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ObjectiveTo evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).MethodsWe enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria.ResultsAfter a median follow-up of 50 months (IQR 25–82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement ( ≥ 3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥ 30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma.ConclusionsOur study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥ 30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive.

We evaluated the effect of DMTs on Covid‐19 severity in patients with MS, with a pooled‐analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid‐19 severity was assessed by multivariate ordinal‐logistic models and pooled by a fixed‐effect meta‐analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti‐CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid‐19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled‐analysis confirms an increased risk of severe Covid‐19 in patients on anti‐CD20 therapies and supports the protective role of interferon.

Objectives To compare brain MRI findings in progressive multifocal leukoencephalopathy (PML) associated to rituximab and natalizumab treatments and HIV infection. Materials and methods In this retrospective, multicentric study, we analyzed brain MRI exams from 72 patients diagnosed with definite PML: 32 after natalizumab treatment, 20 after rituximab treatment, and 20 HIV patients. We compared T2- or FLAIR-weighted images, diffusion-weighted images, T2*-weighted images, and contrast enhancement features, as well as lesion distribution, especially gray matter involvement. Results The three PML entities affect U-fibers associated with low signal intensities on T2*-weighted sequences. Natalizumab-associated PML showed a punctuate microcystic appearance in or in the vicinity of the main PML lesions, a potential involvement of the cortex, and contrast enhancement. HIV and rituximab-associated PML showed only mild contrast enhancement, punctuate appearance, and cortical involvement. The CD4/CD8 ratio showed a trend to be higher in the natalizumab group, possibly mirroring a more efficient immune response. Conclusion Imaging features of rituximab-associated PML are different from those of natalizumab-associated PML and are closer to those observed in HIV-associated PML. Key Points • Nowadays, PML is emerging as a complication of new effective therapies based on monoclonal antibodies. • Natalizumab-associated PML shows more inflammatory signs, a perivascular distribution “the milky way,” and more cortex involvement than rituximab- and HIV-associated PML. • MRI differences are probably related to higher levels of immunosuppression in HIV patients and those under rituximab therapy.

Background Longitudinally extensive transverse myelitis (LETM) is classically related to aquaporin (AQP4)-antibodies (Ab) neuromyelitis optica spectrum disorders (NMOSD) or more recently to myelin oligodendrocyte glycoprotein (MOG)-Ab associated disease. However, some patients remain negative for any diagnosis, despite a large work-up including AQP4-Ab and MOG-Ab. Data about natural history, disability outcome, and treatment are limited in this group of patients. We aimed to (1) describe clinical, biological, and radiological features of double seronegative LETM patients; (2) assess the clinical course and identify prognostic factors; and (3) assess the risk of recurrence, according to maintenance immunosuppressive therapy. Methods Retrospective evaluation of patients with a first episode of LETM, tested negative for AQP-Ab and MOG-Ab, from the French nationwide observatory study NOMADMUS. Results Fifty-three patients (median age 38 years (range 16–80)) with double seronegative LETM were included. Median nadir EDSS at onset was 6.0 (1–8.5), associated to a median EDSS at last follow-up of 4.0 (0–8). Recurrence was observed in 24.5% of patients in the 18 following months, with a median time to first relapse of 5.7 months. The risk of recurrence was lower in the group of patients treated early with an immunosuppressive drug (2/22, 9%), in comparison with untreated patients (10/31, 32%). Conclusions A first episode of a double seronegative LETM is associated to a severe outcome and a high rate of relapse in the following 18 months, suggesting that an early immunosuppressive treatment may be beneficial in that condition.

T cells differentiate into functionally distinct effector subsets in response to pathogen encounter. Cells of the innate immune system direct this process; CD1d-restricted invariant natural killer T (iNKT) cells, for example, can either promote or inhibit Th₁ and Th₂ responses. Recently, a new subset of CD4⁺ T helper cells, called Th₁₇, was identified that is implicated in mucosal immunity and autoimmune disorders. To investigate the influence of iNKT cells on the differentiation of naïve T cells we used an adoptive transfer model of traceable antigen-specific CD4⁺ T cells. Transferred naïve CD25⁻CD62L⁺ CD4⁺ T cells were primed by antigen immunization of the recipient mice, permitting their expansion and Th₁₇ differentiation. This study establishes that in vivo activation of iNKT cells during T-cell priming impedes the commitment of naïve T cells to the Th₁₇ lineage. In vivo cytokine neutralization experiments revealed a role for IL-4, IL-10, and IFN-γ in the iNKT-cell-mediated regulation of T-cell lineage development. Moreover, by comparing IL-17 production by antigen-experienced T cells from unmanipulated wild-type mice and iNKT-cell-deficient mice, we demonstrate an enhanced Th₁₇ response in mice lacking iNKT cells. This invigorated Th₁₇ response reverts to physiological levels when iNKT cells are introduced into Jα18⁻/⁻ mice by adoptive transfer, indicating that iNKT cells control the Th₁₇ compartment at steady state. We conclude that iNKT cells play an important role in limiting development of the Th₁₇ lineage and suggest that iNKT cells provide a natural barrier against Th₁₇ responses.

ObjectiveTo assess the efficacy of tumour necrosis factor-α (TNF-α) inhibitors used as steroid-sparing monotherapy in central nervous system (CNS) parenchymal sarcoidosis.MethodsThe French Multiple Sclerosis and Neuroinflammation Centers retrospectively identified patients with definite or probable CNS sarcoidosis treated with TNF-α inhibitors as steroid-sparing monotherapy. Only patients with CNS parenchymal involvement demonstrated by MRI and imaging follow-up were included. The primary outcome was the minimum dose of steroids reached that was not associated with clinical or imaging worsening during a minimum of 3 months after dosing change.ResultsOf the identified 38 patients with CNS sarcoidosis treated with TNF-α inhibitors, 23 fulfilled all criteria (13 females). Treatments were infliximab (n=22) or adalimumab (n=1) for a median (IQR) of 24 (17–40) months. At treatment initiation, the mean (SD) age was 41.5 (10.5) years and median (IQR) disease duration 22 (14–49.5) months. Overall, 60% of patients received other immunosuppressive agents before a TNF-α inhibitor. The mean (SD) minimum dose of steroids was 31.5 (33) mg before TNF-α inhibitor initiation and 6.5 (5.5) mg after (p=0.001). In all, 65% of patients achieved steroids dosing <6 mg/day; 61% showed clinical improvement, 30% stability and 9% disease worsening. Imaging revealed improvement in 74% of patients and stability in 26%.ConclusionTNF-α inhibitors can greatly reduce steroids dosing in patients with CNS parenchymal sarcoidosis, even refractory.Classification of evidenceThis study provides Class IV evidence that TNF-α inhibitor used as steroid-sparing monotherapy is effective for patients with CNS parenchymal sarcoidosis.

BackgroundSerum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) have emerged as important biomarkers in multiple sclerosis (MS) and aquaporin-4 seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD). However, their interest in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remains unclear. Our aim was to characterise sNfL and sGFAP profile and analyse their usefulness in predicting relapses and disability in MOGAD.MethodsRetrospective study of adult MOGAD patients with serum samples collected at baseline (≤3 months from disease onset) and follow-up (>6 months from baseline sample). sNfL and sGFAP were analysed using Simoa HD-1, and values were compared across time-points. The association between biomarkers and clinical variables and their predictive value for disability and relapses were analysed.ResultsEighty-nine MOGAD patients were included. Baseline sNfL and sGFAP values were high at baseline and decreased over time (p<0.001, p=0.027, respectively). sNfL and sGFAP values were associated with Expanded Disability Status Scale (EDSS) at attacks (β 0.15 (0.06; 0.25), p=0.002; β 0.14 (0.07; 0.21), p<0.001, respectively) and were lower in optic neuritis presentations (β −0.69 (−1.18; −0.19), p=0.007; β −0.42 (−0.76; −0.08), p=0.016). Biomarker deltas[Δ] (baseline values – second samples values) were associated with ΔEDSS (initial EDSS - final EDSS) (ΔsNfL β 0.52 (0.01; 1.04), p=0.046; ΔsGFAP β 1.07 (0.38; 1.75), p=0.003). Finally, sNfL values independently predicted the risk of relapses (HR 2.06 (1.41; 3.01), p<0.001).ConclusionsOur results on sNfL and sGFAP suggest initial neuro-axonal and astrocytic damage in MOGAD and the utility of these biomarkers at onset and follow-up in predicting clinical recovery and relapses.

Our patient is a woman who developed a subacute amnestic syndrome, followed by cognitive impairment, headache, temporal lobe epilepsy and hyponatraemia. An early-stage asymptomatic breast cancer was identified on positron emission tomography (PET) scan. After treatment with immunotherapy with high-dose corticosteroids, intravenous immunoglobulins, upfront rituximab and excision of the tumour, the patient gradually recovered. Partial retrograde and anterograde amnesia persisted during the initial weeks, followed by slow and steady improvement. Autoimmune encephalitis is a severe neurological disorder associated with antibodies against neuronal cell-surface or intracellular onconeural proteins. Anti-leucine-rich glioma inactivated 1 (LGI1) predominantly affects males in the seventh decade of life, and less than 10% of all cases are associated with cancer. Paraneoplastic cases have been associated with malignant thymoma, neuroendocrine tumours and mesothelioma and usually had Morvan syndrome, in which serum antibodies are more frequently directed against CASPR2 than against LGI1. We report the first well-documented case of anti-LGI1 limbic encephalitis in a woman with newly diagnosed breast cancer.

Individuals carrying the amyloidogenic transthyretin (TTR) mutation are predisposed to develop familial amyloid polyneuropathy (FAP). The first clinical manifestations are often subjective sensory symptoms and, therefore, objective markers are needed to confirm the onset of TTR-FAP. The purpose of this study was to evaluate the usefulness of a comprehensive battery of neurophysiological tests to provide early markers of FAP in TTR-mutation carriers. Twenty patients with documented pathogenic TTR mutation were enrolled, including eight clinically asymptomatic carriers and 12 paucisymptomatic carriers who had subjective sensory symptoms or doubtful sensory signs but no firm clinical deficit at clinical examination. Neurophysiological assessment of large fibres consisted of conventional nerve conduction studies. Small-fibre tests included laser evoked potentials, sympathetic skin responses and the measurement of cold and warm detection thresholds and heart-rate variability. Abnormalities in small-fibre tests were found in two of the eight asymptomatic carriers and nine of the 12 paucisymptomatic carriers. In contrast, conventional conduction studies did not show any sign of polyneuropathy. Early neuropathic involvement in TTR-mutation carriers can be detected or confirmed by neurophysiological tests specifically assessing small nerve fibres. These tests did not show any redundancy or difference in their sensitivity, emphasizing the value of combining them for TTR-FAP diagnosis.

T cells differentiate into functionally distinct effector subsets in response to pathogen encounter. Cells of the innate immune system direct this process; CD1d-restricted invariant natural killer T (iNKT) cells, for example, can either promote or inhibit Th 1 and Th 2 responses. Recently, a new subset of CD4 + T helper cells, called Th 17 , was identified that is implicated in mucosal immunity and autoimmune disorders. To investigate the influence of iNKT cells on the differentiation of naïve T cells we used an adoptive transfer model of traceable antigen-specific CD4 + T cells. Transferred naïve CD25 − CD62L + CD4 + T cells were primed by antigen immunization of the recipient mice, permitting their expansion and Th 17 differentiation. This study establishes that in vivo activation of iNKT cells during T-cell priming impedes the commitment of naïve T cells to the Th 17 lineage. In vivo cytokine neutralization experiments revealed a role for IL-4, IL-10, and IFN-γ in the iNKT-cell-mediated regulation of T-cell lineage development. Moreover, by comparing IL-17 production by antigen-experienced T cells from unmanipulated wild-type mice and iNKT-cell-deficient mice, we demonstrate an enhanced Th 17 response in mice lacking iNKT cells. This invigorated Th 17 response reverts to physiological levels when iNKT cells are introduced into Jα18 −/− mice by adoptive transfer, indicating that iNKT cells control the Th 17 compartment at steady state. We conclude that iNKT cells play an important role in limiting development of the Th 17 lineage and suggest that iNKT cells provide a natural barrier against Th 17 responses.