diabetic neuropathy : clinical manifestations and management ak daif, md consultant and professor of...
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Diabetic Neuropathy : Clinical Manifestations and Management
Diabetic Neuropathy : Clinical Manifestations and Management
AK Daif, MD
Consultant and Professor of Neurology
KKUH, college of Medicine
Diabetic NeuropathyDiabetic Neuropathy About 60-70% of people with
diabetes have mild to severe forms of nervous system damage, including: Impaired sensation or pain in the feet
or hands
Slowed digestion of food in the stomach
Carpal tunnel syndrome
Other nerve problems
More than 60% of nontraumatic lower-limb amputations in the United States occur among people with diabetes.
Diabetic Peripheral Nerve DamageDiabetic Peripheral Nerve Damage
Myelinated NeuronMyelinated Neuron
Incidence of Diabetic Neuropathyas a proportion of all diabetics 20 years after
diagnosis
Incidence of Diabetic Neuropathyas a proportion of all diabetics 20 years after
diagnosis
No neuropathy 10%
Asymptomatic 40%
Symptomatic 50%
Risk FactorsRisk Factors
• Glucose control• Duration of diabetes• Damage to blood vessels• Mechanical injury to nerves• Autoimmune factors• Genetic susceptibility• Lifestyle factors
– Smoking– Diet
Underlying MechanismsUnderlying Mechanisms
Agreement not yet reached on exact causal relationship between insulin
imbalance and nerve damage.
The relative importance and inter-relationship of the various mechanisms is the subject of ongoing research and
debate.
Physical manifestationsPhysical manifestations
• Nerve fibres degenerate
• Blood vessels supplying the nerves are ‘grossly diseased’
Any theory needs to account for both
Pathways of actionPathways of action
• Polyol pathway
• Triose phosphate effects
• Failure of nerve growth & repair mechanism
• Fatty acid metabolism
Polyol PathwayPolyol Pathway
• Polyol = Polyhydroxy alcohols• High blood glucose
– Nerve cell and capillary membranes have insulin-independent glucose transport.
– High intra-cellular glucose levels– Conversion of glucose to sorbitol in nerve
cells by aldose reductase enzyme– Sorbitol cannot cross membranes and
therefore accumulates
Polyol PathwayPolyol Pathway
• Consequences of high sorbitol concentration:
– Osmotic damage to nerve cells
– reduction in nerve myoinositol
– Inhibition of nitric oxide (NO) production• Aldose reductase competes for NADPH• NO is vasodilator
– Increased production of free radicals• Superoxide, hydrogen peroxide, hydroxyl• Formed during mitochondrial respiration• Increased oxidative stress (proteins, lipids, DNA)
Polyol PathwayPolyol Pathway
• Treatment possibilities– Aldose reductase inhibitors– Supplemental myoinositol– Nitric oxide stimulation/sensitisation– Vasodilators– Antioxidants
Triose phosphatesTriose phosphates
• High intracellular glucose leads increased production of triose phosphates– Activation of protein kinase C (PKC) via DAG
• Damages capillaries (permeability, contractility)
• Damages nerve function
– Non-enzymic reaction with proteins & DNA• Advanced Glycation End-products (AGEs)
• Damage to capillaries and nerve fibres
• Specific cellular AGE receptors
• Protein cross-linking
Fatty acid metabolismFatty acid metabolism
• Functions of DGLA and AA in nerves– Incorporated into membranes
• required for normal nerve structure, which is required for normal nerve conduction
– Required for regulation of nerve conduction• via inositol/calcium cycle and PGE1
– Required for microvascular system• DLMG - Prostaglandin E1
• AA - Prostacyclin
Pathogenesis of Diabetic Neuropathy
Pathogenesis of Diabetic Neuropathy
• Metabolic factors– High blood glucose– Advanced glycation end products– Sorbitol – Abnormal blood fat levels
• Ischemia
• Nerve fiber repair mechanisms
Natural history of diabetic neuropathy and clinical signs and symptoms with pathological background.
Natural history of diabetic neuropathy and clinical signs and symptoms with pathological background.
• With increasing stage of neuropathy,
there is a progressive loss of nerve fibers that convey sensation.
• When the fibers undergo degeneration or impaired remyelination, they release impulse of positive symptoms.
• With progression of disease, negative symptoms of sensory loss are increased
Multifactorial etiology of diabetic neuropathy. Hyperglycemia exerts increased polyol pathway, enhanced AGE formation, increased
oxidative stress as well as cytokine release. These factors are complicatedly interactive or independently operate for the cause and development of
diabetic neuropathy directly affecting nerve tissues or through nutrient vascular tissues
Mechanisms of how polyol pathway causes neuropathy.
Increased polyol pathway affects differently nerve fibers and supplying vascular tissues. In nerve tissues, polyol yperactivity causes suppression of PKC activity by the inhibition of membranous PKC-a expression while it causes increased PKC activity by elevation of membranous PKC-b expression in vascular wall.
These dichotomous processes eventually elicit decreased Na,K-ATPase activity of nerve tissues and delay of nerve conduction
Pathological findings of sural nerve obtained from diabetic patients with clinically overt neuropathy.
Pathological findings of sural nerve obtained from diabetic patients with clinically overt neuropathy.
There is a marked loss of myelinated
nerve fibers of both large and small caliber. Endoneurial vessels show typical microangiopathic changes exemplified by thickened wall (arrow) (A).
There is also a marked loss of unmyelinated fibers at EM level (B).
Diagnostic TestsDiagnostic Tests
• Assess symptoms - muscle weakness, muscle cramps, prickling, numbness or pain, vomiting, diarrhea, poor bladder control and sexual dysfunction
• Comprehensive foot exam – Skin sensation and skin integrity– Quantitative Sensory Testing (QST)– X-ray
• Nerve conduction studies• Electromyographic examination (EMG)• Ultrasound
Classification of Diabetic Neuropathy
Classification of Diabetic Neuropathy
• Symmetric polyneuropathy
• Autonomic neuropathy
• Polyradiculopathy
• Mononeuropathy
Symmetric PolyneuropathySymmetric Polyneuropathy
• Most common form of diabetic neuropathy
• Affects distal lower extremities and hands (“stocking-glove” sensory loss)
• Symptoms/Signs– Pain– Paresthesia/dysesthesia– Loss of vibratory sensation
Complications of Sensorimotor neuropathy
Complications of Sensorimotor neuropathy
• Ulceration (painless)• Neuropathic edema• Charcot arthropathy• Callosities
Treatment of Symmetric Polyneuropathy
Treatment of Symmetric Polyneuropathy
• Glucose control
• Pain control– Tricyclic antidepressants
– Topical creams
– Anticonvulsants
• Foot care
Essentials of Foot CareEssentials of Foot Care• Examination
– Annually for all patients
– Patients with neuropathy - visual inspection of feet at every visit with a health care professional
• Advise patients to:– Use lotion to prevent dryness and cracking
– File calluses with a pumice stone
– Cut toenails weekly or as needed
– Always wear socks and well-fitting shoes
– Notify their health care provider immediately if any foot problems occur
Autonomic NeuropathyAutonomic NeuropathySymptomatic
Postural hypotension
Gastroparesis
Diabetic diarrhea
Neuropathic bladder
Erectile dysfunction
Neuropathic edema
Charcot arthropathy
Gustatatory sweating
Subclinical abnormalities
Abnormal pupillary reflexes
Esophageal dysfunction
Abnormal cardiovascular reflexes
Blunted counter-regulatory responses to hypoglycemia
Increased peripheral blood flow
Autonomic neuropathyAutonomic neuropathy
• Affects the autonomic nerves controlling internal organs – Peripheral– Genitourinary– Gastrointestinal– Cardiovascular
• Is classified as clinical or subclinical based on the presence or absence of symptoms
Peripheral Autonomic Dysfunction
Peripheral Autonomic Dysfunction
• Contributes to the following symptoms/signs:– Neuropathic arthropathy (Charcot foot)– Aching, pulsation, tightness, cramping, dry skin,
pruritus, edema, sweating abnormalities– Weakening of the bones in the foot leading to
fractures
• Testing– Direct microelectrode recording of
postglanglionic C fibers– Galvanic skin responses– Measurement of vascular responses
Peripheral Autonomic Dysfunction, cont.
Peripheral Autonomic Dysfunction, cont.
• Treatment– Foot care/elevate feet when sitting– Eliminate aggravating drugs – Reduce edema
• midodrine• diuretics
– Support stockings– Screen for CVD
Genitourinary Autonomic Neuropathy
Genitourinary Autonomic Neuropathy
Sign/Symptom TreatmentBladder dysfunction Voluntary urination;
catheterization
Retrograde ejaculation Antihistamine
Erectile dysfunction Sildenafil, tadalafil
Dyspareunia Lubricants; estrogencreams
Gastrointestinal Autonomic Neuropathy
Gastrointestinal Autonomic Neuropathy
• Symptoms/Signs– Gastroparesis resulting in anorexia, nausea,
vomiting, and early satiety– Diabetic enteropathy resulting in diarrhea and
constipation
• Treatment– Other causes of gastroparesis or enteropathy
should first be ruled out– Gastroparesis - Small, frequent meals,
metoclopramide, erythromycin– Enteropathy - loperamide, antibiotics, stool
softeners or dietary fiber
Cardiovascular Autonomic Neuropathy
Cardiovascular Autonomic Neuropathy
• Symptoms/Signs– Exercise intolerance– Postural hypotension
• Treatment– Discontinue aggravating drugs– Change posture (make postural
changes slowly, elevate bed)– Increase plasma volume
PolyradiculopathyPolyradiculopathy• Lumbar polyradiculopathy (diabetic
amyotrophy) – Thigh pain followed by muscle weakness
and atrophy
• Thoracic polyradiculopathy – Severe pain on one or both sides of the
abdomen, possibly in a band-like pattern
• Diabetic neuropathic cachexia– Polyradiculopathy + peripheral neuropathy– Associated with weight loss and
depression
Polyradiculopathy, cont.Polyradiculopathy, cont.
• Polyradiculopathies are diagnosed by electromyographic (EMG) studies
• Treatment– Foot care– Glucose control– Pain control
MononeuropathyMononeuropathy• Peripheral mononeuropathy
– Single nerve damage due to compression or ischemia
– Occurs in wrist (carpal tunnel syndrome), elbow, or foot (unilateral foot drop)
– Symptoms/Signs• numbness• edema• pain• prickling
• Cranial mononeuropathy– Affects the 12 pairs of nerves that are
connected with the brain and control sight, eye movement, hearing, and taste
– Symptoms/Signs• unilateral pain near the affected eye• paralysis of the eye muscle • double vision
• Mononeuropathy multiplex
Mononeuropathy, cont.Mononeuropathy, cont.
Mononeuropathy, cont.Mononeuropathy, cont.
• Treatment– Foot care– Glucose control– Pain control
Other Treatment OptionsOther Treatment Options
• Aldose reductase inhibitors
• ACE inhibitors
• Weight control
• Exercise
Anticonvulsant Drugs for Neuropathic Pain DisordersAnticonvulsant Drugs for
Neuropathic Pain Disorders
• Postherpetic neuralgia
– gabapentin*
– pregabalin *
• Diabetic neuropathy
– carbamazepine
– phenytoin
– gabapentin
– lamotrigine
– pregabalin *
• HIV-associated neuropathy
– lamotrigine
• Trigeminal neuralgia
– carbamazepine*
– lamotrigine
– oxcarbazepine
• Central poststroke pain
– lamotrigine
*Approved by FDA for this use.HIV = human immunodeficiency virus.
Tricyclic Antidepressants: Adverse Effects
Tricyclic Antidepressants: Adverse Effects
• Commonly reported AEs (generally anticholinergic):
– blurred vision
– cognitive changes
– constipation
– dry mouth
– orthostatic hypotension
– sedation
– sexual dysfunction
– tachycardia
– urinary retention
• Desipramine
• Nortriptyline
• Imipramine
• Doxepin
• Amitriptyline
FewestAEs
Most AEs
AEs = adverse effects.
Principles of Opioid Therapy for Neuropathic Pain
Principles of Opioid Therapy for Neuropathic Pain
• Opioids should be titrated for therapeutic efficacy versus AEs
• Fixed-dose regimens generally preferred over prn regimens• Document treatment plan and outcomes• Consider use of opioid written care agreement• Opioids can be effective in neuropathic pain• Most opioid AEs controlled with appropriate specific
management (eg, prophylactic bowel regimen, use of stimulants)
• Understand distinction between addiction, tolerance, physical dependence, and pseudoaddiction
ReferencesReferences
American Diabetes Association: Preventive Foot Care in Diabetes(Position Statement). Diabetes Care 27 (Suppl.1): S63-S64, 2004
Feldman, EL: Classification of diabetic neuropathy. In UpToDate.Wellesley, MA, UpToDate, 2003
National Diabetes Information Clearinghouse. Diabetic Neuropathies:The Nerve Damage of Diabetes. Bethesda, MD: National Institute ofDiabetes and Digestive and Kidney Diseases, National Institutes ofHealth (NIH), DHHS; 2002
National Diabetes Information Clearinghouse. Prevent DiabetesProblems: Keep Your Feet and Skin Healthy. Bethesda, MD: NationalInstitute of Diabetes and Digestive and Kidney Diseases, NationalInstitutes of Health (NIH), DHHS; 2003
References, cont.References, cont.
Feldman, EL: Pathogenesis and prevention of diabeticpolyneuropathy. In UpToDate. Wellesley, MA, UpToDate, 2003.
Feldman, EL, McCulloch, DK: Treatment of diabetic neuropathy. InUpToDate. Wellesley, MA, UpToDate, 2003.
Stevens, MJ: Diabetic autonomic neuropathy. In UpToDate.Wellesley, MA, UpToDate, 2003.
Feldman, EL: Clinical manifestations and diagnosis of diabeticpolyneuropathy. In UpToDate. Wellesley, MA, UpToDate, 2003.