Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Factors influencing quality of life in multiple sclerosis patients: disability, depressive mood, fatigue and sleep quality.

OBJECTIVES: In a series of 504 patients with multiple sclerosis (MS), quality of life (QOL) and its main clinical and demographic determinants were assessed in comparison with healthy individuals. MATERIALS AND METHODS: A postal questionnaire with self-completed measures of disability (Expanded Disability Status Scale, EDSS), QOL (Quality of Life Index, QLI), depressive mood (Self-rating Depression Scale, SDS), fatigue severity (Fatigue Severity Scale, FSS) and sleep quality (Pittsburgh Sleep Quality Index, PSQI) was sent to this sample of MS patients. RESULTS: Most patients were severely disabled; almost half were mildly to severely depressed, suffering from reduced sleep quality and/or fatigue. The multiple sclerosis patients had significantly lower QLI scores than healthy controls. EDSS and SDS scores were found to be predictors of global QLI score. Regarding the different QLI domains, mean SDS scores remained predictive for all QLI items, while mean EDSS, PSQI and FSS scores were only predictive for physical domains. CONCLUSION: Our study clearly demonstrates that depressive mood is the main factor influencing QOL. The disability status, fatigue and reduced sleep quality have an impact mainly on physical domains of life quality.

Genetic variants in the tumor necrosis factor receptor II gene in patients with multiple sclerosis.

Common genetic variants have been shown to influence disease susceptibility, disease course, or both in multiple sclerosis (MS). Several studies have suggested a role for tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of MS. Recently, it has been reported that the TNF receptor (TNFR) II plays an essential role in the pathology and progression of experimental autoimmune encephalomyelitis, an animal model of MS. To investigate whether TNFR II polymorphisms influence susceptibility and/or clinical progression of MS, genomic DNA of 321 samples of the Austrian Genetics in MS study group and DNA of 174 platelet donors, who served as healthy controls, were genotyped for five polymorphic sites in the TNFR II gene: exon 6 nucleotide (nt) 676*T-->G, exon 6 nt 783*G-->A (both are associated with non-conserved amino acid substitution), exon 10 nt 1663*G-->A, exon 10 nt 1668*T-->G, and exon 10 nt 1690*T-->C (all of which are located in the 3' non-coding region of the gene). We found a significant association between exon 10 nt 1668*T-->G polymorphism and susceptibility to MS. The other investigated nucleotide substitutions were not associated with susceptibility to or clinical parameters in MS.

Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis.

OBJECTIVE: The apolipoprotein E (APOE) polymorphism is known to impact on various neurologic disorders and has differential effects on the immune system and on CNS repair. Previous findings concerning a possible modulation of the clinical course of MS have been inconsistent, however. METHODS: In a cross-sectional study, the authors investigated 374 patients with clinically definite MS and a disease duration of at least 3 years and related their clinical and demographic findings to the allelic polymorphism of the APOE gene. The genotype distribution of patients with MS was compared with a cohort of 389 asymptomatic, randomly selected elderly volunteers. RESULTS: The authors found no significant differences in the distribution of genotypes between patients with MS and controls. However, patients with MS with the epsilon4 allele (n = 85) had a significantly higher progression index of disability (0.46 +/- 0.4 versus 0.33 +/- 0.26; p < 0.004) and a worse ranked MS severity score (5.1 +/- 1.9 versus 5.7 +/- 1.7; p = 0.05) than their non-epsilon4 counterparts, despite significantly more frequent long-term immunotherapy in epsilon4 carriers (74% versus 58%; p < 0.007). The annual relapse rate in epsilon4 carriers (0.87 +/- 0.56) was significantly higher than in patients with MS without an epsilon4 allele (0.71 +/- 0.47; p = 0.03). CONCLUSIONS: These results suggest no effect of the APOE genotype on susceptibility to MS, but indicate an association of the APOE epsilon4 allele with a more severe course of the disease.

Electrophysiological, neuropsychological and clinical findings in multiple sclerosis patients receiving interferon beta-1b: a 1-year follow-up.

We assessed serial event-related potentials (ERPs) as well as neuropsychological and clinical test findings in a group of multiple sclerosis (MS) patients (n = 14) treated with interferon beta-1b (INF-beta-1b) compared to normal controls (n = 14). All investigations were done within 1 week before INF-beta-1b therapy was started and 12 months later. An auditory oddball paradigm was employed. No significant differences in the N100, P200, N200 or P300 latencies between patients and control group were found, but 3 out of 14 MS patients developed abnormal P300 latencies (more than 2 standard errors from the mean) after 1 year of INF-beta-1b therapy. This was not reflected by the respective neurological impairment as assessed by the Expanded Disability Status Scale score. ERPs might be a useful tool in clinical studies in order to evaluate drug effects on cognition, but for a final statement, the analysis of ERPs in a larger group of patients is required.

Apolipoprotein E polymorphism: survival and neurological outcome after cardiopulmonary resuscitation.

BACKGROUND AND PURPOSE: The apolipoprotein E 3/3 (apoE 3/3) genotype is associated with a reduced risk of developing Alzheimer's disease and with a favorable neurological outcome after traumatic head injury. In vitro studies suggest that the most common genotype, apoE 3/3, may be involved in neuroprotective and neuroregenerative mechanisms. The aim of this study was to determine whether the apoE 3/3 genotype has an impact on survival and neurological outcome after cardiopulmonary resuscitation. METHODS: Eighty patients with cardiac arrest were investigated prospectively for their apoE genotype. Epidemiological data were assessed according to recommended guidelines. Patients were divided into 2 groups, ie, with the apoE 3/3 genotype present or absent, and tested for differences in survival and neurological outcome. Further statistical analysis with respect to survival and neurological outcome was performed by using a stepwise logistic regression analysis. RESULTS: Patients with the apoE 3/3 genotype had a significantly higher survival rate (64% versus 33%, P:=0.007) and more often a favorable neurological outcome (55% versus 27%, P:=0. 013) compared with patients with other apoE genotypes. The apoE 3/3 genotype was shown to be a substantial predictive factor for a favorable neurological outcome (odds ratio 3.2) and was, apart from other essential factors, predictive for survival (odds ratio 4.4) after cardiopulmonary resuscitation. CONCLUSIONS: These data give evidence that patients with the apoE 3/3 genotype have a better chance of recovery after cardiopulmonary resuscitation than do patients with apoE genotypes other than 3/3.

The impact of apolipoprotein E genotypes on age at onset of symptoms and phenotypic expression in Wilson's disease.

Wilson's disease is a disorder of biliary copper excretion that may result in severe neurological symptoms and advanced liver disease. The wide variation of phenotypic disease expression cannot be fully explained by the different mutations of the Wilson disease gene. In neurological disorders, such as Alzheimer's disease, temporal lobe epilepsy and cerebral trauma, the presence of the apolipoprotein E (ApoE) allele epsilon4 is associated with an increased vulnerability of the brain to the effects of the disease, whereas the presence of the ApoE genotype epsilon3/3 appears to provide moderate neuroprotection. We examined whether this hypothesis holds true for the development of neurological symptoms in patients with Wilson's disease. The ApoE genotype and the H1069Q mutation (the most common in Wilson's disease) status were determined by polymerase chain reaction-based mutation assays in 121 well-characterized, symptomatic index patients with Wilson's disease. An investigation profile was established in which the patients were grouped according to the clinical symptoms at presentation, the ApoE genotypes and the status of the H1069Q mutation. Fifty-nine per cent of the 121 patients had the allele combination ApoE epsilon3/3 (21% ApoE epsilon3/4, 19% ApoE epsilon3/2, 1% ApoE epsilon4/2). The distribution of ApoE genotypes did not deviate from known distributions in healthy European subjects. Within the group of 40 H1069Q-homozygous patients, the onset of symptoms was significantly delayed in patients with the ApoE epsilon3/3 genotype (25 +/- 6 years at presentation) compared with patients with the ApoE epsilon3/4 genotype (20 +/- 3 years at presentation). In this study, the ApoE genotype was established as an important factor delaying the onset of neurological and hepatic symptoms, but not modifying phenotypic disease expression in a homogeneous group of patients with Wilson's disease (all H1069Q-homozygotes, similar genetic background). The presence of ApoE epsilon3/3 attenuates clinical manifestations in Wilson's disease by mechanisms which might involve the antioxidant and membrane-stabilizing properties of the ApoE 3 protein.

Vaccinations and steroids in MS: effects on disease progression and mood.

OBJECTIVE: To investigate the effects of vaccinations and steroids on disease progression and mood in patients with multiple sclerosis (MS). MATERIAL AND METHODS: Twenty-three patients with clinically definite MS were questioned with respect to vaccination history and the cumulative dose of steroids given during their life-time. EDSS scores and MRI scans of the brain were obtained and used to quantify clinical and MRI disease progression. Mood was assessed by using a self-estimated adjective mood scale. RESULTS: The number of vaccinations showed no effect on disease progression or mood. High cumulative steroid doses were associated with rapid MRI disease progression and the number of supratentorial MRI lesions. The absence of band-like MRI lesions was correlated with rapid clinical and MRI disease progression. Self-estimated mood tended to be worse in patients with chronic-progressive MS compared to those with relapsing-remitting MS. CONCLUSION: Neither clinical nor MRI-documented disease progression nor mood are influenced by the total number of vaccinations whereas high cumulative steroid doses and the absence of band-like MRI lesions indicate rapidly progressive MS. Self-estimated mood tends to be worse in patients with chronic-progressive MS compared to patients with relapsing-remitting MS.

[Urgent diagnostic steps in acute manifestation of intraspinal processes]. / Dringliche diagnostische Schritte bei akuter Manifestation von intraspinalen Prozessen.

Immediate diagnostic clarification is required in patients who develop acute or subacute symptoms suggestive of an intraspinal lesion. In case of symptoms indicating a monoradicular lesion a spinal CT investigation is mostly sufficient. Since polyradicular syndromes are often due to inflammation, examination of the cerebrospinal fluid is the most important diagnostic measure. However, in case of symptoms suggestive of intramedullary lesions, spinal MRT is by far the most effective diagnostic procedure. In patients with symptoms suggestive of a lesion of the cauda equina spinal CT is sufficient in most cases as a first measure, particularly if the lesion can be precisely localized by clinical examination. The decision as to which diagnostic method should be performed first is relevant mainly because of the limited availability of MRT examinations within the daily clinical routine. MRT should thus be used selectively in patients with lesions that cannot be identified by alternative diagnostic methods.

Assessment of neurotoxicity and "neuroprotection".

Coronal brain slices allow the study of neurotoxicity and "neuroprotection" under conditions where the differentiation-state and interrelationships of the neurones and glial cells are closer to those occurring in the intact tissue than is the case for co-cultured cell systems. The involvement of glial cells in the excitotoxicity of kainate and the potentiation of this toxicity by inhibition of glutamine synthase can be demonstrated. Longer-term toxicity of kainate may also be compounded by depletion of glutathione levels resulting from inhibition of gamma-glutamylcysteine synthase. The involvement of nitric oxide formation in the toxicity of N-methyl-D-aspartate can also be shown. The neurotoxicity of 1-methyl-4-phenylpyridinium can be readily demonstrated in coronal slice preparations. Taurine affords protection against this neurotoxicity. The possible mechanisms of these effects are considered in terms of the cyclic interrelationships between the different events which can lead to cell death.

Spinal cord lesions in patients with multiple sclerosis: comparison of MR pulse sequences.

PURPOSE: To compare T2-weighted conventional spin-echo (CSE), fast spin-echo (FSE), shorttau inversion recovery (STIR) FSE, and fluid-attenuated inversion recovery (FLAIR) FSE sequences in the assessment of cervical multiple sclerosis plaques. METHODS: Twenty patients with clinically confirmed multiple sclerosis and signs of cervical cord involvement were examined on a 1.5-T MR system. Sagittal images of T2-weighted and proton density-weighted CSE sequences, T2-weighted FSE sequences with two different sets of sequence parameters, STIR-FSE sequences, and FLAIR-FSE sequences were compared by two independent observers. In addition, contrast-to-noise measurements were obtained. RESULTS: Spinal multiple sclerosis plaques were seen best on STIR-FSE images, which yielded the highest lesion contrast. Among the T2-weighted sequences, the FSE technique provided better image quality than did the CSE technique, but lesion visibility was improved only with a repetition time/echo time of 2500/90; parameters of 3000/150 provided poor lesion contrast but the best myelographic effect and overall image quality. CSE images were degraded by prominent image noise; FLAIR-FSE images showed poor lesion contrast and strong cerebrospinal fluid pulsation artifacts. CONCLUSIONS: The STIR-FSE sequence is the best choice for assessment of spinal multiple sclerosis plaques. For T2-weighted FSE sequences, shorter echo times are advantageous for spinal cord imaging, long echo times are superior for extramedullary and extradural disease. FLAIR-FSE sequences do not contribute much to spinal imaging for multiple sclerosis detection.

Dopamine D2 receptor binding is reduced in Wilson's disease: correlation of neurological deficits with striatal 123I-iodobenzamide binding.

To visualise and quantify dopamine D2 receptor binding in the corpus striatum of patients with neurological Wilson's disease (WD) 123I-Iodobenzamide (IBZM) binding was measured using single photon emission computer tomography (SPECT). Ratios of striatal to frontal countrates were calculated in 8 patients and in 21 healthy control subjects. We found reduced IBZM binding ratios in all patients with WD in comparison to those in controls (1.48 +/- 0.13 vs. 1.73 +/- 0.09). The reduction in IBZM binding was correlated with the overall severity of neurological deficits and the severity of dysarthria (correlation coefficients -0.86 [p < 0.01] and -0.79 [p < 0.01], respectively). When patients of three different subgroups of neurological WD were compared no differences in IBZM binding were found. We conclude that assessing basal ganglia function in vivo using IBZM-SPECT is a valuable diagnostic tool in WD.

MR of cerebral Whipple disease.

A case of cerebral Whipple disease is reported. MR findings of the brain are discussed in relation to neuropathologic lesions reported previously. Repeated MR investigations may serve as a valuable tool to evaluate long-term efficacy of treatment in cerebral Whipple disease.

Alteration in the glial cell metabolism of glutamate by kainate and N-methyl-D-aspartate.

Incubation of coronal slices of rat brain with neurotoxic concentrations of kainate (300 microM) and N-methyl-D-aspartate (NMDA; 500 microM) for 40 min reduced the activity of the glial enzyme, glutamine synthetase, by 33% and 21%, respectively. The immunoreactivity of the neuronal enzyme, gamma gamma-enolase (neuron-specific enolase), was also decreased, but to a lesser extent than glutamine synthetase. Pre-incubation of the slices with L-methionine-S-sulphoximine (500 microM), an irreversible inhibitor of both glutamine synthetase and gamma-glutamylcysteine synthetase, before addition of either kainate or NMDA produced a supra-additive reduction in the activity of the enzyme in both cases. Neither kainate nor NMDA directly inhibited the activity of glutamine synthetase, but kainate did inhibit gamma-glutamylcysteine synthetase, a rate-limiting enzyme of the gamma-glutamyl cycle, which is responsible for maintaining glutathione levels within cells. Pre-incubation of the slices with L-NG-nitroarginine, a competitive inhibitor of nitric oxide synthase, effectively prevented the NMDA-induced reduction in glutamine synthetase and neuron specific enolase, but did not diminish the kainate-induced decrease in the activity of either enzyme. These results provide evidence that NMDA, as well as kainate, indirectly affects the activity of glutamine synthetase in brain slices, yet does so by a different mechanism from kainate. The results are discussed in terms of the possible mode of action of each toxin in inhibiting the glial cell metabolism of glutamate.

Posturographic measurement of body sway in survivors of severe closed head injury.

Postural imbalance was measured in 39 survivors of severe closed head injury 7 to 66 months after head injury using a posturographic platform. The results were compared with those derived from age-matched healthy control subjects. Severe postural imbalance, particularly in an anteroposterior direction, was found in 16 patients, whereas 9 patients showed moderate imbalance and 14 patients showed normal results in the posturographic investigation. Low initial Glasgow Coma Scale scores and deep parenchymal brain lesions demonstrated by magnetic resonance imaging were shown to be significant indicators of subsequent severe postural imbalance. The duration of posttraumatic amnesia, the localization and size of cortical contusions and subcortical white matter lesions, on the contrary, were not associated with postural imbalance in the long-term outcome.

Wilson's disease: evidence of subgroups derived from clinical findings and brain lesions.

Using exploratory factor analysis, we prospectively investigated neuropsychiatric symptoms and structural brain lesions of 47 patients with proven Wilson's disease and identified three subgroups. The first subgroup clinically exhibited bradykinesia, rigidity, cognitive impairment, and an organic mood syndrome and by MRI showed a dilatation of the third ventricle. The second subgroup was characterized by ataxia, tremor, reduced functional capacity, and focal thalamic lesions. The third subgroup showed dyskinesia, dysarthria, an organic personality syndrome, and focal lesions in the putamen and in the pallidum.

Reduction of striatal N-methyl-D-aspartate toxicity by inhibition of nitric oxide synthase.

Coronal slices of rat brain were incubated for 40 min in 300 microM kainate (KA) or 500 microM N-methyl-D-aspartate (NMDA). Histological examination showed neuronal degeneration accompanied by significant losses in the activity of neuron-specific enolase (NSE; EC 4.2.1.11) (-23% KA; -26% NMDA). The activity of the glial enzyme glutamine synthetase (GS; EC 6.3.1.2) was also reduced (-32% KA; -27% NMDA). Pre-incubation with 100 microM L-NG-nitroarginine (L-N-ARG), an inhibitor of nitric oxide (NO) synthase (EC 1.14.23.-), for 20 min attenuated the toxicity of toxicity of NMDA, but not KA. NSE levels after successive incubation in L-N-ARG and NMDA were 95% of controls incubated in Krebs bicarbonate medium only (GS activity 89% of controls). In contrast, pre-incubation with L-N-ARG prior to the addition of KA resulted in neuronal degeneration and significant reductions in NSE levels and GS activities. These observations suggest that the unrestricted function of NO synthase is significant in mediating NMDA neurotoxicity whereas KA toxicity is associated with alternative mechanisms not linked to NO production.

[Guidelines for drug treatment of multiple sclerosis]. / Richtlinien für die medikamentöse Behandlung der Multiplen Sklerose.

Strategies proposed for the treatment of multiple sclerosis are numerous and sometimes contradictory. This review summarizes the most recent studies on the treatment of multiple sclerosis. Possibilities of influencing progression of the disease and the degree of disability suffered by patients are discussed. The treatment of acute relapses with high-dose intravenous glucocorticoids is now widely accepted because it has been shown that the duration of the relapse is reduced. Interval therapy between relapses and treatment of the chronic progressive variant of multiple sclerosis are still under debate. Immunosuppression, in particular with azathioprine, appears to have a positive effect on the long-term outcome. Whether other regimens, e.g., treatment with recombinant lymphokines, have a therapeutic effect, is difficult to assess at present since these substances have either never been tested in controlled double blind studies or the results of these studies are not yet available.

Different risk factor profiles in young and elderly stroke patients with special reference to cardiac disorders.

The risk factors of ischemic cerebrovascular disorders in 77 young patients (< or = 40 years) were compared to those in 138 older patients (> 40 years). The risk factor profile of patients with juvenile stroke was considerably different from that of older patients. Migrainous headache and mitral valve prolapse occurred more frequently in the younger age group, whereas hypertension, diabetes mellitus, high levels of cholesterol and triglycerides were found more often in older patients with stroke. 65% of the women under the age of 40 took oral contraceptives which compares to the baseline community value of 28% of women in childbearing age in this country. Cardiac disorders such as atrial fibrillation, left ventricular hypertrophy, coronary heart disease including a history of myocardial infarction, as well as mitral valve disease were demonstrated more often in the group of elderly patients. 7 out of 77 younger patients (9.1%), and 59 out of 138 older patients (42.8%) were considered to belong to a group with "high cardiac risk for stroke". The results of this study indicate that electrocardiographic screening is of prime importance for detecting cardiac risk factors. However, echocardiographic examination often yields additional diagnostic information, particularly in younger patients. The conflicting opinions concerning the relevance of certain risk factors for ischemic stroke could partly be explained by the fact that these risk factors are distributed unevenly depending on age.