Cancer and multiple sclerosis: 2023 recommendations from the French Multiple Sclerosis Society.

BACKGROUND: Epidemiological data reveal that 45% of persons with multiple sclerosis (PwMS) in France are more than 50 years. This population more than 50 is more susceptible to cancer, and this risk may be increased by frequent use of immunosuppressive drugs. Consequently, concerns have arisen about the potential increased risk of cancer in PwMS and how patients should be screened and managed in terms of cancer risk. OBJECTIVE: To develop evidence-based recommendations to manage the coexistence of cancer and multiple sclerosis (MS). METHODS: The French Group for Recommendations in MS collected articles from PubMed and university databases covering the period January 1975 through June 2022. The RAND/UCLA method was employed to achieve formal consensus. MS experts comprehensively reviewed the full-text articles and developed the initial recommendations. A group of multidisciplinary health care specialists then validated the final proposal. RESULTS: Five key questions were addressed, encompassing various topics such as cancer screening before or after initiating a disease-modifying therapy (DMT), appropriate management of MS in the context of cancer, recommended follow-up for cancer in patients receiving a DMT, and the potential reintroduction of a DMT after initial cancer treatment. A strong consensus was reached for all 31 recommendations. CONCLUSION: These recommendations propose a strategic approach to managing cancer risk in PwMS.

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.

Minor Salivary Gland Biopsy for the Diagnosis of Neurosarcoidosis.

INTRODUCTION: The definite diagnosis of neurosarcoidosis is challenging since it requires a compatible histology of the nervous system. When neurosarcoidosis is suspected, other systemic manifestations are investigated to confirm the diagnosis. A minor salivary gland biopsy (MSGB) is often performed since it is minimally invasive. The objective of the present study was to assess its performance for the diagnosis of neurosarcoidosis. METHODS: A retrospective single-center study included patients who underwent a MSGB in a tertiary neurological university hospital (Lyon, France) between 2015 and 2018. Clinical presentations unlikely to be compatible with neurosarcoidosis were excluded. Positive cases of neurosarcoidosis were defined as definite, probable, and possible cases, according to the latest international neurosarcoidosis diagnostic criteria from the Neurosarcoidosis Consortium Consensus Group. RESULTS: A total of 529 patients underwent a MSGB for clinical manifestations compatible with neurosarcoidosis. Among the 13 who fulfilled the criteria for neurosarcoidosis, only one had a positive MSGB. The sensitivity of MSGB was 7.7% (95% CI [0.2-36.0%]) and the specificity was 100.0% (95% CI [99.3-100%]). CONCLUSION: Considering the low sensitivity of MSGB for the diagnosis of NS, MSGB should be performed in selected indications, including a suspicion of spinal cord sarcoidosis, or when there is a strong clinical, laboratory, and radiological suspicion of NS. MSGB should rather not be performed when the chest CT-scan does not show signs of pulmonary or lymph node sarcoidosis.

Pregnancy and multiple sclerosis: 2022 recommendations from the French multiple sclerosis society.

OBJECTIVE: The objective of this study was to develop evidence-based recommendations on pregnancy management for persons with multiple sclerosis (MS). BACKGROUND: MS typically affects young women in their childbearing years. Increasing evidence is available to inform questions raised by MS patients and health professionals about pregnancy issues. METHODS: The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed PubMed and university databases (January 1975 through June 2021). The RAND/UCLA appropriateness method was developed to synthesise the scientific literature and expert opinions on healthcare topics; it was used to reach a formal agreement. Fifty-six MS experts worked on the full-text review and initial wording of recommendations. A group of 62 multidisciplinary healthcare specialists validated the final proposal of summarised evidence. RESULTS: A strong agreement was reached for all 104 proposed recommendations. They cover diverse topics, such as pregnancy planning, follow-up during pregnancy and postpartum, delivery routes, locoregional analgesia or anaesthesia, prevention of postpartum relapses, breastfeeding, vaccinations, reproductive assistance, management of relapses and disease-modifying treatments. CONCLUSION: The 2022 recommendations of the French MS society should be helpful to harmonise counselling and treatment practice for pregnancy in persons with MS, allowing for better and individualised choices.

Pregnancy and neuromyelitis optica spectrum disorders: 2022 recommendations from the French Multiple Sclerosis Society.

BACKGROUND: In 2020, the French Multiple Sclerosis (MS) Society (SFSEP) decided to develop a national evidence-based consensus on pregnancy in MS. As neuromyelitis optica spectrum disorders (NMOSD) shares a series of commonalities with MS, but also some significant differences, specific recommendations had to be developed. OBJECTIVES: To establish recommendations on pregnancy in women with NMOSD. METHODS: The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed PubMed and universities databases (January 1975 through June 2021). The RAND/UCLA appropriateness method, which was developed to synthesise the scientific literature and expert opinions on health care topics, was used to reach a formal agreement. Fifty-six MS experts worked on the full-text review and initial wording of recommendations. A sub-group of nine NMOSD experts was dedicated to analysing available data on NMOSD. A group of 62 multidisciplinary healthcare specialists validated the final proposal of summarised evidence. RESULTS: A strong agreement was reached for all 66 proposed recommendations. They cover diverse topics, such as pregnancy planning, follow-up during pregnancy and postpartum, delivery routes, loco-regional analgesia or anaesthesia, prevention of postpartum relapses, breastfeeding, vaccinations, reproductive assistance, management of relapses, and disease-modifying treatments. CONCLUSION: Physicians and patients should be aware of the new and specific evidence-based recommendations of the French MS Society for pregnancy in women with NMOSD. They should help harmonise counselling and treatment practise, allowing for better individualised choices.

["Diagnosis of multiple sclerosis, diagnostic criteria and contribution of imaging to diagnosis"]. / Diagnostic de la sclérose en plaques.

"Diagnosis of multiple sclerosis, diagnostic criteria and contribution of imaging to diagnosis The diagnosis of multiple sclerosis is a probabilistic diagnosis, based on a combination of clinical and imaging evidence. The current diagnostic criteria are the MacDonald 2017 criteria; they allow for a safer and earlier diagnosis and minimize the risk of overdiagnosis. These criteria should only be used in patients with a subacute or progressive clinical presentation already highly suggestive of MSs. MRI is becoming an increasingly important part of the process, but like clinical and biological findings, it must be analyzed ex¬pertly, always keeping in mind the red flags calling for alternative diagnoses. When the diagnosis of multiple sclerosis is made, the announcement stage is fundamental and conditions the therapeutic alliance and the quality of the subsequent care."

"Diagnostic de la sclérose en plaques Le diagnostic de sclérose en plaques est un diagnostic probabiliste, reposant sur un faisceau d'arguments cliniques et d'imagerie. Les critères diagnostiques en vigueur sont ceux de McDonald 2017 ; ils permettent un diagnostic plus sûr et plus précoce et minimisent le risque de diagnostic par excès. Ces critères ne doivent être utilisés que chez des patients ayant une présentation clinique subaiguë ou progressive déjà très fortement suggestive de SEP. L'IRM tient une place de plus en plus importante dans la démarche mais, comme la clinique et la biologie, elle doit donner lieu à une analyse experte, gardant toujours à l'esprit les drapeaux rouges appelant des diagnostics alternatifs. Lorsque le diagnostic de sclérose en plaques est posé, l'étape de l'annonce est fondamentale et conditionne l'alliance thérapeutique et la qualité du parcours de soins ultérieur."

Challenging Mimickers in the Diagnosis of Sarcoidosis: A Case Study.

Sarcoidosis is a systemic granulomatous disease of unknown cause characterized by a wide variety of presentations. Its diagnosis is based on three major criteria: a clinical presentation compatible with sarcoidosis, the presence of non-necrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. Many conditions may mimic a sarcoid-like granulomatous reaction. These conditions include infections, neoplasms, immunodeficiencies, and drug-induced diseases. Moreover, patients with sarcoidosis are at risk of developing opportunistic infections or lymphoma. Reliably confirming the diagnosis of sarcoidosis and better identifying new events are major clinical problems in daily practice. To address such issues, we present seven emblematic cases, seen in our department, over a ten-year period along with a literature review about case reports of conditions misdiagnosed as sarcoidosis.

TNF-α inhibitors used as steroid-sparing maintenance monotherapy in parenchymal CNS sarcoidosis.

OBJECTIVE: To assess the efficacy of tumour necrosis factor-α (TNF-α) inhibitors used as steroid-sparing monotherapy in central nervous system (CNS) parenchymal sarcoidosis. METHODS: The 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. RESULTS: Of 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%. CONCLUSION: TNF-α inhibitors can greatly reduce steroids dosing in patients with CNS parenchymal sarcoidosis, even refractory. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that TNF-α inhibitor used as steroid-sparing monotherapy is effective for patients with CNS parenchymal sarcoidosis.

Sarcoidosis: A Clinical Overview from Symptoms to Diagnosis.

Sarcoidosis is a multi-system disease of unknown etiology characterized by the formation of granulomas in various organs. It affects people of all ethnic backgrounds and occurs at any time of life but is more frequent in African Americans and Scandinavians and in adults between 30 and 50 years of age. Sarcoidosis can affect any organ with a frequency varying according to ethnicity, sex and age. Intrathoracic involvement occurs in 90% of patients with symmetrical bilateral hilar adenopathy and/or diffuse lung micronodules, mainly along the lymphatic structures which are the most affected system. Among extrapulmonary manifestations, skin lesions, uveitis, liver or splenic involvement, peripheral and abdominal lymphadenopathy and peripheral arthritis are the most frequent with a prevalence of 25-50%. Finally, cardiac and neurological manifestations which can be the initial manifestation of sarcoidosis, as can be bilateral parotitis, nasosinusal or laryngeal signs, hypercalcemia and renal dysfunction, affect less than 10% of patients. The diagnosis is not standardized but is based on three major criteria: a compatible clinical and/or radiological presentation, the histological evidence of non-necrotizing granulomatous inflammation in one or more tissues and the exclusion of alternative causes of granulomatous disease. Certain clinical features are considered to be highly specific of the disease (e.g., Löfgren's syndrome, lupus pernio, Heerfordt's syndrome) and do not require histological confirmation. New diagnostic guidelines were recently published. Specific clinical criteria have been developed for the diagnosis of cardiac, neurological and ocular sarcoidosis. This article focuses on the clinical presentation and the common differentials that need to be considered when appropriate.

Multiple sclerosis broke my heart.

We report 5 cases of acute heart failure (AHF) related to multiple sclerosis (MS) relapses. AHF was inaugural in 3 patients, always preceded or accompanied by signs of brainstem dysfunction; it was severe, requiring intensive care management. Echocardiography showed left ventricular hypokinesis. No other cause of AHF has been found. All patients showed a new medullary lesion on brain magnetic resonance imaging. All had rapid and complete recovery of ventricular function after intravenous corticosteroids. We concluded that the cases represent a takotsubo phenomenon. Physicians should be aware of rare cases of takotsubo cardiomyopathy in MS relapses. Ann Neurol 2017;81:754-758.

History of multiple sclerosis in 2 successive pregnancies: A French and Italian cohort.

OBJECTIVE: To evaluate the risk of relapses during pregnancy and in the first 3 months after delivery in 2 successive pregnancies in a cohort of French and Italian women with multiple sclerosis (MS). METHODS: A total of 93 women were included if they had had 2 pregnancies followed prospectively after MS onset between January 1993 and 2013. The association of a relapse during pregnancy or the first postpartum trimester in pregnancy 1 and pregnancy 2 was evaluated by univariate logistic regression. RESULTS: A majority of women did not experience any exacerbation in the 3 months after delivery (31.2% and 23.7%, respectively, relapsed after pregnancy 1 and 2; p = 0.32). A total of 7.6% had a relapse after both pregnancies. The risk of relapse after pregnancy 2 was not associated with the number of relapses in the prepregnancy year (odds ratio [OR] 1.52 [0.57-4.05]) or during pregnancy (OR 1.57 [0.52-4.79]) or with the occurrence of a relapse after pregnancy 1 (OR 0.86 [0.29-2.50]). CONCLUSIONS: Our work provides original data on the evolution of successive pregnancies in MS, showing a similar (and even lower) disease activity in the second pregnancy. There was no correlation of activity in successive pregnancies. Therefore, counseling of women with MS who consider having a second baby should be the same as for the first one.

Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions.

Our knowledge of multiple sclerosis (MS) neuropathology has benefited from a number of studies that provided an in-depth description of plaques and, more recently, diffuse alterations of the normal-appearing white or grey matter. However, there have been few studies focusing on the periplaque regions surrounding demyelinated plaques, notably in MS spinal cords. In this context, the present study aimed to analyze the molecular immunopathology of periplaque demyelinated lesions (PDLs) in the spinal cord of patients with a progressive form of MS. To achieve this goal, the neuropathological features of PDLs were analyzed in postmortem tissues derived from the cervical spinal cord of 21 patients with primary or secondary progressive MS. We found that PDLs covered unexpectedly large areas of incomplete demyelination and were characterized by the superimposition of pro- and anti-inflammatory molecular signatures. Accordingly, macrophages/microglia accumulated in PDLs but exhibited a poor phagocytic activity toward myelin debris. Interestingly, while genes of the oligodendrocyte lineage were consistently down-regulated in PDLs, astrocyte-related molecules such as aquaporin 4, connexin 43 and the glutamate transporter EAAT1, were significantly upregulated in PDLs at the mRNA and protein levels. Overall, our work indicates that in the spinal cord of patients with a progressive form of MS, a tissue remodeling process that is temporally remote from plaque development takes place in PDLs. We propose that in spinal cord PDLs, this process is supported by subtle alterations of astrocyte functions and by low-grade inflammatory events that drive a slowly progressive loss of myelin and a failure of remyelination.

Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords.

OBJECTIVE: A link between diffuse axonal loss and diffuse inflammation has been established in the brain of patients with progressive multiple sclerosis (MS). In the present paper, we sought to determine whether such a link could be similarly demonstrated in the spinal cord of patients with progressive MS. METHODS: A neuropathological quantitative assessment of inflammation and axonal loss was performed in the cervical spinal cord of 18 patients with progressive MS and 5 control subjects. RESULTS: As previously reported, we found a mean 25% decrease of axonal density in the normal-appearing white matter (NAWM) of MS versus control spinal cords. T-cell perivascular infiltrates were rare, but a robust diffuse inflammation was observed in both the normal-appearing parenchyma and the meninges. The extent of diffuse axonal loss in the NAWM correlated with both the density of major histocompatibility complex (MHC) class II(+) microglia in the NAWM and, surprisingly, the density of CD3(+) T cells in the meninges. Interestingly, close interactions between T cells and MHC class II(+) macrophages were observed in the meninges of spinal cords from MS patients. INTERPRETATION: Recent studies assigned a major role to meningeal B-cell follicles in the pathophysiology of secondary progressive MS. The present work also emphasizes the link between meningeal inflammation and parenchymal lesions and points to a specific role exerted by both meningeal T cells and activated microglia in diffuse axonal loss in the spinal cord.

Metabotropic glutamate receptor type 1 autoantibody-associated cerebellitis: a primary autoimmune disease?

OBJECTIVES: To report the third case of subacute cerebellar ataxia associated with metabotropic glutamate receptor type 1 autoantibodies (mGluR1-Abs), an uncommon syndrome known to be part of the group of paraneoplastic cerebellar degeneration syndromes linked to antineuronal antibodies and previously reported in only 2 other patients with long-term remission of Hodgkin lymphoma, and to discuss the underlying immunopathogenesis. DESIGN: Case report. SETTING: University hospital. PATIENT: A 50-year-old woman admitted for acute severe isolated static and kinetic cerebellar syndrome. Magnetic resonance imaging of the brain showed diffuse abnormal hyperintensity in the whole cerebellum on fluid-attenuated inversion recovery and diffusion sequences. RESULTS: Results of the biological workup were negative for general inflammation, vitamin deficiency, and bacterial and viral infections. Immunohistochemical analysis of the serum and cerebrospinal fluid of the patient demonstrated staining for Purkinje cell bodies and the molecular layer of the cerebellum. Finally, mGluR1-Abs were detected in serum and cerebrospinal fluid by a cell-based assay. Complete clinical examination, thoracoabdominal-pelvic computed tomography, and whole-body fludeoxyglucose F 18-positron emission tomography failed to show any underlying tumor, including Hodgkin lymphoma. The disease was stabilized after a course of intravenous immunoglobulins and continuous mycophenolate mofetil treatment during a follow-up of 40 months. CONCLUSIONS: Cerebellitis associated with mGluR1-Abs should be considered in the differential diagnosis of patients with subacute cerebellar ataxia. This first case without any tumor found suggests a possible idiopathic autoimmune rather than a paraneoplastic mechanism. In consideration of this possible primitive autoimmune ataxia involving the directly pathogenic mGluR1-Abs, immunoactive therapy should be initiated as early as possible.

From bone marrow to microglia: barriers and avenues.

Microglia form a unique population of brain-resident macrophages. Although microglia have been involved in multiple disorders of the central nervous system (CNS), the issue of microglial renewal, under normal or pathological conditions, has been controversial. In mice, results from bone marrow chimera studies indicated that microglia are slowly but continuously replenished by bone marrow-derived cells. Moreover, such a microglial turnover was found to be greatly accelerated under multiple neurological conditions. However, recent works questioned the use of irradiation/reconstitution experiments to assess microglial turnover. Based on these different studies, we propose here a re-evaluation of microglia origin(s) in the inflamed CNS. We also discuss the therapeutic perspectives offered by the demonstration of an adult microglial lineage, from bone marrow to brain.