Neuroimaging in Multiple Sclerosis: Neurotherapeutic Implications

Imaging techniques, in particular magnetic resonance imaging (MRI), play an important role in the diagnosis and management of multiple sclerosis (MS) and related demyelinating diseases. Findings on MRI studies of the brain and spinal cord are critical for MS diagnosis, are used to monitor treatment response and may aid in predicting disease progression in individual patients. In addition, results of imaging studies serve as essential biomarkers in clinical trials of putative MS therapies and have led to important insights into disease pathophysiology. Although they are useful tools and provide in vivo measures of disease-related activity, there are some important limitations of MRI findings in MS, including the non-specific nature of detectable white matter changes, the poor correlation with clinical disability, the limited sensitivity and ability of standard measures of gadolinium enhancing lesions and T2 lesions to predict future clinical course, and the lack of validated biomarkers of long term outcomes. Advancements that hold promise for the future include new techniques that are sensitive to diffuse changes, the increased use of higher field scanners, measures that capture disease related changes in gray matter, and the use of combined structural and functional imaging approaches to assess the complex and evolving disease process that occurs during the course of MS.     

The effects Of Interferon Beta-1a on Proton MR Spectroscopic Imaging in Patients With Multiple Sclerosis,A Controlled Study,Preliminary Results

To evaluate the effects of interferon beta-1a(INFβ-1a) on brain metabolites in patients with multiple sclerosis (MS), we performed Magnetic Resonance Spectroscopy Imaging (MRSI) on five patients treated with INFβ-1a (Rebif 44 μg), and on five untreated patients. Six healthy volunteers were used as controls. Patients were evaluated at the beginning, in the first, third, sixth, and twelfth month. There were no significant differences in normal appearing white matter (NAWM) metabolite peaks of the control group and patients with MS. However, in white matter lesions (WML) and NAWM there was significant differences between the basal and the other months’ metabolic peaks (p < 0.05) in the treatment group although no differences emerged in the untreated group. These data suggest that INFβ-1a has a favorable effect on restoration of metabolites in MS lesions.     

Clinical and Radiological Characteristics in Multiple Sclerosis Patients with Large Cavitary Lesions

Background: Large cavitary lesions are not typical for multiple sclerosis (MS). Cavitary white matter changes may be seen in megalencephalic leukoencephalopathy with subcortical cysts, Alexander disease, mitochondrial leukoencephalopathies, vanishing white matter disease, leukoencephalopathy with calcifications and cysts, cytomegalovirus infection, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Objective: To analyze clinical and radiological characteristics in MS patients with large cavitary lesions. Methods: We studied MS patients with large cavitary brain lesions. Patient characteristics, disease onset/duration/subtype, expanded disability status scale (EDSS), Mini Mental State (MMS), corpus callosum lesions, history of segmental myelitis, CSF oligoclonal bands (OCB), visual evoked potentials (VEP), vanishing white matter disease genetic analysis, and characteristics of the cavitary lesions were analyzed. Results: Nine patients were analyzed, 1 man and 8 women. Mean age of disease onset was 38.5 years. Mean disease duration was 9 years. Three patients had initial relapsing-remitting MS and 6 patients had primary-progressive MS. Mean EDSS was 4.5. Mean MMS was 20/30. Segmental myelitis was present in 6 cases. OCB were found in 6 patients. VEP was performed in 6 patients, and pathological in all but one. Vanishing white matter disease genetic analysis was performed and negative in 5 patients. Inferior corpus callosum lesions were seen in all patients with available sagittal FLAIR sequences. Cavitary lesions were strictly supratentorial, and located inside the diffuse leukoencephalopathy, with often a posterior predominance. Conclusion: MS patients with large cavitary lesions seem to represent an MS subgroup, predominantly women, with relatively late disease onset, predominantly primary-progressive type, relatively high EDSS scores, and severe cognitive dysfunction.     

Physical Activity, Self-Efficacy, and Quality of Life in Multiple Sclerosis

Background Quality of life (QOL) is compromised among individuals with multiple sclerosis (MS). Self-efficacy and physical activity have been positively associated with QOL in persons with MS, and based on a social cognitive perspective, the relationship between physical activity and QOL might be indirect and accounted for by self-efficacy. Purpose We tested the hypothesis that physical activity would be indirectly associated with QOL through a pathway that included self-efficacy. Methods Participants were 133 individuals with a definite diagnosis of MS who completed the Godin Leisure-Time Exercise Questionnaire, Multiple Sclerosis Self-Efficacy scale, and Multiple Sclerosis Impact Scale. Results Path analysis indicated that those with MS who were more physically active had greater self-efficacy for function and control, and self-efficacy for function and control were associated with greater physical and psychological components of QOL. Conclusions Our findings support physical activity as a possible modifiable behavior for mitigating reductions of QOL by improving self-efficacy in individuals with MS.     

Synaptic Loss in Multiple Sclerosis Spinal Cord

Disability in multiple sclerosis (MS) is considered primarily a result of axonal loss. However, correlation with spinal cord cross-sectional area—a predictor of disability—is poor, questioning the unique role of axonal loss. We investigated the degree of synaptic loss in postmortem spinal cords (18 chronic MS, 8 healthy controls) using immunohistochemistry for synaptophysin and synapsin. Substantial (58–96%) loss of synapses throughout the spinal cord was detected, along with moderate (47%) loss of anterior horn neurons, notably in demyelinating MS lesions. We conclude that synaptic loss is significant in chronic MS, likely contributing to disability accrual. ANN NEUROL 2020;88:619–625     

多发性硬化误诊脑肿瘤（附3例报告）

目的：多发性硬化（MS）以占位病变为临床表现时,临床及影像学均难以与肿瘤相鉴别,本文旨在通过病例报道及相关文献复习,分析其临床特征,提高对此类病变的认识。方法：报告3例经病理证实的以占位病变为首发症状的MS病例。结果：MS以占位病变为临床表现时,最易被误诊为神经胶质瘤,病变部位以额顶叶为多,约半数在疾病较早期或病程中出现头痛,恶心等颅内高压征,MS与肿瘤的误诊易发生在急性期。结论：对已怀疑或诊断为MS的患者,临床表现和影像学提示占位者,应考虑脱髓鞘性假瘤的可能性,可试用激素,定期复查,对于首次发病和表现为占位征象,影像学亦支持者,应密切结合诱发电位,MRI,免疫学检查以及定期随访,必要时行活组织检查,以明确诊断,除外MS。     

感染后脑炎和多发性硬化患者临床随诊与影像学比较的研究

目的 探讨感染后脑炎（PIE）与多发性硬化（MS）的临床和影像学特点、疗效与预后及其发病机制。方法 对我科1995－2000年诊断为PIE和MS的临床表现、影像学改变、实验室检查结果及疗效和预后进行前瞻性比较研究。结果 （1）两组病例在起病方式、发病年龄和性别方面无差异；（2）PIE组均为单发病时相，病灶局限在大脑半球脑室旁，MS组多为多发病时机，病灶分布在中枢神经系统各部位；两组患者的症状和体征与磁共振所见病灶相符；（3）PIE的疗效和预后明显优于MS（P＜0．01）。结论 PIE和MS可能是发病机制不同的两种疾病，它们的疗效和预后亦明显不同。     

Tumefactive Demyelinating Lesions in Multiple Sclerosis and Associated Disorders

Tumefactive demyelinating lesions are rare consequences of central nervous system (CNS) idiopathic inflammatory demyelinating diseases. Tumefactive demyelinating lesions pose a diagnostic challenge because they can mimic tumors and abscesses and because they can be caused by a heterogeneous range of disorders. This article reviews the recent literature on the clinical presentation; radiographic features; prognosis; and management of tumefactive demyelinating lesions in multiple sclerosis, acute demyelinating encephalomyelitis, neuromyelitis optica, and the rare variants of multiple sclerosis including Schilder’s disease, Marburg acute multiple sclerosis, and Balo’s concentric sclerosis.     

多发性硬化患者血清尿酸水平的变化及意义

目的 :探讨多发性硬化 (MS)患者血清尿酸 (UA)水平变化与病情活动性的关系。方法 :比较复发 缓解型MS(relapsing remittingmultiplesclerosis ,RRMS)患者急性期及经大剂量甲泼尼龙 (甲基强的松龙 )冲击治疗后缓解期血清UA值 ,并与其他非炎症性神经系统疾病 (non inflammatoryneurologicaldisease ,NIND)作对照 ,同时对比治疗前后头颅MRI增强检查情况。结果 :RRMS患者急性期血清UA水平显著低于缓解期及NIND组 ,缓解期血清UA值虽低于对照组 ,但差异无显著性。治疗前头颅MRI显示病灶明显强化 ,治疗后强化病灶显著减少 ,同时伴随着UA水平回升 ,临床症状改善。结论 :血清UA水平变化与MS患者病情变化相关 ,UA可作为观察MS病情活动性及激素疗效的指标之一。     

Paramagnetic Rim Lesions are Specific to Multiple Sclerosis: An International Multicenter 3T MRI Study

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on magnetic resonance imaging by their paramagnetic rims, and increasing evidence supports their association with severity of clinical disease. We studied their potential role in differential diagnosis, screening an international multicenter clinical research-based sample of 438 individuals affected by different neurological conditions (MS, other inflammatory, infectious, and non-inflammatory conditions). Paramagnetic rim lesions, rare in other neurological conditions (52% of MS vs 7% of non-MS cases), yielded high specificity (93%) in differentiating MS from non-MS. Future prospective multicenter studies should validate their role as a diagnostic biomarker. ANN NEUROL 2020;88:1034–1042     

抗心磷脂抗体与多发性硬化

目的　探讨抗心磷脂抗体 ( ACA)与多发性硬化 ( MS)的关系。方法　采用 ELISA方法检测 3 5例活动期MS、45例对照组血清中 ACA-Ig G、ACA-Ig M、ACA-Ig A结合指数 ( BI)。结果　活动期 MS的 ACA-Ig G BI、ACA-Ig M BI、ACA-Ig A BI的均数与对照组相比差异无统计学意义。 MS组中 4例 ACA-Ig G BI、1例 ACA-Ig MBI阳性 ,对照组无一例阳性。MS组阳性率 ( 5 /3 5 ,1 4.2 9% )与对照组 ( 0 /4 5 ,0 % )比较差异有显著性 ( P <0 .0 5 )。视神经脊髓型 MS ACA阳性率 ( 3 /1 3 ,2 3 .0 8% )与非视神经脊髓型 ( 2 /2 2 ,9.0 9% )差异无显著性 ( P >0 .0 5 )。结论　ACA与部分 MS可能存在某种联系 ,但确切的关系尚不清楚 ,尚待积累更多资料进一步探讨。     

Review of the novelties presented at the 27th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (I)

The new insights presented at the 5th Joint Triennial Congress of the European and Americas Committees on Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS) held in Amsterdam, the Netherlands, 19-22 October 2011, have been summarized at the fourth edition of Post-ECTRIMS meeting held in Madrid in November 2011. Further evidence from epidemiological studies yield a possible relationship between nutrition and alterations of the microbiota that may result in the development of multiple sclerosis (MS) and that may trigger the exacerbation of disease symptoms. Also show the magnitude of impact of comorbidities in multiple sclerosis course as well as the impact of early identification and management. Review of current data on chronic cerebrospinal venous insufficiency and MS sclerosis concludes that there is no role of chronic cerebrospinal venous insufficiency in either multiple sclerosis risk or MS severity. New diagnostic criteria for MS have simplified requirements for demonstrating dissemination of lesions in time. High-field magnetic resonance imaging improves cortical visualization and become a promising tool to detect remyelinization and cortical and medullary lesions, and optical coherence tomography is established as a powerful tool for neuroprotection trials. Diffuse meningeal inflammation through B-cell follicle-like structures is associated with cortical pathology and an accelerated clinical course in secondary progressive MS sclerosis. Systemic inflammation may contribute to neurodegeneration processes in MS, and with regard to grey matter damage recent findings conclude that occurs early in disease course, and correlates with future MS-related disability.     

Atrophy of the Brain and Spinal Cord in Multiple Sclerosis

The destructive nature of the multiple sclerosis disease process is of growing clinical and neuroscientific interest. Axonal transection, neuronal loss, Wallerian degeneration, and chronic demyelination likely contribute to macroscopic atrophy of the brain and spinal cord in patients with the disease. This neurodegenerative process belies the traditional view of multiple sclerosis as an inflammatory demyelinating disease. Magnetic resonance imaging is a key tool in the diagnosis and longitudinal monitoring of central nervous system atrophy. This supplement to theJournal of Neuroimaging is devoted to brain and spinal cord atrophy in MS, with a focus on the role of magnetic resonance imaging. The authors and topics of the articles have been chosen by the Guest Editor to provide a state‐of‐the‐art review of this important field. An emphasis is placed on several key issues pertaining to central nervous system atrophy in multiple sclerosis: pathogenesis, magnetic resonance imaging techniques for quantification, clinical relevance, and effects of disease‐modifying therapies.     

Acute Multiple Sclerosis Lesion: Conversion of Restricted Diffusion Due to Vasogenic Edema

It is widely accepted that acute demyelinating plaques in patients with multiple sclerosis (MS) demonstrate increased apparent diffusion coefficient (ADC) and increased diffusion weighted imaging (DWI) signals on MRI. These imaging characteristics in acute MS lesions have been postulated to be due to peripheral vasogenic edema that typically increases the ADC. This assumption is commonly used to differentiate stroke from MS lesions since acute and subacute stroke lesions demonstrate increased DWI signal with reduced ADC due to acute cytotoxic edema. We report a case of active relapsing‐remitting MS with two new symptomatic contrast‐enhancing lesions. The lesions had reduced diffusion on the ADC map in the early acute phase of MS exacerbation. The reduced ADC signal was subsequently “converted” to increased ADC signal that coincided with the development of profound peripheral vasogenic edema seen on T2‐weighted images. To our knowledge, this is the first serial MRI study describing decreased ADC signal in the early acute phase of contrast‐enhancing MS lesion. The implications of decreased diffusion in the acute phase of MS lesions for the disease pathogenesis are discussed.     

Cognitive Impairment in Multiple Sclerosis

Cognitive impairment (CI) is a serious complication of multiple sclerosis (MS), and the domains affected are well established, but new affected domains such as theory of mind are still being identified. The evidence that disease-modifying therapies (DMTs) improve and prevent the development of CI in MS is not solid. Recent studies on the prevalence of CI in MS among people treated with DMT, although not as solid as studies completed prior to DMT introduction, suggest that CI remains a problem even among people on DMTs and that CI occurs frequently even at the very earliest stages of MS. Functional MRI studies and studies using diffusion tractography show that the impact of lesions on cognition depends on the particular cortical networks affected and their plasticity. Cognitive rehabilitation and L-amphetamine appear promising symptomatic treatments for CI in MS, while, cholinesterase inhibitors and memantine have failed, and data on Ginkgo and exercise are limited. We need more work to understand better CI in MS and develop treatments for this serious complication of MS.     

Higher cerebral dysfunction in a case with atypical multiple sclerosis with concentric lesions

Abstract A patient with atypical multiple sclerosis (MS) with clear concentric structure was studied using high field magnetic resonance imaging (MRI). This case was considered to be Balo's concentric sclerosis. Magnetic resonance imaging showed diffuse multiple concentric demyelinating lesions in the bilateral centrum semiovales, which finally regressed with the necrotic lesions remaining when the patient was discharged. During his clinical course, he showed some higher cerebral dysfunctions, such as memory disturbance, constructual apraxia and acalculia. He was treated with glycerin, prednisone and rehabilitation; all of which were effective in his recovery. Over a 4 month period, the patient recoveredclinically, but some intellectual impairment remained.     

Acquired inflammatory white matter diseases

Objects: During the last decades there have been various attempts to define the characteristics of white matter inflammatory diseases. Most of the authors concerned agree in considering Schilder’s myelinoclastic diffuse sclerosis (SD), Devic’s neuromyelitis optica (NMO) and Balo’s concentric sclerosis to be variants of typical multiple sclerosis (MS). Moreover, in childhood even typical MS presents more aggressive behaviour, with frequent evidence of giant, tumefactive, necrotic or haemorrhagic plaques. Methods: The authors review the literature and cite atypical cases that appear to be intermediate between MS and SD, NMO and SD. Conclusions: Finally, some critical revisions are proposed concerning cases with clinical presentation, history, laboratory and MR findings intermediate between those of acute disseminated encephalomyelitis and of MS. Received: 22 January 2000     

Primary Position Upbeat Nystagmus during an Acute Attack of Multiple Sclerosis

Background and Purpose

Ocular manifestation is one of the frequent signs of an acute attack in multiple sclerosis (MS), although primary position upbeat nystagmus (PPUN) is rare. The purpose of this study is to determine the incidence of PPUN in MS and to determine the lesions that are responsible for this sign.

Methods

The medical records of 120 MS patients with acute brain lesions were reviewed over a consecutive period of 9 years; of these, 6 patients were found to have PPUN. Other ocular motor abnormalities were analyzed in combination with upbeat nystagmus, video-oculographic findings, and lesions detected on brain MRI.

Results

Lesions in the pontine tegmentum involving the medial longitudinal fasciculus (MLF) and ventral tegmental tract (VTT) were the most common, being observed in three of the six patients with PPUN. One patient exhibited caudal medullary lesions bilaterally affecting the paramedian portion of the posterior tegmentum, and two patients exhibited multiple lesions involving the pons with the cerebral peduncle or medulla. In five patients, other ocular motor dysfunctions, such as gaze-evoked nystagmus (n=3) and internuclear ophthalmoplegia (n=1), were found in combination with upbeat nystagmus.

Conclusions

PPUN is an infrequent, ocular manifestation noted during an acute attack of MS, and was observed in 5% of the present cases. Brainstem lesions in these cases primarily involved the pontine tegmentum and the caudal medulla. These findings support the theory that upbeat nystagmus is attributable to damage to the upward vestibulo-ocular reflex pathway related to the vestibular nucleus, VTT, and interconnecting pathways.     

Triple-Dose Versus Single-Dose Gadoteridol in Multiple Sclerosis Patients

Nine patients with multiple sclerosis underwent brain magnetic resonance imaging (MRI) to evaluate the contrast enhancement of individual lesions after a single dose and a triple dose of gadolinium. A single dose (0.1 mmol/kg) of gadoteridol was administered and after a delay, axial T1-weighted images were obtained. After an additional 0.2-mmol/kg dose, the same T1-weighted sequence was repeated. An unblinded reader simultaneously viewed the images from both doses, and utilizing a computer console to rule out flow artifacts, created a gold standard of “definite” enhancing lesions. Using this system, he determined that there was a total of 12 definite enhancing lesions among the patients. This reader also evaluated lesion conspicuity. The contrast-noise ratio was calculated for each lesion. A second reader, blinded to the dose used, then evaluated the number of enhancing lesions at both doses. The unblinded reader noted increased lesion conspicuity after the triple dose. Contrast-noise ratios were significantly (p < 0.001) higher after the triple dose (mean, 9.19) than after the single dose (mean, 2.97). The blinded reader detected 11 of the 12 definite lesions on MRis after the triple dose (sensitivity, 92 %) but saw only 6 on MRis after the single dose (sensitivity, 50%). The difference was significant (p < 0.001 ). Subjective analysis of the films revealed an increase in “ghosting artifacts” at the high dose. Administration of tripledose gadolinium provides increased lesion conspicuity and an improved lesion detection rate when compared to single-dose gadolinium in patients with multiple sclerosis.