Subclinical Central Neuropathy In Type 2 Diabetes Mellitus Biology Essay

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DM with clinical manifestations of peripheral neuropathy (pain, distal paresthesiae, distal sensory loss, loss of vibration sense, loss of deep tendon reflexes and muscle weakness) supported by the electrophysiological tests (abnormal sensory and motor conduction studies in the form of a delay in sensory and motor conduction of two or more nerves).(1) They were six males and nine females, with a mean age of 47.33±7.10 years, and a mean duration of diabetes of 8.17±6.20 years.

Group 2: Included fifteen patients with type 2 DM without any clinical or electrophysiological evidence of peripheral neuropathy. They were five males and ten females, with a mean age of 45.00±5.33 years, and a mean duration of diabetes of 5.08±3.17 years.

Group 3: Included fifteen healthy individuals as a control group. They were six males and nine females, with a mean age of 45.50±5.17 years.

All subjects were selected from those attending

the outpatient clinics at the Main Alexandria University Hospital, Alexandria, Egypt. Subjects with a history of any neurological disorder, cerbrovascular disease, hypertension, systemic disease especially connective tissue disease, hepatic and renal diseases, malignancy or a history of alcohol intake or smoking, and also those receiving potentially neurotoxic medications were excluded. Diabetics with overt nephropathy were also excluded. All patients were on oral hypoglycemic agents including sulphonylureas and metformin. All subjects had a normal hearing, as determined by assessing the auditory threshold during the clinical examination and BAEP study, and also a good vision. They were cooperative and tolerated the electrophysiological tests. Informed written consents were taken from all participants before inclusion, and the study was approved by the local ethical committee.

All patients and controls were subjected to:

1-Detailed history taking and complete physical examination.

2-Laboratory investigations including: Complete blood cell count (CBC),(11) fasting plasma glucose (FPG),(12) glycated hemoglobin (HbA1c),(13) serum total cholesterol, serum triglycerides, blood urea, serum creatinine and 24-hour urinary albumin excretion (UAE).(12)

3-Electrophysiological study: It was performed using the Nihon Kohden electrophysiological apparatus (Neuropack 2) and included:

i.Superficial peroneal and sural nerve-sensory conduction studies and peroneal and tibial

nerve-motor conduction studies,(14) to confirm (group 1) or to exclude (group 2) the presence of peripheral neuropathy.

ii.Evaluation of central neuropathy using the following electrophysiological tests:

a.Cortical and spinal recording of the tibial nerve somatosensory evoked potentials (SEP), with recording of the cortical latency of the tibial nerve SEP (P40) and its evoked potential amplitude (peak to peak) and recording of the spinal latency of the tibial nerve SEP (N22), as well as evaluation of the interpeak latency (IPL) between the cortical and spinal latencies (N22-P40). This could reflect the central conduction pathway and exclude the peripheral impact of the peripheral nerve affection. The used sweep speed was 10 msec/division, sensitivity of 1-5 mV/division and a filter band setting between 2 Hz-10 KHz. The stimulation frequency was done with a pulse duration of 0.5 msec and a frequency of 1 Hz. The patient was examined in the supine position with a completely relaxed state. A total of 128 stimuli were commonly used (with at least 60 stimuli if a good response was recorded or, on the other hand, more stimuli if unsatisfactory response was recorded). A nerve tract damage increases the latency and reduces the amplitude of the response.(14)

b.Motor evoked potentials (MEP) of both lower limbs: These were recorded from the tibialis anterior muscle after transmagnetic stimulation using single pulse stimulator, magstim 200 (Magstim company, Whiteland, Wales, United Kingdom) equipped with a high power 90 mm circular coil, capable of generating 2 -tesla maximum filed density.(15) The muscle responses were recorded using 7 mm surface disc electrodes filled with electrode jelly. Filter settings were set with a low filter setting of 3 Hz and a high frequency filter 3 KHz. Responses were amplified and the gain set was applied with 0.5-2 mV/division and adjusted according to the amplitude of the response, so that the responses produce a deflection of at least 50% of the maximal excursion, but do not go off scale. The time base was set with a sweep speed of 10 msec / division and the following was determined:(15)

-MEP threshold: Defined as the lowest intensity that gives three reproducible responses, and expressed as a percentage (%) of the maximum output of the stimulator.

-Central motor conduction time (CMCT): Calculated as the difference between the cortical and peripheral latencies of the MEP. Where, the cortical latency (msec) is the shortest latency determined to the onset of the negative peak, and the peripheral latency (msec) = minimal F wave (msec) + M wave latency (msec)-1/2.

The M wave was obtained by supramaximal stimulation of the peroneal nerve above the neck of fibula. The F wave was obtained like the M wave, but with the cathode proximal to avoid anodal block.

-MEP amplitude percentage quotient: Determined

by determining the maximal amplitude of the

MEP (peak to peak), and expressed as a ratio

of the amplitude of the M wave (peak to peak)

as follows: Maximum MEP amplitude (mV)

/ Maximum M response (mV) %.

-Duration of the MEP: Measured from the onset of the negative deflection to the return to the baseline.

-Number of phases of the MEP: Counted as the number of base line crosses + 1.

c.Visual evoked potentials (VEP): These were recorded with a sweep speed of 5 msec / division, sensitivity of 50 µV / division and a filter band setting between 5 Hz and 0.2 KHz. The equipment used was capable of producing shifting pattern of checker board squares made on a television monitor. The patient was sitting on a chair one meter away from the monitor in a dark room, with the untested eye closed, and carefully watching the shifting checker board squares on the monitor. The patient watched a dot in the centre of the screen, with certain that the patient was actually watching the screen. The stimulation frequency was 2 Hz. The latency of the P100 wave and the peak to peak amplitude were recorded. It is commonly accepted that the P100 wave is the most consistent and important component of the VEP.(16,17)

d.Brainstem auditory evoked potentials (BAEP): These were recorded with a sweep speed of 1 msec / division, a sensitivity of 10 µV / division and a filter setting band between 100 Hz to 5 KHz. The stimulation was in the form of clicks generated in an earphone by using an electrical square wave impulse of about 0.1 msec. The noise stimulus had a frequency of 3 Hz with a condensation and rarefaction pattern and a mask noise in the other ear with 60 decibels (dB). The intensity in the examined ear differed according to the hearing threshold of the examined patient (60 dB over the hearing threshold). The patient was relaxed and lying supine in an isolated room. Five waves (I-V) are distinguished in the BAEP, each represent a specific anatomic structure in the auditory pathway. The latency of each wave was recorded and also, the IPL between the first and the third wave (I-III IPL), the third and the fifth wave (III-V IPL), and the first and the fifth wave (I-V IPL).(16,17)

DM is a disease of metabolic dysregulation, most notably abnormal glucose metabolism, accompanied by characteristic long-term complications. The risk of the various diabetic complications may be modified by different factors.(18)

Neuropathies are important complications of

DM and are associated with sensory loss, pain

and may be weakness.(19) The initial abnormalities

that trigger the development of these neuropathies are disputed and many hypotheses are suggested including excessive polyol flux in peripheral nerves, nerve microangiopathy, nonspecific glycosylation of structural nerve proteins, early targeting of sensory and autonomic neurons in the ganglia, deficiency

of specific trophic nerve factors, excessive

oxidative stress and nitric oxide toxicity.(20-23) Pierzchala(24) found that inspite that delayed

MEP latency in diabetic patients indicated the presence of subclinical diabetic encephalopathy, yet cranial diabetic neuropathy had not necessarily influenced the CMCT. He concluded that diabetic encephalopathy seems to be dependent on both the metabolic and vascular changes.

Different neurological complications might be caused by different mechanisms; for example a metabolic mechanism for peripheral sensori-

motor neuropathies, and a vascular one in mono-neuropathies. Unfortunately, the available studies are so fragmentary that no coherent pathogenetic mechanism has been established.(18)

The peripheral nervous system has been previously investigated a lot in DM. However, the term central diabetic neuropathy has been unknown until recently. Electrophysiological studies are sensitive in determining peripheral and central neuropathy in diabetic patients. Decreased nerve conduction velocity has been demonstrated in many patients with normal clinical examination. Abnormalities of the central afferent and efferent pathways can be measured by evoked potential studies. These are useful and non invasive tests in establishing the diagnosis of neuropathies developing in the CNS, and include the SEP, MEP, VEP and BAEP. They can be affected together, but isolated abnormalities are more frequently encountered.(8,25,26)

In this study, evoked potential abnormalities were more common (specially the interpeak latencies of the BAEP) and more severe in type 2 diabetics with peripheral neuropathy (group 1) than those without these manifestations (group 2). This was in agreement with previous studies.(2,,24,27) The present study showed statistically significant differences between all studied groups as regard the cortical latency of the tibial nerve SEP (P40) and its evoked potential amplitude (P40 amp), the spinal latency of the tibial nerve SEP (N22), the N22-P40 IPL of the tibial nerve SEP, the threshold and number of phases of the MEP and the latency of the waves III, IV and V of the BAEP. On the other hand, there were statistically significant differences on comparing group 1 and group 2 with group 3 only in the VEP P100 latency and its amplitude, the MEP CMCT, MEP amplitude percentage quotient, duration of the MEP, and the BAEP wave II latency. The wave I-III, wave III-V, and wave I-V IPL showed a statistically significant delay only in group 1. The significantly prolonged latency of waves II, III, IV and V in both diabetic groups reflected the

central affection while, the insignificant differences as regard the wave I latency excluded the

afferent component (auditory nerve lesion). The observed prolongation of the N22-P40 IPL

supports the central spinal cord affection while,

the BAEP III-V IPL and the VEP abnormalities support the central brain affection in the

studied patients. Also, identification of abnormal central findings in the diabetics without peripheral neuropathy supports subclinical central neuropathy in type 2 DM, and is an evidence that the peripheral and central nervous systems could be affected independently in diabetics. Similar conclusions

were previously reported.(28-30) In line with the present data, Dolu et al(8) demonstrated central evoked potential abnormalities in type 2 diabetics without peripheral neuropathy, with more frequent changes in patients with peripheral neuropathy. Rajewski et al(2) had recently identified similar findings in both type 1 and type 2 diabetics. Furthermore, Gregori et al(31) found significant slowing of VEP in both type 1 and type 2 diabetic patients compared to healthy controls, with a more slowing in patients with peripheral neuropathy compared to those without peripheral neuropathy.

In addition, Goldsher et al(32) demonstrated BAEP abnormalities in 44% of type 1 diabetic patients

with peripheral neuropathy compared to only

12% of patients without peripheral neuropathy. All together, the available findings highly recommend investigating central neuropathy in diabetics, even

in asymptomatic patients. Their early detection

with subsequent early therapeutic intervention may enhance the patient prognosis.

The correlation study showed a statistically significant positive correlation between the cortical latency of the tibial nerve SEP (P40), MEP CMCT, VEP P100 latency and BAEP wave III-V IPL and the age of the diabetic patients, and between the cortical latency of the tibial SEP, N22-P40 IPL of the tibial nerve SEP, MEP CMCT and VEP latency and the duration of diabetes. In this regard,

Dolu et al(8) reported a significantly positive correlation between most of the evoked potential parameters and the duration of diabetes and between some of them and the patient age.

Also, a significantly positive correlation was observed between the cortical latency of the tibial nerve SEP, IPL of the tibial nerve SEP, MEP CMCT and VEP latency and the glycated hemoglobin (HbA1c). Das et al(9) concluded that in type 2 diabetic patients strict glycemic control could influence and retard the progression of central conduction involvement, and that the VEP abnormalities could be reversible. Also, the central neural conduction, primarily tested by BAEP, was significantly prolonged in slow acetylators compared with fast acetylators, in their study, and they suggested that this might predispose to the central neuropathy in these patients.

Davis et al(33) found that the patient age,

duration of diabetes, fasting glucose and urinary albumin excretion were all positively associated with peripheral neuropathy in type 2 diabetics. Tesfaye et al(34) concluded that the cumulative incidence of peripheral neuropathy was significantly associated with the duration of diabetes, glycated hemoglobin value, dyslipidemia and urinary albumin excretion. As regard the association of these risk factors with central diabetic neuropathy in the present study, statistically significant positive correlations were observed between the cortical latency of the tibial nerve SEP (P40), MEP CMCT, VEP latency (P100) and BAEP wave III-V IPL

and the serum total cholesterol level, between

the VEP latency (P100) and BAEP wave III-V

IPL and the serum level of triglycerides, and between the cortical latency of the tibial nerve

SEP (P40), VEP latency (P100) and BAEP wave

III-V IPL and the urinary albumin excretion. The presence of correlation of some central neurological abnormalities with the glycated hemoglobin,

serum total cholesterol, serum triglycerides and urinary albumin excretion suggests the importance of identifying these risk factors in the assessment

of central neuropathic affection. This might lead

to risk-reduction strategies. In this respect, there

is evidence from in vitro and animal studies that lipid lowering therapy has multiple potentially neuroprotective effects through improvement in Schwann cell and polyol pathway function and improved neuronal blood supply.(35,36) However, further prospective studies are recommended before reaching such a conclusion.

The lack of homogeneity in the significance between the studied parameters of one evoked potential and the other, and the finding that not all central neurological abnormalities correlated with the demographic and biochemical data further support the hypothesis that central changes affect different areas of the CNS in a rather non-homogenous bizarre manner.(37)

In conclusion, central neuropathy in type 2 diabetics is not uncommon even in absence of peripheral neuropathy. It is related to the patient age, duration of diabetes, glycated hemoglobin value, dyslipidemia and diabetic nephropathy. The use of more than one modality of the electrophysiological tests (multimodal evoked potential studies) can buffer the fallacies of a single mode and is advisable in evaluating central neuropathy in patients with type 2 DM. Early diagnosis of central neuropathy is recommended to offer an early opportunity for a proper management.