William D. Graf

Pediatric neuroenhancement: Ethical, legal, social, and neurodevelopmental implications

The use of prescription medication to augment cognitive or affective function in healthy persons—or neuroenhancement—is increasing in adult and pediatric populations. In children and adolescents, neuroenhancement appears to be increasing in parallel to the rising rates of attention-deficit disorder diagnoses and stimulant medication prescriptions, and the opportunities for medication diversion. Pediatric neuroenhancement remains a particularly unsettled and value-laden practice, often without appropriate goals or justification. Pediatric neuroenhancement presents its own ethical, social, legal, and developmental issues, including the fiduciary responsibility of physicians caring for children, the special integrity of the doctor–child–parent relationship, the vulnerability of children to various forms of coercion, distributive justice in school settings, and the moral obligation of physicians to prevent misuse of medication. Neurodevelopmental issues include the importance of evolving personal authenticity during childhood and adolescence, the emergence of individual decision-making capacities, and the process of developing autonomy. This Ethics, Law, and Humanities Committee position paper, endorsed by the American Academy of Neurology, Child Neurology Society, and American Neurological Association, focuses on various implications of pediatric neuroenhancement and outlines discussion points in responding to neuroenhancement requests from parents or adolescents. Based on currently available data and the balance of ethics issues reviewed in this position paper, neuroenhancement in legally and developmentally nonautonomous children and adolescents without a diagnosis of a neurologic disorder is not justifiable. In nearly autonomous adolescents, the fiduciary obligation of the physician may be weaker, but the prescription of neuroenhancements is inadvisable because of numerous social, developmental, and professional integrity issues.

Active Comparator-Controlled, Rater-Blinded Study of Corticotropin-Based Immunotherapies for Opsoclonus-Myoclonus Syndrome

To test the efficacy and safety of corticotropin-based immunotherapies in pediatric opsoclonus-myoclonus syndrome, 74 children received corticotropin alone or with intravenous immunoglobulin (groups 1 and 2, active controls); or both with rituximab (group 3) or cyclophosphamide (group 4); or with rituximab plus chemotherapy (group 5) or steroid sparers (group 6). There was 65% improvement in motor severity score across groups (P < .0001), but treatment combinations were more effective than corticotropin alone (P = .0009). Groups 3, 4, and 5 responded better than group 1; groups 3 and 5 responded better than group 2. The response frequency to corticotropin was higher than to prior corticosteroids (P < .0001). Fifty-five percent had adverse events (corticosteroid excess), more so with multiagents (P = .03); and 10% had serious adverse events. This study demonstrates greater efficacy of corticotropin-based multimodal therapy compared with conventional therapy, greater response to corticotropin than corticosteroid-based therapy, and overall tolerability.

The autism “epidemic” Ethical, legal, and social issues in a developmental spectrum disorder

Classic autism has gradually evolved into the concept of a larger “spectrum disorder.” The rising prevalence of autism and autism spectrum disorder (autism/ASD) diagnoses can be largely attributed to broader diagnostic criteria, adoption of dimensional assessment strategies, increased awareness, linking of services to diagnosis, and the inclusion of milder neurodevelopmental differences bordering on normality. The spectrum disorder diagnosis raises numerous bioethical issues for individuals and society. Three groups of caregivers have important ethical, legal, and social obligations to individuals with autism/ASD: (1) families and advocates of individuals with autism/ASD; (2) health care and other professionals; and (3) governments. Each group may have different views of autism/ASD diagnostic criteria, screening, testing, and the effectiveness of various interventions. All see timely diagnosis as desirable, but earlier diagnosis may not be better, morally or practically. The growing practice of genetic testing in milder ASD raises ethical questions because of its uncertain scientific validity and limited clinical utility. Individuals with autism/ASD have various kinds of needs but all want acceptance and most deserve better accommodations. Governments struggle to provide a fair allocation of appropriate special education and supportive services. This article examines the evolving dimensions of the autism/ASD diagnosis, outlines certain bioethics principles related to its evaluation and management, reviews relevant laws and disability rights, and emphasizes the societal obligation to recognize neurodevelopmental variation and human neurodiversity. Future directions in the evaluation and care of autism/ASD should attempt to integrate the roles and responsibilities of all agents caring for each unique autistic individual.

Intermediate filament proteinopathies From cytoskeletons to genes to functional nosology

We take a handful of sand from the endless landscape of awareness around us and call that handful of sand the world. . .The handful of sand looks uniform at first, but the longer we look at it the more diverse we find it to be. Each grain of sand is different. No two are alike. Some are similar in one way, some are similar in another way, and we can form the sand into separate piles on the basis of this similarity and dissimilarity. Shades of color in different piles—subtypes of grain shapes in different piles—grades of opacity in different piles—and so on, and on, and on. You’d think the process of subdivision and classification would come to an end somewhere, but it doesn’t. It just goes on and on.1—Robert M. Pirsig The history of clinical neurology parallels advancements in science and technology. In the beginning there was clinical description, genetic correlation, and conventional morphologic investigation. In the recent past came electron microscopy (EM), immunocytochemistry (ICC), and CT/MRI. Today the achievements in molecular genetics are leading to a predictable reclassification of many human disorders and diseases. For clinicians, such reclassification is practicable when it is utility-driven, namely when disease classification, based …

Addressing the problem of ADHD medication as neuroenhancements

The prevalence of attention deficit hyperactivity disorder (ADHD) diagnoses is rising. ADHD is closely linked to its treatment with medications such as methylphenidate and amphetamines, which have popular appeal as neuroenhancement drugs by persons without a neurological disorder. The three main reasons for the increase in ADHD medication demand, production, and consumption are a) the inclusion of milder ADHD diagnoses; b) the vast marketing of ADHD medications by the pharmaceutical industry; and c) the illegal diversion of controlled ADHD medication to consumers seeking stimulants as neuroenhancements. Rapidly rising rates of any neurological disorder – especially a behaviorly-defined disorder closely linked to potent medications currently prescribed to more than 5% of the population – deserves ongoing scrutiny. Major social and ethical problems arise from vague-symptom medicalization, neurological disorder trivialization, medication overuse, and controlled substances diversion to healthy persons for nonmedical purposes. We argue against the ‘spectrumization’ of ADHD in an effort to curtail further diagnosis creep.

Prenatal-onset neurodevelopmental disorders secondary to toxins, nutritional deficiencies, and maternal illness.

Neurodevelopmental disorders result from an inordinate number of genetic and environmental causes during the embryological and fetal periods of life. In the clinical setting, deciphering precise etiological diagnoses is often difficult. Newer screening technologies allow a gradual shift from traditional nature-versus-nurture debates toward the focused analysis of gene-by-environment interactions (G X E). Further understanding of developmental adaptation and plasticity requires consideration of epigenetic processes such as maternal nutritional status, environmental toxins, maternal illnesses, as well as genetic determinants, alone or in combination. Appreciation of specific G X E mechanisms of neurodevelopmental pathogenesis should lead to better risk-modifying or preventive strategies. We provide a brief overview of clinical and experimental observations that link prenatal-onset toxic exposures, metabolic disturbances, and maternal illnesses to certain neurodevelopmental disorders.

Enhancement in Children and Adolescents: Scrutinizing Effects Beyond Cognition

determined even in individuals with a sincere belief in equality (Terbeck et al. 2012). Consequently, Vrecko’s subjects might not have had sufficient self-reflecting ability to recognize the nature of their motivation. To take it further, the fact that the students were taking illegally prescribed drugs and accepting the side effects would indicate that they were very motivated, even more than others, to perform well. Clearly more research is needed, perhaps especially using unobtrusive measures of motivation rather than self-reports. In conclusion, the fact that the students are taking performance enhancing drugs strongly contradicts the findings that students are not motivated about their work or performance. Otherwise, why would they bother taking it?

Can bioinformatics help trace the steps from gene mutation to disease

In this issue of Neurology , Minassian et al. expand their earlier contributions on Lafora’s disease using new informational technology to seek homologies between regions of the EMP2A gene product laforin and other proteins of known biological activity.1 This direct application of genomics to a clinical problem may clarify a mechanism of pathogenesis and provide rationale for future therapies. Genomics uses 1) DNA sequence data and 2) computational systems to store, access and analyze the data. Together, these constitute the new field of bioinformatics. Gene sequence data were historically obtained from messenger RNA transcripts of well-known proteins (such as hemoglobin and ovalbumin). The Human Genome Project (HGP) provides DNA sequences for “new” genes without known function, based on nucleotide patterns characteristic of gene structure. The path from these newly discovered genes to the biological activities of their products requires a multifaceted approach.2 Sequence data from the HGP also allows a correlation to be made between a change in genetic structure (a mutation, deletion, or recombination) and the occurrence of disease. Bioinformatics will not explain how a gene is regulated or how changes in regulation induce disease. However, new technology to define patterns of gene transcription (a key to gene expression) is rapidly developing (table 1). View this table: Table 1. Applications for bioinformatics in research and medicine Broad access to genomic information is now possible through highly refined user-friendly software. BLAST (Basic Local Alignment Search Tool), for example, is a sensitive and time effective program for detection of biologically significant relationships between genetic molecular structure and …

Pediatric neuroenhancement: Ethical, legal, social, and neurodevelopmental implicationsAuthor Response

The recent article on pediatric neuroenhancement is an excellent review of the ethical aspects of stimulant drug use.1 However, the authors may be off point. Most children initially receive stimulant medications from general pediatricians and family physicians who believe that they are treating attention deficit disorder (ADD). These physicians do not believe that they are prescribing drugs for neuroenhancement. It is rare for children taking these drugs to have received psychometric testing and these drugs are frequently started in elementary …

BRAF Gene Deletion Broadens the Clinical Spectrum Neuro-Cardio-Facial-Cutaneous Syndromes:

Point mutations in the human BRAF gene are associated with a group of heterogeneous autosomal dominant neuro-cardio-facial-cutaneous syndromes. We identified a novel 93 kb intragenic deletion of the BRAF gene in a boy with severe developmental encephalopathy using microarray-based comparative genomic hybridization. The unique genotype and phenotype in this patient expands the spectrum of BRAF-related neurodevelopmental disorders. We propose a BRAF gene loss-of-function mechanism to best explain the biological basis of this severe developmental encephalopathy with postnatal growth deficiency.