1. Introduction
Peripheral neuropathies (PNPs) encompass a large group of disorders of different etiologies that may present with sensory and/or motor deficits and/or autonomic dysfunction depending on the predominant nerve fiber being affected. They are common disorders linked to severe impairment and poor prognosis [1].
PNPs cause loss of sensation, and the risk of feet ulceration may lead to infections. Loss of protective sensation is the first sign and when identified must be followed with the appropriate preventive measures. Peripheral neuropathy is a complication seen in approximately 50% of patients with diabetes, but up to 50% of patients with peripheral neuropathy may be asymptomatic [2, 3].
Peripheral neuropathies may result from a broad spectrum of diseases including diabetes, toxic exposures such as alcohol and chemotherapy; immune-mediated conditions and gene mutations. Neuropathies are very common disorders with an incidence of 77/100,000 inhabitants per year and a prevalence of 1–12% in all age groups and up to 30% in older people [4, 5, 6, 7].
One of the most common worldwide chronic diseases is diabetes mellitus (DM). According to the International Diabetes Federation (IDF), DM affects 425 million people worldwide, and for the year 2045, this figure is projected to rise to 628 million [8]. Increasing prevalence of diabetes type 1 and type 2 results in an increase of diabetes-related complications, which conversely impact the quality of life (QoL) [9].
2. Diabetic peripheral neuropathy
Diabetic peripheral neuropathy (DPN) is the most common long-term complication of diabetes and the primary cause of foot ulcers and lower-extremity amputation. Diabetic peripheral neuropathy has significant impact on the quality of life. It may present with the typical feet involvement to a more wide range of symptoms and signs from myelopathy-like to a myopathy-like symptoms to even death.
Diabetic neuropathy affects between 23 and 76% of people [10]. The progression of DPN is related to poor glycemic control, aging, long diabetes duration, visceral obesity, hypertension, smoking, hyperinsulinemia, and dyslipidemia [11]. Improved glycemic control, early detection, and preventive care can avoid adverse outcomes.
DPN is a well-known microvascular complication of type 2 diabetes mellitus resulting from chronic hyperglycemia and defined by a peripheral nerve dysfunction in a diabetic patient after other etiologies have been excluded. Neuropathy develops in about 5–10% of diabetic patients in the first year, and 60–70% of diabetic patients experience some type of diabetic peripheral neuropathy after 20 years of duration of diabetes [12, 13].
2.1 Pathogenetic mechanisms
Peripheral nerve damage in diabetic peripheral neuropathy is caused by a variety of mechanisms; the most important are oxidative stress, inflammation, and mitochondrial dysfunction. Diabetes activates inflammatory molecules, causing a functional nitric monoxide deficit, activation of alternative metabolic pathways, accumulation of glycation end products, oxidative stress, and inflammation.
The expression of pro-inflammatory cytokines including C-reactive protein, TNF-, and IL-6 is higher in people with diabetes. Chronic hyperglycemia causes cytokines to infiltrate vascular tissue, which will reduce the body’s ability to heal by its own [14].
Chronic hyperglycemia stimulates macrophages, such as cells secrete TNF-, resulting in an increased of cytokine released. TNF- boosts the expression of endothelial cell adhesion molecules, precipitating atherosclerosis. In patients with poorly regulated diabetes, increased TNF development as a result of hyperglycemia is a factor in exacerbating insulin resistance. The effect of TNF- on Schwann cells also explains local demyelination in peripheral neuropathy [15].
Hyperglycemia primarily affects Schwann cells, resulting in cell damage, altered axon integrity, and impaired growth factor signaling [16, 17, 18]. Defective inflammatory pathways in axons and Schwann cells, including advanced glycation end product/receptor (AGE/RAGE) signaling, have been observed in diabetic neuropathy in animal models that lead to nerve damage [19].
Sensory neurodegeneration in the chronic stage of diabetes was linked to early damage to the distal axons of both upper and lower limb neurons in a study involving both human and animal models, revealing a pattern that explains the glove and stocking distribution loss of sensation seen in DPN. These changes are accompanied by widespread defects in electrophysiology and gene expression, all of which contribute to a degenerative phenotype [20].
Existing data about the development of DPN, such as increased oxidative and nitric oxide stress, polyol accumulation, microangiopathy, abnormal AGE-RAGE signaling, and/or mitochondrial dysfunction, account for a variety of mRNA modification that modify miRNA expression patterns, resulting in a wide range of DPN phenotypes.
Endothelial nitric oxide synthase (eNOS) dysfunction can play a key role in the pathogenic pathway that leads to diabetic vascular complications, such as DPN. As a result, eNOS is thought to be a potential cause for DPN progression. Hyperglycemia is associated with defects in the vasa nervorum and nerve fiber loss in the early stages of DPN. The ischemia and hypoxia in the nerves of patients with type 2 diabetes mellitus due to microangiopathy of vasa nervorum have always been observed and possibly a pathogenic mechanism of DPN [21, 22, 23].
2.2 Clinical manifestations
Diabetes can damage different parts of the peripheral nervous system with distal symmetric polyneuropathy (DSP) being the most common presentation. The symptoms are symmetric and with predominant sensory symptoms over motor involvement. Sensory symptoms such as numbness, tingling, and pain are common in DSP patients.
These characteristics begin in the feet and spread proximally in a length-dependent pattern known as stocking-and-glove distribution [24]. Other patterns of injury include small-fiber predominant neuropathy, radiculo-plexopathy and autonomic neuropathy, among others.
DSP has an effect on the physical and emotional well-being of patients. Sensory loss caused by DSP often causes trouble walking, which can lead to falls. DSP is one of major risk factors for falls in diabetic patients along with retinopathy and vestibular dysfunction. Diabetic DSP patients are 2–3 times more likely than diabetics without neuropathy to fall.
Diabetes is the leading cause of lower extremity amputations, with a 15-fold increase in the likelihood of this life-changing complication. Moreover, 80,000 lower extremity amputations are performed each year in patients with diabetes [25, 26, 27].
Neurogenic pain, numbness, a lack of control of voluntary movements, and a susceptibility to foot ulceration that contributes to infections and toe or foot amputations are all signs of diabetic neuropathy. Diabetic patients have a 15-fold higher risk of toe or foot amputations than nondiabetic patients [28].
According to Toronto Consensus Panel on Diabetic Neuropathy, DPN is defined as a symmetrical, length-dependent sensorimotor polyneuropathy that develops in the background of long-standing hyperglycemia, associated de-arrangements, and cardiovascular risk factors [29].
Different studies reported that some patients with prediabetes develop neuropathic complications, whereas others reported little evidence of neuropathy even after long-standing diabetes. This observation confirms the involvement of genetic etiological factors associated with the development of DPN [30].
Neuropathic pain is one of the major disabling symptoms of patients with DSP. It is estimated that diabetic neuropathic pain (DNP) develops in 10–20% of the diabetic population overall and can be found in 40–60% with documented neuropathy. Like other types of neuropathic pain, DNP is characterized by burning, electric, and stabbing sensations with or without numbness [31, 32, 33]. It is characteristically more severe at night often resulting in sleep disturbance. Together with painful symptoms during the day, this often leads to a reduction in quality of life.
In one study, the burden of painful DPN was reported to be significant, resulting in persistent discomfort following polypharmacy and high resource usage, as well as limitations in everyday activities and dissatisfaction with treatments that were frequently deemed ineffective. DPN that is chronic, persistently painful, and highly distressing is linked to severe depression, anxiety, and sleep loss [34, 35]. Other types of diabetic neuropathies includes small-fiber polyneuropathy, mononeuropathy, mononeuropathy multiplex, radiculopathy, plexopathy (diabetic amyotrophy), autonomic neuropathy, and treatment-induced neuropathy.
3. Screening or diagnostic assessment
A staging system, which has four stages, was used to provide a framework for diagnosis and management for DPN (Table 1) [36].
| Stage of diabetic peripheral neuropathy | Characteristics | |
|---|---|---|
| Stages 0/1 | No clinical neuropathy | Asymptomatic |
| Stage 2 | Chronic painful | Positive symptomatology nocturnal pain, burning, shooting, stabbing pains ± pins, and needles |
| It may have absent sensation to several modalities and reduced or absent reflexes | ||
| Acute painful | Less common | |
| It may be associated with initiation of glycemic therapy in poorly control diabetes | ||
| Normal or minor sensory features in the peripheral neurological examination | ||
| Painless with complete/partial sensory loss | No symptoms or numbness/deadness of feet; reduced thermal sensitivity; painless injury | |
| Signs of reduced or absent sensation with absent of reflexes | ||
| Stage 3 | Late complications of clinical neuropathy | Foot lesions, e.g., ulcers |
| Neuropathic deformity, e.g., Charcot joint | ||
| Nontraumatic amputation | ||
Table 1. – The staging system of diabetic peripheral neuropathy.
The prevalence of neuropathy is determined by subjective complaints, signs, or nerve conduction studies. Electrodiagnostic findings provide a higher level of specificity for the diagnosis of polyneuropathy and should be included as a part of the assessment. Nerve conduction studies (NCSs) are the most informative part of electrodiagnostic evaluation, which commonly includes both NCS and needle electromyography. NCSs have been a criterion or gold standard test for confirming the diagnosis of peripheral neuropathies.
A simplified scoring system, the Diabetic Neuropathy Symptom Score (DNS), assesses pain, numbness, tingling, and ataxia. The maximum score of DNS is four points, one point or more indicates neurological abnormalities [37, 38, 39].
To quantify clinical neuropathy, the Neuropathy Symptom Profile, the Neuropathy Symptom Score, and the Neuropathy Disability Score were developed. The Michigan Neuropathy Rating Scale consists of two parts. The first part is the Neuropathy Screening Instrument, which consists of a 15-item questionnaire on foot sensation, including numbness, burning, and sensitivity. The second part is the Diabetic Neuropathy Score, which consists of clinical neurological examination and nerve conduction studies. Sensation, including vibration, pin prick, and light touch; distal muscle strength; and reflexes (biceps, triceps, quadriceps femoris, and Achilles) are assessed [40].
The performance of the protective sensation of the foot in diabetic patients is monitored using a variety of instruments. Pain perception, vibration perception, temperature perception, and deep reflexes are some of the most popular screening methods for DPN. Monofilaments, such as Semmes-Weinstein Monofilament Testing (SWMT), are one of the safest and most cost-effective ways to screen DPNs. SWMT is calibrated to the point that if a force of 10 g is applied to the point where the monofilament bends, but the patient does not notice it, that point is deemed insensate.
This is a basic test that predicts the likelihood of foot ulceration in diabetic patients. To assess the presence of sensation, certain points on the feet are stimulated by placing monofilament on the skin. It has a high sensitivity for detecting the possibility of foot ulceration and helps to prevent traumatic injuries [41, 42, 43].
In order to assess pain, several scales are used. Most common and oldest is the Numerical Pain Rating Scale, which is an 11-point Likert scale (0 = no pain to 10 = worst possible pain). Other validated scales such as Neuropathic Pain Symptom Inventory [44], Modified Brief Pain Inventory [45], neuropathic pain questionnaire [46], the LANNS pain scale [47], and McGill Pain Questionnaire [48] are often used.
Quality of life (QoL) might be assessed with neuropathy-specific instruments that are based on patient’s experience of neuropathic pain, such as NeuroQoL [49], Norfolk Quality of Life Scale [50], and Neuropathic Pain Impact on Quality of Life Questionnaire (NePIQoL) [51]. The impact of painful symptomatology on mood can be evaluated using scales such as Hospital Anxiety and Depression Scale (HADS) [52].
The other scoring systems such as Clinical Neurological Examination (CNE), Diabetic Neuropathy Examination (DNE), Diabetic Neuropathy Symptom score (DNS), Michigan Neuropathy Screening Instrument (MNSI), Neuropathy Disability Score (NDS), Neuropathy Impairment Score (NIS), Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Neuropathy Symptom Profile (NSP), Neuropathy Symptom Score (NSS), Toronto Clinical Scoring System (TCSS) can be used to screen and determine the severity of DPN [39].
Clinical care guidelines have recommended that annual screening for peripheral neuropathy occurs in all patients with diabetes, as part of routine evaluation to prevent complications.
Routine NCSs include evaluation of motor function of the median, ulnar, peroneal and tibial nerves and sensory function of median, ulnar, radial, and sural nerves. Different nerves attributes such as amplitudes are used in the assessment of axonal status; and latencies, conduction velocities, and F-waves latencies as function of myelination.
Amplitudes are reduced in axonal damaged. In demyelinating neuropathies, nerve conduction latencies and F-waves latencies are prolonged and conduction velocities are reduced.
4. Management
Clinicians face a significant challenge in assessing and treating DPN, and an empathic and multidisciplinary approach is essential because the effect of painful DPN is varied and multidimensional. Ideally, a multidisciplinary team might include input from nutritionists, endocrinologists, neurologists, pain specialists, nurse practitioners, podiatrists, psychologists, physiotherapists, and others [53].
There is a general consensus that good blood glucose control should be the first step in the management of any form of diabetic neuropathy. Hypertension and hyperlipidemia, which are risk factors of large vessel diseases, are also commonly seen in DPN, and it is also important to address them.
Some of the commonly prescribed treatments include physiological glucose control (HbA1C 6–7%), along with lifestyle modifications (i.e. diet, exercise). Tricyclic antidepressants (TCAs) such as amitriptyline and imipramine promote successful analgesia to thermal, mechanic, and electrical stimuli in diabetic patients by the inhibition of noradrenalin and/or serotonin reuptake synapses of central descending pain-controlled systems.
Serotonin and noradrenalin reuptake inhibitors (SNRIs) such as duloxetine and venlafaxine relieve pain by increasing the synaptic availability of 5-hydroxytryptamine and noradrenaline in the descending inhibitory pathway against pain.
The two anticonvulsants most commonly used to treat neuropathic pain are gabapentin and pregabalin, which bind to the α-2-δ subunit of the calcium channel, reducing calcium influx and thereby resulting in decreased synaptic neurotransmitter release into the hyperexcited neuron [54, 55, 56].
According to the European Federation of Neurological Societies’ recommendations, first-line therapies could include TCAs, SNRIs, gabapentin, or pregabalin. The National Institute for Health and Clinical Excellence in the United Kingdom recently released recommendations on the treatment of neuropathic pain in nonspecialist settings, which included a section on painful DPN management.
Despite the fact that the level of evidence for pain effects with duloxetine, pregabalin, and gabapentin is comparable, the National Institute for Health and Clinical Excellence recommends that oral duloxetine be used first, with amitriptyline as an alternative and pregabalin as a second-line treatment [57, 58, 59].
There are wide ranges of alternative therapies available for DPN pain, which include acupuncture [60], near-infrared phototherapy [61], low-intensity laser therapy [62], transcutaneous electrical stimulation [63], frequency-modulated electromagnetic neural stimulation therapy [64], high-frequency external muscle stimulation [65], and as a last resort, the implantation of an electrical spinal cord stimulator [66].
The integrity of joints, muscles, and neural structures, especially the small joints and intrinsic muscles of the foot and ankle, is compromised as neuropathy progresses, resulting in poor dynamic stability of the foot, inadequate foot mobility, and impaired locomotor tasks.
All of these losses have an impact on load absorption and transmission while the patient is walking, exposing the foot to mechanical overloads that lead to tissue breakdown and decreases the quality of life [67].
Most of the treatments that diabetic patients receive are passive. Plantar load relief is only recommended when critical neuropathy outcomes, such as foot deformities, ulcerations, and amputations, are already present. Active and preventive therapeutic actions, on the other hand, are strongly recommended for delaying or even preventing sensory, motor, and tissue complications, thus reducing the effect of disease on quality of life [68, 69, 70].
The uniform distribution of plantar pressure is hampered by foot deformities and defects in the extrinsic and intrinsic foot and ankle muscles. These factors cause the toes and hallux to participate inefficiently while the foot swings during walking, making the individuals at a higher risk of tissue damage.
Ulceration is linked to both restricted joint mobility and high plantar loads. Thus preventive measures for the maintenance of joint mobility are highly recommended from the onset of disease [71, 72].
The reduction of tissue stress is considered as the main goal of interventions in patients with neuropathy. Those are achieved by prescribing shoes and custom-made insoles, orthotics with rocker soles. The primary aim of these orthotic devices is to change the foot rollover and thus passively redistribute plantar pressure.
Exercise therapy for the foot and ankle, on the other hand, has the potential benefit of actively adjusting the foot loading, resulting in improvements in force absorption and transmission due to improved muscle function and joint stability.
Thus, the use of an orthotic device for the prevention of foot ulceration along with a regimen of therapeutic exercises to improve the functionality of the individual’s foot is recommended [73, 74].
Even though exercises do not directly prevent ulcer development, they do target musculoskeletal defects by trying to maintain or enhance the muscle and joint function of the distal segments, which can lead to improved individual functioning, a better health status, a higher quality of life, and a lower risk of falling [75, 76, 77].
Therapeutic exercises also enable patients to maintain for as long as possible the residual biomechanical capability of interacting safely with the ground while walking and standing, and they can potentially be associated with prevention of tissue breakdown.
Interventions that combined foot-ankle strengthening exercises and balance exercises showed improvement in the support time during single stance, tandem, and functional reach as well as in the equilibrium and confidence scores on their Activities Specific Balance Confidence Scale Questionnaires [78, 79].
Also gait training strategies to reduce plantar loads have shown modest results in neuropathic individuals. The proposed exercise program aims to integrate peripheral benefits for foot function during everyday locomotor activities using segmental exercises (muscle strengthening and range of motion).
The clinical outcomes were favorable, with improvements in foot muscle control, foot and ankle function, and neuropathy symptoms. For further information on the therapy of painful polyneuropathy, refer to chapter on Peripheral Neuropathy Treatment and Management.
5. Conclusion
The screening of symptoms and signs of diabetic peripheral neuropathy is essential in all diabetic patients for an early recognition and management of diabetic neuropathies.
Acknowledgments
The authors sincerely thank Dr. G. Bakthavathsalam, Chairman, Mrs. Vasanthi Ragu, Vice Chairman, Mrs. Vaijeyanthi M. Das, CEO, Mr. Prabhu Kumar, CEO, and Prof V. Mohan Gandhi, CEO, KG Hospital, Coimbatore, India, for their support.
Authors
Manoharlal Manoj Abraham
K.G. College of Physiotherapy, Coimbatore (Affiliated to the Tamil Nadu Dr. M.G.R Medical University, Chennai), India
Subramaniam Hari Hara Sudan
K.G. College of Physiotherapy, Coimbatore (Affiliated to the Tamil Nadu Dr. M.G.R Medical University, Chennai), India
Venugopal Pavithra
K.G. College of Physiotherapy, Coimbatore (Affiliated to the Tamil Nadu Dr. M.G.R Medical University, Chennai), India
Attribution
Abraham, Manoharlal, Sudan, Subramaniam, Pavithra, Venugopal. “Diabetic Peripheral Neuropathy” In Demyelination Disorders, edited by Stavros Baloyannis, Fabian Rossi, Welwin Liu. London: IntechOpen, 2022. 10.5772/intechopen.100859
