Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies.

BACKGROUND AND OBJECTIVES: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. METHODS: Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. RESULTS: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. DISCUSSION: Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

Added value of [18F]FDOPA PET to the management of high-grade glioma patients after their initial treatment: a prospective multicentre study.

BACKGROUND: Diagnostic value of 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine ([18F]FDOPA) PET in patients with suspected recurrent gliomas is recognised. We conducted a multicentre prospective study to assess its added value in the practical management of patients suspected of recurrence of high grade gliomas (HGG). METHODS: Patients with a proven HGG (WHO grade III and IV) were referred to the multidisciplinary neuro-oncology board (MNOB) during their follow-up after initial standard of care treatment and when MRI findings were not fully conclusive. Each case was discussed in 2 steps. For step 1, a diagnosis and a management proposal were made only based on the clinical and the MRI data. For step 2, the same process was repeated taking the [18F]FDOPA PET results into consideration. A level of confidence for the decisions was assigned to each step. Changes in diagnosis and management induced by [18F]FDOPA PET information were measured. When unchanged, the difference in the confidence of the decisions were assessed. The diagnostic performances of each step were measured. RESULTS: 107 patients underwent a total of 138 MNOB assessments. The proposed diagnosis changed between step 1 and step 2 in 37 cases (26.8%) and the proposed management changed in 31 cases (22.5%). When the management did not change, the confidence in the MNOB final decision was increased in 87 cases (81.3%). Step 1 had a sensitivity, specificity and accuracy of 83%, 58% and 66% and step 2, 86%, 64% and 71% respectively. CONCLUSION: [18F]FDOPA PET adds significant information for the follow-up of HGG patients in clinical practice. When MRI findings are not straightforward, it can change the management for more than 20% of the patients and increases the confidence level of the multidisciplinary board decisions.

Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial.

BACKGROUND: Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody-drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. METHODS: In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. RESULTS: There were 639 randomized patients (median age 60, range 22-84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82-1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70-1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56-0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61-0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3-4), causing 12% to discontinue. CONCLUSIONS: Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.

Diagnostic workup in children with arthrogryposis: description of practices from a single reference centre, comparison with literature and suggestion of recommendations.

INTRODUCTION: Arthrogryposis multiplex congenita (AMC) refers to a clinical presentation of congenital contractures involving two or more body areas. More than 400 distinct conditions may lead to AMC, making the aetiological diagnosis challenging. The objective of this work was to set up evidence-based recommendations for the diagnosis of AMC by taking advantage of both data from our nation-wide cohort of children with AMC and from the literature. MATERIAL AND METHODS: We conducted a retrospective single-centre observational study. Patients had been evaluated at least once at a paediatric age in the AMC clinic of Grenoble University Hospital between 2007 and 2019. After gathering data about their diagnostic procedure, a literature review was performed for each paraclinical investigation to discuss their relevance. RESULTS: One hundred and twenty-five patients were included, 43% had Amyoplasia, 27% had distal arthrogryposis and 30% had other forms. A definitive aetiological diagnosis was available for 66% of cases. We recommend a two-time diagnostic process: first, non-invasive investigations that aim at classifying patients into one of the three groups, and second, selected investigations targeting a subset of patients. CONCLUSION: The aetiological management for patients with AMC remains arduous. This process will be facilitated by the increasing use of next-generation sequencing combined with detailed phenotyping. Invasive investigations should be avoided because of their limited yield.

Validity, reliability and responsiveness to change of the French version of the drooling impact scale.

BACKGROUND: work still needs to be done to measure the impact of sialorrhea on quality of life and define the efficacy of different therapies. The Drooling Impact Scale showed good validity and sensitivity to change, especially after botulinum toxin injection. The aim of this study is to present its French translation and to explore its validity, reliability and responsiveness to change in a group of children with Cerebral Palsy. METHODS: multicentre study at six rehabilitation centres in France. Children with Cerebral Palsy aged 4-18 years with sialorrhea problems were included (n = 55), either in a control group (n = 33) or in the intervention group (n = 22, with 3 drug treatment and 19 botulinum toxin injections). The French Drooling Impact Scale was administered twice, 1 month apart. RESULTS: The French Drooling Impact Scale total score at inclusion was meanly 53.9 (Standard Deviation 11.9) in the stable control group and 66.0 (16.1) in the intervention group (p = 0.0058). The validity of the scale was established, as well as an adequate internal consistency (Cronbach's α = 0.71); correlations between each item and the total score were found between 0.5 and 0.71 except for item 5 (r = 0.38) and item 7 (0.41). The test-retest reliability in stable children was good (Lin coefficient = 0.83, bias correction factor = 0.92 and Pearson correlation coefficient = 0.89). There was a high responsiveness to change, mean change was -40.0 in the intervention group and -3.6 in the stable group (p < 0.0001), with Standard Error of Measurement = 2.6. CONCLUSION: the French Drooling Impact Scale has shown sufficient clinometric properties to be used now by clinicians or researchers.IMPLICATIONS FOR REHABILITATIONThe Drooling Impact scale has now its French version.The French version of the Drooling Impact Scale has shown its validity and a good test-retest reliability.The responsiveness to change was explored in a group of children undergoing saliva-control interventions and the scale was able to show a big change.The authors recommend to use this questionnaire in a semi-directed interview conducted by a health professional.

Glial Fibrillary Acidic Protein (GFAP) Astrocytopathy Presenting as Mild Encephalopathy with Reversible Splenium Lesion.

INTRODUCTION: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is scarce and usually presents as meningoencephalomyelitis. Here, we offer the case of an atypical presentation of GFAP-astrocytopathy. CASE PRESENTATION: We report the case of a 26-year-old woman admitted to our neurology department for a 3-week progressive and worsening neurologic picture, with secondary worsening. Initial imaging showed a Mild Encephalitis with Reversible Splenium of corpus callosum lesion (MERS). Full infectious and autoimmune workup then revealed positivity of GFAP antibodies, leading us to diagnose GFAP astrocytopathy. DISCUSSION: Our case is the first reported association between MERS and GFAP astrocytopathy in an adult patient. Clinical presentation of GFAP astrocytopathy usually includes various neurologic symptoms and can lead to misdiagnosis.

Marburg Multiple Sclerosis Variant: Complete Remission with Very Early Administration of Mitoxantrone-A Case Report.

Marburg variant is a severe and fulminant pseudotumor form of multiple sclerosis (MS) with high morbidity and mortality rates. Because of its scarcity, it remains incompletely characterized and physicians' experiences will influence the treatment. We report the inflammatory explosive case of a 31-year-old woman presenting with rapid neurological degradation of histology proven Marburg's disease, successfully treated with early administration of Mitoxantrone (MITX). To our knowledge, it is the first case describing complete remission after MITX in a biopsy-proven condition.

Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study.

BACKGROUND AND OBJECTIVES: To report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies. METHODS: We retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers. RESULTS: We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies. DISCUSSION: GFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.

Cerebrospinal Fluid IL-17A Could Predict Acute Disease Severity in Non-NMDA-Receptor Autoimmune Encephalitis.

Introduction: Most of our knowledge into autoimmune encephalitis (AE) comes from N-Methyl-D-Aspartate Receptor (NMDAR) encephalitis. The concentrations of cytokines in cerebrospinal fluid (CSF) including IL-17A have been found to be increased and associated with poor outcome. However, data on the cytokine concentration in CSF and its correlation with outcome is lacking for other types of AE. Objective: To report the concentrations of CSF sIL-2R, IL-6, IL-8, IL-10 and IL-17A and to correlate it with acute disease severity and the 1-year outcome in non-NMDAR AE. Methods: We measured the CSF concentration of each cytokine in 20 AE patients, and compared IL-6 and IL-17A concentrations with 13 patients with CNS demyelinating diseases and 20 non-inflammatory controls. Patients were > 18yr and had at least 1-year clinical follow-up. Intracellular and NMDAR antibody (Ab) -mediated encephalitis were excluded. A mRS ≤ 2 was retained as a 1-year good outcome. Results: The IL-17A concentration in CSF was higher in AE patients than in both control groups (p<0.01). No difference was observed in CSF concentration of IL-6 between groups. At disease onset, a high CSF IL-17A concentration correlated with a high modified Rankin Scale (p<0.05), a high Clinical Assessment Scale for Autoimmune Encephalitis score (p<0.001) and ICU admission (p<0.01). There was no correlation between the concentration of all CSF cytokines and the 1-year clinical outcome. Conclusion: Our results show that CSF IL-17A could be interesting to assess initial severity in non-NMDAR AE. Thus, CSF IL-17A could be an interesting therapeutic target and be useful to assess early selective immunosuppressive therapy.

Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults.

BACKGROUND: Diffuse hemispheric gliomas, H3 G34-mutant (DHG H3G34-mutant) constitute a distinct type of aggressive brain tumors. Although initially described in children, they can also affect adults. The aims of this study were to describe the characteristics of DHG H3G34-mutant in adults and to compare them to those of established types of adult WHO grade IV gliomas. METHODS: The characteristics of 17 adult DHG H3G34-mutant, 32 H3.3 K27M-mutant diffuse midline gliomas (DMG), 100 IDH-wildtype, and 36 IDH-mutant glioblastomas were retrospectively analyzed. RESULTS: Median age at diagnosis in adult DHG H3G34-mutant was 25 years (range: 19-33). All tumors were hemispheric. For 9 patients (56%), absent or faint contrast enhancement initially suggested another diagnosis than a high-grade glioma, and diffusion-weighted imaging seemed retrospectively more helpful to suspect an aggressive tumor than MR-spectroscopy and perfusion MRI. All cases were IDH-wildtype. Most cases were immunonegative for ATRX (93%) and Olig2 (100%) and exhibited MGMT promoter methylation (82%). The clinical and radiological presentations of adult DHG H3G34-mutant were different from those of established types of adult grade IV gliomas. Median overall survival of adult DHG H3G34-mutant was 12.4 months compared to 19.6 months (P = .56), 11.7 months (P = .45), and 50.5 months (P = .006) in H3.3 K27M-mutant DMG, IDH-wildtype, and IDH-mutant glioblastomas, respectively. CONCLUSIONS: Adult DHG H3G34-mutant are associated with distinct characteristics compared to those of established types of adult WHO grade IV gliomas. This study supports considering these tumors as a new type of WHO grade IV glioma in future classifications.

Amyoplasia and distal arthrogryposis.

Arthrogryposis multiplex congenita (AMC) consists of congenital joint contractures that affect at least two joints. There are two types: in the first, arthrogryposis is an additional sign in the context of various pathologies (neuromuscular diseases); in the second, it is the main and constant symptom. In the first type, the progression of the causal underlying disease must be considered. In the second type, there are two specific forms: Amyoplasia corresponds to a significant congenital absence of muscles (epigenetic disease or vascular origin) while distal arthrogryposis has a genetic component and is transmissible. The orthopedic surgeon's purpose, which is usually to enhance movement, is not appropriate for an arthrogryposis patient. One must keep in mind that without muscle, movement is impossible. The goal differs between the upper and lower limbs: for the upper limb, it is to allow grasping, and, if possible, to bring the hand to the mouth; for the lower limb, it is to ensure ambulation with plantigrade support, and the knees extended, which is the only stable position possible with little to no muscles. The rehabilitation, orthoses and/or surgical techniques are chosen to achieve this singular aim. While it may appear modest, it is crucial for patients. The goal is to achieve useful mobility, not maximum mobility. This multidisciplinary treatment, which evolves over time, must be explained to the family to get its adherence.

Clinical, molecular, and radiomic profile of gliomas with FGFR3-TACC3 fusions.

BACKGROUND: Actionable fibroblast growth factor receptor 3 (FGFR3)-transforming acidic coiled-coil protein 3 fusions (F3T3) are found in approximately 3% of gliomas, but their characteristics and prognostic significance are still poorly defined. Our goal was to characterize the clinical, radiological, and molecular profile of F3T3 positive diffuse gliomas. METHODS: We screened F3T3 fusion by real-time (RT)-PCR and FGFR3 immunohistochemistry in a large series of gliomas, characterized for main genetic alterations, histology, and clinical evolution. We performed a radiological and radiomic case control study, using an exploratory and a validation cohort. RESULTS: We screened 1162 diffuse gliomas (951 unselected cases and 211 preselected for FGFR3 protein immunopositivity), identifying 80 F3T3 positive gliomas. F3T3 was mutually exclusive with IDH mutation (P < 0.001) and EGFR amplification (P = 0.01), defining a distinct molecular cluster associated with CDK4 (P = 0.04) and MDM2 amplification (P = 0.03). F3T3 fusion was associated with longer survival for the whole series and for glioblastomas (median overall survival was 31.1 vs 19.9 mo, P = 0.02) and was an independent predictor of better outcome on multivariate analysis.F3T3 positive gliomas had specific MRI features, affecting preferentially insula and temporal lobe, and with poorly defined tumor margins. F3T3 fusion was correctly predicted by radiomics analysis on both the exploratory (area under the curve [AUC] = 0.87) and the validation MRI (AUC = 0.75) cohort. Using Cox proportional hazards models, radiomics predicted survival with a high C-index (0.75, SD 0.04), while the model combining clinical, genetic, and radiomic data showed the highest C-index (0.81, SD 0.04). CONCLUSION: F3T3 positive gliomas have distinct molecular and radiological features, and better outcome.

Early Toxicities After High Dose Rate Proton Therapy in Cancer Treatments.

BACKGROUND: The conventional dose rate of radiation therapy is 0.01-0.05 Gy per second. According to preclinical studies, an increased dose rate may offer similar anti-tumoral effect while dramatically improving normal tissue protection. This study aims at evaluating the early toxicities for patients irradiated with high dose rate pulsed proton therapy (PT). MATERIALS AND METHODS: A single institution retrospective chart review was performed for patients treated with high dose rate (10 Gy per second) pulsed proton therapy, from September 2016 to April 2020. This included both benign and malignant tumors with ≥3 months follow-up, evaluated for acute (≤2 months) and subacute (>2 months) toxicity after the completion of PT. RESULTS: There were 127 patients identified, with a median follow up of 14.8 months (3-42.9 months). The median age was 55 years (1.6-89). The cohort most commonly consisted of benign disease (55.1%), cranial targets (95.1%), and were treated with surgery prior to PT (56.7%). There was a median total PT dose of 56 Gy (30-74 Gy), dose per fraction of 2 Gy (1-3 Gy), and CTV size of 47.6 ml (5.6-2,106.1 ml). Maximum acute grade ≥2 toxicity were observed in 49 (38.6%) patients, of which 8 (6.3%) experienced grade 3 toxicity. No acute grade 4 or 5 toxicity was observed. Maximum subacute grade 2, 3, and 4 toxicity were discovered in 25 (19.7%), 12 (9.4%), and 1 (0.8%) patient(s), respectively. CONCLUSION: In this cohort, utilizing high dose rate proton therapy (10 Gy per second) did not result in a major decrease in acute and subacute toxicity. Longer follow-up and comparative studies with conventional dose rate are required to evaluate whether this approach offers a toxicity benefit.

Effects of dual tasking on postural and gait performances in children with cerebral palsy and healthy children.

Simultaneous execution of motor and cognitive tasks is embedded in the daily life of children. 53 children of 7-12 years and 22 adults (study 1), 20 healthy children and 20 children of 7-12 years with cerebral palsy (study 2) performed a Stroop-animal task simultaneously with a standing or a walking task in order to determine the attentional demand of postural control and locomotion. Dual-task cost decreased with advancing age in healthy children during balance. CP and healthy children were similarly affected by dual-task constraints during standing and walking. Children with diplegia were more affected by the DT during the postural task than children with hemiplegia. We found that adults could benefit from dual-tasking for standing. The integrated model of task prioritization might explain our results regarding postural reserve of each population.

Complementary and alternative medicine use in glioma patients in France.

PURPOSE: Complementary and alternative medicine (CAM) use increases in cancer patients, including adult patients with diffuse gliomas. METHODS: Questionnaires addressing CAM use were distributed to adult patients with gliomas of WHO grades II-IV and ECOG performance score of 0-2 during hospital visits and filled in anonymously. The study was conducted in nine centers in France from May 2017 to May 2018. Descriptive cohort analyses and comparative analyses according to gender, age, WHO grade, and recurrent versus newly diagnosed disease were conducted. RESULTS: Two hundred twenty-seven questionnaires were collected; 135 patients (59%) were male. Median age was 48 years, 105 patients (46%) declared having glioblastoma, 99 patients (43%) declared having recurrent disease. Hundred-three patients (45%) had modified their alimentary habits after the glioma diagnosis. At the time of the questionnaire, 100 patients (44%) were on complementary treatment, mainly vitamins and food supplements, and 73 patients (32%) used alternative medicine approaches, mainly magnetism and acupuncture. In total, 154 patients (68%) declared using at least one of these approaches. Expenditures exceeding 100 € per month were reported by users in 14% for modification of alimentary habits, in 25% for complementary treatment, and in 18% for alternative medicines. All approaches were commonly considered as improving quality of life and experienced as efficient, notably those associated with more expenditures. CONCLUSIONS: CAM are frequently used by glioma patients in France. Underlying needs and expectations, as well as potential interactions with tumor-specific treatments, and financial and quality of life burden, should be discussed with patients and caregivers.

Immunoglobulin G4-related hypertrophic pachymeningitis: A case-oriented review.

Objective: Meningeal involvement in Immunoglobulin G (IgG)-4-related disease is rare and only described in case reports and series. Because a review into the disease is lacking, we present 2 cases followed by a literature review of IgG4-related hypertrophic pachymeningitis (IgG4-HP). Methods: Two IgG4-HP cases were reported, one involving the spinal cord and responding to surgical management and a second involving the brain and responding to Rituximab therapy. We then review clinical cases and case-series of histologically proven IgG4-HP that were published in the PubMed-NCBI database. Results: Forty-two case reports and 5 case-series were studied (60 patients, 20 women). The median age was 53. Eighteen patients had systemic involvement and 24 had single-organ IgG4-HP. Fifty-five percent of patients had an elevated serum IgG4. Treatment was surgical in 20/53 cases. Steroid therapy and immunosuppressors were effective in 85% and more than 90% of the cases, respectively. The rate of disease relapse was 42.1% after steroid therapy was discontinued. Discussion/conclusion: IgG4-HP is characterized by the lack of extra-neurologic organ-involvement and systemic signs. Histopathologic studies should be performed as it is crucial for diagnosis because serum markers are rarely informative. 18F-FDG positon tomography can be useful to characterize systemic forms. There is no specific CSF marker for IgG4-HP and the diagnostic value of CSF IgG4 levels needs to be studied with larger samples. We provide a treatment algorithm for IgG4-HP. Such treatment strategies rely on early surgery, steroids, and early immunosuppressive therapy to prevent neurologic complications.

Correction to: 18F-DOPA PET/CT in brain tumors: impact on multidisciplinary brain tumor board decisions.

Jérôme Barriere was inadvertently missing in the original version of this article. He has participated to the study design, protocol writing and inclusion of a significant number of patients.

18F-DOPA PET/CT in brain tumors: impact on multidisciplinary brain tumor board decisions.

PURPOSE: This study aimed to assess the therapeutic impact and diagnostic accuracy of 18F-DOPA PET/CT in patients with glioblastoma or brain metastases. METHODS: Patients with histologically proven glioblastoma or brain metastases were prospectively included in this monocentric clinical trial (IMOTEP). Patients were included either due to a clinical suspicion of relapse or to assess residual tumor infiltration after treatment. Multimodality brain MRI and 18F-DOPA PET were performed. Patients' data were discussed during a Multidisciplinary Neuro-oncology Tumor Board (MNTB) meeting. The discussion was first based on clinical and MRI data, and an initial diagnosis and treatment plan were proposed. Secondly, a new discussion was conducted based on the overall imaging results, including 18F-DOPA PET. A second diagnosis and therapeutic plan were proposed. A retrospective and definitive diagnosis was obtained after a 3-month follow-up and considered as the reference standard. RESULTS: One hundred six cases were prospectively investigated by the MNTB. All patients with brain metastases (N = 41) had a clinical suspicion of recurrence. The addition of 18F-DOPA PET data changed the diagnosis and treatment plan in 39.0% and 17.1% of patients' cases, respectively. Concerning patients with a suspicion of recurrent glioblastoma (N = 12), the implementation of 18F-DOPA PET changed the diagnosis and treatment plan in 33.3% of cases. In patients evaluated to assess residual glioblastoma infiltration after treatment (N = 53), 18F-DOPA PET data had a lower impact with only 5.7% (3/53) of diagnostic changes and 3.8% (2/53) of therapeutic plan changes. The definitive reference diagnosis was available in 98/106 patients. For patients with tumor recurrence suspicion, the adjunction of 18F-DOPA PET increased the Younden's index from 0.44 to 0.53 in brain metastases and from 0.2 to 1.0 in glioblastoma, reflecting an increase in diagnostic accuracy. CONCLUSION: 18F-DOPA PET has a significant impact on the management of patients with a suspicion of brain tumor recurrence, either glioblastoma or brain metastases, but a low impact when used to evaluate the residual glioblastoma infiltration after a first-line radio-chemotherapy or second-line bevacizumab.

De novo convulsive status epilepticus in patients with multiple sclerosis treated with dalfampridine.

BACKGROUND: Dalfampridine extended release (DAL) is a broad-spectrum voltage-gated potassium channel blocker that is indicated in multiple sclerosis to improve the nerve conduction of demyelinated axons. Seizures are a known side effect of DAL, which is contraindicated in patients with a history of epilepsy. OBJECTIVE: Three cases of multiple sclerosis (MS) with de novo convulsive status epilepticus (CSE) probably related to dalfampridine administration are described. METHODS: No patients had a history of seizures or renal impairment. Biological tests were normal. A brain magnetic resonance imaging (MRI) showed diffuse cortical and subcortical atrophy without active inflammatory lesions. RESULTS: All three patients presented with CSE that was attributed to DAL and so was discontinued. CONCLUSION: These case reports illustrate that, aside from seizures, de novo CSE is a potential complication of MS patients treated with DAL.

Bevacizumab: Is the lower the better for glioblastoma patients in progression?

INTRODUCTION: Based on the radiological responses obtained with a schedule of ten mg/kg every two weeks bevacizumab was approved by the FDA for recurrent glioblastomas. Due to the negative results concerning overall survival of patients receiving bevacizumab, the European application was rejected. Despite this, many centers apply an off-label prescription. Our aim was to evaluate the safety and efficacy of schedules of low doses of bevacizumab. METHODS: From September 2013 to August 2016, we recruited patients with progressive glioblastoma, whatever the previous treatments. We compared a routine control group (CG) of ten mg/kg, to a low dose group (LDG) composed of 5 subgroups: G5: five mg/kg, G4: four mg/kg, G3: three mg/kg, G2: two mg/kg, G1: one mg/kg; each patient was treated with the same dose every two weeks. RESULTS: Fifty-three patients were treated: 20 women and 33 men, 24 in the CG and 29 in the LDG. The median age at diagnosis was 62 years [35.0-77.0]. No statistical difference was found in overall survival either for the CG or the LDG (P=0.086) or among groups (P=0.251), with even a trend toward improvement for LDG: 62 weeks [20-145] versus 73 weeks [18-178]. The median progression free survival was comparable: 19.5 weeks [6.0-54.0] for the CG and 15.0 weeks [0.0-134.0] for the LDG (P=0.221). Bevacizumab was stopped either due to progression (45.1%) or toxicity (52.9%), without significant differences between doses but maybe less toxicities in the LDG (16.7% for toxicity in G1). DISCUSSION: Use of bevacizumab at progression at lower than usual doses seems to give the same results as the standard dose without giving additional toxicity.