A 52-year-old man developed acute amnestic syndrome after being found unconscious for over 12 hours. After roughly 24 hours, his delirium had cleared and his neurological examination was normal except for memory deficits. His Mini-Mental State Exam score was 18/30, due to disorientation, attentional deficit and delayed recall impairment. Urine drug screen was positive for fentanyl. Brain magnetic resonance imaging (MRI) revealed restricted diffusion in both hippocampi with associated T2 FLAIR hyperintensities (Figure 1). His hippocampal injuries were thought to be due to a direct toxic effect of fentanyl and from hypoxaemia secondary to opioid-related hypoventilation.^{Reference Barash, Ganetsky and Boyle1} He received supportive management, and workup for other potential aetiologies with bloodwork and electroencephalogram were unremarkable.

Figure 1: MRI brain without contrast. Brain MRI showed (A) restricted diffusion on diffusion-weighted images and (B) T2 FLAIR hyperintensities in the hippocampi bilaterally.

Over the next month, the patient developed rigidity, rest tremor and a shuffling gait. Follow-up MRI demonstrated diffuse leukoencephalopathy (Figure 2A). He was started on a trial of levodopa-carbidopa. At 5-month follow-up, his parkinsonism had improved where only his resting tremor remained. Neuropsychology testing showed minimal recognition memory, poor volition, impaired attention with preserved general knowledge and reasoning. MRI at 5-month follow-up showed significant improvement of diffuse leukoencephalopathy (Figure 2B). When last seen, he was still admitted to the hospital awaiting placement in a long-term care facility.

Figure 2: Follow-up brain MRI without contrast. (A) T2 FLAIR images showed diffuse white matter hyperintensities at 1-month follow-up. (B) T2 FLAIR images at 5-month follow-up showed significant improvement of white matter hyperintensities.

Isolated bilateral hippocampal lesions are a rare neuroimaging finding that has characteristically been associated with toxic aetiologies such as opioids, cocaine or carbon monoxide.^{Reference Barash and Kofke2} This neuroimaging finding has recently been described in a cluster of cases in the context of fentanyl overdose.^{Reference Barash, Ganetsky and Boyle1} Familiarity with this relationship is important given the ongoing opioid crisis in Canada, primarily driven by the use of fentanyl from both prescription and illegal sources.^{Reference Belzak and Halverson3} The predilection for injury to the hippocampi in opioid use is supported by reversible hypoxia/hypoglycaemia animal models demonstrating worse recovery to this brain region with opioid use.^{Reference Ammon-Treiber, Stolze, Schröder, Loh and Höllt4} Peculiarly, another reported reversible hypoxia/hypoglycaemia model comparing various opioid types demonstrated a negative effect of morphine but not fentanyl,^{Reference Ammon-Treiber, Stolze and Höllt5} which is contradicted by the clinical literature in humans showing this can occur with various opioids among other substances.^{Reference Barash, Somerville and DeMaria6} It is also possible that an interaction of various substances increases the likelihood of this complication, as has been suggested by numerous reports.^{Reference Barash, Somerville and DeMaria6–Reference Kesari, Fleet, Alenzi and Goodman8}

A unique feature of our case is the availability of follow-up imaging that demonstrated a delayed-onset diffuse leukoencephalopathy with partial improvement at 5-month follow-up imaging. We are not aware of any prior case demonstrating the progression of findings from isolated hippocampal ischaemia to diffuse leukoencephalopathy, in the context of fentanyl overdose. Prior reports demonstrate similarities in the clinical findings and neuroimaging features of delayed leukoencephalopathy in the context of substance abuse.^{Reference Kesari, Fleet, Alenzi and Goodman8–Reference Zanin, Masiero, Severino, Calderone, Da Dalt and Laverda10} Our report brings attention to this unique presentation and neuroimaging findings of fentanyl overdose associated with an acute amnestic syndrome and selective hippocampal ischaemia that progresses to a delayed-onset leukoencephalopathy.