CHAPTER 23 PERIPHERAL AND AUTONOMIC NEUROPATHY IN DIABETES Rodica Pop-Busui, MD, PhD, Andrew J. M. Boulton, MD, DSc (Hon), FACP, FICP, FRCP, and Jay M. Sosenko, MD

Dr. Rodica Pop-Busui is Professor of Internal Medicine, Metabolism, Endocrinology and Diabetes in the Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, and Co-Director of the Neuropathy Center, University of Michigan, Ann Arbor, MI. Dr. Andrew J. M. Boulton is Professor of Medicine, University of Manchester, and Consultant Physician, Manchester Royal Infirmary, Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, United Kingdom, and Visiting Professor, University of Miami, Miami, FL. Dr. Jay M. Sosenko is Professor of Medicine, Pediatrics, and Epidemiology, Department of Medicine, Division of Endocrinology, University of Miami Miller School of Medicine, Miami, FL.

SUMMARY

Diabetes is the most common cause of neuropathy in the United States. Of hospital discharges between 2005 and 2010 among those age ≥18 years, 7.8% had an International Classification of Diseases, Ninth Revision (ICD-9), code of Diabetes with Neurological Manifestations, and 4.6% of discharges had a code of Polyneuropathy in Diabetes. This far exceeds hospital discharges coded for any other cause of neuropathy.

Classification systems have been developed for a number of manifestations of neuropathy. Among these various forms, the most common is distal symmetrical polyneuropathy (DSPN). The reported incidence and prevalence vary widely from study to study. These differences are likely attributable to several factors, including the population studied, the criteria used to diagnose DSPN, and the modalities used to detect the condition. Among type 1 diabetes patients, one prospective study found a 29% cumulative incidence after approximately 5 years of follow-up, while another found a cumulative incidence of 35% over a follow-up of 13–14 years.

DSPN is associated with several risk factors, of which glucose levels and the duration of diabetes appear to be the most influential. However, associations have been found with other characteristics, including height, blood pressure, and lipid levels.

Autonomic neuropathy is another troubling complication of diabetes. Of its multiple manifestations, cardiovascular autonomic neurop- athy (CAN) has been the most studied. Similar to DSPN, incidence and prevalence estimates vary. In a large study of patients with type 1 diabetes who had normal autonomic function at baseline, less than 10% were found to have CAN after approximately 5 years of follow-up. CAN increases substantially with diabetes duration to rates as high as 35% after 22 years in individuals with type 1 diabetes and to 60% in patients with type 2 diabetes. Differences in prevalence and incidence estimates of CAN also could be attributable to differences in study populations, diagnostic criteria, and tests utilized for detection.

Risk factors have been identified for autonomic neuropathy. Although glycemia is a risk factor among individuals with type 1 diabetes, it has not clearly been identified as such for individuals with type 2 diabetes. Autonomic neuropathy has also been associated with cardio- vascular risk factors.

In an analysis performed for Diabetes in America, 3rd edition, heart rate (beats/minute) was significantly higher in adults with diagnosed diabetes (mean 75.8) compared with those with normal glucose levels (mean 68.9). Heart rate was also higher in those who were diag- nosed at the study visit with diabetes (mean 73.9) or prediabetes (mean 70.5) than in those with normal glucose levels. Of those with diabetes, the heart rate was significantly higher among diabetic individuals with glycosylated hemoglobin (A1c) ≥11.0% (mean 85.0) than among those with A1c <7.0% (mean 74.1). The basis for the higher heart rate among diabetic patients and the relation of heart rate to A1c are unknown. However, it is possible that heart rate, even within the normal range, is related to autonomic dysfunction.

A number of questions need to be answered with regard to diabetic neuropathy, such as whether glucose variability influences its development beyond the effects of the degree and duration of hyperglycemia. Such information should ultimately lead to a better under- standing of how to treat and prevent the disorder.

Received in final form May 9, 2016. 23–1 DIABETES IN AMERICA, 3rd Edition

INTRODUCTION

Of all the long-term complications of neuropathy has received strong support diabetes, clinical differences do exist in diabetes, none affects as many organs or from landmark studies, such as the the natural history and the prevalence of systems as the group of conditions that are Diabetes Control and Complications Trial the various forms of neuropathy (6). The included under the term “diabetic neurop- (DCCT) (1,2,3). In the DCCT, the benefits of epidemiology and natural history of the athies.” The frequency with which diabetes 6.5 years of intensive glucose control were neuropathies are not well defined, in large affects the nervous system and the diverse maintained for at least 13–14 years after part due to variable diagnostic criteria manifestations of neuropathies might well the end of the study (4,5). and patient populations studied. The late explain the earlier view that diabetes was sequelae of neuropathy are well recognized, a consequence of, rather than a cause The hallmark of the diabetic neuropathies with foot problems, including ulceration (7), of, nerve dysfunction. Neuropathies is a progressive loss of all populations gangrene, and Charcot neuroarthropathy have been described in patients with of nerve fibers, which can be assessed (8), representing the most common cause diabetes of differing causes, suggesting a in a variety of ways. Although there are of hospitalization among diabetic patients common etiologic mechanism based on no major structural differences in nerve in most Western countries. Not surpris- chronic hyperglycemia. The importance pathology between the two main types ingly, diabetic neuropathy often has an of hyperglycemia in the pathogenesis of of diabetes, type 1 diabetes and type 2 adverse effect on quality of life (9,10,11).

DEFINITION OF DIABETIC NEUROPATHIES

The consensus in the field is that symptoms, however, cannot be equated neuropathy should not be diagnosed on diabetic neuropathies are defined with absence of neuropathy, as asymp- the basis of one symptom, sign, or test by “the presence of symptoms and/ tomatic neuropathy is quite common alone: a minimum of two abnormalities or signs of peripheral and autonomic (12,13,14,15). The exclusion of nondia- (from symptoms and signs) confirmed nerve dysfunction in people with betic causes has also been emphasized, by nerve conduction abnormalities, diabetes after the exclusion of other as up to 10% of peripheral neuropathy in quantitative sensory testing (QST), or causes” that are confirmed by a careful diabetic patients may be of nondiabetic quantitative autonomic tests is recom- clinical examination (12). Absence of etiology (13,15,16). In addition, diabetic mended (14,17,18).

CLASSIFICATION OF THE DIABETIC NEUROPATHIES

Many classification systems for diabetic associated with microvessel retinal and to 50% of patients may eventually develop neuropathy have been proposed over kidney disease, but other causes of symptoms and/or signs of DSPN (14,15). the years based on their anatomical neuropathy must be excluded (18). DSPN occurring in patients with abnormal distribution (e.g., polyneuropathy or glucose metabolism that is nonetheless mononeuropathy, proximal or distal, Among these various forms of diabetic insufficient to diagnose diabetes is some- symmetric or asymmetric, focal or multi- neuropathy, the most studied both in times classified as “impaired glucose focal or diffuse), clinical course (e.g., acute, experimental and clinical trials are DSPN tolerance” or “prediabetic” neuropathy (19). subacute, or chronic), or characteristic and cardiovascular autonomic neurop- features (painful or non-painful, sensory, athy (CAN) (18,19,20,22,23). Therefore, The symptoms and sensory loss in DSPN motor, or autonomic) (14,18,19,20,21). findings presented in this chapter are associated with large and small fiber A new, simplified, yet comprehensive mainly pertinent to these two forms of involvement are generally restricted to classification, based on the classifi- neuropathy. a “stocking distribution” (19). The “asleep cations proposed by the American or numb” sensation reflecting large fiber Diabetes Association (ADA) (13), is now DISTAL SYMMETRICAL damage is not usually particularly painful, recommended for use in clinical practice POLYNEUROPATHY contrasting with the tingling, stabbing, (Table 23.1) (13,14,15). DSPN is the most common form of diabetic and burning sensations that likely reflect neuropathy, and most of the available small fiber involvement and ultimately The most typical form of diabetic evidence regarding the epidemiology, result in persistent neuropathic pain neuropathy is a chronic, distal pathogenesis, and treatment is relevant to affecting about 20% of diabetic patients (length-dependent) symmetrical poly- this form. It is usually of gradual onset and (19,21,25). Late sequelae of DSPN include neuropathy (DSPN) that accounts for may be present at the diagnosis of type 2 insensate foot ulceration, Charcot neuro- about 75% of cases (19). It is frequently diabetes in >10% of subjects (15,24). Up arthropathy, and even amputation (15).

23–2 Peripheral and Autonomic Neuropathy in Diabetes

TABLE 23.1. Recommended Classification for Diabetic Neuropathies documentation requires additional testing, including measures of thermal thresholds, Diabetic neuropathies heart rate variation, sweat production, or A. Diffuse neuropathy skin biopsy (19). There are also forms Distal symmetrical polyneuropathy (DSPN) Primarily small fiber neuropathy of SFN associated with weight loss or Primarily large fiber neuropathy treatment (19), including with rapid blood Mixed small and large fiber neuropathy (most common) glucose lowering (26). The symptoms Autonomic Cardiovascular usually gradually improve with establish- Reduced heart rate variability ment of stable blood glucose levels (26). Resting tachycardia Orthostatic hypotension Sudden death (malignant arrhythmia) Chronic Inflammatory Gastrointestinal Demyelinating Polyneuropathy Diabetic gastroparesis Chronic inflammatory demyelinating poly- Diabetic enteropathy (diarrhea) Colonic hypomotility (constipation) neuropathy (CIDP) is an immune-mediated Urogenital neuropathy that has been suggested to Diabetic cystopathy (neurogenic bladder) occur more commonly in people with Erectile dysfunction Female sexual dysfunction diabetes. However, its relationship to Sudomotor dyfunction diabetes is controversial, since it could Distal hypohydrosis/anhidrosis be a chance occurrence of two common Gustatory sweating Hypoglycemia unawareness disorders. An unmasking of mild diabetes Abnormal pupillary function among some CIDP patients treated with B. Mononeuropathy (mononeuritis multiplex) (atypical forms) corticosteroids is possible (19). As CIDP Isolated cranial or peripheral nerve (e.g., CN III, ulnar, median, femoral, peroneal) may present clinically in a similar fashion Mononeuritis multiplex (if confluent may resemble polyneuropathy) to DRPN and often responds to immuno- C. Radiculopathy or Polyradiculopathy (atypical forms) therapy, the differential diagnosis between Radiculoplexus neuropathy (also known as: lumbosacral polyradiculopathy, proximal motor amyotrophy) Thoracic radiculopathy these two conditions is very important. Nondiabetic neuropathies common in diabetes DIABETIC AUTONOMIC NEUROPATHY Pressure palsies Chronic inflammatory demyelinating polyneuropathy Diabetic autonomic neuropathy (DAN) Acute painful small fiber neuropathies (treatment-induced) can involve a number of different systems, SOURCE: Reference 15, copyright © 2017 American Diabetes Association, reprinted with permission from The including cardiovascular, gastrointestinal, American Diabetes Association urogenital, and sudomotor. This might result in an array of symptoms and signs, ATYPICAL FORMS OF Focal limb neuropathies are often due to such as postural hypotension, decreased DIABETIC NEUROPATHY entrapment; the most susceptible nerves bowel motility, decreased bladder contrac- Diabetic Radiculoplexus Neuropathy include the median, ulnar, radial, lateral tility, erectile dysfunction, and sweating Diabetic radiculoplexus neuropathy femoral cutaneous, fibular, and plantar 19( ). disorders. More advanced disease, mani- (DRPN), also called proximal motor Oculomotor palsy is the most common fested by debilitating symptoms and neuropathy, most often presents with a cranial neuropathy. It presents with acute signs, is usually very difficult to treat and lumbosacral distribution (also known as onset of unilateral headache, ptosis, and fortunately rare. Some of the various mani- diabetic amyotrophy). It affects about impaired extraocular movements, but with festations are described below. Symptoms 1% of diabetic patients who are typically a pupil that responds normally to light (19). of the various forms of DAN are listed in middle aged or older and have type 2 Table 23.2 (15). Among all forms of DAN, diabetes (19). DRPN presents subacutely Acute Painful Small most available evidence from experimental with girdle-like pain, usually very difficult Fiber Neuropathies and clinical studies regarding natural to manage, followed by asymmetric prox- Acute painful small fiber neuropathies history, pathogenesis, and treatment is imal leg weakness and profound atrophy. (SFN) are characterized by the subacute pertinent to CAN (15,19,27). It has a monophasic course, with improve- onset of painful sensations in the legs, ment beginning within 9–12 months, progressing over days to weeks to Cardiovascular Autonomic Neuropathy although recovery can be incomplete and unremitting burning dysesthesias and allo- The earliest sign of CAN is impaired heart protracted over years (19). dynia. They are associated with minimal rate variability (HRV), which may be or absent sensory loss and preserved completely asymptomatic (15,23,28,29). Focal Peripheral Neuropathies ankle reflexes. Since small nerve fiber In more advanced cases, patients may Focal peripheral neuropathies usually involvement is not evaluated by conven- present with resting tachycardia and involve cranial, thoracic, or extremity nerves. tional neurophysiological studies, its exercise intolerance due to a reduced

23–3 DIABETES IN AMERICA, 3rd Edition

TABLE 23.2. Symptoms Associated With Diabetic Autonomic Neuropathy both in diabetic and nondiabetic patients. These factors should be considered before CARDIOVASCULAR GASTROINTESTINAL UROGENITAL a diagnosis of diabetic gastroparesis is AUTONOMIC NEUROPATHY AUTONOMIC NEUROPATHY AUTONOMIC NEUROPATHY confirmed (30). Advanced cases dominated Resting tachycardia Gastroparesis Bladder dysfunction by severe nausea and postprandial vomiting § Nausea § Frequency Abnormal blood pressure § Bloating § Urgency can complicate diabetes control and reduce regulation § Loss of appetite § Nocturia the quality of life (30). § Non-dipping § Early satiety § Hesitancy § Reverse dipping § Postprandial vomiting § Weak stream Intestinal dysfunction may manifest as Exercise intolerance § Dribbling Esophageal dysfunction § Urinary incontinence profuse and watery diarrhea sometimes § Heartburn Orthostatic hypotension § Urinary retention alternating with constipation. This may be § Lightheadedness § Dysphagia for solids Male sexual dysfunction challenging to treat. Diabetic diarrhea is § Weakness Diabetic diarrhea § Faintness § Erectile dysfunction typically intermittent, occurring at night, § Profuse and watery diarrhea § Decreased libido § Dizziness § Fecal incontinence and is more likely to occur in patients § Visual impairment § Abnormal ejaculation with other forms of autonomic dysfunc- § Syncope Constipation Female sexual dysfunction (all with standing) § Decreased sexual desire tion (30). The prevalence rates of a pure § Increased pain during autonomic diabetic diarrhea are unclear, intercourse given that diarrhea may be associated with § Decreased sexual arousal § Inadequate lubrication many other conditions that can coexist in diabetes, such as infectious causes, various SOURCE: Adapted from Reference 15, copyright © 2017 American Diabetes Association, reprinted with permission from The American Diabetes Association drugs, and irritable bowel disease. People with diabetes may also experience fecal response in heart rate and blood pres- From these limited data, idiopathic gast- incontinence due to poor sphincter tone. sure, as well as blunted increases in roparesis appears to be the most common cardiac output with exercise (Table 23.2) category, followed by diabetic gast- Urogenital Autonomic Neuropathy (15,23,28,29). roparesis (32). Data from the Rochester Bladder dysfunction may occur in up Epidemiology Project, a database of linked to 50% of people with diabetes (30). Orthostatic hypotension (a fall in systolic medical records of residents of Olmsted Symptoms are diverse and include or diastolic blood pressure in response County, Minnesota, showed that the frequency, urgency, nocturia, hesitancy, to a postural change from supine to age-adjusted incidence of definite gast- a weak stream, dribbling and urinary incon- standing) occurs in diabetes largely as roparesis per 100,000 person-years for tinence, and urinary retention (Table 23.2). a consequence of efferent sympathetic 1996–2006 was 9.8 for women and 2.4 vasomotor denervation, causing reduced for men in the general population (33). Erectile dysfunction is present in vasoconstriction of the splanchnic and 30%–75% of diabetic men (30). It has other peripheral vascular beds (23,28,29). Regarding diabetic gastroparesis, most data a multifactorial etiology that includes are from selected case series rather than autonomic neuropathy, other vascular Gastrointestinal Autonomic larger populations, and there is inconsis- risk factors (hypertension, hyperlipidemia, Neuropathy tency in the outcome measure used (31) or obesity, endothelial dysfunction, smoking, The effect of autonomic neuropathy on the in excluding other factors with direct effect and cardiovascular disease), concomitant gastrointestinal system can have several on gastrointestinal motility (31). Earlier medication, and psychogenic factors. manifestations. reports, that predated the routine use of intensive glucose management, described Female sexual dysfunction may occur in Esophageal dysfunction results, at least in prevalence rates of up to 50% of patients diabetic women and present as decreased part, from vagal dysfunction. Associated with longstanding diabetes (30). More sexual desire, increased pain during inter- symptoms include heartburn and recently, in the only community-based study course, decreased sexual arousal, and dysphagia for solids. of gastroparesis in diabetes, the cumulative inadequate lubrication. incidence of symptoms and delayed gastric Gastroparesis is due to delayed gastric emptying over 10 years was higher in type Other Manifestations of emptying and may manifest with a broad, 1 diabetes (5%) than in type 2 diabetes (1%) Autonomic Neuropathy but nonspecific, spectrum of symptoms and controls (1%) (34). However, there are Autonomic neuropathy can lead to and signs (Table 23.2) (30,31). The prev- several classes of medication (especially sudomotor dysfunction with such manifes- alence data on gastroparesis are limited, opioids, other pain management agents, tations as anhidrosis, heat intolerance, dry mainly because gastric emptying studies, glucagon-like peptide-1 [GLP-1] receptor skin, and hyperhidrosis (35). An unaware- necessary for proper diagnosis, may be agonists, pramlintide) and other factors that ness of hypoglycemia could also possibly difficult to perform in population studies. may considerably delay gastric emptying be related to autonomic neuropathy.

23–4 Peripheral and Autonomic Neuropathy in Diabetes

ASSESSMENT OF DIABETIC NEUROPATHIES

This section focuses on assessments of composite scores of symptoms have Revascularization Investigation 2 DSPN and CAN, which have been most been developed, such as the Neuropathy Diabetes (BARI 2D) (27,43). Second, the studied in epidemiologic and random- Symptom Score (NSS), the Neuropathy simplified neuropathy disability score ized clinical studies (27). For details on Symptom Profile (NSP) 24( ), and the (NDS) requires a simple clinical examina- the other forms of diabetic neuropathy, symptoms questionnaire of the Michigan tion that sums abnormalities of reflexes readers are referred to detailed texts Neuropathy Screening Instrument and sensory assessments. It has been (19,21,36). (MNSI). The MNSI comprises a 15-item, used in clinical practice and in epidemio- yes/no symptom questionnaire that is logic studies (24,44). DISTAL SYMMETRICAL supplemented by a simple clinical exam. POLYNEUROPATHY The simplified NSS and the MNSI have Quantitative Sensory Testing The diagnosis and staging of DSPN are been used for epidemiologic studies QST assesses the patient’s ability to important not only for day-to-day clinical (24,38,39) and can be easily applied in detect a variety of sensory stimuli that practice but also for research assessing clinical practice for diagnosis or patient characterize both large and smaller nerve etiology, natural history, pathogenesis, follow-up, as they are easy to administer. fibers. This methodology also has a large and new treatments. The Peripheral Nerve The McGill Pain Questionnaire, which is degree of subjectivity, as results are a Society issued a Consensus Statement on a general pain instrument, also has been function of the patient’s concentration measures to assess efficacy in controlled used by several research groups. and cooperation. Moreover, an abnormal trials of new therapies for neuropathy in finding does not necessarily indicate 1995 (37), and more recently, in 2009, In addition, the quality of life has increas- peripheral neuropathy; the abnormality the Toronto Consensus on Diabetic ingly been emphasized as an important may lie anywhere in the afferent Neuropathies panel reviewed the defi- factor in the natural history of neuropathic neural pathway. QST methods vary in nitions and diagnostic criteria of DSPN symptomatology, and specific instruments complexity: the simpler instruments can for possible, probable, confirmed, and have been developed and validated for be used in day-to-day clinical practice, subclinical categories (18). use in diabetic neuropathy, such as the whereas the more sophisticated instru- NeuroQoL (40), the MNSI (41), and the ments, usually requiring more expensive The Toronto panel defined possible DSPN Norfolk QOL-DN (42). equipment and an external power source, as appropriate sensory symptoms OR are commonly used for more detailed signs (symmetrical decrease in distal Clinical Signs assessment and for follow-up assess- sensation or unequivocally abnormal Simple clinical observation of the feet and ments in clinical trials. Some of the more ankle reflexes). Probable DSPN was legs after the removal of shoes and socks commonly used techniques are now defined as at least two abnormalities may identify a neuropathic foot: evidence briefly described. among sensory symptoms, sensory signs, might include small muscle wasting, or ankle reflexes. Confirmed DSPN was clawing of the toes, prominent metatarsal Semmes-Weinstein monofilaments defined as symptoms OR signs (sensory heads, dry skin and callus (secondary to comprise sets of nylon filaments of vari- or ankle reflexes) AND an abnormal nerve sympathetic autonomic dysfunction), and able diameter that buckle at a predefined conduction study, whereas subclinical occasionally the typical foot deformity force when applied to the testing site— DSPN was defined as an abnormal secondary to Charcot neuroarthropathy. usually the dorsal aspect of the halluces nerve conduction study, without signs at the metatarsal-phalangeal joints area or symptoms (18,19). Two simple instruments can be used and plantar surfaces. They are widely in clinical practice or for clinical trial used in clinical practice and are particu- In clinical practice, DSPN remains assessment. First, the clinical examina- larly helpful in identifying individuals who a clinical diagnosis, and equipment tion part of the MNSI, which includes are at risk of neuropathic foot ulceration. requiring an electrical power source or foot examination, the assessment of The inability to perceive pressure of 10 g referral to a neurologist is not usually ankle reflexes, and the measurement of (5.07) monofilaments has been shown needed in the assessment of peripheral vibration perception at the great toe (see in prospective studies to be indicative of nerve function (13,24), except in situations the Quantitative Sensory Testing section) higher risk for neuropathic ulceration (45). where the clinical features are atypical, (41), is a sensitive and specific instrument the diagnosis is unclear, and a different for diagnosis of DSPN (38,41). It has Vibration perception, indicative of myelin- etiology is suspected (14,22). been used in major large clinical trials, ated fiber function, can be assessed with including the DCCT/Epidemiology of several devices. The vibration perception Symptoms Diabetes Interventions and Complications threshold increases with age in nondia- The accurate recording of symptoms study (EDIC) (38,39), the Action to betic individuals and tends to be higher is a basic element of the assessment Control Cardiovascular Risk in Diabetes in the lower extremities. As well as being of neuropathy. A number of simplified (ACCORD), and the Bypass Angioplasty useful in clinical practice, the vibration

23–5 DIABETES IN AMERICA, 3rd Edition perception threshold has been used (14,18). However, electrophysiological Cardiovascular Autonomic in clinical research and epidemiologic testing or referral to a neurologist is rarely Reflex Tests studies (19,27). A simple pocket-sized needed for diagnosis of DSPN in clinical Based on the strongest lines of evidence disposable device, the Vibratrip, has been practice, except in situations where the available to date, cardiovascular auto- validated as a useful tool in the clinical clinical features are atypical, the diag- nomic reflex tests (CARTs) are the setting and may also be useful for the nosis is unclear, or a different etiology is most sensitive, specific, reproducible, prediction of patients at risk for foot ulcer- suspected, as recommended in the ADA safe, and standardized measures ation in the research setting (46). Statement on Diabetic Neuropathy based (15,23,28,29,35,54). Therefore, their use on most recent evidence (15). is recommended as the gold standard for Thermal and cooling thresholds are also clinical autonomic testing (15,28). used to assess sensory function. Warm Skin Biopsy and Corneal and cold sensations are transmitted Confocal Microscopy These tests, first described in the 1970s by small myelinated and unmyelinated Immunohistochemical quantification (55,56), assess cardiovascular autonomic fibers and can be assessed with of intra-epidermal nerve fiber density function using provocative physiological several devices. Since these tend to (IENFD) using punch skin biopsies has maneuvers and include: (1) changes in be expensive, they are used mostly for increasingly been used to quantify small R-R interval from an electrocardiogram clinical research and for detailed clinical fiber neuropathies in diabetes (50). The (ECG) with deep breathing, a measure of assessment (24). introduction of corneal confocal micros- sinus arrhythmia during quiet respiration copy (CCM) represents a novel reiterative reflecting primarily parasympathetic Computer assisted sensory examination in vivo clinical examination technique function (35); (2) the R-R response to (CASE) is a complex methodology that is that is capable of imaging corneal nerve standing, inducing reflex tachycardia regarded as the state of the art for clinical fibers in a noninvasive technique (51). followed by bradycardia, which is jointly trials. It is a computerized device that can CCM has the capacity to detect early vagal- and baroreflex-mediated; (3) the measure touch, pressure, vibration, and nerve fiber repair 6 months after resto- Valsalva ratio, which evaluates cardiovagal warm/cold thresholds using a forced- ration of euglycemia following pancreas function in response to a standardized choice algorithm. CASE is not typically transplantation in type 1 diabetes increase in intrathoracic pressure used in day-to-day clinical practice (18). patients (52). (Valsalva maneuver); and (4) orthostatic hypotension (28). Although no test is Electrophysiology CARDIOVASCULAR clearly superior (28), the deep breathing Electrophysiological tests are objective, AUTONOMIC NEUROPATHY test is the most widely used due to its high noninvasive, and highly reliable measures Several diagnostic approaches with reproducibility, approximately 80% spec- that do not depend on a patient’s varying degrees of complexity are ificity (57), and ease of use (28,35,57). response. However, these tests only available to diagnose CAN in practice or The Valsalva maneuver requires greater measure large fiber afferent and motor research, including the assessment of patient cooperation. Due to the associated nerve function and, therefore, are of cardiovascular reflex testing, HRV, 24-hour increase in intrathoracic, intraocular, and limited use in the evaluation of small- blood pressure profiles, orthostatic hypo- intracranial pressure, it could theoretically fiber deficits47 ( ,48,49). The 2009 tension, baroreflex sensitivity, cardiac result in intraocular hemorrhage or lens Toronto Consensus Panel concluded sympathetic imaging, microneurography, dislocation; thus, it cannot be universally that composite sum scores based on or occlusion plethysmography. performed (28), although there is no clear deviations (from percentiles) of nerve evidence regarding the extent of this risk. conduction study attributes (e.g., fibular Assessment of Symptoms Test abnormalities should be defined using and tibial conduction velocity, sural ampli- Symptoms associated with CAN include age-specific normative data 28( ). Detailed tude) performed best among these tests exercise intolerance, orthostatic intoler- descriptions of CART standardization, for diagnosing DSPN (18). More easily ance, and syncope (Table 23.2) (15,53). analysis, and staging are provided else- applied criteria (e.g., use of ≥1 abnormal The correlation between symptom where (28,58). attribute in two separate lower extremity scores and deficits is generally weak in nerves based on 1st and 99th percentile mild CAN, as these symptoms usually Heart Rate Variability values) perform well (19). occur late in the disease process. Using In normal individuals, beat-to-beat a validated self-report measure of auto- variability with respiration, increasing Composite scores that combine elec- nomic symptoms in a population-based with inspiration and decreasing with trophysiological measures with clinical, study, Low et al. found that autonomic expiration, is due to the direct influence quantitative, and sensory assessments symptoms were present more commonly of sympathetic and parasympathetic are often used in research studies in type 1 diabetes than in type 2 stimuli. A decrease in HRV is the earliest evaluating the natural history of DSPN diabetes (53). clinical indicator of CAN (23,58,59). or the efficacy of various interventions HRV can be evaluated in the time and

23–6 Peripheral and Autonomic Neuropathy in Diabetes frequency domain, derived from ECG average of normal R-R intervals (SDANN), (<0.04 Hz) are essentially related to fluctu- recordings, ideally under paced breathing. and root-mean square of the difference of ations in vasomotor tone associated with Longer ECG recordings (e.g., 24-hour) successive R-R intervals (rMSSD) (60). thermoregulation or activity (58). A variety were initially used exclusively, but of mathematical methods used to analyze shorter recordings also provide reliable The frequency domain measures are HRV and the commercially available soft- information on cardiovascular autonomic obtained by spectral analysis of R-R ware programs for assessment of HRV are function (23,58,60). interval and other respiratory and cardio- broadly covered in Bernardi et al. (58). It is vascular signals (58). It is traditionally generally recommended that HRV testing Time domain measures of the normal R-R accepted that the parasympathetic system be used for research and in conjunction intervals, basically reflecting parasym- affects the high frequency components with CART (58). The accuracy of all HRV pathetic activity, include: the difference (0.15–0.4 Hz), the sympathetic activity measures is affected by various arrhyth- between the longest and shortest R-R essentially influences a rather narrow mias, and the analysis requires normal interval, standard deviation of 5-minute band around 0.1 Hz (low frequency), and sinus rhythm and atrioventricular-nodal the very low frequency components function.

PATHOGENESIS OF THE DIABETIC NEUROPATHIES

The specific mechanisms contributing to mitochondrial production of free radicals with deficits in peripheral and autonomic diabetic DSPN are not completely under- and increased oxidative/nitrosative stress, nerve fibers (59,66,68). Altered mitochon- stood. It is generally accepted that the formation of advanced glycation endprod- drial bioenergetics in dorsal root ganglia pathogenesis of diabetic DSPN is multi- ucts, downregulation of the soluble neurons appear to be modulated by the factorial, involving complex interactions receptor for advanced glycation endprod- heat shock protein (Hsp) 70. Ciliary neuro- between the degree of glycemic control, ucts (sRAGE), activation of the polyol and trophic factors also could be important diabetes duration, age-related neuronal protein kinase C pathways, activation (19,69,70). attrition, and other factors, such as blood of polyADP ribosylation, and activation pressure, lipid levels, and weight (19). of genes involved in neuronal damage, Emerging data in human studies suggest These promote progressive peripheral and cyclooxygenase-2 activation, endothelial that peripheral nerve dysfunction and autonomic neural dysfunction in a fashion dysfunction, altered function of the Na+/ changes in the sympathetic and para- that begins distally and progresses prox- K+-ATPase pump, impaired C-peptide- sympathetic system function may occur imally. Hyperglycemia plays a key role related signaling pathways, endoplasmic prior to the development of diabetic range in the activation of various biochemical reticulum (ER) stress with resulting hyperglycemia in individuals with features pathways related to the metabolic and/or accumulation of unfolded or misfolded of the metabolic syndrome or in patients redox state of the cell, which in concert proteins within the ER lumen, and acti- with impaired glucose tolerance (71,72). with impaired nerve perfusion contribute vation of several apoptotic processes These changes appear to correlate with an to the development and progression of (19,23,59,61,62,63,64,65). increase in adipose tissue-derived inflam- diabetic neuropathies. matory markers (73,74). A detailed review Low-grade inflammatory processes of these mechanisms and their complex Experimental data implicate a number of may also play an important role in the interactions is beyond the scope of this pathogenic pathways that may impact pathogenesis of diabetic neuropathies. chapter. the peripheral and autonomic neuronal Some could be mediated by NF-kappaB function in diabetes, including: increased activation and downstream effects (66,67)

TREATMENT

In line with the evidence discussed above, (disease-modifying therapies) and those long-time protection, especially for CAN this section provides a general overview for symptomatic relief (75). Some inter- (4,5,27,78). of treatments for DSPN and CAN. For ventions have efficacy in both areas. more detailed information and for other The effects of glycemic control on forms, readers are referred to detailed DISEASE-MODIFYING TREATMENTS DSPN or CAN are less conclusive for texts (19,21). Of disease-modifying therapies, tight and type 2 diabetes (27). Data from the 1990s stable glycemic control, implemented suggested that glucose control was bene- There is a distinction between therapies early in the course of diabetes, is most ficial if implemented earlier in the disease that might alter (slow) the progressive supported by data to delay development course in patients with fewer comorbid- loss of nerve fiber function that charac- of DSPN and CAN in patients with type 1 ities (79). ACCORD, the largest type 2 terizes the natural history of neuropathy diabetes (1,2,3,27,76,77) and to promote diabetes trial, reported a significant DSPN

23–7 DIABETES IN AMERICA, 3rd Edition risk reduction in the intensive glycemia FIGURE 23.1. Indices of Cardiovascular Autonomic Neuropathy Are Improved by Lifestyle strategy arm after 5 years of follow-up Modification, Diabetes Prevention Program (80), although other large studies did Heart rate not confirm these findings (81,82,83,84). Placebo Metformin Lifestyle Some studies have suggested that rapid improvement in blood glucose may induce 6.6 symptoms and signs of neuropathy, espe- cially neuropathic pain (26). 65.4 Beatsmin Emerging data suggest that, in type 2 ‡ diabetes, the strategies used to reach 63.2 glycemic goals may be as important as the glucose control achieved (27). The SDNN BARI 2D trial reported that specific glucose-lowering strategies and medica- 2.5 tions used to reach glycemic goals also ‡ have different effects in preventing DSPN 25

in type 2 diabetes (85). Milliseconds

22.5 Lifestyle interventions, particularly diet and exercise consisting of moderately intense aerobic and resistance training, rMSSD improve neuropathic symptoms and 33 IENFD among patients with DSPN associ- ated with impaired glucose tolerance and ‡ with diabetes (86,87). 2 Milliseconds An intensive multifactorial cardiovascular risk factor intervention targeting glucose, 25 blood pressure, lipids, smoking, and other lifestyle factors reduced the progression QT index or the development of CAN among type 2 diabetes patients (88). Data regarding the impact of lifestyle interventions in preventing 1 progression of CAN are emerging (71). In †

the Diabetes Prevention Program, indices Percent .5 of CAN improved more in the lifestyle modification arm than in the metformin or placebo arms (Figure 23.1) (71). Some smaller trials reported that the combination QTc duration of strictly supervised endurance training and dietary changes was associated with improved HRV in overweight patients 413 † who had minimal abnormalities (29). This outcome was possibly mediated by the 4 effects of weight loss on cardiovascular Milliseconds autonomic function (89). 41 Earlier trials of potential disease- 1 2 3 4 Year from Randomiation modifying therapies, including aldose- reductase inhibitors, various antioxidants, Changes in heart rate, heart rate variability indexes, and QT duration over time by treatment arm. QTc, Bazett’s correction; rMSSD, root mean square of successive differences between all normal-to-normal R-R intervals; SDNN, recombinant nerve growth factors, and standard deviation of all normal-to-normal R-R intervals. acetyl-carnitine, did not show appreciable * p<0.05, placebo versus lifestyle † p<0.05, placebo versus metformin benefit (61,90,91). Other therapies, such ‡ p<0.05, metformin versus lifestyle as alpha-lipoic acid (92,93,94), C-peptide SOURCE: Reference 71, copyright © 2006 American Diabetes Association, reprinted with permission from The American Diabetes Association

23–8 Peripheral and Autonomic Neuropathy in Diabetes

(95,96), actovegin (97), and a combina- SYMPTOMATIC TREATMENT available evidence on the most effective tion of L-methylfolate, methylcobalamin, Whereas a number of treatments are avail- agents for treating neuropathic pain in and pyridoxal-5’-phosphate (98), have able for painful symptomatic DSPN, there diabetes, including U.S. Food and Drug shown some promise on symptomatic are no specific therapies for patients with Administration-approved drugs and other relief for DSPN, but the evidence from painless neuropathy or for other symp- agents that should be considered in clin- multicenter randomized clinical trials toms. However, as stated below, all of ical decision making (15). Given the high on objective measures of DSPN is very these patients warrant foot care education risk of addiction, abuse, sedation, and limited, with most being largely nega- and regular podiatric care (45). other complications and psychosocial tive as disease-modifying treatments. issues even with short-term opioid use, Most recently, a phase IIb clinical trial Neuropathic pain can affect several opioids are not recommended in the treat- evaluating the efficacy and safety of long- aspects of a patient’s life, so a multidisci- ment of painful DSPN before failure of acting synthetic C-peptide in patients with plinary approach is essential in managing other agents (15) that do not have these type 1 diabetes and mild DSPN reported the condition. In many cases, the clinical associated concerns. no difference in nerve conduction studies assessment indicates the need for psycho- and clinical outcomes of DSPN compared logical or physical therapy in addition As indicated above, a number of troubling with placebo (99). to standard pharmacologic treatments. symptoms can occur from manifestations Support and information on practical of CAN or other forms of DAN, including Regarding CAN, few phase II randomized measures, such as using a bed cradle to orthostatic hypotension, gastroparesis, controlled trials have shown favorable lift the bed clothes off hyperesthetic skin, diabetic diarrhea, erectile dysfunction, effects on HRV indices using the anti- often prove invaluable. Pharmacologic and bladder dysfunction. There is no oxidant alpha-lipoic acid, vitamin E, or agents include anticonvulsants, serotonin overall treatment for these entities; each C-peptide (23,28). Larger studies are and norepinephrine reuptake inhibitors, treatment must be individualized. needed to confirm these findings, as well tricyclic antidepressants, topical and as to evaluate new, effective potential physical treatments. The ADA Statement pathogenetic treatments. on Diabetic Neuropathy summarized the

EPIDEMIOLOGY AND NATURAL HISTORY OF DISTAL SYMMETRICAL POLYNEUROPATHY AND CARDIOVASCULAR AUTONOMIC NEUROPATHY

Diabetes is by far the most common studies of the natural history and epide- several large studies. In the observational cause of neuropathy in the United States. miology of diabetic neuropathy should be follow-up of the DCCT cohort, the EDIC study, The National Hospital Discharge Survey examined with attention to the specific 25% and 35%, respectively, of the former provides strong evidence for this. In a assessments and criteria for neuropathy intensive and conventional treatment new analysis for Diabetes in America, 3rd that were used. Other factors also should groups had confirmed clinical neurop- edition, data from hospital discharges be considered, such as characteristics of athy at year 13–14 (4). In the Wisconsin between 2005 and 2010 among those age the study population, the type of diabetes, Epidemiologic Study of Diabetic Retinopathy ≥18 years, showed that 7.8% of discharges and study design. (WESDR) (76), depending on characteristics of had an International Classification of the type 1 diabetes patients who were studied, Diseases, Ninth Revision (ICD-9), code of Although a great deal of natural history there was decreased tactile sensation Diabetes with Neurological Manifestations, and epidemiologic information has been in 19%–25% and decreased temperature and 4.6% of discharges had a code of obtained from studies performed in the sensitivity in 11%–19% after 10 years of Polyneuropathy in Diabetes (data not United States, valuable information has follow-up. In the Pittsburgh Epidemiology shown). In comparison, the percentage also been obtained from studies in other of Diabetes Complications Study (EDC), in of discharges with a code for Alcoholic locales. Thus, findings from those other which patients with type 1 diabetes were Polyneuropathy, Polyneuropathy due to studies are included in this discussion. followed, the cumulative incidence of DSPN Drugs, or Polyneuropathy due to Other As mentioned, the vast majority of studies over a period of 5.3 years was 29% (77). Toxic Agents was extremely low (<0.001% have examined the natural history and for Alcoholic Polyneuropathy; number epidemiology of DSPN and CAN. Thus, The importance of methodology in of discharges for Polyneuropathy due to these forms are the focus of this section. considering epidemiologic findings is Drugs or Polyneuropathy due to Other Toxic particularly evident in studies of type 2 Agents was too small for a valid estimate). DISTAL SYMMETRICAL diabetes patients, such as the San Luis POLYNEUROPATHY Valley Study. In that study, the incidence Since there are a number of methods by Incidence and Prevalence of DSPN without a confirmatory exam- which the presence and degree of severity Incidence estimates of DSPN among type ination was approximately 5 per 100 of diabetic neuropathy are assessed, 1 diabetes patients have been examined in person-years, whereas the incidence was

23–9 DIABETES IN AMERICA, 3rd Edition

<1 per 100 person-years when a confir- symptoms have ranged from 3% to >20% frequency and 32% for high frequency). matory examination was performed (100). (7,13,16,103). Marked differences in the This should be considered in estimating The prevalence of vibratory perception prevalence of hypoesthesia have been the actual prevalence of hearing loss abnormalities in adult patients is highly observed according to the mode of QST attributable to diabetes. dependent on the site of measurement. assessment. In one study, the prevalence The more distal the measurement, the varied between 8% and 34% according Comparisons of DSPN prevalence higher the prevalence, even from the to the specific sensory test 104( ). between individuals with type 1 diabetes lateral malleolus to the hallux (101). Studies using combined assessments or type 2 diabetes are clouded by age of neuropathy have also shown marked differences. In the SEARCH for Diabetes Temporal trends can be an important differences in the prevalence of DSPN. in Youth Study (108), the prevalence consideration in assessing the incidence In one such study, the EURODIAB IDDM of DSPN was higher in those with type of DSPN. Data from the EDC revealed a Complications Study (105), the preva- 2 diabetes than in those with type 1 decline in the incidence of DSPN over a lence ranged from <20% to >50% among diabetes (17.7% vs. 8.5%, p<0.001). period of years (102). Among those with the participating sites. However, despite the young study popu- a 25-year duration of type 1 diabetes, the lation, those with type 2 diabetes were cumulative incidence for those diagnosed Ethnicity can be a major determinant of still older. After adjustments for estab- between 1970 and 1974 was significantly prevalence. Even within the American lished risk factors measured over time, lower than among those diagnosed Indian population of the Strong Heart youth with type 2 diabetes had signifi- between 1965 and 1969. Study (106), there was marked variation; cantly higher odds of DSPN versus youth the percentage of those with at least 5 (of with type 1 diabetes (adjusted odds ratio The prevalences of the various manifesta- 10) incorrect monofilament responses was 2.52, 95% confidence interval [CI] 1.43– tions of DSPN have varied widely. In the 22% in Arizona and only 8% in Oklahoma. 4.43, p=0.001) (108). In a cross-sectional National Health Interview Survey 1989 multicenter study that included 6,487 of an adult population, the prevalence Studies have examined hearing loss in randomly selected patients with type 1 of pain and/or tingling among those diabetic individuals, which could possibly diabetes and type 2 diabetes, the preva- with diabetes was 27% (6). However, an be related to neuropathy. The National lence was 22.7% (95% CI 21.0%–24.4%) appreciable proportion of those without Health and Nutrition Examination Surveys in type 1 diabetes and 32.1% (95% diabetes also had those symptoms; the (NHANES) 1999–2004 (107) revealed CI 30.6%–33.6%) in type 2 diabetes. prevalence was approximately 5%–10%. that low to middle frequency and high However, the overall prevalence of DSPN Thus, the difference between these frequency hearing deficits were more increased with age, from 5% (95% CI estimates could be a better indication common (21% and 54%, respectively) in 3.1%–6.9%) in the 20–29 years age of the prevalence of painful neuropathy diabetic patients. However, such hearing group to 44.2% (95% CI 41.1%–47.3%) in attributable to diabetes. In other studies, deficits were also appreciable in the the 70–79 years age group (109). estimates of the prevalence of painful nondiabetic population (9% for low/mid

TABLE 23.3. Prevalence of Distal Symmetrical Polyneuropathy in Observational Studies Performed in the United States

STUDY, YEARS (REF.) TYPE OF DIABETES (N)* RACE/ETHNICITY AGE (YEARS) ASSESSMENT(S) PREVALENCE Epidemiology of Diabetes Type 1 (363) Diverse ≥18 Clinical 18–29 years: 18% Complications (EDC) Study, ≥30 years: 58% 1981 (77) Epidemiology of Diabetes Type 1 (1,186) White 47±7 Clinical + 25% vs. 35% (former intensive vs. Interventions and electrophysiology former conventional Diabetes Complications (EDIC), Control and Complications Trial 2006–2008 (4,78) treatment groups) SEARCH for Diabetes in Youth Type 1 (329) Diverse Type 1: 17.9±4.1† Clinical Type 1: 8.5% Study, 2011–2015 (108) Type 2 (70) Type 2: 22.1±3.5 Type 2: 17.7% National Health Interview Type 1 (124) Diverse ≥18 Pain 27% Survey, 1989 (6) Type 2 (2,268) Strong Heart Study, Type 2 (2,051) American Indian 45–74 Monofilament 8%–22% 1993–1995 (106) (depending on study site) Seattle Prospective Diabetic Type 2 (778) 78% white (veterans) 63.2‡ Monofilament 50% Foot Study, 1988 (125) * If reported as IDDM, indicated as type 1 in the table; if reported as NIDDM, indicated as type 2 in the table. † Mean±standard deviation ‡ Mean value calculated from available data SOURCE: References are listed within the table.

23–10 Peripheral and Autonomic Neuropathy in Diabetes

Table 23.3 provides a summary of the TABLE 23.4. Prevalence of ≥1 Monofilament Errors Among Adults Age ≥40 Years With prevalence of neuropathy found in obser- Diagnosed Diabetes, by A1c Value, U.S., 1999–2004 vational studies performed in the United PERCENT (STANDARD ERROR) States. The wide variation in prevalence Diagnosed Diabetes, A1c is evident. As indicated, this could well be attributable to variation in age, ethnicity, <7.0% ≥7.0%–<9.0% ≥9.0%–<11.0% ≥11.0% Normal Glucose Levels and type of diabetes. The table shows 23.6 (2.52)* 30.7 (2.63)* 32.3 (6.40)* 36.7 (9.08)† 8.5 (0.85) why it is important to specify these Monofilament errors are the number of insensate areas on both feet (range 0–6). Diagnosed diabetes is based on self-report. Normal glucose is based on fasting plasma glucose <100 mg/dL and A1c <5.7%. Conversions for A1c and factors, and others, in assessing the prev- glucose values are provided in Diabetes in America Appendix 1 Conversions. A1c, glycosylated hemoglobin. alence of DSPN. * p<0.001 compared to persons with normal glucose levels † p<0.01 SOURCE: National Health and Nutrition Examination Surveys 1999–2004 Natural History The onset and course of DSPN are at risk of foot ulceration attributable to increased slightly after an average still not fully clear. It is possible that insensitivity (83). However, in a study of follow-up of 6.5 years among the inten- the pathologic process of DSPN may type 2 diabetes patients that utilized the sive treatment group participants (from begin even before the onset of diabetes. 10 g monofilament, the development of 7% to 9%), but substantially more in the Neuropathic changes in small nerve fibers insensitivity was not marked in the years conventional treatment subjects (from 5% are common in individuals with impaired following diagnosis (106). to 17%) (1). Adjusting for the presence of glucose tolerance (110), a frequent confirmed DSPN at baseline in the DCCT, precursor of both type 1 diabetes and DSPN usually persists once it occurs. This the risk reduction for incident neuropathy type 2 diabetes. Also, clinical evidence is especially evident from such measures with intensive treatment was 64% (95% CI of neuropathy has been reported in indi- as QST and nerve conduction. Although 45%–76%) (1,2,78). Observational studies viduals with impaired glucose tolerance pain from neuropathy can eventually remit, have also shown associations between (72,111,112). Moreover, in the NHANES this is not necessarily attributable to the occurrence of DSPN and glucose 1999–2004 (113), prediabetic and undi- improvement in neuropathy. In one study levels (76,105). In the WESDR of type 1 agnosed (i.e., diagnosed with diabetes (117), a slight improvement in electro- diabetes patients, it was estimated that a at the NHANES visit) individuals age ≥40 physiological testing with pain remission 2% decrease in glycosylated hemoglobin years tended to have more areas of the was evident. Patients with pain remission (A1c) values over 4 years would be associ- foot insensate to 10 g monofilament tended to develop their symptoms after a ated with a 9%–23% decrease (depending stimulation than individuals with normal metabolic change, weight loss, or a short upon the study group) in the 10-year inci- glucose values. Other factors besides duration of diabetes. In a clinical trial of dence of the loss of tactile sensation (76). glucose could play a role in those indi- Japanese patients with type 2 diabetes In the EURODIAB study, the prevalence viduals, such as the presence of vascular (79), intensive insulin treatment with of DSPN increased with increasing A1c disease. multiple insulin injections was associated values (120). with an improvement of DSPN. This Abnormalities in some neuropathy was mainly based on improvement in Data from clinical trials of type 2 diabetes measurements have been observed nerve conduction studies. There is some patients have mostly supported the asso- relatively early in the course of both evidence that the rate of progression ciation between DSPN and the degree type 1 diabetes and type 2 diabetes. becomes more rapid after decreased of glycemia (27). In the UKPDS (83), a Vibration thresholds were found to be sensation is first evident 118( ,119). This large trial designed to assess the impact higher in children and adolescents with has been observed both with regard to of glucose control in type 2 diabetes type 1 diabetes than those who were vibration and thermal thresholds. patients, the incidence of a decline in nondiabetic (114). In another study vibratory sensation was lower in the of type 1 diabetes patients, thermal Risk Factors intensive treatment group than in the thresholds increased more than vibra- Among studies of type 1 diabetes conventional treatment group after 15 tion thresholds among those followed patients, the DCCT (1,2,4) has provided years of follow-up. However, differences 5 years after diagnosis (115). Among the most definitive information of the between the groups were marginal when individuals newly diagnosed with type association between DSPN and the the intervals of follow-up were shorter. 2 diabetes, decreases in vibration and degree of glycemia. During the DCCT, the As mentioned, in the clinical trial of thermal sensitivities were observed prevalence of confirmed DSPN (defined Japanese type 2 diabetes patients (79), after 2 years of follow-up (116). In the as at least two positive findings among those on more insulin injections had United Kingdom Prospective Diabetes sensory symptoms, signs, or reflex abnor- better neurologic outcomes. Although the Study (UKPDS), 13% of patients at the malities, and abnormal nerve conduction ACCORD trial of type 2 diabetes patients diagnosis of type 2 diabetes had neurop- studies in two or more nerves among was terminated early, intensive glucose athy of sufficient severity to put them the median, peroneal, and sural nerves) control was associated with a reduction

23–11 DIABETES IN AMERICA, 3rd Edition in the prevalence of several DSPN entire battery of DCCT assessments CARDIOVASCULAR measures after 5 years of follow-up (80). (4,122). Although there was a significant AUTONOMIC NEUROPATHY However, in the Veteran Affairs Diabetes difference in the raw incidence, with an Incidence and Prevalence Trial (VADT) of type 2 diabetes patients, adjustment for neurologic status at the The incidence and prevalence of CAN despite appreciable A1c differences end of the DCCT, there was no longer have varied substantially among studies. between the intervention and control evidence of a metabolic memory effect on Such data are highly dependent on the groups, there was little difference in the the primary DSPN endpoint. However, the diagnostic criteria, type of tests, definitions occurrence of DSPN (121). It should difference persisted for nerve conduction of normal, and patient characteristics be noted that the VADT relied heavily studies (4,78). (27). Among the DCCT participants who on self-reporting, and DSPN was not a had normal autonomic function at base- primary outcome measure (27). Glucose variability has been assessed line, <10% of the conventional and <5% of as a risk factor for DSPN. In studies that intensive treatment groups were found to Data from the NHANES 1999–2004 have examined the possible impact of have CAN after approximately 6 years of were analyzed for Diabetes in America such variability, findings have been incon- follow-up (1,3). In contrast, in a European to examine the relation between sensory sistent (123,124). cohort of patients with diabetes contempo- impairment (as indicated by ≥1 areas in rary with the DCCT cohort, abnormalities the foot insensate to a 10 g monofilament) Constitutional factors can influence in individual indices of heart rate variability and A1c among individuals age ≥40 the risk of DSPN. Height is a risk factor were reported in up to 31% (131). years with diabetes. Table 23.4 shows the (101,103,106,125), with an increasing percentages with ≥1 incorrect responses effect the more distal the assessment CAN increases substantially with diabetes to monofilament stimulation according (101). The basis for this is not known, but duration regardless of type of diabetes to A1c categories among those with diag- it is possible that height is a surrogate (5,23,28,132). Evaluations performed nosed diabetes. The percentage tended to for nerve length; longer nerves could be after 13–14 years of follow-up of the increase with increasing A1c levels (from more susceptible to pathologic factors. DCCT participants enrolled in the EDIC 23.6% for A1c <7.0% [<53 mmol/mol] to Neurologic function declines with age study demonstrated CAN prevalence 36.7% for A1c ≥11.0% [≥97 mmol/mol]). in both diabetic and nondiabetic popu- rates as high as 35% in the conventionally Those in the A1c <7.0% category had a lations (126). Moreover, associations treated cohort (5). In the EURODIAB substantially higher percentage of mono- of DSPN with other risk factors can study, autonomic dysfunction was present filament scores ≥1 than did those with vary with age (77). Studies have shown in one-third of type 1 diabetes patients normal glucose levels (23.6% vs. 8.5%, associations between DSPN and genetic at follow-up (133). Prevalence rates of p<0.001). factors in both type 1 diabetes and type 60% and higher were reported in cohorts 2 diabetes patients (127,128). of patients with longstanding type 2 Despite evidence that DSPN is associ- diabetes (28,53,134) and in patients with ated with the degree of glycemia, there Some studies have shown associations longstanding type 1 diabetes who were is much more to be learned about the of DSPN with blood pressure and lipid candidates for a potential pancreas trans- nature of that relationship. For instance, measures (120), possible surrogates plantation (135). it has been postulated that higher of vascular disease. Findings of studies glucose levels for even a limited period examining associations of DSPN with Estimates of prevalence for other mani- could have a marked impact on the risk alcohol consumption (101,106,125) and festations of DAN, such as gastrointestinal of DSPN. Follow-up data from the EDIC cigarette smoking (101,106,125,129) have manifestations, bladder dysfunction, and study of former DCCT subjects have been inconsistent. erectile dysfunction, have been reported been utilized to assess whether there is to be at least 25% or higher in populations a “metabolic memory” effect for DSPN. Information regarding risk factors for with longstanding type 1 diabetes or type When DCCT participants were followed diabetic hearing loss is limited. In the 2 diabetes that have been studied (30,63). after the trial’s completion, DSPN NHANES 1999–2004 (130), hearing continued to be more common in the loss was associated with DSPN, low Temporal trends should also be consid- conventional treatment group several high-density lipoprotein (HDL) choles- ered. Among those with a 20-year years later, in spite of a narrowing in the terol levels, and coronary heart disease. duration of type 1 diabetes in the EDC, A1c levels between the groups, which Interestingly, there was no association of the incidence of symptomatic autonomic were no longer different starting at hearing loss with either the duration of neuropathy steadily declined comparing EDIC year 5 (39). Since the neurologic diabetes or the degree of glucose control. those diagnosed between 1965 and 1969 assessments for that study were less with those diagnosed between 1975 and extensive than they were in the DCCT, a 1980 (p<0.05). However, the difference in subsequent EDIC study of former DCCT the decline among those with a 25-year participants was performed with the duration was borderline (p<0.06) (102).

23–12 Peripheral and Autonomic Neuropathy in Diabetes

Natural History TABLE 23.5. Mean Heart Rate Among Adults Age ≥40 Years, by Diabetes Status, Age, and The natural history of CAN is not well Race/Ethnicity, U.S., 1999–2004 defined. Changes in CAN measures and MEAN HEART RATE IN BEATS PER MINUTE (STANDARD ERROR) a possible shift in the sympathetic/para- Diagnosed Undiagnosed Normal sympathetic balance favoring sympathetic CHARACTERISTICS Diabetes Diabetes Prediabetes Glucose Levels tone were described in individuals with All 75.8 (0.48)* 73.9 (1.22)* 70.5 (0.43)† 68.9 (0.40) glucose values in a prediabetes range in the Framingham Heart Study (136). Age (years) 40–64 78.2 (0.70)* 74.6 (1.64)‡ 70.9 (0.57)‡ 69.2 (0.43) Abnormalities have also been observed ≥65 72.7 (0.67)* 72.9 (1.62)‡ 69.6 (0.51)† 67.7 (0.55) in cohorts of individuals with impaired Race/ethnicity glucose tolerance (71,137). Non-Hispanic white 76.1 (0.66)* 73.6 (1.45)‡ 70.7 (0.52)‡ 69.1 (0.43) Non-Hispanic black 75.8 (0.76)* 73.9 (1.53)‡ 70.8 (1.13) 68.4 (0.57) Although overt clinical manifestations of Hispanic 74.9 (0.91)* 74.5 (2.31)‡ 69.1 (0.56)‡ 66.7 (0.60) CAN are not usually present at the time Diagnosed diabetes is based on self-report. Undiagnosed diabetes is based on FPG ≥126 mg/dL or A1c ≥6.5%; prediabetes is based on FPG 100–125 mg/dL and/or A1c 5.7%–6.4%; and normal glucose is based on FPG <100 of diagnosis of diabetes, abnormalities mg/dL and A1c <5.7%. Conversions for A1c and glucose values are provided in Diabetes in America Appendix 1 such as changes in HRV or CART can Conversions. A1c, glycosylated hemoglobin; FPG, fasting plasma glucose. * p<0.001 compared to persons with normal glucose levels be present early in its course. Children † p<0.05 with diabetes have consistently been ‡ p<0.01 found to have higher average heart rates SOURCE: National Health and Nutrition Examination Surveys 1999–2004 than those without diabetes (138,139). The basis for the increased heart rate is groups. The VA Cooperative Study with higher risk of developing diabetes unknown, but a relation to autonomic demonstrated no difference in the (144). In the Steno-2 study, an inten- dysfunction is a possibility. prevalence of autonomic neuropathy in sive multifactorial cardiovascular risk type 2 diabetes patients after 2 years intervention targeting glucose, blood Risk Factors of tight glycemic control compared to pressure, lipids, smoking, and other life- The DCCT demonstrated that intensive those without tight control (140). Similar style factors reduced the progression or glucose management for type 1 diabetes results were reported by the VADT the development of CAN among type 2 reduced the incidence of CAN by 53% (121), although there is a question as diabetes patients with microalbuminuria compared to conventional therapy (1,3). to whether the CAN outcome measures (88). A beneficial effect of the intensive During EDIC, CAN progressed substan- were sufficiently sensitive. In a trial of glycemic intervention alone on CAN was tially in both formerly treated groups, but type 2 diabetes Japanese patients (79), not clearly evident. the prevalence and incidence of CAN in there were no significant differences in EDIC remained significantly lower in the the prevalence of postural hypotension The impact of lifestyle interventions in group that had been intensively treated or abnormal heart rate variation between preventing the progression of CAN was than in the group that had been conven- the intensively and conventionally treated evident in patients with impaired glucose tionally treated, in spite of an equalization groups. tolerance participating in the Diabetes in the A1c between groups starting at Prevention Program (71), and popula- EDIC year 5 (5). This suggests that meta- Associations between CAN and glucose tion-based studies suggest that higher bolic memory could be a determinant of levels have been found in observational activity levels have beneficial effects CAN. Treatment group differences in the studies of type 1 diabetes patients on cardiovascular autonomic function mean A1c level during DCCT and EDIC (133,141,142). Among young type 1 (145). In another study, weight loss in explained virtually all of the beneficial diabetes patients in the SEARCH for obese patients was accompanied by effect of intensive therapy on the risk of Diabetes in Youth Study, decreased HRV improvement in cardiovascular autonomic incident CAN. This finding supports the was more evident in those with A1c ≥7.5% function (89). Another study showed view that intensive treatment of type 1 (≥58 mmol/mol) (143). Data pertaining to an association between DAN and lower diabetes should be initiated as early as is a role of glucose variability in the patho- income (146). safely possible. physiology of CAN are limited. However, in one study, CAN was not associated with Association Between Heart In contrast to the DCCT, randomized glucose variability (123). Rate and Hyperglycemia clinical trials of type 2 diabetes patients In a new analysis for Diabetes in America, tend to show little evidence of an asso- In studies of other risk factors, CAN NHANES 1999–2004 data were used ciation between CAN and the degree has been associated with hypertension, to examine the association between of glycemia. After 10 years of follow-up lipid measures, smoking, and adiposity heart rate and hyperglycemia. The in the UKPDS, there was no difference indexes (133,142), while the presence of sitting heart rate was measured for 60 between the intervention and control autonomic dysfunction was associated seconds in NHANES participants age

23–13 DIABETES IN AMERICA, 3rd Edition

≥40 years with diagnosed diabetes, TABLE 23.6. Mean Heart Rate Among Adults Age ≥40 Years With Diagnosed Diabetes, by previously undiagnosed diabetes (i.e., A1c Value, U.S., 1999–2004 diagnosed at their NHANES visit by MEAN HEART RATE IN BEATS PER MINUTE (STANDARD ERROR) fasting plasma glucose [FPG] ≥126 mg/dL Diagnosed Diabetes, A1c [≥6.99 mmol/L] or A1c ≥6.5% [≥48 Normal Glucose mmol/mol]), prediabetes (FPG 100–125 <7.0% ≥7.0%–<9.0% ≥9.0%–<11.0% ≥11.0% Levels mg/dL [5.55–6.94 mmol/L] and/or A1c 74.1 (0.65)* 75.2 (0.94)* 80.4 (1.33)* 85.0 (0.40)* 68.9 (0.40) 5.7%–6.4% [39–46 mmol/L]), or normal Diagnosed diabetes is based on self-report. Normal glucose is based on fasting plasma glucose <100 mg/dL and A1c <5.7%. Conversions for A1c and glucose values are provided in Diabetes in America Appendix 1 Conversions. A1c, glucose levels (FPG <100 mg/dL and A1c glycosylated hemoglobin. <5.7%). Table 23.5 shows the mean heart * p<0.001 compared to persons with normal glucose levels rate according to the state of glycemia. SOURCE: National Health and Nutrition Examination Surveys 1999–2004 The heart rate was significantly higher in those with diagnosed diabetes than in diagnosed diabetes, there was a trend for glucose to be associated with heart rate those with normal glucose levels (75.8 vs. higher heart rates with increasing A1c rather than the A1c value. Also, it is 68.9 beats per minute, p<0.001). These values (Table 23.6), but there was no doubtful that the minor glucose elevation trends were also evident when age and trend for fasting plasma glucose levels in the prediabetic group would result in a race/ethnicity subgroups were analyzed. (data not shown). decreased plasma volume. Although the Mean heart rate was higher among those analysis suggests that subtle autonomic with undiagnosed diabetes and those The data suggest that a decreased dysfunction is an explanation for the with prediabetes compared to those with plasma volume does not explain higher elevated heart rate in diabetes, a direct normal glucose levels (73.9 and 70.5 vs. heart rates in diabetic individuals. If that effect of hyperglycemia on heart rate 68.9 beats per minute, respectively, were the explanation, one would expect and myocardial dysfunction could still be p<0.001 and p<0.05). Among those with the more contemporaneous fasting a factor.

SECONDARY COMPLICATIONS: DIABETIC FOOT ULCERS/CHARCOT NEUROARTHROPATHY

Although end-stage complications of a clinically important and potentially discharges. The percentage decreased diabetic neuropathies, including foot devastating disorder; in the 21st century, to 0.7% of discharges that did not list ulceration and Charcot neuroarthrop- diabetes is the most common cause diabetes (Table 20.19). athy, are discussed in detail in Chapter of this condition in Western countries 20 Peripheral Arterial Disease, Foot (147). A high degree of awareness and Although several risk factors for diabetic Ulcers, Lower Extremity Amputations, suspicion may enable early diagnosis and foot ulcers have been identified, DSPN and Diabetes, brief mention is made effective intervention. Any patient with is perhaps the most important. This here. Several longitudinal studies have known neuropathy who has a unilateral, was strongly supported by evidence of confirmed that DSPN is a major contrib- unexplained, swollen, warm foot should be an association between foot ulcers and utory factor in the pathogenesis of foot considered to have acute Charcot neuro- the extent of vibration insensitivity in ulceration in diabetes (8,24,44,45). arthropathy until proven otherwise. a case-control study (148). Moreover, Screening of all patients with diabetes prospective data have shown that DSPN at least annually is recommended for The epidemiology of diabetic foot ulcers is is predictive of foot ulceration (149,150). identification of neuropathic feet at risk discussed in Chapter 20. As indicated in Evidence suggests a pathogenetic of ulceration (45). The ADA recommends that chapter, estimates of foot ulcers vary sequence of hypoesthesia, increased that a simple clinical examination should depending on the national survey used plantar pressures, and finally, foot ulcer- be sufficient to identify the patient at risk to report the data. Based on data from ation (151,152). of ulceration: for neuropathy, the use of the Behavioral Risk Factor Surveillance monofilaments, plus one other test that System 2000–2007, for which foot lesions might include simple vibration percep- were self-reported as ever having lesions tion using a tuning fork or pin-prick, is that took more than 4 weeks to heal, prev- sufficient 45( ). Any patient found to have alence was appreciable (11.0%–13.0%) neuropathy of sufficient severity to put among telephone-interviewed diabetic them at risk of foot ulceration requires participants age ≥18 years (Table 20.20). education in preventive foot care and Data from the National Hospital Discharge podiatric care (45). Survey, which is based on estimates of the percentage of hospital discharges that Charcot neuroarthropathy is much less list foot ulcers, indicated that in 2002– common than foot ulceration but is 2009, foot ulcers were listed in 4.2% of

23–14 Peripheral and Autonomic Neuropathy in Diabetes

CONCLUSIONS

Even though the observed frequencies neuropathy. These include: (1) Is there Diabetic neuropathy and its sequelae can of diabetic neuropathy vary according to truly a metabolic memory, and if so, when have a major impact on the health and several factors, it is clearly a common is it most significant during pathogenesis? quality of life of those afflicted. Much complication of diabetes. Among risk (2) Is the effect of hyperglycemia simply has been learned about the disorder, but factors for diabetic neuropathy that have a matter of its degree and duration or are there is clearly a need to learn a great deal been identified, several are modifiable. other factors important, such as glucose more, so that diabetic neuropathy can be Among these, glycemia appears to be the variability? (3) To what extent is the effect effectively prevented and treated. most impactful with regard to the occur- of hyperglycemia modified by genetic rence and progression of neuropathy. factors and constitutional factors, such as However, important questions remain nerve length? Other modifiable risk factors regarding the influence of glycemia on also require further study.

LIST OF ABBREVIATIONS CONVERSIONS A1c ...... glycosylated hemoglobin Conversions for A1c and glucose ACCORD . . . . .Action to Control Cardiovascular Risk in Diabetes values are provided in Diabetes in ADA ...... American Diabetes Association America Appendix 1 Conversions. BARI 2D ...... Bypass Angioplasty Revascularization Investigation 2 Diabetes trial CAN ...... cardiovascular autonomic neuropathy CART ...... cardiovascular autonomic reflex test CASE ...... computer assisted sensory examination ACKNOWLEDGMENTS/ CCM ...... corneal confocal microscopy FUNDING CI ...... confidence interval Dr. Pop-Busui’s institution received CIDP ...... chronic inflammatory demyelinating polyneuropathy research support from Astra Zeneca DAN ...... diabetic autonomic neuropathy and Impeto. DCCT ...... Diabetes Control and Complications Trial DRPN ...... diabetic radiculoplexus neuropathy DSPN ...... distal symmetrical polyneuropathy ECG ...... electrocardiogram DUALITY OF INTEREST EDC ...... Epidemiology of Diabetes Complications study EDIC ...... Epidemiology of Diabetes Interventions and Complications study Drs. Pop-Busui, Boulton, and ER ...... endoplasmic reticulum Sosenko reported no conflicts of FPG ...... fasting plasma glucose interest. HRV ...... heart rate variability IENFD ...... intra-epidermal nerve fiber density MNSI ...... Michigan Neuropathy Screening Instrument NHANES . . . . .National Health and Nutrition Examination Survey NSS ...... Neuropathy Symptom Score QST ...... quantitative sensory testing SFN ...... small fiber neuropathies UKPDS ...... United Kingdom Prospective Diabetes Study VADT ...... Veterans Affairs Diabetes Trial WESDR ...... Wisconsin Epidemiologic Study of Diabetic Retinopathy

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