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Diabetic Polyneuropathy
The presence of symptoms and/ or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes

DM Stats
est. 20.8 million people with DM in the US (2005) 6th leading cause of death 25% of diabetics develop foot complications at some point > 1/2 of lower extremity amputations (86,000/year) 80% after foot ulcer or injury

Diabetes Mellitus Neuropathy

DiabetesMellitus is the most common cause of peripheral neuropathy in the developed world 50% experience painful symptoms 20% seek treatment Affects 50-90% of patients with Diabetes Mellituts Average yearly cost of pain meds: $1600

Incidence depends on Diabetes Mellitus duration and glycemic control.

Complications
calluses skin changes vascular problems infections joint abnormalities

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charcot ulcerations amputation

- 50-75% of nontramatic amputation (Duby et al)

Pathophysiology of Diabetic Foot Ulcers

Quality of life Issue

Emotional reactions Energy Pain Physical mobility sleep employment recreation social interactions

Risk Factors
Poor Glycemic control Cigarette smoking HTN Height

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hypercholesterolemia

Positive Symptoms
Pain and paresthesia Burning pain knife like electrical sensation constricting hurting freezing throbbing allodynia

Negative Symptoms
Sensory Loss More prevalent than positive Asleep "Dead" Numbness Tingling Prickling

Differentials
10% of Neuropathy in Diabetes Mellitus are not caused by Diabetes Mellitus Autoimmune Monoclonal Gammopathy Multiple Myeloma Sjogren's Syndrome Genetic Disease Hereditary motor and sensory neuropathy Hereditary motor and autoimmune neuropathy Fabry's Disease Infectious Disease HIV

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Hepatitis Virus Leprosy Tabes Dorsalis Lyme Disease Inflammatory Causes Chronic Inflammatory Demyelinating Polyneuropathy Paraneiplastic Neuropathy Metabolic Disease Uremia (including renal Failure) Hypothyroidism Nutritional Deficiencies Alcoholism Vitamin B deficiencies Toxic Causes Heavy metal poisoning Drugs (paclitaxel, metronidazole, amiodarone, dapsone, nitrofurantoin, linezolid) Vasculitis Polyarthritis nodosa (including Churg-Strauss variant) Wegner's Granulomatosis Charcot Marie Tooth HIV Toxins - lead, arsenic Vitamin B deficiency Leprosy Amyloid neuropathy Renal Insufficiency Myeloma Chronic alcoholism (nutritional deficiency)Malabsorption disease Guillian-Barre Syndrome Drugs - cholchicine, hydralazine Vasculitis

Differential Diagnosis Clinical Evaluation

Semmes-Weinstein monofilament 128hz tuning fork Sharp/ dull light touch

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Warm cold Distribution - mononeuropathy - focal lesion of a single nerve - polyneuropathy Duration Demyelinating Vs. Axonal - Electrodiagnosis studies Course

Laboratory Investigation
Hematology CBC, ESR, CRP, Vit B-12, folate Biochemical and endocrine comprehensive metabolic panel (fasting blood glucose, renal function, liver function), glycosylated Hb (HbA1C), thyroid function test, serum protein electrophoresis. Specialized test for specific diseases connective tissue disease, vasculitis, nerve biopsy etc.

Testing
Quantitative Sensory Testing Computer-based, nonivasive, psychophysical, semiobjective measure Measure thermal and vibration sensations and cold-or-heat evoked pain threshold Not specific to peripheral nerve function

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Depressed nerve conduction velocity velocity usually indicates demyelination Nerve Conduction velocity diminishes gradually DPN Changes in nerve conduction velocity does not correlate with onset or severity of DPN pain or other clinical symptoms Insensitive to pathological changes associated with DPN pain Figure 1 Algorithm showing a stepwise approach to the assessment and investigation of a possible neuropathy. CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CMT, Charcot-MarieTooth; EMG, electromyography; GBS, Guillain-Barre syndrome; HNPP, hereditary neuropathy with liability to pressure palsies; NCS, nerve conduction studies.

PT Education Classification: Clinical Patterns

Symmetrical Diabetic Poplyneuropathy Diabetic autonomic neuropathy "diabetic cachexia" Painful distal neuropathy associated with weight loss Insulin neuritis Hypoglycemic neuropathy Asymmetrical Diabetic radiculoplexus neuropathies Lumbosacral Thoracic

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Cervical

Mononeuropathies Median neuropathy at the wrist Ulnar neuropathy at the elbow Peroneal neuropathies at the Fibular head Cranial neuropathy oculomotor palsy abducens palsy

Clinical Types of Peripheral Diabetic Neuropathy Why Distal and symmetrical?

Pathologically and electrophysiologically all nerves are affected in DPN - large sensory or autonomic fibers predominate Chronic DPN usually reveals a symmetrical sensory loss to all modalities in a stocking distribution - Nerve fibers are affected in a length dependent fashion * greater distance from the parent body Small less myelinated fibers are affected first, Sensory rather motor

Effects of Ischemia
Focal Fiber Loss

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Ischemic neuropathy - multiple regenerating fascicles, replace areas devoid of myelinated fibers Decreased VEGF(A)

Cause of Diabetic Neuropathy

2 mechanisms direct hyperglycemia-induced damage to nerve paremchyma alteration in key enzymes (reduction in Na+/K+ ATP activity) Reduction of neurotrophic factors apoptosis neuron loss neuronal ischemia brought about indirectly by hyperglycemia induced blood flood endoneuronial edema increased endoneurial pressure Capillary closure schemia Reduction in a NO decreased vasorelaxation

Microvascular Disease
Blood flow decreased by 50% to peripheral nerves (Packer) Vascular changes precede the development of DPN Direct correlation between vessel damage and severity of DPN Small blood vessels changes thickening of the basement membranes of endoneurial capillaries - ischemic nerve injury endothelial cell activation and proliferation Pericyte degeneration Monocyte adhesion

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Histopathological Characteristics DPN

Nerves Characterized by a loss of myelinated and unmyelinated fibers observed in transverse nerve sections thickening of axons- Increase in intracellular fluid decrease in monofilaments Capillary narrowing involving small myelinated or non-myelinated c-fibers

Mechanisms of hyperglycemia-induced vascular damage

In general, the adverse effects of hyperglycemia can cause vascular dysfunction by: - generating toxic and reactive metabolites - alternating intracellular signaling pathways Aldose Reductase (Polyol Pathway) Theory Advanced Glycation Endproduct Theory Reactive Oxygen Intermediate Theory Protein Kinase C Theory

Overall Pathways involved in Diabetic Complications Aldose Reductase Pathway

Evidence: In Lab animals, osmotic imbalance that produces (edema) generative Schwaan cell changes Some prevention of the pathological changes in rodent models of diabetic neuropathy, retinopathy, and nephropathy Increased levels of AR in the lens--> cataract Increased NADH/NAD+ ratio, alter gene expression, complications Decline in NADPH, decrease generation of NO in endothelial cells

NO
a mediator of cell-to-cell communication and potent vasodilator

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Macrophages use as a cytotoxic agent Impaired neuronal NO generation induces hyperalgesia

AGE Evidence
Aminoguanidine has been shown to block the development of microvascular complications of diabetes in animal models Direct relationship between AGE levels and endothelium-dependent and independent vasodilation Decreased endothelium prostacyclin (PGI2) production Increased endothelial permeability to macromolecules

AGE Overview
Hyperglycemia, natural aging process Maillard Reaction irreversible binding of sugar to protein nonenzymatic glycation AGE damage cells by impairing the function of a wide range of proteins (i.e. basic fibroblast growth factor), hormones, cytokines Binding of AGE to RAGE produces a cascade of cellular signaling event

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Modifications of extracellular structural proteins such as collagen and intracellular proteins Inhibits production of NO

AGE and NO
decreases the bioavailability and activity of endothelium derived NO NO inhibits many mechanisms the contribute to the artherosclerosis - leukocyte adhesion - vascular smooth muscle cell growth - platelet adhesion

AGE Agents

ROS
One of the oldest theories of Diabetic Complications

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Decreased levels of antioxidants such as reduced Glutathione, NADPH Vitamin C, and Vitamin E in patients with diabetes Increased levels of makers of Oxidative stress (oxidized LDLP and urinary isoprostanes) Decreases equivalents used to drive the synthesis of ATP

Effects of ROS
increased oxidant levels stress reduces NO levels - altered vasoregulation - less detoxification of ROS damages cellular proteins - Vit E and Lipoic acid have improved early hemodynamic changes in the kidney, retina,and peripheral nervespromotes leukocyte adhesion to the endothelium while inhibiting its barrier function

Protein Kinase C Theory

intracellular signaling molecule, regulates many vascular functions permeability vasodilator release endothelial activation growth factor signaling Increased levels in various tissues of animals w/ diabetes Inhibitors have been shown to block may abnormalities in endothelial cells Activation of Protein Kinase C in the blood vessels of the retina, kidney, and nerves can produce increased permeability NO dysregulation increased leukocyte adhesion alterations in blood flow PKC inhibitors- reversed

Treatment
Tight glycemic control emphasis of management DCCTS (Diabetes Control and Complications Trail) - Intensive therapy of Type I diabetes reduces the frequency of appearance of neuropathy by 60% over a 5 year period in patients who did not have neuropathy at the onset of the study UK Prospective Diabetes Study, Steno Study Rochester

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Treatment According to Symptoms

Topical Capsaicin- depletes tissues of substance P and reduces chemically induced pain Topical Nitrate Physical Therapy percutanous nerve stimulation, static magnetic field therapy, low intensity laser therapy, monochromatic infrared light Accupuncture?

Surgical Decompression
Longitudinal view of tibial nerve

Distal ends compressed Neurolysis of the common peroneal nerve at the fibular neck, and deep peroneal at the dorsum of the foot release of the 4 medial ankle tunnel - tarsal, medial and lateral plantar, calcaneal Internal neurolysis of the tibial nerve Prospective study 60 DM; 40 of unknown eitology

Treatment: Opiods
Non-traditional agents Most effective in elderly (more tolerated) Tramadol- opiod-like centrally acting synthetic narcotic analgesic effects on presynaptic Cl channels Oxycodone controlled release Addiction! Possible add on therapy?

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Mechanisms of action of medications used in treating painful diabetic neuropathy

Treament
TCA mainstay in many centers Use is restricted due to frequency and severity of S.E. Attempts to target mainly NE and 5HT Reason for SE: affects many types of receptors such as muscurinic, histamine, dopamine, NMDA and alpha one receptors Cymbalta (Duloxetine) equal affinity for 5HT and NE - primarily related to Anti-ACh actions: dry mouth blurred vision, cardiac arrhythmias, sedation, urinary retention, conatipation,and postural hypertention - Caution with: Monoamine oxidase inhibitor, those with uncontrolled narrowangle glucoma, pts taking thioridazine Anticonvulsants (Pregablin) MOA: NA channel blockade Potentiation of GABA activity Ca+2 channel blockade NMDA anatagonist Pregabalin Derivative of GABA.

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How it works: Attaches to overfiring nerve cells bonds to Ca2+ channel modualtes influx of Ca2+ in the hyperexcited neuron Decreases the flow of Ca2+ into the axon during depolarization or firing of the neuron decreasing the neurotransmitter release from the neuron - Decreases in excitatory neurotransmitter (glutamate, NE, Substance P and Calcitonin gene- related peptide

Treatment: Future
VEFG (vacular endothelial growth factor) - gene transfer in DM rats: restored NCV, nerve blood flow, nerve vessel numbers to normal Identify the common pathway used by glucose to exert their effects - New therapies against Protein Kinase C Neutralization of specific glucotoxins such as ROS and AGE - inhibitors of AR, AGE inhibitors, antioxidants, and anti-inflammatory agents - Lack of efficacy due to dose limiting S.E. and inability to achieve adequate drug tissue levels

Treatment: Alpha Lipoic Acid

Free radical scavenger - acts as an antioxidant in preventing the oxidative stress associated w/ DPN Germany > 30 years Replenishes Glutathione

Summary
Diabetic neuropathy is a frequent complication of DM Hyperglycemia and it's metabolites can cause bewildering array of biomechanical and biological changes in vascular and peripheral neuronal tissues

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The multiplicity of pathways by which hyperglycemia can generate toxic metabolites likely explains the general lack of efficacy of intervention targeted to a specific glucotoxin

References
Argoff CE,Cole B. et al. Diabetic Peripheral Neuropathic Pain: Clinical and Quality-of-Life Issues. Mayo Clinical Preceedings. 2006; 81: S3-S11 Lu D, Dauphinee D. Morphological and Functional in the Diabetic Peripheral Nerve Using Diagnostic Ultrasound and Neurosurgery to Select Candidates for Nerve Decompression. Journal American Podiatric Medical Association. 2005; 95:433-437 Sinnreich M, et al. Diabetic Neuropathies: Classification, Clinical Features, and Pathophysiological Basis. The Neurologist. 2005; 11:63-79 Dudy JJ, et al. Diabetic Neuropathy: AN Intensive Review. American Journal Health-System Pharm. 2004; 61: 160-176 King RH. The Role of Glycation in the Pathogensis of Diabetic Polyneuropathy. Journal Clinical Pathology: Med Pathol 2001; 54: 400-408 Simmons Z, Feldman E. Update on Diabetic Neuropathy. Curr Opin Neurology 2002;15: 595603 Bril et al. Sural Nerve Sorbitol in Patients with Diabetic Sensorimotor Polyneuropathy. Diabetic Care 2004; 27 1160-1163 Bulton AJM et al. Diabetic Neuropathies. Diabetic Care 2005; 28: 956-962 Rather HM, Boulton AJM. Recent Advances in the Diagnosis and Management of Diabetic Neuropathy. The Journal of Bone and Joint Surgery 2005; 87:1605-1610 Packer, Lester. Oxidative Stress, The Antioxidant Network, and Prevention of Diabetes Complications by Alpha-Lipoic Acid. Environmental & Nutritional Interactions 1999; 3:47- 76 Sheetz M, King G. Molecular Understanding of Hyperglycemia's Adverse Effects For Diabetic Complications. JAMA 2002. 288: 2578-2588 Goldin A et al. Advanced Glycation End Products: Sparking the Development of Diabetic Vascular Injury. Circulation 2006. 114: 597-605 Zangaro, G et al. Diabetic Neuropathy: Pathophysiology and Prevention of Foot Ulcers. Clinical Nurse Specialist 1999. 13: 57-65 Giancarlo C, Massimo C. Metabolic Neuropathies. Current Opinion in Neurology 1998. 11:523529 Westanmo A, Gayken J et al.Duloxetine: A Balanced and Selective Norepinephrine- and Serotonin-reuptake inhibitor. American Journal Health System Pharm 2005. 62: 2481- 2490 Vinik, Aron. Clinical Review: Use of Antiepileptic Drugs in the Treatment of Chronic Painful Diabetic Neuropathy. The Journal of Clinical Endocrinolgy 2005. 90:4936-4945

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David, Nathan. The Pathophysiology of Diabetic Complications : How Much Does the Glucose Hypothesis Explain? Annals of Internal Medicine 1996. 124:86-89

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