|Year : 2022 | Volume
| Issue : 1 | Page : 9-14
Evaluation of diabetic neuropathies
Amit Varma1, Kapil Sharma2, Sumita Sharma3
1 Department of General Medicine, SGRRIM&HS, Dehradun, Uttarakhand, India
2 Department of General Medicine, AIIMS, Bilaspur, Himachal Pradesh, India
3 Department of Biochemistry, AIIMS, Bilaspur, Himachal Pradesh, India
|Date of Submission||13-Feb-2022|
|Date of Decision||15-Feb-2022|
|Date of Acceptance||16-Feb-2022|
|Date of Web Publication||29-Jun-2022|
Department of General Medicine, AIIMS, Bilaspur, Himachal Pradesh
Source of Support: None, Conflict of Interest: None
Diabetes mellitus is a major health problem globally that increases the economic burden of every country. According to the International Diabetes Federation (IDF) in 2021, 1 in 10 adults are living with diabetes. About 352 million adults have uncontrolled glycemic profiles worldwide. Diabetes is likely to affect 552 million people worldwide by 2030. Diabetes and its complications are emerging as the leading cause of morbidity and mortality. Diabetes neuropathies are estimated to affect approximately 50% of people suffering with diabetes. Neuropathy, the most prevalent microvascular complication of diabetes mellitus, includes distal symmetric polyneuropathy, radiculoplexus neuropathy, autonomic neuropathy, mononeuropathy, and treatment-induced neuropathy. Early diagnosis and appropriate management of diabetic neuropathy are essential to alleviate disabling symptoms and to improve the quality of life of patients. This review discusses clinical manifestations and evaluation of diabetic neuropathies as well as appropriate objective tests helpful in diagnosing diabetic neuropathies.
Keywords: Complications of diabetes mellitus, diabetic autonomic neuropathy, diabetic neuropathies
|How to cite this article:|
Varma A, Sharma K, Sharma S. Evaluation of diabetic neuropathies. J Cardio Diabetes Metab Disord 2022;2:9-14
| Introduction|| |
Diabetic neuropathies are considered the most prevalent chronic microvascular complications of diabetes. This heterogeneous group of conditions affects peripheral and cranial nerves and presents with varied clinical manifestations. Nearly 50% of people with diabetes are affected by diabetic neuropathies during their lifetime. It is associated with significant morbidity which not only includes pain and paresthesia but also the risk of developing diabetic foot ulcers and lower limb amputation. Its prevalence varies between 6% and 51% among adults with diabetes depending on age, duration of disease, glucose control, and type of diabetes. The spectrum of diabetic neuropathies manifestation encompasses asymptomatic state to extremally painful neuropathic symptoms. The risk of diabetic foot ulcer and lower limb amputation is substantial with diabetic peripheral neuropathy; hence, aggressive and dedicated screening and management in terms of good glycemic control, regular foot exams and care, and pain management are important. Focus on lifestyle interventions such as weight loss and physical activity is also being explored as part of its management. The prevalence is higher in older age and among adults with long-standing diabetes. There is some evidence to suggest that the prevalence is somewhat less in the Asian population.
| Pathogenesis|| |
The major factors on which the development of diabetic neuropathies depends upon are duration and severity of hyperglycemia. In a study, Dyck et al. reported that the incidence and severity of diabetic neuropathies were associated with the duration and severity of hyperglycemia. In the DCCT study in which 1441 patients with type 1 diabetes were recruited, the tight glycemic control arm showed a significant reduction in the incidence of neuropathy, retinopathy, and nephropathy. The development of peripheral diabetic neuropathy was reduced by 60%. Other factors which might have contributed to the development of neuropathies included hypertension, hyperlipidemia, and smoking. Vascular disease, both macrovascular and microvascular, and an inflammatory immune response are also significant contributors to some form of diabetic neuropathy.
| Clinical Classification of Diabetic Neuropathies|| |
The existence of multiple pathogenic mechanisms of diabetic neuropathies, such as hyperglycemia, microvascular changes, inflammation, and dysregulated immune response, results in a number of different forms of neuropathies. Diabetic neuropathy can be understood on the basis of the pattern of the nerve fibers involved and the clinical signs and symptoms.
A simple classification depending on the type and location of the nerve involved is given in [Table 1].
Clinically, it may be classified based on the presenting symptoms, as depicted in [Table 2].
| Evaluation of Diabetic Neuropathies|| |
Various diagnostic criteria have been used in clinical research, and they are usually applicable to distal symmetrical polyneuropathy (DSPN), the most common form of diabetic neuropathies. Some criteria are based solely on symptoms and clinical examination only, whereas others make use of diagnostic tools to diagnose it. An expert panel at the International Symposium on Diabetic Neuropathy in Toronto, 2009 proposed the diagnostic criteria for typical DSPN as follows: (1) possible DSPN—the presence of symptoms such as decreased sensation and positive sensory symptoms or signs such as symmetric decrease of distal sensation or unequivocally reduced or absent ankle reflexes; (2) probable DSPN—the presence of a combination of symptoms and signs of neuropathy; (3) confirmed DSPN—the presence of abnormalities on nerve conduction study (NCS) with both the presence of a combination of symptoms and signs of neuropathy and if the results of NCS are equivocal or ambiguous, other validated measures of small fiber function may be used; and (4) subclinical DSPN—no neuropathic symptoms or signs but confirmed neuropathy with NCS or other validated methods.
| History Taking and Bedside Examination|| |
The patient should be inquired about the onset and progression of neuropathic symptoms. DSPN usually has slow onset and progression. Sudden onset and rapid worsening point to radiculoplexus neuropathy or inflammatory neuropathies, such as Guillain–Barré syndrome (GBS). Different individuals may show a wide degree of variation in their symptoms. A careful history should be taken to determine whether the symptoms are due to large or small fiber involvement. The distribution of sensory symptoms should be located by describing the boundaries of sensory deficits during neurological examination.
In DSPN, distal symmetric loss of both pinprick and vibration sensation is seen. Vibration sensation may be tested on the index finger in the upper limb or the great toe in the lower limb. A 128-Hz tuning fork is usually placed on the bony prominence of the distal interphalangeal joint of the toe or finger of the patient, and they are then asked whether they can feel the vibration. The vibration sensation is considered to be abnormal if the patient does not feel the vibration or feels it for a lesser duration when compared with the examiner. Pinprick sensation can be tested with a toothpick: one should avoid a metal pin lest it may result in a blood-borne infection. Vibration and pinprick sensation should be compared with opposite limbs, and a distal-to-proximal gradient should be determined. Deep tendon reflex is examined using a flexible hammer. The ankle reflex may not be present or may be decreased at age ≥ 60 years.
For the systematic workup of neuropathy in diabetics, we need to answer the following questions:
Step 1: Which fibers of the peripheral nerve are involved?
Step 2: Distribution of weakness?
Only distal motor weakness- Hereditary SMA
Only distal sensory loss- DM and other metabolic disorders
Distal + proximal (sensory + motor) weakness, symmetrical- GBS and CIDP
If asymmetrical- DM, meningeal carcinomatosis, sarcoidosis, amyloidosis, hereditary.
Step 3: If sensory involvement?
Loss of pain and temperature
Loss of vibration and proprioception
Any numbness, hyperaesthesia, allodynia, tingling, burning, aching pain
Characteristic of neuropathic pain
Either sharp shooting pain if carried by A-delta fibers or dull boring nature of pain if carried by polymodal C type fibers.
Step 4: Is there any evidence of upper motor neuron (UMN) involvement? e.g., distal symmetrical sensory symptoms + UMN involvement suggestive of combined degeneration with neuropathy as seen in vitamin B12 deficiency, Cu deficiency, HIV, and adrenomyeloneuropathy.
Step 5: What is temporal evaluation?
Acute—GBS, acute intermittent porphyria, critical illness polyneuropathy, diptheric neuropathy
Subacute—nutritional deficiency, paraneoplastic syndrome, exposure to toxins, CIDP
Coarse—monophasic/progressive/relapsing (seen in GBS, CIDP, HIV, porphyria, Refsum’s disease)
Step 6: Is there any evidence of hereditary neuropathy??
Slowly progressive distal weakness over many years
No sensory symptoms felt by the patient but sensory deficit on clinical examination
Examination ± high arch or flat arch feet, hammertoe, and scoliosis may be seen.
Step: Any associated medical condition including cancer, autoimmune disease, HIV, leprosy, Lyme’s disease, any drug history, overuse of alcohol, vitamin B6 deficiency, etc.
| Patterns of Diabetic Neuropathies|| |
Different patterns of diabetic neuropathies that may be seen are as follows.
Distal symmetrical polyneuropathy
DSPN, the most common type of diabetic neuropathy, usually begins insidiously, 5–10 years after diagnosis of diabetes. It progresses symmetrically from the distal end of lower limbs and gradually progresses to proximal parts manifesting as a “glove-and-stocking” pattern. Due to the involvement of large-diameter sensory fibers, the patient complains of pins and needles (positive symptoms) sensation, tingling, as well as numbness (negative symptoms). The involvement of small sensory fibers (Aδ and C-fibers) causes burning or lancinating pain along with various symptoms or signs of autonomic system involvement. This small fiber involvement is the cause of painful diabetic neuropathy, which is present in 25% of patients with DSPN.
In a few patients, instead of loss of deep sensation, ataxia, atony of bladder, and slight weakness of limbs resembling tabes dorsalis are seen.
Acute diabetic mononeuropathy
It is mainly seen in aged individuals and is usually caused by vascular obstruction after which adjacent neuronal fascicles take over the function of those infarcted. It has acute painful onset.
Practically, all the major peripheral nerves in isolation may be involved in diabetes but the ones most commonly affected are the femoral, sciatic, and peroneal nerves, in that order of frequency.
This neuropathy involves third nerve followed by the trochlear and facial nerves in order of frequency. There is isolated third-nerve palsy with pupillary sparing, and it is considered as the hallmark of diabetic oculomotor palsy.
It is painful, asymmetrical, asynchronous sensory and motor peripheral neuropathy involving isolated damage to at least two separate nerve areas. In some cases, this variety has been described in diabetic patients.
Acute painful diabetic neuropathy
Acute painful diabetic neuropathy (APDN) is a distinct diabetic polyneuropathy and it has two subtypes: treatment-induced neuropathy (TIN) and diabetic neuropathic cachexia. The characteristic features of APDN are (1) involvement of small fiber, (2) occurrence after good glycemic control, (3) severe pain sensation, and (4) eventual recovery after some time. It appears pertinent to be aware of this distinct neuropathy in the light of the current recommendation of the good glycemic target.
Diabetic autonomic neuropathy
Diabetes involves autonomic nerve fibers and autonomic neuropathy was reported to have prevalence rates of 16.8% in DM1 patients and 34.3% in those with DM2. It is most commonly associated with DSPN. It may present as cardiovascular autonomic neuropathy, gastrointestinal neuropathy, or genitourinary neuropathy. Its salient features are presented in [Table 3].
It is also known as asymmetrical proximal neuropathy, which is caused by injury to the proximal limb and nerve root at one or more thoracic or lumbar levels with axonal degeneration. Diabetic lumbosacral plexopathy is also known as diabetic amyotrophy or Bruns–Garland syndrome.
Peripheral sudomotor autonomic neuropathy
It is characterized by loss of sweat function in stocking and glove distribution due to involvement of the peripheral sympathetic cholinergic system, which is involved in the regulation of sweat function and thermoregulation. Clinical features include dry skin in distal parts due to anhidrosis with compensatory hyperhidrosis in proximal parts, hyperthermia, changes in the texture of the skin, edema, loss of nails, itching, and callus formation.
| Questionnaires for Screening of Diabetic Neuropathies|| |
Organized and validated questionnaires should be used for the assessment of diabetic neuropathies. The American Diabetes Association recommends screening for diabetic neuropathy at the time of diagnosis and annual assessment for patients with diabetes.
The Michigan Neuropathy Screening Instrument (MNSI) is the most widely used questionnaire for screening of diabetic neuropathy. This questionnaire includes two separate chapters. The first consists of a 15-item questionnaire that elicits “yes” or “no” responses from patients regarding sensory abnormalities. A score of more than 7 is considered abnormal. The second part involves physical inspection and neurological examination, done on both the left and right sides. Eight correct answers out of 10 questions are considered abnormal.
The Michigan Diabetic Neuropathy Score (MDNS) is a tool that includes more detailed neurological examination and NCS data. The MDNS is used to confirm the presence of neuropathy and its severity in patients with positive results on MNSI. Diabetic Neuropathy Examination and Diabetic Neuropathy Symptom Score are tools designed for screening of DSPN.
Composite Autonomic Symptom Score (COMPASS-31): It can be used for screening to evaluate autonomic dysfunction. This questionnaire is composed of 31 questions in 6 domains, i.e., vasomotor, orthostatic intolerance, gastrointestinal, secretomotor, bladder, and pup illomotor. The score obtained from COMPASS-31 is quantified according to clinical significance, and it is consistent with the severity of the results of the autonomic function testing.
| Ancillary Diagnostic Tests in Diabetic Neuropathies|| |
With advances in diagnostic technology, detailed and accurate diagnosis is now possible for diabetic neuropathies. When in doubt, more objective tests may be used to confirm the presence of neuropathy, to measure its severity, and to rule out other possible causes of the symptoms.
Nerve conduction studies
NCS is the gold standard test for diagnosing peripheral neuropathy including diabetic neuropathy and it should be performed to confirm its presence, assess its severity, and rule out other causes of neuropathy. Its use as a reliable indicator of DSPN has been advocated by experts. Its disadvantage is that it can only assess the large fiber. Electromyography (EMG) is often used as the common term for electrodiagnostic tests and as a mixture of NCS. However, EMG is not necessary for the evaluation of neuropathy and is performed only when a patient has the involvement of motor system.
Autonomic function test (AFT)
The current AFT includes measurement of heart rate variability during deep breathing and the Valsalva maneuver and head-up-tilt test to assess cardiovagal and sympathetic adrenergic function. It can be assessed by the quantitative sudomotor axon reflex test (QSART), performed in specialized laboratories to assess the sympathetic cholinergic function.
Heart rate variability to deep breathing (HRVDB) is a commonly used, simple, and reliable test to assess cardiovagal function. The heart rate increases during deep inspiration, whereas the opposite happens during expiration, due to the effects of respiration on intrathoracic pressure and venous return. In this test, the patient is asked to inhale slowly and regularly 5–6 times/min. ECG is recorded simultaneously in which R-R interval appears as sinusoidal curves. HRVDB is assessed by calculating the average ratio of the maximum to minimum heart rate (E: I ratio) or the average of the fastest rate minus the slowest (E–I difference). Early cardiac autonomic neuropathy involves parasympathetic nerves, followed by sympathetic adrenergic dysfunction. Hence, reduced HRVDB is a good indicator of cardiac autonomic dysfunction.
The head-up-tilt test is used to evaluate orthostatic intolerance. Alternatively, it can be assessed by measuring the blood pressure during sitting and standing. A fall of >20 mmHg in systolic blood pressure and >10 mmHg in diastolic blood pressure within 3 min of standing signifies orthostatic hypotension.
Sudomotor function is important for the maintenance of body temperature and can be assessed by the QSART. In this test, 10% acetylcholine is used to stimulate nerve terminals in sweat glands. Due to the initiation of axon reflex, sweat response is induced in adjacent sweat glands. Sudomotor function can be assessed by measuring the amount of sweat produced. QSART is considered the most sensitive test for detecting postganglionic sympathetic cholinergic dysfunction and is currently used in various clinical conditions. Another simple method to evaluate sweat production semi-quantitatively is by using a neuropad. After exposure to adequate sweat, the neuropad changes color from blue to pink, whereas lack of color change indicates hypohidrosis.
Quantitative sensory test
In this psychophysiological test, sensory perception thresholds to predefined sensory stimuli are assessed. It is useful when the patient is suspected to have predominant small fiber involvement. The use of specialized equipment and the long duration of time taken to conduct it limit its use in day-to-day practice. Hence, QST should be used as a complementary test rather than as a single diagnostic test.
Intraepidermal nerve fiber density (IENFD) can be assessed using skin biopsy, and it provides an objective, quantitative measure of somatic C-fibers. A 3-mm punch biopsy is obtained from the distal and proximal parts of the leg. Intraepidermal perpendicular sprouting axons per cubic millimeter measured under microscopy are used to calculate IENFD. Significant loss of small fiber is seen in diabetic neuropathies. Additionally, morphological changes, such as axonal swelling, are seen. Exploration of the dermis also provides useful information regarding innervation to the sweat glands or erector pili muscles.
It is rarely used in diabetic neuropathy unless in patients who are being suspected of vasculitis or amyloidosis.
Serum soluble Fas ligand (sFasL)
sFasL concentration decreases significantly with severity of neuropathy in type 2 DM and may be considered a serum marker to assess the severity of DPSN.
| Conclusion|| |
Diabetic neuropathies show a wide spectrum of clinical features. It should be kept in mind that although diabetic neuropathies are the most common forms of neuropathies in diabetes, other treatable neuropathies should also be looked for. A detailed history, meticulous examination, and appropriate use of diagnostic testing are required to properly evaluate diabetic neuropathies. A neurologist consultation is advised if another form of neuropathy is suspected. As it is a major cause of morbidity among diabetic patients, a systematic approach in evaluating the diabetic patient would prevent or delay the development of neuropathy and its associated complications.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]