Metabolic Neuropathies Research Articles

Diabetic peripheral neuropathy based on Schwann cell injury: mechanisms of cell death regulation and therapeutic perspectives.

Diabetic peripheral neuropathy (DPN) is a complication of diabetes mellitus that lacks specific treatment, its high prevalence and disabling neuropathic pain greatly affects patients' physical and mental health. Schwann cells (SCs) are the major glial cells of the peripheral nervous system, which play an important role in various inflammatory and metabolic neuropathies by providing nutritional support, wrapping axons and promoting repair and regeneration. Increasingly, high glucose (HG) has been found to promote the progression of DPN pathogenesis by targeting SCs death regulation, thus revealing the specific molecular process of programmed cell death (PCD) in which SCs are disrupted is an important link to gain insight into the pathogenesis of DPN. This paper is the first to review the recent progress of HG studies on apoptosis, autophagy, pyroptosis, ferroptosis and necroptosis pathways in SCs, and points out the crosstalk between various PCDs and the related therapeutic perspectives, with the aim of providing new perspectives for a deeper understanding of the mechanisms of DPN and the exploration of effective therapeutic targets.

Differential diagnosis of polyneuropathies in diabetes mellitus

Diabetic polyneuropathy (DPN) is heterogeneous in its clinical course and clinical manifestations. Depending on the primary lesion of large or small nerve fibers, different onset, course and clinical manifestations of polyneuropathy are possible. In patients with diabetes, the incidence of associated lesions of the peripheral nervous system is high. When verifying the diagnosis of DPN, it is necessary to carry out a differential diagnosis with a number of diseases: paraneoplastic neuropathies, metabolic neuropathies, neuropathies in vasculitis, toxic neuropathies, autoimmune neuropathies, inflammatory neuropathies and hereditary neuropathies. Diabetes is not the only cause of polyneuropathy. Up to 50% of all cases of polyneuropathies in diabetes have additional causes. Diagnosis of diabetic polyneuropathy - diagnosis of exclusion. The development of polyneuropathy in patients with a duration of type 1 diabetes less than 5 years, the absence of nephropathy and / or retinopathy, asymmetry in symptoms and signs, the predominance of motor symptoms, beginning with upper limb lesions, rapid progression should justify the doctor for differential diagnostic search. You should also take into account the characteristics of the patient (old age, vegetarianism and alcohol use), medical and toxic effects (taking metformin> 3 years and> 2 g / day; cytostatics, chemotherapy, heavy metals), family history of neuropathy. Therapeutic tactics should be individualized and take into account the polyneuropathy polyetiology. The purpose of this review is to discuss the most common reasons peripheral neuropathy in diabetes mellitus. The differential diagnosis of the diabetic polyneuropathy is the focus of this article.

The different causes of branchial plexus injuries

Many etiologies have been reported to account for injuries to the brachial plexus, peripheral nerves and trauma. Additionally, many diseases have also been reported to cause the injury with many different pathophysiologies. For instance, some diseases have been classified as the primary diseases of the peripheral nerves including hereditary neuropathy. In the same context, brachial plexus damage or injury might also result secondary to a systemic disease, leading to a significant peripheral nerve injury as in cases with most metabolic neuropathies, which may result secondary to renal insufficiency, diabetes, amyloidosis and many other diseases. Furthermore, toxic and iatrogenic causes were also reported as potential causes for brachial plexus injuries. However, traumatic events are the most commonly reported, owing to motorcycle accidents, being the most common etiology. Although evidence is now abundant regarding the etiology, further studies are needed to furtherly validate the evidence and for more specification of the etiology and the underlying mechanisms.

Clinical Scales for Diabetic Neuropathy and Chemotherapy-induced Neuropathy

Diabetic neuropathy and chemotherapy-induced peripheral neuropathy are complex disorders affecting different nerve fiber group and remain as major source of morbidity and decreased quality of life of the patients. Given the recent advance in understanding the pathophysiological mechanism of these neuropathies and the development of new drugs, it is imperative to set proper scales to rate the severity of symptoms or signs. Moreover, well-designed, highly sensitive and valid scales could get scientific reliability and clinical utility if they are combined with objective neurophysiological measures. This review will discuss about the reliable and validated scales used in these common toxic and metabolic neuropathies.

The Role of Protein Adduction in Toxic Neuropathies of Exogenous and Endogenous Origin.

The peripheral (axonal) neuropathy associated with repeated exposure to aliphatic and aromatic solvents that form protein-reactive γ-diketones shares some clinical and neuropathological features with certain metabolic neuropathies, including type-II diabetic neuropathy and uremic neuropathy, and with the largely sub-clinical nerve damage associated with old age. These conditions may be linked by metabolites that adduct and cross-link neuroproteins required for the maintenance of axonal transport and nerve fiber integrity in the peripheral and central nervous system.

Orphan Peripheral Neuropathies.

Objectives:Generally, neuropathies of peripheral nerves are a frequent condition (prevalence 2–3%) and most frequently due to alcoholism, diabetes, renal insufficiency, malignancy, toxins, or drugs. However, the vast majority of neuropathies has orphan status. This review focuses on the etiology, frequency, diagnosis, and treatment of orphan neuropathies.Methods:Literature reviewResults:Rareness of diseases is not uniformly defined but in the US an orphan disease is diagnosed if the prevalence is <1:200000, in Europe if <5:10000. Most acquired and hereditary neuropathies are orphan diseases. Often the causative variant has been reported only in a single patient or family, particularly the ones that are newly detected (e.g. SEPT9, SORD). Among the complex neuropathies (hereditary multisystem disorders with concomitant neuropathies) orphan forms have been reported among mitochondrial disorders (e.g. NARP, MNGIE, SANDO), spinocerebellar ataxias (e.g. TMEM240), hereditary spastic paraplegias (e.g UBAP1), lysosomal storage disease (e.g. Schindler disease), peroxisomal disorders, porphyrias, and other types (e.g. giant axonal neuropathy, Tangier disease). Orphan acquired neuropathies include the metabolic neuropathies (e.g. vitamin-B1, folic acid), toxic neuropathies (e.g. copper, lithium, lead, arsenic, thallium, mercury), infectious neuropathies, immune-mediated (e.g. Bruns-Garland syndrome), and neoplastic/paraneoplastic neuropathies.Conclusions:Though orphan neuropathies are rare per definition they constitute the majority of neuropathies and should be considered as some of them are easy to identify and potentially treatable, as clarification of the underlying cause may contribute to the knowledge about etiology and pathophysiology of these conditions, and as the true prevalence may become obvious only if all ever diagnosed cases are reported.

Assessing and Treating Chronic Pain in Patients with End-Stage Renal Disease.

Pain is one of the most common symptoms among patients with end-stage renal disease (ESRD), and is often under recognized and not adequately managed in hemodialysis (HD) patients. Barriers to adequate pain management include poor awareness of the problem, insufficient medical education, fears of possible drug-related side effects, and common misconceptions about the inevitability of pain in elderly and HD patients. Caregivers working in HD should be aware of the possible consequences of inadequate pain assessment and management. Common pain syndromes in HD patients include musculoskeletal diseases and metabolic neuropathies, associated with typical intradialytic pain. Evaluating the etiology, nature, and intensity of pain is crucial for choosing the correct analgesic. A mechanism-based approach to pain management may result in a better outcome. Pharmacokinetic considerations on clearance alterations and possible toxicity in patients with ESRD should drive the right analgesic prescription. Comorbidities and polymedications may increase the risk of drug-drug interactions, therefore drug metabolism should be taken into account when selecting analgesic drugs. Automedication is common among HD patients but should be avoided to reduce the risk of hazardous drug administration. Further research is warranted to define the efficacy and safety of analgesic drugs and techniques in the context of patients with ESRD as generalizing information from studies conducted in the general population could be inappropriate and potentially dangerous. A multidisciplinary approach is recommended for the management of complex pain syndromes in frail patients, such as those suffering from ESRD.

A Case of Superior Mesenteric Artery Syndrome in Perianal Crohnʼs Disease

Superior Mesenteric Artery (SMA) syndrome is a rare condition caused by compression of the duodenum between the aorta and SMA due to loss of mesenteric and retroperitoneal fat. Among IBD patients, SMA syndrome occurs more commonly in patients with ulcerative colitis (UC) after ileal pouch anal anastomosis (IPAA). This is the first reported case of SMA syndrome in a patient with perianal Crohn's disease (CD). A 32 year old female with perianal CD and diverting loop sigmoid colostomy on infliximab presented with 1 month of progressive, colicky, postprandial abdominal pain, nausea, sitophobia, diarrhea, and a 7 lb weight loss leading to an episode of orthostatic syncope. Contrast enhanced computed tomography showed distension of the stomach and proximal duodenum, but no obstruction, bowel wall thickening, or intraabdominal abscess. Small bowel follow through showed delayed transit through the duodenum in the region of the SMA as well as small bowel dilation proximal to the region of the SMA consistent with SMA syndrome. Magnetic resonance enterography showed no evidence of active CD. Serum inflammatory markers were within normal limits. Alternative etiologies such as delayed motility from diabetes, hypothyroidism, and other metabolic neuropathies were ruled out, and she was diagnosed with SMA syndrome. Despite modest improvement of her nausea with scheduled metoclopramide, total parenteral nutrition was started for inadequate nutrition prior to hospital discharge. SMA syndrome in IBD patients is most commonly associated with IPAA, which is performed for refractory ulcerative colitis or for resection of IBD-associated colon cancer. One proposed mechanism for this phenomenon is surgery-induced stretching of the SMA, flattening it against the aorta to cause duodenal narrowing. This is the first reported case of SMA syndrome in perianal CD status post diverting loop sigmoid colostomy. Perianal CD is an uncommon variant of CD and phenotypically mimics limited UC. Although our patient's surgery did not involve significant bowel resection as in an IPAA, perhaps this phenotypic similarity and post-surgical anatomic changes predisposed her to increased risk of SMA syndrome. For IBD patients presenting with obstructive symptoms such as nausea, vomiting, sitophobia, and abdominal pain, clinicians must maintain a low threshold for considering SMA syndrome since treatment differs significantly from treatment of IBD exacerbation.Figure: CT abdomen and pelvis axial image showing compression of duodenum between the superior mesenteric artery (SMA) and aorta.Figure: CT abdomen and pelvis sagittal image showing acute angulation of the superior mesenteric artery (SMA) and the aorta.

P 158 Peripheral nerve ultrasound scoring systems in polyneuropathy – benchmarking and comparative analysis

Much progress has been done in the recent past concerning the additive value of nerve ultrasound in polyneuropathies. Most authors go along, that – generally spoken – the enlarged cross-sectional areas are the most evident pathology in PNP. Overall, demyelinating neuropathies display nerve enlargement, while most axonal types do not or only rarely. CSA measurements alone are not all, however, without CSA measurements all is nothing. Increased nerves are not pathognomonic at all; they appear in inherited (Charcot Marie Tooth), inflammatory (CIDP, GBS) and metabolic neuropathies (amyloidosis, metachromatic leukodystrophy), in focal (MMN, MADSAM) and asymmetric generalized (vasculitis) neuropathies. Therefore, quantification and pattern analysis of nerve enlargement might be the key to success. Scoring systems have been presented bang up-to-date, e.g. the nerve pattern classification in CIDP by Padua and colleagues, the Bochum ultrasound score for immune-mediated neuropathies, the quantification of nerve enlargement in demyelinating neuropathies by Zaidman et al., or the ultrasound pattern sum score and the homogeneity score. All of these scores have their strength in accuracy and exclusion of certain neuropathies, however all fail by incompleteness concerning others, e.g. rarer variants. Although we can assume generalized nerve enlargement in inherited neuropathies, and more regional enlargement in inflammatory neuropathies, the philosopher’s stone is not yet found. Further effort must be done, even including fascicle next to CSA pathology, echogenicity and physiologic aspects (age, height, weight and ethnicity). Nevertheless - to the best of our knowledge – some simple rules can simplify daily practice. First, if any nerve enlargement is found, heredity or immune mediation should be checked with caution. Second, simple critical landmarks could help to preselect certain neuropathies (as shown in Fig. 1): the brachial plexus/the cervical roots and the vagus (particularly for CIDP and GBS), the median and ulnar nerve in the forearm (e.g. for MMN and MADSAM) and the tibial and the sural nerve in the ankle (e.g. for vasculitis). The accuracy of these marks would not be 100%, but can facilitate the following diagnostic steps.

Metabolic, Hereditary, Traumatic, and Neoplastic Optic Neuropathies

Metabolic, Hereditary, Traumatic, and Neoplastic Optic Neuropathies

Inherited neuropathies: Clinical overview and update

Inherited neuropathy is a group of common neurologic disorders with heterogeneous clinical presentations and genetic causes. Detailed neuromuscular evaluations, including nerve conduction studies, laboratory testing, and histopathologic examination, can assist in identification of the inherited component beyond family history. Genetic testing increasingly enables definitive diagnosis of specific inherited neuropathies. Diagnosis, however, is often complex, and neurologic disability may have both genetic and acquired components in individual patients. The decision of which genetic test to order or whether to order genetic tests is often complicated, and the strategies to maximize the value of testing are evolving. Apart from rare inherited metabolic neuropathies, treatment approaches remain largely supportive. We provide a clinical update of the various types of inherited neuropathies, their differential diagnoses, and distinguishing clinical features (where available). A framework is provided for clinical evaluations, including the inheritance assessment, electrophysiologic examinations, and specific genetic tests.

Methylglyoxal Activates Nociceptors through Transient Receptor Potential Channel A1 (TRPA1): A POSSIBLE MECHANISM OF METABOLIC NEUROPATHIES

Neuropathic pain can develop as an agonizing sequela of diabetes mellitus and chronic uremia. A chemical link between both conditions of altered metabolism is the highly reactive compound methylglyoxal (MG), which accumulates in all cells, in particular neurons, and leaks into plasma as an index of the severity of the disorder. The electrophilic structure of this cytotoxic ketoaldehyde suggests TRPA1, a receptor channel deeply involved in inflammatory and neuropathic pain, as a molecular target. We demonstrate that extracellularly applied MG accesses specific intracellular binding sites of TRPA1, activating inward currents and calcium influx in transfected cells and sensory neurons, slowing conduction velocity in unmyelinated peripheral nerve fibers, and stimulating release of proinflammatory neuropeptides from and action potential firing in cutaneous nociceptors. Using a model peptide of the N terminus of human TRPA1, we demonstrate the formation of disulfide bonds based on MG-induced modification of cysteines as a novel mechanism. In conclusion, MG is proposed to be a candidate metabolite that causes neuropathic pain in metabolic disorders and thus is a promising target for medicinal chemistry.

Thioctic Acid–Induced Acute Cholestatic Hepatitis

To report a case of severe cholestatic hepatitis caused by thioctic acid in a patient with diabetic peripheral polyneuropathy and mild chronic renal failure. A 63-year-old man with type 2 diabetes, hypertension, hypothyroidism, and stage 2 chronic renal failure was referred to the outpatient liver clinic with fever, asthenia, nausea, and pruritus. Because of the presence of symptomatic diabetic neuropathy, he began treatment with thioctic acid 600 mg/day. Serum transaminase levels were measured before starting thioctic acid treatment and values were within the normal range. Symptoms progressively worsened and the patient developed a low-grade fever and evidence of increased serum liver enzyme levels 45 days after starting thioctic acid treatment: aspartate aminotransferase (AST) (114 IU/L [reference range <40]), alanine aminotransferase (ALT) (191 IU/L [<35]), alkaline phosphatase (ALP) (562 IU/L [<130]), and γ-glutamyltransferase (GGT) (592 IU/L [<50]). Thioctic acid treatment was discontinued 2 days after admission. Four months after the initial presentation, his AST, ALT, and ALP levels normalized and GGT level had decreased (88 IU/L). As the patient's neuropathic symptoms worsened, thioctic acid therapy was restarted. Two months after restarting therapy, pruritus, nausea, and asthenia reappeared and the patient's liver enzyme levels became clearly abnormal again (AST 100 IU/L, ALT 129 IU/L, ALP 161 IU/L, GGT 180 IU/L). Thioctic acid was stopped, and the patient's liver enzyme levels returned to normal 2 months later. Alpha-lipoic acid, also known as thioctic acid, improves metabolic glucose control and peripheral neuropathies associated with diabetes mellitus. Its administration appears to be safe and, as far as we know, there are no reports of liver toxicity associated with its use. Our patient developed acute cholestatic hepatitis after beginning treatment with thioctic acid. Use of the Roussel Uclaf causality assessment scale indicated that the association between thioctic acid treatment and our patient's drug-induced liver injury was highly probable; use of the Maria and Victorino scale indicated that the association was probable. To our knowledge, this is the first report of probable liver toxicity due to thioctic acid, a proposed "hepatoprotectant."

Artificial control of blood-nerve barrier: a novel therapeutic approach to peripheral neuropathies

Blood-nerve barrier (BNB) is a "Janus-faced" structure for the peripheral nerve parenchyma. Healthy BNB may contribute to stabilize the internal milleu of peripheral nervous system (PNS) and to stop the entrance of toxic substances and harmful leukocytes into nerve parenchyma. On the other hand, healthy BNB may sometimes be a drawback because the peripheral nerve parenchyma cannot receive enough amount of nutrients and growth factors and cannot excrete toxic substances into systemic circulation because of its presence. Here we present a future therapeutic strategy to control BNB function, based on the basic knowledge acquired from recently developed human immortalized cell lines of BNB origin. If we can artificially regulate the BNB permeability and the expression of adhesion molecules on the surface of BNB-forming endothelial cells, and stop the entrance of toxic substances as well as pathogenic leukocytes into PNS parenchyma, the treatment of inflammatory neuropathies may make great progresses. For hereditary, metabolic and ischemic neuropathies, the promotion of the entrance of growth factors into PNS parenchyma and of the excretion of toxic substances should powerfully encourage the regeneration of axons.

Nerve conduction and excitability studies in peripheral nerve disorders

The review is aimed at providing information about the role of nerve excitability studies in peripheral nerve disorders. It has been known for many years that the insight into peripheral nerve pathophysiology provided by conventional nerve conduction studies is limited. Nerve excitability studies are relatively novel but are acquiring an increasingly important role in the study of peripheral nerves. By measuring responses in nerve that are related to nodal function (strength-duration time constant, rheobase and recovery cycle) and internodal function (threshold electrotonus, current-threshold (I/V) relationship) it is possible to assess the function of transient and persistent Na+, fast and slow K+ and HCN inward rectifying channels as well as ion pumps. This has allowed insight into normal axon physiology and normal fluctuations of electrolyte concentrations. Studies of different metabolic neuropathies have assessed the influence of uremia, diabetes and ischemia, and the use of these methods in toxic neuropathies has allowed pinpointing damaging factors. Various mutations in ion channels associated with central nervous system disorders have been shown to have counterparts in the peripheral nervous system, in some instances without peripheral nervous system symptoms. Both hereditary and acquired demyelinating neuropathies have been studied and the effects on nerve pathophysiology have been compared with degeneration and regeneration of axons. Excitability testing holds promise for further understanding of peripheral nerve pathophysiology but is as yet not universally available. Interpretation may be challenging as changes in parameters may have different explanations, and modeling has been helpful in the use of the methods in clinical neurophysiology.

Genotype–phenotype correlations in mitochondrial optic neuropathies

Metabolic optic neuropathies present in a very similar fashion but yet show some distinct variations. Investigations have revealed that the common pathologic basis of these optic neuropathies is a dysfunction of oxidative phosphorylation in mitochondria leading to retinal ganglion cell degeneration. This impairment can be genetic or acquired. Leber’s hereditary optic neuropathy and dominant optic atrophy are the two primary inherited optic neuropathies, whereas acquired metabolic optic neuropathies can be due to toxins or nutritional deficiencies. Mitochondria are remarkable cytoplasmic organelles carrying their own DNA and are also influenced by nuclear DNA. The genetic background is pivotal in understanding the molecular mechanisms and the wide spectrum of clinical phenotypes of these disorders. Understanding the genetic, environmental and epigenetic interplays will be important for the development of therapeutic strategies aimed to protect against retinal ganglion cell death.

Metabolic neuropathies and myopathies in infancy and childhood.

Metabolic neuropathies and myopathies in infancy and childhood.

Assessment of nerve excitability in toxic and metabolic neuropathies

Measurement of nerve excitability by threshold tracking provides complementary information to conventional nerve conduction studies and may be used to infer the activity of a variety of ion channels, energy-dependent pumps, and ion exchange processes activated during the process of impulse conduction. This review highlights recent clinical excitability studies that have suggested mechanisms for nerve involvement in a range of metabolic and toxic neuropathies. While clinical nerve excitability studies are still in their infancy, and it is too early to know whether they have diagnostic value, there is growing evidence of their utility to provide novel insights into the pathophysiological mechanisms involved in a variety of neuropathic disturbances.

Hypoxia‐inducible factor 1α may be a marker for vasculitic neuropathy

Neuromuscular biopsy is still an essential method for diagnosing vasculitic neuropathy, although its diagnostic sensitivity is at most 60%. Our objective was to examine the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) in peripheral nerves and to evaluate its usefulness in diagnosing vasculitic neuropathy, especially for discrimination from other axonal neuropathies. Forty-one patients with vasculitic neuropathy consisting of 20 definite, 14 probable and seven possible diagnoses, 15 patients with metabolic neuropathy, five with motor neuron disease and six with chronic inflammatory demyelinating polyneuropathy were included. Nerve biopsy specimens were immunohistochemically examined for HIF-1alpha and various cell markers. Distinct immunoreactivity (IR) was observed in nuclei of endoneurial cells in 54% (22/41) of vasculitic patients, while specimens from metabolic neuropathies showed less nuclear IR and the difference of mean density of HIF-1alpha-positive nuclei was significant. Two patients with possible vasculitis who showed HIF-1alpha-positive nuclei in endoneurium, were later confirmed to have vasculitis by skin biopsies. Most of the cells expressing HIF were demonstrated to be Schwann cells. There was a trend in the vasculitic patients with early phase nerve damage to display higher endoneurial HIF-1alpha-IR. HIF-1alpha may be an immunohistochemical marker for vasculitic neuropathy, especially when the observed section contains no vasculitic lesions.

Melanocortins and the Treatment of Nervous System Disease: Potential Relevance to the Skin?

For several decades melanocortins have been implicated in the modulation of brain function. More recently, this idea has been supported by the identification and cloning of melanocortin (MC) receptors in the nervous system. MCs stimulate axonal growth in fetal neural tissue or in neural cell lines in culture. This feature was utilized in screening their neurotrophic or neuroprotection potential in animal studies of nervous system disease (peripheral nerve and spinal cord trauma, toxic and metabolic neuropathies, EAN, EAE, etc.). Some of these effects may be mediated by MC4 receptor activation, although as yet unknown receptors may also be involved (for instance, protection by Org 2766). To what extent MC-nervous system effects are related to known effects of MCs in skin- and neuro-immune systems, remains to be discovered. Nevertheless, it is of interest to note that activation of brain MC4 receptors profoundly affects care behavior for the body surface (skin and fur). The excessive grooming response in rodents exhibits a remarkable functional correlation with MSH activity in a brain-skin axis.