Gastric motility dysfunction in patients with multiple sclerosis assessed by gastric emptying scintigraphy

1Nuclear Medicine Unit and 2Neurology Department, Faculty of Medicine, Cairo University, Egypt Correspondence: Dr Tarek AF El-Maghraby, Leiden University Medical Center, Department of Nuclear Medicine, C4Q, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. Telephone 31-71-526-3475, fax 31-71-526-6751, e-mail tarek116@hotmail.com and t.hagendoorn@lumc.nl Received for publication January 2, 2004. Accepted June 8, 2004 TAF El-Maghraby, NM Shalaby, MH Al-Tawdy, SS Salem. Gastric motility dysfunction in patients with multiple sclerosis assessed by gastric emptying scintigraphy. Can J Gastroenterol 2005;19(3):141-145.

T he autonomic nervous system innervates every organ in the body and is actively involved in the function of these organs (1).Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS).MS is the most common disabling neurological disorder affecting people between 20 and 45 years of age.Current prevalence rates for MS are 1/1000 in the United States and 2/1000 in Europe.MS affects women more commonly than men, with a ratio of 2:1 (2)(3)(4)(5).
MS involves myelinated white matter pathways in the brain and spinal cord and is caused by an autoimmune attack of CNS myelin leading to loss of saltatory conduction and conduction velocity in axonal pathways.It is characterized by periventricular demyelination with preservation of axons.MS is a chronic demyelinating disease characterized by disseminated, multifocal lesions that lead to extensive multiple clinical features related to the involvement of the autonomic nervous system (1,6).
The autonomic dysfunction encountered in MS includes impairment of cardiovascular autonomic reflexes leading to hypotension and urinary tract and sexual dysfunctions, which are present in the majority of patients with MS (5,7,8).
The gastrointestinal tract (GIT) constitutes one of the largest organs whose motor, transport, secretory, storage and excretion functions are controlled by the autonomic nervous system (9).Control of gastrointestinal motility involves an integrated chain of neural centres present along the walls of the digestive system, prevertebral sympathetic ganglia, spinal cord and the brain (10).
Gastrointestinal symptoms, especially constipation and/or fecal incontinence, are common in patients with MS.However, GIT symptoms are often overlooked in MS (11).
The aim of the present study was to assess gastric emptying in patients with MS, to detect the severity of autonomic disturbances in the gastrointestinal tract.The second goal was to find the relationship between lower bowel disturbances and the rate of gastric emptying from the stomach.

Patients
The present study was conducted on 49 patients with definite MS, according to criteria proposed by Poser et al (12).Twenty healthy control subjects, who were age-and sex-matched with the patient group, were included.Patients were recruited in the period from March 2001 to April 2003 from the inpatient ward of the Neurology Department, Cairo University Hospital.Patients with relapsing remitting (RR-MS), secondary progressive (SP-MS), and primary progressive (PP-MS) types were included.RR-MS was defined as episodes of acute worsening of neurological function followed by a variable degree of recovery.SP-MS was defined as initial RR disease course followed by progression with or without occasional relapses, minor remissions and plateaus, and PP-MS was defined as disease progression from onset with occasional plateaus and minor improvements (13).Most patients were in acute relapse or showed disease progression by clinical evidence.Patients with possible causes of dysautonomia, such as those with endocrinal disorders such as diabetes mellitus, were excluded.Other causes for exclusion were collagen vascular diseases and a history of drug intake that might affect autonomic function (eg, anticholinergic medications or narcotic analgesics).All patients included in the study were subjected to full clinical evaluation and full neurological examination.Assessment of the clinical disability was performed using the Kurtzke Multiple Sclerosis Rating Scales, the Expanded Disability Status Scale and the Functional Systems Scale (14).Radiological assessment was carried out by magnetic resonance imaging (MRI) of the brain and the spinal cord (cervical and dorsal areas).Verification of the site of plaques was interpreted thoroughly by a specialized neuroradiologist to be correlated with autonomic dysfunction.

Radionuclide gastric emptying (scintigraphy)
Radiopharmaceuticals and equipment: All patients were prepared by fasting for a period of 4 h to 6 h before the gastric emptying study.Three mCi (111 MBq) of technetium-99m colloid were mixed with two scrambled eggs and cooked.The labelled meal consisted of the cooked eggs placed inside bread slices (in sandwich form) and was eaten with one glass of water (200 mL).The imaging was performed using a large field of view gamma camera with dual detectors (Adac, Vertex, USA).The gamma camera was equipped with an all-purpose parallel holes collimator.The energy window was 20% centred at 140 KeV.

Imaging protocol
The two camera heads were located anteriorly and posteriorly to the whole abdominal area to get the best view.Serial static digital images (64×64) at 15 min intervals were acquired immediately after the patient finished ingesting the scrambled eggs meal.Acquisition of images continued for a total time of 2 h.Processing of the images and display: A region of interest was drawn around the entire stomach in both the anterior and posterior projections.The small intestine was excluded from these regions of interest as much as possible in each image.The counts in each image were corrected for decay.The results were plotted in a timeactivity curve format with 'time' on the x-axis and decay-corrected 'gastric counts' on the y-axis (Figures 1 and 2).The best linear fit to the data was estimated, and the gastric emptying half-time from the fitted data was calculated by drawing a horizontal line through the y-axis at a point corresponding to half the maximum (initial) counts.Then half-time was calculated from the x-axis at the point where it was crossed by the drawn line.The normal values for the

Interpretation of the results
There is some variation in the shape of the time-activity curve for the clearance of gastric contents from the standard model of lag and linear emptying phases, because the study was not acquired in a continuous dynamic mode.Therefore, the linear disappearance slope describes the emptying rate.In addition, visual inspection of the serial static images and the calculated half-time with qualitative description was performed.A semiquantitative score based on visual analysis for the disappearance slope of the gastric emptying curve was implemented in the current work.The scoring system was a 5-point scale where 1 = definite slow descent in the disappearance slope (almost plateau), 2 = slow descent in the disappearance slope, 3 = normal descent in the disappearance slope (linear descent), 4 = fast descent in the disappearance slope and 5 = definite fast descent in the disappearance slope (very steep).

Statistical analysis
Data management and statistical analysis were performed using the Statistical Analysis System (SAS Institute Inc, USA).Numerical values were summarized as mean ± SD or frequency when appropriate.Categorical variables were presented as percentages.Differences among different subgroups in the study were evaluated by the Mann-Whitney nonparametric significance test, which is suitable for small sample sizes and is equivalent to Student's t test.

RESULTS
The Autonomic dysfunction in the form of gastrointestinal symptoms was present in all patients.By clinical history and carefully analyzed GIT symptoms, the patients were categorized as having constipation when they had passage of excessive dry, small or infrequent stools less often than every other day and less than 50 g a day provided that they had adequate dietary intake.The fecal incontinence group included those patients who had lack of sphincteric control over the act of defecation, provided there was no diarrhea or loose stools.In the current study, of the 49 patients with MS, 28 patients (57%) complained of constipation, 18 (36.7%)suffered from fecal incontinence more than once during the course of the disease, and three patients (6.3%) gave symptoms of dyspepsia not related to steroid therapy.The total number and the percentage of distribution of MS plaques in MRI results of the brain and spinal cord imaging are presented in Table 2.The highest numbers of plaques were present in the periventricular region, brain stem and spinal cord regions.

Gastric emptying by scintigraphy
Five studies of gastric emptying scintigraphy were excluded due to technical artifacts in three studies and vomiting in two patients.The remaining 44 patients were included in the analysis.Twenty-one patients (47.7%) showed slow emptying curves (grades 1 and 2) as illustrated in Figure 3; 15 (34.1%) showed normal curves (grade 3), and eight (18.2%)showed fast clearance curves (grades 4 and 5) (Figure 2).The mean half-time of gastric emptying in patients was 96.6±22.4min and the controls showed a mean of 41.3±18.7 min, with a significant statistical difference between the two groups (P<0.05)(Figure 4).

Gastric emptying half-time and GIT symptoms
The mean half-time was greater in patients with constipation (64.4±23.2min); nevertheless, there was no statistically significant difference between patients with constipation and patients without constipation (P=0.197).Moreover, although the mean half-time was lower in patients with fecal incontinence (49.9±16.8min), there was no statistically significant difference when compared with those without fecal incontinence (P=0.654)(Table 3).

DISCUSSION
Autonomic dysfunction is frequently observed in patients with MS, but clinical studies have shown contradictory findings regarding the frequency and type of abnormalities in autonomic function tests (1).
In the present study, the gastric emptying rate was prolonged in MS patients compared with controls, as evidenced by the longer mean half-time in the former (P<0.05).This was consistent with the reports that document gastric dysfunction in patients with MS who presented with symptoms of delayed gastric emptying.The complaints reported were mainly a sense of fullness, nausea and persistent vomiting, recurrent hiccups and gastroesophageal reflux (15,16).

Prevalence of lower bowel dysfunction
The prevalence of lower bowel dysfunction in patients with MS is much higher and has been reported to range from 41% to 68% in different studies (17)(18)(19)(20).
In the present study, the symptoms of bowel dysfunction encountered were mainly constipation, in approximately 59% of patients, and fecal incontinence, either alone or in association with constipation, in approximately 36%.Many studies are in agreement with these findings.Sullivan and Ebers (21) reported that 53% of their patients with MS had constipation, and Minderhoud et al (22) reported that 52.7% of MS patients complained of irregularities in their defecation pattern.Another study (18) of 77 patients with MS found that 52% had bowel dysfunction.Among a group of 209 patients with MS, 41.3% reported bowel dysfunction (19).Hennessey et al (11) reported that 54% of 221 patients with MS were constipated and 29% suffered from fecal incontinence.
In the current work, although the main symptoms of GIT automatic dysfunction were related to the large bowel, the method used to assess GIT motility was 'gastric emptying' because of its availability and because it is relatively simple to perform.In addition, the use of gastric emptying scintigraphy was supported by literature data stating that gastric emptying may be altered by small bowel or colonic dysfunction and that chronic intestinal dysmotility is associated with prolonged gastric emptying (23,24).Moreover, experimental rectal distension or constipation can impair gastric emptying and upper GIT motility (25).

Gastric emptying in lower bowel dysfunction
Our results showed that the mean half-time was longer in patients with constipation, implying a slower rate of gastric emptying.On the other hand, the mean half-time was shorter in patients with fecal incontinence, indicating a faster rate of gastric emptying.Nevertheless, these differences in the rate of gastric emptying between patients with constipation or fecal incontinence and patients without constipation or fecal incontinence was not statistically significant (P=0.197 and P=0.654, respectively).
This agrees with the findings of Chatterton (26), who stated that there is often a poor correlation between lower bowel symptoms and the degree of gastric emptying.
This explanation for this poor correlation is partly related to the fact that the causes for lower bowel disorders are not fully understood.A number of possible pathophysiological mechanisms, rather than a single neurological deficit, are thought to result in these constipation and incontinence symptoms (20).
Constipation in MS can result from the absence of normal increment in colonic motility after eating (27,28).Chia et al (29) found that paradoxical puborectalis contraction is present in MS patients and can lead to constipation.Other nonneurological factors that contribute to constipation are lack of exercise arising from immobility, inadequate dietary fibre and hydration, and the effects of certain medications such as anticholinergics used to control irritative bladder symptoms and tricyclic antidepressants (20,30).
The pathophysiological causes for fecal incontinence in MS patients are related to poor voluntary squeeze pressure (28), abnormal rectal sensation (31) and obstetric injury causing weakness of the anal sphincter (a peculiar contributing factor in multiparous women with MS) (32).

Gastric emptying and the severity of MS
No statistically significant correlation was detected between gastric emptying abnormalities and the Expanded Disability Status Scale score in the current study.In agreement with our results, Minderhoud et al (22) and Chia et al (29) found that severe constipation could occur in patients with little general neurological disability due to MS.There was no statistically   significant correlation between gastric emptying abnormalities and the duration of the disease or the number of attacks.Also, no difference existed between males and females or among the different types of MS.In agreement with this, Minderhoud et al (22) found that bowel disturbances have no correlation to the age, sex and disease duration in MS patients.There was no particular association between the mean halftime and the MRI findings, which agrees with the findings of Hawker and Frohman (30) that bowel disturbances were not due to a specific neurological lesion in the CNS but were instead due to the reasons mentioned previously.

CONCLUSIONS
Autonomic function impairment is common in MS patients and GIT autonomic disturbances are frequently encountered.The gastric emptying rate was clearly slower in MS patients than in the controls.As for lower bowel disturbances, although statistical significance was not found, the gastric emptying rate was obviously affected in patients complaining of constipation and fecal incontinence.

Figure 1 ) 2 )
Figure 1) Gastric emptying scintigraphy illustrating the obvious delay Figure 2) Gastric emptying scintigraphy showing rapid rate of gastric emptying with half-time of only 16 min.This patient was complaining of fecal incontinence in gastric emptying as denoted from the slope of the curve and the prolonged half-time (half-time = 68 min) Gastric emptying abnormalities in multiple sclerosis Can J Gastroenterol Vol 19 No 3 March 2005 143 El-Maghraby et al Can J Gastroenterol Vol 19 No 3 March 2005 144

Figure 4 )
Figure 4) Comparison between the mean value for the half-time of gastric emptying in patients with multiple sclerosis (MS) and the normal control group study included 49 patients and 20 normal control subjects.The patients included 30 females and 19 males, with age ranging from 19 to 50 years, with a mean age of 33.5±7.65 years.The controls included 10 males and 10 females.The age of the con-

TABLE 1
Demographic data for the subjects included in the study Distribution of different patterns of gastric emptying rate in the patients with multiple sclerosis Gastric emptying half-time and MRI findings Separate analysis for the half-time values according to the site of plaques in the MRI was carried out.There was no significant difference in the mean half-time between different patient subgroups with periventricular, centrum semiovale, corpus callosum, cerebellar, brainstem or spinal cord plaques (P>0.05 for all).

TABLE 3
Half-time (T1/2) rate of gastric emptying in the subgroups of multiple sclerosis (MS) patients included in the present work