Hans-Jürgen von Giesen

Inhibitory actions of motor cortex following unilateral brain lesions as studied by magnetic brain stimulation

Noninvasive transcranial magnetic stimulation (TMS) of the motor cortex not only induces shortlatency, motor-evoked potentials (MEP) in contralateral muscles, but also inhibitory phenomena. One type of inhibitory action appears directly after the MEP in contralateral muscles and can be visualized by blockade of tonic, voluntary electromyographic (EMG) activity (postexcitatory inhibition, PI). Evidence for a cortical origin of PI, especially in its later part, was derived from double cortical stimulation in previous studies and is further supported by examination of PI in patients with focal hemispheric unilateral brain lesions in the present study. Thirty patients with different sites of vascular or tumour lesions were studied by TMS. In 6 patients with circumscribed lesions of the primary sensorimotor cortex a significant shortening of PI to contralateral muscles was observed. In 7 patients with focal lesions of the thalamus or internal capsule, in 6 patients with lesions of the premotor cortex and in 5 patients with lesions restricted to the parietal or temporal lobe, a significant prolongation of PI to the contralateral muscles was detected. Six patients with transient ischemic attacks showed either prolongation or shortening of PI. We conclude that PI is predominantly generated in the primary motor cortex, correspondingly its damage causes shortening of PI. In contrast, damage to brain areas that project to the primary motor cortex is followed by prolongation of PI. This remote effect on the primary motor cortex may result from disinhibition of cortical interneurones.

Cerebral network underlying unilateral motor neglect: evidence from positron emission tomography

In 4 male patients (age range 50-73 years) with unilateral motor hemineglect as a sequelae of circumscribed cerebral infarction, depressions of the regional cerebral glucose metabolism (rCMRGlu) were mapped to identify the metabolically affected cerebral structures. Motor neglect was defined according to Castaigne by lack of spontaneous and pain-induced motor activity on one side of the body in the absence of paresis, pyramidal signs, and sensory loss. The depressions of the rCMRGlu as determined by positron emission tomography (PET) were found to exceed the areas of structural damage but to be restricted to the affected cerebral hemisphere. Significant mean rCMRGlu depressions followed a focal pattern involving the premotor, prefrontal, parietal and cingulate cortex, as well as the thalamus. In correspondence to the lack of significant mean rCMRGlu depressions in primary sensorimotor cortex, basal ganglia, and cerebellum the cortico-spinal pathway was spared as indicated by preserved magnetic evoked motor potentials. Our data provide evidence suggesting that motor hemineglect is a disturbance in a cerebral network of higher order cortical areas subserving motor activity in the presence of an intact motor cortical output system.

Therapeutic effects of nucleoside analogues on psychomotor slowing in HIV infection

ObjectiveSince psychomotor slowing predicts the development of HIV-1-associated dementia, AIDS and death independently of the immune status, there is urgent need for a neurological therapeutic rationale. MethodsThe therapeutic efficacy of nucleoside analogues with different abilities to penetrate into the cerebrospinal fluid was assessed in 410 HIV-1-seropositive patients using the results of detailed fine motor tests, which detect minor motor deficits. Patients were selected who showed pathological psychomotor slowing as signs of central nervous system (CNS) dysfunction before therapy onset and who were then treated only with nucleoside analogues for at least 6 months. ResultsBoth zidovudine and didanosine improve CNS function to an equal degree when given as monotherapy. Adding a second nucleoside analogue (didanosine, lamivudine, zalcitabine) to zidovudine does not further improve psychomotor performance. However, adding a second nucleoside after a period of zidovudine monotherapy does result in a second but less remarkable therapeutic effect. Combinations containing stavudine are as effective as those including zidovudine when given as first antiretroviral treatment. Furthermore, stavudine effectively improves motor performance even after pretreatment with zidovudine.

Diagnostic criteria and clinical procedures in HIV-1 associated progressive multifocal leukoencephalopathy

The diagnosis of definite progressive multifocal leukoencephalopathy (PML) has been a neuropathological domain. We reviewed all Human Immunodeficiency Virus Type 1 (HIV-1) seropositive patients in our institution between 01.01.1989 and 31.12.1994 and identified 20/823 cases with PML by clinical and imaging criteria. Diagnosis was neuropathologically confirmed in 5 cases. Diagnostic criteria included rapid onset (< 2 weeks) of multifocal neurological signs and symptoms, advanced immunosuppression and asymmetric uni- or multifocal white matter lesions without mass effect, contrast enhancement or cortical atrophy in magnetic resonance imaging (MRI). The overall incidence of PML was stable over the observation period (approximately equal to 2.5%). The mean age at onset (41.7 years) was significantly lower compared to HIV-1 seronegative PML patients (peak in the sixth decade of life), male patients prevailed (100%). Mean survival (3.9 months) was extremely short. Human polyoma virus JC (JCV) polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) demonstrated a considerable rate of possible cerebral co-infection with HIV-1 and JCV as well as subclinical infection with JCV. Therefore demonstration of JCV deoxyribonucleic acid by PCR in the CSF alone is not sufficient for clinical PML diagnosis. We present diagnostic criteria on the basis of epidemiological, neuroradiological and CSF parameters that allow us to make the clinical diagnosis of PML. Although quick and safe, routine stereotactic brain biopsy is not necessary to confirm the diagnosis.

TNFα reduces glutamate induced intracellular Ca2+ increase in cultured cortical astrocytes

Abstract The proinflammatory cytokine TNFα is locally released during various inflammatory CNS diseases and high cerebrospinal fluid (CSF) titers of TNFα were found in meningitis patients. We know from previous studies that TNFα also depolarizes astrocytes by reducing their inwardly rectifying K+ currents. We have now investigated the effect of TNFα on the glutamate induced intracellular Ca2+ increase in astrocytes, a process which seems to be involved in glial mediated modulation of neuronal synaptic transmisssion. Incubation with TNFα (50–1000 U/ml for 60 min) reduces the glutamate induced intracellular Ca2+ increase in astrocytes but not in neurons and this seems to be a phenomenon secondary to the TNFα induced depolarization. While other proinflammatory cytokines (interleukin 1β, IL-2, IL-6) did not interfere with the astrocytic glutamate response, incubation in CSF from septic meningitis patients (CSF–SM) also reduced the glutamate induced intracellular Ca2+ increase. The application of a neutralizing anti-TNFα antibody to the CSF–SM prior to cell incubation partially restored the glutamate response. Our data suggest that inflammatory molecules such as TNFα impair astrocytes’ response to glutamate and this may indirectly affect neuronal synaptic transmission.

HIV-1 protein Tat reduces the glutamate-induced intracellular Ca2+ increase in cultured cortical astrocytes

The trans‐activator protein Tat of the human immunodeficiency virus type 1 (HIV‐1) is regarded as an injurious molecule in the pathogenesis of HIV‐1 associated encephalopathy (HIVE). We investigated the effects of Tat on neuroligand‐induced intracellular Ca2+ increase in cultured astroglial cells. Rat cortical astrocytes, human glioblastoma cells and glial restricted precursor cells, from a human embryonic teratocarcinoma cell line, were incubated with recombinant Tat (100 ng/mL for 60 min) which induced a significant reduction of glutamate or ATP‐induced intracellular Ca2+ increase (‘glutamate response’, ‘ATP response’). The reduction of the glutamate response was also observed following cell incubation with cell extracts of HeLa‐T4+ cells transiently transfected with an expression plasmid coding for Tat. However, inactivation of the transcriptional trans‐activity of Tat, by using a mutant form of Tat, as well as inhibition of de novo protein synthesis by cycloheximide abolished the effect on the glutamate response. This suggests that Tat acts upon induction of a so far unknown cellular gene whoes gene product causes the reduction of glutamate responses. As the effect of Tat resembles the effect of TNFα on glutamate responses [Köller et al. (2001) Brain Res., 893, 237–243] which is locally released within the brains of HIVE patients, we also tested for synergistic effects of Tat and TNFα on the glutamate response. Low concentrations of Tat in combination with subthreshold concentrations of TNFα also elicited a marked reduction of astroglial glutamate responses. Our data suggest that Tat and TNFα, both by itself and synergistically, induce astroglial dysfunction.

HIV-specific changes in the motor performance of HIV-positive intravenous drug abusers.

Motor tests comprising the analysis of postural tremor, most rapid voluntary alternating index finger movements (MRAM) and the rise time of most rapid index finger extensions (CT) allow us to quantify HIV-associated minor motor deficits electrophysiologically. The electrophysiological results in 57 HIV-positive individuals who acquired HIV infection by intravenous drug abuse (IVDA) were compared with those of 57 matched HIV-positive homosexuals and 98 HIV-negative controls to evaluate a possible additional influence of IVDA on motor performance. Motor deficits showed no differences between HIV-positive IV drug abusers and homosexuals, revealing a highly significant slowing of MRAM and prolongation of CT to an almost identical extent. Thus, in HIV-infected individuals minor motor deficits are characteristic early signs of subclinical central nervous system involvement regardless of the mode of HIV infection.

Serum and cerebrospinal fluid levels of interleukin-18 in human immunodeficiency virus type 1–associated central nervous system disease

Interleukin-18 (IL-18) is a proinflammatory cytokine released by macrophages that strongly stimulates the production of interferon-γ, thereby linking innate and acquired immunity. Its role in human immunodeficiency virus (HIV) pathogenesis is under debate and little is known about its role in neuro-AIDS (acquired immunodeficiency syndrome). Serum and cerebrospinal fluid (CSF) levels of IL-18 were determined by a commercially available enzyme-linked immunosorbent assay (ELISA) in 22 HIV-seropositive patients without neurological symptoms (HIV+), 21 patients with AIDS dementia complex (ADC), and 31 patients with AIDS-defining opportunistic infections (OIs) of the brain. Thirty-two HIV seronegative patients (HIV−) served as controls. Compared to HIV− controls, serum IL-18 levels were increased in HIV+ and ADC but not in OI patients. In contrast, CSF IL-18 levels were elevated in OI patients whereas HIV+ and ADC patients were not different from HIV− controls. We provide evidence for an significantly increased IL-18 level in the CSF of HIV+ patients with cerebral OIs, suggestive of a role for IL-18 in the intrathecal host response to OIs.

Persistent organic personality change as rare psychiatric manifestation of MELAS syndrome.

Sirs: The encephalomyopathy MELAS syndrome is clinically characterized by mitochondrial myopathy, ragged red fibers in muscle, encephalopathy with seizures and/or dementia, lactate acidosis and “stroke” before the age of 40 years and, additionally, normal early development, recurrent headaches and vomiting [1, 2]. Mitochondrial genome point mutation at position 3243 accounts for 80 to 90 % of MELAS syndromes. Psychiatric abnormalities with the exception of dementia are rare and mainly consist of schizophrenialike symptoms such as auditory or visual hallucinations, delusions of persecution and disorganized behaviour [3, 7, 9, 10]. A 37 year old male patient was admitted to a psychiatric clinic owing to his aggressive behavior that had been increasing in intensity during several months. His wife reported a personality change during the last three years with a loss of interests, phases of inactivity and apathy and neglect of body care or phases of disturbed impulse control with aggressive behavior. The patient’s history revealed a normal psychomotor development. However, with a height of 170 cm his stature was shorter than that of his three brothers. He also had finished school at lower levels than his brothers but he was able to start and finish education as watchmaker, electrician and storekeeper; however, he was not able to stay in a position for more than a few months. At the time of examination, he had been unemployed for one year. In the family history no neurological or psychiatric diseases were reported. His medical history included hearing disability on both sides since the age of 22 years and phases of migraine headache and of remittent vomiting. Epileptic seizures had occurred for the first time 2 years ago and two further seizures were reported. His physical examination disclosed incomplete deafness on both sides, a mild central hemiparesis and hemiataxia of the right side and a mild unsteadiness while standing or walking with closed eyes. He did not show any muscular atrophy or muscle weakness. His psychiatric examination revealed difficulties in memory tests, concentration and alertness in neuropsychologial testing, affective instability with aggressive incidents but no evidence for paranoid delusions or hallucinations. He constantly denied that he was ill. MRI revealed disseminated signal alterations without abnormalities on MR-angiography and diffusion weighted imaging (Fig. 1). Laboratory findings showed elevated lactate in serum (2.5 to 3.5 mM) and CSF (6.1 mM). EEG did not show any epileptic activity but a diffuse dysrhythmia. The cardiovascular examination disclosed a preexcitation syndrome (Wolff-ParkinsonWhite syndrome) and hypertrophic cardiomyopathy. There was no diabetes mellitus or abnormalities in endocrine laboratory testing but infertility due to azoospermia had been diagnosed. The electromyography was unremarkable and gave no evidence for myopathy. The muscle biopsy specimen of the left deltoid, however, revealed LETTER TO THE EDITORS

Soluble cerebrospinal fluid factors induce Ca2+ dysregulation in rat cultured cortical astrocytes in HIV-1-associated dementia complex.

ObjectivesTo investigate the effect of cerebrospinal fluid (CSF) of HIV-1-seropositive patients with and without HIV-1-associated dementia complex (HADC) on the intracellular Ca2+ regulation of cultured cortical astrocytes. DesignIn a blinded study the effects of CSF samples from HADC patients and from HIV-1-seropositive but not demented patients on intracellular Ca2+ regulation of cultured cortical astrocytes were investigated. Astrocytes were chosen because they contribute to both electrophysiological and immunological processes within the brain. MethodsAstrocytes were incubated in CSF samples for 1 h, loaded with the Ca2+ indicator dye Fura-2 and intracellular Ca2+ responses upon glutamate application were measured. ResultsCSF samples from 10 out of 11 HADC patients induced a significant reduction of the intracellular Ca2+ increase upon glutamate application. On the contrary, seven out of 10 CSF samples from HIV-1-seropositive patients without HADC as well as 10 out of 10 CSF samples from HIV-1-seronegative controls did not affect the intracellular Ca2+ response. ConclusionsOur data strongly confirm the hypothesis that CSF samples of HADC patients contain soluble factors which interfere with the function of astrocytes. These factors may include HIV-1 proteins, locally released cytokines or neurotoxins.