**4.1 Basal ganglion lesions emphasized on the globus pallidus (GP)**

The basal ganglion includes the putamen, caudate nucleus, and GP. GP lesions are often considered as pathognomonic signs for patients with CO intoxication, however the

Tightness across the forehead, headache, throbbing in the temples, nausea, vomiting, dimness of vision, dizziness, general weakness, syncope, convulsion, and coma are commonly found in patients with CO exposure within one day (Choi 2001). Cortical blindness with initially normal visual evoked potentials has also been reported in a case (Katafuchi, Nishimi et al. 1985). The pathogenesis contributing to the clinical manifestations includes change of blood flow (Penney 1990; Lo, Chen et al. 2007), hypoxia (Lo, Chen et al.

Following initial neurological deficits after acute CO intoxication, some patients experience progressive neurological deterioration, while others nearly complete recovery of symptoms. Some patients have a delayed onset of neurological deficits after an initial symptom-free period (Lee and Marsden 1994). The latter is often termed as delayed neuropsychiatric sequela in CO intoxication. The lucid interval after acute CO poisoning, on average, is around 20 days, varying from one to 240 days (Choi 1983; Lee and Marsden 1994; Ernst and Zibrak 1998; Pavese, Napolitano et al. 1999; Hsiao, Kuo et al. 2004), with a prevalence of 0.2- 40% (Hsiao, Kuo et al. 2004; Otubo, Shirakawa et al. 2007). Delayed neuropsychiatric sequelae include parkinsonism (Lee and Marsden 1994), chorea (Park and Choi 2004), akinetic mutism (Lee and Marsden 1994), increased irritability, verbal aggressiveness, violence, impulsiveness (Meredith and Vale 1988), mood disorders (Weaver 2009), dementia (Meredith and Vale 1988; Ernst and Zibrak 1998; Weaver 2009), psychosis (Ernst and Zibrak 1998), sleep disturbances (Weaver 2009), cortical blindness (Quattrocolo, Leotta et al. 1987;

The cognitive deficits are often very diverse (Hurley, Hopkins et al. 2001; Parkinson, Hopkins et al. 2002; Raub and Benignus 2002) including impairment in verbal or visual episodic memory, language, visuospatial ability, executive function and calculation (Chang, Chang et al. 2010). No specific neuropsychiatric battery has been designed for the cognitive deficits in CO intoxication. For general cognitive performance, most researchers apply the mini-mental state examination (Folstein, Folstein et al. 1975) or Wechsler Adult Intelligence Scale (Dorken and Greenbloom 1953) for evaluation. Chang *et al*. (Chang, Lee et al. 2009) used the clinical dementia rating scale (Morris 1997) to evaluate the functional capability of these patients since they may have physical disabilities. Tasks that have been used for evaluation are as follows: Alzheimer's Disease Assessment Scale-Cognitive wordrecognition test (Rosen, Mohs et al. 1984) for verbal episodic memory; recollection of Rey-Osterrieth complex figures for visuospatial ability (Boone 2000); Boston naming test for language ability (Boone 2000); digit span, digit-symbol, digit backward (Cronholm and Viding 1956; Sherman and Blatt 1968; Rudel and Denckla 1974); Trail Making Part A and Part B, block design, and design fluency (Gieseking, Lubin et al. 1956; Arbuthnott and Frank 2000) for executive function; and neuropsychiatric inventory for behavioral changes

**4. Neuroimaging study results of CO intoxication by anatomical classification** 

The basal ganglion includes the putamen, caudate nucleus, and GP. GP lesions are often considered as pathognomonic signs for patients with CO intoxication, however the

**4.1 Basal ganglion lesions emphasized on the globus pallidus (GP)** 

**3.2 Symptoms in the acute phase** 

**3.3 Symptoms in the late phase** 

(Cummings, Mega et al. 1994).

2007), and neurochemistry abnormalities (Penney 1990).

Senol, Yildiz et al. 2009) and incontinence (Ernst and Zibrak 1998).

prevalence differs among studies (Silver, Cross et al. 1996; O'Donnell, Buxton et al. 2000). One study showed 63% of abnormal lesions in the GP with 26% in the rest of the basal ganglia (O'Donnell, Buxton et al. 2000). Another study with 73 patients revealed only one patient (1.4%) with basal ganglia lesions scanned two weeks after CO poisoning (Parkinson, Hopkins et al. 2002).

#### **4.1.1 Imaging features suggesting edematous change in the acute phase**

Low density GP lesions, commonly seen in computed tomography (CT), are considered as characteristic findings in patients with CO intoxication (Kanaya, Imaizumi et al. 1992; Gotoh, Kuyama et al. 1993; Uchino, Hasuo et al. 1994; Chu, Jung et al. 2004; Kinoshita, Sugihara et al. 2005; Hopkins, Fearing et al. 2006). Low density lesions of the putamen and caudate nucleus, in contrast, have only been reported in one case (Ferrier, Wallace et al. 1994). The nature of GP lesions has been studied further by diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) mapping (Chu, Jung et al. 2004; Kinoshita, Sugihara et al. 2005). One case report interpreted low ADC values and high intensity GP lesions on DWI as restriction of water diffusion (i.e. cytotoxic edema) (Kinoshita, Sugihara et al. 2005). Vasogenic edema can also be visualized on ADC and DWI as increased signal intensity lesions (Chalela, Wolf et al. 2001). The high signal on DWI is due to the T2 shine-through effect.

Fig. 1. Magnetic resonance imaging study in the acute stage of carbon monoxide intoxication.

Six days after CO intoxication, a 42-year-old woman with a globus pallidus interna lesion with hyperintensity in diffusion weighted imaging (1A), hypointensity in apparent diffusion coefficient (1B), hypointensity in T1 weighted image (WI) (1C), hyperintensity in T2WI (1D), and hyperintensity in fluid-attenuated inversion recovery (1E).

#### **4.1.2 Imaging features suggesting necrosis**

Imaging studies showing cavity-changes by T1 or T2WI often suggest necrosis of the GP (Mendelsohn and Hertzanu 1983; Pulst, Walshe et al. 1983; Ko, Ahn et al. 2004). Autopsies of patients with CO intoxication have confirmed the histology of necrosis and/or neuronal degeneration of the GP (Jones, Lagasse et al. 1994). The pathogenesis of necrosis is believed to be due to edema-induced ischemia or hemorrhage transformation (Chang, Han et al.

Neuroimaging Studies in Carbon Monoxide Intoxication 359

Calcification of the GP has also been reported in the literature (Illum 1980; Lugaresi, Montagna et al. 1990; Adam, Baulac et al. 2008). The clinical presentations included acute neurological deficits with loss of initiative and slowness of thinking and acting (Adam, Baulac et al. 2008), and delayed neurological deficits with personality changes and akinesia (Lugaresi, Montagna et al. 1990). However one case was free of any neurological sequelae

[18F]fluorodeoxyglucose (FDG) PET has been used to evaluate glucose metabolism activity. Decreased metabolism in the basal ganglion and frontal lobe has been frequently reported (Tengvar, Johansson et al. 2004; Hon, Yeung et al. 2006). The largest series on PET and CO intoxication with basal ganglion lesions included eight patients with their behavioral and MRI patterns (Laplane, Levasseur et al. 1989). Seven patients revealed hypometabolism of the prefrontal cortex in relation to other parts of the brain, leading to a concept of prefrontalpallidum circuit dysfunction. A functional study using [18F] F-DOPA showed presynaptic dopaminergic deficits in one case with parkinsonism symptoms after CO intoxication (Rissanen, Paavilainen et al. 2010). In this case, normal uptake of [11C] raclopride implicated

Single photon emission computed tomography (SPECT) provides perfusion patterns of GM and the basal ganglion (Chang, Liu et al. 2008) with tracers such as 99mTc-ethylcysteinate dimer and 99mTc-Hexamethylpropyleneamine oxime. (99mTc-ECD) brain SPECT is considered to be more sensitive than brain CT for the early detection of hypoperfusion status (Wu, Changlai et al. 2003). In the acute stage, 50% to 85% of the patients with CO intoxication have been reported to have basal ganglion hypoperfusion (Wu, Changlai et al.

Fig. 4. [18F]fluorodeoxyglucose positron emission tomography (PET) of two patients after

Two and a half months after CO intoxication, a 33-year-old patient's CT showed low intensity of the globus pallidus (4A) on brain computed tomography (CT) while PET revealed a remarkably reduced uptake of FDG in bilateral striatum (arrows) and thalamus (4B). Five months after CO intoxication, another 36-year-old patient's CT showed no

**4.1.4 Imaging features suggesting calcification** 

**4.1.5 Functional imaging features suggesting hypometabolism** 

normal postsynaptic dopaminergic function (Rissanen, Paavilainen et al. 2010).

after 48 years of follow-up (Illum 1980).

2003; Pach, Hubalewska et al. 2004).

CO poisoning.

1992). Follow-up GP images often show volume shrinkage (Vieregge, Klostermann et al. 1989; Kanaya, Imaizumi et al. 1992).

Fig. 2. Magnetic resonance imaging in the delayed stage of carbon monoxide intoxication.

Four years after CO intoxication, a 41-year-old woman with a globus pallidus lesion showed hypointensity in T1 weighted image (T1WI) (2A) and cavity changes with hyperintensity in T2WI (2B).

#### **4.1.3 Imaging features suggesting hemorrhage**

Hemorrhage of the GP is seen both in the acute and delayed stages after CO intoxication (Silverman, Brenner et al. 1993; Bianco and Floris 1996), while only one case report has demonstrated putaminal hemorrhage by CT (Schils, Cabay et al. 1999). Temporal sequences in conventional MRI have been noted to be similar to intracranial hemorrhage (Bradley 1993). Hemorrhage may occur within days after CO intoxication with high signal intensity in T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) (Bianco and Floris 1996). High T1WI and low T2WI signals have been observed up to two months after intoxication, suggesting delayed hemorrhage (Yoshii, Kozuma et al. 1998). One case report described abnormal signals in the GP, with shorter T1 characteristics and longer T2 characteristics suggesting a prior focal hemorrhage three years after CO intoxication (Silverman, Brenner et al. 1993). In one study, widespread multiple pin point hemorrhages in the thalamus and GP were found in 40% of postpartum autopsies (Mehta, Niyogi et al. 2001).

Two days after CO intoxication, a 57-year-old woman with hemorrhage in the globus pallidus showed hyperdensity in CT (3A) and a follow-up one month later with low signal intensity on gradient echo (3B).

1992). Follow-up GP images often show volume shrinkage (Vieregge, Klostermann et al.

Fig. 2. Magnetic resonance imaging in the delayed stage of carbon monoxide intoxication. Four years after CO intoxication, a 41-year-old woman with a globus pallidus lesion showed hypointensity in T1 weighted image (T1WI) (2A) and cavity changes with hyperintensity in

Hemorrhage of the GP is seen both in the acute and delayed stages after CO intoxication (Silverman, Brenner et al. 1993; Bianco and Floris 1996), while only one case report has demonstrated putaminal hemorrhage by CT (Schils, Cabay et al. 1999). Temporal sequences in conventional MRI have been noted to be similar to intracranial hemorrhage (Bradley 1993). Hemorrhage may occur within days after CO intoxication with high signal intensity in T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) (Bianco and Floris 1996). High T1WI and low T2WI signals have been observed up to two months after intoxication, suggesting delayed hemorrhage (Yoshii, Kozuma et al. 1998). One case report described abnormal signals in the GP, with shorter T1 characteristics and longer T2 characteristics suggesting a prior focal hemorrhage three years after CO intoxication (Silverman, Brenner et al. 1993). In one study, widespread multiple pin point hemorrhages in the thalamus and GP

Fig. 3. Computed tomography and gradient echo T2WI after carbon monoxide intoxication. Two days after CO intoxication, a 57-year-old woman with hemorrhage in the globus pallidus showed hyperdensity in CT (3A) and a follow-up one month later with low signal

were found in 40% of postpartum autopsies (Mehta, Niyogi et al. 2001).

1989; Kanaya, Imaizumi et al. 1992).

**4.1.3 Imaging features suggesting hemorrhage** 

T2WI (2B).

intensity on gradient echo (3B).
