[Animal models in neurology: prospects and limitations]. / Tiermodelle in der Neurologie: Möglichkeiten und Grenzen.

Animal models play an important role for exploration of the aetiology, pathogenesis and therapy of various neurological diseases. Their benefit and limitations are being discussed mainly focussed at experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). To answer specific questions concerning the genetics, pathogenesis, diagnostics and treatment of inflammatory, degenerative, ischemic, traumatic und neoplastic diseases of the nervous system different animal models are needed. So far, these are only partially available. Rarely there are alternative methods such as cell, tissue and organ cultures and computer simulations. New phase-specific biomarkers are needed in order to improve the potency of experimental results to be translated into clinical practice.

Incidence of multiple sclerosis: a periodic or stable phenomenon.

For diseases of unknown aetiology, the question as to whether the incidence is constant or variable is very important. A study on multiple sclerosis in a defined northern area of the German Democratic Republic showed a prevalence of 68.6 and an incidence rate of 3.0. Retrospective and prospective investigations concerning an observation period of 22 years revealed cyclic periods (6-7 years) of high incidence rates (up to 4.5) interrupted by shorter intervals (4-5 years) with low rates (about 1.8). The differences (1963-1968 vs. 1969-1973, 1974-1978 vs. 1979-1983) are significant. In accordance with the findings of Kurtzke et al. on a cyclic outbreak of multiple sclerosis in the Faroes and Iceland, our results are considered to be a consequence of environmental factors, such as epidemic viral infections.

MS-related material in blood of multiple sclerosis patients: results with the leucocyte adherence inhibition assay.

To determine the value of laboratory methods proposed as tests for multiple sclerosis (MS), the reactivity of leucocytes to a preparation of an antigen from the blood of patients with MS (MS-related material) was studied in the leucocyte adherence inhibition (LAI) test. The results point to the existence of an antigenic substance in the blood of MS patients. When the LAI test was modified by the addition of calf serum there was a significant reaction of the leucocytes of MS compared to other neurological diseases and controls. The relatively high positive rate in MS previously reported was not detected. Therefore, further analyses concerning the characterisation of the antigen and the conditions of the test system will be necessary before the method can be used for diagnosis.

[The macrophage electrophoretic mobility LAD test - a diagnostic method for multiple sclerosis.]. / Der Makrophagen-Elektrophorese-Mobilitäts-LAD-Test als diagnostisches Verfahren für die multiple Sklerose.

With the MEM test (Field) one can establish a cellular immune reaction because the sensitized lymphocytes release the macrophage slowing factor (MSF) upon interaction with the appropriate antigen. A macrophage migration inhibition was detected in some neurological diseases with destruction of the parenchyma. The modification MEM-LAD (linoleic acid depression) test made further differentiation possible in the 146 neurological patients and normals. The reduction of macrophage mobility inhibition was 94.7+/-4.7% in multiple sclerosis (MS) cases as compared with that of normals of 55.1+/-3.7% and of other neurological diseases of 47.8+/-7.1%. There were no significant differences due to the course and duration of the disease or to immunosuppressive therapy. The pathogenically important results in relatives of MS patients with values between the MS and normal group (78.5+/-0.7%) in mothers suggested a familial (genetic) disposition. The same value was found in a monozygotic twin of an MS patient. The results in the children studied showed that besides the endogenic metabolic component the aetiopathogenically important exogenic factors can operate early in life. In correlation with the principle of the MEM-LAD test the suppressive action of linoleic acid can result in a further therapeutic concept.

[The macrophage electrophoretic mobility LAD test--a diagnostic method for multiple sclerosis (author's transl)]. / Der Makrophagen-Elektrophorese-Mobilitäts-LAD-Test als diagnostisches Verfahren für die multiple Sklerose

With the MEM test (Field) one can establish a cellular immune reaction becarus the sensitized lymphocytes release the macrophage slowing factor (MSF) upon interaction with the appropriate antigen. A macrophage migration inhibition was detected in some neurological diseases with destruction of the parenchyma. The modification MEM-LAD (linoleic acid depression) test made further differentiation possible in the 146 neurological patients and normals. The reduction of macrophage mobility inhibition was 94.7 + 4.7% in multiple sclerosis (MS) cases as compared with that of normals of 55.1 + 3.7% and of other neurological diseases of 47.8 + 7.1%. There were no significant differences due to the course and duration of the disease or to immunosuppressive therapy. The pathogenically important results in relatives of MS patients with values between the MS and normal group (78.5 + 0.7%) in mothers suggested a familial (genetic) disposition. The same value was found in a monozygotic twin of an MS patient. The results in the children studied showed that besides the endogenic metabolic component the aetiopathogenically important exogenic factors can operate early in life. In correlation with the principle of the MEM-LAD test the suppressive action of linoleic acid can result in a further therapeutic concept.

[Demonstration of a factor in cerebrospinal fluid with inhibitory activity for electrophoretic cell mobility in multiple sclerosis (author's transl)]. / Nachweis eines Faktors mit elektrophoretischer Zellmobilitätshemmung im Liquor cerebrospinalis bei Multipler Sklerose

Inhibition of electrophoretic cell migration using cerebrospinal fluid (CSF) directly was investigated by the modified MEM (macrophage electrophoretic mobility) and TEEM (tanned sheep erythrocyte electrophoretic mobility) tests, respectively. An inhibitory activity of macrophage slowing factor (MSF)--one of in vivo lymphokines--in CSF was established in cases of multiple sclerosis (17.5 +/- 3.8%), and neurolues. The value of this MSF assay turned out to be significantly different from the remaining inflammatory ailments of the nervous system (10.1 +/- 6.8%). Results of other neurological diseases were found to be very much lower (5.1 +/- 4.2%). It seems important, for immunopathogenesis and the diagnosis of neuroimmunological diseases with enhanced cellular immunoreaction, to evaluate MSF activity in CSF. To characterize the active factor in CSF (and serum) these fluids were fractionated by gel filtration chromatography as well as supernatants from lymphocyte-antigen incubation in MS patients. The main activity for inhibition of electrophoretic cell mobility was eluated in the same fraction in these fluids. It could be shown that units have a molecular weight of about 15000 Daltons; this value for MSF lies below those for other inhibitory lymphokines.

Anomalous lymphocyte-antigen reaction in relatives of multiple sclerosis patients. A study of a possible genetic factor in the disease.

A combined familial study of multiple sclerosis (MS) in England and in the Rostock area of the GDR using the macrophage electrophoretic mobility (MEM)-LAD test embracing 132 relatives has revealed a closely similar pattern of distribution of "anomalous" LAD (Linoleic Acid Depression) values in relatives (77% type of reaction) to that originally reported in the British study. The anomaly in predominantly associated with females--all mothers of MS patients being affected, whilst daughters and sisters are also represented. In addition unusual full MS type of reaction (90% reduction) has been found in some children related to patients. There is clearly a genetic element in the development of MS probably mainfested in the inborn mishandling of unsaturated fatty acids suggested by Thompson; no recognizable pattern of inheritance is noticeable even within the combined material. There is evidence that the metabolic anomaly alone does not inevitably lead to MS, and the full abnormality may be present at an early age. A survey about the examinations and a selection of characteristic family trees of MS are given, illustrating the manner in which the 77% type anomaly is distributed with occasional omission of a generation.

Aspects of cellular immunity in multiple sclerosis. Antigen-reactivity of lymphocytes and lymphokine activity.

Some new results of cell-mediated immunity in multiple slcerosis (MS) are presented, based on the determination of charge-changing lymphokines as products of antigen sensitive lymphocytes (C PAL), obtained by several forms of the electrophoretic mobility (EM) method. Lymphocytes from MS react to myelin basic protein (BP), the reactivity in other neurological diseases depending on the degree of destruction of nervous parenchyma. Applying a membrane-associated antigen from normal brain (NTA), positive reactivity of MS lymphocytes was obtained. Besides the usual determination of lymphokines in vitro the sensitive EM test allows the demonstration of lymphokine activities in vivo; i.e. in body fluids such as cerebrospinal fluid (CSF) and serum. In CSF of MS a high lymphokine activity was found. The differentiation of lymphokines and comparison between in vitro and in vivo activity were carried out. Moreover, a characteristic lymphokine pattern for MS with high activities in all regions of molecular weight, especially in the CSF, could be detected. On the basis of these findings, important also from the pathogenetic point of view, a diagnostic scheme for MS is suggested, consisting of a program of determination of the immuno-reactive CSF syndrome and some special procedures, including examination of lymphocyte reactivity.

[Basic principles and application of cerebrospinal fluid immunoelectrophoresis]. / Grundlagen und Anwendung der Immunelektrophorese des Liquor cerebrospinalis1

The basic principles, prerequisites, and limitations of the immunoelectrophoresis of the cerebrospinal fluid are discussed. Major emphasis has been placed on the characteristics of normal and pathological immunoelectropherograms of the liquor cerebrospinalis as well as on the results of studies of inflammatory and neuroimmunological diseases. The detection of a barrier profile, the method of determining special qualitative alterations of immunoglobulins of the liquor cerebrospinalis due to neuroimmunological diseases, and additional applications are discussed in detail. The procedure has been critically reviewed because the results obtained are, for the most part, of a general and nonspecific character and the method cannot be standardized adequately and also does not yield sufficient quantitative data. The advantages (differentiated qualitative changes) and disadvantages (technique troubles) are pointed out.

[Cerebrospinal fluid diagnosis of multiple sclerosis]. / Liquordiagnostik bei der Multiplen Sklerose

Starting from the knowledge accumulated with respect to the etiopathogenesis and the components of immunoreaction a minimal to maximal program by steps has been developed for the cerebrospinal fluid (CSF) in multiple sclerosis (MS). It is based on fundamental methods (I), special supplementary methods (II), and relatively specific immunological methods (III). For MS five possible conditions of the CSF could be determined from alterations of cells and variations in protein: a (1) typically complete and (2.) typically incomplete immunoreactive encephalomyelitic (encephalitic) syndrome, a (3.) nonspecific CSF-syndrome of low degree and less typical character (in the sense of an acute or subacute irritation syndrome) an (4.) atypical syndrome of a considerable degree, and a (5.) normal condition of the cerebrospinal fluid. The significance of immunoreactive cerebrospinal fluid syndromes to the diagnostic criteria of multiple sclerosis as well as further relatively disease-specific methods (such as the MEM test and MSF assay) of determining cellular immunity, are discussed.

[Etiology and pathogenesis of multiple sclerosis: current aspects of causative factors in the disease course]. / Atiologie und Pathogenese der Multiplen Sklerose: derzeitige Aspekte zu den Ursachefaktoren des Erkrankungsablaufs.

The components of pathogenesis of multiple sclerosis are presented. (I.) Genetic and metabolic factors were found to be fundamental for cellular immune reaction; the association with class 2 MHC (HLA-DR; IR) antigens is more relevant than that of class 1 MHC (HLA-ABC) antigens. (II.) A reaction to several viruses may be significant for the induction and the heterogenous course of disease; some mechanisms of an immune-dysbalance--induced by viruses--are exposed. (III.) Disturbances of cellular immunoregulation, a reduced activity of T-suppressor-lymphocytes, a break of immune tolerance and cytotoxic effector mechanisms are decisive for the autoimmune processes. In all, on the basis of multi-genetic anomalies a multi-phase pathogenesis may be assumed, developing in manner of a cascade in several steps and phases.

[Development of the neurophysiologic department in Rostock--a contribution to the specialization of the specialty of neurology]. / Zur Entwicklung der Neurologischen Abteilung in Rostock--Ein Beitrag zur Spezialisierung des Fachgebietes Neurologie.

The development of the subject of neurology has been stated with special regard to the department of neurology of the university of Rostock--from the time when Sayk took the professorship 22 years ago. The specialization beginning in this period before all concerns the scope of diagnostics (neuroradiology, neuro-electrodiagnostics, cerebrospinal fluid--resp. laboratory diagnostics) and--arising from the requirements of clinical neurology--the concentration upon distinct centres of scientific activities. Beside the representation of the tasks of work are given data about several results of research in the traditional field of cerebrospinal fluid (CSF cytology) and the branch of neuroimmunology (cell-mediated immunity) in Rostock. Some questions of basic research and special subjects as well as the actual trends--relevant for neurology--are presented.

[Encephalomyelitis syndrome in the cerebrospinal fluid in correlation to disease course criteria in multiple sclerosis]. / Encephalomyelitis-Syncrome im Liquor cerebrospinalis in Korrelation zu Verlaufskriterien bei der Multiplen Sklerose.

Basing on a classification of the dynamic forms of multiple sclerosis according to prognostic-social aspects and in view to different degrees of defect the incidence of the five possible syndromes of cerebrospinal fluid were subjected to a correlation in 345 cases. In moderate till severe grades of neurologic disturbances and courses of illness an immunoreactive syndrome of cerebrospinal fluid - typically complete to incomplete - was doing found (in ca 40%). The slighter forms of the disease predominantly presented the whole spectrum of possible findings of cerebrospinal fluid; in it the syndromes with unimportant deviations were prevailing. In the course of multiple sclerosis alterations in the constellation of cerebrospinal fluid in manner of a retrograde tendency were scarcely noted. An increase of pathologic parameters in cerebrospinal fluid did rather show the slighter forms, in the severe progredient courses the syndromes turned out to be comparatively constant.

Mixed lymphocyte reaction in multiple sclerosis.

The mixed lymphocyte reaction (MLR) as measured by the macrophage electrophoretic mobility (MEM) test is markedly reduced between unrelated multiple sclerosis (MS) patients. This is not the case with other neurological diseases (OND). Within an MS family, the MLR between the propositus and members of the family falls into the low (MS type) range or into the normal or OND range. Those members who give the low results are those who have a MEM-LAD test result of about 77 per cent, i.e. halfway between that of normal and MS. There is thus a parallelism between the anomalous response to linoleic acid and an unexpectedly low MLR with known MS lymphocytes. Lymphocytes from apparently normal children who have a high (MS-type) linoleic acid depression result take part in an MLR with MS cells, as if they were themselves true MS cells. Some possible implications these findings may have for the pathogenesis of MS are discussed.

[Aspects of immunologic diagnosis of brain tumors. Results with tumor-associated membrane antigens and the electrophoretic mobility test (author's transl)]. / Aspekte der immunologischen Diagnostik von Hirntumoren. Ergebnisse mit tumorassoziierten Membranantigenen und dem Elektrophorese-Mobilitäts-Test.

In cell-mediated immune processes the products of antigen-sensitive lymphocytes are detectable as charge-changing lymphokines by means of the cell electrophoretic mobility method (EM test). the improvement of the method concerns the measuring procedures (indicator particle and automation) and the application of specific antigens. The employment of special membrane antigens (3 M KCl extracts) from tissue of normal brain and brain tumors is decisive for further differentiating results. The application of tumor-associated membrane antigens (TAA) from various kinds of brain tumors shows some diagnostically important reaction patterns. Using a common tumor antigen, the TAA-X3 mixture, a (1) characteristic result of general significance for neoplasms can be obtained; in applying the different TAA of brain tumors the findings in EM test point out an (2) organospecific reactivity and/or a (3) histogenetic reaction pattern. The distinct neuroepithelial and mesodermal brain tumors produce predominantly an organospecific reaction and only partly a histogenetical profile. For this type of reactivity to the TAA in brain tumors, a series of factors depending on neuroimmunological specialities are important.

Classical and modern methods of cerebrospinal fluid analysis. Report on the First All-German Symposium of the Society for Laboratory Medicine (FRG) and the Study Group for CSF Analysis and Clinical Neurochemistry of the Society for Psychiatry and Neurology (formerly GDR) in Marburg a. d. Lahn, October 5-6, 1990.

The aim of the symposium was to prepare an inventory of cerebrospinal fluid (CSF) analysis used in Germany, and to evaluate them in comparison with modern methods. From the large field of CSF analysis, four main topics were selected, all related to the practical application of the methods. The following conclusions were drawn: Classical techniques of cytodiagnosis are clinically important. Therefore, manual and mechanized techniques must be further improved with respect to counting, collection, and differentiating of CSF cells. As cytokines and complement factors are early mediators of diverse processes in CNS, highly sensitive techniques must be developed for their routine analysis e.g. in CNS inflammation. Recent efforts to detect specifically viral and bacterial agents (e.g. by polymerase chain reaction, Particle Counting Immuno-Assay, Enzyme Immuno-Assay) or antibodies (e.g. affinity-mediated immunoblot, specific antibody index) in CSF must be continued in order to develop definite and practicable assays for daily routine. For the detection of intrathecally produced antibodies, qualitative procedures appear to be more reliable then quantitative ones, provided that the former are highly sensitive and specific.

[Experimental prevention and suppression of neuroallergic diseases]. / Zur experimentellen Prävention und Suppression neuroallergischer Erkrankungen.

For concepts of therapy for neuro-allergic diseases, especially of the encephalomyelitis disseminata type the experimental allergic encephalomyelitis (EAEM)--as a neuro-immunological disease of the first order and a classic pattern for the specification of immunological processes--can be used for more and more extensive testing. After an exposition of the different forms of treatment (prevention, suppression and therapy) and their value the possibility of inducing tolerance a versus the encephalitogenic protein is discussed following the EAEM example--taking the view that all measures taken up to now in the case of neuro-allergic diseases have been unspecific and consequently not set down. In addition emphasis was laid on the assumption of tolerance induction after sensitization which is important to the formation of a therapy for encephalomyelitis disseminata.

[Aspects of the value of humoral antibodies in encephalomyelitis of neuroallergic origin]. / Aspekte des Bedeutungswertes humoraler Antikörper bei der Encephalomyelitis neuroallergischer Genese

The importance of humoral antibodies formed in the course of neuroallergic diseases characterized by a cytergic type of reaction and especially in the course of experimental allergic encephalomyelitis (EAEM) is discussed, special attention being given to the importance of pathogenetic, immunodynamic, diagnostic, and therapeutic factors. The circulating antibodies of EAEM induced by cellular and humoral immunoprocesses are assumed to produce either intensifying or mitigating effects. Among the most important functions are the influence of immune globulins on the blood/brain boundary lesion, the gliotoxic and myelinotoxic effects, and the detection of a blockade of the intraneural transmission. The therapeutical effect to be discussed in the light of the protective effects of humoral antibodies is a mere conception in view of incompletely understood mechanisms including those governing the chronology and dynamics of immunoprocesses associated with multiple sclerosis, especially since the antigen-specific induction of tolerance appears to be far more essential.