Mechanisms Of Peripheral Neuropathy Research Articles

Pharmacological rescue of cognitive function in a mouse model of chemobrain

BackgroundAfter chemotherapy, many cancer survivors suffer from long-lasting cognitive impairment, colloquially known as “chemobrain.” However, the trajectories of cognitive changes and the underlying mechanisms remain unclear. We previously established paclitaxel-induced inositol trisphosphate receptor (InsP3R)-dependent calcium oscillations as a mechanism for peripheral neuropathy, which was prevented by lithium pretreatment. Here, we investigated if a similar mechanism also underlay paclitaxel-induced chemobrain.MethodMice were injected with 4 doses of 20 mg/kg paclitaxel every other day to induced cognitive impairment. Memory acquisition was assessed with the displaced object recognition test. The morphology of neurons in the prefrontal cortex and the hippocampus was analyzed using Golgi-Cox staining, followed by Sholl analyses. Changes in protein expression were measured by Western blot.ResultsMice receiving paclitaxel showed impaired short-term spatial memory acquisition both acutely 5 days post injection and chronically 23 days post injection. Dendritic length and complexity were reduced in the hippocampus and the prefrontal cortex after paclitaxel injection. Concurrently, the expression of protein kinase C α (PKCα), an effector in the InsP3R pathway, was increased. Treatment with lithium before or shortly after paclitaxel injection rescued the behavioral, cellular, and molecular deficits observed. Similarly, memory and morphological deficits could be rescued by pretreatment with chelerythrine, a PKC inhibitor.ConclusionWe establish the InsP3R calcium pathway and impaired neuronal morphology as mechanisms for paclitaxel-induced cognitive impairment. Our findings suggest lithium and PKC inhibitors as candidate agents for preventing chemotherapy-induced cognitive impairment.

Magnetic resonance neurography findings in three critically ill COVID-19 patients with new onset of extremity peripheral neuropathy

PurposeCoronavirus-19 (COVID-19) is most commonly associated with respiratory syndromes, although patients are presenting more frequently with neurological symptoms. When they occur, neurological conditions most commonly involve the central nervous system, and peripheral nervous system effects, particularly in the extremities, have been less commonly described. The mechanisms of peripheral neuropathy in critically ill patients with COVID-19 are likely to be multifactorial, and extremity peripheral nerve imaging in these cases has not been well described.Case presentationIn this case series, we describe the magnetic resonance neurography (MRN) findings in 3 critically ill patients who presented with new onset of peripheral neuropathies in the extremities, and we discuss possible common mechanisms of nerve injury, including the role of position-related nerve injury.ConclusionsMRN can be useful in identifying and localizing peripheral nerve abnormalities in the extremities of COVID-19 patients, and patients who are placed in the prone position during ventilation may be more susceptible to these injuries.

Schwann cell-specific Pten inactivation reveals essential role of the sympathetic nervous system activity in adipose tissue development

There is increasing evidence that the sympathetic nervous system (SNS) plays an important role in adipose tissue development. However, the underlying molecular mechanism(s) associated with this remains unclear. SNS innervation of white adipose tissue (WAT) is believed to be necessary and sufficient to elicit WAT lipolysis. In this current study, mice with Schwann cell (SC)-specific inactivation of phosphatase and tensin homolog (Pten) displayed enlarged inguinal white adipose tissue (iWAT). This serendipitous observation implicates the role of SCs in mediating SNS activity associated with mouse adipose tissue development. Mice with SC-specific Pten inactivation displayed enlarged iWAT. Interestingly, the SNS activity in iWAT of SC-specific Pten-deficient mice was reduced as demonstrated by decreased tyrosine hydroxylase (TH) expression level and neurotransmitters, such as norepinephrine (NE) and histamine (H). The lipolysis related protein, phosphorylated hormone sensitive lipase (pHSL), was also decreased. As expected, AKT-associated signaling pathway was hyperactivated and hypothesized to induce enlarged iWAT in SC-specific Pten-deficient mice. Moreover, preliminary experiments using AKT inhibitor AZD5363 treatment ameliorated the enlarged iWAT condition in SC-specific Pten-deficient mice. Taken together, SCs play an essential role in the regulation of SNS activity in iWAT development via the AKT signaling pathway. This novel role of SCs in SNS function allows for better understanding into the genetic mechanisms of peripheral neuropathy associated obesity.

Conference lecture: Electrophysiological diagnosis of inflammatory demyelinating neuropathies

Electrophysiology plays a crucial role in the characterization and diagnosis of peripheral neuropathies. It provides insight in the type and mechanism of peripheral neuropathy by giving information on the spatial pattern, the fibre type involved, pathology (axonal, demyelinating), and the severity and time course. Inflammatory demyelinating neuropathies constitute a significant proportion of the acquired peripheral neuropathies. They include Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), multifocal demyelinating neuropathy with persistent conduction block (Lewis-Sumner syndrome), and paraproteinemic neuropathies. A proper diagnosis as early as possible is very important because timely immune treatment can largely reduce morbidity and disability. The diagnosis is based on a constellation of clinical and laboratory features, including electrophysiological studies, spinal fluid examination, and in selected cases serological studies and peripheral nerve biopsy. Electrophysiological studies are key in the early detection and characterization of inflammatory demyelinating neuropathies and in differentiating these from primary axonal neuropathies. In CIDP, electrophysiological criteria for demyelination are designed to exclude abnormalities that can be explained by axonal degeneration (Eur J Neurol 2010). Therefore, lesser degrees of demyelination cannot be defined with certainty. Optimised electrophysiological criteria are capable, however, to support the diagnosis with different levels of probability (possible, probable, definite) in the very large majority of cases. In GBS, much effort has gone into developing criteria which can distinguish axonal and demyelinating subtypes. The discovery of reversible conduction failure (RCF) has led to the concept of nodopathy/paranodopathy, where conduction slowing and conduction block are due to the immune attack mainly at the nodal axolemma level. There is no actual demyelinisation as defined pathologically and if the immune attack continues, conduction failure may not reverse and axonal degeneration will ensue. Recent electrophysiological studies support this pathophysiological mechanism and show that the dichotomous distinction between axonal and demyelinating in GBS is not tenable (Muscle nerve, 2018).

Genetic Susceptibility to Bortezomib-Induced Peripheral Neuroropathy: Replication of the Reported Candidate Susceptibility Loci.

The introduction of proteasome inhibitors in the treatment of multiple myeloma (MM) patients has been a therapeutic success. Peripheral neuropathy (PNP) remains one of the most frequent side-effects experienced by patients who receive these novel agents. Recent investigations on the mechanisms of PNP in patients treated with bortezomib have suggested genetic susceptibility to neurotoxicity. We used data from a genome-wide association study conducted on 646 bortezomib-treated German MM patients to replicate the previously reported associations between single-nucleotide polymorphisms (SNPs) in candidate genes and PNP in MM patients, including 298 SNPs with a nominal significance (p value <0.05). Twelve associations were confirmed at a significance level p value <0.05. The corresponding SNPs are located in genes involved in drug metabolism (ABCC1, ABCC6), development and function of the nervous system (POGZ, NFAT pathway, EDN1), modulation of immune responses (IL17RD, IL10RA) and the NF-κB signaling pathway (PSMB4, BTCR, F2). We systematically investigated functional consequences of those variants using several bioinformatics tools, such as HaploRegV4.1, RegulomeDB and UCSC Genome Browser. Expression quantitative trait loci (eQTL) data suggested that some of the identified SNPs might influence gene expression through a differential recruitment of transcription factors. In conclusion, we confirmed some of the recently reported associations between germline variation and PNP. Elucidating the mechanisms underlying these associations will contribute to the development of new strategies for the prevention or reduction of PNP.

Evaluation of Pregabalin Therapy in Peripheral Neuropathy

The mechanism of peripheral neuropathy has not been sufficiently clarified, and medical therapy for peripheral neuropathy is not established. Only a few reports have evaluated the analgesic effects of pregabalin in different diseases. In the present study, the effects of pregabalin in both orthopedic patients and surgical patients were compared, and the improvement of peripheral neuropathy was quantified. A questionnaire-based study was performed on numbness and the intensity of pain in orthopedic patients with organic diseases like spinal canal stenosis and in surgical patients with neuropathy from anti-cancer treatment. The data for patients who were prescribed pregabalin were examined using a numerical rating scale (NRS). Improvement of symptoms was observed in categories such as numbness, pain with numbness, and pain without numbness in orthopedic patients. NRS value decreased by 33 % in all patients who were prescribed pregabalin. Drowsiness, a side effect of pregabalin, mostly disappeared over 4 weeks after pregabalin administration. Further, when combining drugs with pregabalin, the frequency of numbness and pain with numbness tended to be decreased by two agents (pregabalin + NSAID), and was significantly decreased by three agents (pregabalin + NSAID + muscle relaxant), as compared with pregabalin-only treatment. The present study revealed the analgesic effect of pregabalin with regards to pain both with and without numbness. The data suggest that pregabalin is effective especially in orthopedic patients with organic injury of nerves. Keywords: Analgesic effect, muscle relaxant, NRS, NSAID, numbness, organic injury, orthopedic, pain, pregabalin, surgical.

General Aspects and Mechanisms of Peripheral Neuropathy Associated With Bortezomib in Patients With Newly Diagnosed Multiple Myeloma

Introduction of the proteasome inhibitor bortezomib (Velcade, Millennium Pharmaceuticals, The Takeda Oncology Company, Cambridge, MA) has substantially improved outcomes for patients with multiple myeloma (MM), and has become one of the cornerstones of current anti-myeloma treatment regimens. However, with the introduction of bortezomib it has become clear that peripheral neuropathy (PN) is one of the most frequent, potentially disabling, nonhematologic complications of bortezomib, often requiring dose modification or discontinuation, with a potential negative impact on clinical endpoints and quality of life. To find a balance between maximal benefit of bortezomib treatment, while maintaining quality of life, it is necessary to minimize toxicity. Here, we discuss all aspects of bortezomib-induced peripheral neuropathy (BiPN), and elaborate on the mechanisms underlying the development of BiPN.

Subacute Sensorimotor Polyneuropathy as Sole Manifestation of Occult Non Hodgkin’s Lymphoma: Infiltrative or Paraneoplastic?

Sir, The mechanisms of peripheral neuropathy in any malignancy can be because of a direct effect of the cancer by invasion or compression of nerves, a remote or paraneoplastic effect, or an iatrogenic effect of treatment. Focal or multifocal cranial neuropathies, radiculopathies, and plexopathies typically result from tumor infiltration, herpes zoster infection, or radiation-induced injury. Apart from sensorimotor polyneuropathies, which are the most frequently encountered peripheral nerve syndromes, motor neuropathies, sensory neuronopathies, polyradiculoneuropathies, and autonomic neuropathies can also occur. Although uncommon, paraneoplastic mechanisms should be considered in a patient with malignancy and an associated peripheral nerve disorder, especially in the setting of small-cell lung cancer or lymphoproliferative cancer [1]. A 63 years old, non alcoholic, male presented to us with chief complaints of tingling paresthesias in glove and stocking distribution of the limbs and mild weakness in feet since 3 months. The complaints were insidious in onset and were progressive. He gave history of inability to hold the chappals and frequent slipping of the chappals from feet. There were no weakness in the hands. He did not give any history suggestive of proximal muscle weakness. He was nondiabetic and was not taking any drugs. There was no history of fever of weight loss. General examination did not reveal anything significant apart from mild pallor. There was no evidence of postural hypotension. Examination of skin was normal and there were no thickened/tender nerves on palpation. Other systems examination was normal. In CNS examination higher functions, cranial nerves were normal. Motor system examination revealed mild weakness in plantar flexors of the ankle (patient was unable to stand on the ball of feet without support). Bilateral ankle and knee reflexes were lost. Sensory examination showed hyperasthesia in both legs up to knee joints, position sense was intact and vibration sensation was impaired up to both medial malleolus. On investigations Hb was 9 gm%, TLC 5500/mm3, DLC polymorphs 62%, lymphocytes 34%, monocytes 2%, eosinophil 2%, few atypical lymphocytes were seen. Absolute platelet count 225000/mm3. All red cell indices (MCV, MCH, MCHC) were within normal limits. Urine examination was normal. Liver and kidney function tests were normal. Fasting blood sugar 98 mg%, PPBS 138 mg%. Serum electrophoresis did not reveal any M spike. ELISA for HIV was negative. Bone marrow examination revealed marrow hyperplasia with some places showing infiltration by atypical lymphocytes. Thyroid profile was normal. CXR showed rounded, homogenous opacity in the left hilar region suggestive of mass (Fig. 1). USG abdomen was normal. EMG/NCV was conducted which revealed decreased nerve conduction velocities, prolonged distal latencies without any conduction block. Compound muscle action potential (CMAP) was normal, suggesting a predominantly demyelinating type of neuropathy. HRCT of thorax revealed left hilar mass (Fig. 2). A CT-guided FNA was done from the left hilar mass for cytological analysis and non Hodgkin’s lymphoma (NHL) was diagnosed (Fig. 3a, b). Immunophenotyping was carried out which was positive for CD 20 and CD 22 suggesting that the lymphoma was of B cell origin. Patient did not give consent for sural nerve biopsy and immunophenotyping. Anti neuronal antibodies status was not done because the patient could not afford. Fig. 1 Chest X-ray PA view showing left sided hilar opacity suggestive of mass Fig. 2 HRCT of thorax highlighting the mass and mediastinal lymphadenopathy Fig. 3 a, b Cytological smears 10× and 40× view stained with MGG stain showing cellular smears with predominant lymphocytic population. Lymphocytes are large and atypical with coarse chromatin and prominent nuclei, there is also presence of macrophages, ... He was started with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), regime. He tolerated the first cycle well though there was no significant improvement in the symptoms of neuropathy and awaits the second cycle.

Peripheral neuropathy caused by high-dose cytosine arabinoside treatment in a patient with acute myeloid leukemia

The central nervous system toxicity of high-dose cytosine arabinoside is well recognized, but the toxicity of cytosine arabinoside in the peripheral nervous system has been infrequently reported. A 49-year-old Japanese man was diagnosed with acute myeloid leukemia. After he achieved complete remission, he received high-dose cytosine arabinoside treatment (2 g/m2 twice a day for 5 days; total, 20 g/m2) as consolidation therapy. The first course of high-dose cytosine arabinoside resulted in no unusual symptoms, but on day 21 of the second course of treatment, the patient complained of numbness in his right foot. Electromyogram and nerve-conduction studies showed peripheral neuropathy in both peroneal nerves. This neuropathy was gradually resolving; however, after the patient received allogeneic bone marrow transplantation, the symptoms worsened, with the development of graft-versus-host disease, and the symptoms subsequently responded to methylprednisolone. Although the mechanisms of peripheral neuropathy are still unclear, high-dose cytosine arabinoside is a therapy that is potentially toxic to the peripheral nervous system, and auto/alloimmunity may play an important role in these mechanisms.

Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 1

Peripheral neuropathy (PN) has been found to be among the complications of hepatitis C virus (HCV) infection. Although the mechanisms of PN in patients with HCV infection are still unknown, cryoglobulinemia has been implicated as a possible cause of ischemic peripheral nerve impairment mediated by vasoconstriction, altered blood viscosity, and thrombosis of small vessels. However, available information is mostly based on referral patients with chronic HCV infection. In this study, an unselected sample of cases with newly diagnosed HCV infection has been examined to assess the prevalence and type of PN and to correlate the disease with the presence of cryoglobulinemia. The study population included 41 patients with HCV infection and no documented risk factors for PN (18 women and 23 men, aged 17 to 72 years) referred to the neurophysiology units of 7 Italian centers (Genova, Lodi, Messina, Monza, Napoli, Padova, and Siena) for a clinical and electrophysiological screening of peripheral nerve disease. The mean latency between diagnosis of HCV infection (interpreted as a surrogate of the duration of infection) and study entry was 6.8 months (range 1–12). PN was documented in 13 cases (31.7%). Of these, 7 had mononeuropathy and 6 had polyneuropathy. Cryoglobulinemia was present in 4 patients (9.8%) and 3 of them had PN (polyneuropathy 2, mononeuropathy 1). The odds ratio of PN in patients with cryoglobulinemia, adjusted for age, sex, and duration of infection, was 4.4 (95% confidence interval, CI: 0.3–68.2) and was fairly similar (4.1; 95% CI 0.3–56.3) when the analysis was limited to the presence of polyneuropathy. The lack of statistical significance may by explained by the small sample size. Based on these findings, cryoglobulinemia can be interpreted as an independent risk factor for PN at the presence of HCV infection. However, given the fairly high prevalence of PN in patients with newly diagnosed HCV infection and the high proportion of cases not attributable to cryoglobulinemia (9 out of 13), other factors should be investigated to clarify the mechanisms of HCV neuropathy.

Effects of acute, subacute, and chronic diabetes on carbohydrate and energy metabolism in rat sciatic nerve. Relation to mechanisms of peripheral neuropathy

Effects of acute, subacute, and chronic diabetes on carbohydrate and energy metabolism in rat sciatic nerve. Relation to mechanisms of peripheral neuropathy

Uncompacted myelin lamellae in polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome. Ultrastructural study of peripheral nerve biopsy from 22 patients.

Mechanisms of peripheral neuropathies in polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome are poorly understood. A peripheral nerve biopsy was performed in 22 patients. Of these 9 had histological features of Castleman's disease on lymph node biopsies, and 19 had a monoclonal lambda light chain in their serum. Certain nerve fragments were paraffin embedded, others were frozen and studied by direct immunofluorescence, and others were fixed for ultrastructural examination. Paraffin-embedded fragments did not show any amyloid deposits, and at direct immunofluorescence there was no immunoglobulin fixation. At ultrastructural examination, features of uncompacted myelin lamellae (UML) were present in 19 patients, and their frequency varied from 1% to 16% of myelinated fibres. Up to now UML have been reported only in 7 patients with POEMS syndrome in the literature. UML have also been noticed in a few cases of inflammatory demyelinating polyradiculoneuritis and inherited tendency to pressure palsy.