Front. Endocrinol., 26 May 2021 | https://doi.org/10.3389/fendo.2021.671257
Advances in Screening, Early Diagnosis and Accurate Staging of Diabetic Neuropathy
1Diabetes and Vascular Research Centre, National Institute for Health Research, Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom
2Peripheral Neuropathy Group, Imperial College, London, United Kingdom
3Internal Medicine, Ishibashi Medical and Diabetes Centre, Hiroshima, Japan
The incidence of both type 1 and type 2 diabetes is increasing worldwide. Diabetic peripheral neuropathy (DPN) is among the most distressing and costly of all the chronic complications of diabetes and is a cause of significant disability and poor quality of life. This incurs a significant burden on health care costs and society, especially as these young people enter their peak working and earning capacity at the time when diabetes-related complications most often first occur. DPN is often asymptomatic during the early stages; however, once symptoms and overt deficits have developed, it cannot be reversed. Therefore, early diagnosis and timely intervention are essential to prevent the development and progression of diabetic neuropathy. The diagnosis of DPN, the determination of the global prevalence, and incidence rates of DPN remain challenging. The opinions vary about the effectiveness of the expansion of screenings to enable early diagnosis and treatment initiation before disease onset and progression. Although research has evolved over the years, DPN still represents an enormous burden for clinicians and health systems worldwide due to its difficult diagnosis, high costs related to treatment, and the multidisciplinary approach required for effective management. Therefore, there is an unmet need for reliable surrogate biomarkers to monitor the onset and progression of early neuropathic changes in DPN and facilitate drug discovery. In this review paper, the aim was to assess the currently available tests for DPN’s sensitivity and performance.
Diabetes is one of the fastest-growing health challenges of the 21st century, with the number of adults living with diabetes having more than tripled over the past 20 years ( 1 ). The International Diabetes Federation reported that in 2019, the prevalence of diabetes was 9.3% (463 million people worldwide) with a predicted rise to 10.9% (700 million people) by 2045 ( 2 ). Furthermore, it has been shown that over 1.1 million children and adolescents below 20 years have type 1 diabetes. On top of these staggering figures, are the number of people with impaired glucose tolerance (IGT) or metabolic syndrome with 373.9 million in 2019 (7.5%) and predicted rise to 548.4 million (8.6%) by 2045 ( 2 ).
In the UK alone, there were 4.8 million people with diabetes in 2019. Diabetes is on the rise. Figures from Diabetes UK shows that someone is diagnosed with diabetes every two minutes, with 5.3 million expected to be living with the condition by 2025 ( 3 ).
Diabetes is strongly associated with both microvascular and macrovascular complications. As a result, 10% of global health expenditure, equal to USD 760 billion, is directed toward diabetes and its complications ( 2 ). Microvascular changes lead to nephropathy, retinopathy and neuropathy. Among these complications, diabetic peripheral neuropathy (DPN) is the most common and costly diabetes-associated complication, occurring in around 50% of individuals with diabetes ( 4 ). Distal symmetric polyneuropathy (DSPN) ( 5 ) typically follows a distal-proximal course and results in symmetrical symptoms and signs between the body’s left and right sides. Common symptoms include burning, numbness, tingling, pain and/or weakness starting in the distal lower extremities which progress into more extreme symptoms of neuropathic pain in around 10-30% of affected patients ( 6 , 7 ). Symptoms may be sporadic or constant but can be debilitating and in many people lead to depression, sleep disorders and overall reduced quality of life ( 8 ).
The true prevalence of DPN is underestimated as its assessment is challenging. However, DPN is recognized as the most common complication of diabetes.
DPN is the strongest initiating risk factor for diabetic foot ulceration (neuropathic ulcer) ( 9 , 10 ), and existing ulcers may be further exacerbated from damage to sensory neurones. Resultant limb numbness causes ulcers to remain undetected for longer periods ( 10 ); thus, corrective actions are not taken nor advice sought at early stages of the disease. Often the first sign that a person has diabetic peripheral neuropathy (DPN) is a foot ulcer, which may lead to irreversible tissue damage, lower limb amputation and significant morbidity.
In the UK, people with diabetes account for more than 40% of hospitalizations for major amputations and 73% of emergency admissions for minor amputations. A single diabetes related foot ulcer can take over 240 days to put into remission and costs £8,000 pa to treat. Ulcers frequently recur and eventually may require the amputation of a lower limb. DPN is hugely costly to our NHS (>£1.1 billion pa in direct medical costs) and to the wider UK economy (~£4 billion), is particularly debilitating and distressing for patients and their families and can lead to an untimely death ( 11 , 12 ), with five-year mortality ranging from 52 to 80 percent after major amputation ( 13 ).
Furthermore, with diabetes related lower limb amputations increasing at the rate of almost 20% per annum in line with the increasing prevalence of diabetes, there is a huge strain on NHS budgets which are unable to keep up.
Autonomic neuropathies are a class of DPN which share similar diffuse pathophysiology with DSPN, but differ by being largely non-sensory ( 4 ). These typically affect the cardiovascular, urogenital and gastrointestinal systems. Patients may also suffer from sudomotor dysfunction, hypoglycemia obliviousness, and abnormal pupillary function ( 5 ). Rare forms of DPN include mononeuropathies, polyradiculopathies and treatment-induced neuropathies ( 5 ). These atypical forms are generally self-limiting and resolve with medical management and physical therapy, usually over several months ( 11 ).
In clinical settings, there are several different approaches to assess diabetic peripheral neuropathy (DPN), and the choice of the test will depend on the aim of testing. It is usually sufficient in a busy clinic to establish whether a patient is symptomatic, particularly of painful DPN ( 12 ), and whether or not they are at high risk of foot ulceration typically through monofilament testing. However, to fully assess damage and phenotype of DPN, sensory deficits must be detected early. Those accurate biomarkers are available for monitoring of DPN and for use in clinical trials of potential new treatments.
Currently, there are no simple markers for early detection of DPN in routine clinical practice. The measures we use are crude and detect the disease very late in its natural history. Even the benefits gained by standardizing clinical assessment with scored clinical evaluations remain subjective, heavily reliant on the examiners’ interpretations.
This paper reviews the current knowledge and the optimal approaches for diagnosis and screening of diabetic peripheral neuropathy.
Types of Nerve Fibers
Peripheral nerve fibers can be classified using Erlanger and Gasser’s classification, which defines nerves based on diameter, conduction speed, and myelination level ( Table 1 ). A-fibers have the largest diameter, with the thickest myelination and fastest conduction speed, and act as sensory and motor fibers within the somatic nervous system. They may be further divided into large nerve fibers that have sensory and motor functions (Aα and Aβ), and small nerve fibers (Aγ which has motor functions, and Aδ which may be autonomic or sensory fibers) ( 14 ).
Table 1 Classification of nerve fibers in the peripheral nervous system according to modified Erlanger and Gasser.
Group B-fibers are small, with moderate myelination and slower conduction velocities than A-fibers. B-fibers act mainly as general visceral afferent and pre-ganglionic fibers and are found only in the autonomic nervous system.
Group C-fibers have a small diameter, low conduction velocity and are the only unmyelinated group. They act as somatic, afferent fibers that carry sensory information relating to temperature and pain, as well as having autonomic functions such as the stimulation of the sweat glands ( 14 ).
The prevalence of diabetic peripheral neuropathy (DPN) reported in various studies ranges from 6% to 51% depending on the population ( 15 , 16 ). In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DDCT/EDIC) Study, the prevalence of DPN in adults with type 1 diabetes was 6% at baseline and increased to 30% after 13–14 years of follow-up ( 17 ). The prevalence of DPN among adults with type 1 diabetes in the Pittsburgh Epidemiology of Diabetes Complications was 34% and increased significantly with age (18–29 years: 18%; ≥30 years: 58%). It has been estimated that half of all children with diabetes with a duration of 5 years or longer already have diabetic neuropathy ( 18 ) and nearly 25% of pediatric patients with newly diagnosed diabetes have abnormal findings on nerve conduction studies (NCS), indicating nerve damage ( 19 ).
The prevalence of DPN is somewhat higher in patients with T2DM when compared to T1DM ( 4 ). The ‘Action to Control Cardiovascular Risk in Diabetes’ (ACCORD) ( 20 ) trial and the ‘Veteran Affairs Diabetes Trial’ ( 21 ) found that DPN was present in 42% and 39% of adults with type 2 diabetes, respectively, at baseline measurement. A study comparing magnetic resonance imaging (MRI) scans of the sciatic nerve in T1DM, and T2DM patients with DPN found that the predominant type of nerve lesion differed between the two ( 22 ). This study found that in T1DM, lesions were predominantly associated with poor glycemic control and loss of nerve conduction, whereas in T2DM lesions were associated with changes in lipid metabolism. This raises the question of whether damage to peripheral nerves results in different patterns of nerve damage, and thus would require different types of preventive treatment.
In both main types of diabetes, the prevalence and severity of DPN increases with disease duration and increasing age ( 16 ). A large study of 1172 patients with diabetes assessed for neuropathy at baseline reported that patients who had developed neuropathy by roughly ten-year follow-up were on average 3.8 years older and had diabetes for 3.3 years longer at baseline ( 16 ). Furthermore, the study found that in both T1DM and T2DM, higher hemoglobin A1c (HbA1c) level was a significant predictor of the development of diabetic neuropathy ( 16 ).
In cohorts of patients with T2DM, several metabolic syndromes such as hypertension, abdominal obesity, lower high-density lipoprotein (HDL) levels and hypertriglyceridemia have been consistently associated with DPN development ( 23 ), with additional independent risk factors including alcohol abuse and increased height ( 24 ). In a cohort of patients with T1DM, the EURODIAB prospective complications ( 25 ) study reported similar modifiable risk factors to those identified in T2DM, explicitly having an association with raised triglyceride level, obesity, smoking and hypertension. Several genes have also been linked to an increased risk of diabetic neuropathy. Still, only ACE (encoding angiotensin-converting enzyme) and MTHFR (encoding methylenetetrahydrofolate reductase) polymorphisms have been confirmed using large patient cohorts in multiple populations ( 24 ). Research into the role of genetics in diabetic neuropathy is currently limited, and many more studies are required.
Significantly lower levels of clinical neuropathy in South Asian patients have been reported compared to Europeans and Afro-Caribbean ( 26 ). A recent study found that in a population of people with type 2 diabetes, South Asians had significantly better-preserved small nerve fiber integrity than equivalent Europeans ( 27 ). However, this patient cohort was recruited from primary care, and most patients had no or mild neuropathy, so it was not representative of the diabetic population overall. A proposed explanation for the reduced risk was the differences in the transcutaneous partial pressure of oxygen (TCpO2) and height between the ethnicities ( 27 ). However, the study suggesting this explanation did not adjust for a range of possible confounders such as obesity, and alcohol intake, between ethnicities, all of which are established risk factors for developing DPN. A more recent study suggested that the variation may be due to differences in height and adiposity between the ethnic groups, as the adjustment for these factors rendered the difference insignificant ( 28 ).
There is currently no Food and Drug Administration (FDA) approved therapy to prevent or reverse human DPN ( 4 ). The current management approach focuses on reasonable glycemic control, lifestyle modifications, and management of associated pain. The reasonable glycemic control consists of not only strict HbA1c control but also reduced glycemic variability, because glycemic variability has recently emerged as an another measure of glycemic control, which might constitute an additive, or even better predictor of microvascular complications including neuropathy than mean HbA1c levels ( 29 , 30 ).
Previous studies have found that improving HbA1c levels does affect DPN progression in patients with T2DM ( 20 , 31 ). The ACCORD study ( 20 ) found that intensive treatment caused delay in onset of albuminuria and it reduced neuropathy, MNSI socre, loss of ankle jerks, loss of light touch at end of the study. The veterens study ( 31 ) assessed whether new evidence of clinical neuropathy occurred during the period of intensive versus normal control and had quite severe criteria for definaitions. The Epidemiology of Diabetes Interventions and Complications (EDIC) trial reported that intensive glucose control significantly delayed the development and progression of diabetic neuropathy in T1DM patients over time ( 17 ). Another study, following a cohort of T1DM patients over 24 years confirmed these findings. Patients who had stable, near-normal HbA1c levels (mean