Autologous Haematopoietic Stem Cell Transplantation in Multiple Sclerosis: a Review of Current Literature and Future Directions for Transplant Haematologists and Oncologists.

Purpose of Review: We summarise the current development of autologous haematopoietic stem cell transplantation (AHSCT) in treating multiple sclerosis (MS) and discuss future directions for the general neurologist, transplant haematologist and oncologist. Recent Findings: AHSCT was initially performed to treat MS over 20 years ago. Over recent years, the evidence base has grown, especially in relapsing-remitting MS (RRMS), with significant improvements in safety and efficacy through better patient selection, choice of transplant technique and increase in centre experience. Summary: AHSCT is now a treatment option in very carefully selected patients with severe, treatment-resistant RRMS. However, it is important for transplant haematologists and oncologists to work closely with specialist MS neurologists in patient selection, during transplant and in long-term follow-up of patients. Data should be registered into international transplant registries and, ideally, patients should be enrolled on prospective clinical trials in order to build the evidence base and refine transplant techniques

Cognitive speed and white matter integrity in secondary progressive multiple sclerosis

BACKGROUND: Processing speed (PS) deficits have been consistently observed in secondary progressive multiple sclerosis (SPMS). However, the underlying neural correlates have not been clarified yet. The present study aimed to investigate the relationship between macrostructural and microstructural white matter (WM) integrity and performance on different cognitive measures with prominent PS load. METHODS: Thirty-one patients with SPMS were recruited and underwent neurological, neuropsychological, and MRI assessments. The associations between a composite index of PS abilities and scores on various tests with prominent PS load and T1-weighted and diffusion tensor image parameters were tested. Analyses were carried out using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS). RESULTS: VBM results showed that only the semantic fluency task correlated with grey matter (GM) volume in a range of cortical and subcortical areas bilaterally as well as the corpus callosum and the superior longitudinal fasciculus. TBSS analysis revealed consistent results across all the cognitive measures investigated, showing a prominent role of commissural and frontal associative WM tracts in supporting PS-demanding cognitive operations. CONCLUSIONS: In patients with SPMS, PS abilities are mainly dependent on the degree of both macrostructural and microstructural WM integrity. Preservation of associative WM tracts that support information integration seems crucial to sustain performance in tasks requiring fast cognitive processes

Wearable sensors can reliably quantify gait alterations associated with disability in people with progressive multiple sclerosis in a clinical setting

Gait disability in people with progressive multiple sclerosis (MS) is difficult to quantify using existing clinical tools. This study aims to identify reliable and objective gait-based biomarkers to monitor progressive multiple sclerosis (MS) in clinical settings. During routine clinical visits, 57 people with secondary progressive MS and 24 healthy controls walked for 6 minutes wearing three inertial motion sensors. Fifteen gait measures were computed from the sensor data and tested for between-session reliability, for differences between controls and people with moderate and severe MS disability, and for correlation with Expanded Disability Status Scale (EDSS) scores. The majority of gait measures showed good to excellent between-session reliability when assessed in a subgroup of 23 healthy controls and 25 people with MS. These measures showed that people with MS walked with significantly longer step and stride durations, reduced step and stride regularity, and experienced difficulties in controlling and maintaining a stable walk when compared to controls. These abnormalities significantly increased in people with a higher level of disability and correlated with their EDSS scores. Reliable and objective gait-based biomarkers using wearable sensors have been identified. These biomarkers may allow clinicians to quantify clinically relevant alterations in gait in people with progressive MS within the context of regular clinical visits

Autologous haematopoietic stem cell transplantation for refractory stiff-person syndrome: the UK experience

Stiff Person Syndrome (SPS) is a rare immune-mediated disabling neurological disorder characterised by muscle spasms and high GAD antibodies. There are only a few case reports of autologous haematopoietic stem cell transplantation (auto-HSCT) as a treatment for SPS. Objective To describe the UK experience of treating refractory SPS with auto-HSCT. Methods Between 2015 and 2019, 10 patients with SPS were referred to our institution for consideration of auto-HSCT. Eight patients were deemed suitable for autograft and four were treated. Of the treated patients, three had classical SPS and one had the progressive encephalomyelitis with rigidity and myoclonus variant. All patients were significantly disabled and had failed conventional immunosuppressive therapy. Patients were mobilised with Cyclophosphamide (Cy) 2 g/m2 + G-CSF and conditioned with Cy 200 mg/kg + ATG followed by auto-HSCT. Results Despite their significantly reduced performance status, all patients tolerated the procedure with no unexpected toxicities. Following autograft, all patients improved symptomatically and stopped all forms of immunosuppressive therapies. Two patients were able to ambulate independently from being wheelchair dependent. One patient’s walking distance improved from 300 meters to 5 miles and one patient’s ambulation improved from being confined to a wheelchair to be able to walk with a frame. Two patients became seronegative for anti-GAD antibodies and normalised their neurophysiological abnormalities. Conclusions Auto-HSCT is an intensive but well tolerated and effective treatment option for patients with SPS refractory to conventional immunotherapy. Further work is warranted to optimise patient selection and establish the efficacy, long-term safety, and cost-effectiveness of this treatment

Is a wearable sensor-based characterisation of gait robust enough to overcome differences between measurement protocols? A multi-centric pragmatic study in patients with multiple sclerosis

Inertial measurement units (IMUs) allow accurate quantification of gait impairment of people with multiple sclerosis (pwMS). Nonetheless, it is not clear how IMU-based metrics might be influenced by pragmatic aspects associated with clinical translation of this approach, such as data collection settings and gait protocols. In this study, we hypothesised that these aspects do not significantly alter those characteristics of gait that are more related to quality and energetic efficiency and are quantifiable via acceleration related metrics, such as intensity, smoothness, stability, symmetry, and regularity. To test this hypothesis, we compared 33 IMU-based metrics extracted from data, retrospectively collected by two independent centres on two matched cohorts of pwMS. As a worst-case scenario, a walking test was performed in the two centres at a different speed along corridors of different lengths, using different IMU systems, which were also positioned differently. The results showed that the majority of the temporal metrics (9 out of 12) exhibited significant between-centre differences. Conversely, the between-centre differences in the gait quality metrics were small and comparable to those associated with a test-retest analysis under equivalent conditions. Therefore, the gait quality metrics are promising candidates for reliable multi-centric studies aiming at assessing rehabilitation interventions within a routine clinical context

A case of multiple sclerosis—like relapsing remitting encephalomyelitis following allogeneic hematopoietic stem cell transplantation and a review of the published literature

Complications involving the central nervous system (CNS) occur in 9–14% of patients following allogeneic hematopoietic stem cell transplantation (HSCT), including stroke-like episodes, demyelination, encephalitis, and nonspecific neurological symptoms. Here we report a case of multiple sclerosis (MS) like relapsing remitting encephalomyelitis following allogeneic HSCT, which did not respond to disease modifying therapies (DMTs) and “domino” autologous HSCT. A 53-year-old male was treated with allogeneic HSCT for lymphoid blast transformation of chronic myeloid leukemia. Ten months later he presented with confusion, slurred speech, left sided facial weakness and ataxia. A magnetic resonance imaging brain scan showed multiple enhancing tumefactive lesions. Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibodies were negative. After extensive investigations for infections, autoimmune disorders and recurrence of malignancy, he underwent brain biopsy, which showed a macrophage rich lesion with severe myelin loss but axonal preservation indicating a demyelinating pathology. Although his symptoms improved with corticosteroids, he relapsed five months later. In the absence of any systemic features suggesting graft versus host disease (GvHD), his presentation was thought to be compatible with MS. The illness followed an aggressive course that did not respond to glatiramer acetate and natalizumab. He was therefore treated with “domino” autologous HSCT, which also failed to induce long-term remission. Despite further treatment with ocrelizumab, he died of progressive disease. An autopsy limited to the examination of brain revealed multifocal destructive leukoencephalopathy with severe myelin and axonal loss. Immunohistochemistry showed macrophage located in the perivascular area, with no T or B lymphocytes. The appearance was unusual and not typical for chronic MS plaques. Reported cases of CNS demyelination following allogeneic HSCT are very limited in the literature, especially in relation to histopathological examination. Although the clinical disease course of our patient following allogeneic HSCT resembled an “MS-like” relapsing remitting encephalomyelitis, the autopsy examination did not show any evidence of active inflammation. The impact of DMTs and HSCT on the histological appearance of “MS-like” CNS pathologies is unknown. Therefore, reporting this and similar cases will improve our awareness and understanding of underlying disease mechanisms

The Relationship between Speed of Processing and White Matter Integrity in Secondary Progressive Multiple Sclerosis: A VBM and TBSS Study

Objective. This study aimed at investigating: the relationship between WM integrity and processing speed (PS) performance, and the PS-dependent relationship between WM integrity and higher order cognitive functions in patients with SPMS. Background. Secondary progressive multiple sclerosis (SPMS) is a neurodegenerative disease in which patients develop grey and white matter (GM, WM) degeneration and cognitive impairment, including PS deficits. However, the relationship between WM integrity and PS has yet to be clarified. Methods. Thirty one patients with SPMS (mean age, 52.5 years; mean disease duration, 15.5years; mean EDSS, 6.4) had detailed neuropsychological assessment (Trail Making Test A, Stroop test, Digit Cancellation, category and letter fluency). A PS index was computed by combining TMT-A, Stroop speed, and Digit Cancellation. T1-weighted and diffusion weighted MR images were acquired. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) techniques were used to investigate: the correlations between WM/GM measures and cognitive variables; and the differences in WM/GM measures between high (HP) and low performers (LP) divided on the bases of the PS index. Results. VBM analysis showed that only the PS index and timed fluency tasks correlated with left-lateralised WM tracts. Moreover, the HP subgroup had more WM than LP in the same WM tracts. Consistent results were found for fractional anisotropy (FA) in the TBSS analysis: correlations were seen mainly in a wide network of associative tracts only for PS-dependent tests. Furthermore, HP showed higher FA and lower mean diffusivity than LP in similar WM tracts: namely the left superior longitudinal fasciculus and left inferior fronto-occipital fasciculus. Conclusions. In SPMS, PS relies on WM rather than GM integrity as does performance in PS-dependent higher order cognitive functions. WM associative tracts supporting fast integration of information across the brain seem to be crucially involved in tasks requiring effective management of time