Human papillomavirus lesions in 16 MS patients treated with fingolimod: Outcomes and vaccination.

Few cases of human papillomavirus (HPV) diseases have been reported in multiple sclerosis (MS) patients treated with fingolimod. We describe a case series of 16 MS patients (11 women, 5 men) developing HPV lesions after the onset of fingolimod, without previous HPV history. Fingolimod had to be discontinued in six patients. Six patients received vaccination for HPV, with good tolerance. Our report highlights that systematic HPV screening and discussion about HPV vaccination before fingolimod onset are crucial. In case of occurrence of HPV lesions during fingolimod treatment, a comprehensive workup of HPV disease is necessary, with discussion of HPV vaccination to prevent secondary lesions. Prevalence studies of HPV lesions are needed in MS patients with the different disease-modifying therapies.

Anxiety, emotional processing and depression in people with multiple sclerosis.

BACKGROUND: Despite the high comorbidity of anxiety and depression in people with multiple sclerosis (MS), little is known about their inter-relationships. Both involve emotional perturbations and the way in which emotions are processed is likely central to both. The aim of the current study was to explore relationships between the domains of mood, emotional processing and coping and to analyse how anxiety affects coping, emotional processing, emotional balance and depression in people with MS. METHODS: A cross-sectional questionnaire study involving 189 people with MS with a confirmed diagnosis of MS recruited from three French hospitals. Study participants completed a battery of questionnaires encompassing the following domains: i. anxiety and depression (Hospital Anxiety and Depression Scale (HADS)); ii. emotional processing (Emotional Processing Scale (EPS-25)); iii. positive and negative emotions (Positive and Negative Emotionality Scale (EPN-31)); iv. alexithymia (Bermond-Vorst Alexithymia Questionnaire) and v. coping (Coping with Health Injuries and Problems-Neuro (CHIP-Neuro) questionnaire. Relationships between these domains were explored using path analysis. RESULTS: Anxiety was a strong predictor of depression, in both a direct and indirect way, and our model explained 48% of the variance of depression. Gender and functional status (measured by the Expanded Disability Status Scale) played a modest role. Non-depressed people with MS reported high levels of negative emotions and low levels of positive emotions. Anxiety also had an indirect impact on depression via one of the subscales of the Emotional Processing Scale ("Unregulated Emotion") and via negative emotions (EPN-31). CONCLUSIONS: This research confirms that anxiety is a vulnerability factor for depression via both direct and indirect pathways. Anxiety symptoms should therefore be assessed systematically and treated in order to lessen the likelihood of depression symptoms.

The neuronal component of gray matter damage in multiple sclerosis: A [(11) C]flumazenil positron emission tomography study.

OBJECTIVE: Using positron emission tomography (PET) with [(11) C]flumazenil ([(11) C]FMZ), an antagonist of the central benzodiazepine site located within the GABAA receptor, we quantified and mapped neuronal damage in the gray matter (GM) of patients with multiple sclerosis (MS) at distinct disease stages. We investigated the relationship between neuronal damage and white matter (WM) lesions and evaluated the clinical relevance of this neuronal PET metric. METHODS: A cohort of 18 MS patients (9 progressive and 9 relapsing-remitting) was compared to healthy controls and underwent neurological and cognitive evaluations, high-resolution dynamic [(11) C]FMZ PET imaging and brain magnetic resonance imaging. [(11) C]FMZ binding was estimated using the partial saturation protocol providing voxel-wise absolute quantification of GABAA receptor concentration. PET data were evaluated using a region of interest (ROI) approach as well as on a vertex-by-vertex basis. RESULTS: [(11) C]FMZ binding was significantly decreased in the cortical GM of MS patients, compared to controls (-10%). Cortical mapping of benzodiazepine receptor concentration ([(11) C]FMZ Bmax) revealed significant intergroup differences in the bilateral parietal cortices and right frontal areas. ROI analyses taking into account GM volume changes showed extensive decrease in [(11) C]FMZ binding in bilateral parietal, cingulate, and insular cortices as well as in the thalami, amygdalae, and hippocampi. These changes were significant in both progressive and relapsing-remitting forms of the disease and correlated with WM T2-weighted lesion load. [(11) C]FMZ cortical binding correlated with cognitive performance. INTERPRETATION: This pilot study showed that PET with [(11) C]FMZ could be a promising and sensitive quantitative marker to assess and map the neuronal substrate of GM pathology in MS.

Brain networks disconnection in early multiple sclerosis cognitive deficits: an anatomofunctional study.

Severe cognitive impairment involving multiple cognitive domains can occur early during the course of multiple sclerosis (MS). We investigated resting state functional connectivity changes in large-scale brain networks and related structural damage underlying cognitive dysfunction in patients with early MS. Patients with relapsing MS (3-5 years disease duration) were prospectively assigned to two groups based on a standardized neuropsychological evaluation: (1) cognitively impaired group (CI group, n = 15), with abnormal performances in at least 3 tests; (2) cognitively preserved group (CP group, n = 20) with normal performances in all tests. Patients and age-matched healthy controls underwent a multimodal 3T magnetic resonance imaging (MRI) including anatomical T1 and T2 images, diffusion imaging and resting state functional MRI. Structural MRI analysis revealed that CI patients had a higher white matter lesion load compared to CP and a more severe atrophy in gray matter regions highly connected to networks involved in cognition. Functional connectivity measured by integration was increased in CP patients versus controls in attentional networks (ATT), while integration was decreased in CI patients compared to CP both in the default mode network (DMN) and ATT. An anatomofunctional study within the DMN revealed that functional connectivity was mostly altered between the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) in CI patients compared to CP and controls. In a multilinear regression model, functional correlation between MPFC and PCC was best predicted by PCC atrophy. Disconnection in the DMN and ATT networks may deprive the brain of compensatory mechanisms required to face widespread structural damage.

Challenges of switching towards anti-CD20 monoclonal antibodies in RR-MS: A monocentric study.

BACKGROUND: Anti-CD20 monoclonal antibodies (mAb) have demonstrated their drastic efficacy in the treatment of active relapsing-remitting multiple sclerosis (RR-MS). This study investigates the management of their initiation after another disease modifying therapy (DMT). The objective of this study was to assess the frequency and the risk factors of relapses during the wash-out period (WP) between cessation of last DMT and initiation of anti-CD20 mAb in RR-MS. METHODS: All non-naive RR-MS patients who initiated a treatment with Rituximab or Ocrelizumab between 2016 and 2019 have been included in this retrospective monocentric study. Univariate and multivariate analysis were conducted to evaluate risk factors of relapses during the WP. RESULTS: 73 patients (mean age 35.3 years, standard deviation (SD): 8.7 years) were included, with a mean number of 3.1 (SD: 1.3) previous DMTs. The DMT most frequently received before the switch was Fingolimod (Fg, 31 patients, 42.5%). 20 patients (27.4%) experienced relapses during the WP. Risk factors were previous treatment by Fg (p = 0.001) and WP duration (p = 0.032). Among patients switching from Fg, the probability of experiencing a relapse was 35% after 1 month of wash-out. CONCLUSION: This study suggests to shorten the WP duration when switching towards anti-CD20 mAb, especially after Fg, to avoid relapses.

Association of Central Hypersomnia and Fatigue in Patients With Multiple Sclerosis: A Polysomnographic Study.

OBJECTIVE: To evaluate sleepiness and central hypersomnia in multiple sclerosis (MS)-associated fatigue, we performed long-term polysomnography in patients with MS and healthy controls. METHODS: Patients with MS and healthy controls completed questionnaires on sleep, fatigue, sleepiness, and depression. They underwent nocturnal polysomnography, multiple sleep latency tests, and bed rest 24-hour polysomnography. Patients were divided into 3 groups (fatigue and sleepiness, fatigue and no sleepiness, neither fatigue nor sleepiness). RESULTS: Among 44 patients with MS, 19 (43.2%) had fatigue and sleepiness, 15 (34%) had only fatigue, and 10 (22.7%) had neither fatigue nor sleepiness. Compared to 24 controls, patients with fatigue and sleepiness had higher REM sleep percentages (median [interquartile range] 20.5% [19.6-24.7] vs 18.1% [12.6-20.6]), lower arousal indexes (12.7 [7.5-17.0] vs 22.4 [14.3-34.4]), and shorter daytime mean sleep latencies (8.6 [6.3-14.3] vs 16.6 [12.6-19.5] min). Restless leg syndrome, periodic leg movements, and sleep apnea had similar frequencies between groups. Central hypersomnia was found in 10 (53%) patients with fatigue and sleepiness (narcolepsy type 2, n = 2), in 2 (13%) patients with fatigue only, and in 3 (30%) patients with neither fatigue nor sleepiness. Patients with central hypersomnia were younger and sleepier than those without hypersomnia, but had similar levels of fatigue, disability, depression, cognitive performance, and frequencies of the human leukocyte antigen DQB1*0602 genotype. The severity of fatigue increased with higher depression scores, higher sleepiness severity, and lower sleep efficacy. CONCLUSION: Central hypersomnias are frequent in MS when fatigue and sleepiness are present. Screening them through polysomnography studies is recommended.

Relapses During High-Dose Biotin Treatment in Progressive Multiple Sclerosis: a Case-Crossover and Propensity Score-Adjusted Prospective Cohort.

High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Some reports have suggested that HDB treatment may be associated with an increased risk of relapse. We evaluate the relationship between exposure to HDB for treating PMS and the risk of relapse. We screened for PMS patients prospectively registered in a French regional cohort being part of the OFSEP national registry. In a case-crossover design among patients who received HDB, we first compared number of relapses before and after initiation of HDB. Second, time to the first clinical relapse was compared between patients who received HDB (biotin group) and a control group using a Cox survival analysis after a propensity score (PS) matching (1:1) and inverse probability of treatment weighting (IPTW) method. In the 42 PMS patients who received HDB, the number of relapses was statistically and clinically significant higher after biotin initiation than before biotin initiation (incident rate ratio [IRR] 7.4, 95% confidence interval [CI] 3.5-15.9, p < 0.0001). With the PS matching method, the risk of relapse was significantly higher in the biotin group compared to the control group (hazard ratio [HR] 4.3, 95% CI 1.4-13.3, p = 0.01). The IPTW method with 440 control patients revealed consistent results (HR 5.1, 95% CI 2.3-11.3, p < 0.0001). In our non-randomized study, HDB treatment for PMS was associated with an increased risk of relapse. The follow-up of PMS patients initiating HDB should include careful assessment of clinical and radiological activity to monitor the potential pro-inflammatory effect of biotin.

Evaluation of an integrated multidisciplinary approach in multiple sclerosis care: A prospective, randomized, controlled study.

BACKGROUND: Disabled multiple sclerosis (MS) patients often need intervention of multiple specialists, resulting in a complex organization of care. How this multidisciplinary care should be organized and structured has not been studied. OBJECTIVE: The objective of this article is to address the effectiveness of an integrated multidisciplinary approach versus usual care in MS patients. METHODS: This is a prospective, randomized, controlled, monocentric clinical trial in MS patients. Two treatment strategies were compared: (i) an integrated multidisciplinary (IMD) approach, consisting of a half-day individually tailored comprehensive assessment in the MS clinic; and (ii) a standard care. The primary outcome was the impact of the strategy on quality of life (QoL) measured using the MSIS-29 scale at inclusion and after six months. RESULTS: Fifty MS patients were included. Median MSIS 29 score decreased over six months in the control group (-4.89) and increased in the IMD group (+2.00), with a significant difference between the two groups (p = 0.03). However, in the multivariate analysis, after adjustment of HAD-D and INTERMED score, this difference was no longer significant. CONCLUSIONS: This prospective, randomized study is the first attempt to evaluate the multidisciplinary approach in MS patients. The results show that, contrary to our expectations, an integrated multidisciplinary approach is not superior to usual care on QoL.

Clinical and MRI characterization of MS patients with a pure and severe cognitive onset.

BACKGROUND AND OBJECTIVE: Cognitive and behavioural symptoms are common in multiple sclerosis (MS), but they are rarely the inaugural and predominant manifestation of the disease. Our objective is to characterize the clinical and radiological features of cognitive-multiple sclerosis (cog-MS), defined as MS subjects who entered into the disease with cognitive symptoms, which subsequently remain the predominant manifestation. METHODS: We describe the disease course, and clinical and radiological features of 18 subjects with a cognitive form of MS. RESULTS: Memory loss and behavioural changes were the primary symptoms at disease onset. They remained prominent and led to severe cognitive impairment during disease course. The main associated manifestations were depression, pathological laughing and/or crying, urinary incontinence and gait disturbance suggestive of high-level gait disorder. Motor, sensory or cerebellar abnormalities were uncommon. During disease course, superimposed neurological relapses occurred in 61% of cases. Brain MRI revealed multiple periventricular lesions that were extensive and confluent in half of cases, and a severe atrophy measured as an increase in the third ventricular width compared to age-matched healthy controls. Gadolinium-enhancing lesions were common (72%). The mean diagnosis delay from disease onset was 2 years. A principal component analysis on the neuropsychological results revealed that verbal memory assessment is complementary to global cognitive functioning evaluation in these patients with severe cognitive deficit. Verbal memory deficit was associated with high EDSS. CONCLUSIONS: cog-MS patients might represent a challenging diagnosis, which needs to be individualized for an early management.