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Keywords:

  • glomerular filtration rate;
  • neurogenic detrusor overactivity;
  • quality of life;
  • renal function;
  • spinal cord injury

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Objectives

To investigate the therapeutic effects of repeated detrusor onabotulinumtoxinA injections on treatment outcomes, quality of life (QoL), and glomerular filtration rate (GFR) in chronic spinal cord injured (SCI) patients with neurogenic lower urinary tract dysfunction and urinary incontinence.

Materials and Methods

Patients with SCI who failed antimuscarinic treatment were enrolled. All patients had urodynamic detrusor overactivity (DO) or increased detrusor tonicity without anatomical bladder outlet obstruction or intrinsic sphincter deficiency. They were randomly assigned to receive 200-U or 300-U onabotulinumtoxinA detrusor injections every 6 months. The primary endpoint was 6 months after the second injection. The urodynamic parameters, QoL measures, and 99mTc renal scans were evaluated at baseline and every 3 months and compared between dosages.

Results

A total of 72 patients were enrolled, including 43 men and 29 women and mean injury duration of 8.7 years. Among them, 38 patients received 200-U and 34 received 300-U onabotulinumtoxinA injections. At the end-point, the urodynamic parameters and incontinence severity improved significantly, without a significant difference between the two groups. QoL also improved in both groups, without differences between groups. Uninhibited DO improved more in 300-U group compared to 200-U group at end-point (P = 0.01). The GFR did not change significantly in either group. The most common complication was urinary tract infection, which occurred in one third of patients.

Conclusions

Either 200-U or 300-U repeated detrusor onabotulinumtoxinA injections improved incontinence, urodynamic parameters, and QoL in SCI patients with neurogenic DO. Renal function was maintained in patients receiving both dosage of repeated injections. Neurourol. Urodynam. 33:129–134, 2014. © 2013 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Spinal cord injury (SCI) can lead to severe urinary tract dysfunction, including detrusor overactivity (DO), detrusor areflexia, and detrusor sphincter dyssynergia (DSD).[1] Urinary incontinence caused by neurogenic detrusor overactivity (NDO) is common and disturbing to SCI patients.[2] Without adequate treatment, upper urinary tract damage occurs in almost 25% of SCI patients.[3] Although antimuscarinic therapy with or without clean intermittent catheterization is the first-line treatment for SCI patients with NDO,[4] the long-term therapeutic effects of anticholinergic therapy may be suboptimal and patients may suffer from intolerable adverse effects, such as dry mouth and constipation. Detrusor onabotulinumtoxinA injection is an effective alternative therapy for SCI patients refractory to antimuscarinic therapy.[5-7]

Detrusor onabotulinumtoxinA injection therapy was first used to treat NDO in 2000.[8] According to previous studies, onabotulinumtoxinA inhibits acetylcholine release at presynaptic cholinergic nerve terminals, decreases substance P and calcitonin-gene-related peptide release in afferent nerves, and reduces the expression of transient receptor potential vanilloid subfamily 1 and purinergic receptor P2X expression in the bladder wall.[9-11] Therefore, onabotulinumtoxinA treatment results in detrusor muscle paralysis, delays the urge sensation, and keeps the bladder in low pressure status to prevent upper urinary tract damage. Vesicoureteral reflux or renal pelvis dilatation also improved after injection of 300-U of onabotulinumtoxinA in the detrusor muscle.[12, 13] Good therapeutic effects on urinary incontinence were noted after injection of 200-U of onabotulinumtoxinA in the detrusor in patients with NDO,[14, 15] but no significant improvement of renal function was reported after repeated 200-U onabotulinumtoxinA injections in the detrusor.[16]

Recently, large, randomized, placebo-controlled, multicenter clinical trials revealed that the therapeutic effects were comparable between 200-U and 300-U of onabotulinumtoxinA injected into the detrusor.[17-19] However, the impact of detrusor onabotulinumtoxinA injections on renal function has not been evaluated between the 200-U and 300-U treatment modalities. Therefore, we investigated the differences in therapeutic effects of bladder and renal function between repeated 200-U and 300-U onabotulinumtoxinA detrusor injections in chronic SCI patients.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

This study was approved by the Institutional Review Board and Ethics Committee of the hospital (IRB-098-88). Each patient was informed about the study rationale, procedures and possible complications, and written, informed consent was obtained before treatment.

This single-center, randomized, prospective study collects the chronic SCI patients with urinary incontinence in Hualien Tzu Chi General Hospital from February 2010 to January 2012. These SCI patients went to urological clinics for help due to urinary incontinence. Other lower urinary tract symptoms, such as urinary frequency, urgency and difficult urination may also be mentioned. All patients were previously treated with antimuscarinic therapy and clean intermittent catheterization, which failed to eradicate their urinary incontinence. Video-urodynamic studies were performed before enrollment to prove the presence of DO with or without DSD, and to exclude patients with detrusor underactivity, prostatic obstruction, intrinsic sphincter deficiency, and urethral stricture. Patients were also excluded if they had an active urinary tract infection, urinary tract cancer, history of lower urinary tract surgery or chronic systemic diseases.

All patients underwent 99mTc-labelled diethtlenetriamine penta-acetic acid (99mTc-DTPA) renal scans for measuring glomerular filtration rate (GFR) after enrollment. The total GFR was measured by 99mTc-DTPA clearance renal scintigraphy using a dual head camera (Infinia or Infinia Hawkeye 4; General Electric Medical Systems, Waukesha, WI). The absolute renal clearance was calculated by measuring the fractional radionuclide accumulation by the kidneys divided by the injected dose. Single-shot 99mTc-DTPA clearance has been shown to be an accurate and practical method of determining GFR in patients with SCI.[20] It will be more accurate than using creatinine clearance because SCI patients might loss urine on diaper and could not collect daily urine completely.

Video-urodynamic studies were performed in accordance with the recommendations of the International Continence Society.[21] DO was defined as involuntary detrusor contractions (IDC) or increased detrusor tonicity during the filling phase, which may be spontaneous or provoked. The urodynamic parameters of cystometric bladder capacity (CBC, bladder volume at the first voiding detrusor reflex during cystometry), maximum flow rate (Qmax), post-void residual (PVR) volume, voided volume, and voiding detrusor pressure at maximum flow rate (Pdet.Qmax) were recorded in detail. In addition, the quality of life due to lower urinary tract symptoms were evaluated using the Urogenital Distress Inventory short form (UDI-6), Incontinence Impact Questionnaire (IIQ-7),[22] and the quality of life (QoL) index of the International Prostatic Symptom Score questionnaire.[23]

The patients were randomly assigned to receive either 200-U or 300-U repeated onabotulinumtoxinA injections in the detrusor muscle using the permuted block randomization code. The onabotulinumtoxinA injection was performed at baseline and 6 months after the first injection. The patients were regularly evaluated every 3 months for the therapeutic effect, QoL scores, and GFR. Video-urodynamic studies and 99mTc-DTPA renal scans were regularly performed for evaluation of the sequential changes of the bladder and renal function at 3 months (during the major improvement) and at 6 months (when results might start declining). At the end of this study, the changes in urodynamic parameters, GFR, and QoL measures from baseline to end-point were compared between the two study groups. The incontinence severity was also evaluated according to the patient's subjective description of urinary leakage (urinary incontinence caused by all etiologies) at each follow-up visit. The score for incontinence severity was adapted from three items on the UDI-6, including urgency incontinence, stress incontinence, and leakage without sensation.

Patients were admitted for injection of 200-U or 300-U of onabotulinumtoxinA (Allergan, Inc., Irvine, CA) into the detrusor muscle under light intravenous general anesthesia in the operating room. The onabotulinumtoxinA was diluted with 30 ml of normal saline and the diluted solution was injected into 30 sites in the bladder wall, excluding the bladder trigone. Injection was performed using a rigid cystoscopic injection instrument (22-Fr, Richard Wolf, Knittlingen, Germany) and a 23-gauge injection needle. After treatment, a 14-Fr Foley indwelling catheter was placed for 1 day, and oral antibiotics was prescribed for 7 days. Patients were discharged on the next day if no complication, such as massive bleeding or fever occurred after removal of the catheter. Patients were monitored in the outpatient clinic 2 weeks later and then monthly thereafter. Autonomic dysreflexia (AD) was evaluated based on patients' report and symptoms and elevated blood pressure during urodynamics study.

Continuous variables are expressed as means ± standard deviations; categorical data are expressed as numbers and percentages. Statistical comparisons between the groups were tested using Fisher's exact test for categorical variables. The Wilcoxon rank sum test was used for continuous variables between groups and Student's paired t-test was used for comparison of variables at different time points within groups. Multiple measurement analysis was used to compare the continuous changes of variables between the groups. All statistical assessments were two-sided and considered significant at P < 0.05. Statistical analyses were performed using SPSS version 15.0 statistical software (SPSS, Inc., Chicago, IL).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

Eligible subjects were assigned to two study groups in a 1:1 ratio by permuted block randomization code, using a 2 × 2 blocking size design. Sample size was determined by power of the test set 0.9, value for α 0.05, and effect size difference was 0.8. Estimated total sample size was 68 patients which calculated by G power 3.15. With about an estimated 20% drop out rate in this study, a total of 82 patients were recruited to this study. After the first treatment, 10 dropped out after the first treatment, and 72 patients completed the trial and were evaluable in this study, including 29 women and 43 men. Their mean age was 41.5 years (range, 22–74 years) and the mean injury duration was 8.7 ± 8.1 years. Of these patients, 31 had cervical SCIs, 39 had thoracic SCIs, and two had lumbar SCIs. Fifty-six patients (77.8%) experienced complete injury, while the other 16 patients (22.2%) had incomplete injury. The injury and the American Spinal Injury Association (ASIA) classifications are listed in Table I.

Table I. Injury Level and ASIA Classification of Spinal Cord Injuries in Patients Undergoing OnabotulinumtoxinA (BoNT-A) Therapy
Injury level200-U BoNT-A (n = 38)300-U BoNT-A (n = 34)Total (n = 72)
  1. ASIA classification: the American Spinal Injury Association classification.

Cervical47.4% (18)38.2% (13)43.1% (31)
Thoracic47.4% (18)61.8% (21)54.2% (39)
Lumbar5.3% (2)02.8% (2)
ASIA classification
A76.3% (29)79.4% (27)77.8% (56)
B2.6% (1)8.8% (3)5.6% (4)
C10.5% (4)5.9% (2)8.3% (6)
D7.9% (3)5.9% (2)6.9% (5)
E2.6% (1)01.4% (1)

Among the overall patients, 47 (65.3%) used periodic or intermittent CIC to empty their bladders. At the end-point, 38 patients were randomized to receive 200-U of onabotulinumtoxinA and 34 patients were assigned to receive 300-U of onabotulinumtoxinA injected into the detrusor muscle. All of these patients completed the injection and visitation protocols. The distribution of injury severity and injury level were similar between the two groups. The median injury duration was 8.5 years in the 200-U dosage group and 8.0 years in the 300-U dosage group (P = 0.282).

Table II shows the changes in urodynamic parameters after repeated onabotulinumtoxinA injections. Significant increases of CBC and PVR and a significant decrease of Pdet.Qmax were noted after onabotulinumtoxinA injections in both groups. There were no significant differences in the changes in CBC, PVR, and Pdet.Qmax between the groups at the end of the study.

Table II. Therapeutic Effects of Derusor OnabotulinumtoxinA (BoNT-A) Injection With Different Doses on Changes of Urodynamic Parameters by Dosage Group
 200-U BoNT-A (n = 38)300-U BoNT-A (n = 34)P-valueb
  1. CBC, cystometric bladder capacity; Pdet, detrusor pressure; PVR; post-void residual; Qmax; maximum flow rate.

  2. a

    P < 0.05 compared to baseline data.

  3. b

    Comparison of the changes from baseline to end-point between 200-U and 300-U dosage groups.

CBC (ml)
Baseline213.5 ± 114.8305.9 ± 167.70.870
12 Mo376.9 ± 179.7a437.6 ± 114.3a 
Pdet (cmH2O)
Baseline40.7 ± 21.336.1 ± 22.20.807
12 Mo23.1 ± 17.6a12.9 ± 16.9a 
Qmax (ml/s)
Baseline5.18 ± 5.684.56 ± 4.750.021
12 Mo2.00 ± 4.01a3.54 ± 8.85 
Volume (ml)
Baseline75.7 ± 97.879.6 ± 95.10.028
12 Mo31.1 ± 61.7a59.2 ± 125.1 
PVR volume (ml)
Baseline137.8 ± 101.6226.3 ± 138.20.232
12 Mo345.8 ± 194.5a378.5 ± 142.1a 
Compliance
Baseline26.9 ± 26.830.6 ± 29.10.140
12 Mo31.8 ± 27.129.0 ± 19.6 

Figure 1 shows the therapeutic results of onabotulinumtoxinA on incontinence and QoL measures including the UDI-6, IIQ-7, and QoL-I scores between baseline and end-point by dosage group. A significant improvement in these measures was noted after repeated onabotulinumtoxinA injections in both dosage groups, and there was no significant difference in the changes between the two groups. The UDI-6 score decreased from 11.4 ± 3.6 to 7.61 ± 3.75 and 10.4 ± 4.13 to 7.43 ± 2.24 in the 200-U and 300-U groups, respectively (all P < 0.001). The IIQ-7 decreased from 13.1 ± 6.38 to 6.71 ± 6.25 and 11.9 ± 5.22 to 5.57 ± 4.97 (all P < 0.001), and the QoL-I decreased from 4.47 ± 1.37 to 2.29 ± 1.49 and 4.00 ± 1.24 to 2.21 ± 1.48 (all P < 0.001) in the 200-U and 300-U dosage groups, respectively. The total incontinence severity score also improved after repeated detrusor onabotulinumtoxinA injections in both 200-U (6.29 ± 2.55 to 3.13 ± 3.24) and 300-U groups (5.09 ± 2.94 to 2.93 ± 2.27) (all P < 0.001). There was no significant difference in the change in incontinence severity between the two groups.

image

Figure 1. Changes in quality of life measures (UDI-6, IIQ-7, QoL-I) and incontinence severity by dosage group after repeated detrusor onabotulinumtoxinA injections. The onabotulinumtoxinA injections were performed at baseline and 6 months later.

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The occurrence of IDC during urodynamic study was 91.7% (64/72 patients) at baseline, including 89.5% (34/38 patients) in the 200-U group and 94.1% (32/34 patients) in the 300-U group, respectively. At the end-point, the incidence of IDC was noted in 89.5% (22/31 patients) of the patients in the 200-U group and 44.1% (15/34 patients) in the 300-U group, respectively. Figure 2 shows the occurrence of IDC at different time-points between two groups. The occurrence of IDC decreased significantly after the second onabotulinumtoxinA injection in the 300-U group compared to the 200-U group (P = 0.001).

image

Figure 2. Occurrence of involuntary detrusor contractions after repeated detrusor onabotulinumtoxinA injections by dosage group.

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During the follow-up period, the changes in GFR from baseline to all time points did not differ significantly within each group or between the two groups. At baseline, the GFR was 94.2 ± 22.1 ml/min and 84.2 ± 19.6 ml/min in 200-U and 300-U groups, respectively. At the end-point, the GFR was 90.5 ± 24.2 ml/min and 88.0 ± 28.2 ml/min in the 200-U and 300-U groups, respectively (Fig. 3). The changes of GFR from baseline to the end-point showed no statistical significance between 300-U group and 200-U group (P = 0.197). If we compared the changes of GFR from baseline to end-point between patients with bladder compliance ≥30 and <30, no significant difference was noted, either in 200-U group or 300-U group.

image

Figure 3. Changes in glomerular filtration rate after repeated detrusor onabotulinumtoxinA injections by dosage group.

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Four patients in the 200-U group and two in 300-U group had increased detrusor tonicity during the filling phase without IDC. The results also showed good response (less incontinence and increased CBC) to onabotulinumtoxinA injections and renal function improved in 4 of them (2 in 200 U and 2 in 300 U group).

We further compared the therapeutic results in both groups of patients with injury durations of more than 10 years or 10 years or less. The urodynamic parameters, QoL measures, incontinence severity, and GFR between the 200-U and 300-U groups did not differ significantly. The complication rate was also evaluated. Urinary tract infection was the most common complication in both dosage groups (34.2% in the 200-U group and 29.4% in the 300-U group). At baseline 13 (34.2%) patients in 200-U and 11(32.3%) patients in 300-U group had AD. Among them, 8 and 6 patients had AD improved and 5 and 5 had AD exacerbated in 200 U and 300 groups, respectively. De novo AD occurred after onabotulinumtoxinA injection in 23.7% of patients (9 in 38) in the 200-U group and 17.6% of patients (6 in 34) in the 300-U group (Table III).

Table III. Adverse Events After Repeated Detrusor OnabotulinumtoxinA (BoNT-A) Injections by Dosage
 200-U BoNT-A (n = 38)300-U BoNT-A (n = 34)P-value
  1. AD, autonomic dysreflexia.

De novo AD9 (23.7%)6 (17.6%)0.369
Difficult urination1 (2.63%)1 (2.94%)0.725
Hematuria7 (18.4%)5 (14.7%)0.581
Urinary tract infection13 (34.2%)10 (29.4%)0.575

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

This study revealed that the incontinence related therapeutic outcomes were comparable between chronic SCI patients receiving repeated 200-U and 300-U detrusor injections of onabotulinumtoxinA. Renal function was maintained at 12 months after the first injection in both groups.

Initially, there was no consensus regarding the optimal dose of onabotulinumtoxinA for treatment of NDO. After several recent large-scale multicenter clinical trials, 200-U of onabotulinumtoxinA is considered an adequate dose to treat NDO in patients with SCI or multiple sclerosis.[24] Nonetheless, only few studies reported changes in renal function after onabotulinumtoxinA injection in SCI patients with NDO.

Three previous studies evaluated the improvement of vesicoureteral reflux and renal pelvis dilatation in patients with NDO after detrusor injection of 300-U of onabotulinumtoxinA[12, 13, 25]; however, the true renal function was not evaluated in detail. We reported previously that the GFR could be maintained, but not improved, after four repeated detrusor injections of 200-U of onabotulinumtoxinA in SCI patients with NDO,[16] suggesting that GFR might not have improved due to insufficient dosing of onabotulinumtoxinA. In the current study, we investigated the renal function change between different doses of repeated onabotulinumtoxinA therapy. The GFR was maintained in the SCI patients after treatment regardless of the dose of onabotulinumtoxinA. The urodynamic parameters improved significantly in both the 200-U and 300-U groups, which implies that although detrusor onabotulinumtoxinA injections kept the bladder in low pressure status and improved clinical symptoms, renal function could only be maintained and perhaps needed more time to recover.

We also found that IDC decreased significantly after the second detrusor injection of 300-U of onabotulinumtoxinA compared to that in the 200-U group. This result implies that the urinary bladder could be more often in high-pressure status in patients receiving 200-U of onabotulinumtoxinA compared to patients receiving 300-U. More detrusor hyperplasia and fibrosis combined with long-term high intravesical pressure status could be the cause of gradual renal function deterioration in patients receiving insufficient doses of onabotulinumtoxinA. Therefore, earlier and repeated detrusor onabotulinumtoxinA injections could be beneficial to SCI patients with upper urinary tract deterioration. The concept of early treatment to prevent renal function deterioration was previously reported.[26]

The reason why detrusor onabotulinumtoxinA injection might only maintain renal function without obvious improvement is that renal function deterioration in SCI patients with bladder dysfunction is multifactorial, including high intravesical pressure and low renal plasma flow.[27-29] Detrusor onabotulinumtoxinA injections help decrease the intravesical pressure, but cannot change the renal plasma flow, therefore, the renal function does not improve after single or repeated detrusor onabotulinumtoxinA injections. However, since renal function deteriorates gradually with age and injury duration in SCI patients using different traditional bladder management methods,[30] repeated detrusor onabotulinumtoxinA injections provide a safe therapeutic modality not only to improve incontinence symptoms but also can preserve renal function.

Another interesting finding was that de novo AD occurred in some SCI patients after detrusor onabotulinumtoxinA injections (23.7% in the 200-U group and 17.6% in 300-U group). In this study, we also found AD might improved or exacerbated after BoNT-A injection, which is comparable with other observation.[31] According to Ginsberg and colleagues, some patients developed AD after detrusor onabotulinumtoxinA injection.[19] It is likely that de novo AD after onabotulinumtoxinA injection is triggered via noxious stimuli due to transient bladder wall inflammation after multiple detrusor injections.

In patients with SCI and NDO, the frequency of urinary incontinence episodes and QoL improved significantly after detrusor onabotulinumtoxinA injection, and there was no significant difference in therapeutic effects between 200-U and 300-U of onabotulinumtoxinA.[17-19] In those studies, retreatment was performed on-demand when the lower urinary tract symptoms relapsed.[18, 19] In our study, we injected onabotulinumtoxinA regularly at 6-month intervals. Although the protocol for onabotulinumtoxinA injection was different from other studies, the results of this study still showed good therapeutic effects. We have previously injected SCI patients and found the improvement of urinary incontinence and QoL assessed by UDI-6 and IIQ-7 show fluctuation with improvement at 3 months but fared less at 6 months.[16] In this study, we attempted to evaluate the serial changes of therapeutic effects and GFR at 3 months and 6 months between two groups in this study. In fact, patients usually enjoy the improvement after BoNT-A injection, but will request for a repeat injection when their symptoms turning bad although the symptoms are still improved compared to the baseline level.

Additionally, according to a European study in 2011,[18] the therapeutic duration seemed to be longer in patients receiving 300-U of onabotulinumtoxinA than 200-U (51.4 weeks with 300-U vs. 49.9 weeks with 200-U). In this study, we found a lower incidence of IDC in the 300-U group than in the 200-U group after the second onabotulinumtoxinA injection, suggesting the therapeutic duration of 300-U of onabotulinumtoxinA might be longer than that of 200-U and a cumulative effect for onabotulinumtoxinA on NDO exists with repeated onabotulinumtoxinA injections.

There are some limitations in this study. Although 99mTc-DTPA renal scanning is a study for accurately evaluating renal function, GFR is best evaluated by measuring the plasma and urinary concentration of creatinine or other metabolites, which is also less expensive and does not involve radiation.[32] These factors may introduce bias into this study. In addition, the short follow-up period also limits renal function improvement with time in low intravesical pressure status after detrusor onabotulinumtoxinA injections. Longer term follow-up of renal function of SCI patients after repeated BoNT-A injections is required. Furthermore, the urodynamic testing every 3 months was designed to investigate the sequential changes of bladder function and renal function specifically designed in this study after onabotulinumtoxinA injections and should not be considered as clinical indication.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES

The incontinence severity, urodynamic parameters, and QoL measures of chronic SCI patients significantly improved regardless of whether 200-U or 300-U of onabotulinumtoxinA was injected. Renal function was maintained in most patients who received repeated detrusor onabotulinumtoxinA injections, without any significant difference between the 200-U and 300-U dosages. Therefore, repeated detrusor injections of 200-U of onabotulinumtoxinA may be beneficial and cost-effective for the chronic SCI patients with NDO. However, a lower incidence of IDC in the 300-U group than in the 200-U group after the second injection, suggesting the therapeutic duration of 300-U of onabotulinumtoxinA might be longer than that of 200-U.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. REFERENCES
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