Interaction between magnesium and methylglyoxal in diabetic polyneuropathy and neuronal models.

OBJECTIVE: The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Because reduced magnesium and increased methylglyoxal levels have been implicated in the development of both type 2 diabetes and neuropathic pain, we aimed to assess the putative interplay of both molecules with diabetic sensorimotor polyneuropathy. METHODS: In a cross-sectional study, serum magnesium and plasma methylglyoxal levels were measured in recently diagnosed type 2 diabetes patients with (n = 51) and without (n = 184) diabetic sensorimotor polyneuropathy from the German Diabetes Study baseline cohort. Peripheral nerve function was assessed using nerve conduction velocity and quantitative sensory testing. Human neuroblastoma cells (SH-SY5Y) and mouse dorsal root ganglia cells were used to characterize the neurotoxic effect of methylglyoxal and/or neuroprotective effect of magnesium. RESULTS: Here, we demonstrate that serum magnesium concentration was reduced in recently diagnosed type 2 diabetes patients with diabetic sensorimotor polyneuropathy and inversely associated with plasma methylglyoxal concentration. Magnesium, methylglyoxal, and, importantly, their interaction were strongly interrelated with methylglyoxal-dependent nerve dysfunction and were predictive of changes in nerve function. Magnesium supplementation prevented methylglyoxal neurotoxicity in differentiated SH-SY5Y neuron-like cells due to reduction of intracellular methylglyoxal formation, while supplementation with the divalent cations zinc and manganese had no effect on methylglyoxal neurotoxicity. Furthermore, the downregulation of mitochondrial activity in mouse dorsal root ganglia cells and consequently the enrichment of triosephosphates, the primary source of methylglyoxal, resulted in neurite degeneration, which was completely prevented through magnesium supplementation. CONCLUSIONS: These multifaceted findings reveal a novel putative pathophysiological pathway of hypomagnesemia-induced carbonyl stress leading to neuronal damage and merit further investigations not only for diabetic sensorimotor polyneuropathy but also other neurodegenerative diseases associated with magnesium deficiency and impaired energy metabolism.

Diagnosis and management of sensory polyneuropathy.

Sensory polyneuropathies, which are caused by dysfunction of peripheral sensory nerve fibers, are a heterogeneous group of disorders that range from the common diabetic neuropathy to the rare sensory neuronopathies. The presenting symptoms, acuity, time course, severity, and subsequent morbidity vary and depend on the type of fiber that is affected and the underlying cause. Damage to small thinly myelinated and unmyelinated nerve fibers results in neuropathic pain, whereas damage to large myelinated sensory afferents results in proprioceptive deficits and ataxia. The causes of these disorders are diverse and include metabolic, toxic, infectious, inflammatory, autoimmune, and genetic conditions. Idiopathic sensory polyneuropathies are common although they should be considered a diagnosis of exclusion. The diagnostic evaluation involves electrophysiologic testing including nerve conduction studies, histopathologic analysis of nerve tissue, serum studies, and sometimes autonomic testing and cerebrospinal fluid analysis. The treatment of these diseases depends on the underlying cause and may include immunotherapy, mitigation of risk factors, symptomatic treatment, and gene therapy, such as the recently developed RNA interference and antisense oligonucleotide therapies for transthyretin familial amyloid polyneuropathy. Many of these disorders have no directed treatment, in which case management remains symptomatic and supportive. More research is needed into the underlying pathophysiology of nerve damage in these polyneuropathies to guide advances in treatment.

Regressive pyridoxine-induced sensory neuronopathy in a patient with homocystinuria.

Pyridoxine (vitamin B6) is an essential vitamin playing a crucial role in amino acid metabolism. Pyridoxine is used for isoniazid side-effects prevention, pyridoxine-dependent epilepsy treatment and cystathionine beta-synthase deficiency (homocystinuria) treatment. However, vitamin B6 hypervitaminosis is neurotoxic and may provoke a progressive sensory neuronopathy (sensory ganglionopathy), usually when daily uptake is above 50 mg. We describe the case of a 30-year-old patient with homocystinuria who was treated with pyridoxine 1250-1750 mg/day for 20 years and developed progressive sensory neuropathy with ataxia and impaired sensation in the extremities. Electrodiagnostic testing demonstrated non-length-dependent abnormalities of sensory nerve potentials, and sensory ganglionopathy was diagnosed. Pyridoxine dosage was reduced to 500 mg/day, resulting in the disappearance of sensory symptoms and ataxia, and the normalisation of sensory nerve potentials. Our case indicates that pyridoxine-induced sensory ganglionopathy may be reversible, even after prolonged ingestion of high doses of vitamin B6 for more than 20 years.

Suramin-Induced Neurotoxicity: Preclinical Models and Neuroprotective Strategies.

Suramin is a trypan blue analogon originally developed to treat protozoan infections, which was found to have diverse antitumor effects. One of the most severe side effects in clinical trials was the development of a peripheral sensory-motor polyneuropathy. In this study, we aimed to investigate suramin-induced neuropathy with a focus on calcium (Ca2+) homeostasis as a potential pathomechanism. Adult C57Bl/6 mice treated with a single injection of 250 mg/kg bodyweight suramin developed locomotor and sensory deficits, which were confirmed by electrophysiological measurements showing a predominantly sensory axonal-demyelinating polyneuropathy. In a next step, we used cultured dorsal root ganglia neurons (DRGN) as an in vitro cell model to further investigate underlying pathomechanisms. Cell viability of DRGN was significantly decreased after 24-hour suramin treatment with a calculated IC50 of 283 µM. We detected a suramin-induced Ca2+ influx into DRGN from the extracellular space, which could be reduced with the voltage-gated calcium channel (VGCC) inhibitor nimodipine. Co-incubation of suramin and nimodipine partially improved cell viability of DRGN after suramin exposure. In summary, we describe suramin-induced neurotoxic effects on DRGN as well as potentially neuroprotective agents targeting intracellular Ca2+ dyshomeostasis.

n-Hexane intoxication in a Chinese medicine pharmaceutical plant: a case report.

BACKGROUND: n-Hexane is a well-known neurotoxicant. Polyneuropathy due to occupational n-hexane exposure has been reported worldwide, however, our case is the first report in the Chinese herb industry. CASE PRESENTATION: A 25-year-old Asian man experienced progressive weakness and numbness in his hands and feet after working as an operator in a Chinese medicine pharmaceutical plant for the manufacture of Chinese herbal pain relief patches for 10 months. Electrophysiological studies indicated a reduction in nerve conduction velocity, prolongation of distal latencies, mildly positive sharp waves, and reduced recruitment with polyphasic potentials, particularly at distal sites. Demyelination with axonal degeneration caused by occupational n-hexane exposure was strongly suspected. Through investigation of our patient's workplace, the ambient n-hexane concentration in air was found to considerably exceed the permissible exposure limit/time-weighted average for n-hexane in Taiwan. His symptoms were gradually relieved after 4 months of cessation of exposure to n-hexane. He was then confirmed as a case of occupational n-hexane intoxication. Further effective control measures should be implemented as soon as possible to prevent exposure of workers to n-hexane. CONCLUSIONS: Despite a typical clinical presentation, his exposure at workplace was appropriately investigated. Chemical exposure in Chinese medicine pharmaceutical plants could be an emerging issue that may affect workers' health. The lack of knowledge and management of solvents could endanger the health of workers. This case has profound educational implications for occupational health and is worthy of further follow-up for improving hazards control.

[Efficiency of therapeutically applied physical factors for vibration disease caused by exposure to local vibration (review of literature).]

Important role in treatment and prophylaxis for vibration disease due to local vibration is played by physical factors. If high frequency components prevalent in occupational vibration, treatment with electric therapy, laser, magnetic fields, lymphatic drainage, hydrotherapy provides influence on leading chains of systemic microangiopathies pathogenesis - dysbalance of regulation influences by vegetative nervous system, vasoconstriction and intravascular changes, vascular permeability and microcirculation disorders. If low frequency coomponents prevalent in occupational vibration, treatment of polyneuropathies and locomotory disorders incorporates trophic processes activation: transcranial electroanalgesia, surface application of mineral waters, manual and subwater massage, ozone therapy, local spark discharges, peloids. Complex use of physical methods also increases human adaptational resources.

Electrophysiologic confirmation of heterogenous motor polyneuropathy in young cats.

BACKGROUND: Reports of motor polyneuropathies in young cats are scarce. Further, in-depth electrophysiologic evaluation to confirm a motor polyneuropathy in young cats of various breeds other than 2 Bengal cats is lacking. HYPOTHESIS/OBJECTIVES: To confirm a motor polyneuropathy in young cats of various breeds. ANIMALS: Five young cats with heterogenous chronic or relapsing episodes of weakness. METHODS: Retrospective case series. Cats were presented for evaluation of generalized neuromuscular disease and underwent electrophysiologic examination including electromyography, nerve conduction, and repetitive nerve stimulation. Minimum database and muscle and nerve biopsy analyses were carried out. Descriptive statistics were performed. RESULTS: Disease onset was at 3 months to 1 year of age and in 5 breeds. The most common clinical sign (5 of 5 cats) was weakness. Additional neurologic deficits consisted of palmigrade and plantigrade posture (4/4), low carriage of the head and tail (4/4), and variable segmental reflex deficits (5/5). Motor nerve conduction studies were abnormal for the ulnar (4/4), peroneal (5/5), and tibial (2/2) nerves (increased latencies, reduced amplitudes, slow velocities). A marked decrement was observed on repetitive nerve stimulation of the peroneal nerve in 3 cats for which autoimmune myasthenia gravis was ruled out. All sensory nerve conduction studies were normal. Histologic evaluation of muscle and nerve biopsies supported heterogenous alterations consistent with motor polyneuropathy with distal nerve fiber loss. CONCLUSIONS AND CLINICAL IMPORTANCE: Heterogenous motor polyneuropathies should be considered in young cats of any breed and sex that are presented with relapsing or progressive generalized neuromuscular disease.

Pyridoxine-induced sensory ataxic neuronopathy and neuropathy: revisited.

High dose pyridoxine is neurotoxic. Previous case reports were sparse and little is known about the clinical and electrodiagnostic findings. Three patients with pyridoxine-induced sensory ataxic neuropathy were studied and a review of the involved literature was performed. Three patients, aged 80, 83 and 83 years old, presented with sensory ataxia for 3-8 months. Examination showed signs of polyneuropathy and sensory ataxia. Six hundred milligrams of pyridoxine was consumed each day for 3-10 years, in the form of vitamin B1-6-12 combination tablet. Investigations for other causes of neuropathy were unremarkable. Blood levels of vitamin B6 were markedly elevated at 104.6, 81.4 and 66.9 times of upper normal limits. Electrodiagnostic tests showed symmetric axonal sensory polyneuropathy in two patients. Two years after vitamin discontinuation, all patients showed no significant improvement in the neuropathy and gait. In conclusion, consumption of high dose pyridoxine can cause sensory neuronopathy and axonal sensorimotor polyneuropathy, leading to sensory ataxia which may not be reversible.

Subacute peripheral neuropathy under duodopa therapy without cobalamin deficiency and despite supplementation.

Continuous jejunal levodopa infusion is an increasingly used therapy option in patients with Parkinson's disease who experience severe fluctuations from oral levodopa. In a number of recent reports polyneuropathy in patients receiving jejunal levodopa infusion was referenced to cobalamin (vitamin B12) deficiency. We describe one of three cases from our hospital with severe subacute polyneuropathy that developed during jejunal levodopa infusion, and occurred despite vitamin substitution therapy and normal vitamin B12 and holotranscobalamin serum levels.

Sensory polyneuropathy in human immunodeficiency virus-infected patients receiving tuberculosis treatment.

SETTING: Human immunodeficiency virus (HIV) infection and treatments for HIV infection and tuberculosis (TB) are associated with the risk of developing sensory polyneuropathy (SPN). Vitamin B6 and genetically determined slow isoniazid (INH) acetylation are believed to play key roles in the development of SPN in a TB treatment setting. OBJECTIVE: To investigate slow acetylation and risk factors for SPN in HIV-infected patients receiving TB treatment, and establish vitamin B6 status and its association with SPN. METHODS: HIV-infected in-patients were prospectively assessed after initiating TB treatment and vitamin B6 supplementation, and monthly during hospitalisation. SPN was defined as ≥1 symptom plus ≥1 sign. NAT2 genotyping predicted acetylation status, and plasma high performance liquid chromatography estimated vitamin B6 status. A survival analysis estimated hazard ratios (HRs) for SPN during TB treatment. RESULTS: Of 116 participants, 56% had SPN at study entry. Participants developed SPN at a rate of 26/100 person-months (95%CI 18-35) during TB treatment, which was independently associated with slow acetylation (HR 2.5; 95%CI 1.1-5.9), as well as black race, previous TB and extra-pulmonary/disseminated TB. Vitamin B6 status was normal, irrespective of SPN. CONCLUSIONS: Risk factors for SPN suggest a multi-factorial pathogenesis related to INH and other potential nervous system insults. SPN developed despite normal vitamin B6 status, suggesting other mechanisms of injury.

Myeloneuropathy due to copper deficiency: clinical and MRI findings after copper supplementation.

Acquired copper deficiency constitutes an under-recognised cause of myelopathy. Aim of the study was to describe the clinical and imaging features at admission and after copper supplementation of a patient with acquired copper deficiency myeloneuropathy. A 73-year-old woman presented with anaemia and signs of posterior column dysfunction. Somatosensory evoked potentials showed impaired central pathway conduction. Serum copper and caeruloplasmin levels were low. Nerve conduction assessment revealed axonal polyneuropathy. Spinal magnetic resonance imaging (MRI) showed posterior column hyperintensity. Diffusion tensor imaging disclosed decreased fractional anisotropy (FA) corresponding to the hyperintensity. Copper supplementation normalised the haematological picture, whereas vibratory sensitivity was only slightly improved. Control MRI revealed a slight hyperintensity at C1-C2 level; FA values normalised. In conclusion, in acquired copper-deficiency-associated myelopathy, correction of blood and MRI alterations precedes that of neurological manifestations, which may remain suboptimal.

Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy.

BACKGROUND: HIV-associated distal sensory polyneuropathy (HIV-DSP) is a painful condition with limited effective treatment. Capsaicin desensitizes cutaneous nociceptors resulting in reduced pain. We report a placebo-controlled study of a high-concentration capsaicin dermal patch (NGX-4010) for the treatment of painful HIV-DSP. METHODS: This double-blind multicenter study randomized 307 patients with painful HIV-DSP to receive NGX-4010 or control, a low-concentration capsaicin patch. After application of a topical anesthetic, NGX-4010 or control was applied once for 30, 60, or 90 minutes to painful areas on the feet. The primary efficacy endpoint was percent change in Numeric Pain Rating Scale (NPRS) from baseline in mean "average pain for past 24 hours" scores from weeks 2 to 12. RESULTS: A single NGX-4010 application resulted in a mean pain reduction of 22.8% during weeks 2 to 12 as compared to a 10.7% reduction for controls (p = 0.0026). Following a transient treatment-related pain increase, pain was reduced; significant improvement was apparent by week 2 and continued throughout the controlled 12-week observation period. Mean pain reductions in the NGX-4010 30-, 60- and 90-minute groups were 27.7%, 15.9%, and 24.7% (p = 0.0007, 0.287, and 0.0046 vs control). One third of NGX-4010-treated patients reported >or=30% pain decrease from baseline as compared to 18% of controls (p = 0.0092). Self-limited, mild-to-moderate local skin reactions were commonly observed. CONCLUSIONS: A single NGX-4010 application was safe and provided at least 12 weeks of pain reduction in patients with HIV-associated distal sensory polyneuropathy. These results suggest that NGX-4010 could provide a promising new treatment for painful HIV neuropathy.

Urtica ferox neuropathy.

A 21-year-old student developed an acute, symmetrical, predominantly motor polyneuropathy within 48 h of walking through a patch of nettles (Urtica ferox). Two companions had similar but less severe symptoms. Nerve conduction studies demonstrated markedly reduced compound muscle action potentials and prolonged distal motor latencies. Recovery occurred over a period of a few weeks. This case demonstrates that cutaneous exposure to Urtica ferox can cause an acute polyneuropathy and that its stinging hairs contain an unidentified neurotoxin.

Lower limb neuropathy after spinal anesthesia in a patient with latent thiamine deficiency.

We present the case of a 65-year-old man with latent thiamine deficiency who manifested lower limb neuropathy after receiving spinal anesthesia. We discuss our care of this patient and include a discussion of thiamine deficiency generally, its possible origins, symptoms, and recommended techniques for treatment of these patients.

A cluster of polyneuropathy and Wernicke-Korsakoff syndrome in a bariatric unit.

BACKGROUND: Wernicke-Korsakoff syndrome and peripheral neuropathy are very uncommon in bariatric surgical practice. The literature indicates that these complications tend to strike patients receiving unbalanced diets or undergoing rapid weight-loss. METHODS: In a retrospective analysis of the initial experience of a bariatric team in the city of Belem, Pará, in northern Brazil, 5 cases were diagnosed in the first year, 4 of them following gastric bypass and the last one after therapy with an intragastric balloon. RESULTS: All episodes followed periods of severe vomiting, which certainly interfered with intake of food as well as of routine vitamin supplements, resulting in severe polyneuropathy and other neurologic manifestions, mostly damaging motility of lower limbs. Therapy consisted of pharmacologic doses of vitamin B1 along with restoration of adequate diet and multivitamin prescriptions. Physical therapy was employed to prevent atrophy and accelerate normalization of muscle strength. All patients responded to this program after variable intervals without significant sequelae. CONCLUSIONS: Thiamine-related neurologic derangements were a cause for much concern and prolonged morbidity in this series, but responded to vitamin B1 replenishment. A high degree of clinical suspicion in bariatric patients and urgent therapeutic intervention whenever postoperative vomiting persists for several days, especially during the first 2-3 months after operation, are the safest approach to these uncommon episodes. It is speculated whether peculiarities in the regional diet of this area in Brazil could have influenced the high incidence of the neurologic aberrations.

Postgastrectomy polyneuropathy with thiamine deficiency.

OBJECTIVE: Polyneuropathy has been reported after gastrectomy performed to treat various lesions. Although thiamine deficiency is a possible cause of this neuropathy, the pathogenesis still remains to be clarified. Seventeen patients with peripheral neuropathy with thiamine deficiency after gastrectomy are described. METHODS: Seventeen patients with polyneuropathy after gastrectomy accompanied by thiamine deficiency were selected. Patients were restricted to those with total or subtotal gastric resection to treat ulcer or neoplasm. Patients who had undergone operations to treat morbid obesity were excluded. RESULTS: Intervals between the operation and onset of neuropathy varied from 2 months to 39 years. Most patients did not seem malnourished. Serum concentrations of B vitamins other than thiamine were nearly normal. Symmetric motor-sensory polyneuropathy, predominantly involving the lower limbs, had progressed over intervals varying from 3 days to 8 years. Relative degrees of motor and sensory impairment also varied extensively. Some cases that progressed rapidly mimicked Guillain-Barré syndrome. Electrophysiological and pathological findings were those of axonal neuropathy. Substantial functional recovery from polyneuropathy was seen in most patients by 3 to 6 months after initiating thiamine supplementation. Motor recovery was better than sensory recovery. CONCLUSIONS: Various symptoms were seen in patients with postgastrectomy neuropathy. Thiamine deficiency should be considered in the differential diagnosis of motor-sensory polyneuropathy after gastrectomy.

Are low magnesium levels in type 1 diabetes associated with electromyographical signs of polyneuropathy?

OBJECTIVE: Our aim was to study the relationship between the magnesium status in type 1 diabetic patients and disturbances in nerve conduction velocity. Furthermore we wanted to investigate whether repletion of magnesium depletion could improve the decreased nerve conduction velocity measurements. In a cross-sectional study, 154 type 1 diabetic patients were screened for their erythrocyte magnesium content and an electrophysiological measurement of the peripheral nervous system was carried out. In a subsequent intervention study, out of this screened population, 23 type 1 patients, with disturbed nerve conduction velocity measurements and low erythrocyte magnesium levels [< 2.3 mmol/L) were given oral magnesium supplements, during 1 year. Twenty type 1 patients with identical characteristics served as controls. In the cross-sectional study disturbed nerve conduction velocities were found in the older patients, in patients with a longer duration of diabetes and a worse metabolic control. EMG polyneuropathy signs were significantly more frequent in diabetic patients with low erythrocyte Mg. The intervention study demonstrated that under unchanged metabolic control, supplementation with magnesium could improve nerve conduction, especially in younger patients with a shorter duration of diabetes. Erythrocyte Mg was lower in type 1 diabetic patients with polyneuropathy. Mg supplementation increasing Mg RBC might (possibly?) improve nerve conduction measured by electromyography at least in younger patients with a short duration of diabetes and presenting early signs of the neurological complication.

[The use of combined methods of magnetoelectrotherapy in treating polyneuropathies]. / Primenenie sochetannykh metodov magnitoélektroterapii v lechenii polinevropatii.

A comparative evaluation by such parameters as alleviation of pain syndrome, improvement of peripheral resistance and vegetotrophic processes, a decline in pareses and sensory disorders has been performed in 3 groups of patients: group 1 underwent benzohexonium electrophoresis, group 2 benzohexonium electrophoresis in the magnetic field produced by the unit "Polyus-I" followed by low-frequency electrotherapy with bipolar impulse current, group 3 benzohexonium electrophoresis in the magnetic field from the unit "ADMT-Magnipuls" followed by low-frequency electrotherapy with bipolar impulse current. The best clinical and physiological results were reported in group 3 patients.