Diabetic Neuropathy

Introduction

Diabetes mellitus is growing by an alarming rate worldwide, including developing nations such as India. Neuropathic syndromes are common complications of diabetes mellitus. The prevalence of neuropathy is 8%- 45% in people with type 2 diabetes mellitus (T2DM)¹ . The most prevalent is chronic diabetic peripheral sensorimotor neuropathy (DPN), affecting up to 50% of people with diabetes. DPN leads to two significant clinical consequences—diabetic foot ulceration and neuropathic pain, further leading to devastating outcomes, such as lower limb amputation and death. Up to half of the patients with DPN suffer from painful DPN. The duration of diabetes and glycemic control is the most significant risk factors for DPN. 

Other risk factors associated with DPN include obesity, hypertension, smoking, and dyslipidemia. Currently, the mainstay of management is to control the risk factors for DPN and prevent and manage its complications. It is essential to make an early and accurate diagnosis so that the measures to reduce the risk of diabetic foot complications may be implemented. In future, treatments geared towards obesity and metabolic syndrome will likely be needed rather than solely focusing on hyperglycemia.^2-6

Definition

The Toronto Diabetic Neuropathy Expert Group defined DPN as “symmetrical, length-dependent sensorimotor polyneuropathy attributable to metabolic and microvessel alterations because of chronic hyperglycemia exposure (diabetes) and cardiovascular risk covariates.”⁷

Classification

The American Diabetes Association has recently developed a simplified classification for diabetic neuropathies as follows:⁸ 

A. Diffuse neuropathy

Distal Symmetric Poly Neuropathy (DSPN)

• Primary small-fiber neuropathy
• Primary large-fiber neuropathy
• Mixed small- and large-fiber neuropathy (most common)

Autonomic

• Cardiovascular: reduced heart rate variability (HRV), resting tachycardia, orthostatic hypotension, sudden death (malignant arrhythmia)
• Gastrointestinal: diabetic gastroparesis, diabetic enteropathy (diarrheal), colonic hypomotility (constipation)
• Gastrointestinal: diabetic gastroparesis, diabetic enteropathy (diarrheal), colonic hypomotility (constipation)
• Sudomotor dysfunction: distal hypo hidrosis/ anhidrosis, gustatory sweating
• Hypoglycemic unawareness
• Abnormal pupillary function

B. Mononeuropathy (mononeuritis multiplex; Atypical forms)

Isolated cranial or peripheral nerve (eg, CN III, ulnar, median, femoral, and peroneal) Mononeuritis multiplex

C. Radiculopathy or Polyradiculopathy (Atypical forms) 

• Radiocomplexes neuropathy (lumbosacral polyradiculopathy, proximal motor amyotrophy)
• Thoracic radiculopathy

Pathogenesis

Several molecular pathways that have been suggested to be contributing to diabetic polyneuropathy are as follows:^9,10 

• Polyol pathway activation
• Oxidative stress
• Protein kinase C activation
• Advanced glycation end-product formation
• Dyslipidemia and elevated triacylglycerols: These act as sources of non-essential fatty acids (NEFA), which are metabolised by β-oxidation. It further leads to increased accumulation of acetyl-CoA, a β-oxidation product, and its conversion into toxic acylcarnitine. It also results in extensive reactive oxygen species (ROS) production and inflammatory pathway activation exacerbating nerve injury, activating caspase-3, and inducing dioxyribonucliec acid (DNA) degradation.¹¹

Altered sphingolipid metabolism has been suggested in individuals with T2DM, which results in the formation of atypical, neurotoxic deoxy sphingolipids. Deoxysphingolipids are toxic to neurons and to pancreatic beta cells. ^12,13 Recently, gene sequencing technology has led to the exploration of potential genetic factors predisposing to several chronic diseases, including diabetic polyneuropathy. Several genes eg, human leukocyte antigen (HLA), catechol-O-methyltransferase (COMT), µ-opioid receptor gene (OPRM1), tumor necris factor-α (TNF-α), interleukin 6 (IL-6), and guanosine triphosphate cyclohydrolase 1 (GCH1), are found to be associated with neuropathic pain. A recent study found that patients with Nav 1.7 mutations and small fiber neuropathy treated with the anticonvulsant lacosamide had significantly improved pain compared with placebo.^14,15

Diagnosis

Once a patient is diagnosed with DM, periodic diabetic foot screening should be an essential part of physical examination to prevent complications. Patients with T2DM should be screened for DPN from diagnosis, and in type 1 diabetes, foot screening should commence 5 years after diagnosis. Subsequently, all patients should be assessed on an annual basis for lower limb sensory and vascular deficits. 

Other causes of neuropathy must be excluded and should involve a comprehensive history and examination, including temperature/pinprick sensation testing to assess small-fiber function, vibration sensation testing with 128 Hz tuning fork and assessment of ankle reflexes to assess large fiber function, and 10 g monofilament for the assessment of protective sensation.

The routine biochemical assay should include fasting glucose, haemoglobin A1c (HbA1c), and oral glucose tolerance test (OGTT) along with the tests to rule out other causes of peripheral neuropathy (eg, coeliac disease, vitamin B12 deficiency, hypothyroidism, infectious/inflammatory disease, gammopathy-induced neuropathy, and alcoholic neuropathy).

The neurological history and examination lead to the identification of an underlying cause of neuropathy in 64% of cases with an additional 10% of causes identified after the simple blood tests that are outlined above. Warning signs of atypical neuropathy, such as asymmetry, predominant weakness, non-length dependence, and acute/sub-acute onset should prompt additional testing, including nerve conduction study (NCS)/electromyogram (EMG). NCSs remain the gold standard measure of large-fiber function. NCS/EMG helps in determining the type and severity of neuropathy as well as aids in ruling out other atypical forms. For diagnosing small-fiber neuropathy, quantitative sensory testing (QST) and skin biopsy may be used.

Diagnostic tests for diabetic autonomic neuropathy

Cardiovascular autonomic testing

Tests of predominantly parasympathetic function

• Resting heart rate
• Heart rate variability to deep breathing (ie supine position with the subject breathing at a fixed rate of five breaths per minute during a six-minute period): Analyzed by the HRV and the expiratory to the inspiratory ratio
• Heart rate response to standing (30:15 ratio)
• Heart rate response to Valsalva manoeuvre (the Valsalva ratio) 

Tests of sympathetic function

• Blood pressure response to a Valsalva manoeuvre (drop in phase 2, the phase 4 overshoot)
• The systolic and diastolic blood pressure change in response to tilt table testing or active standing
• Handgrip dynamometer

Tests of sympathetic cholinergic function

• Quantitative sudomotor axon reflex testing (QSART)
• Thermoregulatory sweat testing (TST)
• Sympathetic skin response (SSR)

Direct assessment of cardiac autonomic integrity by scintigraphy imaging

• Gastrointestinal autonomic testing 
• Gastric emptying scintigraphy 
• Isotope-based breath test 
• Anorectal manometry for evaluating sphincter tone

Urologic autonomic function testing

• Post-void residual urine
• Urodynamic studies
• Measurement of nocturnal penile tumescence
• Measurement of penile and brachial blood pressure with Doppler probes
• Calculation of the penilebrachial pressure index (<0.7 suggests penile vascular disease)

Pupillary autonomic function testing

• Pupillometry

Recently, more advanced diagnostic techniques have emerged that may be able to diagnose diabetic polyneuropathy at an early stage. These are corneal and retinal innervation studies, intraepidermal nerve fibre density (IENFD), neurometer, DPN check, and sudomotor testing.

Corneal and retinal innervations 

Corneal confocal microscopy (CCM) is a rapid and non-invasive modality for the study of corneal innervation. It has a high sensitivity (68%-92%) and a specificity of 40%-64% to diagnose DPN. Retinal nerve fiber layer (RNFL) loss measured by optical coherence tomography (OCT) is observed in patients with diabetes and correlates with the stage of diabetic neuropathy. Limitations are that currently they are not widely available.¹⁶

Skin biopsy and quantification of intra-epidermal nerve fiber density 

It is based on the principle that the natural rate of epidermal innervation depletion is accelerated in DPN and IENFD may act as an early marker for DPN. IENFD has a sensitivity of 61%-90% and specificity of 64%- 82.8% for diagnosing DPN. Skin biopsy and IENFD are invasive tests, so they unlikely to be an appropriate screening tool for DPN.¹⁷

Neurometer

The neurometer is a painless, non-invasive QST device, which measures the current perception threshold (CPT). However, as with other QST techniques, CPT abnormalities are not specific to DPN, and the test may be influenced by many factors, including psychological factors.¹⁸

DPN Check

DPN Check is a handheld device, which measures the sural nerve amplitude and conduction velocity without the need for an expert neuro electrophysiologist. It has a sensitivity of 95% and 71% of specificity to diagnose DPN. The drawback associated with DPNCheck is that it overestimates sural nerve conduction velocity. In addition to this, any sural nerve amplitudes below 1.5 μV are adjusted to zero. Still, this simple device has the potential to measure sensory nerve function quickly, cheaply accurately, and can be used as a screening tool.¹⁹

Sudomotor testing

Methods that are commonly used to determine sudomotor function in DPN are QSART and TST. Neuropad and Sudoscan are the recent sudomotor tests that are noninvasive. Neuropad has a sensitivity of 86%-95%, but a specificity of only 45%-69.8% for diagnosing DPN. Though it is easy to use, its relatively poor specificity limits its applicability. Sudoscan is a Food and Drug Administration (FDA)-approved device for the diagnosis of DPN. It has a sensitivity ranging between 70%-87.5% and specificity between 76.2%-92% to detect DPN. However, there still is insufficient evidence to support that Sudoscan as a measure of sensory nerve fiber function, so further validation is required.^20,21

Treatment

As no disease-modifying treatment is available that can reverse the underlying nerve damage, the treatment is mainly focussed on the prevention of risk factors and symptomatic treatment. Achieving optimal glucose control is the most important factor in type 1 and type 2 diabetes to prevent or slow the progression of DPN. However, the evidence for good glycemic control in the prevention of DPN is much greater for type 1 than type 2 diabetes. The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study found that intensive therapy significantly reduced the risk of DPN in patients with type 1 diabetes. However, the benefits for both glucose and multifactorial risk factor control on DPN are inconclusive in T2DM. It has been found that patients with T2DM when treated with insulin sensitizing therapies had exhibited a significantly reduced incidence of DPN compared with insulin providing treatments.

Symptomatic treatment

Duloxetine and Pregabalin are the only treatments, which have received regulatory FDA approval for the treatment of painful DPN. The treatment algorithm is as follows:^22-25

• First-line medication: Serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), or gabapentinoid
• Second-line medication: Add or replace with medication from a different class of first-line medication (do not attempt pregabalin after gabapentin)
• Only try medications with limited or no evidence after attempting at least one medication from each class and preferably two
• Avoid opioids for chronic, non-cancer pain, given the evidence supporting adverse outcomes

The α2δ agonists ie, gabapentin and pregabalin modulate α2δ-1 and α2δ-2 subunits of voltagesensitive calcium channels. The side effects associated with gabapentin are most commonly dizziness and somnolence. Pregabalin has a side effect profile, such as gabapentin, ie, dizziness, somnolence along with weight gain, and peripheral edema. Role of other anticonvulsant therapies (eg, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, and lacosamide) in the treatment of painful DPN remains limited, but may be effective in some individuals (eg, in patients with a genetic mutation involving sodium channel Nav 1.7, lacosamide has been found to be effective).

SNRIs increase the synaptic availability of 5-hydroxytryptamine and noradrenaline; hence, increasing the activity of descending pain inhibition pathways. SNRIs uses include duloxetine and venlafaxine. The most common side effects include nausea, somnolence, dizziness, constipation, dry mouth, and reduced appetite, although these are commonly mild and transient.

TCAs have a multimodal analgesic action, including blocking of serotonin and noradrenaline reuptake from synaptic clefts and varying degrees of anticholinergic receptor inhibition. Amitriptyline, nortriptyline, and desipramine are commonly used TCAs. Side effects are mainly related to their anticholinergic action and include dry mouth, constipation, postural hypotension, and somnolence, and should be used with caution in elderly patients and patients with cardiac disease.

Opioids (tramadol, tapentadol) are an effective means for the treatment of painful DPN; however, the risk of addiction, side effect,s and psychosocial complications should limit their use.

Topical treatments (lidocaine patches, capsaicin cream, and topical vasodilators) have been used in the treatment of DPN, but have limited evidence to suggest efficacy.

Other treatments, such as alpha-lipoic acid, epalrestat, and benfotiamine have also been used for the treatment of DPN.

Non-pharmacological treatments (acupuncture, transcutaneous electrical nerve stimulation [TENS], and meditation) have also been tried but without any significant evidence.

Newer modalities

Spinal cord stimulation (SCS) is emerging as a newer treatment modality in the treatment of painful diabetic polyneuropathy, which is refractory to conventional medical treatment. In SCS, an electrode is positioned posteriorly in the epidural space to the dorsal column at the level of the nerve roots that transmit the nociceptive information from the painful area. The epidural lead is connected to a battery producing an electrical current, which induces paraesthesia, a sensation that suppresses the pain according to the Gate Control theory²⁶ . Patients can reduce or increase the intensity of the electric current by means of a device that uses radiofrequency transmission. However, the treatment is not without risks. The most common complications are hardware related (lead migration, lead fracturing, connection failure, and discomfort), infection, subcutaneous hematomas, and CSF leak^27,28. The ongoing SENZA-PDN is the largest prospective, multicentre, randomised control trial studying the role of 10-KHz SCS in improving the clinical outcome and quality of life in patients with painful diabetic neuropathy. Its data is expected by 2022^29.

Treatment of diabetic autonomic neuropathy

Cardiac autonomic neuropathy (CAN) is the most studied form of autonomic neuropathy. The preventive treatment of CAN and all forms of diabetic autonomic neuropathy is like all other forms of diabetic neuropathy. Treatment of orthostatic hypotension (OH) involves stopping of drugs that worsens it, volume correction, and strength training. Pharmacological therapy includes fludrocortisone (0.1-0.4 mg) and midodrine (2.5-5 mg) twice a day. They should be used carefully because of the risk of supine hypertension.

Treatment of diabetic gastroparesis involves stopping dipeptidyl peptidase-4 (DPP4) inhibitors and glucagonlike peptide 1 (GLP-1) analogues. Treatment of diabetic gastroparesis involves taking small frequent meals along with prokinetic agents, such as low fiber and low-fat diet with avoidance of carbonated drinks and chewing gum. For diabetic diarrhea, avoid metformin and use loperamide on an SOS basis. Treatment of gastroesophageal reflux disease (GERD) involves the use of proton pump inhibitors with prokinetic agents and non-pharmacological methods.

Diabetic bladder dysfunction should be evaluated with post-void residual ultrasound and a detailed urodynamic study, if indicated. Avoid drugs that impair detrusor activity and those which increase urethral tone along with strict voluntary urination schedule frequently coupled with Credé manoeuvre. Erectile dysfunction in diabetic men requires the use of phosphodiesterase inhibitors. Treatment of peripheral sudomotor and vasomotor neuropathy requires good control of diabetes and meticulous foot care.³⁰

Treatment of induced diabetic neuropathy (TIND)

This form of neuropathy characterized by dysautonomia and neuralgia is seen in patients where rapid glycemic control is achieved in the presence of high pre-treatment HbA1c. Dysautonomia improves over a period of time.³¹ 

Summary

Periodic thorough neurological examination is the key for an early diagnosis of patients with diabetic neuropathy; hence, preventing further dreadful complications of neuropathy.

New metabolic risk factors (obesity) and mechanisms (dyslipidemia and deoxysphingolipids) can lead us to the development of new disease-modifying therapies for neuropathy.

New diagnostic tests are available (IENFD, CCM, neurometer, DPNCheck, and Sudomotor testing), which can diagnose the DPN early in the process and can phenotypically categorize the type of neuropathy.

Good glycemic control is essential (with strong evidence in type 1 diabetes).

At present, the treatment of DPN is mainly symptomatic.

Newer modalities, such as spinal cord stimulation have a potential role in the treatment of refractory painful diabetic polyneuropathy.

Conflict of Interest

None.