Psychosomatics 42:530-533, December 2001
© 2001 The Academy of Psychosomatic Medicine
Delayed Post-Hypoxic Leukoencephalopathy
Hochang B. Lee, and
Constantine G. Lyketsos
Received June 1, 2000; revised June 28, 2001; accepted July 2, 2001. From the Neuropsychiatry Service, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD. Address correspondence and reprint requests to Dr. Lee, Osler 327, Department of Psychiatry and Behavioral Science, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287–5371.
Key Words: Delirium • Leukoencephalopathy
The syndrome of delayed neurologic deterioration with cerebral demyelination has been reported in the literature several times as occurring in the setting of carbon monoxide poisoning.1–4 However, this syndrome is now more commonly seen in the context of drug overdose with heroin or benzodiazepine and in other situations that lead to severe hypoxia.5,6 It is well known that anoxic or hypoxic injury produces acute neurologic deficits. It is less well known that severe neurologic consequences may be delayed for days or weeks after the injury and that the corresponding radiological findings may be delayed even later.1–6
This case report illustrates a case of delayed-onset leukoencephalopathy due to hypoxic injury. Generally, a psychiatrist encounters post-hypoxic leukoencephalopathy in an inpatient setting as a consulting physician for a patient who has just been subjected to an extensive medical workup. The goal is to demonstrate how the temporal separation between the injury and the neuropsychiatric sequelae and/or radiological findings presents a diagnostic challenge for the clinician. Also, two recent reports on delayed post-hypoxic demyelination suggest an association with pseudodeficiency of arylsulfatase A as a predisposing factor.5,6 As far as we know, this is the second report of a patient with normal arylsulfatase A activity who developed delayed post-hypoxic demyelination.10
Case Report
Ms. Z. is a 71-year-old white real estate saleswoman with no prior known psychiatric or medical history other than recent low back pain. On the night of an accidental overdose, Ms. Z. mistook three of her husband's 2-mg alprazolam tablets as her pain relievers, and the next morning she was found unconscious by her husband. When she was taken to a local hospital, chest x ray found Ms. Z. to have a large left-side infiltrate. She had a fever of 100.4° F and was moderately hypoxic (with corresponding arterial blood gas results: pH=7.29, PCO2=, PO2=55 on room air); white blood cell count was 14,500. On the basis of this presentation, Ms. Z. was thought to have developed aspiration pneumonia while intoxicated on alprazolam. Within 3 days of appropriate antibiotic regimen and supportive measures, she recovered fully, walked out of the hospital under her own power, and resumed her daily routine as a real estate agent for the next 2 weeks.
However, on Day 14 after overdose, Ms. Z. began acting oddly, as she repeatedly called her co-worker every 10 minutes to ask for directions to her workplace where she had worked for the past 10 years. Alarmed, her co-worker contacted Ms. Z.'s son, who minutes later found his mother disoriented and confused in the driver seat of her car in the driveway. Ms. Z.'s son took her to the same hospital emergency department where she was noted to be alert but disoriented to time and place but with normal physical and neurological examinations. She was admitted with an initial diagnosis of "delirium of unknown etiology." Initial work up, including comprehensive metabolic panel, liver function test panel, Heme 8, and thyroid-stimulating hormone level, was within normal range. Electroencephalogram (EEG) showed diffuse delta wave pattern, which was consistent with delirium but otherwise not informative. Magnetic resonance image (MRI) of her brain (Figure 1) on the day after her admission was normal. During the next 2 days of her rehospitalization, Ms. Z. deteriorated steadily. She became increasingly unredirectable, drowsy, and incontinent of urine and stool. She developed increased tone in extremities and a shuffling gait. She was no longer able to walk without extensive assistance from others. Further tests, including photon emission computed tomography scanning, cerebrospinal studies, and rheumatological investigation, were done without yielding positive results. Because Ms. Z. showed no improvement and steadily deteriorated during her next 4 days of hospitalization, her family requested that Ms. Z. be transferred to another hospital.
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FIGURE 1. Magnetic resonance image of MsZ which appears normal at Day 17 after the overdose (2 days after the onset of her delirium)
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On Day 20 after the overdose (7 days after the onset of her delirium), Ms. Z. was transferred to the Geriatric Psychiatry Inpatient Unit at Johns Hopkins Hospital. On arrival, her mental status examination revealed a well-nourished white female, who was very drowsy and inattentive. Her level of consciousness was waxing and waning. She blinked her eyes constantly as if trying to stay awake. She was inappropriately scratching her genitalia during the mental status exam, and her speech was notable for being monosyllabic. Her answers consisted of "yes" and "no" only. Occasionally she would nod her head or shake her head, at times inappropriately. She was unable to cooperate with assessment of mood, hallucinations, delusions, anxiety symptoms, cognitive assessment or assessment of patient's fund of knowledge, judgment or insight. She scored 0/30 on the Mini-Mental State Exam.7 Her physical examination was essentially normal with normal vital signs, and she was afebrile. Her neurological examination did not reveal any focality, and her cranial nerve examination II-XII were also grossly normal. Reflexes were increased symmetrically in all joints; gait was significant for shuffling and retropulsion. She could not comply with the cerebella examination, but she did not have truncal ataxia. Repeat EEG showed bilateral moderate-voltage theta and delta activity symmetrically, and no lateralizing signs or epileptiform abnormalities were detected. Ms. Z. was admitted with a diagnosis of "delirium of unknown origin."
On transfer, Ms. Z.'s urine toxicology was positive for opioid and benzodiazepine, given during recent lumbar puncture and MRI procedures for sedation at the previous hospital in Florida. However, since these might also have affected her cognitive state and attention, the treatment team initially waited and observed her with the hope that the apparent delirium would gradually improve. However, even after 4 days, the symptoms of cognitive impairment, gait disorder, and incontinence remained unimproved and appeared to plateau. On Day 24 after the overdose, neurology was consulted, and the consulting neurology team raised additional differential diagnostic considerations: progressive supranuclear palsy; Pick's disease; Creutzfeldt-Jakob disease; normopressure hydrocephalus; and frontal lobe tumor. Therefore, aggressive delirium work up was repeated. Repeat EEG showed intermittent slow activity bilaterally and symmetrically, again consistent with a diffuse cerebral disturbance; there was no epileptiform discharges or lateralizing signs. Repeat lumbar puncture was conducted. The opening pressure was within normal range, and the cerebrospinal fluid (CSF) was obtained again for appropriate viral, fungal, and bacterial culture. A portion of CSF sample was sent to the National Institutes of Health for screening for the prion disease. All these tests were normal. However, when the MRI of head (Figure 2, A and B) was repeated, it revealed diffuse degenerative white matter periventricular changes, not seen on her first MRI at the onset of symptoms 2 weeks earlier. Extensive literature review revealed that the history, symptoms, signs, and MRI findings corresponded to the syndrome of delayed-onset post-hypoxic leukoencephalopathy.
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FIGURE 2. Magnetic resonance images of MsZ that show diffuse periventricular white matter lesions 3 weeks after the onset of her delirium
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On Day 31 after overdose, Ms. Z. began to improve at a very gradual pace with supportive therapy only. She became more responsive and began to recognize her family. She expressed distress when she was about to urinate or defecate. She also began to speak simple sentences in efforts to communicate. After more than a month of extensive physical rehabilitation and occupational therapy, her gait improved to the point that she could walk independently. She was no longer incontinent. Her cognition improved but she was still severely impaired (MMSE=18/30), and she needed extensive cueing to carry out her activities of daily living at time of discharge. On Day 47 after overdose, Ms. Z. was transferred to a rehabilitation unit at another hospital.
Six months after the onset of her symptoms, Ms. Z. regained most of her cognitive power and resumed independent living in Florida. On her latest visit to Johns Hopkins, she scored 28/30 on the MMSE. She had a normal neurological exam with slight wide-based gait. She was tested for arylsulfatase A activity to screen for pseudodeficiency of arylsulfatase A. Results were within the normal range: 59 nanomoles substrate cleaved/mg protein cleaved (control mean±2SD=55±22 nanomoles substrate cleaved/mg). Ms. Z.'s clinical history, MRI images, and arylsulfatase A activity were submitted to the Delayed Postanoxic Demyelination Registry.9
Discussion
Ms. Z.'s case illustrates delayed demyelination of cerebral white matter after a hypoxic episode due to drug intoxication. The differential diagnoses of delayed demyelination include multiple sclerosis, acute disseminated encephalomyelitis, allergic encephalomyelitis, progressive multifocal leukoencephalopathy, radiation therapy-induced delayed encephalopathy, chemotherapy-induced neurotoxicity, and several rare forms of leukodystrophy. Our patient's relapsing clinical course and eventual recovery were similar to other reports of delayed hypoxic leukocencephalopathy1–6 These cases have in common a hypoxic insult, followed by a period of full recovery, and then profound deterioration with MRI or CT evidence of diffuse periventricular white matter changes in brain.
Other neurologic sequelae such as urinary incontinence, gait disturbance, mutism, tremor, weakness, and speech disturbance have been similarly described in previous reports of post-hypoxic delayed leukoencephalopathy.1–6 The hypo/akinetic motor syndromes (parkinsonism, akinetic mutism, or motor neglect) among these patients suggest lesions in the motor circuits involving basal ganglia (i.e., globus pallidus). Among the basal ganglia motor circuits, diffuse demyelination involving the tracts of the indirect motor circuit pathway (supplementary motor area-caudate-internal pallidum-ventrolateral thalamocortical) is a likely culprit of the motor neglect and akinetic mutism among these patients. Late remyelination of the pathways would account for the gradual clinical improvement.
How much hypoxia is needed to cause demyelination is debatable. Ginsberg et al.,11 who reviewed 36 cases of hypoxic-ischemic leukoencephalopathy, report that hypoxia itself need not be profound as these lesions typically spare gray matter structures. In fact, one of Ginsberg's own three cases also had moderate hypoxia as well (arterial PO2=52–56). In our patient, the documented level of hypoxia was modest (arterial PO2=55). However, because half-life of alprazolam is between 5 and 12 hours, we believe that the level of hypoxia in our patient might have been more profound prior to her arrival at the Emergency Department several hours after the ingestion.
The striking aspect of this case is the 2-week delay of the demyelination process relative to the hypoxic injury. Choi4 reports that 2.75% of the 2,360 victims of acute carbon monoxide intoxication had delayed neurologic sequelae 2–40 days (mean=22.4 days) after the initial injury. Two victims of drug overdose reported by Weinberger et al.6 and Gottfried et al.5 had 14 and 24 days of delay preceding the onset of symptoms. The two recent reports on delayed post-hypoxic demyelination suggest an association with pseudodeficiency of arylsulfatase A as a predisposing factor.5,6 Weinberger et al.6 and Gottfried et al.5 reported that both patients had pseudo-deficiency of arylsulfatase A as shown by measured arylsulfatase activity between 10% and 50% of normal. Complete absence of arylsulfatase A causes a lysosomal accumulation of sulfatide within oligodendrocytes and Schwann cells and disrupts myelin metabolism. This results in metachromatic leukodystrophy, a congenitally acquired disease that is inherited as an autosomal recessive trait. However, arylsulfatase A pseudodeficiency is a genetic defect not known to produce cerebral disease independently.8 Gottfried et al.5 and Weinberg et al.6 speculate that this normally asymptomatic condition may predispose a small percentage of patients exposed to hypoxia to the development of delayed white matter loss. Weinberger et. al.6 hypothesize that following a cerebral hypoxic insult, greatly increased need for myelin turnover may have exceeded the residual arylsulfatase A capacity of their patients with arylsulfatase A pseudodeficiency. On the basis of this theory, the delay in development of neurological symptoms reflects the depletion period of the partially deficient arylsulfatase A capacity among patients with pseudodeficiency.
However, Heckmann et al.10 reported a 65-year-old man with delayed hypoxic leukoencephalopathy with normal arylsulfatase A activity in the peripheral leukocytes. Our similar finding of the normal arylsulfatase A activity in Ms. Z.'s case also supports the view that pseudo-deficiency of arylsulfatase A is not a necessary precondition for development of post-hypoxic demyelination. Heckmann et al.10 hypothesize that the delay is caused by the selective necrosis of myelin-producing glia cells in the border zones of the white matter. The clinical consequences would be delayed due to the long half-life of myelin (2.5–8.7 days) as the necrosis of the myelin sheaths is known to follow the cell necrosis after 10–14 days.12 However, the rarity of this condition seems to suggest unidentified individual susceptibilities to hypoxic neuronal injury. Aside from partial arylsulfatase A deficiency, deficiency of other enzymes involved in myelin synthesis or breakdown may still be important.
The diagnosis of post-hypoxic delayed demyelination syndrome should not be missed because prognosis of this syndrome is quite good. Choi4 reported 75% full recovery in 1 year, and Shillito and Drinker1 reported 50% full recovery within 2 years. Wainapel et al.13 reported a dramatic functional recovery 3.5 months after admission for a man who developed severe spastic quadriplegia from a mixed drug overdose-induced post-hypoxic leukoencephalopathy; they emphasized the importance of early and continued vigorous rehabilitation therapy for patients with post-hypoxic leukoencephalopathy. There are no controlled trials of specific therapy or prophylaxis for delayed neurologic sequelae of hypoxia. Steroids, aspirin, and cerebral vasodilators were used in attempts to prevent and treat delayed neurologic sequelae, but they were reported to be ineffective.4 High-potency neuroleptic medications should be avoided for their higher tendency to cause rigidity and other extrapyramidal signs, which may already be present in these patients with post hypoxic delayed demyelination syndrome. Also, given that these patients have propensity for developing delirium, psychotropic medication should be minimized.
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