Michael Sailer

Differentiation of idiopathic Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and healthy controls using magnetization transfer imaging

The differentiation of multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) from idiopathic Parkinsons disease (IPD) is difficult. Magnetization transfer imaging (MTI), a measure that correlates with myelination and axonal density, was employed in this study in the attempt to distinguish between these disorders. Measurements were carried out in 15 patients with IPD, 12 patients with MSA, 10 patients with PSP, and in 20 aged-matched healthy control subjects. The main finding was a change in the magnetization transfer ratio in the globus pallidus, putamen, caudate nucleus, substantia nigra, and white matter in IPD, MSA, and PSP patients, matching the pathological features of the underlying disorder. Furthermore, stepwise linear discriminant analysis provided a good classification of the individual patients into the different disease groups. All IPD patients and control subjects were correctly separated from the MSA and PSP cohort, and all PSP patients and 11 of 12 MSA patients were correctly separated from the IPD and control cohort. There was also a fairly good discrimination of IPD patients from control subjects and of MSA from PSP patients. In conclusion, MTI revealed degenerative changes in patients with different parkinsonian syndromes matching the underlying pathological features of the different diseases, underlining the high potential of this method in distinguishing MSA and PSP from IPD.

Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study.

In patients with relapsing-remitting multiple sclerosis (MS), IVIG was shown to reduce the relapse rate and progression of disability. In patients with chronic progressive MS, a beneficial effect of IVIG was not documented in placebo controlled studies. This trial investigated the influence of IVIG in primary (PPMS) and secondary (SPMS) chronic progressive MS. Two-hundred and thirty-one patients stratified for PPMS (n = 34) and SPMS (n = 197) were randomly assigned to IVIG 0.4 g/kg per month or to placebo for 24 months. Primary endpoints were 1) the time to sustained progression of disease identified as worsening of the expanded disability status scale (EDSS) sustained for 3 months, and 2) the improvement of neurological functions defined by a patients best EDSS score. Secondary endpoints were the proportion of patients with sustained progression, the relapse rate, the assessment of fine motor skills, visual evoked potentials, contrast sensitivity, depression and quality of life. Analysis of the intention-to-treat (ITT) population of combined PPMS and SPMS patients showed that the mean time to sustained progression was 74 weeks in the IVIG compared with 62 weeks in the placebo group (P = 0.0406). When PPMS and SPMS patients were analysed separately, the time to sustained progression was also longer in the IVIG group, but the difference was not significant. There was no IVIG-mediated improvement in neurological functions. In the combined per protocol (PP) treated patients, IVIG treatment prolonged time to sustained progression by 13 weeks (P = 0.0396). PPMS patients, but not SPMS patients showed a slight favourable IVIG effect on the best EDSS score. In the combined ITT population there were less patients with sustained progression in the IVIG than in the placebo group (P = 0.028). The difference was significant in PPMS ( P = 0.016), but not in SPMS patients. In the combined PP population, there was a trend for a favorable IVIG effect on the rates of patients with sustained progression. In patients with PPMS, this IVIG effect reached significance (P = 0.036). Other secondary endpoints did not show significant differences between treatment groups. Eighteen patients with PPMS and 102 patients with SPMS withdrew from the study for various reasons. Treatment was generally well tolerated. It was concluded that monthly IVIG infusion could delay progression of disease in patients with PPMS, and that there was a trend in favour of IVIG treatment in patients with SPMS. Multiple Sclerosis 2007; 13: 1107—1117. http://msj.sagepub.com

Positron emission tomography and magnetic resonance imaging for cerebral involvement in patients with systemic lupus erythematosus

Abstract Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) remains difficult to diagnose, particularly since structural abnormalities may not be revealed by magnetic resonance imaging (MRI). Glucose utilisation was measured by positron emission tomography (PET) in 35 SLE patients to detect signs of CNS involvement. The patients were examined by a standardised neurological examination, a battery of tests to evaluate neuropsychological performance and MRI. Antineuronal antibodies were determined to investigate their putative role in CNS involvement in SLE. Twenty patients had distinct neurological (17) and/or psychiatric (3) symptoms. Ten patients had pronounced cognitive impairment. Neurological and cognitive deficits were thus found to be unrelated disorders in SLE. Global glucose utilisation of SLE patients did not differ significantly from that of normal controls, nor were differences found between SLE patients with or without neurological or cognitive abnormalities. On MRI of the brain, the number and size of white matter lesions correlated with the presence of neurological deficits but were unrelated to the severity of cognitive impairment. Within the normal range, lower global glucose utilisation tended towards lower values with increasing number and size of white matter lesions. Patients with lesions larger than 8 mm also showed distinctly increased IgG anticardiolipin antibody titres, whereas measuring antineuronal antibodies did not reveal any relation to the variables investigated. We conclude that the demonstration of CNS lesions by MRI can contribute confirmatory evidence for CNS involvement in SLE, but PET or the presence of antineuronal antibodies adds little if any information beyond that obtained by clinical examination, neuropsychological testing, and MRI.

Cognitive Impairment in Primary and Secondary Progressive Multiple Sclerosis

The aim of this study was to use neuropsychological data to characterize two subtypes of multiple sclerosis (MS) patients in a large patient sample. We studied patients with primary-progressive MS (PPMS) and secondary-progressive MS (SPMS). A group of 121 MS patients (36 PPMS, 85 SPMS) and 40 healthy controls were administered a brief battery of cognitive tests. Executive functioning, memory and attention were studied. Results demonstrate that PPMS patients exhibited slightly more impairment than patients with SPMS, although this difference is not significant (50% vs 37%). However, PPMS patients revealed a significantly poorer performance in verbal learning (p < 0.05) and in verbal fluency (p < 0.05). Whereas PPMS patients had significantly shorter disease durations (p < 0.05), there was no statistical difference in disability between both groups. We conclude from our study that cognitive deficits in progressive MS are frequent. Patients with PPMS tend to be more frequently and severely affected than SPMS patients. Our findings of high prevalence of cognitive involvement in PPMS have not been reported previously. We are grateful to the examiners Mrs. Kleinhubbert from Bochum, Mrs. Hallecker from Münster and Mrs. Deutsch-Schaab from Wiesbaden for their help in assessing the patients. Some of the patients were investigated in a study funded by NOVARTIS (principal investigator Dr. Pöhlau).

Classifications and treatment responses in chronic immune-mediated demyelinating polyneuropathy.

Background: Chronic immune-mediated demyelinating polyneuropathy (CIP) represents a heterogeneous pool of motor, sensory, sensorimotor, symmetric, or asymmetric syndromes. Objective: To evaluate published diagnostic classifications and characterize predictors of treatment response. Methods: One hundred two of 158 patients with a working diagnosis of CIP were included and clinically characterized because they had electrophysiologic and/or histologic evidence of demyelination. The biostatistical profile of patients with symmetric clinical manifestation was analyzed using three proposed classifications (American Academy of Neurology [AAN] criteria, modified AAN criteria, European Federation of Neurological Societies/Peripheral Nerve Society [EFNS/PNS] criteria). Treatment responses to IV immunoglobulins (IVIg) and their positive predictors were investigated. Results: Sensitivities (0.52 [AAN] vs 0.83 [modified AAN] vs 0.95 [EFNS/PNS]) and negative predictive values (0.68 vs 0.85 vs 0.92) differed markedly, whereas specificities (0.94 vs 0.90 vs 0.96) and positive predictive values (0.89 vs 0.89 vs 0.97) were similar. In CIP patients treated with IVIg, a positive response was found in 62 of 76 (82%). Patients with a monophasic or relapsing–remitting course or a more than twofold CSF protein increase had the highest probability to respond to IVIg, most evident when using the modified AAN criteria. Conclusions: The European Federation of Neurological Societies/Peripheral Nerve Society criteria for chronic inflammatory demyelinating polyneuropathy improve treatment of patients with chronic immune-mediated demyelinating polyneuropathy, particularly with respect to diagnostic issues. To predict IV immunoglobulin treatment response, the modified American Academy of Neurology criteria are the most valuable classification provided an increased CSF protein level.

Effect of creatine supplementation on metabolite levels in ALS motor cortices

Mitochondrial pathology is an early observation in motor neurons and skeletal muscle of patients with amyotrophic lateral sclerosis (ALS). To clarify the relevance of this finding, we determined the effects of a 1-month oral administration of creatine on (1)H NMR-visible metabolites in the motor cortices of 15 controls and 15 patients with sporadic ALS, most of whom had mitochondrial pathology in skeletal muscle. In the motor cortex of the ALS group the N-acetylaspartate (NAA)/creatine (Cr(t)) metabolite ratio was lower than in our control group, indicating NAA loss. Upon creatine supplementation we observed in the controls a decline in the NAA/Cr(t), NAA/choline (Cho), glutamate + glutamine (Glx)/Cr(t), and Glx/Cho metabolite ratios. In contrast, in the ALS patient group the NAA/Cr(t) and the NAA/Cho metabolite ratios remained unchanged, while the Glx/Cr(t) and Glx/Cho metabolite ratios decreased. These data are compatible with the interpretation that creatine supplementation causes an increase in the diminished NAA levels in ALS motor cortex as well as an increase of choline levels in both ALS and control motor cortices. Because NAA is synthesized by mitochondria in an energy-dependent manner and the NAA/Cho metabolite ratios in the ALS motor cortices were found to be correlated to the degree of mitochondrial pathology in ALS skeletal muscle, our results can be explained by a deficiency of enzymes of mitochondrial respiratory chain in the ALS motor cortex which might affect motor neuron survival.

Constraint-induced aphasia therapy following sub-acute stroke: a single-blind, randomised clinical trial of a modified therapy schedule

Background and purpose The trend towards a shorter stay in rehabilitation clinic has implications for future language therapy. Constraint-induced aphasia therapy (CIAT) is administered 3 h per day for a total of 30 h of treatment. It was evaluated for patients with chronic aphasia. In the present study we investigated the efficacy of a modified CIAT schedule and included patients with sub-acute stroke. We conducted a randomised, single-blind, parallel-group study. The results were compared to those of patients who received identically intensive treatment focusing on conventional aphasia therapy. Methods Fifty patients were treated with our modified version of CIAT and 50 received a standard aphasia therapy at the same intensity and duration. Inclusion criteria were clinical diagnosis of first-ever stroke, aphasia in the sub-acute stage and German speakers. Language function was evaluated using the Aachen Aphasia Test and the Communicative Activity Log directly before therapy onset, after the training period and at 8-week and 1-year follow-ups. Results Patients of both groups improved significantly in all sub-tests of the Aachen Aphasia Test Battery. The improvements remained stable over a 1-year follow-up period. Patients and relatives of both groups rated daily communication as significantly improved after therapy. Conclusions Both CIAT and conventional therapy performed with equal intensity are efficacious methods for patients with sub-acute aphasia. The modified CIAT schedule is practical in an everyday therapeutic setting. Our results indicate that a short-term intensive therapy schedule in the early aphasia stage leads to substantial improvements in language functions. Clinical Trial Registration Information Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01625676

The balance of pro-inflammatory and trophic factors in multiple sclerosis patients: effects of acute relapse and immunomodulatory treatment

Background: In multiple sclerosis inflammation is primarily injurious to the central nervous system, but its therapeutic suppression might inhibit repair-promoting factors. Objectives: We aimed at better describing the complexity of biological effects during an acute relapse and analysed the effects of intervention with high-dose i.v. glucocorticoids and immunomodulatory treatment with interferon-beta (IFNβ). Methods: We studied the intracellular expression levels of the pro-inflammatory mediators tumour necrosis factor alpha (TNFα) and inducible nitric oxide synthase (iNOS) together with the neurotrophins ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) in freshly isolated peripheral blood mononuclear cells of multiple sclerosis patients during an acute relapse, after intervention with i.v. methylprednisolone and at baseline, using a highly quantitative flow-cytometric approach. Results: We demonstrated the expression of CNTF in human leucocytes. We showed that CNTF levels differed in acutely relapsing multiple sclerosis patients compared with controls and increased after corticosteroid treatment. CNTF can counteract the toxicity of TNFα towards oligodendrocytes and we found TNFα increased during acute relapses. Following corticosteroids, neither TNFα nor iNOS expression was reduced. Levels of BDNF were not affected by glucocorticoids, but increased during IFNβ therapy. However, IFNβ also increased the expression of iNOS and major histocompatibility complex class I (MHC-I), underlining its immunomodulatory potential. Conclusions: Multiple sclerosis patients might benefit from reparative, and not solely from anti-inflammatory, effects of glucocorticoids. Interactive effects of glucocorticoid- and IFNβ-treatment need to be considered to improve neuroprotection and remyelination resulting from immunomodulatory treatment.

Histopathology and serial, multimodal magnetic resonance imaging in a multiple sclerosis variant.

Defining tools in magnetic resonance imaging (MRI) representing specific pathological processes is needed to understand the complex relationship between inflammation, myelin breakdown, axonal injury and clinical symptoms in multiple sclerosis (MS) and its variants. Here, we describe a case of histologically-defined MS, in which the radiological appearance of the lesion and clinical course support the diagnosis of Balos concentric sclerosis. Serial magnetization transfer, diffusion tensor imaging and 1H-magnetic resonance spectroscopy, from 14 days to 13 months after biopsy, allow the contextual interpretation of specific pathological changes. In our case, acute inflammation was sensitively traced by fractional anisotropy and increased lactate in spectroscopy. In contrast, magnetization transfer ratio and the apparent diffusion coefficient monitor the sequential loss of tissue in selected rings of the lesion. The delay from the peak of symptoms in a dramatic clinical course to the maximum tissue destruction indicated through MRI suggests that compromise of axonal function may be decisive for the acute clinical situation. This is the first report comparing 1Hmagnetic resonance spectroscopy, magnetization transfer and diffusion tensor imaging with histopathology in a patient with Balos concentric sclerosis. Multiple Sclerosis 2007; 13: 471-482. http://msj.sagepub.com

How reliable is the classification of cognitive impairment across different criteria in early and late stages of multiple sclerosis

BACKGROUND Prevalence rates of cognitive impairment (CI) in multiple sclerosis (MS) vary between 40% and 80%. Differences in classification criteria for CI may explain this variance. OBJECTIVE This study reviewed and compared classification criteria for CI in patients with early and late MS. METHODS The paper consists of two parts: a systematic review of published classification criteria and the presentation of new data. Criteria were reviewed in respect to percentage of abnormal parameters and cut-offs concerning standard deviations. Thereafter, criteria were applied to cognitive data of 25 patients with early MS (duration ≤ 2 y), 52 matched patients with late MS (≥ 12 y), and 75 matched controls. The test battery assessed alertness, divided attention, mental flexibility, verbal and visual learning, memory, and visuospatial abilities. RESULTS Seventy classification criteria were revealed and grouped into 20 distinct approaches that can be subdivided into three basic classification strategies. Most commonly, CI was defined as performing 1.5 SD or 2 SD below the normative mean in 18-30% of test parameters (n=42). Other criteria utilized cognitive domains (n=6), composite indices (n=8), or combinations of cut-offs and strategies. The stringency of the criteria was correlated with the prevalence rate of CI (r=-.43) and disease duration (r=.48). In the new data, a substantial effect of classification criteria was found with a prevalence rate ranging from 0 to 68% in early and 4 to 81% in late MS. Increased rates of CI in patients vs. controls were found following 18 out of 20 criteria in the sample of late MS. In early MS, an increased rate of CI was only found following a liberal 1.5 SD cut-off criterion. Inter-rater reliability between all criteria was moderate. However, between criteria of comparable stringency the inter-rater reliability was found to be strong. CONCLUSION Classification based on different published criteria is not fully comparable and criteria need to be better homogenized.