The concept of multimodal complex treatment combines treatment by physicians with intensive conservative treatment. The therapy duration is often 14-21 days. Investigations showing the benefit of this treatment for multiple sclerosis patients are currently missing. A total of 220 patient records were retrospectively analyzed with respect to the Barthel index, the expanded disability status scale (EDSS) score and early rehabilitation assessment (Fruhreha-Assessment). Subgroup analysis was used to examine variations in clinical severity, age and disease duration. The motor subscore was improved (p = 0.031) in the total sample. The subgroup analysis showed that in particular patients with an average disease duration (11-20 years) and age (41-60 years) showed the greatest benefits. In addition to the group of moderately affected patients the group of severely affected patients (Barthel index 36-64 and < 35) also showed an improvement in the Barthel index. Multimodal complex treatment for MS patients can lead to a significant improvement in motor abilities and reduction of the need of nursing. In particular intermediately affected patients showed the strongest improvement in contrast to the results of the current appraisal of the German Medical Review Board of the Health Insurance Funds (MDK).

Das Konzept der „multimodalen Komplexbehandlung“ kombiniert ärztliche Behandlung mit intensiver konservativer Therapie. Diese Therapieform wird oft über 14 bis 21 Tage durchgeführt. Untersuchungen, die den Nutzen dieser Therapieform bei Multipler Sklerose (MS) belegen, fehlten bislang.

Background: Clinical assessment of motor symptoms in Huntington's Disease (HD) is commonly performed using the Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) (HSG 1996). Clinical diagnosis of HD is based on the presence of characteristic motor symptoms in the UHDRS-TMS. Therefore results of clinical trials are limited by (1) possible subjective error of raters (inter-rater and intra-rater variability), (2) the limited sensitivity of the categorical rating scale (non-continuous measure), and (3) insensitivity in pre-manifest subjects (de Boo et al., 1998).

In addition to many other symptoms, Huntington’s Disease (HD) also causes an impairment of oculomotor functions. In particular, saccadic eye movements become progressively slower and more difficult to initiate; ultimately, patients are forced to recur to large head thrusts as means to initiate gaze shifts. We wondered whether, as a precursor of this condition, head movements would facilitate gaze shifts already in early stages of the disease. We studied horizontal head movements and eye–head coordination in 29 early stage HD patients (Ps) and 24 age matched controls (Cs). Subjects tracked random horizontal steps of visual or auditory targets while their heads were either stabilised (saccade amplitudes ≤40°) or free to move (amplitudes ≤160°). Subjects were to react either immediately (reactive mode), or wait until a go signal was sounded (delayed mode), or by antisaccades. Ps’ head velocity was found to depend on the age of disease onset in a similar way as their saccadic eye velocity does, being clearly reduced in early affected Ps, but increasing to normal levels in lately affected Ps. Yet, saccade and head velocity were only loosely correlated although both exhibited a negative correlation with the severity of Ps’ genetic condition (number of Ps’ CAG repeats). Eye–head coordination turned out to be identical in Ps and Cs except for quantitative differences caused by the lower saccade and head velocities of Ps. Specifically, the timing between head and eyes and the head contribution to gaze shifts were similar in both groups. Moreover, preventing head movements did not affect the saccade latency or accuracy of Ps. Although Ps made more small involuntary head movements in this condition than Cs, these movements were not instrumental in generating saccades since they occurred only late after saccade onset. Thus, the head manoeuvres of severely affected patients must be considered a late adaptive behaviour. Finally, the ability of both Ps and Cs to suppress immediate reactions in the delayed and antisaccade conditions diminished as target distance decreased, with failure rates in Ps being much larger than in Cs. Unlike eye and head velocity, these failure rates were not correlated with age and, by the same token, neither with the variations in head and eye velocity nor with the number of CAG repeats. Hence, the pattern of brain areas prominently affected by HD is likely to vary significantly among individuals.

Malaria is an infectious disease that is caused by a group of parasites of the genus Plasmodium. Characterizing the association between polymorphisms in the parasite genome and measured traits in an infected human host may provide insight into disease aetiology and ultimately inform new strategies for improved treatment and prevention. This, however, presents an analytic challenge since individuals are often multiply infected with a variable and unknown number of genetically diverse parasitic strains. In addition, data on the alignment of nucleotides on a single chromosome, which is commonly referred to as haplotypic phase, is not generally observed. An expectation-maximization algorithm for estimating and testing associations between haplotypes and quantitative traits has been described for diploid (human) populations. We extend this method to account for both the uncertainty in haplotypic phase and the variable and unknown number of infections in the malaria setting. Further extensions are described for the human immunodeficiency virus quasi-species setting. A simulation study is presented to characterize performance of the method. Application of this approach to data arising from a cross-sectional study of n=126 multiply infected children in Uganda reveals some interesting associations requiring further investigation.

Organized by the Huntington Study GroupTo be held on Saturday, 1 December 2007, in the Rooftop Ballroom at the Omni Parker House, Boston

Kognitive Defizite gehören zu den Kernsymptomen der Huntington-Krankheit (Morbus Huntington, MH). Sie lassen sich in einem frühen Stadium der Erkrankung nachweisen und sind bereits bei präsymptomatischen Mutationsträgern häufig vorhanden. In dieser Übersicht sollen Untersuchungen kognitiver Funktionen von MH-Patienten und von präsymptomatischen Mutationsträgern mittels funktionell bildgebender Verfahren dargestellt und diskutiert werden. Nuklearmedizinische und funktionell magnetresonanztomographische Untersuchungen belegen bei MH-Patienten eine Störung multipler kortikaler und subkortikaler Regionen und ergänzen damit die mittels konventioneller radiologischer Methoden nachweisbaren strukturellen Veränderungen. Bei präsymptomatischen Mutationsträgern kann frühzeitig ein funktionelles Defizit lateral präfrontaler und zingulärer Regionen aufgezeigt werden; eine Überaktivierung posteriorer Areale reflektiert möglicherweise einen kompensatorischen neuronalen Mechanismus vor dem Auftreten manifester kognitiver Defizite. Die Untersuchung präsymptomatischer Mutationsträger mithilfe funktionell bildgebender Verfahren könnte über die Identifizierung funktioneller Biomarker hinaus zur Bestimmung geeigneter klinischer Endpunkte beitragen. Die Bedeutung funktionell bildgebender Verfahren als Instrument zur Verlaufsuntersuchung kognitiver Defizite bei MH-Patienten muss indessen noch anhand entsprechender Studien an geeigneten Kollektiven evaluiert werden.

Background and purpose: Functional neuroimaging studies have suggested a dysfunction of prefrontal regions in clinically pre-symptomatic individuals with the Huntington's disease (HD) gene mutation (pre-HD) during cognitive processing. The objective of this study was to test the impact of cognitive demand on prefrontal connectivity in pre-HD individuals. Methods: Sixteen healthy controls and sixteen pre-HD subjects were studied using functional MRI and a verbal working memory task with increasing cognitive load. Load-dependent functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) was investigated by means of psychophysiological interactions. Results: In pre-HD subjects, aberrant functional connectivity of the left DLPFC was found at high working memory load levels only. Compared with healthy controls, pre-HD individuals exhibited lower connectivity strength in the left putamen, the right anterior cingulate and the left medial prefrontal cortex. Pre-HD individuals close to the onset of motor symptoms additionally exhibited lower connectivity strength in the right putamen and the left superior frontal cortex. The connectivity strength in the left putamen was associated with several clinical measures including CAG repeat length, Unified Huntington's Disease Rating Scale motor score and predicted years to manifest symptom onset. Conclusion: These findings suggest that early prefrontal connectivity abnormalities in pre-HD individuals are modulated by cognitive demand.

In den letzten Jahren konnte gezeigt werden, dass im frühen Krankheitsstadium der schubförmigen Multiplen Sklerose (MS) neben der entzündlichen Aktivität auch eine frühe axonale Degeneration für den Krankheitsprogress und irreversible Defizite verantwortlich ist. Es ist auch bekannt, dass die etablierten immunmodulatorischen Therapien diesen Prozess beeinflussen. Ziel der vorliegenden prospektiven Studie war, den degenerativen Prozess in der frühen Krankheitsphase der MS unter einer Therapie mit Glatirameracetat (GLAT) mittels der Hirnparenchymfraktion (BPF) zu bestimmen und diese mit klinischen und neuropsychologischen Parametern zu korrelieren.

Introduction:In the treatment of Parkinson's disease (PD), psychiatric complications are common. Depressive syndromes have a prevalence of up to 50%. Psychoses are rarely observed in untreated PD but are a well known phenomenon in dopaminergically treated PD patients. Known risk factors are higher age, microvascular changes, brain atrophy, cognitive impairment, and polymedication. Case reports have described psychoses under all today commonly used dopamine agonists (DA), but so far no systematic investigation concerning the potential of the different dopaminergic drugs to cause psychosis has been performed.

Clinical GeneticsVolume 70, Issue 1 p. 78-79 Cerebrospinal fluid levels of orexin-A are not a clinically useful biomarker for Huntington disease M Björkqvist, M Björkqvist Neuronal Survival Unit, Dept. of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden Unit of Molecular Metabolism, Dept. Experimental Medical Sciences, Lund University, Lund, Sweden These authors contributed equally to this workSearch for more papers by this authorÅ Petersén, Å Petersén Neuronal Survival Unit, Dept. of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden These authors contributed equally to this workSearch for more papers by this authorJ Nielsen, J Nielsen Dept. of Medical Genetics, University of Copenhagen, Copenhagen, DenmarkSearch for more papers by this authorD Ecker, D Ecker Dept. of Neurology, University of Ulm, Ulm, GermanySearch for more papers by this authorH Mulder, H Mulder Unit of Molecular Metabolism, Dept. Experimental Medical Sciences, Lund University, Lund, SwedenSearch for more papers by this authorMR Hayden, MR Hayden Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, Dept. of Medical Genetics, and the Brain Research Centre, University of British Columbia, Vancouver, BC, CanadaSearch for more papers by this authorB Landwehrmeyer, B Landwehrmeyer Dept. of Neurology, University of Ulm, Ulm, GermanySearch for more papers by this authorP Brundin, P Brundin Neuronal Survival Unit, Dept. of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, SwedenSearch for more papers by this authorBR Leavitt, Corresponding Author BR Leavitt Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, Dept. of Medical Genetics, and the Brain Research Centre, University of British Columbia, Vancouver, BC, Canada Blair R. Leavitt Department of Medical Genetics Center for Molecular Medicine and Therapeutics University of British Columbia 950 West 28th Ave Vancouver BC Canada V5Z 4H4 Tel.: +1 604 875 3801 Fax: +1 604 875 3840 e-mail: [email protected]Search for more papers by this author M Björkqvist, M Björkqvist Neuronal Survival Unit, Dept. of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden Unit of Molecular Metabolism, Dept. Experimental Medical Sciences, Lund University, Lund, Sweden These authors contributed equally to this workSearch for more papers by this authorÅ Petersén, Å Petersén Neuronal Survival Unit, Dept. of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden These authors contributed equally to this workSearch for more papers by this authorJ Nielsen, J Nielsen Dept. of Medical Genetics, University of Copenhagen, Copenhagen, DenmarkSearch for more papers by this authorD Ecker, D Ecker Dept. of Neurology, University of Ulm, Ulm, GermanySearch for more papers by this authorH Mulder, H Mulder Unit of Molecular Metabolism, Dept. Experimental Medical Sciences, Lund University, Lund, SwedenSearch for more papers by this authorMR Hayden, MR Hayden Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, Dept. of Medical Genetics, and the Brain Research Centre, University of British Columbia, Vancouver, BC, CanadaSearch for more papers by this authorB Landwehrmeyer, B Landwehrmeyer Dept. of Neurology, University of Ulm, Ulm, GermanySearch for more papers by this authorP Brundin, P Brundin Neuronal Survival Unit, Dept. of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, SwedenSearch for more papers by this authorBR Leavitt, Corresponding Author BR Leavitt Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, Dept. of Medical Genetics, and the Brain Research Centre, University of British Columbia, Vancouver, BC, Canada Blair R. Leavitt Department of Medical Genetics Center for Molecular Medicine and Therapeutics University of British Columbia 950 West 28th Ave Vancouver BC Canada V5Z 4H4 Tel.: +1 604 875 3801 Fax: +1 604 875 3840 e-mail: [email protected]Search for more papers by this author First published: 23 June 2006 https://doi.org/10.1111/j.1399-0004.2006.00636.xCitations: 27 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume70, Issue1July 2006Pages 78-79 RelatedInformation

Thirty patients with multiple sclerosis were randomized to 500 or 2,000 mg of methylprednisolone (MP) over 5 days. They were prospectively studied neuropsychologically before and at days 6 and 60 after onset of the therapy, using a double-blind study design. Patients showed selective deterioration of declarative memory retrieval at day 6, which was fully reversible at day 60. Although the sample size was small, these effects were independent of the administered MP dose.

The pattern of motor, behavioral and cognitive symptoms in Huntington's disease (HD) implicates dysfunction of basal-ganglia-thalamo-cortical circuits. This study explored if cognitive performance in HD is correlated with localized cerebral changes. Psychomotor functions were investigated by verbal fluency, Stroop color word and Digit Symbol tests in 44 HD patients and 22 controls. Three-dimensional magnetic resonance imaging (MRI) data were analyzed with regard to regional gray matter changes by use of the observer-independent whole-brain-based approach of voxel-based morphometry (VBM). Using statistical parametric mapping, the MRI data of the HD patients were analyzed in an ANCOVA including the individual results of the neuropsychological tests. Besides striatal areas, symmetrical regional atrophy of the thalamus was found to co-vary significantly with cognitive performance (P < 0.001, corrected for multiple comparisons). In particular, thalamic subnuclei projecting to prefrontal areas (dorsomedial subnucleus) and connected to the striatum (centromedian/parafascicular and ventrolateral nuclear complex) displayed volume loss, in agreement with neuropathological studies. These results suggest that thalamic degeneration contributes in an important way to the impairment of executive function in early HD. Patients who are impaired in executive tests display structural double lesions of the basal-ganglia-thalamo-cortical circuitry both at the striatal and at the thalamic level.

Die hereditäre hämorrhagische Teleangiektasie (HHT) ist eine autosomal-dominant vererbte Erkrankung des Gefäßbindegewebes. Pulmonale arteriovenöse und zerebral-vaskuläre Malformationen stellen Risikofaktoren für neurologische Komplikationen wie paradoxe Embolien und intrazerebrale Blutungen dar. Wir berichten von 2 Patientinnen, die an einer HHT mit pulmonalen arteriovenösen Malformationen erkrankt waren und paradox-embolische Insulte erlitten. Nach Coil-Embolisation der Fisteln kam es zu keinen weiteren zerebral-ischämischen Ereignissen. Bei ischämischen Insulten unklarer Ätiologie sollte an eine HHT als Ursache mit Behandlungsoption gedacht werden.

Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole. Methods. 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP’s were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an “intent-to-treat” (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion. Results. Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance. Conclusion. Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.