Diabetic Neuropathies

Diabetic NeuropathiesAARON I. VINIK, MD, PHDMARIE T. HOLLAND, MDJEAN M. LE BEAU, PHD

FRANCIS J. LJUZZI, PHDKEVIN B. STANSBERRY, BSLARRY B. COLEN, MD

Diabetic neuropathy is a common complication of diabetes that may be associatedboth with considerable morbidity (painful polyneuropathy, neuropathic ulceration)and mortality (autonomic neuropathy). The epidemiology and natural history ofdiabetic neuropathy is clouded with uncertainty, largely caused by confusion in thedefinition and measurement of this disorder. We have reviewed various clinicalmanifestations associated with somatic and autonomic neuropathy, and we hereindiscuss current views related to the management of the various abnormalities.Although unproven, the best evidence suggests that near-normal control of bloodglucose in the early years after diabetes onset may help delay the development ofclinically significant nerve impairment. Intensive therapy to achieve normalization ofblood glucose also may lead to reversibility of early diabetic neuropathy, but again,this is unproven. Our ability to manage successfullly the many different manifesta-tions of diabetic neuropathy depends ultimately on our success in uncovering thepathogenic processes underlying this disorder. The recent resurgence of interest inthe vascular hypothesis, for example, has opened up new avenues of investigation fortherapeutic intervention. Paralleling our increased understanding of the pathogenesisof diabetic neuropathy, refinements must be made in our ability to measure quan-titatively the different types of defects that occur in this disorder. These tests must bevalidated and standardized to allow comparability between studies and more mean-ingful interpretation of study results.

FROM THE DIABETIC NEUROPATHY STUDY GROUP, EASTERN VIRGINIA MEDICAL SCHOOL, NORFOLK,

VIRGINIA.

ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO AARON I. VINIK, MD, PHD, THE DIABETES

INSTITUTES, EASTERN VIRGINIA MEDICAL SCHOOL, 855 W. BRAMBLETON AVENUE, NORFOLK, VA, 23510.

I D D M , INSUUN-DEPENDENT DIABETES MELLITUS; N I D D M , NON-INSULIN-DEPENDENT DIABETES MELLI-

TUS; A F T , AUTONOMIC FUNCTION TESTING; N D S , NEUROPATHY DISABILITY SCORE; N S S , NEUROPATHY

SYMPTOM SCORE; DCCT, DIABETES CONTROL AND COMPLICATIONS TRIAL; LDL, LOW-DENSITY UPOPRO-

TEIN; HDL, HIGH-DENSITY LIPOPROTEIN; BMI, BODY MASS INDEX; NCV, NERVE CONDUCTION VELOCITIES;

STZ, STREPTOZOCIN; ARI, ALDOSE REDUCTASE INHIBITOR; DAG, DIACYLGLYCEROL; GAD, GLUTAMATE

DECARBOXYLASE; GABA, T-AMINOBUTYRIC ACID; NGF, NERVE GROWTH FACTOR; DRG, DORSAL ROOT

GANGLION; SP, SUBSTANCE-P; CGRP, CALCITONIN GENE-RELATED PEPTIDE; IGF, INSULINLIKE GROWTH

FACTOR; IGF-I, INSULINLIKE GROWTH FACTOR I; IGF-II, INSULINLIKE GROWTH FACTOR II; BFGF, BASIC

FIBROBLAST GROWTH FACTOR; B D N F , BRAIN-DERIVED NEURITROPHIC FACTOR; C N T F , CILIARY NEUROTRO-

PHIC FACTOR; EGF, EPIDERMAL GROWTH FACTOR; ZE, ZOLLINGER ELLISON; IMCC, INTERDIGESTIVE

MIGRATING MOTOR COMPLEX; P P , PANCREATIC POLYPEPTIDE; G I P , GLUCOSE-DEPENDENT INSULIN-RELEASING

PEPTIDE; SRIF, SOMATOSTATIN; EPI, EPINEPHRINE; NE, NOREPINEPHRINE; HAFF, HYPOGLYCEMIA-

ASSOCIATED AUTONOMIC FAILURE; E M G , ELECTROMYOGRAM; Q S T , QUANTITATIVE SENSORY TESTING; C V ,

COEFFICIENT OF VARIATION; T S T , THERMOREGULATORY SWEAT TEST; Q S A R T , QUANTITATIVE SUDOMOTOR

AXON REFLEX TEST.

D iabetic neuropathy encompasses awide range of abnormalities affect-ing both peripheral and autonomic

nerve function. The disorder may bemanifested either clinically, through nu-merous different symptoms, or subclini-cally, with abnormalities detectable onlyby careful testing. Frequently, the diag-nosis of diabetic neuropathy is difficult tomake because the manifestations arenonspecific and may occur in numerousother conditions. Neuropathy is not con-fined to a single type of diabetes, but canoccur in IDDM, NIDDM, and variousforms of acquired diabetes (1-3). Al-though considerable uncertainty exists asto the prevalence of neuropathy amongdiabetic individuals, it is generally ac-cepted that neuropathy is the most com-mon, and often the most troublesome, ofthe major complications afflicting thosewith diabetes.

CLASSIFICATION— Diabetic neu-ropathy is not a single entity, but rathera number of different syndromes, eachcarrying a range of clinical and subclin-ical manifestations. Pathologically, thedifferent syndromes may be distin-guished by the type of nerve fiber af-fected and the site of the lesion. Clini-cally, each syndrome is associated with arange of manifestations, many of whichoverlap, thus often making it impossibleto classify individual cases (4).

Numerous schemes have beenproposed for the classification of diabeticneuropathy, with continual revision be-ing made as more is learned about theepidemiology, clinical course, and etiol-ogies of the different neuropathic syn-dromes that occur in diabetes. From anetiological perspective, one useful frame-work for the classification of diabeticneuropathy was put forth by Sullivan(5), who advocated differentiating themore commonly occurring diffuse sym-metrical pattern of neuropathy from theless commonly occurring focal and pre-dominantly asymmetrically distributedpattern of neuropathy. Since then, other

1926 DIABETES CARE, VOLUME 15, NUMBER 12, DECEMBER 1992

Vinik and Associates

Table 1—Classification and staging of diabetic neuropathy

SUBCUN1CAL NEUROPATHY

ABNORMAL ELECTRODIAGNOSTIC TESTS

DECREASED NERVE CONDUCTION VELOCITY

DECREASED AMPLITUDE OF EVOKED MUSCLE OR NERVE ACTION POTENTIAL

ABNORMAL QST

VIBRATORY/TACTILE

THERMAL WARMING/COOLING

OTHER

ABNORMAL AUTONOMIC FUNCTION TESTS

ABNORMAL CARDIOVASCULAR REFLEXES

ALTERED CARDIOVASCULAR REFLEXES

ABNORMAL BIOCHEMICAL RESPONSES TO HYPOGLYCEMIA

CLINICAL NEUROPATHY

DIFFUSE SOMATIC NEUROPATHY

DISTAL SYMMETRIC SENSORIMOTOR POLYNEUROPATHY

PRIMARILY SMALL-FIBER NEUROPATHY

PRIMARILY LARGE-FIBER NEUROPATHY

MIXED

AUTONOMIC NEUROPATHY

CARDIOVASCULAR AUTONOMIC NEUROPATHY

ABNORMAL PUPILLARY FUNCTION

GASTROINTESTINAL AUTONOMIC NEUROPATHY

GASTROPARESIS

CONSTIPATION

DIABETIC DIARRHEA

ANORECTAL INCONTINENCE

GENITOURINARY AUTONOMIC NEUROPATHY

BLADDER DYSFUNCTION

SEXUAL DYSFUNCTION

HYPOGLYCEMIA UNAWARENESS/UNRESPONSIVENESS

SUDOMOTOR DYSFUNCTION

FOCAL NEUROPATHY

MONONEUROPATHY

MONONEUROPATHY MULTIPLEX

AMYOTROPHY

Based on the San Antonio Convention for neuropathy. To be diagnosed, patients must have a minimumof a sign or a symptom, and an abnormal electrodiagnostic test.

researchers have emphasized further dis-tinctions among the diffuse symmetricalneuropathies between those neuropa-thies that are primarily sensory, andthose that are primarily motor (4,6,7).On the basis of pathological studies ofactual nerve lesions, Brown et al. (8)have more recently suggested that sen-sory neuropathy be subclassified evenfurther, according to whether primarilysmall or large nerve fiber involvement isobserved. The usefulness of this distinc-tion in terms of the pathogenesis of dia-betic neuropathy has yet to be deter-mined.

In 1988, a consensus statementfrom the San Antonio Conference on Di-abetic Neuropathy recommended that atleast one parameter from each of the fol-lowing five categories be measured toclassify diabetic neuropathy: symptomprofiles, neurological examination, QST,nerve conduction studies, and AFT (9).The panel recommended that the neuro-logical examination be a systematic as-sessment "of neuropathic signs andsymptoms, including sensory, motor andreflex measures in upper and lower ex-tremities, cranial nerves and autonomicfunction." Suggested nerve conduction

studies included motor- and sensory-evoked amplitudes and conduction ve-locities from both an arm and a leg. Dycket al. (10) subsequently assessed the re-producibility of these suggested mea-surements over a 5-yr period, as part ofthe Rochester Diabetic NeuropathyStudy. The NDS (particularly the weak-ness subset of the NDS), vibrationthresholds, motor and sensory nerve ac-tion potentials, and motor NCVs werehighly reproducible measurements ofneuropathy over time. The least reliablemeasurement was the NSS, the assess-ment of symptoms: among the subsets ofthe NDS, the symptoms portion of theNDS had the worst reproducibility.

Table 1 offers a current classifica-tion of neuropathy that clearly will bemodified as our understanding of thedisease process improves.

PREVALENCE OF NEUROPATHY—Prevalence data for diabetic neuropathyare sparse, and it is virtually impossibleto obtain reliable estimates of the preva-lence of neuropathy among the diabeticpopulation. Few population-based stud-ies have been undertaken, and becausethe prevalence of undiagnosed diabetesin the general population is estimated tobe at least as great as the prevalence ofdiagnosed diabetes (11), most publishedstudies entail substantial selection biasesbecause they are limited to that portionof the diabetic population that has accessto clinical care. In addition, lack of con-sensus as to the appropriate diagnosticcriteria for diabetic neuropathy has re-sulted in a wide range of prevalence es-timates reported in the literature—from0 to 93% (12).

Probably the best data regardingprevalence of neuropathy come from theextensive study of nearly 4500 clinic pa-tients by Pirart (13-15), who reported aprevalence rate ranging from 7% for in-dividuals within 1 yr of diagnosis of di-abetes to 50% for those with diabetes for>25 yr. In Pirart's study, neuropathywas defined as loss of Achilles reflexeswith symptoms or objective signs of

DIABETES CARE, VOLUME 15, NUMBER 12, DECEMBER 1992 1927

Diabetic neuropathies

polyneuropathy. Comparable prevalencerates were reported by Franklin et al.(16), who also used a combination ofsymptom and objective information todiagnose neuropathy in their study ofNIDDM patients in the San Luis ValleyDiabetes Study. Although Brown and As-bury (8) have estimated that >50% of allpatients receiving insulin have symptom-atic neuropathy, and Goodman et al.(17) reported pain and paresthesias to bepresent in 62% of all cases in their series,Boulton et al. (18) have suggested thatmost prevalence studies overestimate thetrue prevalence of symptomatic neurop-athy because their diagnostic criteria arenonspecific. Thus, these researchers de-fined symptomatic neuropathy as thepresence of symptoms and signs of nervedysfunction in the absence of peripheralvascular disease and found that 10.4% ofinsulin-treated patients <60 yr of age intheir clinic population had symptomaticneuropathy. An additional 8.9% exhib-ited absent knee and ankle reflexes in theabsence of significant symptoms, and an-other 6.3% exhibited absent foot pulses(18). This estimate is similar to that ob-tained by Fry et al. (19), who observedsymptoms in association with significantsigns present in 13% of their patients.

Signs of peripheral neuropathyare frequently demonstrable on clinicalexamination in diabetic patients. In a se-ries of 1175 unselected patients from adiabetes outpatient clinic, Pirart (15)found that 12% already had signs of di-abetic neuropathy at the time of diagno-sis of diabetes. Ankle reflexes were ab-sent in 19.6% of a diabetic populationstudied by Boulton et al. (18), and Nils-son et al. (20) found that Achilles reflexwas absent in 10.5% of short-durationdiabetic patients and 15.2% of long-duration diabetic patients. Interestingly,though, Nilsson et al. (20) also observedabsence of Achilles reflexes in 8.5% ofnondiabetic control subjects and in 25%of nondiabetic control subjects >60 yr ofage. Loss of ankle vibration and/or Achil-les tendon reflexes was found among40.8% of 503 Mexican subjects with

NIDDM, although in this group, 32.2%of subjects had symptoms attributable toperipheral neuropathy (21). By using abroader set of criteria, Haimanot and Ab-dulkadir (22) found that 54% of diabeticpatients had objective sensory deficits inthe extremities, reduction or loss of deeptendon reflexes, and autonomic distur-bances or mononeuropathy without anobvious alternative cause. Prevalenceranged from 42% for individuals withduration of diabetes <5 yr to 80% forindividuals with duration of diabetes>15 yr. Moreover, these findings werepresent in only 8% of a nondiabetic con-trol population.

Clinically, detectable diabeticneuropathy is more common than gen-erally thought, if its presence is soughtby careful examination. In a cohort of278 healthy IDDM subjects enrolled inthe feasibility phase of the DCCT, clinicalperipheral polyneuropathy was detect-able in 39% of the subjects on carefulexamination, despite the fact that pa-tients with known neuropathy of suffi-cient severity to require medical atten-tion were excluded (23). Thus, theprevalence of detectable but subtle (andoften asymptomatic) peripheral somaticneuropathy in a generally healthy cohortof subjects with IDDM of <15 yr dura-tion is quite high.

Although uncommon, neuropa-thy occasionally occurs in diabetic chil-dren. Reduction in motor NCVs haveeven been documented among diabeticchildren (24,25), as have reductions invibratory sensation (26). Symptomaticneuropathy is found only rarely amongyoung diabetic patients.

Few published estimates exist ofthe prevalence of other syndromes of so-matic neuropathy, mainly because theseconditions occur so infrequently. In twoAfrican populations, the prevalence ofmononeuropathy (including mononeur-opathy multiplex) among patients withdiabetes was reported to be 3.7 (22) and1.1% (27). Prevalence rates for radicul-opathy and amyo trophy in these popu-lations ranged from 0 to <2%. In a sam-

ple of 351 patients admitted to aninpatient diabetes clinic, we observedprevalence rates for mononeuropathy,radiculopathy, and amyotrophy to be3.0, 3.5, and 2.1%, respectively (A.I.V.,B.D. Mitchell, unpublished observa-tions).

No adequate studies are availableon the prevalence of symptomatic auto-nomic neuropathy. A wide range hasbeen reported in the prevalence rates fordifferent autonomic symptoms, but theserates are difficult to interpret because ofthe high frequency with which many ofthese symptoms can occur in the nondi-abetic population. Impotence, for exam-ple, may be present in as many as 50% ofdiabetic men, although this condition isnot infrequent in the nondiabetic popu-lation. In one study, Jeyarajah et al. (29)found that 38.5% of their patients expe-rienced one or more of the autonomicsymptoms (intermittent diarrhea, sweat-ing abnormality, giddiness on standing,gastric fullness, or hypoglycemic un-awareness), but only —50% had abnor-mal AFTs.

Estimates of the prevalence of au-tonomic neuropathy based on the pres-ence of abnormalities of cardiovascularautonomic reflexes have ranged in theliterature from 14 to nearly 50% (29-33). Burke et al. (33), who observed that14% of their clinic patients experiencedboth an abnormal heart-rate variationduring deep breathing and an abnormalheart-rate response to standing, then ob-served that 61.9% of these patients alsoexperienced one or more of the followingsymptoms: postural dizziness, chronicdiarrhea, impotence, postprandial sweat-ing, dysphagia, or urinary symptoms. Atthe other extreme, Jeyarajah et al. (29)observed AFT abnormalities in 46.2% oftheir diabetic patients, but also in 15% oftheir healthy control subjects. The prev-alence of AFT abnormalities has beenfound to be associated both with dura-tion of diabetes (32) and age (29), al-though these correlations may not holdfor all indexes of autonomic function.

It formerly was thought that dia-



betic autonomic neuropathy was a dis-ease only of 1DDM, but Veglio et al. (34)have reported, the prevalence is equal oreven greater in NIDDM than IDDM. Italso has been observed that an individu-al's age is more important a predictor ofthe appearance of autonomic neuropathythan duration of neuropaths to suddendemise, for which no apparent reasonhas been found. Epidemiological datasuggest that autonomic neuro pathy maycosegregate with factors predisposing tomacrovascular events. A striking associ-ation has been found between autonomicneuropathy and hypertension, elevationof LDL cholesterol, and a reduction ofHDL cholesterol (35), and somewhatsurprisingly, an increased prevalenceamong females and individuals with araised BMI (36). Therefore, it is not sur-prising that these individuals are mostsusceptible to an attenuated life span be-cause of cosegregation of all the risk fac-tors for cardiovascular mortality with au-tonomic neuropathy.

Risk factorsDespite extremely poor control of theirdiabetes, up to 50% of all diabetic sub-jects never develop symptoms of neurop-athy, even after >20 yr duration of dia-betes (13-15) . Conversely, someunfortunate subjects develop neuropathysoon after the onset of diabetes, evenwhen glycemic control is relatively good.These well-known observations impli-cate the involvement of factors otherthan glycemia in the etiology of diabeticneuropathy.

A genetic predisposition for thedevelopment of diabetic neuropathy hasbeen sought (13-15,20,37-39) but, asyet, not identified. At least two studieshave failed to find an association be-tween signs of peripheral neuropathyand family history of NIDDM ( 1 3 -15,20), thus suggesting that a single geneis not responsible for both NIDDM andperipheral neuropathy. Chochinov et al.(39) speculated that other genetic factorsmay be involved, so they measured vi-bration sensation in diabetic subjects,

their immediate family members, andnormal control subjects. The researchersfound that, although vibration sensationwas reduced in the diabetic subjects, sen-sation in family members was not re-duced, and was no different than in nor-mal control subjects. The question thathas not been investigated adequately iswhether genes exist that segregate inde-pendently of diabetes, affect susceptibil-ity to neuropathy, but are expressed onlyin the presence of diabetes. Heritable de-fects (i.e., genes) may be present, forexample, that predispose neural (andvascular) tissue to further injury in themetabolic milieu of diabetes. A more de-tailed understanding of the specific bio-chemical defects present in neuropathy isrequired before this issue can be elabo-rated on further.

The relationship between neu-ropathy and various constitutional fac-tors has been investigated by several re-searchers. Gadia et al. (40) recentlyreported an inverse correlation betweenvibratory sensation and height and be-tween peroneal motor NCVs and heightin a group of subjects with NIDDM.They suggested that body stature may bea proxy for neuron length, with largerneurons being more susceptible to met-abolic injury than shorter neurons.Moreover, a causal relationship betweenheight and peripheral neuropathy couldexplain the association between malegender and peripheral neuropathyamong subjects with IDDM recently re-ported in the Diabetes Control and Com-plications Trial (41). Grenfell et al. (42),on the other hand, observed an associa-tion between the presence of nephropa-thy and short stature among individualswith diabetes onset during childhoodand hypothesized that poor diabetic con-trol may retard growth in childhood,thus making short stature a marker forthe early development of complications.At least two studies have investigated apossible relationship between obesity(percentage of ideal body weight) andthe presence of peripheral polyneuropa-thy, and both failed to find an association

(13-15,43), notwithstanding the associ-ation of an increased BMI and autonomicneuropathy (36).

The relationship between puber-tal changes and development of neurop-athy was investigated by Sosenko et al.(26), who found that vibration sensationwas significantly reduced in postpubertalchildren compared with prepubertalchildren. This observation needs to beconfirmed; possibly, the increased phys-iological stress on the body that occursduring puberty increases susceptibility toneuropathy.

Nutritional factors, including vi-tamin deficiencies, have long been rec-ognized as possible contributing factorsto the development of neuropathy, in-cluding diabetic neuropathy (44). De-ranged Vitamin B12 metabolism is onepossible pathway that has been impli-cated theoretically (45), but no data areavailable to support this hypothesis.Some researchers have suggested that theinteraction of malnutrition with diabetesmight account for the high prevalence ofneuropathy seen in the diabetic popula-tion in underdeveloped countries (46).

NATURAL HISTORY— Slowing ofNCVs is among the earliest neuropathicabnormalities that occur in diabetes andoften is present even at diagnosis of dia-betes (47-50). After diagnosis, slowingof NCV generally progresses and is cor-related with duration of diabetes (51).Sensory fibers usually are affected first,followed by motor fibers (52).

Although slowing of NCVs iscommon in diabetes and often occursearly in the course of the disease, con-siderable uncertainty exists as to the rel-evance of these abnormalities to the fu-ture development of either subclinicalmanifestations or clinically apparent di-abetic neuropathy. Although most stud-ies have documented that symptomaticpatients are more likely to have slowerNCVs than patients without symptoms(18,22,27,52-54), NCV does not appearto be related to the severity of symptoms(55).



The relationship between the ob-jective signs of neuropathy and neuro-pathic symptoms is also not well defined.The observed manifestations of neurop-athy are thought to depend on the typeof nerve fiber affected. Small nerve fiberdamage, which usually, although not al-ways, precedes large nerve fiber damage,is manifested first in the lower limbs,with a loss of thermal sensitivity, andreduced light-touch and pin-prick sen-sation occurring early (J. Jaspan, unpub-lished observations). When pain occurs,NCV is often normal or only minimallyreduced (57), suggesting that pain is anearly (small fiber) manifestation of dia-betic polyneuropathy. When pain ispresent, it typically resolves on its own,but whether this is reflective of the re-versibility of early nerve damage or pro-gression to nerve death is not clear. Largefiber neuropathies are manifested by re-duced vibratory sensation and depressedtendon reflexes. In two follow-up stud-ies, progressive reduction of vibratorysensation and loss of tendon reflexeshave been observed in patients who atthe same time reported an improvementin pain symptoms (58,59). The situationis further complicated by the fact thatmost diabetic peripheral neuropathy is ofmixed variety, with both large and smallnerve fiber involvement. In our ownclinic population, only 15.0% of diabeticsubjects with clinically confirmed symp-toms of neuropathy had no objectivesigns of neuropathy, and 63.7% of pa-tients with signs had no symptoms (28).Other investigators have reported evensmaller proportions of pure small nervefiber and pure large nerve fiber neurop-athies (8,56).

Autonomic neuropathy may be aprerequisite in the development of footulceration in diabetes that is convention-ally classified as a manifestation of distalsymmetric polyneuropathy (60,61). An-imal studies have suggested that auto-nomic neuropathy alone may precipitateplantar ulceration (62). Callus formation,which predates plantar foot ulceration,may arise in part from excess blood

flow—as it disappears if peripheral vas-cular disease develops (63). Hariot ar-thropathy (neuroarthropathy) is an un-derdiagnosed complication of thediabetic neuropathic foot in which bonefractures occur and are followed by bonedisorganization and increased risk of sec-ondary ulceration. This traditionally isascribed solely to distal symmetric poly-neuropathy in diabetes. High peripheralblood flow, which causes weakening ofbones in the foot, may predispose to frac-tures in the insensitive foot (64,65).

Much remains to be learned ofthe natural history of diabetic autonomicneuropathy. Testing of cardiovascular re-flexes has revealed that signs of auto-nomic neuropathy may occur relativelyearly in the course of diabetes (29,32,66). Both sympathetic and parasympa-thetic nerve fibers may be affected, withparasympathetic dysfunction precedingsympathetic dysfunction (32,66,67). Im-provements in the methods to measuresympathetic function have now shownthat sympathetic damage may occur ear-lier than previously thought (68). By us-ing infrared pupillometry, Ziegler et al.(50) have demonstrated that the speed ofpupillary dilation may be slowed even atthe diagnosis of IDDM.

Of all parasympathetic nerve fi-bers, —75% are in the vagus nerves(10th cranial nerve), where they pass tothe entire thoracic and abdominal re-gions of the body. Early autonomic nervedysfunction has been attributed to vagaldamage, with manifestations appearingin several organ systems. A battery ofdiagnostic tests to assess cardiovascularautonomic function have been devisedthat measure heart-rate responses undervarious conditions. Among the defectsindicative of cardiac autonomic damagedemonstrable by these tests are: an in-crease in resting heart rate (tachycardia),abnormal heart-rate response to the Val-salva maneuver, loss of beat-to-beat vari-ability in heart rate, and loss of the im-mediate heart-rate response to standing(32,66,69). These tests were initiallythought to reflect cardiac parasympa-

thetic integrity, but researchers now ap-preciate that the autonomic pathways in-volved in these reflexes are complex andthese that tests may reflect both parasym-pathetic and sympathetic innervation(70). Once these tests become abnormal,they usually remain abnormal (71,72).

Sympathetic failure usually fol-lows vagal denervation and may involvethe following processes: cardiac denerva-tion (in combination with parasympa-thetic denervation), loss of peripheraland splanchnic (visceral) vasoconstric-tion, loss of vasomotor control, and in-crease in peripheral blood flow (68).Among the symptoms that may be man-ifested by these defects are postural hy-potension, sweating disturbances, andhypoglycemic unawareness. Direct in-jury to small myelinated and unmyeli-nated sympathetic nerve fibers signalingpain and temperature also may occur,leading possibly to painful peripheralneuropathy.

Although symptomatic periph-eral neuropathy usually precedes the de-velopment of symptomatic autonomicneuropathy (6,73), signs of parasympa-thetic neuropathy sometimes may appearbefore signs of peripheral neuropathy(74). In contrast, sympathetic nerve ab-normalities are rarely found in the ab-sence of signs of peripheral neuropathy(74). Isolated abnormalities on auto-nomic function tests are occasionallyfound, however, in nondiabetic individ-uals (29).

The mortality for diabetic auto-nomic neuropathy has been estimated tobe ~44% within 2.5 yr of diagnosis ofsymptomatic autonomic neuropathy(66). Early studies by Ewing et al. (70) inScotland caused much concern becausemost people died of conditions otherthan autonomic neuropathy, such as re-nal failure, and the only patients fol-lowed were those who were symptom-atic. Table 2 is a summary of availabledata on the influence of autonomic neu-ropathy on mortality and IDDM. As thissummary shows, although Ewing's ob-servations were thought to be an overes-



Table 2—Influence of autonomic neuropathy on mortality in IDDM

482.

71.

74A.

246.245.10.

REFERENCES

EWING ET AL., 1980

WATKINS, 1980

HASSLACHER, 1983

SAMPSON, 1990

KAHN AND VINIK, 1987

O'BRIEN, 1991

N

40

64

16413084

SELECTION CRITERIA

AUTONOMIC SYMPTOMS AND

ABNORMAL A F T

AUTONOMIC SYMPTOMS AND

ABNORMAL A F T

ABNORMAL BEAT-TO-BEAT

ABNORMAL AFT

ABNORMAL AFT

ABNORMAL AFT

LENGTH OF

FOLLOW-UP

(YR)

19 MO-5

3-5

5555

OVERALL

MORTALITY

(%)

53

27

19244627

timate, it is apparent that based onasymptomatic subjects with only abnor-malities in AFTs, the overall mortalityrate may be as high as 25-40% (75).

PATHOGENESIS— Table 3 and Fig. 1summarize the current theories of patho-genesis of diabetic neuropathy. The mostimportant pathological change in diabeticpolyneuropathy is loss of myelinated andunmyelinated nerve axons. Distal nervesare more affected than proximal nerves, as

Table 3—Factors that have been implicatedin the etiology of diabetic complications

METABOLIC CONSEQUENCES OF HYPERGLYCEMIA

POLYOL PATHWAY ABNORMALITIES

MYO-INOSITOL DEFICIENCY

N A + - K + - A T P A S E DEFICIENCY

ENZYMATIC GLYCATION OF PROTEINS

NONENZYMATIC FATTY ACID AND

PROSTAGLAND1N ALTERATIONS

PROTEIN KINASE C ALTERATIONS

GROWTH HORMONE EXCESS

VASCULAR COMPLICATIONS OF HYPERGLYCEMIA

EPINEURAL VESSEL ATHEROSCLEROSIS

ENDONEURIAL MICROVASCULAR DISEASE

ALTERED ENDOTHEUAL CELLS

THICKENED BASEMENT MEMBRANES

MICROVASCULAR OCCLUSIONS

DECREASED ERYTHROCYTE DEFORMATION

DISORDERED HEMOSTASIS (PLATELET

HYPERAGGREGABIUTY)

AUTOIMMUNITY

DISORDERED NERVE SURVIVAL AND REGENERATION

ALCOHOL AND TOBACCO

HYPOGLYCEMIA

determined by postmortem nerve fiberdensity determinations (76) and electro-physiological observations (77).

This axon loss is also accompa-nied by demyelination, as shown byThomas and Lascelles (78) with teased-fiber preparations 25 years ago. Segmen-tal demyelination in diabetes may be pri-mary, from loss of individual Schwanncells, or secondary, the result of responsesto changes in axonal caliber (79).

Recently, Sima et al. (80) de-scribed subtle changes at the nodes ofRanvier along human diabetic nerves, in-cluding paranodal swelling and alter-ations of Schwann cell attachments toparanodal axons, termed axo-glial dys-junction. This anatomical abnormality isassociated with nerve-conduction slow-ing that improves with therapy (81). Thedefect is still inadequate to account for amajor portion of the nerve-conductionslowing in diabetes that is not explainedby loss or demyelination of the large cal-iber axons (82). However, it does occurwith other experimental metabolic neu-ropathies (83,84) and, therefore, maynot be unique to diabetes.

For at least 60 years, pathologistshave known that patients with diabeteshave abnormal nerve blood vessels.Fagerberg (85) called attention to theparallel between the severity of neuro-pathic abnormalities and endoneurialbasement membrane thickening. Nu-merous other researchers have now con-firmed this relationship (86,87), al-though the observations do not prove a

direct causal relationship between abnor-malities in vasa nervorum and the sever-ity of neuropathy. Others have demon-strated focal infarctive lesions inproximal diabetic nerves obtained frompatients who appeared to have a length-dependent polyneuropathy (88,89).

Acute ischemia has been impli-cated in certain mononeuropathies, butalso may participate in the developmentof polyneuropathy. An acute multifocalischemic basis for diffuse polyneuropa-thy is unlikely because nerves are highlyresistant to ischemia and have a rich col-lateral circulation with low metabolic re-quirements (83,90). Furthermore, acutevascular insufficiency causes focal, notdiffuse, injury (91). Nonetheless, multi-focal ischemic lesions could have a patho-genic role in diabetic polyneuropathy.

Indeed multifocal infarcts havebeen found in proximal nerves of pa-tients with diabetic polyneuropathy—when such changes were sought at au-topsy (88,89). The ischemic lesionsresemble those found in the case of prox-imal motor neuropathy (92).

Microvascular theory ofpathogenesis of neuropathyIt is now widely accepted that mononeur-opathy is a vascular disease. The acute on-set independent of relationship to diabetescontrol and the spontaneous resolutionwithout treatment testify to a vascular na-ture. Occlusion of vasa nervorum has beendocumented in isolated third nerve pulsessupporting the contention (92).

That microvascular disease playsa primary role in the pathophysiology ofdistal symmetric diabetic neuropathy hasbeen postulated for various reasons; thistheory has gained increasing supportamong its believers, and it is a hotlydebated issue among metabolists. Argu-ments in support of the vascular theoryare: 1) the strong association between thepresence of neuropathy and microvascu-lar disease in diabetes (20,93-95); 2) thebasement membrane abnormality that ischaracteristic of diabetes, which has beenreported by several authors to involve



Metabolic—»^polyols, sorbitol

+ fructose

rmyoinositol

fNa+/K+ ATP

Axonal AtrophyDemyelenation

DIABETES+

Genetic/Environmental

(Alcohol,Tobacco)

AutoimmuneAnti Ganglioside

AntiGAD

-•ClinicalNeuropathy

Vascularheight

SegmentalDemyelination

Closure of

Vasa Nervorum

EndoneurialHypoxia V

Trauma

Other Hemoglycemic AbnormalitiesPlatelet Aggregationrbc deformability

Circulating Immune ComplexesHe mato logicAdvanced Glycosylation Endproducts (AGE)

Figure 1—Model for pathogenesis of diabetic neuropathy.

the vasa nervorum in diabetes (82,87,96); 3) reports of thrombosis in medium-sized intraneural arterioles (92); 4) ax-onal stasis, swelling, and secondary de-myelination in the rat sciatic nervesecondary to acute ischemia (97); 5) re-duced nerve blood flow, and decreasednerve oxygen tension and increased vas-cular resistance in STZ-induced diabeticrats (98); 6) the prevented-by-oxygensupplementation of the nerve conduc-tion abnormality in STZ-induced dia-betic rats (99), reduced sural nerve oxy-gen tension, and increased vascularresistance in diabetes (100); 7) suralnerve biopsies from patients with dia-betic polyneuropathy reveal an increasein the number of endothelial nuclei percapillary closure in patients with neurop-athy, which also positively correlateswith the severity of neuropathy (101).

Careful clinical examination oftensuggests a patchy multifocal distribution ofthe sensory loss unlike that of a metabolicdisease but more compatible with a vascu-lar etiology. Our own studies that link to-bacco smoking (102) and other evidenceof microvascular disease also favor this.Furthermore, several pathological studiessupport an ischemic mechanism as a causeof loss of nerve fibers (103). Disorderedhemostasis is the hallmark of diabetes,with an increased propensity to plateletaggregation (104,105) and abnormal hem-orrheology decreased erythrocyte deform-ability. A verifying theory for the patho-genesis of neuropathy, retinopathy,nephropathy, and macrovascular diseasewould require consideration of a gener-alized small vessel disease. Thus, micro-vascular pathological abnormalities andischemia may be involved in the patho-

genesis of diabetic polyneuropathy. Theymay not represent the cause(s) of allforms nor contribute to every variety, butthey may be of great significance in cer-tain subsets of patients with neuropathy.

More recent studies have shownthat within 2 -3 wk of STZ-induced di-abetes in the rat, if glycemic control ispoor, a diffuse distal nerve fiber loss oc-curs with multiple proximal nerve inf-arcts, giving the erroneous impressionthat the disorder is one of a distal axon-apathy, as is nerve fiber loss in diabetesin humans. Waxman (91) has discussedthe theoretical explanation of a diffuseprocess that causes predominantly distalsymptoms as a result of excess vulnera-bility of the longest fibers to injury. Focalnerve destruction restricted to proximalsegments also could produce diffuse dis-tal fiber loss. The interweaving axons de-scending down a nerve change the ap-pearance to a homogeneous pattern thatmimics a dying-back neuropathy.

Epidemiological laboratory evi-dence implicates hyperglycemia and otherconsequences of insulin deficiency in thepathogenesis of neuropathy. The putativemechanism by which hyperglycemia ini-tiates or sustains tissue damage in diabetesremains controversial. Several glucose-induced metabolic abnormalities, includ-ing nonenzymatic protein glycation (106),glucose-dependent gene induction (107),and polyol pathway activation (108,109),have been invoked as potential tissue-specific mediators of glucose toxicity.

A relationship between polyolpathway activation and the acutely re-versible slowing of nerve conduction wasinitially described in diabetic rodents byGabbay (110). Activation of the polyolpathway by glucose is a prominentmetabolic feature of peripheral nerve inanimals with acute diabetes, where itpromotes sorbitol and fructose accumu-lation, myo-inositol depletion, and slow-ing of nerve conduction (110-112).Similar, although not identical, meta-bolic changes have been noted in periph-eral nerves from diabetic humans (113-


Vinih and Associates

116); and where ARls diminish sorbitolaccumulation (113,115), an increase innerve conduction also occurs (117). Fur-thermore, the accumulation of sorbitoland depletion of myo-inositol are accom-panied by a secondary abnormality inphosphoinositide metabolism and a de-crease in Na+-K+-ATPase pump regula-tion and hence, signal transduction,which in turn may contribute to func-tional and structural abnormalitieswithin the peripheral nervous system(118). The acutely reversible componentof nerve-conduction slowing has beenattributed to reduction in the restingmembrane potential that correspondedto a four- to fivefold increase in intra-axonal Na+, consistent with a reductionin activity of the electrogenic Na+-K+-ATPase (81,119,120).

Taken together, these studies at-tribute the rapidly reversible componentof nerve-conduction slowing in theacutely diabetic rats to polyol pathway-induced myo-inositol-related alterationin neural Na+-K+-ATPase activity. Animportant effector limb of the phosphoi-nositide signal transduction system (121)is endogenous DAGs, largely derivedfrom ntyo-inositol—containing phospho-lipid. Impairment in phosphoinositideturnover with a reduction in the genera-tion of DAGs may be responsible for thedecrease in activation of the Na+-K+-ATPase, as has been observed in eryth-rocytes from STZ-induced diabetic rats(122). These observations are consistentwith the notion that a component of phos-phoinositide turnover is involved in pro-tein kinase C-mediated regulation of Na+-K+-ATPase activity and the altered polyolpathway activity in peripheral nerve.

However, structural and func-tional defects in nerve fibers appear to beresponsible for the majority of the clini-cally significant effects in diabetic neu-ropathy. Ward et al. (123) report ele-vated nerve sorbitol levels but normalmyo-inositol levels in peripheral nervetissue from diabetic patients. Dyck et al.(124) found no increase in sorbitol orfructose in nerves taken from maturity

onset diabetic subjects. In contrast, May-hew et al. (114) found markedly elevatedsorbitol levels and diminished myo-inositol levels in femoral nerve speci-mens obtained at autopsy from diabeticsubjects. Dyck et al. (113), in a widevariety of patients with diabetes, found arise in nerve sorbitol that was not statis-tically significant, but no reduction inmyo-inositol levels. Numerous explana-tions have been suggested for these dis-crepancies, including differences be-tween fresh and autopsy material and thecross-section of sample measured. Differ-ences may exist between tissues obtainedfrom IDDM and NIDDM subjects. Forexample, sorbitol levels were found to behigher in IDDM subjects compared withNIDDM subjects, despite comparablenerve glucose levels, and myo-inositolwas consistently decreased in bothgroups of diabetic subjects (114,125).

In diabetes in humans, the ex-pected decrease in myelinated nerve fiberdensity and morphometric evidence ofnerve fiber atrophy and Wallerian degen-eration (80) has been found, but, con-trasting with the animal studies, axo-glial dysjunction is not uniformly foundin NIDDM and is not statistically in-creased over age-matched control sub-jects, although it appears to be a signifi-cant abnormality in nerves of IDDM. Onthe other hand, Wallerian degenerationis increased in the NIDDM group (80).The nonrandom distribution pattern ofnerve fiber loss has been interpreted bysome authors (126,127) as indicative ofvascular ischemic damage that may be afunction of age, duration of diabetes, andtype of diabetes, but this has been con-tested by others (80)

HypoglycemiaHypoglycemia also has received attentionfor its possible role in the developmentof diabetic neuropathy. The develop-ment of peripheral neuropathy associ-ated with insulinoma-related hypoglyce-mia was documented by Jaspan et al.(128) in 1982. Although the pathwaythrough which hypoglycemia leads to

nerve damage in this disorder is unclear,this association has led to the hypothesisthat hypoglycemia, and hyperglycemia,may contribute to nerve injury in dia-betic individuals. Frier and Hilsted (129)have hypothesized the involvement of avascular pathway, whereby hypoglyce-mia induces an increase in hematocritand blood viscosity, a decrease in capil-lary blood flow, and subsequent hypoxiaand ischaemia to already threatened mi-crovasculature. The importance of hypo-glycemia as a contributing factor to dia-betic neuropathy is probably not great,although no experimental or clinical dataare available.

AlcoholMounting evidence indicates that alco-hol, a known neurotoxin, may play a rolein the initiation or exacerbation of symp-tomatic diabetic neuropathy. McCulloch(130) observed that the prevalence ofneuropathic symptoms increased withincreasing levels of alcohol among dia-betic males in his clinic population. Wepreviously reported a threefold increasein the prevalence of symptomatic neu-ropathy among drinkers compared withnondrinkers, although no dose-responserelationship was apparent, and the asso-ciation was observed among IDDM malesonly (131).

AutoimmunityAwareness of the possible contribution ofautoimmunity to the development of di-abetic neuropathy has increased. Wehave reported on the presence of au-toantibodies in the circulation of diabeticpatients to sciatic nerve, postganglionicsympathetic neurons, and structureswithin the vagus nerve (132). Whetheror not these contribute to the pathogen-esis of this disorder or are simply mark-ers of neuronal destruction remains to beelucidated.

It long has been recognized thatautoimmune pancreatic P-cell destruc-tion, which is attributable to loss of im-munological tolerance to self-antigenspresent in insulin-secreting

DIABETES CASE, VOLUME 15, NUMBER 12, DECEMBER 1992 1933


within the pancreatic islets, is a majorevent in the pathogenesis of insulin de-ficiency in IDDM (133-135). One ormore susceptibility factors are encodedby the major histocompatibility complexon chromosome 6, probably by the DQAl and Bl loci (136,137). The nature ofthe antigen has, however, been elusive,and whether or not the (3-cell is the cul-prit or the victim of the autoimmuneresponse has not been resolved. One ofthe identified antigens is a 64,000-Mr

islet protein.

Autoantibodies to a 64,000-Mr

islet cell protein are associated withIDDM and have been detected years be-fore the onset of symptoms (138-140).In addition, other IDDM-associated au-toantibodies, such as those against insu-lin and cytoplasmic gangliosides of isletcells, appear later, possibly as a conse-quence of the release of these antigens(or their precursors) from the damagedislet cells. The identification of autoanti-bodies to GAD in the stiff man syndrome(141), a disorder associated with IDDM,led to a search for the possible identity ofGAD antibodies with those to the64,000-Mr islet cell autoantigen.

Baekkeskov et al. (142) reportedthat the 64,000-Mr islet cell autoantigenis indeed a form of GAD, the enzymeresponsible for the synthesis of GABA inthe brain, peripheral neurons, pancreas,and other organs (143). Tobin et al.(144) have identified two GADs, a65,000 Mr and 67,000 Mr, which differin molecular size, amino acid sequence(with —30% sequence divergence), andin their intracellular distributions and in-teractions with GAD cofactor pyridoxalphosphate (144-147). In the brain neu-rons, GAD65 is preferentially associatedwith axon terminals, whereas GAD67 ispresent in both terminals and cell bodies(144).

Recently it has been suggestedthat autoantibodies to one or both formsof GAD are present in the sera of IDDMpatients long before symptoms of neu-ropathy appear. Individual sera showeddistinctive profiles of epitopic recogni-

tion, and antibodies to GAD tend to de-cline after diabetes onset but appear topersist in those individuals who haveneuropathy. Attempts to define an etio-logical role for these antibodies is basedmainly on circumstantial evidence.

Hirsch and Shamoon (148) havenoted a selective defect in EPI secretionin response to hypoglycemia with pres-ervation response to exercise.

Cross-sectional studies havenoted the presence of complement-fixingantiadrenal medullary antibodies in 30%of IDDM patients, which decreases after16 yr of diabetes (149), suggesting thatthe antibodies may play a causative rolein the development of neuropathy of theadrenergically innervated adrenal me-dulla. Furthermore, we have previouslydescribed antisympathetic ganglia au-toantibodies in IDDM (135), which maybe associated with the diminished cate-cholamine response to a change in pos-ture (150) and orthostasis, further sup-porting the notion that the adrenergicnervous system is indeed a target forautoimmune destruction.

We have hypothesized that theincreased prevalence of complement-fixing adrenomedullary antibodies insubjects with diabetes of <16 yr dura-tion may precede the onset of autonomicneuropathy, but a cause and effect rela-tionship between the presence of theseantibodies and neuronal dysfunction hasnot been clearly established.

More recently, we examined thesera of 120 IDDM patients for the pres-ence of complement-fixing antisciaticnerve antibodies (135): 26 of 120 (22%)had fluorescent scores exceeding any andall of those in 66 normal control sub-jects. Surprisingly, 3 of 12 (25%)NIDDM patients were also positive forcomplement-fixing antibodies, and apossible role in the pathogenesis of so-matic neuropathy was raised. The anti-bodies found in our studies differed fromthose reported above. It is well estab-lished that circulating antibodies mayhave a pathogenetic role in neuropathiesassociated with amyloidosis, myeloma,

macroglobulinemia, lymphoma, and cer-tain leukemias (151) and antibodies togangliosides; anti-GMl and anti-asialoGM1 antibodies are associated with in-flammatory neuropathy and parapro-teinemia. We therefore studied 46 sub-jects, 26 IDDM and 20 NIDDM, withmild peripheral neuropathy comparedwith 26 nondiabetic control subjects andshowed that —33% of diabetic patientshad antibodies concentrations >5 SDabove the nondiabetic control subjects forGM1 and asialo GM1, and that a signifi-cant correlation was observed between theantibody level and sural amplitudes.

These studies on the presence ofantibodies—to GAD and various glyco-proteins and nervous tissue—raise theinteresting question of whether thesesimply are attributable to damage result-ing in an antigen leak provoking an im-mune response, or whether they play aprimary role in the development of neu-ropathy. Further studies clearly areneeded to determine the natural historyof the antibodies in relationship to neurop-athy and examination of various models ofneuropathy to establish the pathogeneticcapabilities. This will be of vital impor-tance in future directions for manage-ment of neuropathic complications at-tributable to an autoimmune, as opposedto metabolic or vascular, etiology.

DISORDERED NERVE SURVIVALAND REGENERATION INDIABETES— Any hypothesis directedat the pathogenesis of neuropathy mustaddress the characteristics of axonal de-generation, demyelination and atrophy,and decreased NCV, which typify thedisease (4). Recently, some attention hasbeen directed to the role of growth fac-tors in diabetic neuropathy, with partic-ular attention to NGF. Because neuronalgrowth factors can promote the survival,maintenance, and regeneration of neu-rons subject to the noxious effects of di-abetes, the relative success of diabeticpatients in maintaining normal morphol-ogy and function of their nerves ulti-mately may depend on normal expres-



sion of these factors. Many of theneuronal changes characteristic of dia-betic neuropathy are similar to those ob-served after removal of target-derivedgrowth factors by axotomy or depletionof endogenous NGF by experimental in-duction of NGF autoimmunity. Currentknowledge of growth factors and theirpossible role in the pathogenesis of dia-betic neuropathy will be discussed.

Throughout life, an intimate neu-ron-target interaction occurs that affectsthe normal functioning of both neuronand target for their survival and mainte-nance. One aspect of this interaction is aneuronal dependence on retrogradelytransported, target-derived growth fac-tors. In the cell body, these growth fac-tors regulate neuronal gene expression,and consequently protein synthesis, andthereby play a role in cell survival andmaintenance of the cell and its processes.Moreover, during development or afteraxonal injury, various grow factors en-hance axonal growth.

NGF, discovered nearly 50 yearsago, is the most thoroughly studied of agrowing list of NGFs. It has been knownsince the pioneering work of Levi-Montalcini (152-154) that neural crest-derived cells, sympathetic neurons, andDRG neurons, are developmentally de-pendent on NGF. More recently, it hasbeen shown that adult DRG and sympa-thetic neurons, both of which are popu-lations of neurons affected in diabeticneuropathy, are dependent on NGF ei-ther for their maintenance (155) or theirsurvival (156).

Faradji and Sotelo (157) haveshown a decline in serum NGF levels indiabetic patients compared with normalcontrol subjects. Moreover, the declinein serum NGF levels was greater in pa-tients with greater neurological impair-ment. Although these data suggest a de-cline in NGF synthesis in diabetes as acausative factor in diabetic neuropathy, arecent study of STZ-induced diabetic ratsreported increases in NGF levels in mostNGF-producing tissues (158). Yet, de-spite the increases in target-tissue NGF

levels in this study, NGF levels in thesuperior cervical ganglion, an NGF-dependent population of neurons, wasreduced dramatically.

Moreover, Hellweg et al. (159)showed that retrograde transport of NGFin the sciatic nerve was reduced in STZ-induced diabetic rats. Decreased retro-grade NGF transport in axons of theSTZ-induced diabetic rat ileal mesentericnerves has been reported by Schmidt etal. (160) preceding the development offrank distal axonopathy.

After sciatic nerve section in nor-mal adult rats, a significant number ofthe axotomized neurons in the involvedDRGs die (156,161,162). This cell losscan be completely eliminated by the ap-plication of exogenous NGF to the cutproximal end of the nerve (156). More-over, those DRG neurons do not die aftersciatic nerve section (156) or in vivo. NGFdepletion (155) exhibits significant atro-phy of their cell bodies and axons. Thisatrophy is reversed at least partially by theapplication of exogenous NGF (156).

One possible mechanism under-lying the NGF-induced reversal of DRGneuronal atrophy was demonstrated re-cently by Verge et al. (163). Theyshowed that an axotomy-induced down-regulation of neurofilament gene expres-sion in DRG neurons that express NGFreceptors was reversed by intrathecal in-fusion of NGF. Neurofilaments are be-lieved to be important in maintaining cellbody size and axon diameter (164,165);and therefore, by controlling neurofila-ment gene expression, NGF can regulatecell size and axonal diameter. NGF af-fects neurofilament gene expression onlyin DRG neurons with NGF receptors(163).

Atrophy of DRG neuronal cellbodies in experimental diabetes has beenreported (166). Moreover, considerableevidence indicates reduced axonal diam-eters and concomitant slowed conduc-tion velocities in diabetic patients and inanimal models of diabetes (167,168). Arole for NGF in the maintenance of nor-mal axon diameter by its effect on neu-

rofilament gene expression has been dis-cussed above, however, neurofilamentsynthesis in large, light DRG neuronsapparently is regulated by other, non-NGFs derived from skeletal muscle(169). It is reasonable to expect that ret-rograde transport of these factors alsomight be disturbed in diabetes and hencelead to a downregulation of neurofila-ment gene expression in non-NGF-receptive neurons.

A study by Larsen and Sidenius(170) supports, in part, the idea of adownregulation in neurofilament geneexpression in STZ-induced diabetic rats.They showed a reduction in the amountof high molecular neurofilament proteintransported by slow axonal transport indiabetic rats. This reduction could reflecta reduced synthesis of the protein causedby a downregulation of the gene.

NGF is also important in the reg-ulation of SP synthesis in adult DRGneurons (171,172). SP is found in thesympathetic nervous system and in a sub-population of DRG neurons (173). It hasbeen implicated in diverse and widespreadactivities, including vasodilation, gut mo-tility, and nociception (173), all of whichare perturbed in diabetic neuropathy.

Lindsay and Hamar (172) haveshown that NGF is involved in the reg-ulation of mRNAs that encode the pre-cursor molecules of SP and CGRP. Theyshowed that in vitro NGF deprivationcaused cultured adult DRG neurons todownregulate the mRNAs for the SP andCGRP precursor molecules. Moreover,when adult rats are immunized againstmouse NGF, a procedure that causes anautoimmune depletion of NGF, SP levelsare reduced in the DRG, spinal cord, andskin by - 6 5 % (171).

Perturbations of pain sensation ischaracteristic of diabetic neuropathy,and the levels of SP, which has beenimplicated as a nociceptive transmitter(173), are reduced in diabetic rats. Cal-cutt et al. (174) have reported a slightreduction in SP levels in DRG neurons.In addition, the amount of anterogradelytransported SP is reduced in STZ-in-



duced diabetic rats (174-176). Neithertreatment with an ARI (sorbinil) alonenor with gangliosides affected theamount of SP transported in sciaticnerves of diabetic rats (174-176). Fromtheir observations, Calcutt et al. (174)concluded that a selective downregula-tion of SP precursor gene expressioncaused by a decline in NGF reaching theganglia via retrograde transport could ex-plain a reduction in SP synthesis andtransport in STZ-induced diabetic rats. Itremains to be established that the reduc-tion in SP is pertinent to the symptomcomplex of neuropathy.

IGFs also may be implicated inthe pathogenesis of diabetic neuropathybecause of their shared structural homol-ogy with insulin, widespread distribu-tion throughout the nervous system, andprofound effect on developing neurons.IGF-I and IGF-II are known growth fac-tors that have been implicated in thegrowth and differentiation of neurons.Both insulin and IGF-II can promoteneurite outgrowth of neuroblastoma cellsin vitro (177,178), and IGF-I has beenimplicated in the survival and differenti-ation of fetal rat brain neurons in culture(179).

Kanje et al. (180, 181) haveshown that IGF-I is important in deter-mining successful peripheral nerve tissuein vivo. They showed that administrationof exogenous IGF-I to nerve repair sitesvia miniosmotic pumps significantly en-hanced nerve regeneration. Likewise, re-generation was inhibited if the nerve wasperfused with antibodies directed againstnative IGF-I.

To date, little research has beenconducted that associates reduced IGFprotein levels, whether attributable toimpaired transport or synthesis, with theoccurrence of diabetic neuropathy. Onestudy showed that animals with de-creased plasma levels of IGF-I because ofexperimentally induced diabetes show amarked impairment in peripheral nerveregeneration (182). Interestingly, previ-ous studies that examined peripheralnerve regeneration in animals with ex-

perimentally induced diabetes alsoshowed an impairment in nerve regener-ation (183). The molecular basis of thisimpairment is at present unknown.However, given that unidentified solubleneuronal and Schwann cell-promotingfactors are produced and released duringnormal conditions of peripheral nerverepair (184,185), it is possible that theexpression of these factors is compro-mised in a diabetic state similar to thatreported for IGF-I.

Neurotrophic factors andneuropathyWith our new understanding of the roleof growth factors in the control of growthinitiation, proliferation, and the apop-totic process whereby remodeling ofneurons occurs, it becomes possible toconsider the use of neurotrophic factorsin the treatment of diabetic neuropathy.Aided by the availability of large quanti-ties of recombinant neurotrophic factors,it is feasible to consider their possibleplace in the management of diabetic neu-ropathy. The choice of the optimal neu-rotrophic factor is dependent on anawareness of the neuronal population in-volved in the disease process and an un-derstanding of the specificity of each fac-tor for a specific neuronal populationaffected by the disease process. This em-phasizes the need for more specific de-lineation of the neuronal population in-volved in the disease process and thespecific syndrome present in a particularpatient.

Sympathetic and DRGs expressreceptors for the neurotrophins, NGF,bFG, and BDNF; thus, these agents mayprove efficacious for the treatment of thesmall fiber sensory and autonomic neu-ropathies (186,187). The motor neurop-athies are candidates for treatment withvarious growth factors, including CNTF,IGF-1, bFGF, and certain other muscle-derived growth factors (188-190).

The optimum approach to mixedsensory neuropathies may be the use offactors with less specificity for motor orsensory neurons. Some factors, such as

CNTF, exert trophic actions on both sen-sory and motor neurons (191,192) andwill be worthy of trial in mixed neurop-athies. Alternatively, the use of combina-tions of growth factors, each with actionson a component of the neuropathic pro-cess, may prove to be the appropriateapproach.

Stimulating nerve growth and re-generation as well as remodeling growthfactors that target neurons may decreasethe vulnerability to damage by the dia-betic disease process and may enhanceneuronal ability to compensate for recov-ery from the regenerative process. NGFhas been considered for the treatment ofAlzheimer's disease because of the loss ofcholinergic neurons in this disease andthe pronounced and selective trophic ac-tion of NGF on cholinergic neurons(193). Recombinant NGF has beenshown to reverse experimental cholin-ergic injury in animals (194,195). bFGFand BDNF also protect cholinergic cellbodies, although not as well as NGF(196,197).

Evidence also indicates thatdopaminergic neurons may be responsi-ble to treatment with growth factors.BDNF, bFGF, IGF-1, and EGF promotedevelopmental differentiation of thedopaminergic neurons affected in Par-kinson's disease (198-201).

Even motoneurons may be pro-tected from cell death. CNTF rescuesmotoneurons from naturally occurringcell death during chick embryo develop-ment and may retard motoneuron de-generation in the adult (190,192).

Early results of treatment of toxicneuropathies with growth factors are en-couraging. The small fiber sensory neu-ropathy induced by taxol can be pre-vented by the administration of NGF(202). The large fiber neuropathy induceby the antitumor agent cisplatinum withprominent propioceptive deficits can beprevented in rodents (203) treated withNGF (204), which also has been shownto prevent or delay the development ofsensory neuropathy in STZ-induced dia-betes. CNTF supports the survival of cul-



Table 4—Neurotrophic factors and possible therapeutic strategies for diabetic neuropathies

SOMATIC AUTONOM1C

MOTOR SENSORY MIXED ADRENERGIC CHOLINERGIC DOPAMINERGIC

GROWTH FACTORS

CNTF + - + +1GF-1 + - - - - +BFGF + + - + + +

MUSCLE-DERIVED + — — — — —

NGF - + - + +BDNF + - + + +EGF - - +

COMBINATIONS — — + — — —

tured neurons and promotes motor neu-ron survival after axotomy (190,192) andthus shows special promise for the treat-ment of the pure motor neuropathies indiabetes. A table is included that showsthe prospective uses of growth factors innerve damage (Table 4).

The question as to how growthfactors will gain access to neurons maynot be as difficult as once believed. 1m-plantable pumps, now used extensivelyin the treatment of diabetes, may permitdelivery of adequate concentrations ofgrowth factors to peripheral nerveswhere they may act locally. The future isalso promising for the implanting of ge-netically engineered cells (205,206). It isalso within the realms of possibility thatpharmacological agents will be able toselectively modify the activity of neuro-trophic agonists (207,208), as has beenshown for certain alkaloidlike com-pounds.

In summary, although the mech-anism of action remains unknown, thecurrent knowledge of growth factors andtheir relationship to diabetic neuropathysuggests a pathophysiological role for re-duced levels of NGF and possibly theIGFs available to neuronal cell bodies. Inthis regard, it is now conceivable thatneuronal function, atrophy, and possiblycell death may be compromised in dia-betic neuropathy by this reduction.Whether the growth factor deficiency iscaused by decreased synthesis, an inabil-

ity of the factor to bind to its receptor,disturbances in retrograde axonal trans-port, or intraneuronal processing re-mains to be established. However, fur-ther studies aimed at understanding thegene and protein expression of potentialperipheral NGFs during diabetic neurop-athy, and their receptor-binding andsubsequent transport from sites of syn-thesis to sites of action should shed con-siderable light on the relationship be-tween growth factor expression anddiabetic neuropathy.

CLINICAL MANIFESTATIONS —From a clinical perspective, it is useful toclassify diabetic neuropathy into the twobroad categories of somatic and auto-nomic neuropathies, each with its ownfurther subdivisions. The somatic neu-ropathies tend to fall into three majorsubdivisions: symmetric distal polyneu-ropathies, proximal motor neuropathies,and focal neuropathies. Although it isconvenient to consider these separately,in practice, observed patterns often over-lap and involvement of sensory, motor,and autonomic nerves usually coexist(8,209,210).

Although cooling-detectionthresholds are advocated by some as asensitive and reproducible assessment ofperipheral small fiber function (211), apractical and reproducible method of as-sessment is not yet readily available. Thisis disappointing because small fiber de-

fects may occur early in diabetes, andmay be the first sign of the developmentof neuropathy (68). Defects of peripheralthermal sensation may occur indepen-dently of vibration perception and mayreflect similar defects in the small pe-ripheral autonomic fibers (212-214).

CLINICAL PRESENTATION

Somatic neuropathiesSymmetrical distal polyneuropathy.This is the most common and widelyrecognized form of diabetic neuropathy.The onset is usually insidious but occa-sionally acute, and it follows stress orinitiation of therapy of diabetes. The def-icit is predominantly sensory with lesserinvolvement of motor fibers. Signs in-clude depression or loss of ankle jerksand vibratory sensation with calf tender-ness and hyperalgesia in some patients.The neurological deficit is peripheral, in-volving the distal sensorimotor nerves ina glove and stocking distribution. Thelower extremities receive the major bruntof the affliction. The stocking is not asingle line of loss of one modality ofsensation but rather multiple gloves andstockingsare noted, one for each modal-ity. In general, the long fibers that areaffected most severely, such as those forposition, sense, and touch, have thehighest stocking and the short pain fibersthe lowest stocking. If all the levels co-incide, then one must be alert to thepossibility of a conversion reaction orhysteria. The long and short fibers areaffected differentially. The conditionstarts distally and proceeds proximally.The type of neuropathy varies with thetype of nerve fiber involved. Large fibersare associated with loss of position andvibration sense, and half of light touchand sensory ataxia with loss of anklereflexes. The symptoms may be minimal,such as sensations of walking on cottonwool and floors feeling strange; or theymay be more severe, such as the inabilityto turn the pages of a book or discrimi-nate coins. In contrast, the small fiberneuropathy is associated with a loss of



pain sensation and loss of the awarenessof temperature differences.

Painful neuropathy—Some pa-tients may develop a predominantlysmall fiber neuropathy, which is mani-fested by pain and paresthesia. Symp-toms are often exacerbated at night andare manifested in the feet more than thehands. Spontaneous episodes of painmay be severely disabling. The pain var-ies in intensity and character. In somepatients, the pain has been described asburning, lancinating, stabbing, tearing,aching, or like a dog gnawing at thebones. In others, it has been described asdull, like a toothache in the bones of thefeet, or even crushing or cramp-like. Painoften is accompanied by paresthesia orepisodes of distorted sensation, such aspins and needles, tingling, coldness,numbness, or burning (79). The lowerlegs may be exquisitely tender to touch,with any disturbance of the hair folliclesresulting in excruciating pain. Becausepain may be aggravated by repeated con-tact of the lower limbs with foreign ob-jects, even basic daily activities such assitting at a desk may be disrupted. Painoften occurs at the onset of the disease(57) and often times is made worse byinitiation of therapy with insulin or sul-phonylureas (215-217). In this earlyform of the painful syndrome, the con-dition often remits spontaneously andthe management entails supportive ther-apy. It may be associated with profoundweight loss and severe depression andhas been termed diabetic neuropathic ca-chexia (218). The syndrome occurs pre-dominantly in males and may occur atany time in the course of both IDDM andNIDDM.

Unfortunately, another variety ofpainful polyneuropathy exists with onsetoccurring later in diabetes, often years,and in which the pain persists and be-comes quite debilitating.

This condition may lead to habit-uation to narcotics and analgesics andfinally addiction. This latter variety, al-though relatively infrequent, is inordi-nately resistant to all forms of interven-

Pain

Threshold

No Pain

Good Neural Function Bad

Figure 2—Starling's curve for pain in diabetic neuropathy.

tion and can be most trying to patientsand their physicians.

The mechanism for acute pain insmall fiber neuropathy is not well under-stood. In some patients, the heraldingfeatures of their diabetes may be the on-set of acute painful neuropathy (218),whereas in others the condition appearssoon after initiation of therapy (217).Hyperglycemia per se may be a factor inlowering the pain threshold (219), how-ever, in others a striking amelioration ofsymptoms has been observed with thelowering of blood glucose (57,216). Aplausible theory relates to the regenera-tion of small, unmyelinated fibers caus-ing spontaneous discharges of impulsesthat subserve pain (215,220). It is alsofeasible that with the recovery from theinitial episode of hyperglycemia, thesesmall fibers grow and cause pain (Fig. 2).This hypothesis, however, may not becompatible with the observation that re-generation of all nerve fibers has beenfound with both the painful and painlessvarieties of neuropathy (221). It is alsofeasible that with loss of the balancinginfluences of large fibers comes a pre-dominant effect of small fiber signaltransmission, which then is associatedwith pain; in other words, a large fiberneuropathy theoretically could generatepain, even with intact small fibers. Thishypothesis remains, however, to be

proven. On the other hand, pain notinfrequently occurs when objective mea-sures suggest actual recovery from theneuropathy, implying that regrowth ofsmall fibers is an important constituentof this syndrome. Indeed, loss of painwith evidence of progression of the dis-ease may be indicative of nerve death,and thus may not be a welcome occur-rence.

Motor weakness may occur in theperipheral symmetric neuropathies, butwasting of the small muscles of the handsand feet is characteristic. This usuallyoccurs in very advanced cases and mayresemble motor neuron disease, al-though the latter has no sensory compo-nent. Loss of the deep tendon reflexes isa hallmark of peripheral symmetricalneuropathy, and when pure motor neu-ropathy is found, causes other than dia-betes must be excluded. A similar neu-ropathy has been described in patientswith insulinomas (128), and the possi-bility that this syndrome is related tooverzealous treatment with insulin hasyet to be excluded.

Neuropathic (perforating) ulcer—Foot ul-cer constitutes a major source of morbid-ity among individuals with diabetes. Lossof protective sensation and repetitivetrauma, such as walking, are the majorcauses. Ulceration occurs most fre-quently over the metatarsal heads, but



also appears at other areas of increasedpressure. Loss of tone in the small mus-cles of the feet leads to an imbalancebetween the flexors and extensors, ulti-mately resulting in the classic hammer-claw toe. The altered architecture of thefoot is associated with increased pressureover the ball of the foot, which corre-sponds to the heads of the metatarsals.Also, the normal person constantly shiftsthe area of pressure in the foot whilewalking or running, whereas the diabeticindividual with neuropathy is unable todo so because of lack of the sensory in-put from the soles of the feet. This con-stant pressure causes calluses with in-crease in pressure and ultimatelyulceration in the high pressure areas. In-fection develops after the skin breaksdown. Infection in the milieu of ischemiacan eventually lead to gangrene. Thus,the three important factors in foot ulcer-ation in the diabetic individual are vas-cular disease, neuropathy, and infection(222).

Recently, the role of the autonomicnervous system in the pathogenesis ofneuropathic ulcers has been increasinglyrecognized. The hyperhydrosis, thecracked dry skin, and the increased smallblood vessel flow create an excellent mi-lieu for infection to take hold and pro-liferate (223).Neuropathic arthropathy (Charcot's joints)—Neuropathic arthropathy, or Charcot'sjoints, occurs in the presence of impairedsensations of pain and proprioception,intact motor power, and repeated minortrauma and occurs usually in feet withnormal pulses and warmth. The clinicalcourse is painless and is characterized bynonedematous swelling of the foot sothat the foot becomes shorter, wider,everted, and externally rotated with aflattening of the arch. The gait becomesabnormal, and the clubfoot develops. Itis practically limited to the ankle andtarsal joints in diabetes. Pathologicalroentgenographic features include bonelysis, fragmentation, and eburnation.Disarticulation and dissolution of thejoints occurs with bony overgrowth and

calcification in and around the joints fol-lowing. Eventually pressure ulcers, infec-tion, and osteomyelitis develop. The feetof diabetic individuals often have bound-ing pulses that suggest an adequate largeblood vessel supply. The impression iserroneous, however, and the boundingpulses are now thought to be caused bythe shunting of blood through the smallarteriovenous fistulae normally regulatedby the sympathetic nervous system. Theenhanced blood flow may be conduciveto excessive bone resorption, fractures,and osteoarthropathy (224,225).Proximal motor neuropathies.Diabetic amyotrophy—This syndromemay be recognized by the triad of pain,severe muscle atrophy in the limb girdledistribution, and fasciculation of themuscles. The onset is usually acute(226), but it may be subacute and grad-ually evolve over weeks (227). Patientsalso experience generalized weight lossand diabetic cachexia. Asymmetrical,proximal muscle weakness and wastingof lower extremities, involving predomi-nantly the iliopsoas, quadriceps, and ad-ductor muscles, occur. Patients oftencannot stand unsupported, climb stairs,or rise from the kneeling or sitting posi-tion. The differential diagnosis is Cush-ing's syndrome, thyrotoxicosis or a neo-plasm, all of which produce a proximalmyopathy without evidence of nerve le-sions and are characterized by intact re-flexes. Other differential diagnoses in-clude the proximal neuropathies inwhich no pain or fasciculation is ob-served, such as Guillain Barre syndrome.Diabetic amyotrophy often is accompa-nied by pain in the thigh muscles andsometimes lumbar or perineal regions.The knee jerks are depressed, but little orno sensory involvement is found. Theanterolateral muscle group in the lowerleg also may be involved, producing theanterior compartment syndrome. Occa-sionally, the upper limb girdle also isaffected, and wasting of the deltoids isseen. The syndrome occurs primarily inolder NIDDM patients who frequentlyhave only mild diabetes. It has been pos-

tulated that the acute and chronic vari-eties of the syndrome derive from differ-ences in pathogenesis, with the acutevariety being attributable to multiple in-farcts in the proximal nerve trunks andthe lumbosascral plexus, whereas theslowly evolving variety may be attribut-able to metabolic factors alluded toabove (228). The condition resolvesspontaneously but this may take from1-3 yr.

Truncal mononeuropathy (or radiculopa-

thy)—This syndrome is primarily a sen-sory neuropathy affecting the root distri-bution, which is almost always unilateraland asymmetrical. The sex distribution isequal, with primarily older patients be-ing affected. Occasionally, young pa-tients with IDDM of long duration alsomay be affected. It usually is associatedwith peripheral neuropathy and may re-semble diabetic cachexia. Hyperaesthesiaoften is found in the root distribution,and the clinical presentation may mimicacute abdominal or thoracic crisis result-ing in unnecessary invasive procedures.Denervation of muscles in the root seg-ment also may occur (229-233). Thissyndrome may resemble Herpe's Zosterinfection in the prevesicular phase andoccasionally spinal cord compressionfrom neoplasms or other causes. Noctur-nal exacerbation of pain is troublesome,but spontaneous clearing occurs, usuallywithin 3 mo of the onset.Focal neuropathies. Focal and multifo-cal diabetic neuropathies cause neuro-logical deficits that are confined to thedistribution of a single nerve (mononeu-ropathy) or multiple single nerves(mononeuropathy multiplex). The onsetis typically acute, often heralded by se-vere pain, and the differential diagnosismust generally exclude a vascular catas-trophe. No clear relationship has beendetermined with the age or sex of thepatient nor is a relationship apparentwith the type of diabetes, its duration,the degree of diabetes control, or treat-ment.



Table 5—Autonomic neuropathy clinical manifestations

SYSTEM INVOLVED MANIFESTATIONS

PUPILLARY ABNORMALITIES

CARDIOVASCULAR ABNORMALITIES

MOTOR DISTURBANCES OF

GASTROINTESTINAL TRACT

GENITOURINARY TRACT DISTURBANCES

SWEATING DISTURBANCES

METABOLIC

DECREASED DIABETER OF DARK-ADAPTED PUPIL

ARGYLL-ROBERTSON TYPE PUPIL

TACHYCARDIA, EXERCISE INTOLERANCE

CARDIAC DENERVATION

ORTHOSTATIC HYPOTENSION

HEAT INTOLERANCE

SKIN TEMPERATURE REVERSAL, DRY SKIN, AND DEPENDENT EDEMA

ESOPHAGEAL ENTEROPATHY

GASTROPARESIS DIABETICORUM

CONSTIPATION

DIARRHEA

FECAL INCONTINENCE

NEUROGENIC VESICAL DYSFUNCTION

SEXUAL DYSFUNCTION

MALE

IMPOTENCE

RETROGRADE EJACULATION

FEMALE

DEFECTIVE LUBRICATION

AREAS OF SYMMETRICAL ANHIDROSIS

GUSTATORY SWEATING

HYPOGLYCEMIA U N A W A R E N E S S , HYPOGLYCEM1A UNRESPONSIVENESS,

AND HAAF

Cranial nerve lesions—Lesions in the cra-nial nerves are manifested as isolated ormultiple palsies, which occur primarilyin the older age-group and may occur inthe absence of other evidence of neurop-athy. The onset is generally abrupt, andalthough painless in 50% of patients,may be extremely painful in others forreasons that are not understood (234).The III nerve lesion is most common. Itcharacteristically presents as sudden on-set with a severe ipsilateral headache of-ten preceding the neurological deficit byseveral days. Ptosis and ophthalmoplegiaare found, but, in contrast with the an-terior communicating aneurysm rupture,the pupils usually are spared (235). Ofthe other extraocular ophthalmoplegias,the VI nerve is less commonly involved,and the IV nerve seldom is involved. TheVII nerve is not infrequently affected, re-sulting in an isolated Bell's palsy. Allother cranial nerves have been reportedto be involved but much less commonly.

Recovery is generally complete

within 6 -8 wk and does not appear tobe a function of changing diabetes con-trol.Isolated peripheral nerve lesions—Isolatedperipheral nerves involve particularly theulnar, median, radial, femoral, and lat-eral cutaneous nerves of the thigh. Car-pal tunnel syndrome occurs twice as fre-quently in a diabetic populationcompared with a normal healthy popu-lation, and its increased prevalence indiabetes may be related to repeated un-detected trauma, metabolic changes, oraccumulation of fluid or edema withinthe confined space of the carpal tunnel.The nerves involved are usually motor,but pure sensory lesions occasionally oc-cur. Nerves that are at risk for compres-sion are the peroneal nerve at the head ofthe fibula, ulnar nerve at the elbow, themedian at the wrist, and the lateral cuta-neous nerve of the thigh. Affected pa-tients may present with unexplainedpain and hyperaesthesia in the upperouter quadrant of the thigh and the per-

oneal nerves (236,237). Again, these le-sions are self-limiting but may takesomewhat longer to resolve than the cra-nial nerve lesions.

Autonomic neuropathiesDiabetic autonomic neuropathy may in-volve any system in the body. Its mani-festations are protean, and the onset isoften insidious. Subclinical abnormalitiesin cardiovascular (238) and gastrointes-tinal function (239) may be found atdiagnosis (47) or even in teenage dia-betic patients (240). The clinical featuresare often unsuspected and, without care-ful scrutiny, may go undetected. By us-ing cardiovascular reflex tests, the prev-alence is reported to be 17-40% (240-244). Of teenagers with IDDM, 31%have abnormal tests (240). The relation-ship with sensorimotor neuropathy isvariable, but, in general, autonomic andsensory motor abnormalities coexist. Inpeople with peripheral neuropathy, 50%will have asymptomatic autonomic neu-ropathy. When symptoms of autonomicneuropathy are present, the anticipatedmortality is 15-40% within 5 yr (72,75,245,246). With gastroparesis, 35% diewithin 3 yr, usually of aspiration pneu-monia. Reduced exercise tolerance,edema, paradoxical supine or nocturnalhypertension (247), intolerance of heatdue because of defective thermoregula-tion, silent myocardial infarction, respi-ratory failure, and sudden death are haz-ards for the diabetic patient with cardiacautonomic neuropathy (248-251). It is,therefore, vitally important to make thisdiagnosis early, so that appropriate inter-vention can be instituted. In the sectionthat follows, the clinical presentations ofautonomic neuropathy, the diagnostictests, and the various forms of manage-ment currently available will be discussed.

Table 5 lists a current approachto the differential classification of auto-nomic neuropathy.

Pupillary abnormalities. Pupillary ab-normalities may proceed all other evi-dence of autonomic dysfunction, if care-ful pupillometry testing is conducted



(250). In affected subjects, Argyll-Rob-ertson-type pupillary responses in whichthe pupils react slowly to light if at alland accommodate normally may befound. The pupillary abnormalities donot tend to produce any significant func-tional deficit, however, unless associatedwith failure of dark adaptation and diffi-culty with driving at night (251).Orthostatic hypotension without com-pensatory tachycardia. Orthostatic hy-potension is defined as a fall in the sys-tolic blood pressure of >30 mmHgwithin 2 min of standing. This defecttends to occur late in the course of dia-betes and signifies advanced involvementof the autonomic nervous system. It of-ten is found incidentally and is not al-ways symptomatic. After treatment, thesymptoms often abate without any realchange in the blood pressure. The defectis thought to be attributable primarily toinvolvement of the sympathetic nervoussystem, which provides vasoconstrictiveinput into the skeletal muscle andsplanchnic bed as well as inotropic andchronotropic stimulation of the heart.Because blood pressure is maintained bya product of the cardiac output and pe-ripheral vascular resistance, loss of ad-renergic input anywhere along the pathmay have pathogenetic significance, al-though the nature of autonomic involve-ment in this syndrome is obscure. A hy-poadrenergic variety has been described,ostensibly attributable to disease of theautonomic nervous system involving theperipheral nerves (252,253) with a re-duction in the synthesis and release ofNE at postganglionic sympathetic neu-rones (254). A hyperadrenergic varietyalso has been described, which is attrib-utable to a reduction in the plasma vol-ume with loss into an edema compart-ment, the presence of which is notunusual in patients with autonomic neu-ropathy (255). Abnormalities in plasmacatecholamines have not been univer-sally found (256), although we haveshown that a progressive decrease in a-2adrenergic receptors occurs with worsen-ing of the neuropathy, with the greatest

deficit occurring in those patients withpostural hypotension. If this phenome-non reflected the loss of the postgangli-onic a-2 vasoconstricting receptor, itmight explain the postural hypotension.On the other hand, this observation maysimply reflect an adaptive response, be-cause in diabetic subjects with auto-nomic neuropathy, a 10-fold increase inthe sensitivity to NE occurs (257), as inother conditions associated with sympa-thetic denervation. Nonetheless, in pa-tients with deficient a-adrenoreceptors,a paradoxical rise in blood pressure isfound when treated with the a-2 adren-ergic agonist clonidine (258).

The loss of adrenergic a-recep-tors may in some instances be associatedwith an excess of adrenergic f$-receptors,hence the occasional successful outcomeof treatment with (3-receptor blockingdrugs. There may also be a cardiac ele-ment with decrease in inotropic andchronotropic responses of the heart be-cause of a cardiopathy involving the au-tonomic nervous system (258-260).One especially prominent feature may bethe provocation of hypotension soon af-ter the administration of insulin(261,262), and this may be mistakenlydiagnosed as hypoglycemia and exacer-bated by meal ingestion (263) or drugsthat accentuate hypotension, such as ni-troglycerine, ganglion-blocking drugs,and diuretics used in the treatment ofhypertension. Patients may even displaythe paradoxical features of supine hyper-tension, rises in blood pressure withREM sleep (264), and failure of the nat-ural rise in pressure as the day progresses(75).Vasomotor instability.Skin-temperature reversal—A result ofloss of the sympathetic fibers in the feetmay be sweating in the upper body as ameans of dissipating heat. In some in-stances, this can prove uncomfortableand can mimic the flushing episodesfound in patients with the carcinoid syn-drome, unless the observer is aware ofthe condition. Loss of the sympatheticinnervation of the small peripheral blood

capillaries in the feet leads to loss ofvasomotor tone, arteriovenous shunting,and diapedesis with resultant dependentedema, and drying and cracking of theskin (65,224,264); it also may predis-pose the individual to foot ulceration andultimately gangrene and limb loss. Theedema may respond to treatment withthe adrenergic agonist, ephedrine (265).Cardiac denervation—Autonomic neu-ropathy has now been reported as in-volving the cardiovascular system withresting tachycardia, dysfunction of bothleft ventricular diastolic filling and sys-tolic ejection, and painless myocardialinfarction. Patients with autonomic neu-ropathy have high sleep and waking rest-ing heart rates that are unresponsive tovagotonic maneuvers, such as the Val-salva and deep, slow respiration (266).In the absence of other causes of tachy-cardia such as fever, anemia, thyrotoxi-cosis, and pheochromocytoma, theabove signs suggest vagal neuropathy.Because these abnormalities are foundearly in the course of diabetes, it wasspeculated that they were attributable toloss of the relatively long vagal fiberscompared with the short fibers (245).More recently, this new notion has beendisputed (246). With progression of thedisease, complete cardiac denervationensues, and the heart rate returns to nor-mal but does not regain the reflex re-sponses to breathing and to change inposture. We have shown previously that—33% of patients with diabetic auto-nomic neuropathy have depressed leftventricular systolic function on radionu-clide ventriculography in the absence ofischemic heart disease, and this corre-lates with the severity of the neuropathy(267). We have further demonstratedthat left ventricular diastolic filling is ab-normal in those patients with the mostsevere neuropathy, and that the degree ofabnormality correlates with a reductionin circulating catecholamines and pos-tural hypotension (260). In 30 subjectsattending a diabetes clinic, we examinedthe effects of maximal treadmill responseto exercise and measured the pressure-



rate products at rest and maximal exer-cise. Of the subjects who were found tohave autonomic neuropathy, 17 hadhigher resting pressure-rate products, afunction of the resting tachycardia, butimpaired responses to exercise. Thus,cardiac autonomic neuropathy is associ-ated with impairment of the hemody-namic responses to exercise in the ab-sence of ischemic heart disease. On thebasis of this observation, we now cautionpatients against embarking on aggressiveexercise programs without first havinga cardiovascular work-up to exclude oc-cult autonomic cardiomyopathy.Whether autonomic cardiomyopathyleads to impaired exercise tolerance ordysrhythmias is not known.

The cardiac denervation also maypredispose to painless myocardial infarc-tion, with a risk of sudden death(100,249,250,268-270). It has been re-ported that silent myocardial infarctionoccurs 6-7 times more frequently in thediabetic population than the populationat large (100). We also have found apositive correlation between autonomicneuropathy, prolongation of the QT in-terval, and sudden death (245). We havein unpublished observations noted thatindividuals with decreased uptake of theadrenergic screening agent metaiodoben-zylguanidine by the heart are at greaterrisk of sudden death (245).Respiratory dysfunction—Clinical abnor-malities in respiratory function do notappear to derive from autonomic neu-ropathy. As reviewed by Ewing andClarke (244), numerous of conflictingreports have been made on abnormalitiesin airways resistance, sleep apnea, andthe response to hypercarbia. It is alsodoubtful that these abnormalities con-tribute to the sudden death phenomenonof diabetic autonomic neuropathy. Ourobservations indicate that the respiratorydysfunction in patients with autonomicneuropathy comprises the failure of ini-tiation of respiratory drive under condi-tions of hypoxia (271). Thus, patientshave to rely on the hypercarbic drive, asituation that presents a real danger dur-

ing anesthesia when oxygen levels aremaintained, and CO2 is driven off. Im-paired hypoxic respiratory drive alsomay account for sleep apnea and forsome of the unexplained deaths. Thishypothesis has not, however, been estab-lished irrefutably.Motor disturbances of gastrointestinaltract. The gut is a prime focus of auto-nomic neuropathy and may be affectedin its entirety. Abnormalities may be ex-pressed both in motor function and inthe regulation of gastrointestinal hor-mone secretion.

Esophageal enteropathy—Disturbances inesophageal function in diabetes are ex-tremely common but probably of nogreat consequence. Esophageal enterop-athy is frequently detectable through so-phisticated upper GI series and dynamicscintiscanning in diabetic patients. Onlyrarely, however, do patients present withdysphagia, retrosternal discomfort, andheartburn (244).

Gastroparesis diabeticorum—This clinicalsyndrome was described initially by Kas-sander (272) and comprises anorexia,nausea, vomiting, fullness, and early sa-tiety. These are general symptoms andare more frequently found among de-pressed people with gastroparesis. Forthis reason, the suspicion of a lesionmandates an emptying study. Not infre-quently, however, patients will complainof vomiting of meals that were ingestedsome days beforehand. Meals, such asthose containing garlic, sausage, or sea-soning, may be tasted on their breath fordays after the meal. Physical examinationof affected patients often reveals a hip-pocratic succussion splash in which aninitial delay of emptying of solids occurs(273-276) and subsequently of liquids(239). The gastric acid secretory re-sponse to insulin-induced hypoglycemia,as well as that to sham feeding, is re-duced (276,277), and gastrin levels maybe elevated, presumably because of theautovagotomy (278,279). Indeed, pa-tients may be diagnosed mistakenly withthe ZE syndrome, leading us to term thecondition diabetic pseudo-ZE syndrome

(280). Diabetic pseudo-ZE syndrome isreadily distinguished from ZE syndromeby a measurement of the gastric acid,which is low in the former and high inthe latter syndrome. In normal humans,an agastric pacemaker initiates theIMMC, and a pressure wave proceedsfrom the region of the esophagogastricjunction towards the duodenum andsmall intestine. In patients with gastro-paresis, the IMMC is lost. Reappearanceof the IMMC with the administration ofmetoclopropamide by the intravenousroute generally heralds a good clinicalresponse to the drug (281). Hyperglyce-mia per se abolishes the IMMC andcauses a profound delay in gastric emp-tying. Thus, it is important when mea-suring gastric emptying to do the studyonly after the glucose is marked normal.The major nonnutritional problem withgastroparesis is the irregular absorptionof fuels, which accentuates poor diabetescontrol. A significantly prolonged gastricemptying time has been observed in peo-ple with brittle diabetes—no personshould be labeled as brittle until the gas-tric emptying study has been completed.In addition, the risk is present with theingestion of soluble fibers, such as guarand pectin, of developing fiber bezoars(282). Thus, extreme care must be exer-cised in prescribing fiber in the diet. Gas-troparesis may become an intractableproblem with persistent anorexia, nau-sea, abdominal pain, and weight loss andmay present a near insurmountableproblem in clinical management.Diabetic enteropathy—Enteropathy in-volving the large colon is common andmay produce constipation in up to 66%of patients with long-standing diabetes(239). The opposite symptom complexalso may occur, the outcome of which istroublesome and explosive diabetic diar-rhea, which has been called paroxysmalnocturnal diarrhea. The paroxysms occurexplosively and without warning, andthe patients may produce pools of liquidfeces in embarrassing situations. Withthe associated loss of perirectal and peri-anal sensation that occurs, the patients



may not be aware of soiling themselves.Anal sphincteric control and tone is lost(283,284) and with it the ability to retainfeces. The condition often fluctuatesfrom day to day, may occur at night butmay occur at any time of the day ornight, and may exhibit seasonal fluctua-tion (285). Proximal small intestinal mo-tility disturbances may be found duringthe episode, and the gastrointestinaltransit time becomes prolonged in theremissions (286). In addition, a numberof factors may contribute to the diarrhea,which include stasis of bowel contentswith bacterial overgrowth (286), bile ac-id-induced intestinal hurry and malab-sorption (287,288), and a diminution inpancreatic exocrine secretions, presum-ably due both to the need for insulin tomaintain exocrine pancreatic functionand the vagal pancreatic neuropathy(289). A further defect in a-2 adrenergicreceptor function has been postulatedand forms the basis of recommendedtreatment with adrenergic agonists (290,291). However, no evidence has sug-gested a secretory component to the di-arrhea, although it has been shown torespond to antisecretory agents (292,293).

Gut neuroendocrine abnormalities—Al-though it is clear that the abnormalitiesin the autonomic nerves per se contrib-ute to the extensive dysfunction of thegut, the autonomic nervous system isintimately involved in the regulation ofmany gut neuroendocrine hormonalpeptides, including gastrin, PP, SRIF,glucagon, GIP, and motilin, among oth-ers. These peptides have important func-tions in regulating insulin secretion, glu-cose counterregulation in response tohypoglycemia, gut motility, intestinal se-cretions, and digestion and absorption ofnutrients. The clinical consequences ofgastroparesis, diarrhea, and constipationderive from disease of the autonomicnerves; and the abnormalities in peptidesecretion appear to be secondary to theneuropathy. Notwithstanding, the ab-normalities in peptide secretion may playan important role in perpetuating the

disorder and initiating a vicious cycle ofneuropathy, gut dysfunction, peptideabnormality, and further gut dysfunc-tion. Even if the abnormalities in thesepeptides have no biological conse-quence, detection of these abnormalitieshas provided investigators with usefultools to detect the failure of autonomicfunction early in the course of the disease(294,295).

Of all the gut hormones mea-sured, PP may be the most useful, be-cause its release from the pancreas isunder exquisite cholinergic, if not vagal,control (296,297). The PP response tohypoglycemia (295,298), meal ingestion(297), and sham feeding (295) all areabolished by atropine and are markedlyreduced by vagotomy performed withinthe preceding 6 mo. We originallyshowed that the PP response to hypogly-cemia was impaired in diabetic patientswith impaired cardiovascular autonomicreflexes and proposed this as a test ofvagal integrity (299). Krarup et al. (300)have shown that the response to hypo-glycemia becomes progressively reducedwith increasing duration of diabetes, pre-sumably because of worsening of the au-tonomic dysfunction. More recently, thePP secretory response has been used todetermine those patients at risk for hy-poglycemia during intensive diabetescontrol (301). Current studies are aimedat determining the earliest and most sen-sitive indicator of paraympathetic dys-function, and the PP response to hypo-glycemia is a prime candidate. In theyears before the advent of human insu-lins, the measurement of PP as a markerfor progress of the neuropathy was ham-pered by the presence of PP antibodies inthe serum of many patients treated withcrude insulins. The PP antibodies werepresumably attributable to the contami-nation of the crude insulins with porcineor beef PP. Today crude insulins are nolonger used in many institutions, and itshould be possible to monitor the naturalhistory of vagal neuropathy by measur-ing PP responsiveness serially. A test in-volving hypoglycemia is unfortunately

not well-tolerated by most subjects, andit may be that the early response to foodingestion (244) or sham feeding (295)may be less traumatic for the subject andboth are reduced in patients with auto-nomic neuropathy, as is the response toexercise (302), which may, however, re-flect both parasympathetic and sympa-thetic dysfunction (296).

Glucagon secretion may becomedistinctly abnormal in patients with au-tonomic neuropathy. It is establishedthat the neural system is involved in theregulation of glucagon secretion(303,304) with the response to hypogly-cemia impaired in diabetic individualswith established autonomic neuropathy(305,307); a deficiency may impair theability to recover from hypoglycemia.The glucagon response to hypoglycemiamay, however, be attenuated as a conse-quence of neuropathy (308-310). In ourview, this observation should not ques-tion the role of the autonomic nervoussystem in glucagon regulation but rathershould alert diabetes experts to exercisecaution in selecting individuals appropri-ate for intensive therapy. In contrast tothe diminished glucagon responses tohypoglycemia are the exaggerated re-sponses of glucagon to meal ingestionand to arginine infusion observed amongNIDDM patients with autonomic neu-ropathy (306). Possibly, these elevatedsecretory responses may be a function ofthe rate of gastric emptying. This un-usual combination of deficient responsesto hypoglycemia and exaggerated re-sponses to food may contribute signifi-cantly to the apparently brittle diabetesencountered in these individuals (300).

Other hormonal peptides underneural control also affect insulin secre-tion. GIP secretion, for example, is di-minished in response to meal ingestionin patients with autonomic neuropathy(311). Because GIP may be a major gutfactor enhancing the insulin response toglucose, a function known as an incretin,deficiency may compromise insulin se-cretion in NIDDM and contribute in partto the severity of the diabetes. Further



complexity is added by the observationthat secretion of SR1F (an inhibitor ofinsulin and glucagon secretion) is alsounder vagal control (312) and may bediminished in autonomic neuropathy(307,309). Ultimately contributing, in acomplex manner, to dysregulation of di-abetes and its instability of control.

The clinical disorders of gastricsecretion and motility, which have beendiscussed above, are largely mediated bythe hormone gastrin, which is central tothe control of acid secretion, the growthand replication of cells in the stomachand upper small bowel, and motility ofthe stomach. In humans, gastrin secre-tion is regulated partly by the sympa-thetic nervous system (300) but is alsounder tonic inhibitory control by the va-gus (313). High fasting and postprandialconcentrations of this hormone are ob-served in diabetic patients with cardiacautonomic neuropathy (279,313) andgastroparesis (276). The consequences ofthese findings are not clear, but mistakendiagnoses of a gastrin secreting tumor isnot unusual. High gastrin levels also maybe attributable to loss of acid secretion,which is found in patients with the vari-ety of IDDM associated with autoimmu-nity, antibodies to gastric mucosa, andatrophic gastritis.

The rhythmic neuronal dischargecoupled with pressure waves known asthe interdigestive myoelectric complex islost in patients with gastroparesis anddiabetic enteropathy (281). Coupledwith this rhythmic pressure change,which proceeds from the esophagogas-tric junction distally, is a rhythmic re-lease of PP and motilin. This latter hor-mone qualifies as the "sweeper of thegut" and may have an important role inclearing the intestine during the interdi-gestive period. Although we reportedthat the responses to hypoglycemia wereimpaired in diabetic patients with auto-nomic neuropathy (314), thus resem-bling the observations in vagotomizedpeople, more striking was the observa-tion that the rhythmic oscillations per-sisted in the hormone at levels consider-

ably higher than those in normal subjects(281,300). This is one of the rare situa-tions in which a gut hormone is overse-creted in autonomic neuropathy, and itsrhythmicity is retained. The heightenedsecretion rhetorically seems to be an at-tempt of the body to increase the secre-tion of the motility factor when intrinsicneuronal control is failing. However, animportant regulation by insulin occurs(315), and the flacid bowel found in un-controlled diabetes may be a conse-quence of this effect of insulin on guthormone secretion. The impact of insu-lin and hyperglycemia on neurohormon-ally mediated gut function is fascinatingand deserves further investigation.Genitourinary tract disturbancesNeurogenic vesical dysfunction—The earli-est and most frequent form is loss ofbladder sensation, and the patient is un-aware that the bladder is full. Motorfunction tends to remain intact, and theusual problem is dribbling with overflowcontinence. One often is surprised whenexamining such people to find a bladderat the level of the umbilicus of which thepatient is entirely unaware.Impotence—The most common form oforganic sexual dysfunction in male dia-betics is erectile impotence. Unfortu-nately, many physicians shy away fromasking about the issue. Up to 75% ofmale patients who have had diabetes for15-20 yr suffer some degree of erectileimpotence. In evaluating such patients, itis important to exclude pyschogeniccauses. Impotence associated with or-ganic causes may be differentiated by itsgradual onset, association with the lossof nocturnal erections, and uniformitywith all partners. Vascular causes can beexcluded by a history of buttock claudi-cation and by using Doppler ultrasoundto determine the penile/brachial arterialratio. If vascular and pyschogenic causesare excluded, neuropathic impotencemay be detected by clinical examinationof perianal sensation, (stroking alongside the anus and watching the anus con-tract [the anal wink reflex]) or, applyingpressure to the glans penis, which causes

a reflex contraction of the anal sphincter.These reflexes and sensations are lost inautonomic neuropathy because of paral-lel loss of somatic and autonomic sacralsegments 2, 3, and 4.Retrograde ejaculation—Retrograde ejacu-lation may be diagnosed by the presenceof azoospermia in the ejaculate or thefinding of live motile sperm in the urinepostcoitus. This diagnosis may be impor-tant to the relatively young diabetic pa-tient who desires to procreate, in whichinstance, sperm may be recovered fromthe urine, and artificial insemination ofthe prospective mother conducted.Sweating disturbances. This is a sudo-motor dysfunction characterized by dis-tal anhidrosis and bilateral symmetricalloss of the thermoregulatory response.This may be troublesome to patients whodo not perspire in their lower limbs andhave as a reflex excessive perspiration ofthe upper body and face.Hypoglycemia unawareness and unre-sponsiveness. In nondiabetic individu-als, a fall in blood glucose concentrationis attended by an outpouring of EPI, glu-cagon, growth hormone, and cortisol(314). The initial response to hypoglyce-mia is bradycardia and a slight fall inblood pressure, followed by a sympa-thetic discharge and the appearance ofadrenergic symptoms such as sweating,diaphoresis, and palpitations. In 1963,Sussman (316) observed that patientswith long-standing diabetes may losetheir sensitivity to hypoglycemia andcoined the term hypoglycemia unrespon-siveness. Unawareness of a severe hypo-glycemic reaction is because of bluntingof the EPI responses to hypoglycemia, aconsequence of autonomic neuropathy(306,307,310,317,318). Affected pa-tients lose their early warning and mayfail to take appropriate preventive mea-sures until neuroglycopenic symptomssupervene, which is often times too latewhen coma occurs. These people maynot be suitable candidates for intensifiedinsulin therapy (310,319), and cautionin aggressive management is prudent,despite being contrary to the notion that



improved diabetes control is an impor-tant component of reversing neural dys-function. Diminished glucagon responseto hypoglycemia also may occur in af-fected patients (311,315,316,320-322).Because the combination of EP1 and glu-cagon deficiency are potent mechanismsfor the loss of the counterregulatory re-sponse to hypoglycemia (318), these pa-tients may experience both a steeper fallin blood glucose and protracted hypo-glycemia, as they are unable to return theblood glucose to near-normal levels. Thismay be an important and prominentcause of erratic control of diabetes, butnot everyone concurs. It should benoted, however, that patients with dia-betes who have been intensively treatedwith either pump therapy or intensiveconventional therapy also have a similarreduction in EPI and glucagon responsesto hypoglycemia (319) and thus presentwith a profile that may be difficult todistinguish from autonomic dysfunction.This distinction must be made, however,because it is critical that the former pa-tients not be overheated, and their con-trol not be managed as strictly as patientswith intact glucose counterregulatory re-sponses.

HAAF. Three hypoglycemia-associatedclinical syndromes in individuals withIDDM—defective glucose counterregu-lation, hypoglycemia unawareness, andelevated glycemic thresholds for symp-toms, and activation of counterregula-tory systems during effective intensivetherapy—have much in common. Theysegregate together, are associated with anincreased frequency of severe iatrogenichypoglycemia, and share several patho-physiological features, including reducedautonomic nervous system responses to agiven degree of hypoglycemia. These in-clude reduced (elevated glycemic thresh-olds for) sympathochromaffin (EPI) andparasympathetic (PP) responses. In thesetting of reduced (often absent) gluca-gon responses, the reduced adrenomed-ullary EPI responses play a key role inthe pathogenesis of iatrogenic hypogly-cemia in affected patients. Thus, these

syndromes are examples of HAAF inIDDM, a disorder distinct from classicaldiabetic autonomic neuropathy. The re-cent finding that short-term antecedenthypoglycemia results in reduced symp-tomatic and autonomic, including adre-nomedullary, responses to subsequenthypoglycemia in nondiabetic humanssuggests that one potential pathogeneticmechanism is recent antecedent iatro-genic hypoglycemia that reduces bothsymptoms of and defenses against devel-oping hypoglycemia, resulting in recur-rent severe hypoglycemia, thus creating avicious cycle.

HAAF appears to be distinctform of classical diabetic autonomic neu-ropathy in several ways. First, the twodisorders do not cosegregate, i.e., theytend to occur in different patients(311,322-332). Second, in HAAF thedeficient autonomic responses appear tobe specific for the stimulus of hypogly-cemia (148,328,333), whereas reducedsympathetic and parasympathetic re-sponses to multiple stimuli characterizeclassical diabetic autonomic neuropathy(324,325). Third, whereas substantiallyreduced adrenomedullary EPI responsesto a given degree of hypoglycemia are acentral feature of HAAF (148,301,310,322-338), plasma EPI responses are re-duced little, if at all, in classical diabeticautonomic neuropathy. AlthoughHilsted et al. (324,325) found slightlylower EPI responses to hypoglycemia inpatients with, compared with those with-out, classical diabetic autonomic neurop-athy, the EPI responses of the formerpatients were greater than those of non-diabetic control subjects. This is consis-tent with evidence that classical diabeticautonomic neuropathy is largely an ax-onal lesion (339,340), probably the re-sult of nerve fiber loss. Fourth, in sharpcontrast with HAAF, clear evidence in-dicates that classical diabetic autonomicneuropathy does not cause excessive iat-rogenic hypoglycemia in IDDM (341-344). Fifth, recent data (345-347) sug-gest, but do not prove, that HAAF mightbe, at least in part, reversible for reasons

discussed shortly. No evidence suggeststhat classical diabetic autonomic failureis reversible.Lowered glycemia thresholds. With re-cent attempts at intensification of ther-apy to achieve lower blood glucose levelsin people with IDDM, it appears thatblunting of the responses to hypoglyce-mia may occur with lowering the thresh-old. Indeed, a single episode of afternoonhypoglycemia has been shown to reducethe symptomatic and neuroendocrine re-sponse to a given degree of hypoglycemiathe following morning (255,326,335). Ithas been suggested that a poor correla-tion exists between altered thresholds,unawareness of hypoglycemia, and thepresence of diabetic autonomic neurop-athy (324). It has thus been postulatedthat the defective glucose counterregula-tion, hypoglycemia unawareness, and el-evated glycemic thresholds during effec-tive therapy cosegregate in the samepatient, they are associated with high fre-quency of iatrogenic hypoglycemia andhave reduced autonomic responses to agiven degree of hypoglycemia. Thesehave been grouped together by Cryer etal. (333) as HAAF to be distinguishedfrom autonomic neuropathy on the fol-lowing basis: They do not cosegregate.All responses are reduced in autonomicneuropathy, whereas only those to hypo-glycemia are impaired in HAAF. EPI re-sponses to hypoglycemia are relativelyunimpaired in autonomic neuropathybut are uniquely impaired in HAAF. Incontrast to HAAF, little evidence indi-cates that autonomic neuropathy con-tributes to iatrogenic hypoglycemia, andHAAF appears to be in part reversible.Therefore, it seems that the vicious cycleis initiated by repeated episodes of hy-poglycemia that reset the threshold forthe response, thus generating further ep-isodes of hypoglycemia and failure of thenormal counterregulatory response.

Autonomic symptoms (anxiety,palpitations, sweating, irritability, andtremor) began at 58 ± 2 mg/dl, whichwas significantly (P = 0.0001) lower.Neuroglycopenic symptoms (hunger,



dizziness, tingling, blurred vision, diffi-culty thinking, and faintness) and dete-rioration in cognitive function tests be-gan at 51 ± 3 and 49 ± 2 mg/dl.

The studies by Cryer (348) andGerich (337) yielded identical thresh-olds for symptoms (—3.0 mM) and forglucagon and EPI release (—3.9 mM) innormal subjects.

To test for the presence of thesesyndromes requires elaborate and expen-sive equipment and is best done in aresearch environment. For the sake ofcompleteness they are described here.The stepped hypoglycemic clamp tech-nique, applied to normal subjects(337,348) and IDDM patients (330), hasbeen described in detail. Briefly, after anovernight fast (and overnight i.v. insulininfusion to achieve near euglycemia be-fore the test in IDDM), insulin (2.0Mu • kg"1 • min"1) is infused continu-ously and an i.v. glucose infusion is var-ied either to maintain euglycemia (5.0mM) throughout (euglycemia control) orto achieve hourly glucose clamps of 5.0,4.4, 3.9, 3.3, and 2.8 (or even 2.2) mM.Symptoms and hormone responses areassessed at the end of each glycemic step.Cognitive function also can be assessed(337,349). The test is labor intensive re-quiring a minimum of two people (typ-ically a physician and nurse); a third per-son is needed if cognitive function isassessed. It also requires accurate glucosemeasurements (with a Beckman or YSIanalyzer, not with a glucose monitor) atthe bedside and the analytical capacity toperform the hormone measurements.Cognitive assessment generally requires acollaborating psychologist.

DIAGNOSIS OF DIABETICNEUROPATHIES

Clinical evaluationA thorough clinical examination withspecial attention to the feet, examiningfor dryness, shiny skin, cracking of theskin, ulceration, loss of hair, levels of lossof sensory modalities with particular no-tice of vibratory sensation, reflexes, and

motor power is essential in the evalua-tion of patients suspected of neuropathy.It must be emphasized, however, that theclassic neurological examination is basedon the clinician's interpretation of thepatient's response to standard questionsand procedures. The clinician makesskilled but entirely subjective judgmentsconcerning such aspects as motor func-tion, sensation, and reflexes. Typically,such judgments involve decidingwhether signs are present or not orwhether a specific function is normal orabnormal.

Diabetic neuropathy is diagnosedby exclusion of various other causes ofneuropathy. Systematic questioning, in-cluding family history of nondiabetic pe-ripheral nerve disease and the presenceof toxic, metabolic, mechanical, and vas-cular causes of nerve disease, should beconducted. If any other potentially neu-ropathic factors are present, other diag-nostic methods should be used to deter-mine the etiology of nerve disease. Someof the disorders to be considered includenutritional deficiencies, collagen vasculardisease, malignancies, tabes dorsalis,toxin exposure (e.g., alcohol, occupa-tional toxins, vitamin B6, and medica-tions known to be associated with pe-ripheral neuropathy [dilantin therapy fordecades, nitrofurantoin, amiodarone,metronidazole, vincristine, cisplatinum,taxol]), hypothyroidism, perniciousanemia, dysproteinemias, amyloidosis,AIDS, chronic idiopathic demyelinat-ing neuropathy, spinal cord disease,cauda equina syndrome, and other me-chanical conditions that damage pe-ripheral nerve tissue. Appropriate lab-oratory screening for these disordersshould be performed.

To aid in the assessment of neu-ropathy during a clinical exam, codedexaminations of neurological functionhave been developed that allow assign-ment of broad categories of functionalabnormalities based on the clinical ex-amination (1 = normal; 2 = mild ab-normality; 3 = moderate abnormality;4 = severe abnormality; and 5 = total

loss of function). Both signs and symp-toms may be scored. Such ordinal ratingsmay be invaluable as evaluation tools inclinical studies of neuropathy, but, un-fortunately, these are all that are avail-able in a typical examination situation.In addition, in many instances, thesesorts of nominal or ordinal ratings areoften too restrictive to detect reliablysmall but clinically relevant changes infunction.

The quantification of symptomsis probably best accomplished by usingsome version of the Lekert scale, whereintensities of the sensation may be ratedon a numerical scale by the patient. Sucha scale typically would have as its endpoints 0 intensity (not present) and somerepresentation of a maximum possiblevalue. This maximum value often pre-sents a difficulty, as patients may havedifficulty relating any verbal descriptionof maximum intensity of a sensation tothe sensation that they experience. Sucha scoring system should allow the patientto rate the pain present over a period oftime without recourse to comparisonwith previous records. Otherwise theevaluation of minimal changes may againbe fraught with difficulty in interpreta-tion, as the patient's expectancy effectswill begin to play a crucial role.

Equally important and neglectedin the routine physical examination arethe functional correlates of nerve impair-ment. An activity instrument to measurethe functional impact of neuropathy hasbeen developed by us, which measuresthe degree of restriction associated with anumber of daily tasks, including the abil-ity to put on a shirt, button a shirt,squeeze toothpaste, use a fork, turn thepages of a book. These timed tests havenot been widely applied in the evaluationof diabetic neuropathy and offer a meansof evaluating restriction of activities thatare of vital importance to the patient.The broad battery of neurological teststhat has now evolved for the assessmentof neural impairment in diabetes willlead to a better understanding of the nat-



ural history and epidemiology of neurop-athy.

Electrophysiological testing indiabetic neuropathyElectrophysiological testing plays an im-portant role in detecting, characterizing,and measuring progress of the differentforms of diabetic neuropathies. Neurop-athy in diabetes may preferentially affectdifferent types of nerve fibers such aseither the small unmyelinated or thinlymyelinated fibers or the larger, moreheavily myelinated fibers (350). Nerveconduction studies involve stimulationof either motor or sensory nerves withsubsequent recording of either a sensoryor a compound motor action potential.Evaluation of several parameters, includ-ing latency, conduction velocity, andamplitude, is helpful in determining thetype of fiber involvement. The amplitudeof the evoked response is a function ofthe number and size of nerve and musclefibers and may be decreased in axonop-athies. Amplitude reduction, however,also may be seen when the range of con-duction velocities is greater than normal,causing temporal dispersion of the re-corded response. In these cases, mea-surement of the area under the curvemay be a more accurate reflection of ax-onal number and size (351).

Conduction velocity provides ameasure of transmission time in the larg-est myelinated fibers. Transmission timemay be influenced by numerous factors,including fiber size, degree of myelina-tion, nodal and internodal length, axonalresistance, and temperature (352). In dif-fuse neuropathies, slowing of conductionvelocity may become more apparent ifmeasurement is obtained over long nervesegments. F-response latency measure-ment, which includes conduction overthe entire motor nerve, is thus a sensitivemethod/or detecting neuropathy (353).F-wave latencies also provide a means ofassessing proximal motor nerve function,which may be useful in conditions suchas diabetic amyotrophy (354). Conduc-tion studies also may help identify and

localize focal lesions within a nerve bydemonstrating localized slowing or con-duction block, both of which may occurin diabetic neuropathy. This is helpful,especially when coincident entrapment isapparent, as in the carpal tunnel or tarsaltunnel, to which diabetic individuals aresusceptible.

Needle electromyography shouldbe used in conjunction with nerve con-duction studies in the evaluation of dia-betic neuropathy. Although quantifica-tion of abnormalities of motor units maybe difficult and less reliable than mea-surements of nerve conduction, recogni-tion of fibrillation potentials in musclesat rest is often straightforward and lesssubject to individual interpretation. Fi-brillation may be the most sensitive in-dicator of axonal degeneration and maybe present in asymptomatic patients,preceding other clinical or electrophysi-ological evidence of neuropathy (355).

The needle examination is alsohelpful in determining the distribution ofnerve involvement in various diabeticconditions. EMG, for instance, is theelectrodiagnostic study of choice in theevaluation of diabetic polyradiculopathy(356,357) and provides important infor-mation in the assessment of proximalmotor neuropathy (354,358) and plex-opathy.

Additional quantitative testingcan be done with single fiber electro-myography, which allows measurementof muscle fiber density and evaluation ofneuromuscular transmission (352). Mus-cle fiber density is increased in cases ofaxonal loss with subsequent reinnerva-tion by collateral sprouting. Ongoingcollateral sprouting also may be assessedquantitatively by the jitter, which reflectsneuromuscular transmission.

Other modalities that are usefulin the evaluation of diabetic neuropathy,but which may not be available at allcenters, include near-nerve recording,somatosensory evoked potentials, or re-petitive stimulation with measurement ofrefractory periods.

The utility of electrophysiological

testing lies in its reliability and reproduc-ibility. Furthermore, these are measure-ments that are largely independent ofpatient cooperation and are reproducibleamong different examiners in differentcenters. They also have been shown toplay an important role in studies evalu-ating disease progression or regressionand the response to medical treatment(359,360). Data are available to supportthe notion that electrophysiological testscorrelate well with nerve biopsy data onhistology.

It is, however, important whenperforming these tests to control forsources of error (9). One factor of par-ticular importance is that of limb tem-perature. Amplitude, latency, and con-duction velocity all vary with limbtemperature (351). As the limb cools,less dispersion of the evoked responseoccurs, and the amplitude subsequentlyincreases. At the same time, decreases inconduction velocity and increases in dis-tal latencies are seen. It is generally rec-ommended, therefore, that limb temper-atures should be kept at 32-36°C (355),with warming of limbs occasionally nec-essary to maintain them in the idealrange. It may be difficult in some patientsto maintain proper temperature second-ary to ischemia or denervation, in whichcase corrections may be made as outlinedin other texts (355).

Electrophysiological findings indiabetic neuropathyA brief discussion of the electrophysio-logical abnormalities in the various neu-ropathic states will be given.Subclinical neuropathy. It has beenwell-demonstrated that abnormalities ofboth nerve conduction studies and EMGoccur in many neurologically asymptom-atic diabetic patients. In fact, these find-ings may be found before the diagnosisof diabetes (361). NCVs in this grouphave mean values 10-30% below thenormal (352). Reduction of amplitudealso is found, particularly in sensorynerves. Sensory action potentials and so-matosensory evoked responses have



been shown to be more sensitive thanmotor studies in detecting early nerveinvolvement (362,363).

Lower extremity distal nerves, inparticular, the peroneal and sural nerves,frequently show the most significant ab-normalities (77,364). Studies of proxi-mal nerve function such as somatosen-sory evoked responses and F-wavetesting may show changes as well, some-times exceeding abnormalities in moredistal segments (353).

The presence of fibrillations po-tentials on EMG, especially in the intrin-sic foot muscles, also may be found inthe asymptomatic diabetic patient, re-flecting axonal loss.Painful neuropathies. Painful neuropa-thy may develop in the diabetic patientin which the symptoms predominantlyconsist of pain and dysesthesias. Neuro-logical deficit may be minimal or absentconsistent with small fiber involvement.It is not surprising, therefore, that nerveconduction studies show either mild orno abnormalities, similar to findings inasymptomatic diabetic patients (57).These tests, therefore, are useful to iden-tify a subset of patients destined to belowsymptomatic and who would benefitfrom treatment.Symptomatic diffuse symmetrical pe-ripheral neuropathy. Once symptomsdevelop, electrophysiological testing re-veals even more significant abnormalitiesof both sensory and motor nerves than isfound in asymptomatic patients. De-creased amplitudes of sensory nerve ac-tion potentials are the most frequentlyseen disturbances. Evoked responsesmay be so small that signal averagingtechniques are needed to record the po-tentials. Plantar nerve responses tend tobe lost first (364), followed by the suraland superficial peroneal nerve responses.

Mild to moderate reduction inconduction velocities in motor and sen-sory nerves and mild prolongations ofdistal latencies frequently are observed(352). F-wave latencies typically areslightly prolonged, and fibrillation po-tentials are frequently noted in the in-

trinsic foot muscles and occasionallyelsewhere, such as the paraspinal mus-cles.Diabetic amyotrophy. Diabetic amyot-rophy, the electrodiagnostic abnormali-ties characteristic of amyotrophy gener-ally are superimposed on a diffusesymmetrical peripheral neuropathy(365). The typical findings include dis-turbances of proximal motor function.F-wave latencies are frequently absent orsignificantly slowed out of proportion tomore distal peripheral nerve abnormali-ties (354,358). EMG changes are alsoprominent with fibrillations recorded inmost proximal lower extremity muscles,especially those innervated by the L2through the L4 nerve roots (358). Wide-spread fibrillations also are noted in theparaspinal muscles at many levels, differ-entiating diabetic amyotrophy from lum-bar monoradiculopathy. Reduction in re-cruitment of motor units also isfrequently noted, consistent with a neu-ropathic process.

Focal neuropathies. Identification of amononeuropathy can be difficult when adiffuse peripheral neuropathy is alsopresent. This matter is simplified if aconduction block is present, however,usually the examiner must make the di-agnosis based on focal slowing of con-duction, which is out of proportion tothe slowing seen in other parts of thenerve or in other nerves either in thesame or opposite extremity.

Mononeuropathy, which also oc-curs in the peroneal nerve with axonalloss (92), leads to reduction or loss ofcompound muscle action potentials andsensory nerve action potentials. Conduc-tion velocity, when measurable, is lessseverely affected. Fibrillations typicallyappear 10-14 days after the onset andmay be followed by the appearance ofpolyphasic potentials as regeneration andsprouting occur (351).

Focal radiculopathies may alsopresent in the thoracic region of diabeticindividuals, causing pain in the back,abdomen, or chest (356). For these pa-tients, electromyography is the only way

of identifying this condition, by detect-ing fibrillations in the involved paraspi-nal muscles. These abnormalities are uni-lateral and localized, differentiating thisdisorder from diabetic amyotrophy inwhich the clinical and electromyographicfindings are more widespread and oftenasymmetric.

In conclusion, nerve conductionstudies and electromyography play animportant role in the detection and char-acterization of many of the diabetic neu-ropathies. Studies should be individual-ized to the patient's clinical diagnosisand examination to provide meaningfulinformation regarding the underlyingprocess.

Quantification of cutaneoussensitivityQST is the determination of the sensorythreshold, defined as the minimal energyreliably detected for a particular modal-ity. It is a logical extension of the sensoryportion of the clinical neurological exam-ination and has the principal advantageof assigning a numerical value. Recentyears have seen the development of anumber of relatively inexpensive devicesthat allow suitable assessment of somato-sensory function, including vibration,thermal energy, and light touch.

QST can be used to documentsubtle sensory loss, characterize patientsat the onset of a clinical trial, and mon-itor a modality known to be associatedwith a specific complication of diabeticneuropathy (366-368). The evaluationcontributes to the differentiation of therelative deficit in small (e.g., tempera-ture) versus large (e.g., vibration) diam-eter axons, and polyneuropathy versusmononeuropathy.

Calibration and units of measureshould be expressed in standard termi-nology such as |xm (vibration), °C (tem-perature), and dynes/cm2 Gight touch);and the physical dimensions of stimula-tion (e.g., waveform, frequency, rise-time) should be reported.

Two testing procedures areemerging as the standards in the field: 1)



modified up-down stimulation with twoalternative forced-choice responses; 2)ramping of stimulus intensity (method oflimits) combined with yes-no paradigm(369). By using the first procedure, themost common definition of threshold isthe stimulus intensity corresponding tothe 75% correct response point. For thesecond procedure, threshold is usuallydefined as the stimulus intensity corre-sponding to 50% correct detection. Tobe acceptable, the two alternative proce-dures must allow sufficient reversals toconverge on a true threshold. The yes-noparadigm must include catch trials(where stimulus is not delivered) in suf-ficient numbers and variable ramps tominimize guessing. More details con-cerning the different psychophysicalmethods, response paradigms, and theircritical evaluation can be found in Mau-rissen (370).Modalities measurable.Vibration-perception testing—This mea-sure is the most widely studied QST pro-cedure and is associated with the mostextensive normal and neuropathy databases. If frequencies of 120-200 Hz areused, it principally assesses function inMeissner and Pacinian corpuscles andtheir associated large-diameter fibers.Typical sites of assessment are the gla-brous skin of the fingers and toes.Thermal-perception testing—This mea-sure assesses function in free-nerve end-ings and their associated unmyelinatedand thinly myelinated fibers. The valueand reliability of this measure is en-hanced by separately assessing warm andcold perception. Although thermalthresholds have proved especially vari-able, they uniquely index small fiber dys-function (371).

Light touch—Quantitative esthesiometrytechniques require a relatively sophisti-cated stimulus delivery system. Thismeasure tests the integrity of Merkeltouch domes and Meissner corpusclesand their associated large-diameter fi-bers. The expanded use of this techniquein assessing diabetic neuropathy will be afunction of the anticipated increased

availability of devices specific for thismodality.

In addition to the above modali-ties, QST procedures are available forpain thresholds and cutaneous currentperception (372). Pain thresholds testnociceptors and C fibers. Although theymay be important for selected studies,the committee felt they should not beincluded in a general assessment of dia-betic neuropathy because of subject dis-comfort and the limited experience inmulticenter trials. Current perception as-sesses the detection threshold for sinewave stimuli produced by a constantcurrent generator and delivered to theskin through surface electrodes. Noknown receptors exist for electrical cur-rent, and this form of stimulation ap-pears to excite directly the cutaneous ax-ons. Multiple frequencies have beenreported to excite different neuronal sub-groups, but this claim awaits validation.Studies in diabetic individuals suggeststrong correlations with other QST mea-sures (367,373), however, additionalstudies are required to explore the spec-ificity and sensitivity of current percep-tion for the assessment of diabetic neu-ropathy.

Strong correlations betweennerve conduction indexes and QST, andbetween sensory symptom status andQST, have been reported (374-376). Byusing electrophysiology and symptomsto identify neuropathic patients, a de-fined elevated vibration threshold wasassociated with a sensitivity of 73% and afalse positive rate of 7% (374). Asymp-tomatic diabetic patients have signifi-cantly higher thresholds than nondia-betic individuals, suggesting that QSTmay be useful to detect subclinical neu-ropathy.

Average intrasubject CVs for nor-mal subjects have been reported as lowas 7-10% for vibration perception. Indiabetic subjects, CVs for vibrationthresholds are on the order of 10-20%,whereas levels >20% have been ob-served for thermal thresholds.

To thoroughly assess the neuro-

logical state of patients presenting withclinical signs or symptoms of a periph-eral sensory neuropathy, the level of af-ferent neural function of the peripheralskin is an essential concern. Recent tech-nological advancements have providedmore sophisticated measures of some di-mensions of sensory function. Variousinstrumented equipment is now avail-able for the detection of impairment inthermal sensitivity and vibration percep-tion, as well as electrical current, pres-sure, and pain perception. These types ofinstruments allow for cutaneous sensoryfunctions to be assessed noninvasively,and their measurements are by definitioncorrelates of specific neural fiber func-tion. The proper application of these in-struments will lead to advances in de-scribing cutaneous sensitivity with thelevel of detail necessary to make infor-mation concerning the magnitude of im-pairment of different cutaneous sensorymodalities useful to both the researcherand the clinician. Information concern-ing fiber specificity and progression ofsensory neuropathies cannot be fully as-sessed until advances in the quantifica-tion of cutaneous sensory function areput to use in both research and clinicalassessments of sensory neuropathies.The use of standardizable equipment todetermine levels of cutaneous sensitivityprovides distinct advantages over other-wise-derived assessments, primarilythrough its allowance for improvementsin scaling techniques, and more exactingand standardized methods of stimuluspresentation and response.Scaling techniques—The use of standard-izable, instrumented equipment allowsthe assessment of sensory gradation toachieve an interval scale, a marked im-provement over the nominal or ordinalscales possible in the typical clinicalexam. The use of proper equipmentalone is capable of accomplishing an in-terval scale. For example, instrumentedmachinery currently allows for thermalsensation to be described as the mini-mum temperature difference betweentwo distinct stimuli necessary to produce



a perceptual event of a magnitude thatallows the perceiver to correctly identifythe relative temperature of the two stim-uli. In this manner, it is possible to arriveat a difference threshold that is measuredin °C, which in itself represents a sub-stantial advancement from the skilledbut subjective clinical rating of thermalsensation as being "normal" or "abnor-mal", "present" or "absent", or even anominal scale such as impairment levelsfrom 0 to 4. The units in an interval scaleadvance sequentially as the amount ofstimulus increases, and they refer to anexternally identifiable scale that has pre-cisely uniform intervals (hence the terminterval scale). The advantages of usingstandardizable equipment to achieve aninterval scale are essentially fourfold(377-379).

Initially, the use of instrumentedequipment that achieves assessments onan interval scale almost entirely removesthe subjectivity of the examiner, becausethe instrumentation of the equipment it-self provides the rating that will be as-signed. Secondly, it greatly enhances thepossibility of observing changes in sensi-tivity of the tissue under investigationover time, primarily because of the inclu-sion of a much larger number of possiblescores or ratings than can be found in theordinal or nominal ratings of the typicalclinical exam. Thirdly, the use of a stan-dardized interval scale can allow for agreater level of confidence when assess-ing the extent of a sensory deficit. Forexample, the extent of neurological dam-age that separates "mildly impaired" tis-sue from "severely impaired" tissue isdifficult to define, particularly if theseratings come from different raters. How-ever, if the sensitivity of some particulartissue allows a subject to consistentlyidentify a minimum difference of 3°Cbetween two stimuli, that is quantifiablydifferent from the ability of some tissueto allow the subject to identify a mini-mum difference of 15°C. This sort ofquantification allows for a description ofthe sensitivity of the tissue to thermalstimuli in which the extent of apparent

neurological deficit of the less sensitivetissue is reflected as a decrement of func-tion equal to 12°C. Lastly, this sort ofscaled quantification also allows for thedefinition of normal tissue sensitivitywith its levels of variability between sub-jects using descriptive statistics; andgiven this definition of normal sensitiv-ity, it becomes feasible to determine asensitivity level beyond which the tissuecan be confidently classified as being ab-normal to a specific extent. These aspectsof interval scaling are necessarily of cru-cial importance in research, but eventu-ally, they also will allow for the clinicianto assess particular treatment needs andefficacies more easily and accurately.Methods of stimulus presentation and re-sponse—For many years, perceptual the-orists from many disciplines have beenattempting to explain an all too commonphenomenon that has plagued percep-tual research: perceptual thresholds al-most never appear to be completely con-sistent, even when interfering stimuli arethought to be well controlled (380,381).As long ago as 1888, Joseph Jastrow(382) acknowledged that a number ofpsychological variables are likely to affectthe measurement of perceptual thresh-olds. Attention, fatigue, and practicewith identification of a stimulus are themost obvious psychological state vari-ables that may account for some of thesefluctuations within individuals. Numer-ous relevant personality variables may beof even greater concern when makinginferences concerning differences be-tween individuals or groups of individu-als, as these differences can exist in evengreater intensities as state and trait vari-ables intrinsic to individuals or groups ofindividuals. When coupled with the de-mands of an experimental or diagnostictask, these personality variables maycause unacceptable variance in percep-tual measures (383-385).

The variance that may be derivedfrom any of these nonphysiologicalsources must be held to an absolute min-imum to make valid inferences about thephysiology of individuals or groups

based on their perceptual performance.The inferences made by researchers gen-erally are concerned with group perfor-mance, whereas the clinician is typicallymore concerned with describing individ-ual performance in an effort to diagnoseand treat the individuals. For either toadequately achieve sensory results thatare of meaning, the adoption of a methodof stimulus presentation and responsethat will accomplish sensory thresholddetermination with optimum precisionand accuracy becomes a necessity. Nu-merous methods are available from pastand current research in perception, andeach has fairly distinct advantages anddisadvantages (378,379).

In discussing the various meth-ods available, the manner in which thestimulus intensity is varied or adjustedfrom trial to trial is a primary concern.Variations of the method of limits (as-cending, descending, single, and multi-ple passes) tend to give quick but oftencrudely rough estimates of absolute anddifference thresholds (378,379). Themethod of constant stimuli tends to yieldmore accurate estimates of sensorythresholds; however, arguments con-cerning its efficiency in terms of accuracyper number of stimulus presentations re-main unresolved (386,387). Arguably, toassure appropriate administration, algo-rithms that use the method of constantstimuli will typically require a ratherlarge number of stimulus presentationsto achieve optimum accuracy, and,thereby, may become exorbitantly timeconsuming for the clinician and mayeven impinge on fatigue and attentionalvariables (382). Signal detection theory(377,388) offers the ability to observeand quantify both the ability of a subjectto detect a stimulus and guessing behav-ior of the subject on dichotomousforced-choice trials. However, it also typ-ically requires a large number of trials,and it assumes an advanced level ofknowledge of the mathematical tech-niques involved in the quantificationprocess of both of the constructs that it



measures for interpretations of results tobe valid (389).

Various other methods have beendescribed. Magnitude estimation(378,390) may indeed be the most effec-tive method for analyzing suprathresholdsensitivities, such as difference thresh-olds necessary in the assessment of ther-mal sensation (391). Various matchingtechniques within and across modalitiesalso show promise for suprathreshold as-sessments of differential sensitivity (390,392,393).

An adaptive model commonlyknown as the staircase method was firstdescribed by Bekesy (394) for use in au-ditory assessment. It is essentially an al-teration of the method of limits, withstimulus intensities tracking the thresh-old, and it may be considered as a clin-ically appropriate compromise. It incor-porates some of the aspects of both themethod of limits and method of constantstimuli, and if a forced-choice model ofstimulus response is incorporated into it,some of the principles of signal detectiontheory may remain applicable to the re-sults obtained. Additionally, staircasemethods allow for the observer to assessadaptation that may occur within a mo-dality over a single testing session,whereas none of the other methods easilyallow for this type of assessment to occurdirectly.

To reduce the variance that maystem from intersubject differences in re-luctance to report a mild perceptualevent, it is highly desirable to incorpo-rate a forced-choice method of responsesto stimuli into any method of stimulusadjustment that may be used (378,379).When attempting to identify absolute(perceptibility) thresholds, a forced-choice method is made possible throughtrials that include the presentation ofnull (n > 1) and positive (usually n = 1)stimuli, and the subject is required toidentify the positive stimulus. With dif-ference thresholds, which are particu-larly necessary with thermal perception,a forced-choice method is made possibleby the use of two or more separate stim-

uli of differing temperatures, and thesubject is required to identify the relativetemperature of stimuli (i.e., report whichare warmer or colder than others). Whenusing a forced-choice paradigm, levels ofstimulus intensity that are near or at100% correct performance are clearly su-prathreshold, whereas intensities atwhich performance falls to near or belown (positive stimuli)/n(all stimuli) accuracyare inter- or subthreshold.A proposed algorithm—The blending offorced-choice responses into a staircasemethod of stimulus adjustment for de-termination of an absolute detectabilitythreshold will result in an algorithm thathas many of the following characteristics.

To establish an initial range ofstimulus intensities within which to be-gin forced-choice adaptive staircasing,multiple passes that use both ascendingand descending method of limits mayfirst be used in an effort to locate a rangeof stimulus intensities that appears toinclude the threshold. The upper limit ofthis range should represent the loweststimulus that is clearly suprathreshold.The lower limit of this initial rangeshould represent the highest stimulus in-tensity that is clearly subthreshold. Thisrange would correspond to the intervalof uncertainty in the typical method oflimits algorithm (379).

To more accurately assess thethreshold intensity and to achieve a sin-gle number as a threshold estimate, theinitial interval of uncertainty may be di-vided into a serially incremented set ofstimulus intensities, any of which may beused as intensity levels for future stair-cased stimulus presentations. The sim-plest sorts of rules for this incrementingwould be to merely divide the initial in-terval of uncertainty by a set number, orto use a predetermined increment withinthe interval of uncertainty. Note that themagnitude of these increments maylimit, in part, the accuracy of the thresh-old determination or force an unneces-sarily large number of stimulus presen-tations. In addition, if inferences are tobe made concerning the interval of un-

certainty itself, then the stimulus incre-ments should be similar across all testingsessions about which inferences are to bemade.

The starting point for staircasingmay be at any point within, above, orbelow the initial interval of uncertainty,with a number of concerns affecting thatdecision. Chief among those concerns isthe allowance for practice effects andconcerns over the number of trials thatone is willing to present before reachinga change in the direction of stimulusadjustments. The staircased, forced-choice trials then may be presented, withstimulus intensities being lowered after ntrials, where n = number of correct re-sponses achieving or surpassing a targetlevel of probability that a subject couldhave randomly achieved success at alevel. Stimulus intensities are converselyraised as a result of incorrect responsesby a set unit, depending on the targetlevel of correct performance. Note thatparticularly low target levels of correctperformance may result in psychologicalfatigue and even antagonistic effects, assubjects may tend to resent what canamount to multiple unsolvable problems(395).

The trials continue, with intensi-ties being adjusted according to the sub-ject's performance and any applied rulesfor attaining some desired level of per-formance. The session may be termi-nated according to any of the followingrequirements: ]) the subject has com-pleted a set number of trials that shouldinclude some minimum number ofchanges in the direction of stimulus in-tensity adjustments; 2) the stimulus in-tensity adjustments have changed direc-tion some minimum number of times; or3) the subject has achieved some desiredlevel of performance which, by defini-tion, includes a minimum number of tri-als; or 4) any of a number of additivecombinations of 1, 2, or 3.

The threshold is often definableas the arithmetic mean of stimulus inten-sities at all or certain types of changes inthe staircase direction of travel. For in-



Table 6—Performance characteristics of the forced-choice staircase algorithm

PERCEPTUAL MODALITY

WARM

COLD

VIBRATION

PRESSURE

5 Hz NEUROMETRY

250 Hz NEUROMETRY

2000 Hz NEUROMETRY

PRECISION

(TEST-RETEST)

R

0.7100.7610.6150.7860.4230.3270.770

CLINICAL

CUTOFF

LEVEL

1.7°C

l.rc3.1*3.9t163 MA

2 8 9 M A

5 4 5 MA

SENSITIVITY

P (HIT)

0.8330.8330.9440.7890.5290.4310.588

SPECIFICITY P(CORRECT REJECT)

0.9330.9330.9330.9330.9331.0001.000

PREDICTIVE VALUES

POSITIVE

0.9250.9250.9340.9220.8881.0001.000

NEGATIVE

0.8450.8450.9440.8160.6650.6380.708

•"Vibration stimulus intensity is expressed here as peak to peak amplitude in microns.tPressure intensity is the loglO (force), where force is grams pressure [see Semmes-Weinstein apparatus for details]. Sampling parameters consisted of 8 normalcontrol subjects and 29 diabetic neuropathic patients (by clinical diagnosis, all of whom retained measurable cutaneous perceptual function).

stance, it may be calculated in any of thefollowing ways: I) the mean of transi-tions in staircase direction from decreas-ing to increasing (typically the initialpoints at which errors are made); 2) themean of transitions from increasing todecreasing (typically the points at whichtargeted levels of probability that a sub-ject could have randomly achieved suc-cess are re- established); or 3) the meansof all of the directional changes. Each ofthese yields a number that representssomewhat particular aspects of thethreshold. From the first option, directlyabove, a threshold is derived that willallow more confidence that its result isthe transition to subthreshold. The tran-sition to suprathreshold is probably bestrepresented by option two above, andoption three is a somewhat more generalestimate of both types of transitions. Theresulting interval of uncertainty will typ-ically be much reduced from that whichthe initial method of limits supplied, andmay be calculated as the range of mini-mum to maximum of the intensities usedin the above calculations. It also may beappropriate to use the variance or SD ofthose intensities to represent the remain-ing interval of uncertainty in certain sit-uations (378,379).

The above described modelmerely represents one of many standard-izable methods for attaining estimates ofcutaneous thresholds that are easily ap-

plied by the clinician and researcheralike. Any of the vast number of availablemodels may be more accurate or moretime efficient, but most that attainequally acceptable accuracy levels shouldbe difficult to apply in either the researchor clinical physician's practice. Percep-tual research is continuously evaluatingand re-evaluating the many methodsavailable, and offering new solutions topresently observed difficulties by estab-lishing more sophisticated models. Giventhe current status of psychophysical scal-ing methods, algorithms, such as thatpresented herein, provide a substantialfirst step towards clinic estimation of cu-taneous sensitivity in the necessary detailadequate to provide more accurate andusable information about physiologicalfunctions and the effects of neuropathieson them.

In preliminary research with aversion of the above algorithm, the per-formance characteristics of the thresh-olds obtained were calculated (summa-rized in Table 6). Precision, the tendencyof a test to consistently yield the sameresult in the same situation, is probablythe most important characteristic. If atest yields vastly different scores undersimilar testing situations (for example,testing the same subject on repeated oc-casions) , then the results from any singletesting session may be meaningless. Note

that the precision varies for each modal-ity tested.

The sensitivity of a test refers toits ability to detect a clinically importantlevel of sensory impairment consistentwith the diagnosis of,in this case, a neu-ropathy. It often is expressed as theprobability of a hit or identification of animpairment. Specificity refers to the like-lihood that a test will correctly rejectnormal control subjects by identifyingthem as having normal scores. By usingROC curves from signal detection the-ory, the most efficient clinical cutoff level(threshold level above which the diagno-sis of neuropathic impairment is sug-gested) was determined for each modal-ity. At this most efficient level, thesensitivity and specificity of each modal-ity were calculated (Table 5). Predictionvalues indicate the probability of a cor-rect identification of impairment or non-impairment when the subject's status isunknown. Differences between modali-ties indicate to some extent the variabil-ity of the modality itself, as the measure-ment technique involved herein was heldconstant.

BiopsyBiopsy of nerve tissue may be helpful forexcluding other causes of neuropathy,such as the familial hypertrophicforms—amyloid, sarcoid, and othergranulomata—but the pathology of dia-



betic neuropathy is not unique. The pa-thology of the early sensorimotor neu-ropathy is not known. In establishedneuropathy, the characteristic picture isthat of distal fiber loss and degeneration.Histological data recently have been re-examined in light of the subtle asymme-tries and focal nature of the clinical pre-sentation, with the evidence lendingfavor to the hypothesis that differencesexist in the types of neuropathies occur-ring in IDDM and NIDDM. In NIDDM,the major observation is that of Walle-rian degeneration, which may be patchyand irregular, supporting the notion of avascular origin of the disease (87,88,94,101,396-398). Although these findingscannot clearly be distinguished fromother causes of neuropathy, a microvas-cular occlusive picture in the absence ofknown vasculitides may, however, bepathognomonic of diabetes. In contrast,the pathological findings in IDDM maydiffer from those in NIDDM with theaxoglial dysjunction and widening of theintemodal distance, findings interpretedas supporting a metabolic rather thanvascular etiology and similar to thosefound in animal models of diabetic neu-ropathy (399).

Special tests of autonomic function.Cardiovascular. A series of simple non-invasive tests are capable of detectingcardiovascular autonomic neuropathy.These were developed by Ewing et al.(70) and have been applied sucessfullyby others (269,399) including ourselves(256-260,282). These measures of car-diac integrity can be done at the bedsidevery simply and provide an index of theneuropathy that correlates well withother measures of somatic and gut neu-ropathy (70,400,401). Beat-to-beat vari-ability in the heart rate is among theearliest and most sensitive test of cardiacneuropathy, and although this is mostsensitively evaluated with the Hokansonmonitor, the tried and tested expiration-inspiration ratio of the heart rate duringdeep breathing at 6 breaths/min, alsogives reliable results. Although the car-

diac autonomic reflexes are complex andmay involve both sympathetic and para-sympathetic innervation, for all intentsand purposes, blood pressure responsesmay be taken to reflect sympathetic andvariations in pulse rate parasympatheticnerve disease. In evaluating the severityof the neuropathy, we have developed anindex that is simply a sum of the numberof abnormal tests. This index has beenshown to correlate well with the mea-sured indexes of cardiac dysfunction(256-260). The following is a list of themeasures and the normal values.

Resting heart rate >100 beats perminute is considered abnormal (normal<100 beats/min).Beat-to- beat heart-rate variationWith the patient at rest and supine,breathing 6 breaths/min with heartrate monitored by EKG, a difference(maximal-minimal) in heart rate of>15 beats/min is normal, 10 beats/min is abnormal. RR variation wasconsidered to be exclusively under thecontrol of the parasympathetic ner-vous system. However, subsequentstudies demonstrate that both fi-ad-renergic stimulation (isoproternol)(402) and (3-adrenergic blockade(propranolol)(43) decrease RR varia-tion. Both parasympathetic, cholin-ergic, blockade (atropine), and (3-ad-renergic stimulation can nearly abolishRR variation (402). Thus, a small de-crease in RR variation results from,sympathetic neuropathy, or stress,whereas a large decrease in RR varia-tion can result from either parasympa-thetic neuropathy or stress (P-adren-ergic stimulation).Valsalva maneuver

The subject blows into mouthpiece ofmanometer to 40 mmHg for 15 s withcontinuous EKG monitoring before,during, and after the procedure. Healthysubjects normally develop tachycardiaand peripheral vasoconstriction duringstrain; and an overshoot rise in bloodpressure and bradycardia on release.The valsalva ratio is:

longest RR/shortest RR. The normal value is£1.21.

Heart-rate response to standingThe subject stands with continuousECG monitoring, and one measuresthe RR interval at beats 15 and 30. The30/15 ratio is normally >1.03. Nor-mal is tachycardia at beat 15, brady-cardia at beat 30.Systolic blood pressure response to stand-ing The response is abnormal if bloodpressure falls >30 mmHg within 2 minof standing.

Photoplethysmographic beat-to - beatblood pressure recording may havesignificant advantages and can be usedto evaluate the components of the Val-salva maneuver (403).Diastolic blood pressure rise with sus-tained exercise

A hand grip dynamometer is squeezedto 30% of maximum (predeterminedin the subject) for 5 min. The normalresponse is a rise of diastolic bloodpressure >16 mmHg.Examination of the EKG may reveal aprolonged QT interval in patients withcardiac autonomic neuropathyThe QT interval corrected for the car-diac cycle length (QTc is = QT/squareroot of longest-shortest R-R interval).Normal is a QTc < 440 ms.

Gastrointestinal.Technetium resin and chicken liver gas-tric emptying studies (281).A positive test is retention of > 50% ofthe radioacivity in the stomach forlonger than 100 min.Pressure/motility studies of intestinal

function (281)Insulin hypoglycemia test of PP and cat-echolamine responses (299,300,307,310,317)

Special tests of bladder function.In suspect cases of a vesical dysfunc-tion, a need may arise to do specialtests.CystometrySphincter electromyographyUroflometryUrethral pressure profile



Electrophysiological test of bladder inner-vation

Special tests of penile function.Severe dysfunction among males iscommon in diabetes. Pain with com-pression of the testis is normal and islost with autonomic neuropathy. Var-ious tests have been developed toquantitate erectile impotence. Theseare in essence designed to excludepsychogenic from organic and vascu-lar from neuropathic and include:Doppler ultrasound measurement ofbra-chial and penile systolic blood pressurePenile tumescence measurement bystrain gauge

Penile tumescence measured by postagestampBulbocavernosus reflex response latency

Sudomotor sympathetic function.Sudomotor function may be evaluatedwith the TST, QSART, skin potentials,or sweat imprint quantitation. TheTST is a sensitive test of sweat distri-bution (404). The subject is dustedwith an indicator powder that turnspurple when moist. This quantitativetest can be rendered semiquantitativeby charting the percentage of anteriorbody surface that is anhidrotic.

The skin potential can be recordedwith standard EMG equipment, fromthe palm and sole (401). The stimulusis an electric shock, an inspiratorygasp, or other stimuli that activatetype II and III mechanoreceptor affer-ents. The skin potential is readilyevoked but habituates.

The silastic skin imprint is obtainedafter the application of silastic materialto stimulated skin (385). The sweatdroplet indents the imprint, and thecount and diameter distribution canbe determined. The usual stimulus ispilocarpine administered by iontro-phoresis.

In QSART (405,406), the stimulusconsists of the iontrophoresis of ace-tylcholine via the stimulus compart-ment of a multicompartmental sweatcell. Postganglionic sympathetic nerveterminals are activated, and the nerve

impulse travels retrogradely, reaches abranch point, then travels or-thogradely to activate a second popu-lation of sweat glands. The sweat re-sponse from this second population ofsweat glands is recorded by a sudor-ometer. The stimulus compartmentsurrounds the central recording com-partment, separated by an air gap andtwo ridges (to block diffusion). Thistest evaluates the integrity of the distalpostganglionic sympathetic sudomo-tor axon. Four recording sites (distalforearm and three lower extremitysites) are used. The test has high sen-sitivity, a CV of 20% and, when usedin conjunction with the thermoregula-tory sweat test, defines the pre- orpostganglionic site of the lesion. Thetest requires specialized equipment,trained technicians, and 20-30 min tocomplete.

Peripheral skin blood flow reactions.Microvascular skin blood flow may beaccurately measured noninvasively byusing laser Doppler flowmetry (407).Smooth-muscled microvasculature inthe periphery reacts sympatheticallyand parasympathetically to numerousstressor tasks.Orienting response

Typically, an orienting response canbe observed as a microvascular con-striction and resulting drop in periph-eral (index finger, pulpar surface) skinblood flow when a healthy subject at-tenuates to speech after several min-utes of relaxation with music.Mental arithmetic

Mental arithmetic as a serial subtrac-tion task typically results in a 30%reduction in peripheral (index finger,pulpar surface) skin blood flow from aresting baseline.Hand grip

Peripheral contralateral (index finger,pulpar surface) response to sustained40% maximum grip on a dynamome-ter is biphasic over 60 s. The initialresponse is a 40-50% reduction offlow from basal during the initial20-30 s, followed by a dilation result-

ing in a return to typically superbasallevels.Cold pressorImmersion of the contralateral hand incold (ice) water typically results in anintense (50-60%) reduction in pe-ripheral skin blood flow at the pulparindex surface. In some individuals,this response becomes biphasic afterprolonged exposure (30 s) to such in-tense cold, because it is extremely un-comfortable.

Laser flowmetry measure erythro-cyte velocity (although not linearly)and volume. In healthy individuals,the most distinct changes that occur inrelation to these tasks are associatedprimarily with changes in volume ofblood. Blood velocity is slightly in-creased during most stressors, whileblood volume accounts for the dra-matic reductions in overall flow to theregion being measured from.

Hypoglycemia unawareness/unresponsivenessTo test for the presence of these syn-dromes requires elaborate and expensiveequipment and is best done in a researchenvironment. For the sake of complete-ness, they are described herein. Thestepped hypoglycemic clamp technique,applied to normal subjects (337,349)and IDDM patients (330) has been de-scribed in detail. Briefly, after an over-night fast (and overnight i.v. insulin in-fusion to achieve near euglycemia beforethe test in IDDM), insulin (2.0Mu • kg"1 • min"1) is infused continu-ously and an intravenous glucose infu-sion is varied either to maintain euglyce-mia (5.0 mM) throughout (euglycemiacontrol) or to achieve hourly glucoseclamps of 5.0, 4.4, 3.9, 3.3, and 2.8 (oreven 2.2) mM. Symptoms and hormoneresponses are assessed at the end of eachglycemic step. Cognitive function alsocan be assessed (337,349). The test islabor intensive, requiring a minimum oftwo people (typically a physician andnurse); a third person is needed if cog-nitive function is assessed. It also re-



quires accurate glucose measurements(with a Beckman or YSI analyzer, notwith a glucose monitor) at the bedsideand the analytical capacity to performthe hormone measurements. Cognitiveassessment generally requires a collabo-rating psychologist.

The insulin infusion test, appliedto normal subjects and IDDM patients,also has been described in detail (301).Briefly, after an overnight fast (and over-night i.v. insulin infusion to achieve neareuglycemia prior to the test in IDDM),insulin (67 mU • kg"1 • min"1) is in-fused continuously and glucose is notinfused because the plasma glucose con-centration is the primary end point. Thetest is continued until the plasma glucoseplateaus at 2.0 mM, neuroglycopenia de-velops, or both (defective glucose coun-terregulation). Hormone levels andsymptoms are preferably measured seri-ally (assessment of cognitive function ismore problematic given the time re-quired to perform cognitive tests). How-ever, serial measurements of the plasmaglucose concentration and assessmentsof mental status are sufficient for clinicalinterpretation of the test. The test re-quires two individuals, one of whichmust be a physician (because a medicaljudgment must be made as to whether ornot an end point is reached, and insulininfusion should be stopped). It also re-quires accurate glucose measurements atthe bedside.

MANAGEMENT — Management maybe divided into general and specific mea-sures. The general measures include di-abetes control, and the specific measuresinclude symptomatic, palliative, andsupportive treatment directed at thesymptom complex present.General measuresDiabetes control.—Although some retro-spective studies suggest that the preva-lence of diabetic neuropathy increases indirect proportion to worsening control ofdiabetes (13-15), data indicate that thiscomplication, more than retinopathy andnephropathy, may improve with better

diabetes control (408-413). Some neu-ropathic patients who experience tre-mendous pain may benefit from a periodof intravenous insulin administration ir-respective of the degree of improvementin glycemic control or HbAx. Prospectivestudies that have compared conventionaltherapy with that of an intensified regimeeither by continuous subcutaneous insu-lin infusion or multiple injections eachday have shown improvement in motorNCV velocity (412-416) with resistanceof improvement in sensory function; al-though in studies where treatment hasbeen prolonged for 8 mo to 2 yr(412,413,415), improvement in all mo-dalities of nerve function has been found.One problem with the evaluation ofthese studies, however, is the lack of datapertinent to the relationship betweennerve conduction studies and the symp-tom complex. In neuropathies involvingthe small nerve fibers, which are slowconductors and thus contribute little tothe overall measurement of nerve con-duction, little or no change in the EMGmay be detected, even in the face of dra-matic clinical effects of normalization ofthe blood glucose. It is not apparent fromthese studies whether the improvementis related to a reduction in the endoneu-ral edema, improvement of the vascularsupply to the nerves, or regrowth ofdamaged neurons. Until the outcome ofthe multicenter DCCT (417) is known in7 yr, the prudent advice is to normalizediabetes control as much as possible, es-pecially in those individuals who haveevidence of early neuropathy.Nutritional factors.—Several different fac-tors have been implicated in the patho-genesis of neuropathy, including vitaminB12 deficiency, vitamin A deficiency,pyridoxine (B6) deficiency, and a host ofmacro- and micronutrients. Althoughthe beneficial effects of some of thesenutritional factors have been suggested,studies have not been controlled, and thepresent recommendation is to maintainadequate and healthy nutrition.

Trials of specific therapyARIs.—The trials of ARIs are still in theresearch arena, and although somepromising reports have been issued onimprovement in symptoms and in someobjective measures of neuropathy, thedegree of benefit obtained has not beenby any means outstanding. Currently, itis too early to evaluate the place of ARIsin the management of diabetic neuropa-thy.

In recent years, numerous studieshave been reported in which ARIs havebeen used to treat diabetic neuropathy(117,360,418-428). Enthusiasm for thisform of treatment has been based on theobservation that the excessive accumula-tion of the sugar alcohol sorbitol andfructose within the major target tissues isrelevant to the diabetic complications,namely the retina, the kidney, and theperipheral nerves.

Alrestatin, the first available AR1to be used, generated conflicting results(360,418-420), probably because of apoor selection of cases with fairly ad-vanced neuropathy so that reversal of thecondition was unlikely.

Sorbinil, a spirol hydantoin, hasbeen shown in human diabetic neurop-athy to be effective in producing both asignificant improvement in the symp-toms of pain and paresthesia and also inmotor NCV (117), where the increasewas small but statistically significant. Theresponse may be limited, however, be-cause longer duration of treatment ortreatment with smaller doses has notachieved any significantly greater effectthan that found with short-term treat-ment (360). The major problem relatingto the use of the hydantoin is the devel-opment of significant toxicity in ~16%of cases (421,422), which is character-ized by lymphadenopathy and a macularpapular erythematous rash associatedwith fever and pancytopenia. Thesesymptoms usually appear within the first1-2 wk of starting therapy, but disap-pear with cessation of the drug. As aresult, further studies involving the useof this ARI for the treatment of diabetic



neuropathy have been suspended. Itshould be noted that a significant im-provement in the autonomic measures ofcardiac function also has been shownafter treatment with sorbinil (421; M.A.Pfeiffer, unpublished observations). Ifthese data indicate reversibility of auto-nomic dysfunction, then the clinicalramifications are considerable in light ofthe high mortality associated with dia-betic autonomic neuropathy. Tolrestat, acompound that has no hydantoinlikestructure, was shown after 1 yr of treat-ment to generate significant but modestimprovement in nerve conduction whenused in a dose of 200 mg/day (426).After longer term treatment, the im-provement continues but even moremodestly (427). This drug is relativelyfree of side effects, with only 4% of pa-tients developing abnormalities in liverenzymes.

None of the ARIs are currentlyapproved for clinical use in the U.S.; allpatients currently receiving treatment areparticipants of trials conducted by thevarious centers. A major problem relatedto the interpretation of the data gener-ated in the early studies has been the lackof standardization of the approachesused to determine: I) clinical symptom-atic responsiveness; 2) electrophysiolog-ical means of monitoring thermal andvibratory changes; 3) the optimum elec-trophysiological measurement used toquantitate neuropathic change or im-provement; and 4) use of surrogate his-tological data to support the notion ofnerve regeneration. Furthermore, vari-ability in the measurements conductedby different centers in control studies hasbeen considerable, thus highlighting theneed for minimizing both inter- and in-tracenter variability. Thus, for trials ofthis nature to be successful and formeaningful results to be achieved, it willbe necessary to standardize carefully theclinical measurements of symptoms andphysical findings as well as those forquantitative physiological testing and toprospectively identify the histologicalend points to be used as primary goals of

therapy. We believe such a study is nowbeing conducted at various centers in theU.S. with tolrestat.

As alluded to earlier, patient se-lection is also an important consider-ation, with ideal candidates afflicted withonly mild or very modest neuropathy.But because many of these patients willexperience predominantly small fiberneuropathy, which is not detected onelectrophysiological measurements,quantitation of nerve defects are basedpredominantly on subjective responses.Thus, these studies need to be blindedand placebo controlled.Myo-inositol.—Myo-inositol deficiencyhas been reported in animal models andintolerance to myo-inositol in diabetes inhumans. Results from several studiessuggest that myo-inositol supplements ofthe normal diet will improve neuropathy(55,430-432), but the treatment mayhave to be prolonged for at least 6 mo fora significant effect to be achieved (55). Indesperate situations, however, individu-als with a normal myo-inositol intake of800 mg/day may have this increased to1600 mg/day. This is easily obtainable bypurchasing Brewer's yeast from a phar-macy where it comes in two forms, onecontaining 400 mg and one containing800 mg of inositol with the appropriatenumber of tablets prescribed per day.Gangliosides.—Gangliosides are sialogly-colipids found in nerve cell membranesand nerve growth cones. A series of stud-ies reported from Europe (359,433-437) and one from the U.S. (438) insmall groups of patients have shownsome improvement in lower extremitysensation but without changes in theelectrophysiological measures of nervefunction. Although these studies holdpromise, they need to be conducted in acontrolled manner in larger series of pa-tients.

Evening primrose oil.—On the basis thatdiabetic subjects have a deficiency in theability to generate arachidoninc acidfrom their membrane phospholipids andthus a deficient substrate for the synthe-sis of certain prostaglandin derivatives,

one research group has treated diabeticsubjects for 1 yr and longer with 7-lino-lenic acid and has documented improvednerve function compared with a placebo-treated group (439). The results gener-ated by this small trial are exciting be-cause 7-linolenic acid also has animportant lipid-lowering effect and thuscould be useful in the general manage-ment of diabetes. Further exploration ofthis area is needed.Aminoguanidine.—New studies in ratshas shown that aminoguanidine may beof value in reversing the glycation of pro-teins implicated in the pathogenesis ofthe complications of diabetes. Studies arebeing conducted on a research basis, andthe product is not yet available for hu-man use.Pain controlControl of pain in diabetic neuropathymay present one of the most trying prob-lems for both physician and patient. Of-ten patients are depressed, and the de-pression does not appear to be a functionof the extent or severity of the neuropa-thy but rather a sense of uselessness. Anaccompanying sense of weakness alsomay be present, and this often is notbecause of a muscle deficit, but rather afeeling of hopelessness. Enrollment ofsome patients to various drug trials hasyielded improvement in ~50% of sub-jects, even before institution of drugtherapy or the administration of placebo.This trial effect highlights the need forphysicians to treat these patients withcompassion, sympathy, understanding,and a sense of hope. Simple maneuvers,such as wearing body stockings to de-crease movement of hair follicles, can behelpful.

Generally, two types of pain areexhibited in neuropathy. In one variety,the pain consists of marked hyperaesthe-sia and a burning, laminating dysesthestccomponent. This subgroup may respondto topical application of capsaicin (440).In the second type, the pain is akin to adeep-seated, gnawing toothache; it gen-erally does not do well with topical ther-



SIMPLE PHYSICAL MEASURESWarm baths, body stockings, TENS

SIMPLE ANALGESICSAspirin, paracetamol, NSAIDS

EPICRITICBurning, Dysesthesia

(sensitivity to gentle stimulation)

TPROTOPATHICDeep-seated, gnawing,

"toothache" poorly localized

ITRIAL OF TROPICAL AGENT

Capsaicin

TRIAL OF "BENIGN" DRUGSInsulin infusion

Clonidine 100-500 ^ H S1 Metoclopramide 10 mg/tid

Mexilitene<10mg/Kd/d

Pentoxifylline 400 mg/tid

TRIAL OF ANTIDEPRESSANTS ± PHENOTHIAZINESAmitriptyline 50 -150 mg nocte

±fluphenazine 1 • 6 mg/d

Clonazepam 0.5 - 3.0 mg/d

Figure 3—Suggested sequence for treatment of painful diabetic neuropathy.

apy and should therefore follow the fol-lowing path (Fig. 3).Analgesics.—Various analgesic drugshave been used for the management ofpain in diabetic neuropathy, includingaspirin, paracetomol, the non-steroidalanti-inflammatory drugs, and demerol.Care must be exercised in the use ofmore potent analgesics for fear of addic-tion.Dilantin.—Dilantin, long advocated inthe treatment of pain, is generally notthought to be of value in diabetic neu-ropathy (441,442). One problem is thatit tends to yield toxicity with macrocyticanemia, hypertrophic gums, and ataxiabefore a therapeutic effect is observed.

Carbamazepine.—Carbamazepine ishighly useful in the management of epi-lepsy in children and has been shown tobe effective for certain individuals indouble-blind placebo-controlled studies(443-445). In general, however, thisdrug is too toxic to be considered as thefirst line drug.Clonidine.—Interest in clonidine in themanagement of painful diabetic neurop-athy has been motivated by the consid-erable success achieved by this drug inthe management of patients who havebeen withdrawn from alcohol and otherdrugs. It also seems to work reasonablywell in many causalgic situations. Oneshould start with a small dose of 75-100

|xg given at night to avoid hypotensionand sleepiness, and the dose then shouldbe increased gradually until a desiredeffect is achieved. About 33% of the pa-tients will respond in this manner.Amitriptyline.—Several studies have ex-amined the effects of various tricyclicdrugs in combination with phenothiaz-ines and have reported a beneficial effectthat is unrelated to the relief of depres-sion (446-448). The usual doses are50-150 mg amitryptyline in divideddoses plus 1-2 mg fluphenazine orally atnight. Unfortunately, however, dysauto-nomia, dry mouth, and visual distur-bances caused by the tricyclics may belimiting; and the tardive dyskinesia withthe phenothiazines is troublesome. Re-cently reported is the benefit of treat-ment with the tricyclics alone in double-masked placebo-controlled studiesindicating greater effectiveness of thedrug compared with placebo alone(449,450). As mentioned earlier, manyof these patients are extremely de-pressed, and a trial of imipramine aloneor amitriptyline given together with flu-phenazine may be of benefit in manypatients.

Transcutaneous nerve stimulation.—Trans-cutaneous nerve stimulation must beconsidered, if only for the reason that itrepresents one of the most benign ap-proaches to management. Often this ap-proach is abandoned prematurely whenthe practitioner fails to move the elec-trodes around sufficiently to identify sen-sitive areas. When the approach is effec-tive, salutary results are usually obtainedonly after the electrodes are moved tomultiple areas, including those not in thedistribution of the nerves involved.Nerve blocking.—The administration oflidocaine by slow infusion of 5 mg/kgover 30 min has been shown to providerelief of intractable pain for a period of3-21 days (451). When the pain is lo-calized to a nerve root distribution, thetemporary pain relief provided by thelocal nerve blockers may constitute suf-ficient management, because such pain isself-limiting.



Rheological agents.—Pentoxyfylline is arheological agent that increases the de-formability of erythrocytes and increasesblood flow with enhanced oxygena-tion of tissues. Use of this agent hasbeen reported sporadically in diabeticneuropathy, and it merits the currentsix center clinical investigation of thesafety and efficacy in painful diabeticneuropathy.Neuropathic ulcersIt must be stressed that neuropathic ul-cers constitute the greatest hazard to lossof limbs in patients with diabetes, and itis the responsibility of the physician toinsure that the patient understands theimportance of foot care.Meticulous foot care.—Drying betweenthe toes after bathing, application of dry-ing powder such as Johnson's baby pow-der and application of softening creamssuch as lanolin are critical measures forthe prevention of foot ulcers. Daily in-spection of the feet is tantamount, andpatients must be taught nail-cuttingskills.

Orthotic devices.—If one finds markedloss of sensation with the development ofulcers in the pressure areas indicatedabove, then the purchase of a shoe onesize larger than regular with an insert ofplastozet or alzet, which will mold to thefoot and distribute the pressure, can re-sult in healing of ulcers within severalmonths.Ulcer care.—Ulcer care requires debride-ment of necrotic tissue, repeated steriledressings, removal from further pressurewith supportive devices, or even bed restor a plaster cast. Infection must be ag-gressively treated, with appropriate anti-biotics often for at least 3 wk and theunderlying osteomyelitis excluded byx-ray. Trials of topical platelet-derivedgrowth factor as a means of acceleratingwound healing are being undertaken inseveral cities in the U.S. This area prob-ably constitutes the single greatest causeof mismanagement of diabetic patients,which often gives rise to medico/legalsuits.

Charcot joints—orthotic devicesOnce destruction of a charcot joint iscomplete and total loss of joint pain andperception has occurred, the only meansof treatment is orthotic devices.MononeuropathiesPhysiotherapy is important to preventcontractures, and the joints should beprotected until spontaneous recovery oc-curs.Postural hypotensionThe management of postural hypoten-sion in the individual with diabetic au-tonomic neuropathy can be complex.One has to tread a narrow path betweenelevating the blood pressure in the stand-ing position and ensuring that supinehypertension does not occur. The situa-tion is further complicated by the com-plex nature of the pathogenesis of theneuropathy.

Supportive garments.—The first step in thetreatment of postural hypotension shouldalways be to attempt to increase venousreturn from the periphery with supportiveelements, such as total body stockings.These stockings should be applied whilethe individual is lying in bed and shouldnot be taken off until the individual returnsto the supine position. Unfortunately,some patients find them uncomfortable,particularly during the summer months. Insevere cases, an Air Force antigraviry suitmay be required (452).Drug therapy.—The treatment with 9-a-fluohydrocortisone (0.5 mg gd) (453,454) and supplementary salt (2-6 g)may relieve individuals of symptoms, butthe inherent danger of developingedema, congestive cardiac failure, andsupine hypertension is always present. Infact, one does not see relief of the symp-toms of postural hypotension untiledema occurs. In the event that thesemeasures fail, if the a- and (3-adrenergicreceptor status is known, one can make areasonable guess as to which drug theindividual is likely to respond. If there isa dopamine excess, metoclopramide orReglan 10 mg rid may be useful (455). Ifthere is an a-adreno receptor excess,then the a-2-antagonist yohimbine (10

mg/tid) will be helpful. In the event thatP-receptors are increased in number, asoccurs in a small portion of cases, inderal(propranolol) (456) 10 mg/qid or pin-dolol may be of more value. If, however,there is an a-receptor deficiency(256,257), then the use of clonidine mayparadoxically raise blood pressure ratherthan decrease it. One needs, of course, tostart with a small dose and then increasethe dose to 400 u.g/day. In the event thatall of these measures fail, then the directa -adrenerg ic agonist midodrine(Gutron) 2.5-40 mg q 6 h or dihydro-ergotamine 2.5-40 |xg q 6 h given incombination with caffeine (457) may beof value. Of particular note is the pos-tural hypotension that occurs in someindividuals soon after meal ingestionwhich may prove particularly refractoryto treatment. Hoeldtke (458) has shownthat a small dose of the analogue of so-matostatin, sandostatin, 0.1-0.5 |xg/kggiven as a single s.c. injection in themornings may allow these subjects tolive normally and remain normotensivethroughout the day. The mechanism ofaction has not yet been resolved but doesnot appear to be related to effects on theadrenergic nervous system. Care must beexercised, because slightly higher dosesmay result in hypertension which couldbe dangerous in these individuals.Gastropathy

The initial management of gastropathyshould include multiple small feedingswith a reduction in the fat content whichtends to delay gastric emptying. If this isnot helpful, metoclopramide given 10mg by mouth up to 4 times a day may beof value (459-462). If marked gastro-paresis is present with a large gastric re-sidual volume filled with fluid, however,then the drug is poorly absorbed, andone needs to commence therapy withintravenous administration of fuels andgastric suction until it has been shownthat the stomach is beginning to emptyand only then to switch to the oral form.Other agents such as cholinergic agonists(bethanechol chloride: 10 mg/qid (462)and cholinesterase inhibitors (pyridostig-



mine bromide: 1-2 mg/day) may pro-duce marked drying of secretions in themouth, blurring of vision, and colicwithout enhancing gastric emptying.Two investigational drugs, 10-40 mgdomperidone 30 min before meals and10-40 mg cisapride 30 min before mealshave proved to be useful in some patientsbut probably is of no greater value thanmetoclopramide (463). Erythromycingiven as liquid or suppository stimulatesIMMC and may be helpful. In the eventthat all else fails, we have resorted toplacing a jejunostomy tube transabdom-inally and feeding by this route into anarea of bowel that has normal function.Nutrients are given during the night,thus freeing the patient for their dailyactivities during the day. This approachsimplifies matters because it allows theinsulin requirements to be tailored to thenocturnal feeding (464).Enteropathy

Diabetic enteropathy can be the mosttrying and difficult of all diabetes com-plications to treat.Antibiotics. A broad spectrum antibioticis usually the treatment of choice. Thismay be tetracycline (465), bactrim, orwhat appears to work best of all, metron-idazole (Flagyl), in a dose of 750 mg/ted.It is important, however, to continuetreatment for a minimum of 3 wk and, ifpossible, to check that the breath hydro-gen test has returned to normal, whichindicates that bacterial overgrowth iscontrolled.Cholestyramine. Retention of bile some-times occurs, which may be highly irri-tant to the gut (287), and chelation ofbile salts with 4 g/tid cholestyraminemixed in fluid and given orally (288)may be of considerable help.Diphenoxylate HC1 plus atropine: lomotil 2mg/qid (PO). The use of diphenoxylate isa last resort measure, and extreme careshould be exercised because toxic mega-colon can occur.

Gluten-free diet may be of valuein those patients who have the addedinsult of poor digestion.

Pancreatic exocrine insufficiency. Viokaseshould be added to the treatment regi-men in doses that are large (e.g., 10-18tabs/day) if it is to be effective. Many ofthese patients have evidence of pancre-atic exocrine insufficiency and replace-ment of the exocrine secretions with 18tablets/day of viokase may be helpful.

Clonidine may prove useful in themanagement of some of these patients(290,291), but unfortunately only a sin-gle small trial involving few patients hasevaluated its efficacy.

In resistant cases, we have used a com-bination of SRIF analogue together withlithium and have been successful intreating cases refractory to all otherforms of intervention (292,293).

Withdrawal from narcotics should beavoided at all costs, because this can leadto a cycle of chronic constipation fol-lowed by explosive episodes of diarrhea,sometimes with toxic megacolon.CystopathyProbably the first step in the manage-ment of patients who are insensitive to afull bladder is to educate the individualto do repeated palpations of their lowerabdomen to determine whether or notthe bladder is full. Such patients oftenwill be able to initiate micturition simplyby applying pressure to the bladder, aprocedure known as Crede's maneuver.When this procedure fails, the use ofparasympathomimetics such as bethane-chol chloride (10 |xg/qid) may be con-sidered, although this may produce colicwithout allowing adequate bladder emp-tying. A most useful and simple ap-proach that we have used is repeatedbladder self-catherizations (466), withinfection resulting only infrequently. Inmale patients, bladder neck surgery canbe done to relieve the spasm of the in-ternal sphincter. Continence is preservedbecause of the somatic supply of the ex-ternal sphincter.Erectile failureAs mentioned earlier (467-469), this ab-normality is probably one of the mostsignificant, at least to the patient, presen-tations of autonomic dysfunction as it

may result in matrimonial and other dis-harmony. Counseling and managementof behavioral problems is cardinal to thecare of these patients. Today, numeroustreatment modalities are available, in-cluding use of inflatable devices (470).These devices operate on the principal ofobstruction of venous outflow aided bynegative pressure to increase inflow andhave been used with some degree of suc-cess. In addition, the a-adrenergic an-tagonist yohimbine given as 10 mg/tidmay help in —33% of cases, and lastly,the direct intrapenile injection of regitineand papaverine has met with some suc-cess. This latter regimen, however, in-variably is associated with a small pro-portion of patients developing infections,priapism, and ultimately fibrosis. It does,however, provide the patient with reliefof symptoms for a period of time rangingfrom months to years, and this may be agodsend. Finally, in the event of failureof these therapies, rigid and semirigidprotheses are available, and this optionshould be discussed with the patient andthe significant other.

Retrograde ejaculation may betreated with 8 mg twice a day bromphe-niramine, an anticholinergic (471), 25mg/tid imipramine (472), or 60 mg phe-nylephrine i.v., an a-adrenergic agonist(473).Gustatory sweatingGustatory sweating and sudomotor dis-turbance appear to respond to somedegree to propantheline hydrobromide15 mg/tid (PO) and to scopolaminepatches.Hypoglycemia unawareness/unre-sponsiveness/HAAFPatients with this complication pose agenuine dilemma for the physician. Ifone believes that autonomic neuropathymay reverse with intensive therapy andsubsequent normalization of blood glu-cose and HbAj, then the objective is totry and normalize these measures. Onthe other hand, considerable risk isposed to these patients who are notaware of the hypoglycemia and lack thecounterregulatory response to mount a



Patient with diabetes

NIDDM

Evaluate AN functionafter 5 years thenyearly thereafter

Evaluate AN functionat diagnosis thenyearly thereafter

yearly evaluationscontrol diabetesconsider preventivetherapy eg. Aldosereductase inhibitors

supervise exerciseregulate BP - nocturnal

- exerciseperioperative - preparationfoot carerelax - intensity of diabetes

control (hypoglycemiaunawareness &unresponsiveness

thermoregulation - hydration inhot environment

specific Rx. - system dependent

Figure 4—Suggested paradigm for management ofautonomic neuropathy.

means of combating their fall in bloodglucose concentration. Thus, it is ourcontention that if pump therapy is to beused, one should avoid boluses; and ifintensive conventional therapy is to beused, one should elect to use long-actinginsulins with very small boluses. In gen-eral, one should not aim for normalHbAx and normal blood glucose levelswhen this complication supervenes.Scrupulous avoidance of hypoglycemia ismandatory.

The following is paradigm for themanagement of autonomic neuropathy.

SUGGESTED MANAGEMENT OFAUTONOMIC NEUROPATHY1. General measures

a. Improve diabetes control and gen-eral nutrition

2. Trials of specific therapya. ARIs(in Research Arena)b. Myo-inositol: diet containing 1650

-3200 mg/day (normal < 800 mg/day)

3. A paradigm (Fig. 4)

PROGNOSIS— The tendency forneuropathy, nephropathy, and retinopa-thy to cluster together in the same pa-tient has long been recognized (474) andis now referred to as a tripoathy with thisclustering appearing independently ofage and duration of diabetes (13-15).Neuropathy is often the first of thesecomplications to become manifest andthus may serve as a marker for those athigh risk for future development of reti-nopathy, as suggested by Knowler (475)

and perhaps for other diabetic complica-tions.

Peripheral and possibly auto-nomic neuropathy is also an importantcontribution to the development of neu-ropathic foot ulceration, which can be adevastating complication for some unfor-tunate patients. It has been estimatedthat > 50% of all nontraumatic amputa-tions in this country occur in diabeticpatients and that 50% of these are po-tentially preventable (476). These statis-tics highlight the need for careful atten-tion to foot care in diabetic patients.

The presence of autonomic neu-ropathy also may lead to accelerated de-velopment of other morbid conditions.Among women with diabetes, for exam-ple, it is reported that those with cardio-vascular autonomic neuropathy have ahigher prevalence rate of bacteriuria thanwomen of similar age, duration of diabe-tes, and GHb but without cardiovascularautonomic neuropathy (477). Hypothe-sizing that cardiovascular autonomic ab-normalities might be an indicator of au-tonomic bladder dysfunction, theseresearchers suggested that a causal asso-ciation between autonomic neuropathyand bladder involvement could explainpreviously reported associations betweendiabetes and urinary tract infections(477-481).

The increased mortality risk asso-ciated with diabetic autonomic neuropa-thy has been well publicized, primarilyby the work of Ewing et al. (72,482,483). Among 73 clinic patients withsymptoms of autonomic neuropathy fol-lowed for up to 5 yr, these researchersobserved an overall mortality rate of35%. Among subjects with abnormal au-tonomic function tests at baseline, the.mortality rate was 44% at 2.5 yr and56% at 5 yr as compared with 15% at 2.5yr and 21% at 5 yr for the group testingnormal at baseline (482). The poorersurvival of the abnormal group could noteasily be explained by selection factors,because no significant differences wereobserved in age, duration of diabetes,and duration of autonomic neuropathy



symptoms between the two groups atbaseline. Patients who died were, how-ever, more likely to present with posturalhypotension, gastric symptoms, and hy-poglycemic unawareness at baseline ex-amination. Possible mechanisms for theincreased risk associated with diabeticautonomic neuropathy have been dis-cussed earlier.

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Diabetic Neuropathies

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