Diabetic/peripheral neuropathy

Diabetic neuropathy is a complications of diabetes mellitus (both type 1 and type 2). It is a major risk factor for the development of foot ulcers in diabetic patients. It may be a mononeuropathy, polyneuropathy, amyotrophy (a

ffecting thighs, hips, buttocks and legs and causing muscle wasting) or it may lead to autonomic neuropathy.

It is the most common complication of diabetes (others being nephropathy, retinopathy and peripheral vascular disease) with around 50% of diabetic patients being affected.

Pathophysiology

Diabetic neuropathy occurs due to both metabolic alterations as well as microvascular complications associated with diabetes.

Hyperglycaemia, as a result of insulin resistance, also leads to the production of advanced glycation end products (AGEs). These are the result of the interactions of sugars with proteins or lipids. It leads to glycation of these proteins and lipids which leads to cross-linked structures that have altered structure and function. AGEs also interact with specific receptors such as the receptor for advance glycation end products (RAGE) which initiates signalling of inflammatory pathways, oxidative stress and tissue injury. Protein kinase C pathways are stimulated along with hexosamine pathways which initiate a cascade of events that results in aberrant expression of growth factors, cytokines and adhesion molecules that ultimately result in neuroinflammation and endothelial dysfunction.

Diabetes also leads to microvascular changes such as capillary basement membrane thickening and endothelial dysfunction. This leads to ischaemia to the nerve.

Chronic hyperglycaemia and oxidative stress impair DNA repair mechanisms which exacerbates the neurodegeneration. Schwann cells become dysfunctional due to impaired production of neurotrophic factors (factors that allow for nerve growth) and issues relating to myelination. This disrupts the myelin sheath of nerves which impairs nerve conduction and predisposes it to damage and inflammation.

Altered lipid metabolism in diabetes also leads to lipid accumulation around the axons and nerves which exacerbates the nerve damage.

⚠️ Risk factors

🔢 Classification

As mentioned previously, there are multiples types of diabetic neuropathies:

1. Diffuse neuropathy:
• ⭐️ Distal symmetric sensorimotor polyneuropathy - this is the most common type of diabetic neuropathy and is often synonymous with the term. It is characterised by loss of sensory axons leading to progressive loss of distal sensation (most commonly in the foot). The distribution of the sensory loss is characteristically a stocking-glove distribution. This can then progress to motor weakness when there is loss of motor axons (in more severe cases)
• ⭐️ Diabetic autonomic neuropathy (DAN) - this is also a common complication of diabetes that is seen in most diabetics. The autonomic nervous system is responsible for regulation of our hear rate, blood pressure, digestive processes, bladder function. When the autonomic nerves are affected, issues relating to such processes appear. They often have an insidious onset. As it can be difficult to identify whether this is due to diabetes or another disease it is a diagnosis of exclusion.
2. Mononeuropathy:
• Isolated cranial or peripheral nerve mononeuropathy - this is when there is a single nerve affected. It may be a cranial nerve or a peripheral nerve. The
• The most common cranial mononeuropathies occur in the nerves supplying the extraocular muscles (cranial nerves III, IV, VI) which supply the extraocular muscles: oculomotor, abducens, and trochlear. If the facial nerve is affected it can lead to Bell’s palsy (facial mononeuropathy).
• The most common peripheral mononeuropathy in diabetic patients is median mononeuropathy (at the wrist). Another upper limb mononeuropathy is ulnar mononeuropathy (at the elbow, and less commonly, at the wrist). In the lower extremities, peroneal mononeuropathies are seen more commonly. Common peroneal palsy leads to foot drop.
• Mononeuritis multiplex/asymmetric polyneuropathy - this refers to multiple mononeuropathies in the same patient. It is also called asymmetric mononeuropathy, due to the asymmetric distribution of symptoms depending on which specific nerves have been damaged. This asymmetry is the major differentiating factor bewteen this type and distal symmetric sensorimotor polyneuropathy, which is majorly symmetrical. The other major disorder that can produce this syndrome is vasculitis, which should also be considered in affected patients.
3. Radiculopathy or polyradiculopathy:
• Radiculoplexus neuropathy/lumbosacral polyradiculopathy/diabetic amyotrophy - the aetiology is uncertain at this point. Several mechanisms (ischemic, metabolic, and/or inflammatory) have been proposed. Of these, the most likely cause is ischaemic injury from a non-systemic microvasculitis. This neuropathy involves damage within the lumbosacral plexus and peripheral nerves. The traditional features of diabetic amyotrophy include the acute, asymmetric, focal onset of pain followed by weakness involving the proximal leg, with associated autonomic failure and weight loss.
• Thoracic radiculopathy - although less common than the one mentioned above, thoracic polyradiculopathy can cause marked symptoms of severe abdominal pain (sometimes in a band-like pattern) and frequently have undergone extensive gastrointestinal diagnostic studies in attempts to identify the aetiology of their pain.
4. Treatment-induced neuropathy of diabetes - sometimes referred to as insulin neuritis. This is an acute neuritis affecting diabetic patients after establishment of glycaemic control. It manifests as length-dependent (toes and soles first), burning, and stabbing neuropathic pain that begins abruptly and intensely 2–6 weeks after the improvement of glycaemic control. It can be associated with autonomic symptoms and rapid worsening of other microvascular complications.

😷 Presentation

🧠 Autonomic neuropathy

🦶

Diabetic autonomic neuropathy (DAN):

• Genitourinary autonomic dysfunction
• Sexual dysfunction
• Neurogenic bladder, such as:
• Urinary retention
• Bladder distension
• Incomplete bladder emptying
• Overflow incontinence
• Poor urinary stream

• Cardiovascular autonomic dysfunction
• Decreased heart rate variability - this is because there is less variability at times of stress and rest due to the absence of sympathetic and parasympathetic control of the SA node.
• Postural hypotension
• Tachycardia at rest

• Gastrointestinal autonomic dysfunction
• Diabetic gastoparesis - delayed gastric emptying that is not related to mechanical obstructions.
• Changes to bowel habit
• Oesophageal dysmotility

Other signs of autonomic neuropathy include:

• Impaired pupillary tone
• Sudomotor dysfunction - this refers to the control over the sweat glands in activity to environmental and physiological factors
• Dry skin
• Heat intolerance
• Abnormal sweating - such as anhidrosis or gustatory sweating (profuse sweating immediately after eating food)
• Hypoglycaemia unawareness - this is when one is unable to identify autonomic signs of hypoglycaemia such as diaphoresis, tachycardia, weakness and trembling. Instead they develop the onset of neuroglycopenia as the primary presentation.

🔍 Investigations

⭐️ The diagnosis of diabetic neuropathy is a diagnosis of exclusion/clinical diagnosis. 

Other investigations that are needed include:

• Fasting blood glucose - as many people may not know they have diabetes and diabetic neuropathy is their first presentation of the disease (in type 2 diabetes).
• HbA1c - for the same reason mentioned above.
• TSH - to exclude thyroid dysfunction
• Vitamin B12 - to exclude deficiency
• U&Es - to exclude renal disease
• Lipid profile
• LFTs - to exclude hepatic disease
• FBC & ESR - to exclude anaemia and inflammatory disorders
• Electromyography - to assess conduction issues.
• Serum/urine immunoelectrophoresis - to exclude multiple myeloma.
• Corneal confocal microscopy - to identify corneal nerve fibre damage.
• Urodynamic, cardiovascular, gastrointestinal tests - may need to be done if suspecting autonomic neuropathy.

🧰 Management