Linking structural, metabolic and functional changes in multiple sclerosis

In patients with multiple sclerosis (MS), conventional magnetic resonance imaging (MRI) has markedly improved our ability to detect the macroscopic abnormalities of the brain and spinal cord. New quantitative magnetic resonance (MR) approaches with increased sensitivity to subtle normal-appearing white matter (NAWM) and grey matter changes and increased specificity to the heterogeneous pathological substrates of MS may give information complementary to conventional MRI. Magnetization transfer imaging (MTI) and diffusion-weighted imaging (DWI) have the potential to provide important information on the structural changes occurring within and outside T2-visible lesions. Magnetic resonance spectroscopy (MRS) adds information on the biochemical nature of such changes. Functional MRI might quantify the efficiency of brain plasticity in response to MS injury and improve our understanding of the link between structural damage and clinical manifestations. The present review summarizes how the application of these MR techniques to the study of MS is dramatically changing our understanding of how MS causes irreversible neurological deficits.     

Magnetization transfer MRI in multiple sclerosis and other central nervous system disorders

The present review summarizes the major contributions given by magnetization transfer-magnetic resonance imaging to provide an accurate in vivo picture of the heterogeneity of central nervous system pathology and, ultimately, to improve our ability to monitor the evolution of various neurological conditions.     

Depressive symptoms and MRI changes in multiple sclerosis

To determine whether changes in specific regions of the brain can contribute to the development of depression in patients with multiple sclerosis (MS). We prospectively studied 90 patients with clinically definite MS. Disability, independence, cognitive performances, and depressive and anxiety symptoms have been assessed at baseline and 2 years later. At these two time-points, patients underwent a 1.5-T magnetic resonance examination of the brain including T1- and T2-weighted images. Calculation of regional and total lesion loads (LL) have been performed by a semiautomatic technique; total and regional brain volumes have been calculated by a fully automatic highly reproducible computerized interactive program. Measurements of LL did not show any significant difference between depressed and non-depressed patients. Brain atrophy was significantly more conspicuous in the left frontal lobe (P=0.039), in both frontal lobes (P=0.046) and showed a trend towards a difference in the right frontal lobe (P=0.056), in the right temporal lobe (P=0.057) and in both temporal lobes (P=0.072) of depressed patients. Disability, independence and cognitive performances were similar in depressed and non-depressed patients (P=NS). Spearman correlation analysis and multiple-regression analysis demonstrated that the severity of the depressive symptoms score was associated both with the disability score and the right temporal brain volume. Destructive lesions in the right temporal lobe can contribute to the severity of depression in patients with MS but the influence of the severity of neurological impairment should be taken into account.     

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.     

Mitoxantrone treatment in multiple sclerosis: a 5-year clinical and MRI follow-up

Mitoxantrone (MTX) is an antineoplastic agent approved for treatment of secondary progressive and rapidly worsening relapsing-remitting multiple sclerosis (MS). We designed a longitudinal open-label prospective study to evaluate the efficacy and toxicity of MTX over a 2-year treatment period with a further 3-year follow-up. Fifty consecutive MS patients were included and received MTX intravenously (8 mg/m² every 2 months for a total of 12 infusions). Efficacy was assessed clinically and by brain MRI performed before MTX therapy, at the end of treatment and at the end of each year of follow-up. Forty-nine patients completed the 5-year study, 44 (89.8%) completed the MTX course, five (10.2%) interrupted the treatment because of side effects. Fifteen (30.6%) patients showed Expanded Disability Status Scale (EDSS) progression on treatment and nine (18.4%) during follow-up. Seventeen (34.7%) patients had enhancing lesions at baseline, nine (18.4%) at the end of treatment, but none at the end of follow-up. In conclusion, we observed EDSS progression in about 1/3 of the patients during the treatment period and in 1/5 during the further 3-year follow-up period. This evidence suggests a delayed beneficial effect after MTX treatment is completed with only a minority of patients showing disability progression once the drug was suspended.     

Volumetric quantitation by MRI in primary progressive multiple sclerosis: volumes of plaques and atrophy correlated with neurological disability

In primary progressive multiple sclerosis (PPMS) abnormalities in brain magnetic resonance imaging (MRI) differ from abnormalities in other subtypes of multiple sclerosis (MS). It was investigated whether the extent of brain and spinal cord MRI abnormalities is reflected in the neurological disability in PPMS. Focal and diffuse changes and atrophy in central nervous system (CNS) in patients with PPMS (n = 28) and healthy controls (n = 20) were assessed by semi-automatic MRI segmentation and volumetric analysis. The measurements were related to neurological disability as expressed by the expanded disability status scale (EDSS), the regional functional scoring system (RFSS), the arm index and the ambulation index. Plaques in T1- and/or T2-weighted images were seen in all brains, while spinal plaques were detected in 23 of 28 patients (82%). The total volumes of brain and spinal cord were significantly smaller in patients than in controls (P = 0.001 and 0.000, respectively). The volumes of T1 or T2 lesions in the brain correlated to the ambulation index (r = 0.51, P = 0.005 and r = 0.53, P = 0.004, respectively). No correlations were detected between MRI measurements and total EDSS score, but relative brain atrophy correlated inversely with the total RFSS scores, poor arm index and higher cerebral disturbances (r = -0.53, P = 0.004; r = -0.53, P = 0.004; and r = -0.52, P = 0.005, respectively). Although the number of spinal T2 lesions correlated with sensory disturbances (r = 0.60, P = 0.001), no correlations were found between EDSS subscores and spinal cord atrophy. These findings show that marked atrophy of brain and spinal cord detected by volumetric quantitation correlates with neurological disability. This observation indicates the importance of neurodegenerative events in PPMS.     

Brain MRI in late-onset multiple sclerosis

Multiple sclerosis (MS) with clinical onset after 50 years of age is unusual (between 1 and 6%) and is frequently misdiagnosed. Furthermore, brain magnetic resonance imaging (MRI) abnormalities are frequently observed in subjects over 50 years of age. The aim of this study was to describe brain MRI in late-onset MS to evaluate the sensitivity and specificity of radiological MS criteria in patients aged over 50 years. We evaluated the brain MRI of 20 patients with onset of MS after 50 years of age. We compared these MRI with 26 controls matched for age, sex and vascular risk factors. MRI were blindly analysed by two neuroradiologists according to Paty et al.'s [Neurology38 (1988) 180] criteria, Fazekas et al.'s [Neurology38 (1988) 1822] criteria and Barkhof et al.'s [Brain120 (1997) 2059] criteria. The mean age at MRI scanning was 58 years. Sensitivity was 90% for Paty et al.'s criteria, 80% for Fazekas et al.'s criteria and 85% for Barkhof et al.'s criteria. Specificity was 54% for Paty et al.'s criteria, 69% for Fazekas et al.'s criteria and 65% for Barkhof et al.'s criteria. Barkhof et al.'s criteria are less specific in older patients than in young patients. We suggest that spinal cord MRI and cerebrospinal fluid analysis should be systematically performed in suspected late-onset MS in order to increase the specificity of the diagnosis.     

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.     

Sensitivity of delayed gadolinium-enhanced MRI in multiple sclerosis

Introduction - We performed this study to define the sensitivity of delayed gadolinium-enhanced magnetic resonance imaging (MRI) in detecting active lesions in the brains of patients with multiple sclerosis (MS). Material and methods - T₁weighted images were obtained in 27 patients with relapsing-remitting or secondary progressive MS before, 5–7 min and 20–30 min after the injection of 0.1 mmol/kg gadolinium-DTPA. Results - One-hundred-and-three enhancing lesions were found on the early and 110 on the delayed scans (increase = 6.4%). Six patients had 8 additional lesions in the delayed scans, while 1 patient had 1 more lesion on the early scan. Two of the 12 (17%) patients with no enhancing lesions on the early scans had 2 enhancing lesions on the delayed scans. The average increase of enhancing lesion detection with delayed scanning was 14.5% for those patients who already had enhancing lesions on the early post-contrast scans. A significant increase of the enhancing lesion volume was found with delayed scanning (P=:0.004). Conclusion - These data indicate that it is possible to increase MRI sensitivity in detecting MS active lesions by delaying the scanning after gadolinium injection.     

Translating pathology in multiple sclerosis: the combination of postmortem imaging,histopathology and clinical findings

Background – Studies combining postmortem magnetic resonance imaging (MRI) and histopathology have provided important insights into the abnormalities reflected by MRI. Materials and methods – A short overview of these studies applied to multiple sclerosis (MS) is provided in this review, and the Amsterdam postmortem imaging protocol is specifically highlighted. Conclusion – Postmortem MRI and histopathology correlation studies have enabled a direct translation of basic pathology in MS to the clinical setting, and have simultaneously served as a biological validation of new MRI techniques.     

Blood cholesterol and MRI activity in first clinical episode suggestive of multiple sclerosis

OBJECTIVES: The present study was planned to investigate the relationship between the plasma lipid profile and disease activity in patients with a first clinical episode suggestive of multiple sclerosis (MS). MATERIAL AND METHODS: Eighteen consecutive out-patients underwent a monthly brain magnetic resonance imaging (MRI), blood sample and neurological assessment over 6 months. Blood samples were used to evaluate total cholesterol and triglyceride levels as well as their lipoprotein fractions. Plasma total apolipoprotein E concentration was also determined. RESULTS: We found a significant correlation between the mean number of enhancing lesions and the mean plasma level of both total and low density lipoprotein cholesterol. The total plasma cholesterol level increased on average by 4.4 mg/dl for each enhancing lesion. CONCLUSION: Our preliminary data suggest a potential role of plasma cholesterol level as a biological marker of disease activity after a first demyelinating event. Further studies need, however, to be designed to determine whether the plasma cholesterol level is of practical use in monitoring the disease course.     

Magnetization transfer can predict clinical evolution in patients with multiple sclerosis

The clinical course of multiple sclerosis (MS) is highly variable ranging from benign to aggressive, and is difficult to predict. Since magnetization transfer (MT) imaging can detect focal abnormalities in normal-appearing white matter (NAWM) before the appearance of lesions on conventional MRI, we hypothesized that changes in MT might be able to predict the clinical evolution of MS. We assessed MR data from MS patients who were subsequently followed clinically for 5 years. We computed the mean MT ratio (MTr) in gray matter, in lesions identified on T2-weighted MRI, and in NAWM, as well as in a thick central brain slice for each patient. Patients were divided into stable and worsening groups according to their change in Expanded Disability Status Scale (EDSS) scores over 5 years. We calculated the sensitivity, specificity, predictive value, and odds ratio of the baseline MTr measures in order to assess their prognostic utility. We found significant differences in baseline MTr values in NAWM (p = 0.005) and brain slice (p = 0.03) between clinically stable and worsening MS patients. When these MTr values were compared with changes in EDSS over 5 years, a strong correlation was found between the EDSS changes and MTr values in both NAWM (SRCC = −0.76, p < 0.001) and in the brain slice (SRCC = 0.59, p = 0.01). Baseline NAWM MTr correctly predicted clinical evolution in 15/18 patients (1 false positive and 2 false negatives), yielding a positive predictive value of 77.78 %, a negative predictive value of 88.89 %, and an odds ratio of 28. The relationship between 5-year changes in EDSS and MTr values in T2 weighted MRI lesions was weaker (SRCC = −0.43, p = 0.07). Our data support the notion that the quantification of MTr in the NAWM can predict the clinical evolution of MS. Lower MTr values predict poorer long-term clinical outcome. Abnormalities of MTr values in the NAWM are more relevant to the development of future patient disability than those in the T2-weighted MRI lesions. Received: 3 May 2001, Received in revised form: 11 October 2001, Accepted: 22 October 2001     

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.     

Correlation between magnetic resonance imaging and clinical parameters in multiple sclerosis

In this study, the course of 60 consecutive multiple sclerosis patients (relapsing-remitting (RR), relapsing-progressive (RP), primary-progressive (PP)) was compared with the number and mean size of the lesions as well as the total load of the lesions as shown on magnetic resonance imaging (MRI). Significant differences were found between RR and RP patients in total load and number of lesions. Between RR and PP patients statistical significant differences were found in total load, number and size of the lesions when correlated with EDSS. Between RP and PP patients statistical differences were found in total load and size of the lesions on MRI. Patients with a relapsing course of the MS (RR or RP) had a higher total load and size of the lesions than PP patients. The total load, number and size of the lesions corrected for EDSS were also lower compared to relapsing patients. Factor analysis showed a correlation between clinical progression rate and progression rate of MRI abnormalities. No correlation between EDSS and total load of MRI lesions could be found. In conclusion, this study confirms the results of previous studies of differences between MRI scans of patients with a different course of MS.     

Urodynamic findings in primary progressive multiple sclerosis are associated with increased volumes of plaques and atrophy in the central nervous system

OBJECTIVE: Voiding dysfunction is more frequent in primary progressive multiple sclerosis (PPMS) than in other subtypes of MS. We investigated whether lower urinary tract disorders are reflected in the extent of changes in brain and spinal cord detected by magnetic resonance imaging (MRI). METHODS: Micturition symptoms and specific urodynamic findings in 24 patients with PPMS were related to MRI abnormalities as analysed by segmentation and volumetric analysis. RESULTS: Urgency and urge incontinence were the most frequent urinary symptoms (83 and 75 %), while detrusor sphincter dyssynergia (DSD) (71%), detrusor hyperreflexia (58%) and obstruction (58%) were the most common micturition dysfunctions. Comparison between patients with detrusor hyperreflexia and those with normal bladder function revealed higher volumes of T2-weighted plaques in the brains of former (P = 0.01). In patients with hypotonic bladder the total brain volume was smaller (P = 0.02) and the number of thoracic plaques in T2-weighted images higher (P = 0.02) compared to patients with normal bladder function. Furthermore, DSD was associated with a higher volume of T2-weighted plaques in the brain (P = 0.02). CONCLUSIONS: Voiding dysfunction in PPMS is associated with increasing brain and spinal cord abnormalities. Urodynamic investigation is, however, needed for specific definition of micturition disturbances and should be made before therapeutic decisions.     

The role of MRI of the brain and spinal cord, and CSF examination for the diagnosis of primary progressive multiple sclerosis

The clinical applicability of the revised McDonald diagnostic criteria of primary progressive multiple sclerosis (PPMS) was assessed in 17 patients with a longstanding PPMS diagnosis (mean 15 years). All patients were re-evaluated with clinical examinations, magnetic resonance imaging (MRI) of the brain and the spinal cord, extensive laboratory tests, and 12 patients underwent cerebrospinal fluid (CSF) examination. No diagnosis more likely than PPMS was disclosed. All patients had brain and spinal cord lesions on MRI. In 15 patients the brain lesions and in 14 the spinal cord lesions fulfilled the revised McDonald criteria for positive scans. No contrast-enhancing lesion was observed despite administration of triple doses of gadolinium. In total, 12 patients fulfilled the revised McDonald MRI criteria for PPMS. Of the remaining five patients who incompletely fulfilled the revised MRI criteria, all had CSF findings supporting the diagnosis PPMS. Thus, CSF analysis was required in addition to MRI in about one-third of the patients to establish the diagnosis of PPMS.     

Relevance of callosal and periventricular MRI lesions to oligoclonal bands in multiple sclerosis

OBJECTIVES: To evaluate the association between callosal or periventricular lesions, and the presence of oligoclonal IgG bands (OB) or the IgG index in Japanese patients with multiple sclerosis (MS). MATERIALS AND METHODS: Brain magnetic resonance imaging (MRI) was studied in 34 Japanese clinically definite MS cases. Sagittal 2-mm fast fluid-attenuated inversion-recovery (FLAIR) imaging was added to the routine MRI studies. RESULTS: Among the 34 patients, 20 (59%) were OB positive. Among the 20 patients with OB-positive MS, 17 (85%) had callosal lesions, although only two (14%) of 14 OB-negative MS patients had callosal lesions. The periventricular lesion area was significantly larger in the OB-positive patients compared with the OB-negative patients. CONCLUSIONS: The present study clearly demonstrated a strong association between the periventricular lesions and OB in Japanese MS. Certain OB-related immune mechanisms may contribute to the development of callosal and periventricular lesions in MS. OB may be an important factor to understand the pathomechanisms of MS lesions.