1362748623 4 chapter4


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1362748623 4 chapter4

  1. 1. 13 Chapter IV PATHOPHYSIOLOGY OF DIABETIC FOOT  DEVELOPMENT OF SENSORY, MOTOR AND AUTONOMIC NEUROPATHY  ASSOCIATIONS CONTRIBUTORY TO SENSORY NEUROPATHY IN DEVELOPING THE ULCERS  MOTOR NEUROPATHY AND MECHANISMS OF INJURY  AUTONOMIC NEUROPATHY IN DIABETIC FOOT  PERIPHERAL VASCULAR DISEASE IN DIABETIC FOOT  INFECTIONS AND RELATED ISSUES  PAINFUL NEURO-RADICULOPATHY IN DIABETES For a person with diabetes to develop a diabetic foot one or more of the following three components are essential neuropathy, vasculopathy and infection. The fourth extremely important risk factor is increased plantar pressure leading to ulceration. Neuropathy and peripheral vasculopathy can be independent risk factors or could be responsible in combination.12 Following is a description of what each of these components contributes to the development of diabetic foot and its pathophysiologic mechanism. Diabetic Polyneuropathy: The major components of diabetic polyneuropathy are: 1. Sensory neuropathy 2. Motor neuropathy and 3. Autonomic Neuropathy 1. Sensory Neuropathy:
  2. 2. 14 Hyperglycemia is 'the' trigger that starts the cascade of neuropathy. It is well known that the subsequent progressive unrelenting deterioration of sensorimotor and autonomic function is a phenomenon related to the diabetic state per say and even the rigorous control of blood glucose after the neuropathy sets in does not often help. Given this, every effort at tight control which may include early aggressive life style modification, drugs, diet and insulinization from the stage of diagnosis may go a long way. The sensory neuropathy can cause loss of a variety of sensation like touch, pressure, temperature, vibration, position and pain. When the sensation of pain is lost it gives rise to an insensate foot. The loss of pain sensation makes the foot vulnerable to trivial trauma as it is not sensed. This causes a break in the skin and even if it is inconspicuous and miniscule, it can become a portal of entry for the bacteria to enter. As many as 81% amputations have been found to be due to initial minor trauma.14 Several mechanisms detailed below finally lead to the development of an ulcer. Trauma, whether trivial or more substantial, needs to be of the repetitive nature to become responsible for ulceration. Because the foot is insensate, the same type of trauma can occur without the patient realizing that it is recurring. That leads to a break in the skin and will lead to a noticeable ulcer that causes further facilitation to the entry of bacteria and for infection to set in. Distal symmetric sensory motor polyneuropathy is the most common form of neuropathy in diabetes resulting either in pain, parasthesias, muscle atrophy or loss of variety of sensations mentioned above. Radiculopathy due to thrombosis of vasa nervorum leads to unilateral leg pain and weakness. Entrapment syndromes are common in persons with diabetes like tarsal tunnel syndrome causing sensory impairment of plantar skin and the weakness of the intrinsic pedal musculature.12 An insensate foot also gets pressure necrosis. Because of loss of sensation a patient tends to keep his feet in the same position whether he stands for a long time or while he is lying in the hospital bed or at home. This leads to the necrosis of the foot skin under pressure at the pressure point. This happens particularly to heels in patients lying in. The necrosis causes the skin to break down and an ulcer forms. Glycosilation and the change in the shape of foot: The glycosilation in the ligaments changes its properties. This results in restricted movements of joints. This Limited Joint Mobility (LJM) affects the cycle of walking. At the take off stage in the cycle of walking the normal extension of 1st MTP joint is restricted. The subcutaneous pad of fat is thinner and it slips forward and does not cover the joint. Therefore the joint bears extra pressure. This repetitive trauma of walking starts the process of inflammation as during every cycle of walking there is anoxia that does not recover fully in diabetes due to metabolic and vascular factors. This causes warmth and erythema. Other associations of sensory neuropathy: Persons with diabetes loose proprioception, i.e., the sense of foot position with loss of pain. This does not allow the patient to know how he places his feet. That results in abnormal foot positions. An unevenly placed foot in varying or in the similar kind of
  3. 3. 15 position, repetitively, develops unequal pressure areas on the plantar surface of the foot. The part of the foot that gets excessive pressure and unnoticed repetitive trauma can develop an ulcer. There are other causes of such unequal pressures also. If the loss of pain sensation, numbness and loss of proprioception are present, there will also be pressure unawareness. These patients do not tend to move their feet from any one position. This causes continuous pressure. Loss of temperature sensation: The heat and cold sensations are carried by C fibers. Small Fibers sub-serve warm, cold and pain sensation also. The rate of conduction for these sensations is slower, have a period of latency of about 500 milliseconds before the impulse gets initiated. Consequently there is a compounded delay in the sensation reaching the cortical areas, its registration of the sensation and response to it. The rate of rise or fall of temperature in degrees as well as time is also a determinant of cognition of these sensations. Heat and Cold Pain: In addition to the sensation of heat and cold there is the concept of heat pain and cold pain that should be understood. These thresholds are higher and lower than heat and cold sensation thresholds respectively. C Fibers are unmyelinated, without specialized nerve endings, lying naked in tissues and are distinct from A delta fibers that are responsible for deep aches and pain. Abnormalities of C fibers are supposedly responsible for early occurrence of symptoms. Other somatic sensations of pressure, touch, vibration, proprioception are likely as not, may not be affected at this stage.29 Some authors have considered C fibers to be the first to be affected in diabetic neuropathy.30 Symptomatic progression: Various symptoms occur initially when there is on going damage to the nerves. Later relief of symptoms to a pain free state signifies further damage and not amelioration. Amelioration of pain appears due to depletion of the neuropeptides, substance P that are needed for the pain sensations as well as the decrease in Nerve Growth Factors that maintain the C fibers. Adequacy of insulin, either endogenous or exogenously administered in diabetic state maintains the integrity of the nerve fibers. Vasomotion: Diabetes affects rhythmic vasomotion of small arterioles due to sympathetic damage early in disease. Loss of warm thermal threshold also occurs early with C fiber damage and correlates significantly to reduced vasomotion.31 Exact cause effect or association between vasomotion and C fiber damage as a time relationship is not established.31 Skin biopsies in persons with Diabetes show uniform depletion of substance P, CGRP and the cytoplasmic proteins, for small fiber specificity.32 Glabrous skin of the foot is far more affected by Diabetes than that of hand. Since these deficits may occur as a part of sensory neuropathy a patient is not likely to be aware if his feet come in contact with a hot object. This causes necrosis of the skin leading to ulcers. Some of the examples of this kind of thermal injuries cited by Indian workers are the contact of feet on the hot exhausts of motor-bikes or the cover of the engine in the driver's cabin in public transport system, where people tend to rest their feet after removing whatever foot wear they have. Another common cause
  4. 4. 16 of thermal injury is that Indians to go for hot fomentations or immersing the feet in hot water. There are numerous examples of people with diabetes developing ulcers walking on hot tiles barefoot within temple complexes, as religious reasons forbid use of footwear. (Fig 8) The nature of repetitive trauma: Vigorous massage with counter irritants causes sliding of skin over fascia. This possibly happens because of loss of subcutaneous fat tissue due to lipolysis. This factor damages the underlying blood vessels. This in turn causes areas of patchy gangrene in the skin. (Fig 9) Foreign bodies in shoes are not sensed by the diabetic foot and can remain in the shoe causing repeated trauma giving rise to high pressure at certain points. It may cause small puncture wounds. (Fig 10) Walking is the most frequent example of repetitive stress and trauma. In normal foot, the pressure on the forefoot at its peak while walking is 600 kilo Pascals. To get an idea of the kilopascal, we should know that the systolic pressure of 120mm of mercury is an equivalent of 15 kilopascals. So it is easy to imagine how easily the forefoot gets ischemic during walking, repeatedly. Absence of recovery from anoxia and ischemia leads to inflammation that manifests as warmth and erythema. This has important clinical implication. If the patient monitors the temperature of the foot by back of the hand at 1st, 3rd and 5th metatarsal heads daily, especially at the end of the day, he will immediately notice the increased warmth. At this point of time if patient restricts the activity then the inflammation resolves. If patient continues the same level of activity, then the exudate collects and the blister forms which breaks down resulting in to a classical diabetic foot ulcer, commonly on 1st MTP joint. Therefore it is necessary to remember that majority of the foot ulcer in diabetes are from within out and not from outside in. Thus majority of these can be averted by simply educating the patient in basic foot care. Other pathogenetic mechanisms: A-V shunting: These cycles of anoxia are enhanced by arteriovenous shunting if it is present. The mechanism of A-V shunting is described elsewhere. The anoxia will lead to inflammation in the deeper tissues but there is no pain and patients keep walking. The inflammatory process then leads to tissue necrosis that leads to the formation of ulcer. Shear Forces: In addition to this, the feet are subjected to shear forces that are comparable to walking on the rollers. Shear forces are perpendicular to the vertical pressure exerted on the feet by patient's weight. There are anteroposterior and mediolateral shears that are roughly a sixth of the vertical pressure forces. The longer the stride, the higher are the shear forces. The faster one walks or longer, the greater will be the shear forces. These forces are also quite damaging to the feet. (Fig 11) The other causes of developing pressure points are found primarily in the motor component of neuropathy. We will elaborate on foot pressures and its correlations in biomechanics later.
  5. 5. 17 Injuries of other kinds: The various types of the injuries which act like trigger factors in the presence of concomitant neuropathy and vasculopathy are home surgery, insect bites, chemical injuries, footwear injury, pressure injury and thermal injury. The insect bites occur in insensitive foot because the foot is exposed. The rodents are attracted by the smell of the callous of the exposed foot and nibble at it, as the foot is insensate. The simple precaution of routine use of socks can prevent this type of injury to an extent. Use of strong chemicals and counter irritants to relive pain could be damaging. 2. Motor Neuropathy: Motor neuropathy and some components of autonomic neuropathy cause change in the shape of the foot. Motor neuropathy leads to the weakness and / or atrophy of the interosseous muscles of the foot, resulting in the loss of ability of the small or the intrinsic muscles to hold the foot in normal shape and place it in the correct position. This leads to the deformity of foot. Once a foot is deformed then the pressure distribution is unequal and some points develop excessive pressure. Such a foot then becomes maladapted to the shoes one wears and the abnormal point of contact becomes a pressure area. The repetitive pressure leads to keratosis and callus formation. (Fig 12) The keratosis is said to develop more inappropriately in the presence of sensory neuropathy that is almost always present. Development of a callous is a good indicator of severity of neuropathy. The high pressure at the callus results in the damage to the tissues of the foot and can start the formation of ulcer below the callus that later on, breaks through. The pressure at callus point is nearly 20 times higher than the surrounding skin. Allowing the patient to walk with callus is akin to patient walking with pebble in his shoes. It is expressed by authorities like AJM Boulton that motor neuropathy and some deformity as a consequence thereof can precede the development of sensory neuropathy. It means that motor neuropathic abnormalities also would be high in prevalence like sensory neuropathy which is known to be frequent. The common deformities due to motor neuropathy: Crowding of toes: The crowded tows tend to get above or below the adjacent toes or come to lie in an oblique direction, while in the same plain. These tows may then hurt the adjacent toes with their nails. (Fig 13) Crowding of toes in the presence of sensory loss and poor foot hygiene can cause extensive web space fungal infection that leads to gangrene. Teaching the patient to separate the toes with cotton wool, foam pads or commercially available toe separators can avert this. Cock up toes: The toes, especially the great toe could cock up and is not level with the other toes of the foot. This makes them susceptible to trauma if shoes are habitually worn. They come in repetitive traumatic contact with the upper of the shoes and develop ulceration. There are other reasons for developing ulcers if there are cock up toes. In these cases the fibro-fatty pad of the metatarsal head moves forward and exposes metatarsal head to direct pressure and trauma. (Fig 14) Hallux valgus is a great toe not in alignment with the next and causes deformity. (Fig 15)
  6. 6. 18 Hallux rigidus does not move with the movement of the foot does not bend or extend hence becomes the site for repetitive injury and ulcer. (Fig 16) Clawing of toes: Due to an imbalance in the muscle tone of the intrinsic muscles of the foot the toes bend down. (Fig. 25) This brings the tips of the toes in contact with the surface and bear pressure. The tips do not have the fatty insulation the toes in normal position have. There is little between the skin and the bone and the pressure thus tends to ulcerate the tips of the toes. The cock up toes, clawed toes, hallux valgus or hallux rigidus develop an ulcer by one more mechanism. The diabetic state is known to give rise to the glycation of long lasting collagen fibres of the ligaments that hold various joints. The subsequent inflammatory changes leading to advanced glycated end products make the ligaments inflexible resulting in various abnormal postures of feet and toes making them susceptible to ulceration. Persons with diabetes tend to choose tighter shoes because then only they can feel the presence of it on their foot. This, along with deformities causes pressure points, bunions and ulcerations. (Fig 17) The hammer toes (Fig 11) cause the tip of the Hallux to bear the pressure as the toe flexes. At this point the bone is directly in contact with the ground with no cushion of fat in between. This leads to ulceration. 3. The pathophysiologic contribution of autonomic neuropathy: Autonomic neuropathy results in two distinct mechanisms that contribute to diabetic foot ulceration, i.e. sudomotor dysfunction and arterio-venous shunting in the foot. Sudomotor dysfunction: It is the dysfunction of the sympathetic nerves supplying the sweat glands in the foot. This results in the reduction or absence of sweating which normally keeps the feet moist. Feet become dry and the skin cracks more easily.12 It is said that feet that sweat do not ulcerate. Autonomic Neuropathy: Decrease in the flair reaction to a noxious stimulus is also due to autonomic neuropathy resulting in reducing blood flow to the wound or infected area. 13 Arteriovenous shunting: It has two aspects - The mechanism by which it develops and the disastrous effects it causes in the development of deformities leading to the development of diabetic foot. Development of AV shunts: Arteriovenous shunts connecting small arterioles to small veins and small venules normally exist. They are preferentially either closed or are regulated under rigid sympathetic control so that excess blood does not flow through them but is preferentially directed to arterioles and from there to veins through capillary bed. (Fig18.) Arterioles are less richly innervated by sympathetic nerves than are the arteriovenous shunts. When sympathetic degeneration takes place the arteriovenous shunts open much more, the rigid control closing them down normally, is now gone.
  7. 7. 19 But the arterioles do not dilate to the similar extent causing greater resistance to blood flow than the wider open AV shunt offers. That is how the blood gets shunted through AV shunts. The plantar circulation is organized with the small subcutaneous arteries penetrating the dermis and anastomizing in the cutaneous arteriolar plexus. The arterioles arise from these plexus and ascend to form sub-papillary plexuses. If AV shunting is present they are likely to be deprived of the normal blood supply causing ischemia to the skin and subcutaneous areas. The effects of AV shunting on diabetic foot: Since the blood is not perfused through the capillary bed via the arteriole but gets shunted off earlier to that, at the level of larger arteriole, the tissues are left hypoxic, the dermal capillary plexuses do not get perfused with blood resulting in lower transcutaneous oxygen tension and lower skin temperature. The veins become turgid, venous oxygen tension is high and in an operative setting the foot that is hypoxic, paradoxically bleeds more profusely. Hypoxia affects the bones of the feet. There is resorption of the bone that leads to osteopenia, i.e. decrease in calcium content of the bones. These changes lead to increase in frequency of fractures of the small bones. Since it is an insensate foot, the patient continues to walk despite the fractures, as there is no pain. These two factors can lead to considerable joint deformities, subluxation of talonavicular joint and lateral migration of toes. These changes lead to more deformities and greater susceptibility to ulceration as described above. This is the setting of Charcot's joint. (Fig 19, 20) The two classic deformities that finally lead to the Charcot's arthropathy are: The rocker bottom deformity in which there is sub-luxation and displacement of tarsal bones downwards. The medial convexity that results from the displacement of talonavicular joint or from tarso-metatarsal dislocations, results in toes overlapping each other. Such toes can cause injury to the adjacent toes by their nails and this can happen repeatedly leading to small puncture wound and ulceration. Alternatively, if the shoe size is small then a bunion may form on the medial side of 1st metatarsophalangeal joint that can then get injured and infection may start. (Fig 21) Nails and diabetic foot ulcers: Hypertrophied nails are possibly an effect of neuropathy. They can cause sub- ungual ulcerations, or could be in growing to cause ulceration there. The irregularly grown nails can and do injure adjacent toes to cause ulcers. (Fig 22) A word on painless / painful foot and leg: Persons with diabetes may have feet that are numb and insensate but get severe nocturnal pains in their lower limbs. Deep calf pains are characteristic at night and can be extremely severe. Prevalence of pain has been reported to be as high as 33 %
  8. 8. 20 in diabetic feet.10 Sudden increase of pain in a painless chronic ulcer is indicative of worsening of infection or reduced vascularity. If there is global pain of sudden onset with cold feet and is of severe nature it could indicate an acute embolization or thrombosis in a large artery. All persons with diabetes who have painful legs and feet do not have diabetic polyneuropathy. In one series of 117 patients, 65.5 % had peripheral neuropathy of possibly diabetic origin of the distal symmetric type. 7% had femoral neuropathy 11% had peripheral vascular disease, 4% had tarsal tunnel syndrome, 4% had lumbar canal stenosis, 3% had reflex sympathetic dystrophies and 6% had other miscellaneous causes. Hence it is essential to keep other causes in mind.10 4. Peripheral (macro)vascular disease causing diabetic foot ulceration: The most significant lesion in peripheral vessel that contributes to the development of ulceration is the atherosclerotic disease of tibial and peroneal vessels that leads to decreased flow of blood through the foot, resulting in decreased delivery of oxygen, nutrients and antibiotics to the foot further hampering the chances of healing, although it does not affect the plantar arch. Some of the characteristics of the diabetic peripheral (macro)vascular disease as described in the international consensus of the diabetic foot are, 16 more common (than normal population), affects younger individuals. There is clear evidence from studies in India that the diabetes detection age is lowered by a decade now. There is no sex difference among persons with diabetes.15 Women with diabetes had more PAD than non-diabetic women in Framingham study with greater claudication as well as higher cardiac disease.17 There is faster progress, the affliction is multi- sequential, i.e. tandem lesions, is more distal, (more typically the infra-popliteal, tibial, peroneal segments)15 Vascular surgery is more common on persons with diabetes.18 Smoking complicates the PVD, doubles the risk in both sexes and is dose related. The impact was discernible in advanced age.19,20,12 Smoking is atherogenic, decreases the blood flow through vasospasm and increases blood viscosity and clotting factors. Low HDL-cholesterol in Indians is now well-documented as is hypertriglyceridemia. This pattern is considered atherogenic. Understanding macrovascular disease in diabetes: While diffuse atherosclerotic tandem lesions in diabetes can occur and do occur in the proximal femoropopliteal arteries the characteristic arteries involved in diabetes are below the trifurcation of the popliteal arteries tibial and peroneal.33 Reconstructive surgery is most frequently done for these vessels. The autonomic neuropathy leads to the decreased flair reaction. Microangiopathy is not believed to be the cause of foot ulceration.15 Monckeberg sclerosis affects the vascular media by calcification is considered to leave the lumen intact and therefore does not jeopardize the foot from the ischemic point of view, though in 15% of cases with diabetes where ankle pressure is measured medial sclerosis gives an abnormally high ankle pressure due to the non compressibility of the vessel.35 The smaller arteries: It is not uncommon to have ischemia in the arteries of toe as evident from toe pressure measurements while the ankle pressure may be normal.34
  9. 9. 21 Cholesterol emboli can affect the smaller vessels and convert them in end arteries resulting in blue toe syndrome that will lead to gangrene. Hypertension is well known to be associated with atherosclerosis.16a Microangiopathy: It is not a significant factor in the development of foot ischemia. In many instances there will be enough patent vessels below the ankle to allow for reconstructive surgery on tibioperoneal vessels. Another protective factor is the really rich collateral circulation within the plantar and dorsal arches and between the two arches, as well as smaller unnamed communications all over the foot tissues usually allows major operations and make bypasses useful. 34 Infections and compromise of the foot vessels: Puncture or penetrating wounds of the plantar region or the web space infections may go up in the central non expansible plantar space. The inflammatory exudate that collects causes pressure on the small arteries in the tissues and will lead to thrombosis or obliteration. This will lead to gangrene. In diabetes the choice of treatment is important. ACE inhibitors are preferred. The role of a small dose of diuretics has been recognized in therapy. Despite the beneficial effects of beta-blockers to the cardiac outcome within the subgroup of diabetes it will be very contentious to use beta blockers in significant peripheral arterial disease. If it is used it will have to have adequate justification.21,12 Pathogenetic contribution of vasculopathy to the development of neuropathy: 50% of diabetic patients who have had ulceration / amputation have (in the western countries at least) co-existing neuropathy and peripheral vascular disease.1,2 Peripheral ischemia of lower limb can lead to ischemic nerve conduction failure.3 The lower endoneurial hypoxia is the possible mechanism in human beings.4 The presence of peripheral vascular disease co-relates with the peripheral neuropathy.5 Neuropathy is also caused by the lower transcutaneous oxygen tension but is probably due to shunting and not due to peripheral vascular disease.6 The abnormal vasa nervorum causing local ischemia have been proposed to be responsible for this since vasodilators and vasoconstrictor PGI2 antagonists have been shown to produce improvement.7,8,9 As discussed earlier - the recurrent ischemia of the forefoot on walking cannot be compensated fully and immediately in the presence of peripheral vascular disease and results in chronic hypoxia, inflammation etc. Similarly use of beta blockers in significant peripheral arterial disease will have to have adequate justification, due its propensity to vasoconstriction, despite its beneficial effects in cardiac disease, although selective beta blockers like metoprolol or bisoprolol do not seem to be contraindicated.21, 12 5. The infection and related issues: The source of infection is usually the contamination of the break in the skin, which may be imperceptible like cracks or fissures, puncture wounds or a major wound in a neuropathic foot due to trauma of any cause. Staphylococcus aureus and beta haemolytic streptococci rapidly colonise the break in the skin. The other sources would the web space fungal infections and paronychia, viz, tinea pedis,
  10. 10. 22 Onychomycosis. The devastating developments subsequent to an infected ulcer that lead to the development of gangrene, necrotising fascitis and life threatening situations like multi-organ failure should be guarded against. The pathophysiology of these events can be constructed in the following sequence: In persons with diabetes, infection results in microthrombi formation in the smaller vessels unlike persons without diabetes where it results in vasodilatation. This impairs blood flow in diabetes, converting the small arteries of the toes into end arteries resulting in gangrene of the toes. Osteomyelitis can be difficult to diagnose and remains a focus of uneradicated infection and fails to indicate to the physician the need for longer antibiotic regimen. The diagnosis of Osteomyelitis was missed in as many as two thirds of bone culture proven cases.22 Excessive reliance on plain X rays by primary care physicians does not help.23 Simple probing the bone can make a diagnosis of Osteomyelitis, while scanning techniques are not always successful, some like Tc99 lack specificity, but MRI is proving helpful.24, 25, 26 Clinically the trophic ulcers in diabetic neuropathy occur in the area of metatarsophalangeal joints. The flexor tendons of the corresponding joint are involved. The infected tendon carries the infection proximally in the leg, may become devasularized and lead to loss of the sling support of the arch. This can enhances the chances of the collapse of the arch. This is more likely to happen in case of ulcers over the 1st MTP joints. Therefore eradication of the infection and salvage of the foot is at the cost of the collapse of the arch. It is known that surgical procedures on the foot in a person with diabetes can accelerate the process developing neuroarthropathy. Diabetes mellitus as an immunocompromized state Failure of persons with diabetes to control the spread Poor granuloma formation and inability to localise the infection is probably due to the immunocompromized state, along with impaired wound healing and persistence of abscesses.29 As a result of that an ulcer spreading deeper can contaminate a tendon causing tenosinovitis. Tendons are avascular and are enclosed in loose facial sheaths. They do not offer resistance to upward spread of the infection towards mid leg. The soft tissue, which could be hypoxic either because of AV shunting or peripheral vascular disease, does not offer resistance to infection. There is a concept of plantar spaces like the palmer spaces. These are spaces that contain the nerves and blood vessels and communicate with each other. Usually it is the medial or lateral plantar space that gets infected and forms an abscess corresponding to the original ulcer through which bacteria have entered. Infections along the Flexor Hallucis Longus can go up to the level of middle of the leg. Pathogenetically it is important to remember that the ulcers may look small or benign but may indicate deeper abscesses. They are like a tip of the iceberg. Necrotising fascitis, one of the dreaded complications is an aftermath of this upwardly spreading infection.
  11. 11. 23 Hyperglycaemia is responsible for alternations of immune functions of the white cells.27 Some of the commonly mentioned abnormalities are as follows: Bacterial endotoxemia, in presence of hyperglycaemia causes slower response in the number of polymorphonuclear cells and also the speed of response. In one study where granulocyte colony stimulating factor was used to augment the granulocyte response in diabetic infected foot lesions suggested that along with increase in the number of polymorphs, the study indicated that G-CSF may be deficient or functionally sub-optimal in diabetic infection.11 Cruciani has indicated that use of G- CSF may not reduce the duration of healing but significantly reduces the need for both surgical intervention and amputation on a need to treat basis. There is no mention about costs involved.36 Diabetes or uncontrolled hyperglycaemia cause decreased diapedesis towards the site of infection, decreased chemotaxis, lower adherence that is normalised by correction of hyperglycaemia. The phagocytosis is supposedly poor, especially in diabetic ketoacidosis (an infected foot is likely to present with DKA).28 Killing after phagocytosis is also poor due to affectation possibly of superoxide bursts. Natural killer cells have a reduced capacity to kill in presence of hyperglycaemia that gets restored by normoglycaemia. CD4+ lymphocytes and antibody dependant cellular cytotoxicity is supposed to decrease in the presence of hyperglycaemia. The monocytes have decreased lectin like receptors with decreased affinity. An overview of the pathophysiology of diabetic foot: The diabetic state per se will result in peripheral neuropathy, peripheral vasculopathy also and autonomic neuropathy leading to deformities, abnormal pressure dynamics and ulcer. The ischemic-immunocompromized state in the face of anatomical peculiarities of foot will cause spread of infection. The development of gangrene: It is always the end result of the vascular closure to a part of the body. In spreading infection, either vasculitis, or microthrombi or pressure of an inflammatory exudate in plantar spaces could lead to vascular closure. References: 1. Edmonds ME, Blundell MP, Morris ME, et al. Improved survival of the diabetic foot: The role of the specialist foot clinic. QJ Med 1986; 232:763-771. 2. Thomson FJ, VevesA, Ashe H,et al. A team approach to diabetic foot care: The Manchester experience. Foot1991; 2:75-82. 3. Low PA Recent advances in the pathogenesis of diabetic neuropathy. Muscle nerve 1987; 10:121-128.
  12. 12. 24 4. Newrick PG, Wilson AJ, Jakubowski J, et al. Sural nerve oxygen tension in persons with diabetes. BMJ1986; 293:1053-1054. 5. Ram Z, Sadeh M, Walden R, et al. Vascular insufficiency quantitatively aggravates diabetic neuropathy. Arch Neurol 1991; 48:1239-1242. 6. Young MJ, Veves A, Walker MG, et al. Correlations between nerve function and tissue oxygenation in diabetic patients: Further clues to diabetic neuropthy? Diabetologia1992; 35:1146-1150. 7. Auwerx J, Bouillion R, Collen D, et al. Tissue type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus. Arterisclerosis 1988; 8:68-72. 8. Beach KW, Strandness DE, Arteriosclerosis obliterans and associated risk factors in insulin dependant and non-insulin dependant diabetes. Diabetes 1980; 29:882-888. 9. Fontboonne AM, et al. Insulin and cardiovascular disease: a Paris prospective study. Diabetes Care 1991; 6:461-469. 10. Marvin E Levin. Overview of the diabetic foot: Pathogenesis, management and prevention of Lesions, In International J of Diabetes in Developing countries. 11. Andrew Gogh, Mary Clapperton, Nancy Rolando, Alethea V M Foster, John Philpott- Howard, Michael Edmunds, randomised Placebo Controlled Trial of Granulocyte Colony Stimulating Factor in Diabetic Foot Infection. The Lancet, Vol 350, September 30, 1997 pp 855 - 859. 12. Bowker, John H and Pfeifer, Michael A (2001) Levin and O'Neal's The Diabetic Foot. 6th Edition,. Mosby St.Louis, pp - 219. 13. Parkhouse N, LeQuesne PM: Impaired neurogenic vascular response inpatients with diabetes and neurogenic foot lesions. N Engl J Med 318:1306, 1988. 14. Pecoraro RE, Rieber GE, Burgess EM: Pathways to diabetic limb amputation: basis for prevention. Diabetes Care 16:1187-1189, 1993. 15. LoGerfo FW, Coffman JD: Vascular and microvascular disease of the foot in diabetes. N Engl J Med 311:1516, 1984. 16. International Consensus on the Diabetic foot by the International Working Group on the Diabetic Foot 1999. 16a. Wilson PWF, Kannel WB, Epidemiology of hyperglycemia and atherosclerosis. In Ruderman N, Williamson J, Brownlee M, (eds): Hyperglycemia, Diabetes and Vascular Disease, New York, Oxford University Press, 1992. 17. Malone JM, Snyder M, Anderson G et al: Prevention of amputation by diabetic education Am J Surg, 158:520, 1989. 18. Delbridge L, Appleberg M, Reeve TS: Factors associated with the development of foot lesions in the diabetic. Surgery 93:78, 1983. 19. Beach KW, Strandness DE Jr: Arteriosclerosis obliterans and associated risk factors in insulin dependent diabetes. Diabetes 29:882, 1980.
  13. 13. 25 20. Bowker, John H and Pfeifer, Michael A (2001) Levin and O'Neal's The Diabetic Foot. 6th Edition. Mosby, St.Louis, pp 225 21. Newman LG, Walker J, Palestro CJ, Unsuspected Osteomyelitis in diabetic foot ulcers. JAMA, 266:1246-1251, 1991. 22. Edelman D, Matchar DB: Clinical and radiographic findings that lead to intervention in Diabetic patients with foot ulcers: A nationwide survey of primary care physicians. Diabetes Care 19:755-757, 1996. 23. Grayson ML, Gibbons GW, Balogh K, et al: probing to bone in infected pedal ulcers: A clinical sign of underlying Osteomyelitis in diabetic patients. JAMA 273:712-728, 1995. 24. Littenberg B, Mushalin AI: The diagnostic technology assessment consortium: Technetium bone scanning in the diagnosis of Osteomyelitis: A meta analysis of the test performance. J Gen Intern Med 7:158-163, 1992. 25. Durham JR: The role of magnetic resonance imaging in the management of foot abscess in the diabetic patients. In Yao JST, Pearce WH (eds): The ishcemic extremity: Advances in treatment. East Norwalk, CT: Appleton & Lange, 1995. 26. Mac Mahon MM, Bistrian BR: Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am 9:1-10, 1995. 27. Sentochnik DE, Eliopoulos GM: Infection and Diabetes. In Kahn CR, Weir GC, (eds): Joslin's Diabetes Mellitus, 13th ed. Philadelphia: Lea and Febiger, 1994, pp 867-888. 28. Lipsky BA, Pecoraro RE, Larson SA et al: Outpatient management of uncomplicated lower extremity infections in diabetic patients. Arch Intern Med 150:790-797, 1990. 29. Aron Vinik Exp Clin Endocrinol Diabetes, 109 (2001) Suppl 2). 30. Jamal et al, 1987, Dyck, 1988, Hanson et al, 1992, as quoted by Vinik vide above. 31. (Vinik ibid). 32. Levy et al, 1992,Wallargren et al, 1995, Lauria et al, 1998, and others. 33. Levin ME, Sicard GA: Evaluating and treating diabetic peripheral vascular disease: Part 1. Clin Diabetes 5:62, 1987. 34. Chapter 9 pp 223 as quoted by Bowker and Pfeifer in The Diabetic Foot, Sixth edition. 35. LoGerfo FW, Coffman JD: Vascular and microvascular disease of the foot in diabetes. N Engl J Med 311:1516, 1984. 36. Cruciany et al, Diabetes Care 28:454-460, 2005.