Clinical value of negative skin tests to iodinated contrast media.

BACKGROUND: Several studies have shown that skin tests are useful tools for the diagnosis of iodinated contrast medium (ICM) allergy, but the real number of false negative results is not known. OBJECTIVE: To evaluate the negative predictive value of ICM skin tests. MATERIAL AND METHODS: One hundred and fifty-nine patients tested in our department because of a previous ICM reaction over the last 9 years were called and asked standardized questions about ICM re-exposure. RESULTS: Twenty-nine patients had been re-exposed to ICM. There were 20 (69.0%) females and the median age was 55 (34-60) years. The median time interval between the reaction and skin testing was 11.9 (1.6-21.5) years. Twenty-four patients (82%) had an immediate reaction, four a non-immediate (13.8%) reaction and no data were available for one patient. Two patients had positive ICM skin tests previously and were re-exposed to a negatively skin-tested ICM and did not react. Only two patients presented a mild reaction during ICM re-injection: one immediate (generalized urticaria lasting for 3 days) and one non-immediate maculopapular reaction. The patient with urticaria was re-tested and re-challenged (negative). The other patient was unable to return for re-testing. CONCLUSION: Skin testing for ICM hypersensitivity has a negative predictive value of 96.6% (95% CI: 89.9-103.2) and none of the reactions in skin-test-negative patients were severe. Multi-centric large surveys are still needed for confirmation.

Autism, language delay and mental retardation in a patient with 7q11 duplication.

Chromosomal rearrangements are found in a subset of patients with autism. Duplications involving loci associated with behavioural disturbances constitute an especially good candidate mechanism. The Williams-Beuren critical region (WBCR), located at 7q11.23, is commonly deleted in Williams-Beuren microdeletion syndrome (WBS). However, only four patients with a duplication of the WBCR have been reported to date. Here, 206 patients with autism spectrum disorders were screened for the WBCR duplication by quantitative microsatellite analysis and multiple ligation-dependent probe amplification. One male patient with a de novo interstitial duplication of the entire WBCR of paternal origin was identified. The patient had autistic disorder, severe language delay and mental retardation, with mild dysmorphism. The present report concerns the first patient with autistic disorder and a WBCR duplication. This observation indicates that the 7q11.23 duplication could be involved in complex clinical phenotypes, ranging from developmental or language delay to mental retardation and autism.

Autism, language delay and mental retardation in a patient with 7q11 duplication.

BACKGROUND: Chromosomal rearrangements, arising from unequal recombination between repeated sequences, are found in a subset of patients with autism. Duplications involving loci associated with behavioural disturbances constitute an especially good candidate mechanism. The Williams-Beuren critical region (WBCR), located at 7q11.23, is commonly deleted in Williams-Beuren microdeletion syndrome (WBS). However, only four patients with a duplication of the WBCR have been reported to date: one with severe language delay and the three others with variable developmental, psychomotor and language delay. OBJECTIVE AND METHODS: In this study, we screened 206 patients with autism spectrum disorders for the WBCR duplication by quantitative microsatellite analysis and multiple ligation-dependent probe amplification. RESULTS: We identified one male patient with a de novo interstitial duplication of the entire WBCR of paternal origin. The patient had autistic disorder, severe language delay and mental retardation, with very mild dysmorphic features. CONCLUSION: We report the first patient with autistic disorder and a WBCR duplication. This observation indicates that the 7q11.23 duplication could be involved in complex clinical phenotypes, ranging from developmental or language delay to mental retardation and autism, and extends the phenotype initially reported. These findings also support the existence of one or several genes in 7q11.23 sensitive to gene dosage and involved in the development of language and social interaction.

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.

T cell response to Hu-D peptides in patients with anti-Hu syndrome.

The anti-Hu syndrome is the most common paraneoplastic neurologic syndrome but the exact mechanism of immune mediated neuronal injury remains unknown. Anti-Hu antibodies do not appear to play a pivotal role in the pathogenesis of the disease. To assess cell-mediated immunity, we selected 51 peptides from the Hu-D sequence and tested their ability to bind to six common HLA class I molecules. Stable complexes with purified HLA molecules were obtained with 19/51 (37%) selected peptides. Subsequently, the ability of the 19 HLA-binding peptides to stimulate T cells from 10 patients and 10 control subjects was evaluated by detecting IFN-gamma secretion. An anti-peptide T-cell response was observed in 7/10 Hu-positive patients but also in 3/10 control subjects. Overall, a significant T-cell activation occurred in response to 74% (14 out of 19) of the selected peptides in the Hu-positive patients vs. 16% (3 out of 19) in the control group (p < 0.001). In addition, T cells of patients tested within 3 months of the onset of anti-Hu syndrome responded to 82% (14 out of 17) of assessed Hu-D peptides vs. 37% (7 out of 19) in patients tested 1 year or more after developing the syndrome (p < 0.01). Thus, the present study suggests a role of cellular immunity during the course of anti-Hu syndrome.

Multidrug resistance-associated protein MRP1 expression in human gliomas: chemosensitization to vincristine and etoposide by indomethacin in human glioma cell lines overexpressing MRP1.

The 190 kDa multidrug resistance protein MRP1 is likely to be involved in the multidrug resistance phenotype of human gliomas. MRP1 expression was evaluated in surgical tumor samples from 17 patients with gliomas. In addition, the impact of the MRP's inhibitor, indomethacin, on the chemosensitivity to etoposide (VP16) and vincristine (VCR) of two glioblastoma cell lines expressing MRP1 (GL15 and 8MG) was investigated. When evaluated in tumor samples, MRP1 expression was observed in all of them with more than 90% of stained tumor cells in 14/15 high-grade gliomas. MRP1 was also strongly expressed at the membrane of the vascular endothelial cells in the same 14 tumor samples, suggesting that the permeability to anticancer drugs could be also limited across brain tumor vessels. At concentrations comprised between 5 and 50 microM, indomethacin significantly increased the cytotoxic effect of etoposide in both cell lines but it was more efficient in increasing the cytotoxicity of VCR on GL15 cells, as compared with 8MG cells. These results suggest that the association of indomethacin to VCR or etoposide could be of interest in the clinical management of gliomas.

Paraneoplastic antineuronal antibodies in patients with systemic autoimmune diseases.

Sera from 71 patients with primary Sjögren's syndrome (PSS) and from 102 patients with systemic lupus erythematosus (SLE) were tested by immuno-dot blotting against HuD, Ri, Yo and amphiphysin recombinant proteins. For Ri, Yo and amphiphysin antigens, no immunoreactivity was found in the 173 sera tested. One PSS patient with a clinical picture of subacute sensory neuronopathy had high titers of anti-Hu antibodies. An extensive search for an underlying tumor was initially negative but a small cell lung cancer was eventually discovered three years later. Another patient with SLE and a clinical picture of demyelinating polyradiculoneuropathy had anti-Hu antibodies. Repeated search for an underlying tumor remains negative after five years follow-up in this young non-smoking patient. In addition, the neuropathy progressively improved and the anti-Hu antibodies titer slowly decreased from 1:8000 to 1:2000, making the diagnosis of paraneoplastic syndrome unlikely in this patient. This study indicates that the detection of anti-Hu antibodies in patients with known symptomatic systemic autoimmune diseases such as PSS or SLE should induce the same work-up than the detection of these antibodies in the absence of other immune diseases, i.e. repeated search for occult cancer during several years. As illustrated by our first patient, this strategy may be fruitful. Nevertheless, the clinician should know that anti-Hu antibodies may exceptionally (0.6% in this series) occur in systemic autoimmune disorders with neurological complications, in the absence of an underlying neoplastic disease.

Oligoclonal T-cells in blood and target tissues of patients with anti-Hu syndrome.

T-cell clones of unknown significance (TCUS), assessed by monoclonal or oligoclonal T-cell patterns in PCR-DGGE, were detected in blood of 7/9 patients with anti-Hu syndrome. Clonal patterns were also detected in 2/2 neoplastic lymph nodes, and in 2/2 inflamed dorsal root ganglia from three patients. Only some T-cell clones found in target tissues were also detected in blood or non-target tissues, and likely corresponded to TCUS. In one patient, an identical T-cell clone was found in both neoplastic lymph node tissue and dorsal root ganglia, but not in blood. Dorsal root-infiltrating lymphocytes were cytotoxic CD8(+) TIA-1(+) T-cells. They were often found in close contact to sensory neurons, most of which expressed MHC-1. Taken together, these data support a direct effector role of cytotoxic CD8(+) T-cells, the same clones being likely operative in sensory neuron damage and immune-mediated tumor growth control.

Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients.

We reviewed 200 patients with paraneoplastic encephalomyelitis (PEM) and anti-Hu antibodies to show possible clinical differences with respect to previous series, and to identify patient, tumour and treatment-related characteristics associated with neurological disability and survival. The median age of the 200 patients was 63 years (range 28-82 years) and 75% were men. The predominant neurological syndromes were sensory neuropathy (54%), cerebellar ataxia (10%), limbic encephalitis (9%) and multifocal involvement (11%). Sensorimotor neuropathies with predominant motor involvement were observed in only 4% of the patients. Pathological or X-ray evidence of a tumour was obtained in 167 patients (83%) and was a small-cell lung cancer (SCLC) in 74% of those with histological diagnosis. Coexistence of extrathoracic tumours with SCLC was rare (0.5%). Positive Hu immunoreactivity was observed in the extrathoracic tumours of six out of seven patients in whom autopsy or long-term follow-up ruled out a coexisting SCLC. PEM preceded the diagnosis of the tumour in 71% of patients (mean delay +/- SD 6.5 +/- 7.0 months; range 0.1-47 months). In the 24 patients in whom the tumour diagnosis was the initial event, PEM predicted the progression or relapse of the tumour in 87% of them. No tumour was found in 33 patients, including four who had a post-mortem study and four with >5 years of follow-up. In a logistic regression analysis, treatment of the tumour, associated or not with immunotherapy, was an independent predictor of improvement/stabilization of PEM [odds ratio 4.56; 95% confidence interval (CI) 1.62-12.86]. Cox multivariate analysis indicated that the variables independently associated with mortality were: age >60 years [relative risk (RR) 1.49; 95% CI 1.05-2.12], Rankin score at diagnosis >3 (RR 1.60; 95% CI 1.12-2.28), more than one area of the nervous system affected (RR 1.61; 95% CI 1.08-2.40), and absence of treatment (RR 2.56; 95% CI 1.76-3.71). We conclude that, unlike previous series, the majority of our patients were male, and there was a low occurrence of predominantly motor neuropathies and extrathoracic tumours coexisting with SCLC. When the diagnosed extrathoracic tumour expresses Hu antigens, further tests to rule out a coexisting SCLC are probably unnecessary. Finally, the predictors of mortality and PEM evolution found in the study may be important in the design of future therapeutic protocols, and emphasize the importance of early diagnosis and treatment of the underlying tumour.

[Subacute neuropathy, multiple cancers, and Gougerot-Sjögren syndrome: contribution of anti-Hu antibody]. / Neuropathie subaiguë, cancers multiples et syndrome de Gougerot-Sjögren: intérêt des anticorps anti-Hu.

We report the case of a patient presenting a subacute, predominantly sensory neuropathy. The work up revealed a Sjögren's syndrome and a breast carcinoma. The presence of anti-Hu antibodies, identified by Western Blot using purified recombinant HuD protein, and the absence of the Hu antigen in the breast carcinoma ruled out the responsibility of the Sjögren's syndrome or breast carcinoma. In this context, the most likely diagnosis was a subacute neuropathy associated with small cell lung cancer, which was indeed discovered 3 years later.

Association of herpes simplex virus encephalitis and paraneoplastic encephalitis - a clinico-pathological study.

A 57 year-old woman developed acute limbic encephalitis and brainstem dysfunction. Anti-HU antibodies were repeatedly detected in serum and CSF. Postmortem examination showed necrotic and hemorrhagic lesions in the temporal lobes characteristic of herpes simplex virus encephalitis, which was confirmed by immunocytochemistry, and Purkinje cell loss with proliferation of Bergman glia and myelin loss in the external aspect of the dentate nuclei characteristic of paraneoplastic encephalitis. PCR-assay performed on temporal tissue extracts was positive for HSV-1. There was no identifiable neoplasm. This unusual association raises the possibility of a link between the two diseases.

Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies.

Paraneoplastic encephalomyelitis or subacute sensory neuronopathy associated with small-cell lung cancer (SCLC) and high titers of anti-HuD antibodies, also called the "anti-Hu syndrome," is believed to result from an immune response triggered by tumor antigens and misdirected to the neurons. To further assess the issue of cell-mediated immunity in this disease, the peripheral blood lymphocyte surface phenotype was studied in 15 patients suffering from the anti-Hu syndrome (seropositive group) and in two control groups consisting of 12 seronegative SCLC patients without neurological syndrome and 15 healthy volunteers. In addition, the recombinant human HuD protein was used to stimulate in vitro peripheral blood mononuclear cells of 10 seropositive patients and of 10 patients from each control group. Phenotypic analysis of the peripheral blood lymphocytes revealed a significant increase of the memory helper (CD45RO+CD4+) T cells in the seropositive group in comparison with the two control groups. Antigen-specific proliferation of peripheral blood mononuclear cells, measured by [3H]thymidine uptake after HuD antigen stimulation, was much higher in the seropositive group than in the two control groups, and phenotypic analysis of proliferating cells revealed a significant expansion of the CD45RO subpopulation of T cells in the seropositive group. Furthermore, after HuD stimulation, a significant increase of the interferon-gamma/interleukin-4 ratio was found in culture supernatants of the seropositive group compared with seronegative SCLC patients and normal controls. Taken together, these results indicate that HuD protein is an antigenic target for autoreactive CD4+ T cells, presumably of the Th1 subtype, which could therefore be directly involved in cell-mediated injury of the nervous system as well as in antitumoral immunity.

[Paraneoplastic intestinal pseudo-obstruction revealing small cell lung carcinoma: "the anti-Hu syndrome"]. / Pseudo-obstruction intestinale paranéoplasique révélatrice d'un carcinome pulmonaire à petites cellules: le syndrome anti-Hu.

A 67-year-old woman was admitted for intestinal pseudoobstruction associated with peripheral sensitive neuropathy. Jejunal biopsies performed during laparotomy, showed axonal degeneration and lympho-plasmocytic infiltration in myenteric plexus. High titer of seric anti-Hu antibodies suggested a paraneoplastic syndrome. Thoracic CT scan showed mediastinal lymph nodes. Their histological examination confirmed the diagnosis of metastatic small-cell lung carcinoma. Her condition gradually deteriorated despite supportive parenteral nutrition, chemotherapy, steroids and intravenous immunoglobulins. She died 12 months after the onset of symptoms.

[Asphyxiating intra-alveolar hemorrhage: a rare form of fat embolism syndrome]. / Hémorragie intra-alvéolaire asphyxiante: forme rare du syndrome d'embolie graisseuse.

We report a case of a 23-year-old patient admitted for a right femur fracture resulting from a traffic accident. An intra-alveolar haemorrhage occurred 48 hours later, with asphyxia anaemia, haematic bronchial aspirations, and bilateral alveolar opacities at chest X-ray. This symptomatology was associated with fever, sub-conjunctival petechiae, major hypocholesterolemia, deterioration of renal function, and cholestasis. All these features suggested a fat embolism. Other possible aetiologies were discarded because of normal cardiovascular and immunologic systems and absence of infection. The outcome under symptomatic treatment was satisfactory within 15 days. The occurrence of intra-alveolar haemorrhage in post-traumatic fat embolism is a rare event caused by pulmonary capillary obstruction by fat emboli.

[Arterial thrombosis in the course of nephrotic syndrome. Report of three cases]. / Les thromboses artérielles au cours du syndrome néphrotique. A propos de trois observations.

Vascular thrombosis remains severe complication in patients with nephrotic syndrome. Both venous and arterial thrombosis are observed. We report three new cases of arterial thrombosis in patients with nephrotic syndrome. The role of acquired hemostasis disorders, inducing hypercoagulability, is predominant. Extramembranous glomerulonephritis remains the most frequent cause of nephrotic syndrome, complicated by vascular thrombosis. Treatment is based on anticoagulation and corticosteroid therapy. Search for proteinuria should be part of the etiology work-up in all patients with vascular thrombosis of undetermined origin.

The pathophysiology of paraneoplastic neurological syndromes.

Paraneoplastic neurological diseases are a group of neurological disorders associated with neoplastic tumors but not due to tumoral extension, metabolic, infectious, vascular or toxic complications of these tumors or their treatment. In the majority of paraneoplastic neurological disorders, circulating autoantibodies directed against neurons have been found in the serum and/or the CSF suggesting, and in some cases implicating, autoimmunity in the pathophysiology of these diseases. The finding of autoimmune phenomena during the course of paraneoplastic neurological disorders is of importance: from a practical point of view, since the detection of anti-neuronal autoantibodies is of great diagnostic help and should lead to the thorough search of the associated tumor often at an early stage of its development; from a theoretical point of view, these disorders represent a peculiar type of molecular mimicry. Tumoral neontigens having structural homology or identity with neuronal autoantigens elicit autoreactivity. The immunological effector mechanisms involved in the pathophysiology of paraneoplastic syndromes appear to differ according to the disease: autoantibodies are pathogenic in Lambert-Eaton syndrome whereas, in paraneoplastic cerebellar degeneration and in the Hu syndrome, the cellular immune response might play a greater role.

[Glomangioma of the popliteal fossa. Apropos of a case]. / Glomangiome du creux poplité. A propos d'un cas.

Glomus tumours are relatively uncommon lesions most frequently found in the extremitis, usually in the digits. They are most often solitary lesions but multiple tumours have been reported. If the triad of pain, tenderness and cold intolerance should raise the clinical suspicion of a digital glomus. The histological exam is necessary in the extra digital glomus. We reported a case of fossa poplitea glomangioma with tibialis nerve compression. The treatment of choice was a surgical exision. But the tumour have been redivided a year later without malign transformation.

[Arterial complications of Behcet's disease. Report of 13 cases]. / Les complications artérielles de la maladie de Behçet. A propos de 13 cas.

Vascular involvement, usually venous thrombosis, is common in Behçet's disease. Arterial manifestations, usually aneurysms or more rarely occlusion, are less common. We analyzed 13 cases of Behçet's disease with arterial complications. This fourth series in the literature was collected over 11 years. There were 12 men and 1 woman, mean age 41 +/- 7 years. Mean delay to arterial complications was 5.8 years (maximum 20 years) after the first sign of the disease. In the 13 patients in our series, there were a total of 18 arterial lesions, including one aneurysm and one stenosis of the internal carotid artery. There were 2 cases (10%) with lesions of the aorta (aneurysms). Approximately half of the arterial lesions (7/18) involved the femoral artery. There were 11 localizations on the femoropopliteal axis (11 aneurysms). One aneurysm of the humeral artery was the only localization in the upper limb. Vascular involvement was limited to arterial lesions in 9/13 patients with multiple lesions at different localizations in 2 patients. In two others, a second arterial localization occurred secondarily. All patients except one were operated. Mid-term complications are: 1 death and 4 thrombi including 3 with good results after reoperation. In these patients with Behçet's disease, risk of severe complications is important, requiring long-term surveillance.