Autonomic nerve function in adult patients with cyclic vomiting syndrome
A part of this study was presented at the American College of Gastroenterology (ACG) annual meeting, San Diego, CA, USA. Oct 2009.
Address for Correspondence Richard W. McCallum, MD, FACP, FRACP (Aust), FACG, Founding Chair, Department of Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, 4800 Alberta Ave, El Paso, TX 79905, USA.
Tel: (915) 545 6626; fax: (915) 545 6634;
Background Cyclic vomiting syndrome (CVS) in adults is a disorder characterized by recurrent and stereotypic episodes of severe nausea and vomiting separated by symptom-free periods. Autonomic dysfunction has been a postulated mechanism for the pathogenesis of this disorder in children but has not been explored in adults.
Methods Our goals were to investigate autonomic nerve function in adult patients with CVS. The sympathetic nervous system was evaluated through postural changes in heart rate and blood pressure and sympathetic skin response in the hand and foot. The parasympathetic nervous system was tested through heart rate response to deep breathing [expiration/inspiration (E/I)], Valsalva and postural indices (30 : 15 ratio). All patients had a 4-h standard isotope labeled egg beater meal gastric emptying test (GET).
Key Results Twenty-two adult (18 female), mean age 35 ± 11 (range 19–61 years), who met Rome III criteria for CVS were included. History of migraine headache was reported in three patients. Five (23%) had pediatric onset. Of 21 patients who completed the test, nine patients had 21 abnormalities detected in their autonomic nerve testing profile and the remaining 12 had normal autonomic function results. Orthostatic tachycardia was observed in two (mean heart rate increase 39 beats min−1) and a decline in blood pressure (BP) in three patients (mean BP drop 30/14 mmHg). Parasympathetic abnormalities were elicited in six patients with an abnormal response to deep breathing and E/I index <1.25. Sympathetic nerve dysfunction was reported in seven patients with absent sympathetic skin response in the foot and/or hand. Twelve (57%) of CVS group had rapid GET (<50% retention at 1 h). The frequency of abnormal autonomic nerve function was not significantly higher in rapid GET subgroup.
Conclusions & Inferences (i) Autonomic nerve dysfunction is common in adult CVS patients, being observed in 43% of our cohort; (ii) Sympathetic abnormalities dominate; and (iii) Rapid gastric emptying, present in 57% of patients, did not correlate with autonomic testing results. These new data provide more insight into the pathophysiology of CVS in adults and help explain the spectrum of clinical manifestations observed in this entity.
cyclic vomiting syndrome
gastric emptying test
Cyclic vomiting syndrome (CVS) is a disease characterized by recurrent episodes of incapacitating nausea and vomiting interspersed with relatively symptom-free intervals that might last anywhere from a few days to several months.1 It was first described in the late 19th century and was essentially thought to be a disorder of childhood, but it is increasingly being recognized in adults over the last 20 years.2 The diagnostic criteria for adult CVS according to the Rome III criteria are stereotypic episodes of vomiting with the following characteristics: a sudden or acute onset, usual duration of less than a week, three or more discrete episodes occurring in the prior year and absence of symptoms between attacks. Supportive criteria include a personal or family history of migraine.3 Although the Rome III criteria were originally defined in children the adult onset of CVS is defined as a separate category in Rome III classification. Migraine headache are reported as a frequent comorbid disease and anxiety and/or depression often coexist with CVS.4,5 The pathophysiology and pathogenesis of CVS is the subject to scientific and therapeutic investigations that have yet to clarify the etiopathogenesis. Cyclic vomiting syndrome has increasingly been diagnosed in adults. There is an emerging consensus that CVS appears to involve dysregulated central neural pathways and neuro-endocrine mediators involved in the afferent and efferent brain-gut pathways of nausea and vomiting.6 Dysauthonomia was observed in a pediatric CVS population7,8 but there is a very limited data in adults.9 On the other hand the majority of patients with CVS show a rapid gastric emptying10–14 in the same range as patients presenting with symptoms of the dumping syndrome. The purpose of this study is: (i) to define the autonomic nerve function testing and determine the frequency and characteristics of dysautonomia in adult patients with CVS, (ii) to evaluate the association of autonomic nerve function characteristics with different degrees of gastric emptying (normal and rapid) based on standard radionuclide 4-h gastric emptying studies in adult patients with CVS.
Patients and methods
Twenty-two patients with the primary diagnosis of cyclic vomiting syndrome were included. All patients were initially referred for outpatient evaluation because of upper gastrointestinal (GI) symptoms, and all underwent careful history taking and clinical examination, upper GI endoscopy, routine biochemistry such as, complete blood count, hemoglobin, hematocrit, electrolytes and liver function test, upper abdominal ultrasound and gastric emptying test as part of their assessment before making the diagnosis of adult CVS. Only patients in whom we established the diagnosis of CVS based on Rome III criteria and who had no other abnormalities identified by these additional studies are included in the report. Patients with documented organic or intestinal pseudo-obstruction, primary eating or swallowing disorders, rumination syndrome, psychogenic vomiting, functional vomiting,3 systemic sclerosis, thyroid and adrenal problems, chemical dependency, a diagnosis of cancer, renal failure, or a positive pregnancy test were excluded. The study protocol was approved by the Human Subjects Committee at the University of Kansas Medical Center.
Autonomic nerve testing We performed autonomic nervous system testing using Critikon (Critikon Inc., Tampa, FL, USA) for blood pressure measurements, Nicolet Viking (Nicolet Biomedical Inc., Madison, WI, USA) for sympathetic skin responses and Qmed Monitor (Qmed Inc., Clark, NJ, USA) for rest of the autonomic testing. All of the patients were tested as outpatients when they were essentially ‘in remission’ and essentially ‘between acute episodes’. Testing consisted of standard, previously validated clinical cardiovascular and sympathetic components.7,8 In one patient parasympathetic and sympathetic testing was not performed because of severe dizziness and pre-existing atrial fibrillation.
Sympathetic vasomotor function was assessed by obtaining the orthostatic blood pressure measurements and sympathetic sudomotor function was tested by sympathetic skin response.
Orthostatic blood pressure testing: After explaining the procedure to the subject, they are asked to lie flat for 10 min prior to the test. Two resting blood pressure measurements are taken and subject is asked to stand as quickly as possible. The blood pressure measurements are obtained every 3 min until four standing blood pressure measurements are obtained. The diastolic blood pressure normally decreases <10 mmHg and the systolic blood pressure (BP) <20 mmHg, from lying to standing positions. The heart rate increase is normally less than 28 beats per minute.14–16 Values above these are considered abnormal.
Sympathetic skin response (SSR): The median and tibial nerves are stimulated and SSRs are recorded from an electrode placed on the hand and foot.
Parasympathetic nervous system function was assessed by measuring the baroreflex control of heart rate during maneuvers which modify blood pressure. These include the heart rate (HR) response to deep breathing (E/I ratio), Valsalva ratio and the postural index (30 : 15 ratio).
Heart rate response to deep breathing (E/I ratio): Subjects are asked to take deep breaths and blow out slowly at the count of 10. This is repeated for 1 min. The longest expiration R–R interval and the shortest inspiration R–R interval, averaging at least three consecutive 10-s cycles are measured (Nl > 1.25).
Valsalva ratio: The subject maintains a 40-mmHg pressure gradient with an open glottis for 15 s while HR and BP are continuously monitored. The Valsalva ratio consists of the fastest HR during pressure exertion (termed phase II, sympathetically mediated) divided by the lowest HR after pressure release (termed phase IV, parasympathetically mediated; normal values for this age group (Nl ≥ 1.21).
Postural Index (30 : 15 ratio): The resting heart rate is obtained with subject relaxed. Subject is then asked to stand up as quickly as possible for 1 min and heart rate is remeasured. This is repeated for total of three times. The R–R interval is measured at 15 and 30 s and ratio (30 : 15) is calculated (Nl ≥ 1.04).
Gastric emptying studies Gastric emptying time (GET) was assessed by standard 4-h scintigraphic method using a low fat solid meal.17,18 Scintigraphic GET was performed in the morning after an overnight fast with prokinetics and proton pump inhibitors (PPI) stopped for at least 3 days and narcotic medication withhold for more than 12 h. This standardized method for gastric emptying consists of a scrambled egg substitute [120 g of Free Cholesterol & Fat Free Egg; Sunny Fresh Foods, Inc., Monticello, MN, USA; (60 kcal)] labeled with 99mTc sulfur-colloid (1 mCi), two slices of whole wheat bread (120 kcal), 30 g jelly (75 kcal), and 120 mL of water. The meal has a total caloric value of 255 kcal (nutritional composition: 72% carbohydrate, 24% protein, 2% fat, and 2% fiber). Anterior and posterior images of the stomach were taken immediately after eating, and then hourly for 4 h. Patients remained upright, standing walking or sitting during the 4 h of the test and did not recline or go to sleep. Gastric retentions of gamma counts were calculated by the Department of Nuclear Medicine using geometric and decay correction. Delayed gastric emptying for this study was defined as isotope retention of >10% at 4 h based on normal data established for this standardized gastric emptying test. Rapid emptying was defined as isotope retention <50% at 1st hour based on the range of normative values and as discussed in our recent publication.12,13,19 The values of normal and fast were based on a multicenter study, which provided GE values in healthy subjects utilizing data obtained in a large sample size with that same meal and methodology.17,18
Results are expressed as means (±SD at 95% confidence levels). Chi-squared test was used for statistical analysis and a P < 0.05 was used for statistical significance.
Twenty-two adult (18 female), mean age 40 ± 5 (range 19–61 years), who met Rome III criteria for CVS were included. History of migraine headache was reported in three patients. Five (23%) had pediatric onset (Table 1). Overall nine patients had 21 abnormalities detected in their autonomic testing profile and the remaining 11 had normal autonomic function results (Table 2). Orthostatic tachycardia was observed in two (mean HR increase 39 beats min−1) and a decline in BP in three patients (mean BP drop 30/14 mmHg). Parasympathetic abnormalities were elicited in six patients with an abnormal response to deep breathing and E/I index <1.25. Sympathetic nerve dysfunction was reported in seven patients with absent sympathetic skin response in the foot and/or hand. When compared group of patient with abnormal with normal autonomic function group the only significant difference between two groups was age of onset that was older in abnormal autonomic function group (19 ± 8 vs 13 ± 4 years, P < 0.05) (Table 3).
Table 1. Summary of demographic and clinical profiles of 21 adult patients with cyclic vomiting syndrome
| Mean ± SD||35 ± 11|
|Age of onset (years)|
| Mean ± SD||17 ± 6|
|Age of first diagnosis of CVS (years)|
| Mean ± SD||25 ± 4|
|Gastric emptying test (n)|
Table 2. Summary of abnormalities in autonomic function test observed in 9/21 adult patient with cyclic vomiting syndrome
|1||21||F||↓2/7 mmHg||↑42 beats min−1||1.37||1.67||1.32||Present|
|2||44||F||↓31/9 mmHg||↑15 beats min−1||1.14||1.23||1.07||Absent|
|3||24||M||↑13/10 mmHg||↑12 beats min−1||1.18||1.93||1.41||Absent|
|4||44||F||↓28/18 mmHg||No change||1.07||1.51||1.07||Absent|
|5||43||F||↑7/5 mmHg||↑14 beats min−1||1.10||1.86||1.17||Present|
|6||50||F||↓11/2 mmHg||↑15 beats min−1||1.04||1.18||1.01||Absent|
|7||50||F||↓5/2 mmHg||↑24 beats min−1||1.21||1.70||1.02||Absent|
|8||27||F||↑11/8 mmHg||↑35 beats min−1||1.58||1.59||1.38||Absent|
|9||19||F||↑15/7 mmHg||↑16 beats min−1||1.43||1.73||1.50||Absent|
Table 3. Distribution of demographic, gastric emptying and autonomic function test results in 21 adult patients with CVS
| Mean ± SD||33 ± 7.8||38 ± 12.7|
|Age of onset (years)*|
| Mean ± SD||13 ± 4||19 ± 8|
|Age of first diagnosis of CVS (years)|
| Mean ± SD||26 ± 4||24 ± 6|
Other demographic variables such as age, gender comorbid disorder such as migraine and irritable bowel syndrome (IBS) did not differ between two groups. Twelve (57%) of CVS group had rapid GET (<50% retention at 1 h), nine (43%) had normal GET. The frequency of abnormal autonomic nerve function was not significantly higher in rapid GET subgroup (Table 3).
To our knowledge, this is one of the first reports of detailed autonomic testing in adult patients with CVS. Nine patients demonstrated abnormalities in autonomic testing, ranging from abnormal orthostatic change in blood pressure and/or heart rate in five patients, abnormal cardiac responses to deep breathing (E/I index) (six patients), Valsalva maneuver (Valsalva index) (one patient), and the posture index in two patients suggesting abnormal cardiac parasympathetic innervations. An abnormal sympathetic skin response suggesting abnormalities in sympathetic nervous function was observed in seven patients. These findings support the previous reports in pediatric CVS population.7,20 Our data indicate that autonomic nerve dysfunction was a common finding in adult CVS patients, being observed in 9/21 (43%) of our cohort. Interestingly sympathetic abnormalities were the dominate dysfunction that is consistent with recent report in adult CVS patients.9 When we compared the group of patients with abnormal autonomic function test with normal autonomic group the only significant difference between two groups was age of onset that was older in the abnormal autonomic function group and the other demographic variables for example, age, gender, comorbid disorder such as migraine and IBS did not differ between two groups. Hence in the adult age autonomic dysfunction may be in the background, compared to a pediatric onset often associated with migraine headache and the mitochondrial DNA abnormalities.21 This re-emphasize that this group have shorter duration of disease and this could be attributable to underlying autonomic dysfunction as one of the potential explanation. Moreover adult CVS data did not indicate two distinct groups while 56% of abnormal autonomic function group were rapid gastric emptier and 58% of normal autonomic CVS group were also rapid.
The pathophysiology and pathogenesis of CVS is subject to scientific and therapeutic investigations that have yet to clarify the etiopathogenesis of CVS. There is an emerging consensus that CVS appears to involve dysregulated central neural pathways and neuro-endocrine mediators involved in the afferent and efferent brain-gut pathways of nausea and vomiting.22 Despite an incomplete understanding of the mechanisms underlying this dysregulation, important advances are being made in the clinical understanding of this disorder which may open the way for new treatments. Several pieces of evidence from different lines of investigation point towards an important role of altered brain responses to visceral and to emotional stimuli. Evidence has accumulated which suggest additional pathogenic roles for autonomic, GI, central, neuroendocrine, and mitochondrial metabolic factors.6
One proposed model attempts to integrate the various systems and pathways suggested to be involved in CVS. This model suggests that common triggering stressors (e.g., infectious, psychological) initiate the vomiting cascade in subjects with specific susceptibility factors (e.g., autonomic and GI dysfunction, family history of migraines, energy deficits related to mitochondrial dysfunction) that render affected individuals to respond with repeated episodes of emesis. The defect that enables this cascade to feed forward for hours to days is unknown.6 The autonomic nervous system plays a prominent role in the responses to a range of emetic activators. An integrated series of brainstem nuclei receives input from vagal and sympathetic afferent nerves during emetic stimulation. Efferent signals are then generated in the brainstem nuclei which initiate the stereotypic and coordinated muscular actions involved in vomiting. Using several tests of autonomic function including postural adjustment ratio, heart rate variability, tilt table and sudomotor testing, three groups of investigators have observed increases in sympathetic tone in children with CVS.6,7,20,22 The most common shared finding in these reports was an adrenergic abnormality, but coexistent vagal cholinergic function abnormalities were reported. Comorbid dysautonomic symptoms commonly experienced by CVS patients include migraine headaches, gut dysmotility, complex regional pain syndrome and postural orthostatic tachycardia syndrome (POTS).23,24 Based on these studies describing dysautonomic features in CVS patients, investigators have hypothesized that sympathetic autonomic imbalance may render patients more susceptible to over-respond to central emetic signals.6
Rapid gastric emptying, present in 57% of our patients, did not correlate with autonomic testing results suggesting that rapid gastric emptying frequently seen in adult CVS patients should be explained by other mechanisms such as a hormonal theory.25 One area of additional research would be whether autonomic function findings may improve after inducing remission with tricyclics antidepressants. As far as improving therapy there may be a need for anti anxiety agents as adjunctive therapy. And according to our abnormal autonomic findings such as postural changes in blood pressure and heart rate there may a role to add other adjunctive classes of medication such as beta-blockers and midodrine to address specific autonomic dysfunction and optimizing fluid balance which could lead to better control of CVS outcome as already reported.9
In conclusion our observation of increased frequency of abnormal autonomic nerve testing and particularly sympathetic nerve abnormalities is a new observation in adult CVS patients. These new data provide more insight into the pathophysiology of CVS in adults and help to explain the spectrum of clinical manifestations observed in this entity.
Conflict of interest