Histopathologic correlates of opioid-associated injury in CHANTER syndrome: first report of a post-mortem examination.

Opioid-associated brain injury may involve selective regions, including the hippocampi alone, globi pallidi, and cerebellar hemispheres. Opioid-associated amnestic syndrome, for example, is one clinical correlate of hippocampal injury as manifest by MRI abnormality. When all three regions are involved in what may be a more fulminant injury, the syndrome is termed "cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER)", initially described in 2019. Until now, to our knowledge, there have been no histopathologic correlates to the imaging findings specifically in CHANTER syndrome. Here, for the first time, we present histopathologic findings of the post-mortem brain from a patient who died from complications of CHANTER syndrome following fentanyl intoxication. These observations included microhemorrhage, reactive and necrotic vasculature, eosinophilic neuronal necrosis, axonal swelling and spheroids, and frank infarction. The findings support previous experimental models implicating both hypoxic-ischemic and cytotoxic mechanisms in the tissue damage associated with CHANTER syndrome, though further work is needed to better characterize the exact cellular pathways involved to develop targeted treatments.

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.

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.

Veterans health administration information systems as a resource for rare disorders research: Creutzfeldt-Jakob disease as a paradigm.

OBJECTIVE: To illustrate the application of Veterans Health Administration (VHA) information systems in both clinical and epidemiologic investigations of a rare disease, our specific aims were: (1) to determine the number and incidence of Creutzfeldt-Jakob disease (CJD) diagnoses in the VHA from fiscal year (FY) 1997 through FY 2010 and (2) to describe the relevant clinical features associated with those diagnoses. METHODS: The VHA Medical SAS Datasets were queried for all unique, incident CJD diagnoses between FY 1997 and 2010. Electronic health records were then reviewed to validate diagnoses using modified criteria. RESULTS: During the study period, 115 CJD diagnoses (43 definite, 27 probable, 19 possible, and 26 suspected) were identified. Annual incidence ranged between 0.8 per million (95% CI, 0.3-1.7) in FY 2009 and 3.7 per million (95% CI, 2.1-6.4) in FY 1997. Dementia was documented in 111 cases (96.5%) and myoclonus in 73 (63.5%). Discharges consistent with CJD were noted in 31 of 78 patients (39.7%) with documented electroencephalography. CONCLUSIONS: For certain rare diseases, VHA information systems can be used to assemble a substantive case series for clinical study. However, the VHA's distinctive demographic characteristics and population dynamics may limit the external validity of epidemiologic investigations.

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.

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.

Is surgery a risk factor for Creutzfeldt-Jakob disease? Outcome variation by control choice and exposure assessments.

OBJECTIVE: To determine whether methodological differences explain divergent results in case-control studies examining surgery as a risk factor for Creutzfeldt-Jakob disease (CJD). METHODS: After case-control studies were systematically identified using PubMed, we performed a homogeneity analysis and applied models to effect sizes (odds ratio [OR] with 95% confidence interval [CI]) using 2 parameters: type of control subject used and consistency of data ascertainment. The hospitals and communities were located in Europe, Japan, and Australia. Patients were CJD case subjects and age- and sex-matched control subjects in the hospital or community. Because of the natural history of the disease, CJD subjects are not considered reliable sources of information for these studies. Therefore, individuals who are considered close to the subjects and who have knowledge of their medical history, including spouses and relatives, are necessarily identified as proxy informants for the surgical record of the case subjects. RESULTS: Overall, the effect sizes lacked homogeneity (P<.0001). Three studies that used control subjects from the community revealed a significantly elevated risk of CJD for patients who underwent surgery (OR, 1.82; 95% CI, 1.41-2.35 [P<.0001]), whereas 3 investigations that used control subjects from the hospital revealed a significantly reduced risk (OR, 0.69; 95% CI, 0.52-0.90 [P=.0069]). Two studies that used proxy informants to acquire information about case subjects and control subjects (consistent ascertainment) found that the risk of CJD was significantly lower in those subjects who underwent surgery (OR, 0.65; 95% CI, 0.48-0.87 [P=.0043]). Conversely, 4 studies in which proxy informants acted only on behalf of case subjects (inconsistent data ascertainment) found a significant positive association between surgery and CJD (OR, 1.67; 95% CI, 1.32-2.12 [P<.0001]). Both models fit the data very well, leaving no remaining variance in effect sizes to explain. CONCLUSION: Variation in the type of control subjects used and in exposure assessment in case-control studies may partially explain conflicting data regarding the association between surgery and CJD. However, there was almost complete confounding of these 2 parameters, making interpretation more difficult. Planning of future investigations must carefully consider these design elements.

A systematic review of sporadic Creutzfeldt-Jakob disease clusters: do clinical, epidemiologic, and genetic features reflect infectious clustering mechanisms?

BACKGROUND: While the cause of sporadic Creutzfeldt-Jakob disease (sCJD) is unknown, case clustering could suggest infectious transmission in some instances. METHODS: Publications of sCJD clusters were systematically identified and pooled to determine if their clinical, epidemiologic, and genetic features reflected potential infectious clustering mechanisms. RESULTS: The search yielded five clusters involving 23 cases. Most notably, among 12 cases with reported residential histories, patients lived for a median of 30.0 years (25th percentile: 26.5 years; 75th percentile: 51.0 years) in their respective cluster regions. Of 19 cases that underwent genotyping for polymorphic codon 129, seventeen were methionine homozygotes (89.5%; 95% CI 67.4-98.3%); none were heterozygous. CONCLUSIONS: Prolonged residency duration and Prnp codon 129 methionine homozygosity may be consistent with underlying disease-clustering mechanisms, although larger, controlled investigations might help to exclude the possibility that these findings reflect the normal distribution of these features among relevant comparison populations.