Near nerve local insulin prevents conduction slowing in experimental diabetes

Insulin may have direct effects on axons through its actions on insulin receptors or through cross occupancy of insulin-like growth factor-1 receptors. We tested the hypothesis that insulin itself influences conduction of myelinated fibers independent of hyperglycemia in experimental diabetes. Low dose intermittent (0.2 units thrice weekly) Toronto (regular) insulin was injected at the sciatic notch and knee near the left sciatic nerve of rats rendered diabetic with citrate buffered streptozotocin or nondiabetic rats given citrate only. Identical volumes of normal saline were injected near the contralateral right sciatic nerve. The diabetic rats developed hyperglycemia, elevated glycosylated hemoglobin levels and had slowing of right (saline treated) sciatic tibial motor and caudal sensory conduction velocity. In contrast, local insulin treatment on the left side prevented conduction slowing, unilaterally increasing conduction velocity. In nondiabetic rats, conduction velocities were slightly higher on the insulin treated side, but the influence of insulin was less robust than in diabetics. The insulin treated sural branches of the sciatic nerves in diabetics had a higher percentage of small (≤9.0 μm diameter) myelinated fibers than the saline treated nerves. Local insulin has a trophic influence on myelinated fibers that is prominent in diabetic nerves and is independent of hyperglycemia.     

Mild ischemia causes severe pathological changes in experimental diabetic nerve.

Nerve ischemia is considered one of etiological factors in the development of structural changes in peripheral nerves associated with diabetes mellitus. To assess the effect of mild ischemia on diabetic nerve, a subthreshold dose of polystyrene microspheres was injected intraarterially to occlude microvessels of the sciatic nerve and its branches in 20-week streptozotocin-induced diabetic and control rats. Diabetic sciatic and tibial nerves showed severe pathological change of myelinated fibers, whereas nondiabetic nerves were normal or had minor structural abnormalities. Morphometrical evaluation confirmed a greater frequency of abnormal myelinated fibers in diabetic nerves especially in central fascicular regions. The results indicate that diabetic nerve has an increased morphological susceptibility to nerve ischemia. Endoneurial hypoxia, which may result from hemorheological and vascular abnormalities, is likely to cause a lowered threshold to ischemic tolerance in diabetic nerve. This increased vulnerability to ischemia may render diabetic nerve unduly susceptible to hyperglycemia-induced systemic tissue abnormalities.     

Conduction slowing in diabetic distal polyneuropathy

The pathophysiologic significance of motor conduction slowing observed in diabetic distal symmetrical polyneuropathy (DSP) remains controversial. We have used multiple linear regression analysis of compound muscle action potential (CMAP) amplitude vs. motor conduction velocity (CV) and distal latency (DL) in 57 patients with diabetic DSP and 34 patients with amyotrophic lateral sclerosis (ALS) to determine whether motor conduction slowing in diabetic DSP is due mainly to loss of large axons as in ALS or whether there is an additional demyelinative component. We found amplitude-dependent slowing of CV and DL in both diabetic DSP and ALS in the upper and lower extremities, consistent with a loss of large myelinated fibers. However, in diabetic DSP, there was also significant amplitude-independent slowing in intermediate but not distal nerve segments, supportive of an additional demyelinative component. CMAP amplitude vs. CV and DL regression analyses using ALS as a control group for relatively pure axon loss may provide pathophysiologic information about motor nerves in other neuropathic disorders.     

Reduced sensory and motor conduction velocity in 25-week-old diabetic [ ] mice

Motor and sensory conduction velocities were measured in sural and tibial nerves of 25-week-old genetically diabetic ( ) mice and their nondiabetic littermates. For motor conduction velocity determination, the sciatic nerve was stimulated at the hip and the tibial nerve subsequently stimulated at the ankle while recording interosseous muscle potentials from needle electrodes placed in the foot. Sensory conduction velocities were determined by recording compound action potentials directly from sural and tibial nerves at the ankle after sciatic nerve stimulation. Control and diabetic conduction velocities were compared by Student's t test. The motor conduction velocity was reduced by approximately 20% from the control, and the distal motor latency was increased in mice by 22% more than the control latency. Conduction velocity was also reduced in some sensory fibers, an observation not previously reported in the mouse. Sensory fibers most severely affected were the faster-conducting fibers of the sural nerve, whose conduction velocity was decreased by 18% from the control. Slower-conducting sensory fibers in sural and tibial nerves were only midly affected, whereas fast-conducting sensory fibers of the tibial nerve appeared to remain normal. These data suggest that not all nerve fibers react alike to the diabetic state in the genetically diabetic ( ) mouse.     

Interrelationship among nerve conduction velocity, amplitudes of compound muscle and compound nerve action potentials in diabetic neuropathy]

In order to clarify the relationship among amplitudes of compound nerve action potential (CNAP), compound muscle action potential (CMAP) and nerve conduction velocity parameters, data of nerve conduction studies were analyzed in 102 patients with diabetes mellitus. In motor conduction studies CMAP amplitudes after stimulations at the distal nerve trunk, and the polyneuropathy index (PNI), a mean percentage of normal for 12 indices from 4 nerves concerning to the velocity or long distance latency, were evaluated. CNAP was recorded in the median and ulnar nerves from an intrafascicularly inserted microelectrode at the elbow after wrist stimulation. CMAP amplitudes were high in the median and ulnar nerves, and were reduced in the tibial and peroneal nerves. A close relationship was found between PNI and CNAP amplitudes. Among CMAP amplitude parameters tibial nerve, not median or ulnar nerves, had a good correlation with PNI and CNAP amplitude. Along with the progression of diabetic neuropathy, neuropathic signs or symptoms become conspicuous, and nerve conduction velocity drops as is expressed by the PNI level, which reflects the change in nerve conduction velocity in the upper and lower limbs. At the same time CNAP amplitude or CMAP amplitude in the tibial nerve decreases, but in nerves of the upper limb CMAP amplitude doesn't always decrease. So, tibial nerve is best among CMAP amplitude parameters in evaluating the degree of diabetic neuropathy. It is necessary to judge the degree of diabetic neuropathy after due consideration of these facts.     

Hypertension-induced peripheral neuropathy and the combined effects of hypertension and diabetes on nerve structure and function in rats

Diabetic neuropathy includes damage to neurons, Schwann cells and blood vessels. Rodent models of diabetes do not adequately replicate all pathological features of diabetic neuropathy, particularly Schwann cell damage. We, therefore, tested the hypothesis that combining hypertension, a risk factor for neuropathy in diabetic patients, with insulin-deficient diabetes produces a more pertinent model of peripheral neuropathy. Behavioral, physiological and structural indices of neuropathy were measured for up to 6 months in spontaneously hypertensive and age-matched normotensive rats with or without concurrent streptozotocin-induced diabetes. Hypertensive rats developed nerve ischemia, thermal hyperalgesia, nerve conduction slowing and axonal atrophy. Thinly myelinated fibers with supernumerary Schwann cells indicative of cycles of demyelination and remyelination were also identified along with reduced nerve levels of myelin basic protein. Similar disorders were noted in streptozotocin-diabetic rats, except that thinly myelinated fibers were not observed and expression of myelin basic protein was normal. Superimposing diabetes on hypertension compounded disorders of nerve blood flow, conduction slowing and axonal atrophy and increased the incidence of thinly myelinated fibers. Rats with combined insulinopenia, hyperglycemia and hypertension provide a model for diabetic neuropathy that offers an opportunity to study mechanisms of Schwann cell pathology and suggests that hypertension may contribute to the etiology of diabetic neuropathy.     

Conduction velocity versus amplitude analysis: Evidence for demyelination in diabetic neuropathy

Motor conduction velocities (CVs) were correlated with distal compound muscle action potential (CMAP) amplitudes for tibial, peroneal, and median nerves in patients with biopsy-proven chronic inflammatory demyelinating polyneuropathy (CIDP), diabetic neuropathy, and amyotrophic lateral sclerosis. Only in the diabetic patients did CV significantly correlate with CMAP amplitude. The data show that diabetic neuropathy produces conduction velocity slowing that cannot be explained by axon loss alone, and that differentiation between diabetic neuropathy and CIDP in an individual nerve is difficult. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1228–1230, 1998.     

Proximal and segmental motor nerve conduction in the sciatic nerve produced by percutaneous high voltage electrical stimulation

Percutaneous high voltage electrical stimulation was applied to the proximal sciatic nerve at the hip in 18 normal subjects to evaluate motor conduction in the proximal sciatic nerve, and short-segment stimulation of the sciatic and posterior tibial nerves was given in 6 normal subjects. Compound muscle action potentials (CMAPs) were recorded from the abductor hallucis (AH) and extensor digitorum brevis (EDB) muscles. Supramaximal stimulation was easily obtained at the proximal sciatic nerve and all the sites in the short-segment stimulation. The motor nerve conduction velocity of the sciatic nerve between the hip and the popliteal fossa was 49.2 ± 4.24 m/sec in the tibial division and 54.1 ± 6.48 m/sec in the peroneal division. The respective peak-to-peak amplitude and negative-peak areas of the CMAPs at the hip were reduced to 86.8 ± 5.65% and 97.3 ± 5.36% for the tibial division, and 93.4 ± 7.06% and 96.8 ± 5.09% for the peroneal division as compared to the values for the popliteal fossa. The negative-peak duration of the CMAPs at the hip point were increased to 109.2 ± 7.2% for the tibial nerve and 107.1 ± 5.68% for the peroneal nerve as compared with the duration at the popliteal fossa. This method is non-invasive and useful for evaluating motor nerve conduction in the lower limb.     

Sarcoid polyneuropathy: a histologically proved case

A 58-year-old patient had subacute polyneuropathy. Electrophysiological studies showed inexcitability of the distal portion of the peroneal and posterior tibial nerves and minimal reduction in amplitude of the muscle potential with minimal slowing in motor nerve conduction velocity. The sural nerve biopsy showed multiple sarcoid granulomas in the epineurial and perineurial spaces, periangiitis and panangiitis, and axonal degeneration. Remarkable clinical improvement followed corticosteroid treatment.     

A case of hereditary motor and sensory neuropathy of neuronal type with retardation of motor development

An atypical case of hereditary motor and sensory neuropathy of neuronal type with retardation of motor development was described. The patient was a 15-year-old boy who had suffered from distal muscle weakness with atrophy of four limbs and deformities of hands and feet since age 6 months. These symptoms were slowly progressive. He had never walked. His parents were not consanguinous. His parents and two siblings were unremarkable on neurological examination and on nerve conduction studies. On neurological examination, he showed severe degree of muscle weakness and atrophy in the distal upper and lower limbs, moderate degree of muscle weakness and atrophy in the proximal upper limbs and slight degree of made weakness and atrophy in the proximal upper limbs. Deep tendon reflexes in four limbs were decreased or absent. Vibration sensation was moderately decreased in the distal parts of four limbs. On the nerve conduction studies, no sensory nerve potential was recorded in the median, ulnar and sural nerves bilaterally. Motor nerve conduction velocity of the right tibial nerve was 21 m/sec and the amplitude of the compound muscle action potential (M-wave) was 0.15 mV, and no M-wave was elicited with the electrical stimulation of the median, ulnar and peroneal nerves. Neelde EMG showed fibrillation potentials and giant spikes with a reduction of the number of motor units. On sural nerve biopsy, the densities of both myelinated and unmyelinated fibers were severely decreased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of diabetes on motor conduction velocity in different branches of the rat sciatic nerve

Motor nerve conduction velocity was measured in six branches of the sciatic nerve in streptozotocin-diabetic rats. It was markedly reduced in nerves to the gastrocnemius, soleus, tibialis anterior, and extensor digitorum longus muscles. The branch to the plantaris muscle remained unaffected. In control rats none of these branches showed any evidence of conduction velocity maturation over the 2-month experimental period. Motor nerve conduction velocity to the interosseus muscles of the foot did show a normal maturation effect, which was halted by diabetes. We conclude that large-caliber motor fibers in mature nerves are particularly susceptible to diabetes.     

Differentiation between axonal and demyelinating neuropathies: Identical segments recorded from proximal and distal muscles

The presence of significant slowing of motor nerve conduction velocity is considered one of the electrodiagnostic hallmarks of demyelinating neuropathies; however, slowing of conduction velocity may also accompany severe axonal loss. When compound muscle action potential (CMAP) amplitudes are markedly reduced, it is frequently difficult to determine if conduction velocity slowing is due to axonal loss with dropout of the fastest conducting fibers or demyelination. To evaluate the relationship between conduction velocity and axonal dropout, we compared conduction velocities through the same segment of nerve recording from distal and proximal peroneal muscles in patients with chronic neuropathies, in patients with motor neuron disease, and in control subjects. In controls and patients with motor neuron disease, conduction velocities were normal with no significant difference between proximal and distal sites. In patients with axonal neuropathies, conduction velocities were preferentially slowed when recording from distal muscles and relatively normal when recording from proximal sites. Patients with demyelinating neuropathies showed marked slowing of conduction at both sites. We conclude that comparing conduction velocity obtained from proximal versus distal muscle recordings provides a simple, reliable aid for differentiating between chronic axonal and demyelinating polyneuropathies, especially in cases with conduction velocity slowing and low CMAP amplitudes. © 1995 John Wiley & Sons, Inc.     

Sensory (1a) and F-wave conduction velocity in the proximal segment of the tibial nerve

The F-wave was used to estimate the fastest motor nerve conduction velocity (MNCV) along the proximal segment (spinal cord to knee) of the axons of the tibial nerve in 65 control subjects, 8 patients with diabetic polyneuropathy, and 4 patients with Charcot-Marie-Tooth disease. Terminal latencies and MNCV along the distal segment (knee to ankle) of the nerve were also estimated with the conventional M-response technique. This article describes another method for estimating sensory nerve conduction velocity (SNCV) along 1a fibers of the tibial nerve for the spinal cord-to-knee segment. Proximal and distal MNCV showed moderate slowing in patients with diabetic polyneuropathy and severe slowing in those with Charcot-Marie-Tooth disease. In 17 control subjects, proximal MNCV for the axons supplying the abductor hallucis muscle was compared to that estimated for the axons to the gastrocnemius muscle. MNCV for the proximal is faster than that for the distal small muscle. In 2 patients, M- and F-responses were not obtained from the abductor hallucis; in these patients, effective estimation of the proximal MNCV was made from the gastrocnemius muscle and showed marked reduction.     

Nerve conduction changes and fine structural alterations of extra- and intrafusal muscle and nerve fibers in streptozotocin diabetic rats

Streptozotocin-induced diabetes mellitus in known to cause a reduction of both conduction velocity and axon caliber in sciatic nerves and also a decrease in muscle fiber size. The present study investigates whether the distal parts of the peripheral nervous system, including extra- and intrafusal muscle fibers, are more severely affected than the proximal segments in the diabetic state. Proximal and distal sensory nerve conduction velocities were monitored during a period of 3 months in rats rendered diabetic by injection of streptozotocin. Segments of the sciatic and ventral coccygeal nerves, and of the biceps femoris and lumbrical muscles, were studied by light and electron microscopy, including morphometric analysis. In contrast to previous studies, daily suboptimal insulin injections were given to prevent acute metabolic complications. Sensory conduction velocity in the ventral coccygeal nerve was significantly (P > 0.05) decreased in the diabetic rats compared to controls. Proximal and distal nerve segments were equally affected. Mean cross-sectional axon area of the sciatic nerve was moderately, but significantly (P < 0.05), smaller in insulin-treated diabetic rats than in controls. In both the sciatic nerve and the terminal, intrafusal nerve segments, occasional axons showed moderate dystrophic changes. Fibers of the intrafusal nerve segments appeared to be equally affected compared to the fibers in the sciatic nerve, although no quantitative comparison was made. The increase of small caliber skeletal muscle fibers in experimental streptozotocin-induced diabetes was confirmed. These findings indicate that proximal and distal segments of peripheral nerves are affected equally in the early stages of experimental diabetic neuropathy.© 1995 John Wiley &Sons, Inc.     

Comparison of organophosphate-induced delayed neuropathy between branches of the tibial nerve and the biventer cervicis nerve in chickens.

Delayed neuropathy induced by organophosphorus esters has been reported to be more selective for large diameter myelinated fibers, especially in distal portions of long nerves. This concept was re-evaluated in chickens by quantitatively comparing the effects of the organophosphates tri-ortho-tolyl (TOTP) and phenyl saligenin phosphate (PSP) on two separate nerves, the branch of the tibial nerve that supplies the gastrocnemius muscle, and the small cervical nerve that innervates the biventer cervicis muscle. Histograms illustrating the distribution of myelinated fibers within each nerve showed that the biventer nerve is composed of a population of fibers smaller than those within the tibial nerve branch. However, the number of myelinated fibers measured per mm2 of endoneurium was reduced in both nerves 10 and 15 days after organophosphate administration, providing indirect evidence that fiber diameter is not critical in determining susceptibility to organophosphorus-induced delayed neuropathy (OPIDN). More direct evidence was provided by fiber diameter histograms of both biventer nerves and tibial nerve branches taken from hens that received PSP. In comparison to control values, there was a decrease in all fiber sizes in both nerves, indicating that factors other than axonal size are important in determining nerve fiber susceptibility to OPIDN.     

Transient conduction block following acute peripheral nerve ischemia

We studied the effects of transient focal ischemia on the electrophysiologic function of rat sciatic nerves. Focal and generalized impairment of impulse conduction, measured by falling evoked muscle and nerve compound action potential amplitudes, occurred within 10 minutes of femoral artery occlusion. Conduction failure reached a nadir at 45-60 minutes and then improved to normal within 24 hours. Fastest motor and mixed nerve conduction velocities were reduced less than 15% of baseline values during the period of acute conduction block. There were no detectable morphological abnormalities at the site of conduction failure. Transient ischemia produces reversible conduction block without evident structural changes. The fall in amplitude without significant conduction slowing implies that slower conducting myelinated fibers are relatively more sensitive to the effect of acute ischemia.     

Comparison of short-term effects of insulin and essential fatty acids on the slowed nerve conduction of streptozotocin diabetes in rats.

Early effects of insulin and essential fatty acids on nerve conduction were studied. Insulin-dependent diabetes was induced in rats using streptozocin (65 mg/kg, i.p.); control rats were treated with buffer. Five weeks later, diabetic rats were divided into 5 groups. Two groups were given oral essential fatty acids (75% linoleic and 9% gamma-linolenic acids) for a further 3 and 5 days, respectively. Two other groups received subcutaneous insulin for a further 3 or 5 days. A group of diabetic rats were left without further treatment. Motor nerve conduction velocity was measured terminally in all rats by stimulating the sciatic nerve and recording EMGs in the gastrocnemius muscle under urethane anaesthesia. Sensory nerve conduction velocity was measured by stimulating and recording from the saphenous nerve trunk. Diabetic rats had significantly slowed motor and sensory nerve conduction velocities after 5 weeks (16.7%, P less than 0.001). Three days treatment with either insulin or fatty acids corrected the slowed motor nerve conduction velocity to a normal level. Conduction velocity in myelinated sensory nerves was still 10% slower in diabetic rats treated with insulin for 3 days (P less than 0.01). It was above the control level by 11% in diabetic rats treated with fatty acids for the same period (P less than 0.01). Conduction velocities in both sensory and motor nerves were normal in diabetic rats treated with either insulin or fatty acids for 5 days. It was concluded that both insulin and essential fatty acids had early effects on nerve conduction in diabetic rats. The speed of their actions, and the magnitudes of responses were different in sensory and motor nerves.     

Severe Guillain-Barré syndrome: sorting out the pathological hallmark in an electrophysiological axonal case

Abstract   We describe a clinicopathological study of a patient presenting with severe and electrophysiological axonal Guillain-Barré syndrome (GBS). An 83-year-old man had a 2-day history of distal acroparesthesias and ascending weakness culminating in quadriplegia, the patient dying 1 month after onset. On day 3, motor conduction velocity (MCV) and distal motor latency values were normal or minimally delayed; most F waves were present with latencies normal or barely delayed. Compound muscle action potential (CMAP) amplitudes were variably reduced. On day 10, there was reduction of CMAPs with relative preservation of MCV. On histological study, the density of myelinated fibers was normal in L5 ventral and dorsal roots, where outstanding lesions included dark fibers, scattered macrophage infiltration, and occasional images of de-remyelination or axonal degeneration. In the fifth spinal nerve, there was widespread loss of myelinated fibers with focal areas showing almost complete fiber loss and variable fascicular combination of extensive de-remyelination and axonal degeneration. Wallerian-like degeneration predominated in femoral and sciatic nerves. Peripheral neuron cell bodies showed central chromatolysis. We conclude that the pathological hallmark of this electrophysiological axonal GBS case is extensive but variable de-remyelination of proximal nerve trunks with superimposed nerve ischemia and axonal degeneration.     

Pathogenesis of diabetic neuropathy

Samples of lumbosacral trunk, posterior tibial nerve, and sural nerve obtained at autopsy from diabetic and nondiabetic patients without mononeuropathy multiplex were evaluated using 1-mu-thick epoxy sections and teased nerve fiber preparations. Focal fascicular lesions characterized by reduced density of myelinated axons within fascicles were found predominantly in the specimens from diabetics, mainly in the posterior tibial nerve and lumbosacral trunk. In severe examples, the perineurium and even surrounding epineurium were damaged, stamping the lesions as ischemic. In addition, identical lesions were found in biopsies of nerves of nondiabetics with vasculitis. Density of myelinated fibers at the three sites demonstrated a proximal-distal graded loss that was significantly greater in the diabetic samples. The loss from the lumbosacral trunk to the posterior tibial nerve was correlated with the density of focal lesions in the lumbosacral trunk in the diabetic (p = 0.025), indicating that distal fiber loss was partly due to the focal lesions. Teased nerve fiber abnormalities were common only in sural nerves of diabetics, suggesting that they are secondary. We conclude that beyond the possible metabolic abnormalities involved in the genesis of diabetic polyneuropathy, focal fascicular lesions, likely due to diabetic microangiopathy, are also important in the development of diabetic neuropathy.     

Reinnervation of spinal cord anterior horn cells after median nerve repair using transposition with other nerves

Our previous studies have confirmed that during nerve transposition repair to injured peripheral nerves, the regenerated nerve fibers of motor neurons in the anterior horn of the spinal cord can effectively repair distal nerve and target muscle tissue and restore muscle motor function. To observe the effect of nerve regeneration and motor function recovery after several types of nerve transposition for median nerve defect(2 mm), 30 Sprague-Dawley rats were randomly divided into sham operation group, epineurial neurorrhaphy group, musculocutaneous nerve transposition group, medial pectoral nerve transposition group, and radial nerve muscular branch transposition group. Three months after nerve repair, the wrist flexion test was used to evaluate the recovery of wrist flexion after regeneration of median nerve in the affected limbs of rats. The number of myelinated nerve fibers, the thickness of myelin sheath, the diameter of axons and the cross-sectional area of axons in the proximal and distal segments of the repaired nerves were measured by osmic acid staining. The ratio of newly produced distal myelinated nerve fibers to the number of proximal myelinated nerve fibers was calculated. Wet weights of the flexor digitorum superficialis muscles were measured. Muscle fiber morphology was detected using hematoxylin-eosin staining. The cross-sectional area of muscle fibers was calculated to assess the recovery of muscles. Results showed that wrist flexion function was restored, and the nerve grew into the distal effector in all three nerve transposition groups and the epineurial neurorrhaphy group. There were differences in the number of myelinated nerve fibers in each group. The magnification of proximal to distal nerves was 1.80, 3.00, 2.50, and 3.12 in epineurial neurorrhaphy group, musculocutaneous nerve transposition group, medial pectoral nerve transposition group, and radial nerve muscular branch transposition group, respectively. Nevertheless, axon diameters of new nerve fibers, cross-sectional areas of axons, thicknesses of myelin sheath, wet weights of flexor digitorum superficialis muscle and cross-sectional areas of muscle fibers of all three groups of donor nerves from different anterior horn motor neurons after nerve transposition were similar to those in the epineurial neurorrhaphy group. Our findings indicate that donor nerve translocation from different anterior horn motor neurons can effectively repair the target organs innervated by the median nerve. The corresponding spinal anterior horn motor neurons obtain functional reinnervation and achieve some degree of motor function in the affected limbs.