Diabetic neuropathy (Journal Summary)

Eva L. Feldman, Brian C. Callaghan, Rodica Pop-Busui, Douglas W. Zochodne, Douglas E. Wright, David L. Bennett, Vera Bril, James W. Russell and Vijay Viswanathan. 2019

DOI: https://doi.org/10.1038/ s41572–019–0092–1

A great piece on diabetic neuropathy that was recently posted in Nature. Just summarizing it for the benefit of future reference and knowledge. My own points in this study would be bold to distinguish information from the paper and my own.

What it actually is:

Typically it presents in a ‘stocking and glove’ pattern that affects the peripherals of the body. These include the retraction and dying back of sensory neurons due to the metabolic effects for diabetes. Hence, diabetic neuropathy is typically referred to as a length dependent neuropathy as the longer sensory fibers get affected first. This is why we typically see most symptoms happen at the feet and the lower legs first before the hands get affected.

Risk factors:

These would be the duration of diabetes and haemagoblin A1c levels which have been identified as major predictors of diabetic neuropathy. Metabolic syndrome factors include hypertriglyceridemia, hypertension, abdominal obesity and low high-density lipoprotein (HDL) levels. Whilst independent factors include smoking, alcohol abuse, increased height and older age.

Mechanisms:

Hyperglycemia

The overload of glucose can influence the substrate balance and processes in the function of healthy neuron activity. An overload of glucose can cause the formation of acylcarnitines that are harmful to Schwann Cells and DRG neurons. which are essential components in the neuronal system.

Increases in glucose level results in increased reactive oxygen species and subsequent inflammation through the production of radicals and AGE products that further harms Schwann cells and mitochondria that support the neuronal framework. Dysfunctional mitochondria produce insufficient energy that would be required to regulate neuronal traffic along axons, which would presumably be more impactful to longer neuronal fibers.

Hyperlipidemia

Oxidization of increased LDLs lead to a series of cascade that perpetuates the production of ROS and subsequent inflammation leading to progressive nerve injury.

Signs and Mechanisms of Pain

Symptoms can present as a burning sensation, or a hypersensitivity to stimuli that would typically not elicit pain (Such as feet touching on the marble floor or touching a blanket) and numbness. This could be accompanied by a reduction in sensory function. A situation where a patient can feel a constant pain at the foot but not sensate can also be expected.

Peripheral Sensory System

Hyperexcitability or dysfunction in the neural network could be due to the changes in ion channel regulation and function in the peripheral sensory system. Several ion channels that are responsible for impulse conduction the the central nervous system could have been altered and modified due to increased expression of reactive metabolites by hyperglycemia.

There also could be a genetic component in influencing the extent of this change where some diabetic patients can have a lower impact whilst others higher.

Central Sensory System

As the input from the peripheral sensory system gets passed onto the dorsal horn and subsequently to the brain, enhanced response can occur due to spatial and temporal summation of inputs. Changes to the shape of spinal neurons and changes in the gilial cells in the dorsal horn have been associated with diabetic painful neuropathy and this could be the reason for an amplified nociceptive signaling response.

Diagnosis

Diagnosis is determined by the conscientious history taking exercise and use of objective assessments to rule out potential differentials. However, medical history would otherwise suffice in zeroing in on the diagnosis.

Location

Numbness, tingling, pain and weakness and unsteadiness, starting distally (at the toes) and spreading proximally and then to the upper limb digits m typically when lower-limb symptoms reach the knees.

Nature of pain (when there is pain)

Distal painful symptoms of burning, lancinating, freezing pain that are greater at rest.

Clinical Findings

A loss of sensation to pinprick, temperature (mostly cold), vibration and proprioception in a ‘stocking and glove’ distribution. Locally, this is measurable in podiatry clinics with the use of the neurotheismeter and monofilament. A loss of ankle reflexes, small foot muscle strength and dorsiflexor strength can also be observed to support diagnosis.

Nerve conduction studies could pick up changes in function in long nerve fibers which would be useful in 1. Determining the extend of diabetes neuropathy or 2. Excluding diabetic neuropathy when symptoms of distal small fibers neuropathy do not preclude more proximal neuropathy in upper structures. One thing to take note when suggesting nerve conduction studies is that it does not test function in smaller fibers that are typically influenced by diabetic neuropathy. This is done by the use intraepidermal nerve fiber density with skin punch biopsy but this is not usually done due to it being intrusive and not clinically appropriate.

Differential Diagnosis and consideration

Neuropathy can also be caused by alcohol abuse, genetic neuropathies, neoplasia and quite commonly; as a side effect from HIV or Chemotherapy medications. A particular diet that lacks B12 vitamins can also be a contributory factor to neuropathy. Hence, even though a patient is diabetic, the patient’s neuropathy could be influenced other factors as mentioned. A understanding of presenting symptoms can also tell a different story. Such symptoms include a subacute or acute (sudden) development of neuropathy, non-length dependent neuropathy (numbness in the upper limbs prior to lower limbs) , motor neuropathy and a stark asymmetrical presentation of symptoms. If such occur, going through the list of possible differential causes can be helpful. Otherwise, an onward referral to a neurologist would be timely to rule out other acute systemic or immunological diseases.

Screening

Annual screening for neuropathy is recommended yearly for T1DM and T2DM. Currently, the procedure of diabetic foot screening in Singapore is satisfactory in this regard. The only issue is whether the catchment of annual screening is a significant portion or entirety of diabetic patients in a catchment area. There needs to be a movement to catch people early yet also provide the onward services to reduce the risk of deterioration related to diabetic neuropathy.

Prevention and management

The keypin of management would be to reduce hyperglycemic events and levels in both T1DM and T2DM patients. Studies have shown that the reduction of hyperglycemia seems to have a bigger impact on T1DM patients in regards to diabetic neuropathy than T2DM. Moreover, some classes of glucose-lowering agents have an impact on regulating other metabolic factors such as dyslipidemia which could also impact the diabetic neuropathic process. Overall it is still worthwhile to control blood sugar levels in T2DM patients as well.

Exercise is also a key strategy as it has the potential to prevent nerve injury and nerve regeneration to a certain extent. Lifestyle and diet changes go hand in hand with exercise as well. This provides an overall metabolic benefit to diabetes patients, such as a decrease in BMI and reduction in LDLs, which in turn influences the neuropathic processes. However, a balance has to be struck when some diabetes patients are not as mobile due to structural deformities, or have recurrent breakdowns due to mechanical pressure or tissue loss (active ulcers or blisters). The trick would be to encourage being active when the type of exercise could increase risk of other acute diabetic issues. Can exercise be doing stationary cycle machines? Open chain exercises? Sit to stand exercises? Research probably needs to go in this direction to have a more clinically relevant outcome for diabetic patients.

A overall holistic approach that incorporates the benefits of these interventions and limits of the patient’s capacity needs to established for each individual diabetic patient.

Disease modifying therapies are currently not at a stage of delivery to patients experiencing symptoms of diabetic neuropathy

Pain-control

Medication

Currently, 1st line pain medication therapies include the use oft anticonvulsants (Gabapentin or Pregabalin), serotonin and noradrenaline reuptake inhibitors and tricyclic antidepressants (Amitriptyline). Anticonvulsants are the most researched medication and are on the lower spectrum of adverse reactions for painful diabetic neuropathy but efficacy is mixed between patients. Amitriptyline have demonstrated some efficacy in small randomized, blinded, placebocontrolled clinical trials. SNRIs have also shown efficacy in some clinical trials but are more on the higher spectrum of adverse reactions as compared to anticonvulsants.

Opoids although effective, should be avoided due to the high risk of dependency to them, addiction and safety concern of the patient in the long run.

Vitamin B supplements such as Neurobion has been suggested to improve pain symptoms and nerve function relating to neuropathy. However, currently we are unsure whether Neurobion can effectively alleviate painful diabetic neuropathy and even less on the improvement of nerve function can be obtained by this supplement. In a 2016 review from the Singapore Medical Journal found no evidence that the use of oral vitamin B12 supplements is associated with improvement in the clinical symptoms of diabetic neuropathy(Jayabalan & Low, 2016).

Behavioural therapies:

Therapies such as cognitive behavior therapy and other forms of pain control therapies could benefit and has been shown to have some benefit to the management of painful diabetic neuropathy. How we can marry these forms of treatment with a patient’s already long list of concurrent treatments due to the diabetic process would be difficult and considerable effort needs to be put in place to balance clinical benefit with personal cost from the patient’s perspective.

Final Word:

Diabetic neuropathy and its complications such as painful diabetic neuropathy have a drastic impact in the quality of life of diabetic patients. Whilst, it is currently hard to reverse the impacts of diabetic neuropathy in patients, there is a case to reduce this phenomenon from deteriorating. This would have to be done by conscientious and consistent education and care from the point a diabetes diagnosis is known. Moreover, clinicians that are involved in the diabetic care of the patient have to be more informed in diabetic neuropathy to be able to guide and educate the patient on expectations and management of the pathology. Podiatrists stand at an awkward yet advantageous position currently as we are with patients for treatment routinely and are the first ones to see neurological changes in the foot. What can we do more in our limited capacity to help provide more value care for patients? I think that is something that we need to change if we were to effectively deal with this diabetes pandemic.

Acknowledgements:

This is a great journal article for all! I am not taking any credit from the article and it just helps in my thinking and growth as a podiatrist. Do credit the journal researchers if you do use their points elsewhere:)

Citation:

Jayabalan, B., & Low, L. L. (2016). Vitamin B supplementation for diabetic peripheral neuropathy. Singapore Medical Journal, 57(02), 55–59. https://doi.org/10.11622/smedj.2016027