TABLE 21-1. NEUROPATHIES ASSOCIATED WITH ENDOCRINOPATHIESVarious 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.
TABLE 21-1. NEUROPATHIES ASSOCIATED WITH ENDOCRINOPATHIES
Diabetes Mellitus
Distal symmetric sensory and sensorimotor polyneuropathy
Autonomic neuropathy
Diabetic neuropathic cachexia
Polyradiculoplexus neuropathy
Mononeuropathy/multiple mononeuropathies
Acute treatment–induced painful neuropathy
Hypoglycemia/Hyperinsulinemia
Generalized sensory or sensorimotor polyneuropathy
Acromegaly
Generalized sensory or sensorimotor polyneuropathy
Carpal tunnel syndrome
Hypothyroidism
Carpal tunnel syndrome
Generalized sensory or sensorimotor polyneuropathy
DIABETIC NEUROPATHYDM 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.
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
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.
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.
Figure 21-1. Diabetic neuropathy. Sural nerve biopsy demonstrates asymmetric loss of myelinated nerve fibers between and within nerve fascicles (A). Higher power reveals loss of large and small fibers and active axonal degeneration (B). Plastic sections stained with toluidine blue.
Figure 21-2. Diabetic neuropathy. Sural nerve biopsy demonstrates marked loss of myelinated nerve fibers and blood vessels with markedly thickened basement membrane (arrowheads). Plastic sections stained with toluidine blue.
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
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
Figure 21-3. Mechanisms of diabetic neuropathy. Factors linked to type 1 diabetes (orange), type 2 diabetes (blue), and both (green) cause DNA damage, endoplasmic reticulum stress, mitochondrial complex dysfunction, apoptosis, and loss of neurotrophic signaling (A). This cell damage can occur in neurons, glial cells, and vascular endothelial cells, as well as trigger macrophage activation, all of which can lead to nerve dysfunction and neuropathy (B). The relative importance of the pathways in this network will vary with cell type, disease profile, and time. AGE, advanced glycation end products; LDL, low-density lipoprotein; HDL, high-density lipoprotein; FFA, free fatty acids; ROS, reactive oxygen species (red star); ER, endoplasmic reticulum; PI3 K, phosphatidylinositol-3-kinase; LOX1, oxidized LDL receptor 1; RAGE, receptor for advanced glycation end products; TLR4, toll-like receptor 4. (Reproduced with permission from Callaghan BC, Cheng HT, Stables CL, et al: Diabetic neuropathy: Clinical manifestations and current treatments. Lancet Neurol. 2012;11(6):521–534).
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
TABLE 21-2. TREATMENT OF PAINFUL SENSORY NEUROPATHIES
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
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.
Degeneration of sympathetic and parasympathetic neurons along with inflammatory infiltrates within the ganglia have been appreciated.49
The pathogenic basis for autonomic neuropathy is unknown but may be similar to DSPN.
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.
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.
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.
Nerve biopsies demonstrate severe loss of large myelinated axons with relative sparing of small myelinated and unmyelinated fibers.52
The pathogenic basis for the disorder is not known.
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.
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.
This is the most common form of polyradiculopathy or radiculoplexus neuropathy associated with DM (also known as diabetic amyotrophy, Bruns–Garland syndrome, diabetic lumbosacral radiculoplexopathy, and proximal diabetic neuropathy).54–62 It more commonly affects older patients with DM type 2, but it can affect type 1 diabetic patients. It can be the presenting manifestation of DM in approximately one-third of patients. Typically, patients present with severe pain in the low back, hip, and thigh in one leg. Rarely, the diabetic polyradiculoneuropathy begins in both legs at the same time. Nevertheless, in such cases nerve involvement is generally asymmetric. About 50% of patients also complain of numbness and paresthesia. Atrophy and weakness of proximal and distal muscles in the affected leg become apparent within a few days or weeks. The term “proximal diabetic neuropathy” stems from the observation that muscles innervated by the L2–L4 myotomes are the most commonly affected, producing weakness of hip flexion, hip adduction, and knee extension. The knee jerk on the affected side is virtually always diminished or lost in many cases. However, any leg muscle may be affected.55 In fact, we have seen cases with L5 or S1 monoradiculopathy patterns of pain and weakness in newly diagnosed diabetics without compressive lesions. Conversely and unfortunately, we have seen many patients undergo unnecessary laminectomies because of incidental magnetic resonance imaging (MRI) findings in the presence of severe radicular pain and weakness suggesting structural impingement. Although the onset is typically unilateral, it is not uncommon for the contralateral leg to become affected several weeks or months later. As with DNC, the polyradiculoneuropathy is often accompanied or heralded by severe weight loss. Weakness progresses gradually or in a stepwise fashion, usually over several weeks or months, but can continue to progress for 18 months or more.55 Most patients usually have underlying DSPN. Eventually, the disorder stabilizes, and slow recovery ensues over 1–3 years. However, in many cases there is significant residual weakness, sensory loss, and pain.
Rather than the more typical lumbosacral radiculoplexus neuropathy, some patients develop thoracic radiculopathy.50,60 Patients describe pain radiating from the posterolateral chest wall anteriorly to the abdominal region, with associated loss of sensation anterolaterally. Weakness of the abdominal wall may lead to herniations of the viscera. A cervical variant of diabetic radicular plexus neuropathy manifesting as acute pain, weakness, and sensory loss in one or both upper limbs can rarely occur as well.57,58
Lumbar puncture usually reveals an elevated CSF protein with a normal cell count. Erythrocyte sedimentation rate is often increased. MRI scans of the nerve roots and plexus can reveal enhancement.55,59 NCS reveal features suggestive of multifocal axonal damage to the roots and plexus with reduced or low amplitudes of SNAPs and CMAPs.55–57,60,62 Conduction velocities in the affected limbs are normal or mildly slow. Autonomic studies may be abnormal as well.57,60 Needle EMG reveals positive sharp waves and fibrillation potentials and reduced recruitment of affected proximal and distal muscles in the affected limbs and paraspinal muscles in keeping with the radiculoplexus localization. Large-amplitude, long-duration, polyphasic MUAPs are seen after 3–6 months as reinnervation occurs.
Sural, superficial peroneal, and lateral femoral cutaneous nerve biopsies, if performed, reveal loss of myelinated nerve fibers, which is often asymmetric between and within nerve fascicles.55,57,61,63–67 Active axonal degeneration and clusters of small, thinly myelinated regenerating fibers are appreciated. Mild perivascular inflammation and, less commonly, vasculitis with fibrinoid necrosis involving epineurial and perineurial blood vessels have been noted on some nerve biopsies (Fig. 21-4).57,61,62 Again, nerve biopsy is not recommended in the vast majority of cases.
Figure 21-4. Lumbosacral radiculoplexus neuropathy. Superficial peroneal nerve biopsy reveals perivascular inflammation of a small epineurial vessel. H&E stain.
Some authorities have speculated that diabetic radiculoplexus neuropathy is an immune-mediated microangiopathy; however, the pathogenic mechanism is unclear.61–63
Small retrospective studies have reported that intravenous immunoglobulin (IVIG), prednisone, and other forms of immunosuppressive therapy appear to be helpful in some patients with diabetic amyotrophy.54,60–63 We have been impressed by that short courses of corticosteroids ease the pain associated with the severe radiculoplexus neuropathy; this can allow the patients to undergo physical therapy. However, the natural history of this neuropathy is gradual improvement, so the actual effect, if any, of these immunotherapies on the radiculoplexus neuropathy is not known. Prospective, double-blind, placebo-controlled trials are necessary to define the role of various immunotherapies in this disorder.
The second major group of diabetic polyradiculopathy or radiculoplexus neuropathy manifests as progressive, relatively painless, symmetrical proximal and distal weakness that typically evolves over weeks to months, such that it clinically resembles CIDP.57,60,63,66–73 Whether this neuropathy represents the coincidental occurrence of CIDP in a patient with DM, or this is a distinct form of diabetic neuropathy, is unclear and controversial.73 This type of neuropathy occurs in both type 1 and type 2 DM.
The pattern of weakness resembles CIDP in that there is symmetric distal and proximal weakness affecting the legs more than the arms. Distal muscles are more affected than proximal muscles. In our experience there is usually distal arm weakness, but proximal arm involvement is often less noticeable than that seen in patients with idiopathic CIDP. Unlike the more common “diabetic amyotrophy” discussed in the previous section, the onset of weakness is not heralded or accompanied by such severe back and proximal leg pain, and the motor weakness is relatively symmetric. However, distal dysesthesias, perhaps secondary to a superimposed DSPN, are occasionally present.
CSF protein concentration is often increased. NCS demonstrate mixed axonal and demyelinating features, with absent or reduced SNAP and CMAP amplitudes combined with slowing of NCVs, prolongation of distal latencies, and absent or prolonged latencies of F waves.57,63,66,68,69,73 Rarely, conduction block and temporal dispersion are found.57,66,69 Occasionally, the electrophysiological features can fulfill research criteria for demyelination, but these patients generally have patterns that are more axonal in nature than seen in idiopathic CIDP.66,67,69 EMG reveals fibrillation potentials and positive sharp waves diffusely, including multiple levels of the paraspinal musculature. Autonomic studies may demonstrate abnormalities in sudomotor, cardiovagal, and adrenergic functions.57,60
Sural nerve biopsies, if performed, demonstrate a loss of large and small myelinated nerve fibers with axonal degeneration and clusters of small regenerating fibers as well as perivascular inflammation or the so-called “microvasculitis.”57,60,63,66,68,73 Nerve biopsies may show immunoreactivity for matrix metalloproteinase-9 as seen in idiopathic CIDP.72 A study out of the Mayo Clinic compared pathological features of nerve biopsies of this painless, symmetric, diabetic radiculoplexus neuropathy to the more typical painful, asymmetric, diabetic radiculoplexus neuropathy and to 25 CIDP biopsies.73 Nerve biopsies of two types of diabetic radiculoplexus neuropathies were similar, showing features of ischemic injury (multifocal fiber loss), perineurial thickening, injury neuroma, neovascularization, and microvasculitis (epineurial perivascular inflammation, prior bleeding, vessel wall inflammation). In contrast, CIDP biopsies did not show ischemic injury or microvasculitis but revealed demyelination and onion bulbs. However, the study did not include any biopsies of patients who may have had diabetes and coincidental CIDP that was responsive to immunotherapy.
The pathogenic basis for this form of polyradiculoneuropathy is unknown and perhaps is multifactorial. This neuropathy may represent part of the spectrum of diabetic amyotrophy, believed by some to result from microvasculitis.73 We suspect that rare cases represent CIDP occurring coincidentally in patients with DM, as some appear to improve with various immunotherapies. However, this apparent response does not imply that the patients have CIDP, because these patients can improve spontaneously without treatment and because microvasculitis may be responsive to immunotherapies as well.57,60 Alternatively, the disorder in some patients may represent a distinct form of diabetic neuropathy caused by associated metabolic disturbances, such as uremia.
As noted, some patients improve with immunotherapy [i.e., IVIG, plasma exchange (PE), and corticosteroids], suggesting that this type of diabetic neuropathy may be immune mediated.57,60,63,66,68,70 We often perform lumbar puncture on these patients. If the CSF protein is normal, then we would not proceed with immunotherapy, as it is highly unlikely that the patient has CIDP. If the CSF protein is elevated, one does not know if the patient has CIDP or the protein is elevated because of the diabetes. In these cases, we give a trial of plasmapheresis, because it generally works quickly in patients with CIDP, and we can avoid the potential side effects of corticosteroids and IVIG in these patients. If PE is effective, then we would continue with courses of PE or consider IVIG or prednisone, suspecting that they have an immune-mediated neuropathy and concluding that the benefit of these agents may offset the risks.
Diabetic patients are vulnerable to developing mononeuropathies and multiple mononeuropathies, including cranial neuropathies.1,74 Most of the time patients have underlying DSPN. The mononeuropathies are usually insidious in onset and presumably mechanical in nature due to entrapment or compressive mechanisms. Mononeuropathies that have an abrupt onset and a presumed ischemic mechanism (e.g., a diabetic third nerve palsy), are more likely to occur in individuals not yet identified as being diabetic. The most common neuropathies are median neuropathy at the wrist and ulnar neuropathy at the elbow, but peroneal neuropathy at the fibular head and sciatic, lateral femoral cutaneous, and cranial neuropathies also occur. In regard to cranial mononeuropathies, a seventh nerve palsy is most common, followed by third, sixth, and, less frequently, fourth nerve palsies. The multiple mononeuropathies, perhaps in combination with a radiculoplexus neuropathy, may give the appearance of a mononeuropathy multiplex pattern.
As mentioned previously, chronic painful neuropathies are common in diabetic patients. However, some patients suffer from severe acute neuropathic pain. This may occur in the setting of DNC or anorexia associated with severe weight loss. Rarely, severe pain develops soon after starting intensive glycemic treatment with rapid control of the glycemia, so-called treatment-induced neuropathy or insulin neuritis.75–79 This can occur in patients with type 1 or type 2 diabetes following treatment with insulin or oral hypoglycemic agents. The pain is usually in a length-dependent distribution but can be diffuse. Many patients, particularly those with type 1 DM, suffer from autonomic symptoms (orthostatic lightheadedness, nausea, vomiting, diarrhea, early satiety, and erectile dysfunction in men). Worsening retinopathy also parallels the course of the neuropathic pain. On examination, pain and temperature sensation are reduced, while most patients have hyperalgesia and allodynia. Muscle strength is not impaired.
NCS may be normal or abnormal, similar to DSPN. Autonomic testing usually reveals abnormal heart rate response to deep breathing and abnormal Valsalva ratio with diminished variability in the heart rate as well as orthostatic hypotension.75
When performed, sural nerve biopsies have revealed variable loss of myelinated fibers, acute axonal degeneration, and some clusters of regenerating myelinated fibers which is indistinguishable from other forms of diabetic neuropathy.75 Skin biopsies usually demonstrate a reduction in intraepidermal nerve fiber density.75
The pathogenic basis of acute treatment–induced neuropathy is not known, but the phenotype suggests diffuse damage to the unmyelinated and lightly myelinated nerve fibers.75
The pain associated with this neuropathy is very difficult to control. Fortunately, it is a spontaneously reversible disorder, and typically patients report pain improvement after many months of continued glucose control.
NEUROPATHIES ASSOCIATED WITH OTHER ENDOCRINOPATHIESPolyneuropathy has been associated with persistent hypoglycemia secondary to an islet cell tumor of the pancreas, hyperinsulinemia, or in early stages of treatment of DM.80–83 The neuropathy is characterized by progressive numbness and paresthesias in the hands and feet. Over time, distal motor weakness and atrophy may develop. Muscle stretch reflexes are generally reduced in a length-dependent fashion. With correction of the hypoglycemia, the sensory symptoms usually improve; however, muscle atrophy and weakness often remain to some extent.
NCS reveal SNAPs that are reduced in amplitude or absent.81,83 The CMAP amplitudes are slightly decreased, while the conduction velocities are normal or only mildly reduced. Needle EMG may demonstrate fibrillation potentials, positive sharp waves, and reduced recruitment of large polyphasic MUAPs in the distal limb muscles.80–83
Very few nerve biopsies have been performed on individuals with this disorder, but axonal loss primarily affecting the large myelinated fibers has been reported.81
The basis for the polyneuropathy is not known but is felt to be directly attributable to reduced glucose levels in peripheral nerves. A rat model of recurrent episodes of severe hypoglycemia was associated with early vascular anomalies in endoneurial microvessels in rat sciatic nerves without any observable changes in nerve fibers.84 Other studies demonstrated that acute lowering of glucose levels under hypoxic conditions in rats leads to apoptosis of dorsal root ganglia neurons.85 Hypoxia-induced cell death was decreased when dorsal root ganglia neurons were maintained in high-glucose medium, suggesting that high levels of substrate protected against hypoxia. Apoptosis was completely prevented by increasing the concentration of nerve growth factor.
Patients should be treated for the underlying cause of the hyperinsulinemia.
Acromegaly can be associated with several types of neuropathy, in addition to myopathy.86–90 Carpal tunnel syndrome is the most common neuropathy complicating acromegaly.86,88 A generalized sensorimotor peripheral neuropathy, characterized by numbness, paresthesias, and mild distal weakness beginning in the feet and progressing to the hands, is less frequent. Clinical or electrophysiological evidence of carpal tunnel syndrome has been demonstrated in 82% of patients and a generalized sensorimotor peripheral neuropathy in 73% of patients with acromegaly.86 In addition, the bony overgrowth in or about the spinal canal and neural foramina can result in spinal cord compression or polyradiculopathies.
NCS in patients with generalized polyneuropathy demonstrate reduced amplitudes of SNAPs with prolonged distal latencies and slow CVs.86 The CMAPs are usually normal, but there may be slightly reduced amplitudes, prolonged distal latencies, and slow motor conduction velocities.
Nerve biopsies in patients with acromegaly and generalized polyneuropathy may reveal an increase in endoneurial and subperineurial connective tissue and an overall increase in the fascicular area, combined with a loss of myelinated and unmyelinated nerve fibers.86,90
The pathogenic basis of the polyneuropathy associated with acromegaly is unknown. The neuropathy may be related to superimposed DM in some cases. Increased growth hormone and upregulation of insulin-like growth factor receptors may result in proliferation of endoneurial and subperineurial connective tissue, which could make the nerve fibers more vulnerable to pressure and trauma.
It is unclear at this time if the polyneuropathy improves with treatment of this endocrinopathy.
Hypothyroidism is more commonly associated with a proximal myopathy, but patients are predisposed to develop carpal tunnel syndrome.91–96 Rarely, a generalized sensory polyneuropathy, characterized by painful paresthesias and numbness in both the hands and the legs, also complicates hypothyroidism.92,93,97
NCS features suggestive of carpal tunnel syndrome are most common, but a generalized sensorimotor polyneuropathy may be demonstrated.91–93 In patients with a generalized neuropathy, the SNAP amplitudes are reduced and distal latencies may be slightly prolonged.94,95 CMAPs reveal normal or slightly reduced amplitudes, mild-to-moderate slowing of CVs, and slight prolongation of motor distal latencies.
Nerve biopsies, when performed, have revealed a loss of myelinated nerve fibers, mild degrees of active axonal degeneration, and segmental demyelination with small onion-bulb formations.91,94 Skin biopsies have shown reduced intraepidermal nerve fiber density in patients with hypothyroid neuropathy, but also in patients with asymptomatic hypothyroidism.97,98
Carpal tunnel syndrome is most likely the result of reduced space within the flexor retinaculum as a result of associated edematous changes. The etiology of the generalized neuropathy associated with hypothyroidism is not known.
Correction of the hypothyroidism usually at least halts further progression of the polyneuropathy, and in some cases leads to improvement.
SUMMARYDM is the most common etiology of neuropathy (at least in industrialized nations) when the cause of the neuropathy is found. There are several types of neuropathy associated with DM as discussed. Treatment is aimed at control of the blood sugar and symptomatic management of pain. Aside from diabetic neuropathies, the endocrine-related neuropathies are relatively uncommon, although hyperinsulinemia, hypothyroidism, and acromegaly have also been associated with neuropathy.
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