Duodeno-Gastric-Esophageal Reflux—What is Pathologic? Comparison of Patients with Barrett’s Esophagus and Age-Matched Volunteers

Introduction The aim of the study was to analyse pH- and bile-monitoring data in patients with Barrett’s esophagus and in age- and gender-matched controls.
Introduction
The incidence rates for adenocarcinoma (AC) of the esophagus and gastric cardia have risen rapidly in Western industrialized countries.1 Besides nicotine and alcohol abuse, nutritional factors, high body mass index, acidic gastric reflux, and Barrett’s esophagus are believed to be critical factors of carcinogenesis.2–4 Recent studies have shown that the presence of biliary reflux in combination with acidic gastric reflux damages the esophageal mucosa and causes complications of gastro-esophageal reflux disease (GERD), e.g., development of Barrett’s mucosa (BM).5,6 Duodeno-gastric reflux into the esophagus (DGER), in particular, appears to be important to the pathogenesis of Barrett’s esophagus.7 Prolonged esophageal aspiration studies have documented increased bile acids in patients with severe esophagitis and Barrett’s esophagus.8 Eighty percent of patients with Barrett’s esophagus on proton-pump inhibitors show a normal esophageal pH profile, but 60% show abnormal esophageal exposure to bile as measured by Bilitec 2000.9
In the past, direct and prolonged quantification of duodenoesophageal reflux has been difficult to achieve. Now, bilirubin concentration can be directly measured by spectrophotometry, based on the specific absorption at a wavelength of 453 nm. Biliary reflux can be measured with a transnasally passed, ambulatory fiberoptic probe (Bilitec 2000), which records bile absorption. A number of papers have already been published on the exposure of the esophagus10–13 and stomach14–16 using this technique. However, in these studies, the control patients were between 25 and 35 years old. In clinical practice, patients with Barrett’s mucosa tend to be older. In addition, the authors of each study used varying reference values to measure biliary reflux in the esophagus, making comparison of the measured values difficult.
The aim of the present study was to analyze data of pH and bile monitoring in a collective of healthy age- and gender-matched controls and patients with Barrett’s esophagus.
Subjects and Methods
Subjects
Selection of controls was carried out according to a strict protocol. Healthy volunteers treated from 1999 to 2000 between the ages of 40 and 60 years were included in the study. None of the controls were on acid suppressing or gut motility medications, had a history of upper gastrointestinal disease, had undergone upper or major abdominal surgery, or had had therapeutic endoscopic procedures of the upper gastrointestinal tract. Diagnostic endoscopy and barium swallows were not performed, but gallstone disease was excluded by ultrasound scan.
From 1999 to 2002, 24 patients with histologically confirmed Barrett’s mucosa were included in the study. For additional comparison, we include a group of patients with esophagitis (stage I to III according Savary and Miller) without Barrett’s esophagus, which had the same diagnostic procedures before planned laparoscopic fundoplication. During the aforementioned time span, 21 patients age older than 40 years were available for this study. Exclusion criteria were history of esophageal, gastric, or biliary surgery, history of abdominal or thoracic radiotherapy, or presence of peptic ulcer disease, active gastrointestinal bleeding, esophageal or fundic varices, esophageal or upper small intestine chronic disease, or neoplastic disease. All drugs potentially affecting gastrointestinal motility and secretion were discontinued at least 1 week before the study.
Upper Gastrointestinal Endoscopy
All patients underwent classical upper gastrointestinal endoscopy. If sedation was necessary, intravenous administration of propofol (up to 200 mg) was normally used, or occasionally, midazolam (up to 5 mg) was used. During endoscopy, the presence and extent of esophagitis, Barrett’s esophagus, and hiatal hernia was noted. Biopsies were taken from the Barrett’s mucosa.
Ambulatory Esophageal/Gastric pH and Bile Monitoring
All groups underwent esophageal manometry and 24-h pH and simultaneous bile monitoring using a standardized protocol. Ambulatory pH monitoring was performed using a transnasally inserted antimony pH electrode with a separate skin reference electrode (Synetics Medical, Stockholm, Sweden). The data were stored on a portable digital recorder (Digitrapper MkIII, Synectics Medical Stockholm, Sweden). Before each study, the pH probe was calibrated in buffer solutions of pH 7 and 1. An episode of acid reflux was defined as a decrease in esophageal pH to less than 4 for more than 10 s.
To quantify duodeno-esophageal reflux, a transnasally passed, ambulatory fiberoptic spectrophotometer (Bilitec 2000, Synectics, Sweden) was used. The system consists of a miniaturized probe of 1.5-mm diameter that carries light signals into the esophagus and back via a plastic fiberoptic bundle. Before each study, the probe was calibrated in water. Corresponding to the current literature, a bilirubin absorption >0.25 was used as a reference for noxious biliary reflux.14
The bile and pH probes were taped together and passed transnasally into the esophagus and stomach, as described in detail elsewhere.17 The upper tips of the probes were positioned 5 cm above the upper border of the lower esophageal sphincter as defined by esophageal manometry. The distal pH electrode and fiberoptic sensor were placed in the fundus of the stomach, 10 cm distal to the lower esophageal sphincter (Fig. 1). Controls and patients were asked to follow a strict protocol of three meals per day, with no liquids between meals. Recumbent phases of recording were permitted only at night. Patients were asked to keep a diary recording of the exact nature of meals, the supine and erect phases of measurement, and the sensations of heartburn and regurgitation.
Figure 1Position of the pH- and bilirubin-probes in the stomach and in the esophagus. (UES = upper esophageal sphincter; LES = lower esophageal sphincter).
The simultaneous biliary and pH monitoring was done with administration of a colorless “white diet” (WD) including liquid and solid foods with a maximum in vitro bile absorbance of 0.25 [absorbance scale ranging from 0 (plain water) to 1 (total screen)]. The meals included water, milk, toast, potatoes, chicken, dry biscuits, and fish.
Data Acquisition and Interpretation
After completion of the measurements, probes were withdrawn from the patients, and data were stored via interface on an IBM-compatible computer equipped with Polygram® software (Medtronic). The data of each second of the 24-h measurements were used for analysis. To assess the presence of gastric or esophageal biliary reflux, the percentage of time when absorbance was greater than 0.25 was calculated for the following periods: total supine, upright, and postprandial. The postprandial period was defined as 2 h after the end of meals. The percentage of time with esophageal pH lower than 4 and median gastric pH and the percentage of time with gastric pH measuring 1, 2, 3–7, and >7 was also calculated for the above periods. The mean duration of the ambulatory pH and Bilitec monitoring study was 22 h, 40 min in patients and 23 h, 44 min in the controls.
Statistical Analysis
The SPSS (version 11.0, Chicago, Illinois) program was used to analyze the results. For graphical presentation, we used the program MedCalc for Windows, (Version 9.0, MedCalc Software, Belgium). Median, interquartile range (IQR or 25th to 75th percentile) values were established. The nonparametric tests (Mann–Whitney and Kruskal–Wallis analysis) were used to assess the relationship between variables. Box and Whisker plots were used to present some of the data. In these plots, the box represents the IQR, and the Whiskers represent the highest and lowest values. Outliers are also plotted, defined as more than 1.5 times the IQR from the 75th centile. Extreme values were defined as more than three times the IQR from the 75th centile.
A receiver operator characteristic (ROC) curve was used to find a cutoff value for optimal sensitivity and specificity according Zweig and Campbell.18 The area under the curve (AUC) as a measurement of diagnostic performance of the test was used. The results are given as point with the 95% confidence interval (95% CI) and graphically for presentation of all data. As the positive group, we used the patients with Barrett’s mucosa, and the negative test group was defined by the healthy volunteers. A nonparametric distribution of the area under the curve was assumpted.
The assumptions for calculation of the required sample size were alpha = 0.05, beta = 0.80, and that a test is only valid for daily use if less than 20% of the healthy controls and at least 80% of the patients have positive test results. The calculated sample size for each group was 20.
Ethics
The study protocol was approved by the ethics committee of the University of Cologne. Each subject gave written informed consent.
Results
Twenty-four patients with Barrett’s esophagus (mean age: 58 years), 21 patients with esophagitis (mean age: 57 years), and 19 healthy controls with a mean age of 51 years were included in the study. Patients with BM showed esophagitis grade 0 (4 cases), grade I (12 cases), and grade II (8 cases). The control group of patients with esophagitis showed nine cases with grade I, eight cases with grade II, and three cases with grade III. Demographics of patients and volunteers are displayed in Table 1 (the data of one volunteer was not usable due to technical problems).
Table 1Demographic Data of Patients with Barrett-Mucosa or Esophagitis and Healthy VolunteersParametersPatients with Barrett’s Esophagus (n = 24)Patients with Esophagitis (n = 21)Controls (n = 19)Significance Pat. with Barrett vs ControlsAge (median) 57 years58 years51 years–Min–max29–75 years42–77 years39–62 yearsGender m:f16:811:1011:8n.s.BMI (median) min–max27.0 kg/m2 (18.6–33.1)26.9 kg/m2 (17.9–31.5)24.1 kg/m2 (19.62–27.34)p = 0.003Smokers (%)n = 5 (20.8)n = 4 (19.0)n = 6 (31.6)n.s.No alcohol %n = 3 (12.5)n = 5 (23.8)n = 5 (26.3)n.s.BMI Body mass index
Acidic Gastric Reflux (AGR)
Patients with Barrett’s esophagus, 19 of 24 (79%) and 20 of 21 control patients with esophagitis (95%) had pathologic AGR [pH < 4 in >5% of total measuring time (TMT)], but also 6 of the 19 healthy controls (32%) showed pathologic AGR without any symptoms (p = 0.002). During the TMT, the median AGR was 10.6% for Barrett patients and 3.2% for controls (p < 0.01). In particular, measurements of long acid reflux (LAR), defined as reflux pH < 4 lasting longer than 5 min, showed significant differences between patients and controls. Pathologic AGR was found in patients during both the supine and upright fasting measuring periods. In contrast, pathologic AGR in healthy controls occurred only in the upright position (Table 2).
Table 2Median of Acidic Gastric Reflux into the Esophagus in Patients with BM or with Esophagitis and in Healthy ControlsParametersPatients with Barrett’s Esophagus (n = 24) [median (LQ-UQ)]Patients with Esophagitis (n = 21) [median (LQ-UQ)]Controls (n = 19) [median (LQ-UQ)]Significance Pat. with Barrett vs ControlsPercentage of total measuring time pH < 4 (%)10.6 (6.2–38.3)19.9 (1.6–71.7)3.2 (0.9–5.5)p = 0.01Percentage of upright measuring time pH < 4 (%)11.7 (6.03–6.4)18.9 (8.7–60.8)2.4 (0.9–6.1)p < 0.05Percentage of supine measuring time pH < 4 (%)10.9 (0.4–27.1)6.3 (0.0–13.3)0.3 (0.0–4.2)p = 0.004LQ Lower quartile, UQ upper quartile
24-h Intragastric pH and Bile Monitoring
Gastric pH monitoring showed no significant differences between patients and controls for all measuring periods (Table 3). Gastric bilirubin exposure, indicating biliary reflux, was significantly more frequent in patients than in controls during all measuring periods (Table 3). Biliary exposure in the supine position typically occurred during the early hours of the morning during sleep, represented by increased absorbance over 2–3 h, with a rapid return to baseline values around the time the subject resumed the upright position. Over the same time period, gastric pH monitoring showed increased pH levels to greater than 2 (Fig. 2).
Table 3Results of 24-H Intragastric pH and Bile Monitoring in Patients with Barrett Esophagus and Healthy ControlsParametersPatients (n = 24) [Median (LQ–UQ)]Controls (n = 19) [Median (LQ–UQ)]SignificanceMedian of intragastric pH during TMT1.3 (1.0–1.4)1.4 (1.1–1.7)n.s.Bilirubin exposure percentage (%) of TMT 7.8 (1.6–17.8)0.0 (0.0–1.0)p = 0.001Bilirubin exposure percentage (%) of upright time6.9 (0.1–12.9)0.0 (0.0–1.3)p < 0.01Bilirubin exposure percentage (%) of supine time2.0 (0.0–28.6)0.0 (0.0–0.0)p = 0.001LQ Lower quartile, UQ upper quartile, TMT total measuring timeFigure 224h intragastric pH- and bile monitoring in a patient with Barrett’s esophagus demonstrating the duodenogastric reflux in the early morning. a. Bilitec®-monitoring, b. pH-monitoring.
Bilirubin Exposure of the Esophagus
Over the TMT, the median of esophageal biliary reflux was 7.8% for patients with Barrett’s esophagus (LQ–UQ = 1.6–17.8%) and 3.5 (LQ–UQ = 0.1–13.5) for control patients, in contrast to 0% for the controls (LQ–UQ = 0–1.0%), p = 0.001). Figure 3 shows that esophageal bile monitoring in patients with Barrett’s esophagus and healthy controls varied during the total measuring and supine periods.
Figure 3Results of the esophageal bile-monitoring in 24 patients with Barrett’s esophagus, 21 patients with esophagitis and 19 healthy controls a) total measuring period (Kruskal-Wallis Test = 0.01) b) supine period (Kruskal-Wallis Test p = 0.01).
The receiver operating curve, plotting the true positive rate (patients with Barrett’s esophagus identified by bilirubin exposure) in function of the false positive rate (healthy controls with high bilirubin exposure) is shown in Fig. 4. With an area under the curve of 0.78 (95% CI = 0.56–0.89), the ROC analysis of biliary monitoring showed the optimal value for patients at 1% of the TMT [75% sensitivity (95% CI = 53–90%), 84% specificity (95% CI = 60–96%)]. Therefore, the cutoff value to distinguish normal vs pathologic biliary reflux using 24-h biliary monitoring in the esophagus (absorbance threshold >0.25) should be fixed at 1% of TMT.
Figure 4ROC-curve with 95% confidence intervals for pathologic bile-monitoring in patients with Barrett esophagus compared to age and sex matched healthy controls.
Barrett patients, 18 of 24 (75%), 15 of 21 control patients with esophagitis (71%), and 3 of 19 controls (16%) showed biliry reflux into the esophagus more than 1.1% of the TMT (p < 0.001). Using this cutoff value, none of the controls, 10 of the control patients (48%), and 11 of 24 Barrett’s patients (46%) had pathologic bilirubin exposure during sleep.
Discussion
The results of our study confirm that patients with Barrett’s esophagus have significantly more frequent duodenogastric reflux into the esophagus than age- and sex-matched healthy controls. In addition, this reflux, measured by acid and bilirubin exposure, remains longer in the esophagus, especially during sleep.
The role of acid and nonacid reflux into the esophagus as a causative factor of symptoms and mucosal lesions has been addressed in a number of studies. Not only the duration, but possibly the composition of the reflux, is instrumental in the development of such lesions.13 Twenty-four-hour intragastric bile monitoring has provided the clinician with unequivocal evidence of excessive duodenogastric reflux (DGR) in 41% of patients with endoscopic esophagitis, gastroesophageal reflux (GER) symptoms, and gastric symptoms suggestive of DGR.19 Reflux of duodenal contents into the stomach, especially postprandially, is a physiological event;20 however, biliary reflux is a large contributor to mucosal lesions in the whole stomach.21
In our study, the control group of patients with different grades of esophagitis showed no significantly different measurements of acidic or bile reflux into the stomach or the esophagus compared to Barrett’s patients. This may be caused by selection of patients with esophagitis, which were candidates for fundoplication, but both groups of patients differed significantly compared to healthy controls. Therefore, our results are of great clinical relevance especially for preoperative diagnostic.
Marshall et al. compared healthy controls to patients with different grades of reflux-esophagitis and Barrett’s esophagus with regard to bile measurements in the stomach.22 In this study, the average age of the control patients was 25 years, and that of the patients in Groups I, II, and III was 42, 50, and 60 years, respectively. The bilitec-probe was positioned 10 cm below the lower esophageal sphincter (LES). The threshold of bilirubin absorbance was 0.14, and although no difference was found between groups over the TMT, gastric bilirubin exposure was higher in the supine than in the upright position. In the current study, the control group was older than that of the Marshall study. More duodeno-gastric reflux was recorded in both study and control patients during all periods of measurement. These findings may be due to improved study conditions.
We used an esophageal threshold of 0.25 for bilirubin absorbance. Fein et al.,14 in an in vitro study of absorption of different white meals, showed that the least food interference during bile monitoring was measured with an absorbance > 0.25.
Tack et al. reported the influence of meal consistency on Bilitec measurement results in healthy subjects.23 They compared two groups of young controls. The subjects took either liquid meals only, not absorbing light of the same wavelength as bilirubin, or solid food, avoiding diets that interfere with bilirubin absorbance. The authors found significant differences between the two groups using a bilirubin absorbance threshold >0.14 with a median percentage (interquartile range) over the TMT of 10.9 % (6.7–19.3) for solid meals and 0.3% (0.0–2.8) for liquid meals. Major meal artifacts were present in two-solid-meal (10%) and no-liquid-meal subjects. In our study, we found such a meal artifact in one patient and one control, but the values of bilirubin absorbance were lower than 0.25, and therefore, not relevant to our results.
It is not unusual for gastro-esophageal reflux to contain bile, duodenal, and pancreatic secretions. Utilization of the Bilitec spectrophotometric probe has demonstrated a higher prevalence of abnormal esophageal bilirubin exposure in patients with Barrett’s metaplasia when compared to those with erosive injury or without signs of esophagitis.6,8,10,13 In those studies, patients were consistently older than volunteers included in the control group. However, other studies have shown an increased prevalence of gastroesophageal reflux with age.24 For these reasons, we studied age and sex matched healthy controls and patients with Barrett’s esophagus or with esophagitis. We found pathologic acid and biliary reflux of the esophagus in one-third of the controls. Perhaps, this may be caused by artefacts or by violation of the protocol by the volunteers. But in a previous published study, we could show that younger healthy controls had no such pathologic reflux.17 Possibly, these phenomena are caused by relaxations which occur more often in older people. In contrast, nearly all patients with Barrett’s esophagus (87%) and all patients with esophagitis (100%) showed pathologic acidic reflux and/or bile reflux measured with combined pH and bile monitoring. Bile reflux into the esophagus during sleep, in particular, was only found in patients with BM or with esophagitis.
In our study, we measured the intragastric pH and the bile reflux from the duodenum into the stomach (DGR). The median of the intragastric pH was similar in both groups. But patients with Barrett’s esophagus had significantly longer duodenogastric reflux during the 24-h measuring period than controls. More DGR was demonstrated at night than during the day in both groups of study patients and in healthy controls. This could be associated with an alkaline shift in the pH, according to previously published studies.25–27 The precise mechanism by which nocturnal DGR occurs and the roles posture plays remain unclear.
Bowrey et al. were unable to establish either gastro-esophageal or duodenogastric reflux as the predominant cause of inflammation in gastric cardiac mucosa with use of the Bilitec 2000 device.16 This is understandable, as the amount of reflux into the stomach (DGR) does not necessarily correlate with DGER into the esophagus. In this study, the authors demonstrated more DGR in females during the supine period, while males presented more DGER. At the same time, there was no correlation between bile levels in the stomach and esophagus. The controls were, however, much younger than the patients. We found significant differences in bile measurements of the stomach and esophagus between BM patients and controls. In contrast to Bowrey et al., we saw more DGER in females during the supine period and more DGR in male patients.
In contrast, Banki reported similar esophageal exposure to refluxed acid and bilirubin in females and in males with Barrett’s mucosa.28 Pfaffenbach et al.29 studied esophageal bile and acid reflux in patients with long segment Barrett’s esophagus (LSBE), short segment Barrett’s esophagus (SSBE) and patients with gastro-esophageal reflux disease (GERD). Subjects underwent esophageal manometry and simultaneous 24-h pH and bile monitoring (Bilitec 2000) with an absorbance value >0.2 for 10.9% of the total period. GER did not differ between the groups. However, DGER differed between patients with LSBE (14.7%), SSBE (2.1%), and GERD (2.1%).
In summary, the analysis of reference values of esophageal acid and bile-reflux measurements in a collective of healthy, age- and gender-matched controls compared to patients with BM led to the following conclusions:
Although about 30% of the healthy controls showed acid reflux in pH monitoring, patients with BM had significantly more acid reflux during all measured periods.Healthy controls did not have relevant duodeno-gastric-esophageal reflux measured by bilirubin absorbance. Especially during the supine period, there was no bile reflux.The optimal threshold for pathological bile reflux is 1.1 % (bile monitoring with an absorbance of 0.25).

esophagus
barrett’s mucosa
spectrophotometry
acid reflux
bile reflux
reference value bilitec


Long term outcome of cavotricuspid isthmus cryoablation for the treatment of common atrial flutter in 180 patients: A single center experience

Objective Recent literature has shown that common type atrial flutter (AFL) can recur late after cavotricuspid isthmus (CTI) catheter ablation using radiofrequency energy (RF). We report the long term outcome of a large group of patients undergoing CTI ablation using cryothermy for AFL in a single center.
Introduction
Ablation of the cavotricuspid isthmus (CTI) for the treatment of atrial flutter (AFL) has become standard practice. Most of the procedures are performed using radiofrequency energy (RF) [1–5]. High chronic success rates are described but the majority of the data comes from a relatively short term follow-up [1–13]. A recent study by Chinitz et al. [14] reported some interesting data regarding the long term follow-up of 80 patients with common type AFL who underwent CTI ablation using RF. They found a 12.5% (ten patients) recurrence rate at an average of 21 months after the procedure with most patients having a recurrence after the first year post ablation. Our prior experience using cryothermy in a limited number of patients [15] also showed that AFL may recur 1 year after CTI cryoablation.
The purpose of this study was to evaluate the long term outcome of CTI cryoablation in a large patient population with common type AFL in a single center.
Methods
One hundred and eighty patients with sustained symptomatic common type AFL referred for CTI ablation were enrolled prospectively from July 2001 to July 2006 in our institution. Signed written consent, approved by the local ethics committee, was obtained from all participants.
Before CTI cryoablation, anticoagulation with warfarin aiming a therapeutic international normalized ratio of 2 to 3 was kept for at least 3 weeks. Antiarrhythmic drugs were not discontinued before ablation.
Electrophysiologic study and ablation
We focused our study on the clinical aspects and long term follow-up of patients with AFL who were submitted to CTI cryoablation.
Our CTI cryoablation protocol has been already reported [15]. Briefly, our methodology was as follows: under local anesthesia and via the femoral route, a decapolar catheter is positioned in the distal coronary sinus (for evaluation of left atrial activation), a duodecapolar catheter (2-mm interelectrode spacing, Halo catheter, Biosense Webster, Baldwin Park, CA) for mapping the right atrial lateral wall and a quadripolar catheter in the His bundle area. A deflectable, 10.5 F, 6.5 mm tip cryoablation catheter (CryoCor Inc., San Diego, CA) is inserted into the right atrium through a 12F, 65-cm-long sheath (DAIG, St. Jude Medical Inc., St. Paul, MN) [15–19].
Entrainment to confirm the isthmus dependence of the AFL circuit was performed in every patient in whom AFL was present or could be induced at the start of the procedure, according to previously published techniques [2, 10, 15, 16, 20, 21]. If AF, requiring cardioversion, was present or developed during stimulation or if we were unable, even under isoproterenol infusion, to induce AFL, CTI ablation was performed during sinus rhythm. Linear lesions were created by use of a point-by-point technique with gradual pullback of the cryocatheter in a ventricular atrial fashion. The first application was delivered at the ventricular insertion of the isthmus and applications were continued for an average of 3 min. In patients in whom ablation of the posterior isthmus proved insufficient, an attempt was made to ablate the septal isthmus (four patients). After documentation of bidirectional isthmus conduction block, the atrial pacing (from the proximal coronary sinus) protocol (up to three atrial extrastimuli at three pacing cycle lengths and incremental atrial pacing) was performed without and with isoproterenol infusion (1 to 3 μg/min). Acute success was defined as bidirectional isthmus conduction block, 30 min after the last application without and with isoproterenol infusion [22].
All patients were studied in the fasting state without sedation. Those presenting in AF while on the catheterization table were converted to sinus rhythm by internal or external cardioversion. During the procedure intravenous heparin was given as a 100-IU/kg bolus dose after the venous sheaths were inserted. The 12-lead ECG and intracardiac electrograms were recorded and stored by the BARD Labsystem PRO.
Post ablation management
All patients were monitored in hospital for 24 h and oral anticoagulation was started the day of ablation. Antiarrhythmic drugs (AAD) were stopped after the procedure in patients without a history of AF; in those with AF/AFL the same AAD were continued. All patients had anticoagulation for at least 1 month. Subsequently, the need for chronic anticoagulation was assessed by the amount of recurrences of AFL/AF and the presence of risk factors for thromboembolic events.
All patients had a 12-lead ECG and a 24 h Holter recording at discharge and during each clinic visit (1 month, 3, 6, 9, 12 months and yearly thereafter) or earlier if they had symptoms.
Due to the logistics of the Maastricht area—and also the presence of a dedicated research nurse (S. P.) who was available to address patients’ concerns and questions at any time—we were able to follow every patient on an individual basis.
Statistical analysis
Continuous variables are presented as mean ± SD, where appropriate. In cases of a non-Gaussian distribution, medians and quartiles are given. Categorical variables are expressed as numbers and percentages of patients.
Statistical analysis was performed using the Student t test for unpaired data. All values were considered significant at P < 0.05.
The authors had full access to the data and take responsibility for its integrity.
Results
Of the 180 enrolled patients, 39 patients (22%) were women with a mean age of 58 (from 18 to 80) years. More than half of the patients (92 patients, 52%) had structural heart disease: arterial hypertension: 57 patients, coronary artery disease: 22 patients, valvular heart disease: 13 patients, congenital heart disease: 11 patients, idiopathic cardiomyopathy: 18 patients. Counterclockwise AFL was documented in 91% (164) of the patients and clockwise AFL in 9% (16 patients).
The mean left atrial diameter and the mean left ventricular ejection fraction were 44 ± 7 mm and 57 ± 7%, respectively. A prior history of AF was present in 123 (69%) of the patients. The clinical characteristics of the patients, related to the presence or absence of AF before ablation, are described in Table 1. Note that AF during follow-up is significantly higher in the group with a prior history of this arrhythmia.
Table 1Characteristics of the 180 patients with atrial flutter referred for CTI cryoablation related to the presence or absence of atrial fibrillation AF before ablation AF/AFL patients (123 patients), 69%AFL only (57 patients), 31%p valueAge (year)57 ± 1358 ± 13nsWomen19% (23 patients)28% (16 patients)nsNo SHD55% (68 patients)32% (18 patients)< 0.05LAd (cm)4.44.5nsLVEF (%)5855nsAcute failuresa5% (6 patients)5% (3 patients)nsAF in long term follow up69% (85 patients)35% (20 patients)< 0.05aPatients in whom CTI cryoablation did not result in bidirectional block (failed procedure).AF Atrial fibrillation, AFL atrial flutter, CTI cavotricuspid isthmus, Lad left atrium diameter, LVEF left ventricular ejection fraction, SHD structural heart disease
Total fluoroscopic—mean of 30 ± 18 min (range, 12 to 152 min)—and procedure times—mean of 2.6 ± 1.1 h (range, 1 to 6.5 h)—decreased throughout our study with a long duration of a procedure and fluoroscopy being attributed mainly to the learning curve of a new technology. An average of 7 (3 to 20) applications per patient were delivered with a mean temperature and duration of −88°C and 3 min, respectively.
The acute success rate for cryoablation of the CTI was 95% (171 patients). There were no complications. Of the nine patients in whom bidirectional CTI block was not achieved, three underwent a successful reablation. The other six patients had much improvement of their symptoms (despite an incomplete line) and preferred not to have another procedure.
After a mean follow-up of 27 ± 17 (range from 12 to 60) months, recurrences of symptomatic AFL occurred in 15 patients (9%) resulting in a 91% chronic success rate. Those recurrences occurred in six patients within the first 3 months post ablation, in four patients from 3 to 6 months post ablation, in four patients from 6 to 9 months post ablation and in one patient at 14 months post ablation (Fig. 1). Ten of those 15 patients underwent a second successful cryoablation of the CTI. The other five had not only reablation of the isthmus but also pulmonary vein cryoisolation (PVI) for AF during the second procedure.
Fig. 1Percentage of patients (171 successfully ablated) free of common type atrial flutter over time
Despite the success as far as AFL was concerned, AF was still present in 85 patients (69%) with a prior history of this arrhythmia. Those patients were treated by AAD (69 patients, 81%), PVI (14 patients, 16%) or AV nodal ablation with pacemaker implantation (two patients, 3%). New episodes of AF developed in 20 (35%) of those 57 patients without documented AF prior to CTI cryoablation and were all controlled by AAD.
Discussion
Main findings
Our current study showed a 91% chronic success rate of CTI cryoablation in a large population (180 patients) with AFL followed for a long period of time (1 to 5 years, mean of 27 months).
According to the most recent ACC/AHA/ESC guidelines for the management of supraventricular arrhythmias CTI ablation is the only therapy with a class I indication for the long term management of AFL [2]. The majority of those ablations are done using RF energy. Concerning the follow-up length of those procedures, most of the literature available reports on a relatively short period, the majority of them being less than 2 years. However Chinitz et al. [14] published a study of 80 patients with AFL submitted to CTI ablation using RF that had up to 6 years follow-up. Interestingly, they found a 12.5% recurrence of AFL that occurred on an average of 21 months post ablation, ratifying the need of data with a longer follow-up. It is important to keep in mind though, that arrhythmias after ablation do not always correlate with symptoms [23, 24] and one could question if those patients with such a late recurrence had those episodes much earlier than what is reported. That might be one reason why our results, where most of our recurrences happened within 1 year, are discrepant with those from their study. The intrinsic characteristics of our hospital, our clinical follow-up and the population of Maastricht could be responsible for our ability to find those recurrences earlier.
Regarding cryothermy as energy source, a 9 months follow-up study in 39 patients undergoing CTI cryoablation with a different system was reported [25]. They achieved a chronic success rate of 100% in the cryoablated group, despite documenting reconduction through the isthmus in 31% of patients during a 3 month follow-up electrophysiologic study. The CRAAFT trial presented the results in 32 patients with AFL submitted to either cryo- or RF ablation of the CTI [26]. They report an 84% success rate after a follow-up of 14 months. Those two small studies, with a relatively short follow-up, reported similar success rates with RF and cryothermy for AFL ablation. The results from our study—which included a significant larger patient population (180) with a longer follow-up (1 to 5 years, mean of 27 months)—reinforces the effectiveness of cryothermy for the treatment of AFL, being the outcomes comparable to those reported in the literature using RF (where most outcome data also comes from non invasive follow-up) [1, 4–7, 11, 12, 27, 28]. Therefore, cryothermy can be considered as an efficient energy source for the treatment of common type AFL.
The relation of AF with AFL
The close relation between AF and AFL is well described [1, 5–14, 21, 29–39]. Our data showed a high prevalence of AF (123 out of 180 patients, 69%) in patients with predominant AFL referred for CTI ablation. A recent study by Ellis and colleagues [40] strengthened even more this association. They followed 363 patients with lone AFL who underwent CTI RF ablation—during a mean follow-up of 39 months—and reported an 82% incidence of drug refractory AF in their patient population.
The new development of AF in our patient population without a prior history of AF preceding AFL ablation may be a sign of an already present electrical and morphological change in the right and left atria. If in addition, a functional or anatomical line of block between the two venae cavae (or elsewhere) occurs, atypical AFL(s) may develop either in the right (because the CTI is already ablated) or in the left atrium [11, 14, 21, 31, 32, 37–39].
Study limitations
Our recurrence data rely mostly on the subjective assessment by the patient, like the great majority of RF data [1, 4, 6–8, 12]. Only an objective measurement (such as a repeat electrophysiological study with documented bidirectional block) will determine the long lasting effect of CTI ablation for the treatment of common type AFL.
Conclusions
In this prospectively studied large population of patients with common type AFL, cryoablation of the CTI has a 91% chronic success rate during long term follow-up (range 1 to 5 years, mean of 27 months). These results are similar to those obtained with RF, validating cryothermy as an efficient alternative energy source. We also were able to ratify the frequent association of AF with AFL.

cavotricuspid isthmus
cryoablation
atrial flutter
long term follow-up
atrial fibrillation


Neurogenic bladder: etiology and assessment

A review of the various causes of neurologic impairment to the lower urinary tract in children was the aim of this presentation. The emphasis was on diagnosis, pathophysiology, and treatment that strive to maintain as normal a function as possible in order to achieve eventual urinary continence and health of the upper urinary tract. The latest principles based on the most up to date evidence are promulgated but with an eye towards historical prospective. The reader should gain an adequate understanding of various disorders that comprise this condition and feel comfortable with proposing options for management when faced with the responsibility of caring for an affected child.
Introduction
Neurogenic bladder dysfunction in children is an ever-evolving condition. The expansion of its understanding and treatment over the past 50 years has been just remarkable. In the mid 1950s there were few insights and minimal alternatives to the child’s being in diapers or wearing an appliance over an abdominal wall stoma. Starting with the development of adequate X-ray assessment and reliable urodynamic investigation, the advent of clean intermittent catheterization, artificial sphincter implantation, continent urinary conduits and a plethora of drug therapies that modulate lower urinary tract function, we have learned a great deal about the pathophysiology, pathogenesis and treatment of this disorder and the evidence specific ways to manage it. With the promise of tissue engineering and stem cell therapy, new vistas for treatment seem to be on the horizon.
The most common cause of neurogenic bladder dysfunction in children is neurospinal dysraphism, primarily an open back lesion, but an occult or closed dysraphic state is being diagnosed with more frequency as neonatal spinal ultrasound and magnetic resonance imaging (MRI) are used with increasing regularity to visualize any lower midline spinal cutaneous or gluteal cleft malformation. It was thought that folic acid deficiency was a cause of this disease and that its replacement in women of childbearing age would practically eliminate the condition, but this has not happened. There has been a definite decrease in its incidence; however, in parts of the USA its prevalence has not diminished at all [1–4].
Other causes of neurogenic dysfunction involving the spine include sacral agenesis, tethered spinal cord associated with imperforate anus, cloacal malformations, and spinal cord injuries from sporting injuries and motor vehicle accidents. Central nervous system abnormalities include spastic diplegia (cerebral palsy) and learning disabilities, i.e. attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD). Terminology used throughout this manuscript will conform to the standardization document recently published in the Journal of Urology [5].
Urodynamic studies
A urodynamic study consists of the following components. The child is catheterized with a triple-lumen urodynamic catheter after a small amount of liquid lidocaine (1%) has been injected into the urethra and held in place for a moment or two. First, intravesical pressure is recorded; then, the bladder is drained and the residual urine carefully measured, yielding a pressure at residual volume (this helps determine detrusor compliance at natural filling and is more accurate than cystometric compliance measured during even slow filling of the bladder). A small balloon catheter is passed into the rectum to measure intra-abdominal pressure during the cystometrogram to identify artifacts of motion and monitor increases in abdominal pressure during the filling and emptying phases of the study. The side-hole port of the urethral pressure channel is positioned at the highest point of resistance in the urethra and kept in place, measuring this resistance throughout bladder filling and emptying to determine the leak point pressure. External urethral sphincter electromyography (EMG) is performed using a 24-gauge concentric needle electrode inserted perineally in boys or para-urethrally in girls and advanced into the skeletal muscle component of the sphincter until individual motor unit action potentials are seen or heard on a standard EMG recorder. The characteristics of the individual motor unit potentials at rest, in response to various sacral reflexes (i.e. bulbocavernosus, anocutaneous, Valsalva and Credé maneuvers) and bladder filling and emptying are recorded to detect degrees of denervation. Next, the bladder is filled through the second port while intravesical pressure is monitored via the third port of the tri-lumen urodynamic catheter. The rate of filling is set at 10% of expected capacity for age [age (in years) +30 × 30 = expected capacity in milliliters] [6]. Detrusor pressure measurements are continuously recorded throughout filling to calculate compliance, and during voiding or leaking to denote emptying pressure. Detrusor overactivity is defined as any short-lived pressure rise of >15 cm H2O from baseline before capacity is reached [6]. Sometimes, the urodynamics study is combined with fluoroscopic video-imaging using a dilute radio-opaque contrast agent to visualize the appearance of the bladder wall and bladder neck or to detect the presence of vesicoureteral reflux during the test. Alternatively, a radionuclide agent is instilled, with the patient lying above a nuclear camera, to determine at what pressure reflux occurs, when it is known to be present beforehand. The study is not considered complete until the child actually urinates or leaks and the ‘voiding’ pressure is measured. The small size of the urodynamic catheter does not seem to affect the voiding pressure adversely, even in very young children. The normal end filling pressure should be <10 cm H2O, while the normal voiding pressure varies from 55 cm to 80 cm H2O in boys and from 30 cm to 65 cm H2O in girls [5]. Detrusor overactivity is considered an abnormal finding at any time [6].
The examination findings are considered normal when there is an appropriate capacity, good compliant bladder, with no overactivity, and normal innervation of the sphincter with normal sacral reflexes, and an increase in sphincter activity during filling and complete silencing during emptying. An upper motor neuron lesion is present when there is detrusor overactivity and/or hyperactive EMG responses to sacral reflexes and/or a failure of the sphincter muscle, on EMG, to relax (either partially or completely) with a bladder contraction or leaking at capacity. A lower motor neuron lesion is noted when there are no contractions of the detrusor muscle and/or there is a degree of denervation, either partial or complete, in the sphincter muscle, with characteristic EMG changes in the motor units or no motor unit activity at all, respectively, and little or no response in the sphincter to sacral reflexes and/or bladder filling or emptying [7].
Neurospinal dysraphism
Myelomeningocele
With regard to embryology, the developing spinal canal begins on the 18th day of gestation and is completed by day 35, closing in a caudad direction from the cephalic end of the body. Failure of mesodermal in-growth over the developing spinal cord results in an open lesion, most commonly seen in the lumbo-sacral area and, with decreasing regularity, in the thoracic and cervical areas (Table 1). The exposed spinal cord and its nerve roots, some of which may protrude into the meningocele sac, and tension on the spinal cord as the cord ‘rises up’ the canal with elongation of the fetus (from L2, L3 in mid- to late fetal life, to L1 at birth), contribute to a variable picture of neural injury to the lower urinary tract and lower extremities [8]. Coupled with obstruction of the aqueduct to the fourth ventricle (Chiari malformation), with possible herniation of the brainstem and the center for micturition coordination (the pontine mesencephalic center), additional layers of dysfunction are added to those nerve pathways already affected.
Table 1Spinal bony level of myelomeningocele (uppermost vertebral abnormality)LocationIncidence (%)Cervical-high thoracic2Low thoracic5Lumbar26Lumbosacral47Sacral20
The over-riding issue at birth is whether or not the child has detrusor external urethral sphincter dyssynergy and whether the infant can empty the bladder completely at low pressure. All newborns with radiologic abnormalities at birth (5–10% with hydronephrosis, reflux) have active obstruction of the bladder outlet that had caused these changes to occur in utero [9]. The presence of elevated detrusor filling pressure, bladder sphincter dyssynergy or high voiding or leaking pressures (above 40 cm H2O) at capacity, which can result in upper urinary tract deterioration in as many as 63% of children [9], warrants early intervention with clean intermittent catheterization (CIC) and anticholinergic drugs [10–13]. Thus, the investigation of these children when newborn includes a renal and bladder ultrasound, a catheterized measurement of urine residual after voiding or leaking, a determination of serum creatinine concentration after 7 days of life and a urodynamic study that incorporates both detrusor pressure measurements and urethral sphincter electromyography. Voiding cystography is undertaken when hydronephrosis is present and/or urodynamic studies indicate bladder outlet obstruction with either increased pressure at capacity or bladder sphincter dyssynergy. The incidence of reflux when there is functional obstruction of the bladder outlet can range as high as 50% [14, 15].
Although some clinicians still preach watchful waiting if the renal ultrasound findings are normal, and do not recommend urodynamic studies in the newborn period, opting instead for instituting CIC and drug therapy only with the first sign of ureteral or renal pelvic dilation [16, 17], most centers within the USA now advocate full investigation of the lower urinary tract and initiate prophylactic treatment if there are signs of outlet obstruction and/or elevated bladder filling or voiding pressure [18–20]. The incidence of urinary tract deterioration can be greater than 50% [11, 12, 20] when children with the potential for deterioration are followed with expectant and not preemptive therapy. Even though the ‘watchful waiters’ demonstrate that they can reduce the presence of hydronephrosis and, possibly reflux, the changes in detrusor dynamics are not as easily reversed, and the need for subsequent aggressive management of the bladder to control incontinence and a poorly compliant bladder is commonplace (Table 2). Therefore, CIC is begun when detrusor sphincter dyssynergy, elevated leak point pressures greater than 40 cm H2O, and/or reflux grade 3 or higher (on a scale of 1 to 5) are present. Instituting CIC and anticholinergic therapy in infancy has revealed many advantages over time [19–21]: the parents and the child adapt to the routine of CIC much easier than they would have if it were to be begun when the child is older; the bladder often remains very compliant, expanding as the child grows and maintaining appropriate wall thickness as noted on bladder echography; hydronephrosis and vesicoureteral reflux develop in fewer than 10%; continence is readily achieved in greater than 50% with no additional maneuvers; and the need for augmentation cystoplasty to maintain a reasonable organ for storage is markedly reduced from almost 60% to 16% when compared with that in children followed expectantly [22].
Table 2Surveillance in infants with myelodysplasia (until age 5 years) (IVP intravenous pyelogram, ECHO sonogram, UDS urodynamic study, VCUG voiding cystourethrogram, RNC radionuclide cystogram)Sphincter activityRecommended testsFrequencyIntact-synergicPost-void residual volumeEvery 4 monthsIVP or renal ECHOEvery 12 monthsUDSEvery 12 monthsIntact-dyssynergicaIVP or renal ECHOEvery 12 monthsUDSEvery 12 monthsVCUG or RNCbEvery 12 monthsPartial denervationPost-void residual volumeEvery 4 monthsIVP or renal ECHOEvery 12 monthsUDScEvery 12 monthsVCUG or RNCbEvery 12 monthsComplete denervationPost-void residual volumeEvery 6 monthsRenal ECHOEvery 12 monthsaPatients receiving intermittent catheterization and anticholinergic agentsbIf detrusor hypertonicity or reflux is already presentcDepending on degree of denervation
When vesicoureteral reflux is present, CIC effectively lowers the intravesical emptying pressure when the bladder is drained. In addition, anticholinergic medication can be added to lower detrusor filling pressure, increasing compliance without fear of causing urinary retention when combined with CIC. The lowered filling and emptying pressures has proven to be very beneficial; in 30–50% of children reflux is resolved within 2–3 years of its discovery and initiation of therapy.
The disadvantages are few and include a higher rate of bacteriuria (60–70% versus 30%) but a lower rate of symptomatic urinary tract infection (20% versus 40%) during childhood than in children followed expectantly [23, 24]. Because the subsequent risk of reflux is lower, the effect on renal function and the development of scarring is reduced when these prophylactically treated children are compared to those monitored with watchful observation [16, 25].
Credé voiding is not an efficacious form of bladder emptying in children with myelodysplasia, especially if the urethral sphincter is partially or fully innervated. Because most children have intact motor function above L1, any increase in abdominal pressure from a Credé maneuver can lead to a reflexive increase in urethral sphincter activity, thus producing an increase in bladder outlet resistance resulting in “high voiding pressure”. This can be particularly noxious in children with moderate or severe grades of reflux. In addition, as the child grows, the bladder resides more in the pelvis and not intra-abdominally, further reducing the effectiveness of the Credé maneuver.
The key to a stable bladder and, consequently, renal function is the maintenance of a good capacity, highly compliant, detrusor muscle, combined with periodic and complete emptying of the bladder at low pressure. Anticholinergic medication (primarily oxybutynin, tolterodine, glycopyrrolate, hyoscyamine or trospium) and CIC achieve that in a majority of children and provide an added benefit of continence if the child has reasonable bladder outlet resistance [9]. Several alpha sympathomimetic agents, such as phenylpropanolamine, ephedrine or pseudoephedrine, are used to increase bladder outlet resistance when it is not sufficient to maintain continence between CICs. A variety of surgeries has been devised when these conditions cannot be met. A detailed description of the surgical treatment is beyond the scope of this discussion, but, suffice it to say, bowel augmentation onto the bladder has been a common practice to lower pressure and increase capacity in order to make the bladder a useful organ for storage. Disadvantages abound, including problematic mucus production, recurrent urinary infection, electrolyte imbalance, stone formation and the recently documented risk for the late occurrence of cancer in the augmented segment [26].
A plethora of surgical procedures has been designed to increase bladder outlet resistance in those children with a level that is insufficient to maintain continence between catheterizations, that include implantation of an artificial urinary sphincter, bladder neck tightening, using adjacent tissue, a fascial sling, and various bulking agents. All can provide more resistance, but no one procedure is ideally suited for every patient.
Creating a catheterizable urinary stoma has become fashionable in those children with intractable urethral incontinence (with obliteration of the bladder neck) or inability to catheterize their urethra easily due to obesity, poor eye–hand coordination or caretaker issues surrounding genital organ privacy. Long-term success has been achieved that provides the individual with a degree of independence, but problems with stomal stenosis can occur.
Occult spinal dysraphism
Occult spinal dysraphism has been diagnosed with increasing frequency since the advent of spinal ultrasound and MR imaging [27]. An intraspinal lipoma or lipomeningocele, a diastematomyelia, a fatty filum with tethering, or a dermal sinus tract make up the extent of these disorders. Most pediatricians now will image the back of any newborn with a cutaneous lower midline back lesion, which can be detected in 90% of affected individuals [28]. These lesions include a subcutaneous mass, dermal vascular malformation, hypertrichosis, a midline dimple or sinus tract, a skin tag or an asymmetric gluteal cleft. These lesions often signify an underlying bony and/or spinal cord malformation. Ultrasound within the first 3 months of the infant’s life can easily visualize the intraspinal space. After the infant has reached that age MR imaging is needed to diagnose and/or confirm the presence of a dysraphic state.
Most infants have no other manifestation of this disease (other than the cutaneous lesion) because lower extremity neurologic function is normal. In the past, before intraspinal imaging was feasible, these lesions often went undetected until urinary and/or fecal incontinence became problematic or lower extremity difficulties became evident [28–31]. This frequently occurred around the time of a pubertal growth spurt, when increased traction on the spinal cord took place [32]. As the imaging techniques evolved and urodynamic studies in children were performed at an early age, it became clear that most babies had minimal neurologic impairment at first but that the neurologic lesion progressed with advancing age [33].
The pathophysiology involves apparent tension on the lower end of the spinal cord as the child grows. Normally, the conus medullaris ends at L1, L2 at birth but ‘rises’ cephalad to T12, L1 at puberty. The differential growth rate between the spinal cord and the vertebral bodies stretches the lower cord and cauda equina due to fixation of the filum terminale to the bottom of the vertebral canal, or the nerves roots emanating from the cord become compressed by an expanding intraspinal lipoma. With time, this stretching and/or compression affects the oxidative process of the neural tissue that then leads to impaired function of the lower extremities and/or lower urinary tract [34, 35].
Initial investigation of the affected child includes a urodynamics study and a renal and bladder ultrasound. The findings of urodynamics studies in children less than 1 year old are invariably normal, but when abnormal they are not coupled with abnormalities in the lower extremities [33, 36]. When findings are abnormal, partial denervation in the urethral sphincter muscle or failure of the sphincter to relax during a detrusor contraction are the most common findings in infancy, while extensive denervation of the sphincter and/or an acontractile detrusor combined with changes in lower extremity function are the most common abnormalities in an older child [37]. As noted previously for myelomeningocele in children, a voiding cystourethrogram is warranted only when the urodynamics parameters suggest risk to the upper urinary tract from increased bladder outlet resistance or poor detrusor compliance. Vesicoureteral reflux, hydronephrosis and urinary incontinence are all managed in the same fashion as one would treat children with similar neurologic impairment due to an open spinal abnormality.
The abnormal condition tends to improve following spinal cord de-tethering in the infant, but this normalization is unlikely when an older child is operated on [33, 37–39]. Therefore, specific urologic therapy is not instituted following delineation of an abnormality in infants until urodynamics studies have been repeated 3 months after the condition has been repaired. If the findings have not changed, or the child is older (when the chance that the neurologic abnormality will not improve), treatment based on principles outlined in the section on open spinal lesions is instituted.
Thirty percent of children will have secondary spinal cord tethering over time, some as late as puberty or just beyond it, when the last growth spurt occurs [28, 37, 39]. Therefore, careful surveillance and repeated assessment at the first sign of incontinence or changing lower extremity function is warranted. No child is considered risk free until he or she has reached full adult height.
Sacral agenesis
Partial or complete absence of the lowermost vertebral bodies is labeled sacral agenesis. The condition can range from the absence of just the last two or three sacral bodies to the absence of sacral and several lumbar bones as well (sirenomyelia). This can be seen in offspring of insulin-dependent diabetic mothers (1%) [40], but it may be part of a genetic disorder due to a deletion of part of chromosome 7 (7q36), leading to absence of an important transcription factor that plays a role in the development of the caudal end of the spinal cord and vertebral column [41]. In familial cases of sacral agenesis associated with the Currarino triad syndrome (presacral mass, sacral agenesis and anorectal malformation), deletions in chromosome 7 (7q) resulting in HLXB9 genetic mutations have been found [42]. A mutation in HLXB9, a homeodomain gene of a 403 amino acid protein, which appears to be responsible for neural plate infolding, has been identified in 20 of 21 patients with familial Currarino triad syndrome and in two of seven sporadic cases of this syndrome [43, 44]. Heterozygote carriers within these families have also been identified [45]. Thus, sacral agenesis may represent one point on a spectrum of abnormalities that encompass a sacral meningocele and ano-rectal malformations [46].
In the newborn period (and even afterwards) these infants appear normal, with no lower extremity abnormality. Unless it is thought of during the examination of a newborn of a diabetic mother, such babies often go undiagnosed. With time, as they have difficulty in toilet training or have urinary infection, it becomes evident that there is a problem [40, 47]. The pathognomic sign is absence of the upper end of the gluteal cleft, with flattened buttocks. When the diagnosis is considered a lateral spine film (or a spinal ultrasound in infants) will confirm the abnormality. A spinal MR reveals a sharp cut off to the cord at about T-12, with nerve roots streaming from it. Approximately 90% of children develop neurogenic bladder dysfunction [48].
An equal number of children have an overactive detrusor with sphincter dyssynergy or an acontractile detrusor with complete denervation in the urethral sphincter [47, 49]. The former is often associated with recurrent urinary infection and vesicoureteral reflux, whereas the latter produces continuous incontinence. The type of neurologic impairment affecting the lower urinary tract cannot be predicted from the level of absent or abnormal vertebral bones [47]. Obviously, management depends on the type of dysfunction present. CIC, anticholinergic medication and antibiotics are instituted in those with an upper motor neuron type lesion, while surgical measures with CIC are needed in those with an incompetent sphincter mechanism.
Associated conditions
Imperforate anus
Failure of the lowermost portion of the developing colon in the fetus to canalize fully, resulting in a closed rectum that does not open onto the anal skin verge, is a rare anomaly, but one that needs immediate attention after delivery. In boys there is a fistula from the end of the rectal canal to the posterior urethra, whereas a stenotic, anteriorly placed anal canal that ends at the posterior aspect of the vestibule, may be noted in girls (Table 3). Usually, a colostomy is performed, or, more recently, definitive repair is undertaken in the first 24 h of life in boys, while anal dilatation is begun in girls.
Table 3Wingspread classification of anorectal malformationsFemaleMaleHighHigh Anorectal agenesis Anorectal agenesis  With rectovaginal fistula  With rectourethral (prostatic) fistula  Without fistula Without fistula Rectal atresia Rectal atresiaIntermediateIntermediate  Rectovestibular fistula  Rectovestibular urethral fistula  Rectovaginal fistula Anal agenesis without fistula  Anal agenesis without fistulaLowLow Anovestibular fistula Anocutaneous fistula Anocutaneous fistula Anal stenosis Anal stenosis Rare malformationCloacal malformationRare malformation
From a urologic standpoint, this condition is often part of a constellation of abnormalities known as the VATER or VACTERL association (the mnemonic denotes all affected organs: V vertebral; A anal; C cardiac; TE tracheoesophageal fistula; R renal; L limb). Unilateral renal agenesis, vesicoureteral reflux and spinal cord tethering are the most common abnormalities affecting the urinary tract [50]. Urinary, and fecal, incontinence issues that become prominent as the child matures, due to progressive denervation of the lowermost nerves modulating bladder and urethral and anal muscle function, are likely clinical scenarios. This is most commonly seen in children where the rectum has ended above the levator ani muscle (50%), but it is also seen when the rectum ends below that pelvic floor muscle (18%) [51]. A spinal vertebral bony image is not a reliable sign that spinal cord abnormality is present [52]. A spinal ultrasound in newborns, and MRI of the spine in older children, are a mandatory part of the investigation in these children. An upper motor neuron lesion with detrusor overactivity and/or detrusor sphincter dyssynergy are most likely to develop, but an acontractile detrusor and sphincter denervation are also seen as a result of spinal cord tethering [49, 53]. It has been shown that the earlier neurosurgical intervention is undertaken, the better the individual’s chances of having normal sacral spinal cord and lower urinary tract function [54]. Therefore, early detection of this condition is necessary to improve the child’s chance of maintaining healthy kidneys and becoming continent.
Central nervous system disorders
Cerebral palsy
This condition results from a non-progressive injury to the brain, occurring in the perinatal period, that produces a neuromuscular disability or a specific symptom complex of cerebral dysfunction [55]. It is caused by perinatal infection or a period of anoxia (or hypoxia) affecting the tissues of the central nervous system [56] (Table 4). It appears in babies who are less than 2 kg at birth, have had intraventricular hemorrhage, experienced a neonatal seizure or received mechanical ventilation for a prolonged period of time in the postnatal period [57]. The incidence of cerebral palsy is increasing, as more severely premature infants are surviving and going home.
Table 4Perinatal risk factors in cerebral palsy. Adapted from [61] used with permission. UMN upper motor neuron lesion, LMN lower motor neuron lesionFactorUMN (no. of patients)LMN (no. of patients)Prematurity101Respiratory distress/arrest/apnea92Neonatal seizures5–Infection51Traumatic birth5–Congenital hydrocephalus3–Placenta previa/abruption22Hypoglycemia seizures2–Intracranial hemorrhage2–Cyanosis at birth13No specific factor noted15–
Affected children have delayed gross motor development, abnormal fine motor performance, altered muscle tone, abnormal stress gait, tight heel cords and exaggerated deep tendon reflexes [58]. These findings can vary substantially, from being quite obvious to very subtle, unless a careful neurologic examination is performed. These abnormalities may not be manifest in the early postnatal period, but become evident over time, because myelination of axons and maturation of neurons in the basal ganglia are required before spasticity, dystonia, and athetosis become apparent. Some less affected children have even milder forms of the disease, with only learning disabilities, attention deficit, or attention deficit hyperactivity disorders being seen.
Most children with cerebral palsy develop total urinary control, albeit at an age later than most unaffected children. Incontinence is a feature in some (24% of surveyed families in one study) [59], but the exact incidence has never been truly determined. The presence of incontinence is often related to the extent of the physical impairment, primarily because the handicap prevents the child from reaching the bathroom on time, causing an episode of wetting [60]. Urinary infection and vesicoureteral reflux are not features of this disease, and the kidneys are invariably normal on ultrasonic imaging.
An upper motor neuron type of bladder dysfunction with detrusor overactivity (80%), but not necessarily with detrusor sphincter dyssynergy (5%), is invariably present, but lower motor neuron injury with sphincter denervation due to spinal cord involvement can be seen as well (11%) [61] (Tables 5 and 6). Volitional control over sphincter function is present, and affected children have some ability to prevent leaking from an overactive detrusor by tightening the muscle for a variable period of time. Children with milder forms of dysfunction, with just learning disabilities without spasticity, have an overactive detrusor leading to either urgency (with or without incontinence) and nocturia, or day and night wetting. Therefore, modulating the overactivity with anticholinergic medication is the treatment of choice. However, this must be done judiciously, with careful monitoring of residual urine to prevent the development of retention.
Table 5Lower urinary tract function in cerebral palsyTypeNumberUpper motor neuron lesion49Mixed upper + lower motor neuron lesion5Incomplete lower motor neuron lesion1No urodynamic lesion2Table 6Urodynamics findings in cerebral palsy (some patients had more than one finding)Type of LesionNo. of PatientsUpper motor neuron (detrusor or sphincter)Detrusor overactivity35Detrusor sphincter dyssynergy7Overactive sacral reflexes6No voluntary control3Smaller than expected bladder capacity2Poorly compliant2Lower motor neuron (abnormal motor unit potentials)Excessive polyphagia of sphincter5↑ Amplitude + ↑ duration potentials4
Trauma
Traumatic injuries to the spine
Fortunately, spinal cord injuries in children are rare (2.6 per million) [62]. The incidence tends to increase geometrically with age [63]. When an injury does occur, it is more likely to happen in a boy than in a girl, and it is usually the result of a motor vehicle or bicycle accident (24–52%), a fall from a high place, a gunshot wound, or a diving or sports incident. Injuries may also occur iatrogenically after surgery to correct scoliosis, kyphosis or other intraspinal processes, congenital aortic anomalies, or patent ductus arteriosus operations [62, 64–67]. Newborns are particularly prone to a hyperextension injury during high forceps delivery [68].
Spinal cord injuries in children are intrinsically different from those in adults, owing to a variety of factors, including the mechanism of injury and the difference in configuration of the cord in children compared with that in adults. In addition, the horizontal versus vertical orientation of the facet joints in vertebral bodies that predisposes to anteroposterior subluxation in children, the delayed supportive effect of the paraspinous musculature and ligaments, and the relative heaviness of the head, which causes a fulcrum of maximal flexion of the upper cervical region in infants and young children, all contribute to a high degree of hypermobility that places the child’s spinal cord at risk for ischemic necrosis [65].
The lower urinary tract dysfunction that ensues is not likely to be an isolated event but is usually associated with loss of sensation and paralysis of the lower limbs. Radiologic investigation of the spine may not reveal any bony abnormality, although momentary subluxation of osseous structures resulting from the elasticity of the vertebral ligaments can result in a neurologic injury. This condition has been seen only in children (usually younger than 8 years old) and has been labeled SCIWORA (spinal cord injury without radiologic abnormality) [69]. Overall, SCIWORA can account for up to 38% of spinal cord injuries in children [70]. Often, what appears to be a permanent lesion initially turns out to be a transient phenomenon with time. Although sensation and motor function of the lower extremities may be restored relatively quickly, the dysfunction involving the bladder and rectum may persist considerably longer.
During the acute phase of the injury, the bladder is often acontractile and the urethral sphincter nonreactive, although normal-appearing bioelectric potentials can be recorded on sphincter EMG (spinal shock). Over a variable but unpredictable period of time, detrusor contractility and sphincter reactivity return as spinal cord edema subsides. With this return of function, an overactive detrusor and bladder-sphincter dyssynergy may develop if the lateral reticulospinal cord pathways to and from the brainstem have been disrupted. When the lesion affects the cauda equina, there is probably little to no return of bladder or sphincter function. Sacral sensation and peripheral reflexes are not good indicators of ultimate lower urinary tract function [71]. Over time, the predominant urodynamic pattern in patients with a thoracic-level lesion is an overactive detrusor with sphincter dyssynergy, high voiding pressures, eventual hydronephrosis and vesicoureteral reflux. Patients with an upper thoracic or cervical lesion are likely to exhibit autonomic dysreflexia with a spontaneous discharge of α1 stimulants during bladder filling and with contractions of the detrusor that require careful monitoring of their blood pressure during any investigational studies of the lower urinary tract [72, 73].
Foley catheter draining in the immediate post-injury phase is needed, but CIC should be begun as soon as feasible after that time [74–76]. When a child starts volitional voiding, CIC can be tapered and stopped as residual urines are measured and found to be insignificant (less that 5 ml). Urodynamics studies should be undertaken no earlier than 6 weeks after the injury, to allow for the manifestation of the extent of the neurologic injury [77]. Periodic reassessment of bladder and sphincter function is appropriate up to 2 years after the injury, due to the potential for change during that time. Renal ultrasonography should be part of the assessment, but voiding cystography is only needed when there are signs of potential risk (i.e. sphincter dyssynergy or poor detrusor compliance). Low detrusor filling and voiding pressures with complete emptying are the goal [78]. When this is not present during testing, starting or continuing CIC and adding anticholinergic medication is paramount to insuring the long-term health of the lower and upper urinary tract [79].
Conclusions
Neurogenic bladder dysfunction in children takes in a very wide spectrum of conditions that include congenitally acquired conditions that may even be preventable today, conditions that are associated with specific anatomic abnormalities, and acquired conditions that may occur perinatally or from accidents or sports or motor vehicle related injuries. Despite the etiology, the guiding principles for management are similar; insuring and maintaining an adequate sized, normally compliant, reservoir that evacuates urine completely, at a relatively low pressure, is the key to maintaining a healthy environment for the kidneys. A plethora of methods has come into existence, especially since the advent of clean intermittent catheterization and the advancement of pharmacologic understanding and manipulation. Future prospects look bright for affected children, with the overall health of the individual the most paramount goal to be achieved.

myelodysplasia
pediatric neurogenic bladder
diagnosis and evaluation