Carbon monoxide (CO) is a colorless and odorless toxic gas produced as a by-product of incomplete combustion of carbon-based fuels and substances. It is the most common lethal poison worldwide, and neurologic sequelae are the most frequent form of morbidity [1–3]. The pathophysiologic mechanisms of CO toxicity can be divided into hypoxic and cellular theories [1, 4]. The affinity of CO for heme protein is approximately 250 times that of oxygen, and the formation of carboxyhemoglobin reduces the oxygen-carrying capacity of blood, causing tissue hypoxia [1, 5]. CO inhibits the mitochondrial electron transport enzyme system and activates polymorphonuclear leukocytes, which undergo diapedesis and cause brain lipid peroxidation, leading to the delayed effects of CO poisoning [2, 3, 5]. The clinical presentations and imaging features of CO poisoning are diverse. The purpose of this essay is to illustrate the spectrum of brain injury patterns after CO inhalation.

Acute brain injury in CO-exposed patients appears to arise largely from hypoxia. Studies with mice, however, have shown that cerebral blood flow initially increases within minutes of CO exposure. Blood flow remains elevated until loss of consciousness, when transient cardiac compromise causes blood pressure to decrease [2, 6]. Because of this, autoregulation until cardiovascular homeostasis is exhausted and asphyxia or apnea begins; brain hypoxia is probably not an initial feature of CO poisoning [3]. Neurons are the cells in the CNS most vulnerable to hypoxic–ischemic insult, and they have the highest oxygen and glucose demands. Acute and intense CO poisoning can lead directly to diffuse hypoxic–ischemic encephalopathy predominantly involving the gray matter (Fig. 1A, 1B). Acute CO poisoning that focally involves the cerebral cortex has been reported far less frequently [5]. There is a predilection for the temporal lobe and the hippocampus [5]. The injury can be transient vasogenic edema or frank necrosis (infarction) without occlusion of cerebral arteries. Diffusion-weighted MRI is helpful for differentiating these two conditions (Fig. 2A, 2B, 2C, 2D, 2E).

The globus pallidus is the most common site of involvement in CO poisoning [5, 7]. The damage usually occurs immediately [7]. The predilection for the globus pallidus is unclear but may be related to the hypotensive effects of CO poisoning in the watershed territory of the arterial supply or to CO binding to the iron-rich globus pallidus [7, 8]. Necrosis of the globus pallidus is not necessarily related to the development of parkinsonism and vice versa [4], probably because the damage to the nigrostriatal pathway is incomplete. CT usually shows symmetric hypodensity. On MRI, the medial portions of the globus pallidus appear as bilateral areas of low signal intensity on T1-weighted images and of high signal intensity on T2-weighted and FLAIR images. In the acute stage of CO poisoning, contrast-enhanced T1-weighted images may show patchy or peripheral enhancement in the necrotic areas (Fig. 3A, 3B, 3C, 3D, 3E). Diffusion-weighted MRI and apparent diffusion coefficient maps show restriction of water diffusivity due to cytotoxic edema from acute tissue necrosis [8].

The caudate nucleus, putamen, and thalamus occasionally are involved in CO poisoning but less so than the globus pallidus. The lesions usually appear as asymmetric hyperintense foci on T2-weighted and FLAIR images [5]. Involvement of the brainstem and cerebellum may be a reflection of more severe poisoning because the posterior structures are more resistant to hypoxia [5] (Figs. 4A, 4B and 5A, 5B, 5C, 5D).

Energy production and mitochondrial function are restored after carboxyhemoglobin levels decrease, but the transient changes can cause neuronal necrosis and apoptotic death, which lead to diffuse brain atrophy [1–3, 9] (Fig. 6A, 6B, 6C, 6D). CT and MRI show interval enlargement of the sulcal CSF space and an increased ventricle-to-brain ratio. Porter et al. [10] used quantitative MRI to assess atrophy of the corpus callosum. Those investigators found that marked atrophic change had occurred in 80% of cases within 6 months of CO exposure and that cognitive impairment had developed in one half of the patients. The atrophic change, however, did not correlate well with the cognitive impairment.

Demyelination of the cerebral white matter is usually not a feature of the acute stage of CO poisoning [5]. The most commonly involved areas are the periventricular white matter and centrum semiovale [5, 11]. In severe cases, however, demyelination can extend to the subcortical white matter, corpus callosum, and external and internal capsules [11]. CT usually shows diffuse and confluent hypodensity in these areas. The MRI finding of hypointensity on T1-weighted images and hyperintensity on T2-weighted and FLAIR images may reflect the demyelination process (Figs. 7A, 7B, 7C, 7D and 8A, 8B). Some results [2, 3, 5] have suggested that the underlying mechanism is most likely diapedesis of the polymorphonuclear leukocytes, which causes lipid peroxidation and myelin breakdown.

White matter demyelination is believed to be responsible for delayed neuropsychiatric syndrome [11–13]. After acute CO poisoning, a small proportion of patients who recover consciousness within minutes to hours of exposure appear to have no persisting neurologic deficit initially but experience delayed neuropsychiatric syndrome after a lucid interval [5, 11–14]. The most frequent symptoms of delayed neuropsychiatric syndrome are mental deterioration (amnesia, cognitive dysfunction), emotional disorder (depression, anxiety, mutism), urinary and fecal incontinence, and motor disorder (gait disturbance, Parkinson's disease–like symptoms) [11]. Diffusion-weighted MRI and apparent diffusion coefficient maps [7, 12, 13] of patients with CO poisoning have shown the development of delayed and slowly progressive cytotoxic edema in the cerebral white matter, possibly as the result of delayed cell death and demyelination (Fig. 9A, 9B). The interval also parallels the development of delayed neuropsychiatric syndrome [13]. In animal studies, hyperbaric oxygen therapy has been found to prevent the lipid peroxidation process, and this therapy may prevent the development of delayed neuropsychiatric syndrome [2–4, 10, 15].

As a result of various pathophysiologic mechanisms, a number of patterns of brain injury can be seen in patients with CO poisoning. CT and MRI help to show the extent of disease and are useful for understanding the pathophysiologic mechanism.

Address correspondence to C. P. Lo ([email protected]).

Partially supported by the Tri-Service General Hospital Research Funds TSGH-C95-3-S06.

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