Neuropathy

Neuropathy is a common complication of diabetes affecting up to 50% of people who have had diabetes more than 25 years. It classically presents as symmetrical loss of sensation in the feet but may also present with pain or unpleasant alteration of touch sensation (allodynia) in the feet. In addition to peripheral neuropathy, other manifestations include autonomic neuropathy and diabetic mono-neuropathies.

Prevention

What are the main strategies for prevention of neuropathy?

The prevention of neuropathy relies on good glycaemic control.

The importance of good glycaemic control was convincingly demonstrated by the original DCCT and UKPDS trials for T1DM and T2DM respectively. Subsequent investigations have supported these findings.

What glycaemic targets should be applied?

The 'one size fits all' strategy of using a single HbA1c target for the whole diabetic population is a blunt approach and it is increasingly recognised that individualised targets should be set with each patient.

The fundamental challenge is that the lower the HbA1c, generally speaking, the more frequent hypoglycaemia will be. Thus for a newly diagnosed patient who is adapting well to life with diabetes and is actively engaging with education and other aspects of self management, setting a target below 7.5% (58 mmol/mol) without experiencing unacceptably frequent hypoglycaemia is a realistic aim.

However, for a 75-year-old patient with a 10-year history of T2DM and an HbA1c of 9% (75 mmol/mol), attempting reduction to less than 7.5% (58 mmol/mol) will probably confer no survival advantage and may even increase mortality rate as shown by the recent ADVANCE, ACCORD and VADT trials.

Other examples of groups where caution should be applied regarding zealous reduction of HbA1c include the advanced elderly (e.g. over 80-years-old, younger if significant comorbidity is present), those with frequent hypoglycaemia and hypoglycaemia unawareness, and those who have had diabetes for many decades and have developed autonomic neuropathy, gastroparesis and other comorbidity that render coping with hypoglycaemia especially difficult.

Are there any other strategies for prevention of neuropathy?

More recently, some evidence supporting the use of fibrates (specifically fenofibrate) has emerged for the prevention of neuropathy (FIELD study). It should however be emphasised that this has not yet become widely accepted practice and has not as yet been incorporated into the major national guidelines.

Other research has shown that a combined approach of intensive simultaneous control of hyperlipidaemia, blood pressure and glycaemia in T2DM (STENO 2 study) also produces a modest risk reduction of neuropathy.

Management

Overview

The management of diabetic peripheral neuropathy involves screening to detect early neuropathy, optimising glycaemia in order to prevent worsening as much as possible, a high standard of routine foot care to prevent diabetic foot complications and treating painful diabetic neuropathy.

In addition, managing any associated autonomic neuropathic manifestations such as gastroparesis and postural hypotension requires careful attention.

Screening

The diabetes annual review should include two-modality peripheral neuropathy screening.

This is usually performed by 10g monofilament sensation testing at five anatomical sites on both feet and by vibration sensation testing, ideally using a neurosthesiometer but, if not, by use of a 128Hz tuning fork.

Screening will often detect neuropathy before the patient is aware of it.

Patient education

Once neuropathy is detected, this should be discussed with the patient in particular focusing on the implications of loss of foot sensation.

They should be educated about the importance of good footwear, avoiding unnecessary risks such as walking bare foot and advised to inspect their feet daily to detect any injuries that they may not have felt.

Podiatry

Regular (e.g. three monthly) podiatry for all neuropathic patients is advisable. The main benefit of this derives from regular, expert foot surveillance and early detection of imminent ulceration or infection.

Glycaemic management

Although near-perfect glycaemia will not reverse the underlying axonal damage of neuropathy, it is still a highly desirable goal in order to reduce progression as much as possible.

Thus, if possible given hypoglycaemia and other potentially limiting factors, an HbA1c of <7.5% (58 mmol/mol) should be aimed for.

Painful diabetic neuropathy

Unlike loss of sensation due to neuropathy, the pain of PDN is amenable to pharmacological intervention. This can be a therapeutically challenging area and the patient should be reassured that there are a number of different drugs to be used and if the first one isn’t successful, there is still a reasonable chance that a subsequent medicine will be.

There are four drugs in particular that are often useful in treating this condition: 

1. Amitriptyline should be started at a dose of 25 mg nocte and titrated up to a maximum of 150 mg od if necessary. Often the patient will develop dose limiting side effects (usually day time somnolence) before the higher doses are reached. If there is little or no therapeutic response after several weeks on the maximum tolerated dose, the next agent should be tried.

2. Gabapentin can often be an efficacious drug but is limited by a rather complicated dosing schedule: it should be started at 300 mg od on day on, bd on day two and tds on day three, and then progressively titrated up to a maximum of 3.6 g per day in 300 mg increments every third day until adequate therapeutic response is achieved or until dose limiting side effects are encountered.

3. Pregabalin should be started at a dose of 150 mg bd and this can be increased if necessary to 300 mg bd. 

4. Duloxetine is the most recently approved PDN drug. It has already been incorporated in to the recent NICE guidance on management of painful neuropathies. The starting dose 60 mg od and this can be increased if necessary to 120 mg od.

It is usual to try these agents sequentially, combinations are not usually used. Gabapentin and Pregabalin should not be withdrawn suddenly.

When should a doctor refer to a neurologist?

Patients with diabetic neuropathy should be referred to a neurologist if there is doubt over the diagnosis or if management of painful neuropathy is proving particularly challenging and there is a neurologist with an interest in PDN locally.

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