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Clinicians are reporting what is believed to be the first documented case of toxic leukoencephalopathy (TLE) caused by inhaling fentanyl.

"While heroin has been the principal opiate associated with TLE, this case highlights the importance of recognizing other opiates such as fentanyl as potentially causative," Christopher Eden, MD, a second-year resident in internal medicine at the Oregon Health & Science University (OHSU) School of Medicine, who was part of the patient's treatment team, told Medscape Medical News.

Eden and colleagues described the case in a paper online on April 29 in BMJ Case Reports.

'Under the Radar'

Fentanyl is 50-100 times more potent than morphine. The synthetic opioid can be smoked, injected subcutaneously or intravenously, swallowed, or sniffed.

Previous case reports have shown that opiates, mainly heroin, may lead to TLE. And there have been reports of TLE after oral ingestion of fentanyl patches as well as intravenous ingestion of fentanyl, but not apparently after inhaled fentanyl.

In their case report, Eden and colleagues described a previously healthy 47-year-old man who arrived by ambulance to the emergency department (ED) at OHSU after being found unresponsive in his hotel room.

Crushed pills and white residue were found on a nearby table, and TLE induced by inhaling heroin was initially suspected.

The initial urine drug screen on admission was negative for opioids. However, a urine screen for fentanyl was subsequently positive with a level of 137.3 ng/mL.

"Fentanyl is not routinely tested on all urine drug tests; thus, providers need to be suspicious of its presence and to work with their local laboratories to have it added to the standard drug testing platforms," Eden told Medscape Medical News.

Brain MRI revealed reduced diffusivity and fluid-attenuated inversion recovery hyperintensity symmetrically in the bilateral supratentorial white matter, cerebellum, and globus pallidus.

"Doctors should be aware that toxic leukoencephalopathy is a syndrome caused by a variety of toxic etiologies including fentanyl. On MRI, symmetric diffusion restriction in the bilateral cerebellar hemispheres, deep grey nuclei, hippocampi, and supratentorial white matter should raise consideration for opioid toxicity," Eden told Medscape Medical News.

Eden said it's likely that TLE due to fentanyl use is happening "under the radar," given that diagnosis is made by MRI, "which is expensive and time-consuming and probably why other cases are not being recognized."

"Often times, fentanyl cases like this presenting to the ED may be incorrectly attributed to hypoxic brain injury due to opioids causing respiratory depression and low oxygen levels. Importantly, hypoxic brain injury and toxic leukoencephalopathy are distinct pathologies, which require MRI imaging," Eden noted.

The patient made a slow recovery after 26 days in the hospital, followed by a stay in a skilled nursing facility.

Undiagnosed or Misdiagnosed

Reached for comment, Shaheen Lakhan, MD, neurologist, and researcher based in Miami, noted that TLE is "frequently underrecognized and under-detected, with many cases likely being missed. This case underscores the need to consider TLE in patients with acute encephalopathy and characteristic neuroimaging findings."

"The clinical presentation of TLE can be nonspecific, and the imaging findings may be attributed to other conditions if the possibility of toxin exposure is not considered. As a result, many cases of TLE, particularly those caused by opioid abuse or accidental exposure, may be overlooked or misinterpreted," said Lakhan, who wasn't involved in the case.

"It is crucial for clinicians to maintain a high index of suspicion for TLE, especially in cases of unexplained acute encephalopathy with characteristic neuroimaging findings, and to collaborate closely with laboratories to ensure appropriate toxicology testing is performed.
Early recognition and diagnosis are essential for initiating appropriate management and potentially improving outcomes in these patients," Lakhan told Medscape Medical News.

This research had no specific funding. Eden and Lakhan had no relevant disclosures.