Ocular sequelae from the illicit use of class A drugs

Aim: To highlight the changes that may take place in the visual system of the class A drug abuser. Methods: A literature review was carried out of ocular/visual sequelae of the more common class A drugs. These include stimulants (cocaine and crack cocaine), narcotics (heroin, morphine, methadone) and hallucinogenics (ecstasy, lysergic acid diethylamide, magic mushrooms, mescaline, phencyclidine). Results: Ocular sequelae affecting visual acuity, the eye and its adnexa, ocular posture and ocular motility can result from recreational use of these drug(s). Conclusions: Awareness of the consequences of illicit drug use should lead to more pertinent questioning during history-taking

Acute esotropia in the setting of heroin withdrawal

Acute onset of concomitant esotropia presenting with diplopia can be seen in the setting of heroin withdrawal. We report a case of acute esotropia in a young white male during heroin withdrawal. A sudden onset of eye deviation is usually considered an ominous sign and patients are subjected to a multitude of diagnostic tests and investigations. Acute esotropia in the setting of heroin withdrawal is typically self-limiting. This case presentation can increase the awareness among physicians for a timely diagnosis, and prevent unnecessary diagnostic testing and further consultations.Includes bibliographical reference

Ocular comorbidities in neonatal abstinence syndrome

Chronic opioid exposure in utero places the infant at risk of Neonatal Abstinence Syndrome (NAS), a clinical diagnosis of neurological, autonomic, and/or gastrointestinal withdrawal symptoms from opioid abstinence at birth. The prevalence of NAS is rising concurrently with the recent epidemic of opioid misuse among the general population in the United States, including pregnant women. Opioid misusing women typically receive methadone or buprenorphine as a treatment throughout pregnancy. However, the opioid misuse during pregnancy is associated with higher obstetric complications and a higher incidence of NAS in infants, at times requiring pharmacological intervention. The exact consequences to the human development from opioid exposure in utero remain unclear. Animal studies suggest that the fetal impacts of opioid exposure may differ from the consequences for an adult who uses opioids. Furthermore, there may be neurodevelopmental alterations in myelin physiology, dendritic length in the brain, and neurotransmitter systems when a child is exposed to opioids in utero. Clinical studies highlight associations between perinatal opioid exposure and gene mutation variants, cranial abnormalities on imaging, and a high prevalence of ocular and visual comorbidities. Ocular and visual comorbidities are of particular interest, because they may be treatable when detected early. The current literature about NAS infants and ocular and visual comorbidities is limited by the retrospective and small case-control study designs employed by the majority of the research groups. The proposed study design is a prospective study comparing groups of opioid exposed and non-opioid exposed infants born at Boston Medical Center in Boston, Massachusetts. The ocular and visual comorbidities detected in each group will be quantified, while analyzing the relationship and the relative risk attributable to the infant’s and mother’s demographics. The social context of opioid misuse may complicate the interpretation of the data; however, the design anticipates sufficient recruitment and generalizability as it is conducted at a safety net hospital. Ultimately, the goal of this proposal is to reduce the risk to the fetus with perinatal opioid exposure and build the knowledge base about ocular comorbidities in NAS infants so that optimal and comprehensive care can be provided in the future

Flash visual evoked potentials and early visual development in infants born to drug misusing mothers

Background / Aims: Maternal drug misuse in pregnancy is a significant clinical and public health problem. Consequences for the newborn infant include prematurity, intrauterine growth restriction (IUGR) and neonatal abstinence syndrome (NAS). There is increasing evidence that maternal drug misuse in pregnancy may have longer term adverse effects on infant visual and neurodevelopmental outcome. Most of the evidence regarding visual outcomes in particular derives from small uncontrolled studies with a lack of adequately powered, controlled studies to date. The visual evoked potential (VEP) can be used to assess the integrity and maturity of the infant visual pathway and both visual and neurodevelopmental abnormalities can be predicted by abnormal VEPs in infancy. Drug misuse is also associated with alteration of the VEP in adults and in animal models. Many drugs used in pregnancy can cross the placenta and enter the fetal circulation, including illicit drugs and prescribed methadone, which is the currently recommended treatment for pregnant opiate-dependent women. Hitherto few studies have investigated the effects of maternal drug misuse upon the newborn infant VEP. This study investigates in detail the effects of prescribed methadone and additional illicit drug use in pregnancy upon the infant VEP recorded at birth and at six months of age, and explores any association with NAS. The range and incidence of visual and neurodevelopmental abnormalities at six months of age is described, and how these relate to a history of NAS and the pattern of in utero drug exposure is explored. Pilot work: Pilot work demonstrated the feasibility of recording neonatal flash VEPs in a small group of infants exposed to methadone in utero, and showed that drug exposed infants had abnormal VEPs compared to unmatched controls. A further pilot study described longer term visual outcomes, which included nystagmus, reduced visual acuity and strabismus, in a selected group of infants and children exposed to methadone in utero, thus informing clinical and electrophysiological assessment at six months of age. The pilot studies were followed by a major prospective cohort study. Prospective Study: One hundred and two term infants of mothers prescribed substitute methadone during pregnancy and 50 comparison infants matched for birth weight, gestation and socio-economic group were recruited in the neonatal period. Flash and flicker VEPs were recorded from the occipital scalp of infants within three days of birth. Drug exposure was determined by maternal history, maternal and infant urine and meconium toxicology. Excess alcohol exposure in utero was determined by elevated fatty acid ethyl esters in meconium. Neonatal flash VEPs were classified as mature, typical, or immature according to waveform morphology, and amplitude and latencies measured. Flicker VEPs were analysed using a fast-Fourier transformation and responses at each flicker frequency determined. The same cohort of drug-exposed and comparison infants was invited for clinical visual evaluation at six months of age in conjunction with pattern-onset VEPs and Griffiths developmental assessment. Results: Neonatal testing: Neonatal VEPs were successfully recorded from 100 drug-exposed infants and 50 matched comparison infants at a median age of 24 hours (IQR 13-44). Gestational age, birth weight and socio-economic group did not differ between groups. Flash VEPs from methadone-exposed infants had fewer P1 components (p=0.001), and were more likely to be of immature waveform (p<0.001) compared to comparisons. VEPs from methadone-exposed infants were also smaller in overall amplitude (median 27µV vs 39.5µV, p<0.001). The relative risk of an abnormal VEP in the methadone-exposed cohort was 5.6 with an attributable risk percent of 82%. The majority of infants were exposed to illicit drugs in addition to prescribed methadone, most commonly opiates (74%) and benzodiazepines (66%). VEPs did not differ between infants exposed to opiates only, those additionally exposed to benzodiazepines and those exposed to stimulants. Regression analysis confirmed that the difference in VEP parameters between drug-exposed and comparison infants was associated with methadone exposure and not other drugs of misuse. 48% of the methadone-exposed cohort developed NAS requiring pharmacological treatment; there was no association between neonatal VEPs and subsequent onset or severity of NAS. Flicker VEP analysis demonstrated an optimal flicker frequency of 4.6 Hz in both groups, but there were few differences in the proportion of responses between groups. Six month follow-up: Retention rate to six month follow-up was 79% for the methadone-exposed cohort and 52% for comparison infants. Age at assessment (median 27 weeks, range 26-30 wk), weight and OFC did not differ between groups. The demographic characteristics of comparison infants who were followed up were compared to those of comparison infants who were not followed up. There were no significant differences in birth weight (2 sample t-test p=0.445), OFC (2 sample t-test p=0.712), gestation (Mann-Whitney test p=0.984), 5-minute Apgar score (Mann-Whitney test p=0.263) or DEPCAT score (Mann-Whitney test p=0.258) between groups. Methadone-exposed infants were more likely to have visual abnormalities than comparison infants, even after correcting for excess in utero alcohol exposure (40% vs 8%; adjusted p=0.007). Abnormalities in the methadone-exposed cohort included nystagmus (11%), strabismus (25%) and reduced visual acuity (22%). The relative risk of an abnormal visual outcome in the methadone-exposed cohort was 5.1 with an attributable risk percent of 80%. Electrophysiological abnormalities persisted at six months of age: methadone- exposed infants had smaller amplitude pattern VEPs (25 μV vs 34 μV; p=0.005) with delayed peak latencies (115ms vs 99ms; p=0.019) and fewer responses at the small check size (p=0.003), compared to controls. Methadone-exposed infants had significantly lower neurodevelopmental scores compared to comparison infants (GQ 97 for cases vs 105 for controls; p<0.001), even after correcting for maternal smoking, antidepressant treatment and excess alcohol consumption during pregnancy. Infants exposed to poly-drug misuse and treated for NAS in the newborn period performed particularly poorly on their neurodevelopmental scores. Visual impairment was an independent predictor of poor neurodevelopmental outcome and most infants scoring <85 on neurodevelopmental assessment had co-existing visual problems. Conclusions: In utero exposure to prescribed methadone and other substances of misuse is associated with an alteration in visual electrophysiology in the newborn period suggestive of immature visual maturation. These changes are independent of additional benzodiazepine or stimulant exposure, and appear to be associated with prescribed substitute methadone. At six months of age, there is a high incidence of clinical visual abnormalities in infants exposed to methadone and other drugs of misuse in utero. Persistence of electrophysiological abnormalities beyond the neonatal period suggests that opiates may have a longer term effect on the developing visual system. Drug-exposed infants also have poorer neurodevelopmental scores than matched comparison infants after correcting for maternal smoking and excess alcohol intake. The bias of loss to follow-up was minimised by the high retention rate of drug-exposed infants. Although there was a higher loss of comparison infants, there were no differences in demographic characteristics between comparison infants followed up and those not followed up, suggesting the groups were similar. In addition, published data suggest the incidence of visual abnormalities described in the comparison population to be representative of the larger population. Infants born to drug-misusing mothers are highly vulnerable and warrant early comprehensive visual assessment

A Chance to Survive: Neonatal Narcoric Addiction

As far back as man has been recording about himself and prbably a great deal further, he has been using narcotic drugs to help him relieve his tensions , anxiety, pain and fear

Long-term outcome of children with prenatal exposure to opioid maintenance therapy : Visual function, motor skills, visual-motor integration and brain morphology

Bakgrunn: Opiatavhengighets-syndrom er et verdensomspennende helseproblem og rammer også barn som utsettes for opiat-eksponering i fosterlivet. Legemiddelassistert rehabilitering (LAR) er standard behandling til pasienter med opiat-avhengighet, det gjelder også gravide. I Norge er prevalensen for barn født av mødre i LAR 0,6-0,8/1000, mens forekomsten i USA er det tidobbelte. Barn født av mødre i LAR har færre neonatale komplikasjoner og høyere fødselsvekt enn barn født av mødre med ubehandlet heroinavhengighet, men dyreforsøk og studier på menneskefostre, spebarn og førskolebarn har vist at prenatal LAR- eksponering gir økt risiko for synsvansker, utviklingsforstyrrelser og morfologiske forandringer i hjernen. Kunnskapen om barnas utvikling på lang sikt er imidlertid mangelfull. Hovedmålet med denne studien var å undersøke mulige langtidsvirkninger etter prenatal eksponering for LAR-medikamenter: kartlegge (1) synsfunksjon, (2) motoriske ferdigheter og (3) visuo-motorisk utvikling samt (4) morfologiske forhold i hjernen og om det var en sammenheng mellom eventuelle morfologiske funn og motoriske / visuo-motoriske vansker. I tillegg ønsket vi å sammenligne prestasjonene til barn som hadde vært eksponert for hhv. metadon og buprenorfin. Materiale og metode: 63 barn med prenatal LAR-eksponering i alderen 5-13 år ble rekruttert gjennom journalsystemene på Haukeland universitetssjukehus og Sørlandet sykehus, og likeledes 63 kontroll-barn uten eksponering, matchet for kjønn og alder. Data om foreskrevne / ikke-foreskrevne medikamenter og rusmidler, sigarett- og alkoholbruk i svangerskapet ble innhentet fra mødre- journalen. Vi undersøkte (1) synsskarphet, (2) øyemotorisk status, (3) refraksjon, (4) fargesyn og (5) synsfelt. Motoriske ferdigheter ble testet med Movement-ABC test, visuo-motorisk integrasjon med Beery-VMI test og nevromotoriske «soft signs» med Motorisk funksjonsnevrologisk undersøkelse (MFNU) test. 55 LAR-eksponerte barn og 59 kontroll-barn gjennomførte MR undersøkelse av hjernen, og vi estimerte totalt intrakranielt volum (ICV) og volum av basalganglier, amygdala m.m. samt mål på kortikal overflate og tykkelse med dataprogrammet FreeSurfer®. Resultater: Det var høy-signifikante forskjeller på LAR-eksponerte barn og kontroll-barn på flere områder. LAR-eksponerte barn hadde lavere gjennomsnittsverdi for synsskarphet og høyere andel manifest skjeling (30%, vs. 4.8%) enn kontrollbarna. 16% av LAR-eksponerte barn hadde nystagmus men kun ett av kontroll-barna. Metadon-eksponerte barn hadde dårligere synsfunksjon enn buprenorfin-eksponerte. Videre var forekomsten av motoriske vansker høyere hos de LAR-eksponerte, høyre andel hadde visuo-motoriske problemer og nevromotoriske «soft signs». ICV og relative volumer av basalganglier og amygdala var signifikant lavere hos LAR-eksponerte barn, og de hadde mindre kortikal overflate i venstre midtre frontale gyrus og høyre nedre parietale lobulus. Det var en lett korrelasjon mellom visuo-motorisk integrasjon og ICV. Prenatal eksponering for nikotin var en viktig konfunderende faktor, særlig for ICV og skjeling. Konklusjon / klinisk relevans: Denne studien støtter antagelsen om at prenatal opiat-eksponering hos barn av mødre i LAR kan ha en negativ innvirkning på fosterhjernen og gi økt risiko for synsproblemer og motoriske / visuo-motoriske vansker på lang sikt. Vi håper at studien vil bidra til en bedre forståelse for utviklingsvanskene mange barn av mødre i LAR kan oppleve. Basert på våre funn, støtter vi særlig behandlingsalternativet i LAR-retningslinjene for gravide om nedtrapping av LAR-medikamenter, for å sikre best mulig fosterhelse og utvikling for barnet på lang sikt.Background: Opioid use disorder (OUD) is a worldwide health problem also affecting infants born after prenatal opioid exposure. Opioid maintenance therapy (OMT) with long-acting opioids is the recommended treatment to people suffering from opioid addiction, including pregnant women. In Norway, the prevalence of childbirth to women in OMT is 0.6-0.8/1000 while the United States has a tenfold higher number. OMT-pregnancy is favorable to untreated OUD-pregnancy as regards neonatal outcome. However, preclinical research and studies on human fetuses, infants and small children have demonstrated that prenatal OMT-exposure increases the risk for visual impairments, developmental problems and altered brain morphology. Less is known about the outcome in older children. Aims: This study seeks to give knowledge about long-term effects of prenatal OMT-exposure. We aimed to explore (1) visual function, (2) motor skills and (3) visual-motor integration, and possible differences between buprenorphine- and methadone-exposed children. We also aimed to (4) examine brain morphology and possible associations between brain morphology and motor / visual-motor function. Materials and methods: 63 prenatally OMT-exposed children aged 5-13 years and 63 age and sex matched comparison children were recruited from medical registers in two Norwegian hospitals. To assess visual function we examined visual acuity, orthoptic status, refractive state, color vision and visual field. Motor skills were assessed by the Movement-ABC test and visual-motor integration by the Beery-VMI test. We used the Neuromotor assessment test (MFNU) to examine neuromotor “soft signs”. 55 of the OMT-exposed and 59 of the comparison children carried out MRI brain scans, and by means of the automated software FreeSurfer® we obtained total intracranial volume (ICV), volume of subcortical structures and estimates of cortical surface area and thickness. Results: The OMT-exposed children had poorer mean visual acuity (p<0.001), and manifest strabismus was more frequent in the OMT-group, 30%, vs. 4.8% in the control group. Nystagmus was present in 16% of the exposed children compared to one child among the un-exposed. Methadone-exposed children had poorer visual functional outcome than the buprenorphine-exposed. Also, exposed children had higher prevalence of motor impairments (p=0.001), visual-motor integration problems (p<0.001) and neuromotor “soft signs” (p<0.001). ICV and relative volumes of basal ganglia, amygdala and parts of corpus callosum were significantly smaller, and the left middle frontal gyrus and right inferior parietal lobule had smaller surface area. There was a weak correlation between visual-motor function and ICV. Prenatal nicotine exposure is an important confounder, particularly for strabismus and ICV. Conclusions: This thesis supports the assumption that prenatal OMT-exposure have long-term effects on brain morphology. Exposed children had increased risk of visual problems, motor impairments and deviant visual-motor integration. Our study may hopefully contribute to a better understanding of the lasting problems many children may experience after prenatal OMT-exposure. We propose a stronger emphasis in the Norwegian OMT guidelines that tapering OMT in residential care is the safest way to ensure normal fetal development. Residential management of OMT pregnancies may also be well suited for further research.Doktorgradsavhandlin

Children had increased risks of impaired motor and visual-motor skills after prenatal exposure to opioid maintenance therapy

Aim: Preschool children prenatally exposed to opioid maintenance therapy (OMT) have an increased risk of neurodevelopmental impairments. We aimed to investigate long-term motor and visual-motor integration outcome in children aged 5–13 Years, born to mothers in OMT. Methods: From January 2018 to June 2021, 63 children prenatally exposed to OMT and 63 comparison children matched for age and gender, were examined at two Norwegian hospitals. Motor skills were assessed by the Movement-ABC test and visualmotor integration by the Beery VMI test. A motor function neurological as- sessment test was used to examine neuromotor soft signs. Results: In the OMT-exposed group, 16% had motor impairment, 35% had motor problems and 19% had visual-motor integration problems. Forty-three percent of the exposed children had neuromotor soft signs. Strabismus had some influence on motor and visual-motor outcomes but could not explain the group differences. Conclusion: Children prenatally exposed to opioid maintenance therapy have an increased risk of long-term motor impairment and visual-motor problems. In addition, they exhibit significantly more neuromotor soft signs, which may affect general wellbeing, leisure activities and school performancepublishedVersio

Visual function in Norwegian children aged 5–13 years with prenatal exposure to opioid maintenance therapy: A case–control study

Purpose: To assess various aspects of visual function in school children prenatally exposed to opioid maintenance therapy (OMT) and to explore possible outcome differences between prenatal methadone and buprenorphine exposure. Methods: In a cross-sectional case–control study, 63 children aged 5–13 years with prenatal OMT exposure were compared with 63 age- and gender-matched, non-exposed controls regarding important visual parameters, such as visual acuity, orthoptic status, refractive state, colour vision, and visual field. Results: The OMT-exposed children had significantly poorer visual acuity, both for the best eye, the worst eye and binocularly. Two children had mild visual impairment. Manifest strabismus was more frequent in the OMT group, 30%, vs. 4.8% in the control group. The most frequent types of strabismus were accommodative esotropia and intermittent exotropia. Manifest nystagmus was present in 10 (16%) of the exposed children compared to one among the non-exposed children. The accommodative amplitude was decreased in the OMT group compared to the controls. After adjusting for polydrug exposure and SGA (small-for-gestational-age), the between-group differences in visual acuity, strabismus, and nystagmus remained. The methadone-exposed children had poorer visual acuity, increased frequency of strabismus and a higher percentage of nystagmus, hypermetropia and astigmatism compared to the buprenorphine-exposed children. Conclusions: School-age children exposed to methadone or buprenorphine in utero had a higher prevalence of strabismus and nystagmus, and a lower visual acuity and accommodation amplitude. Buprenorphine exposure was associated with more favourable results than methadone exposure on most visual outcome measures and should be the preferred substance in OMT.publishedVersio

Impaired vision in children prenatally exposed to methadone: an observational cohort study

Background/objectives: To examine prevalence of failed visual assessment at 8–10 years in children born to methadone-maintained opioid dependent (MMOD) mothers and relate this to known in utero substance exposure. Subjects/methods: Follow up of observational cohort study of methadone-exposed and comparison children matched for birthweight, gestation and postcode of residence at birth. Participants were 144 children (98 exposed, 46 comparison). Prenatal drug exposure was previously established via comprehensive maternal and neonatal toxicology. Children were invited to attend for visual assessment and casenotes were reviewed. Presence of acuity poorer than 0.2 logMAR, strabismus, nystagmus and/or impaired stereovision constituted a ‘fail’. Fail rates were compared between methadone-exposed and comparison children after adjusting for known confounding variables. Results: 33 children attended in person: data were also derived from casenote review for all children. After controlling for maternal reported tobacco use, methadone-exposed children were more likely to have a visual ‘fail’ outcome, adjusted odds ratio 2.6, 95% CI 1.1–6.2; adjusted relative risk 1.8 (95% CI 1.1–3.4). Visual ‘fail’ outcome rates did not differ between methadone-exposed children who had (n = 47) or had not (n = 51) received pharmacological treatment for neonatal abstinence/opioid withdrawal syndrome (NAS/NOWS); fail rate 62% vs 53% (95% CI of difference—11–27%). Conclusions: Children born to MMOD mothers are almost twice as likely as unexposed peers to have significant visual abnormalities at primary school age. Prenatal methadone exposure should be considered in the differential diagnosis of nystagmus. Findings support visual assessment prior to school entry for children with any history of prenatal opioid exposure. Trial registration: The study was prospectively registered on ClinicalTrials.gov (NCT03603301), https://clinicaltrials.gov/ct2/show/NCT03603301

Visual function in Norwegian children aged 5–13 years with prenatal exposure to opioid maintenance therapy: A case–control study

Purpose: To assess various aspects of visual function in school children prenatally exposed to opioid maintenance therapy (OMT) and to explore possible outcome differences between prenatal methadone and buprenorphine exposure. Methods: In a cross-sectional case–control study, 63 children aged 5–13 years with prenatal OMT exposure were compared with 63 age- and gender-matched, non-exposed controls regarding important visual parameters, such as visual acuity, orthoptic status, refractive state, colour vision, and visual field. Results: The OMT-exposed children had significantly poorer visual acuity, both for the best eye, the worst eye and binocularly. Two children had mild visual impairment. Manifest strabismus was more frequent in the OMT group, 30%, vs. 4.8% in the control group. The most frequent types of strabismus were accommodative esotropia and intermittent exotropia. Manifest nystagmus was present in 10 (16%) of the exposed children compared to one among the non-exposed children. The accommodative amplitude was decreased in the OMT group compared to the controls. After adjusting for polydrug exposure and SGA (small-for-gestational-age), the between-group differences in visual acuity, strabismus, and nystagmus remained. The methadone-exposed children had poorer visual acuity, increased frequency of strabismus and a higher percentage of nystagmus, hypermetropia and astigmatism compared to the buprenorphine-exposed children. Conclusions: School-age children exposed to methadone or buprenorphine in utero had a higher prevalence of strabismus and nystagmus, and a lower visual acuity and accommodation amplitude. Buprenorphine exposure was associated with more favourable results than methadone exposure on most visual outcome measures and should be the preferred substance in OMT.publishedVersio