Methadone-induced encephalopathy: a case series and literature review

Background Accidental ingestion or consumption of supra-therapeutic doses of methadone can result in neurological sequelae in humans. We aimed to determine the neurological deficits of methadone-poisoned patients admitted to a referral poisoning hospital using brain magnetic resonance (MR) and diffusion weighted (DW) imaging. Methods In this retrospective study, brain MRIs of the patients admitted to our referral center due to methadone intoxication were reviewed. Methadone intoxication was confirmed based on history, congruent clinical presentation, and confirmatory urine analysis. Each patient had an MRI with Echo planar T1, T2, FLAIR, and DWI and apparent deficient coefficient (ADC) sequences without contrast media. Abnormalities were recorded and categorized based on their anatomic location and sequence. Results Ten patients with abnormal MRI findings were identified. Eight had acute- and two had delayed-onset encephalopathy. Imaging findings included bilateral confluent or patchy T2 and FLAIR high signal intensity in cerebral white matter, cerebellar involvement, and bilateral occipito-parietal cortex diffusion restriction in DWI. Internal capsule involvement was identified in two patients while abnormality in globus pallidus and head of caudate nuclei were reported in another. Bilateral cerebral symmetrical confluent white matter signal abnormality with sparing of subcortical U-fibers on T2 and FLAIR sequences were observed in both patients with delayed-onset encephalopathy. Conclusions Acute- and delayed-onset encephalopathies are two rare adverse events detected in methadone-intoxicated patients. Brain MRI findings can be helpful in detection of methadone-induced encephalopathy.


Background
Methadone is a synthetic opioid that is increasingly used as an analgesic and in maintenance therapy of opioidaddicted patients [1,2]. Accidental ingestion of methadone or consumption of its supra-therapeutic doses have been shown to cause multi-organ damage in both humans and animals [1,[3][4][5].
There have been several previous case reports describing acute-onset encephalopathy (AOE) and delayed-onset leukoencephalopathy (DOL) as adverse complications of methadone intoxication [4][5][6]. AOE presents with MRI abnormalities within the first admission of the patient. DOL, however, manifests with abnormalities detected on MRI in patients who have initially responded to treatment (complete resolution of symptoms), but are then readmitted after a period of lucidity (usually days to weeks post the primary event) with neurological or psychiatric deterioration [7][8][9][10].
DOL was first described in a 24-year-old patient who developed apathy and disorientation after the initial improvement from a mixed methadone-benzodiazepine poisoning [16]. Other case studies have reported a range of DOL symptoms, including disorientation, paranoid and bizarre behavior, and severe progressive cognitive decline with bilateral cerebral white matter hyperintensities. MRI changes in these case reports have included diffuse abnormal T2 and FLAIR signals in the corona radiate, centrum semiovale and subcortical white matter throughout all lobes, and signal abnormalities in temporomesial, substantia nigra, and basal ganglia [6,8,9,12,13,[17][18][19][20][21]. The aim of our study was to identify and describe the pattern of neurological deficits and associated brain magnetic resonance imaging (MRI) changes in methadone-poisoned patients.

Methods
In this retrospective file audit, the clinical records of all patients admitted to our referral poisoning hospital with the diagnosis of methadone intoxication between May 2016 and March 2018 were reviewed. A total of 2930 cases were identified, of whom only 10 fulfilled the inclusion criteria.

Definitions
Methadone intoxication was defined based on history, clinical presentations of respiratory depression (opioid toxidrome) or loss of consciousness (LOC) responsive to administration of naloxone, as well as detection of methadone in urine analysis. The patients were classified into two subtypes: acute-and delayed-onset encephalopathy (AOE and DOL, respectively) based on clinical history. Patients with persistent neurological deficits in their first admission were categorized to have AOE based on their MRI changes. Those who had been discharged after either complete or partial recovery from acute intoxication, but then deteriorated with neurological signs or symptoms within several days or weeks necessitating readmission were considered to have DOL [7][8][9]. The most prevalent delayed symptoms included psychotic delirium, fluctuating state of consciousness, depression, apathy, and bizarre behaviors [9][10][11][12][13]. Complete knowledge of time courses and clinical presentation was a prerequisite in categorization of the patients. Imaging was performed due to persistent neurological deficits several days after admission or if there was re-occurrence of neurotoxicity after a lucid interval of at least 1 week.

Inclusion criteria
AOE: Patients who had been admitted due to methadone intoxication and had undergone imaging due to persistent neurological deficits were enrolled in AOE group.
DOL: Neurological deficits were defined as a deterioration of neurologic function leading to readmission within one to 3 weeks after discharge without any new toxic exposure. Patients fulfilling this criteria were enrolled into the DOL group.

Exclusion criteria
If methadone diagnosis was not confirmed after the review of the history, presentation, and urine analysis. Patients who had co-ingestions confirmed by urine analysis were also excluded (e.g. Alcohol). Any cases with possible intoxication, with a coingestants known to cause MRI complications (carbon monoxide [CO], methanol, cyanide, etc.) were excluded.

Imaging
Scans were performed by a 1.5-T multi-planar MRI device. Echo planar T1 (TR: 591 ms, TE:15 ms, Spatial Resolution: 6.2 mm slice thickness, FoV: 230 mm*230 mm), T2 (TR: 4048 ms, TE:90 ms, Spatial Resolution: FLAIR, diffusion weighted imaging (DWI) and apparent deficient coefficient (ADC) sequences without contrast media were performed. The scan time was 15 min. All images were reviewed by a single radiologist experienced in MRI. Detected abnormalities were recorded and categorized based on their anatomic location and sequence. The areas with both restriction in DWI and low signal in abnormal diffusion restriction (ADC) were considered abnormal.

Results
Eight patients had a brain MRI performed during their first admission due to persistent neurological deficit despite active treatment (AOE group; Tables 1 and 2). This group included four children (aged 23 months to 16 years) who had accidentally ingested methadone. The other two had developed new neurological deficits days after the initial recovery from intoxication (DOL group; Table 3). All ten patients had abnormal findings on MRI.

AOE group
Seven patients in this group were male and median age was 23 years [range; 23 months to 33 years). Based on urine analysis, three cases had positive urine for other drugs. One had received benzodiazepine as a part of medical management. Other two were multi-opioid abusers, but had only overdosed on methadone. Imaging findings in this group included bilateral confluent or patchy T2 and FLAIR high signal intensity areas in cerebral white matter in six ( Fig. 1), cerebellar involvement in four (Fig. 2), and bilateral occipitoparietal cortex signal abnormality (low on T1 and high on T2) associated with diffusion restriction (confirmed with low signal intensity in ADC) in three cases ( Fig. 3) and without restriction in one case. Internal capsule involvement was detected in two patients with hyper-signal corpus callosum in one. Abnormalities in the globus pallidus and the head of caudate nuclei were reported in only one patient. The MRIs were performed at 2-and 12-day intervals after initial presentation with methadone intoxication (defined as the primary toxic event).

DOL group
The two patients in this group were 47 and 49 years old and had a 9-and 18-day lucid interval, respectively, between the initial presentation and clinical relapse (Table 3). Confluent bilateral symmetrical cerebral white matter signal abnormality with sparing of subcortical U-fibers on T2 and FLAIR sequences were observed in both of these patients (Fig. 4).

Discussion
Methadone-induced encephalopathy is a rare event. To date, this phenomenon remains poorly characterized [4,5,21]. The brain MRI changes reported in the literature are summarized in Table 4 and include: cerebellum   [4,5,11,12,14], signal changes in hippocampus [10], globus pallidus [13], and in a single case report in the head of caudate nuclei [4]. In addition, there is a single case report of a 2-year-old infant found to have cerebral white matter, cerebellar, and globus pallidus hypodensities based on computed tomography (CT) scan [22]. In our AOE patients, the most frequent MRI finding was bilateral confluent or patchy cerebral white matter hyperintensity (n = 5). Cerebellar abnormalities were detected in only three cases despite this was the most common observed abnormality in previous studies [1,10,13]. A consistent (n = 4) and new finding in these patients was bilateral parieto-occipital cortex T2 and FLAIR hyperintensity. This radiological finding has also been reported in patients with posterior reversible encephalopathy syndrome (PRES [23];). PRES has been reported as a consequence of or in conjunction with a variety of critical illness states including severe hypertension, hemolyticuremic syndrome, thrombocytopenic thrombotic purpura, and in association with drug toxicities such as cisplatin, cyclophosphamide, interferon [23][24][25], and opiates such as morphine [26,27]. In keeping with the findings in PRES, three of our patients had bilateral parieto-occipital cortex restriction in DWI which was confirmed by ADC sequence. Additionally, restriction was observed in one patient with internal capsule involvement (case 7). Restriction in bilateral cerebral white matter has previously been reported secondary to methadone toxicity [4,11]. One study suggested that "deep watershed infarct" resulted in the restriction imaging observed [11]. Given our observations and previous published reports, it can be postulated that the changes in AOE due to methadone could result in PRES.
We also had two patients who had internal capsule involvement. This finding is in accordance with previously published reports as a characteristic of heroin toxicity [28]. In our both patients, morphine and methadone were detected in urine analysis. Therefore, heroin use cannot be ruled out. Additional confirmatory testing for supplementary heroin metabolites would have been useful in these two individuals. However this was not available in our center. One of them (Case 5) demonstrated lesions in splenium of corpus callosum, a finding never reported before in either heroin or methadone intoxication. This finding may be a transient lesion of splenium and has been associated with various clinical conditions such as seizures, metabolic disturbances, infections, CNS malignancy, and drugs and toxins (antidepressants, antiepileptics, antipsychotics, chemotherapy agents, and pesticides) [15,[28][29][30][31][32][33][34][35][36][37][38]. We also had a single patient (case 8) who showed involvement of the globus pallidus and head of caudate nuclei. This finding has been observed  in association with methadone toxicity [4,13]. Previously, brain imaging changes associated with methadone intoxication were suggested to be as a consequence of hypoxic events secondary to overdose [12]. However, hypoxia-associated cerebral adverse effects on imaging seem to be only a result of prolonged hypoxia [39,40]. Majority of our patients did not have a persistent documented hypoxic insult. Brain neuroimaging was performed on admission, and before the worsening of patient's condition. Secondly, brain and cerebellar damage demonstrated at both diagnosis and follow-up showed a clear-cut prominent involvement of the subcortical white matter. In adulthood, hypoxic-ischemic insults usually result in watershed zone infarcts when mild to moderate, and affect the gray matter in the basal ganglia, thalami, cerebral cortex, cerebellum, and hippocampi when severe. Furthermore, severe insult generally includes a stage of diffuse cerebral edema with loss of differentiation between gray and white matter, a finding that was not noted in the patients reported.
Furthermore, acute and early subacute phases of hypoxia-induced encephalopathy primarily affect the basal ganglia, thalamus, and cortex [41]. We reported bilateral cerebral white matter and cerebellum abnormalities as the most common brain MRI finding.
To date, only 8 case reports evaluating 11 patients have been published reporting delayed-onset methadone-induced leukoencephalopathy [6,10,[16][17][18][19][20], summarized in Table 5. The most frequent imaging findings in case reports of patients with DOL is bilateral cerebral white matter T2 and FLAIR hyperintensity [6,8,9,16,18,20] followed by corpus callosum [9,16] and globus pallidus [8] involvement. This is in keeping with our observation of bilateral cerebral white matter hyperintensity. However, the findings in DOL group are not generalizable, as there were only two cases in this group, who also lacked imaging in their acute phase for comparison with the DOL phase imaging. Furthermore, during examination of DWI and ADC, no restriction was found in either case. Four patients have been described  with restriction in DWI scans, although a correlation with ADC was not reported in them [9,17,18,20]. It is possible that the restrictions observed in these patients is related to T2 shine through, as this phenomenon has also been observed in our patients.
Almost all published case reports to date are in adult patients, except for a single case of 30-month-old infant. There are no previous publications on DOL due to other reasons (strangulation, CO poisoning, benzodiazepine overdose, etc.) in adults younger than 30 years [7]. Since both of our patients were also adults, it is possible that DOL is a phenomenon more common among adult patients. DOL has been previously suggested to be due to hypoxia [6,16]. However, given that neither of our patients had history of prolonged unconsciousness or respiratory depression, hypoxia as an etiology can be  excluded. The lucid intervals of one to 5 weeks have been reported in earlier case reports [7], which was reinforced with our cases.

Conclusion
Methadone intoxication can result in a spectrum of encephalopathies ranging from AOE to DOL which can be diagnosed using MRI findings. Future studies on larger sample sizes are required to elucidate this association with its possible imaging findings. Our study is the first to demonstrate that MRI changes due to methadone intoxication can parallel those observed in PRES in both adults and children. Given that both heroin and morphine have been previously reported to present with changes suggestive of PRES, it is reasonable to extrapolate this to be an opioid class effect. In DOL, bilateral T2 and FLAIR white matter hyperintensity was the common finding. Therefore, in patients with a recent history of methadone intoxication who represent with relapsing neurological symptoms, DOL needs to be considered.