[Show abstract][Hide abstract] ABSTRACT: Background
Survival in amyotrophic lateral sclerosis varies considerably. About one third of the patients die within 12 months after first diagnosis. The early recognition of fast progression is essential for patients and neurologists to weigh up invasive therapeutic interventions. In a prospective, population-based cohort of ALS patients in Rhineland-Palatinate, Germany, we identified significant prognostic factors at time of diagnosis that allow prediction of early death within first 12 months.Methods
Incident cases, diagnosed between October 2009 and September 2012 were enrolled and followed up at regular intervals of 3 to 6 months. Univariate analysis utilized the Log-Rank Test to identify association between candidate demographic and disease variables and one-year mortality. In a second step we investigated a multiple logistic regression model for the optimal prediction of one-year mortality rate.ResultsIn the cohort of 176 ALS patients (mean age 66.2 years; follow-up 100%) one-year mortality rate from diagnosis was 34.1%. Multivariate analysis revealed that age over 75 years, interval between symptom onset and diagnosis below 7 months, decline of body weight before diagnosis exceeding 2 BMI units and Functional Rating Score below 31 points were independent factors predicting early death.Conclusions
Probability of early death within 12 months from diagnosis is predicted by advanced age, short interval between symptom onset and first diagnosis, rapid decline of body weight before diagnosis and advanced functional impairment.Trial registrationClinicalTrials.gov (NCT01955369, registered September 28, 2013).
[Show abstract][Hide abstract] ABSTRACT: Hintergrund: Die amyotrophe Lateralsklerose (ALS) ist eine neurodegenerative Systemerkrankung, die zu einem progredienten Untergang peripherer und zentraler Motoneurone führt, mit einer Überlebensdauer von wenigen Monaten bis zu mehreren Jahren. Einige wenige populationsbasierte prospektive Studien haben prädiktive Faktoren für die Überlebensdauer identifiziert, wobei die Bedeutung einiger Faktoren umstritten ist.
Welche Faktoren sind für die Prognose der Überlebensdauer von ALS-Patienten von Bedeutung?
Methoden: Das ALS-Register Rheinland-Pfalz hat zwischen 10/2009 und 09/2012 200 Inzidente Patienten mit einer ALS-Erstdiagnose erfasst, und in sechsmonatigen Abständen nachuntersucht. Um eine möglichst vollständige Erfassung zu gewährleisten wurden mehrere überlappende Methoden benutzt. Pseudonymisierte Todesbescheinigungen der Gesundheitsämter dienten zur Erhebung/Kontrolle der Todesfälle.
Die Zielgröße war das Patientenüberleben nach Erstdiagnose (ED). Für die multivariate Modellbildung wurde die Überlebensdaueranalyse nach Cox eingesetzt, unter stufenweise Elimination nicht signifikanter Prädiktorvariablen.
Ergebnisse: 176 ALS-Patienten (96 Männer, 80 Frauen) wurden in diese Studie eingeschlossen. Das mittlere Erkrankungsalter betrug 66,2 Jahre (SD 10,3; Median 68). Die Dauer der Nachbeobachtung war mindestens 12 Monate (Median: 16.5; Maximum: 48 Monate). Das mittlere Intervall zwischen Symptombeginn und Erstdiagnose (ISE) lag bei 12,5 Monaten (SD 12,8; Median 9). Die Einjahresmortalitätsrate ab Erstdiagnose lag bei 34,1% (60 Patienten) . Die mediane Überlebenszeit dieser 60 Patienten betrug ab Erstdiagnose 19 Monate, ab Erstsymptomatik i 29 Monate. Bei der multivariaten Modellbildung blieben das Alter (Hazard Ratio (HR) von 1,6 66- 75 Jahre; 3,4 bei >75 Jahre), log10(ISE) (HR 0.053), El-Escorial-Kriterien (HR 3,0 bei sicherer ALS), BMI-Veränderung in den letzten 6 Monaten vor ED als signifikant prädiktive Variable übrig. Für Geschlecht, bulbären Symptombeginn, Alkoholkonsum, Rauchen, FRS bei ED und alleine lebend konnte kein signifikanter Einfluss auf die Überlebenswahrscheinlichkeit ab ED festgestellt werden.
Schlussfolgerungen: Die Daten unserer Studie weisen darauf hin, dass die Überlebensprognose bei ALS-Patienten bereits zum Zeitpunkt der Erstdiagnose möglich ist, aus Patientenalter, ISE, dem Grad der neurologischen Beeinträchtigung (El-Escorial-Kriterien) und der BMI-Veränderung.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The clinical spectrum of amyotrophic lateral sclerosis (ALS) is characterized by a considerable variation. Different phenotypes have been described by previous studies. We assessed clinical variability and prognostic relevance of these phenotypes in a prospective, population-based cohort of ALS patients in Rhineland-Palatinate, Germany.
Incident ALS cases, diagnosed between October 2009 and September 2012, were prospectively enrolled and classified according to established ALS phenotype classification (bulbar, classic, flail arm, flail leg, pyramidal, respiratory). Survival probability was described using Kaplan-Meier method. Moreover, the influence of an additional frontotemporal dementia (FTD) was analysed.
Phenotypes of all 200 patients were determined. Bulbar and classic phenotypes accounted for 75% of all cases. Deterioration of functional impairment during disease progression was lowest in flail leg and pyramidal variants, and most pronounced in bulbar and classic phenotypes. A poor survival prognosis was observed for bulbar, classic or respiratory phenotypes. Patients with an additional FTD showed an even worse outcome.
Results suggest that ALS is a heterogeneous disease, as ALS phenotypes differ in disease progression and survival time. Patients classified as suffering from bulbar, classic and respiratory ALS, as well as those with an additional FTD, show a marked reduction of survival time.
Journal of the Neurological Sciences 07/2014; 345(1-2). DOI:10.1016/j.jns.2014.07.033 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is a lack of prospective and population based epidemiological data on amyotrophic lateral sclerosis in Germany to date. The ALS registry Rhineland-Palatinate was established to investigate the incidence, course and phenotypic variety of ALS in this south-west German state of about 4 million inhabitants. During the period 2010-2011, consecutive incident patients with amyotrophic lateral sclerosis according to the revised El Escorial criteria were included and followed up using multiple overlapping sources of case ascertainment. One hundred and forty-six patients were enrolled. The annual crude incidence for amyotrophic lateral sclerosis in Rhineland-Palatinate was 1.8/100,000 person-years (95% CI 1.6-2.2). Male to female ratio was 1.1:1. Incidence increased with age reaching a peak in the 70-74 years age group and declined thereafter. Late-onset ALS (≥ 75 years) was found in 14.4% of patients. About 32% of patients presented with bulbar onset. In conclusion, incidence rate of amyotrophic lateral sclerosis in Rhineland-Palatinate is within the range of other prospective population based registers in Europe and North America. Gender ratio is nearly balanced.
[Show abstract][Hide abstract] ABSTRACT: Increases in CSF dopamine in HIV patients are due to the dopamine transporter 10/10-repeat allele which is more frequent in HIV-infected individuals Abstract Dysfunction of dopaminergic neurotransmis-sion has been implicated in HIV infection. We showed previously increased dopamine (DA) levels in CSF of therapy-nave HIV patients and an inverse correlation between CSF DA and CD4 counts in the periphery, sug-gesting adverse effects of high levels of DA on HIV infection. In the current study including a total of 167 HIV-positive and negative donors from Germany and South Africa (SA), we investigated the mechanistic background for the increase of CSF DA in HIV individuals. Interest-ingly, we found that the DAT 10/10-repeat allele is present more frequently within HIV individuals than in uninfected subjects. Logistic regression analysis adjusted for gender and ethnicity showed an odds ratio for HIV infection in DAT 10/10 allele carriers of 3.93 (95 % CI 1.72–8.96; p = 0.001, Fishers exact test). 42.6 % HIV-infected patients harbored the DAT 10/10 allele compared to only 10.5 % uninfected DAT 10/10 carriers in SA (odds ratio 6.31), whereas 68.1 versus 40.9 %, respectively, in Ger-many (odds ratio 3.08). Subjects homozygous for the 10-repeat allele had higher amounts of CSF DA and reduced DAT mRNA expression but similar disease severity compared with those carrying other DAT geno-types. These intriguing and novel findings show the mutual interaction between DA and HIV, suggesting caution in the interpretation of CNS DA alterations in HIV infection solely as a secondary phenomenon to the virus and open the door for larger studies investigating consequences of the DAT functional polymorphism on HIV epidemiology and progression of disease.
[Show abstract][Hide abstract] ABSTRACT: Studies about recovery from cerebellar stroke are rare. The present study assessed motor deficits in the acute phase after isolated cerebellar stroke focusing on postural impairment and gait ataxia and outlines the role of lesion site on motor outcome, the course of recovery and the effect of treadmill training. 23 patients with acute and isolated cerebellar infarction participated. Deficits were quantified by ataxia scores and dynamic posturography in the acute phase and in a follow up after 2 weeks and 3 months. MRI data were obtained to correlate lesion site with motor performance. Half of the patients that gave informed consent and walked independently underwent a 2-week treadmill training with increasing velocity. In the acute phase patients showed a mild to severe ataxia with a worse performance in patients with infarction of the superior in comparison to the posterior inferior cerebellar artery. However, after 3 months differences between vascular territories were no longer significant. MRI data showed that patients with larger infarct volumes had a significantly more severe ataxia. In patients with ataxia of stance, gait and lower limbs lesions were more common in cerebellar lobules IV to VI. After 3 months a mild ataxia in lower limbs and gait, especially in gait speed persisted. Because postural impairment had fully recovered, remaining gait ataxia was likely related to incoordination of lower limbs. Treadmill training did not show significant effects. Future studies are needed to investigate whether intensive coordinative training is of benefit in patients with cerebellar stroke.
[Show abstract][Hide abstract] ABSTRACT: Objective In Assessment of OraL Laquinimod in PrEventing ProGRession in Multiple SclerOsis (ALLEGRO), a phase III study in relapsing-remitting multiple sclerosis (RRMS), oral laquinimod slowed disability and brain atrophy progression, suggesting laquinimod may reduce tissue damage in MS. MRI techniques sensitive to the most destructive aspects of the disease were used to further investigate laquinimod's potential effects on inflammation and neurodegeneration.
Methods 1106 RRMS patients were randomised 1:1 to receive once-daily oral laquinimod (0.6 mg) or placebo for 24 months. White matter (WM), grey matter (GM) and thalamic fractions were derived at months 0, 12 and 24. Also assessed were evolution of gadolinium-enhancing and/or new T2 lesions into permanent black holes (PBH); magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT), WM, GM and T2 lesions; and N-acetylaspartate/creatine (NAA/Cr) levels in WM.
Results Compared with placebo, laquinimod-treated patients showed lower rates of WM at months 12 and 24 (p=0.004 and p=0.035) and GM (p=0.004) atrophy at month 12 and a trend for less GM atrophy at month 24 (p=0.078). Laquinimod also slowed thalamic atrophy at month 12 (p=0.005) and month 24 (p=0.003) and reduced the number of PBH at 12 and 24 months evolving from active lesions (all p<0.05). By month 24, MTR decreased significantly in NABT (p=0.015), WM (p=0.011) and GM (p=0.034) in placebo-treated patients, but not in laquinimod-treated patients. WM NAA/Cr tended to increase with laquinimod and decrease with placebo at 24 months (p=0.179).
Conclusions Oral laquinimod may reduce (at least in the initial phase of treatment) some of the more destructive pathological processes in RRMS patients.
Trial registration The ALLEGRO trial identifier number with clinicaltrials.gov is NCT00509145.
Journal of neurology, neurosurgery, and psychiatry 09/2013; 85(8). DOI:10.1136/jnnp-2013-306132 · 6.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fragestellung: Die vorliegende Studie untersuchte in einem dreiarmigen Design, ob Amphotericin B plus Flucytosin oder Amphotericin B plus Fluconazol der Monotherapie mit Amphotericin B überlegen ist.Hintergrund: Die Kryptokokken-Meningitis ist weltweit mit mehr als einer Million Fälle und 625.000 Toten pro Jahr eine der häufigsten und unangenehmsten Pilzinfektionen des Gehirns . In Deutschland sind dabei am häufigsten Patienten mit HIV-Erkrankung sowie Migranten aus afrikanischen Staaten betroffen. In der Therapie verblieb zum einen unklar, ob die Kombinationstherapie Amphotericin B plus Flucytosin besser wirksam ist als die Monotherapie mit Amphotericin B. Zudem ist Flucytosin nicht in allen Teilen der Welt problemlos erhältlich, sodass Fluconazol eine billigere und besser erhältlichere Therapie bereits in der Induktionstherapie darstellen könnte.Patienten und Methodik: Insgesamt wurden 299 Patienten mit klinisch und serologisch bestätigter akuter Kryptokokken-Meningitis in die Stu ...
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury remains one of the leading causes of residual neurological and neuropsychological deficits in every age group independent from socioeconomic status. Posterior fossa trauma affects structures within the posterior fossa, that is, brainstem and cerebellum. It consists of intra-axial lesions such as contusions, hematoma or diffuse axonal injury, and extra-axial lesions such as epidural and subdural hematoma as well as subarachnoid hemorrhage. Imaging should guide surgical and conservative treatment. CT imaging is the method of choice since it is easier to conduct than MRI and readily available. However, in some cases, MRI is necessary to detect subtle lesions within the brainstem and to visualize long-term complications such as olivary pseudohypertrophy or superficial siderosis of the CNS. In spite of advances in intensive care management, especially control of raised intracranial pressure, and neurosurgical methods, mortality of posterior fossa trauma remains high and a high proportion of surviving patients exhibit substantial neurological deficits.
Handbook of the Cerebellum and Cerebellar Disorders, 01/2013: pages 2055-2078; , ISBN: 978-94-007-1332-1
[Show abstract][Hide abstract] ABSTRACT: HIV-associated dementia and its precursors are frequently observed complications of HIV infection, even in the presence of combination antiretroviral treatment (cART). The development, surveillance and treatment of this condition are still not completely understood. Cytokines, as immunological transmitters, may be one key to gaining a deeper understanding of the disease. A total of 33 HIV-positive male patients were evaluated by neuropsychological testing, lumbar and venous puncture, neuroimaging and neurological examination. The cytokine content in the CSF (cerebrospinal fluid) was examined by a solid-phase protein array. The Digit-Symbol Test, contraction time analysis, Rey-Osterrieth Figure and Grooved-Pegboard Test showed inferior results in the presence of an inflammatory CSF environment, whereas neuroprotective or anti-inflammatory conditions were correlated to better results in contraction time analysis. Higher CSF levels of cytokines were independently correlated with the duration of HIV infection. The study showed a correlation of cytokine levels in the CSF of HIV patients with test results of their neuropsychological functioning. The effect was pronounced with regard to the more complex executive tasks. Determining CSF cytokine levels may be a useful supplement to the assessment of HIV patients and contribute helpful information to predict neurocognitive performance. Therapeutic strategies to ameliorate a negative impact of an altered cytokine milieu may aid in slowing the evolution of neurocognitive dysfunction.
Journal of NeuroVirology 04/2012; 18(3):157-61. DOI:10.1007/s13365-012-0091-4 · 2.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1.
We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage.
At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001).
Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).
New England Journal of Medicine 03/2012; 366(15):1404-13. DOI:10.1056/NEJMoa1200933 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
Two proof-of-concept clinical trials have provided evidence that laquinimod reduces disease activity in patients with relapsing-remitting multiple sclerosis.
We conducted a randomized, double-blind, phase 3 study at 139 sites in 24 countries. A total of 1106 patients with relapsing-remitting multiple sclerosis were randomly assigned in a 1:1 ratio to receive oral laquinimod at a dose of 0.6 mg once daily or placebo for 24 months. The primary end point was the annualized relapse rate during the 24-month period. Secondary end points included confirmed disability progression (defined as an increase in the score on the Expanded Disability Status Scale that was sustained for at least 3 months) and the cumulative number of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted magnetic resonance imaging.
Treatment with laquinimod as compared with placebo was associated with a modest reduction in the mean (±SE) annualized relapse rate (0.30±0.02 vs. 0.39±0.03, P=0.002) and with a reduction in the risk of confirmed disability progression (11.1% vs. 15.7%; hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; P=0.01). The mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted images were lower for patients receiving laquinimod than for those receiving placebo (1.33±0.14 vs. 2.12±0.22 and 5.03±0.08 vs. 7.14±0.07, respectively; P<0.001 for both comparisons). Transient elevations in alanine aminotransferase levels to greater than three times the upper limit of the normal range were observed in 24 patients receiving laquinimod (5%) and 8 receiving placebo (2%).
In this phase 3 study, oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing-remitting multiple sclerosis. (Funded by Teva Pharmaceutical Industries; ClinicalTrials.gov number, NCT00509145.).
Oral laquinimod for multiple sclerosis. [N Engl J Med. 2012]
New and old: notable drug developments for clinical practice. [J Neurol. 2012]
New England Journal of Medicine 01/2012; 366(11):1000-1009. DOI:10.1056/NEJMoa1104318. · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this cross-sectional study we used magnetic resonance imaging (MRI)-based voxel based morphometry (VBM) in a sample of HIV positive patients to detect structural gray and white matter changes. Forty-eight HIV positive subjects with (n = 28) or without (n = 20) cognitive deficits (mean age 48.5 ± 9.6 years) and 48 age- and sex-matched HIV negative controls underwent MRI for VBM analyses. Clinical testing in HIV patients included the HIV dementia scale (HDS), Unified Parkinson's Disease Rating Scale (UPDRS) and the grooved pegboard test. Comparing controls with HIV positive patients with cognitive dysfunction (n = 28) VBM showed gray matter decrease in the anterior cingulate and temporal cortices along with white matter reduction in the midbrain region. These changes were more prominent with increasing cognitive decline, when assigning HIV patients to three cognitive groups (not impaired, mildly impaired, overtly impaired) based on performance in the HIV dementia scale. Regression analysis including all HIV positive patients with available data revealed that prefrontal gray matter atrophy in HIV was associated with longer disease duration (n = 48), while motor dysfunction (n = 48) was associated with basal ganglia gray matter atrophy. Lower CD4 cell count (n = 47) correlated with decrease of occipital gray matter. Our results provide evidence for atrophy of nigro-striatal and fronto-striatal circuits in HIV. This pattern of atrophy is consistent with motor dysfunction and dysexecutive syndrome found in HIV patients with HIV-associated neurocognitive disorder.
Journal of Neurology 06/2011; 258(6):1066-75. DOI:10.1007/s00415-010-5883-y · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to examine if the most frequent cognitive disorders after cortical damage with a well-known cerebral lateralization, namely aphasia, neglect and extinction, are present in an unselected series of continuously admitted patients with acute cerebellar stroke. Twenty-two adults with acute cerebellar stroke were compared with 22 age- and education-matched healthy control subjects. High-resolution magnetic resonance images showed infarctions of the left cerebellar hemisphere in 12 and of the right hemisphere in ten patients. Standard aphasia tests revealed no statistically significant difference comparing patients with right- and left-sided ischemia and controls, whereas patients with left-sided ischemia showed mild deficits in a verb generation task. Neglect and extinction tasks revealed no significant differences between groups. Our findings support previous observations in the literature that cerebellar patients frequently perform within the normal range in standard neuropsychological tests. This does not exclude, however, that abnormalities may be present in more sophisticated testing of language and visuospatial functions.
The Cerebellum 12/2010; 9(4):556-66. DOI:10.1007/s12311-010-0197-2 · 2.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The relevance of the sensory system in the pathophysiology of cervical dystonia (CD) has been discussed since the description of sensory tricks associated with this disorder. Our objective was to locate changes in somatosensory processing of patients with CD responding in a passive sensory task of body regions that are not affected by dystonic symptoms. We used functional magnetic resonance imaging (fMRI) in 17 patients with CD and 17 healthy controls performing a strictly passive 30-degree forearm movement task with the left arm. TSUI and TWSTRS rating scales were used for clinical assessment. All patients were treated with botulinum neurotoxin type A (BoNT-A; Dysport®). Patients with CD showed BOLD-signal increase in the contralateral primary and secondary sensory cortex, the cingulate cortex and cerebellum bilaterally compared to healthy controls. We found a strong positive correlation of this activation with BoNT-A dosage in the supplementary motor area (SMA) and a negative correlation with the TWSTRS in that same region. The observed sensory overactivation suggests a general disinhibition of the somatosensory system in CD as it was not limited to the motor-system or the direct neuronal representation of the affected dystonic musculature alone.
Movement Disorders 11/2010; 25(15):2627-33. DOI:10.1002/mds.23321 · 5.68 Impact Factor