Chapter 31 – Diabetic Neuropathies

Updated December 1, 2011

Introduction

Diabetic neuropathy (DN) is the most common and troublesome complication of diabetes mellitus, leading to the greatest morbidity and mortality and resulting in a huge economic burden for diabetes care 1 2. It is the most common form of neuropathy in the developed countries of the world, accounts for more hospitalizations than all the other diabetic complications combined, and is responsible for 50-75% of non-traumatic amputations 2 3.  DN is a set of clinical syndromes that affect distinct regions of the nervous system, singly or combined.  It may be silent and go undetected while exercising its ravages; or it may present with clinical symptoms and signs that, although nonspecific and insidious with slow progression, also mimic those seen in many other diseases.  DN is, therefore, diagnosed by exclusion. Unfortunately both endocrinologists and non endocrinologists have not been trained to recognize the condition 4, and even when DN is symptomatic less than one third of physicians recognize the cause or discuss this with their patients 4.

The true prevalence is not known and reports vary from 10% to 90% in diabetic patients, depending on the criteria and methods used to define neuropathy 2 3 5 6. Twenty five percent of patients attending a diabetes clinic volunteered symptoms; 50 % were found to have neuropathy after a simple clinical test such as the ankle jerk or vibration perception test; almost 90% tested positive to sophisticated tests of autonomic function or peripheral sensation 7. Neurologic complications occur equally in type 1 and type 2 diabetes mellitus and additionally in various forms of acquired diabetes 6. The major morbidity associated with somatic neuropathy is foot ulceration, the precursor of gangrene and limb loss. Neuropathy increases the risk of amputation 1.7 fold; 12 fold, if there is deformity (itself a consequence of neuropathy), and 36 fold, if there is a history of previous ulceration 8. Each year 96,000 amputations are performed on diabetic patients in the United States, yet up to 75% of them are preventable 3. Globally there is an amputation every 30 seconds. Diabetic neuropathy also has a tremendous impact on patients’ quality of life predominantly by causing weakness, ataxia and incoordination predisposing to falls and fractures 9.  Once autonomic neuropathy sets in, life can become quite dismal and the mortality rate approximates 25-50% within 5-10 years 10 11.

Scope of the Problem

Diabetic peripheral neuropathy (DPN) is a common late complication of diabetes. It results in a variety of syndromes for which there is no universally accepted classification. They are generally subdivided into focal/multifocal neuropathies, including diabetic amyotrophy, and symmetric polyneuropathies, including sensorimotor polyneuropathy (DSPN). The latter is the most common type, affecting about 30% of diabetic patients in hospital care and 25% of those in the community 12;13.  DPN has been recently defined as a symmetrical, length-dependent sensorimotor polyneuropathy attributable to metabolic and microvascular alterations as a result of chronic hyperglycemia exposure (diabetes) and cardiovascular risk covariates 14.   Its onset is generally insidious, and without treatment the course is chronic and progressive. The loss of small fiber-mediated sensation results in the loss of thermal and pain perception, whereas large fiber impairment results in loss of touch and vibration perception. Sensory fiber involvement may also result in “positive” symptoms, such as paresthesias and pain, although up to 50% of neuropathic patients are asymptomatic. DPN can be associated with the involvement of the autonomic nervous system, i.e., diabetic autonomic neuropathy that rarely causes severe symptoms 15;16, but in its cardiovascular form is definitely associated with at least a three-fold increased risk for mortality 17-19. More recenty diabetic autonomic neuropathy or even autonomic imbalance betweent he sympathetic and the parasympathetic nervous systems have been implicated as a predictor of cardiovascular risk  18 19.

Pain is the reason for 40% of patient visits in a primary care setting and about 20% of the presenting patients have had pain for greater than 6 months 20. Chronic pain may be nociceptive, which occurs as a result of disease or damage to tissue wherein there is no abnormality in the nervous system or there may be no somatic abnormality. In contrast Experts in the Neurology and Pain community define neuropathic pain as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system” 21. Persistent neuropathic pain interferes significantly with quality of life (QOL), impairing sleep and recreation; it also significantly impacts emotional well being , and is associated if not the cause of  depression, anxiety, loss of sleep, and non compliance with treatment  22.  Diabetic neuropathy pain (DNP) is a difficult-to-manage clinical problem.  It is often associated with mood and sleep disturbances, and patients with DNP are more apt to seek medical attention than those with other types of diabetic neuropathy. Two population-based studies showed that neuropathic pain is associated with a greater psychological burden than nociceptive pain 23 and is considered to be more severe than other pain types.  Early recognition of psychological problems is critical to the management of pain, and physicians need to go beyond the management of pain per se if they are to achieve success.  Patients may also complain of decreased physical activity and mobility, increased fatigue, and negative effects on their social lives.  Providing significant pain relief markedly improves quality-of-life measures, including sleep and vitality 9;24.

Classification of Diabetic Neuropathies

Figure 1 and Table 1 describe the classification proposed by Thomas 25 and modified by us 12 26 27. It is important to note that different forms of DN often coexist in the same patient (e.g. distal polyneuropathy and carpal tunnel syndrome)

Figure 1. 28

 

Table 1. Classification of diabetic neuropathies.

Rapidly reversible Hyperglycemic neuropathy

Generalized symmetric polyneuropathy Acute sensory neuropathy Chronic sensorimotor neuropathy or distal symmetric polyneuropathy (DPN) Small-fiber neuropathy Large-fiber neuropathy Autonomic neuropathy

Focal and multifocal neuropathies Focal-limb neuropathy Cranial neuropathy Proximal-motor neuropathy (amyotrophy) Truncal radiculoneuropathy Coexisting chronic inflammatory demyelinating neuropathy (CIDP)

Natural History of Diabetic Neuropathies (DN)

The epidemiology and natural history of DN remain poorly defined, in part because of variable criteria for the diagnosis, failure of many physicians to recognize and diagnose the disease, and lack of standardized methodologies used for the evaluation of these patients 16.  It has nonetheless been estimated that 50% of patients with diabetes have DN and 2.7 million have painful neuropathy in the US. DN is grossly under diagnosed and under treated.  The natural history of DN separates them into two very distinctive entities, namely those which progress gradually with increasing duration of diabetes, and those which remit usually completely. Sensory and autonomic neuropathies generally progress, while mononeuropathies, radiculopathies, and acute painful neuropathies, although manifesting severe symptoms, are short-lived and tend to recover 29.  Progression of DN is related to glycemic control in both type 1 and type 2 diabetes 30 31.  It appears that the most rapid deterioration of nerve function occurs soon after the onset of type 1 diabetes; then within 2-3 years there is a slowing of the progress with a shallower slope to the curve of dysfunction.  In contrast, in type 2 diabetes, slowing of nerve conduction velocities (NCVs) may be one of the earliest neuropathic abnormalities and often is present even at diagnosis 32.  After diagnosis, slowing of NCV generally progresses at a steady rate of approximately 1 m/sec/year, and the level of impairment is positively correlated with duration of diabetes. Although most studies have documented that symptomatic patients are more likely to have slower NCVs than patients without symptoms, these do not relate with the severity of symptoms. In a long term follow up study of type 2 diabetes patients 33, electrophysiologic abnormalities in the lower limb increased from 8% at baseline to 42% after 10 years; in particular, a decrease in sensory and motor amplitudes (indicating axonal destruction) was more pronounced than the slowing of the NCVs. Using objective measures of sensory function such as the vibration perception threshold test, the rate of decline in function has been reported as 1-2 vibration units/year. However, there now appears to be a decline in this rate of evolution. It appears that host factors pertaining to general health and nerve nutrition are changing. This is particularly important when doing studies on the treatment of DN, which have always relied on differences between drug treatment and placebo, and have apparently been successful because of the decline in function occuring in placebo-treated patients 34.  Recent studies have pointed out the changing natural history of DN with the advent of therapeutic lifestyle change and the use of statins and ACE inhibitors, which have slowed the progression of DN and drastically changed the requirements for placebo-controlled studies 35.  It is also important to recognize that DN is a disorder wherein the prevailing abnormality is loss of axons that electrophysiologically translates to a reduction in amplitudes and not conduction velocities; therefore changes in NCV may not be an appropriate means of monitoring progress or deterioration of nerve function.  Small, unmyelinated nerve fibers are affected early in DM and are not reflected in NCV studies. Other methods of measuring DN that do not depend on conduction velocities, such as quantitative sensory testing, autonomic function testing, or skin biopsy with quantification of intraepidermal nerve fibers (IENF), are necessary to identify these patients 36 37  38. New techniques for evaluation of small fiber function are being developed and will be alluded to later.

Pathogenesis of Diabetic Neuropathies

Causative factors include persistent hyperglycemia, microvascular insufficiency, oxidative and nitrosative stress, defective neurotrophism, and autoimmune-mediated nerve destruction.  Figure 2 summarizes our current view of the pathogenesis of DN 12.  Detailed discussion of the different theories is beyond the scope of this Chapter and there are  several excellent recent reviews. However, DN is a heterogeneous group of conditions with widely varying pathology, suggesting differences in pathogenic mechanisms for the different clinical syndromes. Recognition of the clinical homologue of these pathologic processes is the first step in achieving the appropriate form of intervention.

Figure 2. Pathogenesis of diabetic neuropathies: Modified from Vinik et al . Ab, antibody; AGE, advance glycation end products; C’, complement; DAG, diacylglycerol; ET, endothelin; EDHF, endothelium-derived hyperpolarizing factor; GF, growth factor; IGF; insulin-like growth factor; NFkB, nuclear factor kB; NGF, nerve growth factor; NO, nitric oxide; NT3, neurotropin 3; PKC, protein kinase C; PGI2, prostaglandin I2; ROS, reactive oxygen species; TRK, tyrosine kinase .

 

Clinical Presentation

The spectrum of clinical neuropathic syndromes described in patients with diabetes mellitus includes dysfunction of almost every segment of the somatic peripheral and autonomic nervous system 39. Each syndrome can be distinguished by its pathophysiologic, therapeutic, and prognostic features.

Focal and multifocal neuropathies

 

Focal Neuropathies comprise focal-limb neuropathies and cranial neuropathies.
Focal limb neuropathies are usually due to entrapment, and mononeuropathies must be distinguished from these entrapment syndromes (Table 2) 27 40. Mononeuropathies often occur in the older population; they have an acute onset, are associated with pain, and have a self-limiting course resolving in 6–8 weeks. Mononeuropathies can involve the median (5.8% of all diabetic neuropathies), ulnar (2.1%), radial (0.6%), and common peroneal nerves 41. Cranial neuropathies in diabetic patients are extremely rare (0.05%) and occur in older individuals with a long duration of diabetes 42. Entrapment syndromes start slowly, and will progress and persist without intervention. Carpal tunnel syndrome occurs three times as frequently in diabetics compared with healthy populations 43 and is found in up to one third of patients with diabetes.  Its increased prevalence in diabetes may be related to repeated undetected trauma, metabolic changes, or accumulation of fluid or edema within the confined space of the carpal tunnel 40. The diagnosis is confirmed by electrophysiological studies. Treatment consists of rest, aided by placement of a wrist splint in a neutral position to avoid repetitive trauma.  Anti-inflammatory medications and steroid injections are sometimes useful. Surgery should be considered if weakness appears and medical treatment fails 16 27.  It consists of sectioning the volar carpal ligament or unentrapping the nerves in the ulnar canal or the peroneal nerve at the head of the fibula and release of the medial plantar nerve in the trsal tunnel amongst others 44.

Table 2. Distinguishing  Characteristics of Mononeuropathies, Entrapment Syndromes and Distal Symmetrical Polyneuropathy

Feature	Mononeuropathy	Entrapment syndrome	Neuropathy
Onset	Sudden	Gradual	Gradual
Pattern	Single nerve but may be multiple	Single nerve exposed to trauma	Distal symmetrical poly neuropathy
Nerves involved	CN III, VI, VII, ulnar, median, peroneal	Median, ulnar, peroneal, medial and lateral plantar	Mixed, Motor, Sensory, Autonomic
Natural history	Resolves spontaneously	Progressive	Progressive
Treatment	Symptomatic	Rest, splints, local steroids, diuretics, surgery	Tight Glycemic control, Pregabalin, Duloxetine, Antioxidants, “Nutrinerve”, Research Drugs.
Distribution of Sensory loss	Area supplied by the nerve	Area supplied beyond the site of entrapment	Distal and symmetrical. “Glove and Stocking” distribution.

CN, cranial nerves.
NSAIDs, non steroid anti-inflammatory drugs

 

Proximal motor neuropathy (Diabetic amyotrophy) and chronic demyelinating neuropathies

For many years proximal neuropathy has been considered a component of DN.  Its pathogenesis was ill understood 45, and its treatment was neglected with the anticipation that the patient would eventually recover, albeit over a period of some 1-2 years and after suffering considerable pain, weakness and disability. The condition has a number of synonyms including diabetic amyotrophy and femoral neuropathy.  It can be clinically identified based on the occurrence of these common features: 1) primarily affects the elderly (50 to 60 years old) with type 2 diabetes; 2) onset can be gradual or abrupt; 3) presents with severe pain in the thighs, hips and buttocks, followed by significant weakness of the proximal muscles of the lower limbs with inability to rise from the sitting position (positive Gower's maneuver); 4) can start unilaterally and then spread bilaterally; 5) often coexists with distal symmetric polyneuropathy; and 6) is characterized by muscle fasciculation, either spontaneous or provoked by percussion . Pathogenesis is not yet clearly understood although immune-mediated epineurial microvasculitis has been demonstrated in some cases. Immunosuppressive therapy is recommended using high dose steroids or intravenous immunoglobulin 46.  The condition is now recognized as being secondary to a variety of causes unrelated to diabetes, but which have a greater frequency in patients with diabetes than the general population.  It includes patients with chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy, circulating GM1 antibodies, and inflammatory vasculitis 47 48 42 43.

In the classic form of diabetic amyotrophy, axonal loss is the predominant process 49. Electrophysiologic evaluation reveals lumbosacral plexopathy 50. In contrast, if demyelination predominates and the motor deficit affects proximal and distal muscle groups, the diagnoses of CIDP, monoclonal gammopathy of unknown significance (MGUS), and vasculitis should be considered 51 52.  The diagnosis of these demyelinating conditions is often overlooked, although recognition is very important because unlike DN, they are sometimes treatable. Furthermore, they occur 11-times more frequently in diabetic than nondiabetic patients 53 54.  Biopsy of the obturator nerve reveals deposition of immunoglobulin, demyelination and inflammatory cell infiltrate of the vasa nervorum 55 47. Cerebrospinal fluid (CSF) protein content is high and there is an increase in the lymphocyte count.  Treatment options include: intravenous immunoglobulin for CIDP 56, plasma exchange for MGUS, steroids and azathioprine for vasculitis, and withdrawal of drugs or other agents that may have caused vasculitis. It is important to divide proximal syndromes into these two subcategories, because the CIDP variant responds dramatically to intervention 51 57, whereas amyotrophy runs its own course over months to years. Until more evidence is available, they should be considered separate syndromes.

Diabetic truncal radiculoneuropathy

Diabetic truncal radiculoneuropathy affects middle-aged to elderly patients and has a predilection for male sex.  Pain is the most important symptom and it occurs in a girdle-like distribution over the lower thoracic or abdominal wall. It can be uni- or bilaterally distributed. Motor weakness is rare. Resolution generally occurs within 4-6 months.

Rapidly reversible Hyperglycemic neuropathy

Reversible abnormalities of nerve function may occur in patients with recently diagnosed or poorly controlled diabetes. These are unlikely to be caused by structural abnormalities, as recovery soon follows restoration of euglycemia.  Rapidly reversible hyperglycemic neuropathy usually presents with distal sensory symptoms, and whether these abnormalities result in an increased risk of developing chronic neuropathies in the future remains unknown 16 58.

Generalized symmetric polyneuropathy

•  Acute sensory neuropathy

Acute sensory (painful) neuropathy is considered by some authors a distinctive variant of distal symmetrical polyneuropathy. The syndrome is characterized by severe pain, cachexia, weight loss, depression and, in males, erectile dysfunction. It occurs predominantly in male patients and may appear at any time in the course of both type 1 and type 2 diabetes.  It is self-limiting and invariably responds to simple symptomatic treatment. Conditions such as Fabry's disease, amyloidosis, HIV infection, heavy metal poisoning (such as arsenic), and excess alcohol consumption should be excluded 25.

Patients report unremitting burning, deep pain and hyperesthesia especially in the feet. Other symptoms include sharp, stabbing, lancinating pain; “electric shock” like sensations in the lower limbs that appear more frequently during the night; paresthesia; tingling; coldness and numbness 59. Signs are usually absent with a relatively normal clinical examination, except for allodynia (exaggerated response to non-noxious stimuli) during sensory testing and, occasionally, absent or reduced ankle reflexes.

Acute sensory neuropathy is usually associated with poor glycemic control but may also appear after sudden improvement of glycemia and has been associated with the onset of insulin therapy, being termed "insulin neuritis" on occasions 60. Although the pathologic basis has not been determined, one hypothesis suggests that changes in blood glucose flux produce alterations in epineurial blood flow, leading to ischemia.  A study using in vivo epineurial vessel photography and fluorescein angiography demonstrated abnormalities of epineurial vessels including arteriovenous shunting and proliferating new vessels in patients with acute sensory neuropathy 61. Other authors relate this syndrome to diabetic lumbosacral radiculoplexus neuropathy (DLRPN) and propose an immune mediated mechanism 38.

The key in the management of this syndrome is achieving blood glucose stability 60.  Most patients also require medication for neuropathic pain. The natural history of this disease is resolution of symptoms within one year 62.

b.  Chronic Sensorimotor Neuropathy or Distal Symmetric Polyneuropathy (DPN)

Clinical Presentation:

DPN is probably the most common form of the diabetic neuropathies 16 38.  It is seen in both type 1 and type 2 DM with similar frequency and it may be already present at the time of diagnosis of type 2 DM 33.  A population survey reported that 30% of type 1 and 36 to 40% of type 2 diabetic patients experienced neuropathic symptoms 63. Several studies have also suggested that impaired glucose tolerance (IGT) may lead to polyneuropathy, reporting rates of IGT in patients with chronic idiopathic polyneuropathies between 30 and 50% 64 65 66 67. Studies using skin and nerve biopsies have shown progressive reduction in peripheral nerve fibers from the time of the diagnosis of diabetes or even in earlier pre-diabetic stages (IGT and metabolic syndrome) 37 68.  Sensory symptoms are more prominent than motor symptoms and usually involve the lower limbs. These include pain, paresthesiae, hyperesthesiae, deep aching, burning and sharp stabbing sensations similar to but less severe than those described in acute sensory neuropathy.  In addition, patients may experience negative symptoms such as numbness in the feet and legs, leading in time to painless foot ulcers and subsequent amputations if the neuropathy is not promptly recognized and treated.  Unsteadiness is also frequently seen due to abnormal propioception and muscle sensory function 69 70. Alternatively, some patients may be completely asymptomatic and signs may be only discovered by a detailed neurological examination.

On physical examination a symmetrical stocking like distribution of sensory abnormalities in both lower limbs is usually seen. In more severe cases hands may be involved. All sensory modalities can be affected, particularly vibration, touch and position perceptions (large Aα/β fiber damage); and pain, with abnormal heat and cold temperature perception (small thinly myelinated Aδ and unmyelinated C fiber damage, see figure 3). Deep tendon reflexes may be absent or reduced, especially in the lower extremities.  Mild muscle wasting may be seen but severe weakness is rare and should raise the question of a possible non-diabetic etiology of the neuropathy 6 16 38. DPN is frequently accompanied by autonomic neuropathy, which will be described in more detail below. It is important to remember that all patients with DPN are at increased risk of neuropathic complications such as foot ulceration and Charcot´s neuroarthropathy.

Figure 3a. Clinical presentation of small and large fiber neuropathies:7172

Aα fibers are large myelinated fibers, in charge of motor functions and muscle control. Aα/β fibers are large myelinated fibers too, with sensory functions such as perception to touch, vibration and position. Aδ fibers are small myelinated fibers, in charge of pain stimuli and cold perception. C fibers can be myelinated or unmyelinated and have both sensory (warm perception and pain) and autonomic functions (blood pressure and heart rate regulation, sweating, etc.) GIT, GastroIntestinal Tract; GUT, GenitoUrinary Tract .

Clinical manifestations of small fiber neuropathies (Figure 3a):

• Small thinly myelinated Aδ and unmyelinated C fibers are affected.
• Prominent symptoms with burning, superficial, or lancinating pain often accompanied by hyperalgesia, dysesthesia and allodynia.
• Progression to numbness and hypoalgesia (Disappearance of pain may not necessarily reflect nerve recovery but rather nerve death, and progression of neuropathy must be excluded by careful examination).
• Abnormal cold and warm thermal sensation.
• Abnormal autonomic function with decreased sweating, dry skin, impaired vasomotion and skin blood flow with cold feet.
• Intact motor strength and deep tendon reflexes.
• Negative NCV findings.
• Loss of cutaneous nerve fibers on skin biopsies.
• Can be diagnosed clinically by reduced sensitivity to 1.0g Semmes Weinstein monofilament and prickling pain perception using the Waardenberg wheel or similar instrument.
• Patients at risk of foot ulceration and subsequent gangrene and amputations.

Clinical manifestations of large fiber neuropathies (Figure 3a)

• Large myelinated, rapidly conducting Aα/β fibers are affected and may involve sensory and/or motor nerves.
• Prominent signs with sensory ataxia (waddling like a duck), wasting of small intrinsic muscles of feet and hands with hammertoe deformities and weakness of hands and feet.
• Abnormal deep tendon reflexes.
• Impaired vibration perception (often the first objective evidence), light touch and joint position perception.
• Shortening of the Achilles tendon with pes equinus.
• Symptoms may be minimal: sensation of walking on cotton, floors feeling "strange", inability to turn the pages of a book, or inability to discriminate among coins.  In some patients with severe distal muscle weakness, inability to stand on the toes or heels.
• Abnormal NCV findings
• Increased skin blood flow with hot feet.
• Patients at higher risk of falls, fractures, and development of Charcot Neuroarthropathy
• Most patients with DPN, however, have a "mixed" variety of neuropathy with both large and small nerve fiber damages.

Figure 3b

Figure 4. Clinical manifestation of small fiber neuropathies.72

Diagnosis of Diabetic Neuropathies

           
Diabetic peripheral neuropathy is a common late complication of diabetes. It results in a variety of syndromes for which there is no universally accepted unique classification. They are generally subdivided into focal/multifocal neuropathies, including diabetic amyotrophy, and symmetric polyneuropathies, including sensorimotor polyneuropathy (DSPN). The latter is the most common type, affecting about 30% of diabetic patients in hospital care and 25% of those in the community 14.  Because of the lack of agreement on the definition and diagnostic assessment of neuropathy, several consensus conferences were convened to overcome the current problems, the most recent of which has re-defined the minimal criteria for the diagnosis of typical DSPN  as summarized below 14..

Toronto Classification of Distal Symmetric  Diabetic Polyneuropathies   14

1)         Possible DSPN: The presence of symptoms or signs of DSPN may include the following: symptoms–decreased sensation, positive neuropathic sensory symptoms (e.g., “asleep numbness,” prickling or stabbing, burning or aching pain) predominantly in the toes, feet, or legs; or signs–symmetric decrease of distal sensation or unequivocally decreased or absent ankle reflexes.

2)         Probable DSPN: The presence of a combination of symptoms and signs of neuropathy including any 2 or more of the following: neuropathic symptoms, decreased distal sensation, or unequivocally decreased or absent ankle reflexes.

3)         Confirmed DSPN: The presence of an abnormality of nerve conduction and a symptom or symptoms, or a sign or signs, of neuropathy confirm DSPN.  If nerve conduction is normal, a validated measure of small fiber neuropathy (SFN) (with class 1 evidence) may be used. To assess for the severity of DSPN, several approaches can be recommended: for e.g. the graded approach outlined above; various continuous measures of sum scores of neurologic signs, symptoms or nerve test scores; scores of function of activities of daily living; or scores of predetermined tasks or of disability.

4)         Subclinical DSPN: The presence of no signs or symptoms of neuropathy are confirmed with abnormal nerve conduction or a validated measure of SFN (with class 1 evidence).  Definitions 1, 2, or 3 can be used for clinical practice and definitions 3 or 4 can be used for research studies.

5)         Small fiber neuropathy (SFN): SFN should be graded as follows: 1) possible: the presence of length-dependent symptoms and/or clinical signs of small fiber damage; 2) probable: the presence of length-dependent symptoms, clinical signs of small fiber damage, and normal sural nerve conduction; and 3) definite: the presence of length-dependent symptoms, clinical signs of small fiber damage, normal sural nerve conduction, and altered intraepidermal nerve fiber density (IENFD) at the ankle and/or abnormal thermal thresholds at the foot 14 (see Figure 4).

The Diagnosis of DSPN

           
The diagnosis of DSPN should rest on the findings of the clinical and neurological examinations, i.e., the  presence of neuropathic symptoms (positive and negative, sensory and motor) and signs (sensory deficit, allodynia and hyperalgesia, motor weakness, absence of reflexes).

According to the American Academy of Neurology (AAN) report on the case definition of distal symmetric polyneuropathy, there is good evidence (Grade IIa, level B) that: 

1.  symptoms alone have poor diagnostic accuracy in predicting the presence of polyneuropathy,
2.  signs are better predictors than symptoms,
3.  multiple signs are better predictors than a single sign, and
4.  relatively simple examinations are as accurate as complex scoring systems 73.

Thus, both symptoms and signs should be assessed.
           
The basic neurological assessment comprises the general medical and neurological history, inspection of the feet, and neurological examination of sensation using simple semi-quantitative bed-side instruments such as the 10g Semmes-Weinstein monofilament or Neuropen 74 ( to assess touch/pressure),  NeuroQuick 75 or Tiptherm 76 (temperature), calibrated Rydel-Seiffer tuning fork (vibration), pin-prick (pain), and tendon reflexes (knee and ankle).  In addition, assessment of joint position and motor power may be indicated. The normal range for the tuning fork on the dorsal distal joint of the great toe is ≥5/8 scale units in persons 21-40 years old,  ≥4.5/8 in those 41-60 years old,  ≥4/8 in individuals 61-71 years old, and ≥3.5/8 scale units in those 72-82 years old (Level 1a Grade A) 77. An indicator test for the detection of sudomotor dysfunction is the Neuropad which assesses plantar sweat production by means of a colour change from blue to pink. The patch contains the complex salt anhydrous cobalt-II-chloride.  In the presence of water, this salt absorbs water molecules, normally changing its colour from blue to pink. If the patch remains completely or partially blue within 10 min, the result is considered abnormal Level 111, Grade B 78.  The Sudoscan, an instrument capable of detecting ion flux in response to a very low current is being investigated by us in the United States to measure sudomotor dysfunction.  The advantage of the Sudoscan over other measures of sweating has yet to be determined but the entire evaluation takes only 2 minutes and can be done in an ambulatory setting. (No Level or Grade as yet)
           
The following findings should alert the physician to consider causes for DSPN other than diabetes and referral for a detailed neurological work-up: 1.) pronounced asymmetry of the neurological deficits, 2.) predominant motor deficits, mononeuropathy, or cranial nerve involvement, 3.) rapid development or progression of the neuropathic impairments, 4.) progression of the neuropathy despite optimal glycemic control, 5.) symptoms from the upper limbs, 6.) family history of non-diabetic neuropathy, and 7.) diagnosis of DSPN cannot be ascertained by clinical examination 79.

Conditions mimicking diabetic neuropathy

There are a number of conditions that can be mistaken for painful diabetic neuropathy: intermittent claudication in which the pain is exacerbated by walking; Morton’s neuroma, in which the pain and tenderness are localized to the intertarsal space and are elicited by applying pressure with the thumb in the appropriate intertarsal space; osteoarthritis, in which the pain is confined to the joints, made worse with joint movement or exercise, and associated with morning stiffness that  improves with ambulation; radiculopathy in which  the pain originates in the shoulder, arm, thorax, or back and radiates into the legs and feet; Charcot neuropathy in which the pain is localized to the site of the collapse of the bones of the foot, and the foot is hot rather than cold as occurs in neuropathy; plantar fasciitis, in which there is shooting or burning in the heel with each step and there is exquisite tenderness in the sole of the foot; and tarsal tunnel syndrome in which the pain and numbness radiate from beneath the medial malleolus to the sole and are localized to the inner side of the foot. These contrast with the pain of DPN which is bilateral, symmetrical, covering the whole foot and particularly the dorsum, and is worse at night interfering with sleep.  

The most important differential diagnoses from the general medicine perspective include neuropathies caused by alcohol abuse, uremia, hypothyroidism, vitamin B12 deficiency, peripheral arterial disease, cancer, inflammatory and infectious diseases, and neurotoxic drugs 80.

Clinical assessment tools for diabetic neuropathy

Clinical assessment should be standardized using validated scores for both the severity of symptoms and the degree of neuropathic deficits which are sufficiently reproducible.  These would include the Michigan Neuropathy Screening Instrument (MNSI) 81; the Neuropathy Symptom Score (NSS) for neuropathic symptoms; and the Neuropathy Disability (NDS) or the Neuropathy impairment score (NIS) for neuropathic deficits (impairments) 5. The neurological history and examination should be performed initially and then with all subsequent visits.  Minimum criteria for the clinical diagnosis of neuropathy according to the NSS and NIS are: 1.) moderate signs with or without symptoms, or 2.) Mild signs with moderate symptoms.  However, this means that the exclusive presence of neuropathic symptoms without deficits is not sufficient to diagnose DSPN.  Therefore, early stages of DSPN or a painful small fiber neuropathy with or without minimal deficits can only be verified using more sophisticated tests such as thermal thresholds or skin biopsy.

Objective devices for the diagnosis of neuropathy

Skin biopsy has become a widely used tool to investigate small caliber sensory nerves including somatic unmyelinated intraepidermal nerve fibers (IENF), dermal myelinated nerve fibers, and autonomic nerve fibers in peripheral neuropathies and other conditions 82-84.  Different techniques for tissue processing and nerve fiber evaluation have been used.  For diagnostic purposes in peripheral neuropathies, a recent guideline has recommended a 3-mm punch skin biopsy at the distal leg and quantification of the linear density of IENF in at least three 50-µm thick sections per biopsy, fixed in 2% PLP or Zamboni's solution, by bright-field immunohistochemistry or immunofluorescence with anti-protein gene product (PGP) 9.5 antibodies. 85  Quantification of IENF density appeared more sensitive than sensory nerve conduction study or sural nerve biopsy in diagnosing SFN. (Level 1a, Grade A)

The neurological examination should focus on the lower extremities and should always include an accurate foot inspection for deformities, ulcers, fungal infection, muscle wasting, hair distribution or loss, and the presence or absence of pulses.  Sensory modalities should be assessed using simple handheld devices (touch by cotton wool or soft brush; vibration by 128 Hz tuning-fork; pressure by the Semmes-Weinstein 1 and 10 g monofilament; pinprick by Wardenburg wheel, Neurotip or a pin temperature by cold and warm objects) Level 1a, Grade A 86.  Finally, theAchilles reflexes should be tested26;87 (Table 3). Quantitative sensory testing (QST) enables more accurate assessment of sensory deficits - also those related to small fiber function - by applying controlled and quantified stimuli and standardized procedures. There is no definite evidence of its accuracy and usefulness in diagnosing distal symmetric polyneuropathy 73, but QST measuring vibration and thermal perception thresholds is probably an effective tool in DSPN (Level 1b, Grade B)88. Moreover, assessment of thermal thresholds is a key element in the diagnostic pathway of small fiber polyneuropathy 16;89.

Table 3.  Examination - Bedside Sensory Tests

Sensory Modality	Nerve Fiber	Instrument	Associated Sensory Receptors
Vibration	Ab (large)	128 Hz Tuning fork	Ruffini corpuscle mechanoreceptors
Pain (pinprick)	C (small)	Neuro-tips	Nociceptors for pain and warmth
Pressure	Ab, Aa (large)	1 g and 10 g Monofilament	Pacinian  corpuscle
Light touch	Ab, Aa (large)	Wisp of cotton	Meissner’s corpuscle
Cold	Ad (small)	Cold tuning fork	Cold thermoreceptors

An atypical pattern of presentation of symptoms or signs, i.e., the presence of relevant motor deficits, an asymmetrical or proximal distribution, or rapid progression, always requires referral for electrodiagnostic testing (see above).  Furthermore, in the presence of such atypical neuropathic signs and symptoms other forms of neuropathy should be sought and excluded.  A good medical history is essential to exclude other causes of neuropathy: a history of trauma, cancer, unexplained weight loss, fever, substance abuse or HIV infection suggests that an alternative source should be sought. As recommended for all patients with distal symmetric polyneuropathy 90, screening laboratory tests may be considered in selected patients with DSPN, serum B12 with its metabolites and serum protein immunofixation electrophoresis being those with the highest yield of abnormalities 90.

Validated scoring systems for symptoms and signs are available in the form of questionnaires or checklists, such as the Neuropathy Symptom Score 91 and the Michigan Neuropathy Screening Instrument Questionnaire 81 for symptoms; and the Michigan Neuropathy Screening Instrument 81 and the Neuropathy Disability Score 91 1993) for signs. (Level Ia, Grade A)
           

Corneal Confocal Microscopy

Corneal confocal microscopy (CCM) is a noninvasive technique used to detect small nerve fiber loss in the cornea which correlates with both increasing neuropathic severity and reduced IENFD in diabetic patients 92;93.  A novel technique of real-time mapping permits an area of 3.2 mm² to be mapped with a total of 64 theoretically non-overlapping single 400 µm² images (Level IIa, Grade B) 94 .

Contact Heat Evoked Potentials

Contact Heat Evoked Potentials (CHEPS) has now been studied in healthy controls, newly diagnosed diabetics, established diabetics, and patients with the metabolic syndrome. It does appear that CHEPS is capable of detecting small fiber neuropathy  in the absence of other indices, and that CHEPS correlates with quantitative sensory perception  and objective tests of small fiber function such as the cooling detection threshold and cold pain (Level IIa, Grade B) 95.

Summary of Clinical Assessment of DPN

Symptoms of neuropathy are personal experiences and vary markedly from one patient to another. For this reason, a number of symptom screening questionnaires with similar scoring systems have been developed.  The Neurologic Symptom Score (NSS) has 38 items that capture symptoms of muscle weakness, sensory disturbances and autonomic dysfunction. These questionnaires are useful for patient follow-up and to assess response to treatment.

A detailed clinical examination is the key to the diagnosis of DPN.  The last position statement of the American Diabetes Association recommends that all patients with diabetes be screened for DN at diagnosis in type 2 DM and 5 years after diagnosis in type 1 DM. DN screening should be repeated annually and must include sensory examination of the feet and ankle reflexes 26. One or more of the following can be used to assess sensory function: pinprick (using the Waardenberg wheel or similar instrument), temperature, vibration perception (using 128-Hz tuning fork) or 1 & 10-g monofilament pressure perception at the distal halluces. For this last test a simple substitute is to use 25 lb strain fishing line  cut into 4 cm and 8 cm lengths, which translate to 10 and 1 g monofilaments respectively96. The most sensitive measure has been shown to be the vibration detection threshold, although sensitivity of 10-g Semmes-Weinstein monofilament to identify feet at risk varies from 86 to 100%  97 98. Combinations of more than one test have more than 87% sensitivity in detecting DPN 26 99. Longitudinal studies have shown that these simple tests are good predictors of foot ulcer risk 100. Numerous composite scores to evaluate clinical signs of DN, such as the Neuropathy Impairment Score (NIS) are currently available. These, in combination with symptom scores, are useful in documenting and monitoring neuropathic patients in the clinic 101. The feet should always be examined in detail to detect ulcers, calluses and deformities, and footwear must be inspected at every visit.

Multiple studies have proven the value of Quantitative Sensory Testing (QST) measures in the detection of subclinical neuropathy (small fiber neuropathy), the assessment of progression of neuropathy, and the prediction of risk of foot ulceration  99 102 103 104. These standardized measures of vibration and thermal thresholds also play an important role in multicenter clinical trials as primary efficacy endpoints. A consensus subcommittee of the American Academy of Neurology stated that QST receive a Class II rating as a diagnostic test with a type B strength of recommendation 88.

The use of electrophysiologic measures (NCV) in both clinical practice and multicenter clinical trials is recommended 105 106. In a long term follow-up study of type 2 diabetic patients 33 NCV abnormalities in the lower limbs increased from 8% at baseline to 42% after 10 years of disease. A slow progression of NCV abnormalities was seen in the Diabetes Control and Complication Trial (DCCT). The sural and peroneal nerve conduction velocities diminished by 2.8 and 2.7 m/s respectively, over a 5-year period 31. Furthermore, in the same study, patients who were free of neuropathy at baseline had a 40% incidence of abnormal NCV in the conventionally treated group versus 16% in the intensive therapy treated group after 5 years. However, the neurophysiologic findings vary widely depending on the population tested and the type and distribution of the neuropathy. Patients with painful, predominantly small fiber neuropathy have normal studies. There is consistent evidence that small, unmyelinated fibers are affected early in DM and these alterations are not diagnosed by routine NCV studies. Therefore, other methods, such as QST or skin biopsy with quantification of intraepidermal nerve fibers (IENF) are needed to detect these patients 36 37 38. Nevertheless electrophysiological studies play a key role in ruling out other causes of neuropathy and are essential for the identification of focal and multifocal neuropathies 16 40.

The importance of the skin biopsy as a diagnostic tool for DPN is increasingly being recognized 37 107 108. This technique quantitates small epidermal nerve fibers through antibody staining of the pan-axonal marker protein gene product 9.5 (PGP 9.5). Though minimally invasive (3-mm diameter punch biopsy), it enables a direct study of small fibers, which cannot be evaluated by NCV studies. It has led to the recognition of the small nerve fiber syndrome as part of IGT and the metabolic syndrome (Figure 4). When patients present with the “burning foot or hand syndrome“, evaluation for glucose tolerance and the metabolic syndrome (including waist circumference, blood pressure, and plasma triglyceride and HDL-C levels) becomes mandatory.  Therapeutic life style changes 109 can result in nerve fiber regeneration, reversal of the neuropathy, and alleviation of symptoms (see below). 

Figure 5.  Loss of cutaneous nerve fibers that stain positive for the neuronal antigen protein gene product 9.5 (PGP 9.5) in metabolic syndrome and diabetes

IENF, intraedpidermal nerve fiber

It is widely recognized that neuropathy per se can affect the quality of life (QOL) of the diabetic patient. A number of instruments have been developed and validated to assess QOL in DN. The NeuroQoL measures patients’ perceptions of the impact of neuropathy and foot ulcers 110. The Norfolk QOL questionnaire for DN is a validated tool addressing specific symptoms and the impact of large, small and autonomic nerve fiber functions. The tool has been used in clinical trials and is available in several validated language versions. It was recently tested in 262 subjects (healthy controls, diabetic controls and DN patients). Differences between DN patients and both diabetic and healthy controls were significant (p<0.05) for all item groupings (small fiber, large fiber, and autonomic nerve function; symptoms; and activities of daily living (ADL)). Total QOL scores correlated with total neuropathy scores. The ADL, total scores and autonomic scores were also greater in diabetic controls compared to healthy controls (p<0.05), suggesting that diabetes per se impacts some aspects of QOL 9.

The diagnosis of DPN is mainly a clinical one with the aid of specific diagnostic tests according to the type and severity of the neuropathy. However other non-diabetic causes of neuropathy must always be excluded, depending on the clinical findings (B12 deficiency, hypothyroidism, uremia, CIDP, etc) (Figure 6)

Figure 6. A diagnostic algorithm for assessment of neurologic deficit and classification of neuropathic syndromes: B12, vitamin B12; BUN, blood urea nitrogen; CIDP, chronic inflammatory demyelinating polyneuropathy; EMG, electromyogram; Hx, history; MGUS, monoclonal gammopathy of unknown significance; NCV, nerve conduction studies; NIS, neurologic impairment score (sensory and motor evaluation); NSS, neurologic symptom score; QAFT, quantitative autonomic function tests; QST, quantitative sensory tests .

Figure 6. The Evaluation of the patient suspected of having DPN

Treatment of Diabetic Polyneuropathies

Treatment of DN should be targeted towards a number of different aspects: firstly, treatment of specific underlying pathogenic mechanisms; secondly, treatment of symptoms and improvement in QOL; and thirdly, prevention of progression and treatment of complications of neuropathy 111.

1.   Treatment of specific underlying pathogenic mechanisms

Figure 7.   Treatment of DPN Based upon pathogenesis. .  

 

Glycemic and metabolic control

 

Several long-term prospective studies that assessed the effects of intensive diabetes therapy on the prevention and progression of chronic diabetic complications have been published. The large randomized trials such as the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS) were not designed to evaluate the effects of intensive diabetes therapy on DSPN, but rather to study the influence of such treatment on the development and progression of the chronic diabetic complications 112;113. Thus, only a minority of the patients enrolled in these studies had symptomatic DSPN at entry. Studies in type 1 diabetic patients show that intensive diabetes therapy retards but does not completely prevent the development of DSPN.  In the DCCT/EDIC cohort, the benefits of former intensive insulin treatment persisted for 13-14 years after DCCT closeout and provided evidence of a durable effect of prior intensive treatment on polyneuropathy and cardiac autonomic neuropathy (“hyperglycemic memory”) Level 1a, Grade A114;115.

In contrast, in type 2 diabetic patients, who represent the vast majority of people with diabetes, the results were largely negative. The UKPDS showed a lower rate of impaired VPT (VPT >25 V) after 15 years for intensive therapy (IT) vs. conventional therapy (CT) (31 vs. 52%). However, the only additional time point at which VPT reached a significant difference between IT and CT was the 9-year follow-up, whereas the rates after 3, 6, and 12 years did not differ between the groups. Likewise, the rates of absent knee and ankle reflexes as well as the heart rate responses to deep breathing did not differ between the groups 113. In the ADVANCE study including 11,140 patients with type 2 diabetes randomly assigned to either standard glucose control or intensive glucose control, the relative risk reduction (95% CI) for new or worsening neuropathy for intensive vs. standard glucose control after a median of 5 years of follow-up was −4 (−10 to 2), without a significant difference between the groups 116.  Likewise, in the VADT study including 1,791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes, after a median follow-up of 5.6 years no differences between the two groups on intensive or standard glucose control were observed for DSPN or microvascular complications 117. In the ACCORD trial 118, intensive therapy aimed at HbA1c <6.0% was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy after 3.7 years on average. At transition, loss of sensation to light touch was significantly improved on intensive vs standard diabetes therapy. At study end after 5 years, MNSI score >2 and loss of sensation to vibration and light touch were significantly improved on intensive vs standard diabetes therapy. However, because of the premature study termination and the aggressive HbA1c goal, the neuropathy outcome in the ACCORD trial is difficult to interpret.

In the Steno 2 Study 119, intensified multifactorial risk intervention including intensive diabetes treatment, angiotensin converting enzyme (ACE)-inhibitors, antioxidants, statins, aspirin, and smoking cessation in patients with microalbuminuria showed no effect on DSPN after 7.8 (range: 6.9-8.8) years and again at 13.3 years, after the patients were subsequently followed for a mean of 5.5 years.  However, the progression of cardiac autonomic neuropathy (CAN) was reduced by 57%. Thus, there is no evidence that intensive diabetes therapy or a target-driven intensified intervention aimed at multiple risk factors favorably influences the development or progression of DSPN as opposed to CAN in type 2 diabetic patients.  However, the Steno study used only vibration detection, which measures exclusively the changes in large fiber function.

Oxidative stress

A number of studies have shown that hyperglycemia causes oxidative stress in tissues that are susceptible to complications of diabetes, including peripheral nerves. Figure 2 presents our current understanding of the mechanisms and potential therapeutic pathways for oxidative stress-induced nerve damage. Studies show that hyperglycemia induces an increased presence of markers of oxidative stress, such as superoxide and peroxynitrite ions, and that antioxidant defense moieties are reduced in patients with diabetic peripheral neuropathy 120. Therapies known to reduce oxidative stress are therefore recommended. Therapies that are under investigation include aldose reductase inhibitors (ARIs), α-lipoic acid, γ-linolenic acid, benfotiamine, and protein kinase C (PKC) inhibitors.

Advanced glycation end-products (AGE) are the result of non-enzymatic addition of glucose or other saccharides to proteins, lipids, and nucleotides. In diabetes, excess glucose accelerates AGE generation that leads to intra- and extracellular protein cross-linking and protein aggregation. Activation of RAGE (AGE receptors) alters intracellular signaling and gene expression, releases pro-inflammatory molecules, and results in an increased production of reactive oxygen species (ROS) that contribute to diabetic microvascular complications. Aminoguanidine, an inhibitor of AGE formation, showed good results in animal studies but trials in humans have been discontinued because of toxicity 121. Benfotiamine is a transketolase activator that reduces tissue AGEs. Several independent pilot studies have demonstrated its effectiveness in diabetic polyneuropathy. The BEDIP 3-week study demonstrated subjective improvements in neuropathy scores in the group that received 200 mg daily of benfotiamine tablets, with a pronounced decrease in reported pain levels 122. In a 12-week study, the use of benfotiamine plus vitamin B6/B12 significantly improved nerve conduction velocity in the peroneal nerve along with appreciable improvements in vibratory perception. An alternate combination of benfotiamine (100 mg) and pyridoxine (100 mg) has been shown to improve diabetic polyneuropathy in a small number of diabetic patients 123. The use of benfotiamine in combination with other antioxidant therapies such as α-Lipoic acid (see below) will soon be commercially available.

ARIs reduce the flux of glucose through the polyol pathway, inhibiting tissue accumulation of sorbitol and fructose. In a 12-month study of zenarestat a dose dependent improvement in nerve fiber density was shown 124. In a one year trial of fidarestat in Japanese diabetics, improvement of symptoms was shown 125, and a 3 year study of epalrestat showed improved nerve function (NCV) as well as vibration perception 126. Newer ARIs are currently being explored, and some positive results have emerged 127, but it is becoming clear that these may be insufficient per se and combinations of treatments may be needed 27.

Gamma-Linolenic acid can cause significant improvement in clinical and electrophysiological tests for neuropathy 128.

Alpha-Lipoic acid or thioctic acid has been used for its antioxidant properties and for its thiol-replenishing redox-modulating properties. A number of studies show its favorable influence on microcirculation and reversal of symptoms of neuropathy 129 130 131 132. A meta-analysis including 1,258 patients from four randomized clinical trials concluded that 600 mg of i.v. α-Lipoic acid daily significantly reduced symptoms of neuropathy and improved neuropathic deficits 133. The recently published SYDNEY 2 trial showed significant improvement in neuropathic symptoms and neurologic deficits in 181 diabetic patients with 3 different doses of α-Lipoic acid compared to placebo over a 5-week period 134. The results of the NATHAN study, which examined the long-term effects on electrophysiology and clinical assessments, were presented at the 2007 ADA meeting.  The study showed that 4 years of treatment with α-lipoic acid in mild to moderate DSP is well tolerated and improves some neuropathic deficits and symptoms, but not nerve conduction 135.

Protein kinase C (PKC) activation is a critical step in the pathway to diabetic microvascular complications. It is activated by both hyperglycemia and disordered fatty-acid metabolism, resulting in increased production of vasoconstrictive, angiogenic, and chemotactic cytokines including transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), endothelin (ET-1), and intercellular adhesion molecules (ICAMs). A multinational, randomized, phase-2, double blind, placebo-controlled trial with ruboxistaurin (a PKC-β inhibitor) failed to achieve the primary endpoints although significant changes were observed in a number of domains 136. Nevertheless, in a subgroup of patients with less severe DN (sural nerve action potential greater than 0.5 μV) at baseline and clinically significant symptoms, a statistically significant improvement in symptoms and vibratory detection thresholds was observed in the ruboxistaurin-treated groups as compared with placebo 137. A smaller, single center study recently published showed improvement in symptom scores, endothelium dependent skin blood flow measurements, and quality of life scores in the ruboxistaurin treated group 35. These studies and the NATHAN studies have pointed out the change in the natural history of DN with the advent of therapeutic lifestyle change, statins and ACE inhibitors, which have slowed the progression of DN and drastically altered the requirements for placebo-controlled studies.

Growth factors

There is increasing evidence that there is a deficiency of nerve growth factor (NGF) in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) and that this contributes to the clinical perturbations in small-fiber function 138. Clinical trials with NGF have not been successful but are subject to certain caveats with regard to design; however, NGF still holds promise for sensory and autonomic neuropathies 139. The pathogenesis of DN includes loss of vasa nervorum, so it is likely that appropriate application of vascular endothelial growth factor (VEGF) would reverse the dysfunction. Introduction of VEGF gene into the muscle of DM animal models improved nerve function 140. There are ongoing VEGF gene studies with transfection of the gene into the muscle in humans. INGAP peptide comprises the core active sequence of Islet Neogenesis Associated Protein (INGAP), a pancreatic cytokine that can induce new islet formation and restore euglycemia in diabetic rodents. Maysinger et al showed significant improvement in thermal hypoalgesia in diabetic mice after a 2-week treatment with INGAP peptide 141.

Immune therapy

Several different autoantibodies in human sera have been reported that can react with epitopes in neuronal cells and have been associated with DN. We have reported a 12% incidence of a predominantly motor form of neuropathy in patients with diabetes associated with monosialoganglioside antibodies (anti GM1 antibodies) 55. Perhaps the clearest link between autoimmunity and neuropathy has been the demonstration of an 11-fold increased likelihood of CIDP, multiple motor polyneuropathy, vasculitis and monoclonal gammopathies in diabetes 53. New data, however, support a predictive role of the presence of antineuronal antibodies on the later development of neuropathy, suggesting that these antibodies may not be innocent bystanders but neurotoxins 142 143. There may be selected cases, particularly those with autonomic neuropathy, evidence of antineuronal autoimmunity, and CIDP, that may benefit from intravenous immunoglobulin or large dose steroids 51.

2.  Treatment of symptoms and improvement in QOL

Pain and Quality of Life in Diabetic Neuropathy

Pain is the reason for 40% of patient visits in a primary care setting and about 20% of these have had pain for greater than 6 months 20. Chronic pain may be nociceptive which occurs as a result of disease or damage to tissue wherein there is no abnormality in the nervous system or there may be no somatic abnormality. In contrast Experts in the Neurology and Pain community define neuropathic pain as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system” 21. Persistent neuropathic pain interferes significantly with quality of life (QOL), impairing sleep and recreation; it also significantly impacts emotional well being , and is associated with if not the cause of  depression, anxiety, loss of sleep, and non compliance with treatment 22.  Diabetic neuropathy pain (DNP) is a difficult-to-manage clinical problem. It is often associated with mood and sleep disturbances, and patients with DNP are more apt to seek medical attention than those with other types of diabetic neuropathy. Two population-based studies showed that neuropathic pain is associated with a greater psychological burden than nociceptive pain 23 and is considered to be more severe than other pain types.  Early recognition of psychological problems is critical to the management of pain and physicians need to go beyond the management of pain per se if they are to achieve success. Patients may also complain of decreased physical activity and mobility, increased fatigue, and negative effects on their social lives.  Providing significant pain relief markedly improves quality-of-life measures, including sleep and vitality 9;24.

Definition of Neuropathic pain         

A definition of peripheral neuropathic pain in diabetes, adapted from a definition proposed by the International Association for the Study of Pain 21, is “pain arising as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes” 14. A grading system for the degree of certainty of the diagnosis of neuropathic pain has been proposed. It is based on four simple criteria, namely:

• whether the pain has a distinct neuroanatomical distribution,
• whether the history of the patient suggests the presence or absence of a lesion or disease of the peripheral or central somatosensory system, 
• whether either of these findings is supported by at least one confirmatory test,
• and whether there is an abnormality of nerve conduction 21.

Degree of certainty is defined according to the number of criteria met: 1 to 4 (definite neuropathic pain); 1 and 2, plus 3 or 4 (probable neuropathic pain); or only 1 and 2 (possible neuropathic pain). 21  This system is necessary because there is no consensus on the diagnostic validity of the criteria, since  neuropathic pain is a composite of pain and other sensory symptoms associated with nerve injury. For example: sensory deficits; abnormal spontaneous or induced sensations, such as paresthesias (e.g., tingling); spontaneous attacks of electric shock-like sensations; abnormally evoked pain due to normally non painful stimuli vs. allodynia preclude a simple definition (see below).

The Diagnostic Workup for pain

Because of its complexity the presentation of pain poses a diagnostic dilemma for the clinician who needs to distinguish between neuropathic pain arising as a direct consequence of a lesion or disease of the somatosensory system, and nociceptive pain that is due to trauma, inflammation or injury. It is imperative to try to establish the nature of any predisposing factor including the pathogenesis of the pain if one is to be successful in its management.  Management of neuropathic pain requires a sound relationship between patient and physician, with an emphasis on a positive outlook and encouragement that there is a solution.  This requires patience and targeted pain-centered strategies that deal with the underlying disorder rather than the usual band aid prescription of drugs approved for general pain, which do not address the disease process. The inciting injury may be focal or diffuse and may involve single, or more likely, multiple mechanisms such as metabolic disturbances encompassing hyperglycemia, dyslipidemia, glucose fluctuations, or intensification of therapy with insulin.  On the other hand, the injury might embrace autoimmune mechanisms, neurovascular insufficiency, deficient neurotrophism, oxidative and nitrosative stress, or inflammation 12.  Because pain syndromes in diabetes may be focal or diffuse, proximal or distal, acute or chronic, each has its own pathogenesis and the treatment must be tailored to the underlying disorder if the outcome is to be successful.

Establish Presence of Diabetes, Impaired Fasting Glucose, or Impaired Glucose Tolerance

           
The presence of diabetes must be established if this has not already been done.  An A1c or random glucose may suffice but in rare instances a full 75g glucose tolerance test may need to be done 144. It is now clear, however, that this form of neuropathy may precede the onset of diabetes and occurs in IFG and IGT 145.

Pathogenetic mechanism of neuropathic pain

Neuropathic pain could arise from neuronal dysfunctions all along the somatosensory system from its most peripheral part, i.e. the nociceptor terminal membrane, to the cortical neurons. Nerve damage may induce peripheral sensitization.  This is related to the release of inflammatory mediators which activate intracellular signal transduction pathways in the nociceptor terminal, prompting an increase in the production, transport, and membrane insertion of transducer channels and voltage-gated ion channels 146;147. Following nerve injury, different types of voltage-gated sodium channels are up-regulated at the site of the lesion and in the dorsal root ganglion membrane, promoting ectopic spontaneous activity along the primary afferent neuron and determining hyperexcitability associated with lowered activation threshold, hyperreactivity to stimuli, and abnormal release of neurotransmitters such as substance P and glutamate 89;147-150. As a consequence of this hyperactivity in primary afferent nociceptive neurons, important secondary changes may occur in the dorsal horn of the spinal cord and higher up in the central nervous system leading to neuron hyperexcitability. This phenomenon, called central sensitization, is a form of use-dependent synaptic plasticity, considered a major pathophysiological mechanism of neuropathic pain 146. Different studies have demonstrated that thalamic dysfunction occurs in patients with diabetes as well as in experimental models 151. Cortical disinhibition has also been demonstrated in patients with PDPN using the transcranial magnetic stimulation technique 152. In addition, nerve injury appears to suspend the inhibitory modulation exerted by noradrenergic descending pathways, letting facilitatory modulation by serotoninergic descending pathways prevail.  Finally, pre- and post-synaptic GABAergic inhibition is lost and this may produce paradoxical excitation, contributing to neuron hyperexcitability and even to spontaneous neuron activity 146.

Distinction between Nociceptive and Non-nociceptive pain

A number of tools have been developed to differentiate  non-nociceptive stimuli (allodynia), increased pain sensitivity to stimuli (hyperalgesia) 153,  and summation, which is progressive worsening of pain caused by repeated mild noxious stimuli Level IIb, Grade B 154.

A number of self-administered questionnaires have been developed, validated, translated, and subjected to cross-cultural adaptation both to diagnose and distinguish neuropathic as opposed to non-neuropathic pain  (screening tools such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) Pain Scale, Douleur Neuropathique en 4 questions (DN4), Neuropathic Pain Questionnaire (NPS), pain DETECT, and ID-Pain) 154;155;155-160, and to assess pain quality and intensity (assessment questionnaires (12-14) such as the Short-Form McGill Pain Questionnaire, the Brief Pain Inventory (BPI), and the Neuropathic Pain Symptom Inventory (NPSI)) 155;161;162. Level IIIb, Grade B

According to IMMPACT (Initiative on Methods, Measurement and Pain Assessment in Clinical Trials) the following pain characteristics should be evaluated to assess the efficacy and effectiveness of chronic pain treatment: 1. pain intensity measured on a 0 to 10 numerical rating scale (NRS); 2. physical functioning assessed by the Multidimensional Pain Inventory (MPI) and Brief Pain Inventory (BPI) Interferences scale; 3. emotional functioning, assessed by the Beck Depression Inventory (BPI) and Profile of Mood states; and 4. patient rating of overall improvement, assessed by the Patient Global Impression of Change (PGI-C) 163. Level III, Grade B

Laboratory Tests to evaluate neuropathic pain

Since neuropathic pain is subjective there are no tests that can quantify this in humans. For that matter, all tests of pain in animal studies are really measures of reaction time to heat or other stimuli, which is one of the reasons for failure of translation of animal studies to man. Thus, laboratory tests do not reflect spontaneous pain but rather the function of the nociceptive system and, ultimately, with Quantitative Sensory Testing (QST), the evoked positive sensory phenomena associated with neuropathic pain, i.e., hyperalgesia and allodynia. This means that the results of laboratory tests become useful only in the context of a comprehensive clinical examination.

Among the tests, late laser-evoked potentials (Ad-LEPs) are the easiest and most reliable neurophysiological tools for assessing nociceptive Ad fiber pathway function in both peripheral and central neuropathic pain, with the limitation of very low availability Level IIb, Grade B 164. The morphological study of cutaneous nerve fibers (IENF, intraepidermal nerve fiber) using skin biopsy and IENF density assessment is regarded as a reproducible marker of small fiber sensory pathology.  In particular, distal leg skin biopsy with quantification of IENF density is a reliable and efficient technique to assess the diagnosis of small fiber neuropathy [European Federation of Neurological Societies (EFNS) Level Ia, Grade A recommendation] 83 but is still not widely available. Functional neuroimaging techniques, such as Positron Emission Tomography (PET) for the central nervous system and functional Magnetic Resonance Imaging (fMRI) for both central and peripheral nervous systems (MR neurography), have been used mainly for research purposes to evaluate the central mechanisms of pain in chronic pain conditions or to visualize intraneural and extraneural lesions of peripheral nerves Level IV, Grade C 165.

The intensity (severity) of neuropathic pain and its course should be assessed using an 11-Point numerical rating scale (Likert scale) or a visual analogue scale. Various screening tools (with or without limited bed-side testing) such as the Pain Detect, LANSS, NPQ, DN-4, and ID-Pain have been developed to identify neuropathic pain. These questionnaires use verbal descriptors and pain qualities as a basis for distinguishing neuropathic pain from other types of chronic pain such as nociceptive pain 154.

Evaluation of pain intensity is essential for monitoring response to therapy. There are a number of symptom-based screening tools such as the NTSS-6, Brief Pain Inventory, QOL-DN, SF-36, Visual Analog Scale for Pain Intensity, Neuro-QOL, and Norfolk Neuropathy Symptoms Score Level 1a, Grade A 166.  With the visual analog scale the patient marks the intensity of their pain on a scale from 0-10, allowing an assessment of the response to intervention. Simultaneously, the patient should complete a quality of life tool such as the Norfolk QOL DN  which needs to include comorbidities such as anxiety, depression, and sleep interference Level 1a, Grade A 9.  Such a tool permits evaluation of the impact of the pain on quality of life (QOL), anxiety and depression, all of which are known to be accompanying features of DPN.

Quality of life

Several studies have consistently found that neuropathic pain has a negative impact on global health-related quality of life. A systematic review of 52 studies in patients with one out of 6 different disorders associated with neuropathic pain, including PDPN, established that neuropathic pain impairs physical and emotional functioning, role functioning including participation in gainful employment, sleep and, to a lesser degree, social functioning. In addition, there is also evidence suggesting an association between neuropathic pain and depression, as for other types of pain 22;167.

The impact of pain on Quality of Life (QOL) in PDPN has recently been shown in 1111 patients: physical and mental QOL were significantly more impaired in patients with PDPN vs. both diabetic patients devoid of neuropathy and those with non-painful DSPN 168. Also the nature of pain may be important, as Daousi et al. has reported significantly poorer QOL in patients with PDPN vs. diabetic patients with non-neuropathic pain 169.

Targeted studies in diabetic patients have shown that (1) chronic and severe pain significantly interferes with overall diabetes self-management (p=0.002 and p=0.0003, respectively), and (2) neuropathic pain significantly interferes with the quality of sleep measured by the Medical Outcomes Study Sleep Scale (MOS-Sleep Scale), the results of which were significantly worse in a sample of 255 PDPN patients than in the general population (n=1011), a chronic disease sample (n=3445), and postherpetic neuralgia patients (n=89) 170;171.

Pain and its Comorbidities

Neuropathic pain is the consequence of an array of diseases or injuries to the peripheral or central nervous system. It is often chronic and if inadequately treated patients may experience anxiety, depression, catastrophising behaviour (an inability to accept chronic pain), and sleep disturbances. Treatment of peripheral neuropathic pain conditions can benefit from further understanding of the impact of pain response and QOL including ADLs and sleep.

Castro et al 172 studied 400 patients with depression, anxiety, and sleep disturbances. Two thirds of the depressed patients had pain; three quarters of the anxious patients did so too; but the group worst affected by pain were the sleep deprived patients, of whom >90% had experienced pain.  As a corollary Gore et al 173 showed that with increasing pain severity there was a linear increase in HADs pain and Depression scores. Depression complicated diabetes management, increased the length of hospital stays, and almost doubled the yearly cost of diabetes management from $7000 to $11,000  174.  Moreover Gupta et al showed that higher scores for anxiety, depression, and sleep disturbances predicted the development of pain 175. 

The pain circuit therefore involves not only the peripheral sensory pathways but also the central emotional and cognitive neural pathways (Figure 8)  The microanatomy of pain is only beginning to evolve, and recent studies using functional MRI 176 and CHEPS 177 are beginning to define the role of the thalamus, limbic region, and cerebral cortex in pain manifestations.  It is becoming increasingly clear that pain has strong neuro-endocrine, autonomic,  pro-inflammatory, and neuro-degenerative underpinnings 178-180. There is increasing evidence for a role of inflammatory cytokines such as IL6, TNFa, chemokines, adhesion molecules and acute phase reactants, and activation of the oxidative/nitrosative stress pathway invoking NFkb, all of which play a significant role in the complex interplay among the adipose tissue, macrophages, and glial and dendritic cells in the nervous system. Of particular note is the activation of the autonomic nervous system and the association between pain, anxiety, and autonomic nervous system dysfunction 181. Martinez Lavin has shown that infusion of norepinephrine heightens the pain experienced, and Rainsville has shown that negative emotions exacerbate  pain 182. There is also a significant impact of chronic pain on immune function 183, with increases in circulating levels of IL6, IL 8 and IL1-ra.  IL-8  is a proinflammatory cytokine which mediates sympathetic pain;  IL1-ra is involved with stress; and IL-6 activates sympathetic pain and is involved with stress, fatigue, hyperalgesia, and depression.Thus, it should be recognized that pain management programmes based on cognitive behavioral principles, are the treatment of choice.  Evaluation of outcomes should be standard practice, assessing distress and the emotional impact of pain.  Sankar et al  studied 67 patient s with painful neuropathy, 66% of whom had depression/anxiety.  Anxiety resulted in reporting a significantly higher pain intensity score [NPS: 8.0 (1.4) vs. 6.5 (2.5); P=.009].  Patients with anxiety also reported significantly higher scores in all sub-categories of Norfolk QOL 9.  Subjects who were depressed were less likely to accept pain [CPAQ depression vs. no depression, pain willingness: 55.8 (11.3) vs. 71.9 (14.4); P=.008] and engage in social and/or physical activity [CPAQ, activities engagement: 30.9 (10.4) vs. 48.6 (9.3); P<0.001].

Vinik et al examined data from 5 DPN, 4 post-herpetic neuralgia (PHN), and 1 DPN/PHN double-blind, placebo-controlled, randomized clinical trials of 8-13 weeks duration. Study entry criteria for subjects included age >18 years, A1C <11%, and painful neuropathy or PHN >3 months after rash disappeared.  Average pain score at study entry was >4 on Likert NRS, or >40 mm on short-form McGill. Primary efficacy was measured with the 11-point NRS, in which percent pain reduction was ruled substantial if ≥50%, moderate if 30-50%, and minimal if 15-30%.   No improvement equaled a 0% change in pain reduction. Secondary endpoints consisted of PGIC and the SF-36 scale. ITT population comprised 2349 patients and 836 placebo.  Pearson correlations and pathway analysis were used in the analysis. The data showed a direct relationship between the reduction in pain and enhanced sleep, as well as improvement in social functioning on the SF36 scale. Indeed, the improvement in social functioning depended on pain relief and sleep improvement equally well. In addition, the effects of pregabalin on pain relief were mediated directly and indirectly through its effects on sleep improvement about equally 184. Level 1a Grade A This speaks to the need for determining sleep status in the evaluation of pain and choosing an agent capable of enhancing sleep if pain relief is to be achieved.   Recently Boyd et al have shown that relief of pain with the anti-epileptic drug topiramate is associated with improvement in subjective and objective measures of nerve function as well as intraepidermal nerve fiber regeneration Level 1b Grade A 185.

Epidemiology of Neuropathic Pain

Neuropathic pain is not uncommon. A population-based survey of 6000 patients treated in family practice in the UK reported a 6% prevalence of pain predominantly of neuropathic origin 186.  Similarly a large population-based study in France showed that 6.9 % of the population had neuropathic pain 23. Interestingly, in a Dutch population survey of >362,000 persons, younger people with pain tended to be mostly women, but with advancing age the gender differences disappeared.  Perhaps a little recognized fact is that mononeuritis and entrapments were 3 times as common as diabetic peripheral neuropathy (DPN), and fully one third of the diabetic population has some form of entrapment 187 which, when recognized is readily amenable to intervention 188. Even more salutary is the mounting evidence that even with impaired glucose tolerance (IGT), patients may experience pain 109;168;189. In the general population (region of Augsburg, Southern Germany), the prevalence of painful PN was 13.3% in the diabetic subjects, 8.7% in those with IGT, 4.2 % in those with impaired fasting glucose (IFG), and 1.2% in those with normal glucose tolerance (NGT) 190. Among survivors of myocardial infarction (MI) from the Augsburg MI Registry, the prevalence of neuropathic pain was 21.0% in the diabetic subjects, 14.8% in those with IGT, 5.7% in those with IFG, and 3.7% in those with NGT 189. Thus, subjects with macrovascular disease appear to be prone to neuropathic pain. The most important risk factors of DSPN and neuropathic pain in these surveys were age, obesity, and low physical activity, while the predominant co-morbidity was peripheral arterial disease, highlighting the paramount role of cardiovascular risk factors and diseases in prevalent DSPN.

As a corollary, patients presenting with painful neuropathy have impaired fasting glucose or impaired glucose tolerance and, about 50% of the time, are overweight and have autonomic dysfunction 109. Even in the absence of elevated fasting blood glucose (FBG <100 mg/dl), pain may be the presenting feature of the metabolic syndrome and cosegregates with elevated triglycerides and a low HDL-C 82. Indeed, a risk factor for neuropathic pain in diabetic and non-diabetic populations is an impairment of peripheral vascular function 189;191.

Pain Characteristics

Pain associated with a peripheral nerve injury has several distinct clinical characteristics. In a clinical survey including 105 patients with painful DSPN, the following locations of pain were most frequent: 96% feet, 69% balls of feet, 67% toes, 54% dorsum of foot, 39% hands, 37% plantar surface of the foot, 37% calves, and 32% heels. The pain was most often described by the patients as ‘burning/hot’, ‘electric’, ‘sharp’, ’achy’, and ‘tingling’ and was worse at night time and when tired or stressed 192. The average pain intensity was moderate, approximately 5.75/10 on a 0-10 scale, ranging from  3.6 to 6.9/10.  Allodynia (pain due to a stimulus which does not normally cause pain, e.g. stroking) may occur. The symptoms may be accompanied by sensory loss, but patients with severe pain may have few clinical signs. Pain may persist over several years 193, causing considerable disability and impaired QOL in some patients 192, whereas it may remit partially or completely in others 80;194 despite further deterioration in small fiber function 194. Pain exacerbation or even acute onset of pain  tends to be associated with sudden metabolic change, short duration of pain or diabetes, or preceding weight loss; it has less severe or no sensory loss, and normal strength and reflexes 80;194.

Neuropathic pain derived from small nerve fibers is often burning, lancinating or shooting in quality with unusual, tingling or crawling sensation referred to as formication. Some describe bees stinging through the socks while others talk of walking on hot coals. The pain, worse at night, keeps the patient awake and is associated with sleep deprivation  9.  Patients volunteer that they have allodynia or pain from normal stimuli, such as the touch of bedclothes, and may have hyperaesthesias (increased sensitivity to touch), hyperalgesia (increased sensitivity to painful stimuli), or even altered sensation to cold or heat. These may be paradoxical with differences in sensation to one or another modality of stimulation. Unlike animal models of DPN, the pain is spontaneous and does not need provocation such as a hot plate or laser heat. It has a glove and stocking distribution. Small fiber neuropathies usually present with pain in the feet or hands, do not have abnormalities in sensation, lack weakness or loss of reflexes, and are electrophysiogically silent, thus often leading to the erroneous diagnosis of hysteria or conversion reactions.

Large fiber neuropathy presents with characteristic weakness, ataxia, loss of reflexes, and impaired nerve conduction.  Pain is deep-seated and gnawing in quality, “like a toothache” in the foot, or “a dog gnawing at the bones of the feet”, or the “feet feel as if they are encased in concrete”.

In contrast, the nociceptive pain of arthritis does not have these qualities. It is localized to the joints, starts with morning stiffness, and improves as the day wears on 28.  Fasciitis pain is localized to the fascia; entrapment produces pain in a dermatome; and claudication is made worse by walking. 

The Diagnosis of Neuropathic Pain

The diagnosis of neuropathic pain - as opposed to pain from causes other than neuropathy - is first and foremost made by careful history taking. Pain in the first three fingers is carpal tunnel syndrome; pain in the pinky is ulnar entrapment; pain on the lateral side of the shin is peroneal entrapment; pain on the medial side of the foot is medial plantar entrapment; and pain in the space between the first and second metatarsal heads is a Morton’s neuroma.  Somatosensory, motor, and autonomic bedside evaluation can be done and is complimented by use of one of the screening tools listed above (DN4, Pain DETECT, etc) 154. The physician should ensure that all the features of pain such as distribution, quality, severity, timing, associated symptoms, and exacerbating and alleviating factors (if any) are recorded. In particular, the presence of numbness, burning, tingling, lightening pain, stabbing and prickling should be recorded, as is done in the  Norfolk QOLLevel 1a, Grade A 9, the NTSS 195, and  the Pain Detect 154.    Secondly, pain intensity and quality should be assessed, using pain intensity scales (Visual Analogue Scale or NRS) Level 1a, Grade A196 and pain questionnaires (BPI, NPSI). A number of tools and questionnaires have been developed to quantify the pain impact on sleep, mood, and QOL, mainly to be used in clinical trials. In clinical practice the Brief Pain Inventory Interference, the Profile of Moods, or the hospital scale for anxiety and depression ( HADS ) can provide a simple measure of pain impact on QOL. Responses to treatment by self reporting using a diary can document the course of painful symptoms and their impact on daily life Level 1a , Grade A 197. Diaries are also most useful for outcomes measures in clinical trials on drugs used for pain relief.      

Management of Neuropathic Pain

Control of pain is one of the most difficult management issues in DN. It often involves different classes of drugs and requires combination therapies. In any painful syndrome, special attention to the underlying condition is essential for the overall management and for differentiation from other conditions that may coexist in patients with diabetes (i.e. claudication, Charcot’s neuroarthropathy, fasciitis, osteoarthritis, radiculopathy, Morton’s neuroma, tarsal tunnel syndrome). Small nerve fiber neuropathy often presents with pain but without objective signs or electrophysiologic evidence of nerve damage. Large nerve fiber neuropathies produce numbness, ataxia and incoordination. A careful history of the nature of pain, its exact location, and detailed examination of the lower limbs are mandatory to ascertain alternate causes of pain. Pain can be caused by dysfunction of different types of small nerve fibers (Aδ fiber versus C fiber) that are modulated by sympathetic input with spontaneous firing of different neurotransmitters to the dorsal root ganglia, spinal cord and cerebral cortex. Figure 8 describes the pathophysiological basis for the generation of neuropathic pain. Different types of pain respond to different types of therapies 27. Figure 9 describes the different nerve fibers affected and possible targeted treatments.

Figure 8. Schematic representation of the generation of pain: (A) Normal: Central terminals of c-afferents project into the dorsal horn and make contact with secondary pain-signaling neurons. Mechanoreceptive Aβ afferents project without synaptic transmission into the dorsal columns (not shown) and also contact secondary afferent dorsal horn neurons. (B) C-fiber sensitization: Spontaneous activity in peripheral nociceptors (peripheral sensitization, black stars) induces changes in the central sensory processing, leading to spinal-cord hyperexcitability (central sensitization, gray star) that causes input from mechanoreceptive Aβ (light touch) and Aδ fibers (punctuate stimuli) to be perceived as pain (allodynia). (C) C-fiber loss: C-nociceptor degeneration and novel synaptic contacts of Aβ fibers with “free” central nociceptive neurons, causing dynamic mechanical allodynia. (D) Central disinhibition: Selective damage of cold-sensitive Aδ fibers that leads to central disinhibition, resulting in cold hyperalgesia. Sympat, sympathetic nerve.27

Figure 8.  Schematic representation of the generation of pain

 

Figure 9. Different mechanisms of pain and possible treatments:

C fibers are modulated by sympathetic input with spontaneous firing of different neurotransmitters to the dorsal root ganglia, spinal cord and cerebral cortex. Sympathetic blockers (e.g. clonidine) and depletion of axonal substance P used by C fibers as their neurotransmitter (e.g. by capsaicin) may improve pain. In contrast Aδ fibers utilize Na+ channels for their conduction and agents that inhibit Na+ exchange such as antiepileptic drugs, tricyclic antidepressants, and insulin may ameliorate this form of pain. Anticonvulsants (carbamazepine, gabapentin, pregabalin, topiramate) potentiate activity of g-aminobutyric acid and inhibit Na+ and Ca2+ channels, N-methyl-D-aspartate receptors, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors. Dextromethorphan blocks N-methyl-D-aspartate receptors in the spinal cord. Tricyclic antidepressants, selective serotonin reuptake inhibitors (e.g. fluoxetine), and serotonin and norepinephrine reuptake inhibitors inhibit serotonin and norepinephrine reuptake, enhancing their effect in endogenous pain-inhibitory systems in the brain. Tramadol is a central opioid analgesic. α2 antag, α 2 antagonists; 5HT, 5-hydroxytryptamine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; DRG, dorsal root ganglia; GABA, g-aminobutyric acid; NMDA, N-methyl-D-aspartate; SNRIs, serotonin and norepinephrine reuptake inhibitors; SP, substance P; SSRIs, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; modified from Vinik et al.27

Treatment based on pathogenetic concepts of Pain

Painful symptoms in DSPN may constitute a considerable management problem. The efficacy of a single therapeutic agent is not the rule, and simple analgesics are usually inadequate to control the pain. There is agreement that patients should be offered the available therapies in a stepwise fashion Level 1a, Grade A 198-201. Effective pain treatment considers a favourable balance between pain relief and side effects without implying a maximum effect. The following general considerations in the pharmacotherapy of neuropathic pain require attention:

The appropriate and effective drug has to be tried and identified in each patient by carefully titrating the dose based on efficacy and side effects.
Lack of efficacy should be judged only after 2-4 weeks of treatment using an adequate dose.

Because the evidence from clinical trials suggests only a maximum response of »50% for any monotherapy, analgesic combinations may be useful. Potential drug interactions have to be considered given the frequent use of polypharmacy in diabetic patients.

The relative benefit of an active treatment over a control in clinical trials is usually expressed as the relative risk, the relative risk reduction, or the odds ratio. However, to estimate the extent of a therapeutic effect (i.e. pain relief) that can be translated into clinical practice, it is useful to apply a simple measure that serves the physician in selecting the appropriate treatment for the individual patient. Such a practical measure is the "number needed to treat" (NNT), i.e. the number of patients who need to be treated with a particular therapy to observe a clinically relevant effect or adverse event in one patient. This measure is expressed as the reciprocal of the absolute risk reduction, i.e. the difference between the proportion of events in the control group (Pc) and the proportion of events in the intervention group (Pi): NNT = 1/(Pc-Pi). The 95% confidence interval (CI) of NNT can be obtained from the reciprocal value of the 95% CI for the absolute risk reduction. The NNT and NNH (number needed to harm) for the individual agents used in the treatment of painful diabetic neuropathy are given in Table 2 Usually, drugs with NNTs exceeding 6 for ³50% pain relief are regarded as showing limited efficacy. However, some authors have cautioned that summary NNT estimates may have limited clinical relevance, due to problems of heterogeneity 202.

Impact of Pain on Comorbidities, Sleep disturbances, Anxiety and Depression

Quality of life

The growing knowledge about the neural and pharmacologic basis of neuropathic pain is likely to have important treatment implications, including development and refinement of a symptom/mechanism-based approach to neuropathic pain and implementation of novel treatment strategies using the newer antiepileptic agents, which may address the underlying neurophysiologic aberrations in neuropathic pain, allowing the clinician to increase the likelihood of effective management. The neuropharmacology of pain is also becoming better understood. For example, recent data suggest that gamma-aminobutyric acid (GABA), voltage-gated sodium channels, and glutamate receptors may be involved in the pathophysiology of neuropathic pain. Many of the newer agents have significant effects on these neurophysiologic mechanisms. Hyperglycemia may be a factor in lowering the pain threshold. Pain is often worse with wide glycemic excursions. Paradoxically acute onset of pain may appear soon after initiation of therapy with insulin or oral agents 203. Adding to the confusion, it has been reported that a  striking amelioration of symptoms can occur with continuous subcutaneous insulin administration, which may reduce the amplitude of excursions of blood glucose 203. This dichotomy is not well explained. There is a sequence in DN, beginning when Ab and C nerve fiber function is intact and there is no pain. With damage to C fibers there is sympathetic sensitization and peripheral autonomic symptoms are interpreted as painful. Topical application of clonidine causes anti-nociception by blocking emerging pain signals at the peripheral terminals via alpha-2 adrenoreceptors 204, in contrast with the central actions of clonidine on blood pressure control.  With the death of C-fibers there is nociceptor sensitization. Ab fibers conduct all varieties of peripheral stimuli such as touch, and these are interpreted as painful, e.g. allodynia. With time there is reorganization at the cord level and the patient experiences cold hyperalgesia and ultimately, even with the death of all fibers, pain is registered in the cerebral cortex whereupon the syndrome becomes chronic without the need for peripheral stimulation.  Disappearance of pain may not necessarily reflect nerve recovery but rather nerve death. When patients volunteer the loss of pain, progression of the neuropathy must be excluded by careful examination (as shown in Table 3). 

Adrenergic blockers

           
Initially, when there is ongoing damage to the nerves, the patient experiences pain of the burning, lancinating, dysesthetic type often accompanied by hyperalgesia and allodynia.  Because the peripheral sympathetic nerve fibers are also small unmyelinated C-fibers, sympathetic blocking agents (clonidine) may improve the pain.

Topical capsaicin

C-fibers utilize the neuropeptide substance P as their neurotransmitter, and depletion of axonal substance P (through the use of capsaicin) will often lead to amelioration of the pain. Prolonged application of capsaicin depletes stores of substance P, and possibly other neurotransmitters, from sensory nerve endings. This reduces or abolishes the transmission of painful stimuli from the peripheral nerve fibers to the higher centers 205. Recent analysis of randomized and controlled studies revealed that either a repeated application of low doses of capsaicin or single application of high doses affords pain relief 206. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is an alkaloid and the most pungent ingredient in the red pepper. It depletes tissues of substance P and reduces neurogenic plasma extravasation, the flare response, and chemically induced pain. Substance P is present in afferent neurons innervating skin, mainly in polymodal nociceptors, and is considered the primary neurotransmitter of painful stimuli from the periphery to the central nervous system. Several studies have demonstrated significant pain reduction and improvement in quality of life in diabetic patients with painful neuropathy after 8 weeks of treatment with capsaicin cream 0.075% 207. It has been criticized that a double-blind design is not feasible for topical capsaicin due to the transient local hyperalgesia (usually mild burning sensation in >50% of the cases) it may produce as a typical adverse event. Treatment should be restricted to a maximum of 8 weeks, as during this period no adverse effect on sensory function (due to the mechanism of action) was noted in diabetic patients. The 8% capsaicin patch (Qutenza), which is effective in postherpetic neuralgia, 208 is contraindicated in painful diabetic neuropathy due to desensitization of nociceptive sensory nerve endings which may theoretically increase the risk of diabetic foot ulcers. Level Ib, Grade B

Lidocaine.  A multicenter randomized, open label, parallel-group study with a drug washout phase of up to 2 weeks and a comparative phase of 4-week treatment periods of 5% lidocaine (n = 99) vs. pregabalin (n = 94) showed that Lidocaine was as effective as pregabalin in reducing pain and was free of side effects 209. This form of therapy may be of most use in self-limited forms of neuropathy.  If successful, therapy can be continued with oral mexiletine.  This class of compounds targets the pain caused by hyperexcitability of superficial, free nerve endings 210. The AAN recomendations are:

• Capsaicin and isosorbide dinitrate spray should be considered for the treatment of PDN (Level Ib Grade B).
• Clonidine, pentoxifylline, and mexiletine should probably not be considered for the treatment of PDN (Level IIb, Grade B).
• The Lidoderm patch may be considered for the treatment of PDN (Level IIa, Grade B).
• There is insufficient evidence to support or refute the usefulness of vitamins and a-lipoic acid in the treatment of PDN (Level Ia, Grade A).

Opioids

Tramadol and NMDA Receptor antagonists

There are two possible targeted therapies. Tramadol is a centrally acting weak opioid analgesic for use in treating moderate to severe pain.  Tramadol was shown to be better than placebo in a randomized controlled trial 211 of only  6-weeks duration, but a subsequent follow-up study suggested that symptomatic relief could be maintained for at least six months  212.  Side-effects are, however, relatively common, and are similar to other opioid-like drugs. Another spinal cord target for pain relief is the excitatory glutaminergic N-methyl-D-aspartate (NMDA) receptor.  Blockade of NMDA receptors is believed to be one mechanism by which dextromethorphan exerts analgesic efficacy 213. The NMDA receptors play an important role in central sensitization of neuropathic pain. Their use, however, has not been widespread in part due to dose-limiting side effects Level1a Grade A 214.

Tramadol acts directly via opioid receptors and indirectly via monoaminergic receptor systems. Because the development of tolerance and dependence during long-term tramadol tratment is uncommon and its abuse liability appears to be low, it is an alternative to strong opioids in neuropathic pain 211. One conceivable mechanism for the favourable effect of tramadol could be a hyperpolarization of postsynaptic neurons via postsynaptic opioid receptors. Alternatively, the reduction in central hyperexcitability by tramadol could be due to a monoaminergic or a combined opioid and monoaminergic effect.

Most severe pain requires administration of strong opioids such as oxycodone. Although there is little data available on combination treatment, combinations of different substance classes have to be used in patients with pain resistant to monotherapy. Several add-on trials have demonstrated significant pain relief and improvement in quality of life following treatment with controlled-release oxycodone, a pure μ-agonist in patients with painful DSPN whose pain was not adequately controlled on standard treatment with antidepressants and anticonvulsants 215;216. As expected, adverse events were frequent and typical of opioid-related side effects. A cross-over study examined the maximum tolerable dose of a combination treatment of gabapentin and morphine as compared to monotherapy of each drug. The maximum tolerable dose was significantly lower, and efficacy was better, during combination therapy than with monotherapy, suggesting an additive interaction between the two drugs 216. The results of these studies suggest that opioids should be included among the therapeutic options for painful DSPN, provided that careful selection of patients unresponsive to standard treatments, regular monitoring, appropriate dose titration, and management of possible opioid-specific problems (analgesic misuse or addiction, tolerance, opioid-induced hyperalgesia) are ensured. Recent recommendations have emphasized the need for clinical skills in risk assessment and management as a prerequisite to safe and effective opioid prescribing 201. Treatment of painful DSPN with opioid agonists should generally be reserved for patients who have failed to respond to or cannot tolerate the first-line medications.

Tapentadol is a novel centrally active analgesic with a dual mode of action: µ-opioid receptor agonist and norepinephrine-reuptake inhibitor. A recent phase III, randomized-withdrawal, placebo-controlled trial evaluated the safety and efficacy of tapentadol extended release (ER) in painful diabetic DSPN.  Patients with at least a ≥1 point reduction in pain intensity at the end of a 3-week open-label titration phase were randomized to receive placebo or their optimal fixed dose over 12 weeks. Compared with placebo, tapentadol ER 100-250 mg bid was associated with a statistically significant difference in the maintenance of the initial improvement of pain and was well-tolerated 217. Further studies to confirm this finding are underway. The AAN recommendations are: dextromethorphan, morphine sulfate, tramadol, and oxycodone should be consid­ered for the treatment of PDN (Level 1a, Grade A). Data are insufficient to recommend one agent over the other.

The response rates to analgesic monotherapy in painful diabetic DSPN are only around 50%. Therefore, combination pharmacotherapy is required in patients who have only partial response or in whom the drug cannot be further titrated due to intolerable side effects. A recent trial showed that the combination of nortriptyline and gabapentin at the maximum tolerated dose was more effective than either monotherapy despite a lower maximum tolerable dose as compared with monotherapy 218. Appropriate analgesic combinations include antidepressants with anticonvulsants, or each of these with opioids. Some patients may even require a triple combination of these drug classes.

Antidepressants:

Antidepressants are now emerging as the first line of agents in the treatment of chronic neuropathic pain 198. Clinical trials have focused on interrupting pain transmission utilizing antidepressant drugs that inhibit the reuptake of norepinephrine or serotonin. This central action accentuates the effects of these neurotransmitters, essentially  activating endogenous pain-inhibitory systems in the brain that modulate pain transmission cells in the spinal cord 219. Putative mechanisms of pain relief by antidepressants include the inhibition of norepinephrine and/or serotonin reuptake at synapses of central descending pain control systems and the antagonism of N-Methyl-D-Aspartate receptors that mediate hyperalgesia and allodynia. Imipramine, amitriptyline, and clomipramine induce a balanced reuptake inhibition of both norepinephrine and serotonin, while desipramine is a relatively selective norepinephrine inhibitor. The NNT (CI) for ³ 50% pain relief by TCAs in painful neuropathies is 2.1 (1.9-2.6). The number needed to harm (NNH) in patients with neuropathic pain for one drop out of the study due to adverse events is 16 (11-26) 199.

The most frequent adverse events of TCAs include tiredness and dry mouth. The starting dose should be 25 mg (10 mg in frail patients) taken as a single night time dose one hour before sleep. It should be increased by 25 mg at weekly intervals until pain relief is achieved or adverse events occur. The maximum dose is usually 150 mg per day.

TCAs should be used with caution in patients with orthostatic hypotension and are contraindicated in patients with unstable angina, recent (<6 months) myocardial infarction, heart failure, history of ventricular arrhythmias, significant conduction system disease, and long QT syndrome. Their use is limited by relatively high rates of adverse events and several contraindications. Thus, there is a continuing need for agents that exert efficacy equal to or greater than that achieved with TCAs but that have a more favourable side effect profile. (Level 1a, Grade A)

Selective serotonin reuptake inhibitors (SSRI)

Because of the relatively high rates of adverse effects and several contraindications of TCAs, it has been reasoned that patients who do not tolerate them due to adverse events could alternatively be treated with selective serotonin reuptake inhibitors (SSRI). SSRIs specifically inhibit pre-synaptic reuptake of serotonin but not norepinephrine; and, unlike the tricyclics, they lack the postsynaptic receptor blocking effects and quinidine-like membrane stabilization. Unfortunately, only weak effects on neuropathic pain were observed after treatment with fluoxetine, paroxetine, citalopram, and escitalopram. The NNT (CI) for  ³50% pain relief by SSRIs in painful neuropathies is 6.8 (3.9-27) 199. Because of these limited efficacy data, SSRIs have not been licensed for the treatment of neuropathic pain. (Level IIb, Grade B)

Serotonin noradrenaline reuptake inhibitors (SNRI)

Because SSRIs have been found to be less effective than TCAs, recent interest has focused on antidepressants with dual selective inhibition of serotonin and noradrenaline such as duloxetine and venlafaxine. The efficacy and safety of duloxetine were evaluated in 3 controlled studies using a dose of 60 and 120 mg/day over 12 weeks 220. In all three studies, the average 24 hour pain intensity was significantly reduced with both doses as compared to placebo treatment, the difference between active and placebo achieving statistical significance after 1 week. The response rates, defined as ³ 50% pain reduction, were 48.2% (120 mg/day), 47.2% (60 mg/day), and 27.9% (Placebo), giving a NNT of 4.9 (95% CI: 3.6-7.6) for 120 mg/day and 5.3 (3.8-8.3) for 60 mg/day. Pain severity, but not variables related to diabetes or neuropathy, predicts the effects of duloxetine in diabetic peripheral neuropathic pain. Patients with higher pain intensity tend to respond better than those with lower pain levels 221. The most frequent side effects of duloxetine (60/120 mg/day) include nausea (16.7/27.4%), somnolence (20.2/28.3%), dizziness (9.6/23%), constipation (4.9/10.6%), dry mouth (7.1/15%), and reduced appetite (2.6/12.4%). These adverse events are usually mild to moderate and transient. To minimize them the starting dose should be 30 mg/day for 4-5 days. In contrast to TCAs and some anticonvulsants duloxetine does not cause weight gain, but a small increase in fasting blood glucose may occur  222.

Venlafaxine is another SNRI that has mixed action on catecholamine uptake. At lower doses, it inhibits serotonin uptake and at higher doses it inhibits norepinephrine uptake 223. The extended release version of venlafaxine was found to be superior to placebo in diabetic neuropathic pain in non depressed patients at doses of 150-225 mg daily, and when added to gabapentin there was improved pain, mood, and quality of life 224.

In a 6-week trial comprised of 244 patients the analgesic response rates were 56%, 39%, and 34% in patients given 150-225 mg venlafaxine, 75 mg venlafaxine, and placebo, respectively. Because patients with depression were excluded, the effect of venlafaxine (150-225 mg) was attributed to an analgesic, rather than antidepressant, effect. The most common adverse events were tiredness and nausea 225. Duloxetine, but not venlafaxine, has been licensed for the treatment of painful diabetic neuropathy. (Level Ia, Grade A)

Antiepileptic drugs

Antiepileptic drugs (AEDs) have a long history of effectiveness in the treatment of neuropathic pain, dating back to case studies of the treatment of trigeminal neuralgia with phenytoin in 1942 and carbamazepine in 1962 226. Principal mechanisms of action include sodium channel blockade (felbamate, lamotrigine, oxcarbazepine, topiramate, zonisamide), potentiation of gamma-aminobutyric (GABA) activity (tiagabine, topiramate), calcium channel blockade (felbamate, lamotrigine, topiramate, zonisamide), antagonism of glutamate at N-methyl-d-aspartate (NMDA) receptors (felbamate) or α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) (felbamate, topiramate), and mechanisms of action as yet to be fully determined (gabapentin, pregabalin, levetiracetam) 227. An understanding of the mechanisms of action of the various drugs leads to the concept of “rational polytherapy,” wherein drugs with complementary mechanisms of action can be combined for synergistic effect. For example, one might choose a sodium channel blocker such as lamotrigine to be used with a glutamate antagonist such as felbamate. Furthermore, a single drug may possess multiple mechanisms of action, perhaps increasing its likelihood of success (e.g. topiramate). If pain is divided according to its derivation from different nerve fiber types (e.g. Ad vs. C-fiber), spinal cord or cortical, then different types of pain should respond to different therapies.

In addition to providing efficacy against epilepsy, these new AEDs may also be effective in neuropathic pain. For example, spontaneous activity in regenerating small-caliber primary afferent nerve fibers may be quelled by sodium channel blockade, and hyperexcitability in dorsal horn spinal neurons may be decreased by the inhibition of glutamate release - 2 mechanisms of action possessed by the AED lamotrigine 228,229. Clinical trials, however, have not been salutary 9.  Another potential use of AEDs in PDN is exemplified by felbamate:, the “wind-up” phenomenon caused by nerve injury and the kindling that occurs in hippocampal neurons in patients with mesial temporal sclerosis both enlist activation of NMDA receptors 230,231, which can be antagonized by felbamate 227. The evidence supporting the use of AEDs for the treatment of PDN continues to evolve 223. Patients who have failed to respond to one AED may respond to another or to 2 or more drugs in combination.  Level 1a, Grade A 232.

Topiramate

Although topiramate failed in three clinical trials due to the use of the wrong endpoint 233, it has been shown to successfully reduce pain and induce nerve regeneration. 82;234  Topiramate has the added advantages of causing weight loss and improving the lipoprotein profile, both of which are particularly useful in overweight type 2 diabetic patients.

Calcium channel modulators (a2-δ ligands)

Gabapentin is an anticonvulsant structurally related to g-aminobutyric acid (GABA), a neurotransmitter that plays a role in pain transmission and modulation. The exact mechanisms of action of this drug in neuropathic pain are not fully elucidated. Among others, they involve an interaction with the L-amino acid transporter system and high affinity binding to the a2-δ subunit of voltage-activated calcium channels. In an 8-week multicenter dose-escalation trial including 165 diabetic patients with painful neuropathy 60% of the patients on gabapentin (3600 mg/day achieved in 67%) had at least moderate pain relief compared to 33% on placebo. Dizziness and somnolence were the most frequent adverse events, occurring in about 23% of the patients in each group 235. The NNT (CI) for  ³50% pain relief by gabapentin in painful neuropathies is 6.4 (4.3-12). Due to this relatively high NNT and publication bias towards unpublished negative trials 236, the overall level of evidence in favor of gabapentin in painful DSPN is weak.

Pregabalin is a more specific a2-δ ligand with a 6-fold higher binding affinity than gabapentin. The efficacy and safety of pregabalin were reported in a pooled analysis of 6 studies over 5-11 weeks in 1346 diabetic patients with painful neuropathy. The response rates defined as ³50% pain reduction were 46% (600 mg/day), 39% (300 mg/day), 27% (150 mg/day) and 22% (Placebo), giving a NNT of 4.2, 5.9, and 20.0. The most frequent side effects for 150-600 mg/day are dizziness (22.0%), somnolence (12.1%), peripheral oedema (10.0%), headache (7.2%), and weight gain (5.4%) 237. The evidence supporting a favourable effect in painful diabetic neuropathy is more solid and dose titration is considerably easier for pregabalin than gabapentin. (Level 1a, Grade A)

Sodium channel blockers

Although carbamazepine has been widely used for treating neuropathic pain, it cannot be recommended in painful diabetic neuropathy due to very limited data. Its successor drug, oxcarbazepine, as well as other sodium channel blockers such as valproate, mexiletine, topiramate, and lamotrigine showed only marginal efficacy and have not been licensed for the treatment of painful diabetic neuropathy.

Lacosamide

Lacosamide is a novel anticonvulsant which selectively enhances the slow inactivation of voltage dependent sodium channels but, in contrast to the aforementioned sodium channel blockers, does not influence the fast sodium channel inactivation. Its second putative mechanism is an interaction with a neuronal cytosolic protein, the collapsin response mediator protein 2 (CRMP-2), which plays an important role in nerve sprouting and excitotoxicity. Lacosamide has been evaluated in several studies in painful diabetic neuropathy. However, the drug was not approved by the FDA and EMEA for painful diabetic neuropathy in 2008.  Further clinical trials may follow in the future. (Level Ib, Grade B)

Local treatments

           

Sodium Channel Blockers:

Voltage-gated sodium channels are crucial determinants of neuronal excitability and signaling. After nerve injury hyperexcitability and spontaneous firing develop at the site of injury and also in the dorsal root ganglion cell bodies. This hyperexcitability results at least partly from accumulation of sodium channels at the site of injury 238.  Carbamazepine and oxcarbazepine are most effective against the “lightning” pain produced by such spontaneous neuronal firing 239.

Calcium Channel modulators:

Five types of voltage gated calcium channels have been identified and the L- and N-types of channels have a role to play in the neuromodulation of sensory neurons of the spinal cord. Gabapentin and pregabalin are medications that bind at the alpha 2 delta subunits of the channels. Unlike traditional calcium channel antagonists they do not block calcium channels but modulate their activity and sites of expression.  The exact mechanism of action of this group of agents on neuromodulation has yet to be clearly defined.  (Level 11b, Grade B)

Botulinum toxin

Botulinum toxin has been tried for trigeminal neuralgia 240 and has been shown to have long-lasting anti-nociceptive effects in carpal tunnel syndrome with no electrophysiologic restoration 241.

Non-pharmacological treatment of painful neuropathy

Because there is no entirely satisfactory pharmacotherapy of painful diabetic neuropathy, non-pharmacological treatment options should always be considered. As for the pharmacological options, considerable efforts must also be made to develop effective non-pharmacological approaches. A recent systematic review assessed the evidence from rigorous clinical trials and meta-analyses of complementary and alternative therapies for treating neuropathic and neuralgic pain. Data on the following complementary and alternative medicine treatments were identified: acupuncture, electrostimulation, herbal medicine, magnets, dietary supplements, imagery, and spiritual healing. The conclusion was that the evidence is not fully convincing for most complementary and alternative medicine modalities in relieving neuropathic or neuralgic pain. The evidence can be classified as encouraging and warrants further study for cannabis extract, magnets, carnitine, and electrostimulation  242. (Level III, Grade C)

The AAN recommendations are:

• If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level 1a, Grade A).
• Gabapentin and sodium valproate should be considered for the treatment of PDN (Level 1a, Grade B).
• There is insufficient evidence to support or refute the use of topiramate for the treatment of PDN (Level 1a, Grade B).
• Oxcarbazepine, lamotrigine, and lacosamide should probably not be considered for the treat­ment of PDN (Level 1a, Grade B).
• Percutaneous electrical nerve stimulation should be considered for the treatment of PDN (Level III, Grade C).
• Electromagnetic field treatment, low-intensity la­ser treatment, and Reiki therapy should probably not be considered for the treatment of PDN (Level III, Grade C).
• Evidence is insufficient to support or refute the use of amitriptyline plus electrotherapy for treat­ment of PDN (Level III, Grade C) 242.

Psychological support

A psychological component to pain should not be underestimated. Hence, an explanation to the patient that even severe pain may remit, particularly in poorly controlled patients with acute painful neuropathy or in those painful symptoms precipitated by intensive insulin treatment. Thus, the empathetic approach addressing the concerns and anxieties of patients with neuropathic pain is essential for their successful management 243.

Physical measures

The temperature of the painful neuropathic foot may be increased due to arterio-venous shunting. Cold water immersion may reduce shunt flow and relieve pain. Allodynia may be relieved by wearing silk pyjamas or the use of a bed cradle. Patients who describe painful symptoms on walking as comparable to walking on pebbles may benefit from the use of comfortable footwear 243.

Acupuncture

In a 10-week uncontrolled study in diabetic patients on standard pain therapy, 77% showed significant pain relief after up to 6 courses of traditional Chinese acupuncture without any side effects. During a follow-up period of 18-52 weeks, 67% were able to stop or significantly reduce their medications and only 24% required further acupuncture treatment 244. Controlled studies using placebo needles should be performed to confirm these findings.

Electrical stimulation

Transcutaneous electrical nerve stimulation (TENS) influences neuronal afferent transmission and conduction velocity, increases the nociceptive flexion reflex threshold, and changes the somatosensory evoked potentials. In a 4-week study of TENS applied to the lower limbs, each for 30 minutes daily, pain relief was noted in 83% of the patients compared to 38% of a sham-treated group. In patients who only marginally responded to amitriptyline, pain reduction was significantly greater following TENS given for 12 weeks as compared with sham treatment. Thus, TENS may be used as an adjunctive modality combined with pharmacotherapy to augment pain relief 245.

One randomized controlled study showed a better effect of mid-frequency external muscle stimulation (MFEMS) than TENS on neuropathic symptoms after 1 week [81], but longer-term controlled studies are not available. Frequency-modulated electromagnetic nerve stimulation (FREMS) applied during 10 sessions over 3 weeks resulted in a significant pain reduction as compared to placebo stimulation. A larger-scale multicenter study is currently ongoing. (Level 11b, Grade B)

In diabetic painful neuropathy that was unresponsive to drug treatment, electrical spinal cord stimulation (ESCS) with electrodes implanted between T9 and T11 resulted in a pain relief >50% in 8 out of 10 patients. In addition, exercise tolerance was significantly improved. Complications of ESCS included superficial wound infection in 2
patients, lead migration requiring reinsertion in 2 patients, and “late failure“ after 4 months in a patient who had initial pain relief 246. This invasive treatment option should be reserved for patients who do not respond to drug treatment. (Level 11b, Grade B)

Surgical decompression

Surgical decompression at the site of anatomic narrowing has been promoted as an alternative treatment for patients with symptomatic DSPN. A systematic review of the literature revealed only Class IV studies concerning the utility of this therapeutic approach. Given the current evidence available, this treatment alternative should be considered unproven (Level 1V, Grade CU). Prospective randomized controlled trials with standard definitions and outcome measures are necessary to determine the value of this therapeutic intervention 247;248.

The odds ratios for efficacy and withdrawal from medications are given in Table 5 and Figure 4. In addition Table 4 , 6 and 7 show the dosages of the different drugs and the commonly encountered side effects.

Table 4.  Treatments for Symptomatic Diabetic Polyneuropathy Pain-Dosing and Side Effects249

Drug Class	Drug	Dose	Side Effects
Tricyclics	Amitryptyline	50-150 QHS	Somnolence, dizziness, dry mouth, tachycardia,
	Nortriptyline	50-150 QHS	constipation, urinary retention, blurred vision
	Imipramine	25-150 QHS	Confusion
	Desipramine	25-150 QHS
SSRIs	Paroxetine	40 QD	Somnolence, dizziness, sweating, nausea, anorexia,
	Citalopram	40 QD	diarrhea, impotence, tremor
SNRIs	Duloxetine	60 QD	Nausea, somnolence, dizziness, anorexia
Anticonvulsants	Gabapentin	300-1200 TID	Somnolence, dizziness, Confusion, ataxia
	Pregabalin	50-150 TID	Somnolence, confusion, edema, weight gain
	Carbamazepine/ Oxcarbezepine	Up to 200 QID	Dizziness, somnolence, Nausea, leukopenia
	Topiramate	Up to 400 QD	Somnolence, dizziness, ataxia, Tremor
Opiods	Tramadol	50-100 BID	Nausea, constipation, HA Somnolence
	Oxycodone CR	10-30 BID	Somnolence, nausea, constipation, HA
Topical	Capsaicin	0.075% QID	Local irritation
	Lidocaine	0.04% QD	Local irritation
Injection	Botulinum toxin		None

Figure 10.  Efficacy analysis of drugs used for the treatment of PDN

Table 5.  Odds Ratios for Efficacy and Withdrawal,
Numbers Needed to Treat (NNT) and Numbers Needed to Harm (NNH)249

	Drug Class Odds Ratio – Efficacy Odds Ratio – Withdrawal 2o to AE NNT NNH Tricyclics 22.2 (5.8-84.7) 2.3 (0.6-9.7) 1.5-3.5 2.7-17.0 Duloxetine 2.6 (1.6-4.8) 2.4 (1.1-5.4) 5.7-5.8 15.0 Traditional Anticonvulsants 5.3 (1.8-16.0) 1.5 (0.3-7.0) 2.1-3.2 2.7-3.0 Newer Generation Anticonvulsants 3.3 (2.3-4.7) 3.0 (1.75-5.1) 2.9-4.3 26.1 Opioids 4.3 (2.3-7.8) 4.1 (1.2-14.2) 2.6-3.9 9.0

Table 6. Summary of American Academy of Neurology 250 Recommendations.

Recommended drug and dose	Not recommended
Level A            Pregabalin, 300–600 mg/d
Level B            Gabapentin, 900–3,600 mg/d                         Oxcarbazepine
Sodium valproate, 500–1,200 mg/d               Lamotrigine
Venlafaxine, 75–225 mg/d                              Lacosamide
Duloxetine, 60–120 mg/d                                Clonidine
Amitriptyline, 25–100 mg/d                             Pentoxifylline
Dextromethorphan, 400 mg/d                                    Mexiletine
Morphine sulphate, titrated to 120 mg/d         Magnetic field treatment
Tramadol, 210 mg/d                                       Low-intensity laser therapy
Oxycodone, mean 37 mg/d, max 120 mg/d  Reiki therapy
Capsaicin, 0.075% QID
Isosorbide dinitrate spray
Electrical stimulation,                         percutaneous nerve stimulation x3–4 weeks

Table 7. Drugs Approved by the FDA for Treatment of Neuropathic Pain Syndromes

Medication	Indication	Beginning Dosages	Titration	Maximum Dosage	Duration of Adequate Trial
Gabapentin	Postherpetic neuralgia	100-300 mg every night or 100-300 mg 3×/d	Increase by 100-300 mg 3×/d every 1-7 d as tolerated	3600 mg/d (1200 mg 3 ×/d); reduce if low creatinine clearance	3-8 wk for titration plus 1-2 wk at maximum tolerated dosage
Pregabalin	DPN	50 mg three times a day	Increase upto 100 mg three times a day	600 mg a day	Start with 50mg TID and increase upto 100mg TID over 1 week
Lamotrigine	Postherpetic neuralgia	200-400 mg every night.	Start with 25 to 50 mg every other day and increase by 25 mg every week.	500 mg a day	3 to 5 wk for titration ad 1 -2 wk at maximum tolerated dosage.
Carbamazepine**	Trigeminal neuralgia	200 mg/d (100 mg bid)	Add up to 200 mg/d in increments of 100 mg every 12 h	1200 mg/d
Duloxetine	DPN	30 mg	30 mg weekly	120 mg	2 wk
5% lidocaine patch	Postherpetic neuralgia	Maximum of 3 patches daily for a maximum of 12 hr	None needed	Maximum of 3 patches daily for a maximum of 12 hr	2 wk
Opioid analgesics*	Moderate to severe pain	5-15 mg every 4 hr as needed	After 1-2 wk, convert total daily dosage to long-acting medication as needed	No maximum with careful titration; consider evaluation by pain specialist at dosages exceeding 120-180 mg/d	4-6 wk
Tramadol hydrochloride	Moderate to moderately severe pain	50 mg 1 or 2×/d	Increased by 50-100 mg/d in divided doses every 3-7 d as tolerated	400 mg/d (100 mg 4×/d); in patients older than 75 yr, 300 mg/d in divided doses	4 wk
Tricyclic antidepressants (eg, nortriptyline hydrochloride or desipramine hydrochloride)	Chronic pain	10-25 mg every night	Increase by 10-25 mg/d every 3-7 d as tolerated	75-150 mg/d; if blood level of active drug and its metabolite is <100 ng/mL, continue titration with caution	6-8 wk with at least 1-2 wk at maximum tolerated dosage
Duloxetine Serotonin/norepinephrine Reuptake inhibitor	Diabetic neuropathic pain	30 mg bid	Increase by 60 to 60 bid No further titration		4 wk
Fluoxetine Serotonin/norepinephrine Reuptake inhibitor	Diabetic neuropathic pain	30 mg bid	Increase by 60 to 60 bid.  No further titration		4 wk

*Dosages given are for morphine sulfate.
**Source: Tegretol [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2003.

Guidelines for treatment of painful neuropathy

Figure 10 is an algorithm that we propose for the management of painful neuropathy in diabetes. This presumes that the cause of the pain has been attributed to DPN and that all causes masquerading as DPN have been excluded.  The identification of neuropathic pain as being focal or diffuse dictates the intial course of action.  Focal neuropathic pain is best treated with diuretics to reduce edema in the canal, splinting and surgery to release entrapment. Diffuse neuropathies are treated with medical therapy and in a majority of cases, need multidrug therapy.  Essential to the evaluation is the identification of the comorbidities and the choice of drugs which can serve dual actions:  e.g. pregabalin improves sleep and pain both by direct and indirect pathways whereas duloxetine may reduce depression and anxiety which accompany pain. Immune mediated neuropathies are treated with intravenous immunoglobulin, steroids or other immunomodulators.  When single agents fail, combinations of drugs with different mechanisms of action are in order. Also provided is the evidence-based recommendation of the AAN and the numbers needed to treat, the numbers needed to harm, and the likelihood ratios for use of the drugs and for non adherence.   Comorbidities that accompany pain include depression, anxiety, and sleep disturbances, all of which must be addressed for successful management of pain.  Treatment of peripheral neuropathic pain conditions can benefit from further understanding of the impact of pain response and QoL, including ADLs and sleep.  As Winston Churchill said “We need to go from failure to failure without losing our enthusiasm and ultimately we will succeed……”

Recommendations for future research have been suggested by AAN and include the following:

• A formalized process for rating pain scales for use in all clinical trials should be developed.

• Clinical trials should be expanded to include ef­fects on QOL and physical function when evalu­ating efficacy of new interventions for PDN; the measures should be standardized.

• Future clinical trials should include head-to-head comparisons of different medications and combi­nations of medications.

• Because PDN is a chronic disease, trials of longer duration should be done.

• Standard metrics for side effects to qualify effect sizes of interventions need to be developed.

• Cost-effectiveness studies of different treatments should be done.

• The mechanism of action of electrical stimulation is unknown; a better understanding of its role, mode of application, and other aspects of its use should be studied.

Figure 11. Algorithm for the Management of Symptomatic Diabetic Neuropathy:

 Non-pharmacological, topical, or physical therapies can be useful at any time (capsaicin, acupuncture, etc.). The only two drugs approved in the US for the treatment of painful diabetic neuropathy are pregabalin and duloxetine. However, based on the NNT (number needed to treat), tricyclic antidepressants are the most cost-effective ones. SNRIs: serotonin and norepinephrine reuptake inhibitors. Modified from Vinik et al.Vinik 249 2010 

Autonomic Neuropathy

Introduction

The autonomic nervous system (ANS) supplies all organs in the body and consists of an afferent and an efferent system, with long efferents in the vagus (cholinergic) and short postganglionic unmyelinated fibers in the sympathetic system (adrenergic). A third component is the neuropeptidergic system with its neurotransmitters substance P (SP), vasoactive intestinal polypeptide (VIP) and calcitonin gene related peptide (CGRP) amongst others. Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes but remains among the least recognized and understood. Diabetic autonomic neuropathy (DAN) can cause dysfunction of every part of the body, and has a significant negative impact on survival and quality of life 251. The organ systems that most often exhibit prominent clinical autonomic signs and symptoms in diabetes include the pupils, sweat glands, genitourinary system, gastrointestinal tract, adrenal medullary system, and the cardiovascular system (Table 8). Clinical symptoms generally do not appear until long after the onset of diabetes. However, subclinical autonomic dysfunction can occur within a year of diagnosis in type 2 diabetes patients and within two years in type 1 diabetes patients 252.

Table 8. Clinical manifestations of autonomic neuropathy.

Cardiovascular Central: Tachycardia/ Bradycardia Systolic and diastolic dysfunction Decreased exercise tolerance Orthostasis, Orthostatic tachycardia and bradycardia syndrome Sleep apnea Anxiety/ depression Cardiac denervation syndrome Paradoxic supine or nocturnal hypertension Intraoperative and perioperative cardiovascular instability Peripheral: Decreased thermoregulation Decreased sweating Altered blood flow Impaired vasomotion Edema

Gastrointestinal Esophageal dysmotility Gastroparesis diabeticorum Diarrhea Constipation Fecal incontinence

Genitourinary Erectile dysfunction Retrograde ejaculation Neurogenic bladder and cystopathy Female sexual dysfunction (e.g., loss of vaginal lubrication)

Sudomotor Anhidrosis Hyperhidrosis Heat intolerance Gustatory sweating Dry skin

Metabolic Hypoglycemia unawareness Hypoglycemia unresponsiveness

Pupillary Pupillomotor function impairment (e.g., decreased diameter of dark adapted pupil) Pseudo Argyll-Robertson pupil

Defective blood flow in the small capillary circulation is found with decreased responsiveness to mental arithmetic, cold pressor, hand grip and heating 253. The defect is associated with a reduction in the amplitude of vasomotion 254 and resembles premature aging 253. There are differences in the glabrous and hairy skin circulations. In hairy skin a functional defect is found prior to the development of neuropathy 255 1999 and is correctable with antioxidants 256. The clinical counterpart is a dry cold skin, loss of sweating, and development of fissures and cracks that are portals of entry for organisms leading to infectious ulcers and gangrenes. Silent myocardial infarction, respiratory failure, amputations and sudden death are hazards for diabetic patients with cardiac autonomic neuropathy 257. Therefore, it is vitally important to make this diagnosis early so that appropriate intervention can be instituted 258.

Disturbances in autonomic nervous system may be functional, e.g. gastroparesis with hyperglycemia and ketoacidosis, or organic wherein nerve fibers are actually lost. This creates inordinate difficulties in diagnosing, treating and prognosticating as well as establishing true prevalence rates. Tests of autonomic function generally stimulate entire reflex pathways. Furthermore, autonomic control for each organ system is usually divided between opposing sympathetic and parasympathetic innervation, so that heart rate acceleration, for example, may reflect either decreased parasympathetic or increased sympathetic nervous system stimulation. Since many conditions affect the autonomic nervous system and AN is not unique to diabetes, the diagnosis of diabetic autonomic neuropathy rests with establishing the diagnosis and excluding other causes. The best studied diagnostic methods, for which there are large databases and evidence to support their use in clinical practice, relate to the evaluation of cardiovascular reflexes. In addition the evaluation of orthostasis is fairly straightforward and is readily done in clinical practice, as is the establishment of the cause of gastrointestinal symptoms and erectile dysfunction. The evaluation of pupillary abnormalities, hypoglycemia unawareness and unresponsiveness, neurovascular dysfunction, and sweating disturbances are for the most part done only in research laboratories, require specialized equipment and familiarity with the diagnostic procedures, and are best left in the hands of those who have a special interest in the area. Table 10 and 11 below present the diagnostic tests that would be applicable to the diagnosis of cardiovascular autonomic neuropathy. These tests can be used as a surrogate for the diagnosis of AN of any system since it is generally rare to find involvement (although it does occur) of any other division of the ANS in the absence of cardiovascular autonomic dysfunction. For example if one entertains the possibility that the patient has erectile dysfunction due to AN, then prior to embarking upon a sophisticated and expensive evaluation of erectile status, a measure of heart rate and its variability in response to deep breathing would - if normal - exclude the likelihood that the erectile dysfunction is a consequence of disease of the autonomic nervous system. The cause thereof would have to be sought elsewhere. Similarly it is extremely unusual to find gastroparesis secondary to AN in a patient with normal cardiovascular autonomic reflexes.

The role of over-activation of the autonomic nervous system is illustrated in Figure 11 259.

Figure 12. Role of over-activation of autonomic nervous system

There are few data on the longitudinal trends in small fiber dysfunction. Much remains to be learned of the natural history of diabetic autonomic neuropathy. Recently, Karamitsos et al 260 reported that the progression of diabetic autonomic neuropathy is significant during the 2 years subsequent to its discovery.

The mortality for diabetic autonomic neuropathy has been estimated to be 44% within 2.5 years of diagnosing symptomatic autonomic neuropathy Levitt 1996. In a meta analysis, the Mantel-Haenszel estimates for the pooled prevalence rate risk for silent myocardial ischemia was 1.96, with 95% confidence interval of 1.53 to 2.51 (p<0.001; n = 1,468 total subjects). Thus, a consistent association between CAN and the presence of silent myocardial ischemia was shown 259in figure 12.

Figure 13. Association between CAN and silent MI.

 

Table 9. Differential diagnosis of diabetic autonomic neuropathy

Clinical Manifestations	Differential Diagnosis
Cardiovascular Resting tachycardia, Exercise intolerance Orthostatic tachycardia and bradycardia syndromes Cardiac denervation, painless myocardial infarction Orthostatic hypotension Intraoperative and perioperative cardiovascular instability	Cardiovascular disorders Idiopathic orthostatic hypotension, multiple system atrophy with Parkinsonism, orthostatic tachycardia, hyperadrenergic hypotension Shy-Drager syndrome Panhypopituitarism Pheochromocytoma Hypovolemia Congestive heart disease Carcinoid syndrome
Gastrointestinal Esophageal dysfunction Gastroparesis diabeticorum Diarrhea Constipation Fecal incontinence	Gastrointestinal disorders Obstruction Bezoars Secretory diarrhea (endocrine tumors) Biliary disease Psychogenic vomiting Medications
Genitourinary Erectile dysfunction Retrograde ejaculation Cystopathy Neurogenic bladder	Genitourinary disorders Genital and pelvic surgery Atherosclerotic vascular disease Medications Alcohol abuse
Neurovascular Heat intolerance Gustatory sweating Dry skin Impaired skin blood flow	Other causes of neurovascular dysfunction Chaga's disease Amyloidosis Arsenic
Metabolic Hypoglycemia unawareness Hypoglycemia unresponsiveness Hypoglycemia associated autonomic failure	Metabolic disorders Other cause of hypoglycemia, intensive glycemic control and drugs that mask hypoglycemia
Pupillary Decreased diameter of dark adapted pupil Argyll-Robertson type pupil	Pupillary disorders Syphilis

Table 10. Diagnosis and Management of Autonomic Nerve Dysfunction

Symptoms	Assessment Modalities	Management
Resting tachycardia, exercise intolerance, early fatigue and weakness with exercise	HRV, respiratory HRV, MUGA thallium scan, 123I MIBG scan	Graded supervised exercise, beta blockers, ACE-inhibitors
Postural hypotension, dizziness, lightheadedness, weakness, fatigue, syncope, tachycardia/bradycardia	HRV, blood pressure measurement lying and standing	Mechanical measures, clonidine, midodrine, octreotide, erythropoietin, pyridostigmine
Hyperhidrosis	Sympathetic/parasympathetic balance	Clonidine, amitryptylline, trihexyphenidyl, propantheline, or scopolamine ,botox, Glycopyrrolate

Table 11.  Diagnostic tests of cardiovascular autonomic neuropathy

TEST	METHOD/ PARAMETERS
* These can now be performed quickly (<15 min) in the practitioners' office, with a central reference laboratory providing quality control and normative values. VLF,LF, HF =low, very low and high frequency peaks on spectral analysis. These are now readily available in most cardiologist's practice.** Lowest normal value of E/I ratio: Age 20-24:1.17, 25-29:1.15, 30-34:1.13, 35-30:1.12, 40-44:1.10, 45-49:1.08, 50-54:1.07, 55-59:1.06, 60-64:1.04, 65-69:1.03, 70-75:1.02 .
Resting heart rate Beat-to-beat heart rateVariation*	>100 beats/min is abnormal.With the patient at rest and supine (no overnight coffee or hypoglycemic episodes), breathing 6 breaths/min, heart rate monitored by EKG or ANSCORE device, a difference in heart rate of >15 beats/min is normal and <10 beats/min is abnormal, R-R inspiration/R-R expiration >1.17. All indices of HRV are age-dependent**.
Heart rate response to Standing*	During continuous EKG monitoring, the R-R interval is measured at beats 15 and 30 after standing. Normally, a tachycardia is followed by reflex bradycardia. The 30:15 ratio is normally >1.03.
Heart rate response to Valsalva maneuver*	The subject forcibly exhales into the mouthpiece of a manometer to 40 mmHg for 15 s during EKG monitoring. Healthy subjects develop tachycardia and peripheral vasoconstriction during strain and an overshoot bradycardia and rise in blood pressure with release. The ratio of longest R-R shortest R-R should be >1.2.
Spectral analysis of heart rate variation , very low frequency power (VLFP 0.003-0.04) and high frequency power (HFP 0.15-0.40 Hz)	Series of sequential R-R intervals into its various frequent components. It defines two fixed spectral regions for the low-frequency and high-frequency measure.
Systolic blood pressure response to standing	Systolic blood pressure is measured in the supine subject. The patient stands and the systolic blood pressure is measured after 2 min. Normal response is a fall of <10 mmHg, borderline is a fall of 10-29 mmHg, and abnormal is a fall of >30 mmHg with symptoms.
Diastolic blood pressure response to isometric exercise	The subject squeezes a handgrip dynamometer to establish a maximum. Grip is then squeezed at 30% maximum for 5 min. The normal response for diastolic blood pressure is a rise of >16 mmHg in the other arm.
EKG QT/QTc intervalsSpectral analysis with respiratory frequency	The QTc (corrected QT interval on EKG) should be <440 ms.VLF peak (sympathetic dysfunction)LF peak (sympathetic dysfunction) HF peak (parasympathetic dysfunction)LH/HF ratio (sympathetic imbalance)
Neurovascular flow	Using noninvasive laser Doppler measures of peripheral sympathetic responses to nociception.

Table 12. Diagnostic Assessment of Cardiovascular Autonomic Function.

Parasympathetic	Sympathetic
Resting heart rate Beat to beat variation with deep breathing (E:I ratio) 30:15 heart rate ratio with standing Valsalva ratio Spectral analysis of heart rate variation , high frequency power (HFP 0.15-0.40 Hz) Spectral Analysis of HRV respiratory frequency	Resting heart rate Spectral analysis of heart rate variation , very low frequency power (VLFP 0.003-0.04) Orthostasis BP Hand grip BP Cold pressor response Sympathetic skin galvanic response (cholinergic) Sudorimetry (cholinergic) Cutaneous blood flow (peptidergic)

Figure 14.  

 

Figure 15. The Evaluation Of The Patient Suspected Of Gastroparesis.

 

Prevention and reversibility of autonomic neuropathy

It has now become clear that strict glycemic control 31 and a stepwise progressive management of hyperglycemia, lipids, and blood pressure as well as the use of antioxidants 261 and ACE inhibitors 262 reduce the odds ratio for autonomic neuropathy to 0.32 263. It has also been shown that early mortality is a function of loss of beat to beat variability with MI. This can be reduced by 33% with acute administration of insulin 264. Kendall et al 265 reported that successful pancreas transplantation improves epinephrine response and normalizes hypoglycemia symptom recognition in patients with long standing diabetes and established autonomic neuropathy. Burger et al 266 showed that a reversible metabolic component of CAN exists in patients with early CAN.

Figure 16. This is a sample power spectrum of the HRV signal from a subject breathing at an average rate of 7.5 breaths per minute (Fundamental Respiratory Frequency, FRF = 0.125 Hz). The method using HRV alone defines two fixed spectral regions for the low-frequency (LF) and high-frequency (HF) measure (dark gray and light gray, respectively). It is clear that the high-frequency (light gray) region includes very little area under the HRV spectral curve, suggesting very little parasympathetic activity. The great majority of the HRV spectral activity is under the low-frequency (dark gray) region suggesting primarily sympathetic activity. These representations are incorrect because the slow-breathing subject should have a large parasympathetic component reflective of the vagal activity. This parasympathetic component is represented correctly by the method using both HRV and respiratory activity which defines the red and blue regions of the spectrum in the graph. The blue region defined by the FRF represents purely parasympathetic activity whereas the remainder of the lower frequency regions (red region) represents purely sympathetic activity.

 

Management of Autonomic Neuropathy

Table 13. Pharmacologic treatment of autonomic neuropathy

Clinical status	Drug	Dosage	Side effects
Orthostatic hypotension
	9α flouro hydrocortisone, mineralocorticoid	0.5-2 mg/day	Congestive heart failure, hypertension
	Clonidine, α2 adrenergic agonist	0,1-0,5 mg, at bedtime	Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.
	Octreotide, somatostatin analogue	0.1-0.5 mg/kg/day	Injection site pain, diarrhea
Orthostatic tachycardia and bradycardia syndrome
	Clonidine, α2 adrenergic agonist	0.1-0.5 mg, at bedtime	Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.
	Octreotide, somatostatin analogue	0.1-0.5 μg/kg/day	Injection site pain, diarrhea
Gastroparesis diabeticorum
	Metoclopramide, D2 -receptor antagonist	10 mg, 30-60 min before meal and bedtime	Galactorrhea, extra pyramidal symptoms
	Domperidone, D2-receptor antagonist	10-20 mg, 30-60 min before meal and bedtime	Galactorrhea
	Erythromycin, motilin receptor agonist	250 mg, 30 minutes before meals	Abdominal cramps, nausea, diarrhea, rash
	Levosulphide, D2-receptor antagonist	25 mg, 3 times/day	Galactorrhea
Diabetic diarrhea
	Metronidazole, broad spectrum antibiotics	250 mg, 3 times/day, minimum 3 weeks	Anorexia, rash, GI upset, urine discoloration, dizziness, disulfiram like reaction.
	Clonidine, α2 adrenergic agonist	0.1 mg, 2-3 times/day	Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.
	Cholestyramine, bile acid sequestrant	4 g, 1-6 times/day	Constipation
	Loperamide, opiate-receptor agonist	2 mg, four times/day	Toxic megacolon
	Octreotide, somatostatin analogue	50 μg, 3 times/day	Aggravate nutrient malabsorption (at higher doses)
Cystopathy
	Bethanechol, acetylcholine receptor agonist	10 mg, 4 times/day	Blurred vision, abdominal cramps, diarrhea, salivation, and hypotension.
	Doxazosin, α1 adrenergic antagonist	1-2 mg, 2-3 times/day	Hypotension, headache, palpitation
Exercise Intolerance
	Graded supervised exercise	20 minutes, 3 times/week	Foot injury, angina.
Hyperhidrosis
	Clonidine, α2 adrenergic agonist	0.1-0.5 mg, at bedtime and divided doses above 0.2 mg	Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.
	Amitryptiline, Norepinephrine & serotonin reuptake inhibitor	150 mg/ day	Tachycardia, palpitation
	Propantheline, Anti-muscarinic.	15 mg/ day PO	Dry mouth, blurred vision
	Trihexyphenidyl,	2-5 mg PO	Dry mouth, blurred vision, constipation, tachycardia, photosensitivity, arrhythmias.
	Botox,
	Scopolamine, anti-cholinergic	1.5 mg patch/ 3 days; 0.4 to 0.8mg PO	Dry mouth, blurred vision, constipation, drowsiness, and tachycardia.
	Glycopyrrolate, anti-cholinergic	1-2 mg, 2-3 times daily.	Constipation, tachycardia, dry mouth.
Erectile dysfunction
	Sildenafil (Viagra), GMP type-5 phosphodiesterase inhibitor	50 mg before sexual activity, only once per day	Hypotension and fatal cardiac event (with nitrate-containing drugs), headache, flushing, nasal congestion, dyspepsia, musculoskeletal pain, blurred vision
	Tadalafil (Cialis), GMP type-5 phosphodiesterase inhibitor	10 mg PO before sexual activity only once per day.	Headache, flushing, dyspepsia, rhinitis, myalgia, back pain.
	Verdenafil (Levitra), GMP type-5 phosphodiesterase inhibitor	10 mg PO, 60 minutes before sexual activity.	Hypotension, headache, dyspepsia, priapism.

Postural Hypotension

The syndrome of postural hypotension is posture-related dizziness and syncope. Patients who have Type 2 diabetes mellitus and orthostatic hypotension are hypovolemic and have sympathoadrenal insufficiency; both factors contribute to the pathogenesis of orthostatic hypotension 267. Postural hypotension in the patient with diabetic autonomic neuropathy can present a difficult management problem. Elevating the blood pressure in the standing position must be balanced against preventing hypertension in the supine position.

Supportive Garments: Whenever possible, attempts should be made to increase venous return from the periphery using total body stockings. But leg compression alone is less effective, presumably reflecting the large capacity of the abdomen relative to the legs 268. Patients should be instructed to put them on while lying down and to not remove them until returning to the supine position.

Drug Therapy: Some patients with postural hypotension may benefit from treatment with 9-flurohydrocortisone. Unfortunately, symptoms do not improve until edema occurs, and there is a significant risk of developing congestive heart failure and hypertension. If fluorohydrocortisone does not work satisfactorily, various adrenergic agonists and antagonists may be used. If the adrenergic receptor status is known, then therapy can be guided to the appropriate agent. Metoclopramide may be helpful in patients with dopamine excess or increased sensitivity to dopaminergic stimulation. Patients with α2-adrenergic receptor excess may respond to the α2-antagonist yohimbine. Those few patients in whom ß-receptors are increased may be helped with propranolol. α2-adrenergic receptor deficiency can be treated with the α2-agonist clonidine, which in this setting may paradoxically increase blood pressure. One should start with small doses and gradually increase the dose. If the preceding measures fail, midodrine, an α1-adrenergic agonist, or dihydroergotamine in combination with caffeine may help. A particularly refractory form of postural hypotension occurs in some patients post-prandially and may respond to therapy with octreotide given subcutaneously in the mornings.

Sleep Apnea

During sleep, increased sympathetic drive is a result of repetitive episodes of hypoxia, hypercapnia and obstructive apnea acting through chemoreceptor reflexes. Increased sympathetic drive has been implicated in increased blood pressure variability with repetitive sympathetic activation and blood pressure surges impairing baroreflex and cardiovascular reflex functions 259. A direct relationship between the severity of OSA and the increase in blood pressure has been noted. Furthermore, the use of continuous positive airway pressure (CPAP) for the treatment of OSA has been shown to lower blood pressure and improve cardiovascular autonomic nerve fiber function for individuals with OSA . Withdrawal of CPAP for even a short period (i.e., 1 week) has been shown to result in a marked increase in sympathetic activity 259.

Gastropathy

Gastrointestinal motor disorders are frequent and widespread in type 2 diabetic patients, regardless of symptoms 269 and there is a poor correlation between symptoms and objective evidence of a functional or organic defect. The first step in management of diabetic gastroparesis consists of multiple, small feedings. The amount of fat should be decreased, as it tends to delay gastric emptying. Maintenance of glycemic control is important 270 271. Metoclopramide may be used. Cisapride and domperidone 272 273 have been shown to be effective in some patients, although probably no more so than metoclopramide. Cisapride has however been withdrawn from the market. Erythromycin given as either a liquid or suppository also may be helpful. Erythromycin acts on the motilin receptor, "the sweeper of the gut," and shortens gastric emptying time 274. If medications fail and severe gastroparesis persists, jejunostomy placement into normally functioning bowel may be needed. Different treatment modalities for gastroparesis include dietary modifications, prokinetic and antiemetic medications, measures to control pain and address psychological issues, and endoscopic or surgical options in selected instances 275.

Enteropathy

Enteropathy involving the small bowel and colon can produce both chronic constipation and explosive diabetic diarrhea, making treatment of this particular complication difficult.

Antibiotics: Stasis of bowel contents with bacterial overgrowth may contribute to the diarrhea. Treatment with broad-spectrum antibiotics is the mainstay of therapy, including tetracycline or trimethoprim and sulfamethoxazole. Metronidazole appears to be the most effective and should be continued for at least 3 weeks.

Cholestyramine: Retention of bile may occur and can be highly irritating to the gut. Chelation of bile salts with cholestyramine 4g tid mixed with fluid may offer relief of symptoms.

Diphenoxylate plus Atropine: Diphenoxylate plus atropine may help to control the diarrhea; however, toxic megacolon can occur, and extreme care should be used.

Diet: Patients with poor digestion may benefit from a gluten-free diet. Beware of certain fibers in the neuropathic patient that can lead to bezoar formation because of bowel stasis in gastroparetic or constipated patients.

Sexual Dysfunction

Erectile dysfunction (ED) occurs in 50-75% of diabetic men, and it tends to occur at an earlier age than in the general population. The incidence of ED in diabetic men aged 20-29 years is 9% and increases to 95% by age 70. It may be the presenting symptom of diabetes. More than 50% notice the onset of ED within 10 years of the diagnosis, but it may precede the other complications of diabetes. The etiology of ED in diabetes is multifactorial. Neuropathy, vascular disease, diabetes control, nutrition, endocrine disorders, psychogenic factors as well as drugs used in the treatment of diabetes and its complications play a role 276 277. The diagnosis of the cause of ED is made by a logical stepwise progression 276 277 in all instances. An approach to therapy has recently been presented to which the reader is referred; figure 16 below shows a flow chart modified from Vinik et. al., 1998. 276.

Figure 17. Evaluation of Diabetic patients with Erectile Dysfunction.

 

A thorough work-up for impotence will include: medical and sexual history; physical and psychological evaluations; blood tests for diabetes and levels of testosterone, prolactin, and thyroid hormones; tests for nocturnal erections; tests to assess penile, pelvic, and spinal nerve function; and a test to assess penile blood supply and blood pressure. The flow chart provided is intended as a guide to assist in defining the problem.
The healthcare provider should initiate questions that will help distinguish the various forms of organic erectile dysfunction from those that are psychogenic in origin. Physical examination must include an evaluation of the autonomic nervous system, vascular supply, and the hypothalamic-pituitary-gonadal axis.

Autonomic neuropathy causing ED is almost always accompanied by loss of ankle jerks and absence or reduction of vibration sense over the large toes. More direct evidence of impairment of penile autonomic function can be obtained by (1) demonstrating normal perianal sensation, (2) assessing the tone of the anal sphincter during a rectal exam, and (3) ascertaining the presence of an anal wink when the area of the skin adjacent to the anus is stroked or contraction of the anus when the glans penis is squeezed, i.e., the bulbo-cavernosus reflex. These measurements are easily and quickly done at the bedside and reflect the integrity of sacral parasympathetic divisions.

Vascular disease is usually manifested by buttock claudication but may be due to stenosis of the internal pudendal artery. A penile/brachial index of <0.7 indicates diminished blood supply. A venous leak manifests as unresponsiveness to vasodilators and needs to be evaluated by penile Doppler sonography.

In order to distinguish psychogenic from organic erectile dysfunction, nocturnal penile tumescence (NPT) measurement can be done. Normal NPT defines psychogenic ED, and a negative response to vasodilators implies vascular insufficiency. Application of NPT is not so simple. It is much like having a sphygmomanometer cuff inflate over the penis many times during the night while one is trying to have a normal night's sleep and the REM sleep associated with erections. The individual may have to take home the device and become familiar with it over several nights before one has a reliable estimate of the failure of NPT.

Treatment of erectile dysfunction

A number of treatment modalities are available and each treatment has positive and negative effects; therefore patients must be made aware of both aspects before a therapeutic decision is made. Before considering any form of treatment, every effort should be made to have the patient withdraw from alcohol and eliminate smoking. First and foremost, the patient should be removed, if possible, from drugs that are known to cause erectile dysfunction. Additionally, metabolic control should be optimized.

According to more recent research, relaxation of the corpus cavernosus smooth muscle cells is caused by NO and cGMP, and the ability to have and maintain an erection depends on NO and cGMP. Sildenafil (Viagra) exerts its effect by transiently increasing NO and cGMP levels. Sildenafil is a GMP type-5 phospodiesterase inhibitor that enhances blood flow to the corpora cavernosae with sexual stimulation. A 50 mg tablet taken orally is the usual starting dose, 60 minutes before sexual activity. Lower doses should be considered in patients with renal failure and hepatic dysfunction. The duration of the drug effect is 4 hours. Before it is prescribed, it is important to exclude ischemic heart disease. It is absolutely contraindicated in patients being treated with nitroglycerine or other nitrate-containing drugs. Severe hypotension and fatal cardiac events can occur 278. Sildenafil was well tolerated, effective and increased the number of successful attempts of intercourse. Sildenafil should be considered as first line treatment for erectile dysfunction in men with Type 2 diabetes mellitus 279. Tadalafil at 10 and 20 mg improved erectile function irrespective of the type of diabetes, presence of microvascular complications, or type of diabetes treatment 280 Vardenafil statistically improved erectile function and was generally well tolerated in diabetic patients with ED. Vardenafil treatment was effective in increasing intercourse success rates at all levels of baseline ED severity, at each level of plasma HbA1c, and for type 1 and 2 diabetes. Treatment-emergent adverse events were primarily mild to moderate headache, flushing, and rhinitis
281. Direct injection of prostacyclin into the corpus cavernosum will induce satisfactory erections in a significant number of men. Also, surgical implantation of a penile prosthesis may be appropriate. The less expensive type of prosthesis is a semirigid, permanently erect type that may be embarrassing and uncomfortable for some patients. The inflatable type is three times more expensive and subject to mechanical failure, but it avoids the embarrassment caused by other devices.

Female Sexual Dysfunction

Women with diabetes mellitus may experience decreased sexual desire and more pain on sexual intercourse, and they are at risk of decreased sexual arousal, with inadequate lubrication 282. Diagnosis of female sexual dysfunction using vaginal plethysmography to measure lubrication and vaginal flushing has not been well established.

Cystopathy

In diabetic autonomic neuropathy, the motor function of the bladder is unimpaired, but afferent fiber damage results in diminished bladder sensation. The urinary bladder can be enlarged to more than three times its normal size. Patients are seen with bladders filled to their umbilicus, yet they feel no discomfort. Loss of bladder sensation occurs with diminished voiding frequency, and the patient is no longer able to void completely. Consequently, dribbling and overflow incontinence are common complaints. A postvoiding residual of greater than 150 cc is diagnostic of cystopathy. Cystopathy may put the patients at risk for urinary infections.

Treatment of cystopathy

Patients with cystopathy should be instructed to palpate their bladder and, if they are unable to initiate micturition when their bladders are full, use Crede's maneuver (massage or pressure on the lower portion of abdomen just above the pubic bone) to start the flow of urine. The principal aim of the treatment should be to improve bladder emptying and to reduce the risk of urinary tract infection. Parasympathomimetics such as bethanechol are sometimes helpful, although frequently they do not help to fully empty the bladder. Extended sphincter relaxation can be achieved with an alpha-1-blocker, such as doxazosin . Self-catheterization can be particularly useful in this setting, with the risk of infection generally being low.

Sweating Disturbances

Hyperhidrosis of the upper body, often related to eating (gustatory sweating), and anhidrosis of the lower body, are a characteristic feature of autonomic neuropathy. Gustatory sweating accompanies the ingestion of certain foods, particularly spicy foods, and cheeses. There is a suggestion that application of glycopyrrolate (an antimuscarinic compound) might benefit diabetic patients with gustatory sweating 283. Low-dose oral glycopyrrolate in the dose of 1 mg to 2 mg once daily can be tolerated without problematic adverse effects to alleviate the symptoms of the diabetic gustatory sweating. Although more long-term data are needed, the use of glycopyrrolate for diabetic gustatory sweating may be a viable option 284. Symptomatic relief can be obtained by avoiding the specific inciting food. Loss of lower body sweating can cause dry, brittle skin that cracks easily, predisposing one to ulcer formation that can lead to loss of the limb. Special attention must be paid to foot care.

Metabolic Dysfunction

Hypoglycemia unawareness

Blood glucose concentration is normally maintained during starvation or increased insulin action by an asymptomatic parasympathetic response with bradycardia and mild hypotension, followed by a sympathetic response with glucagon and epinephrine secretion for short-term glucose counter regulation, and growth hormone and cortisol secretion for long-term regulation. The release of catecholamine alerts the patient to take the required measures to prevent coma due to low blood glucose. The absence of warning signs of impending neuroglycopenia is known as "hypoglycemic unawareness". The failure of glucose counter regulation can be confirmed by the absence of glucagon and epinephrine responses to hypoglycemia induced by a standard, controlled dose of insulin 285.

In patients with type 1 diabetes mellitus, the glucagon response is impaired with diabetes duration of 1-5 years; after 14-31 years of diabetes, the glucagon response is almost undetectable. Absence of the glucagon response is not present in those with autonomic neuropathy. However, a syndrome of hypoglycemic autonomic failure occurs with intensification of diabetes control and repeated episodes of hypoglycemia. The exact mechanism is not understood, but it does represent a real barrier to physiologic glycemic control. In the absence of severe autonomic dysfunction, hypoglycemia unawareness is at least in part reversible.

Patients with hypoglycemia unawareness and unresponsiveness pose a significant management problem for the physician. Although autonomic neuropathy may improve with intensive therapy and normalization of blood glucose, there is a risk to the patient, who may become hypoglycemic without being aware of it and who cannot mount a counterregulatory response. It is our recommendation that if a pump is used, boluses of smaller than calculated amounts should be used and, if intensive conventional therapy is used, long acting insulin with very small boluses should be given. In general, normal glucose and HbA1 levels should not be goals in these patients to avoid the possibility of hypoglycemia 286.

Further complicating management of some diabetic patients is the development of a functional autonomic insufficiency associated with intensive insulin treatment, which resembles autonomic neuropathy in all relevant aspects. In these instances, it is prudent to relax therapy, as for the patient with bona fide autonomic neuropathy. If hypoglycemia occurs in these patients at a certain glucose level, it will take a lower glucose level to trigger the same symptoms in the next 24-48 hours. Avoidance of hypoglycemia for a few days will result in recovery of the adrenergic response.

Diabetic neuropathies: prospects for the future

Management of DN encompasses a wide variety of therapies. Treatment must be individualized in a manner that addresses the particular manifestation and underlying pathogenesis of each patient's unique clinical presentation, without subjecting the patient to untoward medication effects. There are new areas being explored in an attempt to enhance blood flow via vasa nervorum, such as Nutrinerve, the prostacyclin analogue beraprost, blockade of thromboxane A2, and drugs that normalize Na/K-ATPase activity, such as cilostazol, a potent phosphodiesterase inhibitor, and α-lipoic acid. Some of them, however, have not reached the clinical arena.

Summary

DN is a common complication of diabetes that often is associated both with considerable morbidity and mortality. The epidemiology and natural history of DN is clouded with uncertainty, largely due to confusion regarding the definition and measurement of this disorder.

The recent resurgence of interest in the vascular hypothesis, oxidative stress, the neurotrophic hypothesis, and the possibility of a role for autoimmunity have opened up new avenues of investigation for therapeutic intervention. Paralleling our increased understanding of the pathogenesis of DN, there must be refinements in our ability to measure quantitatively the different types of defects that occur in this disorder, so that appropriate therapies can be targeted to specific fiber types. These tests must be validated and standardized to allow comparability between studies and a more meaningful interpretation of study results. Our ability to manage successfully the many different manifestations of DN depends ultimately on our success in uncovering the pathogenic processes underlying this disorder.