DIABETIC NEI]ROPATHY

Ricbard J. Zirm, DPM

Alan S. Banks, DPM

Of the sk million diabetics in the United States,belween 5 and 60 per cent have been reported tobe affected with peripheral neuropathy. The widerange in these figures reflects the lack of uniformcriteria with which to diagnose and classify thiscomplication of diabetes. Further complicatingthe matter is the fact that physicians may not rec-ognize the various sensory, motor, and autonom-ic manifestations of the disease. This chapterreviews the forms, proposed etiologies, diagnosis,classification, and treatment of diabetic neuropa-thy with the hope that early recognition andtreatment will improve the clinical managementof these patients.

PATTIOPHYSIOLOGY

Many physiological mechanisms have been pro-posed to explain the development of diabeticneuropathy. Simply stated, the function of theSchwann ce1ls is impaired resulting in a loss ofmyelin. Even in those nerves which do not pos-sess myelin, the relationship between theSchwann cell and the axon is quite intimate. Theinitial consequence is a reduction in nerve con-duction velocity, but actual axon damage anddegeneration follows.'

Nele tissue is unique as it does not requireinsulin for glucose to be absorbed into the cells.Consequently, the glucose 1eve1s within nerveaxons will be directly proportional to that of theblood. Most authorities feel that the damageinduced by the hyperglycemia is mediatedthrough the polyol pathway. Glucose is trans-formed in the Schwann cell to sorbitol and fruc-tose which eventually leads to numerous bio-chemical and functional abnormalities. Mostimportant is the decreased concentration ofmyoinositol which is required for proper function

of the axonal membranes. As the rate of the poly-o1 pathway is directly dependent upon the levelof glucose, persistent hyperglycemia feeds thisprocess.'

It has also postulated that neuropathy iscaused by occlusive vascular disease or infarctswhich result in nerwe ischemia. However, mostauthorities now tend to support a metabolicderangement such as that described above formost cases of neuropathy. Specific neuropathieswhich tend to develop due to ischemia or vascu-lar infarcts will be noted.

CI-A.SSIFICATION OFDIABETIC NEUROPATHY

\fith the onset of diabetic neuropathy, a widevariety of manifestations may develop. The diffi-culty in adequately classifying this process is thatmixed syndromes are frequent. Brown,/Asbury3advocate using broad subdivisions as follows:

Distal symmetrical polyneuropathy:Usually insidious in onset and progressive

Proximal symmetrical motor neuropathy:"diabetic amyotrophy"

Focal neuropathies:Rare, sudden, transient events.

-Asymmetrical proximal motor neuropathy-Cranial neuropathy-Mononeuropathy/mononeuropathymultiplex

-Entrapment neuropathy

The discussion that follows will focus on the vari-ous neuropathies that affect the lower limb.

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Distal Symmetrical Polyneuropathy

This is the most commonly recognized form ofdiabetic neuropathy. The estimated prevaience ofthe various subtypes are provided in Table 1.3

Perhaps the most striking feature of this clas-sification is the large number of patients that will

TABLE 1.

Prevalence of the Various Subtypes of Diabet-ic Neuropathy

Subtype o% of cases

Mixed sensory-motor-autonomic 70Predominately sensory 30Predominateiy motor <1Predominately autonomic <1

exhibit clinical manifestations of neuropathy of allthree fiber types. Most clinicians have been keen-ly aware of sensory neuropathy, while otherforms of nerwe disease have not been fully appre-ciated. The discussions which follow are an effortto help those who treat diabetic patients to morereadily distinguish the numerous characteristics ofthis mixed syndrome.

Sensory deficits and symptoms appear in themost distal portions of the extremities andprogress in a "stocking and g1ove" distribution.The first symptoms may be numbness and pares-thesias in the feet, most marked in the evening.They are often relieved by ambulation) rnassage,and hot or cold soaks. The paresthesias may bevariously described as coldness, burning, tingling,ache, cramp-like, or crushing. Often a patientrelates a sensation of walking on air or pillows,or feeling that their feet are swoilen. With pro-gression of the neuropathy, pain in the lowerlimbs may become the most prominent feature,although this does not seem to be the case in themajority of instances. Many patients will notrecall any specific symptoms, yet fail to recognizethe degree to which sensation has been impaired.Sensory neuropathy is appropriately detected inmost instances, and much has already beenwritten about this particular component ofneuropathy.

While a majority of the symproms and signsin the legs may be sensory, muscle weakness

almost invariably accompanies the sensory loss.In evaluating diabetic patients at the Institute, ithas been the authors' finding that a consistentnumber will present with a variable pattern oflower extremity muscle weakness. The loss of agrade of muscle strength may initially seembenign, but in this patient population the effect is

Elreater than imagined. Many of the parients willpresent with mr-rscle weakness which exceedsone grade. The motor neuropathy usuallyinvolves the interosseous muscles of the feet andresults in claw toe contractures and increasedpressure beneath the metatarsal heads. One mayalso see the weakness involving the anterior legmuscles which may be profound enough to callsea dropfoot.

Milder forms of weakness may not be asreadily detected, yet still lead to a distinct dynam-ic imbalance which creates or exacerbates anankle equinus deformity. Equinus not onlyincreases the forces affecting the metatarsal area,but places additional stress on the mid- or rear-foot which may cause Charcot collapse. Vhencombined with a concurrent sensory loss, thepatient is at a higher risk for developing ulcera-tion. When present with autonomic neuropathy,bone which has already been weakened due tohyperemia may not be able to withstand theseadditional forces and may eventually collapse.

Autonomic neuropathy, or autosympathecto-my, occLtrs in up to 70o/o of diabetics.3 Evidenceindicates that the autonomic component of theperipheral neuropathy may precede the onset ofeither sensory or motor involvement. Sympatheticfibers supply the small arteries and arterioles ofthe lower extremity, the sweat glands, and thearrectores pilaris muscles. Autonomic dysfunctionresults in vascular calcification resembling Mon-ckeberg's medial calcific sclerosis, anhidrosis, andeventually loss of hair growth.

The vascular implications of autonomic neu-ropathy are great. Loss of sympathetic toneresuits in a vasodilation of the vessels causing anincreased bloocl flow to the skin, subcutaneoustissues, and bone. Numerous studies have shownthat the neuropathic foot is extremely weil per-fused.t4 Many patients may possess a foot whichdemonstrates neuropathic edema due to theshunting of blood at the arteriovenousanastomoses.T

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Vascular calcification should not be inter-preted as occlusive disease as Edmoncls, et al.,have noted that the only explanation for this phe-nomena is neuropathy.'At times the calcificationmay make palpation of the pulses irnpossible.

Typically the diabetic limb has been felt tosuffer from microangiopathy, however, no objec-tive evidence has been founci to support thepresence of an occlusive microvascttlar clisease.

Yet many diabetics may not receive adequate footcare due to the misconception concerning thevascular status of the lower extremity.e'l. Unlessproximal large vessel disease is present, thepatient who possesses autonomic neuropathy willpresent with a good blood supply to the fbot.

Autonomic neuropathy will usually aff'ectthe lower extremity first, then may exhibit moreproximal manifestations as well. This facet of thedisease may affect many organ systems. Althoughbeyond the confines of the lower extremity, evi-dence of the more proximal aspects of the dis-ease confirm the fact that autosympathectomy is

present in the lower extremity. The anhidroticskin founcl in the foot and leg may be contrastedwith a compensatory increase in perspirationover the trunk. This hyperhidrosis is reqr-rired tooffset the redr.rced ability of the lower lirnb to dis-sipate heat. The patient may complain of heatintolerance or sweating attacks. Gustatory sweat-ing may occur over the face, head, and neckwithin seconds of eating spicy foods.

Cardiac function may be affected by auto-nomic neuropathy and initially result in a restingtachycardia. However, if the skin and splanchnicbeds are diseased the patient is prone to posturalhypotension. The heafi rate is typically fixed ancl

fails to show the typical change to position andexertion. This may result in orthostatic hypoten-sion which is quite disturbing. Some authoritiesalso attribute the prevalence of silent myocardialinfarction in diabetics to alltonomic neuropathy."

The gastrointestinal and urinary systems maydemonstrate a variety of problems including dia-betic gastroparesis (early satiety, abdominal full-ness, nausea, and vomiting), diabetic cliarrheawith involvement of the small bowel, or constipa-tion when the colon is affected. Bladder distur-bances are occasionally present and may result inincomplete voiding, decreased frequency of void-ing, incontinence) and impotence."

Treatment of symmetricalpolyneuropathy

The treatment of peripheral neuropathy is bestcentered upon preventing the initial nerue dam-age. An improved metabolic control with nearnorrnal daily blood glucose profiles is the firstand foremost step. Although clinical trials havereally not demonstrated that this makes a defini-tive long term difference, most expefis continueto support the need for tight glucose control."

Various pharmacologic agents have alsobeen studied to determine if neuropathy may beprevented by blocking the polyol pathway. If thismetabolic process could be arrested, then onernight prevent the accumulation of noxious sub-stances within the nerve. Specifically the medica-tions most commonly employed to date havebeen agents which inhibit the enzyme aldosereductase (Alrestatin, Sorbinil, Tolrestat).Although theoretically of value, these drugs haveyielded only equivocal results in clinical trials.Two studies have found significant improvementin nerve conduction r,.elociry as well as subjectiveassessments of patient sympioms.'r'a Other inves-tigators have been unable to reproduce thesereslllts."'u However, the effectiveness of thesedrugs may be related to the degree of nerue dam-age present when pharmacologic therapy is insti-tuted. Those patients who have benefited themost in the clinical trials were yollnger andexhibited less established disease.

One must also be concerned over potentialside effects of this type of medication andwhether or not the potential benefits outweighthe long term risks. Aldose reductase catalyzes anumber of other metabolic reactions in the bodyand it is not known if the inhibition of these pro-cesses is of conseqllence.'-

Another agent which has been used for dia-betic neuropathy is myoinositol. This substance is

an important component of neuronal cell mem-branes. In diabetic laboratory rats the nerve con-tent of myoinositol is diminishecl. Normalizalionby oral supplements results in an increase innerve conduction velocity. However, clinical trialsin humans so far have been disappointing.'"

The "antineuritic" vitamins, thiamine, pyri-doxine and vitamin B L2 have all been experi-mentally used in diabetics. The supposition wasthat they may be beneficial if some correlation

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was present with alcoholic or nutritional neu-ropathies. However, deficits of these vitamins hasnever been found in diabetic subjects. Most cur-rent researchers feel that there rs no objectivedata to justify the use of neurotrophic vitamins.l,

Unfortunately, we have to deal with a largegror-lp of patients who either possess, or will pos-sess, varying degrees of neuropathy. Severaithings can be done to minimize the risk for com-plications in these individuals. Adequate protec-tive measures must be taken with shoes and/orofihotic devices. The device should be designedto accommodate the excessive forces acting onthe foot. Often one may forget the benefit ofadding a rocker sole to the shoe to assist in pro-tecting the metatarsal area.,e Muscular imbalances(equinus) must be accommodated as well. Thismay be accomplishecl by adding an appropriatesize heel lift to the shoe. In most cases between3/t" to 1 ',/r" will be adequate. Despite other sup-pofiive measures, failure to recognize and protectthe foot from equinus stil1 leaves the foot at riskfor Charcot joint collapse.

Muscle imbalance may be improved throughthe use of a controlled physical therapy program.The patient may be seen by a physical therapisras some individuals lose interest in exercising ontheir own. Specifically, one is attemptinpl tostrengthen the anterior leg muscles, while stretch-ing the posterior group. Stretching should bedone gently, so as not to encollrage excessivestress within the foot. The danger is that the footmay be used as a lever against the triceps. IfCharcot collapse has already taken place thenphysical therapy may have to be limited tostrengthening of the anterior muscle group.

Symmetrical Proximal Motor Neu-fopathy

Other somatic manifestations of diabetic neuropa-thy may occur in the hip and thigh muscles. Hereweakness may be associated with aching thighpain. Most affected individuals are middle-agedor older who wili give a history of recent weightloss. The proposed etiology of this process is feltto be metabolic in nature owing to the concomi-tant history of weight loss andlor poor glycemiccontrol. This syndrome has also been associatedwith alcoholism."

Generally these individuals recover motorfunction to some degree, although the interuen-

ing period may be quite distressing. Ambularion,stair-climbing, and arising from a sitting positionmay all become difficult if not impossible to per-form. Several such patients in our practice haveresponded to physical therapy, while others, withmore protracted weakness have failed to demon-strate significant improvement.

Focal and Multifocal Neuropathies

Asymmetrical proximal motor neuropathy primar-ily affects the cranial and intercostal nerves,although it rnay also be seen in the lower extrem-ity. Generally speaking the evidence seems tosupport an acute ischemic process as the etiologyfor these clinical syndromes. The onset of theneuropathy is usually rather rapid and pain isusually associated with the loss of strength. In thelower extremity this syndrome may resemble aradiculopathy and most commonly affects thefemoral, obturator, and sciatic nen/es. However,such presentations should not be casually dis-missed as "diabetic radiculopathy" since this is adiagnosis assigned after other pathologies havebeen excluded. Overali the prognosis is good,although recovery of function may take months.

Nerwe entrapments are also more commonin diabetics. Generally speaking, the entrapmentneuropathy is felt to be due to compfession. Thepatient who already possesses some degree ofnerve damage will be more vulnerable to anycompressive effects or strictures about a nele. Inthe lower extremity, compression of the lateralfemoral cutaneous nerye may result in meralgiaparesthetica, pain and numbness overlying thelateral thigh. The common peroneal nerue is alsoreported to occasionally manifest with entrap-ment syndromes. However, the authors have yetto witness this presentation. Carpal tunnel syn-drome is seen with greater frequency in diabeticpatients.l

Treatment for each of these entrapment neu-ropathies is the same as that for nondiabeticpatients with resolution occt-trring in a similarmanner.

Painful Diabetic Neuropathy

Pain may be a feature of any type of diabeticneuropathy. Focal neuropathies will result in asharp, sudden onset along the course of thenelve which is afflicted. Typically ir is asymmetri-

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cal and lasts for weeks or months before sponta-neously disappearing.

Pain in peripheral polyneuropathy usuallystarts insidiously and may be symmetrical. How-ever, in the authors experience most patientshave presented with unilateral complaints. Sever-a1 types of symptoms may be described includingspontaneous episodes of generalized discomfofi,contact sensitivity, shooting or stabbing, burning,or a deep aching. Although the onset may occurat any time of the day, most patients relate thatthey are particularly uncomfortable in theevening, and often can not sleep through thenight."

It is paradoxical that insensitivify to pain andspontaneous pain coexist. Although not fullyunderstood, the most logical explanation for thediscomfort appears to be damage to the smallnelve fibers which calrses a subsequent increasedactivity of these units. It has been shown thatregenerating nerve fibers fire rapidly and atabnormally low thresholds. Depolarization ofthese damaged or regenerating fibers may be themechanism which elicits pain.3

Treatment of Painftrl DiabeticNeuropathy

One of the best means of treating this conditionis through effective, strict blood glucose control.Hyperglycemia is felt to enhance pain sensitivityand relief of symptoms is often obtained afterseveral weeks of stable metabolic control. How-ever, in some individuals painful neuropathy maybe induced by rapid normalization of hyper-glycemia."

Chronic pain has been treated by a varietyof pharmacologic agents. Tricyclic antidepressantshave been used with sllccess in a number ofpatients, although critics point out that no con-tro1led, double-blind studies have been per-formed. Generally these medications work bestfor deep, aching pain. However, if orthostatichypotension is a problem for the patient (as itmay often be in those with autonomic involve-ment in the heart), then tricyclic medications mayaggravate the condition.3'" Those with shooting orstabbing pains appear to respond more favorably

with either phenytoin or carhamazepine.3 Carba-

mazepine is the only drug which has been showneffective in a controlled clinical trial." Phenl'toinhas a less demonstrable effect and high doses

tend to inhibit insulin secretion. Trazodone, a

nontricyclic antidepressant also has its advo-cates.2r Others have tried combinations of tricyclicantidepressants and phenothiazines.3

More recently capsaicin (Zostrk, Axsain) has

been advocated for neuropathic pain associatedwith diabetes. This substance is applied topically,and therefore, may obviate the systemic effects ofthe other pharmacologic approaches. However,the medication is expensive and even when suc-

cess is achieved il may well require severalweeks of treatment. Furthermore, like so many ofthe other means of treating this condition, a largenumber of patients will fail to respond.

Unfortunately, many patients fail to findrelief with any of the medications describedabove. Other conservative methods which mayhelp to a certain degree are the application ofcool towels or dressings, or the use of a mildlycompressive stocking.

CONCLUSION

Peripheral neuropathy like other diabetic compli-cations are characterrzed by early functionalreversible changes followed by later permanentstructural damage. It is possible that some of theagents currently undergoing evaluation may at

some point induce positive effects related to earlyfunctional disease. A tremendous amount ofmoney and effort is being expended at the pre-sent with little real evidence of a conclusiveanswer. Currently only early preventative treat-

ment in the primary stages of diabetes has yieid-ed any success. Early, tight and near normaliza-tion of blood glucose levels appears to be themost effective means of limiting diabetic neu-ropathy as well as other organ system disease.

Appropriate protection of the foot with edu-

cation of the patient appear to be the best pre-ventative measures to date.

)l

REFERENCES

Clements RS, Bell DS: Diabetic neuropathy: pathogene-sis and classification. Cardiouas-cular Reuieus andRepofis 5:78-23, 7987.Greene DA, Lattimer S, Ulbrecht J, Carroll P: Glucoseinduced alterations in nerve metabolism: cllrrent per,spective on the pathogenesis of diabetic neuropathyand future directions for research and therapy. Dia-betes Care 8:2)0-2)). 1995.Brown MJ, Asbury AK: Diabetic neuropathy. Ann Neu-r"ol 75:2-1.2, 7984.Edmonds ME: The neuropathic fbot in diabetes, part 1:

blood flow. Diabetic Meclicine 3:177-775, 1986.Edmonds ME, Clarke MB, Newton S, Barrett J, \X/atkinsPJ: Increased uptake of bone radiopharmaceutical indiabetic neuropathy. Q J Merl 224:843-855, 1985.Eclmonds ME, Roberts VC, \iTatkins PJ: Blood flow inthe diabetic neuropathic foot. Diabetologia Z2:)-15,1982.

Boulton AJM, Scarpello JHB, \X/ard JD: Venous oxy-genation in the diabetic neuropathic foot: evidence ofarteriovenous shunting? Diabetologia 22:6-8, 7982.Edmonds ME, Morison N, Laws J$7, \Watkins PJ: Medialarterial calcification and diabetic neuropathy. Brrt Med J281:928-930, 7982.Logerfo F\X/, Coftman JD: Vascular and microvasculardisease of the foot in diabetes. Neu Engl J Med371:7675-761.9, 1984.Flynn MD, Edmonds ME, Tooke JE, \tratkins PJ: Directmeasurement of capillary blood flow in the diabeticneuropathic foot. Diabetologia 37 :652-656, 1988.Clarke BF, Ewing DJ, Campbell I\fl: Diabetic auroflomic neuropathy . Diabetologia 77:795-212. 7979.Crepaldi G, Fedele D: Treatment of diabetic somaticneuropathies. In Andreani D, and others (eds.): Diabet-ic Complications: Early Diagnosis and Treatmenr. JohnlXziley & Sons, Ltd., 1987.

Judzewitch RG, Jaspan JB, I,olonsky KS, et a1.: Aldosereductase lnhibition improves nerwe conduction velocityin diabetic patients. New Engl./ Med 308:119-125, 1983.

Jaspan Jts, Maselli R, Herold K, et a1.: Treatment ofseverely painful diabetlc neuropathy with an aldosereductase inhibitor: Relief of pain and improved somaticand autonomic nerwe function. Lancet 2158-762. 7983.Fagius J, Brattberg A. Jameson S, et a1.: Limited benefitof treatment of diabetic polyneuropathy with an aldosereductase inhlbitor: a 24 week controlled trial. Dia-b eto log ia 28 : 323 - 329, 7{)85.Lewin IG, O'Brien IAD, Morgan MH, et a1.: Clinical andneurophysiological studies with the aldose reductaseinhibitor, sorbinil, in symptomatic diabetic neuroparhy.Diabetologia 26:145-448, 7981.\flhite LK, Martin DB: Aldose reductase inhibitors. 11os-piral Tberapy 73:63-72, 1988.Gregersen G: Myoinositol supplementation. In Dyck PJ,

and others (.eds): Diabetic Neuropathy, \78 Sanders Co,Philadelphia, 1987.Navnoczenski DA, Birke JA, Coleman \MC: Effect ofrocker sole design on plantar fbreloot pressures. /,42Podiatr Med Assoc 78:455-160, 1988.

Clements RS, Be11 DS: Diabetic neuropathy, peripheraland autonomic syndromes. Postgrdd Mecl 77:50-67,7982.Thomas, PK, Scadding |V: Treatment of pain in diabeticneuropathy. In Dyck PJ, and others, (eds): DiabeticNeuropatb!, WB Saunders Co, Philadelphia, 7987.Ru1l JA, Quibrera R, Gonzalez-Miller H, et al.: Symp-tomatic treatment of peripheral diabetlc neuropathywith carbamazepine: double-blind crossover study. Dia-betologia 5 :275-278, 796c).

Riblet LA, Taylor DP: Pharmacology and neurochem-istry of trazodone. J Clin Psycbopbarmacol 1:775-225,1981.

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