MET immunolabelling is a useful predictive tool for MET gene amplification in glioblastoma.

AIMS: MET gene amplification is rare in glioblastoma (GBM) and represents a potential target for MET inhibitors. An immunohistochemical screening may be useful to identify MET amplification. The aim of our study was to establish how MET immunolabelling correlates with MET amplification. METHODS: Three cohorts including 108 GBM (cohort 1, prospective), 104 GBM (cohort 2, retrospective) and 52 GBM (cohort 3, prospective) were investigated for MET expression by immunohistochemistry. MET amplification was assessed by comparative genomic hybridization on microarray (CGH-array) in all cohorts and by fluorescent in situ hybridization (FISH) in cohorts 2 and 3. Active form of MET was assessed using p-MET (Y1349) immunohistochemistry. RESULTS: Diffuse MET amplification detectable by CGH-array was associated with diffuse, strong MET immunolabelling (four cases in cohort 1 and one case in cohort 2). Focal MET amplification detectable only by FISH was observed in small foci of strongly immunopositive cells in two GBM (cohort 2). In both cohorts, MET amplification was never detected in GBM devoid of strongly immunopositive cells. MET overexpression, observed in 23% of unamplified GBM, was associated with a predominant weak-to-moderate staining intensity and with necrosis (P < 0.005). p-MET was detected in all MET-amplified GBM and in perinecrotic areas of nonamplified GBM. A strong MET immunostaining intensity, at least focal and distant from necrosis, showed 100% sensitivity and 84% specificity for predicting MET amplification in cohort 3. CONCLUSIONS: MET amplification is characterized by strongly immunopositive cells. Only GBM showing strong MET immunostaining is appropriate for the assessment of MET amplification.

[Bevacizumab for the treatment of cerebral radionecrosis]. / Bévacizumab dans le traitement des radionécroses cérébrales.

Bevacizumab is a monoclonal antibody, which neutralizes the effect of vascular endothelium growth factor (VEGF) allowing regression of tumour vessels and a decrease in the permeability of the blood-brain barrier. Already used in oncology as adjuvant treatment for certain metastatic cancers and in second line for high-grade gliomas, it has been recently used as a treatment of cerebral radionecrosis resisting conventional drug treatment and hyperbaric oxygen. This article presents three patients with cerebral radionecrosis and treated by monthly infusions of bevacizumab (10 mg/kg per month). The patients had developed cerebral radionecrosis after radiation therapy for a malignant brain tumour. The radionecrosis was proved by magnetic resonance imaging and spectroscopy. The first patient received only one perfusion of bevacizumab, as the development of a lymphopenia prevented the patient from continuing with the treatment. The second patient received four infusions, but the absence of improvement of the clinical symptoms and progression of the radiolesion led to discontinuation of the treatment. The third patient developed several severe side effects, a transient ischemic accident and a perforated corneal ulcer, resulting again in premature discontinuation of treatment. The development of severe side effects, combined with the absence of notable clinical and radiologic improvements resulting from the use of bevacizumab as a treatment resulted in the premature interruption of such treatment, in all three patients.

Successful treatment of refractory generalized myasthenia gravis with rituximab.

OBJECTIVE: Myasthenia gravis (MG) is an autoimmune neuromuscular disorder for which current therapies carry a high risk of side-effects and may be insufficient in stabilizing the clinical status. Many therapeutic options can be ruled, such as thymectomy, corticosteroids, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate, intravenous immunoglobulin (IVIg) or less frequently plasmapheresis must be ruled. METHODS: We followed prospectively six patients with MG who presented with a poor response to two or three lines of immunosuppressive conventional drugs associated with oral corticosteroids. All but one were acetylcholine receptor negative and three were anti-MuSK positive. IVIg did not improved the neurological status and all patient required high doses of cholinesterase inhibitors. RESULTS: Rituximab was introduced with a mean follow-up of 1.5 years (375 mg/m(2), days 1, 8, 15, 28 during the first month and then one dose every 2 months). After 2 years of follow-up, all patients stopped corticosteroids and tapered off cholinesterase inhibitors from 60 to 180 mg/day without severe infectious events. CONCLUSION: Rituximab, a chimeric IgG k monoclonal antibody that target CD20 is used for the treatment of relapsing/refractory CD20 positive low-grade non-Hodgkin's lymphoma and other autoimmune neuromuscular diseases. Four previous short reports have described a good response of MG associated with lymphoma with rituximab. It appears to be a promising and effective drug for the treatment of MG without lymphoma, with a substantial benefit to the clinical status and good tolerability.

[De Seze et al. criteria: application to a series of 14 patients presenting a first severe acute demyelinating event]. / Application des critères de de Seze et al. sur une série de 14 patients ayant présenté un premier événement démyélinisant aigu sévère.

INTRODUCTION: The application of de Seze et al. criteria (2007) to patients presenting a first severe acute demyelinating event helps to distinguish acute disseminated encephalomyelitis (ADEM) from other CNS inflammatory diseases, with 83% sensitivity and 95% specificity. We applied these criteria to 14 patients who presented a first severe acute demyelinating event and whose later clinical course enabled clear identification of the neurological diagnosis. METHOD/PATIENTS: This study concerned 14 patients who presented a first acute demyelinating event. Initially, there were 16 patients but two were excluded because their initial clinical condition (isolated acute retrobulbar optic neuritis in one and acute cervical myelitis in the other) would have excluded them in the princeps article. We identified 11 women (78.6%) and three men (21.4%) with a mean age of 33.7+/-12.5 years. Follow-up ranged from three months to 11.5 years after the initial episode (average four years). At last follow-up, the diagnosis was ADEM in seven patients (50%) and multiple sclerosis (MS) in seven (50%). Five of seven patients in the MS group had a tumor-like presentation (71.4%), this parameter partly explaining the initial discrepancy in diagnosis. When applied to our series, de Seze criteria for ADEM exhibited 85.7% sensitivity and 71.4% specificity. CONCLUSION: Applying the new criteria, we did not find the same sensitivity, specificity, and positive and negative predictive values as in the original article. The lack of specificity arose from the misclassification of MS patients with a tumor-like presentation (two out of five false negatives). One of the explanations is that the clinical criteria used can be part of atypical forms of MS, in particular in its tumor-like presentation. De Seze et al. criteria can be an invaluable help for the clinician in the diagnosis of a first severe demyelinating event. Considering our results, these criteria should not be applied for patients with a tumor-like form of MS. A prospective study in a larger cohort is needed to confirm or invalidate these preliminary results.

Treatment of newly diagnosed symptomatic pure low-grade oligodendrogliomas with PCV chemotherapy.

Based on studies relating to anaplastic oligodendroglioma (OG) chemosensitivity and benefit of time to progression or overall survival, chemotherapy for pure OG has been proposed. Several studies have reported the efficacy of various chemotherapeutic agents in a small number of patients with low-grade gliomas, e.g. pure astrocytomas, OG or mixed histologies. The 5-year survival rate varies from 61% to 89% with a mean time to progression of 5 years. We report the outcome of 33 consecutive patients with pure low-grade OG diagnosed between 1990 and 2006 systematically treated for residual or non-removable tumor with PCV chemotherapy regimen as the front-line treatment after surgery. All the tumors were low grade (grade II) pure OG according to the WHO classification. All patients were symptomatic at presentation and underwent neurosurgical procedure for histological diagnosis. Response was evaluated by clinical assessment and brain magnetic resonance imaging. Twenty-one men and 12 women with a mean age at pathological diagnosis of 46.5 years were studied. The most common first symptom was partial epileptic seizure (73.7%). Six patients (18%) had initial gadolinium enhancement, associated with methoxyisobutyl (MIBI) hypermetabolism (P < 0.001). The resection was partial in seven cases (21%), and 26 patients (79%) had biopsy only. Eleven patients (36%) had a malignant transformation during the follow-up with a median time to progression of 19 months. Favorable prognostic factors were lack of contrast enhancement (P < 0.0001), and age <40 years (P < 0.0003); 90% of patients were progression-free at 1 year. Survival rates at 2, 5 and 10 years were 85%, 75% and 50%, respectively. Up-front chemotherapy with PCV regimen is a good treatment for symptomatic pure low-grade OG, as it increases the number of progression-free patients and time to progression. These results suggest that radiotherapy could be postponed until the malignant transformation occurs to delay cognitive side effects of irradiation.

[Phenotypical aspects and clinical course of multiple sclerosis in 76 patients with a North African ethnic background followed at the Nice University Hospital]. / Caractéristiques phénotypiques et évolutives de la SEP chez des patients originaires du Maghreb et suivis au CHRU de Nice (à propos d'une cohorte de 76 patients).

AIMS: In the European multiple sclerosis (MS) database registered in Nice, about 8p.cent of the patients have a North African ethnic background. PATIENTS AND METHODS: We performed a descriptive retrospective study of a cohort of 76 MS patients with a North African ethnic background followed in the Neurology Department of Nice University Hospital. This group was compared with a regional MS cohort (n=968) from our EDMUS database. Statistical analysis enabled classification of patients into three subgroups which had been submitted to different environmental factors according to where they were born and their age at immigration. There were prognostic aspects specific to each group. RESULTS: Regarding the entire cohort, poor prognostic factors included male gender, onset with sequellae, and substantial brain lesions on initial T2-weighted MRI. For the subgroups, prognostic aspects specific to each group were: 1) patients of North African origin born in France had an early age of onset, delayed diagnosis, remission between two long initial expressions of MS, and rapidly developed cerebellar problems with a secondary progressive course: 2) patients having migrated after age 15 had a late age of onset, delayed diagnosis, remission between two short initial expressions of MS, an onset characterized by one symptom, which was often a motor symptom involving the spinal cord or brain stem, but late-developing cerebellar problems and secondary progressive course are frequent; 3) patients having migrated before age 15 had an onset characterized by one symptom, often a visual problem, with sequellae and rapid development of cerebellar problems. CONCLUSION: The present study was consistent with the more unfavorable course of MS in patients of North African ethnic background previously reported in the literature. One should distinguish the subgroups to improve management of MS. Early administration of treatment should be considered for these patients, including earlier and more frequent use of immunosuppressive agents.

[Neurosarcoidosis treated with mycophenolate mofetil: two cases]. / Neurosarcoïdose et mycophénolate mofétil.

INTRODUCTION: Neurosarcoidosis is a rare (5 cases for one million) immune-mediated disease generally observed in young adults. Neurological symptoms are present in the half of patients, and symptoms remain limited to neurological system in 10p.cent. Histological criteria are mandatory to prove the diagnosis. The sensitivity and complications of biopsy are variable. The best sensitivity appears to be achieved with muscle biopsies which in addition have a lower risk of complications. Neurosarcoidosis is usually treated with corticosteroid therapy and immunosuppressive drugs (cyclophosphamide, cyclosporine, aziathoprine, methotrexate), but frequently resists standard schedules. In addition the many contraindications, side effects and cumulated toxicities of immunosuppressive drugs compromises their use. Knowledge of the effectiveness of other treatments would therefore be useful. Mycophenolate mofetil (MMF) has been used for treatment of many immune-mediated neurological diseases, like polymyositis, multifocal motor neuropathy, myasthenia or chronic inflammatory demyelinating polyradiculoneuropathy. MMF is efficient and well tolerated, but there is no case-report about neurosarcoidosis. CASE REPORT: We report two observations of young patients (14 and 27 years) with a diagnosis of resistant neurosarcoidosis treated with MMF (2 g/j) and corticosteroids. A significant and rapid effectiveness was clinically and radiologically observed, with good clinical and hematologic tolerance. CONCLUSION: The MMF seems to be an interesting rescue treatment for neurosarcoidosis. Further evaluation is needed.

[Turcot's syndrome confirmed by molecular biological tests]. / Syndrome de Turcot confirmé par biologie moléculaire.

INTRODUCTION: Turcot's syndrome is characterized clinically by the concurrence of a primary brain tumor and a familial adenomatous polyposis or a hereditary nonpolyposis colorectal cancer. OBSERVATION: We report a case of a 45-year-old woman who underwent in 1995 neuro-oncological treatment for an anaplastic astrocytoma (grade III according to the World Health Organization classification). Treatment included complete surgery, radiotherapy, a first-line nitrosourea-based chemotherapy regimen and a second-line platinium salt-based regimen. It was then noted that the patient's brother had colorectal cancer. A genetic study detected a germ-line mutation on the hMSH2 gene specific of HNPCC syndrome (Human Non Polyposis Colorectal Cancer). Colonoscopy was normal. Eight years after the diagnosis, the patient developed a gliomatosis cerebri and died. CONCLUSION: Relevant personal and familial history can provide the clue to the diagnosis of Turcot's syndrome. Molecular diagnosis may contribute to appropriate care of affected patients.

[Relapsing remitting multiple sclerosis or multiphasic disseminated encephalomyelitis?]. / Sclérose en plaques rémittente ou encéphalomyélite multiphasique disséminée?

INTRODUCTION: The imaging presentation of some forms of multiple sclerosis may be misleading. In patients with a history of recent infection or vaccination, especially for adolescents or young adults, the differential diagnosis with acute disseminated encephalomyelitis can be difficult. CASE REPORT: We report an unusual clinical and radiological presentation of multiple sclerosis, mimicking acute disseminated encephalomyelitis. We discuss clinical and radiological differential diagnosis, and the outcome after immunosuppressive treatment. CONCLUSION: Distinguishing between acute disseminated encephalomyelitis and the first relapse of multiple sclerosis can be difficult. Brain imaging is a precious tool for differentiating between the two diseases.

[Recurrent aseptic meningitis associated with primary biliary cirrhosis]. / Méningite récurrente aseptique associée à une cirrhose biliaire primitive.

INTRODUCTION: The etiological diagnosis of recurrent aseptic meningitis often requires difficult investigations. We report a case of recurrent aseptic meningitis associated with a primary biliary cirrhosis. CASE REPORT: A 37-year-old woman presented four recurrences of isolated meningitic syndrome with fever. Intravenous steroid treatment was effective. Investigations revealed an old right tympano-labyrinthine fracture with, on MRI, an abnormal enhancement of the posterior wall of the internal auditory canal. Serum tests were also significantly positive for antimitochondria antibodies subtype M2. CONCLUSION: Definitive diagnosis was recurrent puriform aseptic meningitis secondary to an inflammatory non-septic ears-nose-throat focus in a latent autoimmune context of primary biliary cirrhosis. To our knowledge, this is the first case reported in literature.

[Epileptic Münchausen syndrome by idiosyncratic of effect antiepileptic drugs]. / Syndrome de Münchausen épileptique par allergie grave à la phénytoïne.

Between 1996 and 2000, a 36-year-old woman was admitted four times for the presumed diagnosis of status epilepticus. Major skin allergy followed by collapsus occurred each time after intravenous phenytoin therapy. Video-EEG demonstrated non epileptic, psychogenic seizure leading to the diagnosis of Münchausen syndrome by idiosyncratic reaction to antiepileptic drugs.

[Relapsing-remitting inflammatory disease of the central nervous system with normal MRI: multiple sclerosis or phenocopy in a series of 15 patients]. / Maladie inflammatoire du système nerveux central évoluant par poussées avec IRM conventionnelle normale: sclérose en plaques ou phénocopie? A propos de 15 observations.

Multiple sclerosis is a demyelinating disease of central nervous system. Although many sub-types and clinical forms are identified, diagnosis is clearly related to the detection of MS lesions on brain MRI. We report data of 15 patients admitted in Nice for suspicion of MS after clinical relapsing-remitting or progressive symptoms. Extensive screening tests (i.e blood sample, CSF, MRI, spectroscopy) were performed at onset and at each relapse. All patients had normal-appearing white matter on spinal cord and brain MRI. Nevertheless, 11 patients can be considered as MS according to McDonald criteria.

[Intravenous immunoglobulins for relapsing-remitting multiple sclerosis after failure of treatment with other immuno-modulators]. / Evaluation du traitement par immunoglobulines intraveineuses dans la sclérose en plaques progressive après échappement aux autres traitements immunomodulateurs.

Intravenous immunoglobulins are used in the treatment of different autoimmune diseases. Recent trials suggest their efficacy in relapsing remitting multiple sclerosis. We report the results of an efficacy and safety trial using monthly intravenous injections of immunoglobulins for patients with secondary progressive multiple sclerosis. Eighteen patients in clinical progression, who have been previously treated with immunomodulatory or immunosuppressive drugs, were given monthly intravenous immunoglobulin infusions (0.4 g/kg/d for 5 days). At the beginning, the mean EDSS score was 6.77. At the end of the study, an improvement of EDSS was noted in 61.1 p. cent of patients, with less than 1 and 0.75 for secondary and primary progressive diseases respectively. No worsening was reported. Surprisingly, some patients had partial improvement of neurological functions which were considered as sequelae. Indications for intravenous immunoglobulins in the treatment of the multiple sclerosis need to be evaluated.

[Treatment of progressive multiple sclerosis with monthly pulsed cyclophosphamide-methylprednisolone: predictive factors of treatment response]. / Association cyclophosphamide-méthylprednisolone en traitement de fond des scléroses en plaques de type progressif: facteurs prédictifs d'une réponse clinique.

INTRODUCTION: Cyclophospamide is used in the treatment of progressive multiple sclerosis. We were looking for predictive indicators of treatment response. MATERIAL AND METHODS: Forty-seven patients with secondary progressive multiple sclerosis and seven others with primary progressive received monthly infusions of cyclophosphamide (750mg/m2) and methylprednisolone (500mg). During the year before cyclophosphamide the EDSS had worsened one point in all patients with or without surimposed relapses. Evaluation was based on EDSS change at 6, 12, 24 months and 5 years. RESULTS: Among secondary progressive patients, 91 per 100 (43/47) were stable or improved at 12 months, 65 per 100 (26/40) at 24 months and 22 per 100 (5/23) at 5 years. Annual relapse rate decreased from 0.81 before treatment to 0.48 during treatment and 0.12 after treatment (p<0.001). At 24 months, efficacy was correlated to a progressive phase lasting less than 5 years (p<0.01) and to a rapid increase of EDSS of at least 2 points the year before treatment (p<0.05). There were no influences of age, EDSS and surimposed relapses at the beginning of treatment, and other immunoactive drugs administrated before cyclophosphamide. There was no significant difference in quality of response to treatment between patients with primary progressive and secondary progressive multiple sclerosis. CONCLUSION: Cyclophosphamide appears to be more efficient in early stage of progressive multiple sclerosis independently of age, relapses or neurological disability scale.

[The contribution of automatic anatomical matching of sequential brain MRI scans in the monitoring of multiple sclerosis lesions]. / Intérêt du recalage automatique des IRM cérébrales dans le suivi des scléroses en plaques.

INTRODUCTION: Magnetic resonance imaging (MRI) has transformed management of patients with multiple sclerosis. The exact contribution of brain MRI remains a subject of debate, but it is generally considered to provide a more specific and more sensitive outcome measure for monitoring purposes and for testing new therapies. The choice of MRI techniques, and measurement reproducibility for multiple sclerosis brain lesions are not defined with precision for routine practice. There are many sources of error when comparing successive images which can be overcome to some extent with repositioning and image processing techniques. METHODS: We evaluated the impact of image repositioning on treatment decision-making for twelve relapsing remitting patients. Brain MRIs were performed every three months for a one-year period. Two neurologists interpreted the non-repositioned and repositioned images giving their analysis of changes in the lesions visualized on the T2 sequences and their therapeutic decisions. RESULTS: For the first neurologist, analysis of the non-repositioned images yielded six patients whose lesions had worsened while for the repositioned images there were only three. For the second neurologist, four patients had more lesions with the non-repositioned images and only three with repositioning. The subjective interpretations were the same for the two neurologists when they used repositioned images. CONCLUSIONS: Comparison by two neurologists of non-repositioned and repositioned MRI, with no other image processing, affected the analysis and in certain cases propositions for treatment.

[Castleman's disease located in the central nervous system]. / Maladie de Castleman localisée au système nerveux central.

A 26-year-old woman complained of trijeminal nevralgy and ocular symptoms revealing a paracavernal tumor which had progressed for three months. Histopathological analysis after partial resection led to the diagnosis of Castleman's disease. Six months later, the patient was considered cured after focal adjuvant radiotherapy. Castleman's disease is a lymphoproliferative disorder. Solitary intracranial involvement is unusual. Unlike multifocal disease, localized Castleman's disease has an excellent prognosis.

[Neoadjuvant chemotherapy for symptomatic non operable grade II fibrillary astrocytoma in adults]. / Chimiothérapie néoadjuvante dans les astrocytomes fibrillaires de grade II symptomatiques non opérables de l'adulte.

We collected 6 case-reports of symptomatric non removable low grade fibrillary astrocytoma of adults treated with a procarbazine-CCNU-vincristine chemotherapy regimen. All patients had drug-resistant epilepsy but brain imaging was stable. Total gross resection was rejected because of Volume or tumor location. After 4 to 7 cycles of chemotherapy, 2 patients had partial response and one minor response on brain MRI. All of them were seizure-free. Progression free survival was not reached at 5 Years. Up-front chemotherapy for low-grade astrocytomas may be useful and has to be prospectively evaluated.

A French observational study of botulinum toxin use in the management of children with cerebral palsy: BOTULOSCOPE.

BACKGROUND: Dystonia and spasticity are common symptoms in children with Cerebral Palsy (CP), whose management is a challenge to overcome in order to enable the harmonized development of motor function during growth. AIM: To describe botulinum toxin A (BTX-A) use and efficacy as a treatment of focal spasticity in CP children in France. METHODS: This prospective observational study included 282 CP children mostly administered according to French standards with BTX-A in lower limbs. Realistic therapeutic objectives were set with parents and children together before treatment initiation and assessed using the Visual Analogue Scale (VAS). Child management was recorded and the efficacy of injections was assessed during a 12-month follow-up period by physicians (Modified Ashworth Scale, joint range of motion, Physician Rating Scale, Gillette Functional Assessment Questionnaire and Gross Motor Function Measure-66) and by patients/parents (Visual Analogue Scale). RESULTS: BTX-A treatment was administered in different muscle localizations at once and at doses higher than those recommended by the French Health Authorities. Children were treated in parallel by physiotherapy, casts and ortheses. Injections reduced spasticity and improved joint range of motion, gait pattern and movement capacity. Pain was reduced after injections. BTX-A administration was safe: no botulism-like case was reported. The log of injected children who were not included in the study suggested that a large population could benefit from BTX-A management. CONCLUSIONS: We showed here the major input of BTX-A injections in the management of spasticity in CP children. The results are in favor of the use of BTX-A as conservative safe and efficient treatment of spasticity in children, which enables functional improvement as well as pain relief.