No abstract

Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with reduced performance on multiple domains of cognitive function and with evidence of abnormal structural and functional brain magnetic resonance imaging (MRI). Cognitive deficits may occur at the very earliest stages of diabetes and are further exacerbated by the metabolic syndrome. The duration of diabetes and glycemic control may have an impact on the type and severity of cognitive impairment, but as yet we cannot predict who is at greatest risk of developing cognitive impairment. The patho-physiology of cognitive impairment is multifactorial, although dysfunction in each interconnecting pathway ultimately leads to discordance in metabolic signaling. The pathophysiology includes defects in insulin signaling, autonomic function, neuroinflammatory pathways, mitochondrial (Mt) metabolism, the sirtuin-peroxisome proliferator-activated receptor-gamma co-activator 1α (SIRT-PGC-1α) axis, and Tau signaling. Several promising therapies have been identified in pre-clinical studies, but remain to be validated in clinical trials.

The management of chronic neuropathic pain is challenging and is best achieved with the use of a multidisciplinary team. Pain is a subjective experience, and it is important to validate a patient's pain, address psychosocial comorbidities, and set realistic treatment goals. Evidence-based guidelines are available to guide treatment, but frequently, high-quality evidence-based recommendations are lacking.

Objective: Autonomic symptoms may occur frequently in diabetic and other neuropathies. There is a need to develop a simple instrument to measure autonomic symptoms in subjects with neuropathy and to test the validity of the instrument. Methods:The Survey of Autonomic Symptoms (SAS) consists of 11 items in women and 12 in men. Each item is rated by an impact score ranging from 1 (least severe) to 5 (most severe). The SAS was tested in observational studies and compared to a previously validated autonomic scale, the Autonomic Symptom Profile (ASP), and to a series of autonomic tests.Results: The SAS was tested in 30 healthy controls and 62 subjects with neuropathy and impaired glucose tolerance or newly diagnosed diabetes. An increased SAS score was associated with the previously validated ASP (rank order correlation ϭ 0.68; p Ͻ 0.0001) and with quantitative measures of autonomic function: a reduced quantitative sudomotor axon reflex test sweat volume (0.31; p Ͻ 0.05) and an abnormal 30:15 ratio (0.53; p Ͻ 0.01). The SAS shows a high sensitivity and specificity (area under the receiver operating characteristic curve 0.828) that compares favorably with the ASP. The SAS scale domains had a good internal consistency and reliability (Cronbach ␣ ϭ 0.76). The SAS symptom score was increased in neuropathy (95% confidence interval [CI] 2.99-4.14) compared to control (95% CI 0.58-1.69; p Ͻ 0.0001) subjects. Conclusions:The SAS is a new, valid, easily administered instrument to measure autonomic symptoms in early diabetic neuropathy and would be of value in assessing neuropathic autonomic symptoms in clinical trials and epidemiologic studies. Neurology ® 2011;76:1099-1105 GLOSSARY ASP ϭ Autonomic Symptom Profile; AUC ϭ area under the curve; CAN ϭ cardiac autonomic neuropathy; CASS ϭ Composite Autonomic Scoring Scale; CI ϭ confidence interval; COMPASS ϭ Composite Autonomic Symptom Scale; E:I ϭ expiration: inspiration ratio; HRR ϭ heart rate range; IENFD ϭ intraepidermal nerve fiber density; IFG ϭ impaired fasting glucose; IGR ϭ impaired glucose regulation; IGT ϭ impaired glucose tolerance; NCS ϭ nerve conduction studies; OR ϭ odds ratio; QSART ϭ quantitative sudomotor axon reflex test; QST ϭ quantitative sensory testing; ROC ϭ receiver operating characteristic; SAS ϭ Survey of Autonomic Symptoms; SSR ϭ sympathetic skin response; TIS ϭ total symptom impact score.Impaired glucose regulation (IGR) is associated with peripheral neuropathy in at least 40% of cases.1,2 The neuropathy associated with IGR and early diabetes is a small-fiber neuropathy that is often accompanied by mild autonomic symptoms and abnormalities.3-8 A recent consensus statement by the American Diabetes Association recognizes that glycemic burden is a strong predictor of adverse outcomes and that IGR represents a continuum of risk.9 Thus, for the purposes of this study, subjects with neuropathy and prediabetes or newly diagnosed diabetes are described as having IGR or early diabetic neuropathy.