I’ve mentioned my father before, in other blogs.  He passed away a few months ago.  He spent his career as OB-GYN.  When I asked why he choose that field, he had a curious answer.  He said that Monday morning conversations among the doctors who dealt with cancer, or heart disease, or other problems were often centered around who had died over the weekend, or who was expected to die that coming week.  Among the OBs, however, the conversation was about who had been born.  To him, OB just seemed bright and optimistic, while the other fields were heavier and often fatalistic.

Despite that optimism, as a doctor, my father encountered many patients whose medical problems just seemed to deteriorate despite everything he tried.  I don’t mean that they were dying, but rather that their quality of life was plummeting.  These patients had started out as healthy and vibrant young women, and yet as they moved into their thirties and forties, their health devolved.  They had migraines, complained of depression or anxiety, suffered with allergies, sinus problems, and even asthma.  Some reported uncomfortable gastric motility problems, like IBS or reflux, and many were dealing with issues getting to sleep or staying asleep.   In other cases, the women were experiencing all over pain or debilitating fatigue.  These problems can affect men, too, but across the board, they affect women far more than men.

Many of my father’s colleagues recognized the pattern within this group, but they would quickly become frustrated by their inability to effectively treat these patients, and many chalked these problems up to “female hysterics” and referred to them as “crazy”.  Others claimed that the women were lying, sometimes even saying it to their faces.  Fortunately, my father was intellectually honest enough to admit that the patients were sane and telling hi the truth.  He was also humble enough to accept that he just didn’t know how to treat them.  (Ugly medical history fact: the term hysterectomy actually comes from the 19th century belief that performing this radical sterilization procedure removed the hysteria from women.)

I first heard about vagus nerve stimulation (VNS) in 1998, while working with a neurosurgeon who told me that it was approved for treating epilepsy.  He knew that the company, Cyberonics, was also trying to get an approval for the treatment of depression.  He told me that they had tried to get an approval for obesity, but that they had encountered a lot of trouble, mostly, he thought, because they had run the wrong studies.  I became interested in working on VNS in 2005, when I put together two pieces of information: (i) the idea that neurostimulation could be a better clinical solution than cutting a nerve; and (ii) a report that anaphylactic reactions could be blunted by cutting the vagus nerve.   The former was advice that same neurosurgeon had given me years earlier, and the latter was an old Russian study from the 1960s that I found one Saturday afternoon, in 2005, while searching the internet for scientific papers that included the words “cut nerve”.

Our first animal studies in anaphylaxis were remarkably successful, and they led to studies in endotoxic shock and hypovolemic shock.  Percutaneous treatments for asthma in humans led to the invention of a non-invasive treatment (nVNS) that no longer needed to be used in a hospital setting.  Non-invasive technology led to the discovery of effectiveness in headache conditions, and even a series of FDA clearances for migraine and cluster headaches.  Along the way, however, we collected a mountain of experience that suggested VNS could be helpful for many different ailments, ranging from wellness applications like enhancing sleep and mood and strengthening stress resilience, to signs that it might treat hypertension, metabolic disease conditions, and even auto-immune conditions.  I was also hearing about studies in fibromyalgia, rheumatoid arthritis, and inflammatory bowel disease.  A lot of the work being done in the field of inflammatory diseases was being pioneered by Kevin Tracey, another neurosurgeon, who had reported his own discovery of a remarkable mechanism, now called the cholinergic anti-inflammatory pathway.

It turns out that 95% of human diseases, medical conditions, and even reasons why people feel badly when they are stressed out and run down, is because of inflammation.  So, if VNS could help to reduce inflammation, it seemed like there was an entire ocean to boil.  I preferred to say that we were trying to boil water, and the amount of water would figure itself out.  The truth is, as a small company, we had to pick one condition to start with, and we chose headache.

With the good data pouring in, I stepped back and started to wonder how we were going to influence payers and patients to pony up the money necessary to provide us with the revenue we needed to cover the costs of developing the technology.  We were, after all, in business, and our investors were invested in the hopes of making a return on that money.  As I searched for good arguments for why treating migraines was worth several hundred dollars per month, I found an article from 2004, written by two nurses, Jacqueline Pesa and Maureen Lage.  They had been interested in how the costs of managing mental health (depression and anxiety) patients tracked when patients also suffered with migraines.  They found that the comorbidity of migraine and mental health condition was extremely expensive compared with controls. (total annual healthcare costs were $12,642 versus $5,179 for anxiety and migraine, and $11,290 versus $3,135 for depression and migraine).

It was a pretty remarkable paper, and so we decided to go over to the UK to do some work looking into the healthcare research utilization trends of severe headache patients (mostly because there was a group of clinical pharmacists over there who were willing to help us gather a LOT of data).  After a few weeks they came to us and showed us their preliminary findings.  They had a spreadsheet with the entire diagnostic histories for fifty patients.  It was actually far more information than I had expected to see about the patients, but I was immediately struck by the fact that the medical trajectories of these patients looked identical.  They all had headaches, to be sure, but they also had allergies or asthma, sleep problems, depression and/or anxiety, GI problems, and many had pain conditions ranging from endometriosis to fibromyalgia.  Frankly, they were the worst cases scenarios of what Pesa and Lage had written about more than a decade earlier.

The interesting thing for me, of course, was that these were all the conditions that I was seeing and reading about being treated with VNS.  So, I had an idea.  I asked the clinical pharmacist team to go out and not just focus on headache patients, but rather to provide me with a spreadsheet of ALL the diagnostic histories on ALL the patients in the various practices they had searched.  They warned me that the spreadsheet would be massive, and they were right.  The first couple of practices produced a spreadsheet that was over 150 lines long.  It crashed my computer about every 15 minutes.

Sixteen hours later, however, I had uncovered something that was really remarkable.  I had sorted all the patients into whether they had ever had any diagnoses for any of the conditions I had seen and read about, and therefore thought VNS might help treat.  There were 6 condition “buckets”: Headache, Depression or Anxiety, Gastric Motility Problems, Sleep Conditions, Asthma or Allergies (or chronic sinusitis), and Widespread Pain.  Forty percent of the population in this group of thousands of patients had never been diagnosed with any of these conditions, and they seldom (if ever) went to their primary doctor, took medication, had trips to the hospital, or saw a specialist.  Another 30 percent had been diagnosed with only one of the 6 conditions, and they were pretty cheap as well … about the average.  It was the next 30 percent, who had multiple diagnoses for these conditions, where things got interesting, and most incredible among a group of about 12-15% of the population who were simultaneously diagnosed with 4, 5, or even 6 of these conditions.  That group was off the charts in terms of how often they were seeking medical attention.

I figured that was the group we for whom our nVNS treatments might be ideal.  So, we set up a very simple study with the practices from whom we had gotten the data.  Actually, the doctors didn’t really even want to see these patients anymore, because they were there all the time, but they said we could recruit them to come in to meet with one of our clinical pharmacists.  They told us that mass mailers would bring in about 1 or maybe 2% of the people.  Boy, were they wrong!  Twenty percent of the people we wrote to showed up with the letter in their hands, asking how we know that they experienced all of the symptoms we listed.  In most cases, we’d look at their records and say, “you haven’t been diagnosed with that one,” and they would respond that they never got a diagnosis because they didn’t want to have to take any more medications, but that they were living with those symptoms also!  When we explained to them that we believed that all of their symptoms might be related and that there might be one underlying way to treat it, well, we had grown men tear up.  Almost all of them responded with some form of, “I knew it, but nobody would listen,” and they would then tell our pharmacists that their problems all stemmed from some event in their lives (illness, trauma, stress, surgery, or emotional loss) and that they, “had not been the same since.”

We offered them our nVNS device to try and asked them to complete a simple 5 question Quality of Life questionnaire every month.  Literally, ninety-six percent of the patients took us up on the offer.  I’ll tell you how they did in a minute, but first …

While this study was taking off, I was introduced to a group that worked for the UK government.  They keep a searchable database that holds the medical records over six million people, and they were so taken by what we had found, that they did the equivalent of $300,000 worth of database analytics to confirm what we had found with the pharmacists.  They were blown away.  Back here in the U.S. we shared what we had found with the research team at Mercy Health Systems, which was the second largest integrated health system in the country.  They not only confirmed what we found among their eight million patients, they found that the most expensive subgroup of patients they had in their system was this group of multi-symptomatic patients that were costing $2 billion dollars per year and the cost was rising astronomically.

In the wake of that revelation, I decided to enlist the help of a data analytics firm called GNS Healthcare from Cambridge, Mass.  They had access to a 100 million patient database of healthcare costs spanning a six-year period.  I asked them to test the two theories that were swirling: that comorbidity across these 6 conditions were way outside the bounds of what might be randomly expected, and the fact that multisymptomatic patients were astronomically more expensive.  As expected, their results confirmed what was seen in both the UK as well as what Mercy Health Systems had uncovered.

The last bit of analytics we did was with one of the leading neurologists in the country, who was board certified in epidemiology as well as headache.  When I shared with him the findings we had made from the original UK study, he realized that there was enough data in the spreadsheets to do what he referred to as a latent causation analysis, which is basically a mathematical test to determine if one of the conditions was really driving everything else, or if there had to be something underlying all the conditions.  If it was the latter, it would basically mean that the different conditions were really just symptoms of something else underlying all of the conditions, explaining why they seemed to all happen in the same people, and all start around the same time.  Of course, that’s exactly what the analysis showed, but it left a big unanswered question, which was: What was the underlying problem?

Let’s return to that study we ran in the UK with the multisymptomatic patients.  Not all of the patients stuck with treatment with the nVNS device.  In fact, we lost about a third the first month.  But the ones who did stick with it started reporting back absolutely remarkable benefits across every aspect of their symptoms.  The most consistent comments were around improved sleep, less pain (especially headaches), less anxiety, better mood, and better breathing.  Some patients reported other benefits as well, including weight loss and better cognitive function.  Most importantly, the improvement in the Quality of Life scores kept rising over the course of three months, and then maintained this high level for more than a year.  The amount of improvement was about the same amount of improvement that people report with a total knee replacement, except the benefits weren’t limited to mobility, it was across all aspects of the questionnaire.

Now, you’d think with this sort of data in hand, we would have had a blockbuster product on our hands, but we still didn’t have the first FDA clearance in the U.S., and it would be another year and a half before the final letter allowing us to commercialize the product arrived, and it was limited to acute treatment of Cluster Headaches, a tiny segment of the market.  (Of course, the pain of a Cluster Headache is extraordinarily horrific, and the suicide rate among those who suffer with those attacks is about twenty times higher than the general population, so it was very important to have this clearance.)  This meant that running any parallel studies in the U.S. to show this benefit across so many different conditions was not possible.  What we could do, however, is try to figure out exactly what nVNS was doing, and why it was fixing this latent cause underlying so many different symptoms.

The answer we found is that the innate immune and autonomic nervous systems exist in a coupled state that vacillates between a sympathetic/inflammatory state and a parasympathetic/anti-inflammatory state.  We often refer to them as a “fight or flight” state that is high stress and high inflammation, and a low stress/low inflammation state that is all about rest, digest, restore, and rebuild.  In the relaxed state, our bodies recharge and regenerate under the command and control of innate immune cells that are anti-inflammatory, doing their housekeeping tasks that maintain our organs and other tissues.  In the stressed state, those innate immune cells are inflamed and distracted from doing their housekeeping tasks.  Organ dysfunction, from kidneys, digestive tract, and reproductive organs, to our hearts, lungs, liver, and even our brain, gets progressively more advanced.  In this state, any attempt to treat a specific symptom is most likely going to fail immediately, or it will have its benefits wane quickly after any initial benefit. That is, if the body is in a sympathetic state of high inflammation, getting better is like trying to climb a sheer rock face with no ropes or pitons.  If the rest, digest and restore mode can be induced, then the two most powerful forces in health (the nervous and immune systems) are working for you and getting better will be a downhill slide.

What does all of this mean?  It means that nVNS doesn’t actually treat or cure anything.  It simply makes you more capable of staying healthy, or if you are experiencing symptoms of a condition that has autonomic dysfunction and innate immune system activation (inflammation), it shifts those system back into the state that is working with you to feel better, and not against you.  Make nVNS part of what you do every day, to keep you healthy, or give your body the best chance of getting back to that place as quickly and easily as possible.  If you are experiencing these issues, you may find yourself writing a letter to us saying the words we hear most often …

“Thank you for giving me my life back!”   

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