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Biomedical subjects

F Graus

Publications and source records attributed to F Graus.

At least 19 recordsLinked to original sources
PubMed2006

Effect of glatiramer acetate (Copaxone) on the immunophenotypic and cytokine profile and BDNF production in multiple sclerosis: a longitudinal study.

We assessed the effect of glatiramer acetate (GA) on the immunophenotypic and cytokine profile and the BDNF production by peripheral blood mononuclear cells, and their association with the clinical response in 19 naïve-treated MS patients prospectively followed-up after GA therapy. Two patients withdrew the therapy. After a median follow-up of 21 months, twelve were considered responders and five as non-responders. Non-responder patients had significant longer disease duration and a higher EDSS score at baseline. In the responder group, a significant decrease in the percentage of INF-gamma producing total lymphocytes, CD4+ and CD8+ T cells, and reduced percentage of IL-2 producing CD4+ and CD8+ T cells were observed at 12, 18 and 24 months. These changes were associated with a significant increase in the percentage of CD3+, CD4+ and CD4(+) CD45RA(+) T cells, and BDNF production from month 6 that remained significant throughout the study. We did not observe significant changes in the nonresponder group for any of the parameters studied. Our data suggest that GA treatment induces a downmodulation of proinflammatory cytokines associated with the regulation of the peripheral T cell compartment and with increased production of BDNF that might be related to the clinical response.

Adjuvants, Immunologic↗
PubMed2006

Protein kinase Cgamma autoimmunity in paraneoplastic cerebellar degeneration and non-small-cell lung cancer.

BACKGROUND: The clinical and immunological profiles of patients with paraneoplastic cerebellar degeneration (PCD) and non-small-cell lung cancer (NSCLC) are not well known. OBJECTIVE: To review the clinical and immunological features of patients with PCD, NSCLC and without well-characterised onconeural antibodies. METHODS: The clinical features of nine patients with the diagnosis of classical PCD and NSCLC, included in our archives, were retrospectively reviewed. The presence of antibodies to cerebellar components was determined by immunohistochemistry and immunoblot of rat cerebellum. A cDNA library of human cerebellum was screened with the positive sera to identify the antigen. RESULTS: Nine patients with PCD and NSCLC were identified. Six patients were men, and the median age at diagnosis of PCD was 63 (range 47-73) years. PCD was completely reversed in two patients, and partially in one, after treatment of the tumour. The serum of one of the patients with PCD showed a unique reactivity with Purkinje cells. The screening of a cerebellar-expression library resulted in the isolation of protein kinase Cgamma (PKCgamma). PKCgamma immunoreactivity was not observed in the serum of 170 patients with non-paraneoplastic neurological syndromes, 27 patients with PCD, no onconeural antibodies and small-cell lung cancer, and 52 patients with NSCLC without paraneoplastic neurological syndromes. The NSCLC from 11 patients without PCD did not express PKCgamma at either the RNA or protein level. However, many cells of the NSCLC of the patient with PKCgamma antibodies expressed PKCgamma. CONCLUSION: PCD occurs in patients with NSCLC without typical onconeural antibodies and is associated with immune reactions against key proteins of the Purkinje cells.

Aged↗
PubMed2006

Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence-based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG-PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.

Advisory Committees↗
PubMed2006

EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force.

The objectives have been to establish evidence-based guidelines and identify controversies regarding the management of patients with brain metastases. The collection of scientific data was obtained by consulting the Cochrane Library, bibliographic databases, overview papers and previous guidelines from scientific societies and organizations. A tissue diagnosis is necessary when the primary tumor is unknown or the aspect on computed tomography/magnetic resonance imaging is atypical. Dexamethasone is the corticosteroid of choice for cerebral edema. Anticonvulsants should not be prescribed prophylactically. Surgery should be considered in patients with up to three brain metastases, being effective in prolonging survival when the systemic disease is absent/controlled and the performance status is high. Stereotactic radiosurgery should be considered in patients with metastases of 3-3.5 cm of maximum diameter. Whole-brain radiotherapy (WBRT) after surgery or radiosurgery is debated: in case of absent/controlled systemic cancer and Karnofsky Performance score of 70 or more, one can either withhold initial WBRT or deliver early WBRT with conventional fractionation to avoid late neurotoxicity. WBRT alone is the treatment of choice for patients with single or multiple brain metastases not amenable to surgery or radiosurgery. Chemotherapy may be the initial treatment for patients with brain metastases from chemosensitive tumors.

Advisory Committees↗
PubMed2006

[MM1 variant of sporadic Creutzfeldt-Jakob disease with long duration akinetic mutism state].

INTRODUCTION: When patients present with a characteristic clinical picture of Creutzfeldt-Jakob disease (CJD) associated with positive 14-3-3 assay, periodic sharp wave complexes, high-signal of the striatum on magnetic resonance imaging, and homozygosis methionine (M) in codon 129, the median survival is 4 to 6 months. CLINICAL CASE: We report a 58-year-old woman with these typical features who survived 21 months, 19 of them in an akinetic mutism state. The autopsy confirmed the diagnosis of the most common CJD phenotype (MM1), usually associated with a shorter survival, and demyleinitation of the white matter (panencephalopathic form). CONCLUSIONS: The MM1 variant of CJD, with a rapidly progressive course leading into an akinetic mutism shortly after disease onset can be followed by a long akinetic mutism state. This profile is suggestive of panencephalopathic form and should be taken into account when counselling about survival.

Akinetic Mutism↗
PubMed2005

No association of the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) to multiple sclerosis.

Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by neurons and immune cells, promotes neuronal survival and repair during development and after CNS injury. The BDNF-Val66Met polymorphism is functional and induces abnormal intracellular trafficking and decreased BDNF release. Therefore, we investigated the impact of the BDNF-Val66Met polymorphism on the susceptibility and clinical course in a case-control study of 224 multiple sclerosis (MS) Spanish patients and 177 healthy controls. We found no evidence for association to susceptibility or severity of the disease in our population. Moreover, we did not observe, in a subgroup of 12 MS patients, that the methionine substitution at position 66 in the prodomain had negative impact in the capacity to produce BDNF by peripheral blood mononuclear cells (PBMC).

Adult↗
PubMed2005

Evolution of brain-derived neurotrophic factor levels after autologous hematopietic stem cell transplantation in multiple sclerosis.

A neuroprotective role of inflammation has been suggested based on that immune cells are the main source of brain-derived neurotrophic factor (BDNF). We investigated the 3-year evolution of BDNF levels in serum, CSF and culture supernatant of peripheral blood mononuclear cells (PBMC), unstimulated and stimulated with anti-CD3 and soluble anti-CD28 antibodies, in 14 multiple sclerosis patients who underwent an autologous hematopoietic stem cell transplantation (AHSCT). BDNF levels were correlated with previously reported MRI measures that showed a reduction of T2 lesion load and increased brain atrophy, mainly at first year post-transplant. A significant decrease of serum BDNF levels was seen at 12 months post-transplant. BDNF values were found significantly lower in stimulated but not in unstimulated PBMC supernatants during the follow-up, supporting that AHSCT may induce a down-regulation of BDNF production. The only significant correlation was found between CSF BDNF levels and T2 lesion load before and 1 year after AHSCT, suggesting that BDNF reflects the past and ongoing inflammatory activity and demyelination of these highly active patients. Our study suggests that AHSCT can reduce BDNF levels to values associated with lower activity. This decrease does not seem to correlate with the brain atrophy measures observed in the MRI.

Antibodies↗
PubMed2005

Anti-glial nuclear antibody: marker of lung cancer-related paraneoplastic neurological syndromes.

We describe a new antibody, called anti-glial nuclear antibody (AGNA), in patients with paraneoplastic neurological syndromes (PNS) and small-cell lung carcinoma (SCLC). AGNA was initially identified in 24 sera of our archives by immunohistochemistry on rat cerebellum. AGNA positive sera showed a characteristic nuclear staining of the Bergmann glia in the Purkinje cell layer. Immunoblots and probing a cerebellar expression library with AGNA sera did not identify the antigen. Twenty of the 24 patients with AGNA had PNS and all but two had lung cancer. AGNA was identified in 13/113 (11.5%) patients with SCLC compared with 0/122 with other types of cancer (p<0.0001). The frequency of AGNA was not higher than expected for the presence of SCLC in the different PNS subtypes except in LEMS (p=0.0002). AGNA was present in 13/30 (43%) of LEMS patients with SCLC, compared with 0/19 of LEMS patients without cancer (p=0.0006). We conclude that the recognition of AGNA is helpful since this antibody is found in PNS associated with SCLC, particularly LEMS, in which other onconeural antibodies are absent.

Animals↗
PubMed2004

Value of Hu antibody determinations in the follow-up of paraneoplastic neurologic syndromes.

The long-term evolution of Hu antibody (Hu-Ab) titers in patients with paraneoplastic neurologic syndromes (PNSs) is not known. Described is the evolution of Hu-Ab titers in 35 patients with PNS with a median follow-up of 32 months (range 6 to 108 months). No correlation was observed between Hu-Ab titers and neurologic outcome, tumor evolution, or type of treatment. Serial Hu-Ab determinations are not useful for monitoring the clinical outcome of patients with PNS.

Adult↗
PubMed2004

Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer.

OBJECTIVE: To determine whether serum Zic4 antibodies associate with paraneoplastic neurologic disorders (PND) and small-cell lung cancer (SCLC), and the association of these antibodies with other onconeuronal immunities associated with SCLC. DESIGN/METHODS: The authors studied 498 patients (215 with PND and 283 without PND or without cancer). The presence of antibodies was tested with immunoblots of Zic4, HuD, and CRMP5 proteins. The tumor expression of these proteins was determined by immunohistochemistry. RESULTS: Zic4 antibodies were identified in 61 patients. Ninety-two percent of patients with Zic4 antibodies had SCLC; detection of these antibodies segregated with the presence of PND (p = 0.031). Intrathecal synthesis of Zic4 antibodies was demonstrated in 5/7 patients with PND. None of 175 control patients without PND or cancer had Zic4 antibodies. Because of the robust association between Zic autoimmunity and SCLC, all patients were tested for other SCLC-related antibodies; concurrent Zic4, Hu, or CRMP5 antibodies occurred in the serum or CSF of 27% of SCLC patients with PND. Patients with isolated Zic4 antibodies were more likely to develop predominant cerebellar dysfunction than patients with several immunities (p < 0.001). Tumors of patients with and without onconeuronal antibodies coexpressed Zic, Hu, and CRMP5 proteins, indicating that the tumor expression of these antigens is necessary, but not sufficient, for immunologic activation. CONCLUSIONS: In patients with neurologic symptoms of unknown cause detection of Zic4 antibodies predicts a neoplasm, usually a SCLC, and suggests that the neurologic disorder is paraneoplastic. Detection of Zic4 antibodies often associates with anti-Hu or CRMP5 antibodies. Patients with isolated Zic4 antibodies are more likely to develop cerebellar dysfunction than those with concurrent immunities.

Aged↗
PubMed2004

Clinical and MRI outcome after autologous hematopoietic stem cell transplantation in MS.

The authors report the outcome of 14 patients with severe multiple sclerosis treated with autologous hematopoietic stem cell transplantation (AHSCT) after a median follow-up period of 3 years. The 3-year actuarial probability of progression-free survival was 85.7% and that of disease activity-free survival was 46.4%. On MRI, no T1-enhanced lesions were detected after AHSCT. The mean change in T2 lesion volume from baseline to the third year was -20.2% and that of the corpus callosum area was -12.7%; 50% of this reduction was seen during the first year.

Actuarial Analysis↗
PubMed2004

Clinical and genetic features of human prion diseases in Catalonia: 1993-2002.

We describe the clinical and genetic characteristics of the 85 definite or probable human prion diseases cases died between January 1993 and December 2002 in Catalonia (an autonomous community of Spain, 6 million population). Seventy-three (86%) cases were sporadic Creutzfeld-Jakob diseases (sCJD) (49 definite, 24 probable), with a median age at onset of 66 years. The clinical presentation was dementia in 29 cases, ataxia in 14 and visual symptoms in five. The median survival was 3 months. The 14-3-3 assay was positive in 93% cases, 62% presented periodic sharp wave complexes (PSWC) in EEG but only 18% the typical signs on MRI. Forty-eight sCJD were studied for codon 129 PRNP polymorphism: 69% were methionine/methionine (M/M), 14.5% valine/valine (V/V) and 16.5% M/V. Six out of seven V/V cases did not present PSWC and in two survival was longer than 20 months. Eleven cases (13%) were genetic: five familial fatal insomnia and six familial CJD (fCJD). Up to four (67%) fCJD lacked family history of disease, two presented seizures early at onset and one neurosensorial deafness. The only iatrogenic case was related to a dura mater graft. No case of variant CJD was registered. The study confirms in our population the consistent pattern reported worldwide on human prion diseases. Atypical features were seen more frequently in sporadic 129 V/V CJD and fCJD cases.

14-3-3 Proteins↗