Repurposing chemotherapy-induced peripheral neuropathy grading.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is perceived differently by patients and physicians, complicating its assessment. Current recommendations advocate combining clinical and patient-reported outcomes measures, but this approach can be challenging in patient care. This multicenter European study aims to bridge the gap between patients' perceptions and neurological impairments by aligning both perspectives to improve treatment decision-making. METHODS: Data were pooled from two prospective studies of subjects (n = 372) with established CIPN. Patient and physician views regarding CIPN were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Total Neuropathy Scale-clinical version (TNSc) items, and the disease-specific quality of life - Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20) from the European Organization for Research and Treatment of Cancer (EORTC). To identify inherent neurotoxic severity patterns, we employed hierarchical cluster analysis optimized with k-means clustering and internally validated by discriminant functional analysis. RESULTS: Both NCI-CTCAE and TNSc demonstrated a significant difference in the distribution of severity grades in relation to QLQ-CIPN20 scores. However, a proportion of subjects with different neurotoxic severity grades exhibited overlapping QLQ-CIPN20 scores. We identified three distinct clusters classifying subjects as having severely impaired, intermediately impaired, and mildly impaired CIPN based on TNSc and QLQ-CIPN20 scores. No differences in demographics, cancer type distribution, or class of drug received were observed. CONCLUSIONS: Our results confirm the heterogeneity in CIPN perception between patients and physicians and identify three well-differentiated subgroups of patients delineated by degree of CIPN impairment based on scores derived from TNSc and QLQ-CIPN20. A more refined assessment of CIPN could potentially be achieved using the calculator tool derived from the cluster equations in this study. This tool, which facilitates individual patient classification, requires prospective validation.

Diagnostic and prognostic biomarkers in immune checkpoint inhibitor-related encephalitis: a retrospective cohort study.

Background: Immune checkpoint inhibitor-related encephalitis (ICI-encephalitis) is not well characterised and diagnostic and prognostic biomarkers are lacking. We aimed to comprehensively characterise ICI-encephalitis and identify diagnostic biomarkers and outcome predictors. Methods: This retrospective observational study included all patients with ICI-encephalitis studied in the French Reference Centre on Paraneoplastic Neurological Syndromes (PNS) and Autoimmune Encephalitis (2015-2023). ICI encephalitis was considered definite in case of inflammatory findings at paraclinical tests and/or well-characterised neural antibodies. Predictors of immune-related adverse event (irAE) treatment response, defined as a Common Terminology Criteria for Adverse Events v5.0 grade < 3 at any time after therapeutic intervention, were assessed by logistic regression analysis, and predictors of mortality by Cox regression analysis. Neurofilament light chain (NfL) was measured by enzyme-linked immunosorbent assay. Findings: Sixty-seven patients with definite encephalitis were identified (median age, 69 years; 66% male). A focal syndrome was observed in 43/67 patients (64%; limbic encephalitis, cerebellar ataxia, and/or brainstem encephalitis), while 24/67 (36%) had meningoencephalitis, a non-focal syndrome with altered mental status (22/24 patients, 92%) and pleocytosis (24/24 patients, 100%). Patients with focal encephalitis more frequently had abnormal brain MRI (26/42, 62% versus 8/24, 33%, p = 0.025), PNS-related antibodies (36/43, 84% versus 1/24, 4%, p < 0.001), and neuroendocrine cancers (22/43, 51% versus 1/24, 4%; p < 0.001) than patients with meningoencephalitis. Focal encephalitis patients had a lower rate of irAE treatment response (7/39, 18%) and higher mortality (27/43, 63%) compared to meningoencephalitis patients (12/22, 77% and 5/24, 21%, respectively, p < 0.001 each). PNS-related antibodies were associated with less irAE treatment response, independently of age, sex, and baseline severity (adjusted OR 0.05; 95%CI [0.01; 0.19]; p < 0.001) as well as higher mortality, independently of age and cancer type (adjusted HR 5.07; 95% CI [2.12; 12.12]; p < 0.001). Serum NfL discriminated patients with definite ICI-encephalitis (n = 27) from cancer-matched controls (n = 16; optimal cut-off >273.5 pg/mL, sensitivity 81%, specificity 88%, AUC 0.87, 95% CI [0.76; 0.98]) and irAE treatment responders (n = 10) from non-responders (n = 17, optimal cut-off >645 pg/mL, sensitivity 90%, specificity 65%; AUC 0.75, 95% CI [0.55; 0.94]). Interpretation: ICI-encephalitis corresponds to a set of clinically-recognisable syndromes. Patients with focal encephalitis, PNS-related antibodies, and/or higher serum NfL have low irAE treatment response rates. Research is needed on the underlying immunopathogenesis to foster therapeutic innovations. Funding: Agence Nationale de la Recherche.

REM and NREM Sleep Parasomnia in Anti-NMDA Receptor Encephalitis.

OBJECTIVES: Encephalitis with anti-N-methyl-d-aspartate receptor antibodies (anti-NMDARe) is a rare disorder characterized by cognitive impairment, psychosis, seizures, and abnormal movements. Abnormal behaviors during REM sleep have not been described in anti-NMDARe. METHODS: Patients were monitored by video-polysomnography on a first night followed by multiple sleep latency tests and 18 hours of bed rest. RESULTS: Two patients with anti-NMDARe developed during the acute and postacute phase parasomnias including REM sleep behavior disorder and continuous finalistic quiet gesturing during a mixed N2/R sleep. The parasomnia disorder was improved by gabapentin and clonazepam. DISCUSSION: Video-polysomnography avoids misdiagnosing these parasomnia behaviors for seizure or movement disorders and allows adequate treatment.

CAR T-cell therapy induces a high rate of prolonged remission in relapsed primary CNS lymphoma: Real-life results of the LOC network.

The prognosis of relapsed primary central nervous system lymphoma (PCNSL) remains dismal. CAR T-cells are a major contributor to systemic lymphomas, but their use in PCNSL is limited. From the LOC network database, we retrospectively selected PCNSL who had leukapheresis for CAR-T cells from the third line of treatment, and, as controls, PCNSL treated with any treatment, at least in the third line and considered not eligible for ASCT. Twenty-seven patients (median age: 68, median of three previous lines, including ASCT in 14/27) had leukapheresis, of whom 25 received CAR T-cells (tisa-cel: N = 16, axi-cel: N = 9) between 2020 and 2023. All but one received a bridging therapy. The median follow-up after leukapheresis was 20.8 months. The best response after CAR-T cells was complete response in 16 patients (64%). One-year progression-free survival from leukapheresis was 43% with a plateau afterward. One-year relapse-free survival was 79% for patients in complete or partial response at CAR T-cell infusion. The median overall survival was 21.2 months. Twenty-three patients experienced a cytokine release syndrome and 17/25 patients (68%) a neurotoxicity (five grade ≥3). The efficacy endpoints were significantly better in the CAR T-cell group than in the control group (N = 247) (median PFS: 3 months; median OS: 4.7 months; p < 0.001). This series represents the largest cohort of PCNSL treated with CAR T-cells reported worldwide. CAR T-cells are effective in relapsed PCNSL, with a high rate of long-term remission and a reassuring tolerance profile. The results seem clearly superior to those usually observed in this setting.

Predictors and Clinical Characteristics of Relapses in LGI1-Antibody Encephalitis.

BACKGROUND AND OBJECTIVES: Relapses occur in 15%-25% of patients with leucine-rich glioma-inactivated 1 antibody (LGI1-Ab) autoimmune encephalitis and may cause additional disability. In this study, we clinically characterized the relapses and identified factors predicting their occurrence. METHODS: This is a retrospective chart review of patients with LGI1-Ab encephalitis diagnosed at our center between 2005 and 2022. Relapse was defined as worsening of previous or appearance of new symptoms after at least 3 months of clinical stabilization. RESULTS: Among 210 patients, 30 (14%) experienced a total of 33 relapses. The median time to first relapse was 23.9 months (range: 4.9-110.1, interquartile range [IQR]: 17.8). The CSF was inflammatory in 11/25 (44%) relapses, while LGI1-Abs were found in the serum in 16/24 (67%) and in the CSF in 12/26 (46%); brain MRI was abnormal in 16/26 (62%) relapses. Compared with the initial episode, relapses manifested less frequently with 3 or more symptoms (4/30 patients, 13% vs 28/30, 93%; p < 0.001) and had lower maximal modified Rankin scale (mRS) score (median 3, range: 2-5, IQR: 1 vs 3, range: 2-5, IQR: 0; p = 0.001). The median mRS at last follow-up after relapse (2, range: 0-4, IQR: 2) was significantly higher than after the initial episode (1, range: 0-4, IQR: 1; p = 0.005). Relapsing patients did not differ in their initial clinical and diagnostic features from 85 patients without relapse. Nevertheless, residual cognitive dysfunction after the initial episode (hazard ratio:13.8, 95% confidence interval [1.5; 129.5]; p = 0.022) and no administration of corticosteroids at the initial episode (hazard ratio: 4.8, 95% confidence interval [1.1; 21.1]; p = 0.036) were significantly associated with an increased risk of relapse. DISCUSSION: Relapses may occur years after the initial encephalitis episode and are usually milder but cause additional disability. Corticosteroid treatment reduces the risk of future relapses, while patients with residual cognitive dysfunction after the initial episode have an increased relapse risk.

Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies.

BACKGROUND AND OBJECTIVES: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. METHODS: Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. RESULTS: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. DISCUSSION: Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

Neurological autoimmunity in melanoma patients: a comparison between those exposed and non-exposed to immune checkpoint inhibitors.

BACKGROUND: The clinical spectrum of melanoma-associated neurological autoimmunity, whether melanoma-associated paraneoplastic neurological syndromes (PNS) or induced by immune checkpoint inhibitors (ICI), is not well characterized. We aim to describe the clinical spectrum of melanoma-associated neurological autoimmunity. METHODS: A systematic review of the literature combined with patients from French databases of paraneoplastic neurological syndromes was conducted. All melanoma patients with a possible immune-mediated neurologic syndrome were included and classified according to whether they had previously been exposed to ICI (ICI-neurotoxicity) or not (ICI-naïve) at first neurological symptoms. RESULTS: Seventy ICI-naïve (literature: n = 61) and 241 ICI-neurotoxicity patients (literature: n = 180) were identified. Neuromuscular manifestations predominated in both groups, but peripheral neuropathies were more frequent in ICI-neurotoxicity patients (39.4% vs 21.4%, p = 0.005) whereas myositis was more frequent in ICI-naïve patients (42.9% vs 18.7%, p < 0.001). ICI-naïve patients had also more frequent central nervous system (CNS) involvement (35.7% vs 23.7%, p = 0.045), classical paraneoplastic syndrome (25.7% vs 5.8%, p < 0.001), and more frequently positive for anti-neuron antibodies (24/32, 75.0% vs 38/90, 42.2%, p = 0.001). Although more ICI-neurotoxicity patients died during the acute phase (22/202, 10.9% vs 1/51, 2.0%, p = 0.047), mostly myositis patients (14/22, 63.6%), mortality during follow-up was higher in ICI-naïve patients (58.5% vs 29.8%, p < 0.001). There was no significant difference in the frequency of life independence (mRS ≤ 2) in the surviving patients in both groups (95.5% vs 91.0%, p = 0.437). CONCLUSIONS: Melanoma-associated PNS appear remarkably rare. The clinical similarities observed in neurological autoimmunity between ICI-treated and ICI-naïve patients, characterized predominantly by demyelinating polyradiculoneuropathy and myositis, suggest a potential prior immunization against melanoma antigens contributing to ICI-related neurotoxicity.

Dysautonomia in anti-Hu paraneoplastic neurological syndromes.

BACKGROUND AND OBJECTIVES: Dysautonomia has been associated with paraneoplastic neurological syndrome (PNS)-related mortality in anti-Hu PNS, but its frequency and spectrum remain ill-defined. We describe anti-Hu patients with dysautonomia, estimate its frequency, and compare them to patients without dysautonomia. METHODS: Patients with anti-Hu antibodies diagnosed in the study centre (1990-2022) were retrospectively reviewed; those with autonomic signs and symptoms were identified. RESULTS: Among 477 anti-Hu patients, 126 (26%) had dysautonomia (the only PNS manifestation in 7/126, 6%); gastrointestinal (82/126, 65%), cardiovascular (64/126, 51%), urogenital (24/126, 19%), pupillomotor/secretomotor (each, 11/126, 9%), and central hypoventilation (10/126, 8%). Patients with isolated CNS involvement less frequently had gastrointestinal dysautonomia than those with peripheral (alone or combined with CNS) involvement (7/23, 30% vs. 31/44, 70% vs. 37/52, 71%; P = 0.002); while more frequently central hypoventilation (7/23, 30% vs. 1/44, 2.3% vs. 2/52, 4%; P < 0.001) and/or cardiovascular alterations (18/23, 78% vs. 20/44, 45% vs. 26/52, 50%; P = 0.055). Median [95% CI] overall survival was not significantly different between patients with (37 [17; 91] months) or without dysautonomia (28 [22; 39] months; P = 0.78). Cardiovascular dysautonomia (HR: 1.57, 95% CI [1.05; 2.36]; P = 0.030) and central hypoventilation (HR: 3.51, 95% CI [1.54; 8.01]; P = 0.003) were associated with a higher risk of death, and secretomotor dysautonomia a lower risk (HR: 0.28, 95% CI [0.09; 0.89]; P = 0.032). Patients with cardiovascular dysautonomia dying ≤ 1 year from clinical onset had severe CNS (21/27, 78%), frequently brainstem (13/27, 48%), involvement. DISCUSSION: Anti-Hu PNS dysautonomia is rarely isolated, frequently gastrointestinal, cardiovascular and urogenital. CNS dysfunction, particularly brainstem, associates with lethal cardiovascular alterations and central hypoventilation, while peripheral involvement preferentially associates with gastrointestinal or secretomotor dysautonomia, being the latest more indolent.

Impact of Immune Checkpoint Inhibitors on the Course of Multiple Sclerosis.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are increasingly used in cancer treatment. Their mechanism of action raises the question of possible exacerbation of preexisting multiple sclerosis (MS). The aim of our study was to assess the risk of increased MS activity, defined by the occurrence of a relapse and/or a new MRI lesion, after ICI initiation. METHODS: This French multicentric study collected retrospective and prospective data on patients with MS treated with ICIs after a cancer diagnosis. RESULTS: We identified 18 patients with a median age of 48 years. Three of them (17%), all aged 50 years or younger, with a relapsing-remitting course, showed clinical and/or radiologic signs of MS activity 3 to 6 months after ICI initiation. They had stopped disease-modifying treatment (DMT) several months earlier, at the time of cancer diagnosis. Only one had both clinical and MRI activity, with mild severity and complete recovery. DISCUSSION: Our study suggests that the overall risk of MS activity under ICI is low and could be mainly driven by DMT discontinuation, as in MS in general. Although larger studies are needed for better risk assessment in younger patients with more active disease, ICI should be considered when needed in patients with MS.

Mononeuritis multiplex following immune checkpoint inhibitors in malignant pleural mesothelioma.

Introduction: Mononeuritis multiplex is frequently related to vasculitic neuropathy and has been reported only sporadically as an adverse event of immune checkpoint inhibitors. Methods: Case series of three patients with mononeuritis multiplex-all with mesothelioma-identified in the databases of two French clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; OncoNeuroTox, Paris; January 2015-October 2022) set up to collect and investigate n-irAEs on a nationwide level. Results: Three patients (male; median age 86 years; range 72-88 years) had pleural mesothelioma and received 10, 4, and 6 cycles, respectively, of first-line nivolumab plus ipilimumab combined therapy. In patient 1, the neurological symptoms involved the median nerves, and in the other two patients, there was a more diffuse distribution; the symptoms were severe (common terminology criteria for adverse events, CTCAE grade 3) in all patients. Nerve conduction studies indicated mononeuritis multiplex in all patients. Peripheral nerve biopsy demonstrated necrotizing vasculitis in patients 1 and 3 and marked IgA deposition without inflammatory lesions in patient 2. Immune checkpoint inhibitors were permanently withdrawn, and corticosteroids were administered to all patients, leading to complete symptom regression (CTCAE grade 0, patient 2) or partial improvement (CTCAE grade 2, patients 1 and 3). During steroid tapering, patient 1 experienced symptom recurrence and spreading to other nerve territories (CTCAE grade 3); he improved 3 months after rituximab and cyclophosphamide administration. Discussion: We report the occurrence of mononeuritis multiplex, a very rare adverse event of immune checkpoint inhibitors, in the three patients with mesothelioma. Clinicians must be aware of this severe, yet treatable adverse event.

Hypersomnia in anti-glutamic acid decarboxylase 65 (GAD65) associated neurological syndromes: A pilot study.

BACKGROUND AND PURPOSE: Despite their detrimental impact on the quality of life in autoimmune encephalitis, sleep disorders have not been investigated in anti-glutamic acid decarboxylase (GAD65) associated neurological syndromes. METHODS: Six consecutive adult patients diagnosed with anti-GAD65-associated neurological syndromes (four with limbic encephalitis and two with stiff-person syndrome) and 12 healthy controls were enrolled. Participants underwent sleep interviews and sleep studies including night-time video-polysomnography, followed by five daytime multiple sleep latency tests (MSLTs, to assess propensity to fall asleep) and an 18 h bed rest polysomnography (to assess excessive sleep need). RESULTS: Patients reported the need for daily naps and that their cognition and quality of life were altered by sleepiness, but they had normal scores on the Epworth sleepiness scale. Compared with controls, sleep latencies during the MSLT were shorter in the patient group (median 5.8 min, interquartile range [IQR] 4.5, 6.0 vs. 17.7 min, IQR 16.3, 19.7, p = 0.001), and the arousal index was reduced (2.5/h, IQR 2.3, 3.0 vs. 22.3/h, IQR 13.8, 30.0, p = 0.002), although total sleep time was similar between groups (621 min, IQR 464, 651 vs. 542.5 min, IQR 499, 582, p = 0.51). Remarkably, all six patients had MSLT latencies ≤8 min, indicating severe sleepiness. No parasomnia or sleep-disordered breathing was detected. CONCLUSION: Central hypersomnia is a relevant characteristic of anti-GAD65-associated neurological syndromes.

Late-onset vascular complications of radiotherapy for primary brain tumors: a case-control and cross-sectional analysis.

PURPOSE: Radiotherapy (RT) is a recognized risk factor for cerebrovascular (CV) disease in children and in adults with head and neck cancer. We aimed to investigate whether cerebral RT increases the risk of CV disease in adults with primary brain tumors (PBT). METHODS: We retrospectively identified adults with a supratentorial PBT diagnosed between 1975 and 2006 and with at least 10 years follow-up after treatment. We analyzed demographic, clinical, and radiological features with special attention to CV events. We also described CV events, vascular risk factors, and intracranial artery modifications in a cross-sectional study of irradiated patients alive at the time of the study. RESULTS: A total of 116 patients, treated with RT (exposed group), and 85 non-irradiated patients (unexposed group) were enrolled. Stroke was more frequent in irradiated PBT patients than in the unexposed group (42/116 (36%) vs 7/85 (8%); p < 0.001), with higher prevalence of both ischemic (27/116 (23%) vs 6/85 (7%); p = 0.004) and hemorrhagic (12/116 (10%) vs 1/85 (1%); p = 0.02) stroke. In the irradiated group, patients with tumors near the Willis Polygon were more likely to experience stroke (p < 0.016). Fourty-four alive irradiated patients were included in the cross-sectional study. In this subgroup, intracranial arterial stenosis was more prevalent (11/45, 24%) compared to general population (9%). CONCLUSIONS: Stroke prevalence is increased in long-surviving PBT patients treated with cranial RT. IMPLICATIONS FOR CANCER SURVIVORS: CV events are frequent in long survivors of PBT treated with cerebral RT. We propose a check list to guide management of late CV complications in adults treated with RT for PBT.

Revisiting anti-Hu paraneoplastic autoimmunity: phenotypic characterization and cancer diagnosis.

Anti-Hu are the most frequent antibodies in paraneoplastic neurological syndromes, mainly associated with an often limited stage small cell lung cancer. The clinical presentation is pleomorphic, frequently multifocal. Although the predominant phenotypes are well characterized, how different neurological syndromes associate is unclear. Likewise, no specific study assessed the performance of new-generation CT and PET scanners for cancer screening in these patients. Herein, we aimed to describe the clinical pattern and cancer screening in a retrospective cohort of 466 patients with anti-Hu autoimmunity from the French Reference Centre on Paraneoplastic Neurological Syndromes registry. Clinical presentation, cancer screening and diagnosis were analysed. Among the 466 patients, 220 (54%) had multifocal neurological involvement. A hierarchical cluster analysis grouped the patients into (i) mainly limbic encephalitis, (ii) predominantly peripheral neuropathy and (iii) broad involvement of the nervous system (mixed group). Compared with limbic encephalitis and mixed groups, patients in the neuropathy group more frequently had a chronic onset of symptoms (29 versus 13 and 17%), elevated CSF proteins (83 versus 47 and 67%) and died from cancer progression (67 versus 15 and 28%; all P < 0.05). No significant difference in overall survival was observed between groups. Dysautonomia and brainstem signs were associated with a higher risk of death from the neurological cause; cancer diagnosis was the main predictor of all-cause death, especially when diagnosed within 2 years from clinical onset (all P < 0.05). Three hundred and forty-nine (75%) patients had cancer: in 295 (84%) neurological symptoms preceded tumour diagnosis, being lung cancer in 262 (89%), thereof small cell lung cancer in 227 (87%). First CT scan revealed lung cancer in 205/241 (85%), and PET scan shortened the interval to diagnosis when the initial CT scan was negative [7 months (1-66) in 27 patients versus 14 months (2-45) in 6; P < 0.001]. Although cancer diagnosis mostly occurred within 2 years from clinical onset, 13/295 (4%) patients exceeded that threshold. Conversely, 33 patients (7%) were 'cancer-free' after 2 years of follow-up. However, 13/33 (39%) had initial suspicious imaging findings that spontaneously regressed. In conclusion, although anti-Hu autoimmunity clinical presentation is mostly multifocal, we observed patients with a predominant limbic syndrome or isolated sensory neuropathy. Early implementation of PET scan shortens the interval to cancer diagnosis, which was the strongest predictor of death, especially if diagnosed ≤2 years from clinical onset. As cancer was diagnosed >2 years after clinical onset in few patients, screening should be extended up to 5 years. In addition, tumour regression was suspected in a substantial proportion of 'cancer-free' patients.

Different Genetic Signatures of Small-Cell Lung Cancer Characterize Anti-GABAB R and Anti-Hu Paraneoplastic Neurological Syndromes.

OBJECTIVE: Small-cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular (Hu) or neuronal surface (GABAB R) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti-GABAB R or anti-Hu PNS compared with SCLC without PNS. METHODS: A total of 76 SCLC tumor samples were collected: 34 anti-Hu, 14 anti-GABAB R, and 28 SCLC without PNS. The study consisted of 4 steps: (1) pathological confirmation; (2) next generation sequencing using a panel of 98 genes, including those encoding the autoantibodies targets ELAVL1-4, GABBR1-2, and KCTD16; (3) genome-wide copy number variation (CNV); and (4) whole-transcriptome RNA sequencing. RESULTS: CNV analysis revealed that patients with anti-GABAB R PNS commonly have a gain in chromosome 5q, which contains KCTD16, whereas anti-Hu and control patients often harbor a loss. No significantly different number of mutations regarding any onconeural genes was observed. Conversely, the transcriptomic profile of SCLC was different, and the differentially expressed genes allowed effective clustering of the samples into 3 groups, reflecting the antibody-based classification, with an overexpression of KCTD16 specific to anti-GABAB R PNS. Pathway analysis revealed that tumors of patients with anti-GABAB R encephalitis were enriched in B-cell signatures, as opposed to those of patients with anti-Hu, in which T-cell- and interferon-γ-related signatures were overexpressed. INTERPRETATION: SCLC genetic and transcriptomic features differentiate anti-GABAB R, anti-Hu, and non-PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti-GABAB R PNS. ANN NEUROL 2023;94:1102-1115.

Anti-leucine-rich glioma-inactivated 1 encephalitis revealed by a manic episode: insights from frontal lobe dysfunction in neuropsychiatry through neuropsychology and metabolic imaging. A case report.

Background: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is a limbic encephalitis that rarely presents as an isolated psychiatric syndrome. Case presentation: A 70-year-old patient first presented with behavioral disorder including hyperactivity, euphoria, with disinhibition and accelerated speech associated with severe insomnia and cognitive disorder. A manic episode was diagnosed and he received various psychotropic medications with no improvement. Invesitgations were negative (MRI showed T2 aspecific hyperintensities with no hyperintensities in limbic regions and EEG was normal). He was transferred to a nursing home, with a diagnosis of neurodegenerative condition. Later, he was referred to our unit for further investigations. A cerebral 18F-FDG-PET revealed an association of frontal hypometabolism and temporal and striatum hypermetabolism and CSF analysis revealed slightly increased white blood cell counts. Plasmatic anti-LGI1 antibodies were detected. The patient was treated with intra-venous immunoglobulin (IvIg) but showed no improvement. Second-line treatment (a combination of rituximab and cyclophosmphamide) was then administered for a year, leading to an improvement of neuropsychiatric symptoms and normalization of metabolic impairment on 18F-FDG-PET. Conclusion: In this report, we describe a novel case of a patient withanti-LGI1 encephalitis with a predominant long-term psychiatric presentation. An atypical presentation (such as atypical psychiatric symptoms, neurocognitive disorder, and hyponatremia) should prompt further investigations such as CSF analysis, considering that MRI and EEG may be normal. FDG-PET might be of interest but few data are available in the literature. Early treatment of anti-LGI1 encephalitis is crucial for overall prognosis and may delay the development of dementia in some cases.

Neurological outcomes in immune checkpoint inhibitor-related neurotoxicity.

While the spectrum of neurological immune checkpoint inhibitor-related adverse events is expanding, patients' outcomes are not well documented. This study aimed to assess outcomes of neurological immune-related adverse events and to identify prognostic factors. All patients experiencing grade ≥2 neurological immune-related adverse events identified at two clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; and OncoNeuroTox, Paris) over five years were included. Modified Rankin scores were assessed at onset, 6, 12, 18 months, and last visit. A multi-state Markov model was used to estimate the transition rates between minor disability (mRS <3), severe disability (mRS 3-5), and death (mRS 6), over the study period. The state-to-state transition rates were estimated using maximum likelihood and variables were introduced into the different transitions to study their effects. A total of 147 patients were included out of 205 patients with a suspicion of neurological immune-related adverse events. The median age was 65 years (range 20-87) and 87/147 patients (59.2%) were male. Neurological immune-related adverse events involved the peripheral nervous system in 87/147 patients (59.2%), the central nervous system in 51/147 (34.7%), and both systems in 9/147 (6.1%). Paraneoplastic-like syndromes were observed in 30/147 patients (20.4%). Cancers included lung cancers (36.1%), melanoma (30.6%), urological cancers (15.6%), and others (17.8%). Patients were treated with programmed cell death protein (ligan) 1 (PD(L)1) inhibitors (70.1%), CTLA4 inhibitors (3.4%) or both (25.9%). Severe disability was reported in 108/144 patients (75.0%) at onset and in 33/146 patients (22.6%) at last visit (median follow-up duration: 12 months, range 0.5-50); 48/147 (32.7%) patients died, from cancer progression (17/48, 35.4%), neurological toxicity (15/48, 31.2%), other causes (10/48, 20.8%) or unknown causes (6/48, 12.5%). The rate of transition from severe to minor disability independently increased with melanoma [compared to lung cancer, hazard ratio = 3.26, 95%CI (1.27; 8.41)] and myositis/neuromuscular junction disorders [hazard ratio = 8.26, 95%CI (2.90; 23.58)], and decreased with older age [hazard ratio = 0.68, 95%CI (0.47; 0.99)] and paraneoplastic-like syndromes [hazard ratio = 0.29, 95%CI (0.09; 0.98)]. In patients with neurological immune-related adverse events, myositis/neuromuscular junction disorders and melanoma increase the transition rate from severe to minor disability, while older age and paraneoplastic-like syndromes result in poorer neurological outcomes; future studies are needed to optimize the management of such patients.

Spatial and Ecological Factors Modulate the Incidence of Anti-NMDAR Encephalitis-A Systematic Review.

Anti-NMDAR encephalitis has been associated with multiple antigenic triggers (i.e., ovarian teratomas, prodromal viral infections) but whether geographic, climatic, and environmental factors might influence disease risk has not been explored yet. We performed a systematic review and a meta-analysis of all published papers reporting the incidence of anti-NMDAR encephalitis in a definite country or region. We performed several multivariate spatial autocorrelation analyses to analyze the spatial variations in the incidence of anti-NMDA encephalitis depending on its geographical localization and temperature. Finally, we performed seasonal analyses in two original datasets from France and Greece and assessed the impact of temperature using an exposure-lag-response model in the French dataset. The reported incidence of anti-NMDAR encephalitis varied considerably among studies and countries, being higher in Oceania and South America (0.2 and 0.16 per 100,000 persons-year, respectively) compared to Europe and North America (0.06 per 100,000 persons-year) (p < 0.01). Different regression models confirmed a strong negative correlation with latitude (Pearson's R = -0.88, p < 0.00001), with higher incidence in southern hemisphere countries far from the equator. Seasonal analyses showed a peak of cases during warm months. Exposure-lag-response models confirmed a positive correlation between extreme hot temperatures and the incidence of anti-NMDAR encephalitis in France (p = 0.03). Temperature analyses showed a significant association with higher mean temperatures and positive correlation with higher ultraviolet exposure worldwide. This study provides the first evidence that geographic and climatic factors including latitude, mean annual temperature, and ultraviolet exposure, might modify disease risk.

Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. SIGNIFICANCE: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.

Brain Metabolic Alterations in Seropositive Autoimmune Encephalitis: An 18F-FDG PET Study.

INTRODUCTION: Autoimmune encephalitis (AE) diagnosis and follow-up remain challenging. Brain 18F-fluoro-deoxy-glucose positron emission tomography (FDG PET) has shown promising results in AE. Our aim was to investigate FDG PET alterations in AE, according to antibody subtype. METHODS: We retrospectively included patients with available FDG PET and seropositive AE diagnosed in our center between 2015 and 2020. Brain PET Z-score maps (relative to age matched controls) were analyzed, considering metabolic changes significant if |Z-score| ≥ 2. RESULTS: Forty-six patients were included (49.4 yrs [18; 81]): 13 with GAD autoantibodies, 11 with anti-LGI1, 9 with NMDAR, 5 with CASPR2, and 8 with other antibodies. Brain PET was abnormal in 98% of patients versus 53% for MRI. The most frequent abnormalities were medial temporal lobe (MTL) and/or striatum hypermetabolism (52% and 43% respectively), cortical hypometabolism (78%), and cerebellum abnormalities (70%). LGI1 AE tended to have more frequent MTL hypermetabolism. NMDAR AE was prone to widespread cortical hypometabolism. Fewer abnormalities were observed in GAD AE. Striatum hypermetabolism was more frequent in patients treated for less than 1 month (p = 0.014), suggesting a relation to disease activity. CONCLUSION: FDG PET could serve as an imaging biomarker for early diagnosis and follow-up in AE.

Narcolepsy secondary to anti-Ma2 encephalitis: two case reports.

Recent studies suggest that sleep disorders are present in two-thirds of patients with autoimmune encephalitis. In anti-Ma2 encephalitis, hypersomnia appears to be frequent. However, only few cases of type 1 narcolepsy have been reported to date with anti-Ma2 encephalitis. We report 2 new cases of patients with narcolepsy secondary to anti-Ma2 encephalitis. Patient 1, a 68-year-old man, had narcolepsy type 1, including sleep attacks, cataplexy, abnormal Multiple Sleep Latency Tests and hypocretin-1 deficiency (< 50 ng/L) in the cerebrospinal fluid (CSF), associated with a cerebellar syndrome. Anti-Ma2 antibodies were present in the serum and CSF and antivoltage-gated potassium channel antibodies in the serum. He benefited from a treatment with pitolisant. Patient 2, a 42-year-old man, had narcolepsy type 2, including hypersomnolence, no cataplexy, intermediate CSF levels of hypocretin-1 (138 ng/L), abnormal Multiple Sleep Latency Tests, and a limbic encephalitis presentation. Anti-Ma2 antibodies were present in the serum and CSF, and anti-Ma1 antibodies were in the CSF. For both, repeated polysomnographies were necessary to establish the precise diagnosis of central hypersomnia, emphasizing the importance of carrying out sleep investigations in a tertiary neurology center with sleep medicine expertise in patients with anti-Ma2 encephalitis. CITATION: Brunet de Courssou J-B, Testard P, Sallansonnet-Froment M, et al. Narcolepsy secondary to anti-Ma2 encephalitis: two case reports. J Clin Sleep Med. 2023;19(4):837-841.