INTRODUCTION

 

Diabetic autonomic neuropathy (DAN) has received less attention than the other diabetic complications¹, it is one of the most overlooked of all serious complications of diabetes² and among the least recognized and understood diabetic complications despite it has a significant negative impact on survival and quality of life in people with diabetes.³

DAN is a subtype of the peripheral polyneuropathies that accompany diabetes, it may be either clinically evident or subclinical.⁴ Subclinical autonomic dysfunction can occur within a year of diagnosis in type 2 diabetes patients and within two years in type 1 diabetes patients, however, Clinical symptoms of DAN generally do not occur until long after the onset of diabetes.⁵ The reported prevalence of DAN vary from as low as 16% in newly diagnosed diabetic patients⁶ to as much as 75% in established diabetes.⁷

The manifestations of DAN includes dysfunction of one or more organ systems (such as cardiovascular, gastrointestinal (GI), genitourinary, sudomotor, or

ocular)⁴, cardiovascular autonomic neuropathy (CAN) is the most clinically important form of DAN⁸, it results from damage to the autonomic nerve fibers that innervate the heart and blood vessels leading to dysfunctional heart-rate control and abnormal vascular dynamics⁹, which manifested clinically by decrease in heart rate variation (HRV) during deep breathing¹⁰, postural hypotension, exercise intolerance, intraoperative cardiovascular labiality, and silent myocardial ischemia/infarction.⁹

Some studies have found CAN to be associated with sudden cardiac death¹¹ and to be an independent predictor of mortality.¹² The mortality rate among patients with CAN across several studies reported to be 27% among diabetic subjects with CAN compared with 5% among those without.¹³

 

Aim of Work

Since CAN often develops in parallel with diabetic neuropathy as a confounder¹⁴, we aimed to investigate the potential association between diabetic polyneuropathy and the increased risk of cardiovascular events with correlating cardiovascular risk with severity of polyneuropathy to be used as a marker of cardiovascular disease in diabetic patients.

 

PATIENTS AND METHODS

 

This study was conducted in the neurology and internal medicine departments at Riyadh National Hospital, Riyadh, Saudi Arabia. A database was created of 67 patients with Diabetes Mellitus, from whom only 55 completed the study until its end.

The study had been approved by the scientific committee at Riyadh National Hospital and with the Helsinki Declaration of 1975, as revised in 1983. Informed consent was taken from the patients to participate in this study.

Patients included in this study should satisfy the following criteria; (i) diagnosis of type 2 diabetes mellitus according to World Health Organization 1999 criteria, and (ii) willingness to sign informed consent form. Exclusion criteria includes (i) patients with other causes of neuropathy rather than diabetic, (ii) pregnant women, because of possible temporary changes in blood chemistry, circulation and pain sensitivity, and (iii) albuminuria (urinary albumin-to-creatinine ratio >30 mg/g, elevated S-creatinine >120 mmol/L) (For avoidance of the confounding effect of diabetic nephropathy).

A data collecting sheet was filled by the internal medicine doctor to record demographic data and relevant medical history, then were screened for diabetic peripheral neuropathy by a neurologist using Michigan Neuropathy Screening Instrument (MNSI).¹⁵ It consists of a two-step program. The first part assessed a Neuropathic symptom by a history questionnaire consists of 15 "yes or no" questions on foot sensation including pain, numbness and temperature sensitivity. The second part is a brief physical examination involving an inspection of the feet and evaluation of ankle reflexes, vibration sensation and fine touch.

Neuropathy is defined operationally as seven or more positive responses on the MNSI questionnaire or a score >2.0 on the MNSI examination, thresholds defined by prior validation studies.¹⁶ The screening method for fine touch sensation, vibration perception and ankle reflex using 10-g SWM, 128-Hz tuning fork and reflex hummer was followed the practical guideline from Michigan Diabetes Research and Training Center.¹⁵

The Neuropathy severity assessed by Toronto Clinical Neuropathy Scoring System (TCSS): Sensory testing was performed on the first toe. Symptom scores: present =1, absent =0. Reflex scores: absent =2, reduced =1, normal =0. Sensory test score: abnormal =1, normal =0. Total scores range from normal =0 to maximum of 19. A score ≤5 was recorded as showing no neuropathy, 6–8 mild, 9–11 moderate, and >11 equated to severe neuropathy.

Electro-diagnostic studies (EDS) were performed with standard electrophysiological and electro-myographic equipment provided by major manufacturers (Nicolet®, Teca®, and Disa®). Digital skin thermometers accurate to 0.1°C to ensure that skin temperatures were at least 32°C. Trained electro-physiologists performed the examinations. Velocity was determined for the distal sural and ulnar sensory nerves and for the peroneal motor nerve (knee to ankle) unilaterally on the nondominant side. Response amplitude was measured overlying the dorsal surface of the foot for the sural nerve, at the fifth finger for the ulnar nerve and overlying the extensor digitorum brevis muscle for the peroneal nerve.

Patients have been further subdivided into 2 groups; group 1 included 32 patients with CAN (+CAN), and group 2 included 23 patients without CAN (–CAN), according to the outcome of four autonomic function tests; heart rate variability (HRV) during deep breathing, valsalva ratio, lying-to standing test, and blood pressure response to standing up. Patient with CAN (+CAN) was defined as two or more abnormal tests¹⁷, and age-normative values were used to define abnormality.¹⁸

The lying-to-standing heart rate ratio was determined after at least 5 min rest in the supine position, and HRV was determined by calculating the maximal to minimal heart rate ratio; the longest R-R interval, measured around the 30^th beat after standing up, to the shortest R-R interval, measured around the 15th beat after standing up.

The Valsalva test consisted of forced exhalation into a mouthpiece with a pressure of 40 mmHg for 15 seconds, and the ratio of the maximum R-R after the maneuver to the minimum R-R during the maneuver was calculated. The test was performed three times, and the mean value of the ratios was used.

Orthostatic hypotension was defined as a decrease in systolic blood pressure (SBP) of 30 mmHg when changing from supine to the upright position. Measurements were taken every minute for at least 3 minutes.

Glycemic control was assessed via HbA1c levels. Body mass index (BMI) was calculated using the equation [weight in kilogram/(height in meter)²]. Categorized as Normal (< 25 kg/m2), overweight (25-30 kg/m2) and obese (>30 kg/m2).

 

Statistical Analysis

For descriptive statistics the frequency and percentage were calculated for qualitative variables, the mean values ±standard deviation (SD), and range were used for quantitative variables. For comparison between two groups student t-test was calculated. For correlation, Pearson correlation was used. Statistical computations were done using the computer software SPSS version 16 (Chicago, IL, USA). Statistical significance was predefined as P ≤0.05.

 

RESULTS

 

One hundred diabetic patients were screened using MNSI, of whom 89% had diabetic polyneuropathy, 36 patients were +CAN and 41 were -CAN, the results for the remaining 12 patients were not conclusive so they were excluded from the research. Of the total number of patients, 55 patients have completed the study to its end (23 patients +CAN, and 32 patients –CAN). Sixty percent of our patients were females and 40% were males. Ages varied from 35 years to 82 years (mean ±SD, 55.78 ±10.75 years). Clinical characteristics of the patient with diabetic polyneuropathy with or without CAN are summarized in (Tables 1).

Age, BMI, HbA_1c within the last 3 months, lipid profile, diastolic blood pressure and serum creatinine were comparable among +CAN and –CAN group. Therefore, none of these parameter can be used as a marker for CAN, while longer duration of diabetes and higher systolic blood pressure were present in +CAN patients compared to –CAN group patients (Table 1).

In the studied groups, male patient had a longer duration of diabetes compared to females, males are also older than female with mean age of 62.30±12.10 years in the +CAN group and 62.00±9.40 years in the –CAN group (Table 1).

HbA_1C percentage was higher among men in both groups compared to women refecting bad glycemic control in men. Serum creatinine and triglycerides were higher in men compared to women in both groups, while the rest of the laboratory findings were comparable among both sexes (Table 1).

Diabetic neuropathy questioner (DNS) and diabetic neuropathy examination (DNE) showed high statistically significant correlation with the presence of autonomic cardiovascular neuropathy (Table 2).

Our results revealed that CAN correlates with the severity of diabetic neuropathy measured by TCSS as there is a strong statistical correlation between severity of diabetic neuropathy and presence of the CAN. The mean of TCSS was reduced markedly in +CAN compared to–CAN group (Table 6), Moreover, the presence of CAN correlates with changes in the nerve conduction velocity and amplitude in sural nerve, popliteal nerve and ulnar nerve (Table 3).

By comparing the means and standard deviations of nerve conduction velocity (NCV) among the +CAN patients group and –CAN patients group there was reduction of NCV in +CAN group compared to –CAN group (Table 3).

Also by comparing the compound motor action potential amplitude in +CAN group of patients and –CAN group of patients there were statistically significant reduction of the mean of nerve amplitude (Table 3).

 

 

 

Figure 1. Toronto clinical scoring system in Cardiac Autonomic Neuropathy positive and negative patients.

Table 1. Clinical characteristics of patients with and without Cardiac Autonomic Neuropathy.

 

Data are expressed as mean ±SD,

BMI body mass index, +CAN patients with Cardiac autonomic neuropathy, -CAN patients without Cardiac autonomic neuropathy,  DBP diastolic blood pressure, NS non-significant statistically, SBP systolic blood pressure, Yr years, CAN: Cardiac autonomic neuropathy

^*Significant at P<0.05

 

Table 2. Diabetic Neuropathy severity measured by Toronto Clinical Scoring System in patients with and without Cardiac autonomic neuropathy.

 

	+ CAN Patients	- CAN Patients	P-value
Diabetic Neuropathy Symptoms	9.88±1.44	7.44±0.67	<0.01*
Diabetic Neuropathy Examination	3.11±1.07	1.02±0.48	<0.01*
Toronto Clinical Scoring System	13.39±2.06	8.25±1.11	<0.01*

Data are expressed as mean ± SD

^*Significant at P<0.01

 

Table 3. Comparing nerve conduction studies between patients with and without Cardiac Autonomic Neuropathy.

 

Data are expressed as mean ± SD

^*Significant at P<0.05

 

 

DISCUSSION

 

Cardiac autonomic neuropathy represents a serious complication as it carries an approximately five-fold risk of mortality in patients with diabetes.¹⁰

Our results showed an increasing in risk of neuropathy severity with increasing duration of diabetes affection and with poor glycemic control, confirming the previously reported strong contributions of glycemic control and duration of diabetes to the risk of neuropathy.¹⁹ While the duration of diabetes mellitus was statistically significantly prolonged in +CAN compared to –CAN patients, glycemic control failed to get significant difference between the two groups.

The EURODIAB data showed an association of low HDL cholesterol and high triglycerides in patients with cardiovascular autonomic neuropathy, suggesting a role for an adverse lipid profile in the pathogenesis of CAN²⁰, but our results failed to detect statistically significant differences between +CAN and –CAN groups regarding the HDL cholesterol and high triglycerides.

Our results showed a significant reduction of the mean SBP in +CAN group compared to –CAN group (124.57±14.53 to 134.06±14.28 respectively), while the mean DBP in +CAN group show insignificant reduction compared to –CAN group. Finding in agreement with that obtained by other studies, that showed falls in arterial pressure, especially in the standing position and after insulin administration in diabetes patients with either abnormal baroreceptor reflexes or autonomic neuropathy.²¹

A relationship of diabetic polyneuropathy with autonomic cardiovascular dysfunction has already been observed. However, it does not seem to us the presence of any data correlating association between EDS, DNS and DNE with CAN in literatures. To date, few investigators have examined the relationships between different measures of neurophysiological function in diabetic peripheral neuropathies.²² In the current study, the Diabetic Neuropathy Symptom score (DNS), DNE, TCSS and EDS are further validated with the CAN. Our results revealed a statistically significant relationship between the DNS, DNE, EDS scores and +CAN, so by assessing the DNS and DNE scores at the outpatient clinic, a good predictor is given for presence or absence of CAN. These results are consistent with Jesper Fleischer studies who stated that there is a clear association between the degree of diabetic autonomic imbalance and peripheral neuropathy.² But our results were in contrary with  Gibbons and colleagues (2010), who concluded that neurophysiological tests may not be specific for small, large, or autonomic nerve fiber subtypes and in the absence of pathological confirmation, they are unable to determine whether test variation is due to nerve dysfunction, demyelination, or axonal loss.²³

Although there is no specific therapeutic interventions are available for neuropathy except strict glycemic control, instruction to avoid complication of diabetes, and symptomatic treatment, the early detection of the cardiovascular abnormality and preventive measures application has a crucial role enabling the physician, in screening, prevention, and instruction for early management autonomic neuropathy. The performance of the DNS and DNE scores, eventually in combination with EDS, may be sufficiently be used to subsequently reduce the morbidity and mortality among +CAN patients.¹⁴

 

Conclusion

This study revealed that the DNS, DNE and TCSS scores could allow discrimination between patients with and without diabetic CAN. These scores are strongly related to EDS and CAN tests subsequently could confirm the strength of the DNS and DNE scores in diagnosing diabetic CAN in clinical practice. Further research should be done to specify an optimal set of diagnostic categories for diabetic CAN.

 

[Disclosure: Authors report no conflict of interest]

 

REFERENCES

1.        Hosking DJ, Bennett T, Hampton JR. Diabetic autonomic neuropathy. Diabetes. 1978; 27:1043-55.

2.        Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007; 115:387-97.

3.        Vinik AI, Erbas T. Recognizing and treating diabetic autonomic neuropathy. Cleve Clin J Med. 2001; 68:928-44.

4.        Report and recommendations of the San Antonio conference on diabetic neuropathy. Consensus statement. Diabetes. 1988; 37:1000-4.

5.        Pfeifer MA, Weinberg CR, Cook DL, Reenan A, Halter JB, Ensinck JW, et al. Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care. 1984; 7:447-53.

6.        O'Brien IA, McFadden JP, Corrall RJ. The influence of autonomic neuropathy on mortality in insulin-dependent diabetes. Q J Med. 1991; 79:495-502.

7.        Navarro X, Kennedy WR, Sutherland DE. Autonomic neuropathy and survival in diabetes mellitus: effects of pancreas transplantation. Diabetologia. 1991; 34 (Suppl 1):S108-12.

8.        Ewing DJ. Cardiovascular reflexes and autonomic neuropathy. Clin Sci Mol Med. 1978; 55:321-7.

9.        Freeman R. Cardiovascular autonomic neuropathy. In: Dyck PJ TPE, editor.  Diabetic Neuropathy. Second ed. Philadelphia: WB Saunders; 1999. p. 541-54.

10.     Ziegler D. Diabetic cardiovascular autonomic neuropathy: prognosis, diagnosis and treatment. Diabetes Metab Rev. 1994; 10:339-83.

11.     Rathmann W, Ziegler D, Jahnke M, Haastert B, Gries FA. Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diabet Med. 1993; 10:820-4.

12.     Wirta O, Pasternack A, Mustonen J, Laippala P. Renal and cardiovascular predictors of 9-year total and sudden cardiac mortality in non-insulin-dependent diabetic subjects. Nephrol Dial Transplant. 1997; 12:2612-7.

13.     Orchard TJ, LLoyd CE, Maser RE, Kuller LH. Why does diabetic autonomic neuropathy predict IDDM mortality? An analysis from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Res Clin Pract. 1996; 34 (Suppl):S165-71.

14.     Mogensen UM, Jensen T, Kober L, Kelbaek H, Mathiesen AS, Dixen U, et al. Cardiovascular autonomic neuropathy and subclinical cardiovascular disease in normoalbuminuric type 1 diabetic patients. Diabetes. 2012; 61:1822-30.

15.     Michigan Neuropathy Screening Instrument [homepage on the Internat]. No date [cited 2014 Oct 1]. Availble from: http://www.med.umich.edu/borc/profs/survey.html

16.     Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994; 17:1281-9.

17.     Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010; 33:2285-93.

18.     Bernardi L, Spallone V, Stevens M, Hilsted J, Frontoni S, Pop-Busui R, et al. Methods of investigation for cardiac autonomic dysfunction in human research studies. Diabetes Metab Res Rev. 2011; 27:654-64.

19.     Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M, Ionescu-Tirgoviste C, et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia. 1996; 39:1377-84.

20.     Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005; 352:341-50.

21.     Page MM, Watkins PJ. Provocation of postural hypotension by insulin in diabetic autonomic neuropathy. Diabetes. 1976; 25:90-5.

22.     Hamdy O, Abou-Elenin K, Logerfo FW, Horton ES, Veves A. Contribution of nerve-axon reflex-related vasodilation to the total skin vasodilation in diabetic patients with and without neuropathy. Diabetes Care. 2001; 24:344-9.

23.     Gibbons CH, Freeman R, Veves A. Diabetic neuropathy: a cross-sectional study of the relationships among tests of neurophysiology. Diabetes Care. 2010; 33:2629-34.