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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.

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.

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., (Copyright 2000 S. Karger AG, Basel)

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.

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.

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.

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.

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.

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.

Detailed neurological examinations and body sway measurements with a stable force measuring platform were carried out on 30 healthy adults between 21 and 63 years of age. The results were analyzed for sex- and age-associated changes with regard to three different sway components (total sway, anterio-posterior sway, lateral sway) and two different conditions (eyes open, eyes closed). Sex-associated differences were highly significant for all sway components in the oldest age group (51-65 years) in which men exhibited more spontaneous postural sway than women in the condition eyes open. With eyes closed these differences increased. Middle-aged men (36-50 years) also exhibited significantly more postural sway than women of the same age. In the condition eyes open especially total sway and anterioposterior sway were increased, whereas in the condition eyes closed total sway and lateral sway were predominantly higher in men than in women. In the youngest age group (21-35 years) no sex-related differences in postural sway were found. Age-associated differences were significant for anterioposterior sway (eyes open) in men, increasing continuously from the young to the middle-aged, and again from the middle-aged to the older age group. Anterioposterior sway in women, on the contrary, did not change with age. Age-associated differences in women were found for total sway (eyes open) and lateral sway (eyes closed). However, the highest values for total sway and lateral sway within the female group were obtained from young women in both conditions eyes open and eyes closed.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronal slices of rat brain were incubated in Krebs bicarbonate medium containing kainate (300 microM), or N-methyl-D-aspartate (500 microM). Degeneration of striatal neurons by both these toxins was apparent after 40 min incubation, and was accompanied by a 33% (kainate) and 21% (N-methyl-D-aspartate) reduction in striatal glutamine synthetase activity. Pre-incubation of the slices with 500 microM L-methionine sulfoximine, an inhibitor of glutamine synthetase, for 20 min prior to the exposure to either kainate or N-methyl-D-aspartate, again showed extensive degeneration of striatal neurons, and a supra-additive reduction in glutamine synthetase activity in the tissue. The activity of the neuronal marker enzyme, neuron-specific enolase, was also reduced by pre-incubation of the slices with L-methionine sulfoximine before the addition of kainate or N-methyl-D-aspartate, but to a much lesser extent than glutamine synthetase. The results are discussed in terms of a possible mechanism of interaction between either kainate or N-methyl-D-aspartate, and glial cell metabolism.

Forty-five patients with Wilson's disease (WD) were prospectively studied: 27 had neurological deficits, 12 hepatic signs, and 6 were asymptomatic. Kayser-Fleischer rings occurred in 23 of the neurological patients and in only 4 of the hepatic patients. Neurological features were extremely variable with respect to frequency and severity. Most frequent were dysdiadochokinesis (25 patients), dysarthria (23), bradykinesia (17), and posture tremor (14). Fifteen, mainly long-term treated patients, presented with rather discrete neurological abnormalities which predominantly consisted of dysarthria and various forms of tremor. Eight patients had a parkinsonian type of neurological WD associated with signs of an organic mood syndrome. Three patients were predominantly hyperkinetic, presenting with dystonic and choreatic movements. In 1 patient, ataxia was the predominant neurological feature. There was a clear-cut correlation between the severity of neurological impairment and the restriction in functional capacity. Nine patients were not able to engage in salaried employment or were retired. Psychiatric symptoms and behavioural disorders were common, varying from mild personality and psychological disturbances to severe psychiatric illness resembling psychotic disorders and major depressive syndromes. Significant mental deterioration was not found in the patients. Disturbances of mood were observed in 12 patients, all of whom had neurological abnormalities. There was a history of an attempted suicide in 7 patients, and a history of an organic delusional syndrome in 3.

Forty-one patients suffering subarachnoid hemorrhage (SAH) of unknown etiology were re-investigated at an average of 91 months after the bleed to determine functional capacity. Nineteen patients were performing at their previous level of work, five were employed part-time, and four could not work due to the SAH. Five patients showed a moderate disability in activities of daily living but were not dependent on help, one patient was severely disabled, and two had died. There was one rebleed. Early prognosis of an unfavorable outcome was possible on the basis of three clinical variables on admission: a history of hypertension, a Hunt and Hess grade of greater than II, and the presence of focal neurological deficits. In addition, the presence of an organic mental syndrome at discharge was identified as a predictive factor for reduced functional capacity later on. Other clinical variables in the acute stage, including sex, age, history of headache, interval between SAH and admission, impaired consciousness, and cognitive deficits, were not related to a limited functional level. Residual neurological deficits and the Glasgow Outcome Scale score on discharge were also not predictive of restrictions in global functions evaluated by means of the Karnofsky Performance Scale status at follow-up review.

Sixty-seven patients surviving spontaneous subarachnoid haemorrhage (SAH) have been followed up for 2-12 years (mean: 7 years) in order to determine prognostic factors concerning the long-term disability in familial and social functioning. A correlation was found between the severity of the neurological deficit at the time of admission and the degree of familial and social disability at the end of the observation period. In addition, the Barthel-Index on discharge was shown to be of prognostic value for readjustment for social--but not for familial--functioning. Other clinical variables in the acute stage, however, including source of bleeding, sex, age, interval between SAH and admission, level of consciousness, cognitive functions, as well as initial Hunt and Hess grading and Glasgow Coma Scale scoring, did not influence the long-term social prognosis. Furthermore, residual neurological signs, cognitive dysfunctions, and the Glasgow Outcome score on discharge were not related to the extent of social handicap in the long-term outcome. At the end of the observation period, significant correlations were found between the presence of persisting neurological and cognitive deficits but also disability in ADL functions and occupational capacity and the decline in familial and social functioning.

A total of 800 posturographic measurements--each characterized by four values (sway path, sway area, anteroposterior sway and lateral sway)--was carried out for this study. Eight different conditions (interfoot distances of 0, 4, 10 and 20 cm, each with eyes open and eyes closed) were compared by statistical means. All sway values were diminished by vision in small interfoot distances. At large interfoot distances, however, the presence of visual control resulted in an increase of lateral sway. Comparing the different foot positions, an increase of anteroposterior sway and a decrease of all other components were found at large interfoot distances no matter whether the eyes were open or closed.

Nine cases of different types of morphea and two of lichen sclerosus et atrophicus were investigated for the presence of neurologic symptoms. The Borrelia origin of morphea and lichen sclerosus et atrophicus was verified by the presence of antibodies against Borrelia burgdorferi and by the visualization of spirochetes on histologic sections by immunohistochemical methods. One patient had intrathecally synthesized IgG antibodies against B. burgdorferi that indicated intrathecal infection. A second patient had an elevated cell count and oligoclonal bands of unknown specificity in cerebrospinal fluid. In another patient a disturbance of the blood-brain barrier was detected. Seven patients had signs of peripheral neural involvement, mostly lesional dysesthesias. Our findings indicate frequent neural involvement in morphea and lichen sclerosus et atrophicus, suggesting the necessity of adequate antibiotic treatment in these diseases.

The course of leukemic disease in a male adolescent with meningeal leukemia is described. The bone marrow aspirates showed a conversion from an acute lymphatic leukemia to an eosinophilic leukemia. Four weeks after the peripheral shift of phenotype two different cell clones were detected in one CSF smear. While under ultrahigh dose araC therapy the patient died 3 months after conversion. Possible explanation for the shift of phenotype and the peculiar leptomeningeal infiltration are discussed.