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INTRODUCTION:
Diabetic
neuropathy
is
commonest
complication
of DM
with
varied
clinical
presentation
and
significant
morbidity.
The
aetiopathogenesis,
treatment
and
relation
with
glycemic
control
is
always
controversial
and
challenge
to
physicians.
Various
new
treatment
protocols
are on
trial.
It was
described
by Rollo
about
200
years
ago. In
1864
Michael
de Calvi
proposed
that
neuropathy
is due
to
Diabetes.
In 1945
Rundles
first
gave
the
comprehensive
description.
There
are 3
proposed
stages
of
neuropathy
giving
emphasis
on early
diagnosis
and
treatment
. They
are a)
Functional
neuropathy-
reversible
biochemical
alteration
in
nerves
b)
Structural
neuropathy
–
structural
damage
to nerve
cells
but
reversible
c) Nerve
death -
Irreversible.
PHYSIOLOGY
&
METABOLISM
OF NERVE
CELLS
Normally
the
production
and
utilization
of
energy
depending
on the
rate of
production
and
utilization
of
adenosine
triphsophate
(ATP) is
a
balanced
state in
the
cells.
Whenever
the ATP
production
is
restricted
the
cells
adopt by
either
decreasing
energy
requirement
for
biological
activities,
increasing
glycolysis
for ATP
production
or using
phosphocreatine
stores
for ATP
production.
Endoneurium
glucose
is the
major
substrate
for
energy
production
in
peripheral
nerves,
which is
independent
of
Insulin.
In
ischemic
conditions
there is
reduced
oxygen
supply,
glucose
supply
for
glycolysis
and ATP
production
resulting
in
lactate
accumulation
and
acidosis
which
effects
the
structure
and
function
of
neuronal
tissues.
AETIOPATHOGENESIS
The
mechanism
of
multifactorial.
They are
vascular
and
metabolic.
The
various
factors
responsible
are
hyperglycemia,
increased
polyol
pathway
activity,
myoinositol
depletion,
Na/K
ATpase
activity,
endoneural
hypoxia
due to
micro
vascular
disease
and
vasonervorum
involvement.
Metabolic
Theory:
a.
Polyol
Pathway:
Normally
1%
glucose
is
metabolized
through
this
which is
independent
of
insulin.
Hyperglycemia
leads to
intracellular
glucose
accumulation
which is
converted
to
sorbitol
by
enzyme
aldose
reductase.
Some
sorbitol
is
fructose
by
sorbitol
dehydrogenase.
Sorbitol
and
Fructose
damage
the
Schwann
cell by
more
osmolarity
and
effect
nerve
conduction.
b.
Myoinositol
Pathway:
Myoinositol
, a
cyclic
hexitol
is
normally
found in
plasma
and
mammalian
cells
and
major
constituent
of
phospholipids
and cell
membrane.
Higher
levels
are
found in
peripheral
nerve.
The
tissue
level is
maintained
by
synthesis
from
glucose
6-phosphate
and
recovery
from
phosphinositol
hydrolysis.
Increased
polyol
activity
leads to
depletion
of
myoinositol
concetration
by
unknown
mechanism,
which
inhibits
Na+/K+
ATpase
activity
leading
to
reduced
myoinosital
uptake.
c.
Lipids –
Myelin
synthesis
is
reduced
due to
reduction
of
membrane
cholesterol,
cerebroside,
sphingomyelin
and
phosphatidyl
serine –
phosphatidyl
inositol.
Vascular
Theory:
Chronic
hypoxia
causing
structural
damage
to
nerves
is due
to
reduced
endoneural
blood
flow. In
diabetes
the
normal
vascular
autoregulations
is lost.
Endoneural
hypoxia
with
reduced
Na+/
K+
ATpase
reduce
nerve
conduction
velocity
and
cause
axonal
atrophy.
In
diabetes
there is
multifocal
loss of
proximal
fibres
and
diffuse
loss of
distal
fibre.
However
both
metabolic
and
vascular
mechanisms
are
overlapped.
Changes
occur in
endoneuroal
and
perineural
blood
vessels
in the
form of
endothelial
proliferation
with
luminal
narrowing
,
pericyte
basement
membrane
hyperplasia,
perivascular
space
thickening
and
closed
capillaries
In
general
metabolic,
vascular
factors
along
with
glycosylation
of
protein,
hyperaggregation
of
platelets
and
altered
haematology
combindly
responsible
for
neuropathy.
Hyperglycaemia
reduce
pain
threshold.
Increased
blood
flow to
extremities
with
hyperglycaemia,
loss of
vascular
tone
produce
pain.
PATHOLOGY:
Peripheral
nerve
are
classified
as
motor,
sensory,
autonomic
and
small or
large
and
degree
of
lyelination
and each
with a
distinct
function.
Both
large
and
small
fibres
are
involved
and on
biopsy
show
axonal
degeneration,
segmental
demyelination,
intraneural
vascular
thrombi,
loss of
myelin
due to
Schwann
cell
damage.
ELECTROPHYSIOLOGICAL
CHANGES:
The
nerve
conuction
are more
helpful
than
clinical
and
histological
studies.
In
majority
cases –
axonopathy
–
reduced
evoked
motor
response
and
sensory
action
potential
with
preservation
of
conduction
velocity.
Focal
nerve
entrapments:
Carpal
tunnel,
cubital
tunnel,
common
peroneal
tunnel
etc.,
Presence
of
mononeuropathy
simplex/multiplex
are
detected.
Newer
techniques
like:
Motor
unit
counting,
near
nerve
action
potential
and
refractory
period,
Needle
electromyography
–
(recent,
sophisticated),
Sensory
action
potential
and
autonomic
function
test are
sensitive.
Sequential
EMG
changes
ranging
from
reduced
recruitment
of motor
unit
potentials,
presence
of
fibrillation
potential,
polyphasic
high
amplitude
long
duration
motor
unit
potential,
absent
of F
waves
occur at
various
stages
of
axonal
damage.
CLINICAL
CLASSIFICATION
:
On the
basis of
clinical
presentation
the
arbitrary
classification
for
better
understanding
is
accepted.
1.
Gradual
onset
type:
Distal
symmetrical
polyneuropathy:
Usually
mixed or
Predominantly
sensory
with
autonomic
neuropathy
2.
Acute
onset
type:
Painful
symmetric
polyneuropathy,
Diabetic
amyotrophy
(plexopathy),
Mononeuropathies
(Cranial,
truncal,
isolated,
multiple
mononeuropathies).,
Radiculopathies,
Neuropathic
cachexia,
3.
Autonomic
neuropathy
are
Sympathetic
and
Parasympathetic
CLINICAL
JUDGEMENT
OF
SEVERITY
By using
UK
screening
test the
severity
can be
graded.
Part – 1
�
What is
the
sensation
felt? –
burning
numbness
or
tingling
in the
feet (2
points)
fatigue,
cramping
or
arching
(1
point).
Maximum
is 2
points.
�
What is
the
location
of
symptoms?
Feet (2
points)
calves
(1
Point):
elsewhere
(no
points)
maximum
is 2
points.
�
Have the
symptoms
ever
woken
you at
night ?
yes (1
point)
�
What is
the
timing
of
symptoms
?Worse
at night
( 2
points)
present
day and
night (1
point):
Present
only
during
the day
( no
point)
maximum
is 2
points.
�
How are
symptoms
relieved
:
walking
around (
2
points)
standing
(1
points);
sitting
or lying
or no
relief (
no
points)
maximum
2
points.
�
The
total
symptom
score
can then
be
determined:
0 to 2 –
normal,
3-4 –
mild
neuropathy,
5-6 –
moderate
neuropathy
& 7-9 –
severe
neuropathy.
Part - 2
A
similar
quantitative
score
can be
made for
the
physical
findings:
�
What is
the
Achilles
tendon
reflex?
- absent
(2
points
for each
foot);
present
with
reinforcement
(1 point
for each
foot).
�
What is
vibration
sense?
Absent
or
reduced
(1 point
for each
foot)
�
What is
pin
prick
sensation
? –
Absent
or
reduced
(1 point
for each
foot)
�
What is
temperature
sensation
? (
reduced
( 1
point
for each
foot)
The
neurologic
signs
score
can then
be
determined.
0-2
normal
,3-5
mild
neuropathy,
6-8
moderate
neuropathy
and 9-10
sever
neuropathy
Peripheral
neuropathy
is
considered
to be
present
if there
are
moderate
or sever
signs (
6
points)
even in
the
absence
of
symptoms
or if
there
are at
least
mild
signs (
3 point)
in the
presence
of
moderate
symptoms
( 5
points).
A
neurologic
sign
score
or 8 or
more
indicates
that the
patients
feet are
at high
risk for
ulceration.
CLINICAL
PRESENTATION
I.
GRADUAL
ONSET
TYPE
Distal
symmetrical
polyneuropathy
Commonest
presentation,
developing
over few
years,
detected
on
routine
examination
by
absent
ankle
jerk.
Though
all
somatic
nerve
fibres
are
effected,
the
distal
parts of
limbs
(feet >
hands)
are more
effected,
giving
rise to
typical
“glove
and
stocking”
presentation.
The
symptoms
are
often
symmetrical
and
exacerbate
at
night.
The
symptoms
and
signs
vary
depending
on
predominant
small or
large
fibre
involvement.
�
Small
sensory
neuropathy
–
undetected
trauma
to
extremities
specially
to feet
inform
of scald
by hot
water or
ulcer,
infection
with
minor
injury.
May have
absent
or
diminished
sensation
(cold or
numb)
May
present
as
parasthesia
or
dysthesias
in form
of
“tingling”
or “pin
and
needle”
sensation
in
extremities.
Many
complain
severe
burning
or pain
described
as
tearing
,
gnawing
, aching
or deep
seated.
�
Large
fibre
involvement:
May have
loss of
vibration
sensation
followed
by touch
and
position
sense,
producing
sensory
ataxia,
unsteady
gait and
positive
Romberg’s
sign.
Involvement
of
afferent
fibres
of
stretch
receptors
lead to
loss of
reflexes.
�
Due to
loss of
touch
and pain
sensation
there
may be
neuropathic
arthropathy
or
perforating
ulcer in
feet ,
associated
with
diminished
muscle
strength
and
vascular
dysfunction.
�
Diabetic
neuroarthropathy
involves
small
joints
of foot
and
ankle.
In
initial
phase
the foot
is
swollen,
painless
and red
without
fever or
leucocytosis
(differ
from
infective
arthropathy).
The
condition
resembling
tabes
dorsalis
so
called
“Diabetic
pseudotabes”.
�
In a
classical
presentation
neurogenic
atrophy
of small
muscle
of
plantar
arch
leads to
flat
foot and
chronic
flexion
of the
metatarsophalangeal
joints
producing
callus
over
metatarsal
heads
and
ulceration.
The foot
is warm
with
palpable
dorsalis
pedis
and
intact
veins.
Neuropathic
ulcers
are seen
at other
contact
points
of feet
like ill
fitted
shoes.
�
Distal
symmetric
polyneuropathy
may show
motor
involvement
although
masked
by
sensory
component.
In Some
predominant
motor
involvement
shows
flexor
and
extensor
of foot
which
may be
atrophied
later.
Involvement
of small
muscles
of hand
and feet
lead to
claw
hand,
claw
foot or
pescavus
deformity.
Predominant
motor
neuropathy
though
rare is
associated
with
insulinoma
induced
repeated
hypoglycaemia.
�
Distal
symmetrical
polyneuropathy
is
usually
associated
with
autonomic
neuropathy.
II.
ACUTE
ONSET
TYPE
A.
Painful
symmetric
polyneuropathy
:
o
Commonest
acute
onset
painful
neuropathy.
It is
very
painful
with
nocturnal
exacerbation.
It tends
to
develops
3 weeks
after
stressful
conditions
like
surgery,
ketosis,
infection
etc.,
May
develop
after
insulin
initiation
under
rapid
and
repeated
hypoglycemia.
Seen in
severe
diet
restriction
with
undernourishment.
This
neuropathy
remains
for 6-18
months
and
disappears.
o
Motor
involvement
is
common
and
severe
than
gradual
onset
type.
B.
Diabetic
amytrophy
(Plexopathy)
o
Seen in
elderly
diabetes
of short
duration.
It is
painful
and
associated
with
stress.
Typically
there is
painful
weakness
and
atrophy
of
pelvic
girdle
and
thigh
muscles
involving
ileo-psoas,
quadriceps
relative
sparing
of hip
extensors
and
hamstrings.
Occasionally
the
peroneal
and
tibial
muscles
are
effected.
o
Sensory
sign and
symptoms
may
occur
like
pain,
paraesthesia
of
anterior
thigh
and
anteromedial
leg
radiating
to
dorsum
of foot
or pain
from
sacroiliac
region
radiating
to back
. The
knee
jerk is
absent.
o
The
plexopathy
is
usually
unilateral
at onset
but
other
side is
somewhat
involved.
Shoulder
girdle
plexopathy
is rare.
C.
Mononeuropathies:
i.
Cranial
nerve
involvement:
Isolated
or
multiple
nerve
involvement
may be
seen
without
any sign
of
peripheral
neuropathy.
The III
and VI
are
commonly
involved
and IV
th is
rarely
alone.
The
diplopia
is acute
onset
with
pain
behind
and
above
the
affected
eye (
may be
due to
involvement
of 1st
and 2nd
part of
Vth
nerve).
The
pupil is
spared.
Symptoms
resolve
after
6-12
weeks.
The
VIIth
Cranial
nerve
may be
affected
rarely
where
the
prognosis
is less
favorable
than III
and VI
cranial
nerve.
Other
upper
cranial
nerves
may be
rarely
involved
while
the
lower
cranial
nerves
are
never
effected.
ii.
Isolated
peripheral
nerve
lesion.
Relatively
more
common.
The
cause
may be
due to
vascular,
trauma
or
entrapment
to
superficial
nerves.
Any
major
nerve
may be
involved.
When
several
nerves
are
affected
simultaneously
it is
called
“mononeuritis
multiplex”.
The
nerves
commonly
involved
are
median,
ulnar,
radial,
femoral,
sciatica
and
peroneal
,
lateral
cutaneous
nerve of
thigh.
The sign
and
symptoms
dpends
on the
nerve
involved.
The
onset is
usually
acute
painful
but
rarely
indiduous.
iii.
Radiculopathy:
Relatively
uncommon
but
correct
diagnosis
is
necessary
for
unnecessary
intervention.
Root
involvement
at
different
segmental
levels
mimic
different
emergency
conditions
like
constructive
chest
pain,
pain
abdomen.
The
cause of
involvement
though
not
definitive
, may be
ischaemia.
EMG of
involved
muscles
and
recovery
after
some
period
without
residual
damage
is
helpful.
iv.
Diabetic
neuropathic
cachexia:
Recognized
as a
separate
entity,
where
painful
, acute
onset
symmetrical
neuropathy
associated
with
much
weightloss.
The
nerve
involvement
usually
disappears
within
6-12
months.
III.
AUTONOMIC
NEUROPATHY
Usually
associated
with
gradual
onset
type. It
varies
from
mild
involvement
to
severe
masking
other
presentations.
But mild
involvement
may
produce
significant
incapacity.
A.
Cardiovascular
�
Postural
hypotension
:
Commonest
manifestation
when
postural
drop
occurs
more
than 20
mm of
Hg. In
some the
postural
drop
occurs
after
insulin
therapy
greatest
effect
being 1
to 3
hours
after
injection.
�
Cardiac
denervation:
May show
partial
or
complete
denervation
with a
fixed
P/R of
80/90
which
does not
change
with
stress,
exercises
or
sleep.
There
also
occurs
adnergic
supersensitivity.
These
two
factors
lead to
greater
incidence
of
coronary
artery
spasm,
painless
MI, and
sudden
death.
�
Exercise
intolerance:
Besides
cardiac
involvement
changes
in the
autonomic
tone may
prevent
an
adequate
rerouting
of the
blood
flow
after
exercise.
Pre-exercise
evaluation
is
required
for
diabetic
before
advising
exercise
therapy.
B.
Gastrointestinal
tract
�
Oesophageal
dysmotility:
May
cause
dysphagia,
regurgitation
due to
low tone
of LES
and
sense of
retrosternal
fullness
and
discomfort.
�
Gastroparesis
diabeticorum
– In 50%
of cases
of
diabetes
due to
impaired
gastric
acid
secretion
and
motility
produce
early
satiety,
anorexia,
nausea,
vomiting,
epigastric
discomfort
and
bloating
.
Usually
associated
with
bezoars.
Interference
of
nutrient
delivery
to small
intestine
disrupts
glucose
absorption
and
exogenous
insulin
administration
resulting
a state
of
apparent
“brittle
diabetes”
state.
�
Diarrhoea:
Common
disturbing
manifestation
preceded
by
abdominal
discomfort
having
nocturnal
frequency
may have
faecal
incontinence.
The
stool is
usually
watery
but may
be
steatorrhic,
with a
frequency
of 25-30
times
/day.
The
attack
may be
intermittent
with
interval
of
normality
or
constipation.
The
cause of
diarrhoea
may be
due to
hypermotility
by
decreased
sympathetic
tone,
bacterial
over
growth,
pancreatic
insufficiency,
diabetic
sprue
and bile
salt
malabsorption.
�
Constipation
is a
common
symptoms
in some
studies.
�
Gastric
and
colonic
atony
and
enlarged
gall
bladder
are
common.
C.
Genitourinary
System:
�
Bladder
dysfunction
is
common.
Initially
may have
diminished
frequency
with
nocturia
and
later
there
may be
incontinence
, over
flow
dribbling,
residual
urine
leading
to
infection.
�
Impotency
in form
of
erectile
dysfunction
found in
more
than 50%
of male.
Retrograde
ejaculation
may be
seen.
Neurogenic
sexual
dysfunction
occur in
25-30%
of
females.
Loss of
testicular
sensations
in few
studies
reported.
D.
Pseudomotor
function
�
Sweating
disturbances
manifest
as
abnormal
and
bizarre
pattern
commonly
absence
of
sweating
over
distal
parts of
lower
limb
(like
distal
symmetrical
neuropathy)
with
compensatory
hyperhydrosis
of trunk
and
face.
Patient
shows
heat
intolerance
and
there
occurs
nocturnal
sweating.
Facial
sweating
during
meal is
rare. It
is more
with
cheese
and
tyramine
containing
foods
and
starts
after
chewing.
Starting
from
forehead
it
spreads
to face
, scalp,
back and
upper
chest.
Anticholinergic
drugs
are less
helpful
E.
Pupillary
Changes:
Pupil
may be
constricted
and that
may be
Argyll –
Robertson
type
pupil.
It
reflects
duration
of
diabetes,
metabolic
factors
and
other
associated
complications.
F.
Metabolic:
Hypoglycemia
associated
autonomic
dysfunction
– As
glucagons
and
adrenal
medulla
depend
on
functional
integrity
of ANS,
the
signs
and
symptoms
of
hypoglycemia
are
diminished.
G.
Respiratory
system:
Respiratory
arrest
may
rarely
occur
H.
Vasomotor:
Changes
like
loss of
skinvasomotor
response,
peripheral
vascular
changes,
osteopathy
and
charcot’s
arthropathy
and
dependant
oedema
may
occur.
MANAGEMENT
The
protocol
consists
of
management
of
hyperglycemia
,
metabolic
abnormality
,
painful
neuropathy
and
autonomic
neuropathies.
I.
Treatment
of
hyperglycemia
By
assessing
the
glycaemic
status
drugs
are
tried to
maintain
good and
sustained
glycaemic
control.
In Type
2 DM
diet
control
and oral
drugs
may be
enough.
Insulin
maybe
tried as
its
membrane
stabilizing
effect.
In some
poorly
controlled
diabetes
pain may
be
aggravated
when
tight
sugar
control
is done
by
insulin
which
subside
after
stabilization.
Stable
glucose
control
relieves
pain and
slow the
progress
of
neuropathy.
II.
Treatment
metabolic
abnormalities:
i.
Aldose
reductase
inhibitors
(ARI) –
Alrestatin
and
Sorbinil
are two
drugs.
-
Alrestatin
– Not
used due
to
average
side
effect
-
Sorbinil
– In
dose of
250mg/day
improves
peroneal,
median
and
sensory
conduction
velocity
in 2
months,
reduction
of
sciatic
nerve
sorbitol
content
and
restoration
of
myoinositol
is
achieved.
Side
effects
of
hypersensitivity
causing
fever,
rash ,
lymphadenopathy
has
restricted
its use.
ii.
Gangliosides
–
Facilitates
neural
sprouting
of
regenerating
nerves
producing
subjective
and
objective
improvement.
Myoinositol
is
another
trial
drug.
Seafood
and
vegetables
like
drumstick
are
myoinositol
rich
foods.
iii.
Protein
kinase C
inhibitors
(PKC) –
Its role
in
preventing
neuropathy
is under
trial.
iv.
Gamma
linoleic
Acid (GLA)
– GLA ,
an
essential
fatty
acid is
required
for
arachadonic
acid
derivatives
like
prostaglandin
production,
helpful
in
diabetic
neuropathy.
v.
Antioxidants
–
Several
drugs
have
shown
good
results.
Alpha
lipoic
acid, a
potent
hydrophilic
antioxidant
improves
nerve
blood
flow,
nerve
glucose
uptake,
myoinosital
content
and
sensory
nerve
conduction
velocity.
vi.
Neurotrophins
– A
group of
soluble
proteins
like
NGF,
BTNT,
NT3,
NT4, NT5
affecting
growth ,
differentiation,
maturation
,
function
and
survival
of
particular
set of
neurons
are
under
trial.
vii.
Mecobalamin
– It is
an
active
coenzyme
form of
Vit B12.
It is a
cofactor
in the
methionine
synthetase
which
functions
for
methyl
transfer
of
methionine
from
homocysteine.
It is
related
to
folate
metabolism
which is
responsible
for
purin
and
pyramidines
of DNA.
It acts
as a
methyl
donor
for
synthesis
of
lecithin,
a
component
of
myelin
sheath.
Mecobalamin
is
better
transported
than
cyanocobalamin
into
nerve
cells
prompting
nucleic
acid
regeneration
and
protein
synthesis.
It
promotes
axonal
transport
and
regeneration.
Mecobalamin
promotes
myelination
(phospholipid
synthesis
) and
lecithin
synthesis
of lipid
sheath
and
inceases
meylination
of
neurons.
In a
dose of
500 gm
I/M or
I/V
thrice
in a
week or
orally
500 to
1000mgm/
daily in
effective.
viii.
Nandrolone
– a
nonsteroidal
anabolic
drug in
a dose
of 25 mg
weekly
for two
months.
III.
Treatment
of
painful
neuropathy
Many
drugs
have
been
tried to
relieve
this
painful
condition
with
various
degree
of
relief.
a.
NSAID
and
Analgesics:
-
Tramadol
a
non-narcotic
centrally
acting
analgesic
in a
dose of
50 mg
daily
increasing
by 50 mg
daily to
maximum
400mg/day
is
commonly
used at
bed
time.
-
Analgesics
like
propoxyphene
and
acetaminophen
given in
evening
before
bed
reduces
pain.
Use of
NSAID
are to
be
carefully
considered
due to
GI and
Renal
complications.
They may
be used
as short
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