diabetic neuropathy ...pptx

Case scenario
• 65yr old female with 5 yr history of type 2 diabetes reports recent
onset of burning ,tingling and stabbing pain in her feet that is worse
at night and interferes with sleep and activities of daily living .Her
medications include 500mg metformin and 2mg glimepiride each take
twice daily.
• On examination she has reduced sensation to pinpricks in the knees ,
reduced ability to detect vibration from 128Hz tuning fork and loss
of proprioception and sensation to monofilament ( 1-g) inn her toes .

• Strength in the lower legs is 5/5 proximally and 4/5 distally. And there
is slightly weak dorsiflexion of both big toes , with no indication of
entrapment.Her ankles reflexes are absent .she has no foot ulcers and
her pulses are easly palpable.
• How should her case be further evaluated and managed?

• Heterogenous condition manifests in different forms.
• Proximal/distal nerve fibers
• Mononeuritis/entrapments involving small/large fibers
• Somatic/ autonomic nerve fibers

• Distal symmetric polyneuropathy – most common form of diabetic
neuropathy
• Is chronic, length dependent , sensorimotor polyneuropathy
• Affects at least 1/3 of persons with type1 or 2 diabetes
• Skin biopsy – progressive reduction in the intraepidermal nerve fibers
from the time of diagnosis.

Manifest as
1. diffuse neuropathy
(distal symmetrical polyneuropathy and/or autonomic neuropathy)
2. Mononeuropathy/ Mononeuritis multiplex
3. Radiculopathy/Polyradiculopathy

• As with other complications of DM, development of neuropathy
corelates with the duration of diabetes and glycemic control
• Additional risk factors: BMI, smoking ,the presence of CVD, elevated
triglycerides and hypertension .
• Both myelinated and unmyelinated nerve fibers are affected- features
both axonal degeneration and demyelination

Metabolic alterations in diabetes and the
pathogenesis of neuropathy
• Polyol pathway
• Oxidative stress and advance glycation
• Nitrosative stress, PARP activation , endoplasmic reticulum stress and
pro inflammatory mechanisms

DISTAL SYMMETRICAL POLYNEUROPATHY (DSPN)
• Most common form of diabetic neuropathy
• Most frequently presents with distal sensory loss and pain
• Upto 50% of patients do not have symptoms
• Symptoms: sensation of numbness, tingling, sharpness or burning pain that
begins in the feet and spreads proximally
• Hyperesthesia, paresthesia and dysesthesia may also occur
• Pain typically involves the lower extremities, is usually present at rest and
worsens at night

• As neuropathy progresses, pain subsides and eventually disappears,
but a sensory deficit persists and motor defects may develop
• Severe impairment of pain and temperature - results in distal
ulceration and arthropathy (Acrodystrophic neuropathy)
• Physical examination:
❖ sensory loss
❖ loss of ankle DTR
❖abnormal position sense, loss of vibration
❖muscular atrophy or foot drop

• Annual screening for DSPN should begin 5 years after diagnosis of
type 1 DM and at the time of diagnosis of type 2 DM
• Aimed at detecting loss of protective sensation (LOPS) - risk factor
for foot ulceration and falls - predispose to LL amputation

AUTONOMIC NEUROPATHY
• Involve parasympathetic (cholinergic) and sympathetic(adrenergic)
systems
• Affect multiple organ systems - CVS, GI, genitourinary, sudomotor and
metabolic systems
• CVS- decreased heart rate variability, resting tachycardia, orthostatic
hypotension
• Reports of sudden death in DM have been attributed to autonomic
neuropathy affecting the CVS and predisposing to severe
hypoglycemia, both of which may prolong the QTc interval

• Hypoglycemia unawareness: reduced counterregulatory hormone
release (epinephrine) leading to an inability to sense hypoglycemia
appropriately –risk of severe hypoglycemia
• Hyperhidrosis of upper extremities and anhidrosis of lower
extremities – sympathetic nervous system dysfunction
• Anhidrosis – dry skin with cracking ,foot ulcers

GI system:
• delayed gastric emptying (gastroparesis)
• altered small and large bowel motility (constipation and diarrhea)

• Genitourinary :
• Cystopathy - inability to sense a full bladder and failure to void
completely
• as it worsens - bladder capacity & postvoid residual increases -
symptoms of urinary hesitancy , decreased frequency, incontinence,
recurrent UTI
• Female sexual dysfunction - reduced sexual desire, dyspareunia
• Erectile dysfunction, retrograde ejaculation in males

MONONEUROPATHY
• dysfunction of isolated cranial or peripheral nerves
• less common than polyneuropathy
• presents with pain and motor weakness in the distribution of a single
nerve
• can be compressive - entrapment at sites such as carpal tunnel or be
noncompressive

• 3rd CN involvement is most common - diplopia
• o/e - ptosis and ophthalmoplegia
• sparing of pupillary reflex differentiates a diabetes induced palsy
from from compressive lesions
• other CNs- 4,6 or 7(bell’s palsy)
• peripheral mononeuropathies or simultaneous involvement of more
than one nerve (mononeuropathy multiplex) may also occur

• onset is usually acute, asymmetric pain f/b by weakness involving
proximal leg
• may become more widespread and symmetrical with time
• progression occurs over months - progress to affect the contralateral
limb and distal legs
• usually self limiting - resolve over 6-12 months
• DD - idiopathic LRPN (lumbosacral radiculoplexus neuropathy)
• CMV & HIV can rarely cause similar condition

CLINICAL MANAGEMENT
• Lifestyle interventions may prevent or possibly reverse neuropathy
• Diet and exercise regimen – increased intradermal nerve-fiber
density and reduced pain
• Strength and balance training to increase strength of knee extension
and foot dorsiflexion and improve gait stability may reduce the risk of
falls among patients with large-fiber neuropathy

• Overzealous control of bp and blood glucose levels should be avoided
• Rational glycemic control recommended
• In ACCORD (action to control cardiovascular risk in diabetes ) trial
tight glycemic control resulted in modest reductions in neuropathic
symptoms but no significant reduction in risk of development of
neuropathy after 5 yrs

• In BARI 2D (bypass angioplasty revascularization investigation 2
diabetes ) trial patients randomly assigned to receive insulin-
sensitizing agents as compared with insulin-providing agents had
improved glycemic control and had a significantly lower incidence of
neuropathy at 4 years.

• In another trial based on a multifactorial strategy that involved
control of blood pressure and lipid levels, the use of antioxidants, and
lifestyle modification (intensive therapy) as compared with
conventional therapy, the incidence of autonomic neuropathy was
significantly lower.

PHARMACOTHERAPY
• Anticonvulsants
• Gabapentin and Pregabalin - α2δ2 voltage gated calcium modulators
• Relieve pain by direct mechanisms and by improving sleep
• In contrast to gabapentin, pregabalin has linear and dose-
proportional absorption in the therapeutic dose range (150 to 600 mg
per day);
• it also has a more rapid onset of action than gabapentin and a more
limited dose range that requires less adjustment.

• Tricyclic antidepressants
• their use is often limited by adverse cholinergic effects such as
blurred vision, dry mouth, constipation, and urinary retention,
particularly in elderly patients
• The secondary amines, nortriptyline and desipramine, tend to have
less bothersome anticholinergic effects than amitriptyline or
imipramine

• Tricyclic antidepressants should be used with caution in patients with
known or suspected cardiac disease; electrocardiography should be
performed before these drugs are initiated to rule out the presence of
QT-interval prolongation and rhythm disturbances

• SNRIs
• serotonin–norepinephrine reuptake inhibitors (SNRIs) venlafaxine
and duloxetine have proved to be effective in relieving neuropathic
pain
• These agents inhibit reuptake of both serotonin and norepinephrine
without the muscarinic, histamine-related, and adrenergic side effects
that accompany the use of the tricyclic antidepressants

• Opiod analgesics
• opioids should generally be used only in selected cases and only after
other medications have failed to be effective
• Tramadol, an atypical opiate analgesic, also inhibits the reuptake of
norepinephrine and serotonin and provides effective pain relief
• Extended-release tapentadol has similar actions and has been
approved for the treatment of diabetic neuropathic pain

Coexisting conditions and choice of therapy
• In contrast to duloxetine, which increases fragmentation of sleep,
pregabalin and gabapentin have been shown to improve the quality
of sleep
• An SNRI or a tricyclic antidepressant may be preferred in patients
with depression
• Pregabalin, gabapentin, or an SNRI may be appropriate choices for
patients with anxiety, although gabapentin and pregabalin may cause
weight gain

Areas of uncertainty
• It is possible that the methylcobalamin component was helpful for
persons taking metformin who had vitamin B12 deficiency; the
overall effectiveness of this treatment regimen are uncertain.
• Antioxidants have been proposed for treatment. A randomized trial
involving patients with diabetes who had moderate distal symmetric
polyneuropathy showed that alpha lipoic acid had no significant
benefit with regard to the primary outcome

Summary and recommendations
• The woman described in the vignette has characteristic features of
large-fiber and small-fiber neuropathy that are consistent with
diabetic sensorimotor neuropathy.
• Laboratory tests should include measurement of glucose, hemoglobin A1C ,
lipid, and thyrotropin levels, a complete blood count, serum protein
electrophoresis, and an assessment of vitamin B12 and folate levels
• vitamin B12 deficiency is associated with metformin use and is
manifested as impaired perception of vibration and loss of ankle
reflexes

• Quantitative tests of sensory and autonomic function should also be
performed to obtain a definitive diagnosis and serve as baselines
from which the progression or resolution of the neuropathy can be
followed

• In patients with distal predominantly sensory neuropathy, as is seen
in this patient, lifestyle changes (diet and exercise) and adjustment
of medications should be recommended routinely to improve
glycemic control, lipid levels, and blood pressure.
• An overly rapid lowering of the hemoglobin A1C level (by more than
1% per month) and the development of hypotension should be
avoided.
• For this patient, physical therapy should be recommended for
strength training (and focused on the weakness of dorsiflexion of the
big toe), and training to improve balance and reaction times would
be advisable to reduce the risks of falls and fractures.

• most commonly used for treatment include pregabalin or gabapentin,
tricyclic antidepressants, and SNRIs.
• Since this patient has a sleep disturbance, pregabalin or gabapentin
may be appropriate first choices, but monitoring will be required for
weight gain, fluid retention, and diminished glycemic control.
• It would be best to start with lower doses (e.g., 75 mg of pregabalin
twice daily) and to adjust the dose upward if there is no reduction in
pain within the first 2 weeks

• If there is no response after 1 month of treatment, a switch to an
agent from another drug class would be advisable.
• If the vitamin B12 level is below 450 pg per milliliter, supplementation
with oral methylcobalamin (2000 μg per day) could be initiated,
although there are as yet no data that show that supplementation
reduces neuropathy in the absence of frank deficiency.
• Alpha lipoic acid can be given to relieve pain (starting at a twice-daily
oral dose of 300 mg), although formal studies of its use in this regard
have not been conducted

diabetic neuropathy ...pptx

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