Central Nervous System Changes Following BotulinumtoxinA Injection in the Bladder

A Prospective Study of Higher Neural Control Changes Following Intradetrusor Injection of BotulinumtoxinA in Patients With Multiple Sclerosis and Lower Urinary Tract Symptoms.

The purpose of this prospective research study is to evaluate higher neural changes following intradetrusor injection of Botulinum toxin-A (BTX-A) in patients with Multiple Sclerosis (MS). Concurrent Urodynamic and Functional Magnetic Resonance (fMRI) data will be recorded pre- and post- intravesical injection of BTX-A in patients with Multiple Sclerosis (MS) and neurogenic detrusor activity (NDO).

Other objectives are to evaluate the role of urinary biomarkers such as brain-derived neurotropic factor (BDNF) and nerve growth factor (NGF) associated with bladder overactivity and, to determine whether the common validated urgency questionnaires correlate with fMRI findings and urinary biomarker concentration pre- and post- BTX-A injection in patients with MS and NDO.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis; Lower Urinary Tract Symptoms; Urge Incontinence; Neurogenic Bladder; Detrusor, Overactive
• Intervention / Treatment: Drug: Intradetrusor injection of Botulinum Toxin-A

Detailed Description

Multiple Sclerosis is a severe debilitating disease that affects patient's quality of life. Up to 90% of patients with MS will develop lower urinary tract dysfunction within the first 18 years of the disease. Lower urinary tract symptoms (LUTS) can range from urgency to urge urinary incontinence and/or hesitancy and incomplete bladder emptying. Urgency, frequency, and neurogenic detrusor overactivity (NDO) are the most common urologic findings (34-99%) during diagnostic evaluations of patients with MS. Even though anticholinergic or beta agonist drugs have limited effectiveness and adverse side effects, they are the first line pharmacotherapy for patients with NDO if behavioral modifications and pelvic floor physical therapy are unsuccessful. Botulinum toxin-A (BTX-A) intradetrusor injection is a highly effective treatment option for patients with NDO who are refractory to more conservative management. BTX-A blocks the release of acetylcholine at the neuromuscular junction and leads to a temporary chemodenervation of the bladder (paralysis of the muscle). Motor effects of BTX-A on the bladder have been extensively studied and widely reported in the literature, and the US Food and Drug Administration has approved BTX-A for the treatment of detrusor overactivity in neurogenic and non-neurogenic patients. However, the sensory effects of BTX-A injection correlating to central nervous system regional perception/localization of urgency, frequency, and urge incontinence in humans are not well known.

Over the past decades, functional MRI (fMRI) has been used to study the activation of supraspinal lower urinary tract control centers in healthy subjects during the storage and voiding phases. Given these facts, the investigators are interested in evaluating the role of intradetrusor injection of BTX-A in afferent response in patients with MS and NDO. High-resolution neuroimaging techniques will help investigators to further understand how MS affects the bladder-brain controls. This study will use fMRI and task-related blood oxygen level dependent (BOLD) signal to evaluate patients with MS and NDO prior to, and 6-10 weeks after intradetrusor injection of BTX-A with simultaneous urodynamic evaluation.

Clinical correlation between women with these chronic urologic problems and new discoveries at level of CNS activity will give a better understanding of this disorder, leading to the development of more effective diagnostic and treatment modalities.

• Study Type: Observational
• Enrollment (Actual): 28

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Female subjects diagnosed with Multiple Sclerosis and lower urinary tract symptoms who are refractory to conservative management for neurogenic detrusor overactivity.

Description

Inclusion Criteria:

• Patients with clinical diagnosis of neurogenic bladder.
• History of any neurologic illness or injury (including but not limited to spinal cord injury, Multiple Sclerosis, spina bifida, Parkinson's, major spine surgery).
• 18 years or older.
• Female patients.

Exclusion Criteria:

• Male
• History of any incontinence surgery (sling, MMK, Burch).
• History of any lower urinary tract surgery or manipulation (urethral dilation).
• Positive urine pregnancy test at enrollment .

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Pre- BTX-A injection; Female patients with confirmed diagnosis of Multiple Sclerosis referred to our Neurourology clinic with neurogenic lower urinary tract dysfunction prior to receiving intradetrusor injection of Botulinum Toxin-A.
Post- BTX-A injection; Female patients with confirmed diagnosis of Multiple Sclerosis referred to our Neurourology clinic with neurogenic lower urinary tract dysfunction who receive intradetrusor Botulinum Toxin-A.	Drug: Intradetrusor injection of Botulinum Toxin-A; Using cystoscopy, Botulinum Toxin-A is injected into the bladder.; Other Names: OnabotulinumtoxinA, Botox®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Oxygen Level Dependent (BOLD) Signals in brain	During fMRI measurements BOLD signal intensity in regions of interest will be measured at baseline and will be compared to the signals 6 weeks following the injection of BotulinumtoxinA, these signals may be increased or decreased.	2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urodynamic study data	The urodynamic data will be correlated with the functional MRI data. Neurogenic Detrusor Overactivity will be correlated to BOLD signal activation at regions of interest.	2 months

Collaborators and Investigators

• Sponsor: Rose Khavari, M.D.
• Collaborators: The Methodist Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 1, 2014
• Primary Completion (ACTUAL): March 1, 2019
• Study Completion (ACTUAL): March 1, 2019

Study Registration Dates

• First Submitted: July 15, 2016
• First Submitted That Met QC Criteria: January 24, 2017
• First Posted (ESTIMATE): January 26, 2017

Study Record Updates

• Last Update Posted (ACTUAL): March 25, 2020
• Last Update Submitted That Met QC Criteria: March 24, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Neurogenic Bladder, Detrusor Overactivity, Botox, fMRI
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Urologic Diseases; Urinary Bladder Diseases; Urological Manifestations; Neurologic Manifestations; Urination Disorders; Urinary Incontinence; Multiple Sclerosis; Sclerosis; Urinary Bladder, Overactive; Lower Urinary Tract Symptoms; Urinary Bladder, Neurogenic; Urinary Incontinence, Urge; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
• Other Study ID Numbers: Pro00010110

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No