Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

Sense of happiness in Polish patients with multiple sclerosis

Introduction. Happiness is crucial to patient well-being and their acceptance of their disease. The aim of this study was to assess the sense of happiness in persons with multiple sclerosis (PwMS), compare it to the level of happiness in patients with other neurological conditions, and determine which factors affect the sense of happiness in PwMS. Material and methods. Five hundred and eighty-nine PwMS and 145 control subjects (post-stroke patients with chronic pain syndromes and neuropathies) were included in the study. Due to the differences between the groups in terms of demographic variables, an adjusted group of PwMS (n = 145) was selected from the entire group of PwMS. All patients were assessed using the Oxford Happiness Questionnaire (OHQ), the Satisfaction with Life Scale (SLS), and the Family APGAR Questionnaire. Based on regression analysis, the study examined which variables affected the level of happiness in the groups. Results. Analysis of the OHQ scores showed that PwMS had a lower sense of happiness compared to the control group in the overall score [113.21 (25–42) vs. 119.88 (25–49), respectively; p = 0.031] and the subscales (OHQ subscale 1 — 54.52 vs. 57.84, respectively; p = 0.027; subscale 2 — 35.61 vs. 37.67; respectively; p = 0.044). Based on linear regression analysis, life satisfaction (β = 0.40; p < 0.001), positive orientation (β = 0.32; p < 0.001), and primary education (β = 0.08; p = 0.009) were the most significant predictors of a higher level of happiness in PwMS. Similar results were found in the control group. Conclusions. The sense of happiness in PwMS was lower than in patients with other conditions. The most important factors influencing happiness included life satisfaction and positive orientation. Influencing these predictors should be the aim of psychological interventions, especially in patients with a reduced sense of happiness

Alemtuzumab – a new drug in the therapy of relapsing-remitting multiple sclerosis. The first or second line of treatment?

Alemtuzumab is a humanized monoclonal antibody aimed against glycoprotein CD52, which causes the depletion (elimination) of circulating T and B cells. The recovery process for the two cell populations differs, leading to disturbances in the immune system. These changes result in a reduction in the disease activity. The efficacy of alemtuzumab has been confirmed in three clinical studies: one phase II – CAMMS223 study, and two phase III – CARE-MS I and CARE-MS II studies. They have shown the clinical effectiveness of intravenous alemtuzumab in patients with the remitting form of multiple sclerosis. Interferon beta-1a was administered subcutaneously as the comparator. CAMMS223 and CARE-MS I showed the drug to have significant impact on the decrease of the relapse rate as compared to interferon, whereas CAMMS223 and CARE-MS II showed it to slow down the increase of disability in patients. Treatment with alemtuzumab, however, has not been free of significant side effects, falling essentially into three major groups: side effects directly related to the administration of the drug, severe infections, and autoimmune disorders (idiopathic thrombocytopenic purpura, impaired thyroid function, and nephropathy). Alemtuzumab therapy can be both effective and safe, provided that an appropriate programme is maintained, aimed at monitoring the adverse events.Alemtuzumab jest humanizowanym przeciwciałem monoklonalnym skierowanym przeciwko glikoproteinie CD52, powodującym deplecję (eliminację) krążących limfocytów T i B. Proces odtwarzania obu populacji limfocytów przebiega odmiennie, co prowadzi do zaburzeń w układzie odpornościowym. Zmiany te skutkują zmniejszeniem aktywności procesu chorobowego. Skuteczność alemtuzumabu została potwierdzona w trzech badaniach klinicznych: jednym fazy drugiej – CAMMS223 oraz dwóch fazy trzeciej – CARE-MS I i CARE-MS II. W badaniach tych wykazano skuteczność kliniczną podawanego dożylnie alemtuzumabu u chorych z postacią rzutową stwardnienia rozsianego. Komparatorem był podawany podskórnie interferon beta-1a. W CAMMS223 i CARE-MS I wykazano istotny wpływ alemtuzumabu na spadek wskaźnika rzutów w porównaniu z interferonem, a w CAMMS223 i CARE-MS II – wpływ na zwolnienie narastania niesprawności. Terapia z zastosowaniem alemtuzumabu nie była wolna od istotnych działań niepożądanych, które należały do trzech zasadniczych grup: działania niepożądane bezpośrednio związane z podawaniem leku, ciężkie infekcje oraz zaburzenia autoimmunologiczne (samoistna plamica małopłytkowa, zaburzenia funkcji tarczycy i nefropatia). Terapia alemtuzumabem może być zarówno skuteczna, jak i bezpieczna, jednakże pod warunkiem zachowania właściwego programu monitorowania działań niepożądanych

Zespół apatii w konsekwencji uszkodzenia mózgu – trudny problem neurorehabilitacji

Primary, biological dysfunction of motivational factor in a widely understood goal-oriented behaviour is in clinical practice a wellknown consequence of brain injury, and it causes serious difficulties in neurorehabilitation. The deficit of motivation, also known as apathy syndrome, is particularly frequently observed in patients with stroke and other type of brain injury. It results in limitation of emotional expression and reacting to the environment, loss of ability to care about oneself and others, and causes passive participation in rehabilitation. All these symptoms significantly decrease the chances of physical and social recovery. Hypothetically, it is claimed that the dysfunction of fronto-subcortical neural system, overlapping medial parts of prefrontal cortex, thalamus and basal ganglia, is a pathomechanism of apathy. Damage of these structures results in dysfunction of dopaminergic system which is called a “behavioural activating system” as it modulates the level of activation, attention and emotions. Apathy can co-exist with cognitive impairment, but these two deficits are treated relatively separately. This paper aims to make a detailed description of the apathy syndrome and to draw attention of professionals working in neurorehabilitation to biological foundation of some patients’ behaviour, who are wrongly described as not dedicated and motivated to participate actively in rehabilitation. The authors – on the grounds of literature review – describe problems of differential diagnosis and treatment. They draw attention to differentiating apathy from depression, dementia and consciousness disorder. There are still no systematic studies about efficient pharmacotherapy in the organic apathy syndrome. This paper presents preliminary results of clinical studies suggesting therapeutic efficacy of dopamine agonists and other stimulants.Pierwotne, biologiczne zaburzenie czynnika motywacyjnego w najszerzej rozumianym wymiarze celowego, świadomego zachowania człowieka jest w praktyce klinicznej znaną konsekwencją uszkodzenia mózgu i stanowi poważne utrudnienie w prowadzeniu procesu rehabilitacji. Deficyt motywacji, nazywany inaczej zespołem apatii, jest szczególnie często obserwowany u chorych po udarze i urazie mózgu. Powoduje ograniczenie emocjonalnego przeżywania i żywego reagowania na otoczenie, utratę troski o siebie i innych, bierne uczestnictwo w procesie rehabilitacji. Wszystko to drastycznie utrudnia fizyczny i społeczny powrót do zdrowia. Hipotetycznie przyjmuje się, że patomechanizmem apatii jest dysfunkcja czołowo-podkorowego systemu neuronalnego, obejmującego przyśrodkowe części kory przedczołowej oraz wzgórze i jądra podstawy. W wyniku uszkodzenia wymienionych struktur następuje dysfunkcja systemu dopaminergicznego, który jest nazywany „behawioralnym systemem aktywującym” bowiem moduluje m.in. stan wzbudzenia, uwagi i emocji. Apatia może współwystępować z zaburzeniami poznawczymi, ale te dwa elementy są traktowane jako względnie rozdzielne. Celem artykułu jest szczegółowy opis zespołu apatii oraz zwrócenie uwagi profesjonalistom praktycznie zajmującym się neurorehabilitacją na biologiczne podłoże zachowań niektórych chorych, którym niesłusznie przypisuje się brak zaangażowania i słabą motywację do aktywnego uczestnictwa w procesie rehabilitacji. Autorzy – na podstawie przeglądu piśmiennictwa omawiają problemy diagnostyki różnicowej oraz leczenia. Zwraca się uwagę na odróżnianie apatii od depresji, otępienia i zaburzeń świadomości. Ciągle brak systematycznych badań na temat skutecznej farmakoterapii w organicznym zespole apatii. W artykule prezentowane są wyniki wstępnych badań klinicznych, sugerujących m.in. skuteczność terapeutyczną agonistów dopaminy i innych stymulantów

Analysis of statistical model-based optimization enhancements in Generalized Self-Adapting Particle Swarm Optimization framework

This paper presents characteristics of model-based optimization methods utilized within the Generalized Self-Adapting Particle Swarm Optimization (GA– PSO) – a hybrid global optimization framework proposed by the authors. GAPSO has been designed as a generalization of a Particle Swarm Optimization (PSO) algorithm on the foundations of a large degree of independence of individual particles. GAPSO serves as a platform for studying optimization algorithms in the context of the following research hypothesis: (1) it is possible to improve the performance of an optimization algorithm through utilization of more function samples than standard PSO sample-based memory, (2) combining specialized sampling methods (i.e. PSO, Differential Evolution, model-based optimization) will result in a better algorithm performance than using each of them separately. The inclusion of model-based enhancements resulted in the necessity of extending the GAPSO framework by means of an external samples memory - this enhanced model is referred to as M-GAPSO in the paper

Case reportsCerebral bleeding as a leading manifestation of infectious endocarditis

Infectious endocarditis is frequently complicated with acute cerebral events. In most cases they represent the consequences of cerebral embolism. In the presented case the first clinical manifestation of aortic valve endocarditis was intracerebral bleeding. After exclusion of intracerebral aneurysm the aortic valve was replaced and the further course was uncomplicated