Luiz Clemente Rolim

Neuropatia autonômica cardiovascular diabética: fatores de risco, impacto clínico e diagnóstico precoce

Cardiovascular autonomic neuropathy (CAN) is one of the most clinically significant complications of diabetes mellitus (DM), but one of the least frequently diagnosed. In this review, we discuss the major risk factors for the development and progression of CAN in patients with DM, the natural history of autonomic neuropathy and its impact on cardiovascular disease in DM, as well as the tests for the early diagnosis and staging of CAN in the clinical practice. The bibliographic research was based on two databases: Medline and Tripdatabase, with the following descriptors: diabetic cardiovascular autonomic neuropathy and cardiovascular autonomic neuropathy and diabetes. We selected English and German articles, written between 1998 and 2007. In its initial stages (early and intermediate), CAN may be diagnosed and reversed. However, in advanced cases (severe stage), the only treatment that remains is a symptomatic one. CAN is associated with higher cardiovascular morbidity and mortality rates and poor quality of life in diabetic individuals.

Tests for Early Diagnosis of Cardiovascular Autonomic Neuropathy: Critical Analysis and Relevance

INITIAL CONSIDERATIONS Despite its high prevalence in individuals with diabetes mellitus (DM) neuropathies are the most underdiagnosed and undertreated diabetic chronic complication (1). The involvements of somatic and autonomic nerve fibers in DM present complex pathophysiologies (1–4). The impairment of sympathetic and parasympathetic divisions of the autonomic nervous system (ANS) leads to diabetic autonomic neuropathy (DAN), a condition that may affect different organ systems such as cardiovascular, gastrointestinal, genitourinary, sudomotor, and visual (4). Cardiovascular autonomic neuropathy (CAN), within the context of DAN, occurs when there is an impairment of autonomic control of the cardiovascular system after ruling out other causes of dysautonomia (1). It is known that CAN is an early and frequent complication of DM, affecting from 7 to 15% of newly diagnosed patients to 90% of those in line for a double transplant. In addition, CAN is among one of the most disabling complications of DM in terms of life expectancy and quality. Clinical manifestations of CAN are pleomorphic and appear in late stages, and in isolation do not present enough sensitivity and specificity for diagnosis requiring the use of objective autonomic tests (3, 4). Thus, detection of CAN in a diabetic patient requires sensitive and specific tests in order to establish differential diagnosis and quantify the severity of dysautonomia (3). Specifically, the presence of symptoms or signs suggestive of autonomic changes – such as erectile dysfunction, dizziness, intermittent visual impairment, postprandial hypotension, resting tachycardia, or exercise intolerance (dyspnea) in persons with DM – should be investigated and confirmed by performing objective diagnostic tests for CAN (3, 4).

Cardiovascular Autonomic Neuropathy Contributes to Sleep Apnea in Young and Lean Type 1 Diabetes Mellitus Patients

Knowledge about association between sleep apnea and cardiovascular autonomic neuropathy (CAN) in type 1 diabetes mellitus (T1DM) might give some insight into the pathogenesis of this condition in these patients. In obese patients, excessive central adiposity, including a large neck circumference, can contribute to obstructive sleep apnea (OSA). Its presence in non-obese patients, however, indicates that it could be correlated with autonomic neuropathy. The aim of this study was to compare the prevalence of OSA in young and lean T1DM patients with and without CAN. We studied 20 adult, non-obese, T1DM patients who were divided into two groups according to the results of the cardiovascular autonomic reflex tests (CARTs). These two groups (9 with CAN and 11 without CAN) were compared to a control group of 22 healthy individuals, who were matched by age and BMI. A polysomnography was performed and sleep was analyzed. The CAN+ group had a significantly higher prevalence of sleep apnea compared to the other groups (67% CAN+; 23% CAN−; 4.5% controls: CAN+ vs. Control; p = 0.006 and CAN+ vs. CAN−; p = 0.02). The CAN− group had higher sleep efficiency compared to the CAN+ group, demonstrating impaired sleep architecture in diabetics with this chronic complication. In conclusion, OSA may be related to the presence of CAN in young and lean T1DM patients. It could contribute to worse the prognosis and reducing the quality of life of these patients without specific treatment of these conditions.

Unusual occurrence of intestinal pseudo obstruction in a patient with maternally inherited diabetes and deafness (MIDD) and favorable outcome with coenzyme Q10

Maternally inherited diabetes and deafness (MIDD) has been related to an A to G transition in the mitochondrial tRNA Leu (UUR) gene at the base pair 3243. This subtype of diabetes is characterized by maternal transmission, young age at onset and bilateral hearing impairment. Besides diabetes and deafness, the main diagnostic features, a wide range of multisystemic symptoms may be associated with the A3243G mutation. Organs that are most metabolically active, such as muscles, myocardium, retina, cochlea, kidney and brain are frequently affected. Gastrointestinal tract symptoms are also common in patients with mitochondrial disease and constipation and diarrhea are the most frequent manifestations. However, there are few prior reports of intestinal pseudo obstruction in MIDD patients. Here we report the case of a patient with MIDD associated with the mtDNA A3243G mutation who developed chronic intestinal pseudo obstruction, and the introduction of Coenzyme Q10 as adjunctive therapy led to a solution of the pseudo obstruction.

Heterogeneidade clínica e coexistência das neuropatias diabéticas: diferenças e semelhanças entre diabetes melito tipos 1 e 2

OBJECTIVE: To evaluate the heterogeneity and the coexistence of diabetic neuropathy (DNP) in type 1 (T1DM) and 2 (T2DM) diabetes mellitus. METHODS: 74 T2DM and 20 T1DM patients were evaluated according to age (years), time from diagnosis of diabetes (TDD, years), body mass index (BMI, kg/m2), HbA1c and DNP type (American Diabetes Association criteria). RESULTS: T1DM was younger (32.7 ± 11.0 versus 56.9 ± 10.3; p = 0.0001), leaner (BMI: 23.6 ± 3.85 versus 28.4 ± 5.3; p = 0.0005) and they had longer TDD (17.1 ± 9.7 versus 10.4 ± 6.8; p = 0.003). Cardiovascular autonomic neuropathy (CAN) (60% versus 32.4%; p = 0.02) and its coexistence with polyneuropathy (PN) (62.5% versus 33.3%; p = 0.03) were more common in T1DM. Chronic painful polyneuropathy (CPP) was more prevalent in T2DM (60.8% versus 30.0%; p = 0.009). Logistic regression showed HbA1c as an independent variable related to PN (p = 0.04) in both groups. TDD (p = 0.03) and CPP (p = 0.003) were related to CAN in T1DM. Age (p = 0.0004) was related to CPP in T2DM. CONCLUSIONS: The DNP have shown a heterogeneity distribution in type 1 and type 2 diabetes mellitus. The related factors to different phenotypes of this complication, apart from hyperglycemia, may be variable between these two types of diabetes mellitus.

Coronary calcification score is higher in type 2 diabetic patients with cardiovascular autonomic neuropathy

However, the pathophysiology of this association is still under discussion. Silent myocardial ischemia is common in diabetics with CAN. Both parasympathetic and sympathetic pathways may be involved. 3 There are data suggesting that the extent of coronary calcifi cation and the development of ischemic heart disease seem to be closely related to diabetic complications. 4 The present study was aimed at investigating the degree of coronary artery calcifi cation in type 2 diabetes mellitus individuals (T2DMs) with CAN (WCAN; n = 9) and without CAN (WOCAN; n = 9). A pilot study was conducted on 18 T2DMs, using the following inclusion criteria: diabetes diagnosed more than 10 years earlier (TDDM), normal resting electrocardiogram, non-smoking and being asymptomatic for coronary artery disease. The exclusion criteria were drug use for hyperlipidemia, glomerular fi ltration rate lower than 50 ml/min, congestive heart failure and history of stroke. Informed written consent was obtained from all patients and the Ethics Board of Universidade Federal de Sao Paulo had previously approved the protocol. Fasting serum C-peptide (normal value): 0.36-3.4 ng/ml), HbA1c (A1c Hemoglobin; normal value: 3.4-6.8%), lipids and urinary albumin/creatinine ratio were measured by standard laboratory tests. Arterial hypertension and electrocardiogram (EKG) (Marquette MAC500) were also evaluated. Electron beam computed tomography imaging was performed using an ultrafast scanner (C-150 Imatron) and the coronary calcium score (CaS) was calculated using Agatston’s method. 5 The CAN diagnosis was based on two or more abnormal cardiovascular autonomic tests on two different occasions. These tests were, fi rstly, the heart rate variability (HRV) at six deep breaths per minute (mean); secondly the 30:15 ratio appraised for the relationship between the longest RR interval of EKG around the thirtieth beat and the shortest interval around the fi fteenth beat after the patient was standing; and fi nally, the orthostatic hypotension that was present when systolic blood pressure decreased by at least 20 mmHg in the third minute of standing. The differences between WCAN and WOCAN were analyzed using the Mann-Whitney or Student t test. The signifi cance level chosen was 0.05 for all statistical tests. The two groups did not differ in relation to: sex (males: 44.4% versus 55.5%), age (54.7 ± 5.5 versus 59.2 ± 3.9 years), TDDM (14.4 ± 4.0 versus 13.7 ± 2.9 years), body mass index (28.2 ± 2.9 versus 27.6 ± 4.0 kg/m 2

A Systematic Review of Treatment of Painful Diabetic Neuropathy by Pain Phenotype versus Treatment Based on Medical Comorbidities

Background Painful diabetic neuropathy (PDN) is a serious, polymorphic, and prevalent complication of diabetes mellitus. Most PDN treatment guidelines recommend a selection of drugs based on patient comorbidities. Despite the large numbers of medications available, most randomized clinical trials (RCTs) conducted so far have yielded unsatisfactory outcomes. Therefore, treatment may require a personalized approach based on pain phenotype or comorbidities. Methods To evaluate whether or not a patient’s pain phenotype or comorbidities can influence the response to a specific PDN treatment, we conducted a systematic review using two different approaches: pain phenotype and associated comorbidities-based treatment. Results Out of 45 identified papers, 7 were thoroughly reviewed. We found four RCTs stratified according to pain phenotype with three main results: (1) paroxysmal pain had a better response to pregabalin; (2) the preservation of thermal sensation or nociception anticipated a positive response to the topical treatment of pain; and, (3) after a failure to duloxetine (60 mg/day), the patients with evoked pain or severe deep pain had a better response to association of duloxetine/pregabalin while those with paresthesia/dysesthesia benefited from duloxetine monotherapy (120 mg/day). By contrast, the other three papers provided weak and even contradictory evidence about PDN treatment based on comorbidities. Conclusion Although more studies are needed to provide an adequate recommendation for clinical practice, our systematic review has provided some evidence that PDN phenotyping may optimize clinical outcomes and could, in the future, lead to both less empirical medicine and more personalized pain therapeutics.

Impaired awareness of hypoglycemia is associated with progressive loss of heart rate variability in patients with type 1 diabetes

Background Hypoglycemia unawareness affects approximately 25% of patients with type 1 diabetes and is strong associated with severe hypoglycemia. Cardiovascular Autonomic Neuropathy (CAN) is one important factor related to hypoglycemia unawareness, although its role is not fully understood due to conflicting data in the literature. Heart rate variability (HRV) in time and frequency domain has been described as a more accurate method to assess CAN. The objective of the present study was to investigate the relationship between hypoglycemia unawareness and autonomic dysfunction assessed by HRV in time and frequency domain.

Grip force control and hand dexterity are impaired in individuals with diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) affects the sensory function of the hands and, consequently, may negatively impact hand dexterity, maximum grip strength (GSMax), and hand grip force (GF) control during object manipulation. The aims of this study were to examine and compare the GF control during a simple holding task as well as GSMax and hand dexterity of individuals with DPN and healthy controls. Ten type 2 diabetic individuals diagnosed with DPN and ten age- and gender-matched healthy controls performed two traditional timed hand dexterity tests (i.e., nine-hole peg test and Jebsen-Taylor hand function test), a GSMax test, and a GF control test (i.e., hold a instrumented handle). The results indicated that individuals with DPN and controls produced similar GSMax. However, individuals with DPN took longer to perform the hand dexterity tests and set lower safety margin (exerted lower GF) than controls when holding the handle. The findings showed that mild to moderate DPN did not significantly affect maximum hand force generation, but does impair hand dexterity and hand GF control, which could impair the performance of daily living manipulation tasks and put them in risk of easily dropping handheld objects.

Association between severity of hypoglycemia and loss of heart rate variability in patients with type 1 diabetes mellitus

The occurrence of hypoglycemia has been associated with the presence of cardiovascular autonomic neuropathy. Cardiovascular autonomic reflex tests are the gold standard diagnostic method for cardiovascular autonomic neuropathy. Nevertheless, impaired heart rate variability indices on spectral analysis have been reported before cardiovascular autonomic reflex test abnormalities arise. The objective of the present study was to analyse the association between the severity of hypoglycemia and indices of heart rate variability on spectral analysis.