February 17, 2022
Roughly five of every thousand women (0.5%) have epilepsy, a neurological disorder characterized by sudden recurrent episodes of sensory disturbance, loss of consciousness, or convulsions, associated with abnormal electrical activity in the brain. Primary treatment consists of anti-seizure medications (ASMs).
Yet, research has shown that ASMs cross the human placenta. In rodents, ASMs have been shown to lead to abnormal neuronal development, and some research has pointed to the risk of adverse birth outcomes and neurodevelopmental disorders in humans. But samples have been too small for reliable conclusions, and in most cases confounding factors are not addressed.
For a more comprehensive evaluation of risk from ASMs, an international team of researchers examined a nationwide cohort using Swedish national registers that track health outcomes for virtually the entire population.
Using the Medical Birth Register, the National Patient Register, and the Multi-Generation Register, they were able to identify 14,614 children born from 1996-to 2011 to mothers with epilepsy.
Through the prescribed Drug Register, they also examined the first-trimester use of anti-seizure medications (ASMs) by these mothers. The three most frequently used ASMs "frequent enough to yield useful data“ were valproic acid, lamotrigine, and carbamazepine.
The researchers identified ADHD in offspring in one of two ways: ICD-10 (international classification of Diseases, 10th Revision) diagnoses, or filled prescriptions of ADHD medication.
Finally, they consulted the Integrated Database for Labor Market Research and the Education Register to explore potential confounding variables. These included maternal and paternal age at birth, the highest education, cohabitation status, and country of origin. They also included maternal and paternal disposable income in the year of birth and a measure of neighborhood deprivation.
Using the medical registers, they considered parental psychiatric and behavioral problems diagnosed before pregnancy, including bipolar disorder, suicide attempt, schizophrenia diagnosis, substance use disorder, and criminal convictions. They adjusted for inpatient diagnosis of seizures in the year before pregnancy to capture and adjust for indication severity.
Other covariates explored included year of birth, birth order, child sex, maternal-reported smoking during pregnancy, and use of other psychotropic medications.
After fully adjusting for all these confounders, children of mothers who were taking valproic acid were more than 70% more likely to develop ADHD than those of mothers not taking an anti-seizure medicine during pregnancy. The sample size was 699, and the 95% confidence interval stretched from 28% to 138% more likely to develop ADHD.
By contrast, children of mothers who were taking lamotrigine were at absolutely no greater risk(Hazard Ratio = 1) of developing ADHD than those of mothers not taking an anti-seizure medicine during pregnancy.
Finally, children of mothers who were taking carbamazepine were 18% more likely to develop ADHD than those of mothers not taking an anti-seizure medicine during pregnancy, but this result was not statistically significant (the 95% confidence interval ranged from 9% less likely to 52% more likely).
The authors concluded, "The present study did not find support for a causal association between maternal use of lamotrigine in pregnancy and ASD [Autism Spectrum Disorder] and ADHD in children. We observed an elevated risk of ASD and ADHD related to maternal use of valproic acid, while associations with carbamazepine were weak and not statistically significant. Although we could not rule out all potential confounding factors, our findings add to a growing body of evidence that suggests that certain ASMs (i.e., lamotrigine) may be safer than others in pregnancy."
Kelsey K. Wiggs, Martin E. Rickert, Ayesha C. Sujan, Patrick. Quinn, Henrik Larsson, Paul Lichtenstein, A. Sara Oberg, and Brian Onofrio, "Antiseizure medication use during pregnancy and risk of ASD and ADHD in children" Neurology(2020),95:e3232-e3240, published online,https://doi.org/10.1212/WNL.0000000000010993.
What are we to make of adults who exhibit the diagnostic criteria for ADHD, but are nevertheless high-functioning and successful? A trio of British investigators has just published six case studies that explore this question. It would have been better for them to have conducted a much larger, controlled research study but, in the absence of such data in the area, these case studies are intriguing and may help guide more informative research.
The authors recruited six successful men between the ages of 30 and 65 from a National Health Service tertiary service in London. Four were in long-term relationships, with children. All had good jobs.
In open-ended taped interviews of up to an hour in length, each was asked three questions:
1. What do you think are the advantages and disadvantages of having ADHD?
2. Please describe a time when you felt that your ADHD helped you to achieve something?
3. What aspects of your ADHD would you miss if it went away?
Hyper-focus in ADHD is generally considered a deficit, inset-shifting, and task-switching. But the authors report that participants associated it with productivity. One said, “I think the energy that the ADHD brain seems to have....it’s unfocused, quite scattered, chaotic and a bit random...but give that brain something that you can tune into, and it’s your interest, then all that random stuff just goes boom... I get this incredible intense concentration and that’s great for work.”
Participants also saw advantages in divergent thinking, with one stating, “I’m an artist.... a creative type... a Bohemian.... you are most likely to be a creative person if you are a divergent thinker....and not convergent... I am very creative and that’s through and through... I’m a fine art graduate, a musician, a published poet, an entrepreneur, a performer.”
All the participants reported being seen as nonconformists. Depending on a viewpoint, that can be seen as either detrimental or advantageous.
Impulsivity is a core symptom of ADHD. Participants however related it to bravery, and more specifically adventurousness, spontaneity, and thrill-seeking. One said, “thrill-seeking is an ADHD thing... I can list in my life have done white water rafting, bungee jumping, hand-glider pilot … I have done a lot in my life and achieved a lot and experienced a lot... Furthermore, I would see a lot of that as being quite positive, and a lot of that is ADHD drive.”
Another common theme was high energy and “spirit.” One participant said, “I’ve got all this energy.... a lot of energy... whatever it's to do with... nature/nurture/spiritual stuff.”
These testimonials are useful as a check on the usual narrative of impairment. ADHD does not predestine all it afflicts to an unfulfilling life. Many, often assisted by medication, still lead exciting, successful, rewarding lives. Yet, we must be cautious in concluding that these individuals were successful because of their ADHD. It is possible, even likely, that they had other strengths such as high intelligence that compensated for their ADHD symptoms. We can not know from this report if their lives had been even more fulfilling or successful in the absence of ADHD. See, for example, my blog about highly intelligent people with ADHD: https://www.linkedin.com/pulse/20141126141502-65669938-smart-people-can-have-adhd-too/.
While the authors concede that “generalizing the findings of this study is not easy to do,” they inexplicably “also argue that the positive aspects we found are relevant to other adults with ADHD regardless of sample size, age, gender or ethnicity.” It is not possible to draw such a definitive conclusion without a much larger sample.
On a hopeful note, they conclude, “This is a study that reaches out to people with lived experience of ADHD: service users, patients, family members, carers, partners, to say that not all symptoms of ADHD are maleficent. Recovery, high functionality, and flourishing with ADHD are possible. Too often people with lived experience hear about ADHD deficits, functional impairments, and associations with substance misuse, criminality, or other disadvantages on almost every level of life (school, work, relationships). … This study affirms the positive human qualities, assets, and attributes in ADHD that can promote and sustain high functioning and flourishing.” I fully endorse the idea that those with ADHD can have wonderful lives, especially if they receive appropriate treatment, both medical and psychological.
China is the outstanding economic growth story of the early twenty-first century. According to the World Bank, China has “experienced the fastest sustained expansion by a major economy in history – and has lifted more than 800 million people out of poverty.”
That expansion has been accompanied by major investments in medical research, and medical treatment capability, especially in the major urban centers that have spearheaded the boom. Life expectancy has risen from 71 in 2000 to 77 in 2019, nearing the U.S. level of 79.
Yet when it comes to pharmaceutical treatment of ADHD, China is an outlier, as revealed by a new study exploring the data in the two main medical insurance programs for its urban population.
The Urban Employee Basic Medical Insurance(UEBMI) covers both employers and employees in public and private workplaces, while the Urban Residents Basic Medical Insurance (BMI) covers the unemployed. As of 2014, these programs cover over 97% of urban residents. The China Health Insurance Research Association (CHIRA) database is a random sampling database from the UEBMI and UBMI databases.
The study population consisted of residents of the 63 cities in the CHIRA database from 2013 through 2017. Prescription prevalence was calculated by dividing the total number of patients prescribed ADHD medications in the CH IRA database by the urban population of the included cities, which was two hundred million as of 2017.
Other studies have found the prevalence of ADHD among Chinese children and adolescents to be about 6.5%, comparable to North American and European countries. Yet, the prescription prevalence of ADHD medications was 0.036% among those aged 0–14 years in 2017 in China. In other words, only about one in every two hundred youths with ADHD were being prescribed pharmaceutical treatments.
For further context, among other economically prosperous countries in Asia, Australia, North America, and Europe, the lowest prescription prevalence of ADHD medications is 0.27% in France, which is still over seven times higher than the Chinese level.
Among Chinese urban dwellers from 15 through 64 years of age, ADHD prescription prevalence in 2017 dropped by a further order of magnitude (over tenfold) to 0.003%, and among those 65 and older, to a scant 0.001%.
The Chinese study team suggested several likely contributing factors:
Sleep disorders are one of the most commonly self-reported comorbidities of adults with ADHD, affecting 50 to 70 percent of them. A team of British researchers set out to see whether this association could be further confirmed with objective sleep measures, using cognitive function tests and electroencephalography (EEG).
Measured as theta/beta ratio, EEG slowing is a widely used indicator in ADHD research. While it occurs normally in non-ADHD adults at the conclusion of a day, during the day it signals excessive sleepiness, whether from obstructive sleep apnea or neurodegenerative and neurodevelopmental disorders. Coffee reverses EEG slowing, as do ADHD stimulant medications.
Study participants were either on stable treatment with ADHD medication (stimulant or non-stimulant medication) or on no medication. Participants had to refrain from taking any stimulant medications for at least 48 hours prior to taking the tests. Persons with IQ below 80 or with recurrent depression or undergoing a depressive episode were excluded.
The team administered a cognitive function test, The Sustained Attention to Response Task (SART). Observers rated on-task sleepiness using videos from the cognitive testing sessions. They wired participants for EEG monitoring.
Observer-rated sleepiness was found to be moderately higher in the ADHD group than in controls. Although sleep quality was slightly lower in the sleepy group than in the ADHD group, and symptom severity slightly greater in the ADHD group than the sleepy group, neither difference was statistically significant, indicating extensive overlap.
Omission errors in the SART were strongly correlated with sleepiness level, and the strength of this correlation was independent of ADHD symptom severity. EEG slowing in all regions of the brain was more than 50 percent higher in the ADHD group than in the control group and was highest in the frontal cortex.
Treating the sleepy group as a third group, EEG slowing was highest for the ADHD group, followed closely by the sleepy group, and more distantly by the neurotypical group. The gaps between the ADHD and sleepy groups on the one hand, and the neurotypical group on the other, were both large and statistically significant, whereas the gap between the ADHD and sleepy groups was not. EEG slowing was both a significant predictor of ADHD and of ADHD symptom severity.
The authors concluded, “These findings indicate that the cognitive performance deficits routinely attributed to ADHD … are largely due to on-task sleepiness and not exclusively due to ADHD symptom severity. … we would like to propose a simple working hypothesis that daytime sleepiness plays a major role in cognitive functioning of adults with ADHD. … As adults with ADHD are more severely sleep deprived compared to neurotypical control subjects and are more vulnerable to sleep deprivation, in various neurocognitive tasks they should manifest larger sleepiness-related reductions in cognitive performance. … One clear testable prediction of the working hypothesis would be that carefully controlling for sleepiness, time of day, and/or individual circadian rhythms would result in a substantial reduction in the neurocognitive deficits in replications of classic ADHD studies.”
