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Toxocariasis is a worldwide-occurring parasitic infection leading to tissue damage in various organs due to wandering Toxocara larvae (visceral larva migrans). More than 40 cases of CNS involvement in children and immunocompetent adults have been documented in detail to date. Here, we present evidence of eosinophilic meningomyelitis in an adult without known risk factors and with positive Toxocara antibody response in CSF, but not in blood. Toxocariasis has to remain among the differential diagnosis in patients with eosinophilic CNS infection even if serological tests in blood are negative. Adult cases seem to be more frequent than previously thought (about 60%).

In this single-center retrospective study, 155 consecutive patients with leptomeningeal metastasis (LM) were analyzed for the prognostic role of patient- and therapy-related variables. Ten percent of the patients received radiotherapy alone, 32% had chemotherapy alone, 31% received radiochemotherapy, 17% had supportive therapy only, and 10% were not evaluable for therapy. Chemotherapy was systemic (17%), combined systemic and intrathecal (10%), or intrathecal only (35%). Clinical improvement was noted in 41% of the patients. Overall median survival time (MST) was 4.8 months. Survival varied considerably depending on the type of primary tumor in this largest published cohort of LM patients. Univariate Cox regression analysis revealed that age >60 and elevated cerebrospinal fluid (CSF) albumin or lactate levels were therapy-independent predictors of poor survival in the entire cohort as well as in the subgroup of patients with systemic primary tumors (n=105). The assessment of three therapy-independent parameters allows to group LM patients into groups of low, intermediate, and high risk of poor survival. Moreover, the application of systemic chemotherapy was a positive prognostic factor in patients with subarachnoid lesions detected by neuroimaging (RR 1.94, p=0.001) or with extra-CNS tumor deposits (RR 1.52, p=0.05). The results of this study suggest that systemic chemotherapy alone or in combination with other therapeutic modalities may improve outcome in patients with subarachnoid tumor cell deposits detectable by neuroimaging.

The migratory behaviour of malignant gliomas relies on the interaction of integrins with extracellular matrix (ECM) components. Transforming growth factor-beta(1) (TGF-beta(1)) potently stimulates glioma cell motility whereas TGF-beta(2) is known for its immunosuppressive properties. Here, we show that both TGF-beta(1) and TGF-beta(2) promote migration of glioma cells. In parallel, TGF-beta(1) and TGF-beta(2) induce alpha(V) and beta(3) intergrin mRNA expression and enhance cell surface expression of alpha(V)beta(3) integrin. TGF-beta-mediated promotion of migration is abrogated by echistatin, a Arg-Gly-Asp (RGD) peptide antagonist of alpha(V)beta(3) integrin, and by a neutralizing anti-alpha(V)beta(3) integrin antibody. Taken together, we report a novel mechanism by which TGF-beta modulates cell ECM interactions and promotes glioma cell motility., (Copyright 2000 Academic Press.)

Glioblastoma multiforme is a lethal neoplasm refractory to radiochemotherapy. Although glioma cells undergo apoptosis when exposed to the death ligand, CD95 (Fas/APO-1) ligand, the therapeutic use of CD95L is considered impossible because of lethal side effects. Here, we report that the locoregional application of Apo2 ligand (Apo2L) exerts strong antitumor activity on preestablished intracranially growing human U87MG glioma xenografts in athymic mice. Two repetitive intratumoral injections of 2 microg Apo2L resulted in long-term survival of mice (>100 days), whereas the median survival of mock-treated mice was 36 days. The assessment of tumor volumes at 21 and 35 days after inoculation showed complete eradication of glioma xenografts in Apo2L-treated mice. Histology and TUNEL assay confirmed the induction of apoptosis by Apo2L in glioma cells in vivo. Importantly, the intracerebral injection of Apo2L does not result in acute or delayed neurotoxicity. We propose that a phase 1 trial of intralesional Apo2L therapy for human glioblastoma multiforme is warranted., (Copyright 1999 Academic Press.)

Changes of the second suppressive period (ES2) of the exteroceptive suppression of the temporalis muscle activity are found in patients with chronic tension-type headache (TTH) and are suggested to reflect an abnormal endogenous pain control system. We investigated whether similar changes are found in patients with the fibromyalgia syndrome (FMS) that is also believed to result from disturbed central pain processing. The ES2 values of 27 patients with FMS were compared with those of 18 patients with TTH and 40 healthy volunteers. The duration of ES2 (+/-SD) in FMS patients was 30.6+/-7.5 ms and was not significantly different from the control group (33.1+/-7.8 ms), whereas it was significantly shortened in TTH patients (22.9+/-11.5 ms). Our results indicate that, despite similar concepts on the pathophysiology of the two chronic pain disorders, there are no comparable changes of this brain stem reflex activity in FMS.

Malignant gliomas are rather refractory to current therapeutic approaches including surgery, radiotherapy, chemotherapy and immunotherapy. Acquired alterations in the pathways required for apoptotic cell death are thought to be responsible to the failure of glioma to respond to therapy. Here we have examined the expression of several proteins involved in the susceptibility to apoptosis in 20 human gliomas, including the BCL-2 family proteins BCL-2, BCL-X, BAX and MCL-1, as well as p53 and RB. Most gliomas expressed several BCL-2 family proteins. There was good correlation between expression of the functional antagonists, BCL-2/BCL-X and BAX, suggesting that changes in the BCL-2+BCL-X/BAX ratio are not responsible for the differential response of glioma patients to chemotherapy. The immunochemistry data were also analysed in regard to response to therapy and clinical outcome. All patients had cytoreductive surgery and received radiotherapy and nitrosourea-based adjuvant chemotherapy. There was no prominent association of outcome with the expression patterns of p53, RB, BCL-2, BCL-X or BAX. We find, however, that expression of the MCL-1 protein is associated with early tumour recurrence and shorter survival in this group of glioma patients. This preliminary observation will have to be confirmed in a larger independent sample of glioma patients.

During single word processing the negative cortical DC-potential reveals a left frontal preponderance in normal right-handers as well as in patients with a history of transient aphasia. Lateralization of DC-negativity therefore provides a reliable and robust method for the assessment of language dominance. In 11 stroke patients with permanent aphasia this physiological pattern changed to bilateral activation reflecting an additional right-hemispheric involvement in compensatory mechanisms in aphasia. Along with complete clinical recovery the classical aphasic syndromes revealed specific differences in changes of their lateralization patterns. In Broca's aphasia the initial right-hemispheric preponderance changed to a left frontal lateralization while in Wernicke's aphasia a presumably permanent shift towards the right hemisphere occurred. Differences in lateralization patterns might reflect different mechanisms of recovery such as the initial disinhibition of homologous areas contralaterally and subsequent collateral sprouting and synaptic modulation. The assessment of changes in lateralization of the cortical DC-potential during language tasks in a non-invasive, safe method with excellent time resolution that might provide further insights in the neural basis of recovery from aphasia.

We compared the diagnostic sensitivity of traditional visual tests such as the Snellen-test and pattern reversal VEPs with psychophysical and electrophysiological tests involving motion processing and psychophysical tests of contrast processing in detecting visual deficits in a group of MS patients. A total of 30 patients with a definite diagnosis of MS and 22 age-matched controls selected from a pool of healthy volunteers participated in this study. Visual evoked potentials elicited by reversing checkerboards and moving random dot patterns (motion-onset VEPs) were recorded. The recognition of motion-defined forms (motion-defined letter test, MDL-test) and of contrast reduced optotypes was measured psychophysically. Of 30 patients, 29 showed deficits in at least one of the tests applied. The highest detection rate was obtained for a simple psychophysical test, the MDL-test, which revealed abnormalities in 80% of the patients. This is about 12% more than pattern VEPs could detect. Conversely, abnormalities in motion-onset VEPs were found in only 16% of the patients. Our results show that by adding a simple psychophysical test of form-from-motion analysis our capability to demonstrate an involvement of the visual system in MS patients may be promoted considerably.

We have developed a method to observe and quantify the phasic relationship between the burst patterns of antagonistic muscles in any roughly periodic movement, such as tremor, for up to 24 h. This paper describes our approach, in which long-term EMG recordings are evaluated by a procedure based on cross-spectral analysis. The method is then illustrated by data from 6 patients with essential tremor. Our data confirm earlier observations that a particular patient may show different burst patterns at different times. However, as opposed to tremor analysis based on short-term recording, our method allows quantitative statements on the relative frequency of the burst patterns, as they occur under everyday conditions. In addition, our data suggest that in ET (a) alternating tremor activity in one hand may occur simultaneously with synchronous activity in the other hand; (b) along with the classical alternating and co-contracting patterns there may be significant 'non-classical' activity, that cannot be called alternating or synchronous.

Patients with idiopathic Parkinson's syndrome, most of them in early stages of the disease, and matched healthy controls participated in a continuous performance task while their EEGs were recorded from 15 electrodes. During preparation of movements, a contingent negative variation (CNV) maximal at central and posterior sites was visible. This CNV was reduced in the patient population. A large P3-like positive deflection occurred after go and no-go stimuli that called for execution (go) or suppression (no-go) of a button press. Compared to healthy controls, the positive wave in Parkinson patients was significantly reduced after go stimuli and maximally attenuated when no-go stimuli had indicated to suppress the motor response. In contrast, P3 amplitudes after irrelevant "ignore' stimuli was not significantly reduced in the patients. These results are interpreted in the framework of a model of striatal function postulating (i) that populations of cortical and striatal neurons form distributed functional units (Hebbian cell assemblies), and (ii) that mutual inhibition between such cortico-striatal cell assemblies is mediated by the neostriatum, the forebrain structure primarily affected in Parkinson's disease.

Cerebello-cerebral interaction plays a fundamental role in movement processing. Extensively studied in monkeys, cerebello-thalamo-cerebral information processing is less clear in humans. Taking advantage of the tight linkage between cerebellum and cerebral motor cortex, the objective of this experiment was to gain information on cerebellar function, dysfunction and recovery by analyzing movement-related cortical potentials (MRCPs). MRCPs were recorded prior to voluntary repetitive finger movements from two cerebellar stroke patients, in the acute phase of cerebellar stroke and after clinical recovery. Ten normal subjects served as controls. The main result was a significant depression of late MRCP components over the contralateral motor cortex when patients performed index finger movements of the affected side in the acute phase, and improvement of depressed components after clinical recovery, 8-10 months later. Topographic maps of late MRCP components showed diffusely enlarged potential fields with ataxic movements in the acute phase, and re-focused fields on follow-up. We conclude that (1) late MRCP components are particularly sensitive to cerebellar input in humans and can reflect different functional states of the cerebellum, (2) disturbance of motor cortex function after cerebellar stroke (diaschisis) can occur as a temporary phenomenon that reverses with good clinical recovery.

We have developed a method of long-term EMG recording that has proven suitable for the quantification of pathological tremor. In the present paper we show that the principal parameters of the method (tremor occurrence, tremor intensity, tremor frequency) are highly reproducible and that the method is specific and sensitive for detection of pathological tremor. Twelve patients with essential tremor (ET) and 13 patients with Parkinson's disease (PD) were recorded repeatedly on 3 successive days. For each patient group and for each parameter the intersubject variability was much larger than the intersubject variability. The intraclass correlation coefficient "R" was in the order of 0.9 for each parameter and the mean of Pearson's correlation coefficient between successive days was also approximately 0.9. Recordings from normal controls demonstrated that the method's specificity for pathological tremor is 94.1% and its sensitivity is 96%.

Interleukins (IL) 1, 2, 4, 6 and soluble IL-2 receptor (sIL-2R), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) were measured in CSF and serum from patients with relapsing-remitting and chronic multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, HIV infection, bacterial meningitis, viral encephalitis, meningeal carcinomatosis, hematologic meningeal malignancies, and disseminated melanoma. Our findings suggest that monitoring of disease activity in neuroimmunologic disorders by means of IL-1 beta, IL-2, sIL-2R, or IL-4 determination will not prove useful. IL-6, on the other hand, indicates relapse in multiple sclerosis and active disease in Guillain-Barré syndrome and meningeal carcinomatosis. High CSF TNF-alpha in metastatic melanoma and frequent detection in CSF of the multifunctional B-cell growth factor, IL-6 (27/30) and oligoclonal immunoglobulin bands (33%) in meningeal carcinomatosis confirm an intrathecal immune response in disseminated leptomeningeal neoplasia which might be amenable to therapeutic immunomodulation.

Compound muscle action potentials (CMAPs) were recorded from anterior tibial (TA) and soleus (SOL) muscles following transcranial magnetic stimulation of motor cortex in 10 healthy subjects: (1) while standing upright without support, (2) while sitting, and (3) while lying supine. The results of this study demonstrate a significant influence of posture upon the amplitudes of CMAPs. Postural facilitation presented itself, firstly, in terms of a higher incidence of bilateral activation of distal leg muscles during stance and, secondly, as significant enhancement of the amplitude of CMAPs while standing as compared to lying supine. The onset latency, however, did not disclose a significant shortening during stance. To assess the effects of preinnervation subjects voluntarily adjusted the level of TA activity to 5%, 10% and 20% of maximum isometric force respectively before cortex stimulation. Voluntary background contraction resulted in a significant increase of amplitude of CMAPs but, in contrast to postural facilitation, concomitant with a significant decrease in onset latency. These results point to a somewhat different mechanism of facilitation during stance as compared to voluntary preinnervation. But it cannot be decided whether cortical mechanisms, different descending systems, the spinal circuitry or a combination of these factors is responsible for the observed effects.

Posturography was performed in 41 patients with cerebellar diseases by means of a force measuring platform using an on-line computer program which calculated sway path, sway area, antero-posterior and lateral sway components and the amount of visual stabilization. Postural ataxia was quantitatively studied in 8 patients with spinal ataxia (Friedreich's), 6 patients with vestibulocerebellar lesions, 11 patients with anterior lobe atrophy, 7 patients with hemispheral cerebellar lesions, and 9 patients with a disease affecting all parts of the cerebellum. Patients with lesions of the cerebellar hemispheres could not be separated from normals by means of posturography. Lesions of the spino-cerebellar afferents (Friedreich' ataxia) caused an omnidirectional low frequency sway with preserved visual stabilization. Patients with anterior lobe atrophy showed a predominant antero-posterior sway, often with a spontaneous high frequency body tremor around 3 Hz. Vestibulo-cerebellar lesions exhibited omnidirectional low frequency sway poorly stabilized by vision. Quantitative posturography helps to localize cerebellar lesions and allows for quantitative follow-up studies of cerebellar diseases.

The present study compares the results of sensory evoked potentials after stimulation of the tibial nerve with measurements of short (M1), medium (M2) and long-loop latency (M3) responses of leg muscles in 42 patients suffering from multiple sclerosis. EMG responses were elicited by a movable platform which was tilted in pitch toe-up around the subject's ankle joint. The short latency response of the triceps surae muscle was nearly always normal in latency. The M2 response was lacking in about 30% of the patients and 10% of normals. The long latency response (M3) in the antagonistic anterior tibial muscle was significantly delayed (beyond 162 msec = AM + 2.5 S) in 69% of the patients. The delayed M3 response was found to indicate demyelination as reliably as the delayed somatosensory evoked potential (66% of the patients). The frequency of coincident results in the entire group was 86%. Additional information is gained in cases where SEPs are normal, but M3 is delayed (7%). Furthermore, patients lacking P40 of the SEP still exhibit M3 responses, the latency of which may be measured (24%). The results favour the assumption that M3 is mediated by a supraspinal pathway.

Movements of the arms (execution) in standing human subjects are preceded (preparation), accompanied, and followed (compensation) by muscular activity in postural trunk and leg muscles. Postural muscular activity compensates inertial forces acting on the body at the beginning and during arm movements and keeps the centre of gravity within the limits of stable upright standing. Standing normal subjects and patients performed bilateral arm elevations in response to an acoustic trigger. The beginning of EMG activity in the anterior deltoid muscle reflects the reaction time. Postural activity prior to the arm movement was observed in anterior tibialis, paraspinalis, and hamstring muscles. Compensatory muscular action occurred in the triceps surae. Motor preparation and compensation thus are an integral part of a motor programme. Muscles involved, latencies, and amount of EMG activity change with variations in the motor task (e.g. range of arm movement, changes in inertia of the arm, changes in initial body position). Reaction times and the pattern of preparatory and compensatory postural EMG activity were normal in most of the patients with Parkinson's disease. Reaction times were significantly increased in patients with cerebellar atrophy. The most prominent pathological feature in cerebellar patients was the inadequate temporal sequence of motor preparation and execution. Our results indicate that the basal ganglia play a minor role in motor preparation, whereas the cerebellum seems to coordinate the relative timing between motor preparation and execution.

In order to elucidate further the possible pathways and the functional significance of long-loop reflexes we recorded short-, medium- and long-latency responses from leg muscles in 27 patients with spinal lesions, 20 patients with central lesions of the internal capsule or cerebral hemisphere, and in 18 control patients with frontal or occipital lesions without motor or sensory disturbances. Our normal population included 50 subjects, who were age and sex matched to the patients. The mean latency of the long-latency response (LL) in the anterior tibial muscle was significantly delayed in patients with spinal (164.5 msec) and central lesions (145.1 msec) compared to control patients (123.5 msec) and the normals (125.3 msec). This delay of LL could be observed in patients who exhibited only motor or sensory disturbances or a combination of both. The medium-latency response (ML) was absent in 47% of the records in patients with spinal lesions, mainly on the side which was clinically more affected. Its latency was normal if the response occurred. The integral of the LL response was enlarged in patients with spinal or central lesions, but was also enlarged in the control group. The results indicate that the ML response is segmental, but that its amplitude is modulated by supraspinal structures. The LL response probably corresponds to a transcortical 'reflex.'

Thirty patients with unilateral lesions of the cerebral hemisphere and clinical signs of an affected somatosensory system (mainly disturbances of kinesthesia and stereoesthesia) were investigated. SEP recordings were abnormal in 27. The degree of sensory loss (especially kinesthesia) correlated well with the SEP abnormalities in 26. These SEP abnormalities could be segregated into 4 groups (types 1-4). A type 1 SEP with pathological evoked potentials from P15 on (but a normal P13/14 complex with ear- or extracephalic reference recordings) correlated with lesions of the thalamus, the internal capsule, and the centrum semiovale. A type 2 SEP characterized by loss or severe attenuation of N20 and the following components was found in patients with lesions of the postcentral gyrus. A variant (type 2a) showed isolated loss of N20, but preserved subsequent components and may be due to lesions restricted to area 3b. A third pattern of SEP abnormality is characterized by a preserved primary cortical response and loss of all the subsequent potentials. It is assumed to correlate with lesions of the parietal association cortex. In only 1 case was a type 4 SEP found, with pathological features from N3 (N55) on, caused by an ischemic stroke in area 39. Loss of all evoked responses after P13/14, including P15, suggests a lesion between thalamus and centrum semiovale. Lesions located close to the postcentral cortex lead to a loss of N20 and a variable cut off of the rising negativity following P15. Preservation of the primary cortical complex and distortion or loss of the later components point to a parietal lesion. Severe disturbances of kinesthesia and stereognosia in patients with a normal primary cortical complex and isolated abnormality of the following potentials suggests that the adjacent association cortex may be important for the perception of this complex somatosensory information. Thus the neuronal activity underlying the primary cortical response does not suffice for perception of motion and for stereoesthesia.

A series of experiments were performed in the Spacelab-1 mission on November/December, 1983, pre-, in-, and postflight. These experiments covered various aspects of the functions of the vestibular system, the inflight tests comprising threshold measurements for linear movements in three orthogonal axes, optokinetic stimulation, vestibulo-ocular reflexes under linear and angular accelerations, caloric stimulation with and without linear accelerations; pre- and postflight tests repeated the inflight protocol with the addition of subjective vertical and eye counter-rotation measurements using a tilt table. One of the most surprising and significant results was the caloric test: strong caloric nystagmus on the two subjects tested was recorded inflight; this was contrary to what was expected from Barany's convection hypothesis for caloric nystagmus.