Neuropsychological outcomes following HSCT in MS: A systematic review.

BACKGROUND: Autologous haematopoietic stem cell transplant (HSCT) is considered an effective treatment for highly active multiple sclerosis (MS). To date, most research has focused primarily on disease outcome measures, despite the significant impact of neuropsychological symptoms on MS patients' quality of life. The current systematic review aimed to examine whether HSCT for MS impacts neuropsychological outcome measures such as cognition, fatigue, mood, and quality of life. METHODS: The review was registered with the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD42023474214). Systematic searches were carried out in six databases (PsycINFO, PubMed, Embase, Scopus, CINAHL and Web of Science) based on the following inclusion criteria: (i) published in peer-reviewed journals in English; (ii) longitudinal studies of adults with MS (iii) at least one neuropsychological outcome was assessed pre- and post-HSCT using standardised measures. Risk of bias was assessed using the National Heart, Lung and Blood Institute (NHLBI) quality assessment tools. A narrative synthesis was used to present results. RESULTS: Eleven studies were included in the review. Long-term improvements in quality of life post-HSCT were identified. In terms of cognition and fatigue, the evidence was mixed, with some post-HSCT improvements identified. Decline in cognitive performance in the short-term post-HSCT was observed. No changes in mood were identified post-HSCT. Arguments for interpreting these results with caution are presented based on risk of bias. Arguments for interpreting these results with caution are presented based on risk of bias. Limitations of the evidence are discussed, such confounding variables and lack of statistical power. CONCLUSION: The evidence base for the impact of HSCT for MS on neuropsychological outcomes is limited. Further research is required to progress understanding to facilitate clinician and patient understanding of HSCT treatment for MS.

Neuropsychology intervention for managing invisible symptoms of MS (NIMIS-MS) group: A pilot effectiveness and acceptability study.

BACKGROUND: People with MS (pwMS) commonly experience a range of hidden symptoms, including cognitive impairment, anxiety and depression, fatigue, pain, and sensory difficulties. These "invisible" symptoms can significantly impact wellbeing, relationships, employment and life goals. We developed a novel bespoke online group neuropsychological intervention combining psychoeducation and cognitive rehabilitation with an Acceptance and Commitment Therapy (ACT)-informed approach for pwMS in an acute tertiary hospital. This 'Neuropsychological Intervention for Managing Invisible Symptoms' in MS (NIMIS-MS) consisted of 6 sessions, each with a psychoeducation and ACT component. The content included psychoeducation around managing cognitive difficulties, fatigue, pain, sleep and other unpleasant sensations in MS with the general approach of understanding, monitoring, and recognising patterns and potential triggers. Specific cognitive rehabilitation and fatigue management strategies were introduced. The ACT-informed component focussed on three core ACT areas of the 'Triflex' of psychological flexibility (Harris, 2019): Being Present, Opening Up, and Doing What Matters. METHODS: 118 pwMS attended the NIMIS-MS group intervention which was delivered 14 times in six-week blocks over an 18-month period. To evaluate the effectiveness and acceptability, participants completed measures of depression and anxiety (HADS), functional impairment (WSAS), Values- Progress (VQ) and Values- Obstruction (VQ), and Acceptance of MS (MSAS) pre and post NIMIs-MS group intervention. Qualitative feedback was obtained during focus groups after the final session and via online feedback questionnaires RESULTS: Pre-post analysis showed that symptoms of depression and anxiety were significantly lower and acceptance of MS was significantly higher following completion of the NIMIS-MS group. Qualitative feedback showed that participants reported that they felt more equipped to manage the "invisible" symptoms of MS following completion of the group, and benefited from using ACT-based strategies and techniques. Participants highly valued the peer support that evolved during the NIMIS-MS groups. The online format was considered more accessible than in-person groups, due to less concerns of travel time, cost, fatigue, and comfort and infection. CONCLUSION: Evaluation suggests that our novel NIMIS-MS groups is an acceptable, beneficial and feasible approach for providing neuropsychological interventions to individuals with MS.

Premorbid cognitive functioning influences differences between self-reported cognitive difficulties and cognitive assessment in multiple sclerosis.

Cognitive difficulties are reported in up to 60% of people with MS (pwMS). There is often a discrepancy between self-reported cognitive difficulties and performance on cognitive assessments. Some of this discrepancy can be explained by depression and fatigue. Pre-MS cognitive abilities may be another important variable in explaining differences between self-reported and assessed cognitive abilities. PwMS with high estimated premorbid cognitive functioning (ePCF) may notice cognitive difficulties in daily life whilst performing within the average range on cognitive assessments. We hypothesised that, taking into account depression and fatigue, ePCF would predict (1) differences between self-reported and assessed cognitive abilities and (2) performance on cognitive assessments. We explored whether ePCF predicted (3) self-reported cognitive difficulties. Eighty-seven pwMS completed the Test of Premorbid Functioning (TOPF), the Brief International Cognitive Assessment for MS (BICAMS), self-report measures of cognitive difficulty (MS Neuropsychological Questionnaire; MSNQ), fatigue (MS Fatigue Impact Scale; MFIS) and depression (Hospital Anxiety and Depression Scale; HADS). Results revealed that, taking into account covariates, ePCF predicted (1) differences between self-reported and assessed cognitive abilities, p < .001 (model explained 29.35% of variance), and (2) performance on cognitive assessments, p < .001 (model explained 46.00% of variance), but not (3) self-reported cognitive difficulties, p = .545 (model explained 35.10% of variance). These results provide new and unique insights into predictors of the frequently observed discrepancy between self-reported and assessed cognitive abilities for pwMS. These findings have important implications for clinical practice, including the importance of exploring premorbid factors in self-reported experience of cognitive difficulties.

Word finding, prosody and social cognition in multiple sclerosis.

BACKGROUND: Impairments in speech and social cognition have been reported in people with multiple sclerosis (pwMS), although their relationships with neuropsychological outcomes and their clinical utility in MS are unclear. OBJECTIVES: To evaluate word finding, prosody and social cognition in pwMS relative to healthy controls (HC). METHODS: We recruited people with relapsing MS (RMS, n = 21), progressive MS (PMS, n = 24) and HC (n = 25) from an outpatient MS clinic. Participants completed a battery of word-finding, social cognitive, neuropsychological and clinical assessments and performed a speech task for prosodic analysis. RESULTS: Of 45 pwMS, mean (SD) age was 49.4 (9.4) years, and median (range) Expanded Disability Severity Scale score was 3.5 (1.0-6.5). Compared with HC, pwMS were older and had slower information processing speed (measured with the Symbol Digit Modalities Test, SDMT) and higher depression scores. Most speech and social cognitive measures were associated with information processing speed but not with depression. Unlike speech, social cognition consistently correlated with intelligence and memory. Visual naming test mean response time (VNT-MRT) demonstrated worse outcomes in MS versus HC (p = .034, Nagelkerke's R2  = 65.0%), and in PMS versus RMS (p = .009, Nagelkerke's R2  = 50.2%). Rapid automatised object naming demonstrated worse outcomes in MS versus HC (p = .014, Nagelkerke's R2  = 49.1%). These word-finding measures showed larger effect sizes than that of the SDMT (MS vs. HC, p = .010, Nagelkerke's R2  = 40.6%; PMS vs. RMS, p = .023, Nagelkerke's R2  = 43.5%). Prosody and social cognition did not differ between MS and HC. CONCLUSIONS: Word finding, prosody and social cognition in MS are associated with information processing speed and largely independent of mood. Impairment in visual object meaning perception is potentially a unique MS disease-related deficit that could be further explored and cautiously considered as an adjunct disability metric for MS.

Interpreting the clinical importance of the relationship between subjective fatigue and cognitive impairment in multiple sclerosis (MS): How BICAMS performance is affected by MS-related fatigue.

BACKGROUND: There is evidence that subjective fatigue can influence cognitive functioning in multiple sclerosis (MS). DeLuca et al.'s (2004) Relative Consequence Model proposes that impairments to other high-level cognitive functions, such as memory, result from the disease's effect on information processing speed. OBJECTIVE: The primary aims of the study were to investigate both 1) the relationship between subjective fatigue and cognitive functioning, as measured by the widely used Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in MS; and 2) the consequential effect of fatigue on information processing speed as predicted by the Relative Consequence Model. METHODS: 192 participants with MS attending tertiary referral MS centre completed the Modified Fatigue Impact Scale and BICAMS. RESULTS: Multiple correlation analyses determined that there were statistically significant relationships between all domains assessed by the BICAMS and levels of fatigue, such that higher levels of self-reported fatigue were associated with lower performance on information-processing, and visual and verbal learning. After controlling for information processing speed, the strength of correlation between fatigue and learning performance weakened. Linear regression analysis showed that fatigue predicted the most variance in verbal learning and 11.7% of the overall variance in BICAMS performance. CONCLUSION: Subjective fatigue and objective cognitive performance in MS are related. Caution is advised in the interpretation of BICAMS scores in cases where high levels of fatigue are present, and more detailed neuropsychological assessments may be required in order to accurately identify objective cognitive impairment independent of subjective fatigue.

Neuromyelitis optica spectrum disorders and anti-myelin oligodendrocyte glycoprotein positive optic neuropathies.

AIM: To describe the clinical characteristics and treatments associated with antibody positive optic neuropathies including anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin 4 (AQP4), alongside diagnostic modalities, investigations, and outcomes. METHODS: A cross-sectional single-centre retrospective case series consisting of 16 patients including 12 anti-MOG positive patients and 4 anti-AQP4 positive patients. Each of these patients had clinical signs and symptoms of optic neuritis and consisted of all patients who had a positive blood antibody result in our centre. Clinical findings including presence of a relative afferent pupillary defect, colour vision and disc assessment were recorded. Structured clinical exam and multimodal imaging was undertaken sequentially on each. Optical coherence tomography (OCT) scanning was preformed to examine the correlation between ganglion cell layer (GCL) thickness and visual acuity (VA) at presentation and as a determinant of final visual outcome in both groups. Initial and long-term treatment is also summarised. RESULTS: A total of 16 patients were included in the study consisting of 12 anti-MOG and 4 anti-AQP4 positive patients. Nine of the 16 patients were female and the average age of onset was 29.2y in the MOG group and 42y in the AQP4 group. There was no statistically significant correlation (Pearson correlation) between GCL thickness and presenting and final VA [r(10)=0.081, P=0.08 and r(10)=0.089, P=0.34 respectively]. The same statistical analysis was performed for the correlation between retinal nerve fibre layer (RNFL) and VA and similar outcomes were observed [r(10)=0.04, P=0.22 and r(10)=0.09, P=0.04]. No correlation was seen for initial RNFL thickness and final visual outcome in this group either [r(2)=0.19, P=0.38]. Visual field testing and radiological findings for each group are described. CONCLUSION: No correlation between initial VA or RNFL and final visual outcome is identified. A broad range of visual field and radiographic findings are identified, a consensus on treatment of neuromyelitis optica spectrum disorders and anti-MOG positive optic neuropathies has yet to be accepted but initial high dose immunosuppression followed by low dose maintenance therapy is favoured.

Investigating the association of mood and fatigue with objective and subjective cognitive impairment in multiple sclerosis.

Discrepancies between subjective cognitive difficulties and objective measures of cognitive function in people with MS have been identified and may be related to mood and fatigue. The aim of the present study was to examine associations of depression and fatigue with discrepancies between subjective and objective cognitive functioning in pwMS. 177 participants with MS attending a University Hospital Department of Neurology MS Outpatient clinic completed the Brief International Cognitive Assessment for MS (BICAMS), MS Neuropsychological Questionnaire (MSNQ), Hospital Anxiety and Depression Scale (HADS) and Modified Fatigue Impact Scale (MFIS). To quantify the discrepancy between objective (BICAMS) and subjective (MSNQ) cognitive functioning, discrepancy scores were calculated by subtracting MSNQ z-score from composite BICAMS z-score. Based on their discrepancy score, participants were grouped as 'Underestimated', 'Overestimated' and 'Non-discrepant'. 39% of the total sample demonstrated poorer subjective cognitive functioning than their objective cognitive performance suggested ('Underestimated'). 23% of the total sample indicated lower objective scores than their subjective report suggests ('Overestimated'). 38% participants indicated relatively no discrepancy between objective and subjective cognitive measures ('Non-discrepant'). Significant differences were observed between the discrepancy groups in terms of depression and fatigue, with the 'Underestimated' group demonstrating greater levels of depression and fatigue (ps < .01). Regression analysis indicated that cognitive fatigue and depression significantly contributed to variance in subjective cognitive functioning. Our findings suggest that subjective reports of cognitive function may be influenced by depression and fatigue, emphasising the importance of cognitive, mood and fatigue screening as part of routine clinical care.

The effects of dimethyl fumarate and fingolimod on T-cell lymphocyte proliferation in patients with multiple sclerosis.

OBJECTIVE: The disease-modifying therapies (DMT), dimethyl fumarate (DMF) and fingolimod (FTY) improve the outcomes in multiple sclerosis (MS) by reducing relapses and numbers and volume of lesions. They mediate their effects through reduction of immune reactivation, which may potentially lead to lymphopaenia and increased risk of infections. Previous studies have examined the effects of these therapies on lymphocyte subsets; however, the in vivo effects on circulating lymphocyte proliferation require further elucidation. The aim of this study was to determine the effects of DMF and FTY on T-cell proliferation in patients with MS. METHOD: We examined T-cell lymphocyte proliferation and lymphocyte subsets in ten patients (five on DMF, five on FTY) before starting DMT and again 4 to 11 months after being maintained on DMT. RESULTS: In the FTY-treated group, the mean percentage proliferation was significantly lower using both assays (PHA assay mean percentage change - 51.2 ± 25.97, p < 0.05; anti-CD3/CD28 assay mean percentage change - 39.74 ± 27.85, p < 0.05). There was no statistical difference in T-cell lymphocyte proliferation in the DMF-treated group for either assay (PHA, p = 0.316; anti-CD3/CD28, p = 0.373). CONCLUSIONS: This pilot study suggests that the T-lymphocytes of patients on FTY have an abnormal proliferation response as well as being reduced in the circulation.

Skin care advice to patients with multiple sclerosis on Fingolimod treatment at increased risk of skin malignancy-room for improvement?

Fingolimod is used to treat relapsing-remitting multiple sclerosis. It has an immunosuppressive effect that predisposes to skin malignancies. The Summary of Product Characteristics recommends that persons receiving Fingolimod be educated regarding photoprotection and vigilance of skin lesions and should undergo a dermatological evaluation at initiation of treatment and 6-12 monthly thereafter. The incidence of keratinocytic carcinomas in those on long-term immunosuppression following solid organ transplantation is declining. This trend coincided with temporal changes in immunosuppressive protocols and the introduction of skin cancer prevention programmes suggesting that the risk of developing these malignancies may be mitigated by the provision of education to patients amongst other measures. The aim of our study was to assess if health care professionals are explaining skin advice and documenting the discussion when prescribing Fingolimod in a University Hospital outpatient setting. Clinical records of consecutive patients on Fingolimod were reviewed. Data on demographics, documented provision of advice on skin protection and who provided the advice was collected. Fifty patients with multiple sclerosis were identified. Median age was 40.5 years (range 25-63). Forty-two were female (42/50, 84%). Provision of advice regarding skin protection was documented in 20% (10/50). This was provided by nurse specialists in 14% (7/50), doctors in 10% (5/50) and both in 4% (2/50). The risk of developing skin cancers can be reduced by the adoption of simple preventative measures; patients on Fingolimod are at an increased risk of developing these cancers. This study demonstrates a need for improvement in the documentation of advice around skin protection.

Five-year follow up of the original Irish BICAMS validation cohort.

INTRODUCTION: Cognitive impairment is common in multiple sclerosis at all stages of the condition. The natural history of cognition in multiple sclerosis has been considered to be deterioration of cognitive functioning over time. The development of the Brief International Cognitive Assessment for Multiple Sclerosis(BICAMS) has allowed standardization of a screening tool for cognitive impairment which can be easily performed in the neurology clinic. Cross-sectional and validation studies using BICAMS have been widely reported, however minimal longitudinal assessment of cognition using BICAMS has taken place to date. OBJECTIVES: The objective of this study was to evaluate the prevalence of cognitive impairment at a five-year interval in participants of an original BICAMS validation study. We will also evaluate change of the BICAMS subtests over time. MATERIALS AND METHODS: Participants of the original BICAMS validation study were invited to participate in the study. Demographic and clinical details were collected. BICAMS subtests, anxiety, depression and fatigue questionnaires were completed. RESULTS: Fifty out of the original 67 participants completed BICAMS five years post original assessment. The prevalence of cognitive impairment in this cohort with a mean age of 49 and a median EDSS of 2.5 (EDSS of 2.0 at initial BICAMS testing) remained stable five years following initial BICAMS screening assessment, X2(1)=0.36, p=.548. There was no significant difference in SDMT scores between 2014 and 2019 t(48) = 1.08, p=.15. There was an improvement in CVLT-II, t(49)=-3.03; p=.004 and BVMT-R, t(49)=-3.38; p=.001. CONCLUSIONS: This study demonstrates overall stability in the prevalence of cognitive impairment as assessed by the BICAMS. The interval of five years between assessment reduces the possibility of practice effects, although familiarity with the testing protocol may exert an influence.

Vaccine hesitancy among people with multiple sclerosis.

BACKGROUND: The current severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has raised awareness of vaccine hesitancy. Specific reasons for vaccine hesitancy among people with multiple sclerosis (pwMS) have not been fully described. Notably, pwMS may experience higher morbidity from vaccine-preventable diseases such as influenza, pneumococcal disease, and human papillomavirus (HPV)-associated warts and malignancies. Furthermore, screening for immunity against measles, mumps and rubella (MMR) is not standard practice, despite a resurgence of measles and mumps outbreaks in Europe and worldwide. We aimed to evaluate general vaccination status among pwMS to better inform vaccine practices in this cohort. METHODS: This was a prospective audit of pwMS attending an Irish tertiary referral MS centre. We designed a questionnaire that explored awareness, uptake, and hesitancy for the influenza, pneumococcal, SARS-CoV-2, HPV, and MMR vaccines. The clinician administered the questionnaire during the outpatient MS clinic. RESULTS: One-hundred-and-five pwMS participated in the audit, mean (SD) age 47.3 (12.8) years, mean MS disease duration 14.1 (9.5) years, median Expanded Disability Severity Scale (EDSS) score 2.0 (IQR 1.0-6.0), forty-nine (46.7%) were taking either maintenance immunosuppressive or immune reconstitution therapies. SARS-CoV-2 vaccine willingness among pwMS was higher (90.5 vs 60-80%) than that reported in other Western countries, and higher than that for the influenza and pneumococcal vaccines (∼80%) for which perceived unnecessity and unfamiliarity respectively were the main limiting factors. The primary reason for SARS-CoV-2 vaccine hesitancy was safety concern. PwMS who were explicitly advised by a healthcare professional to obtain the influenza vaccine were more likely to do so than those who were not (odds ratio, 8.1, 95% CI 2.8 - 23.4, p<0.001). Of pwMS currently receiving B-cell therapy (ocrelizumab/rituximab, n=12), all but one (n=11, 91.7%) have never received the pneumococcal vaccine, and a quarter (n=3) were uncertain whether to obtain this in the future. Patient-reported uptake of HPV (1.0%) and MMR (51.4%) vaccines were suboptimal. Prevalence of vaccine promotion among healthcare professionals was low (influenza vaccine, 4.8 - 32.4%; pneumococcal vaccine, 0 - 18.1%). CONCLUSIONS: Vaccine hesitancy is common (10-20%) in pwMS, consequent to insufficient knowledge and misconceptions about vaccination among pwMS and suboptimal vaccine promotion by healthcare professionals who manage pwMS. Conscientious and context-specific vaccination counselling is necessary to tackle vaccine hesitancy among pwMS, including (i) avoiding infection-associated disability accrual during MS relapses, (ii) reducing the potentially higher risk of life-threatening/treatment-refractory complications that may be observed in those who develop vaccine-preventable infections while receiving certain DMTs, and (iii) avoiding attenuated vaccine responses or delayed/interrupted DMT with early pre-treatment vaccine delivery where possible.

Postural stability is a valid and meaningful disability metric in progressive MS with potential for use in neuroprotective therapy trials.

BACKGROUND: Balance impairment is observed in up to 70% of people with MS (pwMS) and worsens with disease progression. Posturography using a force platform is the current gold standard in the measurement of balance. However, posturography has not been adequately studied or widely accepted for use as a disability outcome measure for pwMS. Importantly, the recent emergence of both successful and failed neuroprotective therapy trials in progressive MS has emphasised the need for new disability outcome measures for people with progressive MS. The main objectives of this study were to evaluate the clinical validity, reliability and feasibility of posturography as a disability metric in progressive MS. METHODS: This was a prospective cross-sectional study. We recruited 73 people with progressive MS (age 18-65 years, EDSS 3.5-6.0). Participants stood in the centre of a force platform, feet comfortably apart, under various conditions: (i) eyes open (EO), (ii) eyes closed (EC) - a single task, each lasting ninety seconds; and simultaneous EO with a cognitive test: (iii) N-Back, a three-minute test whereby participants were instructed to click the mouse when two identical letters were displayed consecutively on a screen, (iv) Sustained Attention Response Task, a five-minute test whereby participants were instructed to click the mouse for every number "1″ to "9″ except "3″ - i.e., dual-tasks. Additionally, we performed a battery of validated physical and cognitive outcome measures. Posturographic data was processed using Matlab. Statistical analysis was performed using SPSS version 26. We used multiple linear regression modelling to determine whether significant univariate correlations between posturography and clinical metrics were independent of covariates that may influence the associations seen. A two-tailed significance level of 0.05 was used. RESULTS: Of 73 participants, mean age 52.4 (8.5) years, mean MS disease duration 13.8 (10.3) years, median EDSS 5.0 (IQR 4.0-6.0), 44 (60.4%) were female. EO-Path-Length independently predicted upper extremity function (9-Hole-Peg-Test) with a larger effect size (adjusted R2=20.0%, p = 0.001) than that for walking measures (Timed 25-Foot Walk, adjusted R2=1.6%, p = 0.01; Two-Minute Walk Test, adjusted R2=7.2%, p = 0.002), while controlling for age, disease duration, height, weight, and sex. The addition of EO-Mediolateral-Displacement to the MS Functional Composite (MSFC) created a four-component z-score that increased the variance explained for quality of life (QOL) by 62.1%. Postural stability was significantly lower with mediolateral vs anteroposterior direction of sway, removal of vision, increased body weight, male sex, and fampridine use. Postural stability improved during dual-tasks compared to EO single task. Posturography detected significant worsening of balance over a single prolonged stance. CONCLUSION: Postural stability independently predicted a wide range of clinical metrics including upper extremity function, walking ability, cognition and QOL, therefore establishing construct and concurrent validity as a disability outcome measure for people with progressive MS. Additionally, posturography is a quantitative, non-invasive, quick-and-easy-to-administer, and highly sensitive device, demonstrating its high feasibility for use as a time- and resource-efficient disability metric in neuroprotective therapy trials for progressive MS.

Multiscale entropy derived complexity index analysis demonstrates significant mediolateral sway in persons with multiple sclerosis compared to healthy controls.

Clinical assessment of Multiple Sclerosis relies heavily on the Expanded Disability Status Scale, a non-linear rating system based on physician assessment of disease progression and walking ability. This inherently makes this method both subjective and limited in repeatability. This study developed a technically derived outcome measure of posture to compare a cohort of Multiple Sclerosis and Control subjects during an Eyes-Open and Eyes-closed task. Analysing traditional sway parameters and a multiscale entropy derived complexity index of posturography showed a significant difference in medio-lateral sway between groups during the Eyes-Open condition. This technically derived outcome measure may be of clinical benefit in the longitudinal assessment of the functional impact of balance in MS cohorts and assist in the evaluation of pharmaceutical and rehabilitation interventions.

MELAS, an important consideration in the adult population presenting with unusual and recurrent stroke-like episodes.

A 48-year-old man was admitted for workup of stroke-like symptoms and generalised tonic-clonic seizures. History and examination revealed that the patient had background diagnoses of type 2 diabetes mellitus, epilepsy and had suffered a temporal lobe infarct 3 years ago. The unusual presentation and physical findings, along with subsequent MRI findings led to a diagnosis of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). MELAS is a mitochondrial disorder typified by the aforementioned symptoms, and is typically diagnosed in the first two decades of life.