Introduction

Diabetic neuropathy is a common complication of diabetes. The goal of this chapter is to present the symptoms, understand the demographics, provide differential diagnosis and diagnostic criteria, explore treatment options, and understand disease prognosis. Diabetic amyotrophy is also discussed as a less frequent but potentially debilitating complication of diabetes. It refers to the weakness and pain, particularly along the lumbosacral plexus, which can be associated with diabetes. It can be idiopathic or related to diabetes. Diabetic amyotrophy is also known as Bruns-Garland syndrome, diabetic myelopathy, proximal diabetic neuropathy, diabetic lumbosacral plexopathy, or diabetic lumbosacral radiculoplexus neuropathy. It differs from peripheral neuropathy, which is commonly seen in diabetic patients, because it is specific to the proximal muscles. It can be associated with weakness and excruciating pain. Other causes can be idiopathic.

Presentation

Diabetic polyneuropathy can present at any point in patients with diabetes but is more common in patients who have had poorly controlled diabetes. It results from a loss of myelination in large and small nerve fibers. A decrease in myelination in small fibers can cause impairment in pain, light touch, and temperature. A decrease in myelination in large fibers can cause impairment in vibratory sense and proprioception. Diabetic polyneuropathy follows a stocking-glove-like pattern, but neuropathy can ascend.

Demographics

Diabetic neuropathy is a common complication of diabetes and is seen most commonly in the West. A landmark study done over 25 years showed that neuropathy most commonly occurs the longer the duration of diabetes, and by 25 years of having diabetes, 50% of people exhibit symptoms of neuropathy. The ethnic background can also influence symptoms. In the United Kingdom, it was seen that patients of South Asian descent often have symptoms of painful neuropathy. It has also been found that the worse the control of diabetes, the more likely the patients are to develop neuropathy. Neuropathy is much more common in patients with type 2 diabetes than in patients with type 1 diabetes.

Diabetic amyotrophy is more commonly seen in patients with long-standing type 2 diabetes. A prospective study on patients with diabetes showed that the mean age of diagnosis was 65 years and the mean duration of diabetes was 4 years when diabetic amyotrophy was diagnosed. These patients did not necessarily have poorly controlled diabetes. In fact, their mean A1C was 7.5. Most patients were older and had diabetes for longer. A gender or ethnic distribution was not seen. Weakness and pain were the main complaints. These patients were found to have weight loss. They ultimately required ambulatory aids, including wheelchair or cane.

Diagnostic Criteria

Many patients are diagnosed with diabetic neuropathy based only on their symptoms, and these may have a poor correlation to clinical neurologic abnormalities on physical examination. Historically, the diagnosis of diabetic neuropathy has been based on a set of symptoms and signs, such as loss of vibratory and/or light touch sensation, loss of lower extremity reflexes, and complaints of numbness and burning pain.

The first official meeting regarding diabetic neuropathy took place in 1988, where a group of diabetologists and neurologists proposed a comprehensive set of criteria, called the San Antonio Consensus statement, to diagnose diabetic neuropathy. These criteria were updated in 2009 in Toronto and are summarized in Table 10.1 .

Although the Toronto criteria are useful for research purposes, they are difficult to apply to clinical practice and are more suited for research. Therefore, several screening tests to diagnose diabetic neuropathy have been developed. The Michigan Neuropathy Screening Instrument (MNSI) is an assessment that has two parts; the first part is a patient questionnaire that requires at least 7 of 13 points to make a diagnosis of neuropathy. The second portion of the questionnaire is scored by a healthcare professional and is based on physical examination findings, with a score of three or more indicating neuropathy. The MNSI has been validated as a sensitive screening test for diabetic peripheral neuropathy (DPN) (see Table 10.2 ).

The diagnosis of diabetic amyotrophy is mainly clinical. If a diabetic patient has proximal weakness and/or pain, diabetic amyotrophy should be considered. Most patients with diabetic amyotrophy are known to have diabetes at diagnosis. Diagnosis of amyotrophy specifically involves a thorough physical examination and evaluation of muscle strength and sensation. Diagnosis also includes electrodiagnostic studies.

Risk Factors and Pathophysiology

The risk factors of neuropathy are not fully understood; they range from hyperglycemia to duration of diabetes, as well as hypertension, blood pressure, lipid levels, and obesity. The vast majority of theories regarding the mechanisms underlying hyperglycemia-induced diabetic neuropathy include vascular damage and focus on five major mechanisms: increased flux of glucose and other sugars through the polyol pathway, increased intracellular formation of advanced glycation end products (AGEs), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C (PKC) isoforms, and overactivity of the hexosamine pathway.

Experimental evidence shows that hyperglycemia, glucose toxicity, and impaired insulin signaling act in concert with other risk factors and activate several biochemical pathways that affect cellular metabolism. The changes in blood sugars promote structural changes such as segmental demyelination, axonal loss, and microangiopathy and induce dorsal root ganglia neuronal apoptosis, resulting in subsequent damage to and loss of myelinated and unmyelinated sensory fibers.

Metabolic disorders are the primary cause of diabetic neuropathy. Hyperglycemia, induced through decreased insulin secretion or insulin resistance, is responsible for the enhancement of the polyol pathway activity. This pathway is pathogenic primarily by increasing the turnover of cofactors such as nicotinamide adenine dinucleotide phosphate and nicotinamide adenine dinucleotide, which leads to a decrease in the reduction and regeneration of glutathione, as well as an increase of AGE production and activation of diacylglycerol and PKC isoforms. Depletion of glutathione could be the primary cause of oxidative stress and be related to the accumulation of toxic species. Oxidative stress could also be initiated by the autoxidation of glucose and their metabolites, increased intracellular formation of AGEs, increased expression of the receptor for AGEs and their activating ligands, altered mitochondrial function, activation of PKC isoforms, and overactivity of the hexosamine pathway.

Microvascular impairment also plays a role in diabetic neuropathic pain (DNP). Nerve ischemia occurs when peripheral perfusion is reduced. An increase in the wall thickness and hyalinization of the basal lamina of vessels that feed the peripheral nerves can cause nerve ischemia. Nerve ischemia can further decrease intraepidermal nerve fiber density. This leads to axonal retraction and regeneration and myelin sheath alteration.

In humans, observational studies have shown that hyperglycemia is critical for the development of DNP in both type 1 and type 2 diabetes. Surprisingly, the importance of hyperglycemia as an independent risk factor for diabetic DSP was not confirmed in a randomized controlled trial (RCT) until 1993, when the Diabetes Control and Complications Trial strongly demonstrated that intensive glycemic control is essential to preventing DNP in patients with type 1 diabetes.

The cause of diabetic amyotrophy is likely multifactorial. The proposed mechanisms include metabolic damage from hyperglycemia, ischemic, inflammatory, and immune mediated. Multiple studies have evaluated the type of injury at a pathologic level and have found multifocal fiber loss, perineural thickening, neovascularization, and impaired regeneration of nerve fibers. Experts have questioned hyperglycemia as a cause of diabetic amyotrophy. Studies have found that the majority of patients with diabetic amyotrophy did not have significantly worse glycemic control than those without the disorder. Those with diabetic amyotrophy also usually do not have many of the chronic complications typically associated with poor glycemic control, such as retinopathy or nephropathy. Also, the nerve damage of diabetic amyotrophy is unlike the microvessel disease (deterioration of pericytes and reduplication of basement membranes) associated with chronic hyperglycemia. An alternative explanation implicates an immune-mediated microvasculitis, causing inflammatory injury and microinfarcts of nerves. The degree of inflammation of biopsied nerves in subjects with diabetic amyotrophy has been found to be significantly greater than in healthy controls and in patients with diabetic polyneuropathy. Consequently, the leading explanation as to the cause of diabetic amyotrophy is ischemic injury secondary to a nonsystemic vasculitis of nerve roots, lumbosacral plexus, and peripheral nerves.

Differential Diagnosis

It is important to consider a differential diagnoses for diabetic neuropathy because similar symptoms may be caused by drug use, such as alcohol, nitrofurantoin, and isoniazid. Heavy metals can also cause distal symmetric neuropathy. Other illnesses, such as pernicious anemia (vitamin B ₁₂ deficiency), chronic inflammatory demyelinating polyneuropathy, hypothyroidism, paraneoplastic syndromes from malignancy, Sjögren syndrome, vasculitides, Guillian-Barré syndrome, and uremia, need to be excluded through a thorough history, physical examination, and laboratory testing. Various studies have suggested that 10%–50% of individuals with diabetes may have an additional potential cause of a peripheral neuropathy and some may have more than one cause.

Diagnostic Tests

The MNSI and other screening assessments have demonstrated the need to combine history with physical examinations findings, to more accurately diagnosis diabetic neuropathy. Studies have shown that “numbness of the feet” is a poor indicator of polyneuropathy in patients with type 2 diabetes. An office neurologic examination is fast and simple but can have substantial variation between providers. It is important to standardize the examination as much as possible. It is recommended that a 128-Hz tuning fork be used when assessing vibration sense, as this has shown to have the best sensitivity for detecting neuropathy. Many prospective studies have confirmed that loss of pressure sensation using the 10-g monofilament is highly predictive of an ensuing foot ulcer. Screening for sensory loss with the 10-g monofilament has been validated in many studies, including the Seattle Diabetic Foot Study. Most experts recommend testing 10 sites on the feet with the monofilament. Using a 10-g monofilament can help predict foot ulceration, as can the Achilles reflex, but both may be insensitive to the early detection of neuropathy. Some experts have proposed that a 1-g monofilament could increase sensitivity of detecting early neuropathy from 60% to 90%. Although the monofilament assessment is an important and the most common way to evaluate diabetic neuropathy, a diagnosis should not rest solely on this test because studies have shown a wide range of sensitivity and specificity in detecting neuropathy.

Diabetic neuropathy involves a slowing of nerve conduction velocity as a result of demyelination and a decrease in nerve action potential amplitudes from a loss of axons. Although nerve conduction studies are the most objective noninvasive measure of neuropathy, in clinical practice they are not typically part of the diagnostic workup for diabetic neuropathy. One reason they are not useful in this context is that small nerve fibers, which are affected early in the disease course of diabetic neuropathy, do not contribute to the sensory action potential detected by routine nerve conduction studies. However, some advocate for their use if the etiology of the neuropathy is uncertain and if the distribution differs from the usual distal symmetric polyneuropathy of diabetes. Electrodiagnostic studies can help establish whether the neuropathy is the result of axonal neuropathy or demyelinating neuropathy, or both (mixed). Normal nerve conduction studies significantly decrease the possibility of peripheral neuropathy, whereas abnormal nerve conduction findings confirm the diagnosis.

Nerve biopsies can be useful when the etiology of a neuropathy is unclear or when treatments such as chemotherapy or drugs for autoimmune disorders are being considered. They are often used to diagnose cases of neuropathy related to vasculitis, sarcoidosis, amyloidosis, and CIDP. These neural biopsies are able to differentiate between causes. Sural and superficial fibular nerves are the ones usually biopsied. Epidermal skin biopsy can be performed in patients in whom small, unmyelinated nerve fibers are suspected to be the cause. Small nerve fiber damage may represent the earliest stages of some peripheral neuropathies and cannot be identified by electrodiagnostic studies. The majority of patients with diabetes experience a distal, symmetric polyneuropathy, and nerve biopsies are not necessary.