Natural history of benign multiple sclerosis: Clinical and HLA correlates in a Western Australian cohort.

BACKGROUND: Benign multiple sclerosis (BMS) is a controversial term that has been used for MS patients with minimal disability decades after disease onset. Herein, we evaluated disease status after 20 years in a Western Australian cohort defined as BMS based on an Expanded Disability Status Scale (EDSS) score ≤ 3.0 at 10 years from onset. METHODS: MS patients with an EDSS score ≤ 3.0 at 10 years from onset and minimum of 20 years follow up were included in the study. The 20-year EDSS score was considered the primary outcome. Associations with demographic and clinical characteristics and HLA-DRB1 genotype were investigated. RESULTS: Among 120 patients with a benign course at 10 years, 78 (65%) remained benign at the 20-year follow up, but patients with an EDSS ≥ 2.5 were more likely to go on to develop more severe disability in the next decade. When considering factors associated with an increase in EDSS score ≤ 1 from 10 to 20 years, indicating limited progression, apart from the EDSS score at 10 years, poly-symptomatic presentation (p = 0.004) and cerebellar/brainstem mono-symptomatic presentation (p = 0.016) were independently associated with more rapid progression compared with other mono-symptomatic presentations. Carriage of the high risk HLA-DRB1*1501 allele was marginally associated with slower progression. CONCLUSIONS: In this geographically isolated MS cohort of predominantly Anglo-Celtic origin clinical progression in the benign MS group was similar to that in other published series from Western countries. These results are in keeping with the view that patients labeled as benign MS are part of a heterogeneous continuum of disease progression and do not possess unique clinical characteristics. Possible genetic determinants of a benign course warrant further investigation.

Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females.

BACKGROUND: In recent years, a relationship between Helicobacter pylori and many disease conditions has been reported, however, studies in its relationship with multiple sclerosis (MS) have had contradictory results. OBJECTIVE: To determine the association between the H. pylori infection and MS. METHODS: 550 patients with MS were included in the study and were matched by gender and year of birth to 299 controls. Patients were assessed for clinical and demographic parameters. An enzyme immunoassay was used to detect the presence of specific IgG antibodies against H. pylori in the serum sample of both groups. RESULTS: H. pylori seropositivity was found to be lower in the patients with MS than in controls (16% vs 21%) with the decrease pertaining to females (14% vs 22%, p=0.027) but not males (19% vs 20%, p=1.0). When adjusted for age at onset, year of birth and disease duration, H. pylori seropositive females presented with a lower disability score than seronegative females (p=0.049), while among males the reverse was true (p=0.025). There was no significant association between H. pylori seropositivity and relapse rate. CONCLUSIONS: Our results could reflect a protective role of H. pylori in the disease development. However, it may be that H. pylori infection is a surrogate marker for the 'hygiene hypothesis', a theory which postulates that early life infections are essential to prime the immune system and thus prevent allergic and autoimmune conditions later in life. The fact that the association between H. pylori seropositivity and MS risk was seen almost exclusively in females requires further investigation.

Atypical idiopathic inflammatory demyelinating lesions: prognostic implications and relation to multiple sclerosis.

Atypical lesions of a presumably idiopathic inflammatory demyelinating origin present quite variably and may pose diagnostic problems. The subsequent clinical course is also uncertain. We, therefore, wanted to clarify if atypical idiopathic inflammatory demyelinating lesions (AIIDLs) can be classified according to previously suggested radiologic characteristics and how this classification relates to prognosis. Searching the databases of eight tertiary referral centres we identified 90 adult patients (61 women, 29 men; mean age 34 years) with ≥ 1 AIIDL. We collected their demographic, clinical and magnetic resonance imaging data and obtained follow-up (FU) information on 77 of these patients over a mean duration of 4 years. The AIIDLs presented as a single lesion in 72 (80 %) patients and exhibited an infiltrative (n = 35), megacystic (n = 16), Baló (n = 10) or ring-like (n = 16) lesion appearance in 77 (86 %) patients. Additional multiple sclerosis (MS)-typical lesions existed in 48 (53 %) patients. During FU, a further clinical attack occurred rarely (23-35 % of patients) except for patients with ring-like AIIDLs (62 %). Further attacks were also significantly more often in patients with coexisting MS-typical lesions (41 vs. 10 %, p < 0.005). New AIIDLs developed in six (7 %), and new MS-typical lesions in 29 (42 %) patients. Our findings confirm the previously reported subtypes of AIIDLs. Most types confer a relatively low risk of further clinical attacks, except for ring-like lesions and the combination with MS-typical lesions.

Clinical relevance of serum natalizumab concentration and anti-natalizumab antibodies in multiple sclerosis.

BACKGROUND: Antibodies against natalizumab have been found in 4.5-14.1% of natalizumab-treated multiple sclerosis (MS) patients. If antibodies persist, they are associated with an adverse effect on treatment response. However, it has proved to be difficult to standardize anti-drug antibody measurements. OBJECTIVES: The purpose of this study was to evaluate the clinical and radiological impact of serum natalizumab concentrations and their relation with anti-natalizumab antibodies in MS patients. METHODS: In this prospective observational cohort study of 73 consecutive patients treated with natalizumab, we measured serum natalizumab levels and antibody titers before the start of natalizumab treatment, at weeks 12 and 24 and annually after natalizumab initiation. Antibodies against natalizumab were measured by radioimmunoassay and serum natalizumab concentrations using a newly developed enzyme linked immunosorbent assay (ELISA). Magnetic resonance imaging (MRI) scan and clinical evaluation were performed before the start of natalizumab treatment and subsequently every year. RESULTS: Antibodies were detected in 58% of the natalizumab-treated patients. All patients developed their antibodies before week 24. The large majority of these patients reverted to neutralizing antibody (NAb) negative status during follow-up. The presence of antibodies was inversely correlated with serum natalizumab concentration (p<0.001). Only high antibody titers are associated with very low or undetectable serum natalizumab concentration. Both high antibody titers and low serum natalizumab concentrations are associated with relapses and gadolinium-enhancing lesions on MRI. CONCLUSIONS: Our data show that both low natalizumab serum concentration and high antibody titers are associated with a lack of efficacy of natalizumab. Measuring serum natalizumab, using a highly specific assay, might lead to more enhanced precision using natalizumab in individual patients.

Imaging the tip of the iceberg: visualization of cortical lesions in multiple sclerosis.

BACKGROUND: Cortical lesions (CLs) occur frequently in multiple sclerosis (MS), but only few CLs are observed on conventional magnetic resonance imaging (MRI). Why some CLs are visible and others are not is currently unknown. Here, we investigated whether CLs that are visible on conventional MRI differ from MRI-invisible CLs in terms of underlying histopathology and quantitative MRI (qMRI) measures. METHODS: A total of 16 brain slices from 10 patients with chronic MS were analysed histopathologically and with conventional and qMRI. A region-of-interest approach was used to compare MRI-visible CLs with MRI-invisible CLs. RESULTS: Although under-powering cannot be completely excluded in this study, MRI-visible CLs did not seem to differ from MRI-invisible CLs in terms of histopathology or qMRI measures. They were, however, significantly larger than their invisible counterparts (mean 13.3 ± 1.7 mm(2) versus 6.9 ± 1.3 mm(2); p = 0.001). Furthermore, the number of MRI-visible lesions correlated with the overall number of CLs in the brain slice (r = 0.96, p < 0.01) and with the overall percentage of demyelination (r = 0.78, p < 0.01) per hemispheric brain slice. CONCLUSION: MRI visibility of CLs is determined by lesion size, and not by any distinctive underlying pathology. Visible CLs are associated with a higher total cortical lesion load, which suggests that when CLs in patients with MS become detectable on MRI, they merely represent 'the tip of the pathological iceberg'.

Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations.

BACKGROUND: White matter hyperintensities (WMH), lacunes and microbleeds are regarded as typical MRI expressions of cerebral small vessel disease (SVD) and they are highly prevalent in the elderly. However, clinical expression of MRI defined SVD is generally moderate and heterogeneous. By reviewing studies that directly correlated postmortem MRI and histopathology, this paper aimed to characterise the pathological substrates of SVD in order to create more understanding as to its heterogeneous clinical manifestation. SUMMARY: Postmortem studies showed that WMH are also heterogeneous in terms of histopathology. Damage to the tissue ranges from slight disentanglement of the matrix to varying degrees of myelin and axonal loss. Glial cell responses include astrocytic reactions--for example, astrogliosis and clasmatodendrosis--as well as loss of oligodendrocytes and distinct microglial responses. Lipohyalinosis, arteriosclerosis, vessel wall leakage and collagen deposition in venular walls are recognised microvascular changes. Suggested pathogenetic mechanisms are ischaemia/hypoxia, hypoperfusion due to altered cerebrovascular autoregulation, blood-brain barrier leakage, inflammation, degeneration and amyloid angiopathy. Only a few postmortem MRI studies have addressed lacunes and microbleeds to date. Cortical microinfarcts and changes in the normal appearing white matter are 'invisible' on conventional MRI but are nevertheless expected to contribute substantially to clinical symptoms. CONCLUSION: Pathological substrates of WMH are heterogeneous in nature and severity, which may partly explain the weak clinicoradiological associations found in SVD. Lacunes and microbleeds have been relatively understudied and need to be further investigated. Future studies should also take into account 'MRI invisible' SVD features and consider the use of, for example, quantitative MRI techniques, to increase the sensitivity of MRI for these abnormalities and study their effects on clinical functioning.

No association of abnormal cranial venous drainage with multiple sclerosis: a magnetic resonance venography and flow-quantification study.

BACKGROUND: Recent studies using colour-coded Doppler sonography showed that chronic impaired venous drainage from the central nervous system is almost exclusively found in multiple sclerosis (MS) patients. This study aimed to investigate the intracranial and extracranial venous anatomy and the intracerebral venous flow profile in patients with MS and healthy controls using magnetic resonance venography (MRV). METHODS: Twenty patients with definite MS and 20 age- and gender-matched healthy controls were examined. MR imaging was performed on a whole-body 3T MR system including both 3D phase-contrast and dynamic 3D contrast-enhanced MRV as well as flow quantification of the internal cerebral veins and the straight sinus. Image analysis was performed by two experienced interventional neuroradiologists blinded to clinical data and structural brain imaging. The intracranial and extracranial neck veins were analysed for stenosis/occlusion and alternative venous drainage pattern. RESULTS: A completely normal venous anatomy was observed in 10 MS patients and 12 controls. Anomalies of the venous system (venous stenosis/occlusions) were found in 10 MS patients and eight healthy controls. An anomalous venous system in combination with associated alternative venous drainage was observed in six MS patients and five healthy controls. Flow quantification showed no venous backflow in any MS patient or control. CONCLUSIONS: Findings suggestive of anomalies of the cranial venous outflow anatomy were frequently observed in both MS patients and healthy controls. Given the normal intracranial venous flow quantification results, it is likely that these findings reflect anatomical variants of venous drainage rather than clinically relevant venous outflow obstructions.

Natalizumab drug holiday in multiple sclerosis: poorly tolerated.

It has been suggested that natalizumab-associated progressive multifocal leukoencephalopathy may be prevented by structured interruptions of treatment. Evidence supporting such a drug holiday is not yet available. Here we present initial observations in 10 multiple sclerosis patients who were stringently monitored up to 6 months after discontinuation of the infusions. Cumulatively, a combination of clinical relapse and new and/or enhanced lesions on magnetic resonance imaging had occurred in 7 of 10 patients. Although numbers are small, our data suggest that in patients who were switched to natalizumab because of disease activity despite first-line treatment, a natalizumab drug holiday without reinstatement of alternate disease-modifying therapy is poorly tolerated.

Diffusely abnormal white matter in chronic multiple sclerosis: imaging and histopathologic analysis.

BACKGROUND: Diffuse abnormalities in the white matter (WM), ie, the so-called diffusely abnormal WM (DAWM), as observed on magnetic resonance imaging (MRI), may contribute to the development of clinical disability in multiple sclerosis (MS). Underlying pathologic and MRI characteristics of DAWM are largely unknown. OBJECTIVES: To explore and describe the histopathologic and radiologic characteristics of DAWM in chronic MS. DESIGN: An MRI and histopathologic postmortem correlative study. METHODS: We analyzed 17 formalin-fixed hemispheric brain slices from 10 patients with chronic MS using histopathologic analysis and qualitative and quantitative MRI. A region-of-interest approach was applied to compare radiologically defined DAWM, normal-appearing WM, and focal WM lesions and to correlate quantitative MRI measures with histopathologic findings. MAIN OUTCOME MEASURES: The DAWM consisted of extensive axonal loss, decreased myelin density, and chronic fibrillary gliosis, all of which were substantially abnormal compared with normal-appearing WM and significantly different from focal WM lesion pathology. Increased T1- and T2-relaxation times and decreased fractional anisotropy values were found in DAWM regions of interest, in association with extensive axonal loss and reduced myelin density. Increased T1- and T2-relaxation times were associated with chronic gliosis. CONCLUSIONS: This study classifies DAWM in chronic MS as an abnormality that is different from normal-appearing WM and focal WM lesions, most likely resulting from the cumulative effects of ongoing inflammation and axonal pathology. As such, DAWM is likely to substantially contribute to disease progression and may prove to be an important new disease marker in clinical trials focusing on the neurodegenerative aspects of MS.

Quantitation of brain tissue changes associated with white matter hyperintensities by diffusion-weighted and magnetization transfer imaging: the LADIS (Leukoaraiosis and Disability in the Elderly) study.

PURPOSE: To explore the value of diffusion-weighted imaging (DWI) and magnetization transfer imaging (MTI) for the improved detection and quantification of cerebral tissue changes associated with ageing and white matter hyperintensities (WMH). MATERIALS AND METHODS: DWI (n = 340) and MTI (n = 177) were performed in nine centers of the multinational Leukoaraiosis And DISability (LADIS) study investigating the impact of WMH on 65- to 85-year-old individuals without prior disability. We assessed the apparent diffusion coefficient (ADC) and magnetization transfer ratio (MTR) of normal appearing brain tissue (NABT) and within WMH and related them to subjects' age and WHM severity according to the Fazekas score. RESULTS: ADC and MTR values showed a significant inter-site variation, which was stronger for the MTR. After z-transformation multiple regression analysis revealed WMH severity and age as significant predictors of global ADC and MTR changes. Only lesional ADC, but not MTR was related to WMH severity. CONCLUSION: ADC and MTR are both sensitive for age and WMH related changes in NABT. The ADC is more sensitive for tissue changes within WMH and appears to be more robust for multicenter settings.

Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement.

Gadolinium-DTPA (Gd-DTPA) is routinely used as a marker for inflammation in MRI to visualize breakdown of the blood-brain barrier (BBB) in multiple sclerosis. Recent data suggest that ultra-small superparamagnetic particles of iron oxide (USPIO) can be used to visualize cellular infiltration, another aspect of inflammation. This project aimed to compare the novel USPIO particle SHU555C to the longitudinal pattern of Gd-DTPA enhancement in multiple sclerosis. Nineteen relapsing-remitting patients were screened monthly using Gd-enhanced MRI. In case of new enhancing lesions, USPIO were injected and 24 h later, MRI was performed and blood was collected to confirm USPIO loading of circulating monocytes. Lesion development was monitored by 3 monthly Gd-DTPA-enhanced scans and a final scan 7-11 months after injection. USPIO-enhancement was observed as hyperintensity on T1-weighted images, whereas no signal changes were observed on T2-weighted-gradient-echo images. In 14 patients with disease activity, 188 USPIO-positive lesions were seen, 144 of which were Gd-negative. By contrast, there were a total of 59 Gd-positive lesions, 15 of which were USPIO negative. Three patterns of USPIO-enhancement were seen: (i) focal enhancement; (ii) ring-like enhancement and (iii) return to isointensity of a previously hypointense lesion. The latter pattern was most frequently observed for lesions that turned out to be transiently hypointense on follow-up scans, and ring-enhancing lesions were less likely to evolve into black holes at follow-up than lesions without ring-like USPIO-enhancement; we speculate this to be associated with repair. In 4% of the USPIO-positive/Gd negative lesions, USPIO-enhancement preceded Gd-enhancement by 1 month. USPIO-enhancement remained visible for up to 3 months in 1.5% of all USPIO-positive lesions. In 29% of the lesions enhancing with both contrast agents, USPIO-enhancement persisted whereas Gd-enhancement had already resolved. In conclusion, the new nano-particle SHU555C provides complementary information to Gd-enhanced MRI, probably related to monocyte infiltration. The use of USPIO-enhanced MRI is likely to lead to more insight in the pluriformity of inflammation in multiple sclerosis.

MTI of white matter hyperintensities.

The severity of tissue changes associated with incidental white matter hyperintensities (WMH) in the elderly cannot be sufficiently determined by conventional MRI. We, therefore, performed a regional analysis of the magnetization transfer ratio (MTR) maps obtained on a 1.5 T scanner from 198 neurologically asymptomatic participants of the Austrian Stroke Prevention Study (mean age 70, age range 52-87 years) in regard to WMH and predefined areas of normal appearing brain tissue. Fluid attenuated inversion recovery MRI was used to grade lesion severity and for lesion volume measurements. The MTR of WMH was always significantly lower than that of normal appearing white matter (NAWM) with an overall relative reduction of approximately 10% and decreased significantly with increasing scores of WMH severity (P = 0.02) and WMH volume (r = -0.24, P = 0.0016). NAWM MTR was not different between subjects with very few and extensive WMH and the WMH volume was associated with NAWM MTR of the frontal lobes only. Concerning a possible impact on cerebral functioning the MTR of the frontal NAWM was significantly associated with fine motor dexterity (P = 0.04) but not with cognitive performance. A significant decline of the MTR with aging was seen in both NAWM and cortex but not in WMH. We conclude that MTR measurements can serve to quantify WMH associated tissue damage. It is predominantly focal, relatively mild, increases with lesion size and may have remote effects on the frontal white matter.