Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia

We report on a serum autoantibody associated with cerebellar ataxia. Immunohistochemical studies of sera from four patients referred for autoantibody testing revealed binding of high-titer (up to 1:5,000) IgG antibodies, mainly IgG1, to the molecular layer, Purkinje cell layer, and white matter on mouse, rat, porcine, and monkey cerebellum sections. The antibody bound to PC somata, dendrites, and axons, resulting in a binding pattern similar to that reported for anti-Ca/anti-ARHGAP26, but did not react with recombinant ARHGAP26. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic anti-neural autoantibodies. The characteristic binding pattern as well as double staining experiments suggested inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) as the target antigen. Verification of the antigen included specific neutralization of the tissue reaction following preadsorption with ITPR1 (but not ARHGAP26) and a dot-blot assay with purified ITPR1 protein. By contrast, anti-ARHGAP26-positive sera did not bind to ITPR1. In a parallel approach, a combination of histoimmunoprecipitation and mass spectrometry also identified ITPR1 as the target antigen. Finally, a recombinant cell-based immunofluorescence assay using HEK293 cells expressing ITPR1 and ARHGAP26, respectively, confirmed the identification of ITPR1. Mutations of ITPR1 have previously been implicated in spinocerebellar ataxia with and without cognitive decline. Our findings suggest a role of autoimmunity against ITPR1 in the pathogenesis of autoimmune cerebellitis and extend the panel of diagnostic markers for this disease

Balance Impairment in Radiation Induced Leukoencephalopathy Patients Is Coupled With Altered Visual Attention in Natural Tasks

Background: Recent studies have shown that alterations in executive function and attention lead to balance control disturbances. One way of exploring the allocation of attention is to record eye movements. Most experimental data come from a free viewing of static scenes but additional information can be leveraged by recording eye movements during natural tasks. Here, we aimed to provide evidence of a correlation between impaired visual alteration in natural tasks and postural control in patients suffering from Radiation-Induced Leukoencephalopathy (RIL).Methods: The study subjects were nine healthy controls and 10 patients who were diagnosed with RIL at an early stage, with isolated dysexecutive syndrome without clinically detectable gait or posture impairment. We performed a balance evaluation and eye movement recording during an ecological task (reading a recipe while cooking). We calculated a postural score and oculomotor parameters already proposed in the literature. We performed a variable selection using an out-of-bag random permutation and a random forest regression algorithm to find: (i) if visual parameters can predict postural deficit and, (ii) which are the most important of them in this prediction. Results were validated using the leave-one-out cross-validation procedure.Results: Postural scores indeed were found significantly lower in patients with RIL than in healthy controls. Visual parameters were found able to predict the postural score of RIL patients with normalized root mean square error (RMSE) of 0.16. The present analysis showed that horizontal and vertical eye movements, as well as the average duration of the saccades and fixations influenced significantly the prediction of the postural score in RIL patients. While two patients with very low MATTIS-Attention sub score showed the lowest postural scores, no statistically significant relationship was found between the two outcomes.Conclusion: These results highlight the significant relationship between the severity of balance deficits and the visual characteristics in RIL patients. It seems that increased balance impairment is coupled with a reduced focusing capacity in ecological tasks. Balance and eye movement recordings during a natural task could be a useful aspect of multidimensional scoring of the dysexecutive syndrome

Mononeuritis multiplex following immune checkpoint inhibitors in malignant pleural mesothelioma

IntroductionMononeuritis multiplex is frequently related to vasculitic neuropathy and has been reported only sporadically as an adverse event of immune checkpoint inhibitors.MethodsCase 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.ResultsThree 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.DiscussionWe 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

Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes

The contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS.A panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project.The panel proposed to substitute "classical syndromes" with the term "high-risk phenotypes" for cancer and introduce the concept of "intermediate-risk phenotypes." The term "onconeural antibody" was replaced by "high risk" (>70% associated with cancer) and "intermediate risk" (30%-70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided.The proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

Relevance of Brain 18F-FDG PET Imaging in Probable Seronegative Encephalitis With Catatonia: A Case Report

Autoimmune encephalitis (AIE) is a rare, severe, and rapidly progressive encephalopathy, and its diagnosis is challenging, especially in adolescent populations when the presentation is mainly psychiatric. Currently, cerebral 18-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) imaging is not included in the diagnosis algorithm. We describe a 16-year-old patient with probable seronegative encephalitis with catatonia for which several cerebral PET scans were relevant and helpful for diagnosis, treatment decision making, and follow-up monitoring. The patient recovered after 2 years of treatment with etiologic treatment of AIE and treatment of catatonia. This case suggests a more systematic assessment of the clinical relevance of 18F-FDG-PET imaging in probable seronegative AIE

Correspondence between neurophysiological and clinical measurements of chemotherapy-induced peripheral neuropathy: secondary analysis of data from the CI-PeriNoms study

Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN

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