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Voice-over: Welcome to Spotlight on Migraine, The Professional Series, hosted by the Association of Migraine Disorders. Join us as we dive deeper into migraine topics with guests from the medical field. This episode includes educational content intended for medical professionals but may be interesting to some patients as well.

In this episode, Dr. Christopher Vélez compares cyclic vomiting syndrome and other functional nausea and vomiting disorders. He then describes the overlap between cyclic vomiting syndrome and migraine disorders and explains the commonalities between treatment plans for these two conditions.

This episode is brought to you in part by our generous sponsor, Lilly.

Dr. Christopher Vélez: Hello. My name is Christopher Vélez, and I’m a member of the Division of Gastroenterology at Massachusetts General Hospital and a part of the Center for Neurointestinal Health. And today I am talking about cyclic vomiting syndrome and the functional nausea and vomiting disorders — specifically, their commonality with migraine.

In terms of an outline for the talk, first I’m going to discuss symptoms, definitions, and epidemiology of functional nausea and vomiting disorders. Next I’ll discuss the pathophysiology of cyclic vomiting syndrome. Then I’ll begin with a case discussion, follow through with treatment paradigms for cyclic vomiting syndrome, and then wrap up the discussion with clinical pearls that I hope you can take home with you when it comes to the management of cyclic vomiting syndrome.

So starting off with symptoms, definitions, and epidemiology — this is an organization scheme that is the bread and butter of what I do as a gastroenterologist. So, as a gastroenterologist, I have a focus on GI motility and sensory disorders, and these are sometimes termed “functional.” I’ll review what that actually means in the field of gastroenterology. It’s a bit different than how it’s used, I believe, in neurology. 

But the way that we think about functional nausea and vomiting disorders, according to the Rome IV classification scheme, is that there are a multitude of insults that combine and can be present in different patients that end up resulting in the common endpoint of functional GI disorder development. So there are considerations in early life — for example, genetics, culture, and environment. There are psychosocial factors such as life stress, personality traits, psychological state, etc., and physiology related to motility and to sensation that often involve some degree of disturbance along the brain-gut axis and the connection between the CNS and the enteric nervous system.

What ends up happening — you have these different stressors within the biopsychosocial conceptual model — is that you get FGID presentation, or the presence of FGIDs. And then you have variations of FGIDs that have specific symptoms, severity that can vary from patient to patient, and behaviors that patients either adopt as coping mechanisms or may contribute to FGID presentation but then results in specific outcomes that — I think you will recognize the negative outcomes that occur with FGIDs because they share a lot in common with migraines.

So, for example, there’s increased healthcare usage. There’s impairment of daily function. There’s impaired quality of life that can actually be more severe than bona fide organic disorders of the GI tract, such as cirrhosis, and increased healthcare costs to the system overall.

Now, I’d like to spend a little bit of time focusing on what I mean by functional GI disorder. So in terms of the main domains of illness when it comes to the gastrointestinal system, they mainly come in three buckets. The more familiar with anyone would be the organic bucket, meaning this is a disorder of the organ — structural, usually, in nature — that explains patient symptoms. So these are things like ulcer or cancer that can manifest as gastrointestinal distress. 

The second bucket for different GI disorders are motility disorders. These are disorders of impaired or too rapid function — rather, movement or motility through the GI tract, and these can be the more familiar gastroparesis or delayed gastric emptying that some of you may be aware of, or it may be chronic idiopathic constipation. 

The bucket that I’m going to spend more time talking about, and the bucket that involves cyclic vomiting syndrome and the functional nausea and vomiting disorders, is this functional GI disorder bucket. So unlike the other disorders, they’re defined predominantly by an illness experience. They’re defined by symptoms versus a hard diagnostic criteria like a laboratory abnormality or an abnormality in imaging. There is a component of it that’s driven, perhaps, by visceral hypersensitivity or autonomic dysfunction. Again, that’s the link in between the functional nausea and vomiting disorders and migraine. And these can include diseases that are familiar to all of us like irritable bowel syndrome or dyspepsia.

So this is an article highlighting FGIDs and their classification, and this is where we are spending most of our time today in terms of focus. In terms of gastroduodenal FGIDs, there are variants within that family. The ones that we’re going to focus on are the nausea and vomiting disorders. So the ones that we are most familiar with include cyclic vomiting syndrome or cannabis hyperemesis syndrome — I’ll discuss a little bit more about cannabis hyperemesis syndrome later on during the talk — but also chronic nausea vomiting syndrome. 

And the way that we think about the diagnostic criteria — I’m not going to read the slide to you — basically, one key clinical point is people who are seeking care from you regarding migraines or say they have cyclic vomiting syndrome may have been mislabeled. And there’s a specific diagnostic criteria — set of criteria that are important to follow when diagnosing someone as having cyclic vomiting syndrome: so, generally, stereotypical episodes of acute-onset vomiting that occur for less than a week; at least three discrete episodes in the prior year and two episodes in the past six months occurring at least one week apart; absence of vomiting between episodes, although milder symptoms can be present; and the symptoms have to be present for the past three months, with onset at least six months prior.

The Rome IV criteria considers cannabis hyperemesis syndrome as a variant of CVS, which is basically CVS that is in a setting of cannabis usage, although I think that is an overdiagnosis that’s made often by clinicians who seek to turn the blame on patients in order to say that there’s something that they’re doing to provoke suffering.

So this table is looking at a group of people that either have diagnostic criteria that are consistent with functional nausea and vomiting disorders in this bucket right here or do meet criteria for having a functional nausea and vomiting disorder. And, basically, what this slide is showing is that there’re definite differences between people who have functional nausea and vomiting disorders and who don’t have them. 

So, for example, they tend to be female, two-thirds of the time in the case of those meeting functional nausea and vomiting disorders. They tend to be single. They tend to have higher degrees of symptom severity. They tend to have higher chance of having overlapping other functional GI disorders, so someone who has, for example, cyclic vomiting syndrome but then also has an independent diagnosis of irritable bowel syndrome. And there is definite markers of increased medical management of symptoms — not too surprising. People with functional nausea and vomiting disorders are more likely to be on antiemetics, they’re more likely to be on pain medications, they’re more likely to be on psychotropics.

So why is that, and, I think, why am I speaking with you today? Why do we care about disorders like cyclic vomiting syndrome or functional nausea and vomiting disorders as it relates to migraines? And, basically, it becomes pathophysiology. You’re going to recognize some things that are very much in common with migraines when I discuss cyclic vomiting syndrome. 

So before we get into that type of discussion, what’s very important is that we define symptoms precisely. Patients are going to use the terms nausea, vomiting in ways that you think you know what they mean, but they actually may be describing a different phenomenon, and you need to try to get them to explain. Usually, I use a script that’s something simple along the lines of “When you say you’re nauseated or you say you’re vomiting, what do you mean? What’s actually happening?”

So, nausea, as the precise definition, is an unpleasant and difficult-to-describe psychic experience that is generally associated with decreased GI motility and increase in tone of the small intestine. Retching or dry heaves refers to spasmodic respiratory movements that are occurring with a closed glottis. This is associated with an antrum that’s contracting while the fundus and cardia are relaxing in order to allow for vomition to occur. Emesis or vomition is when you actually physically have the expulsion of gastric or small intestine contents that are propelled up to and out of the mouth.

So in terms of what happens during vomiting, it’s a very highly regulated physiologic event. So what happens during an episode of vomiting is you have a deep breath. The glottis is closed, and the larynx is raised in order to protect the respiratory tree from gastric contents and aspiration. You then have an opening of the esophagus as well as distal esophageal sphincter. While this is occurring, you have other muscles that are recruited — for example, in the abdominal wall — that squeeze the stomach and elevate intragastric pressure, which, with the conduit from esophageal relaxation, allows for contents to be expelled from the mouth.

In terms of what happens during vomiting, bilateral vomition centers in the reticular formation of the medulla integrate various signals from different parts of the body in order to trigger vomition. The chemoreceptor trigger zone is a bilateral set of centers in the brain stem lying under the floor of the fourth ventricle, and it responds to various insults that the body responds to by provoking vomition.

So I always hesitate discussing different neural pathways to a group of people who may have a neurology focus, just because I’m a neurology dilettante versus a dedicated neurologist. And what I can say, though, that cyclic vomiting syndrome does share some components of migraine. Cyclic vomiting syndrome patients have increased salience network connectivity. They have increased connectivity to other parts of the brain that are also associated with migraine. 

In terms of CVS and migraine, this study basically shows that patients with CVS, like patients with migraine, can have different autonomic dysfunction. And in terms of a detailed breakdown in pathophysiology, what you’re going to notice here is that the same factors that are involved in migraine formation or migraine presence are also present in cyclic vomiting syndrome or functional nausea and vomiting disorders. So there is a combination of genetics, neuroendocrine, cognitive and emotional factors, substance use, and environment that provoke cyclic vomiting syndrome. 

Additional factors are listed on the left, but it’s really what — when I think about and explain cyclic vomiting syndrome to patients, particularly those that have migraine, I describe it more as the autonomic nervous system running amok. And people understand things like neuropathy when it comes to diabetes or things like that, but it is something that allows them to understand cyclic vomiting syndrome more.

Cyclic vomiting syndrome — clearly vomiting is an important part of the diagnosis, but there are other symptoms that can be present, like abdominal pain; nausea independent of vomiting, where nausea isn’t just something that precedes vomiting; as well as anorexia or lack of a desire to eat and even diarrhea and constipation.

The way that we think about cyclic vomiting syndrome is that we think about it as a cycle. This is going to resonate very strongly with people who focus on migraines. So we think there’s an interepisodic period where people are more or less functioning normally. Then there’s a prodrome, where the clouds are starting to form over the patient’s life. And then there are two ways that you can diverge. Either you attempt to arrest the episode of cyclic vomiting through different mechanisms I’ll discuss later, or if you’re unable to do so, you vomit and then you have an episode that then needs treatment. And then you recover, and then you enter back that interepisodic period.

Now we’ll have a case discussion to put these themes in a clinical context. So I saw a 71-year-old man that was diagnosed with many years of cyclic vomiting syndrome, managed on nortriptyline 25 mg, and he does use medical marijuana. Symptoms started in his early 60s, and episodes include dry heaving in the morning without any vomitus associated with nausea. So the questions I would encourage you to have: Are you satisfied by this diagnosis? Would you recommend abstinence in medical marijuana? Does nortriptyline seem reasonable in this case?

So I think this is an important clinical pearl, especially for those of you who aren’t gastroenterologists. Let’s think back about what the word functional means. Functional means that, basically, in our routine diagnostic testing, there isn’t an organic or motility explanation for their complaint. So it really means that you really have to make sure that an upper endoscopy has been done, a gastric emptying scan has been done, there’s been abdominal imaging, lab tests have been done, ordering cross-sectional imaging of the brain to make sure there isn’t an intracranial lesion that is causing vomiting. You want to make sure that you’re assessing for alarm signs that may suggest a need for diagnostic testing or ensure that those have been done before you settle on a diagnosis of cyclic vomiting syndrome.

In terms of medical marijuana, I think another important point I want to make, I think that cannabis hyperemesis syndrome is vastly overdiagnosed, especially in people who frequently present to the ER. I think that this graph shows, basically, that a minority of patients who use cannabis can have cannabis be considered the cause of their cyclic vomiting syndrome. I think that for me, I ask two questions, mainly: (1) did the vomiting occur before they started using marijuana? and (2) if they’ve stopped using marijuana — if so, how long? 

If I truly think someone is using cannabis and it may be causing their cyclic vomiting syndrome to not be managed well, I’ll ask them at least to stop for an 8-to-12-week period. The motivated patient who really wants to get better will do this. And then from there, if there’s no improvement in cyclic vomiting syndrome frequency and they feel that cannabis improved their symptoms, I allow them to resume use of cannabis because I think that it’s something that, given what we know about the endocannabinoid system as it relates to brain function, can have possible treatment benefit. 

I want to emphasize, though, it’s not my first-, not my second-line treatment, and I don’t physically, for example, prescribe medical marijuana to treat cyclic vomiting syndrome. It is something I may consider in people that are having a difficult time with traditional pharmacotherapy or are unable to apply other treatment modalities.

So in terms of treatment paradigms for cyclic vomiting syndrome, this is going to look very similar to the way that you would treat migraines. So in terms of managing someone who has a diagnosis of cyclic vomiting syndrome, there are general measure that you do, like lifestyle, avoiding triggers, appropriate sleep, diet, doing exercise, and stress management, giving patient resources. And then once you are confident in the diagnosis of cyclic vomiting syndrome, then it’s assessing the severity of cyclic vomiting syndrome. 

Mild cases of cyclic vomiting syndrome are generally people who don’t need to visit the ER. They have fewer than four episodes a year. You generally only manage these with abortive treatments — again, similar to migraines. You can use triptans, you can use ondansetron, you can use other agents to help them.

Moderate to severe patients will be going to the ER recurrently. They will be hospitalized. They’re having more than four episodes a year. They’re having moderate to severe symptoms that are having an impact on their quality of life. That’s when you want to start a prophylactic regimen, a baseline regimen, typically starting with a tricyclic antidepressant and then offering abortive therapies.

In terms of other contributing conditions, migraine is one condition that can contribute to CVS, but also autonomic dysfunction, anxiety, depression can also contribute to cyclic vomiting syndrome.

The agents that we use for prophylactic treatment or baseline treatment are basically the same classes of medications that you would use to treat migraines, so I don’t think I need to go through this list too in depth. But you will see frequently used medications that are used when you’re treating cyclic vomiting syndrome.

So in terms of the 71-year-old that I discussed, he was not felt to have cyclic vomiting syndrome. I included this because this is someone that maybe falls under the spectrum of either chronic unexplained nausea vomiting or within the broader functional nausea and vomiting disorder umbrella. We felt that he had some elements of cyclic vomiting syndrome. My mentors in medical school used to say, “Diseases don’t read textbooks.” So we felt that he warranted treatment as if he did have cyclic vomiting syndrome. 

In terms of the time frame for his cannabis use versus symptom onset, we didn’t feel that it was cannabis hyperemesis syndrome. We thought that he may have had possible impaired gastric accommodation, so we thought about adding buspirone. We didn’t prescribe benzodiazepines, though, because he had infrequent visits to the ER. 

In terms of the Mass General GI CVS protocol, we typically try as long as we can to manage symptoms abortively at home using Zofran and Ativan. But we encourage patients, if they’re not able to improve symptoms after two or three doses of these medications, that they come to the ER because the longer they wait, the longer they’re going to need treatment. 

Our treatment protocol, I have listed here — basically identical to what you would use to treat a migraine: IV fluids, dark, quiet surroundings. And I think they key here is we use doses of Ativan that tend to make the ER or inpatient services raise an eyebrow. We really want patients, when they come to Mass General with a CVS flare, to be, what we in slang terms say, “snowed.” So we want them to get high doses of Ativan, clearly making sure that we use the usual metrics before giving high-dose benzodiazepine therapy. But we want them to be able to sleep it off, and we also want them to avoid opiate analgesia because that’ll only contribute to symptoms by delaying gastric motility.

So to summarize and to wrap up the presentation, in terms of pathophysiology, demographics, comorbidities, and medical management, there are lots of overlap between cyclic vomiting syndrome and functional nausea and vomiting disorders and migraine. In general, you can only settle on a diagnosis of cyclic vomiting syndrome or of functional nausea and vomiting disorder if pathology has been ruled out. 

The functional nausea and vomiting disorders are likely underdiagnosed, and it’s something that I encourage you all to assess when you are taking care of patients with migraine. Cannabis hyperemesis syndrome is a disorder. I do think it’s overdiagnosed, so try to tease apart with a history of what’s going on.

Maintenance therapy for cyclic vomiting syndrome — the mainstay is tricyclic antidepressant. Again, it’s very similar to migraine. And we use a lot of the same abortive regimens when it comes to treating severe attacks of cyclic vomiting syndrome.

Thank you.

*The contents of this podcast are intended for general informational purposes only and do not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. The speaker does not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.