New Perspective on Diabetic Neuropathy

 Diabetic neuropathy was the subject of a dedicated plenary session at the congress of the Francophone Diabetes Society. This already prevalent issue is becoming more prevalent and remains inadequately addressed. Phenotyping patients is essential, and the use of neurofilament for this purpose is insufficient. Electromyography (EMG), too, can be misleading, said Agnès Hartemann, MD, PhD, head of the diabetology department at Pitié-Salpêtrière Hospital in Paris, France.

"The number of people affected by diabetic neuropathy has more than tripled worldwide since 1990, reaching 206 million in 2021," said Liane Ong, PhD, lead research scientist at the University of Washington in Seattle and coauthor of the 2021 Global Burden of Disease, Injuries, and Risk Factors Study.

According to the literature, 25%-30% of individuals with diabetic peripheral neuropathy have neuropathic pain. Not surprisingly, pain progresses with age. Over the 26 years of follow-up of the Epidemiology of Diabetes Interventions and Complications study, the observational follow-up of the DCCT trial (1982-1993), the prevalence of neuropathic pain (Q2: "Have you ever felt burning sensations in your legs and/or feet?" and/or Q6: "Does it hurt when bed covers touch your skin?") increased from 8.5% to 19.8%. The rate of a Michigan Neuropathy Screening Instrument score higher than 2 increased from 22.9% to 43.5%.

"The monofilament has taken an excessive place in screening," said Hartemann, who described the pathophysiology of neuropathic pain at the congress. "It has long been believed that sensory neuropathy affected small fibers and that painful neuropathy affected large fibers. However, this distinction no longer holds true because there can be involvement of both types of fibers in both types of neuropathy." Indeed, there are two forms of nerve suffering in peripheral neuropathy: Firstly, the loss of fibers leading to loss of function (so-called "sensory" neuropathy), and secondly, neuropathy with hyperactivity of fibers, hyperexcitability that constitutes a gain of function. This hyperactivity involves dysfunctional ion channels with spontaneous, iterative, untimely activation at the peripheral level with repercussions at the spinal junctions.

Loss and Gain of Function

The loss of function (sensory neuropathy) corresponds to a rarefaction of large (> 30 m/s) and small (3-30 m/s for thinly myelinated and < 3 m/s for unmyelinated) nerve fibers. "When you look for this loss of function in large fibers, that's where you'll find the abolition of osteotendinous reflexes, decreased vibration and proprioception perception, sensitivity to touch and pressure," said Hartemann. This is what the 10-g monofilament test explores: A light contact between touch and pressure. The rarefaction of small fibers leads to decreased pain sensitivity (as gauged by the needle test), perception of heat and cold, and sensitivity to pressure, which seems to be shared between large and small fibers.

Moreover, painful neuropathy (gain of function) concerns not just small fibers as previously thought because hyperexcitability "can come from large fibers," said Hartemann. Thus, patients describe a sensation that the foot is caught in a vice, as well as mechanical allodynia (rubbing of sheets or with cotton). Hyperexcitability of the small fibers causes the well-known symptoms of pricking, painful cold (the sensation of walking barefoot on snow), burning, itching, thermal allodynia, hyperalgesia, and electric shocks.

The spine sustains a loss of inhibitory pain function. Hyperexcitability has repercussions in the brain in the form of increased depression, anxiety, and sleep disturbances secondary to pain. The frequency and duration of these disturbances, however, exceed what is observed with chronic pain of similar intensity but of another origin, with an amplification by a peripheral-spinal-central vicious circle.

Whether neuropathy begins with hyperactivity of fibers or loss of function is unclear. The percentage of patients presenting one of the neuropathies, the other, or both depends on the population and the tools used. In one study involving 232 patients with type 1 and type 2 diabetes (74%), with an average age of 63 years and neuropathy confirmed by EMG or biopsy, researchers found deafferentation in 54%, "irritable nociceptors" in 15%, and both in 31%.

EMG When in Doubt

The diagnosis of fiber rarefaction (ie, sensory neuropathy) is essentially clinical. EMG may present anomalies only if the loss of function affects large fibers. Therefore, without anomalies on the EMG, it is possible to incorrectly conclude the absence of diabetic neuropathy, although there is targeted involvement of small fibers.

Skin biopsy at the ankle, revealing rarefaction of small fibers in the epidermis and dermis, is used in clinical research to phenotype patients. Confocal corneal microscopy (indirect vision of small fiber loss) has not yet been standardized.

The diagnosis of hyperactivity (excitability) is also clinical. EMG, skin biopsy, and confocal corneal microscopy may be normal and, therefore, useless for positive diagnosis. "We must refer our patients to pain centers so that they are phenotyped and receive the most appropriate treatment for the type of pain," said Hartemann. Recognizing diabetic neuropathy is crucial, especially in patients with diabetes, who may suffer from various pains, especially in the lower limbs.

For this purpose, the DN4 screening questionnaire has been revalidated by several teams in diabetic neuropathy. A score > 4 suggests diabetic neuropathy with a sensitivity of 83% and a specificity of 90%.

A study published in 2013 in which Hartmann participated found that 14% of patients with type 1 diabetes and 24% of patients with type 2 diabetes had diabetic neuropathy. About 70% had consulted a clinician for pain, but only 38% had received appropriate treatment.

Certain characteristics may raise doubts about the diagnosis of diabetic neuropathy, including the speed of onset, symmetry, severe motor deficit, or proximal involvement, which require referral to a neurologist.

Concomitant diagnoses may include radiculopathy associated with cervical, dorsal, and lumbar regions. In these cases, EMG and MRI are relevant. Other etiologies to consider are poststroke neuropathy, Parkinson's disease, chemotherapy, knee osteoarthritis, and peripheral arterial disease.

Neuropathy is characterized by microangiopathy, which results from damage to the microvessels that innervate the nerves. But neuropathy has multiple risk factors, including glycemia and metabolic syndrome, overweight, cardiovascular diseases, dyslipidemia, hypertension, and smoking. "It even begins in type 2 prediabetes," said Hartemann. Therefore, there is an effect of chronic hyperglycemia (microangiopathy on endoneurial capillaries) as well as axonal insulin resistance related to the same risk factors as for muscles. There is axonal mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum stress.

https://www.medscape.com/viewarticle/new-perspective-diabetic-neuropathy-emerges-2024a10008lj