[Cerebrospinal fluid diagnostics in Germany since 1950 : Developments in the GDR and FRG in the context of society and science]. / Liquordiagnostik in Deutschland nach 1950 : Entwicklungen im Kontext von Wissenschaft und Gesellschaft in DDR und BRD.

The 40 years of separated development in two countries with extremely different political and social utopias allow consideration of the connection between science and society. The society-dependent development of cerebrospinal fluid (CSF) diagnostics in the German Democratic Republic (GDR) and the Federal Republic of Germany (FRG) is shown in the context of the international scientific development of the post-war era with new paradigms in physics, biology and genetics. As part of this contribution to the philosophy of science the consequences of the complex life science for a new view of disease research are discussed in contrast to the currently dominating, reductionistic medical industrial complex.

Intrathecal IgM synthesis in pediatric MS is not a negative prognostic marker of disease progression: quantitative versus qualitative IgM analysis.

BACKGROUND: Intrathecal IgM synthesis is reported to be associated with a worse prognosis in adults with multiple sclerosis (MS). OBJECTIVE: To study the predictive value of intrathecal IgM synthesis for the clinical course of pediatric MS. METHODS: Seventy children with onset of MS before the age of 16 years and followed for a median period of 10.4 years (range: 0.4-22.8 years) were studied. The two subgroups with (n=44) or without (n=26) intrathecal IgM synthesis were distinguished by a new, very sensitive, evaluation of quantitative analysis in cerebrospinal fluid (CSF)/serum quotient diagrams (Reibergrams). The clinical course and EDSS (Expanded Disability Status Scale) scores at five and ten years were compared with IgM frequencies between both groups with a new statistics program for CSF data. RESULTS: The cohort of children without intrathecal IgM production had higher numbers of attacks in the first two years and shorter time intervals between first and second attack, although this was not statistically significant (p=0.04, p=0.15 respectively). In addition there was also a trend for girls without intrathecal IgM synthesis to have a higher EDSS score after 10 years compared with the group with IgM synthesis. CONCLUSION: Intrathecal IgM synthesis is not associated with a more rapid progression of disability in pediatric MS. Reevaluation of data from previous reports about the negative predictive value of intrathecal IgM synthesis in adult MS with a CSF statistics tool show that the apparent contradiction is due to a methodological bias in the qualitative detection of 'oligoclonal' IgM or linear IgM index.

Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction.

Immune and inflammatory mechanisms are detected in a subgroup of treatment resistant hospitalized affective and schizophrenic spectrum disorder patients. We analysed albumin, IgG, IgA, IgM, oligoclonal IgG and specific antibodies in paired cerebrospinal fluid (CSF) and serum samples. Numerical and graphical interpretation of CSF protein data was performed by Reibergrams with a new CSF statistics tool for nonlinear group analysis with reference to a large control group (n=4100). In 41% of the psychiatric patients (n=63) we observed CSF pathologies: 14% displayed intrathecal humoral immune responses, 10% slightly increased CSF cell counts (5-8/microL) and 29% had moderate blood-CSF barrier dysfunctions, in 24% as the only pathological sign with normal IgG, IgA and IgM concentrations in CSF (p=0.9 testing the null hypothesis for intrathecal synthesis with reference to Qmean of the reference group). In the group of affective (n=24) spectrum disorders 20% displayed a systemic immune reaction as detected by oligoclonal IgG. CSF analysis and interdisciplinary clinical approach revealed 6% of psychiatric patients likely to represent a virusspecific, bacterial or autoimmune associated disorder with CNS involvement. Elevated CSF neopterin concentration in 34% of the patients was interpreted as an increased release from astrocytes or from other glia cells. The low level immune response and barrier dysfunctions are discussed on the base of a mild encephalitis pathomechanism in subgroups of psychiatric patients. CSF analysis is shown to be a useful diagnostic tool for differential diagnosis in psychiatric diseases.

Paediatric and adult multiple sclerosis: age-related differences and time course of the neuroimmunological response in cerebrospinal fluid.

We investigate common pathophysiology in paediatric and adult multiple sclerosis (MS) by comparison of cerebrospinal fluid (CSF) data. We compared cerebrospinal fluid (CSF) data from eight patient groups with onset of MS at 7 to 29 years (n = 184). A new statistics program allows sensitive detection, quantifies the mean amount of intrathecal Ig synthesis in groups based on the 96% reference range of 4100 non-inflammatory controls, corrects for age-related increase of blood-derived albumin and immunoglobulins in CSF, and presents graphical data interpretation in Reibergrams. Already at onset of MS before puberty (< or =10 years) the frequency of intrathecal IgG synthesis (oligoclonal IgG) was 100% like in adults with 98%, but the amount of intrathecal IgG increases twofold during puberty. Intrathecal IgM synthesis is most frequent before and during puberty (in 57-67% of patients) compared with 41% in adults. The amount of intrathecal IgM synthesis before puberty is only 30% of that in adults. IgG and IgM Index are biased evaluations not suitable for characterizing age-related dynamics. A twofold age-related increase of the albumin quotient, Q(Alb), as a measure of the blood-CSF barrier function, represents normal physiological growth. Cell counts in CSF are low. The pre-puberty gender ratio is about 1:1. Intrathecal antibodies against measles, rubella and/or varicella zoster virus are detected in 73% of patients before puberty compared with 89% of adults. Individual paediatric patients (n = 17), with sequential punctures over 2-5 years, show constant quantities of intrathecal IgM and specific antibodies. In conclusion, paediatric MS already at first clinical manifestation shows the complete, neuroimmunological data pattern in CSF, i.e. inflammatory signs are not gradually evolving. Paediatric and adult MS differ quantitatively but not qualitatively in neuroimmunological patterns which does not allow for discrimination between 'early' and 'late' onset MS. CSF analysis may help to discriminate between acute and mono-symptomatic chronic inflammatory disease already at earliest clinical manifestation.

Cerebrospinal fluid analysis for diagnosis of noninflammatory, dementive and psychiatric diseases.

CSF analysis contributes to differential diagnosis of noninflammatory diseases by: 1) exclusion of a chronic or acute inflammation. 2) detection of particular brain-derived proteins, surrogate markers, corresponding to the suggested diagnosis (tumor, dementia, brain hypoxia, hemorrhage, autoimmune disease, psychiatric disease, metabolic disorder, rhinorhea, Table 1) and 3. differential cell count in CSF. Interpretation of brain-derived proteins in CSF uses absolute concentrations (in contrast to CSF/serum quotients for blood-derived proteins) and must discriminate between different sources: Neuronal or glial proteins like NSE, or tau protein are evaluated using their absolute concentrations in CSF for maximal sensitivity without reference to QAlb. The leptomeningeal proteins like beta trace or cystatin C are evaluated as absolute concentrations with reference to QAlb. As application examples we review the group of dementive and psychiatric diseases. Alzheimer's disease, Parkinson's disease dementia, Lewy-body disease and frontotemporal dementia are the major causes of neurodegenerative memory impairment and dementia. Combined analysis of Tau-Protein and Beta Amyloid 1-42 in CSF represent the classic approach, meanwhile extended with further surrogate markers. In 15% of psychiatric patients with schizophrenic or affective disorders an inflammatory process could be detected which points to a brain-organic involvement. In 24% of these patients with a psychiatric disease a moderately increased albumin quotient was observed as the only unexplained pathological sign. In psychiatric diseases it has to be regarded as a serious deficit not to make at least once a CSF analysis in the patients which could modify the diagnosis (in 6%).

Quantitation of intrathecal antibodies in cerebrospinal fluid of subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis: discrimination between microorganism-driven and polyspecific immune response.

The detection of intrathecal antibody synthesis by qualitative methods or the Antibody-Index (AI) is a relevant tool for diagnosis of inflammatory neurological diseases. An increased AI can be observed for a causative antigen as well as part of a polyspecific immune response. The quantitation of the intrathecal antibody fraction in cerebrospinal fluid (CSF), F(S), helps to discriminate both cases. In contrast to AI, F(S) needs an absolute antibody concentration detected in the ELISA in mg/L. The intrathecally synthesized, "local" antibody concentration in CSF (AB(Loc)) is expressed as the specific fraction of the intrathecally synthesized total IgG (IgG(Loc)) in CSF with F(S)=AB(Loc)/IgG(Loc) x 100 in %. F(S) for HSV or measles has about 20- to 60-fold higher values in virus-caused antibody synthesis in acute herpes simplex encephalitis (mean HSV-F(S)=8.9%) or subacute sclerosing panencephalitis (mean measles-F(S)=18.8%) compared to the polyspecific immune response against these antigens e.g., in multiple sclerosis (0.14% or 0.52%, correspondingly). F(S) helps also to avoid misinterpretations of an increasing AI in cases of therapy control, and allows direct comparison of relative antibody concentrations (R(S)) in blood and intrathecally synthesized fractions in CSF (F(S)): In multiple sclerosis patients F(S):R(S) has a mean ratio of about 3 for the measles, rubella and VZV antibodies. Together with the large variability we find by ranking that about two third of MS patients have no direct correlation of the relative concentrations in serum and intrathecal synthesis. So this concept gains increasingly relevance for analysis of the polyspecific immune response in brain.

Intrathecal polyspecific immune response to neurotropic viruses in multiple sclerosis: a comparative report from Cuban patients.

OBJECTIVE: Intrathecal measles(M)- rubella(R)- and varicella zoster(Z)-antibody synthesis in German and Cuban multiple sclerosis (MS) patients are compared considering the different rubella epidemiology in the tropics. PATIENTS AND METHODS: Twenty-three Cuban MS patients with a representative age distribution and gender ratio like the group of 177 German MS patients were analysed for albumin, IgG, IgA IgM, oligoclonal IgG and MRZ- antibodies in cerebrospinal fluid (CSF) and serum. RESULTS: Cuban MS patients show similar CSF data patterns like German patients and high frequencies of intrathecal measles- (78/78%) and varicella zoster- (59/55%) antibody synthesis correspondingly. A lower frequency of intrathecal rubella antibody synthesis (rubella-AI >or= 1.5) in Cuban patients (30%, gender ratio of increased rubella - AI m:f = 1:6) compared with German patients (60%, m:f = 1:1.8) is explained by low incidence of rubella infections in Cuba. Only about 10% of the male population (not immunized before 1986, in contrast to females) had rubella antibodies compared to at least 60% in a European male population, representing the relation of increased rubella-AI in male MS patients. CONCLUSION: In MS the frequency of intrathecal antibody synthesis is limited by the fraction of seropositives in the population. Natural infection or vaccination are a necessary and equivalent precondition contributing to the arguments against microorganisms as a cause of MS.

Immunoglobulins and virus-specific antibodies in patients with Creutzfeldt-Jakob disease.

OBJECTIVES: Cerebrospinal fluid (CSF) pattern in patients with neuropathologically diagnosed Creutzfeldt-Jakob disease was analyzed. MATERIAL AND METHODS: Routine tests included white blood cells count, protein, albumin, immunoglobulins and the presence of oligoclonal immunoglobulin G (IgG) in the CSF as well as the calculation of intrathecal synthesis of immunoglobulins by standard methods. In addition, antibodies against neurotropic viruses such as measles, rubella, varicella zoster and herpes simplex were measured and the specific antibody index was calculated. RESULTS: A blood-CSF barrier dysfunction was observed in six of 25 cases. In CSF/serum quotient diagrams, no patient had intrathecally synthesized immunoglobulins, but in two of 25 patients oligoclonal bands were detected. Two patients had intrathecally synthesized antibodies against varicella zoster and three against herpes simplex virus. CONCLUSION: In conclusion, in the routine diagnosis, the CSF in CJD is normal in most cases. In some patients, abnormalities include the blood-CSF barrier dysfunction, mild pleocytosis, oligoclonal bands and intrathecally synthesized viral antibodies.

CSF characteristics in early-onset multiple sclerosis.

The authors studied CSF characteristics in 136 patients with multiple sclerosis (MS) with a disease onset before age 16. In the initial diagnostic lumbar puncture, CSF-pleocytosis was observed in 66%, blood-CSF barrier dysfunction in 13%, and oligoclonal IgG in 92% of the early-onset MS (EOMS) patients. CSF oligoclonal IgG supports the early diagnosis of MS in childhood with a sensitivity similar to adult-onset MS.

[Molecular diffusion/cerebrospinal fluid flow theory]. / Teoria de la difusión molecular/flujo del líquido cefalorraquídeo.

AIM: To review the fundamental aspects of the theory of the molecular flow/ cerebrospinal flux described recently and it can explained a group of events in the physiology of the cerebrospinal fluid and the physiopathology of neurological diseases. DEVELOPMENT: This theory was based on the postulate that a decrease of the flux rate of the cerebrospinal fluid was accompanied by an increment of the protein concentration in it and in the nervous system tissue. The increment of the protein transport from the blood to the cerebrospinal fluid not require structural changes or an increase of permeability. The reibergram or Reiber's quotient diagram, with the discriminatory hyperbolic function with its theoretical basis and its clinical relevance confirm the acceptance of the present theory. This theory was based on the first and second Fick's diffusion laws The increment of the molecular diffusion is the cause of the non-linear decrease of the cerebrospinal flux rate because of the blood-cerebrospinal fluid barrier dysfunction. CONCLUSIONS: This theory explain that an increase of the albumin quotient does not means a morphologic change on the barrier structures. The change in the cerebrospinal flux rate it has been considered the principal modulator of the protein concentration in cerebrospinal fluid in pathological conditions characterized by a blood-cerebrospinal fluid barrier dysfunction.

Beta-trace protein as sensitive marker for CSF rhinorhea and CSF otorhea.

OBJECTIVE: Beta-trace protein concentrations in cerebrospinal fluid (CSF), serum and nasal secretions are investigated with a new quantitative, immunonephelometric assay. RESULTS: The mean beta-trace concentration of normal lumbar CSF (18.4 mg/l) and normal serum (0.59 mg/l), from n = 132 control patients, were 10% higher than reported earlier for smaller control groups. The reference range of beta-trace protein in nasal secretions is very low (median: 0.016 mg/l, range <0.003-0.12 mg/l, for n = 29 controls). Clinically confirmed cases of CSF rhinorhea (n = 20) showed beta-trace concentrations between 0.36 and 53.6 mg/l, with a median of 2.4 mg/l. We propose a cut-off value of 0.35 mg/l above which a CSF contamination in the secretion is plausible. A clinically confirmed CSF otorhea had a value of 1.75 mg/l. CONCLUSION: This new beta-trace protein assay offers a fast, sensitive and reliable routine method to detect a CSF rhinorhea or otorhea.

Chlamydia pneumoniae in children with MS: frequency and quantity of intrathecal antibodies.

The authors investigated the frequency and quantity of intrathecal antibody synthesis against Chlamydia pneumoniae and the presence of C pneumoniae antigen in 25 children with MS. C pneumoniae genome was present in two children. In seven children an intrathecal synthesis of C pneumoniae antibodies was detected, representing only a small part of the total intrathecal immunoglobulin G, suggesting that this intrathecal synthesis is part of a polyspecific, oligoclonal immune response.

[Intrathecal synthesis pattern of immunoglobulins in meningoencephalitis epidemic due to echovirus 9]. / Patrones de síntesis intratecal de inmunoglobulinas en epidemia de meningoencefalitis por echovirus 9.

INTRODUCTION: Epidemics of meningoencephalitis due to echovirus 9 were commonly occurred when a children population become susceptible for the first time in front the virus. OBJECTIVE: To present the intrathecal synthesis pattern of immunoglobulins of the epidemic that affected Cuba in 1999 and to probe the usefulness of reibergram and antibody index in the diagnostic and characterization of the outbreak. PATIENTS AND METHODS: 23 pediatric patients suffering from viral meningoencephalitis due to echovirus 9 were studied in the income moment. Serum and cerebrospinal fluid IgA, IgM, IgG, albumin and glucose were quantified. Cerebrospinal fluid total protein content and lactate were quantified. Titles of antibodies against echo 9 and Coxsackie A9 and differential cell count were performed. RESULTS: A mean of 555 cells/10 6 L mainly lymphocytes were obtained. Glucose in cerebrospinal fluid was over 50%, serum glucose and lactate levels below 2.1 mmol/L. In the reibergram an absence of intrathecal synthesis was predominant (15/23), IgM synthesis (6/23) and IgM+IgA (2/23). Blood cerebrospinal fluid dysfunction was observed in 15 patients. The mean antibody index was 1,8 for echo 9 and 0,9 for Coxsackie A9. CONCLUSIONS: The intrathecal synthesis pattern of immunoglobulins was different from other enterovirus and from echovirus 9 in non epidemic situations before this epidemic, probably with alteration of viral genome.

[Neuroimmune epidemiological value of reibergram in the first echovirus 16 meningoencephalitis outbreak in Cuba]. / Valor neuroinmunoepidemiologico del reibergrama en la primera epidemia de meningoencefalitis por echovirus 16 en Cuba.

INTRODUCTION: During the third quarter of 2000, an outbreak of echovirus 16 meningoencephalitis was firstly occurred in Cuba and produced vomiting, headache, fever and exanthem that differentiate it from other enterovirus epidemies. OBJECTIVE: To describe the intrathecal immunoglobulin synthesis pattern of the epidemie from the reibergram. PATIENTS AND METHODS: Diagnostic serum and cerebrospinal fluid from 18 children during the acute phase by nephelometrie assay, besides cytochemical and virological study. RESULTS: A predominant absence of intrathecal immunoglobulin synthesis and two patients with IgA and IgM synthesis was produced. 66% of cerebrospinal blood barrier dysfunction, 6.26 10 3 mean albumin ratio, lactate below 2.1 mmol/L and glucose concentration in cerebrospinal fluid was 50% over glucose blood content and 168 cells 10 6 L mainly lymphocytes were observed. CONCLUSIONS: The intratecal immunoglobulin synthesis pattern differs from other enterovirus outbreaks that have affected this population and it seems the one found for the diagnostic period in adults. This finding alerts the possibility of genetic changes in echovirus 16 strain, interesting from the neuroimmunoepidemiological point of view.

Dynamics of brain-derived proteins in cerebrospinal fluid.

BACKGROUND: The recent theory of blood-cerebrospinal fluid (CSF) barrier function and dysfunction connects molecular flux and CSF flow rate. A reduced CSF flow rate is sufficient to account for the observed hyperbolic relation between different blood-derived protein concentrations in CSF in cases of a blood-CSF barrier dysfunction. METHODS: The dynamics of brain-derived proteins in CSF are investigated with reference to the CSF flow rate measured by CSF/serum albumin concentration quotient. RESULTS: Proteins from neurons or glial cells, tau protein, neuron-specific enolase, S-100 protein, all enter CSF primarily in the ventricular and cisternal space. Their concentration between normal ventricular and lumbar CSF is decreasing (in contrast to blood-derived proteins), and in the case of pathologically decreasing CSF flow rate, the concentration in lumbar CSF remains invariantly constant. Concentrations of the primarily leptomeningeal proteins, beta-trace protein and cystatin C, increase between normal ventricular and lumbar CSF, and in the case of pathologically decreased CSF flow rate they increase linearly in lumbar CSF (concentrations of blood-derived proteins increase non-linearly). CONCLUSIONS: A satisfactory physiological explanation can now be given for the dynamics of proteins in CSF consisting of both brain- and blood-derived fractions (transthyretin, soluble intercellular adhesion molecule (s-ICAM)), as well as the disputed decrease of leptomeningeal protein concentrations (beta-trace protein, cystatin C) in cases of bacterial meningitis is also explained. The biophysical treatment of dynamics in the ventricular and lumbar CSF extends the new theory and shows that CSF flow rate is the most relevant parameter for understanding the pathological changes of both blood- and brain-derived proteins in CSF. The impact on diagnosis of neuro-degenerative diseases is discussed.