Rate and characteristics of inflammatory neuropathies associated with brentuximab vedotin therapy.

BACKGROUND AND PURPOSE: Peripheral neuropathy is a frequent complication of brentuximab vedotin (BV), used in CD30+ lymphoma treatment. Classic BV-induced neuropathy (BV-CN) is a mild distal sensory axonal polyneuropathy. Severe BV-induced inflammatory neuropathies (BV-IN) have been described. BV-IN contribute to lymphoma-associated morbidity but might be immunotherapy-responsive. Our primary objective was to evaluate the rate of BV-IN. Our secondary objectives were to determine risk factors and warning signs. METHODS: We conducted a retrospective cohort study on all patients treated with BV at our center between April 2014 and September 2021. Clinical, biological, and electrophysiological data were collected. BV-induced neuropathy was defined as the occurrence of neuropathy up to 3 months after BV discontinuation. BV-IN was defined with criteria adapted from European Academy of Neurology/Peripheral Nerve Society 2021 electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. Other neuropathies were classified as BV-CN. RESULTS: Among 83 patients, 41 (49%) developed neuropathy: 35 BV-CN and 6 BV-IN. Thus, the rate of BV-IN was 7.2%. Compared to patients with BV-CN, no predisposing factor was identified. However, patients with BV-IN more frequently presented muscle weakness (67% vs. 5.7%, p < 0.05), gait disorders (83% vs. 20%, p < 0.05), or acute or subacute onset (67% vs. 14%, p < 0.05). BV-IN was frequently more severe (Common Terminology Criteria for Adverse Events grade ≥3; 50% vs. 0%, p < 0.05). Four patients were treated with immunotherapy. CONCLUSIONS: Brentuximab vedotin-induced neuropathy is an overlooked complication. Based on four easily identifiable "red flags", we provide an algorithm to help non-neurologist physicians that care for BV-treated patients to detect BV-IN. The aim of the algorithm is to decrease the diagnostic and management delay of this disabling neuropathy.

Broadening the spectrum of the neurological complications in systemic lupus erythematosus: A patient with meningoradiculitis.

BACKGROUND: Neurological complications of systemic lupus erythematosus (SLE) are wide and may rarely involve the peripheral nervous system. However, no case of meningoradiculitis has been well-detailed. METHODS: We report a patient with lupus-associated meningoradiculitis. RESULTS: A 57-year-old woman had SLE without neurological involvement, treated with hydroxychloroquine, methotrexate, and prednisone for 10 years. Six months after the drug discontinuation for SLE, she acutely developed gait instability, paresthesia, and neuropathic pain of the four limbs. The neurological examination and nerve conduction studies were consistent with radiculopathies. Cerebrospinal fluid (CSF) analysis showed lymphocytic meningitis. The spinal magnetic resonance imaging (MRI) revealed thickening and an enhancement of the lumbosacral roots consistent with meningoradiculitis. The extensive investigations did not argue for a differential diagnosis of SLE. The patient dramatically improved upon corticosteroids. At the last follow-up, the patient still reported mild paresthesia but the clinical examination, the CSF, and the spinal MRI were normal. CONCLUSION: This well-detailed case of meningoradiculitis broadens the spectrum of neurological complications in SLE. Early recognition of such complications might lead to efficient immunotherapy.

Aversive state processing in the posterior insular cortex.

Triggering behavioral adaptation upon the detection of adversity is crucial for survival. The insular cortex has been suggested to process emotions and homeostatic signals, but how the insular cortex detects internal states and mediates behavioral adaptation is poorly understood. By combining data from fiber photometry, optogenetics, awake two-photon calcium imaging and comprehensive whole-brain viral tracings, we here uncover a role for the posterior insula in processing aversive sensory stimuli and emotional and bodily states, as well as in exerting prominent top-down modulation of ongoing behaviors in mice. By employing projection-specific optogenetics, we describe an insula-to-central amygdala pathway to mediate anxiety-related behaviors, while an independent nucleus accumbens-projecting pathway regulates feeding upon changes in bodily state. Together, our data support a model in which the posterior insular cortex can shift behavioral strategies upon the detection of aversive internal states, providing a new entry point to understand how alterations in insula circuitry may contribute to neuropsychiatric conditions.

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice.

Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin(+) neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin(+) neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin(+) neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin(+) neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin(+) neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.