Urinary complications and risk factors in symptomatic multiple sclerosis patients. Study of a cohort of 328 patients
- Conflict of interest: none.
- Dirk De Ridder led the peer-review process as the Associate Editor responsible for the paper.
Lower urinary tract dysfunctions (LUTD) are very common in Multiple Sclerosis (MS), have a significant social impact, while the organic impact is discussed. We studied urinary complications and their risk factors in our cohort of MS patients, in order to improve the management of LUTD in MS.
Between 2004 and 2009, all patients affected by MS and managed for LUTD were included in a retrospective study. We studied the epidemiological data (age, gender), the clinical data (duration of MS, EDSS score, progression of MS) and the paraclinical data (urinary creatinine clearance, urine culture, urinary tract ultrasonography and in some cases urodynamic assessment and cystography). We then identified the urinary complications and their risk factors.
Three hundred twenty eight patients, mean age 49.9 ± 12.3 years, with a MS for 14.3 ± 10 years on average and with a median EDSS score equal to 6 (1–9), were managed for LUTD. One hundred seventy eight (54%) patients developed one or more urinary complications. We identified duration of MS greater than 8.5 years and an EDSS above 7 as risk factors.
Urinary complications are common in symptomatic MS, these results imply screening and specialized care to limit the impact on the quality of life but also to prevent urinary complications. Neurourol. Urodynam. 34:32–36, 2015. © 2013 Wiley Periodicals, Inc.
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system affecting mostly young adults. Lower urinary tract dysfunctions (LUTD) are very common in MS. On average 80% of patients are subject to them during the progression of their disease,[1-5] they appear on average 6 years after disease onset.[1, 4-6] Their presence is often associated with a severe form of the disease. LUTD can occur in a number of forms. From a clinical perspective, storage symptoms affect 37–99% of patients and voiding symptoms affect 34–79%.[1, 4, 6-9] From an urodynamic perspective, detrusor overactivity occurs in 34–99% of cases, and detrusor underactivity is described in 0–40% of cases; detrusor–sphincter dyssynergia (DSD) is reported in 5–83% of cases. Detrusor overactivity and DSD can occur concomitantly in 43–80% of patients.
LUTD have a significant social impact, but the organic impact is discussed. Studies found high rates of complications: Amarenco and Hennessey reported, respectively 56% and 20% of urinary complications, whereas Gallien reported 33% of lower urinary tract infection and 23% of upper urinary tract infection. At last, Giannantoni found 30% of lower urinary tract damage, 5% of vesicoureteral reflux, 6% of upper urinary tract dilatation, and 6% of lithiasis. On the other way, studies reported lower rates of complications : Koldewijn found 12% of lower urinary tract infections, and 11% of upper urinary tract infection; Onal 5% of abnormal lower urinary tract and 5% of abnormal upper urinary tract; Krhut 3% of renal failure and 5% of abnormal urinary tract.
Risk factors are also variable across studies; the main identified risks are the duration of MS, the presence of an indwelling catheter, high amplitude neurogenic detrusor contractions, and permanent high detrusor pressure.
The aim of the present work was to retrospectively study the urinary complications, their frequency, and their risk factors in our cohort of patients suffering from MS and LUTD, to guide and improve their management.
MATERIALS AND METHODS
A retrospective study covering 328 cases was conducted into urinary complications and risk factors, in all MS patients treated for LUTD between 2004 and 2009.
We developed a regional organization for the management of LUTD in MS patients since 2004, which has provided us a large cohort of patients.
We studied the age, gender, duration of MS, and progression of MS.
We studied the urinary symptoms suffered by patients during the first evaluation, the medical history of urinary complications and the level of disability measured with the expanded disability status scale (EDSS) score, which evaluates pyramidal, cerebellar, brainstem, visual, cerebral, sensitive, bowel, and bladder functions (functional system scores) and the ability to walk. The disease severity is scored from 0 (normal) to 10 (death due to MS) with 0.5 point intervals. Patients with an EDSS score between 0 and 4 are able to walk without any help and the score depends only on the functional system scores. Above 4, EDSS score depends on how far the patients are able to walk and the necessity of assistance : between 4.5 and 5.5 they are able to walk mostly without any help whereas between 6 and 6.5 they are able to walk mostly with help. Between 7 and 8 they are not able to walk and stay in a wheelchair and between 8.5 and 9.5 they stay at bed.
Urine culture, urinary creatinine clearance, and urinary tract ultrasonography with post-void residual urine volume determination were systematically measured. If patients suffered from isolated storage symptoms, without complications, well improved by anticholinergics and without significant post-void residual volume, we did not conduct urodynamic assessment, according to the UK recommendations.
Retrograde cystography was systematically performed in the event of a medical history of upper urinary tract infections or lumbar pain on voiding.
Complications were identified from the medical history, clinical, and paraclinical data. They were classified as lower urinary tract complications (lower urinary tract infection, bladder morphological damage, bladder cancer) and upper urinary tract complications (pyelonephritis or urinary sepsis, ureteral dilatations, vesico-uretral reflux, urinary lithiasis, impaired renal function defined by urinary creatine clearance lower than 90 ml/min on two consecutive measurements). One patient could have one or more complications in the lower and the upper urinary tract.
The descriptive analysis and the urinary complications risk factors analysis were performed using the software “SPSS statistics 17.0.”
Epidemiological, clinical, and urodynamic data were compared between patients with no urinary complications (group “without complications”) and those who had (group “with urinary complications”). Quantitative parameters were compared using Student's t-test and qualitative parameters using the Chi2 test. The level of significance was set at 5%.
A multivariate logistic regression was made from variables that were significantly different when comparing the two groups to determine the independent risk factors of urinary complications.
Missing data (only EDSS, progression and duration of MS) were excluded from the analysis. It concerned 14 out of 328 patients.
A Classification and Regression tree method (STATISTICA v10. http://www.statsoft.fr) was applied to determine threshold values for predictors (determined from the logistic regression). Gini impurity was used as a measure of the quality of the split of a set into two subsets. Splitting was allowed to continue until all terminal nodes were pure or contained no more than a specified minimum number of cases (here five cases). The optimal classification tree (and the corresponding threshold values) was obtained after pruning on misclassification error and V-fold cross-validation.
We then studied separately the risk factors associated with lower urinary tract complications and the upper urinary tract complications in applying the same method.
Between 2004 and 2009, 328 patients (223 women/105 men, sex-ratio = 2.1/1) affected by MS, mean age 49.9 ± 12.3 years (19–82), with a MS for 14.3 ± 10 years (1–50 years) on average and with a median EDSS score equal to 6 (1–9), were managed for LUTD. One hundred forty (43%) patients had a relapsing-remitting form, 111 (34%) a secondary progressive form, 66 (20%) a progressive form and 11 (3%) an undetermined form.
During the first consultation, 7 patients (2%) suffered from no urinary troubles, 28 (9%) from urinary complications, 118 (36%) from storage symptoms, 73 (22%) from voiding symptoms, and 102 (31%) from both storage and voiding symptoms.
Results are reported in Table I.
Table I. Global Prevalence and Details of Urinary Complications in a Cohort of 328 Patients with MS
|Lower urinary tract||74 (23%)|
|Upper urinary tract||67 (20%)|
|Both lower and upper urinary tract||37 (11%)|
|Lower urinary tract|
|Lower urinary tract infection||81 (25%)|
|Bladder morphological damage||48 (15%)|
|Bladder cancer||1 (0,3%)|
|Upper urinary tract|
|Ureteral dilatations||12 (4%)|
|Vesico-uretral reflux||13 (4%)|
|Renal failure (CL < 90 ml/min)||50 (16%)|
|Cl = 90−60 ml/min||29 (9%)|
|Cl = 60−30 ml/min||19 (6%)|
|Cl < 30 ml/min||2 (1%)|
One hundred seventy eight patients had urinary complications: 74 patients (23%) in the lower urinary tract, 67 patients (20%) in the upper urinary tract, and 37 patients (11%) in both lower and upper urinary tract.
Concerning the lower urinary tract complications, 81 patients (25%) had lower urinary tract infections, 48 (15%) bladder morphological damages, and 1 a bladder cancer.
Among the upper urinary tract complications, 59 patients (18%) had pyelonephritis or urinary sepsis, 19 (4%) lithiasis, 13 (4%) vesico-ureteral reflux, 12 (3.7%) ureteral dilatation, and 50 (16%) an impaired renal function.
Considering the severity of complications, we found that 3 patients (1%) had deleterious complications (bladder cancer, severe renal failure), 134 (41%) mild complications (urinary infections, vesico-ureteral reflux, lithiasis), and 41 (12,5%) potential complications (any symptoms such as bladder morphological complications, ureteral dilatation, mild, or moderate renal failure).
Results are reported in Table II.
Table II. Comparison of Epidemiological, Clinical, and Urodynamic Data between the Group of Patients without Urinary Complications and the One with Urinary Complications
|Number of patients||150||178|| |
|Age||47 ± 1||52 ± 0.9||Student's t < 0.001|
|Gender|| || ||Chi2|
|Men||61 (41%)||44 (25%)||P = 0.002|
|Women||89 (59%)||134 (75%)|| |
|Duration of MS||10.8 ± 0.7||17.3 ± 0.8||Student's t < 0.001|
|EDSS||4.9 ± 0.17||5.9 ± 0.15||Student's t < 0.001|
|Progression of MS|| || ||Chi2|
|RR||72 (48%)||68 (38%)||P = 0.09|
|SP||40 (27%)||71 (40%)|| |
|P||32 (21%)||34 (19%)|| |
|Undetermined||6 (4%)||5 (3%)|| |
|Normal||8 (6%)||1 (1%)||P = 0.08|
|DO||24 (20%)||22 (16%)|| |
|DSD||21 (18%)||19 (14%)|| |
|DO + DSD||39 (33%)||51 (37%)|| |
|OUS||14 (12%)||28 (20%)|| |
|DU||13 (11%)||17 (12%)|| |
There were significant differences between the group of patients “without complications” and the other group “with urinary complications” concerning the age (P < 0.01), the gender (P = 0.002), the duration of MS (P < 0.01), and the EDSS score (P < 0.01).
There was no significant difference concerning the progression of MS (P = 0.09) or the urodynamic data (P = 0.08).
Logistic multivariate regression identified the duration of MS, the gender and the EDSS score as independent risk factors (respectively P = 0.0001; 0.001; 0.02).
The threshold values were a duration of MS greater than 8.5 years and EDSS above 7.
The lower urinary tract complications
The results are presented in Table III.
Table III. Comparison of Epidemiological, Clinical, and Urodynamic Data between the Group of Patients without Lower Urinary Tract Complications and the One with Lower Urinary Tract Complications, and between the Group of Patients without Upper Urinary Tract Complications and One with Upper Urinary Tract Complications
|Number of patients||217||111|| ||224||104|| |
|Age||48.7 ± 0.83||52 ± 1.18||Student's t = 0.022||48.1 ± 0.83||53.7 ± 1.11||Student's t P < 0.0001|
|Gender|| || ||Chi2|| || ||Chi2|
|Men||80 (37%)||25 (23%)||P = 0.008||74 (33%)||31 (30%)||P = 0.56|
|Women||137 (63%)||86 (77%)|| ||150 (67%)||73 (70%)|| |
|Duration of MS||12.9 ± 0.65||17 ± 1.03||Student's t = 0.001||12.75 ± 0.66||17.7 ± 1||Student's t P < 0.0001|
|EDSS||5.27 ± 0.15||5.8 ± 0.19||Student's t = 0.022||5.1 ± 0.14||6.3 ± 0.2||Student's t P < 0.0001|
|Progression of MS|| || ||Chi2|| || ||Chi2|
|RR||92 (42%)||48 (43%)||P = 0.43||108 (48%)||32 (31%)||P = 0.031|
|SP||69 (32%)||42 (38%)|| ||69 (31%)||42 (40%)|| |
|P||47 (22%)||19 (17%)|| ||40 (18%)||26 (25%)|| |
|Undetermined||9 (4%)||2 (2%)|| ||7 (3%)||4 (4%)|| |
|Normal||8 (5%)||1 (1%)||P = 0.37||8 (4%)||1 (1%)||P = 0.13|
|DO||29 (18%)||17 (18%)|| ||37 (20%)||9 (12%)|| |
|DSD||27 (16%)||13 (14%)|| ||29 (16%)||11 (15%)|| |
|DO + DSD||58 (35%)||32 (35%)|| ||63 (35%)||27 (36%)|| |
|OUS||20 (12%)||10 (11%)|| ||20 (11%)||10 (14%)|| |
|DU||23 (14%)||19 (21%)|| ||26 (14%)||16 (22%)|| |
There were significant differences between the group “without complications in the lower urinary tract” and the group “with lower urinary tract complications” concerning the age (P = 0.0022), the gender (P = 0.008), the duration of MS (P = 0.01), and the EDSS score (P = 0.022).
There was no significant difference concerning the progression of MS (P = 0.43) or the urodynamic data (P = 0.37).
Logisitic multivariate regression identified the duration of MS and the gender as independent urinary risk factors (respectively P = 0.002; 0.005).
The threshold value was duration of MS greater than 7.5 years.
The upper urinary tract complications
The results are presented in Table III.
There were significant differences between the group “without upper urinary tract complications” and the group “with upper urinary tract complications” concerning the age (P < 0.01), the duration of MS (P < 0.01), the EDSS score (P < 0.01), and the progression of MS (P = 0.031).
There was no significant difference concerning the gender (P = 0.56) or the urodynamic data (P = 0.13).
Logistic multivariate regression identified the duration of MS and the EDSS score as independent urinary risk factors (respectively P = 0.001; 0.023).
The threshold values were duration of MS greater than 8.5 years and EDSS score above 7.
To our knowledge no other studies of LUTD in MS had such a large cohort of patients. We showed that urinary complications were frequent (54% of patients) in symptomatic patients, the identified risk factors were female gender, duration of MS greater than 8.5 years and EDSS score above 7.
Characteristics of Our Population
Our population was comparable to that of the other major studies concerning the sex ratio, duration of MS, EDSS score.[1, 4, 7, 11]
Moreover, the frequency and type of urinary symptoms were consistent with those found in the literature, mostly storage symptoms (67%) and frequent voiding symptoms (53%). Data that had never been reported in the literature, to our knowledge, was the notion of urinary complications as the cause of the first consultation. This was not uncommon in our population, reported in 9% of cases. This highlights the frequency of urinary complications.
The frequency was high similar to that reported in the study of Amarenco (54% vs. 56%), which was the only study to our knowledge in which all complications were noted. Moreover, in their study, the population was large (n = 225) and the duration of MS similar to ours (13.3 years). As other studies were less systematic at reporting urinary complications, it is understandable to note a lower reported prevalence.[9, 11, 12] Moreover, the duration of MS was an urinary complications risk factor, so studies in which the duration of MS was less than 10 years, necessarily had a significantly lower prevalence of complications than in our study.[9, 11, 16]
Low urinary tract complications
The frequency was high (34%). The lower urinary tract infection rate was consistent with that found in the literature (between 13 and 80% depending on the study, vs. 25% in our study), and the rate of bladder morphological damage too (between 4 and 49% depending on the study vs. 15% in our study).
Upper urinary tract complications
The frequency was also high, higher than in most studies (between 0 and 25% depending on the study vs. 31% in our study).
Rates of pyelonephritis, vesicoureteral reflux, ureteral dilatation, and lithiasis were close to those found in the literature (respectively 8%, 5%, 8%, and between 2–11% in the literature vs. 18%, 4%, 4%, and 6% in our study).
However, we found a high rate of impaired renal function, whereas it was rare in the literature. We systematically measured urinary creatinine clearance. It was retested to overcome measurement errors related to intrasubject variability, and if necessary a complete 24 hr collection of urine was set up with an indwelling catheter. This rigor may explain the difference with other studies that only calculated the creatinine clearance.[7, 11, 12] Urinary creatinine clearance is not the best technique to evaluate glomerular filtration, but is the easiest to use in clinical practice. The use of serum creatinine is unsuitable in MS patients, who present reduced levels of creatinine not correlated with glomerular filtration rate. Our results were also consistent with those of Calabresi who showed an impairment of glomerular filtration in 36% of progressive MS patients. This impairment of renal function is important to consider because the use of nephrotoxic drugs is not uncommon in MS, and the dosage should be adjusted to avoid overdose or iatrogenic complications.
Age greater than 50 years may be a risk factor for uro-nephrological complications according to various studies.[1, 7] Although our patients with urinary complications were significantly older than those without complications (52 years vs. 48.7 years), the age was not recognized as an independent risk factor. The age difference seems to be primarily related to the duration of MS, which is a risk factor, widely reported in the literature and also in our study.
Duration of MS
The duration of MS has been recognized in our study as an independent risk factor for urinary complications. The threshold for onset of complications and upper urinary tract complications was determined over 8.5 years. It was slightly earlier (7.5 years) for complications in the lower urinary tract. These results are consistent with data reported by de Seze et al. where the risk of complications was accentuated between 6 and 8 years.
Thus, it is important that attention be paid, implying rigorous and regular LUTD evaluation after 8.5 years of MS duration in symptomatic patients.
In our study, female gender was a risk factor of urinary complications and more specifically of the lower urinary tract. The risk factor “female gender” had previously been reported in the study of Gallien. But lower urinary tract infections are more common in women in the general population, probably the result was not related to MS but to female gender as in the general population.
We did not identify male gender as a risk factor of upper urinary tract complications. This result is consistent with the findings of Giannantoni and Amarenco.
In our study patients with urinary complications had significantly more disabilities. It was an independent risk factor.
EDSS worsened with the evolution of MS, but was identified as an independent risk factor of urinary complications, unlike age.
EDSS is a factor correlated with the presence of urinary disorders in the literature. The severity of pyramidal symptom score is correlated with the prevalence of complications,[6, 7, 20] this data was not available in our cohort. The EDSS was not clearly identified in the literature as a complicating factor, however in the study of Krhut among the 92 patients those with morphological abnormalities as seen by ultrasound, or those who had abnormal creatinine clearance had an EDSS score > 5.5. These results therefore go in the same direction as ours.
Thus, our results also imply rigorous and regular LUTD evaluation should be performed when the EDSS score is above seven in symptomatic MS patients.
Progression of MS
In our study, secondary progressive and primary progressive MS have been recognized as risk factors only of upper urinary tract complications. It has not been reported in the literature but progressive (both primary and secondary) MS has already been recognized as being associated with a higher frequency of LUTD.
Urodynamic presentation was not significantly associated with urinary complications in our study, this is consistent with the results reported by Nakipoglu. However, in the literature DSD is associated with an increased frequency of upper urinary tract complications.[9, 20] We did not systematically perform urodynamic exploration, in accordance with UK recommendations, especially if the patient complained only of storage symptoms without complications. Our urodynamic data were therefore not exhaustive and we cannot conclude as to their relationship with the occurrence of complications.
This was a retrospective study, where data were analyzed from the cohort of all MS patients referred for LUTD. Most of the asymptomatic patients and those undetected by their general practitioner or neurologist, so probably paucisymptomatic were not referenced. So we did not study the prevalence of LUTD or urinary complications in the general population of patients with MS, but only in symptomatic MS patients.
These results justify regular monitoring and appropriate management of LUTD in symptomatic MS patients, especially after a duration of MS > 8.5 years and EDSS score > 7.
Moreover, it is essential to measure urinary creatinine clearance, which is in practice currently the easiest and most reliable way to estimate the glomerular filtration rate, even to place an indwelling catheter for 24 hr to have complete collection. Indeed, the high frequency of impaired renal function requires rigor and caution in the use of nephrotoxic drugs.
It is now necessary to assess the impact of early and specialized care of LUTD in MS on the occurrence of urinary complications, and urinary morbidity and mortality.
Urinary complications are frequent (54% of patients) in symptomatic MS patients. We identified female gender, EDSS score > 7 and duration of MS > 8.5 years, as risk factors. These results imply screening and specialized neuro-urological care to limit the impact on the quality of life but also to prevent urinary complications.
The authors thank Josette Pastor for its assitance in statistical analysis.