Biomedical subjects
Publications and source records attributed to K Felgenhauer.
A 57-year-old man on long-term renal dialysis presented with speech dyspraxia, a symptom characteristic of early aluminium encephalopathy. Once fully developed, this condition has a poor prognosis despite deferoxamine (DFO) treatment.
An immunocytochemical technique allowing repeated use of antisera is applied to identify immunoglobulin-containing cells (ICC) of the IgG, IgA, and IgM class in the cerebrospinal fluid (CSF) of 298 patients with various neurological disorders. The demonstration of ICC in the CSF is highly indicative of an inflammatory disease (p less than 0.0001; Chi-square test). In the group of noninflammatory disorders ICC are only found in three cases of lymphomas, two dysgerminomas, and one glioblastoma. ICC of all classes are seen in acute viral and bacterial infections of the CNS including tick-borne meningopolyneuritis Bannwarth. IgG-positive ICC predominate in chronic inflammatory disorders like multiple sclerosis and HIV encephalitis. In HIV-positive patients IgA- or IgM-positive cells are strongly indicative of an opportunistic infection of the brain. Persistent high levels of ICC in three patients with bacterial meningitis are associated with a fatal outcome.
Early diagnosis of acute cerebral ischaemia is still unsatisfactory, because X-ray computed tomography (CT) does not reveal the site and extent of hypoperfusion within the first 24 h. Single photon emission computed tomography (SPECT) using 99mTc-hexamethylpropylene amine oxime (HMPAO) may offer earlier information, since the distribution of HMPAO follows the actual cerebral perfusion pattern. We therefore investigated 53 patients suffering from acute cerebral ischaemia (10 with transient ischaemic attacks, 9 with prolonged ischaemic reversible neurological deficits, 34 with completed stroke). SPECT and CT examinations were performed on days 1, 3, and 14. On day 1, SPECT revealed hypoperfused areas in 42 patients, whereas CT showed hypodensities only in 5. The sensitivity of SPECT was higher in cortical compared with subcortical ischaemia. In patients suffering from reversible neurological deficits SPECT normalized in the follow-up, corresponding to clinical improvement. In completed stroke, SPECT demonstrated variable perfusion patterns with hypo-, normo-, and hypoperfused areas on day 3 and especially on day 14. In contrast to CT, HMPAO SPECT leads to early diagnosis of cerebral ischaemia, in particular within the cerebral cortex.
Multiple sclerosis lesions may occur predominantly in the hemispheric white matter and cause various psychiatric disorders such as remitting-relapsing endoform or exogenous psychosis, organic personality alterations and dementia. Nineteen patients suffering from this encephalitic form of multiple sclerosis as diagnosed by characteristic CSF immunoglobulin findings are analysed according to established psychopathological criteria. All cases began with psychiatric symptoms and neurological signs were either absent or overlooked. Several patients developed typical encephalomyelitic symptoms in successive relapses, but other remained with psychiatric disorders over many years. Only four patients had retrobulbar neuritis, but seven suffered from epileptic seizures. The humoral immune response was characterized by a strong dominance of IgG and a local synthesis of polyspecific antibodies against measles, rubella and varicella/zoster virus. The mononuclear CSF pleocytosis was comparatively marked with cell counts up to 180/microliter.
Applying the immunoblot technique a sensitive and specific method was developed for the detection of intrathecally synthesized antibodies against individual specific proteins that are antigens of various infectious agents causing encephalitis. Paired serum and cerebrospinal fluid (CSF) samples from five patients with herpes virus infections of the central nervous system (CNS) (three herpes simplex virus encephalitis, one varicella zoster virus encephalitis, one zoster ganglionitis) were investigated for the presence of locally produced IgG against the electrophoretically separated antigens of herpes simplex virus (HSV), varicella zoster virus (VZV) and human cytomegalovirus (HCMV), as well as for IgM antibodies in one case of HSV encephalitis. In two cases (HSV encephalitis and VZV encephalitis) four and one antibody, respectively, were found that were synthesized intrathecally only. In the other cases the patterns of sera and CSF antibodies were similar, the CSF antibodies showing an all-over stronger reaction, at identical IgG concentrations. In contrast to the conception of a 'limited heterogeneity' of intrathecal antibody synthesis in encephalitis, we thus found an 'expanded heterogeneity' of the intrathecally synthesized antibodies in comparison to the corresponding serum antibodies.
Six patients with herpes simplex encephalitis were investigated. Antibody activities against different viral antigens were determined in serum and cerebrospinal fluid with an enzyme-linked immunosorbent assay after adjusting both fluids to identical immunoglobulin G concentrations. In serum, the strength of the antiviral reaction remained low and no qualitative changes became detectable. In cerebrospinal fluid, at first locally synthesized antibodies were directed against the same antigens as in serum. Ten days later, the intrathecal reaction increased with additional antibodies against at least two antigens. Once established, this expanded heterogeneity remained stable during the course of the disease.
Intrathecally synthesized antibodies against measles and rubella were determined in 221 patients with multiple sclerosis (MS) and in 476 control cases. A local production was detectable in more than 80% of the MS cases but in none of the control group. These results show that the demonstration of intrathecally synthesized antibodies against neurotropic viruses not related with respective infections may serve as helpful test in the diagnosis of MS.
A method is presented that allows the immunocytochemical detection of varicella zoster virus antigen-binding cerebrospinal fluid cells in zoster ganglionitis. Antigen-binding cells were found only in patients suffering from this disease. The technique is sensitive, specific, inexpensive and relatively fast, and is potentially applicable to other inflammatory central nervous system diseases with immunoglobulin-containing cells (ICC) in CSF. The detection of antigen-binding CSF cells may represent a very early diagnostic test comparable with the early IgM antibodies of the systemic immune response.
Intrathecal antibody responses to HIV were investigated by a highly sensitive immunoblot assay. Serum and CSF specimens were tested for reactivity with the recombinant HIV gag proteins p15, p17 and p24 and with the recombinant transmembrane protein p41. Autochthonous production of virus-specific IgG to one or more HIV structural proteins was seen in 8 of 10 asymptomatic seropositive subjects, in 3 of 4 men with AIDS-related complex, and in 9 of 13 patients with AIDS. These results were consonant with an elevated CSF/serum antibody ratio to total HIV antigen. The high frequency of local HIV-specific antibody synthesis in seropositive individuals without related clinical symptoms indicates an early involvement of the CNS in HIV infections.
A patient is described who developed complex partial seizures with secondary generalization 3 years after a severe viral encephalitis with a CT and EEG identified lesion in the left insular cortex and its surrounding structures. When the seizures first occurred CT and MRI as well as repeated interictal conventional EEG recordings were entirely normal. Single photon emission computed tomography (SPECT), however, revealed an area of increased 99mTc-hexamethyl propyleneamine oxime (HMPAO) uptake in the left insular cortex. After anticonvulsive therapy the seizures and the SPECT findings disappeared. 99mTc-HMPAO SPECT is a highly sensitive method for the demonstration of functional alterations in brain tissue. It can improve diagnosis of epilepsy and may provide additional information to monitor anticonvulsive therapy.
To establish a reliable procedure for the early detection of central nervous system involvement in HIV infection, paired cerebrospinal fluid and serum samples of 59 patients were analysed. Fifteen were HIV antibody positive without clinical symptoms (stage I), 12 had lymphadenopathy syndrome or AIDS-related complex (stage II), and 32 had AIDS (stage III). Intrathecal synthesis of HIV antibodies was determined by a modified ELISA. Antibodies in CSF and serum were evaluated at identical immunoglobulin G levels to correct for the actual blood-CSF-barrier permeability. A CSF/serum quotient above 1.5 is indicative of intrathecal antibody synthesis, which was found in 47% of the patients in stage I, 67% in stage II, and 84% in stage III. These findings indicate an early and frequent invasion of the CNS.
Combined medical, neurological, and serological investigations were carried out in 59 patients infected with human immunodeficiency virus (HIV). In stage I clinical and neuropsychiatric testing did not reveal evidence for HIV encephalitis as diagnosed by local antibody production in CSF. Neuropsychiatric abnormalities, brain atrophy, memory and cognitive impairment reliably indicated HIV encephalitis in later stages. The commonest symptoms were cerebellar and brainstem signs, followed by dementia. Epileptic fits and hemiparesis always were associated with cerebral toxoplasmosis. A polyneuropathy was frequently found but other causes have to be considered.
In two cases of acute encephalitis, there was an intrathecal antibody synthesis against measles virus, as determined with an enzyme-linked immunosorbent assay. The clinical findings were not consistent with a usual measles infection, subacute sclerosing panencephalitis or acute multiple sclerosis.
Cells containing immunoglobulins G, A, and M were evaluated in paired cerebrospinal fluid (CSF) and peripheral blood (PB) samples. These were obtained from 12 patients with bacterial meningitis, 14 patients with viral meningitis, 6 cases of lymphocytic meningoradiculitis (LMR), 10 cases of multiple sclerosis (MS), 6 cases of herpes zoster ganglionitis and 27 patients with non-infectious disorders of the CNS. PB cells from 20 healthy donors served as controls. Using alkaline phosphatase (AP)-conjugated antibodies to human immunoglobulin (Ig) G, A, and M in a carrageenan solution it was possible to demonstrate repeatedly intracytoplasmic Igs over more than 1 year without any detectable loss of specificity and staining intensity. Immunoglobulin-containing cells (ICC) could be detected in the CSF of 96% of patients with inflammatory diseases of the central nervous system (CNS) or with MS but not in the control cases.
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We found that eight of 22 patients with meningeal carcinomatosis from different primary tumors produced local IgG in the CSF, as indicated by elevated IgG index and/or oligoclonal IgG subfractions. Local IgG production, when present, appears in an early stage of the leptomeningeal manifestation and remains detectable over extended observation periods. In autopsied cases with local IgG production, we observed numerous perivascular round-cell infiltrates containing plasma cells and large lymphocytes within the leptomeningeal tumor tissue. After incubation with immunoperoxidase, only these cells showed IgG-specific staining, indicating the site of local IgG production.