Peripheral Nerve Demyelination Research Articles

Enhancing Neuromuscular Disease Diagnosis through Electrophysiology

Electrophysiologic testing plays an important role in evaluating peripheral nerve, muscle, and neuromuscular junction diseases, aiding in diagnosis and treatment strategies by offering real-time assessment. Demyelination of peripheral nerves results in increased conduction delay, temporal dispersion, conduction block, and stimulation threshold. The localization or diffusion of these changes is crucial in understanding disease pathogenesis, necessitating stimulation at multiple points along nerve pathways. When axonal degeneration occurs, the amplitude is reduced, with mild conduction delay. Acute axonal degeneration may require 1 week to develop into Wallerian degeneration. During this time, conductivity was preserved in the nerve peripheral to the lesion. When MG or LEMS is suspected, repetitive nerve stimulation tests and single-fiber EMG are valuable for the diagnosis and pathophysiological evaluation. Notably, the latter is highly sensitive but not specific. Needle electromyography (EMG) assists in differentiating between myopathies and neurogenic diseases, and in determining whether the patient is in an acute or chronic stage. Integration of these tests contribute to an accurate diagnosis when considering the presenting symptoms.

PRESenting a Challenge: Posterior Reversible Encephalopathy Syndrome in Pediatric Patients With Guillain-Barré Syndrome: A Case Series and Review of Literature

BackgroundGuillain-Barré syndrome (GBS) is an autoimmune disorder characterized by demyelination of peripheral nerves. GBS-associated posterior reversible encephalopathy syndrome (PRES) is a rare and potentially life-threatening complication in the pediatric population. We aimed to report and analyze the clinical features, management, and outcomes of three cases of GBS-associated PRES in our setting in the light of the existing literature. MethodsMedical records of 75 pediatric patients with GBS were reviewed for autonomic changes and GBS-associated PRES. Thirty-one developed dysautonomia while three were identified to have PRES. Clinical, radiological, laboratory, and treatment data were collected and analyzed. ResultsAll three patients were male and presented with symptoms of acute flaccid paralysis and respiratory distress requiring mechanical ventilation. All three patients experienced various complications, including hypertension, seizures, and hyponatremia, and were subsequently diagnosed with PRES. Multimodal intensive care resulted in patient improvement and discharge in an ambulatory state after an average of 104 days of care. ConclusionsGBS-associated PRES is a rare and potentially life-threatening complication that can occur in pediatric patients with GBS. Our findings suggest that early recognition, prompt intervention, and multimodal intensive care can improve patient outcomes. Further studies are needed to determine optimal treatment strategies for GBS-associated PRES.

Association of the neonatal Fc receptor promoter variable number of tandem repeat polymorphism with immunoglobulin response in patients with chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease with humoral and cellular autoimmunity causing demyelination of peripheral nerves, commonly treated with intravenous immunoglobulins (IVIg). The neonatal Fc receptor (FcRn), encoded by the FCGRT gene, prevents the degradation of immunoglobulin G (IgG) by recycling circulating IgG. A variable number of tandem repeat (VNTR) polymorphism in the promoter region of the FCGRT gene is associated with different expression levels of mRNA and protein. Thus, patients with genotypes associated with relatively low FcRn expression may show a poorer treatment response to IVIg due to increased IVIg degradation. VNTR genotypes were analyzed in 144 patients with CIDP. Patients' clinical data, including neurological scores and treatment data, were collected as part of the Immune-Mediated Neuropathies Biobank registry. Most patients (n = 124, 86%) were VNTR 3/3 homozygotes, and 20 patients (14%) were VNTR 2/3 heterozygotes. Both VNTR 3/3 and VNTR 2/3 genotype groups showed no difference in clinical disability and immunoglobulin dosage. However, patients with a VNTR 2 allele were more likely to receive subcutaneous immunoglobulins (SCIg) than patients homozygous for the VNTR 3 allele (25% vs. 9.7%, p = 0.02) and were more likely to receive second-line therapy (75% vs. 54%, p = 0.05). The VNTR 2/3 genotype is associated with the administration of SCIg, possibly reflecting a greater benefit from SCIg due to more constant immunoglobulin levels without lower IVIg levels between the treatment circles. Also, the greater need for second-line treatment in VNTR 2/3 patients could be an indirect sign of a lower response to immunoglobulins.

Cutting edge of diagnosis and treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) based on the EAN/PNS guideline 2021

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a most common chronic immune-mediated demyelinating neuropathy, and includes a number of clinical subtypes. The major phenotype is "typical CIDP", which is characterized by symmetric polyneuropathy and "proximal and distal" muscle weakness. During the historical changes in the concept of CIDP, multifocal motor neuropathy, anti-myelin-associated glycoprotein (MAG) neuropathy, and autoimmune nodopathy have been excluded. Currently CIDP is considered as a syndrome including typical CIDP and CIDP variant such as distal CIDP and multifocal CIDP. In 2021, the international guideline of diagnosis and treatment for CIDP, European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) Guideline, was published. This review article introduces the putline of the guideline with medical-social situation in Japan. The diagnosis of CIDP is based on (1) phenotype of typical CIDP or variant, (2) electrophysiologic evidence of peripheral nerve demyelination, and (3) exclusion criteria. The first-line treatments are corticosteroids or immunoglobulin therapy, and plasma exchange should be considered if the 2 treatments were not effective sufficiently. This guideline recommends intravenous or subcutaneous immunoglobulin as a maintenance therapy, and suggests other immune-suppressive agents. In the near future, new treatment with biologics, such as monoclonal antibodies against neonatal Fc receptors, complements, and CD19/20 will be approved.

Chronic Inflammatory Demyelinating Polyneuropathy and Evaluation of the Visual Evoked Potentials: A Review of the Literature.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune disorder characterised by the progressive demyelination of peripheral nerves, resulting in motor and sensory deficits. While much research has focused on clinical and electrophysiological aspects of CIDP, there is an emerging interest in exploring its impact on the visual system through visual evoked potentials (VEPs). This comprehensive review synthesises existing literature on VEP findings in CIDP patients, shedding light on their potential diagnostic and prognostic value. The review thoroughly examines studies spanning the last two decades, exploring VEP abnormalities in CIDP patients. Notably, VEP studies have consistently revealed prolonged latencies and reduced amplitudes in CIDP patients compared to healthy controls. These alterations in VEP parameters suggest that the demyelinating process extends beyond the peripheral nervous system to affect the central nervous system, particularly the optic nerve and its connections. The correlation between VEP abnormalities and clinical manifestations of CIDP, such as visual impairment and sensory deficits, underscores the clinical relevance of VEP assessment in CIDP management. Furthermore, this review addresses the potential utility of VEPs in aiding CIDP diagnosis and monitoring disease progression. VEP abnormalities may serve as valuable biomarkers for disease activity, helping clinicians make timely therapeutic decisions. Moreover, this review discusses the limitations and challenges associated with VEP assessment in CIDP, including variability in recording techniques and the need for standardised protocols. In conclusion, this review highlights the evolving role of VEPs as a non-invasive tool in CIDP evaluation. The consistent VEP abnormalities observed in CIDP patients suggest the involvement of the central nervous system in this demyelinating disorder. As our understanding of CIDP and its pathophysiology continues to evolve, further research in this area may lead to improved diagnostic accuracy and monitoring strategies, ultimately enhancing the clinical management of CIDP patients.

Macrophages are scavengers for injured myelin in a rabbit model of acute inflammatory demyelinating polyneuropathy.

In acute inflammatory demyelinating polyneuropathy (AIDP), myelin vesiculation mediated by complement activation contributes to nerve injury. Macrophage infiltration of the spinal roots has been demonstrated in AIDP, but its pathological significance remains uncertain. The present study aimed to investigate the role of macrophages in the pathogenic sequence of AIDP. A rabbit model of AIDP was induced by immunization with galactocerebroside. Immunostaining was performed to localize the macrophages and myelin injury. The rabbit developed tetraparesis with electrophysiological and pathological features of peripheral nerve demyelination. Immunostaining demonstrated colocalization of IgG antibodies, complement deposition and myelin injury apart from macrophages. Immunostaining and electron microscopy showed myelin injury preceded macrophage infiltration. There was significant disruption of voltage-gated sodium channel clusters at the nodes of Ranvier in the spinal roots. Macrophages acted may as scavengers to remove myelin debris following complement activation-mediated demyelination in the AIDP rabbit. Lesions at the node of Ranvier contribute to conduction failure and muscle weakness.

Avian riboflavin deficiency causes reliably reproducible peripheral nerve demyelination and, with vitamin supplementation, rapid remyelination.

Riboflavin deficiency produces severe peripheral neve demyelination in young, rapidly growing chickens. While this naturally-occurring vitamin B2 deficiency can cause a debilitating peripheral neuropathy, and mortality, in poultry flocks, it can also be a useful experimental animal model to study the pathogenesis of reliably reproducible peripheral nerve demyelination. Moreover, restitution of normal riboflavin levels in deficient birds results in brisk remyelination. It is the only acquired, primary, demyelinating tomaculous neuropathy described to date in animals. The only other substance that causes peripheral nerve demyelination similar to avian riboflavin deficiency is tellurium and the pathologic features of the peripheral neuropathy produced by this developmental neurotoxin in weanling rats are also described.

Role of Fibrinogen in Type-2 Diabetes Mellitus with Diabetic Neuropathy and its Preliminary Mechanism.

Diabetic peripheral neuropathy (DN) is the most common complication of type 2 diabetes mellitus (T2DM). This study aimed to explore the role of fibrinogen (FIB) in T2DM neuropathy and its preliminary mechanism. Ten male Sprague-Dawley rats were divided into a normal control group (NC group) and a T2DM neuropathy model group (DN group). The DN group was given a high-energy diet and streptozotocin, while the NC group was given a normal diet and a citric acid buffer. The expression levels of related proteins were analysed. Electrophysiology: Compared with the NC group, the conduction latency of the somatosensory-evoked potential and nerve conduction velocity was prolonged in the DN group, while the motor nerve action potential was decreased. As seen under a light microscope, the peripheral nerve fibres in the DN group were swollen, and the nerve fibres in the posterior funiculus of the spinal cord were loose or missing. Moreover, as seen under an electron microscope, the peripheral nerve demyelination of the DN group was severe, with microvascular blood coagulation, luminal stenosis, and collapse. Compared with the NC group, in the DN group, the expression of FIB was positively correlated with the expression of both ionised calcium-binding adaptor molecule-1 and glial fibrillary acidic protein. Compared with the NC group, in the DN group, the expression of platelet/endothelial cell adhesion molecule-1 and B-cell lymphoma 2 was negatively correlated. The increased concentration of FIB may be the cause of neuropathy, and its mechanism may be related to its promotion of inflammatory response, blood coagulation, and vascular stenosis.

Multiparametric Quantitative MRI of Peripheral Nerves in the Leg: A Reliability Study.

Patients with polyneuropathies typically have demyelination and/or axonal degeneration in peripheral nerves. Currently, there is a lack of imaging biomarkers to track the changes in these pathologies. To develop and evaluate the reliability of a multiparametric quantitative magnetic resonance imaging (qMRI) method of peripheral nerves in the leg. Prospective. Seventeen healthy volunteers (36.2 ± 13.8 years old, 9 males) with 10 of them scanned twice for test-retest. 3 T, three-dimensional gradient echo and diffusion tensor imaging. A qMRI protocol and processing pipeline was established for quantifying the following nerve parameters that are sensitive to myelin and axonal pathologies: magnetization transfer (MT) ratio (MTR), MT saturation index (MTsat), T2 *, T1 , proton density (PD), fractional anisotropy (FA), and mean/axial/radial diffusivities (MD, AD, and RD). The qMRI protocol also measures the volume of nerve fascicles (fVOL) and the fat fraction (FF) of muscles. The intersession reproducibility and inter-rater reliability of each qMRI parameter were assessed by Bland-Altman analysis and intraclass correlation coefficient (ICC). Pairwise Pearson correlation analyses were performed to investigate the intrinsic association between qMRI parameters. Distal-to-proximal variations were evaluated by paired t-tests with Bonferroni-Holm multiple comparison corrections. P < 0.05 was considered statistically significant. The MTR, MTsat, T2 *, T1 , PD, FA, AD, and fVOL of the sciatic and tibial nerves, and the FF of leg muscles, had an overall good-to-excellent test-retest agreement (ICC varying from 0.78 to 0.99). All the qMRI parameters had good-to-excellent inter-rater reliability (ICC > 0.80). The data demonstrated a pattern of distal-to-proximal changes of an increased nerve MTsat and FA, and a decreased nerve T1 , PD, MD, and RD, as well as a significantly increased muscle FF. The proposed multiparametric qMRI method of the peripheral nerves is highly reproducible and provided healthy control data which will be used in developing monitoring biomarkers in patients with polyneuropathies. 1 TECHNICAL EFFICACY: Stage 2.

A novel approach to mitigate muscle atrophy in Guillain-Barre syndrome

Guillain-Barre syndrome (GBS) is the most common cause of acute paralytic neuropathy worldwide. GBS manifests as rapidly progressive, symmetrical numbness, paresthesia, and weakness secondary to either peripheral nerve demyelination or axonal loss. Despite effective disease modifying therapies (e.g., intravenous immunoglobulin) and individualized rehabilitation programs, many individuals recovering from GBS experience substantial muscle atrophy and incomplete recovery of strength with resultant long-term functional impairment. This narrative review explores the therapeutic potential of omega-3 fatty acid supplementation on enhancing recovery of people with GBS. This purported benefit may occur through several potential mechanisms, supported indirectly through studies using both experimental animal and clinical human models. These mechanisms include: (i) Anti-atrophic effects on skeletal muscle undergoing disuse and systemic inflammation; (ii) the use of omega-3s as a key building block comprising myelin; (iii) immune modulating effects optimizing conditions for remyelination; and (iv) preventing excitotoxic-like neuron death. The physiological mechanisms are explored in detail with examination of relevant clinical trials conducted to date. Through this exploration, there is sufficient support to justify future investigations directly examining the role omega-3 fatty acid supplementation may play as an adjunctive intervention that could have significant benefit at low cost and minimal risk of adverse events.

Regulation of the V-ATPase subunit ATP6V0D2 and its role in demyelination after peripheral nerve injury

After peripheral nerve injury, demyelinating Schwann cells discharge myelin debris and macrophages execute myelin degradation, leading to demyelination of degenerating axons, which is essential for efficient nerve regeneration. In this study, we show that vacuolar-type proton ATPase subunit d2 (Atp6v0d2) is among the most highly upregulated genes in degenerating mouse sciatic nerves after nerve injury using microarray analysis. ATP6V0D2 is mostly expressed in macrophages of injured nerves. Atp6v0d2 knockout mice display delayed peripheral nerve demyelination and significantly attenuated myelin lipid digestion after nerve injury. However, macrophage recruitment and Schwann cell dedifferentiation are unaffected by loss of Atp6v0d2 expression. Taken together, these data demonstrate that ATP6V0D2 in macrophages is specifically required for demyelination during Wallerian degeneration.

Clinical and Neurophysiological Follow-Up of Chronic Inflammatory Demyelinating Polyneuropathy Patients Treated with Subcutaneous Immunoglobulins: A Real-Life Single Center Study.

chronic idiopathic demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated neuropathy characterized by weakness, sensory symptoms and significant reduction or loss of deep tendon reflexes evolving over 2 months at least, associated with electrophysiological evidence of peripheral nerve demyelination. Recently, subcutaneous immunoglobulins (SCIg) have been introduced in clinical practice as a maintenance therapy for CIDP; nevertheless, electrophysiological and efficacy data are limited. to evaluate SCIg treatment efficacy, we retrospectively reviewed data from 15 CIDP patients referring to our clinic, receiving SCIg treatment and who performed electrophysiological studies (NCS) and clinical scores (MRC sumscore, INCAT disability score and ISS) before starting the treatment and at least one year after. NCS showed no significant changes before and during treatment for all the nerves explored. Clinical scores did not significantly change between evaluations. Correlation analysis evidenced a positive correlation of cMAPs distal amplitude with MRC sumscore and a trend of negative correlation with the INCAT disability score. SCIg maintenance therapy preserves nerve function in CIDP with a good efficacy and safety. Treatment effectiveness can be assessed with ENG, which represents a useful instrument in the follow-up and prognostic assessment of CIDP.

Immune Modifying Effect of Drug Free Biodegradable Nanoparticles on Disease Course of Experimental Autoimmune Neuritis.

Guillain-Barre syndrome (GBS) is an autoimmune disease of demyelination and inflammation of peripheral nerves. Current treatments are limited to plasma exchange and intravenous immunoglobulins. Cargo-free nanoparticles (NPs) have been evaluated here for their therapeutic benefit on the disease course of experimental autoimmune neuritis (EAN), mimicking the human GBS. NPs prepared from poly-lactic co-glycolic acid (PLGA) with variable size and surface charge (i.e., 500 nm vs. 130 nm, polyvinyl alcohol (PVA) vs. sodium cholate), were intravenously administered in before- or early-onset treatment schedules in a rat EAN model. NP treatment mitigated distinctly the clinical severity of EAN as compared to the P2-peptide control group (P2) in all treatments and reduced the trafficking of inflammatory monocytes at inflammatory loci and diverted them towards the spleen. Therapeutic treatment with NPs reduced the expression of proinflammatory markers (CD68 (P2: 34.8 ± 6.6 vs. NP: 11.9 ± 2.3), IL-1β (P2: 18.3 ± 0.8 vs. NP: 5.8 ± 2.2), TNF-α (P2: 23.5 ± 3.7 vs. NP: 8.3 ± 1.7) and elevated the expression levels of anti-inflammatory markers CD163 (P2: 19.7 ± 3.0 vs. NP: 41.1 ± 6.5; all for NP-PVA of 130 nm; relative to healthy control). These results highlight the therapeutic potential of such cargo-free NPs in treating EAN, which would be easily translatable into clinical use due to their well-known low-toxicity profile.

P.88 Long-term follow-up of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated peripheral nerve disorder characterized by muscle weakness and sensory deficits evolving over a period of more than 8 weeks, with electrodiagnostic evidence of peripheral nerve demyelination. Considering the rarity of the disease and the ongoing evolution in diagnosis and treatment, little is known about the long-term course of these patients. We describe the treatment and evolution over a period of more than 15 years in 29 patients. Patients had a median follow-up time of 16.5 years. All patients were treated with at least one treatment modality (corticosteroids, immunoglobulins, plasmapheresis, or other immunosuppressive treatments). 38% of patients were in remission at the end of follow up, 49% of patients were still treatment-dependent, and 17% showed a progressive course regardless of treatment. At 15-year follow up visit, 59% of patients had a better or unchanged disability status compared to time of diagnosis, and 41% was more disabled. Longer treatment delay was correlated with unfavourable clinical evolution over 15 years. Robust data on long-term evolution of CIDP patients is still lacking. Our study indicates that an important proportion of patients seem to develop progressive disability over time. Globally, there was no significant difference in disability between diagnosis and 15 years, but there was a trend to worsening, especially for patients with long-term treatment dependence or lack of sustained response. Further research on determining factors of long-term prognosis of CIDP would be desirable. Treatment delay is associated with worse outcome and should therefore be avoided.

Mapping the N-Terminal Hexokinase-I Binding Site onto Voltage-Dependent Anion Channel-1 To Block Peripheral Nerve Demyelination.

The voltage-dependent anion channel (VDAC), the most abundant protein on the outer mitochondrial membrane, is implicated in ATP, ion and metabolite exchange with cell compartments. In particular, the VDAC participates in cytoplasmic and mitochondrial Ca2+ homeostasis. Notably, the Ca2+ efflux out of Schwann cell mitochondria is involved in peripheral nerve demyelination that underlies most peripheral neuropathies. Hexokinase (HK) isoforms I and II, the main ligands of the VDAC, possess a hydrophobic N-terminal structured in α-helix (NHKI) that is necessary for the binding to the VDAC. To gain further insight into the molecular basis of HK binding to the VDAC, we developed and optimized peptides based on the NHKI sequence. These modifications lead to an increase of the peptide hydrophobicity and helical content that enhanced their ability to prevent peripheral nerve demyelination. Our results provide new insights into the molecular basis of VDAC/HK interaction that could lead to the development of therapeutic compounds for demyelinating peripheral neuropathies.

Factors Influencing the Diagnosis of Chronic Inflammatory Demyelinating

BACKGROUND: Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is a neurological disorder that leads to demyelination of peripheral nerves presenting with an array of symptoms. Symptoms of CIDP include but are not limited to loss of sensation, loss of reflexes, tingling and pain, and weakness. European Federation Neurological Society (EFNS) has developed guidelines for the diagnosis of this disorder. The objective of this study is to look at the relationship between the EFNS diagnostic criteria and whether patients that have the diagnosis of CIDP met this criteria. Data collection was completed on the patients diagnosed with CIDP and then the patients that were diagnosed but did not meet the criteria were analyzed to see what common outliers exist that led to the diagnosis.&#x0D; &#x0D; RESULTS: A total of 20 patients (13 males and 7 females) were included in the study. Eighty-three percent of patients that were correctly diagnosed using the EFNS/PNS guidelines displayed hyporeflexia at the time of their diagnosis. A large majority of the patients (83%) correctly diagnosed using the EFNS/PNS guidelines displayed distal weakness at the time of their diagnosis. At the time of their diagnosis, EMG showed that majority of those who did not meet the EFNS/PNS criteria had no nerves that displayed increased latency. Fifty-eight percent of those who did meet the criteria outlined by the EFNS/PNS guidelines had two or more nerves that presented with increased latency. Testing the velocity of patients displayed that all of the patients that did not meet the EFNS/PNS criteria did not present with nerves that had diminished velocity.&#x0D; &#x0D; CONCLUSION: CIDP misdiagnosis continues to be an issue leading to mismanagement of these patients. This study showed a preference of the clinical component for diagnosis of CIDP even if electrophysiological criteria was not met.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP): Current Therapies and Future Approaches.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated polyradiculoneuropathy leading to disability via inflammatory demyelination of peripheral nerves. Various therapeutic approaches with different mechanisms of action are established for the treatment of CIDP. Of those, corticosteroids, intravenous or subcutaneous immunoglobulin, or plasma exchange are established first-line therapies as suggested by the recently revised EAN/PNS guidelines for the management of CIDP. In special cases, immunosuppressants or rituximab may be used. Novel therapeutic approaches currently undergoing clinical studies include molecules or monoclonal antibodies interacting with Fc receptors on immune cells to alleviate immune-mediated neuronal damage. Despite various established therapies and the current development of novel therapeutics, treatment of CIDP remains challenging due to an heterogeneous disease course and the lack of surrogate parameters to predict the risk of clinical deterioration. This review summarizes established therapies for CIDP and provides an outlook on future therapeutic approaches.

Severe Progressive Back Pain Causing the Misdiagnoses of Guillain-Barré Syndrome (Twice)

Introduction: Guillain-Barré syndrome (GBS) is a rare autoimmune demyelinating disease. Symptoms vary widely and commonly include ascending bilateral weakness, pain and hyporeflexia. Approximately 30% will develop respiratory failure contributing to the high morbidity and mortality. Advancements in diagnostic and treatment have greatly decreased mortality to now less than 10%. However, GBS is still often misdiagnosed, thus delaying care. Case Description: A 42-year-old female presented with 1 week of back pain that now is affecting her hands and feet. Her neurological exam was within normal limits. Imaging included brain CT and MRI, chest and abdomen CT, were all unremarkable along with labs. She was discharged home with pain medication for unspecified back pain. The next day, the patient presented back to the hospital with progressive weakness and pain now occurring throughout her body. After additional workup was negative, the physicians were now considering drug addiction as a diagnosis. She was discharged home and told to follow up with her primary physician, who urgently referred her to a neurologist. The following morning, the patient saw a neurologist who recommended a lumbar puncture and nerve conduction study but were not performed due to insurance complications. She was now unable to walk and told to immediately return back to the hospital. Upon arrival, her neurological exam deteriorated further, and she was in respiratory distress. A lumbar puncture showed albuminocytologic dissociation. A nerve conduction study showed multifocal demyelinating peripheral neuropathy confirming GBS. Intravenous immunoglobin was initiated but despite several doses, her symptoms continued to worsen. She was intubated and transferred to a tertiary hospital for plasmapheresis. On Day 14 she had a tracheostomy and a percutaneous endoscopic gastrostomy tube placed and was discharged to a Long-Term Acute Care Hospital on Day 25. Discussion: GBS is often misdiagnosed especially when patients present with atypical symptoms, like in this case, back pain. After the more common etiologies for back pain are ruled out, and with a high index of suspicion, initiating early neurology consultation and early therapy will help slow progression. Severe progressive pain, including back pain, is a common presenting symptom and is caused from the demyelination of peripheral nerves. Multiple medical textbooks and resources emphasize the more typical symptoms such as progressive ascending neuropathy, yet few highlight the pain severity. Current studies are underway to help address this matter including increasing physicians’ awareness and comfort with diagnosing and treating GBS.

An Alternative Novel Therapy for the Treatment of Chronic Inflammatory Demyelinating Polyneuropathy: Adult Autologous Telomerase-Positive Stem Cells

Chronic inflammatory demyelinating polyneuropathy, e.g., chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), is a rare autoimmune mediated peripheral neuropathy. CIDP is defined as symptomology of greater than two months duration and electro diagnostic evidence of peripheral nerve demyelination. The estimated overall prevalence of CIDP is 4.8 to 8.9 cases per 100,000 people. Symptomology includes motor, sensory, and autonomic involvement resulting in symmetrical proximal and distal muscle weakness, loss of strength, areflexia of greater than eight weeks duration, numbness, weakness, sensory ataxia, paresthesia, decreased peripheral temperature, and gait disorder. As CIDP progresses there is axonal loss within mixed peripheral nerves secondary to demyelination, which is associated with a poor prognosis. Autoantibodies identified for CIDP thus far include contactin-1 (CNTN1), contactin-associated protein-1 (Caspr1), contactin-2 (CNTN2), neurofascin-155 (Nfasc-155), neurofascin-140/186(Nfasc-140/186), LM1, gliomedin, and vinculin. Another marker of CIDP is sphingomyelin protein in the cerebral spinal fluid. Potential treatment options for CIDP are first-line therapies, such as corticosteroids, plasma exchange, and/or immunoglobulins. If patients are refractory to first-line treatments to halt progression of the disease, then second-line therapies, such as chemotherapeutic drugs, immunosuppressive drugs, and/or immunomodulatory drugs, are utilized. Lastly, if first- and second-line therapies fail, novel unconventional therapies have been utilized, such as high-dose cyclophosphamide to eradicate a defective immune system containing CIDP-associated autoantibodies to nodal and par anodal proteins. This is then followed with either autologous or HLA-matched allogeneic hematopoietic stem cell transplantation (HSCT) with the intent to replace the defective immune system with a normal immune system absent of CIDP-associated autoantibodies. Whatever therapeutic treatment regimen(s) is/are utilized, maintenance treatments are required for years to maintain stasis in individuals with CIDP. Unfortunately, while first-line, second-line, and/or HSCT treatments may halt the progression of the CIDP and maintain individuals in stasis, they do little to restore neurophysiological function to the individual. We proposed an alternative unconventional therapy to treat CIDP, the use of adult autologous adult telomerase positive stem cells to halt progression of the disease and restore (neuro-) physiological function to the tissues. This hypothesis was based on previous clinical studies utilizing telomerase positive stem cells with Parkinson disease, Alzheimer’s disease, age- related dry macular degeneration, traumatic blindness, traumatic spinal cord injury, myocardial infarction, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, celiac disease, systemic lupus erythematosus, and osteoarthritis. Within this small cohort (n=3) clinical study, there were no adverse events reported for any participant treated. While there was no direct proof that the autologous telomerase positive stem cells contributed to the results seen in two of these participants, there was indirect proof for restoration of neurophysiological functions. This was demonstrated with respect to return of motor, sensory, and autonomic functions, e.g., increased strength, return of sensory input, return of reflexes, loss of numbness, increased blood flow, normal body temperature in extremities, and normal gait. Indirectly, this suggested that autologous telomerase positive stem cells are safe and demonstrate a 66% efficacy with respect to halting progression of chronic inflammatory demyelinating polyneuropathy and restoration of neurophysiological functions.

Activation of MAPK/ERK signalling in Merlin-null Schwann cells leads to increased and sustained immune cell infiltration in the peripheral nervous system

Abstract Aims Previous work has shown that increased numbers of macrophages are associated with more rapid schwannoma tumour growth and we are interested in signals that control entry of macrophages and other immune cells into these tumours. Activation of the Raf-kinase domain and the Raf/MEK/ERK pathway within Schwann cells has been observed to induce an inflammatory response in peripheral nerves in the absence of injury. Activation of an inducible Raf-kinase transgene in Schwann cells allows modelling of acute demyelination of peripheral nerves without nerve injury. This Raf-oestrogen receptor fusion protein (Raf-TR) is activated by the oestrogen analogue Tamoxifen and so allows targeted, controlled activation of the Raf/MEK/ERK pathway within the Schwann cells. Here, in order to understand drivers of tumour formation, we assess the effect of MAPK activation in Merlin-null Schwann cells upon immune cell infiltration within the PNS. Method RafTR-P0CRE-NF2fl/fl mice of 4-6 weeks age were injected daily (IP) with 2mg of 4-hydroxy-tamoxifen or vehicle (corn oil) control for 5 consecutive days. RafTR was activated on either a Merlin (NF2) wild-type (NF2 fl/fl, P0-CRE-) or NF2 null (NF2 fl/fl, P0-CRE+) background and effects on immune cell infiltration studied in each condition. Immunofluorescence was performed in the dorsal root ganglia (DRGs) and sciatic nerves of mice to identify various immune cell infiltrates at various timepoints. These will include neutrophils, mast cells, T-Cells and macrophages using the cell markers Csf3r, C-kit, CD3 and IBA1 respectively. Results At 21 days post treatment, a significantly increased infiltration of macrophages within the sciatic nerve and dorsal root ganglia was observed in mice treated with Tamoxifen when compared to vehicle controls. Loss of NF2 led to a massive increase in the number of macrophages recruited to peripheral nerves in tamoxifen-treated mice compared to Cre- mice and Cre+ treated with vehicle alone. Further assessment of other immune cell infiltration including neutrophils, mast cells and T cells are ongoing. Conclusion Raf/MEK/ERK signalling, in the absence of tumour suppressor Merlin, significantly increases the infiltration of inflammatory cells such as macrophages into peripheral nerves even in the absence of injury. As this effect is enhanced in NF2 null mice, this suggests that Merlin plays an important role in inhibiting the inflammatory response in peripheral nerves. It also suggests that Merlin could be involved in maintaining the blood nerve barrier (BNB), as in its absence the greater influx of immune cells into the nerves and DRGs suggests a more complete loss of BNB function than just activation of the Raf/MEK/ERK cascade alone.