Longitudinal assessment of cognitive performance in Holocaust survivors with and without PTSD.

BACKGROUND: There are currently no longitudinal studies of cognitive performance in older patients with Posttraumatic Stress Disorder (PTSD). It is therefore unclear whether relationships between memory and symptoms differ over time among older persons with and without PTSD. METHODS: Twenty-eight Holocaust survivors and nineteen comparison subjects were evaluated 5 years after they had received a memory assessment including paired-associates learning and the California Verbal Learning Test (CVLT). RESULTS: While Holocaust survivors with PTSD showed a diminution in symptom severity (t = 2.99, df = 12, p = .011), they still manifested a decline in paired associates learning, suggesting an acceleration in age-related memory impairment (related word pairs: t = 2.87, df = 13, p = .013; unrelated word pairs: t = 2.06, df = 13, p = .060). The survivors with PTSD showed improvements on several CVLT measures over time. These improvements correlated with symptom improvements, such that group differences at the follow-up were no longer detected. CONCLUSIONS: The discrepancy in the pattern of performance on these two tests of memory following symptom improvement suggests possible differentiation between of aspects of memory functions associated with aging and trauma exposure and those associated with the severity of PTSD symptoms. Performance on the CVLT appeared related to clinical symptom severity while paired associate learning worsened over time in Holocaust survivors with PTSD, consistent with earlier cross-sectional findings.     

Changes of the MS functional composite and EDSS during and after treatment of relapses with methylprednisolone in patients with multiple sclerosis

OBJECTIVES: The Multiple Sclerosis Functional Composite (MSFC) comprises quantitative functional measures of leg, hand/arm and cognitive function. We examined the responsiveness of the MSFC compared with the Expanded Disability Status Scale (EDSS) during treatment of relapses in patients with multiple sclerosis (MS). PATIENTS AND METHODS: 27 patients received 1000 mg intravenous methylprednisolone (i.v.-MP) for 5 days, followed by oral methylprednisolone for 14 days. The MSFC and the EDSS-score were assessed on day 0, before the first corticosteroid treatment, on day 5, after the last course of i.v. MP, and on day 20 after the treatment was finished. Before the first administration of the MSFC, patients were trained for the paced auditory addition test (PASAT) performing three test trials. In order to analyse practice effects, 10 MS patients without an acute exacerbation were tested three times under the same conditions as the treated group. RESULTS: The median EDSS-score was 2.5 in both groups. On day 5 it remained unchanged in all treated patients, on day 20 a decrease of 0.5 EDSS point occurred in five patients, and in two patients an improvement with a decrease of more than 0.5 point was observed. There was no statistically significant difference between the EDSS-scores on day 0, 5 and 20. The mean MSFC-score in the treated group was -0.14 +/- 0.63 on day 0, 0.17 +/- 0.66 on day 5, and 0.42 +/- 0.59 on day 20. On the last study day, 26 patients improved compared with day 0. The differences between the MSFC-scores at the three points of time were statistically significant for the treated group (P < 0.001), but not for the control group. CONCLUSION: During and after treatment of relapses in patients with MS, the MSFC appears to be more sensitive in detecting changes in function than the EDSS.     

糖皮质激素不同给药方式治疗急性期多发性硬化的疗效观察

目的探讨糖皮质激素3种不同给药方式治疗急性期多发性硬化(multiple sclerosis，MS)的疗效及安全性。方法将1998～2002年于我科治疗的48例MS患者按主要治疗方法的不同分为鞘内注入地塞米松(DXM)组、甲基强的松龙(MPS)冲击组及常规使用激素组。比较治疗后各组不同时间的Kurtzke扩充致残量表(Kurtzke expanded disability status scale，EDSS)评分减少数及副作用的发生率。结果鞘内注入DXM组治疗早期EDSS评分减少较其它两组显著，尤其对于脊髓受累为主的MSEDSS评分改善更为明显。结论鞘内注入DXM与两种常规方法比较见效快，建议用于脊髓受累为主的急性期MS。     

Cytokines and soluble IL-4 in patients with acute optic neuritis and multiple sclerosis

We measured the cerebrospinal fluid (CSF) and plasma concentrations of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, TNF-β, interferon (IFN)-γ, the IL-1 receptor antagonist, and soluble IL-4 receptor (sIL-4r) by ELISA in 12 patients each with acute, monosymptomatic, idiopathic optic neuritis (ON), ON as part of MS, other attack forms of MS, and in neurological control subjects. CSF concentrations of IL-1β, IL-2 and IFN-γ differed significantly between the different patient groups and were detected most commonly at the highest concentrations in patients with non-ON attacks of MS. TNF-β was detected exclusively in CSF from neurological control patients. The patients with non-ON attacks of MS also had significantly elevated concentrations of sIL-4r in plasma. Increased CSF concentrations of IL-1β, IL-2 and IFN-γ together with increased plasma concentrations of sIL-4r support the concept of MS as an autoimmune disease with preferential activation of proinflammatory or T-helper type 1-like cells. Patients with idiopathic ON or ON as part of MS may, however, differ immunologically from patients with other attack forms of MS.     

T-cell subsets in spinal fluid of multiple sclerosis patients

CSF T-cells and T-cell subsets were characterized by monoclonal antibodies in 15 untreated multiple sclerosis (MS) patients, 17 immunosuppressed chronic progressive MS patients and 9 patients with other neurological diseases. A negative correlation was found between total cell numbers and T suppressor cell percentages in untreated and treated MS patients. A negative correlation (r = -0.71) was found between intrathecal IgG levels and T suppressor cell percentages in untreated MS patients. In peripheral blood, no correlation between T-cells and T-cell subsets with IgG levels was found. It is discussed that T-cell subsets and intrathecal IgG levels may be indicators of the activity of the inflammatory process in the brains of chronic progressive MS patients.     

The effect of methylprednisolone on monocyte eicosanoid production in patients with multiple sclerosis

The in vitro effect of methylprednisolone on prostaglandin E₂ (PGE₂), leukotriene B₄ (LTB₄) and thromboxane B₂ (TXB₂) synthesis by adherent monocytes was examined using samples of peripheral blood from 15 patients with multiple sclerosis and 18 normal controls. Eicosanoid production by monocytes was reduced in patients compared with controls and there was a dose-dependent inhibitory effect of methylprednisolone on eicosanoid production in both groups. In vitro production of PGE₂ and TXB₂ but not LTB₄ was reduced in patients with multiple sclerosis following intravenous treatment with methyl prednisolone compared with pretreatment samples. In a separate cohort of 20 patients with multiple sclerosis and 15 controls, the in vitro inhibition of PGE₂ release by methylprednisolone was not associated with reduced pokeweed-mitogenstimulated immunoglobulin G synthesis by peripheral blood mononuclear cells. These results suggest that methylprednisolone inhibits monocyte-macrophage function, but this effect is not specific to patients with multiple sclerosis.     

Exploring resting-state EEG brain oscillatory activity in relation to cognitive functioning in multiple sclerosis

Objective

Neurophysiologic monitoring parameters related to cognition in Multiple Sclerosis (MS) are sparse. Previous work reported an association between magnetoencephalographic (MEG) alpha-1 activity and information processing speed. While this remains to be replicated by more available electroencephalographic (EEG) methods, also other established EEG markers, e.g. the slow-wave/fast-wave ratio (theta/beta ratio), remain to be explored in this context.

Neuropsychological profile in patients with obsessive-compulsive disorder over a period of 4-month treatment

This study investigated the changes of the neuropsychological functions over a 4-month period of treatment in patients with obsessive-compulsive disorder (OCD). Thirty-nine OCD patients and 31 healthy controls were evaluated with neuropsychological and clinical tests. The same tests were readministered 4-months after pharmacological treatment for the OCD patients. At the first series of tests, compared to the controls, the OCD patients were significantly impaired on the immediate and delayed recall of Rey-Osterrieth Complex Figure Test (RCFT), and on the letter and category of Controlled Oral Word Association Test (COWA). They also showed a prolonged response time on Trail Making Test (TMT), part A. The severity of OCD measured by Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) correlated well with the performance on the immediate and delayed recall of RCFT and the response time on TMT, part A. After 4-months' follow-up, the OCD patients still showed impairment on the immediate and delayed recall of RCFT and COWA category. This is despite the fact that they had improved significantly on these functions in comparison with the controls over the period of treatment. In addition, an association between OCD symptoms and the performance on the neuropsychological tests was not observed. The neuropsychological profile of the OCD patients found in the present study is consistent with current theories proposing that the frontal-striatal system is the possible pathophysiological mechanism underlying the development of OCD.     

The association of HLA-DRB1 and HLA-DQB1 alleles with genetic susceptibility to multiple sclerosis in the Slovak population

Objective: The aim of the present study was to assess the association between HLA-DRB1 and -DQB1 allele groups with the genetic predisposition to multiple sclerosis (MS) in the Caucasian Central European Slovak population.

Methods: A total of 282 unrelated patients with sporadic MS were enrolled in this case-control study. HLA-DRB1 and HLA-DQB1 allele groups were genotyped using a polymerase chain reaction with sequence-specific primers. The DRB1 and DQB1 allele carrier frequencies, genotypes and haplotype frequencies were compared between MS cases and healthy controls.

Results: Positive association with MS was found for alleles HLA-DRB1*15 (OR = 3.64; Pcor = 6.9x10–11), DRB1*03 (after elimination of carriers of DRB1*15, OR = 2.8; Pcor = 0.0029), DQB1*06 (OR = 1.99; Pcor = 7.0x10–4), genotypes HLA-DRB1*15/*15 (OR = 7.6; Pcor = 0.001) and DQB1*06/*06 (OR = 3.81; Pcor = 4.0x10–4) and for haplotype DRB1*15-DQB1*06 (OR = 3.03; Pcor = 0.001). Carriage of alleles DRB1*07 (OR = 0.53; Pcor = 0.04), DRB1*13 (OR = 0.39; Pcor = 4.0x10–4), DQB1*03 (OR = 0.46; Pcor = 1.0x10–4), genotypes HLA-DRB1*13/*11 (OR = 0.12; Pcor = 0.004), DQB1*05/*03 (OR = 0.39; Pcor = 0.035), DQB1*03/*03 (OR = 0.38; Pcor = 0.029) and haplotypes DRB1*13-DQB1*06 (OR = 0.47; Pcor = 0.0128) and DRB1*11-DQB1*03 (OR = 0.58; Pcor = 0.0352) was found to be protective against MS development.

Discussion: This is the first study performed to analyse the association of HLA-DRB1/DQB1 with susceptibility to MS in Slovakia. The results of our study confirm that HLA class II alleles, genotypes and haplotypes are associated with MS risk.     

Evaluation of efficacy,safety and tolerability of fingolimod in patients with the relapsing form of multiple sclerosis – 12-month observation. A preliminary report

Background and purposeOral fingolimod 0.5 mg daily was approved in the European Union in 2011 for the treatment of relapsing multiple sclerosis in the aggressive form and as a second line treatment in patients with high disease activity despite interferon beta therapy. The aim of this study was the evaluation of efficacy, safety and tolerance of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) during a 12-month observation period.Material and methodsThe investigated group consisted of 11 patients aged between 23 and 63 years. All patients underwent immunomodulatory treatment (disease modifying drugs – DMD) or immunomodulatory treatment in combination with mitoxantrone (Mx) without a positive effect for 3–5 years. Patients received oral fingolimod 0.5 mg daily during 12 months. Disability was evaluated with Kurtzke Expanded Disability Status Scale (EDSS) scale. Safety and tolerability of fingolimod were evaluated by adverse events monitoring, laboratory tests, and ophthalmological and skin assessment.ResultsBefore the initiation of fingolimod treatment all the patients progressed in disability and in MRI changes including five cases with gadolinium-enhancing lesions. During fingolimod treatment there was no new relapse in any patient and no patient stopped the treatment because of any adverse event. During the 12-month treatment, EDSS improvement was observed in seven patients, three patients were stable, and one patient progressed by 0.5 point in the EDSS.ConclusionsIn our study patients fingolimod was effective, safe and well tolerated independently of disease activity and previous treatment.     

The potential use of adult stem cells for the treatment of multiple sclerosis and other neurodegenerative disorders

No specific treatment exists for patients with multiple sclerosis (MS) who fail to respond to conventional immunosuppressive and immunomodulating modalities. Furthermore, no method is available for regeneration of existing defect in the central nervous system (CNS). The ultimate goals of MS treatment, similarly to other autoimmune diseases, are twofold: first, to eliminate self-reactive lymphocytes and to prevent de novo development of self-reactivity by induction of self-tolerance. Second, attempting regeneration and repair of existing damage. In the case of MS, there is a need to stop the ongoing process of inflammation against the CNS by self-reactive lymphocytes thus facilitating spontaneous re-myelinization while in parallel attempt to recover existing neurological deficits caused by the autoimmune process resulting in demyelinization. Cell therapy stands out as the most rationale approach for neurological regeneration. In the absence of clinically applicable approaches involving the use of embryonic stem cells, we are investigating the feasibility and efficacy of enriched autologous mesenchymal stromal cells (MSC) injected intrathecally and intravenously to induce in situ immunomodulation and neuroprotection and possibly facilitate repair of the CNS in patients with MS and other neurodegenerative disorders. Our preclinical results suggest that bone marrow cells may provide a source of stem cells with a potential for migration into inflamed CNS and differentiate into cells expressing neuronal and glial cell markers. Based on the preclinical data, we are currently evaluating the safety of a similar therapeutic approach in a small group of patients with MS and other neurodegenerative diseases.     

The effect of tDCS on the fatigue in patients with multiple sclerosis: A systematic review of randomized controlled clinical trials

IntroductionFatigue is one of the most common disabling symptoms in patients with multiple sclerosis (MS) which is present in 75% of these patients and is usually associated with functional disabilities. According to the literature, there is no general agreement on the effectiveness of the existing treatments for fatigue in patients with MS. As transcranial direct current stimulation (tDCS) is a relatively new method in the treatment of fatigue symptoms in patients with MS, the purpose of this study was to systematically review published evidence conducted to assess the effects of tDCS on fatigue in patients with MS.Material & methodsA thorough literature search of published articles was conducted from 1996 to 2019 in different databases including PubMed, Science Direct, OVID, Google Scholar, Cochrane Library, Scopus, Embase, ProQuest and web of science with keywords of “tDCS”, “multiple Sclerosis” and “Fatigue”. Results yielded 1017 studies, which after excluding articles based on duplication and title and abstract, 8 of them were selected for review in this study.ResultsThe results from the literature revealed that six studies indicated positive effects of tDCS stimulation on fatigue reduction. In four studies stimulation was over the right dorsolateral prefrontal cortex (DLPFC); in three studies stimulation placed over the whole body’s primary somatosensory cortex (S1); and in one study stimulation applied over the posterior parietal cortex. In most studies, no serious side effects were reported.ConclusionMost studies revealed that tDCS can reduce the adverse effects of MS-related fatigue in particular cognitive type. As follow-ups were either absent or short period, as well as the application of treatment protocols and measurement instruments were different, it was very difficult to draw strong conclusion on the effects of tDCS in patients with MS. However, further large scale studies with long term follow-up are still recommended.     

Expression pattern of activation and adhesion molecules on peripheral blood CD4 T-lymphocytes in relapsing-remitting multiple sclerosis patients: a serial analysis

We studied the expression of various cell surface molecules (CD25, CD28, CD29, CD45RO, CD56, LFA-1, VLA-4) on peripheral blood CD4⁺ T-cells in 6 relapsing-remitting multiple sclerosis (RR-MS) patients. Furthermore, changes in the expression pattern of these surface markers during intervals of increased disease activity, which was measured by gadolinium (Gd-DTPA) magnetic resonance imaging (MRI) were examined. Although several patients showed signs of increased disease activity during the observation period, this was not paralleled by a relevant change in the expression of these activation and adhesion molecules.     

The influence of human allergic encephalitogenic peptide on cell-mediated cytotoxicity reactions in patients with multiple sclerosis

Multiple sclerosis patients and normal control persons were assayed for cell-mediated cytotoxicity against target cells coated with human allergic encephalitogenic peptide. Coating of different types of target cells resulted in increased cytotoxicity, most clearly seen against homologous lymphocytes and virus-infected fibroblasts. Both patients and controls showed reactivity against coated targets. A possible role for this type of reaction in the pathogenesis of multiple sclerosis is proposed.     

β-干扰素对多发性硬化患者趋化因子mRNA表达的影响

目的　观察干扰素 β 1b(IFNβ 1b)在体外对多发性硬化 (MS)患者趋化因子mRNA表达的影响。方法　取MS患者外周血 ,分离单个核细胞 (MNC) ,以其他非炎性神经系统疾病 (OND)及健康人 (HC)为对照组。MNC在完全培养基中分别与自身抗原髓鞘碱性蛋白 (MBP)、对照抗原AChR及不加抗原组 ,加或不加药物IFNβ 1b共同培养 ,3d后收集细胞 ,涂片 ,用地高辛标记的寡核苷酸探针进行原位杂交 (ISH) ,检测C C趋化因子单核细胞炎性蛋白 1α/ β(MIP 1α/ β)、单核细胞趋化蛋白 1(MCP 1 )和正常T细胞表达及分泌的调节活化因子 (RANTES)mRNA的表达。结果　MBP刺激的MIP 1α及自发产生的MIP 1αmRNA均受到IFN β 1b的抑制 ,但差异无显著意义 (P >0 0 5)。RANTESmRNA的表达受到IFNβ 1b的抑制 ,在MBP诱导下无药物处理时为 30 2± 1 5 0 (细胞数 / 1 0 5,下同 ) ,有药物处理为 1 1 1± 5 3 ,差异有显著意义 (P <0 0 1 ) ;在无抗原诱导下无药物处理时为 1 8 5± 3 3 ,有药物处理为 5 1± 3 2 ,差异亦有显著意义 (P <0 0 1 )。IFNβ 1b在 1 0U/ml浓度下 ,可对MBP刺激的MCP 1mRNA的表达产生抑制作用 (分别为 1 58 4± 1 0 4 3和 63 2± 36 9,差异有显著性意义 ,P <0 0 1 ) ,而对自发产生的MCP 1mRNA作用不明显 ;对MBP刺激     

The effect of repetitive transcranial magnetic stimulation on motor performance, fatigue and quality of life in amyotrophic lateral sclerosis

BACKGROUND: The treatment of amyotrophic lateral sclerosis (ALS) is still disappointing. Repetitive transcranial magnetic stimulation (rTMS) has been suggested to modify the rate of disease progression in ALS. OBJECTIVE: In a pilot controlled study, we tested the effect of 5-Hz rTMS on motor performance, fatigue and quality of life (QoL) in ALS. METHODS: Ten ALS patients underwent a two-week period of daily active or sham 5-Hz rTMS. Outcome measures were assessed with functional, fatigue and QoL scales. Muscle strength was evaluated with the MRC scale and measured with isometric and isokinetic dynamometer. RESULTS: Significant difference at the end of rTMS treatment was found for QoL, maximum voluntary isometric contraction and isokinetic average power when comparing active vs sham treatment. These changes were transitory and outcome measures were not significant two weeks after discontinuation of rTMS. CONCLUSIONS: Though preliminary, our results suggest that 5-Hz rTMS may improve motor function and QoL in ALS. The present data indicate the need of a double-blind therapeutic trial of rTMS in ALS.     

The effect of cyclophosphamide on T lymphocytes and T lymphocyte subsets in patients with chronic progressive multiple sclerosis

ABSTRACT— The lymphocytes in peripheral blood and cerebrospinal fluid of patients with chronic progressive multiple sclerosis (MS) were characterized with monoclonal antibodies to surface antigens of T cells, helper/inducer T cells and suppressor/cytotoxic T cells. The influence of cyclophosphamide treatment on these immune parameters was investigated.
Compared to healthy persons, the mononuclear cell fraction of the peripheral blood of patients with chronic progressive MS consisted of normal %s of T cells and helper/inducer T cells, but decreased %s of suppressor/cytotoxic T lymphocytes. Intensive as well as chronic treatment of MS patients with cyclophosphamide resulted in a decline in the %s of T cells and helper/inducer T cells, whereas the %s of suppressor/cytotoxic T cells returned to normal. In cerebrospinal fluid, cyclophosphamide also induced a relative decrease in the % of helper/inducer T cells and an increase in the % of suppressor/cytotoxic T cells compared to untreated MS patients. Intensive as well as chronic therapy with cyclophosphamide both led to a significant decrease in the absolute number of T cells and T cell subsets in the blood of the patients.     

Effect of treatment with methylprednisolone on the serum levels of IL-12, IL-10 and CCL2 chemokine in patients with multiple sclerosis in relapse

Objectives

Interleukin-12 (IL-12), a proinflammatory cytokine produced by Th1 cells, and interleukin-10 (IL-10), a product of Th2 cells, are involved in the pathogenetic mechanisms of multiple sclerosis (MS). CCL2 chemokine expression is induced by Th2 cytokines and is decreased in MS relapse. The mechanisms responsible for the beneficial effects of IVmethylprednisolone in attacks are not clearly established and the duration of the effect of this treatment remains controversial.

Patients and methods

We measured by enzyme-like immunosorbent assay (ELISA) serum levels of IL-12, IL-10 and CCL2 before, 5 days and 1 month after the initiation of treatment with IVMP in 20 patients with MS in relapse.

Results

A significant increase of IL-10 and decrease of CCL2 serum levels was observed (p = 0.0028 and 0.045 respectively) five days after the onset of steroid treatment but not after one month. Steroid treatment had no influence in serum levels of IL-12.

Conclusions

The clinical improvement of our MS patients with relapse following the treatment with methylprednisolone may be associated with an immediate but not a long-term modification of serum levels of IL-10 and CCL2. IL-12 may not be influenced by steroid treatment.     

Vertebral hemangiomas in the thoracic spine of multiple sclerosis patients are connected with fewer demyelinating lesions at the same level. Possible impact on pathophysiology and clinical course

Objectives: Mechanisms of angiogenesis regulate multiple sclerosis (MS) lesions’ evolution, displaying both neuroprotective and harmful effects. Factors traditionally considered as purely angiogenic, like vascular endothelial growth factor (VEGF), exert complex heterogenous actions on both neural and vascular malformation-derived tissues. Aim of this retrospective study was to examine, for the first time, potential associations between the presence of common vascular malformations, like vertebral hemangiomas (VHs), and several clinico-radiological MS parameters.

Methods: 236 MS patients who were followed in our Outpatient Clinic were recruited in this study. Outcome measures concerned demographics, disease-derived variables, and MS-lesions’ distribution in VHs – positive and negative patients. All data were collected retrospectively. Potential correlations were assessed with univariate statistical analyses (p = 0.05), followed by multivariate regression models, for purposes of confounder-effects elimination.

Results: VH presence showed significant negative correlations with presence of MS lesions in the thoracic (p = 0.005 for thoracic VHs), but not the cervical cord. Trends towards negative associations of VH presence with subtentorial MS lesions and positive family history for MS were also observed.

Discussion: Our observations suggest that VH presence may reduce the risk of thoracic demyelinating lesions in MS patients. They could be explained as part of a multifaceted angiogenic process, concomitantly enhancing neural repair and abnormal hemangioma vascularization.