October 2, 2021
Strabismus is a condition in which the eyes do not properly align with each other. It affects 1 to 5 percent of children worldwide. Exotropia, and outward deviation, are more common in Asian populations. Isotropic, an inward deviation, predominates in European and North American populations.
Besides deviated gaze, strabismus can lead to a lack of depth perception or to lazy eye (amblyopia), in which the brain favors inputs from one eye over the other). It can also impair learning performance and lead to social rejection and low self-esteem.
Two nationwide population studies published this year – one in South Korea, the other in Taiwan – explored the relationship between strabismus and ADHD. Both countries have mandatory single-payer health insurance systems. That makes it easy to conduct nationwide population studies, because virtually every resident is covered, and records are maintained consistently.
Using data from the National Health Claims Database, a Korean research team obtained a nationwide cohort of 327,076 strabismus patients who were 1 to19 year old between 2011 and 2017. They matched these by age and sex with an equal number of randomly selected controls without strabismus.
Among those with strabismus, ADHD was detected in 3.4%, whereas among those without strabismus, ADHD was detected in 2.75%.
After adjusting for continuous age, preterm birth, cerebral palsy, and mental retardation, youths with strabismus were found to be 14% more likely to be diagnosed with ADHD. This outcome was highly statistically significant (p < .0001).
There was a much stronger association with some other neurological disorders, however. Motor disorders were 3.3 times more likely among strabismus patients than controls. Language disorders were 74% more likely, learning disorders 41% more likely, and autism 36% more likely.
On the other hand, there was no significant association between the schizophrenia spectrum and other psychotic disorders, bipolar disorder, depression, or anxiety.
Like South Korea, Taiwan has a mandatory single-payer health insurance system. Almost all (99%) of the island’s more than 23 million inhabitants are tracked in the Taiwan National Health Insurance Research Database (NHIRD). A subset of this database, the Longitudinal Health Insurance Database, randomly selects a million persons from the larger database.
A local study team used the Longitudinal Health Insurance Database to identify every person 18 and under with exotropia or esotropia between 2000 and 2010. The team excluded anyone with a previous diagnosis of ADHD. For each case of exotropia or esotropia, they matched four strabismus-free controls by age and sex.
The case group totaled 2,049 youths, 404 with esotropia, and the other 1,645 with exotropia. There were 8,196 controls, for a combined total sample size of 10,245.
During the decade under observation, ADHD was diagnosed in 29 patients with esotropia, 43 patients with exotropia, and 173 patients in the control group. After further adjustment for known confounders – autism, delayed development, intellectual disability, lower respiratory tract infection, paralysis, and premature birth – strabismus patients were 64% more likely to be diagnosed with ADHD than were controls. The subset of patients with exotropia were44% more likely to be diagnosed with ADHD, and the subset with esotropia was more than twice as likely. The outcomes were highly statistically significant (p< .0001) for strabismus and for esotropia and statistically significant for exotropia (p < .01).
By way of comparison, in the Korean study which found an overall 14% increased risk of ADHD in strabismus patients, esotropia increased the risk by 20% and exotropia by 17%.[1]All outcomes were highly statistically significant (p < .0001).
Both nationwide population cohorts thus revealed highly statistically significant associations between strabismus and ADHD, and between both esotropia and exotropia on the one hand, and ADHD on the other.
Nevertheless, the magnitude of the associations with ADHD was far greater in Taiwan than in South Korea – more than four times the observed risk from strabismus overall, well over twice the risk from exotropia, and over five times the risk from esotropia. Also, whereas the Korean study indicated only a marginally higher risk of ADHD from esotropia than from exotropia, the Taiwanese study found the risk of ADHD from esotropia to be well over double the risk from exotropia. Differences in the adjustment of confounders may explain some differences.
The Taiwanese team concluded, “Our study found a higher cumulative incidence of ADHD in patients with strabismus in a large nationwide database with an average of 6.5 ± 2.9 years of follow-up. The relative risk of ADHD was higher in children with esotropia than in those with exotropia and without strabismus. Further neuroimaging or field survey studies are required to understand the underlying pathomechanisms.â€
[1] There are other subsets of strabismus, which explains why both the esotropia and exotropia risk could be marginally higher than the overall strabismus risk.
Parkinson’s disease is a chronic, progressive neurological disease, characterized by the drastic reduction of dopamine transporters and the dopaminergic neurons upon which they are expressed. The resulting symptoms include bradykinesia (slowness of initiation of voluntary movements), tremors, rigidity, and postural instability.
Taiwan’s National Health Service covers about 99 percent of its 24 million inhabitants, and maintains complete records in its National Health Insurance Research Database. The Longitudinal Health Insurance Database2000 (LHID 2000) is a nationally representative subset of the latter.
Using the LHID 2000, a Taiwanese research team identified10,726 patients with Parkinson’s disease. It paired them with an identical number of randomly selected non-Parkinson’s controls, matched by age, gender, and index date (first date of diagnosis of Parkinson’s disease).
The team then looked retroactively through the database to determine which of the 21,452 individuals had previously been diagnosed with ADHD. Fourteen of the 10,726 Parkinson’s patients had been diagnosed with ADHD, versus five of the 10,726 in the control group.
Parkinson’s patients were thus 2.8 times as likely to have had a previous diagnosis of ADHD as the controls. When adjusted for age, gender, and Carlson Comorbidity Index scores, they were 3.6 times as likely to have had a previous ADHD diagnosis.
The authors cautioned that this association between prior ADHD diagnosis and subsequent Parkinson’s diagnosis is not causal.
Only one in 766 of Parkinson’s patients (a seventh of one percent) had previously been diagnosed with ADHD. So even if there were any causal relationship, it would be extremely weak.
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.”
A growing body of studies suggests a link between inflammation and autoimmune diseases on the one hand and ADHD on the other. It has been hypothesized that excessive release of cytokines (small signaling proteins that regulate immune response and inflammation and repair) and keratinocytes (skin cells) under allergic conditions may cause structural and functional changes to the nervous system and brain, which can contribute to psychiatric disorders, including ADHD.
Noting that previous studies have focused primarily on associations between ADHD and respiratory allergies(asthma) and skin allergies, a joint Chinese and American study team set out to see what, if any, association there might be with food allergies.
To this end, they turned to the national health Interview Survey (NHIS), conducted annually by the National Center for Health Statistics at the Centers for Disease Control and Prevention. This survey relies on a very large, nationally representative sample of the U.S. population.
The study encompassed 192,573 youths aged 4 through 17 years old. Of these, 15,376 had an ADHD diagnosis, 8,603 had food allergies, 24,218 had respiratory allergies, and 18,703 had skin allergies.
After adjusting for age, sex, race/ethnicity, education level, family income to poverty ratio, and geographic region, youths with food allergies were found to be over 70% more likely to be diagnosed with ADHD than those without food allergies. After further mutual adjustment for other allergic conditions, they were still well over 40% more likely to be diagnosed with ADHD than their non-allergic peers.
How did that compare with respiratory and skin allergies? In the same study population, making identical adjustments for potential confounders, youths with respiratory allergies were 50% more likely to be diagnosed with ADHD than those without such allergies. Those with skin allergies were 65% more likely to be diagnosed with ADHD. After further mutual adjustment for other allergic conditions, those with respiratory allergies were still over a third more likely to be diagnosed with ADHD, and those with skin allergies were 50% more likely to be diagnosed with ADHD.
The authors concluded, “The current study found a significant and positive association between common allergic conditions, including food allergy, respiratory allergy, skin allergy, and ADHD in children. Although the detailed mechanisms linking food allergy and other allergic conditions to ADHD remain to be understood, physicians should be aware of the increased risk of ADHD as a comorbidity of children with allergic conditions.â€
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