Hematopoietic stem cell transplantation for multiple sclerosis.

Over the past decades, several effective disease-modifying therapies have been approved for the treatment of multiple sclerosis (MS); however, achieving long-term disease remission remains challenging, particularly for patients with aggressive forms of MS. Intense immunosuppression followed by hematopoietic stem cell transplantation (HSCT) has been increasingly explored as a treatment strategy for aggressive MS. To date, more than 1800 MS patients have undergone HSCT worldwide. In this chapter, we provide a brief overview of the HSCT procedure, with a special focus on the unique considerations for transplanting MS patients (such as fertility preservation, prior therapy washout, and posttransplant monitoring). We also discuss the main evidence of efficacy and safety of the procedure in this context, as well as present preliminary data on the impact of HSCT on cerebrospinal fluid findings, magnetic resonance imaging metrics, and novel serum biomarkers of neurodegeneration and demyelination. In addition, we provide recommendations for patient selection from international guidelines.

HSCT for stiff person syndrome and myasthenia gravis.

Recent advances in neuroimmunology have shed light on the pathogenic mechanisms underlying rare neuroimmunologic conditions such as myasthenia gravis (MG) and stiff person syndrome (SPS). Despite the rarity of these conditions, their complex manifestations and potential for irreversible disability necessitate effective therapeutic strategies. This chapter reviews the current understanding of the safety and efficacy of hematopoietic stem cell transplantation (HSCT) in MG and SPS. Several case reports and retrospective studies have demonstrated promising outcomes following HSCT in refractory MG and SPS, with significant clinical improvement and even discontinuation of chronic immunomodulatory therapy in some cases. Furthermore, HSCT may offer insights into the underlying pathophysiologic mechanisms of these conditions, particularly the role of cellular immunity. Although more research is needed to fully understand the impact of HSCT on disease pathology and outcomes, current evidence suggests that HSCT could be a valuable therapeutic option for patients with refractory MG and SPS.

Introduction to HSCT for neurologic diseases.

The use of hematopoietic stem cell transplantation (HSCT) as a treatment option for severe autoimmune diseases originated from animal studies, with promising results in human patients reported through clinical responses seen in individuals who underwent HSCT for other reasons. Currently, over 3800 HSCT procedures have been performed specifically for autoimmune disorders and the procedure has become a standard of care for conditions such as multiple sclerosis and systemic sclerosis. Despite the growing interest among the neurology community in using HSCT to treat refractory autoimmune disorders, several obstacles must still be overcome for the procedure to become widely accepted. These include increasing the safety of the procedure, determining the most effective conditioning regimen, fostering collaboration between neurology and hematology teams, and providing robust phase III study data to demonstrate the superiority of HSCT over standard immunotherapy. This Handbook aims to provide a valuable resource for all those involved in the care of patients undergoing HSCT, and we hope it will contribute to the efforts to find the correct placement of HSCT in the therapeutic strategy of the treatment of autoimmune disorders of the nervous system.

Ongoing randomized clinical trials on HSCT in multiple sclerosis.

Autologous hematopoietic stem cell transplantation (AHSCT) is emerging as a potent treatment for highly active relapsing remitting multiple sclerosis (RRMS), potentially surpassing the efficacy of traditional disease-modifying therapies (DMTs). Phase II and III randomized controlled trials (RCTs) have demonstrated AHSCT's superiority in reducing relapse rates and delaying disability progression compared to standard DMTs. Despite the evolution of treatment guidelines, questions persist regarding patient selection criteria and optimal conditioning regimens. Notably, ongoing clinical trials in the United Kingdom, the United States, Italy, and Norway aim to address these uncertainties by evaluating the safety, efficacy, and long-term outcomes of AHSCT vs. high efficacy DMTs in both DMT-experienced and treatment-naïve patients with active RRMS or aggressive multiple sclerosis (MS). These trials promise to provide valuable insights into the positioning of AHSCT within the treatment landscape of MS.

Lesion phenotyping based on magnetic susceptibility in pediatric multiple sclerosis.

BACKGROUND AND PURPOSE: Pediatric multiple sclerosis (MS) displays different pathological features compared to adult MS, which can be studied in vivo by assessing tissue magnetic susceptibility with 3T-MRI. We aimed to assess different white matter lesions (WMLs) phenotypes in pediatric MS patients using quantitative susceptibility mapping (QSM) and susceptibility mapping weighted imaging (SMWI) over 12 months. METHODS: Eleven pediatric MS patients [female: 63.6%; mean ± standard deviation (SD) age and disease duration: 16.3 ± 2.2 and 2.4 ± 1.5; median (range) Expanded Disability Status Scale (EDSS) 1 (0-2)] underwent 3 Tesla-MRI exams and EDSS assessments at baseline and after 1 year. QSM and SMWI were obtained using 3-dimensional (3D)-segmented echo-planar-imaging with submillimetric spatial resolution. WMLs were classified according to their QSM appearance and SMWI was used to identify QSM hyperintensities ascribable to veins. Total brain volumes at baseline and follow-up were computed using high-resolution 3D T1-weighted images. RESULTS: Mean ± SD paramagnetic rim lesions (PRLs) prevalence was 7.0% ± 9.0. Fifty-four percent (6/11) of patients exhibited at least one PRL, with one patient exhibiting ≥ 4 PRLs. All patients showed QSM-iso-/hypo-intense lesions, which represented a mean ± SD of 65.8% ± 22.7 of total WMLs. QSM-hyperintense WMLs showed a positive correlation with total brain volume reduction at follow-up (r = 0.705; p =  .02). No lesion was classified as different between baseline and follow-up. CONCLUSION: Chronic compartmentalized inflammation seems to occur early in pediatric MS patients with short disease duration. A high prevalence of iso-/hypo-intense lesions was found, which could account for the higher remyelination potential in pediatric MS.

Multiparametric Characterization and Spatial Distribution of Different MS Lesion Phenotypes.

BACKGROUND AND PURPOSE: MS lesions exhibit varying degrees of axonal and myelin damage. A comprehensive description of lesion phenotypes could contribute to an improved radiologic evaluation of smoldering inflammation and remyelination processes. This study aimed to identify in vivo distinct MS lesion types using quantitative susceptibility mapping and susceptibility mapping-weighted imaging and to characterize them through T1-relaxometry, myelin mapping, and diffusion MR imaging. The spatial distribution of lesion phenotypes in relation to ventricular CSF was investigated. MATERIALS AND METHODS: MS lesions of 53 individuals were categorized into iso- or hypointense lesions, hyperintense lesions, and paramagnetic rim lesions, on the basis of their appearance on quantitative susceptibility mapping alone, according to published criteria, and with the additional support of susceptibility mapping-weighted imaging. Susceptibility values, T1-relaxation times, myelin and free water fractions, intracellular volume fraction, and the orientation dispersion index were compared among lesion phenotypes. The distance of the geometric center of each lesion from the ventricular CSF was calculated. RESULTS: Eight hundred ninety-six MS lesions underwent the categorization process using quantitative susceptibility mapping and susceptibility mapping-weighted imaging. The novel use of susceptibility mapping-weighted images, which revealed additional microvasculature details, led us to re-allocate several lesions to different categories, resulting in a 35.6% decrease in the number of paramagnetic rim lesions, a 22.5% decrease in hyperintense lesions, and a 17.2% increase in iso- or hypointense lesions, with respect to the categorization based on quantitative susceptibility mapping only. The outcome of the categorization based on the joint use of quantitative susceptibility mapping and susceptibility mapping-weighted imaging was that 44.4% of lesions were iso- or hypointense lesions, 47.9% were hyperintense lesions, and 7.7% were paramagnetic rim lesions. A worsening gradient was observed from iso- or hypointense lesions to hyperintense lesions to paramagnetic rim lesions in T1-relaxation times, myelin water fraction, free water fraction, and intracellular volume fraction. Paramagnetic rim lesions were located closer to ventricular CSF than iso- or hypointense lesions. The volume of hyperintense lesions was associated with a more severe disease course. CONCLUSIONS: Quantitative susceptibility mapping and susceptibility mapping-weighted imaging allow in vivo classification of MS lesions into different phenotypes, characterized by different levels of axonal and myelin loss and spatial distribution. Hyperintense lesions and paramagnetic rim lesions, which have the most severe microstructural damage, were more often observed in the periventricular WM and were associated with a more severe disease course.

An aggressive form of MOGAD treated with aHSCT: A case report.

BACKGROUND: Although myelin-oligodendrocyte-glycoprotein (MOG)-antibody-associated disease (MOGAD) has been considered a more favorable demyelinating central nervous system disorder, recent data evidence that some patients might experience severe relapses and high disability. Actual treatment-options are acquired mostly from anti-aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder and rely on clinical experience. Therefore, treatment of aggressive forms of MOGAD can be challenging. OBJECTIVES AND METHODS: To describe a patient with an aggressive MOGAD treated with autologous hematopoietic stem cell transplantation (aHSCT). RESULTS: A 56-year-old man was diagnosed with MOGAD in 2017 because of right optic-neuritis and anti-MOG-antibody positivity. In the following 2 years, he experienced two optic neuritis with good recovery after high-dose steroid. At the end of 2019, he presented sensory and motor impairment at lower limbs with evidence of several spinal, longitudinally extended, tumefactive inflammatory lesions. Despite sequential treatment with rituximab and tocilizumab alongside high-dose steroid, intravenous immunoglobulins and plasma-exchange, he experienced several clinical relapses and exhibited persistent magnetic resonance activity. He was finally addressed to intense immunosuppression with myeloablative conditioning regimen followed by autologous hematopoietic stem cell transplantation (aHSCT). After 2 years follow-up, he is free from disease-activity. CONCLUSIONS: In a patient affected by aggressive, treatment-refractory MOGAD, aHSCT resulted as safe and was able to suppress disease-activity for over 2 years.