Cortical atrophy is relevant in multiple sclerosis at clinical onset

Introduction Increasing evidence suggests relevant cortical gray matter pathology in patients with Multiple Sclerosis (MS), but how early this pathology begins; its impact on clinical disability and which cortical areas are primarily affected needs to be further elucidated. Methods 115 consecutive patients (10 Clinically Isolated Syndrome (CIS), 32 possible MS (p-MS), 42 Relapsing Remitting MS (RR-MS), 31 Secondary Progressive MS (SP-MS)), and 40 age/gender-matched healthy volunteers (HV) underwent a neurological examination and a 1.5 T MRI. Global and regional Cortical Thickness (CTh) measurements, brain parenchyma fraction and T2 lesion load were analyzed. Results We found a significant global cortical thinning in p-MS (2.22 ± 0.09 mm), RR-MS (2.16 ± 0.10 mm) and SP-MS (1.98 ± 0.11 mm) compared to CIS (2.51 ± 0.11 mm) and HV (2.48 ± 0.08 mm). The correlations between mean CTh and white matter (WM) lesion load was only moderate in MS (r = −0.393, p = 0.03) and absent in p-MS (r = −0.147, p = 0.422). Analysis of regional CTh revealed that the majority of cortical areas were involved not only in MS, but also in p-MS. The type of clinical picture at onset (in particular, pyramidal signs/symptoms and optic neuritis) correlated with atrophy in the corresponding cortical areas. Discussion Cortical thinning is a diffuse and early phenomenon in MS already detectable at clinical onset. It correlates with clinical disability and is partially independent from WM inflammatory pathology. Electronic Supplementary Material Electronic Supplementary material is available for this article at and accessible for authorised users. Received in revised from: 8 August 2006     

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.     

Short-term intensive cyclophosphamide treatment in progressive multiple sclerosis

14 patients with chronic progressive multiple sclerosis, selected in a preliminary uncontrolled trial, were given a short course of intensive cyclophosphamide therapy, which was discontinued when the leukocyte count fell to 3000 cu.mm. 5 patients dropped out because of severe side effects. At 1 year follow-up were neurologically unchanged since admission to the trial; 4 remained stable at 2 years. The lack of clinical improvement, the high frequency of side effects and the proven oncogenicity of cyclophosphamide led us to discontinue the trial.

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Sommario 14 pazienti con SM definita e con forma cronica severamente progressiva sono stati trattati con un ciclo a breve termine e ad alto dosaggio di ciclofosfamide (400 mg/die), associata a cortisone (100 mg/die). L'immunosoppressione è stata considerata efficace quando è stata raggiunta una leucopenia di 3.000/mmc e a quel momento il farmaco è stato interrotto. 5 pazienti non hanno terminato il trattamento per la comparsa di gravi effetti collaterali. Dopo 1 anno di follow-up tutti i pazienti erano stazionari rispetto all'ingresso; 4 pazienti hanno terminato il secondo anno di follow-up e in essi la malattia si è mantenuta in fase di stabilizzazione. Nonostante questo, l'assenza di miglioramenti clinici, l'alta frequenza di effetti collaterali, la dimostrata oncogenicità della ciclofosfamide non ci incoraggia a continuare la sperimentazione.

     

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.     

Real-world challenges in the diagnosis of primary progressive multiple sclerosis

Background and purpose

Despite the 2017 revisions to the McDonald criteria, diagnosing primary progressive multiple sclerosis (PPMS) remains challenging. To improve clinical practice, the aim was to identify frequent diagnostic challenges in a real-world setting and associate these with the performance of the 2010 and 2017 PPMS diagnostic McDonald criteria.

Methods

Clinical, radiological and laboratory characteristics at the time of diagnosis were retrospectively recorded from designated PPMS patient files. Possible complicating factors were recorded such as confounding comorbidity, signs indicative of alternative diagnoses, possible earlier relapses and/or incomplete diagnostic work-up (no cerebrospinal fluid examination and/or magnetic resonance imaging brain and spinal cord). The percentages of patients fulfilling the 2010 and 2017 McDonald criteria were calculated after censoring patients with these complicating factors.

Results

A total of 322 designated PPMS patients were included. Of all participants, it was found that n = 28/322 had confounding comorbidity and/or signs indicative of alternative diagnoses, n = 103/294 had possible initial relapsing and/or uncertainly progressive phenotypes and n = 73/191 received an incomplete diagnostic work-up. When applying the 2010 and 2017 diagnostic PPMS McDonald criteria on n = 118 cases with a full diagnostic work-up and a primary progressive disease course without a better alternative explanation, these were met by 104/118 (88.1%) and 98/118 remaining patients (83.1%), respectively (p = 0.15).

Conclusion

Accurate interpretation of the initial clinical course, consideration of alternative diagnoses and a full diagnostic work-up are the cornerstones of a PPMS diagnosis. When these conditions are met, the 2010 and 2017 McDonald criteria for PPMS perform similarly, emphasizing the importance of their appropriate application in clinical practice.     

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.     

Different mechanisms underlying changes in excitability of peripheral nerve sensory and motor axons in multiple sclerosis

Introduction: Subtle involvement of peripheral nerves may occur in multiple sclerosis. Motor excitability studies have suggested upregulation of slow K⁺ currents, probably secondary to altered motoneuron properties resulting from the central lesion. This study concentrates on sensory axons. Methods: Excitability of median nerve axons at the wrist was studied in 26 patients. Results: Sensory recordings were possible in 22 patients, and reduced superexcitability was the sole abnormality. There was no evidence for changes in membrane potential or demyelination. The decrease was significant in patients taking immunomodulatory therapy. These findings could be reproduced in a computer model by changing the gating of fast K⁺ channels. Motor axon findings were consistent with previously reported increased slow K⁺ current. Conclusions: The sensory findings differ from motor findings. They can be explained by a humoral factor, possibly cytokines, which can penetrate the paranode and have been documented to alter the gating of K⁺ channels. Muscle Nerve, 2013     

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.     

Multiple sclerosis with a progressive course from onset in Lorraine-Eastern France

To investigate the patient characteristics, disease progression, and associated risk factors in patients with multiple sclerosis (MS) with a progressive onset, we conducted a longitudinal population-based study of 359 patients (252 with primary progressive MS (PPMS) and 107 with progressive relapsing MS (PRMS)) in Lorraine, France.As outcome measures, we assessed the time from MS onset to reaching disability status scale (DSS) scores of 4, 6 and 7 and the time from assignment of DSS score of 6 to assignment of DSS score of 7.We studied the influence on these outcomes of sex, age of onset and symptoms of onset. We also studied the influence of the time from MS onset to assignment of DSS 6 on the time from MS onset to assignment of DSS 7. There were no significant differences in the demographic data (gender and age at onset of MS) and clinical data (median time to DSS scores of 4, 6 and 7) between the patients with PPMS and PRMS suggesting such a distinction may be unnecessary. The male/female ratio in all 359 patients with MS with a progressive onset was 1/1.36. The median age at onset was 42.7 years (25% Q1 = 34.7; 75% Q3 = 50.0), was lower for male (40.5 years) than for female patients (44.2 years; p = 0.002). The median time to DSS scores of 4, 6 and 7 were (in years) 3.0 (95% CI = 2.8 to 3.7), 9.9 (95% CI = 9.0 to 10.6), and 17.0 (95% CI = 14.9 to 19.0). A cane was required in 25% of patients 5 years after onset and in 75% 15 years after onset.We did not find any significant unfluence of sex, age at onset, or symptoms at onset on the time from MS onset to assignment of scores 6 or 7 or on the time from the assignment of a score of 6 to the assignment of a score of 7.     

Physical dimension of fatigue correlated with disability change over time in patients with multiple sclerosis

To determine the value of fatigue in predicting the change in disability status in patients with multiple sclerosis (MS), we realized a prospective population-based cohort study of 196 patients with clinically definite MS. In 2002, baseline data were collected on fatigue (Modified Fatigue Impact Scale), health-related quality of life (SF-36), and disability status (EDSS score). The EDSS scores were determined again at least three years later. Univariate and multivariate analysis were performed to determine the predictive value of different dimensions of fatigue and other variables (depression and SF- 36) on the change in disability status. Of the 196 patients, 106 (54%) patients had an unchanged status or improvement and 90 (46%) showed a worsening of disability. After three years, with control for gender, age, and baseline disability status, a high baseline level of physical fatigue was associated with a worsening of disability status, whereas a low baseline level of physical fatigue was associated with the absence of worsening of the EDSS score. Other dimensions of fatigue, depression and SF-36 were not associated with a worsening of disability.A patient's perceived fatigue may be not only a clinically and psychosocially meaningful outcome but also a predictor of objective outcomes such as changes in disability status at three years.     

Course and prognosis of chronic progressive multiple sclerosis: Results of an epidemiological study

In studies on the natural course of multiple sclerosis (MS), several forms of the disease are distinguished. The most important are the relapsing remitting and the chronic progressive forms. The relationship between these remains unclear. In a prospective epidemiological survey we studied the course of MS using the year in which the chronic-progressive phase started as a landmark. The reliability of this "year of progression" was examined in an observer agreement study. Data were acquired from 342 patients. Progression of the handicap was most rapid in case of a secondary progressive course, female sex, high relapse rate in the preceding remitting phase and "year of progression" at a higher age. Survival after the "year of progression" was lowest in the secondary progressive group. Determining the "year of progression" seems to be significant for the prognosis.     

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.     

Intravenous immunoglobulin, plasmalymphocytapheresis and azathioprine in chronic progressive multiple sclerosis

Five patients with a severe form of chronic progressive multiple sclerosis no longer responsive to steroid therapy were treated for six months with high-dose intravenous immunoglobulin associated with plasmalymphocytapheresis and azathioprine. In spite of an apparent initial stabilization of the course of the disease, EDSS assesment after six and twelve months of therapy revealed progressive disability in all patients.

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Sommario Cinque pazienti affetti da una grave forma di sclerosi multipla cronica progressiva (SMCP) resistente alla terapia steroidea sono stati trattati per sei mesi con IG e.v. ad alto dosaggio associate a plasmaferesi ed azatioprina. Durante il ciclo di trattamento, ben tollerato in tutti i pazienti, si è osservata una apparente riduzione della disabilità, ma l'osservazione clinica a sei mesi ed a un anno non ha confermato questo dato. L'associazione di IG e.v., plasmalinfocitoaferesi ed azatioprina, pur agendo verosimilmente su parte dei meccanismi umorali e cellulari coinvolti nel determinismo della malattia non sembra influenzare l'evoluzione clinica delle forme severe di SMCP.

     

Clinical and demographical characteristics of primary progressive multiple sclerosis in Isfahan, Iran

Primary progressive multiple sclerosis (PPMS) is an uncommon form of multiple sclerosis (MS) in which the course of disease is progressive from onset. In a retrospective study amongst 1606 MS patients registered in Isfahan MS Society (IMSS) from April 2003 to 31 December 2005, 92 PPMS cases were identified. That means, the frequency of PPMS amongst all included MS patients would be 5.7% (95% CI: 6.7% and 4.7%). The mean expanded disability status scale (EDSS) for the group was 5.09 ± 1.3. The commonest mode of presentation was motor disturbance in 55 (59.8%), other modes of presentation were, vertigo in 15 (16.3%), visual problems in 12 (13%), sensory disturbances in six (6.5%), and diplopia in four (4.3%). The current existing symptoms were motor problems in all 92 (100%), cerebellar symptoms in 46 (50%), and cognitive impairment in only six (6.5%). Interestingly, two (2%) were affected by poliomyelitis during childhood and presenting symptom in both was limb weakness. Primary progressive form of MS is less common in Persian population and some of the rates observed in PPMS patients differ from those in other regions, these differences may be due to different ethnicity of Persian patients or to geographical differences.     

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