Q: What are the other focal and multifocal neuropathies that can
happen as a complication of long standing diabetes?
Q: Describe the etiopathogensis, treatment options and outcome
of "charcoat neuroarthropathy"?
Ans:
Etiopathogensis:
Charcot Arthropathy occurs due to many conditions
including diabetes mellitus, leprosy, syphilis, poliomyelitis,
chronic alcoholism or syringomyelia.
In this repetitive microtrauma exceeds the rate of healing
and results fractures and dislocations. Changes in
circulation cause resorption of bone, weakening the bone
and increasing susceptibility to fracture and dislocation.
According to Shelly A. M. Larson and Patrick R. Burns
(2012) sensory and autonomic neuropathy are
prerequisite to begin the process of uncontrolled
inflammation through proinflammatory cytokines TNFalpha and interleukins, unchecked activation of RANKL,
and the resulting imbalance of osteoclasts and
osteoblasts.
Treatment Options
Non-Surgical
protective splint, walking bra
or cast.
Surgical
open reduction and internal
fusion in early stages
realignment osteotomy and
(correction of deformity) or o
(removal of bony prominenc
cause an ulcer ) in later sta
Recovery and outcome
Healing usually takes several months.
Condition may recur or flare up.
Impairment with this condition is permanent as bilateral
involvement is common.
Patients has to limit standing and walking to that required
for activities of daily living (ADL) as they have to use
protective footwear and orthoses.
Lifelong follow-up is required with a specialist.
The Charcot foot
Charcot neuropathic osteoarthropathy (CN) is a rare
complication of neuropathy that only affects a limited amount of
people who are genetically prone to inflammation. It is a selflimiting condition that causes degeneration of the foot and ankle
joints due to a loss of nerve supply (Kaynak et al., 2013).
The main underlying contributor to CN is inflammation.
Pro-inflammatory cytokines activates osteoclast (breaking
down of bone) activity which leads to excessive bone
turnover. In the presence of sensory loss (diabetic
neuropathy), pain is not felt during minor trauma which
leads to further trauma. Exaggerated inflammation
responses in predisposed individuals lead to increased
osteolysis. An increase in blood flow to the affected areas
is also implicated in the pathophysiology. There is thus
intact vascular functionality which explains the bigger
incidence of the Charcot foot observed in younger people
(Kaynak et al., 2013).
The presentation of CN is a unilateral, red, hot, swollen
and usually painless foot following minor injury or
inflammation. Advanced CN may present with mid-foot
collapse (rocker-bottom deformity). It might be more
prevalent in type 1 diabetes. Diabetes, osteopenia and
overweight are predisposing factors. Although CN mostly
affect only one foot, bilateral CN were observed in about
9% of cases (Kaynak et al., 2013)(Rogers et al., 2011).
Increased morbidity is associated with acute DN, even
after successful treatment, mainly due to the presence of
distal symmetrical neuropahty.
CN is difficult to diagnose and diagnosis include medical
history and clinical examination, X-rays, magnetic
resonance imaging (MRI) and bone scintigraphy (Gouveri
& Papanas, 2011).
Pathogenesis:
◦ Pro-inflammatory cytokines triggers the Receptor
Activator of Nuclear Factor-κB (RANK) pathway.
Activation of the RANK system leads to increased
osteoclast precursor cells and increased osteoclasts.
◦ Depletion of neuropeptides such as Substance P (SP)
and Calcitonin Gene-Related Peptide (CGRP) in
unmyelinated sensory neurons may lead to increased
osteolysis.
◦ Nitric oxide (NO) at low concentrations might increase
bone resorption and inhibits resorption at higher
concentrations.
◦ Hyperglycaemia is associated with triggering the RANK
system and advanced glycation end-products (AGE)
related modifications of collagen, a structural
component of bone (Kaynak et al., 2013).
Treatment options:
Non-surgical: Off-loading (of weight) by total contact cast
(TCC). After swelling of the foot is controlled, Charcot
Restraint Orthotic Walker (CROW), a removable TCC, can be
used.
Pharmacological treatment includes bisphosphonates,
calcitonin, NSAIDS and cortisones. The use of TNF-α
antagonists (infliximab, etanercept) and RANK-L
antagonists (denosumab) are also proposed.
Non-surgical treatment should be followed up by surgical
treatment (removing of bones involved in ulcer formation,
Achilles tendon lengthening or bracing of deformities) and
as last resort, amputation (Gouveri & Papanas, 2011).
Other types of focal and multifocal neuropathies
Focal and multifocal diabetic neuropathies include the
following types:
◦ · Cranial neuropathy
◦ · Truncal neuropathy
◦ · Limp neuropathy
Cranial neuropathies in diabetic patients are extremely
rare (0.05%) and occur in older population with longer
duration of diabetes (Watanabe 1990).
Oculomotor nerve palsy is the most commonly seen type
of cranial neuropathy in diabetic patients ( Said et al
2007). The third and sixth cranial nerves are the most
frequently affected. In all cases of diabetic
ophthalmoplegia it occurs in patients over 50 years of age
in both types. The onset is very rapid within few days.
According to Green et al. (1964) pain occurs before the
onset of diplopia in 14 out of 25 patients. Pain is usually
chronic behind or above the eye and always homolateral
to the oculomotor palsy.
Truncal radiculoneuropathy is usually seen in middle to
elderly aged patients with prevalence in men. Pain is the
most common symptom in a girdle-like pattern over the
lower thoracic or abdominal wall. The distribution can be
uni or bilateral. Resolves within 4-6 months (Vinik et al
2015).
Proximal neuropathy of the lower limp (PDN) is
characterized by the different degree of pain and sensory
loss associated with proximal muscle weakness and
atrophy (Said et al 2007). Also occurs in patients over 50
years old.
Multifocal diabetic neuropathy is characterized by
continuous involvement from weeks to months of roots
and nerves of the lower limps, the trunk and the upper
extremities (Said et al 2007).
Focal limp neuropathies are usually due to entrapment
Feature
Onset
Pattern
Nerves involved
Natural history
Treatment
Distribution
Mononeuropathy
Sudden
Single nerve but maybe multiple
Entrapment syndrome
Gradual
Single nerve exposed to trauma
CN III, VI, VII, ulnar, median,
peroneal
Resolves spontaneously
Symptomatic
Median, ulnar, peroneal, medial
and lateral plantar
Progressive
Rest, splints, local steroids,
diuretics, surgery
Area supplied by the nerve
Area supplied beyond the site of
entrapment
Polyneuropathy
Gradual
Distal symmentrical p
neuropathy
Mixed, Motor, Senso
Autonomic
Progressive
Tight Glycemic cont
Pregabalin, Duloxeti
Antioxidants
Distal and symmetrical.
and stocking distribut
and should be distinguished from mononeuropathies and
distal symmetrical polyneuropathies as seen in Table 1,
adapted from Vinik et al (2004).
The focal and multifocal neuropathies occur relatively infrequently
and affect only a minority of patients with diabetes. However, they
form a major clinical problem in terms of diagnosis and treatment
due to development of significant symptoms and signs prior to
identification and frequent inadequate therapy. Diagnosis requires
accurate and detailed clinical history and neurologic examination
combined with targeted neurophysiologic tests.
Focal and multifocal diabetic neuropathies include:
•
Cranial neuropathy
•
•
Truncal neuropathy and
Limb neuropathy
Cranial neuropathy:
Frequency of involvement of the different cranial nerves – The
third and sixth cranial nerves are the most commonly affected.
Oculomotor nerve palsies are the most common among the cranial
neuropathies.
In almost all cases, diabetic ophthalmoplegia occurs in patients
older than 50 years of age, both in type 1 and type 2 diabetes.
Pain is often attributed to the involvement of the first and second
divisions of the trigeminal nerve within the cavernous sinus, or to
the activation of pain-sensitive endings within the third nerve
sheath while it traverses the cavernous sinus. Pain usually subside
following the onset of diplopia.
Truncal neuropathy:
It is predominantly unilateral. The onset is abrupt or rapid. Pains or
dysesthesias are the main features. The pain may have a spinal
root distribution and is worsened by contact and nocturnally.
Weakness of abdominal muscles may occur. Rarely, isolated
involvement of peripheral nerve of the limbs may occur. Nerve
entrapment may be present.
Limb Neuropathy:
- Proximal Diabetic Neuropathy (PDN) of the lower limbs:
It occurs in diabetic patients usually over the age of 50. Proximal
diabetic neuropathy of the lower limbs is characterized by a
variable degree of pain and sensory loss associated with proximal
muscle weakness and atrophy. This syndrome has been reported
under various terms as follows:
•
•
•
•
•
•
Diabetic myelopathy
Diabetic amyotrophy
Femoral neuropathy
Proximal diabetic neuropathy
Femoral - sciatic neuropathy
Bruns - Garland syndrome
The neurological involvement is limited to the lower limbs and is
usually asymmetrical and unilateral. Clinically, the different
patterns and the course of PDN differ strikingly from length
dependent diabetic polyneuropathy.
The syndrome progresses over weeks or months in most cases,
then stabilises and spontaneous pains decreases. In
approximately one third of the patients there is a definite sensory
loss over the anterior aspect of the thigh. Painful contact
dysesthesia in the distribution of the cutaneous branches of the
femoral nerve may occur, without definite sensory loss. In most
cases the patient’s condition improves after months, but sequelae
in the form of disabling weakness, amyotrophy, sensory loss and
patellar areflexia are common.
- Multifocal diabetic neuropathy:
It is characterized by successive or simultaneous involvement of
roots and nerves of the lower limbs, the trunk and the upper
extremities. It occurs over weeks or months. Distal lower limbs are
involved in all patients, either unilaterally or bilaterally, with an
asynchronous onset in most cases. Additional proximal deficit of
the lower limbs may occur. Thoracic radiculo-neuropathy may be
present bilaterally or unilaterally.
Investigations:
•
CSF protein is increased.
•
Electrophysiological tests reveal axonal pattern,
which is often multifocal.
•
Nerve biopsy shows inflammation, vasculopathy and
axon loss.
Treatment of diabetic focal and multifocal neuropathies:
Proximal diabetic neuropathy is often very painful and often pains
resist to conventional treatments. Treatment with corticosteroids
can be considered in such cases, for a few weeks or months, with
adjustment of diabetic control. All patients with proximal diabetic
neuropathy does not need treatment since spontaneous recovery
occurs in most. However, when multifocal nerve lesions occur,
treatment with corticosteroids is mandatory. Responses to high
doses intravenous immunoglobulins are variable. However,
treatment with corticosteroid yields good response.
Diabetic Charcot foot (Neuropathic osteoarthropathy)
It is a progressive, degenerative condition that affects the
joints of the feet.
The diabetic Charcot foot syndrome is a serious and
potentially limb-threatening lower-extremity complication
of diabetes. Charcot foot is characterised by varying
degrees of bone and joint disorganisation secondary to
underlying neuropathy, trauma, and perturbations of bone
metabolism, (Roger, LC. et al.).
Charcot foot is a break or dislocation of the bones of the
foot usually from minor injury because of weaker bones in
patients with diabetes, (Diabetes Foot Protection Team,
Hull and East Yorkshire Hospitals NHS Trust, 2012).
The patient may not experience pain, therefore may not
realise presence of problem with the foot leading to late
presentation with severe deformity, foot ulcers, disability
and amputation.
Usually the affected limb is inflamed and hotter than the
unaffected side. Xray of the foot will show extent of
damage.
Treatment is in 3 phases- active phase: starts as soon as
problem is known by immobilising with a plaster cast or
walking brace and kept non-weight-bearing for up to 3
months as the case may be; healing phase: partial
weight bearing is allowed, limb still in plaster cast or
walking brace, from the 4th to the 8th month of
commencement of treatment and the rehabilitation
phase: full weight bearing as pain allows and using
special insoles and shoes that support the foot and allow
for any changes that have occurred in the shape of the
foot. If there is severe deformity, surgical intervention,
which may include amputation, might be required.
Good glycemic control, checking the feet daily for damage
or injury and good foot care will prevent development of
Charcot foot.
Diabetic Autonomic Neuropathy (DAN) is one of the poorly
understood and last recognized complication of diabetes
which has a significant negative impact on survival and
quality of life in diabetes. Let's discuss DAN in detail
a) Etiopathogenesis
b) Clinical manifestations
[Please discuss Cardiovascular Autonomic Neuropathy (CAN)
in detail]
c) Clinical assessment of Autonomic dysfunctions (relevant clinical
tests)
d) Investigations designed to diagnose individual autonomic
dysfunctions
e) Management of specific conditions relating to autonomic
dysfunctions (say postural hypotension, gastroparesis, erectile
dysfunction etc etc.......)
Erectile Dysfunction in Diabetes
This is a very common complication of diabetes and is,
unfortunately, often missed by health care providers (HCP) since
we do not enquire about sexual function (Kalter-Leibovici et al.
2005). It is strongly associated with depression, and impairs the
quality of life (QoL) of our patients.
Epidemiology:
Sexual dysfunction consists of erectile dysfunction (ED),
decreased libido and abnormal ejaculation. ED is the most
common form of sexual dysfunction in men. It has an overall
prevalence in the general population of 16%, and is age related.
8% of men aged 20 to 30 years and 37% of men aged 70 to 75
years, suffer from ED (Cunningham and Rosen 2016). In patients
with diabetes, there is an increase in prevalence and severity with
age. The figures quoted are 6% in men aged 20 to 24 years, and
52% in the age group 55 to 59 years (McCulloch 2015).
Etio-pathogenesis:
Normal sexual function requires interactions between vascular,
neuronal, hormonal and psychological systems. The primary event
is a vascular phenomenon, triggered by neurological signals, in the
presence of intact hormonal signaling, particularly testosterone,
and psychological mindset (Cunningham and Rosen
2016). Erectile dysfunction (ED) may be the result of local nerve
damage, impaired blood flow to the penis, psychological factors or,
as in the majority of cases, a combination of these.
Stimuli such as visual, auditory, imaginary, central or penile tactile
stimuli, are modified by psychological factors (libido), and activate
neural pathways. The autonomic pathways required for an erection
are an increase in parasympathetic activity and a decrease in
sympathetic activity, leading to an increase in blood flow into the
corpus cavernosum and a relaxation of the smooth muscle.
The first vascular requirement for an erection is an adequate
arterial inflow to provide intracavernosal oxygen and nitric oxide
(NO) synthase to generate NO. NO plays an important role in the
vasodilatation needed to erect the penis, and 5-cyclic GMP
phosphodiesterase enzymes inactivate NO synthase. Patients with
diabetes are known to have a suboptimal NO synthase activity,
and the process is also impaired in the presence of arteriosclerotic
changes to the micro vasculature (Cunningham and Rosen 2016).
The risk factors associated with Ed in patients with diabetes are
disease duration of diabetes, glycemic control, diuretic therapy,
and the presence of micro vascular complications or
cardiovascular (CVS) compromise (McCulloch 2015).
Clinical evaluation:
It is important to enquire about sexual function regularly. In a
patient with diabetes who admits to ED, other causes should be
excluded and the diagnosis should be confirmed prior to treatment.
This is done by obtaining a thorough medical and psychological
history, a complete clinical examination as well as special
investigations where indicated. The sexual history aids in
understanding the underlying sexual dysfunction and psychological
issues, and should ideally be supported by a validated score or
questionnaire. The differential causes for the complaint of ED are
drugs, vascular disease, endocrine dysfunction, depression, and
alcohol consumption. Patients should be examined to identify
signs of other micro vascular complications such as retinopathy
and neuropathy, peripheral vascular disease, hypertension,
hypogonadism and gynecomastia.
Specifically look for:
· Hypertension (HPT)
· Peripheral pulses
· Femoral pulses and the presence of a femoral bruits indicating
a possible vascular occlusion
· Lack or loss of normal male hair patterns, gynecomastia, and
small testes.
· Penile deformities
· Prostate examination
· Evaluation of the cremasteric reflex, elicited by stroking the
inner thighs and looking for contraction of the scrotum
and elevation of the testis – this is the normal
cremasteric reflex.
· Visual field defects, which could indicate the presence of
pituitary tumors.
Laboratory investigations include the following (Cunningham and
Khera 2015):
·
·
·
·
·
·
·
HbA1c
Lipid profile, if not done within the past 12
FBC, UKE and LFT’s if not recently evaluated
Microalbuminuria spot testing to assess diabetic nephropathy
Thyroid-stimulating hormone (TSH) to rule out thyroid disease
Serum total testosterone to assess gonadal function
Serum prolactin only required when serum testosterone is low.
Other special investigations:
Some patients with ED require further evaluation and should be
referred for a penile duplex Doppler / ultrasound to assess arterial
insufficiency or venous problems. This is also indicated following
penile trauma, priapism, Peyronie’s disease and in patients who do
not respond to treatment with phosphodiesterase-5 (PDE5)
inhibitors and other medications (Cunningham and Khera 2015).
Patients who are candidates for surgical intervention of ED may
require additional tests of peripheral or autonomic nerve function
(McCulloch 2015).
ED and CVS risks: ED and CVS disease share many risk factors,
and patients with ED have an increased risk for CVS events.
Cardiovascular risk factors should be assessed to determine
whether the patient requires a special evaluation for coronary heart
disease. It is recommended that all patients with diabetes and ED
be risk stratified according to the history and clinical examination.
Several risk score models are available such as the Framingham
score, ATIII score and others, and the choice of risk calculator
should be individualized according to patient characteristics. The
Framingham score is often used and has been shown to be
accurate in Caucasian and black individuals (Douglas 2015). Highrisk patients should undergo a cardiologist evaluation prior to
commencing ED treatment. Intermediate risk patients should have
a stress ECG, and if abnormal, be referred for a cardiology
evaluation for coronary heart disease prior to treatment for ED.
Low risk patients may be treated without further evaluation
(Cunningham and Khera 2015).
Management of ED:
Several treatment options are available. Intensive glycemic control
reduces the development of ED but cannot reverse or improve it
once it has developed (McCulloch 2015).
Psychosexual counseling should be performed in all patients with
ED as it underscores the patient’s understanding of the stimuli
required to achieve a normal successful erection. Patients with
diabetes often require additional treatment but the counseling
aspect is important to clarify realistic expectations.
Phosphodiesterase inhibitors (PDE-5) are considered the first-line
treatment for patients with ED. They act by prolonging the
vasodilatory effect of NO to initiate and maintain en erection
(McCulloch 2015). Their efficacy in patients with diabetes and ED
was assessed in a meta-analysis including 8 trials and close to
1000 participants (Vardi and Nini 2007). The weighted mean
difference in successful attempts between the treatment group and
the placebo group was 26,7% (95% CI 23,1 to 30,3%) and the
overall risk ratio for any adverse event was 4,8 (CI 95% 3.74 to
6.16) in the treatment group in comparison to the control group.
The PDE-5 inhibitors cause side effects that are related to their
vasodilatory properties and include headache, dizziness, flushing,
upper respiratory system congestion and abnormal vision. These
side effects are rare and non-serious in patients not taking
concomitant nitrates (McCulloch 2015). Patients should be
informed about the associated risk of concomitant use of PDE-5
inhibitors with nitrates, specifically in the event of their developing
acute chest pain or coronary symptoms. It is imperative that
patients understand this risk and communicate their use of PDE-5
inhibitors to medical personnel attending to them in an emergency.
PDE-5 inhibitors on the market include sildenafil, vardenafil,
tadalafil, and avanafil. They differ in their onset of action and
duration and the choice of specific agent should be made in
collaboration with the patient.
Other treatment options include the following, and are provided by
specialist urologists and sexual dysfunction centers:
· Testosterone supplementation
· Intraurethral alprostadil
· Intracavernosal injections of vasoactive drugs
· Other therapies include vacuum devices, constricting bands,
penile revascularization and penile prosthesis.
The management priorities are firstly PDE-5 inhibitors, secondly
penile self-injectable drugs, intracavernosal alprostadil and
vacuum devices. Third line treatment would be surgery in patients
who do not respond to the recommended treatments.
Diabetic Autonomic Neuropathy (DAN) is associated with
increased risk of cardiovascular mortality. Its prevalence widely
varies depending on the cohort studied and assessment methods,
Vinik et (2003). DAN frequently coexists with other peripheral
neuropathies , but can present in isolation. DAN effects are wide
spread due to longer nerves of the autonomic nervous system
being affected first. DAN may present with clinically evident
features or may be subclinical. The effects on many
organ systems, presents with specific clinical manifestations as
shown in table 1 below:
Table 1: Clinical Manifestations of DAN ( Adapted from: Vinik et al
2003)
Affected Area or organ Disturbances or Clinical Manifestation
system
Gastrointestinal tract
Cardiovascular System
Genito-urinary system
Sudomotor
Oesophageal enteropathy
Gatroparesis
Diarrhoea
Constipation
Faecal incontinence
Resting tachycardia
Exercise intolarence
Orthostatic hypotension
Silent myocardial ischaemia
Erectile dysfunction
Retrograde ejaculation
Bladder dysfunction
Female sexual dysfunction
Anhidrosis due to disruption of microvascular blood flow, impaire
Pupillary
Heat intolerance due to impared thermoregulation
Gustatory sweating
Dry skin
Impairement of pupillomotor function (Decreased diameter of da
pupil)
Argyl-Robertson pupil (constrict to near object but do not react to
Pathogenesis of DAN
According to Lincoln et al (2008), there are many theories on the
pathogenesis of DAN. Hyperglycaemia induced metabolic changes
affect the blood supply of the nerves and other trophic changes of
the nerve support structures.
Oxidative stress due to increased intracellular glucose activates
the polyol pathway and a cascade of events, as stated by (Lincoln
and Shotton, 2008) ; (Vinik et al., 2003) :
◦ Increased production of the reactive oxygen species (ROS).
◦ Accumulation of harmful advanced glycation
products(AGEs)
◦ Activation of Protein Kinase-C stimulates multiple pathways
resulting in vasoconstriction and reduces endoneural
blood flow.
◦ Reduction of neurothrophic growth factors
◦ Deficiency of essential fatty acids
The multifactorial causes of DAN makes treatment difficult and
complex. Different management strategies are employed to target
the various pathogenic pathways.
Diabetic Autonomic Neuropathy (DAN) is one of the poorly
understood and last recognized complication of diabetes which
has a significant negative impact on survival and quality of life in
diabetes. Let's discuss DAN in detail
Diabetic autonomic neuropathy (DAN) represents one of
the least understood complications of diabetes, with a significant
negative impact on survival and quality of life for the diabetic
patient (Vinik et al., 2003). The neuropathologic hallmark of
DAN involves damage to autonomic nerves in the course of
diabetes mellitus in the absence of significant neuron loss. The
damage of autonomic nerves is characterized by axonal and
dendritic pathology in sympathetic ganglia (Schmidt, 2002). The
estimated rates of DAN reach up to 50% of patients with type 1
or type 2 diabetes (Lincoln and Shotton, 2008).
Etiopathogenesis
The development of DAN has been linked with different
pathogenetic mechanisms including:
a) Metabolic changes induced by hyperglycemia
b) Diabetes-induced deficits in the blood supply to nerves
c) Impaired nerve regeneration following a continuous insult
d) Deficient neurotrophic support and
e) Schwann cell abnormalities.
The degree of glycemic control has been regarded as the
most important risk factor for the development of neuropathy,
following the results of the Diabetes control and complications
study (DCCT, 1993). Other changes secondary to an insufficient
glycemic control involve alterations of the vascular system
leading to microangiopathy, adverse effects on Schwann cells
impairing thus tropic support and direct effects on the neuronal
axons. In addition, neurotrophic factors protect the peripheral
nervous system against the negative impact of glycemia and
improve nerve regeneration (Lincoln and Shotton, 2008).
In pathogenetical terms, hyperglycemia may induce
neuropathy in diabetic patients, by promoting oxidative stress
(Lincoln and Shotton, 2008). As depicted in the attached figure,
high intracellular levels of glucose can undergo autoxidation, or
may lead to the activation of aldose reductase and to the
formation of advanced glycation endproducts, which together
with osmotic stress may induce depletion of antioxidants. The
presence of oxidative stress can result to mitochondrial
dysfunction, with the mitochondria producing more reactive
oxygen species in response, leading to a vicious cycle.
Hyperglycemia favors also directly mitochondrial production of
reactive oxygen species, by enhancing flux of NADH through
the electron transport chain and decreasing expression of
uncoupling proteins.
All the neurotrophins, like brain-derived neurotrophic
factor, neurotrophin-3 and -4 as well as nerve growth factor
have been related with a protective impact in diabetes (Lincoln
and Shotton, 2008). Accumulating evidence has shown that
insulin, c-peptide and IGF-1 increase neuronal survival and
neurite outgrowth irrespectively from the presence of
hyperglycemia, as presented from in vivo and in vivo studies.
Moreover, circulating IGF-1 reverses sympathetic neuroaxonal
dystrophy in diabetic rats.
Apart from the above described mechanisms, available evidence
describes differential responses of subpopulations of
sympathetic and myenteric neurons to diabetes (Lincoln and
Shotton, 2008). Characteristic neuropathic changes involve loss
of neurotransmitter in the nerve terminals, swelling of the
varicosities and dystrophy as well as accumulation of
neurotransmitters within the neuronal cell body. However, the
susceptibility any subpopulation of autonomic neurons to the
impact of diabetes is not always expressed via the same
mechanism, while the impact of diabetes on autonomic neurons
is related with the type of expressed neurotransmitter.
Orthostatic hypotension
Orthostatic or postural hypotension (OH) is an inadequate
response to postural changes in blood pressure. In
patients with this condition changing position from sitting
to standing results in sudden drop of blood pressure which
results in light-headedness, dizziness, blurred vision and
syncope (NICE 2015).
Reasons for orthostatic hypotension besides diabetic
autonomic neuropathy can be other disorders that affect
autonomic nervous system as Parkinson’s disease,
multiple system atrophy, loss of blood volume or
dehydration and as a side effect of some antihypertensive
drugs.
The key in management of this condition is an individually
tailored therapy. Non pharmacological treatment of OH is
the first line recommended option that include (Lahrmann
2011):
◦ · Compression stockings
◦ · Blood pressure monitoring
◦ · Increased water (2-2.5l/ per day) and salt ingestion
(>8g per day)
◦ · Education and advice on risk factors that can trigger
OH
◦ · Careful exercise
◦
◦ Pharmacological treatment include (NICE 2015)
(Lahrmann 2011):
◦ · Fludrocortisone (0.1-0.2mg per day Level C)
◦ · Midodrine (Bramox- start with 2.5mg and increase up
to 10mg Level A)
◦ · Ephedrine (15mg TID)
According to NICE (2015) evidence for the use of
midodrine (Bramox) for OH comes from the review by Low
et al (1997) found out that midodrine 10mg TID increased
systolic blood pressure statistically more significantly in
comparison to placebo 1 hour after administration during 3
weeks of treatment.
Jankovic et al (1993) also concluded that after 4 weeks of
treatment the average change in prestanding to post
standing systolic blood pressure was significantly higher
with midodrine administration 10 mg TID than with
placebo (p<0.001).
Gastroparesis is the most important manifestation of
gastrointestinal autonomic neuropathy, which may involve
any organ of the GIT, such as oesophagus, stomach, gall
bladder pancreas, small and large intestines. It affects
both the gastric functionality and homornal secretion,
Gatopoulou, Papanus and Maltezos (2008).
Gastroparesis is characterised by gastric dysmotility, with
patients presenting with prolonged symptoms of nausea,
vomiting and epigastric pain. Reduced gastric emptying
is a common feature, although rapid gastric
emptying can also be observed. The involvement
of intestines , causing intestinal neuropath. It affects up
to 40% of patients with Type 1 diabetes and 30 % of
patients with Type 2 diabetes, Parkman, Fass and FoxxOrenstein (2010).
The following signs and symptoms are indicative of
gastrointestinal autonomic neuropathy depending on the
organ involvement,
◦ Diarrhoea and feacal incontinence due to automanomic
dysfunction of the internal anal sphincter.
◦ Constipation and bloating
◦ Nausea and vomiting
◦ Early satiety
◦ Postprandial fullness and poor glucose control
If there is oesophageal involvement, impairement of the
sphincter tone results in heartburn or dysphagia.
If gastroparesis is suspected, exclusion of other causes
must be perfomed by conducting a complete evaluation,
using the following assessment as outline by Shakil,
Church and Rao (2008):
◦
◦
◦
◦
◦
◦
Patient medical history and physical examination
Laboratory studies, including:
Complete blood count
Thyroid-stimulating hormone test
Amylase test, to rule out pancreatitis
Metabolic panel, to check for diabetes and electrolyte
imbalance
◦ Gastric emptying scintigraphy is recommended to
confirm the diagnosis.
Other tests, include antroduodenal manometry, breath
test, magnetic resonance imaging, electrogastrography
and ultrasonography.
The patient- based gastroparesis cardinal symptom index
(GCSI) can be used to asses the severity of
gastroparesis. The GCS1 involves grading of 9
symptoms by the patient over a period of 2 weeks,
Parkman et al (2010). The proposed
gastroparesis classification is based on the severity of
symptoms , according to Shakil, Church and Rao (2008):
Grade 1: Mild symptoms, easily controlled
by pharmacological agents
Grade 2 : Compensated, with moderate symptoms,
partially controlled by pharmacological agents
Grade 3: Gastric failure, characterised by refractory
symptoms despite treatment and the inability to maintain
nutrition.
Management, involves ensuringthat other causes of
gastroparesis are excluded. For mild gastroparesis, the
use of anti-emetic, prokinetic agents, such as
metoclopramide and dietary modification can alleviate the
symptoms. Other treatment options include, erythromycin,
bethanechol , Boyulinum toxin and surgery. Shakil,
Church and Rao (2008).
Urinary incontinence in in diabetic people:
Prevalence:
A small number of diabetic patients experience preferential
autonomic nervous system involvement causing neurogenic
bladder. <1% of neuropathies are related to neurogenic bladder
which is seen as a comorbidity with gastroparesis, abnormal
sweating, or orthostatic hypertension. Presence of related
comorbidities including obesity increases the risk of urinary
incontinence.
Pathogenesis:
Neurogenic bladder is a progressive disorder. It progresses from
mild loss of sensation of bladder fullness to bladder paralysis. It
occurs as a result of diminished recognition of the need to void due
to autonomic neuropathy. Consequently, the interval between
episodes of micturition gradually increases, ultimately leading to
retention of urine.
Symptoms:
•
Impaired sensation of bladder fullness
•
Weak urine stream
•
Periodic or constant dribbling
•
Unexplained sudden urination
•
Need to strain to void
•
Sensation of incomplete bladder emptying
•
Post-void residual volume of 90–500 ml of urine or
urinary retention
•
Urinary tract infections
Diagnosis:
Physicians must ask questions about urinary incontinence and
related symptoms because patients often do not seek help
regarding this problem leading to delay in diagnosis and treatment.
•
Specific information must be accumulated regarding
frequency, timing, and approximate number of both
continent voids and incontinent episodes.
•
Precipitants of incontinence (cough, sneezing, types
of exercise, activity, surgeries, pregnancies, new
medications, new illness/disease, injuries) need to be
elicited.
•
Lower urinary tract symptoms must be excluded,
such as: hematuria, nocturia, dysuria, hesitancy, poor or
interrupted stream, straining or needing to press down on
the abdominal area to void, perineal pain etc.
A detailed history, physical examination, post-void residual volume
measurement by catheterisation or pelvic USG are crucial for
diagnosis. Patients with overflow incontinence should be referred
for further urodynamic testing. Urodynamic tests include:
multichannel or voiding cystometrogram with electromyography,
uroflowmetry, and cystourethroscopy. Patients should be referred
to a urologist for urodynamic studies.
Treatment:
Educational strategies:
•
Education regarding normal voiding schedule
•
Behavioural techniques:
Bladder retraining (including relaxation techniques)
Pelvic muscle exercises
Biofeedback and
Clean – technique intermittent catheterization:
Treatment of choicefor atonic bladder
Pharmacological approach:
Risk benefit ratio must be evaluated before initiating
pharmacological approach.
•
For urge incontinence: Anticholinergic agents such
as oxbutynin, dicyclomine hydrochloride, and
propantheline are recommended as first-line therapy.
•
For stress incontinence: The first-line therapy is
phenylpropanolamine or pseudoephedrine.
•
In the treatment of stress incontinence or mixed
incontinence in postmenopausal women, estrogen therapy
can be used as an adjunct.
Surgical treatment:
Surgical treatment should be performed after other treatments are
unsuccessful or in the presence of bladder outlet obstruction.
•
Surgical intervention to improve stress incontinence
aims at increasing sphincter outlet resistance. Techniques
include:
Retropubic suspension
Needle bladder neck suspension
Anterior vaginal repair
•
Surgeries that manage sphincter deficiency include:
Sling procedures
Placement of an artificial sphincter.
•
Overflow incontinence due to bladder neck
obstruction can be addressed by surgical procedures to
relieve the obstruction.
Reducing the risk for urinary tract infections is the cornerstone of
management.
Finally, management of diabetes itself and maintaining a tight
glycaemic control are of paramount importance to prevent further
worsening of the condition.