David Levy, MD, FRCP
The devastating consequences of diabetic neuropathy are seen every day both in hospital – more bed days are taken up with the consequences of diabetic foot ulceration than any other diabetic complication – and in primary care, where sensory symptoms, especially pain, and autonomic neuropathy, especially erectile dysfunction, are common, disabling and depressing symptoms that have a major impact on quality of life. Despite decades of research, increased understanding of the pathogenesis of diabetic neuropathy has not yet translated into useful prophylactic treatment for the common polyneuropathy of diabetes, other than determined glucose control in type 1 diabetes, and Steno-2-type multimodal intervention to reduce autonomic, though not somatic, neuropathy in type 2 diabetes. The difficulty of reliably quantifying peripheral neuropathy has limited its inclusion in outcome measurements in the recent type 2 studies, and is partly responsible for the frequent late presentation with ulceration and infection; however, simple tests, for example the monofilament, if widely used, should help identify the highest-risk groups of patients. The evidence base for most aspects of treatment of diabetic neuropathic syndromes is weak, and certainly far less robust than that for other microvascular complications. Finally, it is difficult to estimate even point prevalences of neuropathy because of methodological variability and referral bias. It is certainly common, for example in a contemporary population of adolescents with type 1 diabetes the prevalence, using reliable electrophysiology and autonomic function tests, was 20–25%. Many studies in type 2 diabetes give similar or higher rates….
Enthusiasm for specific drug treatments has waxed and waned. The development of aldose reductase inhibitors in the 1970s and 1980s, initially designed to prevent neuronal accumulation of sorbitol, has been dogged by toxicity or lack of efficacy; supplementation with recombinant nerve growth factor, though logical, was useless. Other treatments have been discredited (evening primrose oil/GLA), despite experimental evidence of efficacy. The protein kinase C inhibitor ruboxistaurin may positively impact on retinopathy (see Chapter 9), but probably does not have a role in other microvascular complications. There is some evidence for the efficacy of the antioxidant alpha-lipoic (thioctic) acid in alleviating the unpleasant positive symptoms of diabetic neuropathy, and it is available in some countries. The drugs that are relatively specific and effective for neuropathic pain frequently have side-effects that limit their use and titration to optimum analgesic effect.
However, despite general gloom on the pharmaceutical front, much can be done to prevent the most devastating consequences of peripheral neuropathy – recurrent foot ulceration and amputation – through education, high-quality podiatric care and provision of footwear. In addition, symptomatic painful neuropathy is often helped by judicious combinations of medication, and the management of erectile dysfunction, once the subject of many a long and generally unhelpful textbook, has been transformed by the introduction of the PDE5 inhibitors.
Diagnosis of neuropathy
‘Neuropathy’ is shorthand for ‘distal sensorimotor polyneuropathy.’
Though not a symptom of somatic neuropathy, the earliest feature in type 2 diabetes is thought to be erectile dysfunction, which is increasingly recognized as a sensitive indicator of endothelial dysfunction (see below).
Somatic neuropathy presents as insidious and often unnoticed numbness with or without paresthesie of the toes, progressing proximally to involve the feet and shins. Neuropathic symptoms may be intermittently present for several years before diabetic symptoms. Clinical involvement above the knee is unusual, and the upper limbs are involved late and to a lesser degree – arms have shorter axons than legs. Consider other diagnoses if there are prominent upper limb features, particularly muscle wasting (bilateral carpal tunnel syndromes or ulnar nerve compression, cervical disc disease, syringomyelia). Symptomatic neuropathy can occasionally be a presenting feature of type 2 diabetes. A differential diagnosis, especially when there is pain, must be in the examiner’s mind; always attributing pain and other foot symptoms to diabetes can be hazardous, particularly when the clinical features are unusual. By analogy with diabetic nephropathy, there may be other causes of peripheral neuropathy, perhaps in up to 50% of patients (neurotoxic medications, alcohol, vitamin B12 deficiency, uremia, vasculitis, chronic inflammatory demyelinating neuropathy or inherited neuropathy); there is possibly an even wider spectrum of treatable causes .
Stocking distribution sensory loss, starting with the tips of the toes, proceeds proximally eventually, typically to mid-shin. Loss is usually to all sensory modalities, with large and small nerve fibres all affected:
- light touch
- pain (pinprick)
However, in some patients, small fibre-mediated modalities (pain and temperature) are preferentially affected, while in others the large-fibre modalities (touch, vibration and proprioception) are primarily involved. In a small proportion, there is severe loss of proprioception, giving rise to a ‘pseudo-tabetic’ variety, with positive Romberg’s sign and instability on standing and walking, especially on uneven surfaces. Wasting of the small muscles of the foot is characteristic, with clawing of the toes and increased exposure of pressure areas on the soles. Clawing is probably due to motor neuropathy with wasting of the intrinsic muscles of the feet, though there may be some contribution from disruption of the plantar fascia.
Feet are often warm and well perfused with bounding pulses and distended veins caused by sympathetic denervation leading to increased blood flow. There is anhidrosis, demonstrated by little or no friction when the back of the examiner’s hand is drawn across the sole of the foot. Hair loss on the dorsum of the foot and great toes is usually claimed as an example of trophic neuropathic changes, but it is an unreliable sign, particularly in the elderly; more significant clinically is atrophy of the fibro-fatty tissue of the heel pad. Impressionistically, there is often a smooth, shiny, rather featureless skin (this may be the equivalent in the foot of absent skin wrinkling in the fingers after immersion in water, thought to be due to advanced sympathetic denervation). More prosaically, always examine the skin between the toes for maceration and fungal infections, often sites of bacterial entry, and a risk factor for the development of cellulitis.
If high-risk features are identified on examination, always ask the help of a podiatrist.
- Callus: always precedes neuropathic ulceration, and is not benign in the neuropathic foot, as it increases focal pressure . Callus recurs very quickly, especially in the typically neuropathic foot with its high arches and increased pressure on the balls of the foot. It requires frequent active removal by a podiatrist. Callus at the tip of a toe may conceal underlying abscess or osteomyelitis. Bleeding into callus requires action.
- Blistering at pressure points, sometimes with infection.
- Deeply fissured dry skin, often at the heels, is a possible portal for infection. Hydrating agents such as Flexitol Heel Balm (UK) are available without prescription and should be recommended for regular use.
- Interdigital fungal infection.
- Ingrowing toenail, especially if infected; subungual hematoma.
Ankle reflexes are usually absent in established neuropathy. Absent knee reflexes (in the absence of other neuromuscular disorders) suggests advanced neuropathy.
Quantitative and semi-quantitative measurements
For routine clinical examination of the foot, the 2008 ADA/AACE report suggests using one, preferably two, of the following five tests to identify the high-risk foot, as indicators of loss of protective sensation:
- 10 g monofilament
- vibration perception threshold (neurothesiometer)
- 128-Hz tuning fork
- pinprick sensation
- ankle reflexes (use reinforcement if necessary).
- 10 g monofilament
Very simple. Apply the 10 g monofilament perpendicularly to the distal great toe (between the nail fold and the distal interphalangeal joint) until it just buckles; this presents a relatively constant pressure. Formally, 10 trials are required: eight or more correct responses is normal, while one to seven correct responses indicates reduced sensation; no correct responses indicates absent sensation. Inability to feel the monofilament is a reliable indicator of neuropathy and is associated with a high risk of progression to foot ulceration.
Vibration perception threshold
Vibration is the simplest sensory modality to quantify. The neurothesiometer (Fig. 10.1b) applies an increasing amplitude of vibration to the great toe pulp; inability to feel vibration at above 25 V predicts progression to foot ulceration. Vibration perception threshold (VPT) correlates broadly with other measurements of nerve function (including electro-physiological measurements of nerve conduction), but all neurological functions deteriorate rapidly with age and for more precise diagnosis an age-related measurement should be used (the 25-V threshold underestimates neuropathy in younger people and overestimates it in older people) . Inability to feel vibration of a standard (128 Hz) tuning fork is a reliable but truly insensitive indicator.
Autonomic function tests
These quantify heart rate and blood pressure responses to various standardized manoeuvres, but the full battery of tests described many years ago cannot easily be done in the routine setting. However, measurement of sinus arrhythmia and postural blood pressure drop are simple and useful in the clinical setting (see below).
Nerve conduction studies
Infrequently used, but they can be useful in differentiating diabetic from other neuropathies. Median nerve studies are routinely performed in patients with suspected carpal tunnel syndrome and atypical neuropathies. The neurophysiologist will often do supplementary tests to confirm diffuse polyneuropathy in the upper limb. Ask for a sural nerve sensory action potential amplitude and common peroneal motor nerve conduction velocity in the lower leg, which are simple measurements. An absent sural nerve sensory action potential is a sensitive indicator of diabetic neuropathy.
The strong link between insidious progression of numbness in the feet, lack of protective sensation, and subsequent painless damage is not at all obvious, even to some professionals.
Systematic review of a limited number of non-biased publications concluded, depressingly, that limited patient education alone does not result in meaningful reductions in ulceration and amputation; this finding should steer us towards a more selective and intensive approach to education of high-risk patients .
Management of diabetic polyneuropathy
In the DCCT, the risk of both peripheral and autonomic neuropathy in type 1 diabetes was reduced by about 50% in the intensively treated group. The EDIC follow-up study used only a standardized questionnaire and clinical examination, but the previously intensively treated group continued to develop symptoms at a greater rate than the previously conventionally treated group . However, clinical signs remained unchanged in both groups, emphasizing the unreliability of clinical examination in detecting neuropathy, and the importance of symptomatic questioning. Reversing established neuropathy is probably not possible. Even prolonged near-normoglycemia after pancreas transplantation improved only nerve conduction velocities – significant, but probably not of major concern to most patients. Autonomic function and clinical signs did not improve.
There is no comparably rigorous data for neuropathy outcomes in type 2 diabetes, and it was not studied in the UKPDS. Intensive glycemic therapy in ACCORD had minor beneficial effects on some measures of peripheral neuropathy, but not VPTs. Multimodal treatment in Steno-2 reduced autonomic, but strangely not peripheral, neuropathy in micro-albuminuric patients, though glycemia in both intensive and conventional groups was similar, and the other interventions must have been responsible for the improvement.
No drug is widely licensed in asymptomatic diabetic polyneuropathy. The aldose reductase inhibitors, despite a generally poor efficacy and safety record, continue to be developed and studied, and one, epalrestat, is available in Japan for symptomatic and asymptomatic neuropathy. Some hold the view that previous agents in this class were underdosed on the basis of targeting sorbitol accumulation and osmotic derangement, both theories now discredited. Benfotiamine, a vitamin B1 derivative, and alpha-lipoic acid are widely used, and there is experimental and some RCT evidence to support their use in symptomatic neuropathy. Avoid other B vitamins (B6 and B12) and folate unless there is documented deficiency; they are of no value in routine treatment and may accelerate coexisting diabetic nephropathy (see Chapter 8).
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK
This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)