The document discusses diabetic peripheral neuropathy (DPN), including its prevalence, impact, signs and symptoms, and strategies for management. DPN is nerve damage caused by diabetes that affects around 50-90% of patients. It can lead to foot ulcers and amputations, as well as other complications. DPN produces both positive symptoms like pain and negative symptoms like numbness. Disease modifying strategies aim to slow progression while symptomatic strategies target pain and other sensations. Diagnostic tests are needed to detect and monitor DPN.

1. The Pharmacological Management of Diabetic Peripheral Neuropathy: Disease Modifying vs. Symptomatic Strategies

2. Presentation Objectives Understand the economic and social impact of DPN Distinguish between positive and negative symptoms of diabetic peripheral neuropathy Describe disease modifying vs. symptomatic strategies in the management of DPN Understand the potential MOA of Metanx ® in the management of positive and negative DPN symptoms

3. “ I marvel that society would pay a surgeon a large sum of money to remove a person’s leg – but nothing to save it.” – George Bernard Shaw

4. Diabetic Peripheral Neuropathy: What is it? Nerve damage and dysfunction secondary to diabetes mellitus type 1 or 2 Consensus definition: “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes” A leading cause of neuropathic pain A very common complication of diabetes

5. DPN Prevalence Tavakoli M, et al. Current Pain and Headache Reports . 2008;12:192-197. Diabetic Neuropathy may occur in 50% to 90% of patients depending on the criteria used for diagnosis

6. Impact of Diabetic Neuropathy 60-70% of foot ulcers are preceded by neuropathy 85% of diabetes related lower limb amputations are preceded by a foot ulcer 3 out of 10 patients who undergo lower limb amputation will lose another leg within 3 years and over half of them will die within the first 5 years of the first amputation Gordois et al. Diabetes Care . 2003;26:1790-1795. Reiber G, et al. Diabetes in America . 1995; 2nd ed:409-428.

7. Impact of Diabetic Neuropathy Largest number of diabetes related hospital bed-days Frykberg R, et al. Journ of Foot and Ankle Surgery 2006;45(5):S2-S8. Most Common Proximate, Nontraumatic Cause of Amputations Reiber GE, Vilekyte L, Bokyo EJ et al. Diabetes Care .1999;22. Pecoraro RE, Reiber GE, Burgess EM. Diabetes Care . 1990;13.

8. Clinical Unmet Needs in DPN There are a wide range of treatments available for neuropathic pain This prescribing pattern suggests that there is no one treatment that addresses all the factors Despite a spectrum of drugs available with different modes of action, many patients remain inadequately treated in several aspects of the disease Datamonitor Research 2008. Increasing level of importance Improved efficacy Improved side effect profile Reduced time to onset of action Fewer drug-drug interactions Reduced pill burden

9. Diabetic Neuropathy: The Forgotten Complication Only one in four survey respondents who experience symptoms of diabetic neuropathy have been diagnosed with the condition. The majority of respondents who experience symptoms (56%) remain unaware of the term diabetic neuropathy. 62% believe that their symptoms are associated with their diabetes, but only 42% have been told by their physician that diabetes is the cause. Approximately one in seven people who said they talked to their doctor about their symptoms and pain reported that no cause was mentioned. Results of the 2005 ADA National Survey May 10, 2005 /PR Newswire via COMTEX.

10. Signs and Symptoms of Diabetic Peripheral Neuropathy Signs Diminished vibratory perception Decreased knee and ankle reflexes Reduced protective sensation, such as pressure, hot and cold, pain Diminished ability to sense position of toes and feet Symptoms Numbness, loss of feeling, prickling, tingling Aching pain Burning pain Lancinating pain Unusual sensitivity or tenderness when feet are touched (allodynia) Boulton AJ, et al. Diabetes Care . 2005 April; 28(4):956-62. Distal symmetrical sensorimotor polyneuropathy is the most common form of DPN. Signs and symptoms may progress from distal to proximal over time.

11. DPN Produces Positive and Negative Symptoms Positive Symptoms Spontaneous Pain Dysesthesias C-Fibers Unpleasant Paresthesias A-Fibers Not Unpleasant Negative Symptoms Loss/impairment of sensory quality Numbness Dry skin Erectile dysfunction Incontinence Gait instability and fall risk Baron R. Clin J Pain . 2000;16(2 suppl):S12-S20. Argoff CE, et al. Mayo Clin Proc . 2006;81(4 Suppl):S3-S11. Boulton AJ, et al. Diabetes Care . 2005;28(4):956-962.

12. Neuropathic Symptoms and Quality of Life Positive and negative symptoms have an impact on functioning, activities of daily living (ADL) and QOL QOL is a unique, individual experience – how persons perceive and react to their health status Psychosocial Morbidity Depression Anxiety Anger Loss of Self-Esteem Societal Consequences Social isolation Strained relationships with family and friends Effects upon intimacy/sexual activity Argoff CE, et al. Mayo Clin Proc . 2006;81(4 Suppl):S3-S11.

13. Diabetic Neuropathy: Symptoms Majority of symptomatic DPN patients are insensate Argoff CE, et al. Mayo Clin Proc . 2006;81:(S4). Boulton AJM, et al. Diabetes Care . 2004;27. Pain Asymptomatic Sensory Loss

14. Clinical Impact of Positive and Negative DPN Symptoms DPN Boulton A. NCVH. Oral Presentations. 2007. Mortality Cost Impairment Disability Handicap Infection (skin, bone) Charcot Foot Foot Ulcers Painful Neuropathy Quality of Life Sensory Loss Surgery, Amputation

15. ADA Consensus Statement “ The effort to optimize foot care for patients with diabetes led to the American Diabetes Association consensus statement on foot care, which recommended that the cutaneous pressure threshold be measured at least once a year” “ The goal of this recommendation is to reduce the risk of ulceration, infection and amputation due to sensory loss that can occur through progressive neuropathy” Barber MA. Journ of APMA . 2001;91(10):508-514.

16. Etiology of Diabetic Neuropathy Vinik A. The Amer Journal of Med . August 1999. DIABETES Hyperglycemia  DAG  PKC Impaired n-6 fatty acid metabolism Polyol pathway Sugar autoxidation Advanced glycation OXIDATIVE STRESS ENDOTHELIAL DYSFUNCTION  capillary blood flow  endoneurial hypoxia NERVE DYSFUNCTION  NCV,  Regeneration, Structural damage  Triglycerides  LDL

17. Endothelial Dysfunction in Diabetic Neuropathy Endothelium : a biologically active organ Deranged nitric oxide pathways Multifactorial Hyperglycemia Insulin resistance FFA production / metabolism Minami M, et al. Journ of Cardiovas Pharmacol . 1998;31(Suppl 1):S467-S469. Wu G and Meininger CJ. Biofactors . 2009;35(1):21-27. Veves A, et al. Diabetes . 1998;47:457-463.

18. ADA Statement Diabetic Neuropathies Classification of Neuropathies Generalized symmetric polyneuropathies Acute sensorimotor Chronic sensorimotor Autonomic Focal and multifocal neuropathies Cranial Truncal Focal limb Proximal (Amyotrophy) Co-existing CIDP Boulton AJ, et al. Diabetes Care . 2005;28(4):956-962.

19. Sensorimotor Neuropathy Most common type of diabetic neuropathy Affects 30-50% of all diabetic population Most commonly involved in diabetic foot problems Diabetic Neuropathies: A Statement by the ADA. Diabetes Care . 2005;28(4):956-962.

20. Sensorimotor Neuropathy Development progressive, initially involving more distal parts Main symptoms are numbness of the legs and feet, muscular cramps, pins and needles, shooting, deep aching and burning pain. Nocturnal exacerbation characteristic Symptoms may be absent or present either in the early or late stages Symptoms Diabetic Neuropathies: A Statement by the ADA. Diabetes Care . 2005;28(4):956-962.

21. Acute Sensory and Chronic Sensory Neuropathies Diabetic Neuropathies: A Statement by the ADA. Diabetes Care . 2005;28(4):956-962. Acute Sensory Chronic Sensorimotor Mode of onset Relatively rapid Gradual, insidious Symptoms Severe burning pain, aching: weight loss usual Burning pain, paresthesia, numbness: weight loss usual Symptom severity +++ 0 to ++ Signs Mild sensory in some: motor unusual Stocking and glove sensory loss: absent ankle reflexes Other diabetic complications Unusual Increased prevalence Electrophysiological investigations May be normal or minor abnormalities Abnormalities unusual in motor and sensory nerves Natural history Complete recovery within 12 months Symptoms may persist intermittently for years: at risk of foot ulceration

22. Autonomic Neuropathy Heart rate abnormalities Postural hypotension Abnormal sweating Gastroparesis Neuropathic diarrhea Impotence Retrograde ejaculation Diabetic Neuropathies: A Statement by the ADA. Diabetes Care . 2005;28(4):956-962.

23. Predictors of Foot Ulceration Rich J, Veves A. Wounds . 2000;12(4):82-87. Variable No Ulcer (127) Ulcer (53) P-value NSS 2.1 + 2.4 2.7 + 2.8 0.297 NDS 13 + 8 18 + 5 0.0001 VPT (volts) 38 + 15 46 + 6 0.0001 SWF 5.90 + 1.20 6.63 + 0.74 0.0001 NP Pedal Pulse 28 (22%) 20 (38%) 0.035 STJ mobility 22 + 7 22 + 11 0.784 1st MTP mobility 71 + 18 61 + 20 0.002 Forefoot PP 6.6 + 2.8 8.2 + 4.3 0.005 Rearfoot PP 3.1 + 1.5 3.4 + 1.8 0.37

24. Other Diagnostic Tools for Detection of DPN 5.07 Semmes-Weinstein Monofilament Biosthesiometer ® Calibrated Tuning Fork Diskcriminator for 2 Point Spacing Neurometer CPT ® (A-beta,A-delta,C fibers) PSSD ® (Earliest detection of pathology of A-beta skin surface/touch fibers Neuropad (correlates with IENFD, p=0.04) Quatrini C, Boulton A, et al. Diabetologia . 2008;51(6):1046-1050. Boulton AJ, et al. Diabetes Care . 2004;27(6):1458-1486. Boulton AJ, et al. Prev and Treatment of Diab and its Compli . 1998;82(4):909-919. Barber MA, et al. J Am Podiatr Med Assoc . 2001;91(10):508-514. Kiso T, et al. Journ of Pharmaco and Experi Therap . 2001;297(1):352-356.

25. Diagnostic Tests for DPNP Nerve Conduction Studies/Electromyogram Measures the speed and amplitude of sensory and motor conduction Objective, parametric, non-invasive Insensitive in acute and small-fiber neuropathy > 50% False Negative for Tarsal Tunnel Syndrome Quantitative Sensory Test Detects sensory thresholds for vibration, heat and pain Useful in tracking the progression of neuropathy in large cohorts and the efficacy of treatment end points in multicenter clinical trials Skin Biopsy (IENFD) Measures density of intraepidermal nerve fibers at various sites in the leg Loss of nerve fibers is associated with increased neuropathic pain Although the test is invasive, it requires a 3mm skin biopsy specimen and enables a direct study of small nerve fibers Pathways: Perspectives in Modern Neurology and Pain Management . Vol 3. July 2007; Page 6.

26. Diagnosing Small Fiber Neuropathy with Skin Punch Biopsy Small Fiber Neuropathy (SFN) is a major cause of painful burning, numbness and tingling in feet/hands SFN often precedes diagnosis of diabetes a.k.a. “impaired glucose tolerance neuropathy” Diagnostic efficiency of skin punch biopsy is ≈ 88% Findings on routine nerve conduction studies and electromyography are typically normal (large fiber only) Management of SFN should involve controlling the symptoms and aggressively treating the underlying cause Tavee et al. Cleveland Clinic Journal of Medicine . May 2009.

27. Skin Biopsy Normal nerve fiber density. Arrow points to the small nerve fiber in the epidermal layer of skin, arrowhead points to the basement membrane that separates the dermis from the epidermis. Low normal nerve fibers, consistent with small fiber neuropathy. The arrow points to the basement membrane of the epidermis. Images Courtesy of Therapath, LLC.

28. Diabetic Neuropathy: Current Treatments 25% NO TREATMENT 53.9% OPIOIDS 39.7% NSAIDS 21.1% SSRIs 11.3% TCAs 11.1% ANTICONVULSANTS Berger A, Dukes EM, Oster G. J Pain . 2004;5. Only Target Positive (Painful) Symptoms

29. Treatment Options for DPNP: Palliative Agents *FDA Approved. Adapted from Tavakoli M and Malik R. Expert Opin Pharmacother . 2008. Class Therapy Dose (mg/day) Aldose reductase inhibitors Epalrestat Only licensed in Japan Angiotensin-converting enzyme inhibitors Trandalopril More studies needed Tricyclic antidepressants Amitriptyline Imipramine 20-150 25-150 SNRIs Duloxetine* 60-120 Anticonvulsants Gabapentin Lamotrigine Carbamazepine Pregabalin* 900-3600 200-400 200-600 300-600 Antiarrhythmics Mexilitene Up to 900 Opioids Tramadol 50-400

30. Current Palliative Treatments Chen H, Lamer TH, Rho RH, et al. Mayo Clin Proceed . 2004;79. Distal Neuropathy C-fibers (dysesthesias, allodynia, burning) A-fibers (paresthesias, radiating, night cramps) Capsaicin cream Clonidine Lidocaine Insulin Infusion Carbamazepine Lidocaine Muscle relaxant NSAIDs Tramadol TCA Gabapentin Pregabalin Duloxetine

31. Treatment Options for DPN: Disease Modifying Agents Adapted from Tavakoli M and Malik R. Expert Opin Pharmacother . 2008. Class Therapy Dose (mg/day) Glucose Control – – Pancreas transplantation – – Antioxidant Alpha Lipoic Acid 600 mg intravenously 1200-1800 mg orally Neurotrophic Support L-methylfolate, P5P, Me-Cbl 2.8 mg, 25 mg, 2 mg, BID

32. L-methylfolate Active form of folate necessary for neural function Works with Methyl B 12 to activate protein, DNA / RNA synthesis Increase nitric oxide synthesis Methylcobalamin Neurologically active form of B 12 Methyl donor in DNA metabolism, Up-regulate gene transcription for peripheral nerve repair & regeneration Enhance protein metabolism in Schwann Cells Pyridoxal 5’-phosphate Active form of B 6 , Necessary for neural function May inhibit effects of advanced glycation end products L-Methylfolate 2.8 mg Methylcobalamin 2 mg Pyridoxal 5’ –phosphate 25 mg METANX ® Metanx ® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy. Verhaar, et al. Circulation . 1998. Yaqub, et al. Clin Neurol and Neuros . 1992. Beck W. New Eng Journ Med . 1988. Goh S and Cooper M. Clin Endocrin & Metabol . 2008. Wantanabe, et al. Journ of Neurolog Scien . 1994.

33. Metanx ® : A Medical Food 1988 via amendments to the Federal Food, Drug and Cosmetic Act: Active ingredient: present in / derived from a food (e.g. folate) Oral dosage form Addresses distinct nutritional requirements of patients with specific diagnosed diseases or conditions (e.g. low plasma / RBC folate, hyperhomocysteinemia, endothelial dysfunction) Efficacy/dosing must be proven in peer-reviewed scientific literature Only under care of health care provider (Available by prescription) Metanx ® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy.

34. Medical Foods Pharmaceutical Medical Food Dietary Supplement (Neutraceutical) Intended Use To treat, prevent, or mitigate a disease or condition Nutritional or dietary management of a specific disease To maintain the well-being of a particular function in the body (e.g. maintain healthy joints Consumer Person suffering from a disease or abnormal condition Person suffering from a disease or abnormal condition Normal, relatively healthy person Evidence Requirements Must have 2+ placebo controlled trials (and a maintenance trial for certain disease states). Usually involves animal testing: Phase 1, 2, & 3 clinical trials The distinct nutritional requirement of the specific disease and product performance must be supported by peer reviewed literature, clinical/scientific study, and medical determination No specific requirements for pre-market testing Safety Pharmacology and toxicology testing required. Must be deemed ‘safe & efficacious’ by the FDAs review of adverse events, drug interactions, dosing and toxicity Ingredients must attain FDA GRAS (Generally Regarded as Safe) status. GRAS denotes broad scale, up-front safety Ingredients have some ‘expectations’ of safety as evidenced by having been sold in the U.S. market prior to October 1994 Medical Care Must be prescribed by a physician or licensed NP/PA Must be used under a physician’s supervision (or licensed) by prescription None. Supplements are typically self-administered by the consumer and are sold over the counter Regulatory Review Body of the FDA Center for Drug Evaluation and Research (CDER) Center for Food Safety and Applied Nutrition (CFSAN) DSHEA – Dietary Supplement Health Education Act (1994) under the same center (CFSAN) as medical foods.

35. Metanx ® Indication and Dosage The distinct nutritional requirements of patients with endothelial dysfunction: Who present with loss of protective sensation and neuropathic pain associated with diabetic peripheral neuropathy and/or hyperhomocysteinemia who present with lower extremity ulceration(s) Identification Statement Metanx ® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy Dosage 1 tablet twice daily Metanx Package Insert 2009.

36. Metanx ® Safety Profile Adverse Reactions: While allergic sensitization has been reported following both oral and parenteral administration of folic acid, allergic sensitization has not been reported with the use of L-methylfolate. Paresthesia, somnolence, nausea and headaches have been reported with P-5-P. Mild transient diarrhea, polycythemia vera, itching, transitory exanthema and the feeling of swelling of the entire body has been associated with cobalamin. Metanx ® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy. Metanx Package Insert 2009.

37. Metanx ® Safety Profile Metanx ® is well tolerated in short-term and chronic use: Side effects and/or discontinuation rates similar to placebo The Ingredients in Metanx ® are generally recognized as safe (GRAS) as designated by the FDA or independent review Precautions: Pyridoxal 5’-phosphate (P-5-P) should not be given in patients receiving levodopa, because the action of levodopa is antagonized by P-5-P. However, P-5-P may be used concurrently in patients receiving carbidopa/levodopa While the concurrent use of phenytoin and folic acid may result in decreased phenytoin effectiveness, no such decreased effectiveness has been reported with the use of L-methylfolate Metanx ® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy. Metanx Package Insert 2009. Abstracts of the 7th Annual Conference on Arteriosclerosis, Thrombosis, and Vascular Biology. Oral Presentations. Arterioscler Thromb Vasc Biol . 2003;26:e43-e52.

38. Vitamin B for Peripheral Neuropathy: Cochrane Database 13 Studies / 741 Patients 2 Studies No Short-Term Pain Reduction 1 Study Vibration Detection Improved (Thiamine derivative) Higher Doses Improved Short-Term Paresthesias, Pain, Temperature, Vibration, Numbness Still Limited Data Ang, CD, Alviar, MJM, Dans, AL, Bautista-Velez, GGP, et al. Cochrane Database of Systemic Reviews. Issue 3, Article #CD004573, 2008.

39. (Metanx ® )L-methylfolate, Me-Cbl, P-5-P: Correlative Data Subjective VAS Study as isolated therapy Subjective VAS study combined with palliative agent Quantitative Sensory Testing Intraepidermal Nerve Fiber Density Testing Jacobs, AM. Abstracts of the New Cardiovascular Horizons Meeting. Orally Administered L-methylfolate, Me-Cbl, P-5-P Reduces the Symptoms of Diabetic Peripheral Neuropathy. Oral Presentations 2008. Jacobs, AM. Abstracts of the New Cardiovascular Horizons Meeting. L-methylfolate, Me-Cbl, P-5-P supplementation to pregabalin partial responders for the treatment of painful diabetic neuropathy. Oral Presentations 2008.

40. Orally Administered L-methylfolate, Me-Cbl, and P-5-P Reduces DPNP Results from a 20 week, randomized, controlled study of 97 patients to evaluate Metanx ® in patients with DPNP. After nutritional management with Metanx ® : The average absolute pain reduction after 20 weeks in the study group was 1.73 compared to .44 in the active group ( P <0.008) Compared to baseline, after 10 weeks the study group demonstrated a reduction in VAS of 32.92% compared to the active control group of 11.57% reduction in VAS ( P <0.01) Compared to baseline, after 20 weeks the study group demonstrated a reduction in VAS of 35.28% compared to the active control group of 11.73% reduction in VAS ( P <0.01) *L-methylfolate, Me-Cbl, P-5-P vs. Acetaminophen at 10 weeks. † L-methylfolate, Me-Cbl, P-5-P vs. Acetaminophen at 20 weeks. Metanx ® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy. Jacobs AM. NCVH Oral Presentations 2008. 0 -0.2 -0.4 -0.6 -0.8 -1 -1.2 -1.4 -1.6 -1.8 -2 0 10 20 Weeks Pain Reduction * P <0.01 † P =0.008 Mean Pain Reduction From Baseline Acetaminophen L-methylfolate, Me-CBl, P-5-P

41. L-Methylfolate, Me-Cbl, and P-5-P Administration to Pregabalin Partial-Responders for Management of DPNP Results from a 20 week, open trial of 24 patients to evaluate Metanx with ≤ 50% response to pregabalin (VAS score). After nutritional management with Metanx: The average absolute pain reduction after 20 weeks in the study group was 3.0 compared to .25 in the active control group ( P <0.001) After 20 weeks, the study group experienced greater pain relief compared to the active control group, 87.5% vs. 25.0% reduction in NPS respectively ( P =0.005) Metanx ® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy. Jacobs AM. NCVH Oral Presentations 2008. 0 -0.5 -1 -1.5 -2 -2.5 -3 -3.5 0 20 Weeks Pain Reduction P <0.001 Mean Pain Reduction From Baseline Pregabalin L-methylfolate, Me-CBl, P-S-P/ Pregabalin

42. Restoration of Cutaneous Sensorum 16 consecutive DPN patients with established sensory loss were quantified utilizing the PSSD Study outcomes were measured at baseline, 6 months and 1 year after L-methylfolate, Me-Cbl, P-5-P for all 8 measurements Walker MJ, et al. Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009. Eight Outcome Measurements Foot Medial Heel Great Toe Pulp Left / Right 1 & 2 point static touch 1 & 2 point static touch

43. Restoration of Cutaneous Sensorum Improved sensory perception at the medial heel and great toe Walker MJ, et al. Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009. Baseline, 6 month, & 1 year follow up 60 50 40 30 20 10 0 gm/mm 2 Baseline 6 months 1 year P <0.001 † P <0.001 ‡ Normal* 2 Point Static Medial Heel Left/Right Combined *<30.0 gm/mm 2 represents normal pressure thresholds for Pressure Specified Sensory Device ™ (PSSD) 99% Confidence level. † Baseline vs. 6 month. ‡ Baseline vs. 1 year. n = 16 60 50 40 30 20 10 0 gm/mm 2 Baseline 6 months 1 year P =0.006 † P <0.001 ‡ Normal* 2 Point Static Great Toe Left/Right Combined *<25.7 gm/mm 2 represents normal pressure thresholds for Pressure Specified Sensory Device ™ (PSSD) 99% Confidence level. † Baseline vs. 6 month. ‡ Baseline vs. 1 year. n = 16

44. The Pharmacological Management of Diabetic Small Fiber Neuropathy Utilizing Metanx ® as a Neurotrophic Agent 11 patients symptomatic DPN patients Baseline / 6 month skin biopsies (n=22) Metanx ® B.I.D. for 6 months demonstrated 97% ↑ ENFD Metanx ® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy. Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009. P =0.004

45. Clinical Case Outcome I Baseline 6 months Patient received baseline skin punch biopsy and given L-methylfolate, Me-Cbl, P-5-P (Metanx ® ) twice daily and followed for six months. Left image represents baseline skin punch biopsy at right calf. Right image represents six month follow up skin punch biopsy at right calf. Patient average increase of 3.02 nerve fibers per mm. Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC Metanx ® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy. Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

46. Clinical Case Outcome II Patient received baseline skin punch biopsy and given L-methylfolate, Me-Cbl , P-5-P (Metanx ® ) twice daily and followed for six months. Left image represents baseline skin punch biopsy at right calf. Right image represents six month follow up skin punch biopsy at right calf. Patient averaged an increase of .76 nerve fibers per mm. Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC. Baseline 6 months Metanx ® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy. Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

47. The Pharmacological Management of Diabetic Small Fiber Neuropathy Utilizing L-Methylfolate, Me-Cbl, P-5-P as a Neurotrophic Agent This preliminary study suggests that the administration of 2.8 mg L-Methylfolate, 2 mg Me-Cbl, 25 mg P-5-P appears to be associated with increased ENFD in patients with DPN. The increased epidermal nerve fiber density may be associated with diminished symptoms of anesthesia, paresthesia, or dysesthesia. Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

48. Summary Distal symmetrical sensorimotor polyneuropathy is the most common form of DPN Etiology of DPN may primarily be microvascular insufficiency Treatment should be based upon individual patient factors Focus on disease modifying agents to manipulate underlying pathophysiology of DPN