Delayed hypoxic leukoencephalopathy is a recognized complication of carbon monoxide poisoning,
1—
3 asphyxial gas poisoning,
4 surgical anesthesia,
4 cardiac arrest,
4,
5 and opiate or benzodiazepine overdose.
6—
10 It typically manifests 2 to 40 days after apparent recovery from an obtunded state, and patients demonstrate cognitive impairment, upper motor neuron signs, gait disturbance, or psychosis.
1,
4
A 39-year-old woman with a history of major depression became obtunded with room air oxygen saturation of 37% following an overdose of liquid methadone and cocaine. After a brief intensive care stay for aspiration pneumonia and hypotension, she was able to return to work. Four weeks after her discharge, she was readmitted with mental status decline. On examination, she was disoriented and tangential, with profound impairment of attention and short-term memory. Her reflexes were diffusely brisk, with a right-sided Babinski response. Gait was unsteady, with stumbling to the left.
An MRI of the brain (Figure 1
) showed diffusely increased T2/FLAIR signal in the white matter of the centrum semiovale extending to the subcortical region, with diffuse restriction on diffusion weighted imaging. The basal ganglia and posterior fossa were normal in appearance. Single voxel magnetic resonance spectroscopy (MRS) showed mildly decreased N-acetylaspartate peaks and no evidence of abnormal lactate. EEG showed continuous polymorphic 2—8/sec delta-alpha waves.
Laboratory studies were significant for elevated CSF myelin basic protein of 46.33 ng/ml (normal range 0.07 to 4.1 ng/ml), with normal protein, glucose, cell count, IgG index, and oligoclonal bands; AST 159 (14—50 U/liter); ALT 97 (9—52 U/liter). Leukocyte arylsulfatase-A was 5.3 (normal greater than or equal to 2.5 units per liter). Erythrocyte sedimentation rate, serum folate, thyroid-stimulating hormone, free T4, T3, Epstein-Barr virus and cytomegalovirus by polymerase chain reaction were normal. Antiglutamic acid decarboxylase, antithyroglobulin, anticardiolipin, beta-2-glycoprotein, double stranded DNA, and antinuclear antibody titers were negative.
Thirty-two weeks after the patient’s overdose, exam showed bilateral gegenhalten with grasp and palmomental reflexis, diffuse hyperreflexia, and flexor plantar responses. One year postoverdose, she continued to have emotional lability, fatigue, and impaired attention that prevented her from working or driving. MRI showed diffuse cerebral volume loss, with incomplete resolution of white matter signal abnormalities. WAIS-R had been administered 10 years prior (following a minor motor vehicle accident). Recognizing psychometric differences between the two editions, WAIS-III administered 1 year postoverdose reflected the following declines: verbal IQ from 102 to 89, performance IQ from 98 to 81, and full scale IQ from 100 to 85, with major declines in immediate memory, abstraction, inductive reasoning, and block design.
A 51-year-old woman treated with transdermal fentanyl for fibromyalgia was switched to oral methadone. Two days later, in an apparent overdose, her family found her unconscious. Following 2 days of intubation she made a complete recovery. Twenty-one days after the event her daughter noted mental status decline, including staring at a blank TV screen, loss of interest in board games, and paranoid delusions that neighbors were watching her. By 28 days after the event, the patient was catatonic, with no participation in activities of daily living or interaction with others, incontinence of bowel and bladder, and frequent automatisms (stroking of the face and rapid sequential hip flexion). Examination showed hypokinetic-rigid mutism, vocalization only to pain, and normal upper extremity reflexes despite asymmetric rigidity. Lower extremity reflexes were absent.
Cerebrospinal fluid studies revealed myelin basic protein 41.33 ng/ml and protein 64 mg/dl (normal range 15—45 mg/dl), with normal glucose, cell count, IgG index, and gram stain; oligoclonal bands were absent. Serum toxicology screen was positive for methadone, and urinalysis was positive for leukocyte esterase and bacteriuria.
A brain MRI showed diffuse symmetric T2/FLAIR hyperintensity in the hemispheric white matter bilaterally. An EEG showed continuous polymorphic 2—6/sec delta-theta waves, with right hemispheric prominence.
Two weeks after the onset of symptoms, the patient showed mild improvement, participating in prompted voiding and walking with physical therapists, but remaining dependent in all respects.
At follow-up 16 weeks postoverdose, the patient was no longer mute and complained of fatigue, cough, generalized weakness, and myalgia. Exam showed Mini-Mental State Examination (MMSE) score of 27/30; she was unable to draw intersecting pentagrams, missed the date, and had 5-minute recall of two-thirds objects. There was mild asymmetric rigidity. Her coordination, strength, and reflexes were normal. Her gait was slow, antalgic, and wide-based.
At 38 weeks postoverdose, short-term memory and balance impairment persisted, and she required continued assistance with self-care. An MRI showed interval cerebral atrophy with incomplete resolution of white matter signal abnormalities.
A 56-year-old woman with a history of depression was admitted with acute renal failure and rhabdomyolysis following intentional overdose of methadone, fentanyl, and benzodiazepines. She was discharged at baseline 11 days later. Day 15 postoverdose she developed severe progressive cognitive decline. An exam showed MMSE score of 15/30, with disorientation and profound impairment of attention and short-term memory. There were a right pronator drift, diffusely brisk reflexes with clonus (except for trace bilateral Achilles), and an unsteady shuffling gait.
Laboratory studies from day 18 postoverdose included normal CBC; complete metabolic panel; and CSF protein, glucose, and cell count. The blood sample for arylsulfatase-A was lost due to an error in the laboratory.
An MRI on day 14 postoverdose showed marked confluent T2/FLAIR hyperintensity, with diffusion restriction involving nearly the entire periventricular and subcortical white matter. Diffusion restriction was still present 31 days postoverdose (Figure 2
). An EEG showed diffuse slowing. At 8 weeks postoverdose, the patient required full-time supervision for self-care and had persistent impairment of short-term memory and attention.
FLAIR images 5 weeks postoverdose (A, B) show hemispheric white matter hyperintensity sparing the u-fibers. One year postoverdose (C, D), there is interval cerebral atrophy with incomplete resolution of white matter changes.
(A) MRI 4 weeks postoverdose shows diffusion restriction with apparent diffusion coefficient correlate (B) throughout hemispheric white matter.