Liver Cancer with Overlapping Myasthenia Gravis, Myocarditis, Seronegative Autoimmune Autonomic Ganglionopathy, and Myositis Symptoms Induced by Atezolizumab.

An 83-year-old man with hepatocellular carcinoma developed muscle weakness, ptosis, and dyspnea 3 weeks after receiving atezolizumab. Soon after, mechanical ventilation was initiated, which was followed by marked blood pressure spikes. The levels of creatine kinase and troponin-I were significantly elevated, and acetylcholine receptor antibodies were positive. The patient was diagnosed with immune checkpoint inhibitor (ICI)-induced myositis, myasthenia gravis (MG), myocarditis, and suspected autoimmune autonomic ganglionopathy (AAG). After immunotherapy, the serum markers and blood pressure normalized, and he was weaned from the ventilator after five months. To our knowledge, this is the first reported case of AAG secondary to ICI-induced myositis, MG, and myocarditis.

Anticonvulsive treatment in autoimmune encephalitis: a systematic literature review.

BACKGROUND: Epileptic seizures are a common manifestation of autoimmune encephalitis (AIE). Immunosuppression (IT) is an efficient therapeutic approach, particularly in AIE associated with antibodies against extracellular structures. The role of antiseizure medication (ASM) is less clear. However, it may be beneficial in disease refractory to IT or in chronic post-AIE epilepsy. METHODS: We conducted a systematic review assessing the PubMed and Cochrane databases to identify all reports on patients with epileptic seizures due to AIE in whom ASM was used and report it according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. We included case series (minimum 3 eligible patients), retrospective and prospective observational studies, and randomized controlled trials. The main outcome assessed was therapeutic efficacy of ASM. Secondary outcomes comprise number, type, and adverse effects of ASM. Descriptive statistics were used. The level of evidence was assessed according to the Centre for Evidence-Based Medicine. RESULTS: We screened a total of 3371 studies and included 30 (7 prospective, 23 retrospective). The reports cover a total of 708 patients, the majority (72.5%) suffering from AIE with antibodies against extracellular structures. Type of AIE, seizure frequency, and number and type of ASM used were heterogenous. While most patients profited from IT and/or ASM, the effect of ASM could rarely be isolated. Nine studies report on patients who received ASM monotherapy or were on ASM for a relevant length of time before IT initiation or after IT failure. One study reports a significant association between seizure freedom and use of sodium channel inhibitors. However, levels of evidence were generally low. CONCLUSION: Few robust data exist on the particular efficacy of ASM in autoimmune epileptic seizures. While these patients generally seem to respond less well to ASM or surgical interventions, sodium channel blockers may have an additional benefit compared to other substances. However, levels of evidence are low and early IT remains the mainstay of AIE therapy. Future trials should address optimal ASM selection and dosing in AIE.

Immune checkpoint inhibitor-induced autoimmune encephalitis in metastatic squamous cell lung cancer.

Because of their efficacy in improving prognosis, immune checkpoint inhibitors (ICIs) are widely used in patients with non-small-cell lung cancer. However, approximately half of patients experience immune-related adverse events, including autoimmune encephalitis, during treatment. Herein the authors present a case of ICI-associated autoimmune encephalitis, resulted in a favorable prognosis after treatment with intravenous immunoglobulin and methylprednisolone. The authors also review the literature regarding ICI-associated autoimmune encephalitis and summarize the clinical features, treatment strategies and prognostic outcomes in patients with non-small-cell lung cancer. The present case suggested that early detection of autoimmune encephalitis might be significant for the management of severe adverse events in patients exposed to ICIs.

Immune checkpoint inhibitors are considered the treatment of choice for patients with lung cancer. However, some rare adverse events are easily overlooked. Herein in the present case, the authors describe a patient developing with autoimmune encephalitis after the exposure to immune checkpoint inhibitors. Finally the patient has achieved a satisfactory outcome after timely treatment. The authors consider that early detection of autoimmune encephalitis might be significant to deal with the rare and severe toxicity.

Metabotropic glutamate receptor 5-related autoimmune encephalitis with reversible splenial lesion syndrome following SARS-CoV-2 vaccination.

RATIONALE: Metabotropic glutamate receptor 5 (mGluR5)-related autoimmune encephalitis (AE) has been rarely reported; however, there are no reports on mGluR5-related AE with reversible splenial lesion syndrome following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PATIENT CONCERNS: A 29-year-old man was admitted with a history of headache and fever for 9 days and 6 days, respectively. DIAGNOSIS: He was initially diagnosed with an intracranial infection, however the final diagnosis was corrected as anti-mGluR5-related AE with reversible splenial lesion syndrome. INTERVENTIONS: He had received an inactivated SARS-CoV-2 vaccine 3 weeks prior to the examination and was initially diagnosed with an intracranial infection. Physical examination revealed bilateral horizontal nystagmus, ataxia, and neck rigidity. Antiinfective therapy was minimally helpful. An analysis of the cerebrospinal fluid did not reveal pathogens for sequencing. Magnetic resonance imaging displayed abnormal signals in the splenium of the corpus callosum. OUTCOMES: We identified mGluR5 antibodies in the cerebrospinal fluid and serum. Subsequently, intravenous methylprednisolone pulse and gamma-globulin pulse therapies were administered, which substantially improved the symptoms. Follow-up did not reveal abnormal neurological symptoms, and the lesion in the corpus callosum had resolved. LESSONS: AE with mGluR5 antibodies could arise from SARS-CoV-2 vaccination, which warrants the awareness of healthcare workers. Reversible splenial lesion syndrome may accompany mGluR5-related AE and mimic intracranial infection. Thus, early treatment can prevent serious residual signs and symptoms.

IgG4-related autoimmune manifestations in Alemtuzumab-treated multiple sclerosis patients.

We aimed to determine whether Alemtuzumab-induced immune reconstitution affects immunoglobulin and complement levels in the serum of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. IgG4-levels were increased 24-months after treatment initiation compared to baseline levels in twenty-nine patients. Alemtuzumab-treated patients with the highest IgG4-levels were more prone to thyroid-related autoimmune manifestations and specific autoimmune adverse events such as Crohn's disease, Graves' disease, and hemolytic anemia. Compared to baseline, total IgG-levels showed a trend towards reduced levels following two-courses of Alemtuzumab, but no significant change of C3 and/or C4-levels was observed. In conclusion, monitoring of IgG4-levels can serve as a marker for secondary autoimmunity risk in multiple sclerosis patients treated with Alemtuzumab.

HLA-B27 association of autoimmune encephalitis induced by PD-L1 inhibitor.

OBJECTIVE: While immune checkpoint inhibitors are increasingly used for various cancers, unpredictable immune-related adverse events (irAEs) such as autoimmune encephalitis is life-threatening. Here, we report an association between human leukocyte antigen (HLA) and atezolizumab-induced encephalitis. METHODS: From an institutional prospective cohort for encephalitis, we identified patients with autoimmune encephalitis after the use of atezolizumab, a PD-L1 (programmed death-ligand 1) inhibitor, from August 2016 to September 2019 and analyzed their HLA genotypes. RESULTS: A total of 290 patients received atezolizumab, and seven patients developed autoimmune encephalitis, and five of whom were enrolled for the analysis. The patients presented altered mentality, seizures, or myelitis. Three patients had the HLA-B*27:05 genotype in common (60%), which is significantly frequent given its low frequency in the general population (2.5%). After Bonferroni correction, HLA-B*27:05 was significantly associated with autoimmune encephalitis by atezolizumab (corrected P < 0.001, odds ratio 59, 95% CI = 9.0 ~ 386.9). INTERPRETATION: Here we found that three in five patients with autoimmune encephalitis associated with atezolizumab had the rare HLA-B*27:05 genotype. Further systematic analyses in larger cohorts are necessary to investigate the value of HLA screening to prevent the life-threatening adverse events.

Seronegative autoimmune autonomic ganglionopathy from dual immune checkpoint inhibition in a patient with metastatic melanoma.

BACKGROUND: Immune checkpoint inhibitors have improved clinical outcomes including survival in several malignancies but have also been associated with a range of immune-related adverse events (irAEs). Neurological irAEs are rare compared to the more typical skin, gastrointestinal, and endocrine toxicities, and are often underrecognized and challenging to diagnose. Here, we report a case of seronegative autoimmune autonomic ganglionopathy (AAG) induced by dual immune checkpoint inhibitor therapy (ICI) in a patient with metastatic melanoma. CASE PRESENTATION: A patient with metastatic melanoma was treated with ipilimumab and nivolumab. He developed a constellation of new symptoms including nausea, fatigue, and severe orthostatic hypotension refractory to fluid resuscitation. An infectious, cardiac, neurologic, and endocrine workup were unrevealing. Cardiovascular autonomic testing revealed poor sympathetic nervous system responses. He was diagnosed with seronegative AAG and significantly improved with immunomodulatory therapies including IVIG and steroids as well as varying doses of midodrine and fludrocortisone. He was able to restart nivolumab without recurrence of his symptoms. However, the AAG reoccurred when he was re-challenged with ipilimumab and nivolumab due to disease progression. While the AAG was manageable with steroids at that time, unfortunately his melanoma became resistant to ICI. CONCLUSIONS: Immune checkpoint inhibitors can have a wide range of unusual, rare irAEs, including neurotoxicity such as AAG. Clinicians should maintain suspicion for this toxicity so that treatment can be rapidly provided to avoid disability.

Brain microglia activation induced by intracranial administration of oligonucleotides and its pharmacological modulation.

Oligonucleotide overloading results in type I interferonopathies such as the Aicardi-Goutiéres Syndrome, a progressive encephalopathy determined by an immune response against endogenous DNA/RNA molecules. No therapy targeting pathogenic mechanisms is available for affected patients. Accordingly, we set up an in vitro/in vivo experimental model aimed at reproducing the pathogenic mechanisms of type I interferonopathies, in order to develop an effective pharmacological modulation and toxicological alterations caused by intracranial delivery of encapsulated CpG. The in vitro model used Aicardi-Goutiéres Syndrome immortalized lymphocytes activated by interferon I and co-cultured with human astrocytes; lymphocyte neurotoxicity was attenuated by the calcineurin-inhibitor Tacrolimus and by the anti-interferon monoclonal antibody Sifalimumab. The in vivo model was set up in mice by subcutaneous injection of encapsulated CpG oligonucleotides; the immune-stimulating activity was demonstrated by cytometric analysis in the spleen. To mime pathogenesis of type I interferonopathies in the central nervous system, CpG oligonucleotides were administered intracranially in mice. In the brain, CpG overload induced a rapid activation of macrophage-like microglial cells and focal accumulation mononuclear cells. The subcutaneous administration of Tacrolimus and, more potently, Sifalimumab attenuated CpG-induced brain alterations. These findings shed light on molecular mechanisms triggered by oligonucleotides to induce brain damage. Monoclonal antibodies inhibiting interferon seem a promising therapeutic strategy to protect brain in type I interferonopathies.

Autoimmune Movement Disorders in Children.

Over the last decade, there have been significant advances in the identification, characterization, and treatment of autoimmune neurologic disorders in children. Many of these diseases include a typical movement disorder that can be a powerful aid to diagnosis. Frequently, movement disorders in autoimmune conditions are the sole or among a few presenting symptoms, allowing for earlier diagnosis of an underlying malignancy or systemic autoimmune disease. Given that early detection and treatment with immunotherapy may confer improved outcomes, recognizing these patterns of abnormal movements is essential for child neurologists. The purpose of this review is to summarize the clinical characteristics, diagnosis, and treatment of movement disorders that occur in pediatric autoimmune disorders.

Neurological Adverse Events Associated with Immune Checkpoint Inhibitors: Diagnosis and Management.

PURPOSE OF REVIEW: Immune checkpoint inhibitors represent a major step forward in the field of oncologic immunotherapy these last years and have significantly increased survival of cancer patients in an ever-growing number of indications. These agents block specific immune checkpoint molecules (programmed cell death protein 1 and its ligand as well as cytotoxic T-lymphocyte-associated antigen 4) that normally downregulate the immune response. These new agents show a specific range of adverse effects induced by abnormal immunologic activation. RECENT FINDINGS: Many different neurologic adverse events have been described, including encephalitis, myelopathy, aseptic meningitis, meningoradiculitis, Guillain-Barré-like syndrome, peripheral neuropathy (including mononeuropathy, mononeuritis multiplex, and polyneuropathy) as well as myasthenic syndrome. Immune checkpoint inhibitors have shown promising results in cancer but can possibly induce autoimmune disorders. Although rare, neurological adverse events require prompt recognition and treatment to avoid substantial morbidity.

Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives.

Cancer treatment strategies based on immune stimulation have recently entered the clinical arena, with unprecedented success. Immune checkpoint inhibitors (ICIs) work by indiscriminately promoting immune responses, which target tumour-associated antigens or tumour-specific mutations. However, the augmented immune response, most notably the T cell response, can cause either direct neurotoxicity or, more commonly, indirect neurotoxic effects through systemic or local inflammatory mechanisms or autoimmune mechanisms. Consequently, patients treated with ICIs are susceptible to CNS disease, including paraneoplastic neurological syndromes, encephalitis, multiple sclerosis and hypophysitis. In this Opinion article, we introduce the mechanisms of action of ICIs and review their adverse effects on the CNS. We highlight the importance of early detection of these neurotoxic effects, which should be distinguished from brain metastasis, and the need for early detection of neurotoxicity. It is crucial that physicians are well informed of these neurological adverse effects, given the anticipated increase in the use of immunotherapies to treat cancer.

Compromised axon initial segment integrity in EAE is preceded by microglial reactivity and contact.

Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal pathology in MS remain elusive. Evidence suggests that axonal pathology is a direct consequence of demyelination, as we and others have shown that the node of Ranvier disassembles following loss of myelin. In contrast to the node of Ranvier, we now show that the axon initial segment (AIS), the axonal domain responsible for action potential initiation, remains intact following cuprizone-induced cortical demyelination. Instead, we find that the AIS is disrupted in the neocortex of mice that develop experimental autoimmune encephalomyelitis (EAE) independent of local demyelination. EAE-induced mice demonstrate profound compromise of AIS integrity with a progressive disruption that corresponds to EAE clinical disease severity and duration, in addition to cortical microglial reactivity. Furthermore, treatment with the drug didox results in attenuation of AIS pathology concomitantly with microglial reversion to a less reactive state. Together, our findings suggest that inflammation, but not demyelination, disrupts AIS integrity and that therapeutic intervention may protect and reverse this pathology. GLIA 2016;64:1190-1209.

Vaccine-associated inflammatory diseases of the central nervous system: from signals to causation.

PURPOSE OF REVIEW: As the most cost-effective intervention in preventive medicine and as a crucial element of any public health program, vaccination is used extensively with over 90% coverage in many countries. As approximately 5-8% of the population in developed countries suffer from an autoimmune disorder, people with an autoimmune disease are most likely to be exposed to some vaccines before or after the disease onset. In fact, a number of inflammatory disorders of the central nervous system have been associated with the administration of various vaccines. These adverse events, be they spurious associations or genuine reactions to the vaccine, may lead to difficulties in obtaining public trust in mass vaccination programs. There is, thus, an urgent need to understand whether vaccination triggers or enhances autoimmune responses. RECENT FINDINGS: By reviewing vaccine-associated inflammatory diseases of the central nervous system, this study describes the current knowledge on whether the safety signal was coincidental, as in the case of multiple sclerosis with several vaccines, or truly reflected a causal link, as in narcolepsy with cataplexy following pandemic H1N1 influenza virus vaccination. SUMMARY: The lessons learnt emphasize a central role of thorough, ideally prospective, epidemiological studies followed, if the signal is deemed plausible or real, by immunological investigations.

Vitamin D and estrogen synergy in Vdr-expressing CD4(+) T cells is essential to induce Helios(+)FoxP3(+) T cells and prevent autoimmune demyelinating disease.

Multiple sclerosis (MS) is a neurodegenerative disease resulting from an autoimmune attack on the axon-myelin unit. A female MS bias becomes evident after puberty and female incidence has tripled in the last half-century, implicating a female sex hormone interacting with a modifiable environmental factor. These aspects of MS suggest that many female MS cases may be preventable. Mechanistic knowledge of this hormone-environment interaction is needed to devise strategies to reduce female MS risk. We previously demonstrated that vitamin D3 (D3) deficiency increases and D3 supplementation decreases experimental autoimmune encephalomyelitis (EAE) risk in a female-biased manner. We also showed that D3 acts in an estrogen (E2)-dependent manner, since ovariectomy eliminated and E2 restored D3-mediated EAE protection. Here we probed the hypothesis that E2 and D3 interact synergistically within CD4(+) T cells to control T cell fate and prevent demyelinating disease. The E2 increased EAE resistance in wild-type (WT) but not T-Vdr(0) mice lacking Vdr gene function in CD4(+) T cells, so E2 action depended entirely on Vdr(+)CD4(+) T cells. The E2 levels were higher in WT than T-Vdr(0) mice, suggesting the Vdr(+)CD4(+) T cells produced E2 or stimulated its production. The E2 decreased Cyp24a1 and increased Vdr transcripts in T cells, prolonging the calcitriol half-life and increasing calcitriol responsiveness. The E2 also increased CD4(+)Helios(+)FoxP3(+) T regulatory (Treg) cells in a Vdr-dependent manner. Thus, CD4(+) T cells have a cooperative amplification loop involving E2 and calcitriol that promotes CD4(+)Helios(+)FoxP3(+) Treg cell development and is disrupted when the D3 pathway is impaired. The global decline in population D3 status may be undermining a similar cooperative E2-D3 interaction controlling Treg cell differentiation in women, causing a breakdown in T cell self tolerance and a rise in MS incidence.

Narcolepsy and A(H1N1)pdm09 vaccination: shaping the research on the observed signal.

Epidemiological data from several European countries suggested an increased risk of the chronic sleep disorder narcolepsy following vaccination with Pandemrix(™), an AS03-adjuvanted, pandemic A(H1N1)pdm09 influenza vaccine. Further research to investigate potential associations between Pandemrix™ vaccination, A(H1N1)pdm09 influenza infection and narcolepsy is required. Narcolepsy is most commonly caused by a reduction or absence of hypocretin produced by hypocretin-secreting neurons in the hypothalamus, and is tightly associated with HLA-II DQB1*06:02. Consequently, research focusing on CD4(+) T-cell responses, building on the hypothesis that for disease development, T cells specific for antigen(s) from hypocretin neurons must be activated or reactivated, is considered essential. Therefore, the following key areas of research can be identified, (1) characterization of hypothetical narcolepsy-specific auto-immune CD4(+) T cells, (2) mapping epitopes of such T cells, and (3) evaluating potential mechanisms that would enable such cells to gain access to the hypothalamus. Addressing these questions could further our understanding of the potential links between narcolepsy and A(H1N1)pdm09 vaccination and/or infection. Of particular interest is that any evidence of a mimicry-based mechanism could also explain the association between narcolepsy and A(H1N1)pdm09 influenza infection.

Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up.

OBJECTIVES: To investigate the association between vaccination with Pandemrix and risk of selected neurological and immune-related diseases including narcolepsy. DESIGN: Population-based prospective cohort study using data from regional vaccination registries and national health registries. SETTING: Seven healthcare regions in Sweden comprising 61% of the Swedish population. SUBJECTS: Study population of 3,347,467 vaccinated and 2,497,572 nonvaccinated individuals (vaccination coverage ≈ 60%) followed between 2009 and 2011 for 6.9 million person-years after exposure and 6.0 million person-years without exposure. MAIN OUTCOME MEASURE AND ANALYSIS: First recorded diagnosis of neurological and immune-related diseases. Relative risks [hazard ratios (HRs) with 95% confidence intervals (CIs)] assessed using Cox regression, adjusted for covariates. RESULTS: For all selected neurological and immune-related outcomes under study, other than allergic vaccine reactions (for which we verified an expected increase in risk) and narcolepsy, HRs were close to 1.0 and always below 1.3. We observed a three-fold increased risk of a diagnosis of narcolepsy (HR: 2.92, 95% CI: 1.78-4.79; that is, four additional cases per 100,000 person-years) in individuals ≤ 20 years of age at vaccination and a two-fold increase (HR: 2.18, 95% CI: 1.00-4.75) amongst young adults between 21 and 30 years of age. The excess risk declined successively with increasing age at vaccination; no increase in risk was seen after 40 years of age. CONCLUSIONS: For a large number of selected neurological and immune-related diseases, we could neither confirm any causal association with Pandemrix nor refute entirely a small excess risk. We confirmed an increased risk for a diagnosis of narcolepsy in individuals ≤ 20 years of age and observed a trend towards an increased risk also amongst young adults between 21 and 30 years.

Prenatal immune challenge compromises the normal course of neurogenesis during development of the mouse cerebral cortex.

Maternal infection during pregnancy is an environmental risk factor for the development of severe brain disorders in offspring, including schizophrenia and autism. However, little is known about the neurodevelopmental mechanisms underlying the association between prenatal exposure to infection and the emergence of cognitive and behavioral dysfunctions in later life. By injecting viral mimetic polyriboinosinic-polyribocytidylic acid (Poly I:C) into mice, we investigated the influence of maternal immune challenge during pregnancy on the development of the cerebral cortex of offspring. Our previous study showed that stimulation of the maternal immune system compromised the expression properties of transcription factors and the synaptogenesis of cortical neurons in upper layers but not those in deeper layers. The objective of the current study was to examine further whether maternal immune challenge has an influence on the cellular-biological features of the cortical progenitors that generate distinct cortical neuronal subtypes. We found the following abnormalities in the cortex of mice given the prenatal Poly I:C injection during later stages of cortical neurogenesis. First, proliferative activity and the expression of Pax6, which is a master regulator of the gene expression of transcription factors, were significantly decreased in the cortical progenitors. Second, the laminar allocation and gene expression were significantly altered in the daughter neurons generated at the same birth dates. These results demonstrate that specific abnormalities in the cortical progenitors preceded deficits in neuronal phenotypes. These changes may underlie the emergence of psychiatric brain and behavioral dysfunctions after in utero exposure to an infection.

Aluminum vaccine adjuvants: are they safe?

Aluminum is an experimentally demonstrated neurotoxin and the most commonly used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum adjuvants, medical science's understanding about their mechanisms of action is still remarkably poor. There is also a concerning scarcity of data on toxicology and pharmacokinetics of these compounds. In spite of this, the notion that aluminum in vaccines is safe appears to be widely accepted. Experimental research, however, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. In our opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community. We hope that the present paper will provide a framework for a much needed and long overdue assessment of this highly contentious medical issue.