Chronic inflammatory demyelinating polyradiculoneuropathy induced by paclitaxel

Background: Peripheral neuropathies in cancer are most often due to neurotoxic chemotherapeutic agents. Approximately 30% of patients receiving neurotoxic chemotherapy (CTX) will suffer from chemotherapy-induced peripheral neuropathy (CIPN). Paclitaxel is an extremely effective chemotherapeutic agent for the treatment of breast, ovarian, and lung cancer. However, paclitaxel-induced peripheral neuropathy occurs in 59-87% of patients who receive this drug. Paclitaxel is an anti-tubulin drug that causes microtubule stabilization, resulting in distal axonal degeneration, secondary demyelination and nerve fiber loss. Case: We present a case of a 68-year-old female patient with history of breast cancer who presented sensorial ataxia and progressive muscle weakness two months after starting CTX with paclitaxel. The physical examination showed tetraparesis with proximal predominance, areflexia, severe hypopalesthesia and postural instability. Electroneuromyography showed the existence of asymmetric demyelinating polyradiculoneuropathy, with conduction block and temporal dispersion in practically all evaluated nerves. The cerebrospinal fluid confirmed the albumin-cytological dissociation. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was confirmed and patient underwent monthly treatment with methylprednisolone with good response. Discussion: Evidences has implicated neuroinflammation in the development of PIPN. While most CTX drugs do not cross the blood-brain-barrier, they readily penetrate the blood-nerve-barrier and bind to and accumulate in dorsal root ganglia and peripheral axons. CTX can induce neuroinflammation through activation of immune and immune- like glial cells. In fact, immune cells (e.g., macrophages, lymphocytes) and glial cells (e.g., Schwann cells) in the peripheral nervous system play important role in the induction and maintenance of neuropathy. Conclusion: CIDP should be included in the spectrum of CIPN.

Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation

Cisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in cancer cells. Furthermore, we show that neurotoxicity of cisplatin requires activation of Sarm1, a key regulator of Wallerian degeneration, as mice lacking the Sarm1 gene do not develop peripheral neuropathy as evaluated by both behavioral or pathological measures. These findings indicate that Sarm1 and/or specific calpain inhibitors could be developed to prevent cisplatin induced peripheral neuropathy.

Altered interplay between endoplasmic reticulum and mitochondria in Charcot–Marie–Tooth type 2A neuropathy

Mutations in theMFN2gene encoding Mitofusin 2 lead to the development of Charcot–Marie–Tooth type 2A (CMT2A), a dominant axonal form of peripheral neuropathy. Mitofusin 2 is localized at both the outer membrane of mitochondria and the endoplasmic reticulum and is particularly enriched at specialized contact regions known as mitochondria-associated membranes (MAM). We observed that expression of MFN2R94Qinduces distal axonal degeneration in the absence of overt neuronal death. The presence of mutant protein leads to reduction in endoplasmic reticulum and mitochondria contacts in CMT2A patient-derived fibroblasts, in primary neurons and in vivo, in motoneurons of a mouse model of CMT2A. These changes are concomitant with endoplasmic reticulum stress, calcium handling defects, and changes in the geometry and axonal transport of mitochondria. Importantly, pharmacological treatments reinforcing endoplasmic reticulum–mitochondria cross-talk, or reducing endoplasmic reticulum stress, restore the mitochondria morphology and prevent axonal degeneration. These results highlight defects in MAM as a cellular mechanism contributing to CMT2A pathology mediated by mutated MFN2.

Demyelinating Neuropathies

Many neuropathies have in common the basic pathophysiological mechanism of demyelination. Our understanding of the normal process of myelination and the molecular structure of myelin, nodes of Ranvier, and internodes has increased in recent years, yielding a greater understanding of the process of demyelination in disease. This chapter focuses on the inherited neuropathies as examples of non-inflammatory demyelinating neuropathies. For these conditions there are ongoing genotype-phenotype correlations and a greater appreciation of the importance of distal axonal degeneration as a consequence of demyelination.

The neurochemistry of peripheral nerve regeneration

ABSTRACTPeripheral nerve injuries (PNIs) can be most disabling, resulting in the loss of sensitivity, motor function and autonomic control in the involved anatomical segment. Although injured peripheral nerves are capable of regeneration, sub-optimal recovery of function is seen even with the best reconstruction. Distal axonal degeneration is an unavoidable consequence of PNI. There are currently few strategies aimed to maintain the distal pathway and/or target fidelity during regeneration across the zone of injury. The current state of the art approaches have been focussed on the site of nerve injury and not on their distal muscular targets or representative proximal cell bodies or central cortical regions. This is a comprehensive literature review of the neurochemistry of peripheral nerve regeneration and a state of the art analysis of experimental compounds (inorganic and organic agents) with demonstrated neurotherapeutic efficacy in improving cell body and neuron survival, reducing scar formation and maximising overall nerve regeneration.

Distal Symmetrical Polyneuropathy in a Dog

A 1.3-year-old Great Dane dog had a chronic progressive neurologic disease clinically expressed as a distal symmetrical polyneuropathy characterized by weakness and bilateral atrophy of bulbar and distal appendicular musculature. Qualitative and quantitative studies showed neurogenic atrophy of muscles below the elbow and stifle. There was Walleriantype degeneration. Schwann cell proliferation and cell bands of Büngner, and marked depletion of medium (5 to 8 μm) to large (9 to 15 μm) diameter myelinated fibers in the distal parts of appendicular and laryngeal nerves. Sensory (saphenous and superficial radial) and autonomic (sympathetic and dorsal vagal trunk) nerves were affected to a lesser degree. A distribution of distal axonal degeneration suggested a dying back process. The disease differed from classical dying back disorders by absence of axonal degeneration in selected pathways of the central nervous system.

A Neuropathy in Goats Caused by Experimental Coyotillo (Karwinskia humboldtiana) Poisoning

Seven goats were poisoned with daily oral doses of coyotillo fruits and killed at various times after day 12. The distribution of lesions was studied in a sensory nerve, in short and long motor nerves, and at proximal and distal sites of a long motor nerve. Fibers with Schwann-cell lesions (swollen Schwann cells or segmental demyelination) were widespread and outnumbered fibers with Wallerian degeneration in most sites. The percentage of fibers that were undergoing Wallerian degeneration was much greater in long motor nerves than in short ones and was much greater at a distal site of a long motor nerve than at a proximal site. The results were compatible with axonal injury being secondary to Schwann-cell injury and cumulative throughout the lengths of affected fibers, resulting in distal axonal degeneration.