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Present e-learning systems

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Hello there. This is Aaron Inarther Vinik speaking and I’m here to talk to you today about Diabetic Neuropathies with new treatment modalities. Not too long ago in fact, in the early ‘80s an editorial was written in the journal the Lancet, the British Journal, which indicated that all we could for diabetic neuropathy was make the diagnosis and commiserate with the patient. We now know that there is a whole lot more that we can do because neuropathies have been shown to be a heterogeneous disorder with multiple different forms. For example there are proximal neuropathies and distal. There are large fiber and small fiber neuropathies. There are semantic and autonomic. Each has a different pathogenious and therefore requires treatment oriented toward this underlying pathogenious. When this is done we can achieve a remarkable rate of success in the management of the different neuropathic complications and this is what I purpose to share with you in the next hour or so.

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In this slide the clinic impact of Diabetic Neuropathies, DN, is shown. Patients may actually present to you with painful symptoms, such as burning, stabbing, tingling symptoms or alternatively present with neuropathic deficits, loss of pain perception, loss of thermal perception, such as the inability to feel heat or cold, or the inability to perceive change in texture of the floor that they are walking on, for example going from the bathroom that is a tile floor to the bedroom which is a carpeted floor. They would not be able to distinguish the difference.

The combination of these two is what leads to the impairment or the disability or the handicap. This can now be evaluated using a tool which is called the Norfolk Quality of Life Diabetic Neuropathy tool which measures the impact of either the painful symptoms or the neuropathic deficits on the quality of life. Which is very distinctive is that pain is associated with an increase in the anxiety level, whereas weakness and loss of sensory perception is associated with depression. The loss of sensory perception together with repeated minor trauma produces foot ulceration and a foot ulcer will lead to a defect in the epidermis through which organisms can penetrate which leads to infection which can penetrate deeper through the skin into the bone which can lead to an osteomilitus.

Alternatively the repeated minor trauma in a foot that is insensate will cause Charcot neuroarthropathy with multiple fractures to the feet leading and requiring surgery or amputation.

There are 86,000 amputations in the United States each year. One every ten minutes; which leads to an increased cost, estimated to be roughly $37 billion per year and leads to increased mortality. Once a person has had one amputation, they have a 50% chance of having another amputation within 5 years and once they’ve had a second amputation, they are likely to die within the next 5 years. An amputation leads to an individual never actually returning to the workforce.

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This slide here illustrates our current understanding of the pathogenous of neuropathy, the disease initiation and progression. We have all come to see patients who despite superb diabetes control end up with a very nasty and aggressive form of neuropathy. As a camaraderie we also see patients who do not take care of themselves at all and yet they remain disease free and do not get neuropathy. We have struggled with this for many years and we are beginning to understand why this is so. If we examine the genetic predisposition there are people, who have an APoE-gn polymorphism and aldose reductase Z2 allele polymorphism as well as an ACE gene polymorphism, have an increased susceptibly to nerve damage so if they then get diabetes they will get a far worse form of neuropathy. In addition to that there is a Tol receptor polymorphism which protects the individuals and it is probably mediated by immune protection. Long before there is an elevation in circulating blood glucose as shown here in the glucation box, we know there is a period of inflammation in which there is an increase in oxidative and nitrative stress, an elevation of the specific beta-2 subunit of protein Kinase C shown as PKC, an increase in a number of Selectins and VCAMS and inflammatory Cytokines such as IL6, TNFα, NFκB. There is also an increased production of reactive oxygen species or ROS, and nitrotyrosines. As the condition evolves or progresses there is lactations of a number of proteins and the formation of advanced lactation in products which leads to neuronal injury and the lactation of poly-ADP-ribos in which DNA molecules are damaged and express jargon information this now leads to initial functional changes in the nerve and progressive pathological changes as we progress. Fortunately this takes months to years to evolve and we do have the opportunity to intervene earlier. But it behooves us to identify this process before it is irreversible with the progressive pathological change.

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During the course of the evolution of diabetic neuropathy when asked what the risk factors might be for conducive to the development thereof. In the Eurodiab study published by Suloman Tesfaye in the New England Journal of Medicine this last year, they’ve looked at 1172 patients. 276 of them developed neuropathy over 7.3 years. What is striking is that there is an increased odds of developing neuropathy with cardiovascular disease, Albuminuria, Hypertension, Smoking, an elevated BMI or obesity, Triglycerides, and elevated total Cholesterol, and an elevated LDL-cholesterol. Strikingly these are the same risk factors leading to macro vascular events such as heart attacks, stroke and gangrene and need to be considered in the approach to prevention not only of macro vascular disease but also of neuropathy. These same risk factors are part of the metabolic syndrome and I will illustrate to you later in the course of this talk that we now recognize the neuropathy that is part of this metabolic syndrome before the advent of hypoglycemia.

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There are many different classifications for neuropathy but most importantly we need to recognize that patients may be asymptomatic with neuropathy or symptomatic. Even in the absence of symptoms, neuropathy may be present and causing the damage that has gone unrecognized. To document that neuropathy is present in these people requires a thorough physical examination or neurological examination in each. To do(?) a conduction study a quantitative autonomic function test (QAFT), a Quantitative Sensory Study (QST) or a Quantitative Motor Test (QMT). Even if people are symptomatic and they have the positive symptoms such as pain, or the negative symptoms such as weakness or loss of sensory perception, one still requires to show that there are two abnormalities in the neurological examination or one of these specialized tests to identify the person with neuropathy.

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If one does this in the clinic and asks the patients about symptoms: pain, nausea, vomiting, constipation, blurred vision, erectile dysfunction, a dry vagina, weakness. All these are signs of neuropathy. 1 in 4 people will volunteer that they have these symptoms in the clinic shown here on the left of the slide. If one does in addition to that a simple part of the exam uses a 128 hertz frequency tuning fork to elicit vibration perception or uses a patella hammer to demonstrate the presence of an Achilles reflex, 50% of patients have neuropathy when being first seen in the clinic. However if one does one of these more sophisticated tests such as a quantitative sensory test, a quantitative autonomic test or a nerve conduction study, 100% of patients may have neuropathy. However as Mark Twain indicated “Things that he stretched but mainly he tells the truth,” that its not a 100% but 95% but it’s just much more effective to make it look as if all patients have neuropathy.

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American Diabetes Association in 2005 did a national survey on about 8 and ½ thousand people. Only 1 in 4 of the survey respondents who experienced symptoms of diabetic neuropathy had been diagnosed. 75% had not been diagnosed despite the fact that they are symptomatic. The majority of respondents, who experienced symptoms, 56%, were unaware of the term diabetic neuropathy. 2/3rds of the people believed their symptoms were related to the diabetes but only 40% had been told by their physician that diabetes was the cause.

Even more alarming is that approximately one in seven people who said they talked to their doctor about the symptoms and pain reported that no cause was mentioned. Thus it is quite apparent that there is a need to education patients about neuropathy as well as the healthcare providers.

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In a recent study carried out the goal A1C by Herman & Kennedy published this last year said “Are we good at recognizing neuropathy?” If they examined 4 and ½ thousand people without neuropathy endocrinologists shown in red and non-endocrinologists shown in green were about equally good at recognizing the absence of neuropathy, in other words that the patient did not have nerve damage. Shown on the right of the slide in 541 is the fact that these people had severe advanced neuropathy. Patients were often confined to wheelchairs. They couldn’t move. They had gross wasting and weakness and yet in 26% of the time the endocrinologist failed to recognize the condition and in 36% of the time the non-endocrinologist failed to do so. The situation is far worse in patients with mild or non-severe neuropathy. In which case, 2/3rds of people the endocrinologists and a little more than that, 70% of the non-endocrinologists failed to make the diagnosis. However, ultimately the problem that is indicated is that for every mistake not made for not knowing, ten are made for not looking and the great majority of cases are missed simply because there were not examined.

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The classification of neuropathy that works in the clinic is the following. They may be focal or diffused Proximal or distal, large fiber or small fiber. Let us first look at the focal forms of neuropathy.

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These can be divided into Mononeuritis or Entrapment.

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Shown here is a patient with diabetic third nerval occulomotor nerve palsy. The presentation is of a sudden onset of totis with pain in the eye and temporal area of the head. If one raises the eye lid the eye is looking down and out. However there are still pupillary reflexes present if one shines a light in the eye or does a confrontation test for accommodation.

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The wonderful thing about this situation here is one can cast one’s healing hand over the eye and say “Sir or Madam, You will be better in six weeks.” God will heal this lesion and the Doctor, the HMO or the PPO will claim the fees.

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The reason for this is simple. We now understand that these lesions are due to an infarction of a fascicule due to decreased blood supply and other fascicules will take over their function. However it’s a trap for the unwary physician since one needs to recognize the difference between a mononeuritis with that entrapment syndrome.

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Mononeurity- the onset is sudden. It’s usually a single nerve but may be multiple nerves. The common nerves are the cranial nerves 3, 6, and 7, the ulnar, the median and the peroneal. It is not progressive and resolves spontaneously. The treatment can be symptomatic as I indicated to you about.

In contrast, with entrapment syndromes, the onset is gradual. Single nerves that are exposed to trauma. Common nerves include similar nerves: the median, the ulnar, the peroneal, the medial and lateral plantar and it is progressive. Thus when a patient says I have pain in my hands, one needs to ask which fingers? If they show the first three fingers that a median nerve or carpal tunnel syndrome. If they show the ring finger and the little finger, that is the ulnar nerve and the entrapments of the elbow. Or if they complain of pain on the outside of their lower leg and they have foot throb, that’s peroneal nerve entrapment at the head of the fibula. Or if they have pain in their feet, one needs to know whether it’s on the inside of the foot or on the outside, to know whether there is medial or lateral plantar entrapment.

Once one realizes that you are dealing with an entrapment, this will respond in general to rest, splints, or diuretics. In people who have a significant amount of pain steroid injections may be necessary into the confined space. And surgery is required if the medical therapy fails and the patient has weakness. The importance is that about a third of patients, 30% of patients or 1 in 3 patients you see in the clinic has some form of entrapment.

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Let us go on now to talk about the diffuse forms of neuropathy. These diffuse proximal forms of neuropathy used to be thought of as being total un-amenable to any form of intervention.

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This here is a picture of the proximal leg in an individual with this condition which used to be called diabetic amyotrophy or diabetic proximal neuropathy today. The syndrome is usually in an older person, usually a male. The pain starts in the buttocks, usually one side, progressing to the other side and then involves the thighs. There is marked vasculation or tremor of the muscles of the thigh. The knee joints are reduced to the proportion to the degree of wasting. It is always associated with peripheral neuropathy and if the person is asked to stand up from a sitting position, they have a great deal of difficulty and have to use their hands to climb up their bodies, much like the Gowers maneuver.

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Now for years, we thought of this condition as being one in which there was no therapy available. But Charlie Chan, the Chinese detective living in Hawaii, said “Your mind is like a parachute, it does not work if not open.

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Over the year’s we have carried biopsies of the observatory nerve, which the little nerve present in the thigh, that doesn’t serve a great degree of function and it seems that the Lord in his or her wisdom gave it to us so we could biopsy it and understand the condition better. If one does this nerve histology immune’s cell infiltrates immunoglobulin deposition in the perineurium, endoneurium, and Nodes of Ranvier. Have vasculitis and demyelization. Critical too this is a marked reduction in Nerve Conduction velocity of the order of less than 30 meters per second with relatively normal amplitudes. This is really a critical distinction of these patients from run of the mill, humanilgarden diabetic neuropathy. Diabetic neuropathy does not produce nerve conduction velocities that are marked. It is a disorder in which there is a reduction in axioms and reduced amplitude of nerve conduction. When one sees profound nerve conduction velocities this means demyelization and this was associated with circulating antibodies to neuronal antigens in an elevated CSF protein.

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This disabling peripheral neuropathy which occurs in older adults occurs as a vasculitis 52% of the time, inflammatory demyelinating polyneuropathy 22% of the time, monoclonal gammopathy 17% and only in 9% is the diagnosis obscure idiopathic or related to diabetes.

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Sharma and colleagues at the University of Miami examined 1127 patients with neurological disorders that had diabetes. 189 such patients, 32 of the 189 had inflammatory demyelinating polyneuropathy or CIDP; whereas of the non-diabetics, 17 of the 938 had CIDP. Thus as show on the right in this slide is there is an 11 fold increase likelihood of CIDP in the patient with diabetes; which explains the findings of the profound reduction in conduction velocity in these subjects. The good news about this is will respond to intravenous immunoglobulin 80% of the time and in the people who failed to respond immunotherapy may be used with a salutary result. Vasculitis patients, one needs to withdraw drugs or use a steroid regimen and in people with monoclonal gammopathy plasmapheresis has become the treatment of choice.

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Let us go on now then to diffuse distal forms of neuropathy which includes the large and small fiber types.

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This slide is a cartoon of a simplified view of the peripheral nervous system; shown as axioms with the yellow and covering that in black dots the myeline. At the thick fibers that are myelinated or A-alpha fibers that are important for motor or muscle strength. Slightly thinner are the A-alpha beta fibers but still myelinated in which are important for touch and vibration perception and position sense. Further but still myelinated are the A-delta fibers which are important for cold and thermal perception and cold pain. But then we have the vast majority of these fibers which are un- myelinated C fibers and those are important for warmth level perception, pain and all the autonomic functions including heart rate, blood pressure, sweating, GIT, GU functions.

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One needs to distinguish the clinical picture of the large fiber neuropathies from the small fiber neuropathies. Large fiber neuropathies are associated with weakness, wasting, impairment of vibration, perception of threshold which translates to a loss of position sense as well as a loss of reflexes and this markedly interferes with quality of life by a reduction in activities and daily living as I mentioned at the beginning of the talk.

In contrast, the small fiber neuropathies are associated with pain which is the burning superficial dysaesthetic type pain with (?). They go on to loss of thermal sensory perception and a disappearance of the pain but also associate with all the autonomic features such as autostatic hypertension, loss of strength, erectile dysfunction, and the like. Strikingly they have normal strength, normal reflexes, and are electrophysiogically silent. This form of neuropathy produces symptoms and leads to great degree of morbidity and mortality. It goes unrecognized by the neurologist since the neurologist would require a patient to have changes in reflexes and electrophysiogiology to diagnose the presence of neuropathy.

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We must then look at the diffuse distal large fiber neuropathies.

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These present with impaired vibration perception. Pain is of the A-Delta type, deep-seated and gnawing pain with numbness and ataxia, wasting of the small muscles of the hands and feet which we call intrinsic minus hands and feet, weakness and an increase in blood flow, the hot foot. Almost all patients with diabetic neuropathy have cold feet and that’s when one sees a hot foot one needs to be alert to the possibility that this foot is at risk of developing Charcot’s.

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When one examines the hands there is a striking loss of atreus muscles. Shown over here is loss of the atreus muscles which leads to weakness of the intrinsic muscles of the hands. Imagine trying to use these hands to work a cash register or a cell phone or to do one’s buttons of one’s shirt or to do the sleeves for the buttons. As a result of which it is clean that large fiber neuropathies have produced this form of weakness or wasting impact quality of life.

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If one examines the feet in these people they also have intrinsic minus feet so that the small muscles of the feet which are required to keep the foot flat on the ground disappear and the large extends the tendons of the foot, take over the function pulling up the toes into this claw toe deformity and which increases the risk of developing a foot ulcer at the dorsal of the toes or at the sole of the foot because of the hammer toe-claw toe deformity.

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If one asks can we make the diagnosis of large fiber neuropathy at the bedside it is awfully simple as Helen Resnick and I showed a number of years ago. If we do sophisticated test of people with large fiber neuropathy shown in yellow compared with diabetic controls shown in red or healthy people shown in blue a two minute walk doesn’t distinguish them, nor does foot tapping or balance walk but simply asking a patient to stand on one foot, and if they can’t do this for 30 seconds as most people can do, then they have large fiber neuropathy. A very easy test to do in the clinic and which can be done in a matter of a few seconds.

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Why is it important to diagnosis large fiber neuropathy with patients with diabetes? The major reason is that diabetic neuropaths who have large fiber neuropathy are 15 times more likely to fall than a non-neuropath. Furthermore older subjects have loss of vibration perception and weakness of foot dorsiflexion so that tripping is not uncommon especially if there are loose carpets or rugs on the floor. This coupled with the fact that they, similar to people with diabetes lose their sensory perception and loose the awareness of their position in space will fall and the cause of fractures in neuropathy is not the osteopenia but the fact that they fall. Treatment for this condition is strength and balance training.

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The good news is that if you embark on a program of strength and balance training, you can improve hand grip, leg pressure, knee extension, foot dorsiflexion, and foot extension. This will lead to an improvement in your backward tandem walking, improvement of the micro vascular, neurovascular profusion of these feet and reduce the likelihood of developing a fracture and falling.

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The management of large fiber neuropathy includes wearing proper shoes, orthotics, muscle strength and coordination building, use of bisphosphonates, and because people have shortening of the Achilles tendon which aids and adds to the deformity of the claw foot tendon lengthening procedure which can be done in ambulatory clinic is recommended. If the foot is collapsed from Charcot’s neuropathy, then surgical reconstruction may be near.

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Now let us move on then and talk about diffuse distal small-fiber neuropathies.

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These neuropathies present clinically as the hot foot, or hot hand syndrome illustrated here in this picture. The pain is of the C-fiber type. It’s burning, superficial and patients have marked allodyna which is the presence of pain that can be invoked with a non-painful stimulus. Early on they are hyperesthetic and hyperalgesic but they may have impaired neurovascular function if this test is carried which is in many research institutes. Later on they become hypoestesitic and hypalgesic, which impairment of warm thermal perception and impairment of pain thresholds decrease in the intraepidermal nerve fibers density. There is a decrease in sweating but as you will recall they have normal strength, normal reflexes and normal EMGs or electrophysiogically.

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If we look at the pathology of the skin in neuropathy, shown here is a biopsy of normal skin stained for the neuronal antigen PGP9.5. The plaxis that accompanies the blood supplies known as the neurovascuplexis at the junction of the epidermis and dermis is shown here with an antibody to PGP9.5 epa-neuronal antigen. Also shown are the branches of the nerve fibers that enter the epidermis that could be quantitated in terms of density as well as length of fiber.

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What has been shown now is that in a prospective screening of patients with this “idiopathic sensory neuropathy”, 30-50% of patients have impaired glucose tolerance and the impaired glucose tolerance neuropathy occurs in overweight people with a family history of diabetes. The neuropathy is primarily a sensory neuropathy and 92% of such patients have pain. The impaired glucose tolerance neuropathy is similar to early diabetic neuropathy and these patients also present with erectile dysfunction or impotence.

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The management of an IGT neuropathy is similar to that of the management of diabetes in general and there are preventive therapies such as a recommendation to reduce the body weight by 5-7%, increase aerobic exercise to 150 minutes per week, work with a nutritionist and exercise physiologist and the pain is treated as with diabetic peripheral neuropathy. It is recommended that the Oral Glucose Tolerance is repeated on an annual basis and if the patient converts to diabetes to treat them simply. Recalling what I said earlier in the talk, we need to examine for macro vascular risk factors and of the metabolic syndrome and treat.

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Shown in this compendium of histological pictures is the intraepidermal nerve hyperplasia in a normal control, that which occurs in diabetes with massive intraepidermal fibers, but here in the center our patient with metabolic syndrome who do not have hyperglycemia, but have a loss of the total intraepidermal nerve hypers, or as shortness in the limb of these intraepidermal and what we have come to call here the stumpy nerve syndrome.

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Thus if one measure intraepidermal nerve fiber length what is shown here is that even in the proximal leg the mean dendritic length is reduced before there is a loss of nerve fibers and this is highly significant.

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So now we ask can we do anything other than measure diabetic neuropathy and commiserate with the patient?

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As William Osler indicated “Who understands pain, knows medicine.”

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We need to distinguish nociceptive versus neuropathic pain states. In the nociceptive state this arises from a stimulus outside of the nervous system and the pain is proportionate to receptor stimulation. When it is acute it serves a protective function and we are fortunate to be able to experience pain. Neuropathic pain on the other hand doesn’t require a stimulus. It arises from a primary lesion or dysfunction of the nervous system. No nociception is required and the response is disproportionate to the stimulation with other evidence of nerve damage.

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If one examines the relationship between pain perception and the stimulus intensity this is shown here in the hyperbole of what you see on a normal situation where we go from innocuous stimulation where there is no pain to noxious stimulation which produces pain as a directly in an algorithmic manner proportional to the intensity of the stimulus. However, with injury this curve becomes shifted to the left and even innocuous stimuli now can be experienced as painful. That this type of patient would then be experiencing hyperalgesia or even allodynia.

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Examples of nociceptive and neuropathic pain are shown in this slide. Nociceptive for example being due to postoperative situations. Arthritis, mechanical low back pain or exercise injury, sickle cell crisis. And neuropathic pain on the other hand occurs with distal symmetric polyneuropathy, postherpetic neuralgia, and central post stroke pain syndrome.

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What then are the treatment approaches? It may be pharmacotherapy, neurostimulatory approaches, interventional regional anesthesia, complementary medicine or alternative approaches, physical rehabilitation, psychological therapy, or lifestyle.

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This is a cartoon which indicates the two different types of pain. The small fiber pain is translated by the C-fiber and the major neurotransmitter is glutamate, which acts to excite the nervous system and to have pain stimuli transmitted from the dorsal root ganglion through the cord into the central nervous system. Another important feature of the transmission of this impulse is the role for calcium channels. In contrast with this the A-beta and delta fibers neurotransmission is via sodium channels interacting through glutamate as the exciter acting as its neurotransmitter at an interneural and at the interneural in formation is transmitted by a GABA neurons through the central nervous system and then there are modulatatry descending ions which have serotonergic, opiod, and alpha2 adren effects on modulation in the neural implement. One can block the release of substance P with topical Capsaicin. That the sodium channels can be modulated by Carbamazepine, trylepto or ozycarbamazepine, trycyclics or even insulin. At the level of GABA this can be modulated with anti-epileptic, Topiramate and NMDA receptors can be blocked with dextromethorphan or couch mixture. When there is a department of calcium channels the drug which has been recently approved by the Food and Drug Administration for treatment of neuropathy is pregabalin. Pregabalin adds on the alpha2 subunit of the calcium channel there by modulating calcium entry into the neuron. It is unlike that of the calcium channel blocker shown to the left which indeed blocks the entry of calcium into which ever target the receptor decides. The modulatry actions of serotonergic, opiodic, and alpha2 adrenergic fibers can also be altered with the use of tricyclics, clonididne, tramadol or duloxetine. Duloxetine is the most recent addition to the solumentarian? Cymbalta, which has also been approved by the Food and Drug Administration for use in diabetic neuropathy.

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Shown here is the successful reduction of pain with two doses of Duloxetine 60 and 120 mgs and of note there is a relief of pain that occurs within the first two weeks of treatment and usually within the first four or five days.

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The untold effects of Duloxetine include nausea, somnolence, dizziness, constipation, a dry mouth, hyperhidrocsis, decreased appetite, anorexia, weakness. Of course is the people who have a tendency toward a bio-polar state which the unmasking thereof may produce a manic type reaction.

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Pregablin on the other hand is shown in this slide which also produces significant improvement on weekly pain scores a 300 or 600 mg per day

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And if one measures the 50% responder rates 300 and 600 mgs achieve this close to 50% of the time. Compared with placebo which is able to only 20% of the time.

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One needs to remember that Pregabalin is still classified as a schedule 5 drug and examples of schedule 5 controlled substances include Robitussin and Lomotil. But the potential is still there.

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The adverse effects of Pregabalin include dizziness, somnolence, peripheral edema, headache, infection and dry mouth.

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Another drug that has been shown to be effective in neuropathic pain is Topamax or Topiramate. This has been shown in three studies not to be successful because of the incorrect evaluation of pain but in one major study has been shown to produce a significant relief of pain on a PVA scale and that when patients are on placebo were crossed over to drug they too have relief of pain. In addition of the effects were shown to be durable and persistent for at least 24 weeks.

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Now let us examine what transpires with patients with neuropathy. When they have good nerves, they have no pain. When the nerve function deteriorates or get to the pain threshold and they now experience pain. As the nerves die off, pain would disappear. If a patient says to you, you are a very good doctor. When I came to you I had lots of pain. It’s disappeared be sure to examine the patient, the nerves may be dying off. If they say to you, you are a bad doctor, because when I came to you I had no pain and now I’ve got pain you will say that’s good, that indicates that your nerve function is good or it is better than.

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Shown in this slide is an illustration of those features. These are normal density and normal length of dendrites in patients who have no symptoms and are non-neuropathic. B over here shows slightly reduced density and abnormal nerve fiber swelling in the proximal thigh in a person with small fiber neuropathy and C show shows complete clearance of the nerve fibers in the calf. And these people in B and C had normal strength, normal reflexes, and normal electrophysiogically.

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In addition to the above, if one examines the nerve fibers around sweat glands, these are lost shown here in B on the left and in D is shown the loss of these nerve fibers that accompany those molecules.

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This results in a dry thickened cracked skin and creates a portal of entry for organisms to produce the infections, the ulcerations, which go on to the amputation.

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Shown here is the penetration with repeated trauma, the ulcer which occurs at the high point with the hammer toe deformity which will lead to the Osteomyelitis and the amputation.

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The management of this condition, small fiber neuropathy include education and padded socks, appropriate shoes with adequate support, regular shoe and foot inspection- give the patient a mono filament and a mirror on the floor of the bathroom and care with exposure to heat injury. Emollients to avoid dryness of the sympathetic dysfunction.

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This picture of a monofilament is simply to illustrate that we provide patients with monofilaments to take home because it induces behavioral modification when they test their feet and its markedly reduced the rate we see in out clinic.

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Shown here is that simple intervention such as education, no patient enters a clinic with shoes on, examining the patient’s feet and shoes, providing written information about the foot care, the use of a mirror on the floor of the bathroom for these people cannot see the soles of their feet and a monofilament to take home results in a 60% reduction in the likelihood of foot ulceration and this was published back in 2000. The figure now is closer to an 85% reduction.

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Ultimately we need to know what the cause of the damage is to the nervous system. Shown here on the left are the Vesa nervorum to the blood vessels that’s applied the nerves. And shown on the right is the damage to these blood vessels which results impair of blood flow to both the small and the large fibers.

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This complex slide illustrates the complex pathogenesis of diabetic neuropathy. Diabetes with hyperglycemia leads to increased polyol pathway activity with accumulation of sorbotal and fructose within nerves. Increase in Dysmetabolism activating the protein kinase c leading to increase in angiotensin II, a decrease in the vasodilators nitric oxide and EDHF. There’s aided and abided by the disorder the essential fatty acid metabolism. In addition to that the disorder lipid metabolism contributes to the increase in Poly ADP-ribose polymerase, autoxidation, accumulation to advanced glycation end products and the accumulation of reactive oxygen species. These ROS binds to nitric oxide to from peroxinitrate leading to damaging of blood vessels leading to loss of the profusion of the blood vessels with A-V shunting culminating in neuropathy. We can block Polyol pathway with aldose reeducate inhibitors. We can block the diacylglycerol, PKC with a PKC inhibitor ruboxistaurin and we can mop up reactive oxygen species with alpha-lipoic acid.

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Shown here is that ruboxistaurin treatment in a clinic trial published last year between 6 months and a year is capable of improving the nerve symptoms score

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And improving vibration perception threshold.

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A number of studies have been carried out with aldose reeducate inhibitors over the years. They are shown in this slide and most of them have failed to reach the clinic for a variety of reasons, shown above including adverse reactions and the fact that many have been withdrawn. Now we are in the situation with Fidarestat that has been shown to well tolerate. It is being used clinically as is Epalrestat which has been marketed in Japan.

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The Migeshe Hotta and Colleagues have shown that Fidarestat is capable in a one year long trial of reducing paraethesias in the lower limbs and hyperthesias in the lower limbs.

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A niche analysis of the study that have been carried out to study the effects of 600 mgs intravenously for 3 days of alpha lipoic acid shows this that this too may relieve symptoms compared with placebo.

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These are the results of 18 weeks of treatment showing that the disappearance of all these nerve fibers in the epidermis reappear with the use of treatment of Topiramate.

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This is accompanied by an increase in blood flow using laser Doppler measurements after 12 weeks, both in the legs as well as the foot

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and the cellulatory observation that weight decreases, BMI improves, diastolic blood pressure improves, systolic blood pressure improves, hemoglobin A1C improves, total neuropathy score also improves.

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In addition peroneal nerve amplitude, intraepidermal nerve function and dendrite length.



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So what I’m trying to show in the course of this presentation is “The life is short, the art so long to learn, opportunities are fleeting, experience is treacherous in journey and judgment is difficult.”

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However one needs to remember diabetic neuropathies can be managed on the basis of their underlying pathology. The mononeuritis, they are vascular ischemic assaults on the nervous system with will resolve spontaneously. Entrapments occur in a third of patients but entrapment can be relieved. Proximal neuropathy for the most part are inflammatory autoimmune and respond to inflammatory agents, IVIg or immunotherapy. Distal symmetric polyneuropathies are small and large and they have very different etiology and very different treatment.



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We need to finish with where we will go in the future with neuropathy prevention. Top of the list is glycemic control. Aldose reductase inhibitors may have reached the clinic in certain countries, certainly in Japan and we are beginning to see greater successes with the neural compounds. PKC inhibitors may have carried out successful in clinical trials but still remain to be proven in the research arena and phase 3 trials. There are some positive reports on ACE inhibitors but this remains to be confirmed. Prostaglandins improve blood flow and need to be studied further in the clinic. AGE blockers have promise in certain instances and we have to see them prove to be safe in these patients. Certain antioxidants such as alpha lipoic acid have made success but the future includes immunophilins and neurotropic agents that appear to have some promise for the prevention of the neuropathy and even in the reversal of that which it is established.



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This is a picture of the Strelitz Diabetes Institute in Norfolk, Virginia and this includes our clinical service as well as the basic science and basic research of polyneural to show that we have an educational mission, a clinical care mission as well as a research and the translation of our basic and clinical research findings into clinical care.