Cognitive sequelae of methanol poisoning involve executive dysfunction and memory impairment in cross-sectional and long-term perspective

Highlights

• Methanol poisoning leads to executive dysfunction and memory deficit, these changes are stable after two years follow-up.

• Methanol patients with extensive involvement on brain MRI had more severe cognitive impairment.

• The data are worldwide unique in sample size and quantity and sensitivity of methods used in the assessment.

Abstract

Methanol poisoning leads to lesions in the basal ganglia and subcortical white matter, as well as to demyelination and atrophy of the optic nerve. However, information regarding cognitive deficits in a large methanol sample is lacking. The principal aim of the present study was to identify the cognitive sequelae of methanol poisoning and their morphological correlates. A sample of 50 patients (METH; age 48 ± 13 years), 3–8 months after methanol poisoning, and 57 control subjects (CS; age 49 ± 13 years) were administered a neuropsychological battery. Forty-six patients were followed in 2 years' perspective. Patients additionally underwent 1.5T magnetic resonance imaging (MRI). Three biochemical and toxicological metabolic markers and a questionnaire regarding alcohol abuse facilitated the classification of 24 patients with methanol poisoning without alcohol abuse (METHna) and 22 patients with methanol poisoning and alcohol abuse (METHa). All groups were compared to a control group of similar size, and matched for age, education, premorbid intelligence level, global cognitive performance, and level of depressive symptoms. Using hierarchical multiple regression we found significant differences between METH and CS, especially in executive and memory domains. METHa showed a similar pattern of cognitive impairment with generally more severe executive dysfunction. Moreover, all METH patients with extensive involvement on brain MRI (lesions in ≥2 anatomical regions) had a more severe cognitive impairment. From a longitudinal perspective, we did not find any changes in their cognitive functioning after 2 years' follow-up. Our findings suggest that methanol poisoning is associated with executive dysfunction and explicit memory impairment, supposedly due to basal ganglia dysfunction and disruption of frontostriatal circuitry proportional to the number of brain lesions, and that these changes are persistent after 2 years' follow-up.

Introduction

Methanol is an industrial solvent that acts as a neurotoxin when ingested. A mass methanol poisoning is often the result of its use as a cheap substitute for ethanol (Hovda et al., 2005, Paasma et al., 2007, Zakharov et al., 2014c). This was the case in the Czech Republic, where from September 2012 to January 2013 a total of 121 subjects were intoxicated by methanol sold in adulterated alcoholic beverages containing a mixture of 20–50% methanol and 50–80% ethanol (Zakharov, Pelclova, Urban, et al., 2014). Empirical evidence related to the effect of methanol poisoning on the brain and behavior is limited (Paasma et al., 2007), with only a small number of case reports or studies on small cohorts of patients (Airas et al., 2008, Anderson et al., 1987, Bezdicek et al., 2014a). A cross-sectional study based on a large cohort of patients with methanol poisoning and without concomitant chronic alcohol abuse is so far lacking.

The pathophysiological mechanisms of methanol poisoning are well known (Zakharov et al., 2014b, Zakharov et al., 2014c). Methanol poisoning has toxic effects due to its metabolite formic acid, preponderantly on the retina, optic nerve, and other parts of the central nervous system (CNS) (Jacobsen and McMartin, 1986, Kraut and Kurtz, 2008, Mégarbane et al., 2005, Sanaei-Zadeh et al., 2011b). The accumulation of formic acid results in metabolic acidosis, damage to the basal ganglia (BG), and visual impairment when the concentration of formic acid is higher than 9.0–11.0 mmol/L (McMartin et al., 1977, Osterloh et al., 1986, Sanaei-Zadeh et al., 2011a, Sejersted et al., 1983, Zakharov et al., 2014a). Thus, methanol poisoning leads to metabolic changes and lesions in specific sites in the CNS, especially in the BG, and primarily in the putamen. The putamen is affected by hemorrhage and subsequent necrosis. To a lesser extent, subcortical white matter (SWM) lesions and demyelination or even atrophy of optic nerve occur (Arora et al., 2007, Blanco et al., 2006, Singh et al., 2013, Vaneckova et al., 2014, Vaneckova et al., 2015). Moreover, methanol is the metabolic precursor of formaldehyde (FA). FA at low concentrations can, in animal models, directly induce tau aggregation and amyloid β (Aβ) peptide deposits in vitro (Su, Monte, Hu, He, & He, 2016).

From previous findings, we hypothesize that methanol poisoning leads to a disruption of the functional architecture of frontostriatal circuitry (Alexander et al., 1986, DeLong and Wichmann, 2007, Owen, 2004) and cognitive decline (Su et al., 2016). The presumable assessment of “cognitive” impairment due to methanol poisoning should, therefore, include 1) assessment of executive function and working memory (WM), due to interconnection of the BG with the frontal lobes via the basal ganglia-thalamocortical circuits (Alexander & Crutcher, 1990); 2) assessment of motor speed due to possible loss of connectivity as a result of SWM lesions (Vaneckova et al., 2014, Vaneckova et al., 2015); and 3) long-term memory assessment due to a general toxic and apoptotic effect on the CNS and also an examination of visual scanning and sustained visual attention due to atrophy of the optic nerve (Bezdicek et al., 2014a, Su et al., 2016, Vaneckova et al., 2014, Vaneckova et al., 2015).

Furthermore, based on an a priori assumption, we hypothesized that chronic alcohol abusers are a subgroup of methanol-poisoned patients and may have a different type of cognitive impairment than “pure” methanol-poisoned patients (Pfefferbaum et al., 1997, Sullivan et al., 2010). We performed, therefore, a classification of methanol poisoning to methanol poisoning with no alcohol abuse and methanol poisoning with alcohol abuse on the basis of biochemical and addictological analyses. The primary objective of the present study was to show how well the methanol poisoning predicts possible cognitive deficits in a cross-sectional analysis and show their evolution in a long-term perspective. Second, we tried to disentangle the “pure” cognitive deficit induced by methanol poisoning with respect to deficits caused by chronic alcohol abuse and concomitant methanol poisoning. Third, we aimed to describe morphological correlates based on MRI that corroborate or refute the frontostriatal circuitry and cognitive deficit hypothesis.