Summary Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic neuropathy of supposed immune origin. Understanding of its pathophysiology has recently improved, although its ...causes remain unclear. The classic presentation of CIDP includes sensory and motor symptoms in the distal and proximal segments of the four limbs with areflexia, evolving over more than 8 weeks. Raised protein concentrations in CSF and heterogeneous slowing of nerve conduction are typical of the condition. In addition to this usual phenotype, distribution of symptoms, disease course, and disability can be heterogeneous, leading to underdiagnosis of the disorder. Diagnosis is sometimes challenging and can require use of imaging and nerve biopsy. Steroids and intravenous immunoglobulin are effective, and plasma exchange can be helpful as rescue therapy. The usefulness of immunosuppressants needs to be established. The identification of specific diagnostic markers and new therapeutic strategies with conventional or targeted immunotherapy are needed to improve the outlook for patients with CIDP.
Peripheral neuropathy is the major dose-limiting side effect of many currently used chemotherapies, such as vincristine (VCR). We recently demonstrated that candesartan, an angiotensin II type 1 ...receptor antagonist, was neuroprotective against resiniferatoxin-induced sensory neuropathy, and that this effect is mediated by stimulation of the angiotensin II type 2 receptor (AT2R). Thus, we evaluated the effect of preventive treatment with candesartan and a specific AT2R agonist, C21, on a mouse model of VCR-induced neuropathy. Vincristine was administered daily for 7 days to male Swiss mice. Treatment with candesartan and C21 was started on day 1, before VCR treatment, and continued until day 7. We evaluated the development of VCR-induced neuropathy and the effect of treatment by functional tests, immunohistochemical analyses of intraepidermal nerve fibers and dorsal root ganglia neurons, and ultrastructural analysis of the sciatic nerve. Mice treated with VCR showed high mechanical allodynia but no modifications of motor performance or mechanical/thermal nociception. Treatment with candesartan and C21 completely restored normal tactile sensitivity of VCR-treated mice. Both drugs prevented VCR-induced nonpeptidergic intraepidermal nerve fiber loss. Only C21 displayed neuroprotective effects against VCR-induced loss and enlargement of myelinated nerve fibers in the sciatic nerve. Our finding that candesartan and C21 are protective against VCR-induced neuropathic pain through AT2R stimulation favors evaluation of its therapeutic potential in patients receiving chemotherapy.
Charcot-Marie-Tooth (CMT) disease, the most frequent form of inherited neuropathy, is a genetically heterogeneous group of disorders of the peripheral nervous system, but with a quite homogeneous ...clinical phenotype (progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss and usually decreased tendon reflexes). Our aim was to review the various CMT subtypes identified at the present time.
We have analysed the medical literature and performed a historical retrospective of the main steps from the individualisation of the disease (at the end of the nineteenth century) to the recent knowledge about CMT.
To date, >60 genes (expressed in Schwann cells and neurons) have been implicated in CMT and related syndromes. The recent advances in molecular genetic techniques (such as next-generation sequencing) are promising in CMT, but it is still useful to recognise some specific clinical or pathological signs that enable us to validate genetic results. In this review, we discuss the diagnostic approaches and the underlying molecular pathogenesis.
We suggest a modification of the current classification and explain why such a change is needed.
Abstract
Whatever the cause of myelin damage of the peripheral nervous system, the initial attack on myelin by a dysimmune process may begin either at the internodal area or in the paranodal and ...nodal regions. The term “nodo-paranodopathy” was first applied to some “axonal Guillain-Barré syndrome” subtypes, then extended to cases classified as chronic inflammatory demyelinating polyradiculoneuropathy bearing IgG4 antibodies against paranodal axoglial proteins. In these cases, paranodal dissection develops in the absence of macrophage-induced demyelination. In contrast, the mechanisms of demyelination of other dysimmune neuropathies induced by macrophages are unexplained, as no antibodies have been identified in such cases. Electron microscopy of longitudinal sections of nerve biopsies is useful to visualize and authenticate the characteristic lesions of paranodes/nodes. However, it should be borne in mind that identical ultrastructural aspects are seen in other types of polyneuropathies: Genetic, experimental, and in a few polyneuropathies for which there is no obvious etiology. Ultrastructural nerve studies confirm the initial involvement of nodes/paranodes in various types of acquired and genetic neuropathies. For some of them, the antibodies or the proteins involved by mutations are clearly identified such as Caspr-1, Contactin-1, NFasc155, and NFasc186; other unidentified proteins are likely to be involved as well.
Chemotherapy‐induced peripheral neuropathy (CIPN) is a major dose‐limiting side effect induced by a variety of chemotherapeutic agents. Symptoms are mainly sensory: pain, tingling, numbness, and ...temperature sensitivity. They may require the tapering of chemotherapy regimens or even their cessation; thus, the prevention/treatment of CIPN is critical to increase effectiveness of cancer treatment. However, CIPN management is mainly based on conventional neuropathic pain treatments, with poor clinical efficacy. Therefore, significant effort is made to identify new pharmacological targets to prevent/treat CIPN. Animal modeling is a key component in predicting human response to drugs and in understanding the pathophysiological mechanisms underlying CIPN. In fact, studies performed in rodents highlighted several pharmacological targets to treat/prevent CIPN. This review provides updated information about ongoing clinical trials testing drugs for the management of CIPN and presents some of their proof‐of‐concept studies conducted in rodent models. The presented drugs target oxidative stress, renin–angiotensin system, glutamatergic neurotransmission, sphingolipid metabolism, neuronal uptake transporters, nicotinamide adenine dinucleotide metabolism, endocannabinoid system, transient receptor potential channels, and serotoninergic receptors. As some clinical trials focus on the effect of the drugs on pain, others evaluate their efficacy by assessing general neuropathy. Moreover, based on studies conducted in rodent models, it remains unclear if some of the tested drugs act in an antinociceptive fashion or have neuroprotective properties. Thus, further investigations are needed to understand their mechanism of action, as well as a global standardization of the methods used to assess efficacy of new therapeutic strategies in the treatment of CIPN.
Sensory defects associated with small-fiber neuropathy (SFN) can lead to profound disabilities. The relationship between the sensory nervous system and modulation of the renin-angiotensin system ...(RAS) has been described and focused on pain and neurodegeneration in several animal models. We have recently developed an experimental model of functional sensory neuropathy showing thermal hypoalgesia and neuropeptide depletion without nerve fiber degeneration. Here, we aimed to determine whether the modulation of angiotensin II (Ang II) activity could prevent sensory neuropathy induced by RTX. Control and RTX mice received ramipril, an Ang II converting enzyme (ACE) inhibitor, (0.5 mg/kg/day) or candesartan, an Ang II type 1 receptor (AT1R) blocker (0.5 mg/kg/day), one day before vehicle or RTX administration, and each day for the next seven days. Ramipril did not have a beneficial effect in RTX mice, whereas candesartan prevented thermal hypoalgesia and reduced neuropeptide depletion in intraepidermal nerve fibers and dorsal root ganglion neurons. The preventive effect of candesartan was not observed in mice deficient for the Ang II type 2 receptor (AT2R) and was counteracted in wild type mice by EMA200, an AT2R antagonist (3 mg/kg/day). Thus, candesartan may promote AT2R activation by blocking AT1R and increasing Ang II production and enhance its mechanisms of neuroprotection in our RTX model. Our finding that candesartan prevents nociception deficits and neuropeptide depletion encourages the evaluation of its therapeutic potential in patients presenting SFN, particularly those who experience chemotherapy-induced SFN.
•Decrease Ang II production has no beneficial effect on RTX-induced hypoalgesia.•AT1R blockade prevents RTX-induced hypoalgesia and CGRP/SP depletion.•AT2R blockade has no beneficial effect on development of RTX-induced hypoalgesia.•Effect of candesartan is counteracted by AT2R blocker and in AT2R KO mice.•Neuroprotective effects of candesartan is indirectly mediated by AT2R stimulation.
Charcot-Marie-Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial ...has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol mg: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A.
In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set.
High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: - 0.37 points; 97.5% CI - 0.68 to - 0.06; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated.
The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot-Marie-Tooth disease type 1A.
Introduction: Amyloid neuropathy is a rare peripheral neuropathy that classically presents as a progressive sensory neuropathy with prominent autonomic involvement. Methods: We describe 5 patients ...with amyloid neuropathy (familial amyloid polyneuropathy or acquired amyloidosis) who were initially mistaken to have chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) based on history, clinical examination, electrodiagnostic studies, and cerebrospinal fluid (CSF) analysis. Results: The diagnosis of CIDP had been retained on clinical and electrophysiological grounds for all patients, but we observed no improvement after immunomodulatory treatment. Nerve biopsy confirmed amyloid deposits in nerves, and molecular genetic analysis showed a mutation of the transthyretin (V30M) gene for 3 patients; the 2 other patients had acquired amyloidosis. Conclusions: This report emphasizes the need to look for an alternative diagnosis in CIDP patients who do not respond to treatment and to look carefully for symptoms or signs of autonomic involvement in such patients. Muscle Nerve 45: 26–31, 2012
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