Laboratory diagnosis of radicular and pseudoradicular syndromes in cerebrospinal fluid (CSF): reliability of methods in consideration of pathogenetic aspects. Report on section "CSF diagnosis" of 4th Klagenfurter Neurology Workshop Conference on radicular and pseudoradicular syndromes, Klagenfurt, Austria, August 28-29, 1992.

Laboratory tests may be used to confirm the clinical differentiation of pseudoradicular syndromes and radicular syndromes. In the presence of pseudoradicular syndromes, CSF and blood samples yield no positive results with either non-specific or specific methods. Radicular syndromes give rise to positive findings; using non-specific methods they can be subdivided into inflammatory and non-inflammatory forms, with and without blood-nerve barrier impairment. Non-specific quantities of CSF routine diagnosis are total protein, albumin, leukocyte counts and differential cell count, L-lactate, intrathecal -IgG, -IgA, -IgM and immunoglobulin-class oligoclonal bands. Oligoclonal bands enable the highly sensitive differentiation of non-inflammatory from subacute-chronically inflammatory forms of radicular syndromes. Most of the specific quantities are the subject of current research, e.g. bacterial antigens, D-lactate, cultivation tests, polymerase chain reaction tests and pathogen-specific oligoclonal bands. Pathomechanisms affecting the permeability of the blood-nerve barrier to increasing concentrations of protein and to leukocyte subsets possibly explain the CSF findings in radicular and pseudoradicular syndromes.

[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.

[Forms of disease progression and prognostic factors in multiple sclerosis]. / Verlaufsformen und Prognosefaktoren der Multiplen Sklerose.

Basing on the diagnostic criteria, an analysis of 687 cases of multiple sclerosis (MS) is represented according to the different forms of course, their frequency and the degree of severity. For the progressive course--either secondary after attacks or primary--a higher proportion of disease with severe disturbances resp. comparatively malignant forms have been found; furthermore, a critical time of progression could be ascertained. The determination of the disability status (using the EDSS) during a longer space of time showed a more unfavourable prognosis for the males. The development of disability was more distinct at onset of disease in the elder-aged groups. The problems of uncertain factors influencing the course and prognosis of disease are pointed out in connection with the heterogeneity of MS, basing on the pathogenetic components.

[The problem and value of therapy in multiple sclerosis]. / Zur Problematik und Wertigkeit der Therapie bei Multipler Sklerose.

Some fundamental problems of therapy in multiple sclerosis (MS) and the difficulties in assessing the results of treatment are represented. Basing on a survey of several principles of therapy, the findings of own therapeutic trials using corticosteroids, immunosuppressive agents (azathioprine, cyclophosphamide, antihumanlymphocyte globulin) are pointed out; in particular, the analysis of a longer period of the course of disease produced few favourable effects. In further therapeutic studies, i.e. plasmapheresis and immunoadsorption, a long lasting observation of the course is lacking; this likewise concerns the study on ultraviolet irradiation of blood. As to the aspects of a multi-stage pathogenesis of MS an appraisal of therapeutic conceptions and procedures is given; in critical evaluation their efficacy is little convincing.

[Heterogenous immune reactivity in brain tumors: results of cellular immunity in relation to brain tissue antigens]. / Heterogene Immunreaktivität bei Hirntumoren: Ergebnisse zur zellulären Immunität gegenüber Hirngewebsantigenen.

In brain tumors and other neurological diseases cell-mediated immune reactions to fetal brain tissue antigens (FBA), normal tissue antigen of adult brain (NTA) and tumor-associated antigens of different brain tumors (TAA) have been analysed. The detection of sensitized lymphocytes using the MEM-(macrophage-electrophoretic-mobility-) test revealed general tumor-related results applying the FBA, in some extent a cross reactivity and partly no kind of reaction. A phase-specific reactivity to normal brain antigens could not be found, only cases of multiple sclerosis produced restrictive results employing the NTA. By testing tumor-associated brain antigens different reaction types were seen: The common TAA caused a tumor-characteristic reaction; the histo-specific TAA predominantly presented a organotypic form of reaction, confined a histo-specific reaction pattern; in some cases there were found inadequate, non-corresponding reactions as well as unreactivity. With regard to different types of reaction the problems of heterogeneity of the brain tumors and the cellular immune response--i.e. a heterogeneity of 1. or 2. order--were discussed including further factors concerning several special conditions in the nervous system.

[Value of MS associated factors for test procedures in multiple sclerosis: 2. Angers' MS-induced substance in the LAI test]. / Wertigkeit von MS-assoziierten Faktoren für Testverfahren bei der Multiplen Sklerose: 2. MS-bedingte Substanz nach Angers im LAI-Test.

Attempts to find test systems specific for multiple sclerosis are directed to the investigation of MS-associated factors in serum. Basing on the methods of the adherence of antigen-reactive leukocytes, the MSRM (MS-related material) a substance conditioned by the disease was derived from blood of MS-patients and applied in the leukocyte adherence-inhibition (LAI)-test. The mean values in the LAI-test showed a significant difference between MS, the other neurological diseases (OND) and the normals. For the limiting value mean NK +/- 2 s a positive LAI-effect resulted in 58% of the intermittent and in 43% of the chronic-progredient cases of MS, yet also in 11% of the OND. The fact that the rate of detection is lower than that reported by Angers, could depend on factors caused by the method used or by anomalies of immune regulation in MS (including the so-called blocking factors in serum). The results received with LAI-test applying the MSRM don't allow any definite diagnostical assessment specific for MS.

[Value of MS associated factors for test procedures in multiple sclerosis: 1. Carp's MS associated agent in the serum]. / Wertigkeit von MS-assoziierten Faktoren für Testverfahren bei der Multiplen Sklerose: 1. MS-assoziiertes Agenz im Serum nach Carp.

The determination of multiple sclerosis-associated factors in serum is grounded on the conception that there exist virus-like particles with a special predicative value for diagnosis. A test system, elaborated by Carp, is basing on the reduction of neutrophilic granulocytes in peripheral blood of mice by a MS-associated agent (MSAA) of serum, cerebrospinal fluid, brain and other organs of MS-patients. Several groups and the present investigators did not always receive constantly positive findings in applying this method. The cause may be the variation of results characteristic for such biological test systems. As well as for some other methods discussed (e.g. the rosette test with measles-infected epithelial cells or the determination of anomalous cells in bone marrow of MS-patients) the procedure shows an only confined valence, not absolutely specific for the disease in the diagnostical relevant case.

[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.

[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.

[Degree of malignancy in multiple sclerosis: clinicopathologic mortality study]. / Zum Malignitätsgrad der Multiplen Sklerose: klinikopathologische Mortalitätsstudie.

Basing on the neuropathologic findings (acute, subacute resp. chronic demyelination) in 58 cases with multiple sclerosis (MS) the determination of the degree of defect in relation to the duration of working capacity and disability has been carried out in comparison with an index made up for progression and malignancy of the disease. In the final phase of illness an acute exacerbation was noteworthy from the morphological point of view in 48.3% of the patients; in these cases was established a hightened index of malignancy. Differences of sex distribution a. o. pointed to a longer lasting defective (chronic) stage in women. The assessment of progression after a five-year period of examination by a limiting malignancy-index allows a probable prognosis to the chances and the risk of the developing process of disease and may be of importance for care.

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.

Multiple sclerosis--relation between HLA haplotype A25, B18 and disease progression.

The HLA typing of 100 patients with multiple sclerosis (MS) and their differentiation according to the dynamics of the disease, the type of course and the degree of defect showed the following results: a significant increase in frequency of HLA B7 (P less than 0.05), independent of the severity of illness, a 4-fold increased frequency of the HLA haplotype A25, B18 with augmented occurrence in slight to moderate severity of the disability degree (P less than 0.05), less so in the dynamics of the disease, and only partially so in the relapsing-remittent course. These HLA constellations provide only a hint at the prognosis of MS; the findings could be an expression of the heterogeneity of the disease.

[Leukocyte migration inhibition test in multiple sclerosis - results of a migration technic according to Clausen using brain specific antigens]. / Leukozytenmigrations-Inhibitionstest bei Multipler Sklerose - Ergebnisse mit der Migrationstechnik nach Clausen bei Anwendung hirhtypischer Antigene.

The leukocyte migration inhibitory factor (LIF) was examined in 57 test persons--27 patients with multiple sclerosis (MS) and 30 normals--with the indirect and the direct leucocyte migration inhibition test in agarose (LMIAT). The stimulation of lymphocytes was carried out by the application of myelin basic protein (BP) and a membrane-associated antigen of normal brain (NTA). The mean value of controls +/- 2 s and the migration index less than or equal to 0,80 were used for limiting. In the indirect technique could be established significant group effects (NTA- and BP-values of MS cases compared to the controls) after 10 hours of incubation. The direct method showed in MS patients a significant lowered migration-index on an average after stimulation with the NTA; controls gave negative findings (except two cases). The valence of the test system and prospective modifications for further results were indicated.

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.

Application of teem-test for investigations of cellular immune phenomena in multiple sclerosis.

Some evidence is presented for usableness of tanned erythrocytes in electrophoretic mobility (TEEM)-test. Two possibilities of application of TEEM-test for immunological investigation in multiple sclerosis are discussed: detection of lymphocyte sensitization against a soluble antigen (3 M KCl extracted) derived from a normal brain and measurement of mixed lymphocyte reactin (MLR) after a short-time lymphocyte culture. Results show some connection between autosensitization (TEEM-test using normal tissue antigen) and predisposition (TEEM-MLR-test).

[Cytopherometry in neurologic diseases (author's transl)]. / Zur Anwendung der Zytopherometrie bei neurologischen Erkrankungen.

Cytopherometry in neurologic diseases is discussed with regard to antigenic reactivity, the formation of cytokines and the direct changes of electrophoretic mobility of immune-competent cells. The Macrophage-Electrophoresis-Mobility (MEM) test, the variants of the method and additional techniques produced some results of diagnostic and immunpathologic value. A general and unspecific sensitization during cellular immune reaction in lesions of the nervous parenchyma was detectable. Using adequate antigens and extended methods of characterisation in the test system, differentiated reactivity, mainly of the inflammatory diseases and in some pathogenetic processes - including a defect of cell-membrane - was found. Typical findings were shown with the MEM-LAD (linoleic acid depression) test in M.S. This technique led to novel pathogenetic, family-genetic and therapeutic aspects. Similar diagnostic progress in various types of brain tumors was shown by using tumorassociated antigens. Analysis of specific factors of cellular immunity was extented by developing a thymosine assay and direct assessment of cytokines, especially fo the MSF (macrophage slowing factor) in the MSF assay. The thymosine assay may prove valuable for the cellular basis of immunologic processes (in particular myasthenia and therapeutic thymectomy). With the direct MSF assay a differentiated high MSF activity in the CSF in chronic neuroimmunologic processes and particularly in M.S. was shown which led to novel aspects of the immunology of the CSF. The characteristics of the MSF, found after column-chromatographic fractionation, showed identical zytokine activity in CSF and the supernatants of lymphocyte-antigen-incubation which lay in the lower range of molecular weight of migration inhibitory lymphokines.