Spectrum of delayed post-hypoxic leukoencephalopathy syndrome: A systematic review

Table 1 Databases queried as well as respective search string

Database	Search string
PubMed	("Delayed post-hypoxic leukoencephalopathy" OR "delayed encephalopathy ") AND ("human" OR "case report" OR "case series")
ScienceDirect	("Delayed post-hypoxic leukoencephalopathy" OR "delayed encephalopathy") AND ("human" OR "case report" OR "case series")
Hinari	("Delayed post-hypoxic leukoencephalopathy" OR "delayed encephalopathy") AND ("human" OR "case report" OR "case series")

Table 2 Cases of delayed-post hypoxic leukoencephalopathy reported

Ref.	Year of publication	Age	Gender	Cause of hypoxia	Comorbidities	Symptomatology	Time to onset of symptoms	Neuroimaging findings	Other neurodiagnostics	Therapeutic interventions	Complications	Outcomes
Aljarallah and Al-Hussain[7]	2015	19	M	Benzodiazepine overdose	None	Comatose	21 days	T2WI: Diffusely increased signal intensity in cerebral white matter. DWI/ADC: Diffuse and symmetric diffusion restriction within the subcortical cerebral white matter and the right globus pallidus. T1WI: Patchy enhancement within cerebral white matter	EEG: Diffuse slowing at 2-3 Hz	Osmolar therapy	Tonsillar herniation and brain death	Death (23rd day of hospitalization)
Arciniegas et al[8]	2004	24	M	Opioid and benzodiazepine overdose	NA	21 days	Executive dysfunction	T2WI: Diffusely increased signal intensity in cerebral white matter	NA	Amantadine	NA	Did not return to baseline
Arimany et al[9]	2017	43	M	Heroin overdose	Schizoaffective disorder	Akinetic mutism and ataxia	21 days	T2WI: Diffuse and symmetric increase in T2 signal	NA	Supportive	NA	Significant improvement at 16 weeks after overdose
Beeskow et al[10]	2018	51	F	Carbon monoxide poisoning	Hypertension, obesity, sleep apnea syndrome, and depression	Agitation, reduced psychomotor activity, strange behavior. Progressed to mutism	21 days	T2WI: Diffusely increased the T2 signal of the bilateral cerebral hemispheres and the basal ganglia	NA	Supportive	NA	Discharged from neurological rehabilitation in 6 weeks. At nine months improvement in leukoencephalopathy with cerebral atrophy
Betts et al[11]	2012	46-59	--	Benzodiazepine overdose, ETOH abuse	Cognitive decline, speech disturbance, and memory loss		17 days, 24 days, and 5 days	T2WI: Diffusely increased T2 signal of the bilateral cerebral hemispheres, including the globus pallidi. MRS: Decreased NAA, increased Cho/Cr ratio	EEG: Diffuse slowing	Supportive	NA	Significant improvement in one patient. Persistent memory dysfunction in other two patients
Brovelli et al[12]	2022	55	F	Opioid intoxication	None	Psychomotor slowing, apathy, cognitive decline, akinetic mutism	14 days	T2WI: Diffusely increased T2 signal within the frontal regions. DWI/ADC: The corresponding diffusion restriction was confirmed on the ADC maps	EEG: Global slowing	Logopedic and physiotherapic treatment	None	Awake and collaborative, with mild hypomimia and decreased spontaneous speech upon discharge
Cardona Quiñones et al[13]	2022	26	M	Opioid intoxication with cardiac arrest	None	Anton-Babinski syndrome	Few days	T2WI: Bilateral cerebral hemisphere hyperintensities including corpus callosum	NA	Supportive	None	NA
Chachkhiani et al[14]	2022	46	M	Opioid intoxication with respiratory failure	Hepatitis C, substance use disorder, mesial temporal lobe epilepsy	Psychomotor agitation and abulia	27 days	T2WI: Bilateral cerebral hemisphere hyperintensities	EEG: Diffuse polymorphic delta activity. CSF: Normal	High dose IVMP, and amantadine	None	Discharged on day 48 with mild abulia and day 138 with a normal clinical exam, except hyperreflexia. Radiographic resolution of cerebral white matter disease
Chen et al[15]	2022	64	M	Nitrite poisoning. Comatose on initial presentation	None	Cognitive decline and mental and behavioral abnormalities	60 days	T2WI: Hyperintensities of the bilateral cerebral hemisphere, involving the basal ganglia and the thalamus. DWI/ADC: Corresponding diffusion restriction involving	NA	Supportive	None	Did not regain functional independence at 6-month follow-up
Choi et al[16]	2013	37	M	Traumatic cervical cord injury	None	Akinetic mutism	7 days	T2WI: Bilateral fronto temporal and basal ganglia hyperintensities	NA	Supportive	None	At 2 months of follow-up, they continued to show cognitive disability and disorientation
Fong et al[17]	2019	61	F	Benzodiazepine overdose	None	Neuropsychiatric symptoms	41 days	T2WI: Confluent cerebral white matter changes DWI/ADC: Associated diffusion restriction	EEG: Generalized slowing. CSF: Normal	Supportive	None	Clinical improvement at follow-up (MoCA: 26/30). Repeat neuroimaging at 3 months showed improvement
Garzón-Hernández et al[18]	2022	68	M	Severe acute respiratory syndrome-coronavirus 2related hypoxia	None	Unresponsiveness	17 days	T2WI: Confluent cerebral white matter hyperintensities. SWI: Cerebral microbleeds	EEG: isolated polymorphic delta waves in the frontal region without epileptiform activity	Supportive	None	Discharged to rehab on day 30 of hospitalization
Geraldo et al[19]	2014	61	M	Carbon monoxide poisoning	None	Disorientation, incoherent speech, and behavior disturbances	39 days	T2WI: Confluent cerebral white matter hyperintensities	CSF: Normal	Hyperbaric oxygen therapy (90 minutes daily sessions, 100 % oxygen at 2.5 atmospheres with a total of 40 sessions)	None	Mild to moderate improvement and discharged to a rehabilitation facility
Gottfried et al[20]	1994	36	M	Opioid overdose	NA	Quadriparesis, myoclonic jerks, encephalopathy, cognitive decline	24 days	T2WI: Increased supratentorial white matter signal. Hyperintense foci within globus pallidi. MRS: Decreased NAA; elevated choline and elevated lactate	NA	NA	NA	Significant improvement
Hakamifard et al[21]	2021	39	M	Opioid (methadone) overdose	Substance use disorder	Aphasia and decreased level of consciousness	Approximately 30 days	T2WI: Confluent cerebral white matter hyperintensities	CSF: Normal	Vitamin E 400 mg/day, vitamin C 1000 mg/day, magnesium-sulfate 1000 mg/day and vitamin B complex	None	Significant improvement in two months
Hamlin et al[22]	2020	29	M	Opioid overdose	Substance use disorder	Malignant catatonia, paroxysmal sympathetic hyperactivity	Approximately 30 days	T1WI and T2WI: Confluent hyperintensities involving the bilateral centrum semiovale	EEG: No epileptiform discharges	Propranolol, clonidine, and lorazepam	Akinetic mutism and sympathetic hyperactivity after electroconvulsive therapy (ECT)	Moderate improvement in 30 days
Hori et al[23]	1991	13		Asphyxiation	NA	Pseudobulbar paralysis, choreoathestosis	7 days	Lesion involving the putamen and caudate nuclei	NA	NA	NA	Significant improvement at 1.5 years
Hsiao et al[24]	2004	11-79		Carbon monoxide poisoning	NA	Cognitive impairment, akinetic mutism, and parkinsonism	14-45 days	T2WI: Increased signal within the subcortical white-matter, basal ganglia, and globus pallidus	NA	NA	NA	Moderate to considerable improvement
Huarcaya-Victoria[25]	2018	37	F	Carbon monoxide poisoning	None	Progressive psychomotor agitation, catatonia, and cognitive decline	Approximately 30 days	T2WI: Confluent cerebral white matter hyperintensities	NA	Hyperbaric oxygen therapy (29 feet for one hour, 2.2 absolute atmospheres, 20 sessions). Aripiprazole and diazepam for the management of catatonia	None	Significant improvement and discharge to rehabilitation facility
Huisa et al[26]	2013	19, 32	--	Opioid overdose	NA	Decreased level of arousal, and encephalopathy	58 days and 112 days	T2WI: Confluent cerebral white matter hyperintensities. ADC: Diffusion restriction in both cases with normalization at follow-up in case two	NA	NA	NA	Persistent deficits in both cases
Jang et al[27]	2017	50	M	Carbon monoxide poisoning	None	Myoclonus, dysarthria, decreased level of consciousness	26 days	T2WI: Bilateral basal ganglia hyperintensities. DTT: Dysconnectivity involving the ascending reticular activating system	NA	Supportive	None	Discharge to rehabilitation facility six weeks from initial presentation. No significant improvement
Jayakrishnan et al[28]	2021	68	F	Myocardial infarction	Hypertension, hyperlipidemia, and myocardial infarction	Drowsiness, behavioral changes, urinary incontinence	21 days	T2WI: Diffuse hyperintensities involving the cortex. ADC: Diffusion restriction involving the basal ganglia	NA	Supportive	None	Discharge to hospice
Jingami et al[29]	2024	47	M	Opioid intoxication	None	Decreased level of consciousness	20 days	T2WI: Confluent cerebral white matter hyperintensities. N-isopropyl-(123I)-p-iodoamphetamine	CSF: Elevated myelin basic protein 135.5 pg/mL	Hyperbaric oxygen (2.0 ATA, 60 minutes, 63 total)	None	Improvement in mini-mental status exam from unmeasurable to 15 on day 40 of hospitalization
Kim et al [30]	2002	54-71		Carbon monoxide poisoning	NA	Memory loss, confabulations, and akinetic mutism	1-4 weeks	T2WI: Confluent white matter hyperintensities in the brain	NA	NA	NA	4 patients with significant improvement
Law-ye et al[31]	2018	58	M	Carbon monoxide poisoning	None	Encephalopathy	14 days	T2WI: Confluent white matter hyperintensities in the brain. ADC: Diffusion restriction in the corresponding area	CSF: Normal	Supportive	None	Significant improvement
Lee et al[32]	2001	71	F	Benzodiazepine overdose	None	Encephalopathy	14 days	T2WI: Confluent cerebral white matter hyperintensities	CSF: Normal. EEG: Diffuse delta wave pattern	Supportive	None	Significant improvement with discharge to rehabilitation facility on day 47
Lou et al[33]	2009	62	F	Cardiac arrest after gastrointestinal hemorrhage	NA	Akinetic mutism, rigidity	14-21 days	T2WI: Confluent cerebral white matter hyperintensities involving the globus pallidi, and basal ganglia	NA	NA	NA	No significant improvement
Manjunath et al[34]	2021	76	M	Acute respiratory distress syndrome	NA	Cognitive decline	Few weeks	T2WI: Confluent cerebral white matter hyperintensities. ADC: Diffusion restriction in corresponding area	NA	Supportive	None	Significant clinical improvement over 3 months. With significant radiographic improvement in 4 months
Mazo et al[35]	2020	66	M	Carbon monoxide poisoning	None	Encephalopathy	12 days	T2WI: Increased signal within the bilateral globus pallidus	CSF: Normal	Supportive	None	No significant improvement
Meyer et al[36]	2013	43	F	Benzodiazepine overdose	None	Encephalopathy	--	T2WI: Confluent cerebral white matter hyperintensities. MRS: High peak for choline and creatinine	EEG: Generalized slowing	Supportive	None	Significant improvement in a few months
Mittal et al[37]	2010	38	M	Polysubstance abuse	NA	Encephalopathy, akinetic mutism	21 days	T2WI: Confluent cerebral white matter hyperintensities	NA	Steroids and antioxidants	None	Significant improvement
Molloy et al[38]	2006	40	F	Opioid overdose	NA	Agitation, echolalia	17 days	T2WI: Confluent cerebral white matter hyperintensities. ADC: With associated restricted diffusion	CSF: Normal	Supportive	None	Significant improvement over 6 months
Newburn et al[39]	2024	19	M	Benzodiazepine overdose	Developmental delay	Cognitive decline	--	DSIR: High signal in the white matter of the brain	NA	Supportive	None	Mild improvement
Newburn et al[39]	2024	20	M	Suicide attempt (hanging)	Substance abuse	Cognitive decline	--	DSIR: High signal in the white matter of the brain	NA	Supportive	None	Mild improvement
Nzwalo et al[40]	2011	55	F	Benzodiazepine overdose	NA	Akinetic mutism	NA	T2WI: Confluent cerebral white matter hyperintensities	CSF: Normal	Supportive	NA	No significant improvement
Pfaff et al[41]	2022	81	M	Unilateral internal carotid artery occlusion	Acute myeloid leukemia, hypertension, hyperlipidemia	Encephalopathy	13 days	T2WI: Increased signal within the left centrum semiovale	NA	Supportive; mechanical thrombectomy	None	Clinical and radiographic improvement on day 92 of hospitalization
Quinn et al[42]	2014	56	F	Opioid overdose	Schizoaffective disorder, cirrhosis	Catatonia	21 days	T2WI: Confluent cerebral white matter hyperintensities	EEG: generalized polymorphic theta waves, 2-3 Hz delta waves, and superimposed beta waves	ECT, methylprednisolone	None	No significant improvement
Rozen et al[43]	2012	59	--	Opioid overdose	NA	Akinetic mutism	21 days	T2WI: Confluent cerebral white matter hyperintensities including the globus pallidi	NA	IV Magnesium	None	Significant improvement
Salazar et al[44]	2012	54	M	Opioid overdose	NA	Encephalopathy, and rigidity	21 days	T2WI: Confluent cerebral white matter hyperintensities. ADC: Diffusion restriction involving the globus pallidi	NA	Levodopa for rigidity	None	Significant improvement
Singu et al[45]	2017	66	M	Left main coronary artery occlusion	Hypertension, hyperlipidemia, diabetes mellitus, myocardial infarction	Aphasia, dysexecutive syndrome	35 days	T2WI: Cerebral white matter hyperintensities involving the L MCA territory. ADC: Corresponding region hypointense. SPECT: 60%-70% decrease in CBF	CSF: Elevated protein	Supportive	None	Moderate improvement
Smolinsky et al[46]	2018	16	F	Traumatic brain injury	None	Encephalopathy	8 days	DWI/ADC: Restricted diffusion involving right frontoparietal lobes, right temporal lobe, and left parietal lobe, and corpus callosum	None	Amantadine	None	Mild improvement
Tahir and Islam[47]	2021	43	M	ETOH abuse	None	Encephalopathy	6 days	DWI/ADC: Diffusion restriction involving the bilateral centrum semiovale	CSF: Normal. EEG: Paroxysmal epileptiform activity	Supportive	None	Death
Tainta et al[48]	2018	43	M	Polysubstance abuse	Schizophrenia	Decreased level of consciousness	21 days	T2WI: Confluent cerebral white matter hyperintensities. DWI/ADC: Diffusion restriction involving the bilateral centrum semiovale	NA	Supportive	None	Significant improvement in 2.5 months
Tan and Teo[49]	2023	64	M	Carbon monoxide poisoning	NA	Psychomotor agitation	7 days	T2WI: Hyperintensities involving the bilateral globus pallidus	NA	Supportive	None	NA
Tormoehlen et al[50]	2013	46	F	Carbon monoxide poisoning	NA	Pseudobulbar affect	14 days	T2WI: Confluent cerebral white matter hyperintensities	NA	Supportive	NA	Unknown
Wallace et al[51]	2009	28	M	Polysubstance abuse	ETOH abuse	Encephalopathy	35 days	T2 BLADE: Hyperintensities involving the bilateral centrum semiovale	EEG: Normal	Supportive	Ventilatory and hemodynamic support	Significant improvement at 12 months
Wang and Yang[52]	2003	15	M	Substance abuse	NA	Seizures, dysphagia, dystonia, and altered mental status	NA	T2WI: Bilateral globus pallidi hyperintensities	NA	Supportive	NA	NA
Weinberger et al[53]	1994	34	--	Benzodiazepine overdose	NA	Encephalopathy, hyperreflexia, clonus, primitive reflexes, and frontal lobe release sign	24 days	Increased signal within the supratentorial white matter	NA	NA	NA	Persistent cognitive decline
Zamora et al[54]	2015	64	M	Cardiopulmonary arrest	NA	Psychomotor agitation	23 days	T2WI: Confluent cerebral white matter hyperintensities. ADC: Increased signal less extensive than T2WI	NA	NA	None	Moderate improvement
Zamora et al[54]	2015	32	M	Opioid abuse	NA	Encephalopathy	32 days	T2WI: Confluent cerebral white matter hyperintensities. ADC: More extensive than T2WI	NA	NA	None	Significant improvement
Zamora et al[54]	2015	63	F	Polysubstance abuse	NA	Akinetic mutism	35 days	T2WI: Confluent cerebral white matter hyperintensities.ADC: Matched signal to T2WI	NA	NA	None	Significant improvement
Zamora et al[54]	2015	65	M	Polysubstance abuse	NA	Encephalopathy	14 days	T2WI: Confluent cerebral white matter hyperintensities. ADC: Increased signal less extensive than T2WI	NA	NA	None	Significant improvement
Zamora et al[54]	2015	59	F	Opioid abuse	NA	Catatonia	14 days	T2WI: Confluent cerebral white matter hyperintensities. ADC: Matched signal to T2WI	NA	NA	None	Deceased
Shprecher et al[55]	2008	39-56	--	Polysubstance abuse	NA	Catatonia, memory loss, disorientation, encephalopathy	31 days-38 weeks	T2WI: Confluent cerebral white matter hyperintensities. ADC: Diffusion restriction in 2 cases. MRS: Decreased NAA	NA	NA	NA	No significant improvement

DWI/ADC: Diffusion-weighted imaging/apparent diffusion coefficient; EEG: Electroencephalogram; ETOH: Ethanol; MRS: Magnetic resonance spectroscopy; NAA: N-acetylaspartate; ADC: Apparent diffusion coefficient; CSF: Cerebrospinal fluid; IVMP: Intravenous methylprednisolone; ECT: Electroconvulsive therapy; DSIR: Divided subtracted inversion recovery; NA: Not applicable; F: Female; M: Male.

Table 3 Joanna Briggs Institute critical appraisal and risk of bias results for case reports/series

Ref.	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Overall	Risk
Aljarallah and Al-Hussain[7]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Arciniegas et al[8]	Y	Y	Y	Y	Y	N	N	Y	6	Moderate
Arimany et al[9]	Y	Y	Y	Y	N	N	N	Y	5	Moderate
Beeskow et al[10]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Betts et al[11]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Brovelli et al[12]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Cardona Quiñones et al[13]	Y	Y	Y	Y	N	N	N	Y	5	Moderate
Chachkhiani et al[14]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Chen et al[15]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Choi et al[16]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Fong et al[17]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Garzón-Hernández et al[18]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Geraldo et al[19]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Hakamifard et al[21]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Hamlin et al[22]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Hori et al[23]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Hsiao et al[24]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Huarcaya-Victoria[25]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Huisa et al[26]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Jang and Kwon[27]	Y	Y	Y	Y	N	Y	Y	Y	7	Low
Jingami et al[29]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Kim et al[30]	Y	Y	Y	Y	Y	N	Y	Y	8	Low
Law-ye et al[31]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Lee et al[32]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Lou et al[33]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Manjunath et al[34]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Mazo et al[35]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Meyer et al[36]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Mittal et al[37]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Molloy et al[38]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Newburn et al[39]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Nzwalo et al[40]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Pfaff et al[41]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Quinn et al[42]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Rozen et al[43]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Salazar et al[44]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Singu et al[45]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Smolinsky et al[46]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Tahir and Islam[47]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Tainta et al[48]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Tan and Teo[49]	Y	Y	Y	Y	Y	N	N	Y	6	Moderate
Tormoehlen et al[50]	Y	Y	Y	Y	Y	N	N	Y	6	Moderate
Wallace et al[51]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Wang and Yang[52]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Weinberger et al[53]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Zamora et al[54]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Shprecher et al[55]	Y	Y	Y	Y	Y	Y	Y	Y	8	Low

Q1: Were the patient’s demographic characteristics clearly described? Q2: Was the patient’s history clearly described and presented as a timeline? Q3: Was the current clinical condition of the patient on presentation clearly described? Q4: Were diagnostic tests or assessment methods and the results clearly described? Q5: Was the intervention(s) or treatment procedure(s) clearly described? Q6: Was the post-intervention clinical condition clearly described? Q7: Were adverse events (harms) or unanticipated events identified and described? Q8: Does the case report provide takeaway lessons? Overall: Sum of points. Y: Yes; N: No.