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Diabetic Neuropathies

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Saved by Robert Rushakoff, MD
on July 8, 2008 at 10:40:30 pm
 

Diabetic Neuropathies

 

Aaron Vinik, MD

Carolina Casellini, M.D.

Abhijeet Nakave, MBBS. 

Chhaya Patel, MBBS.

 

 

 


 

 

 

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 [3][4].  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 but also mimic those seen in many other diseases. It is, therefore, diagnosed by exclusion. Unfortunately both endocrinologists and non endocrinologists have not been trained to recognize the condition [5], and even when symptomatic less than one third of physicians recognize the cause or discuss this with their patients [6]

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 [7][8][9][10]. 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 [11]. Neurologic complications occur equally in type 1 and type 2 diabetes mellitus and additionally in various forms of acquired diabetes [12]. 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 [13]. Each year 96,000 amputations are performed on diabetic patients in the United States, yet up to 75% of them are preventable [14]. 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 [15] Once autonomic neuropathy sets in, life can become quite dismal and the mortality rate approximates 25-50% within 5-10 years [16][17].

 

Definition

DN is defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes. A careful clinical examination is needed for the diagnosis, since asymptomatic neuropathy is common [18]. A minimum of two abnormalities (symptoms, signs, nerve conduction abnormalities, quantitative sensory tests or quantitative autonomic tests) is required for diagnosis and, for clinical studies, one of theses two abnormalities should include quantitative tests or electrophysiology [19][20]. Standardized testing using nerve symptom scores and nerve impairment scores to quantify weakness, loss of reflexes and sensory deficits has proved invaluable in diagnosis and monitoring of progress and is indispensable for clinical trials.

 

Classification

Box 1 describes the classification proposed by Thomas [21] and modified by us [22][23][24]. 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 A.  

 

 

 

Table A. Classification of diabetic neuropathies.

Rapidly reversible

  1. Hyperglycemic neuropathy

Generalized symmetric polyneuropathy

  1. Acute sensory neuropathy

  2. Chronic sensorimotor neuropathy or distal symmetric polyneuropathy (DPN)

    1. Small-fiber neuropathy

    2. Large-fiber neuropathy

  3. Autonomic neuropathy

Focal and multifocal neuropathies

  1. Focal-limb neuropathy

  2. Cranial neuropathy

  3. Proximal-motor neuropathy (amyotrophy)

  4. Truncal radiculoneuropathy

  5. Coexisting chronic inflammatory demyelinating neuropathy (CIDP)

 

 

 

Natural History

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 [25].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 neuropathies 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 symptoms are severe, are short-lived and tend to recover [26]. Progression of DN is related to glycemic control in both type 1 and type 2 diabetes [27][28]. It appears that the most rapid deterioration of nerve function occurs soon after the onset of type 1 diabetes and 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 [29]. 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 to the severity of symptoms. In a long term follow up study of type 2 diabetes patients [30], electrophysiologic abnormalities in the lower limb increased from 8% at baseline to 42% after 10 years, with 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 treatment of DN, which have always relied on differences between drug treatment and placebo and have apparently been successful because of the decline in placebo-treated patients [31]. 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. [32]. 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, and 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, 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 [33][34][35]

 

 

Pathogenesis

Causative factors include persistent hyperglycemia, microvascular insufficiency, oxidative and nitrosative stress, defective neurotrophism, and autoimmune-mediated nerve destruction Figure 1 summarizes our current view of the pathogenesis of DN [36]. Detailed discussion of the different theories is beyond the scope of this review and the reader is referred to 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 1. 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 .

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 ([37]. Each syndrome can be distinguished by its pathophysiologic, therapeutic, and prognostic features.

 

 

FOCAL AND MULTIFOCAL NEUROPATHIES

Focal Neuropathies (Focal-limb neuropathies and cranial neuropathies)

Focal limb neuropathies are usually due to entrapment and mononeuropathies must be distinguished from entrapment syndromes (Table B) [38][39] Mononeuropathies often occur in the older population with an acute onset, associated with pain, and a self-limiting course, resolving in 6–8 weeks. These can involve the median (5.8% of all diabetic neuropathies), ulnar (2.1%), radial (0.6%), and common peroneal nerves [40]. Cranial neuropathies in diabetic patients are extremely rare (0.05%) and occur in older individuals with a long duration of diabetes [41]. Entrapment syndromes start slowly, progress and persist without intervention. Carpal tunnel syndrome occurs 3-times as frequently in diabetics compared with healthy populations [42] 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 [43]. The diagnosis is confirmed by electrophysiological studies. Treatment consists of resting aided by placement of 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 [44][45]. It consists of sectioning the volar carpal ligament [46]

 

 

Table B. Mononeuropathies, Entrapment syndromes and Distal symmetrical polyneuropathy ; CN, cranial nerves.

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.

 

 

 

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 [47], and its treatment was neglected with the anticipation that the patient would eventually recover, albeit over a period of some 1-2 years, 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) 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). 5) can start unilaterally and then spread bilaterally, 6) often coexists with distal symmetric polyneuropathy, and 7) spontaneous muscle fasciculation, or provoked by percussion can be detected. 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 [48]. 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 [49][50][51][52]. In the classic form of diabetic amyotrophy, axonal loss is the predominant process [53]. Electrophysiologic evaluation reveals lumbosacral plexopathy [54]. In contrast, if demyelination predominates and the motor deficit affects proximal and distal muscle groups, the diagnosis of CIDP, monoclonal gammopathy of unknown significance (MGUS) and vasculitis should be considered [55][56]. The diagnosis of these demyelinating conditions is often overlooked, although recognition is very important, because, unlike DN, they are sometimes treatable. They occurs 11-times more frequently in diabetic than nondiabetic patients [57][58]. Biopsy of the obturator nerve reveals deposition of immunoglobulin, demyelination and inflammatory cell infiltrate of the vasa nervorum [59][60]. Cerebrospinal fluid (CSF) protein content is high and there is an increase in the lymphocyte count. Treatment options include: intravenous immunoglobulin for CIDP [61], plasma exchange for MGUS, steroids and azathioprine for vasculitis and withdrawal from 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 [62][63], whereas amyotrophy runs its own course over months to years. Until more evidence is available, they should be considered as 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. 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. It usually presents with distal sensory symptoms and, whether these abnormalities result in an increased risk of developing chronic neuropathies in the future remains unknown [64][65].

 

Generalized symmetric polyneuropathy

Acute sensory neuropathy

Acute sensory (painful) neuropathy is considered by some authors a distinctive variant of the 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. [66].

 

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 [67]. 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 ocations [68]. Although the pathologic basis has not been determined, one hypothesis suggests that changes in blood glucose flux produces alterations in epineurial blood flow, leading to ischemia. A study, using in vivo epineurial vessel photography and fluorescein angiography, demonstrated abnormalities of epineurial vessels in patients with acute sensory neuropathy, with arteriovenous shunting and proliferating new vessels [69]. Other authors relate this syndrome to diabetic lumbosacral radiculoplexus neuropathy (DLRPN) and propose an immune mediated mechanism [70].

 

The key in the management of this syndrome is achieving blood glucose stability [71]. Most patients also require medication for neuropathic pain. The natural history of this disease is resolution of symptoms within one year [72]

 

Chronic Sensorimotor Neuropathy or Distal Symmetric Polyneuropathy (DPN)

Clinical Presentation:

DPN is probably the most common form of the diabetic neuropathies [73][74]

. 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 [75]. A population survey reported that 30% of type 1 and 36 to 40% of type 2 diabetic patients experienced neuropathic symptoms [76]. 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% [77][78][79][80]. 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) [81][82].

Sensory symptoms are more prominent than motor and usually involve the lower limbs. These include pain, paresthesiae, hyperesthesiae, deep aching, burning and sharp stabbing sensations; similar but less severe to those described in acute sensory neuropathy. In addition, patients may experience negative symptoms such as numbness in 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 [83][84]. 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 loss of 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 2). Deep tendon reflexes may be absent or reduced specially on 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 [85][86][87]. 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 2. Clinical presentation of small and large fiber neuropathies: 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 presentation of small and large fiber neuropathies: 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 3):

  1. Small thinly myelinated Aδ and unmyelinated C fibers are affected.

  2. Prominent symptoms with burning, superficial or lancinating pain often accompanied by hyperalgesia, dysesthesia and allodynia.

  3. 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).

  4. Abnormal cold and warm thermal sensation.

  5. Abnormal autonomic function with decreased sweating, dry skin, impaired vasomotion and skin blood flow with cold feet.

  6. Intact motor strength and deep tendon reflexes.

  7. Negative NCVs findings.

  8. Loss of cutaneous nerve fibers on skin biopsies.

  9. Can be diagnosed clinically by reduced sensitivity to 1.0g Semmes Weinstein monofilament and prickling pain perception using the Waardenberg wheel or similar instrument.

  10. Patients at risk of foot ulceration and subsequent gangrene and amputations

 

Clinical manifestations of large fiber neuropathies

  1. Large myelinated, rapidly conducting Aα/β fibers are affected and may involve sensory and/or motor nerves.

  2. Prominents 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.

  3. Abnormal deep tendon reflexes.

  4. Impaired vibration perception (often the first objective evidence), light touch and joint position perception.

  5. Shortening of the Achilles tendon with pes equinus.

  6. 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.

  7. Abnormal NCVs findings

  8. Increased skin blood flow with hot feet.

  9. Patients at higher risk of falls and 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 3. Clinical manifestations of small fiber neuropathies.

Clinical manifestations of small fiber neuropathies. 
 

 

Diagnosis

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 should be screened for DN at diagnosis in type 2 and 5 years after diagnosis of type 1 DM. This should be repeated annually and must include sensory examination of the feet and ankle reflexes [88] 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) and 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 and cut 4 cm and 8 cm lengths, which translate to 10 and 1 g monofilaments [89]. The most sensitive measure has 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%  ([90][91] . Combinations of more than one test have more than 87% sensitivity in detecting DPN [92][93] . Longitudinal studies have shown that these simple tests are good predictors of foot ulcer risk [94] 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 [95]. 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  [96][97][98][99]. 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 . [100]

 

The use of electrophysiologic measures (NCV) in both clinical practice and multicenter clinical trials is recommended [101][102]. In a long term follow-up study of type 2 diabetic patients [103]. 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 [104]. 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 and quantification of intraepidermal nerve fibers (IENF) are needed to detect these patients [105][106][107]. 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 [108][109].

 

The importance of the skin biopsy as a diagnostic tool for DPN is increasingly being recognized [110][111][112]. 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 biopsies), 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 of glucose tolerance and features of the metabolic syndrome such as waist circumference, plasma triglyceride and HDL-C levels as well as blood pressure become mandatory and therapeutic life style changes [113] can reverse this form of neuropathy and alleviate symptoms with nerve fiber regeneration (see below).

 

 

Figure 4. 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 .

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 .

 

 

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  [114]. The Norfolk QOL questionnaire for DN is a validated tool addressing specific symptoms and 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 than in healthy controls (p<0.05) suggesting that diabetes per se impacts some aspects of QOL [115].

 

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 5)

 

 

Figure 5. 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 .

 

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 . 
 
 

TREATMENT

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 [116].

 

 

 

Treatment of specific underlying pathogenic mechanisms

 

Figure B.  

 

 

Glycemic and metabolic control

Numerous studies have shown a relationship between hyperglycemia and the development and severity of DN. The Diabetes Control and Complication Trial (DCCT) research group reported that clinical and electrophysiological evidence of neuropathy was reduced by 50% in those treated intensively with insulin [117]. In the UK Prospective Diabetes Study (UKPDS), control of blood glucose was associated with improvement in vibration perception [118][119]. The Steno trial, using multifactorial intervention reported a reduction in the odds ratio to 0.32 for the development of autonomic neuropathy [120]. Furthermore, the EURODIAB, a prospective study that included 3,250 patients across Europe, has shown that the incidence of neuropathy is also associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension [121]. Treatment of neuropathy should, therefore, include measures to reduce macrovascular risk factors, including hyperglycemia, blood pressure and lipid control and lifestyle modifications including exercise and weight reduction, smoking cessation, a diet rich in omega-3 fatty acids and avoidance of excess alcohol consumption [122]. C-peptide replacement in animal models of type 1 DM has shown improvement of nerve function [123]. Moreover, it is known to have stimulatory effects on endothelial nitric oxide synthase, thereby enhancing endoneurial blood flow [124]. Previous studies in humans have shown significant improvement in sensory nerve conduction velocities, vibration perception and autonomic nerve function [125][126]. In a recent exploratory, multicenter, randomized, placebo-controlled study including 139 patients, 6 weeks of treatment demonstrated improvement in sensory nerve conduction velocities, vibration perception and neurologic impairment scores [127].

 

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 1 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 [128]. 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.

 

Advance 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 [129]. 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 [130]. 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 [131]. 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 [132] In a one year trial of fidarestat in Japanese diabetics, improvement of symptoms was shown [133] and a 3 year study of epalrestat showed improved nerve function (NCV) as well as vibration perception [134]. Newer ARIs are currently being explored, and some positive results have emerged [135], but it is becoming clear that these may be insufficient per se and combinations of treatments may be needed [136].

 

Gamma-Linolenic acid can cause significant improvement in clinical and electrophysiological tests for neuropathy [137].

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 [138][139][140][141]. 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 [142]. 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 [143]. The result of the NATHAN study, which examined the long-term effects on electrophysiology and clinical assessments, presented at the 2007 ADA meeting, showed that 4-year treatment with α-lipoic acid in mild to moderate DSP is well tolerated and improves some neuropathic deficits and symptoms, but not nerve conduction [144].

 

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 (105). 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 (106). 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 (24). These studies and the NATHAN studies have pointed out the change in natural history of DN with the advent of therapeutic lifestyle change, statins and ACE inhibitors, which have slowed the progression of DN and drastically changed 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 (107). Clinical trials with NGF have not been successful but are subject to certain caveats with regard to design and NGF still holds promise for sensory and autonomic neuropathies (108). The pathogenesis of DN includes loss of vasa nervorum, so it is likely that appropriate application of VEGF would reverse the dysfunction. Introduction of VEGF gene into muscle of DM animal models improved nerve function (109). 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 2-week treatment with INGAP peptide (110).

 

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) (46). Perhaps the clearest link between autoimmunity and neuropathy has been the demonstration of an 11-fold increase likelihood of CIDP, multiple motor polyneuropathy, vasculitis and monoclonal gammopathies in diabetes (44). New data, however, support a predictive role of the presence of antineuronal antibodies on the later development of neuropathy, which may not be innocent bystanders but neurotoxins(111,112). 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 (42).

 

Treatment of symptoms and improvement in quality of life

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 is 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 6 describes the pathophysiological basis for the generation of neuropathic pain. Different types of pain respond to different types of therapies (17). Figure 7 describes the different nerve fibers affected and possible targeted treatments.

 

 

 

Figure 6. 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 .

 

 

 

Figure 7. 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 Ad 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, inhibit Na+ and Ca2+ channels and inhibit 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.

 
 
 
 

 

C-fiber pain

Small unmyelinated C-fiber damage gives rise to burning or lancinating pain often accompanied by hyperalgesia and dysesthesia. Peripheral sympathetic fibers are C fibers, too, and spontaneous firing or activation exacerbates the pain, which can be blocked with systemic administration of the a2-adrenergic agonist Clonidine. It can be applied topically, but the dose titration may be more difficult (113). These nerve fibers are peptidergic carrying substance P as the neurotransmitter. Depletion of substance P with local application of capsaicin abolishes transmission of painful stimuli to higher centers (114). Capsaicin is extracted from chili peppers, and a simple cheap mixture is to add one to three tea-spoons of cayenne pepper to a jar of cold cream and apply to the area of 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 (114). Care must be taken to avoid eyes and genitals, and gloves must be worn. Because of capsaicin's volatility it is safer to cover affected areas with plastic wrap. There is initial exacerbation of symptoms followed by relief in 2 to 3 weeks. Targeting higher levels of pain transmission also helps with C-fiber pain (115-117).

 

Aδ -fiber pain

Pain from Aδ fibers is deep-seated, dull and aching. It responds to nerve blocks, Tramadol or dextromethorphan, antidepressants and tricyclic agents. Insulin infusion at a rate of 0.8–1.0 units/h without lowering blood glucose helps in resolution of pain in about 48 hrs (118). N-methyl-D-aspartate (NMDA) receptor antagonists like dextromethorphan exert an analgesic effect in hyperalgesia and allodynia (119) whereas centrally acting opioids such as Tramadol achieve symptomatic relief (120). Nerve Blocking agent lidocaine given by slow infusion has been shown to provide relief of intractable pain for 3 to 21 days. This form of therapy may be of most use in self-limited forms of neuropathy. If successful, therapy can be continued with oral mexiletine. These compounds target the pain caused by hyperexcitability of superficial, free nerve endings (121).

 

Antidepressants in neuropathy

These drugs inhibit reuptake of norepinephrine and/or serotonin. Anticholinergic effects, orthostatic hypotension and sexual side effects limit their use. They remain first-line agents in many centers, but consideration of their safety and tolerability is important in avoiding adverse effects, a common result of treatment of neuropathic pain. Dosages must be titrated on the basis of positive responses, treatment adherence, and adverse events (122). Among the norepinephrine reuptake inhibitors, desipramine, amitriptyline and nortriptyline have been shown to be of benefit. In patients with intolerance to amitriptyline, switching to nortriptyline may lessen some of the anticholinergic effects. Selective serotonin-reuptake inhibitors that have been used for neuropathic pain are paroxetine, fluoxetine, sertraline, and citalopram (123). Paroxetine appears to be associated with more pain relief. Fluoxetine failed a placebo controlled trial (124). Recent interest has focused on antidepressants with dual selective inhibition of serotonin and norepinephrine, such as duloxetine and venlafaxine. Duloxetine has recently been approved for neuropathic pain in the USA. It is a selective, balanced and potent serotonin and norepinephrine reuptake inhibitor (SNRI) in the brain and spinal cord, and its use leads to increased neuronal activity in efferent inhibitory pathways. In a 12-week multicenter, double-blind clinical trial of 457 patients, Goldstein et al showed a 50% reduction in 24-h Average Pain Score (primary endpoint) in 49 to 52% of patients treated with 60 mg and 120 mg of duloxetine vs. 26% of patients in the placebo group (p<0.05) (115). A second study by Raskin et al conducted in 449 patients for 6 months, similarly demonstrated maintenance of pain relief through 28 weeks (125). Nonetheless a number of side effects were reported, including dizziness, somnolence, dry mouth, nausea, constipation and reduced appetite. Physicians must be alert to suicidal ideation, exacerbation of autonomic symptoms, as well as aggravation of depression, and should stop the drug immediately if required (115). Venlafaxine in doses of 150 and 225 mg daily significantly improved pain scores, although side effects included somnolence, nausea and myalgias, and 7 of 244 treated patients developed significant electrocardiographic abnormalities (126).

 

Anticonvulsants in diabetic neuropathy

Anticonvulsants have stood the test of time in treatment of DN. Principal mechanisms of action include sodium-channel blockade, potentiation of g-amino butyric (GABA) activity, calcium-channel blockade, antagonism of glutamate at N-methyl-D-aspartate receptors or α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (28).

Diphenylhydantoin has long been used in the treatment of painful neuropathies. Double-blind crossover studies do not demonstrate a therapeutic benefit of phenytoin compared with placebo in DN (127). Also, side effects mitigate its use in people with diabetes. Its ability to suppress insulin secretion has resulted in precipitation of hyperosmolar diabetic coma.

 

Several double-blind placebo-controlled studies have demonstrated carbamazepine to be effective in the management of pain in DN. At a dose of 200 mg twice daily is useful for patients with shooting or electric, shock-like pain but is rapidly discontinued due to adverse events.

 

Gabapentin is an effective anticonvulsant whose mechanism is not well understood, yet holds additional use as an analgesic agent in painful neuropathy (128). In a placebo-controlled trial gabapentin-treated patients had significantly lower mean daily pain scores and improvement of all secondary efficacy parameters (129). Gabapentin has the additional benefit of improving sleep, which is often compromised in patients with chronic pain (122). In the long term, it is known to produce weight gain, (130) which may complicate diabetes management, and it has not been successful in all trials.

 

Pregabalin produced significant improvements in pain scores within 1 week of treatment, which persisted for 6-12 weeks in four randomized controlled trials including 146-724 patients with diabetic neuropathy (116,131-133). Adverse events included dose related somnolence, ataxia and confusion, peripheral edema and constipation. A recent Canadian study evaluated cost-effectiveness of pregabalin vs gabapentin for the treatment of painful DN concluding that pregabalin was more cost effective when compared with gabapentin (134).

 

In trials with topiramate, a fructose analog, 50% of patients on topiramate versus 34% on placebo responded to treatment, defined as >30% reduction in pain score (P <0.004). Topiramate also reduced pain intensity versus placebo (P <0.003) as well as sleep disruption scores (P <0.02). This drug also lowers blood pressure, has a favorable impact on lipids, decreases insulin resistance and causes growth of intraepidermal nerve fibers and improves quality of life (135,136).

Lamotrigine (200 to 400 mg daily) is an anticonvulsant with dual-action inhibition of neuronal hyperexcitability. Two randomized, placebo-controlled studies including 720 patients showed that the drug was inconsistently effective for the treatment of pain when compared with placebo, although it was generally safe and well tolerated (117).

Another approach is the use of combination treatments. Gilron et al showed that the use morphine and gabapentin together, in an outpatient study, is superior to either alone, although the combination was associated with an increased frequency of side effects (137).

 

As mentioned previously, pain symptoms in neuropathy significantly impact QOL (78) (138). Neuropathic pain therapy is challenging and selection of pain medication and dosages must be individualized, with attention to potential side effects and drug interactions. An algorithm for the Management of Symptomatic Diabetic Neuropathy is described in figure 8.

 

 

Figure 8. 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 by 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 .

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 by 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 .

 

 

 

Adjunctive management and treatment of complications

Management of Large Fiber Neuropathies

Large-fiber neuropathy is manifested by reduced vibration perception and position sense, weakness and muscle wasting and depressed deep-tendon reflexes. Diabetic patients with large-fiber neuropathies are uncoordinated and ataxic, and are 17-times more likely to fall than their non-neuropathic counterparts (139). It is important, therefore, to improve strength and balance in patients with large-fiber neuropathy. Patients can benefit from high-intensity strength training by increasing muscle strength, improving coordination and balance, and thus reducing falls and fracture risks (140). Low-impact activities such as Pilates, yoga, and Tai Chi—which emphasize muscular strength and coordination, and challenge the vestibular system—may also be particularly helpful. In addition, options to prevent and correct foot deformities are available, for example orthotics, surgery and reconstruction.

 

Management of Small Fiber Neuropathies

Basic management of small fiber neuropathies by the patient should be encouraged. These are as follows: foot protection and ulcer prevention by wearing padded socks; regular foot inspection using a mirror to examine the soles of the feet daily; selection of proper footwear; scrutiny of shoes for the presence of foreign objects; avoidance of sun-heated surfaces, hot bathwater or sleeping with feet in front of fireplaces or heaters. Nails should be cut transversely and preferably by a podiatrist. Patient education should reinforce these strategies and, additionally, discourage soaking feet in water. Providing patients with a monofilament for self-testing reduces ulcers. Education will also promote foot care by encouraging emollient creams to help skin retain moisture and prevent cracking and infection. Transcutaneous nerve stimulation (electrotherapy) occasionally may be helpful and certainly represents one of the more benign therapies for painful neuropathy (141). Care should be taken to move the electrodes around to identify sensitive areas and obtain maximal relief.

 

Surgical Decompression for Diabetic Sensorimotor Polyneuropathy:

“The utility of surgical decompression for symptomatic diabetic neuropathy received a grade IV rating; i.e., based on evidence from uncontrolled studies, case reports, or expert opinion. It was assigned a U grading, which is defined as "data inadequate or conflicting given current knowledge, treatment is unproven." (142). “We believe the findings of the American Academy of Neurology’s evidence-based review should be strong evidence that the procedures should not be considered care but, rather, subjected to further research until proven beneficial. Only well-controlled, randomized, double-masked, sham-procedure, controlled clinical trials will allow us to know whether these surgeries are safe and effective for this indication—the same standard that any drug for DPN would have to meet.” (142)

 

 

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 (143). 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 1). 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 (144).

 

 

Table 1. Clinical manifestations of autonomic neuropathy.

Cardiovascular

Central:

  1. Tachycardia/ Bradycardia

  2. Systolic and diastolic dysfunction

  3. Decreased exercise tolerance

  4. Orthostasis,

  5. Orthostatic tachycardia and bradycardia syndrome

  6. Sleep apnea

  7. Anxiety/ depression

  8. Cardiac denervation syndrome

  9. Paradoxic supine or nocturnal hypertension

  10. Intraoperative and perioperative cardiovascular instability

Peripheral:

  1. Decreased thermoregulation

  2. Decreased sweating

  3. Altered blood flow

  4. Impaired vasomotion

  5. Edema

Gastrointestinal

  1. Esophageal dysmotility

  2. Gastroparesis diabeticorum

  3. Diarrhea

  4. Constipation

  5. Fecal incontinence

Genitourinary

  1. Erectile dysfunction

  2. Retrograde ejaculation

  3. Neurogenic bladder and cystopathy

  4. Female sexual dysfunction (e.g., loss of vaginal lubrication)

Sudomotor

  1. Anhidrosis

  2. Hyperhidrosis

  3. Heat intolerance

  4. Gustatory sweating

  5. Dry skin

Metabolic

  1. Hypoglycemia unawareness

  2. Hypoglycemia unresponsiveness

Pupillary

  1. Pupillomotor function impairment (e.g., decreased diameter of dark adapted pupil)

  2. 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 (145). The defect is associated with a reduction in the amplitude of vasomotion (146) and resembles premature aging (145). There are differences in the glabrous and hairy skin circulations. In hairy skin a functional defect is found prior to the development of neuropathy (147) and is correctable with antioxidants (148). The clinical counterpart is a dry cold skin, loss of sweating, develops 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 the diabetic patients with cardiac autonomic neuropathy (149,150). Therefore, it is vitally important to make this diagnosis early so that appropriate intervention can be instituted (151).

 

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 methods, and 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 2 below presents 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-9 (152).

 

 

Figure 9. Role of over-activation of autonomic nervous system .

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 (153) 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 (10). 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 (152) in figure-10.

 

 

Figure 10. Association between CAN and silent MI .

Association between CAN and silent MI .

 

 

Table 2. Differential diagnosis of diabetic autonomic neuropathy

Clinical Manifestations

Differential Diagnosis

Cardiovascular

  1. Resting tachycardia, Exercise intolerance

  2. Orthostatic tachycardia and bradycardia syndromes

  3. Cardiac denervation, painless myocardial infarction

  4. Orthostatic hypotension

  5. Intraoperative and perioperative cardiovascular instability

Cardiovascular disorders

  1. Idiopathic orthostatic hypotension, multiple system atrophy with Parkinsonism, orthostatic tachycardia, hyperadrenergic hypotension

  2. Shy-Drager syndrome

  3. Panhypopituitarism

  4. Pheochromocytoma

  5. Hypovolemia

  6. Congestive heart disease

  7. Carcinoid syndrome

Gastrointestinal

  1. Esophageal dysfunction

  2. Gastroparesis diabeticorum

  3. Diarrhea

  4. Constipation

  5. Fecal incontinence

Gastrointestinal disorders

  1. Obstruction

  2. Bezoars

  3. Secretory diarrhea (endocrine tumors)

  4. Biliary disease

  5. Psychogenic vomiting

  6. Medications

Genitourinary

  1. Erectile dysfunction

  2. Retrograde ejaculation

  3. Cystopathy

  4. Neurogenic bladder

Genitourinary disorders

  1. Genital and pelvic surgery

  2. Atherosclerotic vascular disease

  3. Medications

  4. Alcohol abuse

Neurovascular

  1. Heat intolerance

  2. Gustatory sweating

  3. Dry skin

  4. Impaired skin blood flow

Other causes of neurovascular dysfunction

  1. Chaga's disease

  2. Amyloidosis

  3. Arsenic

Metabolic

  1. Hypoglycemia unawareness

  2. Hypoglycemia unresponsiveness

  3. Hypoglycemia associated autonomic failure

Metabolic disorders

  1. Other cause of hypoglycemia, intensive glycemic control and drugs that mask hypoglycemia

Pupillary

  1. Decreased diameter of dark adapted pupil

  2. Argyll-Robertson type pupil

Pupillary disorders

  1. Syphilis

 

 

Table 3. 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 4. 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 5. Diagnostic Assessment of Cardiovascular Autonomic Function.

Parasympathetic

Sympathetic

  1. Resting heart rate

  2. Beat to beat variation with deep breathing (E:I ratio)

  3. 30:15 heart rate ratio with standing

  4. Valsalva ratio

  5. Spectral analysis of heart rate variation , high frequency power (HFP 0.15-0.40 Hz)

  6. Spectral Analysis of HRV respiratory frequency

  1. Resting heart rate

  2. Spectral analysis of heart rate variation , very low frequency power (VLFP 0.003-0.04)

  3. Orthostasis BP

  4. Hand grip BP

  5. Cold pressor response

  6. Sympathetic skin galvanic response (cholinergic)

  7. Sudorimetry (cholinergic)

  8. Cutaneous blood flow (peptidergic)

 

 

Figure 11.  

 

 

 

Figure 12. The Evaluation Of The Patient Suspected Of Gastroparesis.

The Evaluation Of The Patient Suspected Of Gastroparesis.

 

 

Prevention and reversibility of autonomic neuropathy

It has now become clear that strict glycemic control (20) and a stepwise progressive management of hyperglycemia, lipids, blood pressure and use of antioxidants (155) and ACE inhibitors (156) reduce the odds ratio for autonomic neuropathy to 0.32 (157). 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 (158). Kendall et al (159) 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 (160) showed that a reversible metabolic component of CAN exists in patients with early CAN.

 

 

Figure 13. 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 6. 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 (161). 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 (162). 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 (152). 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(152).

 

Gastropathy

Gastrointestinal motor disorders are frequent and widespread in type 2 diabetic patients, regardless of symptoms (163) and there is a poor correlation between symptoms and objective evidence of a functional or organic defects. 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 (164,165). Metoclopramide may be used. Cisapride and domperidone (166,167) has 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 (168). If medications fail and severe gastroparesis persists, jejunostomy placement into normally functioning bowel may be needed. Different treatment modalities for gastroparesis includes dietary modifications, prokinetic and antiemetic medications, measures to control pain and address psychological issues, and endoscopic or surgical options in selected instances (169).

 

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.

 

Cystopathy

Patients with neurogenic bladder should be instructed to palpate their bladders and, if they are unable to initiate micturition when their bladders are full, use Crede's maneuver to start the flow of urine. 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 α-1-blocker, such as doxazosin (29). Self-catheterization can be particularly useful in this setting, with the risk of infection generally being low.

 

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 (170) (171). The diagnosis of the cause of ED is made by a logical stepwise progression (170) (171) in all instances. An approach to therapy has recently been presented to which the reader is referred; figure below shows flow chart modified from Vinik et. al., 1998. (170).

 

 

Figure 14. Evaluation of Diabetic patients with Erectile Dysfunction.

Evaluation of Diabetic patients with Erectile Dysfunction.

 

 

A thorough work-up for impotence will include: medical and sexual history; physical and psychological evaluations; blood test for diabetes and a check of levels of testosterone, prolactin, and thyroid hormones; test for nocturnal erections; tests to assess penile, pelvic, and spinal nerve function; and test to assess penile blood supply and blood pressure. The flow chart provided is intended as a guide to assist in defining 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 demonstrating normal perianal sensation, assessing the tone of the anal sphincter during a rectal exam, and 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. 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 (172). Sildenafil was well tolerated, effective and increased the number of succesful attempts of intercourse. Sildenafil should be considered as first line treatment for erectile dysfunction in men with Type 2 diabetes mellitus (173). Tadalafil at 10 and 20 mg improved erectile function irrespective of the type of diabetes, presence of microvascular complications, or type of diabetes treatment (174) 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 (175)

Direct injection of prostacylin 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, but they are at risk of decreased sexual arousal, with inadequate lubrication (176). 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, is 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 (antimuscarinic compound) might benefit diabetic patients with gustatory sweating (177). 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 (178). 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 in long-term regulation. 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 in 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 (179).

 

In patients with type 1 diabetes mellitus, the glucagon response is impaired with diabetes duration of 1-5 years, and after 14-31 years of diabetes, the glucagon response is almost undetectable. It 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, hypoglycemic awareness associated with hypoglycemia 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 (180).

 

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.

 

SWEATING DISTURBANCES

Hyperhidrosis of the upper body, often related to eating (gustatory sweating) and anhidrosis of the lower body, is a characteristic feature of autonomic neuropathy. Gustatory sweating accompanies the ingestion of certain foods, particularly spicy foods, and cheeses. Gustatory Sweating is more common than previously believed and topically applied glycopyrrolate (antimuscarinic compound) is very effective treatment in reducing both the severity and frequency (177) (181). 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.

 

Figure Screening, diagnosis, and treatment of diabetic autonomic neuropathy

 

 

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, 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 the Nutrinerve, 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 area.

 

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 the role of 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.

 

 

1. Vinik AI, Mitchell BD, Leichter SB, Wagner AL, O'Brian JT, Georges LP: Epidemiology of the Complications of Diabetes. In Diabetes: Clinical Science in Practice. Leslie RDG, Robbins DC, Eds. Cambridge, United Kingdom, Cambridge University Press, 1995, p. 221-287

2. Holzer SE, Camerota A, Martens L, Cuerdon T, Crystal P, Zagari M: Costs and duration of care for lower extremity ulcers in patients with diabetes. Clin Ther 20:169-181, 1998

3. Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW: Assessment and management of foot disease in patients with diabetes. N Engl J Med 331:854-860, 1994

4. Herman WH, Kennedy L: Underdiagnosis of peripheral neuropathy in type 2 diabetes. Diabetes Care 28:1480-1481, 2005

5. Young MJ, Boulton AJM, MacLeod AF, Williams DRR, Sonksen PH: A multicenter study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 36:1-5, 1993

6. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton III LJ: The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: The Rochester Diabetic Neuropathy Study. Neurology 43:817-824, 1993

7. Vinik A: Diabetic Neuropathy: Pathogenesis and Therapy. Am J Med 107 (2B):17S-26S, 1999

8. Armstrong DG, Lavery LA, Harkless LB: Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care 21:855-859, 1998

9. Vinik, E., Hayes, R., Oglesby, A., Bastyr, E., Barlow, P., Ford-Molvik, S., and Vinik, A. The Development and validation of the Norfolk QOL-DN a New Measure of patients' Perception of the Effects of Diabetes and Diabetic Neuropathy. Diabetes Technol.Ther 7 (3), 497-508. 2005.

10. Levitt NS, Stansberry KB, Wychanck S, Vinik AI: Natural progression of autonomic neuropathy and autonomic function tests in a cohort of IDDM. Diabetes Care 19:751-754, 1996

11. Rathmann W, Ziegler D, Jahnke M, Haastert B, Gries FA: Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diabet Med 10:820-824, 1993

12. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 27:1458-1486, 2004

13. Dyck, P. J. Severity and staging of diabetic polyneuropathy. Textbook of Diabetic Neuropathy , 170-175. 2003. Thieme, Stuttgart.

14. Thomas PK: Classification, differential diagnosis, and staging of diabetic peripheral neuropathy. Diabetes 46 Suppl 2:S54-S57, 1997

15. Vinik A, Ullal J, Parson HK, Casellini CM: Diabetic neuropathies: clinical manifestations and current treatment options. Nat Clin Pract Endocrinol Metab 2:269-281, 2006

16. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D: Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 28:956-962, 2005

17. Vinik AI, Mehrabyan A: Diabetic neuropathies. Med Clin North Am 88:947-99, xi, 2004

18. Watkins PJ: Progression of diabetic autonomic neuropathy. Diabet Med 10 [Suppl 2]:77S-78S, 1993

19. DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 329:977-986, 1993

20. DCCT Research Group: The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 122:561-568, 1995

21. Ziegler D, Cicmir I, Mayer P, Wiefels K, Gries FA: Somatic and autonomic nerve function during the first year after diagnosis of type 1 (insulin-dependent) diabetes. Diabetes Res 7:123-127, 1988

22. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, Uusitupa M: Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333:89-94, 1995

23. Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton LJ, O'Brien PC, Litchy WJ, Windebank AJ, Smith BE, Low PA: The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology 41:799-807, 1991

24. Casellini CM, Barlow PM, Rice AL, Casey M, Simmons K, Pittenger G, Bastyr EJ, III, Wolka AM, Vinik AI: A 6-Month, Randomized, Double-Masked, Placebo-Controlled Study Evaluating the Effects of the Protein Kinase C-{beta} Inhibitor Ruboxistaurin on Skin Microvascular Blood Flow and Other Measures of Diabetic Peripheral Neuropathy. Diabetes Care 30:896-902, 2007

25. Pittenger G, Simmons K, Anandacoomaraswamy D, rice A, Barlow P, Vinik A: Topiramate improves intraepidermal nerve fiber morphology and quantitative neuropathy measures in diabetic neuropathy patients (Abstract). J.Peripher.Nerve System 10 (Suppl 1) : 2005

26. Pittenger GL, Ray M, Burcus NI, McNulty P, Basta B, Vinik AI: Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and nondiabetic patients. Diabetes Care 27:1974-1979, 2004

27. Sinnreich M, Taylor BV, Dyck PJ: Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 11:63-79, 2005

28. Vinik AI: Advances in diabetes for the millennium: new treatments for diabetic neuropathies. MedGenMed 6:13, 2004

29. Vinik AI, Holland MT, LeBeau JM, Liuzzi FJ, Stansberry KB, Colen LB: Diabetic neuropathies. Diabetes Care 15:1926-1975, 1992

30. Vinik A, Mehrabyan A, Colen L, Boulton A: Focal entrapment neuropathies in diabetes. Diabetes Care 27:1783-1788, 2004

31. Wilbourn, A. J. Diabetic entrapment and compression neuropathies. Dyck PJ, Thomas PK (EDS) Diabetic Neuropathy , 481-508. 1999. Philadelphia, Saunders.

32. Watanabe K, Hagura R, Akanuma Y, Takasu T, Kajinuma H, Kuzuya N, Irie M: Characteristics of cranial nerve palsies in diabetic patients. Diabetes Res Clin Pract 10:19-27, 1990

33. Perkins, B., Olaleye, D., and Bril, V. Carpal Tunnel Syndrome in Patients with Diabetic Polyneuropathy. Diabetes Care 25, 565-569. 2002.

34. Dawson DM: Entrapment neuropathies of the upper extremities. N Engl J Med 329:2013-2018, 1993

35. Casellini C, Barlow P, rice A, Casey M, Simmons K, Pittenger G, Bastyr E, Vinik A: Effect of Ruboxistaurin (RBX) on Quantitative Measures of Diabetic Peripheral Neuropathy (DPN) (Abstract). Diabetes 791-P : 2006

36. Llewelyn JG, Thomas PK, King RH: Epineurial microvasculitis in proximal diabetic neuropathy. J Neurol 245:159-165, 1998

37. James, P., Dyck, B., and Windenbank, A. Diabetic and Nondiabetic Lumbosacral Radiculoplexus Neuropathy: New Insights into Pathophysiology. Muscle & Nerve 25, 477-491. 2002.

38. Vinik AI, Pittenger GL, Milicevic Z, Cuca J: Autoimmune Mechanisms in the Pathogenesis of Diabetic Neuropathy. In Molecular Mechanisms of Endocrine and Organ Specific Autoimmunity. 1st ed. Eisenbarth RG, Ed. Georgetown, Landes Company, 1998, p. 217-251

39. Steck AJ, Kappos L: Gangliosides and autoimmune neuropathies: classification and clinical aspects of autoimmune neuropathies. J Neurol Neurosurg Psychiatry 57 [Suppl]:26-28, 1994

40. Said G, Goulon-Goreau C, Lacroix C, Moulonguet A: Nerve biopsy findings in different patterns of proximal diabetic neuropathy. Ann Neurol 35:559-569, 1994

41. Sander HW, Chokroverty S: Diabetic amyotrophy: current concepts. Semin Neurol 16:173-178, 1996

42. Krendel DA, Costigan DA, Hopkins LC: Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 52:1053-1061, 1995

43. Britland ST, Young RJ, Sharma AK, Clarke BF: Acute and remitting painful diabetic polyneuropathy: a comparison of peripheral nerve fibre pathology. Pain 48:361-370, 1992

44. Sharma, K., Cross, J., Farronay, O., Ayyar, D., Sheber, R., and Bradley, W. Demyelinating neuropathy in diabetes mellitus. Arch Neurol 59, 758-765. 2002.

45. Krendel DA, Zacharias A, Younger DS: Autoimmune diabetic neuropathy. Neurol Clin 15:959-971, 1997

46. Milicevic Z, Newlon PG, Pittenger GL, Stansberry KB, Vinik AI: Anti-ganglioside GM1 antibody and distal symmetric "diabetic polyneuropathy" with dominant motor features. Diabetologia 40:1364-1365, 1997

47. Ayyar DR, Sharma KR: Chronic inflammatory demyelinating polyradiculoneuropathy in diabetes mellitus. Curr Diab Rep 4:409-412, 2004

48. Barada A, Reljanovic M, Milicevic Z, Ljubic S, Car N, Benko B, Vinik AI, Metelko Z: Proximal Diabetic Neuropathy-Response To Immunotherapy (Abstract). Diabetes 48 [Suppl 1]:A148, 1999

49. Boulton AJ, Malik RA: Diabetic neuropathy. Med Clin North Am 82:909-929, 1998

50. Bird SJ, Brown MJ: The clinical spectrum of diabetic neuropathy. Semin Neurol 16:115-122, 1996

51. Oyibo SO, Prasad YD, Jackson NJ, Jude EB, Boulton AJ: The relationship between blood glucose excursions and painful diabetic peripheral neuropathy: a pilot study. Diabet Med 19:870-873, 2002

52. Tesfaye S, Malik R, Harris N, Jakubowski JJ, Mody C, Rennie IG, Ward JD: Arterio-venous shunting and proliferating new vessels in acute painful neuropathy of rapid glycaemic control (insulin neuritis). Diabetologia 39:329-335, 1996

53. Archer AG, Watkins PJ, Thomas PK, Sharma AK, Payan J: The natural history of acute painful neuropathy in diabetes mellitus. J Neurol Neurosurg Psychiatry 46:491-499, 1983

54. Harris M, Eastman R, Cowie C: Symptoms of sensory neuropathy in adults with NIDDM in the U.S. population. Diabetes Care 16:1446-1452, 1993

55. Singleton JR, Smith AG, Bromberg MB: Painful sensory polyneuropathy associated with impaired glucose tolerance. Muscle Nerve 24:1225-1228, 2001

56. Singleton JR, Smith AG, Bromberg MB: Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 24:1448-1453, 2001

57. Novella SP, Inzucchi SE, Goldstein JM: The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 24:1229-1231, 2001

58. Sumner, C., Sheth, S., Griffin, J., Cornblath, D., and Polydefkis, M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology , 108-111. 2003.

59. Dyck PJ, Lais A, Karnes JL, O'Brien P, Rizza R: Fiber loss is primary and multifocal in sural nerves in diabetic polyneuropathy. Ann Neurol 19:425-439, 1986

60. Cavanagh PR, Simoneau GG, Ulbrecht JS: Ulceration, unsteadiness, and uncertainty: the biomechanical consequences of diabetes mellitus. J Biomech 26 Suppl 1:23-40:23-40, 1993

61. Katoulis EC, Ebdon-Parry M, Lanshammar H, Vileikyte L, Kulkarni J, Boulton AJ: Gait abnormalities in diabetic neuropathy. Diabetes Care 20:1904-1907, 1997

62. Vinik, A., Erbas, T., Stansberry, K. B., and Pittenger, G. Small fiber neuropathy and neurovascular disturbances in diabetes mellitus. Exp Clin Endocrinol Diabetes 109(Suppl 2), S451-S473. 2001.

63. Bourcier ME, Ullal J, Parson HK, Dublin CB, Witherspoon CA, Ward SA, Vinik AI: Diabetic peripheral neuropathy: how reliable is a homemade 1-g monofilament for screening? J Fam Pract 55:505-508, 2006

64. Kumar S, Fernando DJ, Veves A, Knowles EA, Young MJ, Boulton AJ: Semmes-Weinstein monofilaments: a simple, effective and inexpensive screening device for identifying diabetic patients at risk of foot ulceration. Diabetes Res Clin Pract 13:63-67, 1991

65. Armstrong DG, Lavery LA, Vela SA, Quebedeaux TL, Fleischli JG: Choosing a practical screening instrument to identify patients at risk for diabetic foot ulceration. Arch Intern Med 158:289-292, 1998

66. Vinik AI, Suwanwalaikorn S, Stansberry KB, Holland MT, McNitt PM, Colen LE: Quantitative measurement of cutaneous perception in diabetic neuropathy. Muscle Nerve 18:574-584, 1995

67. Abbott CA, Carrington AL, Ashe H, Bath S, Every LC, Griffiths J, Hann AW, Hussein A, Jackson N, Johnson KE, Ryder CH, Torkington R, Van Ross ER, Whalley AM, Widdows P, Williamson S, Boulton AJ: The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med 19:377-384, 2002

68. Dyck PJ, Melton LJ, III, O'Brien PC, Service FJ: Approaches to improve epidemiological studies of diabetic neuropathy: insights from the Rochester Diabetic Neuropathy Study. Diabetes 46 Suppl 2:S5-S8, 1997

69. Dyck PJ, Dyck PJ, Larson TS, O'Brien PC, Velosa JA: Patterns of quantitative sensation testing of hypoesthesia and hyperalgesia are predictive of diabetic polyneuropathy: a study of three cohorts. Nerve growth factor study group. Diabetes Care 23:510-517, 2000

70. Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJ: Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care 21:1071-1075, 1998

71. Yarnitsky D, Sprecher E: Thermal testing: normative data and repeatability for various test algorithms. J Neurol Sci 125:39-45, 1994

72. Shy, M. E., Frohman, E. M., So, Y., Arezzo, J. C., Cornblath, D. C., Giuliani, M. J., and the subcommittee of the American Academy of Neurology. Quantitative sensory testing. Neurology 602, 898-906. 2003.

73. Consensus statement: Report and recommendations of the San Antonio conference on diabetic neuropathy. American Diabetes Association American Academy of Neurology. Diabetes Care 11:592-597, 1988

74. Diabetic polyneuropathy in controlled clinical trials: Consensus Report of the Peripheral Nerve Society. Ann Neurol 38:478-482, 1995

75. Kennedy WR, Wendelschafer-Crabb G, Johnson T: Quantitation of epidermal nerves in diabetic neuropathy. Neurology 47:1042-1048, 1996

76. Polydefkis M, Hauer P, Griffin JW, McArthur JC: Skin biopsy as a tool to assess distal small fiber innervation in diabetic neuropathy. Diabetes Technol Ther 3:23-28, 2001

77. Smith AG, Russell J, Feldman EL, Goldstein J, Peltier A, Smith S, Hamwi J, Pollari D, Bixby B, Howard J, Singleton JR: Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care 29:1294-1299, 2006

78. Vileikyte L, Peyrot M, Bundy C, Rubin RR, Leventhal H, Mora P, Shaw JE, Baker P, Boulton AJ: The development and validation of a neuropathy- and foot ulcer-specific quality of life instrument. Diabetes Care 26:2549-2555, 2003

79. Cameron, N. E., Eaton, S. E. M., Cotter, M. A., and Tesfaye, S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 44, 1973-1988. 2001.

80. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. [published erratum appears in BMJ 1999 Jan 2;318(7175):29] . BMJ 317:703-713, 1998

81. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854-865, 1998

82. Gaede P, Vedel P, Larsen N, Jensen G, Parving H, Pedersen O: Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes. N Engl J Med383-393, 2003

83. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH: Vascular risk factors and diabetic neuropathy. N Engl J Med 352:341-350, 2005

84. Kamiya H, Zhang W, Sima AA: C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes. Ann Neurol 56:827-835, 2004

85. Stevens MJ, Zhang W, Li F, Sima AA: C-peptide corrects endoneurial blood flow but not oxidative stress in type 1 BB/Wor rats. Am J Physiol Endocrinol Metab 287:E497-E505, 2004

86. Ekberg K, Brismar T, Johansson BL, Jonsson B, Lindstrom P, Wahren J: Amelioration of sensory nerve dysfunction by C-Peptide in patients with type 1 diabetes. Diabetes 52:536-541, 2003

87. Johansson BL, Borg K, Fernqvist-Forbes E, Odergren T, Remahl S, Wahren J: C-peptide improves autonomic nerve function in IDDM patients. Diabetologia 39:687-695, 1996

88. Ekberg K, Brismar T, Johansson BL, Lindstrom P, Juntti-Berggren L, Norrby A, Berne C, Arnqvist HJ, Bolinder J, Wahren J: C-Peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy. Diabetes Care 30:71-76, 2007

89. Ziegler D, Sohr CG, Nourooz-Zadeh J: Oxidative stress and antioxidant defense in relation to the severity of diabetic polyneuropathy and cardiovascular autonomic neuropathy. Diabetes Care 27:2178-2183, 2004

90. Miyauchi Y, Shikama H, Takasu T, Okamiya H, Umeda M, Hirasaki E, Ohhata I, Nakayama H, Nakagawa S: Slowing of peripheral motor nerve conduction was ameliorated by aminoguanidine in streptozocin-induced diabetic rats. Eur J Endocrinol 134:467-473, 1996

91. Haupt E, Ledermann H, Kopcke W: Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study). Int J Clin Pharmacol Ther 43:71-77, 2005

92. Stracke H, Lindemann A, Federlin K: A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes 104:311-316, 1996

93. Greene DA, Arezzo JC, Brown MB: Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology 53:580-591, 1999

94. Hotta, N., Toyota, T., Matsuoka, K., Shigeta, Y., Kikkawa, R., Kaneko, T., Takahashi, A., Sugimura, K., Koike, Y., Ishii, J., Sakamoto, N., and The, S. N. K. Clinical Efficacy of Fidarestat, a Novel Aldose Reductase Inhibitor, for diabetic Peripheral Neuropathy. Diabetes Care 24, 1776-1782. 2001.

95. Hotta N, Shigeta Y, Sakamoto N: Long-term Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy: A 3-y Multicenter Comparative Study, ARI-Diabetes Complications Trial (ADCT) (Abstract). Diabetes 54 :A213, 2005

96. Bril V, Buchanan RA: Long-term effects of ranirestat (AS-3201) on peripheral nerve function in patients with diabetic sensorimotor polyneuropathy. Diabetes Care 29:68-72, 2006

97. Keen H, Payan J, Allawi J, Walker J, Jamal GA, Weir AI, Henderson LM, Bissessar EA, Watkins PJ, Sampson M, Gale EA, Scarpello J, Boddie HG, Hardy KJ, Thomas PK, Misra P, Halonen JP: Treatment of Diabetic Neuropathy with - Linolenic Acid. Diabetes Care 16:8-15, 1993

98. Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O'Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D: The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care 26:770-776, 2003

99. Ruhnau, K. J., Meissner, H. P., Finn, R., Reljanovic, M., Lobisch, M., Schutte, K., Nehrdich, D., Tritschler, H., Mehnert, H., and Ziegler, D. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med 16(12), 1040-1043. 1999.

100. Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, Gries FA: Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 38:1425-1433, 1995

101. Reljanovic, M., Reichel, G., Rett, K., Lobisch, M., Schuette, K., Moller, W., Tritschler, H. J., and Mehnert, H. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res 31(3), 171-179. 1999.

102. Ziegler D, Nowak H, Kempler P, Vargha P, Low PA: Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med 21:114-121, 2004

103. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R: Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 29:2365-2370, 2006

104. Ziegler D, Low PA, Boulton AJ, Vinik AI, Freeman R, Samigullin R, Tritschler H, Munzel U, Maus J, Schuette K, Dyck PJ: Effect of 4-Year Antioxidant Treatment with alpha-Lipoic Acid in Diabetic Polyneuropathy: The NATHAN 1 Trial. (Abstract). Diabetes 56:A2, 2007

105. Vinik A, Bril V, Kempler P, Litchy W, Dyck P, Tesfaye S, Price K, Bastyr E, for the MBBQ Study: Treatment of symptomatic diabetic peripheral neuropathy with protein kinase CB inhibitor ruboxistaurin mesylate during a 1-year randomized, placebo-controlled, double-blind clinical trial. Clinical Therapeutics 27:1164-1180s, 2005

106. Vinik AI, Bril V, Litchy WJ, Price KL, Bastyr EJ, III: Sural sensory action potential identifies diabetic peripheral neuropathy responders to therapy. Muscle Nerve 2005

107. Pittenger G, Vinik A: Nerve growth factor and diabetic neuropathy. Exp Diabesity Res 4:271-285, 2003

108. Vinik AI: Treatment of diabetic polyneuropathy (DPN) with recombinant human nerve growth factor (rhNGF) (Abstract). Diabets 48 [Suppl 1]:A54-A55, 1999

109. Rivard A, Silver M, Chen D, Kearney M, Magner M, Annex B, Peters K, Isner JM: Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am J Pathol 154:355-363, 1999

110. Tam J, Rosenberg L, Maysinger D: INGAP peptide improves nerve function and enhances regeneration in streptozotocin-induced diabetic C57BL/6 mice. FASEB J 18:1767-1769, 2004

111. Granberg V, Ejskjaer N, Peakman M, Sundkvist G: Autoantibodies to autonomic nerves associated with cardiac and peripheral autonomic neuropathy. Diabetes Care 28:1959-1964, 2005

112. Vinik AI, Anandacoomaraswamy D, Ullal J: Antibodies to Neuronal Structures: Innocent bystanders or neurotoxins? Diabetes Care 28:2067-2072, 2005

113. Bays-Smith MG, Max MB, Muir J, Kingman A: Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage 'enriched enrollment' design. Pain 60:267-274, 1995

114. Rains C, Bryson HM: Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging 7:317-328, 1995

115. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S: Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 116:109-118, 2005

116. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U: Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 110:628-638, 2004

117. Vinik AI, Tuchman M, Safirstein B, Corder C, Kirby L, Wilks K, Quessy S, Blum D, Grainger J, White J, Silver M: Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies. Pain 128:169-179, 2007

118. Said G, Bigo A, Ameri A, Gayno JP, Elgrably F, Chanson P, Slama G: Uncommon early-onset neuropathy in diabetic patients. J Neurol 245:61-68, 1998

119. Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB: High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology 48:1212-1218, 1997

120. Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D, Sachdeo R, Siu CO, Karmin M: Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 50:1842-1846, 1998

121. Jarvis B, Coukell AJ: Mexiletine. A review of its therapeutic use in painful diabetic neuropathy. Drugs 56:691-707, 1998

122. Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, Bushnell MC, Farrar JT, Galer BS, Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM: Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 60:1524-1534, 2003

123. Sindrup S, Gram L, Brosen K: The selective serotonin reuptake inhibitor paroxetine is effective in treatment of diabetic neuropathy symptoms. Pain 42:144, 1990

124. Max M, Lynch S, Muir J: Effects of desipramine, amitryptiline and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326:1250-1256, 1992

125. Raskin J, Wang F, Pritchett YL, Goldstein DJ: Duloxetine for patients with diabetic peripheral neuropathic pain: a 6-month open-label safety study. Pain Med 7:373-385, 2006

126. Rowbotham MC, Goli V, Kunz NR, Lei D: Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain 110:697-706, 2004

127. McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A: Anticonvulsant drugs for management of pain: a systematic review. BMJ 311:1047-1052, 1995

128. Gorson KC, Schott C, Herman R, Ropper AH, Rand WM: Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol Neurosurg Psychiatry 66:251-252, 1999

129. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux L, Garofalo E: Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 280:1831-1836, 1998

130. DeToledo JC, Toledo C, DeCerce J, Ramsay RE: Changes in body weight with chronic, high-dose gabapentin therapy. Ther Drug Monit 19:394-396, 1997

131. Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M: Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain 115:254-263, 2005

132. Richter RW, Portenoy R, Sharma U, LaMoreaux L, Bockbrader H, Knapp LE: Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain 6:253-260, 2005

133. Frampton JE, Scott LJ: Pregabalin: in the treatment of painful diabetic peripheral neuropathy. Drugs 64:2813-2820, 2004

134. Tarride JE, Gordon A, Vera-Llonch M, Dukes E, Rousseau C: Cost-effectiveness of pregabalin for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia: a Canadian perspective. Clin Ther 28:1922-1934, 2006

135. rice A, Barlow P, Pittenger G, Simmons K, Vinik A: Topiramate Improves Skin Blood Flow, Epidermal Nerve Fiber Morphology, Neuropathy and the Metabolic Syndrome in Patients with Diabetes (Abstract). Lancet Neurology 2006

136. Vinik A: CLINICAL REVIEW: Use of antiepileptic drugs in the treatment of chronic painful diabetic neuropathy. J Clin Endocrinol Metab 90:4936-4945, 2005

137. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL: Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 352:1324-1334, 2005

138. Vinik EJ, Hayes RP, Oglesby A, Bastyr E, Barlow P, Ford-Molvik SL, Vinik AI: The development and validation of the Norfolk QOL-DN, a new measure of patients' perception of the effects of diabetes and diabetic neuropathy. Diabetes Technol Ther 7:497-508, 2005

139. Cavanagh PR, Derr JA, Ulbrecht JS, Maser RE, Orchard TJ: Problems with gait and posture in neuropathic patients with insulin-dependent diabetes mellitus. Diabet Med 9:469-474, 1992

140. Liu-Ambrose T, Khan KM, Eng JJ, Janssen PA, Lord SR, McKay HA: Resistance and agility training reduce fall risk in women aged 75 to 85 with low bone mass: a 6-month randomized, controlled trial. J Am Geriatr Soc 52:657-665, 2004

141. Somers DL, Somers MF: Treatment of neuropathic pain in a patient with diabetic neuropathy using transcutaneous electrical nerve stimulation applied to the skin of the lumbar region. Phys Ther 79:767-775, 1999

142. Cornblath DR, Vinik A, Feldman E, Freeman R, Boulton AJ: Surgical decompression for diabetic sensorimotor polyneuropathy. Diabetes Care 30:421-422, 2007

143. Vinik, A. I., Maser, R. E., Mitchell, B. D., and Freeman, R. Diabetic Autonomic Neuropathy. Diabetes Care 26(5), 1553-1579. 2003.

144. Pfeifer MA, Weinberg CR, Cook DL, Reenan A, Halter JB, Ensinck JW: Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care 7:447-453, 1984

145. Stansberry KB, Hill MA, Shapiro SA, McNitt PM, Bhatt BA, Vinik AI: Impairment of peripheral blood flow responses in diabetes resembles an enhanced aging effect. Diabetes Care 20:1711-1716, 1997

146. Stansberry KB, Shapiro SA, Hill MA, McNitt PM, Meyer MD, Vinik AI: Impaired peripheral vasomotion in diabetes. Diabetes Care 19:715-721, 1996

147. Stansberry KB: Primary nociceptive afferents mediate the blood flow dysfunction in non-glabrous (hairy) skin of type 2 diabetes. Diabetes Care 22:1549-1554, 1999

148. Haak ES, Usadel KH, Kohleisen M, Yilmaz A, Kusterer K, Haak T: The effect of alpha-lipoic on the neurovascular reflex arc in patients with diabetic neuropathy assessed by capillary microscopy. Microvasc Res 58:28-34, 1999

149. Ziegler D: Diabetic cardiovascular autonomic neuropathy: prognosis, diagnosis and treatment. Diabetes Metabolism Rev 10:339-383, 1994

150. Valensi P: Diabetic autonomic neuropathy: what are the risks? Diabets Metab 24:66-72, 1998

151. Mancia G, Paleari F, Parati G: Early diagnosis of diabetic autonomic neuropathy: present and future approaches. Diabetologia 40:482-484, 1997

152. Vinik AI, Maser RE, Nakave AA: Diabetic Cardiovascular Autonomic Nerve Dysfunction. Endocrine Today 2007

153. Karamitsos DT, Didangelos TP, Athyros VG, Kontopoulos AG: The natural history of recently diagnosed autonomic neuropathy over a period of 2 years. Diabetes Res Clin Pract 42:55-63, 1998

154. Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, Taillefer R, Wittlin SD, Heller GV, Filipchuk N, Engel S, Ratner RE, Iskandrian AE: Detection of Silent Myocardial Ischemia in Asymptomatic Diabetic Subjects: The DIAD study. Diabetes Care 27:1954-1961, 2004

155. Ziegler D, Gries FA: Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes 46 [Suppl 2]:S62-S66, 1997

156. Athyros VG, Didangelos TP, Karamitsos DT, Papageorgiou AA, Boudoulas H, Kontopoulos AG: Long-term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy. Acta Cardiol 53:201-209, 1998

157. Gaede P, Vedel P, Parving HH, Pedersen O: Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomized study. Lancet 353:617-622, 1999

158. Malmberg K, Norhammar A, Wedel H, Ryden L: Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 99:2626-2632, 1999

159. Kendall DM, Rooney DP, Smets YF, Salazar Bolding L, Robertson RP: Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy. Diabetes 46:249-257, 1997

160. Burger AJ, Weinrauch LA, D'Elia JA, Aronson D: Effects of glycemic control on heart rate variability in type I diabetic patients with cardiac autonomic neuropathy. Am J Cardiol 84:687-691, 1999

161. Laederach-Hofmann K, Weidmann P, Ferrari P: Hypovolemia contributes to the pathogenesis of orthostatic hypotension in patients with diabetes mellitus. Am J Med 106:50-58, 1999

162. Denq JC, Opfer-Gehrking TL, Giuliani M, Felten J, Convertino VA, Low PA: Efficacy of compression of different capacitance beds in the amelioration of orthostatic hypotension. Clin Auton Res 7:321-326, 1997

163. Annese V, Bassotti G, Caruso N, De Cosmo S, Gabbrielli A, Modoni S, Frusciante V, Andriulli A: Gastrointestinal motor dysfunction, symptoms, and neuropathy in noninsulin-dependent (type 2) diabetes mellitus. J Clin Gastroenterol 29:171-177, 1999

164. Melga P, Mansi C, Ciuchi E, Giusti R, Sciaba L, Prando R: Chronic administration of levosulpiride and glycemic control in IDDM patients with gastroparesis. Diabetes Care 20:55-58, 1997

165. Stacher G, Schernthaner G, Francesconi M, Kopp HP, Bergmann H, Stacher-Janotta G, Weber U: Cisapride versus Placebo for 8 weeks on glycemic control and gastric emptying in insulin-dependent diabetes: a double blind cross-over trial. J Clin Endocrinol Metab 84:2357-2362, 1999

166. Barone JA: Domperidone: a peripherally acting dopamine2-receptor antagonist. Ann Pharmacother 33:429-440, 1999

167. Silvers D, Kipnes M, Broadstone V, Patterson D, Quigley EM, McCallum R, Leidy NK, Farup C, Liu Y, Joslyn A: Domperidone in the management of symptoms of diabetic gastroparesis: efficacy, tolerability, and quality-of-life outcomes in a multicenter controlled trial. DOM-USA-5 Study Group. Clin Ther 20:438-453, 1998

168. Erbas T, Varoglu E, Erbas B, Tastekin G, Akalin S: Comparison of metoclopramide and erythromycin in the treatment of diabetic gastroparesis. Diabetes Care 16:1511-1514, 1993

169. Abell TL, Bernstein RK, Cutts T, Farrugia G, Forster J, Hasler WL, McCallum RW, Olden KW, Parkman HP, Parrish CR, Pasricha PJ, Prather CM, Soffer EE, Twillman R, Vinik AI: Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil 18:263-283, 2006

170. Vinik AI, Richardson D: Erectile Dysfunction in Diabetes. Diabetes Reviews 6:16-33, 1998

171. Vinik AI, Richardson D: Erectile Dysfunction in Diabetes:Pills for Penile Failure. Clinica Diabetes 16:108-119, 1998

172. Rendell MS, Rajfer J, Wicker PA, Smith MD: Sildenafil Diabetes Study Group. Sildenafil for treatment of erectile dysfunction in men with diabetes: a readomized controlled trial. JAMA 281:421-426, 1999

173. Boulton AJ, Selam JL, Sweeney M, Ziegler D: Sildenafil citrate for the treatment of erectile dysfunction in men with Type II diabetes mellitus. Diabetologia 44:1296-1301, 2001

174. Saenz de Tejada I, Anglin G, Knight JR, Emmick JT: Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care 25:2159-2164, 2002

175. Goldstein I, Young JM, Fischer J, Bangerter K, Segerson T, Taylor T: Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 26:777-783, 2003

176. Enzlin, P., Mathieu, C., Vanderschueren, D., and Demyttenaere, K. Diabetes mellitus and female sexuality: a review of 25 years' research. Diabet Med 15(10), 809-815. 1998.

177. Shaw JE, Abbott CA, Tindle K, Hollis S, Boulton A: A randomised controlled trial of topical glycopyrrolate, the first specific treatment for diabetic gustatory sweating. Diabetologia 40:299-301, 1997

178. Edick CM: Oral glycopyrrolate for the treatment of diabetic gustatory sweating. Ann Pharmacother 39:1760, 2005

179. Meyer C, Hering BJ, Grossmann R, Brandhorst H, Brandhorst D, Gerich J, Federlin K, Bretzel RG: Improved glucose counterregulation and autonomic symptoms after intraportal islet transplants alone in patients with long-standing type I diabetes mellitus. Transplantation 66:233-240, 1998

180. Vinik A: Diagnosis and Management of Diabetic Neuropathy. Clinics in Geriatric Medicine 15:293-319, 1999

181. Shaw JE, Parker R, Hollis S, Gokal R, Boulton A: Gustatory sweating in diabetes mellitus. Diabet Med 13:1033-1037, 1996

 

 

 

Footnotes

  1. Vinik AI, Mitchell BD, Leichter SB, Wagner AL, O'Brian JT, Georges LP: Epidemiology of the Complications of Diabetes. In Diabetes: Clinical Science in Practice. Leslie RDG, Robbins DC, Eds. Cambridge, United Kingdom, Cambridge University Press, 1995, p. 221-287
  2. Holzer SE, Camerota A, Martens L, Cuerdon T, Crystal P, Zagari M: Costs and duration of care for lower extremity ulcers in patients with diabetes. Clin Ther 20:169-181, 1998
  3. Holzer SE, Camerota A, Martens L, Cuerdon T, Crystal P, Zagari M: Costs and duration of care for lower extremity ulcers in patients with diabetes. Clin Ther 20:169-181, 1998
  4. Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW: Assessment and management of foot disease in patients with diabetes. N Engl J Med 331:854-860, 1994
  5. Herman WH, Kennedy L: Underdiagnosis of peripheral neuropathy in type 2 diabetes. Diabetes Care 28:1480-1481, 2005
  6. Herman WH, Kennedy L: Underdiagnosis of peripheral neuropathy in type 2 diabetes. Diabetes Care 28:1480-1481, 2005
  7. Holzer SE, Camerota A, Martens L, Cuerdon T, Crystal P, Zagari M: Costs and duration of care for lower extremity ulcers in patients with diabetes. Clin Ther 20:169-181, 1998
  8. Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW: Assessment and management of foot disease in patients with diabetes. N Engl J Med 331:854-860, 1994
  9. Young MJ, Boulton AJM, MacLeod AF, Williams DRR, Sonksen PH: A multicenter study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 36:1-5, 1993
  10. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton III LJ: The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: The Rochester Diabetic Neuropathy Study. Neurology 43:817-824, 1993
  11. Vinik A: Diabetic Neuropathy: Pathogenesis and Therapy. Am J Med 107 (2B):17S-26S, 1999
  12. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton III LJ: The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: The Rochester Diabetic Neuropathy Study. Neurology 43:817-824, 1993
  13. Armstrong DG, Lavery LA, Harkless LB: Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care 21:855-859, 1998
  14. Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW: Assessment and management of foot disease in patients with diabetes. N Engl J Med 331:854-860, 1994
  15. Vinik, E., Hayes, R., Oglesby, A., Bastyr, E., Barlow, P., Ford-Molvik, S., and Vinik, A. The Development and validation of the Norfolk QOL-DN a New Measure of patients' Perception of the Effects of Diabetes and Diabetic Neuropathy. Diabetes Technol.Ther 7 (3), 497-508. 2005.
  16. Levitt NS, Stansberry KB, Wychanck S, Vinik AI: Natural progression of autonomic neuropathy and autonomic function tests in a cohort of IDDM. Diabetes Care 19:751-754, 1996
  17. Rathmann W, Ziegler D, Jahnke M, Haastert B, Gries FA: Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diabet Med 10:820-824, 1993
  18. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 27:1458-1486, 2004
  19. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 27:1458-1486, 2004
  20. Dyck, P. J. Severity and staging of diabetic polyneuropathy. Textbook of Diabetic Neuropathy , 170-175. 2003. Thieme, Stuttgart.
  21. Thomas PK: Classification, differential diagnosis, and staging of diabetic peripheral neuropathy. Diabetes 46 Suppl 2:S54-S57, 1997
  22. Vinik A, Ullal J, Parson HK, Casellini CM: Diabetic neuropathies: clinical manifestations and current treatment options. Nat Clin Pract Endocrinol Metab 2:269-281, 2006
  23. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D: Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 28:956-962, 2005
  24. Vinik AI, Mehrabyan A: Diabetic neuropathies. Med Clin North Am 88:947-99, xi, 2004
  25. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 27:1458-1486, 2004
  26. Watkins PJ: Progression of diabetic autonomic neuropathy. Diabet Med 10 [Suppl 2]:77S-78S, 1993
  27. DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 329:977-986, 1993
  28. DCCT Research Group: The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 122:561-568, 1995
  29. Ziegler D, Cicmir I, Mayer P, Wiefels K, Gries FA: Somatic and autonomic nerve function during the first year after diagnosis of type 1 (insulin-dependent) diabetes. Diabetes Res 7:123-127, 1988
  30. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, Uusitupa M: Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333:89-94, 1995
  31. Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton LJ, O'Brien PC, Litchy WJ, Windebank AJ, Smith BE, Low PA: The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology 41:799-807, 1991
  32. Casellini CM, Barlow PM, Rice AL, Casey M, Simmons K, Pittenger G, Bastyr EJ, III, Wolka AM, Vinik AI: A 6-Month, Randomized, Double-Masked, Placebo-Controlled Study Evaluating the Effects of the Protein Kinase C-{beta} Inhibitor Ruboxistaurin on Skin Microvascular Blood Flow and Other Measures of Diabetic Peripheral Neuropathy. Diabetes Care 30:896-902, 2007
  33. Pittenger G, Simmons K, Anandacoomaraswamy D, rice A, Barlow P, Vinik A: Topiramate improves intraepidermal nerve fiber morphology and quantitative neuropathy measures in diabetic neuropathy patients (Abstract). J.Peripher.Nerve System 10 (Suppl 1) : 2005
  34. Pittenger GL, Ray M, Burcus NI, McNulty P, Basta B, Vinik AI: Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and nondiabetic patients. Diabetes Care 27:1974-1979, 2004
  35. Sinnreich M, Taylor BV, Dyck PJ: Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 11:63-79, 2005
  36. Vinik A, Ullal J, Parson HK, Casellini CM: Diabetic neuropathies: clinical manifestations and current treatment options. Nat Clin Pract Endocrinol Metab 2:269-281, 2006
  37. Vinik AI, Holland MT, LeBeau JM, Liuzzi FJ, Stansberry KB, Colen LB: Diabetic neuropathies. Diabetes Care 15:1926-1975, 1992
  38. Vinik AI, Mehrabyan A: Diabetic neuropathies. Med Clin North Am 88:947-99, xi, 2004
  39. Vinik A, Mehrabyan A, Colen L, Boulton A: Focal entrapment neuropathies in diabetes. Diabetes Care 27:1783-1788, 2004
  40. Wilbourn, A. J. Diabetic entrapment and compression neuropathies. Dyck PJ, Thomas PK (EDS) Diabetic Neuropathy , 481-508. 1999. Philadelphia, Saunders.
  41. Watanabe K, Hagura R, Akanuma Y, Takasu T, Kajinuma H, Kuzuya N, Irie M: Characteristics of cranial nerve palsies in diabetic patients. Diabetes Res Clin Pract 10:19-27, 1990
  42. Perkins, B., Olaleye, D., and Bril, V. Carpal Tunnel Syndrome in Patients with Diabetic Polyneuropathy. Diabetes Care 25, 565-569. 2002.
  43. Vinik A, Mehrabyan A, Colen L, Boulton A: Focal entrapment neuropathies in diabetes. Diabetes Care 27:1783-1788, 2004
  44. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 27:1458-1486, 2004
  45. Vinik AI, Mehrabyan A: Diabetic neuropathies. Med Clin North Am 88:947-99, xi, 2004
  46. Dawson DM: Entrapment neuropathies of the upper extremities. N Engl J Med 329:2013-2018, 1993
  47. Llewelyn JG, Thomas PK, King RH: Epineurial microvasculitis in proximal diabetic neuropathy. J Neurol 245:159-165, 1998
  48. James, P., Dyck, B., and Windenbank, A. Diabetic and Nondiabetic Lumbosacral Radiculoplexus Neuropathy: New Insights into Pathophysiology. Muscle & Nerve 25, 477-491. 2002.
  49. Vinik AI, Pittenger GL, Milicevic Z, Cuca J: Autoimmune Mechanisms in the Pathogenesis of Diabetic Neuropathy. In Molecular Mechanisms of Endocrine and Organ Specific Autoimmunity. 1st ed. Eisenbarth RG, Ed. Georgetown, Landes Company, 1998, p. 217-251
  50. Steck AJ, Kappos L: Gangliosides and autoimmune neuropathies: classification and clinical aspects of autoimmune neuropathies. J Neurol Neurosurg Psychiatry 57 [Suppl]:26-28, 1994
  51. Watanabe K, Hagura R, Akanuma Y, Takasu T, Kajinuma H, Kuzuya N, Irie M: Characteristics of cranial nerve palsies in diabetic patients. Diabetes Res Clin Pract 10:19-27, 1990
  52. Perkins, B., Olaleye, D., and Bril, V. Carpal Tunnel Syndrome in Patients with Diabetic Polyneuropathy. Diabetes Care 25, 565-569. 2002.
  53. Said G, Goulon-Goreau C, Lacroix C, Moulonguet A: Nerve biopsy findings in different patterns of proximal diabetic neuropathy. Ann Neurol 35:559-569, 1994
  54. Sander HW, Chokroverty S: Diabetic amyotrophy: current concepts. Semin Neurol 16:173-178, 1996
  55. Krendel DA, Costigan DA, Hopkins LC: Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 52:1053-1061, 1995
  56. Britland ST, Young RJ, Sharma AK, Clarke BF: Acute and remitting painful diabetic polyneuropathy: a comparison of peripheral nerve fibre pathology. Pain 48:361-370, 1992
  57. Sharma, K., Cross, J., Farronay, O., Ayyar, D., Sheber, R., and Bradley, W. Demyelinating neuropathy in diabetes mellitus. Arch Neurol 59, 758-765. 2002.
  58. Krendel DA, Zacharias A, Younger DS: Autoimmune diabetic neuropathy. Neurol Clin 15:959-971, 1997
  59. Milicevic Z, Newlon PG, Pittenger GL, Stansberry KB, Vinik AI: Anti-ganglioside GM1 antibody and distal symmetric "diabetic polyneuropathy" with dominant motor features. Diabetologia 40:1364-1365, 1997
  60. Vinik AI, Pittenger GL, Milicevic Z, Cuca J: Autoimmune Mechanisms in the Pathogenesis of Diabetic Neuropathy. In Molecular Mechanisms of Endocrine and Organ Specific Autoimmunity. 1st ed. Eisenbarth RG, Ed. Georgetown, Landes Company, 1998, p. 217-251
  61. Ayyar DR, Sharma KR: Chronic inflammatory demyelinating polyradiculoneuropathy in diabetes mellitus. Curr Diab Rep 4:409-412, 2004
  62. Krendel DA, Costigan DA, Hopkins LC: Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 52:1053-1061, 1995
  63. Barada A, Reljanovic M, Milicevic Z, Ljubic S, Car N, Benko B, Vinik AI, Metelko Z: Proximal Diabetic Neuropathy-Response To Immunotherapy (Abstract). Diabetes 48 [Suppl 1]:A148, 1999
  64. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 27:1458-1486, 2004
  65. Boulton AJ, Malik RA: Diabetic neuropathy. Med Clin North Am 82:909-929, 1998
  66. Thomas PK: Classification, differential diagnosis, and staging of diabetic peripheral neuropathy. Diabetes 46 Suppl 2:S54-S57, 1997
  67. Bird SJ, Brown MJ: The clinical spectrum of diabetic neuropathy. Semin Neurol 16:115-122, 1996
  68. Oyibo SO, Prasad YD, Jackson NJ, Jude EB, Boulton AJ: The relationship between blood glucose excursions and painful diabetic peripheral neuropathy: a pilot study. Diabet Med 19:870-873, 2002
  69. Tesfaye S, Malik R, Harris N, Jakubowski JJ, Mody C, Rennie IG, Ward JD: Arterio-venous shunting and proliferating new vessels in acute painful neuropathy of rapid glycaemic control (insulin neuritis). Diabetologia 39:329-335, 1996
  70. Sinnreich M, Taylor BV, Dyck PJ: Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 11:63-79, 2005
  71. Oyibo SO, Prasad YD, Jackson NJ, Jude EB, Boulton AJ: The relationship between blood glucose excursions and painful diabetic peripheral neuropathy: a pilot study. Diabet Med 19:870-873, 2002
  72. Archer AG, Watkins PJ, Thomas PK, Sharma AK, Payan J: The natural history of acute painful neuropathy in diabetes mellitus. J Neurol Neurosurg Psychiatry 46:491-499, 1983
  73. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 27:1458-1486, 2004
  74. Sinnreich M, Taylor BV, Dyck PJ: Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 11:63-79, 2005
  75. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, Uusitupa M: Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333:89-94, 1995
  76. Harris M, Eastman R, Cowie C: Symptoms of sensory neuropathy in adults with NIDDM in the U.S. population. Diabetes Care 16:1446-1452, 1993
  77. Singleton JR, Smith AG, Bromberg MB: Painful sensory polyneuropathy associated with impaired glucose tolerance. Muscle Nerve 24:1225-1228, 2001
  78. Singleton JR, Smith AG, Bromberg MB: Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 24:1448-1453, 2001
  79. Novella SP, Inzucchi SE, Goldstein JM: The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 24:1229-1231, 2001
  80. Sumner, C., Sheth, S., Griffin, J., Cornblath, D., and Polydefkis, M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology , 108-111. 2003
  81. Pittenger GL, Ray M, Burcus NI, McNulty P, Basta B, Vinik AI: Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and nondiabetic patients. Diabetes Care 27:1974-1979, 2004
  82. Dyck PJ, Lais A, Karnes JL, O'Brien P, Rizza R: Fiber loss is primary and multifocal in sural nerves in diabetic polyneuropathy. Ann Neurol 19:425-439, 1986
  83. Cavanagh PR, Simoneau GG, Ulbrecht JS: Ulceration, unsteadiness, and uncertainty: the biomechanical consequences of diabetes mellitus. J Biomech 26 Suppl 1:23-40:23-40, 1993
  84. Katoulis EC, Ebdon-Parry M, Lanshammar H, Vileikyte L, Kulkarni J, Boulton AJ: Gait abnormalities in diabetic neuropathy. Diabetes Care 20:1904-1907, 1997
  85. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton III LJ: The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: The Rochester Diabetic Neuropathy Study. Neurology 43:817-824, 1993
  86. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 27:1458-1486, 2004
  87. Sinnreich M, Taylor BV, Dyck PJ: Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 11:63-79, 2005
  88. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D: Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 28:956-962, 2005
  89. Bourcier ME, Ullal J, Parson HK, Dublin CB, Witherspoon CA, Ward SA, Vinik AI: Diabetic peripheral neuropathy: how reliable is a homemade 1-g monofilament for screening? J Fam Pract 55:505-508, 2006
  90. Kumar S, Fernando DJ, Veves A, Knowles EA, Young MJ, Boulton AJ: Semmes-Weinstein monofilaments: a simple, effective and inexpensive screening device for identifying diabetic patients at risk of foot ulceration. Diabetes Res Clin Pract 13:63-67, 1991
  91. Armstrong DG, Lavery LA, Vela SA, Quebedeaux TL, Fleischli JG: Choosing a practical screening instrument to identify patients at risk for diabetic foot ulceration. Arch Intern Med 158:289-292, 1998
  92. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D: Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 28:956-962, 2005
  93. Vinik AI, Suwanwalaikorn S, Stansberry KB, Holland MT, McNitt PM, Colen LE: Quantitative measurement of cutaneous perception in diabetic neuropathy. Muscle Nerve 18:574-584, 1995
  94. Abbott CA, Carrington AL, Ashe H, Bath S, Every LC, Griffiths J, Hann AW, Hussein A, Jackson N, Johnson KE, Ryder CH, Torkington R, Van Ross ER, Whalley AM, Widdows P, Williamson S, Boulton AJ: The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med 19:377-384, 2002
  95. Dyck PJ, Melton LJ, III, O'Brien PC, Service FJ: Approaches to improve epidemiological studies of diabetic neuropathy: insights from the Rochester Diabetic Neuropathy Study. Diabetes 46 Suppl 2:S5-S8, 1997
  96. Vinik AI, Suwanwalaikorn S, Stansberry KB, Holland MT, McNitt PM, Colen LE: Quantitative measurement of cutaneous perception in diabetic neuropathy. Muscle Nerve 18:574-584, 1995
  97. Dyck PJ, Dyck PJ, Larson TS, O'Brien PC, Velosa JA: Patterns of quantitative sensation testing of hypoesthesia and hyperalgesia are predictive of diabetic polyneuropathy: a study of three cohorts. Nerve growth factor study group. Diabetes Care 23:510-517, 2000
  98. Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJ: Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care 21:1071-1075, 1998
  99. Yarnitsky D, Sprecher E: Thermal testing: normative data and repeatability for various test algorithms. J Neurol Sci 125:39-45, 1994
  100. Shy, M. E., Frohman, E. M., So, Y., Arezzo, J. C., Cornblath, D. C., Giuliani, M. J., and the subcommittee of the American Academy of Neurology. Quantitative sensory testing. Neurology 602, 898-906. 2003.
  101. Consensus statement: Report and recommendations of the San Antonio conference on diabetic neuropathy. American Diabetes Association American Academy of Neurology. Diabetes Care 11:592-597, 1988
  102. Diabetic polyneuropathy in controlled clinical trials: Consensus Report of the Peripheral Nerve Society. Ann Neurol 38:478-482, 1995
  103. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, Uusitupa M: Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333:89-94, 1995
  104. DCCT Research Group: The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 122:561-568, 1995
  105. Pittenger G, Simmons K, Anandacoomaraswamy D, rice A, Barlow P, Vinik A: Topiramate improves intraepidermal nerve fiber morphology and quantitative neuropathy measures in diabetic neuropathy patients (Abstract). J.Peripher.Nerve System 10 (Suppl 1) : 2005
  106. Pittenger GL, Ray M, Burcus NI, McNulty P, Basta B, Vinik AI: Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and nondiabetic patients. Diabetes Care 27:1974-1979, 2004
  107. Sinnreich M, Taylor BV, Dyck PJ: Diabetic neuropathies. Classification, clinical features, and pathophysiological basis. Neurologist 11:63-79, 2005
  108. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM: Diabetic somatic neuropathies. Diabetes Care 27:1458-1486, 2004
  109. Vinik A, Mehrabyan A, Colen L, Boulton A: Focal entrapment neuropathies in diabetes. Diabetes Care 27:1783-1788, 2004
  110. Pittenger GL, Ray M, Burcus NI, McNulty P, Basta B, Vinik AI: Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and nondiabetic patients. Diabetes Care 27:1974-1979, 2004
  111. Kennedy WR, Wendelschafer-Crabb G, Johnson T: Quantitation of epidermal nerves in diabetic neuropathy. Neurology 47:1042-1048, 1996
  112. Polydefkis M, Hauer P, Griffin JW, McArthur JC: Skin biopsy as a tool to assess distal small fiber innervation in diabetic neuropathy. Diabetes Technol Ther 3:23-28, 2001
  113. Smith AG, Russell J, Feldman EL, Goldstein J, Peltier A, Smith S, Hamwi J, Pollari D, Bixby B, Howard J, Singleton JR: Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care 29:1294-1299, 2006
  114. Vileikyte L, Peyrot M, Bundy C, Rubin RR, Leventhal H, Mora P, Shaw JE, Baker P, Boulton AJ: The development and validation of a neuropathy- and foot ulcer-specific quality of life instrument. Diabetes Care 26:2549-2555, 2003
  115. Vinik, E., Hayes, R., Oglesby, A., Bastyr, E., Barlow, P., Ford-Molvik, S., and Vinik, A. The Development and validation of the Norfolk QOL-DN a New Measure of patients' Perception of the Effects of Diabetes and Diabetic Neuropathy. Diabetes Technol.Ther 7 (3), 497-508. 2005.
  116. Cameron, N. E., Eaton, S. E. M., Cotter, M. A., and Tesfaye, S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 44, 1973-1988. 2001.
  117. DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 329:977-986, 1993
  118. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. [published erratum appears in BMJ 1999 Jan 2;318(7175):29] . BMJ 317:703-713, 1998
  119. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854-865, 1998
  120. Gaede P, Vedel P, Larsen N, Jensen G, Parving H, Pedersen O: Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes. N Engl J Med383-393, 2003
  121. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH: Vascular risk factors and diabetic neuropathy. N Engl J Med 352:341-350, 2005
  122. Gaede P, Vedel P, Larsen N, Jensen G, Parving H, Pedersen O: Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes. N Engl J Med383-393, 2003
  123. Kamiya H, Zhang W, Sima AA: C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes. Ann Neurol 56:827-835, 2004
  124. Stevens MJ, Zhang W, Li F, Sima AA: C-peptide corrects endoneurial blood flow but not oxidative stress in type 1 BB/Wor rats. Am J Physiol Endocrinol Metab 287:E497-E505, 2004
  125. Ekberg K, Brismar T, Johansson BL, Jonsson B, Lindstrom P, Wahren J: Amelioration of sensory nerve dysfunction by C-Peptide in patients with type 1 diabetes. Diabetes 52:536-541, 2003
  126. Johansson BL, Borg K, Fernqvist-Forbes E, Odergren T, Remahl S, Wahren J: C-peptide improves autonomic nerve function in IDDM patients. Diabetologia 39:687-695, 1996
  127. Ekberg K, Brismar T, Johansson BL, Lindstrom P, Juntti-Berggren L, Norrby A, Berne C, Arnqvist HJ, Bolinder J, Wahren J: C-Peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy. Diabetes Care 30:71-76, 2007
  128. Ziegler D, Sohr CG, Nourooz-Zadeh J: Oxidative stress and antioxidant defense in relation to the severity of diabetic polyneuropathy and cardiovascular autonomic neuropathy. Diabetes Care 27:2178-2183, 2004
  129. Miyauchi Y, Shikama H, Takasu T, Okamiya H, Umeda M, Hirasaki E, Ohhata I, Nakayama H, Nakagawa S: Slowing of peripheral motor nerve conduction was ameliorated by aminoguanidine in streptozocin-induced diabetic rats. Eur J Endocrinol 134:467-473, 1996
  130. Haupt E, Ledermann H, Kopcke W: Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study). Int J Clin Pharmacol Ther 43:71-77, 2005
  131. Stracke H, Lindemann A, Federlin K: A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes 104:311-316, 1996
  132. Greene DA, Arezzo JC, Brown MB: Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology 53:580-591, 1999
  133. Hotta, N., Toyota, T., Matsuoka, K., Shigeta, Y., Kikkawa, R., Kaneko, T., Takahashi, A., Sugimura, K., Koike, Y., Ishii, J., Sakamoto, N., and The, S. N. K. Clinical Efficacy of Fidarestat, a Novel Aldose Reductase Inhibitor, for diabetic Peripheral Neuropathy. Diabetes Care 24, 1776-1782. 2001
  134. Hotta N, Shigeta Y, Sakamoto N: Long-term Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy: A 3-y Multicenter Comparative Study, ARI-Diabetes Complications Trial (ADCT) (Abstract). Diabetes 54 :A213, 2005
  135. Bril V, Buchanan RA: Long-term effects of ranirestat (AS-3201) on peripheral nerve function in patients with diabetic sensorimotor polyneuropathy. Diabetes Care 29:68-72, 2006
  136. Vinik AI, Mehrabyan A: Diabetic neuropathies. Med Clin North Am 88:947-99, xi, 2004
  137. Keen H, Payan J, Allawi J, Walker J, Jamal GA, Weir AI, Henderson LM, Bissessar EA, Watkins PJ, Sampson M, Gale EA, Scarpello J, Boddie HG, Hardy KJ, Thomas PK, Misra P, Halonen JP: Treatment of Diabetic Neuropathy with - Linolenic Acid. Diabetes Care 16:8-15, 1993
  138. Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O'Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D: The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care 26:770-776, 2003
  139. Ruhnau, K. J., Meissner, H. P., Finn, R., Reljanovic, M., Lobisch, M., Schutte, K., Nehrdich, D., Tritschler, H., Mehnert, H., and Ziegler, D. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med 16(12), 1040-1043. 1999.
  140. Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, Gries FA: Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 38:1425-1433, 1995
  141. Reljanovic, M., Reichel, G., Rett, K., Lobisch, M., Schuette, K., Moller, W., Tritschler, H. J., and Mehnert, H. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res 31(3), 171-179. 1999.
  142. Ziegler D, Nowak H, Kempler P, Vargha P, Low PA: Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med 21:114-121, 2004
  143. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R: Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 29:2365-2370, 2006
  144. Ziegler D, Low PA, Boulton AJ, Vinik AI, Freeman R, Samigullin R, Tritschler H, Munzel U, Maus J, Schuette K, Dyck PJ: Effect of 4-Year Antioxidant Treatment with alpha-Lipoic Acid in Diabetic Polyneuropathy: The NATHAN 1 Trial. (Abstract). Diabetes 56:A2, 2007

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