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Cell Calcium Jul 2023Alterations in calcium (Ca) signaling is a major mechanism in the development of chemotherapy-induced peripheral neuropathy (CIPN), a side effect caused by multiple...
Alterations in calcium (Ca) signaling is a major mechanism in the development of chemotherapy-induced peripheral neuropathy (CIPN), a side effect caused by multiple chemotherapy regimens. CIPN is associated with numbness and incessant tingling in hands and feet which diminishes quality of life during treatment. In up to 50% of survivors, CIPN is essentially irreversible. There are no approved, disease-modifying treatments for CIPN. The only recourse for oncologists is to modify the chemotherapy dose, a situation that can compromise optimal chemotherapy and impact patient outcomes. Here we focus on taxanes and other chemotherapeutic agents that work by altering microtubule assemblies to kill cancer cells, but also have off-target toxicities. There have been many molecular mechanisms proposed to explain the effects of microtubule-disrupting drugs. In neurons, an initiating step in the off-target effects of treatment by taxane is binding to neuronal calcium sensor 1 (NCS1), a sensitive Ca sensor protein that maintains the resting Ca concentration and dynamically enhances responses to cellular stimuli. The taxane/NCS1 interaction causes a Ca surge that starts a pathophysiological cascade of consequences. This same mechanism contributes to other conditions including chemotherapy-induced cognitive impairment. Strategies to prevent the Ca surge are the foundation of current work.
Topics: Humans; Antineoplastic Agents; Quality of Life; Calcium Signaling; Peripheral Nervous System Diseases
PubMed: 37244172
DOI: 10.1016/j.ceca.2023.102762 -
JAMA Jul 2023
Topics: Humans; Biomarkers; Heart Failure; Natriuretic Peptide, Brain; Peripheral Nervous System Diseases; Spinal Stenosis
PubMed: 37347466
DOI: 10.1001/jama.2023.8977 -
Continuum (Minneapolis, Minn.) Oct 2023This article reviews autoimmune axonal neuropathies, their characteristic clinical features, disease and antibody associations, appropriate ancillary testing, treatment,... (Review)
Review
OBJECTIVE
This article reviews autoimmune axonal neuropathies, their characteristic clinical features, disease and antibody associations, appropriate ancillary testing, treatment, and prognosis.
LATEST DEVELOPMENTS
In 2021, the American College of Rheumatology and the Vasculitis Foundation released new summary guidelines for the treatment of antineutrophil cytoplasmic autoantibody-associated vasculitides. In addition, novel autoantibodies have been recently identified; they are often paraneoplastic and associated with axonal neuropathies.
ESSENTIAL POINTS
Recognition of autoimmune axonal neuropathies is important because of the potential for effective treatment to either reverse deficits or slow the progression of disease. It is necessary to properly assess for associations with other systemic disorders (eg, systemic vasculitis, connective tissue disease, neoplasm) so that adequate treatment for both neurologic and non-neurologic aspects of the disease can be initiated.
Topics: Humans; Autoantibodies; Antibodies, Antineutrophil Cytoplasmic; Vasculitis; Treatment Outcome; Peripheral Nervous System Diseases
PubMed: 37851035
DOI: 10.1212/CON.0000000000001344 -
Antioxidants & Redox Signaling Dec 2023The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance. Axonal degeneration is a feature of peripheral neuropathies, glaucoma,... (Review)
Review
The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance. Axonal degeneration is a feature of peripheral neuropathies, glaucoma, and traumatic brain injury, and an early event in neurodegenerative diseases. Since the discovery of Wallerian degeneration (WD), a molecular program that hijacks nicotinamide adenine dinucleotide (NAD) metabolism for axonal self-destruction, the complex roles of NAD in axonal viability and disease have become research priority. The discoveries of the protective Wallerian degeneration slow (Wld) and of sterile alpha and TIR motif containing 1 (SARM1) activation as the main instructive signal for WD have shed new light on the regulatory role of NAD in axonal degeneration in a growing number of neurological diseases. SARM1 has been characterized as a NAD hydrolase and sensor of NAD metabolism. The discovery of regulators of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) proteostasis in axons, the allosteric regulation of SARM1 by NAD and NMN, and the existence of clinically relevant windows of action of these signals has opened new opportunities for therapeutic interventions, including SARM1 inhibitors and modulators of NAD metabolism. Events upstream and downstream of SARM1 remain unclear. Furthermore, manipulating NAD metabolism, an overdetermined process crucial in cell survival, for preventing the degeneration of the injured axon may be difficult and potentially toxic. There is a need for clarification of the distinct roles of NAD metabolism in axonal maintenance as contrasted to WD. There is also a need to better understand the role of NAD metabolism in axonal endangerment in neuropathies, diseases of the white matter, and the early stages of neurodegenerative diseases of the central nervous system. 39, 1167-1184.
Topics: Humans; Wallerian Degeneration; NAD; Peripheral Nervous System Diseases; Axons; Neurodegenerative Diseases
PubMed: 37503611
DOI: 10.1089/ars.2023.0350 -
Pain Practice : the Official Journal of... Sep 2023
Topics: Humans; Nerve Compression Syndromes; Peripheral Nervous System Diseases; Buttocks
PubMed: 37256543
DOI: 10.1111/papr.13241 -
Hematology/oncology Clinics of North... Aug 2023The immunoglobulin M (IgM)-associated peripheral neuropathies (PN) are a heterogeneous group of disorders representing most paraproteinemic neuropathy cases. They are... (Review)
Review
The immunoglobulin M (IgM)-associated peripheral neuropathies (PN) are a heterogeneous group of disorders representing most paraproteinemic neuropathy cases. They are associated with IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenström macroglobulinemia. Establishing a causal link between a paraprotein and neuropathy can be challenging but is necessary to adopt an appropriate therapeutic approach. The most common type of IgM-PN is Antimyelin-Associated-Glycoprotein neuropathy, but half of the cases are of other causes. Progressive functional impairment is an indication for treatment, even when the underlying disorder is IgM MGUS, involving either rituximab monotherapy or combination chemotherapy to achieve clinical stabilization.
Topics: Humans; Peripheral Nervous System Diseases; Drug Therapy, Combination; Immunoglobulin M; Monoclonal Gammopathy of Undetermined Significance; Rituximab
PubMed: 37385714
DOI: 10.1016/j.hoc.2023.04.007 -
Current Oncology Reports Nov 2023This review aims to discuss pathophysiology, diagnosis, clinical presentation, and treatment of chemotherapy-induced peripheral neuropathy. Agent-specific presentation... (Review)
Review
PURPOSE OF REVIEW
This review aims to discuss pathophysiology, diagnosis, clinical presentation, and treatment of chemotherapy-induced peripheral neuropathy. Agent-specific presentation and pathophysiology is also being discussed.
RECENT FINDINGS
As new systemic oncological treatments continue to be developed, the number of cancer survivors continues to grow. Survivors are living longer with the long-term side effects of oncological treatments. We reviewed the pathophysiology of agent-specific chemotherapy-induced peripheral neuropathy and the updates in its treatment and preventative tools. Chemotherapy-induced peripheral neuropathy is a debilitating long-term side effect that often impairs cancer survivors' function and quality of life. The increasing life expectancy of cancer survivors has resulted in increased prevalence of this condition. Understanding its intricacies can provide physicians with better treatment tools and research opportunities to develop or identify new therapeutic agents.
Topics: Humans; Antineoplastic Agents; Quality of Life; Peripheral Nervous System Diseases; Cancer Survivors; Survivors
PubMed: 37702983
DOI: 10.1007/s11912-023-01449-7 -
Handbook of Clinical Neurology 2024This chapter covers axillary and musculocutaneous neuropathies, with a focus on clinically relevant anatomy, electrodiagnostic approaches, etiologic considerations, and... (Review)
Review
This chapter covers axillary and musculocutaneous neuropathies, with a focus on clinically relevant anatomy, electrodiagnostic approaches, etiologic considerations, and management principles. Disorders of the lateral antebrachial cutaneous nerve, a derivative of the musculocutaneous nerve, are also reviewed. We emphasize the importance of objective findings, including the physical examination and electrodiagnostic evaluation in confirming the isolated involvement of each nerve which, along with the clinical history, informs etiologic considerations. Axillary and musculocutaneous neuropathies are both rare in isolation and most frequently occur in the setting of trauma. Less commonly encountered etiologies include external compression or entrapment, neoplastic involvement, or immune-mediated disorders including neuralgic amyotrophy, postsurgical inflammatory neuropathy, multifocal motor neuropathy, vasculitic neuropathy, and multifocal chronic inflammatory demyelinating polyradiculoneuropathy.
Topics: Humans; Peripheral Nervous System Diseases; Musculocutaneous Nerve; Axilla; Electrodiagnosis
PubMed: 38697736
DOI: 10.1016/B978-0-323-90108-6.00004-1 -
Nature Feb 2024Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a...
Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4 cells, that show a cytotoxic T helper 1 (T1)-like phenotype, and rare CD8 T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3β lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRβ clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.
Topics: Humans; Autoimmunity; Biopsy; CD8-Positive T-Lymphocytes; Guillain-Barre Syndrome; HLA-DR Antigens; Immunodominant Epitopes; Myelin Sheath; Peripheral Nerves; Peripheral Nervous System Diseases; Receptors, Antigen, T-Cell; Th1 Cells; T-Lymphocytes, Cytotoxic; Immunologic Memory
PubMed: 38233524
DOI: 10.1038/s41586-023-06916-6 -
Practical Neurology Mar 2024Strachan's syndrome comprises a triad of optic, auditory and painful sensory peripheral neuropathy. It has been recognised since the late 19th century and is presumed to... (Review)
Review
Strachan's syndrome comprises a triad of optic, auditory and painful sensory peripheral neuropathy. It has been recognised since the late 19th century and is presumed to result from nutritional deficiency. Patients present acute or subacutely after a period of systemic illness, weight loss or, most commonly, dietary restriction, especially veganism, which can cause riboflavin (vitamin B) and vitamin B deficiencies. The syndrome is more common in people who are black British and often of Jamaican descent. We describe the clinical phenotype using a typical case example, review other endemic nutritional peripheral neuropathies and discuss the potential benefit of riboflavin as a treatment.
Topics: Humans; Peripheral Nervous System Diseases; Riboflavin Deficiency; Optic Nerve Diseases; Riboflavin; Vitamins; Vitamin B 12 Deficiency
PubMed: 38290841
DOI: 10.1136/pn-2023-003822