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
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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
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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.
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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
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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
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.
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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
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
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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.
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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
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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.
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Hinweis der Redaktion
Diabetic peripheral neuropathy (DPN) is a diffuse disease and represents a broad term for the many kinds of nerve damage that often accompany diabetes mellitus. The consensus definition includes the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes
We know that diabetes has reached epidemic proportions with over 23 million people in the United States afflicted by this disease. Despite significant advances in technology and medications, the incidence of diabetes has worsened.
The impact of diabetic neuropathy is overwhelming. The predominant feature of DPN is sensory loss. Sensory loss is the number one predictor of foot ulceration and non-traumatic amputations in the United States. The cost of diabetes and the complications of neuropathy to the healthcare system are staggering and as previously mentioned diabetes is getting worse not better.
Of all the problems that diabetes patients have: stroke, heart attack, renal disease etc. Foot infections are the #1 reason for hospitalization (graphic). As a result of the numbness associated with neuropathy, this ends up happening (picture of amputated foot): DPN is much more than just “my feet are numb” or “my feet tingle”. You have to think to yourself-if you can control the glucose and treat the underlying pathology, then maybe this patient would have felt the problem before it got to this point. As previously mentioned most non-traumatic lower extremity ulcerations in the United States are preceded by diabetes induced neuropathy and ulceration. We have to begin thinking about how we can prevent this type of outcome resulting from diabetes.
There are a wide range of treatments available neuropathic pain This prescribing pattern suggests that there is no one treatment that addresses all the factors. Some treatments have specific indications and some are off-label
Results from the 2005 American Diabetes Association National Survey uncovered that: DPN is under diagnosed. Only 1 in 4 people surveyed have been diagnosed with diabetes induced nerve damage The majority of individuals experiencing symptoms are not acutely aware of the term DPN diabetic neuropathy Only 42% of respondents have been told that diabetes is the cause of their symptoms Clearly we have to do a better job at communicating with our patients regarding the various complications associated with diabetes, including peripheral neuropathy
• Along with the range of positive symptoms of neuropathic pain, loss of motor, sensory, or autonomic neuronal function (negative symptoms) may occur. •The nature of the symptoms depends on the functional system that has been affected. Spontaneous pain is the most frequent symptom of all painful neuropathies and presents with a burning quality, localized superficially, or an electric-shocklike pain for several seconds. •Although the terms have been used somewhat interchangeably, the International Association for the Study of Pain has defined dysesthesias as abnormal sensations that are unpleasant and paresthesias as abnormal sensations that are not unpleasant.
Neuropathic symptoms affect simple everyday activities and significantly impacts the quality of life in a negative way. Obviously, quality of life is different for everyone and leads to other disease states such as anxiety and depression. As a result, the cost associated with treating these patients continues to increase.
Almost half of diabetics with neuropathy don’t even know they have it. The majority of diabetics with neuropathy have significant sensory loss which is a real problem. LOPS is the #1 predictor of lower extremity ulceration and amputation. A very small percentage of diabetics with neuropathy actually experience painful symptoms and an even smaller percentage of these patients receive treatment.
Painful symptoms of DPN can lead to disability and reduce overall quality of life The neuronal deficit leading to sensory loss is the real problem. Sensory loss is a significant predictor of foot ulceration, foot deformation and amputation.
Perform a comprehensive foot examination annually on patients with diabetes to identify risk factors predictive of ulcers and amputations. Perform a visual inspection of patients’ feet at each routine visit How many physicians actually perform yearly foot examinations. Specifically, how many primary care physicians are conducting this exam? If a patient is diabetic, they should be taking their shoes and socks off in the exam room. The earlier we can detect foot problems, the earlier we can treat the problem. As we have already mentioned, it isn’t the pain that is leading to ulceration, infection and amputation, it’s the SENSORY LOSS.
It looks a little more complicated, but the common final path in neuropathy may be endothelial dysfunction. And this is caused by several things including insulin resistance, including these metabolic abnormalities advanced glycation end products. But then this results in reduced capillary blood flow, nerve hypoxia and nerve dysfunction. So this seems to show that endothelial dysfunction seems to have primacy in diabetic neuropathy. In HIV treated patients, because of the drugs, they also have endothelial dysfunction and they have neuropathy that is clinically identical to diabetes, so it is sort of a proof of concept in what we are talking about. We are getting away from the blood sugar as a primary cause into a cardiovascular cause.
The endothelium is the largest vascular organ that is responsible for regulating vascular homeostasis Endothelial dysfunction can be characterized by deranged nitric oxide pathways and vasoconstriction This is multifactorial for Hyperglycemia but also for Insulin resistance and from abnormal free fatty acids production and metabolism.
The ADA recently had an expert consensus to classify and treat neuropathies and generally have generalized symmetric neuropathies in diabetes and then they have focal and multifocal neuropathies. We will mostly be talking about chronic sensorimotor under generalized. This is the one that gets our patients into the most trouble. There is also autonomic, and then the cranial, truncal, proximal neuropathy which used to be called amyotrophy. There is also co-existing chronic (enzymatory Demylinating polyneuropathies ??)
Sensorimotor neuropathy is most common and affects about 40% of people with diabetes.
The symptoms are progressive, it usually involves the longest nerves first then marches back inexorably year to year. The main symptoms are numbness, but the important symptom is loss of protective sensation.
Autonomic neuropathic is the largest underappreciated area in this field of neuropathy. You get abnormal sweating, this affects the feet by the way, less sweat, which results in drier skin, impotence we know quite well and heart rate abnormalities.
This is a paper by Dr. Veves and looking at predictors of foot ulceration, we have a neuropathy disability score, the vibratory perception threshold and the Semmes Weinstein monofilament, all pretty much came in as a tie. A nice trifector there. So, any of those modalities can make the diagnosis.
Picture on the left represents NORMAL nerve fiber density. Picture on the right represents LOW-NORMAL nerve fibers consistent with small fiber neuropathy
There are various alternatives in treating the Positive symptoms of DPN. Obviously, these drug therapies have distinct side effects and we have to measure risk vs. benefit to decide on the correct therapy. Twenty-five percent of patients who present to their physicians complaining about symptomatic diabetic neuropathy receive no treatment at all. About 54% of patients who are being treated for symptomatic neuropathy are being treated with opioids. About 40% of patients receive anti-inflammatory medications, though NSAIDS have no role in the treatment of symptomatic diabetic neuropathy. Tricyclic antidepressants and anti-convulsants are the two categories of pharmaceuticals that have the most literature support for the treatment of diabetic neuropathy, but combined these are prescribed by physicians who treat symptomatic diabetic neuropathy less than there are patients who are untreated. (Graphic) The majority of these patients are on opioids which can lead to addiction. None of these therapies manipulate the underlying disease state. They simply treat the positive symptoms only
Treatment of diabetic neuropathy depends on the symptoms and on the patients themselves. It is best to tell patients not to expect 100% relief of symptomatic neuropathic pain. Although that is the goal of treatment, patients need to understand that to control their diabetes, they need to control a number of factors, but in general, they can expect between 30% and 50% relief of pain. Most patients with symptomatic diabetic neuropathy need two drugs to get closer to 100% improvement. The average patient spends $1,000 a year on medication for symptomatic diabetic neuropathy when taking 1 drug. The average patient in the United States spends $1,600 taking 2 drugs for the treatment of symptomatic diabetic neuropathy and as you can see, there are a number of treatments to choose from: Tricyclic antidepressants have been the standard for a long time. When using these, it is important to get a baseline EKG and they are probably not a good treatment for certain types of patients, such as patients with glaucoma. Patients also need to be warned about weight gain, fluid retention, and anti-cholinergic side effects. Amitriptyline is the most effective of the tricyclics, however, it also has the highest side effect profile. Duloxetine HCl (Eli Lilly and Company, Indianapolis, IN) cannot be used in patients with any kind of significant hepatic disease at all. Duloxetine HCl is a selective serotonin, norepinephrine inhibitor, used for treating depression, plus it is FDA-approved for treating symptomatic diabetic neuropathy. It has less side effects than the tricyclic antidepressants, but it is also less effective than the tricyclic antidepressants in head-to-head evaluations. Pregabalin Pfizer, New York, NY) is the newest, FDA-approved agent in its class. Generally, start patients at 50 mg 3 times a day or 75 mg twice a day for 1 to 2 weeks. It has a rapid onset of action and if the patients are doing well, 100 mg 3 times a day seems to be an adequate dose.
Metanx is a prescription medical food containing 3 active components (L-methylfolate, Methylcobalamin and Pyridoxal 5’-phosphate) L-methylfolate – active form of folate recognized by the cell. Main component to increase the synthesis of nitric oxide in the endothelium Methylcobalamin – neurologically active form of B12 involved in protein synthesis within the neuron Pyridoxal 5’-phosphate – active form of B6 that may inhibit the deleterious effects of AGE’s (Nitric Oxide Synthesis Graphic) Clinical evidence suggests that reduced eNOS may be the main cause of endothelial dysfunction and reduced nitric oxide at the foot level in patients with diabetic neuropathy Endothelial cells produce 2x more nitric oxide in the presence of L-methylfolate in the following ways: I BH4 Rescue or Stabilization L-methylfolate may stimulate endogenous BH4 regeneration from inactive BH2 and; May lead to chemical stabilization of BH4 II Antioxidant Effects L-methylfolate may act as a direct antioxidant by scavenging superoxide production III Direct Effect on eNOS L-methylfolate may reduce superoxide generation from ‘uncoupled’ eNOS and; Switch ‘uncoupled’ eNOS to ‘coupled’ eNOS The end result is greater vasodilation and increased vascular flow to the peripheral nerves.
What is a Medical Food: formulated to be consumed or administered enterally under the supervision of a Physician intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Medical foods were derived from the Orphan Drug Act in 1988. Medical foods do not treat a disease but rather, address the underlying condition such as, endothelial dysfunction There must be evidence in peer-reviewed literature demonstrating safety and efficacy and medical foods must be managed by the health care provider
Medical Foods, unlike dietary supplements, are regulated by the FDA and must meet the manufacturing guidelines and standards
There are numerous studies that exist utilizing b vitamins for peripheral neuropathy; however, the data is still limited.
There are several completed trials demonstrating the efficacy of Metanx for diabetic neuropathy including: two DPNP studies; improvement in sensory loss; and increased nerve fiber density
Results from a 20 week, randomized, controlled study of 97 patients to evaluate Metanx ® in patients with DPNP. Metanx twice daily vs. acetaminophen (500mg twice daily) as the active control group There was a statistically significant difference in neuropathic pain between the metanx and acetaminophen group that favors metanx at 10 and 20 weeks
Results from a 20 week, open trial of 24 patients to evaluate Metanx in patients with ≤ 50% response to pregabalin (VAS score). Methodology 24 consecutive patients who received pregabalin > 4 months with partial (<50% NPS reduction) resolution of paresthesias were enrolled. Study group (n=16) continued the pretrial pregabalin dose to which oral L-methylfolate, Me-Cbl, and P-5-P was added twice daily. Control group (n=8) maintained pregabalin therapy. A numeric pain scale (0-10) was evaluated at baseline and 20 weeks. After 20 weeks, the metanx/pregabalin group experienced a statistically significant improvement in neuropathic pain compared to pregabalin group alone.
This is a study in 16 patients with diabetic neuropathy experiencing sensory loss. Patients were given a quantitative sensory test utilizing the PSSD. The PSSD measures 2 pt static touch which correlates with nerve density. Patients received Metanx twice daily and were followed for 1 year. There were 8 outcome measurements for the left and right foot for both 1 and two point static touch at the medial heel and great toe
Graph on the left represents great toe. You can see that the pressure it took to distinguish between the two points was dramatically reduced at 6 months and even more so after 1 year. Graph on the right represents medial heel where you see even more dramatic results which makes sense considering neuropathy is a length dependent disease and the nerves shorter nerves take less time to heal Diabetes patients with sensory loss in this cohort experienced a statistically significant improvement in sensory perception after 6 months and 1 year compared to baseline. This is exciting because it’s the sensory loss that predicts the late complications such as ulceration and amputation
This is a study that was presented at the diabetic global foot conference in march of 2009 that looked at small fiber neuropathy. 11 symptomatic DPN patients were enrolled into this trial and a baseline skin punch biopsy was performed. Patients were given Metanx twice daily and followed for 6 months where a repeat skin punch biopsy was performed. As you can see in the bar chart, after 6 months of Metanx there was a 97% increase in epidermal nerve fiber density which correlated with improvements in numbness, tingling and burning sensations in the feet.
Here is an image from one of the DPN patients in the cohort. As you can see on the left, this patient had reduced nerve fibers marked by the horizontal arrow. Six month follow up image on the left demonstrates an improvement of nerve fiber density suggesting the neurotrophic effect that Metanx may exert on peripheral nerves.
This is an image from another patient in this cohort, again, demonstrating an improvement in small fiber neuropathy after 6 months of Metanx twice daily.
Most patients with peripheral neuropathy experience numbness NOT Pain. It’s the loss of sensation that leads to further complications such as lower-extremity ulcerations and amputations. Most therapies that target neuropathy simply treat the acute pain in an effort to improve quality of life which is important. We need to look for therapies to address the underlying pathology of neuropathy.
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