Progressive multifocal leukoencephalopathy after autologous bone marrow transplantation and alpha-interferon immunotherapy.

A patient with a stage IV mantle cell lymphoma (according to the REAL classification) was treated with high-dose chemotherapy and autologous bone marrow transplantation. One year later while on alpha-interferon immunotherapy she suffered from progressive loss of short-term memory and reported difficulties in recognizing objects. Magnetic resonance imaging (MRI) showed a vast ring-enhancing lesion of the left postcentral parietal area. Serial stereotactic biopsies disclosed progressive multifocal leukoencephalopathy without JC-virus in the cerebrospinal fluid. Therapy with subcutaneous interleukin-2 (IL-2) every other day and intrathecal cytarabine once a week was started. After 4 weeks the patient refused further treatment. Nevertheless her condition improved over the next 8 months and MRI scans showed a marked improvement in the lesions.

Intravenous natural beta interferon treatment of chronic exacerbating-remitting multiple sclerosis: clinical response and MRI/CSF findings.

A preliminary study is reported of clinical response and CSF/MRI findings in nine patients with multiple sclerosis receiving intravenous infusions of natural beta-interferon. The mean patient follow-up was for 1.2 years. Neither exacerbation rates nor CSF-IgG synthesis nor plaque formation as revealed by MRI showed a significant reduction during therapy. One patient developed a severe exacerbation of multiple sclerosis shortly after interferon infusion.

Demonstration of herpes simplex virus DNA in CSF cells by in situ hybridization for early diagnosis of herpes encephalitis.

Herpes simplex virus (HSV) was studied by in situ DNA hybridization with a biotinylated cDNA probe in 56 air-dried methanol-fixed cerebrospinal fluid (CSF) cell preparations which had been collected from 12 patients with herpes simplex encephalitis (HSE) during the previous 5 years. In three additional HSE cases, freshly prepared acetone-fixed CSF cell preparations were available. In all cases, CSF cell preparations were obtained by cytocentrifugation. Herpes simplex virus DNA could be demonstrated in 8 of the 12 HSE cases with methanol-fixed cells (66%) and in all 3 cases with fresh acetone-fixed CSF cells. The earliest CSF sample was available at the onset of symptoms and showed positive DNA hybridization. In three cases hybridization was positive after a clinical course of more than 5 weeks but was usually found in the 1st week of illness before the beginning of specific inthrathecal IgG synthesis. In 54 control cases with other acute inflammatory diseases of the CNS, including 14 cases of varicella-zoster meningitis, no positive hybridization was detected. These findings strongly suggest that in situ hybridization in CSF cells is a reliable tool for the early and rapid diagnosis of HSE, especially at the onset of the disease, when no antibodies can be detected.

Early diagnosis and successful treatment of acute cytomegalovirus encephalitis in a renal transplant recipient.

We report the case of a 40-year-old male HIV-negative renal transplant patient with allograft rejection and immunosuppressive therapy who presented with acute cytomegalovirus (CMV) encephalitis. CT and MRI of the brain were normal but EEG showed diffuse slowing and dysrhythmia. In cerebrospinal fluid (CSF) initially 81 cells/microliters were found and immunocytochemistry showed a decreased CD4/CD8 ratio and increased values of activated lymphocytes, natural killer cells and immunoglobulin-containing cells. CMV-specific IgM antibodies in CSF and serum, immunostaining of CMV antigen in CSF cells and virus culture from CSF and urine were negative. During the first 3 weeks of illness no intrathecal production of immunoglobulins could be detected. Early diagnosis of CMV encephalitis was made by in situ hybridization (ISH) on CSF cell preparations and the polymerase chain reaction (PCR) which was positive in CSF and blood. On day 26 diagnosis was confirmed by detection of CMV-specific intrathecal IgG production. The patient was treated with ganciclovir, anti-CMV immunoglobulins and intrathecal beta interferon. He recovered completely after 2 months. Our data demonstrate the usefulness of ISH and PCR in the early diagnosis of CMV encephalitis and perhaps may encourage the use of intrathecal beta interferon in other patients with this disease.

Changing patterns of glucose metabolism during the course of subacute sclerosing panencephalitis as measured with 18FDG-positron-emission tomography.

18FDG-positron emission tomography performed at different stages in the course of subacute sclerosing panencephalitis revealed a changing pattern of metabolic disturbance. In clinical stage II patients the inflammation in the basal ganglia appeared to lead to neuronal excitation accompanied by hypermetabolism. Widespread cortical functional inhibition of metabolism followed. The striatal inflammation ended with necrosis and hypometabolism, with resulting functional cortical disinhibition; later, deep midbrain structures and brain stem became hypermetabolic. A patient clinically in remission showed no such changes in cerebral glucose metabolism.

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Cerebrospinal fluid and peripheral blood leukocyte subsets in acute inflammation of the CNS.

Leukocyte subsets in CSF and peripheral blood (PB) were determined in 21 patients with acute inflammation of the CNS using the monoclonal antibodies OKT3, OKT4, OKT8, Leu12, and OKM1 in an immunoperoxidase slide assay. There was a predominance of OKT3-positive cells in nearly all samples. Significant differences between acute aseptic and bacterial meningitis only were found in CSF and represented by a higher Leu12 and a lower OKT3 percentage in aseptic inflammation and a higher absolute amount of OKT4-, OKM1- and Leu12-positive cells in bacterial meningitis. Comparison between CSF and PB showed significant differences only in aseptic meningitis with a higher percentage of Leu12-positive cells and a lower percentage of OKT8-positive cells in CSF. The OKT4/OKT8 ratio seems to be generally lower in aseptic meningitis but significant differences only were found in comparison with healthy blood donors. In a case of herpes simplex encephalitis the ratio was strongly increased in CSF during the early phase of specific antibody production because of an absolute rise of OKT4-positive cells.

Low interleukin-10 production is associated with higher disability and MRI lesion load in secondary progressive multiple sclerosis.

Abnormalities in T-cell-derived cytokine production are a well-known phenomenon in multiple sclerosis (MS). An association between disability and the production of interferon gamma has been demonstrated recently. The present study investigated associations between disability, cytokine production in stimulated blood lymphocytes and magnetic resonance imaging data in 37 patients with the secondary progressive course in the stable phase of the disease. Patients with high interleukin-10 (IL-10) production had significantly lower disability scores (p=0.009) and lower T2 lesion load (p=0.03). Interleukin-10 might not only play a role in the pathological process of multiple sclerosis but has an impact on disease outcome as well.

Metabolism of N-nitrosomethylbenzylamine in the mongolian gerbil (meriones unguiculatus).

Adult male gerbils (Meriones unguiculatus) received a single s.c. injection of N-nitroso(methyl-14C) methylbenzylamine (2.5 mg/kg body weight). Of the radioactivity injected 46% was exhaled as 14CO2 within 8-10 hours and an additional 21% was excreted as urinary metabolites. Six hours after injection of the carcinogen, methylation of DNA bases was highest in lung (81.5 mumol 7-methylguanine/mol guanine) followed by liver, esophagus, kidney, forestomach, glandular stomach, spleen, colon and small intestine. The brain DNA no alkylation products were detectable. These data differ significantly from those obtained in rats and mice which under similar experimental conditions metabolized N-nitrosomethylbenzylamine preferentially in esophagus and liver respectively.

Two cases of toxoplasmic encephalitis in patients with acute T-cell leukaemia and lymphoma.

Two cases of opportunistic cerebral infections in HIV-negative cancer patients due to chemotherapy induced immunosuppression are reported. A 61-year-old patient with low grade lymphoma (immunocytoma as referred to the Kiel classification) developed stereotactical biopsy proven toxoplasmic encephalitis 6 months after initiation of fludarabine treatment. The lymphoma had been diagnosed 8 years earlier and had been treated with several different regimens. In the second case, a 55-year-old patient developed neurological symptoms while in complete remission from acute T-cell leukaemia. The patient had been treated with a multidrug chemotherapy regimen including radiotherapy of the brain and intrathecal chemotherapy. When toxoplasmic encephalitis was bioptically diagnosed the patient was on maintenance chemotherapy with methotrexate and mercaptopurine for 12 months. The patients' characteristics and outcome are reported and the potential pathogenesis is discussed.

Review and case report: primary melanoblastosis of the leptomeninges.

A case of primary diffuse leptomeningeal melanoblastosis in a 46-year-old male is reported. His symptoms included headaches, transient hemiparesis, epileptic seizures and a progressive psychosyndrome. CT brain scans showed a slight enhancement of density in the subarachnoidal space. The disease was diagnosed by CSF cytology, using light microscopy, electron microscopy, autoradiography and cell culture. Systemic combined chemotherapy using Cisplatinum, DTIC, and Vindesine was without any significant response and he died 18 weeks after onset of the first complaints. Autopsy showed a diffuse infiltration of the entire leptomeninges by melanotic melanoblastoma cells invading the sagittal superior sinus. A thorough dissection including the orbital contents and skin nevi failed to reveal a primary tumor outside the CNS.

Bell's palsy: electrodiagnostics are not indicative of cerebrospinal fluid abnormalities.

Electrodiagnostic testing (electromyography, electroneuronography, and blink reflex) and cerebrospinal fluid (CSF) examination (cell count, immunoglobulins, and antigen-specific intrathecal immunoglobulin G synthesis against herpes simplex virus, varicella zoster virus, cytomegalovirus, and Borrelia burgdorferi sensu latu) were performed in 56 patients with Bell's palsy. The CSF was normal in 45 patients and abnormal in 11 patients. Acute borreliosis was the most common specific pathological CSF finding (4 of 11). Electromyography revealed abolished volitional activity in 22% of patients with normal CSF and in 36% with pathological CSF. Electroneuronographic tests with an amplitude decrease of more than 90% on the affected side or abolished responses were found in 20% of patients with normal CSF and in 18% with pathological CSF. Abolished orbicularis oculi reflexes were seen in 67% of patients with normal CSF and in 82% with pathological CSF Concerning electrodiagnostic testing, no statistically significant difference between patients with normal and abnormal CSF was found, so we conclude that electrodiagnostic testing has no indicative value for abnormal CSF in Bell's palsy.

[Fatality of purulent meningitis in adults 1950 to 1985. Retrospective study of the case histories of 391 patients of the Cologne Neurologic University Clinic]. / Zur Letalität der purulenten Meningitis des Erwachsenenalters 1950 bis 1985. Retrospektive Untersuchung der Krankengeschichten von 391 Patienten der Neurologischen Universitätsklinik Köln.

Although intensive care medicine and chemotherapy of bacterial infections have made great progress during the last 30 years, therapeutic efficacy in bacterial meningitis in adult patients could not be improved. Retrospective analysis of 391 cases of adult bacterial meningitis between 1950 and 1985 shows no significant changes in etiology and only slight reduction in mortality. The course of the disease depends mostly on age, state of consciousness and CSF cell count. Cases of meningitis in HIV patients and cerebral tuberculosis have not been evaluated in this study.

[Cerebrospinal fluid cytology in meningeal invasion of leukemia and malignant lymphoma. Reliable diagnosis by immunocytochemistry]. / Liquorzytologie bei meningealer Aussaat von Leukämien und malignen Lymphomen. Sichere Diagnose durch Immunzytochemie.

Cerebrospinal fluid cytology was performed in 64 patients who were suspected of having a meningeal infiltration of malignant lymphoma or leukemia. Conventional staining with May Grünwald Giemsa revealed a positive result in 51 cases, and a negative result in one case. In 4 cases diagnosis was hampered by blood contamination or a lack of CSF cells. In the remaining 8 cases with doubtful cytologic specimens, additional immunocytochemic staining allowed definite diagnosis. In 5 of these cases malignancy was confirmed, while in the remaining 3 an inflammatory cell pattern was found and later confirmed by follow-up. In summary, immunocytochemistry was essential for definite diagnosis in 12% of CSF cell specimens suspected of leukemia or malignant lymphoma. It may be concluded that immunocytochemistry in CSF cytology is a valuable tool for enhancement of diagnostic reliability.

Persistence of alkylated DNA bases in the Mongolian gerbil (Meriones unguiculatus) following a single dose of methylnitrosourea +.

Methylated purines were determined in DNA of various gerbil tissues following a single i.v. injection of N-[14C]methyl-N-nitrosourea (10 mg/kg). Enzymic removal of the promutagenic base O6-methylguanine was most efficient in the liver, followed by kidney, lung and brain. In cerebral DNA, 40% of the initial concentration was still present after 6 months. Since the gerbil brain is apparently not susceptible to the oncogenic effect of methylnitrosourea and related carcinogens, these data indicate that the formation and persistence of O6-alkylguanine may constitute a necessary although not sufficient event for the initiation of organ-specific carcinogenesis by monofunctional alkylating agents.