Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy.

AIMS: DN4 (Douleur Neuropathique en 4 Questions) is a screening tool for neuropathic pain consisting of interview questions (DN4-interview) and physical tests. It has not formally been validated in diabetes. We evaluated the validity and diagnostic accuracy of DN4 and DN4-interview in identifying neuropathic pain of painful diabetic polyneuropathy. METHODS: In 158 patients with diabetes, the presence of diabetic polyneuropathy and neuropathic pain was assessed using scoring system for symptoms and signs, quantitative sensory testing, nerve conduction studies, pain history, numerical rating scale, and Short-Form McGill Pain Questionnaire. Painful diabetic polyneuropathy was defined as the presence of diabetic polyneuropathy plus chronic neuropathic pain in the same area as neuropathic deficits. A blinded investigator performed DN4. RESULTS: The DN4 score was significantly related to all the neurological and electrophysiological measurements and to Short-Form McGill Pain Questionnaire (ρ = 0.58, P < 0.0001). DN4 and DN4-interview scores showed a high diagnostic accuracy for painful diabetic polyneuropathy with areas under the receiver operating characteristic curve of 0.94 and 0.93, respectively. At the cut-off of 4, DN4 displayed sensitivity of 80%, specificity of 92%, positive predictive value (PPV) of 82%, negative predictive value (NPV) of 91%, and likelihood ratio for a positive result (LR(+) ) of 9.6. At the cut-off of 3, DN4-interview showed sensitivity and specificity of 84%, PPV of 71%, NPV of 92%, and LR(+) of 5.3. CONCLUSIONS: This is the first validation study of DN4 for painful diabetic polyneuropathy, which supports its usefulness as both a screening tool for neuropathic pain in diabetes and a reliable component of the diagnostic work up for painful diabetic polyneuropathy.

Does autonomic neuropathy play a role in erythropoietin regulation in non-proteinuric Type 2 diabetic patients?

AIMS: Erythropoietin (EPO)-deficient anaemia has been described in Type 1 diabetic patients with both severe autonomic neuropathy (AN) and proteinuria. This study was aimed at distinguishing between the effects of AN and nephropathy on haemoglobin and EPO levels in Type 2 diabetic patients at an early stage of diabetic nephropathy. METHODS: In 64 Type 2 diabetic patients (age 52 +/- 10 years, duration 10 +/- 9 years) without overt nephropathy and other causes of anaemia or EPO deficit, we assessed cardiovascular tests of AN, 24-h blood pressure (BP) monitoring, urinary albumin excretion rate (UAE), a full blood count, and serum EPO. RESULTS: Although the Type 2 diabetic patients with AN did not show differences in haemoglobin and EPO when compared with patients without AN, the presence of haemoglobin < 13 g/dl was associated with the presence of AN (chi(2)= 3.9, P < 0.05) and of postural hypotension (chi(2)= 7.8, P < 0.05). In a multiple regression analysis including as independent variables gender, body mass index, duration of diabetes, smoking, creatinine, 24-h UAE, 24-h diastolic BP, ferritin, erythrocyte sedimentation rate, and autonomic score, we found that the only variables independently related to haematocrit were autonomic score, ferritin and erythrocyte sedimentation rate. Finally, the physiological inverse relationship between EPO and haemoglobin present in a control group of 42 non-diabetic non-anaemic subjects was completely lost in Type 2 diabetic patients. The slopes of the regression lines between EPO and haemoglobin of the control subjects and the Type 2 diabetic patients were significantly different (t = 14.4, P < 0.0001). CONCLUSIONS: This study documents an early abnormality of EPO regulation in Type 2 diabetes before clinical nephropathy and points to a contributory role of AN in EPO dysregulation.

Diagnosis of cardiovascular autonomic neuropathy in diabetes.

The utility of standard cardiovascular tests for diagnosis of cardiac autonomic neuropathy in diabetes has been well documented. Attention must be paid to standardizing the procedure with regard to time of day, metabolic status, distance from meal and insulin, coffee and smoking avoidance, and patient's collaboration. In the presence of cardiovascular disease or drugs affecting the cardiovascular or autonomic nervous system, some caution is needed in interpreting the results. More recent reflex tests, which evaluate mainly sympathetic or baroreflex activity, despite their ability to detect early autonomic involvement, lack sufficient standardization and still need to be proved as valid alternatives. Of the different methods of measuring heart rate variability, spectral analysis has a greater ability to differentiate vagal and sympathetic modulation of heart rate than do time-domain methods. However, since these latter methods are easier and more widely available, they can be used as a screening approach. Twenty-four-hour evaluation of heart rate variability provides data on the circadian rhythm of sympathovagal activity, which can be affected earlier than and differently from cardiovascular reflex tests. Information obtained could have prognostic implications in terms of cardiovascular morbidity and mortality and offer therapeutic opportunities. However, a wide consensus on many technical aspects of both time-domain and frequency-domain methods is needed. Furthermore, large prospective studies in the diabetic population to assess the prognostic value of 24-h heart rate variability parameters on cardiovascular morbidity and mortality are lacking. Recently, I123 meta-iodobenzylguanidine (MIBG) scintigraphy has documented abnormalities of sympathetic myocardial innervation also in newly diagnosed IDDM. The meaning of this finding, whether it is an expression of functional or structural defects, needs to be clarified. Preliminary data point to a possible pathogenetic meaning of the known association between autonomic neuropathy and other diabetic complications. This area of investigation could provide useful insights into the complex and multifactorial pathogenesis of diabetic complications.

Autonomic neuropathy and cardiovascular risk factors in insulin-dependent and non insulin-dependent diabetes.

In 97 IDDM and 64 NIDDM patients aged under 65 years, we evaluated the relationship between autonomic neuropathy (AN) and retinopathy, nephropathy, glycemic control and cardiovascular risk factors. Diabetes duration and HbA1 were significantly higher and body mass index was significantly lower in IDDM patients with AN compared to those without. In NIDDM only age was significantly higher in neuropathic patients. AN was associated with retinopathy in both IDDM (chi2 = 10, P < 0.03) and NIDDM patients (chi2 = 14, P < 0.007), while only in IDDM albumin excretion was significantly higher in patients with AN. Blood pressure (BP) was significantly higher in both IDDM and NIDDM patients with AN compared to those without. There were no differences in smoking and serum lipids between patients with and those without AN. We performed a multiple regression analysis using autonomic score, index of cardiovascular tests impairment, as the dependent variable and age, diabetes duration, body mass index, HbA1, albumin excretion, cholesterolemia, triglyceridemia, systolic BP, and retinopathy as independent variables. With this model in IDDM autonomic score was only related to body mass index (r = -0.29, P < 0.05), to HbA1 (r = 0.46, P < 0.001), and to systolic BP (r = 0.24, P < 0.05), while in NIDDM it was only related to systolic BP (r = 0.54, P < 0.001). In conclusion, AN was related to age in NIDDM, and to diabetes duration and glycemic control in IDDM. AN was associated with retinopathy, with nephropathy (only in IDDM), and with BP levels, but not with dyslipidemia, smoking, or obesity. Excess mortality rate observed in diabetic AN cannot be referred to an association with cardiovascular risk factors.

Autonomic neuropathy and secondary hyperparathyroidism in uraemia.

To evaluate the relationship between autonomic neuropathy, and biochemical and X-ray parameters of secondary hyperparathyroidism, we examined 19 predialysis and 24 haemodialysis non-diabetic uraemic patients. Autonomic neuropathy was assessed using four tests: deep breathing, Valsalva manoeuvre, lying to standing, and postural hypotension. Serum Ca, Ca2+, P, Mg, alkaline phosphatase, iPTH, and osteocalcin were assayed. Hand X-ray was obtained to evaluate acro-osteolysis (score A) and subperiosteal resorption (score B). Ten predialysis patients (52%) and 15 haemodialysis patients (62%) showed one or more abnormal autonomic tests. Age, dialysis duration, and biochemical parameters of secondary hyperparathyroidism did not differ significantly in uraemic patients with and without abnormal autonomic tests. Furthermore, there was no significant relation between autonomic tests and iPTH or osteocalcin. Score A and score B was significantly greater in patients with abnormal tests than in patients without (P less than 0.009 and P less than 0.025). When predialysis and haemodialysis patients were considered separately the correlation between score A, score B, and autonomic neuropathy was confirmed only in haemodialysis patients. In conclusion, autonomic neuropathy does not seem to be related to the biochemical parameters of secondary hyperparathyroidism, while it appears significantly associated with the radiological signs of osteodystrophy, suggesting a possible pathogenetic linkage between autonomic neuropathy and secondary hyperparathyroidism.

Intravenous dexamethasone and subsequent ACTH test in comparison with dexamethasone oral test in the diagnosis of Cushing's syndrome: a report of 20 cases.

Dexamethasone inhibits ACTH secretion in the pituitary corticotropic cells of normal subjects; this ability is variously affected in Cushing's syndrome. The iv infusion of dexamethasone is not time consuming, nor it is influenced by the variability of intestinal absorption or hepatic metabolism, as occurs with oral administration. Iv dexamethasone (1.5 mg/h) over 7 h and an ACTH bolus at the 6th h were administered to 17 patients with Cushing's disease, 3 patients with Cushing's syndrome (2 with adrenal adenoma, 1 with ectopic ACTH secretion) and 13 normal subjects. After 4 days the 20 patients were also given the standard oral low-dose and high-dose dexamethasone test. Two h after starting the drug infusion, cortisol concentrations were inhibited by more than 50% in each control subject. In contrast, in all but one patient they remained higher than 50% over the baseline. At the 6th heach control subject and 15 of the 17 patients with Cushing's disease showed an inhibition of plasma cortisol concentration which was greater than 50%. Inhibition was less than 50% in 2 patients with Cushing's disease and in the 3 patients with non-pituitary dependent Cushing's syndrome. The sensitivity and specificity of this test are comparable with those of the dexamethasone oral test. Although statistically significant, results obtained from ACTH bolus were not sufficiently discriminating. If studies conducted on a larger population confirm these preliminary data, the rapidity and reliability of the dexamethasone infusion test could make it an important new tool in diagnosing Cushing's syndrome.

Pancreatic polypeptide response to a protein-rich meal in diabetic patients with and without neuropathy.

A protein-rich meal and insulin-induced hypoglycemia (ITT) are two of the most important stimuli on pancreatic polypeptide (PP) secretion in diabetic patients. Previous studies have shown a reduced PP response to ITT in diabetic patients with autonomic neuropathy (AN). Twelve patients without AN (mean age 44 +/- 10.8 yr, mean duration of diabetes 11 +/- 5.6 yr), 9 with AN (51.4 +/- 6 yr, 15.8 +/- 6.9 yr) and 9 controls (N) were studied. AN was assessed by the evaluation of the beat-to-beat variation of the heart rate during deep breathing. PP secretion was stimulated by a protein-rich meal (200 g meat, 150 g milk). All insulin-dependent diabetic (IDD) patients lacked circulating PP antibodies. All diabetic patients showed a significant reduction in the early vagal phase compared to controls. This behavior was more evident in diabetic patients with AN and the secondary phase of these two groups overlapped with the response of controls. These data may be explained by the initial alterations of vagal functions not detectable by current methods.

Impaired alpha cell function in conditions with cortisol deficiency.

Plasma immunoreactive glucagon (IRG), insulin (IRI) and blood glucose (BG) were evaluated in the fasting state and during an arginine test (ATT) in 6 subjects with untreated hypopituitarism (H), in 2 hypopituitary subjects with normal cortisol production (H + C), in 3 subjects with Addison's disease (A) and in 14 normal volunteers (N). No increase in BG was observed in H and A after arginine, mean values being significantly lower than in N. Mean fasting and arginine-stimulated IRI levels were lower in H and A than in N; postabsorptive arginine-induced IRG levels were significantly reduced when compared to N. In contrast IRG levels in the two H + C patients were within the normal range. The impaired IRG production in A and in H (but not in H + C) suggests a close relationship between alpha pancreatic function and cortisol levels.