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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.

Background Magnetic resonance imaging (MRI) in tick-borne encephalitis (TBE) is often performed for differential diagnosis, but only a few reports on the morphologic changes in TBE patients and their relation to the disease severity exist. Methods We retrospectively searched for all TBE patients who were admitted to the Departments of Neurology of the Medical University of Graz (Austria) and the Paracelsus Medical University of Salzburg (Austria) between 2003 and 2014. We recorded the clinical and demographic variables and rated overall disease severity as mild, moderate, severe or leading to death due to TBE. MRI scans were screened for morphologic abnormalities. Results Of an initial cohort of 88 patients with TBE, 45 patients with an available MRI of the brain were included in this study (median age 58.0 years, range: 18–80; men n = 28). Their median time spent in the hospital was 18 days (range: 4–174 days). 16 patients had a mild, 18 a moderate and 10 a severe disease course. One patient died due to TBE. TBE related brain abnormalities could be identified in 4 cases. They consisted of diffuse areas of T2–signal hyperintensity, which were located in the crura cerebri in three patients and in the right centrum semiovale in one patient. No contrast enhancement was observed in any of the lesions and their presence was not related to specific clinical findings or the severity of TBE. Conclusion MRI brain lesions in TBE are rare and do not correlate with the course of the disease. Diffuse areas of signal hyperintensity in the crura cerebri appear suggestive of TBE.

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.

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.

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.

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.

Subcortical vascular cognitive impairment is caused by lacunes and widespread ischemic white matter damage which closely resembles white matter abnormalities seen in multiple sclerosis. Recent evidence suggests that the progression rate of ischemic white matter lesions on MRI is very similar to that observed in multiple sclerosis. Consequently, it has been proposed to use MRI for monitoring disease activity not only in multiple sclerosis but also in vascular dementia trials. There is first evidence from magnetization transfer imaging studies that other than in MS normal appearing white matter is not affected in cerebral small vessel disease. This contrasts the hypothesis that ischemic white matter damage extends far beyond changes visible on conventional MR. The cognitive consequences of both diseases are strikingly similar which is at least partly caused by damage to frontal-subcortical circuits. Involvement of these common functional anatomical structures and their modulatory transmitter systems has now led to common interventional approaches such as the use of cholinesterase inhibitors.

Epidemiological studies provide strong evidence that susceptibility to multiple sclerosis (MS) is in part genetically determined. Likewise the heterogeneity in clinical manifestations, temporal course, severity, and in the pathological processes of MS are probably also influenced by our genes. Apolipoprotein E (apoE) polymorphism has been considered a candidate for impacting on MS because of its numerous functions related to brain tissue and evidence for an association with a variety of cerebral disorders, specifically Alzheimer's disease (AD). The apoE alleles epsilon2, epsilon3, and epsilon4 are known to impact differently on aspects such as neuronal growth and repair, neuroprotection and inflammation. After a review of the strong association of the apoE polymorphism with AD, we review the results on MS. These are far less homogenous but have gained support from morphologic and metabolic measures obtained with magnetic resonance imaging indicating a greater extent of brain destruction with the apoE epsilon4 allele. Evidence for a protective role of the epsilon2 allele in MS is weak. In view of the association with AD it is tempting to speculate that neuropsychologic functioning in MS might be even more strongly related to the apoE polymorphism and especially to the epsilon4 allele than other deficits, but few data on this issue are yet available. While part of the association of the apoE polymorphism with AD is supposed to be caused by apoE-isoform dependent effects on amyloid-beta deposition, no single pathogenetically relevant mechanism has yet been confirmed for MS. In summary we presently may assume only subtle effects of the apoE polymorphism on the course of MS. These effects are probably further modulated by other genes and need further investigation.

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

Microangiopathy-related cerebral damage (MARCD) represents a common incidental MRI observation in the elderly. The risk factors of such findings are widely unknown. We therefore performed MRI in 349 randomly selected volunteers (ages 50 to 70 years) without neuropsychiatric disease, and evaluated the association of MARCD with conventional and recently suggested cerebrovascular risk factors such as apolipoprotein E genotypes, plasma concentrations of essential antioxidants and anticardiolipin antibody titres. MARCD was defined as evidence of early confluent and confluent deep white matter hyperintensities and lacunes. It was present in 71 (20.3%) subjects. Individuals with MARCD were older than those without such findings (62.7 years vs 59.6 years; P=0.0001). They had a higher rate of arterial hypertension (45.1% vs 28.1%; P=0.006) and cardiac disease (50.7% vs 37.1%; P=0.04), higher systolic blood pressure readings at exam (144.4 mmHg vs 136.7 mmHg; P=0.004), and higher serum fibrinogen concentrations (327.1 mg/dl vs 292.5 mg/dl; P=0.001). Their levels of total cholesterol (217.6 mg/dl vs 231.2; P=0.009), apolipoprotein A-I (167.3 mg/dl vs 177.4 mg/dl, P=0.02), lycopene (0.17 micromol/l vs 0.24 micromol/l; P=0.003), retinol (1.91 micromol/l vs 2.10 micromol/l; P=0.02) and alpha-tocopherol (27.55 micromol/l vs 31.14 micromol/l; P=0.001) were significantly lower. Forward stepwise regression analysis created a model of independent predictors of MARCD with age entering first (odds ratio 2.01/10 years), fibrinogen second (odds ratio 2.45/100 mg/dl), alpha-tocopherol third (odds ratio 0.55/10 micromol/l), and arterial hypertension fourth (odds ratio 1.96). The association of MARCD with various treatable clinical conditions may have preventive implications.

To further elucidate the relation of cerebral magnetic resonance signal hyperintensities to Alzheimer's disease (AD) we performed a case-control comparison between 30 consecutive patients with probable AD (age range 49-76, mean 65 years) and 60 asymptomatic volunteers matched for age, sex, and major cerebrovascular risk factors. We used a 1.5T magnet and determined the extent of morphologic abnormalities both by visual grading and measurement. AD patients showed comparable grades of deep/subcortical white matter hyperintensities (WMH) and a similar extent of the total WMH area as controls (3.3 cm2 +/- 8.8 vs. 2.0 cm2 +/- 4.6). They had significantly more often a "halo' of periventricular hyperintensity (PVH) (p0.0005) and an increased mean PVH thickness (3.0 mm +/- 1.9 vs. 1.3 mm +/- 1.2; p0.001). This PVH thickness correlated significantly with measures of ventricular enlargement. While univariate logistic regression also suggested a significant association of PVH thickness with a diagnosis of AD this association was lost against atrophy measures in a multivariate analysis. Our results confirm a significantly greater extent of PVH in AD patients than controls even when matched for cerebrovascular risk factors. However, this abnormality was not independently related to the disease but rather appears to be an epiphenomenon of brain atrophy.

Kearns Sayre Syndrome (KSS) belongs to the group of so called ‘mitochondrial encephalopathies’. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) may have the potential to noninvasively detect and monitor disease specific cerebral involvement, as we wish to demonstrate in a patient whom we have followed for 3.5 years. At first presentation with incomplete external ophthalmoplegia, ptosis, pigmentary retinopathy and impaired hearing MRI demonstrated ill defined areas of symmetric T2-prolongation in the dorsal parts of the mesencephalon, the pons and in both cerebellar hemispheres. While the patients clinical symptoms deteriorated, including the onset of dysphagia, signal abnormalities spread downwards into the medulla oblongata involving the glossopharyngeal nuclei and supratentorially into the white matter. Proton MRS performed with the PRESS sequence (TR/TE 1500/136 ms) in the area of white matter damage showed a doublet at 1.33 ppm, which is characteristic for the presence of lactate. Our findings suggest MRI abnormalities to increase in parallel with neurologic progression of KSS and confirm the utility of 1H-MRS in supporting mitochondrial respiratory chain insufficiency as the underlying cause of parenchymal alterations.