History
In type 1 diabetes mellitus, distal polyneuropathy typically becomes symptomatic after many years of chronic prolonged hyperglycemia. Conversely, patients with type 2 diabetes mellitus may present with distal polyneuropathy after only a few years of known poor glycemic control; sometimes, these patients already have neuropathy at the time of diagnosis.
Since diabetic neuropathy can manifest as a wide variety of sensory, motor, and autonomic symptoms, a structured list of symptoms can be used to help screen all diabetic patients for possible neuropathy.
Sensory symptoms
Sensory neuropathy usually is insidious in onset and shows a stocking-and-glove distribution in the distal extremities. Sensory symptoms may be negative or positive, diffuse or focal. Negative sensory symptoms include feelings of numbness or deadness, which patients may describe as being akin to wearing gloves or socks. Loss of balance, especially with the eyes closed, and painless injuries due to loss of sensation are common. Positive symptoms may be described as burning, prickling pain, tingling, electric shock–like feelings, aching, tightness, or hypersensitivity to touch.
Motor symptoms
Motor problems may include distal, proximal, or more focal weakness. In the upper extremities, distal motor symptoms may include impaired fine hand coordination and difficulty with tasks such as opening jars or turning keys. Foot slapping and toe scuffing or frequent tripping may be early symptoms of foot weakness. Symptoms of proximal limb weakness include difficulty climbing up and down stairs, difficulty getting up from a seated or supine position, falls due to the knees giving way, and difficulty raising the arms above the shoulders.
In the most common presentation of diabetic neuropathy with symmetrical sensorimotor symptoms, minor weakness of the toes and feet may be seen; severe weakness is uncommon and should prompt investigation into other causes, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), or vasculitis. More severe weakness may be observed in asymmetrical diabetic neuropathy syndromes. Motor neuropathy may occur along with sensory neuropathy (sensorimotor neuropathy).
Autonomic symptoms
Autonomic neuropathy may involve the cardiovascular, gastrointestinal, and genitourinary systems and the sweat glands. Patients with generalized autonomic neuropathies may report ataxia, gait instability, or near syncope/syncope. In addition, autonomic neuropathies have further symptoms that relate to the anatomic site of nerve damage—gastrointestinal, cardiovascular, bladder, or sudomotor.
Gastrointestinal autonomic neuropathy may produce the following symptoms [52] :
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Dysphagia
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Abdominal pain
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Nausea/vomiting
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Malabsorption
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Fecal incontinence
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Diarrhea
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Constipation
Cardiovascular autonomic neuropathy may produce the following symptoms [53] :
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Persistent sinus tachycardia
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Orthostatic hypotension
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Sinus arrhythmia
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Decreased heart variability in response to deep breathing
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Near syncope upon changing positions from recumbent to standing
Bladder neuropathy (which must be differentiated from prostate or spine disorders) may produce the following symptoms:
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Poor urinary stream
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Feeling of incomplete bladder emptying
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Straining to void
Sudomotor neuropathy may produce the following symptoms:
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Heat intolerance
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Heavy sweating of head, neck, and trunk with anhidrosis of lower trunk and extremities
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Gustatory sweating
Physical Examination
Physical examination of patients with suspected distal sensory, motor, or focal (ie, entrapment or noncompressive) neuropathic symptoms should include assessments for both peripheral and autonomic neuropathy. [54]
Peripheral neuropathy testing
Testing for peripheral neuropathy begins with assessment of gross light touch and pinprick sensation. The first clinical sign that usually develops in diabetic symmetrical sensorimotor polyneuropathy is decrease or loss of vibratory and pinprick sensation over the toes. As disease progresses, the level of decreased sensation may move upward into the legs and then from the hands into the arms, a pattern often referred to as "stocking and glove" sensory loss. Very severely affected patients may lose sensation in a "shield" distribution on the chest.
Vibratory sense in the feet is tested with a 128-Hz tuning fork placed at the base of the great toenail. Test protective sensation with 5.07 Semmes-Weinstein monofilament, briefly applying the tip perpendicular to the plantar surface of the foot, using sufficient force (10 g) to buckle the monofilament. Inability to perceive the tuning fork or the monofilament identifies patients who are at increased risk (ie, 60% in the next 3 years) of developing a foot ulcer. [55] The 2 tests should be performed at least every year. [56]
Test deep tendon reflexes. With neuropathy, these are commonly hypoactive or absent. Perform strength testing and examine for distal intrinsic extremity muscle atrophy, since weakness of small foot muscles may develop. Check dorsal pedal and posterior tibial pulses.
Examine the skin for dryness, tinea pedis, cracks, onychomycoses, acute erythema and tenderness, and fluctuance under calluses.
Perform Tinel testing. Paresthesias or pain suggests median nerve injury.
Perform cranial nerve testing. Have the patient walk on the heels and toes; heel-toe walking tests not only distal lower-extremity strength but balance, as well.
Perkins et al recommended conducting annual screening for diabetic neuropathy using superficial pain sensation testing, monofilament testing, or vibration testing by the on-off method. These researchers also validated a scoring system to document and monitor neuropathy in the clinic. [57] Dyck et al described case report forms for recording symptoms and signs of neuropathy that might be useful in longitudinal follow-up of individual patients. [58]
Autonomic neuropathy testing
Testing for autonomic neuropathies is performed objectively in a specialized autonomic laboratory, evaluating cardiovagal, adrenergic, and sudomotor function. However, the clinician may first perform bedside screening to assess if further, more specialized testing is necessary.
Blood pressure and heart rate measurements with the patient supine and upright are compared. Blood pressure measurements in patients with autonomic neuropathy may show orthostatic hypotension with reduced compensatory tachycardia. Testing for orthostatic hypotension is particularly important in patients with longstanding diabetes mellitus. [59]
The sinus arrhythmia (SA) ratio is measured with the patient breathing 6 times per minute while the heart rate is monitored with a continuous ECG strip. The longest R-R interval during expiration and the shortest R-R interval during inspiration are measured, and the average of the 6 breaths is taken. The SA ratio is R-R expiration/R-R inspiration. The normal ratio is 1:2.
Classification of Diabetic Neuropathy
Diabetic neuropathies are heterogeneous in type; thus, several classifications of diabetic neuropathy have been created and recognized. [60, 5, 54] Two classification systems will be presented here: the Thomas system and symmetrical-versus-asymmetrical neuropathies.
Thomas system
A classification system by Thomas [61] combines anatomy and pathophysiology. It is presented below with a few modifications:
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Hyperglycemic neuropathy (acute)
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Generalized symmetrical polyneuropathies
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Sensory neuropathy
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Sensorimotor neuropathy (chronic, symmetric)
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Autonomic neuropathy (cardiovascular, gastrointestinal, genitourinary, sudomotor)
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Focal and multifocal neuropathies: this category includes cranial neuropathy, proximal motor neuropathy (amyotrophy), thoracic or lumbar radiculopathies, and focal limb neuropathies (entrapment neuropathies)
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Superimposed chronic inflammatory demyelinating polyneuropathy (CIDP)
Symmetrical versus asymmetrical neuropathies
Another generally accepted classification of diabetic neuropathies divides them broadly into symmetrical and asymmetrical neuropathies.
Symmetrical polyneuropathies involve multiple nerves diffusely and symmetrically. Distal symmetrical sensorimotor polyneuropathy is the most common manifestation of diabetic neuropathy. The syndrome has been defined in many ways, but 3 key criteria are commonly accepted:
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The severity of polyneuropathy should be commensurate with the duration and severity of the diabetes
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Other causes of sensorimotor polyneuropathy must be excluded
Distal symmetrical sensorimotor polyneuropathy affects sensory, motor, and autonomic functions in varying degrees, with sensory abnormalities predominating. Chronic symmetrical symptoms affect peripheral nerves in a length-dependent pattern, with the longest nerves affected first. Patients commonly present with painful paresthesias and numbness, which begin in the toes and ascend proximally in a stocking-like distribution over months and years.
When sensory symptoms ascend above the knees, similar symptoms develop in the hands, progressing proximally in a glove-like distribution. At a very late stage, the anterior aspect of the trunk and vertex of the head may be affected. The loss of sensation in the feet predisposes to development of foot ulcers and gangrene. [64] In addition, mild weakness of foot muscles and decreased ankle and knee reflexes occur commonly. With impaired proprioception and vibratory perception, gait may be affected (sensory ataxia).
Small-fiber neuropathy is a distal symmetrical neuropathy involving predominantly small-diameter sensory fibers (A delta and C fibers). It manifests as painful paresthesias that patients perceive as burning, stabbing, crushing, aching, or cramplike, with increased severity at night. There is loss of pain and temperature sensation with relative sparing of distal reflexes and proprioception.
Although some degree of autonomic involvement is present in most patients with distal symmetrical diabetic polyneuropathy, patients may not notice autonomic problems, and pure autonomic diabetic neuropathy is rare. Manifestations of autonomic neuropathy may include orthostatic hypotension, resting tachycardia, loss of normal sinus arrhythmia ratio, anhidrosis, bowel or bladder dysfunction, and small pupils sluggishly reactive to light.
In diabetic neuropathic cachexia, the patient experiences a precipitous and profound weight loss followed by severe and unremitting cutaneous pain, small-fiber neuropathy, and autonomic dysfunction. This condition occurs more often in older men; impotence is common. Muscle weakness is uncommon. The condition usually improves with prolonged glycemic control; however, symptoms are often refractory to other pharmacologic treatment. Limited anecdotal improvement is reported with nonpharmacologic treatments such as sympathectomy, spinal cord blockade, and electrical spinal cord stimulation. Recovery may be incomplete and prolonged over many months
Asymmetrical neuropathies include single or multiple cranial or somatic mononeuropathies. Syndromes include the following:
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Median neuropathy of the wrist (carpal tunnel syndrome)
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Other single or multiple limb mononeuropathies
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Thoracic radiculoneuropathy
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Lumbosacral radiculoplexus neuropathy
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Cervical radiculoplexus neuropathy
These syndromes are distinguished from typical distal diabetic polyneuropathy by the following characteristics:
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They often have a monophasic course
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Some are associated with inflammatory angiitis and ischemia (eg, lumbosacral radiculoplexus neuropathy) and may appear acutely or subacutely
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They have a weaker association with total hyperglycemic exposure than symmetrical polyneuropathies
Cranial mononeuropathy most often involves cranial nerves (CN) III, IV, VI, VII, or II. Disease of CN III, IV, and VI manifests as acute or subacute periorbital pain or headache followed by diplopia. Muscle weakness is typically in the distribution of a single nerve, and pupillary light reflexes are usually spared. Complete spontaneous recovery usually occurs within 3 months.
Facial neuropathy manifests as acute or subacute facial weakness (taste is not normally affected) and can be recurrent or bilateral. Most patients recover spontaneously in 3-6 months.
Anterior ischemic optic neuropathy manifests as acute visual loss or visual-field defects (usually inferior altitudinal). The optic disc appears pale and swollen; flame-shaped hemorrhages may be present.
For more information, see Macular Edema, Diabetic.
Somatic mononeuropathies include focal neuropathies in the extremities caused by entrapment or compression at common pressure points or by ischemia and subsequent infarction. Entrapment and compression tend to occur in the same nerves and at the same sites as in individuals without diabetes. Median nerve entrapment at the wrist (carpal tunnel syndrome) is more common in patients with diabetes and can be treated in the same manner as in patients without diabetes. Symptoms are often bilateral. The susceptibility to ulnar nerve entrapment at the elbow or common peroneal nerve entrapment at the fibular head is not definitely increased among patients with diabetes.
Neuropathy secondary to nerve infarction presents acutely, usually with focal pain associated with weakness and variable sensory loss in the distribution of the affected nerve. Multiple nerves may be affected (mononeuritis multiplex).
Diabetic thoracic radiculoneuropathy presents as burning, stabbing, boring, beltlike, or deep aching pain that usually begins unilaterally and may subsequently become bilateral. Skin hypersensitivity and allodynia (pain with normally innocuous touch) may occur. Numbness follows a dermatomal distribution, most prominent in distal distribution of intercostal nerves. Single or multiple spinal roots are involved. Contiguous territorial extension of symptoms may occur in a cephalad, caudal, or contralateral direction. In the trunk, thoracoabdominal neuropathy or radiculopathy may cause chest and/or abdominal pain in the distribution of thoracic and/or upper lumbar roots. Weakness presents in the distribution of the affected nerve root, such as bulging of the abdominal wall from abdominal muscle paresis (thoracic root). Patients older than 50 years are affected most often; it is more common in diabetes mellitus type 2 and is often associated with significant weight loss. There isoftencoexistingdiabeticdistalsymmetrical polyneuropathy.
Diabetic radiculoplexus neuropathy may occur in the cervical or lumbosacral distributions and is referred to in the literature by various designations, including diabetic amyotrophy, Bruns-Garland syndrome, and diabetic plexopathy. The most frequent initial symptom is sudden, severe, unilateral pain in the hip/lower back or shoulder/neck. Weakness then develops days to weeks later. Atrophy of the limb musculature may occur. Allodynia, paresthesias, and sensory loss are common.
Symptoms usually begin unilaterally and may later spread to the opposite side. Reflexes in the affected limb may be depressed or absent. This condition often occurs in patients older than 50 years with poorly controlled diabetes. It is more common in men than in women. Significant weight loss occurs in 50% of patients. The course is generally monophasic, with improvement over many months; however, some residual deficits often remain.
For more information, see Diabetic Lumbosacral Plexopathyhere.
Staging
Different clinical neurologic scales can be used to assess the severity of diabetic polyneuropathy. [60]
A common staging scale of diabetic polyneuropathy is as follows [65] :
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NO - No neuropathy
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N1a - Signs but no symptoms of neuropathy
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N2a - Symptomatic mild diabetic polyneuropathy; sensory, motor, or autonomic symptoms; patient able to heel walk
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N2b - Severe symptomatic diabetic polyneuropathy (as in N2a, but patient unable to heel walk)
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N3 - Disabling diabetic polyneuropathy
Tables
Fiber Type |
Size |
Modality |
Myelination |
A-alpha (I) |
13-20 micrometers |
Limb proprioception |
Yes |
A-beta (II) |
6-12 micrometers |
Limb proprioception, vibration, pressure |
Yes |
A-delta (III) |
1-5 micrometers |
Mechanical sharp pain |
Yes |
C (IV) |
0.2-1.5 micrometers |
Thermal pain, mechanical burning pain |
No |
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Approach Considerations
- Glycemic Control
- Diabetic Neuropathic Pain Management
- Pain Control in Pregnancy
- Diabetic Gastroparesis
- Dietary Supplements
- Experimental Therapies
- Treatment of Autonomic Dysfunction
- Surgical Treatment
- Pancreatic Transplantation
- Rehabilitation
- Complications of Disease
- Consultations
- Long-Term Monitoring
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- Medication
- Medication Summary
- Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
- Analgesics, Topical
- Anticonvulsant
- Antidepressant, Tricyclic
- Antidepressant, Selective Serotonin/norepinephrine Reuptake Inhibitor (SSNRI)
- Antidepressant, Serotonin Reuptake Inhibitor
- Antiarrhythmic Agent, Class I-b
- Prokinetic Agents
- Antidepressant, Tetracyclic
- Synthetic Adrenocortical Steroids
- Cholinergic Agent
- Laxative, Bowel Evacuant
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