1. Diabetic Neuropathy Beverly J. Mathis, D.O. November 2007

2. Definition Complex syndrome of neurological abnormalities caused by the metabolic and vascular complications of diabetes. Complex syndrome of neurological abnormalities caused by the metabolic and vascular complications of diabetes.

3. Class I Subclinical Neuropathy Abnormal electrodiagnostic tests Abnormal electrodiagnostic tests Decreased nerve conduction velocity Decreased amplitude of evoked muscle or nerve action potential Decreased nerve conduction velocity Decreased amplitude of evoked muscle or nerve action potential Abnormal quantitative sensory testing Vibratory/ warming/cooling Abnormal quantitative sensory testing Vibratory/ warming/cooling Abnormal autonomic function tests Abnormal autonomic function tests Sinus arrhythmia (beat-to-beat heart rate variation) Sinus arrhythmia (beat-to-beat heart rate variation) Increased pupillary latency Increased pupillary latency

4. Class II Clinical Neuropathy Diffuse neuropathy Distal symmetric sensorimotor polyneuropathy Distal symmetric sensorimotor polyneuropathy Primarily small fiber neuropathy Primarily small fiber neuropathy Primarily large fiber neuropathy Primarily large fiber neuropathy Mixed Mixed

5. Class II Clinical Neuropathy Autonomic neuropathy Abnormal pupillary function Abnormal pupillary function Sudomotor dysfunction Sudomotor dysfunction Genitourinary autonomic neuropathy Bladder dysfunction Genitourinary autonomic neuropathy Bladder dysfunction Sexual dysfunction Sexual dysfunction

6. Class II Clinical Neuropathy Autonomic neuropathy Gastrointestinal autonomic neuropathy Gastric atony Gastric atony Gall bladder atony Gall bladder atony Diabetic diarrhea Diabetic diarrhea Hypoglycemic unawareness (adrenal medullary neuropathy) Hypoglycemic unawareness (adrenal medullary neuropathy)

7. Classification Distal symmetric polyneuropathy Distal symmetric polyneuropathy Individual cranial or peripheral nerve palsies, especially cranial nerve III Individual cranial or peripheral nerve palsies, especially cranial nerve III Autonomic neuropathy Autonomic neuropathy Thoracic and lumbar nerve root disease Thoracic and lumbar nerve root disease Mononeuropathy multiplex (assymmetric involvement of peripheral nerves Mononeuropathy multiplex (assymmetric involvement of peripheral nerves

8. Incidence 10-18 percent have evidence at diagnosis of diabetes 10-18 percent have evidence at diagnosis of diabetes Increases up to 41 % at 10 years Increases up to 41 % at 10 years Progession and severity directly correlates with diabetes control Progession and severity directly correlates with diabetes control

9. Glycemic control prevents diabetic neuropathy DCCT, NEJM 1993

10. Signs and Symptoms of Diabetic Peripheral Neuropathy Loss of vibratory sensation and altered proprioception reflecting large-fiber loss Loss of vibratory sensation and altered proprioception reflecting large-fiber loss Impairment of pain, light touch and temperature is secondary to loss of small fibers Impairment of pain, light touch and temperature is secondary to loss of small fibers

11. Complications of Peripheral Neuropathy Foot ulcers due to progressive sensory loss Foot ulcers due to progressive sensory loss Muscular Atrophy Muscular Atrophy Charcot foot with fractures, subluxation and sclerosis of bone Charcot foot with fractures, subluxation and sclerosis of bone

12. Criteria for Diagnosis Loss of touch sensation using a monofilament on the distal toes Loss of touch sensation using a monofilament on the distal toes Loss of vibratory sensation using a 128 Hz tuning fork at the first MCP joint Loss of vibratory sensation using a 128 Hz tuning fork at the first MCP joint Absent achilles reflex Absent achilles reflex Most important is to inspect the feet for callus formation Most important is to inspect the feet for callus formation

13. Differential Vascular disease – ischemia, vasculitis Vascular disease – ischemia, vasculitis Metabolic – thyroid disease, B12 or B6 deficiency Metabolic – thyroid disease, B12 or B6 deficiency Disc disease Disc disease

14. Pathogenesis Metabolic –accumulation of advanced glycosalation end products, accumulation of sorbitol and increased oxidative stress Metabolic –accumulation of advanced glycosalation end products, accumulation of sorbitol and increased oxidative stress Ischemic – small vessel disease Ischemic – small vessel disease Impaired peripheral nerve repair Impaired peripheral nerve repair

15. Prevention GLUCOSE CONTROL GLUCOSE CONTROL Other risk factors though not proven include cigarette smoking, blood pressure control,no alcohol consumption and lipid treatment. Other risk factors though not proven include cigarette smoking, blood pressure control,no alcohol consumption and lipid treatment.

16. Treatment of painful diabetic neuropathy Tier I Tier IPregabalinDuloxetine Tier II Tricyclics, gabapentin, oxycodone

17. Treatment of painful diabetic neuropathy Capsaicin cream Capsaicin cream Anticonvulsants – lamotrigine, carbamazepine, topiramate Anticonvulsants – lamotrigine, carbamazepine, topiramate Anesthetic drugs – mexilitine, lidocaine patches Anesthetic drugs – mexilitine, lidocaine patches Alpha-lipoic acid Alpha-lipoic acid Tramadol Tramadol

18. Less studied treatments L carnitine L carnitine Nitro spray Nitro spray NSAIDS (stay away from this one!) NSAIDS (stay away from this one!) TENS unit TENS unit Venlafaxine Venlafaxine ACE inhibitors ACE inhibitors Aldose reductase inhibitors (too toxic) Aldose reductase inhibitors (too toxic)

19. Autonomic neuropathy Orthostasis – use vasodilators and avoid overdiuresis. Orthostasis – use vasodilators and avoid overdiuresis. Neurogenic bladder – self cath, suprapubic catheter Neurogenic bladder – self cath, suprapubic catheter Gastroparesis – motility agents – metoclopramide, erythromycin, dulcolax, gastric pacemaker Gastroparesis – motility agents – metoclopramide, erythromycin, dulcolax, gastric pacemaker

20. Autonomic neuropathy Diabetic diarrhea – due to stasis, often over treated with antimotility agents which can make it worse Diabetic diarrhea – due to stasis, often over treated with antimotility agents which can make it worse Soluble fiber – Fibercon, metamucil firms up the stoolSoluble fiber – Fibercon, metamucil firms up the stool Cholestyramine, Colistid – bile resin bindersCholestyramine, Colistid – bile resin binders