Large Myelinated Nerve Fibers Research Articles

Patterns of myelinated nerve fibers loss in transthyretin amyloid polyneuropathy and mimics.

ObjectiveThe present study was intended to analyze the characteristics of myelinated nerve fibers density (MFD) of transthyretin amyloid polyneuropathy (ATTR‐PN) and other similar neuropathies.MethodsA total of 41 patients with ATTR‐PN, 58 patients of other common peripheral neuropathies, and 17 age‐and gender‐matched controls who visited the First Hospital of Peking University and performed sural nerve biopsy between June 2007 and August 2021 were included for analysis of MFD.ResultsExcept the vasculitic neuropathy group, the total and small MFD of patients in the ATTR‐PN group were significantly lower than those of other disease groups. There was an obvious negative correlation between the total MFD and the disease course in the ATTR‐PN group. The disease course of early‐onset and late‐onset symptoms was similar, but the loss of large myelinated nerve fibers (MF) was more severe for the latter. In addition, all late‐onset and most early‐onset patients had severely reduced MFD after a 2 years' disease course. The MFD in ATTR‐PN patients was negatively correlated with Neuropathy Impairment Score (NIS) and Norfolk Quality of life‐diabetic neuropathy (Norfolk QOL‐DN) score.ConclusionMF is lost differently in ATTR‐PN and in other common peripheral neuropathies. The late‐onset and early‐onset ATTR‐PN patients have different patterns of loss of large and small MF.

Yoga versus Aerobic Exercise: An Alternative Intervention for Neuropathic Pain Among African Americans with Diabetes

In today’s world, the prevalence of African Americans (AA) with diabetes continues to grow as it is becoming an epidemic. As of 2012, AA adults are two times more likely to be diagnosed with diabetes. Diabetes is most closely associated with being overweight/obese and around 50%–75% of AA that are older than 20 years of age fall into this category. With this disease comes many challenges not only mentally but physically that can decrease the quality of life in individuals that live with this condition. Often times pharmacological management of diabetes is introduced to patients as a means of controlling symptoms, such as neuropathic pain, without discussion of alternative methods. Commonly, side effects of these medicines introduce new problems that are then managed with more medications; this contributes to the rising opioid crisis in the United States. Therefore, alternative methods such as yoga should be employed. Current evidence suggests yoga has many beneficial effects to individuals with diabetes including decreased neuropathic pain. Although this evidence exists for the majority of the population in the United States, few studies have been conducted on AAs using yoga as a means to decrease neuropathic pain. The purpose of this study was to conduct a systematic review regarding neuropathic pain in the AA population and how yoga may be a better alternative to treating this pain versus aerobic exercise only. Using a variety of databases such as PubMed, Google Scholar, and EBSCO Host, studies were reviewed and ranked according to the Oxford Center for Evidence‐Based Medicine. Distal symmetric polyneuropathy (DSPN) is a common neuropathy among individuals with diabetes and this neuropathy can cause pain in the upper and lower distal extremities due to damage of small and large myelinated nerve fibers. While aerobic exercise is commonly used and has shown positive results in helping decrease neuropathic pain as well as promote regrowth of nerve fibers, research shows that yoga can be used as an alternative method for reducing blood glucose levels as well as improvements in nerve conduction velocities leading to a reduction in neuropathic pain. In conclusion, our research provided evidence as to why AA populations should be encouraged to participate in yoga as an effective means of providing relief of neuropathic pain.

A 4-year follow-up of non-freezing cold injury with cold allodynia and neuropathy in 26 naval soldiers.

Background and aims Non-freezing cold injuries (NFCI), which typically may occur in military personnel, may result from exposure to cold, at temperatures around 0 °C or above, and worsened by wind and moisture. The injury is due to cooling but not freezing of tissue like in frostbite. NFCI may result in in chronic neuropathy and cold hypersensitivity. A recent retrospective study of small-and large fibres has suggested that NFCI results in neuropathic pain due to a sensory neuropathy and question a longitudinal study to verify a possible observation of improvement of NFCI over time. The present study is a 4-year follow-up investigation of large - and small-fibre function in 26 naval cadets and officers who were exposed to cold injury during the same military expedition. Methods The 26 soldiers were investigated clinically (with investigation of motor function, reflexes, sensibility), with nerve conduction studies (NCS) of major nerves in upper- and lower extremity, small fibre testing (QST, measurement of thermal thresholds), measurements of subcutaneous fat tissue and maximal O2 uptake. Investigations found place 2 months following the actual military expedition, with follow-up investigations of affected soldiers at 6-12 months and up to 3-4 years. In order to elucidate possible mechanisms (disinhibition of cold pain by myelinated nerve fibres) of cold allodynia, cold pain thresholds were measured following an ischemic block of conduction of large and small myelinated nerve fibres. Results Of 26 soldiers, 19 complained of numbness in feet and a large majority of 16 of cold hypersensitivity 2 months following injury. There were significant alterations of both large- and small-fibre function, indicating a general large- and small-fibre neuropathy. The most prominent finding was a pronounced cold allodynia, inversely correlated with the amount of subcutaneous fat. During the first year, results of NCS and thermal testing gradually normalized in most. Seven soldiers developed chronic symptoms in the form of cold hypersensitivity and with findings of cold allodynia, which was not further enhanced, but abolished following block of conduction of myelinated nerve fibres. Seven soldiers were free of symptoms from that start of the investigation, probably because they had been more eager to keep their legs moving during the exposure to cold. Conclusions Of a total of 26 soldiers, only seven developed chronic symptoms of cold hypersensitivity, corresponding to the finding of cold allodynia by thermal testing. The cold allodynia may not be explained by disinhibition of cold pain by myelinated fibres as in healthy subjects. A large majority recovered from an initial large-and small fibre neuropathy, demonstrating that recovery from NFCI may occur. Implications Although large-and small fibre neuropathy may be restored following cold injury, there is a risk of a permanent and disabling cold hypersensitivity, corresponding to the findings of cold allodynia. It is of uttermost importance to secure military personnel from the risk of cold injuries. It seems important to avoid immobilisation of extremities during exposure to cold.

PROSPECTS OF MAGNETOLASER THERAPY APPLICATION IN TREATMENT OF EXPERIMENTAL NEUROPATHY

The aim of the work is to establish morpho-functional changes of the conducting apparatus of the extracranial part of the rabbit's facial nerve at experimental neuropathy and its correction by magneto-laser therapy.Materials and methods. The material for the study was the extracranial part of the facial nerve (FN) of 15 rabbits, of which 5 intact animals, 5 - were simulated experimental cold neuropathy, 5 - with neuropathy combined with the action of a permanent electromagnetic field and laser radiation. Histologic (coloring by Kulchytsky, Marky, Masson, Renson), electron microscopic methods of research, electroneuromyography and morphometry with statistical processing of data were used.Results. In the process of development of cold neuropathy FN, we have isolated a stage of reactive-dystrophic changes. In most myelinated nerve fibers, uneven coloration, significant edema and destruction of the myelin sheath with axon exposure and the accumulation of myelin residues in the cytoplasm of the neurolemocyte are observed. The number of small and medium-sized ones decreases and the number of large myelinated nerve fibers (NF) increases. A consequence of demyelination of individual axons is an increase in the number of demyelinated NF. At this stage, the amplitude of the M-response decreases; there is a decrease of the amplitude and increase of the latent period of the F wave, and its polyphasicity, while the pulse rate reduction (PRR) is 79.3%, that is indicating a deep morpho-functional reorganization of the nerve conductors.Activation of phagocytosis processes takes place magnetolaser therapy in result of which facilitates the removal of the decay products, which were formed as a result of cold trauma and ischemia, already by 10 days. It reduces the time of demyelination and promotes the activation of remyelinisation processes by improving blood supply. This is confirmed by minor qualitative, quantitative and metric changes in the conducting apparatus of the damaged FN. The electroneuromyographic indicators significantly improve: the speed of impulses in the proximal and distal regions increases, the H-reflex threshold and the ratio of its maximum amplitude to the M-response are more likely to increase, the amplitude increases and the latent period of the F-wave is shortened.Conclusions. Magneto-laser therapy is effective in the treatment of experimental LN neuropathy, since it restores the structural organization of the hemocirculatory system, normalizes the permeability of the vascular wall, which accelerates the utilization of myelin degradation products, improves nutrition of NF and their remyelination.

Investigation of the histological changes in spinal nerve roots post intrathecal ketamine administration

Background: Ketamine is a general anesthetic agent, administered intramuscularly or intravenously. It is generally used for induction and less frequently for the continuation of surgical anesthesia. Although ketamine was initially thought to be used as an intrathecal agent, psychomimetic side effects were observed. Objectives: In this study, the differences in the spinal nerve roots postintrathecal ketamine injection have been examined in the light and electron microscope. Materials and Methods: 30 min, 1 h, and 24-h postintrathecal ketamine (0.5 mg/kg) injection; the rabbits were sacrificed. The tissue samples taken from the injection area fixed with 1st 2% glutaraldehyde and later 1% OsO4. Following dehydration tissue samples embedded in Araldite and sections were taken and examined in the light and electron microscope. Results: There were severe degenerations in the myelinated nerve fibers postintrathecal injection of ketamine. Fading on the myelin lamellae, shrinking and vacuolization of the axoplasm, endoneurial edema, organelle loss, and cystic parts were observed. The vacuolization and lack of organelles in the Schwann cell cytoplasm were clear. The degeneration of the large myelinated nerve fibers was observed more than unmyelinated fibers. Conclusion: The general and local anesthetics used have significant side effects such as respiratory depression or permanent neurological disorders. Therefore, new options are searched, and the effects of the drugs used in different fields of anesthesia were investigated.

Ghrelin alleviates paclitaxel-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions in mice

Paclitaxel is an effective chemotherapeutic agent, but has some treatment-limiting adverse effects that markedly decrease patients’ quality of life. Peripheral neuropathy is one of these, and no treatment for it has been established yet. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is secreted from the stomach and has widespread effects on multiple systems. We investigated the pharmacological potential of ghrelin in preventing paclitaxel-induced peripheral neuropathy using wild-type mice, ghrelin-null mice, and growth hormone secretagogue receptor-null mice. In wild-type mice, ghrelin administration alleviated mechanical and thermal hypersensitivity, and partially prevented neuronal loss of small unmyelinated intraepidermal nerve fibers but not large myelinated nerve fibers. Moreover, ghrelin administration decreased plasma oxidative and nitrosative stress and increased the expression of uncoupling protein 2 (UCP2) and superoxide dismutase 2 (SOD2) in the dorsal root ganglia, which are mitochondrial antioxidant proteins, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a regulator of mitochondrial number. Both ghrelin-null mice and growth hormone secretagogue receptor-null mice developed more severe nerve injuries than wild-type mice. Our results suggest that ghrelin administration exerts a protective effect against paclitaxel-induced neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions, and that endogenous ghrelin has a neuroprotective effect that is mediated by ghrelin/growth hormone secretagogue receptor signaling. Ghrelin could be a promising therapeutic agent for the management of this intractable disease.

Degeneration and regeneration characteristics of nerves and muscles after recurrent laryngeal nerve injury

Objective:We investigated the degeneration and regeneration characteristics of nerves and muscles after different degrees of recurrent laryngeal nerve (RLN) injury, and then discussed the possible relations between them. Method:Ninety-five Sprague Dawley (SD) rats were used in this study, 2 rats died of infection, 2 died during surgery and 1 died in transit. The rest 90 SD rats were classified as having complete injuries (transection,43 rats), incomplete injuries (crush, 43 rats) and conrtol group (4 rats). The characteristics of nerve injuries were evaluated by endoscopic examination, laryngeal electromyography (LEMG), and histopathologic examination at 6 hours, 12 hours, 1 day, 3 day, 5 day, 1 week, 2 weeks, 3 weeks and 4 weeks after the injury. Result:All the vocal folds kept fixation in the completely injury group, where as 41/43 vocal folds in imcompletely injury group got normal activity 2 weeks after surgery, 1 at 3 weeks and 1 at 4 weeks. Fibrillation potentials were found 1 day after transection, and rennervation potentials appeared 4 weeks after transection. LEMG was normal 3 weeks after RLN was crushed. The average muscle fiber number of the left thyroarytenoid (TA) decreased with the time in the completely injury group, which increased in the second week after crush. Degeneration appeared more seriously in the distal region after transaction, and a small amount of large myelinated nerve fibers appeared at 4 weeks after injury. The most serious nerve degeneration appeared in the first day after crush, and 1 week later the ultrastructures of RLN were almost normal. The phagocytosis of Schwann cells occurred within 2 weeks after injury, 3 weeks later we found the apperance of Schwann cells who did not wrap around nerve fibers, especially in the proximal region. In the crush group, the phagocytosis of Schwann cells occurred within 1 week after injury, apoptosis and degeneration appered occasionally. Inflammatory response was more severe in the transection group, the number of fibroblasts and collagen fibers in the mesenchy increased. Conclusion:The degeneration is more severe in the distal nerve when RLN is traversed. Nerve regeneration appears in the fourth week after RLN is traversed. Injuried nerve has the ability to repair itself. Schwann cells play a role in phagocytosis after injury, and immature Schwann cells are found. Nerve fiber disintegration product can accelerate the migration of macrophage activation.

Assessment of small sensory fiber function across the spectrum of severity in carpal tunnel syndrome patients.

In compressive neuropathies, large myelinated nerve fibers are generally thought to be more susceptible. In this study, we investigated small myelinated Aδ and unmyelinated C fiber function in patients with mild, moderate, and severe carpal tunnel syndrome. Forty-four healthy controls and 81 carpal tunnel syndrome patients in the mild, moderate, or severe categories were recruited. Small fiber sensation in the affected hand was determined with quantitative sensory testing. Cold detection thresholds in the severe carpal tunnel syndrome group (18.9 ± 6.8°C) were significantly impaired compared with controls (27.2 ± 2.1°C) (P < 0.01). Similarly, warm detection thresholds were also impaired in the severe carpal tunnel syndrome group (41.2 ± 3.5°C) compared with control (37.1 ± 2.1°C) (P < 0.01). These results support the growing body of evidence that carpal tunnel syndrome can affect small afferent fibers. Muscle Nerve 56: 814-816, 2017.

Histopathological features of a patient with Charcot‐Marie‐Tooth disease type 2U/AD‐CMTax‐MARS

Charcot-Marie-Tooth (CMT) disease is a complex of peripheral nervous system disorders. CMT type 2U (CMT2U) is an autosomal dominant (AD) disease caused by mutations in the MARS gene encoding methionyl-tRNA synthetase; this disease has thus been newly called AD-CMTax-MARS. A few families with mutations in the MARS gene have been reported, without detailed histopathological findings. We describe a 70-year-old woman who had bilateral dysesthesia of the soles since the age of 66 years. Sural nerve biopsy showed a decrease in the density of large myelinated nerve fibers. Increased clusters of regenerating myelinated nerve fibers were noted. Electron microscopic analyses revealed degeneration of unmyelinated nerves. There was no vasculitis or inflammatory cell infiltration. Genetic analysis identified a heterozygous p.P800T mutation, a reported mutation in the MARS gene. We report the detailed histopathological findings in a patient with CMT2U/AD-CMTax-MARS. The findings are similar to those found in CMT2D caused by mutations in the GARS gene, encoding glycyl-tRNA synthetase.

ID 262 – Small-fiber neuropathy related to bulbar and spinal-onset in patients with ALS

We aimed at seeking more precise diagnostic information on the sensory nervous system involvement described in patients with amyotrophic lateral sclerosis (ALS). We investigated large myelinated nerve fibers with nerve conduction study and small-nerve fibers with Quantitative Sensory Testing (QST) (assessing thermal-pain perceptive thresholds) and skin biopsy (assessing intraepidermal nerve fiber density) in 24 consecutive patients with ALS, 11 with bulbar-onset and 13 with spinal-onset. In 23 of the 24 patients, regardless of ALS onset, nerve conduction study invariably showed large myelinated fiber sparing. In patients with bulbar-onset ALS, QST found normal thermal-pain perceptive thresholds and skin biopsy disclosed normal intraepidermal nerve fiber density. Conversely, in patients with spinal-onset, thermal-pain thresholds were abnormal and distal intraepidermal nerve fiber density was reduced. Sensory nervous system involvement in ALS differs according to disease onset. Patients with spinal-onset but not those with bulbar-onset ALS have concomitant distal small-fiber neuropathy. Neurologists should therefore seek this ALS-related non-motor feature to improve its diagnosis and treatment.

The Metabolic Syndrome and Microvascular Complications in a Murine Model of Type 2 Diabetes.

To define the components of the metabolic syndrome that contribute to diabetic polyneuropathy (DPN) in type 2 diabetes mellitus (T2DM), we treated the BKS db/db mouse, an established murine model of T2DM and the metabolic syndrome, with the thiazolidinedione class drug pioglitazone. Pioglitazone treatment of BKS db/db mice produced a significant weight gain, restored glycemic control, and normalized measures of serum oxidative stress and triglycerides but had no effect on LDLs or total cholesterol. Moreover, although pioglitazone treatment normalized renal function, it had no effect on measures of large myelinated nerve fibers, specifically sural or sciatic nerve conduction velocities, but significantly improved measures of small unmyelinated nerve fiber architecture and function. Analyses of gene expression arrays of large myelinated sciatic nerves from pioglitazone-treated animals revealed an unanticipated increase in genes related to adipogenesis, adipokine signaling, and lipoprotein signaling, which likely contributed to the blunted therapeutic response. Similar analyses of dorsal root ganglion neurons revealed a salutary effect of pioglitazone on pathways related to defense and cytokine production. These data suggest differential susceptibility of small and large nerve fibers to specific metabolic impairments associated with T2DM and provide the basis for discussion of new treatment paradigms for individuals with T2DM and DPN.

Characterization of nerve and microvessel damage and recovery in type 1 diabetic mice after permanent femoral artery ligation.

Neuropathy is the most common complication of the peripheral nervous system during the progression of diabetes. The pathophysiology is unclear but may involve microangiopathy, reduced endoneurial blood flow, and tissue ischemia. We used a mouse model of type 1 diabetes to study parallel alterations of nerves and microvessels following tissue ischemia. We designed an easily reproducible model of ischemic neuropathy induced by irreversible ligation of the femoral artery. We studied the evolution of behavioral function, epineurial and endoneurial vessel impairment, and large nerve myelinated fiber as well as small cutaneous unmyelinated fiber impairment for 1 month following the onset of ischemia. We observed a more severe hindlimb dysfunction and delayed recovery in diabetic animals. This was associated with reduced density of large arteries in the hindlimb and reduced sciatic nerve epineurial blood flow. A reduction in sciatic nerve endoneurial capillary density was also observed, associated with a reduction in small unmyelinated epidermal fiber number and large myelinated sciatic nerve fiber dysfunction. Moreover, vascular recovery was delayed, and nerve dysfunction was still present in diabetic animals at day 28. This easily reproducible model provides clear insight into the evolution over time of the impact of ischemia on nerve and microvessel homeostasis in the setting of diabetes. © 2015 Wiley Periodicals, Inc.

Small-fibre neuropathy related to bulbar and spinal-onset in patients with ALS

We aimed at seeking more precise diagnostic information on the sensory nervous system involvement described in patients with amyotrophic lateral sclerosis (ALS). We investigated large myelinated nerve fibres with nerve conduction study and small-nerve fibres with Quantitative Sensory Testing (QST) (assessing thermal-pain perceptive thresholds) and skin biopsy (assessing intraepidermal nerve fibre density) in 24 consecutive patients with ALS, 11 with bulbar-onset and 13 with spinal-onset. In 23 of the 24 patients, regardless of ALS onset, nerve conduction study invariably showed large myelinated fibre sparing. In patients with bulbar-onset ALS, QST found normal thermal-pain perceptive thresholds and skin biopsy disclosed normal intraepidermal nerve fibre density. Conversely, in patients with spinal-onset, thermal-pain thresholds were abnormal and distal intraepidermal nerve fibre density was reduced. Sensory nervous system involvement in ALS differs according to disease onset. Patients with spinal-onset but not those with bulbar-onset ALS have concomitant distal small-fibre neuropathy. Neurologists should therefore seek this ALS-related non-motor feature to improve its diagnosis and treatment.

Effect of high-fat diet on peripheral neuropathy in C57BL/6 mice.

Objective. Dyslipidemia may contribute to the development of peripheral neuropathy, even in prediabetics; however, few studies have evaluated vascular dysfunction and oxidative stress in patients with peripheral neuropathy. Methods. Using high-fat diet- (HFD-) induced prediabetic C57BL/6 mice, we assessed motor and sensory nerve conduction velocity (NCV) using a BIOPAC System and thermal algesia with a Plantar Test (Hargreaves' method) Analgesia Meter. Intraepidermal nerve fiber density and mean dendrite length were tested following standard protocols. Vascular endothelial growth factor-A (VEGF-A) and 12/15-lipoxygenase (12/15-LOX) were evaluated by immunohistochemistry and Western blot, respectively. Results. HFD-fed mice showed deficits in motor and sensory NCV, thermal hyperalgesia, reduced mean dendrite length, and VEGF-A expression in the plantar skin and increased 12/15-LOX in the sciatic nerve (P < 0.05 compared with controls). Conclusion. HFD may cause large myelinated nerve and small sensory nerve fiber damage, thus leading to neuropathy. The mean dendrite length may be a more sensitive marker for early detection of peripheral neuropathy. Reduced blood supply to the nerves and increased oxidative stress may contribute to the development and severity of peripheral neuropathy.

Mechanisms of deep brain stimulation for essential tremor

Although essential tremor is often thought of as benign, it can be disabling to the point of justifying invasive deep brain stimulation (DBS). However, the mechanisms by which thalamic and subthalamic stimulation suppress tremor are poorly understood. In this issue of Brain , Groppa et al. (2014) quantified the performance of seven patients with essential tremor in a reaching task to determine the DBS target structures associated with therapeutic reduction in tremor and with the side effect of stimulation-induced ataxia. The optimum site of stimulation was usually in the posterior subthalamic area, beneath the inferior border of the thalamic nucleus ventralis intermedius. Probabilistic diffusion tractography identified the dentatothalamic tract as the key therapeutic DBS target structure. Supratherapeutic stimulation of this site produced upper limb ataxia, despite continued suppression of tremor. The authors systematically varied stimulation pulse strength and duration to find that stimulation chronaxies of 27 and 52 µs were associated with tremor suppression and the induction of ataxia, respectively. Chronaxie is loosely defined as the minimum duration at which a current twice threshold (minimum current with indefinitely long pulse duration) elicits a response and provides a clue as to the properties of the axons recruited. They reasoned that two different populations of large myelinated nerve fibres were affected: (i) dentatothalamic axons for the therapeutic effect; and (ii) afferent or efferent axons of the red nucleus for the stimulation-induced ataxia. However, the involvement of rubral pathways could not be confirmed with diffusion tractography. This work is an important contribution to a growing literature addressing the mechanisms of DBS and the preferred site of DBS stimulation for essential tremor. Ventralis intermedius has historically been the preferred stereotactic target for thalamotomy and DBS in the treatment of essential tremor and other tremor disorders (Miocinovic et al. , 2013), but recent postoperative correlations …

Impairment of small somatic and autonomic nerve fibres in intensive care unit patients with severe sepsis and critical illness polyneuropathy – a single center controlled observational study

BackgroundAxonal damage in large myelinated nerve fibres occurs in about 70% of patients with severe sepsis, known as critical illness polyneuropathy and contributes significantly to an increased short- and long-term morbidity and mortality in this population. Among other pathophysiological mechanisms, autonomic dysregulation, characterized by high concentrations of circulating catecholamines in the presence of impaired sympathetic modulation of heart and vessels have been discussed. We hypothesize that autonomic small fibre neuropathy play an important role in autonomic failure.Methods/DesignSingle center, non-randomized, controlled, observational study. Skin biopsies of patients with severe sepsis and/or septic shock are compared with those of age-matched controls. In order to assess impairment of small nerve fibres, skin biopsies are taken at onset of severe sepsis, and two and 16 weeks later. Intraepidermal nerve fibre densities are histologically analyzed using anti protein gene product (PGP) 9.5 immunostaining. In addition, standardized clinical examinations, as Medical Research Council (MRC) scores of muscle strength, Rankin scores, and standardized nerve conduction studies of the right median nerve, the right tibial nerve, the left fibular nerve, and both sural nerves are performed, to identify critical illness polyneuropathy and to neurophysiologically quantify the damage of large nerve fibres.DiscussionThe study will allow to describe the frequency of small fibre neuropathy in patients with severe sepsis up to four months after onset of severe sepsis and to evaluate its relationship to critical illness polyneuropathy.Trial registrationThe trial has been registered to the German Clinical Trials Register. The trial registration number is DRKS-ID: DRKS00000642.

Relationship of Limited Joint Mobility and Foot Deformities with Neurological Examination in Patients with Diabetes

The aim is to define the association of forefoot deformity and limited joint mobility in the ankle and hallux joints in patients with diabetes mellitus subject to different diagnostic tests for diabetic neuropathy. Prospective study with 118 type 2 diabetic patients (68 men, mean age of 65.6±9.9 years) enrolled consecutively from the Diabetic Foot Unit of the Complutense University of Madrid subject to evaluation of plantar surface sensitivity by 10-g Semmes-Weinstein Monofilament, vibratory threshold by biothesiometer, and sudomotor dysfunction by Neuropad®. The patients presented with limited joint mobility of the ankle and the first metatarsophalangeal joints, and forefoot deformities were registered. Statistical analysis was done through a univariate model to test the association between neurological and biomechanical alteration. There was an association of abnormal Monofilament (p=0.01; OR=3.9) and biothesiometer tests (p=0.01; OR=2.6) with the presence of forefoot deformity. Furthermore, a relation was found between abnormal Monofilament (p=0.02; OR=4.8) and biothesiometer (p<0.00; OR=12.8) tests with limited mobility of the first metatarsophalangeal joint both in loading and off-loading. Abnormal sudomotor function test was related with limited joint mobility of the ankle joint with the knee flexed (p=0.04; OR=2.8). The results of this study show discordance between biomechanical abnormalities and neuropathy depending on the diagnostic test used. Tests that assess large myelinated nerve fibers are associated with the presence of deformities. Abnormal sudomotor function test is associated with limited joint mobility and this test has a greater capacity for selecting patients at risk.

Dynamics of Structural Rearrangements in the Dorsal Roots of Spinal Nerves in Growing Dogs

Morphological and morphometric studies of the dorsal roots of spinal nerves (segment SI) were studied in nine mongrel dogs aged 2, 5, and 10 months. Longitudinal paraffin sections impregnated with silver nitrate were used, along with semithin transverse sections stained with methylene blue and basic fuchsin. Common features were seen in the structural organization and the characteristics of nerve fiber dispositions at these ages. Increasing age was associated with enlargement of the dorsal roots (most marked before five months), along with increases in the diameter and changes in the ratios of small, intermediate, and large myelinated nerve fibers and decreases in their numbers per unit area.

Small Fiber Neuropathy: Is Skin Biopsy the Holy Grail?

Small fiber neuropathy (SFN) is characterized by negative sensory symptoms (thermal and pinprick hypoesthesia) reflecting peripheral deafferentation and positive sensory symptoms and signs (burning pain, allodynia, hyperalgesia), which often dominate the clinical picture. In patients with pure SFN, clinical and neurophysiologic investigation do not show involvement of large myelinated nerve fiber making the diagnosis of SFN challenging in clinical practice. Over the last 15 years, skin biopsy has emerged as a novel tool that readily permits morphometric and qualitative evaluation of somatic and autonomic small nerve fibers. This technique has overcome the limitations of routine neurophysiologic tests to detect the damage of small nerve fibers. The recent availability of normative reference values allowed clinicians to reliably define the diagnosis of SFN in individual patients. This paper reviews usefulness and limitations of skin biopsy and the relationship between degeneration and regeneration of small nerve fibers in patients with diabetes and metabolic syndrome.

Wireless peripheral nerve stimulation increases pain threshold in two neuropathic rat models

Neurostimulation approaches including spinal cord and peripheral nerve stimulation are typically used to treat intractable chronic pain in individuals who are refractory to pain medications. Our earlier studies have shown that a voltage controlled capacitive discharge (VCCD) method of stimulation of nerve activation is able to selectively recruit activity in large myelinated nerve fibers. In this study, we were able to wirelessly activate the sciatic nerve using the VCCD waveform. The purpose of this study was to determine whether this waveform can effectively improve two of the most troublesome pain symptoms experienced by patients with chronic neuropathic pain mechanical and cold hyperalgesia. Neuropathic mechanical hyperalgesia was reproduced using the Spinal Nerve Ligation (SNL) rat model whereas cold allodynia was reproduced using the Chronic Constriction Injury (CCI) model in male rats. Von Frey and cold plate tests were used to evaluate paw withdrawal threshold and latency to withdrawal before and after stimulation in experimental and control rats. Paw withdrawal threshold increased significantly compared to post-lesion baseline after VCCD stimulation in SNL rats. We also observed a significant improvement in cold allodynia in the active implant CCI rats after stimulation. These results suggest that the VCCD stimulation using a wireless microstimulator may be effective in the treatment of neuropathic pain.