Autonomic dysfunction in multiple sclerosis: cervical spinal cord atrophy correlates

Autonomic dysfunction has rarely been studied in patients suffering from multiple sclerosis (MS). Some hypotheses have concerned the pathophysiology, especially with regard to a possible spinal cord origin. However, there have been no previous studies on autonomic dysfunction in MS and spinal cord lesions. This study assessed the frequency of autonomic dysfunction (AD) in MS and the correlation to spinal cord magnetic resonance imaging (MRI) findings. We prospectively studied 75 MS patients (25 with relapsing-remitting forms, 25 with secondary progressive forms and 25 with primary progressive forms). We performed sympathetic skin response, R-R interval variability and orthostatic hypotension testing. Spinal cord MRI was performed to detect demyelinating lesions (sagittal and axial plane) or spinal cord atrophy. Clinical and laboratory evidence of AD was found in 84 % and 56 % of MS patients, respectively. The correlation of the latter with disability was evaluated using the Extended Disability Status Scale. AD was more frequent in primary progressive MS than in the other two forms. AD was correlated with spinal cord cross-sectional area reduction but not with spinal cord hyperintensities. This study confirms that the frequency of AD in MS, especially in primary progressive forms, has until now been underestimated. Furthermore, AD appears to be more closely related to axonal loss, as demonstrated by spinal cord atrophy, than to demyelinating lesions. Received: 20 March 2000, Received in revised form: 13 October 2000, Accepted: 29 October 2000     

The transverse magnetisation decay characteristics of longstanding lesions and normal-appearing white matter in multiple sclerosis

The characteristics of transverse magnetisation decay of 120 longstanding lesions and 40 regions of normal-appearing white matter have been analysed in 40 patients with multiple sclerosis (MS) and 10 normal controls. Fifty lesions showed a biexponential decay in which two water compartments – one probably intracellular, the other extracellular – could be defined. There was a higher frequency of biexponential lesions in patients with a primary progressive course but no significant difference between benign and secondary progressive groups. Seventy lesions showed a monoexponential decay, of which 31 showed a T2 of greater than 200 ms, implying that these lesions were predominantly composed of extracellular rather than intracellular water. The results imply that an expanded extracellular space within chronic MS brain lesions is a common finding at all levels of disability and disease course. In so far as an expanded extracellular space implies axonal loss, the results suggest that the latter occurs commonly in longstanding MS lesions. The lack of correlation with disability suggests a limited role for the technique in therapeutic monitoring. Received: 2 January 1996 Received in revised form: 7 June 1996 Accepted: 5 August 1996     

Autologous hematopoietic stem cell transplantation (AHSCT) for aggressive multiple sclerosis – whom,when and how

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that leads to an inflammatory process resulting in demyelination and axonal degeneration. The most common form of MS is the relapsing-remitting MS (RRMS) characterized by the presence of numerous relapses. After few years of disease course, 90% of those patients eventually develop a secondary progressive form. About 10% of patients may suffer from a slowly progressive MS form – the primary progressive. The current treatment of RRMS includes immunomodulatory and immunosuppressive agents, which are effective, but usually in earlier and more benign forms. The immunomodulatory treatment has limited efficacy in aggressive forms of RRMS, and relapses occur despite treatment continuation. AHSCT should be considered as a therapeutic approach for patients with aggressive relapsing-remitting and aggressive progressive MS who failed conventional therapy. The mechanism of action of AHSCT for MS results from resetting the aberrant patient's immune system and eliminating the autoreactive T-lymphocytes. AHSCT can serve as an effective and safe procedure only when strict neurological eligibility criteria are adhered. The procedure should be performed in highly specialized hematological centers. The aim of our paper is to summarize the current eligibility criteria for AHSCT in MS patients as well as to present data on efficacy and safety of this approach.     

A brain MRI study of different types of chronic-progressive multiple sclerosis

Introduction –This study was performed to define the pattern of brain magnetic resonance imaging (MRI) abnormalities in chronic-progressive MS (MS). Material and methods — Brain MRIs were obtained for 17 patients with secondary progressive MS (SPMS), 14 with primary progressive MS (PPMS) and 5 with "transitional" progressive MS (TPMS). Results — Total lesion loads were different for the three groups of patients (p<0.01). At post-hoc analysis, there was no difference between patients with TPMS and those with PPMS, while both these groups had lesion loads lower than those of patients with SPMS. Patients with PPMS with clinical signs indicating involvement of both brain and spinal cord had greater total lesion loads than those with clinical isolated spinal cord involvement (p<0.05). Conclusion — These data indicate that brain MRI patterns of abnormalities are related to the clinical manifestations in patients with chronic-progressive MS.     

Advanced MRI in multiple sclerosis: current status and future challenges

MRI has rapidly become a leading research tool in the study of multiple sclerosis (MS). Conventional imaging is useful in diagnosis and management of the inflammatory stages of MS but has limitations in describing the degree of tissue injury and cause of progressive disability seen in later stages. Advanced MRI techniques hold promise for filling this void. These imaging tools hold great promise to increase understanding of MS pathogenesis and provide greater insight into the efficacy of new MS therapies.     

The pathogenesis of primary progressive multiple sclerosis: antibody-mediated attack and no repair?

Primary progressive multiple sclerosis (MS) differs from the more common form of MS which has an initial relapsing-remitting course in a number of ways, including pathological features, clinical course, differential diagnosis and response to treatment. The lesions in primary progressive MS tend to be more diffuse, less inflammatory and less likely to remyelinate than those occurring in relapsing-remitting MS and secondary progressive MS; there are also fewer focal lesions in the brain in primary progressive MS. Recent evidence suggests that antibodies to central nervous system (CNS) antigens have an important role in disease progression. Such antibodies could cause demyelination, inhibit remyelination and cause axonal destruction. Ongoing immune attack by autoantibody and lack of CNS repair could be responsible for the gradually increasing disability in primary progressive MS. Further research on the B-cell and autoantibody response in primary progressive MS might lead to advances in diagnosis and treatment. Inhibition of autoantibody production by inducing B-cell apoptosis with rituximab is a potential new therapy for primary progressive MS.     

A spinal cord MRI study of benign and secondary progressive multiple sclerosis

This study was performed to achieve a better definition of the nature of the disability in multiple sclerosis (MS). Axial spinal cord magnetic resonance imaging (MRI) at C5 was obtained in 15 patients with benign MS, 17 patients with secondary progressive MS and 10 healthy controls. Patients with secondary progressive MS had smaller spinal cord cross-sectional area (P = 0.01) and transverse diameter (P = 0.006) than patients with benign MS. The degree of disability was inversely correlated with both the cross-sectional area (r = –0.6,P = 0.0018) and transverse diameter (r = –0.5,P = 0.0032) of the cord. Spinal cord atrophy was found in 7 (41%) patients with secondary progressive MS and in 2 (13%) with benign MS. These findings suggest that destructive pathology within MS lesions might play a relevant role in the development of disability in MS.     

Multiple sclerosis – more than one disease?

We have previously found an increase in prevalence and incidence of multiple sclerosis (MS) in the county of Hordaland, Western Norway. This study shows that the increase in incidence over a 30-year period is due to an increase of remittent and remittent/progressive MS. The incidence of the chronic progressive form of MS has remained stable during the same period. The two subgroups of MS also vary in symptomatology and age at onset. This suggests that MS has two different forms which behave differently when considered epidemiologically and clinically. The remitting and progressive forms may therefore each have a different etiology.     

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.     

The diagnosis of primary progressive multiple sclerosis

Primary progressive multiple sclerosis (PPMS) is a rather unique form of the more common relapsing inflammatory demyelinative disease. The absence of attacks that typify relapsing forms of MS imposes special challenges for diagnosis, but also provides an opportunity to study the pathogenesis of the more progressive aspects of the disease process in isolation of confounding transient clinical events. In this review, recent advances in diagnostic approaches are considered in relationship to baseline data from a large multinational study designed to better characterize and treat this clinical phenotype. PPMS subjects with cerebral spinal fluid (CSF) findings consistent with intrathecal immunoglobulin production may have a more tissue destructive disease process than those whose CSF lacks evidence of a B-cell immunopathogenic disease component.     

吸烟对多发性硬化病人病情进展影响

目的探讨吸烟对多发性硬化(MS)病人病情进展的影响。方法从2005-01～2010-12,随访三所医院364例临床诊断为MS的病人,分为吸烟组、戒烟组和非吸烟组,根据临床和磁共振成像(MRI)特点,比较各组转化为继发进展型MS的比例、脑实质分数(BPF)和T2高密度病灶体积变化。结果吸烟组与非吸烟组相比,扩展残疾状态量表评分(EDSS)和多发性硬化严重程度评分(MSSS)增加,从复发缓解型MS(RRMS)向继发进展型MS(SPMS)的转化较快,T2加权病灶体积增加,BPF减少。结论研究提示吸烟对MS进展有不利影响,吸烟可加速RRMS向SPMS的转化。     

Immunopathogenesis of multiple sclerosis

Multiple sclerosis (MS) is a suspected autoimmune disease in which myelin-specific CD4+ and CD8+ T cells enter the central nervous system (CNS) and initiate an inflammatory response directed against myelin and other components of the CNS. Acute MS exacerbations are believed be the result of active inflammation, and progression of disability is generally believed to reflect accumulation of damage to the CNS, particularly axonal damage. Over the last several years, the pathophysiology of MS is being appreciated to be much more complex, and it appears that the development of the MS plaque involves a large number of cell populations, including CD8+ T lymphocytes, B cells, and Th17 cells (a population of helper T cells that secrete the inflammatory cytokine IL-17). The axonal transection and degeneration that is thought to represent the basis for progressive MS is now recognized to begin early in the disease process and to continue in the progressive forms of the disease. Molecules important for limiting aberrant neural connections in the CNS have been identified, which suppress axonal sprouting and regeneration of transected axons within the CNS. Pathways have also been identified that prevent remyelination of the MS lesion by oligodendrocyte precursors. Novel neuroimaging methodologies and potential biomarkers are being developed to monitor various aspects of the disease process in MS. As we identify the pathways responsible for the clinical phenomena of MS, we will be able to develop new therapeutic strategies for this disabling illness of young adults.     

The relationship of brain and cervical cord volume to disability in clinical subtypes of multiple sclerosis: a three-dimensional MRI study

OBJECTIVES: Brain and cervical cord volume is a potentially valuable index marker of irreversible pathological processes in multiple sclerosis (MS). Volume in both brain and cervical cord regions in the same patients has only been investigated in a small number of subjects. We aimed at measuring volume in different parts of the central nervous system, and its relationship with clinical measures, in relapsing-remitting (RR) and secondary progressive (SP) MS patients. MATERIAL AND METHODS: Conventional dual echo and three-dimensional (3-D) magnetization prepared rapid acquisition gradient echo imaging was performed on 97 (49 RR and 48 SP) MS patients, and on 31 age- and gender-matched healthy controls. The volumes of the supratentorial brain, lateral ventricles, brainstem, cerebellum and upper cervical cord (UCC) were determined on 3-D magnetic resonance imaging. RESULTS: RR MS patients had significantly smaller supratentorial brain (P=0.002) and larger lateral ventricles (P=0.047) compared with controls, but no differences were found for cerebellum, brainstem and UCC volumes. Significantly smaller supratentorial brain (P<0.0001), cerebellum (P=0.007), brainstem (P=0.0004) and UCC (P<0.0001) volumes, and larger lateral ventricles (P<0.0001) were observed in SP MS patients than in controls. In RR MS, T2-lesion volume correlated with supratentorial (r=-0.46, P=0.0009), lateral ventricular (r=0.65, P<0.0001), cerebellar (r=-0.42, P=0.003) and brainstem (r=-0.35, P=0.01) volumes, but not with UCC volume (r=-0.18, P=0.22). In SP MS, apart from lateral ventricular volume (r=0.52, P=0.0002), none of the estimated structural volumes correlated with T2-lesion volume. The UCC volume correlated with brainstem volume in both RR MS (r=0.35, P=0.016) and SP MS (r=0.38, P=0.007). Multiple regression analysis showed that supratentorial brain volume in RR group, and UCC volume in SP group, were single significant contributors (P=0.01 and 0.04, respectively) to the Expanded Disability Status Scale of all factors entered into the regression model. CONCLUSION: Atrophy is confined to the supratentorial compartment early in the disease course corresponding to the RR stage, but becomes more pronounced in the brain and cervical spinal cord in the SP phase. The estimate of cervical cord volume for SP MS is relevant to functional disability and may be helpful in monitoring MS evolution in the progressive form of disease.     

Blepharoclonus in multiple sclerosis

OBJECTIVE: Keane described 2 patients with gaze-evoked blepharoclonus (BLC), a form of reflex BLC, and multiple sclerosis (MS). A search for common areas of demyelination and focal axonal atrophy (T1 black holes) of the central nervous system (CNS) in 11 patients with MS exhibiting eyelid closure BLC was conducted employing magnetic resonance imaging (MRI). Finding lesions in common CNS locations on these patients can help to elucidate the pathogenesis of this restricted movement disorder. MATERIALS AND METHODS: Eleven adult patients with relapsing-remitting, primary or secondary progressive MS were studied. MRI views were completed employing a 1.5-tesla scanner. Contrast Axial T1 imaging was obtained in 9 patients. RESULTS: TL blackholes were not identified. Ten patients had multiple, scattered periventricular (PV) areas of demyelination. Four patients exhibited brainstem lesions of diverse but inconsistent locations including midbrain, cerebellar peduncle, pons and medulla. In 2 of the patients the brainstem lesions were transient but BLC persisted after the lesions regressed. CONCLUSION: No common areas of CNS demyelination or focal axonal atrophy were identified on these patients with MS and BLC. The pathogenesis and clinical significance of BLC in MS remains to be elucidated.     

Age at onset determines the occurrence of the progressive phase of multiple sclerosis

We investigated the influence of age at disease onset on timing of the progressive phase in 957 patients with multiple sclerosis (MS). Age at onset powerfully predicts the probability of developing a primary progressive form of the disease. Moreover, age at onset strongly determines the time to conversion to secondary progression for patients presenting with a relapsing form. This suggests that age at onset strongly influences the neurodegenerative component of MS.     

Erythrocyte membrane fatty acids in benign and progressive forms of multiple sclerosis

BACKGROUND: There is no good explanation why a proportion of patients with multiple sclerosis (MS) have a relatively benign form of the disease. An imbalance between saturated and unsaturated fatty acids (FA) might influence the disease course of MS. AIM: To assess whether the erythrocyte membrane fatty acid composition, which is a biological marker of long term dietary FA consumption, is different between patients with benign and progressive MS. METHODS: The erythrocyte membrane FA composition was measured by gas chromatography in 23 healthy controls, 27 patients with benign MS, 32 patients with secondary progressive MS and 23 patients with primary progressive MS. None of the patients was following a special diet. RESULTS: No significant differences in levels of saturated and unsaturated FA or in omega-3- and omega-6-polyunsaturated FA were found between controls and patients with the different subtypes of MS. CONCLUSION: Our data suggest that factors other than dietary fatty acid consumption are responsible for the different disease courses of MS.     

Defective regulation of IFNgamma and IL-12 by endogenous IL-10 in progressive MS

BACKGROUND: MS is a chronic inflammatory disease of the CNS postulated to be a Th1 type cell-mediated autoimmune disease. There is increased interferon-gamma (IFNgamma) secretion in MS, and IFNgamma administration induces exacerbations of disease. IFNgamma expression is closely regulated by a number of cytokines produced by different cells of the immune system. Interleukin-12 (IL-12) is a major factor leading to Th1-type responses, including IFNgamma secretion, and there is increased secretion of IL-12 in MS. IL-10 is a potent inhibitor of both IL-12 and IFNgamma expression. METHODS: The authors investigated cytokine production and proliferative responses of peripheral blood mononuclear cells stimulated with soluble anti-CD3 in healthy controls and patients with stable relapsing-remitting MS or progressive MS. RESULTS: The authors found that T cell receptor-mediated IFNgamma and IL-10 secretion were increased in progressive MS, whereas IL-4 and IL-2 secretion and lymphocyte proliferative responses were normal. Anti-IL-12 antibody suppressed raised IFNgamma in progressive MS but did not affect raised IL-10. In addition, neutralization of endogenous IL-10 upregulated IFNgamma in controls but not progressive MS. IL-10 was produced by CD4+ cells whereas IFNgamma was produced by both CD4+ and CD8+ cells. There were no differences in IL-10 receptor expression in MS patients. CONCLUSIONS: These abnormalities in IL-10 regulation were not seen in the relapsing-remitting form of MS. Thus, the defect in regulation of both IL-12 and IFNgamma production by endogenous IL-10 in progressive MS could be an important factor involved in the transition of MS from the relapsing to the progressive stage and has implications for treating MS patients with exogenous IL-10.     

Structural brain indices and executive functioning in multiple sclerosis: A review

Multiple sclerosis (MS) is a neurological disease characterized by lesion-induced white matter deterioration. Brain atrophy and damage to normal appearing white matter (NAWM) and normal appearing gray matter (NAGM) have also been identified as consequences of MS. Neuroimaging has played an integral role in investigating the effects of white and gray matter damage across the three primary clinical phenotypes of the disease—primary progressive (PPMS), relapsing remitting (RRMS), and secondary progressive (SPMS) MS. Both conventional (e.g., T1-weighted imaged) and nonconventional (e.g., diffusion tensor imaging) neuroimaging methods have yielded important information regarding the structural integrity of the brain during the course of the disease. Moreover, it has provided the opportunity to explore the relationship between structural brain indices and cognitive functioning, such as executive functioning, in MS. In this paper, we provide a brief overview of executive functioning in MS, a general review of how structural damage presents in MS by way of sclerotic lesions, atrophy, and microstructural white matter damage, and, finally, how structural brain damage relates to executive dysfunction.     

Localized <Superscript>1</Superscript>H magnetic resonance spectroscopy in mainly cortical gray matter of patients with multiple sclerosis

The brain water fraction (R), the brain water transverse relaxation time (T2), the atrophy index (α) and the absolute concentration of the principal brain metabolites (NAA, Cho and Cr) were measured by localized proton magnetic resonance spectroscopy in the occipito-parietal cortex (mainly gray matter) of 15 relapsing-remitting (R-R) multiple sclerosis (MS) patients, 15 secondary progressive (SP) MS patients and 8 healthy subjects. Significantly lower values of N-acetylaspartate (NAA), creatine (Cr) and the NAA/Cr ratio in the occipito-parietal cortex were detected in SP MS patients than in R-R MS and control subjects (p < 0.01). Moreover, MS patients showed shorter T2 water relaxation times and reduced brain water fraction compared with controls. Higher atrophy indices were also detected in the mainly occipito-parietal gray matter of MS patients, particularly in those with the progressive form. These findings suggest that the pathological process in MS is not limited to either white matter lesions or normal-appearing white matter but extends into the cortical gray matter (occipito-parietal), particularly in the progressive form of the disease. This can involve changes in neural metabolism or neural shrinkage and neuron loss. The significant increase in atrophy indices could be the expression of the relatively higher cerebrospinal fluid signal from the occipito-parietal cortex, even in the absence of obvious cortical atrophy. Received: 18 January 2001, Received in revised form: 16 January 2002, Accepted: 29 January 2002     

Correlation between brain MRI lesion volume and disability in patients with multiple sclerosis

In this study we evaluated the relationships between clinical variables and lesion volumes measured from magnetic resonance imaging (MRI) scans in a large cohort of multiple sclerosis (MS) patients. One hundred and thirty patients with MS entered the study: 36 patients had relapsing-remitting (RR), 39 benign (B), 42 secondary progressive (SP) and 13 primary progressive (PP) courses. There was a significant correlation (r=0.3; p=0.0006) between the total lesion load and the EDSS score when the whole cohort of patients was considered. This correlation increased (r=0.5) when only patients with RRMS and SPMS were considered. Our data indicate that a correlation between disability and MRI lesion volume in MS exists, but its strength is moderate.