Longitudinal Imaging in a Patient With Opioid-associated Amnestic Syndrome

Abstract

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 [¹⁸F]T807 (tau) PET showed no uptake suggestive of tau deposition. This case report supports investigation into the hypothesis that OAS may follow a trajectory of reversible metabolic injury.

Beginning in 2012, a series of individuals with a history of opioid misuse were identified with a sudden-onset amnestic syndrome that is associated with bilateral hippocampal-restricted diffusion on MRI (Barash et al, 2018, 2020). Follow-up imaging of this opioid-associated amnestic syndrome (OAS), while rare, has revealed persistent hippocampal abnormalities (Barash et al, 2017; Butler et al, 2019; Small et al, 2016). Given these observations and multiple postmortem investigations demonstrating excessive tau deposition in the hippocampi and other brain regions of individuals with a history of opioid misuse (Anthony et al, 2010; Kovacs et al, 2015; Ramage et al, 2005), we hypothesized that the chronic phase of OAS might demonstrate in vivo hippocampal tau deposition as a residual marker of the acute, focal injury. Here, we describe the longitudinal imaging of a patient with a history of OAS, from presentation through 53 months later, when tau positron emission tomography (PET) was performed.

CASE REPORT

A 21-year-old woman with a history of attention-deficit hyperactivity disorder and substance use disorder, including opioids (intravenous heroin), benzodiazepines, marijuana, and infrequent cocaine, was brought to the hospital for acute memory loss (Barash et al, 2017). She was not on prescription medication at the time of presentation to the hospital, but had been on stimulant treatment for attention-deficit hyperactivity disorder in the past. On presentation, other than mild tachycardia, her vitals were unrevealing. She was alert, but she asked repetitive questions and could not recall any of 3 words at 5 minutes. Her recollection for events in the prior week was impaired, but more remote memory appeared preserved. She had difficulty spelling “world” in reverse.

ASSESSMENT AND RESULTS

A urine toxicology screen showed the presence of opiates and the absence of detectable amphetamines, barbiturates, benzodiazepines, cocaine, phencyclidine, and cannabinoids. Serum toxicology did not reveal acetaminophen, ethanol, salicylates, or tricyclics. Testing specifically for fentanyl was not performed.

An MRI of the brain demonstrated a hyperintense diffusion-weighted imaging (DWI) signal (Figure 1A) with restricted diffusion (Figure 1B) as well as a mildly prominent T2 and fluid-attenuated inversion recovery (FLAIR) signal of the entirety of both the hippocampi and the globi pallidi (Table 1, Figure 1C). A CT angiography of the head and neck was unremarkable.

FIGURE 1.

MRI of our patient’s brain on presentation. A. Bilateral hippocampal-restricted diffusion with hyperintense signal on DWI. B. Corresponding dark signal on apparent diffusion coefficient weighted MRI sequences (yellow arrows), consistent with restricted diffusion. C. FLAIR sequences showing bilateral hippocampal hyperintensity (yellow arrows); similar changes were observed in the globi pallidi (not shown). D. Magnetic resonance spectroscopy of a right hippocampal region of interest on the third day showing a pattern of mild reduction of the NAA/Cr ratio, slight elevation of the Cho/Cr ratio, and appearance of lactate/lipid peaks (yellow arrow) and Glx peaks (blue arrow), suggestive of mild-to-moderate toxic-metabolic versus ischemic change, but with differential diagnosis including excitotoxic seizure activity and carbon monoxide intoxication. ADC = apparent diffusion coefficient. Cho = choline. Cr = creatine. DWI = diffusion weighted imaging. FLAIR = fluid-attenuated inversion recovery. Glx = glutamate-glutamine. NAA = N-acetyl aspartate.

TABLE 1.

Timeline of Imaging Evaluation

Timing	Imaging Study
Presentation	MRI: Restricted diffusion and T2/FLAIR hyperintensity of the hippocampi and globi pallidi CT angiography of the head and neck: Unremarkable
3 days	MRS: Mild reduction of the N-acetyl aspartate/creatine ratio, slight elevation of the choline/creatine ratio, and appearance of lactate/lipid and glutamate/glutamine peaks
4.5 months	MRI: Resolution of diffusion restriction, minimal anterior T2 and FLAIR hyperintense signal in the right hippocampus remained
53 months	MRI: Normal-appearing hippocampi [18F]T807 (tau) PET: No uptake suggestive of tau deposition

FLAIR = fluid-attenuated inversion recovery. MRS = magnetic resonance spectroscopy. PET = positron emission tomography.

Magnetic resonance spectroscopy of a right hippocampal region of interest on the third day showed a pattern of mild reduction of the N-acetyl aspartate/creatine ratio, slight elevation of the choline/creatine ratio, and appearance of lactate/lipid and glutamate/glutamine peaks (Figure 1D). An echocardiogram revealed a normal ejection fraction and no evidence of a patent foramen ovale.

Based on a hypothesis that the event could be related to a free radical cascade with mitochondrial energy failure (King et al, 2015), the inpatient team administered an off-label antioxidant regimen including vitamins B1 (100 mg daily), B2 (100 mg daily), B6 (50 mg daily), B12 (1000 mcg daily), C (1000 mg daily), and E (400 units daily), as well as coenzyme Q10 (500 mg three times daily), beginning on the second hospital day and ultimately continuing as an outpatient. By discharge on day 8, the patient could recall 3 of 5 words at 5 minutes.

At ~4.5 months, a repeat MRI of the brain showed resolution of the restricted diffusion, but a minimal anterior T2 and FLAIR hyperintense signal in the right hippocampus remained (Figure 2A–B, arrow).

FIGURE 2.

MRI of our patient’s brain at ~4.5 months after presentation. A. Complete resolution of the previously noted bilateral hippocampal-restricted diffusion on DWI. B. Minimal right anterior T2 hyperintense signal remains (yellow arrow). DWI = diffusion weighted imaging.

Imaging at 53 months was performed under an established research protocol to investigate the pathological mechanisms in traumatic brain injury and other disorders associated with tau uptake. PET imaging with [¹⁸F]T807 (tau) and MRI were performed on the same date. As part of the protocol, before imaging that day, the patient completed the Mini-Mental State Examination (Folstein et al, 1975) and Parts A and B of the Trail-Making Test (Reitan, 1958).

On the day of the studies, the patient reported abstinence from substance use since the hospitalization but continued to note mild residual difficulty learning new information. Her Mini-Mental State Examination score was 29/30, with 1 point lost for recall. She completed Part A of the Trail-Making Test in 22 seconds (~55th percentile) and Part B in 57 seconds (~30th percentile) (Tombaugh, 2004). An MRI of her brain revealed normal-appearing hippocampi. Tau PET did not reveal uptake suggestive of tau deposition in the hippocampi or elsewhere in the brain (Figure 3).

FIGURE 3.

[¹⁸F]T807 PET performed at 53 months from presentation showing no uptake suggestive of tau deposition in the hippocampi or other regions of the brain. PET = positron emission tomography.

DISCUSSION

Tau PET imaging that is performed specifically for brain injury associated with opioid use has not been previously emphasized in the medical literature. Despite prior neuropathological evidence of excessive tau deposition in the hippocampi and other brain regions in individuals with a history of opioid use disorder, tau PET performed at 53 months post presentation in our case did not reveal uptake suggestive of tau deposition. Moreover, an MRI at 53 months post presentation demonstrated that our patient’s prior hippocampal abnormalities had resolved. Although the patient’s report of mild residual difficulty learning new information in the absence of long-term imaging findings could be related to subtle injury remaining in a pathway that is not sensitive to these imaging modalities, the role of premorbid attention-deficit hyperactivity disorder should be considered as well.

Ischemia or anoxia that is severe enough to cause restricted diffusion typically involves the cortex more globally and at least some minimal residual T2/FLAIR signal hyperintensity indicating gliosis or tissue injury. Here, the full resolution of restricted diffusion and FLAIR from the first examination, taken together with the magnetic resonance spectroscopy and tau PET findings, support a hypothesis that the damage in OAS is more likely of a potentially reversible, toxic–metabolic etiology than an ischemic or anoxic mechanism. Given the rarity of reported follow-up in cases of OAS, however, future investigations will be needed to assess that premise. Along with these observations, the lack of a known history of unconsciousness or respiratory compromise, as is frequently reported in these cases (Barash et al, 2017), further raises an open question about the exact nature of oxygen availability in the pathogenesis of OAS.

It also remains unclear what, if any, role antioxidant treatment had in influencing the course of this case. While additional studies may address this issue, prior patients who were not reported to have received similar therapy had a range of outcomes―from clinical resolution to persistent memory deficits associated with hippocampal atrophy (Barash et al, 2017, 2020; Butler et al, 2019; Small et al, 2016). These variable trajectories suggest that prognosis may be related more to the degree of injury that is sustained or to other unidentified factors as opposed to the effect of a particular intervention.

Limitations

Several limitations should be noted here and warrant further investigation. First, it is possible that [F¹⁸]T807 did not have sufficient affinity for tau in this case, but [F¹⁸]T807 has co-localized with AT8-positive tau deposits, which were identified neuropathologically in individuals with a history of opioid use disorder (Anthony et al, 2010; Kovacs et al, 2015; Ramage et al, 2005; Smith et al, 2019).

Second, the transient formation and clearance of pathologic tau in earlier phases following brain injury cannot be excluded (Tarasoff-Conway et al, 2015). Therefore, the role of tau PET in individuals in the acute-to-subacute stages of OAS, who have not shown the degree of recovery in our case, should be explored.

Third, other factors may influence tau aggregation in cases of opioid use disorder. In another study, for example, there was an increased number of hyperphosphorylated, tau-positive neuropil threads in the hippocampus of individuals with a history of opioid use disorder compared with controls―a finding that only reached statistical significance in the group that was older than 30 years of age (Anthony et al, 2010).

Last, the rarity of OAS and challenges with follow-up limited our efforts to identify additional individuals with this syndrome. Nevertheless, this case report offers proof of concept for the performance of molecular imaging studies in patient populations with rare disorders and substantial barriers to follow-up.

CONCLUSION

Despite reporting mild residual memory loss, our patient with OAS showed no signs of hippocampal damage on imaging, including tau PET, at 53 months post presentation. Future investigations are needed to assess the hypothesis that OAS and its manifestations on imaging earlier in the course represent a form of potentially reversible metabolic injury. Because a patient with OAS was selected to test an anatomically specific a priori hypothesis, pursuing a study of tau PET imaging in opioid-associated brain injury as a whole may provide additional insights into the more widely distributed tau-related neuropathological findings that have previously been reported in individuals with a history of opioid misuse.

Glossary

FLAIR

fluid attenuated inversion recovery

OAS

opioid-associated amnestic syndrome

PET

positron emission tomography