Neuropsychological, neuroimaging and autopsy findings of butane encephalopathy

Butane is an aliphatic hydrocarbon that is commonly used as a commercial product or chemical agent (e.g., cigarette or charcoal lighter fuel, hair spray, and aerosol). Butane inhalation can cause sudden death by cardiac arrest following cardiac arrhythmia and vagal stimulation [1]. It also causes respiratory depression and hypoxia due to oxygen replacement, leading to encephalopathy [2]. While there have been several reports of fatal cardiac toxicity after butane inhalation [3‐6], cases of acute encephalopathy associated with butane intoxication have rarely been reported [1, 2, 7, 8]. Furthermore, little is known about the serial neuroanatomical and functional changes and neuropsychological sequelae related to butane encephalopathy. We report a patient who presented with cognitive dysfunction after butane inhalation, with serial brain magnetic resonance imaging (MRI), [¹⁸ F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), neuropsychological assessment over an 8-month period, and autopsy findings.

A 38-year-old man was found in his car with butane-containing cans for a portable cooking gas stove 6 days after disappearance and four days later he was brought to the emergency room because of altered mental status. On arrival, he was mildly drowsy and disoriented to time. He could obey commands; however, his reaction was slow. He showed short-term memory deficits and asked the same questions repeatedly. He exhibited emotional blunting. His vital signs and oxygen saturation were within normal limits. He had isocoric pupils without dilatation. Neurological examination findings were unremarkable. Routine laboratory examination results, including arterial blood gas analyses, cardiac markers, COHb (0.1%), and metHb (0.6%) were all normal. There were no abnormalities on the electrocardiogram or echocardiogram. A mini-mental state examination score was 24 of 30. T2-weighted and fluid-attenuated inversion recovery brain MR images showed symmetric high signal intensities involving the bilateral hippocampus and globus pallidus, which were also detected in diffusion-weighted images (Fig. 1A). The apparent diffusion coefficient values were also high. FDG-PET revealed glucose hypometabolism in the bilateral precuneus, occipital, and left temporal areas (Fig. 1C, upper row). An electroencephalogram showed intermittent theta to delta slowing. On the third day of admission, his mental status recovered from drowsiness to alertness. Detailed neuropsychological test results showed deficits in verbal and visual memory and frontal executive function (Table 1). Six days after admission, he remained stable without clinical aggravation. At the 8-month follow-up neuropsychological evaluation, he showed mild improvement compared with his initial performance but still significant deficits in memory and frontal functions in comparison with education-matched, 45-year-old cognitively normal controls (Table 1). However, abnormal behaviors such as irritability, obsession with food, and lethargy became more prominent. Follow-up brain MRIs showed diffuse cortical atrophy with white matter hyperintensities (Fig. 1B). Follow-up FDG-PET revealed glucose hypometabolism more extensively involving the bilateral frontoparietotemporal areas (worse on the left) than the previous one (Fig. 1C, lower row). Two months after the second evaluation, he died unexpectedly, and a brain autopsy was performed. Grossly, there was no definite cortical atrophy. However, necrosis and cavitary lesions in the globus pallidus (Fig. 2A) and atrophy in the hippocampus (Fig. 2B) were detected. Microscopically, hematoxylin and eosin staining revealed severe gliosis, necrotic changes, and neuronal loss in the globus pallidus and hippocampus (Fig. 2C and D). Luxol fast blue staining revealed widespread demyelination of the subcortical white matter (Fig. 3). Immunohistochemical staining for tau, β-amyloid, TAR DNA binding protein, and α-synuclein revealed no abnormalities in immunoreactivity.

Butane is a highly lipophilic and volatile substance frequently used as a fuel source for cooking at home and camping in Korea. Although fatal cardiac arrhythmia due to myocardial sensitization to catecholamine after butane intoxication is well documented, little is known about the potential mechanism of encephalopathy associated butane inhalation [1, 2, 9]. Kile et al. reported a 16-year-old male with acute butane encephalopathy associated with bithalamic lesions. They suggested that bithalamic injury could have been attributed to direct butane toxicity (toxic-metabolic encephalopathy) rather than anoxic or hypoxic brain injury resulting from asphyxia by butane displacing oxygen [7]. Thalamic injury has been described in other types of toxic-metabolic encephalopathies (7) but less so than other lesions, such as the globus pallidus in anoxic or hypoxic encephalopathy (10). Previous reports on butane encephalopathy described brain MRI findings from normal to various brain lesions, including the thalamus, putamen, cerebellum, insula, and occipital cortex [1, 2, 7, 11‐14]. However, as in our case, bilateral hippocampal and globus pallidal lesions have not yet been reported. One case of toxic encephalopathy revealed bilateral hippocampal and white matter damage; however, the toxic substance was propane gas, not butane, although both were liquefied petroleum gases [6]. The globus pallidus is most commonly affected in anoxic–ischemic encephalopathy due to carbon monoxide (CO) poisoning because of its high metabolic demands and weak vascular perfusion [10]. The hippocampus may also be involved in CO poisoning, as it is the region most vulnerable to hypoxic–ischemic injury [15, 16]. Therefore, based on radiological findings, we could assume that hypoxic–ischemic encephalopathy developed after exposure to butane. As the patient did not have any cardiac problems, hypoxic–ischemic events may have resulted from asphyxia after butane inhalation. Indeed, it may be doubtful why restricted diffusion along with high ADC values in predilection areas was observed in our case. There has been a report that transient vasogenic edema can be occurred after acute CO exposure [10]. Alternatively, it could be explained that the initial low ADC values reflecting cytotoxic edema gradually increased (vasogenic edema) during the 4 or 10-day interval from the patient’s exposure to butane to taking the initial MRI. No previous reports of butane encephalopathy have described serial MRI findings. However, diffuse cortical atrophy at the 8-month follow-up MRIs in our case corresponded well to those in prior studies addressing marked atrophic changes occurring within 6 months of CO exposure, and these changes were attributed to neuronal loss and necrosis in the acute stage [10, 17]. Furthermore, diffuse white matter changes on follow-up MRIs are consistent with those detected in delayed posthypoxic encephalopathy, which is evidence of extensive demyelination [18]. The radiological findings after representative toxic encephalopathy or hypoxic-ischemic injury are summarized in Table 2.

Regarding FDG-PET findings, initially predominant glucose hypometabolism in the precuneus progressed to extensive frontoparietotemporal hypometabolism at the 8-month follow-up. Interestingly, the initial finding of selective precuneus hypometabolism partially corresponds with previous research demonstrating reduced functional connectivity between the hippocampus and precuneus in the early stage of Alzheimer’s disease with hippocampal atrophy and structurally unaffected precuneus [19]. Therefore, selective impaired memory in the first neuropsychological test in our case was generally consistent with the initial brain injury pattern. However, his performance remained generally unchanged during the follow-up test and was not correlated with the widely distributed glucose hypometabolism attributed to diffuse cortical atrophy with white matter hyperintensities on follow-up images. Only one previous report has described cognitive performance in detail after butane inhalation. Woods et al. reported a 14-year-old girl with severe verbal and nonverbal declarative memory impairment with normal brain MRI findings after successful resuscitation following ventricular fibrillation arrest [13]. In contrast to our case, the patient’s cognitive function showed improvement or returned to normal at 3-month follow-up [12].

Lastly, autopsy results showing necrosis of the globus pallidus and extensive white matter demyelination confirmed those findings on brain MRIs.

Our case is of particularly interest because, to the best of our knowledge, this is the first report describing serial structural and functional images with autopsy findings associated with butane encephalopathy. However, it should also be noted that these neuroimaging and pathological findings may not be specific for butane encephalopathy but may be present in any patient with hypoxic–ischemic encephalopathy, regardless of any etiological volatile substance.