Peripherin is a biomarker of axonal damage in peripheral nervous system disease.

Valid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain (NfL) is sensitive for detecting axonal pathology but is not specific to PNS damage, as it is expressed throughout the PNS and CNS. Peripherin, another intermediate filament protein, is almost exclusively expressed in peripheral nerve axons. We postulated that peripherin would be a promising blood biomarker of PNS axonal damage. We demonstrated that peripherin is distributed in sciatic nerve, and to a lesser extent spinal cord tissue lysates, but not in brain or extra-neural tissues. In the spinal cord, anti-peripherin antibody bound only to the primary cells of the periphery (anterior horn cells, motor axons and primary afferent sensory axons). In vitro models of antibody-mediated axonal and demyelinating nerve injury showed marked elevation of peripherin levels only in axonal damage and only a minimal rise in demyelination. We developed an immunoassay using single molecule array technology for the detection of serum peripherin as a biomarker for PNS axonal damage. We examined longitudinal serum peripherin and NfL concentrations in individuals with Guillain-Barré syndrome (GBS, n = 45, 179 time points), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 35, 70 time points), multiple sclerosis (n = 30), dementia (as non-inflammatory CNS controls, n = 30) and healthy individuals (n = 24). Peak peripherin levels were higher in GBS than all other groups (median 18.75 pg/ml versus < 6.98 pg/ml, P < 0.0001). Peak NfL was highest in GBS (median 220.8 pg/ml) and lowest in healthy controls (median 5.6 pg/ml), but NfL did not distinguish between CIDP (17.3 pg/ml), multiple sclerosis (21.5 pg/ml) and dementia (29.9 pg/ml). While peak NfL levels were higher with older age (rho = +0.39, P < 0.0001), peak peripherin levels did not vary with age. In GBS, local regression analysis of serial peripherin in the majority of individuals with three or more time points of data (16/25) displayed a rise-and-fall pattern with the highest value within the first week of initial assessment. Similar analysis of serial NfL concentrations showed a later peak at 16 days. Group analysis of serum peripherin and NfL levels in GBS and CIDP patients were not significantly associated with clinical data, but in some individuals with GBS, peripherin levels appeared to better reflect clinical outcome measure improvement. Serum peripherin is a promising new, dynamic and specific biomarker of acute PNS axonal damage.

Celastrol attenuates Guillain-Barré syndrome by inhibiting TLR4/NF-κB/STAT3 pathway-mediated Th1/Th17 cell differentiation.

Guillain-Barré syndrome (GBS) is an acute immune-mediated paralytic neuropathy with variable disease course and outcome. In this study, we aimed to investigate the therapeutic effects of celastrol on GBS and uncover its underlying mechanisms. Experimental autoimmune neuritis (EAN) is a typical animal model for GBS, and thus an EAN rat model was established with the injection of celastrol or/and LPS. We assessed the body weights and EAN clinical scores of rats. HE staining, flow cytometry, RT-qPCR, and Western blotting were respectively employed to measure pathological damage, proportions of cells (Th1, Th17, and Treg), Th1/Th17 cell differentiation-related mRNAs (IFN-γ, TBX21, IL-18, RORγT, IL-17, and IL-23) and TLR4/NF-κB/STAT3 pathway-related proteins (TLR4, NF-κB, p-NF-κB, STAT3, and p-STAT3). We found that celastrol attenuated clinical symptoms and pathological damage of GBS in EAN rats. Moreover, celastrol down-regulated Th1 and Th17 cell proportions, and the levels of IFN-γ, TBX21, IL-18, RORγT, IL-17, and IL-23 in EAN rats. Meanwhile, the levels of TLR4, p-NF-κB, and p-STAT3 were decreased by celastrol. Taken together, celastrol could restrain Th1/Th17 cell differentiation through inhibition of the TLR4/NF-κB/STAT3 pathway in EAN rats. Our findings suggest that celastrol may exert therapeutic effects on GBS by suppressing TLR4/NF-κB/STAT3 pathway-mediated Th1/Th17 cell differentiation.

Relationship between Hypoxic and Immune Pathways Activation in the Progression of Neuroinflammation: Role of HIF-1α and Th17 Cells.

Neuroinflammation is a common event in degenerative diseases of the central and peripheral nervous system, triggered by alterations in the immune system or inflammatory cascade. The pathophysiology of these disorders is multifactorial, whereby the therapy available has low clinical efficacy. This review propounds the relationship between the deregulation of T helper cells and hypoxia, mainly Th17 and HIF-1α molecular pathways, events that are involved in the occurrence of the neuroinflammation. The clinical expression of neuroinflammation is included in prevalent pathologies such as multiple sclerosis, Guillain-Barré syndrome, and Alzheimer's disease, among others. In addition, therapeutic targets are analyzed in relation to the pathways that induced neuroinflammation.

Mental and Lingual Nerve Paresthesia Following Infiltration Anesthesia for Dental Implant Placement in a Patient With Guillain-Barré Syndrome.

Guillain-Barré syndrome (GBS) is a rare rapid onset autoimmune peripheral polyneuropathy, most commonly characterized by inflammatory demyelination of peripheral nerves. Patients with GBS are considered higher risk for anesthetic-induced neurotoxicity caused by demyelination. In the present report, a case is described of a 56-year-old man with GBS who experienced mental and lingual nerve paresthesia following infiltration anesthesia for dental implant placement in the posterior mandible. The pareshesia lasted 5 months postoperatively and subsided spontaneously without any intervention. The patient was successfully restored with fixed partial dental prosthesis without any other complication. This is considered the first report of such complication in patient with GBS after local anesthesia in the oral and maxillofacial region. Possible pathogenic mechanism of the complication and clinical implications are discussed.

Guillain-Barré syndrome.

Guillain-Barré syndrome is the most common cause of acute flaccid paralysis worldwide. Most patients present with an antecedent illness, most commonly upper respiratory tract infection, before the onset of progressive motor weakness. Several microorganisms have been associated with Guillain-Barré syndrome, most notably Campylobacter jejuni, Zika virus, and in 2020, the severe acute respiratory syndrome coronavirus 2. In C jejuni-related Guillain-Barré syndrome, there is good evidence to support an autoantibody-mediated immune process that is triggered by molecular mimicry between structural components of peripheral nerves and the microorganism. Making a diagnosis of so-called classical Guillain-Barré syndrome is straightforward; however, the existing diagnostic criteria have limitations and can result in some variants of the syndrome being missed. Most patients with Guillain-Barré syndrome do well with immunotherapy, but a substantial proportion are left with disability, and death can occur. Results from the International Guillain-Barré Syndrome Outcome Study suggest that geographical variations exist in Guillain-Barré syndrome, including insufficient access to immunotherapy in low-income countries. There is a need to provide improved access to treatment for all patients with Guillain-Barré syndrome, and to develop effective disease-modifying therapies that can limit the extent of nerve injury. Clinical trials are currently underway to investigate some of the potential therapeutic candidates, including complement inhibitors, which, together with emerging data from large international collaborative studies on the syndrome, will contribute substantially to understanding the many facets of this disease.

Peli1 signaling blockade attenuates congenital zika syndrome.

Zika virus (ZIKV) infects pregnant women and causes devastating congenital zika syndrome (CZS). How the virus is vertically transmitted to the fetus and induces neuronal loss remains unclear. We previously reported that Pellino (Peli)1, an E3 ubiquitin ligase, promotes p38MAPK activation in microglia and induction of lethal encephalitis by facilitating the replication of West Nile virus (WNV), a closely related flavivirus. Here, we found that Peli1 expression was induced on ZIKV-infected human monocytic cells, peripheral blood mononuclear cells, human first-trimester placental trophoblasts, and neural stem cell (hNSC)s. Peli1 mediates ZIKV cell attachment, entry and viral translation and its expression is confined to the endoplasmic reticulum. Moreover, Peli1 mediated inflammatory cytokine and chemokine responses and induced cell death in placental trophoblasts and hNSCs. ZIKV-infected pregnant mice lacking Peli1 signaling had reduced placental inflammation and tissue damage, which resulted in attenuated congenital abnormalities. Smaducin-6, a membrane-tethered Smad6-derived peptide, blocked Peli1-mediated NF-κB activation but did not have direct effects on ZIKV infection. Smaducin-6 reduced inflammatory responses and cell death in placental trophoblasts and hNSCs, and diminished placental inflammation and damage, leading to attenuated congenital malformations in mice. Collectively, our results reveal a novel role of Peli1 in flavivirus pathogenesis and suggest that Peli1 promotes ZIKV vertical transmission and neuronal loss by mediating inflammatory cytokine responses and induction of cell death. Our results also identify Smaducin-6 as a potential therapeutic candidate for treatment of CZS.

The underlying mechanism of Guillain-Barré syndrome in a young patient suffered from Japanese encephalitis virus infection: a case report.

BACKGROUND: The presentation of Guillain-Barré syndrome (GBS) caused by Japanese encephalitis virus (JEV) is uncommon, although clusters of GBS cases were observed in China in 2018. The underlying mechanism is unclear, particularly in individuals vaccinated against Japanese encephalitis in childhood. CASE PRESENTATION: We report a patient with acute flaccid paralysis involving four extremities and respiratory muscles, while magnetic resonance imaging of the brain and spine were standard. Electrophysiological examination displayed slowed motor nerve conduction speed and reduced evoked velocity amplitude. GBS was finally considered which was related to JEV infection verified by positive anti-JEV immunoglobulin M antibody and positive immunoglobulin G antibody in the serum. Unfortunately, the patient refused intravenous immunoglobulin and declined the use of mechanical ventilation again. He voluntarily withdrew from the hospital and died on the 36th day after the onset of illness. We also performed a review of previously reported related cases and discussed the underlying mechanism. CONCLUSION: JEV infection-associated GBS is unusual. We should pay attention to the atypical manifestations of JEV infection and explore possible pathogenesis in particular individuals.

Anti-glycan antibodies: roles in human disease.

Carbohydrate-binding antibodies play diverse and critical roles in human health. Endogenous carbohydrate-binding antibodies that recognize bacterial, fungal, and other microbial carbohydrates prevent systemic infections and help maintain microbiome homeostasis. Anti-glycan antibodies can have both beneficial and detrimental effects. For example, alloantibodies to ABO blood group carbohydrates can help reduce the spread of some infectious diseases, but they also impose limitations for blood transfusions. Antibodies that recognize self-glycans can contribute to autoimmune diseases, such as Guillain-Barre syndrome. In addition to endogenous antibodies that arise through natural processes, a variety of vaccines induce anti-glycan antibodies as a primary mechanism of protection. Some examples of approved carbohydrate-based vaccines that have had a major impact on human health are against pneumococcus, Haemophilus influeanza type b, and Neisseria meningitidis. Monoclonal antibodies specifically targeting pathogen associated or tumor associated carbohydrate antigens (TACAs) are used clinically for both diagnostic and therapeutic purposes. This review aims to highlight some of the well-studied and critically important applications of anti-carbohydrate antibodies.

Guillain-Barre Syndrome After Two COVID-19 Vaccinations: Two Case Reports With Follow-up Electrodiagnostic Study.

Guillain-Barre syndrome (GBS) is an immune-mediated acute polyradiculoneuropathy and commonly occurs after a preceding infection or immunization sequalae. Following the severe acute respiratory syndrome-coronavirus-2 virus pandemic with co-introduction of massive vaccinations, several GBS cases associated with coronavirus disease 2019 (COVID-19) infection per se or after vaccination for COVID-19 were reported internationally. Herein, we report two cases of Korean GBS presenting with tetraplegia after two different COVID-19 vaccinations (42-year old man by AstraZeneca and 48-year woman by Pfizer vaccines) within four weeks after vaccination. The patients were diagnosed with clinical examination, serial electromyography, and compatible laboratory results and improved after comprehensive rehabilitative treatment and intravenous immunoglobulin therapy. Furthermore, we performed an electrodiagnostic follow-up study of each case to examine their unique characteristics.

Porphyric neuropathy.

Acute hepatic porphyrias are inherited metabolic disorders that may present with polyneuropathy, which if not diagnosed early can lead to quadriparesis, respiratory weakness, and death. Porphyric neuropathy is an acute to subacute motor predominant axonal neuropathy with a predilection for the upper extremities and usually preceded by a predominantly parasympathetic autonomic neuropathy. The rapid progression and associated dysautonomia mimic Guillain-Barré syndrome but are distinguished by the absence of cerebrospinal fluid albuminocytologic dissociation, progression beyond 4 wk, and associated abdominal pain. Spot urine test to assess the porphyrin precursors delta-aminolevulinic acid and porphobilinogen can provide a timely diagnosis during an acute attack. Timely treatment with intravenous heme, carbohydrate loading, and avoidance of porphyrinogenic medications can prevent further neurological morbidity and mortality.

Explaining Pathogenicity of Congenital Zika and Guillain-Barré Syndromes: Does Dysregulation of RNA Editing Play a Role?

Previous studies of Zika virus (ZIKV) pathogenesis have focused primarily on virus-driven pathology and neurotoxicity, as well as host-related changes in cell proliferation, autophagy, immunity, and uterine function. It is now hypothesized that ZIKV pathogenesis arises instead as an (unintended) consequence of host innate immunity, specifically, as the side effect of an otherwise well-functioning machine. The hypothesis presented here suggests a new way of thinking about the role of host immune mechanisms in disease pathogenesis, focusing on dysregulation of post-transcriptional RNA editing as a candidate driver of a broad range of observed neurodevelopmental defects and neurodegenerative clinical symptoms in both infants and adults linked with ZIKV infections. The authors collect and synthesize existing evidence of ZIKV-mediated changes in the expression of adenosine deaminases acting on RNA (ADARs), known links between abnormal RNA editing and pathogenesis, as well as ideas for future research directions, including potential treatment strategies.

NKT and NKT-like Cells in Autoimmune Neuroinflammatory Diseases-Multiple Sclerosis, Myasthenia Gravis and Guillain-Barre Syndrome.

NKT cells comprise three subsets-type I (invariant, iNKT), type II, and NKT-like cells, of which iNKT cells are the most studied subset. They are capable of rapid cytokine production after the initial stimulus, thus they may be important for polarisation of Th cells. Due to this, they may be an important cell subset in autoimmune diseases. In the current review, we are summarising results of NKT-oriented studies in major neurological autoimmune diseases-multiple sclerosis, myasthenia gravis, and Guillain-Barre syndrome and their corresponding animal models.

Severe rapidly progressive Guillain-Barré syndrome in the setting of acute COVID-19 disease.

There is concern that the global burden of coronavirus disease of 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection might yield an increased occurrence of Guillain-Barré syndrome (GBS). It is currently unknown whether concomitant SARS-CoV-2 infection and GBS are pathophysiologically related, what biomarkers are useful for diagnosis, and what is the optimal treatment given the medical comorbidities, complications, and simultaneous infection. We report a patient who developed severe GBS following SARS-CoV-2 infection at the peak of the initial COVID-19 surge (April 2020) in New York City and discuss diagnostic and management issues and complications that may warrant special consideration in similar patients.

Neurological manifestations of COVID-19: available evidences and a new paradigm.

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

Ultrastructural mechanisms of macrophage-induced demyelination in Guillain-Barré syndrome.

OBJECTIVE: To describe the pathological features of Guillain-Barré syndrome focusing on macrophage-associated myelin lesions. METHODS: Longitudinal sections of sural nerve biopsy specimens from 11 patients with acute inflammatory demyelinating polyneuropathy (AIDP) exhibiting macrophage-associated demyelinating lesions were examined using electron microscopy. A total of 1205 nodes of Ranvier were examined to determine the relationship of the macrophage-associated demyelinating lesions with the nodal regions. Additionally, immunohistochemical and immunofluorescent studies were performed to elucidate the sites of complement deposition. RESULTS: Overall, 252 macrophage-associated myelin lesions were identified in longitudinal sections. Of these, 40 lesions exhibited complete demyelination with no association with the lamellar structures of myelin. In 183 lesions, macrophage cytoplasm was located at internodes without association with the nodes of Ranvier or paranodes. In particular, these internodal lesions were more frequent in one patient (152 lesions). In the remaining 29 lesions, the involvement of nodal regions was obvious. Lesions involving nodal regions were more frequently observed than those involving internodes in four patients. Invasion of the macrophage cytoplasmic processes into the space between the paranodal myelin terminal loops and the axolemma from the nodes of Ranvier was observed in three of these patients. Immunostaining suggested complement deposition corresponding to putative initial macrophage-associated demyelinating lesions. CONCLUSIONS: The initial macrophage-associated demyelinating lesions appeared to be located at internodes and at nodal regions. The sites at which the macrophages initiated phagocytosis of myelin might be associated with the location of complement deposition in certain patients with AIDP.

Perisynaptic Schwann cells phagocytose nerve terminal debris in a mouse model of Guillain-Barré syndrome.

In mouse models of acute motor axonal neuropathy, anti-ganglioside antibodies (AGAbs) bind to motor axons, notably the distal nerve, and activate the complement cascade. While complement activation is well studied in this model, the role of inflammatory cells is unknown. Herein we aimed to investigate the contribution of phagocytic cells including macrophages, neutrophils and perisynaptic Schwann cells (pSCs) to distal nerve pathology. To observe this, we first created a subacute injury model of sufficient duration to allow inflammatory cell recruitment. Mice were injected intraperitoneally with an anti-GD1b monoclonal antibody that binds strongly to mouse motor nerve axons. Subsequently, mice received normal human serum as a source of complement. Dosing was titrated to allow humane survival of mice over a period of 3 days, yet still induce the characteristic neurological impairment. Behaviour and pathology were assessed in vivo using whole-body plethysmography and post-sacrifice by immunofluorescence and flow cytometry. ex vivo nerve-muscle preparations were used to investigate the acute phagocytic role of pSCs following distal nerve injury. Following complement activation at distal intramuscular nerve sites in the diaphragm macrophage localisation or numbers are not altered, nor do they shift to a pro- or anti-inflammatory phenotype. Similarly, neutrophils are not significantly recruited. Instead, ex vivo nerve-muscle preparations exposed to AGAb plus complement reveal that pSCs rapidly become phagocytic and engulf axonal debris. These data suggest that pSCs, rather than inflammatory cells, are the major cellular vehicle for axonal debris clearance following distal nerve injury, in contrast to larger nerve bundles where macrophage-mediated clearance predominates.

A Unique Case of a Pediatric Patient With Blastic Plasmacytoid Dendritic Cell Neoplasm, Guillain Barre Syndrome, and Hemophagocytic Lymphohistiocytosis.

Blastic plasmacytoid dendritic cell neoplasm is a rare hematopoietic malignancy with a poor prognosis that is seen primarily in the elderly population. We describe a pediatric patient with blastic plasmacytoid dendritic cell neoplasm who subsequently developed Guillain Barre syndrome followed by hemophagocytic lymphohistiocytosis. All 3 conditions are uncommon, particularly in the pediatric population. It is unclear whether this patient developed these disease states independently, whether they were due to a viral trigger or if she has an underlying immune dysfunction that could have contributed to the development of these conditions. The patient is currently in remission and awaiting further immune work-up.

The dynamic expression of canonical Wnt/ß-catenin signalling pathway in the pathologic process of experimental autoimmune neuritis.

Background: Guillain-Barré syndrome (GBS), an autoimmune disease and an acute inflammation disorder, is currently the most frequent cause of acute flaccid paralysis worldwide. EAN, an animal model of GBS, is a CD4+ T cell-mediated autoimmune disease of the PNS. Wnt/ß-catenin signals are critically important to several fundamental aspects of peripheral nerve development and play a crucial role in Schwann cell proliferation. Here, we investigate the role of Wnt/ß-catenin signalling cascades in EAN rats.Methods: 28 male Lewis rats weighing 170 ± 10 g were randomly divided into control group (n = 7) and EAN groups (Early group; Peak group and Recovery group. n = 7 per group). EAN rats were immunized with P257-81 peptide; weighed daily, and the neurologic signs of EAN were evaluated every day. The sciatic nerve was taken on the days 10, 17, and 30 p.i. for H&E staining, transmission electron microscopy and immunohistochemical staining; blood samples were collected weekly from caudal vein to detect IFN-γ, IL-4, TGF-ß1; and the sciatic nerve was taken to examinate the dynamics expression of Wnt/ß-catenin pathway molecules.Results: In our study, we chose tail-root injection to better model GBS. Moreover, we observed that IFN-γ levels paralleled clinical EAN, and the levels of TGF-ß1 and IL-4 gradually increased and peaked in the recovery phase. In addition, we have shown that canonical Wnt signalling is upregulated and reached a peak in the late recovery phase.Conclusion: Our findings suggest that Wnt/ß-catenin signalling is associated with the promotion of remyelination in EAN rats.

Guillain-Barre syndrome: demographics, clinical features, and outcome in a single tertiary care hospital, Oman.

OBJECTIVE: Guillain-Barre syndrome (GBS) is an acute autoimmune-mediated peripheral nervous system disease. Different studies from various geographical regions have reported considerable variability regarding its epidemiology, clinical features, and outcome. Our study aimed to document demographics, clinical features, and outcomes among GBS patients admitted to a single tertiary care hospital in Muscat, Oman. METHODS: A retrospective data analysis of 44 GBS patients, who were admitted during a two-year period from January 2016 to December 2018 at Khoula hospital, was carried out. Demographics, antecedent illness, duration of symptoms, muscle power graded by the Medical Research Council scale (MRCs), sensory & autonomic involvements, nerve conduction study results, CSF study, need for ventilation, condition at discharge and subsequent follow-up status were obtained. RESULTS: Ninety-one percent of the patients were Omanis, with male predominant 63.6% and the average age was 42.69 years. Quadriparesis was the predominant presenting complaint (61.3%) and AIDP was the commonest variant (52%). All patients received a single cycle of IVIg and (13.6%) patients admitted to the ICU for mechanical ventilation. The study showed good outcome and recovery in 18 months follow up. CONCLUSION: The clinical presentation of GBS in the majority of patients in Oman is similar to those reported in previous studies, and most patients had favorable prognoses. Our results can be used as baseline data for understanding the characteristics of GBS in Oman and, consequently, for better management.

Synthesis of the Core Oligosaccharides of Lipooligosaccharides from Campylobacter jejuni: A Putative Cause of Guillain-Barré Syndrome.

The chemical synthesis of the highly branched core oligosaccharides of lipooligosaccharides (LOSs) found in Campylobacter jejuni, which causes Guillain-Barré syndrome by a preceding infection, is described. The target LOS mimics, consisting of eight or nine monosaccharides, were classified into three groups as key building blocks: ganglioside-core tetra-/pentasaccharides (GM1-/GD1a-like), l-glycero-d-manno-heptose-containing trisaccharides, and 3-deoxy-d-manno-2-octulosonic acid (KDO) residues. These synthetic fragments were obtained from commercially available monosaccharides. Less obtainable l-glycero-d-manno-heptose and KDO residues, as key components of the LOSs, were synthesized from p-methoxyphenyl d-mannoside and di-O-isopropylidene-protected d-mannose, respectively. The synthesis of α-KDO glycoside, as one of the most difficult stereocontrolled glycosidic constructions, was achieved by treating a 2,3-ene derivative of KDO with phenylselenyl trifluoromethanesulfonate as a suitable α-directing reagent. All synthetic blocks were constructed through a convergent synthetic route, which resulted in the first synthesis of structurally challenging LOS core glycans containing ganglioside GM1 and GD1a-core sequences.