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Canada’s National Newspaper of the CNS Sciences n October 2017 n The Chronicle is committed to maintaining leadership in environmentally sustainable policies, and to encouraging the adoption of “greenaware” practices in healthcare. We invite your comments via e-mail, at: health@chronicle.org

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Editorial: LRCUG a start at reducing harms of cannabis use ......3 Mild stroke patients not being screened for dysphagia ..............11 ADHD severity an indicator of persistence into adulthood ........16 Epilepsy

Transitioning from pediatric to adult epilepsy healthcare

GUIDELINES

n New Ontario guidelines outline best practice steps by Emily Innes-Leroux,

Associate Editor, The Chronicle

ONTARIO EPILEPSY Implementation Task Force (EITF) has developed recommendations for improving the transition from the pediatric to the adult healthcare system for patients with epilepsy (Epilepsia Sept. 2017; 58(9):1502–1517). In 2013, the Ministry of Health and Long Term (MOHLTC) established the EITF to develop and implement a provincial framework to “maximize value from the system of epilepsy care in Ontario.” The EITF has since

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HE

Evaluating the potential risks of

Cannabis

released guidelines on establishing epilepsy monitoring units, on management of epilepsy in adults and children, on provincial epilepsy surgery referrals, on management of medically-refractory epilepsy in adults and children who are not candidates for surgery, and on regional epilepsy surgery centres. In response to the recommendations, the MOHLTC has developed district and regional epilepsy centres that are now operating throughout Ontario in Ottawa, Kingston, Hamilton, Toronto, and London. —please turn to page 7

Stroke

‘The Virtual Brain’ and post-stroke research Computational models based on individualized neuroimaging

please turn to page 12

will generate findings that could help to understand brain physiology and dynamics after a stroke and open the door to new therapeutic opportunities, according to a speaker at the Rotman Research Institute Conference 2017 in Toronto. —See page 14

ADHD

Methylphenidate ADHD dosing tool n Mathematical model has not yet been validated in clinical trials by Louise Gagnon, Correspondent, The Chronicle

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WEB-BASED INTERFACE HAS BEEN DEVELOPED to assist clinicians and patients in the selection of an appropriate regimen of methylphenidate for children with attention deficit-hyperactivity disorder (ADHD), according to a study published in the Journal of Child and Adolescent Psychopharmacology (May 2017; 27(4):320–333). ADHD is one of the most common neurodevelopmental disorders in childhood and methylphenidate is the psychostimulant most prescribed in Canada to treat the condition, —please turn to page 11

This issue’s Chronicle Vitae profiles Toronto-based neuroscientist Gillian Einstein, PhD, who conducts novel research on neurological and hormonal differences in cognition in women. See page 18


F U N D I N G

R E S E A R C H

F U E L I N G

H O P E

Epilepsy Canada is a proud partner to neurology professionals. For over 50 years, we have helped to fund epilepsy research at universities and hospitals across the country. To learn more about our program of student bursaries and Research Fellowships visit www.epilepsy.ca/research

Epilepsy

Épilepsie

CANADA Contact Us at 1-877- 734-8417 V i s i t w w w. e p i le p s y. c a / re s e a rc h Registered Charity #13117 6042 RR0001


“All individuals are imperfect and forgetful and find it difficult to

transcend immediate self-interest. Historically therefore it has been deemed essential to create constitutional bodies that uphold and insist on adherence to certain ethical standards . . . If all these medical ethical bodies are to gain the respect of the public they should remain alert to intervene whenever these standards are threatened.” —Frances Ames, South African neurologist and psychiatrist (1920-2002)

Guest editorial: LRCUG, a start at reducing harms of cannabis CANAdA MOveS TOwARd CANNAbIS legalization in July 2018, medicine and public health are a-buzz with discussion about how to minimize the potential harms of use. As with currently legal substances like alcohol, marijuana use is not without health risk. Similar to the well-established use of low-risk Guidelines for drinking Alcohol,1 lower risk cannabis use guidelines (lRCUG) were developed in 20112 as a health education intervention. The lRCUG were adapted in 2017 as an initiative of CRISM (Canadian Research Initiative in Substance Misuse) to reflect the new context of Dr. Haineslegalization,3 and have been jointly Saah endorsed by the Canadian Centre on Substance Use and Addiction, Canadian Medical Association, Canadian Public health Association, Canadian Society of Addiction Medicine, Dr. Virani and the Centre for Addiction and the Centre for Addiction and Mental health.4 The guidelines contain 10 recommendations for reducing harms, covering: age of initial use, choice of products, routes and practices of administration, use frequency and intensity, individual factors increasing susceptibility to or likelihood of harm, impairment of driving, and abstinence as the ideal practice for safety. The adoption of ‘lower risk’ guidelines by secular authorities is important because of the pragmatic recognition that it is not possible to completely eliminate risk from a psychoactive substance when its use is widespread and normalized. Such guidelines also provide health professionals with a starting point to engage individuals in conversations that can assist in reducing their risk of adverse outcomes, and move toward an objective of abstinence if they so choose. This engagement is particularly crucial in Canada—with the highest rates of cannabis use in the world—where almost half of adults have used cannabis in

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ABOUT THE AUTHORS Dr. Hakique Virani is an assistant clinical professor in the Department of Medicine at the University of Alberta in Edmonton. He is a specialist in public health and preventive medicine. He is a diplomate of the American Board of Addiction Medicine. Dr. Virani is also medical director of Metro City Medical Clinic in Edmonton and Calgary. Rebecca Haines-Saah, PhD, is an assistant professor in the Department of Community Health Sciences, Cumming School of Medicine, University of Calgary. Her research is focused on youth cannabis use and the public health policy implications of cannabis legalization in Canada.

their lifetime and one in five aged 15 to 19 years have used it in the past year.5 Attention on the potential for harms to mental health from cannabis use has centred around two areas: the association with schizophrenia and psychoses among those already predisposed, and the potential irreversible harms to brain development in individuals younger than their mid-twenties. lower risk guidelines are useful tools to advise patients who choose to use, but also to dispel myths about cannabis as a ‘harm-free’ substance that may be held by the general public. PEOPLE WITH FAMILY, PERSONAL HISTORY OF PSYCHOTIC DISORDER SHOULD AVOID CANNABIS For example, while cannabis use is not causal in psychoses, it is sensible to advise people with a family or personal history of risk of psychotic disorders to avoid cannabis use because of strong evidence to support an association between the two. likewise, although we do not yet have a complete picture of how cannabis use in adolescence impacts the developing brain, we do have enough evidence to advise young people that delaying their initiation of use during adolescence may lead to less harms. while the recommendations cannot specify a ‘safe’ age for cannabis use, they note that use before age 16 years “increases the likelihood of developing health, educational, and social problems,” as does using frequently and intensely from a young age.4 Cautions may be perceived as more credible when offered as a suggestion to reduce risk than when they accompany vehement abstinence messages, particularly given the prevalence of cannabis use and the prevailing first-hand experience of limited harm.

LEADING WITH ABSTINENCE COULD BE LIMITATION One potential limitation of the lRCUG comes from leading with the recommendation of abstinence as the best way to avoid all potential harms. This approach may discourage current cannabis users, who may see their use as a ‘safer choice’ than alcohol or other illicit drugs. Taken as a whole, though, the recommendations do not insist on abstinence. Rather, they encourage ‘informed behavioural choices’ for reducing harms. This is compatible with a harm reduction philosophy, which does not exclude abstinence goals where appropriate, but starts from a position of non-judgment in supporting people “where they are at” to make choices about substance use that are realistic for them in the context of their life circumstances. Complete avoidance of all risk behaviours—whether to do with diet, sex, adventure, or substance use—may be the most efficacious way of preventing adverse health outcomes. however, we can be sure that people will engage in personal health practices that expose them to potential harm. while contentious scientific and policy debates persist —Continued on page 12

The Chronicle of Neurology & Psychiatry is published six times annually by the proprietor, Chronicle Information Resources Ltd., with offices at 555 Burnhamthorpe Rd., Ste. 306, Toronto, Ont. M9C 2Y3 Canada. Telephone: 416.916.2476; Fax. 416.352.6199. E-mail: health@chronicle.org. Contents © Chronicle Information Resources Ltd., 2017, except where noted. All rights reserved worldwide. The Publisher prohibits reproduction in any form, including print, broadcast, and electronic, without written permissions. Printed in Canada. Mail subscriptions: $72 per year in Canada, $125 per year in all other countries. Single copies: $12 per issue (plus 13% HST) Canada Post Canadian Publications Mail Sales Product Agreement Number 40016917 The Publisher certifies that advertising placed in this publication meets Revenue Canada requirements for tax deductibility. Volume 20, Number 4, published October 2017

Research n A phase-II trial of the U.S. FDA-

approved antihistamine clemastine fumarate has found the allergy medication can be used to treat chronic demyelinating injury in multiple sclerosis. As well, the authors say their findings suggest that the myelin repair can be achieved even after prolonged damage (The Lancet Oct. 10, 2017, online ahead of print). —Find more info at http://ow.ly/XAsm30fW6t6

n A study in 38 children has found evi-

dence that MRI imaging can reveal changes in the brain associated with multiple sclerosis before clinical symptoms appear, a condition known as radiologically isolated disease (RIS). The children had undergone MRI for other reasons, most frequently headache. Children with RIS had a substantial risk of subsequent clinical symptoms or radiologic evolution. The presence of oligoclonal bands in cerebrospinal fluid and spinal cord lesions on MRI were also found to be associated with an increased risk of a first clinical even (Neurol Neuroimmunol NeuroinflammNov. 2017; 4(6): e395) —Discover more info at http://ow.ly/YNq030fWbjY

n Adjunctive bright light therapy adminis-

tered at midday appears to be effective in helping to alleviate symptoms of bipolar depression, with significantly higher remission rates seen after four weeks of treatment compared to a dim red light placebo. These findings were published online ahead of print in The American Journal of Psychiatry (Oct. 3, 2017). —Learn more at http://ow.ly/bq8230fWdkb

n An MRI study has found abnormally

elevated levels of glutamate and glycine in patients with first-episode psychosis, compared to levels in age-matched healthy controls. The authors write that these findings implicate dysfunction of N-methyl-Daspartate receptor and glutamatergic neurotransmission in the pathophysiology of the acute early phase of psychotic illnesses (Biological Psychiatry Sept. 7, 2017). —Discover more info at http://ow.ly/yqta30fWh0m October 2017 n 3


s Atelier:

s Quick-start guide to The Chronicle, October 2017:

This art piece was created by a woman in her early 20s who had strong suicidal ideation. She lives with her family, but feels isolated and alone. “I feel numb. I know I am depressed. I don’t know why,” she said. “The circle to me is the sun. But I don’t know why I coloured it black. The girl is me. At first, there was no face.” Orange flames, a red cloud, coiling lines inside the black sun, and streaks of smoke all reveal anger. “I feel the anger. Somehow this has exploded everywhere. I don’t even know I am feeling this. My parents tell me not to express anger, and be patient. I cover it up so much, it becomes a habit. I don’t even realize it.” The drawing of a male figure with flowers, fish, a tree, and a football represents a memory of her family being altogether in the past. “He is my dad. I guess I miss him?” A face of “Pikachu” represents both her inner child and her desire for happiness. —Keisei Yevonne Anzai, registered art therapist, Vancouver —More information at www.arttherapy.keisei-anzai.com

Publication Index

n Epilepsy: Non-invasive technology could improve epilepsy surgery outcomes (p. 6) n Cannabis: lower-Risk Cannabis Use Guidelines aim to protect public health and safety (p. 12) n Stroke: “The virtual brain” research could lead to improved post-stroke treatment therapeutics (p. 14) n ADHD: Childhood Adhd severity a factor in persistence into adulthood (p. 16) n CV: Gillian einstein, Phd, discusses her novel work regarding the neurological and hormonal differences in cognition in women (p. 18)

MD, FRCPC

Psychiatry Editor

J. J. Warsh,

MD, FRCPC

Neurology Editor

Sarah A. Morrow,

MD, FRCPC

Editor, Innovation in the Mind Sciences

Roger S. McIntyre,

MD, FRCPC

Managing Editor, N&P

Emily Innes-Leroux Editorial Director

R. Allan Ryan Associate Editor

John Evans Publisher

Mitchell Shannon Sales and Marketing

Peggy Ahearn Susan Latter Operations, Manager

Cathy Dusome Comptroller

Rose Arciero 4 n October 2017

Images from the world of neurological and psychiatric medicine: we invite you to submit your photographs for The ChRONICle OF NeUROlOGy + PSyChIATRy. Send original high-resolution (2 megapixels and higher) JPGs to: health@chronicle.org.

DR. BRENDA MILNER (second from left) received a standing ovation when it was announced that she was the recipient of the McGill University Medal for Exceptional Academic Achievement during the Montreal university’s Health Sciences Convocation Ceremony on May 30, 2017. Joining her was McGill University principal Suzanne Fortier (far left), provost Christopher Manfredi (second from right), and Stuart Cobbett (far right), chair of McGill’s Board of Governors. Dr. Milner began her career at the Montreal Neurological Institute (MNI) in 1950, designing and performing tests of Dr. Wilder Penfield’s neurosurgical patients. A press release from the university noted that the findings from these tests helped define the functional areas of the brain. Her discoveries of the interactions between the brain hemispheres, and the functions of specific areas of the brain such as the hippocampus, have directly benefited patients’ lives. In addition to continuing to be an active researcher, Dr. Milner teaches and mentors young doctors and scientists. In 2009, she announced The Brenda Milner Foundation, which supports young researchers in the field of cognitive neuroscience through postdoctoral fellowships at the MNI. Dr. David Eidelman, vice-principal (Health Affairs) and dean of the Faculty of Medicine, said: “An active researcher at the age of 98, Professor Milner is an inspiration to us all.”

Photo by Owen Egan, McGill University

Founding Editor

Richard Gladstone,


“Fortunately analysis is not the only way to resolve inner conflicts. Life

itself still remains a very effective therapist... The therapy effected by life itself is not, however, within one’s control. Neither hardships nor friendships nor religious experience can be arranged to meet the needs of the particular individual. Life as a therapist is ruthless; circumstances that are helpful to one neurotic may entirely crush another.” —Dr. Karen Horney, German-American psychiatrist (1885-1952)

Schizophrenia pts Testing personalized medicine with dying younger than aim of preventing Alzheimer’s disease general population n Each individual in 100 person trial is a sole unit of observation have a mortality rate that is three times greater each year than those without schizophrenia, and die, on average, eight years earlier than people without schizophrenia, according to a study published in the Canadian Medical Association Journal (Sept. 18, 2017; 189(37)). “Our study shows that individuals with schizophrenia are not benefiting from public health and health care interventions to the same degree as individuals without s ch i z o p h r e n i a ,” said dr. Paul Dr. Kurdyak Kurdyak, senior author, Centre for Addiction and Mental health and Institute for Clinical evaluative Sciences scientist in Toronto and director of health Outcomes with the Medical Psychiatry Alliance, which supported the study. “As health care providers, it is our responsibility to work together across our health care system to provide these patients with better, integrated physical and mental health care. by not doing so, there are dire, tragic consequences and shortened lives.” Researchers studied all deaths during the 20-year period between 1993 and 2012 in Ontario and examined the deaths annually. HIGHER RATES OF CVD Individuals with schizophrenia had higher rates of death for all causes including cardiovascular diseases and chronic medical conditions. while the general population in Ontario has experienced a reduction in cardiovascular deaths, the study showed that individuals with schizophrenia are not experiencing the same reduction. People with schizophrenia have many cardiovascular risk factors such as diabetes, obesity, smoking and sedentary lifestyle, but are more burdened by these risk factors than those without schizophrenia. Medications used to treat schizophrenia can cause weight gain and the development of diabetes. —Read more information at http://tinyurl.com/ybzfjgma

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NeUROSCIeNTIST at Florida Atlantic University (FAU) in boca Raton, Fla. has developed an innovative program in the Comprehensive Center for brain health at FAU called the “dementia Prevention Initiative” (dPI), which abandons generalized methods used to research and treat Alzheimer’s disease (Ad). The approach of dr. James e. Galvin, associate dean for clinical research in FAU’s Charles e. Schmidt College of Medicine, is an “N-of-1 design” that individualizes medicine down to a single patient. Instead of conducting a conventional trial of 100 people all getting the same treatment, he has switched it around and is conducting 100 single trials personalized to the individual. his youngest patient is 61 years of age and the oldest is 86 years old. The findings of the study were published in the Journal of the American Geriatrics Society (Aug. 2, 2017).

AIM TO PREVENT DEMENTIA The dementia Prevention Initiative is a two-year clinical trial and dr. Galvin is developing a best-practice model of personalized care that looks at each individual as the sole unit of observation. The idea is to treat neurodegenerative diseases as a disorder that develops over a lifetime and individualize ways to build a better brain as we age. The ultimate goal is to prevent dementia from occurring in the first place. dr. Galvin’s approach follows a form of personalized treatment similarly used in cancer and delivers an individualized prevention plan, tailored to each patient’s risk profile based on their genetic traits, biomarkers (blood, imaging, and electrophysiology), socio-demographics, lifestyle choices, and co-existent medical conditions. This approach specifically targets the heterogeneity of Ad by identifying person-specific risk factors and applying a customized intervention directed against this risk profile. “while we know that a well-balanced, healthy lifestyle may be the corner-

n Results from a small study in

Photo by Alex Dolce

P

ATIeNTS wITh SChIzOPhReNIA

In the news . . . nine pediatric patients with chronic migraine show that being treated with botulinum toxin injections every 12 weeks over a five-year period resulted in improvements in the frequency, duration and intensity of the patients’ migraines, reports Time (Oct. 23, 2017 ). Among all the 1,000 injections administered in the five-year study, only eight resulted in adverse events. —Find more information at http://ow.ly/dvXD30gdYXP

n Treatment with blood thinners to

stone of disease prevention and brain health, each risk factor such as vascular, lifestyle choices, psychosocial behaviour may both act independently and potentiate the effects of each other. Therefore, a prevention initiative needs to be multimodal and tailored to address individual risks,” said dr. Galvin. Although the single greatest risk factor for Ad is age, Ad is not inevitable. It is estimated that at age 85 years there is a 42% risk of developing Ad, which means that 58% of older adults do not develop dementia, even if amyloid can be detected in the brain. The reasons are unknown, but may be explained in part by a host of modifiable and non-modifiable risk factors. Up to 30% of Ad cases may be preventable through modification of risk factors and behavioural changes to mitigate the effect of those risk factors that can’t be modified. “we know what’s good for the heart is good for the brain and we are changing people’s blood profiles, controlling blood sugars, reducing inflammation, lowering blood pressure, and changing lipids and cholesterol,” said dr. Galvin. “Our patients say that they are in better overall health, their moods have improved and they are more physically fit than before.” even if these precision approaches alone are not successful in preventing Ad, dr. Galvin believes that they may greatly improve the likelihood of amyloid- or tauspecific therapies reaching their endpoints by reducing comorbidities. —Find more information at http://tinyurl.com/yb9r5aa7

reduce stroke risk also reduced risk of developing dementia by 29%, findings from a Swedish study show, reports CTV News (Oct. 25, 2017). Researchers examined the records of a cohort of more than 400,000 Swedish patients with atrial fibrillation, 54% of whom were being treated with anticoagulants on entry into the study. —Read this article at http://ow.ly/PB9A30ge8i0

n Since record keeping began in

2013, anxiety and depression in U.K. workers have risen by 30.5%, reports The Independent (Oct. 9, 2017). The data, released by the UK Council for Psychotherapy as part of Mental Health Awareness Day, notes that part-time workers seem more affected, with the increase in that group being 33.6% in the same period. —Read more at http://ow.ly/e4nV30ge9mw

n The authors of a new study say

their findings cast doubt on adult-onset ADHD as a stand-alone diagnosis, identifying most apparent cases of adult-onset attention deficits among their sample as likely the result of substance abuse or mood problems, reports The New York Times (Oct. 20, 2017).

—Learn more at http://ow.ly/QwLN30gedoj October 2017 n 5


Non-invasive technology could improve epilepsy surgery n Digital simulation of patients’ brains may aid targeting of the epileptogenic zone by Louise Gagnon,

Correspondent, The Chronicle he exISTeNCe OF A vIRTUAl bRAIN COUPled with the emergence of non-invasive technologies will likely produce advances in the surgical management of epilepsy, according to a presenter at the Rotman Research Institute 2017 annual meeting in Toronto. viktor Jirsa, Phd, the director of the Inserm Institut de Neurosciences des Systèmes at Aix-Marseille University and director of research at the Centre National de la Recherche Scientifique in Marseille, France, said that a significant proportion of patients with epilepsy are pharmaco-resistant and that surgery is the only management avenue available to them. For most patients with epilepsy, medDr. Jirsa ical therapies offer control of their seizures. The American Association of Neurological Surgeons estimates that 30% of patients with epilepsy are resistant to medication, making surgery the only therapeutic intervention available to treat their condition.

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EPILEPSY SURGERY UNDERUSED “epilepsy surgery can work pretty well, and it is underused,” dr. Jirsa told attendees to the conference. “It has become less invasive, but the success rate has not improved over the last 50 years, which tells us something in terms of our understanding of epilepsy and the manner in which we perform [surgery for epilepsy].” dr. Jirsa is working with investigators located in various areas of the world including Canada, the U.S., and europe to employ a virtual model to simulate what happens when epileptic patients have seizures. Using non-invasive brain imaging and mathematical and computer modelling, dr. Jirsa and colleagues have developed an epilepsy simulation with the brain scans of a patient diagnosed with bi-temporal lobe epilepsy and have called it the virtual epileptic Patient (veP). The simulations were developed by combining brain scans with mathematical models for epileptic seizures. Information such as timing of delays in the propagation of seizures is coming to light with these investigations, noted dr. Jirsa. INVESTIGATING HOW THE SEIZURES TRAVEL Retrospective research that dr. Jirsa has performed with colleagues involved the creation of personalized, large-scale brain networks for 15 patients with epilepsy. The research identifies the origin of the seizure, in what is called the epileptogenic zone. Investigators have simulated seizure propagation patterns to identify how the seizures travel after they originate in the epileptogenic zone (Brain Mar. 2017; 140(3):641–654). One of the techniques involved includes the application of magnetic resonance imaging (MRI) along with externalized

6 n October 2017

intracranial stereotactic recordings using electroencephalography (eeG) electrodes, aimed at enhancing detection of the epileptogenic zone. PINPOINT OPTIMAL ZONES FOR SURGICAL INTERVENTION Information about how the seizures travel in the brain will pinpoint optimal zones for intervening surgically without affecting healthy tissues that are not involved in seizures. In this way, surgeons would intervene so as not to affect vision or speech and avoid causing any impairment of these vital functions, explained dr. Jirsa. An objective scoring system, such as the engel epilepsy Surgery Outcome Scale, can be used to assess the efficacy of surgical management of epilepsy in patients who are refractory to drug treatment. There are four basic classes of outcomes according to the scoring system: Class I, or being free of disabling seizures; Class II, which is experiencing rare, disabling seizures; Class III, which is worthwhile improvement post-operatively; and Class Iv, which includes no worthwhile improvement following surgery. NEED THOROUGH PRE-SURGICAL EVALUATION with each patient, pre-surgical evaluation should still be performed routinely including the gathering of clinical history, a neurological examination, neuropsychological testing, structural and diffusion MRI, eeG and stereotactic eeG recordings and video monitoring, noted dr. Jirsa. emerging surgery, and surgery that will likely become a standard of treatment in the future that will modulate the brain network, would also be minimally invasive and will avoid the resection of tissue, explained dr. Jirsa. An example of emerging surgery that is minimally invasive is laser interstitial thermal therapy, guided by magnetic resonance, which is a neuroablative form of surgery being increasingly used for epilepsy patients who require surgical management. It is critical that imaging be performed before, during, and after the procedure (J Neuroimaging Mar. 29, 2017). OUTCOMES SHOULD MEASURE QUALITY OF LIFE Surgical intervention should not only be measured in terms of its efficacy in controlling seizures, but also measured in terms of its impact on a patient’s quality of life, according to dr. Jirsa. “In terms of making a decision about surgery, the approach that will be taken should not only take into account efficacy of the technique, but the optimization of quality of life of patients,” he said. It is well-known that major depressive disorder is a comorbidity that is common in patients who have epilepsy, noted dr. Jirsa. Clinicians are encouraged to use screening tools such as the Neurological disorders depression Inventory for epilepsy and the self-rated, seven-item Generalized Anxiety disorder screening instrument (J Affect Disord Mar. 1, 2017; 210:237–240).


Important to start transition from pediatric epileptic care to adult care early —Continued from page 1 dr. O. Carter Snead III, study author and a staff neurologist at The hospital for Sick Children in Toronto, said the transition process is much easier now that these epilepsy centres are available. “Now there is a system that we can all share these complicated patients, and that helps a lot,” he said. A transition working group was formed to assist with the creation of transition process guidelines. The group was composed of pediatric and adult epileptologists, psychiatrists, family doctors, neurologists, nurses, social workers, adolescent medicine physician specialists, a lawyer, an occupational therapist, representatives from community epilepsy agencies, patients with epilepsy, parents of patients with epilepsy and severe intellectual disability, and project managers. The investigators listed four key findings: • The transition process to the adult health care system should start early and does not end when the teenager leaves the pediatric system; • Transition period is the ideal time to re-think diagnosis and management; • Psychosocial screening should be done before and after teens leave the pediatric system; and • Negative genetic investigations done long ago, before next generation sequencing was available, should be redone using current technology. OPPORTUNITY FOR GENETIC TESTING “A lot of these kids who have epilepsy who are reaching 17 to 18 years of age have been followed for a long time, and during the time that they have been followed there has been [an] explosion of the understanding of the genetic abnormalities that lead to epilepsy,” said dr. Snead, also a professor of pediatrics at The University of Toronto. “Genetic abnormalities have been discovered, which is what might be responsible for these kids’ epilepsy, but they were never looked for because nobody had Dr. Snead ever heard of them when the diagnosis was first made. “As they transition, it is an ideal time to revisit the issue of diagnosis to be sure that that is covered,” he said. Genetic testing, according to dr. Snead, can be helpful for directing treatment approaches, but also to provide answers to families who have been seeking explanations for their child’s condition. The authors created a seven step approach for the transition: • Step 1 (ages 12 to 15 years): introduce the concept of transition; • Step 2 (ages 12 to 17 years): explore financial, community, and legal support available; • Step 3 (ages 16 to 17): determine transition

readiness of patients and parents; • Step 4A (ages 12 to 19 years): Identify and address risk factors for unsuccessful transition in adolescents with epilepsy and normal intelligence; • Step 4b (ages 12 to 19 years): identify and address risk factors for unsuccessful transition in adolescents with epilepsy and intellectual disability; • Step 5 (ages 16 to 19): re-evaluate the epilepsy diagnosis; • Step 6 (ages 16 to 17): identify obstacles for continuation of treatment of drug-resistant epilepsies; and • Step 7 (ages 17 to 18): prepare the pediatric discharge package. “I think [an] important recommendation is that for those patients who are young adolescents, who are normal intellectually, they should be involved in their transition,” said dr. Snead. “They need to be taught how to take responsibility for taking their medications . . . so they have an investment in their transition process.” READINESS CHECKLIST A USEFUL TOOL The investigators even note that while patients with epilepsy and intellectual disabilities may not be able to fully be involved in the transition, they “may be able to participate in their own care and decision-making at a higher level than parents and [healthcare providers]

had anticipated.” For Step 3, the investigators suggest using readiness checklists to assist with determining the transition readiness of patients and their parents. They include the “epilepsy transition readiness checklist” within the guidelines as a tool for clinicians. “The readiness checklist was developed in conjunction with the adolescent medicine people and epileptologists and it is really useful to make sure that the transition is complete and all the steps have been taken in terms of educating the family in the change in the system, about looking again at the issue of [reexamining] the diagnosis . . ., and [re-examining] the management [plan],” said dr. Snead. The eITF state in the guidelines that some pediatric epilepsy patients have seizures that are uncommonly seen in patients with adult-onset epilepsy, and therefore the adult healthcare provider may not be familiar treating those types of childhood-onset seizures. Another reason for planning for a successful transition is that while some pediatric epilepsy cases remit as patients get older, comorbidites can remain for these patients. including learning disabilities, impulsivity, depression, anxiety, and other neuropsychiatric issues. dr. Snead said the next step for the eITF is to develop a knowledge translation program to improve dissemination of their findings. October 2017 n 7


For the acute treatment of migraine attacks with or without aura in adults  Pharmacokinetics: Measurable plasma levels of CAMBIA were observed 5 minutes after ingestion in normal healthy subjects.*

 CAMBIA is a powdered formulation of diclofenac potassium for oral solution1

1

30 to 60 mL of water

2

Completely dissolve 1 sachet of CAMBIA in water

3

Drink immediately

CAMBIA (diclofenac potassium) is indicated for the acute treatment of migraine attacks with or without aura in adults 18 years and older.1 Consult the Product Monograph at http://aralez.com/wp-content/ uploads/2015/12/Cambia-English-Prescribing-Information.pdf for important information on:1 • Contraindications in: Perioperative pain setting of coronary artery bypass graft surgery; third trimester of pregnancy; nursing women; severe uncontrolled heart failure; history of asthma, urticaria, or allergic-type reactions after taking ASA or other NSAIDs; active gastric/duodenal/peptic ulcer, active GI bleeding, cerebrovascular, or other bleeding disorders; inflammatory bowel disease; severe liver impairment or active liver disease; severe renal impairment or deteriorating renal disease; known hyperkalemia; children and adolescents less than 18 years of age. • Most serious warnings and precautions: Risk of CV adverse events (such as myocardial infarction, stroke or thombotic events) which can be fatal. Risk may increase with duration of use. Risk of increased blood pressure and/or exacerbation of congestive heart failure. Risk of GI adverse events (such as peptic/duodenal ulceration, perforation, obstruction and GI bleeding) which can be fatal. Elderly patients are at a greater risk. • Other relevant warnings and precautions: Not recommended in individuals over 65 and frail or debilitated patients; hepatic, renal and genitourinary impairment; use in phenylketonuric patients; use in women attempting to conceive, first and second trimesters of

7100 West Credit Avenue, Suite 101 Mississauga, Ontario L5N 0E4

pregnancy; caution in patients with Helicobacter pylori infection, prolonged use of NSAID therapy, excess alcohol intake, smoking, poor general health status; observation for patients with hemophilia or platelet disorders; monitor patients taking warfarin; blood dyscrasias and antiplatelet effects; use in patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa, chronic obstructive pulmonary diseases or chronic infections of the respiratory tract, Quincke’s oedema or urticaria, and patients who are allergic to other substances; serious skin reactions; may mask signs and symptoms of infectious disease; may cause photosensitivity and vision changes upon exposure to sunlight or UV light; neurological adverse events including blurred or diminished vision, decreased alertness or depression; concomitant use with: other NSAIDs, with the exception of low-dose ASA for cardiovascular prophylaxis; diclofenac sodium containing products; anti-coagulants; anti-platelet agents; oral corticosteroids; Selective Serotonin Reuptake Inhibitors; drugs that are known to be potentially hepatotoxic (e.g. acetaminophen, certain antibiotics, antiepileptics). • Conditions of clinical use, adverse reactions, drug interactions and dosing instructions. The Product Monograph is also available by calling Tribute Pharmaceuticals Canada Inc. at 1-866-391-4503. Reference: 1. PrCAMBIA®. Product Monograph. Tribute Pharmaceuticals Canada Inc. January 29, 2015. * Clinical significance has not been established

M-CAM-027 EN 140001


Treating migraine CAMBIA efficacious, with a rapid onset of action

T

he patented, water-soluble buffered powder formulation of diclofenac potassium 50 mg for oral solution (CAMBIA, Tribute Pharmaceuticals Canada) appears to be well-tolerated and efficacious for the treatment of migraine attacks—offering a rapid onset of action analgesic efDr. Finkelstein fect.1,2 “One of the things I love about CAMBIA is that onset of action happens within 15 minutes of taking it, and I think that is exceptional,� said Dr. Ian Finkelstein, Medical Director at the Toronto Headache & Pain Clinic in Toronto. The administration of CAMBIA involves mixing and dissolving the powder into one to two ounces of water said Dr. Finkelstein, who noted that he advises his patients who take CAMBIA to use it at the first sign of a migraine attack. CAMBIA is a prescription non-steroidal anti-inflammatory therapy (NSAID) approved by Health Canada in March 2012 for the acute treatment of migraine attacks with or without aura in adults 18 years of age and older.1 “Neurologists and family doctors have a great deal of experience using NSAIDs like ibuprofen and naproxen for the treatment of headache, and diclofenac is part of that family,� said Dr. Paul Cooper, the Richard and Beryl Ivey Chair, Department of Clinical Neurological Sciences, Schulich

School of Medicine and Dentistry and Chief of Clinical Neurological Sciences, London Health Sciences Centre and St. Joseph’s Health Care in London, Ont. “NSAIDs are beneDr. Cooper ficial for patients not only because they are a blocker of pain,� said Dr. Cooper. “They also have anti-inflammatory capacities that probably contribute to their anti-migraine function that helps turn off a migraine because inflammation is part of what causes the pain in patients with migraine.�

Formulation helps with absorption

The formulation of CAMBIA is novel, said Dr. Finkelstein. Unlike other NSAIDs, CAMBIA is formulated in a water-soluble buffered powder that regulates the pH and assists with its fast rate of absorption and its speed of onset. “So the fact that CAMBIA is absorbed quickly—you get high blood levels quickly,� Dr. Cooper said. “The way the molecule is constructed allows it to be absorbed very quickly, which is good for migraine patients because a lot of these patients have gastroparesis, and as a result migraine medication is not absorbed very quickly,� Dr. Finkelstein said. He added that CAMBIA is rapidly absorbed in the stomach.

Diclofenac plasma concentration (ng/mL)

60

75

90

120

150

180

210

240

powder for oral solution)

AxertÂŽ (almotriptan) Maxalt

600

0

45

Pr Pr

ÂŽ

(rizatriptan)

RelpaxÂŽ (eletriptan)

Pr

15 minutes tablets

200

30

CAMBIAÂŽ (diclofenac potassium

diclofenac potassium immediate release tablets

400

15

Pr

diclofenac potassium for oral solution (CAMBIA )

800

AmergeÂŽ (naratriptan)

Pr

FrovaÂŽ (frovatriptan)

Pr

0

1

2 Time (hours)

3

 max: measurable plasma levels within 5 minutes of dosing, with a peak at 15 minutes in fasted condition max        Data on file. Depomed Inc.7

MEDICATIONS ÂŽ

1000

The Canadian Headache Society (CHS) Guidelines for Acute Drug Therapy for Migraine Headache assessed the evidence base for drugs used for the acute treatment of episodic migraine in Canada. The CHS Guidelines listed CAMBIA as one of the recommended choices for acute treatment of migraine attacks of all severities. In the Guidelines, 18 acute migraine treatments and two adjunctive medications were evaluated. Of the modalities assessed, CAMBIA was ranked as one of the acute medications that received a strong recommendation with supporting high quality evidence for use in acute migraine therapy. The other recommended therapies with strong evidence included: almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan, ASA, ibuprofen, naproxen sodium, diclofenac potassium, and acetaminophen. CAMBIA specifically is recommended

TMAX (MINUTES)

15 minutes: diclofenac potassium for oral solution

1400 1200

CAMBIA ranked by CHS as having strong evidence

TMAX OF CAMBIA VS. ORAL TRIPTANS AND NAPROXEN

TMAX OF CAMBIA VS. DICLOFENAC POTASSIUM TABLETS 1600

CAMBIA reaches measurable plasma levels within five minutes of dosing,3 with a peak at 15 minutes. (See figure 1.)4 Similarly, there is a difference in NSAID pharmacokinetics for naproxen, ibuprofen and diclofenac in terms of plasma concentration absorption. Data show that achievement of peak absorption for naproxen and ibuprofen can take up to two hours, whereas peak absorption with CAMBIA takes 15 minutes. CAMBIA’s Tmax has been shown to be faster than oral triptans and naproxen (see figure 2).4

4

ZomigÂŽ (zolmitriptan)

Pr

     

1

ImitrexÂŽ (sumatriptan)

Pr

Naproxen SodiumÂŽ

Pr

MINUTES Adapted from Canadian Headache Society Acute Migraine Treatment Guideline Development Group, 2013.1

2


Treating migraine

CAMBIA efficacious, with a rapid onset of action opioids because those treatments can precipitate medication overuse, and that is the last thing we want to do for these patients,” he added.

CAMBIA not covered under drug formularies by the Canadian Headache Society Guidelines for use after failure of over-thecounter medications, as a first choice prescription option (see figure 3) for patients with migraine attacks that increase rapidly in intensity and for acute treatment of migraine attacks of all severities.4

CAMBIA has synergistic potential with other treatments

“CAMBIA works great for my patients who tend to be difficult-to-treat chronic migraineurs, who often overuse medications,” said Dr. Finkelstein. For patients with severe and chronic migraines, Dr. Finkelstein noted that he uses CAMBIA synergistically with other migraine therapies. “I tell my patients to take CAMBIA for a broader treatment of their migraine, and if after 15 minutes their headache is not gone then I advise them to follow it with a triptan of choice,” he said. “The combination of both of those treatments tends to work far better than either of the modalities alone, and that has been shown to be true both clinically as well as in scientific literature,” said Dr. Finkelstein. Dr. Finkelstein indicated that for these difficult-to-treat migraine patients, where possible, he attempts to avoid over-thecounter medications altogether. “I also certainly avoid prescribing narcotics and Rx MIGRAINE TREATMENT STRATEGIES AFTER OTC FAILURE1+¶ Mild to moderate attack / prescription NSAIDs after OTC failure CAMBIA® (diclofenac potassium powder for oral solution)

Pr Pr

Voltaren® (diclofenac potassium tablet)

“A downside is that CAMBIA is not included under a lot of the drug formularies that cover seniors’ medications and patients receiving social assistance or disability benefits in Ontario, for example. At the moment that is a disadvantage for patients as well,” said Dr. Cooper. “Another downside is the fact that CAMBIA is not available over-the-counter and it has to be prescribed, which means that the patient has to go to their treating physician to get a script for the medication rather than taking ibuprofen, which they can get off the shelf in the pharmacy,” said Dr. Cooper. Like most NSAIDs, CAMBIA is not indicated for migraine patients who have stomach ulcers, hypertension or kidney disease, said Dr. Cooper. Additionally, CAMBIA is also not recommended for patients who are pregnant, advised Dr. Finkelstein.

Treating early improves pain-free success rate

The optimal time to treat a migraine is when the headache pain is mild, said Dr. Cooper. When patients receive treatment within 60 minutes of the onset of a migraine attack while pain is still mild, data shows that the two-hour pain-free success rate is 65%.5 Additionally, the authors of this report also note that the two-hour pain-free success rate drops to 38% when treatment is initiated after the first 60 minutes of the migraine attack and/or when the pain has progressed to be moderate or severe.5 Data in figure 4 suggests that the

Anaprox® (naproxen sodium)

Pr

All ± metoclopramide

CHANCES OF TREATMENT SUCCESS‡ WITH EARLY INTERVENTION vs. LATE INTERVENTION8§

Moderate to severe attack / prescription NSAID failure

NSAID ± metoclopramide CAMBIA (diclofenac potassium powder for

Pr

®

oral solution)

Voltaren® (diclofenac potassium tablet)

Pr

Anaprox® (naproxen sodium)

Pr

+ a triptan later for rescue if necessary

Triptan

100

Imitrex® (sumatriptan, SC injection, nasa, oral)

Pr

Zomig (zolmitriptan, nasal, oral, water)

Pr

®

Maxalt (rizatriptan, oral, wafer)

Pr

®

Amerge® (naratriptan, oral)

Pr

Relpax® (eletriptan, oral)

Pr

Axert® (almotriptan, oral)

Pr

Treatment Success (%)

NSAID with triptan rescue

90 80 70

All ± metoclopramide

38%

50

n=390/1036

40 30 20 10 0

Frova® (frovatriptan, oral)

Pr

65%

n=90/138

60

Treatment within 60 minutes while pain is still mild

Delayed treatment after 60 minutes and/or until pain has progressed to moderate/severe

‡ Treatment success = two hour pain freedom. § European, prospective, open-label, observational study. 501 patients enrolled into the study, 436 completed the study; ITT analysis (n=454, 1174 attacks). Male and female patients aged 18-65 years presenting with a diagnosis of migraine with or without aura according to IHS criteria. Primary end-point of the study was the percentage of patients who were pain free at 2 h after taking almotriptan 12.5 mg.8 8

Adapted from Canadian Headache Society Acute Migraine Treatment Guideline Development Group, 2013.1 + Mild, moderate and severe migraine attacks, does not include refractory. ¶ Consult respective Product Monographs/Prescribing Information for important information on contraindications, warnings, precautions, adverse reactions, interactions, dosing, pharmacokinetics and conditions of clinical use. OTC = over the counter

3

Adapted from Lanteri-Minet, M, Diaz-Insa, S, Leone, M et al. 2010.8

4

need for migraine treatment that is fastacting is evident. “The mainstay of treatment for migraineurs is that we want treatment to act quickly and have the least number of side effects. Our objective for treatment is to yield a sustained pain-free state at 24 hours, and that is key,” said Dr. Finkelstein. Much like the migraine treatment management goal of clinicians, Dr. Finkelstein added that “patients want their treatment to act quickly, and with few side effects. They also don’t want their headaches to recur,” he said.

References CAMBIA®. Product Monograph. Tribute Pharmaceuticals Canada Inc. January 29, 2015.

1 Pr

2

Diener HC, et al: Efficacy and tolerability of diclofenac potassium sachets in migraine: A randomized, double-blind, cross-over study in comparison with diclofenac tablets and placebo. Cephalalgia 2006; 26(5):537-547.

3

Chen C, Bujanover S, Kareht S, Rappoport AM: Differential pharmacokinetics of diclofenac potassium for oral solution vs. immediate-release tablets from a randomized trial: Effect of fed and fasting conditions. Headache 2015; 55(2):265-275.

4

Canadian Headache Society Acute Migraine Treatment Guideline Development Group, Canadian Headache Society Acute Drug Therapy for Migraine Headache. Can J Neurol Sci 2013; 40(suppl 3):S1-S80.

5

Lanteri-Minet M, et al: Efficacy of almotriptan in early intervention for treatment of acute migraine in a primary care setting: the START study. Int J Clin Pract 2010; 7:936-946.

Supplement to The Chronicle of Neurology + Psychiatry, October 2017. Chronicle is an independent medical news service that provides educational updates regarding medical developments around the world. Views expressed are those of the participants and do not necessarily reflect those of the publisher or sponsor. Support for distribution of this report was provided by Tribute Pharmaceuticals Canada through an unrestricted educational grant without conditions. Information provided in this report is not intended to serve as the sole basis for individual care. Drs. Finkelstein and Cooper each received an honorarium from Tribute Pharmaceuticals for their participation in this report. Printed in Canada for Chronicle Information Resources Ltd., 555 Burnhamthorpe Rd., Suite 306, Toronto, Ont. M9C 2Y3. Telephone 416.916.2476; facsimile 416.352.6199; e-mail: health@chronicle.org. Copyright 2017 by Chronicle Information Resources Ltd., except where noted. All rights reserved. Reproduction in any form is expressly prohibited without written permission of the publisher.


Mild stroke patients not being screened for dysphagia, at risk of complications n Severity of stroke has no impact on negative outcomes including pneumonia, disability, death in patients with difficulty swallowing by John Evans,

Associate Editor, The Chronicle eARly ONe IN FIve PATIeNTS with acute ischemic stroke did not have a documented dysphagia screening within 72 hours of presentation, according to a recent paper. More significantly, while most of those who were not screened had mild strokes, failing a dysphagia screening was associated with poor outcomes regardless of stroke severity. The research, published in Stroke (Oct. 2017; 48(10):900–906), was conducted to not only clarify to what extent existing guidelines for screening for swallowing difficulty were being followed, but also what factors predicted who would be screened and what outcomes patients who failed the screen had.

N

ALL ACUTE STROKE PATIENTS SHOULD BE SCREENED “For quite a few years there have been clinical practice guidelines in place in Canada and internationally recommending that all patients with acute stroke have a swallowing screen before the intake of food,” said the paper’s lead author dr. Raed Joundi, in an interview with T he C hRONICle OF N eUROlOGy + PSyChIATRy.

“but what we have not known is whether those clinical guidelines are being followed, and if patients with acute stroke are truly undergoing the swallowing screen on a routine basis.” dr. Joundi is a neurology resident and researcher at the University of Toronto, and has a particular research interest in stroke outcomes. The study was supervised by dr. Moira Kapral, professor of medicine at the University of Toronto and senior scientist at the Institute for Clinical evaluative Sciences. “we also do not know the Dr. Joundi prognosis of those who fail the swallowing screen in terms of risk of pneumonia and other complications, disability, and mortality,” said dr. Joundi. The retrospective study used data from the Ontario Stroke Registry collected between Apr. 1, 2010 and Mar. 31, 2013. From a total of 7,171 patients, 6,677 were eligible to receive dysphagia screening within 72 hours. Of those eligible, 1,280 (19.2%) did not undergo screening. Patients with mild strokes were found to be half as likely to be screened as those with severe stroke,

even though approximately 30% of screened patients with mild stroke failed. OUTCOMES MUCH WORSE WITH DYSPHAGIA “The patients who failed dysphagia screening had significantly higher rates of pneumonia, disability, and death,” said dr. Joundi. The adjusted odds ratios for poor outcomes were: pneumonia (4.71; 95% confidence interval (CI), 3.43–6.47), severe disability (5.19; 95% CI, 4.48–6.02), discharge to long-term care (2.79; 95% CI 2.11–3.79), and one-year mortality (adjusted hazard ratio 2.42; 95% CI, 2.09–2.80). Similar associations were also seen in patients with mild strokes. dr. Joundi said that although ideally all patients should be screened, it is not particularly surprising that 20% of stroke patients are not being screened in a time ly fashion. he noted that in an acute care situation many health care providers may not consider swallow screening as a priority. Further, he said that the finding is a slight improvement from a prior study of quality outcomes in stroke a few years earlier that counted how many people had swallowing screens during their entire admission. dr. Joundi attributes the improvement in screening —please turn to page 15 rates to a combination of

Methylphenidate dosing model a response to variable prescribing practices

—Continued from page 1

noted dr. Philippe Robaey, one of the study’s authors and a professor of Psychiatry at the University of Ottawa/Children’s hospital of eastern Ontario, in Ottawa.

Comment: “The work is theoretical and

while the mathematical modelling of kinetics appears to be sound, without validation of the model in a clinical trial design, the clinical value is speculative. It is understandable that testing the modelling is likely problematic because it would be limited by the ability to obtain subject informed consent in the relevant age group, but the authors really have to find a way to address this. Otherwise the work will remain of theoretical significance only.” —Dr. Jerry Warsh, Psychiatry Editor

“we were prompted to look at this because of wide variations in [prescribing] practices,” said dr. Robaey. “The idea is to develop a therapeutic target based on pharmacokinetic modelling of measured plasma concentrations of medication in an experimental group.” CLINICIANS USE OWN TREATMENT PLAN Clinicians largely exercise their own judgment in

deciding on a treatment regimen for methylphenidate, attempting to take into account the daily activities of a child and family routines, explained dr. Robaey, who added that variables such as a child’s weight or, soon, genetic variations, would also factor into a decision about choosing an appropriate medication regimen. dr. Robaey also noted methylphenidate is available in short-acting—or immediate-release—(such as Ritalin), and long-acting—or extended-release—formulations (such as Concerta, biphentin), as well as their generic “equivalents”. “The long-acting, or extended-release, was designed to avoid [the need for] multiple doses of the short-acting medication,” said dr. Robaey, noting that extended-release therapy is usually prescribed as a single, daily dose. “In my own experience, the shortacting medication is prescribed much less, at least in children.” Short-acting methylphenidate would typically be prescribed about three times daily—in the morning, at lunch hour, and late afternoon at the end of a school day. The concentration of methylphenidate should be as low as possible just before bedtime. “It should not be prescribed too late, so that it does not interfere with sleep,” said dr. Robaey. One of the concerns that has arisen with prescribing short-actDr. Robaey ing methylphenidate is that children who need to leave class to receive their medication dose can be stigmatized, and it creates a responsibility for school personnel to administer the medica-

tion, said dr. Robaey. “Privacy has been an issue, and school personnel forgetting about providing a dose of [short-acting] medication has been an issue as well,” he said. however, both short-acting and long-acting formulations are sometimes prescribed together to produce optimal therapeutic outcomes while ensuring efficacy throughout the day and minimizing the risk of side effects, said dr. Robaey. “Using this computational approach will avoid too high or too low a concentration of the drug at critical times in a daily routine,” he said. The investigators have found from the available literature that the target window of methylphenidate concentration to provide efficacy when it is most needed should be set at a range of 6 to 20 ng/ml. At bedtime, the concentrations of methylphenidate should be below 6 ng/ml. The application can simulate how methylphenidate is absorbed by and cleared from the body and, thus, how its concentration changes over time for different short and long-acting formulations available in Canada. This concentration is a range of values changing over time, with most children being around the mean, and with fewer and fewer of them getting farther from the mean. This allows testing, in the application, how well a medication regimen, with one or more methylphenidate formulations, is likely to reach its therapeutic target in the plasma before trying it in a real patient. It can provide the optimal dosage, time, and formulation, or combination thereof, to respond to the needs of patients. For example, in their paper, the authors —please turn to page 17 October 2017 n 11


New guidelines aim to reduce risks associated with

cannabis

by Emily Innes-Leroux,

Associate Editor, The Chronicle

W

MANY MISCONCEPTIONS REGARDING CANNABIS “There has been lots of misconceptions [about cannabis] and in a sense we have allowed the illicit market—the drug dealers—to do the marketing. That is clearly not a situation that is allowing us to provide clear information to the public,” said study investigator Dr. Bernard Le Foll, head of the Translational

Addiction Research Laboratory in the Campbell Family Mental Health Research institute and medical head of Addiction Medicine Service, Centre for Addiction and Mental Health (CAMH), Toronto. “We are hoping that with public health education, . . . clear evidence-based information will be disseminated that will allow people to make informed choices,” said Dr. Le Foll. “it is important for users to really [consider] that [cannabis] is not something that is safe 100 per cent. Dr. Le Foll There are risks, and then they have to think of what the real risk is that they want to take,” said Dr. Le Foll. Dr. Le Foll summarized the LRCUG findings by stating that, “we know that people lose control when

LRCUG can help Canadians make best decisions for own health, wellbeing —Continued from page 3 surrounding ‘what the evidence says’ conclusively about the harms of cannabis use, the LRCUG utilize precautionary principles and pragmatism to provide guidance based on the best available evidence. Given uncertainties about exactly who is at risk for harms, or how much use can cause harm, the LRCUG are a sound starting point for making coherent decisions in policy and clinical practice, and to help Canadians to make the best decisions for their own health and wellbeing.

REFERENCES

1. Butt P, Beirness D, Gliksman L, Paradis C, Stockwell T: Alcohol and health in Canada: A summary of evidence and guidelines for low-risk drinking. Ottawa, 2011: Canadian Centre on Substance Use and Addiction. 2. Fischer B, Jeffries V, Hall W, Room R, Goldner E, Rehm J: Lower Risk 12 n October 2017

Cannabis Use Guidelines for Canada (LRCUG): A narrative review of evidence and recommendations. Canadian Journal of Public Health/Revue Canadienne de Santé Publique 2011; 324–327. 3. Fischer B, Russell C, Sabioni P, van den Brink W, Le Foll B, Hall W, Rehm J, Room R: Lower-risk cannabis use guidelines: a comprehensive update of evidence and recommendations. American Journal of Public Health 2017; 107(8), e1-e12. 4. Retrieved from the Centre for Addiction and Mental Health: https://www.camh.ca/en/research/news_and_publications/reports_and_bo oks/Documents/LRCUG.KT.Professiona1.15June2017.pdf 5. Canadian Tobacco, Alcohol, and Drugs Survey, Health Canada 2015: https://www.canada.ca/en/health-canada/services/canadian-tobacco-alcohol-drugs-survey/2015-supplementary-tables.html#a11 (accessed October 4, 2017).

CC BY-SA 2.0 by Chuck Grimmett, French Inhale, via Flickr

iTH THE iMPEnDinG 2018 legalization of cannabis in Canada, the Canadian Research initiative in Substance Misuse have released an updated version of the “Canada’s LowerRisk Cannabis Use Guidelines” (LRCUG) with the stated aim of protecting public health and public safety. The comprehensive update of the evidence and recommendations were published in the American Journal of Public Health (Aug. 2017; 107(8)). The authors also published an evidence brief for clinicians and a two-page brochure for the public. “Experiences from other jurisdictions have suggested that legalization does not necessarily—at least in the short run—translate into consistent public health improvements, but may increase specific problems,” said the investigators. “The data show, cannabis use is associated with a variety of health risks, including several for which the evidence is ‘substantial.’ The primary challenge for public health-oriented cannabis policy is to prevent adolescent or young adult cannabis users from developing severe— acute or chronic—health problems from use.” The guideline features 10 recommendations that focus on abstinence, age of initial use, choice of cannabis products, cannabis use methods and practices, frequency and intensity of use, cannabis use and driving, special-risk populations, and combining risks or risk behaviours.

they use—they develop addiction and some people develop other consequences related to the cannabis use. But if they smoke intermittently, low dose, avoid smoking before driving, [and] . . . reduce exposure to smoke [inhalation], then those are very clear things that they can decide to do that will reduce their individual [health] risks.” Candice E. Crocker, PhD, said these guidelines were necessary because “the basic health information seems to be getting lost in the shuffle.” Dr. Crocker, nova Scotia Early Psychosis Research Unit, assistant professor, Department of Psychiatry, Dalhousie University in Halifax, and colleagues ran focus groups involving high school and college students as part of development of a social media campaign called “Weedmyths” (www.weedmyths.ca). “We really found that by age 15, a lot of the individuals are really set in their thoughts about how safe or unsafe cannabis is. But when you challenged them with ‘well have you ever heard about someone who had a bad trip?,’ they all had stories of somebody who had had a bad experience,” said Dr. Crocker. “it was fascinating and frightening all at the same time.” “There is this attitude that [cannabis] is harmless, [but] nothing that alters your consciousness is harmless,” said Dr. Crocker. Dr. Robert Milin, head of the Division of Addiction & Mental Health and associate professor, Department of Psychiatry, University of Ottawa, said he thinks the guidelines are useful and clear. However, he would also have liked to have seen some additional comments along the lines of ‘at this time we do not have a definition or guidelines for what is safe recreational use of marijuana’ and that continued regular marijuana may be an impairment to achieving one’s potential. —please turn to page 13 “i would use [these


More research and information needed to prepare Canadians for legal cannabis

—Continued from page 12

guidelines] as a tool,” said Dr. Milin, director of the Adolescent Day Treatment Unit, Youth Psychiatry Program, Royal Ottawa Mental Health Centre and consulting psychiatrist at the Dave Smith Youth Treatment Centre for substance use disorders. “I will share this information sheet with agencies and physicians as [cannabis] is presently a pretty hot topic of discussion and they often ask ‘is there something that I can quickly look at that summarizes the important points?.’ It is important to provide a consistent message when it comes to education on this topic.” Dr. Sabina Abidi, assistant professor and child/adolescent psychiatrist in the Department of Psychiatry at Dalhousie University in Halifax, agrees that the investigators “did a good job given the current research.” “Much of the research confirms a very strong association between cannabis, THC (tetrahydrocannabinol) in particular, and risks with driving, cognitive function, [and] . . . early onset psychosis,” said Dr. Abidi. “But . . . proponents of cannabis [focus on] the fact that the research isn’t Dr. Abidi causal—in that we can’t prove the causality.” “What is so interesting to me is that the evidence on the flip side, the evidence related to the . . . potential benefits of THC. It is not conclusive, . . . yet that is being touted as . . . one of the reasons for legalizing [cannabis] for prescribing for doctors,” said Dr. Abidi. Dr. Milin noted it would have been helpful to have added certain anchor points with respect to marijuana use such as “the regular weekly use of marijuana in adolescents has been found to be threshold marker for the risk of developing cannabis use disorder”. RECOMMENDING ABSTAINING FROM CANNABIS USE “I love that the first recommendation [is] abstinence. I think that is super important,” said Dr. Abidi. “When I was training years ago, before we knew what we know now about the risks associated with THC and psychotic disorders, for example, we would have used a harmreduction model associated with cannabis use with adolescents and now . . . I have shifted to starting with a primary recommendation of abstinence. In other words, if we don’t warn youth of the potential risks and how to avoid them, that is in fact, causing more harm, particularly for youth that present with a psychotic experience.” For patients already using cannabis, Dr. Abidi uses motivational interviewing to determine why and how frequently they are using; and she tries harm-reduction at that point. However, she said it is the best policy to be honest with youth, especially those at risk for psychosis, that abstinence is the safest choice.

“Implications of Cannabis Legalization on Youth and Young adults (Apr. 12, 2017) in which they recommend that access to cannabis should not be allowed until 21 years of age and that THC potency should be restricted for those between 21 and 25 years of age because cannabis is associated with an increased risk of schizophrenia. Dr. Crocker and colleagues also noted that cannabis may increase the risk of depression; and higher levels of THC can worsen panic disorder and other anxiety disorders. Dr. Crocker The same age of use recommendation had been proposed by the Canadian Medical Association (CMA) in a submission in response to the federal Task Force on Marijuana Legalization and Regulation (Aug. 29, 2016). Yet, in Bill C-45, the Canadian federal government set the national minimum age for purchase of cannabis at 18 years of age; with no limits on THC potency. An editorial published in the Canadian Medical Association Journal (May 29, 2017; 189(21)) by the interim editor-in-chief, Dr. Diane Kelsall, suggested that by not heeding the CMA’s recommended age for consumption, the bill does not protect the health of Canada’s youth “Cannabis should not be used by young people,” said Dr. Kelsall. “It is toxic to their cortical neuronal networks, with both functional and structural changes seen in the brains of youth who use cannabis regularly.” Dr. Benedikt Fischer, lead author of LRCUG, submitted a response to Dr. Kelsall’s editorial (Canadian Medical Association Journal July 24, 2017; 189:E971-E972), in which he says, “certainly, in theory, all cannabis-related health risks would be best eliminated by abstention, and from a public health perspective, abstention among youth (or everyone in general) would be the ‘ideal’ solution in terms of avoiding these health risks. Yet this is, evidently, not anywhere realistic or feasible.” “For decades, existing prohibition law and policy has aimed to purge cannabis use from the Canadian population—yet a persistent one in three people in the 16–25 years of age group (trends rising) are active users. So youth ‘not using cannabis’ is a futile illusion in current reality, and [Dr.] Kelsall does not propose new or improved approaches to realistically change this,” said Dr. Fischer, senior scientist at CAMH. As an explanation for age 16 years, Dr. Le Foll highlighted his research that found that the risk of life-

time cannabis dependence and lifetime heavy use of cannabis is higher when cannabis is used at a younger age (<14), but the risk decreases with every subsequent year of age of initial use (Accid Anal Prev. Mar. 2015; 76:1-5). In the LRCUG, Dr. Fischer and colleagues do note that the later cannabis use is initiated, the lower the risks for adverse effects are on the user’s “general health and welfare.” Dr. Abidi said that waiting until the brain has matured before using cannabis is the best approach. “The bottom line is if young people or young adults want to use cannabis after the age of 23 or 24, the mental health health and cognitive risks [are] significantly lower,” she said. “It is in that critical period where the brain is developing that has the most impact in terms of negative mental health outcomes.” CONCERNS WITH SPECIAL-RISK POPULATION SECTION Dr. Crocker was concerned with an inclusion in the special-risk population section, which states that individuals who have had a family history of psychosis or other mental health problems are at a higher-risk of cannabis-related adverse effects. “A lot of cases of [cannabis-related] schizophrenia are de novo,” said Dr. Crocker. “We currently have no way of identifying who is at risk of developing psychosis with cannabis use.” Dr. Milin said he would have also described a section in the special-risk population differently, with regard to the authors’ use of the term “cannabisrelated psychosis.” “The question with cannabisrelated psychosis [is that] people sometimes think, ‘well [the psychotic impact] will go away if I stop smoking,’ but it may not. You can experience cannabis-induced psychosis disDr. Milin order, which in itself is not a benign condition, but you can also end up precipitating a schizophrenic disorder, or schizophrenia,” said Dr. Milin. MORE GUIDELINES NEEDED Dr. Abidi said that guidelines like the LRCUG are essential but more research and guidance about cannabis is needed. “Education is important. The more that we have out there that actually speaks the same language and touts the same information, the better the case we can make when we talk to our Canadian youth,” she added.

CONTROVERSIAL AGE OF INITIAL USE The age of initial use recommendation has been controversial. The LRCUG evidence-brief states that “early initiation of cannabis use (i.e., Most clearly that which begins before age 16) is associated with multiple subsequent adverse health and social effects in young adult life.” “I found it a bit curious that in the text of the systematic review that they talk about substantial evidence, which many of us have found, with risks associated with youths before the age of 18, but in the guidelines they put youths before the age of 16,” said Dr. Crocker. Dr. Crocker was involved in the Canadian Psychiatric Association position statement titled October 2017 n 13


‘Virtual Brain’ research could lead to better post-stroke Tx n More targeted therapy, guided by simulation research, could reduce chronic disability function. dr. Solodkin mentioned that “while these initiatives have helped to elucidate changes in brain connectivity in disease, what we are lacking are tools to link these multiple datasets to ‘reconstruct’ the brain, and provide the link between these data and those from a single person. As stated, one of the salient aspects of Tvb is that it can be personalized, using individual neuroimaging data to generate individualized virtual brains. An exciting clinical potential is that therapeutic interventions could be assessed in a person’s virtual brain first to help converge on targets that are most likely to have the best outcome.”

by Louise Gagnon,

Correspondent, The Chronicle

on individualized neuroimaging will generate findings that could help to understand brain physiology and dynamics after a stroke, opening the door to new therapeutic opportunities, according to a speaker at the Rotman Research Institute Conference 2017 in Toronto. “The acute treatments in stroke are greatly improved, so the number of stroke survivors are concomitantly increased,” said Ana Solodkin, Phd, a professor in anatomy, THE VIRTUAL BRAIN SIMULATES BRAIN SIGNALS neurobiology, and neurology at UC dr. Solodkin also highlighted that “The virtual brain platIrvine health, Irvine, Calif., during her form simulates brain signals based on biophysical parameters. presentation. “In consequence, stroke is These biophysical parameters are invisible to brain imaging devices, thus Tvb acts as a ‘compunot the first tational microscope’ that helps to cause of mortalDr. Solodkin determine basic brain mechanisms.” ity, but is the Preliminary research involving number one The acute treatments in The virtual brain has uncovered cause of long-term disability.” According to the U.S. Centers stroke are greatly improved, interesting changes in brain dynamics between healthy controls and stroke for disease Control and so the number of stroke survivors in the chronic stage, Prevention, 27% of stroke survivors spend their life in a nursing survivors are concomitantly explained dr. Solodkin. with colleagues, dr. Solodkin home after they have a stroke and increased. In consequence, has been simulating functional greater than 30% of stroke survivors develop aphasia. In addition, stroke is not the first cause of magnetic resonance imaging (fMRI) signals through modelling local and there is some degree of hemiparesis mortality, but is the global biophysical parameters present in about 50% of patients linked to neural dynamics subseliving with stroke. number one cause of quent to a stroke. dr. Solodkin proposed that long-term disability. In an investigation of 20 new therapeutic approaches will patients and 11 healthy controls, require individualized treatments —Ana Solodkin, PhD, a professor in anatomy, dr. Solodkin and co-investigators focused on cures rather than remedineurobiology, and neurology at simulated resting state fMRI sigation. “whatever we do has to be UC Irvine Health, Irvine, Calif. nals, based on individual anatomipersonalized [treatments] based on cal connections derived from diffubrain mechanisms disrupted after sion tensor imaging data (dwI). Stroke severity was measthe stroke,” she said. ured at different points in time determining motor perPHYSICAL AND EMOTIONAL CHANGES formance before therapy, after therapy, and a year after Not only are there physical disabilities that develop after a therapy to determine maintenance effects. Modelling with stroke, such as impediments in speech or decreased motor The virtual brain showed a remarkable finding as the functioning, but there are emotional changes that occur, said changes in global and local parameters detected after dr. Solodkin. “The prevalence of depression after stroke is stroke were good predictors of motor recovery (eNeuro high.” Apr. 2016; 3(2)). One of the key instruments toward developing a perREDUCTION IN LOCAL INHIBITORY DYNAMICS sonalized approach to management, according to dr. They observed that patients who had experienced a stroke, Solodkin, is the determination of brain dynamics affected compared to healthy controls, had a decrease in the interby the stroke that can be uncovered via modelling with the communication between brain regions along a general “The virtual brain” (Tvb), neuroinformatics platform hyperexcitability of brain regions and a decreased conducwhich can serve in translational research, acting as a bridge tion velocity. between the research community—focused on large sets of Currently, dr. Solodkin is looking to validate these results data—and the clinical community—focused on the individwith a much larger sample of patients. with a larger sample, ual patient. she hopes to develop patient profiles that will influence the therapeutic course focusing on individualized treatments. FINDINGS FROM ‘BIG DATA’ PROJECTS “we are in the beginning stages of developing patient big data projects, such as the human Connectome Project, are providing insights into both normal brain function and dys- profiles,” said dr. Solodkin.

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Changes suggested to dysphagia screening protocols to improve outcomes —Continued from page 11 a greater emphasis placed on these screens in hospitals and stroke systems, and a move away from such screenings being exclusively conducted by speech-language pathologists. “Training nurses and other healthcare practitioners on the frontlines, to actually perform this simple test is obviously advantageous when you only have limited amounts of resources in terms of numbers of speech-language pathologists,” said dr. Joundi. MILDER STROKE PATIENTS STILL AT RISK The more important finding is that patients with mild stroke have similarly increased odds of poor outcomes as patients with more severe stroke if they have difficulty swallowing, said dr. Joundi. “I think that is important because we probably have a cognitive bias toward not being as aggressive with screening and investigations in those with mild findings—really in any condition and particularly in stroke,” he said. This may be due to an erroneous assumption that patients with mild stroke will not have dysphagia due to their mild deficits, or that they will do

well regardless. In light of these findings, dr. Joundi said that physicians have a role to play in ensuring that the need for dysphagia screening is flagged and that they are requesting the appropriate services to administer these tests. “That means, in a practical sense, when physicians see patients with acute stroke, we should make sure we are requesting swallowing screening in a timely fashion.” “And [we need to also ensure] that in the meanwhile, prior to the screening, we are avoiding unsafe oral intake to prevent aspiration.” SYSTEMIC PROTOCOL CHANGES SUGGESTED The way to move forward on improving the number of stroke patients who undergo swallowing assessments may be by implementing systemic procedural changes, said dr. Joundi. ensuring timely screening should ideally be undertaken in a system-wide fashion, where health care workers strive to implement better screening protocols in their hospitals, institutions, or stroke networks, he said.

“I think that is our role as physicians. And [we need to also ensure] that in the meanwhile, prior to the screening, that we are avoiding unsafe oral intake to prevent aspiration, and being aware of the risk of aspiration.” “I think we need to be constantly aware of how we are implementing these practices and what is being missed. It does require conscious effort. It isn’t easy on a busy night when caring for multiple patients, some of which may have stroke, to remember the ‘small things’ like dysphagia screening, but this can ultimately have a big impact if omitted initially.” “I think the answer to that is really systematizing things, so we do not have to think about each of these aspects individually and make conscious decisions. Rather, it is just built-in as part of how stroke patients are cared for.” That might be done via checklists or by modifying admission forms to routinely include dysphagia screening. “That requires a good team,” he said. “That requires prioritizing [dysphagia] as an issue.”

Increased number of stroke patients presenting with preventable risk factors

DESPITE PREVENTION efforts, researchers at the University of Miami Miller School of Medicine have found a significant increase over a 10-year period in the percentage of people with stroke who have high blood pressure, diabetes, smoking, and other risk factors for stroke. The study was published online in the journal Neurology (Oct. 11, 2017). “An estimated 80 per cent of all first strokes are due to risk factors that can be changed, such as high blood pressure, and many efforts have been made to prevent, screen for, and treat these risk factors. Yet we saw a widespread increase in the number of stroke patients with one or more risk factors,” said study author Dr. Fadar Oliver Otite, a neurology resident at the Miller School of Medicine. “These alarming findings support the call for further action to develop more effective methods to prevent and control these risk factors to reduce stroke risk.” For the study, the research team—which included Dr. Seemant Chaturvedi, professor of clinical neurology, and Dr. Ralph L. Sacco, professor and chair of neurology and Olemberg Family Chair in Neurological Disorders—examined a public database of U.S. hospitalizations, and identified 922,451 adult hospitalizations for ischemic stroke between 2004 and 2014.

Of those stroke cases, 93% of people had one or more risk factors. The prevalence of high cholesterol more than doubled during the study period, to 59% from 29% . The prevalence of diabetes increased by 22%, to 38% from 31%. The prevalence of high blood pressure increased by 15%, to 84% from 73% . And the prevalence of drug abuse doubled, to 2.8% from 1.4%. These risk fac-

tors varied by age, race and sex. Researchers found that the incidence of high blood pressure in stroke hospitalizations increased annually by 1%, diabetes increased by 2%, high cholesterol by 7%, smoking by 5% and drug abuse by 7%. Additionally, kidney failure increased annually by 13%, plaque buildup in the carotid artery by 6% and coronary artery disease by 1%. The proportion of people with multiple risk factors also increased over time. While the study did not examine reasons for the increase, researchers say improved screening and detection of some risk factors may have played a role. Dr. Otite said, “while we have made great strides in reducing the proportion of people who die from stroke, we still have progress to make on preventing stroke and better controlling these risk factors.” Limitations of the study include that the definitions of some risk factors may have changed over time and therefore risk factors may not have been recorded consistently. Also, increased prevalence of high cholesterol could be related to more testing being done after studies showed the benefits of statins for stroke prevention. —Read more information at http://tinyurl.com/y9rjp3uu or http://tinyurl.com/ycw4456g October 2017 n 15


Childhood ADHD severity impacts persistence into adulthood n Individuals who grow out of ADHD symptoms may continue to have underlying cognitive deficits not uniquely predict Adhd persistence beyond child-level factors.

by John Evans,

Associate Editor, The Chronicle

presentation of PERSISTENCE LESS COMMON THAN EXPECTED attention-deficit hyperactivity disorder (Adhd) are Overall, the research team saw a lower rate of persistence more likely to have their condition persist into adoles- than they expected, said dr. Schachar, with approximately cence or adulthood, according to findings from a prospective one-third of the children followed experiencing Adhd into study that aimed to identify clinical, sociobiological, and cog- adolescence. based on the existing literature, about 50% would have been expected to persist. nitive predictors of Adhd persistence. “we found a fair number of people who had impairPublished in the Journal of Abnormal Child Psychology (May ment, but their symptoms were 2017; 45(4):765–776), the study no longer at threshold, which was followed 130 children with fascinating,” dr. Schachar said. Adhd, with a mean age of 8.9 Clinically you want to know if “but when we thought about it, years, into adolescence (mean not too surprising.” age 14.0 years). you can possibly figure out who he said the team also identiThe study was inspired fied participants who continued because a large proportion of is likely to show persistence to have symptoms into adolesschool-age children with Adhd versus desistance of their cence, but were no longer seem to no longer be affected by Adhd if they are followed into symptoms, because time is short, impaired by them. “Those are both almost more adolescence and young adultresources are limited, and you interesting groups than persisters hood, said the paper’s senior and people who remit,” he said. author dr. Russell Schachar, in would like to concentrate on while the study did not an interview with T he reveal any clear environmental or ChRONICle OF NeUROlOGy + those who seem to need it most. cognitive risk factors, the investiPSyChIATRy. —Dr. Russell Schachar, senior scientist in the Research gation did reveal that children “This is a really interesting Institute at the Hospital for Sick Children, Toronto. who met the criteria for Adhd problem both clinically and scicontinued to have cognitive entifically,” said dr. Schachar, who is a practicing child and adolescent deficits whether their Adhd persisted or not. “On one hand, that was a disappointment because we psychiatrist. he is also a professor in the department of Psychiatry, University of thought it would be nice if you knew how to predict outToronto, and senior scientist in the comes based on cognitive function,” said dr. Schachar. On Research Institute at the hospital for Sick the other hand, it shows that the cognitive deficits are intertwined with the underlying biology of the disease, he said, Children (SickKids) in Toronto. “Clinically you want to know if you “which is really a very important insight from the perspective can possibly figure out who is likely to of the biology of the disorder.” Dr. Schachar show persistence versus desistance of MONITORING ADHD PATIENTS LONG-TERM RECOMMENDED their symptoms, because time is short, A key take-away from the paper for practitioners managing resources are limited, and you would like to concentrate on children with Adhd, according to dr. Schachar, is that those who seem to need it most.” while the team did identify some associations between severIn the study, the children’s Adhd symptoms and comor- ity and persistence, the links are not sufficiently strong to bidities were assessed through interviews with their parents and allow stratification of patients. “[One] should figure out a teachers. As well, parental psychopathology was assessed, the plan to stay in touch with and monitor all [their] Adhd children’s exposure to neurobiological and psychosocial adversi- patients. It is better to think of [Adhd] as a life-long, ty was indexed, and their cognitive reserve was evaluated. multi-component condition.” Univariate analyses identified childhood inattention and Also, individuals who appear to grow out of Adhd hyperactivity-impulsivity, comorbid oppositional defiant dis- symptoms or impairment may continue to have underlying order, overall impairment, and paternal anxiety and depres- cognitive deficits, said dr. Schachar. These deficits may be of sion as being more common in adolescents with persistent types that can be challenging to identify, such as poor Adhd than in those whose Adhd remitted, though only response inhibition, but may nevertheless be impairing. child-level predictors remained significant in the final multiTools are in development that will make it easier for clivariate model. nicians to assess children with Adhd and to monitor them The authors say these findings suggest that children who are over time, dr. Schachar said. most likely to experience persistent Adhd have a more severe “when they become ready they will help you determine clinical presentation in childhood, which is reflected by increased the likelihood that the patient you are looking at has Adhd, and will help you determine whether the treatments you are levels of inattention, oppositional behaviour, and impairment. These children are also more likely to have fathers offering are having an impact on this cognitive level of dyswith depression or anxiety, though again those concerns do function.”

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More appropriate psychostimulant dosing for ADHD could reduce side-effects —Continued from page 11 showed that the regimen designed by experts in the NIMH-funded Multimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) study could be improved in order to reach their pharmacokinetic target. LIMITATION: RESEARCH NOT TESTED CLINICALLY The current limitation of the research is that it is about modelling and simulation, but it has not been yet tested clinically, noted the investigators. It is known that patients do not respond uniformly to methylphenidate, with some patients requiring a smaller total daily dose and others needing a greater total daily dose for an optimal response. “We are currently working on identifying the parameters of our model that can explain these differences between patients, so that they can be estimated and entered into the model to further individualized the treatment,” said Dr. Robaey. The computational approach to prescribing

methylphenidate can also be applied to adults with ADHD, said Dr. Robaey. “It would assist clinicians in prescribing medication, particularly for situations where timing is critical, as for adults who are shift workers and may have to work evenings or overnight,” he added. More appropriate prescriptions of a psychostimulant such as methylphenidate may also decrease side-effects, reassure parents that the medication they try with their child is the right one, at the right time, and the right dosage. It may also decrease a comorbidity such as anxiety, noted Dr. Robaey. “If a child is able to concentrate and his or her school performance improves, the child may have more confidence and find that his or her anxiety is reduced,” he said. Fahima Nekka, PhD, the study’s lead author, professor at the School of Pharmacy and the Centre de Recherches Mathematiques at the University of Montreal, and Industrial Chair in Pharmacometrics for

Clinical Use: Biphentin® is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Effectiveness for more than 4 weeks has not been systematically evaluated in placebo-controlled trials. Physicians electing to use Biphentin® for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Should not be taken by children under 6 years of age. No data is available for patients >65 years of age. Contraindications: • Anxiety, tension, agitation, thyrotoxicosis, advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension or glaucoma • Patients who are hypersensitive to methylphenidate hydrochloride or to any other ingredient in the formulation or component of the container • Motor tics or with family history or diagnosis of Tourette’s syndrome • Concomitant use of an MAO inhibitor or within a minimum of 14 days following discontinuation of an MAO inhibitor Most Serious Warning and Precaution: • Drug dependence/tolerance. Careful supervision is required during drug withdrawal Other Relevant Warnings and Precautions: • The risk of sudden cardiac death should be considered although incremental risk of adverse cardiac events has not been confirmed • Patients who are involved in strenuous exercise or activities; are using other stimulants or medications for ADHD; or have a family history of sudden cardiac death • Cardiovascular—sudden death and pre-existing structural cardiac abnormalities or other serious heart problems • Screen for cardiovascular and cerebral vascular conditions before initiating treatment and monitor for new conditions during treatment

the National Sciences and Engineering Research Council of Canada, echoed that the absence of rigorous means to evaluate dosing regimens of methylphenidate motivated this study. The web-based application that has been developed to calculate doses of prescribed medication in a Dr. Nekka given day is very robust, according to Dr. Nekka. “The objective function behind the algorithm has been defined by clinical needs,” explained Dr. Nekka. “The computation gives a unique solution [to prescribing methylphenidate].” Non-proprietary and brand names of therapies: methylphenidate short-acting (Ritalin, Novartis Pharmaceuticals Canada Inc); methylphenidate longacting (Concerta, Janssen Inc.; Biphentin, Purdue Pharma).

• Monitor blood pressure at appropriate intervals especially in patients with pre-existing conditions that may result in hypertension • Long-term suppression of growth: Carefully monitor patients requiring long-term therapy. Interrupt treatment in patients not growing or gaining weight as expected • Psychiatric effects: Not for treatment of depression; not for use in treatment or prevention of normal fatigue states; may exacerbate psychosis symptoms in patients with pre-existing psychotic disorder; screen for risk of bipolar disorder in patients with comorbid depressive symptoms; monitor patients for signs of suicide-related behaviour; monitor patients for new psychotic or manic episodes and aggressive behaviour • Neurologic effects: Discontinue if seizure frequency rises • Ophthalmologic effects • Priapism • Associated with peripheral vasculopathy, including Raynaud’s phenomenon • Not for use in pregnant women unless the potential benefit outweighs the risk to the fetus. A risk to the suckling child cannot be excluded • Patients with an element of agitation may react adversely; discontinue therapy if necessary • Patients should be cautious when driving or operating machinery • Drug interactions For more information: Please consult the product monograph at http://www.purdue.ca/files/ Biphentin-PM-EN.pdf for important information relating to adverse reactions, drug interactions, and dosing information which have not been discussed in this piece. The Product Monograph is also available by calling Purdue Pharma at 1-800-387-5349.


“Ultimately, man should not ask what the meaning of his life is, but rather must recognize that it is he who is asked. In a word, each man is questioned by life; and he can only answer to life by answering for his own life; to life he can only respond by being responsible.” —Victor Frankl, Austrian Neurologist (1905–1997)

Dr. Gillian Einstein Distant cousin of Albert Einstein shedding light on neurological and hormonal differences in cognition in women

illian Einstein, PhD, is a cognitive neuroscientist who has been working to expand knowledge of the neurological and hormonal differences in cognition in women. A distant cousin of the physicist Albert Einstein on her father’s side, Dr. Einstein is an associate professor of psychology at the University of Toronto. In that role she investigates aspects of women’s neurological health that she believes have been overlooked by other researchers. These aspects include the whole-body neurological effects of female genital circumcision, developing a ‘sensory homunculus’ map of the female human body, and the neurological and cognitive changes that arise from acute hormone changes, such as those that occur after ovary removal. She published a book, Sex and the brain: A Reader, through MIT Press, which is a compilation of papers on hormones and behaviour. The ChRONICle’S John Evans spoke with Dr. Einstein about her novel research and her passion for a field of study she says does not get enough attention.

G

What led you to take up a career in research, and then to develop a focus on the neurobiology of the female brain? Originally when I started in neuroscience I was interested in vision. I had been a major in art history as an undergraduate. I realized I wanted to understand how people saw things, as described by science, and not so much as described by art historians. I wanted to understand the mechanism, the pathway that light followed. So I started in vision, to better understand the visual system. As my career progressed, I became more and more interested in sex differences in the brain and started reading the literature on that. I started realizing that at the time it was much less understood, but it seemed that women had a much higher prevalence of Alzheimer’s disease, [and] that depression seemed more common in women than in men. I also . . . realized that women’s brains were not much studied and the female brain in animal models was rarely studied. So I felt compelled to carry out some studies myself, to build on that literature—the lit18 n October 2017

tle bit that existed. What impact has that discrepancy in attention [between sexes] had in neurological research and patient experience? I think the big impact is [that] there are whole areas we know nothing about. For example, in phantom pain, we know about the male representation of the body in the brain, and the somatosensory cortex. If a man has an arm amputated or a penis amputated, we can have hypotheses and potentially treatments for filling in the area of the brain that leads to phantom pain. but we do not know that for women. we do not understand. we know a little bit about where the clitoris and the breasts are represented [in the brain], but we do not know anything else about the rest of the body. we do not know how it might change at different reproductive stages of their lives. we do not completely understand how sexual abuse might change the representation of the body in the brain. I think these are fascinating areas that are very much in line with what we now think about the brain, which is that it is plastic. we ought to be filling in this big gap in information, because the big repercussion is that treatments are then not developed for women. For example, women with mastectomy often report phantom breast pain. I do not think anyone has thought about how there might be neural treatments or neural therapies for phantom breast. One of your large areas of research is sex differences in dementia, Alzheimer’s disease in particular. Can you expand on the importance of that area of study? I have been trying to study the effect of hormone deprivation, or estrogen deprivation, on the development of Alzheimer’s disease. we have been studying memory and attention in women who carry the bRCA mutation, and who have their ovaries removed prior to natural menopause. This group of women have twice the likelihood of

Alzheimer’s disease late in life as women who keep their ovaries. And it is titrated by how close to menopause they are, or the age they have their ovaries removed. At least that is what the current epidemiological data show. Overall, in looking into the neurobiological and cultural differences on neurobiology, what has caught your attention as something interesting or unexpected? I can think of a number of things, but with regards to the women with the bRCA mutation—this high-risk group that have had their ovaries removed—one of the things that stood out is until now there has been a complete lack of attention on other body systems. So here are the ovaries, they make 17-beta estradiol. 17-beta estradiol works on every other body system: bone, heart, immune. Until the last couple of years, nobody was looking at the heart and bone. And until now nobody has looked at cognition, except these epidemiological studies . . . I think of that as gendered, because I think the lack of understanding of the importance of the ovaries aside from just for women’s reproductive health is a gendered idea. we have some very interesting results now that we are just about to submit for publication on [transgender men], and cognition in [transgender men]. It has had repercussions for what we understand about cognition in [cisgender] women. There are some neuro-psych tasks where they say there is a male or a female bias to it. One that has a male bias is a spatial rotation task . . . we tested [transgender men] before they had hormone replacement and after and the [transgender men] before hormone replacement had the same performance on spatial rotation as [cisgender] women. This suggests, at least that as far as this cognitive task is concerned, it is not a matter of being born that way, but it is a matter of the hormones that they take activating the circuits that mediate this task. —Who’s making a difference near you? Tell The Chronicle, so we can tell our readers. Write us at health@chronicle.org


Once-daily Biphentin with MLR Bead Technology ®

®

1

Biphentin® is indicated for treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6–11, adolescents 12–18 and adults >18 years of age.

Recommended first-line ADHD treatment in children, adolescents and adults.2*

• Contraindications in patients with anxiety, tension, agitation, thyrotoxicosis, advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension or glaucoma. Motor tics or with family history or diagnosis of Tourette’s syndrome. Concomitant use of an MAO inhibitor or within a minimum of 14 days following discontinuation of an MAO inhibitor.

• Other relevant warnings and precautions regarding risk of sudden cardiac death in patients who are involved in strenuous exercise or activities or have a family history of sudden cardiac death, sudden death, screening for cardiovascular and cerebral vascular conditions, monitor blood pressure, long-term suppression of growth, psychiatric effects: not for treatment of depression; not for use in treatment or prevention of normal fatigue states; may exacerbate psychosis symptoms in patients with pre-existing psychotic disorder; screen for risk of bipolar disorder in patients with comorbid depressive symptoms; monitor patients for signs of suicide-related behaviour, monitor patients for new psychotic or manic episodes and aggressive behaviour, neurologic effects, ophthalmologic effects, priapism, associated with peripheral vasculopathy, including Raynaud’s phenomenon; not for use in pregnant women unless the potential benefit outweighs the risk to the fetus, a risk to the suckling child cannot be excluded; patients with an element of agitation; caution when driving or operating machinery.

• The most serious warning and precaution regarding drug dependence/tolerance. Careful supervision is required during drug withdrawal.

• Conditions of clinical use, adverse reactions, drug interaction and dosing instructions in the Product Monograph.

IN ADULTS: FAST ONSET —SIMILAR TO IR METHYLPHENIDATE1† IN CHILDREN AND ADOLESCENTS: EFFICACY SHOWN TO LAST 10–12 HOURS1‡ Refer to the page in the bottom-right icon for additional safety information and a web link to the Product Monograph discussing:

*Recommended first-line for uncomplicated ADHD in children, adolescents and adults by CADDRA (Canadian Attention Deficit Hyperactivity Disorder Resource Alliance).2 † Rapidly and extensively absorbed with peak blood levels obtained in 1 to 3 hours. The initial peak plasma concentration at 1.7 hours post-dose was similar to 1.8 hours for the immediate-release formulation when fasting.2 ‡ IOWA-C Rating Scale and Conners’ Parent Rating Scale performed at approximately 10 and 12 hours, respectively, post-morning dose in two separate randomized, double-blind crossover studies vs. IR methylphenidate and placebo and vs. IR methylphenidate in children and adolescents ≥6 years of age.1 CR = controlled release; IR = immediate release; MPH = methylphenidate. References: 1. Biphentin® Product Monograph, Purdue Pharma, June 10, 2016 or such later date as posted at www.purdue.ca. 2. Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA): Canadian ADHD Practice Guidelines, Third Edition, Toronto ON; CADDRA, 2011. http://www.caddra.ca/pdfs/caddraGuidelines2011.pdf. Accessed October 18, 2016. Biphentin® and MLR® are registered trademarks of Purdue Pharma. © 2017 Purdue Pharma. All rights reserved.

See additional safety information on page 17


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The Chronicle of Neurology & Psychiatry October 2017  
The Chronicle of Neurology & Psychiatry October 2017  
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