Atypical inflammatory demyelinating lesions and atypical multiple sclerosis

Atypical idiopathic inflammatory demyelinating disorders (IIDDs) of the brain have long been known to be disorders closely related to multiple sclerosis (MS), despite having distinctive clinical and radiological characteristics. Originally, they mostly corresponded to acute-onset variants of MS that classically had poor prognoses, such as Baló’s concentric sclerosis, Marburg variant of MS and Schilder's disease, and their relationship with MS was based on their shared pathological findings and the co-occurrence of these variants in patients with typical MS. More recently, other atypical disorders, such as solitary sclerosis, have also been described as belonging to the MS spectrum, raising the question of their links with MS. Meanwhile, multiple MS mimics have been described and need to be considered in the differential diagnosis of MS. In addition, thorough characterization of these atypical entities, including advanced MRI and biological studies, is now warranted to further improve their management.     

多发性硬化与特发性炎性脱髓鞘疾病诊断的若干问题

多发性硬化(multiple sclerosis,MS)是中枢神经系统(CNS)特发性炎性脱髓鞘疾病(idiopathic inflammatory demyelinating diseases,IIDD)家族的代表和最重要的成员,此家族还包括MS变异型(如Marburg型急性MS、Bal6病和Schilder病)、视神经脊髓炎(NMO)、急性播散性脑脊髓炎(ADEM)、临床孤立综合征(CIS)和瘤样炎性脱髓鞘病(TIDD)等[1].     

特发性脱髓鞘性视神经炎的临床转归

目的 了解特发性脱髓鞘性视神经炎(IDON)临床转归、转化为多发性硬化(MS)或视神经脊髓炎(NMO)的比例以及相关影响因素.方法 对确诊且临床资料完整的IDON患者进行病例回顾及随访,记录视功能和其他神经功能变化以及MS或NMO转化率,应用卡方检验分析不同临床特征对转化率的影响.结果 共入组资料完整且完成随访的IDON患者107例.多数患者视力恢复较好,12例(11.2%)在随访期间转化为MS或NMO.全部12例患者均符合2005年修订的McDonald诊断标准,其中4例符合1999年NMO诊断标准,其余8例中部分表现为"视神经脊髓型MS".复发性IDON较首次发病患者、伴头颅MRI异常较MRI正常者转化为MS或NMO的比例高,分别为23.1%和4.4%(χ2=6.899,P<0.01)以及18.2%和8.1%.是否伴有视乳头水肿以及不同视力损害程度组之间转化为MS或NMO的比例没有差异.结论 该组IDON患者转化为MS或NMO的比例为11.2%.复发性IDON和伴有头颅MRI异常的患者更易转化为MS或NMO.     

Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis

OBJECTIVE: To evaluate the use of estriol in the treatment of experimental autoimmune encephalomyelitis (EAE) and other cell mediated autoimmune diseases. BACKGROUND: Experimental autoimmune encephalomyelitis is a T helper 1 (Th1)-mediated autoimmune demyelinating disease that is a useful model for the study of immune responses in MS. Interestingly, both EAE and MS have been shown to be ameliorated during late pregnancy. METHODS: Estriol, progesterone, and placebo pellets were implanted in mice during the effector phase of adoptive EAE. Disease scores were compared between treatment groups, and autoantigen-specific humoral and cellular responses were examined. RESULTS: Estriol treatment reduced the severity of EAE significantly compared with placebo treatment whereas progesterone treatment had no effect. Estriol doses that induced serum estriol levels that approximated estriol levels during late pregnancy were capable of ameliorating disease. Estriol-treated EAE mice had significantly higher levels of serum antibodies of the immunoglobulin (Ig) G1 isotype specific for the autoantigen myelin basic protein (MBP). Further, MBP-specific T-lymphocyte responses from estriol-treated EAE mice were characterized by significantly increased production of the Th2 cytokine interleukin 10 (IL-10). T lymphocytes were shown to be the primary source of IL-10 within antigen-stimulated splenocyte populations. CONCLUSIONS: Estriol as a hormone involved in immune changes during pregnancy may provide a basis for the novel therapeutic use of estriol for MS and other putative Th1-mediated autoimmune diseases that improve during late pregnancy.     

Atypical childhood chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an uncommon cause of progressive weakness in childhood. The diagnosis is easy when the clinical history and findings are supported by unequivocal electrophysiologic and laboratory evidence of demyelination, but it can be challenging if the criteria for demyelination are not met. We report a case of atypical childhood CIDP to highlight the diagnostic difficulties and the importance of recognizing this treatable condition. Muscle Nerve, 2010     

Occurrence and long-term outcome of tumefactive demyelinating lesions in multiple sclerosis

Although tumefactive multiple sclerosis is a well recognized variant of multiple sclerosis, prognostic uncertainty still exists about long term prognosis. The aim of this study was to estimate the occurrence and long term outcome of tumefactive demyelinating lesions (TDLs) in a cohort of multiple sclerosis patients. We reviewed brain MRI of 443 patients referred to our MS clinic. All patients meeting the McDonald criteria for multiple sclerosis and showing at least one TDL were included. Kaplan–Meier estimates of disease-free survival in patient cohort were compared with control group without TDLs using a log-rank test. Seven cases with TDLs were identified (occurrence 1.58 %). Tumefactive demyelinating lesion recurrence was 16.6 %. Cumulative proportion of patients free from clinical relapse and from new T2 lesions was lower in the control group although not reaching statistical significance (30 vs 50 %; P = 0.666 and 21.7 vs 33.3 %; P = 0.761, respectively). Disability progression analysis showed a not significant trend towards lower probability of remaining progression free for TDL patients (50 vs 61 %; P = 0.295). Occurrence of tumefactive demyelinating lesions in our cohort was higher than those reported in other studies. Overall, TDLs were not predictive of poor outcome in terms of disability progression.     

Nogo-A and nogo receptor expression in demyelinating lesions of multiple sclerosis

A myelin-associated neurite outgrowth inhibitor, Nogo-A, plays a key role in inhibition of axonal regeneration following injury and ischemia in the central nervous system (CNS). Because axonal injury is a pathologic hallmark of multiple sclerosis (MS), we have investigated the expression of Nogo-A and its receptor NgR in four MS and 12 non-MS control brains by immunohistochemistry. Nogo-A expression was markedly upregulated in surviving oligodendrocytes at the edge of chronic active demyelinating lesions of MS and ischemic lesions of acute and old cerebral infarction, whereas NgR expression was greatly enhanced in reactive astrocytes and microglia/macrophages in these lesions when compared with their expression in the brains of neurologically normal controls. Nogo-A and NgR were also identified in a subpopulation of neurons. In contrast, Nogo-A was undetectable in reactive astrocytes and microglia/macrophages and NgR was not expressed on oligodendrocytes in any cases examined. Western blot analysis and double labeling immunocytochemistry identified the constitutive expression of NgR in cultured human astrocytes. These results suggest that Nogo-A expressed on oligodendrocytes might interact with NgR presented by reactive astrocytes and microglia/macrophages in active demyelinating lesions of MS, although biologic effects caused by Nogo-A/NgR interaction among glial cells remain unknown.     

Review: the architecture of inflammatory demyelinating lesions: implications for studies on pathogenesis

Recent technological advances provided the chance to analyse the molecular events involved in the pathogenesis of lesions in human disease. A major prerequisite for such studies is, however, that the pathological material used is exactly defined and characterized. In multiple sclerosis (MS), this is difficult, as several types of active lesions exist, depending upon the stage of the disease, the age and location of these lesions and the inter-individual differences between patients. In addition, within an active lesion, different closely adjacent zones are present reflecting initial tissue injury, debris removal or repair. Here evidence is reviewed, showing that distinct subareas of active MS lesions reflect different pathological hallmarks of lesion evolution. These data provide the basis for our understanding of the pathogenesis of tissue injury in MS and imply that studies on MS pathogenesis have to rely on a clear definition of the lesions analysed and have to focus on specific lesion areas, isolated by microdissection. In addition, these data also imply that molecules, identified in these studies, must be confirmed and validated in the correct context of lesion initiation and/or progression.     

Chronic inflammatory demyelinating polyradiculoneuropathy associated with central nervous system involvement--as compared to multiple sclerosis

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with central nervous system (CNS) demyelinating lesions has recently been reported to mimic multiple sclerosis (MS). In this paper, a series of patients with CIDP were examined to see if they had CNS involvement. CIDP patients with CNS lesions were then compared to patients with MS with peripheral nervous system (PNS) involvement for similarities. CNS and PNS involvement were detected by clinical symptoms, neurological findings, neuro-otological and neuro-ophthalmological tests, electrophysiological examinations such as electroencephalography, evoked potentials, blink reflex, conventional peripheral nerve conduction studies and electromyography, as well as computed tomography and magnetic resonance imaging (MRI). There were 7 of 17 CIDP patients with CNS involvement, but only 2 of 59 MS patients with PNS lesions were found. The rate of CIDP with CNS involvement (41.2%) was higher than that of MS with PNS lesions (3.4%). The CNS signs and symptoms of 7 CIDP patients were not so constant as their PNS symptoms, and consisted of 1 case with optic neuritis, 4 cases with cerebellar atxia and/or nystagmus, and 3 cases with spinal symptoms. These signs and symptoms are all well known in MS. Prolonged latencies on evoked potentials and high signal white matter lesions on T2 weighted MRI, indicating demyelinating CNS lesions were also similar to those found in MS. The CNS involvement in those patients with CIDP was therefore similar in character to those found in MS, but was far less severe than the PNS finding.(ABSTRACT TRUNCATED AT 250 WORDS)     

多发性硬化患者产后复发并发吉兰-巴雷综合征的诊治

目的探讨多发性硬化(MS)患者产后复发并发吉兰-巴雷综合征的临床特点,以期为临床医生提供诊断、鉴别诊断及治疗线索。方法报道本院1例MS患者产后复发并发吉兰-巴雷综合征的临床表现、血液、脑脊液、影像学、电生理检查和治疗,评价治疗前后EDSS评分。分析临床资料特点并随访4个月。结果患者为27岁女性,主要表现为产后四肢无力(下肢重于上肢)、麻木、呼吸困难伴尿便障碍,EDSS评分:9.0分。血液检查正常,腰穿压力测不到,压颈试验不升,脑脊液白细胞数6×106·L,蛋白285mg·d L-1,颈段增强MRI示颈段脊髓肿胀,存在颈段梗阻;肌电图(EMG)示上下肢周围神经源性损害,下肢重于上肢。给予患者甲强龙、丙种球蛋白治疗。出院时EDSS评分:6.0分,随访6月时EDSS评分:4.0分。结论 MS患者产后复发率高,并发吉兰-巴雷综合征病情重,应注意鉴别诊断,可应用丙种球蛋白预防治疗。     

Development of hypointense lesions on T1-weighted spin-echo magnetic resonance images in multiple sclerosis: relation to inflammatory activity

OBJECTIVE: To evaluate whether degree of inflammatory activity in multiple sclerosis, expressed by frequency of gadolinium enhancement, has prognostic value for development of hypointense lesions on T1-weighted spin-echo magnetic resonance images, a putative marker of tissue destruction. DESIGN: Cohort design with long-term follow-up. Thirty-eight patients with multiple sclerosis who in the past had been monitored with monthly gadolinium-enhanced magnetic resonance imaging for a median period of 10 months (range, 6-12 months) were reexamined after a median period of 40.5 months (range, 33-80 months). SETTING: Magnetic Resonance Center for Multiple Sclerosis Research, Amsterdam, the Netherlands, referral center. MAIN OUTCOME MEASURES: The new enhancing lesion rate (median number of gadolinium-enhancing lesions per monthly scan) during initial monthly follow-up; hypointense T1 and hyperintense T2 lesion load at first and last visit. RESULTS: The number of enhancing lesions on entry scan correlated with the new enhancing lesions rate (r = 0.64; P<.001, Spearman rank correlation coefficient). The new enhancing lesion rate correlated with yearly increase in T1 (r = 0.42; P<.01, Spearman rank correlation coefficient) and T2 (r = 0.47; P<.01, Spearman rank correlation coefficient) lesion load. Initial T1 lesion load correlated more strongly with yearly increase in T1 lesion load (r = 0.68; P<.01, Spearman rank correlation coefficient). CONCLUSIONS: Degree of inflammatory activity only partially predicted increase in T1 (and T2) lesion load at long-term follow-up. Initial T1 lesion load strongly contributed to subsequent increase in hypointense T1 lesion load, suggesting that there is a subpopulation of patients with multiple sclerosis who are prone to develop destructive lesions.     

Enhanced expression of MMP-7 and MMP-9 in demyelinating multiple sclerosis lesions

The pathology of multiple sclerosis (MS) is characterised by breakdown of the blood-brain barrier accompanied by infiltration of macrophages and T cells into the central nervous system (CNS). Myelin is degraded and engulfed by the macrophages, producing lesions of demyelination. Some or all of these mechanisms might involve proteinases, and here we have studied the cellular localisation and distribution of two matrix metalloproteinases (MMPs), MMP-7 (matrilysin) and MMP-9 (92-kDa gelatinase), in the normal human CNS and active demyelinating MS lesions. Cryostat sections of CNS samples were immunostained with antisera to MMP-7 and MMP-9. In addition, non-radioactive in situ hybridisation (ISH) was performed using a digoxygenin-labelled riboprobe to detect the expression of MMP-7. MMP-7 immunoreactivity was weakly detected in microglial-like cells in normal brain tissue sections, and was very strong in parenchymal macrophages in active demyelinating MS lesions. This pattern of expression was confirmed using ISH. MMP-7 immunoreactivity was not detected in macrophages in spleen or tonsil, indicating that it is specifically induced in infiltrating macrophages in active demyelinating MS lesions. MMP-9 immunoreactivity was detected in a few small blood vessels in normal brain tissue sections, whereas many blood vessels stained positive in CNS tissue sections of active demyelinating MS lesions. The up-regulation of MMPs in MS may contribute to the pathology of the disease. Received: 19 December 1996 / Revised: 22 May 1997 / Accepted: 4 June 1997     

Treatment response in relation to inflammatory and axonal surrogate marker in multiple sclerosis

BACKGROUND: This study aimed to investigate if treatment response could retrospectively be related to inflammatory or axonal pathology as measured by plasma surrogate markers. METHODS: In this 1-year observational study 30 multiple sclerosis (MS) patients with relapsing-remitting disease were treated with intramuscular IFNbeta-1a or subcutaneous IFNbeta-1b. Responders and nonresponders were defined according to clinical and magnetic resonance imaging criteria. The control group consisted of 14 healthy subjects. Plasma levels of surrogate markers for inflammation (nitric oxide metabolites (NOx)), astrocytic activation (S100B) and axonal damage (NfH(SM135)) were measured using standard assays. RESULTS: There were 11 nonresponders and 19 responders to IFNbeta treatment. Median S100B levels were elevated in a higher proportion of treatment responders (63%, 42.9 pg/mL) compared to nonresponders (18%, 11.7 pg/mL, P < 0.05, Fisher's exact test) and controls (0%, 2 pg/mL, P < 0.001). Levels of NOx were found to be more frequently elevated in nonresponders (72%, 39 microM) compared to healthy controls (0%, 37 microM, P < 0.05). Levels of NfH(SM135) were more frequently elevated in responders (58%, 300 pg/mL, P < 0.001) and nonresponders (72%, 500 pg/mL, P < 0.001) compared to controls (0%, 4.5 pg/mL). CONCLUSION: Patients with relapsing-remitting MS who had surrogate marker supported evidence for astrocytic activation responded more frequently to treatment with IFNbeta.