Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-PD-1 therapy. Histologic analyses revealed robust T-cell infiltration and prominent PD-L1 expression. We identified 209 reported cases in global pharmacovigilance databases—across multiple cancer types—of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4+ T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor (TCR) repertoire, which we localized to activated memory cytotoxic (CD45RO+GZMB+) CD4 cells. We also identified Epstein-Barr-virus-specific T cell receptors and EBV+ lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the 3 cases studied here identify CD4+ and CD8+ T cells as culprits of checkpoint inhibitor-associated immune encephalitis.
Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Myasthenia gravis is an antibody-mediated autoimmune disorder of the post-synaptic neuromuscular junction resulting in fluctuating, fatigable weakness. Most patients first present with extraocular symptoms (diplopia and/or ptosis), and in 15% of cases symptoms will remain restricted to only the extraocular muscles (ocular myasthenia gravis [OMG]). The history and clinical examination are of the utmost importance in correctly identifying OMG patients, as supportive serologic or electrodiagnostic studies are frequently nondiagnostic. In this review, we outline a diagnostic approach to OMG (focusing on key clinical features), discuss therapeutic options, and highlight recent developments in the understanding of OMG.
Background Guillain-Barré Syndrome (GBS) is a rapidly progressive immune-mediated polyneuropathy often associated with an antecedent infectious illness or vaccination. The classic presentation of GBS is characterized by ascending limb weakness and numbness with loss of reflexes. However, atypical variants involving the face and arms or with purely sensory symptoms also exist. In up to 30 percent of cases, GBS progresses to respiratory failure, with patients requiring mechanical ventilation. Case Report We report a case of atypical GBS occurring after COVID-19 vaccination in an otherwise healthy 38-year-old male. The patient's clinical presentation was characterized by bilateral hand and foot paresthesias, dysarthria, bilateral facial weakness, and an absence of classic ascending limb weakness. Albuminocytological dissociation within the cerebrospinal fluid was suggestive of GBS. The patient received intravenous immunoglobulin (IVIG) therapy with modest improvement in his symptoms at the time of the patient's discharge from the hospital. Why Should an Emergency Physician be Aware of This? Patients with GBS are at risk for life threatening complications including respiratory failure requiring mechanical ventilation. It is critical for Emergency physicians to be aware of the manifold presentations of GBS for early recognition and treatment. This may be of particular importance in the context of a worldwide vaccination campaign in response to the COVID-19 pandemic.
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A 61-year-old woman with known neurofibromatosis type 1 (NF1) presented with lower back pain, urinary retention, impaired hearing, and tinnitus. Her lower limb deep tendon reflexes were brisk bilaterally with extensor plantar responses. MRI showed extensive dural ectasia, as well as hemosiderin deposition characteristic of superficial siderosis (figures 1 and 2). CSF analysis showed elevated erythrocyte counts, protein, and ferritin. Dural ectasia and meningocele formation are recognized complications of NF1.1 In this case, friable vessels at the site of the ectatic dura are the likely source of chronic bleeding into the CSF, 2 resulting in diffuse superficial siderosis.
A 47-year-old woman presented with transient episodes of generalized weakness. Interictal neurologic examination was normal. Long exercise testing (Figure 1) demonstrated a delayed decrement in compound motor action potential amplitude, supporting the diagnosis of periodic paralysis.CACNA1S and SCN4A (genes associated with the large majority of primary periodic paralysis 1 ) testing was normal, but a variant of uncertain significance was detected in the KCNJ2 gene (c.291_293del [pPhe99del]).KCNJ2-related periodic paralysis occurs in Anderson-Tawil syndrome (ATS), alongside cardiac abnormalities (prolongation of the QT interval, prominent U waves, prolongation of terminal T-wave downsloping, ventricular ectopy/tachycardia) and skeletal abnormalities (ocular hypertelorism, small mandible, low-set ears, scoliosis, fifth digit clinodactyly). 1,2 On re-examination, bilateral 5th digit clinodactyly and characteristic ECG changes were noted in this case (Figure 2).A diagnosis of ATS should be considered in all cases of periodic paralysis associated with cardiac or skeletal abnormalities. Careful examination for dysmorphic features and review of the ECG is key. In this case, subtle phenotypic clues helped to support the diagnosis of KCNJ2-related ATS.
Transient headache exacerbation during IV dihydroergotamine (DHE) therapy of migraine may prompt clinicians to prematurely discontinue DHE therapy, potentially depriving patients of the full benefit of DHE infusion. In a recent Neurology ® article, Eller et al. evaluated whether or not worsening headache during DHE infusion was associated with suboptimal medium-term headache outcomes. Neurology ® 2016;87:e196-e198 This Journal Club reviews an article by Eller et al.
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