Symptoms of neuropathy are personal experiences and vary markedly from one patient to another. For this reason, a number of symptom screening questionnaires with similar scoring systems have been developed. The Neurologic Symptom Score (NSS) has 38 items that capture symptoms of muscle weakness, sensory disturbances and autonomic dysfunction. These questionnaires are useful for patient follow-up and to assess response to treatment.

A detailed clinical examination is the key to the diagnosis of DPN. The last position statement of the American Diabetes Association recommends, that all patients with diabetes should be screened for DN at diagnosis in type 2 and 5 years after diagnosis of type 1 DM. This should be repeated annually and must include sensory examination of the feet and ankle reflexes (16) One or more of the following can be used to assess sensory function: pinprick (using the Waardenberg wheel or similar instrument), temperature, vibration perception (using 128-Hz tuning fork) and 1 & 10-g monofilament pressure perception at the distal halluces. For this last test a simple substitute is to use 25 lb strain fishing line and cut 4 cm and 8 cm lengths, which translate to 10 and 1 g monofilaments (63). The most sensitive measure has shown to be the vibration detection threshold, although sensitivity of 10-g Semmes-Weinstein monofilament to identify feet at risk varies from 86 to 100%(64,65) . Combinations of more than one test have more than 87% sensitivity in detecting DPN (16,66) . Longitudinal studies have shown that these simple tests are good predictors of foot ulcer risk (67) Numerous composite scores to evaluate clinical signs of DN, such as the Neuropathy Impairment Score (NIS) are currently available. These, in combination with symptom scores, are useful in documenting and monitoring neuropathic patients in the clinic(68). The feet should always be examined in detail to detect ulcers, calluses and deformities, and footwear must be inspected at every visit.

Multiple studies have proven the value of Quantitative Sensory Testing (QST) measures in the detection of subclinical neuropathy (small fiber neuropathy), the assessment of progression of neuropathy and the prediction of risk of foot ulceration(66,69,70) (71). These standardized measures of vibration and thermal thresholds also play an important role in multicenter clinical trials as primary efficacy endpoints. A consensus subcommittee of the American Academy of Neurology stated that QST receive a Class II rating as a diagnostic test with a type B strength of recommendation(72)

The use of electrophysiologic measures (NCV) in both clinical practice and multicenter clinical trials is recommended (73,74). In a long term follow-up study of type 2 diabetic patients (22). NCV abnormalities in the lower limbs increased from 8% at baseline to 42% after 10 years of disease. A slow progression of NCV abnormalities was seen in the Diabetes Control and Complication Trial (DCCT). The sural and peroneal nerve conduction velocities diminished by 2.8 and 2.7 m/s respectively, over a 5-year period (20). Furthermore, in the same study, patients who were free of neuropathy at baseline, had a 40% incidence of abnormal NCV in the conventionally treated group versus 16% in the intensive therapy treated group after 5 years. However the neurophysiologic findings vary widely depending on the population tested and the type and distribution of the neuropathy. Patients with painful, predominantly small fiber neuropathy have normal studies. There is consistent evidence that small, unmyelinated fibers are affected early in DM and these alterations are not diagnosed by routine NCV studies. Therefore, other methods, such as QST or skin biopsy and quantification of intraepidermal nerve fibers (IENF) are needed to detect these patients (26) (25) (27). Nevertheless electrophysiological studies play a key role in ruling out other causes of neuropathy and are essential for the identification of focal and multifocal neuropathies (12,30).

The importance of the skin biopsy as a diagnostic tool for DPN is increasingly being recognized (26,75,76). This technique quantitates small epidermal nerve fibers through antibody staining of the pan-axonal marker protein gene product 9.5 (PGP 9.5). Though minimally invasive (3-mm diameter punch biopsies), it enables a direct study of small fibers, which cannot be evaluated by NCV studies. It has led to the recognition of the small nerve fiber syndrome as part of IGT and the metabolic syndrome (Figure 4). When patients present with the “burning foot or hand syndrome, evaluation of glucose tolerance and features of the metabolic syndrome such as waist circumference, plasma triglyceride and HDL-C levels as well as blood pressure become mandatory and therapeutic life style changes (77) can reverse this form of neuropathy and alleviate symptoms with nerve fiber regeneration (see below).

It is widely recognized that neuropathy per se can affect the quality of life (QOL) of the diabetic patient. A number of instruments have been developed and validated to assess QOL in DN. The NeuroQoL measures patients’ perceptions of the impact of neuropathy and foot ulcers(78). The Norfolk QOL questionnaire for DN is a validated tool addressing specific symptoms and impact of large, small and autonomic nerve fiber functions. The tool has been used in clinical trials and is available in several validated language versions. It was recently tested in 262 subjects (healthy controls, diabetic controls and DN patients) Differences between DN patients and both diabetic and healthy controls were significant (p<0.05) for all item groupings (small fiber, large fiber, and autonomic nerve function, symptoms, and activities of daily living (ADL). Total QOL scores correlated with total neuropathy scores. The ADL, total scores and autonomic scores were also greater in diabetic controls than in healthy controls (p<0.05) suggesting that diabetes per se impacts some aspects of QOL (9).

The diagnosis of DPN is mainly a clinical one with the aid of specific diagnostic tests according to the type and severity of the neuropathy. However other non-diabetic causes of neuropathy must always be excluded, depending on the clinical findings (B12 deficiency, hypothyroidism, uremia, CIDP, etc) (Figure 5)