The role of specialist nurses in detecting spasticity and related symptoms in multiple sclerosis.

BACKGROUND: Spasticity is a frequent symptom of multiple sclerosis (MS), which may negatively influence daily living activities (ADL). OBJECTIVES: To (1) explore the feasibility to conduct a structured interview by specialist nurses about limitations in ADL; (2) determine the percentage of people with MS (PwMS) with limitations in ADL related to spasticity; (3) to assess the knowledge about spasticity and describe its clinical features. DESIGN: Observational, cross-sectional, multicentre study in 16 MS units of Catalonia (Spain). Participants were recruited from the outpatient facility and day-care hospital between July 2018 and June 2019 and met the following criteria: (1) age 18 or older, (2) diagnosis of MS according to McDonald criteria 2010 and (3) no clinical relapse in previous 30 days. METHODS: Specialist nurses conducted a structured interview divided in two parts: the assessment of (1) limitations in the ADL and (2) the presence of spasticity and associated symptoms. The usefulness of this intervention was requested. This study met the STROBE reporting guidelines checklist for observational studies. RESULTS: Three hundred sixty eight pwMS (244 women) with a mean age of 46 years and a median Expanded Disability Status Scale score of 2.5 (range, 0-8.5) were included. 262 (71%) pwMS had limitations in the ADL, and spasticity was reported as the most limiting symptom in 59 (23%). As a result of the interview, spasticity was observed in 199 (76%) participants; 47 (24%) of them were unaware that they had spasticity and 102 (51%) would not have reported it spontaneously. The level of the interview satisfaction was high (90%). CONCLUSIONS: Spasticity is a complex and limiting symptom in MS. The structured interview conducted by specialist nurses is feasible and has good acceptance. PATIENT CONTRIBUTION: Specialist nurses can be proactive in MS clinical assessment, which may help to detect symptoms with negative impact on quality of life.

Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide-loaded tolerogenic dendritic cells in a phase 1b trial.

There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials.

Oligoclonal IgM bands in the cerebrospinal fluid of patients with relapsing MS to inform long-term MS disability.

BACKGROUND: Prognostic markers are needed to guide multiple sclerosis (MS) management in the context of large availability of disease-modifying drugs (DMDs). OBJECTIVE: To investigate the role of cerebrospinal fluid (CSF) markers to inform long-term MS outcomes. METHODS: Demographic features, IgM index, oligoclonal IgM bands (OCMB), lipid-specific OCMB, CSF neurofilament light chain protein levels, expanded disability status scale (EDSS), relapses and DMD use over the study period and peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer (GCIPL) thicknesses in non-optic neuritis eyes (end of follow-up) were collected from relapsing MS (RMS) patients with CSF obtained ⩽2 years after MS onset prospectively followed at the Hospital Clinic of Barcelona. We assessed associations between CSF markers and MS outcomes using multivariable models. RESULTS: A total of 89 patients (71 females; median 32.9 years of age) followed over a median of 9.6 years were included. OCMB were associated with a 33% increase in the annualized relapse rate (ARR; p = 0.06), higher odds for high-efficacy DMDs use (OR = 4.8; 95% CI = (1.5, 16.1)), thinner pRNFL (ß = -4.4; 95% CI = (-8.6, -0.2)) and GCIPL (ß = -2.9; 95% CI = (-5.9, +0.05)), and higher rates to EDSS ⩾ 3.0 (HR = 4.4; 95% CI = (1.6, 11.8)) and EDSS ⩾ 4.0 (HR = 5.4; 95% CI = (1.1, 27.1)). No overall associations were found for other CSF markers. CONCLUSION: The presence of OCMB was associated with unfavorable long-term outcomes. OCMB should be determined in RMS to inform long-term prognosis.

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.

Evaluation of treatment response in adults with relapsing MOG-Ab-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are related to several acquired demyelinating syndromes in adults, but the therapeutic approach is currently unclear. We aimed to describe the response to different therapeutic strategies in adult patients with relapsing MOG-Ab-associated disease. METHODS: This is a retrospective study conducted in France and Spain including 125 relapsing MOG-Ab patients aged ≥ 18 years. First, we performed a survival analysis to investigate the relapse risk between treated and non-treated patients, performing a propensity score method based on the inverse probability of treatment weighting. Second, we assessed the annualised relapse rates (ARR), Expanded Disability Status Scale (EDSS) and visual acuity pre-treatment and on/end-treatment. RESULTS: Median age at onset was 34.1 years (range 18.0-67.1), the female to male ratio was 1.2:1, and 96% were Caucasian. At 5 years, 84% (95% confidence interval [CI], 77.1-89.8) patients relapsed. At the last follow-up, 66 (52.8%) received maintenance therapy. Patients initiating immunosuppressants (azathioprine, mycophenolate mophetil [MMF], rituximab) were at lower risk of new relapse in comparison to non-treated patients (HR, 0.41; 95CI%, 0.20-0.82; p = 0.011). Mean ARR (standard deviation) was reduced from 1.05(1.20) to 0.43(0.79) with azathioprine (n = 11; p = 0.041), from 1.20(1.11) to 0.23(0.60) with MMF (n = 11; p = 0.033), and from 1.08(0.98) to 0.43(0.89) with rituximab (n = 26; p = 0.012). Other immunosuppressants (methotrexate/mitoxantrone/cyclophosphamide; n = 5), or multiple sclerosis disease-modifying drugs (MS-DMD; n = 9), were not associated with significantly reduced ARR. Higher rates of freedom of EDSS progression were observed with azathioprine, MMF or rituximab. CONCLUSION: In adults with relapsing MOG-Ab-associated disease, immunosuppressant therapy (azathioprine, MMF and rituximab) is associated with reduced risk of relapse and better disability outcomes. Such an effect was not found in the few patients treated with MS-DMD.

Clinical profile of patients with paraneoplastic neuromyelitis optica spectrum disorder and aquaporin-4 antibodies.

BACKGROUND: In a minority of patients with neuromyelitis optica spectrum disorder (NMOSD) and aquaporin-4 antibodies (AQP4-IgG), the disease has a paraneoplastic origin. It is unknown whether these patients have distinctive clinical features. OBJECTIVE: To report the clinical features of a series of patients with paraneoplastic NMOSD and AQP4-IgG and to review previously reported cases. METHODS: Retrospective analysis of clinical records of 156 patients with NMOSD and AQP4-IgG and review of previously reported patients with paraneoplastic NMOSD and AQP4-IgG. Paraneoplastic patients were defined as those with cancer identified within 2 years of the diagnosis of NMOSD. RESULTS: Five (3.2%) of 156 patients had paraneoplastic NMOSD, and 12 previously reported patients were identified. The most common tumors were adenocarcinoma of the lung (five patients) and breast (five). Compared with the 151 non-paraneoplastic NMOSD patients, the 17 (5 current cases and 12 previously reported) were older at symptom onset (median age = 55 (range: 17-87) vs 40 (range: 10-77) years; p = 0.006), more frequently male (29.4% vs 6.6%; p = 0.009), and presented with severe nausea and vomiting (41.2% vs 6.6%; p < 0.001). The frequency of longitudinal extensive transverse myelitis (LETM) as heralding symptom was similar in both groups, but patients with paraneoplastic NMOSD were older than those with non-paraneoplastic NMOSD (median age: 63 (range: 48-73) vs 43 (range: 14-74) years; p = 0.001). CONCLUSION: Patients, predominantly male, with NMOSD and AQP4-IgG should be investigated for an underlying cancer if they present with nausea and vomiting, or LETM after 45 years of age.

Impairment of decision-making in multiple sclerosis: A neuroeconomic approach.

OBJECTIVE: To assess the decision-making impairment in patients with multiple sclerosis (MS) and how they relate to other cognitive domains. METHODS: We performed a cross-sectional analysis in 84 patients with MS, and 21 matched healthy controls using four tasks taken from behavioral economics: (1) risk preferences, (2) choice consistency, (3) delay of gratification, and (4) rate of learning. All tasks were conducted using real-world reward outcomes (food or money) in different real-life conditions. Participants underwent cognitive examination using the Brief Repeatable Battery-Neuropsychology. RESULTS: Patients showed higher risk aversion (general propensity to choose the lottery was 0.51 vs 0.64, p = 0.009), a trend to choose more immediate rewards over larger but delayed rewards ( p = 0.108), and had longer reactions times ( p = 0.033). Choice consistency and learning rates were not different between groups. Progressive patients chose slower than relapsing patients. In relation to general cognitive impairments, we found correlations between impaired decision-making and impaired verbal memory ( r = 0.29, p = 0.009), visual memory ( r = -0.37, p = 0.001), and reduced processing speed ( r = -0.32, p = 0.001). Normalized gray matter volume correlated with deliberation time ( r = -0.32, p = 0.005). CONCLUSION: Patients with MS suffer significant decision-making impairments, even at the early stages of the disease, and may affect patients' quality and social life.

Motor polyradiculopathy during pembrolizumab treatment of metastatic melanoma.

INTRODUCTION: Pembrolizumab, a monoclonal antibody directed against the immune checkpoint programmed cell death-1 receptor (PD-1), has improved survival in patients with advanced melanoma. Neuromuscular immune-mediated side effects have been rarely reported. METHODS: We describe a 44-year-old man with metastatic melanoma who presented with progressive muscle weakness after 23 doses of pembrolizumab. RESULTS: The patient developed asymmetric, proximal muscle weakness and atrophy in all four limbs. Cerebrospinal fluid examination showed albuminocytologic dissociation. MRI revealed contrast enhancement of the lumbosacral roots. Electrodiagnostic studies demonstrated widespread fibrillation potentials in all four limbs, suggesting a generalized motor polyradiculopathy. Despite pembrolizumab discontinuation and treatment with steroids and intravenous immunoglobulin, limb weakness worsened. Electrodiagnostic studies were repeated, and showed marked and diffuse axonal motor damage. Seven weeks after clinical onset the patient was treated with plasma exchanges. He showed no further deterioration. DISCUSSION: We report a severe motor polyradiculopathy associated with an anti-PD-1 agent that expands the spectrum of neuromuscular complications of this class of drugs. Muscle Nerve 56: E162-E167, 2017.

Pituitary-ovary axis and ovarian reserve in fertile women with multiple sclerosis: A pilot study.

Since a decline in the ovary function might impact the reproductive potential in women with multiple sclerosis (MS), we investigated the pituitary-ovary axis and ovarian reserve, including anti-Müllerian hormone (AMH) levels and ultrasound imaging of the ovaries, of 25 relapsing-remitting MS patients and 25 age-matched healthy controls. Mean levels of pituitary-gonadal hormones and age-adjusted parameters of ovarian reserve markers were not significantly different between both groups. Patients with higher disease activity (annualized relapse rate >0.5; n=9) had significantly lower AMH levels, total antral follicle count and ovarian volume, than those with lower disease activity. The finding of poorer ovarian reserve associated with higher disease activity should be taken into consideration since it may negatively impact the reproductive prognosis.

Effects of postural and voluntary muscle contraction on modulation of the soleus H reflex by transcranial magnetic stimulation.

Modulation of spinal reflexes depends largely on the integrity of the corticospinal tract. A useful method to document the influence of descending tracts on reflexes is to examine the effects of transcranial magnetic stimulation (TMS) on the soleus H reflex elicited by posterior tibial nerve electrical stimuli (PTS). In 12 healthy volunteers, we investigated how postural or voluntary muscle contraction modified such descending modulation. We first characterized the effects of TMS at 95 % of motor threshold for leg responses on the H reflex elicited by a preceding PTS at inter-stimuli intervals (ISIs) between 0 and 120 ms at rest and, then, during voluntary plantar flexion (pf), dorsal flexion (df), and standing still (ss). During pf, there was an increase in the facilitation of the H reflex at ISIs 0-20 ms. During df, there were no effects of TMS on the H reflex. During ss, there was inhibition at ISIs 40-60 ms. Our observations suggest that muscle contraction prevails over the baseline effects of TMS on the soleus H reflex. While contraction of the antagonist (df) suppressed most of the effects, contraction of the agonist had different effects depending on the type of activity (pf or ss). The characterization of the interaction between descending corticospinal volleys and segmental peripheral inputs provides useful information on motor control for physiological research and further understanding of the effects of spinal cord lesions.

Cognitive functions in multiple sclerosis: impact of gray matter integrity.

OBJECTIVES: Our aim was to investigate the impact of gray matter (GM) integrity on cognitive performance in multiple sclerosis (MS), and its relationship with white matter (WM) integrity and presence of lesions. METHODS: Sixty-seven patients with MS and 26 healthy controls underwent voxel-based analysis of diffusion tensor images (DTI) in GM and tract-based spatial statistics (TBSS) from WM to identify the regional correlations between cognitive functions and integrity. Lesion probability mapping (LPM) was generated for correlation analysis with cognition. Multiple linear regression analyses were used to identify the imaging measures associated with cognitive scores. RESULTS: Compared with controls, patients showed abnormal DTI indices in several GM regions and in most WM tracts. Impairment in DTI indices in specific GM regions was associated with worse performance of distinct cognitive functions. Those regions showed anatomical correspondence with cognitively relevant tracts in TBSS and LPM. The combination of regional GM and WM DTI and lesion volume accounted for 36-51% of the variance of memory and attention scores. Regional GM DTI explained less than 5% of that variance. CONCLUSION: GM and WM integrity of specific networks influences cognitive performance in MS. However, GM damage assessed by DTI only adds a small increment to the explained variance by WM in predicting cognitive functioning.

Seroprevalence of SARS-CoV-2 in Patients with Multiple Sclerosis under Disease-Modifying Therapies: A Multi-Centre Study.

BACKGROUND: The EMCOVID project conducted a multi-centre cohort study to investigate the impact of COVID-19 on patients with Multiple Sclerosis (pwMS) receiving disease-modifying therapies (DMTs). The study aimed to evaluate the seroprevalence and persistence of SARS-CoV-2 antibodies in MS patients enrolled in the EMCOVID database. The DMTs were used to manage MS by reducing relapses, lesion accumulation, and disability progression. However, concerns arose regarding the susceptibility of pwMS to COVID-19 due to potential interactions between SARS-CoV-2 and the immune system, as well as the immunomodulatory effects of DMTs. METHODS: This prospective observational study utilized data from a Multiple Sclerosis and COVID-19 (EMCOVID-19) study. Demographic characteristics, MS history, laboratory data, SARS-CoV-2 serology, and symptoms of COVID-19 were extracted for pwMS receiving any type of DMT. The relationship between demographics, MS phenotype, DMTs, and COVID-19 was evaluated. The evolution of SARS-CoV-2 antibodies over a 6-month period was also assessed. RESULTS: The study included 709 pwMS, with 376 patients providing samples at the 6-month follow-up visit. The seroprevalence of SARS-CoV-2 antibodies was higher among pwMS than the general population, with Interferon treatment being significantly associated with greater seroprevalence (16.9% vs. 8.4%; p 0.003). However, no other specific DMT showed a significant association with antibody presence. A total of 32 patients (8.5%) tested positive for IgG, IgM, or IgA antibodies against SARS-CoV-2 at baseline, but then tested negative at 6 months. Most of the pwMS in the cohort were asymptomatic for COVID-19 and, even among symptomatic cases, the prognosis was generally favourable. CONCLUSION: pwMS undergoing DMTs exhibited a higher seroprevalence of COVID-19 than the general population. Interferon treatment was associated with a higher seroprevalence, suggesting a more robust humoral response. This study provides valuable insights into the seroprevalence and persistence of SARS-CoV-2 antibodies in pwMS and contributes to our understanding of the impact of COVID-19 amongst this population.

Mitochondrial loss indicates early axonal damage in small fiber neuropathies.

Evaluation of nerve fibers in the skin provides a useful tool for the diagnosis of small fiber neuropathies (SFNs). Our aim was to determine whether mitochondria are involved in SFN, indicating early axonal damage. We quantified mitochondrial respiratory chain complex IV (OXPHOS) and axonal (PGP 9.5) fluorescence on skin sections from 32 SFN patients and 14 healthy controls. Also, a group of six patients were recruited before and after 30-day treatment with the mitotoxic antibiotic linezolid. We measured the co-localization of OXPHOS within the intraepidermal and subpapillary dermal axons (PGP-immunoreactive [PGP-ir]). SFN patients with relatively preserved intraepidermal nerve fibers (SFN borderline) showed statistically significant reduction of OXPHOS (50.5 ± 33.9 µm(2) vs. 107.6 ± 81 µm(2) in controls, p < 0.02). A positive correlation was found between both PGP-ir and OXPHOS in controls (Pearson's coefficient r = 0.59, p < 0.001), whereas such correlation was absent in SFN. With respect to baseline measurements, linezolid therapy increased both PGP-ir and OXPHOS, which could be considered an initial compensatory toxic-induced response. This study set out to identify a possible marker of axonal pre-degenerative state in SFN borderline patients.

Regional grey matter microstructural changes and volume loss according to disease duration in multiple sclerosis patients.

The spatio-temporal characteristics of grey matter (GM) impairment in multiple sclerosis (MS) are poorly understood. We used a new surface-based diffusion MRI processing tool to investigate regional modifications of microstructure, and we quantified volume loss in GM in a cohort of patients with MS classified into three groups according to disease duration. Additionally, we investigated the relationship between GM changes with disease severity. We studied 54 healthy controls and 247 MS patients classified regarding disease duration: MS1 (less than 5 years, n = 67); MS2 (5-15 years, n = 107); and MS3 (more than15 years, n = 73). We compared GM mean diffusivity (MD), fractional anisotropy (FA) and volume between groups, and estimated their clinical associations. Regional modifications in diffusion measures (MD and FA) and volume did not overlap early in the disease, and became widespread in later phases. We found higher MD in MS1 group, mainly in the temporal cortex, and volume reduction in deep GM and left precuneus. Additional MD changes were evident in cingulate and occipital cortices in the MS2 group, coupled to volume reductions in deep GM and parietal and frontal poles. Changes in MD and volume extended to more than 80% of regions in MS3 group. Conversely, increments in FA, with very low effect size, were observed in the parietal cortex and thalamus in MS1 and MS2 groups, and extended to the frontal lobe in the later group. MD and GM changes were associated with white matter lesion load and with physical and cognitive disability. Microstructural integrity loss and atrophy present differential spatial predominance early in MS and accrual over time, probably due to distinct pathogenic mechanisms that underlie tissue damage.

Dynamics and Predictors of Cognitive Impairment along the Disease Course in Multiple Sclerosis.

(1) Background: The evolution and predictors of cognitive impairment (CI) in multiple sclerosis (MS) are poorly understood. We aimed to define the temporal dynamics of cognition throughout the disease course and identify clinical and neuroimaging measures that predict CI. (2) Methods: This paper features a longitudinal study with 212 patients who underwent several cognitive examinations at different time points. Dynamics of cognition were assessed using mixed-effects linear spline models. Machine learning techniques were used to identify which baseline demographic, clinical, and neuroimaging measures best predicted CI. (3) Results: In the first 5 years of MS, we detected an increase in the z-scores of global cognition, verbal memory, and information processing speed, which was followed by a decline in global cognition and memory (p < 0.05) between years 5 and 15. From 15 to 30 years of disease onset, cognitive decline continued, affecting global cognition and verbal memory. The baseline measures that best predicted CI were education, disease severity, lesion burden, and hippocampus and anterior cingulate cortex volume. (4) Conclusions: In MS, cognition deteriorates 5 years after disease onset, declining steadily over the next 25 years and more markedly affecting verbal memory. Education, disease severity, lesion burden, and volume of limbic structures predict future CI and may be helpful when identifying at-risk patients.

Telemedicine assessment of long-term cognitive and functional status in anti-leucine-rich, glioma-inactivated 1 encephalitis.

OBJECTIVE: To assess the feasibility of a structured telephone interview examining the long-term cognitive and functional status in anti-leucine-rich, glioma-inactivated 1 (LGI1) encephalitis. METHODS: Telephone interviews were conducted with 37 patients after a median follow-up of 87 months from disease onset and 23 healthy controls matched for age and sex. Cognitive status was assessed with the telephone Mini-Mental State Examination (t-MMSE) and 3 tests exploring verbal memory, fluency, and executive function. Functional status was evaluated with the Functional Activities Questionnaire and the modified Rankin Scale (mRS). Patients were classified as normal, with mild cognitive impairment (MCI), or with dementia based on cognitive and functional status. Assessment of the cognitive reserve was performed with a structured questionnaire. Logistic regression analysis was applied to identify predictors of cognitive impairment. RESULTS: Telephone interviews were successful in 36/37 (97%) patients. Cognitive impairment was detected in 27 (75%) including 17 with MCI and 10 with dementia. Eight (29%) patients would have been misclassified using only the t-MMSE. Twenty-six (72%) patients were functionally independent according to the mRS, but only 9 (35%) were cognitively normal. Independent predictors for long-term cognitive impairment were a low cognitive reserve (OR = 1.36, 95% CI: 1.05-1.76; p = 0.02) and bilateral hippocampal hyperintensity at initial MRI (OR = 27.03, 95% CI: 1.87-390; p = 0.02). CONCLUSIONS: Telemedicine is a feasible tool to assess the cognitive and functional outcome in patients with anti-LGI1 encephalitis. Cognitive impairment is often missed if only functional scales are used. Premorbid cognitive reserve and MRI with bilateral hippocampal hyperintensity were predictors for long-term cognitive impairment.

Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: Analysis of predisposing factors.

BACKGROUND: Rebound of multiple sclerosis (MS) activity has been described after the withdrawal of high-efficacy drugs, but its impact during pregnancy is less known. We describe a series of cases of rebound syndrome after the cessation of fingolimod due to pregnancy planning. METHODS: The clinical and radiological data of 7 MS patients who discontinued fingolimod therapy between May 2012 and March 2018 to plan a pregnancy was analysed. RESULTS: Three (42.8%) of the 7 patients experienced a rebound effect, all of whom became pregnant. During pregnancy, the 3 patients had a mean (SD) of 5.3 (1.3) relapses, and 13 of the 15 relapses were treated with intravenous steroids and/or immunoglobulin. These patients experienced a median increase of 3 points in the Expanded Disability Status Scale (range, 2-4), as well as a median increase of 27 new gadolinium-enhancing lesions (range, 9-40) and 38 new T2 lesions in a post-partum MRI (range, 21-70). The 3 pregnancies resulted in the delivery of healthy babies. A strong correlation was found between the lymphocyte count at fingolimod onset and the annual relapse rate in the period without therapy (r= -0.84, p = 0.005). The time to first relapse was shorter in patients who had <300/µl lymphocytes at fingolimod onset (median time 46 vs 426 days, p = 0.010). CONCLUSION: Rebound activity after fingolimod suspension represents a severe long-lasting inflammatory syndrome that may affect up to 40% of female MS patient who discontinue therapy due to pregnancy planning. Lymphopenia (<300/µl) in the first 3 months of fingolimod onset may predispose patients to suffer earlier and higher disease activity upon cessation.

Impact of Cognitive Reserve and Structural Connectivity on Cognitive Performance in Multiple Sclerosis.

Background: Cognitive reserve (CR) could attenuate the impact of the brain burden on the cognition in people with multiple sclerosis (PwMS). Objective: To explore the relationship between CR and structural brain connectivity and investigate their role on cognition in PwMS cognitively impaired (PwMS-CI) and cognitively preserved (PwMS-CP). Methods: In this study, 181 PwMS (71% female; 42.9 ± 10.0 years) were evaluated using the Cognitive Reserve Questionnaire (CRQ), Brief Repeatable Battery of Neuropsychological tests, and MRI. Brain lesion and gray matter volumes were quantified, as was the structural network connectivity. Patients were classified as PwMS-CI (z scores = -1.5 SD in at least two tests) or PwMS-CP. Linear and multiple regression analyses were run to evaluate the association of CRQ and structural connectivity with cognition in each group. Hedges's effect size was used to compute the strength of associations. Results: We found a very low association between CRQ scores and connectivity metrics in PwMS-CP, while in PwMS-CI, this relation was low to moderate. The multiple regression model, adjusted for age, gender, mood, lesion volume, and graph metrics (local and global efficiency, and transitivity), indicated that the CRQ (ß = 0.26, 95% CI: 0.17-0.35) was associated with cognition (adj R 2 = 0.34) in PwMS-CP (55%). In PwMS-CI, CRQ (ß = 0.18, 95% CI: 0.07-0.29), age, and network global efficiency were independently associated with cognition (adj R 2 = 0.55). The age- and gender-adjusted association between CRQ score and global efficiency on having an impaired cognitive status was -0.338 (OR: 0.71, p = 0.036) and -0.531 (OR: 0.59, p = 0.002), respectively. Conclusions: CR seems to have a marginally significant effect on brain structural connectivity, observed in patients with more severe clinical impairment. It protects PwMS from cognitive decline regardless of their cognitive status, yet once cognitive impairment has set in, brain damage and aging are also influencing cognitive performance.

Characterization of multiple sclerosis lesions with distinct clinical correlates through quantitative diffusion MRI.

Diffusion magnetic resonance imaging can reveal quantitative information about the tissue changes in multiple sclerosis. The recently developed multi-compartment spherical mean technique can map different microscopic properties based only on local diffusion signals, and it may provide specific information on the underlying microstructural modifications that arise in multiple sclerosis. Given that the lesions in multiple sclerosis may reflect different degrees of damage, we hypothesized that quantitative diffusion maps may help characterize the severity of lesions "in vivo" and correlate these to an individual's clinical profile. We evaluated this in a cohort of 59 multiple sclerosis patients (62% female, mean age 44.7 years), for whom demographic and disease information was obtained, and who underwent a comprehensive physical and cognitive evaluation. The magnetic resonance imaging protocol included conventional sequences to define focal lesions, and multi-shell diffusion imaging was used with b-values of 1000, 2000 and 3000 s/mm2 in 180 encoding directions. Quantitative diffusion properties on a macro- and micro-scale were used to discriminate distinct types of lesions through a k-means clustering algorithm, and the number and volume of those lesion types were correlated with parameters of the disease. The combination of diffusion tensor imaging metrics (fractional anisotropy and radial diffusivity) and multi-compartment spherical mean technique values (microscopic fractional anisotropy and intra-neurite volume fraction) differentiated two type of lesions, with a prediction strength of 0.931. The B-type lesions had larger diffusion changes compared to the A-type lesions, irrespective of their location (P < 0.001). The number of A and B type lesions was similar, although in juxtacortical areas B-type lesions predominated (60%, P < 0.001). Also, the percentage of B-type lesion volume was higher (64%, P < 0.001), indicating that these lesions were larger. The number and volume of B-type lesions was related to the severity of disease evolution, clinical disability and cognitive decline (P = 0.004, Bonferroni correction). Specifically, more and larger B-type lesions were correlated with a worse Multiple Sclerosis Severity Score, cerebellar function and cognitive performance. Thus, by combining several microscopic and macroscopic diffusion properties, the severity of damage within focal lesions can be characterized, further contributing to our understanding of the mechanisms that drive disease evolution. Accordingly, the classification of lesion types has the potential to permit more specific and better-targeted treatment of patients with multiple sclerosis.

Retinal and brain damage during multiple sclerosis course: inflammatory activity is a key factor in the first 5 years.

Understanding of the role of focal inflammation, a treatable feature, on neuro-axonal injury, is paramount to optimize neuroprotective strategy in MS. To quantify the impact of focal inflammatory activity on the rate of neuro-axonal injury over the MS course. We quantified the annualized rates of change in peripapillary retinal nerve fiber layer, ganglion cell plus inner plexiform layer (GCIPL), whole-brain, gray matter and thalamic volumes in patients with and without focal inflammatory activity in 161 patients followed over 5 years. We used mixed models including focal inflammatory activity (the presence of at least one relapse or a new/enlarging T2-FLAIR or gadolinium- enhancing lesion), and its interaction with time adjusted by age, sex, use of disease-modifying therapies and steroids, and prior optic neuritis. The increased rate of neuro-axonal injury during the first five years after onset was more prominent among active patients, as reflected by the changes in GCIPL thickness (p = 0.02), whole brain (p = 0.002) and thalamic volumes (p < 0.001). Thereafter, rates of retinal and brain changes stabilized and were similar in active and stable patients. Focal inflammatory activity is associated with neurodegeneration early in MS which reinforces the use of an early intensive anti-inflammatory therapy to prevent neurodegeneration in MS.