Dynamics and prognostic value of serum neurofilament light chain in Guillain-Barré syndrome.

BACKGROUND: Neurofilament light chain (NfL) is a biomarker for axonal damage in several neurological disorders. We studied the longitudinal changes in serum NfL in patients with Guillain-Barré syndrome (GBS) in relation to disease severity, electrophysiological subtype, treatment response, and prognosis. METHODS: We included patients with GBS who participated in a double-blind, randomised, placebo-controlled trial that evaluated the effects of a second course of intravenous immunoglobulin (IVIg) on clinical outcomes. Serum NfL levels were measured before initiation of treatment and at one, two, four, and twelve weeks using a Simoa HD-X Analyzer. Serum NfL dynamics were analysed using linear mixed-effects models. Logistic regression was employed to determine the associations of serum NfL with clinical outcome and the prognostic value of serum NfL after correcting for known prognostic markers included in the modified Erasmus GBS Outcome Score (mEGOS). FINDINGS: NfL levels were tested in serum from 281 patients. Serum NfL dynamics were associated with disease severity and electrophysiological subtype. Strong associations were found between high levels of serum NfL at two weeks and inability to walk unaided at four weeks (OR = 1.74, 95% CI = 1.27-2.45), and high serum NfL levels at four weeks and inability to walk unaided at 26 weeks (OR = 2.79, 95% CI = 1.72-4.90). Baseline serum NfL had the most significant prognostic value for ability to walk, independent of predictors included in the mEGOS. The time to regain ability to walk unaided was significantly longer for patients with highest serum NfL levels at baseline (p = 0.0048) and week 2 (p < 0.0001). No differences in serum NfL were observed between patients that received a second IVIg course vs. IVIg and placebo. INTERPRETATION: Serum NfL levels are associated with disease severity, axonal involvement, and poor outcome in GBS. Serum NfL potentially represents a biomarker to monitor neuronal damage in GBS and an intermediate endpoint to evaluate the effects of treatment. FUNDING: Prinses Beatrix Spierfonds W.OR19-24.

P2X7 receptor antagonists modulate experimental autoimmune neuritis via regulation of NLRP3 inflammasome activation and Th17 and Th1 cell differentiation.

BACKGROUND: Guillain-Barré syndrome (GBS), a post-infectious, immune-mediated, acute demyelinating disease of the peripheral nerves and nerve roots, represents the most prevalent and severe acute paralyzing neuropathy. Purinergic P2X7 receptors (P2X7R) play a crucial role in central nervous system inflammation. However, little is known about their role in the immune-inflammatory response within the peripheral nervous system. METHODS: Initially, we assessed the expression of purinergic P2X7R in the peripheral blood of patients with GBS using flow cytometry and qRT-PCR. Next, we explored the expression of P2 X7R in CD4+ T cells, CD8+ T cells, and macrophages within the sciatic nerves and spleens of rats using immunofluorescence labeling and flow cytometry. The P2X7R antagonist brilliant blue G (BBG) was employed to examine its therapeutic impact on rats with experimental autoimmune neuritis (EAN) induced by immunization with the P0180 - 199 peptide. We analyzed CD4+ T cell differentiation in splenic mononuclear cells using flow cytometry, assessed Th17 cell differentiation in the sciatic nerve through immunofluorescence staining, and examined the expression of pro-inflammatory cytokine mRNA using RT-PCR. Additionally, we performed protein blotting to assess the expression of P2X7R and NLRP3-related inflammatory proteins within the sciatic nerve. Lastly, we utilized flow cytometry and immunofluorescence labeling to examine the expression of NLRP3 on CD4+ T cells in rats with EAN. RESULTS: P2X7R expression was elevated not only in the peripheral blood of patients with GBS but also in rats with EAN. In rats with EAN, inhibiting P2X7R with BBG alleviated neurological symptoms, reduced demyelination, decreased inflammatory cell infiltration of the peripheral nerves, and improved nerve conduction. BBG also limited the production of pro-inflammatory molecules, down-regulated the expression of P2X7R and NLRP3, and suppressed the differentiation of Th1 and Th17 cells, thus protecting against EAN. These effects collectively contribute to modifying the inflammatory environment and enhancing outcomes in EAN rats. CONCLUSIONS: Suppression of P2X7R relieved EAN manifestation by regulating CD4+ T cell differentiation and NLRP3 inflammasome activation. This finding underscores the potential significance of P2X7R as a target for anti-inflammatory treatments, advancing research and management of GBS.

Acute sensorimotor paraneoplastic neuropathy in a patient with small cell prostate cancer.

The authors describe a patient with a background of metastatic small cell prostate cancer who presented with a rapidly evolving sensorimotor neuropathy with bulbar features closely resembling Guillain-Barré syndrome, with a good initial response to intravenous immunoglobulins and platinum-based chemotherapy. This represented a likely paraneoplastic manifestation of the patient's urological malignancy.

Reversible splenial lesion syndrome in patient with acute motor and sensory axonal neuropathy.

Even though the classical clinical concept supports the clear difference between diseases affecting the central and peripheral nervous systems, this difference is becoming less rigid. Here, we report the case of a 50-year-old male patient who presented with acroparaesthesia, headache, and flaccid tetraparesis after febrile diarrhea. Nerve conduction studies indicated action potentials with low amplitudes, which are typical in acute motor and sensory axonal neuropathy. Magnetic resonance revealed a round lesion in the splenium consistent with a diagnosis of reversible splenial lesion syndrome. A polyclonal antiganglioside antibody response was detected. The patient was successfully treated with intravenous immunoglobulins. The coexistence of reversible splenial lesion syndrome and acute motor and sensory axonal neuropathy has not been described in the literature so far. We discuss our diagnostic dilemmas and the possible role of antiganglioside antibodies in the occurrence of simultaneous lesions of the central and peripheral nervous systems.

Guillain-Barré syndrome following primary cytomegalovirus infection in a patient with liver transplantation.

We present the case of a man in his 60s with a 5-month medical history of deceased donor liver transplantation, who developed Guillain-Barré syndrome (GBS) secondary to a primary cytomegalovirus (CMV) infection. This was confirmed by molecular tests and serology antibodies that ruled out other frequent aetiologies. Therapy with intravenous immunoglobulin and valganciclovir was started and the patient gradually improved over the weeks. GBS is the most common aetiology of paralysis worldwide, and it is an autoimmune-mediated neuropathy that is frequently caused by a preceding infection. Few cases of GBS have been reported in the context of liver transplant recipients, and those related to CMV infection are extremely rare. This case highlights the importance of considering GBS as a possible differential diagnosis in patients with solid organ transplantation, and it contributes to the knowledge of other infrequent aetiologies of this condition.

Synergistic effects of immune checkpoints and checkpoint inhibitors in inflammatory neuropathies: Implications and mechanisms.

Immune checkpoint molecules play pivotal roles in the regulation of immune homeostasis. Disruption of the immune checkpoints causes autoimmune/inflammatory as well as malignant disorders. Over the past few years, the immune checkpoint molecules with inhibitory function emerged as potential therapeutic targets in oncological conditions. The inhibition of the function of these molecules by using immune checkpoint inhibitors (ICIs) has brought paradigmatic changes in cancer therapy due to their remarkable clinical benefits, not only in improving the quality of life but also in prolonging the survival time of cancer patients. Unfortunately, the ICIs soon turned out to be a "double-edged sword" as the use of ICIs caused multiple immune-related adverse effects (irAEs). The development of inflammatory neuropathies such as Guillain-Barré syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) as the secondary effects of immunotherapy appeared very challenging as these conditions result in significant and often permanent disability. The underlying mechanism(s) through which ICIs trigger inflammatory neuropathies are currently not known. Compelling evidence suggests autoimmune reaction and/or inflammation as the independent risk mechanism of inflammatory neuropathies. There is a lack of understanding as to whether prior exposure to the risk factors of inflammatory neuropathies, the presence of germline genetic variants in immune function-related genes, genetic variations within immune checkpoint molecules, the existence of autoantibodies, and activated/memory T cells act as determining factors for ICI-induced inflammatory neuropathies. Herein, we highlight the available pieces of evidence, discuss the mechanistic basis, and propose a few testable hypotheses on inflammatory neuropathies as irAEs of immunotherapy.

[Prospect of novel therapies in immune-mediated neuropathies].

The efficacy of immunotherapies such as steroids, plasmapheresis, and intravenous immunoglobulin have been proven in various immune-mediated neuropathies. However, these treatments sometimes lack the efficacy in a part of patients with the immune-mediated neuropathies. In addition, anti-myelin associated glycoprotein (MAG) neuropathy is usually refractory to the treatments. Recently, novel therapies targeting a molecule which are associated with pathogenesis of immune-mediated diseases, have been developed. These molecularly targeted therapies are notable in immune-mediated neuropathies as novel drug candidates. In the present article, current treatments and future prospect of novel therapies in immune-mediated neuropathies will be reviewed.

Guillain-Barré Syndrome.

OBJECTIVE: This article summarizes the clinical features, diagnostic criteria, differential diagnosis, pathogenesis, and prognosis of Guillain-Barré syndrome (GBS), with insights into the current and future diagnostic and therapeutic interventions for this neuromuscular syndrome. LATEST DEVELOPMENTS: GBS is an acute, inflammatory, immune-mediated polyradiculoneuropathy that encompasses many clinical variants and divergent pathogenic mechanisms that lead to axonal, demyelinating, or mixed findings on electrodiagnostic studies. The type of antecedent infection, the development of pathogenic cross-reactive antibodies via molecular mimicry, and the location of the target gangliosides affect the subtype and severity of the illness. The data from the International GBS Outcome Study have highlighted regional variances, provided new and internationally validated prognosis tools that are beneficial for counseling, and introduced a platform for discussion of GBS-related open questions. New research has been undertaken, including research on novel diagnostic and therapeutic biomarkers, which may lead to new therapies. ESSENTIAL POINTS: GBS is among the most frequent life-threatening neuromuscular emergencies in the world. At least 20% of patients with GBS have a poor prognosis and significant residual deficits despite receiving available treatments. Research is ongoing to further understand the pathogenesis of the disorder, find new biomarkers, and develop more effective and specific treatments.

Guillain-Barré syndrome in patients dying with COVID-19 in Italy: a retrospective study.

INTRODUCTION: We presented a four-case series of COVID-19 related deaths occurred in patients with Guillain-Barré syndrome (GBS) between February 2020 and January 2022 in Italy. METHODS: They were extracted from 8,436 medical charts of COVID-19 patients dying. All cases, ranged 48-73 years, showed classical GBS clinical onset - limb weakness, sensory deficits, hypoareflexia - and three of them were admitted in intensive care unit (ICU) for ventilator support. RESULTS: The cerebrospinal fluid showing albumin-cytological dissociation was performed in two cases. Nerve conduction studies supported the diagnosis in all cases. Interstitial pneumonia was documented by chest X-rays or CT scans in all cases: they were treated with intravenous immunoglobulin (IVIg) and the drugs used for COVID-19 infection. CONCLUSIONS: Although the mechanism of GBS onset is still unclear in COVID-19, fatal cases may be more frequent than other virus-related GBS, so that strictly monitoring in high-risk patients could dramatically decrease the mortality of GBS.

Guillain-Barré syndrome as clinical presentation of a recently acquired hepatitis C.

About 40% of the Guillain-Barré syndrome (GBS) cases are associated with prodromal infections; occasionally, it has been associated to chronic hepatitis C or its reactivation. A 38-year-old man came to our attention after transaminase elevation occurred during recovery from GBS. All the possible causes of acute hepatitis were excluded except for the positivity of HCVRNA, and a diagnosis of new onset hepatitis C was made. Recalling patient history, we observed that (i) anti-HCV antibodies were negative and liver enzymes were normal 7 weeks before GBS onset; (ii) in the early stages of ICU admission, liver enzymes started to rise, but the elevation remained mild under steroid treatment; (iii) serum aminotransferase peak occurred 11 weeks after GBS onset; and (iv) HCV RNA was already significantly high when anti-HCV antibodies became positive, consistent with an acute hepatitis. Furthermore, anti-HCV seroconversion was likely delayed or blurred by steroids and immunoglobulin infusions. The interval of time between GBS onset and transaminase elevation compared with the patient clinical history allows us to establish a cause-effect relationship between the two diseases. All patients with GBS should be tested for hepatitis C, or its reactivation if already present, and followed up for an early diagnosis and treatment.

[Guillain-Barré syndrome and its variants: Miller-Fisher syndrome. Description of a clinical case in pediatric age.] / La sindrome di Guillain-Barré e le sue varianti: la sindrome di Miller-Fisher. Descrizione di un caso clinico in età pediatrica.

Miller-Fisher syndrome is a rare acquired nerve disease related to Guillain-Barré syndrome. Clinical features include asthenia, ocular muscle weakness with ophthalmoplegia, impaired limb coordination with instability, and absence of tendon reflexes. Swallowing disorders and rarely respiratory failure may be associated. The article aims to summarize, starting from the presentation of a clinical case, the latest updates which, in clinical practice, can be useful for a correct diagnosis and treatment of this condition which concerns both adult and pediatric patients.

An exploratory international survey of the assessments and interventions used by occupational therapists and physiotherapists during the hospitalization of people with Guillain-Barré syndrome.

Guillain-Barré syndrome is a rare neurological condition. Although some people make a substantial functional recovery, almost half require intensive rehabilitation. Data were collected using a cross-sectional survey which investigated the assessments and interventions used by occupational therapists and physiotherapists for people with Guillain-Barré syndrome. Seventy valid responses were received from 10 countries. The survey highlighted four factors about current practice: (i) practitioners did not identify the use of formal clinical guidelines or protocols for Guillain-Barré Syndrome treatment of the upper limb; (ii) a range of standardized and non-standardized assessment and goal-setting tools are utilized; (iii) interventions include passive and active range of motion exercises, and the prescription of upper limb/hand splints; and (iv) interdisciplinary practice is common in the intensive care unit and during acute phases of Guillain-Barré syndrome, whereas discipline-specific work is more common during rehabilitation. A range of goal-setting and assessment tools are used by occupational therapists and physiotherapists during the hospitalization of people with Guillain-Barré syndrome. The type and duration of interventions vary and may reflect the lack of international protocols for Guillain-Barré syndrome rehabilitation.

Case Report: ICIs-induced Guillain-Barré syndrome recovered from mycophenolate mofetil.

The emergence of immune checkpoint inhibitors (ICIs) has significantly prolonged the survival time of cancer patients. However, it may also lead to various immune-related adverse events (irAEs), including Guillain-Barré syndrome (GBS), a rare type of irAE. Most GBS patients can recover spontaneously due to the self-limited nature of the disease, but severe cases can result in respiratory failure or even death. Here we report a rare case of GBS occurring in a 58-year-old male patient with non-small cell lung cancer (NSCLC) who developed muscle weakness and numbness of the extremities during chemotherapy combined with KN046, a PD-L1/CTLA-4 bispecific antibody. Despite receiving methylprednisolone and γ-globulin, the patient's symptoms did not improve. However, there was significant improvement after treatment with mycophenolate mofetil (MM) capsules, which is not a routine regimen for GBS. To the best of our knowledge, this is the first reported case of ICIs-induced GBS that responded well to mycophenolate mofetil instead of methylprednisolone or γ-globulin. Thus, it provides a new treatment option for patients with ICIs-induced GBS.

Siponimod ameliorates experimental autoimmune neuritis.

BACKGROUND: Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are human autoimmune peripheral neuropathy. Besides humoral immunity, cellular immunity is also believed to contribute to these pathologies, especially CIDP. Sphingosine-1-phosphate receptor 1 (S1PR1) regulates the maturation, migration, and trafficking of lymphocytes. As of date, the therapeutic effect of sphingosine-1-phosphate receptor (S1PR) agonists on patients with GBS or CIDP remains unclear. METHODS: To evaluate the effect of siponimod, an agonist of S1PR1 and S1PR5, on experimental autoimmune neuritis (EAN), an animal model of autoimmune peripheral neuropathy, was used. Lewis rats were immunized with 125 µg of synthetic peptide from bovine P2 protein. Rats in the siponimod group were orally administered 1.0 mg/kg siponimod and those in the EAN group were administrated the vehicle on days 5-27 post-immunization (p.i.) daily. The symptom severity was recorded daily. The changes in the expression of cytokines and transcription factors in the lymph nodes and cauda equina (CE) which correlate with the pathogenesis of EAN and recovery of injured nerve were measured using reverse transcription quantitative PCR. Histological study of CE was also performed. RESULTS: Flaccid paralysis developed on day 11 p.i. in both groups. Siponimod relieved the symptom severity and decreased the expression of interferon-gamma and IL-10 mRNAs in lymph nodes and CE compared with that in the EAN group. The expression of Jun proto-oncogene (c-Jun) mRNA increased from the peak to the recovery phase and that of Sonic hedgehog signaling molecule (Shh) and Glial cell line-derived neurotrophic factor (Gdnf) increased prior to increase in c-Jun with no difference observed between the two groups. Histologically, siponimod also reduced demyelinating lesions and inflammatory cell invasion in CE. CONCLUSIONS: Siponimod has a potential to ameliorate EAN. Shh and Gdnf, as well as C-Jun played a significant role during the recovery of injured nerves.

Two Case Reports of Chronic Inflammatory Demyelinating Polyneuropathy After COVID-19 Vaccination.

The occurrence of chronic inflammatory demyelinating polyneuropathy (CIDP) related to coronavirus disease 2019 (COVID-19) has rarely been reported. We describe two patients who were diagnosed with CIDP after COVID-19 vaccination. A 72-year-old man presented with a progressive tingling sensation and weakness below both knees for two weeks. He had been vaccinated against COVID-19 (mRNA-1273 vaccine) a month before the appearance of symptoms. Demyelinating polyneuropathy was observed in the nerve conduction studies (NCS). Intravenous immunoglobulin (IVIg) was administered under the diagnosis of Guillain-Barré syndrome (GBS), and his symptoms were improved. However, his symptoms relapsed at 10 weeks from the onset. Oral prednisolone, azathioprine, and IVIg were administered as treatment. The second case was a 50-year-old man who complained of a bilateral leg tingling sensation and gait disturbance lasting four weeks. He had received the Ad26.COV2.S vaccine against COVID-19 five weeks prior. Demyelinating polyneuropathy was observed in the NCS. He was treated with oral prednisolone, azathioprine, and IVIg for CIDP because his symptoms had lasted for more than 12 weeks from the onset. A causal relationship has not been established between COVID-19 vaccination and CIDP; however, CIDP may follow COVID-19 vaccination. As CIDP treatment is different from that for GBS, clinicians should closely monitor patients diagnosed with GBS associated with COVID-19 whether they deteriorate after initial treatment.

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.

REFRACTORY GUILLAIN-BARRÉ SYNDROME IN A PATIENT WITH ASYMPTOMATIC MULTIPLE MYELOMA SUCCESSFULLY TREATED WITH LOW-DOSE RITUXIMAB.

Despite being extremely rare, Guillain-Barré syndrome (GBS) has been recognized as a neurological complication of multiple myeloma, with variable responses to plasmapheresis (PEX), intravenous immunoglobulins (IVIG), and anti-myeloma therapies. In this paper, we report a case of a female patient with asymptomatic multiple myeloma (aMM) who initially presented as PEX- and IVIG-refractory GBS. After failure of PEX, IVIG, and anti-myeloma therapy (bortezomib, melphalan, and prednisone), the patient was eventually successfully treated with low-dose rituximab (100 mg/m2 per week in four doses). To the best of our knowledge, this is the first case to report successful treatment of refractory GBS potentially associated to aMM with low-dose rituximab. Additional studies are needed to elucidate the pathophysiological processes and the interplay between the dysregulated immune response, monoclonal immunoglobulin (MG), and neural tissue damage in GBS patients. Also, the potential role of rituximab in the treatment of MG-associated GBS warrants further exploration.

Long-term outcomes of plasma exchange versus intravenous immunoglobulin for the treatment of Guillain-Barré Syndrome: A double-blind, randomized clinical trial.

Background: Most previous studies comparing the effectiveness of Plasma Exchange (PE) or intravenous immunoglobulin (IVIG) in treating Guillain-Barre syndrome (GBS) have focused on the short-term outcome at around 1 month. Objective: To compare the long-term efficacy of PE and IVIG at one year in adult patients with GBS. Methods: Eighty-one adult patients with acute GBS were randomized into two groups with a ratio of 2 : 1: PE (N = 54) and IVIG (N = 27). Patients were assessed with the Medical Research Council sum score (MRC sum score), GBS Disability Scale (GDS), and Functional assessment of acute inflammatory neuropathy (FAAIN) at baseline, ten days, one month, three months, and one year. Neurophysiological examinations were performed at baseline and three months following treatment. Results: There were no significant differences between groups in demographic, clinical, and laboratory data. Both treatments produced a significant improvement in all clinical rating scales in both groups that continued up to one year. There were significant differences in the time course of recovery in the MRC and FAAIN scales, with significantly more improvement in the IVIG group at 1 and 3 months, although there was no significant difference in outcome at one year. However the effect size showed measurable differences between the PE and IVIG groups across the different measures at one-year. Electrophysiological studies showed equal improvement in most measures in both groups at three months, with a slightly greater effect in the IVIG group. Conclusion: long term outcomes of IVIG and PE were equivalent. However the effect size showed measurable differences between the PE and IVIG groups across the different measures at one-year follow-up that indicate the superiorty of IVIG. There was also a tendency for improvement to be slightly faster in the IVIG group.