Gastroparesis is a chronic gastric motility disorder, characterized by delays in the emptying of food contents from the stomach into the small bowel in the absence of a mechanical obstruction . The most frequently reported symptoms of gastroparesis include early satiety, nausea, vomiting, bloating, abdominal discomfort, and postprandial fullness . However, these symptoms of gastroparesis can also be seen when gastric emptying is even normal or rapid and are not specific to the degree of gastric emptying delay . This finding has led some researchers to identify patients who suffer from many of the symptoms of gastroparesis but who exhibit normal or rapid gastric emptying to have a gastroparesis-like syndrome or chronic nausea and vomiting syndrome as designated by ROME IV criteria .
However, this lack of association between delayed gastric emptying and the other characteristics of gastroparesis may also stem from sub-optimal methods in measuring gastric transit, gastric accommodation and gastric motility as not one test measures all these important gastric functions. For example, a meta-analysis of associations between delayed gastric emptying and the symptoms of gastroparesis as measured by scintigraphy and gastric emptying breath test (GEBT) initially documented only weak associations between delayed gastric emptying and gastroparesis symptoms . Nevertheless, that same study, when the analysis focused only on optimal measures of assessing gastric emptying, found significant associations between delayed gastric emptying and other symptoms of gastroparesis, although the findings were limited in diabetics with gastroparesis . Others have found that amongst subjects with chronic undifferentiated nausea and vomiting (CUNV) evaluated by a standardized scintigraphy, that the degree of delay does not correlate with symptom severity. Interestingly. those with diabetes were less likely to have a normal gastric scintigraphy .
Clinical presentations of gastroparesis may thus vary according to its primary underlying etiology, which can be grouped into three major and multiple less common etiologies of gastroparesis, many of which are frequently overlooked in the diagnosis and management of gastroparesis. This chapter first addresses the three major etiologies of gastroparesis—idiopathic, diabetic, and postsurgical gastroparesis —then the minor etiologies, while covering the different clinical presentations of gastroparesis across etiologies. This chapter will also review overlap with functional dyspepsia, a more common gastrointestinal syndrome than gastroparesis. Furthermore, the chapter will differentiate symptoms common to gastroparesis and other conditions which also exhibit upper gastrointestinal symptoms with vomiting as a main manifestation, including cyclic vomiting syndrome, cannabinoid-induced hyperemesis and chronic nausea and vomiting syndrome, designated by ROME IV criteria.
Idiopathic gastroparesis accounts for the largest percentage of documented cases—an estimated 49.4%; with diabetic gastroparesis accounting for approximately 25.3% of cases; medications including narcotics, for 22.9%; connective tissue diseases and autoimmune disorders, for 10.8%; and postsurgical, 7.2% . Less common etiologies of gastroparesis include Parkinson Disease , paraneoplastic syndrome , connective tissue disorders, including Ehlers-Danlos Syndrome , scleroderma , scleroderma and lupus , cystic fibrosis , and chronic intestinal pseudoobstruction .
Primary measures of gastroparesis symptoms
Three of the best means of evaluating the severity of gastroparesis symptoms are via patient-based assessments, including the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM), Gastroparesis Cardinal Symptoms Index (GCSI), and the American Neurogastroenterology and Motility Society’s Gastroparesis Cardinal Symptom Index-Daily Diary (ANMS GCSI-DD) developed in concert with the Food and Drug Administration to provide patient-reported outcome (PRO) endpoints for pharmacologic therapies of and clinical trials performed on patients with gastroparesis.
The PAGI-SYM covers the main symptoms for upper GI disorders, including dyspepsia and chronic nausea and vomiting syndrome, as well as gastroparesis. The PAGI-SYM uses six sub-scales, ranging from 0 for no symptoms to 5 for “very severe” symptoms, across 20 questions. Questions address symptoms of nausea, upper abdominal discomfort or pain, stomach fullness, lower abdominal discomfort or pain, visible abdominal distention, retching, vomiting, early satiety, and postprandial fullness . The well-validated and commonly utilized PAGI-SYM has established that abdominal pain is a common clinical presentation of gastroparesis across its two most common etiologies—idiopathic and diabetic gastroparesis—occurring in nearly 90% of patients, with nausea present in over 94% of patients, despite poor correlations with the severity of the delayed gastric emptying . Nevertheless, gastric emptying has been consistently associated with nausea and vomiting, as well as with postprandial fullness and early satiety .
The GCSI uses three sub-scales from the PAGI-SYM to assess gastroparesis symptoms with a 6-point Likert scale that measures symptoms from 0 to 5 precisely as the PAC-SYM does. At nine questions, the GCSI is brief and easily completed by patients, assessing patients’ nausea, retching, vomiting, early satiety, postprandial fullness, loss of appetite, bloating, and visible abdominal distention. In addition, the GCSI also addresses patients simply feeling that their stomach is full, symptoms also seen in functional dyspepsia thought to be related to a lack of gastric accommodation . Unfortunately, the GCSI leaves out abdominal pain, a symptom commonly seen in patients with gastroparesis. In initial validation studies of the GCSI, factor analysis of a large US-based population survey identified bloating as a significant symptom of gastroparesis, although bloating had previously not been considered a common symptom . The GCSI score is the sum of three sub-scale scores across postprandial fullness/early satiety, pain/bloating, and nausea/vomiting. Consistently, across all symptoms, higher mean GCSI scores were highly associated with clinician ratings of increased symptom severity. In addition, the GCSI also proved sensitive to changes in patients’ gastroparesis status, with higher scores, indicative of increased severity in symptoms, being highly correlated with patients’ bed disability or restricted activity days . Abell Scoring uses the GCSI to assess the overall severity of gastroparesis symptoms by using mean scores across the three main sub-scales, assigning a score of 1–3 for symptom severity. Grade 1 patients have mild, or intermittent symptoms controllable with modification of diet and avoidance of exacerbating agents or habits (such as eating meals immediately before bedtime). Grade 2 patients experience moderately severe symptoms without weight loss but require prokinetic medications, usually with antiemetic agents for control. In contrast, Grade 3 patients are refractory to medications, unable to maintain oral nutrition and require intravenous fluids, plus medications, enteral or parenteral nutrition, and endoscopic or surgical therapy. Grade 3 patients frequently have weight loss with malnutrition, require frequent emergency room visits and some hospitalization .
Both the PAGI-SYM and GCSI ask patients to rate the severity of their gastroparesis symptoms over the two weeks preceding the administration of the questionnaire(s). Because the ANMS GCSI-DD measures the efficacy of therapeutic treatments of gastroparesis, this questionnaire relies on a 24-hour recall period, assessing patients’ symptom severity across five different symptoms: nausea, early satiety, post-prandial fullness, upper abdominal pain , and vomiting ( Table 3.1 contains a representative sample of responses) . All symptoms, excluding vomiting, rely on a 5-point scale to assess severity, with responses including none, mild, moderate, severe, or very severe. Patients are also asked to record the number of vomiting episodes over the last 24 hours . Although the original GCSI included bloating, research using the GCSI, prior to the development of the ANMS GCSI-DD, identified significant overlap between bloating and postprandial fullness, resulting in the ANMS GCSI-DD removing bloating as a symptom . Moreover, fewer than half the patients in the study that validated the ANMS GCSI-DD endorsed the inclusion of bloating as a distinct symptom of gastroparesis .
|Nausea||“I have a low level of nausea all day, like pretty much all day I could throw up and I’m keeping myself from throwing up.”|
|Bloating||“It’s just my whole abdomen area, my whole stomach area that pretty much gets bloated… it just get big, like a beer belly.”|
The different symptoms covered by the PAGI-SYM and GCSI, as well as the different duration assessed by the ANMS GCSI-DD, enable clinicians to capture accurate evaluations of patients’ symptoms and severity that are well correlated with clinician observations of patients’ symptoms of gastroparesis—but not pan-enteric dysmotility. These instruments can provide robust criteria for assessing patients’ symptoms of gastroparesis, especially when augmented with other modalities for assessing delays in gastric emptying that include gastric emptying scintigraphy, wireless capsule motility studies ( Chapter 12 ), GEBT ( Chapter 13 ), antroduodenal manometry ( Chapter 16 ), and barostat and satiety testing ( Chapter 17 ).
Symptoms presentations according to pathophysiology of gastroparesis
Symptoms of diabetic gastroparesis
The term Gastroparesis Diabeticorum was first coined by Kassander et al. in 1958 describing minimal symptoms but finding of “asymptomatic” gastric retention on Upper GI Series . Symptoms of diabetic gastroparesis may vary, attributed to the patients’ glycemic control or of their type of diabetes or duration after diagnosis with Type 1 or Type 2 diabetes. In one community-based study of Olmsted County, Minnesota, patients with Type 1 or Type 2 diabetes reported the same rates of nausea and vomiting as controls . However, another community-based study in Australia documented severe bloating, abdominal discomfort or pain, early satiety, and post-prandial fullness, along with nausea and vomiting in a sample of patients with predominantly Type 2 diabetes . Some patients with diabetes though may present instead with accelerated gastric emptying , while others may report symptoms consistent with rumination syndrome—daily, early post-prandial, effortless regurgitation of food within 10–30 minutes of ingestion . Postprandial fullness, nausea with vomiting 1 hour after food intake are symptoms more suggestive of a delayed gastric emptying, according to some studies .
Because standards for assessing delayed gastric emptying vary widely (see Chapter 10, Chapter 11, Chapter 12, Chapter 13, Chapter 14, Chapter 15, Chapter 16, Chapter 17, Chapter 18 ), and studies have used a variety of methods in assessing rates of gastric emptying, associations between delayed gastric emptying and severity of other symptoms associated with gastroparesis are also absent in some studies while strong in others . These limitations may be responsible for findings in some studies that treatments that improved gastric emptying times failed to impact patients’ symptoms of nausea, bloating, abdominal discomfort, early satiety, and postprandial fullness . Conversely, these same limitations may also account for patients in some studies reporting significant symptom improvement using the GCSI , despite their gastric emptying remaining significantly delayed . Since glucose control impacts the rate of gastric emptying, blood glucose levels less than 275 mg are required prior to undergoing any gastric emptying studies in order to prevent a false diagnosis.
Across studies, only limited evidence indicates associations between increased glycemic control and decreases in severity of gastroparesis symptoms, including nausea, pain, bloating, abdominal discomfort, postprandial fullness, early satiety, and delayed gastric emptying . Despite variations in testing modalities and standards, patients generally experience accelerated gastric emptying during hypoglycemia and delayed gastric emptying during hyperglycemia . Nevertheless, even in diabetics without delayed gastric emptying or significant symptoms characteristic of gastroparesis, the loss of good glycemic control should prompt clinicians to administer the PAGI-SYM or GCSI and consider gastric emptying delay as a cause. Clinicians should also assess patients’ gastric emptying, as gastroparesis may lead to postprandial hypoglycemia or hyperglycemia, since gastric dysmotility can impair absorption of nutrients, as well as of oral hypoglycemic medications . For patients with Type 1 diabetes, severe delays in gastric emptying may be an indication for the use of insulin-pump therapy . In addition, diabetic retinopathy in diabetic patients can be correlated with delays in gastric emptying .
Other factors may impact patients’ reporting of the nature and severity of their gastroparesis symptoms, including some differences in presentations of symptoms between Type 1 and Type 2 diabetes, as well as autonomic and enteric neuropathy stemming from long-term loss of glycemic control . For example, in one 48-week study of patients with both Type 1 and Type 2 diabetes, symptoms on the GCSI at baseline were remarkably similar between both groups, including nausea and postprandial fullness . However, patients with Type 1 diabetes reported increased gastroesophageal reflux disease (GERD) possibly due to more severe delays in gastric emptying due to longer duration of diabetes. In contrast, patients with Type 2 diabetes displayed more severe bloating or distention . Over time, patients with poor glycemic control exhibit severe nausea and vomiting, as well as significantly delayed gastric emptying with some possible explanations being a blunted pancreatic polypeptide response, reducing gastric secretions and stimulation of the vagus nerve responsible for gastric motility .
Symptoms of idiopathic gastroparesis
Idiopathic gastroparesis accounts for an estimated 49.4% of documented cases . Of these cases, in many the onset of symptoms may be due to a viral etiology . An NIDDK Gastroparesis Consortium study found approximately 19% of patients with idiopathic gastroparesis, as well as 28% of patients with both Type 1 and Type 2 diabetic gastroparesis had features indicative of past viral infection, including elevated antibody titers against cytomegalovirus and Epstein-Barr . A study of patients enrolled in the NIDDK Gastroparesis Registry also found significant differences between symptoms reported by patients with idiopathic gastroparesis and those in patients with diabetic gastroparesis. Patients with idiopathic gastroparesis reported the same levels of nausea, but higher rates of upper abdominal pain but decreased instances of vomiting or retching, compared with diabetic patients with gastroparesis . However, given the overlap of infectious gastroparesis in patients with idiopathic and diabetic gastroparesis, increased vomiting could be indicative of either vagal neuropathy in diabetic patients or of post-infectious gastroparesis .
Symptoms of post-infectious gastroparesis
Post-infectious gastroparesis may account for the majority of cases of idiopathic gastroparesis, especially since so few studies have tested for infectious Enteroviruses (EV), many of which cannot even be identified. To date, studies have established that EV involves at least 71 viruses, including Coxsackievirus Groups A & B , Echovirus , and Parechovirus . EV numbers among the most common viruses infecting humans world-wide . Few patients infected with EV likely receive clinical attention for lingering GI symptoms. Additionally, few patients with symptoms of gastroparesis receive testing for EV from gastric biopsies taken during an upper endoscopy done to evaluate symptoms of nausea and vomiting . This finding is similar to outcomes from two other studies, where as many as 82% of patients presenting with symptoms of dyspepsia tested positive for EV . For example, in a small pilot study of 11 patients referred for symptoms of gastroparesis with idiopathic gastroparesis, 82% were positive for gastric EV by qualitative immune staining of gastric mucosa . Significantly, over half of these patients had autonomic dysfunction confirmed by tilt-table testing . These patients were also likeliest to require total parenteral nutrition—Grade 3 gastroparesis, according to Abell scoring on the GCSI . Unsurprisingly, patients with autonomic dysfunction, a common finding in patients with gastroparesis, are the least likely to experience remission of their symptoms following treatment for EV .
Symptoms of post-surgical gastroparesis
Many patients with idiopathic or diabetic gastroparesis have had a cholecystectomy. In some post-surgical cases, removal of the gallbladder for gallstones may possibly surgically disrupt neural pathways to the GI tract, particularly when the vagal nerve is involved . Post-cholecystectomy, gastroparesis-like symptoms include nausea, vomiting, and upper abdominal pain, sometimes diarrhea and often in the absence of delays in gastric emptying .
Complications of gastroparesis which include reflux and aspiration leading to rejection and graft failure are common in the lung transplant population, with delayed gastric emptying reported in 23–91% and new onset of gastroparesis reported in 50% of studies done after transplant . Few retrospective studies have shown that treatment of gastroparesis with pyloric Botulinum Toxin A may improve delayed gastric emptying and thus avoid these complications, however the studies are small and retrospective in design and none of the gastroparesis therapies has been shown to improve graft survival .
Bariatric surgery and fundoplication
Increases in post-surgical gastroparesis-like symptoms also coincide with the rise of bariatric surgery and the use of fundoplication for chronic GERD. The combination of vagotomy, distal gastric resection, and Roux-en-Y surgery predisposes patients to slow emptying from the gastric remnant. Patients with Roux-en-Y Stasis Syndrome report postprandial abdominal pain, bloating, nausea, and vomiting, which may unfortunately prove refractory to most medical treatments for gastroparesis and may in fact be due to another syndrome called dumping syndrome or post-vagotomy syndrome . Of course, gastric emptying using standard protocols has to be modified for gastric surgery and many surgeons thus rely on fluoroscopic upper GI studies instead to better assess pouch emptying. Symptoms frequently include abdominal fullness, satiety, excess sweating, dizziness and diarrhea. These gastroparesis-like symptoms are common in the first three months after fundoplication but persist in only a minority of patients after a year. In one study of 615 patients, these symptoms included early satiety in 88% and bloating in 64% of patients. This is often referred to as “gas-bloat” syndrome due to inability to belch post-fundoplication. Here, the possibility of vagal nerve damage from the fundoplication has to be considered as a causative factor for development of gastroparesis. However, in 90% of patients, all gastroparesis symptoms resolved within a year of the surgery . In patients who suffered symptoms for more than a year following surgery, high correlations between pre- and post-operative symptoms of delayed gastric emptying have been found . In patients reporting refractory GERD symptoms to PPI therapy or even post-fundoplication, clinicians should assess gastric emptying especially if patients are diabetics, as dysmotility can aggravate heartburn and regurgitation —ironically exacerbating the reflux the fundoplication ostensibly addressed.
Provocation drugs: Opioid-induced gastroparesis
Patients with chronic gastroparesis that prominently features abdominal pain may receive treatment with μ-opiate receptor agonists, including morphine , oxycodone , and tramadol , all of which worsen gastric emptying delay and exacerbate symptoms of nausea and vomiting. Thus, opioid medications may lead to a vicious cycle, where patients’ symptoms worsen, as a result of taking opioids, leading to patients requiring more pain management . Of μ-opiate receptor agonists, gastroparesis symptoms may be slightly less exacerbated by tramadol, tapentadol, codeine, or propoxyphene than opioids such as oxycodone, hydrocodone and fentanyl . A recent study of 583 patients diagnosed with gastroparesis in tertiary care centers, found 41% of patients were taking opioids for pain, with 82% of these patients taking potent opioids, including morphine, hydrocodone, oxycodone, methadone, hydromorphone, buprenorphine, or fentanyl . These findings are not surprising, considering that 3% of US adults use opioids for chronic pain . Ironically, opioid use to treat abdominal pain and distention generally results in patients experiencing greater levels of gastric retention, poorer quality of life, increased hospitalizations, and increased use of antiemetic and pain modulator medications . To counter patients’ use of opioids, clinicians may want to consider alternative medications that address nausea and abdominal pain such as neuromodulators as discussed in other chapters or use of peripherally acting μ-receptor antagonists (PAMORAs) which may counteract the effects of opioids .
Symptoms of gastroparesis stemming from various other etiologies
The less-common etiologies of gastroparesis symptoms include diseases that affect extrinsic neural control, including Parkinson Disease and other neurologic disorders such as multiple sclerosis, and connective tissue disorders that result in infiltration or degeneration of smooth muscle in the gut, such as scleroderma and lupus . Other less common diagnoses include Ehlers-Danlos syndrome and Marfan Syndromes that may impact motility through derangement of the composition of the extracellular matrix . Finally, clinicians assessing gastroparesis symptoms should consider mesenteric ischemia, a rare but potentially reversible cause of gastric emptying delay and an equally rare disorder, superior mesenteric artery syndrome, alongside a more common syndrome—median arcuate ligament syndrome—that causes abdominal pain, weight loss, and various degrees of gastric outlet obstruction from compression of the celiac ganglion and can also be initially misdiagnosed as gastroparesis . Lastly, genetic and systemic disorders such as cystic fibrosis are another cause of gastroparesis which may present differently than these other etiologies.
Patients with Parkinson Disease present with a variety of GI impairments, esophageal dysmotility including oropharyngeal and esophageal resembling achalasia, gastroparesis, small bowel bacterial overgrowth syndrome and constipation . Some researchers speculate that gastroparesis impacts 100% of these patients . This speculation reflects both the diverse impacts of the disease on motor function and the specific effects of medications used to treat Parkinson Disease such as levodopa which significantly exacerbate delays in gastric emptying . Routine gastric biopsies and autopsy specimens in patients with PD show presence of α-synuclein inclusions and Lewy bodies in Meissner’s and Auerbach’s plexuses, and deficits in the anti-inflammatory cholinergic pathways leading to delayed gastric emptying . However Parkinson’s patients not on medications for their neurologic disease report gastroparesis symptoms at rates higher than in the general population. These symptoms include nausea, bloating, vomiting, abdominal pain, and postprandial fullness . In fact, some clinicians have argued that the presentation of gastroparesis symptoms may be the one of the earliest indications of the onset of Parkinson Disease .
Most studies attribute these symptoms to delayed gastric emptying, well-documented in both Parkinson patients untreated and treated with levodopa . Conversely, in patients treated with levodopa, delays in gastric emptying affect its absorption, as levodopa must reach the proximal small bowel for full absorption. Delays in gastric emptying and colonic transit times thus cause fluctuations in motor responses of Parkinson patients receiving levodopa therapy, ranging from a delay in the onset of action to complete dose failure . Orally administered levodopa tends to remain in gastroparetic patients’ stomachs unabsorbed, delaying jejunal absorption. Subsequent delays in peak plasma volumes of levodopa make delayed gastric emptying one of the chief determinants of the efficacy of levodopa therapy . In some studies, these delays in gastric emptying remain virtually the same in treated and untreated patients, as well as similar in newly-diagnosed patients and patients with advanced-stage disease . These dopamine agonists, can also create a vicious cycle, where the medications used to treat Parkinson Disease result in increased delays in gastric emptying, exacerbating delays in the absorption of medications and times to peak plasma concentrations . Nevertheless, new medications have been evaluated but await further studies, including administering DuoDopa by infusion but whether they impact patients symptoms remains to be seen .
Connective tissue diseases
Patients with connective tissue disorders—including multiple Ehlers-Danlos Syndrome subtypes, mixed connective tissue disease, scleroderma, and lupus represent a surprisingly large subset of patients with symptoms of gastroparesis. In one study, patients with connective tissue diseases were the third-largest group of patients, after idiopathic and diabetic patients, surpassing the post-surgical group . In fact, the number of patients with connective tissue diseases with gastroparesis may be nearly as high as the numbers of patients with diabetic gastroparesis . In one large study of 2400 patients, one-third of patients attending a clinic for gastroparesis symptoms had undiagnosed joint hypermobility syndrome with abdominal pain reported as their most debilitating symptom .
Ehlers-Danlos Syndrome (EDS) consists of a group of inherited connective tissue disorders impacting the extracellular matrix with considerable clinical and genetic heterogeneity . Regardless of clinical classification, most patients with EDS or joint hypermobility syndrome report abdominal pain, early satiety, postprandial fullness, and bloating most frequently with nausea and vomiting occurring less frequently among these patients .
In the less commonly diagnosed mixed connective tissue disease (MCTD), patients experience similar symptoms, sharing some of the same multi-systemic phenotypic features common to joint hypermobility. However, in MCTD, particularly in cases that progress for years without receiving a diagnosis, patients may experience severe weight loss, following abdominal pain, early satiety, nausea, and vomiting .
Both systemic lupus erythematosus and scleroderma are complex, chronic, multi-systemic diseases with significant impacts on the gut due to their effects on GI tract smooth muscles and can cause GERD and gastroparesis. Although patients are managed well by rheumatologists and their primary practitioners, they frequently fail to receive referrals to gastroenterologists, likely due to lack of recognition of the severity and systemic nature of GI symptoms . Gastroparesis is present in 40–67% of patients with scleroderma and symptoms include abdominal pain and distension, early satiety, postprandial fullness, nausea, and vomiting and these symptoms accompany the dysphagia and severely impaired esophageal motility also prevalent . In contrast, patients with lupus have lower rates of delayed gastric emptying , although the literature on patients with lupus and gastroparesis is relatively scarce . Case reports have been valuable in providing details about the severity of gastroparesis symptoms specific to lupus, focusing on severe abdominal pain, nausea, and vomiting, leading to generalized weakness . Abdominal pain is by far the most frequent symptom reported in 8–40% of patients with lupus . However, lupus patients presenting with severe abdominal pain may also be at risk of serious complications that include abdominal vasculitis, pancreatitis serositis, or peritonitis—thus not all pain is related to impaired gastric emptying. These risk factors should not be overlooked as clinicians assess patients for gastroparesis, especially as many patients with lupus have minimal delays in gastric emptying .
Cystic fibrosis and chronic pancreatitis
Delayed gastric emptying and gastroparesis symptoms occur in about 38% of patients with Cystic Fibrosis , both pre- and post-lung or pancreas transplantation. Gastroparesis symptoms, including accelerated or delayed gastric emptying, are highly associated with CF . Patients may report bloating, nausea, abdominal pain, and early satiety due, not only to the multifactorial nature of CF, but also to exocrine pancreatic insufficiency, which interferes with the absorption of dietary fat and protein in an estimated 90% of patients . Furthermore, patients with CF may use both opiates and anticholinergics, which can delay gastric emptying and increase the severity of symptoms of gastroparesis . Following lung transplantation, CF patients frequently report bloating, nausea, vomiting, abdominal pain, and early satiety and these symptoms may also be due to intestinal dysbiosis and small intestinal dysmotility in addition to gastric dysmotility . Clinicians should consider these symptoms as potential factors in respiratory complications, including aspiration pneumonia, especially in the immediate peri-operative period and malnutrition . As a result, CF care teams should consider patients’ risk for post-operative complications stemming from gastroparesis symptoms.
Differentiation from ROME IVs disorders of gut-brain interaction
The ROME IV criteria classified Functional Gastrointestinal Disorders (FGIDs) as disorders of brain-gut interaction and according to symptoms, rather than physiological disorders. This classification delineates many other disorders with some symptom overlap with gastroparesis but no significant associations with delayed gastric emptying . Of the gastroduodenal FGIDs delineated by ROME IV, gastroparesis shares some common features with functional dyspepsia, as well as chronic nausea and vomiting syndrome, cyclic vomiting, and cannabinoid hyperemesis syndrome, despite gastroparesis symptoms also differing significantly in kind, severity, and onset from these other disorders. Specifically, gastroparetics do not have a cyclic component to their symptoms and have documented delayed gastric emptying, a phenomenon not necessarily seen in these other entities.
Clinical symptoms of gastroparesis have considerable overlap with those of functional dyspepsia although vomiting and weight loss are more prominent in patients with gastroparesis . Based on ROME IV criteria definition, functional dyspepsia has one or more of four cardinal symptoms: bothersome recurrent epigastric pain or burning, postprandial fullness, or early satiety. The definition also includes two subcategories that can overlap—postprandial distress syndrome, characterized by meal-induced dyspeptic symptoms, and epigastric pain that may occur at any time, not only following meals .
Controversy exits over whether gastroparesis and functional dyspepsia are causally related or whether gastroparesis merely represents a more severe form of functional dyspepsia. Moreover, the controversy is exacerbated by an absence of distinguishing symptoms and diagnostic criteria unique to either gastroparesis or functional dyspepsia as patients with functional dyspepsia can have rapid, delayed and normal gastric transit but usually have an impaired gastric accommodation, a common finding in gastroparetic patients due to vagal neuropathy . The considerable overlap between symptoms can lead to misdiagnosis, delaying management of patients’ symptoms . In most definitions, functional dyspepsia is a syndrome with sensory and motor disturbances of the gastroduodenum. On the other hand, gastroparesis is defined almost entirely as a gastric motility disorder although visceral hypersensitivity exists even in patients with gastroparesis similar to functional dyspepsia. Neither the severity of abdominal pain nor its location differentiate gastroparesis from functional dyspepsia . Thus, the distinctions between gastroparesis and functional dyspepsia blur when gastroparesis symptoms fail to correlate with significant delays in gastric emptying . However, improved standards for assessing gastric transit, fundic accommodation, gastric motility, gastric volume and pyloric muscle contraction may clarify the differences between functional dyspepsia and gastroparesis by showing more uniform correlations between gastroparesis symptoms and delayed gastric emptying across gastroparesis stemming from different etiologies . Perhaps further studies may find that gastroparesis should not be solely defined by delayed gastric emptying. In addition, other physiologic parameters, including antral and pyloric contraction patterns and motility index, as well as gastric emptying and transit may be useful in differentiating functional dyspepsia from gastroparesis .
Chronic unidentified nausea and vomiting syndrome or chronic nausea vomiting syndrome
Many researchers investigating functional gastrointestinal disorders have examined symptoms of nausea and vomiting reported by patients, using the terms Chronic Unidentified Nausea and Vomiting syndrome (CUNV) or Chronic Nausea and Vomiting Syndrome (CNVS) . Both CUNV and CNVS have higher reported rates of nausea and vomiting than in patients with gastroparesis. Furthermore, these patients’ symptoms also have mostly poor correlations with delayed gastric emptying . A study of 222 patients with gastroparesis and 66 patients with CUNV found patients with CUNV reported similar symptoms to patients with gastroparesis. However, notable distinctions separated the groups. First, more gastroparesis patients reported abdominal pain as their most severe symptom, while more patients with CUNV reported nausea. Second, interestingly, slightly more gastroparesis patients reported vomiting as their most severe symptom than patients with CUNV, despite the syndrome being named for vomiting symptoms.
Cyclic vomiting syndrome
Cyclic vomiting syndrome (CVS) typically comprises four phases: (I) a pre-emetic period with pallor, sweating, and nausea; (II) intense retching or vomiting frequently occurring with epigastric or abdominal pain, with episodes usually lasting less than a week; (III) a recovery phase with gradual symptom resolution of nausea and vomiting; and (IV) an inter-episodic period without vomiting. Cyclic vomiting attacks are generally longer and more frequent in adults than in children . According to ROME IV criteria, criteria for diagnosis requires that patients experience at least three episodes of cyclic vomiting within a single year, and at least two episodes in the past six months, occurring at least a week apart. Patients typically do not vomit between episodes but experience milder versions of phases I and III during this period which is different than what is seen in patients with gastroparesis where symptoms are chronic and not stereotypic . In moderate/severe cases, patients experience at least four or more episodes annually, some lasting two days or longer. Following episodes, they recover slowly and are for days or weeks. Unsurprisingly, these patients visit emergency rooms or require hospitalization frequently .
Of adult patients with CVS, 58–71% experience episodic and severe abdominal pain . Studies to determine rates of gastric emptying in patients with cyclic vomiting discovered rapid gastric emptying in the phases between vomiting episodes , but delayed gastric emptying during the vomiting cycles . In one study, 5% of patients referred to a major medical center for gastroparesis actually had CVS . Unlike gastroparesis, CVS has a sudden, acute onset . Gastric emptying studies are not necessary for diagnosis of CVS, as symptoms usually resolve between episodes.
Cannabinoid hyperemesis syndrome
Like the other vomiting syndromes, cannabinoid hyperemesis syndrome (CHS) has a sudden onset—unlike gastroparesis symptoms. Patients with CHS may receive a diagnosis of CVS, where over one-third of patients also report marijuana use. However, patients who use cannabinoids chronically receive a diagnosis of CHS despite ROME IV failing to specify whether the type or quantity of cannabis used qualifies a patient as potentially having CHS. Typically, patients experience episodic vomiting identical to the phases experienced in CVS, with the same duration and frequency of episodes. With a sudden onset similar to that in CVS, CHS usually begins after prolonged and excessive use of cannabis, at least daily, for a period of greater than two years . As with patients suffering from CVS, patients with CHS usually receive a delayed diagnosis, following numerous emergency room visits .
Unlike patients with other functional gastrointestinal disorders—and patients with gastroparesis—patients with CHS usually gain relief from vomiting episodes after they stop all use of cannabis . Delayed gastric emptying can be seen with chronic cannabis use in up to 30% of patients in one study . Cannabis is now the world’s most commonly abused drug and legal for recreational use in some countries and US states, with its possession and use decriminalized in other US states and countries. Yet a surprising number of clinicians remain completely unaware of the existence and symptoms of CHS . This lack of awareness may stem from CHS being a seemingly paradoxical syndrome, given cannabis’ well-established anti-emetic effects . Nevertheless, despite widespread abuse of cannabis, CHS is a surprisingly rare disorder despite inaccurate high estimates based on lack of ICD-10 coding and may in fact be due to genetic polymorphisms in P450 enzymes responsible for cannabinoid metabolism, one explanation of its rarity .
Superior mesenteric artery syndrome (SMA)
Superior mesenteric artery syndrome is a rare cause of abdominal pain with symptoms resembling those of gastroparesis but which may be reversible with prompt diagnosis . Patients present with postprandial epigastric pain, nausea, and vomiting, usually accompanied by rapid and significant weight loss, and these symptoms cannot be differentiated from gastroparesis . SMA syndrome is the loss of mesenteric fat due to weight loss that can result in compression of the third portion of the duodenum by the SMA as it courses from the aorta. Radiologic investigations with ultrasound, arteriograms and CT scanning can determine whether patients have SMA syndrome, which should be addressed conservatively with nutrition to restore aortomesenteric fatty tissue and relieve compression of the third part of the duodenum by the SMA . Severe gastroparesis with weight loss can be a risk factor for development of SMA syndrome. Therefore, caution is advised prior to surgical management of SMA syndrome in patients with a previous history of gastroparesis.
Median arcuate ligament syndrome
Also known as celiac artery compression syndrome and Dunbar Syndrome, median arcuate ligament syndrome is an uncommon disorder, characterized by a cluster of symptoms: postprandial abdominal pain, weight loss, and, sometimes, abdominal bruit . The median arcuate ligament is a fibrous arch that crosses the aorta, where it also traverses the celiac axis at the point that axis branches from the abdominal aorta. Deviations of the origin of the celiac axis from normal, placing it higher or lower, makes it susceptible to compression from the median arcuate ligament . In about 10% of patients with median arcuate ligament syndrome, the ligament itself is abnormally positioned and compresses a normally positioned celiac artery .
Patients with median arcuate ligament syndrome typically report postprandial abdominal pain, frequently epigastric . In some patients, exercise may trigger abdominal pain . The abdominal pain can be constant or intermittent , as well as contingent on position—with relief achieved by leaning forward or drawing knees to chest . Approximately half of these patients have unintentional weight loss or 20 lbs. or more . Patients other symptoms have considerable overlap with those of gastroparesis, including bloating, pain and nausea. In one series of 36 patients, 39% reported bloating, and 56%, nausea or vomiting . However, in a larger series, nausea only occurred in 9.7% of patients . Because of its relative rarity and overlap of symptoms with other disorders, typically, patients only receive an accurate diagnosis 34 months after onset of symptoms . These patients also usually require vascular imaging and physiologic testing to establish median arcuate ligament syndrome, which is treated by decompression of the median arcuate ligament’s constriction of the celiac artery . This can be a staged procedure with an endoscopically-guided ultrasound done with celiac axis blockade, prior to any planned laparoscopic surgery . . Unfortunately, most of these patients do not experience chronic relief of symptoms even after surgical repair .
Symptom co-morbidities with gastroparesis
Gastroparesis has comorbidities that may alert clinicians to assess patients for symptoms of gastroparesis, especially for delays in gastric emptying. Depression, migraine headaches and symptoms related to dysautonomia are frequently seen in patients with gastroparesis, with these symptoms negatively impacting patients’ Quality of Life .
Gastroparesis frequently occurs with migraine headaches, with the most frequent symptom similarity being nausea . Traditionally, to be classified as a migraine, a headache must have four characteristics. Migraine (1) lasts from 4 to 72 hours, with or without treatment (2) is not attributed to another disorder, (3) presents with (a) unilateral location, (b) pulsating headache with (c) moderate to severe pain that can be (d) aggravated by routine physical activity and (4) is accompanied by (e) nausea/vomiting and/or sensitivity to light or sound . With migraines, the relationship between nausea and gastric emptying delays is well established, although the causal relationship between the two is the subject of debate . The largest single study of migraine and gastroparesis, focusing on 51,000 people in a single Norwegian county, found the intensity of GI symptoms increased with prevalence of migraines (P < 0.0001). Migraine is highly associated with delays in gastric emptying, with as many as 78% of patients having significant delays during migraine, and 80% between migraine attacks. Moreover, gastric emptying delays nearly doubled between attacks, going from 149.9 minutes in T 1/2 values during a spontaneous migraine attack to 243 minutes interictally. In contrast, controls had T 1/2 times of 111.8 minutes . In one study of diabetic patients with migraine, 47% of patients with migraine had gastroparesis . Clinicians treating patients with migraine should be aware that patients with nausea and migraine have poor responses to oral medications, as delays in gastric emptying impact absorption of the medication . Treatment of migraines may also be complicated by patients with migraines having cyclic vomiting symptoms similar to CVS .
Depression and other impacts on quality of life
Patients with gastroparesis frequently experience significantly diminished qualify of life (QOL) . Of the subset of patients with idiopathic gastroparesis, 23% report feeling depressed . Higher depression and anxiety scores also correlate with severity of patients’ symptoms as evaluated by the GCSI or by the PAGI-SYM. 122,165 Abdominal bloating and pain also account for significant impacts on patients QOL with bloating resulting in moderately impaired QOL, as measured by the PAGI-QOL . The well-validated PAGI-QOL uses 30 questions to assess the impacts of gastrointestinal symptoms on patients’ daily activities, relationships, and emotions . A systematic review of the psychological impacts of gastroparesis on patients found somatization present in 50% of patients, combined anxiety and depression in 24%, depression in 23%, and severe anxiety in 12.4%, with an inverse relationship between QOL and symptom severity . Gastroenterologists treating patients for gastroparesis should take into account their patients’ decreased QOL and consider recommending psychological intervention. One randomized control trial of the impacts of comprehensive psychological intervention in 120 post-surgical gastroparesis patients found considerable improvements in the experimental group . Clearly, further studies on the interactions between psychological interventions, patients’ QOL, and symptom severity can shed light on the efficacy of psychotherapy and counseling as adjuvant therapy in improving patients’ QOL.
Because of the wide array of diseases and syndromes where patients report upper GI symptoms similar to gastroparesis, clinicians should be aware of both the patient populations where gastroparesis is likeliest to exist, as well as of syndromes where symptoms overlap with gastroparesis but where the underlying etiology makes gastroparesis not the primary diagnosis. Assessing the status of gastric emptying using the “gold standard” scintigraphy method and others as discussed in the upcoming chapters, is key to making a diagnosis of gastroparesis. In diabetic gastroparesis similar symptoms may present in normal, delayed or rapid gastric emptying. Thus, for many patients, gastroparesis symptoms may signify a need for a differential diagnosis and appropriate testing to better stratify them into groups that may benefit from prokinetic therapy.