Narrative Review on the Use of Cladribine Tablets as Exit Therapy for Stable Elderly Patients with Multiple Sclerosis.

The number of ageing people with relapsing multiple sclerosis (RMS) is increasing. The efficacy of disease-modifying therapies (DMTs) for RMS declines with age. Also, older persons with MS may be more susceptible to infections, hospitalisations and malignancy. Aging people with MS have higher rates of comorbidities versus aged-matched controls, increasing the individual risk of disability. We review the therapeutic properties of cladribine tablets (CladT) in ageing people with RMS, with regard to their utility for allowing these individuals to cease continuous administration of a DMT (i.e. to act as an "exit therapy"). CladT is thought to be an immune reconstitution therapy, in that two short courses of oral treatment 1 year apart provide suppression of MS disease activity in responders that far outlasts the duration of treatment and post-treatment reductions in lymphocyte counts. Post hoc analyses, long-term follow-up of populations with RMS in randomised trials, and real-world evidence suggest that the efficacy of CladT is probably independent of age, although more data in the elderly are still needed. No clear adverse signals for lymphopenia or other adverse safety signals have emerged with increasing age, although immunosenescence in the setting of age-related "inflammaging" may predispose elderly patients to a higher risk of infections. Updating vaccination status is recommended, especially against pneumococci and herpes zoster for older patients, to minimise the risk of these infections. CladT may be a useful alternative treatment for ageing people with MS who often bear a burden of multiple comorbidities and polypharmacy and who are more exposed to the adverse effects of continuous immunosuppressive therapy.

Highly Effective Therapies as First-Line Treatment for Pediatric-Onset Multiple Sclerosis.

Importance: Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus. Objective: To assess the real-world association of HET as an index treatment compared with MET with disease activity. Design, Setting, and Participants: This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate. Exposure: HET or MET at treatment initiation. Main Outcomes and Measures: The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions. Results: Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09). Conclusions and Relevance: Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.

Expert Narrative Review of the Safety of Cladribine Tablets for the Management of Relapsing Multiple Sclerosis.

Cladribine tablets (CladT) is a highly active oral disease-modifying therapy (DMT) for the management of relapsing multiple sclerosis (RMS). CladT acts as an immune reconstitution therapy, in that two short courses of treatment 1 year apart have been shown to suppress disease activity for a prolonged period in most patients, without need for continued DMT. Each course of CladT induces a profound reduction in B lymphocytes that recovers over months, and serious lymphopenia (Grade 3-4) is uncommon. Smaller reductions in levels of T lymphocytes occur slightly later: on average, these remain within the normal range and repopulate progressively. A larger effect occurs on CD8 vs. CD4 cells. Reactivation of latent or opportunistic infections (e.g. varicella zoster, tuberculosis) is mostly associated with very low lymphocyte counts (< 200/mm3). Screening and managing pre-existing infections, vaccinating non-exposed patients and delaying the 2nd year of treatment with CladT to allow lymphocytes to recover to > 800/mm3 (if necessary) are important for avoiding infections and higher-grade lymphopenia. There was no demonstrable or apparent effect of CladT on the efficacy of vaccinations, including against Covid-19. Adverse events consistent with drug-induced liver injury (DILI) represent a rare but potentially serious complication of CladT therapy in spontaneous adverse event reporting; patients should be screened for liver dysfunction before starting treatment. Ongoing hepatic monitoring is not required, but CladT must be withdrawn if signs and symptoms of DILI develop. There was a numerical imbalance for malignancies when comparing cladribine to placebo in the clinical programme, particularly in short-term data, but recent evidence shows that the risk of malignancy with CladT is similar to the background rate in the general population and to that with other DMTs. Overall, CladT is well tolerated with a favorable safety profile appropriate for the management of RMS.

Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome.

Importance: Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown. Objectives: To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria. Design, Setting, and Participants: This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021. Exposure: Diagnosis of RIS. Main Outcomes and Measures: Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors. Results: Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15]; P < .001), spinal cord lesions (HR, 5.11 [95% CI, 1.99-13.13]; P = .001), and gadolinium-enhancing lesions on index scan (HR, 2.09 [95% CI, 1.13-3.87]; P = .02) were independently associated with an increased risk of conversion to MS. Having 2 factors at the time of the index MRI scan was associated with a risk of 27.9% (95% CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95% CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 [95% CI, 9.08-59.96]; P < .001). Overall, with 80% power to detect an effect size of 60% within 24 months, a total of 160 individuals with RIS were needed assuming an event rate of 20%. Conclusions and Relevance: This study found that age younger than age 37 years, spinal cord involvement, and gadolinium-enhancing lesions on index MRI scan were associated with earlier clinical disease and relevant to the number of enrolled patients needed to detect a potential treatment effect.

Untreated patients with multiple sclerosis: A study of French expert centers.

BACKGROUND AND PURPOSE: Disease-modifying therapies (DMTs) have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (MS) remain untreated. The objectives of the present study were to determine the proportion of untreated patients with MS followed in expert centers in France and to determine the predictive factors of nontreatment. METHODS: We conducted a retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on December 15, 2018, and patients with MS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included. RESULTS: Of the 21,189 patients with MS (age 47.1 ± 13.1 years; Expanded Disability Status Scale (EDSS) score 3.4 ± 2.4), 6,631 (31.3%; 95% confidence interval [CI] 30.7-31.9) were not receiving any DMT. Although patients with a relapsing-remitting course (n = 11,693) were the most likely to receive DMT, 14.8% (95% CI 14.2-15.4) were still untreated (6.8% never treated). After multivariate analysis among patients with relapsing-remitting MS, the main factors explaining never having been treated were: not having ≥9 lesions on brain magnetic resonance imaging (odds ratio [OR] 0.52 [95% CI 0.44-0.61]) and lower EDSS score (OR 0.78 [95% CI 0.74-0.82]). Most patients with progressive MS (50.4% for secondary and 64.2% for primary progressive MS) did not receive any DMT during the study period, while 11.6% of patients with secondary and 34.0% of patients with primary progressive MS had never received any DMT. CONCLUSION: A significant proportion of patients with MS did not receive any DMT, even though such treatments are reimbursed by the healthcare system for French patients. This result highlights the unmet need for current DMTs for a large subgroup of patients with MS.

Long-term effect of natalizumab in patients with RRMS: TYSTEN cohort.

BACKGROUND: Data are needed on long-term effect of natalizumab (NTZ) in relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To evaluate the time of onset of secondary progressive phase in patients with an RRMS treated with NTZ and to investigate predictive factors. METHODS: TYSTEN is an observational study. Patients starting NTZ between 2007 and 2012 were included and followed up until October 2018. Relapses, Expanded Disability Status Scale (EDSS) scores, and results of brain magnetic resonance imaging (MRI) were collected each year. Data were used to estimate the cumulative probability of several poor outcomes such as secondary progressive multiple sclerosis (SPMS) conversion, EDSS worsening, EDSS 4.0, and EDSS 6.0. RESULTS: 770 patients were included. The mean follow-up duration was 97 months and the mean time exposure to NTZ was 66 months. At 10 years, the cumulative probability of SPMS was 27.7%. Predictive factors for poor outcomes were a ⩾1-point increase in EDSS score from baseline, new T2 lesion or T1 gadolinium-enhancing lesion, the occurrence of relapse at 1 or 2 years and No Evidence of Disease Activity (NEDA-3; no relapse, no new T2 or T1 gadolinium-enhancing lesions, no progression) was a protective factor. CONCLUSION: In our cohort of patients treated with NTZ, poor outcomes were infrequent and are driven by disease activity.

Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study.

BACKGROUND: Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy. OBJECTIVE: To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo. METHODS: POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo. RESULTS: Recruitment was stopped prematurely due to slow inclusions (n = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58-1.39), placebo = 0.97 (0.63-1.50) (p = 0.79)). CONCLUSION: POPARTMUS failed showing efficacy of a NOMAc-E2 combination in preventing post-partum relapses.

Progressive multifocal leukoencephalopathy: MRI findings in HIV-infected patients are closer to rituximab- than natalizumab-associated PML.

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.

BEST-MS: A prospective head-to-head comparative study of natalizumab and fingolimod in active relapsing MS.

BACKGROUND: There are few head-to-head studies to compare highly active treatments in multiple sclerosis (MS). OBJECTIVE: The aim of this study was to compare the effectiveness between natalizumab (NTZ) and fingolimod (FTY) in active relapsing-remitting MS. METHOD: Best Escalation STrategy in Multiple Sclerosis (BEST-MS) is a multicentric, prospective study with a 12-month follow-up including patients with active MS. Treatment choice was at the discretion of physician. Clinical and magnetic resonance imaging (MRI) data were collected at baseline and at 12 months. The primary outcome was the proportion of patients reaching no evidence of disease activity (NEDA) at 12 months. Secondary outcomes included annualized relapse rate and MRI activity. RESULTS: A total of 223 patients were included (NTZ: 109 and FTY: 114). Treatment groups were well balanced at baseline. Proportion of NEDA patients was 47.8% in NTZ group versus 30.4% in FTY group (p = 0.015). This superiority was driven by annualized relapse rate and MRI activity. In the multivariate analysis, treatment group was the only factor associated with NEDA at 12 months with a lower probability in FTY group (odds ratio (OR) = 0.49, p = 0.029). CONCLUSION: BEST-MS is a prospective study that compared head-to-head the effectiveness of NTZ and FTY in active relapsing-remitting MS. Our results suggest a superiority of NTZ over FTY.

Inadequate Immune Humoral Response against JC Virus in Progressive Multifocal Leukoencephalopathy Non-Survivors.

JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients. There is currently no effective specific antiviral treatment and PML management relies on immune restoration. Prognosis markers are crucially needed in this disease because of its high mortality rate. In this work, we investigated the compartmentalization of JCV strains as well as the humoral neutralizing response in various matrices to further understand the pathophysiology of PML and define markers of survival. Four patients were included, of which three died in the few months following PML onset. Cerebrospinal fluid (CSF) viral loads were the highest, with plasma samples having lower viral loads and urine samples being mostly negative. Whether at PML onset or during follow-up, neutralizing antibody (NAb) titers directed against the same autologous strain (genotype or mutant) were the highest in plasma, with CSF titers being on average 430-fold lower and urine titers 500-fold lower at the same timepoint. Plasma NAb titers against autologous genotype or mutant were lower in non-survivor patients, though no neutralization "blind spot" was observed. The surviving patient was followed up until nine months after PML onset and presented, at that time, an increase in neutralizing titers, from 38-fold against the autologous genotype to around 200-fold against PML mutants. Our results suggest that patients' humoral neutralizing response against their autologous strain may play a role in PML outcome, with survivors developing high NAb titers in both plasma and CSF.

Evaluation of the performance of SARS-CoV-2 serological tools and their positioning in COVID-19 diagnostic strategies.

Rapid and accurate diagnosis is crucial for successful outbreak containment. During the current coronavirus disease 2019 (COVID-19) public health emergency, the gold standard for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnosis is the detection of viral RNA. Additional diagnostic methods õenabling the detection of current or past SARS-CoV-2 infection would be highly beneficial. We assessed 2 immunochromatographic lateral flow assays (LFA-1, LFA-2) and 2 enzyme-linked immunosorbent assay kits (IgA/IgG ELISA-1, IgM/IgG ELISA-2) using 325 samples: serum samples from polymerase chain reaction-confirmed COVID-19 hospitalized patients (n = 55) and healthcare workers (n = 143) and 127 samples from negative controls. Diagnostic performances were assessed according to days after symptom onset (dso) and the antigenic format used by manufacturers. Clinical sensitivities varied greatly among the assays, showing poor mutual agreement. After 15 dso, ELISA-1 (Euroimmun) and LFA-1 (Biosynex) combining IgM and IgG detection showed the best performances. A thorough selection of serological assays for the detection of ongoing or past infections is advisable.

Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that preferentially affects the spinal cord and optic nerve. Most patients with NMOSD experience severe relapses that lead to permanent neurologic disability; therefore, limiting frequency and severity of these attacks is the primary goal of disease management. Currently, patients are treated with immunosuppressants. Interleukin-6 (IL-6) is a pleiotropic cytokine that is significantly elevated in the serum and the CSF of patients with NMOSD. IL-6 may have multiple roles in NMOSD pathophysiology by promoting plasmablast survival, stimulating the production of antibodies against aquaporin-4, disrupting blood-brain barrier integrity and functionality, and enhancing proinflammatory T-lymphocyte differentiation and activation. Case series have shown decreased relapse rates following IL-6 receptor (IL-6R) blockade in patients with NMOSD, and 2 recent phase 3 randomized controlled trials confirmed that IL-6R inhibition reduces the risk of relapses in NMOSD. As such, inhibition of IL-6 activity represents a promising emerging therapy for the management of NMOSD manifestations. In this review, we summarize the role of IL-6 in the context of NMOSD.

Outcome and risk of recurrence in a large cohort of idiopathic longitudinally extensive transverse myelitis without AQP4/MOG antibodies.

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.

Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France.

Importance: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated. Objective: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013. Design, Setting, and Participants: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018. Exposures: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation. Main Outcomes and Measures: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016). Results: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016. Conclusions and Relevance: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.

Pathologic and MRI analysis in acute atypical inflammatory demyelinating lesions.

BACKGROUND: The diagnosis of atypical inflammatory demyelinating lesions can be difficult. Brain biopsy is often required to exclude neoplasms. Moreover, the relationship between these lesions and multiple sclerosis and NMOSD is not clear. OBJECTIVES: Our objectives were to describe radiological and pathological characteristics of patients with acute inflammatory demyelinating lesions. METHODS: We retrospectively identified patients with brain biopsy performed for diagnostic uncertainty revealing a demyelinating lesion. A complete clinical, biological, radiological and pathological analysis was performed. RESULTS: Twenty patients (15 with a single lesion) were included. MRI disclosed a wide range of lesions including infiltrative lesions (40%), ring-like lesion (15%) Baló-like lesion (15%) and acute haemorrhagic leukoencephalitis (20%). In spite of a marked heterogeneity, some findings were common: a peripheral B1000 hyperintense rim (70%), a slight oedema with mild mass effect (75%) and an open-rim peripheral enhancement (75%). Histopathology revealed that all cases featured macrophages distributed throughout, extensive demyelination, axonal preservation and absence of haemorrhagic changes. In the majority of cases, macrophages were the predominant inflammatory infiltrate and astrocytes were reactive and dystrophic. Aquaporin-4 staining was systematically preserved. After a mean follow-up of 5 years (1-12), 16/20 patients had a diagnosis of monophasic acute atypical inflammatory demyelinating lesion. One patient was diagnosed with MS and 3 with AQP4 negative NMOSD. DISCUSSION: Although imaging findings in patients with atypical inflammatory demyelinating lesions are heterogeneous, some common features such as peripheral DWI hyperintense rim with open-rim enhancement and absence of oedema argue in favour of a demyelinating lesion and should preclude a brain biopsy. In this context, AQP4 staining is systematically preserved and argues against an AQP4-positive NMOSD. Moreover, long-term follow-up is characterized by low recurrence rate.

Imaging spectrum of Bing-Neel syndrome: how can a radiologist recognise this rare neurological complication of Waldenström's macroglobulinemia?

OBJECTIVES: Bing-Neel syndrome (BNS) is a rare neurological complication of Waldenström's macroglobulinemia. The aim of this study is to describe the spectrum of radiological manifestations of this syndrome and their prevalence in order to facilitate its early diagnosis. METHODS: Twenty-four patients with BNS were diagnosed between 1994 and 2016 in eight centres in France. We retrospectively examined the medical records of these patients as well as the corresponding literature, focusing on imaging studies. Recorded data were statistically analysed and radiological findings described. RESULTS: The mean age of our patients was 62.4 years (35-80 years). The vast majority of patients were men, with a male to female ratio of 9:1. Findings included parenchymal or meningeal involvement or both. The most common finding was leptomeningeal infiltration, either intracranial or spinal, with a prevalence reaching 70.8%. Dural involvement was present in 37.5% of patients. In 41.7% (10/24) of patients, there was parenchymal involvement with a higher prevalence of brain comparing to medullar involvement (33.3% and 23.1% respectively). High T2 signal of the parenchyma was identified in 41.7% of patients and high signal in diffusion was evident in 25% of them. Intraorbital or periorbital involvement was also detected in four cases. A proposition regarding the appropriate imaging protocol completed our study. CONCLUSION: BNS's diagnosis remains challenging. Central nervous system MRI findings in the setting of known or suspected Waldenström's macroglobulinemia appear to be highly suggestive of BNS and appropriate imaging protocols should be implemented for their depiction. KEY POINTS: • Diagnosis of Bing-Neel syndrome (BNS) remains challenging and recent expert recommendations include MRI in the diagnostic criteria for the syndrome. • The most common radiological manifestations of BNS are leptomeningeal/dural infiltration or parenchymal involvement of brain or spinal cord, but many atypical forms may exist with various presentations. • Appropriate imaging protocol for BNS should include enhanced MRI studies of both brain and spine.

Testosterone and estrogen in multiple sclerosis: from pathophysiology to therapeutics.

INTRODUCTION: Neuroprotection and remyelination are two unmet needs in the treatment of multiple sclerosis (MS). Therapeutic potential has been identified with sexual hormones, supported in women by a decrease in MS activity during the pregnancy, in men by a greater severity of symptoms and a faster progression than in women. Areas covered: The therapeutic effect of testosterone and estrogens is reviewed. Both hormones have demonstrated an anti-inflammatory effect. Testosterone has an effect in protecting neurons in culture against glutamate-induced toxicity and oxidative stress, and stimulates myelin formation and regeneration mediated through the neural androgen receptor. In experimental autoimmune encephalomyelitis model, estrogens significantly decrease inflammation in the central nervous system via ERα, while its action on ERß leads to myelin and axon reparation. Estriol therapy in two phase 2 trials showed a decrease in clinical disease activity and inflammatory parameters in MRI. However, evidence of a therapeutic effect of testosterone is scarce. Expert commentary: Phase 3 trials with estriol as an add-on supplementation are now mandatory. Testosterone is another candidate to be tested in phase 2 trials. These hormones should be considered as an adjunctive therapy. New validated tools are needed to assess their effect on neuroprotection and remyelination.

FDG PET and MRI Findings in a Case of Bing-Neel Syndrome.

A 64-year-old man was admitted for expressive aphasia with lack of words. He had been diagnosed with Waldenström 4 years before. At that time, he received 6 cycles of single-agent fludarabine, and remission was obtained. Because of acute expressive aphasia, he underwent brain MRI, which showed frontoparietal and insular subcortical gadolinium enhancement; Bing-Neel syndrome was suspected. Fronto-temporo-insular hypometabolism and left parietal hypometabolism were highlighted on FDG PET/CT. Structural and functional brain imaging revealed impairment of brain areas due to white matter changes and reinforced the diagnosis.

Quantitative and qualitative normative dataset for intraepidermal nerve fibers using skin biopsy.

BACKGROUND: Skin biopsy is the most relevant tool to diagnose small-fiber neuropathy. A well-documented normal dataset for intraepidermal nerve fiber in the distal leg is required to improve its diagnostic value. METHODS: Three hundred healthy subjects were enrolled in the study, after clinical and biological screening to exclude neurological and systemic pathologies. A distal leg biopsy was taken and intraepidermal nerve fiber density after protein gene product-9.5 immunocytochemistry with brightfield microscopy was determined. Morphological variations of intraepidermal nerve fibers, previously described in small-fiber neuropathies, were analyzed. One hundred biopsies were also analyzed at the ultrastructural level. FINDINGS: The median number of fibers was lower in men compared to women and decreased with age. Using statistical modeling taking into account age and gender, we calculated the 5th percentile of intraepidermal nerve fiber density as follows: 7.6156-0.0769 x age (years) + 1.5506 x gender (woman = 1; man = 0). We observed a low frequency of large swellings or horizontal branchings but an increasing frequency of small swellings of intraepidermal nerve fibers and irregular distribution along the dermal-epidermal junction with age. Axonal diameter of unmyelinated fibers of the papillary dermis did not vary with age or gender. Ultrastructural analysis also showed that fiber endings in close apposition to Merkel cells should not be mistaken for small-fiber swellings. CONCLUSIONS: Our dataset allows accurate calculation of the normal density of intraepidermal nerve fibers for each year of age and provides original morphological observations that improve the diagnostic value of skin biopsy in the distal leg for small-fiber neuropathy.