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\begin{document}

\title{Mixed treatment for same-severe Mixed Urinary Incontinence: a novel
method}



\author[1]{Daryoush  Hamidi Alamdari}%
\author[2]{Armina  Douzandeh}%
\author[1]{Maliheh  Keshvari Shirvan}%
\author[3]{Behzad Narouie}%
\author[3]{Negar Radpour}%
\affil[1]{Mashhad University of Medical Sciences Emam Reza Hospital}%
\affil[2]{Victoria University}%
\affil[3]{Shahid Beheshti University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\textbf{Introduction}

International continence society defined mixed urinary incontinence
(MUI) as ``complaint of involuntary loss of urine associated with
urgency and also with effort or physical exertion or on sneezing or
coughing''., which include both urgency urinary incontinence (UUI) and
stress urinary incontinence (SUI) complaints. Urinary incontinence
affects social behaviors, financial burden such as using class of drugs,
rehabilitation floor muscles, and psychological suffering such as
dissatisfaction in sexual activity. Diagnosis of urinary incontinence is
based on history, physical examinations and supplemental evaluations
like dye test, cystoscopy, urodynamic study, urine analysis, urine
culture, and imaging technics. (1)

At the first, conservative treatments are performed for patient such as
biofeedback, pelvic floor muscle exercise, electrical stimulation and
drug treatment. In the second step of treatment, surgery is considered.
The surgery is usually used to address the failure of normal anatomic
support of the bladder neck and proximal urethra, and intrinsic
sphincter deficiency, meanwhile its implementation should be approached
with caution for carefully. In some cases, surgery intervention also
failed and other novel interventions should be considered. (2)

Platelet rich fibrin glue, stem cells, butolonium toxins and TVT
separately applied for treatment of patients, but this is the first time
that these mixed modalities were used for the treatment of mixed urinary
incontinence which did not respond to pharmaceutical and surgical
treatment.

\textbf{Case}

A 56 years old multiparous female was referred to the clinic with
complaint of mixed urinary incontinence for 7 years back. She had 6
normal vaginal delivery and history of disc surgery and Burch
colposuspension. She suffered from nocturia and terminal dribbling. She
had the history of 6 natural vaginal delivery, spinal surgery on L4 and
L5 vertebrae after several years suffering from lumbar discopathy and
she had history of surgery on her gallbladder two years before.
Oxybutynin and vesicare(Solifenacin Succinate) and amitriptiline were
prescribed which no improvement was seen. Pelvic muscle training and
biofeedback method were performed followed by anti-incontinence surgery
Burch Colposuspension for patient three years ago. These treatments had
not any effect on improvement. The patient did not have burning
sensation indicative of urinary tract infection, also no flank or
supra-pubic pain. Voiding diary showed frequent episodes of incontinence
during day and night. In the physical examination, no vaginal prolapse
was detected due to previous Burch Colposuspension. kidney Ultrasound
evaluation was normal. Urodynamic study showed high pressure
intravesical pressure and episodes of urge incontinence and UPP
(Urethral pressure profile) exposed sphincter deficiency.Abdominal leak
point pressure (ALPP) was 62 cm H\textsubscript{2}O. In cystoscopy,
fixed open internal sphincter with normal capacity and moderate
trabeculation in the bladder were exposed.

Informed consent was obtained from patient. At the baseline, 1 and 3
months after intervention, the patient were assessed according to cough
test, pad test, urodynamic study, upper tract ultrasonography (UTU),
uroflowmetry (UFL), post voiding residue (PVR), International
Consultation on Incontinence Questionnaire-Urinary incontinence
(ICIQ-UI), and International Consultation on Incontinence Modular
Questionnaire-Quality of Life (ICIQ-QOL).

For patient, platelet rich plasma-fibrin glue-stem cells injection,
butolonium toxins injection and TVT were applied in one session of
surgery under general anesthesia and lithotomy position which took 64
minutes.

\textbf{Preparation of autologous platelets rich plasma-fibrin glue-stem
cell} :

Sixty milliliters of peripheral blood were taken in 9mL of citrate
phosphate dextrose buffer. PRP: blood was centrifugated at 2000 g for 2
minutes, RBC and plasma was separated and plasma was centrifuged at 4000
g for 8 minutes, and the supernatant plasma was separated and 4mL PRP
was separated. Fibrin glue (cryoprecipitation method): the supernatant
plasma was freeze at -80\selectlanguage{ngerman}°C, thawed and centrifuged at 4000 g for 8
minutes. The supernatant plasma was separated to a final volume of 4 mL.
Stem cell: hydroxyethyl starch was added to RBC and left for 45 minutes
RBC sedimentation. Supernatant was separated, centrifuged 400g about 10
minutes, and supernatant was removed to final 4 ml volume. (3)

\textbf{Platelets rich plasma-fibrin glue-stem cell and botulinum
injection}

In operation room, the patient was under general anesthesia and
lithotomy position. PRP, Fibrin glue and stem cell were mixed (12 ml)
before injection. The transurethral endoscopic injection of PRP-Fibrin
glue-stem cell was carried out by a 21-Fr rigid cystoscope. Under
endoscopic vision, a puncture needle was passed through the cystoscope
into the urethra at the region of the external urethral sphincter and
submucosal injections of PRP-Fibrin glue-stem cell was performed.
Initially, 8 ml was injected at a depth of 5 mm into the
rhabdosphincter. Subsequently, 4 ml was equally injected into the
submucosal spaces at 3 and 9 O'clock positions. Hundred unit of
botulinium toxin was injected via cystoscope into vesical detrusor.

\textbf{Tension free Vaginal Tape}

Sixty milliliters of Citanest-Adrenalin (0.25\%) were injected in the
abdominal skin just above the pubis symphysis and retzius space. After 2
cm long transverse skin incision, 40 ml of 0.25\% Citanest-Adrenalin was
injected into the vaginal wall sub- and paraurethrally. 1.5 cm long
incision in the midline starting approximately 0.5 cm from the outer
urethral meatus in the vaginal wall. Laterally a blunt dissection 1.0 cm
long each side of the urethra. By needle the sling was placed around the
urethra: it was inserted into the prepared paraurethral incision on the
right side of the urethra. The urogenital diaphragm was perforated and
the tip of the needle was brought up to the abdominal incision by
'shaving' the back of the pubic bone. The procedure was then repeated on
the left side. When the sling had been placed in a U shape around the
midurethra, owing to the strong adhesive forces (friction) around the
sling no fixation is necessary. The vaginal incision is then closed. A
folly catheter was inserted. One-gram cephazoline was injected
intravenously.

\textbf{Outcome:}

Results:

No complications were observed after injection. After surgery the
patient had compression device for 24 hours and then she was motivated
to walk gently. Catheter was removed the following day after surgery.
Patient was discharged from hospital while is capable to urinate with
acceptable post void residue. In this surgery, the utmost effort was
done to minims the vaginal bleeding in order to not apply the vaginal
tampon for preventing the damage to stem cells. After 3 month follow up,
patient was completely satisfied and her problem was completely sorted
out. At the baseline, cough test and pad test were positive; UTU, UFL
and PVR were normal; ICIQ-UI and ICIQ-QOL were 21 and 24, respectively.
At 1 and 3 months after intervention, cough test and pad test were
negative; UTU, UFL and PVR were normal; ICIQ-UI and ICIQ-QOL were 0 and
104.

After the recovery, she was observed one day in female urology ward and
next day was discharged with prescription. After 3 months, the
incontinency was completely cured and she had not any urinary
complaints.

\textbf{Discussion:}

A single modality may be inadequate for treatment of MUI and multiple
treatment modalities are required. There is a controversy about the
results of pharmaceutical treatment for MUI and surgical treatment is
associated with significant failure rates. It is mentioned that applying
of anti-incontinence procedures may be effective in treating both the
stress and urge components of MUI. (4)

American urology association (AUA) mentioned ``the success rate of TVT
surgery is between 51\% and 87 \%'' (5). Labire et al (6) expressed that
the pharmacological therapy is less effective in comparison to surgery
after 12 months. Surgery is done for those patients who deny
conservative managements or symptoms have not been improved
inadequately. (1) Kulseng-hanssen et,al (7) mentioned ``the TVT
objective care was 87.3\% after 7 months and 82.7 after 38 months. The
subjective care was 60 \% and 53.8\% after 7 and 38 months''.

Botulinum toxin is a neurotoxin which has been used for various clinical
applications for many years, and inhibits the release of the
neurotransmitter acetylcholine at the presynaptic nerve terminals.
Urologists use it for patients with lower urinary tract symptoms
secondary to idiopathic overactive bladder (OAB) and also after initial
therapeutic modalities have failed to improve symptoms. Intradetrusor
botulinum toxin injection has shown to improve urinary urgency,
frequency, nocturia, and urgency urinary incontinence. In the other
hand, not all patients can achieve excellent therapeutic outcomes which
is leakage associated with a rise in abdominal pressure e.g., due to
cough, sneeze and exercise (8). Phelan et al reported that after
injection, 67\% of patients were able to void smoothly with the PVR
decreased by 71\% and voiding pressure decreased by 38\% (9).

For tissue regeneration of muscles; stem cells, PRP and fibrin glue
strongly collaborate together to create new blood vessels and
capillaries, extracellular matrix through cell proliferation,
chemotaxis, cell differentiation, and angiogenesis. PRP provides the
best concentration of growth factors (transforming growth factor--\selectlanguage{greek}β,
\selectlanguage{english}platelet-derived growth factor, insulin-like growth factor, fibroblast
growth factor, epidermal growth factor, vascular endothelial growth
factor, and endothelial cell growth) and bioactive factors (serotonin,
histamine, dopamine, calcium, and adenosine). These factors lead to
wound healing events by modulating the recruitment, duplication,
activation, and differentiation. FG creates a temporary matrix and
stimulating the local proliferation of fibroblasts, collagen synthesis,
new blood vessels formation and connective tissue (3). The malfunction
old cells will be replenished by stem cells which these young workers
actively collaborate in vascularization and muscle tissue repairmen. In
our previous report, peripheral stem cells and PRP are used for
treatment of SUI. (10)

In this case report, PRP-Fibrin Glue- Stem Cell injection, Botox
injection, and TVT has been used for treatment of MUI. Further research
is need to validate the efficacy of these mixed treatments for
recalcitrant MUI.

\textbf{Conclusion:} Mix treatment of PRP-Fibrin Glue- Stem Cell
injection, Botox injection, and TVT may be a very good approach for
treatment of patients with MUI who have a very open sphincter. Further
research is need to validate the efficacy of these mixed treatments for
recalcitrant MUI.

\textbf{Acknowledgments} : None

\textbf{Disclosure:}

Registry and the registration no: N/A

Approval of the research protocol by an Institutional Reviewer Board:
N/A

All human subjects provided written informed consent with guarantees of
confidentiality.

the authors are employed at an academic or research institution where
research or education is the primary function of the entity.

\textbf{Data Availability:} The data that support the findings of this
study are available from the corresponding author, upon reasonable
request.

\textbf{Conflict of Interest}

The authors declare no competing interest regarding the publication of
this article.

\textbf{Funding statement:} N/A

\textbf{Abbreviation:}

\textbf{(MUI):} mixed urinary incontinence

\textbf{(UUI): urgency} urinary incontinence

\textbf{(SUI):} stress urinary incontinence

\textbf{(UTU):} upper tract ultrasonography

\textbf{(UPP):} Urethral pressure profile

\textbf{(PRP):} Platelets rich plasma

\textbf{(TVT):} Tension free Vaginal Tape

\textbf{(UFL):} uroflowmetry

\textbf{(PVR):} post voiding residue

\textbf{(ICIQ-UI):} International Consultation on Incontinence
Questionnaire-Urinary incontinence \textbf{(ICIQ-QOL):} International
Consultation on Incontinence Modular Questionnaire-Quality of Life

\textbf{Authors' contributions:}

Author 1: Writing - original draft, Conceptualization, Project
administration

Author 2: Conceptualization, Methodology

Author 3: Supervision, Investigation

Author 4: Data curation, Supervision

Author 4: Data curation, Methodology

\textbf{References:}

1. Haylen BT, De Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, et
al. An International Urogynecological Association (IUGA)/International
Continence Society (ICS) joint report on the terminology for female
pelvic floor dysfunction. Neurourology and Urodynamics: Official Journal
of the International Continence Society. 2010;29(1):4-20.

2. McDougal WS, Wein AJ, Kavoussi LR, Partin AW, Peters CA.
Campbell-Walsh Urology 11th Edition Review E-Book: Elsevier Health
Sciences; 2015.

3. Shirvan MK, Alamdar DH, Ghorifi A, Rahimi HR. A novel treatment for
urethrovaginal fistula: autologous platelet-rich--plasma injection and
platelet-rich--fibrin-glue interposition. Journal of Gynecologic
Surgery. 2013;29(5):268-70.

4. Gomelsky A, Dmochowski RR. Treatment of mixed urinary incontinence.
Central European journal of urology. 2011;64(3):120.

5. Committee on Practice B-G, the American Urogynecologic S. ACOG
Practice Bulletin No. 155 Summary: Urinary Incontinence in Women. Obstet
Gynecol. 2015;126(5):1120-2.

6. Labrie J, Berghmans BL, Fischer K, Milani AL, Van Der Wijk I,
Smalbraak DJ, et al. Surgery versus physiotherapy for stress urinary
incontinence. New England Journal of Medicine. 2013;369(12):1124-33.

7. Kulseng-Hanssen S, Husby H, Schi\selectlanguage{ngerman}øtz HA. Follow-up of TVT operations
in 1,113 women with mixed urinary incontinence at 7 and 38 months.
International Urogynecology Journal. 2008;19(3):391-6.

8. Kuo HC. Botulinun A toxin urethral sphincter injection for neurogenic
or nonneurogenic voiding dysfunction. Tzu Chi Medical Journal. 2016 Sep
1;28(3):89-93

9. PHELAN MW, FRANKS M, SOMOGYI GT, YOKOYAMA T, FRASER MO, LAVELLE JP,
YOSHIMURA N, CHANCELLOR MB. Botulinum toxin urethral sphincter injection
to restore bladder emptying in men and women with voiding dysfunction.
The Journal of urology. 2001 Apr;165(4):1107-10.

10. Shirvan MK, Alamdari DH, Mahboub MD, Ghanadi A, Rahimi HR, Seifalian
AM. A novel cell therapy for stress urinary incontinence, short\selectlanguage{english}-term
outcome. Neurourology and urodynamics. 2013 Apr;32(4):377-82.

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