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DIABETIC CYSTOPATHY METABOLIC BLADDER

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DIABETIC CYSTOPATHY    METABOLIC BLADDER Powered By Docstoc
					 DIABETIC CYSTOPATHY /
  METABOLIC BLADDER




DR. ISMAIL OSMAN ABDELHAFEEZ
       PROFESSOR OF UROLOGY
  NEUROUROLOGY & UROGYNAECOLOGY
       AIN SHAMS UNIVERSITY
           CAIRO , EGYPT
                                  1
                   Ann Intern Med. 1980 Feb;92(2 Pt 2):318-21.
             Diabetic cystopathy: epidemiology and related disorders.
                                Frimodt-Moller C




•   The incidence and prevalence of diabetic cystopathy (DCP) are difficult to
    determine because of the insidious onset, discrete symptoms.
•   DCP was shown to occur in 43% to 87% of insulin-dependent diabetics, with no
    sex or age differences. 25% of patients on oral hypoglycemic treatment.
•   In diabetics for 10 years, the prevalence of DCP in those who were insulin-
    dependent was 2-4 / 1000 and in those on oral hypoglycemic agents was 1-3/1000.
•   The correlation between DCP and peripheral neuropathy ranged from 75% to
    100%.
•   Nephropathy was seen in 30% to 40% of cases.
•   The higher frequency of UTI in diabetics is not related to DCP but to the frequent
    occurrence of NNBO disorders, especially in older women.


                                                                                         2
                       Ann Intern Med. 1980 Feb;92(2 Pt 2):327-8.
                          Treatment of diabetic cystopathy.
                                   Frimodt-Moller C,



•    NBD in diabetic patients result in insufficient bladder emptying because of loss of
     reflex detrusor contraction.
•    In asymptomatic pts, or have moderate signs of DCP, ttt choices are:
1.   Scheduled voiding by the triple-voiding technique,
2.   Cholinergic treatment either daily or twice weekly, and
3.   Transurethral surgery of the bladder neck.
•    In patients with total urine retention:
1.   Indwelling catheter to decrease the overstretched detrusor muscle,
2.   Cholinergic treatment with initially high parenteral doses of bethanecol may help to
     diminish residual urine,
3.   Transurethral surgery is often mandatory in such cases.
•    Deficient bladder sensation is irreversible in diabetics, and follow-up of treatment
     should be lifelong
                                                                                        3
                Schweiz Med Wochenschr. 1984 Mar 24;114(12):394-9.
                   Urinary tract infection in the diabetic patient
                                    Zimmerli W




•   Diabetic patients are prone to infections.
•   Studies of host defense mechanisms report defects in individual granulocyte
    functions and cell mediated immunity, especially in patients with poorly controlled
    diabetes.
•   Diabetic females have an increased risk of developing urinary tract infections, due
    to local risk factors such as DCP and vaginitis, the latter being frequently associated
    with glucosuria.
•    UTI in diabetic individuals often have a complicated course explained by
    compromised host defense mechanisms.
•   Diabetics have an increased risk not only of lower, but also of upper UTI.
•   UTIs such as emphysematous cystitis and pyelonephritis, as well as papillary
    necrosis as a complication of pyelonephritis, are not uncommon in diabetic patients.
•   Rapid recognition and management of such complicated urinary tract infections is
    important.
                                                                                         4
                    Minerva Med. 1984 Apr 21;75(17):967-74.
     Diabetic neuropathy. III: Autonomic neuropathy. Genito-urinary system
                                    Gentile S




•   Urogenital complications due to diabetic autonomous neurotherapy , have a
    considerable effect on QOL.
•   They are also responsible for severe complications as DCP.
•   This evolves inevitably towards bladder denervation, chronic urinary retention and
    more or less severe septic complications.
•   Retrograde ejaculation and neurogenic ED in diabetics.
•   These situations occur quite frequently, especially in older subjects who have
    suffered from diabetes for more than ten years.
•   Only a diligent examination of signs and symptoms with the aim of early diagnosis
    and the maintenance of good glycometabolic balance are considered to be at all
    effective as preventive measures.


                                                                                         5
                             Eur Urol. 1988;15(1-2):128-31.
    Diabetic cystopathy: neuropathological examination of urinary bladder biopsies.
                                     Van Poppel H,
    Department of Urology, University Clinics, Catholic University of Leuven, Belgium.




•     Neuropathological examination of bladder biopsies was done on 14 patients with
      severe insulin-dependent adult-onset diabetes and compared with the
      acetylcholinesterase and S100 staining of 38 control specimens.
•     A decrease in acetylcholinesterase activity, due to axonal degeneration was found
      in all cases.
•     An increase in S100 positivity was found in the majority and is due to Schwann cell
      proliferation as a regeneration attempt after demyelination or axonal degeneration.
•      When acetylcholinesterase activity decreases and an S100 density increase is found
      in a patient with diabetes, this combination is highly suggestive of thorough DCP
      amenable to early symptomatic treatment.


                                                                                         6
                     J Diabet Complications. 1988 Jul-Sep;2(3):133-9.
                                  Diabetic cystopathy.
                                 Kaplan SA, Blaivas JG.
                  Department of Urology, Columbia University, New York.




•   Diabetic cystopathy refers to the spectrum of voiding dysfunction in patients with
    diabetes mellitus.
•   Diabetic cystopathy is marked by insidious onset and progression with minimal
    symptomology.
•   The most common urodynamic findings are impairment of bladder sensation,
    increased post-void residual volume, decreased detrusor contractility that may
    progress to detrusor areflexia and diminished urinary flow.
•   Treatment of diabetic cystopathy may be complicated by frequently occurring
    coexisting urologic conditions.
•   The most common of these is bladder outlet obstruction.
•   Therefore, treatment of diabetic cystopathy should be tailored to the symptom
    complex and clinical condition of the patient.

                                                                                         7
                               J Urol. 1995 Feb;153(2):352-3.
                  Urodynamic findings in patients with diabetic cystopathy.
                                  Kaplan SA, Blaivas JG.
                   Department of Urology, Columbia University, New York.




•    To ascertain the relationship between voiding dysfunction associated with diabetes and
     bladder and sphincter behavior, the video urodynamic studies of 182 patients were
     retrospectively analyzed.
•    Patients were classified :
1.   on urodynamic diagnosis and
2.   the presence or absence of signs of sacral cord involvement.
•    Urodynamic Results:
1.   100 (55%) had detrusor hyperreflexia,
2.   42 (23%) had impaired detrusor contractility,
3.   20 (11%) had indeterminate findings,
4.   19 (10%) had detrusor areflexia and
5.   1 (1%) was normal.
•    BOO occurred in 66 patients (36%).
•    In the presence of sacral cord signs (42 patients), the most common urodynamic diagnoses
     were either impaired detrusor contractility in 21 (50%) or detrusor areflexia in 10 (24%).
•    These data suggest that classical DCP is not the most common urodynamic findings in
     patients with diabetes mellitus and voiding dysfunction.
                                                                                                  8
                  J Diabetes Complications. 1997 Nov-Dec;11(6):350-1.
     DCP presenting as 1ry AUR in a previously undiagnosed young male diabetic pt.
                                     Walmsley BH.
        Department of Urology, St. Mary's Hospital, Portsmouth, United Kingdom.




•   Lower GU problems are part of the polyneuropathy of diabetes.
•   DCP affects 40%-85% of diabetic pts, although less than 1/2 are symptomatic.
•   We report on a 42-year-old patient who was not known to be diabetic, and who
    presented to the urologists with 1ry acute urinary retention.
•   His underlaying disease was detected by a test for RBS.
•   More common causes were excluded with careful clinical and radiological
    examinations.
•   He was managed with insulin and self-catheterization.
•   Diabetes should be considered as a differential diagnosis in relatively young men
    who present with unexplained acute urinary retention.


                                                                                        9
                                  J Urol. 1999 Aug;162(2):558-66.
    Alterations in the NOS binding sites and non-adrenergic, non-cholinergic mediated smooth
         muscle relaxation in the diabetic rabbit bladder outlet: possible relevance to the
                                       pathogenesis of DCP
                                            Mumtaz FH,
                      Department of Urology, Royal Free Hospital, London, UK.




•     To investigate the effect of DM on the density and distribution of nitric oxide synthase (NOS)
      and the smooth muscle responses to non-adrenergic, non-cholinergic (NANC) nerve
      stimulation and exogenous nitric oxide (NO) in the rabbit LUT.
•     Transverse sections of detrusor, bladder neck and urethra, from control and six months
      alloxan-induced DM New Zealand White rabbits. Responses to NANC nerve stimulation on
      smooth muscle strips from detrusor, bladder neck and urethra were measured in organ baths.
•     NOS binding sites were significantly (p<0.03) more dense in the bladder neck than in the
      detrusor in both DM and control groups.
•     In DM bladder neck, NOS binding sites were significantly (p<0.04) increased compared with
      the controls.
•     NANC nerve-mediated relaxations were significantly impaired (p<0.001) in the DM urethral
      smooth muscle.
•     Alterations of both the NOS binding sites and functional responses to NANC nerve
      stimulation suggest that NO may have a pathophysiological role in the urinary bladder
      dysfunction associated with DM.
                                                                                                  10
                            Scand J Urol Nephrol. 1999 Dec;33(6):392-5.
    Effect of insulin therapy for DCP:urodynamic and histological findings in a rabbit model.
                                             Ayan S,
            Department of Urology, Faculty of Medicine, Cumhuriyet University, Turkey.




•     To investigate the efficacy of insulin therapy in preventing cystopathic changes in
      diabetes using Twenty-four New Zealand white rabbits in 3 groups: 8 in each
      group (control, alloxan induced diabeteswithout therapy, alloxan induced diabetes
      with insulin therapy).
•     Urodynamic investigations were carried out in three groups at the end of 8 weeks.
      Tissue sections prepared from all groups were studied histologically.

•     This animal model indicates that insulin therapy can prevent or delay urodynamic
      and histopathological changes in diabetes mellitus.



                                                                                            11
                     Zhonghua Wai Ke Za Zhi. 2000 Nov;38(11):865-7.
    Changes in bladder compliance and detrusor contraction/relaxation of diabetic rats
                                         Gong Y,
     Urological Center, Southwesten Hospital, Third Millitary Medical University, China.




•   Experimental study on the mechanism of diabetic cystopathy (DCP).
•   The bladder compliance and contraction/relaxation of whole bladder/detrusor strips
    were evaluated in vitro on diabetic rats.
•   Significant decrease of detrusor contraction/relaxation and increase of bladder
    compliance were observed (P < 0.01).




                                                                                           12
                            Pharmacology. 2002;64(3):148-51.
   Alteration of M(3) subtype muscarinic receptors in the diabetic rat urinary bladder.
                                         Tong YC,
Department of Urology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.



•   The M(3) receptor (M(3)-mAChR) is the major muscarinic subtype in the animal bladder
    responsible for detrusor contraction.
•   3-month-old male Wistar rats were divided into two groups: (1) 2-week diabetic rats and (2)
    normoglycemic control rats.
•   Diabetes was induced by a single intravenous injection of 60 mg/kg streptozotocin.
•   The amount of M(3) receptor protein in the rat bladder body tissue was measured by Western
    immunoblotting using monoclonal antibodies.
•   For determination of M(3) muscarinic receptor mRNA in the bladder tissue, the method of
    Northern blotting was employed.
•   The results of the Western immunoblotting showed that the amount of M(3)-mAChR protein
    in the diabetic bladder was significantly increased by about 70% when compared to the
    control bladder (p < 0.05, n = 8).
•   Northern blotting demonstrated a 55% increase of M(3)-mAChR mRNA in the diabetic
    bladder (p < 0.05, n = 8).
•   The findings of the present study demonstrated an upregulation of M(3)-mAChR
    biosynthesis in the diabetic urinary bladder.
•   This phenomenon offers an explanation of the increased contractility after muscarinic
    stimulation of the detrusor muscle of diabetic animals.
                                                                                             13
                               J Urol. 2002 Sep;168(3):1259-64.
    DC correlates with a long-term decrease in NGF levels in the bladder and lumbosacral
                                     dorsal root Ganglia.
                                        Chancellor MB,
        Dep of Urology and Pharmacology, University of Pittsburgh Pennsylvania, USA.



•  It has been proposed that a deficiency in the axonal transport of nerve growth factor
   (NGF) may have an important role in inducing diabetic neuropathy, which
   contributes to DC.
• In streptozotocin induced diabetic rats, the relationship of bladder function with
   NGF levels in the bladder and lumbosacral dorsal root ganglia, which contain
   afferent neurons innervating the bladder was investigated.
• At 6 and 12 weeks after the induction of diabetes:
1. The effects of diabetes on A-delta afferent fiber dependent, conscious voiding were
   evaluated by metabolic cage measurements and awake cystometry.
2. The effects of diabetes on C-fiber mediated bladder nociceptive responses were
   investigated by cystometry with intravesical instillation of 0.25% acetic acid in the
   rats under urethane anesthesia.
3. NGF levels in the bladder and L6 to S1 dorsal root ganglia were measured by
   enzyme-linked immunosorbent assay 3, 6, 9 and 12 weeks after streptozotocin
   injection.                                                                          14
                              J Urol. 2002 Sep;168(3):1259-64.
DC correlates with a long-term decrease in NGF levels in the bladder and lumbosacral dorsal
                                        root Ganglia.
                                       Chancellor MB,
       Dep of Urology and Pharmacology, University of Pittsburgh Pennsylvania, USA.



•   NGF levels in the bladder and L6 to S1 dorsal root ganglia were significantly
    decreased 12 weeks after streptozotocin injection (p <0.01).
•   Bladder capacity and post-void residual volume were significantly increased 12
    weeks after streptozotocin injection (p <0.01).
•   Bladder nociceptive responses revealed by a reduction in inter-contraction
    intervals after acetic acid infusion were significantly decreased in a time dependent
    manner 12 weeks after streptozotocin injection.
•   Rats with streptozotocin induced diabetes mellitus showed a significant time
    dependent decrease in NGF levels in the bladder and L6 to S1 dorsal root ganglia
    that was associated with voiding dysfunction attributable to defects in A-delta
    and C-fiber bladder afferents.
•   Therefore, reduced production of NGF in the bladder and/or impaired transport of
    NGF to L6 to S1 dorsal root ganglia, which contain bladder afferent neurons, may
    be an important mechanism inducing DC.                                              15
                           Urologe A. 2003 Dec;42(12):1556-63.
           Diabetes mellitus and bladder function. What should be considered?
                                       Thuroff JW.
                Urologische Klinik, Johannes-Gutenberg-Universitat, Mainz.




•  The prevalence of DCP (impaired bladder sensation, increased bladder capacity,
   sometimes accompanied by voiding difficulties and residual urine) is:
1. 25% in non-insulin-dependent diabetics and
2. 48% in insulin-dependent diabetics.

•   Autonomic and peripheral neuropathy lead to detrusor hyposensitivity, and chronic
    overstretching of the bladder causes myogenic detrusor hypocontractility.




                                                                                    16
                              Neurourol Urodyn. 2006;25(1):32-8.
        A combined urodynamic and electrophysiological study of diabetic cystopathy.
                                          Karandreas N,
    Dep of Physical and Rehabilitation Medicine, National Rehabilitation Center, Athens, Greece.



•    This prospective study compared UDS and electrophysiological studies in the diagnosis of
     diabetic cystopathy.
•    It included 26 patients with DM diagnosed at least since 5 years; 17 pts with DM type II and
     9 pts with type I.
•    2 groups in respect to LUTS and signs suggestive of LUTD according to the ICS
     standardization.
•    Pts with LUTS/LUTD were included in Group A and pts without LUTS/LUTD in Group B.
•    Pts underwent different studies: urodynamic, somatosensory evoked potentials (SSEP) of
     tibial and pudendal nerves, bulbocavernosus reflex (BCR), bulbocavernosus muscles EMG
     and motor evoked potentials after transcranial magnetic stimulation to indirectly investigate
     bladder's innervation.
•    Abnormal UDS found in 13 pts of group A (93%) and in 5 of group B (47%). This difference
     was statistically significant (P=0.009).
•    Abnormally prolonged latency of P40 of tibial SSEP was found in 11 pts of group A (79%)
     and in 4 of group B (33%) and this difference was also statistically significant (P=0.04).
•    Differences between the two groups concerning: i) peripheral polyneuropathy, ii) pudendal
     SSEP, iii) dysfunction of central nervous system and iv) abnormal BCR were not statistically
     significant.
•    The study of tibial SSEP is an easily performed test and it is well correlated to abnormal
     urodynamics in diabetic patients with and without LUTD/LUTS.                                  17
    Changes in cholinergic and purinergic neurotransmission in the diabetic rabbit bladder.
                                In Vivo. 2006 Jan-Feb;20(1):1-4.
                                          Mumtaz FH, .
    Department of Urology, Royal Free Hospital and University College Medical School, London.




•     DM associated alterations in bladder function have been attributed to changes in
      autonomic receptors and alterations in detrusor structure and function.
•     The changes in cholinergic and purinergic neurotransmission in the DM alloxan
      induced rabbit bladder were evaluated.
•     At 6 months, detrusor and bladder neck muscle strips were obtained and mounted in
      organ baths. Transmural electrical field stimulation (EFS) compared with those
      from controls.
•     A plot of EFS vs. detrusor contractility showed a decrease in the cholinergic
      nerve-mediated component (ANOVA < 0.001), whereas the purinergic nerve-
      mediated component was increased in the DM detrusor (ANOVA < 0.001)
      compared to the control.
•     Results suggest that an enhancement of purinergic and a reduction of cholinergic
      neurotransmission occur in the detrusor muscle of the diabetic rabbit. These
      changes may contribute to the pathophysiology of diabetic cystopathy.
                                                                                            18
    Mechanisms of Disease: the role of NGF in the pathophysiology of bladder disorders.
                     Nat Clin Pract Urol. 2006 Feb;3(2):101-10. Review
                                         Steers WD,
    Department of Urology, University of Virginia School of Medicine, Charlottesville, USA.




•   Remodeling of the micturition pathways occurs following experimental BOO,
    denervation, spinal cord injury, cystitis, and DM.
•    Clinically, NGF levels are elevated in the bladders of men with BPH, women with
    interstitial cystitis and in pts with idiopathic OAB.
•   Blockade of NGF, using either an endogenous antibody or an antibody against the
    NGF receptor, prevents neural plasticity and bladder overactivity in experimental
    models of these conditions.
•   The ability of NGF to trigger bladder overactivity might rely on altering the
    properties of sodium or potassium channels (or their expression) in bladder afferent
    fibers.
•    Therapies based on altered NGF levels, or changes in channel properties in afferent
    nerves, represent an intriguing avenue of investigation for the management of DO
    or DCP.
                                                                                              19
      Time dependent changes in diabetic cystopathy in rats include compensated and
                           decompensated bladder function.
                              J Urol. 2006 Jul;176(1):380-6.
                                       Daneshgari F
                    Cleveland Clinic Foundation, Cleveland, OH USA.




•   Time dependent changes in bladder function investigated in streptozotocin
    induced diabetic rats.
•   CMG and detrusor muscle contractility were examined in control and diabetic
    S-D rats 3, 6, 9, 12 and 20 weeks after diabetes induction.
•   Diabetes decreased average body weight and increased bladder weight,
    capacity and compliance.
•   Pdet leak pressure increased gradually from weeks 3 to 6 to 9 in diabetic rats and
    in controls.
•   At 12 and 20 weeks diabetic rats deviated strongly from this trend with Pdet leak
    pressure decreasing vs controls and PV resting pressures increasing from
    9-week levels vs controls (p <0.0001).
•   Diabetic bladders may undergo a transition from a compensated to a
    decompensated state begining 9 to 12 weeks after induction.
                                                                                      20
              Overactive bladder in diabetes: A peripheral or central mechanism?
                                 Neurourol Urodyn. 2007 Mar 13
                                          Yamaguchi C,
    Central Laboratory Unit, Department of Molecular Diagnosis, Chiba University, Chiba, Japan.



•     A study of DCP with reference to OAB.
•     Retrospective analysis of DC in 2300 case records, data from LUTS questionnaire,
      UDS, and data from neurological examinations.
•     DCP was seen in 4% of cases (84 cases): 58 males, 26 females; mean age, 60.8
      years; duration of diabetes, 143.5 months.
•     DO 55%, and  bladder sensation 14%.
•     The frequency of DO in patients with increased bladder sensation was 58%.
•     DO increased with age, but not with the duration of diabetes.
•     A brain MRI was performed in 32 cases. The frequency of multiple cerebral
      infarction (MCI) in patients with DO was 76.5%.
•     OAB commonly occurs in DCP. Both central and peripheral mechanisms are
      involved, e.g., MCI due to diabetic cerebral vasculopathy for the DO, and, to a
      lesser extent, peripheral nerve irritation for the DO and  bladder sensation.

                                                                                              21
      THANK YOU




                                          22
Urology Department Ain Shams University

				
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