Various peripheral neuropathies are associated with the different endocrinopathies (Table 21-1). In particular, peripheral neuropathy associated with diabetes mellitus (DM) is one of the most common causes worldwide.

DM is the most common endocrinopathy and can be separated into two major subtypes: (1) insulin-dependent DM (IDDM or type 1 DM) and (2) non–insulin-dependent DM (NIDDM or type 2 DM). DM is the most common cause of peripheral neuropathy in developed countries. DM is associated with several types of polyneuropathies: distal symmetric sensory or sensorimotor polyneuropathy, autonomic neuropathy, diabetic neuropathic cachexia (DNC), polyradiculoneuropathies, cranial neuropathies, and other mononeuropathies (Table 21-1).^1,2 The exact prevalence of each subtype of neuropathy among diabetic patients is not accurately known, but it has been estimated that between 5 and 66% of patients with diabetes develop a neuropathy.³ Diabetic neuropathy can occur in children and adults.⁴

Long-standing, poorly controlled DM, and the presence of retinopathy and nephropathy are risk factors for the development of peripheral neuropathy in diabetic patients.⁵ In a large community-based study, 1.3% of the population had DM (27% type 1 DM and 73% type 2 DM).⁵ Of these, approximately 66% of individuals with type 1 DM had some form of neuropathy: generalized polyneuropathy, 54%; asymptomatic median neuropathy at the wrist, 22%; symptomatic carpal tunnel syndrome, 11%; autonomic neuropathy, 7%; and various other mononeuropathies alone or in combination (3%) such as ulnar neuropathy, peroneal neuropathy, lateral femoral cutaneous neuropathy, and diabetic polyradiculoneuropathy. In the type 2 DM group, 45% had generalized polyneuropathy, 29% had asymptomatic median neuropathy at the wrist, 6% had symptomatic carpal tunnel syndrome, 5% had autonomic neuropathy, and 3% had other mononeuropathies/multiple mononeuropathies. Considering all forms of DM, 66% of patients had some objective signs of neuropathy, but only 20% of patients with DM were symptomatic from neuropathy.

DIABETIC DISTAL SYMMETRIC SENSORY AND SENSORIMOTOR POLYNEUROPATHY

Clinical Features

Distal symmetric sensory polyneuropathy (DSPN) is the most common form of diabetic neuropathy.^1,2 It is a length-dependent neuropathy in which affected individuals develop sensory loss beginning in the toes, which gradually progresses over time up the legs and into the fingers and arms.^6,7 When severe, a patient may also develop sensory loss in the trunk (chest and abdomen) in the midline that spreads out laterally toward the spine. Sensory loss is often accompanied by paresthesia, lancinating pains, burning, or a deep aching discomfort in 40–60% of patients with DSPN.^1,8 A severe loss of sensation can lead to increased risk of infection, ulceration, and Charcot joints. Patients with small fiber neuropathy can also develop symptoms and signs of an autonomic dysfunction, as the autonomic nervous system is mediated by small myelinated and unmyelinated nerve fibers. Poor control of DM and the presence of nephropathy correlate with an increased risk of developing or worsening of DSPN.^3,5

Neurological examination reveals loss of small fiber function (pain and temperature sensation) only or pan-modality sensory loss. Those individuals with large fiber sensory loss have reduced muscle stretch reflexes, particularly at the ankles, but reflexes can be normal in patients with only small fiber involvement or in patients whose neuropathy has not ascended far enough proximally to affect the reflex arc of the Achilles deep tendon reflex. Muscle strength and function are typically normal, although mild atrophy and weakness of foot intrinsics and ankle dorsiflexors may be detected. Because patients without motor symptoms or signs on clinical examination often still have electrophysiological evidence of subclinical motor involvement, the term “distal symmetric or length-dependent sensorimotor peripheral neuropathy” is also appropriate.⁹

Laboratory Features

DSPN can be the presenting manifestation of DM as many patients may be unaware of their abnormal glucose metabolism. There may be an increased risk of impaired glucose tolerance (IGT) on oral glucose tolerance test even in those individuals with normal fasting blood sugars (FBS) and hemoglobin A1 C levels. Some studies report IGT (defined as 2-hour glucose of >140 and <200 mg/dL) in as many as 36% and DM (defined as 2-hour glucose of >200 mg/dL or FBS of >126 mg/dL) in up to 31% of patients with sensory neuropathy.^10–12 In patients with painful sensory neuropathy, the incidence of IGT or DM may be even higher. Although we have been impressed with the prevalence of IGT in our patients with burning feet, the linkage of IGT with DSPN remains controversial as other authorities have not found an association.^13,14

Up to 50% of patients with DM have reduced sensory nerve action potential (SNAP) amplitudes and slow conduction velocities of the sural or plantar nerves, while up to 80% of symptomatic individuals have abnormal sensory nerve conduction studies (NCS).^1,15,16 Quantitative sensory testing may reveal reduced vibratory and thermal perception. Autonomic testing may also be abnormal, in particular quantitative sweat testing.¹⁷

Motor NCS are less severely affected than the sensory studies but still are frequently abnormal with low amplitudes and normal or only slightly prolonged distal latencies and slow nerve conduction velocities (NCVs).^1,15 Rarely, the NCV slowing can be within the “demyelinating range” (e.g., less than 30% below the lower limit of normal); however, conduction block and temporal dispersion are not usually appreciated.^15,18 Needle electromyography (EMG) examination may demonstrate fibrillation potentials, positive sharp waves, and large motor unit action potentials (MUAPs) in the distal muscles.

Histopathology

Nerve biopsies are not routinely done in patients with DSPN. In part, this is because of the nonspecific nature of the nerve pathology and the potential for poor wound healing in diabetics. If performed, nerve biopsy can reveal axonal degeneration, clusters of small regenerated axons, and segmental demyelination that is more pronounced distally, as expected in a length-dependent process (Fig. 21-1).¹⁷ An asymmetric loss of axons between and within nerve fascicles may be appreciated. There is often endothelial hyperplasia of epi- and endoneurial arterioles and capillaries along with redundant basement membranes around these small blood vessels and thickening of the basement membrane of the perineurial cells (Fig. 21-2).²⁰ In addition, perivascular infiltrate consisting predominantly of CD8+ T cells can sometimes be seen.

Nerve biopsies may appear normal in patients with pure small fiber neuropathy. However, skin biopsies can demonstrate a reduction of small myelinated intraepidermal nerve fibers in such cases.^21–23 Reduced intraepidermal nerve fiber densities correlate with impaired temperature thresholds on quantitative sensory testing (QST) and the duration of the DM.²³ Patients with IGT are more likely to have a predominantly small fiber neuropathy, compared to patients with DM, who have more involvement of large nerve fibers.¹²

Pathogenesis

The pathogenic basis for DSPN is unknown. Suspected pathogenic mechanisms include abnormalities in various metabolic processes, microangiopathic ischemia, and inflammation (Fig. 21-3).^1,19,24–27 In regard to aberrant metabolism, diabetes is associated with hyperglycemia, dyslipidemia, and impaired insulin signaling. Increased intracellular glucose may damage neurons by causing excessive glycolysis that overloads mitochondria, resulting in the production of reactive oxygen species (ROS).¹ Furthermore, polyol pathway activity may be increased leading to hyperosmolarity and oxidative stress. Hyperglycemia is also associated with glycosylation of reactive carbohydrate groups to various proteins, lipids, nucleic acids, and so-called glycation end products (AGEs), which impair their normal function.¹ Also, these AGEs may bind to a receptor (RAGE), which in turn, leads to activation of inflammatory cascades and oxidative stress. Increased free fatty acids and triglycerides bind to receptors on neurons and Schwann cells leading to increased oxidative stress and inflammation. Diminished insulin production (as seen in type 1 DM) and insulin resistance (seen in type 2 DM) may be associated with abnormal neurotrophic effects.¹

Treatment

The mainstay of treatment is tight control of glucose, as studies have shown that this can reduce the risk of developing neuropathy or improve the underlying neuropathy.^28–31 Pancreatic transplantation may stabilize or slightly improve sensory, motor, and autonomic function but is not a pragmatic solution for most patients.^17,30 More than 20 trials of aldose reductase inhibitors have been performed and most have been negative or associated with unacceptable side effect profiles.^2,32 However, a double-blind, placebo-controlled study of Fidarestat was associated with improvement of subjective symptoms and five of eight electrophysiological parameters.³³ Trials of neurotrophic growth factors have also been disappointing.^34,35 A double-blind study of alpha-lipoic acid, an antioxidant, found significant improvement in neuropathic sensory symptoms such as pain and several other neuropathic end points.³⁶

A variety of medications have been used to treat painful symptoms associated with DSPN, including antiepileptic medications, antidepressants, sodium channel blockers, and other analgesics with variable success (Table 21-2).^37–45 Our first step in patients with just distal leg pain is a trial of lidoderm patches on the feet, as this is associated with fewer systemic side effects. If this is insufficient or patients have more generalized pain, we often start gabapentin at a dose of 300 mg TID or pregabalin (50 mg TID). We typically go with gabapentin initially because it is less expensive. We gradually increase the dosage as tolerated and necessary. If this is still ineffective, we usually add an antidepressant medication: duloxetine (30–120 mg daily), venlafaxine (37.5–225 mg daily), or a tricyclic antidepressant medication (amitriptyline). For breakthrough pain, we prescribe tramadol 50 mg every 6 hours.⁴¹ If this does not control the pain, oxycodone, morphine, or dextromethorphan may be tried. In general, we prefer to limit opioid use to the nighttime, both in an attempt to improve sleep, and to limit opioid exposure and minimize tachyphylaxis. There is little evidence that oxcarbazepine, lamotrigine, topiramate, lacosamide, mexiletine. magnets, or Reiki therapy are of any significant benefit.^1,37,38

DIABETIC AUTONOMIC NEUROPATHY

Clinical Features

Autonomic neuropathy typically is seen in combination with DSPN and only rarely in isolation.^1,46,47 The autonomic neuropathy can manifest as abnormal sweating, dry feet, dysfunctional thermoregulation, dry eyes and mouth, pupillary abnormalities, cardiac arrhythmias, postural hypotension, gastrointestinal abnormalities (e.g., gastroparesis, postprandial bloating, chronic diarrhea, or constipation), and genitourinary dysfunction (e.g., impotence, retrograde ejaculation, and incontinence). Importantly, the presence of autonomic neuropathy doubles the risk of mortality.⁴⁸

Laboratory Features

Tests of autonomic function are generally abnormal, including sympathetic skin responses and quantitative sudomotor axon reflex testing.^46,47 Sensory and motor NCS generally demonstrate the same features described above with DSPN.

Histopathology

Degeneration of sympathetic and parasympathetic neurons along with inflammatory infiltrates within the ganglia have been appreciated.⁴⁹

Pathogenesis

The pathogenic basis for autonomic neuropathy is unknown but may be similar to DSPN.

Treatment

Pancreatic transplantation may stabilize or slightly improve autonomic function.¹⁷ In patients with symptomatic orthostatic hypotension, we try as many nonpharmacologic treatments as possible, including pressure stockings, small frequent meals, raising the head of the bed at night, and avoidance of alcohol. When drug treatment is required, we initiate treatment with fludrocortisone (starting at 0.1 mg BID) or midodrine (10 mg TID).⁴⁷ Pyridostigmine may also be helpful. It is important to note that asymptomatic standing time, rather than improvement in standing blood pressure, is the most important parameter to monitor. Nonsteroidal anti-inflammatory agents may also be of benefit. Metoclopramide is used to treat diabetic gastroparesis, while clonidine may help with persistent diarrhea. Sildenafil and other similar medications are used to treat erectile dysfunction.

DIABETIC NEUROPATHIC CACHEXIA

Clinical Features

DNC is very rare but can be the presenting manifestation of DM.^51–53 This form of diabetic neuropathy is more common in men (usually associated with type 2 DM) than in women (most cases associated with type 1 DM) and generally occurs in their sixth or seventh decade of life. Patients with DNC develop an abrupt onset of severe generalized painful paresthesias involving the trunk and all four limbs, usually setting off significant precipitous weight loss. Mild sensory loss may be detected on examination along with reduced muscle stretch reflexes. Weakness and atrophy are evident in some patients. DNC tends to gradually improve spontaneously, usually preceded by recovery of the weight loss. Rarely, DNC can recur.

Laboratory Features

Cerebrospinal fluid (CSF) protein may be increased. SNAPs may be absent or have very low amplitudes.^51,52 Normal or slightly diminished compound muscle action potential (CMAP) amplitudes with mild slowing of conduction velocities can also be observed. Needle EMG typically demonstrates evidence of active denervation in the form of fibrillation potentials and positive waves in affected muscles.

Histopathology

Nerve biopsies demonstrate severe loss of large myelinated axons with relative sparing of small myelinated and unmyelinated fibers.⁵²

Pathogenesis

The pathogenic basis for the disorder is not known.

Treatment

Most patients improve spontaneously, with control over the DM within 1–3 years. Symptomatic treatment of the painful paresthesias is the same as that described for DSPN.

DIABETIC POLYRADICULOPATHY OR RADICULOPLEXUS NEUROPATHY

Two categories of diabetic radiculoplexus neuropathy can be made on the basis of clinical differences: (1) the more common asymmetric, painful, radiculoplexus neuropathy (i.e., diabetic amyotrophy) and (2) the rare symmetric, relatively painless, radiculoplexus neuropathy.⁵⁴ The latter form is controversial. It may represent chronic inflammatory demyelinating polyneuropathy (CIDP) in a patient with diabetes, a distinct form of diabetic neuropathy, or may just fall within the spectrum of diabetic amyotrophy.