Successful Treatment of Myasthenia Gravis Following PD-1/CTLA-4 Combination Checkpoint Blockade in a Patient With Metastatic Melanoma

Currently, the blockade of certain immune checkpoints such as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) using checkpoint inhibitors is standard of care in patients with metastatic melanoma, especially with BRAF wild-type. However, several checkpoint inhibitor-related complications have been reported, including severe adverse events in the central and peripheral nervous system. In particular, in the recent past, the occurrence of myasthenia gravis following checkpoint inhibitor monotherapy, particularly nivolumab or ipilimumab, has been reported. In contrast, reports on PD-1/CTLA-4 combination blockade—usually with fatal clinical outcome—are scarce. We here report a case with combination immune checkpoint blockade-related myasthenia gravis with favorable clinical outcome

Early life stress and macaque annygdala hypertrophy: preliminary evidence for a role for the serotonin transporter gene

Background: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. the primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals.Methods: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years).Results: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: high cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls.Conclusion: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.National Institute for Mental HealthNIMHNARSAD Mid-investigator AwardSuny Downstate Med Ctr, Dept Psychiat & Behav Sci, Brooklyn, NY 11203 USAUniversidade Federal de São Paulo, Dept Psiquiatria, São Paulo, BrazilMt Sinai Sch Med, Dept Psychiat, New York, NY USAMt Sinai Sch Med, Dept Neurosci, New York, NY USAMt Sinai Sch Med, Dept Radiol, New York, NY USANew York State Psychiat Inst & Hosp, New York, NY 10032 USAMichael E Debakey VA Med Ctr, Mental Hlth Care Line, Houston, TX USABaylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USAYale Univ, Sch Med, Dept Psychiat, New Haven, CT USANatl Ctr PTSD, Clin Neurosci Div, West Haven, CT USANew York State Psychiat Inst & Hosp, Dept Mol Imaging & Neuropathol, New York, NY 10032 USAColumbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USAColumbia Univ, Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY USAComprehensive NeuroSci Corp, Westchester, NY USAUniv Miami Hlth Sytems, Dept Psychiat & Behav Sci, Miami, FL USAEmory Univ, Sch Med, Dept Psychiat & Behav Sci, Emory, GA USAUniversidade Federal de São Paulo, Dept Psiquiatria, São Paulo, BrazilNational Institute for Mental Health: R01MH65519-01National Institute for Mental Health: R01MH098073NIMH: R21MH066748NIMH: R01MH59990AWeb of Scienc

Epilepsy with antibodies against glutamate decarboxylase (GAD)

Epilepsy associated with antibodies against glutamate decarboxylase (GAD) occurs as pure epilepsy or in the context of autoimmune neurological syndromes. Antibodies against GAD are not directly pathogenic but serve as biomarkers for an underlying autoimmune disease. Prognostically, a chronic course with poor response to immunotherapy or other anticonvulsive treatment often develops

Features of scalp EEG in unilateral mesial temporal lobe epilepsy due to hippocampal sclerosis: Determining factors and predictive value for epilepsy surgery

Objective: To investigate determining factors of the ictal scalp EEG pattern at seizure onset and its predictive value for postsurgical outcome in people with unilateral MTLE due to hippocampal sclerosis (MTLE-HS). Methods: Review of consecutive people with chronic MTLE-HS undergoing presurgical video-EEG telemetry. Exclusion criteria were additional epileptogenic lesions or seizure generators or compromised EEG traces at seizure-onset. Mixed linear or logistic regression models were used. Results: Inclusion of 63 patients with 219 seizures with a favorable outcome (no seizures or auras only) in 43 patients at last follow-up. Rhythmic activity at seizure-onset (RA) had a frequency of 4.7 +/- 1.5/s (range 1-8/s), mostly localized in the anterior temporal region. Postsurgical seizure outcome was not associated with any clinical or electrophysiological feature. RA in the delta-band was more often observed with shorter epilepsy duration (p = 0.002). Conclusions: RA on scalp EEG gets faster with increasing epilepsy duration, possibly via time-dependent alterations of epileptogenic networks. Neither the frequency of RA nor other EEG-features appeared to predict postsurgical seizure outcome. Significance: The results challenge the view that if patients with apparent MTLE display RA in the delta-band, seizure-onset in neocortical structures rather than in temporo-mesial tissue should be considered and further investigations should be prompted. (C) 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved

Successful Treatment of Myasthenia Gravis Following PD-1/CTLA-4 Combination Checkpoint Blockade in a Patient With Metastatic Melanoma

Currently, the blockade of certain immune checkpoints such as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) using checkpoint inhibitors is standard of care in patients with metastatic melanoma, especially with BRAF wild-type. However, several checkpoint inhibitor-related complications have been reported, including severe adverse events in the central and peripheral nervous system. In particular, in the recent past, the occurrence of myasthenia gravis following checkpoint inhibitor monotherapy, particularly nivolumab or ipilimumab, has been reported. In contrast, reports on PD-1/CTLA-4 combination blockade—usually with fatal clinical outcome—are scarce. We here report a case with combination immune checkpoint blockade-related myasthenia gravis with favorable clinical outcome

Status epilepticus and benzodiazepine treatment: Use, underdosing and outcome - insights from a retrospective, multicentre registry

Objective: To explore the reasons for and outcomes of non- or undertreatment with benzodiazepines (BZDs) in status epilepticus (SE).Methods: We retrospectively analysed all SE patients from the urban area of Cologne over two years.Results: 328 SE patients were eligible, and only 72% were initially treated with BZDs. Of these, only 21.6% were treated sufficiently with BZDs according to current guidelines. SE patients not initially treated with BZDs were significantly older, had less often known epilepsy, had a prolonged arrival time to the emergency room, and presented more often with a non-generalised convulsive semiology. Regarding adequate dosages, patients with a generalised convulsive SE seemed to benefit from a sufficient BZD dosing with significantly shortened mean ventilation duration (37.1 to 208 h), decreased mean intensive care unit (1.7 to 5 days) and in-hospital stay (4.1 to 8.8 days). In contrary, aggressive BZD treatment in non-generalised convulsive SE resulted in a longer inpatient stay (9.2 to 5.8 days) and lower favourable outcome rates at discharge (16% to 63%).Conclusions: The current SE treatment guidelines for first-line BZD therapy in SE were violated in most patients. Sufficient BZD dosing was beneficial in generalised convulsive SE, but not in other forms of SE. SE semiology might be crucial for treatment decisions with BZDs. Further treatment evidence especially in non-generalised convulsive SE is urgently needed.Keywords: Anticonvulsants; Benzodiazepines; Critical care; Guideline adherence; Seizures

Prehospital Levetiracetam Use in Adults With Status Epilepticus: Results of a Multicenter Registry

Background and PurposeStatus epilepticus (SE) is a neurological emergency due to prolonged seizure activity or multiple seizures without full recovery in between them. Prehospital SE management is crucial since its duration is correlated with higher morbidity and mortality rates. We examined the impact of different therapeutic strategies in the prehospital setting with a focus on levetiracetam.MethodsWe initiated the Project for SE in Cologne, a scientific association of all neurological departments of Cologne, the fourth-largest city in Germany with around 1,000,000 inhabitants. All patients with an SE diagnosis were evaluated over 2 years (from March 2019 to February 2021) to determine whether prehospital levetiracetam use had a significant effect on SE parameters.ResultsWe identified 145 patients who received initial drug therapy in the prehospital setting by professional medical staff. Various benzodiazepine (BZD) derivatives were used as first-line treatments, which were mostly used in line with the recommended guidelines. Levetiracetam was regularly used (n=42) and mostly in combination with BZDs, but no significant additional effect was observed for intravenous levetiracetam. However, it appeared that the administered doses tended to be low.ConclusionsLevetiracetam can be applied to adults with SE in prehospital settings with little effort. Nevertheless, the prehospital treatment regimen described here for the first time did not significantly improve the preclinical cessation rate of SE. Future therapy concepts should be based on this, and the effects of higher doses should in particular be reexamined. Keywords:neurological emergency; prehospital setting; anticonvulsant therapy; benzodiazepines; levetiraceta