Patient characteristics
Of 108 patients hospitalized with acute methanol poisoning, 84 survived. These survivors were asked whether they would be willing to participate in a study that involved a long-term assessment of the effects of methanol poisoning. Of the 54 patients who agreed, in 42 patients (8 females), brain MRI was performed four times during a six-year period and DaT SPECT was performed twice (four and six years after discharge). The patients had not previously been diagnosed with neurological, neurodegenerative, neurovascular, or psychiatric disorders other than chronic alcohol abuse. In 15/42 patients (36%), brain MRI revealed signs of necrotic lesions of the putamen (patients classified as Group I) and in 27 patients, no signs of putaminal damage were detected (classified as Group II). Focal necrotic lesions in the globus pallidus were found in 6 patients (14%), three of them were members of Group I. Of the 42 patients that had undergone DaT SPECT and MRI of the brain, MRI-volumetry was measured in 35 patients (8 females, p = 0.682), 13 patients with necrotic lesions of the putamen and 22 without signs of putaminal damage (p = 0.897). In seven patients, volumetric measurements were technically unfeasible due to the low quality of primary imaging data.
Demographic, clinical, and MRI-volumetric characteristics of patients on their dates of admission and follow-up laboratory data are summarised in Table 1. The two groups did not differ with respect to age, gender, proportion of chronic alcohol abusers or proportion of smokers when admitted to the hospital with acute methanol poisoning. The patients with MRI-detected necrotic lesions of the putamen tended to be more severely poisoned and have lower arterial blood pH and bicarbonate concentrations. They also tended to have increased base deficit, anion gap, and serum lactate levels, which are characteristics of metabolic acidosis. All patients admitted in a coma belonged to Group I and 80% of the patients with PSS 3 poisoning (severe poisoning) were the group (p < 0.001). No difference in treatment modalities (administration of ethanol versus fomepizole for ADH blocking, folate substitution) and in the follow-up laboratory parameters was observed between the two groups. Patients in Group I had lower left putamen, nucleus caudate, and globus pallidus volumes than those of Group II, but did not display different right VOI, which revealed a degree of asymmetry associated with MRI-volumetric findings (Table 1).
Table 1 Basic demographic, clinical, MRI-volumetric characteristics, admission and follow-up laboratory data of the study population
Characteristic
|
All patients
(n = 42)
|
Group I
(n = 15)
|
Group II
(n = 27)
|
P
|
Age (years)
|
46.3±4.2
|
45.5±6.0
|
46.7±5.9
|
0.778
|
Males, no. (%)
|
34 (81)
|
12 (80)
|
3 (81)
|
0.912
|
Chronic alcohol abuse, no. (%)
|
31 (74)
|
9 (60)
|
24 (89)
|
0.089
|
Smoking, no. (%)
|
22 (52)
|
8 (53)
|
14 (52)
|
0.976
|
Time, hours
|
32.1±4.7
|
30.5±8.9
|
32.9±6.0
|
0.643
|
Coma, no. (%)
|
7 (17)
|
7 (47)
|
0
|
--
|
CDT, %
|
3.8±1.4
|
3.0±2.5
|
4.2±1.8
|
0.405
|
S-MetOH, mg/L
|
1380.0±440.0
|
2020.0±990.0
|
1010.0±390.0
|
0.065
|
S-EtOH, mg/L
|
250.0±150.0
|
170.0±180.0
|
300.0±220.0
|
0.337
|
Arterial blood pH
|
7.17±0.07
|
6.97±0.11
|
7.29±0.04
|
<0.001
|
HCO3-, mmol/L
|
11.4±2.3
|
6.2±3.1
|
14.5±2.6
|
<0.001
|
Base deficit, mmol/L
|
16.4±3.4
|
24.5±5.2
|
11.5±3.3
|
<0.001
|
Anion gap, mmol/L
|
27.7±3.1
|
33.5±6.4
|
24.6±3.0
|
0.006
|
S-Formate, mg/L
|
590.0±150.0
|
650.0±280.0
|
550.0±200.0
|
0.566
|
S-Creatinine, mcmol/L
|
93.0±11.0
|
112.0±24.0
|
81.9±7.0
|
0.024
|
S-Glucose, mmol/L
|
8.1±1.2
|
10.4±2.9
|
6.8±0.7
|
0.024
|
S-Lactate, mmol/L
|
3.3±1.3
|
5.5±2.8
|
1.7±0.3
|
0.015
|
PSS 1/2/3, no. (%)
|
20/8/14 (48/19/33)
|
2/1/12 (13/7/80)
|
18/7/2 (67/26/7)
|
<0.001
|
Antidote (ethanol/fomepizol), no. (%)
|
30/12 (71/29)
|
8/7 (53/47)
|
24/5 (89/11)
|
0.073
|
Folate substitution, no. (%)
|
32 (76)
|
12 (80)
|
20 (74)
|
0.638
|
GlycHb (%)
|
34.9±1.9
|
33.3±2.5
|
35.8±2.7
|
0.183
|
Vitamin B12 (mcmol/L)
|
424.0±75.0
|
520.0±190.0
|
371.0±57.0
|
0.133
|
Vitamin B1 (mcmol/L)
|
57.1±3.6
|
60.5±7.4
|
55.3±4.1
|
0.180
|
TSH (IU/L)
|
2.5±0.3
|
2.6±0.4
|
2.5±0.4
|
0.683
|
Volume of putamen right, cm3
|
6.01±0.31
|
5.68±0.63
|
6.21±0.35
|
0.107
|
Volume of putamen left, cm3
|
6.34±0.45
|
5.58±0.96
|
6.78±0.39
|
0.027
|
Volume of nucleus caudate right, cm3
|
4.53±0.24
|
4.41±0.44
|
4.61±0.30
|
0.421
|
Volume of nucleus caudate left, cm3
|
4.19±0.21
|
3.92±0.22
|
4.35±0.30
|
0.022
|
Volume of globus pallidus right, cm3
|
1.83±0.10
|
1.80±0.18
|
1.84±0.12
|
0.678
|
Volume of globus pallidus left, cm3
|
1.79±0.11
|
1.66±0.14
|
1.86±0.15
|
0.049
|
Notes: Group I – patients with MRI signs of necrotic lesions of the putamen; Group II – patients without MRI signs of necrotic lesions of the putamen; Age – age at admission to the hospital; Coma – admitted in coma to the hospital; Time – time span between methanol exposure and hospital admission; CDT – carbohydrate deficient transferrin; S-MetOH – serum methanol concentration at admission; S-EtOH – serum ethanol concentration at admission; HCO3- - bicarbonate concentration at admission; S-Formate – serum formic acid concentration at admission; PSS -Poisoning severity score; GlycHb – serum glycated haemoglobin; TSH – thyroid-stimulating hormone. MR-volumetry data are presented for 35 patients from the study population. The level of significance is p < 0.05 (bold numbers).
Correlation between mean specific binding ratios on DaT SPECT, clinical and laboratory parameters of poisoning severity and outcomes
There was no difference observed between the two groups with regard to the relative variation of background signals, ruling out significant differences in image quality. An assessment of reproducibility between the first and the second examination revealed strong agreement (intraclass correlation coefficients for the SBR for all VOI ranged from 0.853 to 0.933, all p < 0.001). Therefore, mean quantitative indices as the averages of the first and the second measurements were further applied. DaT SPECT results produced significantly lower mean SBR for the whole striatum and for the bilateral putamen, but not for the nucleus caudate, in the patients with necrotic lesions of the putamen detected on brain MRI (Table 2). The greatest difference in the SBR was observed for the bilateral posterior putamen. Certain asymmetry in the SBR for the right and left hemispheres was observed, with lower indices determined for the left putamen, but the difference was not significant (p > 0.05).
Table 2 Specific binding ratios (SBR) for the striatum, putamen, and nucleus caudate in survivors of acute methanol poisoning (means with SD)
Variables
|
All patients
(n = 42)
|
Group I
(n = 15)
|
Group II
(n = 27)
|
P
|
SBR of the striatum
|
Striatum dexter
|
2.13±0.13
|
1.96±0.22
|
2.23±0.15
|
0.042
|
Striatum sinister
|
2.12±0.14
|
1.90±0.29
|
2.25±0.15
|
0.022
|
SBR of the putamen
|
Putamen dexter
|
2.00±0.13
|
1.77±0.22
|
2.13±0.15
|
0.007
|
Putamen sinister
|
1.97±0.15
|
1.70±0.30
|
2.12±0.15
|
0.017
|
SBR of the nucleus caudate
|
Nucleus caudate dexter, mean
|
2.44±0.14
|
2.40±0.25
|
2.46±0.18
|
0.702
|
Nucleus caudate sinister, mean
|
2.42±0.15
|
2.30±0.31
|
2.49±0.17
|
0.241
|
SBR of the putamen anterior
|
Putamen anterior dexter, mean
|
2.15±0.13
|
1.95±0.24
|
2.26±0.16
|
0.026
|
Putamen anterior sinister, mean
|
2.11±0.14
|
1.89±0.30
|
2.23±0.15
|
0.023
|
SBR of the putamen posterior
|
Putamen posterior dexter, mean
|
1.68±0.13
|
1.38±0.21
|
1.85±0.14
|
<0.001
|
Putamen posterior sinister, mean
|
1.70±0.16
|
1.34±0.30
|
1.90±0.16
|
<0.001
|
Notes: Group I – patients with MRI signs of necrotic lesions of the putamen; Group II – patients without MRI signs of necrotic lesions of the putamen. The level of significance is p < 0.05 (bold numbers).
The SBR for the left putamen was strongly positively correlated with its volume (Fig. 2). Correlations between SBR and the volume of the right putamen were significant only for the posterior putamen (r = 0.386, p = 0.022). In contrast, the volume of the nucleus caudate was not correlated with its SBR, and the SBR for the striatum and the putamen (p > 0.05). Finally, the volume of left, but not right, globus pallidus positively correlated with the SBR for the whole putamen (r = 0.344, p = 0.043), and for the posterior putamen (r = 0.378, p = 0.025). No correlation was found between the SBR for the whole striatum and the volume of nucleus caudate or globus pallidus (p > 0.05).
The SBR for the striatum, putamen and nucleus caudate in both hemispheres did not correlate with age, gender, and duration between methanol exposure and hospital admission (p > 0.05). There was a significant positive correlation between chronic alcohol abuse and the SBR for the right, but not left, posterior putamen (r = 0.327, p = 0.037; r = 0.286, p = 0.070, respectively). Smokers had higher mean SBR for the whole striatum (r = 0.319, p = 0.042; r = 0.325, p = 0.038 for the right and the left hemispheres, respectively) and for the nucleus caudate (r = 0.327, p = 0.037; r = 0.348, p = 0.026 for the right and the left hemispheres, respectively) than non-smokers. However, SBR for the putamen did not differ significantly between smokers and non-smokers (p > 0.05).
Strong positive correlation was present between arterial blood pH at admission as the main prognostic parameter of poisoning outcome and the SBR for the putamen (r = 0.396, p = 0.012; r = 0.455, p = 0.004 for the right and the left putamen, respectively). The strongest correlation was observed between arterial blood pH and the SBR for posterior putamen posterior bilaterally (Fig. 3). Serum lactate concentration at admission as an indicator of the severity of metabolic acidosis, strongly negatively correlated with the SBR of the putamen bilaterally (r = -0.474, p = 0.006; r = -0.435, p = 0.013 for the right and the left putamen, respectively). These data also showed the strongest correlation for the posterior putamen (r = -0.596, p < 0.001; r = -0.533, p = 0.002, for the right and the left posterior putamen, respectively).
The SBR for the bilateral posterior putamen was negatively associated with acute stress glycaemia (r = -0.504, p = 0.001; r = -0.468, p = 0.002 for right and left posterior putamen, respectively) and with serum creatinine concentration, which is an indicator of acute kidney damage in severely poisoned patients (r = -0.353, p = 0.025; r = -0.350, p = 0.027 for right and left posterior putamen, respectively). Both laboratory parameters reflected poor outcomes of acute methanol poisoning. No correlations between SBR and serum methanol, ethanol, or formic acid concentrations were identified (p > 0.05). Further, no associations were present between the type of antidote administered at the hospital (ethanol or fomepizole), folate substitution, and the SBR for all VOI assessed in our study (p > 0.05).
Follow-up laboratory parameters demonstrated no correlations between glycated haemoglobin, TSH, vitamin B12 concentrations, and the SBR for all VOI assessed. However, despite the lack of significant differences between serum vitamin B1 concentrations of the two groups, they were negatively correlated with the SBR for the putamen (r = -0.314, p = 0.043; r = -0.382, p = 0.013, for right and left putamen, respectively), with the strongest correlation for the SBR of the left putamen posterior (r = -0.421, p = 0.005).
The SBR for the bilateral posterior putamen positively correlated with global and nasal RNFL of the left eyes (for global RNFL: r = 0.358, p = 0.027, and r = 0.376, p = 0.020; for nasal RNFL: r = 0.362, p = 0.025, and r = 0.382, p = 0.018 for right and left putamen, respectively). However, correlations between SBR and RNFL values of the right eyes were not significant.
Specific binding ratio as the marker of putaminal damage in acute methanol poisoning
ROC and the AUC were used to assess the SBR as an indicator of putaminal damage in survivors of methanol poisoning. ROC analysis of the SBR for the posterior putamen and whole putamen (average of right and left sides) demonstrated a significant AUC of 0.753 (95% CI: 0.604–0.902; p = 0.007) and of 0.746 (95% CI: 0.595–0.897; p = 0.009), respectively (Fig. 4). These data indicated that the SBR for the putamen and specifically for the posterior putamen is potentially a good marker of methanol-induced basal ganglia damage. ROC analyses demonstrated that the AUC for the SBR for the anterior putamen and whole striatum were 0.709 (95% CI: 0.549–0.868; p = 0.027) and 0.702 (95% CI: 0.542–0.863; p = 0.031), respectively. In contrast, the AUC for the SBR of the nucleus caudate was not significant (AUC = 0.563; 95% CI: 0.376–0.750; p = 0.503).
A multivariate regression model demonstrated that arterial blood pH, age at admission to the hospital, and gender were significant association factors for the SBR for the bilateral posterior putamen in survivors of acute methanol poisoning (Table 3). The association of smoking with SBR demonstrated borderline significance for the right, but not left, posterior putamen. The same model was relevant for the whole putamen, but the degree to which arterial blood pH and the age associated with SBR decreased since values of the SBR for the anterior putamen associated to a lesser degree than those for the posterior putamen to laboratory parameters of the severity of methanol poisoning.
Table 3 Summary of association factors for the SBR for the putamen posterior, putamen anterior, and the whole putamen in survivors of acute methanol poisoning
|
|
|
|
95% CI
|
Variable
|
B
|
Standard error
|
Beta
|
t
|
Significance
|
Lower Bound
|
Upper Bound
|
Putamen posterior dexter
|
Constant
|
-5.65
|
1.99
|
|
-2.84
|
0.008
|
-9.70
|
-1.60
|
Arterial pH
|
1.04
|
0.28
|
0.50
|
3.64
|
0.001
|
0.46
|
1.61
|
Age
|
-0.01
|
0.01
|
-0.25
|
-2.06
|
0.047
|
-0.02
|
0.00
|
Gender
|
0.35
|
0.14
|
0.32
|
2.58
|
0.014
|
0.07
|
0.62
|
Chronic alcohol
|
0.18
|
0.14
|
0.19
|
1.33
|
0.193
|
-0.10
|
0.47
|
Smoking
|
0.22
|
0.11
|
0.26
|
2.10
|
0.043
|
0.01
|
0.43
|
Putamen posterior sinister
|
Constant
|
-8.21
|
2.35
|
|
-3.50
|
0.001
|
-12.98
|
-3.44
|
Arterial pH
|
1.42
|
0.34
|
0.56
|
4.23
|
0.000
|
0.74
|
2.10
|
Age
|
-0.01
|
0.01
|
-0.28
|
-2.42
|
0.021
|
-0.02
|
-0.00
|
Gender
|
0.49
|
0.16
|
0.37
|
3.10
|
0.004
|
0.17
|
0.82
|
Chronic alcohol
|
0.15
|
0.16
|
0.12
|
0.93
|
0.360
|
-0.18
|
0.48
|
Smoking
|
0.21
|
0.12
|
0.20
|
1.73
|
0.094
|
-0.04
|
0.46
|
Putamen anterior dexter
|
Constant
|
-1.44
|
2.31
|
|
-0.62
|
0.537
|
-6.13
|
3.25
|
Arterial pH
|
0.49
|
0.33
|
0.24
|
1.49
|
0.145
|
-0.18
|
1.16
|
Age
|
-0.01
|
0.01
|
-0.20
|
-1.37
|
0.180
|
-0.02
|
0.00
|
Gender
|
0.39
|
0.16
|
0.36
|
2.48
|
0.018
|
0.07
|
0.71
|
Chronic alcohol
|
0.22
|
0.16
|
0.22
|
1.34
|
0.189
|
-0.11
|
0.54
|
Smoking
|
0.28
|
0.12
|
0.33
|
2.31
|
0.027
|
0.03
|
0.53
|
Putamen anterior sinister
|
Constant
|
-2.48
|
2.41
|
|
-1.03
|
0.311
|
-7.38
|
2.42
|
Arterial pH
|
0.63
|
0.34
|
0.28
|
1.84
|
0.074
|
-0.07
|
1.33
|
Age
|
-0.01
|
0.01
|
-0.22
|
-1.58
|
0.124
|
-0.02
|
0.00
|
Gender
|
0.39
|
0.16
|
0.33
|
2.38
|
0.023
|
0.06
|
0.72
|
Chronic alcohol
|
0.24
|
0.17
|
0.23
|
1.45
|
0.156
|
-0.10
|
0.58
|
Smoking
|
0.32
|
0.13
|
0.35
|
2.50
|
0.017
|
0.06
|
0.58
|
Putamen dexter
|
Constant
|
-2.79
|
2.14
|
|
-1.30
|
0.201
|
-7.15
|
1.56
|
Arterial pH
|
0.67
|
0.31
|
0.33
|
2.18
|
0.036
|
0.05
|
1.29
|
Age
|
-0.01
|
0.01
|
-0.22
|
-1.64
|
0.111
|
-0.02
|
0.00
|
Gender
|
0.37
|
0.16
|
0.36
|
2.57
|
0.015
|
0.08
|
0.67
|
Chronic alcohol
|
0.20
|
0.15
|
0.21
|
1.35
|
0.187
|
-0.10
|
0.50
|
Smoking
|
0.26
|
0.11
|
0.32
|
2.31
|
0.027
|
0.03
|
0.49
|
Putamen sinister
|
Constant
|
-4.47
|
2.31
|
|
-1.94
|
0.061
|
-9.17
|
0.22
|
Arterial pH
|
0.91
|
0.33
|
0.40
|
2.76
|
0.009
|
0.24
|
1.58
|
Age
|
-0.01
|
0.01
|
-0.26
|
-1.97
|
0.057
|
-0.02
|
0.00
|
Gender
|
0.43
|
0.16
|
0.36
|
2.74
|
0.010
|
0.11
|
0.75
|
Chronic alcohol
|
0.22
|
0.16
|
0.20
|
1.34
|
0.188
|
-0.11
|
0.54
|
Smoking
|
0.28
|
0.12
|
0.30
|
2.32
|
0.026
|
0.04
|
0.53
|
Notes: CI – confidence interval; Arterial pH – arterial blood pH at admission to the hospital with acute methanol poisoning; Age – age at admission to the hospital; Chronic alcohol – chronic alcohol abuse. The level of significance is p < 0.05 (bold numbers).