Certain Central Nervous System Research Articles

St. John's wort extract with a high hyperforin content does not induce P-glycoprotein activity at the human blood-brain barrier.

St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [11C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.

Neonatal Abstinence Signs during Treatment: Trajectory, Resurgence and Heterogeneity.

Neonatal abstinence syndrome (NAS) presents with a varying severity of withdrawal signs and length of treatment (LOT). We examined the course and relevance of each of the NAS withdrawal signs during treatment in a sample of 182 infants with any prenatal opioid exposure, gestational age ≥ 35 weeks, without other medical conditions, and meeting the criteria for pharmacological treatment. Infants were monitored using the Finnegan Neonatal Abstinence Scoring Tool. Daily mean Finnegan scores were estimated using linear mixed models with random subject effects to account for repeated withdrawal scores from the same subject. Daily item prevalence was estimated using generalized estimating equations with a within-subject exchangeable correlation structure. The median LOT was 12.86 days. The prevalence of withdrawal signs decreased from day one to day three of treatment. However, certain central nervous system (CNS) and gastrointestinal (GI) signs showed sporadic increases in prevalence notable around two weeks of treatment, accounting for increases in Finnegan scores that guided pharmacotherapy. We question whether the resurgence of signs with a prolonged LOT is mainly a consequence of opioid tolerance or withdrawal. Monitoring CNS and GI signs throughout treatment is crucial. Future studies directed to better understand this clinical phenomenon may lead to the refining of NAS pharmacotherapy and perhaps the discovery of treatment alternatives.

Mechanism of Action of Atypical Antipsychotic Drugs in Mood Disorders.

Atypical antipsychotic drugs were introduced in the early 1990s. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics are effective against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic but also in affective disorders, on their own or as adjuncts to antidepressant drugs. This review presents the neural mechanisms of currently existing atypical antipsychotics and putative antipsychotics currently being investigated in preclinical and clinical studies and how these relate to their effectiveness in mood disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Typical antipsychotics act almost exclusively on the dopamine system. Atypical drugs, however, modulate serotonin (5-HT), norepinephrine, and/or histamine neurotransmission as well. This multimodal mechanism of action putatively underlies the beneficial effect of atypical antipsychotics in mood and anxiety disorders. Interestingly, novel experimental drugs having dual antipsychotic and antidepressant therapeutic potential, such as histamine, adenosine, and trace amine-associated receptors (TAAR) ligand, are also characterized by a multimodal stimulatory effect on central 5-HT, norepinephrine, and/or histamine transmission. The multimodal stimulatory effect on central monoamine neurotransmission may be thus primarily responsible for the combined antidepressant and antipsychotic therapeutic potential of certain central nervous system (CNS) drugs.

Detection of BRAF V600E Mutation in Ganglioglioma and Pilocytic Astrocytoma by Immunohistochemistry and Real-Time PCR-Based Idylla Test.

The BRAF V600E mutation is an important oncological target in certain central nervous system (CNS) tumors, for which a possible application of BRAF-targeted therapy grows continuously. In the present study, we aim to determine the prevalence of BRAF V600E mutations in a series of ganglioglioma (GG) and pilocytic astrocytoma (PA) cases. Simultaneously, we decided to verify whether the combination of fully automated tests—BRAF-VE1 immunohistochemistry (IHC) and Idylla BRAF mutation assay—may be useful to accurately predict it in the case of specified CNS tumors. The study included 49 formalin-fixed, paraffin-embedded tissues, of which 15 were GG and 34 PA. Immunohistochemistry with anti-BRAF V600E (VE1) antibody was performed on tissue sections using the VentanaBenchMark ULTRA platform. All positive or equivocal cases on IHC and selected negative ones were further assessed using the Idylla BRAF mutation assay coupled with the Idylla platform. The BRAF-VE1 IHC was positive in 6 (6/49; 12.3%) and negative in 39 samples (39/49; 79.6%). The interpretation of immunostaining results was complicated in 4 cases, of which 1 tested positive for the Idylla BRAF mutation assay. Therefore, the overall positivity rate was 14.3%. This included 2 cases of GG and 5 cases of PA. Our study found that BRAF V600E mutations are moderately frequent in PA and GG and that for these tumor entities, IHC VE1 is suitable for screening purposes, but all negative, equivocal, and weak positive cases should be further tested with molecular biology techniques, of which the Idylla system seems to be a promising tool.

Biased M1 receptor-positive allosteric modulators reveal role of phospholipase D in M1-dependent rodent cortical plasticity.

Highly selective, positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer's disease and schizophrenia. Discovery programs have produced a structurally diverse range of M1 receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M1 receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M1 receptor signaling in native systems, and it is not clear whether biased M1 PAMs display differences in modulating M1-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M1-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M1 PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist-induced LTD but also blocked M1-dependent LTD in the PFC. In contrast, biased and nonbiased M1 PAMs acted similarly in potentiating M1-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M1 PAMs to modulate certain central nervous system (CNS) functions and that biased M1 PAMs function differently in brain regions implicated in cognition.

Aerobic exercise promotes hippocampal neurogenesis through skeletal myofiber-derived vascular endothelial growth factor.

Aerobic exercise promotes hippocampal neurogenesis through skeletal myofiber-derived vascular endothelial growth factor.

Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality.

A hallmark of HIV-1 infection is the continuously declining number of the virus’ predominant target cells, activated CD4+ T cells. With diminishing CD4+ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary paths that allow HIV-1 to acquire a wider host cell range by infecting cells with lower CD4 levels, we dissected the evolution of the envelope-CD4 interaction under in vitro culture conditions that mimicked the decline of CD4high target cells, using a prototypic subtype B, R5-tropic strain. Adaptation to CD4low targets proved to severely alter envelope functions including trimer opening as indicated by a higher affinity to CD4 and loss in shielding against neutralizing antibodies. We observed a strikingly decreased infectivity on CD4high target cells, but sustained infectivity on CD4low targets, including macrophages. Intriguingly, the adaptation to CD4low targets altered the kinetic of the entry process, leading to rapid CD4 engagement and an extended transition time between CD4 and CCR5 binding during entry. This phenotype was also observed for certain central nervous system (CNS) derived macrophage-tropic viruses, highlighting that the functional perturbation we defined upon in vitro adaptation to CD4low targets occurs in vivo. Collectively, our findings suggest that CD4low adapted envelopes may exhibit severe deficiencies in entry fitness and shielding early in their evolution. Considering this, adaptation to CD4low targets may preferentially occur in a sheltered and immune-privileged environment such as the CNS to allow fitness restoring compensatory mutations to occur.

Predictors of central vestibular disorders from videonystagmography tests

Abstract The diagnosis of central vestibular lesion is challenging and sometimes there is an overlap in symptoms and signs with a peripheral vestibular lesion. In some selected cases, dizziness is the only presenting symptom and in other patients, mild neurological symptoms as numbness are ignored. Videonystagmography (VNG) is considered a useful method for diagnosing vertigo of peripheral origin; however, not all the patients with central vertigo can be diagnosed easily. Benign paroxysmal positional vertigo and central positional vertigo share common criteria. The aim of the present study is to assess the usefulness of different VNG tests as predictors of central vestibular disorders, to determine the criteria that differentiate central positional nystagmus from the peripheral type, and to attempt to relate the abnormality in different VNG tests to certain central nervous system (CNS) levels. A retrospective study was carried out on 51 patients with possible central vestibular disorders from VNG tests battery and were referred for an MRI for further assessment. According to MRI results, the patients were divided into group A (31 patients), the group with manifest MRI findings, and group B, the group with free MRI (20 patients). Different VNG tests were compared between both groups. Three predictors of CNS lesion by VNG were determined: fixation index (FI), oculomotor tests, and central positional nystagmus; there was a statistically significant difference between both groups in FI, oculomotor tests, and central positional nystagmus, and apogeotropic criteria or nystagmus in multiple plains. There was no relation between any of those predictors and specific levels in the CNS. VNG tests are a good diagnostic tool to differentiate between peripheral and central vestibular lesions. The inclusion of FI and positional tests to the oculomotor tests increases the sensitivity of the VNG. In some cases, it is difficult to distinguish between benign paroxysmal positional vertigo and central positional vertigo; apogeotropic nystagmus and nystagmus in multiple plains should raise the suspicion of CNS lesion. Anterior circulation ischemia may lead to chronic vertigo symptoms. Central vestibular vertigo could be caused by dysfunction or excitation of various structures in the CNS including the vestibular cortex.

Thyrotropin-Releasing Hormone Loaded and Chitosan Engineered Polymeric Nanoparticles: Towards Effective Delivery of Neuropeptides.

Thyrotropin-Releasing Hormone (TRH), a tripeptide amide with molecular formula L-pGlu-L-His-L- Pro-NH2, is used in the treatment of brain/spinal injury and certain central nervous system (CNS) disorders, including schizophrenia, Alzheimer's disease, epilepsy, depression, shock and ischemia due to its profound effects on the CNS. However, TRH's therapeutic activity is severely hampered because of instability and hydrophilicity owing to its peptidic nature which results into ineffective penetration into the blood brain barrier. In the present study, we report the synthesis and stability studies of novel chitosan engineered TRH encapsulated poly(lactide-co-glycolide) (PLGA) based nanoformulation. The aim of such an encapsulation is to allow effective delivery of TRH in biological systems as the peptidase degrade naked TRH. The synthesis of TRH was carried out manually in solution phase followed by its encapsulation using PLGA to form polymeric nanoparticles (NPs) via nanoprecipitation technique. Different parameters such as type of organic phase, concentration of stabilizer, ratio of organic phase and aqueous phase, rate of addition of organic phase were optimized, tested and evaluated for particle size, encapsulation efficiency, and stability of NPs. The TRH-PLGA NPs were then surface modified with chitosan to achieve positive surface charge rendering them potential membrane penetrating agents. PLGA, PLGA-TRH, Chitosan-PLGA and Chitosan-PLGA-TRH NPs were characterized and analyzed using Dynamic Light Scattering (DLS), Transmissiom Electron Microscopy (TEM) and Infra-red spectroscopic techniques.

Molecular Evidence for the Inverse Comorbidity between Central Nervous System Disorders and Cancers Detected by Transcriptomic Meta-analyses

There is epidemiological evidence that patients with certain Central Nervous System (CNS) disorders have a lower than expected probability of developing some types of Cancer. We tested here the hypothesis that this inverse comorbidity is driven by molecular processes common to CNS disorders and Cancers, and that are deregulated in opposite directions. We conducted transcriptomic meta-analyses of three CNS disorders (Alzheimer's disease, Parkinson's disease and Schizophrenia) and three Cancer types (Lung, Prostate, Colorectal) previously described with inverse comorbidities. A significant overlap was observed between the genes upregulated in CNS disorders and downregulated in Cancers, as well as between the genes downregulated in CNS disorders and upregulated in Cancers. We also observed expression deregulations in opposite directions at the level of pathways. Our analysis points to specific genes and pathways, the upregulation of which could increase the incidence of CNS disorders and simultaneously lower the risk of developing Cancer, while the downregulation of another set of genes and pathways could contribute to a decrease in the incidence of CNS disorders while increasing the Cancer risk. These results reinforce the previously proposed involvement of the PIN1 gene, Wnt and P53 pathways, and reveal potential new candidates, in particular related with protein degradation processes.

Institutional experience of paediatric high-grade central nervous system tumours: An analysis of 74 patients and review of the literature

Aim of the studyAlthough the survival for children with certain central nervous system (CNS) tumour types has improved through current surgical and adjuvant treatment modalities, the prognosis of many high-grade tumours remains poor despite aggressive treatment. The aim of this study is to analyse patients with high-grade brain tumours in our institution to determine the histopathology, clinical characteristics, treatment modalities, and survival.Material and methodsA total of 74 patients with a diagnosis of high-grade brain tumour were analysed. There were a total of 31 patients with embryonal tumours, 27 patients with high-grade glial tumours, 12 patients with brain stem gliomas and 4 patients with other high-grade brain tumours.ResultsThere were 48 (65%) boys and 26 (35%) girls (ratio: 1.85) with a median age of 99.7 months (range = 2-204 months). The median follow-up period was 19 months (range = 1-204 months). Tumour recurrence was observed in 38 patients (51.4%). The overall survival rate and event-free survival rate of our patients were 27% and 19.5%, respectively.ConclusionsPediatric high-grade CNS tumours have a very aggressive behaviour and a significant number of children eventually succumb to disease despite multimodal treatment. There is a need of more effective therapeutic approaches for these tumours with poor prognosis. The future improvement in childhood high-grade brain tumour management depends on a better understanding of the molecular genetics and biology of brain tumours.

A Novel Selective Muscarinic Acetylcholine Receptor Subtype 1 Antagonist Reduces Seizures without Impairing Hippocampus-Dependent Learning

Previous studies suggest that selective antagonists of specific subtypes of muscarinic acetylcholine receptors (mAChRs) may provide a novel approach for the treatment of certain central nervous system (CNS) disorders, including epileptic disorders, Parkinson's disease, and dystonia. Unfortunately, previously reported antagonists are not highly selective for specific mAChR subtypes, making it difficult to definitively establish the functional roles and therapeutic potential for individual subtypes of this receptor subfamily. The M(1) mAChR is of particular interest as a potential target for treatment of CNS disorders. We now report the discovery of a novel selective antagonist of M(1) mAChRs, termed VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide]. Equilibrium radioligand binding and functional studies demonstrate a greater than 75-fold selectivity of VU0255035 for M(1) mAChRs relative to M(2)-M(5). Molecular pharmacology and mutagenesis studies indicate that VU0255035 is a competitive orthosteric antagonist of M(1) mAChRs, a surprising finding given the high level of M(1) mAChR selectivity relative to other orthosteric antagonists. Whole-cell patch-clamp recordings demonstrate that VU0255035 inhibits potentiation of N-methyl-D-aspartate receptor currents by the muscarinic agonist carbachol in hippocampal pyramidal cells. VU0255035 has excellent brain penetration in vivo and is efficacious in reducing pilocarpine-induced seizures in mice. We were surprised to find that doses of VU0255035 that reduce pilocarpine-induced seizures do not induce deficits in contextual freezing, a measure of hippocampus-dependent learning that is disrupted by nonselective mAChR antagonists. Taken together, these data suggest that selective antagonists of M(1) mAChRs do not induce the severe cognitive deficits seen with nonselective mAChR antagonists and could provide a novel approach for the treatment certain of CNS disorders.

Comparative Studies of a Real-Time PCR Method and Three Enzyme-Linked Immunosorbent Assays for the Detection of Central Nervous System Tissues in Meat Products

The removal of certain central nervous system (CNS) tissues (part of the bovine spongiform encephalopathy risk material) from the food chain is one of the highest priority tasks associated with avoiding contamination of the human food chain with the agent of bovine spongiform encephalopathy. A recently developed real-time PCR assay and three commercially available enzyme-linked immunosorbent assays (ELISAs) for the detection of CNS tissues in minced meat and three types of heat-treated sausages were evaluated. Bovine brain was used for spiking of internal reference material, and its detectability was examined during storage times of 12 months (for frozen minced meat and liver sausage) and 24 months (for sausages treated with medium and high heat). The real-time PCR method and both ELISA kits detected 0.1% CNS tissue in frozen minced meat and 0.1 or 1% CNS tissue in heat-treated meat products. The detectability of the amplified mRNA target region with the PCR assay was similar to the detectability of antigen by the ELISAs. Because the real-time PCR method also can be used to distinguish cattle, ovine, and caprine CNS tissues from porcine CNS tissues, it seems to be suitable as a routine diagnostic test for the sensitive and specific detection of CNS tissues in meat and meat products.

Anxiety Disorders in Children and Adolescents: Research, Assessment and Intervention

This book arose from an international research conference on anxiety disorders in children and adolescents, held in Leiden, The Netherlands, in May 1997. While 12 of its 16 chapters started as papers presented at the conference, they were “extensively revised or fully rewritten” for this volume. The other four chapters were written specifically for this book. Fifteen of the book’s 25 authors are from Europe, the remainder being from North America, Israel and New Zealand. Anxiety disorders are examined from many perspectives. An unusual and interesting contribution, written by the editors, is the opening chapter on “Anxiety and its disorders in children and adolescents before the twentieth century.” It emerges that Hippocrates (460–370 BC) referred to anxiety in children in his Aphorisms. After that little attention seems to have been paid to the subject until the Middle Ages, but from the sixteenth century onwards there was much discussion of sleep disorders, nightmares, enuresis, hysteria and melancholia. Sadly, it seems that psychiatrically disturbed children were among the victims of the witch burning of the sixteenth century. Gradually, however, the care of those suffering from mental illness was brought into the domain of doctors and away from the clergy. By the latter part of the nineteenth century anxiety played a prominent place in the literature on child and adolescent psychiatry. The remaining chapters range widely, examining the possible contribution of genetic, developmental, cognitive, social, attachment and neuropsychiatric causes. Other chapters deal with post-traumatic stress disorder, epidemiology, treatment and prevention. The two chapters on treatment are the weakest. The one on “psychosocial interventions” is confined mainly to a review of the efficacy of various forms of cognitive-behaviour therapy. Virtually, no mention is made of the possible value of family therapy, nor is there discussion of individual, non-cognitive, psychotherapeutic approaches. The chapter on “pharmacological treatment” is better. It concludes, appropriately, that, “for most anxiety problems, non-pharmacological interventions, such as cognitive-behavioural therapies, family interventions or behavioural programmes are the primary treatment.” It’s a shame that family interventions are not given more attention, though behavioural programming is dealt with elsewhere in the book. Throughout this book the emphasis is on examining the scientific evidence for what is presented. This is, no doubt, because most of the chapters had their origin in an “international research conference.” Thus, each chapter is followed by an extensive list of references and the book will be a valuable source of additional information. Most of the chapters are well written and make for easy reading. This does not, however, apply to Chapter 5, on the “Neuropsychiatry of Paediatric Anxiety Disorders,” in which long, tortuous sentences with redundant words, abound. For example: “Our understanding of the neurobiology of anxiety has been propelled by new pharmacological therapeutic tools specific in their impact on certain central nervous system (CNS) receptors within the ‘stress-response system’.” Surely that could be said more simply! There is much of value in this book, which should certainly be in the libraries of centres in which children or adolescents with anxiety disorders are treated or assessed. There will be few professionals who work with anxious children who will not learn something new from it.

Anesthetic management for tumor amelioration in interventional neuroradiology

Therapeutic embolization is the process of occluding a blood vessel by a foreign substance. Treatment of tumors by this method causes a decrease in tumor vascularity. Consequently, blood loss during surgical extirpation may be lessened resulting in decreased transfusion requirements intraoperatively. In addition, reduction of blood supply may precipitate a reduction in tumor growth. Resection time during surgical extirpation may be shortened, resulting in reduced anesthetic requirements. This article presents certain central nervous system (CNS) tumors of the head, neck, and spine followed by anesthetic management during tumor amelioration in interventional neuroradiology (INR).

Localized delivery of proteins in the brain: can transport be customized?

Certain central nervous system (CNS) diseases are characterized by the degeneration of specific cell populations. One strategy for treating neurodegenerative diseases is long-term, controlled delivery of proteins such as epidermal growth factor (EGF) and nerve growth factor (NGF). Since proteins permeate through brain capillaries very slowly, local administration using polymeric implants, continuous infusion pumps, or transplanted, protein-secreting cells may be required to achieve therapeutic concentrations in the tissue. The efficiency of local distribution, and hence effectiveness of local therapy, depends on the rate of protein migration through tissue. The rate of dispersion of molecules in a quiescent, isotropic medium can be characterized by the molecular diffusion coefficient, D, which can be measured by techniques such as quantitative autoradiography, iontophoresis, and fluorescence photobleaching recovery (FPR). These methods are reviewed, with an emphasis on their application to measurement of D for proteins in the brain. Biophysical techniques yield quantitative descriptions of local protein distribution and may enable discrimination of mechanisms of protein transport in the brain. This capability suggests a new paradigm for design of protein therapies, in which proteins and delivery systems are collectively customized to provide sustained protein availability over predetermined volumes of tissue.

SLOW VIRUS DISEASES OF THE CENTRAL NERVOUS SYSTEM

During the last 3 decades a new concept of an infectious process has been derived by studying certain Central Nervous System (CNS) diseases in animals. These infections are characterized by an incubation period lasting for many months to years and by a predictable, protracted clinical course usually leading to death. It has been found that these disorders, which are refered to as slow virus diseases, are related to unconventional and conventional agents, both of which have been associated with naturally occurring diseases in animals and man. The unconventional agents, which have not been visualized, isolated or characterized reveal unusual biological and physico-chemical properties, unlike any known virus group. These agents are associated with scrapie in sheep, encephalopathy in mink and Kuru or Creuzfeldt-Jakob disease in man. The conventional viruses isolated from slow virus diseased brain material, such as Visna, Subacute Sclerosing Panencephalitis (SSPE). Progressive Rubella Panencephalitis (PRP) or Progressive Multifocal Leukoencephalopathy resemble classical viruses with typical structural, physico-chemical and biological characteristics. For this group of viruses, progress has been made in the understanding of the infectious process, since the isolates provide an experimental basis for virological and immunological studies in these diseases. From a pediatric point of view, only SSPE and PRP are of interest, since the other slow virus diseases are usually not seen in children. SSPE is caused by a measles virus infection. Measles virus (refered to SSPE virus) has been isolated from CNS and lymphoid tissue. Moreover the patients reveal a pronounced antimeasles hyperimmunresponse which is pathognomonic for this disorder. Virological studies indicate that SSPE viruses are related but not identical with typical virus isolated from acute measles. At the present state of investigation, SSPE is considered a late complication of acute measles infection. PRP is associated with a persistent rubella virus infection of the CNS. Virological and immunological data reveal great similarities to SSPE, However, information on the pathogenetic mechanism of this disease process are not available. Previous investigations on slow virus diseases have demonstrated the different ways a virus infection can result in a chronic CNS disorder. Moreover, they have shown that virus-host interactions exist which lead to diseases lacking the common characteristics of an infectious process. Obviously, many virological and immunological problems have to be solved before the complexity of these disorders are understood, but it already can be expected, that other human diseases will be found which are caused by a slow virus infection.