Plasma Exchange in Patients With Myositis due to Immune Checkpoint Inhibitor Therapy.

ABSTRACT: Immune checkpoint inhibitors used to treat malignancies may lead to various immune-related adverse events (irAEs) including conditions such as myositis and myasthenia gravis (MG). Here, we describe 2 cases of myositis treated effectively with therapeutic plasma exchange (PLEX). A 64-year-old man with thymic cancer developed leg weakness and dyspnea 1 month after the second dose of nivolumab with moderate weakness in proximal and distal muscles, with elevated creatine kinase levels. Another 77-year-old man with Stage IIIB squamous cell carcinoma of the lung developed progressive proximal muscle weakness and became nonambulatory after cycle 2 of durvalumab with persistently high creatine kinase levels despite prednisone treatment. Electrophysiology revealed irritative myopathy without evidence of neuromuscular junction dysfunction and MG antibody testing was nonrevealing. With PLEX, both patients noticed rapid improvement in strength. PLEX in conjunction with other immunosuppressive agents can result in rapid improvement in irAE-myositis even in patients without associated MG.

Safety and outcomes with efgartigimod use for acetylcholine receptor-positive generalized myasthenia gravis in clinical practice.

INTRODUCTION/AIMS: Multiple novel therapies have been approved for patients with myasthenia gravis. Our aim is to describe the early experience of efgartigimod use in acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ve gMG). METHODS: This multicenter retrospective study included AChR+ve gMG patients from five major neuromuscular centers who were treated with efgartigimod and had both pre- and post-efgartigimod myasthenia gravis activities of daily living (MG-ADL) scores. Information regarding MG history, concomitant treatment(s), MG-ADL and other MG-specific measures, laboratory data, and adverse events were recorded. RESULTS: A total of 37 patients (M:23, F:14) with a mean age of 65.56 (±14.74) y were included in this cohort. A total of 36/37 patients completed at least one cycle and 28 patients completed at least two cycles of efgartigimod. A total of 72% (26/36) of patients had a clinically meaningful reduction (≥2 point change) in MG-ADL after the completion of the first cycle of efgartigimod (mean pre-efgartigimod 8.02) (±3.09) versus post-efgartigimod 4.33 (±3.62). Twenty-five percent (9/36) achieved minimal symptom expression status after one cycle and 25% (7/28) after the second cycle. Treatment benefit was sustained after cycle 2. Three out of four patients with thymoma in this cohort had clinically significant reductions in MG-ADL scores. Immunoglobulin G (IgG) levels decreased by about 60% (n = 10). One patient had a relapse of Clostridium difficile infection resulting in the discontinuation of therapy. Four patients had mild side effects. DISCUSSION: Efgartigimod led to clinically meaningful improvement in MG-ADL in diverse AChR+ve gMG patients but treatment frequency to achieve optimal symptom control needs to be explored.

Adverse Side Effects Associated with Corticosteroid Therapy: A Study in 39 Patients with Generalized Myasthenia Gravis.

BACKGROUND The tolerability of high-dose oral corticosteroids in patients with generalized myasthenia gravis (gMG) has not been systematically assessed. We evaluated adverse side effects (ASEs) of corticosteroid treatment in patients with gMG. MATERIAL AND METHODS Retrospective analysis was conducted of ASEs reported as being related to corticosteroid treatment in 39 patients with gMG who were treated with oral corticosteroids for ≥1 year. RESULTS Median (interquartile range [IQR]) age was 60 (21) years, 53.8% of patients were women, and 66.7% were aged ≤65 years. Median (IQR) prednisone treatment duration was 14 (2) months; median (IQR) daily dose was 40 (15) mg. The median number of ASEs reported as corticosteroid-related was 2/patient (IQR, 1). Pre-diabetes and weight gain were most common (each 43.6% of patients). Bruising, insomnia, and osteoporosis were more prevalent in patients aged >65 years, while irritability, osteopenia, and pre-diabetes were more common in patients aged £65 years, although differences were not statistically significant. Irritability and weight gain were more prevalent in women (P=0.010 for irritability); osteoporosis and pre-diabetes more common in men (P=0.015 for osteoporosis). ASEs were generally more common in the high-dose prednisone group (>30 mg/day), but were only statistically significant for irritability (P=0.001). CONCLUSIONS Corticosteroid-related ASEs were common in patients with gMG. Some of these ASEs can have serious medical consequences, and certain ASEs appeared to be associated with specific patient characteristics. Demographics and comorbidities of patients with gMG must be carefully considered before corticosteroid initiation. Potential ASEs, such as unanticipated osteoporosis in men, require extra vigilance.

A case of hemothorax secondary to intrapleural fibrinolytic therapy: Considerations for use of fibrinolytics in high-risk patients.

Indwelling Pleural Catheters (IPC) are increasingly being used for management of recurrent pleural effusions (RPEs). Use of IPC for management of both malignant and non-malignant recurrent pleural effusions has been associated with complications such as dysfunctional or nonfunctioning IPCs. Alteplase, a tissue plasminogen activator (tPA) is often used to restore flow of non-draining IPC in symptomatic patients. We present a case of a sixty-eight-year old patient with life-threatening pleural hemorrhage following intrapleural catheter instillation of tPA that was managed successfully by thoracotomy. Our case describe the importance of individualizing the fibrinolytic dose, frequency and the indwelling time in high risk patients. We have reviewed the current literature and recommendations for use of fibrinolytic therapy for IPC in high risk patients on anticoagulation.

Clinical experience with maintenance therapeutic plasma exchange in refractory generalized myasthenia gravis.

BACKGROUND: Despite the availability of several immunomodulatory therapies, about 20% of myasthenia gravis (MG) patients remain refractory to conventional treatments. There is limited evidence to support the use of maintenance therapeutic plasma exchange (TPE) therapy for refractory generalized MG. METHODS: Retrospective chart review of 14 patients with refractory generalized MG treated for 12 months with maintenance TPE therapy. Outcome measures were myasthenia gravis composite (MGC) score, myasthenia gravis activities of daily living (MG-ADL), number of acute exacerbations, medication changes, and adverse events. Data were collected at 3 monthly intervals for 12 months before and after initiation of TPE therapy. RESULTS: Clinically meaningful reductions in mean MG-ADL (>2 points) (mean MG-ADL score: 9.9 ± 0.5; 12-month pre-TPE to 5.2 ± 0.9; 12-month post-TPE) and MGC (>3 points) (mean MGC score: 25.2 ± 1.6; 12-month pre-TPE to 11.7 ± 1.4; 12-month post-TPE) were observed at 3 months following initiation of TPE and were maintained up to 12 months in all patients. After 12 months of TPE therapy, all patients had a significant reduction in daily prednisone and pyridostigmine use. Patients previously on IVIG or rituximab therapy were successfully weaned off both treatments. There was a significant reduction in acute MG exacerbations; 7.8 ± 1.1 mean exacerbations/patient (12-month pre-TPE) to 2 ± 1.1 mean exacerbations/patient (12-month post-TPE). CONCLUSION: Over a period of 12 months, maintenance TPE therapy improved MG-ADL, and MGC with decreased immunosuppressant requirement, while being well-tolerated.

Clinical Experience with Eculizumab in Treatment-Refractory Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis.

BACKGROUND: Although established therapies are effective in most patients with generalized myasthenia gravis (gMG), some patients do not respond or they experience intolerable adverse events, highlighting the need for better tolerated, targeted therapies for treatment-refractory gMG. OBJECTIVE: To describe real-world experience with eculizumab in patients with treatment-refractory acetylcholine receptor antibody-positive (AChR+) gMG. METHODS: Retrospective chart review of 15 patients with treatment-refractory AChR+ gMG treated for 12 months with eculizumab (900 mg/week for 4 weeks then 1200 mg every 2 weeks). Outcome measures were Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores, number of exacerbations, single-breath count test (SBCT) score, medication changes, selected Quantitative Myasthenia Gravis (QMG) evaluations, and adverse events. Data collected at 3-monthly intervals for 12 months before and after eculizumab initiation were analyzed. RESULTS: Clinically meaningful reductions in total MG-ADL scores were observed at 3 months following eculizumab initiation and maintained up to 12 months in all patients. After 12 months' eculizumab treatment, there was a significant reduction in the number of acute exacerbations; mean (SD) SBCT score improved from 28.13 (0.33) to 50.26 (2.86); all patients achieved a 'none' or 'mild' rating for QMG evaluations; all patients reduced their daily prednisone dose; and nine patients had discontinued pyridostigmine. At the end of treatment, intravenous immunoglobulin was discontinued in all six patients receiving this therapy at eculizumab initiation. Eculizumab was well tolerated. CONCLUSIONS: This real-world study demonstrated improvement in outcome measures and decreased concomitant drug requirement within 12 months of eculizumab initiation in patients with treatment-refractory AChR+ gMG.

Malignant Hyperthermia.

Malignant Hyperthermia (MH) is a life-threatening pharmacogenetic disorder which results from exposure to volatile anesthetic agents and depolarizing muscle relaxants. It manifests as a hypermetabolic response resulting in tachycardia, tachypnea, hyperthermia, hypercapnia, acidosis, muscle rigidity and rhabdomyolysis. An increase in the end-tidal carbon dioxide is one of the earliest diagnostic signs. Dantrolene sodium is effective in the management of MH, and should be available whenever general anesthesia is administered. This review also aims to highlight the genetics and pathology of MH, along with its association with various inherited myopathy syndromes like central core disease, multi-mini core disease, Native-American myopathy, and King-Denborough syndrome.

Somatosensory Evoked Potentials as a Tool to Evaluate Brainstem Herniation in the Neuroscience Intensive Care Unit.

Somatosensory evoked potentials (SSEPs) are a sensitive, minimally invasive technique used to localize dysfunction of myelinated peripheral and central axons in the nervous system. The utility of SSEPs in acutely assessing central nervous system function in brainstem herniation in the neuroscience intensive care unit (NICU) has not been well established. We discuss a case of an 18-year-old, postpartum female who presented with intermittent headache, diplopia, nausea/vomiting and cachexia following delivery two months prior. Shortly after arrival to the emergency department, she developed flaccid quadriparesis and complete ophthalmoplegia. Computed tomography (CT) of the head showed effacement of the basal cisterns along with 2 cm cerebellar tonsillar herniation into the foramen magnum concerning for intracranial hypotension. Raising the head of bed caused hemodynamic instability necessitating prolonged Trendelenburg positioning. The patient was evaluated with serial SSEPs which initially showed a bilateral low amplitude N20 response and normal N13 response. Subsequent SSEP testing showed increased N20 amplitude which correlated with clinical improvement in the patient. SSEP is a minimally invasive and sensitive method used to assess the integrity of the somatosensory nervous system pathway; SSEPs may be a useful monitoring adjunct to assess the evolution of posterior fossa lesions leading to brainstem compression.

Delayed Post-hypoxic Leukoencephalopathy: A Case Series and Review of the Literature.

Delayed post-hypoxic leukoencephalopathy (DPHL) is a unique clinical entity that presents with cognitive impairment days to weeks after an episode of acute hypoxic brain injury. Frequently hypoxia is unrecognized as a mechanism for clinical decline and extensive workup ensues. We present two cases of DPHL highlighting the neuroimaging findings. In both patients, a cerebral hypoxic event was followed by a recovery phase with subsequent delayed clinical decline. Patient 1 suffered hypoxia from drug-induced respiratory depression and lack of post-operative positive airway pressure (PAP) support. Her neurological exam on follow-up revealed progressive cognitive decline. Magnetic resonance imaging (MRI) brain showed bilateral white matter changes involving the centrum semiovale. Patient 2 developed a generalized tonic-clonic seizure during an endobronchial biopsy procedure and was found to have multiple air emboli on computed tomography (CT) head scan. She was initially in a drug-induced coma for her seizures. Electroencephalography (EEG) on day 14 of admission showed changes consistent with diffuse encephalopathy. MRI brain showed bilateral white matter changes particularly at the watershed zones and in the centrum semiovale. DPHL is a rare and under-recognized clinical entity that requires clinical suspicion and detailed evaluation for diagnosis. Neuroimaging studies can provide prognostic information regarding the extent of neurological injury.

Thromboelastography With Platelet Mapping is Not an Effective Measure of Platelet Inhibition in Patients With Spontaneous Intracerebral Hemorrhage on Antiplatelet Therapy.

Thromboelastography with platelet mapping (TEG-PM) is a modality to measure platelet function, especially in patients taking antiplatelet medications. It consists of two components: arachidonic acid (AA), which is sensitive to aspirin, and adenosine diphosphate (ADP), which is sensitive to clopidogrel. In patients with spontaneous intracerebral hemorrhages (sICH), the clinical interpretation of platelet mapping is unclear. The objective of this study was to evaluate TEG-PM in patients with sICH on aspirin and/or clopidogrel who receive platelet transfusions. This study was an IRB-approved, retrospective case-control study over three years at an academic medical center. Adult patients with sICH were included if they had an admission computed tomography head (CTH) and platelet mapping followed by a repeat platelet mapping and CTH post platelet transfusion. A threshold of 50% inhibition was used as the benchmark for both ADP and AA inhibition. Around 248 subjects with sICH were identified, and 107 were excluded for incomplete documentation, leaving 141 for analysis. Of these, nine met our inclusion criteria. No statistical significance was found on the antithrombotic effects of aspirin or clopidogrel on TEG-PM (p=1.00 for both). Sensitivity and specificity of TEG-PM for clopidogrel was 100% and 42.9%, respectively, and 80% and 0%, respectively, for aspirin. Platelet transfusion did not significantly change AA or ADP inhibition (p=1.00). Hemorrhagic expansion on CTH was not associated with a decrease AA or ADP inhibition (p=1.00). TEG-PM is not an effective measure of platelet inhibition in sICH patients who were on antiplatelet medications and is not a reliable measurement following platelet transfusion.

Multiple Cranial Neuropathies in a Patient with Diffuse Large B-cell Lymphoma: Case Report and Review of Literature.

Neuropathies can occur in patients with diffuse large B-cell lymphoma (DLBCL) at any stage of the disease as a presenting symptom or during later stages of illness. A wide spectrum of neurological association is known to occur with DLBCL, ranging from cranial nerve palsies to peripheral neuropathies. Evaluation of cranial and peripheral neuropathies in patients with DLBCL requires meticulous clinical, imaging, and electrodiagnostic testing. A 75-year-old right-handed female with a known history of multiple cranial neuropathies and DLBCL presented with acute dysphagia and upper extremity weakness of one-week duration. On evaluation, she was found to have right vagal nerve palsy. Cerebrospinal fluid (CSF) analysis along with flow cytometry testing showed CD19 and CD20 positive B cells, confirming neoplastic infiltration of CSF. We describe the case and review the literature of the association of cranial nerve palsies with DLBCL.

Inadvertent Central Arterial Catheterization: An Unusual Cause of Ischemic Stroke.

Central venous catheter (CVC) insertion is extensively utilized in Intensive Care Units for evaluation of hemodynamic status, administration of intravenous drugs, and for providing nutritional support in critically ill patients. Unfortunately, CVC use is associated with complications including lung injury, bleeding, infection, and thrombosis. We present a patient with an acute ischemic stroke from an inadvertently placed CVC into the right common carotid artery. A 57-year-old male presented to our institution for left hemiplegia and seizures 2 days after a CVC was placed. He was found to have a right frontal ischemic stroke on computed tomography (CT). CT angiography noted that the catheter was arterial and had a thrombosis around it. He was started on a low-dose heparin infusion. A combination of cardiothoracic surgery and interventional cardiology was required to safely remove the catheter. Central arterial catheterization is an unusual cause for acute ischemic stroke and presents management challenges.