Dr. Jagan Pillai is a neurologist at the Lou Ruvo Center for Brain Health, Cleveland Clinic and works to help people with cognitive changes from neurological disorders and to develop diagnostic and treatment strategies in neurodegenerative diseases. He trained as a medical doctor at the University of Kerala, Trivandrum, India. He obtained a PhD from Northwestern University. He trained in Neurology at the Albert Einstein College of Medicine and at the University of California San Diego.
As a neurologist interested in neurodegenerative disorders, I met Phil and a few others with preclinical Huntington’s disease (HD), on a trip to Phoenix, AZ to take in their perspectives. Phil is a self-appointed counselor, caretaker, and community leader of PHDs. He chuckles as he credits his accomplishments to having been born a PHD (in his lingo, Person with Huntington’s disease). HD is a neurodegenerative disorder caused by an expanded number of triplet repeat CAG in the gene encoding the protein Huntingtin. Prevalence is about 4–10 per 100 000 people in the West (1). HD is clinically characterized by motor dysfunction, cognitive decline, and psychiatric disturbance. The age of onset roughly correlates with the number of CAG repeats inherited, with a mean age of onset of 40 years (2).
|in Huntington's Disease, image width 250 µm|
The clinical diagnosis of HD is based on characteristic motor signs in a person with a positive family history and confirmed by genetic testing for HD. However, there is increasing recognition that disease onset may happen many years before clinical diagnosis. Subtle cognitive, motor, and behavioral symptoms and underlying neuropathlogical changes can now be detected by neuroimaging and neuropsychological tools, among individuals who otherwise appear healthy. These people at risk of developing clinical HD are classified preclinical or presymptomatic or preHD (3). We can detect changes in neural connectivity, degeneration of brain regions and behavioral changes including, impaired control of affect following disrupted emotion processing circuits (4,5,6).
For the ‘at risk’ people like Phil, ascribing some of the difficult moments in their life to inherent propensities of HD, even before clinical symptoms are noted by people around them, has pressing implications. Before recognizing preHD as a distinct stage, symptoms tended to brushed aside in the tumble of life as they were often vague. But many preHD symptoms do influence social functional abilities like problems with attention, depression and irritability. It is difficult for patients and physicians to posit meaningful relevance to seemingly nonspecific symptoms unless tied to a diagnosis of preHD. Some people with preHD are often prematurely judged to be liable to slip-up in some situations and even lose jobs, even as they have not yet individually made anything resembling embarrassing blunders (7) and patients themselves may often be fearful of it. Others may have had long frustrating search for answers about changes that they are experiencing and the diagnosis of preHD finally sheds some light on their circumstances.
This profound ability, to know a tangled mind, not by a warm empathetic embrace but by a diagnostic leap and the moral challenges involved, is dramatically portrayed in Ian McEwan’s neuro-lit novel Saturday. Here he describes the internal monologue of Perowne, a neurosurgeon. In the course of the drama, lived out on a single Saturday, an assailant mugs Perowne (‘Life is a wretched gray Saturday, but it has to be lived through,’ Anthony Burgess). But the surgeon recognizes what seem to be early symptoms of HD in his assailant. He intellectually bridges a gap to reach out to his assailant that might be unbridgeable for even the most empathetic among us at a time of startling violent injury and he is able to provide some level of insight to the assailant about his preHD condition. Is real life close to fictional scenarios?
Among the legal cases littering the country’s courtrooms, moral expectations are being challenged by our increasing ability to peer into brains and not limited to HD alone. How did the wife react when she found out her husband with pre HD had just attempted to sexually abuse their 9-year-old daughter? Did it matter that the husband had soon felt remorse and was the one who confessed to her in tears? Or how is a woman who delivered a baby girl in a bathroom at a homeless shelter and the submerged child was pulled from a toilet minutes later by police to be judged? Would any of the victims themselves be willing to take a different moral ground in ascribing eventual culpability to proclivities coming seemingly unbidden from deranged neural clusters and entirely outside the person’s earlier self?
In some cases people ‘at risk’ for such Promethean tragedies did not know they were at risk for making mistakes of judgment as they had not been diagnosed with a disease yet. Some knew of their diagnosis but were not aware of the specifics of the risk involved. The rest stumbled even after they knew where they stood with respect to the implications of a diagnosis, as they felt swept away in a perfect storm of situations overwhelming their arguably dented defenses. The latter is how Phil sees it. Are these startling cases different from a more common event, like being arraigned for issues related to alcoholism? Here a familial predisposition to alcoholism exists and has been used successfully to plead for a lighter sentence (8).
Schematic for preclinical and clinical stages of neurodegenerative diseases
Does self-knowledge from better acquaintance of your neural apparatus have a redemptive value, i.e. enable you in overcoming your neural limitations to live a more valued and valuable life? An answer to this key question would influence everyday decisions and is very likely to be answered in the near future. The popularity of neuroplasticity literature points to our insistent hopes in this regard (9). We have a glimmer of an answer from people ‘at risk’ who are facing many of these pressing questions in their lives. For individuals with a family history of HD, knowing their neurological status is often seen to increase the level of psychological distress. Many even decide to forgo definitive diagnosis. My clinical impression is that HD patients often tend to consciously avoid disease related situations and thoughts. Are these responses related to our present lack of definitive treatments available?
How does the lack of curative treatments impact our moral imperative to alert patients of their preHD status and pending worsening of symptoms? Even as making an early diagnosis in diseases that lack curative treatments bring up questions of moral imperative and appear to be problematic, these diagnoses are often deeply meaningful for individuals and their families. It often brings a sense of closure to the families and helps them rally around the people who need more care and attention. They also enable families to make effective concrete plans for the future whether they may be financial or choosing a place to live. But can knowledge of their own nature help pre HD subjects avoid situational mistakes they are fearful of? How is one to know when their lack of judgment is situational and can be restored, versus more permanent changes to self with their knowledge of their own disease state? Can one improve their lack of specific cognitive abilities through practice? These questions are yet to be looked into carefully and could be relevant in social judgments rendered. Increasingly there is a growing interest in defining pre-disease stages in other neurological conditions including Alzheimer’s disease where many of these questions again become relevant.
Issues related to the pre-disease state are now at the forefront due our ability to push the diagnostic threshold to earlier stages of the disease and from new insights into the nature of the brain changes from disease pathology. But it is also increasingly recognized that there is significant heterogeneity in the time course of these neurodegenerative conditions and in their clinical presentation due to multiple interacting factors. Due our limited understanding at present, we lump everyone with a disease marker in the same category but often fail to recognize the implications of their inherent differences. Among the challenges pre-disease diagnoses would have to address in the future is how to tailor individual treatments (and judge moral standards) taking into account differences in pathology burden, rate of progression of the disease and areas of the brain affected and not render judgments based on a single genetic or pathological marker of a disease state.
We may not stop to think about how we too are at risk and vulnerable to our neural propensities even beyond neurodegeneration. Our awareness of novel neural level differences could force us increasingly to take stock on how much of a fine grain appraisal an individual can be put through to differentiate qualities like interest, skill, motive, memory, judgment before taking on a job or being on trial. The problems the ‘at risk’ groups are already grappling with are in some ways precursors to issues we as a culture might be tackling in the near future.
Want to cite this post?
Pillai, J. (2013). Judging brains with preclinical disease. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2013/01/judging-brains-with-preclinical-disease.html
1. Hoppitt T, Pall H, Calvert M, Gill P, Yao G, Ramsay J, James G, Conduit J, Sackley C. A systematic review of the incidence and prevalence of long-term neurological conditions in the UK. Neuroepidemiology. 2011;36(1):19-28.
2. International Huntington's Disease Collaborative Group, Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR. (2004). "A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length." Clin Genet 65:267-277.
3. Tabrizi SJ, Scahill RI, Durr A, Roos RA, Leavitt BR, Jones R, Landwehrmeyer GB, Fox NC, Johnson H, Hicks SL, Kennard C, Craufurd D, Frost C, Langbehn DR,Reilmann R, Stout JC; TRACK-HD Investigators. Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol. 2011 Jan;10(1):31-42.
4.Lawrence AD, Hodges JR, Rosser AE, Kershaw A, ffrench-Constant C, Rubinsztein DC, Robbins TW, Sahakian BJ. Evidence for specific cognitive deficits in preclinical Huntington's disease. Brain. 1998 Jul;121 ( Pt 7):1329-41.
5. Klöppel S, Stonnington CM, Petrovic P, Mobbs D, Tüscher O, Craufurd D, TabriziSJ, Frackowiak RS. Irritability in pre-clinical Huntington's disease. Neuropsychologia. 2010 Jan;48(2):549-57.
6. Julien CL, Thompson JC, Wild S, Yardumian P, Snowden JS, Turner G, Craufurd D. Psychiatric disorders in preclinical Huntington's disease. J Neurol Neurosurg Psychiatry. 2007 Sep;78(9):939-43.
7. Lenox, Genetic Discrimination in Insurance and Employment: Spoiled Fruits of the Human Genome Project, 23 U. Dayton L. Rev. 189, 190 (1997).
8. Andrews, Body Science, 83 ABA Journal 44, 49 (1997).
9. Silberman. J.H. The Brain That Changes Itself: Stories of Personal Triumph from the Frontiers of Brain Science. Penguin (Non-Classics); 1 Reprint edition (December 18, 2007).