I. Diabetic peripheral neuropathy definition, epidemiology and typing
1. Definition: Diabetic peripheral neuropathy (DPN) refers to the development of symptoms and/or signs associated with peripheral nerve dysfunction in patients with diabetes mellitus when other causes are excluded.
2. Epidemiology: clinically significant DPN often occurs within 10 years of diagnosis in diabetic patients, and its prevalence correlates with the duration of the disease. Neurological function tests reveal varying degrees of DPN in 60% to 90% of patients, and 30% to 40% of patients have no conscious symptoms. The prevalence is higher in patients who smoke, are >40 years old, and have poor glycemic control.
3.Typing: According to different clinical manifestations, the most common typing of DPN is as follows.
(1) Distal symmetric polyneuropathy: the most common type of DPN.
(2) Focal mononeuropathy (or mononeuropathy): it can involve a single cranial nerve or spinal nerve.
(3) Asymmetric multifocal focal neuropathy: a neuropathy that involves multiple single nerves at the same time is called multifocal mononeuropathy (or asymmetric polyneuropathy).
(4) Multiple radiculopathy: The most common one is a series of symptoms caused by multiple radiculopathy in the lumbar segment, mainly in the high lumbar segments such as L2, L3 and L4.
(5) Autonomic neuropathy: Diabetic autonomic neuropathy (DAN) is a common complication of diabetes mellitus, which can involve cardiovascular, digestive, respiratory, genitourinary and other systems.
II. Etiology, pathogenesis and pathology
1. Etiology and pathogenesis: The causes and pathogenesis of DPN have not been completely elucidated, but it is believed that the main causes are oxidative stress, vascular ischemia and hypoxia, and nerve growth factor deficiency caused by metabolic disorders such as blood glucose. In addition, autoimmune factors, vitamin deficiency, genetic and environmental factors may also be related to the occurrence of DPN.
2, pathological changes: the main pathological changes of DPN are axonal degeneration or even disappearance of unmyelinated nerve fibers; segmental or diffuse crinkling or demyelination of myelinated nerve fibers, as well as changes in the inter-nodal length of Longfellow nodes caused by myelin regeneration.
III. Diagnosis
1, medical history: detailed medical history, including the type and duration of diabetes, family history of diabetes, history of smoking, history of alcohol consumption, past medical history, etc.
2.Symptoms and signs.
(1) Distal symmetrical polyneuropathy: the disease is insidious and progresses slowly; the main symptoms are numbness, tingling and abnormal sensation at the end of the limbs, usually in a glove or garter-like distribution, mostly starting from the lower limbs, length-dependent and aggravated at night. Physical examination shows that the skin of the foot is dull, sweat hair is sparse, skin temperature is low; pain and temperature sensation, vibration sensation is reduced or absent, ankle reflex is normal or only mildly diminished, and motor function is basically intact.
(2) Focal mononeuropathy: mainly involving median nerve, ulnar nerve, radial nerve and the third, fourth, sixth and seventh cranial nerves, the incidence of facial palsy is higher in diabetic patients than in non-diabetic patients. Most of them heal spontaneously after several months.
(3) Asymmetrical multiple focal neuropathy: the onset is rapid, with predominantly motor disorders, muscle weakness and atrophy, and diminished ankle reflexes, most of which resolve spontaneously after several months.
(4) Multiple radiculopathy: The onset of multiple radiculopathy in the lumbar segment is more acute and mainly involves the proximal muscle groups of the lower extremities. Patients usually present with pain and weakness in the proximal muscles of a single affected limb. The pain is a deep persistent dull ache that worsens at night, with muscle atrophy appearing within 2 to 3 weeks, progressing progressively, and reaching a plateau after 6 months.
(5) Autonomic neuropathy.
(①Cardiovascular autonomic symptoms: upright hypotension, syncope, abnormal coronary diastolic function, painless myocardial infarction, cardiac arrest or sudden death.
(ii) Autonomic symptoms of the digestive system: constipation, diarrhea, epigastric fullness, gastric discomfort, dysphagia, and erratic reflux.
③Autonomic symptoms of genitourinary system: urination disorder, urinary retention, urinary incontinence, urinary tract infection, loss of libido, impotence, menstrual disorders, etc.
④Other DAN symptoms: such as thermoregulation disorder and abnormal sweating. Decreased sweating or no sweating makes the hands and feet dry and cracked, and the capillaries lack their own tension, leading to venous dilatation and easy formation of local “microvascular tumors” and secondary infection. Inability to perceive hypoglycemic reaction, etc.
3.Nervous system examination.
(1) Screening methods.
①Nociception: The function of peripheral sensory nerves is initially assessed by measuring the different responses of the foot to pinprick pain.
②Temperature sensation: the sensitivity of the foot to the sensation of temperature changes is measured by specific instruments.
③Pressure sensation: Semmes-Weinstein monofilament (5.07/10g monofilament) is commonly used for the detection. The palmar surface of the bunions and the metatarsal heads of the Ⅰ and Ⅴ feet are used as the examination site (avoiding calluses and ulcerated areas), and the monofilament is placed on the examination site and bent for 1 to 2 seconds. If the patient answered incorrectly more than 2 out of 3 times, the pressure sensation was judged to be absent, and if the patient answered correctly more than 2 out of 3 times, the pressure sensation was judged to be present.
Vibratory sensation: A 128-Hz tuning fork is commonly used for this test. The patient’s eyes are closed and the patient is asked if he/she can feel the vibration of the tuning fork. 2 out of 3 incorrect answers are considered to be lack of vibration, while 2 out of 3 correct answers are considered to be vibration.
(5) Ankle reflex: The ankle reflex is classified as hyperreflexic, hyporeflexic or normal, reflecting the function of deep sensation in the lower limbs.
(2) Neurophysiological examination and morphological examination.
①Neurophysiological examination: It is suitable for patients with high suspicion of DPN after the above examination; it can evaluate the ability of the surrounding myelinated thick fiber nerves to conduct electrical signals. If the nerve myelin, Langfinger nodes and axonal lesions are present, the test results are abnormal. The median nerve, ulnar nerve, common peroneal nerve, tibial nerve and peroneal nerve are usually detected.
②Morphological examination: Skin biopsy: A 3-mm diameter skin was taken to observe the density of nerve fibers and the average nerve branch length within the epidermis. The main assessment is fine nerve fiber lesion. Nerve biopsy: the posterior gastrocnemius nerve of the external ankle is a commonly used biopsy site. This test only reflects the information at a certain moment and at a certain site of a nerve, and does not reflect the function of the complete nerve response loop.
(3) Other diagnostic and assessment methods.
(1) Quantitative sensory testing (QST): The QST instrument has multiple sensory measurement modes, including light touch and vibration to assess the function of thick nerve fibers with myelination, and pain and temperature to assess the function of small fine nerve fibers with thin or no myelination. This test is highly subjective and can be used as an aid to diagnosis.
Vibratory threshold measurement (VPT): VPT measurement is simple, noninvasive, reproducible, and has good patient compliance. VPT>25 volts is often used clinically as an important indicator for judging the risk of foot ulcers.
(iii) Neurological function score: more detailed and comprehensive, such as the Michigan scale consisting of a symptom questionnaire consisting of 15 questions completed by the patient and a foot physical examination scale completed by the physician. It is mostly used for epidemiological investigation of DPN.
④Coronal MRI of spinal nerve roots: In suspected multiple nerve root lesions, a thin T1-weighted image (2-3 mm) scan of coronal MRI of spinal nerve roots can be performed. It helps to differential diagnosis and confirm the diagnosis.
4. Diagnostic criteria.
(1) Diagnostic criteria for DPN.
① A clear history of diabetes mellitus.
(②Neuropathy present at or after the diagnosis of diabetes mellitus.
(iii) Clinical symptoms and signs consistent with the manifestations of DPN.
④DPN was diagnosed if two or more of the following five tests were abnormal: abnormal temperature sensation; decreased or absent sensation in the foot by Longscreen; abnormal vibration sensation; absent ankle reflex; and two or more slowed nerve conduction velocities.
Exclude other pathologies such as cervical and lumbar spine lesions (nerve root compression, spinal stenosis, cervical and lumbar degeneration), cerebral infarction, Green’s syndrome, severe arteriovenous vascular lesions (venous embolism, lymphangitis), etc. It is also necessary to identify the neurotoxic effects caused by drugs, especially chemotherapy drugs, and the damage to nerves caused by metabolic toxins due to renal insufficiency.
(2) Diagnostic criteria of DAN.
(1) Diabetic cardiac autonomic neuropathy: there is no uniform diagnostic criteria, and the examination items include heart rate variability, Valsalva test (ratio of longest R-R interval to shortest), fist pump test (continuous fist pump for 3 min to measure blood pressure), postural blood pressure change measurement, 24h ambulatory blood pressure monitoring, spectrum analysis, etc.
②Other DAN: There are no uniform diagnostic criteria, and the diagnosis is mainly based on the corresponding clinical symptoms and characteristics and functional examination, mostly exclusive diagnosis.’
IV. Treatment
1.Prevention.
(1) Control blood sugar, correct dyslipidemia, and control hypertension.
(2) Strengthen foot care: choose footwear with good air permeability and soft quality, check and remove foreign bodies in shoes frequently. Patients should wash their feet daily, and the water temperature should not be too high. In autumn and winter, the feet are prone to dryness and cracking, and can be evenly coated with neutral emollient cream, sweaty feet can sprinkle some talcum powder.
(3) Regular screening and condition evaluation.
(1) DPN should be checked at least once a year after the diagnosis of diabetes.
(2) For patients with a long course of diabetes or combined with microvascular complications such as fundopathy and nephropathy, they should be reviewed every 3 to 6 months; once diagnosed with diabetic polypoidal peripheral neuropathy, the feet with loss of sensation should be especially protected to reduce the risk of skin damage and amputation.
2.Treatment.
(1) Treatment of the cause: active control of hyperglycemia is the most fundamental and important means to prevent and treat DPN, while early active and effective nerve repair is also an important treatment measure for DPN.
(1) Glycemic control: Active and strict control of hyperglycemia and maintaining stable blood glucose are the most important measures to prevent and treat DPN.
②Neural repair: Nerve damage in DPN is usually accompanied by segmental demyelination and axonal degeneration, and its repair is often a long process, such as repairing axonal degeneration takes up to 18 months. It is mainly through enhancing the synthesis of nucleic acid, protein and phospholipid in nerve cells to stimulate axonal regeneration and promote nerve repair. Commonly used drugs include methylcobalamin, etc.
(3) Anti-oxidative stress: By inhibiting lipid peroxidation, increasing blood flow to neurotrophic vessels, increasing neural Na+-K+-ATPase activity and protecting vascular endothelial function. Commonly used drugs such as α-lipoic acid.
④Improve microcirculation: improve the blood supply and oxygen supply to nerve cells. Commonly used drugs such as prostaglandin E2, hexoketococine, scopolamine, cilostazol, and blood-activating herbs.
⑤ Improving metabolic disorders: It works by reversibly inhibiting aldose reductase. New generation aldose reductase inhibitors such as epalrestat.
(6) Others: such as neurotrophic, including neurotrophic factor, C-peptide, inositol, gangliosides and linolenic acid, etc. (2) Symptomatic treatment: The following sequence is usually used to treat patients’ pain symptoms: methylcobalamin and a-monolithic acid, traditional and new generation anticonvulsants, duloxetine, tricyclic antidepressants, opioid analgesics, etc.
①Methylcobalamin and alpha-lipoic acid: can be used as the first-order medication for symptomatic management.
②Traditional anticonvulsants: mainly sodium valproate and carbamazepine.
③New generation anticonvulsants: mainly pregabalin and gabapentin.
④Tricyclic antidepressants: commonly used amitriptyline, promethazine and new antidepressants such as cetepram.
⑤ Opioid analgesics: mainly oxycodone and tramadol, etc.
⑥Local painkillers: mainly used for those with limited pain.
For example, isosorbide nitrate spray and glyceryl trinitrate patch can reduce local pain and burning sensation; capsaicin can reduce the release of painful substances; local application of 5% lidocaine patch can also relieve pain.
V. Prognosis
1, DPN patients are prone to burns, frostbite and stabbing due to loss of pain and temperature sensation, and microcirculatory changes can lead to diabetic foot.
2, diabetic cardiac autonomic neuropathy makes patients unable to sense myocardial ischemia, and the lack of protective response (such as rest, medication, etc.), easy to develop into painless infarction, or even sudden death.
3, Many large clinical trials have confirmed that for patients with early DPN, early active intervention can improve symptoms and delay the development of DPN.