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. Author manuscript; available in PMC: 2022 Mar 2.
Published in final edited form as: Drug Alcohol Depend. 2021 Jun 24;226:108838. doi: 10.1016/j.drugalcdep.2021.108838

Table 1.

Study characteristics.

First author (Pub. year)/ Country Methods Overall sample (Sample with opioids & OD) Diagnosis (Symptoms) Measure (s) impairment Drugs confirmed by toxicology (Num. of subjects) Outcomes (Time frame) Key findings/Summary
Achamallah et al. (2019)/ USA Case series 3 (3) Acute leukoencephalopathy (seizures, tremors, dysautonomia, rigidity, hyperthermia, tachycardia, fever, hypertension) Brain MRI, CT scan Opioids (3)
Amphetamine (1)
Benzodiazepines (1)
Cannabis (1)
Cocaine (1)		 Persistent impairments (Month 2-Year 5)

  • 21-year-old male was non-responsive following an opioid overdose; brain MRI revealed abnormalities in the corpus callosum; patient awoke on day 7 and transferred to long-term care; cognition and functioning improved by year 5; however, motor deficits persisted

  • 34-year-old male was found unresponsive after overdose involving opioids and amphetamines

  • 20-year-old male was found unresponsive; toxicology was positive for opioids, benzodiazepines, cocaine, and cannabis; on day 34, patient was transferred to long-term care facility and at month 8, he continued to have significant cognitive impairments, as well as motor dysfunction

  • All cases reported attributed to heroin inhalation
Adrish et al. (2014)/ USA Case report 1 (1) Renal failure, rhabdomyolysis, gluteal compartment syndrome (lower extremity weakness) CT scan Opioids (1) No brain injury

  • 42-year-old male found unconscious after injecting heroin; mental status improved within 36 h during hospitalization

  • Head CT scan was normal & discharged after ~one week in hospital to short-term rehabilitation for lower extremity weakness
Alquist et al. (2012)/ USA Case report 1 (1) Leukoencephalopathy (N/A) Brain autopsy Oxymorphone (1)
Cocaine (1)
Benzodiazepines (1)
Cannabis (1)		 Death (Day 5)

  • 27-year-old male was found unconscious; patient had Glasgow Coma Score of 3 T and was admitted to the ICU, after no improvement by day 5 the family withdrew life support and the patient died

  • Postmortem brain autopsy revealed diffuse cerebral edema
Alturkustani et al. (2017)/ England Retrospective cohort 5 (5) Leukoencephalopathy (N/A) Brain autopsy Opiates (4)
Cocaine (3)
Cannabis (1)
Benzodiazepines (1)		 N/A

  • Cases defined as autopsy reports from 2002 to 2013 that documented white matter changes due to drug use

  • White matter changes were multifocal and widespread

  • Evidence of bilateral globus pallidus necrosis suggests that cardiorespiratory arrest did not occur at the same time as white matter changes

  • Concluded that drug-induced hypoxic-ischemic injury caused leukoencephalopathy
Andersen and Skullerud (1999)/ Norway Retrospective cohort 100 (92) Brain abnormalities (N/A) Brain autopsy Unavailable N/A

  • Sample included deaths among IV heroin users from 1995 to 1996

  • 92 % had heroin listed as a cause of death or known heroin use prior to death (7 deaths did not result from overdose)

  • Brain abnormalities were found in 38 of 100 cases: 25 had lesions of hypoxic origin, 6 had bilateral hippocampal sclerosis & 9 had pallidal lesions

  • Authors concluded that 5–10% of IV heroin users may have pallidal lesions
Arciniegas et al. (2004)/ USA Case report 1 (1) Delayed encephalopathy (memory impairments, speed processing, and executive functioning; incontinence, ideational dyspraxia, agraphesthesia) Brain MRI, NP Unavailable Improved (Month 5)

  • 24-year-old male was comatose ~18 h after an overdose; had history of stimulant and alcohol misuse, as well as OUD

  • MRI on day 2 confirmed hypoxic/ischemic injury with increased signal intensity in anterior periventricular areas and posterior periventricular white matter

  • Week 2 patient discharged from hospital and 9 days later he experienced gradual impairments in cognition

  • Patient readmitted to the hospital and 2nd MRI 1 week later revealed new lesions in frontal white matter

  • 5 weeks after hospital readmission, patient was transferred to acute neurorehabilitation unit; patient was severely cognitively impaired and incontinent

  • Cognitive testing 4 weeks later revealed impairments in executive functioning and attention

  • Patient’s arylsulphastase A was within normal range

  • Improvements occurred after administration of amantadine HC1 hydrochloride
Barash and Kofke (2018)/ USA Case series 22 (21) Sudden onset of amnesia (memory impairment,
inattention, impaired executive functioning, problems with orientation)		 Brain MRI, NP Opioids (9)
Cocaine (5)
Cannabis (2)
Cannabinoids (2)
Benzodiazepine (3)
Amphetamines (3)
Buprenorphine (1)
Barbiturates (1)
Fentanyl (4)
Norfentanyl (1)		 Persistent impairments (4) (Week 8-Month 22)

  • Synthesis of several case reports of sudden onset of amnesia following drug use that occurred 2012–2017

  • Massachusetts cluster included 18 patients, 17 either had drug tested positive for opioids or patients had a history of opioid use (Small et al., 2016; Barash et al., 2017)

  • 1 case in France resulted from heroin inhalation (Benoilid et al., 2013) and 2 cases in West Virginia had confirmed fentanyl use (Duru et al., 2018) and cocaine use (Barash et al., 2017)

  • MRIs revealed hyperintense signal on both hippocampi

  • Patients had impairments in orientation and attention

  • Authors could not rule out an unknown contaminant in heroin/fentanyl as potential cause of amnesia

  • Follow-up not available for 10 cases

  • Authors conclude, based on epidemiological evidence of increased involvement of fentanyl in overdoses and animal studies of fentanyl, that there is association between fentanyl and hippocampal injury
Barnett et al. (2001)/ Australia Case report 1 (1) Delayed post-anoxic encephalopathy (rhabdomyolysis, incontinence, mutism, immobility) Brain MRI, CT scan, NP Unavailable Partial recovery (Month 9)

  • 45-year-old male sought inpatient drug treatment 8 days after IV heroin overdose that had caused a prolonged period of unconsciousness

  • At day 12, patient had impairments in cognitive functioning and left spatial hemineglect, brain CT was normal and MRI revealed signal change in the bilateral cerebral white matter

  • Testing ruled out Hepatitis and HIV

  • At 3 weeks after admission, patient was incontinent, mute, and immobile; subsequently patient was transferred to a nursing home

  • At 3 months, neuropsychological testing confirmed severe cognitive impairment

  • At 6 months, patient had significant improvements and was discharged from the nursing home

  • At 9 months, neuropsychological testing and MRI suggested near complete recovery of cognitive functioning, although loss of cerebral volume suggests some permanent damage
Beeskow et al. (2018)/ German Case report 1 (1) Delayed leukoencephalopathy (odd behavior, agitation, apathy, myoclonus, mutism) Brain MRI Unavailable Partial recovery (Month 9)

  • 51-year-old woman was comatose and unresponsive to opioid antagonist (naloxone not specified); toxicology not performed and suspected opioid-related overdose

  • CT scan revealed bilateral hyperintensities of the globus pallidus, MRI confirmed lesions

  • 3 weeks after hospitalization, patient displayed odd behavior, apathy and mutism

  • MRI at 5 weeks showed change and MRI at 9 months showed marked regression of leukoencephalopathy
Bileviciute-Ljungar et al. (2014)/ Sweden Case report 1 (1) Delayed leukoencephalopathy (cognitive impairment, gait impairment, spasticity, mania, aggressive, disorientation, incontinence) Brain MRI, CT scan, NP Methadone (1)
Benzodiazepines (1)		 Partial recovery (Month 7)

  • 34-year-old male overdosed on methadone

  • Patient was in the ICU for 8 days; Montreal Cognitive Assessment (MoCA) score on Day 12 was 19/30; MRI on day 23 revealed white matter changes

  • Day 31 patient further deteriorated; cognitive testing confirmed impairment (2 SD below mean) in memory (working and long-term), attention, and visuospatial

  • Day 37 MoCA score 17/30

  • Patient was treated with baclofen and improved; patient continued with outpatient rehabilitation therapy for 3 months
Butler et al. (2019)/ USA Case report 1 (1) Acute-onset anterograde amnesia (tachycardia, disorientation, memory impairment) Brain MRI, CT scan, NP None Persistent impairments (Month 4)

  • 21-year-old male presented with acute-onset anterograde amnesia after self-reported IV fentanyl use

  • Awoke hours after use and brought to ED 36 h after suspected overdose

  • MRI revealed restricted diffusion of the hippocampi

  • Comparison of pre-MRI imaging from 6 months before his overdose and after his overdose revealed 10 % volume loss

  • Neuropsychological testing 4 months later confirmed memory impairments (declarative, episodic, semantic)
Carroll et al. (2012)/ Switzerland Case report 1 (1) Delayed leukoencephalopathy (inappropriate behavior, apathy, incontinence, gait impairment, impaired executive functioning) Brain MRI, CT scan, NP Unavailable Recovered (Month 6)

  • 43-year-old opioid-naïve female experienced an overdose involving methadone and alprazolam (medication packaging found near her)

  • 26 days later patient had inappropriate and apathetic behavior

  • MRI on day 32 revealed increased signaling in the white matter

  • Day 46 patient was admitted to the hospital with impaired executive functioning, memory, speech and motor programming; patient also had incontinence and gait apraxia

  • Testing ruled out HIV, syphilis, Lyme disease, and hepatitis

  • Day 46 MRI revealed white matter changes in the corpus callosum, globus pallidus, and putamen nuclei

  • At 6 months, neuropsychological testing results were normal
Cerase et al. (2011)/ Italy Case report 1 (1) Leukoencephalopathy (comatose, severe physical & cognitive impairment) Brain MRI, CT scan Methadone (1) Recovered (Month 3)

  • 49-year-old male with intentional overdose involving methadone, alcohol & benzodiazepines; known 26 year history of OUD

  • MRI revealed bilateral signal intensities in the cerebral hemispheres

  • Intubated & required mechanical ventilation within 12 h of hospitalization

  • Persistent cognitive deficits (unspecified) noted 1 month after overdose

  • Month 3 follow-up MRI and clinical assessment concluded recovery; authors note that full recovery is rare after a hypoxic-ischemic brain injury
Chang et al. (2009)/ Taiwan Case report 1 (1) Delayed leukoencephalopathy (comatose, delirium, bradykinesia, rigidity, incontinence, mutism, memory impairment) Brain MRI, CT scan, NP Unavailable Partial recovery (Month 5)

  • 42-year-old male, being treated with methadone for an OUD, was found unconscious; was intubated and ventilated in the ICU and transferred to inpatient bed on day 6; he was discharged after 3 weeks of hospitalization

  • Patient developed bradykinesia, rigidity, incontinence & mutism within 3 weeks of hospital discharge; readmitted to the hospital week 7

  • Day 47 MRI revealed signal intensity in white matter & small lesions in bilateral corona radiata; patient required nasogastric feeding

  • Month 3 patient seen in neurology clinic; Cognitive Abilities Screening Instrument score was 67; Mini-Mental State Examination score was 18

  • Month 5 Mini-Mental State Examination score 22; MRI revealed improvement in white matter noting mild cortical atrophy
Cheng et al. (2019)/ Taiwan Case series 2 (2) Delayed leukoencephalopathy (mutism, bradykinesia, bradyphrenia, odd behavior, incontinence, confusion) Brain MRI, CT scan Heroin (2) 1 partial recovery (Month 1), 1 partial recovery (Month 2),

  • Report of 2 new cases and identified 48 cases based on literature search; literature search results were reviewed and reports meeting criteria of this systematic review were included separately

  • 33-year-old male presented to ED with altered mental state, overdose was unconfirmed, patient diagnosed with acute heroin intoxication; hospitalized for 1 week and 6 weeks after hospital discharge patient experienced mutism, bradykinesia, odd behavior and incontinence; baseline CT scan was normal whereas repeated CT scan at 7 weeks showed white matter hypodensities; MRI at week 8 confirmed abnormalities in the periventricular and subcortical regions; improvements demonstrated after one month of antioxidative combined therapy

  • 32-year-old male presented to ED with heroin overdose, CT scan revealed diffuse hypodensities in white matter; 1 month later patient experienced incontinence, mutism, bradykinesia weakness; repeated CT scan revealed hypodensities in the bilateral hemispheres consistent with DPHL; short-term memory remained impaired at 2 months
Chute and Smialek (2002)/ USA Case series
Case report		 10 (5)
1 (1)		 Subarachnoid hemorrhage, encephalopathy, cerebral edema, cardiorespiratory arrest (comatose) CT scan, brain autopsy Opiates (5), Cocaine (1), Alcohol (1)
Unavailable		 Death (Day 1–6)

  • Retrospective review of 10 postmortem cases of pseudo-subarachnoid hemorrhage on CT scans in Maryland from 1997 to 2000; 2 cases died due to narcotic intoxication & in 2 cases opiate use contributed to cause of death

  • 42-year-old female found unresponsive; UDS positive for opiates & cocaine; CT scan revealed subarachnoid hemorrhage & patient died within 8 h of hospitalization; brain autopsy revealed encephalopathy, severe cerebral edema

  • 40-year-old female was found unconscious; CT scan revealed bilateral basal ganglia infracts; toxicology was positive for opiates and alcohol; patient died 36 h after admission; brain autopsy noted changes in the cerebellum

  • 44-year-old female became unconscious after snorting heroin; CT revealed brain edema cause by an anoxic brain injury; hyperdensities noted; patient died within 12 h; brain autopsy revealed subarachnoid hemorrhage

  • 45-year-old female had cardio-respiratory arrest and toxicology positive for opiates; CT scan revealed diffuse cerebral infarction; patient died within 60 h; brain autopsy confirmed global hypoxic-ischemic injury

  • 45-year-old male became comatose after being arrested for driving while intoxicated; toxicology positive for opiates; patient died on day 6; brain autopsy confirmed hemorrhagic necrosis
Cohen and Hack (2019)/ USA Brain abnormalities (unresponsive, rigidity) CT scan & brain MRI Recovery (Day 5)

  • 54-year-old male was unresponsive; MRI 15 h after admission revealed lesions in the bilateral globus pallidus and an edema; patient self-disclosed heroin use

  • Authors noted resolution of symptoms on day 5
Corliss et al. (2013)/ USA Case report 1 (1) Brain abnormalities, rhabdomyolysis (N/A) Brain autopsy Benzodiazepines (1)
Cannabinoids (1)
Methadone (1)		 Death (24 h)

  • 23-year-old male overdosed on methadone and alprazolam (after period of incarceration) which resulted in acute necrosis of the bilateral globus pallidi and systemic rhabdomyolysis

  • Airlifted to tertiary care facility; poor prognosis resulted in removal of life support and death within 24 h

  • Heroin use may cause remote pallidal injury, but authors conclude in this case that the acuity of the injury suggests that it resulted from an overdose
Corre et al. (2013)/France Case report 1 (1) Brain abnormalities (comatose) CT Scan & brain MRI Methadone (1), Cannabis (1), Alcohol (1), Benzodiazepines (1) Recovered
(Unknown)

  • 29-year-old male was found comatose after using 60 milligrams of methadone (as reported by a witness)

  • Toxicology was negative for cocaine, opiates and amphetamines

  • CT scan revealed hypodense signal in right cerebellar hemisphere & MRI revealed hyperdensitites in the basal ganglia

  • Patient had persistent renal failure and kinetic cerebellar syndrome, but authors reported his status as recovered
Darke et al. (2000)/ Australia Case-control 60 (30) N/A NP Unavailable Unknown

  • 30 methadone patients (cases) were matched (age, gender, and education) with 30 non-heroin using controls

  • Premorbid abilities were the same for controls and cases

  • 73 % of cases had experienced a non-fatal overdose, 63 % had a co-occurring alcohol use disorder (AUD) and 67 % had a history of head injury

  • Overall worse cognitive performance was found in cases versus controls

  • Lifetime AUD and number of previous overdoses was associated with worse cognitive performance in cases
Dassanayake et al. (2012)/ Australia Case-control 175 (25) N/A NP Unavailable Unknown

  • Study of patients who presented at the hospital with intentional overdose; cases (n = 107) consisted of CNS-D-related overdoses (25 involved opioids) and controls (n = 68) had overdoses involved SSRIs or SNRIs

  • Cases demonstrated impairment on all measures, but not reported separately for opioids

  • Findings suggest that post-CNS-D overdose results in cognitive impairment that may affect functioning post-hospital discharge

  • Outcomes are reported in Oxley et al., 2015 (see below)
Fatovich et al. (2008)/ Australia Prospective cohort 224 (224) N/A Clinical observation Unavailable Variable

  • Secondary analysis of existing medical records for patients that presented to the ED from 1998 to 1999 with a heroin overdose (adults & adolescents reported at aggregate, could not differentiate those <18 years old)

  • Overdose was determined by Glasgow Coma Scale scores, meiosis, respiration rate <12, history of opiate use or disclosure by patient or bystander, or evidence of injection drug use at scene

  • 11.6 % required hospitalization & only 1 had hypoxic brain injury
Ferrari et al. (2020)/ Italy Case report
Case report		 1 (1)
1 (1)		 Overdose (unresponsive, liver failure, polyneuropathy) CT scan Tramadol (1)
Methadone (1)		 Unknown

  • 49-year-old female found unconscious with empty Tramadol package nearby; CT scan revealed intracranial bleeding; toxicology positive for Tramadol

  • Rescue veno-arterial femoro-femoral extracorporeal life support (VA-ECLS) started and charcoal cartridge used to expediate clearance of Tramadol

  • Patient regained consciousness on day 10; tracheotomy performed on day 16 & discharged to pneumology ward on day 41
Gheuens et al. (2010)/ Belgium Spongiform leukoencephalopathy (hypertonic quadriparesis, catatonia, mutism, unable to eat) Brain MRI, NP Persistent impairments (Month 3)

  • 49-year-old woman was admitted to the ICU following a methadone overdose, she was discharged to outpatient treatment after unspecified time period

  • 2 weeks after the overdose, the patient developed an akineticrigid syndrome; MRI revealed bilateral changes in the white matter; patient gradually worsened, developed hypertonic quadriparesis and was too impaired to complete cognitive assessment; within 2 weeks patient was completely catatonic, mute and required a feeding tube

  • Second MRI indicated progression of white matter abnormalities. Due to severity, a stereotactic brain biopsy was performed which confirmed spongiosis, possible exposure to toxic agent could not be identified.

  • At 3 months, patient showed some improvement and motor functioning improved after botox injections; however, neuropsychological tests confirmed persistent frontal impairments and MRI was unchanged
Ginsberg et al. (1976)/ USA Case series 3 (1) Leukoencephalopathy (N/A) Brain autopsy Unavailable Death (Day 23)

  • Case series of hypoxic-ischemic leukoencephalopathy, one case was associated with an opioid overdose

  • 23-year-old male was comatose due to suspected heroin-related overdose, toxicology was not performed but patient was responsive to naloxone and died on day 23 of hospitalization; postmortem brain autopsy found bilateral lesions in the frontal, parietal and occipital lobes; medial globus pallidus was necrotic bilaterally
Gottfried et al. (1997)/ USA Case report 1 (1) Anterograde and retrograde amnesia (odd behavior, confusion, incontinence, myoclonic jerks) Brain MRI Benzodiazepines (1)
Amphetamines (1)
Opiates (1)		 Persistent Impairments (Month 6)

  • 36-year-old male was found unresponsive following an overdose involving opiates, benzodiazepines, and amphetamines; was comatose for 48 h and discharged on day 8

  • Day 24, patient exhibited odd behavior, confusion, incontinence and experienced myoclonic jerks

  • Day 26 patient was readmitted; drug toxicology was negative; MRI revealed bilateral hyperintensities in the white matter

  • By day 34 patient was comatose and transferred to the ICU; MRI revealed decreased signal in the globus pallidus and right anterior temporal lobe biopsy revealed patchy demyelination

  • Patient showed improvement in functioning at 3 months; however, he was still disorientated at 6 months and had severe anterograde and retrograde amnesia
Grigorakos et al. (2010)/ Greece Retrospective cohort 42 (42) N/A Clinical observation Heroin (42) Variable (ICU discharge)

  • Study included patients admitted to the ICU from 1987 to 2006 for morbidity associated with a heroin overdose (n = 42)

  • 2 patients, who were unresponsive to naloxone in the pre-hospital setting, died in the ICU due to anoxemic encephalopathy; an additional 4 patients died due to severe sepsis

  • 88 % were admitted to ICU due to hypoxemia and 2 patients had persistent mental compromise
Gupta et al. (2009)/ Bahrain Case report 1 (1) Spongiform leukoencephalopathy (unresponsive, tachypnea, altered mental status, bradycardia, facial paresis) CT scan, Brain MRI Opioids (1), Benzodiazepines (1) Partial (Month 6)

  • 42-year-old male was found unconscious, toxicology positive for opioids and diazepam, unsuccessful naloxone reversal

  • CT scan & MRI revealed bilateral hypodensities, including in hippocampus

  • Patient was ventilated for 1 week and did not fully regain consciousness until month 6, patient unable to independently ambulate

  • MRI at month 6 revealedencephalomalacia & resolution of lesions in the hippocampus

  • Authors conclude that leukoencephalopathy was caused by heroin inhalation and it was not associated with hypoxia or ischemia; they noted that the lesions were spongiform
Haghighi-Morad et al. (2020)/ Iran Case series 10 (6) Encephalopathy (intoxication, confusion, neurological deficits) Brain MRI Methadone (6), Opiates (2) Unknown

  • Case series using hospital records of methadone intoxication (overdose) occurring between May 2016-March 2018, cases were included if they had an abnormal MRI finding & toxicology positive only for methadone; 4 cases were under the age of 18

  • In 4 adult cases, imaging documented abnormalities between days 2–12 in the hospital and 2 cases had delayed (9- & 18- days later) onset occurring after hospital discharge

  • Imaging abnormalities discussed in aggregate, cannot differentiate the adult cases
Hill et al. (2000)/ Canada Case report 1 (1) Leukoencephalopathy (comatose) CT Scan, Brain MRI Opioid (1) Death (Day 26)

  • 33-year-old man was found comatose after heroin use; suspected heroin inhalation as track marks were not found

  • CT scan revealed bilateral intensities in pallidum; brain MRI found increased intensity in deep white matter in cerebellum and cerebral hemispheres

  • Laboratory testing ruled out carbon monoxide poisoning, HIV and pulmonary disease

  • Patient never regained consciousness
Holyoak et al. (2014)/ Australia Case series 2 (1) Toxic leukoencephalopathy (hypoxia, hypoglycemia) CT scan, Brain MRI Unavailable Death (Day 60)

  • 26-year-old male was found hypoxic & collateral reported that patient had ingested Oxycodone and Clonazepam; known history of PTSD, OUD, sedative use disorder and previous non-fatal overdoses

  • CT scan revealed bilateral hypodensities in globus pallidus

  • Patient was in the ICU & transferred to inpatient bed on day 12, patient died in hospital on day 60
Hsu et al. (2009)/ Taiwan Case report 1 (1) Rhabdomyolysis and stroke (cognitive impairments, aphasia, limb weakness) Brain MRI Opioids (1) Persistent impairments (Week 2)

  • 33-year-old male presented with rhabdomyolysis and stroke after overdose resulting from IV heroin use; patient was enrolled in a methadone clinic and known to have used methamphetamine

  • Overdose confirmed as patient responsive to naloxone administration; toxicology confirmed opioid use and testing confirmed Hepatitis C

  • Patient remained in ICU for 2 weeks and then transferred to standard hospital bed

  • MRI revealed hyperintensities in bilateral globus pallidi and left cerebral peduncle, believed to be related to pre-existing injury

  • At 2 weeks patient had cognitive impairments, aphasia and limb weakness
Huisa et al. (2013)/ USA Case series 2 (2) Delayed leukoencephalopathy (comatose, confusion, spasticity, myoclonus, insomnia, hallucinations) Brain MRI, NP Methadone (1) 1 Full recovery, 1 Persistent impairments (Year 1)

  • Two patients with delayed post-anoxic leukoencephalopathy after use of diverted methadone

  • In both cases, MRI revealed bilateral lesions within the white matter and neuropsychological testing found impairments in executive functioning

  • One year later one patient had fully recovered while the second had persistent impairment
Jasne et al. (2019)/ USA Case series 6 (4) Encephalopathy, amnesia, acute cerebellar edema, Obstructive hydrocephalus (unconscious, hypoxic, cyanosis) Brain MRI, CT scan Unavailable 1 Death (Hospital), 1 Partial recovery (Month 1), 1 Persistent impairments (Month 6)

  • Convenience sample of patients at two hospitals, between 2014 to 2017, that presented to neurocritical care units with cerebellar edema; 4 cases involved opioid use and presumed overdose

  • Unknown whether drug toxicology was conducted; authors just reported that patients had used opiates, heroin, fentanyl, cocaine and benzodiazepines

  • MRI revealed bilateral symmetric distribution in the gray matter of the cerebellar cortex and hippocampi, and asymmetrically in the basal nuclei

  • Patient presumed to have used fentanyl had profound antegrade amnesia & was unable to live independently, follow-up MRI at 9 months showed improvement
Jensen et al. (1990)/ Denmark Case series 2 (2) Ischemic stroke (comatose, cyanosis, paralysis, aphasia, hemianopia) Brain scintigraphy, CT scan Unavailable 1 Persistent impairment (Year 1), 1 Persistent impairment (Month 15)

  • 30-year-old male found unconscious after injecting heroin and regained consciousness several days later; had aphasia, hemiparalysis & hemianopsia; brain scintigraphy on day 20 revealed infarct in left hemisphere; by month 15 patient had persistent aphasia and hemiparalysis

  • 35-year-old woman found comatose after injecting heroin; patient was aphasic and had paralysis; day 2 CT scan revealed edema but no hypodensities; CT scan on day 18 & day 72 revealed a declining hypodensity in the left basal ganglia; Patient had persistent hemiparalysis at year 1
Khot et al. (2007)/ USA Case report 1 (1) Delayed post-hypoxic demyelination (bradyphrenia, memory deficits, abulia, akinetic, mutism, rigidity) CT scan,
Brain MRI, Brain autopsy		 Morphine (1), Codeine (1) Death (Day 66)

  • 46-year-old male was found unconscious & toxicology was positive for morphine and codeine, although there was no evidence of injection drug use; patient reported unsuccessful attempt to snort heroin which he then rubbed on his gums

  • Patient rapidly declined after an international flight home & demonstrated memory deficits; readmitted to hospital on day 20; CT scan & MRI revealed bilateral hypodensities in the globi pallidi

  • Patient continued to decline & MRI on day 25 revealed new hypodensities; patient’s Arylsulfatase-A activity was normal

  • Patient was transferred to home with hospice due to his vegetative state and he died on day 66

  • Brain autopsy revealed bilateral necrosis in the globi pallidi & extensive demyelination in the cerebral white matter
King et al. (2015)/ USA Case report 1 (1) Delayed post hypoxic leukoencephalopathy (odd behavior, memory deficits incontinence, parkinsonism, bradyphrenia, apathy, mutism) Brain MRI, CT scan Unavailable Persistent impairments (Week 10)

  • 63-year-old male developed delayed post hypoxic leukoencephalopathy (DPHL) 10 days after an opioid overdose, patient was known to have an OUD and AUD

  • Patient had Hepatitis C which had been treated with interferon

  • Initial CT scan following overdose was normal

  • 10 days later patient exhibited odd behavior and MRI confirmed delayed post hypoxic leukoencephalopathy (DPHL)

  • Patient had severe impairments in attention and short-term memory, patient continued to decline and experienced incontinence, parkinsonism, bradyphrenia, apathy, and mutism

  • Clinical deterioration reversed with antioxidant therapy (Vitamins E, C, B-complex; coenzyme Q10)
Koch et al. (2018)/ German Case report 1 (1) Cerebral edema (Comatose, tachycardia, and hypothermia) CT scan U-47,700 (1)
Benzodiazepines (1)		 Death (Day 6)

  • 24-year-old male overdosed on U-47,700 and benzodiazepine (flubromazepam)

  • CT scan revealed cerebral damage and severe brain edema

  • On day 6, ventilation removed and patient died
Koksel et al. (2019)/ USA Case series 87 (20) Leukoencephalopathy Brain MRI Unavailable N/A

  • Cases of suspected acute toxic leukoencephalopathy (ATL) over a 15 year period; included if patient was adult, excluded cases whether ATL resulted from metabolic or infection; ATL was confirmed by imaging; unclear which cases resulted from overdose

  • 20 patients’ ATL was associated with use of opioids
Kuhlman and Gwathmey (2018)/ USA Case series 26 (1) Gluteal compartment syndrome (leg pain, numbness) Brain MRI Opiates (1) No brain injury

  • 2 case reports (only 1 reported Brain MRI) & 24 previously published case reports of gluteal compartment syndrome

  • 28-year-old female was found 6 h after a heroin overdose & sought medical care 4 days later due to leg pain; was diagnosed with gluteal compartment syndrome, brain MRI was normal & cognitive deficits were not reported
Landais (2014)/ France Case report 1 (1) Memory impairment (Hypoxemia, partial consciousness & memory deficits) Brain MRI, NP Unavailable Partial recovery (Month 10)

  • 40-year-old male with intentional morphine overdose was found partially conscious; drug toxicology not reported

  • MRI on day 9 revealed bilateral lesions in the hippocampus & month 10 MRI revealed resolution of lesions

  • Neuropsychological exam (Free and Cued Selective Reminder Test (FCSRT), BEM & DO 80) occurred on day 20 due to patient’s memory deficits which found impairment in verbal and visual memory

  • NP repeated at month 4 and revealed some improvement noting persistent long-term memory deficits
Lefaucheur et al. (2017)/ France Case report 1 (1) Leukoencephalopathy (cognitive impairments, anosognosia, apraxia, memory impairment) Brain MRI, NP Unavailable Recovery (Month 4)

  • 29-year-old male presented with acute cognitive impairments three weeks after a coma caused by an overdose

  • Opioid overdose confirmed by response to naloxone, no signs of hypoxia

  • Patient known to use heroin and alcohol, history of suicide attempts, & depression

  • Brain MRI revealed bilateral hyperintensities in white matter, discharged home after one month with no improvements noted at that time

  • At 4 month follow-up, patient had dramatic improvements in cognitive functioning
Loftsgard et al. (2017)/ USA Case report 1 (1) Hypoxic-ischemic brain injury (multiorgan failure, respiratory failure) CT scan, brain autopsy Opioids (1)
Benzodiazepines (1)		 Death (Day 4)

  • 19-year-old male overdosed involved opioids and benzodiazepines, drugs confirmed by toxicology; patient had multiorgan failure & acute hypoxia; CT scan revealed diffuse anoxic brain injury; patient had neurogenic pulmonary edema; On day 4, patient died after life support was withdrawn

  • Autopsy confirmed that global hypoxic-ischemic brain injury was the cause of death
Long et al. (2013)/ China Case report 1 (1) Leukoencephalopathy (comatose, hydrocephalus) Brain MRI, CT scan Opiates (1) Recovered (Month 1)

  • 34-year-old male presented to hospital after 24 h of being unconscious following a heroin overdose

  • MRI on day 1 revealed bilateral cerebellar abnormalities, repeat MRI on day 5 revealed enlarged lesions in the bilateral cerebellar hemispheres

  • On day 5, patient became comatose and had developed acute hydrocephalus

  • Within 1 month, patient recovered and the lesions were absorbed
McDonald et al. (2013)/ Australia Case-control 225 (148) N/A NP Unavailable Unknown

  • Cases were 125 patients receiving medications for OUD (94 on methadone and 31 on buprenorphine), 50 abstinent opioids users in a residential treatment program and 50 matched controls

  • Social cognition was measured using The Awareness of Social Inference Test (TASIT)

  • After controlling for cognitive performance and other characteristics, number of previous overdoses predicted TASIT I scores (emotional perception)

  • Authors conclude that the areas of the brain damaged by overdose-related hypoxic injuries may impact emotional functioning
Meyer (2013)/ USA Case report 1 (1) Delayed leukoencephalopathy (incontinence, lethargic, socially withdrawn) CT scan, Brain MRI Unavailable Recovered (Year 1)

  • 39-year-old female intentionally overdosed on methadone and diazepam (toxicology not reported); 1 week in hospital and 2 days in psychiatric hospital; clinical assessment did not find any cognitive impairments

  • 3 weeks after discharge she became socially withdrawn, incontinent, lethargic and returned to hospital; CT scan and MRI revealed hypodensities in subcortical white matter; neurological exam found slowed gait, disorientation and poor short-term memory

  • Clinical and radiographic exam at year 1 follow-up confirmed recovery
Molloy et al. (2006)/ England Case report 1 (1) Delayed leukoencephalopathy (confusion, inattention) Brain MRI, NP Unavailable Recovered (Month 9)

  • 40-year-old female presented with confusion and decreased attention 17 days after acute treatment and hospitalization due to morphine overdose

  • Brain imaging consistent with acute disseminated encephalomyelitis

  • Neuropsychological examination at 24 months prior confirmed no pre-existing cognitive impairments

  • Addenbrooke’ s Cognitive Examination score 40/100 (suggesting severe global cognitive impairment – memory and verbal fluency)
Morales Odia et al. (2010)/ USA Case report 1 (1) Encephalopathy, severe cerebellitis, hydrocephalus (confusion, gait impairment, delirium, agitation, disorientation) Brain MRI, CT scan Morphine (1)
Benzodiazepines (1)		 Persistent impairments (Month 3)

  • 46-year-old male presented with multifocal encephalopathy and severe cerebellitis after an overdose involving oxycodone and OxyContin

  • Initially he presented with confusion; on day 2 he had gait impairment, delirium, agitation, and disorientation; treated for acute opiate withdrawal

  • CT scan on day 3 confirmed severe obstructive hydrocephalus

  • Brain MRI revealed bilateral lesions in the cerebellum and globus pallidi, day 6 MRI revealed abnormalities in the basal ganglia had resolved

  • Patient had rehabilitative therapy and cognitive improvements, while speech impairments and ataxia remained
Morrow et al. (2019)/ Canada Retrospective cohort 14,011 (14,011) Encephalopathy (N/A) Clinical observation Unavailable Variable (During hospitalization)

  • Two cohorts included patients admitted to the hospital from 2000 to 2015 for accidental opioid overdose and investigated risk of neurological, respiratory, cardiac and other adverse events

  • First cohort (n = 2433) included patients hospitalized for an accidental opioid overdose and excluded individuals who had an overdose in the past year

  • Second cohort included long-term prescription opioid users, among those who had been hospitalized for an accidental opioid overdose (n = 538) – 20 matched controls were identified for each case (n = 11,040)

  • 3% of opioid-related overdose hospitalizations had encephalopathy and 25 % had an adverse outcome (composite measure)

  • 3% died in the hospital and 5.5 % had respiratory failure; number of hospitalizations with respiratory failure increased during the study period

  • Risk of encephalopathy or other adverse outcomes did not increase with subsequent overdose admissions
Muller et al. (2018)/ Germany Case control 26 (14) Brain abnormalities (N/A) Brain autopsy Unavailable N/A

  • Brain autopsy data compared between cases (n = 14) whose cause of death was a heroin overdose and controls (n = 12)

  • While cases were on average 10 years younger compared to controls, the relative volume of their pallidus externus was smaller

  • Authors conclude that there is evidence of structural and cognitive deficits in individuals with heroin use
Mumma et al. (2009)/ USA Case report 1 (1) Cardiac arrest (comatose, mild dysarthria, cognitive impairment, rhabdomyolysis, slurred speech) CT Scan, Brain MRI, NP Opiates (1), Benzodiazepines (1) Recovered (Month 8)

  • 28-year-old male was comatose; CT scan and brain MRI revealed bilateral hypodensities in the globus pallidum

  • Patient regained consciousness on day 6, had slurred speech and had mild cognitive impairment; was transferred from hospital to rehabilitation facility

  • Month 8 follow-up patient was functioning well and had a Cerebral Performance Category score of 1
O’Brien et al. (2009)/ Ireland Retrospective cohort 43 (21) N/A NP Unavailable Variable (Months 20–37)

  • Prospective outcomes at 31 months were assessed for patients treated in the ICU for drug overdose between 2004–2006; 21 cases involved opioids

  • Karnofsky Index, a measure of functional impairment, at baseline the median score was 60 (range = 0–80) and at follow-up 80 (70–90) suggesting that all of those survived had functional improvements

  • 11 patients died in the hospital and at follow-up, an additional 8 patients had died

  • At follow-up, 54 % of those who survived were unemployed
O’Brien and Todd (2009)/ Australia Case series 10 (10) Brain injury (N/A) CT scans, Brain MRI, NP Unavailable Variable (Year 2–4)

  • Case series of patients presenting to a brain injury rehabilitation facility with hypoxic brain injuries following heroin overdose between July 1997–June 1999

  • 5 patients had normal CT scans & 3 had abnormal findings (1 global hypoxia, 1 bilateral watershed changes, 1 changes in left globus pallidus & basal ganglia)

  • NP included Functional Independence Measure (FIM) and Community Integration Questionnaire (CIQ)

  • Prior to brain injury, all patients were living independently & 9 self-reported a history of heroin use

  • Mean length of inpatient stay at brain injury rehab center was 83 days (range: 15–437); results of NP documented improvements in cognition during rehab

  • Follow-up conducted over the telephone with 9/10 patients; 2 had died; 3 were unable to work & only 3 were living independently
Oehmichen et al. (1996)/ Germany Retrospective cohort 180 (168) N/A Brain autopsy Unavailable N/A

  • Brain autopsies from IV drug users from 1990 to 1993, cases with HIV were excluded

  • Urine or blood was used to confirm presence of illegal drugs, including heroin

  • The case of death in 64 % of cases was acute heroin intoxication (not involving other substances), 19 % had polysubstance intoxication, and 18 % had a delayed drug overdose death

  • Brain edema identified in 90 % of cases of heroin overdose
Ormseth et al. (2019)/ USA Retrospective cohort 300 (15) N/A Brain MRI, CT scan Opioids (15) Polysubstance (10)
Cocaine (3)		 Variable (During hospitalization)

  • Cohort study including patients who presented at a single hospital with cardiac arrest between 2012–2017, who were initially unconscious, following return of spontaneous circulation (ROSC)

  • 9% had an overdose-related cardiac arrest and among those, 86 % involved opioids and 73 % died by hospital discharge

  • Patients with an overdose-related cardiac arrest were more likely to have signs of hypoxic-ischemic brain injury and more likely to have withdrawal of life-sustaining therapy
Oxley et al. (2015)/ Australia Case-control 36 (21) N/A NP Unavailable Variable
(During
hospitalization)

  • Prospective case-control study that compared cognition among patients hospitalized for an intentional overdose between 2013–2014 for Central Nervous System Depressants (CNS-D) (21 cases) and Central Nervous System non-depressant (antide-pressant, acetaminophen) drugs (CNS-ND) (15 controls); follow-up at 7- and 28-days; baseline data reported in Dassanayake et al., 2012 (see above)

  • Cases had greater impairment in cognitive flexibility, cognitive efficiency, and working memory; cases were more likely to be in the 10th percentile on the TMT-B at both follow-up periods – which correlates with driving impairment

  • Authors conclude that additional research is needed to determine whether patients who have CNS-D related overdoses should not drive after hospital discharge
Pearson et al. (1975)/ USA Case-control 11 (11) N/A Brain autopsy Morphine (8)
Methadone (3)		 N/A

  • Random sample of 96 brains among 1140 drug-related deaths (492 specified narcotics); study included a subset of 11 brains of decedents had known OUD compared to 11 controls

  • All subjects were male and controls ranged in age from 15 to 63 years old (1 adolescent case); all cases included because outcomes reported in aggregate

  • OUD brains had significant decrease of neurons within the globus pallidus

  • Only 2 of 11 cases had evidence of acute hypoxic neuronal necrosis; observed damage appears to be progressive

  • Authors conclude that permanent brain damage results from repeat hypoxia
Pfister et al. (2016)/ USA Retrospective cohort 178 (178) N/A Clinical observation Opioids (178) Deaths - 18 (During hospitalization)

  • The study included patients admitted to the ICU for opioid overdose between 2001 – 2014, which was confirmed by toxicology or self-report

  • The opioids most commonly used were oxycodone (41 %) and hydrocodone (28 %), only 16 % had used heroin

  • Mean ICU length of stay was 3 days and 89 % required mechanical ventilation

  • 18 patients died in hospital (9 due to hypoxic brain injury) and 6 were discharged to a nursing home
Pirompanich and Chankrachang (2015)/ Thailand Case report 1 (1) Spongiform leukoencephalopathy (confusion, mutism, akinetic, spastic, hyperreflexive) Brain MRI Heroin (1) Morphine (1) Persistent impairments (Month 6)

  • 41-year-old male presented with opioid overdose; non-responsive to naloxone; discharged home and mild cognitive impairment noted

  • 5 days later patient developed confusion and was unable to complete activities of daily living

  • Upon hospital readmission, patient was mute, akinetic, spastic and hyperreflexive; MRI at 1 week after readmission revealed bilateral brain abnormalities (lesions and involvement in white matter)
Quinn and Abbott (2014)/ USA Case report 1 (1) Delayed leukoencephalopathy (incontinence, nausea, confusion, odd behavior) Brain MRI Opioids (1) Persistent impairments (Year 1)

  • 56-year-old female, with schizoaffective disorder and Hepatitis C-related cirrhosis, had an unintentional overdose involving prescription opioids and she had hypoxic respiratory failure; she was treated in the ICU and hospitalized for 1 week

  • Patient experienced increased symptoms post-discharge including incontinence, nausea, confusion and odd behavior; patient was taking several psychiatric and pain medications

  • Patient was given ECT for catatonia/neuroleptic malignant syndrome; repeated MRI revealed bilateral white matter changes

  • At 1 year, patient continued to be mute and have stupor
Ramirez-Zamora et al. (2015)/ USA Case report 1 (1) Brain abnormalities (confusion, apathy, inattention, memory deficits) Brain MRI Opioids (1)
Cannabinoids (1)		 Persistent impairments (Week 1)

  • Patient called ambulance after taking a high dose of Oxycodone, patient did not lose consciousness

  • Brain MRI conducted within 24 h revealed bilateral abnormalities in the globus pallidus and hippocampi

  • Over 1 week in the hospital, patient demonstrated inattention, apathy, and memory impairment
Revesz and Geddes (1988)/ England Case report 1 (1) Encephalopathy (cardiac arrest, hypothermia, pulmonary edema) CT scan, brain autopsy Methadone (1), Amphetamines (1) Death (Day 6)

  • 35-year-old male was found unconscious 12 h after release from prison, due to an overdose; patient had a known history of OUD; patient had cardiac arrest lasting 30–40 minutes; CT scan on day 6 revealed extensive infarction in thalami and brain stem; life support was removed and patient died

  • Brain autopsy revealed inflammation and symmetrical lesions in the grey structures
Richter et al. (1973)/ USA Case series 42 (Undetermined) Delayed encephalopathy, dementia, Parkinsonian syndrome (hemiballistic movements) Unknown Unavailable Unknown

  • Loosely reported case series of 42 patients with a history of being treated in a hospital for heroin overdose

  • Authors observed 3 cases of dementia & 2 cases of delayed encephalopathy following a heroin overdose

  • 31-year-old had unilateral Parkinsonian syndrome

  • 28-year-old male had hemiballistic movements

  • 3 of 21 had bilateral lesions in the globi pallidi (presumably identified post-mortem)
Rizzuto et al. (1997)/ Italy Case report 1 (1) Delayed spongiform encephalopathy (comatose, heart failure, rhabdomyolysis, renal failure) Brain MRI, brain autopsy Unavailable Death (Week 6)

  • 30-year-old male presented with a heroin overdose, was found unconscious 18 h after injecting heroin, he was responsive to naloxone

  • On day 2 of hospitalization, patient received dialysis due to acute renal failure

  • MRI revealed brain abnormalities in the white matter of the cerebellum, pallidum and centrum ovale; 3 weeks later onset of delayed spongiform encephalopathy and patient died 20 days later

  • Brain autopsy revealed an edema and sponginess of white matter, no evidence of lesions or necrosis
Salazar and Dubow (2012)/ USA Case report 1 (1) Delayed leukoencephalopathy (confusion, lethargy, akinetic mutism) CT scan, Brain MRI Morphine (1) Partial recovery (Day 40)

  • 54-year-old man accidentality overdosed on morphine pills, CT scan & MRI revealed bilateral hypodensities in the globi pallidi; discharged from hospital after unknown duration & patient still had mild confusion

  • Day 20 patient readmitted to the hospital due to confusion, lethargy & akinetic mutism

  • Testing ruled out Lyme disease, West Nile virus, HIV, herpes & other viruses

  • Brain MRI revealed diffuse hyperintensity in the white matter & in the corpus callosum

  • Day 40 patient was discharged to a nursing home
Shprecher et al. (2008)/ USA Case series 3 (3) Delayed leukoencephalopathy, pneumonia (hypotension, memory deficits, disorientation, gait impairment, delusional, catatonia, automatisms, incontinence, mutism, loss of interest, fatigue, inattention, catatonia, imbalance) Brain MRI, NP Unavailable 1 Partial recovery (Year 1), 1 Partial recovery (Week 38), 1 Persistent impairments (Week 8)

  • 39-year-old woman overdosed on methadone and cocaine (toxicology not reported); patient was readmitted to the hospital at week 4 due to memory deficits, disorientation & unsteady gait; MRI revealed increased signal in the white matter; bilateral gegenhalten noted at week 32; at year 1 patient was unable to work or drive due to emotional lability, attention deficits & fatigue; MRI revealed volume loss & persistent signal abnormalities in white matter; comparison of WAIS-III pre-overdose and 1 year after overdose documented declines in verbal IQ and memory

  • 51-year-old was found unconscious after methadone overdose (toxicology not reported); recovered after 2 days; day 21 patient was reported to have loss of interest, declined mental status & paranoid delusions; day 28 patient was catatonic, incontinent, had mutism & automatisms; MRI revealed bilateral hyperintensity in white matter; week 16 Mini-Mental State Examination (MMSE) score of 27 /30; week 38 patient had partial recovery with persistent memory deficits, imbalance & needed help with self-care; MRI documented persistence of signal abnormalities in the white matter

  • 56-year-old woman intentionally overdosed on methadone, fentanyl & benzodiazepines (toxicology not reported) and patient was discharged day 11; day 15 patient had significant cognitive decline confirmed by MMSE score of 15/30; day 14 MRI revealed hyperintensities in white matter; week 8 patient had persistent memory and attention deficits, as well as inability to live independently
Shu et al. (2016)/ Australia Case report 1 (1) Dystonia-Parkinsonism (involuntary movements, gait impairment, jaw spasms, dystonia, bradykinesia) Brain MRI Unavailable Persistent declines (Year 3)

  • 20-year-old male presented to the hospital 2 days after a presumed overdose due to involuntary movements on right side; patient could not recall the first 36 h after injecting heroin (had also used quetiapine & alprazolam)

  • MRI revealed bilateral hyperintensities in the golbus pallidus and caudate nuclei; patient experienced worsening symptoms and MRI at week 1 revealed new hyperintensities

  • Year 3 he presented with persistent declines in gait & ability to ambulate
Singh and Saini (2015)/ Singapore Case report 1 (1) Leukoencephalopathy (inattention, stiffness, mutism, developed bradykinesia, tremors) Brain MRI None Persistent impairments (Week 6)

  • 58-year-old male presented with inattention and stiffness; he became mute within a few days and developed bradykinesia, tremors; toxicology positive for morphine

  • 30 days prior patient had presented for suspected heroin overdose, but toxicology was not performed and CT scan was normal

  • MRI scan at hospital readmission revealed bilateral abnormalities in the white matter

  • At week 2 of hospitalization, minimal improvements were noted and the patient was transferred to long-term care facility
Switzer et al. (2020)/ Canada Case report 1 (1) Delayed leukoencephalopathy, amnesia (rigidity, tremor, gait impairments, inattention, unconscious, memory deficits) Brain MRI, NP Fentanyl (1) Partial recovery (Month 5)

  • 52-year-old male had acute amnesia after being unconscious for 12 h following a fentanyl overdose; MRI confirmed hippocampal injuries & MMSE score of 18/30; within 24 h patient was stable with only memory deficits

  • By month 1 patient developed Parkinsonism symptoms (e.g., rigidity, tremor, slow gait) which partially improved with treatment by month 5

  • Partial recovery at month 5 based on repeated MRI; NP exam found persistent inattention, poor recognition memory & poor violation; notably patient was not able to live independently
Taheri et al. (2011)/ Iran Retrospective cohort 403 (108) Brain abnormalities (comatose) Clinical observation, CT scan Unavailable Variable (During hospitalization)

  • Sample included patients who were unconscious due to drug overdose; overdose was determined by bystander report, evidence at the scene, suicide note or toxicology

  • Mean age was 38 years old and most (79 %) were male

  • 40 % had used opium and 5% involved Tramadol

  • Among those who had used opium: 12 % were determined to be suicides, 29 % were comatose, 15 % had abnormal CT scans and 1 case found evidence of changes in the basal ganglia
Taylor et al. (2019)/ Canada Case report 1 (1) Amnesia (unconscious, confusion) Brain MRI, NP Opiates (1) Persistent deficits (Month 4)

  • 63-year-old pain patient found unconscious after using 3 fentanyl pain patches; regained consciousness after naloxone infusion and toxicology positive for opiates; patient had profound anterograde amnesia

  • Testing ruled out herpes simplex virus, arbovirus & syphilis

  • MoCA score was 19/30 & MRI on day 7 revealed bilateral hyperintensities in hippocampus

  • Day 12 MRI showed resolution of hyperintensities and NP results suggested mild executive impairment

  • Follow-up telephone interview with patient’s husband confirmed persist amnesia
Torralba-Moron et al. (2017)/ Spain Case series 3 (2) Delayed leukoencephalopathy (unresponsive, amnesia, bradypnea, muscle spasm, inattention, fever) Brain MRI, CT scan Methadone (2), Alprazolam (1), Alcohol (1) 1 Persistent deficits (Discharge), 1 Death (Day 40)

  • Two males in their mid-forties overdosed after using methadone (toxicology not reported); patients known to have a 5 year history of heroin use

  • One patient initially had non-specific neuroimaging, but on day 13 experienced fluctuating consciousness & MRI revealed bilateral globus pallidus injury; at discharge patient was amnestic, lack of attention & dysexecutive abnormalities

  • Second patient had been treated for HIV and his initial CT scan revealed decreased density in globus pallidus; then after a few days he deteriorated & MRI revealed bilateral lesions in the globus palldus; patient did not regain consciousness
Vendrame and Azizi (2007) /USA Case report 1 (1) Brain abnormalities (comatose, cyanosis, gait impairment) Brain MRI Opiates (1)
Cocaine (1)
Cannabis (1)		 Partial improvements (Month 3)

  • 23-year-old male had a drug overdosed & became comatose

  • Brain MRI on day 2 revealed bilateral abnormalities in the cerebellum, globis pallidus, and motor cortex; brain MRI at week 2 found that the lesions were reduced

  • Patient discharged on day 24, overall improvement

  • At 3 months, patient still had ambulation problems and was unable to walk independently
Vila and Chamorro (1997)/ Spain Case series 2 (2) Stroke (comatose, ballistic movements) Brain MRI, CT scan Unavailable Recovered (Day 3 & Month 9)

  • 19 and 34-year-old males developed ballistic movements after heroin overdose

  • Case 1 left hospital AMA and returned 1 week later due to involuntary movement in his extremities; CT and MRI scans revealed bilateral globus pallidus hypodensities; patient treated with haloperidol and symptoms resolved at 9 months

  • Case 2 MRI revealed ischemic infarcts right lenticulostriate vascular territory and inferior branch right middle cerebral artery; patient treated with haloperidol and symptoms resolved on day 3
Villella et al. (2010)/ Italy Case report 1 (1) Spongiform leukoencephalopathy (comatose) Brain MRI None Partial improvements (Year 2)

  • 32-year-old male was unconscious following a suspected overdose after injecting heroin; testing ruled out Hepatitis C and HIV

  • Patient discharged from hospital after unspecified number of weeks in the hospital, started outpatient neurological rehabilitation program; continued improvement noted at 2 years
Voigt (2013)/ Germany Case report 1 (1) Brain damage (hypoventilation, bradycardia, hypotension, miosis) CT scan, Brain MRI None No improvements (Day 30)

  • 58-year-old male was found unconscious; drug toxicology was negative; CT scan revealed edema after which physician found 75 mcg fentanyl patch on patient

  • Wife reported that patient had pain after biking & may have applied fentanyl patch obtained from a deceased relative; wife reported that patient thought it was a heat releasing patch

  • CT scan at hour 72 revealed hypoxic brain damage

  • Day 30 patient transferred to rehabilitation center and remained in a vegetative state
Wijdicks (2005)/ USA Case report 1 (1) Encephalopathy (comatose, apathy, memory deficits, rigidity, monotonic, gait impairment) Brain MRI, CT scan Opioids (1)
Benzodiazepines (1)		 No improvements (Month 3)

  • 24-year-old male overdosed and was found comatose

  • CT scan and MRI confirmed bilateral globus pallidus lesions and white matter lesions

  • Known history of mandibular fracture one month earlier resulting from blow to face

  • Within 3 days he regained consciousness, at 4 weeks patient had limited ability to ambulate and no change at 3 months
Yarid and Harruff (2015)/ USA Retrospective cohort 27 (10) N/A Brain autopsy Opiates (8)
Benzodiazepines (2)
Methadone (2)
Cocaine (2)
Methamphetamines (1)		 N/A

  • Cases defined as brain autopsies, from 1994 to 2013, with bilateral basal ganglia lesions

  • 10 deaths attributed to drug overdose involving heroin; 3 of which lived long enough to be diagnosed with anoxic encephalopathy

  • Bilateral injuries are suggestive of global insult

  • Deaths attributed to carbon monoxide had no evidence of globus pallidus or basal ganglia necrosis
Zamora et al. (2015)/ USA Case series 5 (4) Delayed leukoencephalopathy (incontinence, mutism, ataxia, odd behaviors, executive functioning impairment) Brain MRI Unavailable Death -1
Recovery -2, Persistent impairments 1 (Week 2-Week 5)

  • Cases had a hypoxic event characterized by neurological impairments, recovery, and relapse; 4 of 5 had opioid-related overdose; however, toxicological results were not reported

  • Median time to relapse was 23 days, all cases had brain abnormalities confirmed by MRI, which were bilateral, symmetric and involved white matter

NOTES: AMA = against medical advice; ATL = acute toxic leukoencephalopathy; CNS-D = Central Nervous System Depressants; CNS-ND = Central Nervous System non-depressant; DPHL = delayed post hypoxic leukoencephalopathy; ECT = electroconvulsive therapy; ED = emergency department; ICU = intensive care unit; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; OUD = opioid use disorder; NP = neuropsychological testing; ROSC = return of spontaneous circulation (ROSC); SSRI = selective serotonin reuptake inhibitor; TMT-B = Trail making test, part B; WASI-III = Wechsler Abbreviated Scale of Intelligence 3rd Edition.