Impact of autologous haematopoietic stem cell transplantation on disability and brain atrophy in secondary progressive multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (aHSCT) is a valuable option in aggressive relapsing-remitting multiple sclerosis (MS), but its efficacy in secondary progressive (SP)-MS is still controversial. OBJECTIVE: Assessing efficacy of aHSCT in SP-MS by clinical-radiological outcomes. METHODS: Open-label monocentric retrospective study enrolling consecutive SP-MS patients treated with BEAM-aHSCT in the period 1999-2016. RESULTS: In total, 26 SP-MS patients with moderate-severe disability were included. Progression-free survival (PFS) at years 5 and 10 after aHSCT were, respectively, 42% and 30%. Out of 16 patients who worsened, only 6 patients (23% overall) maintained continuous disability accrual (CDA), whereas 10 patients stabilized following one single-step Expanded Disability Status Scale (EDSS) worsening. CDA-free survival was 74% at 5-10 years. No relapses or magnetic resonance imaging (MRI) activity were reported, thus no evidence of disease activity (NEDA)-3 corresponded to PFS. Annualized rate of brain atrophy (AR-BVL) normalized after 1 year in 55% of the cases analysed (12/22). CONCLUSION: BEAM-aHSCT halted CDA and normalized AR-BVL in most of the treated patients, inducing long-term remission of inflammatory activity at a median follow-up of 99 months (range 27-222). These data suggest that CDA might still be mainly driven by inflammation in a subgroup of SP-MS and could therefore be reversed by treatments. CDA should be analysed independently from any isolated disability worsening.

A case of recurrent progressive multifocal leukoencephalopathy after human stem cell transplant, with detection of John Cunningham virus and human herpesvirus 6 on cerebrospinal fluid, treated with Mirtazapine, Olanzapine and Foscarnet.

We reported the case of a John Cunningham virus (JCV) and human herpesvirus 6 (HHV-6) mediated progressive multifocal leukoencephalopathy (PML) after human stem cell transplant, reactivated 6 months later in absence of immunosuppressive therapy, successfully treated with anti-5HT2A receptors agents and antiviral therapy. Few cases of JCV and HHV-6 coinfection associated PML are described in literature and the role of HHV-6 in the pathogenesis and prognosis of PML is not completely clear. Our case suggests that, in a possible PML, the research of HHV-6 and JCV should be always performed on cerebrospinal fluid (CSF) and on blood samples and in case of detection of HHV-6 DNA a chromosomally integrated human herpesvirus 6(ciHHV-6) should be excluded. Furthermore we recommend to start an appropriate therapy with antiviral and anti-5HT2A receptors agents in case of possible PML due to JCV and HHV-6 coinfection.

Longitudinal Study on Low-Dose Aspirin versus Placebo Administration in Silent Brain Infarcts: The Silence Study.

BACKGROUND: We investigated low-dose aspirin (ASA) efficacy and safety in subjects with silent brain infarcts (SBIs) in preventing new cerebrovascular (CVD) events as well as cognitive impairment. METHODS: We included subjects aged ≥45 years, with at least one SBI and no previous CVD. Subjects were followed up to 4 years assessing CVD and SBI incidence as primary endpoint and as secondary endpoints: (a) cardiovascular and adverse events and (b) cognitive impairment. RESULTS: Thirty-six subjects received ASA while 47 were untreated. Primary endpoint occurred in 9 controls (19.1%) versus 2 (5.6%) in the ASA group (p=0.10). Secondary endpoints did not differ in the two groups. Only baseline leukoaraiosis predicts primary [OR 5.4 (95%CI 1.3-22.9, p=0.022)] and secondary endpoint-a [3.2 (95%CI 1.1-9.6, p=0.040)] occurrence. CONCLUSIONS: These data show an increase of new CVD events in the untreated group. Despite the study limitations, SBI seems to be a negative prognostic factor and ASA preventive treatment might improve SBI prognosis. EU Clinical trial is registered with EudraCT Number: 2005-000996-16; Sponsor Protocol Number: 694/30.06.04.

Central vein sign differentiates Multiple Sclerosis from central nervous system inflammatory vasculopathies.

OBJECTIVES: In multiple sclerosis (MS), magnetic resonance imaging (MRI) is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are frequent in clinical practice. Detection of perivenular lesions in the brain (the "central vein sign") improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS-mimicking inflammatory and/or autoimmune diseases, such as central nervous system (CNS) inflammatory vasculopathies, is lacking. In a multicenter study, we assessed the frequency of perivenular lesions in MS versus systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS). METHODS: In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing-remitting MS, 3-dimensional T2*-weighted and T2-fluid-attenuated inversion recovery images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the central vein sign was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed. RESULTS: MS showed higher frequency of perivenular lesions (median = 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behçet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjögren syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, central vein sign discriminated MS from inflammatory vasculopathies with a diagnostic accuracy of 100%. INTERPRETATION: The central vein sign differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. Ann Neurol 2018;83:283-294.

Changes in white matter as determinant of global functional decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and disability) study cohort.

OBJECTIVE: To assess the impairment in daily living activities in older people with age related changes in white matter according to the severity of these changes. DESIGN: Observational data collection and follow-up of a cohort of older people undergoing brain magnetic resonance imaging after non-disabling complaints. SETTING: 11 European centres. PARTICIPANTS: 639 non-disabled older patients (mean age 74.1 (SD 5.0), 45.1% men) in whom brain magnetic resonance imaging showed mild, moderate, or severe age related changes in white matter (Fazekas scale). Magnetic resonance imaging assessment also included cerebral infarcts and atrophy. MAIN OUTCOME MEASURE: Transition from no disability (defined as a score of 0 or 1 on the instrumental activities of daily living scale) to disability (score >/=2) or death over three year follow-up. Secondary outcomes were incident dementia and stroke. RESULTS: Over a mean follow-up period of 2.42 years (SD 0.97, median 2.94 years), information on the main outcome was available for 633 patients. The annual rate of transition or death was 10.5%, 15.1%, and 29.5%, respectively, for patients with mild, moderate, or severe age related changes in white matter (Kaplan-Meier log rank test P<0.001). In a Cox model comparing severe with mild changes and adjusted for clinical factors of functional decline, the risk of transition to disability or death was more than twofold higher (hazard ratio 2.36, 95% confidence interval 1.65 to 3.81). The other predictors were age group, history of atrial fibrillation, and complaint of gait disturbances. The effect of severe changes remained significant independently of baseline degree of atrophy and number of infarcts. Incident stroke and dementia only slightly modified this effect. CONCLUSION: The three year results of the LADIS study suggest that in older adults who seek medical attention for non-disabling complaints, severe age related changes in white matter independently and strongly predict rapid global functional decline.

Selective risk factors profiles and outcomes among patients with stroke and history of prior myocardial infarction. The European Community Stroke Project.

BACKGROUND AND OBJECTIVE: Previous myocardial infarction (MI) has been linked with poorer stroke outcome. Whether this depends on a greater stroke severity is still uncertain. The aim of the study was to assess the effect of previous MI on characteristics and outcome of stroke in a large hospital cohort of patients. METHODS: In a European Union Concerted Action, patients hospitalized for first-in-a-lifetime stroke were assessed for demographics, risk factors, clinical presentation, and 3-month survival and handicap. RESULTS: Out of 4190 study patients, 460 (11%) reported a history of MI. Compared with patients without previous MI, those with MI were significantly older, more often males, smokers, alcohol consumers, and with a more severe pre-stroke level of handicap. They had more frequently atrial fibrillation and a history of transient ischemic attack. The acute neurological state and the 28-day mortality did not differ between the two groups. At 3 months, death or severe handicap were more frequent in the MI group (28.3% vs. 21.7%, P=0.001; 74.8% vs. 65.8%, P=0.008). Controlling by logistic regression analysis for age, sex, vascular risk factors, comorbidities, prior to stroke therapy, pre-stroke level of handicap, and clinical acute phase variables, prior MI remained an independent predictor of 3-month death (OR 1.30; 95% CI, 1.02-1.66) and 3-month handicap (OR 1.46; 95% CI, 1.01-2.11). CONCLUSIONS: Previous MI has no impact on clinical severity of acute stroke, but significantly affects 3-month outcome in terms of handicap and mortality.

Gait in hemiplegia: evaluation of clinical features with the Wisconsin Gait Scale.

OBJECTIVE: To assess the ability of the Wisconsin Gait Scale to evaluate qualitative features of changes in hemiplegic gait in post-stroke patients. DESIGN: A prospective observational study. SUBJECTS: Ten healthy subjects and 56 hemiplegic outpatients, more than 12 months post-stroke, consecutively admitted in a rehabilitation centre. METHODS: Patients were videotaped while walking at a comfortable speed. Quantitative and clinical gait parameters were derived from videotaped walking tasks at admission and at the end of a period of rehabilitation training. Qualitative features were assessed using the Wisconsin Gait Scale. Functional status was rated through the modified Barthel Index. RESULTS: After training, the median Wisconsin Gait Scale score improved significantly (28 vs 26.5; p = 0.003). In particular, "weight shift to paretic side" and patterns during the swing phase of the affected leg were improved. Gait velocity (0.3 vs 0.4 m/sec; p = 0.001) and stride length (77 vs 85 cm; p = 0.0002) increased significantly, whereas number of steps (25 vs 23; p = 0.004), stride period (2.5 vs 2.3 sec; p = 0.04), and stance period (2.1 vs 2 sec; p = 0.03) of the unaffected side were reduced. The Barthel Index score increased (71 vs 78; p = 0.005). CONCLUSION: The Wisconsin Gait Scale is a useful tool to rate qualitative gait alterations of post-stroke hemiplegic subjects and to assess changes over time during rehabilitation training. It may be used when a targeted and standardized characterization of hemiplegic gait is needed for tailoring rehabilitation and monitoring results.

Corpus callosum atrophy is associated with mental slowing and executive deficits in subjects with age-related white matter hyperintensities: the LADIS Study.

BACKGROUND: Previous research has indicated that corpus callosum atrophy is associated with global cognitive decline in neurodegenerative diseases, but few studies have investigated specific cognitive functions. OBJECTIVE: To investigate the role of regional corpus callosum atrophy in mental speed, attention and executive functions in subjects with age-related white matter hyperintensities (WMH). METHODS: In the Leukoaraiosis and Disability Study, 567 subjects with age-related WMH were examined with a detailed neuropsychological assessment and quantitative magnetic resonance imaging. The relationships of the total corpus callosum area and its subregions with cognitive performance were analysed using multiple linear regression, controlling for volume of WMH and other confounding factors. RESULTS: Atrophy of the total corpus callosum area was associated with poor performance in tests assessing speed of mental processing--namely, trail making A and Stroop test parts I and II. Anterior, but not posterior, corpus callosum atrophy was associated with deficits of attention and executive functions as reflected by the symbol digit modalities and digit cancellation tests, as well as by the subtraction scores in the trail making and Stroop tests. Furthermore, semantic verbal fluency was related to the total corpus callosum area and the isthmus subregion. CONCLUSIONS: Corpus callosum atrophy seems to contribute to cognitive decline independently of age, education, coexisting WMH and stroke. Anterior corpus callosum atrophy is related to the frontal-lobe-mediated executive functions and attention, whereas overall corpus callosum atrophy is associated with the slowing of processing speed.

Relationship between periventricular and deep white matter lesions and depressive symptoms in older people. The LADIS Study.

BACKGROUND: Both types of cerebral white matter hyperintensities, periventricular (PVL) and deep white matter lesions (DWML) have been previously associated with the development of depression in older subjects. However, it remains controversial as to whether PVL, DWML, or both are most strongly associated with depression and this was the aim of the current study. METHODS: In a pan-European multicentre study of 626 older subjects, we examined the relationship between PVL and DWML, depressive symptoms (GDS quintile), cognitive status (MMSE), hypertension and history of stroke. RESULTS: In univariate analysis we found that depressive symptoms as assessed by GDS were associated with both types of white matter lesions (Spearman rho = 0.12 p = 0.002 for DWML and rho = 0.09 p = 0.01 for PVL). Using ordinal logistic regression analysis the total DWML score (p = 0.041), rather than PVL (p = 0.9) was found to predict GDS scores. CONCLUSIONS: DWML, but not PVL, were most strongly associated with depressive symptoms in this sample. As DWML (unlike PVL) are associated with vascular ischaemic damage, our findings are consistent with the 'vascular depression' hypothesis. Longitudinal studies are needed to clarify the time course of these relationships, in particular, whether modifying DWML alters the natural history of depression.

Application of a volar static splint in poststroke spasticity of the upper limb.

OBJECTIVE: To evaluate clinical and neurophysiologic effects of 3-month reflex inhibitory splinting (RIS) for poststroke upper-limb spasticity. DESIGN: Pretest-posttest trial. SETTING: Outpatient rehabilitation center. PARTICIPANTS: Forty consecutive patients with hemiplegia and upper-limb spasticity after stroke that had occurred at least 4 months before. INTERVENTION: Patients wore an immobilizing hand splint custom-fitted in the functional position for at least 90 minutes daily for 3 months. MAIN OUTCOMES MEASURES: Patients underwent measurement of (1) spasticity at the elbow and wrist according to Modified Ashworth Scale; (2) passive range of motion (PROM) at the wrist and elbow; (3) pain at the shoulder, elbow, and wrist using a visual analog scale; (4) spasms; and (5) comfort and time of splint application. The instrumental measure of spasticity was the ratio between the maximum amplitude of the H-reflex and the maximum amplitude of the M response (Hmax/Mmax ratio). RESULTS: A significant improvement of wrist PROM (F=8.92, P=.001) with greater changes in extension than in flexion, and a reduction of elbow spasticity (F=5.39, P=.002), wrist pain (F=2.89, P=.04), and spasms (F=4.33, P=.008) were observed. The flexor carpi radialis Hmax/Mmax ratio decreased significantly (F=4.2, P=.007). RIS was well tolerated. CONCLUSIONS: RIS may be used as an integrative treatment of poststroke upper-limb spasticity. It can be used comfortably at home, in selected patients without functional hand movements, and in cases of poor response or tolerance to antispastic drugs.

Evaluation of upper-limb spasticity after stroke: A clinical and neurophysiologic study.

OBJECTIVES: To assess upper-limb spasticity after stroke by means of clinical and instrumental tools and to identify possible variables influencing the clinical pattern. DESIGN: Descriptive measurement study of a consecutive sample of patients with upper-limb spasticity after stroke. SETTING: Neurorehabilitation hospital. PARTICIPANTS: Sixty-five poststroke hemiplegic patients. INTERVENTIONS: Not applicable. Main outcome measures Upper-limb spasticity, as assessed clinically (Modified Ashworth Scale [MAS], articular goniometry) and neurophysiologically (maximum H-reflex [Hmax], maximum M response [Mmax], Hmax/Mmax ratio). RESULTS: Poorer MAS scores were associated with lower passive range of motion (PROM) values at the wrist ( P =.01) and elbow ( P =.002). The flexor carpi radialis Hmax/Mmax ratio correlated directly with MAS scores at the wrist ( P =.005) and correlated inversely with PROM. The presence of pain in the fingers, wrist, and elbow was significantly associated only with lower PROM values at the wrist. CONCLUSIONS: Upper-limb spasticity is involved in the development of articular PROM limitation after a stroke. Pain appears to be related to PROM reduction as well, but the exact causal relationship between these 2 factors is still unclear. The MAS and the Hmax/Mmax ratio correlated when evaluating poststroke spasticity; they characterize 2 different aspects of spasticity, clinical and neurophysiologic, respectively, and they could be used as an integrated approach to study and follow poststroke patients.