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.     

Primary and secondary progressive multiple sclerosis

The progressive phase of multiple sclerosis (MS) is the one most often associated with irreversible accumulation of disability. An important question remains about the place of primary progressive MS (PP-MS): does it form an integral part of the disease spectrum, or is it maybe a distinct entity? This question could apparently be very theoretical, but it is not, as patients with PP-MS remain orphans when regarding disease-modifying treatments. Thus, they are usually excluded from therapeutic trials. A clue to this question could be the comparison between the different MS subtypes with a progressive phase. We discuss here the clinical similarities and differences between secondary and primary progressive MS.     

IFN-β-1a治疗多发性硬化的多中心前瞻开放对照研究

目的 客观观察和评定利比（Rebif,IFN-β-1a）治疗缓解复发型多发性硬化（RRMS）的临床疗效和安全性.方法 60例依据McDonald（2005）标准确诊的RRMS患者纳入利比组（其中疗程6月者38例,疗程12月12例,18月6例,24月4例）,同一时期内性别、年龄、病程和EDSS分值相匹配的60例RRMS患者纳入对照组.利比组RRMS患者接受利比44 μg皮下注射,每周3次,疗程6-24月.对照组患者口服转移因子治疗.每位入选患者在治疗前记录症状、体征、实验室及MRI检查资料,评定EDSS分值.治疗后每3月随访1次,除记录治疗前项目外,增加利比副反应.随访观察期为2年.疗效评估终点选择在（1）治疗后6月;（2）治疗后12月;（3）治疗后18月;（4）治疗后24月.疗效评定考核指标采用（1）MS年平均复发次数;（2）复发间隔时间;（3）EDSS下降值.结果 利比组患者年平均复发次数为（0.57±0.11）次,对照组为（1.23±0.20）次（P〉0.001）.利比组复发间隔时间为（464.7±20.8）d,对照组为（275.4±16.4）d（P〉0.001）.利比组RRMS患者在利比治疗6、12、18、24月后EDSS分别下降（0.48±0.08）、（0.52±0.06）、（0.93±0.08）、（1.05±0.10）分;对照组分别下降（0.23±0.09）、（-0.29±0.08）、（-0.62±0.12）、（-1.12±0.11）分,2组比较有显著差异（P〉0.001）.利比组有4例（6.67%）出现注射部位红肿,4例（6.67%）出现流感样症状,2例（3.33%）转氨酶轻度增高.此三类副反应均较轻微,2周后自行消失,仅个别患者需要对症处理.结论 RRMS患者在缓解期使用利比44 μg,每周3次皮下注射,能够显著减少MS的复发次数、延长复发间歇时间、延缓残疾进展速度;利比注射时间越长效果越好.利比治疗RRMS安全有效.     

Cardiovascular risk factors in secondary progressive multiple sclerosis: A cross-sectional analysis from the MS-STAT2 randomized controlled trial

Background and purpose

There is increasing evidence that cardiovascular risk (CVR) contributes to disability progression in multiple sclerosis (MS). CVR is particularly prevalent in secondary progressive MS (SPMS) and can be quantified through validated composite CVR scores. The aim was to examine the cross-sectional relationships between excess modifiable CVR, whole and regional brain atrophy on magnetic resonance imaging, and disability in patients with SPMS.

Methods

Participants had SPMS, and data were collected at enrolment into the MS-STAT2 trial. Composite CVR scores were calculated using the QRISK3 software. Prematurely achieved CVR due to modifiable risk factors was expressed as QRISK3 premature CVR, derived through reference to the normative QRISK3 dataset and expressed in years. Associations were determined with multiple linear regressions.

Results

For the 218 participants, mean age was 54 years and median Expanded Disability Status Scale was 6.0. Each additional year of prematurely achieved CVR was associated with a 2.7 mL (beta coefficient; 95% confidence interval 0.8–4.7; p = 0.006) smaller normalized whole brain volume. The strongest relationship was seen for the cortical grey matter (beta coefficient 1.6 mL per year; 95% confidence interval 0.5–2.7; p = 0.003), and associations were also found with poorer verbal working memory performance. Body mass index demonstrated the strongest relationships with normalized brain volumes, whilst serum lipid ratios demonstrated strong relationships with verbal and visuospatial working memory performance.

Conclusions

Prematurely achieved CVR is associated with lower normalized brain volumes in SPMS. Future longitudinal analyses of this clinical trial dataset will be important to determine whether CVR predicts future disease worsening.     

C/EBP homologous protein investigation in the serum and cerebro-spinal fluid of relapsing-remitting multiple sclerosis patients

The exact determination of endoplasmic reticulum (ER) stress-associated proteins is not completely elucidated in the multiple sclerosis (MS) patients. We measured CHOP concentrations in the serum and cerebro-spinal fluid (CSF) of relapsing-remitting MS (RRMS) patients (n = 20) in comparison with the non-MS control group (n = 20) to determine whether this marker could be detected in the body fluids of RRMS patients. CHOP marker was not detectable in all harvested CSF samples. However, its levels were detectable in all serums harvested from both non-MS and RRMS patients and its levels in the latter group were not significantly higher than those of the non-MS control group (P value = 0.265). CHOP was not detectable in the CSF of RRMS patients in spite of the recent reports on the RRMS autopsies. Additionally, there were not any significant correlations (Spearman's correlation) between both of EDSS score and age with CHOP serum concentrations in all subjects.     

复发—缓解型多发性硬化患者血清中CRP及Hcy水平分析

目的探讨复发—缓解型多发性硬化(RRMS)患者血清中C反应蛋白(CRP)、同型半胱氨酸(Hcy)、维生素B_(12)及叶酸水平,并探讨上述因子与RRMS发病的关系。方法选取21例急性期的RRMS患者作为RRMS组,21例同期住院的神经性头痛患者作为对照组,测定其血清中CRP、Hcy、叶酸及维生素B_(12)水平,并比较两组之间的水平差异;并比较RRMS组中不同性别、不同残疾程度组之间的血清CRP、Hcy、叶酸及维生素B_(12)水平。结果 RRMS组患者血清中CRP及Hcy水平高于对照组,而叶酸及维生素B_(12)水平低于对照组,(P0.05)。而扩展残疾状况评分量表评分(EDSS)4分的RRMS患者血清中Hcy及CRP水平高于EDSS评分≤4分的RRMS患者,(P0.05)。结论血清中高CRP、Hcy水平可能与RRMS发病及残疾程度有关。     

Clinical outcome of relapsing remitting multiple sclerosis among Hong Kong Chinese

Background

Clinical outcome of Chinese relapsing remitting multiple sclerosis (RRMS) patients is uncertain.

Aim

To study the long-term clinical outcome of Chinese RRMS patients.

Method

RRMS patients with duration of 10 years or longer followed up in our hospital is retrospectively studied.

Results

61 RRMS patients (75% female) were studied. Their mean symptom onset age was 25.9 years and mean duration was 20.6 years (range 10-33); 36% patients had received β-interferon and 30% azathioprine. Their mean EDSS scores were 3.3 (range 1-7) and 4.7 (range 1-8) at 10 years and latest follow-up (mean duration 20.6 years) respectively. At 10 years, 30% patients had EDSS score ≤2, 34% EDSS 2.5-3.5, 20% EDSS 4.0-5.5 and 16% ≥6; 18% developed SPMS. At latest follow-up, 15% patients had EDSS ≤2, 20% EDSS 2.5-3.5, 19% EDSS 4.0-5.5 and 46% ≥6.0; 53% developed SPMS. The median time from symptom onset to EDSS 6 was 22 years. No differences were detected in demographic characteristics, presenting neurological features, number of attacks in first 2 years, neuroradiological findings and disease modifying therapies between patients with EDSS <6 and ≥6 at ten years. EDSS scores at 10 years and latest follow-up were similar for patients who had received β-interferon and those who had not.

Conclusion

Hong Kong Chinese RRMS patients may have worse long-term clinical outcome than Caucasian patients.     

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.     

Cervical cord FMRI abnormalities differ between the progressive forms of multiple sclerosis

Objective: Aim of this study was to compare tactile‐associated cervical cord fMRI activity between primary progressive (PP) and secondary progressive (SP) MS patients and to investigate whether cord recruitment was associated with structural brain and cord damage. Experimental Design: Cervical cord fMRI during a tactile stimulation of the right hand was acquired from 17 healthy controls, 18 SPMS patients, and 16 PPMS patients. Average fMRI activity and its topographical distribution in cord sectors (left vs. right, posterior vs. anterior) were assessed. Correlations between cord recruitment and structural cord and brain MRI were estimated. Principal Observations: Progressive MS patients showed an increased cord recruitment compared with controls (P = 0.003). Despite a similar structural cord damage, cord activity was increased in SPMS compared to PPMS patients (P = 0.05). Regional analysis showed a non‐lateralized pattern of cord recruitment in MS patients. Compared to PPMS, SPMS patients had grey matter (GM) atrophy in several cortical and subcortical regions. In SPMS patients, atrophy of the left postcentral gyrus was correlated with cord activity (r = ?0.48, P = 0.04). Conclusions: Patients with progressive MS had an over‐recruitment of the cervical cord, which was more pronounced in SPMS than PPMS, despite similar cord structural damage. The alteration of the complex modulation of spinal cord interneurons possibly due to a loss of supratentorial inhibition secondary to brain injury might contribute to explain the observed functional cord abnormalities. Hum Brain Mapp 33:2072–2080, 2012. © 2011 Wiley Periodicals, Inc.     

Safety concerns and risk management of multiple sclerosis therapies

Currently, more than ten drugs have been approved for treatment of relapsing‐remitting multiple sclerosis (MS). Newer treatments may be more effective, but have less favorable safety record. Interferon‐β preparations and glatiramer acetate treatment require frequent subcutaneous or intramuscular injections and are only moderately effective, but have very rarely life‐threatening adverse effects, whereas teriflunomide and dimethyl fumarate are administered orally and have equal or better efficacy, but have more potentially severe adverse effects. The highly effective therapies fingolimod, natalizumab, daclizumab, and alemtuzumab have more serious adverse effects, some of which may be life‐threatening. The choice between drugs should be based on a benefit‐risk evaluation and tailored to the individual patient's requirements in a dialogue between the patient and treating neurologist. Patients with average disease activity can choose between dimethyl fumarate and teriflunomide or the “old injectable.” Patients with very active MS may choose a more effective drug as the initial treatment. In case of side effects on one drug, switch to another drug can be tried. Suboptimal effect of the first drug indicates escalation to a highly efficacious drug. A favorable benefit‐risk balance can be maintained by appropriate patient selection and appropriate risk management on therapy. New treatments will within the coming 1‐2 years change our current treatment algorithm for relapsing‐remitting MS.     

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.     

Interferon beta-1a in primary progressive multiple sclerosis

There is currently no disease-modifying treatment proven to be of efficacy in primary progressive multiple sclerosis (PPMS). However, a number of therapeutic trials have recently been specifically designed for this group. These include a randomised controlled trial of interferon beta-1a which is discussed here. It is hoped that therapeutics in primary progressive multiple sclerosis will continue to expand and effective therapeutic agents will be developed.     

Theory of mind and empathy in patients at an early stage of relapsing remitting multiple sclerosis

Introduction

Early after having been diagnosed with relapsing remitting multiple sclerosis (RRMS), young patients coping with the new situation require good social support and interactions. Successful social interaction is critically dependent upon the ability to understand the minds of others and their feelings. Social cognition refers to the ability to understand the mind of others. Theory of mind (ToM) defines the capability to reason about mental states of others. Empathy describes the ability to have insight into emotional stages and feelings of others. Despite the knowledge of cognitive impairment, which can have profound effects on patients daily activities and quality of life in advanced stages of multiple sclerosis, little is known concerning social cognition in early stages of RRMS.

Methods

In this analysis, tests assessing executive functions (working memory, set shifting and inhibition) and instruments measuring theory of mind (the Movie for the Assessment of Social Cognition – MASC) and empathy (Baron-Cohen's Empathy Quotient) were administered to 25 young adult patients at an early stage of RRMS and to 25 healthy controls (HC). Patients and HC were carefully matched according to intellectual level, age, gender, handedness and education. An early stage of the disease was defined as being diagnosed with RRMS in the last 2 years and having an EDSS of 2 or lower.

Results

Patients had significantly more incorrect responses (“missing”) ToM (P < 0.04). Moreover, patients showed a significantly lower level of empathy in the self-rating questionnaire (P < 0.02). Of the cognitive tests and depression, ToM and Empathy Quotient (EQ) scores were only significantly correlated with the interference score of the stroop test.

Conclusions

Our findings suggest that theory of mind and empathy are deficient even at early stages of RRMS. Deficits in theory of mind and empathy might negatively influence interpersonal relationships in patients with RRMS.     

Monitoring disease activity and progression in primary progressive multiple sclerosis using MRI: sub-voxel registration to identify lesion changes and to detect cerebral atrophy

Objective To explore the potential usefulness of two new magnetic resonance imaging (MRI) analysis techniques for assessment of progressive cerebral atrophy and T2 lesion activity in primary progressive multiple sclerosis (PPMS), and thereby assess the relationship between MRI activity and atrophy in this patient group. Background Measurements of cerebral atrophy and net change in T2 lesion volumes are currently used as surrogate markers of disease progression in multiple sclerosis (MS). However, manual implementation of these techniques is time-consuming and the pathological specificity of T2 lesion change is low. Advances in serial scan registration have facilitated the development of a new, fully-automated technique to measure cerebral volume (SIENA; Structural Image Evaluation, using Normalisation, of Atrophy), and a technique to measure the total new T2 lesion volume selectively (MRI difference imaging). Method SIENA measures changes in cerebral size based on sub-voxel detection of shifts in edge contours. The lesion difference imaging method measures differences in lesion volumes over time as defined by a semi-automated outlining technique. The two new methods were validated against the T2 lesion volume contour technique and a previously described measure of partial brain volume (which uses six slices centred on the presumed area of greatest change around the lateral ventricles). All were applied to serially acquired MR images from a cohort of 39 patients with PPMS, who also underwent scoring on the expanded disability status scale (EDSS) twice, two years apart. Results The two measures reflecting cerebral atrophy correlated strongly (r = 0.58, p < 0.001). T2 lesion load measurements using the two techniques correlated very highly (r = 0.999, p < 0.001). 91 % of the total new T2 lesion volume was from enlargement of pre-existent lesions and only 9 % from new, discrete, lesions. No relationship was seen between the traditional measure of net gain in T2 lesion load and either measure of atrophy. However, the fully-automated measure of total new T2 load correlated with both measures of atrophy (SIENA technique, r= −0.37, p= 0.02; six slice measure, r = −0.41, p = 0.01). There was no relationship between the MRI measures and changes in the EDSS. Conclusion Both of the new image analysis techniques appear to be promising as sensitive markers for disease progression in PPMS. The correlation of total new T2 lesion volume with the progression of cerebral atrophy (which is known to be a consequence of axonal loss in progressive disease), compared with a lack of correlation with the traditional net gain in T2 lesion load is interesting and suggests that the total new T2 lesion volume may ultimately be the most useful measure. Received: 24 November 2000, Received in revised form: 23 April 2001, Accepted: 11 June 2001     

Problems in designing and recruiting to therapeutic trials in primary progressive multiple sclerosis

Patients with primary progressive multiple sclerosis have atypical clinical and magnetic resonance imaging (MRI) characteristics which present unique problems in designing and recruiting to therapeutic trials. The first randomised controlled therapeutic trial specifically for primary progressive multiple sclerosis is now underway. Although only an exploratory phase II study, it has provided further insight into difficulties in diagnosis, classification and choice of clinical and MRI outcome measures. Patients with primary progressive multiple sclerosis have a wide differential diagnosis and do not readily conform to the Poser criteria. They may therefore present diagnostic uncertainty, particularly as their classification often relies on a retrospective history. This was highlighted during the recruitment to this study of interferon-β_1a. Of the 138 patients referred with a definite diagnosis of primary progressive multiple sclerosis only 50 were enrolled in the study. Of the 88 patients not included, 50% either did not have primary progressive multiple sclerosis, or the diagnosis was not secure. Outcome measures pose particular problems. Clinically the focus must be on progression, and the measure should be both responsive and reliable. In relation to MRI, the currently recommended measures for therapeutic trials in relapsing/remitting and secondary progressive multiple sclerosis show little change in primary progressive multiple sclerosis, and therefore more pathologically specific MRI measures are required. Strict clinical guidelines and further developments in clinical and MRI measures are required to facilitate future therapeutic trials in primary progressive multiple sclerosis. Received: 24 June 1998 Received in revised form: 21 December 1998 Accepted: 30 December 1998     

1H Magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis

Recent magnetic resonance imaging (MRI) and pathological studies have indicated that axonal loss is a major contributor to disease progression in multiple sclerosis. ¹H magnetic resonance spectroscopy (MRS), through measurement of N-acetyl aspartate (NAA), a neuronal marker, provides a unique tool to investigate this. Patients with primary progressive multiple sclerosis have few lesions on conventional MRI, suggesting that changes in normal appearing white matter (NAWM), such as axonal loss, may be particularly relevant to disease progression in this group. To test this hypothesis NAWM was studied with MRS, measuring the concentration of N-acetyl derived groups (NA, the sum of NAA and N-acetyl aspartyl glutamate). Single-voxel MRS using a water-suppressed PRESS sequence was carried out in 24 patients with primary progressive multiple sclerosis and in 16 age-matched controls. Ratios of metabolite to creatine concentration (Cr) were calculated in all subjects, and absolute concentrations were measured in 18 patients and all controls. NA/Cr (median 1.40, range 0.86–1.91) was significantly lower in NAWM in patients than in controls (median 1.70, range 1.27–2.14; P = 0.006), as was the absolute concentration of NA (patients, median 6.90 mM, range 4.62–10.38 mM; controls, median 7.77 mM, range 6.60–9.71 mM; P = 0.032). There was no significant difference in the absolute concentration of creatine between the groups. This study supports the hypothesis that axonal loss occurs in NAWM in primary progressive multiple sclerosis and may well be a mechanism for disease progression in this group. Received: 22 January 1999 Received in revised form: 11 June 1999 Accepted: 16 June 1999     

The prevalence of multiple sclerosis in the city of São Paulo, Brazil, 1997

July 1, 1997 was stipulated as the day for estimating the prevalence of multiple sclerosis within the city of São Paulo. The patients were identified via various sources, including associated universities and magnetic resonance services of the city of São Paulo. The area covered by the study has a population of 9,380,000, mainly white and of European origin, with a large number of immigrants from Spain and Portugal. The patients were classified in accordance with the criteria of Poser et al. (1983), and only those with defined multiple sclerosis were registered. The study gave a prevalence of 15.0/10⁵ inhabitants, or three times the value obtained in a similar study in 1990. This increase reveals the larger number of cases encompassed by the study, and is attributed to the use of more detailed recording methods, improvements in diagnosis, and better conditions for treatment.