Beyond T cell toxicity - Intrathecal chemokine CXCL13 indicating B cell involvement in immune-related adverse events following checkpoint inhibition: A two-case series and literature review.

BACKGROUND AND PURPOSE: This study was undertaken to raise awareness of a role of B cells in immune checkpoint inhibitor (ICI)-associated neurological immune-related adverse events (nirAE). METHODS: A systematic literature review was made, with case observations of a melanoma and a non-small cell lung cancer (NSCLC) patient who developed ICI-associated nirAE with cerebrospinal fluid (CSF) findings indicating B cell involvement. RESULTS: Two patients receiving ipilimumab/nivolumab for melanoma and chemotherapy/pembrolizumab for NSCLC developed nirAE in the form of myocarditis/myositis/myasthenia gravis overlap syndrome (triple M) and cerebellitis plus longitudinal transverse myelitis (c-LETM), respectively. Intrathecal inflammation with chemokine C-X-C motif ligand (CXCL13) elevation was present in both patients; the triple M case had acetylcholine receptor antibodies, antititin reactivity, altered CD4/CD8 T cell ratio in blood, and depressed programmed death-1 (PD-1) expression on CSF T cells; the c-LETM case showed intrathecal antibody production and plasma cells. Both patients insufficiently responded to first-line treatment. The NSCLC case improved upon administration of B cell-depleting therapy with rituximab, whereas the melanoma patient died before escalation therapy was initiated. Literature research revealed one additional ICI-associated LETM case with intrathecal CXCL13 elevation, three cases with ICI-associated aquaporin-4 antibody neuromyelitis spectrum disorder, and evidence of B cell-mediated toxicity based on antibody-mediated immune pathologies in ICI-associated immune-related adverse events. CONCLUSIONS: The case observations highlight the plethora of uncertainties in diagnosis and treatment of ICI-associated nirAE, exemplify the heterogeneity of immune mechanisms involved, and suggest a role of B cells, which may be underdiagnosed. Intrathecal CXCL13 may serve as a biomarker of B cell involvement in nirAE, supported by intrathecal immunoglobulin synthesis, presence of plasma cells, and/or recruitment of cognate immune cells.

Neurological sequelae of vaccines.

IMPORTANCE: Vaccines are a safe and efficacious way to prevent a variety of infectious diseases. Over the course of their existence, vaccines have prevented immeasurable morbidity and mortality in humans. Typical symptoms of systemic immune activation are common after vaccines and may include local soreness, myalgias, nausea, and malaise. In the vast majority of cases, the severity of the infectious disease outweighs the risk of mild adverse reactions to vaccines. Rarely, vaccines may be associated with neurological sequela that ranges in severity from headache to transverse myelitis, acute disseminated encephalomyelitis, and Guillain-Barre syndrome (GBS). Often, a causal link cannot be confirmed, and it remains unclear if disease onset is directly related to a recent vaccination. OBSERVATIONS: This review serves to summarize reported neurologic sequelae of commonly used vaccines. It will also serve to discuss potential pathogenesis. It is important to note that many adverse events or reactions to vaccines are self-reported into databases, and causal proof cannot be obtained. CONCLUSIONS AND RELEVANCE: Recognition of reported adverse effects of vaccines plays an important role in public health and education. Early identification of these symptoms can allow for rapid diagnosis and potential treatment. Vaccines are a safe option for prevention of infectious diseases.

Fampridine in multiple sclerosis patients with acute phase of cervical transverse myelitis: a double-blind, randomized placebo-controlled trial.

BACKGROUND: Fampridine is a potassium channel blocker drug used to improve walking ability in patients with multiple sclerosis (MS). We evaluated the effect of fampridine in patients with MS in the acute phase of transverse myelitis. METHODS: In a randomized, placebo-controlled trial, 30 patients who had their first episode of cervical myelitis with quadriparesis presentation, with the final diagnosis of MS, were randomly divided into two equal groups. The intervention group received intravenous methylprednisolone (IVMP) for 7 days plus fampridine. The placebo group received IVMP for 7 days plus placebo. To compare the treatment results, we compared the Barthel index (BI) scores of the groups at the start of the trial and the 21st day after the start of treatment. RESULTS: There was no significant difference in baseline characteristics between the intervention and placebo groups in terms of mean age, sex, and mean admission BI (p > 0.05). Mean (SD) admission BI in placebo and intervention groups was 27.20 (7.341) and 27.87(5.78), respectively (p = 0.784). The measured mean (SD) BI after treatment was 48.73 (15.54) in the placebo and 64.93 (11.81) in the intervention group (p = 0.003) after 3 weeks. CONCLUSION: Using fampridine plus IVMP in the acute phase of transverse myelitis in MS patients improved the disease's symptoms and increased the daily activity ability of patients.

A case report of longitudinal extensive transverse myelitis: immunotherapy related adverse effect vs. COVID-19 related immunization complications.

Background: Transverse myelitis (TM) is a rare, acquired neuro-immunological spinal cord disorder that occurs with rapid onset of motor weakness, sensory deficits with bowel and bladder dysfunction. Patients being treated with immune checkpoint inhibitors (ICIs) for advanced malignancy have a known higher propensity of developing neuro immune complications. With the advent of COVID-19 pandemic there have been reported cases of TM with COVID-19 immunization. The reported infrequency of TM with both of the aforementioned causes makes delineation of the etiology challenging.Methods: We present a patient with metastatic small cell lung cancer (SCLC) on maintenance Atezolizumab immunotherapy who developed longitudinal extensive transverse myelitis (LETM) after administration of second dose of COVID-19 mRNA vaccine one day prior to presenting symptoms of acute paralysis of the lower extremity, sensory loss from chest down with overflow incontinence. A clinical diagnosis of myelopathy was supported by MRI of the spine illustrating enhancing lesions from C7-T7 concerning for LETM.Results: A 5-day course of pulsed methylprednisolone followed by therapeutic plasma exchange for 3 days resulted in only minimal improvement in the neurologic exam with increased strength in his lower extremities while the sensory level remained unchanged.Conclusions: This case demonstrates the complication and symptomatology of TM in the setting of anti-PD-L1 monoclonal antibody with coincidental COVID-19 mRNA vaccine administration. The causal relationship between the vaccine and LETM is difficult to establish. However, the presence of a known inciting factor hints at a possible exaggeration of the existing neuro-inflammatory process.

MOG-antibody-associated longitudinal extensive myelitis after ChAdOx1 nCoV-19 vaccination.

This case report describes a 59-year-old man with myelin oligodendrocyte glycoprotein (MOG)-positive longitudinal extensive transverse myelitis (LETM) after being vaccinated with the COVID-19 vaccine ChAdOx1 nCoV-19. He presented with urinary retention, gait disturbance, hypoesthesia and brisk reflexes in his lower extremities without paresis. Due to the ineffectiveness of high-dose intravenous methylprednisolone, therapeutic plasma exchange was performed, gradually improving the patient's condition. Vaccination as a trigger for an excessive immunological response seems plausible, though unspecific for the ChAdOx1 nCoV-19 vaccine.

Longitudinal extensive transverse myelitis after chemoradiation therapy with durvalumab, a rare complication: case report.

BACKGROUND: Longitudinal extensive transverse myelitis is a rare and potentially life-threatening complication of chemoradiation. Certain chemotherapy agents have been proposed to increased neurotoxicity with chemoradiation therapy. One such agent is durvalumab, a human IgG1 monoclonal antibody that blocks programmed death ligand 1, allowing T-cells to recognize and kill tumor cells. Durvalumab and other immune checkpoint inhibitors may also cause transverse myelitis without concomitant treatment with radiation. Durvalumab is a standard therapy for non-small cell lung carcinoma. Here we present a case of a 68-year-old male who presented after chemoradiation and durvalumab therapy with transverse myelitis extending outside the irradiation site. CASE PRESENTATION: A 68-year-old male presented to the emergency department with pain and weakness in his feet and hesitancy of urination. Medical history is significant for non-small cell lung cancer treated with chemoradiotherapy and consolidation therapy with durvalumab for one year. His last radiation treatment was 15 months prior, and his last infusion of durvalumab was 3 months prior. Exam revealed severe weakness of bilateral legs with absent vibration sensation. MRI showed central longitudinal extensive transverse myelitis extending from C4-T11. CSF studies showed 8 WBC with 63% lymphocyte predominance and a protein of 48. Oligoclonal bands and angiotensin-converting enzyme were negative. Serum Neuromyelitis Optica antibody (AQP4-IgG) and Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) were negative. Infectious workup came back negative. The patient was treated with steroids and plasma exchange with mild improvement. Etiology remained unknown, but longitudinal extensive transverse myelitis following durvalumab chemoradiotherapy was thought to be the likely cause. He was discharged on a high-dose prednisone taper with outpatient follow-up. His condition worsened near the end of the steroid taper. High-dose prednisone and cyclophosphamide infusions were started with mild improvement and stabilization of the patient's condition. He transitioned to methotrexate after completion of six cyclophosphamide infusions. The patient expired due to complications from his cancer. CONCLUSION: Longitudinal extensive transverse myelitis is a rare and potentially life-threatening complication of durvalumab therapy. As durvalumab has become a standard treatment for non-small cell lung cancer, it is important to be able to identify and treat side effects.

Severe disease exacerbation after mRNA COVID-19 vaccination unmasks suspected multiple sclerosis as neuromyelitis optica spectrum disorder: a case report.

BACKGROUND: Since the beginning of the COVID-19 pandemic and development of new vaccines, the issue of post-vaccination exacerbation or manifestation of demyelinating central nervous system (CNS) disorders has gained increasing attention. CASE PRESENTATION: We present a case of a 68-year-old woman previously diagnosed with multiple sclerosis (MS) since the 1980s who suffered a rapidly progressive severe sensorimotor paraparesis with loss of bladder and bowel control due to an acute longitudinal extensive transverse myelitis (LETM) after immunization with the mRNA Pfizer-BioNTech COVID-19 vaccine. Detection of Aquaporin-4-antibodies (AQP4) in both serum and CSF led to diagnosis of AQP4-antibody positive neuromyelitis optica spectrum disorder (NMOSD). Treatment with intravenous corticosteroids and plasmapheresis led to a slight improvement of the patient's symptoms. CONCLUSIONS: Pathogenic mechanisms of post-vaccination occurrence of NMOSD are still unknown. However, cases like this should make aware of rare neurological disorders manifesting after vaccination and potentially contribute to improvement of management of vaccinating patients with inflammatory CNS disorders in the future. So far two cases of AQP4-antibody positive NMOSD have been reported in association with viral vector COVID-19 vaccines. To our knowledge, we report the first case of AQP4-antibody positive NMOSD after immunization with an mRNA COVID-19-vaccine.

Longitudinal extensive transverse myelitis following ChAdOx1 nCOV-19 vaccine: a case report.

BACKGROUND: Transverse myelitis (TM) is a relatively uncommon condition, and vaccine-associated myelitis is even rarer. Concern regarding neurological complications following vaccination escalated following the report of TM during the safety and efficacy trials of the COVID-19 vaccine. CASE PRESENTATION: We report the first case of Longitudinal Extensive Transverse Myelitis (LETM) in Malaysia following administration of the chimpanzee adenovirus-vectored (ChAdOx1 nCoV-19) vaccine. A 25-year-old female presented with bilateral lower limb weakness and inability to walk with a sensory level up to T8 with absent visual symptoms. Urgent gadolinium-enhanced magnetic resonance imaging (MRI) of the spine showed long segment TM over the thoracic region. Cerebrospinal fluid autoantibodies for anti-aquaporin-4 and anti-myelin-oligodendrocyte were negative. A diagnosis of LETM following vaccination was made, and the patient was started on a high dose of intravenous methylprednisolone. The patient eventually made a recovery following treatment. CONCLUSION: LETM is a rare but serious adverse reaction following vaccination. Previously reported cases showed an onset of symptoms between 10 to 14 days post-vaccination, suggesting a delayed immunogenic reaction. However, the incidence of myelitis in COVID-19 is much more common, far greater than the risk associated with vaccination.

No laughing matter - Myeloneuropathy due to heavy chronic nitrous oxide abuse.

Chronic nitrous oxide abuse is a known cause of myeloneuropathy. Nitrous oxide irreversibly inactivates vitamin B12 causing demyelination of the dorsal spinal columns, clinically indistinguishable from that which is caused by vitamin B12 deficiency. We report a 37-year-old female who presented with ataxia, loss of lower extremity proprioception, demyelination of her cervical dorsal spinal columns, and other laboratory and physical exam findings consistent with nitrous oxide abuse. The patient reported daily use in excess of 500 nitrous oxide cartridges, also known as "whippits". Nitrous oxide myeloneuropathy should be included in the differential diagnoses for emergency medicine physicians when evaluating a patient with bilateral neurologic deficits and ataxia.

Acute Transverse Myelitis after COVID-19 Vaccination.

The adverse effects of the COVID-19 vaccine have been discovered as the rapid application of the vaccines continues. Neurological complications such as transverse myelitis raise concerns as cases were observed in clinical trials. Transverse myelitis is a rare immune-mediated disease with spinal cord neural injury, resulting in neurological deficits in the motor, sensory, and autonomic system. Vaccine-related transverse myelitis is even rarer. We present a case of acute transverse myelitis after vaccination against COVID-19 with the ChAdOx1 nCOV-19 vaccine (AZD1222), which was the first case reported in Taiwan. Although it rarely occurs, post-vaccination neurological complications should not be ignored. As the pandemic of SARS-CoV-2 continues to spread and concern about vaccination efficacy and safety rises, heterologous vaccination were implemented in health public policy in several countries. A literature review of several clinical trials shows promising effects of mix-and-match vaccination. Further study on different combinations of vaccines can be expected.

Acute transverse myelitis after inactivated COVID-19 vaccine.

Vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been rapidly developed to prevent coronavirus disease 2019 (COVID-19) pandemic. There is increasing safety concerns regarding COVID-19 vaccines. We report a 78-year old woman who was presented with tetraparesis, paresthesias of bilateral upper extremities, and urinary retention of one-day duration. Three weeks before these symptoms, she was vaccinated with CoronaVAC vaccine (Sinovac Life Sciences, China). Spine magnetic resonance imaging showed longitudinally extensive transverse myelitis (TM) from the C1 to the T3 spinal cord segment. An extensive diagnostic workup was performed to exclude other possible causes of TM. We suggest that longitudinally extensive TM may be associated with COVID-19 vaccination in this case. To the best of our knowledge, this is the first report of longitudinally extensive TM developing after CoronaVac vaccination. Clinicians should be aware of neurological symptoms after vaccination of COVID-19.

Acute paraparesis in HIV-infected patient after initiation of highly active antiretroviral therapy.

Neurological syndromes occur in around 40-70% of HIV-infected people. Direct central nervous system involvement by the virus usually manifests as HIV encephalitis, HIV leucoencephalopathy, vacuolar leucoencephalopathy or vacuolar myelopathy. Indirect involvement is usually associated with neurotropic opportunistic infections which include tuberculosis, toxoplasmosis, cryptococcosis and viral encephalitis such as herpes simplex, varicella-zoster, cytomegalovirus and Human polyomavirus 2. We report a case of transverse myelitis in a recently diagnosed HIV patient who was otherwise asymptomatic initially and developed paraparesis after 1 month of initiation of antiretroviral therapy. After ruling out opportunistic infections and other causes of compressive and non-compressive myelopathy, development of transverse myelitis was attributed to immune reconstitution inflammatory syndrome in view of baseline low CD4 count and their improvement after HAART initiation. Prompt treatment with corticosteroids successfully reversed the symptoms.

Transverse myelitis as an unexpected complication following treatment with dinutuximab in pediatric patients with high-risk neuroblastoma: A case series.

Immunotherapy with the anti-GD2 monoclonal antibody ch14.18, or dinutuximab, represents an important therapeutic advance in the treatment of pediatric high-risk neuroblastoma and is now considered part of standard of care in this patient population. To date, transverse myelitis as a result of dinutuximab therapy has not been reported in clinical trials or in the published literature. We describe three patients with clinical symptoms of transverse myelitis, confirmed via magnetic resonance imaging, shortly following initiation of dinutuximab. All patients were discontinued from dinutuximab treatment and received urgent treatment, with rapid improvement in symptoms and resultant functional recovery.

Transverse myelitis following methotrexate treatment of ectopic pregnancy: a case report.

OBJECTIVE: Ectopic pregnancy is a common condition in the field of gynaecology, often treated with methotrexate. Adverse effects are common and usually mild. Severe adverse events are rare amongst patients treated with MTX for this condition. CASE: A 26-year-old healthy woman was admitted and treated medically with MTX for an ectopic pregnancy. The patient was treated in the standard drug labelled protocol with an intramuscular injection of 78 mg of MTX according to body surface area. Soon after, the patient presented to the emergency department with symptoms of bilateral paresthesia of the lower limbs which ascended to the pelvis. After a thorough work up and imaging via MRI a diagnosis of transverse myelitis was made. Treatment was successful with corticosteroids and symptoms subsided. CONCLUSIONS: We propose that MTX should be used with caution and severe toxicity should be kept in mind with high index of awareness for any symptom development following treatment, especially neurological one.

Acute Transverse Myelitis and Nicolau Syndrome after Benzathine Penicillin Injection.

Rare complications have been documented due to inadvertent intravascular administration of penicillin such as Nicolau syndrome (lipoatrophy), transverse myelitis, injury to sciatic nerve as well as Hoigne syndrome (transient central nervous system dysfunction).1 We present a case report where a young male developed Nicolau syndrome and transverse myelitis after receiving benzathine penicillin injection.

Clinical characteristics, radiological features and prognostic factors of transverse myelitis following COVID-19 vaccination: A systematic review.

BACKGROUND: Since introducing COVID-19 vaccines, many neurological complications such as acute transverse myelitis have been reported in the literature. This study aims to identify the clinical characteristics, radiological findings, and prognostic factors in patients with COVID-19 vaccine-associated transverse myelitis (TM). METHODS: We systematically reviewed Scopus, Pubmed, Cochrane library, Google Scholar, and preprint databases using appropriate keywords from inception till 8th April 2022. Besides, we manually searched the reference lists of the included studies and relevant previous reviews. RESULTS: We included 28 studies identifying 31 post-COVID-19 vaccination myelitis patients (17 female and 14 male). The mean age of the included patients was 52±19 years. ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca) was the most common type of vaccine in association with myelitis (12 out of 31), followed by Pfizer (8 out of 31), Moderna (7 out of 31), Sinopharm (3 out of 31), and Janssen vaccine (1 out of 31). The myelitis occurred in 24 and 7 patients after administering the first and second dose of the vaccine, respectively. 21 and 10 patients had good recovery (Modified Rankin Score (MRS) <3 at the follow-up) and poor recovery (MRS≥3 at the follow-up) from myelitis, respectively. Age (OR 1.09, 95%CI 1.01-1.18, pvalue 0.02), and MRS at admission (OR 17.67, 95%CI 1.46-213.76, pvalue 0.024) were two independent risk factors for poor recovery from myelitis. CONCLUSION: The patients with higher age and MRS at admission had a worse prognosis and needed timely and more aggressive therapeutic strategies.

A case report of possible concurrent vasculitis in vertebral bodies and partial transverse myelitis following COVID-19 vaccination.

INTRODUCTION: Cases with organ-specific and systemic vasculitis associated with corona virus disease 2019 (COVID-19) vaccination have been reported. However, acute partial transverse myelitis (APTM) is rare adverse events following received COVID-19 vaccines. To the best of our knowledge, there is no report on vaccine-associated APTM accompanied by possible concurrent vasculitis. Herein we present a case with possible concurrent spinal vasculitis and APTM following the second dose of inactivated COVID-19 vaccine. CASE SUMMARY: A 33-year-old man presented with weakness of left lower limb and aberrant sensation of his left lower trunk and limb (from T9 level to toes) for 2 days following receipt of an inactivated COVID-19 vaccine. Remarkable demyelinating lesion at T7 spinal cord was showed by 3.0T magnetic resonance imaging (MRI) scan. Moreover, vertebral bodies of T3-T7 also presented high signal in T-2 weighted imaging (T2WI) accompanied by multiple sites of flowing void effect indicating possible vasculitis. Oligoclonal band was positive in cerebrospinal fluid (CSF) while it was negative in sera. Intravenous methylprednisolone (1 g/d) was administrated for 5 days followed by subsequent dose-tapering prednisone. His limb weakness and aberrant sensation both improved and he was able to walk unaided after treatment. The MRI recheck also showed remarkable improvement on the lesions in spinal cord and vertebral bodies. CONCLUSION: this case illustrates the concurrence of possible vasculitis in vertebral bodies and acute transverse myelitis (ATM) following COVID-19 vaccination.