Neuropathic Investigation and Anticholinergic Treatment of Bladder Dysfunction in Diabetes and Stroke Patients
| Status: | Withdrawn |
|---|---|
| Conditions: | Overactive Bladder, Neurology, Urology |
| Therapuetic Areas: | Gastroenterology, Nephrology / Urology, Neurology |
| Healthy: | No |
| Age Range: | 21 - 85 |
| Updated: | 9/13/2018 |
| Start Date: | September 15, 2009 |
| End Date: | January 17, 2014 |
Develop and quantify methods for evaluating bladder dysfunction in diabetes and stroke
1. Specific Aims:
1. To investigate clinical bladder dysfunction in a cohort of 10 diabetic and 10
stroke patients as assessed by a combined neurophysiologic and urologic assessment.
2. To develop and quantify appropriate study methods for evaluating symptomatic and
asymptomatic bladder dysfunction in diabetic and stroke patients.
3. To develop pilot data of medical therapy (Toviaz) in diabetic and stroke bladder
dysfunction.
Evaluation:
Incontinence will be defined as losing bladder control at least once per week or
use of an indwelling catheter to control incontinent episodes.
Incontinence will be measured at baseline and follow-up. Urinary frequency is
defined as urinary voiding greater than 8 times per 24-hour period and/or more than
one voiding per night. Pad count, leakage episodes, and nocturia will be measures
of incontinence. The amount and frequency of voiding, and nocturia will also be
measured. These items will be assessed using the Voiding Diary. Overall patient
satisfaction will be assessed using the Analog Scale of Voiding Satisfaction.
Data collected will include medical history, co-morbidities, sensory and motor
symptoms, Voiding Diary for 3 days (attached), Analog Scale of Urinary Voiding
Satisfaction (attached), pad test, bladder symptoms, medical treatment, and
assessment of activities of daily living. In stroke patients the NIH Stroke Scale
Score and the Modified Rankin Scale will be assessed.
In diabetic patients, hemoglobin A1C levels will be measured and the Dyck grading
scheme for diabetic neuropathy will be assessed (Dyck, 1988).
Stage 0 (no neuropathy) = no symptoms and fewer than 2 abnormalities on testing
(nerve conduction, neurological examination, quantitative nerve testing of muscle
strength, threshold for vibration, cooling or warming sensation, or autonomic
function) Stage 1 (asymptomatic neuropathy) = no symptoms but two or more
abnormalities of functional testing Stage 2 = symptoms of a lesser degree than
stage 3 along with two or more functional abnormalities Stage 3 (disabling
neuropathy) = disabling symptoms and two or more functional abnormalities
Examination data will include sensory testing to include quantitative measures of
sensory dysfunction, motor examination to include manual motor testing, and
autonomic testing including postural blood pressures. Neurophysiologic testing as
outlined below will include nerve conduction velocity testing and somatosensory
evoked potentials of the tibial and median nerves. Urodynamic testing will be
performed as outlined below to include sphincter electromyography, urodynamic
evaluation, and clitoral and anal reflexes.
a) Stroke group: Examination data will include neurological testing of sensory and
motor dysfunction, the NIH Stroke Scale Score, and the Modified Rankin Scale.
Postural blood pressures and frequency of constipation (as a measure of
gastrointestinal motility) will be assessed. Laboratory studies will be obtained
and stroke lesion location and size will be documented. Data collected at follow-up
will include a history of new vascular events, medication use, the NIH Stroke Scale
Score, and the Modified Rankin Scale.
(b) Diabetes group: In the diabetes group, laboratory studies including hemoglobin
A1C will be obtained. Diabetic management will occur with the consultation of the
patient's diabetologist to maximize current diabetic therapy based on ADA
Guidelines and provide consistency during the observation period of the study.
Postural blood pressures and frequency of constipation (as a measure of
gastrointestinal motility) will be assessed. The Dyck grading scheme for diabetic
neuropathy will be assessed (Dyck, 1988).
Stage 0 (no neuropathy) = no symptoms and fewer than 2 abnormalities on testing
(nerve conduction, neurological examination, quantitative nerve testing of muscle
strength, threshold for vibration, cooling or warming sensation, or autonomic
function) Stage 1 (asymptomatic neuropathy) = no symptoms but two or more
abnormalities of functional testing Stage 2 = symptoms of a lesser degree than
stage 3 along with two or more functional abnormalities Stage 3 (disabling
neuropathy) = disabling symptoms and two or more functional abnormalities
(c) Neurophysiology evaluation: Neurophysiologic testing will include Pundendal
nerve terminal motor latency (PNTML), nerve conduction velocity testing, and
somatosensory evoked potentials of the tibial and median nerves, sphincter
electromyography, and clitoral urethral and bladder anal reflexes.
All nerve conduction velocity (NCV) studies will be performed using standardized
methodology with temperature monitored and maintained during the study. Adult norms
will be utilized for all studies except F-waves, which will also be age-and,
height-normalized. Standard stimulation sites will be utilized and distances
measured on the skin surface. All latencies, amplitudes, conduction velocities
measured and waveforms will be stored. Motor nerve conduction (NCV) studies of the
peroneal nerve, posterior tibial nerve, and sural nerve will be obtained
bilaterally. Sural sensory distal latency will be obtained. H-reflex studies will
be performed and F-waves determined for the peroneal and tibial nerves. A
somatosensory evoked potential of the tibial and median nerve will be performed.
Pundendal nerve terminal motor latency will be performed (PNTML). Specific
methodologies are described below. All use of needle electrodes will be preceded by
a localized numbing anesthetic spray.
The urethral anal reflex will be performed using the methodology of Bradley
(Bradley, 1972). The urethra is stimulated using electrodes within a catheter with
recording from patch electrodes placed 1 cm lateral to the anal mucocutaneous
junction at 3, 6, and 9 o'clock with the patient in the lithotomy position. The
stimulus is paired with interstimulus interval of 5ms and stimulus duration of 0.1
ms, using constant current stimulator and recording stimulus level in mA. A
nonrecurrent mode is used for the stimulation. Simultaneous two-channel recording
is performed where channel 1 records electrodes at 3 and 6 positions and channel 2
records at the 9 and 6 positions. Sweep speed is 20 ms and the gain setting is 50
uV. Low-filter setting is 10 Hz and high-filter setting is 10kHz. The sensory
threshold is measured in mA and stimulation is performed starting at 2x threshold.
Responses are superimposed and latency measured as the most consistent response.
Normal values are sensory threshold mean 3.4 mA, with SD of 1.76 (cutoff 8 mA),
latency 63 ms, SD 9.4 (cut off 82 ms).
The bladder anal reflex is performed with the same catheter electrode advanced into
the bladder. Impedence testing is performed to assure bladder wall contact with the
electrode on the catheter; an impedence of less than 10 kilo Ohm is sought.
Recording electrodes and stimulation is performed as with the urethral anal reflex
above. The normal values for this reflex are: mean sensory threshold 15.9 mA, SD
10.9 (cutoff 37 mA), and latency 64 ms, SD 13.4 (cut off 95 ms). Responses with
latencies greater than 100 ms are assumed to be voluntary, not reflex. The clitoral
reflex test will be accomplished similarly to the urethral and bladder reflex test.
However, a two-pronged surface electrode will be used rather than the electrode
catheter.
Peroneal and sural nerve testing are used to test the lower extremity motor nerve.
In both of these tests, recording and stimulating electrodes are place in specified
areas of the foot, knee, and calf.
Pudendal Nerve Terminal Motor latency (PNTML) will be performed using a St Mark's
electrode. The vaginal approach to the pudendal nerve will be utilized. Both right
and left pudendal nerves will be tested. Stimulation is performed starting at 2x
threshold.
(d) Urodynamic Evaluation: Patients will present with a full bladder and proceed
with a uroflow study; 8-fr catheter will then be placed and postvoid residual will
be performed leaving the catheter for the filling phase cystometrogram. Flow of
water will be at 50 ml/min with a standard 4-channel recording plus surface
electromyogram performed at 150/300 cc. When maximum bladder capacity has been
reached (or 1000 cc), the voiding phase will begin with the patient moved to a
potty chair. Surface electrodes (patches applied to the perineum) will be utilized
to record pelvic floor electromyographic activity during voiding. Needle
electromyography of the urethral sphincter is performed using needle electrodes
inserted after spray anesthetic is applied before the procedure. Filter settings
are LFF 10 Hz and HFF 10 kHz; sweep speed 10 ms/div; gain 50 UV/div. Insertional
activity, spontaneous activity, recruitment and motor unit potential morphology is
recorded.
Treatment: After urological and neurological evaluation, those patients who meet
the U.S. approved indications for prescribing will be placed on a regimen of Toviaz
4 mg/day taken once daily with liquids and swallowed whole. The Toviaz dose may be
increased to 8 mg/day if there is not a therapeutic response on the 4mg/day. While
we recognize the need for a placebo group in future studies, that is not
appropriate with the number of patients and goals of this pilot study. Patients
will be monitored for side effects of therapy throughout the study observation
period. Drug treatment failure will lead to standard treatment options (Royal
College, 2002). Patients will complete a short weekly log rating incontinence,
complaints and medication compliance.
Follow-Up Contacts and Visits: At 1, 3, and 6 months, the patient will return to
the clinic for review of a 3-day voiding diary, Incontinence Questionnaire (form
has already been approved by the IRB), and a pad test. The pad test will consist of
the patient collecting pads used for urine leakage for 12 hours the day before her
clinic appointment. The pads will be stored in an air-tight plastic bag and given
to the nurse coordinator at the patient's clinic visit. These pads will be weighed
and this data recorded for comparison at each clinic visit. The log forms will be
collected monthly either by mail or at the clinic visit. Patients will be contacted
by phone on alternate months by the nurse coordinator to verify demographic
information, current medications, complaints and response to the drug treatment.
Patients will continue to be followed by their specialty physicians (Neurologists
and Diabetologists) during the follow-up period.
1. To investigate clinical bladder dysfunction in a cohort of 10 diabetic and 10
stroke patients as assessed by a combined neurophysiologic and urologic assessment.
2. To develop and quantify appropriate study methods for evaluating symptomatic and
asymptomatic bladder dysfunction in diabetic and stroke patients.
3. To develop pilot data of medical therapy (Toviaz) in diabetic and stroke bladder
dysfunction.
Evaluation:
Incontinence will be defined as losing bladder control at least once per week or
use of an indwelling catheter to control incontinent episodes.
Incontinence will be measured at baseline and follow-up. Urinary frequency is
defined as urinary voiding greater than 8 times per 24-hour period and/or more than
one voiding per night. Pad count, leakage episodes, and nocturia will be measures
of incontinence. The amount and frequency of voiding, and nocturia will also be
measured. These items will be assessed using the Voiding Diary. Overall patient
satisfaction will be assessed using the Analog Scale of Voiding Satisfaction.
Data collected will include medical history, co-morbidities, sensory and motor
symptoms, Voiding Diary for 3 days (attached), Analog Scale of Urinary Voiding
Satisfaction (attached), pad test, bladder symptoms, medical treatment, and
assessment of activities of daily living. In stroke patients the NIH Stroke Scale
Score and the Modified Rankin Scale will be assessed.
In diabetic patients, hemoglobin A1C levels will be measured and the Dyck grading
scheme for diabetic neuropathy will be assessed (Dyck, 1988).
Stage 0 (no neuropathy) = no symptoms and fewer than 2 abnormalities on testing
(nerve conduction, neurological examination, quantitative nerve testing of muscle
strength, threshold for vibration, cooling or warming sensation, or autonomic
function) Stage 1 (asymptomatic neuropathy) = no symptoms but two or more
abnormalities of functional testing Stage 2 = symptoms of a lesser degree than
stage 3 along with two or more functional abnormalities Stage 3 (disabling
neuropathy) = disabling symptoms and two or more functional abnormalities
Examination data will include sensory testing to include quantitative measures of
sensory dysfunction, motor examination to include manual motor testing, and
autonomic testing including postural blood pressures. Neurophysiologic testing as
outlined below will include nerve conduction velocity testing and somatosensory
evoked potentials of the tibial and median nerves. Urodynamic testing will be
performed as outlined below to include sphincter electromyography, urodynamic
evaluation, and clitoral and anal reflexes.
a) Stroke group: Examination data will include neurological testing of sensory and
motor dysfunction, the NIH Stroke Scale Score, and the Modified Rankin Scale.
Postural blood pressures and frequency of constipation (as a measure of
gastrointestinal motility) will be assessed. Laboratory studies will be obtained
and stroke lesion location and size will be documented. Data collected at follow-up
will include a history of new vascular events, medication use, the NIH Stroke Scale
Score, and the Modified Rankin Scale.
(b) Diabetes group: In the diabetes group, laboratory studies including hemoglobin
A1C will be obtained. Diabetic management will occur with the consultation of the
patient's diabetologist to maximize current diabetic therapy based on ADA
Guidelines and provide consistency during the observation period of the study.
Postural blood pressures and frequency of constipation (as a measure of
gastrointestinal motility) will be assessed. The Dyck grading scheme for diabetic
neuropathy will be assessed (Dyck, 1988).
Stage 0 (no neuropathy) = no symptoms and fewer than 2 abnormalities on testing
(nerve conduction, neurological examination, quantitative nerve testing of muscle
strength, threshold for vibration, cooling or warming sensation, or autonomic
function) Stage 1 (asymptomatic neuropathy) = no symptoms but two or more
abnormalities of functional testing Stage 2 = symptoms of a lesser degree than
stage 3 along with two or more functional abnormalities Stage 3 (disabling
neuropathy) = disabling symptoms and two or more functional abnormalities
(c) Neurophysiology evaluation: Neurophysiologic testing will include Pundendal
nerve terminal motor latency (PNTML), nerve conduction velocity testing, and
somatosensory evoked potentials of the tibial and median nerves, sphincter
electromyography, and clitoral urethral and bladder anal reflexes.
All nerve conduction velocity (NCV) studies will be performed using standardized
methodology with temperature monitored and maintained during the study. Adult norms
will be utilized for all studies except F-waves, which will also be age-and,
height-normalized. Standard stimulation sites will be utilized and distances
measured on the skin surface. All latencies, amplitudes, conduction velocities
measured and waveforms will be stored. Motor nerve conduction (NCV) studies of the
peroneal nerve, posterior tibial nerve, and sural nerve will be obtained
bilaterally. Sural sensory distal latency will be obtained. H-reflex studies will
be performed and F-waves determined for the peroneal and tibial nerves. A
somatosensory evoked potential of the tibial and median nerve will be performed.
Pundendal nerve terminal motor latency will be performed (PNTML). Specific
methodologies are described below. All use of needle electrodes will be preceded by
a localized numbing anesthetic spray.
The urethral anal reflex will be performed using the methodology of Bradley
(Bradley, 1972). The urethra is stimulated using electrodes within a catheter with
recording from patch electrodes placed 1 cm lateral to the anal mucocutaneous
junction at 3, 6, and 9 o'clock with the patient in the lithotomy position. The
stimulus is paired with interstimulus interval of 5ms and stimulus duration of 0.1
ms, using constant current stimulator and recording stimulus level in mA. A
nonrecurrent mode is used for the stimulation. Simultaneous two-channel recording
is performed where channel 1 records electrodes at 3 and 6 positions and channel 2
records at the 9 and 6 positions. Sweep speed is 20 ms and the gain setting is 50
uV. Low-filter setting is 10 Hz and high-filter setting is 10kHz. The sensory
threshold is measured in mA and stimulation is performed starting at 2x threshold.
Responses are superimposed and latency measured as the most consistent response.
Normal values are sensory threshold mean 3.4 mA, with SD of 1.76 (cutoff 8 mA),
latency 63 ms, SD 9.4 (cut off 82 ms).
The bladder anal reflex is performed with the same catheter electrode advanced into
the bladder. Impedence testing is performed to assure bladder wall contact with the
electrode on the catheter; an impedence of less than 10 kilo Ohm is sought.
Recording electrodes and stimulation is performed as with the urethral anal reflex
above. The normal values for this reflex are: mean sensory threshold 15.9 mA, SD
10.9 (cutoff 37 mA), and latency 64 ms, SD 13.4 (cut off 95 ms). Responses with
latencies greater than 100 ms are assumed to be voluntary, not reflex. The clitoral
reflex test will be accomplished similarly to the urethral and bladder reflex test.
However, a two-pronged surface electrode will be used rather than the electrode
catheter.
Peroneal and sural nerve testing are used to test the lower extremity motor nerve.
In both of these tests, recording and stimulating electrodes are place in specified
areas of the foot, knee, and calf.
Pudendal Nerve Terminal Motor latency (PNTML) will be performed using a St Mark's
electrode. The vaginal approach to the pudendal nerve will be utilized. Both right
and left pudendal nerves will be tested. Stimulation is performed starting at 2x
threshold.
(d) Urodynamic Evaluation: Patients will present with a full bladder and proceed
with a uroflow study; 8-fr catheter will then be placed and postvoid residual will
be performed leaving the catheter for the filling phase cystometrogram. Flow of
water will be at 50 ml/min with a standard 4-channel recording plus surface
electromyogram performed at 150/300 cc. When maximum bladder capacity has been
reached (or 1000 cc), the voiding phase will begin with the patient moved to a
potty chair. Surface electrodes (patches applied to the perineum) will be utilized
to record pelvic floor electromyographic activity during voiding. Needle
electromyography of the urethral sphincter is performed using needle electrodes
inserted after spray anesthetic is applied before the procedure. Filter settings
are LFF 10 Hz and HFF 10 kHz; sweep speed 10 ms/div; gain 50 UV/div. Insertional
activity, spontaneous activity, recruitment and motor unit potential morphology is
recorded.
Treatment: After urological and neurological evaluation, those patients who meet
the U.S. approved indications for prescribing will be placed on a regimen of Toviaz
4 mg/day taken once daily with liquids and swallowed whole. The Toviaz dose may be
increased to 8 mg/day if there is not a therapeutic response on the 4mg/day. While
we recognize the need for a placebo group in future studies, that is not
appropriate with the number of patients and goals of this pilot study. Patients
will be monitored for side effects of therapy throughout the study observation
period. Drug treatment failure will lead to standard treatment options (Royal
College, 2002). Patients will complete a short weekly log rating incontinence,
complaints and medication compliance.
Follow-Up Contacts and Visits: At 1, 3, and 6 months, the patient will return to
the clinic for review of a 3-day voiding diary, Incontinence Questionnaire (form
has already been approved by the IRB), and a pad test. The pad test will consist of
the patient collecting pads used for urine leakage for 12 hours the day before her
clinic appointment. The pads will be stored in an air-tight plastic bag and given
to the nurse coordinator at the patient's clinic visit. These pads will be weighed
and this data recorded for comparison at each clinic visit. The log forms will be
collected monthly either by mail or at the clinic visit. Patients will be contacted
by phone on alternate months by the nurse coordinator to verify demographic
information, current medications, complaints and response to the drug treatment.
Patients will continue to be followed by their specialty physicians (Neurologists
and Diabetologists) during the follow-up period.
Inclusion Criteria:
Stroke Population:
- Ischemic or hemorrhagic stroke in the anterior or posterior circulation within the
past month in persons 21 years of age and over
- NIH Stroke Scale Score of 4 or greater one month post-stroke
- Modified Rankin Scale of 2 or greater
- Patients with motor or verbal impairment with surrogacy consent
Inclusion Criteria:
Diabetic Population:
- Clinically stable diabetes type 2 females 21 years of age or older
- Peripheral neuropathy associated with diabetes Dyck stage 2 or 3
- Clinical evaluation by neurologist reveals no other likely cause of neuropathy
Exclusion Criteria:
Stroke Population:
- Men
- Patients with cardiac pacemaker or other indwelling device that would preclude
neurophysiologic testing;
- Patients with an indwelling urinary catheter that cannot be removed
- Patients who are on warfarin or similar anticoagulants that cannot be stopped for the
study procedures
- Patients with a poor prognosis due to stroke or underlying illness who, it is
anticipated, would be unable to participate for the period of the study
- Females with current pregnancy, multiparity >/=4, prior pelvic floor dysfunction, or
pelvic floor tumor. Women with incontinence prior to stroke, cystocele, rectocele, or
urethral stricture
- Patients unable to tolerate Detrol LA; such patients would include those with
significant renal or hepatic disease, those currently taking drugs metabolized by the
cytochrome P450 enzyme system that might confound interpretation of responses (
Delaviridine, indinavir, nelfinavir, ritonavir, amiodarone, aprepitant, cimetidine,
ciprofloxacin, clarithromycin, diltiazem, erythromycin, fluconazole, fluvoxamine,
grapefruit juice, itraconazole, ketoconazole, mifepristone, nefazodone, norfloxacin,
verapamil, efavirenz, nevirapine, carbamazepine, phenobarbital, phenyltoin, rifampin,
St. John's wort, troglitazone, oxcarbazepine, pioglitazone, rifabutin); those with
urinary retention, gastric retention, uncontrolled narrow angel glaucoma, or those
with a known sensitivity to the drug or its ingredients
- Patients who have a history of diabetes
- Pregnancy or actively seeking pregnancy
- Patients who are cognitively impaired
Diabetes Population:
Exclusion Criteria:
- Men
- Patients with cardiac pacemaker or other indwelling device that would preclude
neurophysiologic testing;
- Patients with an indwelling urinary catheter that cannot be removed
- Patients who are on warfarin or similar anticoagulants that cannot be stopped for the
study procedures
- Patients with a poor prognosis due to underlying illness who, it is anticipated, would
be unable to participate for the period of the study
- Females with current pregnancy, multiparity >/=4, prior pelvic floor dysfunction,
pelvic floor tumor, cystocele, rectocele, or urethral stricture
- Patients unable to tolerate Detrol LA; such patients would include those with
significant renal or hepatic disease, those currently taking drugs metabolized by the
cytochrome P450 enzyme system that might confound interpretation of responses (
Delaviridine, indinavir, nelfinavir, ritonavir, amiodarone, aprepitant, cimetidine,
ciprofloxacin, clarithromycin, diltiazem, erythromycin, fluconazole, fluvoxamine,
grapefruit juice, itraconazole, ketoconazole, mifepristone, nefazodone, norfloxacin,
verapamil, efavirenz, nevirapine, carbamazepine, phenobarbital, phenyltoin, rifampin,
St. John's wort, troglitazone, oxcarbazepine, pioglitazone, rifabutin); those with
urinary retention, gastric retention, uncontrolled narrow angel glaucoma, or those
with a known sensitivity to the drug or its ingredients
- Pregnancy or actively seeking pregnancy
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