Predicting loss of employment over three years in multiple sclerosis: clinically meaningful cognitive decline

Cognitive dysfunction is common in multiple sclerosis (MS), yet the magnitude of change on objective neuropsychological (NP) tests that is clinically meaningful is unclear. We endeavored to determine NP markers of the transition from employment to work disability in MS, as indicated by degree of decline on individual tests. Participants were 97 employed MS patients followed over 41.3 ± 17.6 months with a NP battery covering six domains of cognitive function. Deterioration at follow-up was designated as documented and paid disability benefits (conservative definition) or a reduction in hours/work responsibilities (liberal definition). Using the conservative definition, 28.9% reported deteriorated employment status and for the liberal definition, 45.4%. The Symbol Digit Modalities Test (SDMT) and California Verbal Learning Test, Total Learning (CVLT2-TL) measures distinguished employed and disabled patients at follow-up. Controlling for demographic and MS characteristics, the odds ratio of a deterioration based on a change of 2.0 on the CVLT2-TL was 3.7 (95% CI 1.2–11.4 and SDMT by 4.0 was 4.2 (95% CI 1.2–14.8), accounting for 86.7% of the area under the ROC curve. We conclude that decline on NP testing over time is predictive of deterioration in vocational status, establishing a magnitude of decline on NP tests that is clinically meaningful.      

Dystonia in a 13-year-old boy with secondary progressive multiple sclerosis

We report a patient who developed relapsing–remitting multiple sclerosis (MS) at 8 years old, and then had a progressive clinical course and dystonia. Dystonia of the patient is probably due to a lesion of the basal ganglia. Abnormal posture or movement disorder is very rarely found in MS, and progressive clinical course is also rare in childhood. The patient is worthy of attention because of his childhood onset, progressive clinical course and dystonia.     

Interferon beta 1a for secondary progressive multiple sclerosis

This non-systematic review identified four randomised trials that have tested the efficacy of interferon beta in secondary progressive multiple sclerosis (SPMS). Two were trials of interferon beta 1a (IFNb1a) and two of interferon beta 1b (IFNb1b). All have shown significant reductions in relapse rates and accumulation of new magnetic resonance imaging (MRI) lesions, but only one trial (of IFNb1b) showed significant slowing of disability progression. Post hoc analyses of these trials suggest that the differences in outcomes might be partly explained by the differences between the trials in the proportions of patients with relapsing disease. In one of the trials of IFNb1a (the SPECTRIMS trial), the hazard ratio for progression in the treated relapsing patients with relapses in the two pre-study years was 0.74 compared to placebo patients with pre-study relapses and 1.01 in the treated patients compared to the placebo patients without pre-study relapses. In the same trial, the treatment effects on MRI parameters were more marked in the patients who had recent pre-study relapses compared with those who had not. These observations have led to the recommendation in national guidelines that prescribing of IFNb in SPMS be limited to those patients who have had disabling relapses in the last 2 years. These conclusions should be reviewed when the full results of all four trials have been published.     

Impact of cognitive impairment on coping strategies in multiple sclerosis

Objectives: To assess the impact of cognitive impairment (CI) on coping strategies in multiple sclerosis (MS). Materials and methods: Sixty-three patients (40 women, 55 relapsing-remitting and 8 secondary progressive, age 42.6 ± 10.1 years, Expanded Disability Status Scale 2.2 ± 1.7) were assessed using the Coping Orientation for Problem Experiences-New Italian version Inventory, the Beck Depression Inventory and the Rao's Brief Repeatable Battery. Results: MS patients were less likely to use positive and problem-focused strategies, whereas avoiding strategies were adopted more frequently. Twenty-three (36.5%) cases were CI. We found no differences in the type of coping between CI and cognitively preserved patients. Scores on the Stroop test (beta = −0.91, p = 0.04) and on the Word List Generation (beta = 1.15, p = 0.04) were associated with poorer coping strategies. Conclusions: Our study suggests that cognitive functioning (in particular on sustained attention and aspects of executive function) must be considered in a comprehensive account of the factors contributing to successful coping in MS patients.     

A comparison of neuropsychological deficits in primary and secondary progressive multiple sclerosis

Neuropsychological deficits and the relationship to brain pathology were examined in 13 primary progressive (PP) and 12 secondary progressive (SP) multiple sclerosis patients with a similar duration of the progressive phase and comparable physical disability. A battery of neuropsychological tests to assess attention, short-term and working memory was administered to the patients, and their performance was compared to that of 20 healthy controls matched for age and premorbid IQ. Total cerebral lesion load on T2-weighted magnetic resonance imaging was measured in the patients. Both PP and SP patients performed significantly worse than controls in most of the neuropsychological tests. There were only subtle differences between SP and PP on the working memory task although magnetic resonance imaging lesion load was significantly higher in SP than in PP patients. In this exploratory study only subtle differences in cognitive impairment were detected between SP and PP patients matched for physical disability and relevant illness features. The results also suggest that the severity of cognitive impairment cannot be fully explained by the extent of abnormalities detected on conventional T2-weighted magnetic resonance images, and that other pathological abnormalities such as in normal-appearing white matter are likely to be involved. Received: 2 November 1998/Received in revised form: 4 August 1999/Accepted: 6 October 1999     

Serum and cerebrospinal fluid nitrite and nitrate levels in relapsing-remitting and secondary progressive multiple sclerosis patients

Nitric oxide (NO) has been implicated in immune mediated cellular cytotoxicity and inflammatory processes including multiple sclerosis (MS). We aimed to assess NO production in MS patients and to delineate its involvement in different stages. The stable end-products of NO; nitrite(NO₂⁻) and nitrate(NO₃⁻) were analysed both in serum and CSF (cerebrospinal fluid) of patients with MS and non-inflammatory neurological diseases. Nitrite levels were quantified by calorimetric assay based on the Griess reaction. Nitrate levels were examined spectrophotometrically. MS patients exhibited significantly increased serum and CSF levels of NO₂⁻+NO₃⁻ compared with the control subjects. CSF NO₂⁻+NO₃⁻ levels were raised significantly in MS patients with both relapsing remitting (RR) and secondary progressive (SP) course. There was no significant difference between RR and SP MS patients with regard to NO metabolites. No significant correlation was found between NO metabolites and disability score, disease progression index, MRI (magnetic resonance imaging) activity and development of cortical atrophy on MRI. This study provides further evidence for excessive NO production both in CSF and peripheral blood of MS patients. Excessive CSF NO₂⁻+NO₃⁻ levels being more increased than the levels in sera supports pathological inflammatory process within CNS (central nervous system) in both stages of MS. Another implication for the role of NO and INOS inhibitors in the treatment of MS patients with both RR and SP courses was also suggested.     

认知康复治疗在多发性硬化认知功能损害中的积极作用

目的 探讨认知康复治疗在多发性硬化(MS)认知功能损害中的积极作用。 方法 对广州医学院第二附属医院神经内科自2008年9月至2010年10月收治的40例MS存在认知功能损害的患者采用神经心理学测验方法系统评价神经行为认知状况、执行功能及整体认知功能,针对其出现的不同类型认知功能损害早期实行认知康复治疗策略,比较治疗前后患者各神经认知功能评分的差异。 结果 与认知康复治疗前相比,治疗后MS患者智能损害明显改善,神经行为认知状况中定向能力、专注能力、理解、语言、空间结构、记忆、判断等项目评分明显增高,执行功能相关量表评分明显增高,差异均有统计学意义(P＜0.05)。 结论 认知康复治疗能明显改善MS患者认知损害中智商、神经行为认知状况、执行功能的损害,对MS患者的生活状况改善有积极的意义。     

Clinical callosum syndrome in a case of multiple sclerosis

This case report confirms that a clinical callosal disconnection could be observed in multiple sclerosis. Moreover, this case describes a new kind of strange manual behavior related to callosal disconnection. This behavior could neither be considered as a diagonistic dyspraxia nor as an alien hand, but they evoke rather a conflict of intentions.     

Vitamin D as a marker of cognitive decline in elderly Indian population

Objectives:

Very few studies in India have addressed the role of vitamin D in cognitive function. The present study was conducted to assess the serum levels of 25-hydroxyvitamin D (25(OH)D) and its association with markers of cognitive impairment and homocysteine levels in the elderly Indian population.

Materials and Methods:

The study population consisted of patients with dementia (Group A, n = 32), mild cognitive impairment (MCI; Group B, n = 24), and elderly age-matched controls (Group C, n = 30). Measurement of serum levels of 25(OH)D and total homocysteine were done.

Results:

Significant decreased concentration of 25(OH)D and increased concentration of homocysteine was observed. Association of serum levels of vitamin D with markers of cognitive decline as well as serum homocysteine levels was observed in patients with dementia and MCI when compared to controls.

Conclusion:

Correlation of vitamin D with markers of cognitive decline and homocysteine opens a new door for early diagnosis of cognitive impairment.     

多发性硬化患者认知改变与事件相关电位研究

目的研究多发性硬化(MS)患者认知功能障碍的发生情况,及其与事件相关电位(ERPs)的相关关系。方法对70例MS患者进行韦氏智力量表测查及ERPs检查。结果韦氏智力量表测试发现MS组全量表智商(FIQ)不正常者(<90分)的比率为40%(28/70),与正常组比较差异显著(P<0.01)。MS组N2、P300潜伏期明显延长,与对照组比较差异具有显著性(P<0.05)。脑或脑脊髓型及进展型MS患者P300潜伏期明显延长,P300波幅降低。病程与P300潜伏期呈显著正相关。言语量表智商(VIQ)、FIQ与P300潜伏期呈负相关,与P300波幅呈正相关;操作量表智商(PIQ)与P300波幅呈正相关。结论MS患者存在有认知障碍。ERPs检查对MS认知障碍的判断有一定参考意义。     

Corpus callosum atrophy associated with the degree of cognitive decline in patients with Alzheimer's dementia or mild cognitive impairment: A meta-analysis of the region of interest structural imaging studies

Individual structural neuroimaging studies of the corpus callosum (CC) in Alzheimer's disease (AD) and mild cognitive impairment (MCI) with the region of interest (ROI) analysis have yielded inconsistent findings. The aim of this study was to conduct a meta-analysis of structural imaging studies using ROI technique to measure the CC midsagittal area changes in patients with AD or MCI. Databases of PubMed, the Cochrane Library, the ISI Web of Science, and Science Direct from inception to June 2014 were searched with key words “corpus callosum” or “callosal”, plus “Alzheimer's disease” or “mild cognitive impairment”. Twenty-three studies with 603 patients with AD, 146 with MCI, and 638 healthy controls were included in this meta-analysis. Effect size was used to measure the difference between patients with AD or MCI and healthy controls. Significant callosal atrophy was found in MCI patients with an effect size of −0.36 (95% CI, -0.57 to −0.14; P = 0.001). The degree of the CC atrophy in mild AD was less severe than that in moderate AD with a mean effect size −0.69 (95% CI, -0.89 to −0.49) versus −0.92 (95% CI, -1.16 to −0.69), respectively. Comparing with healthy controls, patients with MCI had atrophy in the anterior portion of the CC (i.e., rostrum and genu). In contrast, patients with AD had atrophy in both anterior and posterior portions (i.e., splenium). These results suggest that callosal atrophy may be related to the degree of cognitive decline in patients with MCI and AD, and it may be used as a biomarker for patients with cognitive deficit even before meeting the criteria for AD.     

Autonomic nervous system abnormalities predict cardiovascular changes after initiation of siponimod in secondary progressive multiple sclerosis

ObjectiveThe aim of this study was to identify whether autonomic nervous system (ANS) dysfunction identified prior to treatment initiation can predict siponimod related decrease in heart rate (HR) after treatment initiation.MethodsIn 26 people with secondary progressive multiple sclerosis (SPMS) the following ANS testing protocol was applied: 10-min supine resting position, Valsalva maneuver, deep breathing test, 10 min tilt-up table test, 5-min supine resting period, ingestion of siponimod, followed by 180-min supine resting period recordings. Heart rate variability (HRV) parameters were investigated as possible predictors of decrease in HR (ΔHR) after treatment initiation.ResultsAfter treatment initiation, there was a statistically significant drop in HR (71.1 ± 9.2 to 66.3 ± 8.1, p < 0.001) and elevation of systolic blood pressure (sBP) (113.2 ± 12.4 to 117.1 ± 10.8, p = 0.04). Values of the diastolic BP (dBP) followed similar trend as did sBP, however not reaching statistical significance (72.8 ± 9.6 to 74.9 ± 8.3, p = 0.13). In a multivariable regression model, disease duration and standard deviation of NN intervals (SDNN) were identified as independent predictors for ΔHR, where increase in SDNN and longer disease duration predict smaller ΔHR.ConclusionANS abnormalities may predict cardiovascular abnormalities associated with treatment initiation with siponimod.SignificanceResults of this study may help mitigate risks associated with siponimod treatment.     

The utility of multimodal evoked potentials in multiple sclerosis prognostication

The ability to predict disability development in multiple sclerosis (MS) is limited. While abnormalities of evoked potentials (EP) have been associated with disability, the prognosticating utility of EP in MS remains to be fully elucidated. The present study assessed the utility of multimodal EP as a prognostic biomarker of disability in a cohort of clinically heterogeneous MS patients. Median and tibial nerve somatosensory, visual, and brainstem auditory EP were performed at initial assessment on 63 MS patients (53 relapsing–remitting and 10 secondary progressive) who were followed for an average of 2 years. A combined EP score (CEPS) was calculated consisting of the total number of abnormal EP tests, and was correlated with the Expanded Disability Status Scale (EDSS) at baseline and follow-up. There was a significant correlation between multimodal EP and baseline and follow-up EDSS. Specifically, tibial nerve P37 latencies correlated with EDSS (R_BASELINE = 0.49, p < 0.01; R_FOLLOW-UP = 0.47, p < 0.01), as did the median nerve N13 (R_BASELINE = 0.40, p < 0.01; R_FOLLOW-UP = 0.35, p < 0.05) and N20 latencies (R_BASELINE = 0.43, p < 0.01; R_FOLLOW-UP = 0.47, p < 0.01), and P100 full-field (R_BASELINE = 0.50, p < 0.001; R_FOLLOW-UP = 0.45, p < 0.001) and central field latencies (R_BASELINE = 0.60, p < 0.001; R_FOLLOW-UP = 0.50, p < 0.001). In addition, there was a significant correlation between the CEPS with baseline (R = 0.65, p < 0.001) and follow-up (R = 0.57, p < 0.01) EDSS. In contrast, white matter disease burden, as measured by T2 lesion load, exhibited a weaker correlation with EDSS (R_BASELINE = 0.28, p < 0.05). In conclusion, these findings suggest that abnormalities of EP, as quantified by the novel CEPS, may be a useful biomarker for prognosticating clinical disability in MS, and may aid in the quantification of MS disease severity and in guiding therapeutic decisions.     

Low interleukin-10 production is associated with higher disability and MRI lesion load in secondary progressive multiple sclerosis

Abnormalities in T-cell-derived cytokine production are a well-known phenomenon in multiple sclerosis (MS). An association between disability and the production of interferon gamma has been demonstrated recently. The present study investigated associations between disability, cytokine production in stimulated blood lymphocytes and magnetic resonance imaging data in 37 patients with the secondary progressive course in the stable phase of the disease. Patients with high interleukin-10 (IL-10) production had significantly lower disability scores (p=0.009) and lower T2 lesion load (p=0.03). Interleukin-10 might not only play a role in the pathological process of multiple sclerosis but has an impact on disease outcome as well.     

Rationale for off-label treatments use in primary progressive multiple sclerosis: A review of the literature

BackgroundUntil recently, few therapeutic options, other than symptomatic treatment, were available for patients with primary progressive multiple sclerosis (PPMS). Ocrelizumab is the only approved treatment in this indication, and only since 2017. However, many patients in France are receiving off-label treatments for PPMS, mainly rituximab, mycophenolate mofetil, methotrexate, cyclophosphamide, and azathioprine.ObjectiveTo evaluate published data concerning the efficacy of these five treatments frequently used as off-label disease-modifying therapies.MethodsWe reviewed and summarized the studies published in Pubmed since the inception of the database.ResultsEvidence from randomized controlled trials is lacking to support the use of these treatments as disease-modifying therapies in PPMS.ConclusionThe literature lacks dedicated studies to support the off-label use of these disease-modifying therapies in PPMS. However, some limited data are available in the literature suggesting that the use of rituximab and cyclophosphamide could potentially be of some interest in specific subpopulations.     

Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis

Predicting clinical outcome is one of the major and most interesting issues in MS patients. If the global evolution of disability (usually chosen levels on the Kurtzke's Disability Status Scale) has been widely studied, much less is known about the progression of disability during the secondary progressive phase of the disease. It is usually said that there is a poorer prognosis once patients enter a progressive phase, whether from onset (like in primary progressive MS) or after an initial relapsing-remitting phase. The secondary progressive phase of multiple sclerosis (MS) is the one most often associated with the development of severe and irreversible disability. Despite this fact, there is a lot of information about the initial relapsing-remitting phase in the literature, but much less about the secondary progressive one. We review here information available from the literature and from the Lyon MS database about this secondary progressive phase.     

A short version of Rao's Brief Repeatable Battery as a screening tool for cognitive impairment in multiple sclerosis

Rao's Brief Repeatable Battery (BRB) is the most widely used instrument for cognitive evaluation in multiple sclerosis (MS). We assessed a short version of the BRB in 116 relapsing–remitting participants. We found that the administration of three tests, the Selective Reminding Test, the Paced Auditory Serial Addition Test–3 seconds and the Symbol Digit Modalities Test, was able to detect cognitive impairment with a sensitivity of 94%, a specificity of 84%, and an accuracy of 89%. On the basis of these results we developed a screening algorithm requiring 5 to 15 minutes, which may represent a highly sensitive and rapid tool to detect MS-associated cognitive impairment.     

自体外周造血干细胞移植治疗进展型多发性硬化初步研究

目的　评价自体外周造血干细胞移植术 (APBSCT)治疗进展型多发性硬化的疗效及其安全性和毒性。方法　移植组进展型多发性硬化患者 10例 ,造血干细胞动员应用惠尔血 ,预处理应用卡氮芥、依托泊苷、阿糖胞苷、马法兰 (BEAM方案 ) ,移植前采用CD 3 4 纯化和未纯化两种方法处理。对照组进展型多发性硬化患者 10例 ,应用糖皮质激素或免疫抑制剂治疗。中位随访时间 10个月 (范围 4～ 2 2个月 )。应用扩充神经功能残疾量表 (EDSS)、年平均发作次数和MRI进行疗效评价。结果移植组患者移植后 12个月EDSS评分较对照组降低 (分别为 3 4 1± 0 2 3和 6 31± 1 2 1,P <0 0 1) ,平均年发作次数降低 (分别为 0 37± 0 0 7和 1 83± 0 4 2 ,P <0 0 1)。移植组患者移植后MRI强化病灶数较移植前均减少 (P <0 0 1) ;移植前CD 3 4 纯化者较未纯化者治疗更有效 (P <0 0 1)。动员、预处理和移植期间无一例死亡 ,常见的不良反应为胃肠道反应和感染 ;在移植后 2例患者有一过性轻度神经功能损害 ,1例在 10个月时复发。结论　APBSCT治疗进展型MS患者近期治疗效果是明显的 ,安全性是可靠的 ,长期疗效仍需进一步随访观察。     

Source activity in the human secondary somatosensory cortex depends on the size of corpus callosum

If corpus callosum (CC) mediates the activation of the secondary somatosensory area (SII) ipsilateral to the side of stimulation, then the peak latencies of the contra- and ipsilateral SII activity as well as the amplitude of the ipsilateral SII activity should correlate with the size of CC. Innocuous electrical stimuli of five different intensities were applied to the ventral surface of the right index finger in 15 right-handed men. EEG was recorded using 82 closely spaced electrodes. The size of CC and of seven callosal regions was measured from the mid-sagittal slice of a high-resolution anatomical MRI. The activation in the contralateral and ipsilateral SII was evaluated using spatio-temporal source analysis. At the strongest stimulus intensity, the size of the intermediate part of the callosal truncus correlated negatively with the interpeak latency of the sources in ipsi- and contralateral SII (r = -0.83, P < 0.01). Stepwise regression analysis showed that the large size of the intermediate truncus of CC was paralleled by a latency reduction of peak activity of the ipsilateral SII, whereas both contra- and ipsilateral peak latencies were positively correlated. The peak amplitude of the ipsilateral SII source correlated positively with the size of the intermediate truncus of CC, and with the peak amplitudes of sources in the primary somatosensory cortex (SI) and in the mesial frontal cortex. The results suggest that in right-handed neurologically normal men, the size of the intermediate callosal truncus contributes to the timing and amplitude of ipsilateral SII source activity.     

多发性硬化认知障碍评估及其影响因素分析

目的了解多发性硬化(MS)患者认知功能障碍的特点及其相关因素分析。方法对41例MS患者及41例健康对照组进行蒙特利尔认知评估量表(MoCA)智能测试和常规头颅磁共振(MRI)检查,对41例MS患者进行扩展功能障碍状态量表(EDSS)检查。结果 MS组MoCA得分较对照组明显降低,差异具有统计学意义(P0.01);MoCA评分降低的项目主要以视空间与执行功能、延迟记忆、命名、语言为著,而注意力、抽象能力、计算力及定向力未见明显受损;MoCA评分除与受教育程度、MS分型具有相关性(Pearson相关系数分别为0.576、0.366,P值分别为0.000、0.019)外,与性别、年龄、病程、EDSS评分及常规头颅MRI病灶等级等临床资料均无相关性(P0.05)。结论 MS患者存在认知功能障碍,以视空间与执行功能、命名、延迟记忆、语言为著,注意、计算、抽象、定向能力未见明显受损;MS患者认知功能障碍与患者性别、年龄、病程、神经功能缺损程度、常规头颅MRI所示病灶等级无相关;躯体功能障碍越严重,视空间与执行功能得分越低,即操作智商得分越低。