. The one thoracotomy I've had to do was in a patient who had a diaphragmatic and chest wall resection as part of a cancer operation in his abdomen and had a paralyzed diaphragm and afterwards had significant elevation of it. And so to free up everything and improve his outcome was done open, but all of the other ones have been done minimally invasive. And all of our patients have had an improvement in their ability to lie flat, bend over, and their exercise tolerance is improved from a symptomatic standpoint. And I've already mentioned their length of stay. Next slide, please. The limitations are in the more obese patients, we simply can't push the diaphragm down far enough to affect a significant improvement. It is more challenging on the right side, as I mentioned. We've had two patients that had a recurrence that a couple months. One that comes to mind was a woman who was in her 60s, lived on a farm in West Virginia and took care of herself in the farm. And she called me three months post-op saying I was throwing fertilizer bags around and they weigh 100 pounds and I felt a pop. And the next day I felt two more pops and then I was short of breath again. And so we've really attempted to encourage your patients to avoid heavy lifting because when you're bending over, it increases intra-abdominal pressure. And then when you're lifting at the same time, it dramatically puts more pressure on the diaphragm and can pop the stitches. But with the exception of that, the recurrence rate is very low, the volume is improved, and the paradoxical motion that you can get is eliminated. However, the limitation is it is not normal function. It's just trying to increase the intra-therapeutic space. Next slide. Thanks, Dr. Bauer. So we'll move on and speak about phrenic nerve reconstruction as an expanded option for treatment of symptomatic diaphragm paralysis. The rationale for phrenic nerve reconstruction goes back to the development of peripheral nerve microsurgery techniques that have demonstrated efficacy for 50 years. We use them in all kinds of peripheral nerve injuries throughout the body, facial nerve, arm paralysis, leg paralysis, brachial plexus injuries and the like. The principle of functional restoration of muscular paralysis being preferable to static correction when feasible, the analogy being if someone has a foot dropped due to a perineal nerve injury, the first attempt would be to fix the perineal nerve and not create an ankle fusion. And so when we look at different areas of the body and muscular paralysis, can we restore function to that muscle? We know that phrenic nerve injury is the most likely cause of diaphragm paralysis. So most of the patients that present have a phrenic nerve injury. And if we can evaluate it properly and determine if we can use these techniques, there's a role for this surgery. And also until recently, it's very likely that many cases or most cases of diaphragm paralysis probably go untreated. We're using three basic techniques in nerve reconstruction, one being neuralysis or nerve decompression. Nerve decompression is removing impingement or scar tissue or adhesions from a nerve. The second being intraposition grafting, which also goes by the terms autographed or transplanting and nerve bypassing. So if there's damage to a segment of the nerve, we can take a nerve graft and splice it in to bypass the injury. And the third being nerve transfer and nervousization, which is using a spare part donor nerve to power the phrenic nerve. And I'll show you examples. Here's an example of phrenic nerve decompression on screen left. You can see a casing around the phrenic nerve, which is white in color. And when that enough of that casing is present and starts to compress, it can lead to a reduction in the impulse conduction or the impulse flow. And so we go in and we're relieving that casing, we're relieving that fibrosis. And that can often be from thickened fascia or from adherence scaling muscle. Here's another example of vascular compression. We know that nerves can be compressed by adherent vasculature. And so when there are inflammatory changes in the neck from trauma or injury, the blood vessels that are normally in that anatomical location now become compressive or strangulating to the nerve. And so we sometimes have to go in and release the vasculature. These are additional adhesions you can see on the top left. There's this sort of band of yellowish, reddish tissue that's squeezing the nerve or compressing the nerve. And we're trying to do a dissection that essentially makes the nerve look like an anatomy dissection to create a space to relieve the pressure. We also use prevention measures after the surgery to prevent future scar. We know surgery can create scar. So we use these collagen nerve wraps, which act as insulators to the nerve after we've done our decompression. We perform nerve bypass or interposition grafting in almost all cases. So you can see in this diagram when there's an injured nerve where the axons themselves may be damaged. And so just cleaning out the outside or just doing a decompression may not be enough where we can take a nerve graft and plug it in to the intervening segment. Here's an example of a phrenic nerve. You can see the narrowing on the left. It almost looks like a sausage link where that was actually a patient who had chiropractic manipulation that we presume led to some twisting of the nerve and some compression that led to a narrowing in this mid-segment. And we're using on the right, you can see a nerve graft where we're sewing in above and below the damaged area. We also do nerve transfers, which are basically taking a different nerve either in the neck or chest area. Sometimes the spinal accessory being a donor and we can plug it into the phrenic. We don't sacrifice the spinal accessory nerve, rather we dissect out the two terminal branches. Here's an example of using the spinal accessory nerve to power the phrenic nerve. We've dissected out the phrenic nerve. So the spinal accessory is the one on the left and the five nerve is on the right. And here you can see a connection between the spinal accessory nerve and the phrenic nerve. That's basically over time going to regrow at that one millimeter a day and allow over time the impulses from the spinal accessory nerve branch to power the phrenic nerve and lead to improved impulse in the diaphragm. In the 80s and 90s, there were scattered reports about phrenic nerve reconstruction from the pediatric surgery literature and from acute trauma. Our experience began in 2007 and has continued and expanded until current times. We've evaluated thousands of patients. We've treated more than at least 500 with phrenic nerve reconstruction, not to mention other modalities. And we have two national referral centers, primarily in New Jersey, and we've developed one out at UCLA Medical Center. As I mentioned, it's a multi-disciplinary approach and multi-modality approach. And we believe that given the sort of orphan condition of diaphragm paralysis, this type of condition is better treated at specialty centers that have lots of experience. We've published extensively since 2011 to demonstrate our outcomes and also to look at particulars of the pathology. We've also written chapters in textbooks. We have a section in up-to-date.com on surgical treatment of phrenic nerve injury. And we've written several chapters in thoracic publications. Our first report was in 2011 in CHEST looking at the feasibility in 12 patients where we demonstrated that 89% of those patients improved based upon outcome measures. Hulmarae functions, nift testing, and physical functioning surveys, basically, exercise tolerance. We had a follow-up study in 2014, which was a cohort study in annals of thoracic surgery. We compared phrenic nerve reconstruction to non-surgical care, which was our control group, and a historical cohort of patients that had received diaphragm placation, hoping to add phrenic nerve reconstruction to the standard treatment algorithm. The inclusion criteria for phrenic nerve surgery, phrenic nerve reconstruction was symptomatic patients for greater than eight months who had abnormalities on testing and had an absence of evidence of either systemic disease or organic pathology. We matched 68 patients undergoing phrenic nerve reconstruction to a non-surgical control and 68 patients that were identified in a Prisma meta-analysis who had diaphragm placation. They were matched for age, sex, BMI's, and other factors. Of note, in the phrenic nerve reconstruction group, our follow-up was only one year, so a rather short time when looking at a neuromuscular reconstruction. We did, however, show and demonstrate an increase in spherometry value significant, whereas the non-surgical group had no change. We showed improvements in FEV1 and FVC, and this is the FEV1 graph showing that the phrenic nerve surgery and diaphragm placation groups improved. There was a slight trend that the placation had greater improvement when we looked at our phrenic nerve surgery group at one year and the non-surgical group had no change, same for the FVC. This was our survey reporting that showed significant improvements in quality of life physical functioning compared to non-surgical care. We had significant improvements in our electrodiagnostics. We had deficits in preoperative motor amplitudes and in nerve conduction, and we demonstrated that our motor amplitudes improved by 37%. Our nerve conduction latency improved by 69%. This was significant, and here's our follow-up, a pre and post X-rays showing that the diaphragm, when it regained tone from phrenic nerve reconstruction, allowed the diaphragm to move down and allowed the lung to have more volume. This in a 65-year-old female, this is a 33-year-old male who had diatrogenic injury from prior long thoracic nerve release, and this was a 34-year-old male who had a traumatic injury. So in conclusion, we showed a clear benefit of phrenic nerve reconstruction versus no treatment. Disprometry results were slightly better in the placation group, but statistically equivalent at one year follow-up, and we had demonstrable improvements in ledger diagnostics with a consideration to amend the standard treatment algorithm. We wondered what would happen if we followed our phrenic nerve reconstruction patients longer than one year, because knowing that muscles take a long time to recover after re-innovation. So we looked at 180 patients a few years later and a mean follow-up of 2.7 years. Our demographics are more males than females, greater right side than left side, and most of these were atrogenic injuries followed by trauma. Most of the approaches were cervical. Some of these were intrathoracic approaches, mean operative time, three hours, and a mean length of stay just over one day with a low complication rate. We demonstrated progressive improvements in our pulmonary function testing between pre and post-op in all standard parameters. We also again showed improvements in nerve activity or nerve conduction latencies. After two years, we demonstrated what we hope we would see, which is a much greater improvement in muscle strength or motor amplitudes, which had increased now by 125%. And again, improvements in physical functioning at two and a half years. So what we demonstrated is longer follow-up leads to progressive improvement in spirometry values and that it leads to also progressive improvement in overall diaphragm function. This year, we submitted our 400K series, which represents the largest worldwide experience, the largest database of patients with diaphragm paralysis. Again, our demographics, many age in the mid-50s, ranging from 19 to 79, more males and females, I mean, VMI 30, and more right-sided injuries. Average duration of paralysis was 29 months. And again, acute or chronic trauma and iatrogenic injuries representing the greatest percentage. We started including now patients that had idiopathic paralysis or parsonist turner where in the past we may have not included them, but because we now understood the pathology better and really believe that many of these idiopathic cases are actually compression, wear and tear type of injuries that as long as we rule out systemic disease, we often can include these patients in treatment with nerve reconstruction as an option. And here's what we were able to demonstrate that between post-op year one and post-op year two, we are seeing a stepwise increase in our spirometry values. Again, this goes back to the need for a greater time for recovery. So the surgery's creating improvement in nerve conduction, but it's not creating a strong diaphragm. So we've instituted a much more rigorous postoperative rehabilitation course so that once we demonstrate electrical recovery, we know the patients have to work to strengthen the diaphragm through a postoperative diaphragm physical therapy and conditioning means. And we're able to show that this improvement goes on and on particularly at between the one and two year mark. We demonstrated improvements in MIP values or maximal inspiratory pressure that we're approaching normal. This was at about a year. This is when we started including this testing parameter which I think is an important parameter for measuring inspiratory strength, whereas most of the other spirometry values are done on exhalation. Diaphragm EMG approaching normal values, that's the motor amplitude or muscle strength. And we also included now ultrasound measurements of resting diaphragm thickness as Dr. Brown mentioned as a way to determine muscle bulk which should indicate muscle recovery. So our duration of surgery overall is three hours on average, length of stay for trans cervical approach is one day, sometimes outpatient. Intrathoracic surgery is three days similar to the placation. Complications are Seroma 5% and wound infection hematoma pleural fusion 1% of note. When we do our intrathoracic repairs, it is done through a minimal thorough acotomy, small thorough acotomy, sometimes that's assisted. And going back to our algorithm. So now we can include all these modalities. We're gonna talk in a moment about pacemakers and where that fits in. But what we do know is that when we utilize our electro diagnostics, when we talk about possible mechanisms of injury and whether patients have early benefit from diaphragm physical therapy or not, we can stratify them to either supportive care, phrenic nerve reconstruction, if feasible, and diaphragm placation. We do reserve placation also for failed phrenic nerve reconstruction. So if a patient is a candidate for phrenic nerve reconstruction and ultimately is a failure, they can still have placation whereas we're not so sure that if a placation fails that we can go back and do nerve reconstruction. But moving on to bilateral diaphragm paralysis which is a rather unique presentation. Usually we're seeing unilateral and on occasion we do see bilateral. We think it's related to cervical stenosis or bilateral phrenic nerve compression. We obviously have to rule out systemic neurodegenerative disease in this case. And they present with much more significant symptoms. Really oxygen and bi-pap dependence. Sometimes non-invasive ventilator dependency using a trilogy or other non-invasive ventilator. They have on average resting and exertional dyspnea and their physical function is severely limited. We've developed a protocol for these patients that's multi-modality, multi-disciplinary using phrenic nerve reconstruction on the more severely impacted side as long as it's feasible as well as and simultaneous with laparoscopic implantation of a pacemaker, which is performed by Dr. Bauer. 12 months later, we'll go back and if it's indicated we'll reconstruct the contralateral phrenic nerve. And then in the third stage, we will ex-plant the pacemaker once we've deemed that re-innovation and regeneration has occurred. So we've reported on 14 patients that had bilateral diaphragm dysfunction using this multi-modality treatment protocol. We just submitted it to the European Journal of Cardiothoracic Surgery and we looked at our outcomes. We also compared the side-to-side differences at a year. So the side that was receiving both nerve reconstruction and pacemaker versus pacemaker alone. There were significant deficits in our motor amplitude. So the top row, the ultrasound thickness of the diaphragm and our MIPS studies and pulmonary function values. So the values, the baseline values in these bilateral patients were much more significant and much more troubling than in our unilateral cohort. And what we're able to demonstrate is that using this multi-modality approach that we were able to show MIPS values that improved really into the normal range, diaphragm EMG that had significant improvement. The motor amplitudes improved by quite a lot. Ultrasound measurements of resting diaphragm thickness also improved into normal range. Pulmonary function with significant improvements in FEV1 and FVC. And overall, that we can treat these bilateral patients and bring them back to a functional status using both pacemakers and nerve surgery. The pacemakers play a vital role in these bilateral patients for various reasons. One is to make the anesthetic event itself safer by supercharging the diaphragms to get them out of anesthesia to prevent the contralateral side from having a continued atrophy and to promote regeneration. We also showed that on the side that was receiving both the nerve reconstruction plus pacemaker, there were improvements greater than with pacemaker alone. So the nerve surgery does play a significant role. Moving on to pacemakers, we know the indications, the standard indications are for cervical spinal cord injury, cleat bapnea, and now some controversy over whether ALS patients are candidates. We also have applied them as just mentioned for bilateral diaphragm dysfunction. And we also use them for complex unilateral cases where there might be an old injury, a hostile surgical field or patients that are unable to participate in diaphragm PT maybe because they have bad knees or they're overweight. And that the bottom two categories would be off-label uses of this diaphragm pacemaker. One of the misconceptions that we hear all the time is that we can implant pacemakers in patients that have phrenic nerve injury or unilateral paralysis as a standalone option. And although there have been some studies, if there is no phrenic nerve stimulation, the pacemaker will not be effective. You need to have a stimulatable phrenic nerve for the pacemaker to work. Otherwise, you need to combine modalities. There are different pacemakers available in the US that are approved, FDA approved. This is one that's implanted through the cervical region or it can be a planted around the phrenic nerve in the chest cavity, but basically a fully implantable receiver and electrode with an external transmitter. We place this trans-servically. You can see here an intraoperative view of a pacemaker being placed with the electrode around the phrenic nerve through an incision in the neck. Those other two incisions are chest incisions for the receiver. You can see the receiver on the chest wall, on the left side, and then on the right, the white antenna that's placed over the skin that stimulates transcutaneously. The other device is our laparoscopic implantation device that's performed by Dr. Bauer. There are electrodes that are placed at the nerve-muscle interface. This is a view from a laparoscopic abdominal approach looking up at the diaphragm and a trocar placing electrodes at the nerve-muscle interface. And that's done through nerve mapping, the determined location. This is the external view of the transmitter connected to the externalized port. And this is our experience in looking at patients that require nerve reconstruction with pacemakers. So as I mentioned in patients that have non-stimulatable phrenic nerves, in order to have an effective pacing situation, we first need to reconstruct the phrenic nerve, and this applies to maybe 20 to 25% of cervical spinal cord patients. So we've published our early experience, 2010 to 2015, with 14 patients with high cervical tetriplegia who had previously failed, many of whom had previously failed pacemaker attempts, and we were treating these patients 34 months post-injury, which is a long period of time, a long delay. We included patients with cervical tetriplegia who are chronically ventilator dependent, with no active respiratory infection, adequate cognitive function, and appropriate care support. We placed the device and did our nerve reconstruction either through cervical or intratherastic approaches with intraoperative nerve testing, nerve grafting, and the pacemaker approach. This is an intraoperative, intratherastic view where difficult to make out that basically an electrode placed around the phrenic nerve in the chest cavity with an intercostal graft that's mobilized and transferred and hooked up to the phrenic nerve all through an intratherastic approach. In this series, we demonstrated through electrical testing, electrodiagnostic testing, a 93% successful re-innovation outcome. The time from surgery to re-innovation on average was about seven months. However, 62% achieved sustainable pacing, meaning more than an hour a day. Two patients did recover spontaneous respiratory activity, meaning the nerve reconstruction led to spontaneous improvement, and we were able to achieve a 20% reduction in overall vent dependency. The limitation really was the overall outcome in sustainable pacing. We attribute, at least in part, to almost a three-year delay in getting to these patients with substantial atrophy and neural degeneration. Here's one patient that recovered electrical activity you can see here on the left, the standard blip of the pacemaker and now the activity of the diaphragm function on the right side nine months out. We know the benefits of weaning off of ventilator dramatic in terms of morbidity and mortality, and we've developed a treatment algorithm for these spinal cord patients that includes adding phrenic nerve reconstruction when necessary. Timing is absolutely critical. We submitted and were accepted to Journal of Spinal Cord Medicine with an updated series in 2020. In 10 patients treated between 2015 and 2019, all with cervical spinal cord injury, all completely ventilator dependent, with a newly developed surgical algorithm. Some patients just require pacemakers. If they have stimulatable phrenic nerves, they do not need phrenic nerve reconstruction. The group two would be pacemaker plus phrenic nerve reconstruction when the phrenic nerves are non-stimulatable on one or both sides. And now we've developed a new treatment for long standing spinal cord injury where there's been substantial or near complete muscular denervation atrophy or loss of the potential to restore function to the diaphragm, where we can actually use innervated vascularized muscle using the rectus muscle as a neo diaphragm. Thank you very much for your presentation. They were all high cervical tetraplegics, all had complete spinal cord injury, and at least half of them had attempts at prior pacing. The last column, prior PA, were patients that had undergone prior pacemaker attempts and were told basically that nothing could be done. So patient one, patient two, although yeses, all the why's were patients that had prior pacemaker attempts. The second or last column is the duration between injury and surgery. And in this cohort, we're able to get to these patients at an earlier time apart from patient 10, which was two years. Everybody was under, I'm sorry, it was four years. Everybody was within two or three years of the injury. Several of the patients had intratherastic repairs and a few were just cervical repairs. Again, treatment one was pacemaker alone, though in patient six and patient nine. Group two was pacemaker plus phrenic nerve reconstruction and group three, we had two patients, patient one and patient 10 who underwent pacemaker placement plus diaphragm muscle replacement surgery. And the second to last column was the decrease, the time from surgery to the reduction in ventilator requirements. So in eight of 10 patients, we achieved partial or complete weaning. Partial would be at least one hour a day, completely off of the vent. And complete weaning would be greater than 12 hours a day or the ability for essentially 24 hours a day off the vent of the seven patients that initially failed pacemaker attempts elsewhere. And we're told that would never wean. Five have achieved partial or complete weaning. We feel that with this algorithm, it may provide an opportunity for just about all ventilator dependent spinal cord patients to have a chance to wean. And we know again that timing is critical, a less than one to two years post-injury. So take home points from the lecture. A phrenic nerve reconstruction has been demonstrated as a safe effective treatment for diaphragm paralysis, for restoring functional activity and expanding standard treatment options. We feel that this condition is an orphaned disease, an orphaned condition, which may be better managed to experience multidisciplinary centers. We promote the use of all modalities applied in a systematic manner using a surgical treatment algorithm to achieve optimal outcomes. Thank you very much. We'll take questions. Let's see if we can pull up the chat now. We'll just start going down and Tom and Dave can chime in. The first question I see here is, I have a Guillain-Barre patient that I believe probably has bilateral paralysis. He had cervical neck surgery a year ago and has been slowly decompensating ever since. Noninvasive vent dependent, morbid obesity, now almost bedridden. How should we go into the, work up for this patient? And the person who wrote the question is it's home care RRT who oversees his trilogy use. Well, I think first off is, his treatment options would obviously be limited if he's bedridden and morbidly obese. I'll defer to the group, but I think a work up if possible to determine if indeed it is Guillain-Barre and whether there are motor units available and perhaps the only option that would be likely or even feasible would be a pacemaker placement, either laparoscopically or cervically in the neck, but it would really depend on the work up and the status of his neuromuscular function. Tom, any role for placation here? No, I agree with you that I think, if he had some function that you might be able to improve it as you pointed out, but placation would not likely benefit him. Yeah, let's see. I had to scroll down. Okay, let's see here. You see the next, oh, here it is. Also, and then to follow up is that he also is in great need of more aggressive airway clearance. I mean, I guess obviously you look at more aggressive pulmonary toilet and vest, as you mentioned, obviously a tracheostomy and worst case scenario. Do you see any other questions? I only see that one. No, the other point that I would make Dr. Kaufman is, I think the pulmonologists that have the keen awareness of this and look for it, the more you look for it, the more you find it. And what we've seen from patients that are coming to us from all over is, and there was one written up in Reader's Digest for an individual from, I think it's Tennessee, that these people are seen as their comorbidities, their heart, their plate obesity is the cause for their shortness of breath. And it's not until people start to investigate and notice that the diaphragm's elevated and it's not just because they're a little obese, it's because the diaphragm's paralyzed when they do a SNF test. And then when patients get referred in, not given false hope, they're given an optimistic evaluation and we're able to affect a positive change in these patients. And so I think the most important takeaway is to fully evaluate these patients and not ascribe it to cardiac dysfunction or their obesity. Because when it's identified, we are able to have a significant improvement, however we approach them. Yeah, I agree. I think what we notice amongst the patients that are contacting us is that in some cases, there's a tendency to write off the patient and say that traditionally paralyzed diaphragm, especially unilateral is well tolerated, symptoms are mild and it can be lived with. And we're seeing patients that are suffering, their quality of life is suffering. And as you mentioned, Tom, the sometimes in well conditioned individuals, the outward appearance may be that they're not suffering too badly. I had a gentleman who was a marathon runner and he can still run an eight and a half minute mile, but he's exhausted and his quality of life, his normal baseline has been hindered. And so for everybody, it's a change from their baseline and in some cases it's mild, in some cases it's more severe. There was a question is how common is fredic nerve damage and disorders of the diaphragm with Guillain-Barre? We do see it from time to time. Dave, I don't know if you wanna comment. It's not something we see often. And I don't know if it's related to referral patterns or if it's not as common as maybe we think it is. Obviously, we would expect in patients that have severe Guillain-Barre, there would be some respiratory component. Dave, you wanna comment on that? Yeah, I mean, it is something, can you hear me then? Yes. It is something you see. Usually they respond to IVIG or plasmapheresis and they're weaned from the ventilator. They occasionally then turn into a chronic inflammatory, demyelinating deropathy. And this can go on for months and years in some cases requiring repeated plasmapheresis or IVIG. So it would be part of a chronic condition at that point in time. Right. Is there a bedside test that can confirm diaphragm disorders or paralysis? In general, there's ultrasound, which could be done at the bedside if obviously if the patient is homebound. We use chest fluoroscopy x-rays and SNF tests to really confirm the diagnosis. A bedside sporometry would not be as specific but is something that could be done. We use maximal inspiratory pressure testing. I feel that that's been demonstrated in some cases to be more specific for diaphragm paralysis because it's an inspiratory measure. But really you need the radiographic, you need some kind of radiographic imaging to really hone in that it is a diaphragm issue. We do see patients that think they have a diaphragm problem and they meet all the symptomatic requirements but they don't have the confirmatory imaging and we really do need that. Another question about Guillain-Barre about the severity of phases of Guillain-Barre. IVIG has not been mentioned to this patient. I'm not, that's as far as my knowledge based in Guillain-Barre, but Dave, do you have any other information on severity? Yeah, IVIG is standard treatment right now for GBS and usually that's given right away after the diagnosis is made clinically even in the absence of a spinal tap or EMG. The physicians will jump right on with IVIG with a proper clinical presentation and they'll often run multiple series of that. All right, well, I'd like to thank the speakers. I'd like to thank you, Tom and Dave for doing this and thanks for everybody that was attending this morning and you have our contact, if anybody has additional questions or wants to speak offline, we're happy to address any particulars of patient care or issues related to this topic. Thanks to everybody, have a good morning. Thank you.