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The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

Summary The diagnosis of multiple sclerosis is based on neurological symptoms and signs, alongside evidence of dissemination of CNS lesions in space and time. MRI is often sufficient to confirm the diagnosis when characteristic lesions accompany a typical clinical syndrome, but in some patients, further supportive information is obtained from cerebrospinal fluid examination and neurophysiological testing. Differentiation is important from other diseases in which demyelination is a feature (eg, neuromyelitis optica spectrum disorder and acute disseminated encephalomyelitis) and from non-demyelinating disorders such as chronic small vessel disease and other inflammatory, granulomatous, infective, metabolic, and genetic causes that can mimic multiple sclerosis. Advances in MRI and serological and genetic testing have greatly increased accuracy in distinguishing multiple sclerosis from these disorders, but misdiagnosis can occur. In this Series paper we explore the progress and challenges in the diagnosis of multiple sclerosis with reference to diagnostic criteria, important differential diagnoses, controversies and uncertainties, and future prospects.

A variety of Magnetic Resonance Imaging (MRI) techniques are known to be sensitive to brain iron content. In principle, iron sensitive MRI techniques are based on local magnetic field variations caused by iron particles in tissue. The purpose of this study was to investigate the sensitivity of MR relaxation and magnetization transfer parameters to changes in iron oxidation state compared to changes in iron concentration. Therefore, quantitative MRI parameters including R1, R2, R2∗, quantitative susceptibility maps (QSM) and magnetization transfer ratio (MTR) of post mortem human brain tissue were acquired prior and after chemical iron reduction to change the iron oxidation state and chemical iron extraction to decrease the total iron concentration. All assessed parameters were shown to be sensitive to changes in iron concentration whereas only R2, R2∗ and QSM were also sensitive to changes in iron oxidation state. Mass spectrometry confirmed that iron accumulated in the extraction solution but not in the reduction solution. R2∗ and QSM are often used as markers for iron content. Changes in these parameters do not necessarily reflect variations in iron content but may also be a result of changes in the iron’s oxygenation state from ferric towards more ferrous iron or vice versa.

Besides specific iron accumulation in some neurodegenerative disorders, increased iron deposition in cerebral deep gray matter (DGM) is found in multiple sclerosis. As this is considered largely a white matter (WM) disease, we speculated that patients with more severe ischemic WM hyperintensities (WMH) might also have an increased iron concentration in DGM structures and tested this assumption by using magnetic resonance imaging-based quantitative R2* relaxometry. WMH severity was measured in 61 patients with acute transient neurological symptoms (mean age: 71.5 ± 8.3 years) undergoing 3-Tesla magnetic resonance imaging. Despite a 6-year higher age of patients with more severe (i.e., early confluent or confluent) WMH, their DGM R2* rates did not differ from patients with punctate or no WMH. In the globus pallidum, R2* rates were even lower in patients with severe WMH. WMH volume was not correlated with R2* levels in any of the analyzed DGM structures. These findings argue against WM damage per se causing increased DGM iron deposition in multiple sclerosis and suggest no role of iron accumulation in ischemic small vessel disease.

Purpose To compare Borrelia -specific intrathecal antibodies by two different ELISAs, an immunoblot (IB) and CXCL13. Methods Twenty-seven adults and 23 children with clinical symptoms compatible with NB were tested for Borrelia -specific intrathecal antibodies by flagellum ELISA-AI (flELISA), a recombinant ELISA-AI (rELISA) and by IB. Patients were classified according to the European Federation of Neurological Societies (EFNS) criteria as definite NB, possible NB, or non-NB. CSF CXCL13 levels were measured by ELISA. Results Among 50 patients, definite NB was diagnosed with the rELISA-AI in 29 (58%) patients, confirmed by IB in 19/29 patients, with flELISA-AI in 17 (34%) patients, confirmed by IB in 15/17 patients, and with IB in 20 (40%) patients. CXCL13 was positive in 22 (44%) patients. In 4 of 8 patients with negative AI, IB showed many detectable bands both in the CSF and serum. Conclusions The diagnosis of NB strongly relies on the used test method. The rELISA-AI test appears to be the most sensitive while the flELISA-AI is the least sensitive. However when the ELISA-AIs were confirmed by IB, different patients were identified as NB, while only 26% were identified by all performed test methods. There is a demand for standardized test methods with well-defined sensitivity and specificity to establish validated diagnostic criteria for NB including the use of the IB assay and CXCL13 as an additional non- Borrelia specific determinant in early NB.

Although age-related gait changes have been well characterized, little is known regarding potential functional changes in central motor control of distal lower limb movements with age. We hypothesized that there are age-related changes in brain activity associated with the control of repetitive ankle movements, an element of gait feasible for study with functional magnetic resonance imaging. We analyzed standardized functional magnetic resonance imaging data from 102 right-foot dominant healthy participants aged 20-83years for age-associated effects using FSL and a meta-analysis using coordinate-based activation likelihood estimation. For the first time, we have confirmed age-related changes in brain activity with this gait-related movement of the lower limb in a large population. Increasing age correlated strongly with increased movement-associated activity in the cerebellum and precuneus. Given that task performance did not vary with age, we interpret these changes as potentially compensatory for other age-related changes in the sensorimotor network responsible for control of limb function. © 2014 Elsevier Inc.

Objective Attachment style and temperament could influence a stress–relapse relationship in multiple sclerosis. We therefore aimed to probe for an association of these personality-related variables with disease activity in patients with clinically isolated syndrome and early multiple sclerosis (MS). Methods Study participants completed following psychometric instruments: Adult Attachment Scale (AAS), Temperament and Character Inventory (TCI-125), Hospital Anxiety and Depression Scale (HADS). Clinical data encompassed the expanded disability status scale (EDSS), annualized relapse rate, disease duration and therapy. Relapses and MRI data were recorded at regular outpatient visits. Results Study participants ( n =84), 38 with a clinically isolated syndrome suggestive of MS (CIS) and 46 with relapsing remitting MS (RRMS), were assessed with a low EDSS (median 2). No significant differences concerning personality-related variables were revealed by group comparisons between CIS and RRMS and within the RRMS subgroup based on clinical measures (EDSS/year; within RRMS subgroup: annualized relapse rate). However, a higher lesion load per years of disease duration within the RRMS subgroup was associated with higher values in the temperament trait harm avoidance ( p Conclusions Although harm avoidance may be related to subclinical disease activity in early RRMS adult attachment and temperament do not seem to contribute to differences between CIS and RRMS or clinical variability in early multiple sclerosis.

Summary Background Whether endovascular stroke treatment improves clinical outcomes is unclear because of the paucity of data from randomised placebo-controlled trials. We aimed to establish whether MRI can be used to identify patients who are most likely to benefit from endovascular reperfusion. Methods In this prospective cohort study we consecutively enrolled patients scheduled to have endovascular treatment within 12 h of onset of stroke at eight centres in the USA and one in Austria. Aided by an automated image analysis computer program, investigators interpreted a baseline MRI scan taken before treatment to establish whether the patient had an MRI profile (target mismatch) that suggested salvageable tissue was present. Reperfusion was assessed on an early follow-up MRI scan (within 12 h of the revascularisation procedure) and defined as a more than 50% reduction in the volume of the lesion from baseline on perfusion-weighted MRI. The primary outcome was favourable clinical response, defined as an improvement of 8 or more on the National Institutes of Health Stroke Scale between baseline and day 30 or a score of 0–1 at day 30. The secondary clinical endpoint was good functional outcome, defined as a modified Rankin scale score of 2 or less at day 90. Analyses were adjusted for imbalances in baseline predictors of outcome. Investigators assessing outcomes were masked to baseline data. Findings 138 patients were enrolled. 110 patients had catheter angiography and of these 104 had an MRI profile and 99 could be assessed for reperfusion. 46 of 78 (59%) patients with target mismatch and 12 of 21 (57%) patients without target mismatch had reperfusion after endovascular treatment. The adjusted odds ratio (OR) for favourable clinical response associated with reperfusion was 8·8 (95% CI 2·7–29·0) in the target mismatch group and 0·2 (0·0–1·6) in the no target mismatch group (p=0·003 for difference between ORs). Reperfusion was associated with increased good functional outcome at 90 days (OR 4·0, 95% CI 1·3–12·2) in the target mismatch group, but not in the no target mismatch group (1·9, 0·2–18·7). Interpretation Target mismatch patients who had early reperfusion after endovascular stroke treatment had more favourable clinical outcomes. No association between reperfusion and favourable outcomes was present in patients without target mismatch. Our data suggest that a randomised controlled trial of endovascular treatment for patients with the target mismatch profile is warranted. Funding National Institute for Neurological Disorders and Stroke.

Studies investigating reading and spelling difficulties heavily focused on the neural correlates of reading impairments, whereas spelling impairments have been largely neglected so far. Hence, the aim of the present study was to investigate brain structure and function of children with isolated spelling difficulties. Therefore, 31 children, aged ten to 15 years, were investigated by means of functional MRI and DTI. This study revealed that children with isolated spelling impairment exhibit a stronger right hemispheric activation compared to children with reading and spelling difficulties and controls, when engaged in an orthographic decision task, presumably reflecting a highly efficient serial grapheme-phoneme decoding compensation strategy. In addition, children with spelling impairment activated bilateral inferior and middle frontal gyri during processing correctly spelled words and misspelled words, whereas the other two groups showed bilateral activation only in the misspelled condition, suggesting that additional right frontal engagement could be related to generally higher task demand and effort. DTI analyses revealed stronger frontal white matter integrity (fractional anisotropy) in controls (compared to spelling and reading impaired children), whereas no structural differences between controls and spelling impaired children were observed.

The Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency which recently has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3). Although HIES is characterized by recurrent staphylococcal infections, the microbial invasion of the central nervous system (CNS) is definitively uncommon. We here report on Staphylococcus aureus meningitis and cerebral abscesses acquired in the community in a 31-year-old female patient with a de novo heterozygous mutation of STAT3 and a Dubowitz-like syndrome characterized by growth retardation, microcephaly and eczema. The patient presented with a relative paucity of clinical symptoms despite severe cerebrospinal fluid pathology and multiple cerebral abscesses. Antimicrobial as well as treatment with intravenous immunoglobulin was well tolerated and led to a slow recovery over a 6 months period. Our observation adds community acquired S. aureus meningitis to the list of life-threatening infections in STAT3-deficient HIES and should also raise awareness for the unusual clinical presentation of severe neuroinfection in this syndrome. Whether the association of HIES with Dubowitz-like syndrome was purely coincidental, possibly supportive of the CNS infection, or suggests a genetic overlap of these syndromes, awaits clarification.

Previous data suggest that Dickkopf-1 (Dkk-1), an inhibitor of the canonical/β-catenin cascade of the Wnt pathway, is upregulated in carotid atherosclerosis and acute myocardial ischemia. It is currently unclear if such upregulation also occurs in cerebral ischemia.We measured plasma levels of Dkk-1 in patients with acute ischemic stroke (n=57) within 24h from symptom onset, in patients with clinically stable cerebrovascular disease (n=29) and in healthy controls (n=29). Stroke severity on admission was determined by the National Institutes of Stroke Scale (NIHSS). The modified Rankin Scale (mRS) served to define outcome at day 90. Ischemic stroke subtype and cause was determined by the Oxfordshire Community Stroke Project (OCSP) criteria and the Causative Classification of Stroke System (CCS).Dkk-1 plasma levels were significantly higher in acute stroke patients (median 727.1 pg/ml) as compared to patients with stable cerebrovascular disease (median 534.2 pg/ml; p=0.017) or healthy controls (median 371.3 pg/ml; p0.001). The difference of Dkk-1 levels between patients with stable cerebrovascular disease and healthy controls was also significant (p=0.005). No significant differences in Dkk-1 plasma levels were found between different causes or subtypes of ischemic stroke. No correlation of Dkk-1 levels was found with stroke severity on admission and outcome at day 90.Our study provides for the first time evidence for a release of Dkk-1 into the circulation in patients with acute ischemic stroke and also in patients with clinically stable cerebrovascular disease.

Recognition and processing of emotional facial expression are crucial for social behavior and employ higher-order cognitive and visual working processes. In neuropsychiatric disorders, impaired emotion recognition most frequently concerned three specific emotions, i.e., anger, fear, and disgust. As incorrect processing of (neutral) facial stimuli per se might also underlie deficits in the recognition of emotional facial expressions, we aimed to assess all these aspects in one experiment. We therefore report here a functional magnetic resonance imaging (fMRI) paradigm for parallel assessment of the neural correlates of both the recognition of neutral faces and the three clinically most relevant emotions for future use in patients with neuropsychiatric disorders. FMRI analyses were expanded through comparisons of the emotional conditions with each other. The differential insights resulting from these two analyses strategies are compared and discussed. 30 healthy participants (21 F/9 M; age 36.3 ± 14.3, 17-66 years) underwent fMRI and behavioral testing for non-emotional and emotional face recognition. Recognition of neutral faces elicited activation in the fusiform gyri. Processing angry faces led to activation in left middle and superior frontal gyri and the anterior cingulate cortex. There was considerable heterogeneity regarding the fear versus neutral contrast, resulting in null effects for this contrast. Upon recognition of disgust, activation was noted in bilateral occipital, in the fronto-orbital cortex and in the insula. Analyzing contrasts between emotional conditions showed similar results (to those of contrasting with reference conditions) for separated emotional network patterns. We demonstrate here that our paradigm reproduces single aspects of separate previous studies across a cohort of healthy subjects, irrespective of age. Our approach might prove useful in future studies of patients with neurologic disorders with potential effect on emotion recognition.

With cognitive disorders increasingly common, clinicians urgently need faster and more accurate tools to classify such disorders and to noninvasively monitor therapeutic interventions. In this review, we provide information on MRI techniques that enable the study of the morphology, neuronal integrity, and metabolism of dementing illnesses. In addition, we explore the usefulness of such techniques as surrogate markers of these diseases.

There is an established role for intravenous immunoglobulin (IVIG) in the treatment of certain neurologic autoimmune disorders which affect the peripheral nervous system and a variety of immunomodulatory properties of IVIG have been proposed. This prompted an intense research into the efficacy of IVIG in central nervous system autoimmune disorders and until now several well-controlled clinical trials have been performed in different stages and phenotypes of multiple sclerosis (MS). The results were mixed. Speculations that IVIG might be able to reverse fixed neurologic deficits from MS could not be confirmed. Adding IVIG to the conventional treatment of MS relapses with high-dose IVMP also did not provide any additional benefits. Similarly, trials failed to establish a role for IVIG in the treatment of secondary or primary progressive MS. Most consistent beneficial results with a reduction of relapse rates and a slowing of disability have been obtained in relapsing-remitting MS including clinically isolated syndromes although a most recent study did not confirm a reduction of disease activity based on clinical and MRI findings. Trial results also suggest that IVIG might serve to suppress an increased recurrence of relapses immediately after delivery. Consequently, IVIG treatment may be considered as second line option for these indications although there is still uncertainty regarding the actual mechanism(s) of action and optimal dosage of this treatment.

More than half of all elderly have some degree of white matter lesions (WML) on MRI of the brain. Until recently, the rate of progression of WML was unknown. Recent work within several population based large scale studies was devoted to tackle this question, to identify factors related to WML progression and to establish a relationship with clinical variables and cognitive changes. There is converging evidence that at least a subset of WML demonstrates considerable progression over time. Increases in WML volume have been correlated with increased loss of brain volume and decline in cognitive and motor performance, indicating that progression of WML harbors clinical relevance. Correlative MRI-histopathologic studies and the clustering of vascular risk factors in subjects with progressive WML support a vascular aetiology of WML, particularly in "confluent" MRI phenotypes. Although specific rating scales have been proposed to detect WML progression, quantitative measurements appear superior given their objective and reproducible nature and regarding possibilities of statistical analyses. Measuring changes in the progression of WML may provide a valid surrogate marker in future clinical trials on cerebral small-vessel disease. Power calculations based on quantitative data of the Austrian Stroke Prevention Study (ASPS) suggest that such studies would be feasible.

Objective In view of the herpes simplex virus' neurotropism for the limbic system and the temporal lobe, little is known about potential negative effects of this necrotizing encephalitis on affective functioning and health-related quality of life (HRQoL) after recovery. We therefore set out to explore an association between herpes simplex virus encephalitis (HSE) and both depressive symptoms and HRQoL. Methods A structured telephone interview was conducted in 26 subjects (F/M=10/16; age at follow-up, 49.3±15.0 years; range, 29–80) at a mean time interval of 5.2±3.1 years (range, 1–11) after their initial diagnosis of HSE. WHO-5 Well-Being Index (WHO-5) was used as screening instrument for depression, and Short Form-12 was used as HRQoL instrument. We also determined the spatial extent of morphologic abnormalities on magnetic resonance imaging (MRI). Results Ten of the interviewees (38.5%) had a WHO-5 score below 13, which is considered indicative of a depressive disorder. Accordingly, concerning their HRQoL, patients felt more impaired by affective than by physical symptoms. MRI ratings and WHO-5 score were not correlated. Conclusions While this pilot study does not allow to establish a causal relationship with focal brain damage, findings suggest both a high frequency of depressive symptoms and a low quality of life with respect to mental health following HSE. These results should be confirmed by a prospective trial.

We performed a functional MRI (fMRI) study during the execution of the Paced Visual Serial Addition Task (PVSAT) in 9 patients with a clinically isolated syndrome suggestive of multiple sclerosis (CIS), 9 patients with clinically definite multiple sclerosis (CDMS), and 18 matched healthy control subjects. In controls, the PVSAT elicited a fronto-parietal network with cerebellar activation which we expected for this kind of working memory test and which indicates that this PVSAT version is an appropriate tool for measuring functional changes during a cognitive task. Although there were no significant differences in the actual test results of patients vs. controls, CDMS and CIS patients activated distinct cerebral networks in their attempt to solve the fMRI-PVSAT. Compared to CIS patients, CDMS patients showed increased hippocampal and parahippocampal activation, suggesting the need to additionally support their working memory. In contrast, compared to CDMS patients and healthy controls, CIS patients demonstrated stronger activation of the anterior cingulate cortex, which might indicate focused involvement of executive processes. On the PASAT (Paced Auditory Serial Addition Task) patients also performed similarly to controls but they showed decreased scores on most of the sub-tests of the Wechsler Memory Scale. Based on our observations using the fMRI-PVSAT, we hypothesize that distinct differences in cognitive processing occur with the evolution of MS and that, at these early stages of the disease, they cannot be detected with sufficient sensitivity using only the PASAT.

Item does not contain fulltext Abnormalities in T-cell-derived cytokine production are a well-known phenomenon in multiple sclerosis (MS). An association between disability and the production of interferon gamma has been demonstrated recently. The present study investigated associations between disability, cytokine production in stimulated blood lymphocytes and magnetic resonance imaging data in 37 patients with the secondary progressive course in the stable phase of the disease. Patients with high interleukin-10 (IL-10) production had significantly lower disability scores (p=0.009) and lower T2 lesion load (p=0.03). Interleukin-10 might not only play a role in the pathological process of multiple sclerosis but has an impact on disease outcome as well.

The rate and extent of progression of white matter hyperintensities (WMH) over time in elderly subjects is yet unclear. These abnormalities may represent an early form of subcortical vascular dementia. As to whether such changes could be used, as a surrogate marker for this subtype of vascular dementia remains to be determined. So far there exists only a very limited number of studies determining the rate, clinical predictors and cognitive consequences of WMH evolution. There is evidence that these changes do progress over time, however the results of the different studies cannot be compared due to methodological differences. The Austrian Stroke Prevention Study reported that 17.9% of normal individuals show progression over time. The only published quantitative data demonstrated an absolute increase of 1.1 cm3 over an observational period of 4 years in healthy subjects. Diastolic blood pressure, early confluent or confluent WMH at baseline and genetic variants in the angiotensinogen gene are so far the only known predictors of WMH progression. The Austrian Stroke Prevention Study did not find an association between the evolution of WMH and cognitive functioning but the statistical power of this analysis was small and the relationship needs to be further explored.

Objectives Multiple sclerosis (MS) is a chronic multifocal CNS disorder which can affect higher order cognitive processes. Whereas cognitive disturbances in MS are increasingly better characterised, emotional facial expression (EFE) has rarely been tested, despite its importance for adequate social behaviour. Patients and methods We tested 20 patients with a clinically isolated syndrome suggestive of MS (CIS) or MS and 23 healthy controls (HC) for the ability to differ between emotional facial stimuli, controlling for the influence of depressive mood (ADS-L). We screened for cognitive dysfunction using The Faces Symbol Test (FST). Results The patients demonstrated significant decreased reaction-times regarding emotion recognition tests compared to HC. However, the results also suggested worse cognitive abilities in the patients. Emotional and cognitive test results were correlated. Conclusion This exploratory pilot study suggests that emotion recognition deficits might be prevalent in MS. However, future studies will be needed to overcome the limitations of this study.

Magnetic resonance imaging (MRI) provides objective and detailed insights into morphologic changes of the central nervous system associated with multiple sclerosis (MS). Therefore, it also appears an ideal tool to investigate the possible impact of gender on MS course and severity. Only more recently some studies have specifically addressed this issue and we, therefore, reviewed the literature for investigations which analysed the impact of various factors including gender on MS-related morphologic changes and their evolution. Treatment trials were excluded and the available data refer mainly to relapsing MS with or without secondary progression. A few mostly smaller studies suggest a higher frequency of contrast-enhancing lesions in women. This was not seen in the analysis of a large and pooled dataset of untreated MS patients of the Sylvia Lawry Centre for MS Research. Other large cross-sectional and longitudinal studies found no effects of gender on T2 or T1 lesion burden or on brain atrophy. Findings between male and female MS patients also did not differ when including magnetisation transfer ratio and diffusion tensor imaging for morphologic information. Our review thus indicates no independent gender differences on brain MRI beyond demographic and clinical variables such as age, duration of disease and grade of disability.

The Roussy-Lévy syndrome (MIM #180800) was described in 1926 as a disorder presenting with pes cavus and tendon areflexia, distal limb weakness, tremor in the upper limbs, gait ataxia and distal sensory loss. We report a family with affected members in four generations, showing these clinical signs of Roussy-Lévy syndrome and a partial duplication at chromosome 17p11.2. This genetic defect is commonly found in patients with the hypertrophic form of the Charcot-Marie-Tooth syndrome. Our finding provides evidence against the Roussy-Lévy syndrome as a distinct entity but suggests a close relation with the Charcot-Marie-Tooth syndrome. What causes the additional features of gait ataxia and essential tremor needs further clarification.

Summary Background Multiple sclerosis is an autoimmune disorder characterised by the repeated occurrence of demyelinating lesions within the central nervous system. Uncontrolled studies and experimental evidence suggest beneficial effects of repeated administration of intravenous immunoglobulin (IVIg) by immunomodulating mechanisms and induction or remyelination. We aimed to investigate the efficacy of IVIg in a randomised double-blind multicentre study. Methods Patients with relapsing-remitting multiple sclerosis were randomly assigned a monthly dose of IVIg (0·15–0·2 g/kg bodyweight) or placebo. Duration of treatment was 2 years. The primary outcome measures were the effect of treatment on clinical disability—measured by the absolute change in Kurtzke's expanded disability status scale (EDSS) score—and the proportion of patients with improved, stable, or worse clinical disability (⩾ 1·0 grade on EDSS score). Findings Of the 243 patients screened, 150 met our eligibility criteria and were randomly assigned to IVIg or placebo. Before the start of treatment two patients in the placebo group dropped out, so there were 75 patients in the IVIg group and 73 in the placebo group. Intention-to-treat analysis showed that IVIg treatment had a beneficial effect on the course of clinical disability. The EDSS score decreased in the IVIg-treated patients and increased in the placebo group (−0·23 [95% CI −0·43 to −0·03] vs 0·12 [−0·13 to 0·37], p=0·008). In the IVIg group, the numbers of patients with improved, stable, or worse clinical disability were 23 (31%), 40 (53%), and 12 (16%) compared with ten (14%), 46 (63%), and 17 (23%) in the placebo group. Side-effects were reported in three (4%) IVIg-treated patients and in four (5%) placebo-group patients, but were not directly linked to study medication.

This supplement to the Journal of the Neurological Sciences contains the proceedings of the seventh International Symposium on Multiple Sclerosis, sponsored by Teva Pharmaceutical Industries Ltd and Sanofi-Aventis, entitled ‘Translating new insights into treatment optimisation in multiple sclerosis’, held in Vienna, Austria on 23rd 24th May, 2008. This event brought together 365 neurologists from 35 countries, thus providing a useful opportunity to exchange ideas at an international level. The symposium provided an in-depth review of the current understanding of disease progression as well as strategies for optimising treatment outcomes in clinical practice. In particular, four themes were explored, namely the clinical correlates of the mechanism of action of immunomodulatory treatments (IMTs), comparing efficacy and safety of IMTs, issues in clinical management, and second-line treatment strategies. The presentations during this symposium provoked much discussion and interest among participants and we are sure that they will also provide stimulating reading for readers of the Journal of the Neurological Sciences. The symposium opened with a keynote lecture on the history of multiple sclerosis, ‘The changing frame of the disease over the centuries’, by Professor T. Jock Murray (Halifax, Canada), in which he presented a broad sweep of how our understanding of multiple sclerosis has grown, since the earliest recognisable descriptions of the disease in the mediaeval period through the landmark work of Jean-Marie Charcot in Paris in the midnineteenth century, which permitted the disorder to be named and defined, through to the modern era when multiple sclerosis can be diagnosed and treatments are available that allow the progression of the disease to be modified to some extent. Multiple sclerosis was for a long period considered to be principally an inflammatory demyelinating disease in which axons are relatively spared. However, more recent findings suggest that axonal damage occurs early in the disease process and is responsible for the accumulation of irreversible disability. For this reason, current thinking on treatment encourages early intervention with IMTs in order to optimise the long-term clinical outcome. These ideas were reviewed by

Severe white matter hyperintensities (WMH) represent cerebral small vessel disease and predict functional decline in the elderly. We used fMRI to test if severe WMH impact on functional brain network organization even before clinical dysfunction. Thirty healthy right-handed/footed subjects (mean age, 67.8 ± 7.5 years) underwent clinical testing, structural MRI and fMRI at 3.0T involving repetitive right ankle and finger movements. Data were compared between individuals with absent or punctuate (n = 17) and early confluent or confluent (n = 13) WMH. Both groups did not differ in mobility or cognition data. On fMRI, subjects with severe WMH demonstrated excess activation in the pre-supplementary motor area (SMA), frontal, and occipital regions. Activation differences were noted with ankle movements only. Pre-SMA activation correlated with frontal WMH load for ankle but not finger movements. With simple ankle movements and no behavioral deficits, elderly subjects with severe WMH demonstrated pre-SMA activation, usually noted with complex tasks, as a function of frontal WMH load. This suggests compensatory activation related to disturbance of frontosubcortical circuits.