Anne Kerbrat

Inhibitor of Fatty Acid Amide Hydrolase - Learning from Tragic Failures

The authors reply: Anghelescu comments on the mechanism responsible for the acute neurologic disorders observed in the four volunteers described in our article...To the Editor: Kerbrat et al. (Nov. 3 issue)1 describe the central nervous system clinical signs and symptoms in healthy volunteers who received an investigational drug that inhibits fatty acid amide hydrolase (FAAH). Other causes for the illness were ruled out, so drug toxicity was assumed to be responsible for the tragic acute neurologic disorder. Drug accumulation due to prolonged exposure to increased dosages may have led to off-target effects. Would the authors agree that compound-related toxicity rather than mechanism-based toxicity played the main role in these events? One wonders whether preclinical toxicology studies in animals already showed drug-accumulation–related toxic effects. Moreover, it would be interesting to know what oral dose would have been sufficient to inhibit the FAAH to a clinically meaningful degree (e.g., >50% inhibition) in order to substantially increase intrinsic anandamide levels. Could one assume this would be the maximal dose used in a phase 1 trial? If not, why should higher doses be prescribed, as might have happened in this case? Ion Anghelescu, M.D.

USPIO-positive MS lesions are associated with greater tissue damage than gadolinium-positive-only lesions during 3-year follow-up

Background: Identifying in vivo the processes that determine lesion severity in multiple sclerosis (MS) remains a challenge. Objectives: To describe the dynamics of ultrasmall superparamagnetic iron oxide (USPIO) enhancement in MS lesions and the relationship between USPIO enhancement and microstructural changes over 3 years. Methods: Lesion development was assessed at baseline, Months 3, 6, and 9, using magnetic resonance imaging (MRI) with gadolinium and USPIO. Microstructural changes were assessed at baseline, Months 3, 6, 9, 12, 18, 24, and 36, using relaxometry, magnetization transfer, and diffusion-weighted imaging. Results: We included 15 patients with clinically isolated syndrome. In the 52 MRI scans acquired with USPIO, 22 lesions were USPIO and gadolinium positive, and 44 were USPIO negative but gadolinium positive. Lesions no longer exhibited sustained USPIO enhancement 3 months later. At baseline, lesions that were both USPIO and gadolinium positive had lower magnetization transfer ratio values (common language effect size = 0.84, p = 0.0005) and lower fractional anisotropy values (0.83, p = 0.001) than gadolinium-positive-only lesions. USPIO-positive lesions remained associated with greater damage than gadolinium-positive-only lesions throughout the 3-year follow-up. Conclusion: USPIO enhancement, mainly reflecting monocyte infiltration, is transient and is associated with persistent tissue damage after 3 years.

Objective Evaluation of Multiple Sclerosis Lesion Segmentation using a Data Management and Processing Infrastructure

We present a study of multiple sclerosis segmentation algorithms conducted at the international MICCAI 2016 challenge. This challenge was operated using a new open-science computing infrastructure. This allowed for the automatic and independent evaluation of a large range of algorithms in a fair and completely automatic manner. This computing infrastructure was used to evaluate thirteen methods of MS lesions segmentation, exploring a broad range of state-of-theart algorithms, against a high-quality database of 53 MS cases coming from four centers following a common definition of the acquisition protocol. Each case was annotated manually by an unprecedented number of seven different experts. Results of the challenge highlighted that automatic algorithms, including the recent machine learning methods (random forests, deep learning, …), are still trailing human expertise on both detection and delineation criteria. In addition, we demonstrate that computing a statistically robust consensus of the algorithms performs closer to human expertise on one score (segmentation) although still trailing on detection scores.

A Bayesian Model to Assess \(T_2\) Values and Their Changes Over Time in Quantitative MRI

Quantifying \(T_2\) and \(T_2^*\) relaxation times from MRI becomes a standard tool to assess modifications of biological tissues over time or differences between populations. However, due to the relationship between the relaxation time and the associated MR signals such an analysis is subject to error. In this work, we provide a Bayesian analysis of this relationship. More specifically, we build posterior distributions relating the raw (spin or gradient echo) acquisitions and the relaxation time and its modifications over acquisitions. Such an analysis has three main merits. First, it allows to build hierarchical models including prior information and regularisations over voxels. Second, it provides many estimators of the parameters distribution including the mean and the \(\alpha \)-credible intervals. Finally, as credible intervals are available, testing properly whether the relaxation time (or its modification) lies within a certain range with a given credible level is simple. We show the interest of this approach on synthetic datasets and on two real applications in multiple sclerosis.

Progressive multifocal leukoencephalopathy in a patient with silicosis.

Dear Sirs, Progressive multifocal leukoencephalopathy (PML) is a frequently lethal disease of the central nervous system, caused by reactivation of the JC virus (JCV) [1]. Primary JCV infection is asymptomatic and pathogenic effects are mostly observed in patients with severe cellular immunosuppression. PML is primarily associated with AIDS, although many cases have been reported in patients with other immunological disorders. Silicosis is caused by inhalation of silica particles, leading to inflammatory cell activation, pulmonary fibrosis and granuloma development [2]. We report the first case of silicosis-associated PML in a patient without immunosuppressive long-term treatment. A 79-year-old patient was admitted to the emergency unit for acute left hemiparesis. His past medical history included chronic heart failure, and occupational silicosis, as a former stonemason, diagnosed 20 years earlier. Two months before admission, he developed progressive cognitive impairment, including phasic disorders, difficulties in dressing, and impaired balance. He had no fever. Brain CT scan found a hypodense lesion in the right hemisphere. A few hours after admission, hemiparesis resolved and a post-ictal deficit was finally diagnosed. Hemineglect and minimal conduction aphasia persisted. A brain MRI revealed massive asymmetric bilateral lesions located in the subcortical hemispheric white matter of the occipital and parietal lobes, consistent with PML (Fig. 1). A lumbar puncture yielded a clear cerebrospinal fluid, with a white cell count of 1/lL, normal protein and glucose concentrations, and no oligoclonal band. JCV DNA was detected in the CSF by PCR. Brain biopsy was not performed. HIV test was negative, and serum immunoglobulin levels (IgG, IgA, IgM), were within normal ranges. Blood cells count was remarkable for lymphopenia (760 lymphocytes/lL, N[ 1000), with CD4?, CD8?, and CD19? cells count of 299 (N[ 530), 149 (N[ 330), and 115/lL (N[ 110), respectively. Of note, blood cells count were unremarkable 6 months earlier. A chest CT scan revealed significant progression of silicosis. Apart from a 5-day course of oral methylprednisolone, 48 mg/day, for pulmonary exacerbation 6 months earlier, the patient had never received immunosuppressive treatment. Extensive diagnostic workout found no hematologic disease, no malignancy, and no other chronic inflammatory disorder. The neurological status gradually deteriorated, and the patient died 6 months later. No autopsy was performed. To our knowledge, PML has never been reported in a patient affected with silicosis not treated by immunosuppressive drugs. PML have been reported in association with other lung inflammatory diseases, such as sarcoidosis, mostly in patients treated with prolonged, high doses corticosteroids and/or other immunosuppressive agents. Sarcoidosis-related PML has been reported in the absence of immunosuppressive treatment, in patients with low CD4? T cells count, in the context of lymphocytes sequestration in granulomas [3]. The key role of CD4? T cells in PML & Alexandre Bonnet bonnet.alexandre.df@gmail.com