Diabetic peripheral neuropathy is one of the most common chronic complications of diabetes mellitus, and is a group of peripheral neuropathies with sensory and autonomic symptoms as the main clinical manifestations. It and diabetic nephropathy and diabetic retinopathy together constitute the diabetic triad, seriously affecting the quality of life of diabetic patients.
1.Etiology and pathogenesis
Etiology.
The basic etiology of diabetic peripheral neuropathy is that diabetes is not effectively controlled, resulting in peripheral neuropathy. This is one of the most common chronic complications of diabetes mellitus, with a variety of clinical manifestations and a variety of theories on the mechanism of its occurrence, it is difficult to use a single mechanism to explain such a variety of neuropathy. The combination of multiple pathological mechanisms may ultimately lead to a complex and variable clinical presentation.
Pathogenesis.
Metabolic disorders theory of histone glycosylation: elevated blood glucose can cause glycosylation of histones, and glycosylated protein end products are not only an important factor in the systemic complications of diabetes, but also can damage the myelin structure of peripheral nerves and cause myelin loss. Glycosylation of microfilaments and microtubule proteins can lead to axonal degeneration. This histone glycosylation process can continue in diabetic patients even after blood glucose levels return to normal, causing persistent peripheral nerve damage.
Abnormal inositol metabolism.
Inositol is a substrate for the synthesis of phosphatidylinositol, which not only affects the activity of cell membrane Na -K -ATPase, but is also essential for cellular transmembrane messaging. The cellular uptake of inositol requires a Na-dependent carrier, and inositol is structurally similar to glucose. Hyperglycemia can competitively inhibit the Na-dependent carrier and reduce the cellular uptake of inositol, resulting in a decrease in intracellular inositol levels, which directly affects neural structure and function.
Impaired sorbitol-fructose metabolism.
Hyperglycemia can increase the activity of aldose reductase in peripheral nerve Schwann cells, which accelerates the process of glucose conversion to sorbitol, and sorbitol is oxidized to fructose under the action of sorbitol dehydrogenase, resulting in excessive accumulation of sorbitol and fructose in cells, causing increased intracellular osmotic pressure and water and sodium retention, resulting in necrosis, myelin loss and axonal degeneration in peripheral nerve nerve membrane cells (Schwann cells) The result is necrosis, myelin loss and axonal degeneration of peripheral nerve membrane cells (Chevron cells). Microcirculatory disorders theory
(1) Microangiopathy and ischemia and hypoxia.
Hyperglycemia can cause glycosylation of structural proteins of microvasculature, resulting in vascular endothelial hyperplasia, intimal thickening, vitreous degeneration and basement membrane thickening as well as increased capillary permeability. In severe cases, it can lead to vascular stenosis and even thrombosis, causing ischemic and hypoxic damage to peripheral nerve tissue.
A comparative study of the nail fold circulation in patients with diabetes mellitus alone and diabetes mellitus with peripheral neuropathy showed that the visibility of the microcirculation in patients with diabetes mellitus with peripheral neuropathy was significantly reduced, the visual field was dark red, most of the tubular loops were blurred, and the number was reduced, while the tubular loops were thin and short, and the presence of input branch spasm and microangiomas and peri-loop exudation were seen. The blood flow velocity was significantly slowed down and showed a sediment-like agglomerated flow pattern.
(2) Decrease in vasoactive factors.
Diabetic peripheral neuropathy has decreased vasoactive factor (NO), decreased sensitivity of the trophoblastic vessels of the neurointima to vasodilatory factors, and abnormal smooth muscle diastolic function, leading to microcirculatory disturbances. In addition the abnormal metabolism of arachidonic acid decreases the ratio of prostacyclin (PGl2) and thromboxane (TXA2), vasoconstriction and hypercoagulation of blood, the result of which is ischemia and hypoxia of nerve tissue.
Immune mechanism theory.
Studies have shown that 12% of patients with diabetic peripheral neuropathy are positive for serum anti-GM1 antibodies and are associated with distal symmetric polyneuropathy. 88% of patients are positive for antiphospholipid antibodies, while only 32% of diabetic patients without neurological complications are positive for this antibody. This suggests that the pathogenesis of diabetic peripheral neuropathy is autoimmune related.
The main pathological features of diabetic peripheral neuropathy are the coexistence of axonal degeneration and segmental demyelination with significant myelin regeneration and unmyelinated fiber proliferation. Studies on the spatial distribution of sciatic, peroneal and vagus nerve lesions have shown that both axonal degeneration and demyelination show a reverse degenerative change, i.e. the axons are more degenerated distally and less proximally. Multiple segmental demyelination can be either primary or secondary.
Some patients have pathologic features of mast neuropathy, which manifests as Schwann cell hyperplasia forming onion head-like structures, and collagen fiber hyperplasia with collagen capsule formation is seen. Clinical manifestations are seen in patients with painful neuropathy in which a biopsy of the peroneal nerve reveals selective fine myelinated fiber loss with unmyelinated fiber axon sprouting. Postmortem pathologic observations of diabetic peripheral neuropathy sometimes reveal posterior root ganglion cell and anterior spinal cord cell loss and axonal degeneration of nerve roots and posterior cords.
Vascular lesions are one of the pathologic features of diabetic peripheral neuropathy. The endothelial cells of small vessels in the outer and inner nerve membranes are swollen, the lumen is narrowed or even occluded, and the outer membrane of the vessels is markedly thickened with mononuclear cell infiltration. Thickening of the basement membrane is another pathological feature of diabetic peripheral neuropathy. The basement membrane of the nerve bundle, Schwann cells, and vascular endothelium can all be significantly thickened, with the nerve bundle membrane being the most significant. The longer the course of distal symmetric neuropathy, the more pronounced the thickening of the basement membrane, while the shorter the course of mononeuropathy, the lesser the degree of thickening.
2.Epidemiology
In the late 1970s, the prevalence of diabetes was less than 1.0% among people over 20 years of age in China, but it has increased to about 3.2% in 1996, and is still increasing at a rate of 1.0‰ year by year. The prevalence rate in Beijing and other economically more developed areas is already higher than 5.0%. It is estimated that the number of type 1 diabetic patients in China has reached 4 million, and the number of type 2 diabetic patients is nearly 40 million.
Diabetic peripheral neuropathy is one of the most common complications of all types of diabetes, with an incidence of 60% to 90%. The prevalence is the same in men and women. The incidence of distal sensory neuropathy is 4% within 5 years after the onset of diabetes and 20% after 20 years. The disease is mostly insidious, but can also develop suddenly after poor glycemic control or the onset of diabetic coma. A small number of patients are found to have diabetes only after the onset of peripheral neuropathy symptoms.
3.Clinical manifestations
The clinical manifestations of diabetic peripheral neuropathy are diverse and are usually classified into the following types according to the clinicopathological features
(1) Distal-type primary sensory neuropathy.
It is the most common type of diabetic peripheral neuropathy, which manifests as symmetrical multiple peripheral neuropathies in the distal limbs. It is the most common type of diabetic peripheral neuropathy. It is insidious in origin and first involves the distal lower extremities, progressing from the bottom to the top, and rarely affects the upper extremities. The main symptoms include dull pain, stabbing pain or burning pain from deep in the limbs, especially at night.
(2) Garter-like hyperalgesia or absence of sensation in both lower extremities, and decreased or absent Achilles and knee tendon reflexes.
In severe sensory neuropathy, the ventral part of the lower part of the trunk may be involved, but the dorsal part is not involved, which is called diabetic trunk polyneuropathy, and at this time, if the sensation of the dorsal part of the trunk is ignored, the examination is easily misdiagnosed as myelopathy. In this case, if the sensation of the dorsal side of the trunk is neglected, the diagnosis may be misdiagnosed as myelopathy. Autonomic neuropathy: It is seen in almost all diabetic patients with long duration of disease, and both sympathetic and parasympathetic fibers can be involved.
(3) Cardiovascular autonomic dysfunction.
This manifests as a diminished heart rate response to activity and deep breathing regulation, or even the development of complete cardiac denervation. As a result of sympathetic vasoconstriction, upright hypotension, dizziness, blackness and even syncope may occur when standing up. Symptoms of gastrointestinal autonomic function include slowed esophageal and gastrointestinal motility and prolonged gastric emptying time, known as diabetic gastroparesis. Other gastrointestinal dysfunctions include nausea, vomiting, bloating, constipation and diarrhea.
(4) Autonomic abnormalities of the genitourinary system manifest as hypogonadism, impotence, weakness in urination, high residual urine and urinary retention.
This hypotonic bladder predisposes to urinary tract infections and renal failure. Other symptoms of autonomic nerve damage are pupillary abnormalities and impaired sweat secretion, manifested by narrow pupils, dull reaction to light, absence of sweating in the lower extremities, and compensatory hyperhidrosis of the head and hands.
(5) Diabetic foot.
It is a serious complication of sensory neuropathy, and its occurrence is related to dry and cracked skin caused by autonomic nerve dysfunction, limb end ischemia caused by small vessel disease, and abnormal foot end position sensation caused by limb nociceptive deficiency and joint deformation. The clinical manifestations are long-lasting ulcers on the toes, heels and ankles. In addition to distal sensory impairment of the extremities, a small number of patients also have distal muscle weakness and muscle atrophy, reduced or absent tendon reflexes, and autonomic impairment, which is known as diabetic motor sensory neuropathy or chronic progressive motor sensory autonomic neuropathy.
(6) Acute or subacute proximal-type motor neuropathy, also known as proximal diabetic neuropathy or paralytic diabetic neuritis.
It is officially named diabetic myasthenia gravis by Garland. The incidence is 0.8%, and muscle biopsy pathology shows scattered or small groups of muscle fiber atrophy, both types of fibers can be involved, predominantly type 1, sometimes visible target fibers, and significant interstitial hyperplasia. A nerve biopsy revealed both axonal degeneration and demyelination changes. Neurophysiological examination revealed that the nerve branches of the proximal muscles and paraspinal muscles were predominantly involved, while the distal ones were rarely involved.
(7) Proximal diabetic neuropathy may be acute, subacute, or insidious in onset.
It is seen in all stages of diabetes mellitus and may occur sequentially with distal motor-sensory neuropathy. It mainly involves one or both pelvic girdle muscles, especially the quadriceps, in addition to the iliopsoas, gluteus and adductor muscles of the thigh. The upper extremity band muscles are hardly involved. Early on, the disease starts with muscle weakness and atrophy in the proximal part of one lower limb, and gradually involves the proximal part of both lower limbs in about half of cases.
(8) Diabetic mononeuropathy or multiple mononeuropathies.
(①The femoral nerve, sciatic nerve, brachial plexus nerve and median nerve are commonly involved.
(2) Peroneal nerve, ulnar nerve, supraspinatus nerve and long thoracic nerve: generally have an acute onset and manifest as sudden onset of pain or sensory disturbance in the affected innervation area and muscle weakness.
③Diabetes-induced cerebral nerve damage: the most common is actinic nerve palsy
④Spreading, talipes, facial nerve and trigeminal nerve: sometimes most of the cerebral nerve damage can be manifested. Mostly sudden onset, either unilateral or bilateral, or repeated multiple episodes.
(5) Diabetes-induced entrapment neuropathy mainly manifests as carpal tunnel syndrome, elbow tunnel syndrome and tarsal tunnel syndrome.
(9) Electrophysiological examination.
Patients with diabetic peripheral neuropathy may have slowed nerve conduction velocity and prolonged terminal motor latency, reflecting demyelinating damage to peripheral nerves. Changes in F-wave latency, conduction velocity, wave amplitude and time frame can reflect proximal nerve lesions and compensate for the lack of distal nerve conduction velocity measurements.
The H-reflex can determine the excitability of a motor neuron and the functional state of motor fibers, providing a basis for nerve damage. Single-fiber EMG can reflect the germination of nerve axons and nerve reinnervation by fiber density and tremor parameters.
(10) Cerebrospinal fluid examination.
66% of diabetic peripheral neuropathies may have elevated protein, averaging 0.6 g/L and rarely exceeding 1.2 g/L, with predominantly elevated globulin. Subclinical diabetic peripheral neuropathy with abnormal electrophysiological examination but no clinical symptoms rarely has elevated cerebrospinal fluid proteins.
4.Complications
All complications of diabetes mellitus may coexist with diabetic peripheral neuropathy. The most common is with diabetic nephropathy and diabetic retinopathy, together constitute a diabetic triad, seriously affecting the quality of life of diabetic patients. Others, such as diabetic cerebrovascular disease, genitourinary system infections, and skin infections, are also more common.
5.Check
(1) Laboratory tests.
Blood glucose and glucose tolerance measurement. Other blood tests: including liver function, kidney function, routine blood sedimentation tests; rheumatic series, immunoglobulin electrophoresis and other autoimmune related serological tests. Serum heavy metal (lead, mercury, arsenic, thallium, etc.) concentration test. Urine examination: including urine glucose, urine routine, present – week protein, urine porphyrins and urinary excretion of heavy metals. Cerebrospinal fluid examination.
(2) Other ancillary examinations.
Electromyography and neurophysiological examination. Tissue biopsy (including skin, peroneal nerve, muscle and kidney) if necessary to differentiate from other sensory peripheral neuropathies.
6.Diagnosis
Jiang Yuping proposed the diagnostic criteria for diabetic peripheral neuropathy according to the WHO Collaborative Group on Diabetic Peripheral Neuropathy criteria.
There is definite diabetes mellitus, that is, it meets the diagnostic criteria of diabetes mellitus. There is persistent pain and/or sensory disturbance in the extremities or both lower extremities.
One or both bunions have decreased vibration sensation.
Loss of bilateral ankle reflexes. In addition, F-wave and H-reflex measurements and single-fiber electromyography may provide clues to the diagnosis of proximal and subclinical stages of diabetic peripheral neuropathy.
The conduction velocity of the peroneal nerve on the main side (i.e., the hand side) is one standard deviation below the normal value for the same age group.
7.Differential diagnosis
The first is to confirm the diagnosis and differentiation of diabetes mellitus. Secondly, the disease should be differentiated from other sensory peripheral neuropathies and painful peripheral neuropathies, and diabetic muscular atrophy should be differentiated from quadriceps myopathy, progressive spinal muscular atrophy and quadriceps atrophy caused by lumbosacral radiculopathy.
8.Treatment
Symptomatic treatment: Phenytoin (phenytoin sodium) 0.1g, 2-3 times/d, or carbamazepine 0.1g, 2-3 times/d can be used for pain with anxiety symptoms. alprazolam 0.4mg, 2 times/d or amytriptyline 25mg, 2-3 times/d can be used for patients with pain with anxiety symptoms, which can achieve satisfactory results. Indomethacin (anti-inflammatory pain) and piroxicam (inflammatory pain xicam) may be effective for intractable neuralgia.
Erythromycin can be used to increase the binding of gastric actin to its receptors, strengthen the contraction of the gastric wall muscles and promote gastric emptying in diabetic gastroparesis syndrome. The treatment is erythromycin 200-250mg, 3-4 times/d. Currently, domperidone (morpholine) 10mg, 3 times/d. For hypotonic neurogenic bladder, neostigmine 0.25-0.5mg, intramuscular or subcutaneous injection, along with norfloxacin to prevent and treat urinary tract infections. Etiological treatment to control diabetes: application of hypoglycemic drugs and control of diet to maintain blood glucose at normal levels is the fundamental principle in the treatment and prevention of diabetic peripheral neuropathy.
Inositol therapy: 6g/d for 6 months may achieve certain efficacy. Immunosuppressive therapy: In recent years, it has been found that diabetic patients have anti-islet cell antibodies in their serum, and pathology can be seen with lymphocyte and monocyte infiltration around peripheral neurovascular, indicating that immune mechanism may be involved in its pathogenesis. Intravenous immunoglobulin has been used to treat diabetic myasthenia gravis, which not only can significantly improve muscle strength but also can relieve pain.
It is administered as human blood gammaglobulin (gammaglobulin) 400 mg/(kg・d) for 5 days, followed by prednisone 60 mg/d for at least 3 months, with increased dosage of insulin and hypoglycemic agents and close monitoring of blood glucose. Effective treatment with cyclophosphamide, azathioprine and plasma exchange has also been reported. Pro-neurometabolic and neurotrophic treatment Neurotrophic drugs: vitamin B1, vitamin B6, vitamin B12, adenosine triphosphate (ATP) and niacin are beneficial for mild patients and prevention.
Ganglioside: It can improve the sensory symptoms of diabetic peripheral neuropathy due to its pharmacological effects of enhancing Na -K -ATPase activity, stimulating nerve sprouting, promoting nerve reinnervation and triggering the formation of neuromuscular junction. Usage: 20-40mg/d, intramuscular injection, or 40-80mg/d, intravenous drip.
9.Prognosis
Diabetic peripheral neuropathy is one of the serious complications of diabetes mellitus. Patients with combined autonomic neuropathy have a high risk of disability and death. A prospective follow-up study showed that patients with autonomic symptoms and abnormal autonomic function tests had a mortality rate of 44% after 2.5 years and 56% after 5 years, with half dying from renal failure, half dying from sudden respiratory and circulatory arrest and hypoglycemia. and urinary tract infections secondary to an atonic bladder.
Patients with diabetic myasthenia gravis have a relatively good prognosis, with rapid progression within the first few weeks of disease onset, but extremely slow progression later in the course of the disease. About 1/5 of patients have complete recovery of muscle strength after 6 to 18 months, of which another 1/5 may relapse.
10.Prevention
The main focus is to prevent and treat diabetes. Primary prevention focuses on reasonable diet, moderate exercise, blood sugar control and prevention of complications.