Concept: Jean-Martin Charcot
BackgroundCharcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3).Methods80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes.ResultsThis trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group.ConclusionsThese results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults.Trial registrationEudraCT Number: 2010-023097-40. ClinicalTrials.gov Identifier: NCT01401257. The Committee for Orphan Medicinal Products issued in February 2014 a positive opinion on the application for orphan designation for PXT3003 (EMA/OD/193/13).
- Journal of neurology, neurosurgery, and psychiatry
- Published over 5 years ago
Recent advances in understanding amyotrophic lateral sclerosis (ALS) have delivered new questions. Disappointingly, the initial enthusiasm for transgenic mouse models of the disease has not been followed by rapid advances in therapy or prevention. Monogenic models may have inadvertently masked the true complexity of the human disease. ALS has evolved into a multisystem disorder, involving a final common pathway accessible via multiple upstream aetiological tributaries. Nonetheless, there is a common clinical core to ALS, as clear today as it was to Charcot and others. We stress the continuing relevance of clinical observations amid the increasing molecular complexity of ALS.
Phase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI).
Increasing evidence suggests that some neurodegenerative disorders, such as Parkinson’s disease, are inversely related to cancer. Few epidemiologic studies have examined the relationship between cancer and amyotrophic lateral sclerosis (ALS), another major neurodegenerative disease. This study addresses that gap.
In late 19th century Paris, people with epilepsy were treated alongside those with hysteria in the now famous Salpêtrière Hospital, where both conditions were deemed to have a neurological basis. When Jean Martin Charcot became chief physician at the Salpêtrière Hospital in 1862, he described himself ‘in possession of a kind of museum of living pathology whose holdings were virtually inexhaustible’. He opened the doors of his ‘living museum’ and exhibited his prize specimens to all of Paris. By putting his patients on display, Charcot introduced a vogue for pathology that permeated well beyond the world of medical enquiry and into the public psyche and vernacular. Not only did Charcot’s demonstrations provide the inspiration for high culture in the form of operas, plays and novels, they also provided the inspiration for the ‘gommeuses epileptiques’ (epileptic singers), who entertained the masses at the café concerts. This paper explores the foundations of our current medical approaches to mental illness and epilepsy, with a particular focus on the boundaries that emerged between hysteria and epilepsy in 19th century Paris. These clinical boundaries were both shaped by and reflected in the popular entertainments in the city.
Abstract Hysteria has served as an important driving force in the development of both neurology and psychiatry. Jean Martin Charcot’s devotion to mesmerism for treating hysterical patients evoked the invention of psychoanalysis by Sigmund Freud. Meanwhile, Joseph Babinski took over the challenge to discriminate between organic and hysterical patients from Charcot and found Babinski’s sign, the greatest milestone in modern neurological symptomatology. Nowadays, the usage of the term hysteria is avoided. However, new terms and new classifications are complicated and inconsistent between the two representative taxonomies, the DSM-IV and ICD-10. In the ICD-10, even the alternative term conversion disorder, which was becoming familiar to neurologists, has also disappeared as a group name. The diagnosis of hysteria remains important in clinical neurology. Extensive exclusive diagnoses and overinvestigation, including various imaging studies, should be avoided because they may prolong the disease course and fix their symptoms. Psychological reasons that seem to explain the conversion are not considered reliable. Positive neurological signs suggesting nonorganic etiologies are the most reliable measures for diagnosing hysteria, as Babinski first argued. Hysterical paresis has several characteristics, such as giving-way weakness or peculiar distributions of weakness. Signs to uncover nonorganic paresis utilizing synergy include Hoover’s test and the Sonoo abductor test.
To analyze neurodegenerative causes of death, specifically Alzheimer disease (AD), Parkinson disease, and amyotrophic lateral sclerosis (ALS), among a cohort of professional football players.
Amyotrophic lateral sclerosis (ALS) and Parkinson’s disease, both progressive neurodegenerative diseases, affect >1 million Americans (1,2). Consistently reported risk factors for ALS include increasing age, male sex, and cigarette smoking (1); risk factors for Parkinson’s disease include increasing age, male sex, and pesticide exposure, whereas cigarette smoking and caffeine consumption are inversely associated (2). Relative to cancer or respiratory diseases, the role of occupation in neurologic diseases is much less studied and less well understood (3). CDC evaluated associations between usual occupation and ALS and Parkinson’s disease mortality using data from CDC’s National Institute for Occupational Safety and Health (NIOSH) National Occupational Mortality Surveillance (NOMS), a population-based surveillance system that includes approximately 12.1 million deaths from 30 U.S. states.* Associations were estimated using proportionate mortality ratios (PMRs), standardizing indirectly by age, sex, race, and calendar year to the standard population of all NOMS deaths with occupation information. Occupations associated with higher socioeconomic status (SES) had elevated ALS and Parkinson’s disease mortality. The shifts in the U.S. workforce toward older ages and higher SES occupations(†) highlight the importance of understanding this finding, which will require studies with designs that provide evidence for causality, detailed exposure assessment, and adjustment for additional potential confounders.
The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.
Minimally invasive specific biomarkers of neurodegenerative diseases (NDs) would facilitate patient selection and disease progression monitoring. We describe the assessment of circulating brain-enriched microRNAs as potential biomarkers for Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).