2009, Vol 9, No 2
Pathogenesis of multiple sclerosis
Aktualn Neurol 2009, 9 (2), p. 86-90
ABSTRACT

Multiple sclerosis (MS) is a complex disease requiring exposure to an environmental factor and a genetic predisposition. MS continues to be thought of as an organ-specific autoimmune disease mediated by CD4+ T-cells. The pathological hallmarks of MS are lesions, known as plaques, which are due to focal loss of myelin with relative preservation of axons and astrocytic gliosis. However, axonal loss is present in all phases of the disease. The pathological features of individual lesions vary and depend on location, age and whether or not there has been any regeneration. MS lesions are typically divided into three pathological categories: active (acute), chronic active and chronic inactive. More recently active lesions have been further classified into four subtypes based on the type of inflammatory reaction, the involvement of immunoglobulin and complement, the expression of myelin proteins, the morphology of the plaque edge and the patterns of oligodendrocyte injury. Whether or not these pathological subtypes represent different stages of the disease or autoimmune variants is speculative. Recently, particular interest focused on the cortical pathology associated with MS. Post mortem studies revealed that extensive cortical demyelination is typically present in patients with progressive disease phases. However, despite extensive studies, the factor initiating the cascade of the pathological events remains unknown. The aim of that article is to present the most recent advances in the understanding of the pathogenesis of MS. 

Keywords: multiple sclerosis, pathogenesis, demyelination, axonal loss, regeneration
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Multiple sclerosis in Poland and worldwide – epidemiological considerations
Aktualn Neurol 2009, 9 (2), p. 91-97
ABSTRACT

Neuroepidemiology is a discipline assessing the impact of environmental and genetic factors on the incidence and development of diseases of the nervous system and describes their prevalence and distribution. The basic epidemiological parameters in multiple sclerosis (MS) are the indices of prevalence, incidence, morbidity and mortality, disease duration and mean age at onset. First epidemiological studies concerning MS date back to the twenties the XX century. Prevalence indices worldwide vary from 15 to 180 per 100 000 persons; in northern Europe the mean index is 83 per 100 000 and in Poland – 45-92 per 100 000. Incidence indices vary depending on geographic location: in Europe it varies from 3.5 to 5.5 per 100 000, while in Poland they vary from 2.4 (Szczecin) to 4.3 (Gniezno). Based on these data it may be assumed that 1300-2100 new cases are being diagnosed in Poland each year. In females, the prevalence of MS is about two-fold higher than in males. Mean age of onset in the Lublin region is 30.1 years and in the Szczecin region – 36.49 years in males and 34.16 years in females. It is estimated that 10-years’ survival rate (from the time of diagnosis) is 90-95%, 20-years’ survival rate – 70-75%, 30-years’ survival rate – 50-65% and 40-years’ survival rate – 35-55%. Mean life duration in males and in females was similar and in 1998 amounted to 52.3 and 51.8 years, respectively. Patients with late-onset MS usually survive shorter. In 58% of the patients, the disease takes a relapsing-remitting form, in 27% – secondary progressive, in 9% – primary progressive and in 6% – progressive-relapsing. A more severe course may be expected in late-onset cases, in those with high index of relapses in the initial years of the disease and in those with pronounced demyelinating lesions in MRI scans. On the average, disability increases by 0.3-0.5 EDSS grade per year. 

Keywords: sclerosis multiplex, epidemiology, incidence and prevalence in Poland, mean age at disease onset, survival rate
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Diagnostic criteria for multiple sclerosis
Aktualn Neurol 2009, 9 (2), p. 98-100
ABSTRACT

The recommended diagnostic McDonald criteria after revision in 2005 are presented. The basis of criteria is demonstration of dissemination of lesions in both time and space. The diagnosis is made in grounds of clinical data with support of mainly MRI, but also results of cerebrospinal fluid examination and visual evoked potentials. There is new definition of MRI criteria to demonstrate dissemination of lesions in time what enables faster diagnosis of the disease. The role of detection of the spinal cord lesions was determined and in a new and simpler way criteria for primary progressive multiple sclerosis have been shown. Currently they require to demonstrate in this form of MS one year of disease progression plus two of the following: 1) nine T2 lesions or at least four T2 lesions with positive VEP; 2) at least two focal T2 lesions in spinal cord MRI; 3) positive CSF. 

Keywords: multiple sclerosis, diagnosis, MRI cerebrospinal fluid, visual evoked potentials
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Laboratory diagnosis of multiple sclerosis
Aktualn Neurol 2009, 9 (2), p. 101-108
ABSTRACT

Multiple sclerosis (MS) is a demyelinating disease with damage of central nervous system, dissemination in time and space. Current McDonald’s MS diagnostic criteria are based on complex clinical and laboratory analysis (magnetic resonance imaging, MRI, evoked potentials, and cerebrospinal fluid analysis). Each of these laboratory tests supply different but very important information concerning type and range of central system damage. In MRI, special location and contrast enhancement of MS lesions are very characteristic for multiple sclerosis. Current MRI diagnostic criteria (Barkhof’s criteria) can be used to established evidence of dissemination in space. In dissemination in time, occurrence of a new lesion on T2-weighetd images or contrast enhancement on successive MRI exam is required. Magnetic resonance imaging plays also an important role in monitoring the MS therapy. Evoked potentials investigate visual, auditory, sensory and motor nerve tracts. They can detect clinically silent lesions and provide evidence for dissemination in space. In cerebrospinal fluid analysis the most important for MS diagnosis are the presence of oligoclonal bands and increase of IgG index. Often, more specific markers of the immunologic system damage are also explored. However, in MS, laboratory tests are very important and useful, the diagnosis of MS is still based mainly on clinical observation. 

Keywords: multiple sclerosis, diagnosis of multiple sclerosis, magnetic resonance imaging, evoked potentials, cerebrospinal fluid
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Biomarkers in multiple sclerosis
Aktualn Neurol 2009, 9 (2), p. 109-115
ABSTRACT

The critical analysis of current status in the search of optimal biomarkers in multiple sclerosis was performed. In many cases the clinical as well as MRI patterns are sufficient for the diagnosis. In dubious cases the impact of CSF studies is necessary demonstrating an increase of IgG index indicating an intrathecal production of this proteins as well as the presence of oligoclonal IgG bands. The intensive search for more specific biomarkers continues. However, till now the results are far from satisfactory ones and are not included into the accepted diagnostic tests. Nevertheless, the studies are of a great value for understanding of the disease pathomechanism. The increase of MBP level in the CSF represents a marker of demyelination. An increase in titres of antibodies recognizing myelin proteins manifests no diagnostic value due to significant level differences, similarly as the increase in expression of some cytokines, chemokines and adhesion molecules. The same concerns the relative percentage of superficial antigens of blood mononuclears. Biomarkers tested as predictors of disease progress have a greater future. A very important scientific problem involves the question if it is possible to find genetic markers, which could predict a positive or negative therapeutic response to immunomodulatory or immunosuppressive drugs. Such markers would signify a great advantage in the therapy of multiple sclerosis. 

Keywords: multiple sclerosis, biomarkers, cytokines, chemokines, pharmacogenetics, antimyelin antibodies
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Natural history of multiple sclerosis
Aktualn Neurol 2009, 9 (2), p. 116-125
ABSTRACT

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system (CNS) of unknown aetiology. It affects mostly young adults and is characterised by multifocal and temporally scattered CNS damage of varied symptomatology and clinical course, eventually leading to significant motor impairment. Studies of the natural course of MS provide valuable data on the course of the disease in individual stages of multiple sclerosis. They allow to determine the frequency of relapses, duration of remission and, most importantly, to determine the motor disability increase rate and describe demographic and clinical factors of influence on benign or aggressive course of the disease. Data on the subject come mostly from four patient databases (Lyon; London, Ontario; Gothenburg; Vancouver) including from several hundred to five thousand patients. The results obtained from hitherto conducted analyses are often non-uniform. Peak MS morbidity dates between 20 and 39 years of age. In primary progressive multiple sclerosis (PPMS) patients, the disease onset occurs on average 10 years later than in relapsing-remitting multiple sclerosis (RRMS) patients. The initial symptoms have monosymptomatic character in over 75% of patients. Pyramid signs are the most important predictive factor for clinically definite multiple sclerosis (CDMS) development after a clinically isolated syndrome (CIS) episode. The conversion of RRMS to secondary progressive multiple sclerosis (SPMS) occurs on average 10 years after onset of the disease. Significant motor disability develops after 15-20 years of multiple sclerosis, the strongest adverse prognostic factor is PPMS.

Keywords: multiple sclerosis, natural history, course, disability, prognosis
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Current therapy of multiple sclerosis
Aktualn Neurol 2009, 9 (2), p. 126-131
ABSTRACT

Multiple sclerosis (MS) is an autoimmune disease of the nervous system leading to irreversible disability. The currently used therapies in MS include treatment of relapse, disease-modifying therapies and symptomatic therapy. Steroid treatment is used for therapy of relapse. For disease-modifying therapies three different interferon beta products (IFN), glatiramer acetate (GA), natalizumab and mitoxantrone are approved. All those agents significantly reduce disease activity and delay the increase of disability in relapsing-remitting MS. The highest efficacy for IFN was shown in a very early phase of disease. Natalizumab represents the second-line therapy and is used for the ineffectiveness of IFN or GA treatment, in particular in the MS with frequent relapses. Mitoxantrone is approved for reducing neurologic disability and/or the frequency of clinical relapses in patients with worsening relapsing-remitting or secondary progressive MS. Symptomatic treatment includes spasticity, pain, fatigue, bladder dysfunction, depression and cognitive impairment therapies.

Keywords: multiple sclerosis, treatment of relapse, immunomodulatory therapy, immunosuppressive therapy, symptomatic treatment
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Development of new therapies for multiple sclerosis
Aktualn Neurol 2009, 9 (2), p. 132-139
ABSTRACT

New insights into the complex immunopathogenesis of multiple sclerosis (MS) have led to a development of the promising new therapeutic strategies for this disease during the last 15 years. In that time a number of the novel potential therapeutics have been identified. In this article the present state of therapy of MS is reviewed and the special attention is given to clinical trials performed on natalizumab, rituximab, alemtuzumab, cladribine, fingolimod, teriflunomide, laquinimod and fumarate. Currently available immunomodulatory therapies have been helpful for many MS patients, but for patients not improving on this treatment, the search for new drugs is necessary. Among monoclonal antibodies (MAbs) only natalizumab is approved so far for treatment of MS, but the other analysed MAbs are also very promising. The AFFIRM and SENTINEL studies showed that natalizumab is effective both in monotherapy and in combination with interferon β-1a (IFN β-1a) in patients with relapsing-remitting multiple sclerosis (RRMS). Long-term therapy with rituximab – another MAb – appears safe and effective in some patients with RRMS. In patients with early RRMS, alemtuzumab was more effective than IFN β-1a. Additionally to MAbs, oral drugs gain the major attention in MS therapy recently. One of them, cladribine, may be a promising agent for refractory patients with secondary progressive MS (SPMS). New studies suggest that fingolimod (FTY720), another potential oral drug for MS, may be more effective than currently available treatments. MS patients receiving the low dose of fingolimod experienced a 52% reduction and patients on the higher dose showed a 38% reduction of the number of relapses. Treatment of RRMS with two different doses of teriflunomide was associated with reduced number of active MRI lesions, the higher dose was associated with reduced progression of disability in RRMS. The oral laquinimod was also effective in suppression of the development of active MRI lesions in RRMS. Similarly oral fumarate (BG00012) given three times daily reduced by 69% the mean number of the new Gd+ lesions and reduced the annualised relapse rate by 32% in RRMS. All this data suggest that in the nearest future several new, more effective drugs will be introduced to therapy of MS. 

Keywords: multiple sclerosis, monoclonal antibodies, clinical trials, immunomodulatory treatment, disease relapses, oral treatment
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Contemporary trends of rehabilitation in multiple sclerosis
Aktualn Neurol 2009, 9 (2), p. 140-146
ABSTRACT

The number of reports describing the effectiveness of comprehensive rehabilitation in multiple sclerosis (MS) is systematically growing. The latest scientific data reported the essential difference in health state between those patients who underwent rehabilitation and those who didn’t. The advantage of inpatient rehabilitation against outpatient has been proved. The correlation between disability and quality of life has been also noticed, as well as influence on burden of patient’s caregivers. Multiple sclerosis is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and handicap. Goals of rehabilitation are: to give the management of symptoms and to improve general fitness due to aerobic exercise. First goal can be achieved using facilitation – impairment-based approach, while the second one by use of a new strategy: task-oriented – disability-focused approach. First is the treatment of the main symptoms of MS: fatigue, bladder and bowel disturbances, sexual dysfunction, cognitive and affective disorders, and spasticity. Even though these symptomatic therapies have benefits, their use is limited by possible side effects. Moreover, many common disabling symptoms, such as weakness, are not amenable to drug treatment. However, rehabilitation has been shown to ease the burden of these symptoms by improving self-performance and independence. For these aims the comprehensive multidisciplinary rehabilitation is necessary. Even though rehabilitation has no direct influence on disease progression, studies to date have shown that this type of intervention improves personal activities and ability to participate in social activities, thereby improving quality of life. Since 1890, when Wilhelm Uhthoff for the first time described that increased body temperature from physical exertion may lead to transient impairment of vision in patients with MS, the Uhthoff phenomenon has been defined the strategy of rehabilitation procedures in MS. Heat therapy and physical exercises were restricted because of fear against flare up of disease, aquatic exercises were limited till 30ºC of water temperature. Last years something has been changed. Few reports on randomised controlled trials about progressive exercise program, mainly consisting of resistance training for few months has been published. Findings from those studies suggest overall disability and mobility improvement with the aerobic training. All types of rehabilitation should be tailored to fit patient specific needs. Based on the Uhthoff phenomenon, therapeutic trials with cooling vests are investigated and developed. In this review report of the contemporary trends in comprehensive rehabilitation in MS has been presented. 

Keywords: physiotherapy, rehabilitation, multiple sclerosis, cooling, fatigue
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