Diabetic Neuropathy

Diabetic neuropathy Diabetic neuropathy

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

DISTAL SYMMETRICAL POLYNEUROPATHY 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 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 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 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 PHARMACOTHERAPY Anticonvulsants Gabapentin and Pregabalin - 2 2 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 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 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 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 g 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