patients show increasing declines in cognition , and behavioral symptoms occur in all stages of ad .
while all ad patients can present with depression , agitation , and aggressive behaviors , behavioral difficulties are most pronounced in the advanced stages of the disease.13 rivastigmine , inhibiting both acetylcholinesterase and butyrylcholinesterase , is the first transdermal treatment available for ad patients , and has been widely approved for the symptomatic treatment of ad.4,5 by providing continuous delivery of medication from the skin into the bloodstream , these patches achieve sustained , high drug concentration in the plasma over 24 hours.6 however , the investigation of transdermal exelon in alzheimer s disease ( ideal ) study revealed that ad patients receiving a 10 cm patch frequently suffered from nausea ( 7.2% ) and vomiting ( 6.2%).4 further , japanese ad patients receiving an 10 cm patch also showed similar adverse events , including nausea ( 7.0% ) and vomiting ( 8.0%).5 ad patients have been reported to stop the medication because of these adverse effects ; however , no technique is currently available to predict the occurrence of these adverse effects .
the antiemetic domperidone is often administered in order to administer higher , more effective dosages of cholinesterase inhibitors ( cheis ) , and such a combination with domperidone has been shown to be effective in preventing rivastigmine - related gastrointestinal disturbances when administered orally in the rivastigmine capsule form.7 in the present study , we examined the occurrence of gastrointestinal disturbances related to the use of the rivastigmine patch using the frequency scale for the symptoms of gastroesophageal reflux disease ( fssg),8 bristol stool form scale,9 laboratory data , body weight , and amount of food intake .
in addition , we compared the differences in gastrointestinal disturbances when using a rivastigmine patch with domperidone ( rwd ) and without domperidone ( rwod ) in order to examine the efficacy of domperidone orally .
patients were recruited from february 2012 to january 2013 at the department of neurology , toho university omori medical center , tokyo , japan .
subjects included outpatients diagnosed with ad who lived with or had regular daily visits from a responsible caregiver .
the diagnosis of ad was based on the criteria from the national institute of neurological disorders and stroke and the alzheimer s association.10 the criteria have been established by clinical and neuropsychological examination .
cognitive impairments have to be progressive and be present in two or more areas of cognition .
the onset of the deficits has been between the ages of 40 and 90 years , and finally there must be an absence of other diseases capable of producing a dementia syndrome .
a total of 30 patients with mild - to - moderate ad ( scores 1022 on the mini - mental state examination [ mmse]11 ) were enrolled and randomly allocated to two groups by the envelope method , ie , rwd and rwod ( n = 15 each ) .
dose titrations of rivastigmine patches were performed every 4 weeks using 4.5 mg / day increments from 4.5 mg / day to 18 mg / day .
domperidone was administered orally at a dose of 30 mg / day in the rwd group .
patients received rivastigmine - patch treatment for 20 weeks , and were evaluated for gastrointestinal disturbances at baseline and at weeks 4 , 8 , 12 , 16 , and 20 .
the fssg is a simplified questionnaire for evaluation of the symptoms of gastroesophageal reflux disease ( gerd ) , and has been demonstrated to be a useful tool for objectively evaluating symptoms in gerd patients.8 the questionnaire consists of twelve items that are scored as 04 based on the frequency of the symptom ( 0 = never , 1 = occasionally , 2 = sometimes , 3 = often , and 4 = always ) with total scores ranging from 0 to 48 .
( 2 ) does your stomach get bloated ? ( 3 ) does your stomach ever feel heavy after meals ? ( 4 ) do you sometimes subconsciously rub your chest with your hand ? ( 5 ) do you ever feel sick after meals ? ( 6 ) do you get heartburn after meals ? ( 7 )
( 8) do you feel full while eating meals ? ( 9 ) do some things get stuck when you swallow ? ( 10 ) do you get bitter liquid ( acid ) coming up into your throat ? ( 11 ) do you burp a lot ?
the bristol stool form scale consists of seven types ( 1 , separate hard lumps , like nuts ; 2 , sausage - shaped but lumpy ; 3 , like a sausage or snake , but with cracks on its surface ; 4 , like a sausage or snake , smooth and soft ; 5 , soft blobs with clear - cut edges ; 6 , fluffy pieces with ragged edges , a mushy stool ; and 7 , watery , no solid pieces ) .
the fssg and bristol stool form scale scores were obtained not only from patients but also from their caregivers to obtain accurate information .
if the scores differed between the patient and his / her caregiver , we usually took the caregiver s score , because of the patient s cognitive impairment .
in addition , we evaluated the changes in laboratory data ( hemoglobin [ hb ] , albumin [ alb ] , and total cholesterol [ t - chol ] ) , body weight , and amount of food intake to evaluate the nutritional status of ad patients .
the amount of food intake per day was set as a score of 10 at baseline , and any improvement or loss in appetite was reflected as increased or decreased scores , respectively , based on patient and caregiver feedback .
statistical analysis was performed by statmate ( graph - pad software , la jolla , ca , usa ) , with the mann 
whitney u test and wilcoxon signed - rank test , with p < 0.05 used as the threshold for statistical significance .
all patients and legally accepted caregivers participating in the trial were given an explanation of the trial by the investigators before the start of study , and informed consent to participate in the study was obtained .
consent of patients was obtained orally or in writing , and the consent of legally accepted representatives was always obtained in writing .
overall , three patients from the rwd group discontinued their participation due to skin irritation , and one patient from the rwod group withdrew because of nausea .
no differences were observed between the rwd and rwod groups with respect to mean age , the sex ratio , mmse score , or body weight .
the fssg scores for the rwod group showed significant increases after 12 weeks compared with baseline ( versus 12 weeks , p = 0.035 ; versus 16 weeks , p = 0.034 ; versus 20 weeks , p = 0.034 ) ; however , this was not observed in the rwd group ( figure 1 ) . before initiating rivastigmine - patch therapy ,
23 of 30 patients ( rwd group , eleven of 15 ; rowd group , twelve of 15 patients ) showed the presence of some gastrointestinal symptoms based on the fssg questionnaire .
the median value of the fssg at baseline was 3.8 in the rwd group and 3.1 in the rwod group ; therefore , we set the high - score threshold 4 points and low - score threshold 3 points . in the rwod group ,
the high - score subgroup showed increased fssg scores after 12 weeks compared with baseline scores ( versus 12 weeks , p = 0.038 ; versus 16 weeks , p = 0.035 ; versus 20 weeks , p = 0.034 ) ; however , no such changes were observed in the high - score subgroup in the rwd group ( figure 2 ) . in both rwd and rwod groups ,
the low - score subgroups showed no changes in fssg scores during the dose - escalation phase . the data for mmse , laboratory results ( hb , alb , and t - chol ) , body weight , amount of food intake , and bristol stool form scale scores are shown in table 2 ; no differences were noted between the baseline values and those at week 20 for either group .
we compared the data for the rwd and rwod groups for all the parameters examined .
no significant differences were observed between the two groups for the fssg ( figure 1 ) , mmse , laboratory data , body weight , amount of food intake , or bristol stool form scale scores ( table 2 ) .
overall , three patients from the rwd group discontinued their participation due to skin irritation , and one patient from the rwod group withdrew because of nausea .
no differences were observed between the rwd and rwod groups with respect to mean age , the sex ratio , mmse score , or body weight .
the fssg scores for the rwod group showed significant increases after 12 weeks compared with baseline ( versus 12 weeks , p = 0.035 ; versus 16 weeks , p = 0.034 ; versus 20 weeks , p = 0.034 ) ; however , this was not observed in the rwd group ( figure 1 ) . before initiating rivastigmine - patch therapy ,
23 of 30 patients ( rwd group , eleven of 15 ; rowd group , twelve of 15 patients ) showed the presence of some gastrointestinal symptoms based on the fssg questionnaire .
the median value of the fssg at baseline was 3.8 in the rwd group and 3.1 in the rwod group ; therefore , we set the high - score threshold 4 points and low - score threshold 3 points . in the rwod group ,
the high - score subgroup showed increased fssg scores after 12 weeks compared with baseline scores ( versus 12 weeks , p = 0.038 ; versus 16 weeks , p = 0.035 ; versus 20 weeks , p = 0.034 ) ; however , no such changes were observed in the high - score subgroup in the rwd group ( figure 2 ) . in both rwd and rwod groups ,
the low - score subgroups showed no changes in fssg scores during the dose - escalation phase .
the data for mmse , laboratory results ( hb , alb , and t - chol ) , body weight , amount of food intake , and bristol stool form scale scores are shown in table 2 ; no differences were noted between the baseline values and those at week 20 for either group .
we compared the data for the rwd and rwod groups for all the parameters examined .
no significant differences were observed between the two groups for the fssg ( figure 1 ) , mmse , laboratory data , body weight , amount of food intake , or bristol stool form scale scores ( table 2 ) .
vomiting is a highly specific physical event , defined as  the rapid , forceful evacuation of gastric contents in retrograde fashion from the stomach up to and out of the mouth .  in contrast , nausea is an entirely subjective experience , defined as 
the sensation that immediately precedes vomiting ,  wherein patients feel that they are about to vomit .
rivastigmine patch - related gastrointestinal disturbances have been reported in less than 10% of patients receiving this therapy.4,5 in our study , only one patient from the rwod group discontinued the therapy due to nausea .
however , our fssg questionnaire findings revealed that 23 of 30 ad patients ( > 75% ) suffered from at least one gastrointestinal disturbance before the initiation of the rivastigmine patch .
furthermore , ad patients with higher fssg were observed to show a further increase in the fssg score during the dose - escalation phase .
our results may indicate that ad patients do not report gastrointestinal disturbances because of the memory deficits involved in ad .
domperidone , a dopamine antagonist that acts by blocking dopamine receptors in the chemoreceptor trigger zone , has been previously shown to prevent gastrointestinal disturbances in rivastigmine therapy administered orally.7 in the present study , domperidone was effective in reducing or preventing gastrointestinal disturbances during the dose - escalation phase of rivastigmine - patch therapy in ad patients with higher fssg scores at baseline .
the fssg is a convenient tool for evaluating the symptoms of gerd ; in our experience , patients / caregivers require approximately 1 minute to complete the questionnaire .
the questionnaire consists of twelve detailed items ; therefore , the slightest gastrointestinal problem can be easily detected . in order to obtain accurate information in the present study
, we confirmed the symptoms described by the ad patients using fssg questionnaires completed by their caregivers . at present
, there is no technique for predicting the occurrence of gastrointestinal disturbances with rivastigmine - patch therapy .
it has been suggested that pretreatment with domperidone may protect against the onset of centrally induced nausea and vomiting induced by cheis.12 however , our findings indicate that ad patients with low fssg scores at baseline may not require additional antiemetic and/or antiulcer medications . on the other hand , ad patients with initial high fssg scores showed elevations in the fssg scores during the dose - escalation phase , indicating an increased frequency of gastrointestinal disturbances .
therefore , clinicians should pay careful attention to ad patients with high fssg scores at baseline during the dose - escalation phase to prevent gastrointestinal disturbances and to avoid patient discontinuation of rivastigmine - patch therapy .
domperidone has , on rare occasions , been associated with acute extrapyramidal syndromes;13 however , our ad patients did not show such side effects .
randomized , double - blind clinical trials conducted with other cheis , such as donepezil and galantamine , have provided evidence that these are safe and effective therapies against cognitive dysfunction and behavioral symptoms.1416 however , similar to the side effects of rivastigmine - patch therapy , gastrointestinal disturbances are the primary adverse effects associated with this therapy .
we speculate that the fssg may be a useful tool for predicting and preventing chei - related gastrointestinal disturbances for these drugs .
this study did not include a placebo for domperidone , and was limited by the small sample size ; therefore , improvements in cognitive dysfunction with rivastigmine - patch therapy could not be demonstrated fully .
it is important to optimize the drug for ad in individuals to slow the rate of cognitive dysfunction and behavioral and psychological symptoms of dementia.35,1720 of note , behavior symptoms in patients with ad increase direct costs of care .
for example , a 1-point increase in the neuropsychiatric inventory score21 was calculated to be equivalent to an increased cost of $ 247$409 in total annual direct costs.22 in addition , compared with those who never used cognitive enhancers , patients who used cheis had a significant delay in nursing home admission.23
in summary , the group receiving rivastigmine - patch therapy without domperidone showed significant increases in the fssg score after 12 weeks ( dose - escalation phase ) compared with baseline scores .
domperidone was effective in preventing rivastigmine patch - related gastrointestinal disturbances in ad patients with higher fssg scores at baseline .
further , the fssg questionnaire may be a useful tool for the prediction of gastrointestinal symptoms associated with rivastigminepatch therapy .
 objectivewhile acetylcholinesterase inhibitors , such as donepezil , galantamine , and rivastig - mine , are beneficial in treating behavioral symptoms of patients with alzheimer s disease ( ad ) , their dose - limiting effects include gastrointestinal disturbances , such as nausea , vomiting , and diarrhea . 
 we aimed to predict the occurrence of these gastrointestinal disturbances with rivastigmine therapy for optimal drug choice and improved compliance.materials and methodsthirty patients with mild - to - moderate ad ( scores 1022 on the minimental state examination ) were administered a rivastigmine 18 mg patch with domperidone 30 mg ( rwd ) and without domperidone ( rwod ; n = 15 each ) for 20 weeks . 
 gastrointestinal disturbances were evaluated using a frequency scale for symptoms of gastroesophageal reflux disease ( fssg ) , bristol stool form scale , laboratory data ( hemoglobin , albumin , total cholesterol ) , body weight , and amount of food intake.resultsafter 12 weeks , fssg scores were higher in the rwod group compared to baseline scores ; however , no significant differences were noted between the rwd and rwod groups . 
 we then subdivided each group based on high and low baseline scores ; the rwod high - score ( 4 ) subgroup showed increased fssg after 12 weeks compared with the baseline score . in both rwd and rwod groups , 
 the low - score ( 3 ) subgroups showed no changes during the dose - escalation phase.conclusionfor ad patients with higher fssg scores at baseline , domperidone was effective in preventing rivastigmine - related gastrointestinal disturbances . 
Introduction
Materials and methods
Results
Patient characteristics
Changes during the dose-escalation phase
Comparison between RWD and RWOD groups
Discussion
Conclusion