When the first edition of Diabetes in America was data to warrant a chapter on neuropathy in diabetes. In 1988 a joint conference of the American Diabetes …
Chapter 15
Neuropathy in Diabetes
Richard C Eastman, MD
SUMMARY
P
opulation-based studies of neuropathy inflammation and degeneration of peripheral nerves in persons with diabetes indicate that neuropathy is a common complication of insulin-dependent diabetes mellitus IDDM and noninsulin-dependent diabetes mellitus NIDDM, with 60-70 of patients affected Subclinical neuropathy is much more common than clinical neuropathy Distal symmetrical polyneuropathy is the most common type of neuropathy, followed by carpal tunnel syndrome, other mononeuropathies, and autonomic
neuropathy The frequency distribution for neuropathies is similar in IDDM and NIDDM, as are the frequencies of subclinical and clinical distal polyneuropathy and carpal tunnel syndrome However, severe distal neuropathy is more common in IDDM Prevalence of neuropathy increases with age, duration of diabetes, and worsening of glucose tolerance In the Diabetes Control and Complications Trial DCCT, intensive treatment of diabetes with near-normalization of glycemia reduced by 60 the 5-year incidence of neuropathy in those without neuropathy at study entry
INTRODUCTION
NEUROPATHY COMPLICATIONS IN
DIABETES
When the first edition of Diabetes in America was published, there were insufficient population-based data to warrant a chapter on neuropathy in diabetes The lack of epidemiologic data as of mid-1980 has been reviewed1 Most information available at the time was from clinic- and hospital-based studies, with prevalence of neuropathy ranging from 5-802 Fortunately, this situation has improved and populationbased studies are now available In 1988 a joint conference of the American Diabetes Association and the American Academy of Neurology adopted standardized nomenclature and criteria for diagnosis of neuropathy in diabetes3 Table 151 This classification recognizes subclinical and clinical neuropathy Subclinical neuropathy is defined by an abnormal electrodiagnostic test, quantitative sensory threshold, or autonomic function test in the absence of clinical signs and symptoms Clinical neuropathy is defined as symptoms and signs together, or as symptoms or signs alone plus abnormal test results Standardized definitions, diagnostic criteria, and validated measures have been used in population-based studies of the epidemiology of neuropathy in diabetes and form the basis of this
chapter
339
The most common neuropathy affecting individuals with diabetes is diffuse somatic neuropathy of the distal symmetric sensorimotor type Table 151 Patients most often have a mixed sensorimotor defect and may experience pain, paresthesia, hyperesthesia, dysesthesia, proprioreceptive defect, loss of sensation, and muscle weakness and atrophy4 Autonomic nerve function is often impaired5,6 and occasionally a particular nerve fiber is predominantly affected Small nerve fiber injury leads to painful neuropathy with preservation of large myelinated fiber function Deep tendon reflexes, vibration sense threshold, and proprioreception are preserved Neuropathy affecting predominantly the large nerve fibers leads to motor and proprioreceptive dysfunction This form of neuropathy resembles the neuropathy seen in tabes dorsalis and is termed pseudotabes form of diabetic neuropathy Charcot joint disease of the ankle is also a complication of this form of neuropathy, and sensation may be preserved Neuropathic ulceration is a complication of distal neuropathy that occurs predominantly in individuals with loss of protective sensation The preferred criteria for diagnosis of distal
symmetrical polyneuropathy are abnormalities in two
Table 151
Figure 151
Classification and Staging of Diabetic Neuropathy
Subclinical Neuropathy Abnormal Electrodiagnostic Tests Decreased nerve conduction velocity Decreased amplitude of evoked muscle or nerve action potential Abnormal Quantitative Sensory Threshold 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 dilatation 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
Source: Adapted from References 2 and 3
Frequency Distribution of Neuropathy in the Rochester Diabetes Project,
1945-70
80 70 60 50 40 30 20 10 0 Distal Carpal Tunnel Polyneuropathy Syndrome Other Mononeuropathy Neuropathy 12 10 72
6
Source: Reference 1
oped neuropathy9 However, the retrospective nature of the study may have resulted in ascertainment bias Distal polyneuropathy was the most common diagnosis, followed by carpal tunnel syndrome, other neuropathy, and mononeuropathy Figure 151 The prevalence of polyneuropathy increased from 4 for diabetes of short duration 5 years to 15 after 20 years of diabetes Half the patients who developed neuropathy developed it within 9 years of diagnosis of diabetes Distal polyneuropathy and mononeuropathy were more common in patients with poor glycemic control 24 than in those with good control 10
THE ROCHESTER DIABETIC NEUROPATHY STUDY
The Rochester Diabetic Neuropathy Study RDNS is a population-based cross-sectional survey and longitudinal follow-up study of diabetic neuropathy in Rochester, MN10 It uses quantitative, validated, and unique end points to detect, classify, and stage neuropathy10 Diagnostic criteria for neuropathy have been described in detail8 This study is complementary to the earlier Rochester Diabetes Project and provides
information on all forms of neuropathy, including distal polyneuropathy, proximal symmetric neuropathy, autonomic neuropathy, truncal radiculopathy, cranial neuropathy, and carpal tunnel syndrome The RDNS identified all patients with diabetes in Rochester, MN on January 1, 1986 The prevalence age- and sex-adjusted to the 1990 US Census population of diabetes was 1611 Type of diabetes was classified by C-peptide levels after glucagon challenge10 Forty-three percent 380/870 of the patients with diabetes in the population underwent detailed
340
of three areas: symptoms, signs, and quantitative sensory tests or electrodiagnostic studies3,7,8 Other neuropathies are less common than the distal symmetrical type Occasionally a single nerve or nerve trunk is damaged, leading to pain and motor dysfunction that is usually reversible Compression neuropathies such as carpal tunnel syndrome are common in diabetes Autonomic neuropathy usually occurs in the setting of generalized neuropathy and is diffuse Dysfunction is seen in autonomic fibers in cranial, visceral, and somatic nerves
THE ROCHESTER DIABETES PROJECT
The Rochester Diabetes Project was the first community-based study of neuropathy
in a US population Patients with NIDDM diagnosed during 1945-70 in Rochester, MN were studied9 Based on medical records, 3 of patients had neuropathy at the time diabetes was diagnosed, and 10 subsequently devel-
Figure 152
Figure 154
Prevalence of Neuropathy in the Rochester Diabetic Neuropathy Study, 1986
70 60 50 40 30 20 10 0 All Neuropathy Distal Carpal Tunnel Polyneuropathy Syndrome Autonomic Neuropathy 48 604
Severity of Distal Polyneuropathy in the Rochester Diabetic Neuropathy Study, 1986
40 35 39 IDDM 32 NIDDM
473 317
30 25 20 15 10 5 0 Subclinical Mild More Severe 9 6 1 12
Prevalence figures are age- and sex-adjusted to the Rochester, MN population Source: Reference 11 Source: Reference 11
study for neuropathy Nonparticipants were older, less educated, more likely to be widowed or retired, and had more macrovascular disease12 However, the prevalence of retinopathy, nephropathy, and neuropathy was similar in respondents and nonrespondents, and the study results are applicable to all diabetic patients in Rochester with respect to these complications12 Of the 380 subjects undergoing detailed study, 102 268 had IDDM and 278 732 had NIDDM Almost all participants were
white The prevalence rates for neuropathy age- and sex-adjusted to the Rochester, MN population are shown in Figure 152 The prevalence of distal polyneuropathy was greatest, followed by carpal tunnel syndrome and autonomic neuropathy The prevalence of any neuropathy was 66 for IDDM and 59 for NIDDM Figure 153
Figure 153
The frequency distribution by type of neuropathy was similar for IDDM and NIDDM Figure 153 Severity of distal neuropathy was also similar for IDDM and NIDDM Figure 154 Subclinical neuropathy occurred in 39 of those with IDDM and in 32 of those with NIDDM Symptomatic distal polyneuropathy mild and more severe occurred in 15 of IDDM and 13 of NIDDM Only the more severe form of polyneuropathy occurred more commonly in IDDM 6 of IDDM versus 1 of NIDDM, p002Figure 15411 Asymptomatic carpal tunnel syndrome occurred in 22 of those with IDDM and 29 of those with NIDDM Figure 155 The distribution of symptomatic carpal tunnel syndrome was similar in IDDM and NIDDM, occurring in 11 of IDDM and 6 of NIDDM Figure 155 Electrophysiologic evidence of
Figure 155
Prevalence of Neuropathy in the Rochester Diabetic Neuropathy Study, 1986
70 60 50 40
33 66 59 54 45
Severity of Carpal
Tunnel Syndrome in the Rochester Diabetic Neuropathy Study, 1986
30 25 20 29 IDDM 22 NIDDM
IDDM
NIDDM
35
30 20
12
15 10
7 5
9 4 2 No Symptoms Symptoms 2
10 0
5
33 3
Any Distal Carpal Autonomic Other Not Diabetes Neuropathy Polyneuropathy Tunnel Neuropathy Neuropathy Related Syndrome
0 Symptoms Diagnostic Tests
Source: Reference 11
Source: Reference 11
341
carpal tunnel syndrome correlated significantly with polyneuropathy Autonomic neuropathy was the least common form of neuropathy Age- and sex-adjusted prevalence was 48 confidence interval CI 27-69 Of those with autonomic neuropathy, impotence in men was the most common problem, occurring in 13 of IDDM and 8 of NIDDM Gastroparesis, night diarrhea, urinary incontinence, and postural fainting occurred in 0-1 of those with IDDM and NIDDM Cranial mononeuropathy and truncal polyneuropathy were not observed Mononeuropathy multiplex proximal symmetric polyneuropathy occurred in 1 of those with IDDM and 1 of those with NIDDM Ulnar neuropathy and femoral cutaneous neuropathy meralgia paresthetica occurred in 2 and 1 of those with IDDM and NIDDM, respectively 11
symptoms Only 3 had no history of symptoms Figure 156 In these
latter patients, diagnosis was based on abnormal reflexes and temperature sense and altered vibration threshold Among those with definite neuropathy, a history of symptoms was accompanied by abnormal tendon reflexes 81, abnormal reflexes and temperature sense 10, or abnormal temperature sense alone 6Figure 156 Patients with only symptoms or only one sign were classified as having possible neuropathy Of these individuals, 69 had symptoms only, 29 reflex changes, and 3 abnormal sensation14 Symptoms were qualitatively the same in patients with definite and possible neuropathy with respect to quality, location, and timing of symptoms The only difference between the two groups was that a higher proportion of patients with definite neuropathy had symptoms daily 49, compared with patients with possible neuropathy 29 The prevalence of distal symmetrical neuropathy was associated with age and glucose tolerance status Figure 157 Among patients with diabetes, the prevalence was lowest in those age 20-44 years 103 and highest in those age 65-74 years 323 Ageadjusted prevalence was 39 for subjects with normal glucose tolerance, 112 for those with impaired glucose tolerance IGT, and 258 in those
with diabetes14 Analysis of the data for risk factors for neuropathy in those with diabetes in the study showed that neuropathy was more common in males than in females 34 versus 206 Neuropathy was signifiFigure 157
THE SAN LUIS VALLEY STUDY
The San Luis Valley Study is a geographically based case-control study of NIDDM that used modern diagnostic criteria and validated measures to ascertain distal symmetrical polyneuropathy in 1984-8613-15 The survey sample was the entire population of patients with NIDDM in Alamosa and Conejos counties in southern Colorado Patients were considered to have definite neuropathy if two of three criteria were present: bilateral symptoms of neuropathy, bilateral absent or decreased ankle jerk reflexes, and bilateral absent or altered cold perception Neuropathy was independently confirmed by measuring vibration perception threshold Of all patients, 278 had definite neuropathy; 97 of these had a history of neuropathy
Figure 156
Prevalence of Distal Polyneuropathy by Age and Glucose Tolerance Status, San Luis Valley, CO, 1984-86
35 30 25 20 15 10 10 6 5 3 Reflexes and Temperature Sense 0 20-44 45-64 Age Years 65-74 1 13 10 7 3 4 5 14 13 Normal glucose
tolerance test Impaired glucose tolerance 28 Diabetes Total 19 32
Distribution of NIDDM Patients with Definite Neuropathy According to Neuropathy Criteria, San Luis Valley, CO, 1984-86
90 80 70 60 50 40 30 20 10 0 History and Reflexes History, History and Reflexes, and Temperature Temperature Sense Sense 81
Source: Reference 14
Source: Reference 14
342
Figure 158
Figure 159
Prevalence of Distal Polyneuropathy by Duration of NIDDM, San Luis Valley, CO, 1984-86
60 519 50 412 40 30 20 10 0 0-4 5-9 10-14 15-19 20-24 Duration of Diabetes Years 25 168 177 333 526
Prevalence of Symptoms of Sensory Neuropathy by Sex and Diabetes Status, Age 18 Years, US, 1989
50 45 40 35 30 25 20 15 10 5 0 No Diabetes NIDDM 98 118 Males Females 398 360
Source: Reference 14
Data are based on interview information obtained in the 1989 National Health Interview Survey Source: Reference 17
cantly related to duration of diabetes, increasing from 168 in those with duration of diabetes 4 years to 526 in those with diabetes 25 years Figure 158 After adjusting for age and duration of diabetes, there was no effect of ethnic background on prevalence of neuropathy, which was present in 30 of Anglos and 268
of Hispanics15 Neuropathy occurred with equal prevalence among those who had never used alcohol and those who had The effect of quantity of alcohol consumed in those with a history of alcohol use was not examined Subjects with neuropathy had significantly higher mean hemoglobin A1c than those without neuropathy 112 versus 102 Hemoglobin A1c was also slightly higher in subjects with IGT and neuropathy than in subjects with normal glucose tolerance 75 versus 72
autonomic neuropathy, focal neuropathies, or insensate distal symmetrical neuropathy17 The prevalence of neuropathy symptoms was 302 for IDDM and 36 and 397 for men and women with NIDDM, respectively The prevalence was significantly greater p0001 in subjects with diabetes when compared with nondiabetic subjects but was not significantly different in men and women Figure 159 In the NHIS, 98 of men and 118 of women without a history of diabetes gave a history of neuropathy symptoms The prevalence of symptoms increased with duration of diabetes similarly in men and women Figure 1510 Symptoms were significantly greater in Mexican-American and black subjects with duration of diabetes 5-14 years, but not 15
Figure 1510
1989
NATIONAL HEALTH INTERVIEW SURVEY NHIS
The 1989 NHIS was a population-based structured interview of 84,572 persons age 18 years16 In this sample, 2,405 subjects had a physician diagnosis of diabetes, of whom 993 answered the questionnaire A comparison group of 20,037 subjects without a history of diabetes also answered the questionnaire The questionnaire sought information about sensory symptoms and altered touch and temperature perception affecting the hands and feet The NHIS was based on symptoms, which would tend to overestimate the prevalence of distal sensorimotor neuropathy The most sensitive indicator of neuropathy is an abnormality in nerve conduction, followed by abnormal quantitative sensory examination8,10 Sensory symptoms have the lowest predictive value for diabetic neuropathy On the other hand, a survey based on symptoms might underestimate individuals with
343
Prevalence of Symptoms of Sensory Neuropathy in NIDDM by Sex and Diabetes Duration, Age 18 Years, US, 1989
60 50 40 30 20 10 0 Males Females
389 29 290 319 415 366 332 311
0-1
Diabetes duration years 2-4 5-9 10-14 15-19
457
19
462
532
383 381
Data are based on interview information obtained in the 1989
National Health Interview Survey Source: Reference 17
Figure 1511
Figure 1513
Prevalence of Symptoms of Sensory Neuropathy in NIDDM by Race and Diabetes Duration, Age 18 Years, US, 1989
60 50 40
318 314
Effects of Hyperglycemia and Glycosuria on the Presence of Sensory Neuropathy in NIDDM, Age 18 Years, US, 1989
3 Hyperglycemia 21 2 15 1 05 11 10 10 13 11 17 Glycosuria 26 2 20
Duration years 0-4 5-14 15
384 342 436 417 466
547 414
25
24 23
30 20 10 0 Whites Blacks Mexican Americans
0 Never Rarely Sometimes Most Time Always
Data are based on interview information obtained in the 1989 National Health Interview Survey Source: Reference 17
Data are based on interview information obtained in the 1989 National Health Interview Survey Hyperglycemia and glycosuria were self-reported based on results of self blood glucose monitoring and physicians tests for glucose Source: Reference 17
years, and was increased in Mexican Americans with duration of diabetes 4 years Figure 1511 There was a progressive increase in relative risk for symptoms of neuropathy with increasing duration of diabetes, and for a history of hypertension, which was associated with a 60 risk increase Figure
1512 The relative risk for symptoms of neuropathy also incre 
ased with measures of severity of blood and urine glucose Figure 1513 Comparison of demographic characteristics in subjects with and without neuropathy symptoms showed that absence of symptoms was associated with higher family income 25,000/year and with lower rates
Figure 1512
of retinopathy, nephropathy, proteinuria, macrovascular disease, hypertension, foot and ankle sores, and periodontal disease Patients with neuropathy were more likely to check their feet 1/week and to have their feet checked by a health professional, although only 368 reported being checked 2 times in the preceding 6 months Analysis of the NHIS data by logistic regression showed that duration of diabetes, hypertension, and indices of glycemia were independent risk factors for neuropathy Ethnicity, age, gender, height, and cigarette smoking were not significant risk factors
Figure 1514
Effects of NIDDM Duration and Hypertension on the Presence of Sensory Neuropathy in NIDDM, Age 18 Years, US, 1989
Reflex Changes in Persons with NIDDM, Age 35-74 Years, US, 1976-80
18 16 14 12 10 8 6 4 2 0 Absent knee jerk Absent ankle jerk Absent ankle and/or knee
jerk 102 75 84 67 70 7 112 125
165 168
25 21 2 15 1 05 0 0-4 5-9 10-14 15-19 20 1 10 13 10 1 17 12 16
35-54 No Yes
55-74 Age Years
35-74
Duration of NIDDM Years
Hypertension
Data are based on interview information obtained in the 1989 National Health Interview Survey Source: Reference 17
Measurements of reflex changes were made during a standardized physicians examination NIDDM consists of diagnosed NIDDM ascertained through medical history and undiagnosed NIDDM ascertained by oral glucose tolerance test Source: Harris MI, National Diabetes Data Group, unpublished data from the 1976-80 National Health and Nutrition Examination Survey
344
1976-80 NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY NHANES II
Absence of knee and/or ankle jerks was ascertained in the NHANES II18 Diabetes was ascertained by medical history and oral glucose tolerance test Among all persons with diabetes age 35-74 years, absence of one or both reflexes was noted in 125 and was more common in younger subjects Figure 1514 Absence of reflexes was 15-2 times more common among those with a medical history of diabetes than those with diabetes detected by glucose tolerance test Figure 1515 Reflex
changes were two to three times more common in those with diabetes than in persons without diabetes Figure 1515
Table 152
Hospital Discharges Listing Both Diabetes and Selected Neuropathy Conditions, 1989-91
Percent of ICD9-CM Number of all diabetes code discharges discharges
3572 355 354 34461 265,693 14,801 15,770 22,529 303 017 018 026
Condition
Polyneuropathy in diabetes Mononeuritis of lower limb Mononeuritis of upper limb Neurogenic bladder Diabetes with neurologic manifestations
2506 Idiopathic peripheral neuropathy 3568, 3569 Autonomic nervous system disorders Total 337
204,443 14,504 9,312 547,052
233 017 011 623
NATIONAL HOSPITAL DISCHARGE SURVEY
The National Hospital Discharge Survey is a statistical sample of all hospitalizations in the United States19 Based on this survey, neuropathy was estimated to have been listed as a diagnosis in 547,052 hospitalizations during 1989-91, which represented 62 of hospitalizations where diabetes was listed as a diagnosis Table 152 Since the survey counts hospitalizations rather than patients, it is difficult to know the significance of these figures Ascertainment bias may severely limit the usefulness of these data for
assessing the impact of neuropathy on hospitalization rates
All hospitalizations in which diabetes and the selected neuropathy conditions were listed together on the hospital discharge record are included in the table Because multiple neuropathy codes can be listed in the same hospitalization record, the data have been analyzed in hierarchical fashion so that, for example, the number of hospitalizations for mononeuritis of lower limb ICD9-CM 355 does not include any hospitalizations for polyneuropathy in diabetes ICD9CM 3572; the number of hospitalizations for mononeuritis of upper limb ICD9-CM 354 does not include any hospitalizations in which either polyneuropathy in diabetes or mononeuritis of lower limb are mentioned; etc ICD9-CM codes for diabetes were 250, 2513, 3572, 3620, 36841, 6480, and 7751 The total number of diabetes hospitalizations during 1989-91 was 8,775,364 Source: 1989-91 US National Hospital Discharge Surveys
CLINIC, HOSPITAL, COHORT, AND CONVENIENCE SAMPLES
Figure 1515
Reflex Changes in Persons Age 35-74 Years by Diabetes Status, US, 1976-80
18 16 14 12 10 8 6 4 2 0 Medical History Undiagnosed All Persons with of Diabetes NIDDM Diabetes Without Diabetes
49
38 27 91 78 82 146 169
Absent knee jerk Absent ankle jerk Absent ankle and/or knee jerk
125 112
There are numerous reports on neuropathy in the literature based on clinic, hospital, cohort, and convenience samples2 Comprehensive review of this literature is beyond the scope of this chapter However, several studies are unique or have ascertained neuropathy in large random samples using standardized diagnostic criteria and validated methods These will be discussed
70 7
47
The Diabetes Control and Complications Trial
Neuropathy prevalence was ascertained in 278 wellcharacterized patients with IDDM recruited for the feasibility phase of the DCCT6 Diagnosis was based on the presence of signs, symptoms dysesthesia, paresthesia, hyperesthesia, or burning pain, or decreased or absent deep tendon reflexes6 The prevalence of clinical neuropathy in the cohort was 39 Diagnosis was most commonly based on signs 37, reflex changes 28, or signs and reflex changes
345
Undiagnosed NIDDM detected by oral glucose tolerance test; persons without diabetes were ascertained by medical history and oral glucose tolerance test Measurements of reflex changes were made during a standardized physicians
examination Source: Harris MI, National Diabetes Data Group, unpublished data from the 1976-80 National Health and Nutrition Examination Survey
18 Symptoms alone were the basis for diagnosis in only 6 Patients with neuropathy were older, more often male, had longer duration of diabetes, greater height, and lower stimulated C-peptide levels Hemoglobin A1c was not significantly different between those with and without neuropathy The results of the full DCCT trial have been reported20 Neuropathy was assessed at baseline and after 5 years, and the incidence of neuropathy was reported for patients who did not have neuropathy at study entry Diagnosis of neuropathy was based on the presence of an abnormal neurological examination confirmed by either abnormal nerve conduction studies in two or more nerves or abnormal autonomic nervous system tests In the primary prevention cohort, composed of patients who had no vascular complications at study entry, the prevalence of neuropathy at 5 years was 98 in the group receiving conventional diabetes treatment and 31 in the intensively treated patients Figure 1516 In the secondary prevention cohort, composed of patients who had mild to moderate
vascular complications at study entry, the 5-year prevalence was 161 in the conventional treatment group and 70 in the intensive treatment group Figure 1516 Thus, intensive treatment of glycemia was associated with 69 CI 24-87 and 57 CI 29-73 reductions in the development of neuropathy in the primary and secondary cohorts, respectively20 The risk reduction for the combined cohort was 60 CI 38-74 p0002 Intensive treatment yielded significant reductions in clinical, nerve conduction, and autonomic nervous system testing
Figure 1516
results
The Pittsburgh Epidemiology of Diabetes Complications Study
This is a cohort follow-up study of 628 subjects with IDDM drawn from the Childrens Hospital of Pittsburgh PA Insulin-Dependent Diabetes Mellitus Registry21-23 Analysis of a subset of this population of patients with clinically overt neuropathy has shown that glycemic control, triglyceride concentration, and hypertension are independent risk factors for neuropathy22 In a longitudinal follow-up study of patients with abnormal thresholds for perception of vibration and temperature but without overt neuropathy, reevaluation after 2 years showed limited predictive value of these
quantitative measures for development of clinically overt neuropathy23 Analysis of leisure-time physical activity has shown that neuropathy prevalence is lower in males reporting higher levels of current and historical physical activity24 The effect persisted after controlling for duration
Table 153
Symptoms of Autonomic Neuropathy in 168 Patients with IDDM
No Prevalence
Postural hypotension Orthostatic dizziness Fainting on standing Gastroparesis Dysphagia Anorexia Nausea Vomiting Vague fullness after meals Diabetic diarrhea Nocturnal diarrhea Fecal incontinence 20 bowel movements/day Colonic atony 2 bowel movements/week 1 bowel movement/3days Genitourinary Impotence Retrograde ejaculation Urinary bladder Overflow incontinence Dribbling Incomplete emptying Increased urine volume Decreased frequency Sudomotor abnormality Diminished sweating of legs Feeling of increased sweating elsewhere Hypoglycemia unawareness Reduced awareness of hypoglycemia
Source: Adapted from Reference 26
7 0 3 5 11 4 6 0 2 0 2 4 8 1 0 1 10 4 13 2 7 43
4
Effect of Diabetes Treatment on the Prevalence of Clinical Neuropathy at 5 Years in Subjects Without Neuropathy at Study Entry, DCCT, 1993
18 16 14 12
10 8 6 4 2 0 Primary Prevention Cohort Secondary Prevention Cohort 31 98 70 Conventional Intensive 161
2 3 7 2 4
1
1 2 5 1
1 6 2 8 1 4 26
DCCT, Diabetes Control and Complications Trial Neuropathy was defined by abnormal neurologic examination that was consistent with either abnormal nerve conduction in at least two peripheral nerves or unequivocally abnormal autonomic nerve testing; p0001, intensive versus conventional treatment groups, for both cohorts Source: Reference 20
346
of diabetes in univariate analyses Historical physical activity remained a significant predictor of neuropathy in multivariate analysis A trend was seen in the same direction for females but was not statistically significant, perhaps because of the relatively low level of physical activity in the women studied24 In another report on the Pittsburgh cohort, patients with diabetes of 25 years duration were evaluated; 19 were found to be free of any complications of diabetes25 The prevalence of neuropathy was 50 in those with diabetes for 25-29 years and 72 in those with diabetes for 30 years Health behavior variables recent medical contact, better control of dyslipidemia and blood pressure, regular
glucose monitoring, lower glycated hemoglobin, physical activity in youth, and regular consumption at least weekly of alcohol were more prevalent in subjects without complications Using logistic regression, glycated hemoglobin level was the only independent predictor of complications after adjusting for health behavior variables25
Epidemiology of Diabetes Complications Study26 Heart rate response to deep breathing, standing, and Valsalva were measured by two techniques These were an office-based method and the methods used in the DCCT Data were analyzed in the DCCTs central reading lab for autonomic tests The methods gave comparable results, and the prevalence of symptoms of autonomic neuropathy was low Table 153 Modeling by logistic regression showed that female gender, presence of hypertension, and low- and high-density cholesterol were independent predictors of heart rate variation during deep breathing
Miscellaneous Studies
In other studies, height has been shown to correlate strongly with absent vibration sense27,28 A clinicbased case-control study has also identified smoking current and ex-smokers as a risk factor for distal neuropathy in IDDM but not NIDDM29
Autonomic
Neuropathy
Autonomic neuropathy was ascertained in a cohort of 168 subjects age 25-34 participating in the Pittsburgh
Dr Richard C Eastman is Director of the Division of Diabetes, Endocrinology, and Metabolic Diseases at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
347
REFERENCES
1 Melton JL III, Dyck PJ: Clinical features of the diabetic neuropathies In Diabetic Neuropathy Dyck PJ, Thomas PK, Asbury AK, Winegrad AI, Porte D Jr, Eds Philadelphia, WB Saunders, 1987, p 27-35 2 Vinik AI, Holland MT, Le Beau JM, Liuzzi FJ, Stansberry KB, Colen LB: Diabetic neuropathies Diabetes Care 15:1926-75, 1992 3 American Diabetes Association, American Academy of Neurology: Consensus statement: Report and recommendations of the San Antonio conference on diabetic neuropathy Diabetes Care 11:592-97, 1988 4 Brown MJ, Asbury AK: Diabetic Neuropathy Ann Neurol 15:2-12, 1984 5 Pfeifer MA, Weinberg CR, Cook DL, Reenan A, Halar E, Halter JB, LaCava EC, Porte D: Correlations among autonomic, sensory, and motor neural function tests in untreated non-insulin-dependent diabetic individuals Diabetes Care 8:576-84, 1985 6 The DCCT Research
Group: Factors in development of diabetic neuropathy Diabetes 37:476-81, 1988 7 Dyck PJ, Karnes JL, Daube J, OBrien P Service FJ: Clinical , and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy Brain 108:861-80, 1985 8 Dyck PJ: Evaluation procedures to detect, characterize, and assess the severity of diabetic neuropathy Diabet Med 8:S48S51, 1991 9 Palumbo PJ, Elveback LR, Whisnant JP: Neurologic complications of diabetes mellitus: Transient ischemic attack, stroke, and peripheral neuropathy Adv Neurol 19:593-601, 1978 10 Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton III LJ, OBrien PC, Litchy WJ, Windebank AJ, Smith BE, Low PA, Service FJ, Rizza RA, Zimmerman BR: The Rochester Diabetic Neuropathy Study Neurology 41:799-807, 1991 11 Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, OBrien PC, Melton III LJ, Service FJ: The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a populationbased cohort: The Rochester Diabetic Neuropathy Study Neurology 43:817-24, 1993 12 Melton LJ, Ochi JW, Palumbo PJ, Chu C-P: Sources of disparity in the spectrum of diabetes mellitus at incidence
and prevalence Diabetes 6:427-31, 1983 13 Hamman RF Marshall JA, Baxter J, Kahn LB, Mayer EJ, , Orleans M, Murphy JR, Lezotte DC: Methods and prevalence of non-insulin-dependent diabetes mellitus in a biethnic Colorado population Am J Epidemiol 129:295-311, 1989 14 Franklin GM, Kahn LB, Baxter J, Marshall JA, Hamman RF: Sensory neuropathy in non-insulin-dependent diabetes mellitus: The San Luis Valley Diabetes Study Am J Epidemiol 131:633-43, 1990 15 Hamman RF Franklin GA, Mayer EJ, Marshall SM, Marshall , JA, Baxter J, Kahn LB: Microvascular complications of NIDDM in Hispanics and non-Hispanic whites San Luis Valley Diabetes Study Diabetes Care 14:655-64, 1991 16 National Center for Health Statistics: Current estimates from the National Health Interview Survey, 1989 Vital and Health Statistics Series 10, No 176, 1990 Harris MH, Eastman R, Cowie C: Symptoms of neuropathy in adults with NIDDM in the US population Diabetes Care 16:1446-52, 1993 National Center for Health Statistics: Plan and operation of the Second National Health and Nutrition Examination Survey Vital and Health Statistics, Series 1, No 15 Washington, DC, US Govt Printing Office, 1981 DHHS publ no PHS 811317
National Center for Health Statistics: National Hospital Discharge Survey Annual Summary Vital and Health Statistics, Series 13, No 109, 112 1991 The Diabetes Control and Complications Trial Research Group: The effect of intensive diabetes treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus: The Diabetes Control and Complications Trial N Engl J Med 329:977-86, 1993 Maser RE, Steenkiste AR, Dorman JS, Nielsen VK, Bass EB, Manjoo Q, Drash AL, Becker DJ, Kuller LH, Greene DA, Orchard TJ: Epidemiological correlates of diabetic neuropathy Diabetes 38:1456-61, 1989 Maser RE, Nielsen VK, Dorman JS, Drash AL, Becker DJ, Orchard TJ: Measuring subclinical neuropathy: Does it relate to clinical neuropathy? Pittsburgh epidemiology of diabetes complications study-V [published erratum appears in J Diabetes Complications 1991;5:205] J Diabetes Complications 5:6-12, 1991 Maser RE, Becker DJ, Drash AL, Ellis D, Kuller LH, Greene DA, Orchard TJ: Pittsburgh Epidemiology of Diabetes Complications Study Measuring diabetic neuropathy follow-up study results Diabetes Care 15:525-27, 1992 Kriska AM, LaPorte RE, Patrick SL, Kuller LH, Orchard TJ:
The association of physical activity and diabetic complications in individuals with insulin-dependent diabetes mellitus: The Epidemiology of Diabetes Complications Study– VII J Clin Epidemiol 44:1207-14, 1991 Orchard TJ, Dorman JS, Maser RE, Becker DJ, Ellis D, LaPorte RE, Kuller LH, Wolfson SK Jr, Drash AL: Factors associated with avoidance of severe complications after 25 yr of IDDM Pittsburgh Epidemiology of Diabetes Complications Study I Diabetes Care 13:741-47, 1990 Maser RE, Pfeifer MA, Dorman JS, Kuller LH, Becker DJ, Orchard TJ: Diabetic autonomic neuropathy and cardiovascular risk Pittsburgh Epidemiology of Diabetes Complications Study III Arch Intern Med 150:1218-22, 1990 Sosenko JM, Gadia MT, Fournier AM, OConnell MT, Aguiar MC, Skyler JS: Body stature as a risk factor for diabetic sensory neuropathy Am J Med 80:1031-34, 1986 Gadia MT, Natori N, Ramos LB, Ayyar DR, Skyler JS, Sosenko JM: Influence of height on quantitative sensory, nerve-conduction, and clinical indices of diabetic peripheral neuropathy Diabetes Care 10:613-16, 1987 Mitchell BD, Hawthorne BD, Hawthorne VM, Vinik AI: Cigarette smoking and neuropathy in diabetic patients Diabetes Care 13:434-37,
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