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Journal of Neurology Research

Original Article

Volume 13, Number 1, September 2023, pages 50-55

Measurement of Electrophysiology, Sexual Dysfunction, and Cognitive Impairment in Patients With Diabetes Referred for Neuropathy Symptoms: A Case-Control Study

Diabetes mellitus (DM) is a common metabolic disorder worldwide and has been rising rapidly, especially in low- and middle-income countries [1]. Diabetic patients frequently develop microvascular complications such as nephropathy, retinopathy, peripheral neuropathy (PN), and sexual and cognitive disorders due to capillary dysfunction and metabolic disturbances [2]. All of these can affect the quality of life and impose a considerable social burden. Up to 50% of people with diabetes have some form of PN. Diabetic sensorimotor polyneuropathy (DSPN) is the most common type, which can lead to significant disability [3]. A large number of screening and diagnostic tools are introduced to diagnose DSPN, including electrophysiological studies and standard questionnaires [4]. The findings of the nerve conduction study (NCS) provide objective data for confirmation and diagnosis of diabetic neuropathy [5].

The sexual health of diabetic patients has often been overlooked. Sexual dysfunction (SD) could be a result of central nervous system dysfunction, autonomic or peripheral nerve damage, psychogenic causes, medications, or a combination of these factors [6]. SD in male and female patients with DM is reported in various studies [6, 7]. In addition, anxiety and depression are prevalent among patients with SD [8].

Cognitive dysfunction (CD) is one of the major comorbidities in diabetic patients, which may reflect microvascular brain damage as a consequence of diabetes [9]. People with type 2 diabetes mellitus (T2DM) have approximately 60% greater risk of development of cognitive problems compared with non-diabetes equivalents [10]. Prior data have shown that multiple cognitive domains including psychomotor speed, memory, executive function, and attention are impaired in T2DM patients [11].

No study has assessed the association between diabetic neuropathy, cognitive impairment, and SD together. we aimed to investigate the association between electrophysiological findings of neuropathy and CD and SD.

In this observational study, patients with diagnosed T2DM, who were referred to our university-affiliated electrodiagnostic (EDx) laboratory for the investigation of polyneuropathy between September 2021 and August 2022, were recruited. All patients above 45 years with a minimum of 5 years of education (primary school - secondary school - high school - university) were included in this study. Patients with a history of head trauma, cerebral palsy, intellectual disability, dementia or neurodegenerative disease (such as epilepsy, multiple sclerosis, and Parkinsonism), malignancy, previously documented psychiatric and sleep disorders, those who had an acute systemic disease (endocrine disorder, fluid-electrolyte imbalance, and infection), users of medications (neuroleptics, benzodiazepine, and antidepressant) that may cause cognitive impairment, severe hearing and visual problems, substance and alcohol users, pregnant women and lactating women were excluded. Non-diabetic individuals matched for age and sex who were referred to the EDx study served as a comparison group.

All patients completed a self-administered questionnaire, which addressed diabetes duration, a history of hypertension, ischemic heart disease and medications including neuroleptics, benzodiazepine, and antidepressant. A research nurse calculated the body mass index (BMI) and blood pressure of participants in a sitting position for 10 min. Peripheral venous blood was sent for routine laboratory tests including hemoglobin A1C (HbA1C) under fasting conditions.

The neuropathy symptom score (NSS) questionnaire [12] that is an assessment of four major items that measures the presence, localization, time of appearance, and improvement of neuropathy symptoms, was completed by all participants. The total score ranges from 0 to 10, and the score of 3 - 4, 5 - 6, and 7 - 10 serve as mild, moderate, and severe neuropathy symptoms, respectively. The neuropathy disability score (NDS) questionnaire was completed by an expert neurologist. The NDS grades neuropathy from 0 (no neuropathy) to 28 (severe neuropathy) [13]. A score of 0 - 2 was defined as “no neuropathy,” score of 3 or more were considered as “neuropathy”.

An experienced neurologist performed EDx studies in a quiet room while the participants skin temperature was stabilized to approximately 31 °C. A system from Negar Andishgan Ltd^®. EMG/NCV/EP 5000Q was used for electromyographic measurements of the nerve conduction velocity (NCV). Sensory nerve action potential (SNAP) was antidromically recorded from bilateral sural and superficial radial nerves. The mean amplitude of both sides and sural/radial nerve amplitude ratio (SRAR) was measured for all subjects. Additionally, compound muscle action potential (CMAP) was documented from both tibial nerves recording abductor hallucis brevis muscle, and the mean tibial conduction velocity (CV), mean tibial distal latency (DL) and mean amplitude were calculated.

Montreal cognitive assessment (MoCA) is a widespread and concise screening tool for the assessment of cognitive impairment that has had a significant impact on the evaluation of age-related cognitive decline. The MoCA is a 30-item test that allows healthcare providers to discover cognitive impairment. The test checks language, memory, visual, and spatial thinking, reasoning, and orientation skills and the scores range from 0 to 30. A score of 26 and higher is considered normal. In the initial study data, normal controls had an average score of 27.4. People with mild cognitive impairment (MCI) scored an average of 22.1. People with Alzheimer’s disease had an average score of 16.2 [14].

Beck depression inventory (BDI) is a 21-question multiple-choice self-report inventory, one of the most widely used instruments for measuring the severity of depression. A value of 0 to 3 is assigned for each answer and then the total score is compared to the key score to determine the depression’s severity. The standard cutoffs are as follows: (0 - 10) normal, (11 - 16) mild mood disturbance, (17 - 20) borderline clinical depression, (21 - 30) moderate depression, (31 - 40) severe depression, over 40 extreme depressions.

We used the female sexual function index (FSFI) and the male sexual function index (MSFI) questionnaires for evaluating SD in both patients and control groups. The FSFI is a 19-item self-report questionnaire assessing the six domains of sexual function in women including desire, arousal, lubrication, orgasm, satisfaction, and pain; and the MSFI is a 16-item self-report questionnaire evaluating five domains containing desire, arousal, erection, orgasm, and satisfaction over the previous 30 days. The full-scale score range is between 2 - 36 [15].

Statistical analyses were performed using SSPS version 22.0 (SPSS, Inc., Chicago, IL, USA). To compare the diabetic patients with non-diabetic controls, basic characteristics, including frequency of males and females and frequency of comorbid diseases (hypertension and ischemic heart disease), were analyzed using the Chi-square test. For numerical variables including age, duration of disease, Beck score, MoCA, FSFI, MSFI, and NCS parameters, mean ± standard deviation was calculated, and the Kolmogorov-Smirnov test was used to confirm the normal distribution of the data. Then, values were compared between the two groups using the independent t-test. Finally, to assess the correlation between SRAR, NSS, and NDS values, the Pearson correlation coefficient and Spearman rank coefficient were applied. A P value < 0.05 was considered statistically significant.

The study was approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran (ethics committee number: IR.SBMU.RETECH.RCE.1399.641). The study was conducted in compliance with the ethical standards of the responsible institution on human subjects as well as with the Helsinki Declaration.

Demographic and clinical data for the subjects included in the study are shown in Table 1. A total of 110 patients with diabetes, 57 men and 53 women with a mean age of 58.57 ± 9.64 years, were included in the study. The comparison group consisted of 52 non-diabetic subjects, 20 men and 32 women with 55.73 ± 10.46 years on average. No differences were found between patients and non-diabetic controls for age, sex, as well as Beck depression score. The patients had a significant vascular risk factor including hypertension and ischemic heart disease compared with non-diabetic subjects. The mean ± standard deviation of HbA1c (%) among patients with diabetes was 7.5 ± 1 and only 12 (10.9%) patients had HbA1C level > 7%.

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Table 1. Clinical Features of Study Participation

Table 1 shows the cognitive performance and sexual activity in diabetic patients compared to the comparison group. Although our findings revealed that both groups had low cognitive scores in MoCA, the patients had a significantly lower level of cognitive performance compared to the control group (P < 0.001). In the patients with diabetes, 55 patients (50%) were with MCI and 32 (29.1%) with mild dementia compared to 25 (48.1%) with MCI and nine (17.3%) with mild dementia in the control subjects. No differences were observed between the two groups for sexual activity.

As demonstrated in Table 2, there was a significant difference between scores of NCS in both groups (P = 0.001). Since hypertension and ischemic heart disease can be linked to neuropathy and CD, we conducted analysis of covariance (ANCOVA) to determine the possible confounding effects of hypertension and ischemic heart disease on variables of NCS and MoCA. This analysis demonstrated similar results, even after considering hypertension and ischemic heart disease as confounding factors.

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Table 2. NCS Parameters

According to our results in overall population, there was a significant reverse association between SRAR and severity of NSS and NDS, also a reverse association in each group was observed (Table 3). There was no significant association between MoCA and SRAR. Among patients, a weak negative correlation was observed between NDS, NSS, and MoCA score (r: -0.219; P = 0.02, r: -0.252; P = 0.01, respectively). We found no statistical differences between NCS parameters and sexual function.

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Table 3. Correlation Between SRAR and NSS and NDS

Microvascular complications of DM are prevalent despite advances in diabetes prevention and treatment. The present study attempted to identify associations between clinical findings of SD and CD and quantitative aspects of axonal loss in T2DM patients.

Our findings showed that diabetic patients have a significantly lower score on MoCA compared with non-diabetic subjects, but we found no correlation between CD based on MoCA score and objective NCS findings. CD in individuals with DM can manifest as MCI and dementia [16]. A growing body of evidence has linked diabetes with CD [16-18], We expect that DM with PN to be more associated with CD than DM alone. However, the information about the association of PN and CD is different. A retrospective cohort study containing 94 diabetic participants revealed that diabetic people have poorer cognitive performance, but the CD is not correlated with the severity of neuropathy based on NSS and NDS scores [19]. A recent study demonstrated that although cognitive scores are lower in patients with diabetes, the presence of PN adds no more cognitive decline. The PN is assessed by questionnaire and EDx findings of median, ulnar, and peroneal nerves [20]. Lin et al in their cross-sectional study of 828 participants using neurofilament examination of both feet, showed that the severity of PN is significantly negatively correlated with cognitive performance [21]. This result indicates that CD in patients with diabetes may not be limited to microvascular damage of the brain [22]. In fact, recent data strongly imply that both vascular and neurodegenerative pathologies are associated with cognition in diabetic individuals [9, 23].

In the current study, we analyzed the severity of neuropathy using diabetic neuropathy questionnaires as well as quantitative data of NCS together to increase the sensitivity of results. According to previous research sural SNAP amplitude and the SRAR are probably useful parameters for differentiating normal subjects from those with distal polyneuropathy, especially when age adjustment is performed [24, 25]. Moreover, we observed a negative correlation between NDS, NSS, and MoCA scores; however, this correlation is weak, which implies increasing in sample size is warranted.

Although our findings show diabetic patients do have a worse cognitive function, the control group obtained lower scores as well. Since there was no statistical difference in Beck depression scores between the two groups, this finding may be due to mood disorders or aging effect on cognition [26].

Also, our results indicate no correlation between NCS parameters and sexual function in DM patients. Prior data showed reverse results based on evaluating neuropathy by physical examination. A recent cross-sectional analysis of 1,213 men (206 men with diabetes), assessing erectile dysfunction and PN by a single question self-interview and 10-g monofilament testing, respectively, showed decreased lower extremity sensation is a risk factor for erectile dysfunction in both diabetes and non-diabetes people [27]. A similar study in Japan demonstrated a positive correlation between diabetic neuropathy and severe erectile dysfunction [28]. Moreover, our different results may be as a consequence of small fiber neuropathy-induced sexual impairment, which preserved large fibers and NCS findings [29].

We found no differences regarding SD between the two groups. This finding may be a result of a low Beck depression score in all participants, which is in agreement with previous studies [30].

Our study has several limitations: first, our limited sample size prevented further psychological and neurocognitive evaluations in a different subgroup of DM patients. Future studies should pay particular attention to possible confounding factors such as current life stress and ensure a sufficiently large sample size to take large inter-individual variance into account. Second, although cognitive impairment is not considered a specific feature in patients with DM, a complete neuropsychological assessment is lacking. Third, our hospital is in an area of the city that covers a population with low socio-economic status and lower levels of education, and this might have affected the results of their cognitive performance test. Finally, HbA1C reflects the glycemic status within the last 3 months, to correlate the effect of glycemic control on the NCV findings and overall symptoms in patients with diabetes, we need to conduct a prospective study and check HbA1c in several time points to get a broader view of the glycemic status of the patients.

This study showed that NCS measures of nerve fiber functions, even SRAR, do not necessarily correlate with cognitive performance and sexual function. However, clinical assessments of neuropathy, including NDS and NSS, were negatively correlated with cognitive function.

Acknowledgments

We would like to extend our gratitude to all the staff at the Neurology Clinic of Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran for their cooperation during conducting this research. We also thank the Clinical Research Development Unit (CRDU) of Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences Tehran, Iran for their assistance in this research.

Financial Disclosure

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Conflict of Interest

The authors have declared that there is no conflict of interest.

Informed Consent

Consent to publish is obtained from the participants of this study through informed written consent.

Author Contributions

LS and MK: conceptualization, methodology, project administration, supervision. MR: data curation, formal analysis, methodology, validation, editing. FM and SA: data collection, writing the original draft. ZF, FG, and HK: data collection. EK: final revision, review and editing.

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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