Is there a relationship between opioid use and transient global amnesia?

BACKGROUND AND PURPOSE: Opioid-associated amnestic syndrome (OAS) and transient global amnesia (TGA) are conditions with clinical overlap. We therefore sought to determine whether opioid use might be associated with TGA. METHODS: Data from the Massachusetts Department of Public Health Syndromic Surveillance program were queried to ascertain the frequency of opioid use among emergency department (ED) encounters for TGA compared to that for all other ED visits between January 2019 and June 2023. RESULTS: A total of 13,188,630 ED visits were identified during the study period. Of 1417 visits for TGA, one visit met the exposure definition for opioid use. There were 13,187,213 visits for other indications, 57,638 of which were considered opioid-exposed. The odds ratio for the relationship between opioid use and TGA was 0.16 (95% confidence interval 0.02, 1.14). CONCLUSION: Despite the clinical overlap between OAS and TGA, surveillance data from ED visits in Massachusetts do not suggest that opioid use is a risk factor for TGA, indicating that OAS and TGA are distinct entities.

Longitudinal Imaging in a Patient With Opioid-associated Amnestic Syndrome.

Since 2012, individuals with a history of opioid misuse have infrequently been observed to develop a sudden-onset amnestic syndrome associated with bilateral hippocampal-restricted diffusion on MRI. Follow-up imaging of this opioid-associated amnestic syndrome (OAS) has revealed persistent hippocampal abnormalities. Given these observations, as well as neuropathological studies demonstrating excessive tau deposition in the hippocampi and other brain regions of individuals with opioid misuse, we describe longitudinal imaging of a patient with a history of OAS from presentation through 53 months later, when tau positron emission tomography (PET) was performed. Our patient was a 21-year-old woman with a history of attention-deficit hyperactivity disorder and substance use disorder, including opioids (intravenous heroin), who was hospitalized for acute-onset, dense anterograde amnesia. Her urine toxicology screen was positive for opiates. On presentation, her brain MRI showed restricted diffusion as well as T2 and fluid-attenuated inversion recovery (FLAIR) hyperintensity of the hippocampi and globi pallidi. On day 3, magnetic resonance spectroscopy of a right hippocampal region of interest showed a mild reduction of N-acetyl aspartate/creatine, slight elevation of choline/creatine, and the appearance of lactate/lipid and glutamate/glutamine peaks. At 4.5 months, there was resolution of restricted diffusion on MRI, although a minimal anterior T2 and FLAIR hyperintense signal in the right hippocampus persisted. However, by 53 months, when mild memory loss was reported, the hippocampi appeared normal on MRI, and [ 18 F]T807 (tau) PET showed no uptake suggestive of tau deposition. This case report supports the investigation into the hypothesis that OAS may follow a trajectory of reversible metabolic injury.

Application of an Existing Syndromic Surveillance System to Quantify Possible Cases of Opioid-associated Amnestic Syndrome in Massachusetts.

OBJECTIVES: In recent years, an opioid-associated amnestic syndrome (OAS) was identified in Massachusetts through elicited reporting by health care providers (traditional surveillance, TS). Whether OAS occurs more frequently and with a wider spatiotemporal distribution in Massachusetts remains unclear. We compared the frequency and spatiotemporal characteristics of emergency department (ED) visits for possible OAS (pOAS) using a pre-existing syndromic surveillance system (SyS) with OAS cases captured through TS. METHODS: SyS was queried for Massachusetts ED visits in 15- to 55- year-olds with a chief complaint text and discharge codes for memory loss in association with codes for opioid use (pOAS). SyS data were extracted for 2016-2020, whereas TS was conducted for 2012-2018. Cases identified by SyS and TS were stratified by demographic and spatiotemporal variables. RESULTS: TS ascertained 22 reported cases of OAS (18 males) between 2012 and 2018, ranging from 0 to 5 annually. No identified OAS patients presented between January and March or in western Massachusetts. Between 2016 and 2020, SyS identified 82 ED visits (49 males) with pOAS, ranging from 13 to 22 per year. Over the 5-year period, at least 2 ED visits for pOAS occurred during each month of the year (24 total during January, February, or March) and at least 1 visit occurred in each county except 2, with the second largest number (11) in Berkshire County (at the western border of Massachusetts), where no cases were ascertained through TS. CONCLUSIONS: Although OAS is a relatively rare condition, use of SyS in Massachusetts suggests a broader and more frequent spatiotemporal distribution than previously indicated from TS.

Fentanyl induces autism-like behaviours in mice by hypermethylation of the glutamate receptor gene Grin2b.

BACKGROUND: Environmental factors contribute to autism spectrum disorder. Fentanyl, one of the most widely used opioid analgesics in anaesthesia, can induce neurotoxicity, but its role in autism remains unknown. We determined whether fentanyl induced autism-like behaviours in young mice and the underlying mechanisms. METHODS: Young male and female mice received fentanyl at postnatal days 6, 8, and 10, and performed behavioural tests, including three-chamber social preference, elevated plus maze, grooming behaviour, and open-field test, from postnatal days 30-32. Expression of Grin2b, the gene encoding the GluN2B subunit of the N-methyl-d-aspartate receptor, was assessed in the anterior cingulate cortex of male mice using fluorescence in situ hybridisation histochemistry. We used bisulfite target sequencing to determine Grin2b hypermethylation sites after fentanyl treatment. In the specific activation and rescue experiments, we injected the mu opioid receptor agonist [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin (DAMGO) or Grin2b overexpression lentivirus into the anterior cingulate cortex of male mice. RESULTS: Fentanyl induced autism-like behaviours in both young male and female mice, and downregulated Grin2b expression (0.49-fold [0.08] vs 1.00-fold [0.09]; P<0.01) and GluN2B protein amounts (0.38-fold [0.07] vs 1.00-fold [0.12]; P<0.01) in the anterior cingulate cortex through hypermethylation of Grin2b. The mu-opioid receptor antagonist naloxone and overexpression of Grin2b in anterior cingulate cortex attenuated the fentanyl-induced effects, whereas DAMGO injection into the anterior cingulate cortex induced autism-like behaviours. CONCLUSIONS: These data suggest that fentanyl induces autism-like behaviours in young mice via an epigenetic mechanism. Further research is required to determine possible clinical relevance to autism risk.

Neurotoxicology Syndromes Associated with Drugs of Abuse.

Substance use disorders-and their associated neurologic complications-are frequently encountered by neurologists as well as emergency room physicians, internists, psychiatrists, and medical intensivists. Prominent neurologic sequelae of drug abuse, such as seizure and stroke, are common and often result in patients receiving medical attention. However, less overt neurologic manifestations, such as dysautonomia and perceptual disturbances, may be initially misattributed to primary medical or psychiatric illness, respectively. This article focuses on the epidemiology, pharmacology, and complications associated with commonly used recreational drugs, including opioids, alcohol, marijuana, cocaine, and hallucinogens.

Opioid-associated amnestic syndrome: Description of the syndrome and validation of a proposed definition.

OBJECTIVE: An opioid-associated amnestic syndrome (OAS) characterized by acute onset memory loss and bilateral hippocampal signal abnormalities on brain imaging in the setting of a history of opioid use, most notably fentanyl, has been reported. To date, however, there is no case definition to assist neurologists and other clinicians in identifying this syndrome. A multi-disciplinary collaboration of physicians, including neurologists, propose diagnostic criteria for OAS using cases that have been published in the medical literature or presented at conferences. METHODS: Cases were classified as confirmed, probable, or possible based on brain imaging findings and history or analytical testing supporting opioid use. Published articles and presentations were identified by discussion with public health authorities and a systematic search of PubMed. Included were articles, abstracts or posters through November 2019 that presented case reports or case series of a new-onset amnestic syndrome associated with bilateral hippocampal injury on imaging and/or prior opioid or other substance use. The percentages of cases that would meet confirmed, probable, or possible criteria were calculated. RESULTS: Twenty-three publications from all sources met criteria for inclusion, accounting for 40 unique cases. Based on the case definition of OAS, 50% (20/40) were confirmed, 25% (10/40) were probable and 25% (10/40) were possible. CONCLUSION: The development of a validated, formal case definition for OAS can assist neurologists and other clinicians in evaluating patients with amnesia and a history of opioid use.

Connecting the dots: an association between opioids and acute hippocampal injury.

Acute hippocampal injury represents a relatively rare cause of amnesia. Interestingly however, between 2012 and 2017, 18 patients were reported at hospitals in Massachusetts with sudden-onset amnesia in the setting of complete diffusion-weighted hyperintensity of both hippocampi on magnetic resonance imaging. Notably, 17 of the 18 patients tested positive for opioids or had a recorded history of opioid use. This observation suggests an association between opioids and acute hippocampal injury. With particular attention to the Massachusetts cluster and data on fentanyl and its congeners, the epidemiological and pathophysiological evidence that supports this hypothesis is presented, as are potential underlying mechanisms.

Cluster of an Unusual Amnestic Syndrome - Massachusetts, 2012-2016.

In November 2015, a neurologist in the Boston, Massachusetts, area reported four cases of an uncommon amnestic syndrome involving acute and complete ischemia of both hippocampi, as identified by magnetic resonance imaging (MRI), to the Massachusetts Department of Public Health (MDPH) (1). A subsequent e-mail alert, generated by the Massachusetts Board of Registration in Medicine and sent to relevant medical specialists (including neurologists, neuroradiologists, and emergency physicians), resulted in the identification of 10 additional cases that had occurred during 2012-2016. All 14 patients (mean and median age = 35 years) had been evaluated at hospitals in eastern Massachusetts. Thirteen of the 14 patients underwent routine clinical toxicology screening at the time of initial evaluation; eight tested positive for opioids, two for cocaine, and two for benzodiazepines. Apart from sporadic cases (2-6), this combination of clinical and imaging findings has been reported rarely. The apparent temporospatial clustering, relatively young age at onset (19-52 years), and associated substance use among these patients should stimulate further case identification to determine whether these observations represent an emerging syndrome related to substance use or other causes (e.g., a toxic exposure).

Complete, bilateral hippocampal ischemia: a case series.

Acute and complete ischemia of the hippocampi represents a rare cause of amnesia. This paper describes the features of four such cases presenting to a single tertiary care center over a 3-year period. Interestingly, in three instances, toxicology screening was positive for opioids at the time of presentation, while in the fourth, there was a known, reportedly remote, history of heroin use. Taken together with the known literature on the topic, complete hippocampal ischemia appears at least highly suggestive of a toxic exposure. Further case finding is necessary to better understand the etiology, nature, and prevalence of this unusual clinico-radiologic entity.

Building community capacity: sustaining the effects of multiple, two-year community-based participatory research projects.

BACKGROUND: The time-limited nature of health and public health research fellowships poses a challenge to trainees' and community partners' efforts to sustain effective, collaborative, community-based participatory research (CBPR) relationships. OBJECTIVES: This paper presents CBPR case studies of partnerships between health services research trainees and community organization leaders in a medium-sized city to describe how participation in the partnership altered community partners' understanding and willingness to conduct research and to engage with research-derived data. METHODS: Trainees and faculty used participatory methods with community leaders to identify research questions, and conduct and disseminate research. Throughout the process, trainees and faculty included research capacity building of community partners as a targeted outcome. Community partners were asked to reflect retrospectively on community research capacity building in the context of CBPR projects. Reflections were discussed and categorized by the authorship team, who grouped observations into topics that may serve as a foundation for development of future prospective analyses. RESULTS: Important ideas shared include that trainee participation in CBPR may have an enduring impact on the community by increasing the capacity of community partners and agencies to engage in research beyond that which they are conducting with the current trainee. CONCLUSION: We posit that CBPR with research trainees may have an additive effect on community research capacity when it is conducted in collaboration with community leaders and focuses on a single region. More research is needed to characterize this potential outcome.

Accuracy of administrative diagnostic data for pathologically confirmed cases of Creutzfeldt-Jakob disease in Massachusetts, 2000-2008.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a transmissible disorder that is monitored by public health authorities at the state and national levels in the United States. Little is known about the current accuracy and concurrence of CJD diagnoses across national and state sources of surveillance data. METHODS: Using multiple sources, including the National Prion Disease Pathology Surveillance Center (NPDPSC) registry, we sought to identify all deceased Massachusetts patients with pathologically diagnosed CJD between 2000 and 2008. Pathologically verified CJD cases were then matched to their respective records in the Massachusetts hospital discharge and death certificate datasets. Using these data, we also aimed to estimate the sensitivity and specificity of death certificate diagnoses. RESULTS: Death certificate and hospital discharge dataset diagnoses of CJD combined accounted for 80% (35 of 44) of pathologically confirmed cases. The estimated sensitivity and specificity for death certificate diagnoses alone were 71% (27 of 38) and 75% (9 of 12), respectively. CONCLUSIONS: Death certificate diagnoses were less sensitive for pathologically confirmed CJD than reported previously. Increasing reliance on autopsy over biopsy and an expanding spectrum of health care delivery may be responsible for this discrepancy. The findings reported here underscore the value of using multiple mechanisms in national CJD surveillance.