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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 A total of 147 patients were included out of 205 patients with a suspicion of neurological immune-related adverse events. 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 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, HR = 3.26, 95%CI [1.27; 8.41]) and myositis/neuromuscular junction disorders (HR = 8.26, 95%CI [2.90; 23.58]), and decreased with older age (HR = 0.68, 95%CI [0.47; 0.99]) and paraneoplastic-like syndromes (HR = 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.

CAR-T cells are modified T cells expressing a chimeric antigen receptor targeting a specific antigen. They have revolutionized the treatment of B cell malignancies (aggressive lymphomas, B-ALL), and this has raised hopes for application in many other pathologies (myeloma, AML, solid tumors, etc.). However, these therapies are associated with novel and specific toxicities (cytokine release syndrome and neurotoxicity). These complications, although mostly managed in a conventional hospitalization unit, can sometimes be life threatening, leading to admission of patients to the intensive care unit. Management relies mainly on anti-IL6R (tocilizumab) and corticosteroids. However, the optimal treatment regimen is still a matter of debate, and the management of the most severe forms is even less well codified. In addition to CRS and ICANS, infections, cytopenia and hypogammaglobulinemia are other frequent complications. This article reviews the mechanisms, risk factors, clinical presentation, and management of these toxicities.

Platinum-based chemotherapy is commonly associated with toxic sensory neuropathies, but also, although rarely, with Guillain-Barré syndrome (GBS). We describe five patients who developed GBS while receiving platinum-based chemotherapy for a solid tumor and report the five cases published so far. Most patients had received cumulative platinum doses below known neurotoxic levels, and all of them had an optimal outcome after platinum discontinuation, associated in most cases with administration of intravenous immunoglobulin. Clinical presentation, electroneuromyography, and cerebrospinal fluid analysis help clinicians to differentiate GBS from toxic neuropathy. Platinum compounds are the only chemotherapeutic agents used for solid tumors that have been associated to GBS. Thus, we propose that GBS may constitute a non–dose-dependent side effect of platinum drugs and that awareness needs to be raised among oncologists on this rare but potentially life-threatening complication of platinum chemotherapy. Implications for Practice: Many patients on platinum-based chemotherapy for solid tumors develop sensory neuropathy, a common dose-dependent side effect. The authors propose that Guillain-Barré syndrome may constitute an immune-mediated, non-dose-related side effect of platinum-based chemotherapy. Prompt diagnosis of Guillain-Barré syndrome and distinction from classical toxic neuropathy are crucial for optimal treatment. Platinum discontinuation, associated if needed to intravenous immunoglobulin administration, radically changes the course of the disease and minimizes neurological sequelae.

ObjectiveTo define the characteristics and the outcome of myelitis associated with immune checkpoint inhibitors (ICIs).MethodsWe performed a retrospective research in the databases of the French Pharmacovigilance Agency and the OncoNeuroTox network for patients who developed myelitis following treatment with ICIs (2011–2020). A systematic review of the literature was performed to identify similar cases.ResultsWe identified 7 patients who developed myelitis after treatment with ICIs (anti-PD1 [n = 6], anti-PD1 + anti-CTLA4 [n = 1]). Neurologic symptoms included paraparesis (100%), sphincter dysfunction (86%), tactile/thermic sensory disturbances (71%), and proprioceptive ataxia (43%). At the peak of symptom severity, all patients were nonambulatory. MRI typically showed longitudinally extensive lesions, with patchy contrast enhancement. CSF invariably showed inflammatory findings. Five patients (71%) had clinical and/or paraclinical evidence of concomitant cerebral, meningeal, caudal roots, and/or peripheral nerve involvement. Despite the prompt discontinuation of ICIs and administration of high-dose glucocorticoids (n = 7), most patients needed second-line immune therapies (n = 5) because of poor recovery or early relapses. At last follow-up, only 3 patients had regained an ambulatory status (43%). Literature review identified 13 previously reported cases, showing similar clinical and paraclinical features. All patients discontinued ICIs and received high-dose glucocorticoids, with the addition of other immune therapies in 8. Clinical improvement was reported for 10 patients.ConclusionMyelitis is a rare but severe complication of ICIs that shows limited response to glucocorticoids. Considering the poor functional outcome associated with longitudinally extensive myelitis, strong and protracted immune therapy combinations are probably needed upfront to improve patient outcome and prevent early relapses.

Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1–2 severity and 34% had grade 3–4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3–4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.

Paroxysmal hypothermia (PH) is a rare condition characterized by recurrent episodes of spontaneous hypothermia, bradycardia, disorders of consciousness and, in some cases, hyperhidrosis. When associated with a detectable hypothalamic lesion, PH episodes usually occur shortly after the brain insult.We performed a retrospective study to identify patients who had demonstrated at least one episode of symptomatic spontaneous PH as defined by (i) tympanic temperature 35 °C; (ii) drowsiness and/or confusion state and/or coma; (iii) duration of the episode ≥ 24 h; (iv) absence of other condition resulting in hypothermia RESULTS: Among 8824 patients, we identified four patients with recurrent late-onset PH episodes of 1-26-day duration that occurred 6-46 years after the brain insult. The lesion always involved the diencephalon. All patients suffered from epilepsy and three of hypopituitarism. PH episode typically included severe hypothermia, bradycardia, drowsiness, thrombocytopenia and in some patients central hypoventilation and narcolepsy-like hypersomnia. In ¼ of episodes, confusion was mistaken as non-convulsive epileptic manifestation resulting in benzodiazepine administration which aggravated symptoms. In the two patients with nocturnal hypoventilation, chronic non-invasive ventilation with bi-level positive airway pressure allowed cessation of symptomatic episodes.Late-onset post-lesional PH is exceptional with only a single case hitherto reported in the literature. Distinguishing hypothermia-related disturbances of consciousness from epileptic seizures or post-ictal phenomena is crucial since treatment with benzodiazepines may worsen hypothermia through their action on GABAa receptors. Lastly, PH may be associated with sleep disorders and hypoventilation, for which investigations and treatment should be considered.

Two autologous anti-CD19 chimeric antigen receptors (CAR) T cells (axicabtagene ciloleucel [axi-cel] and tisagenlecleucel [tisa-cel]) are commercially approved in Europe for relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). We performed a retrospective study to evaluate patterns of use, efficacy and safety for axi-cel and tisa-cel. Data from 70 patients who underwent apheresis for commercial CAR T cells between January 2018 and November 2019 in our institution were retrospectively collected. Sixty-one patients were infused. The median age at infusion was 59 years old (range 27-75 years). The median number of prior therapies was 3 (range, 2-6). The overall response rates (ORRs) at 1 month and 3 months were 63% and 45%, respectively, with 48% and 39% achieving a complete response (CR), respectively. After a median follow-up after infusion of 5.7 months, the median progression-free survival (PFS) was 3.0 months (95% CI, 2.8-8.8 months), and the median overall survival (OS) was 11.8 months (95% CI, 6.0-12.6 months). In multivariate analysis, factors associated with poor PFS were the number of previous lines of treatment before CAR T cells (≥4) (P = .010) and a C reactive protein (CRP) value30 mg/L at the time of lymphodepletion (P .001). Likewise, the only factor associated with a shorter OS was CRP30 mg/L (P = .009). Cytokine release syndrome (CRS) of any grade occurred in 85% of patients, including 8% of patients with CRS of grade 3 or higher. Immune cell-associated neurotoxicity syndrome (ICANS) of any grade occurred in 28% of patients, including 10% of patients with ICANS of grade 3 or higher. Regarding efficacy and safety, no significant difference was found between axi-cel and tisa-cel. This analysis describes one of the largest real-life cohorts of patients treated with axi-cel and tisa-cel for R/R aggressive B cell lymphoma in Europe.

Introduction Diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) remains uncertain when nerve conduction studies (NCS) fail to show demyelination. Methods We conducted a retrospective study of patients who presented with clinical criteria of CIDP in whom electrodiagnostic (EDx) criteria of definite or probable CIDP were missing [axonal sensorimotor neuropathy (n = 23), normal EDx with pure sensory presentation (n = 3)]. All patients received immunomodulatory treatment. Twenty-six patients were evaluated with somatosensory evoked potentials (SSEPs), MRI of spinal roots, cerebrospinal fluid analysis, and/or nerve biopsy. Diagnosis of CIDP was considered to be confirmed in patients who responded to immunotherapy. Results Twenty-two of 26 patients (85%) had SSEPs reflecting abnormal proximal conduction in sensory fibers, including 14 who had only clinical and SSEP data in favor of CIDP. SSEPs were abnormal in 16 of 20 responders (80%) to immunotherapy. Conclusion SSEP recording contributes to the diagnosis of CIDP when nerve conduction studies fail to detect peripheral demyelination.

Introduction: Distal hereditary motor neuropathy (dHMN) is characterized by isolated distal muscle atrophy without sensory deficit. Nevertheless, clinical sensory loss has been reported despite preserved sensory nerve conduction in a few patients, thus differentiating these cases from the classical type 2 Charcot-Marie-Tooth disease (CMT2). Methods: We report 4 patients who presented with clinical sensory and motor neuropathy and normal peripheral sensory nerve conduction studies and were investigated with complete electrophysiological studies, including somatosensory evoked potentials (SEP). Results: These patients had a clinical presentation of classical CMT with isolated axonal motor neuropathy suggestive of dHMN. Interestingly, tibial nerve SEPs showed abnormalities suggestive of proximal involvement of dorsal roots that may explain the clinical somatosensory disturbances. Conclusions: These cases support the concept of spinal CMT that should be recognized as an intermediate form between dHMN and CMT2. SEP recording was helpful in defining a more precise phenotype of spinal CMT. Muscle Nerve 46: 603–607, 2012

A 43-year-old woman was admitted in our department for progressive ataxia, headache and altered general status lasting for 3 weeks. Brain magnetic resonance imaging (MRI) showed multifocal lesions in hypersignal T2 and with homogeneous gadolinium enhancement in T1 sequences (Figure 1). Extensive cerebrospinal fluid (CSF) examination with isoelectric focusing, search for malignant or lymphomatous cells, microbacterial analysis, including China ink and mycobacterium cultures and polymerase chain reaction (PCR), trophyrema whippeli PCR was normal. Thorax and abdomen computerized tomography (CT) scan, bone scintigraphy, whole body positron emission tomography (PET) fluorodesoxyglucose (FDG) scan, bones X-rays and bone marrow biopsy did not show any abnormality. Figure 1. Axial and sagittal brain and spine MRI views showing multifocal lesions involving the corpus callosum, right middle cerebellar peduncle, right periventricular white matter, cervical and …

Electroconvulsive therapy (ECT) is a safe and highly effective treatment for certain major mental disorders, including major depressive disorder, bipolar disorder, and certain forms of schizophrenia. The most frequently reported side effects are anterograde amnesia, post-ictal confusion, nausea, headache, myalgia, oral lacerations, and dental injuries. Hyperthermia is not commonly described as a side-effect of ECT. Examination of older texts find reports of fevers occurring after seizures, 1 but the occurrence of hyperthermia after ECT has not been reported since then. We report the case of a patient who experienced four transient high-grade fever episodes following ECT. We provide a differential diagnosis of fever in this particular clinical setting and raise the hypothesis of a neurogenic fever induced by ECT.