Cell transplantation for Huntington's disease Should we continue?

Cell transplantation for Huntington's disease has developed over the last decade to clinical application in pilot trials in the USA, France and the UK. Although the procedures are feasible, and under appropriate conditions safe, evidence for efficacy is still limited, which has led to some calls that further development should be discontinued. We review the background of striatal cell transplantation in experimental animal models of Huntington's disease and the rationale for applying similar strategies in the human disease, and we survey the present status of the preliminary studies that have so far been undertaken in patients. When we consider the variety of parameters and principles that remain poorly defined -- such as the optimal source, age, dissection, preparation, implantation, immunoprotection and assessment protocols -- it is not surprising that clinical efficacy is still unreliable. However, since these protocols are all tractable to experimental refinement, we consider that the potential for cell transplantation in Huntington's disease is greater than has yet been realised, and remains a therapeutic strategy worthy of investigation and pursuit.     

Should we expect "neural signatures" for DSM diagnoses?

Contemporary researchers in psychiatry have sought to develop a nosology based on empirical observation, in line with the principles spelled out by Drs Eli Robins and Samuel B. Guze in 1970. For more than 2 decades, psychiatrists using neuroimaging have aspired to provide one form of "laboratory study" that Robins and Guze said would have to be in place for a psychiatric diagnosis to be valid: researchers have sought "neural signatures" of psychiatric disorders. Our objective was to examine the feasibility of this endeavor. To this end, we examine whether current psychiatric nosology as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) lends itself to the identification of neural signatures for psychiatric diagnoses. Because neuroimaging largely is used only to detect average activation or structural differences between groups of individuals with the same diagnosis and groups of individuals with no diagnosis, it is unlikely that it will be possible to use neuroimaging technologies to determine which psychiatric diagnosis a given individual warrants. In addition, the heterogeneity of psychiatric disorder categories as defined in the DSM reveals that these diagnoses do not reflect neurologically discrete phenomena. Finally, neural correlates of psychopathology generally are not unique to specific diagnoses. Although it is unrealistic to hope that neuroimaging will be used to make psychiatric diagnoses as they are currently conceived, neuroimaging is already being used to make headway in 2 other arenas of psychiatric investigation that we briefly review.     

Prevention of epilepsy: Should we be avoiding clinical trials?

Epilepsy prevention is one of the great unmet needs in epilepsy. Approximately 15% of all epilepsy is caused by an acute acquired CNS insult such as traumatic brain injury (TBI), stroke or encephalitis. There is a latent period between the insult and epilepsy onset that presents an opportunity to intervene with preventive treatment that is unique in neurology. Yet no phase 3 epilepsy prevention studies, and only 2 phase 2 studies have been initiated in the last 16 years. Current prevailing opinion is that the research community is not ready for clinical preventive epilepsy studies, and that animal models should first be refined and biomarkers of epileptogenesis and of epilepsy discovered before clinical studies are embarked upon. We review data to suggest that there is basis to do epilepsy prevention studies now with the current knowledge and available drugs, and that those studies are feasible with currently available tools. We suggest that a different approach is needed from the past in order to maximize chances of success, minimize the cost, and set up platform for future preventive treatment development. That approach should include close coordination of preclinical and clinical development programs in a combined PTE prevention strategy, consideration of polytherapy, and simultaneous, combined clinical development of preventive treatment and of biomarker discovery. We argue that the currently favored approach of eschewing clinical studies until biomarkers are available will delay the discovery of epilepsy prevention treatment by at least 10 years and significantly increase the cost of such discovery.