Diabetic Cystopathy by alphauro


									Diabetic Cystopathy
    Mohamed Shafik, MD
As many as 45% of patients with DM exhibit
diabetic cystopathy
                           Frimodt-Moller, 1976

The prevalence rate of diabetic cystopathy is not
related to the sex and age of the patients.
The prevalence rate increases with the duration of
DM (25% in patients with DM of 10 years’
duration, >50% in patients with DM of 45 years’
duration).                   Frimodt-Moller, 1980
           Effects of Diabetes
          on the Urinary Tract
The classic triad of bladder symptoms
associated with DC includes:
–   decreased bladder sensation,
–   increased bladder capacity, and
–   impaired detrusor contractility with
–   resultant increased postvoid residual (PVR)
Increased PVR leaves the individual prone
to UTIs
           Effects of Diabetes
          on the Urinary Tract
Other complications include:
–   vesicoureteral reflux
–   hydroureteronephrosis (prolonged retention)
–   pyelonephritis
–   nephrolithiasis
–   urosepsis can develop
–   Finally, uremia may develop after continuing
    damages to the kidney function due to diabetic
         Effects of Diabetes
        on the Urinary Tract
The most likely cause of incontinence in the
patient with DC is overflow incontinence,
although the presenting symptoms might
suggest stress or urge urinary incontinence.
Patients with DC also are at increased risk
of detrusor overactivity, but whether this
results from DC alone or cerebral perfusion
issues associated with hypercholesteremia,
transient ischemic attacks, or stroke is not
Pathologic and physiologic studies in
humans as well as in animals revealed that
diabetic cystopathy is induced by
polyneuropathy that predominantly affects
sensory and autonomic nerve fibers
                         (Van Poppel, 1988 )
One of the major mechanisms that induce
diabetic neuropathy is a change in the
availability of neurotrophic factors, such as
nerve growth factor (NGF) that is produced
in target organs
                         (Apfel, 1999)
Several reports demonstrated decreased NGF
levels in various tissues in animals with DM
                              (Schmid, 1999)
A low-affinity NGF receptor, p75NTR, was also
shown to be decreased in patients with DM
                              (Maeda, 1996)
In addition, another neurotrophic factor,
neurotrophin-3 (NT-3), also decreases or increases
in several tissues (skeletal muscle, foot skin, sciatic
nerve, sural nerve, lumbar dorsal root ganglia) in
patients with DM              (Cai, 1999)
Insulin-like growth factor (IGF) was shown to be
altered by DM                 (Bitar, 1998)
        Effects of Diabetes
       on the Urinary Tract
Other possible contributors to diabetic
nerve damage include immune mechanisms,
microvascular insufficiency beside the
deficiency of growth factor.
It even has been suggested that blood
glucose concentration affects the rate at
which aging occurs and that diabetes may
be a syndrome of premature aging.
Age-Related Changes to Urinary
        Tract Function
Lesions in the cortex, such as those caused
by stroke, transient ischemia, or a
dementing illness, affect voluntary control
as a result of damage to the centers for
cerebral control and voiding coordination.
Why it is difficult to circumvent this
Associated pathologies at older age is a common
  Aging dertouser myopathy.
  Aging dertouser neuropathy.
  Cerebral dysfunction.
  Functional disability.
  Noctuornal polyurea.
  Associated medical diseases.
  polypharmacy (diuretics, antipsychotics..etc.)
Assessment of Bladder Dysfunction
History and Symptom Assessment
Because DC is often insidious, the onset may be
difficult to describe precisely.
The classic symptoms of overflow incontinence or
reduced contractility bladder are; weak stream,
hesitancy , dribbling , a sensation of incomplete
emptying, leaking with increased abdominal
pressure, and infrequent voiding.
Some elders present with only urgency and
frequency, others with recurrent UTIs.
Assessment of Bladder Dysfunction
In some cases, it may be recognized as an
infection of urine or a retention after the
development of cystopathy

It is often useful to look for other signs of
peripheral neuropathy; reports revealed
that 75% to 100% of patients with diabetic
peripheral neuropathy develop cystopathy
                         (Buck, 1984)
Assessment of Bladder Dysfunction
The classic type of hypoactive diabetic cystopathy
is sometimes modified by concomitant lesions,
such as bladder outlet obstruction (BOO) or a
history of cerebrovascular disease.
Studies reported a high incidence of detrusor
overactivity, up to 50% or 60%, when bladder
function was examined in a selected population of
diabetic patients who presented with lower
urinary tract symptoms or those with a history of
stroke                            (Kaplan, 1995)
Assessment of Bladder Dysfunction
Despite recent reports of a relatively high
incidence of detrusor overactivity in
symptomatic patients with DM, one should
be aware that autonomic and sensory
neuropathy with diminished bladder
sensation and bladder contractility is the
predominant urological manifestation of
diabetic cystopathy when asymptomatic,
diabetic patients were examined
                        (Ueda, 1997)
Assessment of Bladder Dysfunction
A bladder diary, is also part of the initial
investigation and helps evaluate the amount
and type of fluid ingested and voiding
:Date             Amount/type   Urination      Incontinent episode     ,Activity (eg, coughing      Bowel
Time                 of drink   )in toilet(   )s = small, l = large(      )getting up, walking   movement

         am 7-6

         am 8-7
         am 9-8

        am 10-9

    am 11-10

am-12 pm 11

        pm 1-12

        pm 2-1

        pm 3-2
        pm 4-3

        pm 5-4

        pm 6-5

        pm 7-6

        pm 8-7

        pm 9-8

        pm 10-9

    pm 11-10
 pm-6 am 11
      Physical Examination
Physical examination includes complete
neurologic evaluation with assessment of
anal sphincter tone and saddle anesthesia.

Examination of the rectum assesses stool
presence and consistency and, in men,
prostatic size and shape.
      Physical Examination
In women, a gynecologic examination
assesses pelvic organ prolapse and pelvic
floor muscle tone, estrogenization of the
vaginal tissue, and the presence of Candida
albicans, to which diabetic women are
     Physical Examination
Because DC is a manifestation of autonomic
neuropathy, screening for other signs of
autonomic dysfunction may be included,
particularly heart rate and orthostatic
hypotension assessment measured by blood
pressure while the patient is lying and
Laboratory and Other Investigations
 Microscopic urinalysis (and urine culture, if
 indicated), creatinine, blood urea nitrogen,
 and periodic urine microalbumin.

 Serum glucose and glycosylated
 hemoglobin, which reflects 2 to 3 months of
 glycemic control, also should be obtained.
Laboratory and Other Investigations
 Because one of the hallmarks of DC is an
 increase in residual urine, the PVR should
 be measured.
 Norms for acceptable levels of PVR have
 not been established.
  A suggested normal range in the older
 adult is between 50 mL and 150 mL.
        Urodynamic Studies
Indicated if initial management is not successful or
for patients whose symptoms are mixed, such as
urgency or stress incontinence.
Urodynamic findings common to DC include
impaired sensation, increased bladder capacity,
reduced or absent detrusor contractility, inability
to initiate voiding, and increased PVR.
Detrusor overactivity with reduced contractility,
linked to cerebral lesions for which diabetics are
at increased risk, also may be diagnosed.
        Conflict of UDS and
        Patient`s Symptoms
Because patient symptoms do not always
match actual quantified function,
information from urodynamics can help
develop an appropriate plan of
management, including medications.
To ascertain the relationship between
voiding dysfunction associated with diabetes
and bladder and sphincter behavior.
Urodynamic Findings in Patients
   with Diabetic Cystopathy
These data suggest that classical diabetic
cystopathy is not the most common
urodynamic findings in patients with
diabetes mellitus and voiding dysfunction,
and in fact these patients present with
variable pathophysiological findings.
These findings demonstrate the importance
of urodynamic studies in diagnosing voiding
dysfunction in diabetics before initiation of
Controlling the blood glucose level is the
first step in the management of DM.
The control of blood glucose level, however,
does not mean the prevention of diabetic
The prevalence rate of diabetic cystopathy
in patients on oral hypoglycemic treatment
is 25%
The treatment for diabetic cystopathy is
basically conservative, avoid or eliminate
residual urine.
For asymptomatic patients or those with
moderate signs of cystopathy, the treatment
choices include scheduled time voiding and
possibly drug treatment with cholinergic
receptor agonists.
For severe case, intermittent catheterization
may be added.
Deficient bladder sensation is irreversible in
patients with DM and long-term, follow-up
is necessary.
Advising patients to void every two to four hours
during the day and to use a double voiding
technique may improve bladder emptying,
improve continence, and minimize risk of
 Because DC is gradual in onset, it may be useful
to encourage the diabetic client to begin this habit
even if the PVR is below 150 mL.
 Double voiding involves attempting to empty the
bladder by staying on the toilet and trying to void
more than once with each trip to the toilet.
        Bladder Expression
Bladder expression, either by abdominal straining
(Valsalva maneuver) or manual compression of
the lower abdomen (Credé's maneuver), has been
studied in the spinal cord population but not in
the diabetic population.
 Manual compression is contraindicated in the
presence of increased intravesical (bladder)
pressure, vasal reflux, or vesico-uretero-renal
 Intermittent Catheterization
Intermittent catheterization (IC) is one
approach to achieve bladder emptying in
DC when voiding strategies alone are
Most of the research on IC has involved
patients with spinal cord injury and
children with myelomeningocele.
   Pharmacologic Strategies
No effective medications currently are
available to assist with bladder emptying in
Bethanechol, a parasympathomimetic
agent, has been used with inconsistent
    Pharmacologic Strategies
Research on agents such as aldose reductase
inhibitors, which inhibit the accumulation of
sorbitol and fructose to potentially improve
neuropathy, advanced glycosylation end product,
and neurotrophic factors may lead to future
treatment options.
 Intranasal vasopressin has been used to reduce
nocturnal polyuria, but the safety of this option in
elders is not clear.
Alpha blockers may be helpful in outlet
obstruction from prostatic enlargement.
Future treatment strategies
  Conservative treatments for diabetic cystopathy are limited
  and cannot restore bladder function.
  Recently, several new concepts for treatment of diabetic
  neuropathy occured. The most common is using
  neurotrophic factors.
  NGF restored depletions of calcitonin gene-related peptide
  and substance P in sensory neurons from diabetic mice in
  vitro.                          (Sango, 1994)
  Others demonstrated the restoration of these neuropeptides
  by administration of NGF in diabetic rats in vivo [40,41].
  Pathologically, Unger et al demontrated that NGF
  treatment reversed distinct DM-related alterations in
  myelinated nerve fiber morphology. (Unger, 1998)
In clinical studies (phase 1 and 2) trial of systemic
administration of human recombinant NGF
(rhNGF) was safe and showed significant efficacy
as a treatment for diabetic polyneuropathy; the
phase 3 trial did not demonstrate a significantly
beneficial effect.            (Apfel et al, 2000)

Other studies used neurotrophic factors other
than NGF, such as glial cell line-derived
neurotrophic factor or NT-3, and demonstrated
significant efficacy in the restoration of nerve
functions in diabetic animal.
                             (Akkina et al, 2001)
The feasibility of gene therapy was studied using
replication deficient herpes simplex virus (HSV)
encoding rhNGF genes injected into the bladder
wall in induced diabetic rats.

The decreased NGF levels in bladder and L6 DRG
were restored by the treatment using HSV vectors
encoding rhNGF. Along with the restoration of
tissue NGF levels, NGF gene therapy restored
impaired bladder function by reducing increased
bladder capacity and post-void residual urine
volume in diabetic rats.         (Sasaki et al, 2003)
Diabetic cystopathy refers to the spectrum of
voiding dysfunction in patients with diabetes
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
Therefore, treatment of diabetic cystopathy
should be tailored to the symptom complex
and clinical condition of the patient.
Asymptomatic patients with manifestations of
diabetic cystopathy may be treated with timed
While other modalities such as pharmacologic and
surgical intervention have been described, none
have been consistently effective.
In the future, neurotrophic factors or other
growth factors combined with targeted gene
therapy techniques may be beneficial for the
therapy of patients with diabetic cystopathy.
Thank You

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