- High glucose concentration suppresses a SIRT2 regulated pathway that enhances neurite outgrowth in cultured adult sensory neurons. [Journal Article]
- ENExp Neurol 2018 Aug 10
- In peripheral nerve under hyperglycemic conditions high flux of d-glucose through the polyol pathway drives an aberrant redox state contributing to neurodegeneration in diabetic sensorimotor polyneur...
In peripheral nerve under hyperglycemic conditions high flux of d-glucose through the polyol pathway drives an aberrant redox state contributing to neurodegeneration in diabetic sensorimotor polyneuropathy (DSPN). Sirtuins, including SIRT2, detect the redox state via the NAD+/NADH ratio to regulate mitochondrial function via, in part, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). In adult dorsal root ganglia (DRG) sensory neurons mitochondrial dysfunction has been proposed as an etiological factor in dying-back neuropathy in diabetes. We tested the hypothesis that a high concentration of d-glucose depleted SIRT2 expression via enhancement of polyol pathway activity. We posited that this would lead to impaired mitochondrial function and suppression of neurite outgrowth in cultured sensory neurons. The use of dominant negative mutants or neurons from SIRT2 knockout (KO) mice to block SIRT2 signaling revealed that neurons derived from control or type 1 diabetic rodents required SIRT2 for optimal neurite outgrowth. Over-expression of WT-SIRT2 elevated neurite outgrowth in normal and diabetic cultures. SIRT2 protein isoforms 2.1 and 2.2 were reduced by 20-30% in DRG of type 1 diabetic mice (p < .05). After 72 h exposure to high d-glucose (25 mM vs 5 mM) cultured sensory neurons showed a significant 2-fold (p < .05) decrease in SIRT2 expression, P-AMPK, levels of respiratory Complexes II/III and respiratory capacity. DRG neurons expressed aldose reductase and the aforementioned deficits were prevented by treatment with aldose reductase inhibitors (lidorestat or sorbinil) or sorbitol dehydrogenase inhibitor (SDI-158). In cultures derived from type 1 diabetic rats treatment with SDI-158 elevated expression of SIRT2, P-AMPK/PGC-1α and neurite outgrowth (p < .05). SIRT2 KO neurons exhibited deficits in the LKB-1/AMPK/PGC-1α pathway and mitochondrial function. In cultured neurons the SIRT2 pathway enhances axonal outgrowth and this signaling axis encompassing activation of AMPK/PGC-1α is impaired in DSPN, in part, due to enhanced polyol pathway activity caused by hyperglycemia.
- Surgical Peripheral Nerve Decompression for the Treatment of Painful Diabetic Neuropathy of the Foot - a Level 1 Pragmatic Randomized Controlled Trial. [Journal Article]
- DRDiabetes Res Clin Pract 2018 Aug 03
- CONCLUSIONS: Surgical decompression of lower limb nerves was an effective treatment for decreasing pain in patients with DPN and superimposed nerve compressions.
- Trapped in the epineurium: early entry into the endoneurium is restricted to neuritogenic T cells in experimental autoimmune neuritis. [Journal Article]
- JNJ Neuroinflammation 2018 Aug 01; 15(1):217
- CONCLUSIONS: Our findings suggest that neuritogenic T cells invade the PNS early in the course of disease. However, neuritogenic T cells cross the blood-nerve barrier with a certain delay without preference to dorsal roots. Further understanding of the pathophysiological role of autoagressive T cells may help to improve therapeutic strategies in immune-mediated neuropathies.
- POEMS syndrome: diagnostic delay and successful treatment with lenalidomide, cyclophosphamide and prednisone followed by autologous peripheral stem cell transplantation. [Journal Article]
- BCBMJ Case Rep 2018 Jul 26; 2018
- Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome is a rare systemic disease, often unrecognised in the primary care setting. POEMS syndrome is ass...
Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome is a rare systemic disease, often unrecognised in the primary care setting. POEMS syndrome is associated with plasma cell dyscrasias and upregulation of vascular endothelial growth factor leading to systemic oedema, papilloedema and pulmonary hypertension. A wide constellation of presenting symptoms often leads to late diagnosis. Unrecognised and untreated disease rapidly leads to death from neuropathic exhaustion or cardiopulmonary failure. Treatment is extrapolated from other plasma cell dyscrasias such as multiple myeloma. Autologous peripheral blood stem cell transplantation (PBSCT) is often an important component of treatment. There is no established standard of care for POEMS syndrome. Therapies include lenalidomide, bortezomib and targeted monoclonal antibodies. We present a patient with POEMS syndrome who achieved rapid complete response to triple therapy consisting of lenalidomide, cyclophosphamide and prednisone, followed by high-dose chemotherapy and PBSCT.
- Increased intracranial pressure in Guillain-Barré syndrome: A case report. [Case Reports]
- MMedicine (Baltimore) 2018; 97(30):e11584
- Guillain-Barré syndrome (GBS) is an inflammatory autoimmune demyelinating polyneuropathy that affects most of the peripheral nervous system. Papilledema and raised intracranial pressure (ICP) are see...
Guillain-Barré syndrome (GBS) is an inflammatory autoimmune demyelinating polyneuropathy that affects most of the peripheral nervous system. Papilledema and raised intracranial pressure (ICP) are seen in some patients, and are thought to be associated with elevated cerebrospinal fluid (CSF) protein-though CSF protein levels are normal in some patients, thus the specific mechanisms remain unclear. Interleukin (IL)-17 levels are elevated in the CSF and plasma in GBS patients, and elevated IL-17 in the CSF of patients with idiopathic intracranial hypertension has been reported. Intravenous immunoglobulin (IVIG) exerts therapeutic effects by downregulating IL-17 in GBS patients.
- [Neuromuscular Adverse Events]. [Journal Article]
- GTGan To Kagaku Ryoho 2018; 45(7):1036-1040
- Neuromuscular adverse events(AEs)associated with cancer treatment with immune checkpoint inhibitors(ICIs)include diverse clinical subsets. The general features of neuromuscular AEs have not been eluc...
Neuromuscular adverse events(AEs)associated with cancer treatment with immune checkpoint inhibitors(ICIs)include diverse clinical subsets. The general features of neuromuscular AEs have not been elucidated because the frequency is generally low, ranging from 1-2%of cancer patients undergoing ICIs therapy. The diseases affect the central nervous system, peripheral nerves, neuromuscular junction, and muscle. Disease onset and progression may be rapid with a critical clinical course. The clinical presentation may be different from that of patients unrelated to drugs. Headache, dizziness, and dysgeusia were relatively common and mild treatment-related AEs. In contrast, representative immune-related AEs such as autoimmune encephalitis, demyelinating polyneuropathy, myasthenia, and myositis were serious. There was a tight association between myasthenia, myositis, and myocarditis. There are guidelines for the treatment of neuromuscular immune-mediated AEs. For all but the minimum neurological symptoms, checkpoint inhibitor therapy should be withheld until the nature of the AEs is defined. Immune-modulating medication is generally effective for neuromuscular AEs. Both CD8+ cytotoxic T-cells and autoantibodies are involved in the pathogenesis of neuromuscular AEs. Correct understanding of neuromuscular AEs is required for the best management of cancer patients.
- Clinical presentation, management, and pathophysiology of neuropathic itch. [Review]
- LNLancet Neurol 2018; 17(8):709-720
- Unlike conventional itch, neuropathic itch develops in normal skin from excess peripheral firing or dampened central inhibition of itch pathway neurons. Neuropathic itch is a symptom of the same cent...
Unlike conventional itch, neuropathic itch develops in normal skin from excess peripheral firing or dampened central inhibition of itch pathway neurons. Neuropathic itch is a symptom of the same central and peripheral nervous system disorders that cause neuropathic pain, such as sensory polyneuropathy, radiculopathy, herpes zoster, stroke, or multiple sclerosis, and lesion location affects symptoms more than aetiology. The causes of neuropathic itch are heterogeneous, and thus diagnosis is based primarily on recognising characteristic, disease-specific clinical presentations. However, the diagnosis of neuropathic itch is challenging, different subforms exist (eg, focal vs widespread, peripheral vs central), and the mechanisms of neuropathic itch are poorly understood, resulting in reduced treatment availability. Currently available strategies include treating or preventing causal diseases, such as diabetes or herpes zoster, and topical or systemic medications that calm excess neuronal firing. Discovery of itch mediators such as gastrin releasing peptide, receptors (eg, neurokinin-1), and pathways (eg, Janus kinases) might encourage much needed new research into targeted treatments of neuropathic itch.
- MR neurography biomarkers to characterize peripheral neuropathy in AL amyloidosis. [Journal Article]
- NeurNeurology 2018 Aug 14; 91(7):e625-e634
- CONCLUSIONS: MRN detects and quantifies peripheral nerve injury in AL-PNP in vivo with high sensitivity and in close correlation with the clinical stage. Quantitative parameters are feasible new imaging biomarkers for the detection of early AL-PNP and might help to monitor microstructural nerve tissue changes under treatment.
- Guillain-Barré syndrome in a Child with Ongoing Viral Hepatitis A. [Journal Article]
- IJIran J Child Neurol 2018; 12(3):133-138
- Guillain-Barré syndrome (GBS) belongs to the group of peripheral immune-mediated neuropathies often preceded by an inflammatory episode. GBS is rarely associated with hepatitis A virus (HAV) infectio...
Guillain-Barré syndrome (GBS) belongs to the group of peripheral immune-mediated neuropathies often preceded by an inflammatory episode. GBS is rarely associated with hepatitis A virus (HAV) infection, the latter as a rule antecedent of the neurological disorders. This association is quite rare in childhood, and so far, only isolated cases have been described. We report an unusual case of pediatric GBS which development coincided with the development of HAV IgM (+) viral hepatitis A. From the second to the 14th day after admission to the hospital for mild jaundice of the skin and sclera in a 12-yr-old boy, the following neurological disorders have developed: absent Achilles and knee-jerk reflexes, diminished brachioradialis reflex, moderately decreased muscle power in the upper extremities and more pronounced power loss in the lower extremities. Facial palsy developed bilaterally, more expressed to the right. There was albuminocytologic dissociation of the cerebrospinal fluid and electrodiagnostic study showed findings compatible with the GBS subdivision - Acute inflammatory demyelinating polyneuropathy (AIDP). HAV could trigger GBS in the very beginning of liver inflammation in children. This insight may help wide range of medical professionals to early recognize and treat the peripheral neuropathy.
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- Widespread Cardiac and Vasomotor Autonomic Dysfunction in Non-Val30Met Hereditary Transthyretin Amyloidosis. [Journal Article]
- IMIntern Med 2018 Jul 06
- Objective The autonomic functions of hereditary transthyretin (ATTRm) amyloidosis, traditionally referred to as familial amyloid polyneuropathy, have primarily been investigated in patients with Val3...
Objective The autonomic functions of hereditary transthyretin (ATTRm) amyloidosis, traditionally referred to as familial amyloid polyneuropathy, have primarily been investigated in patients with Val30Met mutations, and information regarding non-Val30Met patients is scarce. The aim of this study was to systematically investigate the cardiac and peripheral vasomotor autonomic functions in non-Val30Met patients. Methods The coefficient of variation of R-R intervals (CVR-R), responses to the Valsalva manoeuvre, head-up tilt test results, noradrenaline infusion test results, and the (123) I-metaiodobenzylguanidine (MIBG) uptake on myocardial scintigraphy were assessed in five patients. The predominant manifestations were neuropathy in three patients (Val94Gly, Val71Ala, and Pro24Ser), cardiomyopathy in one (Thr60Ala), and oculoleptomeningeal involvement in one (Tyr114Cys). Results Although one patient with predominant cardiomyopathy did not manifest orthostatic hypotension during the head-up tilt test, the CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated the presence of cardiac sympathetic and parasympathetic dysfunction in all patients. The total peripheral resistance at 60° tilt did not increase from the baseline values in any of the examined patients. An infusion of low-dose noradrenaline induced an increase in the systolic blood pressure, except in one patient with mild neuropathy. Conclusion Cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in non-Val30Met patients, irrespective of their phenotype, suggesting a common pathology of autonomic involvement. However, the vasoconstrictor function was preserved, even in a patient with advanced neuropathy.