Diabetic Neuropathy

Diabetic Neuropathy identifies the most accurate early biomarkers of nerve damage to better understand pathophysiology and diagnose diabetic neuropathy in the clinical care of patients, and in particular, permit an accurate evaluation of future therapies in clinical trials. This succinct reference focuses on the current data and research on diabetic neuropathy and is essential reading for researchers in endocrinology, neurology and pharmacology, along with clinicians that need to better understand the novel pathogenetic pathways leading to diabetic neuropathy and the treatments.

• Serves as a starting point for researchers and medical professionals on risk factors, prevention and newly discovered mechanisms involved in the pathogenesis and eventually treatments of diabetic neuropathy
• Discusses a broad range of issues relating to diabetic neuropathy, from epidemiology, to pathophysiology, genetics, advances in diagnostic techniques, and the latest clinical trials and clinical management

• Language: English
• Publisher: Elsevier Science
• Release date: Feb 16, 2022
• ISBN: 9780128206706

Book preview

Chapter 1

Classification, risk factors, and clinical presentation diabetic neuropathy

Dilek Gogas Yavuz,    Section of Endocrinology and Metabolism, Marmara University School of Medicine, Istanbul, Turkey

Abstract

Diabetic neuropathy is the most common and debilitating complication that occurs in nearly 50 percent of patients with diabetes. Diabetic neuropathy can cause significant morbidity and mortality. There is no universally accepted classification for diabetic neuropathies, and a classification based upon the clinical manifestation is most preferred in clinical practice. The primary forms are Distal symmetric polyneuropathy and Autonomic neuropathy. Hyperglycemia, duration of diabetes, age, and cardiovascular associated risk factors (obesity, dyslipidemia, hypertension) are typical for diabetic neuropathy.

Although the diagnosis of diabetic neuropathy depends on clinical symptoms and signs, it is challenging to diagnose due to the lack of a consensus for the definition and clinical assessment criteria.

Keywords

Diabetic neuropathy; peripheric distal symmetric neuropathy; painful neuropathy; autonomic neuropathy

Introduction

Diabetes mellitus is a major metabolic disorder. Nearly half a billion people are living with diabetes worldwide. International Diabetes Federation estimated that over four million people aged 20–79 years died from diabetes-related causes in 2019 [1]. The global impact of diabetes is increasing considerably; the number of diabetic patients is expected to increase to 578 million (10.2%) in 2030 and 700 million (10.9%) in 2045 [1].

Type 2 diabetes is the most common form of diabetes, accounting for around 90% of all diabetes worldwide. The prevalence of type 2 diabetes is rising across all continents, associated with population aging, increasing urbanization, and economic development [1,2]. Although there is considerable variation by region, the incidence of type 1 diabetes is increasing worldwide as well [3].

The long-term micro and macrovascular complications of diabetes can be present at diagnosis in type 2 diabetes and can be detected as early as five years after the onset of type 1 diabetes [1].

Morbidity and mortality associated with diabetes primarily result from chronic vascular complications. Complications of diabetes such as retinopathy, nephropathy, and cardiovascular diseases are leading to reduced quality of life, increased need for medical care, disability and decreased life expectancy in diabetic patients [1].

The overall prevalence of ay diabetic neuropathy was estimated to be 35% in diabetic patients [4]. Chronic kidney disease resulting in diabetic nephropathy and other associated conditions was reported to be 25%–%36 in people with diabetes [5]. Diabetic foot complications are associated with neurological disorders and peripheral vascular disease in the lower limbs [6].

The global prevalence of diabetic foot complications varies between 3% and 13%, with a global average of 6.4%. Lower limb amputation in people with diabetes is 10 to 20 times more common than those without diabetes [1,7].

There is a lack of understanding in the management and treatment of diabetic foot complications among healthcare professionals. Less than one-third of physicians recognize the signs of diabetic peripheral neuropathy. Increasing awareness of diabetic foot complications, risk assessments, and foot care by a multidisciplinary team can reduce foot complications and amputations by up to 85% [1,8].

Diabetes is the leading cause of neuropathy in the Western world. Diabetic neuropathies are the most common among the long-term complications of diabetes, affecting up to 50% of patients [1].

Epidemiologic studies indicate that neuropathy in diabetes patients is approximately 20% in community patients [9]. An early study reported that incidence of neuropathy was 50% for patients with diabetes duration more than 25 years [10].

Diabetic neuropathy can cause significant morbidity and mortality. The major problem with Diabetic neuropathy is implicated in 50%–75% of nontraumatic amputations [11]. Therefore it is essential to detect symptoms or signs of diabetic neuropathy and to determine risk factors as early as possible to implement interventions and prevent further neuronal damage.

In clinical practice, detection of diabetic neuropathy is challenging due to the lack of a clear consensus concerning the definition of the optimal clinical assessment criteria to diagnose neuropathy in diabetic patients.

Classification

Chronic hyperglycemia can affect any part of the nervous system. Sensory, autonomic, and motor neurons of the peripheral nervous system are vulnerable to the adverse effects of hyperglycemia in diabetic patients [10].

Various classifications for diabetic neuropathy have been proposed in recent years. Nevertheless, there is no universally accepted classification. Some of the suggested classifications are based on etiology, pathological or topographical features, and a classification based upon the clinical manifestation is most useful in clinical practice.

Thomas originally proposed the classification of neuropathy in diabetic patients in 1997, which most authors generally accept. Thomas divided diabetic neuropathies into four main groups: (1) Hyperglycemic neuropathy, (2) Symmetric polyneuropathy (Sensory/autonomic polyneuropathy, Acute painful diabetic neuropathy), (3) Focal and multifocal neuropathy (Cranial neuropathy, Thoraco-abdominal neuropathy, Focal limb neuropathies, Diabetic amyotrophy), (4) Mixed forms [11].

Recently the American Diabetes Association classified diabetic neuropathies into three main categories: (1) diffuse symmetric (distal symmetric polyneuropathy and autonomic), (2) mononeuropathy (mononeuropathy, mononeuritis multiplex, atypical forms), (3) radiculopathy, or polyradiculopathy [12].

Classification of diabetic neuropathy according to clinical presentation is shown in Table 1.1.

Table 1.1

Clinically, it is essential to distinguish between symmetric and asymmetric neuropathies because they require different diagnostic and therapeutic approaches. Although the most common neuropathy type is distal symmetric polyneuropathy in type 1 and type 2 diabetes, different forms of Diabetic neuropathy usually coexist in the same patient [13].

It is also essential to keep in mind that diabetes may not necessarily cause neuropathy in all diabetic patients. Other etiologic factors rather than diabetes need to be excluded before diagnosing diabetic neuropathy [13].

Risk factors

Hyperglycemia is the primary risk factor for diabetic neuropathy. Improved glycemic control can prevent the progression of diabetic neuropathy in type 1 diabetes but is not effective in preventing distal polyneuropathy in type 2 diabetes [14]. Clinical trials have demonstrated the benefit of tight glucose control by slowing the progression of diabetic peripheral neuropathy in type 1 and type 2 diabetic patients [15]. In an observational study long-term, persistent benefits of strict glycemic control were demonstrated in type 1 diabetic patients [15].

The duration of diabetes is a major risk factor for neuropathy, and it is well recognized that the risk of developing neuropathy increases with the duration of diabetes and age. As hyperglycemia takes time for nerve damage, diabetic neuropathy is more common in older adults (>50 years) [16].

Diabetic neuropathy should be suspected in all patients with type 2 diabetes and those who have had type 1 diabetes for more than five years [13].

Patients with type 2 diabetes develop distal symmetric polyneuropathy (DSPN) despite adequate glycemic control. The presence of multiple comorbidities such as hypertension, obesity, dyslipidemia might have attenuated the beneficial effects of glucose control.

Diabetic neuropathy can be increased by cardiovascular risk factors such as dyslipidemia, hypertriglyceridemia, low high-density lipoprotein, hypertension, abdominal obesity, independently from glycemic control. Obesity is associated with diabetic neuropathy in patients with Type 2 diabetes and in selected type 1 diabetic patients [17,18].

Population base studies showed that obesity is common in patients with neuropathy. Also, clinical studies revealed neuropathy was more prevalent in obese normoglycemic individuals than lean controls, suggesting obesity is an independent risk factor for neuropathy [19].

Observational studies highlighted that weight, Body mass index (BMI), and waist circumference are all associated with neuropathy. Obesity is the second most influential metabolic risk factor for neuropathy after diabetes [19,20].

Hypertension is a risk factor for diabetic neuropathy—it can be developed with diabetes progression or stimulate progression of chronic kidney disease. Essential hypertension can occur in diabetes patients as comorbidity, or diabetic nephropathy can cause secondary hypertension. Hypertension can aggravate polyneuropathies in diabetic patients as blood pressure control is emphasized clinically for distal symmetric polyneuropathy prevention [21].

Dyslipidemia is a common cardiovascular risk factor in diabetes. Hypertriglyceridemia was found to be an important independent risk factor corresponding to a 2.1-fold increase in distal symmetric polyneuropathy occurrence [22]. According to the FIELD study, hypertriglyceridemia was a risk factor for new-onset DPN, and fenofibrate treatment reduced new-onset neuropathy by approximately 18% and reversed baseline neuropathy [23].

Height is considered as a marker for neuronal length, and it was reported as an independent predictor of neuropathy among patients with type 1 diabetes and type 2 diabetes [24].

Cigarette smoking and alcohol consumption are all considered independent risk factors for diabetic neuropathy [24]. Most risk factors for diabetic neuropathy are modifiable and can be controlled or treated, while age, duration of diabetes, and height are not. Risk factors for diabetic neuropathy are summarized in Table 1.2.

Table 1.2

BMI, Body mass index; FPG, fasting plasma glucose; LDL, low-density cholesterol; HbA1c: hemoglobin A1c; HDL, high-density cholesterol.

Symptoms and signs of diabetic neuropathy

The phenotype of diabetic neuropathy is heterogeneous with diverse clinical manifestations; some patients with diabetic neuropathy have few complaints, but their physical examination reveals mild to moderately severe sensory loss. At the other end, patients may have a severe neuropathic deficit with no symptoms [12,25].

Generalized diabetic neuropathy

Distal symmetric polyneuropathy

Distal symmetric polyneuropathy is the most common form among diabetic neuropathies accounting for about 75% of the diabetic neuropathies [12]. The disease's course is chronic and progressive. DSPN predisposes diabetic patients to variable degrees of pain, motor dysfunction, postural instability, gait abnormalities, nerve palsies, ulcers, burns, infections, gangrene, and Charcot's disease. DSPN is the most common cause of foot ulceration and lower extremity amputation. It is also a major contributor to falls and fractures [12,13].

Neuropathic pain can cause physical and psychosocial impairment, disability, and reduced health-related quality of life. A minority number of patients are seen with anorexia, depression, and weight loss [12,13].

The development of DSPN is insidious, usually starting from the distal and progressing proximally to the extremities. Toes and under feet affected first, gradually ascending the leg. Fingertips and hand symptoms usually occur when distal extremity symptoms reach at knee level. Characteristic stocking-glove like distribution of neuropathic symptoms present in long-term diabetic patients [25].

Early symptoms occur in the DSPN disease course due to small nerve involvement followed by large nerve dysfunction. Small- and large-fiber dysfunction most commonly coexist.

DSPN manifests with either pain or gives rise to negative symptoms, but many patients experience both [25,26].

Common symptoms associated with small nerve dysfunction are pain and dysesthesias (unpleasant sensations of burning). Painful DSPN may also be described as a sensation of electricity, shooting pain, contact hyperalgesia, burning, lancinating, tingling, which tend to occur or worsen most at night [12,16]. Pain evoked by contact, for example, with socks, shoes, and bedclothes (allodynia). Small fiber involvement might also give rise to negative symptoms, with selective loss of temperature and pain sensation [25]. Large-fiber dysfunction is characterized by may cause numbness, tingling without pain, and loss of protective sensation is a risk factor for diabetic foot ulceration. Patients frequently complain that their feet feel like they are wrapped in wool or walk on thick socks. Large-fiber dysfunction is a risk factor of falls as the gait might be insecure, either wide-based or high stepping [16,25].

Autonomic neuropathy

Autonomic neuropathy may be observed at any stage of diabetes. Usually, it develops in patients who have had the disease for 20 years. The sympathetic, parasympathetic, and enteric nerves are affected in diabetic autonomic neuropathy [12].

Cardiovascular autonomic neuropathy is a crucial cause of morbidity and mortality in type 1 and type 2 diabetic patients. Its association with increased incidence of malignant arrhythmia and sudden death was demonstrated in diabetes [27].

In type 1 diabetes, autonomy imbalance may result in a prolonged Q.T. interval on the electrocardiogram, which may predispose the patient to life-threatening cardiac arrhythmias and sudden death [27]. Diabetic neuropathy also can reduce appreciation of ischemic pain, which may delay the diagnosis of silent or asymptomatic myocardial infarction [28].

Clinical findings include exercise intolerance, fatigue, syncope or dizziness, persistent sinus tachycardia, decreased heart rate variability, bradycardia, supine hypertension. Vasomotor neuropathy frequently causes orthostatic hypotension [28]. Orthostatic blood pressure measurements may be used to evaluate cardiovascular autonomic dysfunction [12,29].

Gastrointestinal autonomic neuropathy may cause paresis anywhere in the gastrointestinal system. The most common symptoms are gastroparesis, dysphagia, diabetic diarrhea, and constipation [30]. Delayed esophageal transit and gastroparesis occur in approximately 50% and 40% of long-standing diabetics, respectively. Gastroparesis may promote dysphagia, regurgitation, esophageal erosion, and strictures [16]. Delayed gastric emptying and gastric retention can cause early satiety, cramping, bloating, epigastric pain (heartburn), nausea and vomiting, and loss of appetite to the point of anorexia [10,30].

Delayed gastric emptying and gastric retention may impair medication absorption and prone patients to hypoglycemia [27]. Colon abnormalities may result in severe constipation, diarrhea, and fecal incontinence [30]. Symptoms of gastrointestinal autonomic neuropathy do not typically occur until later in the course of diabetes.

Genitourinary autonomic neuropathy affects sexual function and bladder problems which negatively affect quality-of-life issues in diabetes.

Erectile dysfunction can also be mediated by autonomic dysfunction and occurs in approximately 35% to 90% of men with diabetes [10]. In women, diabetic neuropathy may cause vaginal dryness, dyspareunia, and reduced libido [27].

Bladder dysfunction is more frequently observed in type 1 diabetic patients than type 2 diabetes.

Impaired bladder sensation may result in retention and incomplete voiding of urine, overflow incontinence, and urinary tract infections [10]. The most common symptoms of bladder dysfunction include dysuria, frequency, urgency, nocturia, incomplete voiding, and urinary incontinence.

Diabetic Sudomotor Dysfunction: Diabetic autonomic neuropathy initially results in a loss of thermoregulatory sweating, resulting in global anhidrosis. Diabetic autonomic neuropathy can also cause hyperhidrosis, Gustatory sweating, and abnormal sweat production that appears over the face, head, neck, shoulders, and chest after consuming food [31].

Symptoms and consequences of distal symmetric diabetic polyneuropathy and diabetic autonomic neuropathy are summarized in Table 1.3.

Table 1.3

Rare forms of generalized neuropathy

Acute sensory diabetic neuropathy is a rare form of neuropathy that consists of two subtypes: treatment-induced neuropathy and diabetic neuropathic cachexia.

Treatment-induced neuropathy is an iatrogenic form of neuropathy. It typically manifests within days or weeks after rapid glycemic control with severe burning pain, hyperalgesia, or allodynia, and symptoms and signs of autonomic dysfunction. Rapid glycemic control, a decrease in hemoglobin (HbA1c) 2% (22 mmol/mol) per 3 months associated acute sensory symptoms. Decreasing HbA1c 5% (55 mmol/mol) increases the risk of developing treatment-induced neuropathy by 90% [32]. Rapid glycemic control on any therapeutic regimen can be associated with treatment-induced neuropathy.

Diabetic neuropathic cachexia is a rare type of symmetrical painful neuropathy that mainly affects the lower limbs and the lower trunk. It is characterized by unintentional severe (weight loss 10% of baseline body weight) [32].

Diabetic mononeuropathies

Cranial mononeuropathies occur in older diabetic patients with a long duration of diabetes and are extremely rare. Cranial neuropathy commonly involves the oculomotor, facial, and trochlear nerves in diabetic patients. Third nerve palsy with pupillary sparing is the hallmark of diabetic oculomotor palsy [32].

Mononeuropathies have an acute onset, are associated with pain, and have a self-limiting course resolving in two months. Mononeuro-pathies can involve median, ulnar, radial, and common peroneal nerves. Mononeuropathies often emerge during periods of transition in the diabetic illness, for example, after an episode of hyper- or hypoglycemia, when insulin treatment is initiated or adjusted, or when there has been rapid weight loss [33].

When multiple nerves are involved, the term mononeuropathy multiplex is used. Vasculitis should be ruled out as a cause of the symptoms [29].

Entrapment neuropathies and their association with diabetes have been well established. It has been estimated that up to 1/3 of people with diabetes may have entrapment syndrome. However, entrapment neuropathies associated with diabetes are often asymptomatic and discovered by alterations at nerve conduction studies [32]. The most common entrapment neuropathies in diabetes are carpal tunnel syndrome (30% of people with diabetic polyneuropathy and 14% of people without diabetic polyneuropathy), ulnar neuropathy with an observed incidence of 2.1% [34].

Carpal tunnel syndrome presents with numbness, pain, or tingling in the area innervated by the median nerve while motor weakness is uncommon, thenar muscle wasting may be observed, especially in the elderly Electrophysio-logical studies show reduced median nerve sensory and motor conduction velocity [34].

The presence of diabetic polyneuropathy has been associated with an increased risk of developing entrapment syndromes.

Rarely phrenic nerves may be affected in the course of diabetes mellitus; There are case reports of bilateral phrenic neuropathy leading to diaphragmatic paralysis, where subjects presented with orthopnea and respiratory failure [32,34].

Diabetic Radiculopathies

The spectrum of diabetic radiculoplexus neuropathies consists of three subtypes: lumbosacral, thoracic, and cervical radiculoplexus neuropathy. Radiculoplexus neuropathies share similar clinical, neurophysiological, and neuropathological characteristics can occur alone or in combination in people with diabetes [32].

Painful unilateral or multiple asymmetrical neuropathies tend to occur in older patients with relatively mild or even unrecognized diabetes in radiculoplexus neuropathies pain followed by muscle weakness. Although pain is initially the worst symptom, weakness and atrophy become the main problems [33].

Diabetic lumbosacral radiculoplexus neuropathy, also known as diabetic amyotrophy, is the most frequent subtype [35]. It is a rare type of neuropathy affecting approximately 1% of middle-aged people with type 2 diabetes with mild impairment of glucose metabolism and absence of other microvascular complications. It usually begins abruptly and presents with severe, deep thigh pain, progressing to weakness and muscle atrophy. Symptoms present abruptly, unilaterally, and proximally. Lumbosacral radiculoplexus neuropathy is characterized by severe and often debilitating motor involvement manifesting with muscle weakness and atrophy. It is associated with significant morbidity and increased psychological burden due to intense pain and anxiety of disease progression, leading to depression [33,35].

Prognosis is favorable; it is a monophasic disease that improves over time usually lasts two years with a steady but slow improvement. The diagnosis of diabetic lumbosacral radiculoplexus neuropathy is predominantly clinical [33].

Diabetic thoracic radiculoneuropathy affects motor, sensory, and autonomic nerve fibers and represents a rare cause of chronic abdominal pain with unknown prevalence. It primarily affects people with type 2 diabetes, irrespectively of their glycemic control and the concomitance of other microvascular complications [33].

Diabetic cervical radiculoplexus neuropathy manifests with pain accompanied by weakness and may affect the entire brachial plexus or the upper limbs. Presentation is usually unilateral and may progress to bilateral in some cases. Diabetic cervical radiculoplexus neuropathy affects motor, sensory and autonomic nerve fibers and shares clinical and neurophysiological findings [36].

Conclusion

Diabetic neuropathy is the most debilitating complication that can cause significant morbidity and mortality in type 1 and type 2 diabetic patients. It is essential to detect symptoms or signs of diabetic neuropathy and determine risk factors as early as possible to implement interventions and to prevent further neuronal damage. Increasing awareness and knowledge among healthcare professionals about the management of diabetic foot complications is vital to prevent lower leg amputations.

References

1. Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843.

2. American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes. Diabetes Care. 2021;44(Supplement 1):S15 S3.

3. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383:69–82.

4. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis. 2015;2:17.

5. Adler AI, Stevens RJ, Manley SE, et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom prospective diabetes study (UKPDS 64). Kidney Int. 2003;63(1):225–232.

6. Davies M, Brophy S, Williams R, et al. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care. 2006;29:1518–1522.

7. Mishra SC, Chhatbar KC, Kashikar A, Mehndiratta A. Diabetic foot. BMJ. 2017;359(Suppl 1):j5064.

8. Williams R, Karuranga S, Malanda B, et al. Global and regional estimates and projections of diabetes-related health expenditure: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2020;162:108072.

9. Shaw JE, Zimmet PZ. The epidemiology of diabetic neuropathy. Diabetes Rev. 1999;7:245–252.

10. Duby JJ, Campbell KR, Setter MS, White RJ, Rasmussen KA. Diabetic neuropathy: an intensive review. Am J Health Syst Pharm. 2004;61(2):160–173.

11. Thomas PK. Classification of the diabetic neuropathies. In: Gries FA, Cameron NA, Low P, Ziegler D, eds. Textbook of diabetic neuropathy. Stuttgart: Thieme; 2003;175–177.

12. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136–154.

13. Vinik AI, Nevoret ML, Casellini C, Parson H. Diabetic neuropathy. Endocrinol Metab Clin North Am. 2013;42(4):747–787.

14. Callaghan BC, Little AA, Feldman EL, Hughes RAC. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012;6:1–60.

15. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep. 2014;14(9):1–15 528.

16. Zakin E, Abrams R, Simpson DM. Diabetic neuropathy. Semin Neurol. 2019;39(5):560–569.

17. Callaghan BC, Xia R, Banerjee M, et al. Metabolic syndrome components are associated with symptomatic polyneuropathy independent of glycemic status. Diabetes Care. 2016;39:801–807.

18. Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic neuropathy. Nat Rev Dis Prim. 2019;5(1):1–19.

19. Callaghan BC, Xia R, Reynolds E, et al. Association between metabolic syndrome components and polyneuropathy in an obese population. JAMA Neuro l73. 2016;12:1468–1476.

20. Callaghan BC, Gallagher G, Fridman V, Feldman EL. Diabetic neuropathy: what does the future hold?. Diabetologia. 2020;63(5):891–897.

21. Forrest KY, Maser RE, Pambianco G, Becker DJ, Orchard TJ. Hypertension as a risk factor for diabetic neuropathy: a prospective study. Diabetes. 1997;46(4):665–670.

22. Lee KA, Park TS, Yong Jin H. Non-glucose risk factors in the pathogenesis of diabetic peripheral neuropathy. Endocrine. 2020;70(3):465 447.

23. Ansquer JC, Foucher C, Aubonnet P, Le Malicot K. Fibrates and microvascular complications in diabetes-insight. Curr Pharm Des. 2009;15(5):537–552.

24. Adler AI, Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Smith DG. Risk factors for diabetic peripheral sensory neuropathy. Diabetes Care. 1997;20:1162–1167.

25. Gylfadottir SS, Weeracharoenkul D, Toft Andersen S, Niruthisard S, Suwanwalaikorn S, Staehelin Jensen T. Painful and non-painful diabetic polyneuropathy: clinical characteristics and diagnostic issues. J Diabetes Investig. 2019;10(5):1148–1157.

26. Tesfaye S, Boulton AJM, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Toronto Diabetic Neuropathy Expert Group Diabetes Care. 2010;33(10):2285–2293.

27. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26:1553–1579.

28. Ziegler D. Cardiovascular autonomic neuropathy: clinical manifestations and measurement. Diabetes Rev. 1999;7:342–357.

29. Aring AM, Jones DE, Falko JM. Evaluation and prevention of diabetic neuropathy. Am Fam Physician. 2005;71:2123–2128.

30. Wolosin JD, Edelman SV. Diabetes and the gastrointestinal tract. Clin Diabetes. 2000;18:48–51.

31. Deli G, Bosnyak E, Pusch G, Komoly S, Feher G. Diabetic neuropathies: diagnosis and management. Neuroendocrinology. 2013;98:267–280.

32. Samakidou G, Eleftheriadou I, Tentolouris A, Papanas N, Tentolouris N. Rare diabetic neuropathies: It is not only distal symmetrical polyneuropathy. Diabetes Res Clin Pract. 2021;177:1–10.

33. 46 Ropper AH, Samuels MA, eds. Peripheral nerve diseases in Adams and Victor's Principles of Neurology. New York: McGraw-Hill; 2009.

34. Smith BE. Focal and entrapment neuropathies. In: 2014;31–43. Zochodne DW, Malik RA, eds. Handbook of Clinical Neurology Elsevier. 126.

35. Llewelyn D, Llewelyn JG. Diabetic amyotrophy: a painful radiculoplexus neuropathy. Pract Neurol Apr. 2019;19(2):164–167.

36. Laughlin RS, Dyck PJ. Diabetic radiculoplexus neuropathies. Handb Clin Neurol. 2014;126:45–52.

Chapter 2

Pathologic basis for diabetic neuropathy in humans

Soroku Yagihashi¹, ²,    ¹Department of Exploratory Medicine on Nature, Life and Man, Toho University School of Medicine, Inage-cho, Inage-ku, Chiba, Japan,    ²Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan

Abstract

Our physical activities depend on energy supply of glucose and oxygen via blood stream. Peripheral nervous system is a frontline of this activity but is anatomically vulnerable to metabolic or hypoxic insults because of extremely lengthy axons and sparse vascular system. Long-term metabolic aberrations and microangiopathic changes are thus likely to contribute to neuropathy in diabetes. Mode of onset and location of affected nerves determine the different type of neuropathy and contribute to the development of neuropathy. Pathological basis underlying this condition is essential to understand for the clinical management of this perplexing disorder.

Keywords

Diabetic polyneuropathy; pathology; peripheral nerve; microangiopathy

Introduction

Dr. Max Ellenberg, who dedicated his life to the clinical care for patients with diabetic neuropathy in the mid 20th century, concluded that neuropathy is not a complication of diabetes but a concomitant with the same [1]. This foresight has been substantiated by the following clinical evidence that (1) neuropathy may be the initial manifestation of diabetes, (2) neuropathy is the most prevalent among individuals with comorbidities or various complications, (3) neuropathy is often present in prediabetic stage, (4) neuropathy occurs in the absence of overt hyperglycemia or during good control, (5) signs and symptoms of neuropathy are not parallel with severity of diabetes or duration of diabetes. Despite the advancement in knowledge concerning diabetic neuropathy, its complexity continues to be highly perplexing. In February 1988, San Antonio consensus panel announced that diabetic neuropathy is a descriptive term meaning of a demonstrable disorder, either clinically evident or subclinical, that occurs in the setting of diabetes without other causes for peripheral neuropathy [2]. This definition was succeeded by subsequent panel conferences, and the entity of neuropathy includes all manifestations in the somatic and/or autonomic parts of the peripheral nervous system [3]. Hence neuropathy may not simply be one of the complications but is likely to represent diabetes itself.

Patients with neuropathy suffer from intractable pain, uncomfortable sensation, severe autonomic imbalance, and lowered quality of life. Nearly half of the patients with diabetes are affected with such neuropathic complications and often require expensive limb amputation [4]. Care for neuropathy is critical to the management of diabetes not only because of its intractable symptoms but also of serious impact on life expectancy [5,6]. With longer duration of diabetes, the incidence of neuropathy is increased [7,8]. Neuropathy manifests early in prediabetic stage in type 2 diabetes (T2D). Because of the insidious nature of its symptoms, accurate pathologic features in early neuropathy are not well established, although involvement of small nerve fibers has recently been proposed. Currently, there is no effective means for the prevention and suppression of the development of neuropathy except for meticulous blood glucose control. For a better understanding of the pathophysiology of diabetic neuropathy and determination of the treatment design, it will be useful to review the pathologic basis of diabetic neuropathy.

Classification of diabetic neuropathy

Diabetic neuropathy is a complex disorder with metabolic and vascular basis. Long-term hyperglycemia or hyperlipidemia exerts chronic injurious and reparative remodeling of the peripheral nerve tissues. In this setting, degenerative, regenerative, inflammatory lesions develop diffusely in centripetal manner on the basis of metabolic aberration [9,10]. In contrast to metabolic deficits, compromised vascular supply triggers acute infarction or chronic ischemic changes, resulting in mainly focal or multifocal pathological phenotype [11–13]. Thomas divided diabetic neuropathy into two major types of diffuse and focal neuropathy [14] (Table 2.1). Diffuse type represents distal symmetric sensory predominant neuropathy. This type is commonly accompanied by involvement of autonomic nervous system of both sympathetic and parasympathetic nerves [15]. The presence of cardiac autonomic neuropathy markedly reduces the quality of life and shortens life expectancy [16,17]. Distal sensory–predominant neuropathy usually accompanies autonomic neuropathy, and this combination is collectively called diabetic polyneuropathy (DPN).

Table 2.1

Focal type may be subclassified into mononeuropathy and multiple mononeuropathies (mononeuropathy multiplex). Mononeuropathy is typical for cranial neuropathies (oculomotor nerve, abducens nerve, etc.) presenting ophthalmoplegia [18]. Less clearly differentiated are truncal neuropathy and proximal motor neuropathy of the arm or the thigh (diabetic amyotrophy) from multiple mononeuropathies. The latter is now regarded as lumbosacral radiculoplexus neuropathy (LSRPN) [13,19,20]. Mode of the onset may be divided into acute, subacute, or chronic, the former of which is atypical compared to chronically developed DPN. Motor type of cranial neuropathy occurs as sudden or rapid onset of painful oculomotor palsy [18]. In contrast, proximal motor neuropathy manifests acute or subacute focal painful muscle atrophy in the arm, thigh, or thorax [20,21]. In cases with obvious muscle atrophy in extremities or trunk, it was used to have the term of diabetic amyotrophy [22]. This terminology is not used nowadays because it does not indicate the accurate causation. Proximal motor neuropathy is associated with epineurial vasculitis with a pattern of multiple mononeuropathies [19,23,24]. In this case, neurologic deficits involve proximal radiculoplexus neuropathy with motor deficits. The association of vasculitis with muscle atrophy suggests immunogenic basis in its pathogenesis [19,23]. There remain some ambiguities and complexities for the clinical phenotype and their backgrounds. Nevertheless, efforts for the separation of clinical phenotype of neuropathy are meaningful and important for the understanding of the disease and for the decision of treatment design.

Basic pathologic changes in several types of neuropathy

Pathological basis of DPN appears to be distinct in each type of neuropathy. There may be some overlap or transient form of the disorder. For the convenience of understanding, representative features will briefly be introduced in each type, and the implication of the lesions related to the clinical phenotype will be discussed.

Classical pathological studies on diffuse type of DPN were conducted on the materials obtained at the time of autopsy [25–28]. Most conspicuous changes were detected in the peripheral nerve showing loss of nerve fibers, demyelination/remyelination and fibrosis. The changes were more robust in the dorsal root compared to ventral root, suggesting sensory predominance of the lesion [26]. Dorsal column underwent demyelination and gliosis, but there were not any substantial changes in dorsal root ganglia [27]. Sympathetic and parasympathetic nerves contained nerve fibers with degeneration and demyelination [29,30]. Ganglion cells in celiac and mesenteric ganglia were vacuolated and markedly swollen [31]. Autonomic nerve alterations supplying the internal organs also indicated the long-term presence of structural derangement in autopsy cases of diabetic patients [31,32]. Despite the presence of apparent pathological changes such as neuronal loss and reactive gliosis in the spinal cord or dorsal root ganglia, it was not clear whether the changes really represented the alterations caused by diabetes or other factors because of the lack of precise clinical information. Common appearance of neuromatous changes showing bundle of proliferative nerve fasciculi in gastrointestinal walls or vascular walls suggested the repeated injury to internal autonomic nerves and its reactive growth resembling traumatic neuroma [32]. Most of the changes were not specific for diabetes but merely reactive process to chronic injury.

Later systematic investigations of autopsy materials embedded in epon after fixation with glutaraldehyde and osmium provided more precise spatial distribution of nerve lesions in the peripheral nervous system. On the semithin cross-sections of the sciatic, tibial, and sural nerves, nerve fiber loss with thickened endoneurial vascular walls was consistently demonstrated [12,33,34]. The results from these studies were informative, but the subjects investigated were limited and often complicated with uremia, and therefore causal relationships of nerve lesions with clinical phenotype were not well addressed [34]. Such systematic studies are extremely valuable but too laborious to collect the data from sufficient number of subjects to draw an appropriate