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Biomedical subjects

F Graus

Publications and source records attributed to F Graus.

At least 37 records · Page 2Linked to original sources
PubMed2004

Recommended diagnostic criteria for paraneoplastic neurological syndromes.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are defined by the presence of cancer and exclusion of other known causes of the neurological symptoms, but this criterion does not separate "true" PNS from neurological syndromes that are coincidental with a cancer. OBJECTIVE: To provide more rigorous diagnostic criteria for PNS. METHODS: An international panel of neurologists interested in PNS identified those defined as "classical" in previous studies. The panel reviewed the existing diagnostic criteria and recommended new criteria for those in whom no clinical consensus was reached in the past. The panel reviewed all reported onconeural antibodies and established the conditions to identify those that would be labelled as "well characterised". The antibody information was obtained from published work and from unpublished data from the different laboratories involved in the study. RESULTS: The panel suggest two levels of evidence to define a neurological syndrome as paraneoplastic: "definite" and "possible". Each level can be reached combining a set of criteria based on the presence or absence of cancer and the definitions of "classical" syndrome and "well characterised" onconeural antibody. CONCLUSIONS: The proposed criteria should help clinicians in the classification of their patients and the prospective and retrospective analysis of PNS cases.

Antibodies↗
PubMed2004

Diagnosis and treatment of paraneoplastic neurological disorders.

In about two thirds of cases, patients with paraneoplastic neurological disorders present to the neurologist without a known tumor. Due to the ongoing immune response, this tumor tends to stay biologically relatively benign, and therefore difficult to diagnose. In patients with a known tumor, the neurological symptoms often precede a tumor recurrence. In both scenarios, anti-neuronal antibodies are an invaluable diagnostic help to the clinician, and may be supplemented by other diagnostic tests such as MRI, CSF, and electrophysiology. Tumor therapy remains the mainstay of therapeutic options, although early immune therapy must be started in parallel. It is hoped that the recent fundamental advances in understanding the autoimmune pathology of these disorders, especially the role of cytotoxic T cells, will eventually lead to more effective treatment options.

Antibodies↗
PubMed2004

[Cerebellar degeneration associated with anti-Tr antibodies without Hodgkin's disease. Four years follow-up].

The presence of antineuronal anti-Tr antibodies is associated to paraneoplastic cerebellar degeneration due to Hodgkin's disease. The anti-Tr can become negative after successful and early treatment of the tumor, and there could even be remission of the cerebellar symptoms in some patients. There are few cases in which no tumor is found when there are anti-Tr. We report the case of a 66 year old man with a severe cerebellar syndrome and anti-Tr in serum detected by immunohistochemistry. After a 4 year follow-up, no underlying tumor has been found. In addition, anti-Tr spontaneously disappeared. The cerebellar degeneration persists and is incapacitating. This case suggests that in a few instances the origin of anti-Tr is not a tumor but another unknown cause. Alternatively the anti-Tr mediated immune response could have eradicated the underlying lymphoma.

Aged↗
PubMed2003

Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin's disease.

BACKGROUND: Preliminary studies suggested that anti-Tr antibodies identify patients with paraneoplastic cerebellar degeneration (PCD) and Hodgkin disease (HD). OBJECTIVE: To extend the clinical-immunologic analysis to 28 patients with anti-Tr antibodies. METHODS: Anti-Tr antibodies were detected by immunohistochemistry. A competitive inhibition assay was used to ascertain if anti-Tr antibodies of different sera identify common epitopes. Anti-Tr immunoglobulin G (IgG) subclass distribution was determined by immunohistochemistry using monoclonal antibodies against human IgG isotypes. Tr immunoreactivity was analyzed in tumor sections using biotinylated anti-Tr IgG. RESULTS: Median age of the 28 patients was 61 years (range 14 to 75 years) and 22 were male. A cerebellar syndrome was present in 27 patients and a possible limbic encephalitis in one. HD was diagnosed in 25 patients. No tumor was found in three patients; the autopsy of one of them disclosed severe loss of Purkinje cells without inflammatory infiltrates. Anti-Tr antibodies spontaneously disappeared in all patients without tumor and in 10/10 patients after successful HD treatment. Anti-Tr antibodies were absent in the serum but positive in the CSF of two patients. All positive anti-Tr sera inhibited the immunoreactivity of biotinylated anti-Tr IgG. The predominant isotypes of anti-Tr were IgG1 and IgG3. Only 1 out of the 15 HD samples studied presented anti-Tr positivity that was localized in some Reed-Sternberg cells. CONCLUSIONS: This study confirms the strong association between anti-Tr antibodies and PCD associated with HD. Anti-Tr antibodies from different patients recognize similar epitopes. Unlike other antineuronal antibodies, anti-Tr antibodies can be detected in the CSF but not in the serum and may spontaneously disappear during the follow-up, and Tr immunoreactivity is usually lacking in the tumor.

Adolescent↗
PubMed2002

P/Q type calcium-channel antibodies in paraneoplastic cerebellar degeneration with lung cancer.

Raised levels of P/Q type voltage-gated calcium-channel (VGCC) antibodies were found in 16 (41%) of 39 patients with paraneoplastic cerebellar degeneration (PCD) and Hu antibodies were found in nine (23%). Seven of the 16 VGCC antibody-positive patients had Lambert-Eaton myasthenic syndrome (LEMS). Seven of 15 CSF samples had VGCC antibodies, with evidence of intrathecal synthesis in four. VGCC antibodies should be looked for in PCD, even if there are no symptoms of LEMS, and may be related to the cerebellar dysfunction.

Animals↗
PubMed2002

Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study.

RATIONALE: Phase I/II studies of autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis ( MS) were initiated, based on results of experimental transplantation in animal models of multiple sclerosis and clinical observations in patients treated concomitantly for malignant disease. PATIENTS: Eighty-five patients with progressive MS were treated with autologous HSCT in 20 centers and reported to the autoimmune disease working party of the European Group for Blood and Marrow Transplantation (EBMT). 52 (61 %) were female, median age was 39 [20-58] years. The median interval from diagnosis to transplant was 7 [1-26] years. Patients suffered from severe disease with a median EDSS score of 6.5 [4.5-8.5]. Active disease prior to transplant was documented in 79 of 82 evaluable cases. RESULTS: The stem cell source was bone marrow in 6 and peripheral blood in 79, and stem cells were mobilized into peripheral blood using either cyclophosphamide combined with growth factors or growth factors alone. Three patients experienced transient neurological complications during the mobilization phase. The high dose regimen included combination chemotherapy, with or without anti-lymphocyte antibodies or, with or without, total body irradiation. The stem cell transplants were purged of lymphocytes in 52 patients. Median follow-up was 16 [3-59] months. There were 7 deaths, 5 due to toxicity and infectious complications, 2 with neurological deterioration. The risk of death of any cause at 3 years was 10 (+/-7)% (95 % confidence interval). Neurological deterioration during transplant was observed in 22 patients; this was transient in most but was associated with MS progression in 6 patients. Neurological improvement by > or = 1 point in the EDSS score was seen in 18 (21 %) patients. Confirmed progression-free survival was 74 (+/-12)% at 3 years being 66 (+/-23)% in patients with primary progressive MS but higher in patients with secondary progressive or relapsing-remitting MS, 78 (+/-13)%; p = 0.59. The probability of confirmed disease progression was 20 (+/-11)%. MRI data were available in 78 patients before transplant showing disease activity (gadolinium enhancing, new or enlarging lesions) in 33 %. Posttransplant MRI showed activity at any time in 5/61 (8 %) evaluable cases. CONCLUSION: Autologous HSCT suggest positive early results in the management of progressive MS and is feasible. These multicentre data suggest an association with significant mortality risks especially in some patient groups and are being utilised in the planning of future trials to reduce transplant related mortality.

Adult↗
PubMed2002

Antidisialosyl antibodies in chronic idiopathic ataxic neuropathy.

Antidisialosyl antibodies were found in two out of 13 patients with chronic idiopathic ataxic neuropathy (CIAN) and not in 32 patients with different sensory neuropathies of known cause. This finding confirms the association of antidisialosyl antibodies and CIAN regardless of the absence of the M band. These antibodies may have pathogenic relevance; however, larger series are needed to establish their clinical significance.

Aged↗
PubMed2002

T-cell reactivity to glutamic acid decarboxylase in stiff-man syndrome and cerebellar ataxia associated with polyendocrine autoimmunity.

Antibodies to glutamic acid decarboxilase (GAD-Abs) are present in the serum of 60-80% of newly diagnosed type 1 diabetes (DM1) patients and patients with autoimmune polyendocrine syndrome (APS) associated with DM1. Higher titre of GAD-Abs are also present in the serum of 60% of patients with stiff-man syndrome (SMS) and all reported patients with cerebellar ataxia associated with polyendocrine autoimmunity (CAPA). Several studies suggest that GAD-Abs may play a critical role in the pathogenesis of SMS and CAPA but little is known about T-cell responsiveness to GAD-65 in these neurological diseases. To analyse cell-mediated responses to GAD, we studied the peripheral blood lymphocyte proliferation and cytokine responses to recombinant human GAD-65 in 5 patients with SMS, 6 with CAPA, 9 with DM1, 8 with APS and 15 control subjects. GAD-65-specific cellular proliferation was significantly higher in SMS than in CAPA, DM1, APS or controls. In contrast, only T cells from CAPA patients showed a significantly high production of interferon-gamma after GAD stimulation, compared to all other patients and controls. No differences were found for IL-4 production. These results suggest that, despite similar humoral autoreactivity, cellular responses to GAD are different between SMS and CAPA, with a greater inflammatory response in CAPA, and this difference may be relevant to the pathogenesis of these diseases.

Adolescent↗
PubMed2002

Pre-irradiation semi-intensive chemotherapy with carboplatin and cyclophosphamide in malignant glioma: a phase II study.

We undertook a phase II trial in 17 patients with malignant glioma and large measurable disease to assess response rate and survival with pre-irradiation chemotherapy, using higher doses than standard, trying to improve the outcome. Patients characteristics were: male/female 10/7, age 49 (range 23-59), median Karnofsky index 90% (range 70-100), glioblastoma multiforme/anaplastic astrocytoma 14/3. Treatment consisted of 2 cycles of carboplatin 200 mg/m(2) days 1-3 (or AUC x 8, total dose) plus cyclophosphamide 1000 mg/m(2) days 1-3. One partial response (6.5%) and two stabilizations (13.5%) were observed after pre-irradiation chemotherapy. Twelve out of 15 patients (80%) progressed after chemotherapy. Median survival time was 7.6 months and the survival at 1 year was 33%. Main toxicity was hematologic in the first cycle: neutropenia grade 4 in 100%; thrombocytopenia grade 4 in 73% and grade 3 in 27%; anemia grade 3 in 7%; in the second cycle: neutropenia and thrombocytopenia grade 4 in 100% and anemia grade 3 in 50%). No toxic death was related to treatment. This regimen showed limited activity in malignant glioma with large residual disease after surgery or biopsy.

Adult↗
PubMed2001

Antiganglioside antibodies in acute self-limiting ataxic neuropathy: incidence and significance.

Antidisialosyl antibodies have been previously associated to chronic and acute ataxic neuropathies. We studied the presence of these antibodies in nine patients with acute self-limiting ataxic neuropathy (ASLAN) using ELISA and TLC immunodetection. One patient showed serum IgG immunoreactivity against gangliosides GD3 and GQ1b. The patient's IgG was able to bind to the nodes of Ranvier on frozen human dorsal root. Our studies confirmed that antidisialosyl reactivity is associated to ataxic neuropathy and its specific binding to the dorsal root could explain the predominant sensory involvement. Nevertheless, the low incidence of this reactivity indicates that a different pathogenic mechanism should be involved in most ASLAN patients.

Acute Disease↗
PubMed2001

14-3-3 protein in the CSF as prognostic marker in early multiple sclerosis.

Axonal damage probably occurs early in the evolution of MS. Five of 38 (13%) patients had a positive assay for the neuronal 14-3-3 protein in the CSF obtained at the first clinically isolated syndrome suggestive of MS. A positive 14-3-3 assay was the only independent predictor for a shorter time to conversion to clinical definite MS (risk ratio 4.1; 95% CI 1.1 to 15) and to reach an Expanded Disability Status Scale (EDSS) > or =2 at the end of follow-up (odds ratio 14.8; 95% CI 2.86 to 76.8). The detection of the 14-3-3 protein in the CSF at the first neurologic event suggestive of MS may be a useful predictor of short-term evolution.

14-3-3 Proteins↗
PubMed2001

CHOD/BVAM regimen plus radiotherapy in patients with primary CNS non-Hodgkin's lymphoma.

PURPOSE: To assess the efficacy and toxicity, including long-term neurotoxicity, of combined therapy with the CHOD/BVAM regimen given before cranial radiotherapy in the treatment of primary CNS lymphoma (PCNSL). METHODS AND MATERIALS: Thirty-one consecutive patients with PCNSL were treated with one cycle of cyclophosphamide, doxorubicin, vincristine, and dexamethasone (CHOD) and two of carmustine (BCNU), vincristine, cytosine arabinoside, and methotrexate (BVAM), followed by cranial radiotherapy (45 Gy whole brain plus a 10-Gy boost for single lesions). The median age was 59 years (range 21-70) and 39% had poor performance status. The median follow-up of patients was 4.1 years (range 2.7-9.0). RESULTS: Twenty-one patients had no PCNSL at the end of treatment. The 5-year actuarial probability of survival was 31% (95% confidence interval [CI]: 11%-57%), with a median survival of 38 months. Patients < 60 years had a survival significantly longer than those > or = 60 years (4-year survival: 58% (95% CI: 34-82%) vs. 29% (95% CI: 5-53%), respectively; p = 0.04). Two patients died during chemotherapy from pulmonary embolism and bronchopneumonia, respectively, with no evidence of PCNSL at the autopsy. Dementia probably related to treatment occurred in 5 (62%) of the 8 patients 60 years and older, and 4 of them died without evidence of relapse of PCNSL. Dementia correlated with developing brain atrophy and leuco-encephalopathy on serial CT or MR scans. CONCLUSION: This regimen can be given with the planned dose intensity to patients aged less than 70 years, and produces better survival than that reported with radiotherapy alone; however, dementia occurs in the majority of patients aged 60 years of age or more.

Adult↗
PubMed2001

MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS.

OBJECTIVE: To analyze the MRI and CSF oligoclonal bands (OB) changes in patients with MS who underwent an autologous hematopoietic stem cell transplantation (AHSCT). BACKGROUND: AHSCT is evaluated as an alternative therapy in severe MS. In previous series of AHSCT for MS, data on MRI or OB outcome were limited or not provided. METHODS: Five patients with a median Kurtzke's EDSS score of 6.5, more than two attacks, and confirmed worsening of the EDSS in the previous year received an AHSCT. Hematopoietic stem cells were mobilized with cyclophosphamide (3 g/m2) and granulocyte colony-stimulating factor (5 microg/kg/d). The graft was T cell depleted by positive CD 34+ selection. Conditioning regimen included BCNU (300 mg/m(2)), cyclophosphamide (150 mg/kg in 3 days), and antithymocyte globulin (60 mg/kg in 4 days). MRI scans were scheduled at baseline and 1, 3, 6, and 12 months and OB analysis at baseline and 3 and 12 months post-AHSCT. RESULTS: Four patients had a stable or improved EDSS after a median follow-up of 18 months (range, 12 to 24 months). The fifth patient's condition deteriorated during AHSCT. She partially improved and remained stable after month 3 after AHSCT. The baseline CSF OB persisted 1 year after AHSCT. MRI studies after AHSCT showed no enhanced T1 lesions and no new or enlarging T2 lesions. The median percentage change of T2 lesion load was -11.8% (range, -26.6 to -4.0%). All patients had a decrease of corpus callosum area at 1 year (median, 12.4%; range, 7.8% to 20.5%) that did not progress in the two patients evaluated at 2 years after AHSCT. CONCLUSIONS: Although the persistence of CSF OB suggests the lymphocytes were not eliminated from the CNS, the follow-up MRI studies showed no enhanced T1 brain lesions and a reduction in the T2 lesion load that correlated with the clinical stabilization of MS after AHSCT.

Adult↗
PubMed2001

Anti-Yo-associated paraneoplastic cerebellar degeneration in a man with gastric adenocarcinoma.

Paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies is almost always associated with ovarian and breast cancer. We describe a man with anti-Yo-positive PCD and gastric adenocarcinoma. The tumor cells were labeled with anti-Yo antibodies by immunohistochemistry. High serum titers of anti-Yo antibodies were found before surgery and decreased 6 months after resection of the tumor. The expression of Yo antigens by the tumor and the decrease in anti-Yo antibody titers after its removal suggest that the immune response against the Purkinje cells of the cerebellum was triggered by the tumor.

Adenocarcinoma↗
PubMed2001

Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients.

BACKGROUND: Antibodies to glutamic acid decarboxylase (GAD-Ab) are described in patients with insulin-dependent (type 1) diabetes mellitus (IDDM), in stiff-man syndrome, and, recently, in a few patients with cerebellar ataxia. OBJECTIVES: To show a link between GAD-Ab and some patients with cerebellar ataxia and to clarify their clinical and immunologic profiles. METHODS: Serum samples were selected from 9000 samples of 4 laboratories. The selection criterion was an immunohistochemical pattern compatible with GAD-Ab that was confirmed by radioimmunoassay. We identified 22 patients with stiff-man syndrome and 14 with cerebellar ataxia and GAD-Ab. RESULTS: Thirteen of the 14 patients with cerebellar ataxia and GAD-Ab were women, and 11 had late-onset IDDM. Patients did not have clinical or radiologic evidence of brainstem involvement. Ten patients had oligoclonal IgG bands in the cerebrospinal fluid, and intrathecal GAD-Ab synthesis was observed in 5 of the 6 patients studied. The level of GAD-Ab of these patients was similar to those with stiff-man syndrome and significantly higher than those with IDDM or with polyendocrine autoimmunity (P<.001). However, the GAD-Ab levels of 6 of the 9 patients with polyendocrine autoimmunity overlapped with those of patients with cerebellar ataxia. CONCLUSIONS: These results suggest a link between high level of GAD-Ab and some cases of cerebellar ataxia, particularly women with IDDM. If high serum levels of GAD-Ab are detected, the cerebrospinal fluid should be evaluated for the presence of oligoclonal IgG bands and intrathecal synthesis of GAD-Ab to further prove an autoimmune origin of the syndrome.

Adult↗