Anu Gupta  ( Department of Neurology, Postgraduate Institute of Medical Education & Research, Chandigarh, India. )
Yashdeep Gupta  ( Department of Medicine, Government Medical College & Education, Chandigarh, India. )

Diabetic neuropathy (DN) is a descriptive term meaning a demonstrable disorder, either clinically evident or sub-clinical, that occurs in the setting of diabetes mellitus without other causes for peripheral neuropathy. It is the most common and troublesome complication accounting for more hospitalizations than all the other diabetic complications combined, and is responsible for 50% to 75% of non-traumatic amputations.¹
In this review, we have summarized the epidemiology, clinical features, pathogenesis, classification and diagnosis of diabetic neuropathy. The management will be reviewed in Part 2.
Prevalence
The true prevalence is not known and depends on the criteria and methods used to define neuropathy. Of patients attending a diabetes clinic, 25% volunteered symptoms, but 50% were found to have neuropathy after a simple clinical test such as eliciting the ankle reflex or vibration perception test. Almost 90% tested positive on sophisticated tests of autonomic function or peripheral sensation.²
Diabetes is the most common cause of neuropathy worldwide. Diabetic neuropathy occurs in approximately 60% of individuals with long-standing type 1 and type 2 DM.³ A recent cross sectional hospital based study in Lahore done on 113 newly diagnosed T2DM patients found a prevalence of 68.5% in those with poor glycaemic control (HbA1c > 6.5%) and 50 % in those with good glycemic control (HbA1c < 6.5%).⁴
Diabetic autonomic neuropathy is also very common. Definitive Cardiac autonomic neuropathy has been reported in 30% of patients with T2DM in a study from Hyderabad, Pakistan (disease duration > 10 years).⁵
Classification
Diabetic neuropathy can be broadly divided into symmetric and asymmetric types (Figure).


Symmetric neuropathies usually present as chronic neuropathies and include distal sensorimotor polyneuropathies; small fibre; autonomic;/large fibre predominant neuropathies and chronic inflammatory demyelinating polyradiculopathies (CIDP). DSPN is the most common form of diabetic neuropathy.³
The acute onset symmetric neuropathies include diabetic neuropathic cachexia which is an uncommon painful sensory neuropathy occurring in type 1 diabetes in the setting of poor glucose control and weight loss. Insulin neuritis, which is again a painful neuropathy is seen with initiation of insulin treatment.
The asymmetric neuropathies can also be divided into those with acute onset and those with gradual onset. Diabetic truncal radiculoneuropathy, radiculoplexopathy or diabetic amyotrophy, cranial neuropathies (third or sixth nerves) and mononeuritis multiplex constitute the acute onset group. Limb mononeuropathies due to compression/entrapment are of more gradual onset.
An easy and practical way to approach this conundrum of classifications is to classify diabetic neuropathy as typical and atypical. Typical DSPN is chronic, distal, symmetric, sensory predominant, and often painful. Any variation (eg, acute, asymmetric, proximal, or motor involvement) suggests an atypical neuropathy.⁶
Clinical Features
Diabetic neuropathy has a wide spectrum of clinical manifestations, the most common being distal symmetrical sensorimotor loss in the classical \'stocking-glove\' distribution (DSPN).
Diabetic sensorimotor polyneuropathy (DSPN) is a mixed neuropathy with small and large fibre sensory, motor and autonomic involvement in various combinations. Sensory and autonomic symptoms are more prominent. The symptoms start as numbness, tingling, burning or pricking sensation in the feet and spread proximally in a length dependent fashion (stocking glove pattern). Over time gait disturbance and mild distal weakness occur. Associated autonomic symptoms may be present. Examination shows distal loss of pinprick, temperature, touch and vibration sense. with reduced or absent Ankle jerks and weakness of toe flexors and extensors may be present. It predisposes the patients to falls, development of foot ulcers and Charcot joints. The most disabling symptom in these patients is pain which is difficult to treat and substantially affects the quality of life.⁷
Diabetic small fibre neuropathy (DSFN): Small fibre predominant neuropathy in diabetes is being increasingly recognised and is an early manifestation of peripheral nerve involvement. It presents with pain and dyesthesias in the feet and is difficult to diagnose, as the clinical examination and nerve conduction studies may be normal. It often progresses to the typical DSPN.
Diabetic autonomic neuropathy affects various organs of the body resulting in cardiovascular, gastrointestinal, urinary, sweating, pupils, and metabolic disturbances. Orthostatic hypotension, resting tachycardia, and heart rate unresponsiveness to respiration are a hallmark of diabetic autonomic neuropathy.
Diabetic lumbar radiculoplexopathy: Also known as Diabetic amyotrophy or proximal diabetic neuropathy, it presents with abrupt onset, often unilateral severe pain in the anterior thigh, buttock or lower back followed by weakness and wasting in the thigh. Sensory phenomena are minimal and knee jerk is absent. The symptoms after progression over few weeks, stabilise and then gradually improve. Pathological assessment reveals evidence of ischaemic injury and microvasculitis and prognosis is favourable.
Diabetic truncal radiculoneuropathy: It presents with abrupt onset severe pain (burning, stabbing or belt like) with contact hyperesthesia in the thoracic spine, flank, rib cage or upper abdomen. Bulging of abdominal wall may occur because of muscle weakness. It may be confused with intra-abdominal or thoracic disease or herpes zoster.
Cranial neuropathy: The oculomotor nerves are most often affected (third, sixth, rarely fourth). Diabetic third nerve palsy presents with abrupt onset retro-orbital pain, followed by double vision, unilateral ptosis, restriction of medial and upgaze and sparing of the pupil. Aneurysm must be excluded by neuroimaging in atypical cases (pupillary involvement or absence of pain). It improves spontaneously in 3-6 months without any treatment.
Patients with diabetes can also present with mononeuritis multiplex without an underlying rheumatological cause and are at increased risk of entrapment mononeuropathy.
Pathogenesis
Chronic hyperglycaemia is an important contributing factor leading to diabetic complications. A possible unifying mechanism is that hyperglycaemia leads to increased production of reactive oxygen species or superoxide in the mitochondria; these compounds may activate all four pathways (formation of advanced glycosylation end products, sorbitol pathway, protein kinase C pathway and hexosamine pathway), leading to chronic complication of diabetic neuropathy.⁸
The other prominent factors implicated in diabetic neuropathy are dyslipidaemia⁹ and impaired insulin signalling.¹⁰
Additionally, factors such as visceral obesity and hypertension are associated with DPN.¹¹ Microvascular dysfunction in the nerve and decreased endo-neural perfusion are also thought to contribute to neuropathy.¹²
Advances in Diagnosis
It is generally agreed that diabetic neuropathy should not be diagnosed on the basis of one symptom, sign, or test alone. A minimum of two abnormalities (from symptoms, signs, nerve conduction abnormalities, quantitative sensory tests, or quantitative autonomic tests) is recommended.¹³
Diagnostic modalities
Nerve conduction studies
Traditionally, nerve conduction studies (NCSs) have been the most frequently used diagnostic tool for DSPN. As with most other axonal neuropathies, the central feature of DSPN is reduced distal lower extremity sensory nerve action potential amplitudes.¹⁴ But over the years it has been realised that diagnosis of DSFN (Ad-fibres and C fibres) is challenging as the clinical picture can be difficult to interpret and results from nerve conduction studies are often normal. In cases of suspected DSFN, measurement of intraepidermal nerve fibre density (IENFD) and/or analysis of quantitative sensory testing can enable diagnosis. New diagnostic techniques (including measurement of nerve fibre density using corneal confocal microscopy, and nociceptive evoked potentials) may contribute to the diagnostic work-up.¹⁵
Quantitative sensory testing (QST)
QST is an objective index of neurologic functional status. For the evaluation of small nerve fibre dysfunction, only temperature thresholds are measured. The other common parameter measured by QST in clinical practice, reflecting large fiber involvement is vibration sensation. For reliable results, QST requires the patient to be alert and cooperative.¹⁵
Skin biopsy and measurement of IENFD
Pathologically, DSFN is characterized by degeneration of distal terminations of small-diameter sensory fibres, observed as low IENF density (IENFD) on histological analysis of tissue from patients with the condition. For diagnostic purposes in cases of suspected DSFN presenting with length-dependent symptoms and signs, a punch skin biopsy can be taken from the distal part of the leg, within a region 10cm above the lateral malleolus.¹⁶ After anti-PGP 9.5 staining, bright-field immuno-histochemistry or immuno-fluorescence, either with or without confocal microscopy, are used to assess IENF loss.¹⁵ IENFs are counted under the optical microscope and the number is divided by the length of the epidermal surface to obtain a linear density per millimetre; the density reported is the mean of the values calculated from at least three sections from the same biopsy.¹⁵ The diagnostic value of skin biopsy in patients with DSFN has been established.¹⁶ An IENFD below the fifth percentile is usually considered confirmatory for a diagnosis of SFN.
New diagnostic modalities
Corneal confocal microscopy
Over the past decade, the non-invasive technique of in vivo confocal microscopy of the cornea has been developed, mainly for use in patients with diabetic neuropathy. Confocal microscopy in healthy individuals has confirmed that the cornea is innervated by both Ad-fibres and C fibres of trigeminal origin.¹⁷ The technique allows observation of the living eye in situ, at the cellular level.¹⁸ A correlation between low corneal nerve fibre density and severity of the somatic neuropathy and IENF loss in the distal leg has been described.¹⁹
Nociceptive evoked potentials
They are used to selectively activate Ad and C fibres. A relationship between poor nociceptive evoked potential response and severity of IENFD loss has been described.²⁰
Microneurography
Microneurography has made recording of single Ad-fibre and C fibre activity possible, and provides a direct method for measuring sympathetic activity. However the routine use of this technique is limited as it is invasive, time consuming and requires an expert investigator.²¹
Other diagnostic tools include nerve axon reflex/flare response. In the nerve axon reflex, C nociceptive fibres are stimulated by acetylcholine iontophoresis producing vasodilatation which can be quantitatively measured and serves as a measure of small fibre function.²² The laser Doppler imaging flare test evaluates 44°C heat-induced vasodilation and is reduced in subjects with IGT and type 2 diabetic patients with and without neuropathy. These tests still require validation by further studies.²³
Based on signs/symptoms and diagnostic modalities, neuropathy in diabetes has been defined as in Table.⁶


Various clinical composite scores have been developed to screen for and quantify the severity of neuropathy.^24-28 Out of these, Michigan neuropathy screening instrument (MNSI) is a good screening tool for diabetic neuropathy.²⁷ It has been widely used to assess distal symmetrical peripheral neuropathy in clinical practice and in large clinical trials, including the DCCT/EDIC²⁹ and the Action to Control Cardiovascular Disease in Diabetes (ACCORD).³⁰
Summary
To conclude, diabetes is associated with a variety of chronic and acute neuropathies, the commonest form being distal symmetric polyneuropathy. Performing an annual screening through a good neurological history and clinical examination and using a sensitive screening tool can facilitate an early diagnosis. More sensitive and quantitative measures of detecting early peripheral nerve injury including skin biopsy for intra-epidermal and dermal nerve fiber density and confocal corneal microscopy, hold promise to identify neuropathy patients early in their disease course.

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